NZ625965B2 - Kinase inhibitors useful as anti-inflammatory agents - Google Patents
Kinase inhibitors useful as anti-inflammatory agents Download PDFInfo
- Publication number
- NZ625965B2 NZ625965B2 NZ625965A NZ62596512A NZ625965B2 NZ 625965 B2 NZ625965 B2 NZ 625965B2 NZ 625965 A NZ625965 A NZ 625965A NZ 62596512 A NZ62596512 A NZ 62596512A NZ 625965 B2 NZ625965 B2 NZ 625965B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- tert
- triazolo
- tetrahydro
- urea
- naphthalenyl
- Prior art date
Links
- 239000003757 phosphotransferase inhibitor Substances 0.000 title description 8
- 229940116904 ANTIINFLAMMATORY THERAPEUTIC RADIOPHARMACEUTICALS Drugs 0.000 title description 5
- 229940074726 OPHTHALMOLOGIC ANTIINFLAMMATORY AGENTS Drugs 0.000 title description 5
- 239000002260 anti-inflammatory agent Substances 0.000 title description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 390
- -1 urea derivative compounds Chemical class 0.000 claims abstract description 151
- 102100000918 MAPK14 Human genes 0.000 claims abstract description 33
- 108010068338 p38 Mitogen-Activated Protein Kinases Proteins 0.000 claims abstract description 9
- 239000004202 carbamide Substances 0.000 claims description 430
- 125000000217 alkyl group Chemical group 0.000 claims description 355
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 298
- 125000002947 alkylene group Chemical group 0.000 claims description 246
- 125000002993 cycloalkylene group Chemical group 0.000 claims description 243
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 178
- 125000005843 halogen group Chemical group 0.000 claims description 157
- 239000000203 mixture Substances 0.000 claims description 151
- 229910052757 nitrogen Inorganic materials 0.000 claims description 113
- 229910052739 hydrogen Inorganic materials 0.000 claims description 100
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 94
- 239000001257 hydrogen Substances 0.000 claims description 86
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 83
- XSQUKJJJFZCRTK-UHFFFAOYSA-N urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 81
- 150000002829 nitrogen Chemical group 0.000 claims description 72
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 67
- 229910052799 carbon Inorganic materials 0.000 claims description 57
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 52
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 44
- 125000001072 heteroaryl group Chemical group 0.000 claims description 43
- 125000002950 monocyclic group Chemical group 0.000 claims description 43
- 125000004432 carbon atoms Chemical group C* 0.000 claims description 38
- 150000002431 hydrogen Chemical class 0.000 claims description 37
- 150000003254 radicals Chemical group 0.000 claims description 36
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 34
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 33
- 201000010099 disease Diseases 0.000 claims description 31
- 229910052760 oxygen Inorganic materials 0.000 claims description 27
- 125000005842 heteroatoms Chemical group 0.000 claims description 25
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 claims description 25
- 229910052736 halogen Inorganic materials 0.000 claims description 24
- 239000011780 sodium chloride Substances 0.000 claims description 24
- 125000003118 aryl group Chemical group 0.000 claims description 23
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 21
- 239000001301 oxygen Substances 0.000 claims description 21
- MYMOFIZGZYHOMD-UHFFFAOYSA-N oxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims description 21
- 125000004429 atoms Chemical group 0.000 claims description 19
- 125000001188 haloalkyl group Chemical group 0.000 claims description 19
- 150000002367 halogens Chemical class 0.000 claims description 19
- 150000003839 salts Chemical class 0.000 claims description 19
- 230000002401 inhibitory effect Effects 0.000 claims description 18
- OKTJSMMVPCPJKN-UHFFFAOYSA-N carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 17
- 208000006673 Asthma Diseases 0.000 claims description 16
- 125000002618 bicyclic heterocycle group Chemical group 0.000 claims description 16
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 16
- 125000005418 aryl aryl group Chemical group 0.000 claims description 15
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 12
- 229910052727 yttrium Inorganic materials 0.000 claims description 12
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 11
- 239000003814 drug Substances 0.000 claims description 11
- 125000001424 substituent group Chemical group 0.000 claims description 11
- QSTUCCPUDQVYLS-UHFFFAOYSA-N N1(CCCCC1)C1=NN=C2N1C=CC=C2 Chemical compound N1(CCCCC1)C1=NN=C2N1C=CC=C2 QSTUCCPUDQVYLS-UHFFFAOYSA-N 0.000 claims description 10
- 125000002619 bicyclic group Chemical group 0.000 claims description 8
- 229910052717 sulfur Inorganic materials 0.000 claims description 8
- 230000000694 effects Effects 0.000 claims description 7
- 229910052721 tungsten Inorganic materials 0.000 claims description 7
- AXCZMVOFGPJBDE-UHFFFAOYSA-L Calcium hydroxide Chemical group [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 claims description 6
- 125000001624 naphthyl group Chemical group 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 206010001052 Acute respiratory distress syndrome Diseases 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 125000003635 2-dimethylaminoethoxy group Chemical compound [H]C([H])([H])N(C([H])([H])[H])C([H])([H])C([H])([H])O* 0.000 claims description 4
- 201000000028 adult respiratory distress syndrome Diseases 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 101700054498 such-1 Proteins 0.000 claims description 4
- 125000004200 2-methoxyethyl group Chemical compound [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims description 3
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 3
- QOXOZONBQWIKDA-UHFFFAOYSA-N 3-hydroxypropyl Chemical group [CH2]CCO QOXOZONBQWIKDA-UHFFFAOYSA-N 0.000 claims description 2
- YJDXFPVJAMKFDY-UHFFFAOYSA-N CC1=CC(=C(C=C1)N1C=CC=N1)C(C)(C)C Chemical compound CC1=CC(=C(C=C1)N1C=CC=N1)C(C)(C)C YJDXFPVJAMKFDY-UHFFFAOYSA-N 0.000 claims description 2
- 208000002815 Pulmonary Hypertension Diseases 0.000 claims description 2
- 201000009323 chronic eosinophilic pneumonia Diseases 0.000 claims description 2
- 238000002651 drug therapy Methods 0.000 claims description 2
- 230000005713 exacerbation Effects 0.000 claims description 2
- 230000035874 hyperreactivity Effects 0.000 claims description 2
- 150000003672 ureas Chemical compound 0.000 claims 8
- 125000001951 carbamoylamino group Chemical compound C(N)(=O)N* 0.000 claims 1
- 239000002829 mitogen activated protein kinase inhibitor Substances 0.000 abstract description 5
- 206010038683 Respiratory disease Diseases 0.000 abstract description 4
- XNSIGYCUYYNVGK-IOWSJCHKSA-N 1-[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]-3-[(1S,4R)-4-[[3-(2-pyrrolidin-1-ylethyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl]oxy]-1,2,3,4-tetrahydronaphthalen-1-yl]urea Chemical compound C1=CC(C)=CC=C1N1C(NC(=O)N[C@@H]2C3=CC=CC=C3[C@H](OC3=CN4C(CCN5CCCC5)=NN=C4C=C3)CC2)=CC(C(C)(C)C)=N1 XNSIGYCUYYNVGK-IOWSJCHKSA-N 0.000 abstract 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 441
- 239000000543 intermediate Substances 0.000 description 237
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 139
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 126
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 125
- 239000000243 solution Substances 0.000 description 120
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 104
- 239000002904 solvent Substances 0.000 description 77
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 76
- BZKBCQXYZZXSCO-UHFFFAOYSA-N sodium hydride Chemical compound [H-].[Na+] BZKBCQXYZZXSCO-UHFFFAOYSA-N 0.000 description 72
- BDAGIHXWWSANSR-UHFFFAOYSA-N formic acid Chemical compound OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 68
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 68
- 238000006243 chemical reaction Methods 0.000 description 65
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 59
- 235000019439 ethyl acetate Nutrition 0.000 description 58
- 239000000047 product Substances 0.000 description 52
- 238000005160 1H NMR spectroscopy Methods 0.000 description 51
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 51
- ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 43
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N Triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 42
- 238000000034 method Methods 0.000 description 41
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 39
- 239000007787 solid Substances 0.000 description 36
- 239000000843 powder Substances 0.000 description 32
- 239000002585 base Substances 0.000 description 31
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 30
- 239000012267 brine Substances 0.000 description 29
- 239000011541 reaction mixture Substances 0.000 description 29
- 238000000746 purification Methods 0.000 description 28
- 238000004128 high performance liquid chromatography Methods 0.000 description 27
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 24
- 239000000460 chlorine Substances 0.000 description 23
- 238000004108 freeze drying Methods 0.000 description 23
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 22
- 235000019253 formic acid Nutrition 0.000 description 22
- 239000000725 suspension Substances 0.000 description 22
- 108060001945 CRK Proteins 0.000 description 21
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 21
- 239000003921 oil Substances 0.000 description 20
- 235000019198 oils Nutrition 0.000 description 20
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 20
- 239000006260 foam Substances 0.000 description 19
- 238000001816 cooling Methods 0.000 description 18
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 18
- 239000012044 organic layer Substances 0.000 description 18
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 18
- 239000010410 layer Substances 0.000 description 16
- 235000019441 ethanol Nutrition 0.000 description 15
- 239000002480 mineral oil Substances 0.000 description 15
- 235000010446 mineral oil Nutrition 0.000 description 15
- 239000002245 particle Substances 0.000 description 15
- 101710040537 TNF Proteins 0.000 description 14
- XKRFYHLGVUSROY-UHFFFAOYSA-N argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 14
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 14
- 125000006239 protecting group Chemical group 0.000 description 14
- 235000011121 sodium hydroxide Nutrition 0.000 description 14
- 238000005859 coupling reaction Methods 0.000 description 13
- XDTMQSROBMDMFD-UHFFFAOYSA-N cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 13
- VHHHONWQHHHLTI-UHFFFAOYSA-N Hexachloroethane Chemical compound ClC(Cl)(Cl)C(Cl)(Cl)Cl VHHHONWQHHHLTI-UHFFFAOYSA-N 0.000 description 12
- ZFXYFBGIUFBOJW-UHFFFAOYSA-N Theophylline Chemical compound O=C1N(C)C(=O)N(C)C2=C1NC=N2 ZFXYFBGIUFBOJW-UHFFFAOYSA-N 0.000 description 12
- 230000001808 coupling Effects 0.000 description 12
- 238000010168 coupling process Methods 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 11
- 238000001514 detection method Methods 0.000 description 11
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 10
- 102100009534 TNF Human genes 0.000 description 10
- 230000003042 antagnostic Effects 0.000 description 10
- 239000005557 antagonist Substances 0.000 description 10
- 238000009835 boiling Methods 0.000 description 10
- 239000003153 chemical reaction reagent Substances 0.000 description 10
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 10
- 125000004076 pyridyl group Chemical group 0.000 description 10
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 10
- JNWBBCNCSMBKNE-UHFFFAOYSA-N HATU Chemical compound F[P-](F)(F)(F)(F)F.C1=CN=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 JNWBBCNCSMBKNE-UHFFFAOYSA-N 0.000 description 9
- FPGGTKZVZWFYPV-UHFFFAOYSA-M Tetra-n-butylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 9
- 239000000556 agonist Substances 0.000 description 9
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 9
- 238000010828 elution Methods 0.000 description 9
- 239000000284 extract Substances 0.000 description 9
- 239000003112 inhibitor Substances 0.000 description 9
- 239000000651 prodrug Substances 0.000 description 9
- 229940002612 prodrugs Drugs 0.000 description 9
- 238000010992 reflux Methods 0.000 description 9
- 229960000583 Acetic Acid Drugs 0.000 description 8
- FJDQFPXHSGXQBY-UHFFFAOYSA-L Caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 8
- DYHSDKLCOJIUFX-UHFFFAOYSA-N Di-tert-butyl dicarbonate Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 8
- FAMRKDQNMBBFBR-BQYQJAHWSA-N Diethyl azodicarboxylate Chemical compound CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 8
- SECXISVLQFMRJM-UHFFFAOYSA-N NMP Substances CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 8
- CXNIUSPIQKWYAI-UHFFFAOYSA-N Xantphos Chemical compound C=12OC3=C(P(C=4C=CC=CC=4)C=4C=CC=CC=4)C=CC=C3C(C)(C)C2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 CXNIUSPIQKWYAI-UHFFFAOYSA-N 0.000 description 8
- 238000007792 addition Methods 0.000 description 8
- 239000000443 aerosol Substances 0.000 description 8
- 150000001412 amines Chemical class 0.000 description 8
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 8
- 125000001309 chloro group Chemical group Cl* 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 8
- 229910052731 fluorine Inorganic materials 0.000 description 8
- 239000002244 precipitate Substances 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- MTEZLAATISORQK-UHFFFAOYSA-N 2-methoxyacetamide Chemical compound COCC(N)=O MTEZLAATISORQK-UHFFFAOYSA-N 0.000 description 7
- BPZSYCZIITTYBL-YJYMSZOUSA-N Formoterol Chemical compound C1=CC(OC)=CC=C1C[C@@H](C)NC[C@H](O)C1=CC=C(O)C(NC=O)=C1 BPZSYCZIITTYBL-YJYMSZOUSA-N 0.000 description 7
- 229960000278 Theophylline Drugs 0.000 description 7
- 239000002253 acid Substances 0.000 description 7
- 229910052786 argon Inorganic materials 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 7
- 230000002757 inflammatory Effects 0.000 description 7
- 230000000051 modifying Effects 0.000 description 7
- 239000012071 phase Substances 0.000 description 7
- 229910000027 potassium carbonate Inorganic materials 0.000 description 7
- 235000015320 potassium carbonate Nutrition 0.000 description 7
- 238000002360 preparation method Methods 0.000 description 7
- LHJCZOXMCGQVDQ-UHFFFAOYSA-N tri(propan-2-yl)silyl trifluoromethanesulfonate Chemical compound CC(C)[Si](C(C)C)(C(C)C)OS(=O)(=O)C(F)(F)F LHJCZOXMCGQVDQ-UHFFFAOYSA-N 0.000 description 7
- WZPBZJONDBGPKJ-VEHQQRBSSA-N Aztreonam Chemical compound O=C1N(S([O-])(=O)=O)[C@@H](C)[C@@H]1NC(=O)C(=N/OC(C)(C)C(O)=O)\C1=CSC([NH3+])=N1 WZPBZJONDBGPKJ-VEHQQRBSSA-N 0.000 description 6
- 206010061218 Inflammation Diseases 0.000 description 6
- 210000004072 Lung Anatomy 0.000 description 6
- HFPZCAJZSCWRBC-UHFFFAOYSA-N P-Cymene Chemical compound CC(C)C1=CC=C(C)C=C1 HFPZCAJZSCWRBC-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- 239000003054 catalyst Substances 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- 238000010511 deprotection reaction Methods 0.000 description 6
- 239000002158 endotoxin Substances 0.000 description 6
- 150000004675 formic acid derivatives Chemical class 0.000 description 6
- 229920000591 gum Polymers 0.000 description 6
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 6
- 200000000018 inflammatory disease Diseases 0.000 description 6
- 230000004054 inflammatory process Effects 0.000 description 6
- 230000000414 obstructive Effects 0.000 description 6
- UJJLJRQIPMGXEZ-UHFFFAOYSA-M oxolane-2-carboxylate Chemical compound [O-]C(=O)C1CCCO1 UJJLJRQIPMGXEZ-UHFFFAOYSA-M 0.000 description 6
- 239000001184 potassium carbonate Substances 0.000 description 6
- 230000001681 protective Effects 0.000 description 6
- AGGHKNBCHLWKHY-UHFFFAOYSA-N sodium;triacetyloxyboron(1-) Chemical compound [Na+].CC(=O)O[B-](OC(C)=O)OC(C)=O AGGHKNBCHLWKHY-UHFFFAOYSA-N 0.000 description 6
- 239000003643 water by type Substances 0.000 description 6
- KUVIULQEHSCUHY-XYWKZLDCSA-N Beclometasone dipropionate Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(Cl)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)COC(=O)CC)(OC(=O)CC)[C@@]1(C)C[C@@H]2O KUVIULQEHSCUHY-XYWKZLDCSA-N 0.000 description 5
- 229940112141 Dry Powder Inhaler Drugs 0.000 description 5
- 241000400611 Eucalyptus deanei Species 0.000 description 5
- XTULMSXFIHGYFS-VLSRWLAYSA-N Fluticasone furoate Chemical compound O([C@]1([C@@]2(C)C[C@H](O)[C@]3(F)[C@@]4(C)C=CC(=O)C=C4[C@@H](F)C[C@H]3[C@@H]2C[C@H]1C)C(=O)SCF)C(=O)C1=CC=CO1 XTULMSXFIHGYFS-VLSRWLAYSA-N 0.000 description 5
- 102000000589 Interleukin-1 Human genes 0.000 description 5
- 108010002352 Interleukin-1 Proteins 0.000 description 5
- 102000004890 Interleukin-8 Human genes 0.000 description 5
- 108090001007 Interleukin-8 Proteins 0.000 description 5
- 230000004913 activation Effects 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 229940079593 drugs Drugs 0.000 description 5
- 229960002848 formoterol Drugs 0.000 description 5
- 238000000752 ionisation method Methods 0.000 description 5
- 150000002500 ions Chemical class 0.000 description 5
- 229910052751 metal Inorganic materials 0.000 description 5
- 239000002184 metal Substances 0.000 description 5
- AFVFQIVMOAPDHO-UHFFFAOYSA-N methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 5
- YNAVUWVOSKDBBP-UHFFFAOYSA-N morpholine Chemical group C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 5
- 210000002345 respiratory system Anatomy 0.000 description 5
- YOQDYZUWIQVZSF-UHFFFAOYSA-N sodium borohydride Substances [BH4-].[Na+] YOQDYZUWIQVZSF-UHFFFAOYSA-N 0.000 description 5
- 229910000033 sodium borohydride Inorganic materials 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- ODGROJYWQXFQOZ-UHFFFAOYSA-N sodium;boron(1-) Chemical compound [B-].[Na+] ODGROJYWQXFQOZ-UHFFFAOYSA-N 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- LJCZNYWLQZZIOS-UHFFFAOYSA-N 2,2,2-Trichlorethoxycarbonyl chloride Chemical compound ClC(=O)OCC(Cl)(Cl)Cl LJCZNYWLQZZIOS-UHFFFAOYSA-N 0.000 description 4
- VOVIALXJUBGFJZ-VXKMTNQYSA-N Budesonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1C[C@H]3O[C@@H](CCC)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O VOVIALXJUBGFJZ-VXKMTNQYSA-N 0.000 description 4
- LUKZNWIVRBCLON-GXOBDPJESA-N Ciclesonide Chemical compound C1([C@H]2O[C@@]3([C@H](O2)C[C@@H]2[C@@]3(C[C@H](O)[C@@H]3[C@@]4(C)C=CC(=O)C=C4CC[C@H]32)C)C(=O)COC(=O)C(C)C)CCCCC1 LUKZNWIVRBCLON-GXOBDPJESA-N 0.000 description 4
- UAOMVDZJSHZZME-UHFFFAOYSA-N Diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 4
- WMWTYOKRWGGJOA-CENSZEJFSA-N Fluticasone propionate Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@@H](C)[C@@](C(=O)SCF)(OC(=O)CC)[C@@]2(C)C[C@@H]1O WMWTYOKRWGGJOA-CENSZEJFSA-N 0.000 description 4
- QARBMVPHQWIHKH-UHFFFAOYSA-N Methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 4
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 4
- WOFMFGQZHJDGCX-ZULDAHANSA-N Mometasone furoate Chemical compound O([C@]1([C@@]2(C)C[C@H](O)[C@]3(Cl)[C@@]4(C)C=CC(=O)C=C4CC[C@H]3[C@@H]2C[C@H]1C)C(=O)CCl)C(=O)C1=CC=CO1 WOFMFGQZHJDGCX-ZULDAHANSA-N 0.000 description 4
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-Bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 4
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-Chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 4
- XBXCNNQPRYLIDE-UHFFFAOYSA-M N-tert-butylcarbamate Chemical compound CC(C)(C)NC([O-])=O XBXCNNQPRYLIDE-UHFFFAOYSA-M 0.000 description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N Phosphoryl chloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 4
- VZJVWSHVAAUDKD-UHFFFAOYSA-N Potassium permanganate Chemical compound [K+].[O-][Mn](=O)(=O)=O VZJVWSHVAAUDKD-UHFFFAOYSA-N 0.000 description 4
- LPNYRYFBWFDTMA-UHFFFAOYSA-N Potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 4
- MFRIHAYPQRLWNB-UHFFFAOYSA-N Sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 4
- 229910000024 caesium carbonate Inorganic materials 0.000 description 4
- 210000004027 cells Anatomy 0.000 description 4
- 230000001684 chronic Effects 0.000 description 4
- 229960003728 ciclesonide Drugs 0.000 description 4
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 4
- 239000012024 dehydrating agents Substances 0.000 description 4
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 4
- 239000011737 fluorine Chemical group 0.000 description 4
- YCKRFDGAMUMZLT-UHFFFAOYSA-N fluorine atom Chemical group [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 4
- 229960000289 fluticasone propionate Drugs 0.000 description 4
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine hydrate Chemical compound O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 4
- 230000002209 hydrophobic Effects 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-M methanoate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 229940113083 morpholine Drugs 0.000 description 4
- 229910052763 palladium Inorganic materials 0.000 description 4
- 230000036961 partial Effects 0.000 description 4
- 230000002265 prevention Effects 0.000 description 4
- VVWRJUBEIPHGQF-MDZDMXLPSA-N propan-2-yl (NE)-N-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)\N=N\C(=O)OC(C)C VVWRJUBEIPHGQF-MDZDMXLPSA-N 0.000 description 4
- 239000003380 propellant Substances 0.000 description 4
- 239000002464 receptor antagonist Substances 0.000 description 4
- 239000003638 reducing agent Substances 0.000 description 4
- 239000000523 sample Substances 0.000 description 4
- 230000002194 synthesizing Effects 0.000 description 4
- 230000001225 therapeutic Effects 0.000 description 4
- 239000003981 vehicle Substances 0.000 description 4
- KINWYTAUPKOPCQ-YFKPBYRVSA-N (2R)-2-azaniumyl-3-(3-hydroxypropylsulfanyl)propanoate Chemical compound OC(=O)[C@@H](N)CSCCCO KINWYTAUPKOPCQ-YFKPBYRVSA-N 0.000 description 3
- XGEZFYOWXLYYNM-UHFFFAOYSA-N (5-fluoropyridin-2-yl)hydrazine Chemical compound NNC1=CC=C(F)C=N1 XGEZFYOWXLYYNM-UHFFFAOYSA-N 0.000 description 3
- JYUXDXWXTPSAEL-UHFFFAOYSA-N 1,4-dioxane;oxolane Chemical compound C1CCOC1.C1COCCO1 JYUXDXWXTPSAEL-UHFFFAOYSA-N 0.000 description 3
- NRKYWOKHZRQRJR-UHFFFAOYSA-N 2,2,2-trifluoroacetamide Chemical compound NC(=O)C(F)(F)F NRKYWOKHZRQRJR-UHFFFAOYSA-N 0.000 description 3
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 3
- IETKPTYAGKZLKY-UHFFFAOYSA-N 5-[[4-[(3-methyl-4-oxoquinazolin-2-yl)methoxy]phenyl]methyl]-1,3-thiazolidine-2,4-dione Chemical compound N=1C2=CC=CC=C2C(=O)N(C)C=1COC(C=C1)=CC=C1CC1SC(=O)NC1=O IETKPTYAGKZLKY-UHFFFAOYSA-N 0.000 description 3
- JFHROPTYMMSOLG-UHFFFAOYSA-N 6-[3-(dimethylcarbamoyl)phenyl]sulfonyl-4-(3-methoxyanilino)-8-methylquinoline-3-carboxamide Chemical compound COC1=CC=CC(NC=2C3=CC(=CC(C)=C3N=CC=2C(N)=O)S(=O)(=O)C=2C=C(C=CC=2)C(=O)N(C)C)=C1 JFHROPTYMMSOLG-UHFFFAOYSA-N 0.000 description 3
- 206010006451 Bronchitis Diseases 0.000 description 3
- 229960004436 Budesonide Drugs 0.000 description 3
- 108010037462 Cyclooxygenase 2 Proteins 0.000 description 3
- 102000004127 Cytokines Human genes 0.000 description 3
- 108090000695 Cytokines Proteins 0.000 description 3
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 3
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 3
- GUVUOGQBMYCBQP-UHFFFAOYSA-N DMPU Chemical compound CN1CCCN(C)C1=O GUVUOGQBMYCBQP-UHFFFAOYSA-N 0.000 description 3
- 240000000437 Eucalyptus leucoxylon Species 0.000 description 3
- 235000004694 Eucalyptus leucoxylon Nutrition 0.000 description 3
- QZZUEBNBZAPZLX-QFIPXVFZSA-N Indacaterol Chemical compound N1C(=O)C=CC2=C1C(O)=CC=C2[C@@H](O)CNC1CC(C=C(C(=C2)CC)CC)=C2C1 QZZUEBNBZAPZLX-QFIPXVFZSA-N 0.000 description 3
- 206010022114 Injury Diseases 0.000 description 3
- 102000004889 Interleukin-6 Human genes 0.000 description 3
- 108090001005 Interleukin-6 Proteins 0.000 description 3
- GUBGYTABKSRVRQ-UUNJERMWSA-N Lactose Natural products O([C@@H]1[C@H](O)[C@H](O)[C@H](O)O[C@@H]1CO)[C@H]1[C@@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1 GUBGYTABKSRVRQ-UUNJERMWSA-N 0.000 description 3
- BMKINZUHKYLSKI-DQEYMECFSA-N N-[2-hydroxy-5-[(1R)-1-hydroxy-2-[2-[4-[[(2R)-2-hydroxy-2-phenylethyl]amino]phenyl]ethylamino]ethyl]phenyl]formamide Chemical compound C1([C@@H](O)CNC2=CC=C(C=C2)CCNC[C@H](O)C=2C=C(NC=O)C(O)=CC=2)=CC=CC=C1 BMKINZUHKYLSKI-DQEYMECFSA-N 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M NaHCO3 Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- 102100015381 PTGS2 Human genes 0.000 description 3
- 208000005069 Pulmonary Fibrosis Diseases 0.000 description 3
- 206010063837 Reperfusion injury Diseases 0.000 description 3
- 239000002168 alkylating agent Substances 0.000 description 3
- 230000000172 allergic Effects 0.000 description 3
- 201000008937 atopic dermatitis Diseases 0.000 description 3
- 229950000210 beclometasone dipropionate Drugs 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 229910000085 borane Inorganic materials 0.000 description 3
- 229910000090 borane Inorganic materials 0.000 description 3
- MCQRPQCQMGVWIQ-UHFFFAOYSA-N boron;methylsulfanylmethane Chemical compound [B].CSC MCQRPQCQMGVWIQ-UHFFFAOYSA-N 0.000 description 3
- 201000009267 bronchiectasis Diseases 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 239000000969 carrier Substances 0.000 description 3
- 239000003246 corticosteroid Substances 0.000 description 3
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 3
- DMJZZSLVPSMWCS-UHFFFAOYSA-N diborane Chemical compound B1[H]B[H]1 DMJZZSLVPSMWCS-UHFFFAOYSA-N 0.000 description 3
- ROSDSFDQCJNGOL-UHFFFAOYSA-N dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 3
- 201000009910 diseases by infectious agent Diseases 0.000 description 3
- 239000006185 dispersion Substances 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 229960004078 indacaterol Drugs 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- GUBGYTABKSRVRQ-XLOQQCSPSA-N lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 3
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Substances [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 3
- 239000011859 microparticle Substances 0.000 description 3
- 229960002744 mometasone furoate Drugs 0.000 description 3
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 3
- 230000001590 oxidative Effects 0.000 description 3
- 230000000865 phosphorylative Effects 0.000 description 3
- 230000003389 potentiating Effects 0.000 description 3
- 239000003755 preservative agent Substances 0.000 description 3
- 230000000770 pro-inflamatory Effects 0.000 description 3
- 125000006513 pyridinyl methyl group Chemical group 0.000 description 3
- 239000012453 solvate Substances 0.000 description 3
- 239000000600 sorbitol Substances 0.000 description 3
- 235000010356 sorbitol Nutrition 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 239000006188 syrup Substances 0.000 description 3
- 235000020357 syrup Nutrition 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- UORVGPXVDQYIDP-UHFFFAOYSA-N trihydridoboron Substances B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 3
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 2
- WWRCMNKATXZARA-UHFFFAOYSA-N 1-Isopropyl-2-methylbenzene Chemical compound CC(C)C1=CC=CC=C1C WWRCMNKATXZARA-UHFFFAOYSA-N 0.000 description 2
- JLPULHDHAOZNQI-ZTIMHPMXSA-N 1-hexadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/C\C=C/CCCCC JLPULHDHAOZNQI-ZTIMHPMXSA-N 0.000 description 2
- CWLUFVAFWWNXJZ-UHFFFAOYSA-N 1-hydroxypyrrolidine Chemical compound ON1CCCC1 CWLUFVAFWWNXJZ-UHFFFAOYSA-N 0.000 description 2
- NKULBUOBGILEAR-UHFFFAOYSA-N 2,2-difluoroethyl trifluoromethanesulfonate Chemical compound FC(F)COS(=O)(=O)C(F)(F)F NKULBUOBGILEAR-UHFFFAOYSA-N 0.000 description 2
- AKTDHHFJFNIILG-UHFFFAOYSA-M 3,3-diethoxypropanoate Chemical compound CCOC(CC([O-])=O)OCC AKTDHHFJFNIILG-UHFFFAOYSA-M 0.000 description 2
- VZFPSCNTFBJZHB-UHFFFAOYSA-N 3-fluoropyridine-2-carbonitrile Chemical compound FC1=CC=CN=C1C#N VZFPSCNTFBJZHB-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- 206010003246 Arthritis Diseases 0.000 description 2
- OZAIFHULBGXAKX-VAWYXSNFSA-N Azobisisobutyronitrile Chemical compound N#CC(C)(C)\N=N\C(C)(C)C#N OZAIFHULBGXAKX-VAWYXSNFSA-N 0.000 description 2
- 239000005711 Benzoic acid Substances 0.000 description 2
- 206010006458 Bronchitis chronic Diseases 0.000 description 2
- YSHOWEKUVWPFNR-UHFFFAOYSA-N Burgess reagent Chemical compound CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC YSHOWEKUVWPFNR-UHFFFAOYSA-N 0.000 description 2
- 125000006414 CCl Chemical group ClC* 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N Carbon tetrachloride Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- VOPWNXZWBYDODV-UHFFFAOYSA-N Chlorodifluoromethane Chemical compound FC(F)Cl VOPWNXZWBYDODV-UHFFFAOYSA-N 0.000 description 2
- 208000007451 Chronic Bronchitis Diseases 0.000 description 2
- OROGSEYTTFOCAN-DNJOTXNNSA-N Codeine Chemical compound C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC OROGSEYTTFOCAN-DNJOTXNNSA-N 0.000 description 2
- 241000701022 Cytomegalovirus Species 0.000 description 2
- PXBRQCKWGAHEHS-UHFFFAOYSA-N Dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 description 2
- 210000002889 Endothelial Cells Anatomy 0.000 description 2
- 102100011142 GRAP2 Human genes 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- 241000700588 Human alphaherpesvirus 1 Species 0.000 description 2
- 241000701085 Human alphaherpesvirus 3 Species 0.000 description 2
- 241000701041 Human betaherpesvirus 7 Species 0.000 description 2
- 241001502974 Human gammaherpesvirus 8 Species 0.000 description 2
- 241000701027 Human herpesvirus 6 Species 0.000 description 2
- DKYWVDODHFEZIM-UHFFFAOYSA-N Ketoprofen Chemical compound OC(=O)C(C)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 DKYWVDODHFEZIM-UHFFFAOYSA-N 0.000 description 2
- ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 description 2
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 2
- 229940067606 Lecithin Drugs 0.000 description 2
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 2
- 240000007472 Leucaena leucocephala Species 0.000 description 2
- 208000009856 Lung Disease Diseases 0.000 description 2
- 102000038027 MAP kinase family Human genes 0.000 description 2
- 108091007472 MAP kinase family Proteins 0.000 description 2
- 101710029807 MAPK14 Proteins 0.000 description 2
- 229940071648 Metered Dose Inhaler Drugs 0.000 description 2
- 108090000139 Mitogen-Activated Protein Kinase 14 Proteins 0.000 description 2
- 108090000823 Mitogen-Activated Protein Kinases Proteins 0.000 description 2
- ULWOJODHECIZAU-UHFFFAOYSA-N N,N-diethylpropan-2-amine Chemical compound CCN(CC)C(C)C ULWOJODHECIZAU-UHFFFAOYSA-N 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 210000000440 Neutrophils Anatomy 0.000 description 2
- 102100007288 PTGDR2 Human genes 0.000 description 2
- 101710013017 PTGDR2 Proteins 0.000 description 2
- YJVFFLUZDVXJQI-UHFFFAOYSA-L Palladium(II) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 2
- 102000001253 Protein Kinases Human genes 0.000 description 2
- 208000009269 Pulmonary Emphysema Diseases 0.000 description 2
- RZJQGNCSTQAWON-UHFFFAOYSA-N Rofecoxib Chemical compound C1=CC(S(=O)(=O)C)=CC=C1C1=C(C=2C=CC=CC=2)C(=O)OC1 RZJQGNCSTQAWON-UHFFFAOYSA-N 0.000 description 2
- 239000005092 Ruthenium Substances 0.000 description 2
- NDAUXUAQIAJITI-UHFFFAOYSA-N Salbutamol Chemical compound CC(C)(C)NCC(O)C1=CC=C(O)C(CO)=C1 NDAUXUAQIAJITI-UHFFFAOYSA-N 0.000 description 2
- GIIZNNXWQWCKIB-UHFFFAOYSA-N Serevent Chemical compound C1=C(O)C(CO)=CC(C(O)CNCCCCCCOCCCCC=2C=CC=CC=2)=C1 GIIZNNXWQWCKIB-UHFFFAOYSA-N 0.000 description 2
- 210000003491 Skin Anatomy 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- HJUGFYREWKUQJT-UHFFFAOYSA-N Tetrabromomethane Chemical compound BrC(Br)(Br)Br HJUGFYREWKUQJT-UHFFFAOYSA-N 0.000 description 2
- DRUIESSIVFYOMK-UHFFFAOYSA-N Trichloroacetonitrile Chemical compound ClC(Cl)(Cl)C#N DRUIESSIVFYOMK-UHFFFAOYSA-N 0.000 description 2
- ITMCEJHCFYSIIV-UHFFFAOYSA-N Trifluoromethanesulfonic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 2
- SEDZOYHHAIAQIW-UHFFFAOYSA-N Trimethylsilyl azide Chemical compound C[Si](C)(C)N=[N+]=[N-] SEDZOYHHAIAQIW-UHFFFAOYSA-N 0.000 description 2
- 102000011017 Type 4 Cyclic Nucleotide Phosphodiesterases Human genes 0.000 description 2
- 108010037584 Type 4 Cyclic Nucleotide Phosphodiesterases Proteins 0.000 description 2
- CBPNRRGGSAYBKX-SFHVURJKSA-N [(2S)-1-(6-fluoro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)pyrrolidin-2-yl]oxy-tri(propan-2-yl)silane Chemical compound CC(C)[Si](C(C)C)(C(C)C)O[C@H]1CCCN1C1=NN=C2N1C=C(F)C=C2 CBPNRRGGSAYBKX-SFHVURJKSA-N 0.000 description 2
- YYAZJTUGSQOFHG-RZFXJYHSSA-N [(6S,8S,9R,10S,11S,13S,14S,16R,17R)-6,9-difluoro-17-(fluoromethylsulfanylcarbonyl)-11-hydroxy-10,13,16-trimethyl-3-oxo-6,7,8,11,12,14,15,16-octahydrocyclopenta[a]phenanthren-17-yl] propanoate;2-(hydroxymethyl)-4-[1-hydroxy-2-[6-(4-phenylbutoxy)hexylamino] Chemical compound C1=C(O)C(CO)=CC(C(O)CNCCCCCCOCCCCC=2C=CC=CC=2)=C1.C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@@H](C)[C@@](C(=O)SCF)(OC(=O)CC)[C@@]2(C)C[C@@H]1O YYAZJTUGSQOFHG-RZFXJYHSSA-N 0.000 description 2
- ZBIKORITPGTTGI-UHFFFAOYSA-N [acetyloxy(phenyl)-$l^{3}-iodanyl] acetate Chemical compound CC(=O)OI(OC(C)=O)C1=CC=CC=C1 ZBIKORITPGTTGI-UHFFFAOYSA-N 0.000 description 2
- 230000002378 acidificating Effects 0.000 description 2
- ASMXXROZKSBQIH-VITNCHFBSA-N aclidinium Chemical compound C([C@@H](C(CC1)CC2)OC(=O)C(O)(C=3SC=CC=3)C=3SC=CC=3)[N+]21CCCOC1=CC=CC=C1 ASMXXROZKSBQIH-VITNCHFBSA-N 0.000 description 2
- 230000001154 acute Effects 0.000 description 2
- 238000005804 alkylation reaction Methods 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- 235000019270 ammonium chloride Nutrition 0.000 description 2
- 229960001692 arformoterol Drugs 0.000 description 2
- PUJDIJCNWFYVJX-UHFFFAOYSA-N benzyl carbamate Chemical compound NC(=O)OCC1=CC=CC=C1 PUJDIJCNWFYVJX-UHFFFAOYSA-N 0.000 description 2
- 230000027455 binding Effects 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 125000003636 chemical group Chemical group 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 239000006071 cream Substances 0.000 description 2
- 238000006880 cross-coupling reaction Methods 0.000 description 2
- 239000003255 cyclooxygenase 2 inhibitor Substances 0.000 description 2
- 201000003883 cystic fibrosis Diseases 0.000 description 2
- 230000002354 daily Effects 0.000 description 2
- 235000019404 dichlorodifluoromethane Nutrition 0.000 description 2
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 2
- 238000000113 differential scanning calorimetry Methods 0.000 description 2
- 229940043279 diisopropylamine Drugs 0.000 description 2
- 238000006073 displacement reaction Methods 0.000 description 2
- 108010067396 dornase alfa Proteins 0.000 description 2
- 238000009510 drug design Methods 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- STSCVKRWJPWALQ-UHFFFAOYSA-N ethyl 2,2,2-trifluoroacetate Chemical compound CCOC(=O)C(F)(F)F STSCVKRWJPWALQ-UHFFFAOYSA-N 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 238000003818 flash chromatography Methods 0.000 description 2
- WSFSSNUMVMOOMR-UHFFFAOYSA-N formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 2
- 238000005755 formation reaction Methods 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 description 2
- 239000012458 free base Substances 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 230000002140 halogenating Effects 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 125000000623 heterocyclic group Chemical group 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- 125000002883 imidazolyl group Chemical group 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 230000021995 interleukin-8 production Effects 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 125000001786 isothiazolyl group Chemical group 0.000 description 2
- 239000000787 lecithin Substances 0.000 description 2
- 235000010445 lecithin Nutrition 0.000 description 2
- 150000002617 leukotrienes Chemical class 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 230000004301 light adaptation Effects 0.000 description 2
- 230000000670 limiting Effects 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L mgso4 Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 230000000510 mucolytic Effects 0.000 description 2
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 2
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- 239000007800 oxidant agent Substances 0.000 description 2
- 102000002574 p38 Mitogen-Activated Protein Kinases Human genes 0.000 description 2
- 101710004309 p38a Proteins 0.000 description 2
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- 239000000546 pharmaceutic aid Substances 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 238000006366 phosphorylation reaction Methods 0.000 description 2
- 238000002953 preparative HPLC Methods 0.000 description 2
- 230000002335 preservative Effects 0.000 description 2
- DNIAPMSPPWPWGF-UHFFFAOYSA-N propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 2
- 230000002685 pulmonary Effects 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 230000002829 reduced Effects 0.000 description 2
- 238000006268 reductive amination reaction Methods 0.000 description 2
- 229910052707 ruthenium Inorganic materials 0.000 description 2
- 229960002052 salbutamol Drugs 0.000 description 2
- 229960004017 salmeterol Drugs 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 239000000779 smoke Substances 0.000 description 2
- 125000003003 spiro group Chemical group 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 201000000596 systemic lupus erythematosus Diseases 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N t-BuOH Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- FWOBBEOKTITUHK-UHFFFAOYSA-N tert-butyl N-benzylcarbamate Chemical compound CC(C)(C)OC(=O)NCC1=CC=CC=C1 FWOBBEOKTITUHK-UHFFFAOYSA-N 0.000 description 2
- 230000000699 topical Effects 0.000 description 2
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 2
- JRZGPXSSNPTNMA-JTQLQIEISA-N (1S)-1,2,3,4-tetrahydronaphthalen-1-amine Chemical compound C1=CC=C2[C@@H](N)CCCC2=C1 JRZGPXSSNPTNMA-JTQLQIEISA-N 0.000 description 1
- NTNKNFHIAFDCSJ-UHFFFAOYSA-N (2-nitrophenyl) thiohypochlorite Chemical compound [O-][N+](=O)C1=CC=CC=C1SCl NTNKNFHIAFDCSJ-UHFFFAOYSA-N 0.000 description 1
- PKLZSYAHHJSOFE-SSDOTTSWSA-N (2R)-1-(2,2-dimethylpropanoyl)pyrrolidine-2-carboxylic acid Chemical compound CC(C)(C)C(=O)N1CCC[C@@H]1C(O)=O PKLZSYAHHJSOFE-SSDOTTSWSA-N 0.000 description 1
- ZEYYDOLCHFETHQ-JOCHJYFZSA-N (2R)-2-cyclopentyl-2-[4-(quinolin-2-ylmethoxy)phenyl]acetic acid Chemical compound C1([C@@H](C(=O)O)C=2C=CC(OCC=3N=C4C=CC=CC4=CC=3)=CC=2)CCCC1 ZEYYDOLCHFETHQ-JOCHJYFZSA-N 0.000 description 1
- IXBKFJZWNAVSHW-JEDNCBNOSA-N (2S)-1-methylpyrrolidine-2-carboxylic acid;hydrate Chemical compound O.CN1CCC[C@H]1C(O)=O IXBKFJZWNAVSHW-JEDNCBNOSA-N 0.000 description 1
- GULMJNUJAVNDBJ-YFKPBYRVSA-N (2S)-2-methylpyrrolidine-1-carboxylic acid Chemical compound C[C@H]1CCCN1C(O)=O GULMJNUJAVNDBJ-YFKPBYRVSA-N 0.000 description 1
- OSNSWKAZFASRNG-BMZZJELJSA-N (3R,4S,5S,6R)-6-(hydroxymethyl)oxane-2,3,4,5-tetrol;hydrate Chemical compound O.OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O OSNSWKAZFASRNG-BMZZJELJSA-N 0.000 description 1
- IFYHUZDMAIXWOZ-UHFFFAOYSA-N (5-fluoropyridin-2-yl)-morpholin-4-ylmethanone Chemical compound N1=CC(F)=CC=C1C(=O)N1CCOCC1 IFYHUZDMAIXWOZ-UHFFFAOYSA-N 0.000 description 1
- 125000006583 (C1-C3) haloalkyl group Chemical group 0.000 description 1
- BPXZSHHCUKRDHD-HTLUESNNSA-N (E)-but-2-enedioic acid;N-[2-hydroxy-5-[(1R)-1-hydroxy-2-[[(2R)-1-(4-methoxyphenyl)propan-2-yl]amino]ethyl]phenyl]formamide;hydrate Chemical compound O.OC(=O)\C=C\C(O)=O.C1=CC(OC)=CC=C1C[C@@H](C)NC[C@H](O)C1=CC=C(O)C(NC=O)=C1.C1=CC(OC)=CC=C1C[C@@H](C)NC[C@H](O)C1=CC=C(O)C(NC=O)=C1 BPXZSHHCUKRDHD-HTLUESNNSA-N 0.000 description 1
- YFMFNYKEUDLDTL-UHFFFAOYSA-N 1,1,1,2,3,3,3-Heptafluoropropane Chemical compound FC(F)(F)C(F)C(F)(F)F YFMFNYKEUDLDTL-UHFFFAOYSA-N 0.000 description 1
- LVGUZGTVOIAKKC-UHFFFAOYSA-N 1,1,1,2-Tetrafluoroethane Chemical compound FCC(F)(F)F LVGUZGTVOIAKKC-UHFFFAOYSA-N 0.000 description 1
- PAAZPARNPHGIKF-UHFFFAOYSA-N 1,2-Dibromoethane Chemical compound BrCCBr PAAZPARNPHGIKF-UHFFFAOYSA-N 0.000 description 1
- VHJLVAABSRFDPM-UHFFFAOYSA-N 1,4-dimercaptobutane-2,3-diol Chemical compound SCC(O)C(O)CS VHJLVAABSRFDPM-UHFFFAOYSA-N 0.000 description 1
- JWOHBPPVVDQMKB-UHFFFAOYSA-N 1-[(2-methylpropan-2-yl)oxycarbonyl]piperidine-4-carboxylic acid Chemical compound CC(C)(C)OC(=O)N1CCC(C(O)=O)CC1 JWOHBPPVVDQMKB-UHFFFAOYSA-N 0.000 description 1
- HDXFCPZKMFTOLH-UHFFFAOYSA-N 1-amino-2,3-dihydroinden-1-ol Chemical compound C1=CC=C2C(N)(O)CCC2=C1 HDXFCPZKMFTOLH-UHFFFAOYSA-N 0.000 description 1
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-hydroxybenzotriazole Chemical group C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 1
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 1
- KYWXRBNOYGGPIZ-UHFFFAOYSA-N 1-morpholin-4-ylethanone Chemical compound CC(=O)N1CCOCC1 KYWXRBNOYGGPIZ-UHFFFAOYSA-N 0.000 description 1
- XJEVHMGJSYVQBQ-UHFFFAOYSA-N 2,3-dihydro-1H-inden-1-amine Chemical compound C1=CC=C2C(N)CCC2=C1 XJEVHMGJSYVQBQ-UHFFFAOYSA-N 0.000 description 1
- ZGRGIEBNSYIVDS-UHFFFAOYSA-N 2,6-ditert-butyl-3-methylpyridine Chemical compound CC1=CC=C(C(C)(C)C)N=C1C(C)(C)C ZGRGIEBNSYIVDS-UHFFFAOYSA-N 0.000 description 1
- GCUOLJOTJRUDIZ-UHFFFAOYSA-N 2-(2-bromoethoxy)oxane Chemical compound BrCCOC1CCCCO1 GCUOLJOTJRUDIZ-UHFFFAOYSA-N 0.000 description 1
- JCXZKUZXVQKENT-UHFFFAOYSA-N 2-(4-methylpiperazin-1-ium-1-yl)acetate Chemical compound CN1CCN(CC(O)=O)CC1 JCXZKUZXVQKENT-UHFFFAOYSA-N 0.000 description 1
- XDBZJXRPEKFIFR-UHFFFAOYSA-N 2-(oxan-2-yloxy)ethanol Chemical compound OCCOC1CCCCO1 XDBZJXRPEKFIFR-UHFFFAOYSA-N 0.000 description 1
- AFABGHUZZDYHJO-UHFFFAOYSA-N 2-Methylpentane Chemical class CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 1
- WZBHMXRBXXCEDD-UHFFFAOYSA-N 2-[4-[(2-methylpropan-2-yl)oxycarbonyl]piperazin-1-yl]acetic acid Chemical compound CC(C)(C)OC(=O)N1CCN(CC(O)=O)CC1 WZBHMXRBXXCEDD-UHFFFAOYSA-N 0.000 description 1
- DKSKRBVXRDGYAS-UHFFFAOYSA-N 2-[4-[4-(butylcarbamoyl)-2-[(2,4-dichlorophenyl)sulfonylamino]phenoxy]-3-methoxyphenyl]acetic acid Chemical compound C=1C=C(Cl)C=C(Cl)C=1S(=O)(=O)NC1=CC(C(=O)NCCCC)=CC=C1OC1=CC=C(CC(O)=O)C=C1OC DKSKRBVXRDGYAS-UHFFFAOYSA-N 0.000 description 1
- JWYIGNODXSRKGP-UHFFFAOYSA-N 2-[4-acetamido-3-(4-chlorophenyl)sulfanyl-2-methylindol-1-yl]acetic acid Chemical compound C1=2C(NC(=O)C)=CC=CC=2N(CC(O)=O)C(C)=C1SC1=CC=C(Cl)C=C1 JWYIGNODXSRKGP-UHFFFAOYSA-N 0.000 description 1
- LDLCZOVUSADOIV-UHFFFAOYSA-N 2-bromoethanol Chemical compound OCCBr LDLCZOVUSADOIV-UHFFFAOYSA-N 0.000 description 1
- MLDCMXRXWQHBTN-UHFFFAOYSA-N 2-bromoethoxy-[2-bromoethoxy(dimethyl)silyl]oxy-dimethylsilane Chemical compound BrCCO[Si](C)(C)O[Si](C)(C)OCCBr MLDCMXRXWQHBTN-UHFFFAOYSA-N 0.000 description 1
- YMQRPXBBBOXHNZ-UHFFFAOYSA-N 2-chloro-1-morpholin-4-ylethanone Chemical compound ClCC(=O)N1CCOCC1 YMQRPXBBBOXHNZ-UHFFFAOYSA-N 0.000 description 1
- UUOLETYDNTVQDY-UHFFFAOYSA-N 2-chloro-3-nitropyridine Chemical compound [O-][N+](=O)C1=CC=CN=C1Cl UUOLETYDNTVQDY-UHFFFAOYSA-N 0.000 description 1
- 125000003006 2-dimethylaminoethyl group Chemical group [H]C([H])([H])N(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- RXIUEIPPLAFSDF-CYBMUJFWSA-N 2-hydroxy-N,N-dimethyl-3-[[2-[[(1R)-1-(5-methylfuran-2-yl)propyl]amino]-3,4-dioxocyclobuten-1-yl]amino]benzamide Chemical compound N([C@H](CC)C=1OC(C)=CC=1)C(C(C1=O)=O)=C1NC1=CC=CC(C(=O)N(C)C)=C1O RXIUEIPPLAFSDF-CYBMUJFWSA-N 0.000 description 1
- GSLTVFIVJMCNBH-UHFFFAOYSA-N 2-isocyanatopropane Chemical compound CC(C)N=C=O GSLTVFIVJMCNBH-UHFFFAOYSA-N 0.000 description 1
- IPXNXMNCBXHYLQ-UHFFFAOYSA-N 2-pyrrolidin-1-ylacetic acid Chemical compound OC(=O)CN1CCCC1 IPXNXMNCBXHYLQ-UHFFFAOYSA-N 0.000 description 1
- NUTFFLDVSHIZBL-UHFFFAOYSA-N 3,3-dimethylbutanoyl cyanide Chemical compound CC(C)(C)CC(=O)C#N NUTFFLDVSHIZBL-UHFFFAOYSA-N 0.000 description 1
- JSHLMMUXJIDENZ-UHFFFAOYSA-N 3-(4-methylpiperazin-1-ium-1-yl)propanoate Chemical compound CN1CCN(CCC(O)=O)CC1 JSHLMMUXJIDENZ-UHFFFAOYSA-N 0.000 description 1
- KAABRGOOVGMZFB-UHFFFAOYSA-N 3-(5-amino-3-tert-butylpyrazol-1-yl)phenol Chemical compound N1=C(C(C)(C)C)C=C(N)N1C1=CC=CC(O)=C1 KAABRGOOVGMZFB-UHFFFAOYSA-N 0.000 description 1
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 1
- BKLAJZNVMHLXAP-VKGMXUHCSA-N 3-[(1R,5S)-8,8-dimethyl-8-azoniabicyclo[3.2.1]octan-3-yl]-2,2-diphenylpropanenitrile Chemical compound C([C@H]1CC[C@@H](C2)[N+]1(C)C)C2CC(C#N)(C=1C=CC=CC=1)C1=CC=CC=C1 BKLAJZNVMHLXAP-VKGMXUHCSA-N 0.000 description 1
- BSAIUCUXHVGXNK-UHFFFAOYSA-N 3-bromo-2,3-dihydroinden-1-one Chemical compound C1=CC=C2C(Br)CC(=O)C2=C1 BSAIUCUXHVGXNK-UHFFFAOYSA-N 0.000 description 1
- HNGQQUDFJDROPY-UHFFFAOYSA-N 3-bromobenzenethiol Chemical compound SC1=CC=CC(Br)=C1 HNGQQUDFJDROPY-UHFFFAOYSA-N 0.000 description 1
- VBYDSMBICNUTKN-UHFFFAOYSA-N 3-hydrazinylbenzoic acid Chemical compound NNC1=CC=CC(C(O)=O)=C1 VBYDSMBICNUTKN-UHFFFAOYSA-N 0.000 description 1
- MXZMACXOMZKYHJ-UHFFFAOYSA-N 4,4-dimethyl-3-oxopentanenitrile Chemical compound CC(C)(C)C(=O)CC#N MXZMACXOMZKYHJ-UHFFFAOYSA-N 0.000 description 1
- QYBXZYYECZFQRX-UHFFFAOYSA-N 4-(morpholin-4-ylmethyl)benzoic acid Chemical compound C1=CC(C(=O)O)=CC=C1CN1CCOCC1 QYBXZYYECZFQRX-UHFFFAOYSA-N 0.000 description 1
- JVVRCYWZTJLJSG-UHFFFAOYSA-N 4-Dimethylaminophenol Substances CN(C)C1=CC=C(O)C=C1 JVVRCYWZTJLJSG-UHFFFAOYSA-N 0.000 description 1
- MHUMCDAQMVSTBI-UHFFFAOYSA-N 4-[[4-(6-fluoro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)phenyl]methyl]morpholine Chemical compound N12C=C(F)C=CC2=NN=C1C(C=C1)=CC=C1CN1CCOCC1 MHUMCDAQMVSTBI-UHFFFAOYSA-N 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- RGUKYNXWOWSRET-UHFFFAOYSA-N 4-pyrrolidin-1-ylpyridine Chemical compound C1CCCN1C1=CC=NC=C1 RGUKYNXWOWSRET-UHFFFAOYSA-N 0.000 description 1
- IHOXNOQMRZISPV-YJYMSZOUSA-N 5-[(1R)-1-hydroxy-2-[[(2R)-1-(4-methoxyphenyl)propan-2-yl]azaniumyl]ethyl]-2-oxo-1H-quinolin-8-olate Chemical compound C1=CC(OC)=CC=C1C[C@@H](C)NC[C@H](O)C1=CC=C(O)C2=C1C=CC(=O)N2 IHOXNOQMRZISPV-YJYMSZOUSA-N 0.000 description 1
- 239000003406 5-lipoxygenase-activating protein inhibitor Substances 0.000 description 1
- XDBHURGONHZNJF-UHFFFAOYSA-N 6-[2-(3,4-diethoxyphenyl)-1,3-thiazol-4-yl]pyridine-2-carboxylic acid Chemical compound C1=C(OCC)C(OCC)=CC=C1C1=NC(C=2N=C(C=CC=2)C(O)=O)=CS1 XDBHURGONHZNJF-UHFFFAOYSA-N 0.000 description 1
- MVRUSISMSYPYHS-UHFFFAOYSA-N 6-fluoro-1-[2-(oxan-2-yloxy)ethyl]indazole Chemical compound C12=CC(F)=CC=C2C=NN1CCOC1CCCCO1 MVRUSISMSYPYHS-UHFFFAOYSA-N 0.000 description 1
- CFMZDEQEVCDMRN-UHFFFAOYSA-N 6-fluoro-1H-indazole Chemical compound FC1=CC=C2C=NNC2=C1 CFMZDEQEVCDMRN-UHFFFAOYSA-N 0.000 description 1
- ABLOXFHOYVYGQW-UHFFFAOYSA-N 6-fluoro-3-(2-pyrrolidin-1-ylethyl)-[1,2,4]triazolo[4,3-a]pyridine Chemical compound N12C=C(F)C=CC2=NN=C1CCN1CCCC1 ABLOXFHOYVYGQW-UHFFFAOYSA-N 0.000 description 1
- IOWCTYRWLCPJGY-UHFFFAOYSA-N 6-fluoro-3-[(4-methylpiperazin-1-yl)methyl]-[1,2,4]triazolo[4,3-a]pyridine Chemical compound C1CN(C)CCN1CC1=NN=C2N1C=C(F)C=C2 IOWCTYRWLCPJGY-UHFFFAOYSA-N 0.000 description 1
- QTORXJXQBMQBIH-UHFFFAOYSA-N 6-fluoro-3-[2-(4-methylpiperazin-1-yl)ethyl]-[1,2,4]triazolo[4,3-a]pyridine Chemical compound C1CN(C)CCN1CCC1=NN=C2N1C=C(F)C=C2 QTORXJXQBMQBIH-UHFFFAOYSA-N 0.000 description 1
- PFQVLVLFGQQMMK-UHFFFAOYSA-N 6-fluoro-N-methyl-N-[2-tri(propan-2-yl)silyloxyethyl]-[1,2,4]triazolo[4,3-a]pyridin-3-amine Chemical compound C1=CC(F)=CN2C(N(C)CCO[Si](C(C)C)(C(C)C)C(C)C)=NN=C21 PFQVLVLFGQQMMK-UHFFFAOYSA-N 0.000 description 1
- DUYAXJXZPURHBR-UHFFFAOYSA-N 6-fluoro-N-propan-2-yl-[1,2,4]triazolo[4,3-a]pyridin-3-amine Chemical compound C1=CC(F)=CN2C(NC(C)C)=NN=C21 DUYAXJXZPURHBR-UHFFFAOYSA-N 0.000 description 1
- RLHZNOHNAOXSLJ-UHFFFAOYSA-N 6-fluoro-[1,2,4]triazolo[4,3-a]pyridine Chemical compound C1=C(F)C=CC2=NN=CN21 RLHZNOHNAOXSLJ-UHFFFAOYSA-N 0.000 description 1
- RTAPDZBZLSXHQQ-UHFFFAOYSA-N 8-methyl-3,7-dihydropurine-2,6-dione Chemical class N1C(=O)NC(=O)C2=C1N=C(C)N2 RTAPDZBZLSXHQQ-UHFFFAOYSA-N 0.000 description 1
- 229960004308 ACETYLCYSTEINE Drugs 0.000 description 1
- 229940005497 ANTICHOLINERGIC AGENTS Drugs 0.000 description 1
- 102000005869 Activating Transcription Factors Human genes 0.000 description 1
- 108010005254 Activating Transcription Factors Proteins 0.000 description 1
- 206010069351 Acute lung injury Diseases 0.000 description 1
- 229940090167 Advair Drugs 0.000 description 1
- 229940023808 Albuterol Drugs 0.000 description 1
- 206010052613 Allergic bronchitis Diseases 0.000 description 1
- 206010063532 Allergic respiratory disease Diseases 0.000 description 1
- 235000019489 Almond oil Nutrition 0.000 description 1
- JBDGDEWWOUBZPM-XYPYZODXSA-N Ambroxol Chemical compound NC1=C(Br)C=C(Br)C=C1CN[C@@H]1CC[C@@H](O)CC1 JBDGDEWWOUBZPM-XYPYZODXSA-N 0.000 description 1
- 229960005174 Ambroxol Drugs 0.000 description 1
- 229950001163 Amelubant Drugs 0.000 description 1
- PECIYKGSSMCNHN-UHFFFAOYSA-N Aminophylline Chemical compound NCCN.O=C1N(C)C(=O)N(C)C2=NC=N[C]21.O=C1N(C)C(=O)N(C)C2=NC=N[C]21 PECIYKGSSMCNHN-UHFFFAOYSA-N 0.000 description 1
- 229960003556 Aminophylline Drugs 0.000 description 1
- AVKUERGKIZMTKX-NJBDSQKTSA-N Ampicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=CC=C1 AVKUERGKIZMTKX-NJBDSQKTSA-N 0.000 description 1
- 208000003120 Angiofibroma Diseases 0.000 description 1
- 229940064005 Antibiotic throat preparations Drugs 0.000 description 1
- 229940083879 Antibiotics FOR TREATMENT OF HEMORRHOIDS AND ANAL FISSURES FOR TOPICAL USE Drugs 0.000 description 1
- 229940042052 Antibiotics for systemic use Drugs 0.000 description 1
- 229940042786 Antitubercular Antibiotics Drugs 0.000 description 1
- GXDALQBWZGODGZ-UHFFFAOYSA-N Astemizole Chemical compound C1=CC(OC)=CC=C1CCN1CCC(NC=2N(C3=CC=CC=C3N=2)CC=2C=CC(F)=CC=2)CC1 GXDALQBWZGODGZ-UHFFFAOYSA-N 0.000 description 1
- 229960004754 Astemizole Drugs 0.000 description 1
- 206010003557 Asthma exercise induced Diseases 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 206010003816 Autoimmune disease Diseases 0.000 description 1
- MQTOSJVFKKJCRP-BICOPXKESA-N Azithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)N(C)C[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 MQTOSJVFKKJCRP-BICOPXKESA-N 0.000 description 1
- 229960003644 Aztreonam Drugs 0.000 description 1
- MUALRAIOVNYAIW-UHFFFAOYSA-N BINAP Chemical group C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 description 1
- 206010060945 Bacterial infection Diseases 0.000 description 1
- 229950010663 Balaglitazone Drugs 0.000 description 1
- 210000003651 Basophils Anatomy 0.000 description 1
- 208000006752 Brain Edema Diseases 0.000 description 1
- 206010048962 Brain oedema Diseases 0.000 description 1
- XWTYSIMOBUGWOL-UHFFFAOYSA-N Bricaril Chemical compound CC(C)(C)NCC(O)C1=CC(O)=CC(O)=C1 XWTYSIMOBUGWOL-UHFFFAOYSA-N 0.000 description 1
- 206010006482 Bronchospasm Diseases 0.000 description 1
- 229940045348 Brown mixture Drugs 0.000 description 1
- 102100008428 CCL2 Human genes 0.000 description 1
- 101700006000 CCL2 Proteins 0.000 description 1
- 101700070842 CCR3 Proteins 0.000 description 1
- 102100005861 CCR3 Human genes 0.000 description 1
- 101700029727 CCR8 Proteins 0.000 description 1
- 102100008148 CCR8 Human genes 0.000 description 1
- CFBUZOUXXHZCFB-OYOVHJISSA-N CHEMBL511115 Chemical compound COC1=CC=C([C@@]2(CC[C@H](CC2)C(O)=O)C#N)C=C1OC1CCCC1 CFBUZOUXXHZCFB-OYOVHJISSA-N 0.000 description 1
- 102100006400 CSF2 Human genes 0.000 description 1
- LQWOPQSWTXNYSM-QMMMGPOBSA-N C[C@H]1CCCN1c1nnc2ccc(F)cn12 Chemical compound C[C@H]1CCCN1c1nnc2ccc(F)cn12 LQWOPQSWTXNYSM-QMMMGPOBSA-N 0.000 description 1
- LERNTVKEWCAPOY-VOGVJGKGSA-N C[N+]1(C)[C@H]2C[C@H](C[C@@H]1[C@H]1O[C@@H]21)OC(=O)C(O)(c1cccs1)c1cccs1 Chemical compound C[N+]1(C)[C@H]2C[C@H](C[C@@H]1[C@H]1O[C@@H]21)OC(=O)C(O)(c1cccs1)c1cccs1 LERNTVKEWCAPOY-VOGVJGKGSA-N 0.000 description 1
- 206010006895 Cachexia Diseases 0.000 description 1
- 206010007559 Cardiac failure congestive Diseases 0.000 description 1
- 208000005846 Cardiomyopathy Diseases 0.000 description 1
- 208000008787 Cardiovascular Disease Diseases 0.000 description 1
- 229950010713 Carmoterol Drugs 0.000 description 1
- 235000006696 Catha edulis Nutrition 0.000 description 1
- 240000007681 Catha edulis Species 0.000 description 1
- RZEKVGVHFLEQIL-UHFFFAOYSA-N Celecoxib Chemical compound C1=CC(C)=CC=C1C1=CC(C(F)(F)F)=NN1C1=CC=C(S(N)(=O)=O)C=C1 RZEKVGVHFLEQIL-UHFFFAOYSA-N 0.000 description 1
- VDQQXEISLMTGAB-UHFFFAOYSA-N Chloramine-T Chemical compound [Na+].CC1=CC=C(S(=O)(=O)[N-]Cl)C=C1 VDQQXEISLMTGAB-UHFFFAOYSA-N 0.000 description 1
- 229960001231 Choline Drugs 0.000 description 1
- 229950001653 Cilomilast Drugs 0.000 description 1
- 102000020504 Collagenase family Human genes 0.000 description 1
- 108060005980 Collagenase family Proteins 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 229940064701 Corticosteroid nasal preparations for topical use Drugs 0.000 description 1
- 229960001334 Corticosteroids Drugs 0.000 description 1
- 206010011401 Crohn's disease Diseases 0.000 description 1
- FBPFZTCFMRRESA-KAZBKCHUSA-N D-Mannitol Natural products OC[C@@H](O)[C@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KAZBKCHUSA-N 0.000 description 1
- 206010061428 Decreased appetite Diseases 0.000 description 1
- 206010012601 Diabetes mellitus Diseases 0.000 description 1
- 208000007342 Diabetic Nephropathy Diseases 0.000 description 1
- 206010061835 Diabetic nephropathy Diseases 0.000 description 1
- 239000004338 Dichlorodifluoromethane Substances 0.000 description 1
- 229960000533 Dornase alfa Drugs 0.000 description 1
- 208000000059 Dyspnea Diseases 0.000 description 1
- 206010013975 Dyspnoeas Diseases 0.000 description 1
- 101000457332 ELANE Proteins 0.000 description 1
- 239000004150 EU approved colour Substances 0.000 description 1
- 208000005679 Eczema Diseases 0.000 description 1
- 206010014561 Emphysema Diseases 0.000 description 1
- 229940073621 Enbrel Drugs 0.000 description 1
- 206010014824 Endotoxic shock Diseases 0.000 description 1
- 230000036826 Excretion Effects 0.000 description 1
- 208000004657 Exercise-Induced Asthma Diseases 0.000 description 1
- YMTINGFKWWXKFG-UHFFFAOYSA-N Fenofibrate Chemical compound C1=CC(OC(C)(C)C(=O)OC(C)C)=CC=C1C(=O)C1=CC=C(Cl)C=C1 YMTINGFKWWXKFG-UHFFFAOYSA-N 0.000 description 1
- 229960002297 Fenofibrate Drugs 0.000 description 1
- LSLYOANBFKQKPT-UHFFFAOYSA-N Fenoterol Chemical compound C=1C(O)=CC(O)=CC=1C(O)CNC(C)CC1=CC=C(O)C=C1 LSLYOANBFKQKPT-UHFFFAOYSA-N 0.000 description 1
- RWTNPBWLLIMQHL-UHFFFAOYSA-N Fexofenadine Chemical compound C1=CC(C(C)(C(O)=O)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 RWTNPBWLLIMQHL-UHFFFAOYSA-N 0.000 description 1
- 206010017943 Gastrointestinal conditions Diseases 0.000 description 1
- 208000010412 Glaucoma Diseases 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- VPNYRYCIDCJBOM-UHFFFAOYSA-M Glycopyrronium bromide Chemical compound [Br-].C1[N+](C)(C)CCC1OC(=O)C(O)(C=1C=CC=CC=1)C1CCCC1 VPNYRYCIDCJBOM-UHFFFAOYSA-M 0.000 description 1
- 108010017213 Granulocyte-Macrophage Colony-Stimulating Factor Proteins 0.000 description 1
- 229940093922 Gynecological Antibiotics Drugs 0.000 description 1
- 229940093915 Gynecological Organic acids Drugs 0.000 description 1
- 206010018987 Haemorrhage Diseases 0.000 description 1
- 238000006130 Horner-Wadsworth-Emmons olefination reaction Methods 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-O Htris Chemical compound OCC([NH3+])(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-O 0.000 description 1
- 208000006572 Human Influenza Diseases 0.000 description 1
- 241000701074 Human alphaherpesvirus 2 Species 0.000 description 1
- 241000701044 Human gammaherpesvirus 4 Species 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 229940021223 Hypertonic solutions Drugs 0.000 description 1
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 1
- 210000000987 Immune System Anatomy 0.000 description 1
- 102000018358 Immunoglobulins Human genes 0.000 description 1
- 108060003951 Immunoglobulins Proteins 0.000 description 1
- 206010021972 Inflammatory bowel disease Diseases 0.000 description 1
- 206010022000 Influenza Diseases 0.000 description 1
- 229940030980 Inova Drugs 0.000 description 1
- 108010008212 Integrin alpha4beta1 Proteins 0.000 description 1
- 102000003777 Interleukin-1 beta Human genes 0.000 description 1
- 108090000193 Interleukin-1 beta Proteins 0.000 description 1
- 102000003816 Interleukin-13 Human genes 0.000 description 1
- 108090000176 Interleukin-13 Proteins 0.000 description 1
- 102000004388 Interleukin-4 Human genes 0.000 description 1
- 108090000978 Interleukin-4 Proteins 0.000 description 1
- 108010002616 Interleukin-5 Proteins 0.000 description 1
- 102000000743 Interleukin-5 Human genes 0.000 description 1
- 102000002791 Interleukin-8B Receptors Human genes 0.000 description 1
- 108010018951 Interleukin-8B Receptors Proteins 0.000 description 1
- 229960001361 Ipratropium Bromide Drugs 0.000 description 1
- 206010061255 Ischaemia Diseases 0.000 description 1
- NNPPMTNAJDCUHE-UHFFFAOYSA-N Isobutane Chemical compound CC(C)C NNPPMTNAJDCUHE-UHFFFAOYSA-N 0.000 description 1
- 210000002510 Keratinocytes Anatomy 0.000 description 1
- 229940054136 Kineret Drugs 0.000 description 1
- 235000019766 L-Lysine Nutrition 0.000 description 1
- PWKSKIMOESPYIA-BYPYZUCNSA-N L-N-acetyl-Cysteine Chemical compound CC(=O)N[C@@H](CS)C(O)=O PWKSKIMOESPYIA-BYPYZUCNSA-N 0.000 description 1
- 235000014852 L-arginine Nutrition 0.000 description 1
- 206010024324 Leukaemias Diseases 0.000 description 1
- VNYSSYRCGWBHLG-AMOLWHMGSA-N Leukotriene B4 Chemical compound CCCCC\C=C/C[C@@H](O)\C=C\C=C\C=C/[C@@H](O)CCCC(O)=O VNYSSYRCGWBHLG-AMOLWHMGSA-N 0.000 description 1
- 229960003088 Loratadine Drugs 0.000 description 1
- JCCNYMKQOSZNPW-UHFFFAOYSA-N Loratadine Chemical compound C1CN(C(=O)OCC)CCC1=C1C2=NC=CC=C2CCC2=CC(Cl)=CC=C21 JCCNYMKQOSZNPW-UHFFFAOYSA-N 0.000 description 1
- 108009000252 Lung fibrosis Proteins 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 229940076230 MAGNESIUM SULFATE MONOHYDRATE Drugs 0.000 description 1
- 101710029925 MAPK11 Proteins 0.000 description 1
- 102100005529 MAPK11 Human genes 0.000 description 1
- 101710041325 MAPKAPK2 Proteins 0.000 description 1
- 102100008860 MAPKAPK2 Human genes 0.000 description 1
- 101700064507 MARK2 Proteins 0.000 description 1
- 102100000541 MARK2 Human genes 0.000 description 1
- 108090000028 MMP12 Proteins 0.000 description 1
- 102100004961 MMP12 Human genes 0.000 description 1
- 102100006844 MMP9 Human genes 0.000 description 1
- 101700067851 MMP9 Proteins 0.000 description 1
- 210000002540 Macrophages Anatomy 0.000 description 1
- VTHJTEIRLNZDEV-UHFFFAOYSA-L Magnesium hydroxide Chemical class [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 1
- 235000019759 Maize starch Nutrition 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N Mandelic acid Chemical class OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 102000000422 Matrix Metalloproteinase 3 Human genes 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N Meglumine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- 108010006035 Metalloproteases Proteins 0.000 description 1
- 102000005741 Metalloproteases Human genes 0.000 description 1
- 206010027476 Metastasis Diseases 0.000 description 1
- LXCFILQKKLGQFO-UHFFFAOYSA-N Methylparaben Chemical group COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 1
- 210000001616 Monocytes Anatomy 0.000 description 1
- GNSKLFRGEWLPPA-UHFFFAOYSA-M Monopotassium phosphate Chemical compound [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 description 1
- UCHDWCPVSPXUMX-TZIWLTJVSA-N Montelukast Chemical compound CC(C)(O)C1=CC=CC=C1CC[C@H](C=1C=C(\C=C\C=2N=C3C=C(Cl)C=CC3=CC=2)C=CC=1)SCC1(CC(O)=O)CC1 UCHDWCPVSPXUMX-TZIWLTJVSA-N 0.000 description 1
- 208000000112 Myalgia Diseases 0.000 description 1
- 206010062207 Mycobacterial infection Diseases 0.000 description 1
- JLBYUFVBMWAXFL-UHFFFAOYSA-N N'-(5-fluoropyridin-2-yl)-2-(4-methylpiperazin-1-yl)acetohydrazide Chemical compound C1CN(C)CCN1CC(=O)NNC1=CC=C(F)C=N1 JLBYUFVBMWAXFL-UHFFFAOYSA-N 0.000 description 1
- ZDJNTWLXWXIRGE-UHFFFAOYSA-N N'-(5-fluoropyridin-2-yl)-3-(4-methylpiperazin-1-yl)propanehydrazide Chemical compound C1CN(C)CCN1CCC(=O)NNC1=CC=C(F)C=N1 ZDJNTWLXWXIRGE-UHFFFAOYSA-N 0.000 description 1
- MJLPSTAHFJCBFD-UHFFFAOYSA-N N'-(5-fluoropyridin-2-yl)-3-pyrrolidin-1-ylpropanehydrazide Chemical compound N1=CC(F)=CC=C1NNC(=O)CCN1CCCC1 MJLPSTAHFJCBFD-UHFFFAOYSA-N 0.000 description 1
- OCAIMKDYDGVCPS-UHFFFAOYSA-N N'-(5-fluoropyridin-2-yl)-4-(morpholin-4-ylmethyl)benzohydrazide Chemical compound N1=CC(F)=CC=C1NNC(=O)C(C=C1)=CC=C1CN1CCOCC1 OCAIMKDYDGVCPS-UHFFFAOYSA-N 0.000 description 1
- HYKLNCMPZANNPX-UHFFFAOYSA-N N'-(5-fluoropyridin-2-yl)piperidine-1-carbohydrazide Chemical compound N1=CC(F)=CC=C1NNC(=O)N1CCCCC1 HYKLNCMPZANNPX-UHFFFAOYSA-N 0.000 description 1
- WBGPDYJIPNTOIB-UHFFFAOYSA-N N,N-dibenzylethanamine Chemical compound C=1C=CC=CC=1CN(CC)CC1=CC=CC=C1 WBGPDYJIPNTOIB-UHFFFAOYSA-N 0.000 description 1
- OKDQKPLMQBXTNH-UHFFFAOYSA-N N,N-dimethyl-2H-pyridin-1-amine Chemical compound CN(C)N1CC=CC=C1 OKDQKPLMQBXTNH-UHFFFAOYSA-N 0.000 description 1
- OKFDRAHPFKMAJH-UHFFFAOYSA-N N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)-8-(methanesulfonamido)dibenzofuran-1-carboxamide Chemical compound C=12C3=CC(NS(=O)(=O)C)=CC=C3OC2=C(OC(F)F)C=CC=1C(=O)NC1=C(Cl)C=NC=C1Cl OKFDRAHPFKMAJH-UHFFFAOYSA-N 0.000 description 1
- OPKOKAMJFNKNAS-UHFFFAOYSA-N N-Methylethanolamine Chemical compound CNCCO OPKOKAMJFNKNAS-UHFFFAOYSA-N 0.000 description 1
- XMAWMRNILPLCMA-UHFFFAOYSA-L N-carboxylatoiminocarbamate;triphenylphosphane Chemical compound [O-]C(=O)N=NC([O-])=O.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 XMAWMRNILPLCMA-UHFFFAOYSA-L 0.000 description 1
- HTLZVHNRZJPSMI-UHFFFAOYSA-N N-ethylpiperidine Chemical compound CCN1CCCCC1 HTLZVHNRZJPSMI-UHFFFAOYSA-N 0.000 description 1
- 150000001204 N-oxides Chemical class 0.000 description 1
- 102100007454 NDST3 Human genes 0.000 description 1
- 101700045708 NDST3 Proteins 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 239000007832 Na2SO4 Substances 0.000 description 1
- 229940097496 Nasal Spray Drugs 0.000 description 1
- 210000001989 Nasopharynx Anatomy 0.000 description 1
- 206010053643 Neurodegenerative disease Diseases 0.000 description 1
- 206010029379 Neutrophilia Diseases 0.000 description 1
- 241000208125 Nicotiana Species 0.000 description 1
- 235000002637 Nicotiana tabacum Nutrition 0.000 description 1
- 210000001331 Nose Anatomy 0.000 description 1
- ZADPBFCGQRWHPN-UHFFFAOYSA-N OBO Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 description 1
- HMPQTEPEMQZWQH-QZTJIDSGSA-N ONO-6818 Chemical compound N([C@H](C(C)C)[C@@H](O)C=1OC(=NN=1)C(C)(C)C)C(=O)CN(C(C(N)=CN=1)=O)C=1C1=CC=CC=C1 HMPQTEPEMQZWQH-QZTJIDSGSA-N 0.000 description 1
- 206010061877 Obstructive airways disease Diseases 0.000 description 1
- 208000007892 Occupational Asthma Diseases 0.000 description 1
- 229950000175 Oglemilast Drugs 0.000 description 1
- 206010031264 Osteonecrosis Diseases 0.000 description 1
- 206010025310 Other lymphomas Diseases 0.000 description 1
- 229940092253 Ovalbumin Drugs 0.000 description 1
- 108010058846 Ovalbumin Proteins 0.000 description 1
- 101710043203 P23p89 Proteins 0.000 description 1
- 108010028924 PPAR alpha Proteins 0.000 description 1
- 102000024367 PPAR alpha Human genes 0.000 description 1
- 108010015181 PPAR delta Proteins 0.000 description 1
- 108010016731 PPAR gamma Proteins 0.000 description 1
- 102000000536 PPAR gamma Human genes 0.000 description 1
- 101700055558 PRPF3 Proteins 0.000 description 1
- 102100018344 PRPF3 Human genes 0.000 description 1
- 101700059544 PTGR1 Proteins 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 102000003728 Peroxisome Proliferator-Activated Receptors Human genes 0.000 description 1
- 108090000029 Peroxisome Proliferator-Activated Receptors Proteins 0.000 description 1
- 108091000081 Phosphotransferases Proteins 0.000 description 1
- LGRFSURHDFAFJT-UHFFFAOYSA-N Phthalic anhydride Chemical compound C1=CC=C2C(=O)OC(=O)C2=C1 LGRFSURHDFAFJT-UHFFFAOYSA-N 0.000 description 1
- XKJCHHZQLQNZHY-UHFFFAOYSA-N Phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 description 1
- HYAFETHFCAUJAY-UHFFFAOYSA-N Pioglitazone Chemical compound N1=CC(CC)=CC=C1CCOC(C=C1)=CC=C1CC1C(=O)NC(=O)S1 HYAFETHFCAUJAY-UHFFFAOYSA-N 0.000 description 1
- 229960005095 Pioglitazone Drugs 0.000 description 1
- ZEMIJUDPLILVNQ-ZXFNITATSA-N Pivampicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)[C@H](C(S3)(C)C)C(=O)OCOC(=O)C(C)(C)C)=CC=CC=C1 ZEMIJUDPLILVNQ-ZXFNITATSA-N 0.000 description 1
- 206010035664 Pneumonia Diseases 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- UAJUXJSXCLUTNU-UHFFFAOYSA-N Pranlukast Chemical compound C=1C=C(OCCCCC=2C=CC=CC=2)C=CC=1C(=O)NC(C=1)=CC=C(C(C=2)=O)C=1OC=2C=1N=NNN=1 UAJUXJSXCLUTNU-UHFFFAOYSA-N 0.000 description 1
- QELSKZZBTMNZEB-UHFFFAOYSA-N Propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 1
- 108050007059 Prostanoid receptors Proteins 0.000 description 1
- 102000017953 Prostanoid receptors Human genes 0.000 description 1
- 102000001708 Protein Isoforms Human genes 0.000 description 1
- 108010029485 Protein Isoforms Proteins 0.000 description 1
- 108060006633 Protein Kinases Proteins 0.000 description 1
- 208000009305 Pseudorabies Diseases 0.000 description 1
- 210000001147 Pulmonary Artery Anatomy 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- ZDYVRSLAEXCVBX-UHFFFAOYSA-N Pyridinium p-toluenesulfonate Chemical compound C1=CC=[NH+]C=C1.CC1=CC=C(S([O-])(=O)=O)C=C1 ZDYVRSLAEXCVBX-UHFFFAOYSA-N 0.000 description 1
- 101710005260 RPL6A Proteins 0.000 description 1
- 101710005264 RPL6B Proteins 0.000 description 1
- 229940116176 Remicade Drugs 0.000 description 1
- 206010039073 Rheumatoid arthritis Diseases 0.000 description 1
- 206010039083 Rhinitis Diseases 0.000 description 1
- 206010051497 Rhinotracheitis Diseases 0.000 description 1
- MNDBXUUTURYVHR-UHFFFAOYSA-N Roflumilast Chemical compound FC(F)OC1=CC=C(C(=O)NC=2C(=CN=CC=2Cl)Cl)C=C1OCC1CC1 MNDBXUUTURYVHR-UHFFFAOYSA-N 0.000 description 1
- 229960002586 Roflumilast Drugs 0.000 description 1
- YASAKCUCGLMORW-UHFFFAOYSA-N Rosiglitazone Chemical compound C=1C=CC=NC=1N(C)CCOC(C=C1)=CC=C1CC1SC(=O)NC1=O YASAKCUCGLMORW-UHFFFAOYSA-N 0.000 description 1
- UDOFUJZUXCZXKD-VYAAASJMSA-N S-(fluoromethyl) (6S,8S,9R,10S,11S,13S,14S,16R,17R)-6,9-difluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,11,12,14,15,16-octahydrocyclopenta[a]phenanthrene-17-carbothioate;N-[2-hydroxy-5-[1-hydroxy-2-[1-(4-methoxyphenyl)propan-2-ylamino]ethyl]phenyl Chemical compound C1=CC(OC)=CC=C1CC(C)NCC(O)C1=CC=C(O)C(NC=O)=C1.C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@@H](C)[C@@](C(=O)SCF)(O)[C@@]2(C)C[C@@H]1O UDOFUJZUXCZXKD-VYAAASJMSA-N 0.000 description 1
- JNEGMBHBUAJRSX-SHUHUVMISA-N Saframycin A Chemical compound C([C@H](N1C)[C@@H]2C#N)C(C(C(C)=C(OC)C3=O)=O)=C3[C@@H]1[C@H](C1)N2[C@@H](CNC(=O)C(C)=O)C2=C1C(=O)C(C)=C(OC)C2=O JNEGMBHBUAJRSX-SHUHUVMISA-N 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-N Salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 1
- 241000580858 Simian-Human immunodeficiency virus Species 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 229940075582 Sorbic Acid Drugs 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- FDDDEECHVMSUSB-UHFFFAOYSA-N Sulfanilamide Chemical compound NC1=CC=C(S(N)(=O)=O)C=C1 FDDDEECHVMSUSB-UHFFFAOYSA-N 0.000 description 1
- 229940035073 Symbicort Drugs 0.000 description 1
- 210000001744 T-Lymphocytes Anatomy 0.000 description 1
- 229960000195 Terbutaline Drugs 0.000 description 1
- WMXCDAVJEZZYLT-UHFFFAOYSA-N Tert-Butylthiol Chemical compound CC(C)(C)S WMXCDAVJEZZYLT-UHFFFAOYSA-N 0.000 description 1
- 229950002896 Tetomilast Drugs 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N Tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 241000011102 Thera Species 0.000 description 1
- RZWIIPASKMUIAC-VQTJNVASSA-N Thromboxane Chemical compound CCCCCCCC[C@H]1OCCC[C@@H]1CCCCCCC RZWIIPASKMUIAC-VQTJNVASSA-N 0.000 description 1
- AXZWODMDQAVCJE-UHFFFAOYSA-L Tin(II) chloride Chemical compound [Cl-].[Cl-].[Sn+2] AXZWODMDQAVCJE-UHFFFAOYSA-L 0.000 description 1
- 229960000707 Tobramycin Drugs 0.000 description 1
- NLVFBUXFDBBNBW-PBSUHMDJSA-N Tobramycin Chemical compound N[C@@H]1C[C@H](O)[C@@H](CN)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O2)O)[C@H](N)C[C@@H]1N NLVFBUXFDBBNBW-PBSUHMDJSA-N 0.000 description 1
- DHCOPPHTVOXDKU-UHFFFAOYSA-N Tofimilast Chemical compound C1CN2C(C=3SC=CC=3)=NN=C2C2=C1C(CC)=NN2C1CCCC1 DHCOPPHTVOXDKU-UHFFFAOYSA-N 0.000 description 1
- 229950003899 Tofimilast Drugs 0.000 description 1
- 229940024982 Topical Antifungal Antibiotics Drugs 0.000 description 1
- 206010044248 Toxic shock syndrome Diseases 0.000 description 1
- 231100000650 Toxic shock syndrome Toxicity 0.000 description 1
- 229940116362 Tragacanth Drugs 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 206010052779 Transplant rejections Diseases 0.000 description 1
- 208000005765 Traumatic Brain Injury Diseases 0.000 description 1
- OVCXRBARSPBVMC-UHFFFAOYSA-N Triazolopyridine Chemical group C=1N2C(C(C)C)=NN=C2C=CC=1C=1OC=NC=1C1=CC=C(F)C=C1 OVCXRBARSPBVMC-UHFFFAOYSA-N 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H Tricalcium phosphate Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- CYRMSUTZVYGINF-UHFFFAOYSA-N Trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 description 1
- CYTQBVOFDCPGCX-UHFFFAOYSA-N Trimethyl phosphite Chemical compound COP(OC)OC CYTQBVOFDCPGCX-UHFFFAOYSA-N 0.000 description 1
- JLTRXTDYQLMHGR-UHFFFAOYSA-N Trimethylaluminium Chemical compound C[Al](C)C JLTRXTDYQLMHGR-UHFFFAOYSA-N 0.000 description 1
- 102000003298 Tumor Necrosis Factor Receptors Human genes 0.000 description 1
- 108060008683 Tumor Necrosis Factor Receptors Proteins 0.000 description 1
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 1
- 108010001801 Tumor Necrosis Factor-alpha Proteins 0.000 description 1
- 206010047461 Viral infection Diseases 0.000 description 1
- 208000001756 Virus Disease Diseases 0.000 description 1
- LRFVTYWOQMYALW-UHFFFAOYSA-N Xanthine Chemical compound O=C1NC(=O)NC2=C1NC=N2 LRFVTYWOQMYALW-UHFFFAOYSA-N 0.000 description 1
- 229950000339 Xinafoate Drugs 0.000 description 1
- NWGKJDSIEKMTRX-HSACVWGTSA-N [(2R)-2-[(2R,3R,4S)-3,4-dihydroxyoxolan-2-yl]-2-hydroxyethyl] (E)-octadec-9-enoate Chemical compound CCCCCCCC\C=C\CCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O NWGKJDSIEKMTRX-HSACVWGTSA-N 0.000 description 1
- KFDSJOLTGWLQNI-SFHVURJKSA-N [(2S)-1-(6-fluoro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)pyrrolidin-2-yl]methoxy-tri(propan-2-yl)silane Chemical compound CC(C)[Si](C(C)C)(C(C)C)OC[C@@H]1CCCN1C1=NN=C2N1C=C(F)C=C2 KFDSJOLTGWLQNI-SFHVURJKSA-N 0.000 description 1
- HVVNJUAVDAZWCB-YFKPBYRVSA-N [(2S)-pyrrolidin-2-yl]methanol Chemical compound OC[C@@H]1CCCN1 HVVNJUAVDAZWCB-YFKPBYRVSA-N 0.000 description 1
- DGEZNRSVGBDHLK-UHFFFAOYSA-N [1,10]phenanthroline Chemical compound C1=CN=C2C3=NC=CC=C3C=CC2=C1 DGEZNRSVGBDHLK-UHFFFAOYSA-N 0.000 description 1
- IXNWSKQSWUSWLS-UHFFFAOYSA-N [1-(6-fluoro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)piperidin-4-yl]oxy-tri(propan-2-yl)silane Chemical compound C1CC(O[Si](C(C)C)(C(C)C)C(C)C)CCN1C1=NN=C2N1C=C(F)C=C2 IXNWSKQSWUSWLS-UHFFFAOYSA-N 0.000 description 1
- NVEMUJANQDPDSC-DHUJRADRSA-N [1-[9-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]nonyl]piperidin-4-yl] N-(2-phenylphenyl)carbamate Chemical compound C([C@H](O)C=1C=2C=CC(=O)NC=2C(O)=CC=1)NCCCCCCCCCN(CC1)CCC1OC(=O)NC1=CC=CC=C1C1=CC=CC=C1 NVEMUJANQDPDSC-DHUJRADRSA-N 0.000 description 1
- IQPQWNKOIGAROB-UHFFFAOYSA-N [N-]=C=O Chemical compound [N-]=C=O IQPQWNKOIGAROB-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- ZCHPKWUIAASXPV-UHFFFAOYSA-N acetic acid;methanol Chemical compound OC.CC(O)=O ZCHPKWUIAASXPV-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 229940019903 aclidinium Drugs 0.000 description 1
- 229960005012 aclidinium bromide Drugs 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 230000000240 adjuvant Effects 0.000 description 1
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 201000009961 allergic asthma Diseases 0.000 description 1
- 239000008168 almond oil Substances 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001409 amidines Chemical class 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 229960000723 ampicillin Drugs 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000033115 angiogenesis Effects 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000003466 anti-cipated Effects 0.000 description 1
- 230000001387 anti-histamine Effects 0.000 description 1
- 230000003110 anti-inflammatory Effects 0.000 description 1
- 239000000739 antihistaminic agent Substances 0.000 description 1
- 229960000070 antineoplastic Monoclonal antibodies Drugs 0.000 description 1
- 239000003434 antitussive agent Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 201000009596 autoimmune hypersensitivity disease Diseases 0.000 description 1
- 229960004099 azithromycin Drugs 0.000 description 1
- 230000001580 bacterial Effects 0.000 description 1
- 229910052788 barium Inorganic materials 0.000 description 1
- DSAJWYNOEDNPEQ-UHFFFAOYSA-N barium(0) Chemical compound [Ba] DSAJWYNOEDNPEQ-UHFFFAOYSA-N 0.000 description 1
- 150000007514 bases Chemical class 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 125000004604 benzisothiazolyl group Chemical group S1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000004603 benzisoxazolyl group Chemical group O1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid group Chemical group C(C1=CC=CC=C1)(=O)O WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000003354 benzotriazolyl group Chemical group N1N=NC2=C1C=CC=C2* 0.000 description 1
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000003115 biocidal Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000037348 biosynthesis Effects 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 201000010816 bone resorption disease Diseases 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 230000003435 bronchoconstrictive Effects 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 125000002837 carbocyclic group Chemical group 0.000 description 1
- 150000001721 carbon Chemical compound 0.000 description 1
- 201000008031 cardiomyopathy Diseases 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 229960000590 celecoxib Drugs 0.000 description 1
- 201000008779 central nervous system disease Diseases 0.000 description 1
- 230000001889 chemoattractant Effects 0.000 description 1
- 239000002975 chemoattractant Substances 0.000 description 1
- 230000014564 chemokine production Effects 0.000 description 1
- 102000009410 chemokine receptors Human genes 0.000 description 1
- 108050000299 chemokine receptors Proteins 0.000 description 1
- 239000005482 chemotactic factor Substances 0.000 description 1
- 230000035605 chemotaxis Effects 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- CRBHXDCYXIISFC-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CC[O-] CRBHXDCYXIISFC-UHFFFAOYSA-N 0.000 description 1
- 239000000812 cholinergic antagonist Substances 0.000 description 1
- 238000011097 chromatography purification Methods 0.000 description 1
- 235000019504 cigarettes Nutrition 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 230000015271 coagulation Effects 0.000 description 1
- 238000005345 coagulation Methods 0.000 description 1
- 239000003240 coconut oil Substances 0.000 description 1
- 235000019864 coconut oil Nutrition 0.000 description 1
- 229960004126 codeine Drugs 0.000 description 1
- 229960002424 collagenase Drugs 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 201000006233 congestive heart failure Diseases 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 230000000875 corresponding Effects 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000005712 crystallization Effects 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 125000006254 cycloalkyl carbonyl group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- WACQKHWOTAEEFS-UHFFFAOYSA-N cyclohexane;ethyl acetate Chemical compound CCOC(C)=O.C1CCCCC1 WACQKHWOTAEEFS-UHFFFAOYSA-N 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 239000003260 cyclooxygenase 1 inhibitor Substances 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 230000016396 cytokine production Effects 0.000 description 1
- 239000011928 denatured alcohol Substances 0.000 description 1
- 230000001419 dependent Effects 0.000 description 1
- 201000004624 dermatitis Diseases 0.000 description 1
- 230000001066 destructive Effects 0.000 description 1
- 229940042935 dichlorodifluoromethane Drugs 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- WYACBZDAHNBPPB-UHFFFAOYSA-N diethyl oxalate Chemical compound CCOC(=O)C(=O)OCC WYACBZDAHNBPPB-UHFFFAOYSA-N 0.000 description 1
- PWEGVZDXTQLFLQ-UHFFFAOYSA-N dioxidoboron Chemical compound [O-][B][O-] PWEGVZDXTQLFLQ-UHFFFAOYSA-N 0.000 description 1
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000000890 drug combination Substances 0.000 description 1
- 238000007876 drug discovery Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 231100001003 eczema Toxicity 0.000 description 1
- 239000008157 edible vegetable oil Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- SBVYURPQULDJTI-UHFFFAOYSA-N ethyl N-[amino-[4-[[3-[[4-[2-(4-hydroxyphenyl)propan-2-yl]phenoxy]methyl]phenyl]methoxy]phenyl]methylidene]carbamate Chemical compound C1=CC(C(=N)NC(=O)OCC)=CC=C1OCC1=CC=CC(COC=2C=CC(=CC=2)C(C)(C)C=2C=CC(O)=CC=2)=C1 SBVYURPQULDJTI-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000003090 exacerbative Effects 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 230000003419 expectorant Effects 0.000 description 1
- 239000003172 expectorant agent Substances 0.000 description 1
- 239000003925 fat Substances 0.000 description 1
- 235000019197 fats Nutrition 0.000 description 1
- 229960001022 fenoterol Drugs 0.000 description 1
- 229960003592 fexofenadine Drugs 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- 230000003176 fibrotic Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 229960001469 fluticasone furoate Drugs 0.000 description 1
- 229940050287 formoterol / Mometasone Drugs 0.000 description 1
- 229960000193 formoterol fumarate Drugs 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000003193 general anesthetic agent Substances 0.000 description 1
- PEDCQBHIVMGVHV-UHFFFAOYSA-N glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 238000005658 halogenation reaction Methods 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 201000011066 hemangioma Diseases 0.000 description 1
- 125000006588 heterocycloalkylene group Chemical group 0.000 description 1
- 239000008079 hexane Substances 0.000 description 1
- 102000032800 human ELANE protein Human genes 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N hydrogen bromide Chemical class Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 230000003301 hydrolyzing Effects 0.000 description 1
- 230000000222 hyperoxic Effects 0.000 description 1
- 239000000819 hypertonic solution Substances 0.000 description 1
- 229960001680 ibuprofen Drugs 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- 229940079866 intestinal antibiotics Drugs 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N iodine atom Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- LHLMOSXCXGLMMN-VVQPYUEFSA-M ipratropium bromide Chemical compound [Br-].O([C@H]1C[C@H]2CC[C@@H](C1)[N@@+]2(C)C(C)C)C(=O)C(CO)C1=CC=CC=C1 LHLMOSXCXGLMMN-VVQPYUEFSA-M 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 230000002427 irreversible Effects 0.000 description 1
- 239000001282 iso-butane Substances 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 229940011051 isopropyl acetate Drugs 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-M isovalerate Chemical compound CC(C)CC([O-])=O GWYFCOCPABKNJV-UHFFFAOYSA-M 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 229960000991 ketoprofen Drugs 0.000 description 1
- ACKFDYCQCBEDNU-UHFFFAOYSA-J lead(2+);tetraacetate Chemical compound [Pb+2].CC([O-])=O.CC([O-])=O.CC([O-])=O.CC([O-])=O ACKFDYCQCBEDNU-UHFFFAOYSA-J 0.000 description 1
- 230000001665 lethal Effects 0.000 description 1
- 231100000518 lethal Toxicity 0.000 description 1
- 239000003591 leukocyte elastase inhibitor Substances 0.000 description 1
- 239000003199 leukotriene receptor blocking agent Substances 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 201000009673 liver disease Diseases 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 229960003646 lysine Drugs 0.000 description 1
- 235000012254 magnesium hydroxide Nutrition 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229960003390 magnesium sulfate Drugs 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- LFCFXZHKDRJMNS-UHFFFAOYSA-L magnesium;sulfate;hydrate Chemical compound O.[Mg+2].[O-]S([O-])(=O)=O LFCFXZHKDRJMNS-UHFFFAOYSA-L 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 201000004792 malaria Diseases 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 230000035800 maturation Effects 0.000 description 1
- 239000002609 media Substances 0.000 description 1
- 230000001404 mediated Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 201000009906 meningitis Diseases 0.000 description 1
- 229910000000 metal hydroxide Inorganic materials 0.000 description 1
- 150000004692 metal hydroxides Chemical class 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 229960000060 monoclonal antibodies Drugs 0.000 description 1
- 102000005614 monoclonal antibodies Human genes 0.000 description 1
- 108010045030 monoclonal antibodies Proteins 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- 229960005127 montelukast Drugs 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- YZMHQCWXYHARLS-UHFFFAOYSA-L naphthalene-1,2-disulfonate Chemical compound C1=CC=CC2=C(S([O-])(=O)=O)C(S(=O)(=O)[O-])=CC=C21 YZMHQCWXYHARLS-UHFFFAOYSA-L 0.000 description 1
- 239000007922 nasal spray Substances 0.000 description 1
- 239000006199 nebulizer Substances 0.000 description 1
- 230000011234 negative regulation of signal transduction Effects 0.000 description 1
- 201000008383 nephritis Diseases 0.000 description 1
- 230000003959 neuroinflammation Effects 0.000 description 1
- 201000005625 neuroleptic malignant syndrome Diseases 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 239000002687 nonaqueous vehicle Substances 0.000 description 1
- 230000000269 nucleophilic Effects 0.000 description 1
- 229940005935 ophthalmologic Antibiotics Drugs 0.000 description 1
- 229940006093 opthalmologic coloring agents Diagnostic Drugs 0.000 description 1
- 230000003287 optical Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000003204 osmotic Effects 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- CBENFWSGALASAD-UHFFFAOYSA-N ozone Chemical compound [O-][O+]=O CBENFWSGALASAD-UHFFFAOYSA-N 0.000 description 1
- 101710004308 p38b Proteins 0.000 description 1
- 239000003182 parenteral nutrition solution Substances 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 230000001575 pathological Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 230000000275 pharmacokinetic Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- HDOWRFHMPULYOA-UHFFFAOYSA-N piperidin-4-ol Chemical compound OC1CCNCC1 HDOWRFHMPULYOA-UHFFFAOYSA-N 0.000 description 1
- BIFDXOOJPDHKJH-UHFFFAOYSA-N piperidine-1-carbonyl chloride Chemical compound ClC(=O)N1CCCCC1 BIFDXOOJPDHKJH-UHFFFAOYSA-N 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 229960003342 pivampicillin Drugs 0.000 description 1
- 229920001690 polydopamine Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Chemical class [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 1
- 235000011118 potassium hydroxide Nutrition 0.000 description 1
- LWIHDJKSTIGBAC-UHFFFAOYSA-K potassium phosphate Substances [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 229960004583 pranlukast Drugs 0.000 description 1
- 230000000750 progressive Effects 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propanol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-N propionic acid Chemical compound CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 201000004681 psoriasis Diseases 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- GUFUWKKDHIABBW-UHFFFAOYSA-N pyrrolidin-1-ylmethanol Chemical compound OCN1CCCC1 GUFUWKKDHIABBW-UHFFFAOYSA-N 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000001603 reducing Effects 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 230000001105 regulatory Effects 0.000 description 1
- 230000000268 renotropic Effects 0.000 description 1
- 230000001850 reproductive Effects 0.000 description 1
- 230000000241 respiratory Effects 0.000 description 1
- 229960000371 rofecoxib Drugs 0.000 description 1
- 229960004586 rosiglitazone Drugs 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000000467 secondary amino group Chemical group [H]N([*:1])[*:2] 0.000 description 1
- 231100000486 side effect Toxicity 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 230000000391 smoking Effects 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- PODWXQQNRWNDGD-UHFFFAOYSA-L sodium thiosulfate pentahydrate Chemical compound O.O.O.O.O.[Na+].[Na+].[O-]S([S-])(=O)=O PODWXQQNRWNDGD-UHFFFAOYSA-L 0.000 description 1
- 239000011343 solid material Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- WSWCOQWTEOXDQX-UHFFFAOYSA-N sorbic acid Chemical compound CC=CC=CC(O)=O WSWCOQWTEOXDQX-UHFFFAOYSA-N 0.000 description 1
- 239000001593 sorbitan monooleate Substances 0.000 description 1
- 235000011069 sorbitan monooleate Nutrition 0.000 description 1
- 229940035049 sorbitan monooleate Drugs 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 235000015096 spirit Nutrition 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- KXCAEQNNTZANTK-UHFFFAOYSA-N stannane Chemical compound [SnH4] KXCAEQNNTZANTK-UHFFFAOYSA-N 0.000 description 1
- 229910000080 stannane Inorganic materials 0.000 description 1
- 235000011150 stannous chloride Nutrition 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 108091007018 stromelysin Proteins 0.000 description 1
- 238000002305 strong-anion-exchange chromatography Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 229940086735 succinate Drugs 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 229960001663 sulfanilamide Drugs 0.000 description 1
- 238000005694 sulfonylation reaction Methods 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 239000002278 tabletting lubricant Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- PLUYWLVVTBMTAI-NSHDSACASA-N tert-butyl (2S)-2-(6-fluoro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)pyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC[C@H]1C1=NN=C2N1C=C(F)C=C2 PLUYWLVVTBMTAI-NSHDSACASA-N 0.000 description 1
- SLYDTUSOKQQTJM-NSHDSACASA-N tert-butyl (2S)-2-[[(5-fluoropyridin-2-yl)amino]carbamoyl]pyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)NNC1=CC=C(F)C=N1 SLYDTUSOKQQTJM-NSHDSACASA-N 0.000 description 1
- NQYDPOVCLRWDRK-UHFFFAOYSA-N tert-butyl 4-(6-fluoro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1C1=NN=C2N1C=C(F)C=C2 NQYDPOVCLRWDRK-UHFFFAOYSA-N 0.000 description 1
- JSCIRFHGZFHMFH-UHFFFAOYSA-N tert-butyl 4-[(6-fluoro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl]piperazine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCN1CC1=NN=C2N1C=C(F)C=C2 JSCIRFHGZFHMFH-UHFFFAOYSA-N 0.000 description 1
- OMHLRSWPKNNMPU-UHFFFAOYSA-N tert-butyl 4-[(6-fluoro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl]piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1CC1=NN=C2N1C=C(F)C=C2 OMHLRSWPKNNMPU-UHFFFAOYSA-N 0.000 description 1
- YDBBEUHWDQIJTD-UHFFFAOYSA-N tert-butyl 4-[2-[2-(5-fluoropyridin-2-yl)hydrazinyl]-2-oxoethyl]piperazine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCN1CC(=O)NNC1=CC=C(F)C=N1 YDBBEUHWDQIJTD-UHFFFAOYSA-N 0.000 description 1
- ZXZCAJXOSLKQKP-UHFFFAOYSA-N tert-butyl 4-[[(5-fluoropyridin-2-yl)amino]carbamoyl]piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1C(=O)NNC1=CC=C(F)C=N1 ZXZCAJXOSLKQKP-UHFFFAOYSA-N 0.000 description 1
- PQISNIHYSKTPMX-UHFFFAOYSA-N tert-butyl N-(6-fluoro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)-N-propan-2-ylcarbamate Chemical compound C1=CC(F)=CN2C(N(C(=O)OC(C)(C)C)C(C)C)=NN=C21 PQISNIHYSKTPMX-UHFFFAOYSA-N 0.000 description 1
- QKSQWQOAUQFORH-UHFFFAOYSA-N tert-butyl N-[(2-methylpropan-2-yl)oxycarbonylimino]carbamate Chemical compound CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C QKSQWQOAUQFORH-UHFFFAOYSA-N 0.000 description 1
- RXWNEXPXGQHQRH-UHFFFAOYSA-N tert-butyl N-[3-[2-[tert-butyl(dimethyl)silyl]oxyethylsulfanyl]phenyl]-N-[(2-methylpropan-2-yl)oxycarbonylamino]carbamate Chemical compound CC(C)(C)OC(=O)NN(C(=O)OC(C)(C)C)C1=CC=CC(SCCO[Si](C)(C)C(C)(C)C)=C1 RXWNEXPXGQHQRH-UHFFFAOYSA-N 0.000 description 1
- XKXIQBVKMABYQJ-UHFFFAOYSA-M tert-butyl carbonate Chemical compound CC(C)(C)OC([O-])=O XKXIQBVKMABYQJ-UHFFFAOYSA-M 0.000 description 1
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 229960000257 tiotropium bromide Drugs 0.000 description 1
- 210000001519 tissues Anatomy 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
- 229940083878 topical for treatment of hemorrhoids and anal fissures Corticosteroids Drugs 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 230000001131 transforming Effects 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 150000008523 triazolopyridines Chemical class 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 229940029284 trichlorofluoromethane Drugs 0.000 description 1
- 125000002827 triflate group Chemical group FC(S(=O)(=O)O*)(F)F 0.000 description 1
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 description 1
- 201000008827 tuberculosis Diseases 0.000 description 1
- 239000002447 tumor necrosis factor alpha converting enzyme inhibitor Substances 0.000 description 1
- 230000006433 tumor necrosis factor production Effects 0.000 description 1
- 241001529453 unidentified herpesvirus Species 0.000 description 1
- 241000712461 unidentified influenza virus Species 0.000 description 1
- 230000017613 viral reproduction Effects 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
- MWLSOWXNZPKENC-SSDOTTSWSA-N zileuton Chemical compound C1=CC=C2SC([C@H](N(O)C(N)=O)C)=CC2=C1 MWLSOWXNZPKENC-SSDOTTSWSA-N 0.000 description 1
- 229960005332 zileuton Drugs 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C53/00—Saturated compounds having only one carboxyl group bound to an acyclic carbon atom or hydrogen
- C07C53/02—Formic acid
- C07C53/06—Salts thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D231/38—Nitrogen atoms
- C07D231/40—Acylated on said nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
- C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/08—Bridged systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/08—Bridged systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
Abstract
Provided are urea derivative compounds of formula (I), wherein the variables are as defined in the specification. Examples of the compounds include 1-{5-tert-Butyl-2-[3-(2-dimethylamino-ethoxy)-phenyl]-2H-pyrazol-3-yl-3-{(1S,4S)-4-[3-((S)-2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydronaphthalen-1-yl]–urea and 1-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-{(1S,4R)-4-[3-(2-pyrrolidin-1-yl-ethyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea. The compounds are p38 MAP kinase inhibitors. The compounds may be useful in the treatment of respiratory diseases. y]-1,2,3,4-tetrahydronaphthalen-1-yl]–urea and 1-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-{(1S,4R)-4-[3-(2-pyrrolidin-1-yl-ethyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea. The compounds are p38 MAP kinase inhibitors. The compounds may be useful in the treatment of respiratory diseases.
Description
KINASE INHIBITORS USEFUL AS ANTI-INFLAMMATORY AGENTS
This invention relates to compounds and compositions that are p38
MAPK inhibitors, useful as anti-inflammatory agents in the treatment of, inter
alia, diseases of the respiratory tract.
Background to the invention
Mitogen activated protein kinases (MAPK) constitute a family of
proline-directed serine/threonine kinases that activate their substrates by dual
phosphorylation. There are four known human isoforms of p38 MAP kinase,
p38a, p38b, p38g and p38d. The p38 kinases, which are also known as
cytokine suppressive anti-inflammatory drug binding proteins (CSBP), stress
activated protein kinases (SAPK) and RK, are responsible for phosphorylating
(Stein et al., Ann. Rep. Med Chem., 1996, 31, 289-298) and activating
transcription factors (such as ATF-2, MAX, CHOP and C/ERPb) as well as
other kinases (such as MAPKAP-K2/3 or MK2/3), and are themselves
activated by physical and chemical stress (e.g. UV, osmotic stress),
pro-inflammatory cytokines and bacterial lipopolysaccharide (LPS) (Herlaar
E. & Brown Z., Molecular Medicine Today, 1999, 5, 439-447). The products
of p38 phosphorylation have been shown to mediate the production of
inflammatory cytokines, including tumor necrosis factor alpha (TNF a) and
interleukin- (IL)-1, and cyclooxygenase-2 (COX-2). IL-1 and TNFa are also
known to stimulate the production of other proinflammatory cytokines such as
IL-6 and IL-8.
IL-1 and TNFa are biological substances produced by a variety of cells,
such as monocytes or macrophages. IL-1 has been demonstrated to mediate a
variety of biological activities thought to be important in immunoregulation
and other physiological conditions such as inflammation (e.g. Dinarello et al.,
Rev. Infect. Disease, 1984, 6, 51). Excessive or unregulated TNF production
(particularly TNFa) has been implicated in mediating or exacerbating a
number of diseases, and it is believed that TNF can cause or contribute to the
effects of inflammation in general. IL-8 is a chemotactic factor produced by
several cell types including mononuclear cells, fibroblasts, endothelial cells,
and keratinocytes. Its production from endothelial cells is induced by IL-1,
TNF, or lipopolysaccharide (LPS). IL-8 stimulates a number of functions in
vitro. It has been shown to have chemoattractant properties for neutrophils,
T-lymphocytes and basophils. Increase in IL-8 production is also responsible
for chemotaxis of neutrophils into the inflammatory site in vivo.
Inhibition of signal transduction via p38, which in addition to IL-1,
TNF and IL-8 described above is also required for the synthesis and/or action
of several additional pro-inflammatory proteins (e.g., IL-6, GM-CSF, COX-2,
collagenase and stromelysin), is expected to be a highly effective mechanism
for regulating the excessive and destructive activation of the immune system.
This expectation is supported by the potent and diverse anti-inflammatory
activities described for p38 kinase inhibitors (Badger et al., J. Pharm. Exp.
Thera., 1996, 279, 1453 -1461; Griswold et al, Pharmacol. Comm.,1996, 7,
323-229). In particular, p38 kinase inhibitors have been described as potential
agents for treating rheumatoid arthritis. In addition to the links between p38
activation and chronic inflammation and arthritis, there is also data
implicating a role for p38 in the pathogenesis of airway diseases in particular
COPD and asthma. Stress stimuli (including tobacco smoke, infections or
oxidative products) can cause inflammation within the lung environment.
Inhibitors of p38 have been shown to inhibit LPS and ovalbumin induced
airway TNF-a, IL-1b, IL-6, IL-4, IL-5 and IL-13 (Haddad et al, Br. J.
Pharmacol., 2001, 132 (8), 1715-1724; Underwood et al, Am. J. Physiol. Lung
Cell. Mol. 2000, 279, 895-902; Duan et al., 2005 Am. J. Respir. Crit. Care
Med., 171, 571-578; Escott et al Br. J. Pharmacol., 2000, 131, 173-176;
Underwood et al., J. Pharmacol. Exp. Ther. 2000, 293, 281-288). Furthermore,
they significantly inhibit neutrophilia and the release of MMP-9 in LPS, ozone
or cigarette smoke animal models. There is also a significant body of
preclinical data highlighting the potential benefits of inhibition of the p38
kinase that could be relevant in the lung (Lee et al., Immunopharmacology,
2000, 47, 185-200). Thus, therapeutic inhibition of p38 activation may be
important in the regulation of airway inflammation.
The implication of the p38MAPK pathway in various diseases has been
reviewed by P. Chopra et al. (Expert Opinion on Investigational Drugs, 2008,
17(10), 1411-1425). It is believed that the compounds of the present invention
can be used to treat p38 mediated diseases such as: chronic obstructive
pulmonary disease (COPD), asthma, chronic or acute bronchoconstriction,
bronchitis, acute lung injury and bronchiectasis, pulmonary artery
hypertension, tuberculosis, lung cancer, inflammation generally (e.g.
inflammatory bowel disease), arthritis, neuroinflammation, pain, fever,
fibrotic diseases, pulmonary disorders and diseases (e.g., hyperoxic alveolar
injury), cardiovascular diseases, post -ischemic reperfusion injury and
congestive heart failure, cardiomyopathy, stroke, ischemia, reperfusion injury,
renal reperfusion injury, brain edema, neurotrauma and brain trauma,
neurodegenerative disorders, central nervous system disorders, liver disease
and nephritis, gastrointestinal conditions, ulcerative diseases, Crohn’s disease,
ophthalmic diseases, ophthalmological conditions, glaucoma, acute injury to
the eye tissue and ocular traumas, diabetes, diabetic nephropathy, skin-related
conditions, myalgias due to infection, influenza, endotoxic shock, toxic shock
syndrome, autoimmune disease, graft rejection, bone resorption diseases,
multiple sclerosis, psoriasis, eczema, disorders of the female reproductive
system, pathological (but non -malignant) conditions, such as hemangiomas,
angiofibroma of the nasopharynx, and avascular necrosis of bone, benign and
malignant tumors/neoplasia including cancer, leukaemia, lymphoma, systemic
lupus erythematosus (SLE), angiogenesis including neoplasia, haemorrhage,
coagulation, radiation damage, and/or metastasis. Chronic release of active
TNF can cause cachexia and anorexia, and TNF can be lethal. TNF has also
been implicated in infectious diseases. These include, for example, malaria,
mycobacterial infection and meningitis. These also include viral infections,
such as HIV, influenza virus, and herpes virus, including herpes simplex virus
type-1 (HSV-1), herpes simplex virus type-2 (HSV-2), cytomegalovirus
(CMV), varicella-zoster virus (VZV), Epstein-Barr virus, human herpes virus-
6 (HHV-6), human herpesvirus-7 (HHV7), human herpesvirus-8 (HHV-8),
pseudorabies and rhinotracheitis, among others.
Known P38 kinase inhibitors have been reviewed by G. J. Hanson
(Expert Opinions on Therapeutic Patents, 1997, 7, 729-733) J Hynes et al.
(Current Topics in Medicinal Chemistry, 2005, 5, 967-985), C. Dominguez et
al (Expert Opinions on Therapeutics Patents, 2005, 15, 801-816) and L. H.
Pettus & R. P. Wurtz (Current Topics in Medicinal Chemistry, 2008, 8,
1452-1467). P38 kinase inhibitors containing a triazolopyridine motif are
known in the art, for example WO07/091152, WO04/072072, WO06/018727.
International Patent Application WO2010/094956 discloses
triazolopyridine derivatives of formula (I) as being p38 MAP Kinase
inhibitors:
In such compounds, A represents an optionally substituted divalent
arylene radical, an heteroarylene radical, a (C3-C6) divalent cycloalkylene
radical having 5 or 6 ring atoms or a pyperidinylene radical.
The compounds are said to be useful in as anti-inflammatory agents in
the treatment of diseases of the respiratory tract.
The object of the present invention is to identify novel and potent p38
mitogen activated protein kinase inhibitors which are useful in the treatment
of inflammatory and obstructive diseases of the respiratory tract; to identify
novel potent p38 mitogen activated protein kinase inhibitors which show an
appropriate developability profile on inhalatory administration to effectively
treat respiratory obstructive or inflammatory diseases; and/or to at least
provide the public with a useful choice. It is to be understood that such an
appropriate developability profile may be achieved in a number of different
ways by modulation of specific properties; by way of example, it could be
achieved by administration of a low effective dose of the drug thus limiting
side effects or via a long duration of action in the lungs which may reduce the
frequency of administration.
Brief Description of the Invention
The compounds of the present invention are inhibitors of p38 mitogen
activated protein kinase ("p38 MAPK", "p38 kinase" or "p38"), including
p38a kinase, and are inhibitors of cytokine and chemokine production
including TNFa and IL-8 production. They have a number of therapeutic
applications, in the treatment of inflammatory diseases, particularly allergic
and non-allergic airways diseases, more particularly obstructive or
inflammatory airways diseases such as chronic obstructive pulmonary disease
("COPD") and asthma. They are therefore particularly suited for pulmonary
delivery, by inhalation by nose or mouth.
Description of the invention
In one aspect, the invention provides a compound of formula (I) or a
pharmaceutically acceptable salt thereof:
N W A
wherein;
W is NH;
Y is O;
R is a group selected from (IIa) - (IIc):
9 1 10
(IIa) (IIb) (IIc)
8 9 8 9
R and R are each independently hydrogen or C -C alkyl, or R and R
may form together with the nitrogen atom to which they are attached a
membered saturated monocyclic or a fused or spiro bicyclic ring system
optionally containing a further heteroatom which is oxygen or nitrogen, said
nitrogen atom being optionally substituted by C -C alkyl; wherein such C -C
1 6 1 6
alkyl groups may be optionally substituted by a group C -C alkyl, C -C
1 6 3 6
cycloalkyl, hydroxyl or halo;
1 2 3 4 5
X , X , X , X and X are each independently a carbon atom, a nitrogen
atom, a group -(CH)- or a group -NH-; such that each combination thereof
forms an aromatic ring system;
A B
R is selected from a group consisting of: Hydrogen, -CN, -NR R ,
C A B C A B
-N(R )(C -C alkylene)-NR R, -N(R )(C -C cycloalkylene)-NR R ,
2 6 3 7
A B A B
-(C -C alkylene)-NR R , -(C -C cycloalkylene)-NR R , -O-(C -C alkylene)-
1 6 3 7 2 6
A B A B A B
NR R , -O-(C -C cycloalkylene)-NR R , -S-(C -C alkylene)-NR R , -S-(C -
3 7 2 6 3
A B C A B C
C cycloalkylene)-NR R , -N(R )C(O)-(C -C alkylene)-NR R , -N(R )C(O)-
7 1 6
A B C A B
(C -C cycloalkylene)-NR R, -C(O)N(R )-(C -C alkylene)-NR R ,
3 7 2 6
C A B C D
-C(O)N(R )-(C -C cycloalkylene)-NR R , -C(O)N(R )-(C -C alkylene)-OR ,
3 7 2 6
C D C A B A B
-C(O)N(R )-(C -C cycloalkylene)-OR , -N(R )C(O)NR R, -C(O)NR R ,
C C A B C C
-N(R )C(O)N(R )-(C -C alkylene)-NR R, -N(R )C(O)N(R )-(C -
2 6 3
A B D D
C cycloalkylene)-NR R , -(C -C alkylene)-OR , -(C -C cycloalkylene)-OR ,
7 2 6 3 7
-O-(C -C alkylene)-OR , -O-(C -C cycloalkylene)-OR , -S-(C -C alkylene)-
2 6 3 7 2 6
D D C A B
OR, -S-(C -C cycloalkylene)-OR , -N(R )S(O) -(C -C alkylene)-NR R ,
3 7 2 1 6
C A B C
-N(R )S(O) -(C -C cycloalkylene)-NR R, -S(O) N(R )-(C -C alkylene)-
2 3 7 2 2 6
A B C A B C
NR R, -S(O) N(R )-(C -C cycloalkylene)-NR R, -S(O) N(R )-(C -
2 3 7 2 2
D C D C
C alkylene)-OR , -S(O) N(R )-(C -C cycloalkylene)-OR , -N(R )S(O) -(C -
6 2 3 7 2 2
D C D A B
C alkylene)-OR , -N(R )S(O) -(C -C cycloalkylene)-OR , -S(O) N(R R ),
6 2 3 7 2
C D C C C C
-N(R )S(O) R, -N(R )C(O)R, -OR, -SR, -(C -C heterocycloalkyl),
2 3 7
(C -C heterocycloalkyl)-(C -Calkyl), (C -C heterocycloalkyl)(C -
7 1 6 5 7 3
C cycloalkyl)-, and C -C heterocycloalkylcarbonyl; wherein any of such C -
6 3 7 1
Calkyl, C -Ccycloalkyl, -(C -Calkylene)- -(C -Calkylene)-, -(C -
6 3 6 1 6 2 6 3
C cycloalkylene)-, -(C -C heterocycloalkyl), (C -C heterocycloalkyl)-(C -C
7 3 7 5 7 1 6
alkyl), (C -C heterocycloalkyl)-(C -C cycloalkyl) and (C -
7 3 6 3
C heterocycloalkyl)carbonyl portion in the above listed groups may be
optionally substituted by a group C -C alkyl, C -C cycloalkyl, hydroxyl or
1 6 3 7
halo;
11 4
R is linked to X and is selected from a group consisting of:
Hydrogen; -CN; C -C alkyl which is substituted by a group selected
from -CN, -OR , -SR , halo; C -C cycloalkyl which is substituted by a group
C D A B C
selected from C -C alkyl, -CN, -OR , -SR , halo; -NR R , -N(R )(C -
1 4 2
A B C A B
C alkylene)-NR R , -N(R )(C -C cycloalkylene)-NR R , -(C -C alkylene)-
6 3 7 1 6
A B A B A B
NR R , -(C -C cycloalkylene)-NR R , -O-(C -C alkylene)-NR R , -O-(C -
3 7 2 6 3
A B A B
C cycloalkylene)-NR R, -S-(C -C alkylene)-NR R, -S-(C -
7 2 6 3
A B C A B C
C cycloalkylene)-NR R , -N(R )C(O)-(C -C alkylene)-NR R , -N(R )C(O)-
7 1 6
A B C A B
(C -C cycloalkylene)-NR R, -C(O)N(R )-(C -C alkylene)-NR R ,
3 7 2 6
C A B C D
-C(O)N(R )-(C -C cycloalkylene)-NR R , -C(O)N(R )-(C -C alkylene)-OR ,
3 7 2 6
C D C A B A B
-C(O)N(R )-(C -C cycloalkylene)-OR , -N(R )C(O)N(R R ), -C(O)N(R R ),
C C A B C C
-N(R )C(O)N(R )-(C -C alkylene)-NR R, -N(R )C(O)N(R )-(C -
2 6 3
A B D
C cycloalkylene)-NR R , -O-(C -C alkylene)-OR , -O-(C -C cycloalkylene)-
7 2 6 3 7
D D D C
OR , -S-(C -C alkylene)-OR , -S-(C -C cycloalkylene)-OR , -N(R )S(O) -
2 6 3 7 2
A B C A B
(C -C alkylene)-NR R, -N(R )S(O) -(C -C cycloalkylene)-NR R ,
1 6 2 3 7
C A B C
-S(O) N(R )-(C -C alkylene)-NR R, -S(O) N(R )-(C -C cycloalkylene)-
2 2 6 2 3 7
A B C D C
NR R, -S(O) N(R )-(C -C alkylene)-OR, -S(O) N(R )-(C -
2 2 6 2 3
D C D C
C cycloalkylene)-OR, -N(R )S(O) -(C -C alkylene)-OR, -N(R )S(O)
7 2 2 6 2
D A B C D C C
(C -C cycloalkylene)-OR , -S(O) N(R R ), -N(R )S(O) R , -N(R )C(O)R ,
3 7 2 2
OR , SR , -(C -Cheterocycloalkyl), (C -C heterocycloalkyl)-(C -C alkyl),
3 7 5 7 1 6
(C -C heterocycloalkyl)(C -Ccycloalkyl) and (C -C
7 3 6 3 7
heterocycloalkyl)carbonyl, wherein any of such C -C alkyl, C -C cycloalkyl, -
1 6 3 6
(C -Calkylene)- -(C -Calkylene)-, -(C -Ccycloalkylene)-, -(C -
1 6 2 6 3 7 3
Cheterocycloalkyl), (C -C heterocycloalkyl)-(C -C alkyl), (C -C
7 5 7 1 6 5 7
heterocycloalkyl)-(C -C cycloalkyl) and (C -C heterocycloalkyl)carbonyl
3 6 3 7
portion in the above listed groups may be optionally substituted by one, two or
three groups R which are independently selected in the list consisting of: C -
C alkyl, (C -C ) haloalkyl, (C -C )hydroxyalkyl, C -C cycloalkyl, hydroxyl
6 1 3 1 4 3 7
and halo; or
11 4
R is linked to X and is phenyl or 5- or 6-membered monocyclic
heteroaryl, wherein such phenyl or 5- or 6-membered monocyclic heteroaryl is
substituted by a group selected in the list consisting of: C -C alkyl which is
substituted by a group -CN; C -C cycloalkyl which is substituted by a group
C C C A B
selected from: -CN, -OR , -SR or halo; -N(R )(C -C alkylene)-NR R ,
C A B A B
-N(R )(C -C cycloalkylene)-NR R, -(C -C alkylene)-NR R, -(C -
3 7 1 6 3
A B A B
C cycloalkylene)-NR R, -O-(C -C cycloalkylene)-NR R ,
7 3 7
A B A B C
-S-(C -C alkylene)-NR R, -S-(C -C cycloalkylene)-NR R, -N(R )C(O)-
2 6 3 7
A B C A B
(C -C alkylene)-NR R, -N(R )C(O)-(C -C cycloalkylene)-NR R ,
1 6 3 7
C A B C
-C(O)N(R )-(C -C alkylene)-NR R, -C(O)N(R )-(C -C cycloalkylene)-
2 6 3 7
A B C D C
NR R, -C(O)N(R )-(C -C alkylene)-OR, -C(O)N(R )-(C -
2 6 3
D C C A B
C cycloalkylene)-OR, -N(R )C(O)N(R )-(C -C alkylene)-NR R ,
7 2 6
C C A B
-N(R )C(O)N(R )-(C -C cycloalkylene)-NR R, -O-(C -C cycloalkylene)-
3 7 3 7
D D C A B
OR, -S-(C -C cycloalkylene)-OR , -N(R )S(O) -(C -C alkylene)-NR R ,
3 7 2 1 6
C A B C
-N(R )S(O) -(C -C cycloalkylene)-NR R, -S(O) N(R )-(C -C alkylene)-
2 3 7 2 2 6
A B C A B C
NR R, -S(O) N(R )-(C -C cycloalkylene)-NR R, -S(O) N(R )-(C -
2 3 7 2 2
D C D C
C alkylene)-OR , -S(O) N(R )-(C -C cycloalkylene)-OR , -N(R )S(O) -(C -
6 2 3 7 2 2
D C D C D
C alkylene)-OR , -N(R )S(O) -(C -C cycloalkylene)-OR , -N(R )S(O) R ,
6 2 3 7 2
-(C -Cheterocycloalkyl), (C -C heterocycloalkyl)-(C C alkyl),
3 7 5 7 1- 6
(C -C heterocycloalkyl)(C -Ccycloalkyl) and (C -
7 3 6 3
Cheterocycloalkyl)carbonyl, wherein any of such C -Calkyl, C -
7 1 6 3
Ccycloalkyl, -(C -Calkylene)- -(C -Calkylene)-, -(C -C cycloalkylene)-,
6 1 6 2 6 3 7
-(C -Cheterocycloalkyl), (C -C heterocycloalkyl)-(C -C alkyl), (C -C
3 7 5 7 1 6 5 7
heterocycloalkyl)-(C -C cycloalkyl) and (C -C heterocycloalkyl)carbonyl
3 6 3 7
portion in the above listed groups may be optionally substituted by one, two or
three groups R which are independently selected in the group consisting of:
C -Calkyl, (C -C) haloalkyl, (C -C)hydroxyalkyl, C -C cycloalkyl,
1 6 1 3 1 4 3 7
hydroxyl and halo;
R and R are at each occurrence independently hydrogen, C -C alkyl
or C -C cycloalkyl, such C -C alkyl and C -C cycloalkyl being optionally
3 7 1 6 3 7
substituted by a group C -C alkyl, C -C cycloalkyl, -OR , -CN or halo;
1 3 3 7
alternatively, R and R , may form together with the nitrogen atom to which
they are attached a 5 membered saturated heterocyclic monocyclic or
bicyclic ring system which is optionally substituted by one or more group
-OR , -CN, halo, C -C alkyl or C -C cycloalkyl, such C -C alkyl and C -C
1 6 3 7 1 6 3 7
cycloalkyl being optionally substituted by a group C -C alkyl, C -
1 3 3
C cycloalkyl, -OR , -CN or halo; and which 5 membered saturated
heterocyclic monocyclic or bicyclic ring optionally contains a further
heteroatom which is oxygen or nitrogen, said nitrogen atom optionally
substituted by C -C alkyl or C -C cycloalkyl, wherein any of such C -C
1 6 3 6 1 6
alkyl or C -C cycloalkyl may be optionally substituted by a group C -C
3 6 1 6
D A B
alkyl, C -C cycloalkyl, -OR , -CN, or halo; and/or R and R may be linked
to one carbon atom of the -(C -C alkylene)-, -(C -C alkylene)- or -(C -
1 6 2 6 3
C cycloalkylene)- portion of the group linked to the nitrogen to which they are
connected to form a saturated cycle of up to 6 ring atoms;
R is at each occurrence independently hydrogen, C -C alkyl or C -C
1 6 3 6
cycloalkyl, such C -C alkyl and C -C cycloalkyl being optionally substituted
1 6 3 6
by a group C -C alkyl, -OR , -CN or halo;
R is at each occurrence independently hydrogen, -CH or -C H ;
3 2 5
12 13
R and R are independently hydrogen, C -C alkyl, or halogen;
A is a divalent cycloalkylene radical having 5 or 6 ring atoms; said
cycloalkylene ring being attached to W and Y, and fused to a phenyl ring,
such phenyl ring being optionally substituted by one or two groups R ; and
wherein said divalent cycloalkylene radical has the formula
24 24
R is at each occurrence independently selected from the group
consisting of: C -C alkyl, halogen and cyano;
R is a radical of formula (IIIa), (IIIb), (IIIc) or (IIId):
14 15
(IIIa) (IIIb) (IIIc) (IIId)
wherein
R is selected in the group consisting of: -F, -CH , -C H , -CH OH,
3 2 5 2
-CH OMe, -CF CF , -CH SCH , -SCH and -SC H ;
2 2 3 2 3 3 2 5
16
R and R are independently -CH or -C H ;
3 2 5
R is selected from the group consisting of: lone electron pair,
hydrogen, -CF , -NR R , -(C -C cycloalkyl), -(C -C heterocycloalkyl), aryl or
3 3 7 3 7
heteroaryl wherein any of such –(C -C cycloalkyl), -(C -C heterocycloalkyl),
3 7 3 7
aryl or heteroaryl may be optionally substituted by a group C -C alkyl, C -C
1 6 3 7
cycloalkyl, or halo; or
R is a group of general formula (IV)
(IV)
wherein
R is selected in the group consisting of: -F, -CH , -C H , -CH OH,
3 2 5 2
-CH OMe, -CF CF , -CH SCH , -SCH and -SC H ;
2 2 3 2 3 3 2 5
R is -CH or -C H ;
3 2 5
or
21
R and R as defined above may form together with the carbon atom
to which they are attached a saturated 3 membered monocyclic ring;
R and R are each independently C -C alkyl, optionally substituted by
G E F
a group C -C alkyl, -OR , -CN or halo; alternatively, R and R may form
together with the nitrogen atom to which they are attached a 5 membered
saturated monocyclic or bicyclic heterocyclic ring system which is optionally
substituted by one or more groups -OR , -CN, halo, C -C alkyl or C -C
1 6 3 7
cycloalkyl, such C -C alkyl and C -C cycloalkyl being optionally substituted
1 6 3 7
by a group C -C alkyl, C -C cycloalkyl, -OR , -CN or halo; and which 5
1 3 3 7
membered saturated monocyclic or bicyclic heterocyclic ring optionally
contains a further heteroatom which is oxygen or nitrogen, said nitrogen atom
optionally substituted by C -C alkyl or C -C cycloalkyl, wherein any of such
1 6 3 6
C -C alkyl or C -C cycloalkyl may be optionally substituted by a group C -
1 6 3 6 1
C alkyl or C -C cycloalkyl;
6 3 7
R is hydrogen, -CH or -C H ;
3 2 5
R is selected in the group consisting of: lone electron pair, hydrogen,
aryl, heteroaryl, -(C -C alkyl), -(C -C cycloalkyl), -(C -C heterocycloalkyl),
1 6 3 7 3 7
(C -C heterocycloalkyl)-(C -Calkyl) and (C -C heterocycloalkyl)-(C -C
7 1 6 5 7 3 6
cycloalkyl), wherein any of such aryl, heteroaryl, -(C -Calkyl), -(C -
1 6 3
C cycloalkyl), -(C -C heterocycloalkyl), (C -C heterocycloalkyl)-(C -C alkyl)
7 3 7 5 7 1 6
and (C -C heterocycloalkyl)-(C -C cycloalkyl) may be optionally substituted
7 3 6
by a group -CN, -OH, halo, -COOR , C -C alkyl, C -C cycloalkyl, -O-(C -
1 6 3 6 1
Calkyl), -O-(C -Ccycloalkyl), -S-(C -Calkyl), -S-(C -C cycloalkyl),
6 3 6 1 6 3 6
H J L H J L H J
-NR R, -N(R )(C -C alkylene)-NR R, -N(R )(C -C cycloalkylene)-NR R ,
2 6 3 7
H J H J
-(C -C alkylene)-NR R, -(C -C cycloalkylene)-NR R, -O-(C -C alkylene)-
1 6 3 7 2 6
H J H J H J
NR R , -O-(C -C cycloalkylene)-NR R , -S-(C -C alkylene)-NR R , -S-(C -
3 7 2 6 3
H J L H J L
C cycloalkylene)-NR R, -N(R )C(O)-(C -C alkylene)-NR R, -N(R )C(O)-
7 1 6
H J L H J
(C -C cycloalkylene)-NR R, -C(O)N(R )-(C -C alkylene)-NR R ,
3 7 2 6
L H J L M
-C(O)N(R )-(C -C cycloalkylene)-NR R , -C(O)N(R )-(C -C alkylene)-OR ,
3 7 2 6
L M L H J H J
-C(O)N(R )-(C -C cycloalkylene)-OR , -N(R )C(O)N(R R ), -C(O)N(R R ),
L L H J L L
-N(R )C(O)N(R )-(C -C alkylene)-NR R, -N(R )C(O)N(R )-(C -
2 6 3
H J M
C cycloalkylene)-NR R , -O-(C -C alkylene)-OR , -O-(C -C cycloalkylene)-
7 2 6 3 7
M M M L
OR , -S-(C -C alkylene)-OR , -S-(C -C cycloalkylene)-OR , -N(R )S(O) -
2 6 3 7 2
H J L H J
(C -C alkylene)-NR R, -N(R )S(O) -(C -C cycloalkylene)-NR R ,
1 6 2 3 7
L H J L
-S(O) N(R )-(C -C alkylene)-NR R, -S(O) N(R )-(C -C cycloalkylene)-
2 2 6 2 3 7
H J L M L
NR R, -S(O) N(R )-(C -C alkylene)-OR, -S(O) N(R )-(C -
2 2 6 2 3
M L M L
C cycloalkylene)-OR , -N(R )S(O) -(C -C alkylene)-OR , -N(R )S(O) -(C -
7 2 2 6 2 3
M H J L L L L L
C cycloalkylene)-OR , -S(O) N(R R ), -N(R )S(O) R , -N(R )C(O)R , OR ,
7 2 2
SR , -(C -C heterocycloalkyl), (C -C heterocycloalkyl)-(C -C alkyl) and (C -
3 7 5 7 1 6 5
C heterocycloalkyl)-(C -C cycloalkyl), wherein any of such C -C alkyl, C -
7 3 6 1 6 3
Ccycloalkyl, -(C -Calkylene)- -(C -Calkylene)-, -(C -C cycloalkylene)-,
6 1 6 2 6 3 7
-(C -C heterocycloalkyl), (C -C heterocycloalkyl)-(C -C alkyl) and (C -C
3 7 5 7 1 6 5 7
heterocycloalkyl)-(C -C cycloalkyl) portion in the above listed groups may be
optionally substituted by a group C -C alkyl, C -C cycloalkyl, -OR or halo;
1 6 3 7
R and R , are at each occurrence independently hydrogen, C -C alkyl
or C -C cycloalkyl, such C -C alkyl or C -C cycloalkyl being optionally
3 6 1 6 3 6
substituted by a group C -C alkyl, -OR , CN or halo;
alternatively, R and R may also together with the nitrogen atom to
which they are attached a 5 membered saturated monocyclic or bicyclic
heterocyclic ring system which is optionally substituted by one or more
groups -OR , -CN, halo, C -C alkyl or C -C cycloalkyl, such C -C alkyl and
1 6 3 7 1 6
C -C cycloalkyl being optionally substituted by a group C -C alkyl, C -
3 7 1 3 3
C cycloalkyl, -OR , CN or halo; and which 5 membered saturated
monocyclic or bicyclic heterocyclic ring optionally contains a further
heteroatom which is oxygen or nitrogen, said nitrogen atom optionally
substituted by C -C alkyl or C -C cycloalkyl, wherein any of such C -C
1 6 3 6 1 6
alkyl or C -C cycloalkyl may be optionally substituted by a group C -C
3 6 1 6
alkyl, C -C cycloalkyl, -OR , CN, or halo;
and/or R and R may be linked to one carbon atom of the -(C -
C alkylene)-, -(C -C alkylene)- or -(C -C cycloalkylene)- portion of the group
6 2 6 3 7
linked to the nitrogen to which they are connected to form a saturated cycle of
up to 6 ring atoms;
R is at each occurrence independently hydrogen, C -C alkyl or C -C
1 6 3 6
cycloalkyl, such C -C alkyl or C -C cycloalkyl being optionally substituted
1 6 3 6
by a group C -C alkyl, -OR , -CN or halo;
R is at each occurrence independently hydrogen, C -C alkyl or C -C
1 6 3 6
cycloalkyl, such C -C alkyl or C -C cycloalkyl being optionally substituted
1 6 3 6
by a group hydroxyl, -CN or halo;
1 2 3 4
z , z , z , and z are independently selected in the group consisting of:
C, N, S, O, a group -CH-, and a group -NH-, in such a combination that the
resulting ring formed is an aromatic system;
19 E F
R is selected from the group consisting of: hydrogen, -CF , -NR R ,
-(C -C cycloalkyl), -(C C heterocycloalkyl), aryl or heteroaryl wherein any
3 7 3- 7
of such -(C -C cycloalkyl), -(C C heterocycloalkyl), aryl or heteroaryl may
3 7 3- 7
be optionally substituted by a group C -C alkyl, C -C cycloalkyl, or halo; or
1 6 3 7
R is a group of general formula (V)
21 E F
wherein R , R , R and R are as above defined;
T is -N= or -CR =;
R is H, halo, -CH , or -CN;
R is H, halo, -CH , or –CN;
q is 0, 1, 2 or 3.
In another aspect, the invention provides a pharmaceutical composition
comprising a compound of the invention, together with one or more
pharmaceutically acceptable carriers.
In another aspect, the invention relates to the use of a compound of the
invention in the manufacture of a medicament for the treatment of diseases or
conditions which benefit from inhibition of p38 MAP kinase activity.
Also described is a compound of formula (I), or a pharmaceutically
acceptable salt thereof:
N W A
wherein;
W is a heteroatom selected from N or O, wherein N is substituted with
hydrogen, C -C alkyl or C -C cycloalkyl;
1 6 3 5
Y is selected in the group consisting of: a group -S(O)p- wherein p is 0,
3 4 5 6 7
1 or 2; a group -O(CR R ) -; a group -(CR R ) -; a group -NR -; a group
-OC(O)-; a group -OC(O)NH-; and a group -OC(O)O-;
3 4 5 6
R , R , R and R are each independently hydrogen, fluorine or C1-C6
3 4 5 6
alkyl, or, respectively, R and R , or R and R may form together with the
carbon atom to which they are attached a saturated 3-6 membered carbocyclic
monocyclic ring optionally substituted by a group C -C alkyl, hydroxyl or
halo;
n is 0, 1, 2 or 3;
R is hydrogen, C -C alkyl, or C -C cycloalkyl wherein such C -C
1 6 3 7 1 6
alkyl or C -C cycloalkyl are optionally substituted by a group C -C alkyl,
3 7 1 3
C -C cycloalkyl, hydroxyl, cyano or halo;
R is a group selected from (IIa) - (IIc):
R N 3 X
1 10
(IIa) (IIb) (IIc)
8 9 8 9
R and R are each independently hydrogen or C -C alkyl, or R and R
may form together with the nitrogen atom to which they are attached a
membered saturated monocyclic or a fused or spiro bicyclic ring system
optionally containing a further heteroatom which is oxygen or nitrogen, said
nitrogen atom being optionally substituted by C -C alkyl; wherein such C -C
1 6 1 6
alkyl groups may be optionally substituted by a group C -C alkyl, C -C
1 6 3 6
cycloalkyl, hydroxyl or halo;
1 2 3 4 5
X , X , X , X and X are each independently a carbon atom, a nitrogen
atom, a group -(CH)- or a group -NH-; such that each combination thereof
forms an aromatic ring system;
A B
R is selected from a group consisting of: Hydrogen, -CN, -NR R ,
C A B C A B
-N(R )(C -C alkylene)-NR R, -N(R )(C -C cycloalkylene)-NR R ,
2 6 3 7
A B A B
-(C -C alkylene)-NR R , -(C -C cycloalkylene)-NR R , -O-(C -C alkylene)-
1 6 3 7 2 6
A B A B A B
NR R , -O-(C -C cycloalkylene)-NR R , -S-(C -C alkylene)-NR R , -S-(C -
3 7 2 6 3
A B C A B C
C cycloalkylene)-NR R , -N(R )C(O)-(C -C alkylene)-NR R , -N(R )C(O)-
7 1 6
A B C A B
(C -C cycloalkylene)-NR R, -C(O)N(R )-(C -C alkylene)-NR R ,
3 7 2 6
C A B C D
-C(O)N(R )-(C -C cycloalkylene)-NR R , -C(O)N(R )-(C -C alkylene)-OR ,
3 7 2 6
C D C A B A B
-C(O)N(R )-(C -C cycloalkylene)-OR , -N(R )C(O)NR R, -C(O)NR R ,
C C A B C C
-N(R )C(O)N(R )-(C -C alkylene)-NR R, -N(R )C(O)N(R )-(C -
2 6 3
A B D D
C cycloalkylene)-NR R , -(C -C alkylene)-OR , -(C -C cycloalkylene)-OR ,
7 2 6 3 7
-O-(C -C alkylene)-OR , -O-(C -C cycloalkylene)-OR , -S-(C -C alkylene)-
2 6 3 7 2 6
D D C A B
OR, -S-(C -C cycloalkylene)-OR , -N(R )S(O) -(C -C alkylene)-NR R ,
3 7 2 1 6
C A B C
-N(R )S(O) -(C -C cycloalkylene)-NR R, -S(O) N(R )-(C -C alkylene)-
2 3 7 2 2 6
A B C A B C
NR R, -S(O) N(R )-(C -C cycloalkylene)-NR R, -S(O) N(R )-(C -
2 3 7 2 2
D C D C
C alkylene)-OR , -S(O) N(R )-(C -C cycloalkylene)-OR , -N(R )S(O) -(C -
6 2 3 7 2 2
D C D A B
C alkylene)-OR , -N(R )S(O) -(C -C cycloalkylene)-OR , -S(O) N(R R ),
6 2 3 7 2
C D C C C C
-N(R )S(O) R, -N(R )C(O)R, -OR, -SR, -(C -C heterocycloalkyl),
2 3 7
(C -C heterocycloalkyl)-(C -Calkyl), (C -C heterocycloalkyl)(C -
7 1 6 5 7 3
C cycloalkyl)-, and C -C heterocycloalkylcarbonyl; wherein any of such C -
6 3 7 1
Calkyl, C -Ccycloalkyl, -(C -Calkylene)- -(C -Calkylene)-, -(C -
6 3 6 1 6 2 6 3
C cycloalkylene)-, -(C -C heterocycloalkyl), (C -C heterocycloalkyl)-(C -C
7 3 7 5 7 1 6
alkyl), (C -C heterocycloalkyl)-(C -C cycloalkyl) and (C -
7 3 6 3
C heterocycloalkyl)carbonyl portion in the above listed groups may be
optionally substituted by a group C -C alkyl, C -C cycloalkyl, hydroxyl or
1 6 3 7
halo;
11 4
R is linked to X and is selected from a group consisting of:
Hydrogen; -CN; C -C alkyl which is substituted by a group selected
from -CN, -OR , -SR , halo; C -C cycloalkyl which is substituted by a group
C D A B C
selected from C -C alkyl, -CN, -OR , -SR , halo; -NR R , -N(R )(C -
1 4 2
A B C A B
C alkylene)-NR R , -N(R )(C -C cycloalkylene)-NR R , -(C -C alkylene)-
6 3 7 1 6
A B A B A B
NR R , -(C -C cycloalkylene)-NR R , -O-(C -C alkylene)-NR R , -O-(C -
3 7 2 6 3
A B A B
C cycloalkylene)-NR R, -S-(C -C alkylene)-NR R, -S-(C -
7 2 6 3
A B C A B C
C cycloalkylene)-NR R , -N(R )C(O)-(C -C alkylene)-NR R , -N(R )C(O)-
7 1 6
A B C A B
(C -C cycloalkylene)-NR R, -C(O)N(R )-(C -C alkylene)-NR R ,
3 7 2 6
C A B C D
-C(O)N(R )-(C -C cycloalkylene)-NR R , -C(O)N(R )-(C -C alkylene)-OR ,
3 7 2 6
C D C A B A B
-C(O)N(R )-(C -C cycloalkylene)-OR , -N(R )C(O)N(R R ), -C(O)N(R R ),
C C A B C C
-N(R )C(O)N(R )-(C -C alkylene)-NR R, -N(R )C(O)N(R )-(C -
2 6 3
A B D
C cycloalkylene)-NR R , -O-(C -C alkylene)-OR , -O-(C -C cycloalkylene)-
7 2 6 3 7
D D D C
OR , -S-(C -C alkylene)-OR , -S-(C -C cycloalkylene)-OR , -N(R )S(O) -
2 6 3 7 2
A B C A B
(C -C alkylene)-NR R, -N(R )S(O) -(C -C cycloalkylene)-NR R ,
1 6 2 3 7
C A B C
-S(O) N(R )-(C -C alkylene)-NR R, -S(O) N(R )-(C -C cycloalkylene)-
2 2 6 2 3 7
A B C D C
NR R, -S(O) N(R )-(C -C alkylene)-OR, -S(O) N(R )-(C -
2 2 6 2 3
D C D C
C cycloalkylene)-OR, -N(R )S(O) -(C -C alkylene)-OR, -N(R )S(O)
7 2 2 6 2
D A B C D C C
(C -C cycloalkylene)-OR , -S(O) N(R R ), -N(R )S(O) R , -N(R )C(O)R ,
3 7 2 2
OR , SR , -(C -Cheterocycloalkyl), (C -C heterocycloalkyl)-(C -C alkyl),
3 7 5 7 1 6
(C -C heterocycloalkyl)(C -Ccycloalkyl) and (C -C
7 3 6 3 7
heterocycloalkyl)carbonyl, wherein any of such C -C alkyl, C -C cycloalkyl,
1 6 3 6
-(C -Calkylene)- -(C -Calkylene)-, -(C -Ccycloalkylene)-, -(C -
1 6 2 6 3 7 3
Cheterocycloalkyl), (C -C heterocycloalkyl)-(C -C alkyl), (C -C
7 5 7 1 6 5 7
heterocycloalkyl)-(C -C cycloalkyl) and (C -C heterocycloalkyl)carbonyl
3 6 3 7
portion in the above listed groups may be optionally substituted by one, two or
three groups R which are independently selected in the list consisting of: C -
C alkyl, (C -C ) haloalkyl, (C -C )hydroxyalkyl, C -C cycloalkyl, hydroxyl
6 1 3 1 4 3 7
and halo; or
11 4
R is linked to X and is phenyl or 5- or 6-membered monocyclic
heteroaryl, wherein such phenyl or 5- or 6-membered monocyclic heteroaryl is
substituted by a group selected in the list consisting of: C -C alkyl which is
substituted by a group -CN; C -C cycloalkyl which is substituted by a group
C C C A B
selected from: -CN, -OR , -SR or halo; -N(R )(C -C alkylene)-NR R , -
C A B A B
N(R )(C -C cycloalkylene)-NR R, -(C -C alkylene)-NR R, -(C -
3 7 1 6 3
A B A B
C cycloalkylene)-NR R, -O-(C -C cycloalkylene)-NR R ,
7 3 7
A B A B C
-S-(C -C alkylene)-NR R, -S-(C -C cycloalkylene)-NR R, -N(R )C(O)-
2 6 3 7
A B C A B
(C -C alkylene)-NR R, -N(R )C(O)-(C -C cycloalkylene)-NR R ,
1 6 3 7
C A B C
-C(O)N(R )-(C -C alkylene)-NR R, -C(O)N(R )-(C -C cycloalkylene)-
2 6 3 7
A B C D C
NR R, -C(O)N(R )-(C -C alkylene)-OR, -C(O)N(R )-(C -
2 6 3
D C C A B
C cycloalkylene)-OR, -N(R )C(O)N(R )-(C -C alkylene)-NR R ,
7 2 6
C C A B
-N(R )C(O)N(R )-(C -C cycloalkylene)-NR R, -O-(C -C cycloalkylene)-
3 7 3 7
D D C A B
OR, -S-(C -C cycloalkylene)-OR , -N(R )S(O) -(C -C alkylene)-NR R ,
3 7 2 1 6
C A B C
-N(R )S(O) -(C -C cycloalkylene)-NR R, -S(O) N(R )-(C -C alkylene)-
2 3 7 2 2 6
A B C A B C
NR R, -S(O) N(R )-(C -C cycloalkylene)-NR R, -S(O) N(R )-(C -
2 3 7 2 2
D C D C
C alkylene)-OR , -S(O) N(R )-(C -C cycloalkylene)-OR , -N(R )S(O) -(C -
6 2 3 7 2 2
D C D C D
C alkylene)-OR , -N(R )S(O) -(C -C cycloalkylene)-OR , -N(R )S(O) R ,
6 2 3 7 2
-(C -Cheterocycloalkyl), (C -C heterocycloalkyl)-(C C alkyl),
3 7 5 7 1- 6
(C -C heterocycloalkyl)(C -Ccycloalkyl) and (C -
7 3 6 3
Cheterocycloalkyl)carbonyl, wherein any of such C -Calkyl, C -
7 1 6 3
Ccycloalkyl, -(C -Calkylene)- -(C -Calkylene)-, -(C -C cycloalkylene)-,
6 1 6 2 6 3 7
-(C -Cheterocycloalkyl), (C -C heterocycloalkyl)-(C -C alkyl), (C -C
3 7 5 7 1 6 5 7
heterocycloalkyl)-(C -C cycloalkyl) and (C -C heterocycloalkyl)carbonyl
3 6 3 7
portion in the above listed groups may be optionally substituted by one, two or
three groups R which are independently selected in the group consisting of:
C -Calkyl, (C -C) haloalkyl, (C -C)hydroxyalkyl, C -C cycloalkyl,
1 6 1 3 1 4 3 7
hydroxyl and halo;
R and R are at each occurrence independently hydrogen, C -C alkyl
or C -C cycloalkyl, such C -C alkyl and C -C cycloalkyl being optionally
3 7 1 6 3 7
substituted by a group C -C alkyl, C -C cycloalkyl, -OR , -CN or halo;
1 3 3 7
alternatively, R and R , may form together with the nitrogen atom to which
they are attached a 5 membered saturated heterocyclic monocyclic or
bicyclic ring system which is optionally substituted by one or more group
-OR , -CN, halo, C -C alkyl or C -C cycloalkyl, such C -C alkyl and C -C
1 6 3 7 1 6 3 7
cycloalkyl being optionally substituted by a group C -C alkyl, C -
1 3 3
C cycloalkyl, -OR , -CN or halo; and which 5 membered saturated
heterocyclic monocyclic or bicyclic ring optionally contains a further
heteroatom which is oxygen or nitrogen, said nitrogen atom optionally
substituted by C -C alkyl or C -C cycloalkyl, wherein any of such C -C
1 6 3 6 1 6
alkyl or C -C cycloalkyl may be optionally substituted by a group C -C
3 6 1 6
D A B
alkyl, C -C cycloalkyl, -OR , -CN, or halo; and/or R and R may be linked
to one carbon atom of the -(C -C alkylene)-, -(C -C alkylene)- or -(C -
1 6 2 6 3
C cycloalkylene)- portion of the group linked to the nitrogen to which they are
connected to form a saturated cycle of up to 6 ring atoms;
R is at each occurrence independently hydrogen, C -C alkyl or C -C
1 6 3 6
cycloalkyl, such C -C alkyl and C -C cycloalkyl being optionally substituted
1 6 3 6
by a group C -C alkyl, -OR , -CN or halo;
R is at each occurrence independently hydrogen, -CH or -C H ;
3 2 5
12 13
R and R are independently hydrogen, C -C alkyl, or halogen;
A is a divalent cycloalkylene radical having 5, 6 or 7 ring atoms; said
cycloalkylene ring being attached to W and Y, and fused to a phenyl ring or to
a monocyclic heteroaryl ring having 5 or 6 ring atoms, such phenyl or
heteroaryl ring being optionally substituted by one or two groups R ;
R is at each occurrence independently selected from the group
consisting of: C -C alkyl, halogen and cyano;
R is a radical of formula (IIIa), (IIIb), (IIIc), or (IIId):
14 15
16 R
(IIIa) (IIIb) (IIIc) (IIId)
wherein
R is selected in the group consisting of: -F, -CH , -C H , -CH OH,
3 2 5 2
-CH OMe, -CF CF , -CH SCH , -SCH and -SC H ;
2 2 3 2 3 3 2 5
16
R and R are independently -CH or -C H ;
3 2 5
R is selected from the group consisting of: lone electron pair,
hydrogen, -CF , -NR R , -(C -C cycloalkyl), -(C -C heterocycloalkyl), aryl or
3 3 7 3 7
heteroaryl wherein any of such –(C -C cycloalkyl), -(C -C heterocycloalkyl),
3 7 3 7
aryl or heteroaryl may be optionally substituted by a group C -C alkyl, C -C
1 6 3 7
cycloalkyl, or halo; or
R is a group of general formula (IV)
(IV)
wherein
R is selected in the group consisting of: -F, -CH , -C H , -CH OH,
3 2 5 2
-CH OMe, -CF CF , -CH SCH , -SCH and -SC H ;
2 2 3 2 3 3 2 5
R is -CH or -C H ;
3 2 5
21
R and R as defined above may form together with the carbon atom
to which they are attached a saturated 3 membered monocyclic ring;
R and R are each independently C -C alkyl, optionally substituted by
G E F
a group C -C alkyl, -OR , -CN or halo; alternatively, R and R may form
together with the nitrogen atom to which they are attached a 5 membered
saturated monocyclic or bicyclic heterocyclic ring system which is optionally
substituted by one or more groups -OR , -CN, halo, C -C alkyl or C -C
1 6 3 7
cycloalkyl, such C -C alkyl and C -C cycloalkyl being optionally substituted
1 6 3 7
by a group C -C alkyl, C -C cycloalkyl, -OR , -CN or halo; and which 5
1 3 3 7
membered saturated monocyclic or bicyclic heterocyclic ring optionally
contains a further heteroatom which is oxygen or nitrogen, said nitrogen atom
optionally substituted by C -C alkyl or C -C cycloalkyl, wherein any of such
1 6 3 6
C -C alkyl or C -C cycloalkyl may be optionally substituted by a group C -
1 6 3 6 1
C alkyl or C -C cycloalkyl;
6 3 7
R is hydrogen, -CH or -C H ;
3 2 5
R is selected in the group consisting of: lone electron pair, hydrogen,
aryl, heteroaryl, -(C -C alkyl), -(C -C cycloalkyl), -(C -C heterocycloalkyl),
1 6 3 7 3 7
(C -C heterocycloalkyl)-(C -Calkyl) and (C -C heterocycloalkyl)-(C -C
7 1 6 5 7 3 6
cycloalkyl), wherein any of such aryl, heteroaryl, -(C -Calkyl), -(C -
1 6 3
C cycloalkyl), -(C -C heterocycloalkyl), (C -C heterocycloalkyl)-(C -C alkyl)
7 3 7 5 7 1 6
and (C -C heterocycloalkyl)-(C -C cycloalkyl) may be optionally substituted
7 3 6
by a group -CN, -OH, halo, -COOR , C -C alkyl, C -C cycloalkyl, -O-(C -
1 6 3 6 1
Calkyl), -O-(C -Ccycloalkyl), -S-(C -Calkyl), -S-(C -Ccycloalkyl), -
6 3 6 1 6 3 6
H J L H J L H J
NR R , -N(R )(C -C alkylene)-NR R , -N(R )(C -C cycloalkylene)-NR R , -
2 6 3 7
H J H J
(C -C alkylene)-NR R, -(C -C cycloalkylene)-NR R, -O-(C -C alkylene)-
1 6 3 7 2 6
H J H J H J
NR R , -O-(C -C cycloalkylene)-NR R , -S-(C -C alkylene)-NR R , -S-(C -
3 7 2 6 3
H J L H J L
C cycloalkylene)-NR R, -N(R )C(O)-(C -C alkylene)-NR R, -N(R )C(O)-
7 1 6
H J L H J
(C -C cycloalkylene)-NR R, -C(O)N(R )-(C -C alkylene)-NR R ,
3 7 2 6
L H J L M
-C(O)N(R )-(C -C cycloalkylene)-NR R , -C(O)N(R )-(C -C alkylene)-OR ,
3 7 2 6
L M L H J H J
-C(O)N(R )-(C -C cycloalkylene)-OR , -N(R )C(O)N(R R ), -C(O)N(R R ),
L L H J L L
-N(R )C(O)N(R )-(C -C alkylene)-NR R, -N(R )C(O)N(R )-(C -
2 6 3
H J M
C cycloalkylene)-NR R , -O-(C -C alkylene)-OR , -O-(C -C cycloalkylene)-
7 2 6 3 7
M M M L
OR , -S-(C -C alkylene)-OR , -S-(C -C cycloalkylene)-OR , -N(R )S(O) -
2 6 3 7 2
H J L H J
(C -C alkylene)-NR R, -N(R )S(O) -(C -C cycloalkylene)-NR R ,
1 6 2 3 7
L H J L
-S(O) N(R )-(C -C alkylene)-NR R, -S(O) N(R )-(C -C cycloalkylene)-
2 2 6 2 3 7
H J L M L
NR R, -S(O) N(R )-(C -C alkylene)-OR, -S(O) N(R )-(C -
2 2 6 2 3
M L M L
C cycloalkylene)-OR , -N(R )S(O) -(C -C alkylene)-OR , -N(R )S(O) -(C -
7 2 2 6 2 3
M H J L L L L L
C cycloalkylene)-OR , -S(O) N(R R ), -N(R )S(O) R , -N(R )C(O)R , OR ,
7 2 2
SR , -(C -C heterocycloalkyl), (C -C heterocycloalkyl)-(C -C alkyl) and (C -
3 7 5 7 1 6 5
C heterocycloalkyl)-(C -C cycloalkyl), wherein any of such C -C alkyl, C -
7 3 6 1 6 3
C cycloalkyl, -(C -C alkylene)- -(C -C alkylene)-, -(C -C cycloalkylene)-,--
6 1 6 2 6 3 7
(C -C heterocycloalkyl), (C -C heterocycloalkyl)-(C -C alkyl) and (C -C
3 7 5 7 1 6 5 7
heterocycloalkyl)-(C -C cycloalkyl) portion in the above listed groups may be
optionally substituted by a group C -C alkyl, C -C cycloalkyl, -OR or halo;
1 6 3 7
R and R , are at each occurrence independently hydrogen, C -C alkyl
or C -C cycloalkyl, such C -C alkyl or C -C cycloalkyl being optionally
3 6 1 6 3 6
substituted by a group C -C alkyl, -OR , CN or halo;
alternatively, R and R may also together with the nitrogen atom to
which they are attached a 5 membered saturated monocyclic or bicyclic
heterocyclic ring system which is optionally substituted by one or more
groups -OR , -CN, halo, C -C alkyl or C -C cycloalkyl, such C -C alkyl and
1 6 3 7 1 6
C -C cycloalkyl being optionally substituted by a group C -C alkyl, C -
3 7 1 3 3
C cycloalkyl, -OR , CN or halo; and which 5 membered saturated
monocyclic or bicyclic heterocyclic ring optionally contains a further
heteroatom which is oxygen or nitrogen, said nitrogen atom optionally
substituted by C -C alkyl or C -C cycloalkyl, wherein any of such C -C
1 6 3 6 1 6
alkyl or C -C cycloalkyl may be optionally substituted by a group C -C
3 6 1 6
alkyl, C -C cycloalkyl, -OR , CN, or halo;
and/or R and R may be linked to one carbon atom of the -(C -
C alkylene)-, -(C -C alkylene)- or -(C -C cycloalkylene)- portion of the group
6 2 6 3 7
linked to the nitrogen to which they are connected to form a saturated cycle of
up to 6 ring atoms;
R is at each occurrence independently hydrogen, C -C alkyl or C -C
1 6 3 6
cycloalkyl, such C -C alkyl or C -C cycloalkyl being optionally substituted
1 6 3 6
by a group C -C alkyl, -OR , -CN or halo;
R is at each occurrence independently hydrogen, C -C alkyl or C -C
1 6 3 6
cycloalkyl, such C -C alkyl or C -C cycloalkyl being optionally substituted
1 6 3 6
by a group hydroxyl, -CN or halo;
1 2 3 4
z , z , z , and z are independently selected in the group consisting of:
C, N, S, O, a group -CH-, and a group -NH-, in such a combination that the
resulting ring formed is an aromatic system;
19 E F
R is selected from the group consisting of: hydrogen, -CF , -NR R ,
-(C -C cycloalkyl), -(C C heterocycloalkyl), aryl or heteroaryl wherein any
3 7 3- 7
of such -(C -C cycloalkyl), -(C C heterocycloalkyl), aryl or heteroaryl may
3 7 3- 7
be optionally substituted by a group C -C alkyl, C -C cycloalkyl, or halo; or
1 6 3 7
R is a group of general formula (V)
21 E F
wherein R , R , R and R are as above defined;
T is -N= or -CR =;
R is H, halo, -CH , or -CN;
R is H, halo, -CH , or -CN;
q is 0, 1, 2 or 3;
3 4 10
with the proviso that when Y is a group -O(CR R ) -, n is 1 and R is
A B C A B C
-NR R, -N(R )C(O)-(C -C alkylene)-NR R, -N(R )C(O)-(C -
1 6 3
A B C A B C C
C cycloalkylene)-NR R, -N(R )C(O)N(R R), -N(R )C(O)N(R )-(C -
A B C C A B
C alkylene)-NR R, -N(R )C(O)N(R )-(C -C cycloalkylene)-NR R, or
6 3 7
-N(R )C(O)R , then X is nitrogen.
In one embodiment, there is described a compound of formula (IP), or a
pharmaceutically acceptable salt thereof:
(IP)
wherein;
W is a heteroatom selected from N or O, wherein N is substituted with
hydrogen or C -C alkyl or C -C cycloalkyl;
1 6 3 5
Y is selected in the group consisting of: a group -S(O) - wherein p is 0,
3 4 5 6 7
1 or 2; a group -O(CR R ) -; a group -(CR R ) -; a group -NR -; a group -
OC(O)-; a group -OC(O)NH-; and a group -OC(O)O-;
3 4 5 6
R , R , R and R are each independently hydrogen, fluorine or C -C
3 4 5 6
alkyl, or, respectively, R and R , or R and R may form together with the
carbon atom to which they are attached a saturated 3-6 membered carbocyclic
monocyclic ring optionally substituted by a group C -C alkyl, hydroxyl or
halo.
n is 0, 1, 2 or 3
R is hydrogen, C -C alkyl, or C -C cycloalkyl wherein such C -C
1 6 3 7 1 6
alkyl or C -C cycloalkyl are optionally substituted by a group C -C alkyl,
3 7 1 3
C -C cycloalkyl, hydroxyl, cyano or halo;
R is a group selected from (IIa) - (IIc);
R N 3 X
1 10
(IIa) (IIb) (IIc)
8 9 8 9
R and R are each independently hydrogen or C -C alkyl, or R and R
may form together with the nitrogen atom to which they are attached a
membered saturated monocyclic or a fused or spiro bicyclic ring system
optionally containing a further heteroatom which is oxygen or nitrogen, said
nitrogen atom being optionally substituted by C -C alkyl; wherein such C -C
1 6 1 6
alkyl groups may be optionally substituted by a group C -C alkyl, C -C
1 6 3 6
cycloalkyl, hydroxyl or halo;
1 2 3 4 5
X , X , X , X and X are each independently a carbon atom, a nitrogen
atom, a group -(CH)- or a group -NH-; such that each combination thereof
forms an aromatic ring system;
A B
R is selected from a group consisting of: Hydrogen, -CN, -NR R ,
C A B C A B
-N(R )(C -C alkylene)-NR R, -N(R )(C -C cycloalkylene)-NR R ,
2 6 3 7
A B A B
-(C -C alkylene)-NR R , -(C -C cycloalkylene)-NR R , -O-(C -C alkylene)-
1 6 3 7 2 6
A B A B A B
NR R , -O-(C -C cycloalkylene)-NR R , -S-(C -C alkylene)-NR R , -S-(C -
3 7 2 6 3
A B C A B C
C cycloalkylene)-NR R , -N(R )C(O)-(C -C alkylene)-NR R , -N(R )C(O)-
7 1 6
A B C A B
(C -C cycloalkylene)-NR R, -C(O)N(R )-(C -C alkylene)-NR R ,
3 7 2 6
C A B C D
-C(O)N(R )-(C -C cycloalkylene)-NR R , -C(O)N(R )-(C -C alkylene)-OR ,
3 7 2 6
C D C A B A B
-C(O)N(R )-(C -C cycloalkylene)-OR , -N(R )C(O)NR R, -C(O)NR R ,
C C A B C C
-N(R )C(O)N(R )-(C -C alkylene)-NR R, -N(R )C(O)N(R )-(C -
2 6 3
A B D D
C cycloalkylene)-NR R , -(C -C alkylene)-OR , -(C -C cycloalkylene)-OR ,
7 2 6 3 7
-O-(C -C alkylene)-OR , -O-(C -C cycloalkylene)-OR , -S-(C -C alkylene)-
2 6 3 7 2 6
D D C A B
OR, -S-(C -C cycloalkylene)-OR , -N(R )S(O) -(C -C alkylene)-NR R ,
3 7 2 1 6
C A B C
-N(R )S(O) -(C -C cycloalkylene)-NR R, -S(O) N(R )-(C -C alkylene)-
2 3 7 2 2 6
A B C A B C
NR R, -S(O) N(R )-(C -C cycloalkylene)-NR R, -S(O) N(R )-(C -
2 3 7 2 2
D C D C
C alkylene)-OR , -S(O) N(R )-(C -C cycloalkylene)-OR , -N(R )S(O) -(C -
6 2 3 7 2 2
D C D A B
C alkylene)-OR , -N(R )S(O) -(C -C cycloalkylene)-OR , -S(O) N(R R ),
6 2 3 7 2
C D C C C C
-N(R )S(O) R, -N(R )C(O)R, OR, SR, -(C -C heterocycloalkyl),
2 3 7
(C -C heterocycloalkyl)-(C -C alkyl),
7 1 6
(C -C heterocycloalkyl)(C -Ccycloalkyl)-, and C -C
7 3 6 3 7
heterocycloalkylcarbonyl, wherein any of such alkylene, cycloalkylene,
heterocycloalkyl, heterocycloalkyl-(C -C alkyl), heterocycloalkyl-(C -
1 6 3
C cycloalkyl) and heterocycloalkylcarbonyl may be optionally substituted by
a group C -C alkyl, C -C cycloalkyl, hydroxyl or halo.
1 6 3 7
11 4
R is linked to X and is selected from a group consisting of:
Hydrogen; -CN; C -C alkyl which is substituted by a group selected
from -CN, -OR , -SR , halo; C -C cycloalkyl which is substituted by a group
C D A B C
selected from C -C alkyl, -CN, -OR , -SR , halo; -NR R , -N(R )(C -
1 4 2
A B C A B
C alkylene)-NR R , -N(R )(C -C cycloalkylene)-NR R , -(C -C alkylene)-
6 3 7 1 6
A B A B A B
NR R , -(C -C cycloalkylene)-NR R , -O-(C -C alkylene)-NR R , -O-(C -
3 7 2 6 3
A B A B
C cycloalkylene)-NR R, -S-(C -C alkylene)-NR R, -S-(C -
7 2 6 3
A B C A B C
C cycloalkylene)-NR R , -N(R )C(O)-(C -C alkylene)-NR R , -N(R )C(O)-
7 1 6
A B C A B
(C -C cycloalkylene)-NR R, -C(O)N(R )-(C -C alkylene)-NR R ,
3 7 2 6
C A B C D
-C(O)N(R )-(C -C cycloalkylene)-NR R , -C(O)N(R )-(C -C alkylene)-OR ,
3 7 2 6
C D C A B A B
-C(O)N(R )-(C -C cycloalkylene)-OR , -N(R )C(O)N(R R ), -C(O)N(R R ),
C C A B C C
-N(R )C(O)N(R )-(C -C alkylene)-NR R, -N(R )C(O)N(R )-(C -
2 6 3
A B D
C cycloalkylene)-NR R , -O-(C -C alkylene)-OR , -O-(C -C cycloalkylene)-
7 2 6 3 7
D D D C
OR , -S-(C -C alkylene)-OR , -S-(C -C cycloalkylene)-OR , -N(R )S(O) -
2 6 3 7 2
A B C A B
(C -C alkylene)-NR R, -N(R )S(O) -(C -C cycloalkylene)-NR R ,
1 6 2 3 7
C A B C
-S(O) N(R )-(C -C alkylene)-NR R, -S(O) N(R )-(C -C cycloalkylene)-
2 2 6 2 3 7
A B C D C
NR R, -S(O) N(R )-(C -C alkylene)-OR, -S(O) N(R )-(C -
2 2 6 2 3
D C D C
C cycloalkylene)-OR, -N(R )S(O) -(C -C alkylene)-OR, -N(R )S(O)
7 2 2 6 2
D A B C D C C
(C -C cycloalkylene)-OR , -S(O) N(R R ), -N(R )S(O) R , -N(R )C(O)R ,
3 7 2 2
OR , SR , -(C -Cheterocycloalkyl), (C -C heterocycloalkyl)-(C -C alkyl),
3 7 5 7 1 6
(C -C heterocycloalkyl)(C -Ccycloalkyl), C -C heterocycloalkylcarbonyl,
7 3 6 3 7
wherein any of such alkylene, cycloalkylene, heterocycloalkyl,
heterocycloalkyl-(C -Calkyl), heterocycloalkyl-(C -Ccycloalkyl) and
1 6 3 6
heterocycloalkylcarbonyl may be optionally substituted by a group C -C
alkyl, C -C cycloalkyl, hydroxyl or halo; or
11 4
R is linked to X and is phenyl or 5- or 6-membered monocyclic
heteroaryl, wherein such phenyl or 5- or 6-membered monocyclic heteroaryl is
substituted by a group selected in the list consisting of: C -C alkyl which is
substituted by a group -CN; C -C cycloalkyl which is substituted by a group
C C C A B
selected from: -CN, -OR , -SR or halo; -N(R )(C -C alkylene)-NR R ,
C A B A B
-N(R )(C -C cycloalkylene)-NR R, -(C -C alkylene)-NR R, -(C -
3 7 1 6 3
A B A B
C cycloalkylene)-NR R, -O-(C -C cycloalkylene)-NR R ,
7 3 7
A B A B C
-S-(C -C alkylene)-NR R, -S-(C -C cycloalkylene)-NR R, -N(R )C(O)-
2 6 3 7
A B C A B
(C -C alkylene)-NR R, -N(R )C(O)-(C -C cycloalkylene)-NR R ,
1 6 3 7
C A B C
-C(O)N(R )-(C -C alkylene)-NR R, -C(O)N(R )-(C -C cycloalkylene)-
2 6 3 7
A B C D C
NR R, -C(O)N(R )-(C -C alkylene)-OR, -C(O)N(R )-(C -
2 6 3
D C C A B
C cycloalkylene)-OR, -N(R )C(O)N(R )-(C -C alkylene)-NR R ,
7 2 6
C C A B
-N(R )C(O)N(R )-(C -C cycloalkylene)-NR R, -O-(C -C cycloalkylene)-
3 7 3 7
D D C A B
OR, -S-(C -C cycloalkylene)-OR , -N(R )S(O) -(C -C alkylene)-NR R ,
3 7 2 1 6
C A B C
-N(R )S(O) -(C -C cycloalkylene)-NR R, -S(O) N(R )-(C -C alkylene)-
2 3 7 2 2 6
A B C A B C
NR R, -S(O) N(R )-(C -C cycloalkylene)-NR R, -S(O) N(R )-(C -
2 3 7 2 2
D C D C
C alkylene)-OR , -S(O) N(R )-(C -C cycloalkylene)-OR , -N(R )S(O) -(C -
6 2 3 7 2 2
D C D C D
C alkylene)-OR , -N(R )S(O) -(C -C cycloalkylene)-OR , -N(R )S(O) R ,
6 2 3 7 2
-(C -Cheterocycloalkyl), (C -C heterocycloalkyl)-(C C alkyl),
3 7 5 7 1- 6
(C -C heterocycloalkyl)(C -Ccycloalkyl), C -C heterocycloalkylcarbonyl,
7 3 6 3 7
wherein any of such alkylene, cycloalkylene, heterocycloalkyl,
heterocycloalkyl-(C -Calkyl), heterocycloalkyl-(C -Ccycloalkyl) and
1 6 3 6
heterocycloalkylcarbonyl may be optionally substituted by a group C -C alkyl,
C -C cycloalkyl, hydroxyl or halo;
R and R are at each occurrence independently hydrogen, C -C alkyl
or C -C cycloalkyl, such C -C alkyl and C -C cycloalkyl being optionally
3 7 1 6 3 7
substituted by a group C -C alkyl, C -C cycloalkyl, -OR , -CN or halo;
1 3 3 7
alternatively, R and R , may form together with the nitrogen atom to which
they are attached a 5 membered saturated monocyclic or bicyclic ring
system which is optionally substituted by one or more group OR , CN, halo,
C -C alkyl or C -C cycloalkyl, such C -C alkyl and C -C cycloalkyl being
1 6 3 7 1 6 3 7
optionally substituted by a group C -C alkyl, C -C cycloalkyl, OR , CN or
1 3 3 7
halo; and which 5 membered saturated monocyclic or bicyclic ring
optionally contains a further heteroatom which is oxygen or nitrogen, said
nitrogen atom optionally substituted by C -C alkyl or C -C cycloalkyl
1 6 3 6
wherein any of such alkyl or cycloalkyl may be optionally substituted by a
D A B
group C -C alkyl, C -C cycloalkyl, -OR , -CN, or halo; and/or R and R
1 6 3 7
may be linked to one carbon atom of the alkylene or cycloalkylene portion of
the group linked to the nitrogen to which they are connected to form a
saturated cycle of up to 6 ring atoms;
R is at each occurrence independently hydrogen, C -C alkyl or C -C
1 6 3 6
cycloalkyl, such C -C alkyl and C -C cycloalkyl being optionally substituted
1 6 3 6
by a group C -C alkyl, -OR , -CN or halo;
R is at each occurrence independently hydrogen, -CH or -C H ;
3 2 5
12 13
R and R are independently hydrogen, C -C alkyl, or halogen;
A is a divalent cycloalkylene radical having 5, 6 or 7 ring atoms; said
cycloalkylene ring being attached to W and Y, and fused to a phenyl ring or to
a monocyclic heteroaryl ring having 5 or 6 ring atoms, such phenyl or
heteroaryl ring being optionally substituted by one or two groups R ;
R is at each occurrence independently selected from the group
consisting of: C -C alkyl, halogen and cyano;
R is a radical of formula (IIIa), (IIIb), (IIIc), or (IIId):
14 15
16 R
(IIIa) (IIIb) (IIIc) (IIId)
wherein
R is selected in the group consisting of: -F, -CH , -C H , -CH OH,
3 2 5 2
-CH OMe, -CF CF , -CH SCH , -SCH and -SC H ;
2 2 3 2 3 3 2 5
16
R and R are independently -CH or -C H ;
3 2 5
R is selected from the group consisting of: lone electron pair,
hydrogen, -CF , -NR R , -(C -C cycloalkyl), -(C -C heterocycloalkyl), aryl or
3 3 7 3 7
heteroaryl wherein any of such cycloalkyl, heterocycloalkyl, aryl or heteroaryl
may be optionally substituted by a group C -C alkyl, C -C cycloalkyl, or
1 6 3 7
halo; or
R is a group of general formula (IV)
(IV)
wherein
R is selected in the group consisting of: -F, -CH , -C H , -CH OH,
3 2 5 2
-CH OMe, -CF CF , -CH SCH , -SCH and -SC H ;
2 2 3 2 3 3 2 5
R is -CH or -C H ;
3 2 5
or;
21
R and R as defined above may form together with the carbon atom
to which they are attached a saturated 3 membered monocyclic ring;
R and R are each independently C -C alkyl, optionally substituted by
G E F
a group C -C alkyl, -OR , -CN or halo; alternatively, R and R may form
together with the nitrogen atom to which they are attached a 5 membered
saturated monocyclic or bicyclic ring system which is optionally substituted
by one or more groups -OR , -CN, halo, C -C alkyl or C -C cycloalkyl, such
1 6 3 7
C -C alkyl and C -C cycloalkyl being optionally substituted by a group C -C
1 6 3 7 1 3
alkyl, C -C cycloalkyl, -OR , -CN or halo; and which 5 membered
saturated monocyclic or bicyclic ring optionally contains a further heteroatom
which is oxygen or nitrogen, said nitrogen atom optionally substituted by
C -C alkyl or C -C cycloalkyl wherein any of such alkyl or cycloalkyl may
1 6 3 6
be optionally substituted by a group C -C alkyl, C -C cycloalkyl;
1 6 3 7
R is hydrogen, -CH or -C H ;
3 2 5
R is selected in the group consisting of: lone electron pair, hydrogen,
aryl, heteroaryl, -(C -C alkyl), -(C -C cycloalkyl), -(C -C heterocycloalkyl),
1 6 3 7 3 7
(C -C heterocycloalkyl)-(C -Calkyl) or (C -C heterocycloalkyl)-(C -C
7 1 6 5 7 3 6
cycloalkyl), wherein any of such aryl, heteroaryl, alkyl, cycloalkyl,
heterocycloalkyl, heterocycloalkyl-(C -C alkyl), or heterocycloalkyl-(C -C
1 6 3 6
cycloalkyl) may be optionally substituted by a group -CN, -OH, halo,
-COOR, C -Calkyl, C -Ccycloalkyl, -O-(C -Calkyl), -O-(C -
1 6 3 6 1 6 3
H J L
Ccycloalkyl), -S-(C -Calkyl), -S-(C -Ccycloalkyl), -NR R, -N(R )(C -
6 1 6 3 6 2
H J L H J
C alkylene)-NR R, -N(R )(C -C cycloalkylene)-NR R, -(C -C alkylene)-
6 3 7 1 6
H J H J H J
NR R, -(C -C cycloalkylene)-NR R, -O-(C -C alkylene)-NR R, -O-(C -
3 7 2 6 3
H J H J
C cycloalkylene)-NR R, -S-(C -C alkylene)-NR R, -S-(C -
7 2 6 3
H J L H J L
C cycloalkylene)-NR R, -N(R )C(O)-(C -C alkylene)-NR R, -N(R )C(O)-
7 1 6
H J L H J
(C -C cycloalkylene)-NR R, -C(O)N(R )-(C -C alkylene)-NR R ,
3 7 2 6
L H J L M
-C(O)N(R )-(C -C cycloalkylene)-NR R , -C(O)N(R )-(C -C alkylene)-OR ,
3 7 2 6
L M L H J H J
-C(O)N(R )-(C -C cycloalkylene)-OR , -N(R )C(O)N(R R ), -C(O)N(R R ),
L L H J L L
-N(R )C(O)N(R )-(C -C alkylene)-NR R, -N(R )C(O)N(R )-(C -
2 6 3
H J M
C cycloalkylene)-NR R , -O-(C -C alkylene)-OR , -O-(C -C cycloalkylene)-
7 2 6 3 7
M M M L
OR , -S-(C -C alkylene)-OR , -S-(C -C cycloalkylene)-OR , -N(R )S(O) -
2 6 3 7 2
H J L H J
(C -C alkylene)-NR R, -N(R )S(O) -(C -C cycloalkylene)-NR R ,
1 6 2 3 7
L H J L
-S(O) N(R )-(C -C alkylene)-NR R, -S(O) N(R )-(C -C cycloalkylene)-
2 2 6 2 3 7
H J L M L
NR R, -S(O) N(R )-(C -C alkylene)-OR, -S(O) N(R )-(C -
2 2 6 2 3
M L M L
C cycloalkylene)-OR , -N(R )S(O) -(C -C alkylene)-OR , -N(R )S(O) -(C -
7 2 2 6 2 3
M H J L L L L L
C cycloalkylene)-OR , -S(O) N(R R ), -N(R )S(O) R , -N(R )C(O)R , OR ,
7 2 2
SR , -(C -C heterocycloalkyl), (C -C heterocycloalkyl)-(C -C alkyl), and (C -
3 7 5 7 1 6 5
C heterocycloalkyl)-(C -C cycloalkyl), wherein any of such alkyl,
7 3 6
cycloalkyl, alkylene, cycloalkylene, heterocycloalkyl, heterocycloalkyl-(C -C
alkyl), and (heterocycloalkyl)-(C -C cycloalkyl) may be optionally
substituted by a group C -C alkyl, C -C cycloalkyl, OR or halo;
1 6 3 7
R and R , are at each occurrence independently hydrogen, C -C alkyl
or C -C cycloalkyl, such C -C alkyl or C -C cycloalkyl being optionally
3 6 1 6 3 6
M H J
substituted by a group C -C alkyl, OR , CN or halo; alternatively, R and R
may also together with the nitrogen atom to which they are attached a 5
membered saturated monocyclic or bicyclic ring system which is optionally
substituted by one or more group OR , CN, halo, C -C alkyl or C -C
1 6 3 7
cycloalkyl, such C -C alkyl and C -C cycloalkyl being optionally substituted
1 6 3 7
by a group C -C alkyl, C -C cycloalkyl, OR , CN or halo; and which
1 3 3 7
membered saturated monocyclic or bicyclic ring optionally contains a
further heteroatom which is oxygen or nitrogen, said nitrogen atom optionally
substituted by C -C alkyl or C -C cycloalkyl wherein any of such alkyl or
1 6 3 6
cycloalkyl may be optionally substituted by a group C -C alkyl, C -C
1 6 3 7
M H J
cycloalkyl, -OR , -CN, or halo; and/or R and R may be linked to one carbon
atom of the alkylene or cycloalkylene portion of the group linked to the
nitrogen to which they are connected to form a saturated cycle of up to 6 ring
atoms;
R is at each occurrence independently hydrogen, C -C alkyl or C -C
1 6 3 6
cycloalkyl, such C -C alkyl or C -C cycloalkyl being optionally substituted
1 6 3 6
by a group C -C alkyl, OR , CN or halo;
R is at each occurrence independently hydrogen, C -C alkyl or C -C
1 6 3 6
cycloalkyl, such C -C alkyl or C -C cycloalkyl being optionally substituted
1 6 3 6
by a group hydroxyl, CN or halo;
1 2 3 4
z , z , z , and z are independently selected in the group consisting of:
C, N, S, O, a group -CH-, and a group -NH-, in such a combination that the
resulting ring formed is an aromatic system;
19 E F
R is selected from the group consisting of: hydrogen, -CF , -NR R ,
-(C -C cycloalkyl), -(C C heterocycloalkyl), aryl or heteroaryl wherein any
3 7 3- 7
of such cycloalkyl, heterocycloalkyl, aryl or heteroaryl may be optionally
substituted by a group C -C alkyl, C -C cycloalkyl, or halo or;
1 6 3 7
R is a group of general formula (V)
21 E F
wherein R , R , R and R are as above defined;
T is -N= or -CR =;
R is H, halo, -CH , or -CN;
R is H, halo, -CH , or -CN;
q is 0, 1, 2 or 3;
3 4 10
with the proviso that when Y is a group -O(CR R ) -, n is 1 and R is
A B C A B C
-NR R, -N(R )C(O)-(C -C alkylene)-NR R, -N(R )C(O)-(C -
1 6 3
A B C A B C C
C cycloalkylene)-NR R, -N(R )C(O)N(R R), -N(R )C(O)N(R )-(C -
A B C C A B
C alkylene)-NR R, -N(R )C(O)N(R )-(C -C cycloalkylene)-NR R, or
6 3 7
-N(R )C(O)R , then X is nitrogen.
Also described are pharmaceutical compositions comprising a
compound of the invention, together with one or more pharmaceutically
acceptable carriers and/or excipients. Particularly preferred are compositions
adapted for inhalation for pulmonary administration.
Also described is the use of a compound of the invention for the
treatment of diseases or conditions which benefit from inhibition of p38 MAP
kinase activity. The treatment of obstructive or inflammatory airways diseases
is a preferred use. All forms of obstructive or inflammatory airways diseases
are potentially treatable with the compounds of the present invention, in
particular an obstructive or inflammatory airways disease that is a member
selected from the group consisting of chronic eosinophilic pneumonia, asthma,
COPD, COPD that includes chronic bronchitis, pulmonary emphysema or
dyspnea associated or not associated with COPD, COPD that is characterized
by irreversible, progressive airways obstruction, adult respiratory distress
syndrome (ARDS), exacerbation of airways hyper-reactivity consequent to
other drug therapy and airways disease that is associated with pulmonary
hypertension, chronic inflammatory diseases including cystic fibrosis,
bronchiectasis and pulmonary fibrosis (Idiopathic). Efficacy is anticipated
when p38 kinase inhibitors are administered either locally to the lung (for
example by inhalation and intranasal delivery) or via systemic routes (for
example, oral, intravenous and subcutaneous delivery).
Terminology
As used herein, the terms “halogen” or “halo” include fluorine,
chlorine, bromine and iodine atoms.
As used herein, the term "C -C alkyl" wherein x and y are integers,
refers to a straight or branched chain alkyl radical having from x to y carbon
atoms. Thus when x is 1 and y is 6, for example, the term includes methyl,
ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl and n-
hexyl.
As used herein, the term “C -Chaloalkyl” refers to the above
“C -C alkyl” group wherein one or more hydrogen atoms are replaced by one
or more halogen atoms.
As used herein, the term “C -C hydroxyalkyl” refers to the above
“C -C alkyl” group wherein one hydrogen atom is replaced by one hydroxyl
group.
As used herein, the term "C -C alkylene" wherein x and y are integers,
refers to a C -C alkyl radical having in total two unsatisfied valencies, such as
a divalent methylene radical.
As used herein, the term "carbocyclic" refers to a mono-, bi- or tricyclic
radical having up to 16 ring atoms, all of which are carbon, and includes aryl
and cycloalkyl.
As used herein, the term "C -C cycloalkyl" wherein z and k are integers
refers to a monocyclic saturated carbocyclic radical having from z to k carbon
atoms and includes, for example, cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cycloheptyl and cyclooctyl. Comprised within the scope of the
term "C -C cycloalkyl", are those radicals having two unsatisfied valencies on
the same carbon atom which will link to any C -C alkyl, C -C alkylene C -
x y x y z
Ccycloalkyl C -Ccycloalkylene, C -Cheterocycloalkyl, C -
k z k z k z
C heterocycloalkylC -C alkyl, C -C heterocycloalkylC -C cycloalkyl or (C -
k x y z k z k z
C )heterocycloalkylcarbonyl group by replacement of two hydrogen atoms
placed on the same carbon. In such circumstances, this radical forms a gem–
disubstituted or spiro system together with the C -C alkyl, C -C alkylene C -
x y x y z
Ccycloalkyl C -Ccycloalkylene, C -Cheterocycloalkyl, C -
k z k z k z
C heterocycloalkylC -C alkyl, C -C heterocycloalkylC -C cycloalkyl or (C -
k x y z k z k z
C )heterocycloalkylcarbonyl group it is linked to.
The term "C -C cycloalkylene radical" refers to a C -C cycloalkyl
z k z k
radical having two unsatisfied valencies on different cycle carbon atoms as
follows:
As used herein, the unqualified term "aryl" refers to a mono- or bi-
cyclic carbocyclic aromatic radical, and includes radicals having two
monocyclic carbocyclic aromatic rings which are directly linked by a covalent
bond. Illustrative of such radicals are phenyl, biphenyl and naphthyl.
As used herein, the unqualified term "heteroaryl" refers to a mono- or
bi-cyclic aromatic radical containing one or more heteroatoms selected from
S, N and O, and includes radicals having two such monocyclic rings, or one
such monocyclic ring and one monocyclic aryl ring, which are fused through a
common bond. Illustrative examples of 5,6-membered heteroaryl are: are
thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, isothiazolyl, pyrazolyl, oxazolyl,
isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, oxadiazolyl, pyridinyl,
pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl. Illustrative examples of
8,10-membered heteroaryl are: benzothienyl, benzofuryl, benzimidazolyl,
benzothiazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl,
benzotriazolyl, indolyl and indazolyl.
As used herein, the unqualified term "heterocyclyl" or "heterocyclic"
and relates to a saturated mono-, bi- or tri-cyclic non-aromatic radical
containing one or more heteroatoms selected from S, N and O. In the case of
bicyclic heterocyclic systems, included within the scope of the term are fused,
spiro and bridged bicyclic systems. In particular, the term “C -
C heterocycloalkyl” refers to monocyclic (C -C )cycloalkyl groups, in which
k z k
at least one ring carbon atom is replaced by a heteroatom (e.g. N, NH, S or O).
Examples of (C -C)heterocycloalkyl include pyrrolidinyl, thiazolidinyl,
piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl.
By analogy, the term “C -C heterocycloalkylene”, refers to a divalent
C -C heterocycloalkyl radical, wherein C -C heterocycloalkyl is as above
z k z k
defined.
The term “C -C heterocycloalkylC -Calkyl” refers to the above
z k x y
“C -C alkyl” group wherein one or more hydrogen atoms are replaced by one
or more “C -C heterocycloalkyl” groups. Comprised within the scope of the
term “C -C heterocycloalkylC -C alkyl” are systems where two hydrogen
z k x y
atoms linked to the same carbon atom in “C -C alkyl” group are replaced by
one “C -Cheterocycloalkyl” group. Such radical thus form a gem-
disubstituted “C -C heterocycloalkylC -Calkyl” system, such as a 1,2-
z k x y
dimethyl-pyrrolidinyl radical.
The term “C -C heterocycloalkylC -C cycloalkyl” refers to the above
z k z k
“C -C cycloalkyl” group wherein one or more hydrogen atoms are replaced by
one or more “C -C heterocycloalkyl” groups.
The expression “(C -C)cycloalkylcarbonyl” refers to
(C -C )cycloalkyl-CO- groups wherein the group “(C -C )cycloalkyl” has the
z k z k
meaning above defined.
The expression “(C -C)heterocycloalkylcarbonyl” refers to
(C -C)heterocycloalkyl-CO- groups wherein the group
“(C -C )heterocycloalkyl” has the meaning above defined.
Compounds of the invention may exist in one or more geometrical,
optical, enantiomeric, diastereomeric and tautomeric forms, including but not
limited to cis- and trans-forms, E- and Z-forms, R-, S- and meso-forms, keto-,
and enol-forms. Unless otherwise stated a reference to a particular compound
includes all such isomeric forms, including racemic and other mixtures
thereof. Where appropriate such isomers can be separated from their mixtures
by the application or adaptation of known methods (e.g. chromatographic
techniques and recrystallisation techniques). Where appropriate such isomers
may be prepared by the application of adaptation of known methods (e.g.
asymmetric synthesis).
Throughout the specification the use of an asterisk “*” in the definition
of a structural formula, indicates the point of attachment for the radical group
to the rest of the molecule.
As used herein the term “salt” includes base addition, acid addition and
ammonium salts. As briefly mentioned above compounds of the invention
which are acidic can form salts, including pharmaceutically acceptable salts,
with bases such as alkaline metal hydroxides, e.g. sodium and potassium
hydroxides; alkaline earth metal hydroxides e.g. calcium, barium and
magnesium hydroxides; with organic bases e.g. N-methyl-D-glucamine,
choline tris(hydroxymethyl)amino-methane, L-arginine, L-lysine, N-ethyl
piperidine, dibenzylamine and the like. Those compounds of the invention
which are basic can form salts, including pharmaceutically acceptable salts
with inorganic acids, e.g. with hydrohalic acids such as hydrochloric or
hydrobromic acids, sulphuric acid, nitric acid or phosphoric acid and the like,
and with organic acids e.g. with acetic, formic, trifluoroacetic, tartaric,
succinic, fumaric, maleic, malic, salicylic, citric, methanesulphonic,
p-toluenesulphonic, benzoic, benzenesulfonic, glutamic, lactic, and mandelic
acids and the like. Those compounds (I) which have a basic nitrogen can also
form quaternary ammonium salts with a pharmaceutically acceptable counter-
ion such as ammonium, chloride, bromide, acetate, formate,
p-toluenesulfonate, succinate, hemi-succinate, naphthalene-bis sulfonate,
methanesulfonate, trifluoroacetate, xinafoate, and the like. For a review on
salts, see Handbook of Pharmaceutical Salts: Properties, Selection, and Use by
Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).
It is expected that compounds of the invention may be prepared in the
form of hydrates, and solvates. Any reference herein, including the claims
herein, to “compounds with which the invention is concerned” or “compounds
of the invention” or “the present compounds”, and the like, includes reference
to salts hydrates, and solvates of such compounds. The term ‘solvate’ is used
herein to describe a molecular complex comprising the compound of the
invention and a stoichiometric amount of one or more pharmaceutically
acceptable solvent molecules, for example, ethanol. The term ‘hydrate’ is
employed when said solvent is water.
Individual compounds of the invention may exist in several
polymorphic forms and may be obtained in different crystal or co-crystal
habits, and they are intended to be included within the meaning of the term
“compounds of the invention”.
The compounds may also be administered in the form of prodrugs
thereof. Thus certain derivatives of the compounds which may be active in
their own right or may have little or no pharmacological activity themselves
can, when administered into or onto the body, be converted into compounds of
the invention having the desired activity, for example, by hydrolytic cleavage.
Such derivatives are referred to as ‘prodrugs’. Further information on the use
of prodrugs may be found in Pro-drugs as Novel Delivery Systems, Vol. 14,
ACS Symposium Series (T. Higuchi and V.J. Stella) and Bioreversible
Carriers in Drug Design, Pergamon Press, 1987 (ed. E. B. Roche, American
Pharmaceutical Association; C.S. Larsen and J. Østergaard, Design and
application of prodrugs, In Textbook of Drug Design and Discovery, 3
Edition, 2002, Taylor and Francis).
Prodrugs can, for example, be produced by replacing appropriate
functionalities present in the compounds of formula (I) with certain moieties
known to those skilled in the art as
‘pro-moieties’ as described, for example, in Design of Prodrugs by H.
Bundgaard (Elsevier, 1985). Such examples could be a prodrug of a carboxyl
group (such as –CO-O-CH -O-CO-tBu as used in the pivampicillin prodrug of
ampicillin), an amide (-CO-NH-CH -NAlk ) or an amidine (–C(=N-O-CH )-
2 2 3
NH ).
Embodiments of the Invention or as described
It is to be understood that all preferred groups or embodiments
described herebelow for compounds of formula (I) may be combined among
each other and apply as well to compounds of formula (Ia), (Ib), (Ic), (IA),
(IB), (IC), (ID), (IE) or (IF) as below defined mutatis mutandis.
In one embodiment, compounds of formula (Ia) are provided, which are
compounds of formula (I) as above defined wherein carbon stereogenic center
on the cycloalkylene portion of ring A which is linked to group W and
identified with number (1) herebelow, possess the absolute configuration
herebelow represented:
N W A
(Ia)
In another embodiment, compounds of formula (Ib) are provided, which
are compounds of formula (I) as above defined wherein carbon stereogenic
center on the cycloalkylene portion of ring A which are linked to group W and
Y and identified, respectively, with numbers (1) and (2) herebelow, possess
the absolute configuration herebelow represented:
2 (2)
(Ib)
In a further embodiment, compound of formula (Ic) are provided, which
are compounds of formula (I) as above defined wherein carbon stereogenic
center on the cycloalkylene portion of ring A which are linked to group W and
Y and identified, respectively, with numbers (1) and (2) herebelow, possess
the absolute configuration herebelow represented:
2 (2)
N W A
(Ic)
In one embodiment, W is NH or O. In a further embodiment, W is NH.
In one embodiment, Y is a group -S(O) -, a group -O(CR R ) -, a group
6 7
-(CR R ) -, or a group -NR -; p is zero and n is 0, 1 or 2. In another
embodiment, Y is a group -S(O) - or a group -O(CR R ) or; p is zero and n is
0 or 1.
In a further embodiment, Y is a group -O(CR R ) - and n is 0.
3 4 5 6
In one embodiment, R , R , R and R are each independently hydrogen,
3 4 5 6
fluorine or C -C alkyl. In another embodiment, R , R , R and R are
hydrogen.
In one embodiment, R is hydrogen, C -C alkyl, or C -C cycloalkyl.
1 6 3 7
In one embodiment, R is hydrogen.
In one embodiment, A is a divalent cycloalkylene radical having 5 or 6
ring atoms; said cycloalkylene ring being attached to W and Y, and fused to a
phenyl ring or to a monocyclic heteroaryl ring having 5 or 6 ring atoms, such
phenyl or heteroaryl ring being optionally substituted by one or two groups
In a further embodiment, A is group selected in the group consisting of:
* * *
24 24
24 N
24 24
24 R N
R R 24
In a still further embodiment, A is group:
24 24
In an additional embodiment, A is group:
In one embodiment, R is not present or, if present, is at each
occurrence independently selected from the group consisting of: C -C alkyl,
-F, -Cl and cyano; in a further embodiment, R is not present or, if present, is
at each occurrence independently Methyl or -F. In a further embodiment, R
is not present.
In one embodiment, R is a group of formula (IIa):
(IIa)
In a further embodiment, R is a group of formula (IIa):
(IIa)
and R and R form together with the nitrogen atom to which they are
attached a 5 membered saturated monocyclic or a fused or spiro bicyclic
ring system optionally containing a further heteroatom which is oxygen or
nitrogen, said nitrogen atom being optionally substituted by C -C alkyl;
wherein such C -C alkyl groups may be optionally substituted by a group C -
1 6 1
C alkyl, C -C cycloalkyl, hydroxyl or halo.
6 3 6
In an additional embodiment, R is a group of formula (IIa):
(IIa)
and R and R form together with the nitrogen atom to which they are
attached a 5 to 7- membered saturated monocyclic ring system optionally
containing a further heteroatom which is oxygen or nitrogen, said nitrogen
atom being optionally substituted by C -C alkyl. In a still further
embodiment, such saturated monocyclic ring system is a morpholine ring.
In another embodiment, R is a group of formula (IIb):
1 10
(IIb)
In one embodiment, X is a group -(CH)- or a nitrogen atom. In another
embodiment, X is a group -(CH)-.
In one embodiment, R is selected from a group consisting of: -CN,
A B C C
-C(O)N(R R ), and - N(R )C(O)R .
In one embodiment, R is hydrogen, C -C alkyl, or halogen.
In a further embodiment, R is a group of formula (IIb):
1 10
(IIb)
1 10
Wherein X is a group -(CH)-, R is selected from a group consisting
A B C C 12
of:-CN, -C(O)N(R R ), and - N(R )C(O)R ; and R is hydrogen.
In a further embodiment, R is a group of formula (IIc):
(IIc)
In one embodiment, the group (IIc) is a group of formula (IIca) or (IIcb)
which is connected to the group Y through one of the carbons as below
indicated:
(IIcb)
(IIca)
In another embodiment, the group (IIc) is a group of formula (IIca) as
above defined which is connected to the group Y through the carbon adjacent
to X
(IIca)
In one embodiment, X is a carbon atom.
In one embodiment, X is a nitrogen atom.
4 5 3
In another embodiment, X is a carbon atom, X is a nitrogen atom, X
is a nitrogen atom and X is nitrogen.
4 5 3
In another embodiment, X is a carbon atom, X is a nitrogen atom, X
is a nitrogen atom and X is group -CH-.
In another embodiment, X is a nitrogen atom, X is a group
–CH- atom, X is a carbon atom and X is group -CH-.
In one embodiment, R is hydrogen, C C alkyl, or halogen.
1- 6
In a further embodiment, the group (IIc) is a group of formula (IIca) as
above defined which is connected to the group Y through the carbon adjacent
to X
(IIca)
4 5 3
And wherein X is a carbon atom, X is a nitrogen atom, X is a
2 13
nitrogen atom and X is a group -CH-, and R is hydrogen.
11 A B
In one embodiment, R is selected from a group consisting of: -NR R ,
(C5-C7heterocycloalkyl)-(C1-C6alkyl), -(C3-C7heterocycloalkyl), wherein any
of such (C -C heterocycloalkyl)-(C -C alkyl) or -(C -C heterocycloalkyl) may
7 1 6 3 7
be optionally substituted by a group C -C alkyl, C -C cycloalkyl, hydroxyl
1 6 3 7
or halo.
In another embodiment, R is selected from a group consisting of:
A B A B
-NR R, -(C -C alkylene)-NR R, (C -C heterocycloalkyl)-(C -C alkyl),
1 6 5 7 1 6
-(C3-C7heterocycloalkyl), wherein any of such (C5-C7heterocycloalkyl)-(C1-
C alkyl) or -(C -C heterocycloalkyl) may be optionally substituted by one,
6 3 7
two or three groups R which are independently selected in the list consisting
of: C1-C6 alkyl, (C1-C3) haloalkyl, (C1-C4)hydroxyalkyl, C3-C7 cycloalkyl,
hydroxyl and halo.
In another embodiment, R is Phenyl or 5- or 6-membered monocyclic
heteroaryl which is substituted by a group selected from:
(C -C heterocycloalkyl)-(C -C alkyl), -(C -C heterocycloalkyl), wherein any
7 1 6 3 7
of such (C -C heterocycloalkyl)-(C -C alkyl) or -(C -C heterocycloalkyl) may
7 1 6 3 7
be optionally substituted by a group C1-C6 alkyl, C3-C7 cycloalkyl, hydroxyl
or halo.
In another embodiment, R is Phenyl or 5- or 6-membered monocyclic
heteroaryl which is substituted by (C -C heterocycloalkyl)-(C -C alkyl) or
7 1 6
-(C -C heterocycloalkyl), wherein any (C -C heterocycloalkyl)-(C -C alkyl),
3 7 5 7 1 6
-(C -C heterocycloalkyl), may be optionally substituted by one, two or three
groups R which are independently selected in the list consisting of: C -C
alkyl, (C -C ) haloalkyl, (C -C )hydroxyalkyl, C -C cycloalkyl, hydroxyl and
1 3 1 4 3 7
halo.
In one embodiment, R is one, two or three groups independently
selected in the list consisting of: C -C alkyl, (C -C ) haloalkyl, (C -
1 6 1 3 1
C )hydroxyalkyl, C -C cycloalkyl, hydroxyl and halo.
4 3 7
In one embodiment, R and R are at each occurrence independently
hydrogen, C -C alkyl or C -C cycloalkyl, such C -C alkyl and C -C
1 6 3 7 1 6 3 7
cycloalkyl being optionally substituted by a group C -C alkyl, C -
1 3 3
C cycloalkyl, OR , CN or halo.
In another embodiment, R and R form together with the nitrogen
atom to which they are attached a 5 membered saturated monocyclic or
bicyclic heterocyclic ring system which is optionally substituted by one or
more group -OR , CN, halo, C -C alkyl or C -C cycloalkyl, such C -C alkyl
1 6 3 7 1 6
and C -C cycloalkyl being optionally substituted by a group C -C alkyl, C -
3 7 1 3 3
C cycloalkyl, -OR , -CN or halo.
In a still further embodiment, R and R form together with the
nitrogen atom to which they are attached a 5 membered saturated
monocyclic or bicyclic heterocyclic ring system which is optionally
substituted by one or more group -OR , -CN, halo, C -C alkyl or C -C
1 6 3 7
cycloalkyl, such C -C alkyl and C -C cycloalkyl being optionally substituted
1 6 3 7
by a group C -C alkyl, C -C cycloalkyl, -OR , -CN or halo; and which 5
1 3 3 7
membered saturated monocyclic or bicyclic heterocyclic ring contains a
further heteroatom which is oxygen or nitrogen, said nitrogen atom optionally
substituted by C -C alkyl or C -C cycloalkyl, wherein any of such C -C
1 6 3 6 1 6
alkyl or C -C cycloalkyl may be optionally substituted by a group C -C
3 6 1 6
alkyl, C -C cycloalkyl, OR , CN, or halo.
In one embodiment, R is a group:
Wherein R is optionally present and represents one, two. or three
substituents independently selected in the list consisting of: C -C alkyl, (C -
1 6 1
C ) haloalkyl, (C -C )hydroxyalkyl, C -C cycloalkyl, hydroxyl and halo; and
3 1 4 3 7
wherein the asterisk represents the point of attachment for group R to the
rest of the molecule via X .
In further embodiment, R is a group:
Wherein R represents one or two C -C alkyl substituents; and
wherein the asterisk represents the point of attachment for group R to the
rest of the molecule via X .
In one embodiment, R is a group:
Wherein R is optionally present and represents one, two or three
substituents independently selected in the list consisting of: C -C alkyl, (C -
1 6 1
C ) haloalkyl, (C -C )hydroxyalkyl, C -C cycloalkyl, hydroxyl and halo; and
3 1 4 3 7
wherein the asterisk represents the point of attachment for group R to the
rest of the molecule via X .
In a further embodiment, R is a group:
Wherein R represents one, two or three substituents independently
selected in the list consisting of: C -C alkyl, (C -C ) haloalkyl, (C -
1 6 1 3 1
C )hydroxyalkyl, C -C cycloalkyl, hydroxyl and halo; and wherein the
4 3 7
asterisk represents the point of attachment for group R to the rest of the
molecule via X .
In a further embodiment, R is a group:
Wherein R represents one or two C -C alkyl substituents; and
wherein the asterisk represents the point of attachment for group R to the
rest of the molecule via X .
In a further embodiment, R is a group:
wherein the asterisk represents the point of attachment for group R to
the rest of the molecule via X .
In a further embodiment, R is a group:
wherein the asterisk represents the point of attachment for group R to
the rest of the molecule via X .
In a still further embodiment, R is a group:
wherein the asterisk represents the point of attachment for group R to
the rest of the molecule via X .
In one embodiment, R is a radical of formula (IIIa):
14 15
(IIIa)
In one embodiment, R is selected in the group consisting of: -CH ,
-CH OH, or -CH SCH ; in another embodiment, R is -CH .
2 2 3 3
16
In one embodiment, R and R are independently -CH or -C H ; in
3 2 5
16
another embodiment, R and R are -CH .
In another embodiment, R is a radical of formula (IIIa):
14 15
(IIIa)
14 15 16
R is -CH , and R and R are -CH .
In another embodiment, R is a radical of formula (IIIb):
(IIIb)
In one embodiment, R is selected from the group consisting of: lone
electron pair, hydrogen, -CF, -NR R, -(C -C cycloalkyl),
3 3 6
-(C Cheterocycloalkyl), aryl or heteroaryl wherein any of such -(C -
4- 6 3
C cycloalkyl), -(C C heterocycloalkyl), aryl or heteroaryl may be optionally
6 4- 6
substituted by a group methyl, isopropyl or halo. In another embodiment, R
is selected from the group consisting of: lone electron pair, hydrogen, -CF ,
morpholine, cyclohexyl, phenyl or pyridyl.
In another embodiment, R is a group of general formula (IV)
(IV)
In one embodiment, R is selected in the group consisting of: F, -CH ;
-CH OH, -CH OMe, -CH SCH ; in another embodiment, R is selected in the
2 2 2 3
group consisting of: -CH ; -CH OH, -CH OMe. In another embodiment, R is
3 2 2
In one embodiment, R is -CH .
21
In another embodiment, R and R as defined above may form
together with the carbon atom to which they are attached a cyclohexane or
21
cyclopropyl ring; in a further embodiment, R and R as defined above may
form together with the carbon atom to which they are attached a cyclopropyl
ring.
In one embodiment, R is phenyl or heteroaryl which is optionally
substituted by a group -CN, -OH, halo, -COOR , C -C alkyl, C -C cycloalkyl,
1 6 3 6
-O-(C -C alkyl), -O-(C -C cycloalkyl), -S-(C -C alkyl), -S-(C -C cycloalkyl),
1 6 3 6 1 6 3 6
H J L H J L H J
-NR R, -N(R )(C -C alkylene)-NR R, -N(R )(C -C cycloalkylene)-NR R ,
2 6 3 7
H J H J
-(C -C alkylene)-NR R, -(C -C cycloalkylene)-NR R, -O-(C -C alkylene)-
1 6 3 7 2 6
H J H J H J
NR R , -O-(C -C cycloalkylene)-NR R , -S-(C -C alkylene)-NR R , -S-(C -
3 7 2 6 3
H J L H J L
C cycloalkylene)-NR R, -N(R )C(O)-(C -C alkylene)-NR R, -N(R )C(O)-
7 1 6
H J L H J
(C -C cycloalkylene)-NR R, -C(O)N(R )-(C -C alkylene)-NR R ,
3 7 2 6
L H J L M
-C(O)N(R )-(C -C cycloalkylene)-NR R , -C(O)N(R )-(C -C alkylene)-OR ,
3 7 2 6
L M L H J H J
-C(O)N(R )-(C -C cycloalkylene)-OR , -N(R )C(O)N(R R ), -C(O)N(R R ),
L L H J L L
-N(R )C(O)N(R )-(C -C alkylene)-NR R, -N(R )C(O)N(R )-(C -
2 6 3
H J M
C cycloalkylene)-NR R , -O-(C -C alkylene)-OR , -O-(C -C cycloalkylene)-
7 2 6 3 7
M M M L
OR , -S-(C -C alkylene)-OR , -S-(C -C cycloalkylene)-OR , -N(R )S(O) -
2 6 3 7 2
H J L H J
(C -C alkylene)-NR R, -N(R )S(O) -(C -C cycloalkylene)-NR R ,
1 6 2 3 7
L H J L
-S(O) N(R )-(C -C alkylene)-NR R, -S(O) N(R )-(C -C cycloalkylene)-
2 2 6 2 3 7
H J L M L
NR R, -S(O) N(R )-(C -C alkylene)-OR, -S(O) N(R )-(C -
2 2 6 2 3
M L M L
C cycloalkylene)-OR , -N(R )S(O) -(C -C alkylene)-OR , -N(R )S(O) -(C -
7 2 2 6 2 3
M H J L L L L L
C cycloalkylene)-OR , -S(O) N(R R ), -N(R )S(O) R , -N(R )C(O)R , OR ,
7 2 2
SR , -(C Cheterocycloalkyl), (C C heterocycloalkyl)-(C C alkyl), and
3- 7 5- 7 1- 6
(C C heterocycloalkyl)-(C C cycloalkyl), wherein any of such alkyl,
- 7 3- 6
cycloalkyl, alkylene, cycloalkylene, heterocycloalkyl, heterocycloalkyl-(C C
1- 6
alkyl), heterocycloalkyl)-(C C cycloalkyl) and heterocycloalkylcarbonyl may
3- 6
be optionally substituted by a group C -C alkyl, C -C cycloalkyl, -OR or
1 6 3 7
halo. In a further embodiment, R is phenyl substituted by -(C -C alkyl).
In one embodiment, R is -(C -C alkyl) or -(C -C cycloalkyl).
1 6 3 7
1 2 3 4
In one embodiment, z = -CH-, z = C, z and z are N; in another
1 2 3 4 1
embodiment, z = O, z = C, z and z are N; in a further embodiment, z =
2 3 4 1 2
-CH-, z and z are N and z is -CH-; in an additional embodiment, z = N, z
3 4 1 2 3
is C, z is N and z is O; in a still further embodiment, z = N, z is C, z is O
and z is N.
In an additional embodiment, R is a radical of formula (IIIb):
(IIIb)
;
1 2 3 4 18
Wherein z = -CH-, z = C, z is oxygen, z is N, R is a lone pair, and
R is a group of general formula (IV)
(IV)
21
Wherein R is -CH or -CH OH, and R is -CH
3 2 3.
In a further embodiment, R is a radical of formula (IIIb):
(IIIb)
1 2 3 4 17
Wherein z = -CH-, z = C, z and z are N and R is a group of general
formula (IV)
(IV)
21
Wherein R is -CH or -CH OH, and R is -CH
3 2 3.
In another embodiment, R is a radical of formula (IIIb):
(IIIb)
;
1 2 3 4 17
Wherein z = -CH-, z = C, z and z are N and R is a group of general
formula (IV)
(IV)
21 18
Wherein R is -CH or -CH OH, and R is -CH and wherein R is
3 2 3
phenyl, which may be optionally substituted by a group -CN, -OH,
M L H J
-COOR, C -Calkyl, -N(R )(C -C alkylene)-NR R, -(C -C alkylene)-
1 6 2 6 1 6
H J H J M
NR R, -O-(C -C alkylene)-NR R, -O-(C -C alkylene)-OR, -S-(C -
2 6 2 6 2
C alkylene)-OR, (C -C heterocycloalkyl)-(C -C alkyl), and (C -C
6 5 7 1 6 5 7
heterocycloalkyl)-(C -C cycloalkyl), wherein any of such C -C alkyl, -(C -
3 6 1 6 1
C alkylene)-, -(C -C alkylene)-, (C -C heterocycloalkyl)-(C -C alkyl) and
6 2 6 5 7 1 6
(C -C heterocycloalkyl)-(C -C cycloalkyl) may be optionally substituted by a
7 3 6
group C -C alkyl, C -C cycloalkyl, OR or halo.
1 6 3 7
In a further embodiment, R is a radical of formula (IIIb):
(IIIb)
1 2 3 4 17
Wherein z = -CH-, z = C, z and z are N and R is a group of general
formula (IV)
(IV)
21 18
Wherein R is -CH or -CH OH, and R is -CH and R is phenyl,
3 2 3
which is substituted in the para position by a group C -C alkyl.
In an additional embodiment, R is a radical of formula (IIIb):
(IIIb)
1 2 3 4 17
Wherein z = -CH-, z = C, z and z are N and R is a group of general
formula (IV)
(IV)
21 18
Wherein R is -CH or -CH OH, and R is -CH and R is phenyl,
3 2 3
which is substituted in the meta position by a group -O-(C -C alkylene)-
H J H J
NR R or -(C -C alkylene)-NR R .
In another embodiment, R is a radical of formula (IIIb):
(IIIb)
1 2 3 4 17
Wherein z = -CH-, z = C, z and z are N and R is a group of general
formula (IV)
(IV)
21 18
Wherein R is -CH or -CH OH, and R is -CH and R is a 5 or 6-
3 2 3
membered heteroaryl which is optionally substituted by C -Calkyl, -
L H J H J
N(R )(C -C alkylene)-NR R, or -(C -C alkylene)-NR R, wherein any of
2 6 1 6
such C -Calkyl, -(C -Calkylene)-, -(C -Calkylene)-, (C -
1 6 1 6 2 6 5
C heterocycloalkyl)-(C -C alkyl) and (C -C heterocycloalkyl)-(C -C
7 1 6 5 7 3 6
cycloalkyl) may be optionally substituted by a group C -C alkyl, C -C
1 6 3 7
L 18
cycloalkyl, OR or halo. In one embodiment, for such compounds, R is an
imidazole ring which is optionally substituted by C -C alkyl, -N(R )(C -
1 6 2
H J H J
C alkylene)-NR R , or -(C -C alkylene)-NR R .
6 1 6
In another embodiment, R is a radical of formula (IIIb):
(IIIb)
1 2 3 4 17
Wherein z = -CH-, z = C, z and z are N and R is a group of general
formula (IV)
(IV)
21 18
Wherein R is -CH or -CH OH, and R is -CH and R is a group -
3 2 3
(C -C alkyl), optionally substituted by a group –OH or -NR R , or a group
(C -C heterocycloalkyl)-(C -C alkyl) which may be optionally substituted by
7 1 6
a group C -C alkyl.
In a further embodiment, R is a radical of formula (IIIc):
(IIIc)
In one embodiment, R is selected from the group consisting of:
hydrogen, -CF , -NR R , -(C -C cycloalkyl), -(C C heterocycloalkyl), aryl or
3 3 6 3- 6
heteroaryl wherein any of such cycloalkyl, heterocycloalkyl, aryl or heteroaryl
may be optionally substituted by a group C -C alkyl, C -C cycloalkyl, or
1 2 3 5
halo. In another embodiment, R is selected from the group consisting of:
hydrogen, -CF , morpholine, cyclohexyl, phenyl or pyridyl wherein any of
such morpholine, cyclohexyl, phenyl or pyridyl may be optionally substituted
by a group methyl, -F or -Cl.
In another embodiment, R is a group of general formula (V)
.
In one embodiment, T is -N=. In another embodiment, T is -CR =.
In one embodiment, R is H, F, -Cl, -CH , or -CN; in another
embodiment, R is H or F.
In one embodiment, R is H, F, -Cl, -CH , or -CN; in another
embodiment, R is -Cl.
In another embodiment, R is a radical of formula (IIIc):
(IIIc)
Wherein R is -(C C heterocycloalkyl), which is optionally substituted
3- 6
23 22
by a group C -C alkyl, C -C cycloalkyl, or halo; wherein T is -CR =, R is
1 2 3 5
H or F.
In a still further embodiment, R is a radical of formula (IIId):
(IIId)
In one embodiment, q is 0, 1 or 2; in another embodiment, q is 0 or 1. In
a further embodiment, q is zero.
In one embodiment, compounds of formula (IA) are provided wherein
W is NH, Y is a group -O(CR R )n- and n is 0, A is group:
Wherein R is a group of formula (IIca) as above defined which is
connected to the group Y through the carbon adjacent to X
(IIca)
4 5 3
And wherein X is a carbon atom, X is a nitrogen atom, X is a
2 13
nitrogen atom and X is a group -CH-, and R is hydrogen;
Wherein R is a group:
Wherein R is optionally present and represents one, two or three
substituents independently selected in the list consisting of: C -C alkyl, (C -
1 6 1
C ) haloalkyl, (C -C )hydroxyalkyl, C -C cycloalkyl, hydroxyl and halo; and
3 1 4 3 7
wherein the asterisk represents the point of attachment for group R to the
rest of the molecule via X ;
Wherein R is a radical of formula (IIIb):
(IIIb)
1 2 3 4 17
Wherein z = -CH-, z = C, z and z are N and R is a group of general
formula (IV)
(IV)
21 18
Wherein R is -CH or -CH OH, and R is -CH and wherein R is
3 2 3
phenyl, which may be optionally substituted by a group -CN, -OH,
M L H J
-COOR, C -Calkyl, -N(R )(C -C alkylene)-NR R, -(C -C alkylene)-
1 6 2 6 1 6
H J H J M
NR R, -O-(C -C alkylene)-NR R, -O-(C -C alkylene)-OR, -S-(C -
2 6 2 6 2
C alkylene)-OR, (C -C heterocycloalkyl)-(C -C alkyl), and (C -C
6 5 7 1 6 5 7
heterocycloalkyl)-(C -C cycloalkyl), wherein any of such C -C alkyl, -(C -
3 6 1 6 1
C alkylene)-, -(C -C alkylene)-, (C -C heterocycloalkyl)-(C -C alkyl) and
6 2 6 5 7 1 6
(C -C heterocycloalkyl)-(C -C cycloalkyl) may be optionally substituted by a
7 3 6
group C -C alkyl, C -C cycloalkyl, OR or halo.
1 6 3 7
In one embodiment, compounds of formula (IB) are provided wherein
W is NH, Y is a group -O(CR R ) - and n is 0, A is group:
Wherein R is a group of formula (IIca) as above defined which is
connected to the group Y through the carbon adjacent to X
(IIca)
4 5 3
And wherein X is a carbon atom, X is a nitrogen atom, X is a
2 13
nitrogen atom and X is a group -CH-, and R is hydrogen;
Wherein R is a group:
Wherein R is optionally present and represents one, two or three
substituents independently selected in the list consisting of: C -C alkyl, (C -
1 6 1
C ) haloalkyl, (C -C )hydroxyalkyl, C -C cycloalkyl, hydroxyl and halo; and
3 1 4 3 7
wherein the asterisk represents the point of attachment for group R to the
rest of the molecule via X
wherein R is a radical of formula (IIIb):
(IIIb)
1 2 3 4 17
Wherein z = -CH-, z = C, z and z are N and R is a group of general
formula (IV)
(IV)
21 18
Wherein R is -CH or -CH OH, and R is -CH and wherein R is
3 2 3
phenyl, which may be optionally substituted by a group -CN, -OH,
M L H J
-COOR, C -Calkyl, -N(R )(C -C alkylene)-NR R, -(C -C alkylene)-
1 6 2 6 1 6
H J H J M
NR R, -O-(C -C alkylene)-NR R, -O-(C -C alkylene)-OR, -S-(C -
2 6 2 6 2
C alkylene)-OR, (C -C heterocycloalkyl)-(C -C alkyl), and (C -C
6 5 7 1 6 5 7
heterocycloalkyl)-(C -C cycloalkyl), wherein any of such wherein any of such
C -C alkyl, -(C -C alkylene)-, -(C -C alkylene)-, (C -C heterocycloalkyl)-(C -
1 6 1 6 2 6 5 7 1
C alkyl) and (C -C heterocycloalkyl)-(C -C cycloalkyl) may be optionally
6 5 7 3 6
substituted by a group C -C alkyl, C -C cycloalkyl, OR or halo.
1 6 3 7
In one embodiment, compounds of formula (IC) are provided wherein
W is NH, Y is a group -O(CR R ) - and n is 0, A is group:
Wherein R is a group of formula (IIca) as above defined which is
connected to the group Y through the carbon adjacent to X
(IIca)
4 5 3
And wherein X is a carbon atom, X is a nitrogen atom, X is a
2 13
nitrogen atom and X is a group -CH-, and R is hydrogen;
R is a group:
Wherein R is optionally present and represents one, two or three
substituents independently selected in the list consisting of: C -C alkyl, (C -
1 6 1
C ) haloalkyl, (C -C )hydroxyalkyl, C -C cycloalkyl, hydroxyl and halo; and
3 1 4 3 7
wherein the asterisk represents the point of attachment for group R to the
rest of the molecule via X ;
R is a radical of formula (IIIb):
(IIIb)
1 2 3 4 17
Wherein z = -CH-, z = C, z and z are N and R is a group of general
formula (IV)
(IV)
21 18
Wherein R is -CH or -CH OH, and R is -CH and R is a 5 or 6-
3 2 3
membered heteroaryl, which is optionally substituted by C -C alkyl, -
L H J H J
N(R )(C -C alkylene)-NR R, or -(C -C alkylene)-NR R, wherein any of
2 6 1 6
such C -Calkyl, -(C -Calkylene)-, -(C -Calkylene)-, (C -
1 6 1 6 2 6 5
C heterocycloalkyl)-(C -C alkyl) and (C -C heterocycloalkyl)-(C -C
7 1 6 5 7 3 6
cycloalkyl) may be optionally substituted by a group C -C alkyl, C -C
1 6 3 7
cycloalkyl, OR or halo.
In one embodiment, compounds of formula (ID) are provided wherein
W is NH, Y is a group -O(CR R ) - and n is 0, A is group:
24 24
R1 is a group of formula (IIca) as above defined which is connected to
the group Y through the carbon adjacent to X
(IIca)
4 5 3
And wherein X is a carbon atom, X is a nitrogen atom, X is a
2 13
nitrogen atom and X is a group -CH-, and R is hydrogen;
Wherein R is a group:
Wherein R is optionally present and represents one two or three
substituents independently selected in the list consisting of: C -C alkyl, (C -
1 6 1
C ) haloalkyl, (C -C )hydroxyalkyl, C -C cycloalkyl, hydroxyl and halo; and
3 1 4 3 7
wherein the asterisk represents the point of attachment for group R to the
rest of the molecule via X ;
Wherein R is a radical of formula (IIIb):
(IIIb)
1 2 3 4 17
Wherein z = -CH-, z = C, z and z are N and R is a group of general
formula (IV)
(IV)
21 18
Wherein R is -CH or -CH OH, and R is -CH and R is a 5 or 6-
3 2 3
membered heteroaryl, which is optionally substituted by C -C alkyl, -
L H J H J
N(R )(C -C alkylene)-NR R, or -(C -C alkylene)-NR R, wherein any of
2 6 1 6
such C -Calkyl, -(C -Calkylene)-, -(C -Calkylene)-, (C -
1 6 1 6 2 6 5
C heterocycloalkyl)-(C -C alkyl) and (C -C heterocycloalkyl)-(C -C
7 1 6 5 7 3 6
cycloalkyl) may be optionally substituted by a group C -C alkyl, C -C
1 6 3 7
cycloalkyl, OR or halo.
In one embodiment, compounds of formula (IE) are provided wherein
W is NH, Y is a group -O(CR R ) - and n is 0, A is group:
24 24
Wherein R1 is a group of formula (IIca) as above defined which is
connected to the group Y through the carbon adjacent to X
(IIca)
4 5 3
And wherein X is a carbon atom, X is a nitrogen atom, X is a
2 13
nitrogen atom and X is a group -CH-, and R is hydrogen;
wherein R is a group:
Wherein R is optionally present and represents one two or three
substituents independently selected in the list consisting of: C -C alkyl, (C -
1 6 1
C ) haloalkyl, (C -C )hydroxyalkyl, C -C cycloalkyl, hydroxyl and halo; and
3 1 4 3 7
wherein the asterisk represents the point of attachment for group R to the
rest of the molecule via X ;
Wherein R is a radical of formula (IIIb):
(IIIb)
1 2 3 4 17
Wherein z = -CH-, z = C, z and z are N and R is a group of general
formula (IV)
(IV)
21 18
Wherein R is -CH or -CH OH, and R is -CH and R is a group -
3 2 3
(C -C alkyl), optionally substituted by a group –OH or -NR R , or a group
(C -C heterocycloalkyl)-(C -C alkyl) which may be optionally substituted by
7 1 6
a group C -C alkyl.
In one embodiment, compounds of formula (IF) are provided wherein
W is NH, Y is a group -O(CR R ) - and n is 0, A is group:
Wherein R is a group of formula (IIca) as above defined which is
connected to the group Y through the carbon adjacent to X
(IIca)
4 5 3
And wherein X is a carbon atom, X is a nitrogen atom, X is a
2 13
nitrogen atom and X is a group -CH-, and R is hydrogen;
Wherein R is a group:
Wherein R is optionally present and represents one two or three
substituents independently selected in the list consisting of: C -C alkyl, (C -
1 6 1
C ) haloalkyl, (C -C )hydroxyalkyl, C -C cycloalkyl, hydroxyl and halo; and
3 1 4 3 7
wherein the asterisk represents the point of attachment for group R to the
rest of the molecule via X ;
Wherein R is a radical of formula (IIIb):
(IIIb)
1 2 3 4 17
Wherein z = -CH-, z = C, z and z are N and R is a group of general
formula (IV)
(IV)
21 18
Wherein R is -CH or -CH OH, and R is -CH and R is a group -
3 2 3
(C -C alkyl), optionally substituted by a group –OH or -NR R , or a group
(C -C heterocycloalkyl)-(C -C alkyl) which may be optionally substituted by
7 1 6
a group C -C alkyl.
In one embodiment, a compound of formula (I) is selected in the list
consisting of:
1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-(2-
pyrrolidinyl-ethyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-urea;
1-(5-tert-Butylp-tolyl-2H-pyrazolyl)((1S,4R){3-[2-(4-
methyl-piperazinyl)-ethyl]-[1,2,4]triazolo[4,3-a]pyridinyloxy}-1,2,3,4-
tetrahydro-naphthalenyl)-urea;
1-(5-tert-Butylp-tolyl-2H-pyrazolyl)[(1S,4R)(3-piperidin
yl)-[1,2,4]triazolo[4,3-a]pyridinyloxy)-1,2,3,4-tetrahydro-naphthalenyl]-
urea;
1-(5-tert-Butylp-tolyl-2H-pyrazolyl)[(1S,4R)(3-piperidin
yl)-[1,2,4]triazolo[4,3-a]pyridinyloxy)-1,2,3,4-tetrahydro-naphthalenyl]-
urea;
1-(5-tert-Butylp-tolyl-2H-pyrazolyl)[(1S,4R)[3-((S)
methyl-pyrrolidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy)-1,2,3,4-
tetrahydro-naphthalenyl]-urea;
1-(5-tert-Butylp-tolyl-2H-pyrazolyl)[(1S,4R)((S)
pyrrolidinyl-[1,2,4]triazolo[4,3-a]pyridinyloxy)-1,2,3,4-tetrahydro-
naphthalenyl]-urea;
1-(5-tert-Butylp-tolyl-2H-pyrazolyl)[(1S,4R)(3-piperazin
ylmethyl-[1,2,4]triazolo[4,3-a]pyridinyloxy)-1,2,3,4-tetrahydro-naphthalen-
1-yl]-urea;
1-(5-tert-Butylp-tolyl-2H-pyrazolyl)[(1S,4R)(3-
isopropylamino-[1,2,4]triazolo[4,3-a]pyridinyloxy)-1,2,3,4-tetrahydro-
naphthalenyl]-urea;
1-(5-tert-Butylp-tolyl-2H-pyrazolyl)[(1S,4R)(6-cyano-
pyridinyloxy)-1,2,3,4-tetrahydro-naphthalenyl]-urea;
N-(4-{(1S,4S)[3-(5-tert-Butylp-tolyl-2H-pyrazolyl)-ureido]-
1,2,3,4-tetrahydro-naphthalenyloxy}-pyridinyl)methoxy-acetamide;
1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[1-(2-hydroxy-
ethyl)-1H-indazolyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea;
1-(5-tert-Butylp-tolyl-2H-pyrazolyl)[(1S,4R)((R)
pyrrolidinyl-[1,2,4]triazolo[4,3-a]pyridinyloxy)-1,2,3,4-tetrahydro-
naphthalenyl]-urea;
N-(4-{(1R,4S)[3-(5-tert-Butylp-tolyl-2H-pyrazolyl)-ureido]-
1,2,3,4-tetrahydro-naphthalenyloxy}-pyridinyl)methoxy-acetamide;
1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-(4-methyl-
piperazinylmethyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-urea;
1-(5-tert-Butylp-tolyl-2H-pyrazolyl)[(1S,4R)(3-morpholin-
4-ylmethyl-[1,2,4]triazolo[4,3-a]pyridinyloxy)-1,2,3,4-tetrahydro-
naphthalenyl]-urea;
1-(5-tert-Butylp-tolyl-2H-pyrazolyl)[(1S,4R)(3-pyrrolidin-
1-ylmethyl-[1,2,4]triazolo[4,3-a]pyridinyloxy)-1,2,3,4-tetrahydro-
naphthalenyl]-urea;
1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[6-
(morpholinecarbonyl)-pyridinyloxy]-1,2,3,4-tetrahydro-naphthalen
yl}-urea;
1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-(4-
morpholinylmethyl-phenyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl]-urea;
1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-(3-
morpholinylmethyl-phenyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-urea;
1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-(2-
morpholinylmethyl-phenyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-urea;
1-(5-tert-Butylp-tolyl-2H-pyrazolyl)[(1S,4R)(6-morpholin-
4-ylmethyl-pyridinyloxy)-1,2,3,4-tetrahydro-naphthalenyl]-urea;
1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-(1-methyl-
piperidinylmethyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-urea;
1-(5-tert-Butylp-tolyl-2H-pyrazolyl)((1S,4R){3-[1-(2,2-
difluoro-ethyl)-piperidinylmethyl]-[1,2,4]triazolo[4,3-a]pyridinyloxy}-
1,2,3,4-tetrahydro-naphthalenyl)-urea;
1-(5-tert-Butylp-tolyl-2H-pyrazolyl)[(1S,4R)[3-(4-
hydroxypiperidinyl)-[1,2,4]triazolo[4,3-a]pyridineyloxy]-1,2,3,4-
tetrahydro-naphthalenyl]-urea;
1-(5-tert-Butylp-tolyl-2H-pyrazolyl)[(1S,4R){3-[(2-
hydroxy-ethyl)-methyl-amino]-[1,2,4]triazolo[4,3-a]pyridineyloxy]-1,2,3,4-
tetrahydro-naphthalenyl]-urea;
1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-((S)
hydroxy-pyrrolidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-urea;
1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-((S)
hydroxy-pyrrolidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-urea;
1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-((R)
hydroxymethyl-pyrrolidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-urea;
1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-((S)
hydroxymethyl-pyrrolidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-urea;
1-[5-tert-Butyl(3-hydroxymethyl-phenyl)-2H-pyrazolyl]
[(1S,4R)(3-piperidinyl-[1,2,4]triazolo[4,3-a]pyridinyloxy)-1,2,3,4-
tetrahydro-naphthalenyl]-urea;
3-[3-tert-Butyl(3-{(1S,4R)[3-((S)methyl-pyrrolidinyl)-
[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-
ureido)-pyrazolyl]-benzoic acid ethyl ester;
1-[5-tert-Butyl(3-hydroxymethyl-phenyl)-2H-pyrazolyl]
{(1S,4R)[3-((S)methyl-pyrrolidinyl)-[1,2,4]triazolo[4,3-a]pyridin
yloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea;
1-(5-tert-Butylp-tolyl-2H-pyrazolyl)[(1S,4R)(2-morpholin-
4-yl-ethoxy)-1,2,3,4-tetrahydro-naphthalenyl]-urea;
1-[5-tert-Butyl(4-hydroxymethyl-phenyl)-2H-pyrazolyl]
{(1S,4R)[3-((S)methyl-pyrrolidinyl)-[1,2,4]triazolo[4,3-a]pyridin
yloxy]-1,2,3,4-tetrahydro-naphthalenyl}urea;
1-[5-tert-Butyl(4-hydroxymethyl-phenyl)-2H-pyrazolyl]
[(1S,4R)(3-piperidinyl-[1,2,4]triazolo[4,3-a]pyridinyloxy)-1,2,3,4-
tetrahydro-naphthalenyl]-urea;
1-{5-tert-Butyl[3-(2-hydroxy-ethylsulfanyl)-phenyl]-2H-pyrazol
yl}{(1S,4R)[3-((S)methyl-pyrrolidinyl)-[1,2,4]triazolo[4,3-
a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea;
1-[5-(2-Hydroxy-1,1-dimethyl-ethyl)p-tolyl-2H-pyrazolyl]
[(1S,4R)(3-piperidinyl-[1,2,4]triazolo[4,3-a]pyridinyloxy)-1,2,3,4-
tetrahydro-naphthalenyl]-urea;
1-[5-tert-Butyl(4-hydroxymethyl-phenyl)-2H-pyrazolyl]
{(1S,3S)[3-((S)methyl-pyrrolidinyl)-[1,2,4]triazolo[4,3-a]pyridin
yloxy]-indanyl}-urea;
1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-((R)
hydroxy-pyrrolidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-urea;
1-{5-tert-Butyl[3-(2-hydroxy-ethoxy)-phenyl]-2H-pyrazolyl}
[(1S,4R)(3-piperidinyl-[1,2,4]triazolo[4,3-a]pyridinyloxy)-1,2,3,4-
tetrahydro-naphthalenyl]-urea;
1-{5-tert-Butyl[3-(2-dimethylamino-ethoxy)-phenyl]-2H-pyrazol
yl}[(1S,4R)(3-piperidinyl-[1,2,4]triazolo[4,3-a]pyridinyloxy)-
1,2,3,4-tetrahydro-naphthalenyl]-urea;
1-{5-tert-Butyl[3-(4-methyl-piperazinylmethyl)-phenyl]-2H-
pyrazolyl}[(1S,4R)(3-piperidinyl-[1,2,4]triazolo[4,3-a]pyridin
yloxy)-1,2,3,4-tetrahydro-naphthalenyl]-urea;
1-{5-tert-Butyl[3-(2-hydroxy-ethoxy)-phenyl]-2H-pyrazolyl}
{(1S,4R)[3-((S)methyl-pyrrolidinyl)-[1,2,4]triazolo[4,3-a]pyridin
yloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea;
1-(5-tert-Butylp-tolyl-2H-pyrazolyl)((1S,4R){3-[(2-
dimethylamino-ethyl)-methyl-amino]-[1,2,4]triazolo[4,3-a]pyridinyloxy}-
1,2,3,4-tetrahydro-naphthalenyl)-urea;
1-[5-tert-Butyl(3-piperidinylmethyl-phenyl)-2H-pyrazolyl]
[(1S,4R)(3-piperidinyl-[1,2,4]triazolo[4,3-a]pyridinyloxy)-1,2,3,4-
tetrahydro-naphthalenyl]-urea;
1-(5-tert-Butylp-tolyl-2H-pyrazolyl)((1S,4R){3-[methyl-(2-
morpholinyl-ethyl)-amino]-[1,2,4]triazolo[4,3-a]pyridinyloxy}-1,2,3,4-
tetrahydro-naphthalenyl)-urea;
1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-((R)
morpholinyl-ethyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-urea;
1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-((S)
morpholinyl-ethyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-urea;
1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-((S)-1,2-
dimethyl-pyrrolidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-urea;
1-{5-tert-Butyl[3-(2-hydroxy-ethoxymethyl)-phenyl]-2H-pyrazol
yl}[(1S,4R)(3-piperidinyl-[1,2,4]triazolo[4,3-a]pyridinyloxy)-
1,2,3,4-tetrahydro-naphthalenyl]-urea;
1-(5-tert-Butylp-tolyl-2H-pyrazolyl)[(1S,4R)(3-
[1,4]oxazepanyl-[1,2,4]triazolo[4,3-a]pyridinyloxy)-1,2,3,4-tetrahydro-
naphthalenyl]-urea;
1-(5-tert-Butyl{3-[4-(2-hydroxy-ethyl)-piperazinylmethyl]-
phenyl}-2H-pyrazolyl)[(1S,4R)(3-piperidinyl-[1,2,4]triazolo[4,3-
a]pyridinyloxy)-1,2,3,4-tetrahydro-naphthalenyl]-urea;
1-(2-tert-Butylp-tolyl-3H-imidazolyl)[(1S,4R)(3-piperidin-
1-yl-[1,2,4]triazolo[4,3-a]pyridinyloxy)-1,2,3,4-tetrahydro-naphthalen
yl]-urea;
1-{5-tert-Butyl[3-(4-hydroxy-piperidinylmethyl)-phenyl]-2H-
pyrazolyl}[(1S,4R)(3-piperidinyl-[1,2,4]triazolo[4,3-a]pyridin
yloxy)-1,2,3,4-tetrahydro-naphthalenyl]-urea;
1-{5-tert-Butyl[3-(2-hydroxy-ethylsulfanyl)-phenyl]-2H-pyrazol
yl}[(1S,4R)(3-piperidinyl-[1,2,4]triazolo[4,3-a]pyridinyloxy)-
1,2,3,4-tetrahydro-naphthalenyl]-urea;
1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-(4-
hydroxymethyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-urea;
1-(5-tert-Butylp-tolyl-2H-pyrazolyl)[(1S,4S)(3-piperidin
yl-[1,2,4]triazolo[4,3-a]pyridinyloxy)-1,2,3,4-tetrahydro-naphthalenyl]-
urea;
1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-(3-
hydroxymethylmethyl-piperazinylmethyl)-[1,2,4]triazolo[4,3-a]pyridin-
6-yloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea;
1-[5-tert-Butyl(4-hydroxymethyl-phenyl)-2H-pyrazolyl]
{(1S,4R)[3-(4-hydroxy-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridin
yloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea;
1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-((S)
isopropyl-pyrrolidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-urea;
1-(5-tert-Butylp-tolyl-2H-pyrazolyl)[(1S,4R)(3-
dimethylamino-[1,2,4]triazolo[4,3-a]pyridinyloxy)-1,2,3,4-tetrahydro-
naphthalenyl]-urea;
1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-((R)
methyl-pyrrolidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-urea;
1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-((S)
ethyl-pyrrolidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-urea;
1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-((S)
methyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-urea;
1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-((S)
hydroxy-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-urea;
1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-((R)
hydroxy-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-urea;
1-[5-tert-Butyl(4-hydroxymethyl-phenyl)-2H-pyrazolyl]
{(1S,4R)[3-((S)methyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridin
yloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea;
1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-(4-
hydroxyethyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-urea;
1-[(1S,4R)(3-Azepanyl-[1,2,4]triazolo[4,3-a]pyridinyloxy)-
1,2,3,4-tetrahydro-naphthalenyl](5-tert-butylp-tolyl-2H-pyrazol
yl)-urea;
1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-(4-methyl-
piperazineyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-
naphthalenyl}urea;
1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-(4-methyl-
[1,4]diazepanyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-
naphthalenyl}urea;
1-[5-tert-Butyl(4-hydroxy-phenyl)-2H-pyrazolyl][(1S,4R)
(3-piperidinyl-[1,2,4]triazolo[4,3-a]pyridinyloxy)-1,2,3,4-tetrahydro-
naphthalenyl]-urea;
1-[5-tert-Butyl(4-cyano-phenyl)-2H-pyrazolyl][(1S,4R)(3-
piperidinyl-[1,2,4]triazolo[4,3-a]pyridinyloxy)-1,2,3,4-tetrahydro-
naphthalenyl]-urea;
1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4S)[3-((S)
methyl-pyrrolidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-urea;
1-[5-tert-Butyl(4-hydroxy-phenyl)-2H-pyrazolyl]{(1S,4R)
[3-((S)methyl-pyrrolidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-
1,2,3,4-tetrahydro-naphthalenyl}-urea;
1-(5-tert-Butylp-tolyl-2H-pyrazolyl)((1S,4R){3-[4-(1-
hydroxymethyl-ethyl)-piperidinyl]-[1,2,4]triazolo[4,3-a]pyridin
yloxy}-1,2,3,4-tetrahydro-naphthalenyl)-urea;
1-(5-tert-Butylp-tolyl-2H-pyrazolyl)[(1S,4R)(3-pyrrolidin-
1-yl-[1,2,4]triazolo[4,3-a]pyridinyloxy)-1,2,3,4-tetrahydro-naphthalen
yl]-urea;
1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-(1-
dimethylaminomethyl-ethyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-urea;
1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-((R)
hydroxymethyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-urea;
1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-((S)
hydroxymethyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-urea;
1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-(4-hydroxy-
4-methyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-urea;
1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-(1-methyl-
1-pyrrolidinyl-ethyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-urea;
1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-((S)
methyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-urea;
1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-((R)
methyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-urea;
1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-((S)
methyl-morpholinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-urea;
1-(5-tert-Butylp-tolyl-2H-pyrazolyl)((1S,4R){3-[(S)(3-
hydroxy-propyl)-pyrrolidinyl]-[1,2,4]triazolo[4,3-a]pyridinyloxy}-
1,2,3,4-tetrahydro-naphthalenyl)-urea;
1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-((S)
hydroxymethylmethyl-pyrrolidinyl)-[1,2,4]triazolo[4,3-a]pyridin
yloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea;
1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-(1,4-
dimethyl-piperazinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-urea;
1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-((S)-1,4,4-
trimethyl-pyrrolidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-urea;
1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-((S)
methyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-urea;
1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-((R)
methyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-urea;
1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-((R)
methyl-pyrrolidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-urea;
1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-((2S,4R)
fluoromethyl-pyrrolidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-
1,2,3,4-tetrahydro-naphthalenyl}-urea;
1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-((S)
hydroxymethyl-pyrrolidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-urea;
1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-((R)
hydroxymethyl-pyrrolidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-urea;
1-(5-tert-Butylp-tolyl-2H-pyrazolyl)((1S,4R){3-[4-(2-
hydroxy-ethyl)-piperazinyl]-[1,2,4]triazolo[4,3-a]pyridinyloxy}-1,2,3,4-
tetrahydro-naphthalenyl)-urea;
1-{5-tert-Butyl[3-(2-dimethylamino-ethoxy)-phenyl]-2H-pyrazol
yl{(1S,4R)[3-((S)methyl-piperidinyl)-[1,2,4]triazolo[4,3-
a]pyridinyloxy]-1,2,3,4-tetrahydronaphthalenyl]-urea;
1-{5-tert-Butyl[3-(2-dimethylamino-ethoxy)-phenyl]-2H-pyrazol
yl}{(1S,4R)[3-(cis-2,6-dimethyl-piperidinyl)-[1,2,4]triazolo[4,3-
a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea;
1-[5-tert-Butyl(3-morpholinylmethyl-phenyl)-2H-pyrazolyl]
{(1S,4R)[3-((S)methyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridin
yloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea;
1-{5-tert-Butyl[3-(4-methyl-piperazinylmethyl)-phenyl]-2H-
pyrazolyl}{(1S,4R)[3-((S)methyl-piperidinyl)-
[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-
urea;
1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-(1-
dimethylamino-cyclopentyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-urea;
1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-((2S,6R)-
2,6-dimethyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-urea;
1-[(1S,4R)(3-Amino-[1,2,4]triazolo[4,3-a]pyridinyloxy)-1,2,3,4-
tetrahydro-naphthalenyl](5-tert-butylp-tolyl-2H-pyrazolyl)-urea;
1-[5-tert-Butyl(6-methyl-pyridinyl)-2H-pyrazolyl][(1S,4R)-
4-(3-piperidinyl-[1,2,4]triazolo[4,3-a]pyridinyloxy)-1,2,3,4-tetrahydro-
naphthalenyl]-urea;
1-{5-tert-Butyl[3-(2-dimethylamino-ethoxy)-phenyl]-2H-pyrazol
yl}[(1S,4R)(3-diisopropylamino-[1,2,4]triazolo[4,3-a]pyridinyloxy)-
1,2,3,4-tetrahydro-naphthalenyl]-urea;
N-(5-tert-Butylmethoxy{3-[(1S,4R)(3-piperidinyl-
[1,2,4]triazolo[4,3-a]pyridinyloxy)-1,2,3,4-tetrahydro-naphthalenyl]-
ureido}-phenyl)-methanesulfonamide;
1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[8-methyl
((S)methyl-pyrrolidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-urea;
1-{5-tert-Butyl[4-(4-methyl-piperazinylmethyl)-phenyl]-2H-
pyrazolyl}[(1S,4R)(3-piperidinyl-[1,2,4]triazolo[4,3-a]pyridin
yloxy)-1,2,3,4-tetrahydro-naphthalenyl]-urea;
1-(3-tert-Butyl-1'-methyl-1'H-[1,4']bipyrazolylyl)[(1S,4R)(3-
piperidinyl-[1,2,4]triazolo[4,3-a]pyridinyloxy)-1,2,3,4-tetrahydro-
naphthalenyl]-urea;
1-[3-tert-Butyl-1'-(2-dimethylamino-ethyl)-1'H-[1,4']bipyrazolylyl]-
3-[(1S,4R)(3-piperidinyl-[1,2,4]triazolo[4,3-a]pyridinyloxy)-1,2,3,4-
tetrahydro-naphthalenyl]-urea;
N-[5-tert-Butylmethoxy(3-{(1S,4R)[3-((S)methyl-
pyrrolidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-
naphthalenyl}-ureido)-phenyl]-methanesulfonamide;
1-[5-tert-Butyl(2-hydroxy-ethyl)-2H-pyrazolyl]{(1S,4R)[3-
((S)methyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-urea;
1-(5-tert-Butyl-isoxazolyl){(1S,4R)[3-((S)methyl-piperidin-
1-yl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalen
yl}-urea;
1-[3-tert-Butyl-1'-(2-morpholinyl-ethyl)-1'H-[1,4']bipyrazolylyl]-
3-[(1S,4R)(3-piperidinyl-[1,2,4]triazolo[4,3-a]pyridinyloxy)-1,2,3,4-
tetrahydro-naphthalenyl]-urea;
1-[3-tert-Butyl-1'-(3-dimethylamino-propyl)-1'H-[1,4']bipyrazolyl
yl][(1S,4R)(3-piperidinyl-[1,2,4]triazolo[4,3-a]pyridinyloxy)-
1,2,3,4-tetrahydro-naphthalenyl]-urea;
1-[3-tert-Butyl-1'-(3-morpholinyl-propyl)-1'H-[1,4']bipyrazolyl
yl][(1S,4R)(3-piperidinyl-[1,2,4]triazolo[4,3-a]pyridinyloxy)-
1,2,3,4-tetrahydro-naphthalenyl]-urea;
1-{(1S,4R)[3-((2S,6R)-2,6-Dimethyl-piperidinyl)-
[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}
(3-fluoromorpholinyl-phenyl)-urea;
1-[5-tert-Butyl(2-morpholinyl-ethyl)-2H-pyrazolyl]
{(1S,4R)[3-((S)methyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridin
yloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea;
1-Cyclopropyl{(1S,4R)[3-((2S,6R)-2,6-dimethyl-piperidinyl)-
[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-
urea;
1-[5-tert-Butyl(2-hydroxy-ethyl)-2H-pyrazolyl]{(1S,4R)[3-
((2S,6R)-2,6-dimethyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-
1,2,3,4-tetrahydro-naphthalenyl}-urea;
1-{5-tert-Butyl[1-(2-dimethylamino-ethyl)-1H-imidazolyl]-2H-
pyrazolyl}[(1S,4R)(3-piperidinyl-[1,2,4]triazolo[4,3-a]pyridin
yloxy)-1,2,3,4-tetrahydro-naphthalenyl]-urea;
1-[5-tert-Butyl(2-hydroxy-ethyl)-2H-pyrazolyl]{(1S,4R)[3-
((S)methyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-urea;
1-[5-tert-Butyl(2-morpholinyl-ethyl)-2H-pyrazolyl]
{(1S,4R)[3-((2S,6R)-2,6-dimethyl-piperidinyl)-[1,2,4]triazolo[4,3-
a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea;
1-{(1S,4R)[3-(8-Aza-bicyclo[3.2.1]octyl)-[1,2,4]triazolo[4,3-
a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}{5-tert-butyl[3-
(2-dimethylamino-ethoxy)-phenyl]-2H-pyrazolyl}-urea;
1-{5-tert-Butyl[3-(2-dimethylamino-ethoxy)-phenyl]-2H-pyrazol
yl}{(1S,4R)[3-((R)methyl-piperidinyl)-[1,2,4]triazolo[4,3-
a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea;
1-[3-tert-Butyl-1'-(2-morpholinyl-ethyl)-1'H-[1,4']bipyrazolylyl]-
3-{(1S,4R)[3-((2S,6R)-2,6-dimethyl-piperidinyl)-[1,2,4]triazolo[4,3-
a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea;
1-[3-tert-Butyl-1'-(2-dimethylamino-ethyl)-1'H-[1,4']bipyrazolylyl]-
3-{(1S,4R)[3-((2S,6R)-2,6-dimethyl-piperidinyl)-[1,2,4]triazolo[4,3-
a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea;
1-(5-tert-Butylmethyl-2H-pyrazolyl){(1S,4R)[3-((S)
methyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydronaphthalenyl]-urea;
1-[5-tert-Butyl(2-dimethylamino-ethyl)-2H-pyrazolyl]
{(1S,4R)[3-((S)methyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridin
yloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea;
1-[5-tert-Butyl(2-piperidinyl-ethyl)-2H-pyrazolyl]{(1S,4R)-
4-[3-((S)methyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-
1,2,3,4-tetrahydro-naphthalenyl}-urea;
1-{5-tert-Butyl[2-(4-methyl-piperazinyl)-ethyl]-2H-pyrazolyl}-
3-{(1S,4R)[3-((S)methyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridin
yloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea;
1-[5-tert-Butyl(3-morpholinylmethyl-phenyl)-2H-pyrazolyl]
{(1S,4R)[3-((2S,6R)-2,6-dimethyl-piperidinyl)-[1,2,4]triazolo[4,3-
a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea;
1-{5-tert-Butyl[3-(2-morpholinyl-ethyl)-phenyl]-2H-pyrazol
yl}{(1S,4R)[3-((S)methyl-piperidinyl)-[1,2,4]triazolo[4,3-
a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea;
1-{5-tert-Butyl[3-(2-pyrrolidinyl-ethyl)-phenyl]-2H-pyrazol
yl}{(1S,4R)[3-((S)methyl-piperidinyl)-[1,2,4]triazolo[4,3-
a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea;
1-(5-tert-Butyl{3-[2-(ethyl-methyl-amino)-ethyl]-phenyl}-2H-
pyrazolyl){(1S,4R)[3-((S)methyl-piperidinyl)-
[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-
urea;
1-{5-tert-Butyl[3-(2-dimethylamino-ethyl)-phenyl]-2H-pyrazol
yl}{(1S,4R)[3-((S)methyl-piperidinyl)-[1,2,4]triazolo[4,3-
a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea;
1-{5-tert-Butyl[3-(2-piperidinyl-ethyl)-phenyl]-2H-pyrazolyl}-
3-{(1S,4R)[3-((S)methyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridin
yloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea;
1-(5-tert-Butyl{3-[2-(4-methyl-piperazinyl)-ethyl]-phenyl}-2H-
pyrazolyl){(1S,4R)[3-((S)methyl-piperidinyl)-
[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-
urea;
1-{5-tert-Butyl[3-(2-[1,4]oxazepanyl-ethyl)-phenyl]-2H-pyrazol-
3-yl}{(1S,4R)[3-((S)methyl-piperidinyl)-[1,2,4]triazolo[4,3-
a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea;
1-(5-tert-Butyl{3-[2-(4-methyl-[1,4]diazepanyl)-ethyl]-phenyl}-
2H-pyrazolyl){(1S,4R)[3-((S)methyl-piperidinyl)-
[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-
urea;
1-[5-tert-Butyl(2-hydroxy-ethyl)-2H-pyrazolyl]{(1S,4R)[3-
((S)methyl-morpholinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-urea;
1-(5-tert-Butyl{2-[(2-dimethylamino-ethyl)-methyl-amino]-
pyrimidinyl}-2H-pyrazolyl){(1S,4R)[3-((S)methyl-piperidin
yl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-
urea;
1-{5-tert-Butyl[3-(2-dimethylamino-ethoxy)-phenyl]-2H-pyrazol
yl}{(1S,4R)[3-((S)methyl-morpholinyl)-[1,2,4]triazolo[4,3-
a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea;
1-[5-tert-Butyl(2-morpholinyl-ethyl)-2H-pyrazolyl]
{(1S,4R)[3-((S)methyl-morpholinyl)-[1,2,4]triazolo[4,3-a]pyridin
yloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea;
1-{5-tert-Butyl[3-(4-methyl-piperazinylmethyl)-phenyl]-2H-
pyrazolyl}{(1S,4R)[3-((2S,6R)-2,6-dimethyl-piperidinyl)-
[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-
urea;
1-[5-tert-Butyl(3-pyrrolidinylmethyl-phenyl)-2H-pyrazolyl]
{(1S,4R)[3-((2S,6R)-2,6-dimethyl-piperidinyl)-[1,2,4]triazolo[4,3-
a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea;
1-{5-tert-Butyl[3-(2-pyrrolidinyl-ethoxy)-phenyl]-2H-pyrazol
yl}{(1S,4R)[3-((2S,6R)-2,6-dimethyl-piperidinyl)-[1,2,4]triazolo[4,3-
a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea;
1-(5-tert-Butyl{3-[2-(4-methyl-piperazinyl)-ethoxy]-phenyl}-2H-
pyrazolyl){(1S,4R)[3-((2S,6R)-2,6-dimethyl-piperidinyl)-
[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl }-
urea;
1-(5-tert-Butyl{3-[2-(ethyl-methyl-amino)-ethoxy]-phenyl}-2H-
pyrazolyl){(1S,4R)[3-((2S,6R)-2,6-dimethyl-piperidinyl)-
[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-
urea;
1-{(1S,4R)[3-(4-Aza-spiro[2.5]octyl)-[1,2,4]triazolo[4,3-
a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}{5-tert-butyl[3-
(2-dimethylamino-ethoxy)-phenyl]-2H-pyrazolyl}-urea;
1-[5-tert-Butyl(3-morpholinyl-methyl-phenyl)-2H-pyrazolyl]-
3-{(1S,4R)[3-((S)methyl-pyrrolidinyl)-[1,2,4]triazolo[4,3-a]pyridin-
6-yloxy]-1,2,3,4-tetrahydronaphthalenyl}-urea;
1-(5-tert-Butyl{3-[(2-dimethylamino-ethyl)-methyl-amino]-phenyl}-
2H-pyrazolyl){(1S,4R)[3-((S)methyl-piperidinyl)-
[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-
urea;
1-{5-tert-Butyl[3-((R)dimethylaminomethyl-ethoxy)-phenyl]-
2H-pyrazolyl}{(1S,4R)[3-((S)methyl-piperidinyl)-
[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-
urea;
1-{5-tert-Butyl[3-((S)dimethylaminomethyl-ethoxy)-phenyl]-
2H-pyrazolyl}{(1S,4R)[3-((S)methyl-piperidinyl)-
[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-
urea;
1-[2-[3-(2-Dimethylamino-ethoxy)-phenyl](2-hydroxy-1,1-dimethyl-
ethyl)-2H-pyrazolyl]{(1S,4R)[3-((S)methyl-piperidinyl)-
[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-
urea;
1-{5-tert-Butyl[3-(2-pyrrolidinyl-ethoxy)-phenyl]-2H-pyrazol
yl}{(1S,4R)[3-((S)methyl-piperidinyl)-[1,2,4]triazolo[4,3-
a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea;
1-{5-tert-Butyl[3-(2-diethylamino-ethoxy)-phenyl]-2H-pyrazol
yl}{(1S,4R)[3-((S)methyl-piperidinyl)-[1,2,4]triazolo[4,3-
a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea;
1-{5-tert-Butyl[3-(2-morpholinyl-ethoxy)-phenyl]-2H-pyrazol
yl}{(1S,4R)[3-((S)methyl-piperidinyl)-[1,2,4]triazolo[4,3-
a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea;
1-{5-tert-Butyl[3-(2-piperidinyl-ethoxy)-phenyl]-2H-pyrazol
yl}{(1S,4R)[3-((S)methyl-piperidinyl)-[1,2,4]triazolo[4,3-
a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea;
1-(5-tert-Butyl{3-[2-(4-methyl-piperazinyl)-ethoxy]-phenyl}-2H-
pyrazolyl){(1S,4R)[3-((S)methyl-piperidinyl)-
[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-
urea;
1-{5-tert-Butyl{3-[2-(4-fluoropiperidinyl)-ethoxy]-phenyl}-2H-
pyrazolyl}{(1S,4R)[3-((S)methyl-piperidinyl)-
[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-
urea;
1-(5-tert-Butyl{3-[2-(4-methyl-[1,4]-diazepanyl)-ethoxy]-
phenyl}-2H-pyrazolyl){(1S,4R)[3-((S)methyl-piperidinyl)-
[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-
urea;
1-{5-tert-Butyl[3-(2-[1,4]oxazepanyl-ethoxy)-phenyl]-2H-
pyrazolyl}{(1S,4R)[3-((S)methyl-piperidinyl)-
[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-
urea;
1-(2-{3-[2-(8-Aza-bicyclo[3.2.1]octyl)-ethoxy]-phenyl}tert-butyl-
2H-pyrazolyl){(1S,4R)[3-((S)methyl-piperidinyl)-
[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-
urea;
1-(5-tert-Butyl{3-[2-(ethyl-methyl-amino)-ethoxy]-phenyl}-2H-
pyrazolyl){(1S,4R)[3-((S)methyl-piperidinyl)-
[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-
urea;
1-{5-tert-Butyl(3-{2-[(2-methoxy-ethyl)-methyl-amino]-ethoxy}-
phenyl}-2H-pyrazolyl}{(1S,4R)[3-((S)methyl-piperidinyl)-
[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-
urea;
1-(5-tert-Butyl{3-[2-(4-methoxy-piperidinyl-ethoxy]-phenyl}-2H-
pyrazolyl){(1S,4R)[3-((S)methyl-piperidinyl)-
[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-
urea;
1-(5-tert-Butyl{3-[2-(3-oxaaza-bicyclo[3.2.1]octyl)-ethoxy]-
phenyl}-2H-pyrazolyl){(1S,4R)[3-((S)methyl-piperidinyl)-
[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-
urea;
1-{5-tert-Butyl[3-(4-methoxy-piperidinylmethyl)-phenyl]-2H-
pyrazolyl}{(1S,4R)[3-((S)methyl-piperidinyl)-
[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-
urea;
1-[5-tert-Butyl(3-{[(2-methoxy-ethyl)-methyl-amino]-methyl}-
phenyl)-2H-pyrazolyl]{(1S,4R)[3-((S)methyl-piperidinyl)-
[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-
urea;
1-{5-tert-Butyl[3-(4-fluoro-piperidinylmethyl)-phenyl]-2H-
pyrazolyl}{(1S,4R)[3-((S)methyl-piperidinyl)-
[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-
urea;
1-[5-tert-Butyl(3-dimethylaminomethyl-phenyl)-2H-pyrazolyl]
{(1S,4R)[3-((S)methyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridin
yloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea;
1-[5-tert-Butyl(3-pyrrolidinylmethyl-phenyl)-2H-pyrazolyl]
{(1S,4R)[3-((S)methyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridin
yloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea;
1-{(1S,4R)[3-(4-Aza-spiro[2.5]octyl)-[1,2,4]triazolo[4,3-
a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}{5-tert-butyl[3-
(2-morpholinyl-ethoxy)-phenyl]-2H-pyrazolyl}-urea;
1-[5-tert-Butyl(3-piperidinylmethyl-phenyl)-2H-pyrazolyl]
{(1S,4R)[3-((S)methyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridin
yloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea;
1-{5-tert-Butyl[3-(4-methyl-[1,4]diazepanylmethyl)-phenyl]-2H-
pyrazolyl}{(1S,4R)[3-((S)methyl-piperidinyl)-
[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-
urea;
1-{5-tert-Butyl[3-((1S,4S)methyl-2,5-diaza-bicyclo[2.2.1]hept
ylmethyl)-phenyl]-2H-pyrazolyl}{(1S,4R)[3-((S)methyl-piperidin-
1-yl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalen
yl}-urea;
1-[5-tert-Butyl(4-morpholinylmethyl-phenyl)-2H-pyrazolyl]
{(1S,4R)[3-((S)methyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridin
yloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea;
1-[5-tert-Butyl(4-dimethylaminomethyl-phenyl)-2H-pyrazolyl]
{(1S,4R)[3-((S)methyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridin
yloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea;
1-{5-tert-Butyl[4-(4-methyl-piperazinylmethyl)-phenyl]-2H-
pyrazolyl}{(1S,4R)[3-((S)methyl-piperidinyl)-
[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-
urea;
1-{5-tert-Butyl[4-(4-methyl-[1,4]diazepanylmethyl)-phenyl]-2H-
pyrazolyl}{(1S,4R)[3-((S)methyl-piperidinyl)-
[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-
urea;
1-{5-tert-Butyl[4-(4-methoxy-piperidinylmethyl)-phenyl]-2H-
pyrazolyl}{(1S,4R)[3-((S)methyl-piperidinyl)-
[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-
urea;
1-[5-tert-Butyl(4-pyrrolidinylmethyl-phenyl)-2H-pyrazolyl]
{(1S,4R)[3-((S)methyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridin
yloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea;
1-[5-tert-Butyl(4-piperidinylmethyl-phenyl)-2H-pyrazolyl]
{(1S,4R)[3-((S)methyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridin
yloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea;
1-{5-tert-Butyl[4-(4-fluoro-piperidinylmethyl)-phenyl]-2H-
pyrazolyl}{(1S,4R)[3-((S)methyl-piperidinyl)-
[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-
urea;
1-(5-tert-Butyl{4-[(ethyl-methyl-amino)-methyl]-phenyl}-2H-
pyrazolyl){(1S,4R)[3-((S)methyl-piperidinyl)-
[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-
urea;
1-[5-tert-Butyl(4-{[(2-methoxy-ethyl)-methyl-amino]-methyl}-
phenyl)-2H-pyrazolyl]{(1S,4R)[3-((S)methyl-piperidinyl)-
[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-
urea;
1-{5-tert-Butyl[3-(2-dimethylamino-ethoxy)-phenyl]-2H-pyrazol
yl{(1S,4S)[3-((S)methyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridin-
6-yloxy]-1,2,3,4-tetrahydronaphthalenyl]-urea;
And pharmaceutically acceptable salts thereof.
According to another embodiment there is described a compound of
formula (J), or a pharmaceutically acceptable salt thereof:
N W A
Wherein R , W, A and Y have the same meaning as provided above for
compounds of formula (I); and wherein
1 13 2 3 4 5
R is a group (IIc) wherein R , X , X , X and X have the same
meaning as provided above for compounds of formula (I);
(IIc)
And wherein R is phenyl or 5- or 6-membered monocyclic heteroaryl,
wherein such phenyl or 5- or 6-membered monocyclic heteroaryl is substituted
by a group -O-(C -C alkylene)-NR R , wherein such C -C alkylene may be
2 6 2 6
optionally substituted by a group C -C alkyl, C -C cycloalkyl, hydroxyl or
1 6 3 7
halo;
R and R are at each occurrence independently C -C alkyl or C -C
1 6 3 7
cycloalkyl, such C -C alkyl and C -C cycloalkyl being substituted by one or
1 6 3 7
T R S
more group OR , CN or halo; alternatively, R and R , may form together with
the nitrogen atom to which they are attached a 5 membered saturated
monocyclic or bicyclic ring system which is substituted by one or more group
OR , CN, halo, C -C alkyl or C -C cycloalkyl, such C -C alkyl and C -C
1 6 3 7 1 6 3 7
cycloalkyl being optionally substituted by a group C -C alkyl,
C -C cycloalkyl, OR , CN or halo; and which 5 membered saturated
monocyclic or bicyclic ring optionally contains a further heteroatom which is
oxygen or nitrogen, said nitrogen atom optionally substituted by C -C alkyl
or C -C cycloalkyl wherein any of such alkyl or cycloalkyl may be optionally
substituted by a group C -C alkyl, C -C cycloalkyl, OR , CN, or halo; and
1 6 3 7
R is at each occurrence independently hydrogen, -CH or -C H .
3 2 5
Where applicable, all preferred groups or embodiments described
herebelow for compounds of formula (I), (Ia), (Ib) and (Ic) may be combined
among each other and apply as well to compounds of formula (J) as above
defined mutatis mutandis.
Utility
As mentioned above the compounds of the invention are p38MAPK
inhibitors, and thus may have utility for the treatment of diseases or conditions
which benefit from inhibition of the p38 enzyme. Such diseases and
conditions are known from the literature and several have been mentioned
above. However, the compounds are generally of use as anti-inflammatory
agents, particularly for use in the treatment of respiratory disease. In
particular, the compounds may be used in the treatment of chronic obstructive
pulmonary disease (COPD), chronic bronchitis, lung fibrosis, pneumonia,
acute respiratory distress syndrome (ARDS), pulmonary emphysema, or
smoking-induced emphysema, intrinsic (non-allergic asthma and extrinsic
(allergic) asthma, mild asthma, moderate asthma, severe asthma, steroid
resistant asthma, neutrophilic asthma, bronchitic asthma, exercise induced
asthma, occupational asthma and asthma induced following bacterial
infection, cystic fibrosis, pulmonary fibrosis and bronchiectasis.
Also described is the use of the compounds of the invention for the
prevention and/or treatment of any disease or condition which benefit from
inhibition of the p38 enzyme.
Also described is the use of compounds of the invention for the
preparation of a medicament for the prevention and/or treatment of any
disease or condition which benefit from inhibition of the p38 enzyme.
Also described is a method for prevention and/or treatment of any
disease which benefit from inhibition of the p38 enzyme, said method
comprises administering to a patient in need of such treatment a
therapeutically effective amount of a compound of the invention.
Compositions
As mentioned above, the compounds with which the invention is
concerned are p38 kinase inhibitors, and are useful in the treatment of several
diseases for example inflammatory diseases of the respiratory tract. Examples
of such diseases are referred to above, and include asthma, rhinitis, allergic
airway syndrome, bronchitis and chronic obstructive pulmonary disease.
It will be understood that the specific dose level for any particular
patient will depend upon a variety of factors including the activity of the
specific compound employed, the age, body weight, general health, sex, diet,
time of administration, route of administration, rate of excretion, drug
combination and the severity of the particular disease undergoing treatment.
Optimum dose levels and frequency of dosing will be determined by clinical
trial, as is required in the pharmaceutical art. In general, the daily dose range
for oral administration will lie within the range of from about 0.001 mg to
about 100 mg per kg body weight of a human, often 0.01 mg to about 50 mg
per kg, for example 0.1 to 10 mg per kg, in single or divided doses. In general,
the daily dose range for inhaled administration will lie within the range of
from about 0.1 µg to about 1mg per kg body weight of a human, preferably
0.1 µg to 50 µg per kg, in single or divided doses. On the other hand, it may
be necessary to use dosages outside these limits in some cases. For the
purposes described herein, inhaled administration is preferred.
The compounds with which the invention is concerned may be prepared
for administration by any route consistent with their pharmacokinetic
properties. Orally administrable compositions may be in the form of tablets,
capsules, powders, granules, lozenges, liquid or gel preparations, such as oral,
topical, or sterile parenteral solutions or suspensions. Tablets and capsules for
oral administration may be in unit dose presentation form, and may contain
conventional excipients such as binding agents, for example syrup, acacia,
gelatin, sorbitol, tragacanth, or polyvinyl-pyrrolidone; fillers for example
lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting
lubricant, for example magnesium stearate, talc, polyethylene glycol or silica;
disintegrants for example potato starch, or acceptable wetting agents such as
sodium lauryl sulfate. The tablets may be coated according to methods well
known in normal pharmaceutical practice. Oral liquid preparations may be in
the form of, for example, aqueous or oily suspensions, solutions, emulsions,
syrups or elixirs, or may be presented as a dry product for reconstitution with
water or other suitable vehicle before use. Such liquid preparations may
contain conventional additives such as suspending agents, for example
sorbitol, syrup, methyl cellulose, glucose syrup, gelatin hydrogenated edible
fats; emulsifying agents, for example lecithin, sorbitan monooleate, or acacia;
non-aqueous vehicles (which may include edible oils), for example almond
oil, fractionated coconut oil, oily esters such as glycerine, propylene glycol, or
ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate
or sorbic acid, and if desired conventional flavouring or colouring agents.
For topical application to the skin, the drug may be made up into a
cream, lotion or ointment. Cream or ointment formulations which may be used
for the drug are conventional formulations well known in the art, for example
as described in standard textbooks of pharmaceutics such as the British
Pharmacopoeia.
The active ingredient may also be administered parenterally in a sterile
medium. Depending on the vehicle and concentration used, the drug can either
be suspended or dissolved in the vehicle. Advantageously, adjuvants such as a
local anaesthetic, preservative and buffering agents can be dissolved in the
vehicle.
However, for treatment of an inflammatory disease of the respiratory
tract, compounds of the invention may also be formulated for inhalation, for
example as a nasal spray, or dry powder or aerosol inhalers. For delivery by
inhalation, the active compound is preferably in the form of microparticles.
They may be prepared by a variety of techniques, including spray-drying,
freeze-drying and micronisation. Aerosol generation can be carried out using,
for example, pressure-driven jet atomizers or ultrasonic atomizers, preferably
using propellant-driven metered aerosols or propellant-free administration of
micronized active compounds from, for example, inhalation capsules or other
“dry powder” delivery systems.
By way of example, a composition of the invention may be prepared as
a suspension for delivery from a nebuliser or as an aerosol in a liquid
propellant, for example for use in a pressurised metered dose inhaler (PMDI).
Propellants suitable for use in a PMDI are known to the skilled person, and
include CFC-12, HFA-134a, HFA-227, HCFC-22 (CCl F ) and HFA-152
(CH F and isobutane).
In a preferred embodiment of the invention, a composition of the
invention is in dry powder form, for delivery using a dry powder inhaler
(DPI). Many types of DPI are known.
Microparticles for delivery by administration may be formulated with
excipients that aid delivery and release. For example, in a dry powder
formulation, microparticles may be formulated with large carrier particles that
aid flow from the DPI into the lung. Suitable carrier particles are known, and
include lactose particles; they may have a mass median aerodynamic diameter
of greater than 90 μm.
In the case of an aerosol-based formulation, an example is:
Compound of the invention 24 mg / canister
Lecithin, NF Liq. Conc. 1.2 mg / canister
Trichlorofluoromethane, NF 4.025 g / canister
Dichlorodifluoromethane, NF 12.15 g / canister.
The active compounds may be dosed as described depending on the
inhaler system used. In addition to the active compounds, the administration
forms may additionally contain excipients, such as, for example, propellants
(e.g. Frigen in the case of metered aerosols), surface-active substances,
emulsifiers, stabilizers, preservatives, flavorings, fillers (e.g. lactose in the
case of powder inhalers) or, if appropriate, further active compounds.
For the purposes of inhalation, a large number of systems are available
with which aerosols of optimum particle size can be generated and
administered, using an inhalation technique which is appropriate for the
patient. In addition to the use of adaptors (spacers, expanders) and pear-
shaped containers (e.g. Nebulator®, Volumatic®), and automatic devices
emitting a puffer spray (Autohaler®), for metered aerosols, in particular in the
case of powder inhalers, a number of technical solutions are available (e.g.
Diskhaler®, Rotadisk®, Turbohaler® or the inhalers for example as described
EP-A-0505321). Additionally, compounds of the invention may be delivered
in multi-chamber devices thus allowing for delivery of combination agents.
Combinations
Other compounds may be combined with compounds with which the
invention is concerned for the prevention and treatment of inflammatory
diseases, in particular respiratory diseases. Thus the present description is also
concerned with pharmaceutical compositions comprising a therapeutically
effective amount of a compound of the invention and one or more other
therapeutic agents. Suitable therapeutic agents for a combination therapy with
compounds of the invention include, but are not limited to: (1) corticosteroids,
such as fluticasone propionate, fluticasone furoate, mometasone furoate,
beclometasone dipropionate, ciclesonide, budesonide, GSK 685698, GSK
870086, QAE 397, QMF 149, TPI-1020; (2) b2-adrenoreceptor agonists such
as salbutamol, albuterol, terbutaline, fenoterol, and long acting
b2-adrenoreceptor agonists such as salmeterol, indacaterol, formoterol
(including formoterol fumarate), arformoterol, carmoterol, GSK 642444, GSK
159797, GSK 159802, GSK 597501, GSK 678007, AZD3199; (3)
corticosteroid/long acting b2 agonist combination products such as salmeterol/
fluticasone propionate (Advair/Seretide), formoterol/budesonide (Symbicort),
formoterol/fluticasone propionate (Flutiform), formoterol/ciclesonide,
formoterol/mometasone furoate, formoterol/ beclometasone dipropionate,
indacaterol/mometasone furoate, Indacaterol/QAE 397, GSK 159797/GSK
685698, GSK 159802/GSK 685698, GSK 642444/GSK 685698, GSK
159797/GSK 870086, GSK 159802/GSK 870086, GSK 642444/GSK 870086,
arformoterol/ciclesonide;(4) anticholinergic agents, for example muscarinic-3
(M3) receptor antagonists such as ipratropium bromide, tiotropium bromide,
Aclidinium (LAS-34273), NVA-237, GSK 233705, Darotropium, GSK
573719, GSK 961081, QAT 370, QAX 028, EP-101; (5) dual pharmacology
M3-anticholinergic/b2-adrenoreceptor agonists such as GSK961081,
AZD2115 and LAS190792; (6) leukotriene modulators, for example
leukotriene antagonists such as montelukast, zafirulast or pranlukast or
leukotriene biosynthesis inhibitors such as Zileuton or BAY-1005, or LTB4
antagonists such as Amelubant, or FLAP inhibitors such as GSK 2190914,
AM-103; (7) phosphodiesterase-IV (PDE-IV) inhibitors (oral or inhaled), such
as roflumilast, cilomilast, Oglemilast, ONO-6126, Tetomilast, Tofimilast, UK
500,001, GSK 256066; (8) antihistamines, for example selective histamine-1
(H1) receptor antagonists, such as fexofenadine, citirizine, loratidine or
astemizole or dual H1/H3 receptor antagonists such as GSK 835726, GSK
1004723, or selective histamine-4 (H4) receptor antagonists, such as
ZPL3893787; (9) antitussive agents, such as codeine or dextramorphan; (10) a
mucolytic, for example N acetyl cysteine or fudostein; (11) a
expectorant/mucokinetic modulator, for example ambroxol, hypertonic
solutions (e.g. saline or mannitol) or surfactant; (12) a peptide mucolytic, for
example recombinant human deoxyribonoclease I (dornase-alfa and rhDNase)
or helicidin; (13) antibiotics, for example azithromycin, tobramycin and
aztreonam; (14) non-selective COX-1 / COX-2 inhibitors, such as ibuprofen or
ketoprofen; (15) COX-2 inhibitors, such as celecoxib and rofecoxib; (16)
VLA-4 antagonists, such as those described in WO97/03094 and
WO97/02289; (17) TACE inhibitors and TNF-a inhibitors, for example anti-
TNF monoclonal antibodies, such as Remicade and CDP-870 and TNF
receptor immunoglobulin molecules, such as Enbrel; (18) inhibitors of matrix
metalloprotease, for example MMP-12; (19) human neutrophil elastase
inhibitors, such as ONO-6818 or those described in WO2005/026124,
WO2003/053930 and WO06/082412; (20) A2b antagonists such as those
described in WO2002/42298; (21) modulators of chemokine receptor function,
for example antagonists of CCR3 and CCR8; (22) compounds which modulate
the action of other prostanoid receptors, for example a thromboxane A
antagonist; DP1 antagonists such as MK-0524, CRTH2 antagonists such as
ODC9101 and OC000459 and AZD1981 and mixed DP1/CRTH2 antagonists
such as AMG 009 and AMG853; (23) PPAR agonists including PPAR alpha
agonists (such as fenofibrate), PPAR delta agonists, PPAR gamma agonists
such as Pioglitazone, Rosiglitazone and Balaglitazone; (24) methylxanthines
such as theophylline or aminophylline and methylxanthine/corticosteroid
combinations such as theophylline/budesonide, theophylline/fluticasone
propionate, theophylline/ciclesonide, theophylline/mometasone furoate and
theophylline/beclometasone dipropionate; (25) A2a agonists such as those
described in EP1052264 and EP1241176; (26) CXCR2 or IL-8 antagonists
such as SCH 527123 or GSK 656933; (27) IL-R signalling modulators such as
kineret and ACZ 885; (28) MCP-1 antagonists such as ABN-912.
Also described is a kit comprising the pharmaceutical compositions of
compounds of the invention alone or in combination with or in admixture with
one or more pharmaceutically acceptable carriers and/or excipients and a
device which may be a single- or multi-dose dry powder inhaler, a metered
dose inhaler or a nebulizer.
Methods of synthesis
Also described is a process for the preparation of compounds of the
invention, according to general synthetic routes described in this section. In
the following reaction schemes, unless otherwise indicated, the groups
mentioned assume the same meaning as those reported for compounds of
formula (I).
The skilled person may introduce, where appropriate, suitable variations
to the conditions specifically described in the experimentals in order to adapt
the synthetic routes to the provision of further compounds of the invention.
Such variations may include, but are not limited to, use of appropriate starting
materials to generate different compounds, changes in the solvent and
temperature of reactions, replacements of reactives with analogous chemical
role, introduction or removal of protection/deprotection stages of functional
groups sensitive to reaction conditions and reagents, as well as introduction or
removal of specific synthetic steps oriented to further functionalisation of the
chemical scaffold.
Processes which can be used and are described and reported in
Examples and Schemes, should not be viewed as limiting the scope of the
synthetic methods available for the preparation of the compounds of the
invention.
The process described is particularly advantageous as it is susceptible
of being properly modulated, through any proper variant known to the skilled
person, so as to obtained any of the desired compounds of the invention. Such
variants are comprised within the scope of the present description.
From all of the above, it should be clear to the skilled person that any of
the described groups may be present as such or in any properly protected
form.
In particular, functional groups present in the intermediate and
compounds and which could generate unwanted side reaction and by-products,
need to be properly protected before the alkylation, acylation, coupling or
sulfonylation takes place. Likewise, subsequent deprotection of those same
protected groups may follow upon completion of the said reactions.
As used herein, unless otherwise indicated, the term “protecting group”
designates a protective group adapted to preserve the function of the group it
is bound to. Typically, protective groups are used to preserve amino,
hydroxyl, or carboxyl functions. Appropriate protecting groups may thus
include, for example, benzyl, benzyloxycarbonyl,
t-butoxycarbonyl, alkyl or benzyl esters or the like, which are well known to
those skilled in the art [see, for a general reference, T.W. Green; Protective
Groups in Organic Synthesis (Wiley, N.Y. 1981)].
Likewise, selective protection and deprotection of any of the said
groups, for instance including carbonyl, hydroxyl or amino groups, may be
accomplished according to very well known methods commonly employed in
organic synthetic chemistry.
Optional salification of the compounds of formula (I) or N-oxides on
the pyridine ring thereof may be carried out by properly converting any of the
free acidic or amino groups into the corresponding pharmaceutically
acceptable salts. In this case too, the operative conditions being employed for
the optional salification of the compounds of the invention are all within the
ordinary knowledge of the skilled person.
From all of the above, it should be clear that the above process,
comprehensive of any variant thereof for the preparation of suitable
compounds of the invention, may be conveniently modified so that to adapt
the reaction conditions to the specific needs, for instance by choosing
appropriate condensing agents, solvents and protective groups, as the case
may be.
For example compounds of the invention of formula (I) may be
prepared according to the route illustrated in Scheme 1.
Cl 1
2 Cl R
(1b1)
2 N W
(1c)
(1a)
(1b2)
Scheme 1
Compounds of general formula (I) may be prepared from compounds of
general formula (1a) by reaction with a compound of general formula (1b1) or
(1b2) wherein R is as defined in general formula (I), in a suitable solvent such
as dimethyl sulfoxide, 1,4-dioxane, N,N-dimethylformamide or acetonitrile, in
the presence of a base such as diisopropylethylamine at a range of
temperatures, preferably between room temperature and 100°C.
Compounds of general formula (1b1) and (1b2) are either known in the
literature or may be prepared from amines of general formula (1c) according
to known literature procedures (e.g. see for reference WO2006009741,
EP1609789).
Compounds of general formula (1c) are either known in the literature or
may be synthesised by one skilled in the art by adapting appropriate literature
methods (e.g WO2010077836, WO2006009741, WO2008125014, J. Med
Chem., 2007, 50, 4016, Bulletin des Societes Chimiques Belges, 1987, 96,
675-709, Organic & Biomolecular Chemistry, 2006, 4, 4158-4164).
Compounds of general formula (1ca), i.e. compounds of formula (1c)
2 17 18 1 2 3 4
wherein R is a group of formula (IIIb) and R , R , z , z , z and z are as
defined above can be prepared from compounds of formula (1e),
(1e)
using a suitable reducing agent such as tin (II) chloride, iron, or
hydrogen gas with a suitable catalyst such as palladium on carbon, in a
suitable solvent such as methanol, ethanol or acetic acid, at a range of
temperatures, preferably between room temperature and 100°C.
Compounds of general formula (1e) are known in the literature or may
be prepared by those skilled in the art using literature methods
(e.g. WO2008034008, WO20110189167, WO2010068258).
Alternatively, compounds of general formula (1ca) as above defined can
17 18 1 2 3
be prepared from compounds of formula (1f), wherein R , R , z , z , z and
z are as defined above and wherein PG is a suitable compatible protecting
group known to those skilled in the art, such as benzyl, benzyl carbamate or
tert-butyl carbamate,
(1f)
using suitable deprotection conditions such as hydrochloric acid,
trifluoroacetic acid, or hydrogen catalysed by for example palladium on
carbon, in a suitable solvent such as dichloromethane, methanol, ethanol or
acetic acid, at a range of temperatures, preferably between 0°C and 100°C.
Compounds of general formula (1f) can be prepared by reaction of
17 18 1 2 3 4
compounds of formula (1g), wherein R , R , z , z , z and z are as defined
above
(1 g) (1h)
with compounds of formula (1h) as above reported wherein PG is a
suitable protecting group known to those skilled in the art, such as benzyl,
benzyl carbamate or tert-butyl carbamate, using suitable conditions such as in
the presence of a base such as potassium carbonate or diisopropylethyl amine
or under Buchwald conditions (with a catalyst such as Pd(OAc) , a ligand such
as 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl and base such as sodium tert-
butoxide), in a suitable solvent such as toluene or tetrahydrofuran, at a range
of temperatures, preferably between room temperature and 150°C.
Compounds of general formula (1g) and (1h) are known in the literature
or may be prepared by those skilled in the art by adapting appropriate
literature methods (e.g. WO2011042389, Chemistry-A European Journal,
2011, 17, 6606-6609, S6606/1-S6606/38).
Compounds of general formula (1a) may be prepared according to the
route illustrated in Scheme 2.
(2b)
+ (2c)
A 1 10 R
X R A
(2a)
(1a)
(2d)
Scheme 2
Compounds of general formula (1a) may be prepared from compounds
of general formula (2a) by reaction with a compound of general formula (2b),
(2c) or (2d). Wherein G is a suitable chemical group known to those skilled in
the art selected such that it can facilitate a suitable coupling reaction such as
nucleophilic displacement or metal catalysed cross coupling: For example in
cases such that when Y is -O-, -S- or -NR -, examples of G may include
halogen or a suitable leaving group such as mesylate or triflate either directly
linked or attached via a group -(CR R ) -. Examples of the coupling
conditions used may include using a base such as sodium hydride or potassium
tert-butoxide and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone in a
suitable solvent such as N,N-dimethylformamide, toluene, 1,4-dioxane or
acetonitrile at a range of temperatures, preferably between room temperature
and 150°C. For example in cases such that when Y is -O- and G is -OH or -SH
a method to perform this coupling may involve Mitsunobu conditions
(diethylazodicarboxylate / triphenylphosphine) in a suitable solvent such as
tetrahydrofuran or 1,4-dioxane at a range of temperatures preferably between -
°C and 100°C. For example in cases such as when Y is -O-, -S- or -NR -
and G is a group such as halogen, triflate or boronic acid/ester a method to
perform this coupling may be under metal (for example palladium or copper)
catalysed coupling conditions in the presence of a suitable ligand such as
Xantphos or 1,10-phenanthroline in the presence of a base such as caesium
carbonate in a suitable solvent such as tetrahydrofuran, 1,4-dioxane or
N,N-dimethylformamide at a range of temperatures preferably between -10°C
and 150°C. For example in cases such as when Y is -O- and G is a group such
as -COOMe, -COOH, isocyanate, -OCOCl or –NHCOOCH CCl examples of
conditions to perform this coupling may involve the use of a base such as
sodium hydride or triethylamine or a coupling reagent such as HATU in a
suitable solvent such as dichloromethane, tetrahydrofuran, 1,4-dioxane or
N,N-dimethylformamide at a range of temperatures preferably between -10°C
and 150°C.
Compounds of formula (2b) are commercial available, are known in the
literature or may be synthesised from compounds of formula (2e), wherein R
and R are as defined for compounds of formula (I), by adapting appropriate
literature methods (e.g. WO 2006133006) or using methods known to those
skilled in the art such as by reacting (2e) with a suitable alkylating agent such
as dibromoethane or bromoethanol in the presence of a suitable base such as
sodium hydride or potassium carbonate in a suitable solvent such as
tetrahydrofuran, 1,4-dioxane or N,N-dimethylformamide at a range of
temperatures preferably between -10°C and 150°C, or by reacting (2e) with a
suitable aldehyde in the presence of a reducing agent such as sodium
triacetoxyborohydride in a suitable solvent such as dichloroethane or
tetrahydrofuran at a range of temperatures preferably between -10°C and
100°C.
(2e)
Compounds of formula (2e) are commercially available, are known in
the literature or may be synthesised by those skilled in the art using literature
methods.
Compounds of formula (2c) may be synthesised from compounds of
formula (2f).
(2f)
Wherein X and R are defined as for compounds of formula (I), G is a
group such as halogen, -O-PG or - S-PG wherein PG represents a protecting
group such as triisopropylsilyl or tert-butyldimethylsilyl (methods for whose
introduction and removal are well known by those skilled in the art) and J may
represent groups such as halogen, -NH , -OH, -SH, -COOH, -SO Cl which can
be modified using literature methods to introduce an appropriate group R by
those skilled in the art. For example in cases such as when J is halogen, a
method such as nucleophilic substitution with a suitable alcohol, amine or
thiol may be used in the presence of a suitable base such as sodium hydride,
triethylamine or potassium carbonate in a suitable solvent such as
tetrahydrofuran, 1,4-dioxane or N,N-dimethylformamide at a range of
temperatures preferably between -10°C and 150°C. For example in cases such
as when J is -NH , -OH or –SH, a method such as alkylation may be used with
a suitable alkylating agent such as an alkyl halide in the presence of a suitable
base such as sodium hydride or potassium carbonate in a suitable solvent such
as tetrahydrofuran, 1,4-dioxane or N,N-dimethylformamide at a range of
temperatures preferably between -10°C and 150°C. For example in cases such
as where J is -COOH or -SO Cl a method such as reaction with a suitable
amine in the presence of a suitable base such as triethylamine or a coupling
reagent such as HATU in a suitable solvent such as tetrahydrofuran,
1,4-dioxane or N,N-dimethylformamide at a range of temperatures preferably
between -10°C and 150°C.
Compounds of formula (2da), i.e. compounds of formula(2a) wherein
X = C may be prepared according to the routes described in Scheme 3
herebelow:
(3b1)
HO R
2 11
(3b2)
11 3
Cl R
(3d)
R 13
(3a)
(2da)
(3c)
(3e)
Scheme 3
Compounds of general formula (2da) as above defined may be prepared
from compounds of general formula (3e) using a suitable oxidant such as
chloramine T, lead tetracetate or phenyl iodine(III) diacetate, in a suitable
solvent such as dichloromethane or ethanol at a range of temperatures,
preferably between room temperature and 100°C.
Compounds of general formula (3e) may be prepared from compounds
of general formula (3a) by reaction with an aldehyde of general formula (3c)
above reported.
in a suitable solvent such as ethanol or tetrahydrofuran at a range of
temperatures, preferably between room temperature and 80°C.
Compounds of formula (3c) are commercially available, known in the
literature or may be prepared using literature methods by those skilled in the
art.
Alternatively, compounds of formula (2da) may be prepared from
compounds of formula (3d) using a suitable dehydrating agent such as
Burgess’ reagent, triphenyl phosphine and hexachloroethane, phosphorus
oxychloride, acetic acid or Mitsunobu conditions
(diethylazodicarboxylate/triphenylphosphine/trimethylsilylazide), in the
absence or presence of a suitable solvent such as tetrahydrofuran, toluene or
NMP, at a range of temperatures, preferably between room temperature and
150°C.
Compounds of formula (3d) may be prepared from compounds of
formula (3a) by reaction with a compound of general formula (3b1) using a
suitable acylating/dehydrating agent such as
triphenylphosphine/trichloroacetonitrile in the presence of a base such as
diisopropylethylamine, in a suitable solvent such as dichloromethane or
acetonitrile, at a range of temperatures, preferably between room temperature
and 150°C.
Or by reaction with a compound of general formula (3b2) in the
presence of a base such as diisopropylethylamine, in a suitable solvent such as
dichloromethane or THF at a range of temperatures preferably between -10°C
and the boiling point of the solvent.
Compounds of formulae (3b1) and (3b2) are commercially available,
known in the literature or may be prepared by literature methods by those
skilled in the art.
Alternatively, compounds of formula (2da) as above defined may be
prepared according to the route in Scheme 4:
(4c)
G N G N
13 13
(4a)
(4b) (2da)
Scheme 4
Compounds of general formula (2da) may be prepared from compounds
of general formula (4c). Wherein G may represent groups such as halogen,
-CHO, -COOH, -COOEt and SO Cl.
For example, compounds of general formula (2da) may be prepared
from compounds of general formula (4c), wherein G represents halogen,
using methods such as a metal (for example palladium) catalysed coupling
11 5 5
with a suitable R G derivative wherein G is a group such as boronate
acid/ester or stannane in a suitable solvent such as tetrahydrofuran or
1,4-dioxane at a range of temperatures preferably between ambient
temperature and 150°C. An alternative method may involve displacement of
said halogen with a suitable group R H (such as that containing an -NH, -OH
or -SH group) in the presence of a base such as sodium hydride, potassium
tert-butoxide or N,N-diethylisopropylamine in a suitable solvent such as
N,N-Dimethylformamide, toluene, 1,4-dioxane or acetonitrile at a range of
temperatures, preferably between room temperature and 150°C.
The group G may be also transformed from groups such as halogen to
groups such as –CHO, -COOH, -COOEt and SO Cl by means of metal
insertion methods known to those skilled in the art such as palladium
catalysis, Grignard formation or lithium halogen exchange.
Compounds of general formula (2da) wherein R is a group such as -
A B C A B C
CH -NR R, -C(O)N(R )-(C -C alkylene)-NR R, -C(O)N(R )-(C -
2 2 6 3
A B C D C
C cycloalkylene)-NR R, -C(O)N(R )-(C -C alkylene)-OR, -C(O)N(R )-
7 2 6
D A B C
(C -C cycloalkylene)-OR, -C(O)N(R R), -S(O) N(R )-(C -C alkylene)-
3 7 2 2 6
A B C A B C
NR R, -S(O) N(R )-(C -C cycloalkylene)-NR R, -S(O) N(R )-(C -
2 3 7 2 2
D C D
C alkylene)-OR or -S(O) N(R )-(C -C cycloalkylene)-OR may be prepared
6 2 3 7
from compounds of general formula (4c), wherein G represents -CHO,
-COOH, -COOEt and -SO Cl, by reaction with a suitable amine such as
HNR R etc using methods such as reductive amination (using a reagent such
as sodium triacetoxyborohydride) or amide/sulphonamide formation in the
presence of suitable reagents such as HATU with a base such as
N,N-diethylisopropylamine or trimethylaluminium in a suitable solvent such
as dichloromethane, N,N-dimethylformamide, toluene, 1,4-dioxane or
acetonitrile at a range of temperatures, preferably between room temperature
and 150°C.
Compounds of general formula (4c) wherein G is a group such as
–COOEt, may be synthesised from compounds of general formula (4a) by
reaction with a compound such as diethyloxalate in the presence of an acid
such as acetic acid at a range of temperatures, preferably between room
temperature and 120°C.
Compounds of general formula (4c) wherein G is a group such as
bromine or chlorine, may be synthesised from compounds of general formula
(4b) by reaction with a compound such as N-chlorosuccinimide or
N-bromosuccinimide in a solvent such as chloroform at a range of
temperatures, preferably between -10°C and room temperature.
Compounds of general formula (4b) may be synthesised from
compounds of general formula (4a) by reaction with a compound such as
diethoxymethylacetate at a range of temperatures, preferably between room
temperature and 100°C.
Compounds of general formula (2db), i.e. compounds of formula (2d)
wherein X is nitrogen, may be prepared from compounds of general formula
4 11
(4b) wherein X = NH, by reaction with a suitable alkylating agent R in the
presence of a base such as caesium carbonate in a suitable solvent such as
N,N-dimethylformamide at a range of temperatures, preferably between room
temperature and 150°C.
Alternatively, compounds of general formula (1aa), i.e. compounds of
formula (1a) wherein X is CH may be prepared according to the route
illustrated in Scheme 5.
NH Y
2 Y G
3 13
A 13
W PG R 3
(5c) (5b) (5a)
NH R
R 3 PG
PG 2
11 W
X 11
(1aa)
(5d)
(5e)
Scheme 5
Compounds of general formula (1aa) may be prepared from compounds
of general formula (5e) wherein PG is a suitable protecting group known in
the art such as Boc by using the appropriate deprotection conditions such as
trifluoroacetic acid in a solvent such as dichloromethane at a range of
temperatures, preferably between -10°C and room temperature.
Compounds of general formula (5e) may be prepared from compounds
of general formula (5d) using a suitable dehydrating agent such as Burgess’
reagent, triphenyl phosphine and hexachloroethane, phosphorus oxychloride,
acetic acid or Mitsunobu conditions
(diethylazodicarboxylate/triphenylphosphine/trimethylsilylazide), in the
absence or presence of a suitable solvent such as tetrahydrofuran, toluene or
NMP, at a range of temperatures, preferably between room temperature and
120°C.
Compounds of general formula (5d) may be prepared from compounds
of general formula (5c) by reaction with a compound of general formula (3b1)
as above defined using a suitable acylating/dehydrating agent such as
triphenylphosphine/trichloroacetonitrile in the presence of a base such as
diisopropylethylamine, in a suitable solvent such as dichloromethane or
acetonitrile, at a range of temperatures, preferably between room temperature
and 150°C.
or by reaction with a compound of general formula (3b2) as above
defined in the presence of a base such as diisopropylethylamine, in a suitable
solvent such as dichloromethane or THF at a range of temperatures preferably
between -10°C and the boiling point of the solvent.
Compounds of general formula (5c) may be prepared from compounds
of general formula (5b) wherein G is a suitable leaving group such as
halogen, by reaction with a reagent such as hydrazine monohydrate in a
suitable solvent such as ethanol at a range of temperatures preferably between
room temperature and 100°C.
Compounds of general formula (5b) may be prepared from compounds
of general formula (5a) by reaction with a suitable protecting group reagent
known in the art such as Boc anhydride in the presence of a base such as
triethylamine in a suitable solvent such as dichloromethane or tetrahydrofuran
at a range of temperatures preferably between room temperature and 100°C.
Compounds of general formula (5a) can be synthesised by the methods
described above for the synthesis of (1a).
Compounds of general formula (2aa), i.e. compounds of formula (2a)
wherein Y = O,W = NH and PG is a suitable protective group such as
trifluoroacetate may be prepared according to the route illustrated in scheme
6:
O (6b)
(6a) (2aa)
(6c)
Scheme 6
Compounds of general formula (2aa) may be prepared from compounds
of general formula (6b) and (6c) by removal of the protecting group PG using
methods known in the art such as aqueous sodium hydroxide in a solvent such
as methanol at a range of temperatures preferably between room temperature
and 100°C.
Compounds of general formula (6b), wherein PG is a protecting group,
preferably trifluoroacetamide, and the group –OH is placed on the
cycloalkylene portion of ring A may be prepared from compounds of general
formula (6a) by using a chiral reductive method such as using formic acid and
RuCl[S,S-Tsdpen(p-cymene)] in the presence of a base such as triethylamine
in a solvent such as N,N-dimethylformamide at a range of temperatures
preferably between room temperature and 150°C. It will be recognised that
compounds of formula (6a) may be homochiral as illustrated or be the
opposite enantiomer or racemic.
It will be realised by those skilled in the art that any combination of
stereocentres in (2aa) can be prepared using both enantiomers of (6a) and
using RuCl[R,R-Tsdpen(p-cymene)] or RuCl[S,S-Tsdpen(p-cymene)].
Compound (2a) is drawn with no defined stereocentres but any combination
can be obtained as illustrated in Scheme 2.
Compounds of formula (6a) can be prepared from compounds of
formula (6d)
(6d)
using a suitable oxidant such as potassium permanganate and
magnesium sulfate in a suitable solvent methanol/water at a range of
temperatures preferably between room temperature and the boiling point of
the solvent. It will be recognised that compounds of formula (6d) may be
homochiral as illustrated or be the opposite enantiomer or racemic.
Compounds of formula (6d) can be prepared from compounds of
formula (6e) where PG is a suitable protecting group such as trifluoroacetate
or tert-butyl carbonate:
(6e)
using ethyl trifluoroacetate or di-tert-butyl dicarbonate in the presence
of base such as triethylamine or diisopropylethylamine in a solvent such as
methanol or dichloromethane at a range of temperatures preferably between
0°C and the boiling point of the solvent. It will be recognised that compounds
of formula (6e) may be homochiral as illustrated or be the opposite enantiomer
or racemic.
Compounds of formula (6e) are known in the literature and may be
prepared by those skilled in the art by adapting literature methods (e.g. for
S-(+)amino-1,2,3,4-tetrahydronaphthalene see Journal of the Chemical
Society, Perkin Transactions 1: 1985, 2039-44, for (S)-(+)amino-5,6,7,8-
tetrahydroquinoline see Journal of Organic Chemistry, 2007, 72, 669-671 and
for 1-aminoindan see Tetrahedron Letters, 2011, 52, 1310-1312).
Compounds of general formula (2ab), i.e. compounds of formula (2a)
wherein Y = NR and W = NH, may be prepared according to the route
illustrated in scheme 7:
R NH
(7b) Y
(6a)
(7a)
(2ab)
R NH
(7b)
(6b)
or N
(7c)
(6c)
Scheme 7
Compounds of general formula (2ab) may be prepared from compounds
of general formula (7a) by removal of the protecting group PG using methods
known in the art such as aqueous sodium hydroxide in a solvent such as
methanol or trifluoroacetic acid in dichloromethane at a range of temperatures
preferably between room temperature and 100°C.
Compounds of formula (7a) may be prepared from compounds of
general formula (6a) and amines (7b) by reaction under reductive amination
conditions, using a reducing agent such as sodium triacetoxyborohydride and a
solvent such as 1,2-dichloroethane at a range of temperatures preferably
between room temperature and 100°C.
Compounds for formula (7b) are known in the literature and may be
prepared by those skilled in the art using literature procedures. Compounds of
formula (6a) can be prepared as described above.
Alternatively, compounds of formula (7a) may be prepared from
compounds of general formula (7c) wherein G is a suitable chemical group
known to those skilled in the art selected such that it can facilitate a reaction
such as a nucleophilic substitution. For example G is a suitable leaving group
such as halogen or mesylate which can react with a suitable amine (7b) in the
presence of a suitable base such as sodium hydride or potassium tert-butoxide
and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone in a suitable solvent
such as N,N-dimethylformamide, toluene, 1,4-dioxane or acetonitrile at a
range of temperatures, preferably between room temperature and 150°C.
Compounds of formula (7c) can be prepared from compounds of
formulae (6b) or (6c) using halogenating conditions such as carbon
tetrabromide and triphenylphosphine in dichloromethane or activation
conditions such as methane sulfonyl chloride in dichloromethane in the
presence of base such as diisopropylamine.
Alternatively, compounds of general formula (Id), i.e. compounds of
formula (I) wherein Y = S and W = NH may be prepared according to the
route illustrated in scheme 8:
S O S
HO O
(8a) (8b) (8c) (8d) (8e)
(1b1)
O H 1
(2b), (2c) or (2d) Y 1
(1b2) R
(1a) (Id)
(8f) (8g)
Scheme 8
Compounds of general formula (Id) may be prepared from compounds
of general formula (1ab), i.e. compounds of formula (1a) wherein Y = S and
W = NH: using compounds of formula (1b1) or (1b2) in a suitable solvent
such as dimethyl sulfoxide, 1,4-dioxane, N,N-dimethylformamide or
acetonitrile, in the presence of a base such as diisopropylethylamine at a range
of temperatures, preferably between room temperature and 100°C.
Compounds of formula (1ab) as above defined may be prepared from
compounds of formula (8g) using deprotection conditions such as hydrazine in
methanol at a range of temperatures preferably between room temperature and
the boiling point of the solvent.
Compounds of formula (8g) wherein Y = S, can be prepared from
compounds of formula (8f) by reaction with compounds of formulae (2b), (2c)
or (2d). Examples of the coupling conditions used may include using a base
such as sodium hydride or potassium tert-butoxide and 1,3-dimethyl-3,4,5,6-
tetrahydro-2(1H)-pyrimidinone in a suitable solvent such as
N,N-dimethylformamide, toluene, 1,4-dioxane or acetonitrile at a range of
temperatures, preferably between room temperature and 150°C. Alternative
methods to perform this coupling may involve Mitsunobu conditions
(diethylazodicarboxylate / triphenylphosphine) or metal (for example
palladium) catalysed coupling conditions in a suitable solvent such as
tetrahydrofuran or 1,4-dioxane at a range of temperatures preferably between
-10°C and 150°C and starting from the appropriate derivative of formula (2b),
(2c), or (2d).
Compounds of formula (8f) can be prepared from compounds of
formula (8e) using dithiothreitol, monopotassium phosphate, potassium
carbonate in a solvent such as methanol in the presence of acetic acid at a
range of temperatures preferably between room temperature and the boiling
point of the solvent.
Compounds of formula (8e) can be prepared from compounds of
formula (8d) using 2-nitrobenzenesulfenyl chloride in acetic acid at a range of
temperatures preferably between room temperature and 100°C.
Compounds of formula (8d) can be prepared from compounds of
formula (8c) using phthalimide, triphenylphosphine and diisopropyl
azodicarboxylate in a solvent such as tetrahydrofuran at a range of
temperature preferably between 0°C and the boiling point of the solvent.
Compounds of formula (8c) can be prepared from compounds of
formula (8b) using a reducing agent such as sodium borohydride in a solvent
such as methanol at a range of temperatures preferably between 0°C and the
boiling point of the solvent.
Compounds of formula (8b) can be prepared from compounds of
formula (8a) using tert-butanethiol in the presence of a base such as
diisopropylethylamine in a solvent such as tetrahydrofuran at a range of
temperatures preferably between 0°C and the boiling point of the solvent.
Compounds of formula (8a) are known in the literature and can be
prepared by those skilled in the art using literature methods (e.g. 3-bromo-
indanone see WO 2010108058).
Alternatively, compounds of general formula (1ab), i.e. compounds of
formula (1a) wherein Y = CH , W = NH and PG is a suitable protective group
such as trifluoroacetate may be prepared according to the route illustrated in
scheme 9:
(9a) (9b)
(6a)
(1ab)
Scheme 9
Compounds of general formula (1ab) may be prepared from compounds
of general formula (9b) by removal of the protecting group PG using methods
known in the art such as aqueous sodium hydroxide in a solvent such as
methanol at a range of temperatures preferably between room temperature and
100°C.
Compounds of formula (9b) may be prepared from compounds of
general formula (9a) by reaction with a suitable reduction agent for example
hydrogen gas in the presence of a suitable catalyst such as palladium on
activated charcoal in a suitable solvent such as ethanol at a range of
temperatures between room temperature and 70°C and pressures between
atmospheric and 4 Barr.
Compounds of formula (9a) may be prepared from compounds of
general formula (6a) by means of a reaction such as a Wittig (or one of the
closely related variants such as the Horner-Wadsworth-Emmons) with a
suitable substrate such as R -CH -P(O)(OMe) in the presence of a suitable
base such as sodium hydride in a suitable solvent such as tetrahydrofuran at a
range of temperatures preferably between -10°C and 100°C.
Compounds such as R -CH -P(O)(OMe) may be synthesised from
compounds of the general formula R -CH -Hal wherein Hal represents a
halogen such as -Br or -Cl by reaction with a compound such as
trimethylphosphite at a range of temperatures preferably between 0°C and
100°C.
Compounds such as R -CH -Hal may be synthesised from compounds
of formula R -CH by means of a reaction such as a radial halogenation using
a reagent such as N-bromosuccinimide in the presence of a catalyst such as
AIBN in a suitable solvent such as carbon tetrachloride at a range of
temperatures preferably between 0°C and 80°C. Compounds such as R -CH -
Hal may also be synthesised from compounds formula R -CH -OH by means
of using halogenating conditions such as carbon tetrabromide and
triphenylphosphine in dichloromethane or activation conditions such as
methane sulfonyl chloride in dichloromethane in the presence of base such as
diisopropylamine.
Compounds such as R -CH and R -CH -OH may be prepared by
methods outlined above for compounds (2b), (2c) and (2d).
Compounds of formula (1ac), i.e. compounds of formula (1a) where Y =
(CR R ) and W = NH, may be prepared according to the route illustrated in
Scheme 10.
R Y B(OR)
OTf (10f)
A PG
(6a)
(10a)
(10b)
(1ac)
(10c)
Scheme 10
Compounds of formula (1ac) may be prepared from compounds of
formula (10c) wherein PG is a suitable protecting group known to those
skilled in the art, such as trifluoroacetamide, tert-butyl carbamate and benzyl
carbamate by using suitable de-protection conditions such as, sodium
hydroxide in methanol, trifluoroacetic acid in dichloromethane or hydrogen
gas catalysed by for example palladium on carbon in ethanol, at a range of
temperatures, preferably between 0°C and 100°C.
Compounds of formula (10c) may be prepared from compounds of
formula (10b) wherein PG is a suitable protecting group known to those
skilled in the art, such as trifluoroacetamide, tert-butyl carbamate and benzyl
carbamate by using hydrogen gas in the presence of a catalyst such as
palladium on carbon, in a suitable solvent such as methanol or ethanol, in the
presence or absence of an acid such as HCl, at a range of temperatures,
preferably between 0°C and 100°C.
Compounds of formula (10b) may be prepared from compounds of
formula (10a) and (10f) by a reaction such as a cross-coupling using a suitable
catalyst such as tetrakis(triphenylphosphine)palladium (0) or palladium
acetate, and a base such as diisopropylethylamine, sodium tert-butoxide or
caesium carbonate in a suitable solvent such as NMP, toluene or DMF, at a
range of temperatures, preferably between 0°C and 100°C. Alternatively (10b)
may be prepared by adapting literature procedures (e.g those reported in
WO2009022633).
Compounds of formula (10f) are known in the literature or may be
prepared by those skilled in the art by adapting literature procedures (e.g
WO2008063287).
Compounds of formula (10a) may be prepared from compounds of
formula (6a) using a triflating agent such as triflic anhydride, in the presence
of a suitable base such as pyridine or 2,6-bis(tert-butyl)methylpyridine, in a
solvent such as dichloromethane or chloroform at a range of temperatures,
preferably between 0°C and boiling point of the solvent. Alternatively (10a)
may be prepared by adapting literature procedures (e.g those described in
WO2009022633).
General experimental details
Abbreviations used in the experimental section: AcOH = acetic acid; aq. =
aqueous; DCM = dichloromethane; DIAD = Diisopropyl azodicarboxylate; DIPEA
= diisopropylethylamine; DMAP = N,N- dimethylaminopyridine; DMF = N,N-
dimethylformamide; DMSO = dimethyl sulfoxide; EDC = 1-ethyl(3'-
dimethylaminopropyl)carbodiimide Hydrochloride; EtOAc = ethyl acetate; EtOH
= ethanol; EtO = diethyl ether; EtN = triethylamine; EtNiPr =
2 3 2
diisopropylethylamine; FCC = flash column chromatography; h = hour; HATU =
2-(7-aza-1H-benzotriazoleyl)-1,1,3,3-tetramethyluronium hexafluorophosphate;
HOBt = 1-hydroxy-benzotriazole; HPLC = high performance liquid
chromatography; IMS = Industrial Methylated Spirits; LCMS = liquid
chromatography mass spectrometry; NaOH = sodium hydroxide; MeCN =
acetonitrile; MeOH = MeOH; min = minutes; NH = ammonia; NMR = nuclear
magnetic resonance; RT = room temperature; Rt = retention time; sat. = saturated;
SCX-2 = strong cation exchange chromatography; TFA = trifluoroacetic acid; THF
= Tetrahydrofuran; H O = water; IMS = industrial methylated spirit; Xantphos =
4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene; X-Select = Waters
X-select HPLC column; IPA = propanol; LDA = lithium diisopropylamide;
MDAP = mass-directed auto-purification; MeOH = methanol; PhP =
triphenylphosphine; TBAF = tetrabutylammonium fluoride.
In the procedures that follow, after each starting material, reference to a
Intermediate/Example number is usually provided. This is provided merely for
assistance to the skilled chemist. The starting material may not necessarily
have been prepared from the batch referred to.
When reference is made to the use of a “similar” or “analogous”
procedure, as will be appreciated by those skilled in the art, such a procedure
may involve minor variations, for example reaction temperature,
reagent/solvent amount, reaction time, work-up conditions or chromatographic
purification conditions.
The nomenclature of structures was assigned using Autonom 2000
Name software from MDL Inc. When the nomenclature of structures could not
be assigned using Autonom, ACD/Name software utility part of the ACD/Labs
Release 12.00 Product Version 12.5 (Build 45133, 16 Dec 2010) was used.
Stereochemical assignments of compounds are based on comparisons with
data reported in WO2008/043019 for key intermediates. All reactions were
carried out under anhydrous conditions and an atmosphere of nitrogen or
argon unless specified otherwise. Unless otherwise stated all transformations
were carried at ambient temperature (room temperature).
NMR spectra were obtained on a Varian Unity Inova 400 spectrometer
with a 5mm inverse detection triple resonance probe operating at 400 MHz or
on a Bruker Avance DRX 400 spectrometer with a 5 mm inverse detection
triple resonance TXI probe operating at 400 MHz or on a Bruker Avance DPX
300 spectrometer with a standard 5mm dual frequency probe operating at 300
MHz. Shifts are given in ppm relative to tetramethylsilane ( δ = 0 ppm). J
values are given in Hz through-out. NMR spectra were assigned using
DataChord Spectrum Analyst Version 4.0.b21 or SpinWorks version 3.
Where products were purified by flash column chromatography, ‘flash
silica’ refers to silica gel for chromatography, 0.035 to 0.070 mm (220 to 440
mesh) (e.g. Fluka silica gel 60), and an applied pressure of nitrogen up to 10
p.s.i accelerated column elution or use of the CombiFlash® Companion
purification system or use of the Biotage SP1 purification system. All solvents
and commercial reagents were used as received.
Compounds purified by preparative HPLC were purified using a C18-
reverse-phase column (100 × 22.5 mm i.d. Genesis column with 7 µm particle
size), or a Phenyl-Hexyl column (250 x 21.2 mm i.d. Gemini column with 5 µm
particle size), UV detection between 220 - 254 nm, flow 5-20 mL/min), eluting
with gradients from 100-0 to 0-100% water/acetonitrile (containing 0.1% TFA or
0.1% formic acid) or water/MeOH (containing 0.1% TFA or 0.1% formic acid), or
a C18-reverse-phase column (19 × 250 mm, XBridge OBD, with 5 µm particle
size), eluting with gradients from 100-0 to 0-100% water/acetonitrile (containing
0.1% NH OH); or a ChiralPak IC column (10 × 250 mm i.d., with 5 µm particle
size), unless otherwise indicated. Fractions containing the required product
(identified by LCMS analysis) were pooled, the organic solvent removed by
evaporation, and the remaining aqueous residue lyophilised, to give the final
product. Products purified by preparative HPLC were isolated as free base, formate
or TFA salts, unless otherwise stated.
The Liquid Chromatography Mass Spectroscopy (LCMS) and HPLC
systems used are:
Method 1
Waters Platform LC Quadrupole mass spectrometer with a C18-reverse-
phase column (30 × 4.6 mm Phenomenex Luna 3 µm particle size), elution
with A: water + 0.1% formic acid; B: acetonitrile + 0.1% formic acid.
Gradient:
Gradient - Time flow mL/min %A %B
0.00 2.0 95 5
0.50 2.0 95 5
4.50 2.0 5 95
.50 2.0 5 95
6.00 2.0 95 5
Detection - MS, ELS, UV (200 µL split to MS with in-line HP1100
DAD detector). MS ionization method - Electrospray (positive and negative
ion).
Method 2
Waters ZMD quadrupole mass spectrometer with a C18-reverse-phase
column (30 × 4.6 mm Phenomenex Luna 3 µm particle size), elution with A:
water + 0.1% formic acid; B: acetonitrile + 0.1% formic acid. Gradient:
Gradient - Time flow mL/min %A %B
0.00 2.0 95 5
0.50 2.0 95 5
4.50 2.0 5 95
.50 2.0 5 95
6.00 2.0 95 5
Detection - MS, ELS, UV (200 µL split to MS with in-line Waters 996
DAD detector). MS ionization method - Electrospray (positive and negative
ion).
Method 3
Waters ZMD quadrupole mass spectrometer with a C18-reverse-phase
column (30 × 4.6 mm Phenomenex Luna 3 µm particle size), elution with A:
water + 0.1% formic acid; B: acetonitrile + 0.1% formic acid. Gradient:
Gradient - Time flow mL/min %A %B
0.00 2.0 95 5
0.50 2.0 95 5
4.50 2.0 5 95
.50 2.0 5 95
6.00 2.0 95 5
Detection - MS, ELS, UV (200 µL split to MS with in-line HP1100
DAD detector). MS ionization method - Electrospray (positive and negative
ion).
Method 4
VG Platform II quadrupole spectrometer with a C18-reverse-phase
column (30 × 4.6 mm Phenomenex Luna 3 µm particle size, elution with A:
water + 0.1% formic acid; B: acetonitrile + 0.1% formic acid. Gradient:
Gradient - Time flow mL/min %A %B
0.00 2.0 95 5
0.30 2.0 95 5
4.30 2.0 5 95
.30 2.0 5 95
.80 2.0 95 5
6.00 2.0 95 5
Detection - MS, ELS, UV (200 µl/min split to the ESI source with
inline HP1050 DAD detector). MS ionization method - Electrospray (positive
and negative ion).
Method 5
Waters micromass ZQ2000 quadrupole mass spectrometer with an
Acquity BEH C18 1.7um 100 x 2.1mm, Acquity BEH Shield RP18 1.7um 100
x 2.1mm or Acquity HSST3 1.8um 100 x 2.1mm, maintained at 40°C. Elution
with A: water + 0.1% formic acid; B: acetonitrile + 0.1% formic acid.
Gradient:
Gradient - Time flow mL/min %A %B
0.00 0.4 95 5
0.40 0.4 95 5
6.00 0.4 5 95
6.80 0.4 5 95
7.00 0.4 95 5
8.00 0.4 95 5
Detection - MS, UV PDA. MS ionization method - Electrospray
(positive and negative ion).
Method 6
Phenomenex Gemini C18-reverse-phase column (250 × 21.20 mm 5 µm
particle size), elution with A: water + 0.1% formic acid; B: CH CN + 0.1%
formic acid. Gradient - 90% A/10% B to 2% A/98% B over 20 min - flow rate
18 mL/min. Detection - In-line UV detector set at 254 nM wavelength.
Method 7
Agilent 1260 infinity purification system. Column: XSELECT CSH
Prep C18 OBD, particle size 5µm, 30 × 150mm, RT. Elution with A: water +
0.1% formic acid; B: CH3CN + 0.1% formic acid. Gradient - 90% A/10% B to
2% A/95% B over 22 min - flow rate 60 mL/min. Detection - In-line Agilent
6100 series single Quadrupole LC/MS.
Method 8
Agilent 1260 infinity purification system. Column: XBridge Prep C18
OBD, particle size 5µm, 30 × 150mm, RT. Elution with A: water + 0.1%
ammonia; B: CH CN + 0.1% ammonia. Gradient - 90% A/10% B to 2% A/95% B
over 22 min - flow rate 60 mL/min. Detection - In-line Agilent 6100 series single
Quadrupole LC/MS.
Differential Scanning Calorimetry (DSC): it should be recognized that
the endotherm peak as measured is dependent on a number of factors including the
machine used, the rate of heating, the calibration standard, humidity and the purity
of the sample used.
Melting points reported in the experimentals are estimated on the basis of
the onset of endotherm peaks registered during DSC analysis.
It is to be understood by the skilled person that, where the expression
“partial formate salt” is used, it is to be intended as identifying derivatives where
only part of the basic compound has been converted into formate salt and thus
containing less than one equivalent of formate counterion. Exact salt/free base
ratio is provided by associated NMS analysis.
Intermediate A
(1R,4S)Amino-1,2,3,4-tetrahydro-naphthalenol
a. 2,2,2-Trifluoro-N-(S)-1,2,3,4-tetrahydro-naphthalenyl-
acetamide (Intermediate Aa)
Ethyl trifluoroacetate (24.2 mL, 204 mmol) was added dropwise to a
solution of (S)-(1,2,3,4-tetrahydro-naphthalenyl)amine (Alfa Aesar; 25.0 g,
170 mmol) and triethylamine (35.5 mL, 255 mmol) in MeOH (250 mL) at RT
and stirred for 18 h. The mixture was concentrated to approximately 1/3 of its
volume and then partitioned between DCM (200 mL) and water (200 mL). The
aqueous layer was extracted into DCM (3 x) and the combined organic layers
were washed with brine, dried (MgSO ) and concentrated in vacuo to yield the
title compound (41.1 g, 169 mmol, 99%). ¹H NMR (400 MHz, CDCl ):
1.80-1.95 (3H, m), 2.05-2.15 (1H, m), 2.75-2.90 (2H, m), 5.18-5.25 (1H, q, J
5.0 Hz), 6.38-6.48 (1H, br s), 7.12-7.16 (1H, m), 7.20-7.26 (3H, m).
b. 2,2,2-Trifluoro-N-((S)oxo-1,2,3,4-tetrahydro-naphthalenyl)-
acetamide (Intermediate Ab)
Magnesium sulfate monohydrate (46.6 g, 338 mmol) in water (500 mL)
was added to an ice cold solution of Intermediate Aa (41.1 g, 169 mmol) in
acetone (1.0 L). Potassium permanganate (80.1 g, 507 mmol) was added
portionwise (10.0 g portions) over a period of 45 min. The mixture was then
stirred for 18 h. Sodium thiosulfate pentahydrate (126 g, 510 mmol) in water
(400 mL) was added and the reaction stirred for 30 min. The mixture was
concentrated to ~300 mL, then water (1.0 L), Celite (60 g) and EtOAc (1.0 L)
were sequentially added. The mixture was thoroughly stirred, and then filtered
through a pad of Celite. The aqueous layer was extracted into EtOAc (3 x) and
the combined organic layers washed with brine, dried (MgSO) and
concentrated in vacuo to yield the title compound (36.6 g, 142 mmol, 84%).
¹H NMR (400 MHz, CDCl ): 2.20-2.30 (1H, dddd, J 13.3, 10.0, 8.8, 4.5 Hz),
2.43-2.52 (1H, dddd, J 13.3, 7.2, 4.6, 4.6 Hz), 2.67-2.77 (1H, ddd, J 17.4,
10.1, 4.6 Hz), 2.78-2.88 (1H, ddd, J 17.4, 7.1, 4.6 Hz), 5.39-5.47 (1H, td, 8.5,
4.5 Hz), 7.32-7.37 (1H, d, J 7.7 Hz), 7.44-7.49 (1H, t, J 7.6 Hz), 7.59-7.64
(1H, td, J 7.6, 1.4 Hz), 8.03-8.07 (1H, dd, J 7.7, 1.4 Hz).
c. 2,2,2-Trifluoro-N-((1S,4R)hydroxy-1,2,3,4-tetrahydro-
naphthalenyl)-acetamide (Intermediate Ac)
Degassed DMF (argon sparged, 100 mL) was added to Intermediate Ab
(8.00 g, 31.3 mmol) and [N-[(1R,2R)(amino- κN)-1,2-diphenylethyl]
methylbenzenesulfonamidato- κN]chloro[(1,2,3,4,5,6- η)methyl(1-
methylethyl)benzene]-ruthenium (Strem Chemicals Inc.; 594 mg, 0.93 mmol).
Triethylamine (8.66 mL, 62.6 mmol) was added slowly to ice cold formic acid
(2.34 mL, 62.6 mmol) and stirred for 20 min, this was then added to the DMF
solution. The reaction was heated to 60°C for 18 h. After cooling, the mixture
was partitioned between DCM (200 mL) and water (600 mL). The aqueous
layer was extracted DCM (3 x) and the combined organic layers washed with
brine, dried (MgSO ) and concentrated in vacuo. Purification by FCC, using
0-100% EtOAc in cyclohexane, afforded the title compound (7.10 g, 27.4
mmol, 88%). ¹H NMR (400 MHz, CDCl ): 1.88-1.92 (1H, d, J 4.8 Hz), 1.98-
2.18 (4H, m), 4.80-4.88 (1H, m), 5.165-5.24 (1H, m), 6.70-6.80 (1H, br s),
7.25-7.30 (1H, m), 7.30-7.40 (2H, m), 7.45-7.50 (1H, m).
d. (1R,4S)Amino-1,2,3,4-tetrahydro-naphthalenol
(Intermediate A)
Sodium hydroxide (2.10 g, 53.0 mmol) was added to an ice cold
solution of Intermediate Ac (3.43 g, 13.2 mmol) in MeOH/water (2:1, 50 mL)
and stirred for 3.5 h. The mixture was loaded on to a SCX-2 cartridge, eluting
with MeOH then 2M NH in MeOH, to yield the title compound (2.30 g, 13.2
mmol, 99%). ¹H NMR (400 MHz, d -DMSO): 1.66-1.90 (4H, m), 3.71-3.77
(1H, t, J 5.4 Hz), 4.46-4.54 (1H, t, J 5.4 Hz), 7.14-7.22 (2H, m), 7.32-7.38
(1H, m), 7.40-7.46 (1H, m).
Intermediate B
(1S,4S)Amino-1,2,3,4-tetrahydro-naphthalenol
a. 2,2,2-Trifluoro-N-((1S,4S)hydroxy-1,2,3,4-tetrahydro-
naphthalenyl)-acetamide (Intermediate Ba)
Argon was bubbled through a solution of Intermediate Ab (8.00 g, 31.1
mmol) and [N-[(1S,2S)(amino- κN)-1,2-diphenylethyl]
methylbenzenesulfonamidato- κN]chloro[(1,2,3,4,5,6- η)methyl(1-
methylethyl)benzene]-ruthenium (Strem Chemicals Inc.; 0.06 g, 0.93 mmol) in
dry DMF (100 mL) for 10 min. A premixed combination of formic acid
(2.4 mL, 62.2 mmol) and Et N (8.60 mL, 62.2 mmol) was added and the
mixture stirred at 50°C for 24 h. After cooling, the mixture was concentrated
to ~25 mL. Water (70 mL) was added and the resulting precipitate filtered,
and washed with DCM (3 × 30 mL) and diethyl ether (30 mL) to leave a solid
(4.75 g). The filtrate was decanted to leave a dark solid. Subsequent
purification by FCC, using 0-30% EtOAc in cyclohexane, gave a solid. This
was combined with the first obtained solid to give the title compound as a
beige solid (5.93 g, 74%). H NMR (400 MHz, d -DMSO): 1.60-1.83 (2H, m),
2.06-2.17 (2H, m), 4.60 (1H, m), 5.08 (1H, m), 5.28 (1H, d), 7.07 (1H, m),
7.25 (1H, ddd), 7.28 (1H, ddd), 7.50 (1H, dd), 9.78 (1H, d).
b. (1S,4S)Amino-1,2,3,4-tetrahydro-naphthalenol (Intermediate B)
To a grey solution of Intermediate Ba (5.55 g, 21.4 mmol) in MeOH
(50 mL), NaOH (1.28 g, 32.1 mmol) in water (15 mL) was added and the
mixture stirred at RT for 3 days. NaOH (1.28 g, 32.1 mmol) was added and
the brown solution was stirred for 5 h. The solution was loaded on to a SCX-2
cartridge, eluting with MeOH then 2M NH in MeOH, to leave a grey solid.
The solid was suspended in DCM (50 mL), sonicated, filtered and dried under
vacuum to leave the title compound as a pale grey solid (2.93 g, 84%). H
NMR (400 MHz, d -DMSO): 1.41-1.64 (2H, m), 2.02-2.13 (2H, m), 3.82 (1H,
dd), 4.55 (1H, dd), 5.08 (1H, br s), 7.13-7.22 (2H, m), 7.35-7.49 (2H, m).
Example 1
1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-(2-
pyrrolidinyl-ethyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-urea
a. 3-Pyrrolidinyl-propionic acid N'-(5-fluoro-pyridinyl)-
hydrazide (Intermediate 1a)
-fluorohydrazinopyridine (285 mg, 2.24 mmol) and 3-(pyrrolidin
yl)propanoic acid hydrochloride (400 mg, 2.24 mmol) were dissolved in DMF
(15 mL). EDC (516 mg, 2.69 mmol), HOBt (30.0 mg, 0.22 mmol) and
triethylamine (374 µL, 2.69 mmol) were added and the reaction stirred for
18 h. The mixture was loaded onto an SCX-2 cartridge, which was washed
with MeOH then with 2M NH in MeOH. The basic fractions were evaporated
in vacuo then purified by FCC using 0-10% [2M NH in MeOH] in DCM to
give the title compound contaminated with several impurities (400 mg). The
product was used in the next step without further purification.
b. 6-Fluoro(2-pyrrolidinyl-ethyl)-[1,2,4]triazolo[4,3-a]pyridine
(Intermediate 1b)
Intermediate 1a (400 mg) was dissolved in THF (20 mL) and cooled in
an ice/water bath. Triphenylphosphine (643 mg, 2.45 mmol) was added
followed by triethylamine (682 µL, 4.90 mmol) and hexachloroethane
(581 mg, 2.45 mmol). The reaction mixture was stirred for 18 h and then
loaded onto an SCX-2 cartridge, which was washed with MeOH then eluted
with 2M NH in MeOH. The resulting residue was purified by FCC using
0-10% [2M NH in MeOH] in DCM to give the title compound (292 mg, 1.16
mmol, 52%). ¹H NMR (400 MHz, CDCl ): 1.80-1.87 (4H, m), 2.60-2.68 (4H,
m), 3.00-3.10 (2H, t, J 7.3), 3.24-3.34 (2H, t, J 7.3), 7.13-7.21 (1H, ddd, J 9.9,
7.6, 2.3), 7.70-7.77 (1H, dd, J 9.8, 4.5), 8.00-8.04 (1H, m).
c. (1S,4R)[3-(2-Pyrrolidinyl-ethyl)-[1,2,4]triazolo[4,3-
a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenylamine (Intermediate
Intermediate A (189 mg, 1.16 mmol) was added to a suspension of
sodium hydride (60% in mineral oil, 139 mg, 3.48 mmol) in DMF (5 mL). The
reaction was stirred for 20 mins, then Intermediate 1b (292 mg, 1.16 mmol)
was added in DMF (5 mL) and the reaction heated to 60°C for 2 h. The
mixture was cooled and quenched by dropwise addition of MeOH. The
solution was loaded onto an SCX-2 cartridge, which was washed with MeOH
and product eluted with 2M NH in MeOH. The residue was purified by FCC
using 0-10% [2M NH in MeOH] in DCM to give the title compound (270 mg,
0.74 mmol, 64%).¹H NMR (400 MHz, d -MeOD): 1.80-1.86 (4H, m), 1.92-
2.02 (1H, m), 2.05-2.18 (2H, m), 2.30-2.40 (1H, m), 2.62-2.70 (4H, m), 2.99-
3.05 (2H, t, J 7.8), 3.28-3.36 (2H, t, J 7.8), 3.98-4.04 (1H, dd, J 8.6, 5.2), 5.46-
.50 (1H, t, J 4.3), 7.22-7.40 (4H, m), 7.54-7.58 (1H, d, J 7.8), 7.63-7.68 (1H,
dd, J 9.8, 0.7), 7.97 (1H, s), 8.09-8.11 (1H, d, J 1.6).
d. 1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-(2-
pyrrolidinyl-ethyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-urea (Example 1)
Intermediate 1c (270 mg, 0.74 mmol) was dissolved in 1,4-dioxane (6
mL) and (5-tert-butylp-tolyl-2H-pyrazolyl)-carbamic acid 2,2,2-
trichloro-ethyl ester (Synthetic Communications, 2009, 39, 3999-4009; 329
mg, 0.81 mmol) and DIPEA (257 µL, 1.48 mmol) were added. The reaction
was heated to 60°C for 18 h. After cooling, the mixture was partitioned
between EtOAc (50 mL) and water (50 mL), and then extracted into EtOAc (3
x). The combined organic extracts were washed with brine, dried (MgSO ) and
evaporated in vacuo. The residue was purified by FCC, using 0-10% [2M NH
in MeOH] in DCM, then further purified by HPLC (C18 X-select column, 10-
98% MeCN in H O, 0.1% formic acid) to give the title compound (78.0 mg,
0.12 mmol, 17%). LCMS (Method 5): Rt 3.67 mins, m/z 633 [MH ]. ¹H NMR
(400 MHz, d -MeOD): 1.30 (9H, s), 1.90-2.06 (6H, m), 2.07-2.18 (1H, m),
2.22-2.30 (1H, m), 2.39 (3H, s), 3.08-3.16 (4H, m), 3.42-3.50 (4H, m), 4.87-
4.92 (1H, dd, J 9.0, 5.6), 5.43-5.47 (1H, t, J 4.2), 6.33 (1H, s), 7.20-7.36 (10H,
m), 7.62-7.66 (1H, d, J 9.7), 8.07-8.09 (1H, d, J 1.6), 8.45 (0.6H, s).
Example 2
1-(5-tert-Butylp-tolyl-2H-pyrazolyl)((1S,4R){3-[2-(4-
methyl-piperazinyl)-ethyl]-[1,2,4]triazolo[4,3-a]pyridinyloxy}-
1,2,3,4-tetrahydro-naphthalenyl)-urea formate salt
N OH
a. 3-(4-Methyl-piperazinyl)-propionic acid N'-(5-fluoro-pyridin-
2-yl)-hydrazide (Intermediate 2a)
-fluorohydrazinopyridine (295 mg, 2.32 mmol) and 3-(4-methyl
piperazinyl)propionic acid (400 mg, 2.32 mmol) were dissolved in DCM
(15 mL). EDC (536 mg, 2.79 mmol) and HOBt (31.0 mg, 0.23 mmol) were
added and the reaction stirred for 18 h. The mixture was loaded onto an SCX-
2 cartridge, which was washed with MeOH product eluted with 2M NH in
MeOH. Further purification by FCC, using 0-10% [2M NH in MeOH] in
DCM, afforded the title compound (458 mg, 1.63 mmol, 73%). ¹H NMR (400
MHz, CDCl ): 2.32 (3H, s), 2.48-2.54 (2H, t, J 6.0), 2.54-2.70 (8H, br s),
2.69-2.75 (2H, t, J 6.0), 6.60-6.65 (1H, dd, J 8.9, 3.3), 6.75-6.78 (1H, d, J 4.4),
7.25-7.34 (1H, m), 8.02-8.05 (1H, d, J 3.0), 10.50 (1H, s).
b. 6-Fluoro[2-(4-methyl-piperazinyl)-ethyl]-[1,2,4]triazolo[4,3-
a]pyridine (Intermediate 2b)
Intermediate 2a (458 mg, 1.63 mmol) was dissolved in THF (15 mL)
and cooled in an ice/water bath. Triphenylphosphine (854 mg, 3.26 mmol) was
added followed by triethylamine (907 µL, 6.52 mmol) and hexachloroethane
(773 mg, 3.26 mmol). The reaction was stirred for 18 h and then loaded onto
an SCX-2 cartridge, which was washed with MeOH and product eluted with
2M NH in MeOH. Further purification by FCC, using 0-10% [2M NH in
MeOH] in DCM, afforded the title compound (310 mg, 1.18 mmol, 72%).
LCMS (Method 4): Rt 0.28 min, m/z 264 [MH ].
c. (1S,4R){3-[2-(4-Methyl-piperazinyl)-ethyl]-
[1,2,4]triazolo[4,3-a]pyridinyloxy}-1,2,3,4-tetrahydro-naphthalen
ylamine (Intermediate 2c)
Intermediate A (180 mg, 1.11 mmol) was added to a suspension of
sodium hydride (60% in mineral oil, 133 mg, 3.33 mmol) in DMF (5 mL). The
reaction was stirred for 20 min, then Intermediate 2b (310 mg, 1.11 mmol)
was added in DMF (5 mL) and the resulting mixture heated to 60°C for 3 h.
After cooling, the reaction was quenched by dropwise addition of MeOH. The
solution was loaded onto an SCX-2 cartridge, which was washed with MeOH
and product eluted with 2M NH in MeOH. The residue was purified by FCC,
using 2-20% [2M NH in MeOH] in DCM, to give the title compound (200
mg, 0.47 mmol, 43%). LCMS (Method 4): Rt 0.28 min, m/z 407 [MH ].
d. 1-(5-tert-Butylp-tolyl-2H-pyrazolyl)((1S,4R){3-[2-(4-
methyl-piperazinyl)-ethyl]-[1,2,4]triazolo[4,3-a]pyridinyloxy}-
1,2,3,4-tetrahydro-naphthalenyl)-urea formate salt (Example 2)
Intermediate 2c (85.0 mg, 0.21 mmol) was dissolved in 1,4-dioxane
(2 mL) and (5-tert-butylp-tolyl-2H-pyrazolyl)-carbamic acid
2,2,2-trichloro-ethyl ester (Synthetic Communications, 2009, 39, 3999-4009;
96.0 mg, 0.24 mmol) and DIPEA (75.0 µL, 0.43 mmol) were added. The
reaction was heated to 60°C for 18 h. After cooling, the mixture was
partitioned between EtOAc (50 mL) and water (50 mL), and extracted into
EtOAc (3 x). The combined organic layers were washed with brine, dried
(MgSO ) and evaporated in vacuo. The residue was purified by FCC, using 0-
% [2M NH in MeOH] in DCM, then further purified by HPLC (C18 X-
select column, 10-40% MeCN in H O, 0.1% formic acid) to give the title
compound mainly as formic acid salt (43.0 mg, 0.065 mmol, 31%). LCMS
(Method 5) Rt 3.54 mins, m/z 662 [MH ]. ¹H NMR (400 MHz, d -MeOD):
1.30 (9H, s), 1.90-2.05 (2H, m), 2.06-2.15 (1H, m), 2.20-2.30 (1H, m), 2.38
(3H, s), 2.40 (3H, s), 2.55-2.75 (8H, br s), 2.90-2.95 (2H, t, J 7.4), 3.29-3.32
(2H, t, J 7.4), 4.86-4.92 (1H, dd, J 8.8, 5.6), 5.43-5.47 (1H, t, J 4.2), 6.33 (1H,
s), 7.21-7.35 (11H, m), 7.60-7.64 (1H, d, J 9.9), 8.07-8.09 (1H, d, J 1.9), 8.40-
8.50 (0.4H, br s, formate).
Example 3
1-(5-tert-Butylp-tolyl-2H-pyrazolyl)[(1S,4R)(3-piperidin-
1-yl)-[1,2,4]triazolo[4,3-a]pyridinyloxy)-1,2,3,4-tetrahydro-naphthalen-
1-yl]-urea
a. Piperidinecarboxylic acid N'-(5-fluoro-pyridinyl)-hydrazide
(Intermediate 3a)
1-Piperidine carbonyl chloride (348 mg, 0.30 mL, 2.36 mmol) was
added dropwise to a solution of 5-fluorohydrazinyl-pyridine (see for
reference WO2010022076; 0.30 g, 2.36 mmol) and DIPEA (1.2 mL,
7.08 mmol) in DCM (10 mL) at RT under nitrogen and the mixture stirred for
2 h. The solution was washed with water (2 x 15 mL) and dried (Na SO ). The
solvent was evaporated and the residue triturated (diethyl ether) and filtered to
afford the title compound as an off-white solid (475 mg, 84%). LCMS
(Method 1): Rt 1.82 min, m/z 239 [MH ].
b. 6-Fluoropiperidinyl-[1,2,4]triazolo[4,3-a]pyridine
(Intermediate 3b)
Hexachloroethane (826 mg, 3.92 mmol) was added portionwise to a
solution of Intermediate 3a (466 mg, 1.95 mmol), triphenylphosphine (1.03g,
3.92 mmol) and triethylamine (1.1 mL, 7.83 mmol) in dry THF (30 mL) at RT,
and the mixture stirred for 2 h. The resulting precipitate was filtered off and
the filtrate evaporated. The residue was purified by SCX-2, eluting with
MeOH followed by 2M NH in MeOH, to give the title compound as pale
orange coloured gum (206 mg, 48%). LCMS (Method 1): Rt 2.44 min, m/z
221 [MH ].
c. (1S,4R)(3-Piperidin1-yl-[1,2,4]triazolo[4,3-a]pyridinyloxy)-
cis-1,2,3,4-tetrahydro-naphthalenylamine (Intermediate 3c)
Intermediate A (100 mg, 0.61 mmol) was added portionwise to a
suspension of sodium hydride (60% in mineral oil, 73 mg, 1.84 mmol) in dry
DMF (2 mL) at RT, and the mixture stirred for 15 min. Intermediate 3b
(135 mg, 0.61 mmol) was then added in one portion and the mixture heated at
60°C for 3 h. After cooling, saturated NH Cl (ca. 0.2 mL) added. The mixture
was then partitioned between water (15 mL) and ethyl acetate (3 x 15 mL) and
the combined organic extracts washed with brine (2 x 15 mL) and dried
(Na SO ). The solvent was evaporated and the residue purified by SCX-2,
eluting with MeOH followed by NH3 in MeOH, to give the title compound as
brown coloured gum (133 mg, 60%). LCMS (Method 1): Rt 1.95 min, m/z 364
[MH ].
d. 1-(5-tert-Butylp-tolyl-2H-pyrazolyl)[(1S,4R)(3-
piperidin3-yl)-[1,2,4]triazolo[4,3-a]pyridinyloxy)-1,2,3,4-tetrahydro-
naphthalenyl]-urea (Example 3)
The title compound was prepared starting from Intermediate 3c and [5-
tert-butylp-tolyl-2H-pyrazolyl]-carbamic acid 2,2,2-trichloro-ethyl ester
(Synthetic Communications, 2009, 39, 3999-4009) by using an analogous
procedure to that described in Example 1 step d. LCMS (Method 5): Rt 4.79
min, m/z 916 [MH ]. H NMR (400 MHz, CDCl ): 1.32 (9H, s), 1.60-1.77
(6H, m), 1.86-1.95 (1H, m), 2.01-2.11 (2H, m), 2.20-2.27 (1H, m), 2.36 (3H,
t), 3.15 (4H, m), 5.08 (1H, m), 5.18 (1H, m), 5.41 (1H, d, J 9.20), 6.28 (1H, s),
6.48 (1H br s), 6.96 (1H, dd, J 2.12, 9.75), 7.21 (2H, d, J 8.13), 7.24-7.33 (6H,
m), 7.38-7.41 (2H, m), 7.45-7.48 (1H, d, J 9.65).
e. 1-(5-tert-Butylp-tolyl-2H-pyrazolyl)[(1S,4R)(3-
piperidin3-yl)-[1,2,4]triazolo[4,3-a]pyridinyloxy)-1,2,3,4-tetrahydro-
naphthalenyl]-urea (Crystallization of Example 3)
1-(5-tert-Butylp-tolyl-2H-pyrazolyl)[(1S,4R)(3-piperidin
yl)-[1,2,4]triazolo[4,3-a]pyridinyloxy)-1,2,3,4-tetrahydro-naphthalenyl]-
urea (3.974g, Example 3) was dissolved in hot tert-butyl alcohol (~130ml) and
then dried by lyophilisation overnight. The solid material was then slurried in
iso-propyl acetate (120ml) in a maturation chamber which cycled between
ambient and 50°C with four hours spent under each condition. After 3 days the
reaction was cooled to RT and then stirred at RT for four days. The resulting
off-white solid was isolated by filtration and dried at 40°C / 0.5mbar. Yield =
3.67g (92%). Mp = 253˚C.
Example 4
1-(5-tert-Butylp-tolyl-2H-pyrazolyl)[(1S,4R)(3-piperidin-
4-yl)-[1,2,4]triazolo[4,3-a]pyridinyloxy)-1,2,3,4-tetrahydro-naphthalen-
1-yl]-urea
a. 4-[N’-(5-fluoro-pyridinyl)-hydrazinocarbonyl]-piperidine
carboxylic acid tert-butyl ester (Intermediate 4a)
EDC (543 mg, 2.83 mmol) was added portionwise to a stirred solution
of 5-fluorohydrazinyl-pyridine (for reference procedure see
WO2010022076; 0.30 g, 2.36 mmol), piperidine-1,4-dicarboxylic acid mono-
tert-butyl ester (Aldrich, 649 mg, 2.83 mmol) and HOBt (32 mg, 0.24 mmol)
in dry DCM (20 mL). The mixture was stirred at RT for 18 h. The solution
was washed with water (2 x 20 mL), dried (Na SO ) and evaporated. The
residue was triturated (diethyl ether) to give the title compound as an off-white
solid (713 mg, 82%). LCMS (Method 1): Rt 2.76 min, m/z 339 [MH ].
b. 4-(6-Fluoro-[1,2,4]triazolo[4,3-a]pyridinyl)-piperidine
carboxylic acid tert-butyl ester (Intermediate 4b)
Hexachloroethane (990 mg, 4.18 mmol) was added portionwise to a
solution of Intermediate 4a (707 mg, 2.09 mmol), triphenylphosphine (1.103g,
4.18 mmol) and triethylamine (1.2 mL, 8.36 mmol) in dry THF (30 mL) at RT.
The mixture was stirred for 2 h. The resulting precipitate was filtered off and
the filtrate evaporated. The residue was purified by SCX-2, eluting with
MeOH followed by 2M NH in MeOH, to give a pale orange coloured solid.
This was triturated (diethyl ether) to give the title compound as a
buff-coloured solid (540 mg, 80%). LCMS (Method 1): Rt 2.79 min, m/z 321
and 221(-Boc) [MH ].
c. 4-[6-((1S,4R)Amino-1,2,3,4-tetrahydro-naphthalenyloxy-
[1,2,4]triazolo[4,3-a]pyridinyl]-piperidinecarboxylic acid tert-butyl
ester. (Intermediate 4c)
Intermediate A (100 mg, 0.61 mmol) was added portionwise to a
suspension of sodium hydride (60% in mineral oil, 73 mg, 1.84 mmol) in dry
DMF (2 mL) at RT. The mixture was then stirred for 15 min. Intermediate 4b
(193 mg, 0.61 mmol) was added in one portion and the mixture heated at
60°C for 3 h. After cooling, saturated NH Cl (ca. 0.2 mL) added. The mixture
was partitioned between water (15 mL) and ethyl acetate (3 x 15 mL) and the
combined organic extracts washed with brine (2 x 15 mL), dried (Na SO ) and
evaporated. The residue was purified by SCX-2, eluting with MeOH followed
by 2M NH in MeOH, to give the title compound as brown coloured foam
(261 mg, 92%). LCMS (Method 1): Rt 2.19 min, m/z 464 [MH ].
d. 4-(6-[{(1S,4R)[3-(5-tert-Butylp-tolyl-2H-pyrazolyl)-
ureido]-1,2,3,4-tetrahydro-naphthalenyloxy}-[1,2,4]triazolo[4,3-
a]pyridinyl)-piperidinecarboxylic acid tert-butyl ester.
(Intermediate 4d)
The title compound was prepared starting from Intermediate 4c and
[5-tert-butylp-tolyl-2H-pyrazolyl]-carbamic acid 2,2,2-trichloro-ethyl
ester (Synthetic Communications, 2009, 39, 3999-4009) by using an
analogous procedure to that described in Example 1 step d. LCMS (Method
1): Rt 3.89 min, m/z 719 [MH ].
e. 1-(5-tert-Butylp-tolyl-2H-pyrazolyl)[(1S,4R)(3-
piperidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy)-1,2,3,4-tetrahydro-
naphthalenyl]-urea (Example 4)
HCl (4M in dioxane, 1mL) was added dropwise to a solution of
Intermediate 4d (272 mg, 0.37 mmol) in MeOH (1 mL) and the mixture stirred
at RT for 5 h. The reaction mixture was passed down a SCX-2 cartridge,
eluting with MeOH followed by 2M NH in MeOH, to afford a brown foam.
Further purification by HPLC (50-95% MeCN in H O) gave the title
compound as a off-white powder (37 mg). LCMS (Method 5): Rt 3.65 min,
m/z 519 [MH ]. ¹H NMR (400 MHz, CDCl ): 1.33 (9H, s), 1.87-1.97 (5H, m),
2.05-2.13 (2H, m), 2.22-2.29 (1H, m), 2.37 (3H, s), 2.71-2.81 (1H, m), 3.10
(1H, m), 3.19 (2H, m), 5.08 (1H, m), 5.22 (1H, m,), 5.44 (1H, m), 6.29 (1H,
s), 7.06 (1H, dd, J 2.13, 9.80), 7.23-7.32 (7H, m), 7.39-7.45 (3H, m), 7.63
(1H, d, J 9.75).
Example 5
1-(5-tert-Butylp-tolyl-2H-pyrazolyl)[(1S,4R)[3-((S)
methyl-pyrrolidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy)-1,2,3,4-
tetrahydro-naphthalenyl]-urea
a. (S)Methyl-pyrrolidinecarboxylic acid [N’-(5-fluoro-pyridin-
2-yl)-hydrazide (Intermediate 5a)
EDC (271 mg, 1.41 mmol) was added portionwise to a solution of
-fluorohydrazinyl-pyridine (for reference procedure see WO2010022076;
0.15 g, 1.18 mmol), N-methyl-L-proline monohydrate (0.20 g, 1.36 mmol) and
HOBt (16 mg, 0.12 mmol) in dry DCM (5 mL) at RT and stirred for 16 h. The
solution was diluted with DCM (15 mL), washed with water (150 mL), dried
(Na SO ) and evaporated to give the title compound as a pale yellow gum
(189 mg, 67%). LCMS (Method 1): Rt 0.31 min, m/z 239 [MH ].
b. 6-Fluoro((S)methyl-pyrrolidinyl)-[1,2,4]triazolo[4,3-
a]pyridine (Intermediate 5b)
Hexachloroethane (375 mg, 1.59 mmol) was added portionwise to a
solution of Intermediate 5a (189 mg, 0.79 mmol), triphenylphosphine
(416 mg, 1.59 mmol) and triethylamine (0.44 mL, 3.17 mmol) in dry THF
(10 mL) at RT and stirred for 4 h. The resulting precipitate was filtered off
and the filtrate evaporated. The residue was purified by SCX-2, eluting with
MeOH followed by 2M NH in MeOH gave the title compound as a brown
foam (136 mg, 78%). LCMS (Method 1): Rt 0.45 min, m/z 221 [MH ].
c. (1S,4R)[3-((S)Methyl-pyrrolidinyl)-[1,2,4]triazolo[4,3-
a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenylamine.
(Intermediate 5c)
Intermediate A (128 mg, 0.77 mmol) was added portionwise to a
suspension of sodium hydride (60% in mineral oil, 92 mg, 2.30 mmol) in dry
DMF (3 mL) at RT and stirred for 15 mins. Intermediate 5b (169 mg,
0.77 mmol) was then added in one portion and the mixture heated at 60°C for
4 h. After cooling, saturated NH Cl (ca. 0.2 mL) was added. The mixture was
partitioned between water (10 mL) and ethyl acetate (3 x 10 mL). The aqueous
phase was concentrated in vacuo and the residue purified by SCX-2, eluting
with MeOH followed by 2M NH in MeOH, to give the title compound as
brown coloured foam (103 mg, 36%). LCMS (Method 1): Rt 1.34 min, m/z
364 [MH ].
d. 1-(5-tert-Butylp-tolyl-2H-pyrazolyl)[(1S,4R)[3-((S)
methyl-pyrrolidinyl]-[1,2,4]triazolo[4,3-a]pyridinyloxy)-1,2,3,4-
tetrahydro-naphthalenyl]-urea (Example 5)
The title compound was prepared with Intermediate 5c and [5-tert-
butylp-tolyl-2H-pyrazolyl]-carbamic acid 2,2,2-trichloro-ethyl ester
(Synthetic Communications, 2009, 39, 3999-4009) using an analogous
procedure to that described in Example 1 step d. LCMS (Method 5): Rt 3.76
min, m/z 319 [MH ]. ¹H NMR (400 MHz, CDCl ): 1.33 (9H, s), 1.88-2.12
(6H, m), 2.21 (3H, s), 2,21-2.30 (2H, m), 2.33-2.39 (1H, m), 2.37 (3H, s),
3.19-3.24 (1H, m), 3.98-4.02 (1H, m), 5.05-5.12 (1H, m), 5.17 (1H, t, J 4.0),
.25 (1H, d, J 8.7), 6.25-6.27 (2H, m), 7.03 (1H, dd, J 2.0, 9.8), 7.22-7.34 (6H,
m), 7.40 (2H, d, J 8.5), 7.61 (1H, d, J 9.8), 8.27 (1H, m).
Example 6
1-(5-tert-Butylp-tolyl-2H-pyrazolyl)[(1S,4R)((S)
pyrrolidinyl-[1,2,4]triazolo[4,3-a]pyridinyloxy)-1,2,3,4-tetrahydro-
naphthalenyl]-urea
a. (S)[N’-(5-fluoro-pyridinyl)-hydrazinocarbonyl]-pyrrolidine-
1-carboxylic acid tert-butyl ester (Intermediate 6a)
EDC (543 mg, 2.83 mmol) was added portionwise to a stirred solution
of 5-fluorohydrazinyl-pyridine (for reference procedure see
WO2010022076; 0.30 g, 2.36 mmol), N-tert-butylcarbonyl-L-proline (609 mg,
2.83 mmol) and HOBt (32 mg, 0.24 mmol) in dry DCM (15 mL) at RT and
stirred for 18 h. The solution was washed with water (2 x 20 mL) and dried
(Na SO ) and evaporated to give the title compound as a pale yellow foam
(767 mg, 100%). LCMS (Method 1): Rt 2.69 min, m/z 325 [MH ].
b. (S)(6-Fluoro-[1,2,4]triazolo[4,3-a]pyridinyl)-pyrrolidine
carboxylic acid tert-butyl ester (Intermediate 6b)
Hexachloroethane (1.34 g, 5.65 mmol) was added portionwise to a
solution of Intermediate 6a (917 mg, 2.83 mmol), triphenylphosphine (1.48 g,
.65 mmol) and triethylamine (1.6 mL, 11.3 mmol) in dry THF (15 mL) at RT
and stirred for 4 h. The resulting precipitate was filtered off and the filtrate
evaporated. The residue was purified by SCX-2, eluting with MeOH followed
by 2M NH in MeOH, to give the title compound as a buff-coloured foam (669
mg, 77%). LCMS (Method 4): Rt 2.48 min, m/z 307 [MH ].
c. (S)-[6-((1S,4R)Amino-1,2,3,4-tetrahydro-naphthalen
yloxy-[1,2,4]triazolo[4,3-a]pyridinyl]-pyrrolidinecarboxylic acid
tert-butyl ester. (Intermediate 6c)
Intermediate A (150 mg, 0.92 mmol) was added portionwise to a
suspension of sodium hydride (60% in mineral oil, 110 mg, 2.76 mmol) in dry
DMF (2 mL) at RT and stirred for 15 mins. Intermediate 6b (281 mg, 0.92
mmol) was then added in one portion and the mixture heated at 60°C for 3 h.
After cooling, saturated NH Cl (ca. 0.2 mL) was added. The mixture was
partitioned between water (15 mL) and ethyl acetate (3 x 15 mL). The
combined organic extracts were washed with brine (20 mL), dried (Na SO )
and evaporated to give the title compound as brown coloured gum (74 mg,
18%). LCMS (Method 1): Rt 2.08 min, m/z 450 [MH ].
d. (S)(6-[{(1S,4R)[3-(5-tert-Butylp-tolyl-2H-pyrazolyl)-
ureido]-1,2,3,4-tetrahydro-naphthalenyloxy}-[1,2,4]triazolo[4,3-
a]pyridinyl)-pyrrolidinecarboxylic acid tert-butyl ester.
(Intermediate 6d)
The title compound was prepared starting from Intermediate 6c and
[5-tert-butylp-tolyl-2H-pyrazolyl]-carbamic acid 2,2,2-trichloro-ethyl
ester (Synthetic Communications, 2009, 39, 3999-4009) by using an
analogous procedure to that described in Example 1 step d. LCMS (Method
1): Rt 3.88 min, m/z 705 [MH ].
e. 1-(5-tert-Butylp-tolyl-2H-pyrazolyl)[(1S,4R)((S)
pyrrolidinyl-[1,2,4]triazolo[4,3-a]pyridinyloxy)-1,2,3,4-tetrahydro-
naphthalenyl]-urea (Example 6)
HCl (4M in dioxane; 1 mL) was added to a solution of Intermediate 6d
(225 mg, 0.32mmol) in MeOH (0.5 mL) at RT and stirred for 8 h. The solution
was loaded on to a SCX-2 (10g) cartridge, eluting with MeOH followed by
2M NH in MeOH, to give a brown foam. Further purification by HPLC (50-
85% MeCN in H O (0.1%NH )) gave the title compound as an off-white
powder after freeze drying (7 mg, 4%). LCMS (Method 5): Rt 3.73 min, m/z
605 [MH ]. ¹H NMR (400 MHz, CDCl ): 1.29 (9H, s), 1.84-2.07 (5H, m),
2.18-2.31 (3H, m), 2.35 (3H, s), 2.96-3.07 (2H, m), 4.64 (1H, t, J 7.5), 5.01-
.08 (1H, m), 5.19 (1H, t, J 4.0), 5.27 (1H, d, J 8.8), 6.24 (2H, s), 7.02 (1H,
dd, J 2.2, 10.0), 7.19-7.28 (6H, m), 7.37 (2H, d, J 8.4), 7.58 (1H, d, J 10.0),
7.98 (1H, m).
Example 7
1-(5-tert-Butylp-tolyl-2H-pyrazolyl)[(1S,4R)(3-piperazin-
1-ylmethyl-[1,2,4]triazolo[4,3-a]pyridinyloxy)-1,2,3,4-tetrahydro-
naphthalenyl]-urea
a. 4-[N’-(5-fluoro-pyridinyl)-hydrazinocarbonylmethyl]-
piperazinecarboxylic acid tert-butyl ester (Intermediate 7a)
EDC (543 mg, 2.83 mmol) was added portionwise to a solution of 2-(4-
Bocpiperazinyl)acetic acid (576 mg, 2.36 mmol), 5-fluorohydrazinyl-
pyridine (for reference procedure see WO2010022076; 0.30 g, 2.36 mmol) and
HOBt (32 mg, 0.24 mmol) in dry DCM (15 mL) at RT and stirred for 16 h.
The solution was diluted with DCM (20 mL), washed with water (2 x 20 mL)
and dried (Na SO ). The solvent was evaporated to give the title compound as
an off-white solid (667 mg, 80%). LCMS (Method 1): Rt 1.99 min, m/z 354
[MH ].
b. 4-(6-Fluoro-[1,2,4]triazolo[4,3-a]pyridinylmethyl)-piperazine-
1-carboxylic acid tert-butyl ester (Intermediate 7b)
Hexachloroethane (893 mg, 3.77 mmol) was added portionwise to a
solution of Intermediate 7a (667 mg, 1.89 mmol), triphenylphosphine (990
mg, 3.77 mmol) and triethylamine (1.05 mL, 7.55 mmol) in dry THF (20 mL)
at RT and stirred for 4 h. The resulting precipitate was filtered off and the
filtrate evaporated. The residue was purified by SCX-2, eluting with MeOH
followed by 2M NH in MeOH, to give an off-white solid. This was triturated
(diethyl ether) to give the title compound as a colourless solid LCMS (Method
1): Rt 2.33 min, m/z 336 [MH ].
c. 4-[6-((1S,4R)Amino-1,2,3,4-tetrahydro-naphthalenyloxy-
[1,2,4]triazolo[4,3-a]pyridinylmethyl]-piperazinecarboxylic acid
tert-butyl ester. (Intermediate 7c)
The title compound was prepared with Intermediate 7b and Intermediate
A using an analogous procedure to that described in Example 6 step c. LCMS
(Method 1): Rt 1.98 min, m/z 479 [MH ].
d. 4-(6-{(1S,4R)[3-(5-tert-Butylp-tolyl-2H-pyrazolyl)-
ureido]-1,2,3,4-tetrahydro-naphthalenyloxy}-[1,2,4]triazolo[4,3-
a]pyridinylmethyl)-piperazinecarboxylic acid tert-butyl ester.
(Intermediate 7d)
The title compound was prepared starting from Intermediate 7c and [5-
tert-butylp-tolyl-2H-pyrazolyl]-carbamic acid 2,2,2-trichloro-ethyl ester
(Synthetic Communications, 2009, 39, 3999-4009) by using an analogous
procedure to that described in Example 1 step d. LCMS (Method 1): Rt 3.59
min, m/z 734 [MH ].
e. 1-(5-tert-Butylp-tolyl-2H-pyrazolyl)[(1S,4R)(3-
piperazinylmethyl-[1,2,4]triazolo[4,3-a]pyridinyloxy)-1,2,3,4-
tetrahydro-naphthalenyl]-urea (Example 7)
HCl (4M in dioxane; 1 mL) was added to a solution of Intermediate 7d
(92 mg, 0.12mmol) in MeOH (1 mL) at Rt and stirred for 4.5 h. The solution
was loaded on to a SCX-2 cartridge, eluting with MeOH followed by 2M NH
in MeOH, to give a pale yellow foam. Further purification by HPLC (40-80%
MeCN in H O (0.1%NH3)) gave the title compound as an off-white powder
after freeze drying (28 mg, 35%). LCMS (Method 5): Rt 3.59 min, m/z 634
[MH ]. ¹H NMR (400 MHz, CDCl ): 1.33 (9H, s), 1.89-1.98 (1H, m), 2.06-
2.14 (2H, m), 2.25-2.32 (1H, m), 2.38 (3H, s), 2.38-2.48 (4H, m), 2.80-2.83
(4H, m), 4.03 (2H, s), 5.06-5.12 (1H, m), 5.20-5.24 (2H, m), 6.28 (1H, s), 6.34
(1H, br s), 7.08 (1H, dd, J 9.8, 2.0), 7.23-7.36 (6H, m), 7.40 (2H, d, J 7.7),
7.63 (1H, d, J 9.5), 8.14 (1H, m).
Example 8
1-(5-tert-Butylp-tolyl-2H-pyrazolyl)[(1S,4R)(3-
isopropylamino-[1,2,4]triazolo[4,3-a]pyridinyloxy)-1,2,3,4-tetrahydro-
naphthalenyl]-urea
a. 2-(5-Fluoropyridinyl)-N-(propanyl)hydrazinecarboxamide
(Intermediate 8a)
Isopropyl isocyanate (0.25 mL, 2.60 mmol) was added dropwise, over 2
min, to a solution of 5-fluorohydrazinyl-pyridine (for reference procedure
see WO2010022076; 0.30 g, 2.36 mmol) in dry DCM (10 mL) at RT and
stirred for 3 h. The solvent was evaporated and the residue triturated (diethyl
ether) and filtered to give the title compound as a colourless solid (464 mg,
93%). LCMS (Method 1): Rt 1.92 min, m/z 213 [MH ].
b. (6-Fluoro-[1,2,4]triazolo[4,3-a]pyridinyl)-isopropyl-amine.
(Intermediate 8b)
Hexachloroethane (1.77 g, 7.75 mmol) was added portionwise to a
solution of Intermediate 8a 822 mg, 3.87 mmol), triphenylphosphine (2.03 g,
7.75 mmol) and triethylamine (2.2 mL, 15.49 mmol) in dry THF (15 mL) at
RT and stirred for 16 h. The resulting precipitate was filtered off and the
filtrate evaporated. The residue was purified by SCX-2, eluting with MeOH
followed by 2M NH in MeOH, to give the title compound as a buff-coloured
foam (618 mg, 82%). LCMS (Method 1): Rt 1.55 min, m/z 195 [MH ].
c. (6-Fluoro-[1,2,4]triazolo[4,3-a]pyridinyl)-isopropyl-carbamic
acid tert-butyl ester. (Intermediate 8c)
Di-tert-butyl dicarbonate (472 mg, 2.16 mmol) in dry DCM (1 mL) was
added to a solution of Intermediate 8b (168 mg, 0.86 mmol) in DCM (2 mL).
4-(1-Pyrrolidinyl)pyridine (ca. 5 mg) was then added at RT and stirred for 5 h.
The solvent was evaporated and the residue purified by SCX-2, eluting with
MeOH then 2M NH in MeOH, affording a dark coloured foam. Further
purification by FCC, using 0-10% [2M NH in MeOH] in DCM, afforded the
title compound (112 mg). LCMS (Method 4): Rt 2.90 min, m/z 295 [MH ] /
589 [2MH ]
d. [6-((1S,4R)Amino-1,2,3,4-tetrahydro-naphthalenyloxy-
[1,2,4]triazolo[4,3-a]pyridinyl]-isopropyl-carbamic acid tert-butyl ester
(Intermediate 8d)
Sodium hydride (60% in mineral oil, 45 mg, 1.14 mmol) was added
portionwise to a solution of Intermediate A (62 mg, 0.38 mmol) in dry DMF
(1 mL) at RT and stirred for 15 min. Intermediate 8c (112 mg, 0.38 mmol) was
added and the mixture heated at 60°C for 4 h. After cooling, the mixture was
partitioned between water (10 mL) and EtOAc (3 x 10 mL) and the combined
organic extracts washed with brine (2 x 15 mL), dried (Na SO ) and
evaporated. The residue was purified by SCX-2, eluting with MeOH then 2M
NH in MeOH, affording a dark gum. Further purification by FCC, using 0-
% [2M NH in MeOH] in DCM, afforded the title compound (75 mg, 45%).
LCMS (Method 1): Rt 2.20 min, m/z 438 [MH ].
e. (6-{(1S,4R)[3-(5-tert-Butylp-tolyl-2H-pyrazolyl)-ureido]-
1,2,3,4-tetrahydro-naphthalenyloxy}-[1,2,4]triazolo[4,3-a]pyridinyl)-
isopropyl-carbamic acid tert-butyl ester. (Intermediate 8e)
The title compound was prepared starting from Intermediate 8d and [5-
tert-butylp-tolyl-2H-pyrazolyl]-carbamic acid 2,2,2-trichloro-ethyl ester
(Synthetic Communications, 2009, 39, 3999-4009) by using an analogous
procedure to that described in Example 1 step d. LCMS (Method 4): Rt 3.98
min, m/z 693 [MH ].
f. 1-(5-tert-Butylp-tolyl-2H-pyrazolyl)[(1S,4R)(3-
isopropylamino-[1,2,4]triazolo[4,3-a]pyridinyloxy)-1,2,3,4-tetrahydro-
naphthalenyl]-urea (Example 8)
HCl (4.0 M in dioxane; 1 mL) was added to a solution of Intermediate
8e (110 mg, 0.16 mmol) in MeOH (1 mL) at RT and stirred for 5 h. The
solution was loaded on to a SCX-2 cartridge, eluting with MeOH then 2M
NH in MeOH, to afford a dark gum. Further purification by HPLC (eluting
with 50-90% MeCN in H O (0.1%NH3)) gave the title compound as a
colourless powder after freeze drying (10 mg, 11%). LCMS (Method 5): Rt
4.15 min, m/z 593 [MH ]. ¹H NMR (400 MHz, CDCl ): 1.21-1.27 (15H, m),
1.87 (1H, m), 2.00 (2H, m), 2.10 (1H, m), 2.31 (3H, s), 3.85 (1H, br s), 3.94
(1H, m), 5.02 (1H, m), 5.11 (1H, t, J 4.13), 5.59 (1H, d), 6.24 (1H, s), 6.54
(1H, s), 6.84 (1H, dd, J 9.93, 2.05), 7.14 (3H, d, J 8.13), 7.20-7.26 (3H, m),
7.30-7.34 (3H, m).
Example 9
1-(5-tert-Butylp-tolyl-2H-pyrazolyl)[(1S,4R)(6-cyano-
pyridinyloxy)-1,2,3,4-tetrahydro-naphthalenyl]-urea
a. 5-((1R,4S)Amino-1,2,3,4-tetrahydro-naphthalenyloxy)-
pyridinecarbonitrile (Intermediate 9a)
Intermediate A (300 mg, 1.84 mmol) was added to an ice cold stirred
suspension of sodium hydride (60% in mineral oil, 221 mg, 5.52 mmol) in
DMF (15 mL) and stirred for 15 min. 2-Cyanofluoropyridine (224 mg, 1.84
mmol) was added and the reaction warmed to RT. After 90 min, the reaction
was quenched by dropwise addition of water and the mixture partitioned
between EtOAc (75 mL) and water (150 mL). The aqueous layer was then
extracted with EtOAc (3 x). The combined organic layers were washed with
brine, dried (MgSO ), filtered and evaporated in vacuo. The residue was
purified by FCC, using 0-5% [2M NH in MeOH] in DCM, to give the title
compound (255 mg, 0.96 mmol, 52%). LCMS (Method 4): Rt 0.28, 1.73, m/z
266.1 [MH ].
b. 1-(5-tert-Butylp-tolyl-2H-pyrazolyl)[(1S,4R)(6-cyano-
pyridinyloxy)-1,2,3,4-tetrahydro-naphthalenyl]-urea. (Example 9)
The title compound was prepared starting from Intermediate 9a and [5-
tert-butylp-tolyl-2H-pyrazolyl]-carbamic acid 2,2,2-trichloro-ethyl ester
(Synthetic Communications, 2009, 39, 3999-4009) using an analogous
procedure to that described in Example 1 step d. LCMS (Method 5): Rt 5.25
mins, m/z 521 [MH ]. ¹H NMR (400 MHz, CDCl ): 1.29 (9H, s), 1.76-1.88
(1H, m), 2.00-2.20 (3H, m), 2.36 (3H, s), 4.94-4.98 (1H, d, J 8.8), 5.00-5.08
(1H, m), 5.38-5.42 (1H, t, J 3.6), 6.03 (1H, s), 6.22 (1H, s), 7.16-7.20 (1H, m),
7.21-7.26 (3H, m), 7.26-7.32 (3H, m), 7.34-7.38 (2H, d, J 8.3), 7.63-7.66 (1H,
d, J 8.8), 8.36-8.38 (1H, d, J 2.7).
Example 10
N-(4-{(1S,4S)[3-(5-tert-Butylp-tolyl-2H-pyrazolyl)-ureido]-
1,2,3,4-tetrahydro-naphthalenyloxy}-pyridinyl)methoxy-
acetamide
HN O
a. ((1S,4S)Hydroxy-1,2,3,4-tetrahydro-naphthalenyl)-
carbamic acid tert-butyl ester (Intermediate 10a)
Intermediate B (1.62 g, 9.94 mmol) was suspended in acetonitrile
(35 mL) then di-tert-butyl-dicarbonate (2.40 g, 11 mmol) was added. Mixture
stirred at RT for 16 h. Some insoluble material was still present, so mixture
filtered through Celite, washing with DCM. Filtrate was evaporated to give an
off-white solid and then purified by FCC, eluting with 0-80% ethyl acetate in
cyclohexane, to give the title compound as a white solid (2.38 g, 91%). ¹H
NMR (300 MHz, d -DMSO): 1.42 (9H, s), 1.54-1.70 (2H, m), 1.92-2.18 (2H,
m), 4.46-4.73 (2H, m), 5.17 (1H, d, J 6.3), 7.10-7.25 (4H, m), 7.39-7.46 (1H,
b. [(1S,4S)(2-Chloro-pyridinyloxy)-1,2,3,4-tetrahydro-
naphthalenyl]-carbamic acid tert-butyl ester (Intermediate 10b)
Sodium hydride (60% in mineral oil, 0.32 g, 8.00 mmol) was suspended
in dry DMF (15 mL) under argon. To this was added Intermediate 10a (1.05 g,
4.00 mmol) followed by 2-chloronitropyridine (0.64 g, 4.02 mmol). The
dark coloured mixture was stirred at RT under argon for 30 min. The reaction
mixture was diluted with water and extracted with DCM (3 x 30 mL). The
combined organic layers were washed with brine, dried (Na SO ), filtered,
concentrated in vacuo. Purification by FCC, eluting with 0-70% ethyl acetate
in cyclohexane, gave the title compound as a white foam (1.43 g, 95%).
LCMS (Method 3): Rt 4.22 min, m/z 373.1 [MH ].
c. {(1S,4S)[2-(2-Methoxy-acetylamino)-pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-carbamic acid tert-butyl ester (Intermediate 10c)
Intermediate 10b (562 mg, 1.50 mmol), 2-methoxyacetamide (334 mg,
3.75 mmol), Xantphos (173 mg, 0.30 mmol) and potassium carbonate
(518 mg, 3.75 mmol) were suspended in 1,4-dioxane (20 mL), warmed,
degassed, and placed under argon. To this mixture palladium acetate (34.0 mg,
0.15 mmol) was added. The mixture was degassed and then heated at reflux
for 17 h. After cooling, the mixture was filtered through Celite, washing with
DCM, and evaporated to a yellow gum. Purification by FCC, eluting with
0-100% ethyl acetate in cyclohexane, gave the title compound as a white foam
(281 mg, 44%). LCMS (Method 3): Rt 3.27 min, m/z 450.2 [MNa ].
d. N-[4-((1S,4S)Amino-1,2,3,4-tetrahydro-naphthalenyloxy)-
pyridinyl]methoxy-acetamide (Intermediate 10d)
To a solution of Intermediate 10c (272 mg, 0.64 mmol) in DCM (6 mL)
was added TFA (2 mL), and the mixture stirred at RT for 30 min. The mixture
was concentrated in vacuo. The residue was purified on an Isolute SCX-2
cartridge, eluting with MeOH then 0.4-1M NH in MeOH, to give the title
compound as a colourless gum (208 mg, 100%). LCMS (Method 3): Rt 0.44
min, m/z 350.2 [MNa ].
e. N-(4-{(1S,4S)[3-(5-tert-Butylp-tolyl-2H-pyrazolyl)-
ureido]-1,2,3,4-tetrahydro-naphthalenyloxy}-pyridinyl)methoxy-
acetamide (Example 10)
To a solution of Intermediate 10d (204 mg, 0.62 mmol) and DIPEA
(0.127 mL, 0.80 mmol) in 1,4-dioxane (6 mL), (5-tert-butylp-tolyl-2H-
pyrazolyl)-carbamic acid 2,2,2-trichloro-ethyl ester (Synthetic
Communications, 2009, 39, 3999-4009; 315 mg, 0.78 mmol) was added. The
mixture was heated at 80°C under argon for 17 h, and then evaporated to
dryness. The residue was purified by FCC, eluting with 0-100% ethyl acetate
in cyclohexane, to give the slightly impure product (0.262 g). Further
purification by HPLC (Method 6) gave the title compound as a white solid
(102 mg, 28%). LCMS (Method 5): Rt 4.51 min, m/z 583 [MH ]. ¹H NMR
(400 MHz, d -DMSO): 1.26 (9H, s), 1.69-1.81 (1H, m), 1.90-2.24 (3H, m),
2.36 (3H, s), 3.36 (3H, s), 4.05 (2H, s), 4.86-4.94 (1H, m), 5.62-5.67 (1H, m),
6.32 (1H, s), 6.91 (1H, dd, J 2.5, 5.9), 7.03 (1H, d, J 8.4), 7.26-7.37 (8H, m),
7.60 (1H, br d, J 2.0), 8.01 (1H, s), 8.16 (1H, d, J 5.7), 9.90 (1H, s).
Example 11
1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[1-(2-hydroxy-
ethyl)-1H-indazolyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea
a. 6-Fluoro[2-(tetrahydro-pyranyloxy)-ethyl]-1H-indazole
(Intermediate 11a)
A mixture of 6-fluoro-1H-indazole (2.0 g, 14.7 mmol), and 2-(2-bromo-
ethoxy)-tetrahydro-pyran (3.38 g, 16.2 mmol) in DMF (25 mL) was treated
with caesium carbonate (6.1 g, 18.7 mmol) and stirred at RT for 18 h. The
solvent volume was reduced in vacuo, and the residue partitioned between
EtOAc (100 mL) and water (100 mL). The aqueous layer was extracted into
EtOAc (3 x). The combined organic layers were washed with saturated
aqueous sodium chloride solution, dried (MgSO ) and evaporated in vacuo.
The residue was purified by FCC, using 0-50% cyclohexane in EtOAc, to
afford the title product and a yellow oil. LCMS (Method 1): Rt 3.42 min, m/z
181 [MH ] (M-THP). H NMR (300 MHz; CDCl ) 1.52-1.56 (6 H, m), 3.39-
3.49 (1 H, m), 3.57-3.68 (1 H, m), 3.89-3.91 (1 H, m), 4.19-4.21 (1 H, m),
4.56-4.57 (3 H, m), 6.88 (1 H, td, J 9.15 and 2.26), 7.30 (1 H, m), 7.62 (1 H,
m), 8.04 (1 H, s).
b. 2-[6-((1R,4S)Amino-1,2,3,4-tetrahydro-naphthalenyloxy)-
indazolyl]-ethanol (Intermediate 11b)
Intermediate A (212 mg, 1.3 mmol) was added portionwise to a
suspension of sodium hydride (60% in mineral oil, 120 mg, 3.0 mmol) in
DMF (3 mL) at RT and stirred for 20 min. A solution of Intermediate 11a
(264.3 mg, 1.0 mmol) in DMF (1 mL) was then added dropwise and the
resulting mixture stirred at 60°C for 2.5 h. After cooling, the mixture was
diluted with EtOAc (50 mL) and poured onto ice water. The organic layer was
washed with saturated aqueous sodium chloride solution, dried (MgSO ),
filtered and concentrated in vacuo. The residue was loaded on to a SCX-2
cartridge, eluting with MeOH then 2M NH in MeOH. Further purification by
FCC, using 0-10% [2M NH in MeOH] in DCM to give the title compound as
a brown oil. LCMS (Method 1): Rt 1.80 min, m/z 323 [MH ].
c. 1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[1-(2-
hydroxy-ethyl)-1H-indazolyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-
urea (Example 11)
The title compound was prepared starting from Intermediate 11b and (5-
tert-butylp-tolyl-2H-pyrazolyl)-carbamic acid 2,2,2-trichloro-ethyl ester
(Synthetic Communications, 2009, 39, 3999-4009; 315 mg, 0.78 mmol) by
using an analogous procedure to that described in Example 1 step d. LCMS
(Method 5): Rt 4.99 min, m/z 578 [MH ]. ¹H NMR (400 MHz, d -DMSO):
1.22 (9 H, s), 1.81-1.92 (2 H, m), 2.02-2.06 (2 H, m), 2.31 (3 H, s), 3.74-3.75
(2 H, m), 4.34 (2 H, t, J 5.75), 4.78 (2 H, m), 5.53 (1 H, t, J 4.8), 6.28 (1 H, s),
6.74 (1 H, dd, J 8.75 and 2.03), 7.08 (1 H, d, J 8.53), 7.27-7.28 (9 H, m), 7.57
(1 H, d, J 8.75), 7.89 (1 H, s), 7.96 (1 H, s).
Example 12
N N N
1-(5-tert-Butylp-tolyl-2H-pyrazolyl)[(1S,4R)((R)
pyrrolidinyl-[1,2,4]triazolo[4,3-a]pyridinyloxy)-1,2,3,4-tetrahydro-
naphthalenyl]-urea
The title compound was prepared starting from N-tert-butylcarbonyl-D-
proline using analogous procedures to those described in Example 6. LCMS
(Method 5): Rt 3.69 min, m/z 605 [MH ]; ¹H NMR (400 MHz, CDCl ): 1.33
(9H, s), 1.86-2.39 (8H, m), 2.36 (3H, s), 2.96-3.08 (2H, m), 4.51 (1H, t, J 7.4
Hz), 5.04-5.10 (1H, m), 5.24 (1H, t, J 4.0 Hz), 5.52 (1H, d, J 8.1 Hz), 6.30
(1H, s), 6.57 (1H, br s), 7.03 (1H, dd, J 2.2, 10.0 Hz), 7.20 (2H, d, J 7.9 Hz),
7.23-7.34 (4H, m), 7.38 (2H, d, J 7.4 Hz), 7.56 (1H, d, J 9.8 Hz), 7.92 (1H,
m).
Example 13
HN O
N-(4-{(1R,4S)[3-(5-tert-Butylp-tolyl-2H-pyrazolyl)-ureido]-
1,2,3,4-tetrahydro-naphthalenyloxy}-pyridinyl)methoxy-
acetamide
The title compound was prepared starting from Intermediate A by using
analogous procedures to those described in Example 10. LCMS (Method 5):
Rt 4.54 min, m/z 583 [MH ]; ¹H NMR (400 MHz, d -DMSO): 1.21 (9H, s),
1.66-2.11 (4H, m), 2.31 (3H, s), 3.31 (3H, s), 4.0 (2H, s), 4.72-4.81 (1H, m),
.49-5.58 (1H, m), 6.26 (1H, s), 6.86 (1H, dd, J 5.8, 2.2 Hz), 7.07 (1H, d, J 8.5
Hz), 7.19-7.33 (8H, m), 7.68 (1H, d, J 2.2 Hz), 7.96 (1H, s), 8.12 (1H, d, J 5.8
Hz), 9.86 (1H, br s).
Example 14
1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-(4-
methyl-piperazinylmethyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-
1,2,3,4-tetrahydro-naphthalenyl}-urea formate salt
a. (4-Methyl-piperazinyl)-acetic acid N'-(5-fluoro-pyridinyl)-
hydrazide (Intermediate 14a)
5-Fluorohydrazinyl-pyridine (for reference procedure see
WO2010022076; 500 mg, 3.94 mmol) and 4-methylpiperazinyl acetic
acid (684 mg, 4.33 mmol) were dissolved in DMF (10.0 mL). EDC (831 mg,
4.33 mmol) and HOBt (53.0 mg, 0.39 mmol) were added and the reaction
stirred for 18 h. The mixture was loaded onto an SCX-2 cartridge, which was
washed with MeOH then eluted with 2M NH in MeOH. The resulting residue
was purified by FCC, using 4-20% [2M NH in MeOH] in DCM, to give the
title compound (570 mg, 54%). ¹H NMR (400 MHz, CDCl ): 2.32 (3H, s),
2.47-2.56 (4H, br s), 2.62-2.71 (4H, br s), 3.18 (2H, s), 6.56-6.61 (1H, br s),
6.60-6.66 (1H, dd, J 8.9, 3.4 Hz), 7.26-7.32 (1H, m), 8.02-8.05 (1H, d, J 2.9
Hz), 8.93 (1H, br s).
b. 6-Fluoro(4-methyl-piperazinylmethyl)-[1,2,4]triazolo[4,3-
a]pyridine (Intermediate 14b)
Intermediate 14a (570 mg, 2.13 mmol) was dissolved in THF (20.0 mL)
and cooled in an ice/water bath. Triphenylphosphine (1.12 g, 4.27 mmol) was
added followed by triethylamine (1.19 mL, 8.54 mmol) and hexachloroethane
(1.01 g, 4.27 mmol). The reaction was stirred for 18 h. The mixture was
loaded onto an SCX-2 cartridge, washing with MeOH and eluting with 2M
NH in MeOH. The residue was purified by FCC, using 0-10% [2M NH in
MeOH] in DCM, to give the title compound (470 mg, 1.89 mmol, 89%).
LCMS (Method 1): Rt 0.36 min, m/z 250 [MH ].
c. (1S,4R)[3-(4-Methyl-piperazinylmethyl)-[1,2,4]triazolo[4,3-
a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenylamine (Intermediate 14c)
Intermediate A (200 mg, 1.22 mmol) was added to a suspension of
sodium hydride (60% in mineral oil, 146 mg, 3.66 mmol) in DMF (6.0 mL)
and stirred for 20 min. Intermediate 14b (305 mg, 1.22 mmol) was added and
the reaction heated to 60°C for 90 min. The mixture was cooled and quenched
by dropwise addition of MeOH. The solution was diluted with MeOH and
loaded onto an SCX-2 cartridge, washing with MeOH and eluting with 2M
NH in MeOH. The residue was purified by FCC, using 0-10% [2M NH in
MeOH] in DCM to give the title compound (240 mg, 0.61 mmol, 50%). LCMS
(Method 4): Rt 0.29 min, m/z 393 [MH ].
d. 1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-(4-
methyl-piperazinylmethyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-
1,2,3,4-tetrahydro-naphthalenyl}-urea formate salt (Example 14)
Intermediate 14c (120 mg, 0.31 mmol) was dissolved in 1,4-dioxane
(2.0 mL) and [5-tert-butylp-tolyl-2H-pyrazolyl]-carbamic acid 2,2,2-
trichloro-ethyl ester (Synthetic Communications, 2009, 39, 3999-4009; 124
mg, 0.31 mmol) and diisopropylethylamine (106 µL, 0.61 mmol) were added.
The reaction was heated to 60°C for 20 h. After cooling, the mixture was
partitioned between EtOAc (50 mL) and water (50 mL), and extracted into
EtOAc (3 x). The combined organic layers were washed with brine, dried
(MgSO ) and evaporated in vacuo. The residue was purified by FCC, using 0-
% [2M NH in MeOH] in DCM, then further purified by HPLC (C18 X-
select column, 20-70% MeCN in H O, 0.1% formic acid) to give the title
compound as the formic acid salt (103 mg, 0.16 mmol, 52%). LCMS (Method
): Rt 3.63 min, m/z = 648 [MH ]. ¹H NMR (400 MHz, d -MeOD): 1.30 (9H,
s), 1.90-1.99 (1H, m), 1.99-2.07 (1H, m), 2.10-2.19 (1H, m), 2.21-2.30 (1H,
m), 2.37 (3H, s), 2.38 (3H, s), 2.52-2.67 (8H, br s), 4.05-4.09 (1H, d, J 14.3
Hz), 4.11-4.15 (1H, d, J 14.3 Hz), 4.88-4.93 (1H, dd, J 8.9, 5.6 Hz), 5.41-5.44
(1H, t, J 4.3 Hz), 6.33 (1H, s), 7.22-7.36 (11H, m), 7.63-7.67 (1H, d, J 10.0
Hz), 8.21-8.22 (1H, d, J 1.9 Hz), 8.44-8.45 (0.25H, s).
Example 15
1-(5-tert-Butylp-tolyl-2H-pyrazolyl)[(1S,4R)(3-
morpholinylmethyl-[1,2,4]triazolo[4,3-a]pyridinyloxy)-1,2,3,4-
tetrahydro-naphthalenyl]-urea formate salt
The title compound was prepared starting from 1-morpholinoacetic acid
by using analogous procedures to those described for Example 14. LCMS
(Method 5): Rt 4.02 min, m/z = 635 [MH ]. ¹H NMR (400 MHz, d -MeOD):
1.30 (9H, s), 1.90-1.97 (1H, m), 1.97-2.07 (1H, m), 2.10-2.19 (1H, m), 2.23-
2.31 (1H, m), 2.38 (3H, s), 2.42-2.53 (4H, m), 3.60-3.64 (4H, m), 4.01-4.05
(1H, d, J 14.3 Hz), 4.08-4.12 (1H, d, J 14.3 Hz), 4.88-4.93 (1H, dd, J 9.0, 5.6
Hz), 5.42-5.45 (1H, t, J 4.3 Hz), 6.33 (1H, s), 7.22-7.36 (11H, m), 7.63-7.66
(1H, d, J 10.0 Hz), 8.24-8.26 (1H, d, J 2.0 Hz), 8.48-8.52 (0.25H, s).
Example 16
1-(5-tert-Butylp-tolyl-2H-pyrazolyl)[(1S,4R)(3-
pyrrolidinylmethyl-[1,2,4]triazolo[4,3-a]pyridinyloxy)-1,2,3,4-
tetrahydro-naphthalenyl]-urea
The title compound was prepared starting from 1-pyrrolidinyl-acetic
acid hydrochloride (for reference procedure see US5756533) by using
analogous procedures to those described for Example 14. LCMS (Method 5):
Rt 3.72 min, m/z = 619 [MH ]. ¹H NMR (400 MHz, d -MeOD): 1.30 (9H, s),
1.80-1.85 (4H, m), 1.90-2.05 (2H, m), 2.07-2.15 (1H, m), 2.21-2.30 (1H, m),
2.38 (3H, s), 2.65-2.70 (4H, m), 4.21-4.26 (1H, d, J 14.3 Hz), 4.26-4.31 (1H,
d, J 14.3 Hz), 4.87-4.92 (1H, dd, J 8.9, 5.6 Hz), 5.40-5.43 (1H, t, J 4.3 Hz),
6.33 (1H, s), 7.21-7.36 (11H, m), 7.63-7.67 (1H, d, J 9.9 Hz), 8.23-8.24 (1H,
d, J 1.9 Hz), 8.29-8.31 (0.3H, br s).
Example 17
1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[6-
(morpholinecarbonyl)-pyridinyloxy]-1,2,3,4-tetrahydro-naphthalen-
1-yl}-urea
a. (5-Fluoro-pyridinyl)-morpholinyl-methanone (Intermediate
17a)
2-Cyanofluoropyridine (1.00 g, 8.19 mmol) was dissolved in
hydrochloric acid (37% aqueous, 1.0 mL) and heated to 60°C for 18 h and
then evaporated in vacuo. The residue was suspended in DMF (40.0 mL) and
EDC (1.89 g, 9.83 mmol), HOBt (111 mg, 0.82 mmol), morpholine (787 µL,
9.00 mmol) and triethylamine (1.25 mL, 9.00 mmol) were added and the
reaction stirred for 18 h. The reaction was partitioned between water (200 mL)
and EtOAc (100 mL), and extracted into EtOAc (3 x). The combined organic
layers were washed with brine, dried (MgSO ) and evaporated in vacuo. The
residue was purified by FCC, using 0-8% [2M NH in MeOH] in DCM, to
give the title compound (350 mg), contaminated with a single impurity (~10%
by NMR integration). The product was used in the next step without further
purification. LCMS (Method 1): Rt 1.88 min, m/z 211 [MH ].
b. [5-((1R,4S)Amino-1,2,3,4-tetrahydro-naphthalenyloxy)-
pyridinyl]-morpholinyl-methanone (Intermediate 17b)
Intermediate A (150 mg, 0.92 mmol) was added to a suspension of
sodium hydride (60% in mineral oil, 147 mg, 3.66 mmol) in DMF (3.0 mL).
The reaction was stirred for 20 min, then Intermediate 17a (280 mg) in DMF
(3.0 mL) was added and the reaction heated to 60°C for 90 min. The mixture
was cooled and quenched by dropwise addition of MeOH. The solution was
diluted with MeOH and loaded onto an SCX-2 cartridge, which was washed
sequentially with MeOH and 2M NH in MeOH. The basic fractions were
evaporated in vacuo then purified by FCC, using 0-10% [2M NH in MeOH]
in DCM, to give the title compound (234 mg, 0.66 mmol, 72%). LCMS
(Method 4): Rt 1.60 min, m/z 354 [MH ].
c. 1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[6-
(morpholinecarbonyl)-pyridinyloxy]-1,2,3,4-tetrahydro-naphthalen-
1-yl}-urea (Example 17)
Intermediate 17b (234 mg, 0.66 mmol) was dissolved in 1,4-dioxane
(7.0 mL) and [5-tert-butylp-tolyl-2H-pyrazolyl]-carbamic acid 2,2,2-
trichloro-ethyl ester (Synthetic Communications, 2009, 39, 3999-4009; 268
mg, 0.66 mmol) and diisopropylethylamine (229 µL, 1.32 mmol) were added.
The reaction mixture was heated to 60°C for 20 h, then cooled, partitioned
between EtOAc (50 mL) and water (50 mL), and extracted into EtOAc (3 x).
The combined organic layers were washed with brine, dried (MgSO ) and
evaporated in vacuo. The residue was purified by FCC, using 0-10% [2M NH
in MeOH] in DCM, to give the title compound (120 mg, 0.20 mmol, 30%).
LCMS (Method 5): Rt 4.76 min, m/z = 609 [MH ]. ¹H NMR (400 MHz, d -
MeOD): 1.30 (9H, s), 1.85-2.05 (2H, m), 2.05-2.18 (2H, m), 2.38 (3H, s),
3.57-3.76 (8H, br m), 4.86-4.92 (1H, dd, J 8.6, 5.5 Hz), 5.54-5.57 (1H, t, J 4.3
Hz), 6.33 (1H, s), 7.20-7.34 (9H, m), 7.58-7.65 (2H, m), 8.24-8.26 (1H, dd, J
2.4, 0.8 Hz).
Example 18
1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-(4-
morpholinylmethyl-phenyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-
1,2,3,4-tetrahydro-naphthalenyl]-urea
a. 4-Morpholinylmethyl-benzoic acid N'-(5-fluoro-pyridinyl)-
hydrazide (Intermediate 18a)
HOBt (53 mg, 0.39 mmol) was added to (5-fluoro-pyridinyl)-
hydrazine (For reference procedure see WO2010022076; 500 mg, 3.94 mmol),
4-morpholinylmethyl-benzoic acid (1.04 g, 4.72 mmol) and EDC (907 mg,
4.72 mmol) in DCM (5.0 mL) and the reaction stirred for 4 h. The reaction
was partitioned between DCM (75 mL) and saturated aqueous NaHCO (75
mL) and the aqueous layer extracted with DCM (3 x). The combined organic
layers were washed with brine, dried (MgSO ), filtered and evaporated in
vacuo then purified by FCC using [0.5-7.5% 2M NH in MeOH] in DCM to
give the title compound (980 mg, 2.97 mmol, 75%). LCMS (Method 4): Rt
0.27, m/z 331 [MH ].
b. 6-Fluoro(4-morpholinylmethyl-phenyl)-[1,2,4]triazolo[4,3-
a]pyridine (Intermediate 18b)
To an ice cold solution of Intermediate 18a (980 mg, 2.97 mmol) in
THF (15 mL) was added triphenylphosphine (1.56 g, 5.94 mmol),
triethylamine (1.65 mL, 11.9 mmol) and hexachloroethane (1.40 g, 5.94
mmol). The reaction was stirred for 90 min then partitioned between EtOAc
(75 mL) and water (75 mL) and the aqueous layer extracted with EtOAc (3 x).
The combined organic layers were washed with brine, dried (MgSO ), filtered
and evaporated in vacuo then purified by SCX-2, washing with MeOH and
eluting with 2M NH in MeOH to give the title compound (640 mg, 2.05
mmol, 69%). LCMS (Method 2): Rt 0.28, 1.32, m/z 313 [MH ].
c. 1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-(4-
morpholinylmethyl-phenyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-
1,2,3,4-tetrahydro-naphthalenyl]-urea (Example 18)
The title compound was prepared starting from Intermediate 18b using
analogous procedures to those described for Example 14. LCMS (Method 5):
Rt 3.79 mins, m/z = 711 [MH ]. ¹H NMR (400 MHz, CDCl ): 1.29 (9H, s),
1.80-1.90 (1H, m), 1.96-2.08 (2H, m), 2.16-2.24 (1H, m), 2.33 (3H, s), 2.44-
2.49 (4H, t, J 4.2 Hz), 3.56 (2H, s), 3.68-3.71 (4H, t, J 4.6 Hz), 5.00-5.06 (1H,
td, J 8.8, 5.2 Hz), 5.11-5.17 (2H, m), 6.22 (2H, s), 7.06-7.10 (1H, dd, J 9.9,
2.1 Hz), 7.17-7.22 (3H, m), 7.24-7.30 (3H, m), 7.33-7.36 (2H, d, J 8.4 Hz),
7.49-7.53 (2H, d, J 8.1 Hz), 8.68-7.71 (2H, d, J 8.2 Hz), 7.71 (1H, s), 7.81-
7.82 (1H, d, J 1.6 Hz).
Example 19
1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-(3-
morpholinylmethyl-phenyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-
1,2,3,4-tetrahydro-naphthalenyl}-urea
The title compound was prepared starting from 3-morpholin
ylmethyl-benzoic acid by using analogous procedures to those described for
Example 18. LCMS (Method 5): Rt 3.81 mins, m/z 711.3 [MH ]; ¹H NMR
(400 MHz, d -MeOD): 1.29 (9H, s), 1.89-2.10 (3H, m), 2.20-2.28 (1H, m),
2.37 (3H, s), 2.45-2.50 (4H, t, J 4.3 Hz), 3.61 (2H, s), 3.61-3.65 (4H, t, J 4.6
Hz), 4.84-4.88 (1H, dd, J 8.9, 5.7 Hz), 5.36-5.39 (1H, t, J 4.1 Hz), 6.31 (1H,
s), 7.18-7.38 (9H, m), 7.53-7.59 (2H, m), 7.70-7.74 (1H, dt, J 6.4, 2.3 Hz),
7.72-7.75 (1H, d, J 9.9 Hz), 7.80 (1H, s), 8.02-8.04 (1H, d, J 1.7 Hz).
Example 20
1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-(2-
morpholinylmethyl-phenyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-
1,2,3,4-tetrahydro-naphthalenyl}-urea
The title compound was prepared starting from 2-morpholin
ylmethyl-benzoic acid by using analogous procedures to those described for
Example 18. LCMS (Method 5): Rt 4.00 mins, m/z 711.4 [MH ]; ¹H NMR
(400 MHz, d -MeOD): 1.30 (9H, s), 1.82-2.02 (3H, m), 2.04-2.18 (5H, m),
2.38 (3H, s), 3.08-3.16 (4H, br s), 3.50-3.54 (1H, d, J 13.5 Hz), 3.54-3.58 (1H,
d, J 13.5 Hz), 4.81-4.86 (1H, dd, J 8.8, 5.6 Hz), 5.29-5.33 (1H, t, J 4.0 Hz),
6.31 (1H, s), 7.17-7.35 (9H, m), 7.35-7.39 (1H, dd, J 9.9, 2.0 Hz), 7.49-7.59
(6H, m), 7.74-7.78 (1H, d, J 9.9 Hz).
Example 21
O N O
1-(5-tert-Butylp-tolyl-2H-pyrazolyl)[(1S,4R)(6-morpholin
ylmethyl-pyridinyloxy)-1,2,3,4-tetrahydro-naphthalenyl]-urea
Borane dimethylsulfide complex (2M in THF, 99 mL, 0.20 mmol) was
added to a solution of Example 17 (60.0 mg, 0.099 mmol) in THF (3.00 mL). The
reaction stirred for 20 min then heated to 60°C overnight. The reaction was cooled
and further borane dimethylsulfide complex (2M in THF, 99 mL, 0.20 mmol)
added. After stirring for 20 min at RT the reaction was heated to 60°C overnight.
The reaction was cooled and further borane dimethylsulfide complex (2M in THF,
99 mL, 0.20 mmol) added. After stirring for 20 min at RT the reaction was heated
to 60°C overnight. The reaction was cooled and quenched by dropwise addition of
MeOH, then evaporated in vacuo. The residue was then partitioned between
EtOAc and water. The aqueous layer was then extracted with EtOAc (3 ×). The
combined organic layers were washed with brine, dried (MgSO ), filtered and
evaporated in vacuo. The residue was purified by HPLC (C18 X-select column,
-60% MeCN in H O, 0.1% HCO H) to give the title compound as a white
powder after freeze-drying (11 mg, 19%). LCMS (Method 5): Rt 3.78 min, m/z
595.2 [MH ]. ¹H NMR (400 MHz, d -MeOD): 1.30 (9H, s), 1.86-2.15 (4H, m),
2.38 (3H, s), 2.46 (4H, t, J 9.3), 3.57 (2H, s), 3.66 (4H, t, J 9.4), 4.89 (1H, dd, J 8.7,
.7), 5.44 (1H, t, J 8.7), 6.33 (1H, s), 7.19-7.34 (8H, m), 7.44 (1H, d, J 8.5), 7.51
(1H, dd, J 8.7, 2.9), 8.15 (1H, d, J 2.8).
Example 22
1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-(1-methyl-
piperidinylmethyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-urea
a. 4-(6-Fluoro-[1,2,4]triazolo[4,3-a]pyridinylmethyl)-piperidine
carboxylic acid tert-butyl ester (Intermediate 22a)
A dark brown solution of (5-fluoro-pyridinyl)-hydrazine (549 mg, 4.32
mmol) and N-Bocpiperidine acetaldehyde (Aldrich, 982 mg, 4.32 mmol) in
EtOH (10 mL) was stirred at reflux for 30 min, then cooled to 0°C, diluted with
DCM (25 mL) and then (diacetoxyiodo)benzene (1.67 g, 5.18 mmol) was added
portionwise over 1 min. The purple solution was stirred at RT for 30 min, then
aqueous NaOH (1M, 20 mL) was added and the mixture shaken. The aqueous
layer was extracted with DCM (2 × 20 mL), then the combined organics passed
through a hydrophobic frit and concentrated in vacuo to leave an orange solid.
FCC, using 3% MeOH in DCM, gave the title compound as a pale orange solid
(1.53 g, 90%). LCMS (Method 3): Rt 3.15, m/z 235 [M-CO C H +H ].
2 4 9
b. 4-[6-((1R,4S)Amino-1,2,3,4-tetrahydro-naphthalenyloxy)-
[1,2,4]triazolo[4,3-a]pyridinylmethyl]-piperidinecarboxylic acid tert-
butyl ester (Intermediate 22b)
To a solution of Intermediate A (392 mg, 2.40 mmol) in dry DMF (5 mL)
was added NaH (60% dispersion in mineral oil, 240 mg, 6.00 mmol) and the
resulting brown suspension was stirred at RT for 45 min (CARE: gas evolution).
Intermediate 22a (669 mg, 2.00 mmol) was added and the dark brown solution
stirred at 60°C for 2 h. The cooled solution was concentrated in vacuo, redissolved
in MeOH (5 mL), applied to an SCX-2 cartridge (20 g) and washed with MeOH
(100 mL). The product was eluted with 2M NH in MeOH (75 mL); concentration
in vacuo left a dark brown residue. FCC, using 4-9% [2M NH in MeOH] in DCM,
gave the title compound as a brown oil (421 mg, 44%). LCMS (Method 3): Rt 2.45
min, m/z 478 [MH ].
c. 4-(6-{(1R,4S)[3-(5-tert-Butylp-tolyl-2H-pyrazolyl)-ureido]-
1,2,3,4-tetrahydro-naphthalenyloxy}-[1,2,4]triazolo[4,3-a]pyridin
ylmethyl)-piperidinecarboxylic acid tert-butyl ester (Intermediate 22c)
A dark brown solution of (5-tert-butylp-tolyl-2H-pyrazolyl)-carbamic
acid 2,2,2-trichloro-ethyl ester (Synthetic Communications, 2009, 39, 3999-4009;
162 mg, 0.401 mmol), Intermediate 22b (174 mg, 0.364 mmol) and DIPEA (0.079
mL, 0.455 mmol) in DMF (5 mL) was stirred at 100°C for 3 h. The solution was
cooled to RT, concentrated in vacuo, suspended in water (10 mL) and extracted
with DCM (2 × 10 mL). The combined organics were passed through a
hydrophobic frit and concentrated in vacuo to leave a brown gum. FCC, using 2-
6% MeOH in DCM, gave the title compound as an off-white solid (155 mg, 58%).
LCMS (Method 3): Rt 4.16 min, m/z 733 [MH ].
d. 1-(5-tert-Butylp-tolyl-2H-pyrazolyl)[(1S,4R)(3-piperidin-
4-ylmethyl-[1,2,4]triazolo[4,3-a]pyridinyloxy)-1,2,3,4-tetrahydro-
naphthalenyl]-urea (Intermediate 22d)
An orange solution of Intermediate 22c (155 mg, 0.211 mmol) and TFA
(0.157 mL, 2.11 mmol) in DCM (3 mL) was stirred at RT for 3 h. The solution was
concentrated in vacuo, redissolved in MeOH (1 mL), applied to an SCX-2
cartridge (2 g) and washed with MeOH (15 mL). The product was eluted with 2M
NH in MeOH (15 mL); concentration in vacuo left the title compound as a pale
brown solid (116 mg, 87%). LCMS (Method 3): Rt 2.90 min, m/z 633 [MH ].
e. 1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-(1-methyl-
piperidinylmethyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-urea (Example 22)
To a suspension of Intermediate 22d (58 mg, 0.0917 mmol) and
formaldehyde (37%wt in water, 0.074 mL, 0.917 mmol) in DCM-MeOH (4:1, 2.5
mL), were added AcOH (0.0105 mL, 0.183 mmol) and NaBH(OAc) (38.8 mg,
0.183 mmol) sequentially, then the solution stirred at RT for 2.5 h. The solution
was concentrated in vacuo to ~0.5 mL volume, diluted with MeOH (0.5 mL), then
applied to an SCX-2 cartridge and washed with MeOH (15 mL). The product was
eluted with 2M NH in MeOH (15 mL); concentration in vacuo left a pale brown
solid. HPLC (XBridge C18, 40-98% MeCN in H O, 0.1% NH OH) gave the title
compound as a white solid after freeze-drying (15.0 mg, 25%). LCMS (Method 5):
Rt 3.66 min, m/z 647 [MH ]. ¹H NMR (400 MHz, d -DMSO): 1.22 (9H, s), 1.26
(2H, m), 1.58 (2H, d, J 12.6), 1.75 (2H, t, J 11.4), 1.78-1.92 (3H, m), 2.03 (2H, m),
2.07 (3H, s), 2.31 (3H, s), 2.68 (2H, d, J 10.7), 2.97 (2H, d, J 7.0), 4.78 (1H, m),
.48 (1H, t, J 4.5), 6.27 (1H, s), 7.07 (1H, d, J 8.5), 7.11 (1H, dd, J 9.5, 2.0), 7.23-
7.35 (8H, m), 7.63 (1H, d, J 9.8), 8.03 (1H, s), 8.17 (1H, s).
Example 23
1-(5-tert-Butylp-tolyl-2H-pyrazolyl)((1S,4R){3-[1-(2,2-
difluoro-ethyl)-piperidinylmethyl]-[1,2,4]triazolo[4,3-a]pyridinyloxy}-
1,2,3,4-tetrahydro-naphthalenyl)-urea
To an orange solution of Intermediate 22d (58 mg, 0.0917 mmol) and
DIPEA (0.0319 mL, 0.183 mmol) in DCM-MeOH (4:1, 2.5 mL), was added 2,2-
difluoroethyl trifluoromethane-sulfonate (Fluorochem, 29.4 mg, 0.138 mmol) and
the solution stirred at RT for 2 h. DIPEA (0.0319 mL, 0.183 mmol) and 2,2-
difluoroethyl trifluoromethanesulfonate (29.4 mg, 0.138 mmol) were added
sequentially, and the pale green solution stirred at RT for 1 h. Water (2 mL) was
added and the mixture extracted with DCM (2 × 3 mL). The combined organics
were passed through a hydrophobic frit and concentrated in vacuo to leave a pale
green-brown solid. HPLC (XBridge C18, 50-98% MeCN in H2O, 0.1% NH4OH)
gave the title compound as a white solid after freeze-drying (11.5 mg, 18%).
LCMS (Method 5): Rt 3.75 min, m/z 697 [MH ]. ¹H NMR (400 MHz, d -DMSO):
1.22 (9H, s), 1.24-1.33 (2H, m), 1.59 (2H, d, J 13.0), 1.75-1.92 (3H, m), 2.01-2.10
(4H, m), 2.31 (3H, s), 2.62 (2H, td, J 15.8, 4.8), 2.82 (2H, d, J 11.4), 2.98 (2H, d, J
7.2), 4.78 (1H, m), 5.48 (1H, t, J 4.7), 6.04 (1H, tt, J 55.7, 4.4), 6.27 (1H, s), 7.07
(1H, d, J 8.9), 7.11 (1H, dd, J 10.0, 2.2), 7.21-7.35 (8H, m), 7.63 (1H, d, J 9.8),
8.03 (1H, s), 8.17 (1H, d, J 2.0).
Example 24
1-(5-tert-Butylp-tolyl-2H-pyrazolyl)[(1S,4R)[3-(4-
hydroxypiperidinyl)-[1,2,4]triazolo[4,3-a]pyridineyloxy]-1,2,3,4-
tetrahydro-naphthalenyl]-urea
a. 6-Fluoro-[1,2,4]triazolo[4,3-a]pyridine (Intermediate 24a)
(5-Fluoro-pyridinyl)-hydrazine (500 mg, 3.93 mmol) in diethoxymethyl
acetate (5 mL) was stirred at RT for 2 h. The resulting precipitate was diluted with
cyclohexane (5 ml) and filtered to give the title compound (379 mg, 70%). ¹H
NMR (400 MHz, CDCl ): 7.25 (1H, m), 7.84 (1H, m), 8.09 (1H, t), 8.84 (1H, s).
b. 3-Chlorofluoro-[1,2,4]triazolo[4,3-a]pyridine (Intermediate 24b)
A solution of Intermediate 24a (789 mg, 5.98 mmol) and N-
chlorosuccinimide (878 mg, 6.57 mmol) in chloroform (15 mL) was heated at
65°C overnight. The cooled mixture was washed with sat. aq. NaHCO solution (2
× 15 mL) and dried (Na SO ). The solvent was evaporated, then the residue
suspended in diethyl ether (10 mL) and filtered to give the title compound (730
mg, 76%). LCMS (Method 1): Rt 1.83 min, m/z 172 [MH ].
c. 1-(6-Fluoro-[1,2,4]triazolo[4,3-a]pyridinyl-piperidinol
(Intermediate 24c)
A brown solution of Intermediate 24b (855 mg, 4.98 mmol) and 4-
hydroxypiperidine (2.02 g, 19.9 mmol) in DMA (15 mL) was irradiated to 175°C
in the microwave for 3 h. The cooled solution was concentrated in vacuo, then the
residue diluted with water (20 mL) and brine (20 mL). The mixture was washed
with diethyl ether (2 × 50 mL), then extracted with EtOAc (2 × 50 mL). The
combined EtOAc layers were washed with brine (50 mL), dried (Na SO ), filtered
and concentrated in vacuo to leave a yellow oil. The aqueous was further extracted
with DCM (3 × 50 mL). The combined DCM layers were passed through a
hydrophobic frit and concentrated in vacuo to leave a brown oil. The two oils were
combined. FCC, using 4-5% [2M NH in MeOH] in DCM, gave the title
compound as a yellow crystalline solid (514 mg, 44%). LCMS (Method 3): Rt 1.96
min, m/z 237 [MH ].
d. 6-Fluoro(4-triisopropylsilanyloxy-piperidinyl)-
[1,2,4]triazolo[4,3-a]pyridine (Intermediate 24d)
OTIPS
Triisopropylsilyl trifluoromethanesulfonate (395 mg, 1.29 mmol) was added
dropwise to a solution of Intermediate 24c (254 mg, 1.07 mmol) and Et N (0.20
mL, 1.40 mmol) in DMF (3 mL) at RT under N . The mixture was stirred for 1 h
then Et N (0.10 ml, 0.70 mmol) and triisopropylsilyl trifluoromethanesulfonate
(200 mg, 0.65 mmol) were added sequentially, and the mixture stirred for 1 h. The
solvent was evaporated, the residue applied to an SCX-2 cartridge and washed
with MeOH. The product was eluted with 2M NH in MeOH; concentration in
vacuo left the title compound (339 mg, 80%). LCMS (Method 1): Rt 4.74 min, m/z
393 [MH ].
e. (1S,4R)[3-(4-Triisopropylsilanyloxy-piperidinyl-
[1,2,4]triazolo[4,3a]pyridinyloxy]1,2,3,4-tetrahydro-naphthalenylamine.
(Intermediate 24e)
OTIPS
Intermediate A (81 mg, 0.497 mmol) was added dropwise to a suspension of
NaH (60% dispersion in oil, 59 mg, 1.49 mmol) in DMF (3 mL) at RT under N .
The mixture was stirred for 15 min then Intermediate 24d (150 mg, 0.382 mmol)
was added and the mixture stirred at 60°C under N for 3 h. Sat. aq. NH Cl
solution (0.2 mL) was added to the cooled mixture which was then diluted with
water (15 mL) and extracted with EtOAc (3 × 15 mL). The combined organics
were washed with brine (15 mL) and dried (Na SO ). The solvent was evaporated,
the residue applied to an SCX-2 cartridge and washed with MeOH. The product
was eluted with 2M NH in MeOH; concentration in vacuo left the title compound
(180 mg, 90%). LCMS (Method 1): Rt 3.05 min, m/z 536 [MH ].
f. 1-(5-tert-Butylp-tolyl-2H-pyrazolyl)[(1S,4R)[3-(4-
triisopropylsilanyloxy-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridineyloxy]-
1,2,3,4-tetrahydro-naphthalenyl]-urea. (Intermediate 24f)
OTIPS
A mixture of (5-tert-butylp-tolyl-2H-pyrazolyl)carbamic acid 2,2,2-
trichloro-ethyl ester (Synthetic Communications, 2009, 39, 3999-4009; 140 mg,
0.346 mmol), Intermediate 24e (185 mg, 0.346 mmol) and DIPEA (0.18 mL, 1.03
mmol) in DMF (3 mL) was heated at 60°C for 4 h under N . The cooled mixture
was applied to an SCX-2 cartridge and washed with MeOH. The product was
eluted with 2M NH in MeOH; concentration in vacuo left a brown gum. FCC,
using 0.6-6% [2M NH in MeOH] in DCM, gave the title compound (124 mg,
45%). LCMS (Method 4): Rt 5.15 min, m/z 791 [MH ].
g. 1-(5-tert-Butylp-tolyl-2H-pyrazolyl)[(1S,4R)[3-(4-
hydroxypiperidinyl)-[1,2,4]triazolo[4,3-a]pyridineyloxy]-1,2,3,4-
tetrahydro-naphthalenyl]-urea (Example 24)
TBAF (1M in THF, 0.235 mL, 0.235 mmol) was added dropwise to a
solution of Intermediate 24f (124 mg, 0.157 mmol) in dry THF (3 mL) at -30°C for
4 h under N . The mixture was allowed to warm to RT, then stirred for 5 h. The
solution was applied to an SCX-2 cartridge and washed with MeOH. The product
was eluted with 2M NH in MeOH; concentration in vacuo left a brown foam.
HPLC (Gemini C18; 40-90% MeCN in H O, 0.1% NH OH) gave the title
compound as a white powder (77 mg, 77%). LCMS (Method 5): Rt 4.18 min, m/z
635 [MH ]. ¹H NMR (400 MHz, CDCl ): 1.33 (9H, s), 1.71-1.80 (2H, m), 1.87-
1.96 (1H, m), 2.01-2.12 (4H, m), 2.25 (1H, m), 2.36 (3H, s), 3.04-3.11 (2H, m),
3.37-3.44 (2H, m), 3.93 (1H, m), 5.09 (1H, td, J 8.9, 5.3), 5.19 (1H, t, J 4.0), 5.44
(1H, d, J 8.8), 6.28 (1H, s), 6.46 (1H, br s), 6.99 (1H, dd, J 9.9, 2.1), 7.21 (2H, d, J
8.1), 7.25-7.33 (5H, m), 7.39 (2H, d, J 8.1), 7.49 (1H, d, J 9.9).
Example 25
1-(5-tert-Butylp-tolyl-2H-pyrazolyl)[(1S,4R){3-[(2-hydroxy-
ethyl)-methyl-amino]-[1,2,4]triazolo[4,3-a]pyridineyloxy]-1,2,3,4-
tetrahydro-naphthalenyl]-urea
a. 2-(6-Fluoro-[1,2,4]triazolo[4,3-a]pyridinyl)-methyl-amino]ethanol
and 2-[(3-chloro-[1,2,4]triazolo[4,3-a]pyridinyl)-methyl-amino]ethanol
(Intermediate 25a)
HO N
A solution of Intermediate 24b (300 mg, 1.75 mmol) and 2-methylamino
ethanol (660 mg, 8.77 mmol) in NMP (2 ml) was heated at 165°C for 2 h in the
microwave. The cooled mixture was applied to an SCX-2 cartridge and washed
with MeOH. The product was eluted with 2M NH in MeOH; concentration in
vacuo left a brown gum. FCC, using 3-6% [2M NH in MeOH] in DCM, gave a
mixture of the title compounds (240 mg, 65%). LCMS (Method 4): Rt 1.05 min,
m/z 211 [MH ] and Rt 1.76 min, m/z 227 [MH ].
b. (6-Fluoro-[1,2,4]triazolo[4,3-a]pyridinyl)-methyl-(2-
triisopropylsilanyloxy-ethyl)-amine. (Intermediate 25b)
OTIPS
Triisopropylsilyl trifluoromethanesulfonate (454 mg, 1.48 mmol) was added
dropwise to a solution of Intermediate 25a (240 mg, 1.14 mmol) and Et N (0.24
mL, 1.71 mmol) in DMF (2 mL) at RT under N and the mixture was stirred for 3
h. The solvent was evaporated, the residue applied to an SCX-2 cartridge and
washed with MeOH. The product was eluted with 2M NH in MeOH;
concentration in vacuo left a brown gum. FCC, using 0-3% [2M NH in MeOH] in
DCM, gave the title compound (160 mg, 38%). LCMS (Method 4): Rt 4.25 min,
m/z 367 [MH ].
c. [6-((1R,4S)Amino-1,2,3,4-tetrahydro-naphthalenyloxy)-
[1,2,4]triazolo[4,3-a]pyridinyl]-methyl-(2-triisopropylsilanyloxy-ethyl)-
amine. (Intermediate 25c)
O Si
Intermediate A (93 mg, 0.568 mmol) was added dropwise to a suspension of
NaH (60% dispersion in oil, 68 mg, 1.71 mmol) in DMF (3 mL) at RT under N .
The mixture was stirred for 15 min then Intermediate 25b (160 mg, 0.437 mmol)
was added and the mixture stirred at 60°C under N2 for 3 h. Sat. aq. NH4Cl
solution (0.2 mL) was added to the cooled mixture which was then diluted with
water (15 mL) and extracted with EtOAc (3 × 15 mL). The combined organics
were washed with brine (15 mL) and dried (Na2SO4). The solvent was evaporated,
the residue applied to an SCX-2 cartridge and washed with MeOH. The product
was eluted with 2M NH in MeOH; concentration in vacuo left a brown foam.
FCC, using 0-6% [2M NH3 in MeOH] in DCM, gave the title compound (64 mg,
29%). LCMS (Method 1): Rt 2.71 min, m/z 510 [MH ].
d. 1-(5-tert-Butylp-tolyl-2H-pyrazolyl)[(1S,4R){3-[methyl-(2-
triisopropylsilanyloxy-ethyl-amino][1,2,4]triazolo[4,3-a]pyridineyloxy]-
1,2,3,4-tetrahydro-naphthalenyl]-urea. (Intermediate 25d)
O Si
A mixture of (5-tert-butylp-tolyl-2H-pyrazolyl)carbamic acid 2,2,2-
trichloro-ethyl ester (Synthetic Communications, 2009, 39, 3999-4009; 71 mg,
0.175 mmol), Intermediate 25c (64 mg, 0.125 mmol) and DIPEA (0.093 mL, 0.524
mmol) in DMF (2 mL) was heated at 60°C for 4 h under N . The cooled mixture
was applied to an SCX-2 cartridge and washed with MeOH. The product was
eluted with 2M NH in MeOH; concentration in vacuo left a brown gum. FCC,
using 3-6% [2M NH in MeOH] in DCM, gave the title compound (65 mg, 68%).
LCMS (Method 1): Rt 4.78 min, m/z 765 [MH ].
e. 1-(5-tert-Butylp-tolyl-2H-pyrazolyl)[(1S,4R){3-[(2-
hydroxy-ethyl)-methyl-amino]-[1,2,4]triazolo[4,3-a]pyridineyloxy]-1,2,3,4-
tetrahydro-naphthalenyl]-urea (Example 25)
TBAF (1M in THF; 0.127 mL, 0.235 mmol) was added dropwise to a
solution of Intermediate 25d (65 mg, 0.085 mmol) in dry THF (0.3 mL) at -30°C
under N . The mixture was allowed to warm to RT, then stirred for 1 h. The
solution was applied to an SCX-2 cartridge and washed with MeOH. The product
was eluted with 2M NH in MeOH; concentration in vacuo left a pale yellow oil.
Further purification by HPLC. (Gemini C18; 40-100% MeCN in H O, 0.1%
NH OH) gave the title compound as a white powder (32 mg, 62%). LCMS
(Method 5): Rt 4.11 min, m/z 609 [MH ]. ¹H NMR (400 MHz, CDCl ): 1.32 (9H,
s), 1.90-1.99 (1H, m), 2.02-2.12 (2H, m), 2.23-2.30 (1H, m), 2.37 (3H, s), 2.94
(3H, s), 3.11 (1H, ddd, J 14.3, 6.9, 3.5), 3.18 (1H, ddd, J 14.3, 5.6, 3.2), 3.68-3.79
(2H, m), 5.06 (1H, td, J 8.6, 5.5), 5.20 (1H, t, J 4.2), 5.50 (1H, d, J 8.7), 6.31 (1H,
s), 6.42 (1H, s), 6.98 (1H, dd, J 9.9, 2.0), 7.18-7.30 (6H, m), 7.39 (2H, d, J 8.2),
7.49 (1H, d, J 9.9), 7.58 (1H, d, J 2.0).
Example 26
1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-((S)
hydroxy-pyrrolidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-urea
a. (S)(6-Fluoro-[1,2,4]triazolo[4,3-a]pyridinyl)-pyrrolidinol
(Intermediate 26a)
A mixture of Intermediate 24b (300 mg, 1.74 mmol) and (S)
hydroxypyrrolidine (600 mg, 9.96 mmol) in NMP (6 mL) was heated in the
microwave at 160°C for 2 h. The reaction mixture was applied to an SCX-2
cartridge (70 g) and washed with MeOH. The product was eluted with 2M NH in
MeOH; concentration in vacuo gave a residue. FCC, using 0-8% [2M NH in
MeOH] in DCM, gave the title compound (150 mg, 38%). LCMS (Method 1): Rt
1.45 min, m/z 223 [MH ].
b. 6-Fluoro((S)triisopropylsilanyloxy-pyrrolidinyl)-
[1,2,4]triazolo[4,3-a]pyridine (Intermediate 26b)
O Si
Triisopropylsilyl trifluoromethanesulfonate (250 mg, 0.81 mmol) was added
to a solution of Intermediate 26a (150 mg, 0.67 mmol) and Et N (101 mg, 1.00
mmol) in DMF (2 mL) and the mixture stirred at RT for 1 h. The reaction mixture
was applied to an SCX-2 cartridge (5 g) and washed with MeOH. The product was
eluted with 2M NH in MeOH; concentration in vacuo gave the title compound
(220 mg, 86%). LCMS (Method 4): Rt 4.15 min, m/z 379 [MH ].
c. (1S,4R)[3-((S)Triisopropylsilanyloxy-pyrrolidinyl)-
[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalen
ylamine (Intermediate 26c)
O Si
To a solution of Intermediate A (104 mg, 0.640 mmol) in DMF (2 mL) was
added NaH (60% in oil, 70 mg, 1.74 mmol) and the mixture stirred at RT for 20
min, before Intermediate 26b (220 mg, 0.582 mmol) was added. This mixture was
stirred thermally at 60°C for 4 h, then at 60°C in the microwave for 3 h. The
cooled reaction mixture was applied to an SCX-2 cartridge (10 g) and washed with
MeOH. The product was eluted with 2M NH in MeOH; concentration in vacuo
gave a residue. FCC, using 0-10% [2M NH in MeOH] in DCM gave the title
compound as a yellow gum (70 mg, 23%). LCMS (Method 1): Rt 2.89, m/z 522
[MH ].
d. 1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-((S)
triisopropylsilanyloxy-pyrrolidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-
1,2,3,4-tetrahydro-naphthalenyl}-urea (Intermediate 26d)
O Si
A solution of Intermediate 26c (70 mg, 0.134 mmol), (5-tert-butylp-tolyl-
2H-pyrazolyl)-carbamic acid 2,2,2-trichloro-ethyl ester (Synthetic
Communications, 2009, 39, 3999-4009; 81 mg, 0.201 mmol) and DIPEA (70 mg,
0.54 mmol) in DMF (2 mL) was stirred at 60°C for 30 min. The reaction mixture
was applied to an SCX-2 cartridge (5 g) and washed with MeOH. The product was
eluted with 2M NH in MeOH; concentration in vacuo gave a residue. FCC, using
0-10% [2M NH in MeOH] in DCM, gave the title compound as an off-white foam
(19 mg, 23%). LCMS (Method 1): Rt 4.70, m/z 777 [MH ].
e. 1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-((S)
hydroxy-pyrrolidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-urea (Example 26)
To a solution of Intermediate 26d (19 mg, 0.024 mmol) in THF (1 mL) at -
°C was added TBAF (1M in THF, 36 µL, 0.036 mmol) and the mixture was
allowed to warm to RT over 1 h. The reaction mixture was applied to an SCX-2
cartridge (2 g) and washed with MeOH. The product was eluted with 2M NH in
MeOH; concentration in vacuo gave a residue. Purification by HPLC (C6-Ph
column, 35-75% MeCN in H O, 0.1% HCO H) gave the title compound as an off-
white powder after freeze-drying (10.0 mg, 60%). LCMS (Method 5): Rt 4.00 min,
m/z 621 [MH ]. ¹H NMR (400 MHz, CDCl ): 1.29 (9H, s), 1.89-2.09 (4H, m),
2.13-2.29 (2H, m), 2.34 (3H, s), 3.35 (1H, td, J 9.2, 4.6), 3.45 (1H, d, J 11.1), 3.50
(1H, dd, J 11.1, 4.3), 3.60 (1H, m), 4.51 (1H, m), 5.04 (1H, td, J 8.5, 5.3), 5.15
(1H, t, J 4.1), 5.57 (1H, d, J 8.6), 6.26 (1H, s), 6.67 (1H, br s), 6.89 (1H, dd, J 9.9,
1.7), 7.15 (2H, d, J 7.1), 7.24-7.29 (4H, m), 7.30-7.38 (4H, m).
Example 27
1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-((R)
hydroxymethyl-pyrrolidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-urea
O N OH
a. [(R)(6-Fluoro-[1,2,4]triazolo[4,3-a]pyridinyl)-pyrrolidinyl]-
methanol (Intermediate 27a)
A mixture of Intermediate 24b (300 mg, 1.74 mmol) and (R)-(-)
(hydroxymethyl)-pyrrolidine (704 mg, 9.96 mmol) in NMP (6 mL) was heated in
the microwave at 160°C for 2 h. The reaction mixture was applied to an SCX-2
cartridge (75 g) and washed with MeOH. The product was eluted with 2M NH in
MeOH; concentration in vacuo gave a residue. FCC, using 0-10% [2M NH in
MeOH] in DCM, gave the title compound (220 mg, 53%). LCMS (Method 4): Rt
1.50, m/z 237 [MH ].
b. 6-Fluoro((S)triisopropylsilanyloxy-pyrrolidinyl)-
[1,2,4]triazolo[4,3-a]pyridine (Intermediate 27b)
O Si
Triisopropylsilyl trifluoromethanesulfonate (430 mg, 1.40 mmol) was added
to a solution of Intermediate 27a (220 mg, 0.93 mmol) and Et N (190 mg, 1.86
mmol) in a DMF (2 mL) and the mixture stirred at RT for 1 h. The reaction
mixture was applied to an SCX-2 cartridge (10 g) and washed with MeOH. The
product was eluted with 2M NH in MeOH; concentration in vacuo gave the title
compound (170 mg, 47%). LCMS (Method 1): Rt 4.45, m/z 393 [MH ].
c. (1S,4R)[3-((R)Triisopropylsilanyloxymethyl-pyrrolidinyl)-
[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalen
ylamine (Intermediate 27c)
O Si
To a solution of Intermediate A (60 mg, 0.364 mmol) in DMF (2 mL) was
added NaH (60% in oil, 40 mg, 0.99 mmol) and the mixture stirred at RT for 20
min, before Intermediate 27b (130 mg, 0.331 mmol) was added. This mixture was
heated at 60°C in the microwave for 1.5 h. The reaction mixture was applied to an
SCX-2 cartridge (5 g) and washed with MeOH. The product was eluted with 2M
NH in MeOH; concentration in vacuo gave a residue. FCC, using 0-7% [2M NH
in MeOH] in DCM, gave the title compound as a brown oil (50 mg, 28%). LCMS
(Method 4): Rt 2.36, m/z 536 [MH ].
d. 1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-((R)
triisopropylsilanyloxymethyl-pyrrolidinyl)-[1,2,4]triazolo[4,3-a]pyridin
yloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea (Intermediate 27d)
O N O
N Si
A solution of Intermediate 27c (50 mg, 0.093 mmol), (5-tert-butylp-tolyl-
2H-pyrazolyl)-carbamic acid 2,2,2-trichloro-ethyl ester (Synthetic
Communications, 2009, 39, 3999-4009; 56 mg, 0.140 mmol) and DIPEA (70 mg,
0.54 mmol) in DMF (2 mL) was stirred at 60°C for 1 h. The reaction mixture was
applied to an SCX-2 cartridge (5 g) and washed with MeOH. The product was
eluted with 2M NH in MeOH; concentration in vacuo gave a residue. FCC, using
0-10% [2M NH in MeOH] in DCM, gave the title compound as an off-white foam
(27 mg, 36%). LCMS (Method 4): Rt 4.58, m/z 791 [MH ].
e. 1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-((R)
hydroxymethyl-pyrrolidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-urea (Example 27)
To a solution of Intermediate 27d (27 mg, 0.034 mmol) in THF (1 mL) at -
°C was added TBAF (1M in THF, 36 µL, 0.036 mmol) and the mixture was
allowed to warm to RT over 1 h. The reaction mixture was applied to an SCX-2
cartridge (2 g) and washed with MeOH. The product was eluted with 2M NH in
MeOH; concentration in vacuo gave a residue. Purification by HPLC (C6-Ph
column, 10-70% MeCN in H O, 0.1% HCO H) gave the title compound as a white
powder after freeze-drying (10.0 mg, 45%). LCMS (Method 5): Rt 4.18 min, m/z
635 [MH ]. ¹H NMR (400 MHz, CDCl ): 1.25 (9H, s), 1.63-1.75 (1H, m), 1.81-
1.95 (3H, m), 1.97-2.01 (3H, m), 2.26 (1H, m), 2.31 (3H, s), 3.17-3.26 (1H, m),
3.32-3.47 (2H, m), 3.57 (1H, dd, J 11.6, 3.2), 4.07-4.15 (1H, m), 4.99-5.07 (1H,
m), 5.15 (1H, t, J 4.1), 5.57 (1H, d, J 8.9), 6.25 (1H, s), 6.61 (1H, s), 6.91 (1H, d, J
.2), 7.16 (2H, d, J 8.3), 7.20-7.29 (4H, m), 7.32 (2H, d, J 8.0), 7.35-7.41 (2H,
m).
Example 28
1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-((S)
hydroxymethyl-pyrrolidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-urea
O N OH
N N N
a. [(S)(6-Fluoro-[1,2,4]triazolo[4,3-a]pyridinyl)-pyrrolidinyl]-
methanol (Intermediate 28a)
A mixture of Intermediate 24b (300 mg, 1.74 mmol) and L-prolinol (704
mg, 9.96 mmol) in NMP (4 mL) was heated in the microwave at 160°C for 2 h.
The reaction mixture was applied to an SCX-2 cartridge (70 g) and washed with
MeOH. The product was eluted with 2M NH in MeOH; concentration in vacuo
gave a residue. FCC, using 0-10% [2M NH in MeOH] in DCM, gave the title
compound (210 mg, 50%). LCMS (Method 4): Rt 1.50 min, m/z 237 [MH ].
b. 6-Fluoro((S)triisopropylsilanyloxymethyl-pyrrolidinyl)-
[1,2,4]triazolo[4,3-a]pyridine (Intermediate 28b)
Triisopropylsilyl trifluoromethanesulfonate (327 mg, 1.06 mmol) was added
to a solution of Intermediate 28a (210 mg, 0.89 mmol) and Et N (135 mg, 1.33
mmol) in a DMF (3 mL) and the mixture stirred at RT for 1 h. The reaction
mixture was applied to an SCX-2 cartridge (25 g) and washed with MeOH. The
product was eluted with 2M NH in MeOH; concentration in vacuo gave a residue.
FCC, using 0-10% [2M NH in MeOH] in DCM, gave the title compound (110 mg,
31%). LCMS (Method 1): Rt 4.45 min, m/z 393 [MH ].
c. (1S,4R)[3-((S)Triisopropylsilanyloxymethyl-pyrrolidinyl)-
[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalen
ylamine (Intermediate 28c)
To a solution of Intermediate A (50 mg, 0.309 mmol) in DMF (2 mL) was
added NaH (60% in oil, 33 mg, 0.80 mmol) and the mixture stirred at RT for 20
min, before Intermediate 28b (110 mg, 0.280 mmol) was added. This mixture was
heated at 60°C in the microwave for 1.25 h. The reaction mixture was applied to an
SCX-2 cartridge (25 g) and washed with MeOH. The product was eluted with 2M
NH in MeOH; concentration in vacuo gave a residue. FCC, using 0-7% [2M NH
in MeOH] in DCM gave the title compound as a viscous yellow oil (42 mg, 28%).
LCMS (Method 4): Rt 2.55 min, m/z 536 [MH ].
d. 1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-((S)
triisopropylsilanyloxymethyl-pyrrolidinyl)-[1,2,4]triazolo[4,3-a]pyridin
yloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea (Intermediate 28d)
A solution of Intermediate 28c (40 mg, 0.074 mmol), (5-tert-butylp-tolyl-
2H-pyrazolyl)-carbamic acid 2,2,2-trichloro-ethyl ester (Synthetic
Communications, 2009, 39, 3999-4009; 45 mg, 0.112 mmol) and DIPEA (38 mg,
0.296 mmol) in DMF (2 mL) was stirred at 60°C for 30 min. The reaction mixture
was applied to an SCX-2 cartridge (5 g) and washed with MeOH. The product was
eluted with 2M NH3 in MeOH; concentration in vacuo gave a residue. FCC, using
0-7% [2M NH in MeOH] in DCM, gave the title compound as a viscous yellow
oil (38 mg, 65%). LCMS (Method 1): Rt 4.72 min, m/z 791 [MH ].
e. 1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-((S)
hydroxymethyl-pyrrolidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-urea (Example 28)
To a solution of Intermediate 28d (38 mg, 0.048 mmol) in THF (1 mL) at -
°C was added TBAF (1M in THF, 72 µL, 0.072 mmol) and the mixture was
allowed to warm to RT over 1 h. The reaction mixture was applied to an SCX-2
cartridge (5 g) and washed with MeOH. The product was eluted with 2M NH in
MeOH; concentration in vacuo gave a residue. Purification by HPLC (C6-Ph
column, 10-70% MeCN in H O, 0.1% HCO H) gave the title compound as a white
powder after freeze-drying (12 mg, 39%). LCMS (Method 5): Rt 4.20 min, m/z
635 [MH ]. ¹H NMR (400 MHz, d -MeOH): 1.29 (9H, s), 1.78-2.28 (8H, m), 2.38
(3H, s), 3.36-3.46 (1H, m), 3.53 (2H, dd, J 5.0, 1.6), 3.64-3.73 (1H, m), 4.04-4.12
(1H, m), 4.85-4.91 (1H, m), 5.36 (1H, t, J 4.1), 6.32 (1H, s), 7.11 (1H, dd, J 10.0,
2.1), 7.20-7.35 (8H, m), 7.44 (1H, d, J 9.9), 7.99-8.01 (1H, m).
Example 29
1-[5-tert-Butyl(3-hydroxymethyl-phenyl)-2H-pyrazolyl]
[(1S,4R)(3-piperidinyl-[1,2,4]triazolo[4,3-a]pyridinyloxy)-1,2,3,4-
tetrahydro-naphthalenyl]-urea
a. 3-(5-Aminotert-butyl-pyrazolyl)-benzoic acid ethyl ester
(Intermediate 29a)
A solution of 3-hydrazino benzoic acid (5.53 g, 36.4 mmol) and 4,4-
dimethyloxo pentanenitrile (5.00 g, 40.0 mmol) and concentrated sulfuric acid
(2 mL) in EtOH (72 mL) was stirred at reflux for 19 h. The cooled mixture was
concentrated in vacuo, was diluted with 1N NaOH solution (15 mL) and extracted
with EtOAc. The combined organics were dried and concentrated in vacuo. The
residue was purified by FCC, using 0-40% EtOAc in cyclohexane, to give the title
compound as an off-white powder (5.92 g, 56%). LCMS (Method 3): Rt 3.04 min,
m/z 288 [MH ].
b. [3-(5-Aminotert-butyl-pyrazolyl)-phenyl]-methanol
(Intermediate 29b)
To a solution of Intermediate 29a (1.00 g, 3.48 mmol) and Et N (265 µL,
1.91 mmol) in EtOH (35 mL) was added NaBH (198 mg, 5.23 mmol) and the
suspension stirred at RT for 1.5 h. NaBH (198 mg, 5.23 mmol) was added and the
suspension stirred for a further 19 h. NaBH (1.31 g, 34.8 mmol) was added and
the suspension stirred for a further 24 h, then diluted with water and extracted with
DCM. The combined organics were dried and concentrated in vacuo. The residue
was purified by FCC, using 0-10% [2M NH in MeOH] in DCM, to give the title
compound as a white solid (740 mg, 87%). LCMS (Method 3): Rt 2.05 min, m/z
246 [MH ].
c. [5-tert-Butyl(3-hydroxymethyl-phenyl)-2H-pyrazolyl]-carbamic
acid 2,2,2-trichloro-ethyl ester (Intermediate 29c)
O Cl
N Cl
To a bi-phasic mixture of Intermediate 29b (737 mg, 3.00 mmol) in EtOAc
(22.5 mL) and 1N NaOH solution (8.11 mL, 8.11 mmol) at 0°C was added 2,2,2-
trichloroethyl chloroformate (0.45 mL, 3.30 mmol) and the mixture stirred for 1.25
h. The layers were separated and the organic layer was washed with brine, dried
and concentrated in vacuo to give the title compound as an off-white solid (1.26 g,
99%). LCMS (Method 3): Rt 4.00 min, m/z 420, 422 [MH ].
d. 1-[5-tert-Butyl(3-hydroxymethyl-phenyl)-2H-pyrazolyl]
[(1S,4R)(3-piperidinyl-[1,2,4]triazolo[4,3-a]pyridinyloxy)-1,2,3,4-
tetrahydro-naphthalenyl]-urea (Example 29)
A solution of Intermediate 29c (509 mg, 1.21 mmol) and Intermediate 3c
(400 mg, 1.10 mmol) and DIPEA (0.58 mL, 3.30 mmol) in THF (11 mL) was
stirred at reflux for 15 h. The cooled reaction mixture was diluted with water and
extracted with DCM. The combined organics were dried and concentrated in
vacuo. The residue was purified by FCC, using 0-10% [2M NH in MeOH] in
DCM, to give the product. A 50 mg portion of this was further purified by HPLC
(XBridge C18 column, 10-98% MeCN in H O, 0.1% NH OH) to give the title
compound as a white powder after freeze-drying (10 mg, 20%). LCMS (Method
5): Rt 4.23 min, m/z 635 [MH ]. ¹H NMR (400 MHz, d -MeOH): 1.35 (9H, s),
1.57-1.74 (6H, m), 1.89 (1H, t, J 10.7), 2.01-2.08 (2H, m), 2.14-2.22 (1H, m), 3.06
(4H, t, J 5.1), 4.56 (2H, s), 5.09 (1H, m), 5.18 (1H, t, J 4.3), 5.92 (1H, d, J 8.6),
6.40 (1H, s), 6.88 (1H, dd, J 9.9, 2.1), 7.14-7.17 (3H, m), 7.30-7.32 (5H, m), 7.42
(1H, d, J 8.1), 7.50 (1H, s).
Example 30
3-[3-tert-Butyl(3-{(1S,4R)[3-((S)methyl-pyrrolidinyl)-
[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-
ureido)-pyrazolyl]-benzoic acid ethyl ester
a. 3-[3-tert-Butyl(2,2,2-trichloro-ethoxycarbonylamino)-pyrazol
yl]-benzoic acid ethyl ester (Intermediate 30a)
N O Cl
N Cl
The title compound was prepared from Intermediate 29a using an analogous
procedure to that described for Intermediate 29c. LCMS (Method 3): Rt 4.67 min,
m/z 462, 464 [MH ].
b. 3-[3-tert-Butyl(3-{(1S,4R)[3-((S)methyl-pyrrolidinyl)-
[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-
ureido)-pyrazolyl]-benzoic acid ethyl ester (Example 30)
A mixture of Intermediate 5c (163 mg, 0.45 mmol), Intermediate 30a (208
mg, 0.45 mmol) in 1,4-dioxane (3 mL) and DIPEA (119 µL, 0.68 mmol) was
stirred at 90°C for 3 h. The cooled mixture was concentrated in vacuo. The residue
was purified by FCC, using 0-12% MeOH in DCM, to give the product (291 mg,
96%). A 64 mg portion of this was further purified by HPLC (C18 X-select
column, 30-98% MeCN in H O, 0.1% HCO H) to give the title compound as a
white powder after freeze-drying powder (38 mg). LCMS (Method 5): Rt 3.85
min, m/z 677.3 [MH ]. ¹H NMR (400 MHz, d -DMSO): 1.26-1.33 (12H, m), 1.80-
2.27 (11H, m), 2.30-2.39 (1H, m), 3.09-3.16 (1H, m), 3.99 (1H, br t, J 8.2), 4.32
(2H, q, J 7.1), 4.74-4.83 (1H, m), 5.36-5.41 (1H, m), 6.33 (1H, s), 7.11 (1H, d, J
8.6), 7.19-7.37 (5H, m), 7.66 (1H, t, J 7.9), 7.75 (1H, d, J 9.9), 7.80-7.84 (1H, m),
7.93-7.98 (1H, m), 8.07-8.09 (1H, m), 8.22-8.28 (2H, m).
Example 31
(0.5 eq)
1-[5-tert-Butyl(3-hydroxymethyl-phenyl)-2H-pyrazolyl]
{(1S,4R)[3-((S)methyl-pyrrolidinyl)-[1,2,4]triazolo[4,3-a]pyridin
yloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea, partial formate salt
A solution of Example 30 (225 mg, 0.333 mmol) and sodium borohydride
(31.5 mg, 0.833 mmol) in ethanol (3 mL) was stirred at RT for 2.5 h. Sodium
borohydride (31.5 mg, 0.833 mmol) was added and the solution stirred for 90 min.
Sodium borohydride (31.5 mg, 0.833 mmol) was added and the solution stirred for
2.5 h. Sodium borohydride (31.5 mg, 0.833 mmol) was added and the solution
stirred for a further 15.5 h. Water was added followed by sat. aq. NH Cl solution.
The mixture was then extracted with DCM (4 x 20 mL). The combined organic
extracts were dried and concentrated in vacuo. The residue was purified by FCC,
using 0-14% MeOH in DCM, to give the product (150 mg). This was further
purified by HPLC (C18 X-select column, 30-98% MeCN in H O, 0.1% HCO H) to
give the title compound as a white powder after freeze-drying (97 mg, 46%).
LCMS (Method 5): Rt 3.29 min, m/z 635.2 [MH ]. ¹H NMR (400 MHz, d -
DMSO): 1.28 (9H, s), 1.82-2.26 (11H, m), 2.30-2.39 (1H, m), 3.09-3.16 (1H, m),
3.99 (1H, t, J 8.1), 4.57 (2H, s), 4.78-4.86 (1H, m), 5.39 (1H, t, J 4.3), 6.33 (1H, s),
7.11 (1H, d, J 8.4), 7.24-7.38 (7H, m), 7.42-7.48 (2H, m), 7.75 (1H, d, J 9.9), 8.1
(1H, s), 8.20 (0.5H, s), 8.24 (1H, m).
Example 32
1-(5-tert-Butylp-tolyl-2H-pyrazolyl)[(1S,4R)(2-morpholin
yl-ethoxy)-1,2,3,4-tetrahydro-naphthalenyl]-urea
a. 2-((1S,4R)Hydroxy-1,2,3,4-tetrahydro-naphthalenyl)-isoindole-
1,3-dione (Intermediate 32a)
A solution of Intermediate A (150 mg, 0.92 mmol) and phthalic anhydride
(143 mg, 0.97 mmol) in toluene (9 mL) was stirred and heated at reflux for 19.5 h.
After cooling, the mixture was concentrated in vacuo. The residue was purified by
FCC, using 0-50% EtOAc in cyclohexane, to give the title compound as white
powder (215 mg, 79%). LCMS (Method 3): Rt 3.36 min, m/z 316 [MNa ].
b. 2-[(1S,4R)(2-Morpholinyloxo-ethoxy)-1,2,3,4-tetrahydro-
naphthalenyl]-isoindole-1,3-dione (Intermediate 32b)
A solution of Intermediate 32a (115 mg, 0.39 mmol) in dry THF (4 mL)
was added NaH (60% in mineral oil, 23 mg, 0.59 mmol) at RT and stirred for 15
min. 4-(Chloroacetyl)morpholine (56 µL, 0.43 mmol) was then added and the
mixture heated at reflux for 3.5 h. After cooling, the dark brown mixture was
diluted with water and extracted with DCM. The combined organics were dried
and concentrated in vacuo. The residue was purified by FCC, using 0-5% MeOH
in DCM, to give the title compound as light brown foam (103 mg, 62%). LCMS
(Method 3): Rt 3.44 min, m/z 443 [MNa ].
c. 2-((1R,4S)Amino-1,2,3,4-tetrahydro-naphthalenyloxy)
morpholinyl-ethanone (Intermediate 32c)
A solution of Intermediate 32b (100 mg, 0.23 mmol) and hydrazine hydrate
(74 µL, 2.4 mmol) in dry MeOH (6 mL) was stirred at RT for 5 h. The reaction
mixture was concentrated in vacuo. The residue was purified by FCC, using 0-20%
[2M NH in MeOH] in DCM, to give the title compound as an off white foam (50
mg, 72%). LCMS (Method 3): Rt 1.70 min, m/z 291 [MH ].
d. 1-(5-tert-Butylp-tolyl-2H-pyrazolyl)[(1S,4R)(2-morpholin-
4-yloxo-ethoxy)-1,2,3,4-tetrahydro-naphthalenyl]-urea (Intermediate
32d)
A stirred solution of Intermediate 32c (50 mg, 0.17 mmol) and 5-tert-butyl-
2-p-tolyl-2H-pyrazolyl)-carbamic acid 2,2,2-trichloro-ethyl ester (Synthetic
Communications, 2009, 39, 3999-4009; 84 mg, 0.21 mmol) and DIPEA (90 µL,
0.52 mmol) in THF (1.7 mL) was heated at reflux for 21 h. The cooled reaction
mixture was diluted with water and extracted with DCM. The combined organics
were dried and concentrated in vacuo. The residue was purified by FCC, using 0-
% [2M NH in MeOH] in DCM, to give impure product. This residue purified by
HPLC (Gemini C18 column, 30-98% MeCN in H O, 0.1% HCO H) to give the
title compound as a white powder after freeze-drying (37 mg, 39%). LCMS
(Method 5): Rt 4.73 min, m/z 546 [MH ].
e. 1-(5-tert-Butylp-tolyl-2H-pyrazolyl)[(1S,4R)(2-morpholin-
4-yl-ethoxy)-1,2,3,4-tetrahydro-naphthalenyl]-urea (Example 32)
To a solution of Intermediate 32d (50 mg, 62.3 µmol) in THF (1.7 mL) was
added borane (1M in THF, 0.12 mL, 0.12 mmol) and the mixture stirred at 60°C.
After 23 h, further borane (1M in THF, 0.31 mL, 0.31 mmol) was added. After 26
h, further borane (1M in THF, 0.31 mL, 0.31 mmol) was added. After 3 d, the
cooled reaction mixture was diluted with water and extracted with DCM. The
combined organics were dried and concentrated in vacuo. The residue was purified
by HPLC (Gemini C18 column, 20-98% MeCN in H O, 0.1% HCO H) to give the
title compound as a white powder after freeze-drying (15 mg, 47%). LCMS
(Method 5): Rt 3.64 min, m/z 532 [MH ]. ¹H NMR (400 MHz, CDCl ): 1.32 (9H,
s), 1.93-1.96 (3H, m), 2.02-2.07 (1H, m), 2.32 (4H, t, J 4.5), 2.38 (3H, s), 2.47 (1H,
dt, J 13.0, 5.3), 2.61 (1H, ddd, J 13.0, 7.3, 5.4), 3.56-3.58 (5H, m), 3.67-3.68 (1H,
m), 4.35-4.37 (1H, m), 4.98-5.02 (1H, m), 5.50 (1H, d, J 8.8), 6.27 (2H, s), 7.18-
7.28 (5H, m), 7.30-7.32 (1H, m), 7.36 (2H, d, J 8.2).
Example 33
1-[5-tert-Butyl(4-hydroxymethyl-phenyl)-2H-pyrazolyl]
{(1S,4R)[3-((S)methyl-pyrrolidinyl)-[1,2,4]triazolo[4,3-a]pyridin
yloxy]-1,2,3,4-tetrahydro-naphthalenyl}urea
a. [5-tert-Butyl(4-hydroxymethyl-phenyl)-2H-pyrazolyl]-carbamic
acid 2,2,2-trichloro-ethyl ester (Intermediate 33a)
To a suspension of [4-(5-aminotert-butyl-pyrazolyl)-phenyl]-methanol
(WO2011/070368; 3.05 g, 12.4 mmol) in aq. NaOH solution (1 M, 31 mL, 31
mmol) and EtOAc (30 mL) at RT was added 2,2,2-trichloroethyl chloroformate
(1.88 mL, 13.7 mmol) over 3 min (CARE: exotherm to ~35°C) and the mixture
stirred at RT for 1 h. The aqueous layer was extracted with EtOAc (20 mL), then
the combined organics washed with brine (25 mL), dried (Na SO ), filtered and
concentrated in vacuo to leave a pale orange solid. Recrystallisation from hot
cyclohexane-EtOAc (3:1, 30 mL) and drying in vacuo gave the title compound as a
flocculent off-white solid (3.87 g, 74%). LCMS (Method 3): Rt 4.00 min, m/z 420,
422 [MH ].
b. 1-[5-tert-Butyl(4-hydroxymethyl-phenyl)-2H-pyrazolyl]
{(1S,4R)[3-((S)methyl-pyrrolidinyl)-[1,2,4]triazolo[4,3-a]pyridin
yloxy]-1,2,3,4-tetrahydro-naphthalenyl}urea (Example 33)
A mixture of Intermediate 5c (109 mg, 0.300 mmol) and Intermediate 33a
(126 mg, 0.300 mmol) in 1,4-dioxane (3 mL) and DIPEA (78 µL, 0.45 mmol) was
stirred at 80°C for 3 h, and then at 95°C for 2 h. The cooled mixture was
concentrated in vacuo. The residue was purified by FCC, using 0-14% MeOH in
DCM, to give the title compound as an off-white powder after freeze-drying (95
mg, 50%). LCMS (Method 5): Rt 3.26 min, m/z 635.3 [MH ]. ¹H NMR (400 MHz,
d -DMSO): 1.27 (9H, s), 1.81-2.26 (11H, m), 2.31-2.40 (1H, m) 3.10-3.17 (1H,
m), 3.99 (1H, br t, J 8.1), 4.56 (2H, d, J 5.6), 4.78-4.87 (1H, m), 5.29 (1H, t, J 5.7),
.37-5.42 (1H, m), 6.33 (1H, s), 7.11 (1H, d, J 8.7), 7.24-7.47 (9H, m), 7.75 (1H, d,
J 9.7), 8.07 (1H, s), 8.24 (1H, br d).
Example 34
1-[5-tert-Butyl(4-hydroxymethyl-phenyl)-2H-pyrazolyl]
[(1S,4R)(3-piperidinyl-[1,2,4]triazolo[4,3-a]pyridinyloxy)-1,2,3,4-
tetrahydro-naphthalenyl]-urea
A mixture of Intermediate 3c (109 mg, 0.300 mmol) and Intermediate 33a
(126 mg, 0.300 mmol) in 1,4-dioxane (3 mL) and DIPEA (78 µL, 0.45 mmol) was
stirred at 80°C for 3 h, and then at 95°C for 2 h. The cooled mixture was
concentrated in vacuo. The residue was purified by FCC, using 0-14% MeOH in
DCM, to give the title compound as an off-white powder after freeze-drying (95
mg, 50%). LCMS (Method 5): Rt 4.21 min, m/z 635.2 [MH ]. ¹H NMR (400 MHz,
d -DMSO): 1.28 (9H, s), 1.56-2.17 (10H, m), 3.11-3.17 (4H, m), 4.56 (2H, d, J
.7), 4.77-4.86 (1H, m), 5.29 (1H, t, J 5.7), 5.52-5.57 (1H, br t), 6.33 (1H, s), 7.09
(1H, d, J 8.4), 7.16 (1H, dd, J 9.7, 2.2), 7.25-7.47 (8H, m), 7.58-7.64 (2H, m), 8.07
(1H, s).
Example 35
1-{5-tert-Butyl[3-(2-hydroxy-ethylsulfanyl)-phenyl]-2H-pyrazol
yl}{(1S,4R)[3-((S)methyl-pyrrolidinyl)-[1,2,4]triazolo[4,3-
a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea
a. Di-tert-butyl 1-{3-[(2-{[tert-
butyl(dimethyl)silyl]oxy}ethyl)sulfanyl]phenyl}hydrazine-1,2-dicarboxylate
(Intermediate 35a)
S Si
A mixture of 3-bromothiophenol (1.00 g, 5.29 mmol),
bromoethoxydimethylsilyl ether (1.36 mL, 6.35 mmol) and K2CO3 (1.46 g, 10.6
mmol) in acetone (15 mL) was stirred at RT overnight. The mixture was filtered,
evaporated, and the residue re-dissolved in dry THF (15 mL) and cooled to -78°C.
nBuLi (1.6M in hexanes, 4.5 mL, 7.28 mmol) was added dropwise and the mixture
stirred for 10 min. Di-tert-butyl azodicarboxylate (1.54 g, 6.68 mmol) was added
in one portion at -78°C and the mixture stirred for 20 min. The mixture was then
allowed to warm to RT over 2 h. The reaction was quenched with sat. aq. NH4Cl
solution (15 mL), then extracted with EtOAc (3 × 15 mL). The combined organic
extracts were washed with brine (20 mL), dried (Na SO ) and concentrated in
vacuo. The residue was purified by FCC, using 0-20% EtOAc in pentane, to give
the title compound as a pale yellow oil (1.68 g, 64%). ¹H NMR (400 MHz,
CDCl ): 0.04 (6H, s), 0.84 (9H, s), 1.48 (18H, m), 3.04 (2H, t), 3.79 (2H, t), 7.14-
7.28 (3H, m), 7.42 (1H, s).
b. 2-[3-(5-Aminotert-butyl-pyrazolyl)phenylsulfanyl]-ethanol.
(Intermediate 35b)
A mixture of Intermediate 35a (1.68 g, 3.37 mmol), pivaloyl acetonitrile
(0.42 g, 3.37 mmol) and concentrated HCl solution (1.7 mL) in ethanol (10 mL)
was heated under reflux for 3 h. After cooling, the pH was adjusted to ~7 (using
sat. aq. NaHCO solution) and the mixture diluted with water (20 mL) and
extracted with EtOAc (3 × 20 mL). The combined organic extracts were washed
with brine (20mL), dried (Na SO ) and concentrated in vacuo. The residue was
purified by FCC, eluting with 20-80% EtOAc in pentane, to give the title
compound as a pale yellow oil (458 mg, 47%). LCMS (Method 1): Rt 2.35 min,
m/z 292 [MH ].
c. {5-tert-Butyl[3-(2-hydroxy-ethylsulfanyl)-phenyl]-2H-pyrazol
yl}-carbamic acid 2,2,2-trichloro-ethyl ester. (Intermediate 35c)
N Cl
2,2,2-Trichloroethyl chloroformate (0.10 mL, 0.78 mmol) was added to a
solution of Intermediate 35b (176 mg, 0.60 mmol) and DIPEA (0.31 mL, 1.81
mmol) in THF (10 mL) and the mixture stirred at RT for 3 h. The mixture was
diluted with water (15 mL), extracted with EtOAc (3 × 20 mL), then the combined
organic extracts dried (Na SO ) and concentrated in vacuo. The residue was
suspended in cyclohexane, and filtered to give the title compound as a yellow solid
(280 mg, 100%). LCMS (Method 1): Rt 3.93 min, m/z 466, 468 [MH ]
d. 1-{5-tert-Butyl[3-(2-hydroxy-ethylsulfanyl)-phenyl]-2H-pyrazol
yl}{(1S,4R)[3-((S)methyl-pyrrolidinyl)-[1,2,4]triazolo[4,3-
a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea (Example 35)
A mixture of Intermediate 5c (109 mg, 0.3 mmol) and Intermediate 35c
(140 mg, 0.3 mmol) in 1,4-dioxane (3 mL) and DIPEA (78 µL, 0.45 mmol) was
stirred at 90°C for 4 h. The cooled mixture was concentrated in vacuo. The residue
was purified by FCC, using 0-14% MeOH in DCM, to give the title compound as
an off-white powder after freeze-drying (115 mg, 56%). LCMS (Method 5): Rt
3.47 min, m/z 681 [MH ]. ¹H NMR (400 MHz, d -DMSO): 1.28 (9H, s), 1.83-2.26
(11H, m), 2.31-2.39 (1H, m), 3.04 (2H, t, J 6.8), 3.09 (1H, m), 3.59 (2H, q, J 6.0),
3.99 (1H, t, J 8.2), 4.78-4.86 (1H, m), 4.95 (1H, t, J 5.6), 5.36-5.41 (1H, m), 6.33
(1H, s), 7.08 (1H, d, J 8.4), 7.24-7.46 (9H, m), 7.75 (1H, d, J 9.6), 8.12 (1H, s),
8.25 (1H, br d).
Example 36
HO N
1-[5-(2-Hydroxy-1,1-dimethyl-ethyl)p-tolyl-2H-pyrazolyl]
[(1S,4R)(3-piperidinyl-[1,2,4]triazolo[4,3-a]pyridinyloxy)-1,2,3,4-
tetrahydro-naphthalenyl]-urea
The title compound was prepared as an off-white solid (120 mg, 68%) using
Intermediate 3c (100 mg, 0.28 mmol) and [5-(2-hydroxy-1,1-dimethyl-ethyl)p-
tolyl-2H-pyrazolyl]-carbamic acid 2,2,2-trichloro-ethyl ester (WO2009/015000;
138 mg, 0.34 mmol) in a similar manner to Example 34. LCMS (Method 5): Rt
4.02 min, m/z 635 [MH ]. ¹H NMR (400 MHz, d -DMSO): 1.21 (6H, s), 1.58-1.64
(2H, m), 1.69-1.75 (4H, m), 1.81-1.97 (2H, m), 2.00-2.16 (2H, m), 2.36 (3H, s),
3.14 (4H, t, J 5.4), 3.43 (2H, s), 4.55 (1H, br s), 4.79-4.85 (1H, m), 5.54 (1H, t, J
4.3), 6.32 (1H, s), 7.08 (1H, d, J 8.6), 7.16 (1H, dd, J 4.9, 2.3), 7.26-7.39 (8H, m),
7.59-7.63 (2H, m), 8.07 (1H, s).
Example 37
1-[5-tert-Butyl(4-hydroxymethyl-phenyl)-2H-pyrazolyl]
{(1S,3S)[3-((S)methyl-pyrrolidinyl)-[1,2,4]triazolo[4,3-a]pyridin
yloxy]-indanyl}-urea
a. (1S,3S)[3-((S)Methyl-pyrrolidinyl)-[1,2,4]triazolo[4,3-
a]pyridinyloxy]-indanylamine (Intermediate 37a)
(1S,3S)Amino-indanol (110 mg, 0.74 mmol) was added to a
suspension of NaH (60% in mineral oil, 87 mg, 2.17 mmol) in anhydrous DMF (5
mL) at RT and stirred for 20 min. Intermediate 5b (160 mg, 0.72 mmol) was then
added in one portion and the mixture heated at 60°C for 3 h. After cooling the
mixture was diluted with water (20 mL) and extracted with EtOAc (3 × 50 mL).
The combined organics were washed with brine (50 mL), dried (MgSO ) and
evaporated in vacuo. The residue was purified by FCC, using 0-10% MeOH in
DCM, to give the title compound as give a foam (132 mg, 52%). LCMS (Method
1): Rt 0.34 min, m/z 350 [MH ]. ¹H NMR (300 MHz, CDCl ): 1.95-2.16 (6H, m),
2.24 (3H, s), 2.26-2.45 (2H, m), 2.77 (1H, ddd, J 14.1, 7.0, 2.0), 3.23-3.30 (1H, m),
4.02-4.09 (1H, m), 4.71 (1H, t, J 6.8), 5.68 (1H, dd, J 6.2, 1.9), 7.04 (1H, dd, J 9.9,
2.2), 7.29-7.50 (4H, m), 7.64 (1H, dd, J 9.9, 0.9), 8.35 (1H, d, J 2.2).
b. 1-[5-tert-Butyl(4-hydroxymethyl-phenyl)-2H-pyrazolyl]
{(1S,3S)[3-((S)methyl-pyrrolidinyl)-[1,2,4]triazolo[4,3-a]pyridin
yloxy]-indanyl}-urea (Example 37)
A solution of Intermediate 33a (190 mg, 0.454 mmol), Intermediate 37a (132
mg, 0.378 mmol) and DIPEA (132 µL, 0.756 mmol) in anhydrous DMF (3 mL) was
stirred at 100°C for 3 h. After cooling, the mixture was partitioned between EtOAc
(50 mL) and water (50 mL), and then extracted into EtOAc (3 × 50 mL). The
combined organics were washed with brine (50 mL), dried (MgSO ) and evaporated
in vacuo. The residue was purified by FCC, using 0-10% MeOH in DCM, to give
the title compound as give an off-white solid after freeze-drying (143 mg, 61%).
LCMS (Method 5): Rt 3.23, m/z 621 [MH ]. ¹H NMR (400 MHz, d -DMSO): 1.22
(9H, s), 1.95-1.97 (3H, m), 2.07 (3H, s), 2.20-2.23 (3H, m), 2.52-2.53 (1H, m), 3.10
(1H, m), 3.92 (1H, t, J 8.1), 4.51 (2H, d, J 5.6), 5.25-5.27 (2H, m), 5.83 (1H, d, J
.8), 6.25 (1H, s), 6.99 (1H, d, J 7.9), 7.18 (1H, dd, J 9.9, 2.2), 7.24-7.32 (2H, m),
7.35-7.41 (6H, m), 7.67 (1H, d, J 9.9), 8.10 (1H, s), 8.20 (1H, s).
Example 38
1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-((R)
hydroxy-pyrrolidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-urea
a. (R)(6-Fluoro-[1,2,4]triazolo[4,3-a]pyridinyl)-pyrrolidinol
(Intermediate 38a)
A mixture of Intermediate 24b (300 mg, 1.74 mmol) and (R)
hydroxypyrrolidine (607 mg, 9.96 mmol) in NMP (4 mL) was heated in the
microwave at 160°C for 2 h. The reaction mixture was applied to an SCX-2
cartridge (70 g) and washed with MeOH. The product was eluted with 2M NH in
MeOH; concentration in vacuo gave a residue. FCC, using 0-10% [2M NH in
MeOH] in DCM, gave the title compound (170 mg, 44%). LCMS (Method 1): Rt
0.39 min, m/z 223 [MH ].
b. 6-Fluoro((R)triisopropylsilanyloxy-pyrrolidinyl)-
[1,2,4]triazolo[4,3-a]pyridine (Intermediate 38b)
Triisopropylsilyl trifluoromethanesulfonate (280 mg, 0.919 mmol) was
added to a solution of Intermediate 38a (170 mg, 0.766 mmol) and Et3N (116 mg,
1.14 mmol) in a DMF (3 mL) and the mixture stirred at RT for 1 h. The reaction
mixture was applied to an SCX-2 cartridge (10 g) and washed with MeOH. The
product was eluted with 2M NH3 in MeOH; concentration in vacuo gave a residue.
FCC, using 0-10% [2M NH in MeOH] in DCM, gave the title compound (260 mg,
90%). LCMS (Method 3): Rt 4.26 min, m/z 379 [MH ].
c. (1S,4R)[3-((R)Triisopropylsilanyloxy-pyrrolidinyl)-
[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalen
ylamine (Intermediate 38c)
To a solution of Intermediate A (123 mg, 0.755 mmol) in DMF (4 mL) was
added NaH (60% in oil, 82 mg, 2.06 mmol) and the mixture stirred at RT for 20
min, before Intermediate 38b (260 mg, 0.687 mmol) was added. This mixture was
heated at 60°C in the microwave for 3 h. The reaction mixture was applied to an
SCX-2 cartridge (25 g) and washed with MeOH. The product was eluted with 2M
NH in MeOH; concentration in vacuo gave a residue. FCC, using 0-7% [2M NH
in MeOH] in DCM, gave the title compound as a viscous yellow oil (100 mg,
23%). LCMS (Method 1): Rt 2.90 min, m/z 522 [MH ].
d. 1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-((R)
triisopropylsilanyloxy-pyrrolidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-
1,2,3,4-tetrahydro-naphthalenyl}-urea (Intermediate 38d)
A solution of Intermediate 38c (100 mg, 0.191 mmol), (5-tert-butylp-
tolyl-2H-pyrazolyl)-carbamic acid 2,2,2-trichloro-ethyl ester (Synthetic
Communications, 2009, 39, 3999-4009; 115 mg, 0.286 mmol) and DIPEA (100
mg, 0.764 mmol) in DMF (2 mL) was stirred at 60°C for 1 h. The reaction mixture
was applied to an SCX-2 cartridge (10 g) and washed with MeOH. The product
was eluted with 2M NH in MeOH; concentration in vacuo gave a residue. FCC,
using 0-10% [2M NH in MeOH] in DCM, gave the title compound as a viscous
yellow oil (80 mg, 53%). LCMS (Method 4): Rt 4.55 min, m/z 777 [MH ].
e. 1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-((R)
hydroxy-pyrrolidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-urea (Example 38)
To a solution of Intermediate 38d (80 mg, 0.10 mmol) in THF (1 mL) at -
°C was added TBAF (1M in THF, 150 µL, 0.150 mmol) and the mixture was
allowed to warm to RT over 1 h. The reaction mixture was applied to an SCX-2
cartridge (5 g) and washed with MeOH. The product was eluted with 2M NH in
MeOH; concentration in vacuo gave a residue. Purification by HPLC (C6-Ph
column, 35-75% MeCN in H O, 0.1% HCO H) gave the title compound as a white
powder after freeze-drying (22 mg, 35%). LCMS (Method 5): Rt 4.01 min, m/z
621 [MH ]. ¹H NMR (400 MHz, d -MeOH): 1.29 (9H, s), 1.86-2.13 (4H, m), 2.14-
2.28 (2H, m), 2.38 (3H, s), 3.40-3.45 (1H, m), 3.49-3.56 (1H, m), 3.66-3.71 (1H,
m), 3.74-3.81 (1H, m), 4.50-4.55 (1H, m), 4.85-4.91 (1H, m), 5.37 (1H, t J 4.2),
6.33 (1H, s), 7.10 (1H, dd, J 9.8, 2.2), 7.19-7.36 (8H, m), 7.43 (1H, d, J 9.8), 7.76
(1H, d, J 1.6).
Example 39
1-{5-tert-Butyl[3-(2-hydroxy-ethoxy)-phenyl]-2H-pyrazolyl}
[(1S,4R)(3-piperidinyl-[1,2,4]triazolo[4,3-a]pyridinyloxy)-1,2,3,4-
tetrahydro-naphthalenyl]-urea
a. 5-tert-Butyl{3-[2-(tetrahydro-pyranyloxy)-ethoxy]-phenyl}-2H-
pyrazolylamine (Intermediate 39a)
DIAD (847 µL, 4.32 mmol) was added slowly to a solution of 3-(5-amino-
3-tert-butyl-1H-pyrazolyl)phenol (US2006/35922; 500 mg, 2.16 mmol), 2-
(tetrahydro-pyranyloxy)-ethanol (439 µL, 3.25 mmol) and Ph P (1.13 g, 4.32
mmol) in THF (10.0 mL) and the mixture stirred for 72 h. The reaction mixture
was partitioned between EtOAc (75 mL) and H O (75 mL) and the aqueous layer
extracted with EtOAc (3 ×). The combined organic layers were dried (MgSO ),
filtered and evaporated in vacuo. Purification by FCC, using 5-60% EtOAc in
cyclohexane, gave the title compound (1.26 g). LCMS (Method 4): Rt 2.77, m/z
360 [MH ].
b. (5-tert-Butyl{3-[2-(tetrahydro-pyranyloxy)-ethoxy]-phenyl}-
2H-pyrazolyl)-carbamic acid 2,2,2-trichloro-ethyl ester (Intermediate 39b)
O Cl
N Cl
The title compound was prepared starting from 2,2,2-
trichloroethylchloroformate and Intermediate 39a by using an analogous procedure
to that described for Intermediate 35c. LCMS (Method 4): Rt 3.85, m/z 536
[MH ].
c. 1-(5-tert-Butyl{3-[2-(tetrahydro-pyranyloxy)-ethoxy]-phenyl}-
2H-pyrazolyl)[(1S,4R)(3-piperidinyl-[1,2,4]triazolo[4,3-a]pyridin
yloxy)-1,2,3,4-tetrahydro-naphthalenyl]-urea (Intermediate 39c)
N N N
A solution of Intermediate 39b (287 mg, 0.53 mmol), Intermediate 3c (177
mg, 0.49 mmol) and DIPEA (256 µL, 1.46 mmol) in THF (5 ml) was stirred at
60°C for 16.5 h. Water was added and the mixture extracted with DCM (3 × 20
mL). The combined organics were dried and concentrated in vacuo. The residue
was purified by FCC, using 0-5% [2M NH in MeOH] in DCM, to give the title
compound as an off-white powder (361 mg, 99%). LCMS (Method 3): Rt 4.05
min, m/z 749 [MH ].
d. 1-{5-tert-Butyl[3-(2-hydroxy-ethoxy)-phenyl]-2H-pyrazolyl}
[(1S,4R)(3-piperidinyl-[1,2,4]triazolo[4,3-a]pyridinyloxy)-1,2,3,4-
tetrahydro-naphthalenyl]-urea (Example 39)
Pyridinium p-toluenesulfonate (362 mg, 1.44 mmol) was added to a solution
of Intermediate 39c (360 mg, 0.48 mmol) in MeOH (5 mL). The solution was
stirred at 40°C for 19 h, then diluted with water and extracted with DCM (3 × 20
mL). The combined organics were dried and concentrated in vacuo. The residue
was purified by FCC, using 0-7.5% [2M NH in MeOH] in DCM, to give the title
compound as a white powder after freeze-drying (218 mg, 68%). LCMS (Method
): Rt 4.22 min, m/z 665 [MH ]. ¹H NMR (400 MHz, d -DMSO): 1.28 (9H, s),
1.60-1.63 (2H, m), 1.70-1.75 (4H, m), 1.86-1.92 (2H, m), 2.01-2.06 (1H, m), 2.10-
2.16 (1H, m), 3.14 (4H, t, J 5.2), 3.71 (2H, q, J 5.1), 4.03 (2H, t, J 5.0), 4.79-4.82
(1H, m), 4.87 (1H, t, J 5.5), 5.54 (1H, t, J 4.3), 6.33 (1H, s), 6.96 (1H, m), 7.11-
7.22 (4H, m), 7.34-7.46 (5H, m), 7.61-7.64 (2H, m), 8.11 (1H, s).
Example 40
1-{5-tert-Butyl[3-(2-dimethylamino-ethoxy)-phenyl]-2H-pyrazol
yl}[(1S,4R)(3-piperidinyl-[1,2,4]triazolo[4,3-a]pyridinyloxy)-
1,2,3,4-tetrahydro-naphthalenyl]-urea partial formate salt
(0.7 eq)
a. Methanesulfonic acid 2-[3-(3-tert-butyl{3-[(1S,4R)(3-piperidin-
1-yl-[1,2,4]triazolo[4,3-a]pyridinyloxy)-1,2,3,4-tetrahydro-naphthalen
yl]-ureido}-pyrazolyl)-phenoxy]-ethyl ester (Intermediate 40a)
N N N
Methane sulfonyl chloride (46.0 mL, 0.59 mmol) was added to an ice cold
solution of Example 39 (187 mg, 0.28 mmol) and DIPEA (122 mL, 0.70 mmol) in
DCM (3.0 mL). After 2.5 h the reaction was partitioned between DCM and water.
The aqueous layer was then extracted with DCM (3 ×). The combined organic
layers were washed with brine, dried (MgSO ), filtered and evaporated in vacuo to
give the title compound (208 mg, 99%). LCMS (Method 2): Rt 3.38 min, m/z 743
[MH ].
b. 1-{5-tert-Butyl[3-(2-dimethylamino-ethoxy)-phenyl]-2H-pyrazol-
3-yl}[(1S,4R)(3-piperidinyl-[1,2,4]triazolo[4,3-a]pyridinyloxy)-
1,2,3,4-tetrahydro-naphthalenyl]-urea, partial formate salt (Example 40)
Dimethylamine (2M in MeOH, 1.12 mL, 2.24 mmol) was added to a
solution of Intermediate 40a (208 mg, 0.28 mmol) in THF (3.0 mL). The reaction
was heated to 50°C in a sealed environment overnight. Further dimethylamine (2M
in MeOH, 250 mL, 0.50 mmol) was added and heating continued for 8 h then the
mixture was cooled and partitioned between EtOAc and water. The aqueous layer
was then extracted with EtOAc (3 ×). The combined organic layers were washed
with brine, dried (MgSO ), filtered and evaporated in vacuo. The residue was
purified by FCC, using 0-10% [2M NH in MeOH] in DCM. Further purification
by HPLC (C18 X-select column, 20-98% MeCN in H O, 0.1% HCO H) gave the
title compound as a white powder after freeze-drying (110 mg, 57%). LCMS
(Method 5): Rt 3.47 min, m/z 692.5 [MH ]. ¹H NMR (400 MHz, d -MeOD): 1.30
(9H, s), 1.63-1.69 (2H, m), 1.73-1.80 (4H, m), 1.88-2.04 (2H, m), 2.04-2.14 (1H,
m), 2.22-2.32 (1H, m), 2.60 (6H, s), 3.08-3.14 (4H, m), 3.17 (2H, t, J 5.4), 4.23
(2H, t, J 5.4), 4.89 (1H, dd, J 8.7, 5.8), 5.41 (1H, t, J 8.2), 6.34 (1H, s), 7.03-7.07
(1H, ddd, J 8.5, 2.4, 0.6), 7.09-7.13 (2H, m), 7.18-7.25 (3H, m), 7.26-7.31 (2H, m),
7.39-7.44 (1H, t, J 7.8), 7.50-7.54 (2H, m), 8.45 (0.7H, br s).
Example 41
1-{5-tert-Butyl[3-(4-methyl-piperazinylmethyl)-phenyl]-2H-
pyrazolyl}[(1S,4R)(3-piperidinyl-[1,2,4]triazolo[4,3-a]pyridin
yloxy)-1,2,3,4-tetrahydro-naphthalenyl]-urea
To a solution of Example 29 (100 mg, 0.15 mmol) and Et N (65 µL, 0.47
mmol) in THF (7 mL) at 0°C was added mesyl chloride (19 µL, 0.19 mmol), and
the mixture stirred for 30 min. To the solution was added 1-methyl piperazine (52
µL, 0.47 mmol) and the solution heated at reflux for 35 min. Water was added and
the mixture extracted with DCM. The combined organics were dried and
concentrated in vacuo. The residue was purified by HPLC (Gemini C18 column,
-98% MeCN in H O, 0.1% HCO H) to give the title compound as a white
powder after freeze-drying (32 mg, 28%). LCMS (Method 5): Rt 3.52 min, m/z
717 [MH ]. ¹H NMR (400 MHz, CDCl ): 1.34 (9H, s), 1.66 (2H, q, J 5.4), 1.72-
1.76 (4H, m), 1.90-1.99 (1H, m), 2.04-2.13 (3H, m), 2.23 (3H, s), 2.39-2.55 (10H,
m), 3.16 (4H, t, J 5.2), 3.60 (1H, d, J 13.4), 3.62 (1H, d, J 13.4), 5.13 (1H, td, J 8.7,
.3), 5.21 (1H, t, J 4.4), 6.00 (1H, br s), 6.37 (1H, s), 6.91 (1H, br s), 6.97-6.98
(1H, m), 7.23 (1H, d, J 7.5), 7.29-7.54 (9H, m).
Example 42
1-{5-tert-Butyl[3-(2-hydroxy-ethoxy)-phenyl]-2H-pyrazolyl}
{(1S,4R)[3-((S)methyl-pyrrolidinyl)-[1,2,4]triazolo[4,3-a]pyridin
yloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea
O OH
a. 1-(5-tert-Butyl{3-[2-(tetrahydro-pyranyloxy)-ethoxy]-phenyl}-
2H-pyrazolyl){(1S,4R)[3-((S)methyl-pyrrolidinyl)-
[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-
urea (Intermediate 42a)
A mixture of Intermediate 5c (150 mg, 0.410 mmol) and Intermediate 39b
(230 mg, 0.430 mmol) in 1,4-dioxane (4 mL) and DIPEA (113 µL, 0.65 mmol)
was stirred at 90°C for 4.5 h. The mixture was concentrated in vacuo. The residue
was purified by FCC twice, using 0-10% MeOH in DCM, to give the title
compound as a pale yellow foam (234 mg, 76%). LCMS (Method 3): Rt 3.03 min,
m/z 749.2 [MH ].
b. 1-{5-tert-Butyl[3-(2-hydroxy-ethoxy)-phenyl]-2H-pyrazolyl}
{(1S,4R)[3-((S)methyl-pyrrolidinyl)-[1,2,4]triazolo[4,3-a]pyridin
yloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea (Example 42)
A mixture of Intermediate 42a (230 mg, 0.300 mmol) and pyridinium p-
toluenesulfonate (226 mg, 0.900 mmol) in MeOH (3 mL) was stirred at RT for 15
h. Pyridinium p-toluenesulfonate (113 mg, 0.450 mmol) was added and the
mixture stirred at 50-55°C for 8 h. The cooled mixture was diluted with sat. aq.
NaHCO solution and extracted with DCM (3 × 15 mL). The combined organics
were dried and concentrated in vacuo. The residue was purified by FCC, using 0-
14% MeOH in DCM, to give the title compound as a white powder after freeze-
drying (163 mg, 82%). LCMS (Method 5): Rt 3.33 min, m/z 665.3 [MH ]. ¹H
NMR (400 MHz, d -DMSO): 1.28 (9H, s), 1.82-2.27 (11H, m), 2.31-2.39 (1H, m),
3.10-3.17 (1H, m), 3.71 (2H, q, J 5.1), 3.96-4.05 (3H, m), 4.79-4.89 (2H, m), 5.37-
5.41 (1H, m), 6.34 (1H, s), 6.95-6.99 (1H, m), 7.05-7.15 (3H, m), 7.24-7.43 (6H,
m), 7.75 (1H, d, J 9.9), 8.11 (1H, s), 8.25 (1H, br d).
Example 43
1-(5-tert-Butylp-tolyl-2H-pyrazolyl)((1S,4R){3-[(2-
dimethylamino-ethyl)-methyl-amino]-[1,2,4]triazolo[4,3-a]pyridinyloxy}-
1,2,3,4-tetrahydro-naphthalenyl)-urea
a. N-(6-Fluoro-[1,2,4]triazolo[4,3-a]pyridinyl)-N,N',N'-trimethyl-
ethane-1,2-diamine (Intermediate 43a)
A mixture of Intermediate 24b (300 mg, 1.74 mmol) and N,N,N-
trimethylethane-1,2-diamine (900 mg, 8.77 mmol) in NMP (2 mL) was heated in
the microwave at 170°C for 2 h. The reaction mixture was applied to an SCX-2
cartridge (25 g) and washed with MeOH. The product was eluted with 2M NH in
MeOH; concentration in vacuo gave a residue. FCC, using 0-10% [2M NH in
MeOH] in DCM, gave the title compound as a brown oil (190 mg, 46%). LCMS
(Method 4): Rt 0.38 min, m/z 238 [MH ].
b. N-[6-((1R,4S)Amino-1,2,3,4-tetrahydro-naphthalenyloxy)-
[1,2,4]triazolo[4,3-a]pyridinyl]-N,N',N'-trimethyl-ethane-1,2-diamine
(Intermediate 43b)
To a solution of Intermediate A (143 mg, 0.88 mmol) in DMF (3 mL) was
added NaH (60% in oil, 96 mg, 2.4 mmol) and the mixture stirred at RT for 20
min, before Intermediate 43a (190 mg, 0.80 mmol) was added. This mixture was
heated at 60°C in the microwave for 1 h. The reaction mixture was applied to an
SCX-2 cartridge and washed with MeOH. The product was eluted with 2M NH in
MeOH; concentration in vacuo gave a residue. FCC, using 0-20% [2M NH in
MeOH] in DCM, gave the title compound as a pale brown oil (140 mg, 46%).
LCMS (Method 1): Rt 1.34 min, m/z 381 [MH ].
c. 1-(5-tert-Butylp-tolyl-2H-pyrazolyl)((1S,4R){3-[(2-
dimethylamino-ethyl)-methyl-amino]-[1,2,4]triazolo[4,3-a]pyridinyloxy}-
1,2,3,4-tetrahydro-naphthalenyl)-urea (Example 43)
A solution of Intermediate 43b (140 mg, 0.36 mmol), (5-tert-butylp-
tolyl-2H-pyrazolyl)-carbamic acid 2,2,2-trichloro-ethyl ester (Synthetic
Communications, 2009, 39, 3999-4009; 218 mg, 0.54 mmol) and DIPEA (186 mg,
1.44 mmol) in DMF (6 mL) was stirred at 60°C for 1 h. The reaction mixture was
applied to an SCX-2 cartridge (25 g) and washed with MeOH. The product was
eluted with 2M NH in MeOH; concentration in vacuo gave a residue. FCC, using
0-10% [2M NH in MeOH] in DCM, gave a viscous yellow gum. HPLC (C6-Ph
column, 10-40% MeCN in H O, 0.1% HCO H) gave the title compound as an off-
white powder after freeze-drying (80 mg, 35%). LCMS (Method 5): Rt 3.67 min,
m/z 636.3 [MH ]. ¹H NMR (400 MHz, d -MeOH): 1.30 (9H, s), 1.86-2.15 (3H,
m), 2.19-2.30 (1H, m), 2.38 (3H, s), 2.57 (6H, s), 2.92 (3H, s), 3.00 (2H, t J 6.2),
3.46-3.60 (2H, m), 4.89 (1H, m), 5.42 (1H, t, J 3.9), 6.33 (1H, s), 7.16-7.36 (9H,
m), 7.52 (1H, d, J 10.1), 7.90 (1H, s).
Example 44
1-[5-tert-Butyl(3-piperidinylmethyl-phenyl)-2H-pyrazolyl]
[(1S,4R)(3-piperidinyl-[1,2,4]triazolo[4,3-a]pyridinyloxy)-1,2,3,4-
tetrahydro-naphthalenyl]-urea
To a solution of Example 29 (100 mg, 0.15 mmol) and Et N (65 µL, 0.47
mmol) in THF (7 mL) at 0°C was added mesyl chloride (19 µL, 0.19 mmol), and
the mixture stirred for 0.5 h. To the solution was added piperidine (47 µL, 0.47
mmol), and the mixture heated at reflux for 16 h. NaI (24 mg, 0.15 mmol) was
added and the solution heated at reflux for 1 h. The cooled reaction mixture was
diluted with water and extracted with DCM. The combined organics were dried
and concentrated in vacuo. The residue was purified by HPLC (XBridge C18
column, 20-98% MeCN in H O, 0.1% HCO H) to give the impure product. The
residue was re-purified by HPLC (Gemini C18 column, 20-98% MeCN in H O,
0.1% HCO H), the product containing fractions were partitioned between DCM
and saturated NaHCO solution. The combined organics were dried and
concentrated in vacuo to give the title compound as a white powder (14 mg, 12%).
LCMS (Method 5): Rt 3.60 min, m/z 702 [MH ]. ¹H NMR (400 MHz, d -MeOH):
1.34 (9H, s), 1.39-1.44 (2H, m), 1.52-1.55 (4H, m), 1.67-1.71 (2H, m), 1.77-1.80
(4H, m), 2.03-2.08 (3H, m), 2.24-2.33 (1H, m), 3.20 (4H, t, J 5.3), 3.55 (2H, s),
4.93 (1H, dd, J 8.6, 5.6), 5.44 (1H, t, J 4.2), 6.38 (1H, s), 7.21-7.33 (5H, m), 7.40-
7.56 (6H, m).
Example 45
1-(5-tert-Butylp-tolyl-2H-pyrazolyl)((1S,4R){3-[methyl-(2-
morpholinyl-ethyl)-amino]-[1,2,4]triazolo[4,3-a]pyridinyloxy}-1,2,3,4-
tetrahydro-naphthalenyl)-urea
a. (2-Morpholinyl-ethyl)-carbamic acid tert-butyl ester
(Intermediate 45a)
4-(2-Aminoethyl)morpholine (5.00 g, 38.5 mmol) was added to a stirred
mixture of di-tert-butyl dicarbonate (8.38 g, 38.5 mmol) and indium(III)chloride
(85 mg, 0.39 mmol). This mixture was stirred for 1 min before being diluted with
EtOAc (200 mL) and washed with water (× 2). The organic layer was dried
(MgSO ) and was evaporated in vacuo to give the title compound as a clear oil
(8.14 g, 92%). ¹H NMR (400 MHz, CDCl ): 1.45 (9H, s), 2.40-2.50 (6H, m), 3.23
(2H, q, J 5.9), 3.70 (4H, t, J 4.7), 4.96 (1H, br s).
b. Methyl-(2-morpholinyl-ethyl)-amine (Intermediate 45b)
To a solution of Intermediate 45a (6.0 g, 24.6 mmol) in THF (123 mL) was
added lithium aluminium hydride (2.33 g, 61.5 mmol) portionwise, then the
mixture was stirred at reflux for 4 h. A further portion of lithium aluminium
hydride (1.28 g, 33.6 mmol) was added to the cooled solution, then the mixture
was stirred at reflux for a further 8 h. Water (3.75 mL) was added dropwise,
followed by 4N aqueous NaOH (11.3 mL) and water (3.75 ml). The mixture was
filtered, washed with diethyl ether, dried (MgSO ) and concentrated in vacuo to
give the title compound as a yellow oil (3.67 g, 99%). ¹H NMR (400 MHz,
CDCl ): 2.40-2.52 (9H, m), 2.67 (2H, t, J 2.7), 3.70 (4H, t, J 4.5).
c. (6-Fluoro-[1,2,4]triazolo[4,3-a]pyridinyl)-methyl-(2-morpholin
yl-ethyl)-amine (Intermediate 45c)
A mixture of Intermediate 24b (300 mg, 1.74 mmol) and Intermediate 45b
(1.26 g, 8.77 mmol) in NMP (2 mL) was heated in the microwave at 170°C for 2 h.
The reaction mixture was applied to an SCX-2 cartridge (25 g) and washed with
MeOH. The product was eluted with 2M NH in MeOH; concentration in vacuo
gave a residue. FCC, using 0-10% [2M NH in MeOH] in DCM, gave the title
compound as an orange oil (350 mg, 71%). ¹H NMR (400 MHz, CDCl ): 2.41-2.52
(4H, m), 2.58 (2H, t, J 5.6), 3.03 (3H, s), 3.27 (2H, t, J 6.0), 3.62 (4H, t, J 5.2),
7.04-7.08 (1H,m), 7.58-7.65 (1H, m), 8.39 (1H, t, J 2.4).
d. [6-((1R,4S)Amino-1,2,3,4-tetrahydro-naphthalenyloxy)-
[1,2,4]triazolo[4,3-a]pyridinyl]-methyl-(2-morpholinyl-ethyl)-amine
(Intermediate 45d)
To a solution of Intermediate A (225 mg, 1.38 mmol) in DMF (3 mL) was
added NaH (60% in oil, 150 mg, 3.75 mmol) and the mixture stirred at RT for 20
min, before Intermediate 45c (350 mg, 1.25 mmol) was added. This mixture was
stirred at 60°C for 7 h. The reaction mixture was applied to an SCX-2 cartridge (25
g) and washed with MeOH. The product was eluted with 2M NH in MeOH;
concentration in vacuo gave a residue. FCC, using 0-20% [2M NH in MeOH] in
DCM, gave the title compound as an orange oil (270 mg, 51%). LCMS (Method
4): Rt 0.22 min, m/z 423 [MH ].
e. 1-(5-tert-Butylp-tolyl-2H-pyrazolyl)((1S,4R){3-[methyl-(2-
morpholinyl-ethyl)-amino]-[1,2,4]triazolo[4,3-a]pyridinyloxy}-1,2,3,4-
tetrahydro-naphthalenyl)-urea (Example 45)
A solution of Intermediate 45d (270 mg, 0.63 mmol), (5-tert-butylp-
tolyl-2H-pyrazolyl)-carbamic acid 2,2,2-trichloro-ethyl ester (Synthetic
Communications, 2009, 39, 3999-4009; 380 mg, 0.95 mmol) and DIPEA (325 mg,
2.52 mmol) in DMF (8 mL) was stirred at 60°C for 1 h. The reaction mixture was
applied to an SCX-2 cartridge (25 g) and washed with MeOH. The product was
eluted with 2M NH in MeOH; concentration in vacuo gave a residue. FCC, using
0-10% [2M NH in MeOH] in DCM, gave a stiff yellow gum which was further
purified by HPLC (C18 column, 10-45% MeCN in H O, 0.1% HCO H). The
residue was recrystallized from boiling EtOAc to give the title compound as a
white powder (60.0 mg, 14%). LCMS (Method 5): Rt 3.65 min, m/z 678.3 [MH ].
¹H NMR (400 MHz, d -MeOH): 1.30 (9H, s), 1.87-2.15 (3H, m), 2.18-2.27 (1H,
m), 2.32 (4H, t, J 4.4), 2.38 (3H, s), 2.55 (2H, t, J 5.6), 2.96 (3H, s), 3.31-3.40 (6H,
m), 4.89 (1H, m), 5.40 (1H, t, J 4.2), 6.33 (1H, s), 7.19-7.36 (9H, m), 7.53 (1H, d, J
.0), 7.92 (1H, d, J 1.6).
Example 46
1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-((R)
morpholinyl-ethyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-urea and 1-(5-tert-Butylp-tolyl-2H-pyrazol
yl){(1S,4R)[3-((S)morpholinyl-ethyl)-[1,2,4]triazolo[4,3-a]pyridin-
6-yloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea (1:1 mixture of
diastereomers)
O N O N
N N N N
H H H H
a. 2-Morpholinyl-propionic acid N'-(5-fluoro-pyridinyl)-hydrazide
(Intermediate 46a)
N N N
To a solution of (5-fluoro-pyridinyl)-hydrazine (1.62 g, 12.8 mmol), 2-
(morpholinyl)propanoic acid (Enamine, 2.50 g, 12.8 mmol), HOBt.H O (196
mg, 1.28 mmol) and Et N (2.14 mL, 15.3 mmol) in DCM (50 mL) was added EDC
(2.94 g, 15.3 mmol) and the brown solution stirred at RT for 16 h. Water (20 mL)
and brine (20 mL) were added, and the mixture shaken. The aqueous layer was
extracted with DCM (20 mL), then the combined organics were passed through a
hydrophobic frit and concentrated in vacuo to give the title compound as a brown
foam (3.43 g, >99%). LCMS (Method 3): Rt 0.44 min, m/z 269 [MH ].
b. 6-Fluoro(1-morpholinyl-ethyl)-[1,2,4]triazolo[4,3-a]pyridine
(Intermediate 46b)
To a solution of Intermediate 46a (3.43 g, 12.8 mmol), Ph P (6.71 g, 25.6
mmol) and Et N (7.14 mL, 51.2 mmol) in THF (75 mL) at 0°C was added
hexachloroethane (6.06 g, 25.6 mmol) and the solution stirred at RT for 4 h. The
brown suspension was filtered and the solid washed with THF (10 mL). The
combined organics were applied to an SCX-2 cartridge, which was washed with
DCM-MeOH (1:1, 100 mL) and MeOH (100 mL). The product was eluted with
2M NH in MeOH; concentration in vacuo gave an off-white solid. FCC, using 1-
% [2M NH in MeOH] in DCM, gave the title compound as an off-white solid
(1.70 g, 53%). ¹H NMR (300 MHz, CDCl ): 1.66 (3H, d, J 6.8), 2.45-2.60 (4H, m),
3.63-3.76 (4H, m), 4.28 (1H, q, J 6.8), 7.21 (1H, ddd, J 10.0, 7.5, 2.3), 7.76 (1H,
ddd, J 10.0, 4.9, 0.9), 8.50 (1H, ddd, J 3.9, 2.3, 0.9).
c. (1S,4R)[3-((R)Morpholinyl-ethyl)-[1,2,4]triazolo[4,3-
a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenylamine and (1S,4R)[3-
((S)Morpholinyl-ethyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenylam (1:1 mixture diastereomers, Intermediate 46c)
H N H N
A suspension of Intermediate A (343 mg, 2.10 mmol) and NaH (60%
dispersion in oil, 240 mg, 6.00 mmol) in dry DMF (10 mL) at RT under Ar was
stirred for 30 min (CARE: gas evolution), then Intermediate 46b (501 mg, 2.00
mmol) was added and the brown mixture stirred at 60°C under Ar for 1 h. The
solution was concentrated in vacuo, redissolved in MeOH (4 mL) and AcOH (0.60
mL, 10.0 mmol), then applied to an SCX-2 cartridge (20 g) and washed with
MeOH (100 mL). The product was eluted with 2M NH in MeOH (50 mL);
concentration in vacuo gave a dark brown foam. FCC, using 2-8% [2M NH in
MeOH] in DCM, gave the title compounds as a light brown foam (558 mg, 71%).
LCMS (Method 3): Rt 0.44 min, m/z 394 [MH ].
d. 1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-((R)
morpholinyl-ethyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-urea and 1-(5-tert-Butylp-tolyl-2H-pyrazol
yl){(1S,4R)[3-((S)morpholinyl-ethyl)-[1,2,4]triazolo[4,3-a]pyridin-
6-yloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea (1:1 mixture of
diastereomers). (Example 46)
A yellow solution of (5-tert-butylp-tolyl-2H-pyrazolyl)-carbamic acid
2,2,2-trichloro-ethyl ester (Synthetic Communications, 2009, 39, 3999-4009; 223
mg, 0.550 mmol), Intermediate 46c (197 mg, 0.500 mmol) and DIPEA (0.109 mL,
0.625 mmol) in dioxane (10 mL) was stirred at 60°C for 18 h. The cooled solution
was concentrated in vacuo, suspended in water (10 ml) and extracted with DCM (2
× 10 mL). The combined organics were passed through a hydrophobic frit and
concentrated in vacuo to leave a yellow-brown gum. FCC, using 2-7% [2M NH in
MeOH] in DCM, gave the title compounds as a pale yellow solid (192 mg, 59%).
LCMS (Method 5): two peaks in 1:1 ratio, Rt 4.13 and 4.15 min, m/z 649 [MH ].
¹H NMR (400 MHz, d -DMSO): 1.27 (9 H, s), 1.52 (1.5 H, d, J 6.8), 1.53 (1.5 H,
d, J 6.8), 1.83-1.99 (2 H, m), 2.10-2.17 (2 H, m), 2.36 (3 H, s), 2.43 (2 H, t, J 4.5),
2.51-2.55 (2 H, m), 3.47-3.55 (4 H, m), 4.46 (0.5 H, q, J 6.8), 4.49 (0.5 H, q, J 6.8),
4.83 (1 H, m), 5.45 (0.5 H, t, J 4.5), 5.52 (0.5 H, t, J 4.5), 6.33 (1 H, s), 7.10 (1 H,
d, J 8.5), 7.21-7.44 (9 H, m), 7.73 (1 H, dd, J 9.9, 2.6), 8.03 (1 H, s), 8.32 (0.5 H, d,
J 2.1), 8.37 (0.5 H, d, J 2.1).
Example 47
1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-((S)-1,2-
dimethyl-pyrrolidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-urea
a. (S)-1,2-Dimethyl-pyrrolidinecarboxylic acid N'-(5-fluoro-pyridin-
2-yl)-hydrazide (Intermediate 47a)
To a suspension of (S)-1,2-dimethyl-pyrrolidinecarboxylic acid (660 mg,
4.61 mmol), (5-fluoro-pyridinyl)-hydrazine (488 mg, 3.84 mmol) and Et N (1.1
mL, 7.7 mmol) in DCM (20 mL) were added HOBt.H O (51 mg, 0.38 mmol) and
EDCI.HCl (884 mg, 4.61 mmol) and the mixture stirred at RT overnight. The
mixture was partitioned between EtOAc/water and extracted with EtOAc. The
combined organics were dried (Na SO ), filtered and concentrated in vacuo. FCC,
using 0-10% MeOH in DCM, gave the title compound as a brown solid (668 mg,
69%). LCMS (Method 4): Rt 0.40, m/z 253 [MH ].
b. 3-((S)-1,2-Dimethyl-pyrrolidinyl)fluoro-[1,2,4]triazolo[4,3-
a]pyridine (Intermediate 47b)
To a solution of Intermediate 47a (668 mg, 2.64 mmol), Et N (1.5 mL, 11
mmol) and Ph P (1.4 g, 5.3 mmol) in THF (20 mL) at 0°C was added
hexachloroethane (1.25 g, 5.29 mmol). The mixture was stirred at 0°C for 10 min,
then at RT for 1 h. The mixture was partitioned between EtOAc/water and the
aqueous extracted with EtOAc. The combined organics were dried (Na SO ),
filtered and concentrated in vacuo. Purification by FCC, using 0-10% MeOH in
EtOAc, gave the title compound as a pale brown solid (300 mg, 49%). LCMS
(Method 4): Rt 0.39, m/z 235 [MH ].
c. (1S,4R)[3-((S)-1,2-Dimethyl-pyrrolidinyl)-[1,2,4]triazolo[4,3-
a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenylamine (Intermediate
47c)
To a solution of Intermediate 47b (150 mg, 0.64 mmol) and Intermediate A
(126 mg, 0.64 mmol) in DMF (3 mL) was added NaH (60% in mineral oil, 90 mg,
2.24 mmol) portionwise. The mixture was stirred at 60°C for 1.5 h then allowed to
cool to RT. The mixture was carefully quenched by pouring into MeOH (10 mL),
then applied to an SCX-2 cartridge and washed with MeOH. The product was
eluted with 2M NH in MeOH; concentration in vacuo gave a residue. FCC, using
0-10% [2M NH in MeOH] in DCM, gave the title compound as a brown solid
(180 mg, 75%). LCMS (Method 4): Rt 0.49, m/z 378 [MH ].
d. 1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-((S)-1,2-
dimethyl-pyrrolidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-urea (Example 47)
The title compound was prepared as an off-white solid (80 mg, 53%) using
(5-tert-butylp-tolyl-2H-pyrazolyl)-carbamic acid 2,2,2-trichloro-ethyl ester
(Synthetic Communications, 2009, 39, 3999-4009; 80 mg, 0.20 mmol) and
Intermediate 47c (90 mg, 0.24 mmol) in a similar manner to Example 1, step d.
LCMS (Method 5): Rt 3.83 min, m/z 633 [MH ]. ¹H NMR (400 MHz, d -DMSO):
1.27 (9H, s), 1.51 (3H, s), 1.78-1.99 (5H, m), 2.02 (3H, s), 2.03-2.22 (3H, m), 2.36
(3H, s), 2.65 (1H, q, J 8.6), 3.11-3.17 (1H, m), 4.79-4.86 (1H, m), 5.32 (1H, t, J
4.2), 6.32 (1H, s), 7.11 (1H, d, J 8.6), 7.25-7.39 (9H, m), 7.75 (1H, d, J 9.8), 8.05
(1H, s), 8.43 (1H, d, J 2.2).
Example 48
1-{5-tert-Butyl[3-(2-hydroxy-ethoxymethyl)-phenyl]-2H-pyrazol
yl}[(1S,4R)(3-piperidinyl-[1,2,4]triazolo[4,3-a]pyridinyloxy)-
1,2,3,4-tetrahydro-naphthalenyl]-urea
To a solution of Example 29 (204 mg, 0.32 mmol) and Et N (134 µL, 0.97
mmol) in DCM (3.2 mL) at 0°C was added mesyl chloride (39 µL, 0.39 mmol),
and the mixture stirred for 1 h. The solution was washed with water, dried, and
concentrated in vacuo to give methanesulfonic acid 3-(3-tert-butyl{3-[(1S,4R)-
4-(3-piperidinyl-[1,2,4]triazolo[4,3-a]pyridinyloxy)-1,2,3,4-tetrahydro-
naphthalenyl]-ureido}-pyrazolyl)-benzyl ester. This was immediately
dissolved in dioxane (1.5 mL) and ethylene glycol (1.5 mL) and the solution stirred
at 85°C for 1 h. The cooled reaction mixture was suspended in water and filtered to
leave a solid. Purification by HPLC (XBridge C18 column, 40-98% MeCN in
H O, 0.1% NH OH) gave the title compound as a white powder after freeze-drying
(59 mg, 27%). LCMS (Method 5): Rt 4.27 min, m/z 679 [MH ]. ¹H NMR (400
MHz, d -DMSO): 1.28 (9H, s), 1.60-1.64 (2H, m), 1.70-1.75 (4H, m), 1.86-1.93
(2H, m), 2.03 (1H, m), 2.11 (1H, m), 3.14 (4H, t, J 5.2), 3.54-3.48 (4H, m), 4.56
(2H, s), 4.64 (1H, s), 4.80 (1H, m), 5.54 (1H, t, J 4.3), 6.34 (1H, s), 7.07 (1H, d, J
8.6), 7.16 (1H, dd, J 9.8, 2.2), 7.37-7.49 (8H, m), 7.60-7.63 (2H, m), 8.11 (1H, s).
Example 49
1-(5-tert-Butylp-tolyl-2H-pyrazolyl)[(1S,4R)(3-
[1,4]oxazepanyl-[1,2,4]triazolo[4,3-a]pyridinyloxy)-1,2,3,4-tetrahydro-
naphthalenyl]-urea
a. 6-Fluoro[1,4]oxazepanyl-[1,2,4]triazolo[4,3-a]pyridine
(Intermediate 49a)
A solution of Intermediate 24b (429 mg, 2.50 mmol) and homomorpholine
(939 mg, 9.30 mmol) in NMP (10 mL) was heated in the microwave at 170°C for
h. The cooled mixture was applied to an SCX-2 cartridge (70 g), washing with
methanol then eluting basic components with 0.4–2 M NH in MeOH. Product
containing fractions were combined and concentrated in vacuo. The residue was
purified by FCC, using 0-12% [2M NH in MeOH] in DCM, to give impure
product. Further purified by FCC, using 0-12% MeOH in EtOAc gave the title
compound as a pale brown gum (147 mg, 25%). LCMS (Method 3): Rt 2.11 min,
m/z 237 [MH ].
b. (1S,4R)(3-[1,4]Oxazepanyl-[1,2,4]triazolo[4,3-a]pyridin
yloxy)-1,2,3,4-tetrahydro-naphthalenylamine (Intermediate 49b)
To a solution of Intermediate A (145 mg, 0.614 mmol) in DMF (3 mL) was
added NaH (60% dispersion in oil, 74 mg, 1.84 mmol). The mixture was stirred at
RT for 15 min, then a solution of Intermediate 49a (100 mg, 0.614 mmol) in DMF
(3 mL) was added and the mixture stirred at 60°C for 2.25 h. The cooled mixture
was diluted with water and extracted with DCM (4 × 25 mL). The combined
organics were dried and concentrated in vacuo. The residue was purified by FCC,
using 0-12% [2M NH in MeOH] in DCM, to give the title compound as a pale
brown gum (93 mg, 40%). LCMS (Method 3): Rt 0.43 min, m/z 380 [MH ].
c. 1-(5-tert-Butylp-tolyl-2H-pyrazolyl)[(1S,4R)(3-
[1,4]oxazepanyl-[1,2,4]triazolo[4,3-a]pyridinyloxy)-1,2,3,4-tetrahydro-
naphthalenyl]-urea (Example 49)
A solution of Intermediate 49b (90.0 mg, 0.237 mmol) and (5-tert-butyl
p-tolyl-2H-pyrazolyl)-carbamic acid 2,2,2-trichloro-ethyl ester (Synthetic
Communications, 2009, 39, 3999-4009; 97 mg, 0.24 mmol) in 1,4-dioxane (3 mL)
and DIPEA (63 µL, 0.36 mmol) was stirred at 90°C for 4 h, then more DIPEA (63
µL, 0.36 mmol) was added and mixture stirred at 100-110°C for 3.5 h. The cooled
mixture was concentrated in vacuo. The residue was purified by FCC, using 0-12%
[2M NH in MeOH] in DCM, to give the product (31 mg, 21%). This was further
purified by HPLC (C18 X-select column, 35-98% MeCN in H O, 0.1% HCO H) to
give the title compound as a white powder after freeze-drying (20 mg, 13%).
LCMS (Method 5): Rt 4.40 min, m/z 635.2 [MH ]. ¹H NMR (400 MHz, d -
DMSO): 1.27 (9H, s), 1.80-2.18 (6H, m), 2.36 (3H, s), 3.44-3.51 (4H, m), 3.78-
3.85 (4H, m), 4.77-4.85 (1H, m), 5.51 (1H, t, J 4.4), 6.32 (1H, s), 7.10-7.16 (2H,
m), 7.25-7.40 (8H, m), 7.60 (1H, d, J 9.6), 7.65 (1H, d, J 1.5), 8.10 (1H, s).
Example 50
1-(5-tert-Butyl{3-[4-(2-hydroxy-ethyl)-piperazinylmethyl]-
phenyl}-2H-pyrazolyl)[(1S,4R)(3-piperidinyl-[1,2,4]triazolo[4,3-
a]pyridinyloxy)-1,2,3,4-tetrahydro-naphthalenyl]-urea
To a solution of Example 29 (150 mg, 0.24 mmol) and Et N (98 µL, 0.71
mmol) in DCM (7 mL) at 0°C was added mesyl chloride (28 µL, 0.28 mmol), and
the mixture stirred for 1 h. The solution was washed with water, dried, and
concentrated in vacuo to give methanesulfonic acid 3-(3-tert-butyl{3-[(1S,4R)-
4-(3-piperidinyl-[1,2,4]triazolo[4,3-a]pyridinyloxy)-1,2,3,4-tetrahydro-
naphthalenyl]-ureido}-pyrazolyl)-benzyl ester. This was immediately
dissolved in THF (2.5 mL) and DIPEA (83 µL, 0.47 mmol) then 1-(2-
hydroxyethyl) piperazine (87 µL, 0.71 mmol) added and the solution stirred at
reflux for 1 h. Water was added and the mixture extracted with DCM. The
combined organics were dried and concentrated in vacuo. The residue was purified
by HPLC (XBridge C18 column, 20-98% MeCN in H O, 0.1% NH OH) to give
the title compound as a white powder after freeze-drying (45 mg, 25%). LCMS
(Method 5): Rt 3.42 min, m/z 747 [MH ]. ¹H NMR (400 MHz, d -DMSO): 1.28
(9H, s), 1.60-1.64 (2H, m), 1.69-1.75 (4H, m), 1.83-1.94 (2H, m), 2.03-2.12 (2H,
m), 2.29-2.45 (8H, m), 2.33 (2H, t, J 6.4), 3.14 (4H, t, J 5.2), 3.44 (2H, m), 3.49
(2H, s), 4.31 (1H, s), 4.80 (1H, m), 5.54 (1H, t, J 4.4), 6.33 (1H, s), 7.03 (1H, d, J
8.6), 7.16 (1H, dd, J 9.8, 2.2), 7.34-7.46 (8H, m), 7.60-7.63 (2H, m), 8.10 (1H, s).
Example 51
1-(2-tert-Butylp-tolyl-3H-imidazolyl)[(1S,4R)(3-piperidin
yl-[1,2,4]triazolo[4,3-a]pyridinyloxy)-1,2,3,4-tetrahydro-naphthalenyl]-
urea
N O N
a. 2-tert-Butylp-tolyl-1H-imidazole (Intermediate 51a)
A red suspension of 2,2-dimethylpropionamide hydrochloride (Atlantic,
1.00 g, 7.32 mmol), 2-bromo-4’-methylacetophenone (Aldrich, 1.56 g, 7.32 mmol)
and K CO (1.52 g, 11.0 mmol) in DMF (20 mL) was stirred at 75°C for 3 h. The
mixture was cooled to RT, concentrated in vacuo, suspended in water (25 mL) and
extracted with DCM (2 × 25 mL). The combined organics were passed through a
hydrophobic frit, concentrated in vacuo, redissolved in MeOH (5 mL), applied to
an SCX-2 cartridge (20 g) and washed with MeOH (100 mL). The product was
eluted with 2M NH in MeOH (60 mL); concentration in vacuo left a yellow foam
(1.26 g). FCC, using 1-5% MeOH in DCM, gave the title compound as a pale
yellow solid (770 mg, 49%). LCMS (Method 3): Rt 2.26 min, m/z 215 [MH ].
b. 2-tert-Butylnitrosop-tolyl-1H-imidazole (Intermediate 51b)
A yellow solution of Intermediate 51a (390 mg, 1.82 mmol) and isopentyl
nitrite (0.294 mL, 2.18 mmol) in THF (10 mL) was stirred at 50°C for 8 h, then
cooled to RT and concentrated in vacuo to leave a dark green oil. FCC, using 0-
% EtOAc in cyclohexane, gave the title compound as a green solid (154 mg,
%). LCMS (Method 3): Rt 3.82 min, m/z 244 [MH ].
c. 2-tert-Butylp-tolyl-1H-imidazolylamine (Intermediate 51c)
A suspension of Intermediate 51b (150 mg, 0.617 mmol) and Pd/C (10%,
mg) in EtOH (10 mL) was stirred at RT under H for 2 h. The flask was
evacuated and purged with N thrice, then the mixture filtered through Celite, and
the filter-cake washed with EtOH (10 mL). The combined organics were
concentrated in vacuo to leave a red-brown gum. FCC, using 1-6% MeOH in
DCM, gave the title compound as a yellow-orange gum (96.3 mg, 68%). LCMS
(Method 3): Rt 2.26 min, m/z 230 [MH ].
d. (2-tert-Butylp-tolyl-1H-imidazolyl)-carbamic acid 2,2,2-
trichloro-ethyl ester (Intermediate 51d)
HN O
To a solution of Intermediate 51c (45.3 mg, 0.197 mmol) in EtOAc (1 mL)
and aqueous NaOH (1M, 0.49 mL) was added 2,2,2-trichloroethyl chloroformate
(0.0326 mL, 0.237 mmol) and the resulting mixture stirred at RT for 45 min. The
layers were separated and the aqueous extracted with EtOAc (2 mL). The
combined organics were washed with brine (2 mL), dried (Na SO ), filtered and
concentrated in vacuo to leave an orange-red gum. FCC, using 0-50% EtOAc in
cyclohexane, gave the title compound as a pale orange film (44.1 mg, 55%).
LCMS (Method 3): Rt 2.87 min, m/z 404, 406 [MH ].
e. 1-(2-tert-Butylp-tolyl-3H-imidazolyl)[(1S,4R)(3-piperidin-
1-yl-[1,2,4]triazolo[4,3-a]pyridinyloxy)-1,2,3,4-tetrahydro-naphthalen
yl]-urea. (Example 51)
An orange solution of Intermediate 51d (65.4 mg, 0.162 mmol),
Intermediate 3c (55.9 mg, 0.153 mmol) and DIPEA (0.042 mL, 0.242 mmol) in
dioxane (2 mL) was stirred at 60°C for 18 h. After cooling, the mixture was
concentrated in vacuo, suspended in water (5 ml) and extracted with DCM (2 × 5
mL). The combined organics were passed through a hydrophobic frit and
concentrated in vacuo to leave an orange-brown gum. FCC, using 2-8% MeOH in
DCM, gave a pale yellow solid (50.5 mg). Further purification by HPLC (C18
XBridge column, 25-75% MeCN in H O, 0.1% NH OH) gave the title compound
as a white solid after freeze-drying (33.3 mg, 33%). LCMS (Method 5): Rt 3.35
min, m/z 619 [MH ]. ¹H NMR (400 MHz, d -DMSO): 3:1 ratio of tautomers: 1.30
(6.75H, s), 1.31 (2.25H, s), 1.61 (2H, m), 1.72 (4H, m), 1.83-2.00 (2H, m), 2.05
(1H, m), 2.15 (1H, m), 2.30 (0.75H, s), 2.32 (2.25H, s), 3.13 (4H, q, J 5.2), 4.87
(1H, m), 5.54 (1H, t, J 4.3), 7.14-7.19 (2.5H, m), 7.21 (1.5H, d, J 8.2), 7.25-7.40
(4H, m), 7.54 (1.5H, d, J 8.3), 7.60-7.71 (3.5H, m), 11.56 (0.75H, s), 11.68 (0.25H,
Example 52
1-{5-tert-Butyl[3-(4-hydroxy-piperidinylmethyl)-phenyl]-2H-
pyrazolyl}[(1S,4R)(3-piperidinyl-[1,2,4]triazolo[4,3-a]pyridin
yloxy)-1,2,3,4-tetrahydro-naphthalenyl]-urea
To a solution of Example 29 (150 mg, 0.24 mmol) and Et N (98 µL, 0.71
mmol) in DCM (7 mL) at 0°C was added mesyl chloride (28 µL, 0.28 mmol), and
the mixture stirred for 1 h. The solution was washed with water, dried, and
concentrated in vacuo to give methanesulfonic acid 3-(3-tert-butyl{3-[(1S,4R)-
4-(3-piperidinyl-[1,2,4]triazolo[4,3-a]pyridinyloxy)-1,2,3,4-tetrahydro-
naphthalenyl]-ureido}-pyrazolyl)-benzyl ester. This was immediately
dissolved in THF (2.5 mL) and DIPEA (83 µL, 0.47 mmol) then 4-
hydroxypiperidine (83 µL, 0.71 mmol) added and the solution stirred at reflux for
1 h. Water was added and the mixture extracted with DCM. The combined
organics were dried and concentrated in vacuo. The residue was purified by FCC,
using 0-10% [2M NH in MeOH] in DCM, to give the product. This was purified
further by HPLC (XBridge C18 column, 20-98% MeCN in H2O, 0.1% NH4OH) to
give the title compound as a white powder after freeze-drying (30 mg, 18%).
LCMS (Method 5): Rt 3.41 min, m/z 718 [MH ]. ¹H NMR (400 MHz, d -DMSO):
1.28 (9H, s), 1.34-1.40 (2H, m), 1.60-1.75 (7H, m), 1.81-1.96 (3H, m), 2.00-2.15
(4H, m), 2.64-2.69 (2H, m), 3.14 (4H, t, J 5.2), 3.40-3.45 (1H, m), 3.47 (2H, s),
4.51 (1H, d, J 3.9), 4.82 (1H, m), 5.54 (1H, t, J 4.4), 6.33 (1H, s), 7.04 (1H, d, J
8.5), 7.16 (1H, dd, J 9.8, 2.2), 7.26-7.33 (4H, m), 7.35-7.46 (4H, m), 7.60-7.63
(2H, m), 8.10 (1H, s).
Example 53
1-{5-tert-Butyl[3-(2-hydroxy-ethylsulfanyl)-phenyl]-2H-pyrazol
yl}[(1S,4R)(3-piperidinyl-[1,2,4]triazolo[4,3-a]pyridinyloxy)-
1,2,3,4-tetrahydro-naphthalenyl]-urea
A solution of Intermediate 3c (107 mg, 0.29 mmol) and Intermediate 53c
(151 mg, 0.32 mmol) in THF (3 mL) and DIPEA (169 µL, 0.97 mmol) was stirred
at reflux for 20.5 h. The cooled reaction mixture was diluted with water and
extracted with DCM. The combined organics were dried and concentrated in
vacuo. The residue was purified by FCC, using 0-5% [2M NH in MeOH] in
DCM, to give the product. This residue purified further by HPLC (XBridge C18
column, 30-98% MeCN in H O, 0.1% NH OH) to give the title compound as a
white powder after freeze-drying (21 mg, 10%). LCMS (Method 5): Rt 4.42 min,
m/z 681 [MH ]. ¹H NMR (400 MHz, d -DMSO): 1.28 (9H, s), 1.60-1.63 (2H, m),
1.69-1.74 (4H, m), 1.86-1.93 (2H, m), 2.03 (1H, m), 2.13 (1H, m), 3.09 (2H, t, J
6.8), 3.14 (4H, t, J 5.2), 3.59 (2H, q, J 6.2), 4.80 (1H, m), 4.95 (1H, t, J 5.6), 5.54
(1H, t, J 4.3), 6.33 (1H, s), 7.07 (1H, d, J 8.6), 7.16 (1H, dd, J 9.8, 2.1), 7.35-7.47
(8H, m), 7.60-7.64 (2H, m), 8.14 (1H, s).
Example 54
1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-(4-
hydroxymethyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-urea
a. [1-(6-Fluoro-[1,2,4]triazolo[4,3-a]pyridinyl)-piperidinyl]-
methanol (Intermediate 54a)
A solution of Intermediate 24b (593 mg, 3.45 mmol) and 4-
piperidinemethanol (1.59 g, 13.8 mmol) in NMP (10 mL) was heated in the
microwave at 170°C for 3 h. The cooled mixture was applied to an SCX-2
cartridge (70 g), washing with methanol then eluting basic components with 0.4 –
2 M NH in MeOH. Product containing fractions were combined and concentrated
in vacuo. The residue was purified by FCC, using 0-15% MeOH in EtOAc, to give
the title compound as a brown gum (481 mg, 56%). LCMS (Method 3): Rt 2.12
min, m/z 251 [MH ].
b. 6-Fluoro(4-triisopropylsilanyloxymethyl-piperidinyl)-
[1,2,4]triazolo[4,3-a]pyridin (Intermediate 54b)
To a solution of Intermediate 54a (470 mg, 1.88 mmol) and Et N (390 µL,
2.82 mmol) in DCM (5 mL) was added triisopropylsilyltrifluoromethane sulfonate
(607 µL, 2.26 mmol) and the mixture stirred at RT for 0.5 h. The mixture was
washed with sat. aq. NaHCO solution, dried and concentrated in vacuo. The
residue was purified by FCC, using 0-100% EtOAc in cyclohexane, then 10%
MeOH in EtOAc, to give the title compound as a pale yellow solid (565 mg, 74%).
LCMS (Method 3): Rt 5.21 min, m/z 407 [MH ].
c. (1S,4R)[3-(4-Triisopropylsilanyloxymethyl-piperidinyl)-
[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalen
ylamine (Intermediate 54c)
To a solution of Intermediate A (223 mg, 1.37 mmol) in DMF (3 mL) was
added NaH (60% dispersion in oil, 168 mg, 4.20 mmol) and the mixture stirred at
RT for 15 min. A solution of Intermediate 54b (555 mg, 1.37 mmol) in DMF (3
mL) was added and the mixture stirred at 60°C for 1.75 h. The cooled mixture was
diluted with water and extracted with DCM (5 × 20 mL). The combined organics
were dried and concentrated in vacuo. The residue was purified by FCC, using 0-
14% [2M NH in MeOH] in DCM, to give the title compound as a brown gum
(344 mg, 46%). LCMS (Method 3): Rt 3.29 min, m/z 550 [MH ].
d. 1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-(4-
triisopropylsilanyloxymethyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridin
yloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea (Intermediate 54d)
N N N
A solution of Intermediate 54c (171 mg, 0.311 mmol) and (5-tert-butylp-
tolyl-2H-pyrazolyl)-carbamic acid 2,2,2-trichloro-ethyl ester (Synthetic
Communications, 2009, 39, 3999-4009; 132 mg, 0.327 mmol) in 1,4-dioxane (3
mL) and DIPEA (87 µL, 0.50 mmol) was stirred at 90°C for 3 h, and then at 100°C
for 2.5 h. The cooled mixture was concentrated in vacuo. The residue was purified
by FCC, using 0-8% MeOH in DCM, to give the title compound as a pale brown
solid (215 mg, 86%). LCMS (Method 3): Rt 5.70 min, m/z 805.4 [MH ].
e. 1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-(4-
hydroxymethyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-urea (Example 54)
A solution of Intermediate 54d (210 mg, 0.261 mmol) and TBAF (1M in
THF, 0.31 mL, 0.31 mmol) in THF (5 mL) was stirred at RT for 1.25 h. The
mixture was diluted with water and extracted with DCM (3 × 15 mL). The
combined organics were dried and concentrated in vacuo. The residue was purified
by FCC, using 0-16% MeOH in DCM, to give the title compound as an off-white
powder after freeze-drying (134 mg, 79%). LCMS (Method 5): Rt 4.24 min, m/z
649.2 [MH ]. ¹H NMR (400 MHz, d -DMSO): 1.27 (9H, s), 1.38-2.16 (9H, m),
2.36 (3H, s), 2.85-2.97 (2H, m), 3.28-3.49 (4H, m), 4.52 (1H, t, J 5.2), 4.78-4.85
(1H, m), 5.55 (1H, t, J 4.3), 6.32 (1H, s), 7.07 (1H, d, J 8.6), 7.15 (1H, dd, J 9.7,
2.1), 7.25-7.41 (8H, m), 7.60 (1H, d, J 9.7), 7.64 (1H, d, J 1.6), 8.04 (1H, s).
Example 55
1-(5-tert-Butylp-tolyl-2H-pyrazolyl)[(1S,4S)(3-piperidin
yl-[1,2,4]triazolo[4,3-a]pyridinyloxy)-1,2,3,4-tetrahydro-naphthalenyl]-
urea
a. (1S,4S)(3-Piperidinyl-[1,2,4]triazolo[4,3-a]pyridinyloxy)-
1,2,3,4-tetrahydro-naphthalenylamine (Intermediate 55a)
Intermediate B (74.0 mg, 454 µmol) was added to a mixture of NaH (60%
in mineral oil, 27.2 mg, 681 µmol) in DMF (2.5 mL) at RT and stirred for 15 min.
Intermediate 3b (100 mg, 454 µmol) was then added and the resulting mixture
heated to 60°C for 1 h. After cooling, the reaction was quenched with sat. aq.
NH Cl solution. The mixture was diluted with water and extracted with EtOAc.
The combined organic extracts were concentrated in vacuo. The resulting residue
was purified by FCC, using 0 to 10% [2M NH in MeOH] in DCM, to afford the
title compound as an orange residue (122 mg, 74%). LCMS (Method 3): Rt 2.13
min, m/z 364 [MH ].
c. 1-(5-tert-Butylp-tolyl-2H-pyrazolyl)[(1S,4S)(3-piperidin
yl-[1,2,4]triazolo[4,3-a]pyridinyloxy)-1,2,3,4-tetrahydro-naphthalenyl]-
urea (Example 55)
A mixture of Intermediate 55a (120 mg, 0.33 mmol), (5-tert-butylp-tolyl-
2H-pyrazolyl)-carbamic acid 2,2,2-trichloro-ethyl ester (Synthetic
Communications, 2009, 39, 3999-4009; 147 mg, 0.36 mmol), DIPEA (86.0 µL,
0.50 mmol) and 1,4-dioxane (2.5 mL) were heated to 60°C for 18 h. After cooling
the solvent was evaporated in vacuo. The residue was purified by FCC, using 0-
% MeOH in DCM, to give a pale yellow foam. This was lyophilised to provide
the title compound as an off-white solid (28 mg, 20%). LCMS (Method 5) Rt 4.76
min, m/z 619 [MH ]. ¹H NMR (400 MHz, d -DMSO): 1.26 (9H, s), 1.61 (2H, m),
1.72 (5H, m), 2.02-2.17 (3H, m), 2.35 (3H, s), 3.13 (4H, m), 4.90 (1H, m), 5.58
(1H, m), 6.31 (1H, s), 6.99 (1H, d, J 7.8), 7.19 (1H, dd, J 9.7, 2.2), 7.26-7.43 (8H,
m), 7.58-7.64 (2H, m), 7.98 (1H, s).
Example 56
1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-(3-
hydroxymethylmethyl-piperazinylmethyl)-[1,2,4]triazolo[4,3-a]pyridin-
6-yloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea
a. (3-Hydroxymethylmethyl-piperazinyl)-acetic acid ethyl ester
(Intermediate 56a)
A mixture of (1-methylpiperazinyl)methanol dihydrochloride (500 mg,
2.46 mmol), ethyl bromoacetate (410 mg, 2.46 mmol), K CO (1.02 g, 7.38 mmol)
and MeCN (15 mL) were heated to reflux for 18 h. After cooling, the mixture was
filtered and concentrated in vacuo. The title compound was isolated as a colourless
oil (525 mg, 98%) and used without further purification. ¹H NMR (300 MHz,
CDCl ): 1.25 (3H, t, J 7.0), 2.35 (3H, s), 2.35-2.59 (4H, m), 2.76-2.90 (3H, m),
3.19 (2H, m), 3.44 (1H, dd, J 11.3, 2.0), 3.87 (1H, dd, J 11.3, 4.0), 4.15 (2H, q, J
7.1).
b. Sodium (4-methyltriisopropylsilanyloxymethyl-piperazinyl)-
acetate (Intermediate 56b)
O Si
Na O
To a mixture of Intermediate 56a (520 mg, 2.40 mmol), Et N (485 mg, 4.80
mmol) and DCM (15 mL), triisopropylsilyl trifluoromethanesulfonate (774 µL,
2.88 mmol) was added. The mixture was stirred for 1 h. The mixture was diluted
with DCM and washed with water, sat. aq. NaHCO solution and brine, and
concentrated in vacuo. The title compound was isolated as a pale yellow oil (882
mg, quant.) and used without further purification.
A mixture of crude silyl-protected product (440 mg, 1.18 mmol), NaOH
(47.0 mg, 1.18 mmol), water (10 mL) and THF (10 mL) were stirred for 18 h. The
mixture was concentrated in vacuo to give the title compound as a pink solid (393
mg, 91%). LCMS (Method 3): Rt 2.81 min, m/z 345 [M-Na+2H ].
c. (4-Methyltriisopropylsilanyloxymethyl-piperazinyl)-acetic acid
N'-(5-fluoro-pyridinyl)-hydrazide (Intermediate 56c)
O Si
To a mixture of Intermediate 56b (390 mg, 1.06 mmol), (5-fluoro-pyridin
yl)-hydrazine (135 mg, 1.06 mmol) and HOBt.H O (14.4 mg, 106 µmol) in DCM
(15 mL) was added EDC (245 mg, 1.27 mmol) and stirred for 18 h. The mixture
was washed with water, sat. aq. NaHCO and brine, and concentrated in vacuo to
leave the title compound as a brown residue (412 mg, 86%). LCMS (Method 3): Rt
3.00 min, m/z 454 [MH ].
d. 6-Fluoro(4-methyltriisopropylsilanyloxymethyl-piperazin
ylmethyl)-[1,2,4]triazolo[4,3-a]pyridine (Intermediate 56d)
N O Si
Hexachloroethane (426 mg, 1.80 mmol) was added portion-wise to a stirred
mixture of Intermediate 56c (410 mg, 0.90 mmol), Ph P (472 mg, 1.80 mmol) and
Et N (500 µL, 3.60 mmol) in THF (15 mL) at RT. The reaction mixture was stirred
for 18 h, then filtered and concentrated in vacuo. The resulting residue was
purified by FCC, using 0-25% MeOH in EtOAc, to give the title compound (237
mg, 60%). LCMS (Method 3): Rt 2.95 min, m/z 436 [MH ].
e. (1S,4R)[3-(4-Methyltriisopropylsilanyloxymethyl-piperazin
ylmethyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-
naphthalenylamine (Intermediate 56e)
Intermediate A (115.4 mg, 0.71 mmol) was added to a mixture of NaH
(60% in mineral oil, 87.2 mg, 2.18 mmol) in DMF (4 mL) at RT and stirred for 15
min. Intermediate 56d (237 mg, 0.54 mmol) was then added and the resulting
mixture heated to 60°C for 2 h. After cooling, the reaction was quenched with sat.
aq. NH Cl solution. The mixture was diluted with water and extracted with EtOAc.
The combined organic extracts were washed with sat. aq. NaHCO solution and
brine, and concentrated in vacuo. The resulting residue was loaded onto an SCX-2
cartridge, washed with MeOH then eluted with 1M NH in MeOH; concentration
in vacuo gave the title compound as a brown residue (91 mg, 29%). LCMS
(Method 3): Rt 3.08 min, m/z 579 [MH ].
f. 1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-(4-methyl-
3-triisopropylsilanyloxymethyl-piperazinylmethyl)-[1,2,4]triazolo[4,3-
a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea (Intermediate
56f)
A mixture of Intermediate 56e (87.0 mg, 0.15 mmol), (5-tert-butylp-
tolyl-2H-pyrazolyl)-carbamic acid 2,2,2-trichloro-ethyl ester (Synthetic
Communications, 2009, 39, 3999-4009; 66.8 mg, 0.17 mmol), DIPEA (39.2 µL,
0.23 mmol) and 1,4-dioxane (2.5 mL) were heated to 60°C for 18 h. After cooling
the solvent was evaporated in vacuo and the residue purified by FCC, using 0-10%
MeOH in DCM, to provide the title compound as a pale yellow foam (64 mg,
51%). LCMS (Method 3): Rt 3.63 min, m/z 834 [M ].
g. 1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-(3-
hydroxymethylmethyl-piperazinylmethyl)-[1,2,4]triazolo[4,3-a]pyridin-
6-yloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea (Example 56)
A mixture of Intermediate 56f (60.0 mg, 72.0 µmol) and TBAF (1M in
THF, 144 µL, 144 µmol) in THF (3 mL) was stirred at RT for 1 h. The mixture
was diluted with water and extracted with EtOAc (3 ×). The combined organic
extracts were washed with brine, and concentrated in vacuo. The residue was
purified by FCC, using 0-20% MeOH in DCM, to afford the title compound as an
off-white solid (24.9 mg, 51%). LCMS (Method 5): Rt 3.54 min, m/z 678 [MH ].
¹H NMR (400 MHz, d -DMSO): 1.27 (9H, s), 1.82-2.01 (4H, m), 2.01-2.25 (7H,
m), 2.53-2.88 (3H, m), 3.21 (1H, m), 3.54 (1H, m), 3.96-4.11 (2H, m), 4.37 (1H,
dt, J 12.5, 5.4), 4.84 (1H, m), 5.47 (1H, m), 6.32 (1H, s), 7.10 (1H, d, J 8.4), 7.22-
7.44 (9H, m), 7.72 (1H, d, J 10.3), 8.02 (1H, s), 8.30 (1H, m).
Example 57
1-[5-tert-Butyl(4-hydroxymethyl-phenyl)-2H-pyrazolyl]
{(1S,4R)[3-(4-hydroxy-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridin
yloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea
a. 3-(4-Allyloxy-piperidinyl)fluoro-[1,2,4]triazolo[4,3-a]pyridine
(Intermediate 57a)
To an opaque pale yellow solution of Intermediate 24c (510 mg, 2.16
mmol) in dry THF at 0°C under Ar was added NaH (60% dispersion in oil, 216
mg, 5.40 mmol) (CARE: gas evolution) and the resulting suspension was stirred at
0°C for 30 min. Allyl bromide (0.467 mL, 5.40 mmol) was added and the
suspension stirred at RT under Ar for 1 h and at 70°C for 18 h. Water (25 mL) was
added to the cooled solution, then the mixture extracted with EtOAc (3 × 25 mL).
The combined organics were washed with brine (25 mL), dried (Na SO ), filtered
and concentrated in vacuo to leave a dark brown oil. FCC, using 0-8% MeOH in
EtOAc, gave the title compound as a brown oil (171 mg, 29%). LCMS (Method 3):
Rt 2.81 min, m/z 277 [MH ].
b. (1S,4R)[3-(4-Allyloxy-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridin-
6-yloxy]-1,2,3,4-tetrahydro-naphthalenylamine (Intermediate 57b)
A suspension of Intermediate A (108 mg, 0.661 mmol) and NaH (60%
dispersion in oil, 72.1 mg, 180 mmol) in dry DMF (5 mL) at RT under Ar was
stirred for 1 h (CARE: gas evolution). A solution of Intermediate 57a (166 mg,
0.601 mmol) in dry DMF (3 mL) was added and the dark brown solution stirred at
60°C for 90 min. The solution was concentrated in vacuo, and the residue
redissolved in MeOH (5 mL) and AcOH (0.171 mL, 3.00 mmol). The solution was
applied to an SCX-2 cartridge (10 g) and was washed with MeOH (100 mL). The
product was eluted with 2M NH in MeOH (75 mL); concentration in vacuo left a
dark brown solid. FCC, using 2-8% [2M NH in MeOH] in DCM, gave the title
compound as a dark brown oil (204 mg, 81%). LCMS (Method 3): Rt 2.34 min,
m/z 420 [MH ].
c. 1-{(1S,4R)[3-(4-Allyloxy-piperidinyl)-[1,2,4]triazolo[4,3-
a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}[5-tert-butyl(4-
hydroxymethyl-phenyl)-2H-pyrazolyl]-urea (Intermediate 57c)
A yellow-brown solution of Intermediate 33a (99.6 mg, 0.237 mmol),
Intermediate 57b (90.3 mg, 0.215 mmol) and DIPEA (0.047 mL, 0.269 mmol) in
dioxane (3 mL) was stirred at 60°C for 18 h. The solution was concentrated in
vacuo, then the residue suspended in water (5 mL) and extracted with DCM (2 × 5
mL). The combined organics were passed through a hydrophobic frit and
concentrated in vacuo. The residue was purified by FCC, using 2-8% [2M NH in
MeOH] in DCM, to give the title compound as a pale yellow solid (96.4 mg, 65%).
LCMS (Method 3): Rt 3.54 min, m/z 691 [MH ].
d. 1-[5-tert-Butyl(4-hydroxymethyl-phenyl)-2H-pyrazolyl]
{(1S,4R)[3-(4-hydroxy-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridin
yloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea. (Example 57)
Ar was bubbled through a solution of Intermediate 57c (93.0 mg, 0.135
mmol) and 1,3-dimethyl barbituric acid (63.0 mg, 0.404 mmol) in DCM (5 mL) at
RT under Ar for 30 min, then Pd(PPh ) (15.6 mg, 0.0135 mmol) was added and
the orange solution was stirred at RT for 1 h, and then at reflux for 17 h. The
suspension was concentrated in vacuo, the residue redissolved in DCE (10 mL)
and Ar bubbled through the mixture for 30 min. Pd(PPh ) (15.6 mg, 0.0135
mmol) was added and the opaque orange-red solution stirred at 75°C under Ar for
2 h. The cooled solution was concentrated in vacuo to ~3 mL volume, then applied
to an SCX-2 cartridge (5 g) and washed with MeOH (25 mL). The product was
eluted with 2M NH in MeOH (20 mL); concentration in vacuo left an orange
solid. FCC, using 5-15% MeOH in DCM, gave a pale orange solid (46.0 mg).
Further purification by HPLC (XBridge C18 column, 20-80% MeCN in H O,
0.1% NH OH) gave the title compound as a white powder after freeze-drying (27.1
mg, 31%). LCMS (Method 5): Rt 3.59 min, m/z 651 [MH ]. ¹H NMR (400 MHz,
d -DMSO): 1.23 (9H, s), 1.56-1.67 (2H, m), 1.76-1.92 (4H, m), 1.95-2.11 (2H, m),
2.91-2.97 (2H, m), 3.31-3.35 (2H, m), 3.64-3.71 (1H, m), 4.51 (2H, d, J 4.2), 4.70
(1H, d, J 3.9), 4.77 (1H, m), 5.25 (1H, t, J 5.3), 5.50 (1H, t, J 4.4), 6.29 (1H, s),
7.05 (1H, d, J 8.5), 7.10 (1H, dd, J 9.9, 2.1), 7.21-7.25 (2H, m), 7.28-7.34 (2H, m),
7.39 (2H, d, J 9.1), 7.40 (2H, d, J 9.1), 7.56 (1H, dd, J 9.9, 0.8), 7.61 (1H, dd, J 2.1,
0.9), 8.04 (1H, s).
Example 58
1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-((S)
isopropyl-pyrrolidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-urea, partial formate salt
(0.5 eq)
a. (S)Isopropyl-pyrrolidinecarboxylic acid N'-(5-fluoro-pyridin
yl)-hydrazide (Intermediate 58a)
To a solution of (5-fluoro-pyridinyl)-hydrazine (200 mg, 1.57 mmol) in
DMF (15.0 mL) was added (S)isopropyl-pyrrolidinecarboxylic acid (Chem.
Commun. 2006, 14, 1482; 247 mg, 1.57 mmol), EDC (332 mg, 1.73 mmol) and
HOBt.H O (20.0 mg, 0.16 mmol). The reaction was stirred overnight then
partitioned between EtOAc and water. The aqueous layer was then extracted with
EtOAc (3 ×). The combined organic layers were washed with brine, dried
(MgSO ), filtered and evaporated in vacuo. The residue was purified by FCC,
using 0-10% MeOH in DCM, to give the title compound (346 mg, 83%). LCMS
(Method 1): Rt 0.37 min, m/z 267.1 [MH ].
b. 6-Fluoro((S)isopropyl-pyrrolidinyl)-[1,2,4]triazolo[4,3-
a]pyridine (Intermediate 58b)
To a solution of Intermediate 58a (346 mg, 1.30 mmol), Ph P (681 mg, 2.60
mmol) and Et N (723 mL, 5.20 mmol) in THF (10.0 mL) at 0°C was added
hexachloroethane (616 mg, 2.60 mmol). The reaction was stirred at RT overnight
then partitioned between EtOAc and water. The aqueous layer was then extracted
with EtOAc (3 ×). The combined organic layers were washed with brine, dried
(MgSO ), filtered and evaporated in vacuo. The residue was dissolved in MeOH
and loaded onto an SCX-2 cartridge, which was washed with MeOH. The product
was eluted with 2M NH in MeOH; concentration in vacuo gave the title
compound (220 mg, 68%). LCMS (Method 4): Rt 0.32 min, m/z 249.1 [MH ].
c. (1S,4R)[3-((S)Isopropyl-pyrrolidinyl)-[1,2,4]triazolo[4,3-
a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenylamine (Intermediate
58c)
To a suspension of NaH (60% in mineral oil, 142 mg, 3.56 mmol) in DMF
(2.00 mL) was added (1R,4S)amino-1,2,3,4-tetrahydro-naphthalenol
Intermediate A (145 mg, 0.88 mmol) and the reaction stirred for 20 min. A
solution of Intermediate 58b (220 mg, 0.88 mmol) in DMF (2.00 mL) was added
and the reaction heated to 60°C for 1 h. The reaction was cooled and quenched by
dropwise addition of methanol, before being diluted with methanol and loaded
onto an SCX-2 cartridge, which was washed with MeOH. The product was eluted
with 2M NH in MeOH; concentration in vacuo gave a residue. FCC, using 2-10%
[2M NH in MeOH] in DCM, gave the title compound (145 mg, 44%). LCMS
(Method 4): Rt 0.29 min, m/z 392.2 [MH ].
d. 1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-((S)
isopropyl-pyrrolidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-urea, partial formate salt (Example 58)
To a solution of Intermediate 58c (140 mg, 0.37 mmol) in 1,4-dioxane (3.00
mL) was added DIPEA (130 mL, 0.75 mmol) and (5-tert-butylp-tolyl-2H-
pyrazolyl)-carbamic acid 2,2,2-trichloro-ethyl ester (Synthetic
Communications, 2009, 39, 3999-4009; 151 mg, 0.37 mmol). The reaction was
heated to 60°C overnight then cooled and partitioned between EtOAc and water.
The aqueous layer was then extracted with EtOAc (3 ×). The combined organic
layers were washed with brine, dried (MgSO ), filtered and evaporated in vacuo.
The residue was purified by FCC, using 0-5% MeOH in DCM. Further purification
by HPLC (C18 X-select column, 10-98% MeCN in H O, 0.1% HCO H) gave the
title compound as a white powder after freeze-drying (60 mg, 25%). LCMS
(Method 5): Rt 3.84 min, m/z 647.3 [MH ]. ¹H NMR (400 MHz, d -MeOD): 0.99
(6H, d, J 6.5), 1.29 (9H, s), 1.90-2.06 (5H, m), 2.11 (1H, m), 2.22-2.36 (2H, m),
2.38 (3H, s), 2.73-2.84 (2H, m), 3.25 (1H, m), 4.59 (1H, t, J 7.3), 4.90 (1H, dd, J
9.1, 5.7), 5.29 (1H, t, J 4.1), 6.33 (1H, s), 7.20-7.36 (9H, m), 7.65 (1H, d, J 10.0),
8.25 (0.5H, br s), 8.42 (1H, d, J 1.8).
Example 59
1-(5-tert-Butylp-tolyl-2H-pyrazolyl)[(1S,4R)(3-
dimethylamino-[1,2,4]triazolo[4,3-a]pyridinyloxy)-1,2,3,4-tetrahydro-
naphthalenyl]-urea
a. 2-(5-Fluoropyridinyl)-N,N-dimethylhydrazine carboxamide
(Intermediate 59a)
A solution of (5-fluoro-pyridinyl)-hydrazine (500 mg, 3.93 mmol),
dimethylcarbamyl chloride (505 mg, 4.72 mmol) and DIPEA (1.01 g, 7.86 mmol)
in DCM (20 mL) was stirred at reflux for 16 h. The reaction mixture was applied
to an SCX-2 cartridge (25 g) and washed with MeOH. The product was eluted with
2M NH in MeOH; concentration in vacuo and then trituration with diethyl ether
gave the title compound (600 mg, 77%). ¹H NMR (400 MHz, CDCl ): 2.99 (6H, s),
6.46 (2H, m), 6.75 (1H, dd, J 9.1, 3.5), 7.22-7.32 (1H, m), 8.03 (1H, d, J 2.7).
b. (6-Fluoro-[1,2,4]triazolo[4,3-a]pyridinyl)-dimethyl-amine
(Intermediate 59b)
To a solution of Intermediate 59a (590 mg, 2.98 mmol), Ph P (1.56 g, 5.96
mmol) and Et N (1.20 g, 11.9 mmol) in THF (40 mL) was added hexachloroethane
(1.41 g, 5.96 mmol) and the mixture stirred at 60°C for 9 h. The mixture was
diluted with EtOAc (100 mL), washed with water, brine, dried (MgSO ) and then
concentrated in vacuo. The residue was purified by FCC, using 0-10% [2M NH in
MeOH] in DCM, then triturated with diethyl ether to give the title compound (78
mg, 14%). LCMS (Method 1): Rt 2.24 min, m/z 181 [MH ].
c. [6-((1R,4S)Amino-1,2,3,4-tetrahydro-naphthalenyloxy)-
[1,2,4]triazolo[4,3-a]pyridinyl]-dimethyl-amine (Intermediate 59c)
To a solution of Intermediate A (75 mg, 0.458 mmol) in DMF (2 mL) was
added NaH (60% in oil, 50 mg, 1.25 mmol) and the mixture stirred at RT for 20
min, before Intermediate 59b (75 mg, 0.416 mmol) was added. This mixture was
stirred at 60°C for 1 h. The reaction mixture was applied to an SCX-2 cartridge (10
g) and washed with MeOH. The product was eluted with 2M NH in MeOH;
concentration in vacuo gave a residue. FCC, using 0-10% [2M NH in MeOH] in
DCM gave the title compound as a yellow gum (82 mg, 61%). LCMS (Method 4):
Rt 1.49 min, m/z 324 [MH ].
d. 1-(5-tert-Butylp-tolyl-2H-pyrazolyl)[(1S,4R)(3-
dimethylamino-[1,2,4]triazolo[4,3-a]pyridinyloxy)-1,2,3,4-tetrahydro-
naphthalenyl]-urea (Example 59)
A solution of Intermediate 59c (80 mg, 0.25 mmol), (5-tert-butylp-tolyl-
2H-pyrazolyl)-carbamic acid 2,2,2-trichloro-ethyl ester (Synthetic
Communications, 2009, 39, 3999-4009; 150 mg, 0.370 mmol) and DIPEA (129
mg, 1.00 mmol) in DMF (2 mL) was stirred at 60°C for 30 min. The reaction
mixture was applied to an SCX-2 cartridge (10 g) and washed with MeOH. The
product was eluted with 2M NH in MeOH; concentration in vacuo gave a residue.
FCC, using 0-5% [2M NH in MeOH] in DCM, gave the title compound as an off-
white solid (75 mg, 52%). LCMS (Method 5): Rt 4.39 min, m/z 579.1 [MH ]. ¹H
NMR (400 MHz, d -MeOH): 1.29 (9H, s), 1.83-2.17 (3H, m), 2.17-3.00 (1H, m),
2.38 (3H, s), 2.92 (6H, s), 4.88 (1H, dd, J 8.5, 5.4), 5.41 (1H, t, J 3.0), 6.33 (1H, s),
7.14-7.36 (9H, m), 7.50 (1H, d, J 9.7), 7.70 (1H, d, J 1.4).
Example 60
1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-((R)
methyl-pyrrolidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-urea
a. 6-Fluoro((R)methyl-pyrrolidinyl)-[1,2,4]triazolo[4,3-
a]pyridine (Intermediate 60a)
A mixture of (5-fluoro-pyridinyl)-hydrazine (889 mg, 7.00 mmol), N-
methyl-D-proline hydrochloride (1.274 g, 7.7 mmol) and HOBt.H O (95 mg, 0.70
mmol) in DCM (20 mL) was treated with EDC (1.494 g, 7.8 mmol), and the
mixture stirred at RT for 6.5 h. The mixture was then diluted with sat. aq. NaHCO
solution, NaCl added, and the mixture extracted with DCM (8 × 20 mL). The
combined organics were dried and concentrated in vacuo to give (R)methyl-
pyrrolidinecarboxylic acid N'-(5-fluoro-pyridinyl)-hydrazide as a pale orange
solid (1.09 g).
This was dissolved in THF (20 mL) then Ph P (2.40 g, 9.16 mmol), Et N
(2.6 mL, 18.3 mmol), and hexachloroethane (2.17 g, 9.16 mmol) added
sequentially. The mixture was stirred at RT for 4 h, then was filtered, the filter-
cake washed with diethyl ether, and the combined organics concentrated in vacuo.
The residue was purified on a SCX-2 cartridge (50 g), washing with methanol then
eluting basic components with 0.2 – 2 M ammonia in methanol. Product
containing fractions were combined and concentrated in vacuo. The residue was
further purified by FCC, using 0-100% EtOAc in cyclohexane, then 8-10% MeOH
in EtOAc, to give the title compound as a pale red oil (876 mg, 57%). LCMS
(Method 3): Rt 0.55 min, m/z 221 [MH ].
b. (1S,4R)[3-((R)Methyl-pyrrolidinyl)-[1,2,4]triazolo[4,3-
a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenylamine (Intermediate
60b)
To a solution of Intermediate A (245 mg, 1.50 mmol) in DMF (4 mL) was
added NaH (60% dispersion in oil, 180 mg, 4.50 mmol) and the mixture stirred at
RT for 0.5 h. A solution of Intermediate 60a (330 mg, 1.50 mmol) in DMF (5 mL)
was added and the mixture stirred at 60°C for 2 h. The cooled solution was diluted
with water and extracted with DCM (5 × 20 mL). The combined organics were
dried and concentrated in vacuo. The residue was purified by FCC, using 0-15%
[2M NH in MeOH] in DCM, to give the title compound as a brown solid after
freeze-drying (408 mg, 74%). LCMS (Method 3): Rt 0.44 min, m/z 364 [MH ].
c. 1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-((R)
methyl-pyrrolidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-urea (Example 60)
A solution of Intermediate 60b (123 mg, 0.339 mmol) and (5-tert-butylp-
tolyl-2H-pyrazolyl)-carbamic acid 2,2,2-trichloro-ethyl ester (Synthetic
Communications, 2009, 39, 3999-4009; 140 mg, 0.346 mmol) in 1,4-dioxane (4
mL) and DIPEA (91 µL, 0.52 mmol) was stirred at 93°C for 3.25 h. The cooled
mixture was concentrated in vacuo. The residue was purified by FCC, using 0-20%
MeOH in DCM, to give the impure product. Further purification by HPLC (C18
X-select column, 25-70% MeCN in H O, 0.1% formic acid) gave the title
compound as a white powder after freeze-drying (118 mg, 56%). LCMS (Method
): Rt 3.67 min, m/z 619.2 [MH ]. ¹H NMR (400 MHz, d -DMSO): 1.27 (9H, s),
1.80-2.27 (11H, m), 2.31-2.40 (4H, m), 3.11-3.18 (1H, m), 3.98 (1H, t, J 8.2),
4.78-4.86 (1H, m), 5.42 (1H, t, J 4.3), 6.32 (1H, s), 7.09 (1H, d, J 8.5), 7.26-7.42
(9H, m), 7.75 (1H, dd, J 9.7, 1.0), 8.03 (1H, s), 8.28 (1H, d, J 1.0).
Example 61
1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-((S)ethyl-
pyrrolidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-
naphthalenyl}-urea
a. (S)Ethyl-pyrrolidinecarboxylic acid N'-(5-fluoro-pyridinyl)-
hydrazide (Intermediate 61a)
To a solution of (5-fluoro-pyridinyl)-hydrazine (178 mg, 1.39 mmol) in
DMF (10.0 mL) was added (S)ethyl-pyrrolidinecarboxylic acid (200 mg,
1.39 mmol), EDC (293 mg, 1.53 mmol) and HOBt.H O (18.0 mg, 0.14 mmol).
The reaction was stirred for 4 h then partitioned between EtOAc and water. The
aqueous layer was then extracted with EtOAc (3 ×). The combined organic layers
were washed with brine, dried (MgSO ), filtered and evaporated in vacuo. The
residue was purified by FCC, using 0-10% [2M NH in MeOH] in DCM, to give
the title compound (190 mg, 54%). LCMS (Method 4): Rt 0.29 min, m/z 253.1
[MH ].
b. 6-Fluoro((S)ethyl-pyrrolidinyl)-[1,2,4]triazolo[4,3-a]pyridine
(Intermediate 61b)
To a solution of Intermediate 61a (190 mg, 0.75 mmol), Ph P (395 mg, 1.51
mmol) and Et N (419 mL, 3.01 mmol) in THF (6.00 mL) at 0°C was added
hexachloroethane (357 mg, 1.51 mmol). The reaction was stirred at RT overnight
then partitioned between EtOAc and water. The aqueous layer was then extracted
with EtOAc (3 ×). The combined organic layers were washed with brine, dried
(MgSO ), filtered and evaporated in vacuo. The residue was dissolved in MeOH
and loaded onto an SCX-2 cartridge, which was washed with MeOH. The product
was eluted with 2M NH in MeOH; concentration in vacuo gave a residue. FCC,
using 0-10% [2M NH in MeOH] in DCM, gave the title compound (157 mg,
89%). LCMS (Method 2): Rt 0.28 min, m/z 235.2 [MH ].
c. (1S,4R)[3-((S)Ethyl-pyrrolidinyl)-[1,2,4]triazolo[4,3-
a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenylamine (Intermediate
61c)
To a suspension of NaH (60% in mineral oil, 107 mg, 2.68 mmol) in DMF
(2.00 mL) was added Intermediate A (110 mg, 0.67 mmol) and the reaction stirred
for 20 min. Intermediate 61b (150 mg, 0.67 mmol) was added in DMF (2.00 mL)
and the reaction heated to 60°C for 1 h. The reaction was cooled and quenched by
dropwise addition of methanol, before being diluted with methanol and loaded
onto an SCX-2 cartridge, which was washed with MeOH. The product was eluted
with 2M NH in MeOH; concentration in vacuo gave a residue. FCC, using 2-10%
[2M NH in MeOH] in DCM, gave the title compound (72.0 mg, 28%). LCMS
(Method 4): Rt 0.29 min, m/z 378.2 [MH ].
d. 1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-((S)
ethyl-pyrrolidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-urea (Example 61)
To a solution of Intermediate 61c (72.0 mg, 0.19 mmol) in 1,4-dioxane
(2.00 mL) was added DIPEA (66 mL, 0.38 mmol) and (5-tert-butylp-tolyl-2H-
pyrazolyl)-carbamic acid 2,2,2-trichloro-ethyl ester (Synthetic
Communications, 2009, 39, 3999-4009; 77.0 mg, 0.19 mmol). The reaction was
heated to 60°C overnight then cooled and partitioned between EtOAc and water.
The aqueous layer was then extracted with EtOAc (3 ×). The combined organic
layers were washed with brine, dried (MgSO ), filtered and evaporated in vacuo.
The residue was purified by FCC, using 0-7.5% MeOH in DCM. Further
purification by HPLC (C18 X-select column, 20-70% MeCN in H O, 0.1%
HCO H) gave the title compound as a white powder after freeze-drying (37 mg,
31%). LCMS (Method 5): Rt 3.73 min, m/z 633.2 [MH ]. ¹H NMR (400 MHz, d -
MeOD): 0.94 (3H, t, J 7.2), 1.30 (9H, s), 1.89-2.16 (6H, m), 2.22-2.31 (2H, m),
2.31-2.38 (2H, m), 2.38 (3H, s), 2.49 (1H, m), 3.32 (1H, m), 4.11 (1H, t, J 8.0),
4.90 (1H, dd, J 9.0, 5.6), 5.28 (1H, t, J 4.1), 6.33 (1H, s), 7.19-7.36 (9H, m), 7.65
(1H, dd, J 10.0, 0.7), 8.37 (1H, d, J 1.9).
Example 62
1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-((S)
methyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-urea
N N N
a. (S)Methyl-piperidinecarboxylic acid N'-(5-fluoro-pyridinyl)-
hydrazide (Intermediate 62a)
To a solution of (5-fluoro-pyridinyl)-hydrazine (250 mg, 1.96 mmol) in
DMF (20.0 mL) was added (S)methyl-piperidinecarboxylic acid (281 mg,
1.96 mmol), EDC (416 mg, 2.16 mmol) and HOBt.H O (25.0 mg, 0.20 mmol).
The reaction was stirred overnight then partitioned between EtOAc and water. The
aqueous layer was then extracted with EtOAc (3 ×). The combined organic layers
were washed with brine, dried (MgSO ), filtered and evaporated in vacuo. The
residue was taken up in MeOH and loaded onto an SCX-2 cartridge, which was
washed with MeOH. The product was eluted with 2M NH in MeOH;
concentration in vacuo gave residue. FCC, using 0-10% [2M NH in MeOH] in
DCM, gave the title compound (331 mg, 67%). LCMS (Method 1): Rt 0.35 min,
m/z 253.2 [MH ].
b. 6-Fluoro((S)methyl-piperidinyl)-[1,2,4]triazolo[4,3-
a]pyridine (Intermediate 62b)
To a solution of Intermediate 62a (331 mg, 1.31 mmol), Ph P (688 mg, 2.63
mmol) and Et N (731 mL, 5.25 mmol) in THF (13.0 mL) at 0°C was added
hexachloroethane (622 mg, 2.63 mmol). The reaction was stirred at RT overnight
then partitioned between EtOAc and water. The aqueous layer was then extracted
with EtOAc (3 ×). The combined organic layers were washed with brine, dried
(MgSO ), filtered and evaporated in vacuo. The residue was taken up in MeOH
and loaded onto an SCX-2 cartridge, which was washed with MeOH. The product
was eluted with 2M NH in MeOH; concentration in vacuo gave the title
compound (250 mg, 81%). LCMS (Method 4): Rt 0.31 min, m/z 235.1 [MH ].
c. (1S,4R)[3-((S)Methyl-piperidinyl)-[1,2,4]triazolo[4,3-
a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenylamine (Intermediate
62c)
To a suspension of NaH (60% in mineral oil, 171 mg, 4.27 mmol) in DMF
(4.00 mL) was added Intermediate A (175 mg, 1.07 mmol) and the reaction stirred
for 20 min. Intermediate 62b (250 mg, 1.07 mmol) was added in DMF (2.00 mL)
and the reaction heated to 60°C for one hour. The reaction was cooled and
quenched by dropwise addition of methanol, before being diluted with methanol
and loaded onto an SCX-2 cartridge, which was washed with MeOH and product
eluted with 2M NH in MeOH. The resulting residue was purified by FCC, using
2-10% [2M NH in MeOH] in DCM, to give the title compound (287 mg, 71%).
LCMS (Method 1): Rt 1.64, m/z 378.2 [MH ].
d. 1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-((S)
methyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-urea (Example 62)
To a solution of Intermediate 62c (140 mg, 0.37mmol) in 1,4-dioxane (4.00
mL) was added DIPEA (129 mL, 0.74 mmol) and (5-tert-butylp-tolyl-2H-
pyrazolyl)-carbamic acid 2,2,2-trichloro-ethyl ester (Synthetic
Communications, 2009, 39, 3999-4009; 150 mg, 0.37 mmol). The reaction was
heated to 60°C overnight then cooled and partitioned between EtOAc and water.
The aqueous layer was then extracted with EtOAc (3 ×). The combined organic
layers were washed with brine, dried (MgSO ), filtered and evaporated in vacuo.
The residue was purified by FCC, using 0-7.5% MeOH in DCM. Further
purification by HPLC (C18 X-select column, 10-98% MeCN in H O, 0.1%
HCO H) gave the title compound as a white powder after freeze-drying (73 mg,
31%). LCMS (Method 5): Rt 3.75 min, m/z 633.2 [MH ]. ¹H NMR (400 MHz, d -
MeOD): 1.30 (9H, s), 1.45 (1H, m), 1.60-1.83 (3H, m), 1.83-1.93 (2H, m), 1.93-
2.07 (5H, m), 2.11 (1H, m), 2.20-2.33 (2H, m), 2.38 (3H, s), 3.05 (1H, dt, J 11.8,
2.8), 3.79 (1H, dd, J 10.9, 2.8), 4.91 (1H, dd, J 9.0, 5.7), 5.32 (1H, t, J 4.0), 6.33
(1H, s), 7.19-7.36 (9H, m), 7.64 (1H, d, J 10.0), 8.43 (1H, d, J 1.7).
Example 63
1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-((S)
hydroxy-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-urea
a. (S)(6-Fluoro-[1,2,4]triazolo[4,3-a]pyridinyl)-piperidinol
(Intermediate 63a)
A mixture of Intermediate 24b (394 mg, 2.30 mmol), (S)
hydroxypiperidine hydrochloride (1.00 g, 7.27 mmol) and DIPEA (1.27 mL, 7.30
mmol) in DMA (8 mL) was heated in the microwave at 170-180°C for 9.5 h. The
cooled mixture was concentrated in vacuo and applied to an SCX-2 cartridge (70
g), washing with methanol then eluting basic components with 0.4 – 2 M ammonia
in methanol. Product containing fractions were combined and concentrated in
vacuo. The residue was purified by FCC, using 0-20% MeOH in DCM, to give the
title compound as a pale brown solid (204 mg, 38%). LCMS (Method 3): Rt 2.02
min, m/z 237 [MH ].
b. 6-Fluoro((S)triisopropylsilanyloxy-piperidinyl)-
[1,2,4]triazolo[4,3-a]pyridine (Intermediate 63b)
To a solution of Intermediate 63a (204 mg, 0.864 mmol) and Et N (180 µL,
1.3 mmol) in DCM (5 mL) was added triisopropylsilyltrifluoromethane sulfonate
(279 µL, 1.04 mmol) and the mixture stirred at RT for 1 h. The mixture was
washed with sat. aq. NaHCO solution, dried and concentrated in vacuo. The
residue was purified by FCC, using 0-100% EtOAc in cyclohexane, then 10%
MeOH in EtOAc, to give the title compound as a pale brown gum (290 mg, 86%).
LCMS (Method 3): Rt 4.99 min, m/z 393 [MH ].
c. (1S,4R)[3-((S)Triisopropylsilanyloxy-piperidinyl)-
[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalen
ylamine (Intermediate 63c)
To a solution of Intermediate A (116 mg, 0.714 mmol) in DMF (3 mL) was
added NaH (60% dispersion in oil, 44 mg, 1.1 mmol) and the mixture stirred at RT
for 20 min. A solution of Intermediate 63b (280 mg, 0.714 mmol) in DMF (3 mL)
was added and the mixture was stirred at 60°C for 25 min, and up to 150°C over
min. The cooled mixture was diluted with water and extracted with DCM (4 ×
mL). The combined organics were dried and concentrated in vacuo. The residue
was purified twice by FCC, using 0-12% [2M NH in MeOH] in DCM, to give the
title compound as a dark brown gum (141 mg, 37%). LCMS (Method 3): Rt 3.12
min, m/z 536 [MH ].
d. 1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-((S)
triisopropylsilanyloxy-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-
1,2,3,4-tetrahydro-naphthalenyl}-urea (Intermediate 63d)
A solution of Intermediate 63c (140 mg, 0.261 mmol) and (5-tert-butylp-
tolyl-2H-pyrazolyl)-carbamic acid 2,2,2-trichloro-ethyl ester (Synthetic
Communications, 2009, 39, 3999-4009; 106 mg, 0.261 mmol) in 1,4-dioxane (3
mL) and DIPEA (70 µL, 0.4 mmol) was stirred at 90°C for 3 h. The cooled
mixture was concentrated in vacuo. The residue was purified by FCC, using 0-10%
MeOH in DCM, to give the title compound as a pale brown gum (124 mg, 60%).
LCMS (Method 3): Rt 5.43 min, m/z 791 [MH ].
e. 1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-((S)
hydroxy-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-urea (Example 63)
A solution of Intermediate 63d (123 mg, 0.156 mmol) and TBAF (1M in
THF, 195 µL, 0.195 mmol) in THF (4 mL) was stirred at RT for 1 h. The mixture
was diluted with water and extracted with DCM (4 × 15 mL). The combined
organics were dried and concentrated in vacuo. The residue was purified by FCC,
using 0-12% [2M NH in MeOH] in DCM, to give the title compound as a white
powder after freeze-drying (82 mg, 83%). LCMS (Method 5): Rt 4.27 min, m/z
635.2 [MH ]. ¹H NMR (400 MHz, d -DMSO): 1.27 (9H, s), 1.38-1.47 (1H, m),
1.62-1.74 (1H, m), 1.79-1.98 (4H, m), 1.99-2.16 (2H, m), 2.36 (3H, s), 2.78-2.86
(1H, m), 2.89-2.98 (1H, m), 3.20-3.36 (2H, m, under water signal), 3.77-3.86 (1H,
m), 4.77-4.86 (1H, m), 4.90 (1H, d, J 5.2), 5.53 (1H, t, J 4.3), 6.32 (1H, s), 7.08
(1H, d, J 8.7), 7.16 (1H, dd, J 10.1, 2.1), 7.26-7.41 (8H, m), 7.61 (1H, d, J 10.0),
7.69 (1H, d, J 1.4), 8.03 (1H, s).
Example 64
1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-((R)
hydroxy-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-urea
The title compound was prepared starting from (R)hydroxypiperidine
hydrochloride using analogous procedures to those described for Example 63.
LCMS (Method 5): Rt 4.27 min, m/z 635.2 [MH ]. ¹H NMR (400 MHz, d6-
DMSO): 1.27 (9H, s), 1.36-1.47 (1H, m), 1.65-1.76 (1H, m), 1.77-1.98 (4H, m),
1.99-2.17 (2H, m), 2.36 (3H, s), 2.78-2.85 (1H, m), 2.87-2.95 (1H, m), 3.20-3.37
(2H, m, under water signal), 3.75-3.84 (1H, m), 4.78-4.85 (1H, m), 4.90 (1H, d, J
.0), 5.51 (1H, t, J 4.3), 6.32 (1H, s), 7.08 (1H, d, J 8.4), 7.17 (1H, dd, J 10.0, 2.2),
7.26-7.41 (8H, m), 7.61 (1H, d, J 10.0), 7.69 (1H, d, J 1.4), 8.03 (1H, s).
Example 65
1-[5-tert-Butyl(4-hydroxymethyl-phenyl)-2H-pyrazolyl]
{(1S,4R)[3-((S)methyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridin
yloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea, partial formate salt
(0.5 eq)
To a solution of Intermediate 62c (117 mg, 0.31 mmol) in 1,4-dioxane (3.00
mL) was added DIPEA (108 mL, 0.62 mmol) and Intermediate 33a (130 mg, 0.31
mmol). The reaction was heated to 60°C overnight then cooled and partitioned
between EtOAc and water. The aqueous layer was then extracted with EtOAc (3
×). The combined organic layers were washed with brine, dried (MgSO ), filtered
and evaporated in vacuo. The residue was purified by FCC, using 0-10% MeOH in
DCM. Further purification by HPLC (C18 X-select column, 10-98% MeCN in
H O, 0.1% HCO H) gave the title compound as a white powder after freeze-drying
(80 mg, 39%). LCMS (Method 5): Rt 3.31 min, m/z 649.3 [MH ]. ¹H NMR (400
MHz, d -MeOD): 1.31 (9H, s), 1.49 (1H, m), 1.60-2.05 (7H, m), 2.05 (3H, s), 2.10
(1H, m), 2.25-2.35 (2H, m), 3.09 (1H, m), 3.87 (1H, dd, J 10.9, 2.4), 4.65 (2H, s),
4.91 (1H, m), 5.33 (1H, t, J 4.0), 6.34 (1H, s), 7.19-7.33 (5H, m), 7.42-7.51 (4H,
m), 7.65 (1H, d, J 9.6), 8.26 (0.5H, br s), 8.43 (1H, d, J 1.7).
Example 66
1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-(4-
hydroxyethyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-urea
a. [1-(6-Fluoro-[1,2,4]triazolo[4,3-a]pyridinyl)-piperidinyl]-
ethanol (Intermediate 66a)
A mixture of Intermediate 24b (542 mg, 3.17 mmol) and 4-piperidine-
ethanol (1.54 g, 11.9 mmol) in DMA (10 mL) was heated in the microwave at
170°C for 3 h. The cooled mixture was applied to an SCX-2 cartridge (50 g),
washing with methanol then eluting basic components with 0.4 – 2 M ammonia in
methanol. Product containing fractions were combined and concentrated in vacuo.
The residue was purified by FCC, using 0-20% MeOH in DCM, to give the title
compound as a pale brown solid (324 mg, 41%). LCMS (Method 3): Rt 2.28 min,
m/z 265 [MH ].
b. 6-Fluoro(4-triisopropylsilanyloxyethyl-piperidinyl)-
[1,2,4]triazolo[4,3-a]pyridin (Intermediate 66b)
O Si
To a solution of Intermediate 66a (319 mg, 1.21 mmol) and Et N (252 µL,
1.82 mmol) in DCM (10 mL) was added triisopropylsilyltrifluoromethane
sulfonate (319 µL, 1.45 mmol) and the mixture stirred at RT for 1.5 h. The mixture
was washed with sat. aq. NaHCO solution, dried and concentrated in vacuo. The
residue was purified by FCC, using 0-10% MeOH in DCM, to give the title
compound as an orange solid (465 mg, 92%). LCMS (Method 3): Rt 5.35 min, m/z
421 [MH ].
c. (1S,4R)[3-(4-Triisopropylsilanyloxyethyl-piperidinyl)-
[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalen
ylamine (Intermediate 66c)
O Si
To a solution of Intermediate A (122 mg, 0.75 mmol) in DMF (3 mL) was
added NaH (60% dispersion in oil, 60 mg, 1.5 mmol) and the mixture stirred at RT
for 25 min. A solution of Intermediate 66b (315 mg, 0.75 mmol) in DMF (2.5 mL)
was added and the mixture stirred at 60°C for 1.5 h. The cooled mixture was
diluted with water and extracted with DCM (5 × 25 mL). The combined organics
were dried and concentrated in vacuo. The residue was purified by FCC, using 0-
14% [2M NH in MeOH] in DCM, to give the title compound as a dark brown gum
(180 mg, 42%). LCMS (Method 3): Rt 3.35 min, m/z 564 [MH ].
d. 1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-(4-
triisopropylsilanyloxyethyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridin
yloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea (Intermediate 66d)
O Si
A mixture of Intermediate 66c (178 mg, 0.316 mmol) and (5-tert-butylp-
tolyl-2H-pyrazolyl)-carbamic acid 2,2,2-trichloro-ethyl ester (Synthetic
Communications, 2009, 39, 3999-4009; 128 mg, 0.316 mmol) in 1,4-dioxane (3
mL) and DIPEA (83 µL, 0.474 mmol) was stirred at 95°C for 4 h. The cooled
mixture was concentrated in vacuo. The residue was purified by FCC, using 0-10%
MeOH in DCM, to give the title compound as a brown foam (208 mg, 81%).
LCMS (Method 3): Rt 5.96 min, m/z 819 [MH ].
e. 1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-(4-
hydroxyethyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-urea (Example 66)
A solution of Intermediate 66d (207 mg, 0.253 mmol) and TBAF (1M in
THF, 0.303 mL, 0.303 mmol) in THF (4 mL) was stirred at RT for 2.25 h. The
mixture was diluted with water and extracted with DCM (4 × 15 mL). The
combined organic extracts were dried and concentrated in vacuo. The residue was
purified by FCC, using 0-15% MeOH in DCM, to give the product. This was
further purified by HPLC (C18 X-select column, 30-98% MeCN in H O, 0.1%
formic acid) to give the title compound as an off-white powder after freeze-drying
(114 mg, 68%). LCMS (Method 5): Rt 4.29 min, m/z 663.3 [MH ]. ¹H NMR (400
MHz, d -DMSO): 1.27 (9H, s), 1.38-1.51 (4H, m), 1.57-1.68 (1H, m), 1.72-1.97
(4H, m), 1.99-2.16 (2H, m), 2.36 (3H, s), 2.85-2.95 (2H, m), 3.30-3.52 (4H, m,
under water signal), 4.38 (1H, s), 4.77-4.85 (1H, m), 5.55 (1H, t, J 4.3), 6.32 (1H,
s), 7.09 (1H, d, J 8.6), 7.16 (1H, dd, J 9.9, 2.2), 7.26-7.40 (8H, m), 7.61 (1H, d, J
9.9), 7.65 (1H, d, J 1.4), 8.06 (1H, s).
Example 67
1-[(1S,4R)(3-Azepanyl-[1,2,4]triazolo[4,3-a]pyridinyloxy)-
1,2,3,4-tetrahydro-naphthalenyl](5-tert-butylp-tolyl-2H-pyrazolyl)-
urea
a. 6-Fluoroazepanyl-[1,2,4]triazolo[4,3-a]pyridine (Intermediate
67a)
A solution of Intermediate 24b (451 mg, 2.50 mmol) and azapane (990 mg,
.0 mmol) in DMA (10 mL) was heated in the microwave at 175-180°C for 6 h.
The mixture was concentrated in vacuo. The residue was purified by FCC, using 0-
20% MeOH in DCM, to give impure product. Further purification by FCC, using
0-12% MeOH in DCM, gave impure product. Further purification by FCC, using
0-6% MeOH in EtOAc, gave the title compound as a green gum (260 mg, 44%).
LCMS (Method 3): Rt 2.76 min, m/z 235 [MH ].
b. (1S,4R)(3-Azepanyl-[1,2,4]triazolo[4,3-a]pyridinyloxy)-
1,2,3,4-tetrahydro-naphthalenylamine (Intermediate 67b)
To a solution of Intermediate A (137 mg, 0.84 mmol) in DMF (3 mL) was
added NaH (60% dispersion in oil, 68 mg, 1.7 mmol) and the mixture stirred at RT
for 25 min. A solution of Intermediate 67a (197 mg, 0.84 mmol) in DMF (3 mL)
was added and the mixture stirred at 60°C for 1.25 h. The cooled mixture was
diluted with water and extracted with DCM (5 × 20 mL). The combined organics
were dried and concentrated in vacuo. The residue was purified by FCC, using 0-
14% [2M NH in MeOH] in DCM, to give the title compound as a dark brown gum
(175 mg, 55%). LCMS (Method 3): Rt 2.22 min, m/z 378 [MH ].
c. 1-[(1S,4R)(3-Azepanyl-[1,2,4]triazolo[4,3-a]pyridinyloxy)-
1,2,3,4-tetrahydro-naphthalenyl](5-tert-butylp-tolyl-2H-pyrazolyl)-
urea (Example 67)
A solution of Intermediate 67b (173 mg, 0.458 mmol) and (5-tert-butylp-
tolyl-2H-pyrazolyl)-carbamic acid 2,2,2-trichloro-ethyl ester (Synthetic
Communications, 2009, 39, 3999-4009; 186 mg, 0.458 mmol) in 1,4-dioxane (3
mL) and DIPEA (122 µL, 0.700 mmol) was stirred at 95°C for 3.5 h. The cooled
mixture was concentrated in vacuo. The residue was purified by FCC, using 0-14%
[2M NH in MeOH] in DCM. Further purification by FCC, using 0-10% MeOH in
DCM, gave impure product. This was further purified by HPLC (C18 X-select
column, 30-98% MeCN in H O, 0.1% HCO H) to give impure product. Further
purified by HPLC (XBridge column, 35-98% MeCN in H O, 0.1% NH OH) to
give an off-white powder after freeze-drying (50 mg). This material was further
purified by MDAP (Method 7) to give the title compound as a white solid (28 mg,
10%). LCMS (Method 5): Rt 4.77 min, m/z 633.2 [MH ]. ¹H NMR (400 MHz, d -
DMSO): 1.27 (9H, s), 1.64-1.71 (4H, m), 1.74-1.97 (6H, m), 1.99-2.18 (2H, m),
2.36 (3H, s), 3.38-3.43 (4H, m, under water signal), 4.77-4.85 (1H, m), 5.47 (1H, t,
J 4.3), 6.32 (1H, s), 7.07-7.14 (2H, m), 7.25-7.40 (8H, m), 7.55-7.59 (2H, m), 8.06
(1H, s).
Example 68
1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-(4-methyl-
piperazinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-
naphthalenyl}-urea
a. 6-Fluoro(4-methyl-piperazinyl)-[1,2,4]triazolo[4,3-a]pyridine
(Intermediate 68a)
A solution of Intermediate 24b (451 mg, 2.50 mmol) and N-methyl-
piperazine (1.11 mL, 10.0 mmol) in DMA (10 mL) was heated in the microwave at
170°C for 8 h. The mixture was concentrated in vacuo. The residue was purified
by FCC, using 0-20% [2M NH in MeOH] in DCM, to give the title compound as
an orange gum (190 mg, 32%). LCMS (Method 3): Rt 0.43 min, m/z 236 [MH ].
b. (1S,4R)[3-(4-Methyl-piperazinyl)-[1,2,4]triazolo[4,3-a]pyridin-
6-yloxy]-1,2,3,4-tetrahydro-naphthalenylamine (Intermediate 68b)
To a solution of Intermediate A (125 mg, 0.766 mmol) in DMF (3 mL) was
added NaH (60% dispersion in oil, 62 mg, 1.54 mmol) and the mixture stirred at
RT for 0.5 h. A solution of Intermediate 68a (180 mg, 0.766 mmol) in DMF (3
mL) was added and the mixture stirred at 60°C for 1.75 h. The cooled mixture was
diluted with water and extracted with DCM (5 × 25 mL). The combined organics
were dried and concentrated in vacuo. The residue was purified by FCC, using 0-
% [2M NH in MeOH] in DCM, to give the title compound as a pale brown gum
(225 mg, 78%). LCMS (Method 3): Rt 0.44 min, m/z 379 [MH ].
c. 1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-(4-methyl-
piperazineyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-
naphthalenyl}urea (Example 68)
A solution of Intermediate 68b (215 mg, 0.560 mmol) and (5-tert-butylp-
tolyl-2H-pyrazolyl)-carbamic acid 2,2,2-trichloro-ethyl ester (Synthetic
Communications, 2009, 39, 3999-4009; 226 mg, 0.560 mmol) in 1,4-dioxane (3
mL) and DIPEA (146 µL, 0.840 mmol) was stirred at 65°C for 18 h. The cooled
mixture was concentrated in vacuo. The residue was purified by FCC, using 10%
MeOH in DCM, then 0-14% [2M NH in MeOH] in DCM, to give impure product.
Further purification by HPLC (XBridge C18 column, 35-95% MeCN in H O,
0.1% NH OH) gave the title compound as a white powder after freeze-drying (205
mg, 58%). LCMS (Method 5): Rt 3.58 min, m/z 634.2 [MH ]. ¹H NMR (400 MHz,
d -DMSO): 1.27 (9H, s), 1.79-1.98 (2H, m), 1.99-2.15 (2H, m), 2.26 (3H, s), 2.36
(3H, s), 2.52-2.57 (4H, m), 3.15-3.24 (4H, m), 4.78-4.85 (1H, m), 5.56 (1H, t, J
4.4), 6.33 (1H, s), 7.07 (1H, d, J 8.6), 7.15 (1H, dd, J 9.9, 2.1), 7.26-7.40 (8H, m),
7.62 (1H, d, J 9.9), 7.68 (1H, d, J 1.8), 8.04 (1H, s).
Example 69
1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-(4-methyl-
[1,4]diazepanyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-
naphthalenyl}urea
a. 6-Fluoro(4-methyl-[1,4]diazepanyl)-[1,2,4]triazolo[4,3-
a]pyridine (Intermediate 69a)
A solution of Intermediate 24b (451 mg, 2.50 mmol) and 1-methyl-
[1,4]diazepane (1.14 g, 10.0 mmol) in DMA (10 mL) was heated in the microwave
at 175°C for 6 h. The cooled mixture was concentrated in vacuo. The residue was
purified by FCC, using 0-20% [2M NH in MeOH] in DCM, to give the title
compound as a brown oil (480 mg, 77%). LCMS (Method 3): Rt 0.44 min, m/z 250
[MH ].
b. (1S,4R)[3-(4-Methyl-[1,4]diazepanyl)-[1,2,4]triazolo[4,3-
a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenylamine (Intermediate
69b)
To a solution of Intermediate A (183 mg, 1.12 mmol) in DMF (3 mL) was
added NaH (60% dispersion in oil, 149 mg, 2.24 mmol) and the mixture stirred at
RT for 0.5 h. A solution of Intermediate 69a (400 mg, 1.12 mmol) in DMF (3 mL)
was added and the mixture stirred at 60°C for 1.5 h. The cooled mixture was
diluted with water and extracted with DCM (3 × 20 mL) and DCM-MeOH (4:1, 2
× 25 mL). The combined organics were dried and concentrated in vacuo. The
residue was purified by FCC, using 0-25% [2M NH in MeOH] in DCM, to give
the title compound as a dark brown gum (179 mg, 41%). LCMS (Method 3): Rt
0.44 min, m/z 393 [MH ].
c. 1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-(4-methyl-
[1,4]diazepanyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-
naphthalenyl}urea (Example 69)
A solution of Intermediate 69b (170 mg, 0.43 mmol) and (5-tert-butylp-
tolyl-2H-pyrazolyl)-carbamic acid 2,2,2-trichloro-ethyl ester (Synthetic
Communications, 2009, 39, 3999-4009; 174 mg, 0.43 mmol) in 1,4-dioxane (3
mL) and DIPEA (113 µL, 0.65 mmol) was stirred at 65°C for 18 h. The cooled
mixture was concentrated in vacuo. The residue was purified by FCC, using 10%
MeOH in DCM, then 0-15% [2M NH in MeOH] in DCM, to give impure product.
Further purification by HPLC (XBridge C18 column, 35-95% MeCN in H O,
0.1% NH OH) gave the title compound as a white powder after freeze-drying (186
mg, 67%). LCMS (Method 5): Rt 3.57 min, m/z 648.2 [MH ]. ¹H NMR (400 MHz,
d -DMSO): 1.27 (9H, s), 1.79-1.98 (4H, m), 2.00-2.18 (2H, m), 2.31 (3H, s), 2.36
(3H, s), 2.62-2.67 (2H, m), 2.68-2.73 (2H, m), 3.44-3.52 (4H, m), 4.78-4.85 (1H,
m), 5.49 (1H, t, J 4.4), 6.32 (1H, s), 7.08 (1H, d, J 8.5), 7.11 (1H, dd, J 9.7, 2.0),
7.26-7.40 (8H, m), 7.58 (1H, d, J 9.7), 7.63 (1H, d, J 1.9), 8.03 (1H, s).
Example 70
1-[5-tert-Butyl(4-hydroxy-phenyl)-2H-pyrazolyl][(1S,4R)(3-
piperidinyl-[1,2,4]triazolo[4,3-a]pyridinyloxy)-1,2,3,4-tetrahydro-
naphthalenyl]-urea
a. 1-{5-tert-Butyl[4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-2H-
pyrazolyl}[(1S,4R)(3-piperidinyl-[1,2,4]triazolo[4,3-a]pyridin
yloxy)-1,2,3,4-tetrahydro-naphthalenyl]-urea (Intermediate 70a)
The title compound was synthesised from 5-tert-butyl[4-(tert-butyl-
dimethyl-silanyloxy)-phenyl]-2H-pyrazolylamine (ref: US2006/035922) and
Intermediate 3c using analogous procedures to those used in the preparation of
Example 30. Beige solid. LCMS (Method 3) Rt 4.78 min, m/z 735 [MH ].
b. 1-[5-tert-Butyl(4-hydroxy-phenyl)-2H-pyrazolyl][(1S,4R)
(3-piperidinyl-[1,2,4]triazolo[4,3-a]pyridinyloxy)-1,2,3,4-tetrahydro-
naphthalenyl]-urea (Example 70)
A mixture of Intermediate 70a (124 mg, 169 µmol) and TBAF (1M in THF,
0.34 mL, 0.34 mmol) in THF (5 mL) was stirred for 1 h. The mixture was diluted
with water and extracted with EtOAc (3 ×). The combined organic extracts were
washed with brine, and concentrated in vacuo. The residue was purified by FCC,
using 0-20% MeOH in DCM, then further purified by HPLC (30-98% MeCN in
H O, 0.1% HCO H) to give the title compound as an off-white solid (18.4 mg,
18%). LCMS (Method 5) Rt 4.22 min, m/z 621 [MH ]. ¹H NMR (400 MHz, d -
DMSO): 1.25 (9H, s), 1.61 (2H, m), 1.72 (4H, m), 1.79-1.98 (2H, m), 1.99-2.15
(2H, m), 3.13 (4H, m), 4.81 (1H, m), 5.54 (1H, t, J 4.5), 6.29 (1H, s), 6.85 (2H, m),
7.09 (1H, d, J 8.7), 7.14 (1H, dd, J 9.7, 2.0), 7.20-7.39 (6H, m), 7.59-7.64 (2H, m),
7.95 (1H, s), 9.77 (1H, br s).
Example 71
1-[5-tert-Butyl(4-cyano-phenyl)-2H-pyrazolyl][(1S,4R)(3-
piperidinyl-[1,2,4]triazolo[4,3-a]pyridinyloxy)-1,2,3,4-tetrahydro-
naphthalenyl]-urea
a. 4-(5-Aminotert-butyl-pyrazolyl)-benzonitrile (Intermediate
71a)
A cream suspension of 4-cyanophenylhydrazine hydrochloride (1.70 g, 10.0
mmol) and 4,4-dimethyloxopentanenitrile (1.31 g, 10.5 mmol) in EtOH (25 mL)
was stirred at reflux for 4 h, then at RT for 64 h, and again at reflux for 24 h. The
solution was cooled to RT, concentrated in vacuo, and partitioned between water
(50 mL) and EtOAc (75 mL). The organics were washed with brine (50 mL), dried
(Na SO ), filtered and concentrated in vacuo to leave an orange solid (2.28 g,
95%). LCMS (Method 3): Rt 3.45 min, m/z 241 [MH ].
b. [5-tert-Butyl(4-cyano-phenyl)-2H-pyrazolyl]-carbamic acid
2,2,2-trichloro-ethyl ester (Intermediate 71b)
N Cl
To a suspension of Intermediate 71a (2.28 g, 9.49 mmol) in EtOAc (25 mL)
and aqueous NaOH (1M, 23.7 mL, 23.7 mmol) was added 2,2,2-trichloroethyl
chloroformate (1.57 mL, 11.4 mmol) dropwise over 2 min. A precipitate formed
which redissolved after 15 min, then the orange solution was stirred at RT for 90
min. 2,2,2-Trichloroethyl chloroformate (0.391 mL, 2.85 mmol) was added and the
orange mixture stirred at RT for 16 h. The layers were separated and the aqueous
extracted with EtOAc (25 mL). The combined organics were washed with brine
(25 mL), dried (Na SO ), filtered and concentrated in vacuo to leave an orange-red
oil. Recrystallisation from cyclohexane gave an off-white solid (3.12 g, 79%).
LCMS (Method 3): Rt 4.46 min, m/z 415, 417 [MH ].
c. 1-[5-tert-Butyl(4-cyano-phenyl)-2H-pyrazolyl][(1S,4R)(3-
piperidinyl-[1,2,4]triazolo[4,3-a]pyridinyloxy)-1,2,3,4-tetrahydro-
naphthalenyl]-urea (Example 71)
A brown solution of Intermediate 71b (114 mg, 0.275 mmol), Intermediate
3c (91.0 mg, 0.250 mmol) and DIPEA (0.054 mL, 0.313 mmol) in dioxane (3 mL)
was stirred at 60°C for 16 h. The cooled solution was concentrated in vacuo, the
residue suspended in water (4 mL) and extracted with DCM (2 × 4 mL). The
combined organics were passed through a hydrophobic frit and concentrated in
vacuo. FCC, using 3% [2M NH in MeOH] in DCM, gave a pale yellow solid
(99.5 mg, 63%). LCMS (Method 5): Rt 4.63 min, m/z 630 [MH ]. ¹H NMR (400
MHz, d -DMSO): 1.29 (9H, s), 1.60-1.64 (2H, m), 1.70-1.76 (4H, m), 1.86-1.94
(2H, m), 1.99-2.07 (1H, m), 2.11-2.18 (1H, m), 3.14 (4H, t, J 5.2), 4.79 (1H, m),
.54 (1H, t, J 4.3), 6.38 (1H, s), 7.12 (1H, d, J 8.6), 7.16 (1H, dd, J 9.8, 2.2), 7.25
(1H, d, J 7.7), 7.27-7.37 (2H, m), 7.39 (1H, d, J 7.6), 7.60-7.63 (2H, m), 7.78 (2H,
d, J 8.6), 7.98 (2H, d, J 8.6), 8.30 (1H, s).
Example 72
1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4S)[3-((S)methyl-
pyrrolidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-
naphthalenyl}-urea
a. (1S,4S)[3-((S)Methyl-pyrrolidinyl)-[1,2,4]triazolo[4,3-
a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenylamine. (Intermediate
72a)
A solution of Intermediate B (179 mg, 1.10 mmol) in dry DMF (2.5 mL)
was added NaH (60% in mineral oil, 333 mg, 5.00 mmol) at RT and stirred for 15
min. Intermediate 5b (220 mg, 1.00 mmol) in DMF (2.5 mL) was then added and
the mixture heated at 60°C for 1 h. After cooling, the resulting dark brown mixture
was diluted with water and extracted with DCM. The combined organics were
dried and concentrated in vacuo. The residue was purified by FCC, using 0-10%
MeOH in DCM, to give a residue. FCC, using 0-10% [2M NH3 in MeOH] in
DCM, gave the title compound as light brown powder after freeze drying (224 mg,
61%). LCMS (Method 3): Rt 1.34 min, m/z 364 [MH ].
b. 1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4S)[3-((S)
methyl-pyrrolidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-urea (Example 72)
A stirred solution of Intermediate 72a (219 mg, 0.60 mmol) and 5-tert-
butylp-tolyl-2H-pyrazolyl)-carbamic acid 2,2,2-trichloro-ethyl ester
(Synthetic Communications, 2009, 39, 3999-4009; 269 mg, 0.66 mmol) and
DIPEA (317 µL, 1.14 mmol) in THF (6 mL) was heated at reflux for 23 h. The
cooled reaction mixture was diluted with water and extracted with DCM. The
combined organics were dried and concentrated in vacuo. The residue was purified
by FCC, using 0-5% [2M NH in MeOH] in DCM, to give impure product. This
residue was purified further by HPLC (ChiralPak IC column, 50% IPA in
heptanes) to give the title compound as a white powder after freeze-drying (225
mg, 60%). LCMS (Method 5): Rt 3.65 min, m/z 619 [MH ]. ¹H NMR (400 MHz,
d -DMSO): 1.26 (9H, s), 1.74 (1H, m), 1.93-1.99 (3H, m), 2.08 (3H, s), 2.13-2.20
(4H, m), 2.32 (1H, m), 2.36 (3H, s), 3.14 (1H, td, J 8.1, 2.5), 3.95 (1H, t, J 8.1),
4.90 (1H, m), 5.48 (1H, t, J 4.0), 6.32 (1H, s), 7.00 (1H, d, J 8.2), 7.33-7.45 (9H,
m), 7.74 (1H, dd, J 9.9, 0.8), 7.98 (1H, s), 8.24 (1H, d, J 2.1).
Example 73
1-[5-tert-Butyl(4-hydroxy-phenyl)-2H-pyrazolyl]{(1S,4R)[3-
((S)methyl-pyrrolidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-urea
a. 1-{5-tert-Butyl[4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-2H-
pyrazolyl}{(1S,4R)[3-((S)methyl-pyrrolidinyl)-
[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-
urea (Intermediate 73a)
The title compound was synthesised from 5-tert-butyl[4-(tert-butyl-
dimethyl-silanyloxy)-phenyl]-2H-pyrazolylamine (ref: US2006/035922) and
Intermediate 5c using analogous procedures to those used in the preparation of
Example 30. Yellow powder. LCMS (Method 3): Rt 3.59 min, m/z 735 [MH ].
b. 1-[5-tert-Butyl(4-hydroxy-phenyl)-2H-pyrazolyl]{(1S,4R)
[3-((S)methyl-pyrrolidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-urea (Example 73)
A solution of Intermediate 73a (160 mg, 0.21 mmol) and TBAF (1M in
THF, 0.26 mL, 0.26 mmol) in THF (2 mL) was stirred at RT for 30 min, then
diluted with water and extracted with DCM (3 × 20 mL). The combined organics
were dried and concentrated in vacuo. The residue was purified by FCC, using 0-
% [2M NH in MeOH] in DCM, to give the title compound as a white powder
after freeze-drying (107 mg, 79%). LCMS (Method 5): Rt 3.24 min, m/z 621
[MH ]. ¹H NMR (400 MHz, d6-DMSO): 1.26 (9H, s), 1.81-2.25 (11H, m), 2.34-
2.36 (1H, m), 3.12-3.14 (1H, m), 3.99 (1H, t, J 8.2), 4.81-4.84 (1H, m), 5.39 (1H, t,
J 4.3), 6.29 (1H, s), 6.85-6.88 (2H, m), 7.09 (1H, d, J 8.6), 7.28-7.39 (7H, m), 7.75
(1H, dd, J 9.9, 0.8), 7.92 (1H, s), 8.24 (1H, d, J 2.1), 9.72 (1H, s).
Example 74
1-(5-tert-Butylp-tolyl-2H-pyrazolyl)((1S,4R){3-[4-(1-
hydroxymethyl-ethyl)-piperidinyl]-[1,2,4]triazolo[4,3-a]pyridin
yloxy}-1,2,3,4-tetrahydro-naphthalenyl)-urea
a. 2-[1-(6-Fluoro-[1,2,4]triazolo[4,3-a]pyridinyl)-piperidinyl]-
propanol (Intermediate 74a)
A brown solution of Intermediate 24b (666 mg, 3.88 mmol) and 2-
piperidinyl propanol (TCI, 1.39 g, 9.71 mmol) in DMA (10 mL) was irradiated
to 175°C for 3 h in the microwave. The cooled solution was concentrated in vacuo,
suspended in water (10 mL) and brine (10 mL), then extracted with DCM (2 × 20
mL). The combined organics were passed through a hydrophobic frit and
concentrated in vacuo to leave a brown oil (1.3 g). FCC, using 5% MeOH in DCM,
gave the title compound as a pale yellow solid (484 mg, 45%). LCMS (Method 3):
Rt 2.42 min, m/z 279 [MH ].
b. 6-Fluoro[4-(1-methyltriisopropylsilanyloxy-ethyl)-piperidin
yl]-[1,2,4]triazolo[4,3-a]pyridine (Intermediate 74b)
O Si
A solution of Intermediate 74a (480 mg, 1.72 mmol), triisopropylsilyl
trifluoromethane-sulfonate (0.579 mL, 2.16 mmol) and Et N (0.361 mL, 2.59
mmol) in dry DCM (5 mL) under N2 was stirred at reflux for 2 h. The mixture was
cooled to RT, then EtN (0.361 mL, 2.59 mmol) and triisopropylsilyl
trifluoromethanesulfonate (0.579 mL, 2.16 mmol) were added and the orange
solution stirred at reflux for 3 h. To the cooled solution, water (5 mL) was added
and the mixture shaken. The aqueous was extracted with DCM (5 mL), then the
combined organics passed through a hydrophobic frit and concentrated in vacuo to
leave an orange oil. FCC, using 1-3% MeOH in DCM, gave the title compound as
a pale yellow solid (592 mg, 79%). LCMS (Method 3): Rt 5.66 min, m/z 435
[MH ].
c. (1S,4R){3-[4-(1-Methyltriisopropylsilanyloxy-ethyl)-piperidin-
1-yl]-[1,2,4]triazolo[4,3-a]pyridinyloxy}-1,2,3,4-tetrahydro-naphthalen
ylamine (Intermediate 74c)
O Si
To a solution of Intermediate A (129 mg, 0.788 mmol) in dry DMF (2 mL)
at RT under Ar was added NaH (60% dispersion in oil, 45.0 mg, 1.13 mmol)
(CARE: gas evolution) and the resulting opaque brown solution stirred at RT for
45 min. A solution of Intermediate 74b (326 mg, 0.750 mmol) in dry DMF (2 mL)
was added and the resulting dark brown solution stirred at 60°C for 2.5 h. The
solution was concentrated in vacuo, redissolved in MeOH (2 mL) and AcOH
(0.100 mL), applied to an SCX-2 cartridge and washed with MeOH (100 mL). The
product was eluted with 2M NH in MeOH (75 mL); concentration in vacuo gave a
viscous dark brown oil. FCC, using 1-6% [2M NH in MeOH] in DCM, gave the
title compound as a viscous brown oil (131 mg, 30%). LCMS (Method 3): Rt 3.53
min, m/z 578 [MH ].
d. 1-(5-tert-Butylp-tolyl-2H-pyrazolyl)((1S,4R){3-[4-(1-
hydroxymethyl-ethyl)-piperidinyl]-[1,2,4]triazolo[4,3-a]pyridin
yloxy}-1,2,3,4-tetrahydro-naphthalenyl)-urea (Example 74)
A brown solution of (5-tert-butylp-tolyl-2H-pyrazolyl)-carbamic acid
2,2,2-trichloro-ethyl ester (Synthetic Communications, 2009, 39, 3999-4009; 89.6
mg, 0.221 mmol), Intermediate 74c (128 mg, 0.221 mmol) and DIPEA (0.048 mL,
0.277 mmol) in dioxane (3 mL) was stirred at 60°C for 16 h, and at 80°C for 6 h.
The cooled solution was concentrated in vacuo, suspended in water (4 mL) and
extracted with DCM (2 × 4 mL). The combined organics were passed through a
hydrophobic frit and concentrated in vacuo to leave a viscous brown oil. FCC,
using 1-4% [2M NH in MeOH] in DCM) gave 1-(5-tert-butylp-tolyl-2H-
pyrazolyl)((1S,4R){3-[4-(1-methyltriisopropylsilanyloxy-ethyl)-
piperidinyl]-[1,2,4]triazolo[4,3-a]pyridinyloxy}-1,2,3,4-tetrahydro-
naphthalenyl)-urea as a yellow solid (125 mg).
The solid was dissolved in THF (3 mL), treated with TBAF (1M in THF,
0.161 mL, 0.161 mmol) and the solution stirred at RT for 2 h, and then at reflux for
1 h. The solution was cooled to ~40°C, then TBAF (1M in THF, 0.161 mL, 0.161
mmol) added and the solution stirred at reflux for 16 h. The cooled solution was
concentrated in vacuo, suspended in water (10 mL) and extracted with EtOAc-
MeOH (19:1, 2 × 10 mL). The combined organics were washed with brine (10
mL), dried (Na SO ), filtered and concentrated in vacuo to leave a dark green
residue. FCC, using 2-7% MeOH in DCM, gave the title compound as a pale
yellow solid (60.6 mg, 41%). LCMS (Method 5): Rt 4.42 min, m/z 677 [MH ]. ¹H
NMR (400 MHz, d -DMSO): 1.09 (6H, s), 1.27 (9H, s), 1.37-1.44 (1H, m), 1.49-
1.61 (2H, m), 1.80 (2H, d, J 12.6), 1.83-1.96 (2H, m), 2.01-2.10 (2H, m), 2.36 (3H,
s), 2.81-2.90 (2H, m), 3.49 (2H, t, J 11.2), 4.16 (1H, s), 4.81 (1H, td, J 8.5, 5.5),
5.56 (1H, t, J 4.4), 6.32 (1H, s), 7.08 (1H, d, J 8.6), 7.14 (1H, dd, J 9.9, 2.1), 7.27-
7.40 (8H, m), 7.61 (1H, d, J 9.9), 7.66 (1H, d, J 2.0), 8.04 (1H, s).
Example 75
1-(5-tert-Butylp-tolyl-2H-pyrazolyl)[(1S,4R)(3-pyrrolidin
yl-[1,2,4]triazolo[4,3-a]pyridinyloxy)-1,2,3,4-tetrahydro-naphthalenyl]-
urea
a. 6-Fluoropyrrolidinyl-[1,2,4]triazolo[4,3-a]pyridine
(Intermediate 75a)
A mixture of Intermediate 24b (515 mg, 3.00 mmol), pyrrolidine (0.85 g,
12.0 mmol) and DMA (10 mL) was heated to 175°C for 4 h using microwave
irradiation. After cooling, the solvent was removed in vacuo and the resulting
residue purified by FCC, using 0 to 15% MeOH in DCM, to provide the title
compound as a brown gum (285 mg, 26%). LCMS (Method 3): Rt 1.95 min, m/z
207 [MH ].
b. (1S,4R)(3-Pyrrolidinyl-[1,2,4]triazolo[4,3-a]pyridinyloxy)-
1,2,3,4-tetrahydro-naphthalenylamine (Intermediate 75b)
Intermediate A (222 mg, 1.36 mmol) was added to a mixture of NaH (60%
in mineral oil, 163 mg, 4.08 mmol) in DMF (15 mL) at RT and stirred for 30 min.
Intermediate 75a (280 mg, 1.36 mmol) was then added and the resulting mixture
heated to 60°C for 1 h. After cooling, the reaction was quenched with sat. aq.
NH Cl solution. The mixture was diluted with water and extracted with EtOAc.
The combined organic extracts were washed with sat. aq. NaHCO solution and
brine, and concentrated in vacuo. The resulting residue was purified by FCC, using
0 to 15% [2M NH in MeOH] in DCM, to afford the title compound as a brown
solid (65.0 mg, 14%). LCMS (Method 3): Rt 1.89 min, m/z 350 [MH ].
c. 1-(5-tert-Butylp-tolyl-2H-pyrazolyl)[(1S,4R)(3-pyrrolidin-
1-yl-[1,2,4]triazolo[4,3-a]pyridinyloxy)-1,2,3,4-tetrahydro-naphthalen
yl]-urea (Example 75)
A mixture of Intermediate 75b (62.0 mg, 0.18 mmol), (5-tert-butylp-
tolyl-2H-pyrazolyl)-carbamic acid 2,2,2-trichloro-ethyl ester (Synthetic
Communications, 2009, 39, 3999-4009; 78.9 mg, 0.195 mmol), DIPEA (46.3 µL,
0.27 mmol) and 1,4-dioxane (2.5 mL) were heated to 60°C for 18 h. After cooling
the solvent was evaporated in vacuo. The residue was purified by FCC, using 0-
% MeOH in DCM, then further purified by HPLC (30-98% MeCN in H O,
0.1% HCO H) to give the title compound as an off-white solid (22 mg, 20%).
LCMS (Method 5) Rt 4.30 min, m/z 605 [MH ]. ¹H NMR (400 MHz, d -DMSO):
1.27 (9H, s), 1.79-2.15 (8H, m), 2.36 (3H, s), 3.49 (4H, m), 4.81 (1H, m), 5.51
(1H, t, J 4.5), 6.30 (1H, s), 7.03 (1H, dd, J 10.1, 2.2), 7.09 (1H, d, J 8.5), 7.25-7.40
(8H, m), 7.51 (1H, m), 7.83 (1H, m), 8.07 (1H, s).
Example 76
1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-(1-
dimethylaminomethyl-ethyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-urea partial formate salt
(0.5 eq)
a. 2-Dimethylaminomethyl-propionic acid N'-(5-fluoro-pyridinyl)-
hydrazide (Intermediate 76a)
N N N
To a solution of (5-fluoro-pyridinyl)-hydrazine (200 mg, 1.57 mmol) in
DMF (10.0 mL) was added 2-dimethylaminomethyl-propionic acid (206 mg,
1.57 mmol), EDC (332 mg, 1.73 mmol) and HOBt.H O (21.0 mg, 0.16 mmol).
The reaction was stirred overnight then partitioned between EtOAc and water. The
aqueous layer was then extracted with EtOAc (3 ×). The combined organic layers
were washed with brine, dried (MgSO ), filtered and evaporated in vacuo. The
residue was purified by FCC, using 0-10% [2M NH in MeOH] in DCM, to give
the title compound (195 mg, 51%). ¹H NMR (300 MHz, CDCl ): 1.25 (6H, s), 2.28
(6H, s), 6.44 (1H, br s), 6.62 (1H, dd, J 9.1, 3.6), 7.27 (1H, ddd, J 9.1, 8.0, 3.1),
8.03 (1H, d, J 2.9), 9.04 (1H, br s).
b. [1-(6-Fluoro-[1,2,4]triazolo[4,3-a]pyridinyl)methyl-ethyl]-
dimethyl-amine (Intermediate 76b)
To a solution of Intermediate 76a (195 mg, 0.81 mmol), Ph P (426 mg, 1.62
mmol) and Et N (452 mL, 3.25 mmol) in THF (9.00 mL) at 0°C was added
hexachloroethane (385 mg, 1.62 mmol). The reaction was stirred at RT overnight
then partitioned between EtOAc and water. The aqueous layer was then extracted
with EtOAc (3 ×). The combined organic layers were washed with brine, dried
(MgSO ), filtered and evaporated in vacuo. The residue was dissolved in MeOH
and loaded onto an SCX-2 cartridge, which was washed with MeOH and eluted
with 2M NH in MeOH. The reaction showed 50% conversion so was re-submitted
to the reaction conditions overnight at 50°C. The workup and purification
procedures were repeated to give the title compound (153 mg, 85%). ¹H NMR (300
MHz, CDCl ): 1.60 (6H, s), 2.20 (6H, s), 7.16 (1H, ddd, J 9.9, 7.4, 2.4), 7.71 (1H,
ddd, J 9.9, 5.0, 0.8), 8.89 (1H, ddd, J 4.4, 2.4, 0.8).
c. (1S,4R)[3-(1-Dimethylaminomethyl-ethyl)-[1,2,4]triazolo[4,3-
a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenylamine (Intermediate
76c)
To a suspension of NaH (60% in mineral oil, 112 mg, 2.80 mmol) in DMF
(2.50 mL) was added Intermediate A (114 mg, 0.70 mmol) and the reaction stirred
for 20 min. Intermediate 76b (153 mg, 0.70 mmol) was added in DMF (2.50 mL)
and the reaction heated to 60°C for 1 h. The reaction was cooled and quenched by
dropwise addition of methanol, before being diluted with methanol and loaded
onto an SCX-2 cartridge, which was washed with MeOH. The product was eluted
with 2M NH in MeOH; concentration in vacuo gave a residue. FCC, using 2-10%
[2M NH in MeOH] in DCM, gave the title compound (120 mg, 47%). LCMS
(Method 4): Rt 0.31, m/z 366 [MH ].
d. 1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-(1-
dimethylaminomethyl-ethyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-urea, partial formate salt (Example 76)
To a solution of Intermediate 76c (120 mg, 0.33 mmol) in 1,4-dioxane (3.00
mL) was added DIPEA (117 mL, 0.66 mmol) and (5-tert-butylp-tolyl-2H-
pyrazolyl)-carbamic acid 2,2,2-trichloro-ethyl ester (Synthetic
Communications, 2009, 39, 3999-4009; 133 mg, 0.33 mmol). The reaction was
heated to 60°C overnight then cooled and partitioned between EtOAc and water.
The aqueous layer was then extracted with EtOAc (3 ×). The combined organic
layers were washed with brine, dried (MgSO ), filtered and evaporated in vacuo.
The residue was purified by FCC, using 0-8% MeOH in DCM. Further purification
by HPLC (C18 X-select column, 25-60% MeCN in H O, 0.1% HCO H) gave the
title compound as a white powder after freeze-drying (21 mg, 10%). LCMS
(Method 5): Rt 3.86 min, m/z 621.1 [MH ]. ¹H NMR (400 MHz, d -MeOD): 1.30
(9H, s), 1.55 (3H, s), 1.56 (3H, s), 1.88-2.04 (2H, m), 2.10 (1H, m), 2.17 (6H, s),
2.26 (1H, m), 2.38 (3H, s), 4.90 (1H, dd, J 5.7, 8.7), 5.30 (1H, t, J 4.1), 6.33 (1H,
s), 7.20-7.36 (9H, m), 7.60-7.64 (1H, d, J 9.9), 8.51 (0.5H, br s), 8.66 (1H, d, J
1.9).
Example 77
1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-((R)
hydroxymethyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-urea
a. [(R)(6-Fluoro-[1,2,4]triazolo[4,3-a]pyridinyl)-piperidinyl]-
methanol (Intermediate 77a)
A brown solution of Intermediate 24b (565 mg, 3.29 mmol) and R
hydroxymethyl piperidine (Chess GmbH, 948 mg, 8.23 mmol) in DMA (10 mL)
was irradiated at 175°C for 3 h in the microwave. The cooled solution was
concentrated in vacuo, suspended in water (10 mL) and brine (10 mL), and then
extracted with DCM (2 × 20 mL). The combined organics were passed through a
hydrophobic frit and concentrated in vacuo to leave a brown oil. FCC, using 4-5%
MeOH in DCM, gave the title compound as a viscous yellow oil (237 mg, 29%).
LCMS (Method 3): Rt 2.11 min, m/z 251 [MH ].
b. 6-Fluoro((R)triisopropylsilanyloxymethyl-piperidinyl)-
[1,2,4]triazolo[4,3-a]pyridine (Intermediate 77b)
O Si
To a solution of Intermediate 77a (233 mg, 0.931 mmol) and Et N (0.195
mL, 1.40 mmol) in dry DCM (5 mL) at RT under N , was added triisopropylsilyl
trifluoromethanesulfonate (0.313 mL, 1.16 mmol) and the yellow solution stirred
at RT for 30 min. Water (5 mL) was added and the mixture shaken. The aqueous
was extracted with DCM (5 mL), then the combined organics passed through a
hydrophobic frit and concentrated in vacuo to leave a yellow oil. FCC, using 1-5%
MeOH in DCM, gave the title compound as a yellow oil (333 mg, 88%). LCMS
(Method 3): Rt 5.23 min, m/z 407 [MH ].
c. (1S,4R)[3-((R)Triisopropylsilanyloxymethyl-piperidinyl)-
[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalen
ylamine (Intermediate 77c)
O Si
To a solution of Intermediate A (140 mg, 0.860 mmol) in dry DMF (2 mL)
at RT under Ar was added NaH (60% dispersion in oil, 49.0 mg, 1.23 mmol)
(CARE: gas evolution) and the resulting brown suspension was stirred at RT for 45
min. A solution of Intermediate 77b (333 mg, 0.819 mmol) in dry DMF (2 mL)
was added and the resulting dark brown solution stirred at 60°C under Ar for 2.5 h.
The solution was concentrated in vacuo, redissolved in MeOH (2 mL) and AcOH
(0.100 mL), then applied to and SCX-2 cartridge, and washed with MeOH (100
ml). The product was eluted with 2M NH in MeOH (75 mL); concentration in
vacuo left a viscous dark brown oil. FCC, using 2-7% [2M NH in MeOH] in
DCM, gave the title compound as a yellow-brown viscous oil (257 mg, 57%).
LCMS (Method 3): Rt 3.27 min, m/z 550 [MH ].
d. 1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-((R)
triisopropylsilanyloxy-methyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridin
yloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea (Intermediate 77d)
O Si
An orange-brown solution of (5-tert-butylp-tolyl-2H-pyrazolyl)-
carbamic acid 2,2,2-trichloro-ethyl ester (Synthetic Communications, 2009, 39,
3999-4009; 103 mg, 0.255 mmol), Intermediate 77c (140 mg, 0.255 mmol) and
DIPEA (0.055 mL, in dioxane (3 mL) was stirred at 60°C for 16 h and then at
80°C for 2 h. The cooled solution was concentrated in vacuo, suspended in water
(4 mL) and extracted with DCM (2 × 4 mL). The combined organics were passed
through a hydrophobic frit and concentrated in vacuo to ~0.5 mL volume. FCC,
using 2-3% [2M NH in MeOH] in DCM, gave the title compound as a yellow
solid (136 mg, 66%). LCMS (Method 3): Rt 5.65 min, m/z 805 [MH ].
e. 1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-((R)
hydroxymethyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-urea (Example 77)
A brown solution of Intermediate 77d (135 mg, 0.168 mmol) and TBAF
(1M in THF, 0.184 mL, 0.184 mmol) in THF (3 mL) was stirred at RT for 1 h. The
solution was concentrated in vacuo, suspended in water (10 mL) and extracted
with EtOAc-MeOH (19:1, 2 × 10 mL). The combined organics were washed with
brine (10 mL), dried (Na SO ), filtered and concentrated in vacuo to leave a brown
solid. FCC, using 5-9% MeOH in DCM, gave a pale brown solid. Further
purification by HPLC (XBridge C18 column, 25-75% MeCN in H O, 0.1%
NH OH) gave the title compound as a white powder after freeze-drying (63.9 mg,
59%). LCMS (Method 5): Rt 4.33 min, m/z 649 [MH ]. ¹H NMR (400 MHz, d -
DMSO): 1.27 (9 H, s), 1.29-1.35 (1H, m), 1.71-1.77 (3H, m), 1.82-1.96 (3H, m),
2.01-2.17 (2H, m), 2.36 (3H, s), 3.02-3.07 (2H, m), 3.20 (1H, dd, J 11.9, 3.3),
3.25-3.28 (1H, m), 3.42 (1H, dt, J 10.5, 5.0), 3.52-3.58 (1H, m), 4.69 (1H, t, J 5.1),
4.81 (1H, td, J 8.6, 5.4), 5.48 (1H, t, J 4.3), 6.32 (1H, s), 7.09 (1H, d, J 8.3), 7.12
(1H, dd, J 9.9, 2.1), 7.27-7.39 (8H, m), 7.60 (1H, d, J 9.9), 7.80 (1H, d, J 2.1), 8.04
(1H, s).
Example 78
1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-((S)
hydroxymethyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-urea
The title compound was prepared starting from (S)hydroxymethyl
piperidine (Chess GmbH) using analogous procedures to those described in
Example 77. LCMS (Method 5): Rt 4.33 min, m/z 649 [MH ]. ¹H NMR (400
MHz, d -DMSO): 1.27 (9H, s), 1.27 (1H, m), 1.69-1.79 (3H, m), 1.82-1.96 (3H,
m), 2.03-2.14 (2H, m), 2.36 (3H, s), 2.96 (1H, dd, J 11.9, 8.2), 3.02-3.08 (1H, m),
3.24 (1H, dd, J 11.9, 3.3), 3.29 (1H, m), 3.43 (1H, dt, J 10.6, 5.1), 3.47-3.54 (1H,
m), 4.65 (1H, t, J 5.2), 4.81 (1H, td, J 8.5, 5.4), 5.50 (1H, t, J 4.4), 6.32 (1H, s),
7.09 (1H, d, J 8.5), 7.13 (1H, dd, J 9.9, 2.1), 7.27-7.40 (8H, m), 7.60 (1H, d, J 9.9),
7.78 (1H, s), 8.05 (1H, s).
Example 79
1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-(4-hydroxy
methyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-urea
a. 4-Hydroxymethyl-piperidinecarboxylic acid tert-butyl ester
(Intermediate 79a)
To a solution of 1-Bocpiperidone (10.0 g, 50.0 mmol) in diethyl ether
(100 mL) at 0°C was added methylmagnesium bromide (3.0 M in Et O, 22.3 mL,
67.0 mmol) maintaining the temperature below +10°C. The reaction mixture was
allowed to warm to RT over 1 h. The reaction was quenched by addition of sat. aq.
NH Cl solution, then the mixture was extracted with diethyl ether (2 ×). The
combined organic layers were washed with brine, dried (MgSO ), filtered and
evaporated in vacuo. The residue was purified by FCC, using 0-100% EtOAc in
cyclohexane, to give the title compound (6.76 g, 62%). ¹H NMR (400 MHz,
CDCl ): 1.26 (3H, s), 1.45 (9H, s), 1.48-1.62 (4H, m), 3.15-3.32 (2H, m), 3.70
(2H, d, J 12.5).
b. 4-Methyl-piperidinol (Intermediate 79b)
A solution of Intermediate 79a (5.50 g, 25.6 mmol) in TFA (20 mL) and
DCM (40 mL) was stirred at RT for 1 h. The reaction mixture was applied to SCX-
2 cartridges (2 × 70 g) and washed with MeOH. The product was eluted with 2M
NH in MeOH; concentration in vacuo gave the title compound (3.19 g, 99%). ¹H
NMR (400 MHz, CDCl ): 1.24 (3H, s), 1.51-1.61 (4H, m), 2.75-2.87 (2H, m),
2.89-3.02 (2H, m).
c. 1-(6-Fluoro-[1,2,4]triazolo[4,3-a]pyridinyl)methyl-piperidinol
(Intermediate 79c)
A mixture of Intermediate 24b (400 mg, 2.32 mmol) and Intermediate 79b
(1.33 g, 11.6 mmol) in NMP (5 mL) was heated in the microwave at 170°C for 3 h.
The reaction mixture was applied to an SCX-2 cartridge (25 g) and washed with
MeOH. The product was eluted with 2M NH in MeOH; concentration in vacuo
gave a residue. FCC, using 0-8% [2M NH in MeOH] in DCM, gave the title
compound (190 mg, 32%). LCMS (Method 1): Rt 2.01 min, m/z 251 [MH ].
d. 6-Fluoro(4-methyltriisopropylsilanyloxy-piperidinyl)-
[1,2,4]triazolo[4,3-a]pyridine (Intermediate 79d)
O Si
Triisopropylsilyl trifluoromethanesulfonate (550 mg, 1.81 mmol) was added
to a solution of Intermediate 79c (150 mg, 0.60 mmol) and Et N (242 mg, 2.40
mmol) in a DCM (5 mL) and the mixture stirred at reflux for 1 h. The reaction
mixture was diluted with DCM (30 mL), washed with water (2 ×), brine, dried
(MgSO ), and then concentrated in vacuo. The residue was purified by FCC, using
0-10% MeOH in DCM, to give the title compound (235 mg, 96%). ¹H NMR (400
MHz, CDCl ): 1.00-1.20 (21H, m), 1.40 (3H, s), 1.76-1.93 (4H, m), 3.18-3.29 (2H,
m), 3.44-3.58 (2H, m), 7.03-7.12 (1H, m), 7.58-7.69 (2H, m).
e. (1S,4R)[3-(4-Methyltriisopropylsilanyloxy-piperidinyl)-
[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalen
ylamine (Intermediate 79e)
O Si
To a solution of Intermediate A (111 mg, 0.680 mmol) in DMF (2 mL) was
added NaH (60% in oil, 68 mg, 1.70 mmol) and the mixture stirred at RT for 20
min, before Intermediate 79d (230 mg, 0.566 mmol) was added. This mixture was
stirred at 60°C for 1 h. The cooled reaction mixture was diluted with EtOAc (100
mL), washed with water (2 ×), brine, dried (MgSO ) and concentrated in vacuo.
The residue was purified by FCC, using 0-10% [2M NH in MeOH] in DCM, to
give the title compound (160 mg, 51%). LCMS (Method 1): Rt 3.06 min, m/z 550
[MH ].
f. 1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-(4-methyl-
4-triisopropylsilanyloxy-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-
1,2,3,4-tetrahydro-naphthalenyl}-urea (Intermediate 79f)
O Si
A solution of Intermediate 79e (160 mg, 0.291 mmol), (5-tert-butylp-
tolyl-2H-pyrazolyl)-carbamic acid 2,2,2-trichloro-ethyl ester (Synthetic
Communications, 2009, 39, 3999-4009; 176 mg, 0.437 mmol) and DIPEA (150
mg, 1.16 mmol) in DMF (4 mL) was stirred at 50°C for 1 h. The reaction mixture
was diluted with EtOAc and washed with water (2 ×), brine, dried (MgSO ),
filtered and concentrated in vacuo. The residue was purified by FCC, using 0-10%
[2M NH in MeOH] in DCM, to give the title compound (210 mg, 93%). LCMS
(Method 4): Rt 5.32 min, m/z 805 [MH ].
g. 1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-(4-
hydroxymethyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-
1,2,3,4-tetrahydro-naphthalenyl}-urea (Example 79)
To a solution of Intermediate 79f (210 mg, 0.260 mmol) in THF (4 mL) at -
°C was added TBAF (1M in THF, 390 µL, 0.390 mmol) and the mixture was
allowed to warm to RT over 1 h. The reaction mixture was applied to an SCX-2
cartridge (10 g) and washed with MeOH. The product was eluted with 2M NH in
MeOH; concentration in vacuo gave a residue. FCC, using 0-10% [2M NH in
MeOH] in DCM, and then recrystallisation from boiling EtOAc (~40 mL) gave the
title compound as a white powder (67 mg, 40%). LCMS (Method 5): Rt 4.31 min,
m/z 649.1 [MH ]. ¹H NMR (400 MHz, d -MeOH): 1.30 (3H, s), 1.33 (9H, s), 1.71-
1.77 (2H, m), 1.84-1.93 (2H, m), 1.95-2.17 (3H, m), 2.25-2.32 (1H, m), 2.41 (3H,
s), 3.20-3.28 (2H, m), 3.36-3.45 (2H, m), 4.72-4.92 (1H, m), 5.47 (1H, t, J 4.4),
6.36 (1H, s), 6.88 (1H, d, J 9.3), 7.21-7.40 (8H, m), 7.58 (1H, d, J 9.7), 7.62 (1H,
d, J 1.7).
Example 80
1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-(1-methyl
pyrrolidinyl-ethyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-urea
N N N
a. 2-Methylpyrrolidinyl-propionic acid N'-(5-fluoro-pyridinyl)-
hydrazide (Intermediate 80a)
To a solution of (5-fluoro-pyridinyl)-hydrazine (200 mg, 1.57 mmol) in
DMF (10.0 mL) was added 2-methylpyrrolidinyl-propionic acid (246 mg,
1.57 mmol), EDC (332 mg, 1.73 mmol) and HOBt.H2O (21.0 mg, 0.16 mmol).
The reaction was stirred overnight then partitioned between EtOAc and water. The
aqueous layer was then extracted with EtOAc (3 ×). The combined organic layers
were washed with brine, dried (MgSO4), filtered and evaporated in vacuo. The
residue was purified by FCC, using 0-10% [2M NH in MeOH] in DCM, to give
the title compound (260 mg, 62%). ¹H NMR (300 MHz, CDCl ): 1.30 (6H, s),
1.76-1.84 (4H, m), 2.64-2.72 (4H, m), 6.46 (1H, br s), 6.62 (1H, dd, J 9.0, 3.6),
7.28 (1H, ddd, J 9.0, 8.0, 2.9), 8.03 (1H, d, J 2.9), 9.06 (1H, br s).
b. 6-Fluoro(1-methylpyrrolidinyl-ethyl)-[1,2,4]triazolo[4,3-
a]pyridine (Intermediate 80b)
To a solution of Intermediate 80a (260 mg, 0.98 mmol), Ph P (511 mg, 1.95
mmol) and Et3N (544 mL, 3.91 mmol) in THF (10.0 mL) at 0°C was added
hexachloroethane (462 mg, 1.95 mmol). The reaction was stirred at RT overnight
then partitioned between EtOAc and water. The aqueous layer was then extracted
with EtOAc (3 ×). The combined organic layers were washed with brine, dried
(MgSO ), filtered and evaporated in vacuo. The residue was taken up in MeOH
and loaded onto an SCX-2 cartridge, which was washed with MeOH and eluted
with 2M NH in MeOH. The reaction showed 50% conversion so was re-submitted
to the reaction conditions overnight at 50°C. The workup and purification
procedures were repeated to give the title compound (209 mg, 86%). ¹H NMR (300
MHz, CDCl ): 1.64 (6H, s), 1.74-1.82 (4H, m), 2.52-2.57 (4H, m), 7.16 (1H, ddd, J
9.8, 7.4, 2.3), 7.69 (1H, m), 8.93 (1H, ddd, J 4.5, 2.3, 0.7).
c. (1S,4R)[3-(1-Methylpyrrolidinyl-ethyl)-[1,2,4]triazolo[4,3-
a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenylamine (Intermediate
80c)
To a suspension of NaH (60% in mineral oil, 135 mg, 3.37 mmol) in DMF
(4.50 mL) was added Intermediate A (137 mg, 0.84 mmol) and the reaction stirred
for 20 min. Intermediate 80b (209 mg, 0.84 mmol) was added in DMF (1.50 mL)
and the reaction heated to 60°C for 1 h. The reaction was cooled and quenched by
dropwise addition of methanol, before being diluted with methanol and loaded
onto an SCX-2 cartridge, which was washed with MeOH and product eluted with
2M NH in MeOH. The resulting residue was purified by FCC, using 0-10% [2M
NH in MeOH] in DCM, to give the title compound (180 mg, 55%). LCMS
(Method 4): Rt 0.31, m/z 392.2 [MH ].
d. 1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-(1-methyl-
1-pyrrolidinyl-ethyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-urea (Example 80)
To a solution of Intermediate 80c (180 mg, 0.46 mmol) in 1,4-dioxane (5.00
mL) was added DIPEA (160 mL, 0.92 mmol) and (5-tert-butylp-tolyl-2H-
pyrazolyl)-carbamic acid 2,2,2-trichloro-ethyl ester (Synthetic
Communications, 2009, 39, 3999-4009; 185 mg, 0.46 mmol). The reaction was
heated to 60°C overnight then cooled and partitioned between EtOAc and water.
The aqueous layer was then extracted with EtOAc (3 ×). The combined organic
layers were washed with brine, dried (MgSO ), filtered and evaporated in vacuo.
The residue was purified by FCC, using 0-8% MeOH in DCM. Further purification
by HPLC (C18 X-select column, 10-98% MeCN in H O, 0.1% HCO H) gave the
title compound as a white powder after freeze-drying (58 mg, 20%). LCMS
(Method 5): Rt 3.84 min, m/z 647.2 [MH ]. ¹H NMR (400 MHz, d -MeOD): 1.30
(9H, s), 1.60 (6H, s), 1.70-1.76 (4H, m), 1.86-2.06 (2H, m), 2.11 (1H, m), 2.20
(1H, m), 2.38 (3H, s), 2.45-2.52 (2H, m), 2.55-2.62 (2H, m), 4.89 (1H, dd, J 5.6,
8.9), 5.29 (1H, t, J 4.2), 6.33 (1H, s), 7.20-7.36 (9H, m), 7.62 (1H, d, J 9.9), 8.77
(1H, d, J 2.0).
Example 81
1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-((S)
methyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-urea
a. (S)Methyl-piperidinecarbonyl chloride (Intermediate 81a)
Cl N
To a pale yellow solution of triphosgene (742 mg, 2.50 mmol) and pyridine
(0.404 mL, 5.00 mmol) in dry DCM (10 mL) at 10°C under N was added (S)
methyl piperidine (Aldrich, 0.603 mL, 5.00 mmol) cautiously over 2 min. The
vivid orange solution was stirred at RT for 18 h, then pyridine (0.404 mL, 5.00
mmol) and triphosgene (742 mg, 2.50 mmol) were added sequentially (CARE:
exotherm on addition of triphosgene) and the orange solution stirred at RT for 4 h.
Aqueous HCl solution (1M, 10 mL) was added and the mixture stirred vigorously
until gas evolution ceased (30 min). The aqueous layer was extracted with DCM
(10 mL), then the combined organics passed through a hydrophobic frit and
concentrated in vacuo to leave the title compound as a dark red oil (745 mg, 92%).
¹H NMR (300 MHz, CDCl ): 1.25 (3H, d, J 7.0), 1.42-1.77 (6H, m), 3.07 (1H, br
s), 4.17 (1H, dd, J 13.8, 4.0), 4.62 (1H, apparent quin, J 6.3).
b. (S)Methyl-piperidinecarboxylic acid N'-(5-fluoro-pyridinyl)-
hydrazide (Intermediate 81b)
To a solution of (5-fluoro-pyridinyl)-hydrazine (582 mg, 4.58 mmol) and
DIPEA (0.997 mL, 5.72 mmol) in dry DCM (20 mL) was added Intermediate 81a
(740 mg, 4.58 mmol) and the resulting red solution stirred at RT for 66 h, and at
reflux for 4 h. To the cooled solution was added water (20 mL) and the mixture
shaken. The aqueous was extracted with DCM (20 mL), then the combined
organics passed through a hydrophobic frit and concentrated in vacuo to leave a
pale brown solid. FCC, using 0-5% MeOH in DCM, gave the title compound as a
pale yellow solid (657 mg, 57%). ¹H NMR (300 MHz, CDCl ): 1.22 (3H, d, J 6.9),
1.40-1.77 (6H, m), 2.96 (1H, td, J 13.0, 2.9), 3.85 (1H, ddd, J 13.3, 4.5, 2.2), 4.31
(1H, m), 6.50 (1H, s), 6.59 (1H, br s), 6.75 (1H, ddd, J 9.0, 3.6, 0.7), 7.27 (1H,
ddd, J 9.1, 8.1, 3.1), 8.02 (1H, d, J 2.9).
c. 6-Fluoro((S)methyl-piperidinyl)-[1,2,4]triazolo[4,3-
a]pyridine (Intermediate 81c)
To a solution of Intermediate 81b (657 mg, 2.60 mmol), Ph P (1.37 g, 5.21
mmol) and Et N (1.45 mL, 10.4 mmol) in THF (20 mL) at 0°C was added
hexachloroethane (1.23 g, 5.21 mmol) and the resulting yellow suspension was
stirred at RT for 2 h, and at reflux for 19 h. The cooled solution was filtered and
concentrated in vacuo. The brown oil was redissolved in MeOH (3 mL) and
applied to an SCX-2 cartridge (20 g), washing with MeOH (100 mL). The product
was eluted with 2M NH in MeOH (75 mL); concentration in vacuo gave a brown
oil. FCC, using 1-5% [2M NH in MeOH] in DCM, gave the title compound as a
brown oil (542 mg, 89%). LCMS (Method 3): Rt 3.00 min, m/z 235 [MH ].
d. (1S,4R)[3-((S)Methyl-piperidinyl)-[1,2,4]triazolo[4,3-
a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenylamine (Intermediate
81d)
To a solution of Intermediate A (374 mg, 2.29 mmol) in dry DMF (3 mL)
under N was added NaH (60% dispersion in oil, 183 mg, 4.58 mmol) and the
resulting opaque brown solution was stirred at RT for 45 min (CARE: gas
evolution). A solution of Intermediate 81c (537 mg, 2.29 mmol) in dry DMF (7
mL) was added and the dark brown solution stirred at 60°C under N for 90 min.
The cooled solution was concentrated in vacuo, redissolved in MeOH (3 mL) and
AcOH (0.10 mL) and then applied to an SCX-2 cartridge (20 g), washing with
MeOH (50 mL). The product was eluted with 2M NH in MeOH (50 mL);
concentration in vacuo gave a dark brown solid. FCC, using 2-7% [2M NH in
MeOH] in DCM, gave the title compound as a pale brown foam (505 mg, 58%).
LCMS (Method 3): Rt 2.29 min, m/z 378 [MH ].
e. 1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-((S)
methyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-urea. (Example 81)
An orange-brown solution of (5-tert-butylp-tolyl-2H-pyrazolyl)-
carbamic acid 2,2,2-trichloro-ethyl ester (Synthetic Communications, 2009, 39,
3999-4009; 106 mg, 0.263 mmol), Intermediate 81d (94.4 mg, 0.250 mmol) and
DIPEA (0.054 mL, 0.313 mmol) in dry dioxane (3 mL) was stirred at 70°C for 16
h. The cooled solution was concentrated in vacuo, suspended in water (5 mL) and
extracted with DCM (2 × 5 mL). The combined organics were passed through a
hydrophobic frit and concentrated in vacuo to leave a brown gum. FCC, using 2-
6% MeOH in DCM, gave a pale yellow solid (123 mg). Further purification by
HPLC (XBridge C18 column, 40-90% MeCN in H O, 0.1% NH OH) gave the title
compound as a white powder after freeze-drying (72.4 mg, 46%). LCMS (Method
): Rt 5.04 min, m/z 633 [MH ]. ¹H NMR (400 MHz, d -DMSO): 0.91 (3H, d, J
6.3), 1.27 (9H, s), 1.48-1.55 (2H, m), 1.63-1.71 (2H, m), 1.75-1.97 (4H, m), 2.00-
2.16 (2H, m), 2.36 (3H, s), 2.90 (1H, ddd, J 12.1, 9.0, 3.9), 3.16 (1H, dt, J 12.1,
4.3), 3.29 (1H, m), 4.82 (1H, td, J 8.6, 5.5), 5.51 (1H, t, J 4.4), 6.32 (1H, s), 7.08
(1H, d, J 8.6), 7.19 (1H, dd, J 9.9, 2.2), 7.25-7.38 (8H, m), 7.64 (1H, dd, J 9.8, 0.8),
7.69 (1H, d, J 2.1), 8.04 (1H, s).
Example 82
1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-((R)
methyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-urea
The title compound was prepared starting from (R)methyl piperidine
(ABCR) using analogous procedures to those described in Example 81. LCMS
(Method 5): Rt 5.03 min, m/z 633 [MH ]. ¹H NMR (400 MHz, d -DMSO): 0.88
(3H, d, J 6.3), 1.27 (9H, s), 1.48-1.55 (2H, m), 1.65-1.71 (2H, m), 1.76-1.98 (4H,
m), 2.01-2.14 (2H, m), 2.36 (3H, s), 2.94 (1H, ddd, J 12.2, 8.1, 4.8), 3.17 (1H, dt, J
12.1, 4.3), 3.26-3.30 (1H, m), 4.82 (1H, td, J 8.6, 5.4), 5.54 (1H, t, J 4.4), 6.32 (1H,
s), 7.08 (1H, d, J 8.6), 7.18 (1H, dd, J 9.8, 2.2), 7.26-7.38 (8H, m), 7.64 (1H, d, J
9.9), 7.70 (1H, d, J 2.1), 8.04 (1H, s).
Example 83
1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-((S)
methyl-morpholinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-urea, partial formate salt
N N N
(0.4 eq)
a. (R)[N'-(5-Fluoro-pyridinyl)-hydrazinocarbonyl]-morpholine
carboxylic acid tert-butyl ester (Intermediate 83a)
To a solution of (5-fluoro-pyridinyl)-hydrazine (143 mg, 1.13 mmol) in
DCM (10.0 mL) was added (R)-morpholine-3,4-dicarboxylic acid 4-tert-butyl ester
(260 mg, 1.13 mmol), EDC (238 mg, 1.24 mmol) and HOBt.H O (15.0 mg, 0.11
mmol). The reaction was stirred overnight then partitioned between EtOAc and
water. The aqueous layer was then extracted with EtOAc (3 ×). The combined
organic layers were washed with brine, dried (MgSO ), filtered and evaporated in
vacuo. The residue was purified by FCC, using 0-10% [2M NH in MeOH] in
DCM, to give the title compound (375 mg, 98%). LCMS (Method 1): Rt 2.69, m/z
341.2 [MH ].
b. (S)(6-Fluoro-[1,2,4]triazolo[4,3-a]pyridinyl)-morpholine
carboxylic acid tert-butyl ester (Intermediate 83b)
To a solution of Intermediate 83a (375 mg, 1.10 mmol), Ph P (578 mg, 2.20
mmol) and Et N (614 mL, 4.41 mmol) in THF (11.0 mL) at 0°C was added
hexachloroethane (523 mg, 2.20 mmol). The reaction was stirred at RT overnight
then partitioned between EtOAc and water. The aqueous layer was then extracted
with EtOAc (3 ×). The combined organic layers were washed with brine, dried
(MgSO ), filtered and evaporated in vacuo. The residue was taken up in MeOH
and loaded onto an SCX-2 cartridge, which was washed with MeOH and eluted
with 2M NH in MeOH; concentration in vacuo gave the title compound (297 mg,
84%). LCMS (Method 1): Rt 2.73, m/z 323.2 [MH ].
c. 6-Fluoro((S)methyl-morpholinyl)-[1,2,4]triazolo[4,3-
a]pyridine (Intermediate 83c)
To a solution of Intermediate 83b (297 mg, 0.92 mmol) in DCM (8.0 mL) at
0°C was added TFA (400 mL) and the reaction stirred at RT overnight. Further
TFA (600 mL) was added and the reaction stirred for 1 h then partitioned between
DCM and sat. aq. NaHCO solution. The aqueous layer was then extracted with
DCM (3 ×). The combined organic layers were washed with brine, dried (MgSO ),
filtered and evaporated in vacuo. The residue was taken up in DCM (4.0 ml) and
MeOH (3 drops) added. Formaldehyde solution (37 wt% in water, 162 mL, 2.00
mmol) was added followed by sodium triacetoxyborohydride (372 mg, 2.40
mmol). The reaction was stirred overnight then loaded onto an SCX-2 cartridge,
which was washed with MeOH and eluted with 2M NH in MeOH; concentration
in vacuo gave the title compound (75.0 mg, 34%). ¹H NMR (400 MHz, d -MeOD):
2.09 (3H, s), 2.49 (1H, td, J 11.4, 3.8), 2.98 (1H, dt, J 11.9, 2.0), 3.79-3.90 (3H,
m), 3.94 (1H, m), 4.01 (1H, dd, J 10.1, 4.0), 7.50 (1H, ddd, J 10.0, 7.7, 2.2), 7.81
(1H, ddd, J 10.1, 4.9, 0.8), 8.98 (1H, ddd, J 4.0, 2.3, 0.8).
d. (1S,4R)[3-((S)Methyl-morpholinyl)-[1,2,4]triazolo[4,3-
a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenylamine (Intermediate
83d)
To a suspension of NaH (60% in mineral oil, 51.0 mg, 1.27 mmol) in DMF
(1.50 mL) was added Intermediate A (51.0 mg, 0.32 mmol) and the reaction stirred
for 20 min. Intermediate 83c (75.0 mg, 0.32 mmol) was added in DMF (1.50 mL)
and the reaction heated to 60°C for 1 h. The reaction was cooled and quenched by
dropwise addition of methanol, before being diluted with methanol and loaded
onto an SCX-2 cartridge, which was washed with MeOH. The product was eluted
with 2M NH in MeOH; concentration in vacuo gave a residue. FCC, using 0-10%
[2M NH in MeOH] in DCM, gave the title compound (31 mg, 26%). LCMS
(Method 4): Rt 0.32, m/z 380.0 [MH ].
e. 1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-((S)
methyl-morpholinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-urea, partial formate salt (Example 83)
To a solution of Intermediate 83d (31.0 mg, 0.082 mmol) in 1,4-dioxane
(2.00 mL) was added DIPEA (28.0 mL, 0.16 mmol) and (5-tert-butylp-tolyl-2H-
pyrazolyl)-carbamic acid 2,2,2-trichloro-ethyl ester (Synthetic
Communications, 2009, 39, 3999-4009; 33.0 mg, 0.082 mmol). The reaction was
heated to 60°C overnight then cooled and partitioned between EtOAc and water.
The aqueous layer was then extracted with EtOAc (3 ×). The combined organic
layers were washed with brine, dried (MgSO ), filtered and evaporated in vacuo.
The residue was purified by FCC, using 0-10% MeOH in DCM. Further
purification by HPLC (C18 X-select column, 10-98% MeCN in H O, 0.1%
HCO H) gave the title compound as a white powder after freeze-drying (10 mg,
19%). LCMS (Method 5): Rt 3.90 min, m/z 635.2 [MH ]. ¹H NMR (400 MHz, d -
MeOD): 1.30 (9H, s), 1.86-2.06 (3H, m), 2.11 (1H, m), 2.08 (3H, s), 2.25 (1H, m),
2.38 (3H, s), 2.46 (1H, td, J 11.7, 3.5), 2.92 (1H, dt, J 11.8, 1.7), 3.73-3.91 (3H,
m), 3.97 (1H, dd, J 9.9, 4.0), 4.90 (1H, dd, J 8.6, 5.6), 5.39 (1H, t, J 4.1), 6.33 (1H,
s), 7.21-7.36 (9H, m), 7.65 (1H, d, J 9.9), 8.24 (0.4H, br s), 8.55 (1H, d, J 1.4).
Example 84
1-(5-tert-Butylp-tolyl-2H-pyrazolyl)((1S,4R){3-[(S)(3-
hydroxy-propyl)-pyrrolidinyl]-[1,2,4]triazolo[4,3-a]pyridinyloxy}-
1,2,3,4-tetrahydro-naphthalenyl)-urea
a. (S)(2-tert-Butoxycarbonyl-ethyl)-pyrrolidinecarboxylic acid
benzyl ester (Intermediate 84a)
Tert-butyl acrylate (5.00 mL) was added to a solution of L-proline benzyl
ester hydrochloride salt (1.10 g, 4.54 mmol) and Et N (632 mL, 4.54 mmol) in tert-
butanol (5.00 mL). The reaction was heated to 80°C for 3 h then and evaporated in
vacuo. The residue was purified by FCC, using 0-50% EtOAc in cyclohexane, to
give the title compound (1.20 g, 79%). ¹H NMR (300 MHz, CDCl ): 1.43 (9H, s),
1.72-2.00 (3H, m), 2.08 (1H, m), 2.39-2.48 (3H, m), 2.72 (1H, ddd, J 12.2, 8.4,
6.7), 3.00 (1H, dt, J 12.3, 7.8), 3.13 (1H, m), 3.28 (1H, dd, J 8.6, 5.4), 5.13 (1H, d,
J 12.3), 5.18 (1H, d, J 12.3), 7.29-7.39 (5H, m).
b. (S)(2-tert-Butoxycarbonyl-ethyl)-pyrrolidinecarboxylic acid
(Intermediate 84b)
A solution of Intermediate 84a (1.10 g, 3.29 mmol) in IMS (25.0 mL) was
added to palladium on charcoal (10 wt%, 110 mg) and the reaction stirred under H
for 1 h. The mixture was filtered through Celite and evaporated in vacuo to give
the title compound (840 mg, 99%). ¹H NMR (300 MHz, d -MeOD): 1.48 (9H, s),
1.91 (1H, m), 2.02-2.24 (2H, m), 2.41 (1H, m), 2.74 (2H, t, J 7.1), 3.13 (1H, ddd, J
11.1, 10.2, 7.0), 3.32-3.53 (2H, m), 3.72 (1H, ddd, J 11.0, 7.2, 3.5), 3.89 (1H, dd, J
9.5, 5.3).
c. 3-{(S)[N'-(5-Fluoro-pyridinyl)-hydrazinocarbonyl]-pyrrolidin-
1-yl}-propionic acid tert-butyl ester (Intermediate 84c)
HOBt.H O (695 mg, 3.62 mmol) was added to a suspension of (5-fluoro-
pyridinyl)-hydrazine (418 mg, 3.29 mmol), Intermediate 84b (840 mg, 3.29
mmol), and EDC (44.0 mg, 0.33 mmol) in DMF (25.0 mL). The reaction was
stirred overnight then partitioned between EtOAc and water. The aqueous layer
was then extracted with EtOAc (3 ×). The combined organic layers were washed
with brine, dried (MgSO ), filtered and evaporated in vacuo. The residue was
purified by FCC, using 0-10% [2M NH in MeOH] in DCM, to give the title
compound (1.16 g, 99%). LCMS (Method 1): Rt 2.06 mins, m/z 353.3 [MH ].
d. 3-[(S)(6-Fluoro-[1,2,4]triazolo[4,3-a]pyridinyl)-pyrrolidinyl]-
propionic acid tert-butyl ester (Intermediate 84d)
Hexachloroethane (1.56 g, 6.58 mmol) was added to a solution of
Intermediate 84c (1.16 g, 3.29 mmol), Ph P (1.72 g, 6.58 mmol) and Et N (1.80
mL, 13.1 mmol) in THF (30.0 mL) at 0°C. The reaction was stirred overnight then
partitioned between EtOAc and water. The aqueous layer was then extracted with
EtOAc (3 ×). The combined organic layers were washed with brine, dried
(MgSO4), filtered and evaporated in vacuo. The residue was purified by FCC,
using EtOAc then 10% [2M NH in MeOH] in DCM, to give the title compound
(1.06 g, 99%). LCMS (Method 4): Rt 1.97 min, m/z 335.1 [MH ].
e. 3-[(S)(6-Fluoro-[1,2,4]triazolo[4,3-a]pyridinyl)-pyrrolidinyl]-
propanol (Intermediate 84e)
Lithium aluminium hydride solution (2M in THF, 1.64 mL, 3.28 mmol) was
added to a solution of Intermediate 84d (550 mg, 1.64 mmol) in THF (15.0 mL) at
-10°C. The reaction was stirred for 1 h then quenched by dropwise addition of
water (125 mL), sodium hydroxide (3M aqueous, 125 mL) and water (375 mL). The
reaction was stirred for 10 min then partitioned between EtOAc and water. The
aqueous layer was then extracted with EtOAc (3 ×). The combined organic layers
were washed with brine, dried (MgSO ), filtered and evaporated in vacuo. The
residue was purified by FCC, using 2-10% [2M NH in MeOH] in DCM, to give
the title compound (145 mg, 33%). LCMS (Method 4): Rt 0.32 mins, m/z 265.2
[MH ].
f. 6-Fluoro[(S)(3-triisopropylsilanyloxy-propyl)-pyrrolidinyl]-
[1,2,4]triazolo[4,3-a]pyridine (Intermediate 84f)
OTIPS
Triisopropylsilyl chloride (266 mL, 1.24 mmol) was added to a solution of
Intermediate 84e (218 mg, 0.82 mmol) and Et N (266 mL, 1.24 mmol) in DCM
(8.00 mL). The reaction was stirred overnight then 4-(dimethylamino)pyridine
(10.0 mg, 0.082 mmol) added. The reaction was stirred for 3 h then partitioned
between EtOAc and water. The aqueous layer was then extracted with EtOAc (3
×). The combined organic layers were washed with brine, dried (MgSO ), filtered
and evaporated in vacuo. The residue was purified by FCC, using 0-7.5% [2M
NH in MeOH] in DCM, to give the title compound (317 mg, 92%). ¹H NMR (300
MHz, CDCl ): 0.92 (21H, s), 1.56-1.68 (2H, m), 1.89-2.10 (3H, m), 2.21-2.40 (3H,
m), 2.56 (1H, dt, J 12.1, 7.9), 3.40 (1H, m), 3.46-3.64 (2H, m), 4.22 (1H, t, J 8.4),
7.16 (1H, ddd, J 9.9, 7.5, 2.3), 7.71 (1H, ddd, J 10.0, 4.9, 0.6), 8.64 (1H, m).
g. (1S,4R){3-[(S)(3-Triisopropylsilanyloxy-propyl)-pyrrolidin
yl]-[1,2,4]triazolo[4,3-a]pyridinyloxy}-1,2,3,4-tetrahydro-naphthalen
ylamine (Intermediate 84g)
OTIPS
To a suspension of NaH (60% in mineral oil, 121 mg, 3.02 mmol) in DMF
(2.00 mL) was added Intermediate A (122 mg, 0.75 mmol) and the reaction stirred
for 20 min. Intermediate 84f (317 mg, 0.75 mmol) was added in DMF (2.00 mL)
and the reaction heated to 60°C for 1 h. The cooled reaction was quenched by
dropwise addition of methanol, before being diluted with methanol and loaded
onto an SCX-2 cartridge, which was washed with MeOH. The product was eluted
with 2M NH in MeOH; concentration in vacuo gave a residue. FCC, using 2-10%
[2M NH in MeOH] in DCM, gave the title compound (140 mg, 33%). LCMS
(Method 4): Rt 2.37, m/z 564.2 [MH ].
h. 1-(5-tert-Butylp-tolyl-2H-pyrazolyl)((1S,4R){3-[(S)(3-
triisopropylsilanyloxy-propyl)-pyrrolidinyl]-[1,2,4]triazolo[4,3-a]pyridin
yloxy}-1,2,3,4-tetrahydro-naphthalenyl)-urea (Intermediate 84h)
N OTIPS
To a solution of Intermediate 84g (140 mg, 0.25 mmol) in 1,4-dioxane (3.00
mL) was added DIPEA (86.0 mL, 0.50 mmol) and (5-tert-butylp-tolyl-2H-
pyrazolyl)-carbamic acid 2,2,2-trichloro-ethyl ester (Synthetic
Communications, 2009, 39, 3999-4009; 100 mg, 0.25 mmol). The reaction was
heated to 60°C overnight then further (5-tert-butylp-tolyl-2H-pyrazolyl)-
carbamic acid 2,2,2-trichloro-ethyl ester (50.0 mg, 0.12 mmol) was added and
heating at 60°C continued overnight. The reaction was cooled and partitioned
between EtOAc and water. The aqueous layer was then extracted with EtOAc (3
×). The combined organic layers were washed with brine, dried (MgSO ), filtered
and evaporated in vacuo. The residue was purified by FCC, using 0-10% [2M NH
in MeOH] in DCM, to give the title compound (70.0 mg, 34%). LCMS (Method
1): Rt 3.46, m/z 820.4 [MH ].
i. 1-(5-tert-Butylp-tolyl-2H-pyrazolyl)((1S,4R){3-[(S)(3-
hydroxy-propyl)-pyrrolidinyl]-[1,2,4]triazolo[4,3-a]pyridinyloxy}-
1,2,3,4-tetrahydro-naphthalenyl)-urea (Example 84)
TBAF (1M in THF, 100 mL, 0.10 mmol) was added to a solution of
Intermediate 84h (70.0 mg, 0.085 mmol) in THF (2.00 mL). The reaction was
stirred for 2 h then partitioned between EtOAc and water. The aqueous layer was
then extracted with EtOAc (3 ×). The combined organic layers were washed with
brine, dried (MgSO ), filtered and evaporated in vacuo. The residue was purified
by FCC, using 0-10% [2M NH in MeOH] in DCM. Further purification by HPLC
(C18 X-select column, 10-98% MeCN in H O, 0.1% HCO H) gave the title
compound as a white powder after freeze-drying (29 mg, 52%). LCMS (Method
): Rt 3.63 min, m/z 663.3 [MH ]. ¹H NMR (400 MHz, d -MeOD): 1.30 (9H, s),
1.54-1.62 (2H, quin, J 7.0), 1.88-2.15 (6H, m), 2.20-2.37 (4H, m), 2.38 (3H, s),
2.55 (1H, dt, J 12.0, 8.1), 3.32-3.48 (3H, m), 4.11 (1H, t, J 8.0), 4.90 (1H, dd, J 9.1,
.7), 5.31 (1H, t, J 4.0), 6.33 (1H, s), 7.20-7.36 (9H, m), 7.65 (1H, d, J 9.9), 8.32
(1H, d, J 1.7).
Example 85
1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-((S)
hydroxymethylmethyl-pyrrolidinyl)-[1,2,4]triazolo[4,3-a]pyridin
yloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea
N N N
a. (3R,7aS)Trichloromethyl-tetrahydro-pyrrolo[1,2-c]oxazolone
(Intermediate 85a)
A suspension of L-proline (10.0 g, 87.0 mmol) and chloral hydrate (21.6 g,
130 mmol) in chloroform (100 mL) was heated at reflux for 6 h under a soxlet
adapter charged with sodium sulfate. The cooled mixture was washed with water
(2 ×), dried (MgSO ) and concentrated in vacuo. The product was recrystallised
from boiling absolute ethanol to give the title compound as white needles (13.3 g,
63%). ¹H NMR (400 MHz, CDCl ): 1.65-1.83 (1H, m), 1.86-2.01 (1H, m), 2.04-
2.31 (2H, m), 3.06-3.18 (1H, m), 3.36-3.49 (1H, m), 4.12 (1H, dd, J 4.6, 4.0), 5.16
(1H, s).
b. (3R,7aR)-7a-Benzyloxymethyltrichloromethyl-tetrahydro-
pyrrolo[1,2-c]oxazolone (Intermediate 85b)
To a solution of LDA (531 mL, 0.109M, 58.1 mmol) at -78°C was added a
solution of Intermediate 85a (10.0 g, 41.2 mmol) in THF (200 mL) over 30 min
maintaining the temperature below -70°C. The mixture was stirred at -78°C for 2
h, then a solution of benzyloxymethyl chloride (11.6 g, 74.1 mmol) in THF (50
mL) added, maintaining the temperature below -70°C. The mixture was allowed to
warm to -30°C over 3 h before being quenched with dropwise addition of water
(300 mL). The aqueous was extracted with EtOAc (2 ×). The combined organic
layers were dried (MgSO ) and concentrated in vacuo. The residue was purified by
FCC, using 0-60% diethyl ether in cyclohexane, to give the title compound as a
clear oil (6.39 g, 42%). ¹H NMR (400 MHz, CDCl ): 1.63-1.77 (1H, m), 1.94-2.04
(1H, m), 2.08-2.17 (1H, m), 2.26-2.36 (1H, m), 3.22-3.29 (1H, m), 3.30-3.38 (1H,
m), 3.74, (2H, s), 4.62 (2H, s), 4.99 (1H, s), 7.26-7.37 (5H, m).
c. (R)Benzyloxymethyl-pyrrolidinecarboxylic acid methyl ester
(Intermediate 85c)
A solution of Intermediate 85b (6.39 g, 17.9 mmol) and sodium methoxide
(580 mg, 10.8 mmol) in MeOH (100 mL) was stirred at RT for 18 h. The mixture
was cooled to 0°C, then acetyl chloride (28.4 g, 359 mmol) added. This mixture
was stirred at reflux for 1 h, then cooled and concentrated in vacuo. The residue
was divided, applied to SCX-2 cartridges (3 × 70 g) and washed with MeOH. The
product was eluted with 2M NH in MeOH; concentration in vacuo gave the title
compound as a pale yellow oil (3.92 g, 87%). ¹H NMR (400 MHz, CDCl ): 1.62-
1.86 (3H, m), 1.07-2.13 (1H, m), 2.48 (1H, br s), 2.93-3.11 (2H, m), 3.69-3.78
(4H, m), 4.53 (1H, d, J 12.9), 4.55 (1H, d, J 12.9), 7.21-7.37 (5H, m).
d. (R)Benzyloxymethylmethyl-pyrrolidinecarboxylic acid
methyl ester (Intermediate 85d)
A solution of Intermediate 85c (3.37 g, 13.5 mmol) and formaldehyde (37%
aqueous, 4.38 mL, 54.1 mmol) in DCM (140 mL) was stirred at RT for 30 min,
then sodium triacetoxyborohydride (5.74 g, 27.1 mmol) was added. This mixture
was stirred at RT for 18 h then washed with sat. aq. NaHCO solution, dried
(MgSO ) and concentrated in vacuo. The residue was purified by FCC, using 0-
% [2M NH in MeOH] in DCM, to give the title compound as a clear oil (2.59 g,
72%). LCMS (Method 4): Rt 1.85 min, m/z 263 [MH ].
e. (R)Hydroxymethylmethyl-pyrrolidinecarboxylic acid methyl
ester (Intermediate 85e)
HO O
A suspension of Intermediate 85d (2.59 g, 9.84 mmol), palladium hydroxide
on charcoal (10%, 250 mg) and glacial acetic acid (1 mL) in IMS (20 mL) under
an atmosphere of hydrogen (1 atm) was stirred at RT for 5 d. The mixture was
filtered and concentrated in vacuo to give the title compound as a clear oil (1.70 g,
99%), as a mixture of methyl and ethyl esters. Data for major product, methyl
ester: ¹H NMR (400 MHz, CDCl ): 1.75-1.95 (2H, m), 2.01-2.18 (2H, m), 2.36
(3H, s), 2.86-2.99 (2H, m), 3.65 (3H, s), 4.19 (2H, m), 4.91 (1H, br s).
f. (R)Methyltriisopropylsilanyloxymethyl-pyrrolidine
carboxylic acid methyl ester (Intermediate 85f)
Triisopropylsilyl trifluoromethanesulfonate (11.7 g, 38.1 mmol) was added
to a solution of Intermediate 85e (2.20 g, 12.7 mmol) and Et N (12.8 g, 127 mmol)
in DCM (100 mL) at 0°C, then the mixture stirred at RT for 30 min. The mixture
was diluted with DCM and washed with 10% aq. K CO solution, water, brine,
dried (MgSO ) and concentrated in vacuo. The residue was purified by FCC, using
0-5% [2M NH in MeOH] in DCM, to give the title compound as a pale yellow
solid (2.51 g, 65%). ¹H NMR (400 MHz, CDCl ): 0.97-1.15 (21H, m), 1.72-1.96
(2H, m), 2.23-2.35 (2H, m), 2.46 (3H, s), 2.89-2.99 (2H, m), 3.69 (3H, m), 4.12-
4.22 (2H, m).
g. (R)Methyltriisopropylsilanyloxymethyl-pyrrolidine
carboxylic acid (Intermediate 85g)
O OH
A solution of Intermediate 85f (2.50 g, 7.93 mmol) and lithium hydroxide
monohydrate (3.33 g, 79.3 mmol) in MeOH and water (50mL) was stirred at reflux
for 2 h. The cooled solution was acidified with 1M HCl to pH 5. The MeOH was
removed in vacuo and the resulting aqueous layer was extracted with EtOAc (3 ×).
The combined organic layers were dried (MgSO ) and concentrated in vacuo to
give the title compound as a white foam (2.21 g, 92%). ¹H NMR (400 MHz,
CDCl ): 1.00-1.21 (21H, m), 1.93-2.04 (2H, m), 2.32-2.42 (1H, m), 2.43-2.56 (1H,
m), 2.96-3.09 (4H, m), 3.90-4.00 (1H, m), 4.20 (1H, d, J 10.9), 4.22 (1H, d, J
.9).
h. (R)Methyltriisopropylsilanyloxymethyl-pyrrolidine
carboxylic acid N'-(5-fluoro-pyridinyl)-hydrazide (Intermediate 85h)
To a solution of Intermediate 85g (1.08 g, 3.58 mmol), (5-fluoro-pyridin
yl)-hydrazine (500 mg, 3.93 mmol) and DIPEA (1.38 g, 10.7 mmol) in DCM (120
mL) was added HATU (2.04 g, 5.37 mmol) and the mixture stirred at RT for 2 h.
The solution was washed with 10% aq. K CO solution, brine, dried (MgSO ), and
2 3 4
concentrated in vacuo. The residue was purified by FCC, using 0-6% [2M NH in
MeOH] in DCM, to give the title compound as a pale yellow oil (1.37 g, 90%).
LCMS (Method 4): Rt 2.74 min, m/z 425 [MH ].
i. 6-Fluoro((S)methyltriisopropylsilanyloxymethyl-pyrrolidin-
2-yl)-[1,2,4]triazolo[4,3-a]pyridine (Intermediate 85i)
To a solution of Intermediate 85h (1.37 g, 2.08 mmol), Ph P (1.09 g, 4.16
mmol) and EtN (840 mg, 8.32 mmol) in THF (60 mL) was added
hexachloroethane (980 mg, 4.16 mmol) and the mixture stirred at RT for 20 h. The
mixture was diluted with DCM, washed with 10% aq. K CO solution, brine, dried
(MgSO ) and concentrated in vacuo. The residue was purified by FCC, using 0-
100% EtOAc in cyclohexane, to give the title compound as a clear oil (350 mg,
41%). LCMS (Method 4): Rt 3.07 min, m/z 407 [MH ].
j. (1S,4R)[3-((S)Methyltriisopropylsilanyloxymethyl-
pyrrolidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-
naphthalenylamine (Intermediate 85j)
To a solution of Intermediate A (170 mg, 1.03 mmol) in DMF (4 mL) was
added NaH (60% in oil, 103 mg, 2.59 mmol) and the mixture stirred at RT for 20
min, before Intermediate 85i (350 mg, 0.862 mmol) was added. This mixture was
stirred at 60°C for 4 h. The cooled mixture was diluted with EtOAc, washed with
water (3 ×), brine, dried (MgSO ) and concentrated in vacuo. The residue was
purified by FCC, using 0-10% [2M NH in MeOH] in DCM, to give the title
compound as a clear viscous oil (230 mg, 48%). LCMS (Method 1): Rt 2.28 min,
m/z 550 [MH ].
k. 1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-((S)
methyltriisopropylsilanyloxymethyl-pyrrolidinyl)-[1,2,4]triazolo[4,3-
a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea (Intermediate
85k)
A solution of Intermediate 85j (230 mg, 0.418 mmol), (5-tert-butylp-
tolyl-2H-pyrazolyl)-carbamic acid 2,2,2-trichloro-ethyl ester (Synthetic
Communications, 2009, 39, 3999-4009; 253 mg, 0.628 mmol) and DIPEA (215
mg, 1.67 mmol) in DMF (4 mL) was stirred at 50°C for 1 h. The mixture was
diluted with EtOAc, washed with water (2 ×), brine, dried (MgSO ) and
concentrated in vacuo. The residue was purified by FCC, using 0-10% [2M NH in
MeOH] in DCM, to give the title compound as a white foam (250 mg, 48%).
LCMS (Method 3): Rt 3.70 min, m/z 805 [MH ].
l. 1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-((S)
hydroxymethylmethyl-pyrrolidinyl)-[1,2,4]triazolo[4,3-a]pyridin
yloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea (Example 85)
To a solution of Intermediate 85k (250 mg, 0.310 mmol) in THF (10 mL) at
-30°C was added TBAF (1M in THF, 620 µL, 0.620 mmol) and the mixture was
allowed to warm to RT over 2 h. The reaction mixture was applied to an SCX-2
cartridge (10 g) and washed with MeOH. The product was eluted with 2M NH in
MeOH; concentration in vacuo gave a residue. FCC, using 0-10% [2M NH in
MeOH] in DCM, gave a crude product. Recrystallisation from hot diethyl ether (50
mL), EtOAc (10 mL) and cyclohexane (20 mL) gave the title compound as a white
powder (113 mg, 56%). LCMS (Method 5): Rt 3.68 min, m/z 649.1 [MH ]. ¹H
NMR (400 MHz, d -MeOD): 1.29 (9H, s), 1.86-2.34 (11H, m), 2.38 (3H, s), 3.02
(1H, m), 3.09 (1H, dt, J 8.8, 3.5), 4.07 (1H, d, J 11.0), 4.25 (1H, d, J 4.3), 4.52 (1H,
br s), 4.90 (1H, m), 5.25 (1H, t, J 4.3), 6.33 (1H, s), 7.18-7.36 (9H, m), 7.62 (1H, d
J 7.6), 8.44 (1H, s).
Example 86
1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-(1,4-
dimethyl-piperazinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-urea formate salt
a. 2-[N'-(5-Fluoro-pyridinyl)-hydrazinocarbonyl]-piperazine-1,4-
dicarboxylic acid di-tert-butyl ester (Intermediate 86a)
F O N
N Boc
To a solution of piperazine-1,2,4-tricarboxylic acid 1,4-di-tert-butyl ester
(780 mg, 2.4 mmol) and (5-fluoro-pyridinyl)-hydrazine (250 mg, 2.0 mmol) and
Et N (0.83 mL, 6 mmol) in DCM (20 mL) were added HOBt.H O (27 mg, 0.2
mmol) and EDC (542 mg, 2.4 mmol) sequentially, and then the mixture stirred at
RT overnight. The mixture was partitioned between EtOAc/water and extracted
with EtOAc. The combined organics were dried over Na SO , filtered and
concentrated in vacuo. The residue was purified by FCC, using 0-10% MeOH in
DCM, to give the title compound as a brown solid (550 mg, 63%). LCMS (Method
4): Rt 3.28, m/z 440 [MH ].
b. 6-Fluoropiperazinyl-[1,2,4]triazolo[4,3-a]pyridine
(Intermediate 86b)
To a solution of Intermediate 86a (550 mg, 1.25 mmol), Et N (0.69 mL, 5
mmol) and Ph P (657 mg, 2.5 mmol) in THF (20 mL) at 0°C was added
hexachloroethane (590 mg, 2.5 mmol) and the mixture stirred for 10 min. The
solution was allowed to warm to RT, stirred for 1 h, then partitioned between
EtOAc/water and extracted with EtOAc. The combined organics were dried over
Na SO , filtered and concentrated in vacuo. The residue was purified by FCC,
using 0-100% EtOAc in cyclohexane, to give crude 2-(6-fluoro-[1,2,4]triazolo[4,3-
a]pyridinyl)-piperazine-1,4-dicarboxylic acid di-tert-butyl ester, contaminated
with triphenylphosphine oxide, as a pale brown solid (500 mg).
The solid (500 mg) was treated with a 4M HCl solution in dioxane (30 mL)
and the mixture stirred at RT for 2 h. The suspension was diluted with MeOH, then
applied onto an SCX-2 cartridge and washed with MeOH. The product was eluted
with 2M NH in MeOH; concentration in vacuo gave the title compound as a pale
yellow solid (100 mg, 23% over 2 steps). LCMS (Method 4): Rt 0.26, m/z 222
[MH ].
c. 3-(1,4-Dimethyl-piperazinyl)fluoro-[1,2,4]triazolo[4,3-
a]pyridine (Intermediate 86c)
To a suspension of Intermediate 86b (100 mg) in 1,2-dichloroethane (10
mL) were added formaldehyde (30% in water, 104 mL, 1.13 mmol) and
NaBH(OAc) (240 mg, 1.13 mmol) sequentially. The mixture was stirred at RT for
2 h, then applied to an SCX-2 cartridge and washed with MeOH. The product was
eluted with 2M NH in MeOH; concentration in vacuo gave the title compound as
a pale yellow solid (100 mg, 89%). LCMS (Method 4): Rt 0.49, m/z 250 [MH ].
d. (1S,4R)[3-(1,4-Dimethyl-piperazinyl)-[1,2,4]triazolo[4,3-
a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenylamine (Intermediate
86d)
To a solution of Intermediate 86c (100 mg, 0.40 mmol) and Intermediate A
(79 mg, 0.40 mmol) in DMF (3 mL) was added NaH (60% in mineral oil, 56 mg,
1.4 mmol) portion-wise. The mixture was stirred at 60°C for 1.5 h then allowed to
cool to RT. The mixture was carefully quenched by pouring into MeOH (10 mL)
then applied to an SCX-2 cartridge and washed with MeOH. The product was
eluted with 2M NH in MeOH; concentration in vacuo gave a residue. FCC, using
0-20% [2M NH in MeOH] in DCM, gave the title compound as a brown oil (104
mg, 66%). LCMS (Method 4): Rt 0.26, m/z 393 [MH ].
e. 1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-(1,4-
dimethyl-piperazinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-urea formate salt (Example 86)
The title compound was prepared as an off white solid (70 mg, 42%) using
(5-tert-butylp-tolyl-2H-pyrazolyl)-carbamic acid 2,2,2-trichloro-ethyl ester
(Synthetic Communications, 2009, 39, 3999-4009; 107 mg, 0.26 mmol) and
Intermediate 86d (104 mg, 0.26 mmol) in a similar manner to Example 1, step d.
LCMS (Method 5): Rt 3.64 min, m/z 648 [MH ]. ¹H NMR (400 MHz, d -DMSO):
1.27 (9H, s), 1.83-1.98 (5H, m), 2.05-2.25 (6H, m), 2.30-2.42 (5H, m), 2.75 (2H, d,
J 10.7), 2.89-2.94 (1H, m), 3.92-3.95 (1H, m), 4.80-4.86 (1H, m), 5.38-5.46 (1H,
m), 6.32 (1H, s), 7.10 (1H, d, J 8.6), 7.26-7.42 (9H, m), 7.75 (1H, d, J 9.7), 8.04
(1H, s), 8.16 (1H, s), 8.46-8.50 (1H, m).
Example 87
1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-((S)-1,4,4-
trimethyl-pyrrolidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-urea
a. (S)-1,4,4-Trimethyl-pyrrolidinecarboxylic acid (Intermediate 87a)
A suspension of 4,4-dimethyl-L-proline hydrochloride (900 mg, 5.00
mmol), formaldehyde (37% aqueous, 450µL), DIPEA (645 mg, 5.00 mmol) and
palladium on carbon (10%, 400 mg) in IMS (50 mL) was stirred under an
atmosphere of hydrogen (1 atm) for 4 h. The suspension was filtered and
concentrated in vacuo to give the title compound as a viscous pink oil (780 mg,
99%). ¹H NMR (400 MHz, CDCl ): 1.47 (3H, s), 1.49 (3H, s), 2.04-2.16 (1H, m),
2.23-2.34 (1H, m), 2.93 (3H, s), 3.10 (2H, m), 3.78-3.89 (1H, m), 4.86 (1H, br s).
b. (S)-1,4,4-Trimethyl-pyrrolidinecarboxylic acid N'-(5-fluoro-
pyridinyl)-hydrazide (Intermediate 87b)
To a solution of Intermediate 87a (1.70 g, 5.00 mmol), (5-fluoro-pyridin
yl)-hydrazine (600 mg, 5.00 mmol) and DIPEA (1.29 g, 10.0 mmol) in DCM was
added HATU (2.28 g, 6.00 mmol) and the mixture stirred at RT for 1 h. The
reaction mixture was applied to an SCX-2 cartridge (70 g) and washed with
MeOH. The product was eluted with 2M NH in MeOH; concentration in vacuo
gave a residue. FCC, using 0-10% [2M NH in MeOH] in DCM, gave the title
compound as a yellow oil (950 mg, 71%). ¹H NMR (400 MHz, CDCl ): 1.13 (3H,
s), 1.15 (3H, s), 1.74 (1H, dd, J 12.5, 6.2), 2.12 (1H, dd, J 11.6, 10.0), 2.29 (1H, d,
J 8.9), 2.46 (3H, s), 2.88 (1H, d, J 8.9), 3.15 (1H, dd, J 9.7, 6.5), 6.56-6.65 (2H, m),
7.28 (1H dt, J 8.6, 2.9), 8.03 (1H, d, J 2.5), 9.09 (1H, br s).
c. 6-Fluoro((S)-1,4,4-trimethyl-pyrrolidinyl)-[1,2,4]triazolo[4,3-
a]pyridine (Intermediate 87c)
To a solution of Intermediate 87b (950 mg, 3.57 mmol), Ph P (1.87 g, 7.14
mmol) and EtN (1.44 g, 14.28 mmol) in THF (40 mL) was added
hexachloroethane (1.65 g, 7.14 mmol) and the mixture stirred at RT for 20 h. The
reaction mixture was applied to an SCX-2 cartridge (70 g) and washed with
MeOH. The product was eluted with 2M NH in MeOH; concentration in vacuo
gave a residue. FCC, using 0-10% [2M NH in MeOH] in DCM gave the title
compound as a clear oil (750 mg, 84%). ¹H NMR (400 MHz, CDCl ): 1.22 (3H, s),
1.24 (3H, s), 1.84 (1H, dd, J 12.7, 10.8), 2.04 (1H, dd, J 12.4, 7.4), 2.16 (3H, s),
2.25 (1H, d J, 9.1), 3.04 (1H, d, J 9.3), 4.22 (1H, dd, J 10.0, 7.6), 7.14-7.23 (1H,
m), 7.69-7.77 (1H, m), 8.75-8.80 (1H, m).
d. (1S,4R)[3-((S)-1,4,4-Trimethyl-pyrrolidinyl)-[1,2,4]triazolo[4,3-
a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenylamine (Intermediate
87d)
To a solution of Intermediate A (552 mg, 3.89 mmol) in DMF (25 mL) was
added NaH (60% in oil, 338 mg, 8.46 mmol) and the mixture stirred at RT for 20
min, before Intermediate 87c (700 mg, 2.82 mmol) was added. This mixture was
stirred at 60°C for 1 h. The cooled reaction mixture was applied to an SCX-2
cartridge (70 g) and washed with MeOH. The product was eluted with 2M NH in
MeOH; concentration in vacuo gave a residue. FCC, using 0-10% [2M NH in
MeOH] in DCM gave the title compound (820 mg, 74%). LCMS (Method 4): Rt
1.53 min, m/z 392 [MH ].
e. 1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-((S)-1,4,4-
trimethyl-pyrrolidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-urea (Example 87)
A solution of Intermediate 87d (150 mg, 0.383 mmol), (5-tert-butylp-
tolyl-2H-pyrazolyl)-carbamic acid 2,2,2-trichloro-ethyl ester (Synthetic
Communications, 2009, 39, 3999-4009; 232 mg, 0.575 mmol) and DIPEA (198
mg, 1.53 mmol) in DMF (4 mL) was stirred at 50°C for 1 h. The cooled reaction
mixture was applied to an SCX-2 cartridge (10 g) and washed with MeOH. The
product was eluted with 2M NH in MeOH; concentration in vacuo gave a residue.
FCC, using 0-6% [2M NH in MeOH] in DCM, then trituration with diethyl ether
gave the title compound as an off-white powder (170 mg, 68%). LCMS (Method
): Rt 3.80 min, m/z 647.5 [MH ]. ¹H NMR (400 MHz, d -MeOH): 1.15 (3H, s),
1.24 (3H, s), 1.30 (9H, s), 1.85-2.05 (4H, m), 2.14 (3H, s), 2.19-2.31 (2H, m), 2.38
(3H, s), 2.97 (1H, d, J 10.3), 3.45 (1H, dd, J 7.5, 6.1), 4.06 (1H, t, J 9.3), 4.90 (1H,
m), 5.30 (1H, t, J 4.2), 6.33 (1H, s), 7.20-7.36 (9H, m), 7.65 (1H, d, J 10.8), 8.46
(1H, d, J 1.1).
Example 88
1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-((S)
methyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-urea
a. (S)[N'-(5-Fluoro-pyridinyl)-hydrazinocarbonyl]-piperidine
carboxylic acid tert-butyl ester (Intermediate 88a)
N N O
To a solution of (5-fluoro-pyridinyl)-hydrazine (1.27 g, 10.0 mmol), (S)-
1-BOC piperidinecarboxylic acid (Alfa Aesar, 2.29 g, 10.0 mmol) and
HOBt.H O (153 mg, 1.00 mmol) in DCM (50 mL) was added EDC (2.30 g, 12.0
mmol) and the resulting orange solution stirred at RT for 16 h. Water (25 mL) was
added and the mixture shaken. The aqueous was extracted with DCM (25 mL) then
the combined organics were passed through a hydrophobic frit and concentrated in
vacuo to leave a pale brown foam. FCC, using 0-5% MeOH in DCM, gave the title
compound as a pale orange foam (3.21 g, 95%). LCMS (Method 3): Rt 3.14 min,
m/z 361 [MNa ].
b. (S)(6-Fluoro-[1,2,4]triazolo[4,3-a]pyridinyl)-piperidine
carboxylic acid tert-butyl ester (Intermediate 88b)
To a solution of Intermediate 88a (3.21 g, 9.49 mmol), Ph P (4.98 g, 19.0
mmol) and Et N (5.29 mL, 37.9 mmol) in THF (100 mL) at 0°C was added
hexachloroethane (4.49 g, 19.0 mmol) and the resulting opaque orange solution
stirred vigorously at RT for 2 h. The suspension was filtered, and the filter-cake
washed with THF (20 mL). The combined organics were concentrated in vacuo,
redissolved in MeOH (5 mL), applied to an SCX-2 cartridge (70 g) and washed
with MeOH (150 mL). The product was eluted with 2M NH in MeOH (150 mL);
concentration in vacuo gave a pale orange solid (2.62 g). FCC, using 2-5% MeOH
in DCM, gave the title compound as a pale yellow solid (2.01 g, 66%). LCMS
(Method 3): Rt 3.09 min, m/z 221 [M-C H O +H ].
9 2
c. 6-Fluoro(S)-piperidinyl-[1,2,4]triazolo[4,3-a]pyridine
(Intermediate 88c)
A yellow solution of Intermediate 88b (2.01 g, 6.27 mmol) and TFA (11.0
mL, 148 mmol) in DCM (50 mL) was stirred at reflux for 30 min. The cooled
solution was concentrated in vacuo, redissolved in MeOH (3 mL), applied to an
SCX-2 cartridge (50 g) and washed with MeOH (150 mL). The product was eluted
with 2M NH in MeOH (100 mL); concentration in vacuo left the title compound
as a pale orange solid (1.26 g, 91%). LCMS (Method 3): Rt 0.35 min, m/z 221
[MH ].
d. 6-Fluoro((S)methyl-piperidinyl)-[1,2,4]triazolo[4,3-
a]pyridine (Intermediate 88d)
To a yellow solution of Intermediate 88c (220 mg, 1.00 mmol),
formaldehyde (37% in water, 0.811 mL, 10.0 mmol) and AcOH (0.057 mL, 1.00
mmol) in DCM-MeOH (5:1, 12 mL) was added NaBH(OAc) (424 mg, 2.00
mmol) (CARE: gas evolution) and the solution stirred at RT for 2 h. The solution
was concentrated in vacuo to ~5 mL volume, then applied to an SCX-2 cartridge
(10 g) and washed with MeOH (50 mL). The product was eluted with 2M NH in
MeOH (50 mL); concentration in vacuo gave the title compound as a pale yellow
gum, that became a white solid on standing (234 mg, quant.). LCMS (Method 3):
Rt 0.45 min, m/z 235 [MH ].
e. (1S,4R)[3-((S)Methyl-piperidinyl)-[1,2,4]triazolo[4,3-
a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenylamine (Intermediate
88e)
To a solution of Intermediate A (196 mg, 1.20 mmol) in dry DMF (3 mL) at
RT under N was added NaH (60% dispersion in oil, 80 mg, 2.00 mmol) and the
resulting opaque brown solution stirred for 45 min. A solution of Intermediate 88d
(234 mg, 1.00 mmol) in dry DMF (2 mL) was added and the resulting dark brown
solution stirred at 60°C for 90 min. The cooled solution was concentrated in vacuo,
redissolved in MeOH (2 mL) and AcOH (0.1 mL), applied to and SCX-2 cartridge
and washed with MeOH (75 mL). The product was eluted with 2M NH in MeOH
(60 mL); concentration in vacuo left a dark brown solid. FCC, using 3-13% [2M
NH in MeOH] in DCM, gave the title compound as a light brown solid after
freeze-drying (280 mg, 74%). LCMS (Method 3): Rt 0.44 min, m/z 378 [MH ].
f. 1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-((S)
methyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-urea. (Example 88)
An orange-brown solution (5-tert-butylp-tolyl-2H-pyrazolyl)-
carbamic acid 2,2,2-trichloro-ethyl ester (Synthetic Communications, 2009, 39,
3999-4009; 243 mg, 0.600 mmol), Intermediate 88e (151 mg, 0.400 mmol) and
DIPEA (0.122 mL, 0.700 mmol) in dry dioxane (5 mL) was stirred at 65°C for 15
h. The cooled solution was concentrated in vacuo, redissolved in MeOH (2 mL),
applied to an SCX-2 cartridge (10 g) and washed with MeOH (50 mL). The
product was eluted with 2M NH in MeOH (30 mL); concentration in vacuo left a
brown solid. FCC, using 2-7% [2M NH in MeOH] in DCM, gave the title
compound as a pale yellow solid (188 mg, 74%). LCMS (Method 5): Rt 3.63 min,
m/z 633 [MH ]. ¹H NMR (400 MHz, d -DMSO): 1.27 (9H, s), 1.55 (1H, qd, J
11.9, 5.3), 1.68-1.79 (2H, m), 1.83-2.03 (4H, m), 2.06-2.14 (2H, m), 2.22 (1H, t, J
.9), 2.22 (3H, s), 2.36 (3H, s), 2.83 (1H, br d, J 10.9), 3.01 (1H, ddd, J 11.1, 3.6,
1.6), 3.54 (1H, tt, J 11.1, 3.7), 4.83 (1H, td, J 8.4, 5.5), 5.57 (1H, t, J 4.5), 6.33 (1H,
s), 7.09 (1H, d, J 8.5), 7.15 (1H, dd, J 9.8, 2.0), 7.27-7.42 (8H, m), 7.68 (1H, d, J
9.9), 8.03 (1H, s), 8.32 (1H, d, J 2.0).
Example 89
1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-((R)
methyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-urea
The title compound was prepared starting from (R)BOC-piperidine
carboxylic acid (Alfa Aesar) using analogous procedures to those described in
Example 88. LCMS (Method 5): Rt 3.62 min, m/z 633 [MH ]. ¹H NMR (400
MHz, d -DMSO): 1.27 (9H, s), 1.55 (1H, qd, J 12.0, 5.5), 1.67-1.79 (2H, m), 1.82-
2.16 (6H, m), 2.22 (3H, s), 2.23 (1H, t, J 11.0), 2.36 (3H, s), 2.83 (1H, br d, J
11.0), 2.99 (1H, br d, J 11.2), 3.53 (1H, tt, J 11.1, 3.7), 4.83 (1H, td, J 8.4, 5.5),
.57 (1H, t, J 4.5), 6.33 (1H, s), 7.09 (1H, d, J 8.5), 7.16 (1H, dd, J 9.8, 2.1), 7.35-
7.33 (8H, m), 7.68 (1H, d, J 9.9), 8.04 (1H, s), 8.29 (1H, d, J 2.0).
Example 90
1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-((R)
methyl-pyrrolidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-urea
a. (R)[N'-(5-Fluoro-pyridinyl)-hydrazinocarbonyl]-pyrrolidine
carboxylic acid tert-butyl ester (Intermediate 90a)
To a brown solution of (5-fluoro-pyridinyl)-hydrazine (590 mg, 4.64
mmol), (R)N-BOC-beta proline (Manchester Organics, 1.00 g, 4.64 mmol) and
HOBt.H O (71.1 mg, 0.464 mmol) in DCM (20 mL) at RT was added EDC (1.07
g, 5.57 mmol) (CARE: exotherm to ~35°C) and the resulting solution stirred at RT
for 4 h. Water (20 mL) was added and the mixture shaken. The aqueous was
extracted with DCM (20 mL), then the combined organics were passed through a
hydrophobic frit and concentrated in vacuo to ~1 mL volume. FCC, using 1-10%
MeOH in DCM, gave the title compound as a pale brown foam (1.37 g, 91%).
LCMS (Method 3): Rt 2.93 min, m/z 347 [MNa ].
b. (R)(6-Fluoro-[1,2,4]triazolo[4,3-a]pyridinyl)-pyrrolidine
carboxylic acid tert-butyl ester (Intermediate 90b)
To a brown solution Intermediate 90a (1.37 g, 4.22 mmol), Ph P (2.22 g,
8.45 mmol) and Et N (2.35 mL, 16.9 mmol) in THF (25 mL) at 0°C was added
hexachloroethane (2.00 g, 8.45 mmol) in 3 portions at 1 min intervals. The solution
was stirred at 0°C for 30 min and at RT for 3.5 h. The suspension was filtered and
the filter-cake washed with THF (10 mL). The combined organics were applied to
an SCX-2 cartridge (50 g), then washed with DCM-MeOH (1:1, 50 mL) and
MeOH (50 mL). The product was eluted with 2M NH in MeOH (75 mL);
concentration in vacuo gave a brown oil that solidified on standing.
The solid was dissolved in DCM (10 mL) then Et N (0.580 mL, 4.16 mmol)
and BOC anhydride (454 mg, 2.08 mmol) added sequentially. The solution was
stirred at RT for 45 min, then water (10 mL) was added and the aqueous extracted
with DCM (5 mL). The combined organics were passed through a hydrophobic frit
and concentrated in vacuo to leave a brown gum. FCC, using 2.5-3% MeOH in
DCM, gave the title compound as a pale brown solid (933 mg, 73%). LCMS
(Method 3): Rt 2.94 min, m/z 207 [MH -C H O ].
9 2
c. 6-Fluoro(R)-pyrrolidinyl-[1,2,4]triazolo[4,3-a]pyridine
(Intermediate 90c)
A mixture of Intermediate 90b (335 mg, 1.09 mmol) and TFA (0.812 mL,
.9 mmol) in DCM (5 mL) was stirred at reflux for 45 min. The cooled solution
was concentrated in vacuo, redissolved in MeOH (2 mL), applied to an SCX-2
cartridge (10 g) and washed with MeOH (50 mL). The product was eluted with 2M
NH in MeOH; concentration in vacuo left the title compound as a pale yellow
solid (225 mg, >99%). LCMS (Method 3): Rt 0.44 min, m/z 207 [MH ].
d. 6-Fluoro((R)methyl-pyrrolidinyl)-[1,2,4]triazolo[4,3-
a]pyridine (Intermediate 90d)
To a solution of Intermediate 90c (225 mg, 1.09 mmol), formaldehyde (37%
in water, 0.885 mL, 10.9 mmol) and AcOH (0.0625 mL, 1.09 mmol) in DCM (20
mL) and MeOH (1 mL) was added NaBH(OAc) (462 mg, 2.18 mmol) (CARE:
gas evolution) and the pale yellow solution stirred at RT for 16 h. The solution was
concentrated to ~2 mL volume, then was applied to an SCX-2 cartridge and was
washed with MeOH (25 mL). The product was eluted with 2M NH in MeOH (25
mL); concentration in vacuo left the title compound as a pale brown viscous oil
(228 mg, 95%). LCMS (Method 3): Rt 0.44 min, m/z 221 [MH ].
e. (1S,4R)[3-((R)Methyl-pyrrolidinyl)-[1,2,4]triazolo[4,3-
a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenylamine (Intermediate
90e)
To a solution of Intermediate A (203 mg, 1.24 mmol) in dry DMF (3 mL)
under N was added NaH (60% dispersion in oil, 83.0 mg, 2.07 mmol) (CARE: gas
evolution) and the resulting opaque brown solution stirred at RT for 45 min. A
solution of Intermediate 90d (228 mg, 1.03 mmol) in dry DMF (2 mL) was added
and the dark brown solution stirred at 60°C under N for 90 min. The cooled
solution was concentrated in vacuo, redissolved in MeOH (2 mL) and AcOH (0.1
mL), applied to and SCX-2 cartridge (20 g) and washed with MeOH (75 mL). The
product was eluted with 2M NH in MeOH (50 mL); concentration in vacuo gave a
dark brown solid. FCC, using 5-15% [2M NH in MeOH] in DCM, gave the title
compound as a light brown powder after freeze-drying (299 mg, 80%). LCMS
(Method 3): Rt 0.44 min, m/z 364 [MH ].
f. 1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-((R)
methyl-pyrrolidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-urea. (Example 90)
A brown solution of (5-tert-butylp-tolyl-2H-pyrazolyl)-carbamic acid
2,2,2-trichloro-ethyl ester (Synthetic Communications, 2009, 39, 3999-4009; 227
mg, 0.560 mmol), Intermediate 90e (145 mg, 0.400 mmol) and DIPEA (0.111 mL,
0.640 mmol) in dry dioxane (5 mL) was stirred at 65°C for 15 h. The cooled
solution was concentrated in vacuo, redissolved in MeOH (2 mL), applied to an
SCX-2 cartridge (10 g) and washed with MeOH (50 mL). The product was eluted
with 2M NH in MeOH (30 mL); concentration in vacuo gave a brown solid. FCC,
using 2-7% [2M NH in MeOH] in DCM, gave a pale brown solid (195 mg).
Further purification by MDAP (Method 8) gave the title compound as a white
powder after freeze-drying (10.0 mg, 4%). LCMS (Method 5): Rt 3.62 min, m/z
619 [MH ]. ¹H NMR (400 MHz, d -DMSO): 1.27 (9H, s), 1.83-1.98 (2H, m), 2.08-
2.20 (3H, m), 2.32 (3H, s), 2.33-2.40 (1H, m), 2.36 (3H, s), 2.59-2.70 (2H, m),
2.75 (1H, dd, J 9.2, 6.1), 2.96 (1H, t, J 8.7), 3.93-4.01 (1H, m), 4.83 (1H, td, J 8.4,
.4), 5.46 (1H, t, J 4.6), 6.32 (1H, s), 7.10 (1H, d, J 8.5), 7.18 (1H, dd, J 9.9, 2.1),
7.27-7.40 (8H, m), 7.69 (1H, dd, J 9.9, 0.8), 8.04 (1H, s), 8.44 (1H, d, J 2.0).
Example 91
1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-((2S,4R)
fluoromethyl-pyrrolidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-urea
a. (2S,4R)Fluoromethyl-pyrrolidinecarboxylic acid
(Intermediate 91a)
A solution of (2S,4R)fluoropyrrolidinecarboxylic acid (1.00 g, 7.52
mmol), formaldehyde (37%wt in water, 1.00 mL, 30.8 mmol), 12N HCl (0.5 mL)
in IMS (38 mL) was purged with argon. To the solution was added Pd/C (100 mg),
then the flask was evacuated and filled with H the resulting suspension was stirred
at RT for 3 d. The reaction mixture was passed through a pad of Celite and the
mixture was concentrated in vacuo to give the title compound as a pale yellow gum
(600 mg, 54%). ¹H NMR (300 MHz, d -DMSO): 2.29-2.37 (1H, m), 2.63-2.67
(1H, m), 2.97 (3H, s), 3.44-3.53 (1H, m), 4.00-4.04 (1H, m), 4.58 (1H, dd, J 11.6,
7.11), 5.41-5.45 (1H, m).
b. (2S,4R)Fluoromethyl-pyrrolidinecarboxylic acid N'-(5-
fluoro-pyridinyl)-hydrazide (Intermediate 91b)
A solution of (5-fluoro-pyridinyl)-hydrazine (378 mg, 2.98 mmol),
Intermediate 91a (600 mg, 4.08 mmol) and HOBt.H2O (44 mg, 0.12 mmol) in
DCM (10 mL) and DMF (3 mL) was added EDC (628 mg, 3.28 mmol)
portionwise at RT and the mixture stirred at RT for 17 h. The solution was diluted
with water and extracted with DCM. The combined organics were dried and
concentrated in vacuo. The residue was purified by FCC, using 0-7.5% [2M NH
in MeOH] in DCM, to give the title compound as light orange powder (366 mg,
%). LCMS (Method 3): Rt 0.56 min, m/z 257 [MH ].
c. 6-Fluoro((2S,4R)fluoromethyl-pyrrolidinyl)-
[1,2,4]triazolo[4,3-a]pyridine (Intermediate 91c)
A solution of Intermediate 91b (189 mg, 0.79 mmol), Ph P (416 mg, 1.59
mmol) and Et N (0.44 mL, 3.17 mmol) in THF (10 mL) at RT was added
hexachloroethane (375 mg, 1.59 mmol) portion wise and the mixture stirred for 4
h. The solution was diluted with water and extracted with DCM. The combined
organics were dried and concentrated in vacuo. The residue was purified by FCC,
using 0-10% [2M NH in MeOH] in DCM, to give the title compound as light
yellow powder (214 mg, 63%). LCMS (Method 3): Rt 0.42 min, m/z 239 [MH ].
d. (1S,4R)[3-((2S,4R)Fluoromethyl-pyrrolidinyl)-
[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalen
ylamine. (Intermediate 91d)
To a solution of Intermediate A (161 mg, 0.99 mmol) in dry DMF (2.5 mL)
at RT was added NaH (60% in mineral oil, 108 mg, 2.70 mmol) and the mixture
stirred for 15 min. Intermediate 91c (214 mg, 0.89 mmol) in DMF (2.5 mL) was
then added and the mixture heated at 60°C for 1 h. After cooling, the resulting dark
brown mixture was diluted with water and extracted with DCM. The combined
organics were dried and concentrated in vacuo. The residue was purified by FCC,
using 0-10% MeOH in DCM, to give crude product. FCC, using 0-10% [2M NH
in MeOH] in DCM, gave the title compound as light brown foam (175 mg, 51%).
LCMS (Method 3): Rt 0.43 min, m/z 382 [MH ].
e. 1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-((2S,4R)
fluoromethyl-pyrrolidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-urea (Example 91)
A solution of Intermediate 91d (164 mg, 0.43 mmol) and 5-tert-butylp-
tolyl-2H-pyrazolyl)-carbamic acid 2,2,2-trichloro-ethyl ester (Synthetic
Communications, 2009, 39, 3999-4009; 191 mg, 0.47 mmol) and DIPEA (225 µL,
1.14 mmol) in THF (5 mL) was stirred at reflux for 18.5 h. The cooled reaction
mixture was diluted with water and extracted with DCM. The combined organics
were dried and concentrated in vacuo. The residue was purified by FCC, using 0-
% [2M NH in MeOH] in DCM, to give impure product. This residue was
purified further by HPLC (XBridge C18 column, 30-98% MeCN in H O, 0.1%
NH OH) to give the title compound as a white powder after freeze-drying (63 mg,
23%). LCMS (Method 5): Rt 3.88 min, m/z 637 [MH ]. ¹H NMR (400 MHz, d -
DMSO): 1.27 (9H, s), 1.88-1.93 (2H, m), 2.06-2.10 (2H, m), 2.17 (3H, s), 2.30-
2.41 (2H, m), 2.36 (3H, s), 2.61-2.64 (2H, m), 3.49 (1H, ddd, J 25.6, 11.5, 5.5),
4.54 (1H, t, J 7.7), 4.80-4.83 (1H, m), 5.49 (1H, t, J 4.3), 6.32 (1H, s), 7.10 (1H, d,
J 8.5), 7.30-7.42 (9H, m), 7.75 (1H, dd, J 9.9, 0.8), 8.05 (1H, s), 8.35 (1H, d, J 2.1).
Example 92
1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-((S)
hydroxymethyl-pyrrolidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-urea
a. [(S)(6-Fluoro-[1,2,4]triazolo[4,3-a]pyridinyl)-pyrrolidinyl]-
methanol (Intermediate 92a)
A solution of Intermediate 24b (485 mg, 2.83 mmol) and (S)
(hydroxymethyl)pyrrolidine (1.00 g, 9.90 mmol) in DMA (10 mL) was heated in
the microwave at 175°C for 2.5 h. The cooled mixture was concentrated in vacuo.
The residue was purified by FCC, using 0-20% [2M NH in MeOH] in DCM, to
give the title compound as a brown gum (670 mg, quant.). LCMS (Method 3): Rt
0.44 min, m/z 237 [MH ].
b. 6-Fluoro((S)triisopropylsilanyloxymethyl-pyrrolidinyl)-
[1,2,4]triazolo[4,3-a]pyridine (Intermediate 92b)
To a solution of Intermediate 92a (667 mg, 2.83 mmol) and Et N (630 µL,
4.53 mmol)in DCM (5 mL) was added triisopropylsilyltrifluoromethane sulfonate
(950 µL, 3.54 mmol) and the mixture was stirred at RT for 1 h. The mixture was
washed with sat. sodium hydrogen carbonate solution then brine, dried and
concentrated in vacuo. The residue was purified by FCC, 2-6% MeOH in DCM, to
give the title compound as a pale green viscous oil (1.11 g, quant.). LCMS
(Method 3): Rt 4.76 min, m/z 393 [MH ].
c. (1S,4R)[3-((S)Triisopropylsilanyloxymethyl-pyrrolidinyl)-
[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalen
ylamine (Intermediate 92c)
To a solution of Intermediate A (179 mg, 1.10 mmol) in DMF (3 mL) was
added NaH (60% dispersion in oil, 120 mg, 3.00 mmol) and the mixture stirred at
RT for 25 min. A solution of Intermediate 92b (958 mg, 1.10 mmol) in DMF (3
mL) was added and the mixture stirred at 60°C for 1.5 h. The solution was cooled,
water added, and the mixture extracted with DCM (4 × 25 mL). The combined
organics were dried and concentrated in vacuo. The residue was purified by FCC,
using 0-16% MeOH in DCM, to give the title compound as a brown gum (216 mg,
37%). LCMS (Method 3): Rt 3.08 min, m/z 536 [MH ].
d. 1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-((S)
triisopropylsilanyloxy-methyl-pyrrolidinyl)-[1,2,4]triazolo[4,3-a]pyridin
yloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea (Intermediate 92d)
A solution of Intermediate 92c (210 mg, 0.39 mmol) and (5-tert-butylp-
tolyl-2H-pyrazolyl)-carbamic acid 2,2,2-trichloro-ethyl ester (Synthetic
Communications, 2009, 39, 3999-4009; 159 mg, 0.390 mmol) in 1,4-dioxane (4
mL) and DIPEA (105 µL, 0.600 mmol) was stirred at 65°C for 15.5 h and at 90°C
for 1.5 h. The cooled mixture was concentrated in vacuo. The residue was purified
by FCC, using 0-10% MeOH in DCM, to give the title compound as a pale brown
solid (242 mg, 79%). LCMS (Method 3): Rt 5.18 min, m/z 791 [MH ].
e. 1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-((S)
hydroxymethyl-pyrrolidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-urea (Example 92)
To a solution of Intermediate 92d (240 mg, 0.300 mmol) and TBAF (1M in
THF, 0.400 mL, 0.400 mmol) in THF (3 mL) was stirred at RT for 1 h. Water was
added and the mixture extracted with DCM (4 × 20 mL). The combined organics
were dried and concentrated in vacuo. The residue was purified by FCC, using 0-
14% MeOH in DCM, to give the title compound as an off-white powder after
freeze-drying (154 mg, 81%). LCMS (Method 5): Rt 4.01 min, m/z 635.3 [MH ].
¹H NMR (400 MHz, d -DMSO): 1.27 (9H, s), 1.68-1.79 (1H, m), 1.79-1.97 (2H,
m), 1.98-2.14 (3H, m), 2.36 (3H, s), 2.40-2.48 (1H, m), 3.23-3.30 (1H, m), 3.41-
3.64 (5H, m), 4.71 (1H, t, J 5.3), 4.77-4.85 (1H, m), 5.51 (1H, br t, J 4.4), 6.33
(1H, s), 7.03-7.10 (2H, m), 7.25-7.40 (8H, m), 7.53 (1H, d, J 9.9), 7.82 (1H, d, J
1.8), 8.03 (1H, s).
Example 93
1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-((R)
hydroxymethyl-pyrrolidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-urea
The title compound was prepared starting from (R)
(hydroxymethyl)pyrrolidine using analogous procedures to those described in
Example 92. LCMS (Method 5): Rt 4.01 min, m/z 635.3 [MH ]. ¹H NMR (400
MHz, d -DMSO): 1.27 (9H, s), 1.67-1.77 (1H, m), 1.79-1.97 (2H, m), 1.98-2.15
(3H, m), 2.37 (3H, s), 2.40-2.48 (1H, m), 3.25-3.30 (1H, m), 3.41-3.62 (5H, m),
4.71 (1H, t, J 5.3), 4.77-4.85 (1H, m), 5.51 (1H, br t, J 4.3), 6.33 (1H, s), 7.04-7.10
(2H, m), 7.25-7.40 (8H, m), 7.53 (1H, d, J 9.9), 7.82 (1H, d, J 1.6), 8.04 (1H, s).
Example 94
1-(5-tert-Butylp-tolyl-2H-pyrazolyl)((1S,4R){3-[4-(2-
hydroxy-ethyl)-piperazinyl]-[1,2,4]triazolo[4,3-a]pyridinyloxy}-1,2,3,4-
tetrahydro-naphthalenyl)-urea
a. 2-[4-(6-Fluoro-[1,2,4]triazolo[4,3-a]pyridinyl)-piperazinyl]-
ethanol (Intermediate 94a)
A solution of Intermediate 24b (485 mg, 2.82 mmol) and 1-(2-
hydroxylethyl)-piperazine (1.39 mL, 11.3 mmol) in DMA (10 mL) was heated in
the microwave at 170°C for 8 h. The cooled mixture was concentrated in vacuo.
The residue was purified by FCC, using 0-20% [2M NH in MeOH] in DCM, to
give impure product. Further purified by FCC, using 0-7% [2M NH in MeOH] in
DCM gave the title compound as a pale brown gum (175 mg, 23%). LCMS
(Method 3): Rt 0.43 min, m/z 266 [MH ].
b. 6-Fluoro[4-(2-triisopropylsilanyloxy-ethyl)-piperazinyl]-
[1,2,4]triazolo[4,3-a]pyridine (Intermediate 94b)
To a solution of Intermediate 94a (169 mg, 0.64 mmol) and Et N (265 µL,
1.91 mmol) in DCM (6 mL) was added triisopropylsilyl trifluoromethanesulfonate
(189 µL, 0.70 mmol). The solution was stirred for 2.5 h, then diluted with water
and extracted with DCM. The combined organics were dried and concentrated in
vacuo. The residue was purified by FCC, using 0-5% [2M NH in MeOH] in
DCM, to give the title compound as a pale brown gum (242 mg, 90%). LCMS
(Method 3): Rt 2.93 min, m/z 422 [MH ].
c. (1S,4R){3-[4-(2-Triisopropylsilanyloxy-ethyl)-piperazinyl]-
[1,2,4]triazolo[4,3-a]pyridinyloxy}-1,2,3,4-tetrahydro-naphthalen
ylamine (Intermediate 94c)
To a solution of Intermediate A (102 mg, 0.63 mmol) in DMF (1.5 mL) was
added NaH (60% dispersion in oil, 68 mg, 1.71 mmol). The mixture was stirred at
RT for 5 min, then a solution of Intermediate 94b (240 mg, 0.57 mmol) in DMF
(1.5 mL) was added and the mixture stirred at 60°C for 1.25 h. The cooled mixture
was diluted with water and extracted with DCM (4 × 25 mL). The combined
organics were dried and concentrated in vacuo. The residue was purified by FCC,
using 0-10% [2M NH in MeOH] in DCM, to give the title compound as a pale
brown gum (219 mg, 68%). LCMS (Method 3): Rt 2.65 min, m/z 565 [MH ].
d. 1-(5-tert-Butylp-tolyl-2H-pyrazolyl)((1S,4R){3-[4-(2-
triisopropylsilanyloxy-ethyl)-piperazinyl]-[1,2,4]triazolo[4,3-a]pyridin
yloxy}-1,2,3,4-tetrahydro-naphthalenyl)-urea (Intermediate 94d)
A solution of Intermediate 94c (170 mg, 0.42 mmol), 5-tert-butylp-tolyl-
2H-pyrazolyl)-carbamic acid 2,2,2-trichloro-ethyl ester (Synthetic
Communications, 2009, 39, 3999-4009; 170 mg, 0.42 mmol) and DIPEA (199 µL,
1.14 mmol) in THF(4 mL) was stirred at reflux for 15.5 h. The cooled reaction
mixture was diluted with water and extracted with DCM. The combined organics
were dried and concentrated in vacuo. The residue was purified by FCC, using 0-
7.5% [2M NH3 in MeOH] in DCM, to give the title compound as a yellow powder
(293 mg, 93%). LCMS (Method 3): Rt 3.70 min, m/z 820 [MH ].
e. 1-(5-tert-Butylp-tolyl-2H-pyrazolyl)((1S,4R){3-[4-(2-
hydroxy-ethyl)-piperazinyl]-[1,2,4]triazolo[4,3-a]pyridinyloxy}-1,2,3,4-
tetrahydro-naphthalenyl)-urea (Example 94)
A solution of Intermediate 94d (243 mg, 0.29 mmol) and TBAF (1M in
THF, 0.53 mL, 0.53 mmol) in THF (3.5 mL) was stirred at RT for 45 min, then
diluted with water and extracted with DCM (3 × 20 mL). The combined organics
were dried and concentrated in vacuo. The residue was purified by FCC, using 0-
7.5% [2M NH3 in MeOH] in DCM, to give the title compound as a white powder
after freeze-drying (135 mg, 58%). LCMS (Method 5): Rt 3.52 min, m/z 664
[MH ]. ¹H NMR (400 MHz, d -DMSO): 1.27 (9H, s), 1.86-1.92 (2H, m), 2.04-2.11
(2H, m), 2.36 (3H, s), 2.48 (2H, q, J 5.8), 2.66 (4H, t, J 4.8), 3.19 (4H, t, J 4.5),
3.55 (2H, q, J 5.8), 4.44 (1H, t, J 5.4), 4.79-4.82 (1H, m), 5.57 (1H, t, J 4.4), 6.32
(1H, s), 7.07 (1H, d, J 8.5), 7.15 (1H, dd, J 9.9, 2.1), 7.32-7.44 (8H, m), 7.60-7.63
(1H, m), 7.68 (1H, d, J 2.0), 8.04 (1H, s).
Example 95
1-{5-tert-Butyl[3-(2-dimethylamino-ethoxy)-phenyl]-2H-pyrazol
yl{(1S,4R)[3-((S)methyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridin-
6-yloxy]-1,2,3,4-tetrahydronaphthalenyl]-urea
a. 3-(5-Aminotert-butyl-pyrazolyl-phenol (Intermediate 95a)
A mixture of 5-tert-butyl-2H-pyrazolylamine (1 g, 7.18 mmol), 3-
iodophenol (1.7 4g, 7.90 mmol), copper (I) iodide (68 mg, 0.36 mmol), (1S,2S)-
N.N’-dimethyl cyclohexane-1,2-diamine (204 mg, 1.44 mmol) and potassium
carbonate (2.08 g, 15.09 mmol) in toluene (8 mL) was de-gassed and flushed with
argon (3x). The reaction mixture was then treated with microwave irradiation, at
150°C for 1 h. The mixture was diluted with EtOAc (20 mL) and washed with
water (20 mL). The aqueous layer was extracted with a further 20 mL EtOAc and
the combined organic layers were washed with brine (20 mL), dried (MgSO ),
filtered and concentrated in vacuo. The residue obtained was purified by FCC,
using 0-100% EtOAc in cyclohexane to afford the title compound as a brown gum
(1.42 g, 86%). LCMS (Method 3): Rt 2.21 min, m/z 232 [MH ].
b. 5-tert-Butyl{3-[2-(tetrahydro-pyranyloxy)-ethoxy]-
phenyl}-2H-pyrazolylamine (Intermediate 95b)
A solution of intermediate 95a (1.42 g, 6.15 mmol) and triphenyl
phosphine (3.22 g, 12.29 mmol) in THF (50 mL), under an atmosphere of argon
was treated with 2-(tetrahydro-pyranyloxy)-ethanol (1.25 mL, 9.22 mmol),
followed by the dropwise addition of diethyl azodicarboxylate (1.94 mL, 12.29
mmol). The reaction mixture was then stirred at RT for 1 h. Water (0.5 mL) was
added and the mixture was concentrated in vacuo. The residue was taken up in
EtOAc (8 mL) and cyclohexane was added until triphenylphosphine oxide had
precipitated out of solution. This was filtered and the filtrate was concentrated in
vacuo. The residue was purified by FCC, using 0-100% EtOAc in cyclohexane to
afford the title compound as an orange/brown oil (2.98 g, >100%). LCMS (Method
3): Rt 3.20 min, m/z 360 [MH ].
c. (5-tert-Butyl{3-[2-(tetrahydro-pyranyloxy)-ethoxy]-phenyl}-2H-
pyrazolyl)-carbamic acid 2,2,2-trichloro-ethyl ester (Intermediate 95c)
A solution of intermediate 95b (2.21 g, 6.16 mmol) in EtOAc (20
mL) was treated with aqueous NaOH (1M, 11.08 mmol), followed by 2,2,2-
trichloroethyl chloroformate (1.01 mL, 7.39 mmol) and the reaction mixture was
stirred at RT for 1 h. The mixture was partitioned between EtOAc (50 mL) and
water (50 mL). The layers were separated and the aqueous layer was extracted
with a further 50 mL EtOAc. The combined organic layers were dried (MgSO4),
filtered and concentrated in vacuo. The residue was purified by FCC, using 0-
100% EtOAc in cyclohexane to afford the title compound as a dark orange oil
(2.39 g, 73%). LCMS (Method 3): Rt 4.70 min, m/z 534/536 [MH ].
d. 1-(5-tert-Butyl{3-[2-(tetrahydro-pyranyloxy)-ethoxy]-phenyl}-
2-pyrazolyl){(1S,4R)[3-((S)methyl-piperidinyl)-
[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-
urea (Intermediate 95d)
A mixture of intermediate 95c (200 mg, 0.37 mmol), intermediate
81d (141 mg, 0.37 mmol) and DIPEA (98 µL, 0.56 mmol) in dioxane (1.5 mL)
was heated at 70°C for 20 h. The reaction mixture was cooled to RT, diluted with
DCM (5 mL) and washed with water (2 x 5 mL). The organic layer was passed
through a hydrophobic frit and concentrated in vacuo. The residue was purified by
FCC, using 0-10% [2M NH in MeOH] in DCM to afford the title compound as a
yellow glass (158 mg, 55%). LCMS (Method 3): Rt 4.25 min, m/z 763 [MH ].
e. 1-{5-tert-Butyl[3-(2-hydroxy-ethoxy)-phenyl]-2H-pyrazolyl}
{(1S,4R)[3-((S)methyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridin
yloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea (Intermediate 95e)
A mixture of intermediate 95d (158 mg, 0.21 mmol) and pyridinium
p-toluene sulfonate (156 mg, 0.62 mmol) in methanol was heated at 45°C for 18 h.
The mixture was cooled to RT and was partitioned between DCM (5 mL) and
saturated aqueous NaHCO (5 mL). The layers were separated and the organic
layer was passed through a hydrophobic frit and concentrated in vacuo. The
residue was purified by FCC, using 0-10% [2M NH in MeOH] in DCM to afford
the title compound as a beige solid (105 mg, 74%). LCMS (Method 3): Rt 3.64
min, m/z 679 [MH ].
f. 1-{5-tert-Butyl[3-(2-dimethylamino-ethoxy)-phenyl]-2H-pyrazol
yl{(1S,4R)[3-((S)methyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridin-
6-yloxy]-1,2,3,4-tetrahydronaphthalenyl]-urea (Example 95)
To a solution of intermediate 95e (105 mg, 0.15 mmol) and DIPEA (81 µL,
0.46 mmol) in DCM (2 mL) was added methanesulfonyl chloride (16 µL, 0.20
mmol). The reaction mixture was stirred at RT for 30 min. The mixture was
diluted with DCM (5 mL) and washed with water (2 x 5 mL). The organic layer
was passed through a hydrophobic frit and concentrated in vacuo. The residue was
taken up in THF (2 mL) and dimethylamine solution in THF (2M, 1.55 mL) was
added. The reaction mixture was heated at 60°C in a sealed tube for 20 h. The
reaction mixture was cooled to RT and concentrated in vacuo. The residue was
triturated with Et O (1 mL) and the solid obtained was purified by MDAP to afford
the title compound as a glassy solid (44 mg, 40%). LCMS (Method 5): Rt 3.64
min, m/z 706.6 [MH ]. ¹H NMR (400 MHz, d -DMSO): 0.91 (3H, d, J 6.7 Hz),
1.28 (9H, s), 1.46-1.54 (2H, m), 1.63-1.72 (2H, m), 1.75-1.76 (4H, m), 2.00-2.18
(2H, m), 2.22 (6H, s), 2.66 (2H, t, J 5.8 Hz), 2.85-2.95 (1H, m), 3.12-3.20 (1H, m,
obscured by water), 3.27-3.35 (1H, m, obscured by water), 4.10 (2H, t, J 5.4 Hz),
4.78-4.86 (1H, m), 5.52 (1H, t, J 4.0 Hz), 6.33 (1H, s), 6.95-6.99 (1H, m), 7.06-
7.14 (3H, m), 7.19 (1H, dd, J 10.0Hz), 7.25-7.43 (5H, m), 7.64 (1H, d, J 10.6 Hz),
7.69 (1H, d, J 1.8 Hz), 8.12 (1H, s).
Example 96
1-{5-tert-Butyl[3-(2-dimethylamino-ethoxy)-phenyl]-2H-pyrazol
yl}{(1S,4R)[3-(cis-2,6-dimethyl-piperidinyl)-[1,2,4]triazolo[4,3-
a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea formate salt
a. cis-2,6-Dimethyl-piperidinecarboxylic acid N'-(5-fluoro-pyridin
yl)-hydrazide (Intermediate 96a)
Pyridine (2.40 mL, 29.7 mmol) was added dropwise to an ice cold
suspension of triphosgene (4.42 g, 14.9 mmol) in DCM (30.0 mL). cis-2,6-
Dimethylpiperidine (2.00 mL, 14.9 mmol) was added and the reaction stirred for 3
hours, then quenched by dropwise addition of HCl (1M aqueous, 30 mL). The
mixture was extracted into DCM (3 ×). The combined organic layers were washed
with brine, dried (MgSO ), filtered and evaporated in vacuo. The product was used
in the next reaction without purification.
cis-2,6-Dimethylpiperidine-carbamoylchloride (1.79 g, 10.2 mmol) was
dissolved in DCM (90.0 mL) and DIPEA (2.42 mL, 13.9 mmol) was added
followed by (5-fluoro-pyridinyl)-hydrazine (WO2010022076, 1.18 g, 9.30
mmol) and the reaction heated to 45°C overnight. The reaction was cooled and
quenched into water. The mixture was extracted into DCM (3 x). The combined
organic layers were washed with brine, dried (MgSO ), filtered and evaporated in
vacuo. The residue was purified by FCC using 0-6% [2M NH in MeOH] in DCM
to give the title compound (1.38 g, 56%). ¹H NMR (300 MHz, CDCl ): 1.29 (6H,
d, J 7.1 Hz), 1.48-1.90 (6H m), 4.26 (2H, qn, J 6.9 Hz), 6.39 (1H, d, J 2.3 Hz), 6.50
(1H, d, J 2.3 Hz), 6.74 (1H, dd, J 9.0, 3.6 Hz), 7.27 (1H, ddd, J 8.9, 8.0, 2.9 Hz),
8.03 (1H, d, J 2.9 Hz).
b. 3-(cis-2,6-Dimethyl-piperidinyl)fluoro-[1,2,4]triazolo[4,3-
a]pyridine (Intermediate 96b)
To an ice cold solution of Intermediate 96a (1.38 g, 5.19 mmol) in THF
(50.0 mL) was added sequentially triphenylphosphine (2.72 g, 10.4 mmol), Et N
(2.89 mL, 20.8 mmol) and hexachloroethane (2.46 g, 10.4 mmol). The cooling
bath was removed and the reaction was heated to 55°C overnight. The reaction was
cooled and partitioned between EtOAc and water. The aqueous layer was then
extracted with EtOAc (3 ×). The combined organic layers were washed with brine,
dried (MgSO ), filtered and evaporated in vacuo. The residue was taken up in
MeOH and loaded onto an SCX-2 cartridge, which was washed with MeOH and
eluted with 2M NH in MeOH. The residue was concentrated in vacuo then
resubmitted to the reaction conditions overnight. After analogous workup the
residue was concentrated in vacuo to give the title compound (1.03 g, 80%). ¹H
NMR (300 MHz, CDCl ): 0.68 (6H, d, J 6.2 Hz), 1.36-1.68 (3H m), 1.74-1.90 (3H,
m), 3.35 (2H, m), 7.14 (1H, ddd, J 9.8, 7.5, 2.3 Hz), 7.65 (1H, ddd, J 9.9, 4.7, 0.8
Hz), 8.02 (1H, ddd, J 3.2, 2.3, 0.8 Hz).
c. (1S,4R)[3-(cis-2,6-Dimethyl-piperidinyl)-[1,2,4]triazolo[4,3-
a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenylamine (Intermediate
96c)
To a suspension of sodium hydride (60% in mineral oil, 323 mg, 8.06
mmol) in DMF (10.0 mL) was added (1R,4S)amino-1,2,3,4-tetrahydro-
naphthalenol (329 mg, 2.02 mmol) and the reaction stirred for 20 min.
Intermediate 96b (500 mg, 2.02 mmol) was added in DMF (2.00 mL) and the
reaction heated to 60°C for 1 h. The reaction was cooled and quenched by
dropwise addition of methanol, before being diluted with methanol and loaded
onto an SCX-2 cartridge, which was washed with MeOH. The product was eluted
with 2M NH in MeOH. The residue was purified by FCC, using 0-10% [2M NH
in MeOH] in DCM, to give the title compound (453 mg, 57%). LCMS (Method 4):
Rt 2.13, m/z 392 [MH ].
d. 1-(5-tert-Butyl{3-[2-(tetrahydro-pyranyloxy)-ethoxy]-phenyl}-
2H-pyrazolyl){(1S,4R)[3-(cis-2,6-dimethyl-piperidinyl)-
[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-
urea (Intermediate 96d)
To a solution of Intermediate 96c (100 mg, 0.25 mmol) in 1,4-dioxane (3.00
mL) was added DIPEA (89.0 mL, 0.51 mmol) and Intermediate 39b (133 mg, 0.25
mmol). The reaction was heated to 70°C overnight then cooled and partitioned
between EtOAc and water. The aqueous layer was then extracted with EtOAc (3
×). The combined organic layers were washed with brine, dried (MgSO ), filtered
and evaporated in vacuo. The residue was purified by FCC using 0-8% MeOH in
DCM to give the title compound. LCMS (Method 4): Rt 4.09 min, m/z 777 [MH ].
e. 1-{5-tert-Butyl[3-(2-hydroxy-ethoxy)-phenyl]-2H-pyrazolyl}
{(1S,4R)[3-(cis-2,6-dimethyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridin
yloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea (Intermediate 96e)
Pyridinium p-toluenesulfonate (65.0 mg, 0.26 mmol) was added to a
solution of Intermediate 96d in MeOH (2.0 mL). The reaction was heated to 60°C
for 3.5 h then cooled and solvent volume reduced in vacuo. The residue was
partitioned between EtOAc and water. The aqueous layer was then extracted with
EtOAc (3 ×). The combined organic layers were washed with brine, dried
(MgSO ), filtered and evaporated in vacuo to give the title compound (89.0 mg,
99%). LCMS (Method 4): Rt 3.49 min, m/z 693 [MH ].
f. Methanesulfonic acid 2-{3-[3-tert-butyl(3-{(1S,4R)[3-((2S,6R)-
2,6-dimethyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-ureido)-pyrazolyl]-phenoxy}-ethyl ester
(Intermediate 96f)
Methane sulfonyl chloride (11.0 µL, 0.13 mmol) was added to an ice cold
solution of Intermediate 96e (89.0 mg, 0.13 mmol) and DIPEA (27.0 µL, 0.15
mmol) in DCM (1.5 mL). After 1 hour additional DIPEA (27.0 µL, 0.15 mmol)
and methane sulfonyl chloride (11.0 µL, 0.13 mmol) was added. After a further 1
hour additional DIPEA (27.0 µL, 0.15 mmol) and methane sulfonyl chloride (11.0
µL, 0.13 mmol) was added. After 1 hour the reaction was partitioned between
DCM and water. The aqueous layer was then extracted with DCM (3 ×). The
combined organic layers were washed with brine, dried (MgSO ), filtered and
evaporated in vacuo to give the title compound (100 mg, 99%). LCMS (Method 1):
Rt 3.73 min, m/z 771 [MH ].
g. 1-{5-tert-Butyl[3-(2-dimethylamino-ethoxy)-phenyl]-2H-pyrazol
yl}{(1S,4R)[3-(cis-2,6-dimethyl-piperidinyl)-[1,2,4]triazolo[4,3-
a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea formate salt
(Example 96)
Dimethylamine (2M in MeOH, 520 µL, 1.04 mmol) was added to a solution
of Intermediate 96f (100 mg, 0.13 mmol) in THF (1.5 mL). The reaction was
heated to 50°C in a sealed environment overnight. The mixture was cooled and
partitioned between EtOAc and water. The aqueous layer was then extracted with
EtOAc (3 ×). The combined organic layers were washed with brine, dried
(MgSO ), filtered and evaporated in vacuo. The residue was purified by FCC,
using 0-10% [2M NH in MeOH] in DCM. Further purification by HPLC (C18 X-
select column, 10-98% MeCN in H O, 0.1% HCO H) gave the title compound as a
white powder after freeze-drying (50 mg, 54%). LCMS (Method 5): Rt 3.79 min,
m/z 720.5 [MH ]. ¹H NMR (400 MHz, d -MeOD): 0.65 (3H, d, J 6.0 Hz), 0.68
(3H, d, J 6.0 Hz), 1.31 (9H, s), 1.40-1.50 (2H, m), 1.53-1.65 (1H, m), 1.73-1.87
(3H, m), 1.92-2.05 (2H, m), 2.05-2.15 (1H, m), 2.19-2.26 (1H, m), 2.43 (6H, s),
2.92 (2H, t, J 5.2 Hz), 3.24 (2H, m), 4.18 (2H, t, J 5.3 Hz), 4.90 (1H, dd, J 8.7,
5.8), 5.42 (1H, t, J 8.2), 6.34 (1H, s), 7.02-7.06 (1H, ddd, J 8.5, 2.4, 0.6), 7.08-7.13
(2H, m), 7.17-7.25 (3H, m), 7.26-7.31 (2H, m), 7.38-7.44 (1H, t, J 7.8), 7.56-7.60
(1H, dd, J 9.8, 0.7 Hz), 7.86 (1H, d, J 1.8 Hz), 8.45 (0.3H, br s).
Example 97
1-[5-tert-Butyl(3-morpholinylmethyl-phenyl)-2H-pyrazolyl]
{(1S,4R)[3-((S)methyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridin
yloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea formate salt
a. 1-[5-tert-Butyl(3-hydroxymethyl-phenyl)-2H-pyrazolyl]
{(1S,4R)[3-((S)methyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridin
yloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea (Intermediate 97a)
A brown solution of Intermediate 29c (177 mg, 0.420 mmol), Intermediate
81d (151 mg, 0.400 mmol) and DIPEA (0.087 mL, 0.50 mmol) in dry dioxane (5
mL) was stirred at 100°C for 3 h. The cooled solution was concentrated in vacuo,
suspended in water (10 mL) and extracted with DCM (2 × 10 mL). The combined
organics were passed through a hydrophobic frit and concentrated under vacuum to
leave a dark brown gum. FCC, using 3-8% MeOH in DCM, gave the title
compound as an orange solid (188 mg, 72%). LCMS (Method 4): Rt 3.63 min, m/z
649 [MH ].
b. Methanesulfonic acid 3-[3-tert-butyl(3-{(1S,4R)[3-((S)
methyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-ureido)-pyrazolyl]-benzyl ester and 1-[5-tert-
Butyl(3-chloromethyl-phenyl)-2H-pyrazolyl]{(1S,4R)[3-((S)
methyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-urea (1:1 mixture). (Intermediate mixture 97b)
To a solution of Intermediate 97a (187 mg, 0.288 mmol) and DIPEA (0.151
mL, 0.865 mmol) in DCM (5 mL) at 0°C was added mesyl chloride (0.056 mL,
0.721 mmol) and the resulting orange solution stirred at 0°C for 1 h. Water (5 mL)
was added and the mixture shaken. The aqueous layer was extracted with DCM (5
mL), then the combined organics passed through a hydrophobic frit and
concentrated in vacuo to leave the mixture of title compounds as a brown gum.
LCMS (Method 4): 1:1 ratio, Rt 3.87 min, m/z 727 [MH ] and Rt 4.11, m/z 667
[MH ].
c. 1-[5-tert-Butyl(3-morpholinylmethyl-phenyl)-2H-pyrazolyl]-
3-{(1S,4R)[3-((S)methyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridin
yloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea formate salt (Example 97)
A brown solution of Intermediate mixture 97b (0.144 mmol) and
morpholine (0.063 mL, 0.72 mmol) in dry DMF (3 mL) was stirred at 75°C for 2
h. The cooled solution was concentrated in vacuo, suspended in water (10
mL) and extracted with DCM (2 × 10 mL). The combined organics were passed
through a hydrophobic frit and concentrated in vacuo to leave a brown gum. FCC,
3-7% MeOH in DCM, gave a pale yellow solid (58.6 mg). MDAP (Method 7)
gave the title compound as a pale yellow solid (31 mg, 28%). LCMS (Method 5):
Rt 3.59 min, m/z 718.6 [MH ]. ¹H NMR (400 MHz, d -DMSO): 0.91 (3H, d, J
6.3), 1.28 (9H, s), 1.48-1.55 (2H, m), 1.63-1.71 (2H, m), 1.75-1.97 (4H, m), 2.00-
2.16 (2H, m), 2.37 (4H, t, J 4.2), 2.90 (1H, ddd, J 12.2, 9.0, 4.0), 3.15 (1H, dt, J
12.0, 4.2), 3.51 (2H, s), 3.55 (4H, t, J 4.4), 4.82 (1H, td, J 8.6, 5.6), 5.51 (1H, t, J
4.3), 6.33 (1H, s), 7.04 (1H, d, J 8.6), 7.19 (1H, dd, J 9.9, 2.2), 7.25-7.29 (2H, m),
7.31-7.48 (6H, m), 7.64 (1H, dd, J 9.8, 0.8), 7.69 (1H, d, J 2.1), 8.10 (1H, s), 8.16
(1H, s). One 1H signal under solvent peak.
Example 98
1-{5-tert-Butyl[3-(4-methyl-piperazinylmethyl)-phenyl]-2H-
pyrazolyl}{(1S,4R)[3-((S)methyl-piperidinyl)-[1,2,4]triazolo[4,3-
a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea formate salt
The title compound was prepared starting from N-methyl piperazine using
analogous procedures to those described in Example 97. LCMS (Method 5): Rt
3.61 min, m/z 731.6 [MH ]. ¹H NMR (400 MHz, d -DMSO): 0.91 (3H, d, J 6.3),
1.28 (9H, s), 1.48-1.56 (2H, m), 1.63-1.71 (2H, m), 1.75-1.96 (4H, m), 2.00-2.16
(2H, m), 2.12 (3H, s), 2.26-2.43 (8H, m), 2.90 (1H, ddd, J 11.8, 9.2, 4.2), 3.16 (1H,
dt, J 12.0, 4.2), 3.28-3.34 (1H, m), 3.50 (2H, s), 4.82 (1H, td, J 8.6, 5.5), 5.52 (1H,
t, J 4.3), 6.33 (1H, s), 7.04 (1H, d, J 8.6), 7.19 (1H, dd, J 9.9, 2.2), 7.25-7.47 (8H,
m), 7.64 (1H, dd, J 9.8, 0.8), 7.69 (1H, d, J 2.1), 8.11 (1H, s), 8.18 (1H, s).
Example 99
1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-(1-
dimethylamino-cyclopentyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-urea
a. 1-Dimethylamino-cyclopentanecarboxylic acid (Intermediate 99a)
A solution of 1-amino-cyclopentanecarboxylic acid (2.0 g, 15.5 mmol) and
formaldehyde (37% aqueous solution, 3 mL) in formic acid (4 mL) was heated at
80 ºC for 2.5 h. The volatiles were concentrated in vacuo and the resulting residue
was loaded onto an SCX cartridge. The cartridge was washed with MeOH and the
product eluted with 2M NH in MeOH to afford the title compound (1.82 g, 75%).
¹H NMR (400 MHz, CD OD): 1.71-2.02 (6H, m), 2.16-2.29 (2H, m), 2.77 (6H, s).
b. 1-Dimethylamino-cyclopentanecarboxylic acid N'-(5-fluoro-pyridin-
2-yl)-hydrazide (Intermediate 99b)
To a solution of (5-fluoro-pyridinyl)-hydrazine (For reference procedure
see WO2010022076; 200 mg, 1.57 mmol) in DMF (10 mL) were added
Intermediate 99a (247 mg, 1.57 mmol), EDC (333 mg, 1.73 mmol) and HOBt (21
mg, 0.16 mmol). The reaction mixture was stirred at RT for 18 h and then
partitioned between EtOAc and water. The aqueous phase was further extracted
with EtOAc (x 3) and the combined organic layers were washed with brine, dried
(MgSO ) and concentrated in vacuo. The resultant residue was purified by FCC on
silica, using a gradient of 0-8% [2M NH in MeOH] in DCM, to give the title
compound (282 mg, 67%). ¹H NMR (400 MHz, CDCl ): 1.54-1.73 (4H, m), 1.76-
2.04 (4H, m), 2.25 (6H, s), 6.46 (1H, s), 6.64 (1H, dd, J = 9.0, 3.5 Hz), 7.23-7.33
(1H, m), 8.04 (1H, d, J = 3.0 Hz), 8.94 (1H, s).
c. [1-(6-Fluoro-[1,2,4]triazolo[4,3-a]pyridinyl)-cyclopentyl]-dimethyl-
amine (Intermediate 99c)
Hexachloroethane (503 mg, 2.12 mmol) was added portionwise over 5
minutes at RT to a stirred mixture of Intermediate 99b (282 mg, 1.06 mmol),
triethylamine (590 µL, 4.24 mmol) and triphenylphosphine (555 mg, 2.12 mmol)
in THF (11 mL). The reaction mixture was stirred at 50 ºC for 2.5 h and then
partitioned between EtOAc and water. The aqueous phase was extracted with
EtOAc (x 3) and the combined organic layers were washed with brine, dried
(MgSO ) and concentrated in vacuo. The resultant residue was purified by FCC
using SCX-2 cartridge. The cartridge was washed with MeOH and the product was
eluted with 2M NH in MeOH to give the title compound (207 mg, 79%). ¹H NMR
(400 MHz, CDCl ): 1.67-1.78 (4H, m), 2.10-2.22 (8H, m), 2.24-2.34 (2H, m), 7.15
(1H, ddd, J = 10.0, 7.4, 2.3 Hz), 7.69 (1H, dd, J = 10.0, 5.0 Hz), 8.65-8.68 (1H, m).
d. (1S,4R)[3-(1-Dimethylamino-cyclopentyl)-[1,2,4]triazolo[4,3-
a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenylamine (Intermediate
99d)
To a suspension of sodium hydride (60% in mineral oil, 133 mg, 3.34
mmol) in DMF (5 mL) was added Intermediate A (136 mg, 0.83 mmol) and the
reaction mixture was stirred for 20 min. A solution of Intermediate 99c (207 mg,
0.83 mmol) in DMF (3 mL) was added and the reaction mixture was heated at 60
ºC for 90 min. After cooling, the reaction mixture was quenched by careful
addition of MeOH and then loaded onto an SCX cartridge. The cartridge was
washed with MeOH and the product eluted with 2M NH in MeOH. The product
containing fractions were concentrated in vacuo and the resultant residue was
purified by FCC on silica, using a gradient of 0-10% [2M NH3 in MeOH] in DCM,
to give the title compound (211 mg, 65%). LCMS (Method 4): Rt 1.49 min, m/z
392 [MH ].
e. 1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-(1-
dimethylamino-cyclopentyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-urea (Example 99)
A mixture of Intermediate 99d (108 mg, 0.27 mmol), (5-tert-butylp-tolyl-
2H-pyrazolyl)-carbamic acid 2,2,2-trichloro-ethyl ester (For reference
procedure see Synthetic Communications, 2009, 39, 3999-4009; 105 mg, 0.27
mmol) and DIPEA (93 µL, 0.54 mmol) in dioxane (3 mL) was stirred at 60 ºC for
18 h and then at 80 ºC for 4 h. The reaction mixture was diluted with EtOAc and
then poured into water. The aqueous phase was extracted with EtOAc (x 3) and the
combined organic layers were washed with brine, dried (MgSO ) and concentrated
in vacuo. The resultant residue was purified by MDAP (Method 7) to afford the
title compound (23 mg, 13%). LCMS (Method 5): Rt 3.90 min, m/z 647 [MH ]. ¹H
NMR (400 MHz, CD OD): 1.34 (9H, s), 1.59-1.85 (4H, m), 1.91-2.15 (3H, m),
2.18 (6H, s), 2.21-2.36 (5H, m), 2.42 (3H, s), 4.91-4.96 (1H, m), 5.34 (1H, t, J =
4.1 Hz), 6.37 (1H, s), 7.22-7.40 (9H, m), 7.65 (1H, d, J = 9.9 Hz), 8.46 (1H, d, J =
2.2 Hz).
Example 100
1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-((2S,6R)-2,6-
dimethyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-urea
The title compound was prepared starting from Intermediate 96c and (5-tert-
butylp-tolyl-2H-pyrazolyl)-carbamic acid 2,2,2-trichloro-ethyl ester (For
reference procedure see Synthetic Communications, 2009, 39, 3999-4009) using
analogous procedures to those described in Example 3. LCMS (Method 5): Rt 5.33
min, m/z 647 [MH ]. ¹H NMR (400 MHz, CD OD): 0.64-0.74 (6H, m), 1.34 (9H,
s), 1.41-1.72 (3H, m), 1.75-2.19 (6H, m), 2.21-2.31 (1H, m), 2.42 (3H, s), 3.22-
3.35 (2H, m), 4.90-4.98 (1H, m), 5.45 (1H, t, J = 4.1 Hz), 6.37 (1H, s), 7.19-7.40
(9H, m), 7.62 (1H, dd, J = 9.9, 0.8 Hz), 7.89 (1H, d, J = 2.1 Hz).
Example 101
1-[(1S,4R)(3-Amino-[1,2,4]triazolo[4,3-a]pyridinyloxy)-1,2,3,4-
tetrahydro-naphthalenyl](5-tert-butylp-tolyl-2H-pyrazolyl)-urea
a. 2-(5-Fluoropyridinyl)-N,N-di(propen
yl)hydrazinecarboxamide (Intermediate 101a)
To a solution of (5-fluoro-pyridinyl)-hydrazine (For reference procedure
see WO2010022076; 2.54 g, 20.0 mmol) in DCM (150 mL) and DIPEA (3.87 g,
.0 mmol) was added N,N-dipropenyl-carbamic chloride (For reference
procedure see for example Tetrahedron 1996, 52, 13739-13750; 4.13 g, 26.0
mmol) and the reaction mixture was stirred at RT for 18 h. The reaction mixture
was diluted with MeOH (50 mL) and loaded onto an SCX cartridge. The cartridge
was washed with MeOH and the product eluted with 2M NH in MeOH. The
compound containing fractions were concentrated in vacuo and the resulting
residue was purified by FCC on silica, using a gradient of 0-6% [2M NH in
MeOH] in DCM, to afford the title compound (2.30 g, 46%) as a yellow solid.
LCMS (Method 1): Rt 2.26 min, m/z 251 [MH ].
b. Diallyl-(6-fluoro-[1,2,4]triazolo[4,3-a]pyridinyl)-amine
(Intermediate 101b)
Hexachloroethane (4.34 g, 18.4 mmol) was added portionwise over 5 min at
RT to a stirred mixture of Intermediate 101a (2.30 g, 9.2 mmol), triethylamine
(3.71 g, 36.8 mmol) and triphenylphosphine (4.82 g, 18.4 mmol) in THF (90 mL).
The reaction mixture was stirred at RT for 1 h, then diluted with MeOH and
purified by FCC using SCX-2 cartridge. The cartridge was washed with MeOH
and the product was eluted with 2M NH in MeOH. The compound containing
fractions were combined and concentrated in vacuo. The resultant residue was
subjected to the follow purification procedure; FCC on silica (0-6% [2M NH in
MeOH] in DCM), then SCX-2 cartridge (conditions described above) and finally
further FCC on silica (0-2% MeOH in EtOAc), to afford the title compound (1.34
g, 62%). ¹H NMR (400 MHz, CDCl ): 3.87 (4H, d, J = 6.2 Hz), 5.16-5.35 (4H, m),
.85-6.02 (2H, m), 7.11 (1H, ddd, J = 10.0, 7.6, 2.3 Hz), 7.58-7.67 (1H, m), 7.75-
7.80 (1H, m).
c. [6-((1R,4S)Amino-1,2,3,4-tetrahydro-naphthalenyloxy)-
[1,2,4]triazolo[4,3-a]pyridinyl]-bis-((E)-propenyl)-amine (Intermediate
101c)
To a suspension of sodium hydride (40% in mineral oil, 690 mg, 17.31
mmol) in DMF (20 mL) was added Intermediate A (1.12 g, 6.92 mmol) and the
reaction mixture was stirred for 20 min at RT. A solution of Intermediate 101b
(1.34 g, 5.77 mmol) in DMF (20 mL) was added and the reaction mixture was
stirred at RT for 1 h. The reaction mixture was quenched by careful addition of
MeOH and then loaded onto an SCX cartridge. The cartridge was washed with
MeOH and the product eluted with 2M NH in MeOH. The product containing
fractions were concentrated in vacuo and the resultant residue was purified by FCC
on silica, using a gradient of 0-10% [2M NH in MeOH] in DCM, to give the title
compound (1.33 g, 61%) as an orange gum. ¹H NMR (400 MHz, CDCl ): 0.92-
1.13 (1H, m), 1.39 (6H, dd, J = 7.2, 1.7 Hz), 1.82-2.16 (4H, m), 2.26-2.38 (1H, m),
3.93-3.99 (1H, m), 4.99-5.10 (2H, m), 5.18 (1H, t, J = 4.4 Hz), 6.10 (2H, dd, J =
8.2, 2.0 Hz), 7.09 (1H, dd, J = 9.9, 2.2 Hz), 7.25-7.44 (3H, m), 7.48-7.53 (1H, m),
7.57-7.66 (2H, m).
d. 1-[(1S,4R)(3-Amino-[1,2,4]triazolo[4,3-a]pyridinyloxy)-1,2,3,4-
tetrahydro-naphthalenyl](5-tert-butylp-tolyl-2H-pyrazolyl)-urea
(Example 101)
A mixture of Intermediate 101c (1.33 g, 3.54 mmol), (5-tert-butylp-tolyl-
2H-pyrazolyl)-carbamic acid 2,2,2-trichloro-ethyl ester (For reference
procedure see Synthetic Communications, 2009, 39, 3999-4009; 2.0 g, 4.96 mmol)
and DIPEA (1.82, 14.16 mmol) in DMF (20 mL) was stirred at RT for 20 h. The
reaction mixture was diluted with MeOH and loaded onto an SCX cartridge. The
cartridge was washed with MeOH and the product eluted with 2M NH in MeOH.
The product containing fractions were concentrated in vacuo and the resultant
residue was purified by FCC on silica, using a gradient of 0-10% [2M NH in
MeOH] in DCM, followed by recrystallization from 5% MeOH in DCM (few
drops of cyclohexane added to start recrystallization), to give the title compound
(760 mg, 39%) as an off white dust. LCMS (Method 5): Rt 3.81 min, m/z 551
[MH ]. ¹H NMR (400 MHz, CD OD): 1.34 (9H, s), 1.86-2.08 (2H, m), 2.09-2.19
(1H, m), 2.22-2.34 (1H, m), 2.42 (3H, s), 4.89-4.96 (1H, m), 5.32 (1H, t, J = 4.4
Hz), 6.37 (1H, s), 7.05 (1H, dd, J = 10.0, 2.1 Hz), 7.23-7.44 (9H, m), 7.83 (1H, d, J
= 2.0 Hz).
Example 102
1-[5-tert-Butyl(6-methyl-pyridinyl)-2H-pyrazolyl][(1S,4R)
(3-piperidinyl-[1,2,4]triazolo[4,3-a]pyridinyloxy)-1,2,3,4-tetrahydro-
naphthalenyl]-urea
a. [5-tert-Butyl(6-methyl-pyridinyl)-2H-pyrazolyl]-carbamic
acid 2,2,2-trichloro-ethyl ester (Intermediate 102a)
To a mixture of 5-tert-butyl(6-methyl-pyridinyl)-2H-pyrazol
ylamine (For reference procedure see for example WO2003072569; 833 mg, 3.62
mmol) in NaOH (1M in water, 5.4 mL, 4.4 mmol) and EtOAc (5 mL) was added
2,2,2-trichloroethyl chloroformate (548 µL, 3.98 mmol) and the reaction mixture
was stirred at RT for 1 h. Additional NaOH (1M in water, 5.4 mL) and 2,2,2-
trichloroethyl chloroformate (548 µL) were added and stirring at RT was
continued for 1 h. Additional NaOH (1M in water, 5.4 mL) and 2,2,2-
trichloroethyl chloroformate (548 µL) were added and stirring at RT was
continued for 2 h. Additional NaOH (1M in water, 10.8 mL) and 2,2,2-
trichloroethyl chloroformate (1.10 mL) were added and stirring at RT was
continued for 24 h. The aqueous layer was extracted with EtOAc (x 3) and the
combined organic layers were washed with brine, dried (Na SO ) and concentrated
in vacuo. The resultant residue was purified by FCC on silica, using a gradient of
10-50% EtOAc in cyclohexane, to afford the title compound (550 mg, 37%) as a
white foam. LCMS (Method 3): Rt 3.87 min, m/z 405 [MH ].
b. 1-[5-tert-Butyl(6-methyl-pyridinyl)-2H-pyrazolyl]
[(1S,4R)(3-piperidinyl-[1,2,4]triazolo[4,3-a]pyridinyloxy)-1,2,3,4-
tetrahydro-naphthalenyl]-urea (Example 102)
A mixture of Intermediate 102a (84 mg, 0.206 mmol), Intermediate 3c (75
mg, 0.206 mmol) and DIPEA (45 µL, 0.258 mmol) in dioxane (3 mL) was stirred
at 65 ºC for 16 h. After cooling, the volatiles were concentrated in vacuo and the
resultant residue was partitioned between water and DCM. The organic layer was
dried through a separator phase and concentrated in vacuo. The resultant residue
was purified by FCC on silica, using a gradient of 2-7% MeOH in DCM followed
by HPLC (XBridge C18 column, 25-75% MeCN in H O, 0.1% NH OH), to afford
the title compound (41 mg, 32%) as a white solid. LCMS (Method 5): Rt 4.06 min,
m/z 620 [MH ]. H NMR (400 MHz, d -DMSO): 1.27 (9H, s), 1.56-1.66 (2H, m),
1.67-1.77 (4H, m), 1.79-1.96 (2H, m), 1.96-2.20 (2H, m), 2.53 (3H, s), 3.13 (4H, t,
J = 5.2 Hz), 4.75-4.84 (1H, m), 5.54 (1H, t, J = 4.3 Hz), 6.35 (1H, s), 7.06 (1H, d, J
= 8.6 Hz), 7.16 (1H, dd, J = 9.8, 2.2 Hz), 7.23-7.43 (5H, m), 7.58-7.64 (2H, m),
7.81 (1H, dd, J = 8.3, 2.6 Hz), 8.18 (1H, s), 8.59 (1H, d, J = 2.6 Hz).
Example 103
1-{5-tert-Butyl[3-(2-dimethylamino-ethoxy)-phenyl]-2H-pyrazol
yl}[(1S,4R)(3-diisopropylamino-[1,2,4]triazolo[4,3-a]pyridinyloxy)-
1,2,3,4-tetrahydro-naphthalenyl]-urea
a. 2-(5-Fluoropyridinyl)-N,N-di(propanyl)hydrazinecarboxamide
(Intermediate 103a)
To a solution of (5-fluoro-pyridinyl)-hydrazine (For reference procedure
see WO2010022076; 200 mg, 1.57 mmol) in DCM (15mL) was added
triethylamine (328 µL, 2.35 mmol) followed by N,N-diisopropylcarbamoyl
chloride (282 mg, 1.73 mmol). The reaction mixture was heated at 45 ºC for 4 h
then poured into water and extracted with DCM (x 3). The combined organic
layers were washed with brine, dried (MgSO4) and concentrated in vacuo. The
resultant residue was purified by FCC on silica, using a gradient of 0-100% EtOAc
in cyclohexane, to afford the title compound (200 mg, 50%). ¹H NMR (400 MHz,
CDCl3): 1.30 (12H, d, J = 6.8 Hz), 3.80-4.03 (2H, m), 6.17 (1H, s), 6.53 (1H, s),
6.67-6.81 (1H, m), 7.24-7.36-(1H, m), 8.02 (1H, d, J = 3.0 Hz).
b. (6-Fluoro-[1,2,4]triazolo[4,3-a]pyridinyl)-diisopropyl-amine
(Intermediate 103b)
The title compound was prepared starting from Intermediate 103a using
analogous procedures to those described in Intermediate 99c. ¹H NMR (400 MHz,
CDCl ): 1.09 (12H, d, J = 6.5 Hz), 3.60-3.79 (2H, m), 7.11-7.24 (1H, m), 7.44-7.62
(1H, m), 7.98-8.05 (1H, m).
c. [6-((1R,4S)Amino-1,2,3,4-tetrahydro-naphthalenyloxy)-
[1,2,4]triazolo[4,3-a]pyridinyl]-diisopropyl-amine (Intermediate 103c)
To a suspension of sodium hydride (60% in mineral oil, 136 mg, 3.39
mmol) in DMF (5 mL) was added Intermediate A (138 mg, 0.85 mmol) and the
reaction mixture was stirred for 15 min at RT. A solution of Intermediate 103b
(200 mg, 0.85 mmol) in DMF (3 mL) was added and the reaction mixture was
heated at 60 ºC for 1 h. The reaction mixture was quenched by careful addition of
MeOH and then loaded onto an SCX cartridge. The cartridge was washed with
MeOH and the product eluted with 2M NH in MeOH. The product containing
fractions were concentrated in vacuo and the resultant residue was purified by FCC
on silica, using a gradient of 0-10% [2M NH in MeOH] in DCM, to give the title
compound (220 mg, 68%). LCMS (Method 4): Rt 2.07 min, m/z 380 [MH ].
d. 1-(5-tert-Butyl{3-[2-(tetrahydro-pyranyloxy)-ethoxy]-phenyl}-
2H-pyrazolyl)[(1S,4R)(3-diisopropylamino-[1,2,4]triazolo[4,3-
a]pyridinyloxy)-1,2,3,4-tetrahydro-naphthalenyl]-urea (Intermediate
103d)
The title compound was prepared starting from Intermediate 103c and
Intermediate 95c using analogous procedures to those described in Intermediate
95d. LCMS (Method 4): Rt 3.92 min, m/z 765 [MH ].
e. 1-{5-tert-Butyl[3-(2-hydroxy-ethoxy)-phenyl]-2H-pyrazolyl}
[(1S,4R)(3-diisopropylamino-[1,2,4]triazolo[4,3-a]pyridinyloxy)-1,2,3,4-
tetrahydro-naphthalenyl]-urea (Intermediate 103e)
O OH
To a solution of Intermediate 103d (100 mg, 0.13 mmol) in MeOH (2 mL)
was added pyridinium p-toluenesulfonate (65 mg, 0.26 mmol) and the reaction
mixture was heated to reflux temperature for 3 h. The volatiles were concentrated
in vacuo and the resultant residue was partitioned between EtOAc and water. The
aqueous phase was extracted with EtOAc (x 3) and the combined organic layers
were washed with brine, dried (MgSO ) and concentrated in vacuo to afford the
title compound (97 mg, 99%). LCMS (Method 2): Rt 3.39 min, m/z 681 [MH ].
f. Methanesulfonic acid 2-[3-(3-tert-butyl{3-[(1S,4R)(3-
diisopropylamino-[1,2,4]triazolo[4,3-a]pyridinyloxy)-1,2,3,4-tetrahydro-
naphthalenyl]-ureido}-pyrazolyl)-phenoxy]-ethyl ester (Intermediate
103f)
To an ice-bath cooled solution of Intermediate 103e (97 mg, 0.13 mmol) in
DCM (2 mL) was added DIPEA (58 µL, 0.32 mmol) followed by methanesulfonyl
chloride (22 µL, 0.27 mmol). The reaction mixture was stirred for 2 h then
partitioned between DCM and water. The aqueous phase was extracted with DCM
(x 3) and the combined organic layers were washed with brine, dried (MgSO ) and
concentrated in vacuo to afford the title compound (130 mg, quantitative). LCMS
(Method 1): Rt 3.69 min, m/z 759 [MH ].
g. 1-{5-tert-Butyl[3-(2-dimethylamino-ethoxy)-phenyl]-2H-pyrazol
yl}[(1S,4R)(3-diisopropylamino-[1,2,4]triazolo[4,3-a]pyridinyloxy)-
1,2,3,4-tetrahydro-naphthalenyl]-urea (Example 103)
To a solution of Intermediate 103f (130 mg, 0.13 mmol) in THF (1.5 mL)
was added dimethylamine (2M in MeOH, 520 µL, 1.04 mmol). The reaction
mixture was heated at 50 ºC for 18 h, then cooled and partitioned between EtOAc
and water. The aqueous phase was extracted with EtOAc (x 3) and the combined
organic layers were washed with brine, dried (MgSO ) and concentrated in vacuo.
The resultant residue was purified by FCC on silica, using a gradient of 0-10%
[2M NH in MeOH] in DCM followed by HPLC (C18 X-select column, 10-98%
gradient MeCN in H O, 0.1% HCO H), to give the title compound (37 mg, 40%).
LCMS (Method 5): Rt 3.70 min, m/z 708 [MH ]. ¹H NMR (400 MHz, CD OD):
1.05 (12H, dd, J = 6.4, 1.8 Hz), 1.33 (9H, s), 21.89-2.30 (4H, m), 2.43 (6H, s), 2.91
(2H, t, J = 5.2 Hz), 3.62-3.74 (2H, m), 4.19 (2H, t, J = 5.3 Hz), 4.88-4.97 (1H, m),
.42 (1H, t, J = 4.1 Hz), 6.37 (1H, s), 7.04-7.13 (3H, m), 7.19-7.34 (5H, m), 7.44
(1H, t, J = 8.3 Hz), 7.60 (1H, d, J = 9.8 Hz), 7.87 (1H, d, J = 2.1 Hz).
Example 104
N-(5-tert-Butylmethoxy{3-[(1S,4R)(3-piperidinyl-
[1,2,4]triazolo[4,3-a]pyridinyloxy)-1,2,3,4-tetrahydro-naphthalenyl]-
ureido}-phenyl)-methanesulfonamide
O O N
O N N
H H H
a. (5-tert-Butylmethanesulfonylaminomethoxy-phenyl)-carbamic
acid 2,2,2-trichloro-ethyl ester (Intermediate 104a)
O N N O
NaOH (199 mg, 4.97 mmol) was added to an ice-bath cooled solution of N-
[3-amino(1,1-dimethylethyl)methoxyphenyl]-methanesulfonamide (For
reference procedure see for example WO2010026096; 500 mg, 1.84 mmol). The
ice bath was removed and complete dissolution of reagents occurred. 2,2,2-
Trichloroethyl chloroformate (380 µL, 2.76 mmol) was added and the reaction
mixture was warmed to RT and stirred for 90 min. The reaction mixture was
partitioned between EtOAc and water. The aqueous phase was extracted with
EtOAc (x 3) and the combined organic layers were washed with brine, dried
(MgSO ) and concentrated in vacuo. The resultant residue was purified by FCC on
silica, using a gradient of 0-60% EtOAc in cyclohexane, to afford the title
compound (620 mg, 75%) as a white solid. LCMS (Method 1): Rt 3.98 min, m/z
445, 447, 449 [MH ].
b. N-(5-tert-Butylmethoxy{3-[(1S,4R)(3-piperidinyl-
[1,2,4]triazolo[4,3-a]pyridinyloxy)-1,2,3,4-tetrahydro-naphthalenyl]-
ureido}-phenyl)-methanesulfonamide (Example 104)
A mixture of Intermediate 3c (50 mg, 0.14 mmol), Intermediate 104a (62
mg, 0.14 mmol) and DIPEA (48 µL, 0.27 mmol) in dioxane (1.5 mL) was stirred at
70 ºC for 18 h and then at 80 ºC for 48 h. The reaction mixture was diluted with
EtOAc and then poured into water. The aqueous phase was extracted with EtOAc
(x 3) and the combined organic layers were washed with brine, dried (MgSO ) and
concentrated in vacuo. The resultant residue was purified by FCC on silica, using a
gradient of 1-8% MeOH in DCM and then by HPLC (C18 X-select column, 10-
98% gradient MeCN in H O, 0.1% HCO H), to afford the title compound (19 mg,
21%). LCMS (Method 5): Rt 4.47 min, m/z 662 [MH ]. ¹H NMR (400 MHz, d -
DMSO): 1.25 (9H, s), 1.57-1.66 (2H, m), 1.69-1.78 (4H, m), 1.83-1.95 (1H, m),
1.98-2.24 (3H, m), 3.05 (3H, s), 3.15 (4H, t, J = 5.3 Hz), 3.69 (3H, s), 4.87-4.96
(1H, m), 5.59 (1H, t, J = 4.5 Hz), 6.94 (1H, d, J = 2.3 Hz), 7.19 (1H, dd, J = 9.9,
2.1 Hz), 7.31 (1H, dd, J = 8.2, 6.7 Hz), 7.35-7.45 (4H, m), 7.60-7.69 (2H, m), 8.07
(1H, s), 8.19 (1H, d, J = 2.4 Hz).
Example 105
1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[8-methyl
((S)methyl-pyrrolidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-urea
a. N-Benzhydrylidene-N'-(5-fluoromethyl-pyridinyl)-hydrazine
(Intermediate 105a)
A mixture of 2-bromofluoromethyl-pyridine (190 mg, 1.0 mmol),
benzhydrylidene-hydrazine (216 mg, 1.1 mmol), phenylboronic acid (5 mol%, 6
mg) and potassium tert-butoxide (157 mg, 1.4 mmol) in anhydrous toluene (6 mL)
was degassed with a stream of argon, treated with Pd(OAc) (2 mol%, 5 mg) and
racemic (1,1 ′-binaphthalene-2,2 ′-diyl)bis(diphenylphosphine) (2 mol%, 12 mg)
and stirred at 80 ºC for 1 h. After cooling to RT, the reaction mixture was diluted
with EtOAc and washed with water followed by a saturated aqueous solution of
NaHCO . The organic layer was dried (MgSO ) and concentrated in vacuo. The
resultant residue was purified by FCC on silica, using a gradient of 1-10% MeOH
in DCM followed by 100% DCM, to afford the title compound (196 mg, 64%).
LCMS (Method 4): Rt 3.44 min, m/z 306 [MH ].
b. (5-Fluoromethyl-pyridinyl)-hydrazine (Intermediate 105b)
A solution of Intermediate 105a (194 mg, 0.635 mmol) in toluene (13 mL)
was treated with HCl (37%, 3.5 mL) and heated at 110 ºC for 1.5 h. After cooling
to RT, the reaction mixture was diluted with water and extracted with toluene (x
3). The aqueous layer was cooled to 0 ºC, neutralised with 5N NaOH and extracted
with DCM (x 3). The combined organic layers were dried (MgSO) and
concentrated in vacuo to afford the title compound (78 mg, 86%) as a silver/green
solid. LCMS (Method 4): Rt 0.29 min, m/z 142 [MH ].
c. (S)Methyl-pyrrolidinecarboxylic acid N'-(5-fluoromethyl-
pyridinyl)-hydrazide (Intermediate 105c)
A solution of Intermediate 105b (76 mg, 0.537 mmol), (S)methyl-
pyrrolidinecarboxylic acid (55 mg, 0.72 mmol) and HOBT (8 mg, 0.72 mmol)
in anhydrous DCM (5 mL) was treated with EDC (138 mg, 0.717 mmol) and
stirred at RT under a nitrogen atmosphere for 18 h. The reaction mixture was
diluted with DCM and washed with brine. The organic layer was dried (MgSO )
and concentrated in vacuo. The resultant residue was purified by FCC on silica,
using a gradient of 1-10% MeOH in DCM, to afford the title compound (76 mg,
56%). ¹H NMR (400 MHz, CDCl ): 1.74-2.05 (3H, m), 2.15-2.33 (4H, m), 2.34-
2.46 (1H, m), 2.52 (3H, s), 3.02-3.12 (1H, m), 3.15-3.25 (1H, m), 6.70 (1H, s),
7.08-7.18 (1H, m), 7.90 (1H, d, J = 2.8 Hz), 9.52 (1H, br s).
d. 6-Fluoromethyl((S)methyl-pyrrolidinyl)-
[1,2,4]triazolo[4,3-a]pyridine (Intermediate 105d)
Hexachloroethane (141 mg, 0.587 mmol) was added portionwise at RT to a
stirred mixture of Intermediate 105c (74 mg, 0.293 mmol), triethylamine (166 µL,
1.17 mmol) and triphenylphosphine (154 mg, 0.587 mmol) in THF (5 mL). The
reaction mixture was stirred at 80 ºC for 2 h, then cooled to RT and filtered. The
filtrate was concentrated in vacuo and the resultant residue was purified by SCX
cartridge. The cartridge was washed with 10% MeOH in DCM and the product
eluted with 10% (2M NH in MeOH) in DCM. The product containing fractions
were concentrated in vacuo and the resultant residue was purified by FCC on
silica, using a gradient of 1-10% MeOH in DCM, to afford the title compound (59
mg, 86%) as a colourless oil. ¹H NMR (400 MHz, CDCl ): 1.88-2.12 (3H, m),
2.15-2.53 (5H, m), 2.69 (3H, s), 3.28 (1H, t, J = 7.8 Hz), 4.01-4.15 (1H, m), 6.97
(1H, d, J = 8.4 Hz), 8.50 (1H, s).
e. (1S,4R)[8-Methyl((S)methyl-pyrrolidinyl)-
[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalen
ylamine (Intermediate 105e)
A mixture of Intermediate A (44 mg, 0.267 mmol) and sodium hydride
(60% in mineral oil, 29 mg, 0.729 mmol) in anhydrous DMF (1 mL) was stirred at
RT for 20 min under argon atmosphere. To the reaction mixture was added a
solution of Intermediate 105d (57 mg, 0.243 mmol) in anhydrous DMF (2 mL) and
stirring at 60 ºC was continued for 2.5 h. After cooling to RT, the reaction mixture
was diluted with EtOAc and poured into ice-water. The aqueous phase was
extracted with EtOAc (x 3) and the combined organic layers were dried (MgSO )
and concentrated in vacuo. The resultant residue was purified by SCX cartridge by
washing the cartridge with 10% MeOH in DCM and eluting the product with 10%
(2M NH in MeOH) in DCM and then by FCC on silica, using 10% MeOH in
DCM followed by 10% [2M NH in MeOH] in DCM, to give the title compound
(53 mg, 58%). LCMS (Method 1): Rt 0.38, 1.54 min, m/z 378 [MH ].
f. 1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[8-methyl
((S)methyl-pyrrolidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-urea (Example 105)
A mixture of Intermediate 105e (53 mg, 0.14 mmol), (5-tert-butylp-tolyl-
2H-pyrazolyl)-carbamic acid 2,2,2-trichloro-ethyl ester (For reference
procedure see Synthetic Communications, 2009, 39, 3999-4009; 67 mg, 0.168
mmol) and DIPEA (49 µL, 0.28 mmol) in DMF (2 mL) was stirred at 100 ºC for
1.5 h under argon atmosphere. After cooling to RT, the reaction mixture was
diluted with EtOAc and washed with brine. The organic layer was dried (MgSO )
and concentrated in vacuo. The resultant residue was purified by FCC on silica,
using a gradient of 0-100% EtOAc in cyclohexane followed by 10% [2M NH in
MeOH] in EtOAc. The product containing fractions were concentrated in vacuo
and the resultant residue was purified by HPLC (C18 Phenomenex Gemini
column, 5-98% gradient MeCN in H O, 0.1% NH OH), to afford the title
compound (52 mg, 74%). LCMS (Method 5): Rt 3.76 min, m/z 633 [MH ]. ¹H
NMR (400 MHz, d -DMSO): 1.23 (9H, s), 1.75-2.30 (13H, m), 2.32 (3H, s), 2.48
(3H, s), 3.19 (1H, br s), 4.72-4.83 (1H, m), 5.30-5.38 (1H, m), 6.28 (1H, s), 7.03-
7.11 (2H, m), 7.20-7.36 (8H, m), 8.00 (1H, s), 8.11 (1H, s).
Example 106
1-{5-tert-Butyl[4-(4-methyl-piperazinylmethyl)-phenyl]-2H-
pyrazolyl}[(1S,4R)(3-piperidinyl-[1,2,4]triazolo[4,3-a]pyridin
yloxy)-1,2,3,4-tetrahydro-naphthalenyl]-urea
a. 1-[5-tert-Butyl(4-hydroxymethyl-phenyl)-2H-pyrazolyl]
[(1S,4R)(3-piperidinyl-[1,2,4]triazolo[4,3-a]pyridinyloxy)-1,2,3,4-
tetrahydro-naphthalenyl]-urea (Intermediate 106a)
A mixture of Intermediate 3c (100 mg, 0.28 mmol), Intermediate 33a (116
mg, 0.28 mmol) and DIPEA (96 µL, 0.55 mmol) in dioxane (3 mL) was stirred at
80 ºC for 16 h. After cooling, the reaction mixture was partitioned between water
and EtOAc. The aqueous phase was extracted with EtOAc (x 3) and the combined
organic layers were washed with brine, dried (MgSO ) and concentrated in vacuo.
The resultant residue was purified by FCC on silica, using a gradient of 1-10%
MeOH in DCM, to afford the title compound (156 mg, 88%). LCMS (Method 4):
Rt 3.07 min, m/z 635 [MH ].
b. 1-[5-tert-Butyl(4-chloromethyl-phenyl)-2H-pyrazolyl]
[(1S,4R)(3-piperidinyl-[1,2,4]triazolo[4,3-a]pyridinyloxy)-1,2,3,4-
tetrahydro-naphthalenyl]-urea (Intermediate 106b)
To an ice-bath cooled solution of Intermediate 106a (150 mg, 0.25 mmol) in
DCM (3 mL) was added DIPEA (107 µL, 0.61 mmol) followed by
methanesulfonyl chloride (29 µL, 0.37 mmol). The reaction mixture was stirred for
2 h. After warming to RT, additional amount of DIPEA (65 µL) and
methanesulfonyl chloride (30 µL) were added and stirring was continued for 2 h.
The reaction mixture was partitioned between DCM and water. The aqueous phase
was extracted with DCM (x 3) and the combined organic layers were washed with
brine, dried (MgSO ) and concentrated in vacuo to afford the title compound
(Quantitative). Product used in the following step without further purification.
LCMS (Method 4): Rt 3.59 min, m/z 653 [MH ].
c. 1-{5-tert-Butyl[4-(4-methyl-piperazinylmethyl)-phenyl]-2H-
pyrazolyl}[(1S,4R)(3-piperidinyl-[1,2,4]triazolo[4,3-a]pyridin
yloxy)-1,2,3,4-tetrahydro-naphthalenyl]-urea (Example 106)
To a solution of Intermediate 106b (0.25 mmol) in THF (2.5 mL) was added
DIPEA (130 µL, 0.75 mmol) followed by N-methylpiperazine (83 µL, 0.75
mmol). The reaction mixture was heated at 50 ºC for 18 h in a sealed tube, then
cooled and partitioned between EtOAc and water. The aqueous phase was
extracted with EtOAc (x 3) and the combined organic layers were washed with
brine, dried (MgSO ) and concentrated in vacuo. The resultant residue was purified
by FCC on silica, using a gradient of 0-10% [2M NH in MeOH] in DCM
followed by HPLC (C18 X-select column, 10-98% gradient MeCN in H O, 0.1%
HCO H), to give the title compound (13 mg, 7%). LCMS (Method 5): Rt 3.44 min,
m/z 717 [MH ]. ¹H NMR (400 MHz, d -DMSO): 1.27 (9H, s), 1.57-1.66 (2H, m),
1.68-1.77 (4H, m), 1.79-1.95 (2H, m), 1.98-2.19 (5H, m), 2.22-2.46 (8H, m), 3.14
(4H, t, J = 5.3 Hz), 3.49 (2H, s), 4.76-4.85 (1H, m), 5.54 (1H, t, J = 4.4 Hz), 6.33
(1H, s), 7.09 (1H, d, J = 8.6 Hz), 7.17 (1H, dd, J = 9.8, 2.2 Hz), 7.25-7.47 (8H, m),
7.59-7.65 (2H, m), 8.11 (1H, s).
Example 107
1-(3-tert-Butyl-1'-methyl-1'H-[1,4']bipyrazolylyl)[(1S,4R)(3-
piperidinyl-[1,2,4]triazolo[4,3-a]pyridinyloxy)-1,2,3,4-tetrahydro-
naphthalenyl]-urea
To a solution of Intermediate 3c (100 mg, 0.27 mmol) in dioxane (3 mL)
was added DIPEA (90 µL, 0.55 mmol) followed by (3-tert-butyl-1'-methyl-1'H-
[1,4']bipyrazolylyl)-carbamic acid 2,2,2-trichloro-ethyl ester (For reference
procedure see for example US6492529; 109 mg, 0.27 mmol). The reaction mixture
was heated at 60 ºC for 18 h, then cooled and poured into water. The aqueous
phase was extracted with EtOAc (x 3) and the combined organic layers were
washed with brine, dried (MgSO ) and concentrated in vacuo. The resultant
residue was purified by FCC on silica, using a gradient of 0-10% MeOH in DCM
followed by MDAP (Method 7) purification, to give the title compound (100 mg,
61%). LCMS (Method 5): Rt 4.05 min, m/z 609 [MH ]. ¹H NMR (400 MHz, d -
DMSO): 1.24 (9H, s), 1.54-1.66 (2H, m), 1.67-1.76 (4H, m), 1.81-2.18 (4H, m),
3.13 (4H, t, J = 5.2 Hz), 3.86 (3H, s), 4.78-4.87 (1H, m), 5.55 (1H, t, J = 4.1 Hz),
6.26 (1H, s), 7.10-7.18 (2H, m), 7.25-7.41 (4H, m), 7.58-7.64 (3H, m), 7.98-8.02
(2H, m).
Example 108
1-[3-tert-Butyl-1'-(2-dimethylamino-ethyl)-1'H-[1,4']bipyrazolylyl]-
3-[(1S,4R)(3-piperidinyl-[1,2,4]triazolo[4,3-a]pyridinyloxy)-1,2,3,4-
tetrahydro-naphthalenyl]-urea
a. 3-tert-Butyl-1'-[2-(tetrahydro-pyranyloxy)-ethyl]-1'H-
[1,4']bipyrazolylylamine (Intermediate 108a)
To a mixture of 4-iodo[2-(tetrahydro-pyranyloxy)-ethyl]-1H-pyrazole
(For reference procedure see for example WO2010139731; 1.54 g, 4.81 mmol), 5-
tert-butyl-2H-pyrazolylamine (668 mg, 4.81 mmol), copper (I) iodide (45 mg,
0.24 mmol) and K CO (1.39 g, 10.1 mmol) was added a solution of toluene (5
mL), previously degassed by using a stream of argon. (R,R)-(-)-N,N'-Dimethyl-
1,2-cyclohexanediamine (151 µL, 0.96 mmol) was then added and the reaction
mixture was heated at 150 ºC for 2.5 h under microwave irradiation. The crude
reaction mixture was poured into water and extracted with EtOAc (x 3). The
combined organic layers were washed with brine, dried (MgSO ) and concentrated
in vacuo. The resultant residue was purified by FCC on silica, using a gradient of
0-100% EtOAc in cyclohexane, to give the title compound (1.29 g, 81%). LCMS
(Method 1): Rt 2.31 min, m/z 334 [MH ].
b. {3-tert-Butyl-1'-[2-(tetrahydro-pyranyloxy)-ethyl]-1'H-
[1,4']bipyrazolylyl}-carbamic acid 2,2,2-trichloro-ethyl ester (Intermediate
108b)
To a mixture of Intermediate 108a (1.29 g, 3.87 mmol) in water (5 mL) and
EtOAc (13 mL) was added NaOH (310 mg, 7.74 mmol). After 10 min stirring,
2,2,2-trichloroethyl chloroformate (640 µL, 4.65 mmol) was added and the
reaction mixture was stirred at RT for 1 h. The aqueous layer was extracted with
EtOAc (x 3) and the combined organic layers were washed with brine, dried
(MgSO ) and concentrated in vacuo. The resultant residue was purified by FCC on
silica, using a gradient of 0-75% EtOAc in cyclohexane, to afford the title
compound (1.24 g, 63%). LCMS (Method 4): Rt 3.92 min, m/z 508, 510 [MH ].
c. 1-{3-tert-Butyl-1'-[2-(tetrahydro-pyranyloxy)-ethyl]-1'H-
[1,4']bipyrazolylyl}[(1S,4R)(3-piperidinyl-[1,2,4]triazolo[4,3-
a]pyridinyloxy)-1,2,3,4-tetrahydro-naphthalenyl]-urea (Intermediate
108c)
The title compound was prepared starting from Intermediate 3c and
Intermediate 108b using analogous procedures to those described in Intermediate
106a. LCMS (Method 4): Rt 3.27 min, m/z 723.5 [MH ].
d. 1-[3-tert-Butyl-1'-(2-hydroxy-ethyl)-1'H-[1,4']bipyrazolylyl]
[(1S,4R)(3-piperidinyl-[1,2,4]triazolo[4,3-a]pyridinyloxy)-1,2,3,4-
tetrahydro-naphthalenyl]-urea (Intermediate 108d)
To a solution of Intermediate 108c (170 mg, 0.23 mmol) in MeOH (2.5 mL)
was added pyridinium p-toluenesulfonate (118 mg, 0.47 mmol) and the reaction
mixture was heated at 60ºC for 2 h. The resultant mixture was poured into water
and a saturated aqueous solution of NaHCO was added. The aqueous phase was
extracted with EtOAc (x 3) and the combined organic layers were washed with
brine, dried (MgSO ) and concentrated in vacuo. The resultant residue was purified
by FCC on silica, using a gradient of 0-10% MeOH in DCM, to give the title
compound (105 mg, 72%). LCMS (Method 1): Rt 2.96 min, m/z 639 [MH ].
e. Methanesulfonic acid 2-(3-tert-butyl{3-[(1S,4R)(3-piperidin
yl-[1,2,4]triazolo[4,3-a]pyridinyloxy)-1,2,3,4-tetrahydro-naphthalenyl]-
ureido}-[1,4']bipyrazolyl-1'-yl)-ethyl ester (Intermediate 108e)
To an ice-bath cooled solution of Intermediate 108d (105 mg, 0.16 mmol) in
DCM (2 mL) was added DIPEA (43 µL, 0.25 mmol) followed by methanesulfonyl
chloride (15 µL, 0.20 mmol). The reaction mixture was stirred for 2 h and then
quenched with water. The aqueous phase was extracted with DCM (x 3) and the
combined organic layers were washed with brine, dried (MgSO ) and concentrated
in vacuo to afford the title compound (Quantitative). Product used in the following
step without further purification. LCMS (Method 4): Rt 3.09 min, m/z 717 [MH ].
f. 1-[3-tert-Butyl-1'-(2-dimethylamino-ethyl)-1'H-[1,4']bipyrazolyl
yl][(1S,4R)(3-piperidinyl-[1,2,4]triazolo[4,3-a]pyridinyloxy)-
1,2,3,4-tetrahydro-naphthalenyl]-urea (Example 108)
To a solution of Intermediate 108e (0.20 mmol) in THF (2 mL) was added
dimethylamine (2M in MeOH, 0.8 mL, 1.6 mmol) and stirring at RT was
continued for 48 h. The crude reaction mixture was partitioned between EtOAc
and water. The aqueous phase was extracted with EtOAc (x 3) and the combined
organic layers were washed with brine, dried (MgSO ) and concentrated in vacuo.
The resultant residue was purified by FCC on silica, using a gradient of 0-10%
[2M NH in MeOH] in DCM followed by MDAP (Method 7) purification, to give
the title compound (20 mg, 15%). LCMS (Method 5): Rt 3.34 min, m/z 666
[MH ]. ¹H NMR (400 MHz, d -DMSO): 1.24 (9H, s), 1.54-1.65 (2H, m), 1.67-1.77
(4H, m), 1.81-2.13 (4H, m), 2.16 (6H, s), 2.67 (2H, t, J = 6.5 Hz), 3.13 (4H, t, J =
.3 Hz), 4.20 (2H, t, J = 6.5 Hz), 4.79-4.87 (1H, m), 5.55 (1H, t, J = 4.5 Hz), 6.26
(1H, s), 7.11-7.19 (2H, m), 7.26-7.41 (4H, m), 7.58-7.64 (3H, m), 7.99-8.05 (2H,
Example 109
H OH
O N N N
H H H
N-[5-tert-Butylmethoxy(3-{(1S,4R)[3-((S)methyl-pyrrolidin-
2-yl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalen
yl}-ureido)-phenyl]-methanesulfonamide formate salt
A mixture of Intermediate 5c (122 mg, 0.33 mmol), Intermediate 104a (150
mg, 0.33 mmol) and DIPEA (87 µL, 0.50 mmol) in dioxane (2 mL) was stirred at
60ºC for 18 h and then at 85ºC for 48 h. The volatiles were concentrated in vacuo
and the resultant residue was purified by MDAP (Method 7) to afford the title
compound (88 mg, 40%). LCMS (Method 5): Rt 3.41 min, m/z 662 [MH ]. ¹H
NMR (400 MHz, d -DMSO): 1.24 (9H, s), 1.81-2.27 (10H, m), 2.28-2.40 (1H, m),
3.04 (3H, s), 3.11-3.18 (2H, m), 3.67 (3H, s), 3.99 (1H, t, J = 8.3 Hz), 4.83-4.99
(1H, m), 5.43 (1H, t, J = 4.5 Hz), 6.93 (1H, d, J = 2.3 Hz), 7.25-7.44 (7H, m), 7.76
(1H, d, J = 10.3 Hz), 8.05 (1H, s), 8.15 (1H, s), 8.18 (1H, d, J = 2.8 Hz), 8.27 (1H,
d, J = 2.1 Hz).
Example 110
1-[5-tert-Butyl(2-hydroxy-ethyl)-2H-pyrazolyl]{(1S,4R)[3-
((S)methyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-urea
a. 2-(5-Aminotert-butyl-pyrazolyl)-ethanol (Intermediate 110a)
2-Hydrazino-ethanol (2.98 mL, 44.0 mmol) was added to a stirred solution
of 4,4-dimethyloxo-pentanenitrile (5.0 g, 40.0 mmol) in EtOH (IMS grade, 40
mL) at RT followed by concentrated HCl (0.4 mL). The reaction mixture was
heated at reflux temperature for 18 h then cooled and concentrated in vacuo. The
resultant residue was triturated with pentane to give the title compound (7.4 g,
quantitative) as a yellow solid. LCMS (Method 3): Rt 0.81 min, m/z 184 [MH ].
b. [5-tert-Butyl(2-hydroxy-ethyl)-2H-pyrazolyl]-carbamic acid
2,2,2-trichloro-ethyl ester (Intermediate 110b)
2,2,2-Trichloroethyl chloroformate (3.24 mL, 23.5 mmol) was added
dropwise over 5 min to a solution of Intermediate 110a (4.11 g, 22.4 mmol) in
NaOH (1M in water, 33.6 mL, 33.6 mmol) and EtOAc (35 mL) cooled at 0 ºC
under argon atmosphere. The reaction mixture was stirred at RT for 5 h. Additional
2,2,2-trichloroethyl chloroformate (462 µL) was added and stirring at RT was
continued for 16 h. Additional NaOH (1M in water, 15 mL) and 2,2,2-
trichloroethyl chloroformate (462 µL) were added and stirring at RT was
continued for 1 h. The aqueous layer was extracted with EtOAc (x 3) and the
combined organic layers were washed with brine, dried (Na SO ) and concentrated
in vacuo. The resultant residue was dissolved in cyclohexane (100 mL) and left to
stand for 5 days. The resulting suspension was filtered and the solid collected by
filtration washing with additional cyclohexane affording the title compound (3.64
g, 45%) as a white solid. The filtrate was concentrated in vacuo and the resultant
residue was purified by FCC on silica, using a mixture of 50% EtOAc in
cyclohexane, then partitioned between DCM and water. The organic layer was
dried through a phase separator and concentrated in vacuo to afford additional title
compound (1.43 g, 18%) as an orange gum. LCMS (Method 3): Rt 3.72 min, m/z
358 [MH ].
c. 1-[5-tert-Butyl(2-hydroxy-ethyl)-2H-pyrazolyl]{(1S,4R)[3-
((S)methyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-urea (Example 110)
A mixture of Intermediate 110b (143 mg, 0.40 mmol), Intermediate 81d
(1151mg, 0.40 mmol) and DIPEA (82 µL, 0.50 mmol) in dioxane (5 mL) was
stirred at 100 ºC for 4 h. After cooling, the reaction mixture was concentrated in
vacuo and then partitioned between water and DCM. The aqueous phase was
extracted with DCM (x 3) and the combined organic layers were washed with
brine, dried through a phase separator and concentrated in vacuo. The resultant
residue was purified by FCC on silica, using a gradient of 3-15% MeOH in DCM
followed by MDAP (Method 7) purification, to afford the title compound (36 mg,
%) as a glassy white solid. LCMS (Method 5): Rt 4.02 min, m/z 587 [MH ]. ¹H
NMR (400 MHz, d -DMSO): 0.92 (3H, d, J = 6.3 Hz), 1.21 (9H, s), 1.44-1.57 (2H,
m), 1.60-1.74 (2H, m), 1.74-1.87 (2H, m), 1.88-2.22 (4H, m), 2.86-2.96 (1H, m),
3.12-3.20 (2H, m), 3.63-3.71 (2H, m), 3.95 (2H, t, J = 6.0 Hz), 4.82-4.91 (1H, m),
.00 (1H, br s), 5.54 (1H, t, J = 4.3 Hz), 6.07 (1H, s), 7.10 (1H, d, J = 8.6 Hz), 7.22
(1H, dd, J = 9.8, 2.2 Hz), 7.26-7.32 (1H, m), 7.35-7.42 (3H, m), 7.65 (1H, d, J =
.8 Hz), 7.71 (1H, d, J = 2.1 Hz), 8.19-8.23 (1H, m).
Example 111
1-(5-tert-Butyl-isoxazolyl){(1S,4R)[3-((S)methyl-piperidin
yl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-
urea
The title compound was prepared starting from Intermediate 81d and (5-tert-
butyl-isoxazolyl)-carbamic acid 2,2,2-trichloro-ethyl ester (For reference
procedure see WO2006091671) using analogous procedures to those described in
Example 110 step c. LCMS (Method 5): Rt 4.67 min, m/z 544 [MH ]. ¹H NMR
(400 MHz, d -DMSO): 0.91 (3H, d, J = 6.3 Hz), 1.28 (9H, s), 1.44-1.57 (2H, m),
1.60-1.73 (2H, m), 1.74-1.86 (2H, m), 1.88-2.22 (4H, m), 2.86-2.94 (1H, m), 3.12-
3.20 (2H, m), 4.86-4.95 (1H, m), 5.54 (1H, t, J = 4.2 Hz), 6.40 (1H, s), 7.00 (1H, d,
J = 8.6 Hz), 7.21-7.26 (1H, m), 7.27-7.33 (1H, m), 7.34-7.42 (3H, m), 7.64 (1H,
dd, J = 9.8, 0.8 Hz), 7.71 (1H, d, J = 2.10 Hz), 9.31 (1H, s).
Example 112
H OH
1-[3-tert-Butyl-1'-(2-morpholinyl-ethyl)-1'H-[1,4']bipyrazolylyl]-
3-[(1S,4R)(3-piperidinyl-[1,2,4]triazolo[4,3-a]pyridinyloxy)-1,2,3,4-
tetrahydro-naphthalenyl]-urea formate salt
The title compound was prepared starting from Intermediate 108e and
morpholine using analogous procedures to those described in Example 108. LCMS
(Method 5): Rt 3.37 min, m/z 708 [MH ]. ¹H NMR (400 MHz, d -DMSO): 1.24
(9H, s), 1.55-1.65 (2H, m), 1.67-1.76 (4H, m),1.79- 2.19 (4H, m), 2.41 (4H, d, J =
4.7 Hz), 2.72 (2H, t, J = 6.7 Hz), 3.13 (4H, t, J = 5.3 Hz), 3.53 (4H, t, J = 4.6 Hz),
4.23 (2H, t, J = 6.6 Hz), 4.78-4.87 (1H, m), 5.55 (1H, t, J = 4.4 Hz), 6.25 (1H, s),
7.11-7.18 (2H, m), 7.25-7.41 (4H, m), 7.58-7.64 (3H, m), 8.00 (1H, s), 8.05 (1H,
s), 8.16 (1H, s).
Example 113
1-[3-tert-Butyl-1'-(3-dimethylamino-propyl)-1'H-[1,4']bipyrazolylyl]-
3-[(1S,4R)(3-piperidinyl-[1,2,4]triazolo[4,3-a]pyridinyloxy)-1,2,3,4-
tetrahydro-naphthalenyl]-urea formate salt
H OH
a. 4-Iodo[3-(tetrahydro-pyranyloxy)-propyl]-1H-pyrazole
(Intermediate 113a)
To a mixture of 4-iodo-1H-pyrazole (2.0 g, 10.3 mmol) and Cs CO (5.04 g,
.5 mmol) in MeCN (28 mL) was added 2-(3-bromopropoxy)tetrahydro-2H-
pyran (1.84 mL, 10.8 mmol) and the mixture stirred overnight. The crude reaction
mixture was poured into water and extracted with EtOAc (x 3). The combined
organic layers were washed with brine, dried (MgSO ) and concentrated in vacuo.
The resultant residue was purified by FCC on silica, using a gradient of 0-80%
EtOAc in cyclohexane, to give the title compound (2.95 g, 81%). ¹H NMR (300
MHz, CDCl ): 150-1.58 (4H, m), 1.65-1.90 (2H, m), 2.12 (2H, qn, J = 6.4 Hz),
3.35 (1H, dt, J = 10.2, 5.9 Hz), 3.46-3.54 (1H, m), 3.73 (1H, dt, J = 10.2, 5.9 Hz),
3.80-3.88 (1H, m), 4.26 (2H, td, J = 6.9, 1.5 Hz), 4.54 (1H, dd, J = 4.5, 3.1 Hz),
7.46 (1H, s), 7.50 (1H, s).
b. 3-tert-Butyl-1'-[3-(tetrahydro-pyranyloxy)-propyl]-1'H-
[1,4']bipyrazolylylamine (Intermediate 113b)
To a mixture of intermediate 113a (1.50 g, 4.46 mmol), 5-tert-butyl-2H-
pyrazolylamine (620 mg, 4.46 mmol), copper (I) iodide (42 mg, 0.22 mmol) and
K CO (1.29 g, 9.37 mmol) was added a solution of toluene (4.6 mL), previously
degassed by using a stream of argon. (R,R)-(-)-N,N'-Dimethyl-1,2-
cyclohexanediamine (141 µL, 0.89 mmol) was then added and the reaction mixture
was heated at 140 ºC for 2.5 h under microwave irradiation. The crude reaction
mixture was poured into water and extracted with EtOAc (x 3). The combined
organic layers were washed with brine, dried (MgSO ) and concentrated in vacuo.
The resultant residue was purified by FCC on silica, using a gradient of 0-100%
EtOAc in cyclohexane, to give the title compound (1.14 g, 73%). LCMS (Method
4): Rt 2.34 min, m/z 348 [MH ].
c. {3-tert-Butyl-1'-[3-(tetrahydro-pyranyloxy)-propyl]-1'H-
[1,4']bipyrazolylyl}-carbamic acid 2,2,2-trichloro-ethyl ester (Intermediate
113c)
To a stirred mixture of Intermediate 113b (1.14 g, 3.28 mmol) in water (6
mL) and EtOAc (12 mL) was added NaOH (263 mg, 6.57 mmol). After 10 min,
2,2,2-trichloroethyl chloroformate (543 µL, 3.94 mmol) was added and the
reaction mixture was stirred at RT for 1 h. The aqueous layer was extracted with
EtOAc (x 3) and the combined organic layers were washed with brine, dried
(MgSO ) and concentrated in vacuo. The resultant residue was purified by FCC on
silica, using a gradient of 0-100% EtOAc in cyclohexane, to afford the title
compound (1.57 g, 91%). LCMS (Method 4): Rt 3.99 min, m/z 522, 524 [MH ].
d. 1-{3-tert-Butyl-1'-[3-(tetrahydro-pyranyloxy)-propyl]-1'H-
[1,4']bipyrazolylyl}[(1S,4R)(3-piperidinyl-[1,2,4]triazolo[4,3-
a]pyridinyloxy)-1,2,3,4-tetrahydro-naphthalenyl]-urea (Intermediate
113d)
The title compound was prepared starting from Intermediate 3c and
Intermediate 113c using analogous procedures to those described in Intermediate
106a. LCMS (Method 4): Rt 3.34 min, m/z 737 [MH ].
e. 1-[3-tert-Butyl-1'-(3-hydroxy-propyl)-1'H-[1,4']bipyrazolylyl]
[(1S,4R)(3-piperidinyl-[1,2,4]triazolo[4,3-a]pyridinyloxy)-1,2,3,4-
tetrahydro-naphthalenyl]-urea (Intermediate 113e)
To a solution of Intermediate 113d (263 mg, 0.36 mmol) in MeOH (2.5 mL)
was added pyridinium p-toluenesulfonate (179 mg, 0.71 mmol) and the reaction
mixture was heated at 60 ºC for 3 h. The resultant mixture was poured into water
and a saturated aqueous solution of NaHCO was added. The aqueous phase was
extracted with EtOAc (x 3) and the combined organic layers were washed with
brine, dried (MgSO ) and concentrated in vacuo. The resultant residue was purified
by FCC on silica, using a gradient of 3-10% MeOH in DCM, to give the title
compound (163 mg, 70%). LCMS (Method 4): Rt 3.00 min, m/z 653 [MH ].
f. Methanesulfonic acid 3-(3-tert-butyl{3-[(1S,4R)(3-piperidin
yl-[1,2,4]triazolo[4,3-a]pyridinyloxy)-1,2,3,4-tetrahydro-naphthalenyl]-
ureido}-[1,4']bipyrazolyl-1'-yl)-propyl ester (Intermediate 113f)
To an ice-bath cooled solution of Intermediate 113e (163 mg, 0.25 mmol) in
DCM (3 mL) was added DIPEA (174 µL, 1.0 mmol) followed by methanesulfonyl
chloride (39 µL, 0.50 mmol). The reaction mixture was stirred for 1 h and then
quenched with water. The aqueous phase was extracted with DCM (x 3) and the
combined organic layers were washed with brine, dried (MgSO ) and concentrated
in vacuo to afford the title compound (Quantitative). Product used in the following
step without further purification. LCMS (Method 4): Rt 3.12 min, m/z 731 [MH ].
g. 1-[3-tert-Butyl-1'-(3-dimethylamino-propyl)-1'H-[1,4']bipyrazolyl
yl][(1S,4R)(3-piperidinyl-[1,2,4]triazolo[4,3-a]pyridinyloxy)-
1,2,3,4-tetrahydro-naphthalenyl]-urea formate salt (Example 113)
To a solution of Intermediate 113f (0.125 mmol) in THF (1.5 mL) was
added dimethylamine (2M in MeOH, 0.5 mL, 1.0 mmol) and the reaction stirred at
50°C for 24 h. The crude reaction mixture was cooled and partitioned between
EtOAc and water. The aqueous phase was extracted with EtOAc (x 3) and the
combined organic layers were washed with brine, dried (MgSO ) and concentrated
in vacuo. The resultant residue was purified by FCC on silica, using a gradient of
0-10% [2M NH in MeOH] in DCM, followed by MDAP (Method 7) purification,
to give the title compound (10 mg, 12%). LCMS (Method 5): Rt 3.36 min, m/z 680
[MH ]. ¹H NMR (400 MHz, d -DMSO): 1.21 (9H, s), 1.54-1.65 (2H, m), 1.67-1.77
(4H, m), 1.81-1.95 (4H, m), 1.99-2.07 (4H, m) 2.08 (6H, s), 2.16 (2H, t, J = 6.9
Hz), 3.10 (4H, t, J = 5.2 Hz), 4.09 (2H, t, J = 7.1 Hz), 4.79 (1H, td, J = 8.4, 5.5 Hz),
.51 (1H, t, J = 4.5 Hz), 6.21 (1H, s), 7.09-7.14 (2H, m), 7.22-7.37 (4H, m), 7.55-
7.62 (3H, m), 7.97-8.01 (2H, m), 8.22 (0.4H, br s).
Example 114
H OH
1-[3-tert-Butyl-1'-(3-morpholinyl-propyl)-1'H-[1,4']bipyrazolylyl]-
3-[(1S,4R)(3-piperidinyl-[1,2,4]triazolo[4,3-a]pyridinyloxy)-1,2,3,4-
tetrahydro-naphthalenyl]-urea formate salt
The title compound was prepared starting from Intermediate 113f and
morpholine using analogous procedures to those described in Example 113. LCMS
(Method 5): Rt 3.36 min, m/z 722 [MH ]. ¹H NMR (400 MHz, d -DMSO): 1.20
(9H, s), 1.54-1.60 (2H, m), 1.65-1.72 (4H, m), 1.80-1.96 (4H, m), 1.98-2.10 (4H,
m) 2.22 (2H, t, J = 7.0 Hz), 2.24-2.30 (4H, m), 3.10 (4H, t, J = 5.2 Hz), 3.50 (4H, t,
J = 4.6 Hz), 4.09 (2H, t, J = 7.0 Hz), 4.79 (1H, td, J = 8.4, 5.5 Hz), 5.51 (1H, t, J =
4.5 Hz), 6.21 (1H, s), 7.10-7.15 (2H, m), 7.22-7.36 (4H, m), 7.55-7.62 (3H, m),
7.97-8.01 (2H, m), 8.22 (0.3H, br s).
Example 115
1-{(1S,4R)[3-((2S,6R)-2,6-Dimethyl-piperidinyl)-
[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}
(3-fluoromorpholinyl-phenyl)-urea
a. (3-Fluoromorpholinyl-phenyl)-carbamic acid 2,2,2-trichloro-
ethyl ester (Intermediate 115a)
N N O
O Cl
2,2,2-Trichloroethyl chloroformate (1.05 mL, 7.65 mmol) was added to an
ice cold solution of 3-fluoro morpholinylaniline (reference procedure see
EP1102743; 1.0 g, 5.10 mmol) and triethylamine (1.77 mL, 10.2 mmol) in THF
(25 mL). The reaction mixture was stirred at RT for 1.5 h, then quenched with
water. The aqueous layer was extracted with EtOAc (x 3) and the combined
organic layers were washed with brine, dried (MgSO ) and concentrated in vacuo
to afford the title compound (1.89 g, 99%) as a clear oil. LCMS (Method 3): Rt
3.75 min, m/z 371, 373 [MH ].
b. 1-{(1S,4R)[3-((2S,6R)-2,6-Dimethyl-piperidinyl)-
[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}
(3-fluoromorpholinyl-phenyl)-urea (example 115)
The title compound was prepared starting from Intermediate 96c and
intermediate 115a using analogous procedures to those described in Example 99.
LCMS (Method 5): Rt 4.70 min, m/z 614 [MH ]. ¹H NMR (400 MHz, d -DMSO):
0.55 (3H, d, J = 6.3 Hz), 0.59 (3H, d, J = 6.3 Hz), 1.35-1.53 (3H, m), 1.63-1.69
(2H, m), 1.72-1.78 (1H, m), 1.82-1.99 (2H, m), 2.00-2.13 (2H, m), 3.03 (4H, t, J =
4.8 Hz), 3.08-3.20 (2H, m), 3.65-3.69 (2H, t, J = 4.8 Hz), 4.80-4.88 (1H, td, J =
8.7, 5.5 Hz), 5.50 (1H, t, J = 4.0 Hz), 6.31 (1H, dt, J = 12.4, 2.0 Hz), 6.68 (1H, br
s), 6.71 (1H, d, J = 8.9 Hz), 6.81 (1H, dt, J = 11.3, 1.9 Hz), 7.18-7.25 (2H, m),
7.29-7.37 (3H, m), 7.62 (1H, dd, J = 9.8, 0.6 Hz), 7.86 (1H, d, J = 2.0 Hz), 8.51
(1H, s).
Example 116
1-[5-tert-Butyl(2-morpholinyl-ethyl)-2H-pyrazolyl]{(1S,4R)-
4-[3-((S)methyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-
1,2,3,4-tetrahydro-naphthalenyl}-urea
A solution of Example 110 (80 mg, 0.136 mmol), DIPEA (71 µL, 0.409
mmol) and methanesulfonyl chloride (26 µL, 0.34 mmol) in DCM (3 mL) was
stirred at RT for 90 min. Additional DIPEA (71 µL) and methanesulfonyl chloride
(26 µL) were added and stirring was continued for 1 h. Water (1 mL) and a
saturated aqueous solution of NaHCO (2 mL) were added and the reaction
mixture was vigorously stirred for 30 min. The aqueous phase was extracted with
DCM (x 3) and the combined organic layers were dried through a phase separator
and concentrated in vacuo. The resultant residue was dissolved in DMF (2 mL)
and morpholine (36 µL, 0.41 mmol) and heated at 75 ºC for 18 h. After cooling,
the volatiles were concentrated in vacuo and the resultant residue was loaded onto
an SCX cartridge. The cartridge was washed with MeOH and the product eluted
with 2M NH in MeOH. The product containing fractions were combined and
concentrated in vacuo and the resultant residue was purified by MDAP (Method 7)
to afford the title compound (23 mg, 26%) as a white solid. LCMS (Method 5): Rt
3.48 min, m/z 656 [MH ]. ¹H NMR (400 MHz, d -DMSO): 0.92 (3H, d, J = 6.3
Hz), 1.21 (9H, s), 1.46-1.58 (2H, m), 1.63-1.73 (2H, m), 1.74-1.87 (2H, m), 1.89-
2.02 (2H, m), 2.02-2.24 (2H, m), 2.35-2.43 (4H, m), 2.63 (2H, t, J = 7.1 Hz), 2.87-
2.97 (1H, m), 3.14-3.22 (2H, m), 3.55 (4H, t, J = 4.5 Hz), 4.01 (2H, t, J = 7.1 Hz),
4.82-4.92 (1H, m), 5.51-5.57 (1H, m), 6.04 (1H, s), 7.10 (1H, d, J = 8.6 Hz), 7.23
(1H, dd, J = 9.8, 2.2 Hz), 7.27-7.42 (4H, m), 7.65 (1H, d, J = 9.9 Hz), 7.72 (1H, s),
8.37-8.45 (1H, m).
Example 117
H OH
1-Cyclopropyl{(1S,4R)[3-((2S,6R)-2,6-dimethyl-piperidinyl)-
[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-
urea formate salt
The title compound was prepared starting from Intermediate 96c and 4-
nitrophenyl cyclopropylcarbamate (For reference procedure see WO2007/72158)
using analogous procedures to those described in Example 99. LCMS (Method 5):
]. ¹H NMR (400 MHz, d -DMSO): 0.31-0.35 (2H, m),
Rt 4.70 min, m/z 614 [MH 6
0.52-0.60 (8H, m), 1.33-1.56 (3H, m), 1.63-1.70 (2H, m), 1.73-1.88 (3H, m), 1.94-
2.11 (2H, m), 3.08-3.20 (2H, m), 4.78 (1H, td, J = 8.6, 6.8 Hz), 5.47 (1H, t, J = 3.8
Hz), 6.07 (1H, d, J = 2.1 Hz), 6.24 (1H, d, J = 8.9 Hz), 7.15-7.22 (2H, m), 7.27-
7.32 (3H, m), 7.62 (1H, d, J = 9.8 Hz), 7.84 (1H, d, J = 1.7 Hz), 8.12 (0.6H, br s).
Example 118
1-[5-tert-Butyl(2-hydroxy-ethyl)-2H-pyrazolyl]{(1S,4R)[3-
((2S,6R)-2,6-dimethyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-
1,2,3,4-tetrahydro-naphthalenyl}-urea
A mixture of Intermediate 96c (160 mg, 0.41 mmol), Intermediate 110b
(142 mg, 0.41 mmol) and DIPEA (142 µL, 0.82 mmol) in dioxane (5 mL) was
stirred at 80 ºC overnight. After cooling, the reaction mixture was partitioned
between water and DCM. The aqueous phase was extracted with EtOAc (x 3) and
the combined organic layers were washed with brine, dried (MgSO) and
concentrated in vacuo. The resultant residue was purified by FCC on silica, using a
gradient of 1-8% MeOH in DCM followed by MDAP (Method 7) purification, to
afford the title compound (86 mg, 32%) as a glassy white solid. LCMS (Method
): Rt 4.32 min, m/z 601 [MH ]. ¹H NMR (400 MHz, d -DMSO): 0.55 (3H, d, J =
6.2 Hz), 0.58 (3H, d, J = 6.2 Hz), 1.17 (9H, s), 1.35-1.55 (3H, m), 1.63-1.69 (2H,
m), 1.73-1.79 (1H, m), 1.82-2.00 (2H, m), 2.00-2.13 (2H, m), 3.09-3.19 (2H, m),
3.62 (2H, br s), 3.90 (2H, t, J = 5.9 Hz), 4.82 (1H, td, J = 8.6, 5.7 Hz), 4.92-4.98
(1H, br s), 5.50 (1H, t, J = 4.2 Hz), 6.02 (1H, s), 7.04 (1H, d, J = 8.6 Hz), 7.18 (1H,
dd, J = 9.8, 2.3 Hz), 7.20-7.25 (1H, m), 7.30-7.36 (3H, m), 7.62 (1H, dd, J = 9.7,
0.6 Hz), 7.86 (1H, d, J = 2.1 Hz), 8.14 (1H, s).
Example 119
1-{5-tert-Butyl[1-(2-dimethylamino-ethyl)-1H-imidazolyl]-2H-
pyrazolyl}[(1S,4R)(3-piperidinyl-[1,2,4]triazolo[4,3-a]pyridin
yloxy)-1,2,3,4-tetrahydro-naphthalenyl]-urea
N N N
a. 4-Iodo[2-(tetrahydro-pyranyloxy)-ethyl]-1H-imidazole and 5-
Iodo[2-(tetrahydro-pyranyloxy)-ethyl]-1H-imidazole (Intermediate
119a)
To an ice cold mixture of 4-iodo-1H-imidazole (1.0 g, 5.13 mmol) and
sodium hydroxide (226 mg, 5.64 mmol) in DMF (10 mL) was added 2-(2-
bromothoxy)tetrahydro-2H-pyran (1.18 mL, 5.64 mmol) and the mixture stirred
overnight. The crude reaction mixture was poured into water and extracted with
EtOAc (x 3). The combined organic layers were washed with brine, dried (MgSO )
and concentrated in vacuo. The resultant residue was purified by FCC on silica,
using a gradient of 20-100% EtOAc in cyclohexane, to give the title compound
(1.50 g, 91%) as a 2:1 mixture of regioisomers. LCMS (Method 4): Rt 2.03 min,
m/z 323 [MH ].
b. 5-tert-Butyl{1-[2-(tetrahydro-pyranyloxy)-ethyl]-1H-imidazol-
4-yl}-2H-pyrazolylamine (Intermediate 119b)
To a mixture of Intermediate 119a (1.50 g, 4.66 mmol), 5-tert-butyl-2H-
pyrazolylamine (648 mg, 4.66 mmol), copper(I)iodide (44 mg, 0.23 mmol) and
K CO (1.35 g, 9.78 mmol) was added a solution of toluene (10 mL), previously
degassed by using a stream of argon. (R,R)-(-)-N,N'-Dimethyl-1,2-
cyclohexanediamine (147 µL, 0.93 mmol) was then added and the reaction mixture
was heated at 150 ºC for 3 h under microwave irradiation. The crude reaction
mixture was poured into water and extracted with EtOAc (x 3). The combined
organic layers were washed with brine, dried (MgSO ) and concentrated in vacuo.
The resultant residue was purified by FCC on silica, using a gradient of 0-100%
EtOAc in cyclohexane, to give a product consisting of the title compound (550 mg)
in mixture with the un-reacted 5-iodo[2-(tetrahydro-pyranyloxy)-ethyl]-1H-
imidazole isomer. LCMS (Method 4): Rt 2.32 min, m/z 334 [MH ].
c. (5-tert-Butyl{1-[2-(tetrahydro-pyranyloxy)-ethyl]-1H-imidazol-
4-yl}-2H-pyrazolyl)-carbamic acid 2,2,2-trichloro-ethyl ester (Intermediate
119c)
To a mixture of Intermediate 119b (550 mg) in water (3 mL) and EtOAc (6
mL) was added NaOH (132 mg, 3.30 mmol). After 10 min stirring, 2,2,2-
trichloroethyl chloroformate (273 µL, 1.98 mmol) was added and the reaction
mixture was stirred at RT for 2 h. The aqueous layer was extracted with EtOAc (x
3) and the combined organic layers were washed with brine, dried (MgSO ) and
concentrated in vacuo. The resultant residue was purified by FCC on silica, using a
gradient of 0-80% EtOAc in cyclohexane, to afford the title compound (175 mg).
LCMS (Method 4): Rt 4.54 min, m/z 508, 510 [MH ].
d. 1-(5-tert-Butyl{1-[2-(tetrahydro-pyranyloxy)-ethyl]-1H-
imidazolyl}-2H-pyrazolyl)[(1S,4R)(3-piperidinyl-
[1,2,4]triazolo[4,3-a]pyridinyloxy)-1,2,3,4-tetrahydro-naphthalenyl]-
urea (Intermediate 119d)
The title compound was prepared starting from Intermediate 3c and
Intermediate 119c using analogous procedures to those described in Intermediate
106a. LCMS (Method 4): Rt 5.52 min, m/z 723 [MH ].
e. 1-{5-tert-Butyl[1-(2-hydroxy-ethyl)-1H-imidazolyl]-2H-pyrazol-
3-yl}[(1S,4R)(3-piperidinyl-[1,2,4]triazolo[4,3-a]pyridinyloxy)-
1,2,3,4-tetrahydro-naphthalenyl]-urea (Intermediate 119e)
To a solution of intermediate 119d (135 mg, 0.19 mmol) in MeOH (2 mL)
was added pyridinium p-toluenesulfonate (94 mg, 0.37 mmol) and the reaction
mixture was heated at 60 ºC for 3 h. The resultant mixture was poured into water
and a saturated aqueous solution of NaHCO was added. The aqueous phase was
extracted with EtOAc (x 3) and the combined organic layers were washed with
brine, dried (MgSO ) and concentrated in vacuo. The resultant residue was purified
by FCC on silica, using a gradient of 2-10% MeOH in DCM, to give the title
compound (65 mg, 53%). LCMS (Method 4): Rt 2.96 min, m/z 639 [MH ].
f. Methanesulfonic acid 2-[4-(3-tert-butyl{3-[(1S,4R)(3-piperidin-
1-yl-[1,2,4]triazolo[4,3-a]pyridinyloxy)-1,2,3,4-tetrahydro-naphthalen
yl]-ureido}-pyrazolyl)-imidazolyl]-ethyl ester (Intermediate 119f)
To an ice-bath cooled solution of Intermediate 119e (65 mg, 0.10 mmol) in
DCM (1.5 mL) was added DIPEA (71 µL, 0.41 mmol) followed by
methanesulfonyl chloride (16 µL, 0.20 mmol). The reaction mixture was stirred for
1 h and then quenched with water. The aqueous phase was extracted with DCM (x
3) and the combined organic layers were washed with brine, dried (MgSO ) and
concentrated in vacuo to afford the title compound (Quantitative). Product used in
the following step without further purification. LCMS (Method 4): Rt 3.23 min,
m/z 717 [MH ].
g. 1-{5-tert-Butyl[1-(2-dimethylamino-ethyl)-1H-imidazolyl]-2H-
pyrazolyl}[(1S,4R)(3-piperidinyl-[1,2,4]triazolo[4,3-a]pyridin
yloxy)-1,2,3,4-tetrahydro-naphthalenyl]-urea (Example 119)
To a solution of Intermediate 119f (0.10 mmol) in THF (2 mL) was added
dimethylamine (2M in MeOH, 0.4 mL, 0.8 mmol) and the reaction stirred at 50°C
for 24 h. The crude reaction mixture was cooled and partitioned between EtOAc
and water. The aqueous phase was extracted with EtOAc (x 3) and the combined
organic layers were washed with brine, dried (MgSO ) and concentrated in vacuo.
The resultant residue was purified by FCC on silica, using a gradient of 0-10%
[2M NH in MeOH] in DCM followed by HPLC (XBridge C18 column, 30-98%
MeCN in H O, 0.1% NH OH), to give the title compound (12 mg, 18%). LCMS
(Method 5): Rt 3.43 min, m/z 666 [MH ]. ¹H NMR (400 MHz, d -DMSO): 1.21
(9H, s), 1.54-1.60 (2H, m), 1.65-1.71 (4H, m), 1.86-1.94 (2H, m), 1.95-2.05 (1H,
m) 2.13 (6H, s), 2.13-2.16 (1H, m), 2.55 (2H, t, J = 6.3 Hz), 3.10 (4H, t, J = 5.2
Hz), 4.05 (2H, t, J = 7.1 Hz), 4.86 (1H, td, J = 8.4, 5.5 Hz), 5.51 (1H, t, J = 4.5 Hz),
6.32 (1H, s), 7.12 (1H, dd, J = 10.0, 1.9 Hz), 7.20-7.25 (2H, m), 7.28-7.36 (3H, m),
7.56-7.59 (2H, m), 7.63 (1H, d, J = 1.4 Hz), 7.90 (1H, d, J = 8.6 Hz), 9.63 (1H, br
s).
Example 120
1-[5-tert-Butyl(2-hydroxy-ethyl)-2H-pyrazolyl]{(1S,4R)[3-
((S)methyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-urea
N N N
a. (S)Methyl-piperidinecarboxylic acid N'-(5-fluoro-pyridinyl)-
hydrazide (Intermediate 120a)
To a solution of (S)methyl-piperidinecarboxylic acid (250 mg, 1.74
mmol) and (5-fluoro-pyridinyl)-hydrazine (244 mg, 1.92 mmol) in DCM (20
mL) was added HATU (790 mg, 2.09 mmol) and DIPEA (606 µL, 3.48 mmol) and
the reaction stirred for 18 h. The reaction was then heated to 45°C for 1 h then
cooled and partitioned between EtOAc and water. The aqueous phase was
extracted with EtOAc (x 3) and the combined organic layers were washed with
brine, dried (MgSO ) and concentrated in vacuo. The resultant residue was purified
by FCC on silica, using a gradient of 0-10% [2M NH in MeOH] in DCM to give
the title compound (272 mg, 62%). LCMS (Method 4): Rt 0.87 min, m/z 253
[MH ].
b.6-Fluoro((S)methyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridine
(Intermediate 120b)
Hexachloroethane (505 mg, 2.14 mmol) was added portionwise over 5 min
at RT to a stirred mixture of Intermediate 120a (270 mg, 1.07 mmol), triethylamine
(595 µL, 4.28 mmol) and triphenylphosphine (560 mg, 2.14 mmol) in THF (10
mL). The reaction mixture was stirred for 1.5 h and then diluted with methanol and
loaded onto an SCX cartridge. The cartridge was washed with MeOH and the
product eluted with 2M NH in MeOH and concentrated in vacuo. The resultant
residue was purified by FCC on silica, using a gradient of 0-8% [2M NH in
MeOH] in EtOAc to give the title compound (105 mg, 42%). ¹H NMR (400 MHz,
CDCl ): 1.34-1.51 (1H, m), 1.62-1.92 (5H, m), 2.00 (3H, s), 2.20 (1H, td, J = 11.4,
3.7 Hz), 3.06 (1H, m), 3.87 (1H, dd, J = 10.9, 3.3 Hz), 7.18 (1H, ddd, J = 9.8, 7.6,
2.3 Hz), 7.71 (1H, ddd, J = 9.9, 5.0, 0.7 Hz), 8.75-7.79 (1H, m).
c.(1S,4R)[3-((S)Methyl-piperidinyl)-[1,2,4]triazolo[4,3-
a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenylamine (Intermediate
120c)
To a suspension of sodium hydride (60% in mineral oil, 54 mg, 1.34 mmol)
in DMF (1 mL) was added Intermediate A (88 mg, 0.54 mmol) and the reaction
mixture was stirred for 20 min. A solution of Intermediate 120b (105 mg, 0.45
mmol) in DMF (1 mL) was added and the reaction mixture was heated at 60 ºC for
90 min. After cooling, the reaction mixture was quenched by careful addition of
MeOH and then loaded onto an SCX cartridge. The cartridge was washed with
MeOH and the product eluted with 2M NH in MeOH. The product containing
fractions were concentrated in vacuo and the resultant residue was purified by FCC
on silica, using a gradient of 0-10% [2M NH in MeOH] in DCM, to give the title
compound (77 mg, 45%). ¹H NMR (400 MHz, CDCl ): 1.38-1.51 (1H, m), 1.52-
1.90 (6H, m), 1.90-2.05 (1H, m), 2.03 (3H, s), 2.04-2.15 (1H, m), 2.15-2.22 (1H,
m), 2.33-2.44 (1H, m), 2.99-3.06 (1H, m), 3.82 (1H, dd, J = 11.3, 3.2 Hz), 3.99
(1H, dd, J = 7.9, 5.1 Hz), 5.23 (1H, t, J = 4.5 Hz), 7.11 (1H, dd, J = 9.9, 2.2 Hz),
7.23-7.30 (1H, m), 7.34-7.41 (2H, m), 7.60 (1H, d, J = 7.7 Hz), 7.65 (1H, dd, J =
9.9, 0.7 Hz), 8.42 (1H, d, J = 2.2 Hz).
d. 1-[5-tert-Butyl(2-hydroxy-ethyl)-2H-pyrazolyl]{(1S,4R)[3-
((S)methyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-urea (Example 120)
A mixture of Intermediate 120c (35 mg, 0.10 mmol), Intermediate 110b (54
mg, 0.15 mmol) and DIPEA (53 µL, 0.30 mmol) in dioxane (1 mL) was stirred at
50 ºC overnight. After cooling, the reaction mixture was loaded onto an SCX
cartridge. The cartridge was washed with MeOH and the product eluted with 2M
NH in MeOH. The resultant residue was purified by FCC on silica, using a
gradient of 1-8% MeOH in DCM followed by MDAP (Method 7) purification, to
afford the title compound (4 mg, 7%) as a glassy white solid. LCMS (Method 5):
Rt 3.02 min, m/z 586 [MH ]. ¹H NMR (400 MHz, d -MeOD): 1.20-1.30 (2H, m),
1.25 (9H, s), 1.40-1.52 (1H, m), 1.63-1.83 (3H, m), 1.85-1.92 (2H, m), 2.01 (3H,
s), 2.06-2.20 (3H, m), 2.24 (1H, td, J = 11.7, 3.1 Hz), 2.31-2.38 (1H, m), 3.04-3.09
(1H, m), 3.76-3.81 (1H, m), 3.81 (2H, t, J = 5.4 Hz), 4.08 (2H, t, J = 5.4 Hz), 4.98
(1H, dd, J = 8.1, 6.5 Hz), 5.36 (1H, t, J = 3.8 Hz), 6.12 (1H, s), 7.24 (1H, t, J = 7.4
Hz), 7.28-7.37 (3H, m), 7.44 (1H, d, J = 7.8 Hz), 7.66 (1H, dd, J = 9.9, 0.6 Hz),
8.46 (1H, d, J = 1.9 Hz).
Example 121
1-[5-tert-Butyl(2-morpholinyl-ethyl)-2H-pyrazolyl]{(1S,4R)-
4-[3-((2S,6R)-2,6-dimethyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridin
yloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea
a. Methanesulfonic acid 2-[3-tert-butyl(3-{(1S,4R)[3-((2S,6R)-2,6-
dimethyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-ureido)-pyrazolyl]-ethyl ester (Intermediate
121a)
To an ice-bath cooled solution of Example 118 (43 mg, 0.07 mmol) in DCM
(1.5 mL) was added DIPEA (49 µL, 0.18 mmol) followed by methanesulfonyl
chloride (11 µL, 0.11 mmol). The reaction mixture was stirred for 1 h and then
quenched with water. The aqueous phase was extracted with DCM (x 3) and the
combined organic layers were washed with brine, dried (MgSO ) and concentrated
in vacuo to afford the title compound (Quantitative). Product used in the following
step without further purification. LCMS (Method 4): Rt 3.38 min, m/z 679 [MH ].
b. 1-[5-tert-Butyl(2-morpholinyl-ethyl)-2H-pyrazolyl]
{(1S,4R)[3-((2S,6R)-2,6-dimethyl-piperidinyl)-[1,2,4]triazolo[4,3-
a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea (Example 121)
To a solution of Intermediate 121a (0.07 mmol) in THF (2 mL) was added
DIPEA (50 µL, 0.29 mmol) and morpholine (25 µL, 0.29 mmol) and the reaction
stirred at 50°C for 24 h. The crude reaction mixture was cooled and partitioned
between EtOAc and water. The aqueous phase was extracted with EtOAc (x 3) and
the combined organic layers were washed with brine, dried (MgSO) and
concentrated in vacuo. The resultant residue was purified by FCC on silica, using a
gradient of 0-10% [2M NH in MeOH] in DCM followed by MDAP (Method 7)
purification, to give the title compound (19 mg, 39%). LCMS (Method 5): Rt 3.65
min, m/z 670 [MH ]. ¹H NMR (400 MHz, d -DMSO): 0.56 (3H, d, J = 6.2 Hz),
0.59 (3H, d, J = 6.2 Hz), 1.16 (9H, s), 1.37-1.55 (3H, m), 1.63-1.69 (2H, m), 1.73-
1.79 (1H, m), 1.85-2.00 (2H, m), 2.04-2.10 (2H, m), 2.34 (4H, t, J = 4.5 Hz), 2.57
(2H, t, J = 7.2 Hz), 3.09-3.19 (2H, m), 3.50 (4H, t, J = 4.5 Hz), 3.95 (2H, t, J = 7.2
Hz), 4.82 (1H, td, J = 8.6, 5.7 Hz), 5.50 (1H, t, J = 4.2 Hz), 5.99 (1H, s), 6.92 (1H,
d, J = 8.6 Hz), 7.18 (1H, dd, J = 9.8, 2.3 Hz), 7.20-7.26 (1H, m), 7.30-7.36 (3H,
m), 7.62 (1H, dd, J = 9.7, 0.6 Hz), 7.86 (1H, d, J = 2.1 Hz), 8.19 (1H, s).
Example 122
1-{(1S,4R)[3-(8-Aza-bicyclo[3.2.1]octyl)-[1,2,4]triazolo[4,3-
a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}{5-tert-butyl[3-(2-
dimethylamino-ethoxy)-phenyl]-2H-pyrazolyl}-urea formate salt
a. 8-Aza-bicyclo[3.2.1]octanecarbonyl chloride (Intermediate 122a)
Cl N
To a cooled (10°C) solution 8-aza-bicyclo[3.2.1]octane (295 mg, 2.00
mmol) and pyridine (486 µL, 6.02 mmol) in DCM (10 mL) was added triphosgene
(595 mg, 2.00 mmol) portionwise. The reaction was allowed to reach room
temperature and stirred overnight. The mixture was quenched with HCl (1M
aqueous, 10 mL) and stirred for 30 min. The aqueous phase was extracted with
DCM (x 3) and the combined organic layers were washed with HCl (1M aqueous),
brine, dried (MgSO ) and concentrated in vacuo, to give the title compound (244
mg, 70%). ¹H NMR (400 MHz, CDCl ): 1.46-1.70 (4H, m), 1.72-1.92 (5H, m),
2.04-2.11 (2H, m), 4.39-4.44 (2H, m).
b. 8-Aza-bicyclo[3.2.1]octanecarboxylic acid N'-(5-fluoro-pyridin
yl)-hydrazide (Intermediate 122b)
To a solution of Intermediate 122a (240 mg, 1.38 mmol) and (5-fluoro-
pyridinyl)-hydrazine (176 mg, 1.38 mmol) in DCM (10 mL) was added DIPEA
(721 µL, 4.15 mmol) and the reaction stirred for 5 days. The reaction was then
partitioned between DCM and water. The aqueous phase was extracted with DCM
(x 3) and the combined organic layers were washed with brine, dried (MgSO ) and
concentrated in vacuo. The resultant residue was purified by FCC on silica, using a
gradient of 0-10% MeOH in DCM to give the title compound (170 mg, 47%).
LCMS (Method 3): Rt 2.31 min, m/z 265 [MH ].
c. 3-(8-Aza-bicyclo[3.2.1]octyl)fluoro-[1,2,4]triazolo[4,3-a]pyridine
(Intermediate 122c)
Hexachloroethane (296 mg, 1.25 mmol) was added portionwise over 5 min
at RT to a stirred mixture of Intermediate 122b (165 mg, 0.62 mmol),
triethylamine (350 µL, 2.50 mmol) and triphenylphosphine (327 mg, 1.25 mmol)
in THF (10 mL). The reaction mixture was stirred for 3.5 h and then heated to
60°C overnight. The temperature was increased to 70°C for 5 days, then cooled
and concentrated in vacuo. The residue was taken up in dioxane, and re-treated
with hexachloroethane (150 mg, 0.63 mmol) and triethylamine (200 µL, 1.43
mmol) at 115°C overnight. The mixture was cooled and concentrated in vacuo.
The residue was taken up in methanol and loaded onto an SCX cartridge. The
cartridge was washed with MeOH and the product eluted with 2M NH in MeOH
and concentrated in vacuo to give the title compound (117 mg, 76%). LCMS
(Method 3): Rt 2.88 min, m/z 247 [MH ].
d. (1S,4R)[3-(8-Aza-bicyclo[3.2.1]octyl)-[1,2,4]triazolo[4,3-
a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenylamine (Intermediate
122d)
To a suspension of sodium hydride (60% in mineral oil, 51 mg, 1.3 mmol)
in DMF (1.5 mL) was added Intermediate A (73 mg, 0.45 mmol) followed by
intermediate 122c (110 mg, 0.45 mmol) and the reaction mixture was heated at 60
ºC for 1 h. After cooling, the reaction mixture was quenched by careful addition of
NH Cl (saturated aqueous) and the aqueous phase was extracted with EtOAc (x 3).
The combined organic layers were washed with brine, dried (MgSO ) and
concentrated in vacuo. The resultant residue was purified by FCC on silica, using a
gradient of 0-10% [2M NH in MeOH] in DCM to give the title compound (98 mg,
56%). LCMS (Method 3): Rt 2.26 min, m/z 390 [MH ].
e. 1-{(1S,4R)[3-(8-Aza-bicyclo[3.2.1]octyl)-[1,2,4]triazolo[4,3-
a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}{5-tert-butyl[3-(2-
dimethylamino-ethoxy)-phenyl]-2H-pyrazolyl}-urea formate salt (Example
122)
The titled compound was prepared using Intermediate 95c and Intermediate
122d following the procedures described in Example 95. LCMS (Method 5): Rt
3.55 min, m/z 318.5 [MH ]. ¹H NMR (400 MHz, d -DMSO): 1.27 (9H, s), 1.46-
1.58 (3H, m), 1.63-1.79 (3H, m), 1.87-2.16 (8H, m), 2.19 (6H, s), 2.61 (2H, t, J =
.9 Hz), 3.99 (2H, m), 4.08 (2H, t, J = 5.9 Hz), 4.81 (1H, m), 5.52 (1H, m), 6.32
(1H, s), 6.96 (1H, m), 7.05-7.17 (4H, m), 7.25-7.42 (5H, m), 7.56-7.61 (2H, m),
8.14 (1H, s), 8.19 (1H, s).
Example 123
1-{5-tert-Butyl[3-(2-dimethylamino-ethoxy)-phenyl]-2H-pyrazol
yl}{(1S,4R)[3-((R)methyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridin-
6-yloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea partial formate salt
(0.3 eq)
a. 1-{5-tert-Butyl[3-(2-hydroxy-ethoxy)-phenyl]-2H-pyrazolyl}
{(1S,4R)[3-((R)methyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridin
yloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea (Intermediate 123a)
O OH
The title compound was prepared from (R)methyl piperidine using
analogous procedures to those described for the preparation of Intermediate 95e.
LCMS (Method 3): Rt 3.63 min, m/z 679 [MH ].
b. 1-{5-tert-Butyl[3-(2-dimethylamino-ethoxy)-phenyl]-2H-pyrazol-
3-yl}{(1S,4R)[3-((R)methyl-piperidinyl)-[1,2,4]triazolo[4,3-
a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea partial formate
salt (Example 123)
To a solution of Intermediate 123a (108 mg, 0.159 mmol) and DIPEA
(0.083 mL, 0.48 mmol) in DCM (4 mL) was added methanesulfonyl chloride (36.5
mg, 0.318 mmol) and the resulting yellow solution stirred at RT for 20 min. Water
(2 mL) and sat. aq. NaHCO solution (2 mL) were added, then the aqueous
extracted with DCM (4 mL). The combined organics were passed through a
hydrophobic frit and concentrated in vacuo to leave a yellow solid.
The solid was dissolved in THF (2 mL), then dimethylamine (2 M in THF,
1.6 mL, 3.2 mmol) added, and the mixture stirred at 60°C in a sealed vial for 18 h.
The cooled solution was concentrated in vacuo, redissolved in MeOH (1 mL),
applied to an SCX-2 cartridge (5 g), washed with MeOH (20 mL) and eluted with
2 M NH in MeOH (20 mL); concentration in vacuo gave a glassy yellow solid (98
mg). MDAP (Method 7) gave a pale yellow solid (63 mg). Additional purification
by HPLC (Gemini C18, 15-65% MeCN in water, 0.1% HCO H, 20 min, × 2) gave
the title compound as a white solid (18.6 mg, 17%). LCMS (Method 5): Rt 3.62
min, m/z 706.6 [MH ]. ¹H NMR (400 MHz, d -DMSO): 0.88 (3H, d, J = 6.3 Hz),
1.28 (9H, s), 1.48-1.56 (2H, m), 1.65-1.71 (2H, m), 1.76-1.96 (4H, m), 2.00-2.14
(2H, m), 2.17 (6H, s), 2.59 (2H, t, J = 5.8 Hz), 2.95 (1H, ddd, J = 12.2, 8.1, 4.8
Hz), 3.18 (1H, dt, J = 12.1, 4.3 Hz), 3.26-3.29 (1H, m), 4.07 (2H, t, J = 5.8 Hz),
4.81 (1H, td, J = 8.6, 5.6 Hz), 5.53 (1H, t, J = 4.3 Hz), 6.31 (1H, s), 6.95 (1H, dd, J
= 8.4, 2.2 Hz), 7.09 (2H, m), 7.18 (1H, dd, J = 9.8, 2.2 Hz), 7.25-7.41 (6H, m),
7.64 (1H, d, J = 9.9 Hz), 7.70 (1H, d, J = 2.1 Hz), 8.34 (1H, s), 8.50 (0.3H, s).
Example 124
1-[3-tert-Butyl-1'-(2-morpholinyl-ethyl)-1'H-[1,4']bipyrazolylyl]-
3-{(1S,4R)[3-((2S,6R)-2,6-dimethyl-piperidinyl)-[1,2,4]triazolo[4,3-
a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea formate salt
a. 1-{3-tert-Butyl-1'-[2-(tetrahydro-pyranyloxy)-ethyl]-1'H-
[1,4']bipyrazolylyl}{(1S,4R)[3-((2S,6R)-2,6-dimethyl-piperidinyl)-
[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-
urea (Intermediate 124a)
A mixture of Intermediate 96c (200 mg, 0.51 mmol), Intermediate 108b
(261 mg, 0.51 mmol) and DIPEA (178 µL, 1.02 mmol) in dioxane (5 mL) was
stirred at 80 ºC overnight. After cooling, the reaction mixture was partitioned
between water and DCM. The aqueous phase was extracted with EtOAc (x 3) and
the combined organic layers were washed with brine, dried (MgSO) and
concentrated in vacuo. The resultant residue was purified by FCC on silica, using a
gradient of 1-10% MeOH in DCM to afford the title compound (364 mg, 95%) as a
glassy white solid%). LCMS (Method 4): Rt 3.69 min, m/z 751 [MH ].
b. 1-[3-tert-Butyl-1'-(2-hydroxy-ethyl)-1'H-[1,4']bipyrazolylyl]
{(1S,4R)[3-((2S,6R)-2,6-dimethyl-piperidinyl)-[1,2,4]triazolo[4,3-
a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea (Intermediate
124b)
To a solution of Intermediate 124a (239 mg, 0.32 mmol) in MeOH (3.5 mL)
was added pyridinium p-toluenesulfonate (160 mg, 0.64 mmol) and the reaction
mixture was heated at 60 ºC for 3 h. The resultant mixture was poured into water
and a saturated aqueous solution of NaHCO was added. The aqueous phase was
extracted with EtOAc (x 3) and the combined organic layers were washed with
brine, dried (MgSO ) and concentrated in vacuo. The resultant residue was purified
by FCC on silica, using a gradient of 3-10% MeOH in DCM, to give the title
compound (174 mg, 82%). LCMS (Method 4): Rt 3.22 min, m/z 667 [MH ].
c. Methanesulfonic acid 2-[3-tert-butyl(3-{(1S,4R)[3-((2S,6R)-2,6-
dimethyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-ureido)-[1,4']bipyrazolyl-1'-yl]-ethyl ester
(Intermediate 124c)
To an ice-bath cooled solution of Intermediate 124b (174 mg, 0.26 mmol) in
DCM (3 mL) was added DIPEA (182 µL, 1.0 mmol) followed by methanesulfonyl
chloride (41 µL, 0.52 mmol). The reaction mixture was stirred for 1 h and then
quenched with water. The aqueous phase was extracted with DCM (x 3) and the
combined organic layers were washed with brine, dried (MgSO ) and concentrated
in vacuo to afford the title compound (Quantitative). Product used in the following
step without further purification. LCMS (Method 4): Rt 3.47 min, m/z 746 [MH ].
d. 1-[3-tert-Butyl-1'-(2-morpholinyl-ethyl)-1'H-[1,4']bipyrazolyl
yl]{(1S,4R)[3-((2S,6R)-2,6-dimethyl-piperidinyl)-[1,2,4]triazolo[4,3-
a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea formate salt
(Example 124)
To a solution of Intermediate 124c (0.13 mmol) in THF (2.5 mL) was added
DIPEA (90 µL, 0.52 mmol) and morpholine (45 µL, 0.52 mmol) and the reaction
stirred at 50°C for 24 h. The crude reaction mixture was cooled and partitioned
between EtOAc and water. The aqueous phase was extracted with EtOAc (x 3) and
the combined organic layers were washed with brine, dried (MgSO ) and
concentrated in vacuo. The resultant residue was purified by FCC on silica, using a
gradient of 0-10% [2M NH in MeOH] in DCM, followed by MDAP (Method 7)
purification, to give the title compound (26 mg, 26%). LCMS (Method 5): Rt 3.70
min, m/z 736 [MH ]. ¹H NMR (400 MHz, d -DMSO): 0.55 (3H, d, J = 6.2 Hz),
0.58 (3H, d, J = 6.2 Hz), 1.20 (9H, s), 1.34-1.54 3H, m), 1.63-1.68 (2H, m), 1.72-
1.86 (2H, m), 1.89-1.97 (1H, m), 2.01-2.07 (2H, m), 2.37 (4H, t, J = 4.4 Hz), 2.69
(2H, t, J = 6.7 Hz), 3.08-3.18 (2H, m), 3.49 (4H, t, J = 4.6 Hz), 4.19 (2H, t, J = 6.7
Hz), 4.80 (1H, dt, J = 8.6, 5.6 Hz), 5.49 (1H, t, J = 4.3 Hz), 6.22 (1H, s), 7.11 (1H,
d, J = 8.6 Hz), 7.16 (1H, dd, J = 9.8, 2.2 Hz), 7.19-7.25 (1H, m), 7.28-7.33 (3H,
m), 7.59 (1H, s), 7.62 (1H, d, J = 9.6 Hz), 7.84 (1H, d, J = 1.9 Hz), 7.96 (1H, s),
8.02 (1H, s), 8.14 (0.6H, br s).
Example 125
1-[3-tert-Butyl-1'-(2-dimethylamino-ethyl)-1'H-[1,4']bipyrazolylyl]-
3-{(1S,4R)[3-((2S,6R)-2,6-dimethyl-piperidinyl)-[1,2,4]triazolo[4,3-
a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea
To a solution of Intermediate 124c (0.13 mmol) in THF (2.5 mL) was added
dimethylamine (2M in MeOH, 1.3 mL, 2.6 mmol) and the reaction stirred at 50°C
for 24 h. The crude reaction mixture was cooled and partitioned between EtOAc
and water. The aqueous phase was extracted with EtOAc (x 3) and the combined
organic layers were washed with brine, dried (MgSO ) and concentrated in vacuo.
The resultant residue was purified by FCC on silica, using a gradient of 2-10%
[2M NH in MeOH] in DCM, followed by MDAP (Method 7) purification, to give
the title compound (26 mg, 29%). LCMS (Method 5): Rt 3.68 min, m/z 694
[MH ]. ¹H NMR (400 MHz, d -DMSO): 0.55 (3H, d, J = 6.2 Hz), 0.58 (3H, d, J =
6.2 Hz), 1.20 (9H, s), 1.34-1.54 3H, m), 1.63-1.68 (2H, m), 1.72-1.86 (2H, m),
1.89-1.97 (1H, m), 2.01-2.07 (2H, m), 2.23 (6H, br s), 2.77 (2H, br s), 3.08-3.18
(2H, m), 4.22 (2H, br s), 4.80 (1H, dt, J = 8.6, 5.6 Hz), 5.49 (1H, t, J = 4.3 Hz),
6.22 (1H, s), 7.11 (1H, d, J = 8.6 Hz), 7.16 (1H, dd, J = 9.8, 2.2 Hz), 7.19-7.25
(1H, m), 7.28-7.33 (3H, m), 7.60 (1H, s), 7.62 (1H, d, J = 9.6 Hz), 7.84 (1H, d, J =
1.9 Hz), 7.98 (1H, s), 8.02 (1H, s).
Example 126
1-(5-tert-Butylmethyl-2H-pyrazolyl){(1S,4R)[3-((S)
methyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydronaphthalenyl]-urea
a. (5-tert-Butylmethyl-2H-pyrazolyl)-carbamic acid 2,2,2-
trichloro-ethyl ester (Intermediate 126a)
A solution of 5-tert-butylmethyl-2H-pyrazolylamine (0.5 g, 3.26
mmol) in EtOAc (10 mL) was treated with aqueous NaOH (1M, 5.87 mmol),
followed by 2,2,2-trichloroethyl chloroformate (0.54 mL, 3.92 mmol) and the
reaction mixture was stirred at RT for 1 h. The mixture was partitioned between
EtOAc (10 mL) and water (2 x 10 mL). The organic layer was dried (MgSO ),
filtered and concentrated in vacuo. The residue was purified by FCC, using 0-
100% EtOAc in cyclohexane to afford the title compound as a pale orange gum
(0.915 g, 86%). LCMS (Method 3): Rt 3.88 min, m/z 328/330 [MH ].
b. 1-(5-tert-Butylmethyl-2H-pyrazolyl){(1S,4R)[3-((S)
methyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydronaphthalenyl]-urea (Example 126)
A solution of intermediate 126a (70 mg, 0.21 mmol), intermediate 81d (80
mg, 0.21 mmol) and DIPEA (55 µL, 0.32 mmol) in dioxane (1 mL) was heated at
70°C for 18 h. The mixture was triturated with diethyl ether (1 mL) and the solid
obtained was purified by MDAP (Method 7) to afford the title compound as a
glassy solid (25 mg, 21%). LCMS (Method 5): Rt 4.19 min, m/z 557.3 [MH ]. ¹H
NMR (400 MHz, d -DMSO): 0.91 (3H, d, J = 6.1 Hz), 1.20 (9H, s), 1.44-1.57 (2H,
m), 1.61-1.73 (2H, m), 1.74-1.87 (2H, m), 1.87-2.03 (2H, m), 2.03-2.22 (2H, m),
2.87-2.95 (1H, m), 3.13-3.20 (1H, m,), 3.39 (1H, m, obscured by water), 3.57 (3H,
s), 4.83-4.91 (1H, m), 5.54 (1H, t, J = 4.0 Hz), 6.02 (1H, s), 6.93 (1H, d, J = 8.9
Hz), 7.22 (1H, dd, J = 9.8 Hz), 7.26-7.32 (1H, m), 7.35-7.42 (3H, m), 7.65 (1H, dd,
J = 9.7, 1.0 Hz), 7.70-7.73(1H, m), 8.28 (1H, s).
Example 127
1-[5-tert-Butyl(2-dimethylamino-ethyl)-2H-pyrazolyl]{(1S,4R)-
4-[3-((S)methyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-
1,2,3,4-tetrahydro-naphthalenyl}-urea formate salt
a. Methanesulfonic acid 2-[3-tert-butyl(3-{(1S,4R)[3-((S)
methyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-ureido)-pyrazolyl]-ethyl ester (Intermediate
127a)
To a solution of Example 110 (176 mg, 0.300 mmol) and DIPEA (0.157
mL, 0.900 mmol) in DCM (5 mL) at 0°C was added methanesulfonyl chloride
(0.047 mL, 0.600 mmol) and the resulting orange solution stirred at 0°C for 30
min. Water (2 mL) and sat. aq. NaHCO solution (2 mL) were added and the
mixture shaken. The aqueous was extracted with DCM (5 mL) then the combined
organics passed through a hydrophobic frit and concentrated in vacuo to leave the
title compound as a yellow gum (199 mg, 100%). LCMS (Method 3): Rt 3.59 min,
m/z 665 [MH ].
b. 1-[5-tert-Butyl(2-dimethylamino-ethyl)-2H-pyrazolyl]
{(1S,4R)[3-((S)methyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridin
yloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea formate salt. (Example 127)
A yellow solution of Intermediate 127a (0.100 mmol) and dimethylamine
(2M in THF, 1.0 mL, 2.0 mmol) in THF (1 mL) was stirred in a sealed vial at 60°C
for 16 h. The cooled solution was concentrated in vacuo, redissolved in MeOH (2
mL), applied to an SCX-2 cartridge (5 g) and washed with MeOH (15 mL). The
product was eluted with 2M NH in MeOH (15 mL); concentration in vacuo left a
yellow film. MDAP (Method 7) gave the title compound as an off-white solid (42
mg, 62%). LCMS (Method 5): Rt 3.43 min, m/z 614.4 [MH ]. ¹H NMR (400 MHz,
d -DMSO): 0.91 (3H, d, J = 6.3 Hz), 1.21 (9H, s), 1.46-1.56 (2H, m), 1.63-1.72
(2H, m), 1.76-1.85 (2H, m), 1.92-2.01 (2H, m), 2.03-2.11 (1H, m), 2.15-2.19 (1H,
m), 2.21 (6H, s), 2.61 (2H, t, J = 6.9 Hz), 2.91 (1H, ddd, J = 12.2, 9.2, 4.0 Hz),
3.17 (1H, dt, J = 12.2, 4.3 Hz), 3.28-3.36 (1H, m), 3.99 (2H, t, J = 6.9 Hz), 4.87
(1H, td, J = 8.5, 6.2 Hz), 5.53 (1H, t, J = 4.1 Hz), 6.03 (1H, s), 6.97 (1H, d, J = 8.7
Hz), 7.21 (1H, dd, J = 9.8, 2.2 Hz), 7.29 (1H, td, J = 7.3, 2.0 Hz), 7.34-7.41 (3H,
m), 7.65 (1H, dd, J = 9.8, 0.8 Hz), 7.71 (1H, d, J = 2.1 Hz), 8.17 (1.4H, s), 8.48
(1H, s).
Example 128
1-[5-tert-Butyl(2-piperidinyl-ethyl)-2H-pyrazolyl]{(1S,4R)
[3-((S)methyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-urea formate salt
A yellow solution of Intermediate 127a (0.100 mmol) and piperidine (0.049
mL, 0.50 mmol) in dry DMF (2 mL) was stirred at 75°C for 2.5 h. The cooled
solution was concentrated in vacuo, redissolved in MeOH (2 mL), applied to an
SCX-2 cartridge (2 g) and washed with MeOH (20 mL). The product was eluted
with 2M NH in MeOH (15 mL); concentration in vacuo left a yellow solid.
MDAP (Method 7) gave the title compound as an off-white solid (37 mg, 52%).
LCMS (Method 5): Rt 3.68 min, m/z 654.5 [MH ]. ¹H NMR (400 MHz, d -
DMSO): 0.91 (3H, d, J = 6.3 Hz), 1.20 (9H, s), 1.33-1.38 (2H, m), 1.45-1.55 (6H,
m), 1.63-1.72 (2H, m), 1.75-1.86 (2H, m), 1.89-2.02 (2H, m), 2.04-2.12 (1H, m),
2.14-2.21 (1H, m), 2.40 (4H, t, J = 4.7 Hz), 2.61 (2H, t, J = 7.1 Hz), 2.91 (1H, ddd,
J = 12.2, 9.2, 4.2 Hz), 3.16 (1H, dt, J = 12.0, 4.3 Hz), 3.32 (1H, m), 3.99 (2H, t, J =
7.1 Hz), 4.87 (1H, td, J = 8.5, 5.7 Hz), 5.54 (1H, t, J = 4.3 Hz), 6.04 (1H, s), 6.95
(1H, d, J = 8.6 Hz), 7.22 (1H, dd, J = 9.8, 2.2 Hz), 7.29 (1H, td, J = 7.2, 1.8 Hz),
7.34-7.41 (3H, m), 7.65 (1H, dd, J = 9.8, 0.8 Hz), 7.71 (1H, d, J = 2.1 Hz), 8.16
(1.4H, s), 8.29 (1H, s).
Example 129
1-{5-tert-Butyl[2-(4-methyl-piperazinyl)-ethyl]-2H-pyrazolyl}-
3-{(1S,4R)[3-((S)methyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridin
yloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea formate salt
A yellow solution of Intermediate 127a (0.100 mmol) and N-methyl
piperazine (0.056 mL, 0.50 mmol) in dry DMF (2 mL) was stirred at 75°C for 2.5
h. The cooled solution was concentrated in vacuo, redissolved in MeOH (2 mL),
applied to an SCX-2 cartridge (5 g) and washed with MeOH (20 mL). The product
was eluted with 2M NH in MeOH (15 mL); concentration in vacuo left an orange
solid. MDAP (Method 7) gave the title compound as an off-white solid (12 mg,
17%). LCMS (Method 5): Rt 3.36 min, m/z 669.5 [MH ]. ¹H NMR (400 MHz, d -
DMSO): 0.91 (3H, d, J = 6.3 Hz), 1.20 (9H, s), 1.49-1.56 (2H, m), 1.63-1.72 (2H,
m), 1.75-1.85 (2H, m), 1.91-2.02 (2H, m), 2.04-2.10 (1H, m), 2.12 (3H, s), 2.14-
2.21 (1H, m), 2.29 (4H, br s), 2.40 (4H, br s), 2.60 (2H, t, J = 7.1 Hz), 2.91 (1H,
ddd, J = 12.2, 9.0, 4.0 Hz), 3.17 (1H, dt, J = 12.0, 4.3 Hz), 3.28-3.36 (1H, m), 3.97
(2H, t, J = 7.1 Hz), 4.87 (1H, td, J = 8.5, 5.7 Hz), 5.54 (1H, t, J = 4.3 Hz), 6.04
(1H, s), 6.95 (1H, d, J = 8.6 Hz), 7.22 (1H, dd, J = 9.8, 2.1 Hz), 7.29 (1H, td, J =
7.2, 1.7 Hz), 7.34-7.41 (3H, m), 7.65 (1H, dd, J = 9.8, 0.8 Hz), 7.71 (1H, d, J = 2.1
Hz), 8.20 (1H, s), 8.27 (1H, s).
Example 130
1-[5-tert-Butyl(3-morpholinylmethyl-phenyl)-2H-pyrazolyl]
{(1S,4R)[3-((2S,6R)-2,6-dimethyl-piperidinyl)-[1,2,4]triazolo[4,3-
a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea formate salt
a. 1-[5-tert-Butyl(3-hydroxymethyl-phenyl)-2H-pyrazolyl]
{(1S,4R)[3-((2S,6R)-2,6-dimethyl-piperidinyl)-[1,2,4]triazolo[4,3-
a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea (Intermediate
130a)
A mixture of Intermediate 96c (150 mg, 0.38 mmol), Intermediate 29c (161
mg, 0.38 mmol) and DIPEA (133 µL, 0.77 mmol) in dioxane (4 mL) was stirred at
80 ºC for 7 hours. After cooling, the reaction mixture was partitioned between
water and DCM. The aqueous phase was extracted with EtOAc (x 3) and the
combined organic layers were washed with brine, dried (MgSO ) and concentrated
in vacuo. The resultant residue was purified by FCC on silica, using a gradient of
1-10% MeOH in DCM to afford the title compound (364 mg, 95%) as a glassy
white solid%). LCMS (Method 4): Rt 3.50 min, m/z 663 [MH ].
b. Methanesulfonic acid 3-[3-tert-butyl(3-{(1S,4R)[3-((2S,6R)-2,6-
dimethyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-ureido)-pyrazolyl]-benzyl ester (Intermediate
130b)
To an ice-bath cooled solution of Intermediate 130a (175 mg, 0.26 mmol) in
DCM (2.5mL) was added DIPEA (184 µL, 1.0 mmol) followed by
methanesulfonyl chloride (41 µL, 0.52 mmol). The reaction mixture was stirred for
1 h and then quenched with water. The aqueous phase was extracted with DCM (x
3) and the combined organic layers were washed with brine, dried (MgSO ) and
concentrated in vacuo to afford the title compound (Quantitative). Product used in
the following step without further purification. LCMS (Method 4): Rt 3.72 min,
m/z 741 [MH ].
c. 1-[5-tert-Butyl(3-morpholinylmethyl-phenyl)-2H-pyrazolyl]-
3-{(1S,4R)[3-((2S,6R)-2,6-dimethyl-piperidinyl)-[1,2,4]triazolo[4,3-
a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea formate salt
(Example 130)
To a solution of Intermediate 130b (0.17 mmol) in THF (2 mL) was added
DIPEA (122 µL, 0.70 mmol) and morpholine (62 µL, 0.70 mmol) and the reaction
stirred at 50°C for 24 h. The crude reaction mixture was cooled and partitioned
between EtOAc and water. The aqueous phase was extracted with EtOAc (x 3) and
the combined organic layers were washed with brine, dried (MgSO) and
concentrated in vacuo. The resultant residue was purified by FCC on silica, using a
gradient of 0-10% [2M NH in MeOH] in DCM, followed by MDAP (Method 7)
purification, to give the title compound (25 mg, 19%). LCMS (Method 5): Rt 3.75
min, m/z 732 [MH ]. ¹H NMR (400 MHz, d -DMSO): 0.55 (3H, d, J = 6.2 Hz),
0.58 (3H, d, J = 6.2 Hz), 1.23 (9H, s), 1.35-1.53 3H, m), 1.63-1.68 (2H, m), 1.72-
1.86 (2H, m), 1.86-1.92 (1H, m), 2.01-2.07 (2H, m), 2.32 (4H, t, J = 4.1 Hz), 308-
3.20 (2H, m), 3.46 (2H, s), 3.50 (4H, t, J = 4.5 Hz), 4.78 (1H, td, J = 8.6, 5.9 Hz),
5.47 (1H, t, J = 4.2 Hz), 6.28 (1H, s), 6.98 (1H, d, J = 8.6 Hz), 7.15 (1H, dd, J =
9.8, 2.1 Hz), 7.17-7.23 (2H, m), 7.25-7.31 (3H, m), 7.32-7.44 (3H, m), 7.61 (1H, d,
J = 9.7 Hz), 7.83 (1H, d, J = 1.8 Hz), 8.05 (1H, s), 8.12 (1.6H, s).
Example 131
1-{5-tert-Butyl[3-(2-morpholinyl-ethyl)-phenyl]-2H-pyrazolyl}-
3-{(1S,4R)[3-((S)methyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridin
yloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea formate salt
a. 2-[3-(5-Aminotert-butyl-pyrazolyl-phenol]-ethanol
(Intermediate 131a)
A mixture of 5-tert-butyl-2H-pyrazolylamine (629 mg, 4.52
mmol), 2-(3-bromophenyl)-ethanol (1g, 4.52 mmol), copper (I) iodide (43 mg,
0.23 mmol), (1S,2S)-N.N’-dimethyl cyclohexane-1,2-diamine (129 mg, 0.90
mmol) and potassium carbonate (1.31 g, 9.50 mmol) in toluene (8 mL) was de-
gassed and flushed with argon (3x). The reaction mixture was then treated with
microwave irradiation, at 150°C for 3 h and then at 160°C for 16 h. The mixture
was diluted with EtOAc (10 mL) and washed with water (10 mL). The aqueous
layer was extracted with a further 10 mL of EtOAc and the combined organic
layers were washed with brine (10 mL), dried (MgSO ), filtered and concentrated
in vacuo. The residue obtained was purified by FCC, using 0-100% EtOAc in
cyclohexane to afford the title compound as a brown gum (364 mg, 31%). LCMS
(Method 3): Rt 0.43/2.00/2.24 min, m/z 260 [MH ].
b. {5-tert-Butyl[3-[2-(hydroxyethyl)-phenyl]-2H-pyrazolyl}-
carbamic acid 2,2,2-trichloro-ethyl ester (Intermediate 131b)
A solution of Intermediate 131a (364 mg, 1.40 mmol) in EtOAc (5
mL) was treated with aqueous NaOH (1M, 2.53 mmol), followed by 2,2,2-
trichloroethyl chloroformate (231 µL, 1.68 mmol) and the reaction mixture was
stirred at RT for 1 h. The mixture was partitioned between EtOAc (5 mL) and
water (5 mL). The layers were separated and the aqueous layer was extracted with
a further 5 mL EtOAc. The combined organic layers were dried (MgSO4), filtered
and concentrated in vacuo. The residue was purified by FCC, using 0-50% EtOAc
in cyclohexane to afford the title compound as a red gum (516 mg, 85%). LCMS
(Method 3): Rt 4.03 min, m/z 434/436 [MH ].
c. 1-{5-tert-Butyl[3-(2-(hydroxyethyl)-phenyl]-2H-pyrazolyl}
{(1S,4R)[3-((S)methyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridin
yloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea (Intermediate 131c)
A mixture of Intermediate 131b (328 mg, 0.75 mmol), Intermediate
81d (285 mg, 0.75 mmol) and DIPEA (197 µL, 1.13 mmol) in dioxane (4.5 mL)
was heated at 70°C for 20 h. The reaction mixture was cooled to RT, diluted with
DCM (10 mL) and washed with water (2 x 10 mL). The organic layer was passed
through a hydrophobic frit and concentrated in vacuo. The residue was purified by
FCC, using 0-10% [2M NH in MeOH] in DCM to afford the title compound as a
beige solid (358 mg, 72%). LCMS (Method 3): Rt 3.67 min, m/z 663 [MH ].
d. Methanesulfonic acid 2-{3-[3-tert-butyl(3-{(1S,4R)[3-((S)
methyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-ureido)-pyrazolyl]-phenyl}-ethyl ester
(Intermediate 131d)
To a yellow solution of Intermediate 131c (358 mg, 0.540 mmol) and
DIPEA (0.28 mL, 1.6 mmol) in DCM at 0°C was added mesyl chloride (0.084 mL,
1.1 mmol) dropwise over 30 seconds, then the solution stirred at 0°C for 30 min.
Water (10 mL) and sat. aq. NaHCO (10 mL) were added and the mixture shaken.
The aqueous was extracted with DCM (10 mL), then the combined organics passed
through a hydrophobic frit and concentrated in vacuo to leave a brown gum.
LCMS (Method 3): Rt 3.91 min, m/z 741 [MH ].
e. 1-{5-tert-Butyl[3-(2-morpholinyl-ethyl)-phenyl]-2H-pyrazol
yl}{(1S,4R)[3-((S)methyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridin-
6-yloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea formate salt (Example 131)
A solution of Intermediate 131d (44.5 mg, 0.06 mmol) and morpholine
(25.9 µL, 0.30 mmol) in THF (1 mL) was stirred at 60°C for 20 h in a sealed tube.
The mixture was concentrated in vacuo and the residue purified by MDAP
(Method 7). The title product was isolated as an off-white solid (12 mg, 27%).
LCMS (Method 5): Rt 3.64 min, m/z 732.6 [MH ]. ¹H NMR (400 MHz, d6-
DMSO): 0.91 (3H, d, J = 6.2 Hz), 1.28 (9H, s), 1.50 (2H, m), 1.66 (2H, m), 1.76-
2.18 (6H, overlapped m), 2.40 (4H, m), 2.53 (m, obscured by solvent), 2.80 (2H,
m), 2.90 (1H, m), 3.15 (1H, m, obscured by solvent), 3.31 (m, obscured by
solvent), 3.54 (4H, m), 4.82 (1H, m), 5.51 (1H, t, J = 4.0 Hz), 6.32 (1H, s), 7.09
(1H, d, J = 8.7 Hz), 7.19 (1H, dd, J = 9.8, 2.4 Hz), 7.24-7.44 (8H, m), 7.63 (1H,
m), 7.69 (1H, m), 8.10 (1H, s), 8.20 (1H, s).
Example 132
1-{5-tert-Butyl[3-(2-pyrrolidinyl-ethyl)-phenyl]-2H-pyrazolyl}-
3-{(1S,4R)[3-((S)methyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridin
yloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea formate salt
A solution of Intermediate 131d (44.5 mg, 0.06 mmol) and pyrrolidine (24.8
µL, 0.30 mmol) in THF (1 mL) was stirred at 60°C for 20 h in a sealed tube. The
mixture was concentrated in vacuo and the residue purified by MDAP (Method 7).
The title product was isolated as an off-white solid (15 mg, 35%). LCMS (Method
): Rt 3.70 min, m/z 716.6 [MH ]. ¹H NMR (400 MHz, d -DMSO): 0.91 (3H, d, J
= 6.6 Hz), 1.28 (9H, s), 1.50 (2H, m), 1.61-1.72 (6H, m), 1.76-2.18 (6H,
overlapped m), 2.53 (m, obscured by solvent), 2.72 (2H, m), 2.82 (2H, m), 2.90
(1H, m), 3.16 (1H, m, obscured by solvent), 3.31 (m, obscured by solvent), 4.82
(1H, m), 5.52 (1H, t, J = 4.2 Hz), 6.33 (1H, s), 7.10 (1H, d, J = 8.4 Hz), 7.19 (1H,
dd, J = 10.0, 2.0 Hz), 7.24-7.44 (8H, m), 7.64 (1H, m), 7.69 (1H, m), 8.14 (1H, s),
8.19 (1H, s).
Example 133
1-(5-tert-Butyl{3-[2-(ethyl-methyl-amino)-ethyl]-phenyl}-2H-
pyrazolyl){(1S,4R)[3-((S)methyl-piperidinyl)-[1,2,4]triazolo[4,3-
a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea formate salt
A solution of Intermediate 131d (44.5 mg, 0.06 mmol) and N-
ethylmethylamine (25.8 µL, 0.30 mmol) in THF (1 mL) was stirred at 60°C for 20
h in a sealed tube. The mixture was concentrated in vacuo and the residue purified
by MDAP (Method 7). The title product was isolated as an off-white solid (10 mg,
24%). LCMS (Method 5): Rt 3.68 min, m/z 704.6 [MH ]. ¹H NMR (400 MHz, d -
DMSO): 0.91 (3H, d, J = 6.2 Hz), 0.96 (3H, t, J = 7.5 Hz), 1.28 (9H, s), 1.50 (2H,
m), 1.66 (2H, m), 1.76-2.17 (6H, overlapped m), 2.20 (3H, s), 2.42 (2H, q, J = 7.5
Hz), 2.60 (2H, m), 2.78 (2H, m), 2.90 (1H, m), 3.16 (1H, m, obscured by solvent),
3.31 (m, obscured by solvent), 4.82 (1H, m), 5.52 (1H, t, J = 4.4 Hz), 6.33 (1H, s),
7.10 (1H, d, J = 8.5 Hz), 7.19 (1H, dd, J = 9.7, 2.2 Hz), 7.24-7.43 (8H, m), 7.64
(1H, d, J = 9.6 Hz), 7.69 (1H, m), 8.12 (1H, s), 8.20 (1H, s).
Example 134
1-{5-tert-Butyl[3-(2-dimethylamino-ethyl)-phenyl]-2H-pyrazolyl}-
3-{(1S,4R)[3-((S)methyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridin
yloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea formate salt
A solution of Intermediate 131d (44.5 mg, 0.06 mmol) and dimethylamine
solution (2M in THF, 0.6 mL, 1.2 mmol) in THF (1 mL) was stirred at 60°C for 20
h in a sealed tube. The mixture was concentrated in vacuo and the residue purified
by MDAP (Method 7). The title product was isolated as an off-white solid (18 mg,
41%). LCMS (Method 5): Rt 3.63 min, m/z 690.6 [MH ]. ¹H NMR (400 MHz, d -
DMSO): 0.91 (3H, d, J = 6.3 Hz), 1.28 (9H, s), 1.47-1.55 (2H, m), 1.63-1.71 (2H,
m), 1.75-1.97 (4H, m), 2.00-2.16 (2H, m), 2.19 (6H, s), 2.53 (2H, t, J = 8.1 Hz),
2.78 (2H, t, J = 7.6 Hz), 2.90 (1H, ddd, J = 12.2, 9.0, 4.0 Hz), 3.16 (1H, dt, J =
12.1, 4.2 Hz), 3.31 (1H, m), 4.82 (1H, td, J = 8.6, 5.5 Hz), 5.52 (1H, t, J = 4.3 Hz),
6.33 (1H, s), 7.09 (1H, d, J = 8.6 Hz), 7.19 (1H, dd, J = 9.8, 2.2 Hz), 7.24-7.42
(8H, m), 7.64 (1H, dd, J = 9.8, 0.8 Hz), 7.69 (1H, d, J = 2.1 Hz), 8.12 (1H, s), 8.19
(1H, s).
Example 135
1-{5-tert-Butyl[3-(2-piperidinyl-ethyl)-phenyl]-2H-pyrazolyl}-
3-{(1S,4R)[3-((S)methyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridin
yloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea formate salt
A solution of Intermediate 131d (44.5 mg, 0.06 mmol) and piperidine (30
µL, 0.30 mmol) in THF (1 mL) was stirred at 60°C for 20 h in a sealed tube. The
mixture was concentrated in vacuo and the residue purified by MDAP (Method 7).
The title product was isolated as an off-white solid (26 mg, 55%). LCMS (Method
): Rt 3.75 min, m/z 730.7 [MH ]. ¹H NMR (400 MHz, d -DMSO): 0.91 (3H, d, J
= 6.3 Hz), 1.28 (9H, s), 1.31-1.37 (2H, m), 1.43-1.55 (6H, m), 1.62-1.71 (2H, m),
1.75-1.97 (4H, m), 2.00-2.17 (2H, m), 2.41 (4H, t, J = 4.4 Hz), 2.52-2.56 (2H, m),
2.79 (2H, t, J = 7.9 Hz), 2.90 (1H, ddd, J = 12.1, 9.1, 4.0 Hz), 3.16 (1H, dt, J =
11.8, 4.1 Hz), 3.28-3.35 (1H, m), 4.82 (1H, td, J = 8.6, 5.5 Hz), 5.52 (1H, t, J = 4.3
Hz), 6.32 (1H, s), 7.09 (1H, d, J = 8.6 Hz), 7.19 (1H, dd, J = 9.9, 2.1 Hz), 7.24-
7.42 (8H, m), 7.64 (1H, dd, J = 9.8, 0.8 Hz), 7.69 (1H, d, J = 2.1 Hz), 8.11 (1H, s),
8.19 (1.4H, s).
Example 136
1-(5-tert-Butyl{3-[2-(4-methyl-piperazinyl)-ethyl]-phenyl}-2H-
pyrazolyl){(1S,4R)[3-((S)methyl-piperidinyl)-[1,2,4]triazolo[4,3-
a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea formate salt
A solution of Intermediate 131d (44.5 mg, 0.06 mmol) and N-
methylpiperazine (33 µL, 0.30 mmol) in THF (1 mL) was stirred at 60°C for 20 h
in a sealed tube. The mixture was concentrated in vacuo and the residue purified
by MDAP (Method 7). The title product was isolated as an off-white solid (16 mg,
33%). LCMS (Method 5): Rt 3.54 min, m/z 745.6 [MH ]. ¹H NMR (400 MHz, d6-
DMSO): 0.91 (3H, d, J = 6.3 Hz), 1.28 (9H, s), 1.47-1.55 (2H, m), 1.63-1.71 (2H,
m), 1.75-1.97 (4H, m), 2.00-2.08 (1H, m), 2.11 (3H, s), 2.12-2.17 (1H, m), 2.29
(4H, br s), 2.42 (4H, br s), 2.51-2.55 (2H, m), 2.76-2.80 (2H, m), 2.90 (1H, ddd, J
= 12.1, 9.1, 4.1 Hz), 3.16 (1H, dt, J = 11.9, 4.2 Hz), 3.28-3.34 (1H, m), 4.82 (1H,
td, J = 8.6, 5.6 Hz), 5.52 (1H, t, J = 4.3 Hz), 6.32 (1H, s), 7.08 (1H, d, J = 8.6 Hz),
7.19 (1H, dd, J = 9.8, 2.2 Hz), 7.24-7.42 (8H, m), 7.64 (1H, dd, J = 9.8, 0.8 Hz),
7.69 (1H, d, J = 2.1 Hz), 8.10 (1H, s), 8.19 (1.4H, s).
Example 137
1-{5-tert-Butyl[3-(2-[1,4]oxazepanyl-ethyl)-phenyl]-2H-pyrazol
yl}{(1S,4R)[3-((S)methyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridin-
6-yloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea formate salt
A solution of Intermediate 131d (44.5 mg, 0.06 mmol) and
homomorpholine (30.4 mg, 0.30 mmol) in THF (1 mL) was stirred at 60°C for 20
h in a sealed tube. The mixture was concentrated in vacuo and the residue purified
by MDAP (Method 7). The title product was isolated as an off-white solid (15 mg,
31%). LCMS (Method 5): Rt 3.66 min, m/z 746.6 [MH ]. ¹H NMR (400 MHz, d -
DMSO): 0.91 (3H, d, J = 6.3 Hz), 1.28 (9H, s), 1.47-1.55 (2H, m), 1.63-1.71 (2H,
m), 1.73-1.97 (6H, m), 2.00-2.17 (2H, m), 2.66-2.81 (8H, m), 2.90 (1H, ddd, J =
12.2, 9.0, 4.0 Hz), 3.16 (1H, dt, J = 12.2, 4.4 Hz), 3.28-3.34 (1H, m), 3.56-3.59
(2H, m), 3.63 (2H, t, J = 6.0 Hz), 4.82 (1H, td, J = 8.6, 5.5 Hz), 5.52 (1H, t, J = 4.3
Hz), 6.33 (1H, s), 7.08 (1H, d, J = 8.6 Hz), 7.19 (1H, dd, J = 9.8, 2.2 Hz), 7.24-
7.42 (8H, m), 7.64 (1H, dd, J = 9.8, 0.8 Hz), 7.69 (1H, dd, J = 2.1, 0.9 Hz), 8.09
(1H, s), 8.18 (1.3H, s).
Example 138
1-(5-tert-Butyl{3-[2-(4-methyl-[1,4]diazepanyl)-ethyl]-phenyl}-2H-
pyrazolyl){(1S,4R)[3-((S)methyl-piperidinyl)-[1,2,4]triazolo[4,3-
a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea formate salt
A solution of Intermediate 131d (44.5 mg, 0.06 mmol) and N-
methylhomopiperazine (34.3 mg, 0.300 mmol) in THF (1 mL) was stirred at 60°C
for 20 h in a sealed tube. The mixture was concentrated in vacuo and the residue
purified by MDAP (Method 7) to give an off-white solid (22 mg). Prep HPLC
(Gemini C18, 20-60% MeCN in water, 0.1% HCO H, 20 min) and concentration
of the desired fractions removed the MeCN. The aqueous was washed with DCM
(30 mL), then basified with aq. NaOH solution (1M, 0.5 mL) and extracted with
DCM (2 × 10 mL). The combined organics were passed through a hydrophobic
frit, then HCO H (0.01 mL) added and the mixture concentrated in vacuo to leave
the title compound as a clear film that became a solid on standing (10.6 mg, 23%).
LCMS (Method 5): Rt 3.19 min, m/z 759.7 [MH ]. ¹H NMR (400 MHz, d -
DMSO): 0.91 (3H, d, J = 6.3 Hz), 1.28 (9H, s), 1.48-1.55 (2H, m), 1.64-1.74 (4H,
m), 1.77-1.96 (4H, m), 2.00-2.16 (2H, m), 2.29 (3H, s), 2.58-2.62 (4H, m), 2.69-
2.80 (8H, m), 2.91 (1H, ddd, J = 12.4, 9.3, 4.3 Hz), 3.16 (1H, dt, J = 11.9, 4.3 Hz),
3.28-3.34 (1H, m), 4.82 (1H, td, J = 9.0, 5.7 Hz), 5.52 (1H, t, J = 4.3 Hz), 6.33
(1H, s), 7.09 (1H, d, J = 8.6 Hz), 7.19 (1H, dd, J = 9.8, 2.2 Hz), 7.24-7.42 (8H, m),
7.64 (1H, dd, J = 9.8, 0.8 Hz), 7.69 (1H, dd, J = 2.2, 0.9 Hz), 8.10 (1H, s), 8.19
(1.4H, s).
Example 139
1-[5-tert-Butyl(2-hydroxy-ethyl)-2H-pyrazolyl]{(1S,4R)[3-
((S)methyl-morpholinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-urea
a. (S)Methyl-morpholinecarboxylic acid N'-(5-fluoro-pyridin
yl)-hydrazide (Intermediate 139a)
Pyridine (1.60 mL, 19.8 mmol) was added dropwise to an ice cold
suspension of triphosgene (2.94 g, 9.90 mmol) in DCM (20.0 mL). (S)
Methylmorpholine (1.00 mL, 9.90 mmol) was added and the reaction stirred for 3
hours, then quenched by dropwise addition of HCl (1M aqueous, 20 mL). The
mixture was extracted into DCM (3 ×). The combined organic layers were washed
with brine, dried (MgSO ), filtered and evaporated in vacuo to give (S)
methylmorpholine-carbamoylchloride (1.25 g, 77%). The product was used in the
next reaction without purification.
(S)Methylmorpholine-carbamoylchloride (766 mg, 4.33 mmol) was
dissolved in DCM (35.0 mL) and DIPEA (1.03 mL, 5390 mmol) was added
followed by (5-fluoro-pyridinyl)-hydrazine (WO2010022076, 500 mg, 3.94
mmol) and the reaction heated to 45°C overnight. The reaction was cooled and
quenched into water. The mixture was extracted into DCM (3 x). The combined
organic layers were washed with brine, dried (MgSO ), filtered and evaporated in
vacuo. The residue was purified by FCC using 0-10% [2M NH in MeOH] in
DCM to give the title compound (574 mg, 57%). ¹H NMR (300 MHz, CDCl ):
1.36 (3H, d, J = 6.9 Hz), 3.30 (1H, td, J = 12.5, 3.9 Hz), 3.47-3.74 (4H, m), 3.89-
4.03 (2H, m), 6.41 (1H, br s), 6.45 (1H, br s), 6.73 (1H, dd, J = 9.0, 3.5 Hz), 7.29
(1H, ddd, J = 9.0, 7.9, 2.9 Hz), 8.04 (1H, d, J = 2.9 Hz).
b. 6-Fluoro((S)methyl-morpholinyl)-[1,2,4]triazolo[4,3-
a]pyridine (Intermediate 139b)
To an ice cold solution of Intermediate 139a (574 mg, 2.26 mmol) in THF
(23.0 mL) was added sequentially triphenylphosphine (1.18 g, 4.52 mmol),
triethylamine (1.26 mL, 9.04 mmol) and hexachloroethane (1.07 g, 4.52 mmol).
The cooling bath was removed and the reaction was heated to 55°C overnight. The
reaction was cooled and partitioned between EtOAc and water. The aqueous layer
was then extracted with EtOAc (3 ×). The combined organic layers were washed
with brine, dried (MgSO ), filtered and evaporated in vacuo. The residue was taken
up in MeOH and loaded onto an SCX-2 cartridge, which was washed with MeOH
and eluted with 2M NH in MeOH. The residue was concentrated in vacuo and
then re-submitted to the above reaction conditions overnight. The reaction was
cooled and partitioned between EtOAc and water. The aqueous layer was then
extracted with EtOAc (3 ×). The combined organic layers were washed with brine,
dried (MgSO ), filtered and evaporated in vacuo. The residue was purified by FCC
using 0-10% [2M NH in MeOH] in DCM to give the title compound (154 mg,
29%). ¹H NMR (300 MHz, CDCl ): 0.94 (3H, d, J = 6.3 Hz), 3.13 (1H, dt, J =
12.2, 3.1 Hz), 3.32 (1H, ddd, J = 12.4, 9.5, 3.2 Hz), 3.49 (1H, dd, J = 11.1, 8.6 Hz),
3.56-3.68 (1H, m), 3.84 (1H, ddd, J = 12.1, 9.4, 2.7 Hz), 3.92-4.01 (2H, m), 7.16
(1H, ddd, J = 9.9, 7.5, 2.3 Hz), 7.68 (1H, ddd, J = 10.0, 4.8, 0.8 Hz), 7.85 (1H, m).
c. (1S,4R)[3-((S)Methyl-morpholinyl)-[1,2,4]triazolo[4,3-
a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenylamine (Intermediate
139c)
To a suspension of sodium hydride (60% in mineral oil, 187 mg, 4.68
mmol) in DMF (6.0 mL) was added Intermediate A (191 mg, 1.17 mmol) and the
reaction stirred for 20 min. Intermediate 139b (276 mg, 1.17 mmol) was added in
DMF (2.00 mL) and the reaction heated to 60°C for 1 h. The reaction was cooled
and quenched by dropwise addition of methanol, before being diluted with
methanol and loaded onto an SCX-2 cartridge, which was washed with MeOH.
The product was eluted with 2M NH in MeOH. The residue was purified by FCC,
using 0-10% [2M NH in MeOH] in DCM, to give the title compound (250 mg,
56%). LCMS (Method 4): Rt 1.83, m/z 380 [MH ].
d. 1-[5-tert-Butyl(2-hydroxy-ethyl)-2H-pyrazolyl]{(1S,4R)[3-
((S)methyl-morpholinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-urea (Example 139)
A mixture of Intermediate 139c (125 mg, 0.33 mmol), Intermediate
110b (115 mg, 0.33 mmol) and DIPEA (115 µL, 0.66 mmol) in dioxane (3 mL)
was stirred at 80°C overnight. After cooling, the reaction mixture was partitioned
between water and DCM. The aqueous phase was extracted with EtOAc (x 3) and
the combined organic layers were washed with brine, dried (MgSO) and
concentrated in vacuo. The resultant residue was purified by FCC, using a gradient
of 0-10% MeOH in DCM, to afford the title compound (94 mg, 48%). A sample of
this (40.0 mg) was further purified by MDAP (Method 7) purification to afford the
title compound (20 mg) as a white solid. LCMS (Method 5): Rt 3.64 min, m/z 589
[MH ]. ¹H NMR (400 MHz, d -DMSO): 0.83 (3H, d, J = 5.6 Hz), 1.16 (9H, s),
1.83-1.96 (2H, m), 1.97-2.07 (1H, m), 2.08-2.17 (1H, m), 2.95 (1H, ddd, J = 12.0,
7.2, 4.9 Hz), 3.17 (1H, dt, J = 12.2, 3.3 Hz), 3.36-3.44 (2H, m), 3.62 (2H, q, J = 5.5
Hz), 3.72-3.80 (2H, m), 3.81-3.88 (1H, m), 3.88-3.92 (2H, t, J = 6.0 Hz), 4.81 (1H,
td, J = 8.5, 6.1 Hz), 4.96 (1H, t, J = 5.0 Hz), 5.52 (1H, t, J = 4.2 Hz), 6.02 (1H, s),
7.05 (1H, d, J = 8.6 Hz), 7.18 (1H, dd, J = 9.9, 2.1 Hz), 7.22-7.27 (1H, m), 7.30-
7.37 (3H, m), 7.62 (1H, d, J = 9.9 Hz), 7.79 (1H, d, J = 1.9 Hz), 8.16 (1H, s).
Example 140
1-(5-tert-Butyl{2-[(2-dimethylamino-ethyl)-methyl-amino]-
pyrimidinyl}-2H-pyrazolyl){(1S,4R)[3-((S)methyl-piperidin
yl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-
urea
a. 5-tert-Butyl(2-chloro-pyrimidinyl)-2H-pyrazolylamine
(Intermediate 140a)
A mixture of 2,4-dichloropyrimidine (1.0 g, 6.7 mmol), 3-(tert-butyl)-1H-
pyrazolamine (1.03 g, 7.4 mmol) and sodium carbonate (1.42 g, 13.4 mmol) in
1,4-dioxane was treated with 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene
(xantphos) (58 mg, 0.10 mmol) followed by tris(dibenzylideneacetone)dipalladium
(31 mg, 0.03 mmol). The mixture was degassed then heated to 70°C under N for
5h. After cooling to room temperature the mixture was filtered and the filtrate was
concentrated in vacuo. The residue was partitioned between EtOAc and water and
the phases were separated. The aqueous layer was extracted with EtOAc (x2) and
the combined organic phase was washed with brine, dried (Na SO) and
concentrated in vacuo. The residue was purified by FCC, using 0-15% EtOAc in
cyclohexane, to give the title compound (0.59 g, 35%). LCMS (Method 3): Rt 3.97
min, m/z 252.2 [MH ].
b. N-[4-(5-Aminotert-butyl-pyrazolyl)-pyrimidinyl]-N,N',N'-
trimethyl-ethane-1,2-diamine (Intermediate 140b)
A solution of Intermediate 140a (250 mg, 0.99 mmol) and N,N,N’-
trimethylethylenediamine (0.32 mL, 2.48 mmol) in IPA (2.5 mL) was heated to
120°C for 10 mins under microwave irradiation. The cooled reaction mixture was
concentrated in vacuo and the residue was partitioned between EtOAc and water.
The phases were separated and the aqueous layer was extracted with EtOAc (x2).
The combined organic phase was washed with brine, dried (Na SO ) and
concentrated in vacuo to give the title compound (0.31 g, quant.) as a golden oil
that was used in the next step without purification. LCMS (Method 3): Rt 2.51
min, m/z 318.3 [MH ].
c. (5-tert-Butyl{2-[(2-dimethylamino-ethyl)-methyl-amino]-
pyrimidinyl}-2H-pyrazolyl)-carbamic acid phenyl ester (Intermediate
140c)
A solution of Intermediate 140b (129 mg, 0.41 mmol) in DCM (4.1 mL)
was treated with pyridine (0.046 mL, 0.57 mmol) and the mixture was cooled 0°C.
Phenyl chloroformate (0.066 mL, 0.53 mmol) was added and the resulting mixture
was stirred at RT for 16 h. The mixture was cooled to 0°C and treated with
pyridine (0.013 mL, 0.16 mmol) then phenyl chloroformate (0.015 mL, 0.12
mmol) and stirred at RT for a further 1.75 h. Once again the mixture was cooled to
0°C and treated with pyridine (0.013 mL, 0.16 mmol) then phenyl chloroformate
(0.015 mL, 0.12 mmol) and stirred at RT for 1.75 h. The mixture was diluted with
water and the phases were separated. The aqueous layer was extracted with DCM
(x 2) and the combined organic phase was washed with brine, dried (Na SO ), and
concentrated in vacuo to give a yellow gum (236 mg). Trituration with ether and
filtration of the resulting solid gave the title compound as a white solid (75 mg,
39%). LCMS (Method 3): Rt 3.21 min, m/z 438.4 [MH ].
d. 1-(5-tert-Butyl{2-[(2-dimethylamino-ethyl)-methyl-amino]-
pyrimidinyl}-2H-pyrazolyl){(1S,4R)[3-((S)methyl-piperidin
yl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-
urea (Example 140)
A solution of Intermediate 81d (25 mg, 0.066 mmol) in 1,4-dioxane (0.7
mL) was treated with Intermediate 140c (32 mg, 0.073 mmol) and DIPEA (0.014
mL, 0.083 mmol) and the mixture was stirred at 70°C for 18 h. The cooled solution
was concentrated in vacuo, and the residue was partitioned between DCM and
water. The phases were separated and the aqueous layer was extracted with DCM
(x 2). The combined organic phase was washed with brine, dried (Na SO ) and
concentrated in vacuo to a brown gum. FCC, using 0-8% MeOH in DCM, gave a
colourless glass (27 mg). The glass was purified further by HPLC (Phenomenex
Gemini C18 column, 5-95% MeCN in H O, 0.1% HCO H) over 30 mins.
Concentration of the fractions in vacuo gave a colourless glass that was dissolved
in ether. A solid was precipitated out of solution by addition of cyclohexane. The
solid was filtered off to give the title compound as a white solid (8 mg, 17%).
LCMS (Method 5): Rt 4.07 min, m/z 721.6 [MH ]. ¹H NMR (400 MHz, d -
DMSO, 353K): 0.92 (3H, d, J = 6.4 Hz), 1.29 (9H, s), 1.49-1.58 (2H, m), 1.65-1.72
(2H, m), 1.77-1.86 (2H, m), 1.99 (6H, s), 2.00-2.14 (4H, m), 2.20-2.29 (1H, m),
3.12-3.19 (5H, m), 3.30-3.39 (1H, m), 3.58-3.72 (2H, m), 4.94-5.02 (1H, m), 5.42
(1H, t, J = 3.9 Hz), 6.55 (1H, s), 7.03 (1H, d, J = 5.5 Hz), 7.15 (1H, dd, J = 9.8, 2.3
Hz), 7.22-7.27 (1H, m), 7.31-7.37 (2H, m), 7.41-7.45 (1H, m), 7.56-7.61 (2H, m),
7.70 (1H, br s), 8.35 (1H, d, J = 5.5 Hz), 10.18 (1H, br s).
Example 141
1-{5-tert-Butyl[3-(2-dimethylamino-ethoxy)-phenyl]-2H-pyrazol
yl}{(1S,4R)[3-((S)methyl-morpholinyl)-[1,2,4]triazolo[4,3-
a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea formate salt
O OH
a. 1-(5-tert-Butyl{3-[2-(tetrahydro-pyranyloxy)-ethoxy]-phenyl}-
2H-pyrazolyl){(1S,4R)[3-((S)methyl-morpholinyl)-
[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-
urea (Intermediate 141a)
A mixture of Intermediate 139c (125 mg, 0.33 mmol), Intermediate 39b
(177 mg, 0.33 mmol) and DIPEA (115 µL, 0.66 mmol) in dioxane (3 mL) was
stirred at 80°C overnight. After cooling, the reaction mixture was partitioned
between water and DCM. The aqueous phase was extracted with EtOAc (x 3) and
the combined organic layers were washed with brine, dried (MgSO ) and
concentrated in vacuo. The resultant residue was purified by FCC on silica, using a
gradient of 0-10% MeOH in DCM, to afford the title compound (214 mg, 85%).
LCMS (Method 4): Rt 3.65 min, m/z 765 [MH ].
b. 1-{5-tert-Butyl[3-(2-hydroxy-ethoxy)-phenyl]-2H-pyrazolyl}
{(1S,4R)[3-((S)methyl-morpholinyl)-[1,2,4]triazolo[4,3-a]pyridin
yloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea (Intermediate 141b)
To a solution of Intermediate 141a (214 mg, 0.28 mmol) in MeOH (3.0 mL)
was added pyridinium p-toluenesulfonate (141 mg, 0.56 mmol) and the reaction
mixture was heated at 60°C for 3 h. The resultant mixture was poured into water
and a saturated aqueous solution of NaHCO was added. The aqueous phase was
extracted with EtOAc (x 3) and the combined organic layers were washed with
brine, dried (MgSO ) and concentrated in vacuo. The resultant residue was purified
by FCC on silica, using a gradient of 0-10% MeOH in DCM, to give the title
compound (132 mg, 69%). LCMS (Method 4): Rt 3.04 min, m/z 681 [MH ].
c. Methanesulfonic acid 2-{3-[3-tert-butyl(3-{(1S,4R)[3-((S)
methyl-morpholinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-ureido)-pyrazolyl]-phenoxy}-ethyl ester
(Intermediate 141c)
To an ice-bath cooled solution of Intermediate 141b (132 mg, 0.19 mmol) in
DCM (2.0 mL) was added DIPEA (135 µL, 0.78 mmol) followed by
methanesulfonyl chloride (30 µL, 0.39 mmol). The reaction mixture was stirred for
2 h and then quenched with water. The aqueous phase was extracted with DCM (x
3) and the combined organic layers were washed with brine, dried (MgSO ) and
concentrated in vacuo to afford the title compound (Quantitative). Product used in
the subsequent step without further purification. LCMS (Method 4): Rt 3.30 min,
m/z 759 [MH ].
d. 1-{5-tert-Butyl[3-(2-dimethylamino-ethoxy)-phenyl]-2H-pyrazol-
3-yl}{(1S,4R)[3-((S)methyl-morpholinyl)-[1,2,4]triazolo[4,3-
a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea formate salt
(Example 141)
To a solution of Intermediate 141c (0.19 mmol) in THF (2.0 mL) was added
dimethylamine (2M in MeOH, 1.9 mL, 3.8 mmol) and the reaction was heated to
50°C in a sealed tube overnight. The crude reaction mixture was partitioned
between EtOAc and water. The aqueous phase was extracted with EtOAc (x 3) and
the combined organic layers were washed with brine, dried (MgSO) and
concentrated in vacuo. The resulting residue was purified by FCC on silica, using a
gradient of 0-10% [2M NH in MeOH] in DCM, followed by MDAP (Method 7)
purification, to give the title compound (50 mg, 34%). LCMS (Method 5): Rt 3.33
min, m/z 708 [MH ]. ¹H NMR (400 MHz, d -DMSO): 0.83 (3H, d, J = 5.7 Hz),
1.23 (9H, s), 1.78-1.92 (2H, m), 1.94-2.04 (1H, m), 2.04-2.12 (1H, m), 2.16 (6H,
s), 2.59 (2H, t, J = 5.7 Hz), 2.94 (1H, ddd, J = 12.2, 7.3, 4.7 Hz), 3.16 (1H, dt, J =
12.2, 3.3), 3.35-3.43 (2H, m), 3.72-3.80 (2H, m), 3.81-3.87 (1H, m), 4.04 (2H, t, J
= 5.7 Hz), 4.77 (1H, td, J = 8.5, 5.9 Hz), 5.50 (1H, t, J = 4.1 Hz), 6.28 (1H, s),
6.90-6.94 (1H, m), 7.01-7.09 (3H, m), 7.14-7.18 (1H, dd, J = 9.8, 2.1 Hz), 7.20-
7.26 (2H, m), 7.26-7.30 (1H, m), 7.30-7.38 (2H, m), 7.62 (1H, d, J = 9.8 Hz), 7.78
(1H, d, J = 1.8 Hz), 8.09 (1H, s), 8.12 (1.4H, s).
Example 142
1-[5-tert-Butyl(2-morpholinyl-ethyl)-2H-pyrazolyl]{(1S,4R)-
4-[3-((S)methyl-morpholinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-
1,2,3,4-tetrahydro-naphthalenyl}-urea formate salt
a. Methanesulfonic acid 2-[3-tert-butyl(3-{(1S,4R)[3-((S)
methyl-morpholinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-ureido)-pyrazolyl]-ethyl ester (Intermediate
142a)
To an ice-bath cooled solution of Example 139 (54 mg, 0.092 mmol) in
DCM (2.0 mL) was added DIPEA (65 µL, 0.37 mmol) followed by
methanesulfonyl chloride (14 µL, 0.18 mmol). The reaction mixture was stirred for
1 h and then quenched with water. The aqueous phase was extracted with DCM (x
3) and the combined organic layers were washed with brine, dried (MgSO ) and
concentrated in vacuo to afford the title compound (Quantitative). Product used in
the following step without further purification. LCMS (Method 4): Rt 3.04 min,
m/z 667 [MH ].
b. 1-[5-tert-Butyl(2-morpholinyl-ethyl)-2H-pyrazolyl]
{(1S,4R)[3-((S)methyl-morpholinyl)-[1,2,4]triazolo[4,3-a]pyridin
yloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea formate salt (Example 142)
To a solution of Intermediate 142a (0.092 mmol) in THF (2 mL) was added
DIPEA (64 µL, 0.37 mmol) and morpholine (21 µL, 0.37 mmol) and the reaction
stirred at 50°C for 24 h. The crude reaction mixture was cooled and partitioned
between EtOAc and water. The aqueous phase was extracted with EtOAc (x 3) and
the combined organic layers were washed with brine, dried (MgSO) and
concentrated in vacuo. The resultant residue was purified by FCC on silica, using a
gradient of 0-10% [2M NH in MeOH] in DCM, followed by MDAP (Method 7)
purification, to give the title compound (21 mg, 34%). LCMS (Method 5): Rt 3.16
min, m/z 658 [MH ]. ¹H NMR (400 MHz, d -DMSO): 0.83 (3H, d, J = 5.6 Hz),
1.16 (9H, s), 1.83-1.96 (2H, m), 1.97-2.07 (1H, m), 2.08-2.17 (1H, m), 3.34 (4H, t,
J = 4.5 Hz), 2.57 (2H, t, J = 7.1 Hz), 2.95 (1H, ddd, J = 12.0, 7.2, 4.9 Hz), 3.17
(1H, dt, J = 12.2, 3.3 Hz), 3.36-3.43 (2H, m), 3.50 (4H, t, J = 4.5 Hz), 3.72-3.80
(2H, m), 3.81-3.88 (1H, m), 3.92-3.98 (2H, t, J = 7.1 Hz), 4.82 (1H, td, J = 8.5, 6.1
Hz), 5.52 (1H, t, J = 4.2 Hz), 5.99 (1H, s), 6.89 (1H, d, J = 8.6 Hz), 7.18 (1H, dd, J
= 9.9, 2.1 Hz), 7.22-7.27 (1H, m), 7.30-7.38 (3H, m), 7.62 (1H, d, J = 9.9 Hz), 7.79
(1H, d, J = 1.9 Hz), 8.16 (1H, s), 8.16 (0.2H, s).
Example 143
1-{5-tert-Butyl[3-(4-methyl-piperazinylmethyl)-phenyl]-2H-
pyrazolyl}{(1S,4R)[3-((2S,6R)-2,6-dimethyl-piperidinyl)-
[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-
urea formate salt
To a solution of Intermediate 130b (0.25 mmol) in THF (2.5 mL) was added
N-methylpiperazine (277 µL, 2.50 mmol) and the reaction stirred at 50°C for 24 h.
After cooling, the mixture was partitioned between EtOAc and water. The aqueous
phase was extracted with EtOAc (x 3) and the combined organic layers were
washed with brine, dried (MgSO ) and concentrated in vacuo. The resulting
residue was purified by FCC on silica, using a gradient of 0-10% [2M NH in
MeOH] in DCM, followed by MDAP (Method 7) purification, to give the title
compound (37 mg, 19%). LCMS (Method 5): Rt 3.77 min, m/z 745 [MH ]. ¹H
NMR (400 MHz, d -DMSO): 0.55 (3H, d, J = 6.2 Hz), 0.58 (3H, d, J = 6.2 Hz),
1.23 (9H, s), 1.35-1.54 (3H, m), 1.63-1.68 (2H, m), 1.72-1.86 (2H, m), 1.86-1.92
(1H, m), 2.01-2.06 (2H, m), 2.07 (3H, s), 2.26 (4H, br s), 2.34 (4H, br s), 3.08-3.20
(2H, m), 3.46 (2H, s), 4.78 (1H, td, J = 8.6, 5.9 Hz), 5.47 (1H, t, J = 4.2 Hz), 6.28
(1H, s), 7.00 (1H, d, J = 8.6 Hz), 7.15 (1H, dd, J = 9.8, 2.1 Hz), 7.18-7.25 (2H, m),
7.25-7.31 (3H, m), 7.32-7.37 (2H, m), 7.41 (1H, t, J = 7.6 Hz), 7.61 (1H, d, J = 9.7
Hz), 7.83 (1H, d, J = 1.8 Hz), 8.05 (1H, s), 8.12 (1.1H, s).
Example 144
1-[5-tert-Butyl(3-pyrrolidinylmethyl-phenyl)-2H-pyrazolyl]
{(1S,4R)[3-((2S,6R)-2,6-dimethyl-piperidinyl)-[1,2,4]triazolo[4,3-
a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea formate salt
To a solution of Intermediate 130b (0.32 mmol) in THF (3.0 mL) was added
pyrrolidine (530 µL, 6.4 mmol) and the reaction stirred at 50°C for 24 h. After
cooling, the mixture was partitioned between EtOAc and water. The aqueous phase
was extracted with EtOAc (x 3) and the combined organic layers were washed
with brine, dried (MgSO ) and concentrated in vacuo. The resulting residue was
purified by FCC on silica, using a gradient of 0-10% [2M NH in MeOH] in DCM,
followed by MDAP (Method 7) purification, to give the title compound (60 mg,
24%). LCMS (Method 5): Rt 3.79 min, m/z 716 [MH ]. ¹H NMR (400 MHz, d -
DMSO): 0.55 (3H, d, J = 6.2 Hz), 0.58 (3H, d, J = 6.2 Hz), 1.23 (9H, s), 1.35-1.54
(3H, m), 1.60-1.68 (6H, m), 1.72-1.85 (2H, m), 1.86-1.92 (1H, m), 2.01-2.06 (2H,
m), 2.38-2.44 (4H, m), 3.08-3.20 (2H, m), 3.58 (2H, s), 4.77 (1H, td, J = 8.6, 5.9
Hz), 5.48 (1H, t, J = 4.2 Hz), 6.28 (1H, s), 7.00 (1H, d, J = 8.6 Hz), 7.15 (1H, dd, J
= 9.8, 2.1 Hz), 7.18-7.25 (2H, m), 7.26-7.35 (4H, m), 7.37 (1H, s), 7.41 (1H, t, J =
7.6 Hz), 7.61 (1H, d, J = 9.7 Hz), 7.83 (1H, d, J = 1.8 Hz), 8.05 (1H, s), 8.13 (1.2H,
Example 145
1-{5-tert-Butyl[3-(2-pyrrolidinyl-ethoxy)-phenyl]-2H-pyrazol
yl}{(1S,4R)[3-((2S,6R)-2,6-dimethyl-piperidinyl)-[1,2,4]triazolo[4,3-
a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea
Pyrrolidine (36 µL, 0.43 mmol) was added to a solution of Intermediate 96f
(111 mg, 0.14 mmol) in THF (2 mL). The reaction was heated to 60°C in a sealed
vial overnight. The mixture was cooled, evaporated in vacuo and the residue was
purified by FCC, using 0-15% MeOH in DCM, then triturated with Et O to give
the title compound (27 mg, 25%) as an off-white solid. LCMS (Method 5): Rt 3.87
min, m/z 746.6 [MH ]. ¹H NMR (400 MHz, d -DMSO): 0.55 (3H, d, J = 6.0 Hz),
0.58 (3H, d, J 6.0 Hz), 1.23 (9H, s), 1.32-1.54 (3H, m), 1.53-1.78 (7H, m), 1.79-
1.95 (2H, m), 1.96-2.10 (2H, m), 2.49-2.60 (2H, m), 2.68-2.94 (2H, m), 3.06-3.20
(3H, m), 3.27 (1H, m, obscured by water), 4.03-4.14 (2H, m), 4.74-4.83 (1H, m),
.49 (1H, t, J = 4.0 Hz), 6.29 (1H, s), 6.90-6.96 (1H, m), 7.01-7.09 (3H, m), 7.16
(1H, dd, J = 9.7, 2.0 Hz), 7.19-7.25 (2H, m), 7.26-7.32 (2H, m), 7.33-7.39 (1H, m),
7.62 (1H, d, J = 9.7 Hz), 7.84 (1H, m), 8.06 (1H, s).
Example 146
1-(5-tert-Butyl{3-[2-(4-methyl-piperazinyl)-ethoxy]-phenyl}-2H-
pyrazolyl){(1S,4R)[3-((2S,6R)-2,6-dimethyl-piperidinyl)-
[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl }-
urea
1-Methylpiperazine (48 µL, 0.43 mmol) was added to a solution of
Intermediate 96f (111 mg, 0.14 mmol) in THF (2 mL). The reaction was heated to
60°C in a sealed vial overnight. 1-Methylpiperazine (48 µL, 0.43 mmol) was
added and the reaction continued for a further 24 h. The mixture was cooled,
evaporated in vacuo and the residue was purified by FCC, using 0-15% MeOH in
DCM, then triturated with Et O to give the title compound (42 mg, 38%) as an off-
white solid. LCMS (Method 5): Rt 3.76 min, m/z 775.6 [MH ]. ¹H NMR (400
MHz, d -DMSO): 0.60 (3H, d, J = 6.0 Hz), 0.63 (3H, d, J = 6.0 Hz), 1.28 (9H, s),
1.36-1.62 (3H, m), 1.65-1.75 (2H, m), 1.76-1.99 (3H, m), 2.03-2.12 (2H, m), 2.14-
2.26 (3H, m), 2.34-2.61 (5H, m, obscured by solvent), 2.63-2.74 (3H, m), 3.11-
3.24 (2H, m), 3.28-3.38 (2H, m), 4.1 (2H, t, J = 5.8 Hz), 4.78-4.87 (1H, m), 5.50-
5.56 (1H, m), 6.33 (1H, s), 6.93-7.00 (1H, m), 7.05-7.13 (3H, m), 7.20 (1H, dd, J =
9.9, 2.4 Hz), 7.23-7.31 (2H, m), 7.34 (2H, t, J = 8.0 Hz), 7.40 (1H, t, J = 8.0 Hz),
7.67 (1H, d, J = 9.9 Hz), 7.87-7.91 (1H, m), 8.11 (1H, s).
Example 147
H OH
1-(5-tert-Butyl{3-[2-(ethyl-methyl-amino)-ethoxy]-phenyl}-2H-
pyrazolyl){(1S,4R)[3-((2S,6R)-2,6-dimethyl-piperidinyl)-
[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-
urea formate salt
N-Ethylmethylamine (37 µL, 0.43 mmol) was added to a solution of
Intermediate 96f (111 mg, 0.14 mmol) in THF (2 mL). The reaction was heated to
60°C in a sealed vial overnight. N-Ethylmethylamine (37 µL, 0.43 mmol) was
added and the reaction continued for a further 24 h. The mixture was cooled,
evaporated in vacuo and the residue was purified by FCC, using 0-15% MeOH in
DCM, then triturated with Et O. Further purification by HPLC (Gemini C18
column, 10-98% MeCN in H O, 0.1% formic acid) followed by evaporation of the
fractions and trituration with Et O gave the title compound (12 mg, 11%) as an off-
white solid. LCMS (Method 5): Rt 3.85 min, m/z 734.6 [MH ]. ¹H NMR (400
MHz, d -DMSO): 0.55 (3H, d, J = 6 Hz), 0.58 (3H, d, J = 6 Hz), 0.89 (3H, t, J =
7.0 Hz), 1.23 (9H, m), 1.33-1.57 (3H, m), 1.62-1.70 (2H, m), 1.71-1.95 (3H, m),
1.96-2.09 (2H, m), 2.13 (3H, s), 2.35 (2H, q, J = 7.2 Hz), 2.63 (2H, t, J = 5.7 Hz),
3.06-3.20 (3H, m), 3.21-3.36 (2H, m, obscured by solvent), 4.03 (2H, t, J = 5.7
Hz), 4.74-4.83 (1H, m), 5.48 (1H, t, J = 5.5 Hz), 6.28 (1H, s), 6.88-6.94 (1H, m),
7.00-7.10 (3H, m), 7.16 (1H, dd, J = 9.8, 2.0 Hz), 7.18-7.26 (2H, m), 7.26-7.32
(2H, m), 7.35 (1H, t, J = 8.0 Hz), 7.62 (1H, d, J = 9.8 Hz), 7.81-7.86 (1H, m), 8.09
(1H, s), 8.37 (0.2H, s).
Example 148
1-{(1S,4R)[3-(4-Aza-spiro[2.5]octyl)-[1,2,4]triazolo[4,3-a]pyridin-
6-yloxy]-1,2,3,4-tetrahydro-naphthalenyl}{5-tert-butyl[3-(2-
dimethylamino-ethoxy)-phenyl]-2H-pyrazolyl}-urea formate salt
a. 4-Aza-spiro[2.5]octanecarbonyl chloride (Intermediate 148a)
Cl N
To a vigorously stirred pale yellow solution of 4-azaspiro[2.5]octane
hydrochloride (ABCR, 443 mg, 3.00 mmol), pyridine (0.36 mL, 4.5 mmol) and
DIPEA (0.52 mL, 3.0 mmol) in DCM (10 mL) at 0°C was added a solution of
triphosgene (594 mg, 2.00 mmol) in DCM (5 mL) dropwise over 5 min. The
resulting orange solution was stirred at 0°C for 30 min, and at RT for 66 h. Aq.
HCl solution (1M, 15 mL) was added and the mixture stirred for 30 min. The
aqueous was extracted with DCM (4 ×15 mL), then the combined organics passed
through a hydrophobic frit and concentrated in vacuo to leave the title compound
as a red-brown oil (100% yield). ¹H NMR (300 MHz, CDCl ): ~2:1 ratio of
rotamers, 0.71-0.76 (1.33H, m), 0.82 (0.67H, br s), 1.00-1.04 (1.33H, m), 1.09 (0.67H, br
s), 1.53-1.59 (2H, m), 1.64-1.72 (2H, m), 1.75-1.83 (2H, m), 3.61-3.74 (2H, m).
b. 4-Aza-spiro[2.5]octanecarboxylic acid N'-(5-fluoro-pyridinyl)-
hydrazide (Intermediate 148b)
A red solution of (5-fluoro-pyridinyl)-hydrazine (477 mg, 3.75 mmol),
Intermediate 148a (3.00 mmol) and DIPEA (0.78 mL, 4.5 mmol) in DCM (20 mL)
was stirred at reflux for 40 h. To the cooled solution was added water (20 mL) and
the mixture shaken. The aqueous was extracted with DCM (2 × 10 mL), then the
combined organics passed through a hydrophobic frit and concentrated in vacuo.
Flash chromatography (silica 40g, 1-5% [2M NH in MeOH] in DCM) gave the
title compound as a yellow solid (587 mg, 74%). LCMS (Method 3): Rt 2.66 min,
m/z 265 [MH ].
c. 3-(4-Aza-spiro[2.5]octyl)fluoro-[1,2,4]triazolo[4,3-a]pyridine
(Intermediate 148c)
To a solution of Intermediate 148b (587 mg, 2.22 mmol), triphenyl
phosphine (1.17 g, 4.44 mmol) and triethylamine (1.24 mL, 8.88 mmol) in dioxane
(25 mL) at RT was added hexachloroethane (1.05 g, 4.44 mmol). The resulting
opaque solution was stirred at RT for 30 min, and at reflux for 16 h. The cooled
solution was filtered, and the filter-cake washed with THF (5 mL). The combined
organics were applied to an SCX-2 cartridge, which was washed with MeOH (100
mL). The product was eluted with 2M NH in MeOH (75 mL); concentration in
vacuo left a brown oil. Flash chromatography (silica 40 g, 1.5-4.5% MeOH in
DCM) gave the title compound as a brown gum (82%). LCMS (Method 3): Rt 2.92
min, m/z 247 [MH ].
d. (1S,4R)[3-(4-Aza-spiro[2.5]octyl)-[1,2,4]triazolo[4,3-a]pyridin-
6-yloxy]-1,2,3,4-tetrahydro-naphthalenylamine (Intermediate 148d)
To an opaque brown solution of Intermediate A (371 mg, 2.28 mmol) in dry
DMF (5 mL) under N was added sodium hydride (60% dispersion in mineral oil,
273 mg, 6.83 mmol) and the resulting mixture stirred at RT for 30 min. (CARE:
gas evolution) A solution of Intermediate 148c (448 mg, 1.82 mmol) in dry DMF
(5 mL) was added and the resulting dark brown solution stirred at 60 C for 1 h.
The solution was cooled to RT, then water (0.2 mL) added (CARE: gas evolution)
and the mixture concentrated in vacuo. The residue was redissolved in MeOH (10
mL), applied to an SCX-2 cartridge (25 g) and washed with MeOH (100 mL). The
product was eluted with 2M NH in MeOH (75 mL); concentration in vacuo left a
dark brown gum. Flash chromatography (silica 40 g, 4-7% [2M NH in MeOH] in
DCM) gave the title compound as a pale brown foam (446 mg, 63%). LCMS
(Method 3): Rt 2.31 min, m/z 390 [MH ].
e. {5-tert-Butyl[3-(2-hydroxy-ethoxy)-phenyl]-2H-pyrazolyl}-
carbamic acid 2,2,2-trichloro-ethyl ester (Intermediate 148e)
A colourless solution of Intermediate 39b (120 mg, 0.224 mmol) and
pyridinium p-toluenesulfonate (169 mg, 0.673 mmol) in MeOH (5 mL) was stirred
at 40°C for 90 min. The solution was concentrated in vacuo, suspended in water (3
mL) and sat. aq. NaHCO solution (3 mL), then extracted with DCM (2 × 5 mL).
The combined organics were passed through a hydrophobic frit, concentrated in
vacuo and azeotroped with toluene (2 × 5 mL) to leave the title compound as a
white solid (100 mg, 99%). LCMS (Method 3): Rt 4.01 min, m/z 450, 452 [MH ].
f. 1-{(1S,4R)[3-(4-Aza-spiro[2.5]octyl)-[1,2,4]triazolo[4,3-
a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}{5-tert-butyl[3-(2-
hydroxy-ethoxy)-phenyl]-2H-pyrazolyl}-urea (Intermediate 148f)
An orange-brown solution of Intermediate 148d (87.2 mg, 0.224 mmol),
Intermediate 148e (100 mg, 0.224 mmol) and DIPEA (0.049 mL, 0.28 mmol) in
dry dioxane (3 mL) was stirred at 75°C for 16 h. The cooled solution was
concentrated in vacuo, suspended in water (5 mL) and extracted with DCM (2 × 5
mL). The combined organics were passed through a hydrophobic frit and
concentrated in vacuo to leave a brown gum. Flash chromatography (silica 12g, 4-
8% MeOH in DCM) gave the title compound as a pale yellow solid (138 mg,
89%). LCMS (Method 3): Rt 3.57 min, m/z 691 [MH ].
g. Methanesulfonic acid 2-{3-[5-(3-{(1S,4R)[3-(4-aza-spiro[2.5]oct
yl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-
ureido)tert-butyl-pyrazolyl]-phenoxy}-ethyl ester (Intermediate 148g)
A yellow-orange solution of Intermediate 148f (137 mg, 0.198 mmol),
DIPEA (0.10 mL, 0.60 mmol) and methanesulfonyl chloride (45 mg, 0.40 mmol)
in DCM (5 mL) was stirred at 0°C for 30 min, and at RT for 30 min. DIPEA
(0.052 mL, 0.30 mmol) and MsCl (23 mg, 0.20 mmol) were added and the solution
stirred at RT for 30 min. Water (2 mL) and sat. aq. NaHCO solution (2 mL) were
added and the mixture shaken. The aqueous was extracted with DCM (5 mL), then
the combined organics passed through a hydrophobic frit and concentrated in
vacuo to leave the title compound as a yellow solid (100%). LCMS (Method 3): Rt
3.80 min, m/z 769 [MH ].
h. 1-{(1S,4R)[3-(4-Aza-spiro[2.5]octyl)-[1,2,4]triazolo[4,3-
a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}{5-tert-butyl[3-(2-
dimethylamino-ethoxy)-phenyl]-2H-pyrazolyl}-urea formate salt. (Example
148)
A brown solution of Intermediate 148g (0.099 mmol) and dimethylamine
(2M in THF, 0.99 mL, 1.98 mmol) in THF (1 mL) was stirred in a sealed vial at
60°C for 16 h. The solution was decanted and concentrated. MDAP (Method 7)
gave the title compound as a pale yellow solid (50 mg, 65%). LCMS (Method 5):
Rt 3.62 min, m/z 718.6 [MH ]. ¹H NMR (400 MHz, d -DMSO): 0.42-0.53 (4H, m),
1.27 (9H, s), 1.53-1.61 (2H, m), 1.74-1.96 (6H, m), 1.99-2.15 (2H, m), 2.20 (6H, s), 2.63
(2H, t, J = 5.8 Hz), 3.22-3.29 (2H, m), 4.09 (2H, t, J = 5.8 Hz), 4.81 (1H, td, J = 8.6, 5.5
Hz), 5.48 (1H, t, J = 4.3 Hz), 6.33 (1H, s), 6.95-6.98 (1H, m), 7.06-7.12 (3H, m), 7.14
(1H, dd, J = 9.9, 2.2 Hz), 7.25-7.42 (5H, m), 7.56 (1H, d, J = 2.1 Hz), 7.61 (1H, dd, J =
9.8, 0.8 Hz), 8.12 (1H, s), 8.17 (1.4H, s).
Example 149
1-[5-tert-Butyl(3-morpholinyl-methyl-phenyl)-2H-pyrazolyl]
{(1S,4R)[3-((S)methyl-pyrrolidinyl)-[1,2,4]triazolo[4,3-a]pyridin
yloxy]-1,2,3,4-tetrahydronaphthalenyl}-urea formate salt
H OH
a. 1-[5-tert-butyl(3-hydroxymethyl-phenyl)-2H-pyrazolyl]
{(1S,4R)[3-((S)methyl-pyrrolidinyl)-{1,2,4]triazolo[4,3-a]pyridin
yloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea (Intermediate 149a)
A solution of Intermediate 5c (1.60 g, 4.40 mmol) and Intermediate 29c
(1.85 g, 4.40 mmol) in dioxane (20 mL) was treated with DIPEA (1.15 mL, 6.60
mmol) and the reaction mixture was heated at 70°C for 36 h. The mixture was
concentrated in vacuo and the residue was dissolved in DCM (150 mL) and
washed with water (2 x 75 mL) and brine (75 mL). The organic layer was dried
(MgSO ), filtered and concentrated in vacuo and the foam obtained purified by
FCC, using 0-5% MeOH in DCM then 0-5% [2M NH in MeOH] in DCM to
afford the title compound as a yellow foamy solid (0.94 g, 85%). LCMS (Method
3): Rt 2.76 min, m/z 635 [MH ].
b. Methanesulfonic acid 3-[3-tert-butyl(3-{(1S,4R)[3-((S)
methyl-pyrrolidinyl)-{1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-ureido)-pyrazolyl]-benzyl ester (Intermediate
149b)
A solution of Intermediate 149a (200 mg, 0.32 mmol) and DIPEA (164 µL,
0.95 mmol) in DCM (4 mL) was treated with methanesulfonyl chloride (32 µL,
0.41 mmol) and the reaction mixture was stirred at RT for 0.5 h. The mixture was
diluted with DCM (5 mL) and washed with water (10 mL) and brine (10 mL). The
layers were separated and the organic layer was passed through a phase separator
and concentrated in vacuo to afford the title compound as a pale yellow solid (208
mg, 92%). LCMS (Method 3): Rt 3.02 min, m/z 713 [MH ].
c. 1-[5-tert-Butyl(3-morpholinyl-methyl-phenyl)-2H-pyrazolyl]-
3-{(1S,4R)[3-((S)methyl-pyrrolidinyl)-[1,2,4]triazolo[4,3-a]pyridin
yloxy]-1,2,3,4-tetrahydronaphthalenyl}-urea formate salt (Example 149)
A mixture of Intermediate 149b (104 mg, 0.15 mmol) and morpholine
(64 µL, 0.73 mmol) in THF (2 mL) was stirred at 60 ºC for 18 h. The reaction
mixture was cooled to RT, diluted with DCM (5 mL) and washed with water
(5 mL) and brine (5 mL). The organic layer was passed through a phase
separator and concentrated in vacuo and the resultant residue was purified by
prep. HPLC, using 5-50% CH CN in water, buffered with formic acid, on a
Gemini C column, over 20 mins to afford the title compound as an off white
solid (22 mg, 21%). LCMS (Method 5): Rt 2.66 min, m/z 704.6 [MH ]. ¹H NMR
(400 MHz, d -DMSO): 1.28 (9H, s), 1.84-2.11 (6H, m), 2.13 (3H, s), 2.15-2.26
(2H, m), 2.31-2.40 (5H, m), 3.10-3.17 (1H, m, obscured by water), 3.51 (2H, s,
obscured by water), 3.55 (4H, t, J = 4.6 Hz), 3.99 (1H, t, J = 8.0 Hz), 4.78-4.86
(1H, m), 5.39 (1H, t, J = 4.2 Hz), 6.33 (1H, s), 7.06 (1H, d, J = 8.6 Hz), 7.24-7.49
(9H, m), 7.75 (1H, d, J = 9.7 Hz), 8.10 (1H, s), 8.19 (0.6H, br s), 8.24 (1H, d, J =
1.8 Hz).
Example 150
1-(5-tert-Butyl{3-[(2-dimethylamino-ethyl)-methyl-amino]-phenyl}-
2H-pyrazolyl){(1S,4R)[3-((S)methyl-piperidinyl)-
[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-
urea formic acid salt
a. N-(3-Bromo-phenyl)-N,N',N'-trimethyl-ethane-1,2-diamine
(Intermediate 150a)
A solution of N'-(3-bromo-phenyl)-N,N-dimethyl-ethane-1,2-diamine (400
mg, 1.6 mmol) was formed in 1,2-dichloroethane (10 mL). Formaldehyde (250 mL,
37% in water, 3.3 mmol) was added and the mixture stirred for 10 minutes at RT.
Sodium triacetoxyborohydride (700 mg, 3.3 mmol) was added and the mixture
stirred for 2 h at RT. Further formaldehyde (250 mL, 37% in water, 3.3 mmol) and
sodium triacetoxyborohydride (700 mg, 3.3 mmol) were added and the mixture
stirred at RT for 16 h. Mixture quenched with sat. NaHCO (aq) and extracted with
DCM. The combined organic phases were dried (Na2SO4) and concentrated in
vacuo. The residue was purified by FCC, using 0-20% MeOH in DCM, to give the
title compound (200 mg, 47%). LCMS (Method 3): Rt 2.35 min, m/z 257, 259
[MH ].
b. N-[3-(5-Aminotert-butyl-pyrazolyl)-phenyl]-N,N',N'-trimethyl-
ethane-1,2-diamine (Intermediate 150b)
A solution of Intermediate 150a (200 mg, 0.78 mmol), 3-(tert-butyl)-1H-
pyrazolamine (130 mg, 0.93 mmol) and trans-N,N ʹ-dimethylcyclohexane
diamine (22mg, 0.16 mmol) was formed in toluene (2 mL). Potassium carbonate
(226 mg, 1.6 mmol) was added and the mixture degassed by bubbling nitrogen
through it. Copper (I) iodide (15 mg, 0.08 mmol) was added and the mixture was
heated to 150°C for 24 h under microwave irradiation. The cooled reaction mixture
was concentrated in vacuo and the residue was partitioned between EtOAc and
water. The phases were separated and the aqueous layer was extracted with
EtOAc. The combined organic phase was washed with brine, dried (Na SO ) and
concentrated in vacuo. The residue was purified by FCC, using 0-20% MeOH in
DCM, to give the title compound (50 mg, 20%). LCMS (Method 3): Rt 1.84 min,
m/z 316 [MH ].
c. (5-tert-Butyl{3-[(2-dimethylamino-ethyl)-methyl-amino]-phenyl}-
2H-pyrazolyl)-carbamic acid phenyl ester (Intermediate 150c)
A solution of Intermediate 150b (50 mg, 0.16 mmol) in DCM (2 mL) was
treated with pyridine (26 mL, 0.32 mmol) and phenyl chloroformate (32 mL, 0.25
mmol). The resulting mixture was stirred at RT for 2 h. Further pyridine (26 mL,
0.32 mmol) and phenyl chloroformate (32 mL, 0.25 mmol) were added and the
mixture stirred at RT for 16 h. The mixture was diluted with water and the phases
separated. The aqueous layer was extracted with DCM and the combined organic
phase was washed with brine, dried (Na SO ), and concentrated in vacuo. The
residue was purified by FCC, using 0-20% MeOH in DCM, to give the title
compound (30 mg, 43%). LCMS (Method 3): Rt 2.97 min, m/z 436 [MH ].
d. 1-(5-tert-Butyl{3-[(2-dimethylamino-ethyl)-methyl-amino]-
phenyl}-2H-pyrazolyl){(1S,4R)[3-((S)methyl-piperidinyl)-
[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-
urea formic acid salt (Example 150)
A solution of Intermediate 81d (26 mg, 0.07 mmol) in 1,4-dioxane (2 mL)
was treated with Intermediate 150c (30 mg, 0.07 mmol) and DIPEA (24 mL, 0.13
mmol) and the mixture was stirred at 70°C for 18 h. After cooling to RT the
mixture was concentrated in vacuo. The residue was purified by FCC, using 0-20%
MeOH in DCM, then by prep HPLC (C18 column, 10-98% MeCN in H O, 0.1%
HCO H) over 20 mins. Concentration of the fractions in vacuo gave pale yellow
glass. Trituration with Et O gave the title compound as an off white solid (20 mg,
40%). LCMS (Method 5): Rt 3.70 min, m/z 719.6 [MH ]. ¹H NMR (400 MHz, d -
DMSO): 0.91 (3H, d, J = 6.4 Hz), 1.27 (9H, s), 1.47-1.53 (2H, m), 1.64-1.71 (2H,
m), 1.77-1.97 (4H, m), 2.00-2.15 (2H, m), 2.16 (3H, s), 2.39 (2H, t, J = 7.2 Hz),
2.87-2.92 (1H, m), 2.93 (3H, s), 3.13-3.21 (4H, m), 3.35-3.46 (4H, m), 4.80-4.87
(1H, m), 5.52 (1H, t, J = 4.3 Hz), 6.32 (1H, s), 6.68-6.72 (3H, m), 7.13 (1H, d, J =
8.6 Hz), 7.19 (1H, dd, J = 9.7, 2.2 Hz), 7.24-7.38 (5H, m), 7.64 (1H, d, J = 9.7 Hz),
7.69 (1H, m), 8.11 (1H, s).
Example 151
1-{5-tert-Butyl[3-((R)dimethylaminomethyl-ethoxy)-phenyl]-
2H-pyrazolyl}{(1S,4R)[3-((S)methyl-piperidinyl)-
[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-
urea formate salt
.HCO H
a. 2-[3-((R)Benzyloxymethyl-ethoxy)-phenyl]tert-butyl-2H-
pyrazolylamine (Intermediate 151a)
A mixture of Intermediate 95a (0.50 g, 2.2 mmol) in dry THF (17 mL) was
treated with triphenylphosphine (1.13 g, 4.32 mmol) and (S)-(+)Benzyloxy
propanol (0.52 mL, 3.24 mmol). The mixture was cooled to 0°C then
diisopropylazodicarboxylate (0.85 mL, 4.32 mmol) was added dropwise. After
stirring at ambient temperature for 1.75 h the mixture was treated with water (0.2
mL) then applied to a pre-conditioned (with MeOH) SCX-2 cartridge. The
cartridge was eluted with MeOH then 2N NH in MeOH. The product containing
fractions were combined and concentrated in vacuo to a viscous brown oil. The oil
was purified by FCC, using 0-30% EtOAc in cyclohexane, to give the title
compound as a golden oil (0.37 g, 45%). LCMS (Method 3): Rt 3.71 min, m/z
380.3 [MH ].
b. (R)[3-(5-Aminotert-butyl-pyrazolyl)-phenoxy]-propanol
(Intermediate 151b)
A solution of Intermediate 151a (0.37 g, 0.97 mmol) in ethanol (IMS grade,
8 mL) was treated with water (1 mL) and ammonium formate (0.61 g, 9.7 mmol).
The mixture was purged with N then 10% Pd/C (0.31g, 0.29 mmol Pd) was
added. The mixture was heated to reflux for 16 h then filtered through celite and
the filtrate was concentrated in vacuo. The residue was partitioned between EtOAc
and water. The phases were separated and the aqueous layer was extracted with
EtOAc (x2). The combined organic phase was washed with saturated aqueous
sodium bicarbonate solution and brine, dried (Na SO ) and concentrated in vacuo.
The residue was purified by FCC, using 0-75% EtOAc in cyclohexane to give the
title compound (0.22 g, 79%) as a pink gum. LCMS (Method 3): Rt 2.44 min, m/z
290.3 [MH ].
c. {5-tert-Butyl[3-((R)hydroxymethyl-ethoxy)-phenyl]-2H-
pyrazolyl}-carbamic acid 2,2,2-trichloro-ethyl ester (Intermediate 151c)
A solution of Intermediate 151b (112 mg, 0.39 mmol) in EtOAc (2.1 mL)
was treated with aqueous 1N NaOH (0.7 mL, 0.70 mmol) then 2,2,2-trichloroethyl
chloroformate (0.056 mL, 0.41 mmol) and the mixture was stirred at RT for 2.5 h.
The mixture was treated with another portion of 2,2,2-trichloroethyl chloroformate
(0.015 mL, 0.11 mmol) and stirred at RT for a further 1 h. The mixture was diluted
with EtOAc and water and the phases were separated. The aqueous layer was
extracted with EtOAc (x 2) and the combined organic phase was washed with
brine, dried (Na SO ), and concentrated in vacuo to give a pale red gum (195 mg).
The gum was purified by FCC, using 0-40% EtOAc in cyclohexane, to give the
title compound as a pale golden gum (134 mg, 74%). LCMS (Method 3): Rt 4.15
min, m/z 464.2, 466.2 [MH ].
d. 1-{5-tert-Butyl[3-((R)hydroxymethyl-ethoxy)-phenyl]-2H-
pyrazolyl}{(1S,4R)[3-((S)methyl-piperidinyl)-[1,2,4]triazolo[4,3-
a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea (Intermediate
151d)
A solution of Intermediate 151c (102 mg, 0.22 mmol) in 1,4-dioxane (2.0
mL) was treated with Intermediate 81d (75 mg, 0.20 mmol) and DIPEA (0.043
mL, 0.25 mmol) and the mixture was stirred at 70°C for 7.5 h then at 50°C for 64
h. The cooled solution was concentrated in vacuo, and the residue was partitioned
between DCM and water. The phases were separated and the aqueous layer was
extracted with DCM (x 2). The combined organic phase was washed with brine,
dried (Na SO ) and concentrated in vacuo to a brown gum. The gum was purified
by FCC, using 0-10% MeOH in DCM to give the title compound as a yellow glass
(84 mg, 61%). LCMS (Method 3): Rt 3.75 min, m/z 693.5 [MH ].
e. Methanesulfonic acid (R){3-[3-tert-butyl(3-{(1S,4R)[3-((S)
methyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-ureido)-pyrazolyl]-phenoxy}-propyl urea
(Intermediate 151e)
A solution of Intermediate 151d (81 mg, 0.12 mmol) in DCM (2.7 mL) was
treated with DIPEA (0.061 mL, 0.35 mmol) then methanesulfonyl chloride (0.012
mL, 0.15 mmol). After 30 mins the mixture was treated with methanesulfonyl
chloride (0.012 mL, 0.15 mmol) and then, after another 30 mins, with DIPEA
(0.030 mL, 0.18 mmol). The mixture was stirred at RT for 16 h. Another portion of
methanesulfonyl chloride (0.012 mL, 0.15 mmol) was added and then after 30
mins another portion of methanesulfonyl chloride (0.012 mL, 0.15 mmol) and
DIPEA (0.030 mL, 0.18 mmol) were added. After 30 mins the mixture was diluted
with DCM and saturated aqueous sodium bicarbonate solution. The phases were
separated and the aqueous layer was extracted with DCM (x 2). The combined
organic phase was washed with water, saturated aqueous sodium bicarbonate
solution and brine, dried (Na SO ) and concentrated in vacuo to give the title
compound as a brown glass (92 mg, quant.). LCMS (Method 3): Rt 3.97 min, m/z
771.5 [MH ].
f. 1-{5-tert-Butyl[3-((R)dimethylaminomethyl-ethoxy)-phenyl]-
2H-pyrazolyl}{(1S,4R)[3-((S)methyl-piperidinyl)-
[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-
urea formate salt (Example 151)
A solution of Intermediate 151e (89 mg, 0.12 mmol) in THF (0.8 mL) was
treated with a 2M solution of dimethylamine in THF (1.2 mL, 2.3 mmol) and the
mixture was stirred at 60°C for 42 h. The cooled solution was concentrated in
vacuo, and the residue was partitioned between DCM and water. The phases were
separated and the aqueous layer was extracted with DCM (x 2). The combined
organic phase was washed with brine, dried (Na SO ) and concentrated in vacuo to
a brown glass. The glass was purified by HPLC (Phenomenex Gemini C18
column, 5-95% MeCN in H O, 0.1% HCO H) over 25 mins. Concentration of the
fractions in vacuo gave a pale yellow glass. The glass was triturated with ether to
give a solid that was filtered off to give the title compound as a fawn coloured
solid (16 mg, 19%). LCMS (Method 5): Rt 3.68 min, m/z 720.5 [MH ]. ¹H NMR
(400 MHz, d -DMSO): 0.91 (3H, d, J = 6.5 Hz), 1.24 (3H, d, J = 6.1 Hz), 1.27
(9H, s), 1.46-1.56 (2H, m), 1.61-1.72 (2H, m), 1.74-1.98 (4H, m), 1.99-2.16 (2H,
m), 2.17 (6H, s), 2.32-2.39 (1H, m), 2.86-2.95 (1H, m), 3.13-3.19 (1H, m), 3.29-
3.34 (1H, m), 4.56-4.65 (1H, m), 4.79-4.86 (1H, m), 5.52 (1H, t, J = 4.4 Hz), 6.32
(1H, s), 6.94-6.99 (1H, m), 7.03-7.12 (3H, m), 7.19 (1H, dd, J = 9.9, 2.0 Hz), 7.24-
7.41 (5H, m), 7.64 (1H, d, J = 10.2 Hz), 7.68-7.70 (1H, m), 8.15 (1H, s), 8.20 (1H,
Example 152
1-{5-tert-Butyl[3-((S)dimethylaminomethyl-ethoxy)-phenyl]-
2H-pyrazolyl}{(1S,4R)[3-((S)methyl-piperidinyl)-
[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-
urea formate salt
.HCO H
a. 2-[3-((S)Benzyloxymethyl-ethoxy)-phenyl]tert-butyl-2H-
pyrazolylamine (Intermediate 152a)
A mixture of Intermediate 95a (0.50 g, 2.2 mmol) in dry THF (17 mL) was
treated with triphenylphosphine (1.13 g, 4.32 mmol) and (R)-(-)benzyloxy
propanol (0.52 mL, 3.24 mmol) then diisopropylazodicarboxylate (0.85 mL, 4.32
mmol) was added dropwise [the reaction mixture became very warm]. After
stirring at ambient temperature for 1.75 h the mixture was treated with water (0.2
mL) then concentrated in vacuo to a viscous orange oil. The oil was purified by
FCC, using 0-7% EtOAc in DCM. The resulting oil was purified further by FCC,
using 0-30% EtOAc in cyclohexane. The product was applied to a pre-conditioned
(with MeOH) SCX-2 cartridge and eluted with MeOH then 2N NH in MeOH. The
product containing fractions were combined and concentrated in vacuo to give the
title compound as a viscous golden oil (0.39 g, 48%). LCMS (Method 3): Rt 3.77
min, m/z 380.4 [MH ].
b. (S)[3-(5-Aminotert-butyl-pyrazolyl)-phenoxy]-propanol
(Intermediate 152b)
A solution of Intermediate 152a (0.39 g, 1.0 mmol) in ethanol (IMS grade,
mL) was purged with N then 10% Pd/C (0.11g, 0.1 mmol Pd) was added. The
mixture was purged with H then stirred under an atmosphere of H (balloon) at
ambient temperature for 2 h, then at 50°C for 1.5 h and 45°C for 30 mins. Another
portion of Pd/C (0.11 g, 0.1 mmol Pd) was added and the mixture was stirred at
45°C for 16 h. The cooled reaction mixture was purged with N and treated with
water (2 mL) then ammonium formate (0.65 g, 10.3 mmol) and heated to reflux for
. Another portion of ammonium formate (0.65 g, 10.3 mmol) and Pd/C (0.11 g,
0.1 mmol) were added and the mixture was stirred at reflux for 16 h. The mixture
was filtered through celite and the filtrate was concentrated in vacuo. The residue
was partitioned between EtOAc and water. The phases were separated and the
aqueous layer was extracted with EtOAc (x2). The combined organic phase was
washed with saturated aqueous sodium bicarbonate solution and brine, dried
(Na SO ) and concentrated in vacuo. The residue was purified by FCC, using 0-
75% EtOAc in cyclohexane to give the title compound (0.25 g, 83%) as a pink
gum. LCMS (Method 3): Rt 2.44 min, m/z 290.3 [MH ].
c. {5-tert-Butyl[3-((S)hydroxymethyl-ethoxy)-phenyl]-2H-
pyrazolyl}-carbamic acid 2,2,2-trichloro-ethyl ester (Intermediate 152c)
H Cl
A solution of Intermediate 152b (69 mg, 0.24 mmol) in EtOAc (1.2 mL)
was treated with aqueous 1N NaOH (0.4 mL, 0.43 mmol) then 2,2,2-trichloroethyl
chloroformate (0.034 mL, 0.25 mmol) and the mixture was stirred at RT for 2.5 h.
The mixture was treated with another portion of 2,2,2-trichloroethyl chloroformate
(0.010 mL, 0.07 mmol) and stirred at RT for a further 0.75 h. The mixture was
diluted with EtOAc and water and the phases were separated. The aqueous layer
was extracted with EtOAc (x 2) and the combined organic phase was washed with
brine, dried (Na SO ), and concentrated in vacuo to give a pale red gum (121 mg).
The gum was purified by FCC, using 0-40% EtOAc in cyclohexane, to give the
title compound as a pale golden gum (62 mg, 56%). LCMS (Method 3): Rt 4.15
min, m/z 464.2, 466.2 [MH ].
d. 1-{5-tert-Butyl[3-((S)hydroxymethyl-ethoxy)-phenyl]-2H-
pyrazolyl}{(1S,4R)[3-((S)methyl-piperidinyl)-[1,2,4]triazolo[4,3-
a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea (Intermediate
152d)
A solution of Intermediate 152c (59 mg, 0.13 mmol) in 1,4-dioxane (1.3
mL) was treated with Intermediate 81d (44 mg, 0.12 mmol) and DIPEA (0.025
mL, 0.14 mmol) and the mixture was stirred at 70°C for 6.75 h then at 50°C for 64
h. The cooled solution was concentrated in vacuo, and the residue was partitioned
between DCM and water. The phases were separated and the aqueous layer was
extracted with DCM (x 2). The combined organic phase was washed with brine,
dried (Na SO ) and concentrated in vacuo to a brown gum. The gum was purified
by FCC, using 0-10% MeOH in DCM to give the title compound as a pale yellow
glass (49 mg, 61%). LCMS (Method 3): Rt 3.74 min, m/z 693.5 [MH ].
e. Methanesulfonic acid (S){3-[3-tert-butyl(3-{(1S,4R)[3-((S)
methyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-ureido)-pyrazolyl]-phenoxy}-propyl urea
(Intermediate 152e)
A solution of Intermediate 152d (46 mg, 0.066 mmol) in DCM (1.5 mL)
was treated with DIPEA (0.035 mL, 0.20 mmol) then methanesulfonyl chloride
(0.0067 mL, 0.086 mmol). After 30 mins the mixture was treated with
methanesulfonyl chloride (0.0067 mL, 0.086 mmol) and then, after another 30
mins, with DIPEA (0.018 mL, 0.10 mmol). The mixture was stirred at RT for 16 h.
Another portion of methanesulfonyl chloride (0.0067 mL, 0.086 mmol) was added
and then after 30 mins another portion of methanesulfonyl chloride (0.0067 mL,
0.086 mmol) and DIPEA (0.018 mL, 0.10 mmol) were added. After 30 mins the
mixture was diluted with DCM and saturated aqueous sodium bicarbonate
solution. The phases were separated and the aqueous layer was extracted with
DCM (x 2). The combined organic phase was washed with water, saturated
aqueous sodium bicarbonate solution and brine, dried (Na SO ) and concentrated
in vacuo to give the title compound as a brown glass (54 mg, quant.). LCMS
(Method 3): Rt 3.99 min, m/z 771.5 [MH ].
f. 1-{5-tert-Butyl[3-((S)dimethylaminomethyl-ethoxy)-phenyl]-
2H-pyrazolyl}{(1S,4R)[3-((S)methyl-piperidinyl)-
[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-
urea formate salt (Example 152)
A solution of Intermediate 152e (51 mg, 0.066 mmol) in THF (0.4 mL) was
treated with a 2M solution of dimethylamine in THF (0.66 mL, 1.32 mmol) and the
mixture was stirred at 60°C for 42 h. The cooled solution was concentrated in
vacuo, and the residue was partitioned between DCM and water. The phases were
separated and the aqueous layer was extracted with DCM (x 2). The combined
organic phase was washed with brine, dried (Na SO ) and concentrated in vacuo to
a brown glass. The glass was purified by HPLC (Phenomenex Gemini C18
column, 5-95% MeCN in H O, 0.1% HCO H) over 25 mins. Concentration of the
fractions in vacuo gave a pale yellow glass. The glass was triturated with diethyl
ether to give title compound as a fawn coloured solid (2.5 mg, 5%). LCMS
(Method 5): Rt 3.68 min, m/z 720.5 [MH ]. ¹H NMR (400 MHz, d -DMSO): 0.91
(3H, d, J = 6.5 Hz), 1.24 (3H, d, J = 6.5 Hz), 1.27 (9H, s), 1.46-1.56 (2H, m), 1.61-
1.72 (2H, m), 1.74-1.98 (4H, m), 1.99-2.16 (2H, m), 2.18 (6H, s), 2.32-2.38 (1H,
m), 2.86-2.95 (1H, m), 3.12-3.19 (1H, m), 4.56-4.65 (1H, m), 4.78-4.86 (1H, m),
.52 (1H, t, J = 4.1 Hz), 6.32 (1H, s), 6.94-6.99 (1H, m), 7.03-7.11 (3H, m), 7.19
(1H, dd, J = 9.6, 2.4 Hz), 7.24-7.41 (5H, m), 7.64 (1H, d, J = 10.0 Hz), 7.68-7.70
(1H, m), 8.15 (1H, s), 8.21 (1H, s).
Example 153
1-[2-[3-(2-Dimethylamino-ethoxy)-phenyl](2-hydroxy-1,1-dimethyl-
ethyl)-2H-pyrazolyl]{(1S,4R)[3-((S)methyl-piperidinyl)-
[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-
urea formate salt
N .HCO H
a. 3-(tert-Butyl-diphenyl-silanyloxy)-2,2-dimethyl-propionic acid
methyl ester (Intermediate 153a)
A solution of methyl 2,2-dimethylhydroxypropionate (5.0 g, 37.8 mmol)
in DMF (75 mL) was cooled to 0°C and treated with imidazole (3.86 g, 56.7
mmol) then tert-butyl diphenylchlorosilane (11.8 mL, 45.4 mmol). The mixture
was stirred at RT for 22 h then concentrated in vacuo. The residue was partitioned
between EtOAc and water. The phases were separated and the aqueous layer was
extracted with EtOAc (x2). The combined organic phase was washed with 10%
aqueous citric acid solution, saturated aqueous sodium bicarbonate solution and
brine, dried (Na SO ) and concentrated in vacuo to give the title compound as a
golden oil (15.93 g, quant.). LCMS (Method 3): Rt 5.32 min, m/z 393.3 [M+Na ].
b. 5-(tert-Butyl-diphenyl-silanyloxy)-4,4-dimethyloxo-pentanenitrile
(Intermediate 153b)
A suspension of sodium hydride (60% dispersion in oil) (2.12 g, 52.9
mmol) in toluene (65 mL) at reflux under N was added over 55 mins a solution of
Intermediate 153a (15.93 g, assumed 37.8 mmol) and acetonitrile (2.87 mL, 54.9
mmol) in toluene (31 mL). The mixture was heated at reflux for 67 h. The cooled
reaction mixture was slowly acidified to pH 5 with aqueous 1N HCl and extracted
with EtOAc. The aqueous layer was extracted with EtOAc (x2) and the combined
organic phase was washed with brine, dried (Na SO ) and concentrated in vacuo.
The residue was purified by FCC, using 0-50% ether in pentane, to give the title
compound (3.52 g, 25%) as a yellow oil. LCMS (Method 3): Rt 4.94 min, m/z
402.3 [M+Na ].
c. 2-(3-Benzyloxy-phenyl)[2-(tert-butyl-diphenyl-silanyloxy)-1,1-
dimethyl-ethyl]-2H-pyrazolylamine (Intermediate 153c)
A solution of Intermediate 153b (1.00 g, 2.63 mmol) in ethanol (IMS grade,
mL) was treated with 3-benzyloxyphenylhydrazine hydrochloride (0.66 mL,
2.63 mmol) then DIPEA (0.46 mL, 2.63 mmol) and the mixture was heated to
reflux for 114 h. The cooled reaction mixture was diluted with EtOAc and a
saturated aqueous sodium bicarbonate solution and the mixture was filtered and the
phases separated. The aqueous layer was extracted with EtOAc (x 2) and the
combined organic phase was washed with brine, dried (Na SO ), and concentrated
in vacuo to give an orange oil (1.62 g). The gum was purified by FCC, using 0-
% EtOAc in cyclohexane, to give the title compound as a yellow oil (1.21 g,
80%). LCMS (Method 3): Rt 5.40 min, m/z 576.5 [MH ].
d. 3-{5-Amino[2-(tert-butyl-diphenyl-silanyloxy)-1,1-dimethyl-ethyl]-
pyrazolyl}-phenol (Intermediate 153d)
A solution of Intermediate 153c (1.21 g, 2.1 mmol) in ethanol (IMS grade,
mL) was treated with water (1 mL) and ammonium formate (1.33 g, 21 mmol).
The mixture was purged with N then 10% Pd/C (0.67g, 0.63 mmol Pd) was
added. The mixture was heated to reflux for 1 h then filtered through celite and the
filtrate was concentrated in vacuo. The residue was partitioned between EtOAc
and water. The phases were separated and the aqueous layer was extracted with
EtOAc (x2). The combined organic phase was washed with brine, dried (Na SO )
and concentrated in vacuo. The residue was purified by FCC, using 0-40% EtOAc
in cyclohexane, to give the title compound (0.53 g, 41% over 2 steps) as a golden
gum. LCMS (Method 3): Rt 4.55 min, m/z 486.5 [MH ].
e. 5-[2-(tert-Butyl-diphenyl-silanyloxy)-1,1-dimethyl-ethyl]{3-[2-
(tetrahydro-pyranyloxy)-ethoxy]-phenyl}-2H-pyrazolylamine
(Intermediate 153e)
A mixture of Intermediate 153d (0.53 g, 1.09 mmol) in dry THF (8 mL) was
treated with triphenylphosphine (0.57 g, 2.18 mmol) and 2-(tetrahydro-2H-pyran-
2-yloxy)ethanol (0.22 mL, 1.64 mmol). The mixture was cooled to 0°C then
diisopropylazodicarboxylate (0.43 mL, 2.18 mmol) was added dropwise. After
stirring at ambient temperature for 20 h the mixture was treated with water (0.1
mL) and concentrated in vacuo to a yellow oil. The oil was purified by FCC, using
0-30% EtOAc in cyclohexane, to give the title compound as an orange oil (0.41 g,
61%). LCMS (Method 3): Rt 5.25 min, m/z 614.6 [MH ].
f. (5-[2-(tert-Butyl-diphenyl-silanyloxy)-1,1-dimethyl-ethyl]{3-[2-
(tetrahydro-pyranyloxy)-ethoxy]-phenyl}-2H-pyrazolyl)-carbamic acid
2,2,2-trichloro-ethyl ester (Intermediate 153f)
H Cl
A solution of Intermediate 153e (0.41 g, 0.67 mmol) in EtOAc (3.6 mL)
was treated with aqueous 1N NaOH (1.2 mL, 1.2 mmol) then 2,2,2-trichloroethyl
chloroformate (0.10 mL, 0.74 mmol) and the mixture was stirred at RT for 4 h.
The mixture was diluted with EtOAc and water and the phases were separated. The
aqueous layer was extracted with EtOAc (x 2) and the combined organic phase
was washed with brine, dried (Na SO ), and concentrated in vacuo to give a pale
red oil (0.67 g). The oil was purified by FCC, using 0-25% EtOAc in cyclohexane
to give the title compound as a pale golden gum (0.38 g, 72%). LCMS (Method 3):
Rt 5.86 min, m/z 788.3, 790.3 [MH ].
g. 1-[3-(1-{[tert-Butyl(diphenyl)silyl]oxy}methylpropanyl){3-[2-
(tetrahydro-2H-pyranyloxy)ethoxy]phenyl}-1H-pyrazolyl][(1S,4R)
({3-[(2S)methylpiperidinyl][1,2,4]triazolo[4,3-a]pyridinyl}oxy)-
1,2,3,4-tetrahydronaphthalenyl]urea (Intermediate 153g)
A solution of Intermediate 153f (377 mg, 0.48 mmol) in 1,4-dioxane (4.8
mL) was treated with Intermediate 81d (164 mg, 0.43 mmol) and DIPEA (0.095
mL, 0.54 mmol) and the mixture was stirred at 70°C for 30 mins then at 50°C for
64 h then at 70°C for 22 h. The cooled solution was concentrated in vacuo, and the
residue was partitioned between DCM and water. The phases were separated and
the aqueous layer was extracted with DCM (x 2). The combined organic phase was
washed with brine, dried (Na SO ) and concentrated in vacuo to a brown gum. The
gum was purified by FCC, using 0-7% MeOH in DCM to give the title compound
as a brown glass (320 mg, 72%). LCMS (Method 3): Rt 5.66 min, m/z 1017.7
[MH ].
h. 1-{3-(1-{[tert-Butyl(diphenyl)silyl]oxy}methylpropanyl)[3-(2-
hydroxyethoxy)phenyl]-1H-pyrazolyl}[(1S,4R)({3-[(2S)
methylpiperidinyl][1,2,4]triazolo[4,3-a]pyridinyl}oxy)-1,2,3,4-
tetrahydronaphthalenyl]urea (Intermediate 153h)
O OH
A solution of Intermediate 153g (317 mg, 0.31 mmol) in MeOH (3.1 mL)
was treated with pyridinium para-toluenesulfonate (235 mg, 0.93 mmol) and the
mixture was stirred at 45°C for 19 h. The cooled solution was concentrated in
vacuo, and the residue was partitioned between DCM and a saturated aqueous
sodium bicarbonate solution. The phases were separated and the aqueous layer was
extracted with DCM (x 2). The combined organic phase was washed with water, a
saturated aqueous sodium bicarbonate solution, and brine, dried (Na SO ) and
concentrated in vacuo to a cream coloured foam. The foam was purified by FCC,
using 0-10% MeOH in DCM, to give the title compound as a colourless glass (217
mg, 75%). LCMS (Method 3): Rt 5.06 min, m/z 933.7 [MH ].
i. 2-{3-[3-(1-{[tert-Butyl(diphenyl)silyl]oxy}methylpropanyl)
({[(1S,4R)({3-[(2S)methylpiperidinyl][1,2,4]triazolo[4,3-a]pyridin
yl}oxy)-1,2,3,4-tetrahydronaphthalenyl]carbamoyl}amino)-1H-pyrazol
yl]phenoxy}ethyl methanesulfonate (Intermediate 153i)
A solution of Intermediate 153h (214 mg, 0.23 mmol) in DCM (2.3 mL)
was treated with DIPEA (0.12 mL, 0.69 mmol) then methanesulfonyl chloride
(0.037 mL, 0.48 mmol). After 30 mins the mixture was diluted with DCM and
saturated aqueous sodium bicarbonate solution. The phases were separated and the
aqueous layer was extracted with DCM (x 2). The combined organic phase was
washed with water, saturated aqueous sodium bicarbonate solution and brine, dried
(Na SO ) and concentrated in vacuo to an orange gum. The gum was purified by
FCC, using 0-8% MeOH in DCM, to give the title compound as a pale brown glass
(134 mg, 58%). LCMS (Method 3): Rt 5.18 min, m/z 1011.7 [MH ].
j. 1-[3-(1-{[tert-Butyl(diphenyl)silyl]oxy}methylpropanyl){3-[2-
(dimethylamino)ethoxy]phenyl}-1H-pyrazolyl][(1S,4R)({3-[(2S)
methylpiperidinyl][1,2,4]triazolo[4,3-a]pyridinyl}oxy)-1,2,3,4-
tetrahydronaphthalenyl]urea (Example 153j)
A solution of Intermediate 153i (131 mg, 0.13 mmol) in THF (0.8 mL) was
treated with a 2M solution of dimethylamine in THF (1.3 mL, 2.6 mmol) and the
mixture was stirred at 60°C for 18 h. The cooled solution was concentrated in
vacuo, and the residue was partitioned between DCM and water. The phases were
separated and the aqueous layer was extracted with DCM (x 2). The combined
organic phase was washed with brine, dried (Na SO ) and concentrated in vacuo to
a brown gum. The gum was purified by FCC, using 0-8% (2N NH /MeOH) in
DCM, to give the title compound as a white foam (93 mg, 75%). LCMS (Method
3): Rt 3.91 min, m/z 960.6 [MH ].
1-[2-[3-(2-Dimethylamino-ethoxy)-phenyl](2-hydroxy-1,1-dimethyl-
ethyl)-2H-pyrazolyl]{(1S,4R)[3-((S)methyl-piperidinyl)-
[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-
urea formate salt (Example 153)
A solution of Intermediate 153j (90 mg, 0.09 mmol) in THF (0.5 mL) was
treated with a 1M solution of tetrabutylammonium fluoride in THF (0.5 mL, 0.5
mmol) and the reaction mixture was stirred at RT for 1 h then at 50°C for 16 h.
The cooled solution was concentrated in vacuo, and the residue was partitioned
between DCM and a saturated aqueous sodium bicarbonate solution. The phases
were separated and the aqueous layer was extracted with DCM (x 2). The
combined organic phase was washed with brine, dried (Na SO ) and concentrated
in vacuo to a brown gum. The gum was purified by FCC, using 0-8% [2M NH in
MeOH] in DCM, and then purified further by HPLC (Phenomenex Gemini C18
column, 5-95% MeCN in H O, 0.1% HCO H) over 25 mins to give a colourless
glass. The glass was triturated with diethyl ether to give the title compound as a
white solid (11 mg, 16%). LCMS (Method 5): Rt 3.17 min, m/z 722.6 [MH ]. ¹H
NMR (400 MHz, d -DMSO): 0.91 (3H, d, J = 6.3 Hz), 1.21 (6H, s), 1.44-1.57 (2H,
m), 1.62-1.73 (2H, m), 1.74-1.98 (4H, m), 1.99-2.17 (2H, m), 2.18 (6H, s), 2.61
(2H, t, J = 6.0 Hz), 2.86-2.95 (1H, m), 3.12-3.20 (1H, m), 3.27-3.36 (1H, m), 3.44
(2H, s), 4.08 (2H, t, J = 6.0 Hz), 4.78-4.86 (1H, m), 5.52 (1H, t, J = 4.0 Hz), 6.32
(1H, s), 6.94-6.99 (1H, m), 7.06-7.14 (3H, m), 7.19 (1H, dd, J = 10.1, 2.0 Hz),
7.24-7.43 (5H, m), 7.64 (1H, d, J = 9.7 Hz), 7.68-7.71 (1H, m), 8.15 (1H, s), 8.20
(1H, s).
Example 154
1-{5-tert-Butyl[3-(2-pyrrolidinyl-ethoxy)-phenyl]-2H-pyrazol
yl}{(1S,4R)[3-((S)methyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridin-
6-yloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea formate salt
Methanesulfonic acid 2-{3-[3-tert-butyl(3-{(1S,4R)[3-((S)
methyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-ureido)-pyrazolyl]-phenoxy}-ethyl ester
(Intermediate 154a)
Methanesulfonyl chloride (81µL, 1.05 mmol) was added to a stirred
solution of Intermediate 95e (545 mg, 803 mmol) and DIPEA (420 µL, 2.41
mmol) in DCM (20 mL), under argon and the reaction mixture was stirred at RT
for 1.5 h. A further 25 µL, 0.32 mmol of methanesulfonyl chloride was added and
the reaction mixture continued to stir at RT for 2 h. Water (20 mL) was added and
the two layers were shaken thoroughly before being separated. The aqueous layer
was extracted with DCM (2 x 20 mL) and the combined organics were passed
through a phase separator and concentrated in vacuo to afford the title compound
as an orange glass (690 mg, >100%). LCMS (Method 3): Rt 3.89 min, m/z 757
[MH ].
1-{5-tert-Butyl[3-(2-pyrrolidinyl-ethoxy)-phenyl]-2H-pyrazol
yl}{(1S,4R)[3-((S)methyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridin-
6-yloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea formate salt (Example 154)
A solution of Intermediate 154a (50.5 mg, 0.067 mmol) and pyrrolidine (27
µL, 0.33 mmol) in THF (1 mL) was stirred at 60°C for 20 h in a sealed tube. The
mixture was concentrated in vacuo and the residue purified by MDAP (Method 7).
The title product was isolated as an off-white solid (29 mg, 59%). LCMS (Method
): Rt 3.72 min, m/z 732.6 [MH ]. ¹H NMR (400 MHz, d -DMSO): 0.91 (3H, d, J
= 8.0 Hz), 1.28 (9H, s), 1.46-1.56 (2H, m), 1.61-1.72 (6H, m), 1.75-1.98 (4H, m),
1.99-2.18 (2H, m), 2.52 (4H, m, obscured by solvent), 2.80 (2H, t, J = 8.0 Hz),
2.86-2.95 (1H, m), 3.12-3.19 (1H, m, obscured by water), 3.27-3.35 (1H, m,
obscured by water), 4.11 (2H, t, J = 8.0 Hz), 4.78-4.86 (1H, m), 5.52 (1H, t, J = 4.0
Hz), 6.33 (1H, s), 6.97 (1H, dd, J = 8.0 Hz, 4.0 Hz), 7.05-7.14 (3H, m), 7.19 (1H,
dd, J = 8.0 Hz, 4.0 Hz), 7.24-7.42 (5H, m), 7.64 (1H, d, J = 8.0 Hz), 7.69 (1H, d, J
= 4.0 Hz), 8.14 (1H, s), 8.18 (1.3H, s).
Example 155
1-{5-tert-Butyl[3-(2-diethylamino-ethoxy)-phenyl]-2H-pyrazolyl}-
3-{(1S,4R)[3-((S)methyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridin
yloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea formate salt
A solution of Intermediate 154a (50.5 mg, 0.067 mmol) and diethylamine
(34 µL, 0.33 mmol) in THF (1 mL) was stirred at 60°C for 20 h in a sealed tube.
Additional diethylamine (102 µL, 0.99 mmol) was added and the mixture
subsequently stirred at 60°C in a sealed tube for 24 h. The mixture was
concentrated in vacuo and the residue purified by MDAP (Method 7). The title
product was isolated as an off-white solid (22 mg, 45%). LCMS (Method 5): Rt
3.74 min, m/z 734.6 [MH ]. ¹H NMR (400 MHz, d -DMSO): 0.89-0.96 (9H, m),
1.28 (9H, s), 1.46-1.56 (2H, m), 1.62-1.73 (2H, m), 1.74-1.98 (4H, m), 1.99-2.18
(2H, m), 2.52 (4H, m, obscured by solvent), 2.76 (2H, t, J = 8.0 Hz), 2.87-2.94
(1H, m), 3.12-3.19 (1H, m, obscured by water), ~3.30 (1H, m, obscured by water),
4.05 (2H, t, J = 8.0 Hz), 4.77-4.86 (1H, m), 5.52 (1H, t, J = 4.0 Hz), 6.33 (1H, s),
6.95 (1H, dd, J = 8.0 Hz, 4.0 Hz), 7.05-7.13 (3H, m), 7.19 (1H, dd, J = 8.0 Hz, 4.0
Hz), 7.24-7.42 (5H, m), 7.64 (1H, d, J = 8.0 Hz), 7.69 (1H, d, J = 4.0 Hz), 8.13
(1H, s), 8.19 (1H, s).
Example 156
1-{5-tert-Butyl[3-(2-morpholinyl-ethoxy)-phenyl]-2H-pyrazol
yl}{(1S,4R)[3-((S)methyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridin-
6-yloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea partial formate salt
A solution of Intermediate 154a (50.5 mg, 0.067 mmol) and morpholine (29
µL, 0.33 mmol) in THF (1 mL) was stirred at 60°C for 20 h in a sealed tube.
Additional morpholine (29 µL, 0.33 mmol) was added and the mixture
subsequently stirred at 60°C in a sealed tube for 24 h. The mixture was
concentrated in vacuo and the residue purified by MDAP (Method 7). The title
product was isolated as an off-white solid (25 mg, 50%). LCMS (Method 5): Rt
3.66 min, m/z 748.6 [MH ]. ¹H NMR (400 MHz, d -DMSO): 0.91 (3H, d, J = 6.0
Hz), 1.27 (9H, s), 1.46-1.56 (2H, m), 1.61-1.73 (2H, m), 1.75-1.98 (4H, m), 1.99-
2.19 (2H, m), 2.42 (4H, t, J = 4.0 Hz), 2.67 (2H, t, J = 8.0 Hz), 2.86-2.95 (1H, m),
3.12-3.20 (1H, m, obscured by water), ~3.30 (1H, m, obscured by water), 3.53
(4H, t, J = 8.0 Hz), 4.12 (2H, t, J = 8.0 Hz), 4.77-4.86 (1H, m), 5.52 (1H, t, J = 4.0
Hz), 6.33 (1H, s), 6.95-6.99 (1H, m), 7.07-7.13 (3H, m), 7.19 (1H, dd, J = 8.0 Hz,
4.0 Hz), 7.25-7.43 (5H, m), 7.64 (1H, d, J = 8.0 Hz), 7.69 (1H, d, J = 4.0 Hz), 8.13
(1H, s), 8.21 (0.5H, s).
Example 157
1-{5-tert-Butyl[3-(2-piperidinyl-ethoxy)-phenyl]-2H-pyrazol
yl}{(1S,4R)[3-((S)methyl-piperidinyl)-[1,2,4]triazolo[4,3-
a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea formate salt
A solution of Intermediate 154a (66 mg, 88 µmol) and piperidine (44
mL, 0.45 mmol) in THF (2 mL) was heated at 60°C overnight in a sealed
vessel. The reaction mixture was concentrated in vacuo and the residue
purified by MDAP (Method 7) to give the title compound as a white solid (31
mg, 46%). LCMS (Method 5): Rt 3.77 min, m/z 746 [MH ]. ¹H NMR (400
MHz, d -DMSO): 0.91 (3H, d, J = 6.2 Hz), 1.24-1.34 (11H, m), 1.39-1.55 (6H,
m), 1.61-2.18 (8H, m), 2.34-2.43 (4H, m), 2.63 (2H, t, J 6.1 Hz), 2.86-2.94
(1H, m), 3.11-3.19 (1H, m), 3.27-3.36 (1H, m), 4.09 (2H, t, J = 5.9 Hz), 4.77
(1H, m), 5.52 (1H, t, J = 4.0 Hz), 6.32 (1H, s), 6.93-6.98 (1H, m), 7.04-7.13
(3H, m), 7.19 (1H, dd, J = 9.5 Hz, 2.6 Hz), 7.24-7.42 (5H, m), 7.64 (1H, d, J =
9.9 Hz), 7.69 (1H, d, J = 1.8 Hz), 8.12 (1H, s), 8.17 (1.5H, s).
Example 158
1-(5-tert-Butyl{3-[2-(4-methyl-piperazinyl)-ethoxy]-phenyl}-2H-
pyrazolyl){(1S,4R)[3-((S)methyl-piperidinyl)-[1,2,4]triazolo[4,3-
a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea formate salt
A solution of Intermediate 154a (50.5 mg, 0.067 mmol) and 1-
methylpiperazine (37 µL, 0.33 mmol) in THF (1 mL) was stirred at 60°C for 20 h
in a sealed tube. The mixture was concentrated in vacuo and the residue purified
by MDAP (Method 7). The title product was isolated as an off-white solid (28 mg,
55%). LCMS (Method 5): Rt 3.62 min, m/z 761.6 [MH ]. ¹H NMR (400 MHz, d -
DMSO): 0.91 (3H, d, J = 8.0 Hz), 1.28 (9H, s), 1.47-1.56 (2H, m), 1.61-1.73 (2H,
m), 1.74-1.97 (4H, m), 2.00-2.19 (5H, m), 2.21—2.35 (4H, m,), 2.36-2.49 (4H, m),
2.66 (2H, t, J = 8.0 Hz), 2.86-2.95 (1H, m), 3.12-3.19 (1H, m, obscured by water),
3.27-3.35 (1H, m, obscured by water), 4.10 (2H, t, J = 8.0 Hz), 4.78-4.86 (1H, m),
.52 (1H, t, J = 4.0 Hz), 6.33 (1H, s), 6.94-6.98 (1H, m), 7.05-7.13 (3H, m), 7.19
(1H, dd, J = 8.0 Hz, 4.0 Hz), 7.24-7.42 (5H, m), 7.64 (1H, d, J = 8.0 Hz), 7.69 (1H,
d, J = 4.0 Hz), 8.13 (1H, s), 8.17 (1.4H, s).
Example 159
1-{5-tert-Butyl{3-[2-(4-fluoropiperidinyl)-ethoxy]-phenyl}-2H-
pyrazolyl}{(1S,4R)[3-((S)methyl-piperidinyl)-[1,2,4]triazolo[4,3-
a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea formate salt
A solution of Intermediate 154a (50.5 mg, 0.067 mmol) and 4-
fluoropiperdine (34 mg, 0.33 mmol) in THF (1 mL) was stirred at 60°C for 20 h in
a sealed tube. Additional 4-fluoropiperidine (34 mg, 0.33 mmol) was added and
the mixture subsequently stirred at 60°C in a sealed tube for 24 h. The mixture was
concentrated in vacuo and the residue purified by MDAP (Method 7). The title
product was isolated as an off-white solid (24 mg, 47%). LCMS (Method 5): Rt
3.75 min, m/z 764.6 [MH ]. ¹H NMR (400 MHz, d -DMSO): 0.91 (3H, d, J = 8.0
Hz), 1.27 (9H, s), 1.44-1.64 (2H, m), 1.59-1.72 (4H, m), 1.72-1.98 (6H, m), 1.99-
2.19 (2H, m), 2.31-2.40 (2H, m), 2.55-2.64 (2H, m,), 2.68 (2H, t, J = 8.0 Hz), 2.87-
2.95 (1H, m), 3.12-3.19 (1H, m, obscured by water), ~3.30 (1H, m, completely
obscured by water), 4.10 (2H, t, J = 8.0 Hz), 4.51-4.59 (0.5H, m), 4.64-4.71 (0.5H,
m), 4.78-4.86 (1H, m), 5.52 (1H, t, J = 4.0 Hz), 6.33 (1H, s), 6.95-6.99 (1H, m),
7.06-7.13 (3H, m), 7.19 (1H, dd, J = 8.0 Hz, 4.0 Hz), 7.25-7.42 (5H, m), 7.64 (1H,
d, J = 8.0 Hz), 7.69 (1H, d, J = 4.0 Hz), 8.12 (1H, s), 8.18 (1H, s).
Example 160
1-(5-tert-Butyl{3-[2-(4-methyl-[1,4]-diazepanyl)-ethoxy]-
phenyl}-2H-pyrazolyl){(1S,4R)[3-((S)methyl-piperidinyl)-
[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-
urea formate salt
A solution of Intermediate 154a (50.5 mg, 0.066 mmol) and N-methyl
homopiperazine (39 mg, 0.34 mmol) in THF (1 mL) was heated at 60°C
overnight in a sealed vessel. The reaction mixture was concentrated in vacuo
and the residue purified by MDAP (Method 7) to give a white solid of the title
compound (28 mg, 54%). LCMS (Method 5): Rt 3.28 min, m/z 775 [MH ]. ¹H
NMR (400 MHz, d -DMSO): 0.91 (3H, d, J = 6.0 Hz), 1.27 (9H, s), 1.47-1.56
(2H, m), 1.62-1.73 (4H, m), 1.75-2.18 (6H, m), 2.28 (3H, s), 2.56-2.63 (4H,
m), 2.70-2.77 (4H, m), 2.85 (2H, t, J = 6.0 Hz), 2.87-2.95 (1H, m), 3.12-3.20
(1H, m), 3.27-3.35 (1H, m), 4.07 (2H, t, J = 5.6 Hz), 4.77-4.86 (1H, m), 5.52
(1H, t, J = 3.8 Hz), 6.32 (1H, s), 6.93-6.98 (1H, m), 7.04-7.10 (2H, m), 7.14
(1H, d, J = 8.9 Hz), 7.19 (1H, dd, J = 9.8 Hz, 2.2 Hz), 7.24-7.42 (5H, m), 7.64
(1H, d, J = 4.9 Hz), 7.69 (1H, d, J = 1.8 Hz), 8.18 (1H, s), 8.20 (2H, s).
Example 161
1-{5-tert-Butyl[3-(2-[1,4]oxazepanyl-ethoxy)-phenyl]-2H-
pyrazolyl}{(1S,4R)[3-((S)methyl-piperidinyl)-
[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-
urea formate salt
A solution of Intermediate 154a (50.5 mg, 66 µmol) and [1,4]oxazepine
(70 mg, 0.68 mmol) in THF (1 mL) was heated at 60°C for 48 h in a sealed
vessel. The reaction mixture was concentrated in vacuo and the residue
purified by MDAP (Method 7) to give the title compound as a white solid (27
mg, 53%). LCMS (Method 5): Rt 3.68 min, m/z 762 [MH ]. ¹H NMR (400
MHz, d -DMSO): 0.91 (3H, d, J = 6.2 Hz), 1.27 (9H, s), 1.46-1.54 (2H, m),
1.62-2.17 (12H, m), 2.67-2.72 (3H, m), 2.86 (2H, t, J = 6.0 Hz), 2.88-2.94
(1H, m), 3.12-3.19 (1H, m), 3.28-3.34 (1H, m, obscured by water peak), 3.53-
3.58 (2H, m), 3.61 (2H, t, J = 6.0 Hz), 4.09 (2H, t, J = 6.1 Hz), 4.77-4.86 (1H,
m), 5.52 (1H, t, J = 4.3 Hz), 6.33 (1H, s), 6.94-6.99 (1H, m), 7.05-7.12 (2H,
m), 7.19 (1H, dd, J = 8.6 Hz, 2.0 Hz), 7.24-7.42 (5H, m), 7.64 (1H, d, J = 9.8
Hz), 7.69 (1H, d, J = 2.0 Hz), 8.17 (1H, s), 8.18 (1H, s).
Example 162
1-(2-{3-[2-(8-Aza-bicyclo[3.2.1]octyl)-ethoxy]-phenyl}tert-
butyl-2H-pyrazolyl){(1S,4R)[3-((S)methyl-piperidinyl)-
[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-
urea formate salt
A solution of Intermediate 154a (50.5 mg, 66 µmol) and 8-aza-
bicyclo[3.2.1]octane (38 mg, 0.34 mmol) in THF (1 mL) was heated at 60°C
overnight in a sealed vessel. The reaction mixture was concentrated in vacuo
and the residue purified by MDAP (Method 7) to give the title compound as a
white solid (32 mg, 62%). LCMS (Method 5): Rt 3.84 min, m/z 772 [MH ]. ¹H
NMR (400 MHz, d -DMSO): 0.91 (3H, d, J = 6.4 Hz), 1.21-1.36 (11H, m),
1.37-1.54 (4H, m), 1.58-1.72 (4H, m), 1.74-2.18 (8H, m), 2.72 (2H, d, J = 6.4
Hz), 2.86-2.95 (1H, m), 3.11-3.20 (1H, m), 3.22-3.36 (5H, m), 4.09 (2H, t, J =
6.1 Hz), 4.77-4.86 (1H, m), 5.52 (1H, t, J = 4.1 Hz), 6.33 (1H, s), 6.94-6.99
(1H, m), 7.04-7.11 (2H, m), 7.14 (1H, d, J = 8.6 Hz), 7.18 (1H, dd, J = 10.2
Hz, 2.1 Hz), 7.24-7.42 (5H, m), 7.64 (1H, d, J = 10.2 Hz), 7.69 (1H, d, J = 2.0
Hz), 8.17 (1H, s), 8.19 (1.6H, s).
Example 163
1-(5-tert-Butyl{3-[2-(ethyl-methyl-amino)-ethoxy]-phenyl}-2H-
pyrazolyl){(1S,4R)[3-((S)methyl-piperidinyl)-
[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-
urea formate salt
A solution of Intermediate 154a (50.5 mg, 66 µmol) and N-
ethylmethylamine (40 mg, 0.68 mmol) in THF (1 mL) was heated at 60°C for
48 h in a sealed vessel. The reaction mixture was concentrated in vacuo and
the residue purified by MDAP (Method 7) to give the title compound as a
white solid (24 mg, 50%). LCMS (Method 5): Rt 3.69 min, m/z 720 [MH ]. ¹H
NMR (400 MHz, d -DMSO): 0.91 (3H, d, J = 6.3 Hz), 0.94 (3H, t, J = 7.2 Hz),
1.27 (9H, s), 1.46-1.55 (2H, m), 1.64-1.72 (2H, m), 1.76-2.09 (6H, m), 2.19
(3H, s), 2.41 (2H, quart, J = 7.0 Hz), 2.68 (2H, t, J = 4.7 Hz), 2.86-2.94 (1H,
m), 3.12-3.19 (1H, m), 3.29-3.34 (1H, m, obscured by water peak), 4.08 (2H,
t, J = 6.1 Hz), 4.77-4.86 (1H, m), 5.52 (1H, t, J = 4.4 Hz), 6.33 (1H, s), 6.94-
6.98 (1H, m), 7.05-7.13 (3H, m), 7.19 (1H, dd, J = 9.6 Hz, 2.2 Hz), 7.23-7.42
(5H, m), 7.64 (1H, d, J = 10.2 Hz), 7.69 (1H, d, J = 2.2 Hz), 8.13 (1H, s), 8.18
(1H, s).
Example 164
O H O
1-{5-tert-Butyl(3-{2-[(2-methoxy-ethyl)-methyl-amino]-ethoxy}-
phenyl}-2H-pyrazolyl}{(1S,4R)[3-((S)methyl-piperidinyl)-
[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-
urea formate salt
A solution of Intermediate 154a (50.5 mg, 0.067 mmol) and N-(2-
methoxyethyl)methylamine (35 µL, 0.33 mmol) in THF (1 mL) was stirred at 60°C
for 20 h in a sealed tube. Additional N-(2-methoxyethyl)methylamine (35 µL, 0.33
mmol) was added and the mixture subsequently stirred at 60°C in a sealed tube for
24 h. The mixture was concentrated in vacuo and the residue purified by MDAP
(Method 7). The title product was isolated as an off-white solid (24 mg, 48%).
LCMS (Method 5): Rt 3.72 min, m/z 750.6 [MH ]. ¹H NMR (400 MHz, d6-
DMSO): 0.91 (3H, d, J = 8.0 Hz), 1.27 (9H, s), 1.44-1.56 (2H, m), 1.61-1.73 (2H,
m), 1.73-1.98 (4H, m), 1.98-2.22 (2H, m), 2.24 (3H, s), 2.55 (2H, t, J = 8.0 Hz),
2.74 (2H, t, J = 8.0 Hz), 2.86-2.95 (1H, m), 3.12-3.18 (1H, m, obscured by water),
3.19 (3H, s, obscured by water), ~3.30 (1H, m, obscured by water), 3.38 (2H, t, J =
8.0 Hz, obscured by water), 4.07 (2H, t, J = 8.0 Hz), 4.78-4.86 (1H, m), 5.52 (1H,
t, J = 4.0 Hz), 6.33 (1H, s), 6.94-6.99 (1H, m), 7.05-7.14 (3H, m), 7.19 (1H, dd, J =
8.0 Hz, 4.0 Hz), 7.24-7.42 (5H, m), 7.64 (1H, d, J = 8.0 Hz), 7.69 (1H, d, J = 4.0
Hz), 8.13 (1H, s), 8.19 (1H, s).
Example 165
O OH
1-(5-tert-Butyl{3-[2-(4-methoxy-piperidinyl-ethoxy]-phenyl}-
2H-pyrazolyl){(1S,4R)[3-((S)methyl-piperidinyl)-
[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-
urea formate salt
A solution of Intermediate 154a (50.5 mg, 0.066 mmol) and 4-
methoxypiperidine (39 mL, 0.34 mmol) in THF (1 mL) was heated at 60°C
overnight in a sealed vessel. The reaction mixture was concentrated in vacuo
and the residue purified by MDAP (Method 7) to give a white solid of the title
compound (31 mg, 60%). LCMS (Method 5): Rt 3.75 min, m/z 776 [MH ]. ¹H
NMR (400 MHz, d -DMSO): 0.91 (3H, d, J = 6.2 Hz), 1.27 (9H, s), 1.30-1.42
(2H, m), 1.45-1.57 (2H, m), 1.61-2.18 (13H, m), 2.66 (2H, t, J = 5.7 Hz), 2.68-
2.76 (1H, m), 2.86-2.95 (1H, m), 3.04-3.19 (2H, m), 3.16 (3H, s), 3.28-3.34
(1H, m), 4.09 (2H, t, J = 5.9 Hz), 4.77-4.85 (1H, m), 5.52 (1H, t, J = 4.3 Hz),
6.33 (1H, s), 6.93-6.98 (1H, m), 7.04-7.13 (3H, m), 7.18 (1H, dd, J = 10.3 Hz,
2.3 Hz), 7.24-7.42 (5H, m), 7.64 (1H, d, J = 9.5 Hz), 7.69 (1H, d, J = 2.3 Hz),
8.12 (1H, s), 8.16 (1.7H, s).
Example 166
1-(5-tert-Butyl{3-[2-(3-oxaaza-bicyclo[3.2.1]octyl)-ethoxy]-
phenyl}-2H-pyrazolyl){(1S,4R)[3-((S)methyl-piperidinyl)-
[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-
urea formate salt
A solution of Intermediate 154a (50.5 mg, 66 µmol) and 3-oxaaza-
bicyclo[3.2.1]octane (76 mg, 0.68 mmol) in THF (1 mL) was heated at 60°C
for 48 h in a sealed vessel. The reaction mixture was concentrated in vacuo
and the residue purified by MDAP (Method 7) to give the title compound as a
white solid (24 mg, 46%). LCMS (Method 5): Rt 3.72 min, m/z 774 [MH ]. ¹H
NMR (400 MHz, d -DMSO): 0.91 (3H, d, J = 6.3 Hz), 1.28 (9H, s), 1.46-1.54
(2H, m), 1.64-1.71 (4H, m), 1.75-2.17 (8H, m), 2.59 (2H, t, J = 5.9 Hz), 2.86-
2.95 (1H, m), 3.07-3.11 (2H, m), 3.12-3.19 (1H, m), 3.28-3.34 (3H, m,
obscured by water peak), 3.49 (2H, d, J = 9.6 Hz), 4.09 (2H, t, J = 6.3 Hz),
4.78-4.85 (1H, m), 5.52 (1H, t, J = 4.3 Hz), 6.33 (1H, s), 6.94-6.99 (1H, m),
7.05-7.14 (3H, m), 7.19 (1H, dd, J = 9.6 Hz, 2.4 Hz), 7.24-7.42 (5H, m), 7.64
(1H, d, J = 10.0 Hz), 7.69 (1H, d, J = 2.2 Hz), 8.15 (1H, s), 8.20 (1H, s).
Example 167
1-{5-tert-Butyl[3-(4-methoxy-piperidinylmethyl)-phenyl]-2H-
pyrazolyl}{(1S,4R)[3-((S)methyl-piperidinyl)-[1,2,4]triazolo[4,3-
a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea formate salt
a. 1-[5-tert-Butyl(3-hydroxymethyl-phenyl)-2H-pyrazolyl]
{(1S,4R)[3-((S)methyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridin
yloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea (Intermediate 167a)
A mixture of Intermediate 81d (319 mg, 0.85 mmol), Intermediate 29c (335
mg, 0.85 mmol) and DIPEA (294 µL, 1.69 mmol) in dioxane (10 mL) was stirred
at 80°C for 18 hours. After cooling, the reaction mixture was partitioned between
water and DCM. The aqueous phase was extracted with EtOAc (x 3) and the
combined organic layers were washed with brine, dried (MgSO ) and concentrated
in vacuo. The resulting residue was purified by FCC on silica, using a gradient of
0-10% MeOH in DCM, to afford the title compound (362 mg, 66%). LCMS
(Method 4): Rt 3.29 min, m/z 649 [MH ].
b. Methanesulfonic acid 3-[3-tert-butyl(3-{(1S,4R)[3-((S)
methyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-ureido)-pyrazolyl]-benzyl ester (Intermediate
167b)
To an ice-bath cooled solution of Intermediate 167a (316 mg, 0.49 mmol) in
DCM (5.0 mL) was added DIPEA (339 µL, 1.95 mmol) followed by
methanesulfonyl chloride (76 µL, 0.97 mmol). The reaction mixture was stirred for
3 h and then quenched with water. The aqueous phase was extracted with DCM (x
3) and the combined organic layers were washed with brine, dried (MgSO ) and
concentrated in vacuo to afford the title compound (Quantitative, assumed 0.49
mmol). The isolated product was used in the following step without further
purification. LCMS (Method 4): Rt 3.61 min, m/z 727 [MH ].
c. 1-{5-tert-Butyl[3-(4-methoxy-piperidinylmethyl)-phenyl]-2H-
pyrazolyl}{(1S,4R)[3-((S)methyl-piperidinyl)-[1,2,4]triazolo[4,3-
a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea formate salt
(Example 167)
To a solution of Intermediate 167b (0.19 mmol) in THF (2 mL) was added
DIPEA (130 µL, 0.75 mmol) and 4-methoxypiperidine (86 mg, 0.75 mmol) and
the reaction stirred at 50°C for 24 h. The crude reaction mixture was cooled and
partitioned between EtOAc and water. The aqueous phase was extracted with
EtOAc (x 3) and the combined organic layers were washed with brine, dried
(MgSO ) and concentrated in vacuo. The resulting residue was purified by FCC on
silica, using a gradient of 0-10% [2M NH in MeOH] in DCM, followed by
MDAP (Method 7) purification, to give the title compound (20 mg, 14%). LCMS
(Method 5): Rt 3.66 min, m/z 746 [MH ]. ¹H NMR (400 MHz, d -DMSO): 0.86
(3H, d, J = 6.2 Hz), 1.23 (9H, s), 1.30-1.40 (2H, m), 1.42-1.50 (2H, m), 1.58-1.67
(2H, m), 1.70-1.83 (5H, m), 1.83-1.93 (1H, m), 1.96-2.12 (4H, m), 2.56-2.64 (2H,
m), 2.86 (1H, ddd, J = 12.7, 9.0, 3.9 Hz), 3.05-3.12 (3H, m), 3.13 (3H, s), 3.45
(2H, s), 4.77 (1H, td, J = 8.4, 5.7 Hz), 5.47 (1H, t, J = 4.2 Hz), 6.28 (1H, s), 7.00
(1H, d, J = 8.6 Hz), 7.14 (1H, dd, J = 9.8, 2.1 Hz), 7.20-7.30 (4H, m), 7.30-7.37
(3H, m), 7.40 (1H, t, J = 7.7 Hz), 7.59 (1H, d, J = 10.0 Hz), 7.64 (1H, d, J = 1.8
Hz), 8.07 (1H, s), 8.23 (0.3H, s).
Example 168
1-[5-tert-Butyl(3-{[(2-methoxy-ethyl)-methyl-amino]-methyl}-
phenyl)-2H-pyrazolyl]{(1S,4R)[3-((S)methyl-piperidinyl)-
[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-
urea formate salt
To a solution of Intermediate 167b (0.19 mmol) in THF (2 mL) was added
DIPEA (130 µL, 0.75 mmol) and N-(methoxyethyl)methylamine (81 µL, 0.75
mmol) and the reaction stirred at 50°C for 24 h. The crude reaction mixture was
cooled and partitioned between EtOAc and water. The aqueous phase was
extracted with EtOAc (x 3) and the combined organic layers were washed with
brine, dried (MgSO ) and concentrated in vacuo. The resultant residue was purified
by FCC on silica, using a gradient of 0-10% [2M NH in MeOH] in DCM,
followed by MDAP (Method 7) purification, to give the title compound (20 mg,
14%). LCMS (Method 5): Rt 3.65 min, m/z 720 [MH ]. ¹H NMR (400 MHz, d -
DMSO): 0.86 (3H, d, J = 6.2 Hz), 1.23 (9H, s), 1.42-1.48 (2H, m), 1.58-1.67 (2H,
m), 1.72-1.92 (4H, m), 1.96-2.12 (2H, m), 2.12 (3H, s), 2.49 (2H, t, J = 6.0 Hz),
2.86 (1H, ddd, J = 12.7, 9.0, 3.9 Hz), 3.12 (1H, dt, J = 12.1, 4.3 Hz), 3.16 (3H, s),
3.39 (2H, t, J = 6.0 Hz), 3.50 (2H, s), 4.77 (1H, td, J = 8.4, 5.7 Hz), 5.47 (1H, t, J =
4.2 Hz), 6.28 (1H, s), 7.02 (1H, d, J = 8.6 Hz), 7.14 (1H, dd, J = 9.8, 2.1 Hz), 7.20-
7.25 (2H, m), 7.25-7.30 (2H, m), 7.30-7.35 (2H, m), 7.38 (1H, s), 7.40 (1H, t, J =
7.7 Hz), 7.59 (1H, d, J = 10.0 Hz), 7.64 (1H, d, J = 1.8 Hz), 8.07 (1H, s), 8.28
(0.2H, s).
Example 169
1-{5-tert-Butyl[3-(4-fluoro-piperidinylmethyl)-phenyl]-2H-
pyrazolyl}{(1S,4R)[3-((S)methyl-piperidinyl)-[1,2,4]triazolo[4,3-
a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea formate salt
To a solution of Intermediate 167b (0.19 mmol) in THF (2 mL) was added
DIPEA (260 µL, 1.5 mmol) and 4-fluoropiperidine hydrochloride (104 mg, 0.75
mmol) and the reaction stirred at 50°C for 24 h. The crude reaction mixture was
cooled and partitioned between EtOAc and water. The aqueous phase was
extracted with EtOAc (x 3) and the combined organic layers were washed with
brine, dried (MgSO ) and concentrated in vacuo. The resulting residue was
purified by FCC on silica, using a gradient of 0-10% [2M NH in MeOH] in DCM,
followed by MDAP (Method 7) purification, to give the title compound (25 mg,
16%). LCMS (Method 5): Rt 3.68 min, m/z 734 [MH ]. ¹H NMR (400 MHz, d -
DMSO): 0.86 (3H, d, J = 6.2 Hz), 1.23 (9H, s), 1.42-1.50 (2H, m), 1.58-1.70 (4H,
m), 1.70-1.92 (6H, m), 1.95-2.12 (2H, m), 2.23-2.31 (2H, m), 2.86 (1H, ddd, J =
12.7, 9.0, 3.9 Hz), 3.11 (1H, dt, J = 12.2, 4.3 Hz), 3.24-3.30 (2H, m), 3.48 (2H, s),
4.60 (1H, dsp, J = 48.9, 3.5 Hz), 4.77 (1H, td, J = 8.4, 5.7 Hz), 5.47 (1H, t, J = 4.2
Hz), 6.28 (1H, s), 6.98 (1H, d, J = 8.6 Hz), 7.14 (1H, dd, J = 9.8, 2.1 Hz), 7.20-
7.25 (2H, m), 7.25-7.34 (3H, m), 7.35-7.38 (2H, m), 7.40 (1H, t, J = 7.7 Hz), 7.59
(1H, d, J = 10.0 Hz), 7.62 (1H, d, J = 1.8 Hz), 8.05 (1H, s), 8.10 (1.8H, s).
Example 170
1-[5-tert-Butyl(3-dimethylaminomethyl-phenyl)-2H-pyrazolyl]
{(1S,4R)[3-((S)methyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridin
yloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea formate salt
To a solution of Intermediate 167b (0.16 mmol) in THF (2.5 mL) was added
dimethylamine solution (2M THF, 1.6 mL, 3.27 mmol) and the reaction stirred at
50°C for 24 h in a sealed vessel. The crude reaction mixture was cooled and
partitioned between EtOAc and water. The aqueous phase was extracted with
EtOAc (x 3) and the combined organic layers were washed with brine, dried
(MgSO ) and concentrated in vacuo. The resulting residue was purified by FCC on
silica, using a gradient of 0-10% [2M NH in MeOH] in DCM, followed by
MDAP (Method 7) purification, to give the title compound (20 mg, 16%). LCMS
(Method 5): Rt 3.58 min, m/z 676 [MH ]. ¹H NMR (400 MHz, d -DMSO): 0.86
(3H, d, J = 6.2 Hz), 1.23 (9H, s), 1.42-1.50 (2H, m), 1.58-1.67 (2H, m), 1.70-1.90
(4H, m), 1.94-2.03 (1H, m), 2.04-2.12 (2H, m), 2.11 (6H, s), 2.86 (1H, ddd, J =
12.7, 9.0, 3.9 Hz), 3.12 (1H, dt, J = 11.9, 4.1 Hz), 3.39 (2H, s), 4.77 (1H, td, J =
8.4, 5.7 Hz), 5.46 (1H, t, J = 4.2 Hz), 6.27 (1H, s), 7.02 (1H, d, J = 8.6 Hz), 7.15
(1H, dd, J = 9.8, 2.1 Hz), 7.20-7.29 (4H, m), 7.29-7.34 (1H, m), 7.35-7.41 (3H, m),
7.59 (1H, d, J = 10.0 Hz), 7.64 (1H, d, J = 1.8 Hz), 8.07 (1H, s), 8.25 (0.3H, s).
Example 171
1-[5-tert-Butyl(3-pyrrolidinylmethyl-phenyl)-2H-pyrazolyl]
{(1S,4R)[3-((S)methyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridin
yloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea formate salt
To a solution of Intermediate 167b (0.16 mmol) in THF (2 mL) was added
pyrrolidine (273 µL, 3.27 mmol) and the reaction stirred at 50°C for 24 h. The
crude reaction mixture was cooled and partitioned between EtOAc and water. The
aqueous phase was extracted with EtOAc (x 3) and the combined organic layers
were washed with brine, dried (MgSO ) and concentrated in vacuo. The resultant
residue was purified by FCC on silica, using a gradient of 0-10% [2M NH in
MeOH] in DCM, followed by MDAP (Method 7) purification, to give the title
compound (26 mg, 22%). LCMS (Method 5): Rt 3.64 min, m/z 702 [MH ]. ¹H
NMR (400 MHz, d -DMSO): 0.86 (3H, d, J = 6.2 Hz), 1.23 (9H, s), 1.42-1.50 (2H,
m), 1.58-1.66 (6H, m), 1.70-1.84 (3H, m), 1.84-1.92 (1H, m), 1.95-2.12 (2H, m),
2.36-2.42 (4H, m), 2.86 (1H, ddd, J = 12.7, 9.0, 3.9 Hz), 3.12 (1H, dt, J = 11.9, 4.1
Hz), 3.58 (2H, s), 4.77 (1H, td, J = 8.4, 5.7 Hz), 5.46 (1H, t, J = 4.2 Hz), 6.28 (1H,
s), 7.01 (1H, d, J = 8.6 Hz), 7.15 (1H, dd, J = 9.8, 2.1 Hz), 7.20-7.25 (2H, m), 7.26-
7.34 (4H, m), 7.35 (1H, s), 7.39 (1H, t, J = 7.8 Hz), 7.59 (1H, d, J = 10.0 Hz), 7.64
(1H, d, J = 1.8 Hz), 8.07 (1H, s), 8.19 (0.7H, s).
Example 172
1-{(1S,4R)[3-(4-Aza-spiro[2.5]octyl)-[1,2,4]triazolo[4,3-a]pyridin-
6-yloxy]-1,2,3,4-tetrahydro-naphthalenyl}{5-tert-butyl[3-(2-
morpholinyl-ethoxy)-phenyl]-2H-pyrazolyl}-urea formate salt
A brown solution of Intermediate 148g (0.099 mmol) and morpholine (43
mg, 0.50 mmol) in THF (1 mL) was stirred in a sealed vial at 60°C for 18 h. The
solution was decanted and concentrated. MDAP (Method 7) gave the title
compound as an off-white solid (44 mg, 54%). LCMS (Method 5): Rt 3.64 min,
m/z 760.6 [MH ]. ¹H NMR (400 MHz, d -DMSO): 0.41-0.54 (4H, m), 1.27 (9H, s),
1.52-1.62 (2H, m), 1.72-1.81 (3H, m), 1.83-1.96 (3H, m), 1.99-2.15 (2H, m), 2.42 (4H, t,
J = 4.4 Hz), 2.66 (2H, t, J = 5.7 Hz), 3.22-3.29 (2H, m), 3.52 (4H, t, J = 4.58 Hz), 4.11
(2H, t, J = 5.7 Hz), 4.81 (1H, td, J = 8.6, 5.5 Hz), 5.48 (1H, t, J = 4.3 Hz), 6.33 (1H, s),
6.95-6.98 (1H, m), 7.06-7.12 (3H, m), 7.14 (1H, dd, J = 9.9, 2.2 Hz), 7.25-7.42 (5H, m),
7.57 (1H, dd, J = 2.1, 0.9 Hz), 7.61 (1H, dd, J = 9.8, 0.8 Hz), 8.11 (1H, s), 8.16 (1.3H, s).
Example 173
N OH
1-[5-tert-Butyl(3-piperidinylmethyl-phenyl)-2H-pyrazolyl]
{(1S,4R)[3-((S)methyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridin
yloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea formate salt
To a solution of Intermediate 167b (0.22 mmol) in THF (2.5 mL) was added
piperidine (424 µL, 4.3 mmol) and the reaction stirred at 50°C for 24 h. The crude
reaction mixture was cooled and partitioned between EtOAc and water. The
aqueous phase was extracted with EtOAc (x 3) and the combined organic layers
were washed with brine, dried (MgSO ) and concentrated in vacuo. The resultant
residue was purified by FCC on silica, using a gradient of 0-10% [2M NH in
MeOH] in DCM, followed by MDAP (Method 7) purification, to give the title
compound (44 mg, 25%). LCMS (Method 5): Rt 3.69 min, m/z 716 [MH ]. ¹H
NMR (400 MHz, d -DMSO): 0.86 (3H, d, J = 6.2 Hz), 1.23 (9H, s), 1.28-1.33 (2H,
m), 1.38-1.48 (6H, m), 1.58-1.66 (2H, m), 1.70-1.92 (4H, m), 1.95-2.12 (2H, m),
2.26-2.34 (4H, m), 2.86 (1H, ddd, J = 12.7, 9.0, 3.9 Hz), 3.11 (1H, dt, J = 11.9, 4.1
Hz), 3.23-3.29 (1H, m), 3.44 (2H, s), 4.77 (1H, td, J = 8.4, 5.7 Hz), 5.46 (1H, t, J =
4.2 Hz), 6.28 (1H, s), 6.99 (1H, d, J = 8.6 Hz), 7.15 (1H, dd, J = 9.8, 2.1 Hz), 7.20-
7.25 (2H, m), 7.25-7.29 (2H, m), 7.29-7.36 (3H, m), 7.39 (1H, t, J = 7.8 Hz), 7.59
(1H, d, J = 10.0 Hz), 7.64 (1H, d, J = 1.8 Hz), 8.06 (1H, s), 8.12 (1.8H, s).
Example 174
N OH
1-{5-tert-Butyl[3-(4-methyl-[1,4]diazepanylmethyl)-phenyl]-2H-
pyrazolyl}{(1S,4R)[3-((S)methyl-piperidinyl)-[1,2,4]triazolo[4,3-
a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea formate salt
To a solution of Intermediate 167b (0.22 mmol) in THF (2.5 mL) was added
1-methylhomopiperazine (534 µL, 4.3 mmol) and the reaction stirred at 50°C for
24 h. The crude reaction mixture was cooled and partitioned between EtOAc and
water. The aqueous phase was extracted with EtOAc (x 3) and the combined
organic layers were washed with brine, dried (MgSO ) and concentrated in vacuo.
The resultant residue was purified by FCC on silica, using a gradient of 0-10%
[2M NH in MeOH] in DCM, followed by MDAP (Method 7) purification, to give
the title compound (28 mg, 15%). LCMS (Method 5): Rt 3.27 min, m/z 745
[MH ]. ¹H NMR (400 MHz, d -DMSO): 0.86 (3H, d, J = 6.2 Hz), 1.23 (9H, s),
1.42-1.50 (2H, m), 1.58-1.66 (2H, m), 1.68-1.84 (5H, m), 1.84-1.92 (1H, m), 1.95-
2.05 (1H, m), 2.05-2.12 (1H, m), 2.32 (3H, s), 2.58-2.66 (6H, m), 2.69 (2H, t, J =
.7 Hz), 2.86 (1H, ddd, J = 12.7, 9.0, 3.9 Hz), 3.11 (1H, dt, J = 11.9, 4.1 Hz), 3.23-
3.29 (1H, m), 3.62 (2H, s), 4.77 (1H, td, J = 8.4, 5.7 Hz), 5.47 (1H, t, J = 4.2 Hz),
6.28 (1H, s), 7.04 (1H, d, J = 8.6 Hz), 7.14 (1H, dd, J = 9.8, 2.1 Hz), 7.20-7.25
(2H, m), 7.26-7.36 (4H, m), 7.38-7.43 (2H, m), 7.59 (1H, d, J = 10.0 Hz), 7.64
(1H, d, J = 1.8 Hz), 8.12 (1H, s), 8.16 (2.4H, s).
Example 175
1-{5-tert-Butyl[3-((1S,4S)methyl-2,5-diaza-bicyclo[2.2.1]hept
ylmethyl)-phenyl]-2H-pyrazolyl}{(1S,4R)[3-((S)methyl-piperidin
yl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-
urea formate salt
To a solution of Intermediate 167b (0.15 mmol) in THF (20 mL) was added
(1S,4S)methyl-2,5-diaza-bicyclo[2.2.1]heptane (366 mg, 3.3 mmol) and the
reaction stirred at 50°C for 24 h. The crude reaction mixture was cooled and
partitioned between EtOAc and water. The aqueous phase was extracted with
EtOAc (x 3) and the combined organic layers were washed with brine, dried
(MgSO ) and concentrated in vacuo. The resultant residue was purified by FCC on
silica, using a gradient of 0-10% [2M NH in MeOH] in DCM, then further
purified by HPLC (C18 X-select column, 10-75% MeCN in H O, 0.1% formic
acid) to give the title compound (11 mg, 9%). LCMS (Method 5): Rt 3.45 min,
m/z 743 [MH ]. ¹H NMR (400 MHz, d -DMSO): 0.86 (3H, d, J = 6.2 Hz), 1.23
(9H, s), 1.42-1.50 (2H, m), 1.54-1.66 (4H, m), 1.72-1.84 (3H, m), 1.84-1.92 (1H,
m), 1.95-2.15 (2H, m), 2.22 (3H, s), 2.46-2.48 (1H, m), 2.52 (1H, dd, J = 9.6, 2.4
Hz), 2.59 (1H, d, J = 9.7 Hz), 2.71 (1H, d, J = 9.6 Hz), 2.86 (1H, ddd, J = 12.7, 9.0,
3.9 Hz), 3.09-3.13 (2H, m), 3.22 (1H, s), 3.28-3.32 (1H, m), 3.63 (1H, d, J = 13.9
Hz), 3.70 (1H, d, J = 13.9 Hz), 4.77 (1H, td, J = 8.4, 5.7 Hz), 5.47 (1H, t, J = 4.2
Hz), 6.28 (1H, s), 7.04 (1H, d, J = 8.6 Hz), 7.14 (1H, dd, J = 9.8, 2.1 Hz), 7.20-
7.25 (2H, m), 7.26-7.36 (4H, m), 7.36-7.41 (2H, m), 7.59 (1H, d, J = 10.0 Hz),
7.64 (1H, d, J = 1.8 Hz), 8.11 (1H, s), 8.25 (0.7H, s).
Example 176
1-[5-tert-Butyl(4-morpholinylmethyl-phenyl)-2H-pyrazolyl]
{(1S,4R)[3-((S)methyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridin
yloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea
a. 1-[5-tert-Butyl(4-hydroxymethyl-phenyl)-2H-pyrazolyl]
{(1S,4R)[3-((S)methyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridin
yloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea dichloromethane solvate
(Intermediate 176a)
Cl Cl
A red-brown solution of Intermediate 33a (883 mg, 2.10 mmol),
Intermediate 81d (755 mg, 2.00 mmol) and DIPEA (0.44 mL, 2.5 mmol) in dry
dioxane (20 mL) was stirred at 70°C for 16 h, and at 80°C for 5 h. The cooled
solution was concentrated in vacuo, suspended in water (15 mL) and extracted
with DCM (2 × 15 mL). The combined organics were passed through a
hydrophobic frit and concentrated in vacuo to leave a brown oil. Flash
chromatography (silica 80 g, 4-8% MeOH in DCM) gave the title compound as a
pale yellow foam (1.27 g, 87%). LCMS (Method 3): Rt 3.61 min, m/z 649 [MH ].
b. 1-[5-tert-Butyl(4-formyl-phenyl)-2H-pyrazolyl]{(1S,4R)[3-
((S)methyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-urea (Intermediate 176b)
To a solution of Intermediate 176a (1.10 g, 1.70 mmol) in DCM (25 mL) at
0°C was added Dess-Martin periodinane (791 mg, 1.86 mmol) and the resulting
red-brown solution stirred at 0°C for 45 min. Sodium metabisulfite (920 mg),
water (10 mL) and sat. aq. NaHCO solution (10 mL) were added and the mixture
stirred at RT until gas evolution ceased (15 min). The mixture was diluted with
water (25 mL) and extracted with DCM (2 × 25 mL). The combined organics were
passed through a hydrophobic frit and concentrated in vacuo to leave the title
compound as a glassy orange solid (1.10 g, 100%). LCMS (Method 3): Rt 3.91
min, m/z 647 [MH ].
c. 1-[5-tert-Butyl(4-morpholinylmethyl-phenyl)-2H-pyrazolyl]-
3-{(1S,4R)[3-((S)methyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridin
yloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea (Example 176)
To a solution of Intermediate 176b (0.10 mmol) and morpholine (17.4 mg,
0.200 mmol) in DCM (3 mL) was added sodium triacetoxyborohydride (31.8 mg,
0.15 mmol) and the resulting yellow solution stirred at RT for 1 h. Water (3 mL)
was added and the mixture shaken. The aqueous was extracted with DCM (3 mL),
then the combined organics passed through a hydrophobic frit and concentrated in
vacuo to leave a vivid yellow gum. Flash chromatography (silica 12g, 3.5-4.5%
[2M NH3 in MeOH] in DCM) gave a vivid yellow gum (70 mg). Prep HPLC
(Gemini C18, 25-75% MeCN in water, 0.1% HCO H, 20 min) and concentration
of the desired fractions removed the MeCN. The aqueous was extracted with DCM
(3 × 15 mL), then the combined organics passed through a hydrophobic frit and
concentrated in vacuo to leave a glassy orange solid (43.7 mg). Prep HPLC
(Gemini C18, 25-50% MeCN in water, 20 min) and concentration of the desired
fractions removed the MeCN. The aqueous was extracted with DCM (3 × 5 mL),
then the combined organics passed through a hydrophobic frit and concentrated in
vacuo to leave the title compound as a white solid (25.4 mg, 35%). LCMS (Method
5): Rt 3.61 min, m/z 718.6 [MH ]. ¹H NMR (400 MHz, d -DMSO): 0.91 (3H, d, J
= 6.3 Hz), 1.27 (9H, s), 1.47-1.55 (2H, m), 1.63-1.71 (2H, m), 1.76-1.95 (4H, m),
2.00-2.16 (2H, m), 2.37 (4H, t, J = 4.3 Hz), 2.90 (1H, ddd, J = 12.1, 9.0, 3.9 Hz),
3.16 (1H, dt, J = 12.2, 4.3 Hz), 3.29-3.34 (1H, m, obscured by water signal), 3.50
(2H, s), 3.56 (4H, t, J = 4.5 Hz), 4.81 (1H, td, J = 8.6, 5.6 Hz), 5.51 (1H, t, J = 4.3
Hz), 6.34 (1H, s), 7.09 (1H, d, J = 8.6 Hz), 7.19 (1H, dd, J = 9.9, 2.2 Hz), 7.25-
7.37 (4H, m), 7.43 (2H, d, J = 8.7 Hz), 7.45 (2H, d, J = 8.7 Hz), 7.64 (1H, dd, J =
9.8, 0.8 Hz), 7.69 (1H, dd, J = 2.2, 0.9 Hz), 8.08 (1H, s).
Example 177
1-[5-tert-Butyl(4-dimethylaminomethyl-phenyl)-2H-pyrazolyl]
{(1S,4R)[3-((S)methyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridin
yloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea partial formate salt
To an orange solution of Intermediate 176b (0.188 mmol) and
dimethylamine solution (2M in THF, 0.19 mL, 0.38 mmol) in DCM (3 mL) was
added sodium triacetoxyborohydride (60 mg, 0.28 mmol) and the mixture stirred at
RT for 1 h. Water (3 mL) was added and the mixture shaken. The aqueous was
extracted with DCM (3 mL) then the combined organics passed through a
hydrophobic frit and concentrated in vacuo to leave a brown gum. Flash
chromatography (silica 12 g, 4-6.5% [2M NH in MeOH] in DCM) gave a yellow
solid (88 mg). Prep HPLC (Gemini C18, 25-50% MeCN in water, 0.1% HCO H,
min) and concentration in vacuo of the relevant fractions gave a pale yellow
film. Trituration with diethyl ether gave the title compound as on off-white solid
(48.4 mg, 36%). LCMS (Method 3): Rt 2.99 min, m/z 676 [MH ]. ¹H NMR (400
MHz, d -DMSO): 0.91 (3H, d, J = 6.3 Hz), 1.27 (9H, s), 1.45-1.56 (2H, m), 1.62-
1.71 (2H, m), 1.75-1.96 (4H, m), 2.00-2.15 (2H, m), 2.17 (6H, s), 2.90 (1H, dd, J =
12.3, 9.1, 3.9), 3.16 (1H, dt, J = 12.3, 4.3 Hz), 3.28-3.34 (1H, m obscured by water
peak), 3.44 (2H, s), 4.82 (1H, td, J = 8.6, 5.7 Hz), 5.51 (1H, t, J = 4.3 Hz), 6.34 (1
H, s), 7.10 (1H, d, J = 8.6 Hz), 7.19 (1 H, dd, J = 9.8, 2.2 Hz), 7.25-7.47 (8H, m),
7.64 (1H, dd, J = 9.8, 0.8 Hz), 7.69 (1H, dd, J = 2.2, 0.9 Hz), 8.10 (1H, s), 8.16
(0.7H, s).
Example 178
1-{5-tert-Butyl[4-(4-methyl-piperazinylmethyl)-phenyl]-2H-
pyrazolyl}{(1S,4R)[3-((S)methyl-piperidinyl)-[1,2,4]triazolo[4,3-
a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea partial formate
salt
To an orange solution of Intermediate 176b (0.188 mmol) and N-methyl
piperazine (38 mg, 0.38 mmol) in DCM (3 mL) was added sodium
triacetoxyborohydride (60 mg, 0.28 mmol) and the mixture stirred at RT for 1 h.
Water (3 mL) was added and the mixture shaken. The aqueous was extracted with
DCM (3 mL) then the combined organics passed through a hydrophobic frit and
concentrated in vacuo to leave a brown gum. Flash chromatography (silica 12 g, 5-
8% [2M NH in MeOH] in DCM) gave a yellow solid (47 mg). Prep HPLC
(Gemini C18, 25-50% MeCN in water, 0.1% HCO H, 20 min) and concentration
in vacuo of the relevant fractions gave a pale yellow film. Trituration with diethyl
ether gave the title compound as on off-white solid (20.6 mg, 14%). LCMS
(Method 3): Rt 2.98 min, m/z 731 [MH ]. ¹H NMR (400 MHz, d -DMSO): 0.91
(3H, d, J = 6.3 Hz), 1.27 (9H, s), 1.45-1.56 (2H, m), 1.62-1.71 (2H, m), 1.75-1.95
(4H, m), 1.99-2.16 (2H, m), 2.14 (3H, s), 2.26-2.45 (8H, m), 2.90 (1H, ddd, J =
12.2, 9.0, 4.0 Hz), 3.16 (1H, dt, J = 12.2, 4.2 Hz), 3.28-3.34 (1H, m, obscured by
water signal), 3.49 (2H, s), 4.81 (1H, td, J = 8.6, 5.6 Hz), 5.51 (1H, t, J = 4.3 Hz),
6.33 (1H, s), 7.10 (1H, d, J = 8.6 Hz), 7.20 (1H, dd, J = 9.9, 2.1 Hz), 7.25-7.47
(8H, m), 7.64 (1H, dd, J = 9.8, 0.8 Hz), 7.69 (1H, dd, J = 2.2, 0.9 Hz), 8.10 (1H, s),
8.17 (0.6H, s).
Example 179
1-{5-tert-Butyl[4-(4-methyl-[1,4]diazepanylmethyl)-phenyl]-2H-
pyrazolyl}{(1S,4R)[3-((S)methyl-piperidinyl)-[1,2,4]triazolo[4,3-
a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea
To an orange solution of Intermediate 176b (0.188 mmol) and N-methyl
homopiperazine (43 mg, 0.38 mmol) in DCM (3 mL) was added sodium
triacetoxyborohydride (60 mg, 0.28 mmol) and the mixture stirred at RT for 1 h.
Water (3 mL) was added and the mixture shaken. The aqueous was extracted with
DCM (3 mL) then the combined organics passed through a hydrophobic frit and
concentrated in vacuo to leave a brown gum. Flash chromatography (silica 12 g, 7-
11% [2M NH in MeOH] in DCM) gave the title compound as a yellow solid (102
mg, 73%). LCMS (Method 3): Rt 2.84 min, m/z 745 [MH ]. ¹H NMR (300 MHz,
CDCl ): 0.91 (3H, d, J = 6.2 Hz), 1.34 (9H, s), 1.40-1.55 (2H, m), 1.62-1.99 (7H,
m), 2.15-2.02-2.14 (2H, m), 2.21-2.30 (1H, m), 2.33 (3H, s), 2.55-2.69 (8H, m),
2.90 (1H, ddd, J = 12.1, 9.3, 4.1), 3.04 (1H, dt, J = 12.1, 4.2 Hz), 3.23-3.32 (1H,
m), 3.58 (2H, s), 5.09 (1H, td, J = 8.9, 5.2 Hz), 5.19 (1H, t, J = 3.9 Hz), 6.04 (1 H,
br d, J = 8.6 Hz), 6.33 (1 H, s), 6.94 (1H, dd, J = 9.9, 2.1 Hz), 7.22 (1H, br s), 7.25-
7.39 (7H, m), 7.43 (1H, d, J = 2.2 Hz), 7.47 (2H, m).
Example 180
1-{5-tert-Butyl[4-(4-methoxy-piperidinylmethyl)-phenyl]-2H-
pyrazolyl}{(1S,4R)[3-((S)methyl-piperidinyl)-[1,2,4]triazolo[4,3-
a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea partial formate
salt
To an orange solution of Intermediate 176b (0.188 mmol) and 4-
methoxypiperidine (43 mg, 0.38 mmol) in DCM (3 mL) was added sodium
triacetoxyborohydride (60 mg, 0.28 mmol) and the mixture stirred at RT for 1 h.
Water (3 mL) was added and the mixture shaken. The aqueous was extracted with
DCM (3 mL) then the combined organics passed through a hydrophobic frit and
concentrated in vacuo to leave a brown gum. Flash chromatography (silica 12 g,
3.5-6% [2M NH in MeOH] in DCM) gave a yellow solid (140 mg). Prep HPLC
(Gemini C18, 25-50% MeCN in water, 0.1% HCO H, 20 min, × 2) and
concentration in vacuo of the relevant fractions gave a pale yellow film. Trituration
with diethyl ether gave the title compound as on off-white solid (70.5 mg, 48%).
LCMS (Method 5): Rt 3.69 min, m/z 746.6 [MH ]. ¹H NMR (400 MHz, d -
DMSO): 0.91 (3H, d, J = 6.3 Hz), 1.27 (9H, s), 1.37-1.56 (4H, m), 1.62-1.71 (2H,
m), 1.75-1.95 (6H, m), 2.00-2.16 (4H, m), 2.62-2.69 (2H, m), 2.90 (1H, ddd, J =
12.2, 9.1, 4.1 Hz), 3.12-3.18 (2H, m), 3.20 (3H, s), 3.29-3.34 (1H, m), 3.49 (2H, s),
4.82 (1H, td, J = 8.6, 5.6 Hz), 5.51 (1H, t, J = 4.3 Hz), 6.33 (1H, s), 7.10 (1H, d, J =
8.6 Hz), 7.19 (1H, dd, J = 9.8, 2.2 Hz), 7.25-7.46 (8H, m), 7.64 (1H, dd, J = 9.8,
0.8 Hz), 7.69 (1H, dd, J = 2.2, 0.9 Hz), 8.10 (1H, s), 8.16 (0.75H, s).
Example 181
1-[5-tert-Butyl(4-pyrrolidinylmethyl-phenyl)-2H-pyrazolyl]
{(1S,4R)[3-((S)methyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridin
yloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea formate salt
To a solution of Intermediate 176b (0.188 mmol) and pyrrolidine (31.1 µL,
0.38 mmol) in DCM (3 mL), sodium triacetoxyborohydride (59.8 mg, 0.28 mmol)
was added. The mixture was stirred at RT for 1 h. Water was added and the
mixture extracted with DCM. The combined organics were passed through a phase
separator and concentrated to dryness. The resulting residue was purified by RP-
HPLC (C18, 18 mL/min, 20 – 85% MeCN in H O + 0.1% HCO H) and the
relevant fractions combined and concentrated to dryness. The title product was
isolated as a light orange solid (49.5 mg). LCMS (Method 5): Rt 3.66 min, m/z
702.6 [MH+]. ¹H NMR (400 MHz, d -DMSO): 0.91 (3H, d, J = 6.3 Hz), 1.27 (9H,
s), 1.50 (2H, m), 1.69 (6H, m), 1.75-1.95 (4H, m), 1.98-2.17 (2H, m), 2.47 (4H, m,
obscured by solvent), 2.90 (1H, m), 3.15 (1H, m, obscured by solvent), 3.63 (2H, s,
obscured by solvent), 4.81 (1H, m), 5.51 (1H, t, J = 4.3 Hz), 6.33 (1H, s), 7.09
(1H, d, J = 8.9 Hz), 7.19 (1H, dd, J = 9.6, 2.2 Hz), 7.24-7.38 (4H, m),7.43 (4H, m),
7.64 (1H, d, J = 9.6 Hz), 7.69 (1H, d, J = 1.3 Hz), 8.09 (1H, s), 8.16 (1.4H, s).
Example 182
1-[5-tert-Butyl(4-piperidinylmethyl-phenyl)-2H-pyrazolyl]
{(1S,4R)[3-((S)methyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridin
yloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea formate salt
To a solution of Intermediate 176b (0.188 mmol) and piperidine (37.2 µL,
0.38 mmol) in DCM (3 mL), sodium triacetoxyborohydride (59.8 mg, 0.28 mmol)
was added. The mixture was stirred at RT for 1 h. Water was added and the
mixture extracted with DCM. The combined organics were passed through a phase
separator and concentrated to dryness. The resulting residue was purified by RP-
HPLC (C18, 18 mL/min, 20 – 85% MeCN in H O + 0.1% HCO H) and the
relevant fractions combined and concentrated to dryness. The title product was
isolated as an off white solid (14 mg). LCMS (Method 5): Rt 3.71 min, m/z 716.6
[MH+]. ¹H NMR (400 MHz, d -DMSO): 0.91 (3H, d, J = 6.4 Hz), 1.27 (9H, s),
1.36 (2H, m), 1.47 (6H, m), 1.67 (2H, m), 1.76-1.96 (4H, m), 1.98-2.16 (2H, m),
2.33 (4H, m), 2.90 (1H, m), 3.15 (1H, m, obscured by solvent), 3.46 (2H, s,
obscured by solvent), 4.81 (1H, m), 5.51 (1H, t, J = 4.1 Hz), 6.33 (1H, s), 7.09
(1H, d, J = 8.6 Hz), 7.19 (1H, dd, J = 10.0, 2.2 Hz), 7.24-7.46 (8H, m), 7.64 (1H, d,
J = 10.0 Hz), 7.69 (1H, d, J = 1.5 Hz), 8.09 (1H, s), 8.17 (1H, s).
Example 183
1-{5-tert-Butyl[4-(4-fluoro-piperidinylmethyl)-phenyl]-2H-
pyrazolyl}{(1S,4R)[3-((S)methyl-piperidinyl)-[1,2,4]triazolo[4,3-
a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea formate salt
To a solution of Intermediate 176b (0.188 mmol) and 4-fluoropiperidine
(38.8 mg, 0.38 mmol) in DCM (3 mL), sodium triacetoxyborohydride (59.8 mg,
0.28 mmol) was added. The mixture was stirred at RT for 1 h. Water was added
and the mixture extracted with DCM. The combined organics were passed through
a phase separator and concentrated to dryness. The resulting residue was purified
by RP-HPLC (C18, 18 mL/min, 20 – 85% MeCN in H O + 0.1% HCO H) and the
relevant fractions combined and concentrated to dryness. The title product was
isolated as an off white solid (31 mg). LCMS (Method 5): Rt 3.71 min, m/z 734.6
[MH+]. ¹H NMR (400 MHz, d -DMSO): 0.91 (3H, d, J = 6.1 Hz), 1.27 (9H, s),
1.50 (2H, m), 1.67 (4H, m), 1.76-1.96 (6H, m), 1.98-2.17 (2H, m), 2.31 (2H, m),
2.54 (m, obscured by solvent), 2.90 (1H, m), 3.16 (1H, m, obscured by solvent),
3.51 (2H, s, obscured by solvent), 4.66 (1H, dm, J = 48 Hz), 4.82 (1H, m), 5.51
(1H, t, J = 4.2 Hz), 6.33 (1H, s), 7.09 (1H, d, J = 8.7 Hz), 7.19 (1H, dd, J = 9.8, 2.3
Hz), 7.24-7.50 (8H, m), 7.63 (1H, d, J = 10.2 Hz), 7.69 (1H, d, J = 1.4 Hz), 8.10
(1H, s), 8.16 (1H, s).
Example 184
1-(5-tert-Butyl{4-[(ethyl-methyl-amino)-methyl]-phenyl}-2H-
pyrazolyl){(1S,4R)[3-((S)methyl-piperidinyl)-[1,2,4]triazolo[4,3-
a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea formate salt
To a solution of Intermediate 176b (0.188 mmol) and N-ethylmethylamine
(32.3 µL, 0.38 mmol) in DCM (3 mL), sodium triacetoxyborohydride (59.8 mg,
0.28 mmol) was added. The mixture was stirred at RT for 1 h. Water was added
and the mixture extracted with DCM. The combined organics were passed through
a phase separator and concentrated to dryness. The resulting residue was purified
by RP-HPLC (C18, 18 mL/min, 20 – 85% MeCN in H O + 0.1% HCO H) and the
relevant fractions combined and concentrated to dryness. The title product was
isolated as an off white solid (26.1 mg). LCMS (Method 5): Rt 3.65 min, m/z
690.6 [MH+]. ¹H NMR (400 MHz, d -DMSO): 0.91 (3H, d, J = 6.4 Hz), 1.02 (3H,
t, J = 7.1 Hz), 1.27 (9H, s), 1.50 (2H, m), 1.66 (2H, m), 1.74-1.97 (4H, m), 1.98-
2.11 (2H, m), 2.12 (3H, s), 2.40 (2H, q, J = 7.1 Hz), 2.90 (1H, m), 3.16 (1H, m,
obscured by solvent), 3.49 (2H, s, obscured by solvent), 4.81 (1H, m), 5.51 (1H, t,
J = 4.6 Hz), 6.33 (1H, s), 7.09 (1H, d, J = 8.6 Hz), 7.19 (1H, dd, J = 9.6, 2.1 Hz),
7.24-7.47 (8H, m), 7.64 (1H, d, J = 10.2 Hz), 7.69 (1H, d, J = 1.6 Hz), 8.09 (1H, s),
8.17 (1H, s).
Example 185
1-[5-tert-Butyl(4-{[(2-methoxy-ethyl)-methyl-amino]-methyl}-
phenyl)-2H-pyrazolyl]{(1S,4R)[3-((S)methyl-piperidinyl)-
[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-
urea formate salt
To a solution of Intermediate 176b (0.188 mmol) and N-(2-
methoxyethyl)methyl amine (32.7 mg, 0.38 mmol) in DCM (3 mL), sodium
triacetoxyborohydride (59.8 mg, 0.28 mmol) was added. The mixture was stirred at
RT for 1 h. Water was added and the mixture extracted with DCM. The combined
organics were passed through a phase separator and concentrated to dryness. The
resulting residue was purified by RP-HPLC (C18, 18 mL/min, 20 – 85% MeCN in
H O + 0.1% HCO H) and the relevant fractions combined and concentrated to
dryness. The title product was isolated as an off white solid (23.9 mg). LCMS
(Method 5): Rt 3.68 min, m/z 720.5 [MH+]. ¹H NMR (400 MHz, d -DMSO): 0.91
(3H, d, J = 6.3 Hz), 1.27 (9H, s), 1.50 (2H, m), 1.66 (2H, m), 1.74-1.96 (4H, m),
1.98-2.16 (2H, m), 2.17 (3H, s), 2.54 (2H, t, J = 6.0 Hz, obscured by solvent), 2.90
(1H, m), 3.16 (1H, m, obscured by solvent), 3.23 (3H, s, obscured by solvent), 3.45
(2H, t, J = 6.0 Hz, obscured by solvent), 3.54 (2H, s, obscured by solvent), 4.82
(1H, m), 5.51 (1H, t, J = 4.3 Hz), 6.33 (1H, s), 7.09 (1H, d, J = 8.8 Hz), 7.19 (1H,
dd, J = 9.7, 2.2 Hz), 7.24-7.50 (8H, m), 7.64 (1H, d, J = 10.0 Hz), 7.69 (1H, d, J =
1.5 Hz), 8.09 (1H, s), 8.17 (1H, s).
Example 186
1-{5-tert-Butyl[3-(2-dimethylamino-ethoxy)-phenyl]-2H-pyrazol
yl{(1S,4S)[3-((S)methyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridin
yloxy]-1,2,3,4-tetrahydronaphthalenyl]-urea
a. 2-[3-(5-Aminotert-butyl-pyrazolyl)-phenoxy]-ethanol
(Intermediate 186a)
O OH
A solution of Intermediate 95a (1.2 g, 5.2 mmol) and triphenyl phosphine
(2.72 g, 10.4 mmol) in THF (30 mL), under an atmosphere of argon was treated
with 2-(tetrahydro-pyranyloxy)-ethanol (1.05 mL, 7.78 mmol), followed by the
dropwise addition of diisopropylazodicarboxylate (1.64 mL, 10.4 mmol). The
reaction mixture was then stirred at RT for 1 h. The reaction mixture was eluted on
a SCX-2 cartridge using MeOH and 2M NH in MeOH. The basic fractions were
evaporated under reduced pressure and the product was purified by FCC, using
EtOAc/DCM 0-60% to afford the title compound as a brown gum (1.0 g, 80%).
LCMS (Method 3): Rt 2.27 min, m/z 276 [MH ].
b. {5-tert-Butyl[3-(2-hydroxy-ethoxy)-phenyl]-2H-pyrazolyl}-
carbamic acid 2,2,2-trichloro-ethyl ester (Intermediate 148e)
A solution of Intermediate 186a (1.0 g, 3.63 mmol) in EtOAc (20 mL) was
treated with aqueous NaOH (1M, 6.53 mmol), followed by 2,2,2-trichloroethyl
chloroformate (0.529 mL, 3.85 mmol) and the reaction mixture was stirred at RT
for 1 h. The mixture was partitioned between EtOAc (20 mL) and water (20 mL).
The layers were separated and the aqueous layer was extracted with a further 20
mL EtOAc. The combined organic layers were dried (Na SO4), filtered and
concentrated in vacuo. The residue was purified by FCC, using 0-40% EtOAc in
DCM. The combined fractions were evaporated under reduced pressure and the
product was triturated with DCM. The solid was filtered and washed with Diethyl
ether to afford the title compound as a white solid (0.930 g, 58%). LCMS (Method
3): Rt 4.01 min, m/z 450 [M].
c. (1S,4S)[3-((S)Methyl-piperidinyl)-[1,2,4]triazolo[4,3-
a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenylamine (Intermediate
186b)
To a solution of Intermediate B (232 mg, 1.6 mmol) in dry DMF (10 mL)
under N was added sodium (60% dispersion in oil, 320 mg, 8.0 mmol) and the
resulting opaque brown solution was stirred at RT for 45 min (CARE: gas
evolution). A solution of Intermediate 81c (342 mg, 1.46 mmol) in dry DMF (7
mL) was added and the dark brown solution stirred at 60°C under N for 90 min.
The cooled solution was concentrated in vacuo, redissolved in MeOH (3 mL) and
then applied to an SCX-2 cartridge (20 g), washing with MeOH (50 mL). The
product was eluted with 2M NH in MeOH (50 mL); concentration in vacuo gave a
dark brown solid. FCC, using 0-10% [2M NH in MeOH] in DCM, gave the title
compound as a pale brown foam (262 mg, 45%). LCMS (Method 3): Rt 2.30 min,
m/z 378 [MH ].
d. 1-{5-tert-Butyl[3-(2-hydroxy-ethoxy)-phenyl]-2H-pyrazolyl}
{(1S,4S)[3-((S)methyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridin
yloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea(Intermediate 186c)
A mixture of Intermediate 148e (313 mg, 0.7 mmol), Intermediate 186b
(262 mg, 0.7 mmol) and DIPEA (182 µL, 1.05 mmol) in dioxane (4 mL) was
heated at 70°C for 20 h. The reaction mixture was cooled to RT and eluted directly
on SCX-2 using MeOH and 2M NH in MeOH. The basic fractions were
evaporated under reduced pressure. The residue was purified by FCC, using 0-10%
[2M NH in MeOH] in DCM, to afford the title compound as a yellow glass (293
mg). LCMS (Method 3): Rt 3.63 min, m/z 679 [MH ].
e. 1-{5-tert-Butyl[3-(2-dimethylamino-ethoxy)-phenyl]-2H-pyrazol
yl{(1S,4S)[3-((S)methyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridin
yloxy]-1,2,3,4-tetrahydronaphthalenyl]-urea (Example 186)
To a solution of Intermediate 186c (293 mg, 0.44 mmol) and DIPEA (304
µL, 1.76 mmol) in DCM (10 mL) was added methanesulfonyl chloride (103 µL,
1.33 mmol). The reaction mixture was stirred at RT for 1 hour. The mixture was
concentrated in vacuo. The residue was taken up in THF (2 mL) and
dimethylamine solution in THF (2M, 3.3 mL) was added. The reaction mixture
was heated at 60°C in a sealed tube for 72 h. The reaction mixture was cooled to
RT and concentrated in vacuo. The product was purified by HPLC using a Gemini
C18 column and using a gradient of 20-35% +0.1% Formic acid over 10 minutes.
The combined fractions were evaporated under reduced pressure and crystallised
by MeCN/Et2O to afford the title compound as a white solid (90 mg, 30%). LCMS
(Method 3): Rt 3.01 min, m/z 706 [MH ]. ¹H NMR (300 MHz, d -DMSO): 0.91
(3H, d, J = 6.7 Hz), 1.23 (9H, s), 1.46-1.54 (2H, m), 1.63-1.72 (2H, m), 1.75-1.76
(2H, m), 2.00-2.18 (2H, m), 2.43 (6H, s), 2.66 (2H, t, J 5.8 Hz), 2.85-2.95 (2H, m),
3.12-3.20 (4H, m), 4.10 (2H, t, J = 5.4 Hz), 4.78-4.86 (1H, m), 5.52 (1H, t, J = 4.0
Hz), 6.33 (1H, s), 6.95-6.99 (2H, m), 7.06-7.14 (2H, m), 7.19 (1H, dd, J = 10.0Hz),
7.25-7.32 (3H, m), 7.33-7.42 (2H, m), 7.58 (1H, d, J = 10.6 Hz), 7.63 (1H, d, J =
1.8 Hz), 8.17 (1H, s).
Example 187
1-[3-tert-Butyl-1'-(2-dimethylamino-ethyl)-1'H-[1,4']bipyrazolyl
yl]{(1S,4R)[3-((S)methyl-piperidinyl)-[1,2,4]triazolo[4,3-
a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea formate salt
a. 1-{3-tert-Butyl-1'-[2-(tetrahydro-pyranyloxy)-ethyl]-1'H-
[1,4']bipyrazolylyl}{(1S,4R)[3-((S)methyl-piperidinyl)-
[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-
urea (Intermediate 187a)
A mixture of Intermediate 81d (240 mg, 0.64 mmol), Intermediate 108b
(325 mg, 0.64 mmol) and DIPEA (221 µL, 1.27 mmol) in dioxane (6 mL) was
stirred at 80ºC overnight. After cooling, the reaction mixture was partitioned
between water and EtOAc. The aqueous phase was extracted with EtOAc (x 3)
and the combined organic layers were washed with brine, dried (MgSO ) and
concentrated in vacuo. The resultant residue was purified by FCC on silica,
using a gradient of 0-10% MeOH in DCM to afford the title compound
(377 mg, 80%). LCMS (Method 4): Rt 3.48 min, m/z 737 [MH ].
b. 1-[3-tert-Butyl-1'-(2-hydroxy-ethyl)-1'H-[1,4']bipyrazolylyl]
{(1S,4R)[3-((S)methyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridin
yloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea (Intermediate 187b)
To a solution of Intermediate 187a (377 mg, 0.51 mmol) in MeOH
(5 mL) was added pyridinium p-toluenesulfonate (257 mg, 1.02 mmol) and the
reaction mixture was heated at 55ºC for 3 h. The resultant mixture was poured
into water and a saturated aqueous solution of NaHCO was added. The
aqueous phase was extracted with EtOAc (x 3) and the combined organic
layers were washed with brine, dried (MgSO ) and concentrated in vacuo. The
resultant residue was purified by FCC on silica, using a gradient of 3-10%
MeOH in DCM, to give the title compound (250 mg, 75%). LCMS (Method
1): Rt 3.09 min, m/z 653 [MH ].
c. Methanesulfonic acid 2-[3-tert-butyl(3-{(1S,4R)[3-((S)
methyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-
tetrahydro-naphthalenyl}-ureido)-[1,4']bipyrazolyl-1'-yl]-ethyl ester
(Intermediate 187c)
To an ice-bath cooled solution of Intermediate 187b (250 mg,
0.38 mmol) in DCM (4 mL) was added DIPEA (267 µL, 1.53 mmol) followed
by methanesulfonyl chloride (60 µL, 0.77 mmol). The reaction mixture was
stirred for 2 h and then quenched with water. The aqueous phase was extracted
with DCM (x 3) and the combined organic layers were washed with brine,
dried (MgSO ) and concentrated in vacuo to afford the title compound
(Quantitative). Product used in the following step without further purification.
LCMS (Method 4): Rt 3.25 min, m/z 732 [MH ].
d. 1-[3-tert-Butyl-1'-(2-dimethylamino-ethyl)-1'H-[1,4']bipyrazolyl-
5-yl]{(1S,4R)[3-((S)methyl-piperidinyl)-[1,2,4]triazolo[4,3-
a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea formate salt
(Example 187)
To a solution of Intermediate 187c (0.19 mmol) in THF (3 mL) was
added dimethylamine (2M in MeOH, 1.9 mL, 3.8 mmol) and the reaction
stirred at 50°C in a sealed vial overnight. The crude reaction mixture was
partitioned between EtOAc and water. The aqueous phase was extracted with
EtOAc (x 3) and the combined organic layers were washed with brine, dried
(MgSO ) and concentrated in vacuo. The resultant residue was purified by
FCC on silica, using a gradient of 0-10% [2M NH in MeOH] in DCM
followed by MDAP (Method 7) purification, to give the title compound
(46 mg, 33%). LCMS (Method 5): Rt 3.50 min, m/z 680 [MH ]. ¹H NMR
(400 MHz, d -DMSO): 0.87 (3H, d, J = 6.4 Hz), 1.20 (9H, s), 1.43-1.51 (2H,
m), 1.58-1.69 (2H, m), 1.70-1.88 (3H, m), 1.88-1.96 (1H, m), 1.96-2.12 (2H,
m), 2.13 (6H, s), 2.63 (2H, t, J = 6.5 Hz), 2.87 (1H, ddd, J = 12.6, 9.1, 3.9 Hz),
3.12 (1H, dt, J = 12.1, 4.2 Hz), 4.16 (2H, t, J = 6.5 Hz), 4.80 (1H, td, J = 8.5,
.8 Hz), 5.48 (1H, t, J = 4.3 Hz), 6.22 (1H, s), 7.12 (1H, d, J = 8.5 Hz), 7.15
(1H, dd, J = 9.9, 2.2 Hz), 7.21-7.26 (1H, m), 7.28-7.36 (3H, m), 7.58 (1H, s),
7.60 (1H, d, J = 9.5 Hz), 7.66 (1H, d, J = 2.1 Hz), 7.96 (1H, s), 8.00 (1H, s),
8.13 (1H, s).
Example 188
1-[3-tert-Butyl-1'-(2-morpholinyl-ethyl)-1'H-[1,4']bipyrazolyl
yl]{(1S,4R)[3-((S)methyl-piperidinyl)-[1,2,4]triazolo[4,3-
a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea partial
formate salt
To a solution of Intermediate 187c (0.19 mmol) in THF (3 mL) was
added morpholine (166 µL, 1.9 mmol) and the reaction stirred at 50°C
overnight. The crude reaction mixture was partitioned between EtOAc and
water. The aqueous phase was extracted with EtOAc (x 3) and the combined
organic layers were washed with brine, dried (MgSO ) and concentrated in
vacuo. The resultant residue was purified by FCC on silica, using a gradient of
2.5-10% [2M NH in MeOH] in DCM followed by MDAP (Method 7)
purification, to give the title compound (49 mg, 35%). LCMS (Method 5): Rt
3.53 min, m/z 722 [MH ]. ¹H NMR (400 MHz, d -DMSO): 0.87 (3H, d, J =
6.4 Hz), 1.20 (9H, s), 1.43-1.51 (2H, m), 1.58-1.69 (2H, m), 1.70-1.88 (3H,
m), 1.88-1.96 (1H, m), 1.96-2.12 (2H, m), 2.37 (4H, t, J = 4.5 Hz), 2.69 (2H, t,
J = 6.5 Hz), 2.87 (1H, ddd, J = 12.6, 9.1, 3.9 Hz), 3.12 (1H, dt, J = 12.1, 4.2
Hz), 1H UNDER SOLVENT, 3.50 (4H, t, J = 4.6 Hz), 4.20 (2H, t, J = 6.5
Hz), 4.80 (1H, td, J = 8.5, 5.8 Hz), 5.48 (1H, t, J = 4.3 Hz), 6.22 (1H, s), 7.11
(1H, d, J = 8.5 Hz), 7.15 (1H, dd, J = 9.9, 2.2 Hz), 7.21-7.26 (1H, m), 7.28-
7.35 (3H, m), 7.60 (1H, d, J = 9.8 Hz), 7.60 (1H, s), 7.66 (1H, d, J = 2.1 Hz),
7.96 (1H, s), 8.02 (1H, s), 8.12 (0.5H, s).
Example 189
H OH
1-{5-tert-Butyl[3-(4-methyl-piperazinylmethyl)-phenyl]-2H-
pyrazolyl}{(1S,4R)[3-((S)methyl-pyrrolidinyl)-
[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-
urea formate salt
A mixture of Intermediate 149b (87 mg, 0.12 mmol) and
1-methylpiperazine (68 µL, 0.61 mmol) in THF (2 mL) was stirred at 60ºC for
18 h. The reaction mixture was cooled to RT, diluted with DCM (5 mL) and
washed with water (5 mL). The aqueous layer was extracted with DCM
(5 mL). The combined organic extracts were washed with water (2 x 5 mL)
and passed through a phase separator. The filtrate was concentrated in vacuo
and the resultant residue was purified by MDAP (Method 7) to afford the title
compound (23 mg, 27%). LCMS (Method 5): Rt 2.69 min, m/z 717.6 [MH ].
¹H NMR (400 MHz, d -DMSO): 1.28 (9H, s), 1.84-2.11 (6H, m), 2.13 (6H, br
s), 2.15-2.26 (2H, m), 2.26-2.46 (8H, m), 3.13 (1H, m, obscured by water),
3.50 (2H, s, obscured by water), 3.99 (1H, t, J = 8.4 Hz), 4.82 (1H, m), 5.39
(1H, t, J = 4.3 Hz), 6.33 (1H, s), 7.06 (1H, d, J = 8.8 Hz), 7.24-7.48 (9H, m),
7.75 (1H, d, J = 9.7 Hz), 8.10 (1H, s), 8.19 (1.9H, br s), 8.24 (1H, d, J = 1.7
Hz).
Biological assays
P38alpha enzyme inhibition assay
The inhibitory activity of compounds was determined using an
Alphascreen® (Perkin Elmer) based kinase activity assay. Kinase reactions
consisted of 25mM HEPES pH 7.5, 10mM MgCl , 100 μM Na VO , 2mM
2 3 4
DTT, 0.05mg/ml Tween 20, 100pM p38alpha (Invitrogen, PV3304), 1%
DMSO and 0.3µg/ml ATF-2 fusion protein (New England Biolabs, 9224).
Compounds were incubated under these conditions for 2 hours, at 25°C, prior
to the initiation of the kinase activity by the addition of the 250µM ATP.
Reaction volumes were 20uL. After 1hr at 25°C reactions were stopped by the
adding 10uL of 25mM HEPES pH 7.5 containing 62.5mM EDTA, 0.05%
Triton X-100, 10% BSA and 0.83ng/uL anti-phospho-ATF2 antibody (Abcam,
ab28812). Detection was performed by measuring luminescence following the
addition of Alphascreen Donor beads (Perkin Elmer 6765300) and Protein A
Alphascreen Acceptor beads (Perkin Elmer 6760137), both at a final
concentration of 20ug/ml. IC values were determined from concentration-
response curves.
Results are shown in the following Table:
Example p38a inhibition
1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 18, 19,
, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 33,
34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45,
46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57,
58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69,
70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81,
82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93,
94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, ++++
105, 106, 107, 108, 109, 110, 111, 112, 113,
114, 115, 116, 118, 119, 120, 121, 122, 123,
124, 125, 126, 127, 128, 129, 130, 131, 132,
133, 134, 135, 136, 137, 138, 139, 140, 141,
142, 143, 144, 148, 154, 155, 156, 157, 158,
159, 160, 162, 163, 165, 166, 167, 168, 169,
170, 171, 176, 178, 181, 182, 183, 184, 185
21 +++
In the table above, p38a binding potencies (IC values) are indicated as
follows: 7000-500nM ‘+‘; 500-100nM ‘++’; 100-10nM ‘+++’; <10nM
‘++++’.
LPS-stimulated PBMC TNF α release assay
Peripheral Blood Mononuclear Cells (PBMCs) were isolated from
healthy human volunteer blood using a standard density gradient
centrifugation technique. Citrated blood was placed onto Histopaque and
centrifuged. The PBMCs were removed from the density gradient interface
and washed in phosphate buffered saline (PBS). The PBMCs were suspended
in RPMI 1640 medium (without serum), dispensed into a 96-well plate and
incubated at 37 C for 3h in a humidified incubator. After incubation, the
medium was replaced (with medium containing 1% foetal bovine serum) and
the plate incubated at 37 C, for 1h, in the presence of test compound or the
appropriate vehicle. LPS (10ng/ml), or an appropriate vehicle control, was
then added to the cells and the plate returned to the incubator for 18h.
Cell-free supernatants were removed and assayed for TNF α levels using an
ELISA kit from R&D Systems.
A dose response curve to each test compound was performed and the
effect of compound in each experiment was expressed as a percentage
inhibition of the control TNF α release. Dose response curves were plotted and
compound potency (IC ) was determined. Compounds were tested in at least
three separate experiments.
Results are shown in the following Table:
Example numbers p38a inhibition
3, 5, 8, 10, 12, 13, 15, 16, 18, 19, 20, 23, 24,
, 26, 27, 28, 29, 30, 31, 33, 34, 35, 36, 37,
38, 39, 40, 41, 42, 43, 44, 46, 47, 48, 49, 50,
52, 53, 54, 55, 58, 59, 60, 61, 62, 63, 64, 65,
66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77,
++++
78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89,
90, 92, 93, 95, 96, 97, 98, 99, 100, 101, 102,
103, 104, 105, 106, 107, 108, 109, 110, 111,
112, 113, 114, 115, 116, 117, 118, 120, 121,
122, 123, 124, 125, 126, 127, 128, 130
1, 2, 11, 14, 21, 57, 94, 119, 129
4, 7, 9, 22 ++
In the table above, p38a potencies (IC values) are indicated as follows:
>1000 nM ‘+’; 1000-100nM ‘++’; 100-10nM ‘+++’; <10nM ‘++++’. All
compounds tested exhibited IC values <1000nM.
Pre-clinical mouse model of COPD – Tobacco smoke induced
pulmonary inflammation.
Previous studies have established that the number of inflammatory cells
recovered by bronchoalveolar lavage (BAL) is significantly elevated 24h
following the final of four consecutive daily tobacco smoke (TS) exposures.
This timepoint was used in the studies reported here.
Protocols for the exposure of mice to TS, obtaining bronchoalveolar
lavage fluid (BALF) and preparation of cytospin slides for differential cell
counts are as outlined below.
Daily exposure of mice to TS for 4 consecutive days
In this exposure protocol, mice were exposed in groups of 5 in
individual clear polycarbonate chambers (27 cm x 16 cm x 12 cm). The TS
from the cigarettes was allowed to enter the exposure chambers at a flow rate
of 100 ml/min. In order to minimise any potential problems caused by
repeated exposure to a high level of TS, the exposure of the mice to TS was
increased gradually over the exposure period to a maximum of 6 cigarettes.
The exposure schedule used over the four days was as follows:
Day 1: 5 cigarettes (approximately 25min exposure)
Day 2: 7 cigarettes (approximately 35min exposure)
Day 3: 9 cigarettes (approximately 45min exposure)
Day 4: 9 cigarettes (approximately 45min exposure)
A further group of mice were exposed to air on a daily basis for
equivalent lengths of time as controls (no TS-exposure).
Bronchoalveolar lavage (BAL) analysis
Bronchoalveolar lavage was performed as follows: the trachea was
cannulated using a 10mm long Luer-fitting stainless steel cannula. Phosphate
buffered saline (PBS) was used as the lavage fluid. A volume of 0.4ml was
gently instilled and withdrawn 3 times, using a 1ml syringe and then placed in
an Eppendorf tube and kept on ice prior to subsequent determinations.
Cell counts:
Lavage fluid was separated from cells by centrifugation and the
supernatant decanted and frozen for subsequent analyses. The cell pellet was
re-suspended in a known volume of PBS and total cell numbers calculated by
counting a stained (Turks stain) aliquot under a microscope using a
haemocytometer.
Differential cell counts were performed as follows:
The residual cell pellet was diluted to approximately 10 cells per ml. A
volume of 500µl was placed in the funnel of a cytospin slide and centrifuged
for 6min at 800rpm, RCF = 72.26 x g (Shandon Cytospin 3). The slide was
air-dried and stained using Wrights/Giemsa stain as per the proprietary
instructions. When dried and cover-slipped, differential cell counts were
performed using light microscopy. Approximately four hundred cells were
counted by an unbiased operator using light microscopy. Cells were
differentiated using standard morphometric techniques.
Drug Treatment
Rodents such as mice and rats are obligate nose breathers, thus oral
delivery of test materials (such as therapeutic agents) for inhalation will not
produce good lung exposure. As a consequence, delivery of therapeutic agents
to the lungs in rodents is generally achieved by intranasal, intratracheal or
inhalation by either nose-only or whole body aerosol exposure.
Nose-only or whole body aerosol exposure methods utilise large
amounts of test material and are generally reserved for inhalation toxicology
studies rather than more routine pharmacological efficacy studies.
Intratracheal administration is a very efficient delivery method as almost all of
the test material is delivered to the lungs but is an invasive technique. For
studies in the mouse particularly, it is also technically demanding as the
diameter of the trachea is small. The intranasal route is less invasive than the
intratracheal route and so is particularly suitable for repeat dosing studies such
as the four day mouse model described. Following intranasal administration,
~50% of the dose administered is delivered to the lungs (Eyles JE, Williamson
ED and Alpar HO. 1999, Int J Pharm, 189(1):75-9).
As a surrogate route for oral inhalation, mice were dosed intra-nasally
with vehicle (0.2% tween 80 in saline) containing test compound. The control
groups of mice received vehicle 1hr prior to being exposed to air or TS.
Data management and statistical analysis:
All results are presented as individual data points for each animal and
the mean value was calculated for each group. Since tests for normality were
positive, the data were subjected to a one-way analysis of variance test
(ANOVA), followed by a Bonferroni correction for multiple comparisons in
order to test for statistically significant differences between treatment groups.
A “p” value of < 0.05 was considered to be statistically significant. Percentage
inhibitions were automatically calculated within Excel spreadsheets for the
cell data using the formula below:
Treatment group result - air group result
% Inhibition = (1 - ) x 100
TS vehicle group result - air group result
Inhibition data for other parameters were calculated manually using the
above formula.
Example 5 was tested in the above reported model and results are
herebelow reported.
As illustrated in Figure 1, Example 5 significantly inhibited the BAL
cell influx induced by TS at 3, 30 or 100 mg/kg when administered by the
intranasal route. Similar findings were observed with BAL neutrophils (Figure
2). The results demonstrate a clear anti-inflammatory effect in the lungs of
mice exposed to TS.
Brief description of the figures
Figure 1. is a graph that illustrates the effect of intranasal
administration to laboratory mice with vehicle (0.2% tween 80 in saline),
Example 5 (3 mg/kg), Example 5 (30 mg/kg) or Example 5 (100 mg/kg) on the
number of BAL cells induced by tobacco smoke 24 hours post the final
exposure.
Figure 2. is a graph that illustrates the effect of intranasal
administration to laboratory mice with vehicle (0.2% tween 80 in saline),
Example 5 (3 mg/kg), Example 5 (30 mg/kg) or Example 5 (100 mg/kg) on the
number of BAL neutrophils induced by tobacco smoke 24 hours post the final
exposure.
The term ‘comprising’ as used in this specification and claims means
‘consisting at least in part of’. When interpreting statements in this
specification and claims which includes the ‘comprising’, other features
besides the features prefaced by this term in each statement can also be
present. Related terms such as ‘comprise’ and ‘comprised’ are to be
interpreted in similar manner.
In this specification where reference has been made to patent
specifications, other external documents, or other sources of information, this
is generally for the purpose of providing a context for discussing the features
of the invention. Unless specifically stated otherwise, reference to such
external documents is not to be construed as an admission that such
documents, or such sources of information, in any jurisdiction, are prior art, or
form part of the common general knowledge in the art.
WE
Claims (13)
1. A compound of formula (I) or a pharmaceutically acceptable salt thereof: N W A wherein; W is NH; Y is O; 10 R is a group selected from (IIa) - (IIc): R N 3 X R X R (IIa) (IIb) (IIc) 8 9 8 9 R and R are each independently hydrogen or C -C alkyl, or R and R may form together with the nitrogen atom to which they are attached a 15 5 membered saturated monocyclic or a fused or spiro bicyclic ring system optionally containing a further heteroatom which is oxygen or nitrogen, said nitrogen atom being optionally substituted by C -C alkyl; wherein such C -C 1 6 1 6 alkyl groups may be optionally substituted by a group C -C alkyl, C -C 1 6 3 6 cycloalkyl, hydroxyl or halo; 1 2 3 4 5 20 X , X , X , X and X are each independently a carbon atom, a nitrogen atom, a group -(CH)- or a group -NH-; such that each combination thereof forms an aromatic ring system; 10 A B R is selected from a group consisting of: Hydrogen, -CN, -NR R , C A B C A B -N(R )(C -C alkylene)-NR R, -N(R )(C -C cycloalkylene)-NR R , 2 6 3 7 A B A B -(C -C alkylene)-NR R , -(C -C cycloalkylene)-NR R , -O-(C -C alkylene)- 1 6 3 7 2 6 A B A B A B NR R , -O-(C -C cycloalkylene)-NR R , -S-(C -C alkylene)-NR R , -S-(C - 3 7 2 6 3 A B C A B C C cycloalkylene)-NR R , -N(R )C(O)-(C -C alkylene)-NR R , -N(R )C(O)- 7 1 6 A B C A B (C -C cycloalkylene)-NR R, -C(O)N(R )-(C -C alkylene)-NR R , 3 7 2 6 C A B C D 5 -C(O)N(R )-(C -C cycloalkylene)-NR R , -C(O)N(R )-(C -C alkylene)-OR , 3 7 2 6 C D C A B A B -C(O)N(R )-(C -C cycloalkylene)-OR , -N(R )C(O)NR R, -C(O)NR R , C C A B C C -N(R )C(O)N(R )-(C -C alkylene)-NR R, -N(R )C(O)N(R )-(C - 2 6 3 A B D D C cycloalkylene)-NR R , -(C -C alkylene)-OR , -(C -C cycloalkylene)-OR , 7 2 6 3 7 -O-(C -C alkylene)-OR , -O-(C -C cycloalkylene)-OR , -S-(C -C alkylene)- 2 6 3 7 2 6 D D C A B 10 OR, -S-(C -C cycloalkylene)-OR , -N(R )S(O) -(C -C alkylene)-NR R , 3 7 2 1 6 C A B C -N(R )S(O) -(C -C cycloalkylene)-NR R, -S(O) N(R )-(C -C alkylene)- 2 3 7 2 2 6 A B C A B C NR R, -S(O) N(R )-(C -C cycloalkylene)-NR R, -S(O) N(R )-(C - 2 3 7 2 2 D C D C C alkylene)-OR , -S(O) N(R )-(C -C cycloalkylene)-OR , -N(R )S(O) -(C - 6 2 3 7 2 2 D C D A B C alkylene)-OR , -N(R )S(O) -(C -C cycloalkylene)-OR , -S(O) N(R R ), 6 2 3 7 2 C D C C C C 15 -N(R )S(O) R, -N(R )C(O)R, -OR, -SR, -(C -C heterocycloalkyl), 2 3 7 (C -C heterocycloalkyl)-(C -Calkyl), (C -C heterocycloalkyl)(C - 5 7 1 6 5 7 3 C cycloalkyl)-, and C -C heterocycloalkylcarbonyl; wherein any of such C - 6 3 7 1 Calkyl, C -Ccycloalkyl, -(C -Calkylene)- -(C -Calkylene)-, -(C - 6 3 6 1 6 2 6 3 C cycloalkylene)-, -(C -C heterocycloalkyl), (C -C heterocycloalkyl)-(C -C 7 3 7 5 7 1 6 20 alkyl), (C -C heterocycloalkyl)-(C -C cycloalkyl) and (C - 5 7 3 6 3 C heterocycloalkyl)carbonyl portion in the above listed groups may be optionally substituted by a group C -C alkyl, C -C cycloalkyl, hydroxyl or 1 6 3 7 halo; 11 4 R is linked to X and is selected from a group consisting of: 25 Hydrogen; -CN; C -C alkyl which is substituted by a group selected from -CN, -OR , -SR , halo; C -C cycloalkyl which is substituted by a group C D A B C selected from C -C alkyl, -CN, -OR , -SR , halo; -NR R , -N(R )(C - 1 4 2 A B C A B C alkylene)-NR R , -N(R )(C -C cycloalkylene)-NR R , -(C -C alkylene)- 6 3 7 1 6 A B A B A B NR R , -(C -C cycloalkylene)-NR R , -O-(C -C alkylene)-NR R , -O-(C - 3 7 2 6 3 A B A B C cycloalkylene)-NR R, -S-(C -C alkylene)-NR R, -S-(C - 7 2 6 3 A B C A B C C cycloalkylene)-NR R , -N(R )C(O)-(C -C alkylene)-NR R , -N(R )C(O)- 7 1 6 A B C A B 5 (C -C cycloalkylene)-NR R, -C(O)N(R )-(C -C alkylene)-NR R , 3 7 2 6 C A B C D -C(O)N(R )-(C -C cycloalkylene)-NR R , -C(O)N(R )-(C -C alkylene)-OR , 3 7 2 6 C D C A B A B -C(O)N(R )-(C -C cycloalkylene)-OR , -N(R )C(O)N(R R ), -C(O)N(R R ), C C A B C C -N(R )C(O)N(R )-(C -C alkylene)-NR R, -N(R )C(O)N(R )-(C - 2 6 3 A B D C cycloalkylene)-NR R , -O-(C -C alkylene)-OR , -O-(C -C cycloalkylene)- 7 2 6 3 7 D D D C 10 OR , -S-(C -C alkylene)-OR , -S-(C -C cycloalkylene)-OR , -N(R )S(O) - 2 6 3 7 2 A B C A B (C -C alkylene)-NR R, -N(R )S(O) -(C -C cycloalkylene)-NR R , 1 6 2 3 7 C A B C -S(O) N(R )-(C -C alkylene)-NR R, -S(O) N(R )-(C -C cycloalkylene)- 2 2 6 2 3 7 A B C D C NR R, -S(O) N(R )-(C -C alkylene)-OR, -S(O) N(R )-(C - 2 2 6 2 3 D C D C C cycloalkylene)-OR, -N(R )S(O) -(C -C alkylene)-OR, -N(R )S(O) 7 2 2 6 2 D A B C D C C 15 (C -C cycloalkylene)-OR , -S(O) N(R R ), -N(R )S(O) R , -N(R )C(O)R , 3 7 2 2 OR , SR , -(C -Cheterocycloalkyl), (C -C heterocycloalkyl)-(C -C alkyl), 3 7 5 7 1 6 (C -C heterocycloalkyl)(C -Ccycloalkyl) and (C -C 5 7 3 6 3 7 heterocycloalkyl)carbonyl, wherein any of such C -C alkyl, C -C cycloalkyl, - 1 6 3 6 (C -Calkylene)- -(C -Calkylene)-, -(C -Ccycloalkylene)-, -(C - 1 6 2 6 3 7 3 20 Cheterocycloalkyl), (C -C heterocycloalkyl)-(C -C alkyl), (C -C 7 5 7 1 6 5 7 heterocycloalkyl)-(C -C cycloalkyl) and (C -C heterocycloalkyl)carbonyl 3 6 3 7 portion in the above listed groups may be optionally substituted by one, two or three groups R which are independently selected in the list consisting of: C - C alkyl, (C -C ) haloalkyl, (C -C )hydroxyalkyl, C -C cycloalkyl, hydroxyl 6 1 3 1 4 3 7 25 and halo; or 11 4 R is linked to X and is phenyl or 5- or 6-membered monocyclic heteroaryl, wherein such phenyl or 5- or 6-membered monocyclic heteroaryl is substituted by a group selected in the list consisting of: C -C alkyl which is substituted by a group -CN; C -C cycloalkyl which is substituted by a group C C C A B selected from: -CN, -OR , -SR or halo; -N(R )(C -C alkylene)-NR R , C A B A B -N(R )(C -C cycloalkylene)-NR R, -(C -C alkylene)-NR R, -(C - 3 7 1 6 3 A B A B 5 C cycloalkylene)-NR R, -O-(C -C cycloalkylene)-NR R , 7 3 7 A B A B C -S-(C -C alkylene)-NR R, -S-(C -C cycloalkylene)-NR R, -N(R )C(O)- 2 6 3 7 A B C A B (C -C alkylene)-NR R, -N(R )C(O)-(C -C cycloalkylene)-NR R , 1 6 3 7 C A B C -C(O)N(R )-(C -C alkylene)-NR R, -C(O)N(R )-(C -C cycloalkylene)- 2 6 3 7 A B C D C NR R, -C(O)N(R )-(C -C alkylene)-OR, -C(O)N(R )-(C - 2 6 3 D C C A B 10 C cycloalkylene)-OR, -N(R )C(O)N(R )-(C -C alkylene)-NR R , 7 2 6 C C A B -N(R )C(O)N(R )-(C -C cycloalkylene)-NR R, -O-(C -C cycloalkylene)- 3 7 3 7 D D C A B OR, -S-(C -C cycloalkylene)-OR , -N(R )S(O) -(C -C alkylene)-NR R , 3 7 2 1 6 C A B C -N(R )S(O) -(C -C cycloalkylene)-NR R, -S(O) N(R )-(C -C alkylene)- 2 3 7 2 2 6 A B C A B C NR R, -S(O) N(R )-(C -C cycloalkylene)-NR R, -S(O) N(R )-(C - 2 3 7 2 2 D C D C 15 C alkylene)-OR , -S(O) N(R )-(C -C cycloalkylene)-OR , -N(R )S(O) -(C - 6 2 3 7 2 2 D C D C D C alkylene)-OR , -N(R )S(O) -(C -C cycloalkylene)-OR , -N(R )S(O) R , 6 2 3 7 2 -(C -Cheterocycloalkyl), (C -C heterocycloalkyl)-(C C alkyl), 3 7 5 7 1- 6 (C -C heterocycloalkyl)(C -Ccycloalkyl) and (C - 5 7 3 6 3 Cheterocycloalkyl)carbonyl, wherein any of such C -Calkyl, C - 7 1 6 3 20 Ccycloalkyl, -(C -Calkylene)- -(C -Calkylene)-, -(C -C cycloalkylene)-, 6 1 6 2 6 3 7 -(C -Cheterocycloalkyl), (C -C heterocycloalkyl)-(C -C alkyl), (C -C 3 7 5 7 1 6 5 7 heterocycloalkyl)-(C -C cycloalkyl) and (C -C heterocycloalkyl)carbonyl 3 6 3 7 portion in the above listed groups may be optionally substituted by one, two or three groups R which are independently selected in the group consisting of: 25 C -Calkyl, (C -C) haloalkyl, (C -C)hydroxyalkyl, C -C cycloalkyl, 1 6 1 3 1 4 3 7 hydroxyl and halo; R and R are at each occurrence independently hydrogen, C -C alkyl or C -C cycloalkyl, such C -C alkyl and C -C cycloalkyl being optionally 3 7 1 6 3 7 substituted by a group C -C alkyl, C -C cycloalkyl, -OR , -CN or halo; 1 3 3 7 alternatively, R and R , may form together with the nitrogen atom to which they are attached a 5 membered saturated heterocyclic monocyclic or 5 bicyclic ring system which is optionally substituted by one or more group -OR , -CN, halo, C -C alkyl or C -C cycloalkyl, such C -C alkyl and C -C 1 6 3 7 1 6 3 7 cycloalkyl being optionally substituted by a group C -C alkyl, C - 1 3 3 C cycloalkyl, -OR , -CN or halo; and which 5 membered saturated heterocyclic monocyclic or bicyclic ring optionally contains a further 10 heteroatom which is oxygen or nitrogen, said nitrogen atom optionally substituted by C -C alkyl or C -C cycloalkyl, wherein any of such C -C 1 6 3 6 1 6 alkyl or C -C cycloalkyl may be optionally substituted by a group C -C 3 6 1 6 D A B alkyl, C -C cycloalkyl, -OR , -CN, or halo; and/or R and R may be linked to one carbon atom of the -(C -C alkylene)-, -(C -C alkylene)- or -(C - 1 6 2 6 3 15 C cycloalkylene)- portion of the group linked to the nitrogen to which they are connected to form a saturated cycle of up to 6 ring atoms; R is at each occurrence independently hydrogen, C -C alkyl or C -C 1 6 3 6 cycloalkyl, such C -C alkyl and C -C cycloalkyl being optionally substituted 1 6 3 6 by a group C -C alkyl, -OR , -CN or halo; 20 R is at each occurrence independently hydrogen, -CH or -C H ; 3 2 5 12 13 R and R are independently hydrogen, C -C alkyl, or halogen; A is a divalent cycloalkylene radical having 5 or 6 ring atoms; said cycloalkylene ring being attached to W and Y, and fused to a phenyl ring, such phenyl ring being optionally substituted by one or two groups R ; and 25 wherein said divalent cycloalkylene radical has the formula 24 24 R is at each occurrence independently selected from the group consisting of: C -C alkyl, halogen and cyano; R is a radical of formula (IIIa), (IIIb), (IIIc) or (IIId): 14 15 16 R (IIIa) (IIIb) (IIIc) (IIId) wherein R is selected in the group consisting of: -F, -CH , -C H , -CH OH, 3 2 5 2 -CH OMe, -CF CF , -CH SCH , -SCH and -SC H ; 2 2 3 2 3 3 2 5 15 16 10 R and R are independently -CH or -C H ; 3 2 5 R is selected from the group consisting of: lone electron pair, hydrogen, -CF , -NR R , -(C -C cycloalkyl), -(C -C heterocycloalkyl), aryl or 3 3 7 3 7 heteroaryl wherein any of such –(C -C cycloalkyl), -(C -C heterocycloalkyl), 3 7 3 7 aryl or heteroaryl may be optionally substituted by a group C -C alkyl, C -C 1 6 3 7 15 cycloalkyl, or halo; or R is a group of general formula (IV) (IV) wherein R is selected in the group consisting of: -F, -CH , -C H , -CH OH, 3 2 5 2 -CH OMe, -CF CF , -CH SCH , -SCH and -SC H ; 2 2 3 2 3 3 2 5 R is -CH or -C H ; 3 2 5 20 21 5 R and R as defined above may form together with the carbon atom to which they are attached a saturated 3 membered monocyclic ring; R and R are each independently C -C alkyl, optionally substituted by G E F a group C -C alkyl, -OR , -CN or halo; alternatively, R and R may form together with the nitrogen atom to which they are attached a 5 membered 10 saturated monocyclic or bicyclic heterocyclic ring system which is optionally substituted by one or more groups -OR , -CN, halo, C -C alkyl or C -C 1 6 3 7 cycloalkyl, such C -C alkyl and C -C cycloalkyl being optionally substituted 1 6 3 7 by a group C -C alkyl, C -C cycloalkyl, -OR , -CN or halo; and which 5 1 3 3 7 membered saturated monocyclic or bicyclic heterocyclic ring optionally 15 contains a further heteroatom which is oxygen or nitrogen, said nitrogen atom optionally substituted by C -C alkyl or C -C cycloalkyl, wherein any of such 1 6 3 6 C -C alkyl or C -C cycloalkyl may be optionally substituted by a group C - 1 6 3 6 1 C alkyl or C -C cycloalkyl; 6 3 7 R is hydrogen, -CH or -C H ; 3 2 5 20 R is selected in the group consisting of: lone electron pair, hydrogen, aryl, heteroaryl, -(C -C alkyl), -(C -C cycloalkyl), -(C -C heterocycloalkyl), 1 6 3 7 3 7 (C -C heterocycloalkyl)-(C -Calkyl) and (C -C heterocycloalkyl)-(C -C 5 7 1 6 5 7 3 6 cycloalkyl), wherein any of such aryl, heteroaryl, -(C -Calkyl), -(C - 1 6 3 C cycloalkyl), -(C -C heterocycloalkyl), (C -C heterocycloalkyl)-(C -C alkyl) 7 3 7 5 7 1 6 25 and (C -C heterocycloalkyl)-(C -C cycloalkyl) may be optionally substituted 5 7 3 6 by a group -CN, -OH, halo, -COOR , C -C alkyl, C -C cycloalkyl, -O-(C - 1 6 3 6 1 Calkyl), -O-(C -Ccycloalkyl), -S-(C -Calkyl), -S-(C -C cycloalkyl), 6 3 6 1 6 3 6 H J L H J L H J -NR R, -N(R )(C -C alkylene)-NR R, -N(R )(C -C cycloalkylene)-NR R , 2 6 3 7 H J H J -(C -C alkylene)-NR R, -(C -C cycloalkylene)-NR R, -O-(C -C alkylene)- 1 6 3 7 2 6 H J H J H J NR R , -O-(C -C cycloalkylene)-NR R , -S-(C -C alkylene)-NR R , -S-(C - 3 7 2 6 3 H J L H J L C cycloalkylene)-NR R, -N(R )C(O)-(C -C alkylene)-NR R, -N(R )C(O)- 7 1 6 H J L H J 5 (C -C cycloalkylene)-NR R, -C(O)N(R )-(C -C alkylene)-NR R , 3 7 2 6 L H J L M -C(O)N(R )-(C -C cycloalkylene)-NR R , -C(O)N(R )-(C -C alkylene)-OR , 3 7 2 6 L M L H J H J -C(O)N(R )-(C -C cycloalkylene)-OR , -N(R )C(O)N(R R ), -C(O)N(R R ), L L H J L L -N(R )C(O)N(R )-(C -C alkylene)-NR R, -N(R )C(O)N(R )-(C - 2 6 3 H J M C cycloalkylene)-NR R , -O-(C -C alkylene)-OR , -O-(C -C cycloalkylene)- 7 2 6 3 7 M M M L 10 OR , -S-(C -C alkylene)-OR , -S-(C -C cycloalkylene)-OR , -N(R )S(O) - 2 6 3 7 2 H J L H J (C -C alkylene)-NR R, -N(R )S(O) -(C -C cycloalkylene)-NR R , 1 6 2 3 7 L H J L -S(O) N(R )-(C -C alkylene)-NR R, -S(O) N(R )-(C -C cycloalkylene)- 2 2 6 2 3 7 H J L M L NR R, -S(O) N(R )-(C -C alkylene)-OR, -S(O) N(R )-(C - 2 2 6 2 3 M L M L C cycloalkylene)-OR , -N(R )S(O) -(C -C alkylene)-OR , -N(R )S(O) -(C - 7 2 2 6 2 3 M H J L L L L L 15 C cycloalkylene)-OR , -S(O) N(R R ), -N(R )S(O) R , -N(R )C(O)R , OR , 7 2 2 SR , -(C -C heterocycloalkyl), (C -C heterocycloalkyl)-(C -C alkyl) and (C - 3 7 5 7 1 6 5 C heterocycloalkyl)-(C -C cycloalkyl), wherein any of such C -C alkyl, C - 7 3 6 1 6 3 Ccycloalkyl, -(C -Calkylene)- -(C -Calkylene)-, -(C -C cycloalkylene)-, 6 1 6 2 6 3 7 -(C -C heterocycloalkyl), (C -C heterocycloalkyl)-(C -C alkyl) and (C -C 3 7 5 7 1 6 5 7 20 heterocycloalkyl)-(C -C cycloalkyl) portion in the above listed groups may be optionally substituted by a group C -C alkyl, C -C cycloalkyl, -OR or halo; 1 6 3 7 R and R , are at each occurrence independently hydrogen, C -C alkyl or C -C cycloalkyl, such C -C alkyl or C -C cycloalkyl being optionally 3 6 1 6 3 6 substituted by a group C -C alkyl, -OR , CN or halo; 25 alternatively, R and R may also together with the nitrogen atom to which they are attached a 5 membered saturated monocyclic or bicyclic heterocyclic ring system which is optionally substituted by one or more groups -OR , -CN, halo, C -C alkyl or C -C cycloalkyl, such C -C alkyl and 1 6 3 7 1 6 C -C cycloalkyl being optionally substituted by a group C -C alkyl, C - 3 7 1 3 3 C cycloalkyl, -OR , CN or halo; and which 5 membered saturated monocyclic or bicyclic heterocyclic ring optionally contains a further 5 heteroatom which is oxygen or nitrogen, said nitrogen atom optionally substituted by C -C alkyl or C -C cycloalkyl, wherein any of such C -C 1 6 3 6 1 6 alkyl or C -C cycloalkyl may be optionally substituted by a group C -C 3 6 1 6 alkyl, C -C cycloalkyl, -OR , CN, or halo; and/or R and R may be linked to one carbon atom of the -(C - 10 C alkylene)-, -(C -C alkylene)- or -(C -C cycloalkylene)- portion of the group 6 2 6 3 7 linked to the nitrogen to which they are connected to form a saturated cycle of up to 6 ring atoms; R is at each occurrence independently hydrogen, C -C alkyl or C -C 1 6 3 6 cycloalkyl, such C -C alkyl or C -C cycloalkyl being optionally substituted 1 6 3 6 15 by a group C -C alkyl, -OR , -CN or halo; R is at each occurrence independently hydrogen, C -C alkyl or C -C 1 6 3 6 cycloalkyl, such C -C alkyl or C -C cycloalkyl being optionally substituted 1 6 3 6 by a group hydroxyl, -CN or halo; 1 2 3 4 z , z , z , and z are independently selected in the group consisting of: 20 C, N, S, O, a group -CH-, and a group -NH-, in such a combination that the resulting ring formed is an aromatic system; 19 E F R is selected from the group consisting of: hydrogen, -CF , -NR R , -(C -C cycloalkyl), -(C C heterocycloalkyl), aryl or heteroaryl wherein any 3 7 3- 7 of such -(C -C cycloalkyl), -(C C heterocycloalkyl), aryl or heteroaryl may 3 7 3- 7 25 be optionally substituted by a group C -C alkyl, C -C cycloalkyl, or halo; or 1 6 3 7 R is a group of general formula (V) 20 21 E F wherein R , R , R and R are as above defined; T is -N= or -CR =; R is H, halo, -CH , or -CN; 5 R is H, halo, -CH , or –CN; q is 0, 1, 2 or 3.
2. A compound of formula (I) according to claim 1 which is a compound of formula (Ia) wherein carbon stereogenic center on the cycloalkylene portion of ring A which is linked to group W and identified with number (1) herebelow, 10 possess the absolute configuration herebelow represented: N W A (Ia) or a pharmaceutically acceptable salt thereof. 15
3. A compound of formula (I), according to claim 1 or 2, which is a compound of formula (Ib) wherein carbon stereogenic centers on the cycloalkylene portion of ring A which are linked to group W and Y and identified, respectively, with numbers (1) and (2) herebelow, possess the absolute configuration herebelow represented: N W A (Ib) or a pharmaceutically acceptable salt thereof.
4. A compound of formula (I) according to any one of claims 1 to 3, wherein R is a group of formula (IIc): (IIc) or a pharmaceutically acceptable salt thereof.
5 5. A compound of formula (I) according to any one of claims 1 to 4, wherein R is a group of formula (IIca) as above defined which is connected to the group Y through the carbon adjacent to X (IIca) 4 5 3 and wherein X is a carbon atom, X is a nitrogen atom, X is a nitrogen atom 2 13 10 and X is a group -CH-, and R is hydrogen; wherein R is a group: wherein R is optionally present and represents one, two or three substituents 15 independently selected in the list consisting of: C -C alkyl, (C -C ) haloalkyl, 1 6 1 3 (C -C )hydroxyalkyl, C -C cycloalkyl, hydroxyl and halo; and wherein the 1 4 3 7 asterisk represents the point of attachment for group R to the rest of the molecule via X ; wherein R is a radical of formula (IIIb): (IIIb) 1 2 3 4 17 wherein z = -CH-, z = C, z and z are N and R is a group of general formula (IV) (IV) 20 21 18 and wherein R is -CH or -CH OH, R is -CH and R is as defined in claim 3 2 3
6. A compound of formula (I) according to any one of claims 1 to 4, wherein R is a group of formula (IIca) as above defined which is connected to 10 the group Y through the carbon adjacent to X (IIca) 4 5 3 and wherein X is a carbon atom, X is a nitrogen atom, X is a nitrogen atom 2 13 and X is a group -CH-, and R is hydrogen; wherein R is a group: wherein R is optionally present and represents one, two or three substituents independently selected in the list consisting of: C -C alkyl, (C -C ) haloalkyl, 1 6 1 3 (C -C )hydroxyalkyl, C -C cycloalkyl, hydroxyl and halo; and wherein the 1 4 3 7 asterisk represents the point of attachment for group R to the rest of the 5 molecule via X wherein R is a radical of formula (IIIb): (IIIb) 1 2 3 4 17 wherein z = -CH-, z = C, z and z are N and R is a group of general 10 formula (IV) (IV) 20 21 18 and wherein R is -CH or -CH OH, R is -CH and R is as defined in claim 3 2 3
7. A compound according to claim 1 selected from the group consisting 1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-(2- pyrrolidinyl-ethyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4- 20 tetrahydro-naphthalenyl}-urea; 1-(5-tert-Butylp-tolyl-2H-pyrazolyl)((1S,4R){3-[2-(4- methyl-piperazinyl)-ethyl]-[1,2,4]triazolo[4,3-a]pyridinyloxy}-1,2,3,4- tetrahydro-naphthalenyl)-urea; 1-(5-tert-Butylp-tolyl-2H-pyrazolyl)[(1S,4R)(3-piperidin yl)-[1,2,4]triazolo[4,3-a]pyridinyloxy)-1,2,3,4-tetrahydro-naphthalenyl]- 5 urea; 1-(5-tert-Butylp-tolyl-2H-pyrazolyl)[(1S,4R)(3-piperidin yl)-[1,2,4]triazolo[4,3-a]pyridinyloxy)-1,2,3,4-tetrahydro-naphthalenyl]- urea; 1-(5-tert-Butylp-tolyl-2H-pyrazolyl)[(1S,4R)[3-((S) 10 methyl-pyrrolidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy)-1,2,3,4- tetrahydro-naphthalenyl]-urea; 1-(5-tert-Butylp-tolyl-2H-pyrazolyl)[(1S,4R)((S) pyrrolidinyl-[1,2,4]triazolo[4,3-a]pyridinyloxy)-1,2,3,4-tetrahydro- naphthalenyl]-urea; 15 1-(5-tert-Butylp-tolyl-2H-pyrazolyl)[(1S,4R)(3-piperazin ylmethyl-[1,2,4]triazolo[4,3-a]pyridinyloxy)-1,2,3,4-tetrahydro-naphthalen- 1-yl]-urea; 1-(5-tert-Butylp-tolyl-2H-pyrazolyl)[(1S,4R)(3- isopropylamino-[1,2,4]triazolo[4,3-a]pyridinyloxy)-1,2,3,4-tetrahydro- 20 naphthalenyl]-urea; 1-(5-tert-Butylp-tolyl-2H-pyrazolyl)[(1S,4R)((R) pyrrolidinyl-[1,2,4]triazolo[4,3-a]pyridinyloxy)-1,2,3,4-tetrahydro- naphthalenyl]-urea; 1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-(4-methyl- 25 piperazinylmethyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4- tetrahydro-naphthalenyl}-urea; 1-(5-tert-Butylp-tolyl-2H-pyrazolyl)[(1S,4R)(3-morpholin- 4-ylmethyl-[1,2,4]triazolo[4,3-a]pyridinyloxy)-1,2,3,4-tetrahydro- naphthalenyl]-urea; 1-(5-tert-Butylp-tolyl-2H-pyrazolyl)[(1S,4R)(3-pyrrolidin- 1-ylmethyl-[1,2,4]triazolo[4,3-a]pyridinyloxy)-1,2,3,4-tetrahydro- 5 naphthalenyl]-urea; 1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-(4- morpholinylmethyl-phenyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4- tetrahydro-naphthalenyl]-urea; 1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-(3- 10 morpholinylmethyl-phenyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4- tetrahydro-naphthalenyl}-urea; 1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-(2- morpholinylmethyl-phenyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4- tetrahydro-naphthalenyl}-urea; 15 1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-(1-methyl- piperidinylmethyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4- tetrahydro-naphthalenyl}-urea; 1-(5-tert-Butylp-tolyl-2H-pyrazolyl)((1S,4R){3-[1-(2,2- difluoro-ethyl)-piperidinylmethyl]-[1,2,4]triazolo[4,3-a]pyridinyloxy}- 20 1,2,3,4-tetrahydro-naphthalenyl)-urea; 1-(5-tert-Butylp-tolyl-2H-pyrazolyl)[(1S,4R)[3-(4- hydroxypiperidinyl)-[1,2,4]triazolo[4,3-a]pyridineyloxy]-1,2,3,4- tetrahydro-naphthalenyl]-urea; 1-(5-tert-Butylp-tolyl-2H-pyrazolyl)[(1S,4R){3-[(2- 25 hydroxy-ethyl)-methyl-amino]-[1,2,4]triazolo[4,3-a]pyridineyloxy]-1,2,3,4- tetrahydro-naphthalenyl]-urea; 1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-((S) hydroxy-pyrrolidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4- tetrahydro-naphthalenyl}-urea; 1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-((S) hydroxy-pyrrolidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4- 5 tetrahydro-naphthalenyl}-urea; 1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-((R) hydroxymethyl-pyrrolidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4- tetrahydro-naphthalenyl}-urea; 1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-((S) 10 hydroxymethyl-pyrrolidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4- tetrahydro-naphthalenyl}-urea; 1-[5-tert-Butyl(3-hydroxymethyl-phenyl)-2H-pyrazolyl] [(1S,4R)(3-piperidinyl-[1,2,4]triazolo[4,3-a]pyridinyloxy)-1,2,3,4- tetrahydro-naphthalenyl]-urea; 15 3-[3-tert-Butyl(3-{(1S,4R)[3-((S)methyl-pyrrolidinyl)- [1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}- ureido)-pyrazolyl]-benzoic acid ethyl ester; 1-[5-tert-Butyl(3-hydroxymethyl-phenyl)-2H-pyrazolyl] {(1S,4R)[3-((S)methyl-pyrrolidinyl)-[1,2,4]triazolo[4,3-a]pyridin 20 yloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea; 1-[5-tert-Butyl(4-hydroxymethyl-phenyl)-2H-pyrazolyl] {(1S,4R)[3-((S)methyl-pyrrolidinyl)-[1,2,4]triazolo[4,3-a]pyridin yloxy]-1,2,3,4-tetrahydro-naphthalenyl}urea; 1-[5-tert-Butyl(4-hydroxymethyl-phenyl)-2H-pyrazolyl] 25 [(1S,4R)(3-piperidinyl-[1,2,4]triazolo[4,3-a]pyridinyloxy)-1,2,3,4- tetrahydro-naphthalenyl]-urea; 1-{5-tert-Butyl[3-(2-hydroxy-ethylsulfanyl)-phenyl]-2H-pyrazol yl}{(1S,4R)[3-((S)methyl-pyrrolidinyl)-[1,2,4]triazolo[4,3- a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea; 1-[5-(2-Hydroxy-1,1-dimethyl-ethyl)p-tolyl-2H-pyrazolyl] [(1S,4R)(3-piperidinyl-[1,2,4]triazolo[4,3-a]pyridinyloxy)-1,2,3,4- 5 tetrahydro-naphthalenyl]-urea; 1-[5-tert-Butyl(4-hydroxymethyl-phenyl)-2H-pyrazolyl] {(1S,3S)[3-((S)methyl-pyrrolidinyl)-[1,2,4]triazolo[4,3-a]pyridin yloxy]-indanyl}-urea; 1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-((R) 10 hydroxy-pyrrolidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4- tetrahydro-naphthalenyl}-urea; 1-{5-tert-Butyl[3-(2-hydroxy-ethoxy)-phenyl]-2H-pyrazolyl} [(1S,4R)(3-piperidinyl-[1,2,4]triazolo[4,3-a]pyridinyloxy)-1,2,3,4- tetrahydro-naphthalenyl]-urea; 15 1-{5-tert-Butyl[3-(2-dimethylamino-ethoxy)-phenyl]-2H-pyrazol yl}[(1S,4R)(3-piperidinyl-[1,2,4]triazolo[4,3-a]pyridinyloxy)- 1,2,3,4-tetrahydro-naphthalenyl]-urea; 1-{5-tert-Butyl[3-(4-methyl-piperazinylmethyl)-phenyl]-2H- pyrazolyl}[(1S,4R)(3-piperidinyl-[1,2,4]triazolo[4,3-a]pyridin 20 yloxy)-1,2,3,4-tetrahydro-naphthalenyl]-urea; 1-{5-tert-Butyl[3-(2-hydroxy-ethoxy)-phenyl]-2H-pyrazolyl} {(1S,4R)[3-((S)methyl-pyrrolidinyl)-[1,2,4]triazolo[4,3-a]pyridin yloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea; 1-(5-tert-Butylp-tolyl-2H-pyrazolyl)((1S,4R){3-[(2- 25 dimethylamino-ethyl)-methyl-amino]-[1,2,4]triazolo[4,3-a]pyridinyloxy}- 1,2,3,4-tetrahydro-naphthalenyl)-urea; 1-[5-tert-Butyl(3-piperidinylmethyl-phenyl)-2H-pyrazolyl] [(1S,4R)(3-piperidinyl-[1,2,4]triazolo[4,3-a]pyridinyloxy)-1,2,3,4- tetrahydro-naphthalenyl]-urea; 1-(5-tert-Butylp-tolyl-2H-pyrazolyl)((1S,4R){3-[methyl-(2- morpholinyl-ethyl)-amino]-[1,2,4]triazolo[4,3-a]pyridinyloxy}-1,2,3,4- 5 tetrahydro-naphthalenyl)-urea; 1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-((R) morpholinyl-ethyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4- tetrahydro-naphthalenyl}-urea; 1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-((S) 10 morpholinyl-ethyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4- tetrahydro-naphthalenyl}-urea; 1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-((S)-1,2- dimethyl-pyrrolidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4- tetrahydro-naphthalenyl}-urea; 15 1-{5-tert-Butyl[3-(2-hydroxy-ethoxymethyl)-phenyl]-2H-pyrazol yl}[(1S,4R)(3-piperidinyl-[1,2,4]triazolo[4,3-a]pyridinyloxy)- 1,2,3,4-tetrahydro-naphthalenyl]-urea; 1-(5-tert-Butylp-tolyl-2H-pyrazolyl)[(1S,4R)(3- [1,4]oxazepanyl-[1,2,4]triazolo[4,3-a]pyridinyloxy)-1,2,3,4-tetrahydro- 20 naphthalenyl]-urea; 1-(5-tert-Butyl{3-[4-(2-hydroxy-ethyl)-piperazinylmethyl]- phenyl}-2H-pyrazolyl)[(1S,4R)(3-piperidinyl-[1,2,4]triazolo[4,3- a]pyridinyloxy)-1,2,3,4-tetrahydro-naphthalenyl]-urea; 1-{5-tert-Butyl[3-(4-hydroxy-piperidinylmethyl)-phenyl]-2H- 25 pyrazolyl}[(1S,4R)(3-piperidinyl-[1,2,4]triazolo[4,3-a]pyridin yloxy)-1,2,3,4-tetrahydro-naphthalenyl]-urea; 1-{5-tert-Butyl[3-(2-hydroxy-ethylsulfanyl)-phenyl]-2H-pyrazol yl}[(1S,4R)(3-piperidinyl-[1,2,4]triazolo[4,3-a]pyridinyloxy)- 1,2,3,4-tetrahydro-naphthalenyl]-urea; 1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-(4- hydroxymethyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4- 5 tetrahydro-naphthalenyl}-urea; 1-(5-tert-Butylp-tolyl-2H-pyrazolyl)[(1S,4S)(3-piperidin yl-[1,2,4]triazolo[4,3-a]pyridinyloxy)-1,2,3,4-tetrahydro-naphthalenyl]- urea; 1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-(3- 10 hydroxymethylmethyl-piperazinylmethyl)-[1,2,4]triazolo[4,3-a]pyridin- 6-yloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea; 1-[5-tert-Butyl(4-hydroxymethyl-phenyl)-2H-pyrazolyl] {(1S,4R)[3-(4-hydroxy-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridin yloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea; 15 1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-((S) isopropyl-pyrrolidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4- tetrahydro-naphthalenyl}-urea; 1-(5-tert-Butylp-tolyl-2H-pyrazolyl)[(1S,4R)(3- dimethylamino-[1,2,4]triazolo[4,3-a]pyridinyloxy)-1,2,3,4-tetrahydro- 20 naphthalenyl]-urea; 1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-((R) methyl-pyrrolidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4- tetrahydro-naphthalenyl}-urea; 1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-((S) 25 ethyl-pyrrolidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4- tetrahydro-naphthalenyl}-urea; 1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-((S) methyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4- tetrahydro-naphthalenyl}-urea; 1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-((S) hydroxy-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4- 5 tetrahydro-naphthalenyl}-urea; 1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-((R) hydroxy-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4- tetrahydro-naphthalenyl}-urea; 1-[5-tert-Butyl(4-hydroxymethyl-phenyl)-2H-pyrazolyl] 10 {(1S,4R)[3-((S)methyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridin yloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea; 1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-(4- hydroxyethyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4- tetrahydro-naphthalenyl}-urea; 15 1-[(1S,4R)(3-Azepanyl-[1,2,4]triazolo[4,3-a]pyridinyloxy)- 1,2,3,4-tetrahydro-naphthalenyl](5-tert-butylp-tolyl-2H-pyrazol yl)-urea; 1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-(4-methyl- piperazineyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro- 20 naphthalenyl}urea; 1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-(4-methyl- [1,4]diazepanyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro- naphthalenyl}urea; 1-[5-tert-Butyl(4-hydroxy-phenyl)-2H-pyrazolyl][(1S,4R) 25 (3-piperidinyl-[1,2,4]triazolo[4,3-a]pyridinyloxy)-1,2,3,4-tetrahydro- naphthalenyl]-urea; 1-[5-tert-Butyl(4-cyano-phenyl)-2H-pyrazolyl][(1S,4R)(3- piperidinyl-[1,2,4]triazolo[4,3-a]pyridinyloxy)-1,2,3,4-tetrahydro- naphthalenyl]-urea; 1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4S)[3-((S) methyl-pyrrolidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4- 5 tetrahydro-naphthalenyl}-urea; 1-[5-tert-Butyl(4-hydroxy-phenyl)-2H-pyrazolyl]{(1S,4R) [3-((S)methyl-pyrrolidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]- 1,2,3,4-tetrahydro-naphthalenyl}-urea; 1-(5-tert-Butylp-tolyl-2H-pyrazolyl)((1S,4R){3-[4-(1- 10 hydroxymethyl-ethyl)-piperidinyl]-[1,2,4]triazolo[4,3-a]pyridin yloxy}-1,2,3,4-tetrahydro-naphthalenyl)-urea; 1-(5-tert-Butylp-tolyl-2H-pyrazolyl)[(1S,4R)(3-pyrrolidin- 1-yl-[1,2,4]triazolo[4,3-a]pyridinyloxy)-1,2,3,4-tetrahydro-naphthalen yl]-urea; 15 1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-(1- dimethylaminomethyl-ethyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4- tetrahydro-naphthalenyl}-urea; 1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-((R) hydroxymethyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4- 20 tetrahydro-naphthalenyl}-urea; 1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-((S) hydroxymethyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4- tetrahydro-naphthalenyl}-urea; 1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-(4-hydroxy- 25 4-methyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4- tetrahydro-naphthalenyl}-urea; 1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-(1-methyl- 1-pyrrolidinyl-ethyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4- tetrahydro-naphthalenyl}-urea; 1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-((S) methyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4- 5 tetrahydro-naphthalenyl}-urea; 1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-((R) methyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4- tetrahydro-naphthalenyl}-urea; 1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-((S) 10 methyl-morpholinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4- tetrahydro-naphthalenyl}-urea; 1-(5-tert-Butylp-tolyl-2H-pyrazolyl)((1S,4R){3-[(S)(3- hydroxy-propyl)-pyrrolidinyl]-[1,2,4]triazolo[4,3-a]pyridinyloxy}- 1,2,3,4-tetrahydro-naphthalenyl)-urea; 15 1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-((S) hydroxymethylmethyl-pyrrolidinyl)-[1,2,4]triazolo[4,3-a]pyridin yloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea; 1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-(1,4- dimethyl-piperazinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4- 20 tetrahydro-naphthalenyl}-urea; 1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-((S)-1,4,4- trimethyl-pyrrolidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4- tetrahydro-naphthalenyl}-urea; 1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-((S) 25 methyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4- tetrahydro-naphthalenyl}-urea; 1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-((R) methyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4- tetrahydro-naphthalenyl}-urea; 1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-((R) methyl-pyrrolidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4- 5 tetrahydro-naphthalenyl}-urea; 1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-((2S,4R) fluoromethyl-pyrrolidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]- 1,2,3,4-tetrahydro-naphthalenyl}-urea; 1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-((S) 10 hydroxymethyl-pyrrolidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4- tetrahydro-naphthalenyl}-urea; 1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-((R) hydroxymethyl-pyrrolidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4- tetrahydro-naphthalenyl}-urea; 15 1-(5-tert-Butylp-tolyl-2H-pyrazolyl)((1S,4R){3-[4-(2- hydroxy-ethyl)-piperazinyl]-[1,2,4]triazolo[4,3-a]pyridinyloxy}-1,2,3,4- tetrahydro-naphthalenyl)-urea; 1-{5-tert-Butyl[3-(2-dimethylamino-ethoxy)-phenyl]-2H-pyrazol yl{(1S,4R)[3-((S)methyl-piperidinyl)-[1,2,4]triazolo[4,3- 20 a]pyridinyloxy]-1,2,3,4-tetrahydronaphthalenyl]-urea; 1-{5-tert-Butyl[3-(2-dimethylamino-ethoxy)-phenyl]-2H-pyrazol yl}{(1S,4R)[3-(cis-2,6-dimethyl-piperidinyl)-[1,2,4]triazolo[4,3- a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea; 1-[5-tert-Butyl(3-morpholinylmethyl-phenyl)-2H-pyrazolyl] 25 {(1S,4R)[3-((S)methyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridin yloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea; 1-{5-tert-Butyl[3-(4-methyl-piperazinylmethyl)-phenyl]-2H- pyrazolyl}{(1S,4R)[3-((S)methyl-piperidinyl)- [1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}- urea; 1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-(1- 5 dimethylamino-cyclopentyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4- tetrahydro-naphthalenyl}-urea; 1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[3-((2S,6R)- 2,6-dimethyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4- tetrahydro-naphthalenyl}-urea; 10 1-[(1S,4R)(3-Amino-[1,2,4]triazolo[4,3-a]pyridinyloxy)-1,2,3,4- tetrahydro-naphthalenyl](5-tert-butylp-tolyl-2H-pyrazolyl)-urea; 1-[5-tert-Butyl(6-methyl-pyridinyl)-2H-pyrazolyl][(1S,4R)- 4-(3-piperidinyl-[1,2,4]triazolo[4,3-a]pyridinyloxy)-1,2,3,4-tetrahydro- naphthalenyl]-urea; 15 1-{5-tert-Butyl[3-(2-dimethylamino-ethoxy)-phenyl]-2H-pyrazol yl}[(1S,4R)(3-diisopropylamino-[1,2,4]triazolo[4,3-a]pyridinyloxy)- 1,2,3,4-tetrahydro-naphthalenyl]-urea; N-(5-tert-Butylmethoxy{3-[(1S,4R)(3-piperidinyl- [1,2,4]triazolo[4,3-a]pyridinyloxy)-1,2,3,4-tetrahydro-naphthalenyl]- 20 ureido}-phenyl)-methanesulfonamide; 1-(5-tert-Butylp-tolyl-2H-pyrazolyl){(1S,4R)[8-methyl ((S)methyl-pyrrolidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4- tetrahydro-naphthalenyl}-urea; 1-{5-tert-Butyl[4-(4-methyl-piperazinylmethyl)-phenyl]-2H- 25 pyrazolyl}[(1S,4R)(3-piperidinyl-[1,2,4]triazolo[4,3-a]pyridin yloxy)-1,2,3,4-tetrahydro-naphthalenyl]-urea; 1-(3-tert-Butyl-1'-methyl-1'H-[1,4']bipyrazolylyl)[(1S,4R)(3- piperidinyl-[1,2,4]triazolo[4,3-a]pyridinyloxy)-1,2,3,4-tetrahydro- naphthalenyl]-urea; 1-[3-tert-Butyl-1'-(2-dimethylamino-ethyl)-1'H-[1,4']bipyrazolylyl]- 3-[(1S,4R)(3-piperidinyl-[1,2,4]triazolo[4,3-a]pyridinyloxy)-1,2,3,4- 5 tetrahydro-naphthalenyl]-urea; N-[5-tert-Butylmethoxy(3-{(1S,4R)[3-((S)methyl- pyrrolidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro- naphthalenyl}-ureido)-phenyl]-methanesulfonamide; 1-[5-tert-Butyl(2-hydroxy-ethyl)-2H-pyrazolyl]{(1S,4R)[3- 10 ((S)methyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4- tetrahydro-naphthalenyl}-urea; 1-(5-tert-Butyl-isoxazolyl){(1S,4R)[3-((S)methyl-piperidin- 1-yl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalen yl}-urea; 15 1-[3-tert-Butyl-1'-(2-morpholinyl-ethyl)-1'H-[1,4']bipyrazolylyl]- 3-[(1S,4R)(3-piperidinyl-[1,2,4]triazolo[4,3-a]pyridinyloxy)-1,2,3,4- tetrahydro-naphthalenyl]-urea; 1-[3-tert-Butyl-1'-(3-dimethylamino-propyl)-1'H-[1,4']bipyrazolyl yl][(1S,4R)(3-piperidinyl-[1,2,4]triazolo[4,3-a]pyridinyloxy)- 20 1,2,3,4-tetrahydro-naphthalenyl]-urea; 1-[3-tert-Butyl-1'-(3-morpholinyl-propyl)-1'H-[1,4']bipyrazolyl yl][(1S,4R)(3-piperidinyl-[1,2,4]triazolo[4,3-a]pyridinyloxy)- 1,2,3,4-tetrahydro-naphthalenyl]-urea; 1-{(1S,4R)[3-((2S,6R)-2,6-Dimethyl-piperidinyl)- 25 [1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl} (3-fluoromorpholinyl-phenyl)-urea; 1-[5-tert-Butyl(2-morpholinyl-ethyl)-2H-pyrazolyl] {(1S,4R)[3-((S)methyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridin yloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea; 1-Cyclopropyl{(1S,4R)[3-((2S,6R)-2,6-dimethyl-piperidinyl)- [1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea; 5 1-[5-tert-Butyl(2-hydroxy-ethyl)-2H-pyrazolyl]{(1S,4R)[3- ((2S,6R)-2,6-dimethyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]- 1,2,3,4-tetrahydro-naphthalenyl}-urea; 1-{5-tert-Butyl[1-(2-dimethylamino-ethyl)-1H-imidazolyl]-2H- pyrazolyl}[(1S,4R)(3-piperidinyl-[1,2,4]triazolo[4,3-a]pyridin 10 yloxy)-1,2,3,4-tetrahydro-naphthalenyl]-urea; 1-[5-tert-Butyl(2-hydroxy-ethyl)-2H-pyrazolyl]{(1S,4R)[3- ((S)methyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4- tetrahydro-naphthalenyl}-urea; 1-[5-tert-Butyl(2-morpholinyl-ethyl)-2H-pyrazolyl] 15 {(1S,4R)[3-((2S,6R)-2,6-dimethyl-piperidinyl)-[1,2,4]triazolo[4,3- a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea; 1-{(1S,4R)[3-(8-Aza-bicyclo[3.2.1]octyl)-[1,2,4]triazolo[4,3- a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}{5-tert-butyl[3- (2-dimethylamino-ethoxy)-phenyl]-2H-pyrazolyl}-urea; 20 1-{5-tert-Butyl[3-(2-dimethylamino-ethoxy)-phenyl]-2H-pyrazol yl}{(1S,4R)[3-((R)methyl-piperidinyl)-[1,2,4]triazolo[4,3- a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea; 1-[3-tert-Butyl-1'-(2-morpholinyl-ethyl)-1'H-[1,4']bipyrazolylyl]- 3-{(1S,4R)[3-((2S,6R)-2,6-dimethyl-piperidinyl)-[1,2,4]triazolo[4,3- 25 a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea; 1-[3-tert-Butyl-1'-(2-dimethylamino-ethyl)-1'H-[1,4']bipyrazolylyl]- 3-{(1S,4R)[3-((2S,6R)-2,6-dimethyl-piperidinyl)-[1,2,4]triazolo[4,3- a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea; 1-(5-tert-Butylmethyl-2H-pyrazolyl){(1S,4R)[3-((S) methyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4- tetrahydronaphthalenyl]-urea; 5 1-[5-tert-Butyl(2-dimethylamino-ethyl)-2H-pyrazolyl] {(1S,4R)[3-((S)methyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridin yloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea; 1-[5-tert-Butyl(2-piperidinyl-ethyl)-2H-pyrazolyl]{(1S,4R)- 4-[3-((S)methyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]- 10 1,2,3,4-tetrahydro-naphthalenyl}-urea; 1-{5-tert-Butyl[2-(4-methyl-piperazinyl)-ethyl]-2H-pyrazolyl}- 3-{(1S,4R)[3-((S)methyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridin yloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea; 1-[5-tert-Butyl(3-morpholinylmethyl-phenyl)-2H-pyrazolyl] 15 {(1S,4R)[3-((2S,6R)-2,6-dimethyl-piperidinyl)-[1,2,4]triazolo[4,3- a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea; 1-{5-tert-Butyl[3-(2-morpholinyl-ethyl)-phenyl]-2H-pyrazol yl}{(1S,4R)[3-((S)methyl-piperidinyl)-[1,2,4]triazolo[4,3- a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea; 20 1-{5-tert-Butyl[3-(2-pyrrolidinyl-ethyl)-phenyl]-2H-pyrazol yl}{(1S,4R)[3-((S)methyl-piperidinyl)-[1,2,4]triazolo[4,3- a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea; 1-(5-tert-Butyl{3-[2-(ethyl-methyl-amino)-ethyl]-phenyl}-2H- pyrazolyl){(1S,4R)[3-((S)methyl-piperidinyl)- 25 [1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}- urea; 1-{5-tert-Butyl[3-(2-dimethylamino-ethyl)-phenyl]-2H-pyrazol yl}{(1S,4R)[3-((S)methyl-piperidinyl)-[1,2,4]triazolo[4,3- a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea; 1-{5-tert-Butyl[3-(2-piperidinyl-ethyl)-phenyl]-2H-pyrazolyl}- 3-{(1S,4R)[3-((S)methyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridin 5 yloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea; 1-(5-tert-Butyl{3-[2-(4-methyl-piperazinyl)-ethyl]-phenyl}-2H- pyrazolyl){(1S,4R)[3-((S)methyl-piperidinyl)- [1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}- urea; 10 1-{5-tert-Butyl[3-(2-[1,4]oxazepanyl-ethyl)-phenyl]-2H-pyrazol- 3-yl}{(1S,4R)[3-((S)methyl-piperidinyl)-[1,2,4]triazolo[4,3- a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea; 1-(5-tert-Butyl{3-[2-(4-methyl-[1,4]diazepanyl)-ethyl]-phenyl}- 2H-pyrazolyl){(1S,4R)[3-((S)methyl-piperidinyl)- 15 [1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}- urea; 1-[5-tert-Butyl(2-hydroxy-ethyl)-2H-pyrazolyl]{(1S,4R)[3- ((S)methyl-morpholinyl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4- tetrahydro-naphthalenyl}-urea; 20 1-(5-tert-Butyl{2-[(2-dimethylamino-ethyl)-methyl-amino]- pyrimidinyl}-2H-pyrazolyl){(1S,4R)[3-((S)methyl-piperidin yl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}- urea; 1-{5-tert-Butyl[3-(2-dimethylamino-ethoxy)-phenyl]-2H-pyrazol 25 yl}{(1S,4R)[3-((S)methyl-morpholinyl)-[1,2,4]triazolo[4,3- a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea; 1-[5-tert-Butyl(2-morpholinyl-ethyl)-2H-pyrazolyl] {(1S,4R)[3-((S)methyl-morpholinyl)-[1,2,4]triazolo[4,3-a]pyridin yloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea; 1-{5-tert-Butyl[3-(4-methyl-piperazinylmethyl)-phenyl]-2H- pyrazolyl}{(1S,4R)[3-((2S,6R)-2,6-dimethyl-piperidinyl)- 5 [1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}- urea; 1-[5-tert-Butyl(3-pyrrolidinylmethyl-phenyl)-2H-pyrazolyl] {(1S,4R)[3-((2S,6R)-2,6-dimethyl-piperidinyl)-[1,2,4]triazolo[4,3- a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea; 10 1-{5-tert-Butyl[3-(2-pyrrolidinyl-ethoxy)-phenyl]-2H-pyrazol yl}{(1S,4R)[3-((2S,6R)-2,6-dimethyl-piperidinyl)-[1,2,4]triazolo[4,3- a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea; 1-(5-tert-Butyl{3-[2-(4-methyl-piperazinyl)-ethoxy]-phenyl}-2H- pyrazolyl){(1S,4R)[3-((2S,6R)-2,6-dimethyl-piperidinyl)- 15 [1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl }- urea; 1-(5-tert-Butyl{3-[2-(ethyl-methyl-amino)-ethoxy]-phenyl}-2H- pyrazolyl){(1S,4R)[3-((2S,6R)-2,6-dimethyl-piperidinyl)- [1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}- 20 urea; 1-{(1S,4R)[3-(4-Aza-spiro[2.5]octyl)-[1,2,4]triazolo[4,3- a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}{5-tert-butyl[3- (2-dimethylamino-ethoxy)-phenyl]-2H-pyrazolyl}-urea; 1-[5-tert-Butyl(3-morpholinyl-methyl-phenyl)-2H-pyrazolyl]- 25 3-{(1S,4R)[3-((S)methyl-pyrrolidinyl)-[1,2,4]triazolo[4,3-a]pyridin- 6-yloxy]-1,2,3,4-tetrahydronaphthalenyl}-urea; 1-(5-tert-Butyl{3-[(2-dimethylamino-ethyl)-methyl-amino]-phenyl}- 2H-pyrazolyl){(1S,4R)[3-((S)methyl-piperidinyl)- [1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}- urea; 1-{5-tert-Butyl[3-((R)dimethylaminomethyl-ethoxy)-phenyl]- 5 2H-pyrazolyl}{(1S,4R)[3-((S)methyl-piperidinyl)- [1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}- urea; 1-{5-tert-Butyl[3-((S)dimethylaminomethyl-ethoxy)-phenyl]- 2H-pyrazolyl}{(1S,4R)[3-((S)methyl-piperidinyl)- 10 [1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}- urea; 1-[2-[3-(2-Dimethylamino-ethoxy)-phenyl](2-hydroxy-1,1-dimethyl- ethyl)-2H-pyrazolyl]{(1S,4R)[3-((S)methyl-piperidinyl)- [1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}- 15 urea; 1-{5-tert-Butyl[3-(2-pyrrolidinyl-ethoxy)-phenyl]-2H-pyrazol yl}{(1S,4R)[3-((S)methyl-piperidinyl)-[1,2,4]triazolo[4,3- a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea; 1-{5-tert-Butyl[3-(2-diethylamino-ethoxy)-phenyl]-2H-pyrazol 20 yl}{(1S,4R)[3-((S)methyl-piperidinyl)-[1,2,4]triazolo[4,3- a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea; 1-{5-tert-Butyl[3-(2-morpholinyl-ethoxy)-phenyl]-2H-pyrazol yl}{(1S,4R)[3-((S)methyl-piperidinyl)-[1,2,4]triazolo[4,3- a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea; 25 1-{5-tert-Butyl[3-(2-piperidinyl-ethoxy)-phenyl]-2H-pyrazol yl}{(1S,4R)[3-((S)methyl-piperidinyl)-[1,2,4]triazolo[4,3- a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea; 1-(5-tert-Butyl{3-[2-(4-methyl-piperazinyl)-ethoxy]-phenyl}-2H- pyrazolyl){(1S,4R)[3-((S)methyl-piperidinyl)- [1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}- urea; 5 1-{5-tert-Butyl{3-[2-(4-fluoropiperidinyl)-ethoxy]-phenyl}-2H- pyrazolyl}{(1S,4R)[3-((S)methyl-piperidinyl)- [1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}- urea; 1-(5-tert-Butyl{3-[2-(4-methyl-[1,4]-diazepanyl)-ethoxy]- 10 phenyl}-2H-pyrazolyl){(1S,4R)[3-((S)methyl-piperidinyl)- [1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}- urea; 1-{5-tert-Butyl[3-(2-[1,4]oxazepanyl-ethoxy)-phenyl]-2H- pyrazolyl}{(1S,4R)[3-((S)methyl-piperidinyl)- 15 [1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}- urea; 1-(2-{3-[2-(8-Aza-bicyclo[3.2.1]octyl)-ethoxy]-phenyl}tert-butyl- 2H-pyrazolyl){(1S,4R)[3-((S)methyl-piperidinyl)- [1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}- 20 urea; 1-(5-tert-Butyl{3-[2-(ethyl-methyl-amino)-ethoxy]-phenyl}-2H- pyrazolyl){(1S,4R)[3-((S)methyl-piperidinyl)- [1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}- urea; 25 1-{5-tert-Butyl(3-{2-[(2-methoxy-ethyl)-methyl-amino]-ethoxy}- phenyl}-2H-pyrazolyl}{(1S,4R)[3-((S)methyl-piperidinyl)- [1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}- urea; 1-(5-tert-Butyl{3-[2-(4-methoxy-piperidinyl-ethoxy]-phenyl}-2H- pyrazolyl){(1S,4R)[3-((S)methyl-piperidinyl)- [1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}- 5 urea; 1-(5-tert-Butyl{3-[2-(3-oxaaza-bicyclo[3.2.1]octyl)-ethoxy]- phenyl}-2H-pyrazolyl){(1S,4R)[3-((S)methyl-piperidinyl)- [1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}- urea; 10 1-{5-tert-Butyl[3-(4-methoxy-piperidinylmethyl)-phenyl]-2H- pyrazolyl}{(1S,4R)[3-((S)methyl-piperidinyl)- [1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}- urea; 1-[5-tert-Butyl(3-{[(2-methoxy-ethyl)-methyl-amino]-methyl}- 15 phenyl)-2H-pyrazolyl]{(1S,4R)[3-((S)methyl-piperidinyl)- [1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}- urea; 1-{5-tert-Butyl[3-(4-fluoro-piperidinylmethyl)-phenyl]-2H- pyrazolyl}{(1S,4R)[3-((S)methyl-piperidinyl)- 20 [1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}- urea; 1-[5-tert-Butyl(3-dimethylaminomethyl-phenyl)-2H-pyrazolyl] {(1S,4R)[3-((S)methyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridin yloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea; 25 1-[5-tert-Butyl(3-pyrrolidinylmethyl-phenyl)-2H-pyrazolyl] {(1S,4R)[3-((S)methyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridin yloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea; 1-{(1S,4R)[3-(4-Aza-spiro[2.5]octyl)-[1,2,4]triazolo[4,3- a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}{5-tert-butyl[3- (2-morpholinyl-ethoxy)-phenyl]-2H-pyrazolyl}-urea; 1-[5-tert-Butyl(3-piperidinylmethyl-phenyl)-2H-pyrazolyl] 5 {(1S,4R)[3-((S)methyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridin yloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea; 1-{5-tert-Butyl[3-(4-methyl-[1,4]diazepanylmethyl)-phenyl]-2H- pyrazolyl}{(1S,4R)[3-((S)methyl-piperidinyl)- [1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}- 10 urea; 1-{5-tert-Butyl[3-((1S,4S)methyl-2,5-diaza-bicyclo[2.2.1]hept ylmethyl)-phenyl]-2H-pyrazolyl}{(1S,4R)[3-((S)methyl-piperidin- 1-yl)-[1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalen yl}-urea; 15 1-[5-tert-Butyl(4-morpholinylmethyl-phenyl)-2H-pyrazolyl] {(1S,4R)[3-((S)methyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridin yloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea; 1-[5-tert-Butyl(4-dimethylaminomethyl-phenyl)-2H-pyrazolyl] {(1S,4R)[3-((S)methyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridin 20 yloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea; 1-{5-tert-Butyl[4-(4-methyl-piperazinylmethyl)-phenyl]-2H- pyrazolyl}{(1S,4R)[3-((S)methyl-piperidinyl)- [1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}- urea; 25 1-{5-tert-Butyl[4-(4-methyl-[1,4]diazepanylmethyl)-phenyl]-2H- pyrazolyl}{(1S,4R)[3-((S)methyl-piperidinyl)- [1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}- urea; 1-{5-tert-Butyl[4-(4-methoxy-piperidinylmethyl)-phenyl]-2H- pyrazolyl}{(1S,4R)[3-((S)methyl-piperidinyl)- [1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}- 5 urea; 1-[5-tert-Butyl(4-pyrrolidinylmethyl-phenyl)-2H-pyrazolyl] {(1S,4R)[3-((S)methyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridin yloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea; 1-[5-tert-Butyl(4-piperidinylmethyl-phenyl)-2H-pyrazolyl] 10 {(1S,4R)[3-((S)methyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridin yloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea; 1-{5-tert-Butyl[4-(4-fluoro-piperidinylmethyl)-phenyl]-2H- pyrazolyl}{(1S,4R)[3-((S)methyl-piperidinyl)- [1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}- 15 urea; 1-(5-tert-Butyl{4-[(ethyl-methyl-amino)-methyl]-phenyl}-2H- pyrazolyl){(1S,4R)[3-((S)methyl-piperidinyl)- [1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}- urea; 20 1-[5-tert-Butyl(4-{[(2-methoxy-ethyl)-methyl-amino]-methyl}- phenyl)-2H-pyrazolyl]{(1S,4R)[3-((S)methyl-piperidinyl)- [1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}- urea; 1-{5-tert-Butyl[3-(2-dimethylamino-ethoxy)-phenyl]-2H-pyrazol 25 yl{(1S,4S)[3-((S)methyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridin- 6-yloxy]-1,2,3,4-tetrahydronaphthalenyl]-urea; 1-[3-tert-Butyl-1'-(2-dimethylamino-ethyl)-1'H-[1,4']bipyrazolylyl]- 3-{(1S,4R)[3-((S)methyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridin yloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea; 1-[3-tert-Butyl-1'-(2-morpholinyl-ethyl)-1'H-[1,4']bipyrazolylyl]- 5 3-{(1S,4R)[3-((S)methyl-piperidinyl)-[1,2,4]triazolo[4,3-a]pyridin yloxy]-1,2,3,4-tetrahydro-naphthalenyl}-urea; 1-{5-tert-Butyl[3-(4-methyl-piperazinylmethyl)-phenyl]-2H- pyrazolyl}{(1S,4R)[3-((S)methyl-pyrrolidinyl)- [1,2,4]triazolo[4,3-a]pyridinyloxy]-1,2,3,4-tetrahydro-naphthalenyl}- 10 urea; and pharmaceutically acceptable salts thereof.
8. A pharmaceutical composition comprising a compound as claimed in any one of the preceding claims 1 to 7, together with one or more pharmaceutically acceptable carriers. 15
9. Use of a compound as claimed in any of claims 1 to 7 in the manufacture of a medicament for the treatment of diseases or conditions which benefit from inhibition of p38 MAP kinase activity.
10. The use according to claim 9 wherein the disease or condition is selected from the group consisting of chronic eosinophilic pneumonia, asthma, 20 COPD, adult respiratory distress syndrome (ARDS), exacerbation of airways hyper-reactivity consequent to other drug therapy or airways disease that is associated with pulmonary hypertension.
11. A compound as described in any one of claims 1 to 7, substantially herein described and with reference to any example thereof. 25
12. A pharmaceutical composition as described in claim 8, substantially herein described and with reference to any example thereof.
13. A use as described in claim 9 or claim 10, substantially herein described and with reference to any example thereof.
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP11192871.9 | 2011-12-09 | ||
EP11192871 | 2011-12-09 | ||
EP12187931 | 2012-10-10 | ||
EP12187931.6 | 2012-10-10 | ||
PCT/EP2012/074446 WO2013083604A1 (en) | 2011-12-09 | 2012-12-05 | Kinase inhibitors |
Publications (2)
Publication Number | Publication Date |
---|---|
NZ625965A NZ625965A (en) | 2016-08-26 |
NZ625965B2 true NZ625965B2 (en) | 2016-11-29 |
Family
ID=
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US9527846B2 (en) | Kinase inhibitors | |
EP3004097B1 (en) | Kinase inhibitors | |
EP3004098B1 (en) | Kinase inhibitors | |
AU2012347352B2 (en) | Kinase inhibitors | |
CA2858420A1 (en) | Derivatives of 4-hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl urea and their use in the treatment of, inter alia, diseases of the respiratory tract | |
CA2914457A1 (en) | Kinase inhibitors | |
NZ625965B2 (en) | Kinase inhibitors useful as anti-inflammatory agents | |
EP3394059A1 (en) | 1-(3-tert-butyl-phenyl)-3-(4-([1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro- naphthalen-1-yl)-urea derivatives and their use as p38 mapk inhibitors |