ZA200106857B - Amide derivatives. - Google Patents
Amide derivatives. Download PDFInfo
- Publication number
- ZA200106857B ZA200106857B ZA200106857A ZA200106857A ZA200106857B ZA 200106857 B ZA200106857 B ZA 200106857B ZA 200106857 A ZA200106857 A ZA 200106857A ZA 200106857 A ZA200106857 A ZA 200106857A ZA 200106857 B ZA200106857 B ZA 200106857B
- Authority
- ZA
- South Africa
- Prior art keywords
- alkyl
- alkylamino
- methylamino
- alkoxy
- amino
- Prior art date
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- 150000001408 amides Chemical class 0.000 title claims description 49
- -1 cyano, mercapto, nitro, amino, carboxy Chemical group 0.000 claims description 1176
- 125000000217 alkyl group Chemical group 0.000 claims description 269
- 125000003282 alkyl amino group Chemical group 0.000 claims description 211
- 125000003545 alkoxy group Chemical group 0.000 claims description 142
- 125000001424 substituent group Chemical group 0.000 claims description 100
- 125000005236 alkanoylamino group Chemical group 0.000 claims description 90
- 150000001875 compounds Chemical class 0.000 claims description 69
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 52
- 150000003839 salts Chemical class 0.000 claims description 47
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims description 45
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 42
- 125000004195 4-methylpiperazin-1-yl group Chemical group [H]C([H])([H])N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims description 38
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 37
- 125000001153 fluoro group Chemical group F* 0.000 claims description 37
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 36
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 32
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 32
- 125000000623 heterocyclic group Chemical group 0.000 claims description 31
- 125000006264 diethylaminomethyl group Chemical group [H]C([H])([H])C([H])([H])N(C([H])([H])*)C([H])([H])C([H])([H])[H] 0.000 claims description 27
- 125000005843 halogen group Chemical group 0.000 claims description 27
- 125000001072 heteroaryl group Chemical group 0.000 claims description 27
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 27
- 125000003118 aryl group Chemical group 0.000 claims description 25
- 150000002148 esters Chemical class 0.000 claims description 25
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 claims description 23
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 22
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 21
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 20
- 238000006243 chemical reaction Methods 0.000 claims description 20
- 238000000034 method Methods 0.000 claims description 20
- 125000001064 morpholinomethyl group Chemical group [H]C([H])(*)N1C([H])([H])C([H])([H])OC([H])([H])C1([H])[H] 0.000 claims description 20
- 108090000695 Cytokines Proteins 0.000 claims description 19
- 102000004127 Cytokines Human genes 0.000 claims description 19
- 125000004076 pyridyl group Chemical group 0.000 claims description 19
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 18
- 125000006534 ethyl amino methyl group Chemical group [H]N(C([H])([H])*)C([H])([H])C([H])([H])[H] 0.000 claims description 18
- 125000006222 dimethylaminomethyl group Chemical group [H]C([H])([H])N(C([H])([H])[H])C([H])([H])* 0.000 claims description 17
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 17
- 125000006239 protecting group Chemical group 0.000 claims description 17
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims description 16
- 125000001246 bromo group Chemical group Br* 0.000 claims description 15
- 239000001257 hydrogen Substances 0.000 claims description 15
- 229910052739 hydrogen Inorganic materials 0.000 claims description 15
- 125000002541 furyl group Chemical group 0.000 claims description 14
- 125000001544 thienyl group Chemical group 0.000 claims description 14
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 13
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 13
- 125000006479 2-pyridyl methyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 claims description 12
- DGYIJVNZSDYBOE-UHFFFAOYSA-N [CH2]C1=CC=NC=C1 Chemical group [CH2]C1=CC=NC=C1 DGYIJVNZSDYBOE-UHFFFAOYSA-N 0.000 claims description 12
- 125000001589 carboacyl group Chemical group 0.000 claims description 12
- 201000010099 disease Diseases 0.000 claims description 12
- 150000002431 hydrogen Chemical class 0.000 claims description 12
- 238000004519 manufacturing process Methods 0.000 claims description 12
- 125000002757 morpholinyl group Chemical group 0.000 claims description 12
- 125000004193 piperazinyl group Chemical group 0.000 claims description 12
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 12
- 125000003386 piperidinyl group Chemical group 0.000 claims description 11
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 10
- 239000002253 acid Substances 0.000 claims description 10
- 229910052799 carbon Inorganic materials 0.000 claims description 10
- 125000004432 carbon atom Chemical group C* 0.000 claims description 10
- 125000002883 imidazolyl group Chemical group 0.000 claims description 10
- 125000006533 methyl amino methyl group Chemical group [H]N(C([H])([H])[H])C([H])([H])* 0.000 claims description 10
- 125000004601 benzofurazanyl group Chemical group N1=C2C(=NO1)C(=CC=C2)* 0.000 claims description 9
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 9
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 9
- 125000000524 functional group Chemical group 0.000 claims description 9
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 9
- 125000005493 quinolyl group Chemical group 0.000 claims description 9
- 125000000335 thiazolyl group Chemical group 0.000 claims description 9
- 125000003342 alkenyl group Chemical group 0.000 claims description 8
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 8
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 8
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 8
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 claims description 8
- 125000001041 indolyl group Chemical group 0.000 claims description 8
- 125000005956 isoquinolyl group Chemical group 0.000 claims description 8
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 8
- 125000002971 oxazolyl group Chemical group 0.000 claims description 8
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims description 8
- 230000008569 process Effects 0.000 claims description 8
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 8
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 8
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 8
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 8
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 claims description 8
- 125000004947 alkyl aryl amino group Chemical group 0.000 claims description 7
- 125000005115 alkyl carbamoyl group Chemical group 0.000 claims description 7
- 125000004414 alkyl thio group Chemical group 0.000 claims description 7
- 125000005530 alkylenedioxy group Chemical group 0.000 claims description 7
- 125000005239 aroylamino group Chemical group 0.000 claims description 7
- 125000001769 aryl amino group Chemical group 0.000 claims description 7
- 125000004104 aryloxy group Chemical group 0.000 claims description 7
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 claims description 7
- 125000005844 heterocyclyloxy group Chemical group 0.000 claims description 7
- 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 claims description 7
- 125000005344 pyridylmethyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 claims description 7
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 claims description 7
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims description 6
- 125000000304 alkynyl group Chemical group 0.000 claims description 6
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 6
- 125000000609 carbazolyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3NC12)* 0.000 claims description 6
- 125000005509 dibenzothiophenyl group Chemical group 0.000 claims description 6
- 125000005241 heteroarylamino group Chemical group 0.000 claims description 6
- 125000005224 heteroarylcarbonylamino group Chemical group 0.000 claims description 6
- 125000005553 heteroaryloxy group Chemical group 0.000 claims description 6
- 125000001786 isothiazolyl group Chemical group 0.000 claims description 6
- 238000011282 treatment Methods 0.000 claims description 6
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Chemical group C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 claims description 5
- 230000029936 alkylation Effects 0.000 claims description 5
- 238000005804 alkylation reaction Methods 0.000 claims description 5
- 150000001412 amines Chemical class 0.000 claims description 5
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 5
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 5
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 5
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 claims description 5
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 claims description 5
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 claims description 5
- 125000001834 xanthenyl group Chemical group C1=CC=CC=2OC3=CC=CC=C3C(C12)* 0.000 claims description 5
- 125000004364 3-pyrrolinyl group Chemical group [H]C1=C([H])C([H])([H])N(*)C1([H])[H] 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 230000010933 acylation Effects 0.000 claims description 4
- 238000005917 acylation reaction Methods 0.000 claims description 4
- 125000004423 acyloxy group Chemical group 0.000 claims description 4
- 125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 4
- 125000004566 azetidin-1-yl group Chemical group N1(CCC1)* 0.000 claims description 4
- 125000002393 azetidinyl group Chemical group 0.000 claims description 4
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 4
- 230000001404 mediated effect Effects 0.000 claims description 4
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 4
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- 239000005711 Benzoic acid Substances 0.000 claims description 3
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 3
- 235000010233 benzoic acid Nutrition 0.000 claims description 3
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 claims description 3
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 claims description 3
- 125000003006 2-dimethylaminoethyl group Chemical group [H]C([H])([H])N(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 241001465754 Metazoa Species 0.000 claims description 2
- 238000003776 cleavage reaction Methods 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 230000007017 scission Effects 0.000 claims description 2
- 125000003396 thiol group Chemical class [H]S* 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims 7
- 239000000126 substance Substances 0.000 claims 5
- FXHRAKUEZPSMLJ-UHFFFAOYSA-N 1-methyl-1,4-diazepane Chemical compound CN1CCCNCC1 FXHRAKUEZPSMLJ-UHFFFAOYSA-N 0.000 claims 1
- FPZWZCWUIYYYBU-UHFFFAOYSA-N 2-(2-ethoxyethoxy)ethyl acetate Chemical group CCOCCOCCOC(C)=O FPZWZCWUIYYYBU-UHFFFAOYSA-N 0.000 claims 1
- 125000006367 bivalent amino carbonyl group Chemical group [H]N([*:1])C([*:2])=O 0.000 claims 1
- 239000003814 drug Substances 0.000 claims 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 16
- 108700012920 TNF Proteins 0.000 description 10
- 108010002352 Interleukin-1 Proteins 0.000 description 8
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 8
- 239000005864 Sulphur Substances 0.000 description 8
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 8
- 125000005842 heteroatom Chemical group 0.000 description 8
- 229910052757 nitrogen Inorganic materials 0.000 description 8
- 239000001301 oxygen Substances 0.000 description 8
- 229910052760 oxygen Inorganic materials 0.000 description 8
- 239000002585 base Substances 0.000 description 7
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 7
- 125000002619 bicyclic group Chemical group 0.000 description 7
- 125000002950 monocyclic group Chemical group 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 6
- 239000003960 organic solvent Substances 0.000 description 6
- 125000004093 cyano group Chemical group *C#N 0.000 description 5
- 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 5
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 102000002574 p38 Mitogen-Activated Protein Kinases Human genes 0.000 description 5
- 229940002612 prodrug Drugs 0.000 description 5
- 239000000651 prodrug Substances 0.000 description 5
- 125000003635 2-dimethylaminoethoxy group Chemical group [H]C([H])([H])N(C([H])([H])[H])C([H])([H])C([H])([H])O* 0.000 description 4
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 4
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 4
- 150000008064 anhydrides Chemical class 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 150000001721 carbon Chemical group 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 4
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 4
- 239000003701 inert diluent Substances 0.000 description 4
- 239000012442 inert solvent Substances 0.000 description 4
- 239000003112 inhibitor Substances 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 3
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 3
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 3
- KDDQRKBRJSGMQE-UHFFFAOYSA-N 4-thiazolyl Chemical compound [C]1=CSC=N1 KDDQRKBRJSGMQE-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 3
- 206010061218 Inflammation Diseases 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 108091000080 Phosphotransferase Proteins 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 206010040070 Septic Shock Diseases 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 150000001718 carbodiimides Chemical class 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 230000004054 inflammatory process Effects 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 3
- 102000020233 phosphotransferase Human genes 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 206010039073 rheumatoid arthritis Diseases 0.000 description 3
- 230000000638 stimulation Effects 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 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 3
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- 125000000586 2-(4-morpholinyl)ethoxy group Chemical group [H]C([H])(O*)C([H])([H])N1C([H])([H])C([H])([H])OC([H])([H])C1([H])[H] 0.000 description 2
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 description 2
- 125000004174 2-benzimidazolyl group Chemical group [H]N1C(*)=NC2=C([H])C([H])=C([H])C([H])=C12 0.000 description 2
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- 208000030507 AIDS Diseases 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 2
- 201000004624 Dermatitis Diseases 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- 108010063738 Interleukins Proteins 0.000 description 2
- 102000015696 Interleukins Human genes 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 208000001132 Osteoporosis Diseases 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 230000002159 abnormal effect Effects 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 150000008065 acid anhydrides Chemical class 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 150000001266 acyl halides Chemical class 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
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- 201000001245 periodontitis Diseases 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000004934 phenanthridinyl group Chemical group C1(=CC=CC2=NC=C3C=CC=CC3=C12)* 0.000 description 1
- 125000001484 phenothiazinyl group Chemical group C1(=CC=CC=2SC3=CC=CC=C3NC12)* 0.000 description 1
- 125000005954 phenoxathiinyl group Chemical group 0.000 description 1
- 125000001644 phenoxazinyl group Chemical group C1(=CC=CC=2OC3=CC=CC=C3NC12)* 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 230000009894 physiological stress Effects 0.000 description 1
- 230000035409 positive regulation of cell proliferation Effects 0.000 description 1
- 208000001685 postmenopausal osteoporosis Diseases 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 1
- 229910000105 potassium hydride Inorganic materials 0.000 description 1
- CUQOHAYJWVTKDE-UHFFFAOYSA-N potassium;butan-1-olate Chemical compound [K+].CCCC[O-] CUQOHAYJWVTKDE-UHFFFAOYSA-N 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical group CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 1
- 125000004742 propyloxycarbonyl group Chemical group 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 229940024999 proteolytic enzymes for treatment of wounds and ulcers Drugs 0.000 description 1
- 239000003586 protic polar solvent Substances 0.000 description 1
- 208000005069 pulmonary fibrosis Diseases 0.000 description 1
- 125000004307 pyrazin-2-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 description 1
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
- 125000002755 pyrazolinyl group Chemical group 0.000 description 1
- 125000002206 pyridazin-3-yl group Chemical group [H]C1=C([H])C([H])=C(*)N=N1 0.000 description 1
- 125000004940 pyridazin-4-yl group Chemical group N1=NC=C(C=C1)* 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 description 1
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 description 1
- 125000004528 pyrimidin-5-yl group Chemical group N1=CN=CC(=C1)* 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 201000002793 renal fibrosis Diseases 0.000 description 1
- 208000023504 respiratory system disease Diseases 0.000 description 1
- 208000037803 restenosis Diseases 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 230000036303 septic shock Effects 0.000 description 1
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 description 1
- 208000017520 skin disease Diseases 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 125000005415 substituted alkoxy group Chemical group 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- GFYHSKONPJXCDE-UHFFFAOYSA-N sym-collidine Natural products CC1=CN=C(C)C(C)=C1 GFYHSKONPJXCDE-UHFFFAOYSA-N 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000004853 tetrahydropyridinyl group Chemical group N1(CCCC=C1)* 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000004627 thianthrenyl group Chemical group C1(=CC=CC=2SC3=CC=CC=C3SC12)* 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- 108700012359 toxins Proteins 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 125000004665 trialkylsilyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
0 . AMIDE DERIVATIVES
This invention concerns certain amide derivatives which are useful as inhibitors of cytokine mediated disease. The invention also concerns processes for the manufacture of the 5S amide derivatives of the invention, pharmaceutical compositions containing them and their use in therapeutic methods, for example by virtue of inhibition of cytokine mediated disease.
The amide derivatives disclosed in the present invention are inhibitors of the production of cytokines such as Tumour Necrosis Factor (hereinafter TNF), for example
TNFa. and various members of the interleukin (hereinafter IL) family, for example IL-1, IL-6 and IL-8. Accordingly the compounds of the invention will be useful in the treatment of diseases or medical conditions in which excessive production of cytokines occurs, for example excessive production of TNFa or IL-1. It is known that cytokines are produced by a wide variety of cells such as monocytes and macrophages and that they give rise to a variety of physiological effects which are believed to be important in disease or medical conditions such as inflammation and immunoregulation. For example, TNFa and IL-1 have been : implicated in the cell signalling cascade which is believed to contribute to the pathology of disease states such as inflammatory and allergic diseases and cytokine-induced toxicity. Itis ’ also known that, in certain cellular systems, TNFa production precedes and mediates the production of other cytokines such as IL-1.
Abnormal levels of cytokines have also been implicated in. for example, the production of physiologically-active eicosanoids such as the prostaglandins and leukotrienes. the stimulation of the release of proteolytic enzymes such as collagenase. the activation of the immune system, for example by stimulation of T-helper cells, the activation of osteoclast activity leading to the resorption of calcium, the stimulation of the release of proteoglycans from. for example, cartilage. the stimulation of cell proliferation and to angiogenesis.
Cytokines are also believed to be implicated 1n the production and development of disease states such as inflammatory and allergic diseases. for example inflammation of the joints (especially rheumatoid arthritis, osteoarthritis and gout), inflammation of the gastrointestinal tract (especially inflammatory bowel disease, ulcerative colitis, Crohn’s disease and gastritis), skin disease (especially psoriasis, eczema and dermatitis) and respiratory disease (especially asthma. bronchitis, allergic rhinitis, adult respiratory distress syndrome and chronic obstructive pulmonary disease). and in the production and development of various cardiovascular and cerebrovascular disorders such as congestive heart failure, 3 myocardial infarction, the formation of atherosclerotic plaques, hypertension, platelet aggregation, angina, stroke, Alzheimer’s disease, reperfusion injury, vascular injury including restenosis and peripheral vascular disease, and, for example, various disorders of bone metabolism such as osteoporosis (including senile and postmenopausal osteoporosis), Paget's disease, bone metastases, hypercalcaemia, hyperparathyroidism, osteosclerosis, osteoperosis and periodontitis, and the abnormal changes in bone metabolism which may accompany rheumatoid arthritis and osteoarthritis. Excessive cytokine production has also been implicated in mediating certain complications of bacterial, fungal and/or viral infections such as endotoxic shock, septic shock and toxic shock syndrome and in mediating certain complications of CNS surgery or injury such as neurotrauma and ischaemic stroke. Excessive cytokine production has also been implicated in mediating or exacerbating the development of diseases involving cartilage or muscle resorption, pulmonary fibrosis, cirrhosis. renal fibrosis, the cachexia found in certain chronic diseases such as malignant disease and acquired immune deficiency syndrome (AIDS), tumour invasiveness and tumour metastasis and multiple sclerosis.
Evidence of the central role played by TNFa in the cell signalling cascade which gives rise to rheumatoid arthritis is provided by the efficacy in clinical studies of antibodies of
TNFa (The Lancet, 1994, 344, 1125 and British Journal of Rheumatology, 1995, 34, 334).
Thus cytokines such as TNFa and IL-1 are believed to be important mediators of a considerable range of diseases and medical conditions. Accordingly it is expected that inhibition of the production of and/or effects of these cytokines will be of benefit in the prophylaxis, control or treatment of such diseases and medical conditions.
Without wishing to imply that the compounds disclosed in the present invention : —25 possess pharmacological activity only by virtue ot an effect on a single biological process. ir is believed that the compounds inhibit the effects of cytokines by virtue of inhibition of the enzyme p38 kinase. p38 kinase, otherwise known as cytokine suppressive binding protein (hereinafter CSBP) and reactivating kinase (hereinafter RK), is a member of the mitogen- activated protein (hereinafter MAP) kinase family of enzymes which is known to be activated by physiological stress such as that induced by ionising radiation. cytotoxic agents. and toxins. for example endotoxins such as bacterial lipopolysaccharide, and by a variety of agents such as the cytokines. for example TNFa and IL-1. It is known that p38 kinase
" . phosphorylates certain intracellular proteins which are involved in the cascade of enzymatic steps which leads to the biosynthesis and excretion of cytokines such as TNFa and IL-1.
Known inhibitors of p38 kinase have been reviewed by G J Hanson in Expert Opinions on
Therapeutic Patents, 1997, 7, 729-733. p38 kinase is known to exist in isoforms identified as p38a and p38.
The compounds disclosed in the present invention are inhibitors of the production of cytokines such as TNF, in particular of TNFa, and various interleukins, in particular IL-1.
According to a first aspect of the present invention there is provided a compound of the Formula I - (RY),
RN,
H
Seo Ch — (CH), — Q . XP > O wherein X is CH or N;
Y is CH or N; mis 0.1,2o0r3; : R' is hydroxy, halogeno, trifluoromethyl, cyano, mercapto, nitro, amino, carboxy, carbamoyl, formyl. (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, (1-6C)alkylamino. di-[(1-6C)alkyljamino. (1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyljcarbamoy!. (2-6C)alkanoyl, (2-6C)alkanoyloxy, (1-6C)alkanoylamino, N-(1-6C)alkyisulphamoy!,
N,N-di-[(1-6C)alkyl]sulphamoyl, (1-6C)alkanesulphonylamino.
N-(1-6C)alkyl-(1-6C)alkanesulphonylamino, halogeno-(1-6C)alkyl, hydroxy-(1-6C)alky]l. (1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl, amino-(1-6C)alkyl, (1-6C)alkylamino- (1-6C)alkyl, di-[(1-6C)alkyl]amino-(1-6C)alkyl, carboxy-(1-6C)alkyl, (1-6C)alkoxycarbonyl- (1-6C)alkyl. carbamoyl-(1-6C)alkyl, N-(1-6C)alkylcarbamoyl-(1-6C)alkyl,
N,N-di-[(1-6C)alkyl]carbamoyl-(1-6C)alkyl. halogeno-(2-6C)alkoxy. hydroxy-(2-6C)alkoxy. (1-6C)alkoxy-(2-6C)alkoxy, cyano-(1-6C)alkoxy. carboxy-(1-6C)alkoxy. (1-6C)alkoxycarbonyl-(1-6C)alkoxy, carbamoyl-(1-6C)alkoxy, N-(1-6C)alkylcarbamoyl- (1-6C)atkoxy, N,N-di-[(1-6C)alkyl}carbamoyl-(1-6C)alkoxy, amino-(2-6C)alkoxy. (1-6C)alkylamino-(2-6C)alkoxy, di-[(1-6C)alkyljamino-(2-6C)alkoxy, halogeno-
(2-6C)alkylamino, hydroxy-(2-6C)alkylamino, (1-6C)alkoxy-(2-6C)alkylamino, - » cyano-(1-6C)alkylamino, carboxy-(1-6C)alkylamino, (1-6C)alkoxycarbonyl- (1-6C)alkylamino, carbamoyl-(1-6C)alkylamino, N-(1-6C)alkylcarbamoyl-(1-6C)alkylamino,
N,N-di-[(1-6C)alky}]carbamoyl-(1-6C)alkylamino, amino-(2-6C)alkylamino, (1-6C)alkylamino-(2-6C)alkylamino, di-[(1-6C)alkyllamino-(2-6C)alkylamino,
N-(1-6C)alkyl-halogeno-(1-6C)alkylamino, N-(1-6C)alkyl-hydroxy-(2-6C)alkylamino,
N-(1-6C)alkyl-(1-6C)alkoxy-(2-6C)alkylamino, N-(1-6C)alkyl-cyano-(1-6C)alkylamino,
N-(1-6C)alkyl-carboxy-(1-6C)alkylamino, N-(1-6C)alkyl-(1-6C)alkoxycarbonyl- (1-6C)alkylamino, N-(1-6C)alkyl-carbamoyl-(1-6C)alkylamino, N-(1-6C)alkyl-
N-(1-6C)alkylcarbamoyl-(1-6C)alkylamino, N-(1-6C)alkyl-N,N-di-[(1-6C)alkyl]carbamoy!- (1-6C)alkylamino, N-(1-6C)alkyl-amino-(2-6C)alkylamino. N-(1-6C)alkyl-(1-6C)alkylamino- (2-6C)alkylamino, N-(1-6C)alkyl-di-[(1-6C)alkylJamino-(2-6C)alkylamino, halogeno-(2-6C)alkanoylamino, hydroxy-(2-6C)alkanoylamino, (1-6C)alkoxy- (2-6C)alkanoylamino, cyano-(2-6C)alkanoylamino, carboxy-(2-6C)alkanoylamino, (1-6C)alkoxycarbonyl-(2-6C)alkanoylamino, carbamoyl-(2-6C)alkanoylamino,
N-(1-6C)alkylcarbamoyl-(2-6C)alkanoylamino, N,N-di-[(1-6C)alkyl]carbamoyl- (2-6C)alkanovlamino, amino-(2-6C)alkanoylamino, (1-6C)alkylamino-(2-6C)alkanoylamino or di-[(1-6C)alkylJamino-(2-6C)alkanoylamino, or R' is aryl, aryl-(1-6C)alkyl, aryl-(1-6C)alkoxy, aryloxy. arylamino.
N-(1-6C)alkyl-arylamino, aryl-(1-6C)alkylamino, N-(1-6C)alkyl-aryl-(1-6C)alkylamino, aroylamino, arylsulphonylamino. N-arylsulphamoyl, aryl-(2-6C)alkanoylamino. heteroaryl. heteroaryl-(1-6C)alkyl. heteroaryloxy, heteroaryl-(1-6C)alkoxy, heteroarylamino,
N-(1-6C)alkyl-heteroarylamino, heteroaryl-(1-6C)alkylamino, N-(1-6C)alkyl-heteroaryl- (1-6C)alkylamino, heteroarylcarbonylamino, heteroarylsulphonylamino. EE “25 N-heteroaryisulphamoyl; heteroaryl=(2-6C alkanoy amino. heteroary=(1=6C)atkoxy= (1-6C)alkyl, heteroaryl-(1-6C)alkylamino-(1-6C)alkyl, N-(1 -6C)alkyl-heteroaryl- (1-6C)alkylamino-(1-6C)alkyl, heterocyclyl. heterocyclyl-(1-6C)alkyl. heterocyclyloxy. heterocyclyl-(1-6C)alkoxy. heterocyclylamino, N-(1 -6C)alkyl-heterocyclylamino, heterocvclyl-(1-6C)alkylamino. N-(1 -6C)alkyl-heterocyclyl-( 1-6C)alkylamino. heterocyclylcarbonylamino. heterocyclylsulphonylamino, N-heterocyclylsulphamoyl. heterocyclyl-(2-6C)alkanoylamino. heterocyclyl-(1-6C)alkoxy-(1 -6C)alkyl. heterocyclvl- (1-6C)alkylamino-(1-6C)aikyl or N-( 1-6C)alkyl-heterocyclyl-(1-6C)alkylamino-(1-6Calkyl.
© WO 00/55120 PCT/GB00/00914 ‘ * or (R"), is a (1-3C)alkylenedioxy group, and wherein any of the R' substituents defined hereinbefore which comprises a CH, group which is attached to 2 carbon atoms or a CH, group which is attached to a carbon atom may optionally bear on each said CH, or CH, group a substituent selected from hydroxy, amino, (1-6C)alkoxy, (1-6C)alkylamino, di-[(1-6C)alkyl]Jamino and heterocyclyl, and wherein any aryl, heteroaryl or heterocyclyl group in a R' substituent may optionally bear 1 or 2 substituents selected from hydroxy. halogeno, (1-6C)alkyl, (1-6C)alkoxy, carboxy, (1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, amino, (1-6C)alkylamino, di-[(1-6C)alkyl}amino, halogeno-(1-6C)alkyl. hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl, amino-(1-6C)alky]l, (1-6C)alkylamino-(1-6C)alkyl, di-[(1-6C)alkyljamino-(1-6C)alkyl, aryl and aryl-(1-6C)alkyl, nis 0, 1,2 or 3;
R? is hydroxy, halogeno, trifluoromethyl, cyano. mercapto, nitro, amino, carboxy, (1-6C)alkoxycarbonyl, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy. . 15 (1-6C)alkylamino or di-[(1-6C)alkyljamino;
R‘ is hydrogen, halogeno, (1-6C)alkyl or (1-6C)alkoxy; . gis 0, 1,2,3 or 4; and
Q is aryl, aryloxy, aryl-(1-6C)alkoxy, arylamino, N-(1-6C)alkyl-arylamino, aryl-(1-6C)alkylamino, N-(1-6C)alkyl-aryl-(1-6C)alkylamino. aroylamino. arylsulphonylamino, N-arylcarbamoyl, N-arylsulphamoyl, aryl-(2-6C)alkanoylamino. (3-7C)cycloalkyl, heteroaryl. heteroaryloxy. heteroaryl-(1-6C)alkoxy, heteroarylamino.
N-(1-6C)alkyl-heteroarylamino, heteroaryl-(1-6C)alkylamino, N-(1-6C)alkyl-heteroaryl- (1-6C)alkylamino, heteroarylcarbonylamino, heteroarylsulphonylamino.
N-heteroarylcarbamoyl, N-heteroarylsulphamoyl, heteroaryl-(2-6C)alkanoylamino, heterocyclyl, heterocyclyloxy. heterocyclyl-(1-6C)alkoxy, heterocyclylamino, N-(1-6C)alkyl- heterocyclylamino, heterocyclyl-(1-6C)alkylamino, N-(1-6C)alkyl-heterocyclyl- (1-6C)alkylamino, heterocyclylcarbonylamino, heterocyclylsulphonylamino,
N-heterocyclylcarbamoyl, N-heterocyclylsulphamoyl or heterocyclyl-(2-6C)alkanoylamino, and Q is optionally substituted with 1. 2 or 3 substituents selected from hydroxy. halogeno. trifluoromethyl, cyano, mercapto. nitro, amino. carboxy. carbamoyl. formyl, (1-6C)alky]. (2-6C)alkenyl. (2-6C)alkynyl. (1-6C)alkoxy, (1-6C)alkylthio. (1-6C)alkylsulphinyl. (1-6C)alkylsulphonyl. (1-6C)alkylamino, di-|(1-6C)alkyl]amino. (1-6C)alkoxycarbony],
N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoy!. (2-6C)alkanoyl, , (2-6C)alkanoyloxy, (1-6C)alkanoylamino, N-(1-6C)alkylsulphamoy]l,
N,N-di-[(1-6C)alkyl]sulphamoyl, (1-6C)alkanesulphonylamino, N-(1-6C)alkyl- (1-6C)alkanesulphonylamino, halogeno-(1-6C)alkyl, hydroxy-(1-6C)alkyl, (1 -6C)alkoxy- (1-6C)alkyl, cyano-(1-6C)alkyl, amino-(1-6C)alkyl, (1-6C)alkylamino-(1 -6C)alkyl, di-[(1-6C)alkyl}amino-(1-6C)alkyl, carboxy-(1-6C)alkyl, (1-6C)alkoxycarbonyl-(1-6C)alkyl. carbamoyl-(1-6C)alkyl, N-(1-6C)alkylcarbamoyl-(1-6C)alkyl.
N,N-di-[(1-6C)alkyl]carbamoyl-(1-6C)alkyl, halogeno-(2-6C)alkoxy, hydroxy-(2-6C)alkoxy, (1-6C)alkoxy-(2-6C)alkoxy, cyano-(1-6C)alkoxy, carboxy-(1-6C)alkoxy, (1-6C)alkoxycarbonyl-(1-6C)alkoxy, carbamoyl-(1-6C)alkoxy, N-(1-6C)alkylcarbamoyl- (1-6C)alkoxy, N,N-di-[(1-6C)alkyl]carbamoyl-(1-6C)alkoxy, amino-(2-6C)alkoxy, (1-6C)alkylamine-(2-6C)alkoxy, di-[(1-6C)alkyl]amino-(2-6C)alkoxy, halogeno- (2-6C)alkylamino, hydroxy-(2-6C)alkylamino, (1-6C)alkoxy-(2-6C)alkylamino, cyano- (1-6C)alkylamino, carboxy-(1-6C)alkylamino, (1-6C)alkoxycarbonyl-(1-6C)alkylamino, carbamoyl-(1-6C)alkylamino, N-(1-6C)alkylcarbamoyl-(1-6C)alkylamino,
N,N-di-[(1-6C)alkyl]jcarbamoyl-(1-6C)alkylamino, amino-(2-6C)alkylamino, (1-6C)alkylamino-(2-6C)alkylamino, di-[(1-6C)alkylJamino-(2-6C)alkylamino,
N-(1-6C)alkyl-halogeno-(1-6C)alkylamino, N-(1-6C)alkyl-hydroxy-(2-6C)alkylamino,
N-(1-6C)alkyl-(1-6C)alkoxy-(2-6C)alkylamino, N-(1-6C)alkyl-cyano-(1-6C)alkylamino,
N-(1-6C)alkyl-carboxy-(1-6C)alkylamino, N-(1-6C)alkyl-(1-6C)alkoxycarbonyl- (1-6C)alkylamino, N-(1-6C)alkyl-carbamoyl-(1-6C)alkylamino, N-(1-6C)alkyl-
N-(1-6C)alkylcarbamoyl-(1-6C)alkylamino, N-(1-6C)alkyl-N,N-di-{(1-6C)alkyl]carbamoyl- (1-6C)alkylamino, N-(1-6C)alkyl-amino-(2-6C)alkylamino, N-(1-6C)alkyl-(1-6C)alkylamino- (2-6C)alkylamino, N-(1-6C)alkyl-di-[(1-6C)alkyl]amino-(2-6C)alkylamino, halogeno-(2-6Clalkanovlamino. hvdroxv-(2-6Calkanovlamino. (1-6Chalkoxy- (2-6C)alkanoylamino, cyano-(2-6C)alkanoylamino, carboxy-(2-6C)alkanoylamino. (1-6C)alkoxycarbonyl-(2-6C)alkanoylamino, carbamoyl-(2-6C)alkanoylamino,
N-(1-6C)alkylcarbamoyl-(2-6C)alkanoylamino, N.N-di-[(1-6C)alkyl]carbamoyl- (2-6C)alkanoylamino. amino-(2-6C)alkanoylamino, (1-6C)alkylamino-(2-6C)alkanoylamino. di-[(1-6C)alkyl]amino-(2-6C)alkanoylamino, aryl, aryl-(1-6C)alkyl, aryl-(1-6C)alkoxy. aryloxy, arylamino, N-(1-6C)alkyl-arylamino. aryl-(1-6C)alkylamino, N-(1-6C)alkyl-ary!l- (1-6C)alkylamino. aroylamino, arylsulphonylamino, N-arylsulphamoyl. aryl-
: * (2-6C)alkanoylamino, heteroaryl, heteroaryl-(1-6C)alkyl, heteroaryloxy, heteroaryl- (1-6C)alkoxy, heteroarylamino, N-(1-6C)alkyl-heteroarylamino, heteroaryl-(1-6C)alkylamino,
N-(1-6C)alkyl-heteroaryl-(1-6C)alkylamino, heteroarylcarbonylamino, heteroarylsulphonylamino, N-heteroarylsulphamoyl, heteroaryl-(2-6C)alkanoylamino, heteroaryl-(1-6C)alkoxy-(1-6C)alkyl, heteroaryl-(1-6C)alkylamino-(1-6C)alky]l,
N-(1-6C)alkyl-heteroaryl-(1-6C)alkylamino-(1-6C)alkyl, heterocyclyl, heterocyclyl- (I-6C)alkyl, heterocyclyloxy, heterocyclyl-(1-6C)alkoxy, heterocyclylamino, N-(1-6C)alkyl- heterocyclylamino, heterocyclyl-(1-6C)alkylamino, N-(1-6C)alkyl-heterocyclyi- (1-6C)alkylamino, heterocyclylcarbonylamino, heterocyclylsulphonylamino,
N-heterocyclylsulphamoyl, heterocyclyl-(2-6C)alkanoylamino, heterocyclyl-(1-6C)alkoxy- (1-6C)alkyl, heterocyclyl-(1-6C)alkylamino-(1-6C)alkyl and N-(1-6C)alkyl-heterocyclyl- (1-6C)alkylamino-(1-6C)alkyl, or Q is substituted with a (1-3C)alkylenedioxy group, and wherein any of the substituents on Q defined hereinbefore which comprises a CH, group } 15 which is attached to 2 carbon atoms or a CH; group which is attached to a carbon atom may optionally bear on each said CH, or CH, group a substituent selected from hydroxy, amino. . (1-6C)alkoxy. (1-6C)alkylamino, di-[(1-6C)alkyljamino and heterocyclyl, and wherein any aryl, heteroaryl or heterocyclyl group in a substituent on Q may optionally bear 1 or 2 substituents selected from hydroxy, halogeno, (1-6C)alkyl, (1-6C)alkoxy, carboxy. (1-6C)atkoxycarbonyl, N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyljcarbamoy]. (2-6C)alkanoyl, amino, (1-6C)alkylamino. di-[(1-6C)alkyl|amino, halogeno-(1-6C)alkyl. hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl. cyano-(1-6C)alkyl, amino-(1-6C)alkyl. (1-6C)alkylamino-(1-6C)alkyl, di-[(1-6C)alkyl]amino-(1-6C)alkyl, aryl and aryl-(1-6C)alkyl: or a pharmaceutically-acceptable salt or in-vivo-cleavable ester thereof.
According to a second aspect of the present invention there is provided a compound of the Formula I wherein each of X, Y.R', R’. m, n, q and Q have any of the meanings defined hereinbefore and R* is selected from halogeno and (1-6C)alkyl; or a pharmaceutically- acceptable salt or in-vivo-cieavable ester thereof.
In this specification. the term (1-6C)alkyl includes straight-chain and branched-chain alkyl groups such as propyl. isopropyl and tert-butyl, and (3-6C)cycloalkyl groups such as cyclopropyl. cyclobutyl. cyclopentyl and cyclohexyl. However references to individual alkyl groups such as "propyl" are specific for the straight-chain version only, references to individual branched-chain alkyl groups such as "isopropyl" are specific for the branched-chain version only and references to individual cycloalkyl groups such as "cyclopentyl" are specific for that 5-membered ring only. An analogous convention applies to other generic terms, for example (1-6C)alkoxy includes methoxy, ethoxy, cyclopropyloxy and cyclopentyloxy, (1-6C)alkylamino includes methylamino, ethylamino, cyclobutylamino and cyclohexylamino. and di-[(1-6Calkyl]amino includes dimethylamino. diethylamino, N-cyclobutyl-
N-methylamino and N-cyclohexyl-N-ethylamino.
It is to be understood that, insofar as certain of the compounds of Formula | defined above may exist in optically active or racemic forms by virtue of one or more asymmetric carbon atoms. the invention includes in its definition any such optically active or racemic form which possesses the property of inhibiting cytokines. in particular TNF. The synthesis of optically active forms may be carricd out by standard techniques of organic chemistry well known in the art, for example by synthesis from optically active starting materials or by resolution of a racemic form. Similarly, inhibitory properties against TNI' may be evaluated using the standard laboratory techniques referred to hereinafter.
Suitable values for the generic radicals referred to above include those set out below.
A suitable value for R' or Q when it is aryl, for a substituent on Q when it is aryl or for - the aryl group within a R' substituent or a Q group or within a substituent on Q is. for example, phenyl, indenyl, indanyl, naphthyl, tetrahydronaphthyl or fluorenyl, preferably phenyl.
A suitable value for R' or Q when it is heteroaryl. for the heteroaryl group within a R' substituent or a Q group. for a substituent on Q when it is heteroaryl or for the heteroaryl group within a substituent on Q is, for example, an aromatic 5- or 6-membered monocyclic ring, a 9- or 10-membered bicyclic ring or a 13- or 14-membered tricyclic ring cach with up to five ring heteroatoms selected from oxygen. nitrogen and sulphur, for example furyl, pyrrolyl, thienyl. oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl. isothiazolyl, oxadiazolyl. thiadiazolyl. triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1.3.5-triazenyl. benzofuranyl. indolyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl. indazolyl. benzofurazanyl. quinolyl, isoquinolyl, quinazolinyl. quinoxalinyl. cinnolinyl. naphthyridinyl, carbazolyl. dibenzofuranyl. dibenzothiophenyl, S,S-dioxodibenzothiophenyl, xanthenyl. dibenzo-1.4-dioxinyl, phenoxathiinyl, phenoxazinyl. dibenzothiinyl. phenothiazinyl. thianthrenyl. benzofuropyridyl. pyridoindolyl, acridinyl or phenanthridinyl. preferably furyl.
! * thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzofuranyl, indolyl, benzothienyl, benzoxazoly]l, benzimidazolyl, benzothiazolyl, indazolyl, benzofurazanyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, carbazolyl, dibenzofuranyl, dibenzothiophenyl or xanthenyl, more preferably furyl, thienyl, isoxazolyl, thiazolyl, pyridyl, benzothienyl, benzofurazanyl, quinolyl, carbazolyl, dibenzofuranyl or dibenzothiophenyl.
A suitable value for R' or Q when it is heterocyclyl, for a substituent on Q when it is heterocyclyl or for the heterocyclyl group within a R' substituent or a Q group or within a substituent on Q is, for example, a non-aromatic saturated or partially saturated 3- to 10-membered monocyclic or bicyclic ring with up to five heteroatoms selected from oxygen, nitrogen and sulphur, for example oxiranyl. oxetanyl, azetidinyl. tetrahydrofuranyl, tetrahydropyranyl, pyrrolinyl, pyrrolidinyl. 1,1-dioxidoisothiazolidinyl, morpholinyl, tetrahydro-1,4-thiazinyl, 1,1-dioxotetrahydro-1.4-thiazinyl, piperidinyl, homopiperidinyl, piperazinyl, homopiperazinyl, dihydropyridinyl, tetrahydropyridinyl, dihydropyrimidinyl or . 15 tetrahydropyrimidinyl, or, for example, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, or, for example. benzo derivatives thereof such as 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, indolinyl, isoindolinyl, chromany!| and isochromanyl, preferably the heterocyclyl group is pyrrolidin-1-yl, pyrrolidin-2-yl. morpholino, piperidino, piperazin-1-yl or homopiperazin-1-yl.
A suitable value for Q when it is (3-7C)cycloalkyl is, for example, a non-aromatic mono- or bicyclic 3- to 7-membered carbon ring such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or bicyclo[2.2.1]heptyl, preferably cyclobutyl, cyclopentyl. cyclohexyl or cycloheptyl. more preferably cyclohexyl.
Suitable values for various R', R? or R* groups, or for various substituents on Q or on an aryl. heteroaryl or heterocyclyl group within R' or on an aryl, heteroaryl or heterocyclyl group on a substituent on Q include:- for halogeno: fluoro, chloro, bromo and iodo; for (1-6C)alkyl: methyl, ethyl, propyl, isopropyl, tert-butyl, cyclobutyl. cyclopentyl and cyclohexyl: for (2-6C)alkenyl: vinyl and allyl; for (2-6C)alkynyl: cthynyl and 2-propynyl: tor (1-6C)alkoxy: methoxy. ethoxy, propoxy. isopropoxy. cyclopropyloxy.
butoxy, cyclobutyloxy and cyclopentyloxy; ' ' for (1-6C)alkylamino: methylamino, ethylamino, propylamino, cyclobutylamino and cyclohexylamino; for di-[(1-6C)alkyljamino: dimethylamino, diethylamino and N-ethyl-
N-methylamino; for (1-6C)alkoxycarbonyl: methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl and tert-butoxycarbonyl; for N-(1-6C)alkylcarbamoyl: N-methylcarbamoyl, N-ethylcarbamoyl and
N-propylcarbamoyl; for N,N-di-[(1-6C)alkyl]carbamoyl: N,N-dimethylcarbamoyl, N-ethyl-N-methylcarbamoy! and N,N-diethylcarbamoyl; for (2-6C)alkanoyl: acetyl and propionyl; for halogeno-(1-6C)alkyl: fluoromethyl, chloromethyl, bromomethyl, diflucromethyl. dichloromethyl, dibromomcthyl, 2-fluoroethyl, 2-chloroethyl and 2-bromoethyl; for hydroxy-(1-6C)alkyl: hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethy! and 3-hydroxypropyl; for (1-6C)alkoxy-(1-6C)alkyl: methoxymethyl. ethoxymethyl, 1-methoxyethyl, 2-methoxyethyl, 2-ethoxyethy! and 3-methoxypropyl; tor cyano-(1-6C)alkyl: cyanomethyl, 2-cyanoethyl, I-cyanocthyl and 3-cyanopropyl; for amino-(1-6C)alkyl: aminomethyl, 2-aminoethyl, 1-aminoethyl and 3-aminopropyl: for (1-6C)alkylamino-(1-6C)alkyl: methylaminomethyl, ethylaminomethyl, ~~ = 1-methylaminoethyl, 2-methylaminocthyl, 2-cthylaminoethyl and 3-methylaminopropyl; for di-[(1-6C)alkyl}amino-(1-6C)alkyl: dimethylaminomethyl, diethylaminomethyl. 1-dimethylaminoethyl. 2-dimethylaminoethyl and 3-dimethylaminopropyl.
Suitable values for R' or Q and suitable values for a substituent on R' or Q include:- tor aryl-(1-6Cjalkyl: benzyl, 2-phenylethyl, 2-phenylpropyl and 3-phenylpropyl:
, , foraryl-(1-6C)alkoxy: benzyloxy and 2-phenylethoxy; for aryloxy: phenoxy and 2-naphthyloxy; for arylamino: anilino; for N-(1-6C)alkyl-arylamino: N-methylanilino and N-ethylanilino; for aryl-(1-6C)alkylamino: benzylamino, 2-phenethylamino, 2-phenylpropylamino and 3-phenylpropylamino; for N-(1-6C)alkyl-aryl-(1-6C)alkylamino: N-benzyl-N-methylamino; for aroylamino: benzamido and 2-naphthoylamino; arylsulphonylamino: benzenesulphonylamido; for N-arylcarbamoy}!: N-phenylcarbamoyl; for N-arylsulphamoyl: N-phenylsulphamoy]; for aryl-(2-6C)alkanoylamino: phenylacetamido and 3-phenylpropionamido; for heteroaryli-(1-6C)alky!: heteroarylmethyl, 2-heteroarylethyl, 2-heteroarylpropyl and 3-heteroarylpropyl; for heteroaryl-(1-6C)alkoxy: heteroarylmethoxy and 2-heteroarylethoxy; for N-(1-6C)alkyl-heteroarylamino: N-methylheteroarylamino; for heteroaryl-(1-6C)alkylamino: heteroarylmethylamino, 2-heteroarylethylamino and 3-heteroarylpropylamino; for N-(1-6C)alkyl-hetcroaryl-(1-6C)alkylamino: N-methylheteroaryimethylamino and N-methyl-2-heteroarylethylamino: tor heteroaryl-(2-6C)alkanoylamino: heteroarylacetamido and 3-heteroarylpropionamido; for heteroaryl-(1-6C)alkoxy-(1-6C)alkyl: heteroarylmethoxymethyl, 2-heteroarylethoxymethyl and 3-heteroarylpropoxymethy!; for heteroaryl-(1-6C)alkylamino-(1-6C)alky]l: heteroarylmethylaminomethyl, 2-heteroarylethylaminomethyl and 3-heteroarylpropylaminomethyl: for N-(1-6C)alkyl-heteroaryl-(1-6C)alkylamino-(1-6C)alkyl: N-heteroarylmethyl-
N-methylaminomethyl, N-(2-heteroarylethyl)-
N-methylaminomethyl and N-(3-heteroarylpropyl)-
N-methylaminomethyl;
for heterocyclyl-(1-6C)alkyl: heterocyclylmethyl, 2-heterocyclylethyl, . > 2-heterocyclylpropyl and 3-heterocyclylpropyl; for heterocyclyl-(1-6C)alkoxy: heterocyclylmethoxy and 2-heterocyclylethoxy; for N-(1-6C)alkyl-heterocyclylamino: N-methylheterocyclylamino; for heterocyclyl-(1-6C)alkylamino: heterocyclylmethylamino, 2-heterocyclylethylamino and 3-heterocyclylpropylamino; tor N-(1-6C)alkyl-heterocyclyl-(1-6C)alkylamino: N-methylheterocyclylmethylamino and N-methyl-2-heterocyclylethylamino; for heterocyclyl-(2-6C)alkanoylamino: heterocyclylacetamido and 3-heterocyclylpropionamido; for heterocyclyl-(1-6C)alkoxy-(1-6C)alkyl: heterocyclylmethoxymethyl, 2-heterocyclylethoxymethyl and 3-heterocyclyipropoxymethyl; for heterocyclyl-(1-6C)alkylamino-(1-6C)alkyl: heterocyclylmethylaminomethyl, 2-heterocyclylethylaminomethyl and 3-heterocyclylethylaminomethyl; for N-(1-6C)alkyl-heterocyclyl-(1-6C)alkylamino-(1-6C)alkyl: N-heterocyclylmethyl-
N-methylaminomethyl, N-(2-heterocyclylethyl)-
N-methylaminomethyl and N-(3-heterocyclylpropyl)-
N-methylaminomethyl: for (1-3C)alkylenedioxy: methylenedioxy. cthylenedioxy and trimethylenedioxy: tor (1-6C)alkylthio: methylthio, ethylthio and propylthio: tor (1-6C)alkylsulphinyl: methylsulphinyl, ethyisulphinyl and propylsulphinyl; for (1-6C)alkylsulphony!: methylsulphonyl, ethylsulphonyl and propylsulphonyl; 25—for(2=6C)alkanoyloxy: acetoxy-and-propionyloxy: for (1-6C)alkanoylamino: formamido, acetamido and propionamido; for N-(1-6C)alkylsulphamoyl: N-methylsulphamoy!l and N-ethylsulphamoyl. for N,N-di-[(1-6C)alkyl]sulphamoyl: N,N-dimethylsulphamoyl: for (1-6C)alkanesulphonylamino: ~~ methanesulphonylamino and ethanesulphonylamino: for N-(1-6C)alkyl-(1-6C)atkanesulphonylamino: N-methyimethanesulphonylamino and N-methylethanesulphonylamino: for carboxy-(1-6C)alkyl: carboxymethyl. 1-carboxvethyl. 2-carboxyethyl.
L 3 : 3-carboxypropyl and 4-carboxybutyl; for (1-6C)alkoxycarbonyl-(1-6C)alkyl: methoxycarbonylmethyl, ethoxycarbonylmethyl, tert-butoxycarbonylmethyl, 1-methoxycarbonylethyl, 1-ethoxycarbonylethyl, 2-methoxycarbonylethyl,
S 2-ethoxycarbonylethyl, 3-methoxycarbonylpropyl and 3-ethoxycarbonylpropyl; for carbamoyl-(1-6C)alkyl: carbamoylmethyl, 1-carbamoylethyl, 2-carbamoylethy] and 3-carbamoylpropyl; for N-(1-6C)alkylcarbamoyl-(1-6C)alkyl: N-methyicarbamoylmethyl,
N-ethylcarbamoylmethyl, N-propylcarbamoylmethyl, 1-(N-methylcarbamoyl)ethyl, 1-(N-ethylcarbamoyl)ethyl, 2-(N-methylcarbamoyl)ethyl, 2-(N-ethylcarbamoyl)ethyl and 3-(N-methylcarbamoyl)propyl: for N,N-di-[(1-6C)alkyl]carbamoyl-(1-6C)alkyl: N,N-dimethylcarbamoylmethyl,
N-ethyl-N-methylcarbamoylmethyl,
N,N-diethylcarbamoylmethyl, 1-(N,N-dimethylcarbamoyl)ethyl, 1-(N,N-diethylcarbamoyl)cthyl, 2-(N,N-dimethylcarbamoyl)ethyl, 2-(N,N-diethylcarbamoyl)ethyl, 3-(N.N-dimethylcarbamoyl)propyl and 4-(N,N-dimethylcarbamoyl)butyl; for halogeno-(2-6C)alkoxy: 2-chloroethoxy, 2-bromoethoxy, 3-chloropropoxy, ) 1,1,2,2-tetrafluoroethoxy and 2,2,2-trifluoroethoxy: for hydroxy-(2-6C)alkoxy: 2-hydroxyethoxy, 3-hydroxypropoxy, 2-hydroxy-
I-methylethoxy,2-hydroxy-2-propoxy and 4-hydroxybutoxy; for (1-6C)alkoxy-(2-6C)alkoxy: 2-methoxyethoxy. 2-ethoxyethoxy, 3-methoxypropoxy. 2-methoxy-1-methylethoxy and 4-ethoxybutoxy; for cyano-(1-6C)alkoxy: cyanomethoxy. 2-cyanoethoxy and 3-cyanopropoxy:
tor carboxy-(1-6C)alkoxy: carboxymethoxy, 1-carboxyethoxy, 2-carboxyethoxy | R and 3-carboxypropoxy;
for (1-6C)alkoxycarbonyl-(1-6C)alkoxy: methoxycarbonylmethoxy, ethoxycarbonylmethoxy, tert-butoxycarbonylmethoxy,
2-methoxycarbonylethoxy and
3-ethoxycarbonylpropoxy;
for carbamoyl-(1-6C)alkoxy: carbamoylmethoxy and 2-carbamoylcthoxy;
for N-(1-6C)alkylcarbamoyl-(1-6C)alkoxy: N-methylcarbamoylmethoxy, 2-(N-ethylcarbamoyl)ethoxy and
3-(N-methylcarbamoyl)propoxy;
for NN-di-[(1-6C)alkyl|carbamoyl-(1-6C)alkoxy: N N-dimethylcarbamoylmethoxy, 2-(N,N-dimethyicarbamoyl)ethoxy and 3-(N,N-diethylcarbamoyl)propoxy;
for amino-(2-6C)alkoxy: 2-aminoethoxy. 2-amino-1-methylethoxy,
3-aminopropoxy, 2-amino-2-methylpropoxy and
4-aminobutoxy; for (1-6C)alkylamino-(2-6C)alkoxy: 2-methylaminoethoxy,
2-methylamino-1-methylethoxy and 3-ethylaminopropoxy:
for di-[(1-6C)alkyljamino-(2-6C)alkoxy: 2-dimethylaminoethoxy. 2-diethylaminoethoxy. 2-dimethylaminopropoxy. 2-dimethylamino- 2-methylethoxy, 3-dimethylaminopropoxy and 4-dimethylaminobutoxy;
for halogeno-(2-6C)alkylamino: ~~ 2-fluoroethylamino, 2-chloroethylamino, _25 -2-bromoethylamino,-3-fluoropropylamino-and— 3-chioropropylamino; for hydroxy-(2-6C)alkylamino: 2-hydroxyecthylamino. 3-hydroxypropylamino, 2-hydroxy-2-methylpropylamino and 4-hydroxybutylamino;
tor (1-6C)alkoxy-(2-6C)alkylamino: 2-methoxyethylamino, 2-ethoxyethylamino.
3-methoxypropylamino and 3-ethoxypropylamino: for cyano-(1-6C)alkylamino: cyanomethylamino. 2-cyanoethylamino and j WO 00/55120 PCT/GB00/00914 * 7 3-cyanopropylamino; for carboxy-(1-6C)alkylamino: carboxymethylamino, 1-carboxyethylamino, 2-carboxyethylamino and 3-carboxypropylamino; for (1-6C)alkoxycarbonyl-(1-6C)alkylamino: methoxycarbonylmethylamino, 2-(ethoxycarbonyl)ethylamino and 3-(tert-butoxycarbonyi)propylamino; for carbamoyl-(1-6C)alkylamino: ~~ carbamoylmethylamino and 2-carbamoylethylamino; for N-(1-6C)alkylcarbamoy!l-(1-6C)alkylamino: N-methylcarbamoylmethylamino,
N-ethylcarbamoylmethylamino and 2-(N-methylcarbamoyl)ethylamino; for N,N-di-[(1-6C)alkyl]carbamoyl-(1-6C)alkylamino:
N,N-dimethylcarbamoylmethylamino,
N,N-diethylcarbamoylmethylamino and 2-(N,N-dimethylcarbamoyl)ethylamino; ) 15 for amino-(2-6C)alkylamino: 2-aminoethylamino, 3-aminopropylamino. 2-amino-2-methylpropylamino and 4-aminobutylamino; for (1-6C)alkylamino-(2-6C)alkylamino: 2-methylaminoethylamino. 2-ethylaminoethylamino, 2-propylaminoethylamino. 3-methylaminopropylamino, 3-ethylaminopropylamino. 2-methylamino-2-methylpropylamino and 4-methylaminobutylamino; for di-[(1-6C)alkyl]amino-(2-6C)alkylamino: 2-dimethylaminoethylamino, 2-(N-ethyl-N-methylamino)ethylamino, 2-diethylaminoethylamino, 2-dipropylaminoethylamino. 3-dimethylaminopropylamino, 3-dicthylaminopropylamino, 2-dimethylamino-2-methylpropylamino and 4-dimethylaminobutylamino; for N-(1-6C)alkyl-halogeno-(2-6C)alkylamino: N-(2-chloroethyl)-N-methylamino.
N-(2-bromoethyl)-N-methylamino and
N-(2-bromoethyl)-N-ethylamino:
for N-(1-6C)alkyl-hydroxy-(2-6C)-alkylamino: ~~ N-(2-hydroxyethyl)-N-methylaminp,
N-(3-hydroxypropyl)-N-methylamino and
N-ethyl-N-(2-hydroxyethyl)amino; for N-(1-6C)alkyl-(1-6C)alkoxy-(2-6C)alkylamino: N-methyl-N-(2-methoxyethyl)amino, 35 N-methyl-N-(3-methoxypropyl)amino and
N-ethyl-N-(2-methoxyethyl)amino; for N-(1-6C)alkyl-cyano-(1-6C)alkylamino: N-(cyanomethyl)-N-methylamino: for N-(1-6C)alkyl-carboxy-(1-6C)alkylamino: N-carboxymethyl-N-methylamino and
N-(2-carboxyethyl)-N-methylamino; for N-(1-6C)alkyl-(1-6C)alkoxycarbonyl-(1-6C)alkylamino:
N-methoxycarbonylmethyl-N-methylamino.
N-(2-ethoxycarbonylethyl)-N-ethylamino and
N-(2-tert-butoxycarbonylethyl)-N-methylamino; for N-(1-6C)alkyl-carbamoyl-(1-6C)alkylamino: ~~ N-carbamoylmethyl-N-methylamino and
N-(2-carbamoylethyl)-N-methylamino; . for N-(1-6C)alkyl-N-(1-6C)alkylcarbamoyl-(1-6C)alkylamino:
N-(N-methylcarbamoylmethyl)-N-methylamino, :
N-(N-ethylcarbamoylmethyl)-N-methylamino and N-[2-(N-methylcarbamoyl)ethyl]-N-methylamino; for N-(1-6Calkyl-N,N-di-[(1-6C)alkyl]carbamoyl-(1-6C)alkylamino:
N-(N,N-dimethylcarbamoylmethyl)- N-methylamino and
N-[2-(N,N-dimethylcarbamoyl)ethyl]}- N-methylamino: for N-(1-6C)alkyl-amino-(2-6C)alkylamino: N-(2-aminoethyl)-N-methylamino.
N-(3-aminopropyl)-N-methylamino and i
N-(4-aminobutyl)-N-methylamino; for N-(1-6C)alkyl-(1-6C)alkylamino-(2-6C)alkylamino: ~~ N-(2-methylaminoethyl)-
N-methylamino, N-(2-methylaminoethyl)-
N-methylamino, N-(3-methylaminopropyl)-
N-methylamino, N-(3-ethylaminopropyl)-N-ethylamino and N-(4-methylaminobutyl)-N-methylamino: for N-(1-6C)alkyl-di-{(1-6C)alkyl}amino-(2-6C)alkylamino:
N-(2-dimethylaminoethyl)-N-methylamino.
N w N-(2-diethylaminoethyl)-N-methylamino,
N-(3-dimethylaminopropyl)-N-methylamino and
N-(4-dimethylaminobutyl)-N-methylamino; for halogeno-(2-6C)alkanoylamino: 2-chloroacetamido and 3-chloropropionamido; for hydroxy-(2-6C)alkanoylamino: 2-hydroxyacetamido and 3-hydroxypropionamido; tor (1-6C)alkoxy-(2-6C)alkanoylamino: 2-methoxyacetamido and 3-methoxypropionamido; for cyano-(2-6C)alkanoylamino: 2-cyanoacetamido and 3-cyanopropionamido; for carboxy-(2-6C)alkanoylamino: 2-carboxyacetamido and 3-carboxypropionamido; for (1-6C)alkoxycarbonyl-(2-6C)alkanoylamino: ~~ 2-methoxycarbonylacetamido, 2-(tert-butoxycarbonyl)acetamido and 3-methoxycarbonylpropionamido; for carbamoyl-(2-6C)alkanoylamino: 2-carbamoylacetamido, 3-carbamoylpropionamido and 4-carbamoylbutyramido; for N-(1-6C)alkylcarbamoyl-(2-6C)alkanoylamino: 2-(N-methylcarbamoyl)acetamido and 3-(N-ethylcarbamoyl)propionamido; for N,N-di-[(1-6C)alkyl]carbamoyl-(2-6C)alkanoylamino: 2-(N,N-dimethylcarbamoyl)acetamido, 2-(N,N-diethylcarbamoyl)acetamido and 3-(N.N-dimethylcarbamoyl)propionamido; for amino-(2-6C)alkanoylamino: 2-aminoacetamido, 2-aminopropionamido and 3-aminopropionamido; for (1-6C)alkylamino-(2-6C)alkanoylamino: 2-methylaminoacetamido. 2-ethylaminoacetamido, 2-methylaminopropionamido and 3-methylaminopropionamido; for di-[(1-6C)alkyl]amino-(2-6C)alkanoylamino: 2-dimethylaminoacetamido. 2-diethylaminoacetamido, 2-dimethylaminopropionamido and 3-dimethylaminopropionamido.
When. as defined hereinbefore. any of the substituents on R' or Q which comprises a
CH, group which is attached to 2 carbon atoms or a CH, group which is attached to a carbon atom may optionally bear on each said CH, or CH; group a substituent selected from hydroxy.
amino, (1-6C)alkoxy, (1-6C)alkylamino, di-[(1-6C)alkyl]amino and heterocyclyl, sujtable , substituents so formed include, for example, substituted heterocyclyl-(1-6C)alkoxy groups such as 2-hydroxy-3-piperidinopropoxy and 2-hydroxy-3-morpholinopropoxy, substituted amino-(2-6C)alkoxy groups such as 3-amino-2-hydroxypropoxy, substituted (1-6C)alkylamino-(2-6C)alkoxy groups such as 2-hydroxy-3-methylaminopropoxy, substituted di-[(1-6C)alkyljamino-(2-6C)alkoxy groups such as 3-dimethylamino- 2-hydroxypropoxy, 3-[N-(3-dimethylaminopropyl)-N-methylamino]propoxy and 3-[N-(3-dimethylaminopropyl)-N-methylamino]-2-hydroxypropoxy, substituted heterocyclyl- (1-6C)alkylamino groups such as 2-hydroxy-3-piperidinopropylamino and 2-hydroxy- 3-morpholinopropylamino, substituted amino-(2-6C)alkylamino groups such as 3-amino- 2-hydroxypropylamino, substituted (1-6C)alkylamino-(2-6C)alkylamino groups such as 2-hydroxy-3-methylaminopropylamino, substituted di-[(1-6C)alkyljamino-(2-6C)alkylamino groups such as 3-dimethylamino-2-hydroxypropylamino, 3-[N-(3-dimethylaminopropy!)-
N-methylamino]propylamino and 3-[N-(3-dimethylaminopropyl)-N-methylamino]- 2-hydroxypropylamino and substituted (1-6C)alkylamino-(1-6C)alkyl groups such as 2-dimethylaminoethylaminomethyl, 3-dimethylaminopropylaminomethyl, 3-dimethylamino-2.2-dimethylpropylaminomethyl, 2-morpholinoethylaminomethy], 2-piperazin-1-ylethylaminomethyl and 3-morpholinopropylaminomethyl.
For the avoidance of any doubt it is to be understood that, when X or Y is a CH group and the ring in which the X and Y groups are embedded bears one or more R' substituents. a
R' substituent may be located at any suitable location on that ring including on the carbon atom at the X or Y position.
A suitable pharmaceutically-acceptable salt of a compound of the Formula 1 is, for example, an acid-addition salt of a compound of the Formula I which is sufficiently basic. for 25—example-an-acid-addition-salt-with-an-inorganic-or-organic-acid-such-as-hydrochloric - hydrobromic. sulphuric, trifluoroacetic, citric or maleic acid; or, for example a salt of a compound of the Formula I which is sufficiently acidic, for example an alkali or alkaline earth metal salt such as a calcium or magnesium salt, or an ammonium salt, or a salt with an organic base such as methylamine, dimethylamine. trimethylamine, piperidine, morpholine or 1ris-(2-hydroxyethyl)amine.
Various forms of prodrugs arc known in the art. For examples of such prodrug derivatives, see:
© WO 00/55120 PCT/GB00/00914 ' a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methods in
Enzymology, Vol. 42, p. 309-396, edited by K. Widder, ef al. (Academic Press, 1985); b) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and
H. Bundgaard, Chapter 5 “Design and Application of Prodrugs”, by H. Bundgaard p. 113-191 (1991); c) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); d) H. Bundgaard, ef a/., Journal of Pharmaceutical Sciences, 77, 285 (1988); and e) N. Kakeya, ef al., Chem. Pharm. Bull., 32, 692 (1984).
Examples of such pro-drugs may be used to form in-vivo-cleavable esters of a compound of the Formula l. An in-vivo-cleavable ester of a compound of the Formula containing a carboxy group is, for example. a pharmaceutically-acceptable ester which is clcaved in the human or animal body to produce the parent acid. Suitable pharmaceutically- acceptable esters for carboxy include (1-6C)alkoxymethyl esters, for example methoxymethyl; (1-6C)alkanoyloxymethyl esters, for example pivaloyloxymethyl; phthalidyl . 15 esters; (3-8C)cycloalkoxycarbonyloxy(1-6C)alkyl esters, for example
I -cyciohexylcarbonyloxyethyl; 1,3-dioxolan-2-ylmethyl esters, for example 5-methyl- : 1,3-dioxolan-2-ylmethyl; and (1-6C)alkoxycarbonyloxyethyl esters, for example 1-methoxycarbonyloxyethyl; and may be formed at any carboxy group in the compounds of this invention.
Particular novel compounds of the first aspect of the invention include. for example. amide derivatives of the Formula 1, or pharmaccutically-acceptable salts thereof. wherein:- (a) R* is hydrogen, halogeno (such as fluoro, chloro or bromo) or (1-6C)alkyl (such as methyl, ethyl, propyl and isopropyl), preferably R' is hydrogen, chloro, methyl or ethyl. morc preferably hydrogen, chloro or methyl; and X. Y, R', R?, Q. m, n and q have any of the meanings defined hereinbefore or in this section relating to particular novel compounds of the invention; (b) Q is phenyl or a heteroaromatic 5- or 6-membered monocyclic ring or a 9- or 10-membered bicyclic ring with up to five ring heteroatoms selected from oxygen, nitrogen and sulphur which bears a basic substituent selected from the substituents for Q defined hereinbefore: and X. Y, R'. R%, R*, m, n and q have any of the meanings defined hereinbefore or in this section relating to particular novel compounds of the invention:
(c) Q is phenyl. indenyl, indanyl or fluorenyl which optionally bears 1, 2 or 3 substituents selected from the substituents for Q defined hereinbefore; and X, Y, R', R% R*, m, n and q have any of the meanings defined hereinbefore or in this section relating to particular novel compounds of the invention;
(d) Q is phenyl or a heteroaromatic 5- or 6-membered monocyclic ring or a 9- or 10-membered bicyclic ring with up to five ring heteroatoms selected from oxygen, nitrogen and sulphur which bears a basic substituent selected from amino, (1-6C)alkylamino, di-[(1-6C)alkyljamino, amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alky!, di-[(1-6C)alkyl]amino-(1-6C)alkyl, amino-(2-6C)alkoxy, (1-6C)alkylamino-(2-6C)alkoxy,
di-{(1-6C)alkyl]amino-(2-6C)alkoxy, amino-(2-6C)alkylamino, (1-6C)alkylamino- (2-6C)alkylamino. di-[(1-6C)alkyl|amino-(2-6C)alkylamino, N-(1-6C)alkyl-amino- (2-6C)alkylamino, N-(1-6C)alkyl-(1-6C)alkylamino-(2-6C)alkylamino, N-(1 -6C)alkyl- di-[(1-6C)alkylJamino-(2-6C)alkylamino, amino-(2-6C)alkanoylamino, (1-6C)alkylamino- (2-6C)alkanoylamino, di-[(1-6C)alkyl]amino-(2-6C)alkanoylamino, heteroaryl, heteroaryl-
(1-6Clalkyl, heteroaryl-(1-6C)alkoxy, heterocyclyl. heterocyclyl-(1-6C)alkyl and . heterocyclyl-(1-6C)alkoxy, and wherein any heteroaryl or heterocyclyl! group in a basic substituent on Q may optionally bear 1 or 2 substituents selected from halogeno, (1-6C)alkyl, : (2-6C)alkanoy!, amino, (1-6C)alkylamino and di-[(1-6C)alkyljamino; and X, Y, R', R>, R*. m,
n and q have any of the meanings defined hereinbefore or in this section relating to particular novel compounds of the invention; (e) Q is phenyl or a heteroaromatic 5- or 6-membered monocyclic ring or a 9- or 10-membered bicyclic ring with up to five ring heteroatoms selected from oxygen, nitrogen and sulphur which optionally bears 1, 2 or 3 substituents selected from hydroxy. halogeno., trifluoromethyl, cyano, nitro, amino, carboxy, (1-6C)alkyl, (1-6C)alkoxy, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, (1-6C)alkoxycarbonyl, (2-6C)alkanoyl, halogeno-(1-6C)alky!, (1-6C)alkoxy-(1-6C)alkyl. amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl, di-[(1-6C)alkyl]amino-(1-6C)alkyl, halogeno-(2-6C)alkoxy, hydroxy-(2-6C)alkoxy, (1-6C)alkoxy-(2-6C)alkoxy. cyano-(1-6C)alkoxy, carboxy-(1-6C)alkoxy. (1-6C)alkoxycarbonyl-(1-6C)alkoxy, amino-(2-6C)alkoxy, (1-6C)alkylamino-(2-6C)alkoxy.
di-[(1-6C)alkyl]amino-(2-6C)alkoxy, pyridyl, imidazolyl, pyridyl-(1-6C)alkyl. imidazolyl- (1-6C)alkyl. pyridyl-(1-6C)alkoxy. imidazolyl-(1-6C)alkoxy, pyrrolidinyl, piperidinyl.
, . morpholinyl, piperazinyl, 4-(1-6C)alkylpiperazinyl, 4-(2-6C)alkanoylpiperazinyl, pyrrolidinyl-(1-6C)alkyl, piperidinyl-(1-6C)alkyl, morpholinyl-(1-6C)alkyl, piperazinyl- (1-6C)alkyl, 4-(1-6C)alkylpiperazinyl-(1-6C)alkyl, 4-(2-6C)alkanoylpiperazinyl-(1-6C)alkyl, pyrrolidinyloxy, piperidinyloxy, 1-(1-6C)alkylpiperidinyloxy, pyrrolidinyl-(2-6C)alkoxy,
S piperidinyl-(2-6C)alkoxy, morpholinyl-(2-6C)alkoxy, piperazinyl-(2-6C)alkoxy, 4-(1-6C)alkylpiperaziny!-(2-6C)alkoxy and 4-(2-6C)alkanoylpiperazinyl-(2-6C)alkoxy or Q bears a (1-3C)alkylenedioxy substituent; and X, Y, R', R’, R’, m, n and q have any of the meanings defined hereinbefore or in this section relating to particular novel compounds of the invention; (f) Q is phenyl, indenyl, indanyl, fluorenyl or a heteroaromatic 5- or 6-membered monocyclic ring with up to three ring heteroatoms selected from oxygen, nitrogen and sulphur which optionally bears 1, 2 or 3 substituents selected from hydroxy, halogeno, trifluoromethyl, cyano, nitro, amino, carboxy, (1-6C)alkyl, (1-6C)alkoxy, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, (1-6C)alkoxycarbonyl, (2-6C)alkanoyl, (1-6C)alkanoylamino, (1-6C)alkanesulphonylamino, N-(1-6C)alkyl-(1-6C)alkanesulphonylamino, phenyl, furyl, thienyl, azetidinyl, pyrrolinyl, pyrrolidinyl, 1,1-dioxidoisothiazolidinyl, piperidinyl, homopiperidinyl, morpholinyl, piperazinyl, homopiperazinyl, pyrrolidinyl-(1-6C)alkyl. piperidinyl-(1-6C)alkyl, morpholinyl-(1-6C)alkyl and piperazinyl-(1-6C)alkyl, and wherein any phenyl, furyl, thienyl or heterocyclyl group in a substituent on Q may optionally bear 1 or 2 substituents selected from halogeno, (1-6C)alkyl, (1-6C)alkoxy and (2-6C)alkanoyl; and X.
Y.R'.R% R*, m, n and q have any of the meanings defined hereinbefore or in this section relating to particular novel compounds of the invention; (8) Q is phenyl, furyl, thienyl, oxazolyl. isoxazolyl, imidazolyl, pyrazolyl, thiazolyl. isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzofuranyl, indolyl, benzothienyl. benzoxazolyl, benzimidazolyl, benzothiazolyl, indazolyl, benzofurazanyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl or naphthyridinyl which optionally bears 1 or 2 substituents selected from those defined in paragraph (b), (d) or (c) hereinbefore; and X, Y.
R', R% R’, m, n and q have any of the meanings defined hereinbefore or in this section relating to particular novel compounds of the invention: (h) Q is phenyl, 2- or 3-furyl, 2- or 3-thienyl. 2-. 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-. 4- or 5-imidazolyl}, 3- or 4-pyrazolyl, 2-. 4- or 5-thiazolyl. 3-, 4- or 5-isothiazolyl. 2-. 3- or 4-pyridyl. 3- or 4-pyridazinyl. 2-, 4- or 5-pyrimidinyl, 2-pyrazinyl,
2-, 3-, 5- or 6-benzofuranyl, 2-, 3-, 5- or 6-indolyl, 2-, 3-, 5- or 6-benzothienyl, ’ 2-, 5- or 6-benzoxazolyl, 2-, 5- or 6-benzimidazolyl, 2-, 5- or 6-benzothiazolyl, 3-, 5- or 6-indazolyl, 5-benzofurazanyl, 2-, 3-, 6- or 7-quinolyl, 3-, 6- or 7-isoquinolyl, 2-, 6- or 7-quinazolinyl, 2-, 6- or 7-quinoxalinyl, or 1,8-naphthyridin-2-yl or
S 1,8-naphthyridin-3-yl which optionally bears 1 or 2 substituents selected from those defined in paragraph (b), (d) or (e) hereinbefore; and X, Y, R', R>, R’, m, n and q have any of the meanings defined hereinbefore or in this section relating to particular novel compounds of the invention; (1) Q is a heteroaromatic 5- or 6-membered monocyclic ring, a 9- or 10-membered bicyclic ring or a 13- or 14-membered tricyclic ring each with up to five ring heteroatoms selected from oxygen, nitrogen and sulphur which optionally bears 1, 2 or 3 substituents selected from hydroxy, halogeno, trifluoromethyl, cyano, nitro, amino, carboxy, (1-6C)alkyl, (1-6C)alkoxy, (1-3C)alkylenedioxy, (1-6C)alkylamino, di-[(1-6C)alkyl]amino and (1-6C)alkoxycarbonyl; and X, Y, R', R?, R’, m, n and q have any of the meanings defined hereinbefore or in this section relating to particular novel compounds of the invention; : ) Q is a heteroaromatic 13- or 14-membered tricyclic ring each with up to five ring heteroatoms selected from oxygen, nitrogen and sulphur which optionally bears 1, 2 or 3 : substituents selected from hydroxy, halogeno, trifluoromethyl, cyano, nitro, amino, carboxy. (1-6C)alkyl, (1-6C)alkoxy, (1-3C)alkylenedioxy, (1-6C)alkylamino, di-[(1-6C)alkyl}amino and (1-6C)alkoxycarbonyl; and X, Y, R', R’, R’, m, n and q have any of the meanings defined hereinbefore or in this section relating to particular novel compounds of the invention; (k) Q is fury}, thicnyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl. pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzofuranyl, indolyl, benzothiophenyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, indazolyl, benzofurazanyl, quinolyl, ~~ isoquinolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, carbazolyl, dibenzofuranyl, dibenzothiophenyl or xanthenyl which optionally bears 1 or 2 substituents sclected from those defined in paragraph (i) hereinbefore; and X. Y, R', R* R’, m, n and q have any of the meanings defined hereinbefore or in this section relating to particular novel compounds of the invention: (bh) Q is 1-. 2- or 3-carbazolyl, 1-, 2-. 3- or 4-dibenzofurany! or 1-, 2-, 3- or 4-dibenzothiophenyl which optionally bears 1 or 2 substituents selected from thosc defined in
! "paragraph (i) hereinbefore; and X, Y, R', R?, R’, m, n and q have any of the meanings defined hereinbefore or in this section relating to particular novel compounds of the invention; (m) nis0;and X,Y, R', R’, Q, mand q have any of the meanings defined hereinbefore or in this section relating to particular novel compounds of the invention;
(n) nisl and R?is halogeno or (1-6C)alkyl; and X, Y, R', R?, Q, m and q have any of the meanings defined hereinbefore or in this section relating to particular novel compounds of the invention;
(0) qis0,and X, Y,R',R% R’, Q, m and n have any of the meanings defined hereinbefore or in this section relating to particular novel compounds of the invention;
(p) m is } and R' is amino, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, amino-(1-6C)alkyl, (1-6C)alkyiamino-(1-6C)alkyl, di-{(1-6C)alkyijamino-(1-6C)alkyl, amino-(2-6C)alkoxy, (1-6C)alkylamino-(2-6C)alkoxy, di-[(1-6C)alkylJamino-(2-6C)alkoxy, amino-(2-6C)alkylamino, (1-6C)alkylamino-(2-6C)alkylamino, di-[(1-6C)alkyljamino- (2-6C)alkylamino, N-(1-6C)alkyl-amino-(2-6C)alkylamino, N-(1-6C)alkyl-(1-6C)alkylamino-
. 15 (2-6C)alkylamino, N-(1-6C)alkyl-di-[(1-6C)alkylJamino-(2-6C)alkylamino, heteroaryl, heteroaryl-(1-6C)alkyl, heteroaryl-(1-6C)alkoxy, heterocyclyl. heterocyclyl-(1-6C)alkyl,
heterocyclyloxy or heterocyclyl-(1-6C)alkoxy, and wherein any heteroaryl or heterocyclyl group in a R' substituent may optionally bear 1 or 2 substituents selected from hydroxy, halogeno, (1-6C)alkyl, (1-6C)alkoxy, (2-6C)alkanoyl, amino, (1-6C)alkylamino and di-[(1-6C)alkyljamino; and X, Y.
R* R’, Q. n and q have any of the meanings defined hereinbefore or in this section relating to particular novel compounds of the invention;
(q) m is 1 and R' is amino, (1-6C)alkylamino, di-[(1-6C)alkyl}amino, amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl, di-[(1-6C)alkyljamino-(1-6C)alkyl, amino-(2-6C)alkoxy. (1-6C)alkylamino-(2-6C)alkoxy, di-[(1-6C)alkylJamino-(2-6C)alkoxy,
amino-(2-6C)alkylamino, (1-6C)alkylamino-(2-6C)alkylamino. di-[(1-6C)alkyl]amino- (2-6C)alkylamino, N-(1-6C)alkyl-amino-(2-6C)alkylamino, N-(1-6C)alkyl-(1-6C)alkylamino- (2-6C)alkylamino, N-(1-6C)alkyl-di-[(1-6C)alkylJamino-(2-6C)alkylamino, pyridyl, imidazolyl, pyridyl-(1-6C)alkyl. imidazolyl-(1-6C)alkyl, pyridyl-(1-6C)alkoxy. imidazolyl- (1-6C)alkoxy, pyrrolidiny], piperidinyl, morpholinyl, piperazinyl, 4-(1-6C)alkylpiperaziny!.
homopiperazinyl, 4-(1-6C)alkylhomopiperazinyl, 4-(2-6C)alkanoylpiperazinyl, pyrrolidinyl- (1-6C)alkyl, piperidinyl-(1-6C)alkyl, morpholinyl-(1-6C)alkyl, piperazinyl-(1-6C)alky]l, 4-(1-6C)alkyipiperazinyl-(1-6C)alkyl. 4-(2-6C)alkanoylpiperazinyl-(1-6C)alkyl,
pyrrolidinyloxy, piperidinyloxy, 1-(1-6C)alkylpiperidinyloxy, pyrrolidinyl-(2-6C)alkoxy. piperidinyl-(2-6C)alkoxy, morpholinyl-(2-6C)alkoxy, piperazinyl-(2-6C)alkoxy, 4-(1-6C)alkylpiperazinyl-(2-6C)alkoxy or 4-(2-6C)alkanoylpiperazinyl-(2-6C)alkoxy; and X,
Y, R% R’, Q, n and q have any of the meanings defined hereinbefore or in this section relating
S to particular novel compounds of the invention; (r) mis 1 and R' is hydroxy, halogeno, trifluoromethyl, cyano, mercapto, nitro, carboxy, (1-6C)alkoxycarbonyl, (1-6C)alkyl or (1-6C)alkoxy; and X, Y, R*, R*, Q, n and q have any of the meanings defined hereinbefore or in this section relating to particular novel compounds of the invention; (s) m is 2 and the first R' substituent is selected from the substituents specified in paragraph (q) hereinbefore and the second R' substituent is selected from the substituents specified in paragraph (r) hereinbefore; and X. Y, R% R’, Q, n and q have any of the meanings defined hereinbefore or in this section relating to particular novel compounds of the invention: (1) cach of X and Y is a CH group; and R', R*, R’, Q, m, n and gq have any of the meanings defined hereinbefore or in this section relating to particular novel compounds of the invention; and (u) oneorbothof Xand Y is aN group; and R', R*, R, Q, m. n and q have any of the meanings defined hereinbefore or in this section relating to particular novel compounds of the invention.
Particular novel compounds of the second aspect of the invention include. for example. amide derivatives of the Formula I, or pharmaceutically-acceptable salts thereof. wherein:- (a) R'is halogeno (such as fluoro, chloro or bromo) or (1-6C)alkyl (such as methyl, ethyl, “propyl and isopropyl), preferably R* is chloro, methyl or ethyl, more preferably chloro or ~ oo methyl; and X,Y, RR’, Q, m.nand q have any of the meanings defined hereinbefore.
A preferred compound of the first aspect of the invention is an amide derivative of the
Formula [ wherein X 1s CH or N:
Y is CH or N:
R'is hydrogen. fluoro. chloro. bromo, methyl or ethyl: misO.1or2:
R'is hydroxy. fluoro. chloro. bromo. trifluoromethyl. cyano. methyl. ethyl, propyl. methoxy. ethoxy. amino. methylamino. ethylamino. dimethylamino. diethylamino. methylaminomethy!. :
? * ethylaminomethyl, dimethylaminomethyl, diethylaminomethyl, 2-aminoethoxy, 3-aminopropoxy, 2-methylaminoethoxy, 2-ethylaminoethoxy, 3-methylaminopropoxy, 3-ethylaminopropoxy, 2-dimethylaminoethoxy, 2-diethylaminoethoxy, 3-dimethylaminopropoxy, 3-diethylaminopropoxy, 2-amtnoethylamino, 3-aminopropylamino, 5S 2-methylaminoethylamino, 2-ethylaminoethylamino, 3-methylaminopropylamino, 3-ethylaminopropylamino, 2-dimethylaminoethylamino, 2-diethylaminoethylamino, 3-dimethylaminopropylamino, 3-diethylaminopropylamino, N-(2-aminoethyl)-
N-methylamino, N-(3-aminopropyl)-N-methylamino, N-(2-methylaminoethyl)-
N-methylamino, N-(2-ethylaminoethyl)-N-methylamino, N-(3-methylaminopropy]l)-
N-methylamino, N-(3-ethylaminopropyl)-N-methylamino, N-(2-dimethylaminoethyl)-
N-methylamino, N-(2-diethylaminoethyl)-N-methylamino, N-(3-dimethylaminopropyl)-
N-methylamino, N-(3-diethylaminopropyl)-N-methylamino, pyridyl, pyridyimethyl, pyridylmethoxy, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, 4-methylpiperazinyl, - homopiperazinyl, 4-methylhomopiperazinyl, 4-acetylpiperazinyl, pyrrolidinylmethyl, = 15 piperidinyimethyl, morpholinylmethyl, piperazinylmethyl, 4-methylpiperazinyimethyl, : 4-acetylpiperazinylmethyl, pyrrolidinyloxy, I-methylpyrrolidinyloxy, piperidinyloxy, so 1-methylpiperidinyloxy, 2-(pyrrolidinyl)ethoxy, 3-(pyrrolidinyl)propoxy, . 2-(piperidinyl)cthoxy, 3-(piperidinyl)propoxy. 2-(morpholinyl)ethoxy. 3-(morpholinyl)propoxy, 2-(piperazinyl)ethoxy, 3-(piperazinyl)propoxy, 2-(4-methylpiperazinyl)ethoxy, 3-(4-methylpiperazinyl)propoxy, 2-(4-acetylpiperazinyl)ethoxy or 3-(4-acetylpiperazinyl)propoxy; nisOorl;
R? is fluoro, chloro, bromo, methy! or ethyl; q is 0; and
Q is phenyl, furyl. thienyl. oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl. pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzofuranyl. indolyl, benzothienyl, benzoxazolyl. benzimidazolyl, benzothiazolyl, indazolyl, benzofurazanyl, quinolyl, isoquinolyl. quinazolinyl, quinoxalinyl or naphthyridinyl which optionally bears 1 or 2 substituents selected from hydroxy, fluoro. chloro, trifluoromethyl, cyano. amino, methyl, ethyl. methoxy, ethoxy. methylenedioxy, methylamino, ethylamino. dimethylamino, diethylamino. aminomethyl. methylaminomethyl. cthylaminomethyl, dimethylaminomethyl. diethylaminomethyl. 2-hydroxyethoxy, 3-hydroxypropoxy. 2-methoxyethoxy.
2-ethoxyethoxy, 3-methoxypropoxy, 3-ethoxypropoxy, 2-aminoethoxy, 3-aminopropexy. 2-methylaminoethoxy, 2-ethylaminoethoxy, 3-methylaminopropoxy, 3-ethylaminopropoxy, 2-dimethylaminoethoxy, 2-diethylaminoethoxy, 3-dimethylaminopropoxy, 3-diethylaminopropoxy, pyridyl, pyridylmethyl, pyridylmethoxy, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, 4-methylpiperazinyl, homopiperazinyl, 4-methylhomopiperazinyl, 4-acetylpiperazinyl, pyrrolidinylmethyl, piperidinylmethyl, morpholinylmethyl, piperazinylmethyl, 4-methylpiperazinyimethyl, 4-acetylpiperazinylmethyl, pyrrolidinyloxy. 1-methylpyrrolidinyloxy, piperidinyloxy, 1-methylpiperidinyloxy, 2-(pyrrolidinyl)ethoxy, 3-(pyrrolidinyl)propoxy, 2-(piperidinyl)ethoxy, 3-(piperidinyl)propoxy, 2-(morpholinyl)ethoxy, 3-(morpholinyl)propoxy, 2-(piperazinyl)ethoxy, 3-(piperazinyl)propoxy, 2-(4-methylpiperazinyl)ethoxy, 3-(4-methylpiperazinyl)propoxy, 2-(4-acctyipiperazinyi)ethoxy and 3-(4-acetylpiperazinyl)propoxy: or a pharmaceutically-acceptable salt thereof.
A further preferred compound of the first aspect of the invention is an amide derivative of the Formula I wherein
X is CH;
Y is CH or N:
R'is hydrogen. chloro or methyl; mis 0.1 or 2;
R'is hydroxy. fluoro, chloro, bromo, trifluoromethyl, cyano. methyl, ethyl, propyl. methoxy. ethoxy. amino, methylamino, ethylamino, dimethylamino, diethylamino, methylaminomethyl. ethylaminomethyl, dimethylaminomethyl, diethylaminomethyl, 2-aminoethoxy, 3-aminopropoxy, 2-methylaminoethoxy, 2-ethylaminoethoxy, 3-methylaminopropoxy, 3-ethylaminopropoxy, 2-dimethylaminoethoxy, 2-diethylaminoethoxy, ee 3-dimethylaminopropoxys3-diethylaminopropoxy-2-aminoethylamino;3-aminepropylamine— 2-methylaminoethylamino, 2-ethylaminoethylamino, 3-methylaminopropylamino, 3-ethylaminopropylamino, 2-dimethylaminoethylamino, 2-diethylaminoethylamino, 3-dimethylaminopropylamino, 3-diethylaminopropylamino, N-(2-aminoethyl)-
N-methylamino, N-(3-aminopropyl)-N-methylamino, N-(2-methylaminoethyl)-
N-methylamino, N-(2-ethylaminoethyl)-N-methylamino, N-(3-methylaminopropyl)-
N-methylamino, N-(3-ethylaminopropyl)-N-methylamino. N-(2-dimethylaminoethyl)-
N-methylamino, N-(2-diethylaminoethyl)-N-methylamino, N-(3-dimethylaminopropyl)-
' “N-methylamino, N-(3-diethylaminopropyl)-N-methylamino, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2-pyridylmethoxy, 3-pyridylmethoxy, 4-pyridylmethoxy, pyrrolidin-1-yl, piperidino, morpholino, piperazin-1-yl, 4-methylpiperazin-1-yl, homopiperazin-1-yl, 4-methylhomopiperazin-1-yl, 4-acetylpiperazin-1-yl,
S pyrrolidin-1-ylmethyl, piperidinomethyl, morpholinomethyl, piperazin-1-ylmethyl, 4-methylpiperazin-1-ylmethyl, 4-acetylpiperazin-1-ylmethyl, pyrrolidin-3-yloxy,
I-methylpyrrolidin-3-yloxy, piperidin-4-yloxy, 1-methylpiperidin-4-yloxy, 2-(pyrrolidin- 1-ylethoxy, 3-(pyrrolidin-1-yl)propoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 2-piperazin-1-ylethoxy, 3-piperazin- 1-ylpropoxy, 2-(4-methylpiperazin-1-yl)ethoxy, 3-(4-methylpiperazin-1-yl)propoxy, 2-(4-acetylpiperazin-1-yl)ethoxy or 3-(4-acetylpiperazin-1-yl)propoxy; nis 0; q1s 0; and
Q is phenyl, 2-turyl, 2-thienyl, 4-oxazolyl, 5-isoxazolyl, 4-thiazolyl, 5-isothiazolyl, 2-pyridyl. . 15 3-pyridyl, 4-pyridyl, 2-benzofuranyl, 2-indolyl, 2-benzothienyl, 2-benzoxazolyl. 2-benzimidazolyl, 2-benzothiazolyl, 4-benzofurazanyl, 2-quinolyl, 6-quinolyl. 7-quinolyl, 3-isoquinolyl, 6-quinazolinyl, 7-quinazolinyl, 6-quinoxalinyl or 7-quinoxalinyl which optionally bears 1 or 2 substituents selected from hydroxy, fluoro, chloro. trifluoromethyl. cyano, amino. methyl, ethyl, methoxy, ethoxy, methylenedioxy, methylamino. ethylamino, dimethylamino, diethylamino. aminomethyl, methylaminomethyl, ethylaminomethyl. dimethylaminomethyl, diethylaminomethyl, 2-hydroxyethoxy, 3-hydroxypropoxy, 2-methoxyethoxy, 2-ethoxyethoxy, 3-methoxypropoxy, 3-ethoxypropoxy, 2-aminoethoxy, 3-aminopropoxy, 2-methylaminoethoxy, 2-ethylaminoethoxy, 3-methylaminopropoxy, 3-ethylaminopropoxy. 2-dimethylaminoethoxy, 2-diethylaminoethoxy. 3-dimethylaminopropoxy. 3-diethylaminopropoxy. 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2-pyridylmethoxy, 3-pyridyimethoxy. 4-pyridylmethoxy, pyrrolidin-1-yl, piperidino, morpholino, piperazin-1-yl, 4-methylpiperazin-1-yl. homopiperazin-1-yl, 4-methylhomopiperazin-1-yl, 4-acetylpiperazin- 1-yl. pyrrolidin-1-ylmethyl, piperidinomethyl. morpholinomethyl. piperazin-1-ylmethyl. 4-methylpiperazin-1-ylmethyl, 4-acetylpiperazin-1-ylmethyl, pyrrolidin-3-yloxy, 1-methylpyrrolidin-3-yloxy, piperidin-4-yloxy, I-methylpiperidin-4-yloxy, 2-pyrrolidin-
I-ylethoxy, 3-pyrrolidin-1-ylpropoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, ’ 2-morpholinoethoxy, 3-morpholinopropoxy, 2-piperazin-1-ylethoxy, 3-piperazin- 1-ylpropoxy, 2-(4-methylpiperazin-1-yl)ethoxy, 3-(4-methylpiperazin-1-yl)propoxy, 2-(4-acetylpiperazin-1-yl)ethoxy and 3-(4-acetylpiperazin-1-yl)propoxy;
S or a pharmaceutically-acceptable salt thereof.
A turther preferred compound of the first aspect of the invention is an amide derivative of the Formula | wherein X is CH;
Y ts CH or N;
R'is hydrogen, chloro or methyl; mis O.1or2;
R'is hydroxy, fluoro, chloro, bromo, trifluoromethyl, cyano, methyl, ethyl, propyl, methoxy. ethoxy, amino, methylamino. ethylamino. dimethylamino. diethylamino, methylaminomethyl. ethylaminomethyl. dimethylaminomethyl, diethylaminomethyl, 2-aminoethoxy. >-aminopropoxy, 2-methylaminoethoxy, 2-ethylaminoethoxy, 3-methylaminopropoxy, 3-ethylaminopropoxy, 2-dimethylaminoethoxy, 2-diethylaminoethoxy, 3-dimethylaminopropoxy, 3-diethylaminopropoxy. 2-aminoethylamino, 3-aminopropylamino. 2-methylaminoethylamino, 2-ethylaminoethylamino, 3-methylaminopropylamino, 3-ethylaminopropylamino, 2-dimethylaminoethylamino, 2-diethylaminoethylamino, 3-dimethylaminopropylamino. 3-diethylaminopropylamino, N-(2-aminoethyl)-
N-methylamino, N-(3-aminopropyl)-N-methylamino, N-(2-methylaminoethyl)-
N-methylamino, N-(2-ethylaminoethyl)-N-methylamino, N-(3-methylaminopropyl)-
N-methylamino, N-(3-ethylaminopropyl)-N-methylamino, N-(2-dimethylaminoethyl)-
N-methylamino, N-(2-diethylaminoethyl)-N-methylamino, N-(3-dimethylaminopropyl)- ) N-methylamino, N-(3-diethylaminopropyl)-N-methylamino, 2-pyridylmethyl, ~~~ ~~ 3-pyridylmethyl, 4-pyridylmethyl, 2-pyridylmethoxy, 3-pyridylmethoxy, 4-pyridylmethoxy, pyrrolidin-1-yl, piperidino, morpholino, piperazin-1-yl, 4-methylpiperazin-1-yl, homopiperazin-1-yl, 4-methylhomopiperazin-1-yl, 4-acetylpiperazin-1-yl, pyrrolidin-
I-ylmethyl, piperidinomethyl. morpholinomethyl, piperazin-1-ylmethyl, 4-methylpiperazin-1-ylmethyl. 4-acetylpiperazin-1-ylmethyl, pyrrolidin-3-yloxy. 1-methylpyrrolidin-3-yloxy. piperidin-4-yloxy, 1-mcthylpiperidin-4-yloxy, 2-(pyrrolidin- [-yl)ethoxy, 3-(pyrrolidin-1-yl)propoxy. 2-piperidinoethoxy, 3-piperidinopropoxy. 2-morpholinoethoxy. 3-morpholinopropoxy, 2-piperazin-1-ylethoxy. 3-piperazin-
3 WO 00/55120 PCT/GB00/00914 ~ l-ylpropoxy, 2-(4-methylpiperazin-1-yl)ethoxy, 3-(4-methylpiperazin-1-yl)propoxy, 2-(4-acetylpiperazin-1-yl)ethoxy or 3-(4-acetylpiperazin-1-yl)propoxy; nis 0; q is 0; and
Q is phenyl, 2-pyridyl, 3-pyridyl or 4-pyridyl which optionally bears 1 or 2 substituents selected from hydroxy, fluoro, chloro, trifluoromethyl, cyano, amino, methyl. ethyl, methoxy, ethoxy, methylenedioxy, methylamino, ethylamino, dimethylamino. diethylamino, aminomethyl, methylaminomethyl, ethylaminomethyl, dimethylaminomethy}, diethylaminomethyl, 2-hydroxyethoxy, 3-hydroxypropoxy, 2-methoxyethoxy, 2-ethoxyethoxy, 3-methoxypropoxy, 3-ethoxypropoxy, 2-aminoethoxy, 3-aminopropoxy, 2-methylaminoethoxy, 2-ethylaminoethoxy, 3-methylaminopropoxy, 3-ethylaminopropoxy, 2-dimethylaminoethoxy, 2-diethylaminoethoxy, 3-dimethylaminopropoxy, 3-diethylaminopropoxy, 2-pyridyl, 3-pyridyl. 4-pyridyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2-pyridylmethoxy, 3-pyridylmethoxy. 4-pyridylmethoxy, pyrrolidin-1-yl, piperidino, morpholino, piperazin-1-yl, 4-methylpiperazin-1-yl, homopiperazin-1-yl, 4-methylhomopipcrazin-1-yl, 4-acetylpiperazin- 1-yl, pyrrolidin-1-ylmethyl, piperidinomethyl, morpholinomethyl, piperazin-1-ylmethyl, 4-methylpiperazin-1-ylmethyl, 4-acetylpiperazin-1-ylmethyl, pyrrolidin-3-yloxy, 1-methylpyrrolidin-3-yloxy, piperidin-4-yloxy, 1-methylpiperidin-4-yloxy, 2-pyrrolidin-1-ylethoxy, 3-pyrrolidin-1-ylpropoxy. 2-piperidinoethoxy. 3-piperidinopropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 2-piperazin-1-ylethoxy, 3-piperazin-1-ylpropoxy, 2-(4-methylpiperazin-1-yl)ethoxy, 3-(4-methylpiperazin- 1-yl)propoxy. 2-(4-acetylpiperazin-1-yl)ethoxy and 3-(4-acetylpiperazin-1-yl)propoxy: or a pharmaceutically-acceptable salt thereof.
A further preferred compound of the first aspect of the invention is an amide derivative of the Formula I wherein X is CH;
Y is CH or N:
R* is hydrogen, chloro or methyl; mis 1 or 2:
R'is hydroxy. fluoro, chloro. methyl, ethyl, propyl. methoxy, dimethylaminomethy!, diethylaminomethyl. 2-dimethylaminoethoxy. 2-diethylaminoethoxy, 3-dimethylaminopropoxy. 3-dicthylaminopropoxy. 3-dimethylamino-2-hydroxypropoxy.
3-diethylamino-2-hydroxypropoxy, 2-aminoethylamino, 3-aminopropylamino, 4-aminobutylamino, 3-methylaminopropylamino, 2-dimethylaminoethylamino, 2-diethylaminoethylamino, 3-dimethylaminopropylamino, 4-dimethylaminobutylamino, 3-amino-2-hydroxypropylamino, 3-dimethylamino-2-hydroxypropylamino,
N-(2-dimethylaminoethyl)-N-methylamino, N-(3-dimethylaminopropyl)-N-methylamino, pyrrolidin-1-yl, morpholino, piperidino, piperazin-1-yl, 4-methylpiperazin-1-yl, 4-ethylpiperazin-1-yl, 4-(2-hydroxyethyl)piperazin-1-yl, homopiperazin-1-yl, 4-methylhomopiperazin-1-yl, piperazin-1-ylmethyl, 4-methylpiperazin-1-ylmethyl, homopiperazin-1-ylmethyl, 4-methylhomopiperazin-1-ylmethyl, morpholinomethyl, 3-aminopyrrolidin-1-ylmethyl, 3-hydroxypyrrolidin-1-ylmethyl, 4-(2-hydroxyethyl)piperazin- 1-ylmethyl, pyrrolidin-3-yloxy, 1-methylpyrrolidin-3-yloxy, piperidin-4-yloxy, 1-methylpiperidin-4-yloxy, 1-benzylpiperidin-4-yloxy, 2-pyrrolidin-1-ylethoxy, 3-pyrrolidin- 1-ylpropoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, 2-morpholinoethoxy. 3-morpholinopropoxy, 2-pipcrazin-1-ylethoxy, 3-piperazin-1-ylpropoxy, 2-(4-methylpiperazin-1-yl)ethoxy, 3-(4-methylpiperazin-1-yl)propoxy, 2-hydroxy- 3-pyrrolidin-1-ylpropoxy, 2-hydroxy-3-piperidinopropoxy, 2-hydroxy-3-morpholinopropoxy, piperidin-4-ylamino, 1-methylpiperidin-4-ylamino, 1-benzylpiperidin-4-ylamino, 2-pyrrolidin-1-ylethylamino, 3-pyrrolidin-1ylpropylamino, 2-morpholinoethylamino, 3-morpholinopropylamino, 2-piperidinoethylamino, 3-piperidinopropylamino, 2-piperazin- 1-ylethylamino, 3-piperazin-1-ylpropylamino, 2-(4-methylpiperazin-1-yl)ethylamino, 3-(4-methylpiperazin-1-yl)propylamino. 2-(1-methylpyrrolidin-2-yl)ethylamino, 3-(1-methylpyrrolidin-2-yl)propylamino, 2-dimethylaminoethylaminomethyl, 3-dimethylaminopropylaminomethyl, 3-dimethylamino-2,2-dimethylpropylaminomethyl. 2-(1-methylpyrrolidin-2-ylethyl)aminomethyl, 3-pyrrolidin-1-ylpropylaminomethyl, ~~ ~~ 2-morpholinoethylaminomethyl, 3-morpholinopropylaminomethyl, 2-piperazin-
I-ylethylaminomethyl, 3-(4-methylpiperazin-1-ylpropyl)aminomethyl or 2-pyridylmethoxy:; nis 0; q 1s 0: and
Q is 2-pyridyl. 3-pyridyl or 4-pyridyl which bears a substituent selected from pyrrolidin-1-yl, 3-hydroxypyrrolidin-1-yl, 2-hydroxymethylpyrrolidin-1-yl, morpholino. piperidino. 4-hydroxypiperidin-1-y}, piperazin-1-yl and 4-methylpiperazin-1-yl: or a pharmaceutically-acceptable salt thereof.
~ WO 00/5120 PCT/GB00/00914
An especially preferred compound of the first aspect of the invention is an amide derivative of the Formula I wherein X is CH;
YisCHorN;
R? is hydrogen, chloro or methyl; mis 1 and R'is selected from diethylaminomethy!l, N-(3-dimethylaminopropyl)-
N-methylamino, pyrrolidin-1-yl, morpholino, piperidino, piperazin- 1-yl, 4-methylpiperazin- 1-yl, 4-ethylpiperazin-1-yl, homopiperazin-1-yl, 4-methylhomopiperazin-1-yl, piperazin-1-ylmethyl, 4-methylpiperazin-1-ylmethyl, 4-methylhomopiperazin-1-ylmethyl, morpholinomethyl, 3-aminopyrrolidin-1-ylmethyl, 3-hydroxypyrrolidin-1-ylmethyl, pyrrolidin-3-yloxy, piperidin-4-yloxy, 2-pyrrolidin-1-ylethoxy, 2-piperidinoethoxy, 2-morpholinoethoxy, 3-dimethylaminopropylaminomethyl, 3-dimethylamino- 2.2-dimethylpropylaminomethyl, 2-(1-methylpyrrolidin-2-ylethyl)aminomethyl, 3-pyrrolidin- 1-ylpropylaminomethyl, 2-morpholinoethylaminomethyl, 3-morpholinopropylaminomethyi, 2-piperazin-1-ylethylaminomethyl, 3-(4-methylpiperazin-1-ylpropyl)aminomethy! and 2-pyridyimethoxy; : nis 0; q is 0; and
Q is 3-pyridyl or 4-pyridyl which bears a substituent selected from pyrrolidin-1-yl, morpholino, piperidino, piperazin-1-yl and 4-methylpiperazin-1-yl; or a pharmaceutically-acceptable salt thereof.
A further especially preferred compound of the first aspect of the invention is an amide derivative of the Formula | wherein X is CH;
Y is CHorN;
R* is hydrogen, chloro or methyl; mis 1 and R' is N-(3-dimethylaminopropyl)-N-methylamino, 4-methylpiperazin-1-yl, 4-methylhomopiperazin-1-yl, 4-methylpiperazin-1-ylmethy! or pyrrolidin-3-yloxy; nis 0; qis 0; and
Q is 2-morpholinopyrid-4-yl: or a pharmaceutically-acceptable salt thereof.
A particular preferred compound of the invention is, for example :-
N-[3-(4-methylpiperazin-1-ylmethyl)phenyl}-2-methyl-5-(2-morpholinopyrid- . 4-ylcarbonylamino)benzamide,
N-[6-(4-ethylpiperazin-1-yl)pyrid-3-yl}-2-chloro-5-(2-morpholinopyrid- 4-ylcarbonylamino)benzamide,
N-[6-(4-methylpiperazin-1-yl)pyrid-3-yl]-2-chloro-5-(2-morpholinopyrid- 4-ylcarbonylamino)benzamide or
N-{6-[N-(3-dimethylaminopropyl)-N-methylamino]pyrid-3-yl}-2-chloro- 5-(2-morpholinopyrid-4-ylcarbonylamino)benzamide; or a pharmaceutically-acceptable salt thereof.
A preferred compound of the second aspect of the invention is an amide derivative of the Formula | wherein X 1s CH or N;
Y 1s CH or N:
R* is fluoro. chloro. bromo, methyl or ethyl; mis 0. } or 2;
R'is hydroxy, fluoro, chloro. bromo, trifluoromethyl, cyano, methyl, ethyl, methoxy, ethoxy, amino. methylamino, ethylamino, dimethylamino. diethylamino, methylaminomethyl, ethylaminomethyl, dimethylaminomethyl, diethylaminomethyl, 2-aminoethoxy, 3-aminopropoxy, 2-methylaminoethoxy, 2-ethylaminoethoxy. 3-methylaminopropoxy, 3-ethylaminopropoxy. 2-dimethylaminoethoxy. 2-diethylaminoethoxy, 3-dimethylaminopropoxy. 3-diethylaminopropoxy. 2-aminoethylamino, 3-aminopropylamino. 2-methylaminocthylamino, 2-ethylaminoethylamino, 3-methylaminopropylamino, 3-ethylaminopropylamino, 2-dimethylaminoethylamino, 2-diethylaminoethylamino, 3-dimethylaminopropylamino, 3-diethylaminopropylamino, N-(2-aminoethyl)-
N-methylamino, N-(3-aminopropyl)-N-methylamino, N-(2-methylaminoethyl)- ~~ 25_N-methylamino,-N=(2-ethylaminoethyl)-N-methylamino, N-(3-methylaminopropy!)=
N-methylamino, N-(3-ethylaminopropyl)-N-methylamino, N-(2-dimethylaminoethyl)-
N-methylamino, N-(2-diethylaminoethyl)-N-methylamino, N-(3-dimethylaminopropyl)-
N-methylamino, N-(3-diethylaminopropyl)-N-methylamino, pyridyl, pyridylmethyl, pyridylmethoxy, 3-pyrrolinyl, pyrrolidinyl, piperidinyl. homopiperidinyl. morpholinyl. piperazinyl. 4-methylpiperazinyl, 4-ethylpiperazinyl. homopiperazinyl. 4-methylhomopiperazinyl. 4-acetylpiperazinyl, pyrrolidinylmethyl. piperidiny methyl. morpholinvimethyl, piperazinylmethyl. 4-methylpiperazinylmethyl. homopiperazinylmethyl.
’ " 4-methylhomopiperazinylmethyl, 4-acetylpiperazinylmethyl, pyrrolidinyloxy, 1-methylpyrrolidinyloxy, piperidinyloxy, 1-methylpiperidinyloxy, homopiperidinyloxy, 1-methylhomopiperidinyloxy, 2-(pyrrolidinyl)ethoxy, 3-(pyrrolidinyl)propoxy, 2-(piperidinyl)ethoxy, 3-(piperidinyl)propoxy, 2-(morpholinyl)ethoxy, 3-(morpholinyl)propoxy, 2-(piperazinyl)ethoxy, 3-(piperazinyl)propoxy, 2-(4-methylpiperazinyl)ethoxy, 3-(4-methylpiperazinyl)propoxy, 2-(4-acetylpiperazinyl)ethoxy, 3-(4-acetylpiperazinyl)propoxy, 3-dimethylaminopropylaminomethyl, 3-dimethylamino-2,2-dimethylpropylaminomethyl, 2-(1-methylpyrrolidinylethyl)aminomethyl, 3-pyrrolidinylpropylaminomethyl, 2-morpholinylethylaminomethyl, 3-morpholinylpropylaminomethyl, 2-piperazinylethylaminomethyl, 3-(4-methylpiperazinylpropyl)aminomethyl, pyridylmethoxy, imidazolylmethoxy, thiazolylmethoxy and 2-methylthiazolylmethoxy; nisOorl;
R? is fluoro, chloro, bromo, methyl or ethyl; } 15 qis0; and
Q is phenyl, indenyl, indanyl, tetrahydronaphthyl, fluorenyl, furyl, thienyl, oxazolyl, 1soxazolyl, imidazolyl, pyrazolyl, thiazolyl, 1sothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzofuranyl, indolyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, indazolyl, benzofurazanyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, naphthyridiny], carbazolyl. dibenzofuranyl, dibenzothiophenyl or xanthenyl which optionally bears | or 2 substituents selected from hydroxy, fluoro. chloro, trifluoromethyl, cyano, amino, methyl. ethyl. methoxy, ethoxy, propoxy, isopropoxy, cyclopentyloxy, methylenedioxy, methylamino. ethylamino, dimethylamino, diethylamino, acetamido, propionamido, methanesulphonamido,
N-methylmethanesulphonamido, aminomethyl, methylaminomethyl, ethylaminomethyl, dimethylaminomethyl, dicthylaminomethyl, 2-hydroxyethoxy, 3-hydroxypropoxy, 2-methoxyethoxy, 2-ethoxyethoxy, 3-methoxypropoxy, 3-ethoxypropoxy, 2-aminoethoxy. 3-aminopropoxy. 2-mcthylaminoethoxy. 2-ethylaminoethoxy, 3-methylaminopropoxy, 3-ethylaminopropoxy, 2-dimethylaminoethoxy. 2-diethylaminoethoxy, 3-dimethylaminopropoxy, 3-diethylaminopropoxy, phenyl. furyl. thienyl, pyridyl, pyridylmethyl, pyridylmethoxy, azetidinyl. 3-pyrrolinyl, pyrrolidinyl, piperidinyl. homopiperidinyl. morpholinyl, piperazinyl. 4-methylpiperazinyl. homopiperazinyl. 4-methylhomopiperazinyl. 4-acetylpiperazinyl, pyrrolidinylmethyl, piperidinylmethy].
morpholinylmethyl, piperazinylmethyl, 4-methylpiperazinylmethyl, . . 4-acetylpiperazinylmethy!, pyrrolidinyloxy, 1-methylpyrrolidinyloxy, piperidinyloxy, 1-methylpiperidinyloxy, 2-(pyrrolidinyl)ethoxy, 3-(pyrrolidinyl)propoxy, 2-(piperidinyl)ethoxy, 3-(piperidinyl)propoxy, 2-(morpholinyl)ethoxy, 3-(morpholinyl)propoxy, 2-(piperazinyl)ethoxy, 3-(piperazinyl)propoxy, 2-(4-methylpiperazinyl)ethoxy, 3-(4-methylpiperazinyl)propoxy, 2-(4-acetylpiperazinyl)ethoxy and 3-(4-acetylpiperazinyl)propoxy, and wherein any phenyl, furyl, thienyl, pyridyl or heterocyclyl group in a substituent on Q may optionally bear 1 or 2 substituents selected from fluoro, chloro, methyl and methoxy; or a pharmaceutically-acceptable salt thereof.
A further preferred compound of the second aspect of the invention 1s an amide derivative of the Formula | wherein
X is CH:
YisCHorN;
R'is chloro or methyl; mis 0, or 2;
R' is hydroxy, fluoro, chloro, bromo, trifluoromethyl, cyano, methyl, ethyl, propyl, methoxy. ethoxy. amino, methylamino, ethylamino, dimethylamino, diethylamino, methylaminomethyl, cthylaminomethyl, dimethylaminomethyl, diethylaminomethyl, 2-aminoethoxy, 3-aminopropoxy. 2-methylaminoethoxy, 2-ethylaminoethoxy, 3-methylaminopropoxy. 3-ethylaminopropoxy, 2-dimethylaminoethoxy, 2-diethylaminoethoxy, 3-dimethylaminopropoxy, 3-diethylaminopropoxy, 2-aminoethylamino, 3-aminopropylamino, 2-methylaminoethylamino, 2-ethylaminoethylamino, 3-methylaminopropylamino, - 3-ethylaminopropylamino, 2-dimethylaminoethylamino, 2-diethylaminoethylamino. . —....... =. —253=dimethylaminopropyamino; 3=diethylaminopropylamino; N=(2=aminoethyl)=
N-methylamino, N-(3-aminopropyl)-N-methylamino, N-(2-methylaminoethyl)-
N-methylamino, N-(2-ethylaminoethyl)-N-methylamino, N-(3-methylaminopropyl)-
N-methylamino, N-(3-cthylaminopropyl)-N-methylamino, N-(2-dimethylaminoethyl)-
N-methylamino, N-(2-diethylaminoethyl)-N-methylamino, N-(3-dimethylaminopropyl)-
N-methylamino, N-(3-diethylaminopropy!)-N-methylamino, 2-pyridylmethyl. 3-pyridylmethyl, 4-pyridylmethyl, 2-pyridylmethoxy. 3-pyridylmethoxy, 4-pyridylmethoxy. pyrrolidin-1-yl, piperidino, morpholino, piperazin-1-yl, 4-methylpiperazin-1-yl.
! " homopiperazin-1-yl, 4-methylhomopiperazin-1-yl, 4-acetylpiperazin-1-yl, pyrrolidin-1-ylmethyl, piperidinomethyl, morpholinomethyl, piperazin-1-ylmethyl, 4-methylpiperazin-1-ylmethyl, 4-acetylpiperazin-1-ylmethyl, pyrrolidin-3-yloxy, 1-methylpyrrolidin-3-yloxy, piperidin-4-yloxy, 1-methylpiperidin-4-yloxy, 2-(pyrrolidin- 5S 1l-ybethoxy, 3-(pyrrolidin-1-yl)propoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 2-piperazin-1-ylethoxy, 3-piperazin- 1-ylpropoxy, 2-(4-methylpiperazin-1-yl)ethoxy, 3-(4-methylpiperazin-1-yl)propoxy, 2-(4-acetylpiperazin-1-yl)ethoxy or 3-(4-acetylpiperazin-1-yl)propoxy; nis 0; qis 0: and
Q is phenyl, 2-furyl, 2-thienyl, 4-oxazolyl, 5-isoxazolyl. 4-thiazolyl, 5-isothiazolyl, 2-pyridyl. 3-pyridyl. 4-pyridyl, 2-benzofuranyl, 2-indolyl, 2-benzothienyl, 2-benzoxazolyl, 2-benzimidazolyl, 2-benzothiazolyl, 4-benzoturazanyl, 2-quinolyl, 6-quinolyl, 7-quinoly!. 3-isoquinolyl, 6-quinazolinyl, 7-quinazolinyl, 6-quinoxalinyl or 7-quinoxalinyl which ) 1S optionally bears 1 or 2 substituents selected from hydroxy, fluoro, chloro, trifluoromethyl, cyano, amino, methyl, ethyl, methoxy, ethoxy, methylenedioxy, methylamino, ethylamino, dimethylamino, diethylamino, aminomethyl, methylaminomethyl, ethylaminomethyl. - dimethylaminomethyl. diethylaminomethyl, 2-hydroxycthoxy, 3-hydroxypropoxy, - 2-methoxyethoxy, 2-ethoxyethoxy. 3-mcthoxypropoxy, 3-ethoxypropoxy, 2-aminocthoxy. 3-aminopropoxy, 2-methylaminoethoxy, 2-ethylaminoethoxy. 3-methylaminopropoxy. 3-ethylaminopropoxy. 2-dimethylaminoethoxy, 2-diethylaminocthoxy, 3-dimethylaminopropoxy, 3-diethylaminopropoxy, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyridylmethyl, 3-pyridylmethyl. 4-pyridylmethyl, 2-pyridylmethoxy, 3-pyridylmethoxy. 4-pyridylmethoxy, pyrrolidin-1-yl, piperidino, morpholino, piperazin-1-yl, 4-methylpiperazin-1-yl, homopiperazin-1-yl, 4-methylhomopiperazin-1-yl, 4-acetylpiperazin- 1-yl, pyrrolidin-1-ylmethyl, piperidinomethyl, morpholinomethyl, piperazin-1-ylmethyl. 4-methylpiperazin-1-ylmethyl, 4-acetylpiperazin-1-ylmethyl, pyrrolidin-3-yloxy. -methylpyrrolidin-3-yloxy, piperidin-4-yloxy, I-methylpiperidin-4-yloxy, 2-pyrrolidin-
I-ylethoxy, 3-pyrrolidin-1-ylpropoxy, 2-piperidinoethoxy, 3-piperidinopropoxy. 2-morpholinoethoxy. 3-morpholinopropoxy. 2-piperazin-1-ylethoxy, 3-piperazin- 1-ylpropoxy. 2-(4-methylpiperazin-1-ylethoxy, 3-(4-methylpiperazin-1-yl)propoxy. 2-(4-acetylpiperazin-1-yl)ethoxy and 3-(4-acetylpipcrazin-1-yl)propoxy;
or a pharmaceutically-acceptable salt thereof. '
A further preferred compound of the second aspect of the invention is an amide derivative of the Formula I wherein X is CH;
YisCHorN;
R'is chloro or methyl; mis0, 1! or2;
R'is hydroxy. fluoro, chioro, bromo, trifluoromethyl, cyano. methyl, ethyl, propyl, methoxy, ethoxy, amino, methylamino, ethylamino, dimethylamino. diethylamino, methylaminomethyl, ethylaminomethyl, dimethylaminomethyl, diethylaminomethyl, 2-aminoethoxy, 3-aminopropoxy, 2-methylaminoethoxy, 2-ethylaminoethoxy, 3-methylaminopropoxy, 3-ethylaminopropoxy, 2-dimethylaminoethoxy, 2-diethylaminoethoxy, 3-dimethylaminopropoxy, 3-diethylaminopropoxy. 2-aminoethylamino, 3-aminopropylamino. 2-methylaminoethylamino. 2-ethylaminoethylamino, 3-methylaminopropylamino, 3-ethylaminopropylamine, 2-dimethylaminoethylamino, 2-diethylaminoethylamino, 3-dimethylaminopropylamino, 3-diethylaminopropylamino, N-(2-aminoethyl)-
N-methylamino, N-(3-aminopropyl)-N-methylamino, N-(2-methylaminoethyl)-
N-methylamino, N-(2-ethylaminoethyl)-N-methylamino, N-(3-methylaminopropy})- .
N-methylamino, N-(3-ethylaminopropy!)-N-methylamino, N-(2-dimethylaminoethyl)-
N-methylamino, N-(2-diethylaminoethyl)-N-methylamino, N-(3-dimethylaminopropyl)-
N-methylamino, N-(3-diethylaminopropyl)-N-methylamino. 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2-pyridylmethoxy, 3-pyridylmethoxy, 4-pyridylmethoxy, pyrrolidin-1-yl, piperidino, morpholino, piperazin-1-yl. 4-methylpiperazin-1-yl, homopiperazin-1-yl, 4-methylhomopiperazin-1-yl, 4-acetylpiperazin-1-yl, pyrrolidin- 1-ylmethyl, piperidinomethyl, morpholinomethyl, piperazin-1-ylmethyl,” =~ =~ ~~ = © 4-methylpiperazin-1-ylmethyl, 4-acetylpiperazin-1-ylmethyl, pyrrolidin-3-yloxy. 1-methylpyrrolidin-3-yloxy, piperidin-4-yloxy, 1-methylpiperidin-4-yloxy, 2-(pyrrolidin-
I-yl)ethoxy. 3-(pyrrolidin-1-yl)propoxy, 2-piperidinoethoxy. 3-piperidinopropoxy. 2-morpholinoethoxy, 3-morpholinopropoxy, 2-piperazin-1-ylethoxy, 3-piperazin-
I-ylpropoxy. 2-(4-methylpiperazin-1-yl)ethoxy, 3-(4-methylpiperazin-1-yl)propoxy. 2-(4-acctylpiperazin-1-yl)ethoxy or 3-(4-acetylpiperazin-1-yl)propoxy: nis 0; q is 0: and
. - Q 1s phenyl, 2-pyridyl, 3-pyridyl or 4-pyridyl which optionally bears 1 or 2 substituents selected from hydroxy, fluoro, chloro, trifluoromethyl, cyano, amino, methyl, ethyl, methoxy, ethoxy, methylenedioxy, methylamino, ethylamino, dimethylamino, diethylamino, aminomethyl, methylaminomethyl, ethylaminomethyl, dimethylaminomethyl, diethylaminomethyl, 2-hydroxyethoxy, 3-hydroxypropoxy, 2-methoxyethoxy, 2-ethoxyethoxy, 3-methoxypropoxy, 3-ethoxypropoxy, 2-aminoethoxy, 3-aminopropoxy, 2-methylaminoethoxy, 2-ethylaminoethoxy, 3-methylaminopropoxy, 3-ethylaminopropoxy, 2-dimethylaminoethoxy, 2-diethylaminoethoxy, 3-dimethylaminopropoxy, 3-diethylaminopropoxy, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2-pyridylmethoxy, 3-pyridylmethoxy, 4-pyridylmethoxy, pyrrolidin-1-yl, piperidino, morpholino, piperazin-1-yl, 4-methylpiperazin-1-yl, homopiperazin-1-yl. 4-methylhomopiperazin-1-yl. 4-acetylpiperazin- 1-yl, pyrrolidin-1-ylmethyl, piperidinomethyl, morpholinomethyl, piperazin-1-ylmethyl, 4-methylpiperazin-1-ylmethyl, 4-acetylpiperazin-1-ylmethyl, pyrrolidin-3-yloxy, 1-methylpyrrolidin-3-yloxy, piperidin-4-yloxy, 1-methylpiperidin-4-yloxy, 2-pyrrolidin-1-ylethoxy, 3-pyrrolidin-1-ylpropoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 2-piperazin-1-ylethoxy, 3-piperazin-1-ylpropoxy, 2-(4-methylpiperazin-1-yl)ethoxy, 3-(4-methylpiperazin- 1-yl)propoxy, 2-(4-acetylpiperazin-1-yl)ethoxy and 3-(4-acetylpiperazin-1-yl)propoxy; or a pharmaceutically-acceptable salt thereof.
A further preferred compound of the second aspect of the invention is an amide derivative of the Formula I wherein X 1s CH;
Y isCH or N;
R? is chloro or methyl; mislor?2;
R' is hydroxy, fluoro, chloro, methyl. ethyl, propyl, methoxy, dimethylaminomethyl, diethylaminomethyl, 2-dimethylaminoethoxy, 2-diethylaminoethoxy. 3-dimethylaminopropoxy, 3-diethylaminopropoxy. 3-dimethylamino-2-hydroxypropoxy, 3-diethylamino-2-hydroxypropoxy. 2-aminoethylamino, 3-aminopropylamino. 4-aminobutylamino, 3-methylaminopropylamino, 2-dimethylaminoethylamino, 2-diethylaminoethylamino. 3-dimethylaminopropylamino, 4-dimethylaminobutylamino. 3-amino-2-hydroxypropylamino, 3-dimethylamino-2-hydroxypropylamino.
N-(2-dimethylaminoethyl)-N-methylamino, N-(3-dimethylaminopropyl)-N-methylamino, pyrrolidin-1-yl, morpholino, piperidino, piperazin-1-yl, 4-methylpiperazin-1-yl, 4-ethylpiperazin-1-yl, 4-(2-hydroxyethyl)piperazin-1-yl, homopiperazin-1-yl, 4-methylhomopiperazin-1-yli, piperazin-1-ylmethyl, 4-methylpiperazin-1 -yimethyl, homopiperazin-1-ylmethyl, 4-methylhomopiperazin-1-ylmethyl, morpholinomethyl, 3-aminopyrrolidin-1-ylmethyl, 3-hydroxypyrrolidin-1-ylmethyl, 4-(2-hydroxyethyl)piperazin- l-ylmethyl, pyrrolidin-3-yloxy, l1-methylpyrrolidin-3-yloxy, piperidin-4-yloxy:. 1-methylpiperidin-4-yloxy, 1-benzylpiperidin-4-yloxy, 2-pyrrolidin-1-ylethoxy, 3-pyrrolidin- 1-ylpropoxy, 2-piperidinoethoxy, 3-piperidinopropoxy. 2-morpholinoethoxy, 3-morpholinopropoxy, 2-piperazin-1-ylethoxy, 3-piperazin-1-ylpropoxy, 2-(4-methylpiperazin-1-yljethoxy, 3-(4-methylpiperazin-1-yl)propoxy, 2-hydroxy- 3-pyrrolidin-1-ylpropoxy, 2-hydroxy-3-piperidinopropoxy, 2-hydroxy-3-morpholinopropoxy. piperidin-4-ylamino. 1-methylpiperidin-4-ylamino, 1-benzylpiperidin-4-ylamino, 2-pyrrolidin-1-ylethylamino, 3-pyrrolidin-1ylpropylamino, 2-morpholinoethylamino, 3-morpholinopropylamino, 2-piperidinoethylamino, 3-piperidinopropylamino, 2-piperazin- 1-ylethylamino, 3-piperazin-1-ylpropylamino, 2-(4-methylpiperazin-1-yl)ethylamino, 3-(4-methylpiperazin-1-yl)propylamino, 2-(1-methylpyrrolidin-2-yl)ethylamino, 3-(1-methylpyrrolidin-2-yl)propylamino, 2-dimethylaminoethylaminomethyl, 3-dimethylaminopropylaminomethyl, 3-dimethylamino-2,2-dimethyipropylaminomethyl, 2-(1-methylpyrrolidin-2-ylethyl)aminomethyl, 3-pyrrolidin-1-ylpropylaminomethyl, 2-morpholinoethylaminomethyl, 3-morpholinopropylaminomethyl, 2-piperazin- 1-ylethylaminomethyl, 3-(4-methylpiperazin-1-ylpropyl)aminomethyl or 2-pyridylmethoxy; nis 0: gisOiand | Co 25_Q.is.2-pyridyl,_ 3-pyridyl_or 4-pyridyl which bears a substituent selected from_ pyrrolidin-1-yl, 3-hydroxypyrrolidin-1-yl, 2-hydroxymethylpyrrolidin-1-y!, morpholino. piperidino. 4-hydroxypiperidin-1-yl, piperazin-1-yl and 4-methylpiperazin-1-yl; or a pharmaceutically-acceptable salt thereof.
An especially preferred compound of the second aspect of the invention is an amide derivative of the Formula I wherein X 1s CH;
Y is CH or N:
R'is chloro or methyl:
} . mis 1 and R' is selected from diethylaminomethyl, N-(2-dimethylaminoethyl)-
N-methylamino, N-(3-dimethylaminopropyl)-N-methylamino, pyrrolidin-1-yl, morpholino, piperidino, piperazin-1-yl, 4-methylpiperazin-1-yl, 4-ethylpiperazin-1-yl, homopiperazin-1-yl, 4-methylhomopiperazin-1-yl, piperazin-1-ylmethyl, 4-methylpiperazin-1-ylmethyl, 4-methylhomopiperazin-1i-ylmethyl, morpholinomethyl, 3-aminopyrrolidin-1-yimethyl, 3-hydroxypyrrolidin-1-ylmethyl, pyrrolidin-3-yloxy, piperidin-4-yloxy, 2-pyrrolidin-1-ylethoxy, 2-piperidinoethoxy, 2-morpholinoethoxy, 3-dimethylaminopropylaminomethyl, 3-dimethylamino-2,2-dimethylpropylaminomethyl, 2-(1-methylpyrrolidin-2-ylethyl)aminomethyl, 3-pyrrolidin-1-ylpropylaminomethyl, 2-morpholinoethylaminomethyl, 3-morpholinopropylaminomethyl, 2-piperazin-1-ylethylaminomethyl, 3-(4-methylpiperazin-1-ylpropyl)aminomethyl and 2-pyridylmethoxy; nis 0; q1s 0; and
Q is 3-pyridyl or 4-pyridyl which bears a substituent selected from pyrrolidin-1-yl, morpholino, piperidino, piperazin-1-yl and 4-methylpiperazin-1-yl; or a pharmaceutically-acceptable salt thereof.
A further especially preferred compound of the second aspect of the invention is an amide derivative of the Formula I wherein X is CH;
YisCHorN;
R* is chloro or methyl; m is | and R' is selected from diethylaminomethyl, N-(2-dimethylaminoethyl)-
N-methylamino, N-(3-dimethylaminopropyl)-N-methylamino, 3-pyrrolin-1-yl, pyrrolidin- 1-yl, morpholino, piperidino, homopiperidin-1-yl, piperazin-1-yl, 4-methylpiperazin-1-yl, 4-ethylpiperazin-1-yl, homopiperazin-1-yl, 4-methylhomopiperazin-1-yl, piperazin-1-ylmethyl, 4-methylpiperazin-1-ylmethyl, homopiperazin-1-ylmethyl, 4-methylhomopiperazin-1-ylmethyl. morpholinomethyl, 3-aminopyrrolidin-1-ylmethyl, 3-hydroxypyrrolidin-1-ylmethyl, pyrrolidin-3-yloxy, N-methylpyrrolidin-3-yloxy, piperidin-4-yloxy, N-methylpiperidin-4-yloxy, homopiperidin-4-yloxy.
N-methylhomopiperidin-4-yloxy. 2-pyrrolidin-1-ylethoxy, 2-piperidinoethoxy. 2-morpholinoethoxy, 3-dimethylaminopropylaminomethyl, 3-dimethylamino- 2.2-dimethylpropylaminomethyl. 2-(1-methylpyrrolidin-2-ylethyl)aminomethyl.
3-pyrrolidin-1-ylpropylaminomethyl, 2-morpholinoethylaminomethyl, ’ 3-morpholinopropylaminomethyl, 2-piperazin-1-ylethylaminomethyl, 3-(4-methylpiperazin-1-ylpropyl)aminomethyl, 2-pyridylmethoxy, 4-thiazolylmethoxy and 2-methylthiazol-4-ylmethoxy; nisO; q is 0; and
Q is phenyl which bears 1 or 2 substituents selected from tluoro, chloro, trifluoromethyl, methoxy, cyclopentyloxy, acetamido, N-methylmethanesulphonamido, 2-furyl, azetidin-1-yl, 3-pyrrolin-1-yl, pyrrolidin-1-yl, morpholino, piperidino, homopiperidino, piperazin-1-yl, homopiperazin-1-yl, 4-methylpiperazin-1-yl and 4-methylhomopiperazin-1-yl, or Q is 1-fluorenyl or 4-dibenzofuranyl, or Q is 3-pyridyl or 4-pyridyl which bears a substituent selected from azetidin-1-yl, 3-pyrrolin-1-yl. pyrrolidin-1-yl. morpholino. piperidino, homopiperidino, piperazin-I-yl, homopiperazin-1-yl, 4-methylpiperazin-1-yl and 4-methythomopiperazin-1-yl; or a pharmaceutically-acceptable salt thereof.
A further especially preferred compound of the second aspect of the invention is an amide derivative of the Formula 1 wherein X is CH; }
Y is CH or N:
R'is chloro or methyl; mis | and R' is N-(2-dimethylaminoethyl)-N-methylamino, N-(3-dimethylaminopropyl)-
N-methylamino, 4-methylpiperazin-1-yl, 4-ethyipiperazin-1-yl. 4-methylhomopiperazin-1-yl or 4-methylpiperazin-1-ylmethyl: nis 0; oo q is 0; and Co
Q is 2-(pyrrolidin-1-yl)pyrid-4-yl, 2-(3-pyrrolin-1-yl)pyrid-4-yL, 2-piperidinopyrid-4-yl. 2-morpholinopyrid-4-yl. I-fluorenyl, dibenzofuran-4-yl. 3-acetamidopheny!l or 3-(2-turyl)phenyl: or a pharmaceutically-acceptable salt thereof.
A further especially preferred compound of the second aspect of the invention 1s an amide derivative of the Formula | wherein X 1s CH:
Y is CH or N:
R'is chloro or methyl:
) om is 1 and R' is N-(3-dimethylaminopropyl)-N-methylamino, 4-methylpiperazin-1-yl, 4-methylhomopiperazin-1-yl or 4-methylpiperazin-1-ylmethyl; nis 0; q is 0; and
SQ is 2-morpholinopyrid-4-yl; or a pharmaceutically-acceptable salt thereof.
An amide derivative of the Formula I, or a pharmaceutically-acceptable salt or in-vivo- cleavable ester thereof, may be prepared by any process known to be applicable to the preparation of chemically-related compounds. Such processes, when used to prepare a novel amide derivative of the Formula I are provided as a further feature of the invention and are illustrated by the following representative process variants in which, unless otherwise stated,
X,Y,R' R% R’ m,n, qand Q have any of the meanings defined hereinbefore. Necessary starting materials may be obtained by standard procedures of organic chemistry. The preparation of such starting materials is described in conjunction with the following representative process variants and within the accompanying Examples. Alternatively ‘ necessary starting materials are obtainable by analogous procedures to those illustrated which are within the ordinary skill of an organic chemist. ’ (a) A compound of the Formula I, or a pharmaceutically-acceptable salt or in-vivo- cleavable ester thereof, may be prepared by rcacting an aniline of the Formula 11 (RM),
Y— II with a benzoic acid of the Formula Ill, or an activated derivative thereof,
R3 (R?),
HOC
Oo
N~ (CH), — Q Im under standard amide bond forming conditions. wherein variable groups are as defined hereinbefore and wherein any functional group is protected, if necessary, and: (1) removing any protecting groups:
(ii) optionally forming a pharmaceutically-acceptabie salt or in-vivo-cleavable * ester.
A suitable reactive derivative of a carboxylic acid of the Formula 111 is, for example, an acyl halide, for example an acyl chloride formed by the reaction of the acid and an
S inorganic acid chloride, for example thionyl chloride; a mixed anhydride, for example an anhydride formed by the reaction of the acid and a chloroformate such as isobutyl chloroformate; an active ester, for example an ester formed by the reaction of the acid with a phenol such as pentafluorophenol, with an ester such as pentafluorophenyl trifluoroacetate or with an alcohol such as N-hydroxybenzotriazole; an acyl azide, for example an azide formed by the reaction of the acid and an azide such as diphenylphosphoryl azide; an acyl cyanide, for example a cyanide formed by the reaction of an acid and a cyanide such as diethylphosphoryl cyanide; or the product of the reaction of the acid and a carbodiimide such as dicyclohexylcarbodiimide.
The standard amide bond forming conditions conveniently include the presence of a suitable base such as, for example, an alkali or alkaline earth metal carbonate, alkoxide, hydroxide or hydride, for example sodium carbonate, potassium carbonate, sodium ethoxide, potassium butoxide, sodium hydroxide, potassium hydroxide, sodium hydride or potassium hydride, or an organometallic base such as an alkyl-lithium, for example n-butyl-lithium, or a dialkylamino-lithium, for example lithium di-isopropylamide, or, for example, an organic amine base such as. for example, pyridine, 2,6-lutidine. collidine, 4-dimethylaminopyridine. tricthylamine. morpholine or diazabicyclo[5.4.0Jundec-7-ene.
The reaction is also preferably carried out in a suitable inert solvent or diluent, for example methanol, ethanol, tetrahydrofuran, methylene chloride, 1.2-dimethoxyethane, - N.N-dimethylformamide, N,N-dimethylacetamide; N-methylpyrrolidin-2-one, . --.. = : dimethylsulphoXide or acetone, and at a temperature in the range; forexample; 0to 100°C conveniently at or ncar ambient temperature.
Typically a carbodiimide coupling reagent is used in the presence of an organic solvent (preferably an anhydrous polar aprotic organic solvent) at a non-extreme temperature, for example in the region -10 to 40°C, typically at ambient temperature of about 20°C.
Typical standard amide bond forming conditions include activating the carboxy group, for example by treatment with a halo reagent (for example oxalyl chloride) to form an acy! halide in an organic solvent at ambient temperature and then reacting the activated compound
. . with an aniline. Any functional groups are protected and deprotected as necessary.
Conveniently a carbodiimide coupling reagent is used in the presence of an organic solvent (preferably an anhydrous polar aprotic organic solvent) at a non-extreme temperature, for example in the region -10 to 40°C, typically at ambient temperature of about 20°C. h) Protecting groups may in general be chosen from any of the groups described in the literature or known to the skilled chemist as appropriate for the protection of the group in question and may be introduced by conventional methods. Protecting groups may be removed by any convenient method as described in the literature or known to the skilled chemist as appropriate for the removal of the protecting group in question, such methods being chosen so as to effect removal of the protecting group with minimum disturbance of groups elsewhere in the molecule.
Specific examples of protecting groups are given below for the sake of convenience, in which "lower", as in, for example, lower alkyl, signifies that the group to which it is applied preferably has 1-4 carbon atoms. It will be understood that these examples are not exhaustive.
Where specific examples of methods for the removal of protecting groups are given below ’ these are similarly not exhaustive. The use of protecting groups and methods of deprotection not specifically mentioned is of course within the scope of the invention.
A carboxy protecting group may be the residue of an ester-forming aliphatic or arylaliphatic alcohol or of an ester-forming silanol (the said alcohol or silanol preferably containing 1-20 carbon atoms). Examples of carboxy protecting groups include straight or branched chain (1-12C)alkyl groups (for example isopropyl, tert-butyl); lower alkoxy lower alkyl groups (for example methoxymethyl, ethoxymethyl, isobutoxymethyl); lower aliphatic acyloxy lower alkyl groups, (for example acetoxymethyl, propionyloxymethyl, butyryloxymethyl, pivaloyloxymethyl); lower alkoxycarbonyloxy lower alkyl groups (for example 1-methoxycarbonyloxyethyl, I-ethoxycarbonyloxyethyl); aryl lower alkyl groups (for example benzyl, p-methoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, benzhydryl and phthalidyl); tri(lower alky!)silyl groups (for example trimethylsilyl and tert-butyldimethylsilyl); tri(lower alkyl)silyl lower alkyl groups (for example trimethylsilylethyl); and (2-6C)alkenyl groups (for example allyl and vinylethyl). Methods particularly appropriate for the removal of carboxy! protecting groups include for example acid-. base-. metal- or enzymically-catalysed hydrolysis.
Examples of hydroxy protecting groups include lower alkyl groups (for example tert-butyl), lower alkenyl groups (for example allyl); lower alkanoyl groups (for example acetyl); lower alkoxycarbonyl groups (for example tert-butoxycarbonyl); lower alkenyloxycarbony! groups (for example allyloxycarbonyl); aryl lower alkoxycarbonyl groups (for example benzoyloxycarbonyl, p-methoxybenzyloxycarbonyl, o-nitrobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl); tri lower alkylsilyl (for example trimethylsilyl, tert-butyldimethylsilyl) and aryl lower alkyl (for example benzyl) groups.
Examples of amino protecting groups include formyl. aralkyl groups (for example benzyl and substituted benzyl, p-methoxybenzyl, nitrobenzyl and 2.4-dimethoxybenzyl, and tiphenylmethyl); di-p-anisylmethyl and furylmethyl groups; lower alkoxycarbonyl (for example tert-butoxycarbonyl); lower alkenyloxycarbonyl (for example allyloxycarbonyl); aryl lower alkoxycarbonyl groups (for example benzyloxycarbony!, p-methoxybenzyloxycarbonyl. o-nitrobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl: trialkylsilyl (for example trimethylsilyl and tert-butyldimethylsilyl); alkylidene (for example methylidene); benzylidene and substituted benzylidene groups.
Methods appropriate for removal of hydroxy and amino protecting groups include, for example, acid-, base-, metal- or enzymically-catalysed hydrolysis for groups such as p-nitrobenzyloxycarbonyl, hydrogenation for groups such as benzyl and photolytically for groups such as o-nitrobenzyloxycarbonyl.
The reader is referred to Advanced Organic Chemistry. 4th Edition. by Jerry March. published by John Wiley & Sons 1992. for general guidance on reaction conditions and reagents. The reader is referred to Protective Groups in Organic Synthesis, 2nd Edition, by
Green ef al., published by John Wiley & Sons for general guidance on protecting groups.
The benzoic acid of the Formula III may be prepared by the cleavage of the corresponding ester thereof which, in turn, ‘may be prepared bv the reaction of an aniline of the Formula IV
R3 (R2),
ROC
NH, I\Y%
‘ " wherein R is, for example, lower alkyl or benzyl with a carboxylic acid of the Formula V, or an activated derivative thereof as defined hereinbefore,
HO,C — (CH); — Q \Y% under standard amide bond forming conditions as defined hereinbefore, wherein variable groups are as defined hereinbefore and wherein any functional group is protected if necessary. (b) A compound of the Formula I, or a pharmaceutically-acceptable salt or in-vivo- cleavable ester thereof, may be prepared by reacting an aniline of the Formula VI
RS (Re), (Rm,
H oy CL NH,
Ay? O VI with a carboxylic acid of the Formula V, or a reactive derivative thereof as defined hereinbefore,
HO,C — (CHp) —— Q v under standard amide bond forming conditions as defined hereinbefore, wherein variable groups are as defined hereinbefore and wherein any functional group is protected if necessary, and: = (1) removing any protecting groups: and (11) optionally forming a pharmaceutically-acceptable salt or in-vivo-cleavable ester.
The aniline of the Formula VI may be prepared by the reduction of the corresponding nitrobenzene compound of the Formula VII 3 (R2), (Rm
H oy 2 NO, 2 SV VII wherein variable groups are as defined hereinbefore and wherein any functional group is protected if necessary.
Typical reaction conditions for the reduction include the use of ammonium formate or hydrogen gas in the presence of a catalyst. for example a metallic catalyst such as palladium-
on-carbon. Alternatively a dissolving metal reduction may be carried out, for example using iron in the presence of an acid, for example an inorganic or organic acid such as hydrochloric, hydrobromic, sulphuric or acetic acid. The reaction is conveniently carried out in the presence of an organic solvent (preferably a polar protic solvent) and preferably with heating, for example to about 60°C. Any functional groups are protected and deprotected as necessary.
The nitrobenzene compound of the Formula VII may be prepared by the reaction of the aniline of the Formula [1 (Rm
Y— II with a carboxylic acid of the Formula VIII, or a reactive derivative thereof as defined hereinbefore,
R3 (R?),
HO,C
NO, VIII under standard amide bond forming conditions as defined hereinbefore, wherein variable groups are as defined hereinbefore and wherein any functional group is protected if necessary. (¢) A compound of the Formula I wherein R' or a substituent on Q is (1-6C)alkoxy or substituted (1-6C)alkoxy, (1-6C)alkylthio, (1-6C)alkylamino, di-[(1-6C)alkyl]Jamino or substituted (1-6C)alkylamino may be prepared by the alkylation, conveniently in the presence of a suitable basc as defined hereinbefore, of an amide derivative of the Formula I wherein R' or a substituent on Q 1s hydroxy, mercapto or amino as appropriate. oo | The reaction is preferably carried out in the presence of a suitable inert solvent or . oo diluent, for example a halogenated solvent such as methylene chloride, chloroform or carbon tetrachloride. an ether such as tetrahydrofuran or 1.4-dioxan, an aromatic solvent such as toluene, or a dipolar aprotic solvent such as N,N-dimethylformamide,
N,N-dimethylacetamide, N-methylpyrrolidin-2-one or dimethylsulphoxide. The reaction is conveniently carried out at a temperature in the range, for example, 10 to 150°C, preferably in the range 20 to 80°C.
A suitable alkylating agent is. for example, any agent known in the art for the
. _ alkylation of hydroxy to alkoxy or substituted alkoxy, or for the alkylation of mercapto to alkylthio, or for the alkylation of amino to alkylamino or substituted alkylamino, for example an alkyl or substituted alkyl halide, for example a (1-6C)alkyl chloride, bromide or iodide or a substituted (1-6C)alkyl chloride, bromide or iodide, in the presence of a suitable base as defined hereinbefore, in a suitable inert solvent or diluent as defined hereinbefore and at a temperature in the range, for example, 10 to 140°C. conveniently at or near ambient temperature. (d) A compound of the Formula I wherein a substituent on Q is amino, (1-6C)alkylamino, di-[(1-6C)alkyl amino, substituted (1-6C)alkylamino, substituted N-(1-6C)alkyl- (2-6C)alkylamino or a N-linked heterocyclyl group may be prepared by the reaction, conveniently in the presence of a suitable base as defined hereinbefore, of an amide derivative of the Formula 1 wherein a substituent on Q is a suitable leaving group with an appropriate amine.
A suitable leaving group is, for example, a halogeno group such as fluoro, chloro or bromo, a (1-6C)alkanesulphonyloxy group such as methanesulphonyloxy or an ) arylsulphonyloxy group such as 4-toluenesulphonyloxy.
The reaction is conveniently carried out in the presence of a suitable inert diluent or - carrier as defined hereinbefore and at a temperature in the range, for example, 20 to 200°C. - conveniently in the range 75 to 150°C. (e) A compound of the Formula I wherein R' or a substituent on Q is (1-6C)alkanoylamino or substituted (2-6C)alkanoylamino may be prepared by the acylation of a compound of the Formula I wherein R' or a substituent on Q is amino.
A suitable acylating agent is, for example, any agent known in the art for the acylation of amino to acylamino, for example an acyl halide, for example a (1-6C)alkanoyl chloride or bromide, conveniently in the presence of a suitable base, as defined hereinbefore. an alkanoic acid anhydride or mixed anhydride, for example a (1-6C)alkanoic acid anhydride such as acetic anhydride or the mixed anhydride formed by the reaction of an alkanoic acid and a (1-6C)alkoxycarbonyl halide, for example a (1-6C)alkoxycarbonyl chloride, in the presence of a suitable base as defined hereinbefore. In general the acylation is carried out in a suitable inert solvent or diluent as defined hereinbefore and at a temperature, in the range, for example. -30 to 120°C. conveniently at or near ambient temperature. (H) A compound of the Formula 1 wherein R' or a substituent on Q is
Claims (24)
- . . N-(1-6C)alkyl-(1-6C)alkoxy-(2-6C)alkylamino, N-(1-6C)alkyl-cyano-(1-6C)alkylamino, N-(1-6C)alkyl-carboxy-(1-6C)alkylamino, N-(1-6C)alkyl-(1-6C)alkoxycarbonyl- (1-6C)alkylamino, N-(1-6C)alkyl-carbamoyl-(1-6C)alkylamino, N-(1-6C)alkyl- N-(1-6C)alkylcarbamoyl-(1-6C)alkylamino, N-(1-6C)alkyl-N,N-di-[(1-6C)alkyljcarbamoyl-(1-6C)alkylamino, N-(1-6C)alkyl-amino-(2-6C)alkylamino, N-(1-6C)alkyl-(1-6C)alkylamino- (2-6C)alkylamino, N-(1-6C)alkyl-di-[(1-6C)alkyl}amino-(2-6C)alkylamino, halogeno-(2-6C)alkanoylamino, hydroxy-(2-6C)alkanoylamino, (1-6C)alkoxy- (2-6C)alkanoylamino, cyano-(2-6C)alkanoylamino, carboxy-(2-6C)alkanoylamino, (1-6C)alkoxycarbonyl-(2-6C)alkanoylamino, carbamoyl-(2-6C)alkanoylamino,N-(1-6C)alkylcarbamoy!-(2-6C)alkanoylamino, N.N-di-[(1-6C)alkyl]carbamoy!l- (2-6C)alkanoylamino, amino-(2-6C)alkanoylamino, (1-6C)alkylamino-(2-6C)alkanoylamino or di-[(1-6C)alkyl]amino-(2-6C)alkanoylamino, or R' is aryl, aryl-(1-6C)alkyl. aryl-(1-6C)alkoxy, aryloxy, arylamino, N-(1-6C)alkyl-arylamino, aryl-(1-6C)alkylamino, N-(1-6C)alkyl-aryl-(1-6C)alkylamino,aroylamino, arylsulphonylamino, N-arylsulphamoyl, aryl-(2-6C)alkanoylamino, heteroaryl,) heteroaryl-(1-6C)alkyl, heteroaryloxy, heteroaryl-(1-6C)alkoxy, heteroarylamino, N-(1-6C)alkyl-heteroarylamino, heteroaryl-(1-6C)alkylamino, N-(1-6C)alkyl-heteroaryl-(1-6C)alkylamino, heteroarylcarbonylamino, heteroarylsulphonylamino, N-heteroarylsulphamoyl, heteroaryl-(2-6C)alkanoylamino, heteroaryl-(1-6C)alkoxy-(1-6C)alkyl, heteroaryl-(1-6C)alkylamino-(1-6C)alkyl, N-(1-6C)alkyl-heteroaryl- (1-6C)alkylamino-(1-6C)alkyl. heterocyclyl. heterocyclyl-(1-6C)alkyl, heterocyclyloxy. heterocyclyl-(1-6C)atkoxy. heterocyclylamino, N-(1-6C)alkyl-heterocyclylamino. heterocyclyl-(1-6C)alkylamino, N-(1-6C)alkyl-heterocyclyl-(1-6C)alkylamino, heterocyclylcarbonylamino. heterocyclylsulphonylamino, N-heterocyclylsulphamoyl.heterocyclyl-(2-6C)alkanoylamino, heterocyclyl-(1-6C)alkoxy-(1-6C)alkyl, heterocyclyl- (1-6C)alkylamino-(1-6C)alky! or N-(1-6C)alkyl-heterocyclyl-(1-6C)alkylamino-(1-6C)alkyl. or (R"),, is a (1-3C)alkylenedioxy group. and wherein any of the R' substituents defined hereinbefore which comprises a CH, group which is attached to 2 carbon atoms or a CH, group which is attached to a carbon atom may optionally bear on each said CH, or CH, group a substituent selected from hydroxy. amino. (1-6C)alkoxy. (1-6C)alkylamino. di-[(1-6C)alkylJamino and heterocyclyl.and wherein any aryl, heteroaryl or heterocyclyl group in a R' substituent may optionally bear or 2 substituents selected from hydroxy, halogeno, (1-6C)alkyl, (1-6C)alkoxy, carboxy, (1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, amino, (1-6C)alkylamino, di-[(1-6C)alkyl}amino, halogeno-(1-6C)alkyl,hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl, amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl, di-[(1-6C)alkyl}amino-(1-6C)alkyl, aryl and ary!-(1-6C)alkyl, nis0, 1, 2or3;R? is hydroxy, halogeno, trifluoromethyl, cyano, mercapto, nitro, amino, carboxy,(1-6C)alkoxycarbonyl, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylamino or di-[(1-6C)alkyl]amino;Ris hydrogen. halogeno, (1-6C)alky! or (1-6C)alkoxy:qis0,1.2,30or4; andQ is aryl, aryloxy, aryl-(1-6C)alkoxy, arylamino, N-(1-6C)alkyl-arylamino,aryl-(1-6C)alkylamino, N-(1-6C)alkyl-aryl-(1-6C)alkylamino, aroylamino,arylsulphonylamino, N-arylcarbamoyl, N-arylsulphamoyl, aryl-(2-6C)alkanoylamino, : (3-7C)cycloalkyl, heteroaryl. heteroaryloxy, heteroaryl-(1-6C)alkoxy, heteroarylamino, N-(1-6C)alkyl-heteroarylamino, heteroaryl-(1-6C)alkylamino, N-(1-6C)alkyl-heteroaryl- ’ (1-6C)alkylamino, heteroarylcarbonylamino, heteroarylsulphonylamino, N-heteroarylcarbamoyl.N-heteroaryisulphamoyl, heteroaryl-(2-6C)alkanoylamino,heterocyclyl. heterocyclyloxy. heterocyclyl-(1-6C)alkoxy, heterocyclylamino, N-(1-6C)alkyl- heterocyclylamino, heterocyclyl-(1-6C)alkylamino, N-(1-6C)alkyl-heterocyclyl- (1-6C)alkylamino, heterocyclylcarbonylamino, heterocyclyisuiphonylamino.N-heterocyclylcarbamoyl, N-heterocyclylsulphamoy! or heterocyclyl-(2-6C)alkanoylamino. and Q is optionally substituted with 1. 2 or 3 substituents selected from hvdroxy. halogeno, ~ trifluoromethyl, cyano, mercapto, nitro, amino, carboxy, carbamoyl, formyl, (1-6C)alkyl. (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl. (1-6C)alkylamino, di-[(1-6C)alkyl]amino. (1-6C)alkoxycarbonyl.N-(1-6C)alkylcarbamoy!, N,N-di-[(1-6C)alkyl]carbamoyl. (2-6C)alkanoyl. (2-6C)alkanoyloxy, (1-6CJalkanoylamino, N-(1-6C)alkylsulphamoyl.N,N-di-[(1-6C)alkyl]sulphamoyl. (1-6C)alkanesulphonylamino, N-(1 -6C)alkyl- (1-6C)alkanesulphonylamino, halogeno-(1-6C)alkyl. hydroxy-(1 -6C)alkyl, (1-6C)alkoxy- (1-6C)alkyl. cyano-(1-6C)alkyl. amino-(1-6C)alkyl, (1-6C)alkylamimo-(1 -6C)alkyl,} © di-[(1-6C)alkyl]amino-(1-6C)alkyl, carboxy-(1-6C)alkyl, (1-6C)alkoxycarbonyl-(1-6C)alkyl, carbamoyl-(1-6C)alkyl, N-(1-6C)alkylcarbamoyl-(1-6C)alkyl, N,N-di-[(1-6C)alkyl]carbamoyi-(1 -6C)alkyl, halogeno-(2-6C)alkoxy, hydroxy-(2-6C)alkoxy, (1-6C)alkoxy-(2-6C)alkoxy, cyano-(1-6C)alkoxy, carboxy-(1-6C)alkoxy,(1-6C)alkoxycarbonyl-(1-6C)alkoxy, carbamoyl-(1-6C)alkoxy, N-(1-6C)alkylcarbamoy]i- (1-6C)alkoxy, N,N-di-[(1-6C)alkyl]carbamoyl-(1-6C)alkoxy, amino-(2-6C)alkoxy, (1-6C)alkylamino-(2-6C)alkoxy, di-[(1-6C)alkyl}amino-(2-6C)alkoxy, halogeno- (2-6C)alkylamino, hydroxy-(2-6C)alkylamino, (1-6C)alkoxy-(2-6C)alkylamino, cyano- (1-6C)alkylamino, carboxy-(1-6C)alkylamino, (1-6C)alkoxycarbonyl-(1-6C)alkylamino,carbamoyl-(1-6C)alkylamino, N-(1-6C)alkylcarbamoy!-(1-6C)alkylamino, N,N-di-[(1-6C)alkyl}carbamoyl-(1-6C)alkylamino, amino-(2-6C)alkylamino, (1-6C)alkylamino-(2-6C)alkylamino, di-[(1-6C)alkyl}amino-(2-6C)alkylamino, N-(1-6C)alkyl-halogeno-(1-6C)alkylamino, N-(1-6C)alkyl-hydroxy-(2-6C)alkylamino,: N-(1-6C)alkyl-(1-6C)alkoxy-(2-6C)alkylamino, N-(1-6C)alkyl-cyano-(1-6C)alkylamino, . . 15 N-(1-6C)alkyl-carboxy-(1-6C)alkylamino, N-(1-6C)alkyl-(1-6C)alkoxycarbonyl- : (1-6C)alkylamino, N-(1-6C)alkyl-carbamoyl-(1-6C)alkylamino, N-(1-6C)alky!-: N-(1-6C)alkylcarbamoyl-(1-6C)alkylamino, N-(1-6C)alkyl-N,N-di-[(1-6C)alkyl}carbamoyl- (1-6C)alkylamino, N-(1-6C)alkyl-amino-(2-6C)alkylamino, N-(1-6C)alkyl-(1-6C)alkylamino- (2-6C)alkylamino, N-(1-6C)alkyl-di-[(1-6C)alkyljamino-(2-6C)alkylamino,halogeno-(2-6C)alkanoylamino, hydroxy-(2-6C)alkanoylamino, (1-6C)alkoxy- (2-6C)alkanoylamino, cyano-(2-6C)alkanoylamino, carboxy-(2-6C)alkanoylamino. (1-6C)alkoxycarbonyl-(2-6C)alkanoylamino, carbamoyl-(2-6C)alkanoylamino, N-(1-6C)alkylcarbamoyl-(2-6C)alkanoylamino, N,N-di-[(1-6C)alkyl]carbamoy!- (2-6C)alkanoylamino, amino-(2-6C)alkanoylamino, (1-6C)alkylamino-(2-6C)alkanoylamino.di-[(1-6C)alkyl]amino-(2-6C)alkanoylamino, aryl, aryl-(1-6C)alkyl, aryl-(1-6C)alkoxy, aryloxy, arylamino, N-(1-6C)alkyl-arylamino, aryl-(1-6C)alkylamino, N-(1-6C)alkyl-aryl- (1-6C)alkylamino, aroylamino, arylsulphonylamino, N-arylsulphamoyl, aryl- (2-6C)alkanoylamino, heteroaryl, heteroaryl-(1-6C)alkyl, heteroaryloxy, heteroaryl- (1-6C)alkoxy, heteroarylamino, N-(1-6C)alkyi-heteroarylamino, heteroaryl-(1-6C)alkylamino.N-(1-6C)alkyl-heteroaryl-(1-6C)alkylamino, heteroarylcarbonylamino, heteroarylsulphonylamino, N-heteroarylsulphamoyl, heteroaryl-(2-6C)alkanoylamino. heteroaryl-(1-6C)alkoxy-(1-6C)alkyl, heteroaryl-(1 -6C)alkylamino-(1-6C)alkyl,N-(1-6C)alkyl-heteroaryl-(1-6C)alkylamino-(1-6C)alkyl, heterocyclyl, heterocyclyl- ‘ (1-6C)alkyl, heterocyclyloxy, heterocyclyl-(1-6C)alkoxy, heterocyclylamino, N-(1-6C)alkyl- heterocyclylamino, heterocyclyl-(1-6C)alkylamino, N-(1-6C)alkyl-heterocyclyl- (1-6C)alkylamino, heterocyclylcarbonylamino, heterocyclylsulphonylamino, N-heterocyclylsulphamoyl, heterocyclyl-(2-6C)alkanoylamino, heterocyclyl-(1-6C)alkoxy- (1-6C)alkyl, heterocyclyl-(1-6C)alkylamino-(1-6C)alkyl and N-(1-6C)alkyl-heterocyclyl- (1-6C)alkylamino-(1-6C)alkyl, or Q is substituted with a (1-3C)alkylenedioxy group, and wherein any of the substituents on Q defined hereinbefore which comprises a CH, group which is attached to 2 carbon atoms or a CH, group which is attached to a carbon atom may optionally bear on each said CH, or CH; group a substituent selected from hydroxy, amino, (1-6C)alkoxy, (1-6C)alkylamino, di-[(1-6C)alkyl]amino and heterocyclyl, and wherein any aryl, heteroaryl or heterocyclyl group in a substituent on Q may optionally bear 1 or 2 substituents selected from hydroxy, halogeno, (1-6C)alkyl, (1-6C)alkoxy, carboxy, (1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl, N,N-di-{(1-6C)alkyl]carbamoy]l, } (2-6C)alkanoyl, amino, (1-6C)alkylamino, di-[(1-6C)alkyl]Jamino, halogeno-(1-6C)alkyl, hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl, amino-(1-6C)alky]I. . (1-6C)alkylamino-(1-6C)alkyl, di-[(1-6C)alkyl}amino-(1-6C)alkyl, aryl and aryl-(1-6C)alkyl; or a pharmaceutically-acceptable salt or in-vivo-cleavable ester thereof.
- 2. "An amide derivative of the Formula I according to claim 1 wherein R" is selected from halogeno and (1-6C)alkyl; or a pharmaceutically-acceptable salt or in-vivo-cleavable ester thereof.
- 3. An amide derivative of the Formula I according to claim 1 wherein X 1s CH or N; Y 1s CH or N; R'is hydrogen, fluoro, chloro, bromo, methyl or ethyl; mis 0,1 or 2; R' is hydroxy. fluoro, chloro, bromo, trifluoromethyl, cyano, methyl, ethyl, propyl. methoxy, ethoxy. amino, methylamino. ethylamino, dimethylamino, diethylamino, methylaminomethyl. ethylaminomethyl, dimethylaminomethyl, diethylaminomethyl, 2-aminoethoxy, 3-aMINOPrapoxy. 2-methylaminoethoxy, 2-cthylaminoethoxy, 3-methylaminopropoxy,’ ) 3-ethylaminopropoxy, 2-dimethylaminoethoxy, 2-diethylaminoethoxy, 3-dimethylaminopropoxy, 3-diethylaminopropoxy, 2-aminoethylamino, 3-aminopropylamino, 2-methylaminoethylamino, 2-ethylaminoethylamino, 3-methylaminopropylamino, 3-ethylaminopropylamino, 2-dimethylaminoethylamino, 2-diethylaminoethylamino,3-dimethylaminopropylamino, 3-diethylaminopropylamino, N-(2-aminoethyl)- N-methylamino, N-(3-aminopropyl)-N-methylamino, N-(2-methylaminoethyl)- N-methylamino, N-(2-ethylaminoethyl)-N-methylamino, N-(3-methylaminopropyl)- N-methylamino, N-(3-cthylaminopropy!)-N-methylamino, N-(2-dimethylaminocthyl)- N-methylamino, N-(2-diethylaminoethyl)-N-methylamino, N-(3-dimethylaminopropyl)-N-methylamino, N-(3-diethylaminopropyl)-N-methylamino, pyridyl, pyridylmethyl, pyridylmethoxy, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, 4-methylpiperazinyl, homopiperazinyl, 4-methylhomopiperazinyl, 4-acetylpiperazinyl, pyrrolidinylmethyl, piperidinylmethyl, morpholinylmethyl, piperazinylmethyl, 4-methylpiperazinyimethyl,4-acetylpiperazinylmethyl, pyrrolidinyloxy, 1-methylpyrrolidinyloxy, piperidinyloxy, . 15 1-methylpiperidinyloxy, 2-(pyrrolidinyl)ethoxy, 3-(pyrrolidinyl)propoxy, 2-(piperidinyl)ethoxy, 3-(piperidinyl)propoxy, 2-(morpholinyl)ethoxy, : 3-(morpholinyl)propoxy, 2-(piperazinyl)ethoxy, 3-(piperazinyl)propoxy, 2-(4-methylpiperazinyl)ethoxy, 3-(4-methylpiperazinyl)propoxy, 2-(4-acetylpiperazinyl)ethoxy or 3-(4-acetylpiperazinyl)propoxy; nisOor 1; R" is fluoro. chloro, bromo, methyl or ethyl; q is 0; and Q is phenyl, furyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazoly}, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzofuranyl. indolyl, benzothienyl,benzoxazolyl, benzimidazolyl. benzothiazolyl, indazolyl, benzofurazanyl, quinolyl, isoquinolyl, quinazolinyl, quinoxaliny! or naphthyridinyl which optionally bears 1 or 2 substituents selected from hydroxy, fluoro, chloro, trifluoromethyl, cyano, amino, methyl, ethyl. methoxy, ethoxy, methylenedioxy, methylamino, ethylamino, dimethylamino, diethylamino, aminomethyl, methylaminomethyl, ethylaminomethyl, dimethylaminomethyi,diethylaminomethyl, 2-hydroxyethoxy, 3-hydroxypropoxy, 2-methoxyethoxy. 2-ethoxyethoxy. 3-methoxypropoxy, 3-ethoxypropoxy, 2-aminoethoxy, 3-aminopropoxy. 2-methylaminoethoxy, 2-ethylaminoethoxy, 3-methylaminopropoxy, 3-ethylaminopropoxy.2-dimethylaminoethoxy, 2-diethylaminoethoxy, 3-dimethylaminopropoxy, . . 3-diethylaminopropoxy, pyridyl, pyridylmethyl, pyridylmethoxy, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, 4-methylpiperazinyl, homopiperazinyl, 4-methylhomopiperazinyl, 4-acetylpiperazinyl, pyrrolidinylmethyl, piperidinylmethyl, morpholinylmethy], S piperazinylmethyl, 4-methylpiperazinylmethyl, 4-acetylpiperazinylmethyl, pyrrolidinyloxy, 1- methylpyrrolidinyloxy, piperidinyloxy, 1-methylpiperidinyloxy, 2-(pyrrolidinyl)ethoxy, 3-(pyrrolidinyl)propoxy, 2-(piperidinyl)ethoxy, 3-(piperidinyl)propoxy, 2-(morpholinyl)ethoxy, 3-(morpholinyl)propoxy, 2-(piperazinyl)ethoxy, 3-(piperazinyl)propoxy, 2-(4-methylpiperazinyl)ethoxy, 3-(4-methylpiperazinyl)propoxy, 2-(4-acetylpiperazinyl)ethoxy and 3-(4-acetylpiperazinyl)propoxy; or a pharmaceutically-acceptable salt thereof.
- 4. An amide derivative of the Formula I according to claim 1 wherein X is CH: Y isCHorN; R’is hydrogen, chloro or methyl; mis0, 1 or2; R' is hydroxy, fluoro, chloro, bromo, trifluoromethyl, cyano, methyl, ethyl, propyl, methoxy, ethoxy, amino, methylamino, ethylamino, dimethylamino, diethylamino, methylaminomethyi, ethylaminomethyl, dimethylaminomethyl, diethylaminomethyl, 2-aminoethoxy, 3-aminopropoxy, 2-methylaminoethoxy, 2-ethylaminoethoxy, 3-methylaminopropoxy, 3-ethylaminopropoxy, 2-dimethylaminoethoxy, 2-diethylaminoethoxy, 3-dimethylaminopropoxy, 3-diethylaminopropoxy, 2-aminoethylamino, 3-aminopropylamino, 2-methylaminoethylamino, 2-ethylaminoethylamino, 3-methylaminopropylamino, 3-ethylaminopropylamino, 2-dimethylaminoethylamino; 2-diethylaminoethylamino, ~~ ~~ - “25 3-dimethylaminopropylamino, 3-diethylaminopropylamino, N=(2-aminoethyl)- N-methylamino, N-(3-aminopropyl)-N-methylamino, N-(2-methylaminoethyl)- N-methylamino, N-(2-ethylaminoethyl)-N-methylamino, N-(3-methylaminopropyl)- N-methylamino, N-(3-ethylaminopropyl)-N-methylamino, N-(2-dimethylaminoethyl)- N-methylamino, N-(2-diethylaminoethyl)-N-methylamino, N-(3-dimethylaminopropyl)- N-methylamino, N-(3-diethylaminopropyl)-N-methylamino, 2-pyridylmethyl, 3-pyridvimethyl. 4-pyridylmethyl, 2-pyridylmethoxy. 3-pyridylmethoxy. 4-pyridylmethoxy. pyrrolidin-1-yl, piperidino, morpholino, piperazin-1-yl, 4-methylpiperazin-1-yl,N “ homopiperazin-1-yl, 4-methylhomopiperazin-1-yl, 4-acetylpiperazin-1-yl, pyrrolidin- I-ylmethyl, piperidinomethyl, morpholinomethy]l, piperazin-1-ylmethyl, 4-methylpiperazin-1 -ylmethyl, 4-acetylpiperazin-1-ylmethyl, pyrrolidin-3-yloxy, 1-methylpyrrolidin-3-yloxy, piperidin-4-yloxy, 1-methylpiperidin-4-yloxy, 2-(pyrrolidin-l-ylethoxy, 3-(pyrrolidin-1-yl)propoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 2-piperazin-1-ylethoxy, 3-piperazin- 1-ylpropoxy, 2-(4-methylpiperazin-1-yl)ethoxy, 3-(4-methylpiperazin-1-yl)propoxy, 2-(4-acetylpiperazin-1-yl)ethoxy or 3-(4-acetylpiperazin-1-yl)propoxy; nis 0;qis 0; and Q is phenyl, 2-pyridyl, 3-pyridy! or 4-pyridyl which optionally bears 1 or 2 substituents selected from hydroxy, fluoro, chloro, trifluoromethyl, cyano, amino, methyl, ethyl, methoxy. ethoxy, methylenedioxy, methylamino, ethylamino, dimethylamino, diethylamino, aminomethyl, methylaminomethyl, ethylaminomethyl, dimethylaminomethy],} 15 diethylaminomethyl, 2-hydroxyethoxy, 3-hydroxypropoxy, 2-methoxyethoxy, 2-ethoxyethoxy, 3-methoxypropoxy, 3-ethoxypropoxy, 2-aminoethoxy, 3-aminopropoxy, 2-methylaminoethoxy, 2-ethylaminoethoxy, 3-methylaminopropoxy, 3-ethylaminopropoxy, 2-dimethylaminoethoxy, 2-diethylaminoethoxy, 3-dimethylaminopropoxy, 3-diethylaminopropoxy, 2-pyridyl, 3-pyridyl, 4-pyridy]l,2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2-pyridylmethoxy, 3-pyridylmethoxy, 4-pyridylmethoxy, pyrrolidin-1-yl, piperidino, morpholino, piperazin-1-yl, 4-methylpiperazin-1-yl, homopiperazin-1-yl, 4-methylhomopiperazin-1-yl, 4-acetylpiperazin- 1-yl, pyrrolidin-1-ylmethyl, piperidinomethyl, morpholinomethyl, piperazin-1-ylmethyl, 4-methylpiperazin-1-ylmethyl, 4-acetylpiperazin-1-ylmethyl, pyrrolidin-3-yloxy.1-methylpyrrolidin-3-yloxy, piperidin-4-yloxy, 1-methylpiperidin-4-yloxy, 2-pyrrolidin-1-ylethoxy, 3-pyrrolidin-1-ylpropoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 2-piperazin-1-ylethoxy, 3-piperazin-1-ylpropoxy, 2-(4-methylpiperazin-1-yl)ethoxy, 3-(4-methylpiperazin- 1-yl)propoxy, 2-(4-acetylpiperazin-1-yl)ethoxy and 3-(4-acetylpiperazin-1-yl)propoxy:;or a pharmaceutically-acceptable salt thereof.
- 5. An amide derivative of the Formula 1 according to claim 1 wherein X is CH; ’ ‘ YisCHorN; R?* is hydrogen, chloro or methyl; mis | and R' is selected from diethylaminomethy!, N-(3-dimethylaminopropy!)- N-methylamino, pyrrolidin-1-yl, morpholino, piperidino, piperazin-1-yl, 4-methylpiperazin- 1-yl, 4-ethylpiperazin-1-yl, homopiperazin-1-yl, 4-methylhomopiperazin-1-yl, piperazin-1-ylmethyl, 4-methylpiperazin-1-ylmethyl, 4-methylhomopiperazin-1-ylmethyl, morpholinomethyl, 3-aminopyrrolidin-1-ylmethyl, 3-hydroxypyrrolidin-1-ylmethyl, pyrrolidin-3-yloxy, piperidin-4-yloxy, 2-pyrrolidin-1-ylethoxy, 2-piperidinoethoxy, 2-morpholinoethoxy, 3-dimethylaminopropylaminomethyl, 3-dimethylamino- 2,2-dimethylpropylaminomethyl, 2-(1-methylpyrrolidin-2-ylethyl)aminomethyl, 3-pyrrolidin- 1-ylpropylaminomethyl, 2-morpholinoethylaminomethyl, 3-morpholinopropylaminomethyl, 2-piperazin-1-ylethylaminomethyl, 3-(4-methylpiperazin-1-ylpropyl)aminomethyl and 2-pyridylmethoxy; nis 0; . q is 0; and Q is 3-pyridyl or 4-pyridy] which bears a substituent selected from pyrrolidin-1-yl, : morpholino, piperidino, piperazin-1-yl and 4-methylpiperazin-1-yl; or a pharmaceutically-acceptable salt thereof.
- 6. An amide derivative of the Formula I according to claim 1 wherein X is CH; Y is CHorN; R*® is hydrogen, chloro or methyl, oo mis 1 and R' is N-(3-dimethylaminopropy!l)-N-methylamino, 4-methylpiperazin-1-yl, = 4-methylhomopiperazin-1-yl, 4-methylpiperazin-1-ylmethyl or pyrrolidin-3-yloxy; nis 0; q is 0; and Q is 2-morpholinopyrid-4-yl; or a pharmaceutically-acceptable salt thereof.
- 7. An amide derivative of the Formula I according to claim | wherein X is CH or N:. - YisCHorN;R? is fluoro, chloro, bromo, methyl or ethyl; mis0, 1 or2; R' is hydroxy, fluoro, chloro, bromo, trifluoromethyl, cyano, methyl, ethyl, methoxy, ethoxy,amino, methylamino, ethylamino, dimethylamino, diethylamino, methylaminomethyl, ethylaminomethyl, dimethylaminomethyl, diethylaminomethyl, 2-aminoethoxy, 3-aminopropoxy, 2-methylaminoethoxy, 2-ethylaminoethoxy, 3-methylaminopropoxy, 3-ethylaminopropoxy, 2-dimethylaminoethoxy, 2-diethylaminoethoxy, 3-dimethylaminopropoxy, 3-diethylaminopropoxy, 2-aminoethylamino, 3-aminopropylamino,2-methylaminoethylamino, 2-ethylaminoethylamino, 3-methylaminopropylamino, 3-ethylaminopropylamino, 2-dimethylaminoethylamino, 2-diethylaminoethylamino, 3-dimethylaminopropylamino, 3-diethylaminopropylamino, N-(2-aminoethyl)- N-methylamino, N-(3-aminopropyl)-N-methylamino, N-(2-methylaminoethyl)- N-methylamino, N-(2-ethylaminoethyl)-N-methylamino, N-(3-methylaminopropyl)-N-methylamino, N-(3-ethylaminopropyl)-N-methylamino, N-(2-dimethylaminoethyl)-N-methylamino, N-(2-diethylaminoethyl)-N-methylamino, N-(3-dimethylaminopropyl)- N-methylamino, N-(3-diethylaminopropyl)-N-methylamino, pyridyl, pyridylmethyl, pyridylmethoxy, 3-pyrrolinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, morpholinyl, piperazinyl, 4-methylpiperazinyl, 4-ethylpiperazinyl, homopiperazinyl,4-methylhomopiperazinyl, 4-acetylpiperazinyl, pyrrolidinylmethyl, piperidinylmethyl, morpholinylmethyl, piperazinylmethyl. 4-methylpiperazinylmethyl, homopiperazinylmethyl, 4-methylhomopiperazinylmethyl, 4-acetylpiperazinylmethyl, pyrrolidinyloxy, 1-methylpyrrolidinyloxy, piperidinyloxy, 1-methylpiperidinyloxy, homopiperidinyloxy, 1-methylhomopiperidinyloxy. 2-(pyrrolidinyl)ethoxy, 3-(pyrrolidinyl)propoxy,2-(piperidinyl)ethoxy, 3-(piperidinyl)propoxy, 2-(morpholinyl)ethoxy, 3-(morpholinyl)propoxy, 2-(piperazinyl)ethoxy, 3-(piperazinyl)propoxy, 2-(4-methylpiperazinyl)ethoxy, 3-(4-methylpiperazinyl)propoxy, 2-(4-acetylpiperazinyl)ethoxy, 3-(4-acetylpiperazinyl)propoxy, 3-dimethylaminopropylaminomethyl, 3-dimethylamino-2.2-dimethylpropylaminomethyl,2-(1-methylpyrrolidinylethyl)aminomethyl, 3-pyrrolidinylpropylaminomethyl, 2-morpholinylethylaminomethyl, 3-morpholinylpropylaminomethyl.2-piperazinylethylaminomethyl, 3-(4-methylpiperazinylpropyl)aminomethy], “ . pyridylmethoxy, imidazolylmethoxy, thiazolylmethoxy and 2-methylthiazolylmethoxy; nis0Oorl; R? is fluoro, chloro, bromo, methyl or ethyl;qis 0; and Q is phenyl, indenyl, indanyl, tetrahydronaphthyl, fluorenyl, furyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzofuranyl, indolyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, indazolyl, benzofurazanyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, naphthyridinyl,carbazolyl, dibenzoturanyl, dibenzothiophenyl or xanthenyl which optionally bears 1 or 2 substituents selected from hydroxy, fluoro, chloro, trifluoromethyl, cyano, amino, methyl, ethyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopentyloxy, methylenedioxy, methylamino, ethylamino, dimethylamino, diethylamino, acetamido, propionamido, methanesulphonamido, N-methylmethanesulphonamido, aminomethyl, methylaminomethy!, ethylaminomethy!,dimethylaminomethyl, diethylaminomethyl, 2-hydroxyethoxy, 3-hydroxypropoxy, 2-methoxyethoxy, 2-ethoxyethoxy, 3-methoxypropoxy, 3-ethoxypropoxy, 2-aminoethoxy, 3-aminopropoxy, 2-methylaminoethoxy, 2-ethylaminoethoxy, 3-methylaminopropoxy, 3-ethylaminopropoxy, 2-dimethylaminoethoxy, 2-diethylaminoethoxy, 3-dimethylaminopropoxy, 3-diethylaminopropoxy, phenyl, furyl, thienyl, pyridyl,pyridylmethyl, pyridylmethoxy, azetidinyl, 3-pyrrolinyl, pyrrolidinyl, piperidiny!, homopiperidinyl, morpholinyl, piperazinyl, 4-methylpiperazinyl, homopiperazinyl, 4-methylhomopiperazinyl, 4-acetylpiperazinyl, pyrrolidinylmethyl, piperidinylmethyl, morpholinylmethyl, piperazinylmethyl, 4-methylpiperazinylmethyl,So - 4-acetylpiperazinylmethyl, pyrrolidinyloxy,-1-methylpyrrolidinyloxy,-piperidinyloxy,----—25 I=methylpiperidinyloXy, 2=(pytrolidiny})ethoxy. 3=(pyrrolidinyl)propoxy, 2-(piperidinyl)ethoxy, 3-(piperidinyl)propoxy, 2-(morpholinyl)ethoxy, 3-(morpholinyl)propoxy, 2-(piperazinyl)ethoxy, 3-(piperazinyl)propoxy, 2-(4-methylpiperazinyl)ethoxy, 3-(4-methylpiperazinyl)propoxy. 2-(4-acetylpiperazinyl)ethoxy and 3-(4-acetylpiperazinyl)propoxy, and wherein any phenyl,furyl, thienyl, pyridyl or heterocyclyl group in a substituent on Q may optionally bear 1 or 2 substituents selected from fluoro, chloro, methyl and methoxy;\ Co. or a pharmaceutically-acceptable salt thereof.
- 8. An amide derivative of the Formula I according to claim 1 wherein X is CH; Y is CHorN; R'is chloro or methyl; mis 0, 1 or 2; R' is hydroxy, fluoro, chloro, bromo, trifluoromethyl, cyano, methyl, ethyl, propyl, methoxy, ethoxy, amino, methylamino, ethylamino, dimethylamino, diethylamino, methylaminomethyl, ethylaminomethyl, dimethylaminomethyl, diethylaminomethyl, 2-aminoethoxy, 3-aminopropoxy, 2-methylaminoethoxy, 2-ethylaminoethoxy, 3-methylaminopropoxy. 3-ethylaminopropoxy. 2-dimethylaminoethoxy, 2-diethylaminoethoxy, 3-dimethylaminopropoxy, 3-diethylaminopropoxy, 2-aminoethylamino, 3-aminopropylamino. 2-methylaminoethylamino, 2-ethylaminoethylamino, 3-methylaminopropylamino. 3-ethylaminopropylamino, 2-dimethylaminoethylamino. 2-diethylaminoethylamino, 3-dimethylaminopropylamino, 3-diethylaminopropylamino, N-(2-aminoethy!)- . N-methylamino, N-(3-aminopropyl)-N-methylamino, N-(2-methylaminoethyl)- N-methylamino, N-(2-ethylaminoethyl}-N-methylamino, N-(3-methylaminopropyl)- N-methylamino, N-(3-ethylaminopropyl)-N-methylamino, N-(2-dimethylaminoethyl)- N-methylamino, N-(2-diethylaminoethy!)-N-methylamino, N-(3-dimethylaminopropyl)- N-methylamino, N-(3-diethylaminopropyl)-N-methylamino, 2-pyridylmethyl. 3-pyridylmethyl, 4-pyridylmethyl, 2-pyridylmethoxy, 3-pyridylmethoxy, 4-pyridylmethoxy. pyrrolidin-1-yl, piperidino, morpholino, piperazin-1-yl. 4-methylpiperazin-1-yl. homopiperazin-1-yl, 4-methylhomopiperazin-1-yl, 4-acetylpiperazin-1-yl, pyrrolidin- 1-ylmethyl. piperidinomethyl, morpholinomethyl, piperazin-1-ylmethyl. 4-methylpiperazin-1-ylmethyl. 4-acetylpiperazin-1-ylmethyl, pyrrolidin-3-yloxy. 1-methylpyrrolidin-3-yloxy, piperidin-4-yloxy. 1-methylpipcridin-4-yloxy. 2-(pyrrolidin- 1-yhethoxy. 3-(pyrrolidin-1-yl)propoxy. 2-pipcridinoethoxy. 3-piperidinopropoxy, 2-morpholinoethoxy. 3-morpholinopropoxy. 2-piperazin-1-ylethoxy. 3-piperazin- I-ylpropoxy. 2-(4-methylpiperazin-1-yljethoxy, 3-(4-methylpiperazin-1-yl)propoxy. 2-(4-acetylpiperazin-1-yl)ethoxy or 3-(4-acctylpiperazin-1-yl)propoxy: nis 0:qis 0; and te . Q is phenyl, 2-pyridyl, 3-pyridyl or 4-pyridyl which optionally bears 1 or 2 substituents selected from hydroxy, fluoro, chloro, trifluoromethyl, cyano, amino, methyl, ethyl, methoxy, ethoxy, methylenedioxy, methylamino, ethylamino, dimethylamino, diethylamino, aminomethyl, methylaminomethyl, ethylaminomethyl, dimethylaminomethyl, diethylaminomethyl, 2-hydroxyethoxy, 3-hydroxypropoxy, 2-methoxyethoxy, 2-ethoxyethoxy, 3-methoxypropoxy, 3-ethoxypropoxy, 2-aminoethoxy, 3-aminopropoxy, 2-methylaminoethoxy, 2-ethylaminoethoxy, 3-methylaminopropoxy, 3-cthylaminopropoxy, 2-dimethylaminoethoxy, 2-diethylaminoethoxy, 3-dimethylaminopropoxy, 3-diethylaminopropoxy, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2-pyridylmethoxy, 3-pyridylmethoxy. 4-pyridylmethoxy, pyrrolidin-1-yl, piperidino, morpholino, piperazin-1-yl, 4-methylpiperazin-1-yl, homopiperazin-1-yl, 4-methylhomopiperazin-1-yl, 4-acetylpiperazin- I-yl. pyrrolidin-1-ylmethyl, piperidinomethyl, morpholinomethyl, piperazin-1-ylmethyl, 4-methylpiperazin-1-ylmethyl, 4-acetylpiperazin-1-ylmethyl, pyrrolidin-3-yloxy, 1-methylpyrrolidin-3-yloxy, piperidin-4-yloxy, 1-methylpiperidin-4-yloxy, 2-pyrrolidin-1-ylethoxy, 3-pyrrolidin-1-ylpropoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 2-piperazin-1-ylethoxy, 3-piperazin-1-ylpropoxy, 2-(4-methylpiperazin-1-yl)ethoxy, 3-(4-methylpiperazin- 1-yl)propoxy. 2-(4-acetylpiperazin-1-yl)ethoxy and 3-(4-acetylpiperazin-1-yl)propoxy: or a pharmaceutically-acceptable salt thereof.
- 9. An amide derivative of the Formula I according to claim 1 wherein X 1s CH; oe Y is CH-or N:- Se - 25 Ris chloro or methyl; mis | or 2; R'is hydroxy. fluoro. chloro, methyl, ethyl, propyl, methoxy, dimethylaminomethyl. diethylaminomethyl. 2-dimethylaminoethoxy, 2-diethylaminoethoxy, 3-dimethylaminopropoxy. 3-diethylaminopropoxy, 3-dimethylamino-2-hydroxypropoxy. 3-dicthylamino-2-hydroxypropoxy, 2-aminoethylamino, 3-aminopropylamino, 4-aminobutylamino, 3-methylaminopropylamino. 2-dimethylaminoethylamino. 2-diethylaminoethylamino, 3-dimethylaminopropylamiro. 4-dimethylaminobutylamino,. . 3-amino-2-hydroxypropylamino, 3-dimethylamino-2-hydroxypropylamino, N-(2-dimethylaminoethyl)-N-methylamino, N-(3-dimethylaminopropyl)-N-methylamino, pyrrolidin-1-yl, morpholino, piperidino, piperazin-1-yl, 4-methylpiperazin-1-yl, 4-ethylpiperazin-1-yl, 4-(2-hydroxyethyl)piperazin-1-yl, homopiperazin-1-yl, 4-methylhomopiperazin-1-yl, piperazin-1-ylmethyl, 4-methylpiperazin-1-ylmethyl, homopiperazin-1-ylmethyl, 4-methylhomopiperazin-1-ylmethyl, morpholinomethyl, 3-aminopyrrolidin-1-ylmethyl, 3-hydroxypyrrolidin-1-ylmethyl, 4-(2-hydroxyethyl)piperazin- 1-ylmethyl, pyrrolidin-3-yloxy, 1-methylpyrrolidin-3-yloxy, piperidin-4-yloxy, l-methylpiperidin-4-yloxy, 1-benzylpiperidin-4-yloxy, 2-pyrrolidin-1-ylethoxy, 3-pyrrolidin- 1-ylpropoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 2-piperazin-1-ylethoxy, 3-piperazin-1-ylpropoxy, 2-(4-methylpiperazin-1-yl)ethoxy, 3-(4-methylpiperazin-1-yl)propoxy, 2-hydroxy- 3-pyrrolidin-1-ylpropoxy, 2-hydroxy-3-piperidinopropoxy, 2-hydroxy-3-morpholinopropoxy. piperidin-4-ylamino, 1-methylpiperidin-4-ylamino, 1-benzylpiperidin-4-ylamino, . 15 2-pyrrolidin-1-ylethylamino, 3-pyrrolidin-1ylpropylamino, 2-morpholinoethylamino, 3-morpholinopropylamino, 2-piperidinoethylamino, 3-piperidinopropylamino, 2-piperazin- 1-ylethylamino, 3-piperazin-1-ylpropylamino, 2-(4-methylpiperazin-1-yl)ethylamino, 3-(4-methylpiperazin-1-yl)propylamino, 2-(1-methylpyrrolidin-2-yl)ethylamino, 3-(1-methylpyrrolidin-2-yl)propylamino, 2-dimethylaminoethylaminomethyl, 3-dimethylaminopropylaminomethyl, 3-dimethylamino-2.2-dimethylpropylaminomethyl. 2-(1-methylpyrrolidin-2-ylethyl)aminomethyl, 3-pyrrolidin-1-ylpropylaminomethyl. 2-morpholinoethylaminomethyl, 3-morpholinopropylaminomethyl, 2-piperazin- 1-ylethylaminomethyl, 3-(4-methylpiperazin-1-ylpropyl)aminomethyl or 2-pyridylmethoxy: nis 0; qis 0; and Q is 2-pyridyl. 3-pyridy! or 4-pyridyl which bears a substituent selected from pyrrolidin-1-yl. 3-hydroxypyrrolidin-1-yl. 2-hydroxymethylpyrrolidin-1-yl. morpholino. piperidino. 4-hydroxypiperidin-1-yl, piperazin-1-yl and 4-methylpiperazin-1-yl: or a pharmaceutically-acceptable salt thereof.
- 10. An amide derivative of the Formula I according to claim 1 wherein X is CH:YisCHorN; ¢ . R’ is chloro or methyl; mis | and R' is selected from diethylaminomethyl, N-(2-dimethylaminoethy})- N-methylamino, N-(3-dimethylaminopropyl)-N-methylamino, pyrrolidin-1-yl, morpholino, piperidino, piperazin-1-yl, 4-methylpiperazin-1-yl, 4-ethylpiperazin-1-yl, homopiperazin-1-yl, 4-methylhomopiperazin-1-yl, piperazin-1-ylmethyl, 4-methylpiperazin-1-ylmethyl, 4-methylhomopiperazin-1-ylmethyl, morpholinomethyl. 3-aminopyrrolidin-1-ylmethyl, 3-hydroxypyrrolidin-1-ylmethyl, pyrrolidin-3-yloxy, piperidin-4-yloxy, 2-pyrrolidin-1-ylethoxy, 2-piperidinoethoxy, 2-morpholinoethoxy, 3-dimethylaminopropylaminomethyl, 3-dimethylamino-2,2-dimethylpropylaminomethy!, 2-(1-methylpyrrolidin-2-ylethyl)aminomethyl, 3-pyrrolidin-1-ylpropylaminomethyl, 2-morpholinoethylaminomethyl, 3-morpholinopropylaminomethyl, 2-piperazin-1-ylethylaminomethyl, 3-(4-methylpiperazin-1-ylpropyl)aminomethyl and 2-pyridylmethoxy: nis 0: qs 0; and Q is 3-pyridyl or 4-pyridyl which bears a substituent selected from pyrrohidin-1-yli, morpholino, piperidino, piperazin-1-yl and 4-methylpiperazin-1-yl; or a pharmaceutically-acceptable salt thereof.
- 11. An amide derivative of the Formula I according to claim 1 wherein X is CH: YisCHorN; R* is chloro or methyl; — - m is 1 and R! is selected. from diethylaminomethyl, N-(2-dimethylaminoethyl)- hm —25 N-methylamino, N=(3-dimethylaninopropyl)-N-methylamino, 3-pyrrolin-1=yl, pyrrohidin- I-yl. morpholino, piperidino, homopiperidin-1-yl, piperazin-1-yl, 4-methylpiperazin-1-yl. 4-cethylpiperazin-1-yl, homopiperazin-1-yl, 4-methylhomopiperazin-1-yl. piperazin-1-ylmethyl, 4-methylpiperazin-1-ylmethyl, homopiperazin-1-ylmethyl. 4-methylhomopiperazin-| -ylmethyl, morpholinomethyl, 3-aminopyrrolidin-}-ylmethyl, 3-hydroxypyrrolidin-1-yhmethyl, pyrrolidin-3-yloxy, N-methylpyrrolidin-3-yloxy. pipendin-4-yloxy, N-methylpiperidin-4-yloxy, homopiperidin-4-vioxy. N-methylhomopiperidin-4-yloxy, 2-pyrrolidin- 1-ylethoxy, 2-piperidinocthoxy.. . » 2-morpholinoethoxy, 3-dimethylaminopropylaminomethyl, 3-dimethylamino- 2,2-dimethylpropylaminomethyl, 2-(1-methylpyrrolidin-2-ylethyl)aminomethyl, 3-pyrrolidin-1-ylpropylaminomethyl, 2-morpholinoethylaminomethy}, 3-morpholinopropylaminomethyl, 2-piperazin- 1-ylethylaminomethyl, 3-(4-methylpiperazin-1-ylpropyl)aminomethyl, 2-pyridylmethoxy, 4-thiazolylmethoxy and 2-methylthiazol-4-ylmethoxy; nis 0; q is 0; and Q is phenyl which bears 1 or 2 substituents selected from fluoro, chloro, trifluoromethyl, methoxy, cyclopentyloxy, acetamido, N-methylmethanesulphonamido, 2-furyl, azetidin-1-yl, 3-pyrrolin-1-yl, pyrrolidin-1-yl, morpholino, piperidino, homopiperidino, piperazin-1-yl, homopiperazin-1-yl, 4-methylpiperazin-1-yl and 4-methylhomopiperazin-1-yl, or Q is 1-fluorenyl or 4-dibenzofuranyl, or Q is 3-pyridyl or 4-pyridyl which bears a substituent selected from azetidin-1-yl, 3-pyrrolin-1-yl, pyrrolidin-1-yl, morpholino, piperidino, homopiperidino, piperazin-1-yl, homopiperazin-1-yl, 4-methylpiperazin-1-yl and 4-methylhomopiperazin-1-yl; or a pharmaceutically-acceptable salt thereof.
- 12. An amide derivative of the Formula 1 according to claim 1 wherein X is CH; Y is CH or N: R'is chloro or methyl; mis I and R' is N~(2-dimethylaminoethyl)-N-methylamino, N-(3-dimethylaminopropyl)- N-methylamino, 4-methylpiperazin-1-yl, 4-ethylpiperazin-1-yl, 4-methylhomopiperazin-1-yl or 4-methylpiperazin-1-ylmethyl; nis 0: q is 0: and Q is 2-(pyrrolidin-1-yhpyrid-4-yl, 2-(3-pyrrolin-1-yl)pyrid-4-yl, 2-piperidinopyrid-4-yl. 2-morpholinopyrid-4-yl. 1-fluorenyl, dibenzofuran-4-yl. 3-acetamidophenyl or 3-(2-furyl)phenyl. or a pharmaceutically-acceptable salt thereof.
- 13. An amide derivative of the Formula | according to claim 1 wherein X is CH;» : + Y is CH or N; R? is chloro or methyl; m is | and R' is N-(3-dimethylaminopropyl)-N-methylamino, 4-methylpiperazin-1-yl, 4-methylhomopiperazin-1-yl or 4-methylpiperazin-1-ylmethyl; nis 0; gis 0; and Q is 2-morpholinopyrid-4-yl; or a pharmaceutically-acceptable salt thereof.
- 14. An amide derivative of the Formula | according to claim 1 selected from :- N-{3-(4-methylpiperazin-1-ylmethyl)phenyl]-2-methyl-5-(2-morpholinopyrid- 4-ylcarbonylamino)benzamide, N-[6-(4-cthylpiperazin-1-yl)pyrid-3-yl]-2-chloro-5-(2-morpholinopyrid- 4-ylcarbonylamino)benzamide, N-[6-(4-methylpiperazin-1-yl)pyrid-3-yl]-2-chioro-5-(2-morpholinopyrid- 4-ylcarbonylamino)benzamide and N-{6-[N-(3-dimethylaminopropy!)-N-methylamino |pyrid-3-y!l}-2-chloro- 5-(2-morpholinopyrid-4-ylcarbonylamino)benzamide: or a pharmaceutically-acceptable salt thereof.
- 15. A process for the preparation of an amide derivative of the Formula, or a pharmaceutically-acceptable salt or in-vivo-cleavable ester thereof, according to claim 1 : which comprises :- SU (a) reacting an aniline of the Formula Il (RD ED Y= II with a benzoic acid of the Formula I11, or an activated derivative thereof,Co R? (R?), HO,C 0 i (CH), —™ Q 111 under standard amide bond forming conditions, wherein variable groups are as defined in claim 1 and wherein any functional group is protected, if necessary, and: (1) removing any protecting groups; (ii) optionally forming a pharmaceutically-acceptable salt or jn-vivo-cleavable ester; (b) reacting an aniline of the Formula VI Ro (R?), (Rm oY XL, BE Ay? © VI . with a carboxylic acid of the Formula V, or a reactive derivative thereof, © } HO,C — (CH), — Q \ under standard amide bond forming conditions, wherein variable groups are as defined in claim I and wherein any functional group is protected if necessary, and: (1) removing any protecting groups; and (11) optionally forming a pharmaceutically-acceptable salt or in-vivo-cleavable ester; (c) an amide derivative of the Formula [ wherein R' or a substituent on Q is (1-6C)alkoxy or substituted (1-6C)alkoxy, (1-6C)alkylthio, (1-6C)alkylamino, di-[(1-6C)alkyl]amino or substituted (1-6C)alkylamino may be prepared by the alkylation, conveniently in the presence of a suitable base, of an amide derivative of the Formula I wherein R' or a substituent on Q is hydroxy. mercapto or amino as appropriate: (d) an amide derivative of the Formula I wherein a substituent on Q 1s amino, (1-6C)alkylamino. di-[(1-6C)alkyljamino, substituted (1-6C)alkylamino. substituted N-(1-6C)alkyl-(2-6C)alkylamino or a N-linked heterocyclyl group may be prepared by theRR : ! _90- reaction, conveniently in the presence of a suitable base, of an amide derivative of the: . Formula I wherein a substituent on Q is a suitable leaving group with an appropriate amine; (e) an amide derivative of the Formula I wherein R' or a substituent on Qis (1-6C)alkanoylamino or substituted (2-6C)alkanoylamino may be prepared by the acylation of a compound of the Formula | wherein R' or a substituent on Q is amino; (H an amide derivative of the Formula I wherein R' or a substituent on Qis (1-6C )alkanesulphonylamino may be prepared by the reaction of a compound of the Formula I wherein R' or a substituent on Q is amino with a (1 -6C)alkanesulphonic acid, or an activated derivative thereof; (g) an amide derivative of the Formula I wherein R' or a substituent on is carboxy, carboxy-(1-6C)alkyl, carboxy-(1-6C)alkoxy, carboxy-(1-6C)alkylamino, N-(1-6C)alkyl-carboxy-(1-6C)alkylamino or carboxy-(2-6C)alkanoylamino may be prepared by the cleavage of a compound of the Formula I wherein R' or a substituent on Q is (1-6C)alkoxycarbonyl, (1-6C)alkoxycarbonyl-(1-6C)alkyl, (1-6C)alkoxycarbonyl- 156 (1-6C)alkoxy, (1-6C)alkoxycarbonyl-(1-6C)alkylamino, N-(1-6C)alkyl- (1-6C)alkoxycarbonyl-(1-6C)alkylamino or (1-6C)alkoxycarbonyl-(2-6C)alkanoylamino as appropriate; or (h) an amide derivative of the Formula I wherein R' is amino-(1-6C)alkyl. (I1-6C)alkylamino-(1-6C)alkyl, di-[(1-6C)alkyl]amino-(1-6C)alkyl or a heterocyclyl-(1-6C)alkyl group may be prepared by the reaction, conveniently in the presence of a suitable base, of a compound of the Formula IX - (R?), Z-(1-6C)alkyl H > oo DE oy hg "NHCO — (CH,), — Q Ay? 0) B wherein X, Y, R%, RY, n, g and Q have any of the meanings defined in claim 1 and Z is a suitable leaving group with an appropriate amine or heterocycle.
- 16. A pharmaceutical composition which comprises an amide derivative of the Formula 1. or a pharmaceutically-acceptable or in-vivo-cleavable ester thereof. according to claim | in association with a pharmaceutically-acceptable diluent or carrier.PCT/GB00/00914
- 17. The use of an amide derivative of the Formula I, or a pharmaceutically-acceptable salt or in-vivo-cleavable ester thereof, according to claim 1 in the manufacture of a medicament for use in the treatment of diseases or medical conditions mediated by cytokines.
- 18. A substance or composition for use in a method of treating diseases or medical conditions mediated by cytokines, said substance or composition comprising a compound of the Formula I, or a pharmaceutically-acceptable salt or in-vivo-cleavable ester thereof, according to claim 1, and said method comprising administering to a warm-blooded animal an effective amount of said . substance or composition.
- 19. A compound according to claim 1, substantially as herein described and illustrated.
- 20. A process according to claim 15, substantially as herein described and illustrated.
- 21. A composition according to claim 16, substantially as herein described and illustrated.
- 22. Use according to claim 17, substantially as herein described and illustrated.
- 23. A substance or composition for use in a method of treatment according to claim 18, substantially as herein described and illustrated.
- 24. A new compound, a new process for the preparation of a compound, a new composition, a new use of a compound as claimed in claim 1, or a substance or composition for a new use in a method of treatment, substantially as herein described. AMENDED SHEET
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GBGB9906277.0A GB9906277D0 (en) | 1999-03-17 | 1999-03-17 | Amide derivatives |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ZA200106857B true ZA200106857B (en) | 2002-11-20 |
Family
ID=10849910
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ZA200106857A ZA200106857B (en) | 1999-03-17 | 2001-08-20 | Amide derivatives. |
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| Country | Link |
|---|---|
| GB (1) | GB9906277D0 (en) |
| ZA (1) | ZA200106857B (en) |
-
1999
- 1999-03-17 GB GBGB9906277.0A patent/GB9906277D0/en not_active Ceased
-
2001
- 2001-08-20 ZA ZA200106857A patent/ZA200106857B/en unknown
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| Publication number | Publication date |
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| GB9906277D0 (en) | 1999-05-12 |
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