MXPA01009241A - Novel compounds and compositions as protease inhibitors - Google Patents
Novel compounds and compositions as protease inhibitorsInfo
- Publication number
- MXPA01009241A MXPA01009241A MXPA/A/2001/009241A MXPA01009241A MXPA01009241A MX PA01009241 A MXPA01009241 A MX PA01009241A MX PA01009241 A MXPA01009241 A MX PA01009241A MX PA01009241 A MXPA01009241 A MX PA01009241A
- Authority
- MX
- Mexico
- Prior art keywords
- alkyl
- halo
- nr12r12
- hydrogen
- heteroaryl
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 title claims description 492
- 239000000203 mixture Substances 0.000 title claims description 78
- 229940042399 direct acting antivirals Protease inhibitors Drugs 0.000 title description 2
- 239000000137 peptide hydrolase inhibitor Substances 0.000 title description 2
- 150000003839 salts Chemical class 0.000 claims abstract description 58
- 239000011780 sodium chloride Substances 0.000 claims abstract description 54
- 150000001204 N-oxides Chemical class 0.000 claims abstract description 45
- 239000003814 drug Substances 0.000 claims abstract description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 938
- -1 trimethylene, tetramethylene Chemical group 0.000 claims description 302
- 239000001257 hydrogen Substances 0.000 claims description 218
- 229910052739 hydrogen Inorganic materials 0.000 claims description 218
- KXDAEFPNCMNJSK-UHFFFAOYSA-N benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims description 182
- 125000001072 heteroaryl group Chemical group 0.000 claims description 178
- 125000003118 aryl group Chemical group 0.000 claims description 174
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 claims description 152
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 140
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 131
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 76
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 73
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 67
- 201000010099 disease Diseases 0.000 claims description 56
- 125000001475 halogen functional group Chemical group 0.000 claims description 54
- 150000003254 radicals Chemical class 0.000 claims description 52
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 50
- 125000001188 haloalkyl group Chemical group 0.000 claims description 47
- 125000002947 alkylene group Chemical group 0.000 claims description 45
- 239000000651 prodrug Substances 0.000 claims description 41
- 229940002612 prodrugs Drugs 0.000 claims description 41
- 125000004432 carbon atoms Chemical group C* 0.000 claims description 36
- 125000001118 alkylidene group Chemical group 0.000 claims description 32
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 32
- 125000003884 phenylalkyl group Chemical group 0.000 claims description 32
- 125000002723 alicyclic group Chemical group 0.000 claims description 30
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 30
- 125000004043 oxo group Chemical group O=* 0.000 claims description 24
- 229910052799 carbon Inorganic materials 0.000 claims description 22
- 125000002993 cycloalkylene group Chemical group 0.000 claims description 22
- ZKWFSTHEYLJLEL-UHFFFAOYSA-N morpholine-4-carboxamide Chemical compound NC(=O)N1CCOCC1 ZKWFSTHEYLJLEL-UHFFFAOYSA-N 0.000 claims description 22
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 21
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 20
- 230000000694 effects Effects 0.000 claims description 20
- 102000005927 Cysteine Proteases Human genes 0.000 claims description 15
- 108010005843 Cysteine Proteases Proteins 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 15
- 102100015379 CTSS Human genes 0.000 claims description 13
- 108090000613 Cathepsin S Proteins 0.000 claims description 13
- 230000000875 corresponding Effects 0.000 claims description 12
- 239000008194 pharmaceutical composition Substances 0.000 claims description 12
- 238000002360 preparation method Methods 0.000 claims description 11
- 125000005119 alkyl cycloalkyl group Chemical group 0.000 claims description 10
- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 10
- 125000006588 heterocycloalkylene group Chemical group 0.000 claims description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 10
- 125000001424 substituent group Chemical group 0.000 claims description 10
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N Trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 claims description 8
- 238000004519 manufacturing process Methods 0.000 claims description 8
- 208000006673 Asthma Diseases 0.000 claims description 7
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 7
- 150000001408 amides Chemical class 0.000 claims description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 6
- 125000000623 heterocyclic group Chemical group 0.000 claims description 6
- 206010039073 Rheumatoid arthritis Diseases 0.000 claims description 5
- 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 claims description 5
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 claims description 4
- 125000005418 aryl aryl group Chemical group 0.000 claims description 4
- 210000001519 tissues Anatomy 0.000 claims description 4
- 208000005783 Autoimmune Thyroiditis Diseases 0.000 claims description 3
- 206010003816 Autoimmune disease Diseases 0.000 claims description 3
- 208000003807 Graves Disease Diseases 0.000 claims description 3
- 201000004779 Graves' disease Diseases 0.000 claims description 3
- 206010028417 Myasthenia gravis Diseases 0.000 claims description 3
- 101710040468 YBL068W-A Proteins 0.000 claims description 3
- 230000000172 allergic Effects 0.000 claims description 3
- 230000000735 allogeneic Effects 0.000 claims description 3
- 201000008937 atopic dermatitis Diseases 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- 239000000460 chlorine Substances 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
- 230000028993 immune response Effects 0.000 claims description 3
- 201000006417 multiple sclerosis Diseases 0.000 claims description 3
- 210000000056 organs Anatomy 0.000 claims description 3
- 201000011152 pemphigus Diseases 0.000 claims description 3
- 201000001976 pemphigus vulgaris Diseases 0.000 claims description 3
- 201000000596 systemic lupus erythematosus Diseases 0.000 claims description 3
- 238000002560 therapeutic procedure Methods 0.000 claims description 3
- 125000000335 thiazolyl group Chemical group 0.000 claims description 3
- 125000001544 thienyl group Chemical group 0.000 claims description 3
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 2
- PRJWEPRQDKFJHV-UHFFFAOYSA-N 1-methyl-3-nitrobenzene Chemical group [CH2]C1=CC=CC([N+]([O-])=O)=C1 PRJWEPRQDKFJHV-UHFFFAOYSA-N 0.000 claims description 2
- 125000006282 2-chlorobenzyl group Chemical group [H]C1=C([H])C(Cl)=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 125000004847 2-fluorobenzyl group Chemical group [H]C1=C([H])C(F)=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000006283 4-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Cl)C([H])([H])* 0.000 claims description 2
- 125000004176 4-fluorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1F)C([H])([H])* 0.000 claims description 2
- 125000002877 alkyl aryl group Chemical group 0.000 claims description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 2
- 125000004923 naphthylmethyl group Chemical group C1(=CC=CC2=CC=CC=C12)C* 0.000 claims description 2
- 125000006505 p-cyanobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C#N)C([H])([H])* 0.000 claims description 2
- 125000006503 p-nitrobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1[N+]([O-])=O)C([H])([H])* 0.000 claims description 2
- 125000004496 thiazol-5-yl group Chemical group S1C=NC=C1* 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 17
- 102200023292 HOGA1 R15C Human genes 0.000 claims 4
- 125000001999 4-Methoxybenzoyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C(*)=O 0.000 claims 2
- 206010006451 Bronchitis Diseases 0.000 claims 2
- 206010002022 Amyloidosis Diseases 0.000 claims 1
- 206010002023 Amyloidosis Diseases 0.000 claims 1
- 206010003210 Arteriosclerosis Diseases 0.000 claims 1
- 208000008787 Cardiovascular Disease Diseases 0.000 claims 1
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims 1
- 206010012601 Diabetes mellitus Diseases 0.000 claims 1
- 206010035742 Pneumonitis Diseases 0.000 claims 1
- 239000002260 anti-inflammatory agent Substances 0.000 claims 1
- 229940121363 anti-inflammatory agents Drugs 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 claims 1
- 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 claims 1
- 238000005755 formation reaction Methods 0.000 claims 1
- 125000006302 indol-3-yl methyl group Chemical group [H]N1C([H])=C(C2=C([H])C([H])=C([H])C([H])=C12)C([H])([H])* 0.000 claims 1
- 125000006301 indolyl methyl group Chemical group 0.000 claims 1
- QODROJIVRSBGCD-UHFFFAOYSA-N [NH-]CC#N Chemical class [NH-]CC#N QODROJIVRSBGCD-UHFFFAOYSA-N 0.000 abstract 1
- 239000002852 cysteine proteinase inhibitor Substances 0.000 abstract 1
- 101700067048 CDC13 Proteins 0.000 description 109
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 64
- 125000005843 halogen group Chemical group 0.000 description 55
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 37
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N DMSO-d6 Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 28
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 26
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 24
- 125000004429 atoms Chemical group 0.000 description 21
- 239000000243 solution Substances 0.000 description 21
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 21
- 239000002253 acid Substances 0.000 description 19
- 125000006239 protecting group Chemical group 0.000 description 18
- 230000002401 inhibitory effect Effects 0.000 description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 14
- PWXJULSLLONQHY-UHFFFAOYSA-M N-phenylcarbamate Chemical compound [O-]C(=O)NC1=CC=CC=C1 PWXJULSLLONQHY-UHFFFAOYSA-M 0.000 description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 238000001228 spectrum Methods 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- 239000012131 assay buffer Substances 0.000 description 11
- 239000002585 base Substances 0.000 description 11
- 239000002904 solvent Substances 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- 102000004190 Enzymes Human genes 0.000 description 10
- 108090000790 Enzymes Proteins 0.000 description 10
- 238000004166 bioassay Methods 0.000 description 10
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 10
- 239000007787 solid Substances 0.000 description 10
- OKKJLVBELUTLKV-MZCSYVLQSA-N cd3od Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 9
- DFPAKSUCGFBDDF-UHFFFAOYSA-N nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 description 9
- FYSNRJHAOHDILO-UHFFFAOYSA-N Thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 8
- 238000006460 hydrolysis reaction Methods 0.000 description 8
- WHXSMMKQMYFTQS-UHFFFAOYSA-N lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 8
- 229910052744 lithium Inorganic materials 0.000 description 8
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 8
- 239000012085 test solution Substances 0.000 description 8
- 210000004072 Lung Anatomy 0.000 description 7
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 7
- KXDHJXZQYSOELW-UHFFFAOYSA-M carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 150000002148 esters Chemical class 0.000 description 6
- 125000005842 heteroatoms Chemical group 0.000 description 6
- OWIKHYCFFJSOEH-UHFFFAOYSA-N isocyanate Chemical compound N=C=O OWIKHYCFFJSOEH-UHFFFAOYSA-N 0.000 description 6
- DBTDEFJAFBUGPP-UHFFFAOYSA-N methanethione Chemical compound S=C DBTDEFJAFBUGPP-UHFFFAOYSA-N 0.000 description 6
- RFIOZSIHFNEKFF-UHFFFAOYSA-M piperazine-1-carboxylate Chemical compound [O-]C(=O)N1CCNCC1 RFIOZSIHFNEKFF-UHFFFAOYSA-M 0.000 description 6
- 239000011347 resin Substances 0.000 description 6
- 229920005989 resin Polymers 0.000 description 6
- 108090000712 Cathepsin B Proteins 0.000 description 5
- 102000004225 Cathepsin B Human genes 0.000 description 5
- 108090000625 Cathepsin K Proteins 0.000 description 5
- 102000004171 Cathepsin K Human genes 0.000 description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M NaHCO3 Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 5
- 125000001951 carbamoylamino group Chemical group C(N)(=O)N* 0.000 description 5
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 238000000926 separation method Methods 0.000 description 5
- VHJLVAABSRFDPM-UHFFFAOYSA-N 1,4-dimercaptobutane-2,3-diol Chemical compound SCC(O)C(O)CS VHJLVAABSRFDPM-UHFFFAOYSA-N 0.000 description 4
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N Benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 4
- 108090000624 Cathepsin L Proteins 0.000 description 4
- 102000004172 Cathepsin L Human genes 0.000 description 4
- VWQRCMXMVYQOMR-UHFFFAOYSA-N N-[1-(cyanomethylamino)-1-oxohex-4-en-2-yl]benzamide Chemical compound N#CCNC(=O)C(CC=CC)NC(=O)C1=CC=CC=C1 VWQRCMXMVYQOMR-UHFFFAOYSA-N 0.000 description 4
- 102000035443 Peptidases Human genes 0.000 description 4
- 108091005771 Peptidases Proteins 0.000 description 4
- QIQXTHQIDYTFRH-UHFFFAOYSA-N Stearic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 4
- RMVRSNDYEFQCLF-UHFFFAOYSA-N Thiophenol Chemical compound SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 description 4
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 4
- 238000005917 acylation reaction Methods 0.000 description 4
- 125000001931 aliphatic group Chemical group 0.000 description 4
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 238000010511 deprotection reaction Methods 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- TVFIYRKPCACCNL-UHFFFAOYSA-N furan-2-carboxamide Chemical compound NC(=O)C1=CC=CO1 TVFIYRKPCACCNL-UHFFFAOYSA-N 0.000 description 4
- GOLHZPOXCLTFRB-UHFFFAOYSA-N furan-3-carboxamide Chemical compound NC(=O)C=1C=COC=1 GOLHZPOXCLTFRB-UHFFFAOYSA-N 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium;hydroxide;hydrate Chemical compound [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
- SJRJJKPEHAURKC-UHFFFAOYSA-N n-methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L na2so4 Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- 230000000750 progressive Effects 0.000 description 4
- 235000019833 protease Nutrition 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 229910052938 sodium sulfate Inorganic materials 0.000 description 4
- 235000011152 sodium sulphate Nutrition 0.000 description 4
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 4
- DENPQNAWGQXKCU-UHFFFAOYSA-N thiophene-2-carboxamide Chemical compound NC(=O)C1=CC=CS1 DENPQNAWGQXKCU-UHFFFAOYSA-N 0.000 description 4
- DAUYIKBTMNZABP-UHFFFAOYSA-N thiophene-3-carboxamide Chemical compound NC(=O)C=1C=CSC=1 DAUYIKBTMNZABP-UHFFFAOYSA-N 0.000 description 4
- XFKYKTBPRBZDFG-UHFFFAOYSA-N 2-aminoacetonitrile;hydrochloride Chemical compound Cl.NCC#N XFKYKTBPRBZDFG-UHFFFAOYSA-N 0.000 description 3
- FVUKYCZRWSQGAS-UHFFFAOYSA-M 3-carbamoylbenzoate Chemical compound NC(=O)C1=CC=CC(C([O-])=O)=C1 FVUKYCZRWSQGAS-UHFFFAOYSA-M 0.000 description 3
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butanoic acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 3
- 102000005600 Cathepsins Human genes 0.000 description 3
- 108010084457 Cathepsins Proteins 0.000 description 3
- FUZZWVXGSFPDMH-UHFFFAOYSA-N Hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 3
- 206010027476 Metastasis Diseases 0.000 description 3
- 210000002997 Osteoclasts Anatomy 0.000 description 3
- 229940092253 Ovalbumin Drugs 0.000 description 3
- 108010058846 Ovalbumin Proteins 0.000 description 3
- 239000004365 Protease Substances 0.000 description 3
- VIAFLMPQBHAMLI-UHFFFAOYSA-N PyBOP Chemical compound F[P-](F)(F)(F)(F)F.C1CCCN1[P+](N1CCCC1)(N1CCCC1)ON1C2=CC=CC=C2N=N1 VIAFLMPQBHAMLI-UHFFFAOYSA-N 0.000 description 3
- 206010064390 Tumour invasion Diseases 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 230000004913 activation Effects 0.000 description 3
- 125000005213 alkyl heteroaryl group Chemical group 0.000 description 3
- 125000002619 bicyclic group Chemical group 0.000 description 3
- KCXVZYZYPLLWCC-UHFFFAOYSA-N edta Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 3
- 239000012458 free base Substances 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- 150000007529 inorganic bases Chemical class 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
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- 238000006731 degradation reaction Methods 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 229960000673 dextrose monohydrate Drugs 0.000 description 1
- 125000004772 dichloromethyl group Chemical group [H]C(Cl)(Cl)* 0.000 description 1
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- CPELXLSAUQHCOX-UHFFFAOYSA-N hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
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- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 1
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- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 description 1
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- CSNNHWWHGAXBCP-UHFFFAOYSA-L magnesium sulphate Substances [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
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- 201000004792 malaria Diseases 0.000 description 1
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- 239000008267 milk Substances 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
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- LPWAKYISHIZIPO-UHFFFAOYSA-N morpholin-4-ylmethyl benzoate Chemical class C=1C=CC=CC=1C(=O)OCN1CCOCC1 LPWAKYISHIZIPO-UHFFFAOYSA-N 0.000 description 1
- YNAVUWVOSKDBBP-UHFFFAOYSA-N morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 1
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- KVBGVZZKJNLNJU-UHFFFAOYSA-N naphthalene-2-sulfonic acid Chemical compound C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-N 0.000 description 1
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- 125000002971 oxazolyl group Chemical group 0.000 description 1
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- 125000004430 oxygen atoms Chemical group O* 0.000 description 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 1
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 description 1
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- 125000004817 pentamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 1
- 125000005004 perfluoroethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 1
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- 125000004351 phenylcyclohexyl group Chemical group C1(=CC=CC=C1)C1(CCCCC1)* 0.000 description 1
- YGYAWVDWMABLBF-UHFFFAOYSA-N phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 1
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
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- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
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- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- OSFBJERFMQCEQY-UHFFFAOYSA-N propylidene Chemical group [CH]CC OSFBJERFMQCEQY-UHFFFAOYSA-N 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
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- 125000001042 pteridinyl group Chemical group N1=C(N=CC2=NC=CN=C12)* 0.000 description 1
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- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
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- 230000001105 regulatory Effects 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 150000003873 salicylate salts Chemical class 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
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- 238000010898 silica gel chromatography Methods 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000012439 solid excipient Substances 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
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- 239000007921 spray Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
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- 238000007920 subcutaneous administration Methods 0.000 description 1
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- 150000003890 succinate salts Chemical class 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
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- NINIDFKCEFEMDL-UHFFFAOYSA-N sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000002459 sustained Effects 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
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- 150000003892 tartrate salts Chemical class 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 230000001225 therapeutic Effects 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 125000004385 trihaloalkyl group Chemical group 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
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Abstract
The present invention relates to novel N-cyanomethyl amides which are cysteine protease inhibitors, the pharmaceutically acceptable salts and N-oxides thereof, their uses as therapeutic agents and the methods of their making.
Description
NEW COMPOUNDS AND COMPOSITIONS AS PROTEASE INHIBITORS
This application relates to compounds and compositions for treating diseases associated with the activity of cysteine protease, particularly diseases associated with the activity of cathepsins B, K, L or S. FIELD DESCRIPTION Cysteine proteases represent a class of peptidases characterized by the presence of a cysteine residue in the catalytic site of the enzyme. Cysteine proteases are associated with the normal degradation and processing of proteins. However, the aberrant activity of the cysteine proteases, e.g., as a result of increasing expression or enhanced activation, can have pathological consequences. In this regard, certain cysteine proteases are associated with several disease states, including arthritis, muscular dystrophy, inflammation, tumor invasion, glomerulonephritis, malaria, periodontal disease, metachromatic leukodystrophy and others. For example, increased levels of cathepsin B and redistribution of the enzyme are found in tumors; thus, they suggest a role for the enzyme in tumor invasion and metastasis. In addition, the aberrant activity of cathepsin B is implicated in such disease states as rheumatoid arthritis, osteo arthritis, pneu.r? Ocys is carinii, acute pancreatitis, inflammatory airway disease and bone and joint disorders. The prominent expression of cathepsin K in osteoclasts and multinucleated cells related to osteoclasts and its high collagenolytic activity suggests that the enzyme is involved in bone resorption mediated by osteoclasts and, consequently, in bone abnormalities such as occurs in osteoporosis . In addition, the expression of cathepsin K in the lung and its elastinolytic activity also suggests that the enzyme plays a role in lung disorders. Cathepsin L is involved in normal lysosomal proteolysis as well as various disease states, including, but not limited to, melanoma metastases. Cathepsin S is implicated in Alzheimer's disease and certain autoimmune disorders, including but not limited to juvenile diabetes, multiple sclerosis, pemphigus vulgaris, Graves disease, myasthenia gravis, systemic lupus erythematosus, rheumatoid arthritis, and Hashimoto thyroiditis. allergic, including, but not limited to asthma; and allogeneic immune responses, including, but not limited to, rejection of organ transplants or tissue grafts.
In view of the number of diseases where it is recognized that an increase in the activity of the cysteine protease contributes to the pathology and / or symptomatology of the disease, the molecules that are shown to inhibit the activity of this class of enzymes, in particular the molecules that are inhibitors of cathepsins B, K, L and / or S, will be useful as therapeutic agents SUMMARY OF THE INVENTION In a particular embodiment, the present invention relates to the compounds of Formula (I):
(I) in which R1 is a group of Formula (a) or (b)
(a) (b)
wherein X1 and X2 are independently -C (O) - or -CH2S (0) 2-;
R5 and R6 are hydrogen or alkyl (C? .6); R7 and R8 are hydrogen or alkyl (C? _6) or as defined below; R9 and R10 are independently (i) (C6-6) alkyl optionally substituted with cyano, halo or nitro or (ii) a group selected from -X3NR12R12 '-X3NRI2C (O) OR12, - X3NR12C (0) NR12R12, - X3NR12C (NR12) NR12R12, -X3OR12, -X3SR12,
X3C (0) OR12, -X3C (0) NR12R12, -X3S (O) 2NR12R12, -X3P (0) (OR12) OR12, -X3OP (0) (OR12) OR12, -X3NR12C (0) R13, -X3S ( 0) R13, -X3S (0) 2R13, X3C (0) R13, -X3C (0) R14, -X3C (0) OR14, -X3OC (0) R14, -X3NR15C (O) R14, - X3NR15C (0) OR14, -X3C (0) NR14R15, -X3S (O) 2NR14R15, -X3NR15C (O) NR14R15,
-X3NR15C (NRI5) NR14R15, -X4SR14 -X4S (0) R14 -X4S (0) 2R14, -X4OR14, or -XNR14R15, wherein X3 is alkylene (C? -6), X4 is a bond or alkylene (dA, R12 in each occurrence is independently hydrogen, alkyl (C? _6) or halo-substituted alkyl (C? _3), R13 is (C? -6) alkyl or halo (substituted? -C3) alkyl, R14 is (C3-12) cycloalkyl (C0-) alkyl 6., (C3_2) heterocycloalkyl (Co-e), aryl (C6-? 2) alkyl (CoA, heteroaryl (C5.? 2) (C0-ß) alkyl, polycycloaryl (C9-? 2) alkyl ( C0-6 or heteropolycycloaryl (C8-? 2) alkyl (Co-e) and R15 is hydrogen or alkyl (Ci-g) and wherein within R14 said cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or heteropolycycloaryl ring is optionally replaces by a selected group of R16, -X4OR16, -X4SR16, -X4S (0) R16, -X4S (0) 2R16, -X4C (0) R16, -X4C (0) OR16, -X4OC (0) R? e , -X4NR16R17, -X4NR17C (0) R16, -X4NR17C (O) OR16, -X4C (O) NR16R17, XS (0) 2NR16R17, -XNR17C (O) NR16R17 or -X4NR17C (NR17) NR16R17, wherein X4 is a bond or alkylene (C? _6), R16 is hydrogen or alkyl (C? -6) and R17 is (C3-y2) cycloalkyl (C0_s) alkyl, (C3-? 2) heterocycle (C0-β) alkyl / aryl C6-? 2) (C0-6) alkyl, heteroaryl (C5-? 2) ) alkyl (Co-β). polycycloaryl (C9-? 2) alkyl (CoA or heteropolycycloaryl (C8-? 2) alkyl (Co-β) or (iii) a group selected from (C3-12) cycloalkyl (C0-6) alkyl (C3-6 heterocycloalkyl) -i2) (C0-6) alkyl, aryl (C6-? 2) (C0-6) alkyl, heteroaryl (C5-? 2) (C0-6) alkyl / polycycloaryl (C9-? 2) alkyl (CoA and heteropolycycloaryl) (C8-? 2) alkyl (Co-e), wherein said cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or heteropolycycloaryl ring is optionally substituted by a group selected from R16, X4OR16, -X4SR16, -X4S (0) R16, -X4S (0) 2R16, -X4C (0) Rld, -X4C (0) OR16, -X4OC (0) R16, -X4NR16R17, -X4NR17C (0) R16, -X4NR17C (O) OR16, XC (0) ) NR16R17, -X4S (0) 2NR16R17, -X4NR17C (O) NR16R17 or X4NR17C (NR17) NR16R17, wherein X4, R16 and R17 are as defined above; wherein within R9 and / or R10 any present system of alicyclic or aromatic ring present can be further substituted by 1 to 5 radicals independently selected from alkyl (C? -6), alkylidene (C? _6), cyano, halo, alkyl (C? _4) halo-substituted, nitro, -X4NR12R12, X4NR12C (0) OR12, -X4NR12C (0) NR12R12, -X4NR12C (NR12) NR12R12, -X4OR12, -X4SR12, -X4C (0) OR12, -X4C ( O) NR1 R12, -X4S (O) 2NR1 R12, X4P (0) (OR4) OR12, -X4OP (0) (OR12) OR12, -X4OC (0) R13, -X4NR12C (O) R13, -XS (0 ) R13, -X4S (0) 2R13 and -X4C (0) R13, wherein X4, R12 and R13 are as defined above or R9 taken together with R7 and / or R10 taken together with R8 form trimethylene, tetramethylene or phenylene -1,2-dimethylene, optionally substituted with hydroxy, oxo or methylene; and R11 is -X5X6R18, wherein X5 is -C (0) -, -C (0) C (0) - or -S (0) 2-, X6 is a bond, -O- or -NR19-, where R19 is hydrogen or alkyl (C? _6) and R18 is (i) alkyl (C? -? o) optionally substituted by cyano, halo, nitro, -NR12R12, -NR12C (0) OR12, -NR12C (0) NR12R12 , -NR12C (NR12) NR12R12, -OR12, -SR12, -C (0) OR12, -C (0) NR12R12, -S (0) 2NR12R12, -P (O) (OR12) OR12, OP (O) ( OR12) OR12, -NR12C (0) R13, -S (0) R13, -S (0) 2R13, -C (0) R13, -OR20, -SR20, -S (0) R20, -S (0) 2R20, -C (0) R20, -C (0) OR20,
C (O) NR20R21, -NR20R21, -NR21C (O) R20, -NR21C (O) OR20, -NR21C (O) NR20R21 or -NR21C (NR21) NR20R21, wherein R12 and R13 are as defined above, R20 is cycloalkyl (C3-? 2) alkyl (Co-β). (C3-y2) heterocycloalkyl (CoA, aryl (C6-? 2) alkyl (Co-ß), heteroaryl (C5-? 2) alkyl (Co-e) bicycloaryl (C9_? 2) alkyl (C0-G) O heterobicycloaryl (C8-? 2) (C0-6) alkyl and R21 in each occurrence independently is hydrogen or (C? -6) alkyl or (ii) (C3-y2) cycloalkyl (C0-6) alkyl- (C3-6) -cycloalkyl 12) alkyl (C0-6), aryl (C6-? 2) alkyl (C0-e), heteroaryl (C5.22) alkyl (C0-s) bicycloaryl (C9-? 2) alkyl {C .6) or heterobicycloaryl (C8-? 2) (C0-e) alkyl or (iii) (C3_6) cycloalkyl (C0-6) alkyl, (C6-6) heterocycloalkyl, (C0-6) alkyl, phenylalkyl (CoA or heteroaryl ( C5.6) (C0-C) alkyl, wherein said cycloalkyl, heterocycloalkyl, phenyl or heteroaryl is substituted by -X4OR22, -X4SR22, -X4S (0) R22, -X4S (0) 2R22, -X4C (0) R22 , -X4C (0) OR22, -X4C (0) NR22R23, -X4NR22R23, -X4NR23C (O) R22, -X4NR23C (0) OR22, -X4NR23C (0) NR22R23 or -X4NR23C (NR23) NR22R23, wherein X4 is as defined above, R22 is (C3_6) cycloalkyl (C0-e) heterocycloalkyl (C3-6) alkyl (C0-e). phenylalkyl (C0-6) or heteroaryl (C5.6) (C0-6) alkyl and R23 in each occurrence independently is hydrogen or (C? -6) alkyl; wherein within R11 any present alicyclic or aromatic ring system can be further substituted by 1 to 5 independently selected radicals from alkyl (C? -6), alkylidene (C? -6), cyano, halo, alkyl (C? -4) -halo-substituted, nitro, -X4NR12R12, -X4NR12C (O) OR12, X4NR1C (0) NR12R12, -XNR12C (NR1) NR12R12, -X4OR12, -X4SR12, X4C (0) OR12, -X4C (0) NR1R12, -XS (O) 2NR12R12, -X4P (O) (OR3) OR12, -X4OP (0) (OR3) OR12, -X4OC (0) R13, -X4NR12C (O) R13, -X4S (0) R13, X4S (0) 2R13 and -X4C (0) R13, wherein X4, R12 and R13 are as defined above; R2 is hydrogen or (C? -6) alkyl or as defined below; R3 is hydrogen, alkyl (C? -6) or as defined below; and R4 is (i) hydrogen or (C? -6) alkyl, wherein said alkyl is optionally substituted with cyano, halo, nitro, -NR12R12, -NR12C (O) OR12, -NR12C (O) NR12R12, NR12C ( NR12) NR12R12, -OR12, -SR12, -C (0) OR12, -C (O) NR12R12, S (0) 2NR12R12, -P (0) (OR12) OR12, -OP (O) (OR12) OR12, -NR 12 C (0) R 13, -S (0) R 13, -S (0) 2 R 13, -C (0) R 13, -OR 14, -SR 14, -S (0) R 14, -S (0) 2 R 14, -C (0) R14, -C (0) 0R14, -0C (0) NR14, -NR14R15, -NR15C (0) R14,
NR15C (0) OR14, -C (0) NR14R15 -S (0) 2NR14R15, -NR15C (0) NR14R15 or -NR15C (NR15) NR14R15, wherein R12, R13, R14 and R15 are as defined above, or ( ii) a group selected from cycloalkyl (C3-? 2) alkyl (Co-ß), heterocycloalkyl (C3_? 2) alkyl (Co-e), aryl (C6-? 2) alkyl (CoA, heteroaryl (C5_)
12) alkyl (Co-β) # polycycloaryl (C9-12) alkyl (C0-e) and heteropolycycloaryl (C8-? 2) alkyl (Co-e) wherein said cycloalkyl ring, heterocycloalkyl. aryl, heteroaryl, polycycloaryl or heteropolycycloaryl optionally substituted by a group selected from -R16, X4OR16, -X4SR16, -X4S (0) R16, -X4S (0) 2R16, -X4C (0) R16, -X4C (0) ) 0Rld, -X4OC (0) R16, -X4NR16R17, -X4NR17C (0) R16, -X4NR17C (0) OR16, X4C (0) NR16R17, -X4S (0) 2NR16R17, -X4NR17C (O) NR16R17 or
X4NR17C (NR17) NR16R17, wherein X4, R16 and R17 are as defined above; wherein within R9 and / or R10 any present system of alicyclic or aromatic ring present can be further substituted by 1 to 5 radicals independently selected from alkyl (C? -6), alkylidene (CX-6), cyano, halo, alkyl (C _.- 4) halo-substituted, nitro, -X4NR12R12, X4NR12C (0) OR12, -XNR12C (0) NR12R12, -X4NR12C (NR12) NR12R12, -X4OR12, -X4SR12, -X4C (0) OR12, -X4C (0) NR12R12, -X4S (O) 2NR12R12, X4P (0) (OR3) OR12, -X4OP (0) (OR3) OR12, -X4OC (0) R13, -X4NR12C (0) R13, -X4S (0) R13, -X4S (0) 2R13 and -X4C (0) R13, wherein X4, R12 and R13 are as defined above or R4 and R2 taken together form trimethylene, tetramethylene or phenylene-1,2-dimethylene, optionally substituted with hydroxy, oxo or methylene, or R4 and R3 together with the carbon atom to which both R4 and R3 are attached form cycloalkylene (C3-8) or heterocycloalkylene (C3.8); and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers; and the pharmaceutically acceptable salts thereof. In another particular embodiment, the invention relates to a composition of Formula (II):
(II)
wherein: R is hydrogen or alkyl (CiA or as defined below: R3 is hydrogen, alkyl (C6-6) or as defined below: R4 is (i) hydrogen or alkyl (C6-6), wherein said alkyl is optionally substituted with cyano, halo, nitro, -NR12R12, -NR12C (0) OR12, -NR12C (O) NR12R12, -NR12C (NR12) NR12R12, -OR12, -SR12, -C (0) OR12, - C (0) NR12R12, -S (O) 2NR12R12, -P (O) (OR12) OR12, -OP (O) (OR12) OR12, -NR12C (0) R13, -S (0) R13, -S ( 0) 2R13, -C (0) R13, -OR14, -SR14, -S (0) R14, -S (0) 2R14, -C (0) R14, -C (0) OR14, -OC (0) R14, -NR14R15, -NR15C (0) R14, -NR15C (O) OR14, -C (0) NR14R15 -S (O) 2NR14R15, -NR15C (0) NR14R15 or -NR15C (NR15) NR14R15, wherein R12 in each occurrence is independently hydrogen, alkyl (C? -6) or halo-substituted alkyl (C? -3), R13 is alkyl (C? _6), or halo (C? -3) alkyl substituted, R14 is cycloalkyl ( C3_? 2) alkyl (Co-e) heterocycloalkyl (C3-? 2) alkyl. {C0-ß), aryl (C6.12) alkyl (C0_6), heteroaryl (C5_? 2) alkyl (C0-6) polycycloaryl (C9-? 2) alq uilo (Co-ß) or heteropolycycloaryl (C8-12) alkyl (CoA and R15 is hydrogen or (C? -6) alkyl and wherein within R14 said cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or heteropolycycloaryl ring is optionally substituted by a group selected from -R16, -X4OR16, -X4SR16, -X4S (0) R16, -X4S (0) 2R16, -X4C (0) R16, -X4C (0) OR16, -X4OC (0) R16 , -XNR16R17, -X4NR17C (O) R16, -X4NR17C (0) OR16, -X4C (0) NR16R17, -X4S (O) 2NR16R17, -X4NR17C (O) NR16R17 or -X4NR17C (NR17) NR16R17, wherein X4 is a bond or alkylene (d-6), R16 is hydrogen or alkyl (C? -6) and R17 is (C3-12) cycloalkyl (C0-6) alkyl. heterocycloalkyl (C3-12) alkyl (C06) / aryl (C6-12) alkyl (C0-6), heteroaryl (C5-12) alkyl (C0-e). polycycloaryl (C9-? 2) alkyl (C0-6) or heteropolycycloaryl (C8-12) alkyl (CoA or (ii) a group selected from cycloalkyl (C3_?) alkyl (C0-e) heterocycloalkyl (C3_? 2) alkyl (Co-e), aryl (C6-? 2) alkyl (C0-ß), heteroaryl (C5_)
12) (C0_6) alkyl, polycycloaryl (C9-? 2) alkyl (C0-s) and heteropolycycloaryl (C8-? 2) alkyl (Co-e) / wherein said cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or heteropolycycloaryl ring they are optionally substituted by a group selected from R1G, X4OR16, -X4SR16, -X4S (0) R16, -X4S (0) 2R16, -X4C (0) R16, -X4C (0) OR16, -X4OC (0) R16, -X4NR16R17, -X4NR17C (0) R16, -X4NR17C (O) OR16, X4C (0) NR16R17, -X4S (0) 2NR16R17, -X4NR17C (O) NR16R17 or
X4NR17C (NR17) NR16R17, wherein X4, R16 and R17 are as defined above; wherein within R4 any present alicyclic or aromatic ring system can be further substituted by 1 to 5 independently selected radicals from alkyl (C? _6), alkylidene (C? -6), cyano, halo, alkyl (C? ) halo-substituted, nitro, -X4NR12R12, -XNR12C (O) OR12, X4NR12C (0) NR12R12, -X4NR12C (NR12) NR12R12, -X4OR12, -X4SR12,
X4C (0) OR12, -X4C (0) NR12R12, -X4S (O) 2NR12R12, -X4P (O) (OR3) OR12, -X OP (0) (OR3) OR12, -X4OC (0) R13, -X4NR12C (O) R13, -X4S (0) R13, X4S (0) 2R13 and -X4C (0) R13, wherein X4, R12 and R13 are as defined above or R4 and R2 taken together form trimethylene, tetramethylene or phenylene -1, 2-dimethylene, optionally substituted with hydroxy, oxo or methylene, or R4 and R3 together with the carbon atom to which both R4 and R3 are attached form cycloalkylene (C3_8) or heterocycloalkylene (C3_8); R5 is hydrogen or alkyl (C? _6); R7 is hydrogen or alkyl (C? _6); R9 is aryl (C6_? 2) alkyl (C? -6), heteroaryl (C5_? 2) alkyl (C? _6), -X4OR14, -X4SR14, -X4S (0) R14, -X4S (0) 2R14, or -X4NR14R15, wherein X4, R14 and R15 are as defined above and wherein within R9 said aryl or heteroaryl ring is optionally substituted by 1 to 5 independently selected radicals from alkyl (C6-6), cyano, halo, (C? -4) -halo substituted alkyl, nitro, -XNR12R12, -X4NR12C (0) OR12, -X4NR12C (0) NR12R12, -X4NR12C (NR12) NR12R12, -X4OR12, -X4SR12, -X4C (0) R12, -X4C (0) OR12, -X4C (0) NR12R12, -X4S (O) 2NR12R12, -X4P (0) (OR3) OR12, -X40P (0) (OR3) OR12, -X4OC (0) R13, -X4NR12C (O) R13, -X4S (0) R13, -X4S (0) 2R13 wherein X4, R12 and R13 are as defined above; and R11 is -X5X6R18, where X5 is -C (0) -, -C (0) C (0) - or
-S (0) 2-, X6 is a bond, -0- or -NR19-, wherein R19 is hydrogen or alkyl (C? _6) and R18 is (i) alkyl (C? _? 0) optionally substituted by cyano, halo, nitro, -NR12R12, -NR12C (0) OR12, -NR12C (0) NR12R12, -NR12C (NR12) NR12R12, -OR12, -SR12, -C (0) OR12, -C (0) NR12R12, -S (0) 2NR12R12, -P (O) (OR12) OR12, OP (O) (OR12) OR12, -NR12C (0) R13, -S (0) R13, -S (0) 2R13, -C ( 0) R13, -OR20, -SR20, -S (0) R20, -S (0) 2R20, -C (0) R20, -C (0) OR20, C (O) NR20R21, -NR20R21, -NR21C ( O) R20, -NR21C (O) OR20, -NR21C (O) NR20R21 or -NR21C (NR21) NR20R21, wherein R12 and R13 are as defined above, R20 is cycloalkyl (C3.?2) alkyl (C0-s) ), heterocycloalkyl (C3-X2) alkyl (C0-6., aryl (C6-? 2) alkyl (C0-e). heteroaryl (C5-? 2) alkyl (CoA / bicycloaryl (C9-? 2) alkyl (CoA or heterobicycloaryl (C8-? 2) alkyl (Co-ß) and R21 in each occurrence independently is hydrogen or (C? -6) alkyl or (ii) (C3-i2) cycloalkyl (C0-6) alkyl / (C3-heterocycloalkyl) .
12) (C0-6) alkyl, aryl (C6-? 2) (C0-6) alkyl. heteroaryl (C5.12) alkyl (Co-6) bicycloaryl (C9-? 2) alkyl (CoA or heterobicycloaryl (C8-? 2) alkyl (Co-e) or (iii) cycloalkyl (C3_6) alkyl. .6), (C3-6) heterocycloalkyl (C0-6, phenylalkyl (Co-e) or heteroaryl (C5-6) alkyl (Co-e) wherein said cycloalkyl, heterocycloalkyl, phenyl or heteroaryl is substituted by -X4OR22 , -X4SR22, -X4S (0) R22, -X4S (0) 2R22, -X4C (0) R22, -X4C (0) OR22, -X4C (O) NR22R23, -X4NR22R23, -X4NR23C (O) R22, - X4NR23C (0) OR22, -X4NR23C (0) NR2R23 or -X4NR23C (NR23) NR22R23, wherein X4 is as defined above, R22 is cycloalkyl (C6-6) alkyl (CoA, heterocycloalkyl (C3.
6) alkyl (Co-ß) / phenylalkyl (C0-6) or heteroaryl (C5_6) alkyl (C0-6) and R23 in each occurrence independently is hydrogen or alkyl (C? 6), wherein within R11 any system of present alicyclic or aromatic ring can be further substituted by 1 to 5 radicals independently selected from alkyl (C? _6), alkylidene (C? _6), cyano, halo, halo (C? -4) halo-substituted alkyl, nitro, - X4NR12R12, X4NR12C (0) OR12, -X4NR12C (0) NR12R12, -X4NR12C (NR12) NR12R12, -X4OR12, -X4SR12, -X4C (0) OR12, -X4C (0) NR12R12, -X4S (O) 2NR12R12, X4P (0) (OR3) OR12, -X4OP (0) (OR3) OR12, -X4OC (0) R13, -X4NR12C (O) R13, -X4S (0) R13, -X4S (0) 2R13 and -X4C (0 ) R13, wherein X4, R12 and R13 are as defined above, and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers, and the pharmaceutically acceptable salts thereof. particular, the present invention relates to a pharmaceutical composition ica containing a compound of Formula I or an N-oxide derivative, prodrug derivative, single isomer or mixture of isomers; or a pharmaceutically acceptable salt thereof in admixture with one or more suitable excipients. In another particular embodiment, the present invention relates to a method for treating a disease in an animal in which the inhibition of a cysteine protease can be avoided, inhibiting or diminishing the pathology and / or symptomatology of the disease, whose method comprises administering to an animal a therapeutically effective amount of the compound of Formula I or an N-oxide derivative, prodrug derivative, single isomer or mixture of isomers or a pharmaceutically acceptable salt thereof. In another particular embodiment, the present invention relates to processes for preparing compounds of Formula I and the N-oxide derivatives, prodrug derivative, protected derivatives, individual isomers and mixtures of isomers and pharmaceutically acceptable salts thereof as established in the "Detailed Description of the Invention". In another particular embodiment, the present invention relates to a compound of Formula (III):
(III) in which: Rl is a group of Formula (a) or (b)
(a) (b)
where :
X1 and X3 independently are -C (O) - or -S (0) 2- / X2 is -CR8R9-, -CH2CR8R9- or -CR8R9CH2- and X4 is -CHR10-, -CH2CHR10- or -CHR10CH2-, wherein R8 is hydrogen or (C? -6) alkyl, R9 is (i) (C? -6) alkyl or halo (substituted? -C6) alkyl optionally substituted with -OR11 , -SR11, S (0) Rn, -S (0) 2RA -CÍOJR11, -C (0) ORu, -NRX1R12, -NR12C (O) OR11, -C (0) NRnR12, -SYOJaNR ^ R12, -NR12C (O) NR1XR12 or -NR12C (NR12) NR ^ R12, wherein R11 is hydrogen, alkyl (C6-6), cycloalkyl (C3-12) alkyl (C0-3), heterocycloalkyl (C3_2) alkyl (C0-) 3), aryl (C6-12) alkyl (C0-3) or heteroaryl (C5_? 2) alkyl (C0_3) and R12 is hydrogen or alkyl (C? 6) or (ii) cycloalkyl (C3-i2) alkyl (C0) -3), heterocycloalkyl (C3-? 2) alkyl (C0-3), aryl (C6-? 2) alkyl (C0-3), heteroaryl (C5-? 2) alkyl (C0_3), policiclaril (C9_12) alkyl (C0-3) or heteropolycycloaryl (C8_? 2) (C0_3) alkyl optionally substituted with R13, -X5OR13, -X5SR13, -S (0) R13, -S (0) 2R13, -C (0) R13, -C (0) OR13, -X5NR13R14, -X5NR14C (O) OR13, -C (0) NR13R14, -S (0) 2NR13R14, -NR14C (O) NR13R14 or -NR14C (NR14) NR13R14, wherein X5 is a bond or methylene, R13 is (C3_2) cycloalkyl (C0-3) alkyl, (C3_) heterocycloalkyl, (C0-3) alkyl, (C6-12) aryl (C0-3) alkyl, (C5-12) heteroaryl (C0-3), polycycloaryl (C9-? 2) alkyl (C0-3) or heteropolycycloaryl (C8-12) alkyl (C0-3) and R14 is hydrogen or alkyl (C? -6), or (iii) together with R5 when X2 is -CH9- forms trimethylene, tetramethylene or phenylene-1,2-dimethylene, optionally substituted with 1 or 2 hydroxy, oxo, (C? -4) alkyl or methylene; wherein any of 1 to 3 ring atoms of any aromatic ring with available vanes comprising R9 is optionally independently substituted with halo, nitro, cyano, (C? -6) alkyl, halo-substituted (C? -6) alkyl, - OR15, -C (0) R15, -C (0) OR15, -C (0) NR15R15, S (0) 2NR15R15, -X5NR15R15, -X5NR15C (O) OR15, -X5NR15C (0) NR15R15 or -X5NR15C (NR15NR15R15 , wherein X5 is as defined above and each R15 independently is hydrogen or alkyl (C? _6), and R10 is hydrogen or alkyl (C? -4); R5 and R7 are independently hydrogen, alkyl (C? -6) or as defined above, and Rs is -X6X7R16 wherein X6 is -C (O) - or -S (0) 2-, X7 is a bond -O- or -NR17-, wherein R17 is hydrogen or alkyl ( Ci-e), and R16 is (i) alkyl (C? -6) or halo-substituted alkyl (C? -6) optionally substituted with -OR11, -SR11, -S (0) R1: L, -S ( 0) 2RA
-C (0) Ru, -C (0) 0Rn, -NR ^ R12, -NR12C (0) OR11, -C (O) NRX1R12,
## STR4 ## wherein R.sup.11 and R.sup.12 are as defined above, or (ii) (C.sub.3-6) cycloalkyl (C.sub.3-) alkyl, (C.sub.3-6) alkyl (C.sub.3-6) alkyl -3), aryl (C6-i2) alkyl (C0-3), heteroaryl (C5_12) alkyl (C0-3), polycycloaryl (C9-12) alkyl (C0-3) or heteropolycycloaryl (C8-12) alkyl (C0) -3) optionally substituted with 1 to 2 of R13, -X5OR13, -X5SR13, -S (0) R13, -S (0) 2R13, -C (0) 0R13, -X5NR13R14, -X5NR14C (O) OR13, - C (0) NR13R14, -NR14C (0) NR13R14 or -NR14C (NR14) NR13R14, wherein X5, R13 and R14 are as defined above; wherein any of 1 to 3 ring atoms of any aromatic ring with available valences comprising R16 is optionally independently substituted with halo, nitro, cyano (C6-6) alkyl, halo-substituted alkyl (C6-6) -OR15, - C (0) R15, -C (0) OR15, -C (0) NR15R15, -S (0) 2NR15R15, -X5NR15R15, -X5NR15C (O) OR15, -X5NR15C (0) NR15R15, or -X5NR15C (NR15) NR15R15, wherein R5 and R15 are as defined above; R2 is hydrogen, or (C? -6) alkyl as defined below; R3 is hydrogen, alkyl (C? -? 0), or as defined below; and R4 is (i) hydrogen, (ii) alkyl (d-6) or halo-substituted alkyl (Cx-6) optionally substituted with -OR11, -SR11, -SÍOJR11, -S (0) 2RA-CÍOJR11, -CÍOJOR11 , NRX1R12, -NR12C (O) OR11, -C (0) NR11R12, -NR ^ C ^ NR ^ R12 or -NR12C (NR12) NR1XR12, wherein R11 and R12 are as defined above, or (iii) cycloalkyl ( C3_ 12) (C0-3) alkyl, (C3-i2) heterocycle (C0-3) alkyl, (C6-? 2) aryl (C0-3) alkyl, (C5_2) heteroaryl (C0-3) alkyl, polycycloaryl (C9-? 2) (C0-3) alkyl or heteropolycycloaryl (C8_)
12) (C0-3) alkyl optionally substituted with R13, -X5OR13, X5SR13, -S (0) R13, -S (0) 2R13, -C (0) OR13, -X5NR13R14,
X5NR14C (0) OR13, -C (0) NR13R14, -NR14C (O) NR13R14 or NR14C (NR14) NR13R14, wherein X5, R13 and R14 are as defined above; or (iv) together with R2 forms trimethylene, tetramethylene or phenylene-1,2-dimethylene, optionally substituted with hydroxy, oxo, alkyl (C? -4) or methylene or (v) together with R3 forms ethylene, trimethylene or tetramethylene; wherein any of 1 to 3 ring atoms of any aromatic ring with available valences comprising R4 is optionally independently substituted with halo, nitro, cyano, (C? -6) alkyl, halo-substituted (C? -6) alkyl, OR15 , -C (0) R15, -C (0) OR15, -C (0) NR15R15, -S (O) 2NR15R15, -X5NR15R15 -X5NR15C (0) OR15, -X5NR15C (0) NR15R15 or -X5NR15C (NR15) NR15R15, wherein X5 and R15 are as defined above; and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers; and the pharmaceutically acceptable salts thereof. In another particular embodiment, the present invention relates to a method for treating a disease in an animal in which the activity of cathepsin S contributes to the pathology and / or symptomatology of the disease, which method comprises administering to an animal an amount Therapeutically effective of a compound of Formula I:
(I) in which: R2 is a group of Formula (a) or (b):
(a) (b)
wherein: X1 and X2 are independently -C (O) - or -CH2S (0) 2-; R5 and R6 are hydrogen or alkyl (C? _6); R7 and R8 are hydrogen or alkyl (C? _6) or as defined below; R9 and R10 are independently (i) alkyl (C? _6) optionally substituted with cyano, halo or nitro or (ii) a group selected from -X3NR12R12 '-X3NR12C (O) OR12,
X3NR12C (0) NR12R12, -X3NR12C (NR12) NR12R12, -X3OR12, -X3SR12,
X3C (0) OR12, -X3C (0) NR12R12, -X3S (O) 2NR12R12, -X3P (O) (OR12) OR12, -X3OP (0) (OR12) OR12, -X3NR12C (0) R13, -X3S ( 0) R13, -X3S (0) 2R13,
X3C (0) R13, -X3C (0) R14, -X3C (0) OR14, -X3OC (0) R14, -X3NR15C (O) OR14, -X3NR15C (0) OR14, -X3C (0) NR14R15, -X3S (O) 2NR14R15, -X3NR15C (O) NR14R15, -X3NR15C (NR15) NR14R15, -X4SR14 -X4S (O) R14 -X4S (0) 2R14, -X4OR14, or -X4NR14R15, wherein X3 is alkylene (C? 6 ), X4 is a bond or alkylene (C? -6), R12 in each occurrence is independently hydrogen, alkyl (C? -6) or halo-substituted alkyl (C? _3), R13 is alkyl (C? _6) or Halo-substituted alkyl (C? -3), R14 is (C3-? 2) alkylcycloalkyl. { C0-ß). Heterocycloalkyl (C3.
12) alkyl (Co-ß), aryl (C6-? 2) alkyl. { C0.e), heteroaryl (C5-12) alkyl (C0-6), polycycloaryl (C9-? 2) alkyl (C0-6) or heteropolycycloaryl (C8_i2) alkyl (Co-e) and R15 is hydrogen or alkyl (C ? _6) and wherein within R14 said cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or heteropolycycloaryl ring optionally are substituted by a group selected from -R16, -X4OR16, -X4SR16, -X4S (0) R16, -X4S (0 ) 2R16, -X4C (0) R16, -X4C (0) OR16, -X4OC (0) R16, -X4NR16R17, -X4NR17C (0) R16, -X4NR17C (O) OR16, -X4C (O) NR16R17,
X4S (0) 2NR16R17, -X4NR17C (0) NR16R17 or -X4NR17C (NR17) NR16R17, wherein X4 is a bond or alkylene (C? -6), R16 is hydrogen or alkyl (C? -6) and R17 is cycloalkyl (C3-? 2) (C0-6) alkyl (C3-? 2) alkyl (Co-ß) / aryl (C6-2) alkyl (Co-ß) / heteroaryl (C5_? 2) alkyl (Co-) e) polycycloaryl (C9-12) alkyl (CoA or heteropolycycloaryl (C8-? 2) alkyl (Co-e) or (iii) a group selected from cycloalkyl (C3-? 2) alkyl (C0-6 .. heterocycloalkyl (C3_2) alkyl (C0.6), aryl (C6-? 2) alkyl (C0-6) heteroaryl (C5-? 2) alkyl (C0-6) polycycloaryl (C9_? 2) alkyl (C0) -6 and heteropolycycloaryl (C8-y2) alkyl (Co-ß) wherein said cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or heteropolycycloaryl ring is optionally substituted by a group selected from -R16, -X4OR? E, -X4SR16, -X4S (0) R16, -X4S (0) 2R16, -X4C (0) R16, -X4C (0) OR16, -X40C (0) R16, -X NR16R17, -X4NR17C (O) R16, X4NR17C (0) OR16, -X4C (0) NR16R17, -X 4S (O) 2NR16R17, -X4NR17C (O) NR16R17 or -X4NR17C (NR17) NR16R17, wherein X4, R16 and R17 are as defined above; wherein within R9 and / or R10 any present alicyclic or aromatic ring system can be further substituted by 1 to 5 independently selected radicals from alkyl (d-6), alkylidene (d-6), cyano, halo, alkyl ( C? -4) halo-substituted, nitro, -X4NR12R12, X4NR12C (0) OR12, -X4NR12C (0) NR12R12, -X4NR12C (NR12) NR12R12, -X4OR12, -X4SR12, -X4C (0) OR12, -X4C ( 0) NR12R12, -X4S (O) 2NR12R12, X4P (0) (OR4) OR12, -X OP (0) (OR12) OR12, -X40C (0) R13, -X4NR12C (O) R13, -X4S (0) R13, -X4S (0) 2R13 and -X4C (0) R13, wherein X4, R12 and R13 are as defined above or R9 taken together with R7 and / or R10 taken together with R8 form trimethylene, tetramethylene or phenylene 1,2-dimethylen, optionally substituted with hydroxy, oxo or methylene; and R11 is -X5X6R18, wherein X5 is -C (O) -, -C (0) C (0) - or -S (0) 2-, X6 is a bond, -O- or -NR19-, where R19 is hydrogen or alkyl (d-6) and R18 is (i) (C? -10) alkyl optionally substituted by cyano, halo, nitro, -NR12R12, -NR12C (0) OR12, -NR12C (0) NR12R12, -NR12C (NR12) NR12R12, -OR12, -SR12, -C (0) OR12, -C (0) NR12R12, -S (0) 2NR12R12, -P (O) (OR12) OR12,
OP (O) (OR12) OR12, -NR12C (0) R13, -S (0) R13, -S (0) 2R13, -C (0) R13, -OR20, -SR20, -S (0) R20, -S (0) 2R20, -C (0) R20, -C (0) OR20, C (O) NR20R21, -NR20R21, -NR21C (O) R20, -NR21C (O) OR20, -NR21C (O) NR20R21 or -NR21C (NR21) NR20R21, wherein R12 and R13 are as defined above, R20 is (C3-? 2) alkylcycloalkyl (CoA heterocycloalkyl (C3_i2) alkyl (Co-e) aryl (C6-? 2) alkyl (dA) heteroaryl (C5-? 2) alkyl (CoA / bicycloaryl (C9-i2) alkyl (Co-ß) or heterobicycloaryl (C8-?) alkyl (Co-e) and R21 in each occurrence independently is hydrogen or alkyl ( C? -6) or (ii) (C3-? 2) cycloalkyl (Co-β) alkyl, (C3-12) heterocycloalkyl (Co-e) aryl (C6-? 2) alkyl (CoA heteroaryl (C5. 12) alkyl (Co-e), bicycloaryl (C9-?) Alkyl (C0-ß) or heterobicycloaryl (C8_? 2) alkyl (C0-6) or (iii) cycloalkyl (C3_6) alkyl (Co-e) heterocycloalkyl (C3-6) alkyl (dA / phenylalkyl (Co-e) or heteroaryl (C5-6) alkyl (Co-ß) wherein said cycloalkyl, heterocycloalkyl, phenyl or heteroaryl or is replaced by -X4OR22, -X4SR22, -X4S (0) R22, -X4S (0) 2R22, -X4C (0) R22, -X4C (0) OR22, -X4C (O) NR22R23, -X4NR22R23, -X4NR23C (O) R22, -X4NR23C (0) OR22, -X4NR23C (0) NR22R23 or -X4NR23C (NR23) NR22R23, wherein X4 is as defined above, R22 is cycloalkyl (C3_e) alkyl (Co-β). heterocycloalkyl (C3.6) alkyl (C0-6). phenylalkyl (Co-e) or heteroaryl (C5-6) alkyl. { C0.6) and R23 in each occurrence independently is hydrogen or alkyl (d-6); wherein within R11 any present alicyclic or aromatic ring system can be further substituted by 1 to 5 independently selected radicals from alkyl (C? _6), alkylidene (d-6) cyano, halo, alkyl (-4) halo- substituted, nitro, -X4NR12R12, -X4NR12C (O) OR12, X4NR12C (0) NR12R12, -X4NR12C (NR12) NR12R12, -X4OR12, -X SR12,
X4C (0) OR12, -X4C (0) NR12R12, -X4S (O) 2NR12R12, -X4P (O) (OR3) OR12, -X4OP (0) (OR3) OR12, -X4OC (0) R13, -X4NR12C ( O) R13, -X4S (0) R13, X4S (0) 2R13 and -X4C (0) R13, wherein X4, R12 and R13 are as defined above; R2 is hydrogen or alkyl (d-6) or as defined below; R3 is hydrogen, alkyl (CiA or as defined below, and R4 is (i) hydrogen or (C? -6) alkyl, wherein said alkyl is optionally substituted with cyano, halo, nitro, -NR12R12, -NR12C ( 0) OR12, -NR12C (O) NR12R12, -NR12C (NR12) NR12R12, -OR12, -SR12, -C (0) OR12, -C (0) NR12R12, -S (O) 2NR12R12, -P (O) (OR12) OR12, -OP (O) (OR12) OR12, -NR12C (0) R13, -S (0) R13, -S (0) 2RA -C (0) R13, -OR14, -SR14, -S (0) R14, -S (0) 2R14, -C (0) R14, -C (0) OR14, -OC (0) R14, -NR14R15, -NR15C (0) R14, -NR15C (O) OR14 , -C (0) NR14R15 -S (O) 2NR14R15, -NR15C (0) NR14R15 or -NR15C (NR15) NR14R15, wherein R12, R13, R14, and R15, are as defined above, or (ii) a group selected from cycloalkyl (C3-i2) alkyl (CoA, heterocycloalkyl (C3_12) alkyl (C0_6), aryl (C6-? 2) alkyl (dA / heteroaryl (C5_? 2) alkyl (CoA / polycycloaryl (C9-? 2) alkyl (Co-ß) and heteropolycycloaryl (C8_? 2) alkyl (Co-e) wherein said cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or heteropolyol ring Chloroaryl is optionally substituted by a group selected from -R16, X4OR16, -X4SR16, -X4S (0) R16, -X4S (0) 2R16, -X4C (0) R16, -X4C (0) OR16, -X4OC ( 0) R16, -X4NR16R17, -X4NR17C (0) R16, -X4NR17C (O) OR16, XC (0) NR16R17, -X4S (0) 2NR16R17, -X4NR17C (O) NR16R17 or X4NR17C (NR17) NR16R17, wherein X4 , R16 and R17 are as defined above; wherein within R9 and / or R10 any present aromatic alicyclic ring system can be further substituted by 1 to 5 independently selected radicals from alkyl (C? _6), alkylidene (C? -6), cyano, halo, alkyl ( C? -4) halo-substituted, nitro, -X4NR12R12, X4NR12C (0) OR12, -X4NR12C (0) NR12R12, -XNR12C (NR12) NR12R12, -X4OR12, -X4SR12, -X4C (0) OR12, -X4C ( 0) NR12R12, -X4S (O) 2NR12R12, X4P (0) (OR3) OR12, -X4OP (0) (OR3) OR12, -X4OC (0) R13, -X4NR12C (O) R13, -X4S (0) R13 , -X4S (0) 2R13 and -X4C (0) R13, wherein X4, R12 and R13 are as defined above or R4 and R2 taken together form trimethylene, tetramethylene or phenylene-1,2-dimethylene, optionally substituted with hydroxy, oxo or methylene, or R 4 Y 3 together with the carbon atom to which both R 4 and R 3 are attached form cycloalkylene (C 3-8) or heterocycloalkylene (C 3-8); or an N-oxide derivative, prodrug derivative, individual isomer and mixtures of isomers; or a pharmaceutically acceptable salt thereof, but excluding the compounds of the formula
wherein R3 and R4 are each hydrogen or alkyl (C? -6), or together with the carbon atom to which they both bind they form cycloalkylene (C3.5); R5 is hydrogen or alkyl (C? -6); R9 is aryl (C6-? 2) alkyl (C? _e), heteroaryl (C5_? 2) alkyl (C? _6), alkyl (C4-5) or cyclohexylmethyl; and R11 is C (0) R18 wherein R18 is heterocycloalkyl (C3-X2), aryl (C6-? 2) alkyl (Co-ß) or heteroaryl (C5-12) alkyl (C0-e) • In another particular embodiment , the present invention relates to the use of a compound of the Formula (I):
(I) in which: R1 is a group of Formula (a) or (b)
(a) (b)
wherein: X1 and X2 are independently -C (O) - or -CH2S (0) 2-; R5 and R6 are hydrogen or alkyl (C? _6); R7 and R8 are hydrogen or alkyl (C? _6) or as defined below; R9 and R10 are independently (i) (C6-6) alkyl optionally substituted with cyano, halo or nitro or (ii) a group selected from -X3NR1 R12 '-X3NR12C (0) OR12, X3NR12C (0) NR12R12, -X3NR12C (NR12) NR1 R12, -X3OR12, -X3SR12,
X3C (0) OR12, -X3C (0) NR12R12, -X3S (O) 2NR12R12, -X3P (0) (OR12) OR12, -X30P (0) (OR12) OR12, -X3NR12C (0) R13, -X3S ( 0) R13, -X3S (0) 2R13, X3C (0) R13, -X3C (0) R14, -X3C (0) OR14, -X3OC (0) R14, -X3NR15C (O) R14, -X3NR15C (0) OR14, -X3C (0) NR14R15, -X3S (O) 2NR14R15, -X3NR15C (0) NR14R15, -X3NR15C (NR15) NR14R15, -X4SR14 -X4S (O) R14 -X4S (0) 2R14, -X4OR14, or - X4NR14R15, wherein X3 is alkylene (C? -6), X4 is a bond or alkylene (C? -6), R12 in each occurrence is independently hydrogen, alkyl (C? -6) or alkyl (d-3) halo -substituted, R13 is alkyl (C? -6) or halo-substituted alkyl (C? -3), R14 is (C3-y2) cycloalkyl (Co-β) alkyl (C3-12) alkyl (C06) alkyl. aryl (C6-? 2) (C0-6) alkyl, heteroaryl (C5.
12) alkyl (Co-β). polycycloaryl (C9-i2) alkyl (Co-ß) or heteropolycycloaryl (C8-? 2) alkyl (C0_6) and R15 is hydrogen or alkyl (C? -6) and wherein within R14 said cycloalkyl, heterocycloalkyl, aryl ring, heteroaryl, polycycloaryl or heteropolycycloaryl is optionally substituted by a group selected from R1S,
X4OR16, -X4SR1S, -X4S (0) R16, -X4S (0) 2R16, -X4C (0) R16, -X4C (0) OR16, -X4OC (0) R16, -X4NR16R17, -X4NR17C (0) R16, -XNR17C (O) OR16, X4C (0) NR16R17, -X4S (0) 2NR16R17, -X4NR17C (O) NR16R17 or X4NR17C (NR17) NR16R17, wherein X4 is a bond or alkylene (C? _6), R16 is hydrogen or alkyl (C? _6) and R17 is (C3_? 2) cycloalkyl alkyl (CoA heterocycloalkyl (C3-y2) alkyl (C0-?) / aryl (C6-? 2) (C0-6) alkyl heteroaryl (C5-? 2) alkyl (CnA # polycycloaryl (C6-? 2) alkyl (C0-e) or heteropolycycloaryl (C8_? 2) (C0-6) alkyl or (iii) a group selected from cycloalkyl (C3.? 2) alkyl (Co-ß) (C3-? 2) -alkyl (C3-? 2) -alkyl (C6-? 2) alkyl (C0-6) heteroaryl (C5-? 2) (C0-6) alkyl, polycycloaryl (C9-? 2) ) (C0-6) alkyl and (C8-12) heteropolycycloalkyl (Co-ß) alkyl wherein said cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or heteropolycycloaryl ring is optionally substituted by a group selected from R16, -X4OR16 , -X4SR16, -X4 S (0) R16, -X4S (0) 2R16, -X4C (0) R16, -X4C (0) OR16, -X4OC (0) R16, -X4NR16R17, -X4NR17C (0) R16, -X4NR17C (O) OR16 , -X4C (0) NR16R17, X4S (0) 2NR16R17, -X4NR17C (0) NR16R17 or -X4NR17C (NR17) NR16R17, wherein X4, R16 and R17 are as defined above; wherein within R9 and / or R10 any present system of alicyclic or aromatic ring present can be further substituted by 1 to 5 independently selected radicals from alkyl (C? -6), alkylidene (Cx-e), cyano, halo, alkyl (C? -4) halo-substituted, nitro, -X4NR12R12, -X4NR12C (0) OR12, -X4NR12C (0) NR12R12,
X4NR12C (NR12) NR12R12, -X40R12, -X SR12, -X4C (0) OR12, -X4C (0) NR12R12, -X4S (0) 2NR12R12, -X4P (0) (OR4) OR12, -X40P (O) ( OR12) OR12, -X4OC (0) R13, -X4NR12C (0) R13, -X4S (0) R13, -X4S (O) 2R13 and -X4C (0) R13, wherein X4, R12 and R13 are as defined above or R 9 taken together with R 7 and / or R 10 taken together with R 8 form trimethylene, tetramethylene or phenylene-1,2-dimethylene, optionally substituted with hydroxy, oxo or methylene; and R11 is -X5X6R18, wherein X5 is -C (0) -, -C (0) C (0) - or -S (0) 2-, X6 is a bond, -O- or -NR19-, where R19 is hydrogen or alkyl (C? _6) and R18 is (i) alkyl (C? -? o) optionally substituted by cyano, halo, nitro, -NR12R12, -NR1 C (0) OR12, -NR12C (0) NR12R12, -NR12C (NR12) NR12R12, -OR12, -SR12, -C (0) 0R12, -C (0) NR12R12, -S (0) 2NR12R12, -P (0) (OR12) OR12, 0P (0) (0R12) 0R12, -NR12C (0) R13, -S (0) R13, -S (0) 2R13, -C (0) R13, -OR20, -SR20, -S (0) R20, -S (0 ) 2R2 °, -C (0) R2 °, -C (0) 0R20, C (O) NR20R21, -NR20R21, -NR21C (0) R20, -NR21C (0) 0R20, -NR21C (O) NR20R21 or - NR21C (NR21) NR20R21, wherein R12 and R13 are as defined above, R20 is cycloalkyl (C3_? 2) alkyl (CoA / heterocycloalkyl (C3-?) Alkyl (Co-ß) / aryl (C6-i2) alkyl ( CnA / heteroaryl (C5-? 2) alkyl (Co-ß), bicycloaryl (C9-i2) alkyl (dA or heterobicycloaryl (C8.12) alkyl (C0-e) and R21 in each occurrence independently is hydrogen or alkyl (d) -6) or (ii) cycloalkyl (C3-? 2) alkyl (Co-e) heterocycloalkyl (C3_ 1) 2) alkyl (Co-β). aryl (C6-? 2) (C0-6) alkyl heteroaryl (C5.12) alkyl. { C0.6), bicycloaryl (C9-? 2) (C0-ß) alkyl or heterobicycloaryl (C8-? 2) alkyl (Co-e) or (iii) (C3-6) cycloalkyl (C0-e) alkyl, heterocycloalkyl (C3-6) (C0-e) alkyl phenylalkyl (Co-ß) or heteroaryl (C5-6) alkyl. { C0-ß). wherein said cycloalkyl, heterocycloalkyl, phenyl or heteroaryl is substituted by -X4OR22, -X4SR22, -X4S (0) R22, -X4S (0) 2R22, -X4C (0) R22, -X4C (0) OR22, -X4C ( 0) NR2R23, -X4NR22R23, -X4NR23C (O) R22, -X4NR23C (0) OR22, -X4NR23C (0) NR22R23 or -X4NR23C (NR23) NR22R23, wherein X4 is as defined above, R22 is (C3-) cycloalkyl e) alkyl (Co-β) heterocycloalkyl (C3.6) alkyl (CoA # phenylalkyl (Co-6) or heteroaryl (C5-6) alkyl (Co-e) and R23 in each occurrence independently is hydrogen or alkyl (C? -6); wherein within R11 any present alicyclic or aromatic ring system can be further substituted by 1 to 5 independently selected radicals from alkyl (C? -6), alkylidene (C? -6), cyano, halo, alkyl (Ci-? 4) halo-substituted, nitro, -X4NR12R12, -X4NR12C (O) OR12, X4NR12C (0) NR12R12, -X4NR12C (NR12) NR12R12, -X4OR12, -X4SR12, X4C (0) OR12, -X4C (0) NR12R12, -X4S (O) 2NR12R12, -X4P (O) (OR3) OR12, -X4OP (0) (OR3) OR12, -X4OC (0) R13, -XNR12C (O) R13, -X4S (0) R13, X4S ( 0) 2R13 and -X4C (0) R13, wherein X4, R12 and R13 are as defined above; R2 is hydrogen or (C? -6) alkyl or as defined below; R3 is hydrogen, alkyl (d-6) or as defined below; and R4 is (i) hydrogen or (C? -6) alkyl, wherein said alkyl is optionally substituted with cyano, halo, nitro, -NR12R12, -NR1C (0) OR12, -NR12C (0) NR12R12, -NR1C ( NR12) NR12R12, -OR12, -SR12, -C (0) 0R12, -C (0) NR12R12, -S (O) 2NR12R12, -P (O) (OR12) OR12, -0P (0) (OR12) OR12 , -NR12C (0) R13, -S (0) R13, -S (0) 2R13, -C (0) R13, -OR14, -SR14, -S (0) R14, -S (0) 2R14, - C (0) R14, -C (0) 0R14, -OC (0) R14, -NR14R15, -NR15C (0) R14, -NR15C (O) OR14, -C (0) NR14R15 -S (0) 2NR14R15 , -NR15C (0) NR14R15 or -NR15C (NR15) NR14R15, wherein R12, R13, R14, and R15, are as defined above or (ii) a group selected from (C3-12) alkylcycloalkyl (CoA) Heterocycloalkyl (C3_12) alkyl (Co-ß) aryl (C6_?) alkyl (Cn-ß), heteroaryl (C5_12) alkyl (C0_6), polycycloaryl (C9_? 2) alkyl (C0-6) and heteropolycycloaryl (C8_) 2) alkyl (Co-β) wherein said cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or heteropolycycloaryl ring is optionally substituted by a group selected from artir of -R16, X4OR16, -X4SR16, -X4S (0) R16, -X4S (0) 2R16, -X4C (0) R16, -X4C (0) OR16, -XOC (0) R16, -X4NR16R17, -XNR17C (0) R16, -X4NR17C (0) R16, X4C (0) NR16R17, -X4S (0) 2NR16R17, -X4NR17C (O) NR16R17 or X4NR17C (NR17) NR16R17, wherein X4, R16 and R17 are as defined above; wherein within R9 and / or R10 any present aromatic alicyclic ring system can be further substituted by 1 to 5 independently selected radicals from alkyl (C? _6), alkylidene (C? -6), cyano, halo, alkyl ( C? -4) halo-substituted, nitro, -X4NR12R12, X4NR12C (0) OR12, -X4NR12C (0) NR12R12, -X4NR12C (NR12) NR12R12, -X4OR12, -X4SR12, -X4C (0) OR12, -X4C ( 0) NR12R12, -X4S (0) 2NR12R12, X4P (0) (OR3) OR12, -X40P (0) (OR3) OR12, -X4OC (0) R13, -X4NR12C (O) R13, -X4S (0) R13 , -X4S (0) 2R13 and -X4C (0) R13, wherein X4, R12 and R13 are as defined above or R4 and R2 taken together form trimethylene, tetramethylene or phenylene-1,2-dimethylene, optionally substituted with hydroxy, oxo or methylene, or R 4 and R 3 together with the carbon atom to which both R 4 and R 3 are attached form cycloalkylene (C 3-8) or heterocycloalkylene (C 3-8); or an N-oxide derivative, prodrug derivative, individual isomer and mixtures of isomers; or a pharmaceutically acceptable salt thereof, but excluding the compounds of the formula
wherein R3 and R4 are each hydrogen or alkyl (d-6) or together with a carbon atom to which they both bind cycloalkylene (C3.5); R5 is hydrogen or alkyl (C? -6); R9 is aryl (C6-i2) alkyl (C6-6), heteroaryl (C5-? 2) alkyl (C6-6), alkyl (C4-5) or cyclohexylmethyl; and R11 is C (0) R18 wherein R18 is (C3-12) heterocycle, aryl (C3-?) alkyl (dA or heteroaryl (C5-? 2) alkyl (C6-6), in the manufacture of a medicament for treating a disease in an animal whose cathepsin S activity contributes to the pathology and / or symptomatology of the disease In another particular embodiment, the present invention relates to a method for treating a disease in an animal in which the activity of the Cathepsin S contributes to the pathology and / or symptomatology of the disease, which method comprises administering to the animal a therapeutically effective amount of a compound of Formula (III):
(III) in which: Rl is a group of Formula (a) or (b) (a) (b)
wherein: X1 and X3 are independently -C (0) - or -S (0) 2, X2 is -CR8R9-, -CH2CR8R9- or -CR8R9CH2- and X4 is -CHR10-,
-CH2CHR10- or -CHR10CH2-, wherein: R8 is hydrogen or alkyl (C? -6), R9 is (i) alkyl (C? _6) or halo-substituted alkyl (C? -6) optionally substituted with -OR11 , -SR11, SÍOJR11, -S. { 0) 2R11. -C (0) R1: L, -C (0) ORu, -NR ^ R12, NR12C (O) OR11, -C (0) NR11R12, -S (0) 2NR11R12, -NR12C (O) NRX1R12 or -NR12C (NR12) NR ^ R12, wherein R11 is hydrogen, alkyl (d-6), cycloalkyl (C3-? 2) alkyl (C0-3), heterocycloalkyl (C3-? 2) alkyl (C0-3), aryl ( C6-? 2) (C0-3) alkyl or (C5-12) heteroaryl (C0-3) alkyl and R12 is hydrogen or alkyl (C? 6) or (ii) (C3-12) cycloalkyl (C0-3) alkyl ) heterocycloalkyl (C3-? 2) alkyl (C0-3), aryl (C6_? 2) alkyl (C0-3), heteroaryl (C5_? 2) alkyl (C0-3), polycycloaryl (C9_? 2) alkyl (C0) -3) or heteropolycycloaryl (C8-? 2) (C0-3) alkyl optionally substituted with -R13, -X5OR13, -X5SR13, -S (0) R13, -S (0) 2R13, -C (0) R13, -C (0) OR13, -X5NR13R14, -X5NR14C (O) OR13, -C (O) NR13R14,
S (0) 2NR13R14, -NR14C (0) NR13R14 or -NR14C (NR14) NR13R14, wherein X5 is a bond or methylene, R13 is (C3-? 2) cycloalkyl (C0-3) alkyl, (C3-? 2) alkyl (C0-3), aryl (C6-? 2) alkyl (C0-3), heteroaryl (C5-? 2) alkyl (C0-3), polycycloaryl (C9-? 2) alkyl (C0-3) or heteropolycycloaryl (C8-? 2) (C0-3) alkyl and R14 is hydrogen or alkyl (C? -6) or (iii) together with R5 when X2 is -CHR9- form trimethylene, tetramethylene or phenylene-2, 2- dimethylene, optionally substituted with 1 to 2 hydroxy, oxo, alkyl (d-4) or methylene; wherein any of 1 to 3 ring atoms of any aromatic ring with available vanes comprising R9 is optionally independently substituted with halo, nitro, cyano, (C? -6) alkyl, (C? -6) -halo substituted alkyl, - OR15, -C (0) R15, -C (0) 0R15, -C (0) NR15R15, -S (0) 2NR15R15, -X5NR15R15, -X5NR15C (0) OR15, X5NR15C (0) NR15R15 or -X5NR15C (NR15 ) NR15R15, wherein X5 is as defined above and each R15 independently is hydrogen or alkyl (C? -6) and R10 is hydrogen or alkyl (C? -4); R5 and R7 are independently hydrogen, (C? -6) alkyl or as defined above; and R6 is -X6X7R16, wherein X6 is -C (0) - or -S (0) 2-, X7 is a bond, -0- or -NR17-, wherein R17 is hydrogen or alkyl (C? -6) ) and R1S is (i) (C6-6) alkyl or halo-substituted alkyl (C6-6) optionally substituted with -OR11, -SR11, S (0) R11, -SYO ^ R11, -C (0) R1X , -C (0) 0Rn, -NRX1R12, -NR12C (0) OR11, -C (0) NRuR12, -NR12C (0) NR11R12 or -NR12C (NR12) NRX1R12, wherein R11 and R12 are as defined above or (ii) (C3-6) cycloalkyl (C0-3) alkyl, (C3-6) heterocycloalkyl (C0_3) alkyl, (C6-? 2) aryl (C0-3) alkyl, (C5-? 2) alkyl heteroaryl ( C0-3), polycycloaryl (C9. 12) (C0-3) alkyl or heteropolycycloaryl (C8_? 2) (C0-3) alkyl optionally substituted with 1 to 2 of -R13, -X5OR13, -X5SR13, -S (0 ) R13, -S (0) 2R13, -C (0) OR13, -X5NR13R14, -X5NR14C (O) OR13,
C (0) NR13R14, -NR14C (0) NR13R14 or -NR14C (NR14) NR13R14, wherein X5, R13 and R14 are as defined above; wherein any of 1 to 3 ring atoms of any aromatic ring with available valences comprising R16 is optionally independently substituted with halo, nitro, cyano, (C? -6) alkyl, halo-substituted (C? -6) alkyl, OR15 , -C (0) R15, -C (0) OR15, -C (0) NR15R15, -S (O) 2NR15R15, -X5NR15R15, -X5NR15C (0) OR15, -X5NR15C (0) NR15R15 or -X5NR15C (NR15 ) NR15R15, wherein X5 and R15 are as defined above; R2 is hydrogen or (C? -6) alkyl or as defined below; R3 is hydrogen, (C1-10) alkyl or as defined below; and R4 is (i) hydrogen, (ii) (C6-6) alkyl or halo-substituted alkyl (Ci-6), optionally substituted with -OR11, -SR11, -S (0) Ru, -SYOJsR11, -C (0) Rp, -C (0) ORxI, -NRX1R12, -NR12C (O) OR11, -C (0) NR ?: LR12, -NR1C (0) NR11R12 or -NR12C (NR12) NR1XR12, wherein R11 and R12 are as defined above or (iii) (C3-12) cycloalkyl (C0-3) alkyl, (C3-12) heterocycloalkyl (C0-3) alkyl, aryl (C6-X2) (C0-3) alkyl, heteroaryl (C5-? 2) (C0-3) alkyl, polycycloaryl (C9-? 2) (C0-3) alkyl or (C8-? 2) heteropolycycloaryl (C0-3) alkyl optionally substituted with -R13, X5OR13, X5SR13, -S (0) R13, -S (0) 2R13, -C (0) OR13, -X5NR13R14, -X5NR14C (O) OR13, -C (0) NR13R14, -NR14C (O) NR13R14 or -NR14C (NR14) NR13R14, wherein X5, R13 and R14 are as defined above or (iv) together with R2 form trimethylene, tetramethylene or phenylene-1,2-dimethylene, optionally substituted with hydroxy, oxo, (C1-4) alkyl or methylene or (v) together with R3 form ethylene, trimethylene or tetramethylene; wherein any of 1 to 3 ring atoms of any aromatic ring with available valences comprising R4 is optionally independently substituted with halo, nitro, cyano, (C? -6) alkyl, halo-substituted (C? -6) alkyl, - OR15, -C (0) R15, -C (0) OR15, -C (0) NR15R15, S (0) 2NR15R15, -X5NR15R15, -X5NR15C (O) OR15, -X5NR15C (O) NR15R15 or -X5NR15C (NR15 ) NR15R15, wherein X5 and R15 are as defined above; or an N-oxide derivative, prodrug derivative, individual isomer and mixtures of isomers; or a pharmaceutically acceptable salt thereof, but excluding the compounds of the formula
wherein R3 and R4 are each hydrogen or alkyl (C? -6) or together with the carbon atom to which they both bind they form cycloalkylene (C3_5); R5 is hydrogen or alkyl (d-6); R9 is aryl (C6_? 2) alkyl. { C? .6), heteroaryl (C5_? 2) alkyl (C? -6), (C4_5) alkyl or cyclohexylmethyl; and R11 is C (0) R18 wherein R18 is (C3-12) heterocycloalkyl, aryl (C6-y2) alkyl. { C0.6) or heteroaryl (C5-12) alkyl (Co-e) - In another particular embodiment, the present invention relates to the use of a compound of Formula (III):
(III) wherein: R1 is a group of Formula (a) or (b)
(a) (b)
wherein: X1 and X3 are independently -C (O) - or -S (0) 2-.
X2 is -CR8R9-, -CH2CR8R9- or -CR8R9CH2- and X4 is -CHR10-, -CH2CHR10- or -CHR10CH2-, wherein: R8 is hydrogen or alkyl (C? -6), R9 is (i) alkyl ( C? -6) or alkyl (halo-substituted CiA optionally substituted with -OR11, -SR11,
SÍOJR11, -S (0) 2R11, -C (0) R1X, -C (0) 0RX1, -NR ^ R12, NR12C (0) OR11, -C (0) NRX1R12, -SYO ^ NR ^ R12, -NR1C (O) NR ^ R12 or -NR12C (NR12) NRX1R12, wherein R11 is hydrogen, alkyl (d-6), cycloalkyl (C3-12) alkyl (C0-3), heterocycloalkyl (C3.12) alkyl (C0-) 3) . aryl (C6-12) alkyl (C0-3) or heteroaryl (C5-12) alkyl (C0-3) and R12 is hydrogen or alkyl (C? -6) or (ii) cycloalkyl (C3-? 2) alkyl ( C0-3) heterocycloalkyl (C3-? 2) alkyl (C0_3), aryl (C6-? 2) alkyl (C0-3), heteroaryl (C5-? 2) alkyl (C0-3), polycycloaryl (C9-? 2 alkyl (C0-3) or heteropolycycloaryl (C8-?) alkyl (C0-3) optionally substituted with -R13, -X5OR13, -X5SR13, -S (0) R13, -S (0) 2R13, -C (0 ) R13, -C (0) 0R13, -X5NR13R14, -X5NR14C (O) OR13, -C (O) NR13R14, S (0) 2NR13R14, -NR14C (0) NR13R14 or -NR14C (NR14) NR13R14, wherein X5 is a bond or methylene, R13 is (C3-y2) cycloalkyl (C0-3) alkyl, (C3-y2) heterocycle (C0-3) alkyl, (C6-? 2) aryl (C0-3) alkyl, heteroaryl ( C5_? 2) (C0-3) alkyl, polycycloaryl (C9-? 2) (C0-3) alkyl or heteropolycycloaryl (C8-? 2) (C0-3) alkyl and R14 is hydrogen or alkyl (C? -6) or (iii) together with R5 when X2 is -CHR9- form trimethylene, tetramethylene or phenylene-1,2-dimethylene, optionally substituted with 1 to 2 hydroxy, oxo, (1-4C) alkyl or methylene; wherein any of 1 to 3 ring atoms of any aromatic ring with available vanes comprising R9 is optionally independently substituted with halo, nitro, cyano, alkyl (Ci-g), halo-substituted alkyl (d-6), -OR15, -C (0) R15, -C (0) OR15, C (0) NR15R15, -S (0) 2NR15R15, -X5NR15R15, -X5NR15C (O) OR15,
X5NR15C (0) NR15R15 or -X5NR15C (NR15) NR15R15, wherein X5 is as defined above and each R15 independently is hydrogen or alkyl (C? _6) and R10 is hydrogen or alkyl (C? _4); R5 and R7 are independently hydrogen, alkyl (d-6) or as defined above; and R6 is -X6X7R16, wherein X6 is -C (0) - or -S (0) 2-, X7 is a bond, -O- or -NR17-, wherein R17 is hydrogen or alkyl (C? _6) and R16 is (i) alkyl (d-6) or halo-substituted alkyl (C? _6) optionally substituted with -OR11, -SR11,
S (0) RA -S (0) 2RX1. -C (0) R1: L, -CIOJOR11, -NRX1R12, -NR12C (O) OR11, -C (0) NRX1R12, -NR12C (0) NR11R12 or -NR12C (NR12) NR1XR12, wherein R11 and R12 are as was previously defined, or (ii) cycloalkyl (Ci-6) alkyl (C0-3), heterocycloalkyl (C3_6) alkyl (C0-3), aryl (C6_12) alkyl (C0_3), heteroaryl (C5_2) alkyl (C0) -3), polycycloaryl (C9. 12) alkyl (C0-3) or heteropolycycloaryl (C8-i2) alkyl (C0-3) optionally substituted with 1 to 2 of -R13, -X5OR13, -X5SR13, -S (0) R13, -S (0) 2R13, -C (0) OR13, -X5NR13R14, -X5NR14C (O) OR13, C (0) NR13R14, -NR14C (0) NR13R14 or -NR14C (NR14) NR13R14, wherein X5, R13 and R14 are as defined above; wherein any of 1 to 3 ring atoms of any aromatic ring with available valences comprising R16 is optionally independently substituted with halo, nitro, cyano, (C? -6) alkyl, halo-substituted (C? -6) alkyl, OR15 , -C (0) R15, -C (0) OR15, -C (O) NR15R15, -S (O) 2NR15R15, -X5NR15R15, -X5NR15C (0) OR15, -X5NR15C (0) NR15R15 or -X5NR15C (NR15 ) NR15R15, where X5 and R15 are as defined above; R2 is hydrogen or (C? -6) alkyl or as defined below; R3 is hydrogen, alkyl (C? -? 0) or as defined below; and R4 is (i) hydrogen (ii) (C6-6) alkyl or halo-substituted (Ci-6) alkyl, optionally substituted with -OR11, -SR11, -S (0) R1X, -S (0) 2R11 , -C (0) Ru, -C (0) 0Rn, -NR ^ R12, -NR12C (O) OR11, -CYOINR ^ R12, -NR12C (0) NR11R12 or -NR12C (NR12) NR1XR12, wherein R11 and R12 are as defined above or (iii) (C3-12) cycloalkyl (C0-3) alkyl / (C3-12) heterocycle (C0-3) alkyl, (C6-12) aryl (C0-3) alkyl, heteroaryl (C5-? 2) (C0-3) alkyl, polycycloaryl (C9-? 2) (C0-3) alkyl or (C8-12) heteropolycycloaryl (C0-3) alkyl optionally substituted with -R13, X5OR13,
X5SR13, -S (0) R13, -S (0) 2R13, -C (0) OR13, -X5NR13R14, -X5NR14C (O) OR13, -C (0) NR13R14, -NR14C (0) NR13R14 or -NR14C ( NR14) NR13R14, wherein X5, R13 and R14 are as defined above or (iv) together with R2 form trimethylene, tetramethylene or phenylene-1,2-dimethylene, optionally substituted with hydroxy, oxo, alkyl (C? -4) or methylene or (v) together with R3 form ethylene, trimethylene or tetramethylene; wherein any of 1 to 3 ring atoms of any aromatic ring with available valences comprising R4 is optionally independently substituted with halo, nitro, cyano, (C? -6) alkyl, halo-substituted (C? -6) alkyl, - OR15, -C (0) R15, -C (0) OR15, -C (0) NR15R15, S (0) 2NR15R15, -X5NR15R15, -X5NR15C (0) OR15, -X5NR15C (O) NR15R15 or -X5NR15C (NR15 ) NR15R15, wherein X5 and R15 are as defined above; or an N-oxide derivative, prodrug derivative, individual isomer and mixtures of isomers; or a pharmaceutically acceptable salt thereof, but excluding the compounds of the formula
wherein R3 and R4 are each hydrogen or alkyl (C? -6) or together with the carbon atom to which they both bind cycloalkylene (C3.8); R5 is hydrogen or alkyl (C? _6); R9 is aryl (C6-i2) alkyl (C? -S), heteroaryl (C5-12) alkyl (C? _6), (C4_5) alkyl or cyclohexylmethyl; and R11 is C (O) R18 wherein R18 is heterocycloalkyl (C3_? 2), aryl (C6-? 2) alkyl (Co-ß) or heteroaryl (C5-? 2) alkyl (Co-ß) in the preparation of a medicament for treating a disease in an animal in which the activity of cathepsin S contributes to the pathology and / or symptomatology of the disease. DETAILED DESCRIPTION OF THE INVENTION Definitions: Unless stated otherwise, the following terms used in the specification and claims are defined for the purposes of this Application and have the meaning given in this Section: "Alicyclic" means a residue characterized by the arrangement of carbon atoms in closed non-aromatic ring structures that have properties that resemble those of the aliphatic and may be saturated or partially unsaturated with two or more double or triple bonds. "Aliphatic" means a residue characterized by a straight or branched chain order of the constituent carbon atoms and may be saturated or partially unsaturated with two or more double or triple bonds. "Alkyl" indicated alone, means a saturated or unsaturated, straight or branched aliphatic radical having the number of carbon atoms indicated (eg, alkyl (C? -6) includes methyl, ethyl, propyl, isopropyl, butyl, sec-butyl , isobutyl, tert-butyl, vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methylallyl, ethynyl, 1-propynyl, 2-propynyl, and the like).
Alkyl, indicated as part of a large radical (eg, as an arylalkyl) means a saturated or unsaturated straight or branched aliphatic divalent radical having the indicated number of atoms or when indicated 0 atoms means a bond (eg, alkyl (C0-) 3) of cycloalkyl (C3-? 2) alkyl (C0-3) means a bond, methylene, ethylene, trimethylene, 1-methylethylene, or the like). "Alkylene", unless otherwise indicated, means a divalent, aliphatic, saturated or unsaturated straight or branched radical having the number of carbon atoms indicated (e.g., alkylene (C? _6) includes methylene
(-CH2-), ethylene (-CH2CH2-), trimethylene (-CH2CH2CH2-), 2-methyltrimethylene (-CH2CH (CH3) CH2-), tetramethylene (-CH2CH2CH2CH2-), 2-butenylene (-CH2CH = CHCH2-) , 2-methyltetramethylene (-CH2CH (CH3) CH2CH2-), pentamethylene (-CH2CH2CH2CH2CH2-) and the like). For example, the case where R5 is hydrogen and R9 taken together with R7 optionally forms trimethylene substituted, which is illustrated by the following:
wherein R is an optional hydroxy or oxo group and X1 and R11 are as defined in the summary of the invention.
"Alkylidene" means a straight or branched saturated or unsaturated aliphatic radical having the number of carbon atoms indicated (e.g., alkylidene (Ci-6) includes methylene (: CH2), ethylidene (: CHCH3), isopropylidene (: C (CH3) 2), propylidene (: CHCH2CH3), allylidene (: CHCH: CH2) and the like. "Amino" means the radical -NH2. Unless indicated otherwise, the compounds of the invention containing amino residues include protected derivatives thereof. Suitable protecting groups for amino residues include acetyl, tert-butoxycarbonyl, benzyloxycarbonyl and the like. "Animal" includes humans, non-human mammals (e.g. dogs, cats, rabbits, cattle, horses, sheep, goats, pigs, deer, etc.) and non-mammals (e.g. birds, etc.). "Aryl" means a monocyclic or bicyclic ring assembly (fused or linked by a single bond) containing the total number of ring carbon atoms indicated, wherein each ring comprises 6 ring carbon atoms and is aromatic or when merges with a second ring forms a set of aromatic ring. For example, aryl (C6-? 2) includes phenyl, naphthyl and biphenyl. "Aromatic" means a residue in which the constituent atoms make up an unsaturated ring system, all the atoms in the ring system are sp2 hybridized and the total number of pi electrons equals 4n + 2. "Carbamoyl" means the radical - C (0) NH2. Unless indicated otherwise, compounds of the invention containing carbamoyl residues include protected derivatives thereof. Suitable protecting groups for the carbamoyl residues include acetyl, tert-butoxycarbonyl, benzyloxycarbonyl and the like and both protected and unprotected derivatives fall within the scope of the invention. "Carboxi" siignifies the radical -C (0) OH. Unless indicated otherwise, compounds of the invention containing carboxy residues include protected derivatives thereof. Suitable protecting groups for carboxy residues include benzyl, tert-butyl and the like. "Cycloalkyl" means a monocyclic, saturated or partially unsaturated ring, a bicyclic ring assembly (linked directly by a single or fused bond) or a bridged polycyclic ring assembly containing the number of indicated ring carbon atoms and any carbocyclic ketone, thioketone or iminoketone derived therefrom (eg, cycloalkyl (C3-? 2) includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, 2, 5-cyclohexadienyl, bicyclohexylyl, cyclopentylcyclohexyl, bicyclo [2.2.2] octyl, adamantan-1 il, decahydronaphthalenyl, oxocyclohexyl, dioxocyclohexyl, thiocyclohexyl, 2-oxobicyclo [2.2.1] hept-1-yl, etc.). "Cycloalkylene" means a monocyclic, saturated or partially unsaturated ring or bridged polycyclic ring assembly containing the number of indicated ring carbon atoms and any carbocyclic ketone, thioketone or iminoketone derived therefrom. For example the case where R9 and R5 together with the carbon atom to which both R9 and R5 are attached form cycloalkylene (C3.8) ", include, but are not limited to the following:
in which X1 and R7 are as defined in the Summary of the
Invention. "Disease" specifically includes any unhealthy condition of an animal or part thereof and includes an unhealthy condition that may be caused or incident to medical or veterinary therapy applied to that animal, i.e., the "side effects" of such therapy.
"Guanidino" means the radical -NHC (NH) NH2. Unless otherwise indicated, the compounds of the invention containing guanidino residues include protected derivatives thereof. Suitable protecting groups for the amino residues include acetyl, tert-butoxycarbonyl, benzyloxycarbonyl and the like. "Halo" means fluorine, chlorine, bromine or iodine. "Halo-substituted alkyl", as a group or part of a group means "alkyl" substituted by one or more "halo" atoms, as such term is defined in this Application. Halo substituted alkyl includes haloalkyl, dihaloalkyl, trihaloalkyl, perhaloalkyl and the like (eg, halo-substituted alkyl (C? -3) includes chloromethyl, dichloromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, perfluoroethyl, 2, 2, 2-trifluoro-1,1-dichloroethyl and the like). "Heteroaryl" means aryl, as defined in this Application, provided that one or more of the carbon atoms member of the indicated ring is replaced by heteroatom residues selected from -N :, -NR-, -O- or -S- , wherein R is hydrogen, alkyl (d-6) or a protecting group and each ring contained therein is comprised of 5 to 6 ring member atoms. For example, heteroaryl (C5-? 2) as used in this Application includes benzofuryl, benzooxazolyl, benzothiazolyl, [2, 4 '] bipyridinyl, carbazolyl, carbolinyl, chromenyl, cinnolinyl, furazanyl, furyl, imidazolyl, indazolyl, indolyl, indolizinyl isobezofuryl, isochromenyl, isooxazolyl, isoquinolyl, isothiazolyl, naphthyridinyl, oxazolyl, perimidinyl, 2-phenylpyridyl, phthalazinyl, pteridinyl, purinyl, pyrazinyl, pyrazinyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolidinyl, pyrrolyl, pyranyl, quinazolinyl, quinolizinyl, quinolyl , quinoxalinyl, tetrazolyl, thiazolyl, 4-thiazol-4-ylphenyl, thienyl, xanthenyl and the like. Suitable protecting groups include tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, 4-methoxybenzyl, 2-nitrobenzyl and the like. "Heterocycloalkyl" means cycloalkyl, as defined herein, provided that one or more of the ring-member carbon atoms indicated, are replaced by heteroatom residue selected from -N:, - NR-, -0-, -S - or -S (0) 2, wherein R is hydrogen, alkyl (C? _6) or a protecting group and any carbocyclic ketone, thioketone or iminoketone derived therefrom (eg the term heterocycloalkyl (C5-? 2) includes
[1, 4 '] bipiperidinyl, dihydrooxazolyl, morpholinyl, 1-morpholin-4-ylpiperidinyl, piperazinyl, piperidyl, pyrazolidinyl, pyrazolinyl, pyrrolinyl, pyrrolidinyl, quinuclidinyl and the like). Suitable protecting groups include tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, 4-methoxybenzyl, 2-nitrobenzyl and the like. For example, a compound of Formula I wherein R 1 is piperidin-4-ylcarbonyl may exist as either the unprotected derivative or a protected derivative, eg, wherein R 1 is 1-tert-butoxycarbonylpiperidin-4-ylcarbonyl and both the derivative unprotected as the protected fall within the scope of the invention. "Heterocycloalkylene" means cycloalkylene, as defined in this Application, provided that one or more of the ring-member carbon atoms indicated, are replaced by a heteroatom residue selected from -N :, -NR-, -O-, - S- or -S (0) 2-, wherein R is hydrogen or alkyl (d-6). For example, the case where R3 and R4 together with the carbon atom to which both R3 and R4 are attached form hetero (cycloalkyleneC3_8) "includes, but is not limited to the following:
in which R is hydrogen, alkyl (d-6) or a protection group and R2 is as defined in the Summary of the Invention. "Heteropolycycloaryl" means polycycloaryl, as defined herein, except that one or more of the indicated ring carbon atoms is replaced by a heteroatom residue selected from -N :, -NR-, -O-, -S- or -S (0) 2- / wherein R is hydrogen, alkyl (d-6) or a protecting group and any carbocyclic ketone, thioketone or iminoketone derived therefrom (eg, heteropolycycloaryl (C8_? 2) includes 3, 4 -dihydro-2H-quinolinyl, 5, 6, 7, 8-tetrahydroquinolinyl, 3,4-dihydro-2H- [1,8] naphthyridinyl, morpholinylpyridyl, piperidinylphenyl,
1,2,3,4,5,6-Hexahydro- [2,2 '] bipyridinylin, 2,4-dioxo-3,4-dihydro-2-t-quinazolinyl, 3-oxo-2,3-dihydrobenzo [1,4] oxacinyl, etc.). "Residues of heteroatom" includes -N :, -NR-, -O-, -S- or -S (0) 2-, wherein R is hydrogen, alkyl (d-6) or a protecting group. "Hydroxy" means the -OH radical. Unless indicated otherwise, the compounds of the invention containing hydroxy radicals include protected derivatives thereof. Suitable protecting groups for hydroxy residues include benzyl and the like. For example, a compound of Formula I wherein R9 contains a hydroxy residue exists as either the unprotected or protected derivative, e.g. wherein R9 is benzyloxybenzyl, and both derivatives the unprotected and the protected fall within the scope of the invention. "Iminoketone derivative" means a derivative containing the residue -C (NR) -, wherein R is hydrogen or alkyl (d_6). "Isomers" means compounds of Formula I that have an identical molecular formula but differ in the nature or sequence of the union of their atoms or in the order of their atoms in space. The isomers that differ in the order of their atoms in space are called "stereo isomers." Stereo isomers that are not mirror images of one another are termed "diastereomers" and stereo isomers that are not mirror images that can be superimposed are termed "enantiomers" or sometimes "optical isomers". A carbon atom attached to four non-identical substituents is termed a "chiral center". A compound with a chiral center having two enantiomeric forms of opposite chirality is called a "racemic mixture". A compound that has more than one chiral center has 2n'x enantiomeric pairs, where n is the number of chiral centers. Compounds with more than one chiral center can exist as an ether an individual diastereomer or as a mixture of diastereomers called a "diastereomeric mixture". When a chiral center is present a stereoisomer can be characterized by the absolute configuration of that chiral center. The absolute configuration refers to the order in the space of the substituents attached to the chiral center. The enantiomers are characterized by the absolute configuration of their chiral centers and are described by the R- and S- sequencing rules of Cahn, Ingold and Prelog. Agreements for stereochemical nomenclature, methods for the determination of stereochemistry and separation of stereo isomers are well known in the art (eg, see "Advanced Organic Chemistry", 3rd edition, March, Jerry, John Wiley &Sons, New York, 1985). It is understood that the names and illustration used in this Application to describe compounds of Formula I is understood to encompass all possible stereo isomers. Thus, for example, the name 1- (1-cyano-1-methylethylcarbamoyl) -3-methylbutylcarbamate means that it includes 1S- (1-cyano-1-methylethylcarbamoyl) -3-methylbutylcarbamate and 11β- (1-cyano-1) -methylethylcarbamoyl) -3-methylbutylcarbamate and any racemic mixture or other form thereof. "Ketone derivative" means a derivative containing the residue -C (0) -. "Methylene" means the divalent radical -CH2- or CH2 :, where its free valencies can be attached to different atoms or to the same atom. For example, the case where R9 together with R7 form substituted trimethylene methylene includes the following:
wherein X1 and R11 are as defined in the Summary of the Invention and may be referred to as 2, 2-methylene and 1,2-methylene, respectively. "Nitro" means the radical -N02. "Optional" or "optionally" means that the subsequently described event or circumstance may or may not occur and that the description includes cases where the event or circumstance occurs and cases where it does not. For example, the phrase "any of 1 to 3 ring atoms of any aromatic ring with available valencies comprising R6 is optionally substituted independently" means that the referred aromatic ring may or may not be substituted in order to fall within the scope of the invention. . "N-oxide derivatives" means the derivatives of the compound of Formula I in which the nitrogens are in an oxidized state (i.e., 0 <; -N) and that possesses the desired pharmacological activity. "Oxo" means the radical: 0. "Pathology" of a disease means the essential nature, causes and development of the disease as well as the structure and functional changes that result from the processes of the disease. "Pharmaceutically acceptable" means that it is useful for preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable and includes that it is acceptable for veterinary use as well as for human pharmaceutical use. "Pharmaceutically acceptable salts" means salts of compounds of Formula I that are pharmaceutically acceptable, as defined above and which possess the desired pharmacological activity. Such salts include acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like; or with organic acids such as acetic acid, propionic acid, hexanoic acid, heptanic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid , benzoic acid, o- (4-hydroxybenzoyl) benzoic acid, cinnamic acid, maddenic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo [2.2.2] oct-2-ene-l-carboxylic acid, glucoheptonic acid, 4,4'-methylenebis (3-hydroxy-2-ene-1-carboxylic acid) , 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salic acid lic, stearic acid, muconic acid and the like. The pharmaceutically acceptable salts also include base addition salts which can be formed when the acidic protons present are capable of reacting with inorganic or organic bases. Acceptable inorganic bases include sodium hydroxide, sodium carbonate, potassium hydroxide, ammonium hydroxide, aluminum hydroxide and calcium hydroxide. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine and the like. "Phenylene-1,2-dimethylene" means the divalent radical -CH2C6H4CH2-, wherein the methylene residues are joined at positions 1- and 2- of the phenylene residue. For example, a group of Formula (a), wherein R9 together with R7 form optionally substituted phenylene-1,2-dimethylene is illustrated by the following formula:
wherein R is an optional hydroxy or alkyl group (C? -4) and X1 and R11 are as defined in the Summary of the Invention. "polycycloaryl" means a bicyclic ring assembly (directly linked by a single or fused linkage) containing the number of ring member carbon atoms indicated, wherein at least one, but not all, of the fused rings comprising the radical is aromatic and any carbocyclic ketone, thioketone or iminoketone derived therefrom (eg, polycycloaryl (C9-? 2) includes indanyl, indenyl, 1,2,3,4-tetrahydronaphthalenyl, 1,2-dihydronaphthalenyl, cyclohexylphenyl, phenylcyclohexyl, , 4-dioxo-l, 2, 3, 4-tetrahydronaphthalenyl and the like). "Prodrug" means a compound that is convertible in vivo by metabolic means (e.g., by hydrolysis) to a compound of Formula (I). For example, an ester of a compound of Formula (I) containing a hydroxy group can be converted by in vivo hydrolysis to the original molecule. Alternatively, an ester of a compound of Formula (I) containing a carboxy group can be converted by hydrolysis in vivo to the original molecule. Suitable esters of the compounds of the formula (I) containing a hydroxy group are, for example, acetates, citrates, lactates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates, methylene-bis-b-hydroxynaphthalates. , gentisatos, isetionatos, di-p-toluoiltartratos, methanesulfonatos, etanosulfonatos, benzenesulfonatos, p-toluenosulfonatos, cicloexilsulfamatos and kinatos. Suitable esters of the compounds of Formula (I) which contain a carboxy group, are for example those described by F. J. Leinweber, Drug Metab. Res., 1987, 18, page 379. An especially useful class of esters of the compounds of Formula (I) which contain a hydroxy group, can be formed from acid residues selected from those described by Bundgaard et. el., J. Med. Chem., 1989, 32, page 2503-2507, and includes substituted (aminomethyl) -benzoates, for example, dialkylamino-methylbenzoates in which the two alkyl groups can be joined together and / or interrupted by a oxygen atom or by an optionally substituted nitrogen atom, eg an alkylated nitrogen atom, more especially (morpholino-methyl) benzoates, e.g. 3- or 4- (morpholinomethyl) -benzoates and (4-alkylpiperazin-1-yl) benzoates, e.g. 3- or 4- (alkylpiperazin-1-yl) benzoates. "Protected derivatives" means derivatives of the compounds of Formula (I) in which a site or reactive sites are blocked with protecting groups. The protected derivatives of the compounds of the Formula (I) are useful in the preparation of the compounds of the Formula I or in themselves can be active inhibitors of the cysteine protease. A comprehensive list of suitable protection groups can be found in T.W. Greene, Protecting Groups in Organic Synthesis, John Wiley & Sons, Inc. 1981. "Therapeutically effective amount" means that amount which, when administered to an animal to treat a disease, is sufficient to effect such treatment for the disease. "Derivative thioketone" means a derivative containing the residue -C (S) -. "Treatment" or "treating" means any administration of a compound of the present invention and includes: (1) preventing the disease from occurring in an animal that may be predisposed to the disease but does not yet experience or present the pathology or symptomatology of the disease, (2) inhibit the disease in an animal that is experiencing or presenting the pathology or symptomatology of the disease (ie, the suspension of further development of the pathology and / or symptomatology), or (3) alleviate the disease in a animal that is experiencing or presenting the pathology or symptomatology of the disease (ie, reversing the pathology and / or symptomatology). "Ureido" means the radical -NHC (0) NH2. Unless otherwise indicated, compounds of the invention containing ureido residues include protected derivatives thereof. Suitable protecting groups for the ureido residues include acetyl, tert-butoxycarbonyl, benzyloxycarbonyl and the like. For example, a compound of Formula I wherein R9 contains a ureido residue may exist as either the unprotected or protected derivative and the like and both unprotected and protected derivatives fall within the scope of the invention. Presently Preferred Modalities: Although the larger definition of the invention has been established in the Summary of the Invention, certain aspects of the invention are preferred. Preferred are compounds of Formula I in which:
R1 represents a group of Formula (a) wherein within Formula (a): X1 is -C (0) -; R5 represents hydrogen or alkyl (d-e), preferably hydrogen; R7 represents hydrogen or methyl, preferably hydrogen; R9 represents (i) (C6-6) alkyl optionally substituted with -OR14, -SR14, -S (0) R14, -S (0) 2R14. -C (0) R14, -C (0) 0R14, -OC (0) R14, -NR14R15, -NR15C (0) R14, -NR15C (0) OR14,
C (0) NR14R15 -S (0) 2NR1R15, -NR15C (O) NR14R15 or -NR15C (NR15) NR14R15, wherein R14 is (C3-I0) cycloalkyl (C0.6) alkyl, (C3-10) alkylcycloalkyl . { C0.6), aryl (C6-? 0) alkyl (C0-ß) / heteroaryl (C5-10) alkyl (C0-ß) polycycloaryl (C9-? 0) alkyl (C0-6) or heteropolycycloaryl (C8-10 ) alkyl (Co-e) and R15 is hydrogen or alkyl (C? _6) and wherein within R14 said cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or heteropolycycloaryl ring is optionally substituted by a group selected from R16, -X3OR16, -X3SR16, -X3S (0) R16, -X3S (0) 2R16, -X3C (0) R16, -X3C (0) OR16, -X30C (0) R1S, -X3NR16R17, -X3NR17C (0) R1S, -X3NR17C (O) OR16, -X3C (O) NR16R17, X3S (0) 2NR16R17, -X3NR17C (0) NR16R17 or -X3NR17C (NR17) NR16R17, wherein X3 is a bond or alkylene (C? 6), R16 is hydrogen or alkyl (d_6) and R17 is (C3-? 0) cycloalkyl (Co-ß) alkyl, (C3-10) heterocyclealkyl (CoA aryl (C6-? o) alkyl, {C0-ß).
heteroaryl (C5-10) alkyl (CoA, polycycloaryl (C9-? 0) alkyl (C0-6) or heteropolycycloaryl (C8-10) alkyl (CoA or (ii) a group selected from cycloalkyl (C3-? 0) alkyl (CoA, heterocycloalkyl (C3-10) alkyl (C0-e) aryl (C6-? o) alkyl (CoA, heteroaryl (C5-10) alkyl (CoA / polycycloaryl (C9-? 0) alkyl (C0-6) ) and heteropolycycloaryl (C8-10) alkyl (Co-e) / wherein said cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or heteropolycycloaryl ring are optionally substituted by a group selected from R16, -X3OR16, -X3SR16, -X3S (0) R16, -X3S (0) 2R16, -X3C (0) R16, -X3C (0) OR16, X3OC (0) R16, -X3NR16R17, -X3NR17C (0) R1S, -X3NR17C (O) OR16, X3C (0) NR16R17, -X3S (0) 2NR1SR17, -X3NR17C (O) NR16R17 or X3NR17C (NR17) NR16R17, wherein X3, R16 and R17 are as defined above, wherein within R9 any aromatic alicyclic ring system present it can be further substituted by 1 to 5 independently selected radicals from alkyl or (d-6), alkylidene (C? -6), cyano, halo, halo-substituted alkyl (Ci-4) nitro, -X3NR12R12, -X3NR12C (O) OR12, X3NR12C (0) NR12R12, -X3NR12C (NR12 ) NR12R12, -X3OR12, -X3SR12, X3C (0) OR12, -X3C (0) NR12R12, -X3S (O) 2NR12R12, -X3P (O) (OR3) OR12, -X3OP (0) (OR3) OR12, - X3OC (0) R13, -X3NR12C (O) R13, -X3S (0) R13, X3S (0) 2R13 and -X3C (0) R13, wherein X3 is as defined above, R12 in each occurrence independently is hydrogen, alkyl (C? _6) or halo (substituted) alkyl (d_3) and R13 is alkyl (C? _6) or halo (C? -3) alkyl substituted; and R11 represents -X4X5R18, wherein X4 is -C (0) - or -S (0) 2-, X5 is a bond, -0- or -NR19-, wherein R19 is hydrogen or alkyl (d-6) and R18 is (i) alkyl (Ci-io) or (ii) cycloalkyl (C3-y2) alkyl (dA, heterocycloalkyl (C3_2) alkyl (C0-s) / aryl (CS-? 2) alkyl (C0-) e) or heteroaryl (C5_12) alkyl (Co-e) or (iii) cycloalkyl (C? s) alkyl (C0-s), heterocycloalkyl (C? -6) alkyl (Co-b) / phenylalkyl (CoA or heteroaryl (C5-6) alkyl (Co-e) / wherein said cycloalkyl, heterocycloalkyl, phenyl or heteroaryl are substituted by -X9OR24, -X9C (0) R24, -X9C (0) OR24, -X9C (O) NR24R25, -X9NR24R25, -X9NR25C (0) R24, -X9NR25C (0) OR24, -X9NR25C (0) NR24R25 or X9NR25C (NR25) NR24R25, wherein X9 is a bond or alkylene (d-6), R24 is cycloalkyl (C? -6) alkyl (Co-β) heterocycloalkyl (Ci-6) alkyl (C 0 -e) phenylalkyl (Co-β) or heteroaryl (C 5 6) alkyl (C 0-6) and R 25 is hydrogen or alkyl (C 6) , wherein within R11 any present alicyclic or aromatic ring system may further substituted by 1 to 5 substituents independently selected from alkyl (d-6), halo, halo-substituted alkyl (C1-4) -OR12, -X3SR12, -C (0) 0R12 and -X3NR12C (0) OR12, wherein X3 is a bond or alkylene (C? _e) and R14 is hydrogen or alkyl (C? -6). Within Formula (a), R11 particularly represents -X4X5R18, wherein X4 is -C (O) -, X5 is a bond and R18 is (i) is (C3_2) alkylcycloalkyl (CoA, heterocycloalkyl (C3_? 2) alkyl (Co-e) aryl (C6_? 2) alkyl (C0-d) or heteroaryl (C5-?) Alkyl (Co-e) or (ii) phenylalkyl (CoA or heteroaryl (C5-6) alkyl (Co -e) wherein said phenyl or heteroaryl is substituted by X9OR24, -X9C (0) R24, -X9C (0) OR24, -X9C (0) NR24R25, -X9NR24R25, -X9NR25C (0) R24, -X9NR25C (0) ) OR24, X9NR25C (0) NR24R25 or -X9NR25C (NR25) NR24R25, wherein X9 is a bond or alkylene (d-6), R24 is phenylalkyl (CoA or heteroaryl (C5. E) alkyl (CoA and R25 is hydrogen or alkyl (d-6), wherein within R11 any present aromatic ring system can be further substituted by 1 to 5 substituents independently selected from alkyl (C? _6), halo, halo (C? -4) alkyl-substituted -OR12, -X3SR12, -C (0) 0R12 and -X3NR12C (0) OR12, wherein X3 is a bond or alkylene (d-6) and R12 is hydrogen or alkyl (C? _6). Within Formula (a), R 11 more particularly represents benzoyl, furylcarbonyl, phenyloxybenzoyl, pyridylthienylcarbonyl, benzoylbenzoyl, thienylcarbonyl, morpholinylcarbonyl, phenyluriedobenzoyl, cyclohexylcarbonyl or piperazinylcarbonyl, wherein from R 11 any present aromatic ring system may be further substituted by 1 to 2 substituents independently selected from alkyl (C? -6), tert-butoxycarbonylamino, tert-butoxycarbonylaminomethyl, bromine, chlorine, ethoxy fluoro, hydroxy, methoxy and methylsulphanyl. Within Formula (a), R9 particularly represents (i) (C? -6) alkyl optionally substituted with -OR14 or -SR14, wherein R14 is (C? -6) cycloalkyl (C0-6) alkyl, phenylalkyl ( CoA, biphenylalkyl (CoA or heteroaryl (C5.6) alkyl (Co-ß) or (ii) a group selected from cycloalkyl (C6-6) alkyl (C0-d), phenylalkyl (CoA / biphenylalkyl (CoA or heteroaryl (C5_? 0) alkyl { C0.6); wherein within R9 any present alicyclic or aromatic ring system can be further substituted by 1 to 5 independently selected radicals from alkyl (C? -6), alkylidene (d-6), cyano, halo, alkyl (Ci-4) ) halo-substituted nitro, -X3NR12R12, -X3NR12C (O) OR12, X3NR12C (0) NR12R12, -X3NR12C (NR12) NR12R12, -X3OR12, -X3SR12, X3C (0) OR12, -X3C (0) NR12R12, -X3S (O) 2NR12R12, -X3P (0) (OR3) OR12, -X30P (0) (OR3) OR12, -X3OC (0) R13, -X3OC (0) R13, -X3NR12C (0) R13, X3S (0) R13, -X3S (0) 2R13 and -X4C (0) R13, wherein X3, is a bond or alkylene (Ci-g), R12 in each occurrence is independently hydrogen, alkyl (C? -3) or alkyl (d) -3) halo-substituted and R13 is alkyl (C? _3) or halo-substituted alkyl (d-3). Within Formula (a) R9 more particularly represents cyclohexylmethyl, wherein said cyclohexyl can be substituted by 1 to 5 independently selected radicals from (C? -4)) alkyl, alkylidene (CiA or X3OC (0) R13, or phenylmethylsulfanylmethyl or phenylsulfanylethyl wherein said phenyl can be substituted by 1 to 5 radicals independently selected from alkyl (C? -4), cyano, halo, halo (C? -4) alkyl, nitro, -OR12, SR? 2 C ( 0) OR where R is hydrogen (d-3) alkyl (Ci-3) halo-substituted, and R 3 is (C-6) alkyl (C 3) -halo-substituted alkyl Within the Formula (a), R9 more particularly presents a group having the following Formula:
wherein q is 0 to 5 and R26 is each occurrence is independently selected from alkyl (d-4), cyano, halo, halo-substituted alkyl (C? -4), nitro and -OR12, -SR12, and -C (0) 0R12 wherein R12 is hydrogen, (1-3C) alkyl, or halo-substituted (1-3C) alkyl and R13 is halo (C? _6) alkyl or (1-3C) halo-substituted alkyl. Within Formula (a), R 9 preferably represents benzylsulfanylmethyl, 2-bromobenzylsulfanylmethyl, 2-chlorobenzylsulfañyl, 2- (2-chlorophenylsulfanyl) ethyl, cyclohexyl, 4-ethylidenecyclohexyl, 2-iodobenzylsulfanylmethyl, 2-methylbenzylsulfanylmethyl, 3-methyl-3- trifluorocarbonyloxycyclohexylmethyl, 4-methylenecyclohexylmethyl or 2-nitrobenzylsulfanylmethyl. R2 preferably represents hydrogen; R3 is preferably hydrogen or alkyl (d-4) typically hydrogen, or taken with R4 together with the carbon atom to which both R3 and R4 are linked form cycloalkylene (C3_8) (e.g., cyclopropylene or cyclohexylene). R 4 is preferably hydrogen or taken with R 3 together with the carbon atom to which both R 3 and R 4 are attached form cycloalkylene (C 3 8) (e.g., cyclopropylene or cyclohexylene). Compounds of Formula II specifically include those in which R9 represents aryl (C6-12) alkyl (C0-6) # heteroaryl (C5-12) alkyl (C0-6), X4OR14, -X4SR14, -X4S (0) R14 or -X4NR14R15, wherein X4 is a bond or alkylene (C? _
6), R14 is aryl (C6-12) alkyl (Co-e) or heteroaryl (C5-? 2) alkyl (C0-6), and R15 is hydrogen or alkyl (C? _6), and wherein within R9 said aryl or heteroaryl ring optionally substituted by 1 to 5 radicals independently selected from alkyl (C? -6), cyano, halo, halo (C? -4) alkyl-nitro substituted, -X4NR12R12, -X40R12 -X4C ( 0) R12, -X4SR12, wherein X4 is a bond or alkylene (C? -6), R12 in each occurrence is independently hydrogen, (C? -6) alkyl, or halo-substituted (Ci- 3) alkyl, and R 13 is alkyl (d-6) or halo (C 3) -substituted alkyl.
Compounds of Formula II particularly include those in which R9 represents benzyl, benzyloxymethyl, benzylsulfanylethyl, benzylsulfanylmethyl, benzylsulfinylmethyl, iodoylmethyl, naphthylmethyl, phenethyl, phenoxyethyl, phenylamino, pyridylmethyl, pyridylsulfanylethyl, phenylsulfanylethyl, thiazolyl or thienyl, wherein within R9 the Aromatic ring can be further substituted by 1 to 5 radicals independently selected from alkyl (d_6), cyano, halo, halo (substituted C alquilo -4) alkyl, -X4NR1R12, -X4OR12 -XC (0) R12, -X4SR12 , wherein X4 is a bond or alkylene (C? _6), R12 in each occurrence is independently hydrogen, alkyl (C? _6), or halo-substituted (Ci-3) alkyl, and R13 is alkyl (C? -6) ) or halo-substituted alkyl (d-3). Compounds of Formula II more particularly include those in which R9 represents 4-aminobenzyl, benzyl, benzyloxymethyl, 2-benzylsulfanylethyl, benzylsulfanylmethyl, 2-bromobenzylsulfanylmethyl, 4-tert-butylbenzylsulfanylmethyl, 2-chlorobenzyl, 4-chlorobenzyl, 2-chlorobenzylsulfanylmethyl , 4-chlorobenzylsulfanylmethyl, 2- (2-chlorophenylsulfanyl) ethyl, 4-cyanobenzyl, 3,4-dichlorobenzylsulfanylmethyl, 1,6-dichlorobenzyl, 3,5-dimethylbenzylsulfanylmethyl, 2-fluorobenzyl. 4-fluorobenzyl, 2-fluorobenzylsulfanylmethyl, 1-formylindol-3-ylmethyl, indole-3-ylmethyl, 2-iodobenzylsulfanylmethyl, 2-methylbenzylsulfanylmethyl, 3-methylbenzylsulfanylmethyl, 3-methylbenzylsulfanylmethyl, 4-methylbenzylsulfanylmethyl, 2- (2-methylphenylsulfanyl) ethyl. , 4-methoxybenzyl, 4-metoxibencilsulfanilmetilo, 4-metoxibencilsulfinilmetilo, naphth-2-ylmethyl, naphth-2-ilmetilsulfanilmetilo, 3-nitrobenzyl, 1-nitrobencilsulfanilmetilo, 2-nitrobencilsulfanilmetilo, 3 -nitrobencilsulfanilmetilo, 4-nitrobencilsulfanilmetilo, 4-nitrobenzyl, pentafluorobencilsulfanilmetilo , phenylamino, phenethyl, phenethyloxy, 2-phenoxyethyl, 2-phenoxyethyl, 2-phenylsulfanylethyl, pyrid-4-ylmethyl, pyrid-2-ylmethylsulfanylmethyl, pyrid-3-ylmethylsulfanylmethyl, pyrid-4-ylmethylsulfanylmethyl, 2-pyrid-2-ylsulfanylethyl, 2-pyrid-4-ylsulfanylethyl, thiazol-5-yl, thien-2-ylmethyl, 4-trifluoromethylbenzylsulfanylmethyl, 3-trifluoromethylbenzylsulfanylmethyl, 3-trifluoromethoxybenzylsulfanylmethyl, 4-trifluoromethoxybenzylsulfanylmethyl or 4-trifluorosulfanylbenzylsulfanylmethyl. With reference to the preferred embodiments set forth above it is considered to include all combinations of the particular and preferred groups. Additional preferred are compounds of Formula I selected from a group consisting of:
N- (2-benzylsulfanyl-l. -cyanomethylcarbamoylethyl) -4-hydroxybenzamide; N- [2- (2-bromobenzylsulfanyl) -lJ? -cyanomethylcarbamoyl ethyl] benzamide; N- [lJ? -cyanomethylcarbamoyl-2- (2-iodobenzylsulfanyl) ethyl] benzamide; N- [lR-cyanomethylcarbamoyl-2- (2-cyanobenzylsulfanyl) ethyl] morpholin-4-carboxamide; N- [3- (2-chlorophenylsulfanyl) -lR-cyanomethylcarbamoylpropyl) benzamide; N- [lR-Cyanomethylcarbamoyl-2- (2-nitrobenzylsulfanyl) ethyl] morpholine-4-carboxamide N- [lR-cyanomethylcarbamoyl-2- (2-methylbenzylsulfanyl) ethyl] morpholin-4-carboxamide N- [lR-cyanomethylcarbamoyl-2 - (2-methylbenzylsulfanyl) ethyl] benzamide.
Pharmacology and utility: The compounds of the invention are inhibitors of cysteine protease, in particular the compounds of the invention inhibit the activity of cathepsins B, L, K and / or S and as such, are useful for treating diseases in which the activity of catespina B, L, K and / or S contributes to the pathology and / or symptomatology of the disease. For example, the compounds of the invention are useful for treating tumor invasion and metastasis, in particular as anti-angiogenic agents, rheumatoid arthritis, osteo arthritis, acute pneumocystis carinii pancreatitis, inflammatory diseases of the respiratory tract and disorders of the bones and joints. . In addition, the compounds of the invention are useful for treating disorders of bone resorption, e.g. osteoporosis. The compounds of the invention are also useful for treating autoimmune disorders, including but not limited to juvenile diabetes, multiple sclerosis, pemphigus vulgaris, Graves' disease, myasthenia gravis, systemic lupus erythematosus, rheumatoid arthritis and Hashimoto's thyroiditis, allergic disorders, including, but not limited to asthma and allogeneic immune responses, including but not limited to organ transplants or tissue grafts. The inhibitory activities of the cysteine protease of the compounds of the invention can be determined by methods known to those of ordinary skill in the art. Suitable in vi tro analyzes are known to measure the activity of the protease and inhibition thereof by the test compounds. Typically the analysis measures the protease-induced hydrolysis of a peptide-based substrate. Details of the assays for measuring the protease inhibitory activity are set forth in Examples 10, 11, 12 and 13 infra.
Nomenclature: The compounds of Formula I and the intermediates and the starting materials used in their preparation are named according to the IUPAC nomenclature rules in which the characteristic groups have a decreasing priority for the mention according to the group of origin as follow: acids, esters amides and amidines. For example, a compound of Formula I in which R1 is a group of Formula (a), wherein X1 is carbonyl, R5 and R7 are each hydrogen, R9 is benzyl and R11 is tert-butoxycarbonyl and R2, R3 and R4 are each hydrogen; that is, a compound that has the following structure:
is termed tert-butyl lS-cyanomethylcarbamoyl-2-phenylethylcarbamate and a compound of Formula I in which R1 is a group of Formula (a), wherein X1 is carbonyl, R5 and R7 are each hydrogen, R9 is cyclohexylmethyl and R 11 is morpholin-4-ylcarbonyl and R 2, R 3 and R 4 are each hydrogen; that is, a compound that has the following structure:
it is referred to as N- (lS-Cyanomethylcarbamoyl-2-cyclohexylethyl) morpholine-4-carboxamide. Administration and Pharmaceutical Compositions: In general, the compounds of Formula I will be administered in therapeutically effective amounts by any of the usual and acceptable modes known in the art, either alone or in combination with another therapeutic agent. A therapeutically effective amount can vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used and other factors. For example, therapeutically effective amounts of a compound of Formula I can vary from 0.1 micrograms per kilogram of body weight (μg / kg) per day to 10 milligrams per kilogram of body weight (mg / kg) per day, typically 1 μg / kg / day at 1 mg / kg / day. Therefore, a therapeutically effective amount for a human patient of 80 Kg can vary from 10 μg / day to 100 mg / day, typically 0.1 mg / day up to 10 mg / day. In general, one of ordinary skill in the art, who acts in confidence to personal knowledge and the disclosure of this Application, will be able to investigate a therapeutically effective amount of a compound of Formula I to treat a given disease. The compounds of Formula I can be administered as pharmaceutical compositions by one of the following routes: oral, systemic (e.g., transdermal, intranasal or by suppository) or parenteral (e.g., intramuscular, intravenous or subcutaneous). The compositions may take the form of tablets, lozenges, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols or any other suitable composition and are generally comprised of a compound of the Formula I in combination with at least one pharmaceutically acceptable excipient. The acceptable excipients are non-toxic administration aids and do not adversely affect the therapeutic benefit of the active ingredient. Such excipient can be any solid, liquid, semi-solid or in the case of an aerosol composition, gaseous excipient which is generally available to one of skill in the art. Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, calcium carbonate, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, milk skimmed powder and the like. Liquid and semi-solid excipients can be selected from water, ethanol, glycerol, propylene glycol and various oils, including those of petroleum, animal, vegetable or synthetic origin
(e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc.). Preferred liquid carriers, particularly for injectable solutions include water, saline, aqueous dextrose and glycols. The amount of a compound of Formula I in the composition can vary widely depending on the type of formulation, size or dosage unit, class of excipients and other factors known to those of skill in the pharmaceutical science art. In general, a composition of a compound of Formula I for treating a given disease will comprise from 0.01% by weight up to 10% by weight, preferably 0.3% by weight up to 1% by weight, of the active ingredient, the remainder being the excipient or excipients Preferably, the pharmaceutical composition is administered in a single dosage unit form for continuous treatment or in a single dosage unit form ad libitum when the relief of symptoms is specifically required. Pharmaceutically representative formulations containing a compound of Formula I are described in Example 15.
Chemistry:
Processes for Making the Compounds of Formula I: The compounds of Formula I can be prepared by proceeding as in the following Scheme 1:
SCHEME 1
2
l. R'OY 2. optionally deprotecting
I in which Y is hydrogen or an activation group (eg, 2,5-dioxopyrrolidin-1-yl (NBS) and the like) and each R 1, R 2, R 3 and R 4 are as defined in the Summary of the Invention . The compounds of Formula I can be prepared by reacting a compound of Formula 2 or a protected derivative thereof, with a compound of the formula R 1 OY or a protected derivative thereof and then optionally deprotecting it. The reaction is carried out in the presence of a suitable acylation catalyst (eg, trimethylamine) and in a suitable solvent (eg, acetonitrile, N, N-dimethylformamide (DMF), methylene chloride or any suitable combination thereof) from 10 to 30 ° C, preferably at approximately 25 ° C and requires 24 to 30 hours to complete. When Y is hydrogen the reaction can be carried out in the presence of a suitable binding agent (eg, benzotriazola-1-yloxytrispyrrolidinophosphonium hexafluorophosphate (PyBOP®), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC), O- benzotriazol-l-il-N / N / N '/ N' -tetramethyluronium hexaflurorphosphate (HBTU), 1,3-dicyclohexylcarbodiimide (DCC) or similar) and a base
(e.g., N / N-diisopropylethylamine, triethylamine or the like) and requires 2 to 15 hours to complete. Alternatively, when Y is hydrogen the reaction can be carried out by treating the compound of the formula R1OH with N-methylmorpholine and isobutyl chloroformate in a suitable solvent (eg, THF, or the like) at between 0 and 5 ° C for 30 minutes up to one hour and then introducing the compound of Formula 2 into the reaction mixture and allowing the reaction to proceed for 12 to 15 hours. The deprotection can be carried out by any means that removes the protection group and gives the desired product in reasonable production. It can be found in T.W. a detailed description of the techniques applicable to the creation of protection groups and their withdrawal. Greene, Protecting Groups in Organic Synthesis, John Willey & Sons, Inc. 1981. Examples 4, 5, 6 and 8 infra set forth a detailed description of the preparation of a compound of Formula I according to Scheme 1. Alternatively, compounds of Formula I can be prepared by reacting a compound of Formula 2 with a compound of formula R1-SS, wherein SS is a suitable solid support (eg, thiophenol resin or the like). The reaction can be carried out in the presence of a suitable acylation catalyst (e.g., 4-dimethylaminopyridine or the like) and in a suitable solvent (e.g., dry pyrimidine or the like) and required from 60 to 70 hours to complete. The compounds of Formula I can be prepared by proceeding as in the following reaction of Scheme 2:
SCHEME 2
1. NH3 2. (CF3CO) 20, base 3. optionally unprotected
I
wherein each R1, R2, R3 and R4 are as defined in the Summary of the Invention. The compounds of Formula I can be prepared by treating a compound of Formula 3 or a protected derivative thereof with ammonia to provide the corresponding amide, then reacting the amide with a suitable dehydrating agent (eg, trifluoroacetic anhydride). , cyanuric chloride, thionyl chloride, phosphonyl chloride and the like) and optionally deprotect it. The reaction with the ammonia is carried out in a suitable solvent (e.g., methanol) at 0 to 5 ° C and requires 6 to 10 days to complete. The reaction with the dehydrating agent is carried out in the presence of a suitable base (eg, triethylamine) and in a suitable solvent (eg, tetrahydrofuran (THF) and the like) at 0 to 50 ° C and requires 1 2 hours to complete. In Examples 7 and 8 infra a detailed description of the preparation of a compound of Formula I according to Scheme 2 is set forth.
Additional Processes for Preparing Compounds of Formula I: A compound of Formula I can be prepared as a pharmaceutically acceptable acid addition salt by reacting the free base form of the compound with a pharmaceutically acceptable organic or inorganic acid. Alternatively, a pharmaceutically acceptable base addition salt of a compound of Formula I can be prepared by reacting the free acid form of the compound with a pharmaceutically acceptable organic or inorganic base. The inorganic and organic acids and bases suitable for the preparation of pharmaceutically acceptable salts of the compounds of Formula I are set forth in the definitions section of this application. Alternatively, the salt forms of the compounds of Formula I can be prepared using salts of the starting materials or intermediates.
The free acid or free base forms of the compounds of Formula I can be prepared in the form of the corresponding base addition salt or acid addition salt. For example, a compound of Formula I in an acid addition salt form can be converted to the corresponding free base by treating it with a suitable base (e.g., ammonium hydroxide solution, sodium hydroxide, etc.). A compound of Formula I in a base addition salt form can be converted to the corresponding free acid by treating it with a suitable acid (e.g., hydrochloric acid, etc.). The N-oxides of the compounds of Formula I can be prepared by methods known to those of ordinary skill in the art. For example, N-oxides can be prepared by treating a non-oxidized form of the compound of Formula I with an oxidizing agent (eg, trifluoroperacetic acid, permaleic acid, perbenzoic acid, peracetic acid, meta-chloroperoxybenzoic acid, etc.) in a suitable inert organic solvent (eg, a halogenated hydrocarbon such as methylene chloride) at about 0 ° C. Alternatively, the N-oxides of the compounds of Formula I can be prepared from the N-oxide of an appropriate starting material. Compounds of Formula I in non-oxidized form can be prepared from N-oxides of the compounds of Formula I by treating them with a reducing agent (eg, sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride, borohydride sodium, phosphorus trichloride, tribromide, etc.) in a suitable inert organic solvent (eg, acetonitrile, ethanol, aqueous dioxane, etc.) from 0 to 80 ° C. Prodrug derivatives of the compounds of Formula I can be prepared by methods known to those of ordinary skill in the art (eg, for further details see Saulnier et al., (1994), Bioorganic and Medicinal Chemistry Letters 4: 1985 ). For example, appropriate prodrugs can be prepared by reacting a non-derivatized compound of Formula I with a suitable carbamylating agent (e.g., 1,1-acyloxyalkylcarbonchloridate, para-nitrophenyl carbonate, etc. ). The protected derivatives of the compounds of Formula I can be made by means known to those of ordinary skill in the art. A detailed description of the techniques applicable to the creation of protection groups and their removal in T.W. Greene, Protecting Groups in Organic Synthesis, John Willey &; Sons, Inc. 1981. The compounds of Formula I can be prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomer. . Although the resolution of enantiomers can be carried out using covalent diastereomeric derivatives of the compounds of Formula I, dissociable complexes (e.g., crystalline diastereoisomeric salts) are preferred. The diastereomers have different physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and can be easily separated by taking advantage of these disparities. The diastereomers can be separated by chromatography or preferably by separation / resolution techniques based on differences in solubility. The optically pure enantiomer is then recovered, together with the separation agent by any practical means that does not result in racemisation. It can be found in Jean Jacques Andre Collet, Samuel H. Wilen, Enantiomers, Racemates and Resolutions, Honh Wiley & Sons, Inc. (1981) A more detailed description of the techniques applicable to the separation of stereo isomers of compounds from their racemic mixture. In summary, one aspect of the invention is a process for preparing a compound of Formula I, which process comprises: (A) reacting a compound of Formula 2:
or a protected derivative thereof with a compound of the formula RAY or a protected derivative thereof, in which Y is hydrogen or an activation group and each R1, R2, R3 and R4 are as defined in the Summary of the invention; or (B) reacting a compound of Formula 3
?
with ammonia to provide the corresponding amide and then reacting the amide with trifluoroacetic anhydride in which each R1, R2, R3 and R4 are as defined in the Summary of the Invention (C) optionally, deprotecting a protected derivative of a compound of the Formula I to provide the corresponding unprotected derivative; (D) optionally converting a compound of the Formula I into a pharmaceutically acceptable salt;
(E) optionally converting a salt form of a compound of Formula I to a non-salt form; (F) optionally converting a non-oxidized form of a compound of Formula I into a pharmaceutically acceptable N-oxide; (G) optionally converting an N-oxide form of a compound of Formula I into its non-oxidized form; (H) optionally converting a non-derivatized compound of Formula I into a pharmaceutically prodrug derivative; and (I) optionally converting a prodrug derivative of a compound of Formula I to its non-derivatized form.
Processes for Preparing Intermediates: Compounds of Formula 2 can be prepared by reacting a compound of Formula 4:
wherein R19 is an amino protecting group and each R1, R2, R3 and R4 are as defined in the Summary of the Invention with thionyl chloride and then deprotect it. The reaction with thionyl chloride is carried out in the presence of a suitable base (e.g., triethylamine) and in a suitable solvent (e.g. DMF) between 0 and 5 ° C and requires 30 minutes to an hour to complete. Alternatively, the compounds of Formula 2 can be prepared by reacting a compound of Formula 4 with trifluoroacetic anhydride. The deprotection can be carried out by any means that removes the protection group and gives the desired product in reasonable production. In Example 1, infra, a detailed description of the preparation of a compound of Formula 2 is established according to the procedure described above. The compounds of Formula 4 can be prepared by treating a corresponding alkanoyl halide with ammonia. The treatment is carried out in a suitable solvent (eg, dichloromethane, 5% aqueous sodium carbonate, and the like, or any suitable combination thereof) of 10 to 30 ° C and requires 30 minutes to one hour to complete. The alkanoyl halide intermediates can be prepared from the corresponding alkanoic acid by treating it with thionyl chloride in a suitable solvent (e.g. dichloromethane) under nitrogen for 30 minutes to one hour. In Example 1, infra, a detailed description of the preparation of a compound of Formula 2 is established according to the procedures described above.
The compounds of Formula R1-SS can be prepared by reacting a compound of Formula 5 (a) or 5 (b):
R19 R1 \ "xl OH NU X3 ^ ^ OH N X1 R7 ^ X4 N X1 R ° R5 5 (a) 5 (b)
wherein R19 is an amino protecting group (eg, tert-butoxycarbonyl, fluoren-9-ylmethoxycarbonyl or the like) and each X1, X2, X3 R5 and R7 are as defined by Formula I in the Summary of the Invention, with a suitable solid support resin deprotection (eg, Wang (4-benzyloxybenzyl alcohol) resin, thiophenol resin or the like), to provide, respectively, a compound of Formula 6 (a) or 6 (b):
. ^ ss HN X1 .7 ^ X N A * 6 (a) 6 (b)
wherein SS is a solid support and then the compound of Formula 6 (a) or 6 (b) is reacted with a compound of the Formula R6OH (eg, benzoic acid, indole-5-carboxylic acid, methanesulfonic acid or Similary) . The reaction between the compound of Formula 5 (a) or 5 (b) and the resin is carried out in the presence of a suitable binding agent (e.g., benzotriasol-l-yloxytrispyrrolidinephosphonium hexafluorophosphate (eg diisopropylcarbodiimide (DIC), PyBOP®, EDC, HBTU, DCC or the like) and the acylation catalyst (eg, N, N-diisopropylethylamine, triethylamine, 4-dimethylaminopyridine, hydrate 1- hydroxybenzotriazole or the like) in a suitable solvent (eg, methylene chloride, DMF or similar) and requires approximately 3 to 20 hours to complete. The deprotection can be carried out by any means that removes the protection group and gives the desired product in reasonable production. The reaction between the compound of Formula 6 (a) or 6 (b) is carried out with a suitable linking agent and an acylation catalyst. In examples 2 (A-C) and 4 (A-C), infra, a detailed description of the preparation of a compound of the formula R1-SS is established according to the methods described above. The compounds of the formula R10H can be prepared by treating the compound of the formula R1-SS with a suitable acid (e.g., trifluoroacetic acid or the like) in a suitable solvent (e.g., methylene chloride or the like). Alternatively, compounds of the formula R10H wherein X1 is -C (O) - and X2 is -CHR9- can be prepared by alkylation of an organometallic compound of Formula 7 (a) or 7 (b):
7 (a) 7 (b)
with a compound of the formula R9L, in which L is a fermenting group and each X3, X4, R5, R6, R7 and R9 are as defined by Formula I in the Summary of the Invention and then the ethyl ester is converted resulting to the corresponding acid. The alkylation is carried out in a suitable solvent (e.g., THF) at -78 ° C to 0 ° C and requires 1 to 2 hours to complete. The conversion of the acid can be effected by treating the ester with lithium hydroxide for about 15 hours. The organometallic compound is generated by treating a corresponding organic compound with an appropriate base (eg, N, N-diisopropylethylamine, triethylamine and the like) and n-butyllithium or tert-butyllithium at -80 to -70 ° C, preferably at about -78 ° C, for approximately from 30 minutes to one hour. In Example 3, infra, a detailed description of the preparation of a compound of the formula R 10 H is established according to the procedures described above. Examples: REFERENCE 1 Lithium 2S-amino-3-cyclohexylpropionate A solution of methyl 2S-amino-3-cyclohexylpropionate hydrochloride (8.03 mmol, 1 eq) in dichloromethane (80 ml) and saturated NaHCO 3 solution was cooled to 0 ° C (0 ° C). 80 ml) and then the organic layer was treated with a 1.93 M solution of phosgene in toluene (8.3 ml, 2 eq). The mixture was stirred for 10 minutes and then the aqueous was separated and extracted with dichloromethane (3x 27ml). The combined organic layers were dried over sodium sulfate, filtered and concentrated. A portion of the residue (767 μM, 1.0 eq) was stirred under nitrogen together with morpholine (767 μM, 1.0 eq) in dry THF (1 ml) for 12 hours. The mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate (1 ml). The solution was washed with water (3x 1 ml), dried over sodium sulfate and concentrated. The residue was dissolved in methanol (2 ml) and water (37 μl) and the solution was treated with lithium hydroxide monohydrate (19 mg, 1.05 eq) and then stirred for 12 hours. The solution was adjusted to pH 11 with additional lithium hydroxide monohydrate, heated at 60 ° C for 4 hours and then concentrated in vacuo to give lithium 2S-morpholin-4-ylcarbonylamino-3-cyclohexylpropionate. Proceeding as in Reference 1 the following compounds were provided: lithium 2S-piperidin-1-ylcarbonylamino-3-cyclohexylpropionate; lithium 2S- (ert-butoxycarbonylpiperazin-1-ylcarbonylamino) -3-cyclohexylpropionate; lithium 2S- (4-benzylpiperazin-1-ylcarbonylamino) -3-cyclohexylpropionate; lithium 2S- (4-ethoxycarbonylpiperazin-1-ylcarbonylamino) -3-cyclohexylpropionate; lithium 2S- (4-fur-2-ylcarbonylpiperazin-1-carbonylamino) -3-cyclohexylpropionate; REFERENCE 2 3-Cyclohexyl-2S- (3-methoxybenzyloxycarbonylamino) propionic acid A mixture of 2S-amino-3-cyclohexylpropionic acid (2.95 mmol, 1.0 eq) and sodium hydroxide (5.9 mmol, 2 eq) in a mixture was treated. THF / water (14 ml) with 3-methoxybenzyloxyformyl chloride (2.95 mmol, 1.0 eq), stirred for 3 hours and then treated with N, N-diethylethylenediamine (2.95 mmol, 1.0 eq). The mixture was stirred for approximately 12 hours, adjusted to pH 2 with 1M hydrochloric acid solution (13 ml) and then extracted with ethyl acetate (2x 9 ml). The extract was washed with 1M hydrochloric acid solution (6 ml), dried over sodium sulfate and concentrated to give 3-cyclohexyl-2S- (3-methoxybenzyloxycarbonylamino) propionic acid as a yellow oil. EXAMPLE 1 tert-Butyl lS-cyanomethylcarbamoyl-2-phenylethylcarbamate (Compound 1)
A mixture of 2S-ert-butoxycarbonylamino-3-phenylpropionic acid (28.9 g, 0.109 mol), aminoacetonitrile hydrochloride (10.1 g, 0.109 mol), triethylamine (61 ml, 0.436 mol) was stirred at room temperature for 27 hours. ), DMF (40 ml) and acetonitrile (360 ml). The mixture was filtered, concentrated to a volume of 100 ml and emptied into ice water (1000 ml). The mixture was stirred until a precipitate formed. The precipitate was collected, washed with water and dried. The dried product was recrystallized from 55% ethanol / water (80 ml). The crystals were collected and recrystallized from 65% ethanol / water (70 ml). The crystals were collected and dried to provide tert-butyl lS-cyanomethylcarbamoyl-2-phenylethylcarbamate (20.3 g, 0.067 mol) as white needles; A NMR: d 1.39 (s, 9H), d 3.06 (d, 2H, J = 7 Hz), d 4.08 (m, 2H), d 4.34 (dd, ÍH, J = 13, 7 Hz), d 4.97 ( d, HH, J = 8 HZ), d 6.59 (m, HH), d 7.23 (m, 5H, ES-MS m / z 304 (MH +).
By proceeding as in Example 1, the following compounds of Formula I are provided:
Benzyl 55-tert-butoxycarbonylamino-5-cyanomethylcarbamoylpentylcarbamate (Compound 2); A NMR: d 1.37 (m, 15H), d 1.63 (m, ÍH), d 1.78 (m, ÍH), d 3.14 (dd, 2H, J = 13, 6Hz), d 4.07 (m, 2H), d 5.06 (s, 2H), d 5.42 (br s, ÍH), d 7.32 (m, 5H), d 7.48 (br s, ÍH); ES-MS m / z 419 (MH +); cyclohexyl 3S-tert-butoxycarbonylamino-N-cyano methylsuccinamate (Compound 3); A? MR: d 1.35 (m, 17H), d 1.72 (m, ÍH), d 1.83 (m, ÍH), d 2.66 (dd, ÍH, J = 18, 7Hz), d 2.96 (dd, ÍH, J = 18, 5Hz), d 4.15 (dd, 2H, J = 6, 2Hz), d 4 50 (m, ÍH), d 4.77 (m, ÍH), d 5 64 (br s, ÍH), d 7.11 ( br s, ÍH); ES-MS m / z 354 (MH +); ert-butyl 1 S-cyanomethylcarbamoyl-2- (1-formyl-1H-indol-3-yl) ethylcarbamate (Compound 4); A? MR: d 1.44 (s, 9H), d 3.23 (m, 2H), d 4.08 (m, 2H), d 4.46 (m, ÍH), d 4.95 (br s, ÍH), d 7.38 (m, 4H), d 7.62 (br s, ÍH); ES-MS m / z 371 (NH +); tert -butyl 2- (3-benzyloxymethyl-3H-imidazol-4-yl) -1S-cyanomethylcarbamate (Compound 5); 1H NMR: d 1.39 (s, 9H), d 3.09 (d, 2H, J = 7Hz), d 4.00 (d, 2H, J = 6Hz), d 4.42 (m, ÍH), d 4.45 (s, 2H) , d 5.29 (m, 2H), d 5.58 (br d, ÍH, J = 8Hz), d 6.79 (s, ÍH), d 7.29 (m, ÍH), d 7.49 (s, ÍH), d 7.93 (br s); ES-MS m / z 414 (MH +); ert-butyl 2- (4-benzyloxyphenyl) -lS-cyanomethylcarbamoylethylcarbamate (Compound 6); A NMR: d 1.40 (s, 9H), d 3.01 (t, 2H, J = 6Hz), d 4.07 (t, 2H, J = 6Hz), d 4.29 (m, ÍH), d 4.90 (br s, ÍH ), d 5.02 (s, 2H), d 6.40 (br s, ÍH), d 6.92 (d, 2H, J = 8Hz), d 7.09 (d, 2H, J = 8Hz), d 7.37 (m, 5H); ES-MS m / z 410 (MH +); and tert-butyl 1S-cyanomethyl-carbamoyl-2-cyclohexylethyl carbamate (Compound 7); A NMR: d 0.94 (m, 2H), d 1.20 (m, 3H), d 1.44 (m, 11H), d 1.71 (m, 6H), d 4.15 (m, 2H), d 4.30 (m, ÍH) , d 4.87 (br s, ÍH), d 7.04 (br s); ES-MS m / z 210 (M-BuC02).
EXAMPLE 2
N- (2-benzylsulfanyl-J? -cyanomethylcarbamoylethyl) benzamide (Compound 8)
A mixture composed of 2i? -benzoylamino-3-benzylsulfanylpropionic acid (0.508g, 1.61mmol), aminoacetonitrile hydrochloride (0.149g, 1.61mmol), PyBOP® (0.838g, 1.61mmol), N, N-diisopropylethylamine (0.8 ml) 4.83mmol) and DMF (10 ml) was stirred at room temperature for 2.5 hours. The mixture was concentrated and the residue was taken up in dichloromethane. The dichloromethane mixture was washed with 1? of hydrochloric acid, water and aqueous sodium bicarbonate, dried (MgSO4), filtered and concentrated. The product was purified from the residue by silica gel chromatography using 5% methanol in dichloromethane to provide N- (2-benzylsulfanyl-lJ? -cyanomethylcarbamoyl) ethyl) benzamide (541 mg, 1.53 mmol) as an oil. MS: m / e 353.8 (theory 353.1); Proton Rγ spectrum (DMSO-d6): d 8.85 (t, ÍH), d 8.75 (d, ÍH), d 7.99 (d, 2H), 7.5 (m, 3H), d 7.3 (m, 5H) , d 4.7 (m, ÍH), d 4.15 (d, 2H), d 3.75 (s, 2H), d 2.8 (m, 2H) ppm.
By proceeding as in Example 2 the following compounds of Formula I are provided:
N- [l.R-cyanomethylcarbamoyl-2- (4-methylbenzylthioethyl)] benzamide (Compound 9); MS: m / e 367.9 (theory 367.1); Spectrum? MR (DMSO-d6): d 8.82 (t, ÍH), d 8.69 (d, ÍH), d 7.88 (d, 2H), d 7.5 (m, 3H), d 7.16 (d, 2H), d 7.08 (d, 2H), d 4.7 (m, ÍH), d 4.2 (d, 2H), d 3.7 (s, 2H), d 2.75 (m, 2H), d 2.1 (s, 3H) ppm; N- [lJ? -cyanomethylcarbamoyl) -2- (4-methoxybenzylthio ethyl)] benzamide (Compound 10); MS: m / e 383.9 (theory 383.1); Spectrum? MR (DMSO-d6): d 8.8 (t, ÍH) d 8.65 (d, ÍH) d 7.9 (d, 2H), d 7.5 (m, 3H), d 7.25 (d, 2H), d 6.8 (d, d, 2H), d 4.7 (m, HH) d 4.2 (d, 2H), d 3.7 (s, 3H), d 3.3 (s, 2H), d 2.8 (m, 2H) ppm; N- [2-benzyloxy-lS-cyanomethylcarbamoylethyl] benzamide (Compound 11); MS: m / e 337.8 (theory 337.1); Spectrum? MR (DMSO-de): d 8.82 (t, ÍH) d 8.67 (d, J = 7.8Hz, ÍH) d 7.91 (d, J = 7Hz, 2H), d 7.5 (m, 3H), d 7.3 (m, 5H), d 4.8 (m, HH) d 4.54 (s, 2H), d 4.17 (d, 2H), d 3.7 (m, 2H) ppm; benzyl l-cyanomethylcarbamoyl-3-methylthiopropyl carbamate (Compound 12); MS: m / e 321.8 (theory 321.1); Spectrum? MR (DMSO-d6): d 8.7 (t, ÍH) d 7.6 (d, ÍH) d 7.3 (m, 5H), d 5.0 (q, 2H), d 4.1 (m, 3H), d 3.3 ( d, 2H), d 2.4 (m, 2H), d 1.9 (s, 3H,) ppm;
N- [lS-cyanomethylcarbamoyl-3-methylthiopropyl] benzamide (Compound 13); MS: m / e 291.7 (theory 291.1); Spectrum R R (DMSO-d6): d 8.7 (t, J = 5.6Hz, HH), d 8.6 (d, J = 7.7Hz, HH), d 7.9 (m, 2H), d 7.5 (m, 3H ), d 4.5 (m, ÍH), d 4.11 (d, J = 5.6Hz, 2H), d 2.5 (m, 2H), d 2.03 (s, 3H), d 2.0 (m, 2H) ppm; benzyl 2-benzylthio-1,1-cyanomethylcarbamoyl-ethylcarbamate (Compound 14); MS: m / e 383.8 (theory 383.1); Spectrum? MR (DMSO-d6): d 8.8 (t, ÍH), d 7.8 (d, ÍH), d 7.4 (m, 10H), d 5.1 (q, 2H), d 4.1 (m, ÍH), d 4.2 (s, 2H), d 3.8 (s, 2H), d 2.8 (m, ÍH), d 2.6 (m, ÍH) ppm; methyl 4-benzyloxycarbonylamino-4S-cyanomethylcarbamoylbutyrate (Compound 15); MS: m / e 333.6 (theory 333.1); Spectrum? MR (DMSO-d6): d 8.7 (t, ÍH), d 7.7 (d, ÍH), d 7.4 (m, 5H), d 5.0 (q, 2H), d 4.0 (m, ÍH), d 3.55 (s, 3H), d 3.3 (d, 2H), d 2.3 (t, 2H), d 1.8 (m, 2H) ppm; tert-butyl 2-benzyloxy-lS-cyanomethylcarbamoylethyl carbamate (Compound 16); MS: m / e +? A 355.7 (theory 355.1);
Spectrum? MR (DMSO-d6): d 8.7 (t, ÍH), d 7.0 (d, ÍH), d 7.3 (m, 5H), d 4.45 (s, 2H), d 4.2 (m, ÍH), d 4.1 (d, 2H), d 3.55
(m, 2H), d 1.4 (s, 9H) ppm; benzyl 2-benzyloxy-lS-cyanomethylcarbamoylethyl carbamate (Compound 17); Spectrum? MR (DMSO-d6): d 8.8 (t, ÍH), d 7.7 (d, ÍH), d 7.4 (m, 10H), d 5.0 (q, 2H), d 4.5 (s, 2H), d 4.3 (m, ÍH), d 4.1 (s, 2H), d 3.6 (m, 2H) ppm;
N- (1-cyanomethylcarbamoylpent-3-ynyl) benzamide (Compound 18); MS: m / e 269.7 (theory 269.1); Spectrum? MR (DMSO-de): d 8.8 (t, ÍH), d 8.65 (d, ÍH), d 7.9 (d, 2H), d 7.5 (, 3H), d 4.5 (m, ÍH), d 4.1 (d, 2H), d 2.5 (m, 2H), d 1.7 (s, 3H) ppm; N- (1 S-cyanomethyl-carbamoyl-2-naphthalene-1-ylethyl) benzamide (Compound 19); A? MR: d 3.45 (dd, ÍH, J = 14, 9Hz), d 3.73 (dd, ÍH, J = 17, 6Hz), d 3.90 (dd, ÍH, J = 19, 6Hz), d 4.04 (dd , HH, J = 14, 6Hz), d 4.98 (m, HH), d 6.67 (m, HH) d 6.93 (m, HH), d 7.46 (m, 9H), d 7.74 (m, 2H), d 8.23 (d, ÍH, J = 8Hz); ES-MS M / z 358 (? H +); N- [2- (4-chlorophenyl) -lS-cyanomethylcarbamoylethyl] benzamide (Compound 20); 1H? MR: d 3.19 (m, 2H), d 3.96 (dd, ÍH, J = 19, 4Hz), d 4.10 (dd, ÍH, J = 20, 6Hz), d 4.98 (m, ÍH), d 6.79 (d, ÍH, J = 7Hz), d 7.07 (m, 2H), d 7.22 (m, 2H), d 7.43 (m, 4H), d 7.69 (m, ÍH), d 8.08 (d, ÍH, J = 8Hz); ESMS m / z 342 (MH +); N- (lg-cyanomethylcarbamoyl) -2-naphthalene-2-ylethyl benzamide (Compound 21); A? MR: d 3.29 (d, 2H, J = 7Hz), d 3.81 (dd, 2H, J = 18, 6Hz), d 3.98 (dd, ÍH, J = 18, 6Hz), d 5.09 (dd, ÍH , J = 15, 7Hz), d 6.74 (br d, ÍH, J = 7Hz), d 7.37 (m, 6H), d 7.68 (m, 6H); ES-MS m / z 358 (MH +); N- [l-Cyanomethylcarbamoyl-2- (4-cyanophenyl) ethyl] benzamide (Compound 22); A? MR: d 3.18 (dd, ÍH, J = 14, 7Hz), d 3.30 (dd, ÍH, J = 15, 7Hz), d 4.03 (dd, ÍH, J = 17, 6Hz), d 4.15 (dd , ÍH, J = 19, 6Hz), d 4.93 (dd, ÍH, J = 15, 8Hz), d 6.81 (d, ÍH, J = 10Hz), d 7.30 (m, 2H), d 7.43 (m, 3H ), d 7.55 (m, 2H), d 7.67 (d, 2H, J = 8Hz); ES-MS m / z 333 (MH +); N-. { lS-cyanomethylcarbamoyl -2 - [4- (2,6-dichlorobenzyl) phenyl] ethyl} benzamide (Compound 23); 1H? MR: d 3.15 (m, 2H), d 4.08 (t, 2H, J = 6Hz), d 4.84 (dd, ÍH, J = 16, 7Hz), d 5.24 (m, 3H), d 6.87 (d , ÍH, J = 8Hz), d 6.98 (m, 4H), d 7.18 (d, 2H, J = 9Hz), d 7.32 (m, 4H), d 7.78 (d, 2H, J = 8Hz); ES-MS m / z 482 (MH +); cyclohexyl 4-benzoylamino-4S-cyanomethylcarbamoyl butyrate (Compound 24); A? MR: d 1.37 (m, 5H), d 1.53 (m, 2H), d 1.68 (m, 2H), d 1.83 (m, ÍH), d 2.17 (m, 2H), d 2.42 (m, ÍH) ), d 2.66 (m, ÍH), d 4.15 (m, 2H), d 4.68 (m, 2H), d 7.47 (m, 3H), d 7.79 (m, 2H); ES-MS m / z 372 (MH +); N- [2- (4-benzoylphenyl) -lff-cyanomethylcarbamoylethyl] benzamide (Compound 25); A? MR: d 3.27 (m, 2H), d 4.00 (dd, ÍH, J = 15, 6Hz), d 4.13 (m, ÍH, J = 17, 6Hz), d 4.23 (d, ÍH, J = 6Hz ), d 4.97 (dd, ÍH, J = 15, 8Hz), d 6.96 (d, ÍH, J = 9Hz), d 7.46 (m, 9H), d 7.71 (m, 5H); ES-MS m / z 412 (MH +); N- (1 S-cyanomethyl-2-carbamoyl-2-phenylethyl) benzamide (Compound 26); A? MR: d 3.15 (dd, ÍH, J = 12, 6Hz), d 3.25 (dd, ÍH, J = 15, 6Hz), d 4.08 (t, 2H, J = 6Hz), d 4.84 (dd, ÍH , J = 15, 6Hz), d 6.68 (br s, ÍH), d 6.77 (br s, ÍH), d 7.29 (m, 5H), d 7.41 (m, 2H), d 7.53 (m, ÍH), d 7.67 (d, 2H, J = 9Hz); ES-MS m / z 308 (MH +); N- [lS-cyanomethylcarbamoyl-2- (lH-indol-3-yl) ethyl benzamide (Compound 27); A NMR: d 3.25 (dd, ÍH, J = 16, 8Hz), d 3.52 (dd, ÍH, J = 16, 6Hz), d 3.95 (dd, ÍH, J = 18, 4Hz), d 4.07 (dd, ÍH, J = 18, 6Hz), d 4.93 (m, ÍH), d 6.44 (br s, ÍH), d 6.85 (d, ÍH, J = 5Hz), d 7.22 (m, 3H), d 7.38 (m , 3H), d 7.50 (m, ÍH), d 7.67 (m, 2H, J = 8Hz), d 7.74 (d, ÍH, J = 8Hz), d 8.18 (br s, ÍH); ES-MS m / z 347 (MH +); N- [lS-cyanomethylcarbamoyl-2- (4-fluorophenylethyl)] benzamide (Compound 28); A? MR: d 3.15 (m, 2H), d 3.97 (dd, ÍH, J = 18, 6Hz), d 4.11 (dd, ÍH, J = 18, 6Hz), d 4.90 (dd, ÍH, J = 15 , 8Hz), d 6.95 (m, 3H), d 7.20 (m, 2H), d 7.46 (m, 3H), d 7.68 (d, ÍH, J = 8Hz); ES-MS m / z 326 (MH +); N- [2- (2-chlorophenyl) -lS-cyanomethylcarbamoylethyl] benzamide (Compound 29); A? MR: d 3.34 (m, 2H), d 4.04 (dd, ÍH, J = 16, 6Hz), d 4.17 (dd, ÍH, J = 16, 6Hz), d 4.93 (dd, ÍH, J = 16 , 6Hz), d 6.85 (m, ÍH), d 7.24 (m, 4H), d 7.44 (m, 3H), d 7.72 (m, 2H); ES-MS m / z 342 (MH +); N- [l S-cyanomethylcarbamoyl-2- (4-methoxyphenylethyl)] benzamide (Compound 30); A? MR: d 3.13 (m, 2H), d 3.76 (m, 4H), d 4.06 (dd, ÍH, J = 11, 6Hz), d 4.80 (m, ÍH), d 6.83 (m, 4H), d 7.16 (d, ÍH, J = 9Hz), d 7.46 (m, 2H), d 7.66 (m, 2H); ES-MS m / z 338 (MH +);
N- [2- (4-benzyloxyphenyl) -1-cyanomethylcarbamoylethyl] benzamide (Compound 31); A? MR: d 3.07 (m, 2H), d 3.90 (m, ÍH), d 4.02 (, ÍH), d 4.94 (s, 2H), d 4.95 (m, ÍH), d 6.70 (m, ÍH) , d 6.85 (m, 2H), d 7.09 (m, 2H), d 7.38 (m, 7H), d 7.72 (m, 3H); ES-MS m / z 414 (MH +); benzyl N- (lS-cyanomethylcarbamoyl-2-cyclohexylethyl) isophthalamate (Compound 32); A? MR: d 0.86 (m, 2H), d 1.09 (, 2H), d 1.39 (m, 5H), d 1.67 (m, 4H), d 3.04 (m, ÍH), d 3.63 (m, ÍH) , d 4.11 (m, ÍH), d 4.60 (m, ÍH), d 4.77 (, ÍH), d 5.33 (s, 2H), d 7.38 (m, 5H), d 8.01 (d, ÍH, J = 9Hz ), d 8.14 (m, 2H), d 8.45 (d, ÍH, J = 12Hz); ES-MS m / z 448 (MH +); benzyl N- (l-cyanomethylcarbamoyl-2-cyclohexylethyl) terephthalamate (Compound 33); A? MR: d 0.89 (m, 2H), d 1.13
(m, 3H), d 1.38 (m, 4H), d 1.66 (m, 4H), d 3.10 (m, ÍH), d 3.64 (m, ÍH), d 4.10 (m, ÍH), d 4.80 (dd) , ÍH, J = 15, 8Hz), d
. 34 (d, 2H, J = 2Hz), d 7.37 (m, 5H), d 7.84 (d, 2H, J = 7
Hz), d 8.03 (m, 2H); ES-MS m / z 448 (MH +); N- [l-Cyanomethylcarbamoyl-2- (2-fluorophenyl) ethyl] benzamide (Compound 34): A? MR: d 3.23 (m, 2H), d 4.06 (dd, ÍH, J = 18, 6Hz), d 4.15 (dd, ÍH, J = 18, 6Hz), d 4.91 (dd, ÍH, J = 15, 8Hz), d 7.01 (m, 2H), d 7.23 (m, ÍH), d 7.41 (m, 2H), d 7.52 (m, 2H), d 7.68 (d, 2H, J = 8Hz); ES-MS m / z 326 (MH +);
N- (2-benzylthio-1,3-cyanomethylcarbamoylethyl) -2- (3,5-dimethoxyphenyl) thiazole-4-carboxamide (Compound 35); MS: Caled. 496; Find M + 1 = 497; N- (lS-cyanomethylcarbamoyl-2-cyclohexylethyl-2- (3,5-dimethoxyphenyl) thiazole-4-carboxamide (Compound 36); MS: Caled .456; Find M + 1 = 457; N- (l-cyanomethylcarbamoylpent- 3-enyl) benzamide (Compound 37); MS: m / e 271.8 (theory 271.1); Spectrum? MR (DMSO-de): d 8.7 (t, ÍH), d 8.657 (d, ÍH), d 7.9 (d , 2H), d 7.5 (m, 3H), d 5.4 (m, 2H), d 4.5 (m, ÍH), d 4.1 (d, 2H), d 2.5 (m, 2H), d 2.6 (d, 3H) ) ppm; 4-ert-butyl-N- (lS-cyanomethylcarbamoyl-2-cyclohexylethyl) benzamide (Compound 38); 1H? MR (CDC13): d 8.02 (br s, ÍH), d 7.73 (d, 2H, J = 8.7Hz), d 7.43 (d, 2H, J = 8.5Hz), d 7.05 (br d, ÍH, J = 8.5Hz), d 4.79 (dd, ÍH, J = 15.1, 8.7Hz), d 4.10 (dd, 2H, J = 19.9Hz, 5.6Hz), d 1.51 - 1.82 (m, 5H), d 1.30 (s, 9H), d 0.83 - 1.72 (m, 8H); MS (M + = 369.9); N- [lS-cyanomethylcarbamoyl-2-cyclohexylethyl] pyrimidine-5-carboxamide (Compound 39); A? MR (CDC13): d 9.33 (s, ÍH), d 8.77 (s, ÍH), d 8.56 (s, ÍH) ), d 8.14 (br d, ÍH, J = 8.7 Hz), d 7.30 (br s, ÍH), d 4.69 (dd, ÍH, J = 14.9, 9.2Hz), d 4.15 (t, 2H, J = 3.9Hz), d 0.76-2.30 (m, 13H); The MS (M + = 315.9); N- (1-cyanomethylcarbamoyl-2-cyclohexylethyl) naphthalene-1-carboxamide (Compound 40); A? MR (CDC13): d 8.19 (br d, ÍH, J = 10. OHz), d 7.81 - 7.96 (m, 3H), d 7.47 - 7.62 (m, 3H), d 7.35 - 7.44 (m, ÍH ), d 6.69 (d, ÍH, J = 8.7Hz), d 4.90 (dd, ÍH, J = 15.4, 9.0), d 4.03 (d, 2H, J = 4.9Hz), d 0.79 - 1.89 (m, 13H ); The MS (M + = 364.0); N- (lS-cyanomethylcarbamoyl-2-cyclohexylethyl) -4-fluorobenzamide (Compound 41); A? MR (CDC13): d 7.70 - 7.83
(m, 2H), d 7.43 (br s, 1 H), d 7.11 (t, 2H, J = 8.7Hz), d
6. 66 (br d, ÍH, J = 8.5Hz), d 4.69 (dd, ÍH, J = 15.5, 9.4Hz), d 4.14 (dd, 2H, J = 19.6, 8.4Hz), d 0.67 - 1.88 (m, 13H); The MS (M + = 331.6); N- (lS-cyanomethylcarbamoyl-2-cyclohexylethyl) -4-hydroxybenzamide (Compound 42); 1H? MR (CDC13): d 7.64 (d,
2H, J = 9.0Hz), d 7.39 (br s, ÍH), d 6.83 (d, 2H, J = 9.5Hz), d 6.43 (br d, ÍH, J = 11.2Hz), d 4.64 (dd, ÍH , J = 16.8, 5.6Hz), d 4.14-4.09 (m, 2H), d 0.81-1.89 (m, 13H); The MS
(M + = 329.8); N- (lg-cyanomethylcarbamoyl-2-cyclohexylethyl) naphthalene-2-carboxamide (Compound 43); A? MR (CDC13): d 8.29 (s, ÍH), d 7.76 - 7.94 (m, 5H), d 7.51 - 7.61 (m, 2H), d 6.57 (br d, ÍH, J = 19.6Hz), d 4.73 (dd, ÍH, J = 19.6, 11.2Hz), d 4.17 (dd, 2H, J = 13.3, 8.4Hz), d 0.80-2.03 (m, 13H); The MS (M + = 363.9); N- (lS-cyanomethylcarbamoyl-2-cyclohexylethyl) -4-tri fluoromethylbenzamide (Compound 44); 1H? MR (CDC13): d 7.86 -7.91 (m, 2H), d 7.70-7.75 (m, 2H), d 6.85 (br s, ÍH), d 6.48 (br d, ÍH, J = 8.4Hz), d 4.65 (dd, ÍH, J = 19.6, 11.2Hz), d 4.09-4.20 (m, 2H), d 0.86-1.74 (m, 13H); The MS (M + = 381.9); N- (lS-cyanomethylcarbamoyl-2-cyclohexylethyl) -4-methoxybenzamide (Compound 45); A? MR (CDC13): d 7.70-7.73 (m, 3H), d 6.94 (d, 2H, J = 8.5Hz), d 6.29 (br s, ÍH), d 4.57
- 4.69 (m, ÍH), d 4.08 - 4.17 (m, 2H), d 3.85 (s, 3H), d 0.78
- 1.73 (m, 13H); The MS (M + = 343.9); N-cyanomethyl-3-cydohexyl-2-g-methylsulfonylamino propionamide (Compound 46); 1H? MR (CDC13): d 7.05 (br s, ÍH), d 5.29 (br d, ÍH, J = 8.7 Hz), d 4.12 - 4.20 (m, ÍH), d 3.44 (d, 2H, J = 9.7 Hz), d 3.01 (s, 3H), d 0.81-1.92 (m, 13H); N- (1 S-cyanomethylcarbamoyl-2-cyclohexylethyl) acetamide (Compound 47); 1H? MR (CDC13): d 7.51 (br s, ÍH), d 6.15 (br d, ÍH, J = 8.0 Hz), d 4.49 (dd, ÍH, J = 17.8, 11.4 Hz), d 4.11 (t, 2H, J = 18.6Hz), d 2.02 (s, 3H), d 0.72-1.80 (m, 13H); The MS (M + = 251.6); N- (1-cyanomethyl-2-carbamoyl-2-cyclohexylethyl) -3-fluoro-benzamide (Compound 48); A? MR (CDC13): d 7.19 - 7.55 (m,
5H), d 6.72 (br s, ÍH, J = 8.7Hz), d 4.69 (dd, ÍH, J = .10.8,
3. 8Hz), d 4.14 (dd, 2H, J = 2.8, 15.7Hz), d 0. 86 - 1.86 (m,
13H); The MS (M + = 331.9); 4-chloro-N- (l-cyanomethylcarbamoyl-2-cyclohexylethyl) benzamide (Compound 49); 1H? MR (CDC13): d 8.78 (br s, ÍH), d 8.58 (br d, ÍH, J = 8.0Hz), d 7.85 (d, 2H, J = 9.0Hz), d 7.48 (d, 2H, J = 9.2Hz), d 4.64 (dd, ÍH, J = 7.4, 14.1Hz), d 4.16 (dd, 2H, J = 3.1, 6.1Hz), d 0.87 - 1.85 (m, 13H); The MS (M + = 347.9); N- (1-cyanomethylcarbamoyl-2-cyclohexylethyl) -2-tri fluoromethylbenzamide (Compound 50); 1H? MR (CDC13): d 7.42 -7.78 (, 5H), d 6.56 (br d, ÍH, J = 9.0Hz), d 4.81 (dd, ÍH, J = 15.4, 9.2Hz), d 4.10 (t, 2H, J = 5.7Hz), d 0.80-1.79 (m, 13H); The MS (M + = 382.0); N- (1-cyanomethylcarbamoyl-2-cyclohexylethyl) -2-fluorobenzamide (Compound 51); A? MR (CDC13): d 8.00 (t, ÍH, J = 8.4Hz), d 7.64 (br s, ÍH), d 7.50 (dd, ÍH, J = 8.1, 2.5Hz), d 7.24 - 7.30 (m , 1 H), d 7.07 - 7.18 (m, 2H), d 4.76 (dd, ÍH, J = 17.2, 8.2Hz), d 4.16 (dd, 2H, J = 18.0, 6.2Hz), d 0.81 -1.89 ( m, 13H); The MS (M + = 331.9); N- (1-cyanomethylcarbamoyl-2-cyclohexylethyl) -4-tri fluoromethoxybenzamide (Compound 52); 1H? MR (CDC13): d 7.01 -8.02 (m, 6H), d 4.75 (br d, ÍH, J = 14.6 Hz), d 4.14 (dd, 2H, J = 6.0, 18.2Hz), d 0.78 - 1.90 (m, 13H); The MS (M + = 398.0); N- (1-cyanomethylcarbamoyl-2-cyclohexylethyl) -2,6-difluorobenzamide (Compound 53); A? MR (CDC13): d 7.66 (br s, ÍH), d 7.39 (t, ÍH, J = 8.7Hz), d 6.95 (t, 2H, J = 8.7Hz), d 6.74 (br d, ÍH, J = 8.5Hz), d 4.85 (dd, ÍH, J = 14.9, 9.2Hz), d 0.86-1.87 (m, 13H); The MS (M + = 349.9);
N- (1-cyanomethylcarbamoyl-2-cyclohexylethyl) -2,3-difluorobenzamide (Compound 54); A? MR (CDC13): d 8.04 (dd, ÍH, J = 15.3, 8.7Hz), d 7.55 (br s, ÍH), d 6.84 - 7.07 (m, 3H), d 4.74 (dd, ÍH, J = 16.6, 7.9Hz), d 4.16 (dd, 2H, J = 18.0, 5.9Hz), d 0.82-1.89 (m, 13H); The MS (M + = 349.9); N- (1-cyanomethylcarbamoyl-2-cyclohexylethyl) -2,5-difluorobenzamide (Compound 55); A? MR (CDC13): d 7.69 (m, ÍH), d 7.37 (br s, ÍH), d 7.08 - 7.27 (m, 3H), d 4.71 (dd, ÍH, J = 15.1, 6.1Hz), d 4.16 (dd, 2H, J = 18.0, 6.2Hz), d 0.84-1.90 (m, 13H); The MS (M + = 350.1); N- (1-cyanomethylcarbamoyl-2-cyclohexylethyl) -2,4-difluorobenzamide (Compound 56); A? MR (CDC13): d 7.80 (br s, ÍH), d 7.65 (t, ÍH), d 7.14 - 7.36 (m, 3H), d 4.79 (dd, ÍH, J = 14.9, 7.2Hz), d 4.15 (dd, 2H, J = 18.2, 5.9Hz), d 0.80-1.81 (m, 13H); The MS (M + = 349.9); N- (1-cyanomethylcarbamoyl-2-cyclohexylethyl) -3,4-dimethoxybenzamide (Compound 57); A? MR (CDC13): d 7.66 (br s, ÍH), d 7.28 - 7.41 (m, 2H), d 6.86 (d, ÍH, J = 8.4Hz), d 6.73 (br d, ÍH, J = 7.9 Hz), d 4.71 (dd, ÍH, J = 14.1, 8.4Hz), d 4.14 (dd, 2H, J = 17.3, 5.9Hz), d 3.91 (s, 6H), d 0.81 -1.88 (m, 13H); The MS (M + = 374); N- (1-cyanomethylcarbamoyl-2-cyclohexylethyl) -3,5-dimethoxybenzamide (Compound 58); A? MR (CDC13): d 7.41 (br s, ÍH), d 6.88 (d, 2H, J = 2.4Hz), d 6.59 (t, 2H, J = 2.2Hz), d 4.67 (dd, ÍH, J = 16.8, 3.0Hz), d 4.12 (dd, 2H, J = 17.3, 5.7Hz), d 3.81 (s, 6H), d 0.82 - 1.88 (m, 13H); The MS (M + = 374); N- (1-cyanomethylcarbamoyl-2-thiazol-5-ylethyl) benzamide (Compound 59); A? MR (CDC13): d 8.30 (d, 2H, J = 8.7Hz), d 7.72 (br s, ÍH), d 7.38 - 7.67 (m, 4H), d 7.13 (t, 2H, J = 8.0Hz ), d 4.96 (dd, ÍH, J = 12.3, 5.9Hz), d 4.02 (t, 2H, J = 10.5Hz), d 3.48 (dd, 2H, J = 15.7, 5.4Hz); N- (1-cyanomethyl-2-carbamoyl-2-thien-2-ylethyl) -benzamide (Compound 60); A? MR (CDC13): d 7.71 (d, 2H, J = 8.5Hz), d 7.39 - 7.55 (m, 4H), d 7.14 (d, ÍH, J = 11.2Hz), d 6.85 -6.96 (m, 3H), d 4.94 (dd, ÍH, J = 14.6, 6.9Hz), d 4.09 (m, 2H), d 3.41 (t, 2H, J = 6.2Hz); The MS (M + = 313.8); N- (1 Scynomethylcarbamoyl-2-cyclohexylethyl) benzamide (Compound 61); ? MR Proton (300 MHz, CDC13): d 7.79 (d, J = 7Hz, 2H), d 7.67 (bt, ÍH), d 7.44 (m, 3H), d 6.75 (bd, ÍH), d 4.74 (m , ÍH), d 4.10 (, 2H), d 1.50 - 1.88 (m, 8H), d 0.83 -1.44 (m, 5H). MS (electroaspersion): mH + 313.9 (100%); and N-cyanomethyl-3-cyclohexyl-2 S-trifluoromethylsulfonyl aminopropionamide (Compound 62).
EXAMPLE 3
tert-Butyl 5-amino-lS-cyanomethylcarbamoylpentylcarbamate (Compound 63)
A solution comprised of benzyl 5S-tert-butoxycarbonylamino-5-cyanomethylcarbamoylpentyl carbamate (77mg, 184 mmol), prepared as in Example 1, in ethanol (2 ml) was treated with ammonium formate (116 mg, 1.84 mmol) and 10% by weight of palladium on carbon (77 mg). The mixture was stirred for 15 hours and then filtered through Celite. The filter cake was washed with ethanol and the combined filtrates were concentrated on a rotary evaporator to give tert-butyl 5-amino-1S-cyanomethylcarbamoylpetiylcarbamate (61 mg, 184 mmol) as a white solid. 1H NNR (DMSO-d6): d 1.42 (m, 17H), d 2.63 (m, 2H), d 3.09 (m, 2H); ES-MS m / z 323 (MK +).
EXAMPLE 4
N- (lS-Cyanomethylcarbamoyl-2-cyclohexylethyl) isophthalamic acid (Compound 64)
A solution comprised of benzyl N-. { 1S-cyanomethylcarbamoyl-2-cyclohexylethyl) isophthalamate (82.4 mg, 184 μmol, 1.0 eq), prepared as in Example 2, in ethanol (2 ml) was treated with ammonium formate (116 mg, 1.84 mmol, 10.0 eq) and 10% by weight of palladium on carbon (82.4 mg). The mixture was stirred for 15 hours and filtered through Celite. The filter cake was washed with ethanol and the combined filtrates were concentrated on a rotary evaporator to give N- (lS-cyanomethylcarbamoyl-2-cyclohexylethyl) terephthalamic acid (61 mg, 170.7 μmol) as a white solid. A? MR (MeOH-d4): d 0.96 (m, 2H), d 1.26 (m, 2H), d 1.38 (m, 4H), d 1.76 (m, 5H), d 3.23 (d, ÍH, J = 8Hz), d 3.72 (t, ÍH, J = 7Hz), d 4.50 (m, ÍH), d 7.50 (m, ÍH), d 7.97 (, ÍH), d 8.13 (m, ÍH), d 8.46 (m , ÍH); ES-MS m / z 359 (MD +). By proceeding as in Example 4 the following compounds of Formula I are provided: N- (1-cyanomethyl-2-carbamoyl-2-cyclohexylethyl) terephthalamic acid (Compound 65); A? MR (MeOH-d4): d 0.96 (m, 2H), d 1.32 (m, 5H), d 1.81 (m, 6H), d 3.12 (m, 2H), d 4.92 (m, ÍH), d 7.87 (m, 2H), d 8.02 (m, 2H); ES-MS m / z 359 (MD +); N- [l-cyanomethylcarbamoyl-2- (2,6-dichlorophenyl) ethyl] benzamide (Compound 66); A? MR: d 3.45 (m, ÍH), d 3.56 (m, ÍH), d 4.13 (m, 2H), d 5.03 (m, ÍH), d 7.30 (m, 5H), d 7.63 (m, 3H) ); ES-MS m / z 376 (MH +); and N- (l-cyanomethylcarbamoyl-2-cyclohexylethyl) phthalamic acid (Compound 67); A? MR (MeOH-d4): d 0.94 (d, 2H, J =
7Hz), d 0.97 (d, 2H, J = 7Hz), d 1.28 (d, 2H, J = 7Hz), d 1.47 (m, ÍH), d 1.73 (m, 6H), d 3.09 (t, ÍH; J = 6 Hz) d 3.29 (m, ÍH), d 4.45 (dd, ÍH, J = 11, 5Hz), d 7.36 (m, ÍH) d 7.58 (m, 2H), d 7.72 (m, ÍH); ES-MS m / z 359 (MD +). EXAMPLE 5 N- (lS-Cyanomethylcarbamoyl-2-cyclohexylethyl) morpholine-4-carboxamide (Compound 68)
A mixture of lithium 2S-amino-3-cyclohexylpropionate (260 μmol, 1.0 eq), provided as in Reference 1, EDC (286 μmol, 1.1 eq), HOBt (312 μmol, 1.2 eq) and triethylamine (911 μmol, 3.5 eq) in dry dichloromethane (1 ml) was stirred under a nitrogen atmosphere for 5 minutes and then treated with aminoacetonitrile hydrochloride (520 μmol, 2.0 eq). The mixture was stirred 15 hours and then diluted with ethyl acetate (1 ml). The dilution was washed with 1 M hydrochloric acid (2x ml), saturated NaHCO 3 (1 ml) and saturated NaCl (1 ml), dried over Na 2 SO 4, filtered and concentrated on a rotary evaporator to give N- (1 S-cyanomethylcarbamoyl) -2-cyclohexylethyl) molfoline-4-carboxamide. ÍH? MR (CDC13) 0.95 (m, 2H); 1.23 (m, 4H); 1.62 (m, 7H); 3.35 (m, 4H); 3.68 (m, 4H); 4.05 (dd, 2H, J = 16, 6Hz); 4.17 (dd, 2H, J = 18, 6Hz); 4.27 (m, ÍH); 5.01 (d, ÍH, J = 8Hz); 7.93 (t, ÍH, J = 6Hz); ES-MS m / z 323 (MH +).
By proceeding as in Example 5 the following compounds of Formula I are provided:
N- (lS-cyanomethylcarbamoyl-2-cyclohexylethyl) piperidine-1-carboxamide (Compound 69); ÍH? MR 0.95 (CDC13) (m, 2H); 1.24 (m, 6H); 1.60 (m, 11H); 3.54 (m, 4H); 4.11 (m, 2H); 4.33 (m, ÍH); 4.75 (d, ÍH, J = 8Hz); 7.88 (t, ÍH, J = 6Hz); ES-MS m / z 321 (MH +);
tert-butyl 4- (lS-cyanomethylcarbamoyl-2-cyclohexyl ethylcarbamoyl) piperazine-1-carboxylate (Compound 70); ÍH NMR (CDC13) 0.89 (m, 2H); 1.23 (m, 4H); 1.44 (s, 9H); 1.66 (m, 7H); 3.36 (s, 4H); 3.40 (s, 4H); 4.03 (dd, ÍH, J = 18, 5Hz); 4.14 (dd, ÍH, J = 18, 6Hz); 4.38 (dd, ÍH, J = 15, 8Hz); 5.32 (d, ÍH, J = 8Hz); 8.21 (t, ÍH, J = 6Hz); ES-MS m / z 422 (MH +); N- (lS-cyanomethylcarbamoyl-2-cyclohexylethyl) -4-benzylpiperazine-1 -carboxamide (Compound 71); ÍH NMR (CDC13) 0.96 (m, 2H); 1.24 (m, 4H); 1.70 (m, 7H); 2.44 (t, 4H, J = 5Hz); 3.37 (t, 4H, J = 5Hz); 3.52 (s, 2H); 4.06 (dd, ÍH, J = 18, 6Hz); 4.15 (dd, ÍH, J = 18, 6Hz); 4.32 (m, ÍH); 7.30 (m, 5H); 7.72 (t, ÍH, J = 6Hz); ES-MS m / z 412 (MH +); 3-methoxybenzyl IS-cyanomethylcarbamoyl-2-cyclohexyl ethylcarbamic acid (Compound 72); ÍH NMR 0.96 (m, 2H); 1.24 (m, 4H); 1.70 (m, 7H); 3.78 (s, 3H); 4.12 (m, 2H); 4.21 (m, ÍH);5. 11 (m, 2H); 6.89 (m, 3H), 7.32 (m, ÍH); ES-MS m / z 374
(MH +); ethyl 4- (lS-cyanomethylcarbamoyl-2-cyclohexylethyl carbamoyl) piperazine-1-carboxylate (Compound 73); and N- (lS-cyanomethylcarbamoyl-2-cyclohexylethyl) -4-fur-2-ylcarbonylpiperazin-1 -carboxamide (Compound 74).
EXAMPLE 6
N-Cyanomethyl-3-cyclohexyl-2S- (3-phenethylureido) propionamide (Compound 75)
A solution of tert-butyl lS-cyanomethylcarbamoyl-2-cyclohexylethylcarbamate (103 mmol, 1 eq), provided as in Example 1, in diethylether (323 ml) was treated with toluenesulfonic acid monohydrate (206 mmol, 2.0 eq, azeotroped in a rotary evaporator with 2-propanol 3 times, until a white solid formed) for 12 hours. The supernatant was decanted and the solid washed extensively with diethyl ether until a powder formed. A portion of the resulting acid salt (789 μmol, 1 eq) was suspended in dry acetonitrile
(1 ml) and then treated with phenethyl isocyanate (789 μmol,
1. 0 eq) and 4-methylmorpholine (789 μmol, 1 eq) for 12 hours.
The mixture was concentrated in vacuo and the residue was dissolved in methylene chloride. The solution was stirred with 100 mg of Argonaut PS-trisamine resin (345 μmol, 0.4 eq) for 2 hours. The mixture was filtered, diluted with ethyl acetate (1 ml), washed with 1M hydrochloric acid (1 ml), saturated sodium bicarbonate solution and saturated NaCl solution, dried over sodium sulfate, filtered and concentrated provide N-cyanomethyl-3-cydohexyl-2S- (3-phenethylureido) propionamide.
Proceeding as in Example 6, N-cyanomethyl-3-cydohexyl-2 S- (3-isopropylureido) propionamide (Compound 76) was provided. By proceeding in a manner analogous to the procedures exemplified above, the following compounds of Formula I are provided: N- [lS-cyanomethylcarbamoyl-3-phenylpropyl] benzamide
(Compound 77); N- [l S-cyanomethylcarbamoyl-2- (4-hydroxyphenylethyl)] benzamide (Compound 78); N- (1-cyanomethylcarbamoyl-2-cyclohexylethyl) -3-hydroxybenzamide (Compound 79); MR MR 300mHz (DMSO-d6), 8.39 (d, J = 8.5H3, HH), 7.26 (m, 3H), 6.96 (m, HH), 4.64 (m, HH), 4.14 (dd, J = 4.2 and 17.3H3, 2H), 3.30 (m, 2H), 1.71 (m, 7H), 1.68-0.80 (m, 6H); MS = 329.85 M + = 329.40; 1-benzyl-5-benzyloxy-N- (1-cyanomethyl-2-phenylethyl) -2-methyl-1H-indole-3-carboxamide (Compound 80); MS: (m / z [mH +]) 557.0; N- (l-cyanomethylcarbamoyl-2-phenylethyl) -l-furan-2-ylmethyl-5-methoxy-2-methyl-1H-indole-3-carboxamide (Compound 81); MS: (m / z [mH +]) 470.6; N- (1-cyanomethylcarbamoyl-2-methylpropyl) -5-ethoxy-1-furan-2-ylmethyl-2-methyl-1H-indol-3-carboxamide (Compound 82); MS: (m / z [mH +]) 436.9; 1-benzo [1,3] dioxol-4-ylmethyl-N- (2-benzylsulfanyl-1-cyanomethylcarbamoylethyl) 5-methoxy-2-methyl-1-yl-indole-3-carboxamide (Compound 83); MS: (m / z [mH +]) 570.8; benzyl 5- (1-benzo [1.3] dioxol-4-ylmethyl-5-benzyloxy-2-methyl-lH-indol-3-ylcarbonylamino) -5-cyanomethylcarbamoylpentylcarbamate (Compound 84); MS: (m / z [mH +] 716.0; benzyl 5- (1-benzyl-5-benzyloxy-2-methyl-1H-indol-3-ylcarbonylamino) -5-cyanomethylcarbamoylpentylcarbamate (Compound 85); MS: (m / z [mH +) 672.4; benzyl 5-cyanomethylcarbamoyl-5- (l-furan-2-ylmethyl-5-methoxy-2-methyl-lH-indol-3-ylcarbonylamino) pentylcarbamate (Compound 86); MS: (m / z [mH +]) 586.8; N- (1-cyanomethylcarbamoylpent-3-enyl) benzamide (Compound 87); MR MR 300mHz (DMSO-d6), 8.67 (t, J = 6H3, HH), 8.53 (d, J = 8.5H3, HH), 7.86 (m, 2H), 7.50 (m, 3H), 5.35-5.7 ( m, 2H), 4.40 (m, ÍH), 4.12 (d, J = 6H3, 2H), 2.3-2.6 (m, 2H), 1.57 (d, J = 6.9H3, 3H); MS = 271.8 M + = 271.32; ? - (L-Cyanomethylcarbamoylpent-4-enyl) benzamide (Compound 88); MR 300mHz (DMSO-dβ), 8.66 (m, HH), 8.57 (d, J = 8.2H3, HH), 7.89 (m, 2H), 7.47 (m, 3H), 5.80 (m, HH), 4.9 -5.05 (m, 2H), 4.4 (m, ÍH), 4.11 (d, J = 2.5H3.2H), 2.1 (m, 2H), 1.83 (m, 2H); MS = 271.8 M + = 271.32;
N- (1-cyanomethylcarbamoylbutyl) benzamide (Compound
89); ? MR 300mHz (DMSO-d6), 8.66 (t, J = 5.8H3, ÍH), 8.53 (d,
J = 8.8H3, ÍH), 7.90 (m, 2H), 7.46 (m, 3H), 4.41 (m, ÍH), 4.12
(m, 2H), 1.70 (m, 2H), 0.87 (t, J = 8H3.3H); MS = 259.8 M + = 259.31; N- (1-cyanomethylcarbamoylpent-4-ynyl) benzamide (Compound 90); MR MR 300mHz (DMSO-d6), 8.67 (t, HH), 8.61 (d, J = 8.5H3, HH), 7.91 (m, 2H), 7.50 (m, 3H), 4.5 (m, HH), 4.12 (m, 2H), 2.83 (t, J = 2.5H3, ÍH), 2.25 (m, 2H), 1.97 (m, 2H); MS = 269.8 M + = 269.30; 2-chloro-N- (lS-cyanomethylcarbamoyl-2-cyclohexylethyl) benzamide (Compound 91); N- (lS-cyanomethylcarbamoyl-2-cyclohexylethyl) -2-iodobenzamide (Compound 92); A? MR (CDC13): 7.68 (t, J = 6Hz, ÍH), 7.34 (m, 4H), 6.41 (d, J = 8Hz, ÍH), 4.78 (m, ÍH), 4.13 (d, J = 12Hz, 2H), 2.0-0.8 (m, 13H); MS m / e 439.9; 2-bromo-N- (SS-cyanomethyl-carbamoyl-2-cyclohexylethyl) benzamide (Compound 93); A? MR (CDC13): 7.68 (t, J = 5.7Hz, ÍH), 7.58 (dd, J = 3, 12Hz, ÍH), 7.44 (dd, J = 2.1, 12Hz, ÍH), 7.34 (m, 2H ), 7.57 (d, J = 8Hz, ÍH), 4.79 (m, ÍH), 4.13 (d, J = 5.7Hz, 2H), 2.0-0.8 (m, 13H); MS m / e 393.7; N- (lS-cyanomethylcarbamoylhexyl) benzamide (Compound
94); A? MR (DMSO): 8.65 (t, J = 3Hz, ÍH), 8.54 (d, J = 8Hz,
ÍH), 7.91 (d, J = 7Hz, 2H), 7.5 (m, 3H), 4.4 (m, ÍH), 4.13 (d, J = 5Hz, 2H), 1.74 (m, 2H), 1.3 (m, 6H), 0.85 (t, J = 7Hz, 3H); MS: m / e = 287.8; N- (1 S-cyanomethylcarbamoyl-4-phenylbutyl) benzamide (Compound 95); A? MR (DMSO): 8.67 (t, J = 7Hz, ÍH), 8.56 (d, J = 9Hz, ÍH), 7.88 (d, J = 9Hz, 2H), 7.4 (m, 3H), 7.2 (m , 5H), 4.45 (m, ÍH), 4.11 (d, J = 5Hz, 2H), 2.58 (t, J = 8Hz, 2H), 1.7 (m, 4H); MS: m / e = 335.9; N- (1 S-cyanomethylcarbamoyl-2-cyclohexylethyl) 2-methoxy benzamide (Compound 96); N- (lS-cyanomethylcarbamoyl-2-cyclohexylethyl) -3,4,5-trimethoxybenzamide (Compound 97); benzyl S-cyanomethylcarbamoyl-2-cyclohexylethyl carbamate (Compound 98); isobutyl lS-cyanomethylcarbamoyl-2-cyclohexylethyl carbamate (Compound 99); cyclohexylmethyl lS-cyanomethylcarbamoyl-2-hexylethylcarbamic cycle (Compound 100); N- (lS-cyanomethylcarbamoyl-3-cyclohexylpropyl) benzamide (Compound 101); A? MR (DMSO): 8.66 (m, ÍH), 8.52 (d, J = 8Hz, ÍH), 7.88 (d, J = 8Hz, 2H), 7.45 (m, 3H), 4.37 (m, ÍH), 4.12 (m, 2H), 1.9 - 0.08 (m, 15H); MS: m / e = 328.3; N- (lS-cyanomethylcarbamoyl-2-cyclohexylethyl) -2-tri fluoromethoxybenzamide (Compound 102); A? MR (CDC13): 7.90 (dd, J = 3, 10Hz, ÍH), 7.79 (, ÍH), 7.535 (m, ÍH), 7.395 (m, ÍH), 7.31 (m, ÍH), 6.92 (d , J = 8Hz, HH), 4.74 (m, HH), 4.2 (dd, J = 6.17Hz, 1H), 4.1 (dd, J = 6.17Hz, HH), 0.8-1.8 (m, 13H);
MS: m / e = 397.9; N- (lg-cyanomethylcarbamoyl-2-cyclohexylethyl) -3-trifluoromethoxybenzamide (Compound 103); A? MR (CDC13): 7.68 (m, 2H), 7.44 (m, 3H), 7.03 (t, J = 6.6Hz, ÍH), 4.73 (m, ÍH), 4.38 (m, ÍH), 4.11 (m , 2H), 0.8-1.8 (m, 11H); MS: m / e = 397.9; N- (lS-cyanomethylcarbamoyl-2-cyclohexylethyl) -3-iodobenzamide (Compound 104); A? MR (CDC13): 8-1 (t, J = 2.8Hz, ÍH), 7.87 (d, J = 6.9Hz, ÍH), 7.70 (d, J = 7.7Hz, ÍH), 7.19 (t, J) = 17.5Hz, ÍH), 6.9 (m, ÍH), 6.44 (d, J = 12Hz, ÍH), 4.63 (m, ÍH), 4.21 (dd, J = 9.6, 6.6Hz, ÍH), 4.1 (dd, J = 9.6, 6.6Hz, ÍH) 0.8-2.0 (m, 13H); MS: m / e = 440.0; 3-chloro-N- (lS-cyanomethylcarbamoyl-2-cyclohexylethyl) benzamide (Compound 105); A? MR (CDC13): 7.5 (t, J = 5.2 Hz, 1 H), 7.65 (d, J = 7.63 Hz, ÍH), 7.51 (d, J = 6 Hz, ÍH), 7.39 (t, J = 8.8 Hz, ÍH), 6.59 (d, J = 9.9Hz, ÍH), 2.0-0.8 (m, 13H); MS: m / e = 348.0; 2-methoxyethyl-1S-cyanomethylcarbamoyl-2-cyclohexyl ethylcarbamate (Compound 106); N- (1 S-cyanomethylcarbamoyl-2-cyclohexylethyl) cyclohexanecarboxamide (Compound 107), N-cyanomethyl-3-cyclohexyl-2S- [2- (4-methoxyphenyl) acetylamino] propionamide (Compound 108); A? MR (CDC13): 7.83 (t, J = 6Hz, ÍH), 7.13 (d, J = 9Hz, 2H), 6.86 (d, J = 12Hz, 2H), 6.22 (d, J = 8Hz, ÍH) , 4.55 (m, ÍH), 3.95 (m, 2H), 3.78 (s, J = 0Hz, 3H), 0.8-1.8 (m, 13H); MS: m / e = 358.0;
N- (li.-cyanomethylcarbamoyl-2-cyclohexylethyl) -2-methylsulfanylbenzamide (Compound 109); A? MR: (CDC13) 8.11 (t, J = 5.5Hz, ÍH), 7.50 (d, J = 7.5Hz, ), 7.40 (t, J = 7.5Hz, ÍH), 7.30 (d, J = lHz, J = 7.9Hz, ÍH), 7.17 (t, J = 7.7Hz, ÍH), 6.94 (d, J = 8.4Hz , ÍH), 4.88 (m, ÍH), 4.16 (dd, J = 5.7Hz, J = 17.3Hz, ÍH), 4.08 (dd, J = 5.7Hz, J = 17.3Hz, ÍH), 2.46 (s, 3H ), 1.85-0.80 (m, 13H); MS: (M ++ l) 360; N- (lS-cyanomethylcarbamoyl-2-cyclohexylethyl) -3,4-difluoro-benzamide (Compound 110); A? MR (CDC13): 7.5 (t, J = 5.1Hz, ÍH), 5.88 (d, J = 7.7Hz, ÍH), 4.49 (m, ÍH), 4.18 (d, J = 6Hz, ÍH), 4.11 (d, J = 6Hz, ÍH), 2.12-0.8 (m, 24H); MS: m / e = 320.0; N- (lS-cyanomethylcarbamoyl-2-cyclohexylethyl) -3-methoxybenzamide (Compound 111); 1H? MR: (CDC13) 7.63 (m, ÍH), 7.37-7.28 (m, 3H), 7.06 (m, ÍH), 6.76 (d, J = 7.7Hz, ÍH), 4.73 (m, ÍH), 4.20 (dd, J = 5.9Hz, J = 17.3Hz, HH), 4.07 (dd, J = 5.7Hz, J = 17.3Hz, HH), 3.83 (s, 3H), 1.85-0.82 (m, 13H); MS: (M ++ 1) 344; 4-bromo-N- (ÍS-cyanomethylcarbamoyl-2-cyclohexylethyl) benzamide (Compound 112), - A? MR: (CDC13) 7.65-7.57 (m, 4H), 7.10 (m, HH), 6.48 (d, J = 7.7Hz, ÍH), 4.67 (, ÍH), 4.21 (dd, J = 5.9Hz, J = 17.3Hz, ÍH), 4.12 (dd, J = 5.7Hz, J = 17.3Hz, ÍH), 1.85-0.82 (m, 13H); . MS: (M ++ 1) 392/394; N- (lS-cyanomethylcarbamoyl-2-cyclohexylethyl) piperazin-1 -carboxamide (Compound 113);
benzyl 4- (2-benzoylamino-2S-cyanomethylcarbamoyl ethyl) piperidine-1-carboxylate (Compound 114); 3-bromo-N- (15-cyanomethylcarbamoyl-2-cyclohexylethyl) benzamide (Compound 115); A? MR: (CD30D) 8.05 (s, ÍH), 7.83 (d, J = 7.7Hz, ÍH), 7.71 (d , J = 7.5Hz, ÍH), 7.40 (t, J = 7.9Hz, ÍH), 4.67 (dd, J = 6.9Hz, J = 8.7Hz, ÍH), 4.19 (d, J = 17.5Hz, ÍH), 4.11 (d, J = 17.3Hz, ÍH), 1.85-0.82 (m, 13H); MS: (M ++ 1) 392/394; N- (lS-cyanomethylcarbamoyl-2-cyclohexylethyl) -3-methylbenzamide (Compound 116); A? MR (DMSO): 7.64 (t, ÍH), 7.25 (m, 4H), 6.43 (d, J = 12Hz, ÍH), 4.67 (m, ÍH), 4.13 (m, 2H), 2.4 (s, 3H), 2.0-0.7 (m, 13H); MS m / e 327.8; N- (SS-cyanomethylcarbamoyl-2-cyclohexylethyl) pentamide (Compound 117); A? MR (CDC13): 8.11 (t, ÍH), 6.53 (d, J = 8Hz, ÍH), 4.59 (m, ÍH), 4.10 (m, 2H), 2.21 (t, J = 4.5Hz, 2H) , 1.8-0.8 (m, 20H); MS m / e 293.8; N- (lS-cyanomethylcarbamoyl-2-cyclohexylethyl) -2-methylbenzamide (Compound 118); A? MR (CDC13): 7.91 (d, J = 5.7Hz, ÍH), 7.23 (m, 4H), 6.50 (t, J = 3Hz, ÍH), 4.76 (m, ÍH), 4.05 (s, J = 18Hz, ÍH), 2.38 (d, 3H), 2.0-0.8 (m, 13H); MS m / e 328; N- (lS-cyanomethylcarbamoyl-2-cyclohexylethyl) thiophene-3-carboxamide (Compound 119); A? MR (CDC13): 8.1 (m, 2H), 7.32 (m, t, 2H), 7.08 (d, J = 7.9Hz, ÍH), 4.73 (, ÍH), 4.05 (dd, J = 6.17Hz , 2H), 2.0-0.8 (m, 13H); MS m / e 319.80;
2S- [2- (4-benzyloxyphenyl) acetylamino] -N-cyanomethyl-3-cyclohexylpropionamide (Compound 120); A? MR (CDC13): 7.8 (t, ÍH), 7.5-6.9 (m, 9H), 6.10 (d, J = 8Hz, ÍH), 5.0 (s, 2H), 4.5 (m, ÍH), 3.95 ( m, 2H), 3.5 (s, 2H), 1.9-1.0 (m, 13H); MS m / e 434.97; N-cyanomethyl-3-cyclohexyl-2g- [2- (2-methoxyphenyl) acetylamino] propionamide (Compound 121); A? MR (CDC13): 7.58 (t, J = 7.8Hz, ÍH), 7.23 (m, 2H), 6.91 (m, 2H), 6.21 (d, J = 7.2Hz, ÍH), 4.44 (m, ÍH) ), 3.94 (d, J = 5.7Hz, 2H), 3.84 (s, 3H), 3.60 (d, J = 8Hz, ÍH), 3.49 (d, J = 8Hz, ÍH), 1.8-0.5 (m, 13H ); MS m / e 357.89; N-cyanomethyl-3-cyclohexyl -2 - [2- (4-phenoxyphenyl) acetylamino] propionamide (Compound 122); 1H? MR (CDC13): 7.55 (t, J = 3Hz, ÍH), 7.4-6.9 (m, 9H), 6.04 (d, J = 8.8Hz, ÍH), 4.47 (m, ÍH), 4.02 (d, J = 6Hz, 2H), 3.54 (s, 2H), 2.0-0.6 (m, 13H); MS m / e 419. 94; N- (lS-cyanomethylcarbamoyl-2-cyclohexylethyl) isonic tinamide (Compound 123) A? MR (DMSO): 8.68 (d, J = 4.5Hz, 2H), 8.2 (t, J = 6.3Hz, ÍH), 7.85 ( d, J = 7.9Hz, HH), 7.66 (d, J = 4.7Hz, 2H), 4.80 (m, HH), 4.12 (d, J = 6Hz, 2H), 2.0-0.7 (m, 13H); MS m / e 314.8; N- (lS-cyanomethylcarbamoyl-2-cyclohexylethyl) thiophene-2-carboxamide (Compound 124); A? MR: (CDC13) 8.55 (t, J = 5.5Hz, ÍH), 7.75 (d, J = 7.7Hz, ÍH), 7.64 (dd, J = lHz, J = 4Hz, ÍH), 7.48 (dd, J = lHz, J = 5Hz, ÍH), 7.04 (dd, J = 5Hz, J = 4Hz, ÍH), 4.82 (q, J = 7.5Hz, ÍH), 4.13 (dd, J = 5.9Hz, J = 17Hz , ÍH), 3.93 (dd, J = 5.7Hz, J = 17Hz, ÍH), 1.80-0.84 (m, 13H); MS: (M ++ 1) 319.8; N- (lg-cyanomethylcarbamoyl-2-piperidin-4-ylethyl) benzamide (Compound 125); N- [l S-cyanomethylcarbamoyl-2- (l-formyl-1-yl-indol-3-yl) ethyl] benzamide (Compound 126); N- [lS-cyanomethylcarbamoyl-2- (1-formyl-1-yl-indol-3-yl) ethyl] -4-fluorobenzamide (Compound 127); N- (lS-cyanomethylcarbamoyl-2-cyclohexylethyl) nicotinamide (Compound 128); 1H? MR (CDC13): 9.01 (d, J = 4Hz, ÍH), 8.72 (m, ÍH), 8.11 (m, ÍH), 7.83 (t, J = 3Hz, ÍH), 7.39 (m, 2H), 4.77 (m, ÍH), 7.14 (m, 2H), 2.0-0.6 (m, 13H); MS m / e 314.88; tert-butyl 3 - (lff-cyanomethylcarbamoyl-2-cyclohexyl ethylcarbamoyl) phenylcarbamate (Compound 129); N- [lS-cyanomethylcarbamoyl-2- (1-formyl-1H-indol-3-yl) ethyl] -4-hydroxybenzamide (Compound 130); N- (lg-cyanomethylcarbamoyl-2-cyclohexylethyl) -lfi-indole-5-carboxamide (Compound 131); A? MR (CDC13): 11.32 (s, ÍH), 8.64 (t, J = 6Hz, ÍH), 8.35 (d, J = 9Hz, ÍH), 8.22 (s, ÍH), 7.68 (dd, J = 3 , 10Hz, HH), 7.42 (m, HH), 6.54 (m, HH), 4.54 (m, HH), 4.12 (d, J = 5.7Hz, 2H), 2.0-0.7 (m, 13H); MS m / e 352.86; N- (1R-cyanomethylcarbamoyl-2-cyclohexylethyl) -4-methylsulfanylbenzamide (Compound 132);
N- (2-benzylsulfanyl-l.R-cyanomethylcarbamoylethyl) -3-fluorobenzamide (Compound 133); 1H? MR (CDC13): 7.18-7.79 (m, ÍH), 4.70 (dd, J = 13.3, 7.2Hz, ÍH), 4.28 (d, J = 7.7Hz, ÍH), 4.22 (d, J = 7.4Hz , HH), 3.78 (m, 2H), 3.03 (dd, J = 14.1, 6.2Hz, HH), 2.84 (J = 14.1, 7.2Hz, HH); MS: m / e = 371.88; N- (2-benzylsulfanyl-l. -cyanomethylcarbamoylethyl) -4-fluorobenzamide (Compound 134); A? MR (CDC13): 7.74 (m, 2H), 7.47 (t, J = 5.9Hz, ÍH), 7.29 (m, 4H), 7.09 (m, 4H), 4.72 (dd, J = 13.6, 6.9Hz , ÍH), 4.11 (m, 2H), 3.77 (s, 5H), 3.02 (dd, J = 13.8, 6.2Hz, ÍH), 2.83 (dd, J = 13.8, 7.2Hz, ÍH); MS: m / e = 371.79; N- (lS-cyanomethylcarbamoyl-2- (4-methoxybenzyl sulfinyl) ethyl] benzamide (Compound 135); A? MR (DMSO): 8.94 (d, J = 8Hz, HH), 8.87 (d, J = 6Hz, HH) ), 7.87 (d, J = 7Hz, 2H), 7.5 (m, 3H), 7.24 (d, J = 10Hz, 2H), 6.93 (d, J = 10Hz, 2H), 4.80 (dd, J = 4, 12Hz, ÍH), 4.14 (d, J = 14Hz, ÍH), 4.13 (s, 2H), 3.99 (d, J = 14Hz, ÍH), 3.74 (s, 3H), 3.16 (dd, J = 12.14Hz , HH), 3.07 (dd, J = 14.4Hz, HH), MS: m / e = 400.00, N- (lS-cyanomethylcarbamoyl-2-cyclohexylethyl) -4-methylbenzamide (Compound 136); A? MR (DMSO ): 7.7 (t, ÍH), 7.65 (d, 2H), 7.25 (d, 2H), 6.65 (d, ÍH), 4.75 (m, ÍH), 4.2 (dd, ÍH), 4.03 (dd, ÍH) , 2.4 (5, 3H), 2-0.8 (m, 13H); MS: m / e 328.8; N- (lS-cyanomethylcarbamoyl-2-cyclohexylethyl) -3-phenoxybenzamide (Compound 137); A? MR (CDC13) : 8.49 (t, J = 5.5Hz, ÍH), 7.75 (dd, J = 10, 8.5Hz, ÍH), 7.6-6.9 (m, 9H), 4.84 (m, ÍH), 3.95 (m, 2H), 2.0-0.8 (m, 13H); MS: m / e = 405.93; 3-benzoyl-N- (IS-cyanomethylcarbamoyl-2-cyclohexyl ethyl) benzamide (Compound 138); MR (CDC13): 8.19 (t, J = 3Hz, ÍH), 8.0 (m, ÍH), 7.89 (d, J = 8.8Hz, ÍH), 7.76-7.4 (m, 5H), 6.88 (m, ÍH) ), 4.74 (m, 1H), 4.19 (dd, J = 6.6.3Hz, ÍH), 4.08 (dd, J = 6, 6.3Hz, ÍH), 2.0-0.8 (m, 13H); MS: m / e = 417.95; N- (2-benzylsulfanyl-l. -cyanomethylcarbamoylethyl) thiophene-3-carboxamide (Compound 139); 3-acetyl-N- (1J.-cyanomethylcarbamoyl-2-cyclohexyl ethyl) benzamide (Compound 140); 1H? MR: (CDC13) 8.33 (t, J = 1.5Hz, ÍH), 8.08 (dt, J = 1.7Hz, J = 7.7Hz, ÍH), 7.99 (dt, J = 1.7Hz, J = 7.9Hz, ÍH), 7.55 (t, J = 7.7Hz, ÍH), 7.45 (t, J = 6.7Hz, ÍH), 6.92 (d, J = 7.9Hz, ÍH), 4.74 (m, ÍH), 4.23-4.05 ( m, 2H), 2.63 (s, 3H), 1.90-0.84 (m, 13H); MS: (M ++ 1) 355.8; N- (2-benzylsulfanyl-lJ.-cyanomethylcarbamoylethyl) -4-methoxybenzamide (Compound 141); A? MR (CDC13): 7.81 (t, J = 5.7Hz, ÍH), 7.70 (dt, J = 8.9, 2.2Hz, 2H), 7.20-7.32 (m, J = 5H), 7.04 (d, J = 7.7Hz, ÍH), 6.89 (dt, J = 8.9, 2.0Hz, 2H), 4.82 (dd, J = 14.1, 6.7Hz, ÍH), 4.08 (d, J = 5.7Hz, 2H), 3.83 (s, 3H), 3.74 (s, 2H), 3.00 (dd, J = 13.9, 6.7Hz, ÍH), 2.86 (dd, J = 13.9, 6.7Hz, ÍH); MS: m / e = 383.80; N- (2-benzylsuiphanyl-1-R-cyanomethyl-carbamoylethyl) furan-2-carboxamide (Compound 142); 1H? MR (CDC13): 7.49 (m, ÍH), 7.24-7.39 (m, 5H), 7.14 (m, ÍH), 7.04 (m, J = 2H), 6.53 (dd, J3.7, 1.7Hz, ÍH), 4.64 (m, ÍH), 4.13 (dd, J = 5.9, 1.2Hz, 2H), 3.79 (dd, J = 16.1, 13.6Hz, 2H), 3.03 (dd, J = 14.1, 5.9Hz, ÍH) ), 2.80 (dd, J = 14.3 6.9Hz, ÍH); MS: m / e = 343.84; N- (2-benzylsulfanyl-li? -cyanomethylcarbamoylethyl) furan-3-carboxamide (Compound 143); 1H? MR: 8.33 (t, J = 5.45Hz, ÍH), 7.16 - 7.28 (m, 5H), 5.41 (d, J = 7.2Hz, ÍH), 4.52 (dd, J = 13.9, 6.7Hz, ÍH) , 4.06 (d, J = 5.7Hz, 2H), 3.68 (s, 2H), 3.10 (s, 3H), 3.05 (m, ÍH), 3.00 (s, 3H), 2.80 (m = ÍH); MS (320.74); N- (2-benzylsulfanyl-lR-cyanomethylcarbamoylethyl) -2-methoxybenzamide (Compound 144); A? MR (CDC13): 8.75 (D, J = 6.9Hz, ÍH), 8.14 (DDJ = 2.0 7.9Hz, ÍH), 7.50 (m, ÍH), 7.20-7.35 (m, 6H), 7.12 (m, ÍH), 4.78 (dd, J = 12.6, 6.2Hz, ÍH), 4.19 (dd, J = 12.6 6.2Hz, ÍH), 4.07 (dd, J = 13.5, 5.4Hz, ÍH), 3.97 (s, 3H) , 3.80 (d, J = 3.2Hz, 2H), 3.08 (dd, J = 14.0, 3.7Hz, ÍH), 2.86 (dd, J = 14.1, 6.7Hz, ÍH); MS: m / e = 383.93; N- (2-benzylsulfanyl-1R-cyanomethylcarbamoylethyl) -3-methoxybenzamide (Compound 145); A? MR (CDC13): 7.96 (t, J = 5.7Hz, ÍH), 7.16-7.36 (m, 8H), 7.05 (m, ÍH), 4.80 (m, ÍH), 4.08 (d, J = 5.7Hz , ÍH), 3.80 (s, 3H), 3.77 (s, 2H), 2.98 (dd, J = 13.9, 6.4Hz, ÍH), 2.86 (dd, J = 6.9, 3.9Hz, ÍH); MS: m / e = 383.77; N- (2-benzylsulfanyl-IR-cyanomethylcarbamoylethyl) molfoline-4-carboxamide (Compound 146); 1H? MR (CDC13): 7.45 (m, ÍH), 7.23 (m, 5H), 5.28 (m, ÍH), 4.39 (m, ÍH), 4.16 (dd, J = 17.6, 5.9Hz, ÍH), 4.06 (dd, J = 11.1, 5.5Hz, ÍH), 3.74 (s, 2H), 3.67 (t, J = 4.9Hz, 4H), 3.31 (m, 4H), 3.00 (dd, J = 14.1, 6.4Hz, ÍH), 2.77 (dd, J = 13.8, 6.7Hz, ÍH); MS: (362.86); 6-amino-N- (2-benzylsulfanyl-li? -cyanomethylcarbamoyl ethyl) nicotinamide (Compound 147); A? MR (CDC13): 8.42 (d, J = 2.5Hz, ÍH), 7.80 (dd, J = 8.7 2.5Hz, ÍH), 7.18-7.30 (m, 5H), 6.46 (dd, J = 9.4 0.7Hz , HH), 4.64 (t, J = 6.9Hz, HH, 4.08 (s, 2H), 3.70 (S, 2H), 2.80 (M, 2H), MS: m / e = 369.4474, N- (2-benzylsulfanil -lR-cyanomethylcarbamoylethyl) -3-pyrid-3-ylacrylamide (Compound 148); A? MR (CDC13): 8.72 (d, J = 2.2 Hz, 1 H), 8.54 (J = 4.7 1.5 Hz, HI), 7.82 (dt, J = 7.9, 2.2Hz, ÍH), 7.57 (d, J = 15.6Hz, ÍH), 7.18-7.38 (m, 6H), 6.48 (d, J = 15.8Hz, ÍH), 4.61 (m, H), 4.10 (s, 2H), 3.73 (s, 2H), 2.80 (m, 2H), MS: m / e = 380.4706, N- (2-benzylsulfanyl-1J? -cyanomethylcarbamoylethyl) naphthalene-2 -carboxamide ( Compound 149); A? MR (CDC13): 8.28 (m, ÍH), 7.90 (m, 3H), 7.78 (dd, J = 8.4, 1.8Hz, ÍH), 7.57 (m, 2H), 7.17 - 7.38 ( m, 6H), 7.13 (J = 7.2Hz, ÍH), 4.77 (m, ÍH), 4.14 (d, J = 5.9Hz, 2H), 3.81 (s, 2H), 3.12 (dd, J = 14.1, 5.9 Hz, HH), 2.88 (dd, J = 14.1, 7.2Hz, ÍH), MS (403.92), N- (2-benzylsulfanyl-?? -cyanomethylcarbamoylethyl) benzofuran-2-carboxinamide (Compound 150); 1H? MR (DMSO): 7.66 (dt, J = 7.9, 1.2Hz, ÍH), 7.16 - 7.54 (m, 9H), 4.74 (m, ÍH), 4.15 (d, J = 6Hz, 2H), 3.80 ( dd, J = 15.3, 13.6Hz, 2H), 3.07 (dd, J 14.1, 5.9Hz, ÍH), 2.87 (ddJ = 14.1, 7.1Hz, ÍH); MS (393.83); N- (2-benzylsulfanyl-li? -cyanomethylcarbamoylethyl) biphenyl-4-carboxamide (Compound 151); A? MR (CDC13): 7.81 (dt, J = 8.7, 1.5Hz, 2H), 7.66 (m, 2H), 7.59 (m, 2H), 7.26 -7.49 (m, 7H), 7.02 (d, J = 7.2Hz, ÍH), 4.73 (m, ÍH), 4.14 (dd, J = 5.9, 1.2Hz, 2H), 3.80 (s, 2H), 3.10 (dd, J = 14.0, 7.2Hz, ÍH), 2.86 ( dd, J = 14.1, 7.2Hz, ÍH); MS (429.99); N- (2-benzylsulfani 1-lR-cyanomethylcarbamoylethyl) benzo [1,3] dioxol -5-carboxamide (Compound 152); A? MR (CDC13): 7.21 - 7.38 (m, 7H), 6.82 (d, J = 8.2Hz, ÍH), 6.82 (m, ÍH), 4.67 (dd, J = 13.3, 6.9Hz, ÍH), 4.11 (dd, J = 5.7, 1.6Hz, ÍH), 3.77 (s 2H), 3.03 (dd, J = 14.1, 6.2Hz, ÍH), 2.82 (dd, J = 14.1, 6.9Hz, ÍH); MS (397.82); N- (2- e -butylsulfanyl-IR-cyanomethylcarbamoylethyl) benzamide (Compound 153); A? MR (DMSO): 8.77 (t, J = 6Hz, ÍH), 8.69 (d, J = 9Hz, ÍH), 7.89 (d, J = 7Hz, 2H), 7.5 (m, 3H, 4.58 (m, ÍH), 4.13 (t, J = 3Hz, 2H), 3.02 (dd, J = 6.14Hz, ÍH), 2.90 (dd, J = 10.14Hz, ÍH), 1.27 (s, 9H); MS: m / e = 319.80; N- (IR-cyanomethylcarbamoyl-3-phenylsulfanylpropi1) benzamide (Compound 154); A? MR (DMSO): 8.7 (m, 2H), 7.92 (d, J = 7Hz, 2H), 7.53 (m , 3H), 7.3 (m, 4H), 7.2 (m, ÍH), 4.6 (q, J = 7Hz, ÍH), 4.13 (d, J = 6Hz, 2H), 3.0 (m, 2H), 2.05 (m , 2H); MS: m / e 353.83; N- (1S-cyanomethyl-2-carbamoyl-2-cyclohexylethyl) -3-methyl thiophen-2-carboxamide (Compound 155); A? MR: (CDC13) 7.75 (t, J = 6Hz , ÍH), 7.32 (d, J = 5Hz, ÍH), 6.90 (d, J = 5Hz, ÍH), 6.30 (d, J = 7.9Hz, ÍH), 4.72 (m, ÍH), 4.19 (dd, J = 5.7Hz, J = 17.5Hz, ÍH), 4.05 (dd, J = 5.7Hz, J = 17.3Hz, ÍH), 2.51 (s, 3H), 1.85-0.85 (m, 13H), MS: (M + + 1) 333.9; N- (lS-cyanomethylcarbamoyl-2-cyclohexylethyl) -5-methylthiophen-2-carboxamide (Compound 156); A? MR: (CDC13) 8.14 (t, J = 5.7Hz, ÍH), 7.39 ( d, J = 3.7H z, ÍH), 6.93 (d, J = 7.9Hz, ÍH), 6.72 (dd, J = lHz, J = 3.7Hz, ÍH), 4.74 (m, ÍH), 4.17 (dd, J = 5.9Hz, J = 17Hz, ÍH), 3.97 (dd, J = 5.5Hz, J = 17.1Hz, ÍH), 2.50 (s, 3H), 1.80-0.82 (m, 13H); MS: (M ++ 1) 333.8; N- (lS-cyanomethylcarbamoyl-2-cyclohexylethyl) -3-chlorothiophen-2-carboxamide (Compound 157); A? MR: (CDC13) 7.52 (d, J = 5.2Hz, ÍH), 7.43 (t, J = 5.7Hz, ÍH), 7.32 (d, J = 7.4Hz, ÍH), 7.01 (d, J = 5.2 Hz, ÍH), 4.68 (m, ÍH), 4.23 (dd, J = 5.9Hz, J = 17.5Hz, ÍH), 4.08 (dd, J = 6Hz, J = 17.3Hz, ÍH), 1.90-0.85 (m , 13H); MS: (M ++ 1) 353.8; N- (lff-cyanomethylcarbamoyl-2-cyclohexylethyl) -3-chlorobenzo [b] thiophen-2-carboxamide (Compound 158); 1H? MR: (CDC13) 7.90-7.78 (m, 3H), 7.65 (d, J = 7.9Hz, ÍH), 7.51-7.42 (m, 2H), 4.86 (q, J = 8Hz, ÍH), 4.28 ( dd, J = 5.9Hz, J = 17.3Hz, HH), 4.12 (dd, J = 5.7Hz, J = 17.3Hz, HH), 1.90-0.85 (m, 13H); MS: (MAl) 403.8;
N- (lS-cyanomethylcarbamoyl-2-cyclohexylethyl) -5-chlorothiophen-2-carboxamide (Compound 159); A? MR: (CDC13) 8.18 (t, J = 5.7Hz, ÍH), 7.62 (d, J = 7.9Hz, ÍH), 7.40 (d, J = 4Hz, ÍH), 6.88 (d, J = 4Hz, ÍH), 4.70 (q, J = 7.7Hz, ÍH), 4.14 (dd, J = 5.7Hz, J = 17Hz, ÍH), 4.05 (dd, J = 6Hz, J = 17Hz, ÍH), 1.80-0.84 ( m, 13H); MS: (M ++ 1) 353.8; N- (lg-cyanomethylcarbamoyl-2-cyclohexylethyl]) -3-bromothiophen-2-carboxamide (Compound 160); A? MR (CDC13): 7.55-7.39 (m, 3H), 7.07 (d, J = 5.5Hz, ÍH), 4.68 (m, ÍH), 4.25 (dt, ÍH), 4.08 (dt, ÍH), 2.0 -0.8 (m, 13H); MS: m / e = 399.74; N- (lS-cyanomethylcarbamoyl-2-cyclohexylethyl) -5-bromothiophen-2-carboxamide (Compound 161); A? MR (CDC13): 8.18 (t, J = 5.4Hz, ÍH), 7.62 (d, J = 3.5Hz, ÍH), 7.37 (d, J = 4.0Hz, ÍH), 7.04 (d, J = 4.0 Hz, ÍH), 4.70 (dd, J = 7.2, 18.7Hz, ÍH), 4.15 (dd, J = 5.7, 17.8Hz, ÍH), 4.05 (dd, J = 5.7, 17.8, ÍH), 1.5-1.8 ( m, 7H), 0.8-1.50 (m, 6H); MS: m / e (+1) 399.83; N- (lS-cyanomethylcarbapnoyl-2-cyclohexylethyl) benzo [b] thiophen-2-carboxamide (Compound 162); MR (MeOH): 8.06 (s, ÍH), 7.91 (m, 2H), 7.43 (m, 2H), 4.64 (dd, J = 6.7, 8.7Hz, ÍH), 4.21 (d, J = 17.3 Hz, ÍH), 4.13 (d, J = 17.3Hz, ÍH), 1.61-1.90 (m, 8H), 0.89-1.55 (m, 4H); MS: m / e = 369.78; N- (lS-cyanomethylcarbamoyl-2-cyclohexylethyl) -3-ethoxybenzamide (Compound 163); A? MR (MeOH): 8.50 (d, J = 7.4Hz, ÍH), 7.3-7.43 (m, 3H), 7.07 (d, J = 8.2Hz, 1 H), 4.64 (dd, J = 7.7, 19.2 Hz, 2H), 4.15 (d, J = 4.2Hz, 2H), 4.09 (d, J = 6.9Hz, ÍH), 4.04 (d, J = 6.9Hz, ÍH), 1.35 (t, J = 7.0,3H ), 0.9-1.9 (m, 13H); MS: m / e (+1) 357.94; tert-butyl 3- (1S-Corynorethylcarbamoyl-3-methylbutyl carbamoyl) phenylcarbamate (Compound 164); tert-butyl 3- (2-benzy1suiphanyl-IR-cyanomethyl-carbamoylethylcarbamoyl) phenylcarbamate (Compound 165); N- (l-cyanomethylcarbamoyl-3-phenoxypropyl) benzamide (Compound 166); ÍH? MR (DMSO): 8.71 (m, = 2H), 7.90 (d, J = 14Hz, 2H), 7.5 (m, 3H), 7.25 (m, 2H), 6.9 (m, 3H), 4.65 (m , ÍH), 4.14 (d, J = 6Hz, 2H), 4.04 (, 2H), 2.25 (, 2H); MS: m / e = 337.84; tert-butyl lS-cyanomethylcarbamoyl-2- (4-nitrophenyl) ethylcarbamate (Compound 167); N- (1-cyanomethylcarbamoyl-5-fluoropentyl) benzamide (Compound 168); A? MR (DMSO): 8.69 (t, J = 6Hz, ÍH), 8.57 (d, J = 8Hz, ÍH), 7.90 (d, J = 7Hz, 2H), 7.5 (m, 3H), 4.42 (dt) , J = 52.6Hz, 2H), 4.43 (m, ÍH), 4.13 (s, 2H), 1.83-1.3 (m, 6H); MS: m / e 291.84; ert-butyl 3- (lff-cyanomethylcarbamoylpentyl carbamoyl) phenylcarbamate (Compound 169); ert-butyl 3-cyanomethylcarbamoylmethylcarbamoyl phenylcarbamate (Compound 170); N- (2-benzylsulfanyl-IR-cyanomethylcarbamoylethyl) guinolin-3 -carboxamide (Compound 171); 1H? MR (DMSO): 9.30 (d, J = 2.5Hz, ÍH), 8.58 (d, J = 2.5Hz, ÍH), 8.16 (d, J = 8.7Hz, ÍH), 7.90 (d, J = 9.2 Hz, lH), 7.83 (td, J = 8.7, 1.5Hz, ÍH), 7.63 (td, J = 6.9, 1.2Hz, ÍH), 7.17 - 7.42 (m, 5H), 4.77 (dd, J = 11.8, 7.2Hz, ÍH), 3.81 (s, 2H), 3.12 (dd, J = 13.9, 6.2Hz, ÍH), 2.90 (dd, J = 14.0, 7.4Hz, ÍH); MS (404.77); tert-butyl 3- (lS-cyanomethylcarbamoyl-2-cydohexyl ethylcarbamoylbenzyl) carbamate (Compound 172); A NMR (CDC13): 8.15 (bt, J = 5.45Hz, ÍH), 7.63 (d, J = 8.1Hz, 2H), 7.43 (d, J = 7.71Hz, ÍH), 5.18 (s, ÍH), 4.81 (dd, J = 8.4, 18.8Hz, ÍH), 4.25 (d, J = 5.2Hz, 2H), 4.15 (dd, J = 5.9, 17.1Hz, 1H), 3.98 (dd, J = 5.9, 17.1Hz , ÍH), 1.45 (s, 9H), 0.8-1.9 (m, 13H); MS: m / e (+1) 357.94; 3-acetylamino-N- (lg-cyanomethylcarbamoyl-2-cyclohexylethyl) benzamide (Compound 173); A? MR (CDC13): 8.43 (s, ÍH), 8.32 (s, ÍH), 7.94 (3, J = 7.92Hz, ÍH), 7.59 (s, ÍH), 7.54 (s, ÍH), 7.38 (d , J = 7.9Hz, ÍH), 4.83 (dd, J = 7.4, 15.3Hz, ÍH), 4.23 (dd, J = 5.7, 17.3Hz, ÍH), 4.06 (dd, J = 5.7, 17.3Hz, ÍH) , 2.14 (s, 3H), 0.95-1.90 (m, 13H); MS: m / e = 370.85; 2 S- [2 - (4-Butoxy-phenyl) -acetylamino] -N-cyanomethyl-3-cyclohexylpropionamide (Compound 174); ? MR (MeOH): 7.19 (d, J = 8.9Hz, 2H), 6.84 (d, J = 8.9Hz, 2H), 4.38 (dd, J = 5.9, 9.4Hz, ÍH), 4.12 (d, J = 2.2Hz, 2H), 3.94 (t, J = 6.4Hz, 2H), 3.60 (d, J = 14. 1Hz, ÍH), 3.46 (d, J = 14.1Hz, ÍH), 1.40-1.78 (m, 4H ), 1.05-1.3 (m, 3H), 0.95 (t, J = 7.4Hz, 3H); MS: m / e = 399.95; N- [lS-cyanomethylcarbamoyl-2- (4-nitrophenyl) ethyl] morpholin-4-carboxamide (Compound 175);
N-cyanomethyl-3-cydohexyl-2S- (3-naphth-2-ylureido) propionamide (Compound 176); N-cyanomethyl-3-cydohexyl -2S- (3-hexylureido) propionamide (Compound 177); 2S- (3-allylureido) -N-cyanomethyl-3-cydohexyl prropionamide (Compound 178); N-cyanomethyl-3-cyclohexyl-2S- [3- (2, 2, 4-trimethylpentyl) ureido] propionamide (Compound 179); N-. { 2-benzylsulfanyl-li? -cyanomethylcarbamoylethyl) guyolinyl-2-carboxamide (Compound 180); 1H? MR (CDC13): 8.90 (d, J = 7.8Hz, ÍH), 8.35 (m, ÍH), 8.22 (m, 3H), 7.89 (m, ÍH), 7.81 (td, J = 7.2, 1.7Hz , ÍH), 7.66 (td, J = 6.9, l.OHz, ÍH), 7.37 (m, 2H), 7.14 - 7.32 (m, 3H), 4.77 (m, ÍH), 4.16 (m, 2H), 3.82 (s, 2H), 3.11 (dd, J = 14.1, 6.2Hz, ÍH), 3.00 (dd, J = 14.1, 6.9Hz, ÍH); MS (404.8); 3-benzylsulfanyl-N-cyanomethyl-2i.- (3,3-dimethyl ureido) propionamide (Compound 181); 3-benzoyl-N- (2-benzl-suifanyl-IR-cyanomethylcarbamoylethyl) benzamide (Compound 182); 1H? MR (CDC13): 8.19 (t, J = 1.6Hz, ÍH), 7.96 (m, 2H), 7.78 (m, 2H), 7.61 (m, 2H), 7.51 (m, 2H), 7.23 - 7.37 (m, 5H), 6.99 (d, J = 6.2Hz, 2H), 4.64 (m, ÍH), 4.13 (dd, J = 5.9, l.OHz, 2H), 3.80 (d, J = 2.5Hz, 2H ), 3.09 (dd, J = 14.1, 6.9Hz, 2H), 2.81 (dd, J = 14.1, 7.7Hz, ÍH); MS (457.81); N- (lS-cyanomethylcarbamoyl-2-cyclohexylethyl) 5-pyrid-2-thiophen-2-carboxamide (Compound 183); A NMR (CDC13): 8.55 (d, J = 4.95Hz, ÍH), 8; 05 (5, J = 5.4Hz, ÍH), 7.67-7.73 (m, 2H), 7.62 (d, J = 4.0Hz, ÍH), 7.54 (d, J = 4.0Hz, ÍH), 7.21 (m, ÍH), 7.11 (d, J = 7.9Hz, ÍH), 4.77 (dd, J = 8.4, 14.3Hz, ÍH), 4.21 ( dd, J = 5.7, 17.3Hz, HH), 4.06 (dd, J = 5.7, 17.3Hz, HH), 0.8-2.0 (m, 13H); MS: m / e = 396.8; N- (lS-cyanomethylcarbamoyl-2-cyclohexylethyl) 4-methoxythiophen-3-carboxamide (Compound 184); A? MR (CDC13): 8.04 (d, J = 3.7Hz, 2H), 7.74 d, J = 7.4Hz, ÍH), 6.35 (d, J = 3.4Hz, ÍH), 4.68 (dd, J = 8.4, 13.9Hz, ÍH), 4.18 (dd, J = 6.2, 17.3Hz, ÍH), 4.12 (dd, J = 6.2, 17.13Hz, ÍH), 3.91 (s, 3H), 0.8-1.9 (m, 13H); MS: m / e = 349.78; N- (lS-cyanomethylcarbamoyl-2-cyclohexylethyl) 3- (3-methylbenzoyl) aminobenzamide (Compound 185); A? MR (CDC13): 8.47 (s, ÍH), 8.30 (t, J = 5.4Hz, ÍH), 7.98 (d, J = 8.2Hz, ÍH), 7.84 (s, ÍH), 7.68 (m, 2H ), 7.2-7.48 (m, 4H), 4.84 (dd, J = 8.2, 14.6Hz, ÍH), 4.26 (dd, J = 6.2, 17.3Hz, ÍH), 4.02 (dd, J = 6.2, 17.3Hz, ÍH), 2.35 (s, 3H), 0.8-1.9 (m, 14H); MS: m / e = 446.90; 2S- (3-phenylsulfonylureido) -N-cyanomethyl-3-cyclohexylpropionamide (Compound 186); 4-benzoyl-N- (2-benzylsulfanyl-IR-cyanomethylcarbamoylethyl) benzamide (Compound 187); A? MR (CDC13): 8.348 (HH), 8.11 (d, J = 6.6Hz, HH), 7.95 (d, J 6.2Hz, ÍH), 7.56 (m, ÍH), 7.14 - 7.54 (m, 7H), 4.73 (m, ÍH), 4.16 (d, J = 5.9Hz, 2H), 3.80 (m, 2H), 3.08 (dd, J = 13.9, 7.3Hz, ÍH), 2.87 (dd, J = 13.9, 6.2Hz, ÍH), 2.64 (s, 3H); MS (459.86); N- [2- (4-Aminophenyl) -lS-cyanomethylcarbamoylethyl] morpholin-4-carboxamide (Compound 188); N- (2-benzylsulfanyl-1J-cyanomethylcarbamoylethyl) nicotinamide (Compound 189); N-. { 2-benzylsulfanyl-1J? -cyanomethylcarbamoylethyl) isonicotinamide (Compound 190), -2S- (3-ert-butylureido) -N-cyanomethyl-3-cyclohexyl propionamide (Compound 191); N- (lS-cyanomethylcarbamoyl-2-cyclohexylethyl) -4-methylpentanamide (Compound 192); A? MR (CDC13): 8.25 (t, J = 5.7Hz, ÍH), 6.60 (d, J = 8.2Hz, ÍH), 4.60 (dd, J = 8.7, 14.6Hz, ÍH), 4.12 (dd, J = 5.7, 14.8Hz, ÍH), 4.04 (dd, J = 5.7, 14.8Hz, ÍH), 2.20 (t, J = 8.2Hz, 2H), 0.85 (d, J = 6.5, 6H), 1.1-1.8 ( m, 16H); MS: m / e (+1) 307.92; N- (lS-cyanomethylcarbamoyl-2-cyclohexylethyl) cyclopent-1-enecarboxamide (Compound 193); A? MR (CDC13): 7.79 (t, J = 5.9Hz, ÍH), 6.49 (m, ÍH), 6.08 (d, J = 7.9Hz, ÍH), 4.58 (dd, J = 8.4, 14.6Hz, ÍH) ), 4.17 (dd, J = 5.9, 17.3Hz, ÍH), 4.04 (dd, J = 5.9, 17.3Hz, ÍH), 2.52 (m, 4H), 2.0 (m, 2H), 1.68 (m, 8H) , 0.8-1.4 (m, 5H); MS: m / e (+1) 303.82; tert-butyl 2 -benzylsulfanyl-li? -cyanomethylcarbamoyl ethylcarbamate (Compound 194); N- (l-> -cyanomethylcarbamoyl-2-cyclohexylethyl). - H-imidazole-4-carboxamide (Compound 195); A NMR (DMSO): 8.10 (s, ÍH), 7.60 (m, 4H), 4.62 (m, ÍH), 4.10 (d, J = 7.2Hz, 2H), 0.8-1.90 (m, 13H); MS: m / e (+1) 303.79; N- (lS-cyanomethylcarbamoyl-2-cyclohexylethyl) -cyclo pentanecarboxamide (Compound 196); 1H? MR (DMSO): 7.88 (t, J = 5.45Hz, ÍH), 6.15 (d, J = 8.17Hz, ÍH), 4.55 (dd, J = 8.7, 14.6Hz, ÍH), 4.16 (dd, J = 5.7, 17.3Hz, HH), 4.06 (dd, J = 5.7, 17.3Hz, HH), 2.65 (m, HH), 0.8-1.95 (m, 21H); MS: m / e (+1) 305.91; N- (lS-cyanomethylcarbamoyl-2-cyclohexylethyl) cyclohex-1-enecarboxamide (Compound 197); XH? MR (DMSO): 7.65 (t, J = 5.2Hz, ÍH), 6.69 (m, ÍH), 6.02 ( d, J = 7.7Hz, ÍH), 4.56 (dd, J = 8.7, 14.1Hz, ÍH), 4.17 (dd, J = 5.9, 17.3Hz, ÍH), 4.05 (dd, J = 5.9, 17.3Hz, ÍH) ), 2.19 (m, 4H), 1.48-1.85 (m, 13H), 0.8-1.4 (m, 4H); MS: m / e (+1) 317.86; N- (lS-cyanomethylcarbamoyl-2-cyclohexylethyl) -5-methylsulfanylthiophen-2-carboxamide (Compound 198); XH? MR (CDC13): 8.12 (t, J = 5.4Hz, ÍH), 7.42 (d, J = 4.0Hz, ÍH), 7.18 (d, J = 7.7Hz, ÍH), 6.9 (d, J = 4.0 Hz, ÍH), 4.73 (dd, J = 8.2, 14.6Hz, ÍH), 4.18 (dd, J = 8.2, 14.6Hz, ÍH), 2.55 (s, 3H), 1.75 (m, 8H), 0. 8 -1.5 (m, 6H); MS: m / e (+ 1) 365.77; N- (lS-cyanomethylcarbamoyl-2-cyclohexylethyl) isobutylamide (Compound 199); A? MR (CDC13): 7.88 (t, J = 5.7Hz, ÍH), 6.14 (d, J = 7.9Hz, ÍH), 4.55 (dd, J = 8.7, 14.6Hz, ÍH), 4.15 (dd, J = 5.7, 15.6Hz, HH), 4.06 (dd, J = 5.7, 15.6Hz, ÍH), 2.40 (m, HH), 1.57-1.80 (m, 8H), 0.8-1.40 (m, 11H); MS: m / e (+1) 279.89; N- (lS-cyanomethylcarbamoyl-2-cyclohexylethyl) furan-2-carboxamide (Compound 200); A? MR (CDC13): 7.45 (m, 2H), 7.14 (d, J = 3.5Hz, ÍH), 6.67 (d, J = 8.2Hz, ÍH), 6.51 (m, 2H), 4.66 (dd, J = 8.9, 14.1Hz, ÍH), 4.20 (dd, J = 5.9, 17.6Hz, ÍH), 4.06 (dd, J = 5.9, 17.6, ÍH), 1.5-1.9 (m, 7H), 0.8-1.40 (m , 6H); MS: m / e (+1) 303.83; N-cyanomethyl-3-cyclohexyl-2 S- (3-cyclohexylureido) propionamide (Compound 201); N-cyanomethyl-3-cydohexyl-2 S- (3-phenylureido) propionamide (Compound 202); 3-acetylamino-N- (IS-cyanomethylcarbamoylpentyl) benzamide (Compound 203); N- (lS-cyanomethylcarbamoyl-2-cyclohexylethyl) furan-3-carboxamide (Compound 204); A? MR (CDC13): 8.5 (t, J = 6Hz, ÍH), 7.95 (s, ÍH), 7.8 (d, J = 6Hz, ÍH), 7.4 (s, ÍH), 6.65 (s, ÍH), 4.70 (m. ÍH), 4.15 (dd.J = 6.6Hz, ÍH), 3.95 (dd, J = 6.6Hz, ÍH) 2.0-0.8 (m, 13H); MS: m / e = 303.70; N- (lS-cyanomethylcarbamoyl-2-cyclohexylethyl) -6-hydroxynicotinamide (Compound 205); A? MR (DMSO): 12.1 (s, ÍH), 8.8 (t, J = 5.7Hz, ÍH), 8.4 (d, J = 7.5Hz, ÍH), 8.1 (d, J = 2.1Hz, ÍH), 7.9 (dd, J = 3.10Hz, ÍH), 6.43 (d, J = 10Hz, ÍH), 4.5-4.2 (m, ÍH), 4.18 (d, J = 6Hz, ÍH), 1.8-0.8 (m, 13H); MS: m / e = 330.82;
N- (1S-cyanomethylcarbamoyl-2-cyclohexylethyl) benzofuran-2-carboxamide (Compound 206); A? MR (CDC13): 7.95 (t, J = 6Hz, ÍH), 7.8-7.2 (m, 6H), 4.95 (m, ÍH), 4.30 (dd, J = 6.6Hz, ÍH), 4.10 (dd) , J = 6.6Hz, ÍH), 2.0-0.8 (m, 13H); MS: m / e = 303.70; N- (lS-cyanomethylcarbamoyl-2-cyclohexylethyl) quinoline -3-carboxamide (Compound 207); A? MR (DMSO): 9.2 (s, ÍH),
8. 8 (s, ÍH), 8.0 (d, J = 6Hz, 2H), 7.8 (t, J = 6Hz, ÍH), 7.65 (t, J = 6Hz, ÍH), 4.2 (m, 2H), 2.0-0.8 (m, 15H); MS: m / e = 364.86; N- (SS-cyanomethylcarbamoyl-2-cyclohexylethyl) -4-hydroxy-3-nitrobenzamide (Compound 208); A? MR (CDC13): 10.7 (s, ÍH), 8.3 (s, 2H), 7.9 (d, J = 6Hz, ÍH), 7.1 (d, J = 6Hz, ÍH),
4. 9 (m, ÍH), 4.3 (m, 2H), 2.2-0.8 (m, 13H); MS: m / e = 374.83; N- (IS-cyanomethylcarbamoyl-2-cyclohexylethyl) -3-nitrobenzamide (Compound 209); A? MR (DMSO): 8.8-8.2 (m, 4H), 8.1 (d, J = 6.8Hz, ÍH), 7.5 (t, J = 6.8Hz, ÍH), 4.9 (m, ÍH), 4.45 (dd) , J = 6.6, HH), 4.25 (dd, J = 6.6, HH), 2.0-0.8 (m, 13H); MS: m / e = 358.75; N- (1S-cyanomethylcarbamoyl-2-cyclohexylethyl) -3-methyl butylamide (Compound 210); A? MR (CDC13): 7.9 (t, J = 3.6Hz, ÍH), 6.3 (d, J = 6Hz, ÍH), 4.6 (m, ÍH), 4.1 (m, 2H), 2.3-0.8 (m , 22H); MS: m / e = 293.73; N- (2-benzylsulfanyl-lR-cyanomethylcarbamoylethyl) -1H-indole-5-carboxamide (Compound 211); A? MR (CD3OD): 8.12 (s, ÍH), 7.61 (d, J = 7.7Hz, ÍH), 7.39 (d, J = 8.4Hz, ÍH), 7.28 (m, 6H), 7.22 (m, ÍH) ), 7.16 (m, ÍH), 6.52 (m, ÍH), 4.73 (m, ÍH), 4.14 (s, 2H), 3.75 (s, ÍH), 2.97 (m, ÍH), 2.79 (m, ÍH); MS (393.2); N- (2-benzylsulfanyl-lR-cyanomethylcarbamoylethyl) -3-phenoxybenzamide (Compound 212); A? MR (CDC13): 7.55 (m, ÍH), 7.45 (m, ÍH), 7.39 (m, ÍH), 7.26 (m, 6H), 7.12 (m, 3H), 6.97 (m, 2H), 4.67 (m, HH), 4.11 (d, J = 3.7Hz, 2H), 3.72 (d, J = 3.7Hz, 2H), 2.93 (m, HH), 2.73 (m, HH); MS (446.4); tert-butyl 3- (2-benzylsulfanyl-lJ.-cyanomethylcarbamoylethylcarbamoyl) benzylcarbamate (Compound 213); A? MR (CDC13): 7.69 (s, ÍH), 7.62 (m, ÍH), 7.48 (d, J = 7.2Hz, ÍH), 7.41 (d, J = 7.8Hz, ÍH), 7.28 (m, 4H ), 7.12 (J = 7.2Hz, ÍH), 4.74 (dd, J = 13.5, 6.9Hz, ÍH), 4.33 (s, 2H), 4.13 (d, J = 5.4Hz, 2H), 3.77 (s, 2H) ), 3.01 (dd, J = 14.4, 6.3Hz, ÍH), 2.85 (dd, J = 13.8, 7.2Hz, ÍH), 1.45 (s, 9H); MS (483); 3-acetyl-N- (2-benzylsulfanyl-IR-cyanomethylcarbamoyl ethyl) benzamide (Compound 214); A? MR (CDC13): 8.348 (ÍH),
8. 11 (d, J = 6.6Hz, ÍH), 7.95 (d, J 6.2Hz, ÍH), 7.56 (m, ÍH, 7.14 - 7.54 (m, 7H), 4.73 (m, ÍH), 4.16 (d, J = 5.9Hz, 2H), 3.80 (m, 2H), 3.08 (dd, J = 13.9, 7.3Hz, ÍH), 2.87 (dd, J = 13.9, 6.2Hz, ÍH), 2.64 (s, 3H); (396.0); 3- (3-methylbenzoylamino-N- (2-benzylsulfanyl-li.-cyano methylcarbamoylethyl) benzamide (Compound 215); 1H? MR (CDC13):
8. 12 (s, ÍH), 7.95 (m, 2H), 7.70 (s, ÍH), 7.66 (m, ÍH), 7.20-7.47 (m, 8H), 7.12 (d, J = 6.9Hz, ÍH), 4.74 (m, ÍH), 4.16 (d, J = 5.7Hz, 2H), 3.77 (s, 2H), 3.01 (dd, J = 13.7, 5.9Hz, ÍH), 2.86 (dd, J = 13.8, 6.8Hz, ÍH), 2.42 (s, 3H); MS: (487.4); N- [(cyanomethylcarbamoyl) (propoxy) methyl] benzamide (Compound 216); A? MR (DMSO): 9.25 (d, J = 10Hz, ÍH), 8.65 (t, J = 6Hz, ÍH), 7.92 (d, J = 7Hz, 2H), 7.5 (m, 3H), 5.60 (d, J = 10Hz, ÍH), 4.18 (m, 2H), 3.51 (m, 2H), 1.56 (h, J, = 8Hz, 2H), 0.88 (t, J = 8Hz, 3H); N- (3-benzylsulfanyl-IR-cyanomethyl) carbamoylpropi1) benzamide (Compound 217); A? MR (DMSO): 8.69 (t, J = 6Hz, ÍH), 8.63 (d, J = 8Hz, ÍH), 7.90 (d, J = 9Hz, 2H), 7.5 (m, 3H), 7.2 (m , 5H), 4.54 (m, ÍH), 4.13 (d, J = 6Hz, 2H), 3.73 (s, 2H), 2.46 (m, 2H), 2.02 (m, 2H); MS: m / e = 367.81; N- [(cyanomethylcarbamoyl) (cyclohexyloxy) methyl] benzamide (Compound 218); A? MR (DMSO): 9.26 (d, J = 9Hz, ÍH), 8.55 (t, J = 6Hz, ÍH), 7.92 (d, J = 7Hz, 2H), 7.51 (m, 3H), 5.72 (d , J = 10Hz, HH), 4.17 (m, 2H), 3.56 (m, HH), 1.95 (m, 3H), 1.75 (m, 3H), 1.3 (m, 6H); MS: m / e = 315.8; N- (lS-cyanomethylcarbamoyl-2-cyclohexylethyl) succinamic acid (Compound 219) A? MR (CDC13): 4.38 (m, ÍH), 4.05 (s, 2H), 2.45 (d, J = 6.3Hz, 2H), 2.58 (d, J = 6.3Hz, 2H), 0.8-1.9 (m, 15H); MS: m / e (+1) 309.72; 3- [3- (2-chloro-6-methylphenyl) ureido] -N-. { 1 S-cyanomethyl carbamoyl-2-cyclohexylethyl) benzamide (Compound 220); tert-butyl 4- (lff-cyanomethylcarbamoyl-2-cyclohexyl ethylcarbamoyl) phenylcarbamate (Compound 221);
N- (lS'-cyanomethylcarbamoyl-2-pyrid-4-ylethyl) benzamide (Compound 222); 1H? MR: (CDC13) 8.36 (d, J = 6Hz,
2H), 7.80 (d, J = 6.5Hz, ÍH), 7.66 (d, J = 7.3Hz, 2H), 7.47-7.32
(m, 4H), 7.14 (d, J = 6Hz, 2H), 4.79 (m, ÍH), 4.06 (d, J = 17Hz, ÍH), 3.94 (d, J = 17Hz, ÍH), 3.15 (dd, J = 6.6Hz, J = 13.6Hz, ÍH),
3. 01 (dd, J = 7.5Hz, J = 14Hz, ÍH); MS: (MAl) 309; N- [lS-cyanomethylcarbamoyl-2- (4-oxocyclohexyl) ethyl] benzamide (Compound 223); A? MR: (CDC13) 7.93 (m, ÍH), 7.81 (d, J = 7Hz, 2H), 7.59-7.44 (m, 3H), 7.13 (t, J = 8Hz, ÍH), 4.85 (m, ÍH) ), 4.23-4.08 (m, 2H), 2.38-1.25 (m, 11H); MS: (MAl) 328; N- [lS-cyanomethylcarbamoyl-2- (4,4-difluorocyclohexyl) ethyl] benzamide (Compound 224); A? MR: (CDC13) 8.04 (m, HH), 7.80 (d, J = 7.4Hz, 2H) , 7.58-7.42 (m, 3H), 7.20 (d, J = 6Hz, ÍH), 4.84 (m, ÍH), 4.21-4.03 (m, 2H), 2.20-1.23 (m, 11H); MS: (M ++ 1) 350; N- [lS-cyanomethylcarbamoyl-2-cyclohexylethyl] thio morpholin-4-carboxamide (Compound 225); 1H? MR (DMSO): 7.75 (m, HH), 4.99 (m, HH), 4.37 (m, HH), 4.12 (m, HH), 3.7 (m, 4H), 2.61 (m, 4H), 2 -0.8 (m, 13H); MS: m / e 339.4; 4- (lS-cyanomethylcarbamoyl-2-cyclohexylethyl carbamoyl) butyric acid (Compound 226); N- [(cyanomethylcarbamoyl) (phenethyloxy) methyl] benzamide (Compound 227); 1H? MR (DMSO): 9.30 (d, J = 9Hz, ÍH), 8.69 (t, J = 7Hz, ÍH), 7.90 (d, J = 8Hz, 2H), 7.51 (m, 3H), 7.2 (m , 5H), 5.66 (m, HH), 4.19 (m, 2H), 3.77 (m, 2H), 2.92 (m, 2H); MS: m / e = 337.94; 4-amino-N- (SS-cyanomethylcarbamoyl-2-cyclohexylethyl) benzamide (Compound 228); tert-butyl 4- (2-benzylsulfanyl-1-cyanomethylcarbamoylethylcarbamoyl) piperazine-1-carboxylate (Compound 229); A? MR (CDC13): 7.46 (t, J = 5.7Hz, ÍH), 7.31 (m, 5H), 5.27 (d, J = 6.9Hz, ÍH), 4.38 (dd, J = 13.4, 6.7Hz, ÍH) ), 4.15 (dd, J = 17.3, 5.9Hz, ÍH), 4.06 (dd, J = 17.3, 9.9Hz, ÍH), 3.73 (s, 2H), 3.42 (t, J = 4.9Hz, 4H), 3.31 (t, J = 4.9Hz, 4H), 2.97 (dd, J = 14.1, 6.7Hz, ÍH), 2.77 (dd, J = 13.9, 6.7Hz, ÍH), 1.46 (s, 9H); MS (462.4); N- (2-benzylsulfanyl-l. -cyanomethylcarbamoylethyl) -4-fur-2-ylcarbonylpiperazin-1 -carboxamide (Compound 230); 1H? MR (CDC13): 7.59 (t, J = 5.7Hz, ÍH), 7.50 (dd, J = 2.2, l.OHz, ÍH), 7.30 (m, 5H), 7.05 (dd, J = 2.4, 0.7 Hz, ÍH), 6.50
(dd, J = 6.9, 1.7Hz, ÍH), 5.42 (d, J = 6.9Hz, ÍH), 4.42 (dd,
J = 13.3, 6.7Hz, ÍH), 4.15 (dd, J = 11.6, 5.9Hz, ÍH), 4.06
(dd, J = 16.2, 7.2Hz, ÍH), 3.73 (s, 4H), 3.45 (m, 4H), 3.38 (m, 4H), 2.95 (dd, J = 13.9, 6.4Hz, ÍH), 2.78 ( dd, J = 13.9, 6.7Hz, ÍH); MS (456.2); ethyl 4- (2-benzylsulfanyl-l.R-cyanomethylcarbamoylethylcarbamoyl) piperazine-1-carboxylate (Compound 231); 1H? MR (CDCI3): 7.58 (t, J = 5.7Hz, 1H), 7.30 (m, 5H), 5.35 (d, J = 6.9Hz, ÍH), 4.41 (dd, J = 13.3, 6.7Hz, ), 4.15 (q, J = 7.1Hz, 2H), 4.10 (t, J 5.9Hz, 2H), 3.72 (s, 2H), 3.47 (t, J = 4.9Hz, 4H), 3.34 (t, J = 3.7Hz, 4H), 2.93 (dd, J = 13.8, 6.4Hz, ÍH), 2.76 (dd, J = 13.8, 6.9Hz, ÍH), 1.26 (t, J = 7.1Hz, 3H); MS (434.4); N- (2-benzylsulfanyl-l. -cyanomethylcarbamoylethyl) -4-hydroxybenzamide (Compound 232); N- (2-benzylsulfanyl-1R-cyanomethylcarbamoylethyl) -3-hydroxybenzamide (Compound 233); N- [2- (1-Acetylpiperidin-4-yl) -lS-cyanomethylcarbamoylethyl] benzamide (Compound 234); MS: (M ++? A) 379; N- [(cyanomethylcarbamoyl) (phenylamino) methyl] benzamide
(Compound 235); A? MR (DMSO): 9.02 (d, J = 9Hz, ÍH), 8.91
(t, J = 6Hz, ÍH), 7.86 (d, J = 10Hz, 2H), 7.5 (m, 3H), 7.11 (t,
J = 9Hz, 2H), 6.78 (d, J = 8Hz, 2H), 6.65 (t, J = 8Hz, ÍH), 6.08 (d, J = 9Hz, ÍH), 5.87 (m, ÍH), 4.20 (t , J = 3Hz, 2H);
MS: m / e = 308.99; N- [lS-Cyanomethylcarbamoyl-2- (4-methylenecyclohexyl) ethyl] benzamide (Compound 236), -4. ? MR: (CDC13) 7.81-7.75 (m, 3H), 7.58-7.43 (m, 3H), 6.88 (d, J = 8Hz, ÍH), 4.80 (m, ÍH), 4.59 (s, 2H), 4.20 (dd, J = 6Hz, J = 17Hz, ÍH), 4.08 (dd, J = 5.5Hz, J = 17Hz, ÍH), 2.30-1.48 (m, 9H), 1.15-0.96 (m, 2H); MS: (M ++? A) 348; N- [l S-cyanomethylcarbamoyl-2- (4-ethylidenecyclohexyl) ethyl] benzamide (Compound 237); A? MR: (CDC13) 7.87 (t, J = 6Hz, ÍH), 7.80 (d, J = 7Hz, 2H), 7.58-7.43 (m, 3H), 6.94 (d, J = 8Hz, ÍH), 5.12 (q, J = 6.5Hz, ÍH), 4.80 (m, ÍH), 4.20 (dd, J = 6Hz, J = 17Hz, ÍH), 4.08 (dd, J = 5.5Hz, J = 17Hz, ÍH), 2.55 (m, ÍH), 2.17-1.50 (m, 8H), 1.53 (d, J = 6.5Hz, 3H), 1.10-0.91 (m, 2H); MS: (M + + Na) 362; N- [lS-cyanomethylcarbamoyl-2- (4-propylidenecyclohexyl) ethyl] benzamide (Compound 238); A? MR: (CDC13) 8.15 (m, ÍH), 7.81 (d, J = 8Hz, 2H), 7.56- 7.41 (m, 3H), 7.22 (d, J = 7Hz, ÍH), 5.05 (t, J = 7.2Hz, ÍH), 4.84 (q, J = 7M, ÍH), 4.18 (dd, J = 6Hz, J = 17Hz, ÍH), 4.05 (dd, J = 5.5Hz, J = 17Hz, ÍH), 2.48 (m, 2H), 2.11-1.47 (m, 9H), 1.03-0.90 (m, 2H), 0.90 (t , J = 7.7Hz, 3H); MS: (M ++? A) 376; N- [l S-cyanomethylcarbamoyl-2- (l-ethylpiperidin-4-yl) ethyl] benzamide (Compound 239); ÍH? MR: (DMSO) 8.68 (t, J = 6Hz, ÍH), 8.56 (d, J = 7Hz, ÍH), 7.87 (d, J = 7Hz, 2H), 7.54-7.42 (m, 3H), 4.50 (m, HH), 4.10 (m, 2H), 2.77 (m, 2H), 2.24 (m, 2H), 1.79-1.05 (m, 9H), 0.93 (t, J = 7Hz, 3H); MS: (MAI) 343; 4- [2-benzoylamino-2S-cyanomethylcarbamoylethyl] -1-methylcyclohexyltrifluoroacetate (Compound 240); A? MR: (CDC13) 8.25 (t, J = 5Hz, ÍH), 7.80 (d, J = 7Hz, 2H), 7.58-7.39 (m, 4H), 4.86 (q, J = 7.5Hz, ÍH), 4.16 (dd, J = 5.5Hz, J = 17Hz, ÍH), 4.04 (dd, J = 5.5Hz, J = 17Hz, ÍH), 2.28 (m, 2H), 1.84-1.07 (m, 9H), 1.51 ( s, 3H); MS: (M ++ l) 440; N- (2-tert-butyldisulfanyl-1-R-cyanomethylcarbamoyl ethyl) benzamide (Compound 241); A? MR (CDC13): 7.83 (m, ÍH), 7.65 (m, ÍH), 7.55 (m, ÍH), 7.43 (m, 2H), 7.16 (m, ÍH), 5.00 (m, ÍH), 4.19 (m, 2H), 3.33 (m, ÍH), 3.27 (m, ÍH), 1.34 (s, 9H); N- [lS-cyanomethylcarbamoyl-2- (4-hydroxycyclohexyl) ethyl] benzamide (Compound 242); ÍH NMR: (CDC13 + 10% CD3OD) 7.75 (d, J = 7Hz, 2H), 7.54-7.35 (m, 3H), 4.60 (m, ÍH), 4.14 (d, J = 17.5Hz, ÍH), 4.00 (d, J = 17.3Hz, HH), 3.44 (m, HH), 1.91-1.60 (m, 6H), 1.28-0.90 (m, 5H); MS: (MANa) 352; cis-4- (2-benzoylamino-2ff-cyanomethylcarbamoylethyl) cyclohexyl acetate (Compound 243); MS: (M + + Na) 394, (M + -CH 3 COO) 312; N- [(cyanomethylcarbamoyl) (phenethylsulfanyl) methyl] benzamide (Compound 244); A? MR (DMSO): 9.14 (d, J = 10Hz, ÍH), 9.01 (t, J = 7Hz, ÍH), 7.94 (d, J = 9Hz, 2H), 7.5 (m, 3H), 7.2 (m , 5H), 5.88 (d, J = 10Hz, ÍH), 4.22 (m, 2H), 2.90 (m, 4H); MS: m / e 354.01; N- [lS-cyanomethylcarbamoyl-2- (l-thiazol-2-ylpiperidin-4-yl) ethyl] benzamide (Compound 245); A? MR: (CDC13 + 10% CD3OD) 7.77 (d, J = 7Hz, 2H ), 7.51-7.37 (m, 3H), 7.06 (d, J = 3.6Hz, ÍH), 6.48 (d, J = 3.6Hz, ÍH), 4.68 (t, J = 7.3Hz, ÍH), 4.14 (d) , J = 17.3Hz, HH), 4.01 (d, J = 17.3Hz, HH), 3.91-3.85 (m, 2H), 2.99-2.89 (m, 2H), 1.90-1.27 (m, 7H); MS: (M ++? A) 420; - N -, [cyanomethylcarbamoyl) (cyclohexylsulfanyl) methyl] benzamide (Compound 246); A? MR (DMSO): 9.10 (d, J = 10Hz, ÍH), 8.94 (t, J = 6Hz, ÍH), 7.92 (d, J = 9Hz, 2H), 7.50 (m, 3H), 5.80 (d , J = 10Hz, HH), 4.19 (d, J = 6Hz, 2H), 2.96 (m, HH), 2.00 (m, HH), 1.88 (m, HH), 1.67 (m2H), 1.53 (m, ÍH), 1.27 (m 5H); MS: m / e = 331.98; N-cyanomethyl-3-cyclohexyl-2R- (2-ethoxyacetylamino) propionamide (Compound 247); N- (Is-cyanomethylcarbamoyl-2-cyclohexylethyl) -3-methoxypropionamide (Compound 248); A? MR (CDC13): 7.68 (t, J = 5.4Hz, ÍH), 6.66 (d, J = 7.9Hz, ÍH), 4.52 (dd, J = 9.4, 13.4Hz, ÍH), 4.18 (dd, J = 5.9, 17.6Hz, HH), 4.06 (dd, J = 5.9, 17.6Hz, ÍH), 3.65 (m, 2H), 3.38 (s, 3H), 2.50 (t, J = 5.7Hz, 2H), 0.8 -1.70 (m, 13H); cis-N- [lS-cyanomethylcarbamoyl-2- (4-methoxycyclohexyl) ethyl] benzamide (Compound 249); A? MR: (CDC13) 8-01 (s, ÍH), 7.80 (d, J = 7Hz, 2H), 7.55-7.42 (m, 3H), 6.84 (d, J = 8.3Hz, ÍH), 5.26 ( m, ÍH), 4.59 (d, J = 17.2Hz, ÍH), 4.14 (d, J = 17.2Hz, ÍH), 3.54 (m, ÍH), 3.29 (s, 3H), 2.18-0.94 (m, 11H ); MS: (M ++? A) 366; N- (2-benzylsulfanyl-lR-cyanomethylcarbamoylethyl) -3- [3- (1-benzylpyrrolidin-3R-yl) -3-methylureido] benzamide (Compound 250); ESI-MS m / z 585.3 (M + H ++); N- (2-benzylsulfanyl-l. -cyanomethylcarbamoylethyl) -3- [3- (1-benzylpyrrolidin-3S-yl) -3-methylureido] benzamide Compound 251); ESI-MS m / z 585.4 (M + H +); N- (2-benzylsulfanyl-IR-cyanomethylcarbamoylethyl -3- [3- (4-benzylpiperazin-1-ylcarbonyl) amino] benzamide (Compound 252); ESI-MS m / z 571.2 (M + H +); N-. { lR-cyanomethylcarbamoyl-2-pentafluorobenzyl suifanylethibenzamide (Compound 253); N- [lR-cyanomethylcarbamoyl-2-naphthyl-2-ylmethylsulfanyl ethyl) benzamide (Compound 254); XH NMR (CDC13): 7.80 (m, 4H), 7.12-7.74 (m, 9H), 4.80 (m, ÍH), 4.10 (m, 3H), 3.75 (s, 2H), 3.02 (m, ÍH), 2.87 (m, ÍH), 2.2-2.6 (m); N- (2-benzylsulfanyl-lR-cyanomethylcarbamoylethyl) 3- (3- [1,3,4] thiadiazol-2-ylureido) benzamide (Compound 255); 1 H NMR (270 MHz, DMS0-d 6) d 2.78 (m, 1), 2.89 (m, 1), 3.79 (s, 2), 4.18 (d, 2), 4.71 (m, 1), 7.23-7.37 ( m, 5), 7.45 (t, 1), 7.61 (d, 1), 7.71 (d, 1), 7.99 (s, 1), 8.75 (d, 1), 8.77 (t, 1), 9.08 (s) , 1), 9.22 (s, 1); ESI-MS m / z 496.1 (M + H +); N- [2- (4-chlorobenzylsulfanyl) -lR-cyanomethylcarbamoyl ethyl] benzamide (Compound 256); A NMR: (DMSO) 8.85 (t, J = 5Hz, ÍH), 8.73 (d, J = 8.4Hz, ÍH), 7.92 (d, J = 7Hz, 2H), 7.60-7.47 (m, 3H), 7.40 -7.33 (m, 4H), 4.69 (dd, J = 5.2Hz, J = 9.4Hz, ÍH), 4.16 (s, 2H), 3.78 (s, 2H), 2.90 (dd, J = 5.2Hz, J = 13.6Hz, ÍH), 2.77 (dd, J = 9.6Hz, J = 13.8Hz, ÍH); MS: (M ++ 1) 388/390; N- [lR-cyanomethylcarbamoyl-2- (2-methylbenzylsulfanyl) ethyl] benzamide (Compound 257); A? MR: (DMSO) 8.87 (t, J = 5.4Hz, ÍH), 8.74 (d, J = 8.2Hz, ÍH), 7.92 (d, J = 7Hz, 2H), 7.60-7.47 (m, 3H) , 7.25-7.08 (m, 4H), 4.75 (m, ÍH), 4.17 (d, J = 5.7Hz, 2H), 3.80 (s, 2H), 2.98 (dd, J = 5.2Hz, J = 13.6Hz, ÍH), 2.82 (dd, J = 9.6Hz, J = 13.8Hz, ÍH), 2.31 (s, 3H); MS: (M ++ 1) 368; N- [lJ.-cyanomethylcarbamoyl-2- (3,5-dimethylbenzyl sulfanyl) ethyl] benzamide (Compound 258); 1H? MR: (DMSO) 8.86 (t, J = 5.4Hz, ÍH), 8.73 (d, J = 8.2Hz, ÍH), 7.93 (d, J = 7Hz, 2H), 7.60-7.46 (m, 3H) , 6.91 (s, 2H), 6.85 (s, ÍH), 4.71 (m, ÍH), 4.17 (d, J = 5.7Hz, 2H), 3.70 (s, 2H), 2.92 (dd, J = 5.4Hz, J = 13.6Hz, ÍH), 2.76 (dd, J = 9.6Hz, J = 13.8Hz, ÍH), 2.22 (s, 6H); MS: (M ++ 1) 382; N- [lR-cyanomethylcarbamoyl-2- (4-trifluoromethylbenzyl sulfanyl) ethyl] benzamide (Compound 259); A? MR: (DMSO) 8.86 (t, J = 5.4Hz, ÍH), 8.74 (d, J = 7.9Hz , ÍH), 7.93 (d, J = 7Hz, 2H), 7.68 (d, J = 8.2Hz, 2H), 7.60-7.46 (m, 5H), 4.71 (m, ÍH), 4.17 (m, 2H), 3.88 (s, 2H), 2.92 (dd, J = 5.4Hz, J = 13.4Hz, ÍH), 2.79 (dd, J = 9.6Hz, J = 13.8Hz, ÍH); MS: (M ++ 1) 422; N- [l. -cyanomethylcarbamoyl-2- (4-trifluoromethoxybenzylsulfanyl) ethyl] benzamide (Compound 260); 1H? MR: (DMSO) 8.86 (t, J = 5.4Hz, ÍH), 8.74 (d, J = 8.2Hz, ÍH), 7.93 (d, J = 7Hz, 2H), 7.60-7.42 (m, 5H) , 7.31 (d, J = 7.9Hz, 2H), 4.71 (m, ÍH), 4.17 (d, J = 5.7Hz, 2H), 3.83 (s, 2H), 2.92 (dd, J = 5.4Hz, J = 13.8Hz, ÍH), 2.79 (dd, J = 9.6Hz, J = 13.8Hz, ÍH); MS: (M ++ 1) 438; N- [l.R-cyanomethylcarbamoyl-2- (4-trifluoromethyl-sulfyl-anilbenzylsulfanyl) -ethyl] -benzamide (Compound 261); 1H? MR: (DMSO) 8.86 (t, J = 5.4Hz, ÍH), 8.75 (d, J = 8.2Hz, ÍH), 7.92 (d, J = 7Hz, 2H), 7.66 (d, J = 7.9Hz , 2H), 7.60-7.45 (m, 5H), 4.72 (m, ÍH), 4.17 (d, J = 5.7Hz, 2H), 3.86 (s, 2H), 2.92 (dd, J = 5.4Hz, J = 13.8Hz, ÍH), 2.80 (dd, J = 9.6Hz, J = 13.8Hz, ÍH); MS: (M ++ 1) 454; N- [lR-cyanomethylcarbamoyl-2- (3-nitrobenzylsulfanyl) ethyl] benzamide (Compound 262); A? MR: (DMSO) 8.83 (t, J = 5Hz, ÍH), 8.73 (d, J = 7.7Hz, ÍH), 8.21 (s, ÍH), 8.09 (d, J = 8Hz, ÍH), 7.99 ( m, 2H), 7.79 (d, J = 7.7Hz, ÍH), 7.63-7.45 (m, 4H), 4.66 (m, ÍH), 4.14 (d, J = 5Hz, 2H), 3.94 (s, 2H) , 2.90-2.49 (m, 2H); MS: (M ++ l) 399.2; N- [l -cyanomethylcarbamoyl-2- (3-nitrobenzylsulfanyl) ethyl] benzamide (Compound 263); A? MR (DMSO): 8.79 (m, ÍH), 8.48 (d, J = 5Hz, ÍH), 7.93 (d, J = 7Hz, 2H), 7.75 (dt, J = 2.8Hz, ÍH), 7.52 ( m, 5H), 7.26 (m, HH), 4.71 (m, HH), 4.15 (m, 2H), 3.88 (s.2H),, 2.80 (m, 2H); MS: m / e = 354.97; N- (IR-cyanomethylcarbamoyl-2-pyrid-3-ylmethylsulfani1 ethyl) benzamide (Compound 264); A? MR (DMSO): 8.86 (t, J = 6Hz, ÍH), 8.74 (d, J = 9Hz, ÍH) , 8.53 (d, J = 2Hz, ÍH), 8.44 (dd, J = 5.2Hz, ÍH), 7.91 (m, 2H), 7.74 (m, ÍH), 7.54 (m, 3H), 7.34 (m, ÍH) ), 4.72 (m, ÍH), 4.17 (m, 2H), 3.82 (s, 2H), 2.84 (m, 2H); MS: m / e = 355.04; N- (IR-cyanomethylcarbamoyl-2-pyrid-4-ylmethylsulfanyl) ethyl] benzamide (Compound 265); A? MR (DMSO): 8.85 (t, J = 6Hz, ÍH), 8.75 (d, J = 9Hz, ÍH), 8.5 (m, 2H), 7.93 (m, 2H), 7.54 (m, 3H), 7.35 (m, 2H), 4.69 (m, ÍH), 4.16 (d, J = 6Hz, 2H), 3.8 (s 2H), 2.91 (dd, J = 6.15Hz, ÍH), 2.79 (dd, J = 10.15Hz, ÍH); MS: m / e 355.02; 3-amino-N- (15-cyanomethylcarbamoyl) -2-cyclohexylethyl benzamide (Compound 266); 3-amino-N- (2-benzylsulfanyl-IR-cyanomethylcarbamoyl ethyl) benzamide (Compound 267); 3-amino-N- (lS-cyanomethylcarbamoylpentyl) benzamide (Compound 268); methyl 2S-benzoylamino-3-cyclohexylpropionylamino cyanoacetate (Compound 269); MS: (M ++? a) 394; 2S-benzoylamino-3-cyclohexylpropionylamino cyanoacetic acid (Compound 270); MS: (M ++ 1) 358; N- [lJ.-cyanomethylcarbamoyl-2- (3,4-dichlorobenzyl sulfanyl) ethyl] benzamide (Compound 271); 1H? MR (DMSO): 8.8 (d, t, 2H), 7.9 (d, J = 8Hz, 2H), 7.8 (m, 3H), 7.1 (m, 4H), 4.7 (m, ÍH), 4.2 ( S, 2H), 3.7 (s, 2H), 2.9 (m, ÍH), 2.7 (m, ÍH), 2.3 (s, 3H); MS: m / e = 368.0; N- [l.R-cyanomethylcarbamoyl-2- (3-methylbenzylsulfanyl) ethyl] benzamide (Compound 272); N- [l -cyanomethylcarbamoyl-2- (4-nitrobenzylsulfanyl) ethyl] benzamide (Compound 273); A? MR: (DMSO) 8.83 (t, J = 5. 1Hz, ÍH), 8.72 (d, J = 7.7Hz, ÍH), 8.17 (d, J = 8Hz, 2H), 7.89 (d, J = 7Hz , 2H), 7.62-7.45 (m, 5H), 4.67 (m, ÍH), 4.15 (d, J = 5.4Hz, 2H), 3.92 (s, 2H), 2.89 (dd, J = 5.4Hz, J = 13.8Hz, ÍH), 2.77 (dd, J = 9.6Hz, J = 13.8Hz, ÍH); MS: (MAl) 399.2; N- [lR-cyanomethylcarbamoyl-2- (2-nitrobenzylsulfanyl) ethyl] benzamide (Compound 274); A NMR (CDC13): 8.81 (m, ÍH), 8.79 (d, J = 8.0Hz, ÍH), 7.95 (d, J = 3.9Hz, ÍH), 7.84 (m, 2H), 7.42-7.65 (m, 6H), 4.63 (m, ÍH), 4.05 (m, 4H), 3.80 (m, 2H); MS: m / e (+1) 399.2; N- [lJ.-cyanomethylcarbamoyl-2- (3-trifluoromethylbenzyl sulfanyl) ethyl] benzamide (Compound 275); 1H? MR (DMSO): 8.86 (m, ÍH), 8.74 (d, J = 4.9Hz, ÍH), 7.90 (d, J = 8.4Hz, 2H), 4.72 (m, ÍH), 4.15 (d, J = 5.1Hz, 2H), 3.88 (s, 2H), 2.78 (m, 2H), 2.22-2.74 (m, 7H); MS: m / e (+1) 422.2; N- [lR-cyanomethylcarbamoyl-2- (3-trifluoromethylbenzyl sulfanyl) ethyl] benzamide (Compound 276); 1H? MR (DMSO): 8.81 (m, ÍH), 8.76 (d, J = 4.8Hz, ÍH), 7.85 (d, J = 8.4Hz, 2H), 7.10-7.55 (m, 7H), 4.7 (m , ÍH), 4.15 (s, 2H), 3.80 (s, 2H), 2.80 (m, 2H); MS: m / e (+1) 438.2; N- [lR-cyanomethylcarbamoyl-2- (2-methylbenzylsulfanyl) ethyl] morpholin-4-carboxamide (Compound 277); 1H? MR (DMSO): 8.7 (t, J = 6Hz, ÍH), 7.2 (m, 4H), 6.67 (d, J = 7.8Hz, ÍH), 4.4 (m, ÍH), 4.2 (s, 2H) , 3.7 (s, 2H), 3.5 (t, 4H), 3.3 (t, 4H), 2.7 (m, 2H), 2.3 (s, 3H); MS m / e 377.2; N- [lJ.-cyanomethylcarbamoyl-2- (2-nitrobenzylsulfanyl) ethyl] morpholin-4-carboxamide (Compound 278); 1H? MR (DMSO): 8.67 (t, J = 6Hz, ÍH), 7.97 (d, J = 8.1Hz, ÍH), 7.5 (m, 4H), 4.28 (q, ÍH), 4.1 (d, J = 4Hz, 2H), 4.05 (m, 2H), 3.5 (t, 4H), 3.2 (t, 4H), 2.6 (m, 2H); MS m / e 408.4; N- [L-cyanomethylcarbamoyl-2- (3-nitrobenzylsulfanyl) ethyl] morpholin-4-carboxamide (Compound 279); 1H NMR (DMSO):
8. 7 (t, J = 3Hz, ÍH), 8.2 (m, 2H), 7.7 (m, 2H), 6.77 (d, J = 3Hz, ÍH), 4.33 (m, ÍH), 4.16 (m, 2H), 3.85 (d, J = 2.4Hz, 2H), 3.4 (m, 8H), 2.6 (m, 2H); MS m / e 408; N- (lg-cyanomethylcarbamoyl-2-cyclohexylethyl) -1,1-dioxo-l6-thiomorpholin-4-carboxamide (Compound 280); A? MR (DMSO): 8.5 (t, J = 3Hz, ÍH), 6.9 (d, J = 3Hz, ÍH), 4.11 (m, 3H),
3. 8 (t, 4H), 3.1 (t, 4H), 1.8-0.8 (m, 13H); MS m / e 370.8; N- (2-allylsulfanyl, lS-cyanomethylcarbamoylethyl) benzamide (Compound 281); 1H? MR (DMSO): 8.72 (t, ÍH), 8.65 (d, J = 3Hz, ÍH), 7.9 (d, 2H), 7.5 (m, 3H), 5.7 (m, ÍH), 5.1 (m, 2H), 4.1 (d, J = 3Hz, 2H), 2.8 (m, 2H); MS m / e 304.2; N- (1R-cyanomethylcarbamoyl) -2- (2-fluorobenzyl sulfanyl) ethyl] benzamide (Compound 282); 1H? MR (DMSO): 8.85 (m, ÍH), 8.72 (d, J = 4.9Hz, ÍH), 7.90 (d, J = 8.3Hz, 2H), 7.10-7.63 (m, 7H), 4.62 (m , HH), 4.08 (d, J = 5.0Hz, 2H), 3.89 (s, 2H), 2.88 (m, 2H); MS: m / e (+1) 369.8; N- [2- (2-Chlorobenzylsulfanyl) -lR-cyanomethylcarbamoyl ethyl] benzamide (Compound 283); 1H? MR (DMSO): 8.80 (m, ÍH), 8.75 (d, J = 4.8, ÍH), 7.95 (d, J = 8.2Hz, 2H), 7.12-7.58 (m, 7H), 4.75 (m, ÍH), 4.18 (d, J = 4.8Hz, 2H), 3.85 (s, 2H), 2.8 (m, 2H); MS: m / e (+1) 388.2; N- [2- (2-bromobenzylsulfanyl) -lR-cyanomethylcarbamoyl ethyl] benzamide (Compound 284); 1H? MR (DMSO): 8.85 (m, ÍH), 8.73 (d, J = 4.8HZ, ÍH), 7.95 (d, J = 8.2Hz, 2H), 7.4-7.65 (m, 5H), 7.37 (t , J = 7.2Hz, ÍH), 7.20 (t, J = 7.2Hz, ÍH), 4.70 (m, ÍH), 4.08 (d, J = 5.1Hz, 2H), 3.90 (s, 2H), 2.90 (m 2H); MS: m / e (+1) 434.0; N- [lR-cyanomethylcarbarmoyl-2- (2-iodobenzylsulfanyl) ethyl] benzamide (Compound 285); 1H? MR (DMSO): 8.86 (m, ÍH), 8.74 (d, J = 8.1Hz, HI), 7.9 (d, J = 8.4Hz, 2H), 7.83 (d, J = 7.6Hz, 5H) , 7.40-7.60 (m, 4H), 7.33 (t, J = 7.7Hz, ÍH), 6.99 (t, J = 7.4Hz, ÍH), 4.71 (m, ÍH), 4.16 (d, J = 5.5Hz, 2H), 3.83 (s, 2H), 2.88 (m, 2H); MS: m / e (+1) 480.0; N- [2- (4-ert-Butyl-benzylsulfanyl) -IR-cyanomethylcarbamoylethyl] benzamide (Compound 286); 1H? MR (CDC13): 8.16 (m, ÍH), 7.79 (d, J = 7.2Hz, 2H), 7.51 (t, J = 7.3Hz, 2H), 7.40 (t, J = 8.0Hz, 2H), 7.19-7.29 (m, 4H), 4.98 (m, ÍH), 4.08 (m, 2H), 3.72 (m, 2H), 2.94 (m, 2H); N- [3- (2-chlorophenylsulfanyl) -lR-cyanomethylcarbamoylpropyl] benzamide (Compound 287); 1H? MR (DMSO): 8.73 (m, 2H), 7.92 (m, 2H), 7.38-7.56 (m, 5H), 7.32 (t, J = 5.9Hz, ÍH), 7.18 (t, J = 5.9Hz , ÍH), 4.64 (m, HH), 4.14 (d, J = 5.8Hz, 2H), 3.07 (m, 2H), 2.12 (m, 2H); MS: m / e (+1) = 385.9; N- (1R-cyanomethylcarbamoyl-3-o-tolylsulfanylpropyl) benzamide (Compound 288); 1H? MR (DMSO): 8.70 (m, 2H), 7.92 (m, 2H), 7.45-7.60 (m, 3H), 7.30 (d, J = 13.3Hz, ÍH), 7.05-7.21 (m, 3H) , 4.61 (dd, J = 7.7Hz, ÍH), 4.13 (d, J = 5.4Hz, 2H), 3 (m, 2H), 2.28 (s, 3H), 2.10 (m, 2H); MS: m / e (+1) = 366.0; N- (IR-cyanomethylcarbamoyl-3-pyrid-2-ylsulfanyl-propyl) -benzamide (Compound 289); A NMR (DMSO): 8.70 (m, 2H),
8. 39 (m, ÍH), 7.95 (d, J = 13.5.2H), 7.45-7.68 (m, 4H), 7.29
(d, J = 13.5Hz, ÍH), 7.10 (m, ÍH), 4.59 (m, ÍH), 4.13 (d,
J = 5.7Hz, 21-1), 3.20 (m, 2H), 2.14 (m, 2H); MS: m / e (+1) = 353.0; ert-butyl 4- (IR-cyanomethyl-carbamoyl-2-pyrid-2-ylmethylsulfanyl-ethylcarbamoyl) piperidine-1-carboxylate (Compound 290); A NMR (DMSO): 8.72 (t, J = 6.5Hz, ÍH), 8.48 (d, J = 5.2Hz, ÍH), 8.21 (d, J = 11.8Hz, ÍH), 7.75 (t, J = 6.5Hz , ÍH), 7.38 (d, J = 7.9Hz, ÍH), 7.25 (m, ÍH), 4.80 (m, ÍH), 4.14 (d, J = 6.6Hz, 2H), 3.93 (d, J = 13.6Hz , 2H), 3.85 (s, 2H), 3.33 (s, 4H), 2.56-2.83 (m, 4H), 2.35 (m, ÍH), 1.35 (s, 9H); MS: m / e (+1) = 461.4; N- (1R-cyanomethylcarbamoyl-3-pyrid-4-ylsulfanyl-propyl) -benzamide (Compound 291), -A AMR (DMSO): 8.73 (m, 2H), 8.35 (d, J = 6.2Hz, 2H), 7.95 (m, 2H), 7.51 (m, 3H), 7.28 (d, J = 6.2Hz, 2H), 4.62 (q, J = 7.9Hz, ÍH), 4.14 (d, J = 5.7Hz, 2H), 3.13 (m, 2H), 2.14 (m, 2H); MS: m / e (+1) = 355.0; N- [1-Cyanomethyl-carbamoyl) -2-cycloheptyl-ethyl] -benzamide (Compound 292); and 2-Benzylamino-N-cyanomethyl-3-cydohexyl-propionamide (Compound 293). EXAMPLE 11 Cathepsin B Assay The solutions of the test compounds in varying concentrations were prepared in 10 μl of dimethyl sulfoxide (DMSO) and then diluted in an assay regulator (40 μl, comprising: N, N-bis (2- hydroxyethyl) -2-aminoethane sulfonic acid (BES), 50mM (pH 6); polyoxyethylenesorbitan monolaurate, 0.05%; and dithiothreitol (DTT), 2.5 mM). Human cathepsin B (0.025 pMoles in 25 μl of assay buffer) was added to the dilutions. The test solutions were mixed for 5-10 seconds in a shaker dish, covered and incubated for 30 minutes at room temperature. Z-FR-AMC (20 nMoles in 25 μl of the assay buffer) was added to the test solutions and the hydrolysis was followed spectrophotometrically at (? 460 nm) for 5 minutes. Apparent inhibition constants (Ki) were calculated from the progressive curves of the enzyme using standard mathematical models. The compounds of the invention were tested by the assay described above and were observed to exhibit the inhibitory activity of cathepsin B with a Ki of less than or equal to 10 μM. EXAMPLE 12 Cathepsin K Assay The solutions of the test compounds in varying concentrations were prepared in 10 μl of dimethyl sulfoxide (DMSO) and then diluted in an assay buffer (40 μl, comprising: MES, 50 mM (pH 5.5); EDTA, 2.5 mM; and DTT, 2.5 mM). Human cathepsin K (0.0906 pMoles in 25 μl assay buffer) was added to the dilutions. The test solutions were mixed for 5-10 seconds in a shaker dish, covered and incubated for 30 minutes at room temperature. Z-Phe-Arg-AMC (4 nMoles in 25 μl of the assay buffer) was added to the test solutions and the hydrolysis was followed spectrophotometrically at (? 460 nm) for 5 minutes. Apparent inhibition constants (Ki) were calculated from the progressive curves of the enzyme using standard mathematical models. The compounds of the invention were tested by the assay described above and were observed to exhibit the inhibitory activity of cathepsin K with a Ki of less than or equal to 10 μM. EXAMPLE 13 Cathepsin L Assay The solutions of the test compounds in varying concentrations were prepared in 10 μl of dimethyl sulfoxide (DMSO) and then diluted in an assay buffer (40 μl, comprising: MES, 50 mM (pH 5.5); EDTA, 2.5 mM; and DTT, 2.5 mM). Human cathepsin L (0.05 pMoles in 25 μl assay buffer) was added to the dilutions. The test solutions were mixed for 5-10 seconds in a shaker dish, covered and incubated for 30 minutes at room temperature. Z-Phe-Arg-AMC (1 nMole in 25 μl of the assay buffer) was added to the test solutions and the hydrolysis was followed spectrophotometrically at (? 460 nm) for 5 minutes. Apparent inhibition constants (Ki) were calculated from the progressive curves of the enzyme using standard mathematical models. The compounds of the invention were tested by the assay described above and were observed to exhibit the inhibitory activity of cathepsin L with a Ki of less than or equal to 10 μM. EXAMPLE 14 Assay of Cathepsin S The solutions of the test compounds in varying concentrations were prepared in 10 μl of dimethyl sulfoxide (DMSO) and then diluted in an assay buffer (40 μl, comprising: MES, 50 mM (pH 6.5); EDTA, 2.5 mM; and NaCl, 100 mM). Human cathepsin S (0.158 pMoles in 25 μl assay buffer) was added to the dilutions. The test solutions were mixed for 5-10 seconds in a shaker dish, covered and incubated for 30 minutes at room temperature. Z-Phe-Val -Val-Arg-AMC (9 nMoles in 25 μl of the assay buffer) was added to the test solutions and the hydrolysis was followed spectrophotometrically at (? 460 nm) for 5 minutes. Apparent inhibition constants (Ki) were calculated from the progressive curves of the enzyme using standard mathematical models. The compounds of the invention were tested by the assay described above and were observed to exhibit the inhibitory activity of cathepsin S with a Ki of less than or equal to 10 μM. EXAMPLE 15 Ovalbumin Test Mouse C57 (female) mice were sensitized with ovalbumin (10 μg), ip) administered together with aluminum hydroxide adjuvant (20 mg, ip) on days 0 and 12. The mice were tested either on days 22, 23 or 24 by exposure for 60 minutes to an ovalbumin spray ( 10 g / 1) twice, with 4 hours of separation. The mice were dosed p.o. with any vehicle at 5 ml / kg (0.5% MC / 0.2% Tween 80 in H20) or the test compound at 0, 8, 23.5, 29, 33, 48 and 56 hours. The mice were sacrificed with pentobarbitone i.p. after 86 hours (72 hours after the first test). The lungs were insufflated for histological examination as soon as possible after sacrifice. The lungs were insufflated with 10% neutral regulated formalin (NBF), at 30 cm of water pressure. The lungs were removed and placed in 10% NBF vessels. After fixation in 10% NBF for a minimum of 24 hours, the lungs were processed through wax graduated alcohols. Lungs were blocked longitudinally and a 2 μm section was cut for each animal at the level of the main bronchus. The sections were then stained with hematoxylin and eosin. The pathological assessment of the sections was performed and graduation was assigned. The histological evaluation of the lung tissue demonstrated a dose-dependent anti-inflammatory effect in the vascular and mucosal beds after treatment with the compounds of the invention between 0.03 and 30 mg / kg. EXAMPLE 16 Representative Pharmaceutical Formulations Containing a Compound of Formula I
ORAL FORMULATION Compound of Formula I 10-100 mg Citric Acid Monohydrate 105 mg Sodium Hydroxide 18 mg Flavoring Water q.s for 100 mL
INTRAVENOUS FORMULATION Compound of Formula I 0.1-10 mg Dextrose Monohydrate q.s. to make it isotonic Citric Acid Monohydrate 105 mg Sodium Hydroxide 18 mg Water for injection q.s for 1.0 mL
FORMULATION FOR TABLET Compound of Formula I 1% Cellulose Monocrystallized 73% Stearic acid 25% Colloidal silica 1%
Claims (12)
- (I) in which: R1 is a group of Formula (a) or (b) (a) (b) wherein: X1 and X2 are independently -C (0) - or -CH2S (0) 2-; R5 and Rs are hydrogen or alkyl (C? -6); R7 and R8 are hydrogen or (C? -6) alkyl or as defined below; R9 and R10 are independently (i) (C? -6) alkyl optionally substituted with cyano, halo or nitro or (ii) a group selected from -X3NR12R12 '-X3NR12C (O) OR12, -X3NR12C (0) NR12R12, -X3NR12C (NR12) NR12R12, -X3OR12, -X3SR12, X3C (0) OR12, -X3C (0) NR12R12, -X3S (O) 2NR12R12, -X3P (0) (OR12) OR12, -X3OP (0) (OR12 ) OR12, -X3NR12C (0) R13, -X3S (0) R13, -X3S (0) 2R13, X3C (0) R13, -X3C (0) R14, -X3C (0) OR14, -X3OC (0) R14 , -X3NR15C (O) R14, -X3NR15C (0) OR14, -X3C (0) NR14R15, -X3S (O) 2NR14R15, -X3NR1C (O) NR14R15, -X3NR15C (NR15) NR14R15, -X4SR14, -X4S (O) ) R14, -X4S (0) 2R14, -X4OR14, or -X4NR14R15, wherein X3 is alkylene (C? -6), X4 is a bond or alkylene (Ci-β), R12 in each occurrence is independently hydrogen, alkyl (C? _ß) or halo-substituted alkyl (C? -3), R13 is alkyl (Ci-β) or halo-substituted alkyl (C? -3), R14 is (C3-y2) cycloalkyl (C0-? ), (C3-? 2) alkyl heterocycle (Co-β), aryl (C6-? 2) (C0-β) alkyl. heteroaryl (C5-? 2) (C0-β) alkyl polycycloaryl (C9-? 2) (C0-) alkyl or heteropolycycloaryl (C8-? 2) alkyl (Co-β) and R15 is hydrogen or alkyl (Ci-β) ) and wherein within R14 said cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or heteropolycycloaryl ring is optionally substituted by a group selected from R16, -X4OR16, -X4SR16, -X4S (0) R16, -X4S (0) 2R16, -X4C (0) R16, -X4C (0) OR16, X4OC (0) R16, -X4NR16R17, -X4NR17C (0) R16, -X4NR17C (O) OR16, X4C (0) NR1SR17, -X4S (0) 2NR16R17, -X4NR17C (O) NR16R17 or
- X4NR17C (NR17) NR16R17, wherein X4 is a bond or alkylene (d-6), R16 is hydrogen or alkyl (C? -6) and R17 is cycloalkyl (C3-? 2) alkyl (d-?) / Heterocycloalkyl ( C3-? 2) (C0-β) alkyl, (C6-12) aryl (C0-6) alkyl. heteroaryl (C5-12) alkyl (C0-ß), polycycloaryl (C9_? 2) alkyl (Co-ß) or heteropolycycloaryl (C8-? 2) alkyl (C0-ß) or (iii) a group selected from cycloalkyl (C3-i2) alkyl (C0-β). Heterocycloalkyl (C3_ 12) alkyl (Co-ß), aryl (C6.?2) alkyl (C0-ß), heteroaryl (C5_12) alkyl (C0-ß), polycycloaryl (C9_? 2) alkyl (C0-ß) and heteropolycycloaryl ( C8-12) (C0-β) alkyl wherein said cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or heteropolycycloaryl ring are optionally substituted by a group selected from R1S, X4OR16, -X4SR16, -X4S (0) R16, - X4S (0) 2R16, -X4C (0) R16, -X4C (0) OR? E, -X4OC (0) R16, -X4NR16R17, -X4NR17C (O) R16, -X4NR17C (O) OR16, X4C (0) NR16R17, -X4S (0) 2NR16R17, -X4NR17C (O) NR16R17 or X4NR17C (NR17) NR16R17, wherein X4, R16 and R17 are as defined above; wherein within R9 and / or R10 any present system of alicyclic or aromatic ring present can be further substituted by 1 to 5 radicals independently selected from alkyl (C? -6), alkylidene (C? _6), cyano, halo, alkyl (C1-4) halo-substituted, nitro, -X4NR12R12, X4NR12C (0) OR12, -X4NR1C (0) NR12R12, -XNR12C (NR12) NR12R12, -X4OR12, -X4SR12, -X4C (0) OR12, -X4C ( 0) NR12R12, -X4S (O) 2NR1R12, X4P (0) (OR4) OR12, -X4OP (0) (OR12) OR12, -X4OC (0) R13, -X4NR12C (O) R13, -X4S (0) R13 , -X4S (0) 2R13 and -X4C (0) R13, wherein X4, R12 and R13 are as defined above or R9 taken together with R7 and / or R10 taken together with R8 form trimethylene, tetramethylene or phenylene-1 , 2-dimethylene, optionally substituted with hydroxy, oxo or methylene; and R11 is -X5X6R18, wherein X5 is -C (O) -, -C (0) C (0) - or -S (0) 2-, X6 is a bond, -0- or -NR19-, wherein R19 is hydrogen or alkyl (C? -6) and R18 is (i) alkyl (C? -? 0) optionally substituted by cyano, halo, nitro, -NR12R12, -NR12C (0) OR12, -NR12C (0) NR12R12, -NR12C ( NR12) NR12R12, -OR12, -SR12, -C (0) 0R12, -C (0) NR12R12, -S (0) 2NR12R12, -P (0) (OR12) OR12, OP (0) (OR12) OR12, -NR12C (0) R13, -S (0) R13, -S (0) 2R13, -C (0) R13, -OR20, -SR20, -S (0) R20, -S (0) 2R20, -C (0) R20, -C (0) 0R20, C (O) NR20R21, -NR20R21, -NR21C (O) R20, -NR21C (0) OR20, -NR21C (0) NR20R21 or -NR21C (NR21) NR20R21, in where R12 and R13 are as defined above, R20 is (C3-y2) cycloalkyl (C0-β) alkyl. heterocycloalkyl (C3-? 2) alkyl (C0-ß), aryl (C6-i2) alkyl (C0-ß) heteroaryl (C5-12) alkyl (C0-ß). bicycloaryl (C9-? 2) (C0-ß) alkyl or heterobicycloaryl (C8-? 2) (C0-ß) alkyl and R21 in each occurrence independently is hydrogen or (C? -6) alkyl or (ii) (C3) cycloalkyl -? 2) alkyl (C0-ß), heterocycloalkyl (C3-? 2) alkyl (C0-e), aryl (C6-? 2) alkyl (C0-ß), heteroaryl (C5-? 2) alkyl (C0-) ß) bicycloaryl (C9-? 2) (C0-ß) alkyl or heterobicycloaryl (C8-? 2) alkyl (Co-ß) or (iii) (C3_) cycloalkyl (C0-ß) alkyl. (C3-6) heterocycloalkyl (C0-β) alkyl. phenylalkyl (C0-ß) or heteroaryl (C5-6) alkyl (A wherein said cycloalkyl, heterocycloalkyl, phenyl or heteroaryl is substituted by -X4OR22, -X4SR22, -X4S (0) R22, -X4S (0) 2R22, - X4C (0) R22, -X4C (0) OR22, -X4C (0) NR22R23, -X4NR22R23, -X4NR23C (0) R22, -X4NR23C (0) OR22, -X4NR23C (0) NR22R23 or -X NR23C (NR23) NR22R23, where X4 is as defined above, R22 is (C3_6) alkyl (d-ß), (C3-6) alkyl (C0-), phenylalkyl (C0-) or heteroaryl (C5-6) ) alkyl (C0-ß) and R23 in each occurrence independently is hydrogen or alkyl (C? -6); wherein within R11 any present alicyclic or aromatic ring system can be further substituted by 1 to 5 independently selected radicals from alkyl (C? -6), alkylidene (C? -6), cyano, halo, alkyl (C? -4) -halo- substituted, nitro, -X4NR12R12, -X4NR12C (0) OR12,
- X4NR12C (0) NR12R12, -X4NR12C (NR12) NR12R12, -X4OR12, -X4SR12,
- X4C (0) OR12, -X4C (0) NR12R12, -X4S (0) 2NR12R12, -X4P (0) (OR3) OR12, -X40P (0) (OR3) OR12, -X40C (0) R13, -X4NR12C ( O) R13,, -X4S (0) R13, X4S (0) 2R13 and -X4C (0) R13, wherein X4, R12 and R13 are as defined above; R2 is hydrogen or alkyl (C? _6) or as defined below; R3 is hydrogen, alkyl (C? _6) or as defined below; and R4 is (i) hydrogen or (C6-6) alkyl, wherein said alkyl is optionally substituted with cyano, halo, nitro, -NR12R12, -NR12C (O) OR12, -NR12C (0) NR12R12, NR12C (NR12 ) NR12R12, -OR12, -SR12, -C (0) 0R12, -C (O) NR12R12, S (0) 2NR12R12, -P (0) (OR12) OR12, -OP (O) (OR12) OR12, - NR12C (O) R13, -S (0) R13, -S (0) 2R13, -C (0) R13, -OR14, -SR14, -S (0) R14, -S (0) 2R14, -C ( 0) R14, -C (0) OR14, -OC (0) R14, -NR14R15, -NR15C (O) R14,
- NR15C (0) OR14, -C (0) NR14R15 -S (O) 2NR14R15, -NR15C (O) NR14R15 or -NR15C (NR15) NR14R15, wherein R12, R13, R14 and R15 are as defined above or (ii) ) a group selected from cycloalkyl (C3-12) alkyl (Co-ß) / heterocycloalkyl (C3. 12) alkyl (Co-β) aryl (C6-? 2) (C0-6) alkyl. heteroaryl (C5_ 12) alkyl (Co-ß) # polycycloaryl (C9-? 2) alkyl (C0-e) and heteropolycycloaryl (C8-? 2) alkyl (Co-e) wherein said cycloalkyl ring, heterocycloalkyl. aryl, heteroaryl, polycycloaryl or heteropolycycloaryl is optionally substituted by a group selected from -R16, X4OR16, -X4SR16, -X4S (0) R16, -X4S (0) 2R16, -X4C (0) R16, -X4C (0) ) OR16, -X OC (0) R16, -X4NR16R17, -X4NR17C (0) R16, -X4NR17C (O) OR16,
- X C (0) NR16R17, -X4S (0) 2NR16R17, -X4NR17C (O) NR16R17 or X4NR17C (NR17) NR16R17, wherein X4, R16 and R17 are as defined above; wherein within R9 and / or R10 any present system of alicyclic or aromatic ring present can be further substituted by 1 to 5 radicals independently selected from alkyl (C? -6), alkylidene (C? -6), cyano, halo, (C 1-4) halo-substituted alkyl, nitro, -X4NR12R12, X4NR12C (0) OR12, -X4NR12C (0) NR12R12, -X4NR12C (NR12) NR12R12, -X4OR12, -X SR12, -X4C (0) OR12, - X4C (0) NR12R12, -X4S (O) 2NR12R12,
- X4P (0) (OR3) OR12, -X4OP (0) (OR3) OR12, -X4OC (0) R13, -X4NR12C (O) R13, -X4S (0) R13, -X4S (0) 2R13 and -X4C ( 0) R13, wherein X4, R12 and R13 are as defined above or R4 and R2 taken together form trimethylene, tetramethylene or phenylene-1,2-dimethylene, optionally substituted with hydroxy, oxo or methylene, or R4 and R3 together with the carbon atom to which both R4 and R3 are attached form cycloalkylene (C3.8) or heterocycloalkylene (C3-8); or an N-oxide derivative, prodrug derivative, individual isomer and mixtures of isomers; or a pharmaceutically acceptable salt thereof, but excluding the compounds of the formula wherein R3 and R4 are each hydrogen or alkyl (C? -6) or together with the carbon atom to which they both bind cycloalkylene (C3_5); R5 is hydrogen or alkyl (C? _6); R9 is aryl (C6-i2) alkyl (C6-6), heteroaryl (C5-? 2) alkyl (d-6), alkyl (C4-5) or cyclohexylmethyl; and R11 is C (0) R18 wherein R18 is (C3-12) heterocycloalkyl, aryl (C6-? 2) alkyl (C0_ß) or heteroaryl (C5-12) alkyl (Ci-β). in the manufacture of a medicament to treat a disease in an animal in which the activity of cathepsin S contributes to the pathology and / or symptomatology of the disease. 35. A process for preparing a compound of Formula (I)
- I in which: R1 is a group of Formula (a) or (b) (a) (b) wherein: X1 and X2 are independently -C (O) - or -CH2S (0) 2-; R5 and R6 are hydrogen or alkyl (C? -6); R7 and R8 are hydrogen or (C? -6) alkyl or as defined below; R9 and R10 are independently (i) (C6-6) alkyl optionally substituted with cyano, halo, nitro, -NR12R12, NR12C (0) OR12, -NR12C (0) NR12R12, -NR12C (NR12) NR12R12, -OR12, -SR12, -C (0) OR12, -C (0) NR12R12, -S (0) 2NR12R12, -P (O) (OR12) OR12,
- OP (O) (OR12) OR12, -NR1 C (0) R13, -S (0) R13, -S (0) 2R13, -C (0) R13, -OR14, -SR14, -S (0) R14 , -S (0) 2R14, -C (0) R14, -C (0) OR14, -OC (0) R14, -NR14R15, -NR15C (0) R14, -NR15C (O) OR14, -C (0) NR14R15 -S (O) 2NR14R15, -NR15C (0) NR14R15 or -NR15C (NR15) NR14R15, wherein R12 in each occurrence independently is hydrogen, (C? -6) alkyl or halo-substituted (C? -3) alkyl, R13 is alkyl (C) ? -6) or halo-substituted alkyl (C? -3), R14 is (C3-? 2) cycloalkyl (C0-?) Alkyl (C3-? 2) alkyl (C0-6) aryl (C6-? 2) alkyl ) alkyl (C0-6). heteroaryl (C5-12) alkyl (C0-β) polycycloaryl (C9-? 2) alkyl (C0-?) or heteropolycycloaryl (C8_? 2) alkyl (C0_ß) and R15 is hydrogen or alkyl (C? -6) and in wherein within R14 said cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or heteropolycycloaryl ring optionally is substituted by a group selected from -R16, -X3ORls, -X3SR16, -X3S (0) R16, -X3S (0) 2R16, -X3C (0) R16, -X3C (0) OR16, X3OC (0) R16, -X3NR1SR17, -X3NR17C (0) R16, -X3NR17C (O) OR16, X3C (0) NR16R17, -X3S (0) 2NR16R17, -X3NR17C (O) NR16R17 or X3NR17C (NR17) NR16R17, wherein X3 is a bond or alkylene (Ci- 6), R is hydrogen or alkyl (C? _6) and R is cycloalkyl (C3_? 2) alkyl (C0) -H.H) . Heterocycloalkyl (C3-? 2) alkyl (C0-?). aryl (C6-12) alkyl (C0-β). heteroaryl (C5-? 2) alkyl (C0-6), polycycloaryl (C9-? 2) alkyl (C0-e) or heteropolycycloaryl (C8.12) alkyl (Co-β) or (ii) a group selected from cycloalkyl (C3-? 2) alkyl (d-β). heterocycloalkyl (C3-X2) alkyl (C0-e) / aryl (C6-? 2) (C0-6) alkyl. heteroaryl (C5.? 2) (C0-ß) alkyl, polycycloaryl (C9-? 2) (C0-6) alkyl and heteropolycycloaryl (C8_? 2) alkyl (Co-ß) wherein said cycloalkyl, heterocycloalkyl, aryl ring, heteroaryl, polycycloaryl or heteropolycycloaryl optionally substituted by a group selected from -R16, -X3OR16, -X3SR16, -X3S (0) R16, -X3S (0) 2R16, -X3C (0) R16, -X3C (0) OR16, X3OC (0) R16, -X3NR16R17, -X3NR17C (0) R16, -X3NR17C (O) OR16, X3C (0) NR16R17, -X3S (0) 2NR16R17, -X3NR17C (O) NRldR17 or
- X3NR17C (NR17) NR16R17, wherein X3, R16 and R17 are as defined above; wherein within R9 and / or R10 any present alicyclic or aromatic ring system can be further substituted by 1 to 5 independently selected radicals from alkyl. { C? .6), alkylidene (C? -6), cyano, halo, halo-substituted alkyl (C? _4), nitro, -X3NR12R12, X3NR12C (0) OR12, -X3NR12C (0) NR12R12, -X3NR12C (NR12 ) NR12R12, -X3OR12, -X3SR12, -X3C (0) OR12, -X3C (0) NR12R12, -X3S (O) 2NR12R12,
- X3P (0) (OR3) OR12, -X3OP (0) (OR3) OR12, -X3OC (0) R13, -X3NR12C (O) R13, -X3S (0) R13, -X3S (0) 2R13 and -X3C ( 0) R13, wherein X3, R12 and R13 are as defined above or R9 taken together with R7 and / or R10 taken together with R8 form trimethylene, tetramethylene or phenylene-1,2-dimethylen, optionally substituted with hydroxy, oxo or methylene, and R11 is -X4X5R18, wherein X4 is -C (O) -, -C (0) C (0) - or -S (0) 2-, X5 is a bond, -O- or - NR19-, wherein R19 is hydrogen or alkyl (C? -6) and R18 is (i) alkyl (C? _? 0) optionally substituted by cyano, halo, nitro, -NR12R12, -NR12C (0) OR12, - NR12C (0) NR12R12, -NR12C (NR12) NR12R12, -OR12, -SR12, -C (0) OR12, -C (0) NR12R12, -S (0) 2NR12R12, -P (O) (OR12) OR12, OP (O) (OR12) OR12, -NR12C (0) R13, -S (0) R13, -S (0) 2R13, -C (0) R13, -OR20, -SR20, -S (0) R20, -S (0) 2R20, -C (0) R20, -C (0) OR20, C (O) NR20R21, -NR20R21, -NR21C (O) R20, -NR21C (O) OR20, -NR21C (O) NR0R21 or -NR21C (NR21) NR20R21, wherein R12 and R13 are as defined above, R20 is cycloalkyl (C3-i2) a alkyl (C0-ß) (C3-? 2) heterocycloalkyl (C0-ß) alkyl (C6-? 2) alkyl (C0-?), heteroaryl (C5-? 2) alkyl (C0-?) bicycloaryl (C9-) ? 2) alkyl (d-β) or heterobicycloaryl (C8-? 2) alkyl (C0-e) and R1 in each occurrence independently is hydrogen or alkyl (C? -6) or (ii) cycloalkyl (C3_? 2) alkyl (C0-ß), heterocycloalkyl (C3.
- 12) (C0-e) alkyl (C6-? 2) alkyl (C0-β). heteroaryl (C5_12) (C0-ß) alkyl / bicycloaryl (C9-? 2) (C0-b) alkyl or (C8-i2) heterobicycloalkyl (C0-) alkyl or (iii) (C3. Co-e) C3-6 heterocycloalkyl (C0-β) alkyl. phenylalkyl (Co-e) or heteroaryl (C5-6) alkyl (C0-ß) / wherein said cycloalkyl, heterocycloalkyl, phenyl or heteroaryl is substituted by -X3OR22, -X3SR22, -X3S (0) R22, -X3S (0 ) 2R22, -X3C (0) R22, -X3C (0) OR22, -X3C (0) NR22R23, -X3NR22R23, -X3NR23C (O) R22, -X3NR23C (0) OR22, -X3NR23C (0) NR22R23 or -X3NR23C (NR23) NR22R23, wherein X3 is as defined above, R22 is (C3-6) alkyl (d-β) cycloalkyl. heterocycloalkyl (C3. ß) (C0-ß) alkyl phenylalkyl (C0-ß) or heteroaryl (C5-ß) alkyl (C0-e) and R23 in each occurrence independently is hydrogen or alkyl (Ci-β); wherein within R11 any present alicyclic or aromatic ring system can be further substituted by 1 to 5 independently selected radicals from alkyl (C? -6), alkylidene (C? -6), cyano, halo, alkyl (C? -4) halo-substituted, nitro, -X3NR12R12, X3NR12C (0) OR12, -X3NR12C (0) NR12R12, -X3NR12C (NR12) NR12R12, -X3OR12, -X3SR12, -X3C (0) 0R12, -X3C (0) NR12R12, -X3S (O) 2NR12R12, X3P (0) (OR3) OR12, -X3OP (0) (OR3) OR12, -X3OC (0) R13, -X3NR12C (O) R13, -X3S (0) R13, -X3S (0) 2R13 and -X3C ( 0) R13, wherein X3, R12 and R13 are as defined above; R2 is hydrogen or (C? -6) alkyl or as defined below; R3 is hydrogen, alkyl (C? -6) or as defined below; and R4 is (i) hydrogen or (C? -6) alkyl, wherein said alkyl is optionally substituted with cyano, halo, nitro, -NR12R12, -NR12C (O) OR12, -NR12C (O) NR12R12, NR12C ( NR12) NR12R12, -OR12, -SR12, -C (0) OR12, -C (O) NR12R12, S (0) 2NR12R12, -P (O) (OR12) OR12, -OP (O) (OR12) OR12, -NR12C (O) R13, -S (0) R13, -S (0) 2R13, -C (0) R13, -OR14, -SR14, -S (0) R14, -S (0) 2R14, -C (0) R14, -C (0) OR14, -OC (0) R14, -NR14R15, -NR15C (O) R14, NR15C (0) OR14, -C (0) NR14R15 -S (O) 2NR14R15, -NR15C (O) NR14R15 or -NR15C (NR15) NR14R15, wherein R12, R13, R14 and R15 are as defined above or (ii) ) a group selected from cycloalkyl (C3_? 2) alkyl (C0-ß) / heterocycloalkyl (C3-12) alkyl (C0-ß) / aryl (C6-? 2) alkyl (C0-6). heteroaryl (C5-12) alkyl (Co-e). polycycloaryl (C9-? 2) (C0-ß) alkyl and heteropolycycloaryl (C8 ..? 2) (C0-ß) alkyl wherein said cycloalkyl ring, heterocycloalkyl. aryl, heteroaryl, polycycloaryl or heteropolycycloaryl optionally substituted by a group selected from -R16, X3OR16, -X3SR16, -X3S (0) R16, -X3S (0) 2R16, -X3C (0) R16, -X3C (0) 0R1S, -X3OC (0) R16, -X3NR16R17, -X3NR17C (0) R16, -X3NR17C (O) OR16, X3C (0) NR16R17, -X3S (0) 2NR1SR17, -X3NR17C (O) NR16R17 or X3NR17C (NR17) NR16R17, wherein X3, R16 and R17 are as defined above; wherein within R9 and / or R10 any present alicyclic or aromatic ring system can be further substituted by 1 to 5 independently selected radicals from alkyl (d-ß), alkylidene (C? -6), cyano, halo, alkyl (C? -4) halo-substituted, nitro, -X3NR12R12, X3NR12C (0) OR12, -X3NR12C (0) NR12R12, -X3NR12C (NR12) NR12R12, -X3OR12, -X3SR12, -X3C (0) OR12, -X3C (0) NR12R12, -X3S (O) 2NR12R12, X3P (0) (OR3) OR12, -X3OP (0) (OR3) OR12, -X3OC (0) R13, -X3NR12C (O) R13, -X3S (0) R13, -X3S (0) 2R13 and -X3C (0) R13, wherein X3, R12 and R13 are as defined above or R4 and R2 taken together form trimethylene, tetramethylene or phenylene-1,2-dimethylene, optionally substituted with hydroxy, oxo or methylene, or R 4 and R 3 together with the carbon atom to which both R 4 and R 3 are attached form cycloalkylene (C 3-8) or heterocycloalkylene (C 3-8); and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers; and pharmaceutically acceptable salts thereof, which process comprises: (A) reacting a compound of Formula 2: or a protected derivative thereof, with a compound of the formula R10Y or a protected derivative thereof, in the Y is hydrogen or 2,5-dioxopyrrolidin-1-yl and each R1, R2, R3 and R4 are as defined earlier; or (B) reacting a compound of Formula 3: or a protected derivative thereof, with ammonia to provide a corresponding amide and then reacting the amide with trifluoroacetic anhydride, wherein each R1, R2, R3 and R4 are as defined above; (C) optionally deprotecting a protected derivative of a compound of Formula I to provide a corresponding unprotected derivative; (D) optionally converting a compound of Formula I into a pharmaceutically acceptable salt; (E) optionally converting a salt form of a compound of Formula I to a non-salt form; (F) optionally converting a non-oxidized form of a compound of Formula I to a pharmaceutically N-oxide; acceptable; (G) optionally converting an N-oxide form of a compound of Formula I to its non-oxidized form; (H) optionally converting a non-derivatized compound of Formula I into a pharmaceutically derived prodrug; and (I) optionally converting a prodrug derivative of a compound of Formula I to its non-derivatized form.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US60/124,420 | 1999-03-15 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| MXPA01009241A true MXPA01009241A (en) | 2002-05-09 |
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