MXPA01009240A - Amine derivatives as protease inhibitors - Google Patents
Amine derivatives as protease inhibitorsInfo
- Publication number
- MXPA01009240A MXPA01009240A MXPA/A/2001/009240A MXPA01009240A MXPA01009240A MX PA01009240 A MXPA01009240 A MX PA01009240A MX PA01009240 A MXPA01009240 A MX PA01009240A MX PA01009240 A MXPA01009240 A MX PA01009240A
- Authority
- MX
- Mexico
- Prior art keywords
- alkyl
- halo
- hetero
- nr14r14
- aryl
- Prior art date
Links
- 229940042399 direct acting antivirals Protease inhibitors Drugs 0.000 title description 5
- 239000000137 peptide hydrolase inhibitor Substances 0.000 title description 5
- 150000001412 amines Chemical class 0.000 title description 4
- 125000005842 heteroatoms Chemical group 0.000 claims abstract description 334
- 125000004429 atoms Chemical group 0.000 claims abstract description 114
- 150000003839 salts Chemical class 0.000 claims abstract description 68
- 125000004432 carbon atoms Chemical group C* 0.000 claims abstract description 64
- 239000011780 sodium chloride Substances 0.000 claims abstract description 63
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 46
- 150000001204 N-oxides Chemical class 0.000 claims abstract description 38
- 125000002911 monocyclic heterocycle group Chemical group 0.000 claims abstract description 15
- 239000003814 drug Substances 0.000 claims abstract description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 1101
- -1 heteromonocyclic radical Chemical class 0.000 claims description 627
- 150000001875 compounds Chemical class 0.000 claims description 493
- 125000005843 halogen group Chemical group 0.000 claims description 346
- 125000003118 aryl group Chemical group 0.000 claims description 307
- 229910052739 hydrogen Inorganic materials 0.000 claims description 303
- 239000001257 hydrogen Substances 0.000 claims description 302
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 245
- 239000000203 mixture Substances 0.000 claims description 168
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 142
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 claims description 137
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 131
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 121
- ZKWFSTHEYLJLEL-UHFFFAOYSA-N morpholine-4-carboxamide Chemical compound NC(=O)N1CCOCC1 ZKWFSTHEYLJLEL-UHFFFAOYSA-N 0.000 claims description 92
- 150000003254 radicals Chemical class 0.000 claims description 81
- 125000001118 alkylidene group Chemical group 0.000 claims description 71
- 239000002253 acid Substances 0.000 claims description 68
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 68
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 64
- 201000010099 disease Diseases 0.000 claims description 55
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 52
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 52
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 50
- 125000002947 alkylene group Chemical group 0.000 claims description 46
- 125000004043 oxo group Chemical group O=* 0.000 claims description 45
- 125000002723 alicyclic group Chemical group 0.000 claims description 41
- 125000001072 heteroaryl group Chemical group 0.000 claims description 41
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 36
- 239000000651 prodrug Substances 0.000 claims description 36
- 229940002612 prodrugs Drugs 0.000 claims description 36
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 36
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 34
- 150000002431 hydrogen Chemical class 0.000 claims description 34
- 125000003545 alkoxy group Chemical group 0.000 claims description 28
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 27
- VFQXVTODMYMSMJ-UHFFFAOYSA-N Isonicotinamide Chemical compound NC(=O)C1=CC=NC=C1 VFQXVTODMYMSMJ-UHFFFAOYSA-N 0.000 claims description 26
- 125000002993 cycloalkylene group Chemical group 0.000 claims description 26
- 125000006588 heterocycloalkylene group Chemical group 0.000 claims description 19
- 102000005927 Cysteine Proteases Human genes 0.000 claims description 18
- 108010005843 Cysteine Proteases Proteins 0.000 claims description 18
- 230000000694 effects Effects 0.000 claims description 18
- 150000002148 esters Chemical class 0.000 claims description 18
- 125000004287 oxazol-2-yl group Chemical group [H]C1=C([H])N=C(*)O1 0.000 claims description 17
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 14
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 14
- 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 13
- DGOYLVBDCVINQZ-UHFFFAOYSA-N oxane-4-carboxamide Chemical compound NC(=O)C1CCOCC1 DGOYLVBDCVINQZ-UHFFFAOYSA-N 0.000 claims description 13
- 239000008194 pharmaceutical composition Substances 0.000 claims description 13
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 13
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 claims description 12
- 102100015379 CTSS Human genes 0.000 claims description 12
- 108090000613 Cathepsin S Proteins 0.000 claims description 12
- 125000003368 amide group Chemical group 0.000 claims description 12
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 12
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 12
- DPBWFNDFMCCGGJ-UHFFFAOYSA-N piperidine-4-carboxamide Chemical compound NC(=O)C1CCNCC1 DPBWFNDFMCCGGJ-UHFFFAOYSA-N 0.000 claims description 12
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 claims description 11
- 102000015694 estrogen receptors Human genes 0.000 claims description 11
- 108010038795 estrogen receptors Proteins 0.000 claims description 11
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 11
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 11
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 10
- IPEHBUMCGVEMRF-UHFFFAOYSA-N Pyrazinamide Chemical compound NC(=O)C1=CN=CC=N1 IPEHBUMCGVEMRF-UHFFFAOYSA-N 0.000 claims description 10
- 238000010511 deprotection reaction Methods 0.000 claims description 10
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 10
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 10
- DFPAKSUCGFBDDF-UHFFFAOYSA-N nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 claims description 10
- 239000000018 receptor agonist Substances 0.000 claims description 10
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 9
- 125000004494 ethyl ester group Chemical group 0.000 claims description 9
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 9
- 208000006673 Asthma Diseases 0.000 claims description 8
- 125000005418 aryl aryl group Chemical group 0.000 claims description 8
- 125000004190 benzothiazol-2-yl group Chemical group [H]C1=C([H])C([H])=C2N=C(*)SC2=C1[H] 0.000 claims description 8
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 8
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 8
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 8
- 230000001590 oxidative Effects 0.000 claims description 8
- 238000002360 preparation method Methods 0.000 claims description 8
- KVUUQMDVROTSNI-UHFFFAOYSA-N [morpholin-4-yl(phosphono)methyl]phosphonic acid Chemical compound OP(O)(=O)C(P(O)(O)=O)N1CCOCC1 KVUUQMDVROTSNI-UHFFFAOYSA-N 0.000 claims description 7
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 6
- 239000005977 Ethylene Substances 0.000 claims description 6
- 125000003282 alkyl amino group Chemical group 0.000 claims description 6
- 125000004976 cyclobutylene group Chemical group 0.000 claims description 6
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 6
- VGGSQFUCUMXWEO-UHFFFAOYSA-N ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 claims description 6
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 206010039073 Rheumatoid arthritis Diseases 0.000 claims description 5
- 230000004913 activation Effects 0.000 claims description 5
- 239000004480 active ingredient Substances 0.000 claims description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 5
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 5
- 125000004980 cyclopropylene group Chemical group 0.000 claims description 5
- 125000001624 naphthyl group Chemical group 0.000 claims description 5
- 239000011570 nicotinamide Substances 0.000 claims description 5
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 5
- PAYGMRRPBHYIMA-UHFFFAOYSA-N sodium;trihydrate Chemical compound O.O.O.[Na] PAYGMRRPBHYIMA-UHFFFAOYSA-N 0.000 claims description 5
- 125000001424 substituent group Chemical group 0.000 claims description 5
- 210000001519 tissues Anatomy 0.000 claims description 5
- BWRNWWSQZROEOA-UHFFFAOYSA-N 2-morpholin-4-ylacetamide Chemical compound NC(=O)CN1CCOCC1 BWRNWWSQZROEOA-UHFFFAOYSA-N 0.000 claims description 4
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 4
- 206010003816 Autoimmune disease Diseases 0.000 claims description 4
- SESFRYSPDFLNCH-UHFFFAOYSA-N Benzyl benzoate Chemical compound C=1C=CC=CC=1C(=O)OCC1=CC=CC=C1 SESFRYSPDFLNCH-UHFFFAOYSA-N 0.000 claims description 4
- 108090000625 Cathepsin K Proteins 0.000 claims description 4
- 102000004171 Cathepsin K Human genes 0.000 claims description 4
- DBVJJBKOTRCVKF-UHFFFAOYSA-N Didronel Chemical compound OP(=O)(O)C(O)(C)P(O)(O)=O DBVJJBKOTRCVKF-UHFFFAOYSA-N 0.000 claims description 4
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 4
- 230000000172 allergic Effects 0.000 claims description 4
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 4
- 201000008937 atopic dermatitis Diseases 0.000 claims description 4
- 230000015572 biosynthetic process Effects 0.000 claims description 4
- 239000004305 biphenyl Substances 0.000 claims description 4
- 235000010290 biphenyl Nutrition 0.000 claims description 4
- 125000001721 carboxyacetyl group Chemical group 0.000 claims description 4
- 125000004956 cyclohexylene group Chemical group 0.000 claims description 4
- 229960003966 nicotinamide Drugs 0.000 claims description 4
- 235000005152 nicotinamide Nutrition 0.000 claims description 4
- 150000002902 organometallic compounds Chemical class 0.000 claims description 4
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 4
- 239000000546 pharmaceutic aid Substances 0.000 claims description 4
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 3
- 125000004189 3,4-dichlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(Cl)C([H])=C1* 0.000 claims description 3
- 125000004080 3-carboxypropanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C(O[H])=O 0.000 claims description 3
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 3
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 3
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 3
- 125000004199 4-trifluoromethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C(F)(F)F 0.000 claims description 3
- 208000005783 Autoimmune Thyroiditis Diseases 0.000 claims description 3
- 206010006451 Bronchitis Diseases 0.000 claims description 3
- 208000008787 Cardiovascular Disease Diseases 0.000 claims description 3
- 206010012601 Diabetes mellitus Diseases 0.000 claims description 3
- 208000003807 Graves Disease Diseases 0.000 claims description 3
- 201000004779 Graves' disease Diseases 0.000 claims description 3
- 125000006267 biphenyl group Chemical group 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
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 125000004979 cyclopentylene group Chemical group 0.000 claims description 3
- 238000005755 formation reaction Methods 0.000 claims description 3
- 230000028993 immune response Effects 0.000 claims description 3
- 230000000366 juvenile Effects 0.000 claims description 3
- 201000006417 multiple sclerosis Diseases 0.000 claims description 3
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
- 210000000056 organs Anatomy 0.000 claims description 3
- 125000003431 oxalo group Chemical group 0.000 claims description 3
- 201000000596 systemic lupus erythematosus Diseases 0.000 claims description 3
- 238000002560 therapeutic procedure Methods 0.000 claims description 3
- 125000000437 thiazol-2-yl group Chemical group [H]C1=C([H])N=C(*)S1 0.000 claims description 3
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 3
- 206010002023 Amyloidosis Diseases 0.000 claims description 2
- 206010002022 Amyloidosis Diseases 0.000 claims description 2
- 206010003210 Arteriosclerosis Diseases 0.000 claims description 2
- 206010004161 Basedow's disease Diseases 0.000 claims description 2
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 2
- 206010028417 Myasthenia gravis Diseases 0.000 claims description 2
- 208000001132 Osteoporosis Diseases 0.000 claims description 2
- 206010035664 Pneumonia Diseases 0.000 claims description 2
- UGEPSJNLORCRBO-UHFFFAOYSA-N [3-(dimethylamino)-1-hydroxy-1-phosphonopropyl]phosphonic acid Chemical compound CN(C)CCC(O)(P(O)(O)=O)P(O)(O)=O UGEPSJNLORCRBO-UHFFFAOYSA-N 0.000 claims description 2
- 125000003342 alkenyl 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
- 125000004366 heterocycloalkenyl group Chemical group 0.000 claims description 2
- 125000002962 imidazol-1-yl group Chemical group [*]N1C([H])=NC([H])=C1[H] 0.000 claims description 2
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 201000011152 pemphigus Diseases 0.000 claims description 2
- 201000001976 pemphigus vulgaris Diseases 0.000 claims description 2
- SKYZRECXPAJUJO-UHFFFAOYSA-N 4-fluoro-N-(1-oxo-1-thiophen-3-ylbutan-2-yl)benzamide Chemical compound C1=CSC=C1C(=O)C(CC)NC(=O)C1=CC=C(F)C=C1 SKYZRECXPAJUJO-UHFFFAOYSA-N 0.000 claims 1
- 206010006448 Bronchiolitis Diseases 0.000 claims 1
- 125000000815 N-oxide group Chemical group 0.000 claims 1
- 206010052779 Transplant rejections Diseases 0.000 claims 1
- 125000005119 alkyl cycloalkyl group Chemical group 0.000 claims 1
- 230000000735 allogeneic Effects 0.000 claims 1
- 239000002260 anti-inflammatory agent Substances 0.000 claims 1
- 229940121363 anti-inflammatory agents Drugs 0.000 claims 1
- 125000005343 heterocyclic alkyl group Chemical group 0.000 claims 1
- 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims 1
- 239000002852 cysteine proteinase inhibitor Substances 0.000 abstract description 2
- 125000000623 heterocyclic group Chemical class 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 156
- 239000000243 solution Substances 0.000 description 98
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 94
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 48
- 101700067048 CDC13 Proteins 0.000 description 43
- UIIMBOGNXHQVGW-UHFFFAOYSA-M NaHCO3 Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 39
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 38
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 37
- CSNNHWWHGAXBCP-UHFFFAOYSA-L mgso4 Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 37
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 34
- 238000006243 chemical reaction Methods 0.000 description 33
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 30
- ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 30
- 239000012267 brine Substances 0.000 description 27
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 27
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 27
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 25
- HEDRZPFGACZZDS-UHFFFAOYSA-N chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 24
- 239000007787 solid Substances 0.000 description 23
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 22
- 235000019341 magnesium sulphate Nutrition 0.000 description 22
- 125000006239 protecting group Chemical group 0.000 description 22
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N DMSO-d6 Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 20
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 19
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 18
- 239000003921 oil Substances 0.000 description 18
- 235000019198 oils Nutrition 0.000 description 18
- DNUTZBZXLPWRJG-UHFFFAOYSA-M piperidine-1-carboxylate Chemical compound [O-]C(=O)N1CCCCC1 DNUTZBZXLPWRJG-UHFFFAOYSA-M 0.000 description 18
- 239000002904 solvent Substances 0.000 description 17
- 238000003818 flash chromatography Methods 0.000 description 16
- 239000000047 product Substances 0.000 description 16
- 239000002585 base Substances 0.000 description 15
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 14
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 13
- 238000001704 evaporation Methods 0.000 description 13
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- 235000017557 sodium bicarbonate Nutrition 0.000 description 13
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 13
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- XBDQKXXYIPTUBI-UHFFFAOYSA-N propionic acid Chemical compound CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 12
- 239000000377 silicon dioxide Substances 0.000 description 12
- QLNJFJADRCOGBJ-UHFFFAOYSA-N Propanamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 description 11
- 230000000875 corresponding Effects 0.000 description 11
- 239000000284 extract Substances 0.000 description 11
- 229910052757 nitrogen Inorganic materials 0.000 description 11
- 230000002829 reduced Effects 0.000 description 11
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- 238000007792 addition Methods 0.000 description 9
- 239000000706 filtrate Substances 0.000 description 9
- JBCFJMYPJJWIRG-UHFFFAOYSA-M 1,3-oxazole-4-carboxylate Chemical compound [O-]C(=O)C1=COC=N1 JBCFJMYPJJWIRG-UHFFFAOYSA-M 0.000 description 8
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 8
- PJUPKRYGDFTMTM-UHFFFAOYSA-N 1-hydroxybenzotriazole;hydrate Chemical compound O.C1=CC=C2N(O)N=NC2=C1 PJUPKRYGDFTMTM-UHFFFAOYSA-N 0.000 description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 8
- 150000007513 acids Chemical class 0.000 description 8
- 239000008079 hexane Substances 0.000 description 8
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 8
- 230000002401 inhibitory effect Effects 0.000 description 8
- OWIKHYCFFJSOEH-UHFFFAOYSA-N isocyanate Chemical compound N=C=O OWIKHYCFFJSOEH-UHFFFAOYSA-N 0.000 description 8
- DBTDEFJAFBUGPP-UHFFFAOYSA-N methanethione Chemical compound S=C DBTDEFJAFBUGPP-UHFFFAOYSA-N 0.000 description 8
- 238000001914 filtration Methods 0.000 description 7
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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
- 201000008838 periodontal disease Diseases 0.000 description 1
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- 125000005954 phenoxathiinyl group Chemical group 0.000 description 1
- 125000001644 phenoxazinyl group Chemical group C1(=CC=CC=2OC3=CC=CC=C3NC12)* 0.000 description 1
- 125000004351 phenylcyclohexyl group Chemical group C1(=CC=CC=C1)C1(CCCCC1)* 0.000 description 1
- 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- 229920002223 polystyrene Polymers 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M propionate Chemical class CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- OSFBJERFMQCEQY-UHFFFAOYSA-N propylidene Chemical group [CH]CC OSFBJERFMQCEQY-UHFFFAOYSA-N 0.000 description 1
- 230000020978 protein processing Effects 0.000 description 1
- 230000017854 proteolysis Effects 0.000 description 1
- 230000002797 proteolythic Effects 0.000 description 1
- 125000001042 pteridinyl group Chemical group N1=C(N=CC2=NC=CN=C12)* 0.000 description 1
- IUDVBGFRDKKVLA-UHFFFAOYSA-O pyrrolidin-1-ylphosphanium;hexafluorophosphate Chemical compound [PH3+]N1CCCC1.F[P-](F)(F)(F)(F)F IUDVBGFRDKKVLA-UHFFFAOYSA-O 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
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- 239000003638 reducing agent Substances 0.000 description 1
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- YOQDYZUWIQVZSF-UHFFFAOYSA-N sodium borohydride Substances [BH4-].[Na+] YOQDYZUWIQVZSF-UHFFFAOYSA-N 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000001187 sodium carbonate Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- ODGROJYWQXFQOZ-UHFFFAOYSA-N sodium;boron(1-) Chemical compound [B-].[Na+] ODGROJYWQXFQOZ-UHFFFAOYSA-N 0.000 description 1
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- 125000005017 substituted alkenyl group Chemical group 0.000 description 1
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- QAOWNCQODCNURD-UHFFFAOYSA-L sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
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- 150000003892 tartrate salts Chemical class 0.000 description 1
- XCNAWAXVHWFUSF-UHFFFAOYSA-N tert-butyl N-[1-[methoxy(methyl)amino]-1-oxo-4-phenylbutan-2-yl]carbamate Chemical compound CC(C)(C)OC(=O)NC(C(=O)N(C)OC)CCC1=CC=CC=C1 XCNAWAXVHWFUSF-UHFFFAOYSA-N 0.000 description 1
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 1
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- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical class CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
- 125000004385 trihaloalkyl group Chemical group 0.000 description 1
- UORVGPXVDQYIDP-UHFFFAOYSA-N trihydridoboron Substances B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 1
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Abstract
The present invention relates to novel alkanoyl-substituted heterocyclic derivatives which are cysteine protease inhibitors;the pharmaceutically acceptable salts and N-oxides thereof;their uses as therapeutic agents and the methodsof their making;according to Formula (I) in which:A comprises a heteromonocyclic ring containing 5 to 6 ring member atoms or a fused heteropolycyclic ring system containing 8 to 14 ring member atoms, wherein each ring contains 5 to 7 ring member atoms, X1 is a ring member carbon atom and each ring member atom other than X1 is a carbon atom or a heteroatom, with the proviso that (i) at least one ring member atom is a heteroatom and (ii) when A is a heteromonocyclic radical containing 5 ring member atoms, no more than two of the ring member atoms comprising A are heteroatoms;n is 0, 1, 2 or 3;X1 is=C- or -CH-;X2 is a bond or a divalent group of Formula (a) or (b);R1 - R8=as in the application.
Description
AMINE DERIVATIVES AS PROTEASE INHIBITORS
This application relates to compounds and compositions for treating diseases associated with the cysteine protease activity, in particular diseases associated with the activity of cathepsins B, K, L or S. DESCRIPTION OF THE FIELD 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 normal degradation and protein processing. The aberrant activity of cysteine proteases, for example, as a result of increased expression or increasing activation, however, can have pathological consequences. In view of this, certain cysteine proteases are associated with a number of disease states, including arthritis, muscular dystrophy, inflammation, tumor invasion, glomerulonephritis, malaria, periodontal disease, metachromatic leukodystrophy and others. For example, increasing levels of cathepsin B and redistribution of the enzyme are found in tumors; therefore, they suggest a function of the enzyme in the invasion of tumors and metastasis. In addition, the aberrant activity of cathepsin B is implicit in disease states such as rheumatoid arthritis, osteoarthritis, pneumocystis carinii, acute pancreatitis, inflammatory diseases of the respiratory tract and disorders in the bones and joints. The prominent expression of cathepsin K in osteoclasts and multinucleated cells related to osteoclasts and its high collagenolytic activity suggests that the enzyme participates in bone resorption mediated by osteoclasts and, therefore, in bone abnormalities such as those that occur in osteoporosis. In addition, the expression of cathepsin K in the lung and its elastinolytic activity suggests that the enzyme plays an important role also in lung disorders. Cathepsin L is implicit in normal lysosomal proteolysis, as well as several diseases, including, but not limited to, the metastasis of melanomas. Cathepsin S is implicit in Alzheimer's disease and certain autoimmune disorders, including, but not limited to, juvenile onset 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 halogen immunological responses, including, but not limited to, the rejection of organ transplants or tissue grafts.
In view of the number of diseases in which 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 demonstrate 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 protease inhibitors of Formula I:
wherein: A includes a heteromonocyclic ring containing from 5 to 6 ring member atoms or a fused heteropolycyclic ring system containing from 8 to 14 ring member atoms, wherein each ring contains from 5 to 7 ring member atoms, X1 is a ring member carbon atom and each ring member atom other than X1 is a carbon atom or a heteroatom, with the proviso that (i) at least one ring member atom is a heteroatom and (ii) when A is a heteromonocyclic radical containing 5 ring member atoms, not more than two of the ring member atoms including A are heteroatoms; n is 0, 1, 2 or 3; X1 is = C-or-CH-; X2 is a bond of a divalent group of Formula (a) or (b):
(a) (b)
X3 and X4 are independently -C (0) - or -CH2S (0), - R9 and R10 are independently hydrogen, (C6-6) alkyl or as defined below; R11 in each occurrence is independently hydrogen or (C -? - 6) alkyl; R12 and R13 are independently (i) (C-? -6) alkyl optionally substituted with cyano, halo, nitro, -NR14-R14, -NR14C (0) OR14, -NR14C (0) NR14R14, -NR14C (NR14) NR14R14 , -OR14, -SR14, -C (0) OR14, -C (0) NR14R14, -S (0) 2NR14R14, -P (O) (OR14) OR14,
OP (O) (OR14) OR14, -NR14C (0) R15, -S (0) R15, -S (0) 2R15, -C (0) R15, -OR16, -SR16, -S (0) R16, -S (0) 2R16, -C (0) R16, -C (0) OR16, -OC (0) R16, -NR16R17, -NR17C (0) R16, -NR17C (O) OR16, -C (O) NR16R17, -S (O) 2NR16R17, -NR17C (0) NR1SR17 or -NR17C (NR17) NR16R17, wherein R14 in each occurrence is independently hydrogen, (C -? - 6) alkyl or
(C -? - 3) alkyl substituted by halo, R15 is (C -? - 6) alkyl or (C -? _ 3) alkyl substituted by halo, halo, (C -? - 6) alkyl or R16 is
(C-3-12) cycloalkyl (C-0-ß) alkyl, (C-6? 2) aryl (C-0-e) alkyl, hetero (C-5? 2) aryl (C-0-β ) alkyl, (C-9-? 2) phenylcycloaryl (C-0-6) alkyl or hetero (C-8-? 2) polycycloaryl (C-0-6.) alkyl and R17 is hydrogen or (C-? - 6) ) alkyl, and wherein within R16 the aforementioned cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or heteropolycycloaryl ring is optionally substituted by a group selected from -R18, -X5OR18, -X5SR18, -X5S (0) R18, -X5S ( 0) 2R18, -X5S (0) 2R18, -X5C (0) R18, -X5C (0) OR18, -X5OC (0) R18 X5NR18R19, -X5NR19C (O) R18, -X5NR19C (O) OR18, -X5NR19C ( 0) OR18, -XC (0) NR18R19, -X5S (O) 2NR18R19, -X5NR19C (O) NR18R19 or -X5 (NR19) C (NR19) NR18R19), wherein X5 is a bond or (C -? _ 6) ) alkylene, R18 is hydrogen or (C -? - 6) alkyl and R19 is (C-3. 12) cycloalkyl (Co-β) alkyl, hetero (C-3? 2) cycloalkyl (C-0-s) alkyl, (C-6-? 2) aryl (C-0.6) alkyl, hetero (C-5-12) aryl (C-0,6) alkyl, (C-9-12) polycycloaryl (C-0-6. or hetero (C-8. 12) polycycloaryl (C-0- &) alkyl, or (ii) a group selected from (C-3-12) cycloalkyl (C-o-e) alkyl, hetero (C-3.12) cycloalkyl
(Coe) alkyl, (C-0-6) aryl, (C-6_? 2) alkyl, (C-6-12) aryl (C-0-s) alkyl, hetero (C-5-12) aryl, (C-9-12) polycycloaryl (C-0.
6) polycycloaryl and hetero (C-8-12) polycycloaryl (Co-β) alkyl, wherein said ring of cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or heteropolycycloaryl is optionally substituted by a group selected from -R18, -X50R18, -X5SR18, -X5S (0) R18, -X5S (0) 2R18, -X5C (0) R18, -X5C (0) 0R18, -X50C (0) R18, -X5NR18R19, -X5NR19C (0) R18, -X5NR19C (0) OR18, -XsC (0) NR18R19, -X5S (0) 2NR18R19, -X5NR19C (O) NR18R19-X5NR19C (NR19) NR18R19, wherein X5, R18 and R19 are as defined above; wherein within R12 and / or R13 any present alicyclic or aromatic ring system can be subsequently substituted by 1 to 5 radicals independently selected from (C -? - 6) alkyl, (Ci-6) alkylidene, cyano, halo, (C -? _ 4) alkyl substituted by halo, nitro, -X5NR1 R14, -X5NR14C (0) OR14, -X5NR14C (O) NR14R14, -X5NR14C (NR14) NR14R14, -X5OR14, -X5SR14, -X5C (0) OR14, X5C (O) NR14R14, -X5S (0) 2NR14R14, -X5S (0) 2NR14R14, -X5P (0) (OR14) OR14, X50P (0) (OR1) OR14, -X5NR14C (0) R15, -X5S (0) R15, -X5S (O) 2R15 and -X5C (0) R15, wherein X5, R14 and R15 are as defined above; or R12 together with R9 and / or R13 together with R10 form trimethylene, tetramethylene or phenylene-1,2-dimethylene, optionally substituted by 1 to 3 radicals independently selected from (C? -6) alkyl, (C? -6) alkylidene , cyano, halo, (C? -4) alkyl substituted by halo, nitro, oxo, X5NR14C (0) OR14, -X5NR14C (0) NR14R14, -X5NR14C (NR14) NR14R14, -X5OR14, -X5SR14, -X5C (0) ) OR14, -X5C (0) NR14R14, -X5S (O) 2NR14R14,
X5P (0) (OR14) OR14, -X50P (0) (OR14) OR14, -X5NR14C (O) R15, -X5S (0) R15, -X5S (0) 2R15 and -X5C (0) R15, wherein X5 , R14 and R15 are according to the above defined; and R1 is -X6X7R20, where X6 is -C (0) -, -C (0) C (0) -ó-S (O) 2-, X7 is a bond, -O- or -NR21-, where R21 is hydrogen or (Ci-e) alkyl, and R20 is (i) (C6-6) alkyl optionally substituted by cyano, halo, nitro, -NR14R14, -NR14C (0) O14 'NR14C (0) NR14R14, - NR14C (NR14) NR14R14, -O14, -SR14, -C (0) O14, -C (0) NR1 R14, -S (0) 2NR14R14, -P (O) (014014, -OP (0) (0) 4) O14,
NR14C (0) R15, -S (0) R15, -S (0) R15, -C (0) R15, -O22, -SR22, -S (0) R22, -S (0) 2R22, -C ( 0) R22, -C (0) O22, -C (0) NR22R23, -NR22R23,
NR23C (0) R22, -NR23C (0) O22, -NR23C (0) NR22R23 or -NR23C (NR23) NR22R23, where R14 and R15 are as defined above, R22 is (C3-12) cycloalkyl (C0-e) alkyl, hetero (C3-12) cycloalkyl (Co-ß) alkyl, (C6-i2) aryl (Co-e) alkyl, hetero (C5-12) aryl (Co-e) (C9-12) alkyl bicycloaryl (Co-e) alkyl or hetero (C8-i2) bicycloaryl (Co-β) alkyl and R23 in each in each occurrence is independently hydrogen or (C6-6) alkyl, or (ii) (C3-? 2) cycloalkyl (Co-6) alkyl, hetero (C3-? 2) cycloalkyl (Co-e) alkyl, (C6-12) aryl (C0-e) alkyl, hetero (C5-) 2) aryl (Co-e) alkyl, (C9-12) bicycloaryl (Co-e) alkyl or hetero (C8-? 2) bicycloaryl (Co-e) alkyl or hetero (C5-6) aryl or (iii) (C3-6) cycloalkyl (Co-β) alkyl, hetero (C3_6) cycloalkyl (Co-β) alkyl, phenyl (Co-e) alkyl or hetero (C5-6) aryl (Co-e) alkyl, wherein said Cycloalkyl, heterocycloalkyl, phenyl or heteroaryl is substituted by -R24. -X5OR24, -X5SR24, -X5S (0) R24, -X5S (O) 2 R24, -X5C (0) R24, -X5C (0) OR24, -X5C (0) NR24R25, -X5NR24R25, -X5NR25C (0) R24, -XNR25C (0) OR24, -X5NR25C (O) NR24R25 or -X5NR25C (NR25) NR24R25, where X5 as defined above, R24 is (C3-6) cycloalkyl (Co-β) alkyl, hetero (C3 -6) cycloalkyl (Co-β) alkyl, phenyl (C 0-6) alkyl) or hetero (C 5-6) aryl (Co-e) alkyl and R 25 in each occurrence is independently hydrogen or (C 6) alkyl; wherein within R1 any present alicyclic or aromatic ring system can be further substituted by 1 to 5 radicals independently selected from (C? _6) alkyl, (C? -6) alkylidene, cyano, halo, (C? _) substituted alkyl by halo, nitro, -X5NR14R14, X5NR14C (0) OR14, -X5NR14C (0) NR14R14, -X5NR14C (NR14) NR14R14, -X5OR14, -X5SR14, -N5C (0) OR14, -X5NR14C (0) NR14R14, -X5NR14C (NR14) NR1R14, -X5OR14, -X5SR14, -X5C (0) OR14, -X5C (O) NR14R14, -X5S (O) 2NR14R14, -X5P (0) (OR) 14, -X5OP (0) (OR14) OR14, -X5NR14C (O) R15, -X5S (0) R15, -X5S (0) 2R15 and -X5C (0) R15, wherein X5, R14 and R15 are as defined above; or when X 2 is a divalent group of the formula (a) or (b), then R 1 may also represent hydrogen, carboxy, oxalo or carbamoyl; R2 is hydrogen or (C? -6) alkyl; R3 is (i) (C? -6) alkyl optionally substituted with cyano, halo, nitro, -SR26, -C (0) OR26, -C (O) NR26N26, -P (O) (OR26) OR26, -S (0) R27. { or -C (0) R27, wherein R26 in each occurrence is independently hydrogen, (C? _6) alkyl or (C? -3) alkyl substituted by halo and R27 is (C? -6) alkyl substituted by halo, ( C? _3) alkyl and R27 is (C? -6) alkyl or (C? -3) alkyl substituted by halo, or (ii) (C5-6) cycloalkyl (C2-3) alkyl, hetero (C3-6) (C2-3) cycloalkyl alkyl, (C6-i2) aryl (C2-) alkyl or hetero (C5.6) aryl (C2-3) alkyl, wherein said cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted subsequently with 1 to 5 radicals independently selected from (C? -6) alkyl, (C? -6) alkylidene, cyano, halo, (C? -4) alkyl substituted by halo, nitro, -X5NR14C (0) 0R14, -X5NR14C (O) NR14R14, -X5NR14C (NR14) NR14R14, -5OR14, -X5SR14, -X5C (0) OR14, -X5C (O) NR14R14, -X5S (0) 2NR14R14, -X5P (0) (OR14) OR14, - X50P (0) (0R14) 0R14, -X5NR14C (0) R15, -X5S (0) R15, -X5S (0) 2R15 and -X5C (0) R15, wherein -X5, R14 and R15 are in accordance with defined above, with the condition that where R3 is (CX-5) unsubstituted alkyl and R4 is hydrogen or (C1-5) unsubstituted alkyl, then X2 may not represent (i) a bond when R1 is -C (0) R20, -C (0) 2R20 or -S (O) 2R20 wherein R20 is (Ci-β) alkyl, phenyl (C? _) Alkyl, phenyl, (C3.7) cycloalkyl, canfan-10-yl, naphth-1-yl, naphth- 2-yl, phenyl substituted by one or more of (C? -4) alkyl, perfluoro (C? -4) alkyl, (C? -4) alkoxy, hydroxy, halo, amido, nitro, amino,
(C 1-4) alkylamino, (C? -4) dialkylamino, carboxy or (C? -4) alkoxycarbonyl or naphth-l-yl or naphth-2-yl substituted by one or more of (C? -4) alkyl, perfluoro (C 1-4) alkyl, (C? -6) alkoxy, hydroxy, halo, amido, nitro, amino, carboxy or (C? -6) alkoxycarbonyl or (ii) a divalent group of the formula (a) or ( b) in which the R 12 moiety is methyl, isopropyl, n-butyl, sec-butyl, tere-butyl, 1-methylpropyl, benzyl, naphth-1-ylmethyl, naphth-2-ylmethyl, thien-2-ylmethyl, thien -3-ylmethyl, or where R9 and R12 form ethylene, trimethylene, trimethylene substituted by hydroxy, tetramethylene or phenylene-1,2-dimethylene; or R3 and R4 taken together with the carbon atom to which both R3 and R4 are attached form (C3-8) cycloalkylene or (C3-8) heterocycloalkylene, wherein said cycloalkylene or heterocycloalkylene is optionally substituted by 1 to 3 radicals independently selected from (C? -6) alkyl, (C? -6) alkylidene, cyano, halo, (C? -4) alkyl substituted by halo, nitro, -X5SR14, X5C (0) OR14, -X5C (0) NR14R14, -X5S (O) 2NR14R14, -X5P (0) (OR14) OR14, -X50P (0) (OR1) OR14, -X5NR14C (0) R15, -X5S (0) R15, -X5S (O) 2R15 and -X5C (0) R15, wherein X5, R14 and R15 are according to the above defined; R4 is hydrogen, (C? -6) alkyl or as defined above; R5 is hydrogen and R6 is hydroxy or R5 and R6 together form oxo; R7 is a group selected from cyano, halo, nitro, -R29, -X5NR29R30, -X5NR30C (O) OR29. -X5NR30C (0) NR29R30, -X5NR30C (NR30) NR29R30, -X5OR29, -X5SR29, X5C (0) OR29, -X5C (O) NR29R30, -X5S (O) 2 NR29R30, -X5P (0) (OR30) OR29 , -X5OP (O) (OR29) OR29, -X5NR30C (0) R31, -X5S (0) R31 and -X5C (0) R31, where X5 is according to the above defined, R29 is hydrogen or -R31, R30 in each occurrence is hydrogen or (d-6) alkyl and R31 is (C? -6) alkyl, (C3-? 2) cycloalkyl (C0s) alkyl, hetero (C3_? 2) cycloalkyl (C0-6) alkyl, ( C6-?) Aryl (C0-6) alkyl or hetero (C5-? 2) aryl (Co-β) alkyl, wherein within R7 any present alicyclic or aromatic ring system can be further substituted by 1 to 5 independently selected radicals of (C? -6) alkyl, (C? -6) alkylidene, cyano, halo, (C? -4) alkyl substituted by halo, nitro, -X5NR14R14, -X5NR14C (O) OR14, X5NR14C (0) NR14R14, -X5NR14C (NR14) NR14R14, -X5OR14, -X5SR14, X5C (0) OR14, -X5C (0) NR14R14, -X5S (O) 2NR14R14, -X5P (O) (OR14) OR14, -X5OP (0) (OR14 ) OR14, -X5NR14C (0) R15, -X5S (0) R15, -X5S (0) 2R15 and -X5C (0) ) R15, where X5, R14 and R15 are according to the above defined; and R8 in each occurrence is independently selected from (C? -6) alkyl, (C? _6) alkylidene, cyano, halo, (C? -4) alkyl substituted by halo, nitro, -X5NR14R14, -X5NR14C (0) 0R14 , -X5NR14C (0) NR14R14, -X5NR14C (NR14) NR14R14, -X5OR14, -X5SR14, -X5C (0) OR14, -X5C (0) NR14R14, -X5S (O) 2NR14R14, -X5P (O) (OR14) OR14, and -X5OP (0) (OR14) OR14, -X5NR14C (O) R15, -X5S (0) R15, -X5S (0) 2R15 and -X5C (0) R15, where X5, R14 and R15 are in accordance with the previously defined; and N-oxide derivatives, derivatives of prodrugs, protected derivatives, individual isomers and mixtures of isomers; and the pharmaceutically acceptable salts thereof; but excluding the compounds selected from the group consisting of ((S) -l. (S) -l-. {(S) -1- (l-benzooxazol-2-yl-methanoyl) -benzyl ester) 3-methyl-butylocarbamoyl] -3-methyl-butylocarbamoyl, .3-methyl-butyl) -carbamic acid tere-butyl ester. { 1- [1- (1-1H-imidazol-2-yl-methanoyl) -3-methyl-butylcarbamoyl] -3-methyl-butyl} -carbamic, benzyl ester of [(S) -3-methyl-l- ((S) -3-methyl-l-. {l- [1-2 (trimethylsilanyl-ethoxymethyl) -1H-imidazole-2-benzyl ester] il] -methanoyl] -butylcarbamoyl) -butyl] -carbamic; [(S) -1- [(S) -1-1H-imidazol-2-yl-methanoyl) -3-methyl-butylocarbamoyl] -3-methyl-butyl] -carbamic acid benzyl ester, benzyl ester of acid ((S) -1- { [(S) -1- [1- (1-Benzyl-lH-imidazol-2-yl) -methanoyl] -3-methyl-butylocarbamoyl} -3-methyl- butyl) -carbamic, tere-butyl acid ester. { (S) -1- [(S) -1- (1-lH-imidazol-2-yl-menanoyl) -3-methyl-butylcarbamoyl} -3-methyl-butyl) -carbamic acid ethyl ester 3-. { [1- (4-chloro-phenyl) -methanoyl] -amino} -4-oxo-4-pyridin-3-yl-butyric acid ethyl ester 4-furan-2-yl-4-oxo-3-. { [1- (4-trifluoromethyl-phenyl) -methanoyl] -amino} -butyric, 3- (2-methyl-propanoylamino) -4-oxo-4-thiophen-2-yl-butyric acid ethyl ester, 4-oxo-4-thiophen-2-yl-3- [ethyl] ethyl ester (1-p-tolyl-methanoyl) -amino] -butyric acid ethyl ester
4- (5-bromo-thiophen-2-yl) -3-. { [1- (4-chlorophenyl) -methanoyl] amino} - 4-oxo-butyric, ethyl ester of 3- acid. { [1- (4-chloro-phenyl) -methanoyl] amin} -4- (5-Methyl-thiophen-2-yl) -4-oxo-butyric acid ethyl ester of 4-oxo-4-thiophen-3-yl-3- [(1-p-tolyl-methanoyl) - amino] -butyric, ethyl ester of 3- acid. { [1- (4-methoxy-phenyl) -methanoyl] amin} -4-oxo-4 -thiophen-3-yl-butyric acid ethyl ester 3-. { [1- (3,4-dichloro-phenyl) -methanoyl] amino} -4-oxo-4-thiophene-e-yl-butyric acid, 4-f luoro-N- [1- (1-thiophen-3-yl-methanoyl) -propyl] -benzamide, ethyl ester of 4- acid. { [1- (4-fluoro-phenyl) -methanoyl] -amin} -5-oxo-5-thiophen-3-yl-pentanoic ester and ethyl ester of 3- acid. { [1 (-4-fluoro-phenyl) -methanoyl] amino} -2-methyl-4-oxo-4-thiophen-3-yl-butyric acid. In another particular embodiment, the present invention relates to the protease inhibitors of Formula I:
I
wherein: A includes a heteromonocyclic ring containing
to 6 ring member atoms or a fused heteropolycyclic ring system containing 8 to 14 ring member atoms, where each ring contains 5 to 7 ring member atoms, X 1 is a carbon atom ring member and each atom ring member other than X1 is a carbon atom or a heteroatom, with the proviso that (i) at least one ring member atom is a heteroatom and (ii) when A is a heteromonocyclic radical containing 5 member atoms of the ring, not more than two of the ring members of the ring including A are heteroatoms; n is 0, 1, 2 or 3; X1 is = C-or-CH-; X2 is a bond of a divalent group of Formula (a) or (b):
(a) (b)
wherein: X3 and X4 are independently -C (0) - or -CHS (0) 2; - R9 and R10 are independently hydrogen, (C6-6) alkyl or as defined below; R11 in each occurrence is independently hydrogen or (C -? - 6) alkyl; R12 and R13 are independently (i) (C-? -6) alkyl optionally substituted with cyano, halo, nitro, -NR14-R14, -NR14C (0) OR14, -NR14C (0) NR14R14, -NR14C (NR14) NR14R14 , -OR14, -SR14, -C (0) OR14, -C (0) NR14R14, -S (O) 2NR14R14, -P (O) (OR14) OR14, 0P (0) (OR14) OR14, -NR14C ( 0) R15, -S (0) R15, -S (0) 2R15, -C (0) R15, -OR16, -SR16, -S (0) R16, -S (0) 2R16, -C (0) R16, -C (0) OR16, -OC (0) R16, -NR16R17, -NR17C (0) R16, -NR17C (O) OR16, -C (O) NR16R17, -S (0) 2NR16R17, -NR17C ( 0) NR16R17 or -NR17C (NR17) NR16R17, wherein R14 in each occurrence is independently hydrogen, (C -? - 6) alkyl or (C -? - 3) alkyl substituted by halo, R15 is (C -? - 6) ) alkyl or (C-? - 3) alkyl substituted by halo, R16 is (C-3? 2) cycloalkyl (Co-6) alkyl, (C-6?) aryl (C-0-6) alkyl, hetero (C-5-? 2) aryl (Co-β) alkyl, (C-9-? 2) phenylcycloaryl (C-0-6) alkyl or hetero (C-8-? 2) polycycloaryl (Coe) alkyl and R17 is hydrogen or (C -? - 6) alkyl, and wherein within R16 the aforementioned ring of cycloalkyl, heterocycloalkyl, aryl , heteroaryl, polycycloaryl or heteropolycycloaryl is optionally substituted by a group selected from -R18, -X5OR18, X5SR18, -X5S (0) R18, -X5S (0) 2R18, -X5S (0) 2R18, -X5C (0) R18,
X5C (0) OR18, -X5OC (0) R18 X5NR18R19, -X5NR19C (O) R18, -X5NR19C (O) OR18, -X5NR19C (0) OR18, -X5C (0) NR18R19, -X5S (O) 2NR18R19, - X5NR19C (O) NR18R19 or -X5 (NR19) C (NR19) NR18R19), wherein X5 is a bond or (C-6) alkylene, R18 is hydrogen or (C ~? -6) alkyl and R19 is (C-3? 2) cycloalkyl (Coe) alkyl, hetero (C-3-y2) cycloalkyl (Co-β) alkyl, (C-6-? 2) aryl (Co-β) alkyl, hetero (C-) 5-? 2) aryl (C-0-β) alkyl, (C-9-? 2) polycycloaryl (Co-β) alkyl or hetero (C-8-?) Polycycloaryl (Co-β) alkyl, or (ii) ) a group selected from
(C-3_?) Cycloalkyl (C-0-e) alkyl, hetero (C-3? 2) cycloalkyl (Coe) alkyl, (C-0-6) aryl, (Cs-12) alkyl, (C-) 6-? 2) aryl (C-0-6) alkyl, hetero (C-5? 2) aryl, (C-9-? 2) polycycloaryl (Co-β) polycycloaryl and hetero (C-8-i2) polycycloaryl (C-0-β) alkyl, wherein said ring of cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or heteropolycycloaryl is optionally substituted by a group selected from -R18, -X5OR18, -X5SR18, -XsS (0) R18, -X5S (0) 2R18, -X5C (0) R18, -X5C (0) OR18, -X5OC (0) R18, -X5NR18R19, -X5NR19C (O) R18, -X5NR19C (0) OR18, -X5C (0) NR18R19, -X5S (0) 2NR18R19, -X5NR19C (0) NR18R19 -X5NR19C (NR19) NR18R19, wherein X5, R18 and R19 are as defined above; wherein within R12 and / or R13 any present alicyclic or aromatic ring system can be subsequently substituted by 1 to 5 radicals independently selected from (C -? - 6) alkyl, (C-? 6) alkylidene, cyano, halo, (C -? - 4) alkyl substituted by halo, nitro, -X5NR14R14, -X5NR14C (0) OR14, -X5NR14C (O) NR14R14, -X5NR14C (NR14) NR14R14, -X5OR14, -X5SR14, -X5C (0) OR14 , X5C (0) NR14R14, -X5S (0) 2NR14R14, -X5S (0) 2NR14R14, -X5P (0) (OR14) OR14, X50P (0) (OR14) OR14, -X5NR14C (0) R15, -X5S ( 0) R15, -X5S (O) 2R15 and -X5C (0) R15, wherein X5, R14 and R15 are as defined above; or R12 together with R9 and / or R13 together with R10 form trimethylene, tetramethylene or phenylene-1,2-dimethylene, optionally substituted by 1 to 3 radicals independently selected from (C? -6) alkyl, (C? -6) alkylidene , cyano, halo, (C? -4) alkyl substituted by halo, nitro, oxo, XNR14C (0) OR14, -X5NR14C (0) NR14R14, -X5NR14C (NR14) NR14R14, -X5OR14, -X5SR14, -X5C (0) ) OR14, -X5C (0) NR14R14, -X5S (O) 2NR14R14,
X5P (0) (OR14) OR14, -X5OP (0) (OR14) OR14, -X5NR14C (O) R15, -X5S (0) R15, -X5S (0) 2R15 and -X5C (0) R15, wherein X5 , R14 and R15 are according to the above defined; and R1 is -X6X7R20, where X6 is -C (0) -, -C (O) C (O) -ó-S (0) 2-, X7 is a bond, -O- or -NR21-, wherein R21 is hydrogen or (C? -6) alkyl and R20 is (i) (C? -6) alkyl optionally substituted by cyano, halo, nitro, -NR14R14, -NR14C (0) O14 'NR14C (0) NR14R14, - NR14C (NR14) NR14R14, -O14, -SR14, -C (0) O14, -C (0) NR14R14, -S (0) 2NR14R14, -P (0) (014014, -0P (0) (014) 014 ,
NR14C (0) R15, -S (0) R15, -S (0) R15, -C (0) R15, -O22, -SR22, -S (0) R22, -S (0) 2R22, -C ( 0) R22, -C (0) O22, -C (0) NR22R23, -NR22R23,
NR23C (0) R22, -NR23C (0) O22, -NR23C (0) NR22R23 or -NR23C (NR23) NR22R23, where R14 and R15 are as defined above, R22 is (C3-? 2) cycloalkyl (Co -β) alkyl, hetero (C3-? 2) cycloalkyl (Co-e) alkyl, (C6-i) aryl (C0-β) alkyl, hetero (C5-?) aryl (Co-e) alkyl (C9-? 2) bicycloaryl (Co-e) alkyl or hetero (C8-? 2) bicycloaryl (C0-s) alkyl and R23 in each in each occurrence is independently hydrogen or (C? -6) alkyl, or (ii) (C3-) i2) cycloalkyl (Co-β) alkyl, hetero (C3-? 2) cycloalkyl (Co-e) alkyl, (C6-i2) aryl (Co-e) alkyl, diphenyl (Co-e) alkyl, hetero (C5-) ? 2) aryl (C0-ß) alkyl, diethyl (C5-6) aryl (C0-ß) alkyl, (C9_12) bicycloaryl (Co-ß) alkyl or hetero (C8_? 2) bicycloaryl (Co-e) alkyl where said cycloalkyl, heterocycloalkyl, aryl or heteroaryl can be substituted by -R24. -X5OR24, -X5SR24, -X5S (0) R24, -X5S (0) 2 R24, -X5C (0) R24, -X5C (0) OR24, -X5C (0) NR24R25, -X5NR24R25, -X5NR25C (O) R24,
X5NR25C (0) OR24, -X5NR25C (0) NR24R25 or -X5NR25C (NR25) NR24R25, where X5 is as defined above, R24 is (C3-i2) cycloalkyl (Co-β) alkyl, hetero (C3-? 2) cycloalkyl (C0-ß) alkyl, (C6-i2) aryl (C0-ß) alkyl, hetero (C5-? 2) aryl (C0.6) alkyl, (C9-12) bicycloaryl (CO-6) alkyl or hetero (C8-? 2) bicycloaril
(Co-e) alkyl and R25 in each occurrence is independently hydrogen or (C -6) alkyl; wherein within R1 any present alicyclic or aromatic ring system can be further substituted by 1 to 5 radicals independently selected from (C? -6) alkyl, (C? -6) alkylidene, cyano, halo, (C? -) alkyl substituted by halo, nitro, -X5NR14R14, X5NR14C (0) OR14, -X5NR14C (0) NR14R14, -X5NR14C (NR14) NR14R14, -X5OR14, -X5SR14, -N5C (0) OR14, -X5NR14C (0) NR14R14, - X5NR14C (NR14) NR14R14, -X5OR14, -X5SR14, -X5C (0) OR14, -X5C (O) NR14R14, -X5S (O) 2NR14R14, -X5P (0) (OR) 14, -X5OP (0) (OR14 ) OR14, -X5NR14C (O) R15, -X5S (0) R15, -XsS (0) 2R15 and -X5C (0) R15, wherein X5, R14 and R15 are as defined above; or when X 2 is a divalent group of the formula (a) or (b), then R 1 may also represent hydrogen, carboxy, oxalo or carbamoyl; R2 is hydrogen or (C? -6) alkyl; R3 is (i) (C? -6) alkyl optionally substituted with cyano, halo, nitro, -SR24, -C (0) OR24, -C (0) NR24N24, -P (O) (OR24) OR24, -OP (O) (OR24) OR24, -OP (O) (OR24) OR24, -S (0) R25, -S (0) 2R25, or -C (0) R25, wherein R24 in each occurrence is independently hydrogen, (C? -6) alkyl or (C? -3) alkyl substituted by halo and R25 is (C? -6) alkyl substituted by halo, (C? -3) alkyl, or (ii) (C5-6) cycloalkyl (C2-3) alkyl, hetero (C3.6) cycloalkyl (C2-3) alkyl, (C6-? 2) aryl (C2-3) alkyl or hetero (C5-S) aryl (C2-3) alkyl, where said cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally subsequently substituted with 1 to 5 radicals independently selected from (C? -6) alkyl, (C? -6) alkylidene, cyano, halo, (C? -4) alkyl substituted by halo, nitro, -X5NR14C (0) OR14, -X5NR14C (0) NR14R14, -X5NR14C (NR14) NR14R14, -5OR14, -X5SR14, -X5C (0) OR14, -X5C (0) NR1R14, -X5S ( 0) 2NR14R14, -X5P (0) (0R1) 0R14, -X50P (0) (OR14) OR14, -X5NR14C (0) R15, -X5S (0) R15, -X5S (0 ) 2R15 and -X5C (0) R15, wherein -X5, R14 and R15 are as defined above, with the proviso that when R3 is (C1-5) unsubstituted alkyl and R4 is hydrogen or (C1-) 5) unsubstituted alkyl, then X2 could not represent (i) a bond when R1 is -C (0) R20, -C (0) 2R2 ° or -S (0) 2R20 wherein R20 is (C? -6) alkyl, phenyl (C) ? 4) alkyl, phenyl, (C3.7) cycloalkyl, canfan-10-yl, naphth-1-yl, naphth-2-yl, phenyl substituted by one or more of (C1-4) alkyl, perfluoro (Cx-) 4) alkyl, (Cx-4) alkoxy, hydroxy, halo, amido, nitro, amino, (C 1-4) alkylamino, (C 1-4) dialkylamino, carboxy or (C? 4) alkoxycarbonyl or naphth-1-yl or naphth-2-yl substituted by one or more of (C? -4) alkyl, perfluoro (C? -4) alkyl, (C? -6) alkoxy, hydroxy, halo, amido, nitro, amino, carboxy or ( Ci-β) alkoxycarbonyl or (ii) a divalent group of the formula (a) or (b) in which the R 12 moiety is methyl, isopropyl, n-butyl, sec-butyl, tere-butyl, 1-methylpropyl, benzyl , naphth-1-ylmethyl, naphth-2-ylmethyl, thien-2-ylmethyl, thien-3-ylmethyl, or where R 9 and R 12 form ethylene, trimethylene, trimethylene substituted by hydroxy, tetramethylene or phenylene-1,2-dimethylene; or R3 and R4 taken together with the carbon atom to which both R3 and R4 are attached form (C3.8) cycloalkylene or (C3-8) heterocycloalkylene, wherein said cycloalkylene or heterocycloalkylene is optionally substituted by 1 to 3 radicals independently selected from (C? _6) alkyl, (C? -6) alkylidene, cyano, halo, (C? -4) alkyl substituted by halo, nitro, -X5SR14, X5C (0) OR14, -X5C (0) NR14R14 , -X5S (O) 2NR14R14, -X5P (O) (OR14) OR14, -X5OP (0) (OR14) OR14, -X5NR14C (0) R15, -X5S (0) R15, -X5S (O) 2R15 and - X5C (0) R15, where X5, R14 and R15 are according to the above defined; R3 and R4 taken together with the carbon atom to which both R3 and R4 are attached form (C3.8) cycloalkylene or (C3-8) heterocycloalkylene, where the aforementioned cycloalkylene or heterocycloalkylene is optionally substituted by 1 to 3 selected radicals independently of (C? -6) alkyl, (C? -6) alkylidene, cyano, halo, (C? -) alkyl substituted by halo, nitro, -X5SR14, X5C (0) OR14, -X5C (0) NR14R14, -X5S (O) 2NR14R14, -X5P (0) (OR14) OR14, -X50P (0) (0R14) 0R14, -X5NR14C (0) R15, -X5S (0) R15, -X5S (O) 2R15 and -X5C (0) R15, where X5, R14 and R15 are according to the above defined; R4 is hydrogen, (C? -6) alkyl or as defined above; R5 is hydrogen and R6 is hydroxy or R5 and R6 together form oxo; R7 is a group selected from cyano, halo, nitro, -R29, -X5NR29R30, -X5NR30C (O) OR29. -X5NR30C (0) NR29R30, -X5NR30C (NR30)
NR29R30, -X5OR29, -X5SR29, X5C (0) OR29, -X5C (0) NR29R30, -X5S (O) 2
NR29R30, -X5P (0) (OR30) OR29, -X50P (0) (OR29) OR29, -X5NR30C (0) R20, -X5S (0) R20 and -X5C (0) R20 and -C (0) NR42CHR3C ( 0) OR29, where X5 and R20 are defined as above, R29 is hydrogen or -R20, where R20 is defined as above, R30 at each occurrence is hydrogen or (C? -6) alkyl, R42 is hydrogen, (C? _6) ) alkyl or together with R43 forms trimethylene, tetramethylene or phenylene-1,2-dimethylene, optionally substituted with hydroxy or oxo, and R43 is as defined above or is (i) (C?
6) alkyl optionally substituted by cyano, halo, nitro, -NR14R14, -NR14C (0) 0R14, -NR1C (O) NR14R14, -NR14C (NR14) NR14R14, -OR14,
-SR14, -C (0) 0R14, -C (0) NR14R14, -S (O) 2NR14R14, -P (O) (OR14) OR14, -0P (0) (0R1) 0R14, -NR14C (0) R15 , -S (0) R15, -S (0) 2R15, -C (0) R15, - OR16, -R16, -S (0) R16, -S (0) 2R16, -C (0) R16, - OC (0) R16, -OC (0) R16, NR16R17, -NR17C (0) R16, -NR17C (O) OR16, -C (O) NR16R17, -S (O) 2NR16R17, -NR17C (0) NR16R17 or -NR17C (NR17) NR16R17 or (ii) a group selected from (C3-X2) cycloalkyl (Co-β) alkyl, hetero (C3-? 2) cycloalkyl (C0-6) alkyl, (C6-? 2) aryl ( C0-6) alkyl, hetero (C5-? 2) aryl (C0-6) alkyl, (C9-? 2) polycycloaryl (C0-6) alkyl and hetero (C8_? 2) polycycloaryl (C0-s) alkyl, where the mentioned cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or heteropolycycloaryl ring is optionally substituted by a group selected from R18, -X5OR18,
X5CR18, -X5S (0) R18, -X5S (0) 2R18, -X5C (0) R18, X5C (0) OR18, X5OC (0) R18, -X5NR18R19, -X5NR19C (0) R18, -X5NR19C (O) OR18,
X5C (0) NR18R19, -X5S (0) 2NR18R19, -X5NR19C (O) NR18R19 or
X5NR19C (NR19) NR18R19, wherein X5, R14, R15, R17, R18 and R19 are as defined above; wherein within R7 any present alicyclic or aromatic ring system can be further substituted by 1 to 5 radicals independently selected from (C? _6) alkyl, (C? -6) alkylidene, cyano, halo, (CX-4) substituted alkyl by halo, nitro, -X5NR14R14, -X5NR14C (O) OR14, -X5NR14C (O) NR14R1,
X5NR14C (NR14) NR14R14, -X50R14, -X5SR14, -X5C (0) OR14, -X5C (O) NR14R14, -X5S (0) 2NR14R14, -X5P (0) (OR1) OR14, -X5OP (O) (OR14 ) OR14,
X5NR14C (0) R15, -X5S (0) R15, -X5S (O) 2R15 and -X5C (0) R15, wherein X5, R14 and R15 are according to the above defined; and R8 in each occurrence is independently selected from (Cx-s) alkyl, (C? -4) alkyl substituted by halo, (C? -6) alkylidene, cyano, halo, (C? _4) alkyl substituted by halo, nitro , -X5NR14R14, -X5NR14C (O) OR14, -X5NR14C (0) NR14R14, -X5NR14C (NR14) NR14R14, -X5OR14, -X5SR14,
X5C (0) OR14, -X5C (0) NR14R14, -X5S (O) 2NR14R14, -X5P (O) (OR14) OR14, and -X5OP (0) (OR14) OR14, -X5NR14C (0) R15, -X5S (0) R15, -X5S (0) 2R15 and -X5C (0) R15, where X5 is a bond or (C? -6) alkylene, R14 in each occurrence is independently hydrogen, (C? -6) alkyl or ( C? _3) alkyl substituted by halo and R15 (C? _6) alkyl or (C? _ 3) alkyl substituted by halo; and N-oxide derivatives, derivatives of prodrugs, protected derivatives, individual isomers and mixtures of isomers; and the pharmaceutically acceptable salts thereof. In another particular embodiment, the present invention relates to a compound of Formula II:
where :
A includes a heteromonocyclic ring containing from 5 to 6 ring member atoms or a fused heteropolycyclic ring system containing from 8 to 14 ring member atoms, where each ring contains from 5 to 7 ring member atoms, X1 is an atom carbon ring member and each ring member atom other than X1 is a carbon atom or a heteroatom, with the proviso that at least one ring member atom is a heteroatom; n is 0, 1, 2 or 3; X1 is = C-or-CH-; X8 is (C? -2) alkylene; R1 is hydrogen, carboxy, oxalo, carbamoyl or -X6X7R20, where X6 is -C (O) -, -C (0) C (0) -ó-S (O) 2-, X7 is a bond, -0- or -NR21-, wherein R21 is hydrogen or (d-6) alkyl, and R20 is (i) (C? -6) alkyl optionally substituted by cyano, halo, nitro, -NR14R14, -NR14C (0) 014 ' -NR14C (0) NR14R14, -NR14C (NR14) NR14R14, -O14, -SR14, -C (0) O14, -C (0) NR14R14, -S (0) 2NR14R14, -P (0) (014014, - OP (0) (0] 4) 014, -NR14C (0) R15, -S (0) R15, -S (0) R15, -C (0) R15, -O22, -SR22, -S (0) R22, -S (0) 2R22, -C (0) R22, -C (0) O22, -C (0) NR2R23, -NR22R23, -NR23C (0) R22, -NR23C (0) O22, -NR23C ( 0) NR22R23 or
NR23C (NR23) NR22R23, where R14 in each occurrence is independently hydrogen, (C? -6) alkyl or (C? -3) alkyl substituted by halo, R15 is (C? _6) alkyl or (C? -3) alkyl substituted by halo, R22 is (C3_? 2) cycloalkyl (Co-e) alkyl, hetero (C3-? 2) cycloalkyl (Co-e) alkyl, (C6-?) aryl (Co-ß) alkyl, hetero (C5 -?) aryl (Co-e) alkyl (C9-12) bicycloaryl (Co-e) alkyl or hetero (C8-? 2) bicycloaryl (Co-β) alkyl and R23 in each in each occurrence is independently hydrogen or (C ? .6) alkyl, or (ii) (C3-12) cycloalkyl (C0-β) alkyl, hetero (C3-12) cycloalkyl (C0-e) alkyl, (C6-i2) aryl (C0-6) alkyl, hetero (C5-12) aryl (C0-e) alkyl, (C9.12) bicycloaryl (Co-e) alkyl or hetero (C8-? 2) bicycloaryl (C0-e) alkyl or hetero (C5-6) aryl or (iii) (C3-6) cycloalkyl (Co-ß) alkyl, hetero (C3-S) cycloalkyl (Co-ß) alkyl, phenyl (Co-ß) alkyl or hetero (C5-6) aryl (Co-ß) alkyl substituted by -X5OR24, -X5SR24, -X5S (0) R24, -X5S (O) 2 R24, -X5C (0) R24, X5C (0) OR24, -X5 C (0) NR24R25, -X5NR24R25, -X5NR25C (O) R24, X5NR5C (0) OR24, -X5NR25C (O) NR2R25 or -X5NR25C (NR25) NR24R25, where X5 is a bond or (C? _6) alkylene, R24 is (C3-6) cycloalkyl (C0-6) alkyl, hetero (C3-6) cycloalkyl (Co-ß) alkyl, phenyl (C0-6) alkyl) or hetero (C5-6) aryl (Co-ß) alkyl and R25 in each occurrence is independently hydrogen or (C? -6) alkyl; wherein within R1 any present alicyclic or aromatic ring system can be further substituted by 1 to 5 radicals independently selected from (Ci-6) alkyl, (C? -6) alkylidene, cyano, halo, (C? _) substituted alkyl by halo, nitro, -X5NR14R14, -X5NR14C (O) OR14, X5NR14C (0) NR14R14, -X5NR14C (NR14) NR14R14, -X5OR14, -X5SR14, N5C (0) OR14, -X5NR14C (0) NR1R14, -X5NR14C ( NR14) NR14R14, -X5OR14, -X5SR14, -X5C (0) OR14, -X5C (0) NR14R14, -X5S (O) 2NR14R14, -X5P (O) (OR) 14, -X5OP (0) (OR14) OR14 , -X5NR14C (O) R15, -X5S (0) R15, -X5S (O) 2R15 and -X5C (0) R15, wherein X5, R14 and R15 are as defined above; R2 is hydrogen or (C -6) alkyl; R3 is (i) (C6-6) alkyl optionally substituted with cyano, halo, nitro, -NR14R14, -NR14C (0) OR14, -NR14C (0) NR14R14, -NR1C (NR14) NR14R14, -OR14, -SR14 , -C (0) 0R14, -C (0) NR14R14, S (0) 2NR14R14, -P (0) (OR14) OR14, -OP (0) (OR14) OR14, -NR14C (O) R15, -S (0) R15, -S (0) 2R15, -C (0) R15, -OR16, -SR16, -S (0) R16, -S (0) R16, -S (0) 2R16, -C (0) ) R16, -C (0) 0R16, -0C (0) R16, -NR16R17, -NR17C (0) R16, -NR17C (0) OR16, -C (0) NR16R17, -S (0) 2NR16R17, -NR17C (O) NR16R17 or -NR17C (NR17) NR16R17, wherein R14 in each occurrence is independently hydrogen, (C? -6) alkyl or (C? _3) alkyl substituted by halo, R15 is (C? -6) alkyl or (C? _6) alkyl substituted by halo, R16 is (C3-i) cycloalkyl (C0-β) alkyl, hetero (C3.12) cycloalkyl (Co-e) alkyl, (C6-? 2) allyl (C0-6) ) alkyl, hetero (C5-? 2) aryl (C0-β) alkyl, (C9-12) polycycloaryl (Co-e) alkyl or hetero (C8-? 2) polycycloaryl (Co-e) alkyl and R17 is hydrogen or (C? -6) alkyl, and wherein within R16 the aforementioned ring of cycloalkyl, heterocyclic lo-alkyl, aryl, heteroaryl, polycycloaryl or heteropolycycloaryl is optionally substituted by a group selected from -R18, -X5OR18, X5SR18, -X5S (0) R18, -X5S (0) 2R18, -X5C (0) R18, -X5C (0) ) OR18, X5OC (0) R18, -X5NR18R19, -X5NR19C (0) R18, -X5NR19C (O) 0R18,
X5C (0) NR18R19, -X5S (0) 2NR18R19, -X5NR19C (O) NR19C (O) R18, N5NR19C (0) OR18, -X5C (0) NR18R19, -X5S (O) 2NR18R19, -X5NR19C (O) NR18R19 or -X5NR19C (NR19) NR18R19, wherein X5 is as defined above, R18 is hydrogen or (C? -6) alkyl and R19 is (C3-12) cycloalkyl (C0-?) alkyl, hetero (C3-) 2) cycloalkyl (Co-e) alkyl, (C6-? 2) aryl (Co-β) alkyl, hetero (C5-? 2) aryl (Co-e) alkyl, (C9-? 2) polycycloaryl (Co-) ß) alkyl or hetero (C8-? 2) polycycloaryl (Co-β) alkyl, or (ii) a group selected from (C3-? 2) cycloalkyl (Co-e) alkyl, hetero (C3_? 2) cycloalkyl (Co -β) alkyl, (Co-ß) aryl (Co-ß) alkyl, hetero (C5.12) aryl (C0-e) alkyl, (C9-? 2) polycycloaryl (Co-ß) alkyl and hetero (C8-) 2) polycycloaryl (Co-e) alkyl, wherein said ring of cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or heteropolycycloaryl is optionally substituted by a group selected from -R18, -X5OR18, -X5SR18, -X5S (0) R18 , -X5S (0) 2R18, -X5C (0) R18, - X5C (0) OR18, -X5OC (0) R18, -X5NR18R19, -N5NR19C (0) R18, -X5NR19C (O) OR18, -X5C (O) NR18R19,
X5S (0) 2NR18R19, -X5NR19C (0) NR18R19 or -X5NR19C (NR19) NR18R19, wherein R5, R18 and R19 are as defined above; wherein within R12 and / or R13 any present alicyclic or aromatic ring system can be further substituted by 1 to 5 radicals independently selected from (C6-6) alkyl, (C6-6) alkylidene, cyano, halo, (C? -4) alkyl substituted by halo, nitro; -X5NR14R14, X5NR14C (0) OR14, -X5NR14C (0) NR14R14, -X5NR14C (NR14) NR14R14, -X5OR14, -X5SR14, -X5C (0) OR14, -X5C (0) NR14R14, -X5S (O) 2NR14R14, X5P (0) (OR14) OR14, -X5OP (0) (OR14) OR14, -X5NR14C (O) R15, -X5S (0) R15, -X5S (0) 2R15 and -X5C (0) R15, wherein X5 , R14 and R15 are as defined above, or R3 and R4 taken together with the carbon atom to which both R3 and R4 are attached form (C3.8) cycloalkylene or (C3-8) heterocycloalkylene, where the said cycloalkylene or heterocycloalkylene is optionally substituted by 1 to 3 radicals independently selected from (C? -6) alkyl, (C? _6) alkylidene, cyano, halo, (C? _4) alkyl substituted by halo, nitro, X5NR14C (0) OR14, -X5NR14C (0) NR14, -X5NR14C (NR14) NR14R14, -X50R14, -XSSR14, -X5C (0) OR14, -X5C (0) NR14R14, -X5S (O) 2NR14R14, X5P (0) (OR14) OR14, -X5NR14C (0) R15, -X5S (0) R15, -X5S (O) 2R15 and -X5C (0) R15, wherein X5, R14 and R15 are according to the above defined; R4 is hydrogen, (C? -6) alkyl or as defined above; R5 is hydrogen and R6 is hydroxy or R5 and R6 together form oxo; R7 is a group selected from cyano, halo, nitro, -R29, -X5NR29R30, -X5NR30C (O) OR29. -X5NR30C (O) NR29R30, -X5NR30C (NR30) NR29R30, -X5OR29, -X5SR29, X5C (0) OR29, -X5C (O) NR29R30, -X5S (O) 2 NR29R30, -X5P (0) (OR30) OR29 , -X5OP (O) (OR29) OR29, -X5NR30C (O) R31, -X5S (0) R31 and -X5C (0) R31, where X5 is as defined above, R29 is hydrogen or -R31, R30 in each occurrence is hydrogen or (C? _6) alkyl and R31 is (C? -6) alkyl, (C3_? 2) cycloalkyl (Co-β) alkyl, hetero (C3-? 2) cycloalkyl (C0.6) alkyl , (C6-i2) aryl (Co-e) alkyl or hetero (C5_? 2) aryl (C0-ß) alkyl, wherein within R7 any present alicyclic or aromatic ring system can be further substituted by 1 to 5 selected radicals independently of (C? -6) alkyl, (C? -6) alkylidene, cyano, halo, (C? -4) alkyl substituted by halo, nitro, -X5NR14R14, -X5NR14C (0) OR14, X5NR14C (0) NR14R14 , -X5NR14C (NR14) NR14R14, -X5OR14, -X5SR14, X5C (0) OR14, -X5C (0) NR1R14, -X5S (0) 2NR14R14, -X5P (O) (OR14) OR14, -X50P (0) ( 0R14) 0R14, -X5NR14C (0) R15, -X5S (0) R15, -XSS (0) 2R15 and -X5C ( 0) R15, where X5, R14 and R15 are as defined above; and R8 in each occurrence is independently selected from (C? -6) alkyl, (C? -6) alkylidene, cyano, halo, (C? -4) alkyl substituted by halo, nitro, -X5NR14R14,
X5NR14C (0) OR14, -X5NR14C (0) NR14R14, -X5NR14C (NR14) NR14R14, -X5OR14, -X5SR14, -X5C (0) OR14, -X5C (0) NR14R14, -X5S (O) 2NR14R14, -X5P ( O) (OR14) OR14, and -X50P (0) (0R14) 0R14, -X5NR14C (O) R15, -X5S (0) R15, -X5S (0) 2R15 and -X5C (0) R15, where X5, R14 And R15 are in accordance with the previously defined; R9 is hydrogen or (C? -6) alkyl; and R32 is (C? -8) alkyl, (C3-? 2) cycloalkyl (Co-e) alkyl, hetero (C3-? 2) cycloalkyl (Co-β) alkyl, (C6-? 2) aryl (Co-) ß) alkyl, hetero (C? -6) aryl (C0-ß) alkyl, (C9-? 2) polycycloaryl (C0-ß) alkyl or hetero (C8_12) polycycloaryl (Co-ß) alkyl, where within R30 any The present alicyclic or aromatic ring system can be further substituted by 1 to 5 independently selected radicals. { Cx.6) alkyl, (Cx-e) alkylidene, cyano, halo, (CX-4) alkyl substituted by halo, nitro, -X5NR14R14, -X5NR14C (O) OR14, -X5NR14C (O) NR14R14,
X5NR14C (NR14) NR14R14, -X5OR14, -X5SR14, -X5C (0) OR14, -X5C (O) NR14R14, -X5S (0) 2NR14R14, -X5P (0) (0R14) 0R14, -X5OP (O) (OR14 ) OR14, X5NR14C (0) R15, -X5S (0) R15, -X5S (O) 2R15 and -X5C (0) R15, wherein X5, R14 and R15 are as defined above; and the N-oxide derivatives, derivatives of prodrugs, protected derivatives, individual isomers and mixtures of isomers; and the pharmaceutically acceptable salts thereof. In another particular embodiment, the present invention relates to a pharmaceutical composition containing a compound of Formula I or II, or an N-oxide derivative, prodrug derivative, single isomer or mixture of isomers, or a pharmaceutically salt acceptable in a mixture with one or more suitable excipients. In another particular embodiment, the present invention relates to a method for treating a disease in an animal wherein the inhibition of a cysteine protease can prevent, inhibit or improve the pathology and / or symptomatology of the disease, where this method includes administering to the animal a therapeutically effective amount of the compound of Formula I or II or an N-oxide derivative, a prodrug derivative, an individual isomer or a 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 II and N-oxide derivatives, prodrug derivative, protected derivatives, individual isomers and mixtures of isomers, and pharmaceutically acceptable salts of these as stipulated in "Detailed Description of the Invention". In another particular embodiment, the present invention relates to protease inhibitors of Formula III:
wherein: A includes a heteromonocyclic radical containing from 5 to 6 ring atoms or a fused heteropolycyclic radical containing from 8 to 14 ring atoms, wherein each ring contains from 5 to 7 ring atoms, X1 is an annular carbon atom and each ring atom other than X1 is optionally a heteroatom, with the proviso that when A is a heteromonocylic radical containing 5 ring atoms, not more than two of the ring atoms included in the ring are heteroatoms; X1 is selected from = C- and -CH-; X2 is a bond or a divalent group of Formula (a) or (b):
(a) (b)
where :
X3 and X5 are independently -C (0) or -S (0) 2-, X4 is -CHR11-, -CHzCHR11- or -CHR1: LCH2- and X6 is -CHR12-, -CH2CHR12- or -CHR12CH2- where: R11 and R12 are independently (i) (C? -6) alkyl or (C? -S) alkyl substituted by halo optionally substituted by -OR13, -SR13, -S (0) R13, -S (0) 2R13, - C (0) R13, -C (0) OR13, -N13R14, -NR14C (0) OR13, -C (0) NR13R14, -S (O) 2NR13R14, NR14C (0) NR13R14 or -NR14C (NR14) NR13R14, where R13 is hydrogen,
(C? _6) alkyl, (C3_? 2) (C0-3) cycloalkyl, hetero (C3_12) cycloalkyl (C0-3) alkyl, (C6-? 2) aryl (C0-3) alkyl or hetero (C5-) ? 2) aryl (C0-3) alkyl and R14 is hydrogen or (C? -6) alkyl, or (ii) (C3-? 2) (C0-3) cycloalkyl, hetero (C3.12) cycloalkyl (C0) -3) alkyl, (CS-? 2) aryl (C0-3) alkyl, hetero (C5-? 2) aryl (C0-3) alkyl, (C9-? 2) polycycloaryl (C0-3) alkyl or heter ( C8_? 2) polycycloaryl (C0-3) alkyl optionally substituted by -R15, -X7R15, -X7SR15, -S (0) R15, -S (0) R15, -C (0) R15, -C (0) OR15 , -X7NR15R16, -X7NR16C (0) OR15, -C (O) NR15R16, -S (O) 2NR15R16, NR16C (0) NR15R16 or -NR16C (NR16) NR15R16, where X7 is a bond or methylene, R15 is (C3) -i2) (C0-3) cycloalkyl, hetero (C3-? 2) cycloalkyl (C0-3) alkyl, (C6-? 2) aryl (C0-3) alkyl, hetero (C5-? 2) aryl (C0) -3) alkyl, (C9-? 2) polycyl aryl (C0-3) alkyl or hetero (C8-? 2) polycycloaryl (C0-3) alkyl and R16 is hydrogen or (C? -6) alkyl, or (iii) together with R9 or R10, respectively, when X4 is -CHR11- and / or X6 is -CHR12-, form trimethylene, tetramethylene or phenylene-1,2-dimethylene, optionally substituted with hydroxy or oxo; wherein any of 1 to 3 ring atoms of any aromatic ring with available valences including R11 and / or R12 are independently optionally substituted with halo, nitro, cyano, (C? -6) alkyl, (C? _6) substituted alkyl by halo, -OR17, C (0) R17, -C (0) OR17, -C (0) NR17R17, -S (O) 2NR17R17, -X7NR17R17,
X7NR17C (0) OR17, -X7NR17C (0) NR17R17 or -X7NR17C (NR17) NR17R17, wherein X7 is as defined above and each R17 is independently hydrogen or (C6-6) alkyl; and R9 and R10 are independently hydrogen, (C? -6) alkyl or as defined above;
R1 is hydrogen or -X8X9R18, where X8 is -C (O) - or -S (0) 2-, X9 is a bond, -O- or -NR19-, where R19 is hydrogen or (CX-e) alkyl, and R18 is (i) (C? -6) alkyl or (C? -6) alkyl substituted by halo, optionally substituted with -OR13, -SR13, -S (0) R13, -S (0) 2R13, -C (0) R13, -C (0) OR13, -NR13R14, -NR14C (O) OR13,
C (0) NR13R14, -S (0) 2NR13R14, -NR14C (0) NR13R14 or -NR14C (NR14) NR13R14, where R13 and R14 is as defined above, or (ii) (C3-? 2) cycloalkyl (Co -β) alkyl, hetero (C3-? 2) cycloalkyl (Co-e) alkyl, (C6-? 2) aryl (C0-6) alkyl, dif-enyl (C0-ß) alkyl, hetero (C5-12) aryl (Co-β) alkyl, (C5.6) aryl (C0-β) alkyl, (C9. X2) polycycloaryl (Co-e) alkyl or hetero (C8-? 2) polycycloaryl (Co-β) alkyl optionally substituted with -R15, -X7015, -X7SR15, -S (0) R15, -S (0) 2R15, -C (0) R15, -C (0) 015, -X7NR15R16, or
X7NR16C (0) 015, -C (0) NR15R16, -S (0) 2NR15R16, -NR16C (0) NR15R16 or -NR16C (NR16) NR15R16, wherein X7, R15 and R16 are as defined above; wherein any of 1 to 3 cell atoms of any aromatic ring with available valencies including R1 are independently optionally substituted with halo, nitro, cyano, (C? -6) alkyl, (C? _6) alkyl substituted by halo, - O17,
C (0) R17, -C (0) 0R17, -C (0) NR17R17, -S (O) 2NR17R17, -X7NR17R17, X7NR17C (0) OR17, -X7NR17C (O) NR17R17 or -X7NR17C (NR17) NR17R17, where
X7 and R17 are as defined above;
R2 is hydrogen or (C? -6) alkyl;
R3 is phenyl (C2.3) alkyl, hetero (C5-6) aryl (C2.3) alkyl,
(C5-6) (C2.3) cycloalkyl or hetero (C5-6) cycloalkyl (C2-3) alkyl, wherein any of 1 to 3 ring atoms of any aromatic ring with available valencies including R3 are independently substituted optional with halo, nitro, cyano, (C? -6) alkyl, (C? -6) alkyl substituted by halo, -O17, -C (0) R17, -C (0) OR17, -C (O) NR17R17 , - S (0) 2NR17R17, -X7NR17R7, -X7NR17C (O) OR17, -X7NR17C (O) NR17R17 or -X7NR17C (NR17) NR17R17, where X7 and R17 are as defined above, and R4 is hydrogen or R3 and R 4 are both methyl, ethyl or propyl or together with the carbon atom to which both R 3 and R 4 are attached form cyclopropylene, cyclobutylene or cyclopentylene; R5 is hydrogen and R6 is hydroxy or R5 and R6 together form oxo; R7 is halo, nitro, -R20, -OR20, -C (0) R20, -C (0) OR20, -S (O) 2NR20R21, -C (O) NR0R21 or -C (O) NR22CHR3C (O) OR20 and they are attached to any ring carbon atom with a free valence that includes A, where:
R20 is hydrogen or R18, where R18 is as defined above;
R21 is hydrogen or (C? -6) alkyl; R22 is hydrogen, (C? -6) alkyl together with R23 form trimethylene or phenylene-1,2-dimethylene, optionally substituted with hydroxy or oxo; and R23 is as defined above or is (i) (C? -6) alkyl or (C? -6) alkyl substituted by halo, optionally substituted with -OR13, -SR13, -S (0) R13, - S (0) 2R13, -C (0) R13, -C (0) OR13, -NR13R14, -NR14C (0) OR13, -C (0) NR13R14, -S (0) 2NR13R14, -NR14C (0) NRI3R14 or -NR14C (NR14) NR13R14, where R13 and R14 are as defined above, or (ii) (C3.? o) (C0-3) cycloalkyl, hetero (C3-10) cycloalkyl (C0-3) alkyl, (C6-? 2) aryl (C0-3) alkyl, hetero (C5-? 2) aryl (C0-3) alkyl, (C9-? 2) polycycloaryl (C0-3) alkyl or hetero (C8.12) ) polycycloaryl (C0-3) alkyl, optionally substituted with -R15, -X7OR15, -X7SR15, -S (0) R15, -S (0) 2R15, -C (0) R15, -C (0) 0R15, - X7NR15R16, -X7NR16C (0) OR15, -C (0) NR15R16, -S (0) 2NR15R16, NR16C (0) NR15R16 or -NR16C (NR16) NR15R16, where X7, R15 and R16 are as defined above; wherein any of 1 to 3 ring atoms of any aromatic ring with available valencies including R20 and / or R21 are independently optionally substituted with halo, nitro, cyano, (C? -6) alkyl, (C? -6) alkyl substituted by halo, -OR17, C (0) R17, -C (0) 0R17, -C (0) NR17R17, -S (0) 2NR17R17, -X7NR17R17, X7NR17C (0) OR17, -X7NR17C (0) NR17R17 or -X7NR17C (NR17) NR17R17, wherein X7 and R17 are according to the above defined; and R8 is hydrogen, halo, hydroxy, formyl, carboxy, carbamoyl, sulfamoyl or (C? -6) alkyl and is attached to any ring carbon atom with a free valence including A; and N-oxide derivatives, derivatives of prodrugs, protected derivatives, individual isomers and mixtures of isomers; and the pharmaceutically acceptable salts thereof. DETAILED DESCRIPTION OF THE INVENTION Definitions: Unless otherwise indicated, the following terms used in the specification and the claims are defined for the purposes of this specification.
Application and have the meanings provided in this Section: "Alicyclic" means a moiety characterized by the arrangement of carbon atoms in closed non-aromatic ring structures with properties that resemble those of aliphatics and may be saturated or partially unsaturated with two or more double or triple links. "Aliphatic" means a moiety characterized by a straight or branched chain arrangement of the constituent carbon atoms and may be saturated or partially unsaturated with two or more double bonds or tripues. "Alkenyl" means alkyl, according to what is defined in this Application, with the condition that the radical is included at least by a double link. Therefore, (C2.6) optionally substituted alkenyl as used in this Application to define R32 includes 2-bromovinyl (-CHCHBr), buta-1,3-dienyl (-CHCH-CHCH2), 2-chloro- 1-metipropenyl (-C (CH3) CC1-CH3), 2-chlorovinyl (-CHCHC1), 4-isopropenyl (-C (CH3) CH2), 1-methylpropenyl (-C (CH3) CH2-CH3), 2- methylpropenyl (-CHC (CH3) 2), 2-nitrovinyl, (-CHCHNO2), propenyl (-CHCH-CH3), 2-trifluoromethylvinyl (-CHCH-CF3), trifluorovinyl (-CFCF2), and the like). "Alkoxy" means the radical -OR, where R is alkyl according to that defined in this Application, having the indicated number of carbon atoms (for example, (C? _4) alkoxy includes the methoxy, ethoxy, propoxy, isopropoxy radicals , butoxy, sec-butoxy, isobutoxy, tert-butoxy, vinyloxy, allyloxy, 1-propenyloxy, isopropenyloxy, 1-butenyloxy, 2-butenyloxy, 3-butenyloxy, 2-methylallyloxy, ethynyloxy, 1-propynyloxy, 2-propynyloxy, and Similar). "Alkyl" represented by itself means a straight or branched aliphatic radical, saturated or unsaturated, having the indicated number of carbon atoms (for example, (C? -6) alkyl includes methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tere-butyl, vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methylallyl, ethynyl, 1-propynyl, 2-propynyl, and the like). The alkyl represented together with another radical (for example, as in the arylalkyl) means a straight or branched, saturated or unsaturated aliphatic radical, which has the indicated number of atoms or when no atoms are indicated, means a bond (for example, (C6-? 2) aryl (C0-6) alkyl includes phenyl, benzyl, phenethyl, 1-phenylethyl, 3-phenylpropyl, and the like). "Alkylene", unless otherwise indicated, means a divalent aliphatic radical, straight or branched, saturated or unsaturated, having the indicated number of carbon atoms (for example (C? -6) alkylene 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, a group of Formula (a), wherein R 11 is hydrogen and R 12 taken together with R 9 optionally forms substituted trimethylene, is depicted in the following illustration:
wherein R is an optional hydroxy or oxo group and X3 and R1 are as defined in the Summary of the Invention for Formulas I and II.
"Alkylidene" means a divalent radical, aliphatic, straight or branched, saturated or unsaturated, which has the indicated number of carbon atoms (for example,
(C? -6) alkylidene includes methylene (: CH2), ethylidene (: HCH3) isopropylidene (: C (CH3) 2), propylidene (: CHCH2CH3), allylidene
(: CHCH: CH2), and the like). "Amino" means the radical -NH2. Unless otherwise indicated, the compounds of the invention containing amino moieties include protected derivatives thereof. Suitable protecting groups for the amino moieties include acetyl, tere-butoxycarbonyl, benzyloxycarbonyl, and the like. "Animal" includes humans, non-human mammals (e.g., dogs, cats, rabbits, cattle, horses, sheep, goats, pigs, deer, or the like) and non-mammals (e.g., birds, or the like). "Aryl" means a monocyclic or bicyclic ring assembly (fused or linked by a single bond) containing the total number of ring carbon atoms indicated, where each ring consists of 6 ring carbon atoms and is aromatic or when merges with a second ring forms an aromatic ring assembly. For example, (C6-? 2) aryl as used in this Application to define R1 includes phenyl, naphthyl and biphenylyl.
"Aromatic" means a half where the constituent atoms form an unsaturated ring system, all the atoms in the ring system are hybridized with sp2 and the total number of pi electrons equals 4n + 2. "Carbamoyl" means the radical - C (0) NH2. Unless otherwise indicated, compounds of the invention containing carbamoyl moieties include protected derivatives thereof. Suitable protecting groups for the carbamoyl moieties include acetyl, tert-butoxycarbonyl, benzyloxycarbonyl, and the like, and both unprotected and protected derivatives are within the scope of the invention. "Carboxy" means the radical -C (0) OH. Unless otherwise indicated, the compounds of the invention containing carboxy moieties include protected derivatives thereof. Suitable protecting groups for carboxy moieties include benzyl, tere-butyl and the like. For example, a compound of Formula I wherein R7 contains a carboxy moiety may exist as either the unprotected or protected derivative, for example, where R7 is methoxycarbonyl, and both unprotected and protected derivatives are within the scope of the invention. invention. "Cycloalkyl" means a monocyclic ring assembly, bicyclic, saturated or partially unsaturated ring (directly linked by means of a single or fused bond) or a polycyclic ring assembly with bridge containing the number of carbon atoms members of the indicated ring, and any carbocyclic ketone, thioketone or iminoketone derived therefrom (for example, (C3-? 2) cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, 2,5-cyclohexadienyl, bicyclohexylyl, cyclopentylcyclohexyl, bicyclo [2.2.2] octyl , adamantan-l-yl, decahydronaphthalenyl, oxocyclohexyl, dioxocyclohethyl, thiocyclohexyl, 2-oxo-bicyclo [2.2.1] hept-1-yl, and the like). "Cycloalkylene" means a polycyclic ring assembly with monocyclic ring or bridge, saturated or partially unsaturated, containing the indicated number of ring carbon atoms, and any carbocyclic ketone, thioketone or iminoketone derived therefrom. For example, the case where R3 and R4 together with the carbon atom to which they are attached as R3 as R4 form (C? -6) cycloalkylene include, but is not limited to the following:
wherein R2, R5 and R6 are in accordance with that defined in the Summary of the Invention, and any substituted derivative thereof. "Disease" specifically includes any non-healthy condition of an animal or part thereof and includes a diseased condition that may be caused by, or incidental to, medical or veterinary therapy applied to this animal, ie, the "side effects" of this animal. therapy.
"Fused heteropolycyclic ring system" means a saturated, partially unsaturated or aromatic moiety containing two or more rings, wherein at least two ring members of a ring are common to a second ring containing the number of ring members indicated wherein at least one of the ring member atoms is a heteroatom and any carbocyclic ketone, thioketone, iminoketone or substituted derivatives thereof. For example, the term "a fused heteropolycyclic radical containing 8 to 14 ring member atoms" as used in this Application to define A may include acridinyl, benzofuryl, benzooxazolyl, benzothiazolyl, carbazolyl, carbolinyl, chromanyl, chromenyl, cinolinyl. , indazolyl, indolinyl, indolyl, indolizinyl, isobenzofuryl, isochromenyl, isochromanyl, isoindolinyl, isoquinolyl, naphthyridinyl, perimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, fenotiazonilo, phenoxathiinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pirrolizinilo, quinazolinyl, quinolizinyl, quinolyl, quinoxalinyl , quinuclidinyl, xanthenyl and the like. "Guanidino" means the radical -NHC (NH) NH2. Unless otherwise indicated, the compounds of the invention containing guanidino moieties include protected derivatives thereof. Suitable protecting groups for the amino moieties include acetyl, tert-butoxycarbonyl, benzyloxycarbonyl, and the like, and both unprotected and protected derivatives are within the scope of the invention. "Halo" means fluoro, chloro, bromo or iodo. "Alkyl substituted by halo", as a group or part of a group, means "alkyl" substituted by one or more "halo" atoms, as these terms are defined in this Application. The alkyl substituted by halo includes haloalkyl, dihaloalkyl, trihaloalkyl, perhaloalkyl, and the like (for example, (C 3) alkyl substituted by halo 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 herein, provided that one or more of the carbon ring members indicated, are replaced by the heteroatom moiety selected from -N, -NR-, -O- or -S-, wherein R is hydrogen, (C? _6) alkyl or a protecting group, and each ring contained therein includes from 5 to 6 ring member atoms. For example, hetero (C5-? 2) aryl as used in this Application includes benzofuryl, benzooxazolyl, benzothiazolyl, [2, 4 '] bipyridinylin, carbazolyl, carbolinyl, chromenyl, cinolinyl, furazanyl, furyl, imidazolyl, indazolyl, indolyl , indolizinyl, isobenzofuryl, isochromenyl, isooxazolyl, isoquinolyl, isothiazolyl, naphthyridinyl, oxazolyl, perimidinyl, 2-phenylpyridyl, phthalazinyl, fteridinyl, purinyl, pyrazinyl, pyrazinyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolizinyl, pyrrolidinyl, pyrrolyl, pyranyl, quinazolinyl, quinolizinyl , quinolyl, quinoxalinyl, tetrazolyl, thiazolyl, 4-thiazol-4-ylphenyl, thienyl, xanthenyl and the like. "Half heteroatom" includes -N, -NR-, -O-, -S- or -S (0) 2-, wherein R is hydrogen, (d-β) alkyl or a protecting group. "Heterocycloalkyl" means cycloalkyl, as defined herein, so long as one or more of the carbon ring members indicated is replaced by the heteroatom moiety selected from -N, -NR-, -O- or -S-, where R is hydrogen, (C? -6) alkyl or a protecting group, and any carbocyclic ketone, thioketone or iminoketone derived therefrom (for example, the term hetero (C5-12) cycloalkyl includes [1, 4] '] bipiperidinyl, dihydrooxazolyl, morpholinyl, l-morpholin-4-ylpiperidinyl, piperazinyl, piperidyl, pyrazolidinyl, pyrazolinyl, pyrrolinyl, pyrrolidinyl, quinuclidinyl, and the like). Suitable protection 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 or protected derivative, for example, where R 1 is 1- erc-butoxycarbonylpiperidin-4-ylcarbonyl, and both the non-derivatized protected as protected fall within the scope of the invention. "Heterocycloalkylene" means cycloalkyl, as defined in this Application, with the proviso that one or more of the carbon ring members indicated, is replaced by the heteroatom moiety selected from -N, -NR-, - 0-, -S- or -S (0) 2- / wherein R is hydrogen or (C? -6) alkyl. For example, the case where R3 and R4 together with the carbon atom to which both R3 and R4 are attached form hetero (C3-8) cycloalkylene include, but are not limited to, the following:
wherein R is hydrogen, (C? -6) alkyl or a protecting group and R2 is as defined in the Summary of the Invention, and any substituted derivative thereof. "Hetero-monocyclic" means a monocyclic aromatic radical, saturated or partially unsaturated, containing the number of ring member atoms indicated, wherein at least one of the ring member atoms is a heteroatom and any carbocyclic ketone, thioketone, iminoketone or derivative replaced of these. For example, the term "a heteromonocyclic containing 5 to 6 ring member atoms" as used in this Application to define A may include dihydroxazolyl, furazanyl, furyl, imidazolyl, imidazolidinyl, imidazolinyl, isooxazolyl, isothiazolyl, thiazolyl, thienyl. , morpholinyl, oxazolyl, piperazinyl, piperidinyl, pyrazolidinyl, pyrazolinyl, pyranyl, pyrazinyl, pyrazinyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, tetrazolyl, and the like. "Heteropolycycloaryl" means polycycloaryl, as defined herein, with the exception that one or more of the ring member carbon atoms indicated are replaced by a heteroatom moiety selected from -N, -NR-, -O- or -S-, wherein R is hydrogen, (C? -6) alkyl or a protecting group, and any carbocyclic ketone, thioketone or iminoketone derived therefrom. For example, hetero (C8-? 2) polycycloaryl includes 1 ', 2'-dihydro-2H- [1,4'] bipyridinylyl, chromanyl, imidazolinyl, indolinyl, isochromanyl, isoindolinyl, and the like. "Hydroxy" means the -OH radical. Unless otherwise indicated, the compounds of the invention containing hydroxy radicals include protected derivatives thereof. Suitable protecting groups for the hydroxy moieties include benzyl and the like and both unprotected and protected derivatives are within the scope of the invention. "Iminoketone derivative" means a derivative containing the half -C (NR) -, where R is hydrogen or (C? 6) alkyl. "Isomers" means compounds of Formula I that possess identical molecular formulas but differ in the nature or sequence of the bonding of their atoms or in the arrangement of their atoms in space. The isomers that differ in the arrangement of their atoms in space are called "stereoisomers." Stereoisomers that are not mirror images of others are called "diastereoisomers" and stereoisomers that are non-superimposed mirror images are called "enantiomers" or sometimes "optical isomers". A carbon atom linked to four non-identical substituents is called the "chiral center". A compound with a chiral center has two enantiomeric forms of opposite chirality and is called a "racemic mixture". A compound that has more than one chiral center has enantiomeric pairs 2"" 1, where n is the number of chiral centers. Compounds with more than one chiral center can exist as either a single diastereoisomer or as a mixture of diastereoisomers, with the name of a "diastereoisomeric mixture". When a chiral center is present, a stereoisomer may be characterized by the absolute configuration of this chiral center. The absolute configuration refers to the arrangement in 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 standards of Cahn, Ingold and Prelog. Conventions for stereochemical nomenclature, methods for the determination of stereochemistry and separation of stereoisomers are well known in the art (for example, see "Advanced Organic Chemistry", 3rd edition, March, Jerry, John Wiley &Sons, New York, 1985). It is understood that the names and the illustration used in this Application to describe the compounds of Formula I are intended to include all possible stereoisomers and any mixture, racemic or otherwise, of them. "Ketone derivative" means a derivative containing the half -C (0) -. "Nitro" means the radical -N02. "Optional" or "optionally" means that the subsequently described case or circumstance may or may not occur, and that the description includes instances in which the case or circumstance occurs and instances in which it does not. For example, the phrase "(C? -6) alkyl optionally substituted with cyano, halo, nitro" means that the referred alkyl group may be or may not be substituted in order to come within the scope of the invention. "Oxalo" means the radical -C (0) C (0) OH. "N-oxide derivatives" means derivatives of the compound of Formula I wherein the nitrogens are in the oxidized state (ie, O-?) And which possess the desired pharmacological activity. "Oxo" means the radical = O. "Pathology" of a disease means the essential nature, causes and developments of the disease, as well as the structural 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 is not biologically or otherwise undesirable, and includes what is acceptable for vetarinary use as well as for human pharmaceutical use. "Pharmaceutically acceptable salts" means salts of the compounds of Formula I which are pharmaceutically acceptable, as defined above, and which possess the desired pharmacological activity. These salts include acid addition salts formed with inorganic acids such as for example hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or with organic acids such as for example 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, acid citric acid, benzoic acid, o- (4-hydroxybenzoyl) benzoic acid, cinnamic acid, madicalic acid, methanesulfonic acid, hetanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benecenosulfonic acid, p-chlorobenzenesulfonic acid, 2- naphthalenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo [2.2.2] oct-2-ene-l-carboxylic acid, gluoheptonic 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, licicollic, stearic acid, muconic acid and the like. The pharmaceutically acceptable salts also include salts with base addition which may 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 moieties are attached in the 1- and 2- positions of the phenylene moiety. For example, a group of Formula (a) wherein R12 together with R9 forms the optionally substituted phenylene-1,2-dimethylene is illustrated with the following formula:
wherein R is an optional hydroxy group and X3 and R1 are as defined in the Summary of the Invention for Formulas I and II. "Polycycloaryl" means a bicyclic ring assembly (directly linked by a single or fused bond) containing the number of carbon atoms members of the ring indicated, where at least one, but not all, fused rings including the radical is aromatic, and any carbocyclic ketone, thioketone or iminoketone derived therefrom (for example, (C9-12) polycycloaryl includes indanyl, indenyl, 1,2,3,4-tetrahydronaphthalenyl, 1,2-dihydronaphthalenyl, cyclohexylphenyl, phenylcyclohexyl, 2, 4-dioxo-l, 2, 3, 4-tetrahydronaphthalenyl, and the like). "Promedication" means a compound that is convertible in vivo by metabolic means (eg, by hydrolysis) to a compound of Formula (I). For example, an ester of a compound of the formula (I) containing a hydroxy group can be converted by hydrolysis in vivo to the base molecule. Alternatively, an ester of a compound of Formula (I) containing a carboxy group can be converted by hydrolysis in vivo to the base molecule. Suitable esters of the compounds of the formula (I) which contain a hydroxy group are, for example, acetates, citrates, lactates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates, methylene-bis-b-hydroxynaphthalates. , gentisatos, isetionatos, bi-p-toluoiltartratos, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, cyclohexyl sulfamates and kinatos. Suitable esters of the compounds of Formula (I) which contain a carboxy group are, for example, those described by FJ Leinweber, Research on Drug Metabolism, 1987, 18, page 379. An especially useful class of esters of the compounds of Formula (I) containing a hydroxy group can be formed from acid moieties selected from those described by Bundgaard et al., Bulletin of Medicinal Chemistry, 1989, 32, page 2503-2507, and includes (aminomethyl) -benzoates substituted , for example, dialkylamino-methylbenzoates wherein the two alkyl groups can be linked together and / or interrupted by an oxygen atom or by an optionally substituted nitrogen atom, for example, an alkylated nitrogen atom, more particularly (morpholino-methyl) benzoates, for example 3- or 4- (morpholinomethyl) -benzoates, and (4-alkylpiperazin-1-yl) benzoates, for example 3- or 4- (4-alkylpiperazin-1-yl) benzoates. A prodrug derivative of a compound of Formula I wherein R5 and R6 together are ox, is represented by the following formula:
wherein X13 is a bond, straight, saturated ethylene or (-CH2CR41R42CH2-), where R41 and R42 are independently hydrogen, halo or (C? _3) alkyl or taken together form methylene. "Protected derivatives" means derivatives of compounds of Formula I in which a site or reactive sites are blocked with protecting groups. Protected derivatives of the compounds of Formula I are useful in the preparation of compounds of Formula I or in themselves the cysteine protease inhibitors may be active. For example, the compound of Formula I which is 2 _? - amino-N- (2-benzooxazol-2-yl-2-hydroxy-lS-phenethylethyl) -3-cyclohexylpropionamide (ie, Compound 55, described in Example 6, below) may be protected with a suitable amino protecting group, for example 9H-fluoren-9-ylmethoxycarbonyl, or a suitable hydroxy protecting group, for example tert-butyldimethylsilanyl, to provide, respectively, 9H-fluoren-9- ILS- (2-benzooxazol-2-yl-2-hydroxy-1S-phenethylethylcarbamoyl) -2-cyclohexylethylcarbamate (i.e., Compound 51, described in Formula 4, below) and 2S-amino-N- [2 -benzooxazol-2-yl-2- (ert-butyldimethylsilanyloxy) -lS-phenethylethyl] -3-cyclohexylpropionamide (ie, Compound 56, described in Formula 7, below). A complete list of suitable protecting groups can be found in T.W. Greene, Protecting Groups in Organics Synthesis (Protective Groups in Organic Synthesis), John Wiley & Sons, Inc. 1981. "Member of the ring", as in the fused heteropolycyclic ring system containing 8 to 14 ring member atoms, means that the referred atoms are ring members of the fused heteropolycyclic radical, but does take into account The members of the ring of no substituent present. Thus, for example, a heteropolycyclic radical containing 8 ring member atoms includes benzooxaxol-2-yl, benzofur-2-yl, lH-indol-5-yl, benzothiazol-2-yl, and the like. "Sulfamoyl" means the radical -S (0) 2 NH2. Unless otherwise indicated, the compounds of the invention containing sulfamoyl radicals include the protected derivatives thereof. Suitable protecting groups for sulfamoyl radicals include acetyl, tert-butoxycarbonyl, benzyloxycarbonyl, and the like, and both unprotected and protected derivatives are within the scope of the invention. "Therapeutically effective amount" means the amount that, when administered to an animal to treat a disease, is sufficient to effect the aforementioned treatment for the disease. "Derivative of thioketone" means a derivative containing the half -C (S) -. "Treatment" or "treating" means any administration of a compound of the present invention and includes: (1) preventing the occurrence of the disease in an animal that may be predisposed to the disease, but which does yet experience it or shows the pathology or symptomatology of the disease, (2) inhibiting the disease in an animal that is experiencing or showing the pathology or symptomatology of the patient (ie, stopping a further development of the pathology and / or symptomatology), or (3) improving the disease in an animal that is experiencing or showing the pathology or symptomatology of the patient (ie, reversing the pathology and / or symptomatology). Specific Forms of Execution of the Invention: Although the broadest definition of the invention is specified in the Summary of the Invention, certain aspects of the invention are preferred. A preferred aspect of the invention are the compounds of Formula I wherein X 1 is = C-. In particular, system A of the fused heteropolycyclic ring or heteromonocyclic ring is selected from 4,5-dihydrooxazol-2-yl, benzooxazol-2-yl, benzothiazol-2-yl and oxazol-2-yl, each substituted by a group R7 and optionally substituted with a group R8, in particular where R7 is hydrogen, halo, (Cx.4) alkoxy, (C? -4) alkoxycarbonyl, nitro or phenyl and R8 in each occurrence is independently halo, (C? -4) alkoxy, (C _. 4) alkoxycarbonyl, nitro or trifluoromethyl. The ring system A is preferably benzoxazol-2-yl substituted by a group R7 and optionally substituted with a group R8, in particular where R7 is hydrogen, halo, (C? _4) alkoxy, (C? _4) alkoxycarbonyl or nitro and R8 in each occurrence is independently halo, (C? -6) alkoxy, (C? -6) alkoxycarbonyl, nitro or trifluoromethyl. X2 represents in particular a bond or a divalent group of the formula (a); particularly where within Formula (a) X3 is -C (O) -, R9 represents hydrogen, R11 represents hydrogen or methyl, usually hydrogen, and R12 represents particularly (i) (C? -6) alkyl substituted with - SR14, -S (0) R14 or -S (0) 2R14, where R14 is (C6.12) aryl (C0-e) alkyl or hetero (C5-12) aryl (Co-e) alkyl or (ii) ( C3-? 2) (C0-6) cycloalkyl alkyl or (C6-6) aryl (C0-) alkyl; where within R12 present alicyclic or aromatic ring system can be further substituted by 1 to 5 radicals independently selected from (C? -6) alkyl, (C? _6) alkylidene, cyano, halo, (C1-4) alkyl substituted by halo, nitro, -X5NR14R14, X5NR14C (0) R14, -X5NR14C (0) NR14R14, -X5NR14C (NR14) NR14R14, -X50R14, -X5SR14, -X5C (0) 0R14, -X5C (0) NR14R14, -X5S ( O) 2NR14R14, -X5P (0) OR14, -X5OP (0) (OR14) OR14, -X5NR14C (0) R15, -X5S (0) R15, -X5S (O) 2R15 and -X5C (0) R15, where X5 is a bond or (C? -6) alkylene, R14 in each occurrence is independently hydrogen, (C? -6) alkyl or
(C? -3) alkyl substituted by halo and R15 is (C? -6) alkyl or (Ci-3) alkyl substituted by halo. Also preferred, within Formula (a), R12 particularly represents a group having the following formula:
wherein q is 0,1,2,4 or 5 and R33 in each occurrence is independently selected from a group consisting of (C? _4) alkyl, cyano, halo, (C? _4) alkyl substituted by halo, nitro, - X5NR14R14, -X5OR14, X5SR14, -X5C (O) NR14R14, -X5C (0) OR14, -X5S (0) R15, -X5S (0) 2R15 and -X5C (0) R15, where X5 is a bond or
(C? -6) alkylene, R14 in each occurrence is independently hydrogen, (C1-3) alkyl or (C1-3) alkyl substituted by halo and
R15 is (C1-3) alkyl or (C1-3) alkyl substituted by halo; more particularly where q is 0, 1 or 2 and R33 in each occurrence is independently selected from a group consisting of (C? _4) alkyl, cyano, halo, (C? -4) alkyl substituted by halo, nitro, -OR14, -SR14 and -C (0) OR14, wherein R14 is independently hydrogen, (C1-3) alkyl or (C? -3) alkyl substituted by halo; more particularly wherein R33 in each occurrence is independently selected from a group consisting of (C? -4) alkyl, bromine, carboxy, chloro, cyano, difluoromethoxy, fluoro, iodo, methoxy, nitro, trifluoromethoxy, trifluoromethyl and trifluorosulfañil. Also preferred, within Formula (a), R12 particularly represents benzylsulfonylmethyl, 2-chlorobenzylsulfonylmethyl, 2-cyanobenzylsulfonylmethyl, 2-difluoromethoxybenzylsulfonylmethyl, 3,5-dimethylisoxazol-4-ylmethylsulfonylmethyl, 2-methoxybenzylsulfonylmethyl, 6-methylpyrid-2-ylmethylsulfonylmethyl. , 2-nitrobenzylsulfonyl-methyl, pyrid-2-ylmethylsulfonylmethyl, o-tolylmethylsulfonylmethyl or 2-trifluoromethylbenzylsulfonylmethyl. R1 represents particularly -X6X7R20, where ^ is -C (O) - or -S (0) 2-, X7 is a bond, -0- or -NR21-, where R21 is hydrogen or (C? -6) alkyl, and R20 is (i) (C? -6) alkyl optionally substituted by -C (0) OR14 or (ii) (C3-12) cycloalkyl (C0-?) alkyl, hetero (C3.2) cycloalkyl (C0-? ) alkyl, (C6-? 2) aryl (Co-ß) alkyl or hetero (C5-? 2) aryl (C0-ß) alkyl or (iii) (C3-6) cycloalkyl (C0-ß) alkyl, hetero ( C3-6) cycloalkyl (C0-β) alkyl, phenyl (Co-β) alkyl or hetero (C5-6) aryl (C0-β) alkyl, where the aforementioned ring of cycloalkyl, heterocycloalkyl, phenyl or heteroaryl is substituted by - X5OR24, -X5C (0) R24, X5C (0) OR24, -X5C (0) NR24R25, -X5NR24R25, -X5NR25R25C (0) R24, X5NR25C (0) OR24, -X5NR25C (0) NR24R25 or -X5 NR25C (NR25 ) NR24R25 where X5 is a bond or (C? .6) alkylene, R24 is (C3-6) cycloalkyl (C0-ß) alkyl, hetero (C3-6) cycloalkyl (C0-ß) alkyl, phenyl (C0-s) alkyl or hetero (C5-6) aryl (C0-β) alkyl and R25 is hydrogen or (Ci-β) alkyl; wherein within R1 any present alicyclic or aromatic ring system can be further substituted by 1 to 5 substituents independently selected from (C? -6) alkyl, halo, (C? _4) alkyl substituted by halo, (C? _4) alkyl , -OR14 and -C (0) OR14 where R14 is hydrogen or (C-6) alkyl, or when X2 is a divalent group of the formula (a) then R1 may be, but is not limited to, hydrogen or oxalo. R1 is preferably a group selected from acetyl, azetidyl-3-ylcarbonyl, benzyloxycarbonyl, 1-benzyloxycarbonylpiperidin-4-ylcarbonyl, benzylsulfonyl, bicyclo [2.2.2] hept-2-ylcarbonyl, bicyclo [2.2.1] hept-2 ilcarbonyl, tert-butoxycarbonyl, carboxyacetyl, 2-carboxypropionyl, 3-carboxypropionyl, 2-cyclohexylacetyl, 4-cyclohexylbutyryl, 2-cyclohexylethylsulfonyl, cyclohexyl-methoxycarbonyl, 3-cyclohexylpropionyl, 2-cyclopentylethylsulfonyl, 3-cyclopentylpropionyl, di (2- methoxyethyl) -carbamoyl, dimethyl carbamoyl, 6-hydroxypyrid-3-ylcarbonyl, lH-imidazol-4-ylcarbonyl, methoxycarbonyl, methylsulfonyl, 4-methylvleryl, morpholin-4-ylcarbonyl, 2-morpholin-4-ylethylcarbonyl, naft-1 ilacetyl, naphth-1-ylmethylcarbonyl, oxalo, 3-phenylpropionyl, piperazin-1-ylcarbonyl, piperidin-4-ylcarbonyl, pyrazin-2-ylcarbonyl, pyrid-3-ylcarbonyl, pyrid-4-ylcarbonyl, pyrid-3-ylaminocarbonyl, tetrahydro-pyran-4-ylcarbonyl and tetrahydropyran-4-yloxycarbonyl. R1 represents especially morpholin-4-ylcarbonyl, methoxycarbonyl, methylsulfonyl, piperidin-4-ylcarbonyl, pyrazin-2-ylcarbonyl, pyrid-3-ylcarbonyl, pyrid-4-ylcarbonyl, tetrahydropyran-4-ylcarbonyl or tetrahydropyran-4-yloxycarbonyl. R2 is usually hydrogen. R3 represents particularly hydrogen, (C? -6) alkyl (optionally substituted with cyano, halo, nitro, -SR26, C (0) OR26, -C (0) NR26R26, -P (O) (OR26) OR26, -OP (O) (OR26) OR26,
S (0) R27, -S (0) 2R27 or -C (0) R27, where R26 in each occurrence is independently hydrogen, (C? -6) alkyl, or (C? -3) alkyl substituted by halo and R27 is (C? -6) alkyl or (C? -3) alkyl substituted by halo or (C6-? 2) aryl (C2_3) alkyl, where the aforementioned aryl is optionally further substituted with 1 to 5 radicals independently selected from (C? -6) alkyl, (C? -6) alkylidene, cyano, halo, (C? _4) alkyl substituted by halo, nitro, -X5NR1C (O) O14, -X5NR (O) NR14R14, -X5NR14C (NR14 ) NR14R14, -X50R14, -X5SR14, -X5C (0) OR14, -X5C (O) NR14R14, -X5S (0) 2NR14R14, -X5P (0) (OR14) OR14, -X5OP (O) (OR14) OR14, X5NR14C (0) R15, -X5S (0) R15, -X5S (O) 2R15 and -X5C (0) R15, where X5 is a bond or (C? _6) alkylene, R14 in each occurrence is independently hydrogen, (C) ? -6) alkyl or (C? _3) alkyl substituted by halo and R15 is (C? -6) alkyl or (C1-3) alkyl substituted by halo, or R3 and R4 taken together with the carbon atom to which they are attached? joined R3 and R4 form (C3-6) cic loyalkylene. In particular, R3 can be selected from hydrogen, (C? _4) alkyl (for example, methyl, ethyl, n-propyl, n-butyl), phenyl (C2.3) alkyl (for example phenethyl) or (C? -4) alkylsulfonyl (C2.4) alkyl (eg, 2-methylsul-phonylethyl) or R3 and R4 taken together with the carbon atom to which both R3 and R4 are attached form (C3-6) cycloalkylene (e.g. cyclobutylene or cyclohexylene). R3 is preferably (C1-4) alkyl. R4 represents particularly hydrogen or R3 and R4 taken together with the carbon atom to which both R3 and R4 form (C6-6) cycloalkylene (for example, cyclobutylene or cyclohexylene). R5 and R6 preferably together form oxo. Preferred are compounds of Formula II wherein: n is 0; X1 is = C- and the ring system A is selected from
4, 5-dihydrooxazol-2-yl, benzooxazol-2-yl, benzothiazol-2-yl and oxazol-2-yl, each substituted by a group R7 and optionally substituted with a group R8, in particular where R7 is hydrogen, halo, (C? -4) alkoxy, (C? -4) alkoxycarbonyl, nitro or phenyl and R8 in each occurrence is independently (C? -4) alkoxy, (C? -4) alkoxycarbonyl, nitro or trifluoromethyl. X8 is methylene or ethylene; R1, R3 and R4 are according to the above defined; R5 and R6 together form oxo; R9 is hydrogen; and R32 is -X9R34, where X9 is methylene when X8 is methylene and X9 is a bond when X8 is ethylene, R34 is -CR35CHR36 or -CR37NR38, where R35 and R36 together with the atoms to which R35 and R36 are attached form ( C2-6) alkenyl, (C5_2) cycloalkenyl, hetero (C5-? 2) cycloalkenyl, (C6-? 2) aryl, hetero (C6-12) aryl, (C9-? 2) bicycloaryl or hetero (C8-) 12) bicycloaryl and R37 and R38 together with the atoms to which R37 and R38 are attached form hetero (C5-? 2) cycloalkenyl, hetero (C6-12) aryl or hetero (C8-? 2) bicycloaryl, where within R34 said cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl, bicycloaryl or heterobicycloaryl can be further substituted by 1 to 5 radicals independently selected from (C? -6) alkyl, (C? -6,) alkylidene, cyano, halo, (C? _4) ) alkyl substituted by halo, nitro, -X5NR14R14, -X5NR14C (0) OR14, -X5NR14C (0) NR14R14, -X5NR14C (NR14) NR14R14, -X5OR14, -X5SR14, -X5C (0) OR14, -X5C (O) NR14R14, -X5S (O) 2NR14R14, X5 (0) (O R14) OR14, -X5OP (0) (OR14) OR14, -X5NR14C (O) R15, -X5S (0) R15, -X5S (0) 2R15 and -X5C (0) R15, where X5 is a bond or (C) ? 6) alkylene, R 14 in each occurrence is independently hydrogen, (d-β) alkyl or (C? -3) alkyl substituted by halo and R15 is (d-β) alkyl or (CX-3) alkyl substituted by halo. R34 represents particularly (C6-? 2) aryl or hetero (C5-12) aryl, each optionally substituted by 1 to 5 radicals selected from a group consisting of (C1-4) alkyl, cyano, halo, (C? _4) alkyl substituted by halo, nitro, X5NR14R14, -X50R14, -X5SR14, -X5C (0) NR14R14, -X5C (0) OR14,
X5S (0) R15, -X5S (0) 2R15 and -X5C (0) R15, where X5 is a bond or
(C1"2) alkylene, R14 in each occurrence is independently hydrogen, (C1-3) alkyl (C1-3) alkyl substituted by halo and R15 is (C1-3) alkyl or (C1-3) alkyl substituted by halo. R34 more preferably represents biphenyl, isooxazolyl, naphthale, phenyl, pyridyl or thienyl, each optionally substituted by 1 to 5 radicals selected from a group consisting of (C? _4) alkyl, cyano, halo, (C1-4) alkyl substituted by halo, nitro, -X5NR14R14, -X5OR14, -X5SR14, -X5C (0) NR14R14, -X5C (0) OR14, -X5S (0) R15, -X5S (O) 2R15 and -X5C (0) R15, where X4 is a bond or (C? -2) alkylene, R14 at each occurrence is independently hydrogen, (C1-3) alkyl (C? _3) alkyl substituted by halo and R15 is (C? -3) alkyl (C1-) 3) alkyl substituted by halo. R34 more preferably represents biphenyl-2-yl, 2,4-bistrifluoromethylphenyl, 2,5-bistrifluoro-methylphenyl, 4-er-butylphenyl, 2-bromophenyl, 3-bromo-phenyl, 4-bromophenyl, 2-bromo- 5-fluorophenyl, 3-chloro-2-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 5-chlorothien-2-yl, 2-chloro-5-trifluoromethyl, 2-cyanophenyl, 3-cyanophenyl, 4- cyanophenyl, 1,5-dichlorophenyl, 2,6-dichlorophenyl, 3,4-dichlorophenyl, 2,3-difluorophenyl, 2,4-difluorophenyl, 3,4-difluorophenyl, 2-difluoromethoxyphenyl, 3-difluoromethoxyphenyl, 4-difluoromethoxyphenyl, 2 , 5-difluorophenyl, 2,6-difluorophenyl, 3,5-dimethylisoxoxol-4-yl, 3,5-dimethylphenyl, 2-fluoro-6-nitrophenyl, 2-fluorophenyl, 4-fluorophenyl, 2-fluoro-3-trifluoromethylphenyl , 2-fluoro-4-trifluoromethylphenyl, 2-fluoro-5-trifluoromethylphenyl, 2-fluoro-6-trifluoromethylphenyl, 4-fluoro-2-trifluoromethyl-phenyl, 4-fluoro-3-trifluoromethylphenyl, 2-iodophenyl, 3-iodophenyl , 4-iodophenyl, 2-methoxyphenyl, 4-methoxyphenyl, 2-methylphenyl , 3-methylphenyl, 4-methylphenyl, 6-methylpyrid-2-yl, 3-methyl-2-fluorophenyl, naphth-2-yl, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 2, 3, 4, 5 , 6-pentafluorophenyl, phenyl, prop-2-en-l-yl, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, thien-3-yl, o-tolyl, 2-trifluoromethoxyphenyl, -trifluoromethoxyphenyl, 4-trifluoromethoxyphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-trifluoromethylsulphane-phenyl, 3-trifluoromethylsulfanylphenyl, 4-trifluoromethylsulfanylphenyl, 2,3,4-trifluorophenyl, 2,3,5-trifluorophenyl, 2,4,6-trifluorophenyl , 2, 4, 5-trifluorophenyl or 2,3,4-trifluorophenyl. A preferred group of compounds of Formula II are those wherein -X8S (0) 2R32 represents a group having the following formula:
wherein q is 0,1,2,4 or 5 and R33 in each occurrence is independently selected from a group consisting of (C? -4) alkyl, cyano, halo, (C? _4) alkyl substituted by halo, nitro, -X5NR14R14, -X5OR14, X5SR14, -X5C (O) NR14R14, -X5C (0) OR14, - X5S (0) R15, -X5S (0) 2R15 and -X5C (0) R15, where X5 is a bond or
(C? -2) alkylene, R14 in each occurrence is independently hydrogen, (C1-3) alkyl or (C? -3) alkyl substituted by halo and
R15 is (C? -3) alkyl or (C? -3) alkyl substituted by halo; more particularly where q is 0, 1 or 2 and R33 in each occurrence is independently selected from a group consisting of (C? _4) alkyl, cyano, halo, (C? -4) alkyl substituted by halo, nitro, -OR14, -SR14 and -C (0) 0R14, wherein R14 in each occurrence is independently hydrogen, (C? _3) alkyl or (C1-3) alkyl substituted by halo; more particularly wherein R33 in each occurrence is independently selected from a group consisting of (C? -) alkyl, bromine, carboxy, chloro, cyano, difluoromethoxy, fluoro, iodo, methoxy, nitro, trifluoromethoxy, trifluoromethyl and trifluorosulfañil. In particular, -X8S (O) 2R32 represents benzyl sulfonylmethyl, 2-clorobencilsulfonilmetilo, 2-cyanobenzyl sulfonylmethyl, 2-difluorometoxibencilsulfonilimetilo, 3,5-dimethyl-isoxazole -4 -ilmetilsulfonilmetilo, 2-methoxybenzyl sulfonylmethyl, 6-methylpyrid-2 -ylmethylsulfonylmethyl, 2-nitrobenzylsulfonylmethyl, pyrid-2-ylmethylsulfonylmethyl, o-tolylmethyl-sulfonylmethyl or 2-trifluoromethylbenzyl sulfonylmethyl. The reference to the preferred embodiments specified above is intended to include all combinations of particular and preferable groups. The compounds of Formula I are further preferred and are selected from a group consisting of:
2-acetylamino-N- (lS-benzooxazol-2-ylcarbonyl) -3-phenylpropyl) -3-cyclohexylpropionamide; and N- [IS- (lS-benzooxazol-2-ylcarbonyl-3-phenylpropyl-carbamoyl) -2-cyclohexylethylisonicotinamide; and the? -oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers; and the pharmaceutically acceptable salts thereof.
Further preferred are compounds of Formula I selected from a group consisting of: N- [IR- (lS-benzooxazol-2-ylcarbonylbutylcarbamoyl-2-benzylsulfonylethyl] morpholine-4-carboxamide; methyl 1. - (lS-benzooxazol-2 ilcarbonylbutyl carbamoyl) -2-benzylsulfonylethylcarbamate;
N- (lS-benzooxazol-2-ylcarbonylbutyl) -
2R-methy1-sulfonylamino-3-benzylsulfonylpropionamide; N- (lS-benzooxazol-2-ylcarbonylbutylcarbamoyl) -2 / R- (3, 3-dimethylureido) -3- (2-methoxybenzylsulfonyl) propionamide; N- [IR- (lS-benzooxazol-2-ylcarbonylbutylcarbamoyl) -2- (2-difluoromethoxybenzylsulfonyl) ethyl] morpholine-4-carboxamide; N- [1.R- (lS-benzooxazol-2-ylcarbonylbutylcarbamoyl) -2- (2-methoxybenzylsulfonyl) ethyl] morpholine-4-carboxamide; N- [1.R- (lS-benzooxazol-2-ylcarbonylpentylcarbamoyl) -2-benzylsulfonylethyl] morpholine-4-carboxamide; N- [IR- (lS-benzooxazol-2-ylcarbonylpentylcarbamoyl) -2- (2-chlorobenzylsulfonyl) ethyl] morpholine-4-carboxamide;
IR- (lS-benzooxazol-2-ylcarbonylpentylcarbamoyl) 2- (2-difluoromethoxybenzisulfonyl) ethylcarbamate;
N- [IR- (lS-benzooxazol-2-ylcarbonylpentylcarbamoyl)
2- (2-difluoromethoxybenzylsulfonyl) ethyl] morpholine-4-carboxyamide; N- [IR- (lS-benzooxazol-2-ilcarbonilpentilcarbamoilo) - 2- (3, 4-ilmetilsulfoniltil 5dimetilisoxazol-] isonicotinamide; N- [IR- (lS-benzooxazol-2-ilcarbonilpentilcarbamoilo) -2- (2-nitrobenzylsulphonyl) ethyl] morpholine-4-carboxamide; N- [IR- (lS-benzooxazol-2-ilcarbonilpentilcarbamoilo) -2-pyridin-2-ilmetilsulfoniletil] morpholine-4-carboxamide; N- [IR- (lS-benzooxazol-2-ilcarbonilpentilcarbamoilo ) -2 -o-tolilmetilsulfoniletil] morpholine-4-carboxamide; N- [IR- (lS-benzooxazol-2-ilcarbonilpentilcarbamoilo) -2- (2-trifluorometilbencilsulfonil) ethyl] morpholine-4-carboxamide; N- [IR- ( ? l _ - benzooxazol-2-ylcarbonyl-3-phenylpropyl carbamoyl) -2-bencilsulfoniletil] nicotinamide; N- [IR- (l, _.- benzooxazol-2-ylcarbonyl-3-phenylpropyl carbamoyl) -2 -bencilsulfoniletil] pyrazine 2-carboxamide; N- [IR- (lS-benzooxazol-2-ylcarbonyl-3-phenylpropyl-carbamoyl) -2- (2-chlorobenzylsulfonyl) ethy] 3-morpholine-4-carboxamide; N- [IR- (lS-benzooxazole- 2-ylcarbonyl-3-phenylpropyl carbamoyl) -2- (2-cyanob encylsulfonyl) ethyl] isonicotinamide;
N- [IR- (lS-benzooxazol-2-ylcarbonyl-3-methyl-chloulyl carbamoyl) -2- (2-difluoromethoxybenzylsulfonyl) ethyl] morpholine-4-carboxamide; N- [IR- (lS-benzooxazol-2-ylcarbonylpentylcarbamoyl) -2- (2-difluoromethoxybenzylsulfonyl) ethy] isonicotinamide; N- [IR- (lS-benzooxazol-2-ylcarbonyl-3-enylpropyl carbamoyl) -2-benzylsulfonylethylmorpholine-4-carboxamide; N- [IR- (l __? -benzooxazol-2-ylcarbonyl-3-phenylpropyl carbamoyl) -2- (6-methylpyrid-2-ylmethylsulfonyl) ethyl] isonicotinamide; N- [IR- (l-> -benzooxazol-2-ylcarbonyl-3-phenylpropyl carbamoyl) -2- (2-nitrobenzylsulfonyl) ethyl] morpholine-4-carboxamide; N- [IR- (l £? -benzooxazol-2-ylcarbonyl-3-phenylpropyl carbamoyl) -2-pyrid-2-ylmethylsulfonylethyl] morpholine-4-carboxamide; N- [IR- (lS-benzooxazol-2-ylcarbonyl-3-phenylpropyl carbamoyl) -2-o-tolylmethylsulfonylethyl] morpholine-4-carboxamide; N- [IR- (lS-benzooxazol-2-ylcarbonyl-3-phenylpropyl carbamoyl) -2- (2-trifluoromethylbenzylsulfonyl) ethyl] tetrahydropyran-4-carboxamide;
tetrahydropyran-4-yl 1- (lS-benzooxasol-2-ylcarbonyl-3-phenylpropylcarbamoyl) -2-benzylsulfonyl-ethylcarbamate; and N- [IR- (lS-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl) -2- (2-cyanobenzylsulfonyl) ethyl] piperidine-4-carboxamide; and N-oxide derivatives, derivatives of prodrugs, protected derivatives, individual isomers and mixtures of isomers; and the pharmaceutically acceptable salts thereof. A preferred aspect of the invention are the compounds of Formula I wherein X 1 is = C-. In particular, system A of the fused heteropolycyclic ring or heteromonocyclic ring is selected from thien-2-yl, oxazol-2-yl, 4,5-dihydrooxazol-2-yl, fur-2-yl, lH-indole-5- ilo, pyrid-2-yl, pyrid-3-yl, thiazol-2-yl, l-methyl-lH-imidazol-2-yl, 1-benzyl-lH-imidazol-2-yl, benzooxazol-2-yl, benzofur-2-yl, benzothiazol-2-yl, lH-benzoimidazol-2-yl, 1, 1-dioxo-lH-l6-benzo [b] thien-2-yl, quinol-3-yl, [1] 3] dioxolan-2-yl, naphtho [2,3-d] oxazol-2-yl, naphtho [1,2-d] oxazol-2-yl and naphtho [2, 1-d] oxazol-2-yl, each substituted by a group R7 and optionally substituted with a group R8, particularly where R7 is halo, nitro, -R29, -O29, -C (0) R20, -C (0) 029, -SC02? R29R30, -C (0)? R29R30 or -C (O)? HCHR43C (O) OR29, where R20 is (Ci-β) alkyl, (C3_? 2) cycloalkyl (0-ß) alkyl, hetero (C3.? 2) cycloalkyl ( C0-ß) alkyl, (C6-? 2) aryl (C0-ß) alkyl, diphenyl (C0-ß) alkyl, hetero (C5_? 2) aryl (C0-ß) alkyl or hetero (C8.? 2) polycycloaryl (Co-ß) alkyl and R2 9 is hydrogen or -R20, where R20 is defined above, where the aforementioned heterocycloalkyl can be substituted with (C6-? ) aryl (C0-3) alkyl, R30 in each occurrence is hydrogen or (C? -6) alkyl and R43 is (Ci-β) alkyl, and R8 in each occurrence is independently hydrogen, (C? -6) alkyl or (C1-4) alkyl substituted by halo; wherein within R7 any present alicyclic or aromatic ring system can be further substituted by 1 to 5 radicals independently selected from (C? -6) alkyl, (C? _6) alkylidene, cyano, halo, (C1-4) substituted alkyl by halo, nitro, -X6NR1R14, -X6NR14C (0) OR14, -X6NR14-C (0) NR14R14, -X6NR14C (NR14) NR1R14, -X6OR14, -X6SR14, -X6C (0) OR14, -X6C (0) NR14R14 , -X6S (O) 2NR14R14, X6P (0) (OR14) OR14, -X6OP (0) (OR14) OR14, -X6NR14C (O) R15, -X6S (0) R15, -X6S (0) 2R15 and -X6C (0) R15, where X6 is a bond or (C _. 6) alkylene, R14 in each occurrence is independently hydrogen, (C -6) alkyl or (C1-3) alkyl substituted by halo and R15 is (Ci-β ) alkyl or (C? _3) alkyl substituted by halo. The ring system A is preferably oxazol-2-yl, 4,5-dihydrooxazol-2-yl, benzooxazol-2-yl, naphtho [2,3-d] oxazol-2-yl, naphtho [1,2- d] oxazol-2-yl or naphth [2, 1-d] oxazole-2-yl, each substituted by a group R7 and optionally substituted with a group R8, particularly where R7 is halo, -R29, -C (0 ) R20. -C (0) 029, -C (O) NR29R30 or -S (O) 2NR29R30 where R20 is (Ci-β) alkyl, (C3_? 2) cycloalkyl (C0-ß) alkyl, (C6-? 2) aryl (C0-ß) alkyl, hetero (C5-12) aryl (C0-β) alkyl or hetero (C8-? 2) polycycloaryl (C0-6) alkyl.
The ring system A most preferably is oxazol-2-yl, 4,5-dihydrooxazol-2-yl, benzooxazol-2-yl or naphtho [1,2-d] oxazol-2-yl, each substituted by a group R7 and optionally substituted with a group R8, particularly where R7 is adamantan-1-ylmethylcarbamoyl, benzyl, benzyl carbamoyl, benzyl (methyl) carbamoyl, l-benzyloxycarbonyl-3-methylbutylcarbamoyl, 4-benzylpiperidine-l-carbonyl, tere-butyl , chloro, 2,3-dihydroindol-l-ylcarbonyl, 3,4-dihydro-lff-isoquinol-2-ylcarbonyl, 3,4-dihydro-lH-quinol-l-ylcarbonyl, diphenylmethylcarbamoyl, fur-2-ylmethylcarbamoyl, hydrogen, 2- (lff-indol-3-yl) ethylcarbamoyl, methoxy, methoxycarbonyl, methyl, 3-methylbutylcarbamoyl, methylcarbamoyl, 1-methylethylcarbamoyl, naphth-1-ylmethylcarbonyl, nitro, phenyl, phenylcarbamoyl, 2-phenylcyclopropylcarbamoyl, 1- phenyloethylcarbamoyl, sulfamoyl, trifluoromethyl, phenethyl carbamoyl, 3-phenylpropylcarbamoyl, piperid-1-ylcarbonyl, pyrid-2-ylmethiicarbamoyl, pyrid-3-ylmethylcarbam oyl, pyrid-4-ylmethylcarbamoyl or pyrrolidin-1-ylcarbonyl and R8 is methyl. X2 particularly represents a bond or a divalent group of Fomula (a), wherein within Formula (a) X3 is -C (O) -, R9 represents hydrogen, R11 represents hydrogen or methyl, usually hydrogen and R12 represents particularly (C? _6) alkyl, preferably isobutyl, sec-butyl or isopropyl.
R1 represents particularly hydrogen or -X2X9R20, where X8 is -C (0) - or -S (0) 2-, X9 is a bond or -0- and R20 is (C? -6) alkyl, (C3-i2) cycloalkyl (C0-ß) alkyl, hetero (C3_2) cycloalkyl (C0-ß) alkyl, (C6-? 2) aryl (C0-ß) alkyl or hetero (C5-12) aryl (C0-ß) alkyl; wherein within R1 any present alicyclic or aromatic ring system can be further substituted by 1 to 5 radicals independently selected from (C? -6) alkyl, -C (0) 0R14, -X6NR14R14 and -X6NR14C (0) OR14, where X6 is a bond or (C? -6) alkylene, R14 in each occurrence is independently hydrogen, (C1-3) alkyl or (C? -6) alkyl substituted by halo and R15 is (C? -3) alkyl substituted by halo. R1 represents in particular acetyl, benzoyl, benzyloxycarbonyl, benzylsulfonyl, bicyclo [2.2.2] hept-2-ylcarbonyl, tert-butoxycarbonyl, tert-butyryl, 4-tert-butoxycarbonylpiperazin-1-ylcarbonyl, 1- erc-butoxycarbonyl piperidin-4- ilcarbonyl, 2-cyclohexyl acetyl, 4-cyclohexyl butyryl, 2-cyclohexylethylsulfonyl, 3-cyclohexylpropionyl, 2-cyclopentylethylsulfonyl, hydrogen, 4-methylpiperazin-1-ylcarbonyl, methylsulfonyl, 4-methylvaleryl, 3-morpholin-4-ylpropionyl, naphth-2 -methylmethyl, 3-phenylpropionyl, piperazin-1-ylcarbonyl, piperidin-4-ylcarbonyl or pyrid-3-ylcarbonyl, wherein within R1 any present alicyclic or aromatic ring system may be further substituted by 1 to 3 radicals independently selected from -aminomethyl and 3- erc-butoxycarbonylaminomethyl. R2 represents particularly hydrogen. R3 preferably represents (C? _6) alkyl or (C6-? O) aryl (C? -3) alkyl, more preferably phenotyl, or R3 and R4 taken together with the carbon atom to which R3 and R4 are attached form (C3_ß) cycloalkylene, more preferably cyclopropylene. R4 preferably represents hydrogen or (C? -6) alkyl, preferably hydrogen or methyl or R3 and R4 or R3 and R4 taken together with the carbon atom to which both R3 and R4 are attached (C? -6) cycloalkylene, more preferably cyclopropylene. R5 and R6 preferably together form oxo. The reference to the preferred embodiments mentioned above is intended to include all combinations of particular and preferred groups. 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 cathepsin 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, osteoarthritis, pneumocystis carinii, acute 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 bone resorption disorders. The compounds of the invention are inhibitors of cathepsin S and, as such, are useful for treating diseases in which the activity of cathepsin S contributes to the pathology and / or symptomatology of the disease. For example, the compounds of the invention are useful for treating autoimmune disorders, including, but not limited to, juvenile onset diabetes, multiple sclerosis, pansy vulgaris, Graves disease, severe myiastemia, systemic lupus erythematosus, rheumatoid arthritis, and Hashimoto thyroiditis. , allergic disorders, including, but not limited to, asthma, and halogen immune responses, including, but not limited to, organ transplants or tissue grafts. Cathepsin S is also implicit in disorders involving excessive elastolysis, such as chronic obstructive pulmonary disease (eg, emphysema), bronchitis, excessive elastolysis of the airways in asthma and bronchitis, pneumonias and cardiovascular diseases such as for example the rupture of plaques and atheroma. Cathepsin S is implicit in the formation of fibrils and, therefore, cathepsin S inhibitors are used in the treatment of systemic amyloidosis. The inhibitory activities of the systemic protease of the compounds of the invention can be determined by methods known to persons of ordinary skill in the art. Suitable assays are known in vi tro for measuring the activity of the protease and inhibiting it by test compounds. In general, the assay measures the protease-induced hydrolysis of a peptide-based substrate. In addition, the compounds of the invention are useful as intermediates in the preparation of other compounds of Formula I. For example, compounds of Formula I wherein R5 is hydroxy, can be used to prepare compounds of Formula I wherein R5 and R6 taken together form oxo. Nomenclature: The compounds of Formula I and the intermediate and starting materials used in their preparation are named according to the IUPAC nomenclature standards where the characteristic groups have decreasing priority for citation as the group at the beginning of the following Shape: acids, esters, amides, etc.
Alternatively, the compounds are named by AutoNom 4.0 (Beilstein Information Systems, Inc.). For example, a compound of Formula I wherein A is benzooxazol-2-yl; X2 is a group of Formula (a), wherein R9 is hydrogen and R12 is cyclohexylmethyl; R1 is acetyl; R2 is hydrogen; R3 is phenethyl; R4 is hydrogen; and R5 and R6 together form oxo; that is, a compound that forms the following structure:
it is called 2S-acetylamino-N- (l-benzooxazol-2-ylcarbonyl-3-phenylpropyl) -3-cyclohexylpropionamide; and a compound of Formula I wherein A is benzooxazol-2-yl; X2 is a group of Formula (a), wherein R9 is hydrogen and R12 is benzylsulfonylmethyl; R1 is morpholin-4-ylcarbonyl; R2 is hydrogen; R3 is phenethyl; R4 is hydrogen; R5 is hydrogen; and R6 is hydroxy; that is, a compound that has the following structure:
It is named N- [1 S- (2-benzooxazol-2-yl-2-hydroxy-lS-phenethylethylcarbamoyl) -2-benzylsulfonylethyl] -morpholine-4-carboxamide or morpholine-4-carboxylic acid. { (R) -1- [(S) -1- (l-benzooxazol-2-yl-l-hydroxy-methyl) -phenyl-propylcarbamoyl] 2-phenylmethanesulfonyl-ethyl} -amide; and a compound of Formula I wherein A is benzooxazol-2-yl; X2 is a group of Formula (a), wherein R is hydrogen? 2 is cyclohexylmethyl; R1 is carboxyacetyl; R2 is hydrogen; R3 is phenethyl; R4 is hydrogen; R5 is hydrogen; and R5 and R6 together form oxo; that is, a compound that has the following structure:
It is called N- [ÍS- (benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl) -2-cyclohexylethyl] malonamic acid or N-. { (S) -1 - [(S) -1- (1-benzooxazol-2-yl-methanoyl) -3-phenyl-propyl carbamoyl] -2-cyclohexyl-ethyl} -malonamic; and a compound of Formula I wherein A is benzooxazol-2-yl; X2 is a group of Formula (a), wherein R9 is hydrogen and R12 is 2-nitrobenzylsulfonylmethyl; R1 is morpholin-2-ylcarbonyl; R2 is hydrogen; R3 is phenethyl; R4 is hydrogen; R5 is hydrogen; and R5 and R6 together form oxo; that is, a compound that has the following structure:
It is named N- [IR- (l £? -benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl) -2- (2-nitrobenzylsulfonyl) ethyl] morpholine -4 -carboxamide or morpholine-4-carboxylic acid [(R ) -1- [(S) -1 - (l-benzooxazol-2-yl-methanoyl) -3-phenyl-propylcarbamoyl] -2- (2-nitro-phenylmethanesulfonyl) -ethyl] -amide; and a compound of Formula I wherein A is benzooxazol-2-yl; X2 is a group of Formula (a), wherein R9 is hydrogen and R12 is benzylsulfonylmethyl; R1 is tetrahydropyran-4-yloxycarbonyl; R2 is hydrogen; R3 is phenethyl; R4 is hydrogen; R5 is hydrogen; and R5 and R6 together form oxo; that is, a compound that has the following structure:
It is named tetrahydropyran-4-yl IR- (lS-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl) -2-benzylsulfonylethyl carbamate or tetrahydro-pyran-4-yl ester of acid. { (R) -1- [S- l - (l-benzooxazol-2-yl-methanoyl) -3-phenyl-propylcarbamoyl] -2-phenylmethanesulfonyl-ethyl} -carbámico A compound of Formula I wherein A is pyrid-2-yl; X2 is a group of Formula (a), wherein R9 is hydrogen and R11 is 2-methylpropyl; R1 is benzyloxycarbonyl; R2, R4 and R5 each are hydrogen; R3 is phenethyl; and R6 is hydroxy; that is to say; a compound that has the following structure:
it is called benzyl- (lS-pyrid-2-ylcarbonyl-3-phenylpropylcarbamoyl) -3-methylbutylcarbamate or benzyl ester of acid. { (S) -1 - [(S) -1- (l-hydroxy-l-pyridin-2-yl-methyl) -3-phenyl-propylcarbamoyl] -3-methyl-butyl} -carbamic; and a compound of Formula I wherein A is thiazol-2-yl; X2 is a group of Formula (a) wherein R9 is hydrogen and R11 is 2-methylpropyl; R1 is 4-methylpiperazin-4-ylcarbonyl; R2 and R4 each are hydrogen; R3 is phenethyl; and R5 and R6 together form oxo; that is, a compound that has the following structure:
it is named N- [3-methyl-lS- (3-phenyl-l-thiazol-2-ylcarbonylpropylcarbamoyl) butyl] -4-methylpiperazine-l-carboxamide or 4-methyl-piperazine-l-carboxylic acid or. { (S) -3-methyl-l- [(S) -3-phenyl-l- (l-thiazol-2-yl-methanoyl) -propyl carbamoyl] -butyl} -amide; and a compound of Formula I wherein A is 4,5-tetrahydro-4-methoxycarbonyloxazol-2-yl; X2 is a group of Formula (a), wherein R9 is hydrogen and R11 is 2-methylpropyl; R1 is benzyloxycarbonyl; R2 and R4 are each hydrogen; R3 is phenethyl; and R5 and R6 together form oxo; that is, a compound that has the following structure:
It is called methyl 2S- (2S-benzyloxycarbonylamino-4-methylvalerylamino) -4-phenylbutyryl-4,5-dihydrooxazole-4-carboxylate or 2- (S) -2 - ((S) -2) methyl ester -benzyloxycarbonylamino-4-methyl-pennatanoylamino) -4-phenyl-butanoyl] -4,5-dihydro-oxazole-4-caborxyl ester. Certain compounds of Formula I exist in tautomeric equilibrium. Compounds of Formula I that exist as tautomers are named, illustrated or otherwise described in this application as a possible tautomer. However, it should be understood that all possible tautomers are intended to be included in these names, illustrations and descriptions. Certain compounds of Formulas I and II exist in tautomeric equilibrium. The compounds of Formulas I and II that exist as tautomers are named, illustrated or otherwise described in this application as a possible tautomer. However, it should be understood that all possible tautomers are intended to be included in these names, illustrations and descriptions. Administration and Pharmaceutical Compositions: In general, the compounds of Formula I will be administered in therapeutically effective amounts through 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, usually 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, usually 0.1 mg / day to 10 mg / day. In general, a person skilled in the art, acting on the basis of personal knowledge and the presentation of this Application, will be able to evaluate 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 through one of the following routes: oral, systemic (e.g., transdermal, intranasal or suppository) or parenteral (e.g., intramuscular, intravenous or subcutaneous). The compositions may take the form of tablets, pills, capsules, semisolids, powders, sustained-release formulas, solutions, suspensions, elixirs, aerosols, or any other suitable composition and generally consist of a compound of Formula I in combination with at least one pharmaceutically acceptable excipient. Acceptable excipients are non-toxic, aid administration, and do not adversely affect the therapeutic benefit of the active ingredient. This excipient can be any solid, liquid, semi-solid or, in the case of an aerosol composition, a gaseous excipient which is generally available to a person skilled in the art. Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dry skim milk , and similar. Liquid and semi-solid excipients may be selected from water, ethanol, glycerol, propylene glycol and various oils, including those of petroleum, animal, vegetable or synthetic origin (eg, peanut oil, soybean oil, mineral oil, oil sesame, or similar). Preferred liquid carriers, in particular 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 formula, the size of a dosage unit, the type of excipients and other factors known to persons trained in the pharmaceutical sciences technique. In general, a composition of a compound of Formula I for treating a given disease will include 0.01% by weight to 10% by weight, preferably 0.3% by weight to 1% by weight, of the active ingredient with the remainder being the excipient or excipients Preferably, the pharmaceutical composition is administered in a single unit dosage form for continuous treatment or in a single dosage unit form ad libitum when symptom relief is specifically required. The compounds of Formula I can be administered alone or in combination with other compounds of Formula I or in combination with one or more active ingredients. For example, the compounds of Formula I can be administered in combination with a therapeutically active amount of a bisphosphonic acid or an acid ester derivative or any pharmaceutically acceptable salt thereof. Suitable bisphosphonic acids and acid ester derivatives include compounds corresponding to the following formula:
where X11 is a bond or (C? _7) alkylene, each R43 is independently hydrogen or (C? -30) alkyl, R44 and R45 are independently selected from a group consisting of hydrogen, halo, (C? -30) substituted alkyl optionally (C3-30) cycloalkyl, hetero (C5-3o) cycloalkyl, (C6-? o) optionally substituted aryl, hetero (C6-? o) aryl, -NR46R46, -OR46, -SR46, wherein each R46 is independently hydrogen, (C? _? 0) alkyl, (C3-10) cycloalkyl, (C6-? o) optionally substituted aryl, as long as both R44 and R45 are not selected from hydrogen or hydroxy when X11 is a bond; or R44 and R45 taken together form (C2-g) alkylene; where (C3-? 0) cycloalkyl include adamantyl and the like, hetero (C5-10) cycloalkyl includes pyrrolidinyl and the like, (C6-? o) aryl includes phenyl and naphthyl, and hetero (C6-? o) aryl includes quinolyl, isoquinolyl , pyridyl, furyl, imidazolyl, imidazopyridyl and the like. The cases in which R44 and / or R45 are substituted by (C1-30) alkyl may include, but are not limited to, (C? -30) alkyl substituted by hetero (C5-10) cycloalkyl, (C6-? O) aryl, hetero (C6-? o) aryl, -NR47R47, -OR47 and -SR47, wherein each of R47 is independently hydrogen or (C1-10) alkyl; where the hetero (C5-10) cycloalkyl includes pyrrolidinyl and the like, (C-1-yl) aryl includes phenyl and naphthyl, and hetero (C6-? o) aryl includes quinolyl, isoqiunolyl, pyridyl, furyl, imidazolyl, imidazopyridyl and the like. Suitable optionally substituted aryl groups include, but are not limited to, phenyl substituted by halo. A non-limiting class of bisphosphonic acids and acid ester derivatives thereof suitable for administration in combination with the compounds of Formula I, include those in which R44 are selected from the group consisting of hydrogen, hydroxy or halo, and R45 is selects from the group consisting of (C? -30) optionally substituted alkyl, halo and -SR46, where -SR46 is (C? -? 0) alkyl or phenyl. A non-limiting subclass of bisphosphonic acids and acid ester derivatives thereof suitable for administration in combination with the compounds of Formula I, include those in which R44 are selected from the group consisting of hydrogen, hydroxy and chlorine and R45 is selected of the group consisting of (C? -30) optionally substituted alkyl, chloro and chlorophenylthio. A non-limiting example of a bisphosphonic acid suitable for administration in combination with compounds of Formula I includes that wherein X 11 is a bond, each R 43 is hydrogen, R 44 is hydroxy and R 45 is 3-aminopropyl, mainly 4-amino acid. l-hydroxybutylidene-1, 1-bisphosphonic acid (aca-alendronic acid), or the monosodium trihydrate salt thereof, mainly monosodium trihydrate of 4-amino-1-hydroxybutylidene-1, 1-bisphosphonate (monosodium trihydrate from here alendronate), described in United States of America Patents Nos. 4,922,007, to Kieczykowski et al., issued May 1, 1990; 5,019,651, to Kieczykowski et al., Issued May 28, 1991; 5,510,517, for Dauer et al., Issued April 23, 1996; 5,648,491, to Dauer et al., Issued July 15, 1997, all of which are incorporated by reference herein in their entirety. Additional non-limiting examples of bisphosphonic acids suitable for administration in combination with compounds of Formula I include the following: cycloheptylaminomethylene-1,1-bisphosphonic acid (acide cimadronic acid), described in U.S. Patent No. 4,970,335 , for Isomura et al., issued on November 13, 1990; 1, 1-dichloromethylene-1, 1-diphosphonic acid (clodronic acid) and the disodium salt thereof, mainly disodium clodronate, described in Belgian Patent Number 672,205 (1996) and Organic Chemistry Bulletin 32,4111
(1967); 1-Hydroxy-3-pyrrolidin-1-ylpropylidene-1,1-bisphosphonic acid (here EB-1053); 1-hydroxyethylidene-1, 1-diphosphonic acid (etidronic acid);
L-hydroxy-3- (N-methyl-N-pentylamino) propylidene-1,1-bisphosphonic acid (ibandronic acid), described in United States Patent Number 4,927,814, issued May 22, 1990; 6-Amino-l-hydroxyhexylidene-l, 1-bisphosphonic acid
(here acid neridrónico); 3- (Dimethylamino) -1-hydroxypropylidene-1, 1-bisphosphonic acid (olpadromal acid); 3-amino-l-hydroxypropylidene-1, 1-bisphosphonic acid (here pamidronic acid); 2-pyrid-2-ylethylidene-1, 1-bisphosphonic acid (pyridronic acid here), described in U.S. Patent No. 4,761,406; L-hydroxy-2-pyrid-3-ylethylidene-1, 1-bisphosphonic acid (risedronic acid here); 4-Chlorophenylthiomethylenebisphosphonic acid (acetyludonic acid), described in U.S. Patent No. 4,876,248, to Breliere et al., October 24, 1989; and l-hydroxy-2- (1H-imidazol-1-yl) ethylidene-1,1-bisphosphonic acid (zoledronic acid); and all of these patents and other documents referred to above are incorporated by reference herein in their entirety. A non-limiting subclass of bisphosphonic acids suitable for administration in combination with the compounds of Formula I includes those selected from the group consisting of alendronic acid, cimadronic acid, clodronic acid, tiludronic acid, etidronic acid, ibandromic acid, risedronic acid, acid pyridronic acid, pamidronic acid, solendronic acid, pharmaceutically acceptable salts thereof and mixtures thereof. A further example of a bisphosphonic acid suitable for administration in combination with the compounds of Formula I is alendronic acid or a pharmaceutically acceptable salt thereof, and mixtures thereof. An additional non-limiting example is the monosodium trihydrate of alendronate. The compounds of Formula I can be administered in combination with a therapeutically active amount of an estrogen receptor agonist. Non-limiting examples of estrogen receptor agonists suitable for administration in combination with compounds of Formula I include naturally occurring estrogens such as estradiol, estrone and estroil, or synthetic estrogen receptor agonists such as [6-hydroxy-2] - (4-hydroxyphenyl) benzo [b] thien-3-yl] [4- (2-piperidin-1-ylethoxy) phenylmethanone (here raloxifene) and. { 2- [4- (1, 2-diphenylbut-1-enylphenoxy] ethyl] dimethylamine (here tamoxifen) A non-limiting subclass of estrogen receptor agonists suitable for administration in combination with the compounds of Formula I include agonites estrogen receptor partial (ie, estrogen receptor agonists with mixed agonist / antagonist properties), sometimes referred to as estrogen receptor modulators, partial estrogen receptor agonists may exert tissue-selective estrogen agonist effects. example, it selectively exerts an estrogen agonist effect on bones in humans.Any additional adequate estrogen receptor agonists are described in Tissue-Selective Actions of Estrogen Analogs (Selective Actions of Estrogen Analog Tissues), Bones Volume 17, Number 4, October 1995, 181S-190S, Cer 3- [4- (2-phenylindol-1-ylmethyl) phenyl] acrylamides, from filed in U.S. Patent Number 5,985,910 to Miller et al., November 16, 1999; benzotifen compounds, described in U.S. Patent Number 5,985,897 to Meuhl et al., November 16, 1999; naphthyl compounds, described in U.S. Patent Number 5,952,350 to Cullinan et al., September 14, 1999; substituted benzothiophene compounds, described in U.S. Patent No. 5,962,475 to Schmid et al., October 4, 1999, are partial estrogen receptor agonists suitable for administration of the compounds of Formula I; All of these patents and other documents referred to above are incorporated by reference herein in their entirety. More particularly, a pharmaceutical composition of this invention can include a therapeutically effective amount of a compound of Formula I in combination with one or more active ingredients selected from the group consisting of (i) a therapeutically effective amount of a bisphosphonic acid or a acid ester thereof, or a pharmaceutically acceptable salt thereof and (ii) a therapeutically effective amount of an estrogen receptor agonist or a pharmaceutically acceptable salt thereof; and one or more pharmaceutically acceptable excipients. Non-limiting examples of these bisphosphonic acids include 1,1-dichloromethylene-1,1-diphosphonic acid, 1-hydroxy-3-pyrrolidin-1-ylpropylidene-1,1-bisphosphonic acid, 1-hydroxyethylidene-1-hydroxyethylidene, 1- diphosphonic, 1-hydroxy-3- (N-methyl-N-pentylamino) propylidene-1,1-bisphosphonic acid, 6-amino-l-hydroxyhexylidene-1, 1-bisphosphonic acid, 3- (dimethylamino) -1- acid hydroxypropylidene-1, 1-bisphosphonic acid, 3-amino-l-hydroxypropylidene-1, 1-bisphosphonic acid, 2-pyrid-2-ylethylidene-1, 1-bisphosphonic acid, l-hydroxy-2-pyrid-3-ylethylidene -l, 1-bisphosphonic acid, 4-chlorophenylthiomethylenebisphosphonic acid and l-hydroxy-2- (li? -imidazol-1-yl) ethylidene-1,1-bisphosphonic acid or an ester of the acid thereof or a pharmaceutically acceptable salt thereof. the same; in particular 1, 1-dichloromethylene-1,1-diphosphonic acid or a pharmaceutically acceptable salt thereof, and preferably 1,1-dichloromethylene monosodium trihydrate
-1, 1-diphosphonate. Chemistry: esses for Making Compounds of Formula I: Compounds of Formula I wherein R5 and R6 together form oxo can be prepared eeding according to the following Reaction Scheme 1:
wherein n, A, X ^ X2, R1, R2, R3, R4, R7 and R8 are in accordance with that defined in the Summary of the Invention for Formulas I and II.
The compounds of Formula I wherein R5 and R6 together form oxo (Formula I (a)) can be prepared by reacting an organometallic compound of Formula 2 with a compound of Formula 3. The reaction is carried out in a suitable solvent (e.g., tetrahydrofuran (THF), ether, or the like) at -80 to -70 ° C, preferably at about -78 ° C, and requires 30 minutes to one hour to complete. The organometallic compound of Formula 2 is generated by treating a corresponding organo compound, or a brominated derivative thereof, with n-butyl lithium or tert-butyl lithium in a suitable solvent (e.g., THF, ether, or the like) a - 80 at -70 ° C, preferably at about -78 ° C, for about 30 minutes to one hour. The compounds of Formula I wherein the ring formed by X 1 is a 4,5-tetrahydrooxazol-2-yl or oxazol-2-yl or its half, R 5 is hydrogen and R 6 is hydroxy can be prepared eeding according to the following Scheme of Reaction 2: Reaction Scheme 2
wherein X ^ R ^ R ^ R ^ R ^ R7 and R8 are in accordance with that defined in the Summary of the Invention for Formulas I and II. The compounds of Formula I can be prepared by reacting a compound of Formula 4 with a compound of Formula 5 (a). The reaction is carried out in a suitable solvent (for example, chloroform, ethanol, or the like) at reflux temperatures and requires 3 to 24 hours to complete. Similarly, using reaction conditions analogous to those described in Reaction Scheme 1, compounds of Formula I wherein A is a heteropolycyclic radical where X 1 is a ring member atom of an oxazole ring, R 5 is hydrogen and R6 is hydroxy, they can be prepared by reacting a compound of the Formula 4 with a compound of the Formula 5 (b):
wherein n is 0, 1, 2 or 3 and B is a heteromonocyclic radical containing from 5 to 6 ring member atoms or a fused heteropolycyclic radical containing from 8 to 11 ring member atoms, wherein each ring contains from 5 to 7 ring member atoms and each ring member atom is a carbon atom or a heteroatom, and R7 and R8 are as defined in the Summary of the Invention for Formulas I and II. The compounds of Formula I can be prepared by eeding according to the following Reaction Scheme 3: Reaction Scheme 3
l.R ^ OY 2. Optionally unective
wherein Y is hydrogen or an activation group (eg, 2,5-dioxopyrrolidin-1-yl (NBS), or the like) and n, and R 8 are as defined in the Summary of the Invention for Formulas I and II. The compounds of Formula I can be prepared by reacting a compound of Formula 6, or a ected derivative thereof, with a compound of formula RxX2OY, or a ected derivative thereof, and then, optionally, deecting. The reaction is carried out in the presence of a suitable base (e.g., triethylamine, diisoylethylamine, or the like) and in a suitable solvent (e.g., acetonitrile, N, N-dimethylformamide (DMF), dichloromethane, or any suitable combination of these, or similar) at 10 to 30 ° C, preferably at about 25 ° C, and requires 24 to 30 hours to complete. When Y is hydrogen, a suitable coupling agent is required
(eg, benzotriazole-1-yloxytryris pyrrolidinophosphonium hexafluorophosphate (PyBOP®), 1- (3-dimethyl aminoyl) -3-ethylcarbodiimide hydrochloride (EDC), 0-benzotriazol-1-yl-N / N / N hexafluorophosphate ,, N, -tetramethyluronium (HBTU), 0- (7-azabenzotriazol-1-yl) -1, 1,3,3-tetramethyluronium hexafluorophosphate (HATU), 1,3-dicyclohexylcarbodiimide (DCC), or similar) and base (e.g., N, N- diisopropylethylamine, triethylamine, or the like) and the reaction requires 2 to 3 hours to complete. The deprotection can be effected by any means which removes the protecting group and provides the desired product in a reasonable production. A detailed description of the applicable techniques for the creation of protective groups and their removal can be found in T.W. Greene, Protecting Groups in Organic Synthesis (Protective Groups in Organic Synthesis), John Wiley & amp;; Sons, Inc. 1981. Detailed descriptions of the preparation of a compound of Formula I in accordance with Reaction Scheme 3 are specified in Examples 8, 9, 10 and 12, below. The compounds of Formula I can be prepared proceeding as indicated in the following Reaction Scheme: Reaction Scheme 4
wherein R39 is -X7X8R20 and n, x \ x2, X7, X8, R1, R2, R3, R4, R7, R8 and R20 are in accordance with that defined in the Summary of the Invention for Formulas I and II. Additional Processes for Preparing Compounds of Formula I: Compounds of Formula I wherein A is optionally substituted oxazol-2-yl can be prepared by oxidizing a corresponding compound of Formula I wherein A is 4,5-dihydrooxazol-2-yl . The reduction is carried out in the presence of a base (e.g., 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), 1,5-diazabicyclo [3.4.0] non-5-ene (DBN), or similar) in a suitable solvent (for example, dichloromethane, or the like) at 20-25 ° C and requires 6 to 12 hours to complete. The compounds of Formula I wherein R7 is -C (0) OH can be prepared from a corresponding compound of Formula I wherein R7 is methoxycarbonyl. The conversion can be effected by treating the methyl ester with sodium hydroxide in a suitable solvent (eg, ethanol, or the like) at 20-25 ° C and requires 6 to 12 hours to complete. Compounds of Formula I wherein R7 is -C (0) NR42CHR43C (O) OR29, can be prepared by reacting a corresponding compound of Formula I wherein R7 is -C (O) OH with a compound of formula NHR20R21 or NHR42CHR43C (O) OR29, respectively. The reaction is carried out in the presence of a suitable coupling agent (PyBOP®, EDC, HBTU, DCC, or the like) and base (for example, N, N-diisopropylethylamine, triethylamine, or the like) in a suitable solvent ( for example, DMF, or similar) at 20-25 ° C and requires 2 to 4 hours to complete. The compounds of Formula I wherein R1 is -X6X7R20, can be prepared by reacting a compound of Formula I wherein R1 is hydrogen with a compound of the formula R20X7X6OH. The reaction is carried out by analogous procedures to those described above to carry out the Reaction of Reaction Scheme 3. Compounds of Formula I wherein R5 and R6 together form oxo, can be prepared by oxidizing a compound of the Formula I wherein R5 is hydrogen and R6 is hydroxy. Oxidation can be carried out with a suitable oxidizing agent (for example, Dess-Martin periodinate or the like) in a suitable solvent (for example, dichloromethane, or the like) at 15-25 ° C and requires 10 to 20 hours for complete. Compounds of Formula I wherein R12 contains a sulfonyl moiety can be prepared by oxidizing a corresponding compound of Formula I containing a sulfonyl moiety. The oxidation is carried out with a suitable oxidizing agent (for example, potassium peroxymonosulfate (OXONE®, or the like) in a suitable solvent (for example, methanol, water, or the like, or any suitable combination thereof) at temperature It requires 16 to 24 hours to complete a compound of Formula I wherein A is 1,1-dioxo-1H-Iα6-benzo [£>] thien-2-yl can be prepared by oxidizing a corresponding compound of Formula I wherein A is benzo [b] thien-2-yl. Continuing in this manner, benzyl 1- [1- (1,1-dioxo-ltf-l6-benzo [b] thienyl) was prepared 2-ylcarbonyl-3-phenylpropyl carbamoyl] -3-methylbutylcarbamate (Compound 209). "" NMR (CDC13): d 0.83-0.95 (m, ßH), d 1.35-1.52 (m.hour), d 1.61 - 1.69 (m.2H), d 2.07-2.20 (m, 1H), d 2.36-2.71 (m, 3H), d 4.57 (m, 1H), d 4.76 (m, 1H), d 4.98-5.26 (m, 3H) ), d 5.35 (bs, 1H), d 7.06-7.62 (m, 14H): A compound of Formula I can be prepared as an acid addition salt pharmaceutically acceptable by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic 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 inorganic or organic base. Suitable inorganic and organic bases and acids for the preparation of pharmaceutically acceptable salts of the compounds of Formula I are specified in the definitions section of this Application. Alternatively, the salt forms of the compounds of Formula I can be prepared using salts of the initial or intermediate materials. The free acid or free base forms of the compounds of Formula I can be prepared from the form of the acid addition salt or the corresponding base 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 with a suitable base
(for example, solution of ammonium hydroxide, sodium hydroxide, or the like). A compound of Formula I in a base addition salt form can be converted to the corresponding free acid by treating 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 skilled in the art. For example, the N-oxides can be prepared by treating a non-oxidized form of the compound of the Formula I with an oxidizing agent (for example, trifluoroperacetic acid, permaleic acid, perbenzoic acid, peracetic acid, meta-chloroperoxybenzoic acid, or the like) in a suitable inert organic solvent (eg, a halogenated hydrocarbon such as, for example, dichloromethane) 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 the N-oxides of compounds of Formula I by treating with a reducing agent (for example, sulfur, sulfur dioxide, triphenylphosphine, lithium borohydride, sodium borohydride). , phosphorus trichloride, tribromide, or the like) in a suitable inert organic solvent) eg, acetonitrile, ethanol, aqueous dioxane or the like) at 8-80 ° C. Derivatives of prodrugs of the compounds of Formula I can be prepared by methods known to those skilled in the art (for example, for more details see Saulnier et al. (1994), Bioorganic and Medicinal Chemistry Letters). Medicinal) 4: 1985). For example, suitable prodrugs can be prepared by reacting a non-derivatized compound of Formula I with a suitable carbamylating agent (e.g., 1,1-acyloxyalkylcarbonylhydrate, para-nitrophenyl carbonate, or the like). The protected derivatives of the compounds of Formula I can be prepared by means known to those skilled in the art. A detailed description of the applicable techniques for the creation of protective groups and their removal can be found in T.W. Greene, Protectingr Groups in Organic Synthesis (Protective Groups in Organic Synthesis), John Wiley & 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 diastereoisomers and recovering the optically pure enantiomer. . Although resolution of the enantiomers can be carried out using covalent diastereomeric derivatives of the compounds of Formula I, dissociable complexes are preferred (e.g., crystalline diastereoisomeric salts). The diastereoisomers have different physical properties (e.g., melting points, boiling points, solubilities, reactivity, and the like) and can be easily separated by taking advantage of these differences. The diastereoisomers can be separated by chromatography or, preferably, by separation / resolution techniques based on differences in solubility. The optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that does not result in racemization. A more detailed description of the techniques applicable for the resolution of stereoisomers of compounds from their racemic mixture can be found in Jean Jacques Andre Collet, Samuel H. Wilen, Enantiomers, Racemates and Resolutions, John Wiley & Sons, Inc. (1981). In summary, one aspect of the invention is a process for preparing a compound of Formula I, which process includes: (A) reacting an organometallic compound of Formula 2:
with a compound of Formula 3:
where n, A, X ^ X2, R1, R2, R3, R4, R7 and R8 are in accordance with that defined in the Summary of the Invention for Formulas I and II, to provide a compound of Formula I wherein
R5 and R6 together form oxo;
(B) reacting a compound of Formula 4
with a compound of Formula 5 (a) or 5 (b)
wherein the dashed line represents an optional bond and B is a monocyclic radical containing from 5 to 6 ring member atoms or a fused polycyclic radical containing from 8 to 11 ring members, where each ring contains from 5 to 7 atoms members of the ring and each atom member of the ring is a carbon atom or a heteroatom and n, R1, R2, R3, R4, R7 and R8 are in accordance with that defined in the Summary of the Invention for Formulas I and II, for provide a compound of Formula I wherein the ring formed by X1 is a 4,5-tetrahydroozaxol-2-yl or oxazol-2-yl or its half, respectively, R5 is hydrogen and R6 is hydroxy or (C) is reaction a compound of Formula 6: with a compound of the Formula R1X2OY, where Y is hydrogen or an activation group and n, ^^ X2, R1, R2, R3, R4, R7 and R8 are as defined in Summary of the Invention for Formulas I and II, to provide a compound of Formula I in wherein R5 is hydrogen and R6 is hydroxy; or (D) reacting a compound of Formula 7:
7 or a protected derivative thereof, with R39OH, wherein R39 is -X7X8R20 and n, A, X1, X2, X7, X8, R2, R3, R4, R7 and R20 are as defined in the Summary of the Invention for Formulas I and II, and deprotection if necessary, to provide a compound of Formula I wherein R1 is -X7X8R20, (E) optionally oxidizing a compound of Formula I wherein R5 is hydrogen and R6 is hydroxy providing a compound of Formula I wherein R5 and R6 together form oxo;
(F) optionally oxidizing a compound of Formula I wherein A is 4,5-dihydroxyoxazol-2-yl optionally substituted to provide a compound of Formula I wherein A is optionally substituted oxazol-2-yl; (G) optionally converted to a compound of Formula I wherein R7 is -C (0) OH to a compound of Formula I wherein R7 is methoxycarbonyl; (H) optionally converted to a pharmaceutically acceptable salt of a compound of Formula I; (I) optionally converted to a salt form of a compound of Formula I to a non-salt form; (J) optionally converted to a non-oxidized form of a compound of Formula I to a pharmaceutically acceptable N-oxide; (K) optionally converted to an N-oxide form of a compound of Formula I to its non-oxidized form; (L) optionally converted to a compound not derived from the
Formula I to a pharmaceutically prodrug derivative; Y
(M) optionally converted to a prodrug derivative of a compound of Formula I to its non-derivatized form. Processes for Preparing Intermediates: Compounds of Formula 3 can be prepared by reacting a compound of Formula 8: 8 with a compound of the formula R ^ OY, wherein Y is hydrogen or an activation group (NBS, or the like) . The reaction is carried out under conditions analogous to those specified for Reaction Scheme 3. Compounds of Formula 3 can be prepared by reacting a corresponding protected amino carboxylic acid with N, O-dimethylhydroxylamine hydrochloride and then deprotecting them. The reaction with the amine is carried out in the presence of a suitable coupling agent (PyBOP®, EDC, HBTU, DCC, or the like) and base (for example, N / N-diisopropylethylamine, triethylamine, or the like) in a solvent suitable) for example, dichloromethane, DMF, or the like) at 20-30 ° C, preferably at about 25 ° C, and requires 2 to 4 hours to complete (for example, see Reference 1, below). The deprotection can be carried out by any means which removes the protecting group and provides the desired product in reasonable production (for example, see Example 2, below). A detailed description of the preparation of a compound of Formula 8 is specified in References 1 and 6, below.
The compounds of Formula 4 can be prepared by reacting a nitrile of Formula 9:
with ethanol The reaction is carried out by adding the nitrile to a mixture formed by a catalytic amount of dry hydrogen chloride in a suitable solvent (for example, chloroform, ethanol or the like) and then allowing the reaction to continue at 0-25 ° C for 4 to 6 hours. Dry hydrogen chloride is conveniently generated by combining a slightly excessive amount of ethanol with acetyl chloride before adding the imidate to the reaction mixture. Alternatively, the hydrogen chloride is introduced into the reaction medium as a gas. The compounds of Formula 6 can be prepared by methods known to those skilled in the art. For example, compounds of Formula 6 wherein A is optionally substituted benzooxazol-2-yl can be prepared by reacting a compound of Formula 10:
wherein R40 is a protecting group, with 2-aminophenol and with deprotection. The reaction with the phenol is carried out in the presence of a suitable base (for example, diisopropyleethylamine, triethylamine, or the like) and in a suitable solvent (for example, chloroform, or the like) at reflux temperatures at 25 ° C and requires 10 to 12 hours to complete. The deprotection can be carried out by any means which removes the protecting group and provides the desired product in a reasonable production. A detailed description of the preparation of a compound of Formula 6 is specified in reference, below. The compounds of Formula 7 can be prepared by condensing a compound of Formula 6 with a compound of Formula R40X2OY, wherein R40 is a protecting group, and then with deprotection. The condensation is carried out in the presence of a suitable base (e.g., triethylamine, diisopropylethylamine, or the like) and in a suitable solvent (e.g., acetonitrile, DMF, dichloromethane, or any suitable combination thereof, or the like) to 10-30 ° C, preferably at approximately 25 ° C, and requires 24 to 30 hours to complete. When Y is hydrogen, a suitable coupling agent (e.g., PyBOP®, EDC, HBTU, HATU, DCC, or the like) and a base (e.g., N, N-diisopropylethylamine, triethylamine, or the like) and the reaction requires 2 to 3 hours to complete. The deprotection can be carried out by any means that eliminates the protection group and provides the desired group in a reasonable production. The following abbreviations used in this
Application are required as follows: PyBOP® = benzotriazole-1-yloxytris pyrrolidinophosphonium hexafluorophosphate THF = tetrahydrofuran; OXO? E® = potassium peroxymonosulfate; EDC = 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride; DMF = N, N-dimethylformamide; HATU = O- (7-azabenzotriazol-1-yl) -1, 1,3,3-tetramethyluronium hexafluorophosphate; HOBT = 1-hydroxybenzotriazole hydrate. REFERENCE 1 Benzyl ß- (N-methoxy-N-methylcarbamoyl) -3-phenylpropylcarbamate A solution of 2-benzyloxycarbonylamino-4-phenylbutyric acid (5.05 g, 16.1 mmol) in dichloromethane (70 mL) was cooled to 0 ° C and dried. treated with diisopropylethylamine (2.82 mL,
16. 2 mmol) added as drops and then PyBOP® (8.53 g, 16.4 mmol) added in one portion. The mixture was stirred for 5 minutes and then treated with N, 0-dimethylhydroxylamine hydrochloride (1.73 g, 17.71 mmol) in one portion. The mixture was neutralized with diisopropylethylamine
(4.6 mL, 26.44 mmol) added as drops, stirred for 2 hours at room temperature and then diluted with dichloromethane (70 mL). The dilution was washed sequentially with IN aqueous hydrochloric acid (3x 40 mL), saturated sodium bicarbonate (3x 40 mL) and brine (40 mL) and then concentrated. The product was purified from the residue by column chromatography eluting with 2: 3 ethyl acetate / hexane to provide benzyl- (N-methoxy-N-methylcarbamoyl) -3-phenylpropylcarbamate (5.48 g, 15.4 mmol) as an oil . MS (PCI) m / z = 357 (M + 1). Proceeding as in Reference 1, tert-butyl-1S- (N-methoxy-N-methylcarbamoyl) -3-phenylpropyl carbamate was provided.; XH? MR (CDC13): d 1.35 (s, 9H), d 1.64-1-72 (m, 2H), d 2.40-2.54 (m, 1H), d 2.60-2.77 (m, 1H), d 3.00 (d, s, 3H) 3.52 (s, 3H), d 4.23 (m, 1H), d 7.10-7.37 (m, 5H). REFERENCE 2 3- (2-Cyanobenzylsulfonyl) -2R-pyrid-4-i1carbonylaminopropionic acid A mixture of isonicotinic acid (3 g), N-hydroxysuccinimide (2.79 g) and N, N-dicyclohexylcarbodiimide (5.52 g) was stirred in THF (200 g). mL) for 16 hours. The solid was filtered and the solvent was evaporated under reduced pressure. The residue was triturated with ethyl acetate and filtered more solid. The filtrates were concentrated under reduced pressure and 2,5-dioxopyrrolidin-1-yl isonicotinate (5.27 g) was provided. MS: 221 [MH] +. A solution of L-cysteine (6 g) in ethanol (57 mL) was treated sequentially with 2? of aqueous sodium hydroxide solution (30 mL) and 2-bromomethylbenzonitrile (9.71 g). The reaction mixture was stirred for 2 hours at room temperature, then neutralized by the addition of concentrated hydrochloric acid. The resulting solid was collected by filtration and washed sequentially with water, ethanol and diethyl ether to give 2R-amyrodio-3- (2-cyanobenzylsulfaphyl) propionic acid as a white solid. MS: 237 [MH] +. MS: 235 [M]. "A solution of 2R-amino-3- (2-cyanobenzyl sulfaphyl) propionic acid (590 mg) in dichloromethane was treated with 2,5-dioxopyrrolidin-1-yl isonicotinate (1.41 g) and diisopropylmethylamine. (0.435 mL) The reaction mixture was stirred for 6 hours and then concentrated The residue was treated with water and the resulting insoluble solid was filtered The aqueous filtrate was extracted twice with ethyl acetate and the combined extracts were filtered. dried over magnesium sulfate and then concentrated to give 3- (2-cyanobenzylsulfonyl) -2R-pyrid-4-ylcarbonylaminopropionic acid (340 mg) as a gum MS: 342 [MH] + HPLC: RT = 10.63 minutes REFERENCE 3 3-Benzylsulfonyl-2R-tetrahydropyran-4-yloxycarbonylaminopropionic acid A solution of tetrahydropyran-4-ol (200 mg) in acetonitrile (5 mL) was treated with bis (2,5-dioxocyclopentyl) carbonate (0.753 g) and triethylamine ( 0.81 mL) The reaction mixture was stirred for 4 hours at room temperature. ental and then concentrated. The residue was dissolved in ethyl acetate and the solution was washed with a saturated solution of sodium carbonate, dried over magnesium sulfate and then concentrated to give 2,5-dioxo-pyrrolidin-1-yl tetrahydropyran-4-yl. carbonate. A solution of 2R-amino-3-benzylsulphane propionic acid (1 g) and triethylamine (0.8 mL) in dichloromethane (40 mL) was treated with 2,5-dioxo-pyrrolidin-1-yl tetrahydro-pyran-4-yl carbonate (1.15 g). The mixture was stirred for 16 hours at room temperature and then concentrated. The residue was dissolved in ethyl acetate and the solution was washed sequentially with hydrochloric acid and brine, dried over magnesium sulfate and then concentrated. The residue was subjected to flash column chromatography on silica eluting with a mixture of ethyl acetate and pentane (1: 1, v / v) to give 3-benzylsulfonyl-2R-tetrahydropyran-4-yloxycarbonylaminopropionic acid (800 mg) as oil. REFERENCE 4 3-Benzylsulfanyl-2R-morpholin-4-ylcarbonylaminopropionic acid A solution of 3-benzylsulfanyl-2R-aminopropionic acid hydrochloride (25 g, 0.118 mol) in 2N sodium hydroxide (59 mL, 0.118 mol) was cooled in an ice bath and then treated simultaneously with morpholine-4-carbonyl chloride (13.8 mL, 0.118 mol) and 1? of sodium hydroxide (118 mL, 0.118 mol). The mixture was stirred at 0 ° C for 30 minutes and then filtered. The filter was acidified with 5? of hydrochloric acid and extracted with ethyl acetate (5x 100 mL). The combined extracts were dried (MgSO 4), filtered and concentrated to give 3-benzylsulfanyl-2R-morpholin-4-ylcarbonyl aminopropionic acid (19.65 g, 60.6 mmol) as a white solid. REFERENCE 5 3-Benzylsulfonyl-2R-morpholin-4-ylcarbonyl aminopropionic acid A solution of 3-benzylsulfanyl-2R-morpholin-4-ylcarbonylaminopropionic acid (17.58 g, 54.2 mmol), provided as in Reference 4, in methanol (550 mL) was treated with a solution of OXONE® (50 g, 81.4 mL) in water (550 mL). The mixture was stirred at room temperature for 2 hours and then concentrated to dryness. The residue was taken up in water (90 mL) and ethyl acetate (600 mL). The mixture was vigorously stirred and the aqueous layer was separated and extracted with ethyl acetate (2x100 mL). The combined layers of ethyl acetate were dried (MgSO) and concentrated. The residue was triturated with diethyl ether and the solid material was collected by filtration to provide. { 3-benzylsulfonyl-2R-morpholin-4-ylcarbonyl aminopropionic acid REFERENCE 6 2-Amino-N-methoxy-N-methyl-4-phenylbutyramide trifluoroacetic acid salt A solution of tere-butyl 1- (N-methoxy-N-methyl) carbamoyl) -3-phenylpropylcarbamate (9.32 g, 29 mmol), provided as in Reference 1, in dichloromethane (100 mL) was cooled to 0 ° C and then treated with anisole (5 mL, 46.5 mmol) and trifluoroacetic acid ( 50 mL, 296 mmol). The mixture was stirred for 30 minutes, while allowing it to warm to room temperature, and then concentrated. The residue was dissolved in toluene (100 mL) and the solution was concentrated. The residue was dissolved once more in toluene (100 mL) and concentrated to give 2-amino-N-methoxy-N-methyl-4-phenylbutyramide trifluoroacetic acid salt (9.74 g 29 mmol) as the crude product. MS (PCI) m / z = 223 (M + 1).
REFERENCE 7 Ethyl 3S-benzyloxycarbonylamino-2-hydroxy-5-phenylpentanimidate
A suspension formed by lithium aluminum hydride
(0.885 g, 23.3 mmol) in anhydrous diethyl ether was cooled to -45 ° C under nitrogen and then treated with a solution of benzyl- (N-methoxy-N-methylcarbamoyl) -3-phenylpropylcarbamate.
(5.53 g, 15.53 mmol), provided as in Reference 1, in ether (75 mL) and THF (25 mL) added dropwise over a period of 30 minutes such that the temperature of the mixture was maintained at -40 to -45 ° C. The mixture was allowed to warm to 5 ° C and then cooled again to -35 ° C. A saturated solution of sodium bicarbonate (7 mL, 0.5 M) was added in the form of drops and the mixture was allowed to warm to 0 ° C. The mixture was allowed to warm to room temperature and was stirred for 1 hour to provide a precipitate. The precipitate was collected by filtration and washed with ether (100 mL). The filtrate and the washings were combined and washed sequentially with 1? of cold hydrochloric acid on ice (2x 50 mL); saturated sodium bicarbonate (2 x 50 mL) and brine (50 mL), dried (? a2S04) and concentrated in vacuo to give benzyl lS-formyl-3-phenylpropylcarbamate
(4.01 g, 13.5 mmol) as a colorless oil. MS (PCI) m / z = 298
(M + 1)
A solution of benzyl lS-formyl-3-phenylpropyl carbamate (4.557 g, 15.3 mmol) in anhydrous dichloromethane (50 mL) was stirred while sequentially treated with 2-hydroxy-2-methylpropionitrile (4.25 mL, 46.2 mmol) and triethylamine ( 1.28 mL, 9.20 mmol). The mixture was stirred for 4 hours at room temperature and concentrated in vacuo. The residue was dissolved in ether (100 mL) and the solution was washed sequentially with water (5 x 20 mL) and brine (20 mL), dried (MgSO 4) and concentrated to give benzyl 2-cyano-2-hydroxy-3-hydroxypropyl ether. lS-phenethylethylcarbamate (4.957 g, 15.3 mmol) as yellow oil, d 1.75-2.01 (m, 2H), d 2.08-2.24 (m, 1H), d 2.51-2.80 (m, 2H), d 3.70-4.02 (m , 1 H), d 5.07, d 5.33 (m, 3H), d 7.10 - 7.47 (m, 10H). A mixture of chloroform (30 mL) and anhydrous ethanol (30 mL, 510 mmol) was cooled to 0 ° C and then treated with acetyl chloride (32.6 mL, 459 mmol) added as drops over a period of 30 minutes . The mixture was cooled by adding a solution of crude benzyl 2-cyano-2-hydroxy-1S-phenethylethylcarbamate (4.957 g, 15.3) in chloroform (30 mL). The mixture was stirred for 2 hours at 0 ° C and then 6 hours at room temperature and concentrated in vacuo to give ethyl 3S-benzyloxycarbonylamino-2-hydroxy-5-phenylpentanimidate (6.212 g 15.3 mmol) as a crude yellow oil. MS (PCI) m / z = 371 (M + 1). REFERENCE 8 2 S-amino-4-pheny1-1 - (45-phenyl-4, 5-dihydrooxazol-2-yl) butan-ol (a) A mixture formed by ethyl 3S-benzyloxycarbonylamino-2-hydroxy-5 phenylpentanimidate (0.78 g, 1.92 mmol), provided as in Reference 7, diisopropylethylamine (0.218 μL, 1.26 mmol) and 2-amino-2-phenylethanol (0.260 g, 1.9 mmol) in chloroform (25 mL) was heated to reflux for 3 hours and then stirred for approximately 12 hours, while allowing it to cool to room temperature. The mixture was concentrated and the residue was dissolved in ethyl acetate (50 mL). The solution was washed sequentially with 0.5N sodium hydroxide (40 mL) and brine (40 mL), dried (MgSO4) and then concentrated. The product was purified from the residue by flash chromatography eluting with 1: 3 hexane / ethyl acetate to give benzyl 2-hydroxy-2- (5-dihydro-4-ene-pentyloxazol-2-yl) -lS- phenylethyl ethylcarbamate (0.475 g, 1.1 mmol) as an oily mixture of diastereoisomers. MS (PCI) m / z = 445 (M + 1). (C27H8N204). (b) A solution formed by benzyl-2-hydroxy-2- (4,5-dihydro-4S-phenyloxazol-2-yl) -lS-phenylethyl ethylcarbamate (100 mg, 0.22 mmol) in methanol (10 mL) was placed under A nitrogen atmosphere was stirred while the Pearlman catalyst (20 mg) was added. The mixture was stirred vigorously under a hydrogen atmosphere until the reaction was complete and then filtered. The filter was washed with methanol (2 x 25 mL). The combined filtrates were concentrated to provide 2S-amino-4-phenyl-1- (4S-phenyl-4, 5-dihydrooxazol-2-yl) butan-1-ol (51 mg, 0.16 mmol) as a clear oil. MS (PCI) m / z = 311 (M + 1). (Ci9H22N202). Continue as in Reference 8 providing methyl-2- (2S-benzyloxycarbonylamino-l-hydroxy-4-phenylbutyl) -4,5-dihydrooxazole-4-carboxylate. REFERENCE 9 Salt of 2S-amino-l-oxazol-2-yl-4-phenylbutan-1-ol trifluoroacetic acid A solution formed by oxazole (0.25 g, 3.62 mmol) in THF (20 mL) was treated with tetrahydrofuran complex of borane (3.62 mL, 3.62 mmol) under nitrogen and the mixture was stirred for 30 minutes and then cooled to -78 ° C. A solution formed by sec-butyllithium (2.78 mL, 3.62 mmol) in cyclohexane was added dropwise and the mixture was stirred for 30 minutes. A solution consisting of tert-butyl (S) -l-formyl-3-phenylpropylcarbamate (0.476 g, 1.81 mmol) in THF (25 mL) was added and the mixture was stirred and allowed to warm while the reaction continued until its termination. The mixture was then cooled to -78 ° C, cooled by gradually adding 5% acetic acid in ethanol (20 mL), allowed to warm to room temperature and stirred for 18 hours. The mixture was concentrated to dryness and the residue was extracted with ether (2x25 mL). The combined extracts were washed with brine, dried (MgSO4) and concentrated to dryness to give tere-butyl-2-hydroxy-2-oxazol-2-yl-lS-phenethylethylcarbamate (0.125 g, 0.376 mmol) as an oil. yellow. MS (PCI) m / z = 333 (M + 1). A mixture of tert-butyl-2-hydroxy-2-oxazol-2-yl-lS-phenethylethylcarbamate (0.125 g, 0.376 mmol), anisole (0.2 mL) and trifluoroacetic acid (0.6 mL) in dichloromethane (20 mL) was added. stirred at room temperature for 2 hours and then concentrated to provide 2-S-amino-1-oxazol-2-yl-4-phenylbutan-1-trifluoroacetic acid salt (0.08 g, 0.229 mmol) as a yellow oil. MS (PCIm / z = 233 (M + l) REFERENCE 10 Methyl 2- (2S-amino-l-hydroxy-4-phenylbutyl) ozaxol-4-carboxylate A solution formed by methyl 2- (2S-benzyloxycarbonylamino-1) -hydroxy-4-phenylbutyl) -4,5-dihydroxazole-4-carboxylate (0.100 g, 0.235 mmol), provided as in Reference 10, in dichloromethane (3 mL) was cooled to 0 ° C and then treated with DBU (39 mL, 0.26 mmol) and bromotrichloromethane (26 mL, 0.26 mmol) The mixture was stirred for 6 hours at 0 ° C, washed with ammonium chloride (10 mL) and concentrated.The residue was dried (MgSO4) to give methyl 2- (2 _? - benzyloxycarbonylamino-l-hydroxy-4-phenylbutyl) oxazole -4-carboxylate MS (PCI) m / z = 425 (M + 1).
Deprotection afforded methyl 2- (2S-amino-1-hydroxy-4-phenylbutyl) ozaxol-4-carboxylate. REFERENCE 11 2-benzooxazol-2-yl-2- (erc-butyl-dimethyl-silanyloxy) - 1S-phenethylethylamine A solution of 2S-amino-l-benzooxazol-2-yl-4-phenyl-butan-1-ol (600 mg), provided as in Reference 12, in dichloromethane (15 mL) was cooled to 0 ° C and then treated with 2,6-lutidine (0.57 mL) followed by tere-butyldimethylsilyl trifluoromethanesulfonate (1.08 mL). The solution was stirred for 3 hours and then more dichloromethane (50 mL) was added. The mixture was washed sequentially with a saturated solution of sodium bicarbonate (50 mL) and brine (50mL x2), dried over magnesium sulfate and concentrated under reduced pressure to provide 2-benzooxazole -2-I1-2- (eq). -butyl-dimethyl-silanyloxy) -lff-phenethylethylamine as an orange oil. REFERENCE 12 2S-amino-1-benzooxazol-2-yl-4-phenylbutan-1-ol A solution of (S) -2- tert-butoxycarbonylamino-4-phenylbutyric acid (500 g, 179 mmol), EDC (37.8 g) 197 mmol),
HOBT (41.1 g, 269 mmol) and N, 0-dimethyl hydroxylamine hydrochloride (19.2 g, 197 mmol) in dichloromethane (500 mL) was cooled in an ice bath and then treated with a solution of triethylamine (27.5 mL, 197 mmol) in dichloromethane (150 mL). The ice bath was removed and the reaction mixture was stirred at room temperature for approximately 12 hours. The mixture was concentrated by rotary evaporation and the residue was treated with ethyl acetate (450 mL), water (300 mL) and saturated sodium bicarbonate until all the solids dissolved. The ethyl acetate layer was separated and washed sequentially with saturated sodium bicarbonate (100 mL), water (100 mL), IN hydrochloric acid (100 mL), water (100 mL) and brine (50 mL). The solution was dried over anhydrous magnesium sulfate and concentrated to give tert-butyl (S) -1- (N-methoxy-N-methylcarbamoyl) -3-phenylpropylcarbamate (53.41 g, 93% product) as a clear, colorless oil. . The tert-butyl (S) -1 (N-methoxy-N-methylcarbamoyl) -3-phenylpropylcarbamate provided above was divided into three portions (5.0 g 15.5 mmol, 4.88 g, 15.1 mmol, and 4.54 g, 14.1 mmol). Each portion was subjected to azeotropic mixing with toluene by rotary evaporation and dried under reduced pressure to remove residual ethyl acetate and water. Each portion of the ester was taken up in anhydrous diethyl ether (75 mL) and the mixtures were cooled in an ice bath under nitrogen. Each of the mixtures were treated with lithium aluminum hydride (1M in diethyl ether, 23.3 mL, 22.7 mL, and 21.1 mL, respectively) added by syringe and the mixtures were stirred at 0 ° C for 90 minutes. The mixtures were treated with ethyl acetate (5 mL), stirred for 5 minutes, then treated with saturated KH2P04 (5 mL), IN hydrochloric acid (1 mL) and then additional IN hydrochloric acid until the solution was dissolved. solid mass. The resulting solutions were combined and extracted with ethyl acetate (3x200 mL). The extracts were dried over anhydrous magnesium sulfate and concentrated. The residue was dried under reduced pressure to give tert-butyl (S) -1-formyl-3-phenylpropylcarbamate (11.61 g, 99% product). A solution of tert-butyl (S) -l-formyl-3-phenylpropyl carbamate (11.15 g, 42.3 mmol) in dichloromethane (25 mL) was cooled in an ice bath under nitrogen and then sequentially treated with acetone cyanohydrin ( 10.8 mL, 119 mmol) and triethylamine (3.5 mL, 25.4 mmol). The reaction was stirred for about 12 hours at room temperature and then concentrated by rotary evaporation. The residue was dissolved in 1: 1 hexane: ethyl acetate (250 mL) and the solution was washed sequentially with water (3x 100 mL) and brine (50 mL), dried over anhydrous magnesium sulfate and concentrated. The product was purified from the residue by silica gel chromatography using 2: 1 hexane: ethyl acetate as eluent to give tert-butyl-2-cyano-2-hydroxy-1-β-phenethylethyl carbamate (12.05 g, 98% product).
A mixture of chloroform (12.8 mL) and absolute ethanol (9 mL, 153 mmol), under a stream of nitrogen with a bound Firestone valve bubbler, was cooled in an ice bath and then treated with acetyl chloride (9.2 mL , 129 mmol) added by syringe. The mixture was allowed to stand for 5 minutes and then a solution of tert-butyl-2-cyano-2-hydroxy-lS-phenethylethyl carbamate (2.34 g, 8 mmol) in chloroform (19.2 mL) was added. The nitrogen inlet was removed and the mixture was stirred and warmed little by little at room temperature for approximately 12 hours. The mixture was subsequently concentrated by rotary evaporation and the residue was treated with absolute ethanol (40 mL) and o-aminophenol (873 mg, 8 mmol). The mixture was heated at 95 ° C under nitrogen for 5 hours and then stirred at room temperature for approximately 12 hours. The mixture was treated with diethyl ether (150 mL) and the resulting solution was washed repeatedly with IN of KOH until the aqueous wash layer became colorless. The organic phase was dried, dried over anhydrous magnesium sulfate and concentrated. The residue was recrystallized from hot hexane and a minimum amount of ethyl acetate to provide a tan powder (335 mg). The mother liquor was combined with the mixed fractions from a reaction carried out in a similar manner and purified by silica gel chromatography using 5% methanol in dichloromethane to provide 2 S-amino-1-benzooxazole-2-1-4- phenylbutan-1-ol (1.27 g, 52% average product) as a semisolid orange mass. Continue as in Reference 12 providing the following compounds: 2-amino-1-benzooxazol-2-yl-ethanol; 2-amino-1-benzooxazol-2-yl-2-methyl-propan-1-ol; (S) -2-amino-1-benzooxazol-2-yl-hexan-1-ol; 1- (1-amino-cyclopropyl) -l-benzooxazol-2-yl-methanol; (S) -2-amino-l-benzooxazol-2-yl-propan-l-ol; (S) -2-amino-1-benzooxazol-2-yl-4-methanesulfonyl-butan-1-ol; (S) -2-amino-l-benzooxazol-2-yl-pentan-l-ol; (S) -2-amino-1-benzooxazol-2-yl-butan-1-ol; 2-amino-1-benzooxazol-2-yl-3-methoxy-propan-1-ol; "" "H
NMR (CDC13): 7.70 (m, 1H), 7.53 (m, 1H), 7.34 (m, 2H), 4.88-5.0 (m, 1H), 3.60 (m, 1H), 3.53 (m, 3H), 3.37. (s, 1H), 3.30 (s, 1H); EXAMPLE 1 N- [IR- (2-Benzooxazol-2-yl-2-hydroxy-lS-phenethylethylcarbamoyl) -2-benzylsulfonylethyl] -morpholine-4-carboxamide (Compound 1)
A mixture of 2S-amino-1-benzooxazol-2-yl-4-phenylbutan-1-ol (2.2 g, 7.8 mmol), provided as in Reference 12, 2-morpholin-4-ylcarbonylamino-3-benzyl acid Sulfonylpropionic acid (2.78 g, 7.8 mmol), EDC (1.64 g, 8.57 mmol), 1-hydroxybenzotriazole hydrate (1.58 g, 11.7 mmol) and N-methylmorpholine (2.4 mL, 17.1 mmol) in dichloromethane was stirred for 1 hour. The mixture was treated with additional amounts of EDC (0.1 eq) and 1-hydroxybenzo triazole hydrate (0.1 eq) and stirred for 30 minutes. The mixture was treated with an additional amount of EDC (0.1 eq) and stirred for 15 minutes. The mixture was treated with an additional amount of EDC (0.1 eq) and stirred for 30 minutes. The mixture was concentrated and the residue was taken up in ethyl acetate. The mixture was washed sequentially with 1? hydrochloric acid (3x 50 mL), saturated sodium bicarbonate solution (2x 50 mL) and brine (50 mL), dried (MgSO4) and concentrated to give N- [IR- (2-benzooxazole-2-yl- 2-hydroxy-lS-phenethylethylcarbamoyl) -2-benzylsulfonylethyl] -morpholine-4-carboxamide (4 g, 644 mmol); 1H? MR (CDC13): 7.68 (m, 1H), 7.52 (m, 1H), 7.10-7.45 (m, 12H), 6.0-6.25 (m, 1H), 4.95-5.1 (m, 1H), 4.52- 4.80 (m, 1H), 4.15-4.5 (m, 3H), 3.1-3.75 (m, 10H), 2.69 (m, 2H), 2.06 (m, 1H), 1.80 (m, 1H); MS: m / e 621.0; EXAMPLE 2 2S-Acetylamino-N- (2-oxazol-2-yl-2-hydroxy-lS-phenethylethyl) -3-cyclohexylpropionamide (Compound 2)
A mixture formed by 2-acetylamino-3-cyclohexylpropionic acid (0.45 g, 0.211 mmol), PyBOP® (0.11 g,
0. 21 mmol) and diisopropylethylamine (0.037 g, 0.211 mmol) in
DMF (10 mL) was stirred for 15 minutes at room temperature and a solution formed by acid salt was added.
2S-amino-1-oxazol-2-yl-4-phenylbutan-1-ol trifluoroacetic, provided as in Reference 9, in DMF and neutralized with diisopropylethylamine. Additional diisopropyl ethylamine (0.037 g, 0.211 mmol) was added and the mixture was stirred for 2 hours at room temperature and then emptied into 100 mL of ice cold water. The aqueous phase was extracted with ethyl acetate (3 x 25 mL) and the combined organic layers were washed sequentially with IN hydrochloric acid (2 x 25 mL), water (2 x 25 mL) and brine (2 x 25 mL). , dried (MgSO4) and concentrated. The product was purified from the residue by flash chromatography eluting with 1: 3 hexanes / ethyl acetate to provide 2S-acetylamino-N-2-oxazol-2-yl-2-hydroxy-S-phenethylethyl) -3-cyclohexylpropionamide (0.036 g, 0.084 mmol) as oil. MS (ESI) m / z = 428 (M + 1); ^ -? MR (300 MHz, CD30D): d 0.80 (m, 2H), d 1.12 (m, 4H), d 1.40 (m, 2H), d 1.65 (m, 6H), d 1.80 (m, 1H) , d 2.00 (m, 4H), d 2.70 (m, 1H), d 2.80 (m, 1H), d 4.44 (m, 1H), d 4.51 (m, 1H), d 7.11 - 7.47 (m, 6H) , d 7.99 (s, 1H), (C24H33? 304). Continue as in Example 2 to provide the following compounds of Formula I: (Compound 3); MS (ESI) m / z = 448 (M + 1); XH-? MR (300 MHz, CDCl 3): d 0.89 (m, 2H) d 1.20 (m, 4H), d 1.45 (m, 1H), d 1.65 (m, 6H), d 1.80 (m, 1H), d 2.09 (, 4H), d 2.73 (t, J = 4 Hz, 2H), d 4.51 (m, 1H), d 4.96 (, 2H), d 6.00 (m, 1H), d 7.11 - 7.47 (m, 9H), d 7.60 (m, 2H) (C28H35? 203);
2S-acetylamino-N- [2-hydroxy-1S-phenethyl-2- (5-phenyloxazol-2-yl) ethyl] -3-cyclohexypropionamide (Compound 4); MS (ESI) m / z = 505 (M + 1); XH-? MR (300 MHz, CDCl3): d 0.80 (m, 2H), d 1.12 (m, 4H), d 1.40 (m, 2H), d 1.65 (m, 6H), d 1.80 (m, 1H) , d 2.00 (m, 5H), d 2.70 (m, 2H), d 4.51 (m, 1H), d 4.96 (m, 2H), d 6.19 (m, 1H), d 6.98 (m, 1H), d 7.11-7.47 (m, 9H), d 7.62 (m, 2H), (C30H38? 3O4); and N- (lS-benzothiazol-2-ylcarbonyl-3-phenylpropyl) -3-cyclohexy-1-propionamide (Compound 5); XH? MR: d 0.83 (m, 2H), d 1.20 (m, 5H), d 1.48 (q, 2H, J = 9 Hz), d 1.67 (m, 4H), d 2.20 (m, 3H), d 2.48 (m, 1H), v 2.75 (m, 2H), d 5.95 (m, 1H), d 6.35 (d, 1H, J = 9 Hz), d 7.25 (m 5H), d 7.57 (m, 2H) ), d 7.93 (d, 1H, J = 9 Hz), d 8.18 (d, 1H, J = 9 Hz); ES-MS m / z 435 (MH +); and 2S-acetylamino-N- (15-benzothiazol-2-ylcarbonyl-3-phenylpropyl) -3-cyclohexyl-propropionamide (Compound 6); ""? ? MR: d 0.87 (m, 8H), d 1.22 (m, 6H), d 1.92 (m, 1H), d 2.12 (m, 1H), d 2.48 (m, 1H), d 2.78 (m, 2H) , d 3.87 (d, 1H, J = 7 Hz), d 5.62 (m, 1H), d 7.20 (m, 6H), d 7.53 (m, 2H), d 7.98 (d, 1H, J = 7 Hz) , 8.18 (d, 1H, J = 7 Hz); ES-MS m / z 492 (MH +). N- [IS- (lS-phenethyl-2-benzooxazol-2-yl-l-oxoethylcarbamoyl) -2-naphth-2-ylethyl] piperidine-4-carboxamide (Compound 7), XH ™ MR (DMSO-d6) : d 1.32 - 1.76 (m, 4H), d 1.90 - 2.09 (m, 2H), d 2.22 - 2.60 (m, 2H), d 2.65 - 3.26 (m, 6H), d 4.72 - 4.86 (m, 1H) , d 5.26 (m, 1H), d 7.06 - 7.31 (m, 5H), d 7.45 (m, 4H), d 7.55 (dt, J = 1.26, 7.84 Hz, 1H), d 7.65 (dt J = 1.18 , 8.00 Hz, 1H), d 7.72 - 7.88 (m, 3H), d 7.90 (d, J = 8.06 Hz, 1H), d 7.99 (d, J = 7.86 Hz, 1H), d 8.14 (bs, 1H) , d 8.24 (d, J = 8.04 Hz, 1H), d 8.46 (bs, 1H), d 8.94 (d, J = 6.43Hz, 1H); 2S-acetylamino-N- (lS-benzooxazol-2-ylcarbonyl-3-phenylpropyl) -3-cyclohexyl-propropionamide (Compound 8); MS (ESI) m / z = 476 (M + 1); XH-? MR (300 MHz, CDC13): d 0.85 (m, 2H), d 1.26 (m, 4H), d 1.47 (m, 2H), d 1.64 (m, 6H), d 1.99 (s, 3H) , d 2.15 (m, 2H), d 2.41 (m, 1H), d 2.72 (t, J = 6Hz, 2H), d 4.59 (q, J = 4Hz, 1H), d 5.65 (q, J = 2Hz. 1H), d 6.26 (d, J = 6 Hz, 1H), d 7.10 - 7.26 (m, 6H), d 7.41 - 7.65 (m, 3H), d 7.86 (d, J = 6Hz 1H), (C28H33? 304); tert-butyl IS- (lS-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl) -2-cyclohexylethylcarbamate (Compound 9);
N- [l - (benzooxazol-2-ylcarbonyl) -3-phenylpropyl] -3-cyclohexylpropionamide
(Compound 10); 3-cyclohexyl-N- [3S-phenyl-1- (5-phenyloxazol-2-yl carbonyl) propyl] propionamide (Compound 11); MS (ESI) m / z =
445 (M + 1); XH-? MR (300 MHz, DC13): d 0.89 (m, 2H). d 1.20
(m, 4H), d 1.55 (m, 2H), d 1.68 (m.6H). d 2.12 (m, 1H). d
2. 27 (t, J = 4Hz, 2H). d 2.48 (m, 1H). d 2.76 (m, 2H). d 5.70 (m, 1H), d 6.35 (d.J = 4 Hz, 1H), d 7.19 - 7.30 (m, 5H), d 7.48 (m, 3H), d 7.57 (s, 1H), d 7.79 ( d, J = 4Hz, 2H), 2-ene-acetylamino-N- [IS- (5-phenyloxazol-2-ylcarbonyl) -3-phenylpropyl] -3-cyclohexylpropionamide (Compound 12); MS (ESI) m / z = 502 (M + 1); ^ l-? MR (300 MHz, CDCL3): d 0.80 (m, 2H), d 1.12 (m, 4H), d 1.50 (m, 1H), d 1.65 (m, 6H), d 1.80 (m, 1H ), d 2.05 (s, 3H), d 2.12 (m, 1H), d 2.48 (m, 1H), d 2.70 (t, J = 6Hz, 2H), d 4.52 (q, J = 2Hz, 1H), d 5.60 (q, J = 2Hz, 1H), d 5.98 (d, J = 6 Hz, 1H), d 6.92 (d, J = 6Hz, 1H), d 7.19 - 7.30 (m, 5H), d 7.48 ( m, 3H), d 7.57 (s, 1H). d 7.79 (d, J = 4Hz, 2H), (C3oH35? 3? 4); benzyl- (benzooxazol-2-ylcarbonylmethylcarbamoyl) -3-methylbutylcarbamate (Compound 13); benzyl 15- (5-phenylbenzooxazol-2-ylcarbonyl methylcarbamoyl) -3-ethylbutylcarbamate (Compound 14); 25-acetylamino-N- (15-oxazol-2-ylcarbonyl-3-phenylpropyl) -3-cyclohexylpropionamide (Compound 15); MS (ESI) m / z = 426 (M + 1); XH-? MR (300 MHz, CDC13): d 0.85 (m, 2H), d 1.20 (m, 4H), d 1.50 (m, 2H), d 1.65 (m, 6H), d 2.05 (s, 3H) , d 2.48 (m, 1H), d 2.70 (t, J = 6Hz, 2H), d 4.52 (q, J = 2Hz, 1H), d 5.60 (q, J = 2Hz, 1H), d 5.93 (d, J = 6 Hz, 1H), d 6.89 (d, J = 6Hz, 1H), d 7.19 - 7.38 (m, 5H), d 7.47 (s, 1H), d 7.79 (s, 1H), (C24H31? 304 );
benzyl 15-benzooxazol-2-ylcarbonyl-3-phenylpropyl carbamate (Compound 16);
2 - . 2-acetylamino-N- (15-benzooxazol-2-ylcarbonyl-3-phenylpropyl) -3-phenylpropionamide
(Compound 17);
N- (15-benzooxazol-2-ylcarbonyl-3-phenylpropyl) benzyl sulfonamide (Compound 18); XH? MR (CDC13): 7.88 (d, J = 6.2Hz, 1H), 7.67 (d, J = 6.2Hz, 1H), 7.60 (t, J = 6.2Hz, 1H), 7.51 (t, J = 6.2 Hz, 1H), 7.35 (d, J = 6.2Hz, 2H), 7.08-7.29 (m, 7H). 6.96 (t, J = 6.2Hz, 1H), 5.52 (d, JK = 9.4 Hz, 1H), 4.90 (td, J = 9.4, 3.1Hz, 1H), 4.31 (dd, J = 10.9, 10.9Hz, 2H ). 2.80 (m, 1H), 2.27 (m, 1H), 2.04 (m, 1H); MS: m / e = 435.0;
? - (15-benzooxazol-2-ylcarbonyl-3-phenylpropyl) -hexylethanesulfonamide cycle (Compound 19); 1H? MR (CDC13): 7.94 (d, J = 6.3Hz, 1H), 7.70 (d, J = 6.3Hz, 1H), 7.62 (t, J = 6.3Hz, 1H), 7.52 (t, J = 6.3 Hz, 1H), 7.17-7.34 (m, 5H), 5.42 (d, J = 9.5Hz, 1H), 5.17-5.25 (m, 1H), 2.79-3.09 (m, 4H), 2.38-2.55 ( m, 1H), 2.08-2.21 (m, 1H), 1.52-1.79 (m, 7H), 1.08-1.34 (m, 4H), .77-1.01 (m, 2H); MS m / e = 455.1;
N- (l-benzooxazol-2-ylcarbonyl-3-phenylpropyl) -3-cyclopentylpropionamide
(Compound 20); N- (15-benzooxazol-2-ylcarbonyl-3-phenylpropyl) -2-cyclohexylacetamide (Compound 21);
N- (15-benzooxazol-2-ylcarbonyl-3-phenylpropyl) -2-bicyclo [2.2. l] hept-2-ylacetamide
(Compound 22);
N- (15-benzooxazol-2-ylcarbonyl-3-phenylpropyl) -4-methylpentanamide
(Compound 23); N- (15-benzooxazol-2-ylcarbonyl-3-phenylpropyl) -2-naphthalen-1-ylacetamide (Compound 24); XH? MR (CDC13): 7.96 (m, 1H), 7.84 (m, 2H), 7.82 (m, 1H), 7.42-7.75 (m, 6H), 7.14 (m.4H), 6.86 (m.2H) . 6-25 (m, 1H), 5.64 (m, 2H) "4.08 (m, 1H), 2.45 (m, 2H), 2.42 (m, 1H), 1.90 (m, 1H);
N- (l-benzooxazol-2-ylcarbonyl-3-phenylpropyl) -3-phenylpropionamide (Compound 25); 1H? MR (CDC13): 7.90 (d, J = 8.0Hz, 1H), 7.65 (d, J = 8.0Hz, 1H), 7.59 (m, 1H), 7.56 (m, 1H), 7.05-7.35 (m , 11H), 6.20 (d, J = 7.0Hz, 1H), 5.76 (m, 1H), 2.97 (m, 2H), 2.5-2.7 (m, 4H), 2.4 (m, 1H), 2.1 (m, 1 HOUR); methyl 2- [2- (3S-cyclohexylpropionylamino) -4-phenylbutyryl] -4,5-dihydrooxazole-4S-carboxylate (Compound 26); MS
(ESI) m / z = 429 (M + 1); ^ Í-? MR (300 MHz, CDCl3): d 0.89 (m,
2H), d 1.22 (m, 4H), d 1.51 (m, 1H), d 1.65 (m, 6H), d 2.05
(m, 1H), d 2.20 (t, J = 4 Hz, 2H), d 2.46 (m, 1H), d 2.73 (m,
2H), d 3.80 (s, 3H), d 4.55 (m, 1H), d 4.60 (m, 1H), d 5.00 (m, 1H), d 5.45 (m, 1H), d 6.15 (m, 1H) , d 7.13-7.35 (m, 5H), (C24H32N205); methyl 2- [2- (3S-cyclohexylpropionylamino) -4-phenylbutyryl] oxazole-4-carboxylate (Compound 27); MS (ESI) m / z = 427 (M + 1); XH-NMR (300 MHz, CDC13: d 0:89 (m, 2H), d 1.22 (m, 4H), d 1.49 (m, 1H), d 1.65 (m.6H), d 2.20 (m, 3H) , d 2.46 (m, 1H), d 2.74 (m, 2H), d 3.99 (s, 3H), d 5.62 (m, 1H), d 6.20 (d, J = 4Hz, 1H), d 7.15 - 7.35 ( m, 5H), d 8.40 (s, 1H), (C24H3oN205);
benzyl 15- (15-benzooxazol-2-ylcarbonyl) -3-phenylpropyl carbamoyl) -2-naphthalen-2-ylethylcarbamate (Compound 28);
2 - . 2-acetylamino-N- (15-benzooxazol-2-ylcarbonyl-3-phenylpropyl]! -3- (2-fluoropheni) propionamide (Compound 29);
-acetylamino-N- (15-benzooxazol-2-ylcarbonyl-3-phenylpropyl) -2-methylth-3-phenylpropionamide (Compound 30);
ert-butyl 15- (15-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl) -3-phenylpropylcarbamate (Compound 31); N- (l-benzooxazol-2-ylcarbonyl) -3-phenylpropyl) -4-cyclohexylbutyramide (Compound 32); 1H? MR (CDC13): 7-94 (d, J = 7.9Hz, 1H), 7.68 (d, 7.9Hz. 1H), 7.58 (t, J = 7.9Hz, 1H), 7.50 (t, J = 7.9 Hz, 1H), 7.10-7.32 (m.5H), 6.27 (d, J = 11.8Hz, 1H), 5.76-5.89 (m, 1H), 2.74-2.89 (m, 2H), 2.42-2.61 (m, 1H), 2.11-2.32 (, 3H), 1.53-1.79 (m.H8), 1.05-1.32 (m, 4H), 0.79-1.0 (m, 2H); MS: m / e = 433;
methyl 2- [25- (3-cyclohexylpropionylamino) -4-phenylbutyryl] -4,5-dihydrooxazole-45-ylcarboxylate (Compound 33); MS (ESI) m / z = 429 (M + 1); XH-NMR (300 MHz, CDCl 3): d 0.89 (m, 2H), d 1.22 (m, 4H), d 1.51 (m, 1H), d 1.65 (m, 6H), d 2.05 (m, 1H), d 2.20 (t, J = 4 Hz, 2H), d 2.46 (m, 1H), d 2.73 (m, 2H), d 3.80 (s, 3H), d 4.58 (m, 2H), d 5.00 (m, 1H), d 5.45 (m, 1H), d 6.15 (m, 1H), d 7.13-7.35 (m, 5H), (C24H32N205); 3-cyclohexyl-N- [1 - (5-methoxybenzooxazol-2-yl carbonyl)
-3-phenylpropyl] propionamide (Compound 34); MS (ESI) m / z = 449 (M + 1); XH-? MR (300 MHz,
CDC13): d 0.95 (m, 2H), d 1.22 (m, 4H), d 1.51 (m, 2H), d 1.65
(m, 6H), d 2.15 (m, 1H), d 2.20 (t, J = 4 Hz, 2H), d 2.50 (m, 1H), d 2.77 (q, J "= 2 Hz, 2H), d 3.92 (s, 3H), d 5.78 (m,
1H), d 6.37 (m, 1H), d 7.13-7.35 (m, 5H), d 7.53 (d, J = 6
Hz, 1H), (C27H32? 204); 2-acetyl-N- (15-benzooxazol-2-ylcarbonyl-3-phenylpropyl) -1,2,3,4-tetrahydroisoquinoline-35-carboxamide (Compound 35); 25-acetylamino-N- (15-benzooxazol-2-ylcarbonyl-3-phenylpropyl) -3- (2-chlorophenyl) propionamide (Compound 36); 3-cyclohexyl-N- [1- (6-methoxybenzooxazol-2-ylcarbonyl) -3-phenylpropyljpropionamide (Compound 37); MS (ESI) m / z = 449 (M + 1); XH-? MR (300 MHz, CDCl3): d 0.95 (m, 2H), d 1.22 (m, 4H), d 1.51 (m, 2H), d 1.65 (m, 6H), d 2.15 (m, 1H) , d 2.20 (t, J = 4 Hz, 2H), d 2.50 (m, 1H), d 2.77 (q, J = 2 Hz, 2H), d 3.95 (s, 3H), d 5.78 (m, 1H) , d 6.37 (d, J = 6 Hz, 1H), d 7.10-7.35 (m.5H), d 7.77 (d, J = 6 Hz, 1H), (C27H32N204); 3-cyclohexyl-N- [15- (5-trifluoromethylbenzooxazol-2-ylcarbonyl) -3-phenylpropyl] ropionamide (Compound 38); MS (ESI) m / z = 487 (M + 1); ^ I-lMR (300 MHz, CDCl 3): d 0.95 (m, 2H), d 1.22 (m, 4H), d 1.51 (m, 1H), d 1.65 (m, 6H), d 2.20 (m, 3H) , d 2.51 (m, 1H), d 2.80 (q, J = 2 Hz, 2H), d 5.76 (m, 1H), d 6.22 (d, J = 6 Hz, 1H), d 7.15 - 7.35 (m, 5H). d 7.77 (m, 2H), d 8.25 (s, 1H), (C27H29F3? 203); 2-acetylamino-N- (1-benzooxazol-2-ylcarbonyl-3-phenylpropyl-3- (2-trifluoromethylphenyl) propionamide (Compound 39); - (l-benzooxazol-2-ylcarbonyl-3-phenylpropyl) -3 -morpholin-4-ylpropionamide (Compound 40); XH? MR (CDC13): 7.90 (m, 1H), 7.76 (m, 1H), 7.06-7.36 (m, 7H), 4.00 (m, 1H), 3.12 ( m, 4H), 2.50-3.5 (m, 2H), 2.0-2.5 (m.2H), 1.83 (m, 4H), MS: m / e = 421.9, 3-cyclohexyl -N- [15- (5- Nitrobenzooxazole-2-ylcarbonyl) -3-phenylpropyl] propionamide (Compound 41); MS (ESI) m / z = 464 (M + 1); γ -.? MR (300 MHz, CDCl 3): d 0.95 (m, 2H), d 1.22 (m, 4H), d 1.51 (m, 1H), d 1.65 (m, 6H), d 2.20 (m, 3H), d 2.51 (m, 1H), d 2.80 (m, 2H), d 5.67 (m, 1H), d 6.17 (d, J = 6 Hz, 1H), d 7.09 - 7.35 (m, 5H), d 7.77 (d, J = 6Hz, 1H), d 8.50 (d, J = 6 Hz , 1H), d 8.77 (s, 1H), (C26H29N305), methyl 2- [2S- (3-cyclohexylpropionylamino) -4-phenylbutyryl] benzooxazole-6-carboxylate (Compound 42); MS (ESI) m / z = 477 (M + 1); XH-NMR (300 MHz, CDCl 3): d 0.95 (m, 2H), d 1.22 (m , 4H), d 1.51 (m, 1H), d 1.65 (m, 6H), d 2.23 (m, 3H), d 2.50 (m, 1H), d 2.77 (m, 2H), d 4.00 (s, 3H) ), d 5.78 (m, 1H), d 6.27 (d, J = 6 Hz, 1H), 7.15 - 7.35 (m, 5H), d 7.98 (d, J = 6 Hz, 1H), d 8.22 (d, J = 6Hz, 1H), d 8.39 (s, 1H), (C28H32N205); N- [15- (5-Chlorobenzooxazol-2-ylcarbonyl] -3-phenylpropyl] -3-cyclohexylpropionamide (Compound 43); MS (ESI) m / z = 453 (M + 1); XH-NMR (300 MHz , CDC13): d 0.95 (m, 2H), d 1.22 (m, 4H), d 1.53 (m, 2H), d 1.65 (m, 5H), d 2.20 (m, 3H), d 2.50 (m, 1H ), d 2.77 (m, 2H), d 5.74 (m, 1H), d 6.20 (d, J = 6 Hz, 1H), d 7.09-7.35 (m, 5H), d 7.60 (m, 2H), d
7. 90 (s, 1H), (C26H29CIN203);
benzyl 15- (15-benzooxazol-2-ylcarbonyl-3-phenylpropylsulfamylmethyl) -3-methylbutylcarbamate (Compound 44); XH NMR (CDC13): 7.92 (d, J = 7.7Hz, 1H), 7.64 (m, 1H), 7.57 (m, 1H), 7.50 (m, 1H), 7.21-7.34 (m, 10H), 6.30 ( d, J = 9.2Hz, 1H),
. 34 (m.1H), 5.11 (m, 1H), 4.91 (d, J = 9.6Hz, 1H), 4.51 (m, 1H), 3.11 (m, 2H), 2.89 (m, 2H), 2.50 (m , 1H), 2.20 (m, 1H), 1.70 (m, 1H), 1.5 (m, 1H), 1.23-1.46 (m, 1H), 0., 92 (t, J = 7.4Hz, H); MS: m / e = 578.1; N-. { 15- [15- (benzooxazol-2-ylcarbonyl) -3-phenylpropyl sulfamoylmethyl) -3-methylbutyl} acetamide (Compound 45); ^ "H NMR (CDCI3): 7.89 (d, J = 7.7Hz, 1H), 7.62 (m, 1H), 7.55 (m, 1H), 7.49 (m, 1H), 7.18-7.30 (m, 5H), 6.7 (d, J = 8.9Hz, 1H), 5.61 (d, J = 9.4Hz, 1H), 5.34 (m, 1H), 4.86 (m, 1H), 3.06 (m, 2H), 2.90 (t, J) = 7.7Hz, 2H), 2.24 (m, 1H), 2.22 (m, 1H), 2.04 (s, 3H), 1.66 (m, 1H), 1.48 (m, 1H), 1.38 (m, 1H), 0.91 (t, J = 6.2 Hz, 6H); MS: m / e = 486.1; benzyl IR- (15-benzooxazol-2-ylcarbonyl) -3-phenyl propylsulfamoylmethyl) -3-methylbutylcarbamate (Compound 46) 1H NMR (CDCl 3 ): 7.9 (m, 1H), 7.60 (m, 1H), 7.58 (m, 1H), 7.5 (m,
1H), 7.75-7.4 (m, 10H), 5.85 (m, 1H), 5.0-5.4 (m, 3H), 4.2 (m,
1H), 3.15-3.35 (m, 2H), 2.65-2.85 (m, 2H), 2.45 (m, 1H), 2.15
(m, 1H), 1.9 (m, 1H), 1.4-1.7 (m, 3H), 0.9 (m, 6H), MS: m / e = 578.1; and N- [1- (1-benzooxazol-2-ylcarbonyl-3-phenylpropyl-metheamoylmethyl) -3-methylbutyl] -acetamide (Compound 47) ^? NMR (CDCl 3): 7.9 (m, 1H), 7.65 (m, 1H), 7.61 (m, 1H), 7.60 (m, 1H), 7.18-7.30 (m, 5H), 6.0 (m, 1H), 5.85. (m, 1H), 5.28 (m, 1H), 4.50 (m, 1H), 3.20 (m, 1H), 2.85 (m, 1H), 2.70 (m, 1H), 1.8-2.2 (m, 2H), 1.95 (S, 3H), 1.35-1.70 (m, 2H), 0.9 (m, 6H); MS: m / e = 486.0. EXAMPLE 3 tert-butyl IR- (2-benzooxazol-2-yl-2-hydroxy-15-phenethylethylcarbamoyl) -2 (2-cyanobenzylsulfaneyl) ethylcarbamate (Compound 48)
A solution of 2R-tert-butoxycarbonylamino-3- (2-cyanobenzylsulfanyl) propionic acid (336 mg), 25-amino-1-benzooxazol-2-yl-4-phenylbutan-1-ol (282 mg), hydrochloride
1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (211 mg) and 1-hydroxybenzotriazole (197 mg) in dichloromethane (20 mL) was treated with N-methylmorpholine (2.2 mL). The reaction mixture was stirred 0.5 hours and then concentrated by evaporation. The residue was dissolved in ethyl acetate (40 mL) and the solution was washed sequentially with water (20 mL), 1? of hydrochloric acid (30 mL), a saturated solution of sodium bicarbonate (30 mL) and then brine (30 mL), dried over magnesium sulfate and concentrated by evaporation. The residue was subjected to flash column chromatography on silica eluting with diethyl ether to give tert-butyl- (2-benzooxazol-2-yl-2-hydroxy-S-phenethylethylcarbamoyl) -2- (2-cyanobenzylsulfanyl) ethyl carbamate as a whitish solid. MS: 601 [MH] +. Continue as Example 3 to provide tert-butyl IR- (2-benzooxazol-2-yl-2-hydroxy-15-phenethylethylcarbamoyl) -2-benzylsulfanyl ethylcarbamate (Compound 49), MS: 576 [MH] +. EXAMPLE 4 N- [4R (2-Benzooxazol-2-yl-2-hydroxy-lS-phenethylethylcarbamoyl) -2- (2-cyanobenzyl sulphanyl) ethyl] isonicotinamide (Compound 50)
A solution of 3- (2-cyanobenzylsulfaphyl) -2R- (pyrid-4-ylcarbonyl) aminopropionic acid (425 mg), provided as in Reference 2, 2S-amino-l-benzooxazol-2-yl-4-phenylbutan -1-ol (356 mg) and EIATU (356 mg) in dimethylformamide (40 mL) was treated with diisopropylamine (0.239 mL). The reaction mixture was stirred for 16 hours at room temperature and then concentrated by evaporation. The residue was dissolved in ethyl acetate and the solution was washed with saturated sodium bicarbonate solution, dried over magnesium sulfate and then concentrated by evaporation. The residue was subjected to flash column chromatography on silica eluting with ethyl acetate to provide N- [IR- (2-benzooxazol-2-yl-2-hydroxy-lS-phenethylethylcarbamoyl) -2- (2-cyanobenzylsulfane) ethyl. ] iso nicotinamide (216 mg) as gum. MS: 606 [MH] +. HPLC: R t = 13.20 minutes. Continue as in Example 4 to provide 9H-fluoren-9-ylmethyl 15- (2-benzooxazol-2-yl-2-hydroxy-15-phenethyl ethylcarbamoyl) -2-cyclohexylethylcarbamate (Compound 51); 9H-Fluoren-9-ylmethyl 15- [2-benzooxazol-2-yl-2- (erc-butyldimethylsilanyloxy) -15-phenethylethylcarbamoyl] -2-cyclohexyl ethylcarbamate (Compound 52), MS: 772 [MH] +. EXAMPLE 5 2R-Amino-N- (2-benzooxazol-2-yl-2-hydroxy-15-phenethylethyl) -3- (2-cyanobenzylsulfaphyl) propionamide hydrochloride (Compound 53)
A solution of tei-c-butyl IR- (2-benzooxazol-2-yl-2-hydroxy-15-phenethylethylcarbamoyl) 2- (2-cyanobenzylsulfaneyl) ethylcarbamate (145 mg), provided as in Example 3, in dioxane ( 20 mL) was treated with hydrogen chloride, bubbling the gas through the solution for 30 minutes. The reaction mixture was concentrated by evaporation and the residue was triturated with diethyl ether to give 2R-amino-N- (2-benzooxazol-2-yl-2-hydroxy-lS-phenethylethyl) -3- (2-hydrochloride. cyanobenzylsulfane) -propionamide (117 mg) as an off-white solid. MS: 537 [MH] +. Continue as in Example 5 to provide 2R-amino-N- (2-benzooxazol-2-yl-2-hydroxy-15-phenethylethyl) -3-benzylsulfonylpropionamide hydrochloride (Compound 54), MS: 508 [MH] +.
EXAMPLE 6 25-amino-N- (2-benzooxazol-2-yl-2-hydroxy-15-phenethylethyl) -3-cyclohexylpropionamide (Compound 55)
A solution of 9H-fluoren-9-ylmethyl 15- (2-benzooxazol-2-yl-2-hydroxy-lS-phenethylethylcarbamoyl) -2-cyclohexylethylcarbamate (165 mg), provide same as in Example 4, in dichloromethane (30 g). mL) was treated with tris (2-aminoethyl) amine bound to polystyrene beads (4.48 g). The mixture was stirred at room temperature for 48 hours and then filtered. The resin was washed four times with dichloromethane (20 mL) and the combined filtrates were concentrated under reduced pressure to provide 25-amino-N- (2-benzooxazol-2-yl-2-hydroxy-15-phenethylethyl) -3-cyclohexylpropionamide. (147 mg) as a colorless oil.
EXAMPLE 7 25-amino-N- [2-benzooxazol-2-yl-2- (tert-butyldimethylsilanyloxy) -15-phenethylethyl] -3-cyclohexylpropionamide (Compound 56), a protected compound of Formula I
A solution of 9H-fluoren-9-ylmethyl lS- [2-benzo-oxazol-2-yl-2- (tert-butyldimethylsilanyloxy) -15-phenethylethyl carbamoyl] -2-cyclohexylethylcarbamate (1.48 g), provided as in Example 4, in dichloromethane (50 mL) was treated with tris- (2-aminoethyl) amines. (14.4 mL). The reaction mixture was stirred for 75 minutes and then additional dichloromethane (50 mL) was added. The mixture was washed sequentially with brine (50 mL x4) and a buffer solution of pH 5.3 (50 mL x3), dried over magnesium sulfate and concentrated to provide 25-amino-N- [2-benzooxazol-2-yl. -2- (tert-Butyldimethylsilanyloxy) -15-phenethylethyl] -3-cyclohexylpropionamide as orange oil. EXAMPLE 8 tert-buti! 4- [IR- (2-benzooxazol-2-yl-2-hydroxy-15-phenethylethyl carbamoyl] -2- (2-cyanobenzylsulfane) ethylcarbamoylpiperidine-1-carboxylate (Compound 57)
A solution of 2R-amino-N- (2-benzo-oxazol-2-yl-2-hydroxy-15-phenethylethyl) -3- (2-cyanobenzyl sulfaphyl) propionamide hydrochloride (170 mg), provided as in Example 5 , in dimethylformamide (7 mL) was treated with tert-butyl ester of the tetrafluorophenyl ester of 1-tert-butoxycarbonylpiperidine-4-carboxylic acid in resin (excess), prepared according to the procedure described in the International Patent Application Number W099 / 67228, and triethylamine (0.053mL). The suspension was stirred for 16 hours, then filtered, and the filtrate was washed with dimethylfonnamide and then concentrated by evaporation. The residue was subjected to flash column chromatography on silica eluting with ethyl acetate to give tert-Buti! 4 - [IR- (2-benzooxazol-2-yl-2-hydroxy-15-phenethylethyl carbamoyl] -2- (2 -cyanobenzylsulfanyl) ethylcarbamoylpiperidine-1-carboxylate (95mg) as gum MS: 712 [MH] +. Continue as in Example 8 to give benzyl 4- [15- (2-benzooxazol-2-yl-2-hydroxy-15- phenethylethylcarbamoyl) -2-cyclohexylethylcarbamoyl] piperidine-1-carboxylate (Compound 58), MS: 681 [M] + EXAMPLE 9 N- [IR- (2-benzooxazol-2-yl-2-hydroxy-l5-phenethylethyl carbamoyl) -2-benzylsulfonylethyl] -tetrahydropyran-4-carboxamide (Compound 59)
A mixture of 2R-amino-N- (2-benzo-oxazol-2-yl-2-hydroxy-15-phenethylethyl) -3-benzylsulfonyl-propionamide hydrochloride (0.3 g), prepared as in Example 5, tetrahydropyran-4 acid Carboxylic (0.072 g), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.116 g) and 1-hydroxybenzotriazole (0.112 g) in dichloromethane (20 mL) was treated with 4-N-methylmorpholine (0.12 mL) . After stirring at room temperature for 4 hours the reaction mixture was allowed to stand 16 hours and then concentrated by evaporation. The residue was treated with dichloromethane
(50 mL) and the mixture was washed sequentially with solution 1? of hydrochloric acid (5 mL), saturated sodium bicarbonate solution (5 mL) and brine (5 mL), dried over magnesium sulfate and then concentrated by evaporation. The residue was subjected to flash column chromatography on silica eluting with ethyl acetate to provide N- [1R- (2-benzooxazol-2-yl-2-hydroxy-15-phenethylethylcarbamoyl) -2-benzylsulfonylethyl] -tetrahydropyran-4-carboxamide (66 mg) as a creamy solid. MS: 618 [MH] +. Proceed as in Example 9 to provide the following compounds of Formula I: N- [IR- (2-benzooxazol-2-yl-2-hydroxy-15-phenethylethylcarbamoyl) -2-benzylsulfonylethyl] -nicotinamide (Compound 60), MS: 613 [MH] +; N- [IR- (2-Benzooxazol-2-yl-2-hydroxy-15-phenethylethyl carbamoyl) -2-benzylsulfonylethyl] pyrazine-2-carboxamide (Compound 61), MS: 614 [MH] +; 4- [15- (2-benzooxazol-2-yl-2-hydroxy-15-phenethylethylcarbamoyl) -2-cyclohexyl-ethylcarbamoyl] piperidine-1-carboxylate (Compound 62); and N- [15- (2-benzooxazol-2-yl-2-hydroxy-l5-phenethylethyl carbamoyl) -2-cyclohexylethyl] -isonicotinamide (Compound 63) EXAMPLE 10 tert-butyl 4- [IR- (2-benzooxazole -2-yl-2-hydroxy-15-phenethylethylcarbamoyl] -2- (3-methylpyrid-2-ylmethylsulfonyl) ethylcarbamoyl] piperidine-1-carboxylate (Compound 64)
A solution of 2R-amino-N- (2-benzooxazol-2-yl-2-hydroxy-15-phenethylethyl) -3- (3-methylpyrid-2-ylmethylsulfonyl) propionamide (178 mg), HATU (137 mg) and 1-tert-butoxycarbonylpiperidine-4-carboxylic acid (69 mg) in dimethylphomiamide (10 mL) was treated with N, N-diisopropyl ethylamine (0.174 mL). The reaction mixture was stirred for 9 hours and then concentrated by evaporation. The residue was dissolved in ethyl acetate and the solution was washed with saturated sodium bicarbonate solution, dried over magnesium sulfate and then concentrated by evaporation. The residue was subjected to flash column chromatography on silica eluting with ethyl acetate to tert -butyl 4 - [IR- (2-benzooxazol-2-yl-2-hydroxy-15-phenethylethylcarbamoyl] -2- (3-methylpyrid-2 -ylmethylsulfonyl) ethylcarbamoyl] piperidine-1-carboxylate (81 mg) MS: 734 [MH] +. Continue as in Example 10 to provide the following compounds of Formula 1: tetrahydropyran-4-yl IR- (2-benzooxazole) 2-yl-2-hydroxy-15-phenethylethylcarbamoyl) -2-benzylsulfanylethylcarbamate (Compound 65); N- [15- (2-benzooxazol-2-yl-2-hydroxy-15-phenethylethyl carbamoyl) -2-cyclohexylethyl] tetrahydropyran 4-carboxamide (Compound 66), MS: 548 [M] +; and N- [15- (2-benzooxazol-2-yl-2-hydroxy-15-phenethylethyl carbamoyl) -2-cyclohexylethyl] -6-hydroxynicotinamide (Compound 66). Compound 67. EXAMPLE 11 N- [2-Benzooxazol-2-yl-2- (tert-butyldimethylsilanyloxy) -15-phenethylethyl] -3-cyclohexyl-25- (3-pyrid-3-ylureido) propionamide (Compound 68) , a protected compound of Formula I
A solution of 25-amino-N- [2-benzooxazol-2-yl-2- (tert.-butyldimethylsilanyloxy) -15-phenethylethyl] -3-cyclohexyl propionamide (200.1 mg), provided as in Example 7, in dichloromethane (10 mL) was treated with 3-pyridyl isocyanate (48 mg). The mixture was stirred at room temperature for 16 hours and the solvent was evaporated under reduced pressure. The residue was subjected to flash column chromatography on silica eluting with a mixture of pentane and ethyl acetate (2: 1, v / v) to provide N- [2-benzooxazol-2-yl-2- (tert-butyldimethylsilanyloxy) - 15-phenethyl ethyl] -3-cyclohexyl-25- (3-pyrid-3-ylureido) propionamide (172 mg) as a colorless oil. EXAMPLE 12 N-. { 15- [2-Benzooxazol-2-yl-2- (tert-butyldimethyl-silanyloxy) -15-phenethylethylcarbamoyl] -2-cyclohexylethyl} Morpholine-4-carboxamide (Compound 69), a protected compound of Formula I
A solution of 2S-amino-N- [2-benzooxazol-2-yl-2- (erc-butyldimethylsilanyloxy) -15-phenethylethyl] -3-cyclohexyl propionamide (200 mg), provided as in Example 7, in dichloromethane ( 8 mL) was treated with 4-morpholinecarbonyl chloride (0.094 mL) and triethylamine (0.112 mL). The solution was stirred at room temperature for 20 hours. The solvent was evaporated under reduced pressure and the residue was purified by flash chromatography on silica eluting with a mixture of pentane and ethyl acetate (2: 1)., v / v) to provide N-. { 15- [2-Benzooxazol-2-yl-2- (tert-butyl dimethylsilanyloxy) -15-phenethylethylcarbamoyl] -2-cyclohexylethyl} Morpholine-4-carboxamide (143 mg) as a white solid. MH + 663. EXAMPLE 13 tert-butyl 4- [IR- (2-benzooxazol-2-yl-2-hydroxy-15-phenethylethyl carbamoyl] -2- [2-cyanobenzylsulfonyl) ethylcarbamoylpiperidine-1-carboxylate (Compound 70)
A solution of ters-butyl 4- [IR- (2-benzooxazol-2-yl-2-hydroxy-15-phenethylethylcarbamoyl] -2- (2-cyanobenzylsulphane) ethylcarbamoylpiperidine-1-carboxylate (95 mg), provided as in Example 8, in methanol (8 mL) was treated with a solution of OXONE "(246 mg) in water (8 mL) After stirring at room temperature for 10 hours the methanol was distilled under reduced pressure and the remaining aqueous phase extracted four times with ethyl acetate (20mL) The combined extracts were dried over magnesium sulfate and then concentrated by evaporation The residue was subjected to flash column chromatography on silica eluting with ethyl acetate to provide tert-butyl 4- [IR- (2-benzooxazol-2-yl-2-hydroxy-15-phenethylethyl carbamoyl] -2- [2-cyanobenzylsulfonyl) ethylcarbamoylpiperidine-1-carboxylate (35 mg) as gum MS: 744 [MH] + Proceed as in Example 13 to provide N- [1R- (2-benzooxazol-2-yl-2-hydroxy-15-phenethylethyl. carbamoyl) -2- (2-cyanobenzylsulfonyl) ethyl] isonicotinamide (Compound-71), HPLC: R t = 12.89 minutes. EXAMPLE 14 tert-Butyl IR- (2-benzooxazol-2-yl-2-hydroxy-15-phenethyl ethylcarbamoyl) -2-benzylsulfonyl-ethylcarbamate (Compound 72)
A solution of tert-butyl IR- (2-benzooxazol-2-yl-2-hydroxy-15-phenethylethylcarbamoyl) -2-benzylsulfanylethyl carbamate (3.62 g), provided as in Example 3, in dichloromethane (174 mL) was treated with meta-chloroperbenzoic acid (6.9 g). after stirring at room temperature for 5 hours, the reaction mixture was diluted with dichloromethane (100 mL), washed sequentially with a saturated solution of sodium bicarbonate (100 mL) and brine (100 mL), dried over sulfate of magnesium and then concentrated by evaporation. The residue was subjected to flash column chromatography on silica eluting with a mixture of pentane and ethyl acetate (1: 1, v / v) to give tert-butyl IR- (2-benzooxazol-2-yl-2-hydroxy) -15-phenethylethylcarbamoyl) -2-benzylsulfonylethylcarbamate (0.95 g) as a yellow solid. MS: 608 [MH] +. Proceed as in Example 14 to provide N- [1R- (2-benzooxazol-2-yl-2-hydroxy-15-phenethylethylcarbamoyl) -2-pyrid-3-ylmethylsulfonylethyl] pyrazine-2-carboxamide (Compound 73). EXAMPLE 15 N- (2-Benzooxazol-2-yl-2-hydroxy-15-phenethylethyl) -3-cyclohexyl-25- (3-pyrid-3-ylureido) propionamide (Compound 74)
A solution of N- [2-benzooxazol-2-yl-2- (ercbutyldimethylsilanyloxy) -15-phenethylethyl] -3-cyclohexyl-2S- (3-pyrid-3-ylureido) propionamide (172 mg) in tetrahydrofuran
(5 mL), provided as in Example 11, under an inert atmosphere at room temperature was treated with a solution of tetrabutylammonium fluoride in 1M tetrahydrofuran (0.4 mL). After stirring at room temperature for 90 minutes, the solvent is distilled under reduced pressure. The residue was subjected to flash column chromatography on silica eluting with a mixture of ethyl acetate and pentane (5: 1, v / v) to provide N- (2-benzooxazol-2-yl-2-hydroxy-15- phenethylethyl) -3-cydohexyl-25- (3-pyrid-3-ylureido) propionamide (108 mg) as a white solid. Continue as in Example 15 to provide N- [15- (2-benzooxazol-2-yl-2-hydroxy-15-phenethylethylcarbamoyl) -2-cyclohexylethyl] morpholine-4-carboxamide (Compound 75).
EXAMPLE 16 tert-Butyl 4- [IR- (15-benzooxazol-2-ylcarbonyl-3-phenylpropyl carbamoyl) -2- (2-cyano-benzylsulfonyl) -ethylcarbamoyl] piperidine-1-carboxylate (Compound 76)
A solution of tert-butyl 4- [IR- (2-benzooxazol-2-yl-2-hydroxy-15-phenethylethylcarbamoyl] -2- (2-cyanobenzylsulfonyl) -ethylcarbamoylpiperidine-1-carboxylate (35 mg), prepared as in Example 13, in dichloromethane (10 mL) was treated with Dess-Martin reagent (60 mg) The reaction mixture was stirred at room temperature for 5 hours, then washed with sodium thiosulfate in saturated sodium bicarbonate solution. Sodium was dried over magnesium sulfate and then concentrated by evaporation The residue was subjected to flash column chromatography on silica eluting with a mixture of ethyl acetate and pentane (1: 1)., v / v) to provide tert -butyl 4- [IR- (15-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl) -2- (2-cyanobenzyl sulfonyl) -ethylcarbamoyl] piperidine-1-carboxylate (26 mg) as rubber. MS: 742 [MH] +. Proceed as in Example 16 to provide the following compounds of Formula I: N- [IR- (15-benzooxazol-2-ylcarbonyl-3-phenylpropyl carbamoyl) -2-benzylsulfonylethyl] -tetrahydropyran-4-carboxamide (Compound 77) , mp 178-180 ° C, MS: 618 [MH] +; N- [IR- (15-benzooxazol-2-ylcarbonyl-3-phenylpropyl carbamoyl) -2-benzylsulfonylethyl] nicotinamide (Compound 78), m.p. 193-195 ° C, MS: 611 [MH] +; N- [IR- (15-benzooxazol-2-ylcarbonyl-3-phenylpropyl carbamoyl) -2-benzylsulfonylethyl] pyrazine-2 -carboxamide (Compound 79), m.p. 194-196 ° C. MS: 612 [MHr] +; tert-butyl 4- [15- (15-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl) -2-cyclohexylethylcarbamoyl] piperi-1-carboxylate (Compound 80); tert -butyl 4- [15- (15-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl) -2- (6-methylpyrid-2-ylmethylsulfonyl) ethyl carbamoyl] piperi-1-carboxylate (Compound 81), MS: 732 [MH] +, HPLC: Rt = 15.18 minutes; N- [IR- (15-benzooxazol-2-ylcarbonyl-3-phenylpropyl carbamoyl) -2- (2-cyanobenzylsulfonyl) ethyl] isonicotinamide (Compound 82), m.p. 204-206 ° C, MS: 636 [MH] +;
tetrahydropyran-4-yl IR- (lS-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl) -2-benzylsulfonyl ethylcarbamate (Compound 83), m.p. 93 ° C (with decomposition), MS: 634 [MH] +; benzyl 4 - [15- (15-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl) -2-cyclohexylethylcarbamoyl] -piperidine-1-carboxylate (Compound 84), MS: 677 [MH] +; N- (15-benzooxazol-2-ylcarbonyl-3-phenylpropyl) -3-cyclohexyl-25- (3-pyrid-3-ylureido) propionamide (Compound 85), MS: 554 [M] +; N- [15- (15-benzooxazol-2-ylcarbonyl-3-phenylpropyl carbamoyl) -2-cyclohexylethyl] morpholine-4-carboxamide (Compound 86), MS: 547 [MH] +; N- [15- (15-benzooxazol-2-ylcarbonyl-3-phenylpropyl carbamoyl) -2 -cyclohexylethylisonicotinamide (Compound 87), MS: 537 [M] +; N- [15- (15-benzooxazol-2-ylcarbonyl-3-phenylpropyl carbamoyl) -2-cyclohexylethyl] tetrahydropyran-4-carboxamide (Compound 88), MS: 546 [M] +; and N- [15- (15-benzooxazol-2-ylcarbonyl-3-phenylpropyl carbamoyl) -2-cyclohexylethyl] -6-hydroxynicotinamide (Compound 89), MS: 555 [M] +. EXAMPLE 17 N- [IR- (15-Benzooxazol-2-ylcarbonyl) -3-phenylpropylcarbamoyl) -2-benzylsulfonylethyl] morpholine-4-carboxamide (Compound 90)
A mixture of N- [15- (2-benzooxazol-2-yl-2-hydroxy-15-phenethylethylcarbamoyl) -2-benzylsulfonylethyl] morpholine-4-carboxamide (7.2 g, 11.6 mmol), prepared as in Example 1, and Dess-Martin periodinnan (9.87 g, 23.3 mmol) in dichloromethane (57 mL) was stirred at room temperature for 1 hour and then diluted with a 0.26 M solution of sodium thiosulfate in saturated sodium bicarbonate. The dilution was extracted with ethyl acetate and the extract was filtered. The filtrate was concentrated to give N- [1R- (15-benzooxazol-2-ylcarbonyl) -3-phenylpropylcarbamoyl) -2-benzylsulfonylethyl] morpholine-4-carboxamide (2.33 g) as an orange / gold oil. The solids collected from the filtration were absorbed in dichloromethane (700 mL) and the mixture was washed sequentially with water and saturated sodium bicarbonate solution, dried and concentrated to give N- [IR- (15-benzooxazol-2-ylcarbonyl ) -3-phenylpropylcarbamoyl) -2-benzylsulfonylethyl] morpholine-4-carboxamide (4.2 g) as a white powder. XH? MR (DMS0-d6) 8.024 (d, J = 6.68Hz, 1H), 7.9787 (d, J = 7.92Hz, 1H), 7.8857 (d, J = 8.16Hz, 1H), 7.6471 (td, J = 8.41, 0.99 Hz, 1H), 7.5455 (td, J = 8.16, 1.24Hz, 1H), 7.3806 (s, 5H), 7.2479 (m, 5H), 7.1210 (d, J = 4.53Hz), 1H, 5.2578 ( m, 1H), 4.7395 (m, 1H), 4.5059 (s, 2H), 3.5342 (m, 4H), 3.4082 (m, 2H), 3.30 (m, 4H (+ water)), 2.6963 (m, 2H) , 2.2768 (m, 1H), 2.0497 (m, 1H). MS (M + l) 619.2. Continue as in Example 17 to provide the following compounds of Formula I: N- [IR- (2-benzooxazol-2-yl-1, l-dimethyl-2-oxoethyl carbamoyl) -2-benzylsulfonylethyl] morpholine-4-carboxamide (Compound 91); E? MR: (DMSO) 9.26 (1H), 7.79 (d, J = 8Hz, 1H), 7.73 (d, J = 8Hz, 1H), 7.56 (t J = 8Hz, 1H). 7.47 (t, J = 8Hz, 1H), 7.36-5.55 (m, 5H). 6.70 (d, J = 8Hz, 1H), 4.67 (m.1H), 4.39 (d.J = 14Hz, 1H), 4.32 (d, Js = 14Hz, 1H), 3.49-3.00 (m.10H), 1.56 (s, 3H), 1.51 (s, 3H); MS: (M ++ 1) 543; N- [IR- (15-benzooxazol-2-ylcarbonylpentylcarbamoyl) -2- (3,5-dimethylsoxazol-4-ylmethylsulfonyl) ethyl] morpholine-4-carboxamide (Compound 92); 1H? MR: (DMSO) 8.66 (d, J = 6.6Hz,
1H), 7.99 (d, J = 8Hz, 1H), 7.88 (d, J = 8Hz, 1H). 7.62 (t, 10
J = 8Hz, 1H), 7.52 (t J = 8Hz, 1H), 7.02 (d, J = 7.7Hz, 1H), 5.24 (m, 1H), 4.76 (m, 1H), 4.39 (d, J = 14Hz, 1H), 4.27 (d, J = 14Hz.
1H), 3.63-3.20 (m, 10H), 2.33 (s, 3H), 2.15 (s 3H), 1.94 (m, 1H), 1.69 (m, 1H), 1.40-1.22 (m, 4H), 0.84 (t, J = 6.7Hz, 3H); MS: (M ++ 1) 590; and N- [IR- (15-benzooxazol-2-ylcarbonylpentylcarbamoyl) -2-2- (3, 5-dimethylisoxazol-4-ylmethylsulfonylethyl] isonicotinamide (Compound 93); 1H? MR: 15 (DMSO) 9.23 (d, J = 8Hz, 1H), 8.87 (d.I = 7Hz, 1H), 8.71 (m, 2H), 7.98 (d, J = 8Hz, 1H), 7.87 (d, J = 8Hz, 1H), 7.70 (m, 2H), 7.62 (t, J = 8Hz, 1H), 7.51 (t, J = 8Hz, 1H), 5.28 (ro, 1H), 5.10 (m, 1H), 4.44 (d, J = 14Hz, 1H). 4.37 (d, J = 14Hz, 1H), 3.80-3.52 (m, 2H), 2.33 (s, 3H), 2.14 (s, 3H), 1.95 (m, 1H), 1.69 (m, 1H). 1.22 (m. 4H), 0.82 (t, J == 6.7Hz, 3H); MS: (M ++ 1) 582. EXAMPLE 18 N- [IR- (15-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl) -2- (2-cyanobenzy1sulfoni1) eti1] piperidine-4-carboxamide (Compound 94)
A solution of tert -butyl 4- [IR- (15-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl) -2- (2-cyanobenzylsulfonyl) ethylcarbamoyl] pyridine-1-carboxylate (26 mg), provided as in Example 16 , in ethyl acetate (10 mL) was treated with hydrogen chloride, bubbling the gas through the solution for 3 minutes. A white solid formed which was filtered and dried under reduced pressure to give N- [1R- (15-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl) -2- (2-cyanobenzylsulfonyl) ethyl] piperidine-4-carboxamide (19) mg) as solid, mp = 155-157 ° C. MS: 678 [MH] +. Continue as Example 18 to provide N- [15- (15-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl) -2-cyclohexylethyl] piperidine-4-carboxamide hydrochloride (Compound 96), MS: 632 [MH] + HPLC: RT = 12.05 minutes. EXAMPLE 19 N- [15-Benzooxazol-2-ylcarbonylbutyl) -2R-methylsulfonylamino-3-benzylsulfonylpropionamide (Compound 159)
A solution of (R) -2- (2-methylsulfonyl acetylamino) -3-benzylsulfonylpropionic acid (212 mg, 0.66 mmol), (S) -2-amino-1-benzooxazol-2-ylpentan-1-ol (150 mg , 0.66 mmol), EDCI (165 mg, 0.858 mmol) and HOBT (110 mg, 0.726 mmol) in methylene chloride (3 mL) was stirred at room temperature for 2 hours, washed sequentially with hydrochloric acid, sodium bicarbonate solution, Sodium and brine and then concentrated. The residue was dissolved in dichloromethane and the solution was treated with Dess-Martin reagent (340 mg, 0.8 mmol) for 1 hour. The mixture was stirred with a solution of sodium thiosulfate / sodium bicarbonate and the mixture was extracted with ethyl acetate. The extract was washed sequentially with dilute hydrochloric acid, sodium bicarbonate and brine, dried (MgSO4) and then concentrated to give N- [15-benzooxazol-2-ylcarbonylbutyl) -2R-methyl sulfonylamino-3-benzylsulfonylpropionamide (49 mg , 0.09 mmol). XH? MR (DMSO): 9.0 (< U = 7Hz, 1H), 8.0 (d, J = 8Hz, 1H), 7.90 (d, J = 9Hz, 1H), 7.66 (tJ = 8Hz, 1H), 7A5 (U = 9Hz, 1H), 7.39 (5H), 5.32 (m, 1H), 4.55 (m.3H), 3.35 (m, 3H). 2.95 (s, 3H), 1.94 (m. 1H), 1.71 (m, 1H). 1.45 (m, 2H), 0.92 (I, J = 8Hz, 3H); MS: m / e = 522.03. EXAMPLE 20 Methyl IR- (15-benzooxazol-2-ylcarbonylbutylcarbamoyl) -2- benzylsulfonyl ethylcarbamate (Compound 158)
A solution of (R) -2- (2-methoxycarbonylamino) -3-benzylsulfonylpropionic acid (200 mg, 0.66 mmol), (S) -2-amino-1-benzooxazol-2-ylpentan-1-ol (150 mg, 0.66 mmol), EDCI (165 mg, 0.858 mmol) and HOBT (110 mg, 0.726 mmol) in methylene chloride (3 mL) was stirred at room temperature for 2 hours, washed sequentially with hydrochloric acid, sodium bicarbonate solution and brine and then concentrated. The residue was treated with Dess-Martin reagent
(340 mg, 0.8 mmol) in dichloromethane (4 mL) for 1 hour. The mixture was stirred with a solution of sodium thiosulfate / sodium bicarbonate and the mixture was extracted with ethyl acetate. The extract was washed sequentially with dilute hydrochloric acid, sodium bicarbonate and brine, dried
(MgSO4) and then concentrated. The residue was warmed with ethyl acetate and then treated with tert-butyloxymethyl.
The mixture was allowed to stand for about 12 hours and then cooled in an ice bath. The resulting solids were collected by filtration and washed with cold ethyl acetate to provide methyl IR- (15-benzooxazol-2-ylcarbonylbutylcarbamoyl) -2-benzylsulfonylethyl carbamate (133 mg, 0.26 mmol). (133 mg, 0.26 mmol). 1 H NMR (DMSO): 8.77 (d, J = 7Hz, 1H), 8.01 (d, J = 9Hz, 1H), 7.90 (d, J = 9Hz, 1H). 7.6 (m.2H). 7.55 (t, J = 9Hz, 1H), 7.39 (s, 5H),
. 3 (m.1H), 4.68 (m.1H), 4.48 (s, 2H), 3.55 (s, 3H), 3.52- 3.4 (m, 1H), 3.3 (m, 1H), 1.92 (m.1H) . 1.73 (m.I.l.), 1.42 (m, 2H), 0.91 (t, J = 8Hz, 3H); MS: m / e = 502.05. EXAMPLE 21 N- [IR- (15-Benzooxazol-2-ylcarbonylbutylcarbamoyl) -2- benzylsulfonylethyl] morpholine-4-carboxamide (Compound 158)
A solution of (R) -2- (2-morpholin-4-ylcarbonyl amino) -3-benzylsulfonylpropionic acid (356 mg, 1 mmol), EDCI (240 mg, mmol) and HOBT (178 g, mmol) in methylene chloride (8 mL) was (5) -2-amino-1-bezooxazol-2-ylpentan-1-ol (220 mg, mmol). The mixture was stirred at room temperature for 1.5 hours and then treated with additional EDCI (80 mg). The mixture was stirred for an additional 0.5 hours and then poured into cold, diluted hydrochloric acid. The mixture was extracted with ethyl acetate (2x) and the extract was washed sequentially with aqueous sodium bicarbonate and brine, dried (MgSO) and concentrated. The residue was dissolved in methylene chloride (8 mL) and the solution was treated with Dess-Martin reagent (544 mg). The mixture was stirred for 1.5 hours and then stirred in a solution of sodium thiosulfate / sodium bicarbonate for 15 minutes. The mixture was extracted with ethyl acetate (2x) and the extract was washed with brine, dried (MgSO 4) and then concentrated. The residue was triturated with ethyl acetate and then hexanes. The mixture was cooled in an ice bath and the resulting solids were collected and dried to provide N- [IR- (15-benzooxazol-2-ylcarbonylbutyl carbamoyl) -2-benzylsulfonylethyl] morpholine-4-carboxamide (408 mg, 73 % product). XH ™ MR 300mHz: 8.65 (d, J = 7.1H3, 1H), 8.01 (d, J = 8.8H3, 1H). 7.91 (d, J = 9.1H3, 1H), 7.65 0, J = 8.2H3, 1H), 7.55 (t, J = 9.1H3, 1H), 7.38 (s, 5H), 7.05 (d, J = 9A ^ 1H), 5.29 (m, 1H), 4.73 (m, 1H), 4.48 (s, 2H), 3.53 (m, 4H). 3.4-3.2 (m, 6H), 1.94 (m, 1H), 1-73 (m, 1H), 1.42 (m.2H), 0.91 (t, J = 8H3, 3H), MS = 557.21 M + = 556.20. Continue by methods analogous to those described in this Application providing the following compounds of Formula I: 2-acetylamino-N- (2-benzooxazol-2-yl-15-butyl-2-hydroxyethyl) -3-cyclohexylpropionamide (Compound 97 ) - "?? MR (CDC13): 7.67 (d, J = 8.0Hz, 1H), 7.53 (d.5 J = 6.0Hz, 1H), 7.34 (m, 2H), 6.64 (d, J = 8.1Hz , 1H), 5.99 (d, J = 8.1Hz, 1H), 5.03 (m, 1H), 4.39 (m, 2H), 2.02-0.70 (m.22Hz).; MS ESI: MH + 430; 25-acetylamino-N- (15-benzooxazol-2-ylcarbonylpentyl) -3-cyclohexylpropionamide (Compound 98); XH? MR (CDC13): 7.93
(d, J = 7.5Hz, 1H), 7.67 (d, J = 8.1Hz, 1H), 7.54 (t, J = 7.2Hz, 1H), 7.46 (t, J = 7.8Hz, 1H), 6.78 (d , J = 7.2Hz, 1H), 5.91 (d,
J = 8.4Hz, 1H), 5.63 (m, 1H), 10 4.59 (m, 1H), 2.09-0.85 (m,
24Hz); MS ESI: MH + 428; erc-butyl 15- [l-benzooxazol-2-ylcarbonyl) -3-phenylpropylcarbamoyl) -2-cyclohexylethyl] carbamate (Compound 99); 25-acetylamino-N- (1-benzooxazol-2-ylcarbonyl) -3-phenylpropyl) -3-cyclohexylpropionamide (Compound 100); 25-acetylamino-N- (1-benzooxazol-2-ylcarbonylcyclobutyl) -3-cyclohexylpropionamide (Compound 101); 25-acetylamino-N- (IR-benzooxazol-2-ylcarbonyl-3-phenylpropyl) -3-cyclohexylpropionamide (Compound 102);
-acetylamino-N- (2-benzooxazol-2-yl-2-hydroxy-1R-penylethylethyl) -3-cyclohexylpropionamide (Compound 103); N- [15-benzooxazol-2-ylcarbonyl) -3-phenylpropyl carbamoyl] -2-cyclohexylethyl] succinamic acid (Compound 104); XH? MR (CDC13): 7.87 (m, 1H), 7.62 (m, 1H). 7.52 (m, 1H), 7.43 (m, 1H), 7.15 (m, 6H), 6.89 (m, 1H), 5.62 (m, 1H), 4.56 (m, 1H), 2.75 (m, 2H) , 2.70 (m, 1H), 2.48 (m, 2H), 2.16 (m, 1H), 1.6 (m, 7H), 0.7-1.4 (m, 7H); MS: m / e 534; N- [15- (2-Benzooxazol-2-yl-2-hydroxy-15-phenethyl ethylcarbamoyl) -2-cyclohexylethyl] succinamic acid (Compound 105); ? H? MR (CDCI3): 12-04 (s, 1H), 7.89 (m, 1H), 7.80 (m, 1H), 7.65 (m.2H), 7.36 (m, 2H), 7.13-7.29 (m. 4H), 6.08-6.23 (m.H1), 4.62-4.93 (m, 1H), 4.15 (m, 1H). 2.64 (m, 1H). 2.50 (m.H.) 2.34 (m, 6H), 1.78 (m, 1H), 1.45-1.68 (m, 4H), 1.37 (m, 1H). 0.95-1.3 (m, 3H). 0.87 (m, 2H); MS; m / e = 535.8; N- acid. { l5- [15-benzooxazol-2-ylcarbonyl) -3-phenyl-propylcarbamoyl] -2-cyclohexylethyl-oxamic (Compound 106); (Compound 106); 2H? MR (CDC13): 6.6-7.9 (m, 10H), 5.6 (m, 1H), 4.5 (m, 1H), 2.72 (m, 1H), 2.45 (m, 1H), 0.8-2.1 (m, 15H); MS: m / e 506.2; N- [15- (15-benzooxazol-2-ylcarbonyl-3-phenylpropyl carbamoyl) -2-cyclohexylethyl] -3H-imidazole-4-carboxamide (Compound 107); 1H? MR (CDC13): 8.1 (m, 1H), 7.3-7.6 (m, 3H), 6.95-7.2 (m, 8H), 5.62 (m, 1H), 4.74 (m, 1H), 2.77 (m, 2H), 2.38 (m, 1H), 2.25 (m, 1H), 0.8-1.9 (m, 13H); MS; m / e 528.2; N- [15- (2-benzooxazol-2-yl-2-hydroxy-15-phenylethylethyl carbamoyl) -2-cyclohexylethyl] -3H-imidazole-4-carboxamide (Compound 108); XH NMR (CDC13): 7.0-7.6 (m, 12H), 5.05 (m, 1H), 4.5 (m, 1H), 2.75 (m, 2H), 0.6-2.2 (m, 15H); MS: m / e 529.6; Tert-butyl IR- (l-benzooxazol-2-ylcarbonylcyclobutylcarbamoyl) -2-benzylsulfonyl ethylcarbamate (Compound 109), m.p. = 70-85 ° C, MH + 542; N- [15- (15-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl) -2-cyclohexylethyl] malonamic acid (Compound 110); XH? MR (CDC13): 6.8-7.9 (m, 9H), 5.63) (m, 1H), 4.56 (m, 1H), 2.6-2.8 (m, 4H), 2.0-2.4 (m, 2H), 0.7 -2.0 (m, 13H); MS: m / e 520.4; N- [IR- (15-benzooxazol-2-ylcarbonyl-3-phenylpropyl carbamoyl) -2-o-tolylmethylsulfonylethyl] morpholine-4-carboxamide (Compound 111); 1H? MR 300mHz (DMSO-d6) PPM, 8,841 (d, J = 6.2Hz, 1H), 7,942 (d, J = 5.2Hz. 1H), 7,860 (d, J = 8.4Hz, 1H), 7,618 (t , J = 8.1Hz, 1H), 7.516 (t, J = 8.1Hz, 1H), 7.16 (m, 10H), 5.22 (m, 1H), 4.78 (m, 1H), 4.516 (s, 2H), 3.567 (m, 2H), 3,500 (m, 6H), 3.3 (s, 3H), 2.75 (m, 1H), 2.65 (m, 1H), 2.44 (m, 1H), 2.26 (m, 2H), 2.01 ( m, 1H); MS: M + = 633.4 M- = 631.4;
N- [IR- (15-benzooxazol-2-ylcarbonyl-3-phenylpropyl carbamoyl) -2- (2-nitrobenzylsulfonyl) ethyl] morpholine-4-carboxamide (Compound 112); XH ™ MR 300mHz (DMSO-ds) PPM, 8,840 (d, J = 7.0Hz, 1H), 8,025 (d, J = 8.0Hz, 1H), 7,950 (d, J == 8.4Hz, 1H), 7,858 ( d, J = 7.7Hz, 1H), 7.730 (d, J-8.8HZ, 1H), 7.646 (t, J = &4Hz, IH), 7.515 (t, J = 7.7Hz, 1H), 5.223 (m , 1 HOUR) . 5.004 (s, 2H), 4.694 (m, 1H), 3.561 (m, 2H). 3.510 (m, 6H). 2756 (m, 1H). 2652 (m, 1H), 2.429 (m, 2H), 2243 (m, 1H), 1983 (m, 1H); MS: M + = 664.2 M- = 662.4; N- [IR- (15-benzooxazol-2-ylcarbonyl-3-phenylpropyl carbamoyl) -2- (2-chlorobenzylsulfonyl) ethyl] morpholine-4-carboxamide (Compound 113); XH? MR 300mHz (DMSO-d6) PPM, 8851 (d, J = 6.2Hz, 1H), 7,953 (d, J = 8.8Hz. 1H), 7,855 (d, J = 8.4Hz, 1H), 7,627 (t J = 6.6Hz, 1H), 7.498 (m, 3H), 7.365 (m, 2H), 7.211 (m, 6H). 5,220 (m, 1H), 4,774 (m, 1H), 4,659 (m, 2H), 3,578 (m, 2H), 3,499 (m, 6H), 2,752 (m, 1H), 2,648 (m, 1H), 2,472 (m, 2H), 2243 (m, 1H), 1992 (m, 1H); MS: M + = 653.2; N- [IR- (15-benzooxazol-2-ylcarbonylpentylcarbamoyl) -2-benzylsulfonylethyl] morpholine-4-carboxamide (Compound 114); ? MR 300mHz (DMSO-d6), 8.64 (d, J = 7.4H3, 1H), 8.01 (d, J = 8.8H3, 1H), 7.91 (d, J = 9.1H3, 1H), 7.68 (t, J) = 6H3,1H), 7.55 (t, 5 J = 8.2H3, 1H), 7.38 (s, 5H), 7.05 (d, J = 9.6H, 1H), 5.26 (m, 1H), 4.72 (m, 1H ), 4.49 (s, 2H), 3.55 (m, 4H), 3.5-3.2 (m, 6H), 1.96 (m, 1H), 1.76 (m, 1H), 1.38 (m, 4H), 0.87 (t, J = 7.4H3, 3H); MS: 571.24 M + = 570.20; N- [IR- (15-benzooxazol-2-ylcarbonylpentylcarbonyl) -2-o-tolylmethylsulfonylethyl] morpholine-4-carboxamide (Compound 115); ? MR 300mHz 10 (DMS0-d6), 8.70 (d, J = 6.9H3, 1H), 8.01 (d, J = 9.1H3, 1H), 7.91 (d, J = 8.8H3, 1H), 7.67 (t, J = 8H3, 1H), 7.55 (t, J = 8.5H, 3H), 7.3-7.1 (m, 4H), 7.05 (d, J = 9.6H3 H), 5.26 (m, 1H), 4.80 (m, 1H), 4.53 (s, 2H), 3.58 (m, 4H), 3.33 (m, 6H), 2.33 (s, 3H), 1.96 (m, 1H), 1.72 (m, 1H), 1.35 (m, 4H) ), 0.87 (t, J = 7.7H3); MS = 585.30, M + = 584.23; N- [IR- (15-benzoozaxol-2-ylcarbonylpentylcarbamoyl-2- (2-nitrobenzylsulfonyl) ethyl] morpholine-4-carboxamide (Compound 16);? MR 300mHz (DMS0-d6), 8.70 (d, J = 7.2H3 , 1H), 8.1-7.5 (m, 8H), 7.05 (d, J = 9.3H3, 1H), 5.26 (m, 1H), 5.01 (s, 2H), 4.70 (m, 1H), 3.57 (m, 5H), 3.30 (m, 5H), 1.96 (m, 1H), 1.72 (m, 1H), 1.34 (m, 4H), 0.87 (t, J = 7.7H3, 3H), MS: 616.09 M + = 615.20; N- [IR- (15-benzooxazol-2-ylcarbonylpentylcarbamoyl) -2- (2-chlorobenzisulfoni1) eti1] morpholine-4-carboxamide (Compound 117);? MR 300mHz (DMSO-d6), 8.71 (d, J = 7.1 H3, 1H), 8.1-73 (m, 8H), 7.06 (d, J = 9.6H3, 1H), 5.26 (m, 1H), 4.79 (m, 1H), 4.72 (d, J = 15H3, 1H) , 4.65 (d, J = 15H3, 1H), 3.56 (m, H), 3.30 (m, 6H), 1.96 (m, 1H), 1.73 (m, 1H), 1.35 (m, 4H), 0.87 (t , J = 7.7H3, 3H); MS: 605.24 M + = 605.10;
N- [IR- (2-benzooxazol-2-yl-l, l-dimethyl-2-oxoethylcarbamoyl) -2-o-tolylmethylsulfonylethyl] morpholine-4-carboxamide (Compound 118); MS: (M ++ 1) 557; N- [IR- (2-Benzooxazol-2-yl-1, 1-dimethyl-2-oxoethylcarbamoyl) -2- (2-chlorobenzylsulfonyl) ethyl] morpholine-4-carboxamide (Compound 119); MS: (M ++ 1) 578; N- [IR- (2-benzooxazol-2-yl-l, l-dimethyl-2-oxoethyl-carbamoyl-2- (2-nitrobenzylsulfonyl) ethyl] morpholine-4-carboxy ida (Compound 120); XH? MR: ( DMSO) 30 9.34 (1H), 8.02 (d, J = 7.7Hz, 1H), 7.82-7.45 (m, 7H), 6.74 (d, J = 8.8Hz, 1H), 4.87 (m, 2H), 4.64 (m, 1H), 3.44-3.11 (m.10H), 1.56 (s, 3H), 1.50 (s, 3H); MS: (M ++ l) 588; N- [IR- (15-benzooxazole- 2-ylcarbonyl-3-phenylpropyl carbamoyl) -2-pyrid-2-ylmethylsulfonylethyl] piperidine-4-carboxamide (Compound 121); MS: m / e + 1 = 616.2; N- [IR- (15-benzooxazole) -2 -carbonylpentylcarbamoyl) -2-pyrid-2-ylmethylsulfonylethyl] morpholine-4-carboxamide (Compound 122); XH? MR: 8.62 (d, 6.9 Hz, 1 H), 8.55 (d, 3.2 Hz, 1H), 8.00 (d , 7.0 Hz, 1H), 7.86 (m, 2H), 7.65 (t, 6.2 Hz, 1H), 7.48-7.58 (m, 2H), 7.40 (m, 1H), 7.06-7.25 (m, 3H), 5.28 (m, 1H), 4.74 (m, 1H), 4.67 (d, 1.1 Hz, 2H), 3.53 (m, 4H), 3.31 (m, 4H), 1.99 (m, 1H), 1.75 (m, 1H) , 1.32 (m, 4H), 0.87 (4 6.7 Hz, 3H), MS: M + l = 571.8;
N- [IR- (LR-benzooxazol-2-ylcarbonyl-3-phenylpropyl carbamoyl-2-benzylsulfonylethyl] morpholine-4-carboxamide (Compound 123);? - [IR- (l-benzooxazol-2-ylcarbonylcyclobutylcarbamoyl) -2 -benzylsulfonylethyl] morpholine-4-carboxamide (Compound 124); MH + 555; benzyl 15- (2-benzooxazol-2-yl-2-hydroxyethyl carbamoyl) -3-methylbutylcarbamate (Compound 125); 25-acetyl amino-N- (2 -benzooxazol-2-yl-15-methyl-2-oxoethyl) -3-cyclohexyl-propionamide (Compound 126);
(CDC13): 7.92 (d, J = 8.4Hz, 1H), 1. 13 -7. 61 (m, 1H), 7.60-7.48
(m, 2H), 5.94 (d, J = 8.7Hz, 1H), 6.65 (m, 1H), 2.03 (d,
J = 7.2Hz, 2H), 1.64 (m, 6H), 1.56-0.92 (m, 10Hz); MS ESI: MH + 386; tert-butyl IR- (l-benzooxazol-2-ylcarbonylcyclobutylcarbamoyl]) -2-benzylsulfanyl ethylcarbamate (Compound 127); ? - [IR- (15-benzooxazol-2-ylcarbonyl-3-methyl-sulfonyl-propylcarbamoyl) -2-benzylsulfonylethyl] -morpholine-4-carboxamide (Compound 128); ? H? MR (CDC13): 7.89 (d, J = 7.4Hz, 1H), 7.65 (m, 1H), 7.57 (m, 1H), 7.48 (m, 1H), 7.4 (m, 5H), 6.0 ( m, 1H), 5.7 (m, 1H), 4.93 (m, 1H), 4.33 (m, 3H), 3.70 (m, 5H), 3.25-3.4 (m, 7H), 2.93 (m, 3H), 2.8 (m, 1H), 2.35 (m, 1H); MS: m / e 653.2;
N- [1- (15-benzooxazol-2-ylcarbonylpentylcarbamoyl) -3-phenylsulfanylpropyl] morpholine-4-carboxamide (Compound 129); ? H? MR (DMSO); 8.52 (s, J = 8Hz, 1H), 8.98 (d, J = 8Hz, 1H), 8.88 (d, J = 9Hz, 1H), 7.64 (t, J = 8Hz, 1H), 7.53 (t, J = 9Hz, 3H), 7.30 (m, 4H), 7.19 (m, 1H), 5.25 (m, 1H), 4.35 (m, 1H); 3-51 (m, 4H), 3.26 (m, 4H), 2.94 (t, J = 8Hz, 2H), 1.9 (m, 3H), 1.7 (m, 1H), 1.31 (m, 4H), 0.86 ( t, J = 8Hz, 3H), 6.53 (d, J = 9Hz, 1H); MS: m / e = 539.24; N- [IR- (15-benzooxazol-2-ylcarbonylpentylcarbamoyl) -2- (2-trifluoromethylbenzylsulfonyl) ethyl] morpholine-4-carboxamide (Compound 131); XH? MR: (DMSO) 8.78 (d, J = 8Hz, 1H), 8.06-7.50 (m, 8H), 7.04 (d, J = 8Hz, 1H), 5.27 (m, 1H), 4.82-4.64 (m , 3H), 3.65-3.25 (m, 10H), 1.96 (m, 1H), 1.71 (m, 1H), 1.41-1.22 (m, 4H), 0.84 (t, J = 7Hz, 3H). MS: (M ++ 1) 639; N- [IR- (15-benzooxazol-2-ylcarbonyl-3-phenylpropyl carbamoyl) -2-pyrid-2-ylmethylsulfonylethyl] morpholine-4-carboxamide (Compound 132); 1H? MR (DMSO): 8.78 (d, J = 7.2Hz, 1H), 8.56 (d, J = 5.4H2, 1H), 7.98 (d, J = 8.4Hz, 1H), 7.85 (m, 2H), 7.64 (tJ = 12.1Hz, 1H), 7.52 (m, 2H), 7.38 (m, 1H), 7.10-7.34 (m, 8H), 5.25 (m, 1H), 4.70 (m, 3H), 3.55-3.70 (m, 4H), 3.35 (s, 4H), 2.80 (m, 2H), 2.25 (m, 1H), 2.0 (m, 1H); MS: m / c (+1) = 620.0; N- [IR- (15-Benzooxazol-2-ylcarbonyl-3-methylsulfonylpropylcarbamoyl) -2-pyrid-2-ylmethylsulfonylethyl] morpholine-4-carboxamide (Compound 133); XH? MR (DMSO): 8-83 (d, J = 7.6Hz, 1H), 8.55 (d, J = 4.0Hz, 1H), 7.97 (d, J = 7.6Hz, 1H), 7.88 (m, 3H) ), 7.64 (t, J = 7.2Hz, 1H), 7.39-7.54 (m, 4H), 7.15 (d, J = 7.6Hz, 1H), 5.36 (m, 1H), 4.70 (m, 3H), 3.56 (m, 6H), 3.24 (m, 4H), 2.40 (m, 1H), 2.15 (m, 1H), 2.99 (s, 3H); MS: m / e (+1) = 622.2; 2- [2- (l-Benzooxazol-2-ylcarbonylpentyl carbamoyl) -2-morpholine-4-ylcarbonylamino) ethanesulfonylmethyl] pyridine 1-oxide (Compound-134): XH NMR (DMSO): 8.75 (d, J = 6.5Hz, 1H), 8.38 (m, 2H), 7.96 (d, J == 7.7Hz, 1H), 7.89 (d, J = 7.7Hz, 1H), 7.48-7.69 (m, 6H), 7.05 (d , J = 6.8Hz, 1H), 5.22 (m, 1H), 4.95 (d, J = 2.7Hz, 2H), 5.85 (m, 1H), 5.53 (m, 4H), 3.30 (s, 4H), 1.95 (m, 1H), 1.70 (m, 1H), 1.30 (m, 4H), 0.88 (t, J = 5-4Hz, 3H); MS: MW = 587.65 M + l = 588.2; N- [IR- (15-benzooxazol-2-ylcarbonylbutylcarbamoyl) -2- (2-difluoromethoxybenzylsulfonyl) ethyl] morpholine-4-carboxamide (Compound 135); ? MR 300mHz (DMSO-d6), 8.70 (d, J = 7.1H3, 1H), 8.01 (d, J = 8.8H3, 1H), 7.91 (d, J = 9.1H3, 1H), 7.65 Ct, J = = 8H3, 1H), 7.55 (t, J = 8.2H), 7.11 (t J = 8.2H), 7.4-6.8 (m, 5H), 5.28 (m, 1H), 4.76 (m, 1H), 4.5 (s, 2H), 3.55 (m, 4H), 3.3 (m, 6H), 1.93 (m, 1H), 1.71 (m, 1H), 1.42 (m, 2H), 0.91 (t, J = 8H3, 3H ); MS: 623.38 M + = 622.19; N- [3-phenylsulfonyl-1- (15-benzooxazol-2-ylcarbonyl pentylcarbomayl) propyl] morpholine-4-carboxamide (Compound 136); XH .NMR (DMSO): 8.5 (m, 2H), 8.00 ((d, J = 9Hz, IH), 7.9-7.5 (m, 8H), 6.54 30 (t, J = 9Hz, 1H), 4.28 (m , 1H), 3.49 (m, 4H), 3.24 (m, 6H), 1.90 (m, 3H), 1.65 (m, 1H), 1.31 (m, 4H), 0.85 (t, J = 7Hz, 3H); MS: m / e = 571.39; N- [IR- (15-benzooxazol-2-ylcarbonylpentylcarbamoyl) -2- (2-difluoromethoxybenzylsulfonyl) ethyl] morpholine-4-carboxyamide (Compound 137); XH? MR: (DMSO) 8.66 (d, J = 6.6Hz, 1H), 7.99 (d, J = 8Hz, 1H), 7.87 (d, J = 8Hz, 1H), 7.67-6.83 (m, 8H), 5.25 (m, 1H), 4.73 (m, 1H), 4.54 (s.2H), 3.60-3.23 (m, 10H), 1.93 (m, 1H), 1.68 (m, 1H), 1.40-1.22 (m, 4H), 0.84 (t, J) = 6.7Hz, 3H); MS: (M ++ 1) 637; N- [IR- (15-benzooxazol-2-ylcarbonylpentylcarbamoyl) -2- (2-difluoromethoxybenzylsulfonyl) ethyl] isonicotinamide (Compound 138); XH? MR : (DMSO) 9.22 (d, J = 8Hz, 1H), 8.87 (d, J = 6Hz, 1H), 8.70 (m, 2H), 7.97-7.19 (m, 10H), 7.08 (t, JH.p = 74Hz, 1H), 5.30-5.09 (m, 2H), 4.58 (s, 2H), 3.73-3.59 (m, 2H), 1.94 (m, 1H), 1.71 (m, 1H), 1.41-1.22 (m, 4H),), 0.82 (t, J = 6.7Hz, 3H); MS: (M ++ 1) 629; N- [IR- (lS-benzooxazol-2-ylcarbonylpentylcarbamoyl) -2-pyrid-2-ylmethylsulfonyl) ethyl] morpholine-4-carboxamide (Compound 139) z1! MR (DMSO): 8.6 (m, 2H), 8.05 (d, J = 5.1Hz, 1H), 7.85 (m, 2H), 7.3-7.8 (m, 4H), 7.2 (m, 3H), 5.32 ( m, 1H), 4.72 (m, 1H), 4.65 (dJ = 3.1Hz, 2H), 3.21-3.75 (m, 8H), 1.90 (m, 1H), 1.75 (m, 1H), 1.45 (m, 2H) ), 0.90 (t, J = 4.5Hz, 3H); MS: m / e + 1 = 558.2; MS: m / e (+1) = 558.2;
1-oxide of 2 [2R- (lS-benzooxazol-2-ylcarbonylbutyl carbamoyl) -2-morpholin-4-ylcarbonylaminoethylsulfonylmethyl] pyridine (Compound 140); XH NMR (DMSO): 8.57 (m, 3H), 7.97
(m, 1H), 7.63-7.82 (m, 3H), 7.35-7.45 (m, 4H), 6.93 (m, 1H), 4.50-4.95 (m, 2H), 4.18 (m, 2H), 3.10-3.80 (m, 8H), 1.10-1.70
(m, 4H), 0.82 (t, J = 5.4Hz, 3H); MS: m / e (+1) = 574.2; IR- (15-benzooxazol-2-ylcarbonylpentylcarbamoyl) -2- (2-difluoromethoxybenzylsulfonyl) -ethylenecarbonate (Compound 141); MS: (M ++ 1) 582; N- [IR- (15-benzooxazol-2-ylcarbonylpentyl carbamoyl) acid) -2-benzylsulfonylethyl] succinnamic (Compound 142);? H NMR; (DMSO) 12.09 (s, 1H), 8.63 (d, J = 6Hz, 1H), 8.51 (d, J = 8Hz, 1H), 7.98 (d , J = 8Hz, 1H), 7.87 (d, J = 8Hz, 1H), 7.62 (t, J = 8Hz, 1H), 7.52 (t, J = 8Hz, 1H), 7.38-7.30 (m, 5H), 5.25 (m, 1H), 4.84 (m, 1H), 4.46 (s, 2H), 3.53--3.21 (m, 2H), 5.28-5.25 (m, 4H), 1.93 (m, 1H), 1.68 (m , 1H), 1.40-1.22 (m, 4H), 0.84 (t, J = 6.2Hz, 3H); MS: (M + +1) 558; 2R- [3, 3-bis (2-methoxyethyl) ureido] - N-flS-benzooxazol-2-ylcarbonylpentyl) -3-benzylsulfonylpropionamide (Compound 143); XH? MR: (DMSO) 8.50 (d, J = 6.6Hz, 1H), 7.98 (d, J = 8Hz,
1H), 7.88 (d, J = 8Hz, IH), 7.62 (t, J = 8Hz, 1H), 7.52 (t, J = 8Hz, 1H), 7.38-7.30 (m, 5H), 6.82 (d, J = 8Hz, 1H), 5.26 (m, 1H), 4.70 (m, 1H), 4.46 (s, 2H), 3.52-3.22 (m, 10H), 3.31 (s, H), 1.94 (m, lH), 1.69 (m, 1H), 1.40-1.22 (m, 4H), 0.85 (t, J = 6.6Hz, 3H); MS: (M ++ 1) 617;
N- [IR- (lS-benzooxazol-2-ylcarbonyl-3-phenylpropyl carbamoyl) -2- (6-methylpyrid-2-ylmethylsulfonyl) ethyl] isonicotinamide (Compound 144); 1H? MR (DMSO): 8069 (t, J = 6Hz, 1H), 8.55 (d, J = 9Hz, lH), 7.91, (m, 2H), 7.51 (m, 3H), 4.51 (m, 1H) , 4.11 (d, J = 6Hz, 2H), 1.5 (m, 15H); MS; m / e = 328.05; Acid? - [IR- (15-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl) -2-benzylsulfonylethyl] succinnamic acid (Compound 145); MS (ESI) MH + 478.2; N- [IR- (15-benzooxazol-2-ylcarbonyl-3-phenylpropyl carbamoyl) -2- (2-trifluoromethylbenzylsulfonyl) ethyl] tetrahydro pyran-4-carboxamide (Compound 146); N- [IR- (15-benzooxazol-2-ylcarbonyl-3-phenylpropyl carbamoyl) -2-thien-3-ylmethylsulfonylethyl] isonicotinamide (Compound 147); N- [IR- (15-benzooxazol-2-ylcarbonyl-3-phenylpropyl carbamoyl) -2- (6-methylpyrid-2-ylmethylsulfonyl) ethyl] tetrahydro pyran-4 -carboxamide (Compound 148); N- [IR- (1-benzooxazol-2-ylcarbonylcyclobutylcarbamoyl) -2- (2-trifluoromethylbenzylsulfonyl) ethyl] tetrahydro pyran-4-carboxamide (Compound 149); N- [IR- (15-benzooxazol-2-ylcarbonyl-3-phenylpropyl carbamoyl) -2-pyrid-3-ylmethylsulfonylethyl] pyrazine-2-carboxamide (Compound 150);
N- [1- (1-benzooxazol-2-ylcarbonyl-3-phenylpropyl carbamoyl) -2-thien-3-ylmethylsulfonylethyl] piperidine-4-carboxamide (Compound 151); N- [15- (15-benzooxazol-2-ylcarbonyl-3-phenylpropyl carbamoyl) -2-thien-3-ylmethylsulfonylethyl] azetidine-3-carboxamide (Compound 152); N- [IR- (15-benzooxazol-2-ylcarbonyl) butylcarbamoyl) -2-pyrid-3-ylmethylsulphonylethyl] morpholine-4-carboxamide (Compound 153); 1H? MR (DMSO): 8.66 (d, J = 6.7Hz, 1H), 8.56 (m, 3H), 8.01 (d, J = 7.9Hz, 1H), 7.90 (d, J = 8.1Hz, 1H), 7.79
(m, 1H), 7.65 (t, J = 7.1Hz, 1H), 7.55 (t, J = 7.1Hz, 1H), 7.43
(dd, J = 4.9.7.9Hz, 2H), 6.93 (d, J = 8.40Hz, 1H), 5.30 (m,
J = lHz, 1H), 4.76 (m, 1H), 4.57 (d, J = 3.7Hz, 2H), 3.24-3.70
(m, 8H), 1.91 (m, 1H), 1.73 (m, 1H), 1.40 (m, 2H), 0.82 (t, J = 5.4Hz, 3H); MS: m / e (+1) = 555.8; N- [IR- (15-benzooxazol-2-ylcarbonyl-3-phenylpropyl carbamoyl) -2-benzylsulfonylethyl] piperazine-1-carboxamide (Compound 154); N- [IR- (15-benzooxazol-2-ylcarbonyl-3-methylsulfonylpropylcarbamoyl) -2- (2-difluoromethoxybenzylsulfonyl) ethyl] morpholine-4-carboxamide (Compound 155); 1H? MR (CDCL3, 300MHz) 7.8944 (d, J = 7.92Hz, 1H), 7.67 (m, 1H), 7.58 (m, 1H), 4.49 (m, 2H), 7.415 (m, 1H), 7- 24 (m, 3H), 6.5811 (t, J = 73.24Hz, 1H), 5.7633 (m, 1H), 4.9199 (m, 1H), 4.4871 (dd, J = 13.61, 23.75Hz, 2H), 3.7101 (m , 4H), 3.4189 (m, 4H), 3.27 (m, 2H), 2.9289 (s, 3H),. 2.77 (m, 1H), 2.37 (m, 1H); MS: (M +) 687.3 (M ~) 685.6; N- [IR- (15-benzooxazol-2-ylcarbonyl-3-methylsulfonylpropylcarbamoyl) -2- (2-methoxybenzylsulfonyl) ethyl] morpholine-4-carboxamide (Compound 156); 1H? MR (CDC13): 7.89 (m, 1H), 7.45-7.8 (m, 3H), 7.35 (m, 2H), 6.9-7.05 (m, 2H), 5-83-5.9 (m, 1H), 5 5.62-5.8 (m, 1H), 4.82 (m, 1H), 4.40 (m, 2H), 3.89 (s, 3H), 3.70 (m, 5H), 3.25-3.42 (m, 7H), 2.95 (s) 3H), 2.75 (m, 1H), 2.35 (m, 1H); MS: m / e 651.4; N- [IR- (15-benzooxazol-2-ylcarbonylpentylcarbamoyl) -2-benzylsulfonylethyl] piperazine-1-carboxamide (Compound 157); XH? MR: (DMSO) 9.20-9.11 (m, 2H), 8.73 (m, 1H), 7.98 (d, J = 8Hz, 1H), 7.88 (d, J == 8Hz, 1H), 7.63 (t. JA8Hz, 1H), 7.52 3 (t, J = 8Hz, 1H), 7.39-7.30 (m, 5H), 5.24 (m, 1H), 4.74 (m, 1H), 4.50 (s 2H), 3.62-3.30 (m, 6H), 3.05-2.95 (m, 4H), 1.94 (m, 1H), 1.69 (m, 1H), 1.40-1.22 (m, 4H), 0.84 (t J = 6.6Hz, 3H); MS: (M + + 1) 570; N- (15-benzooxazol-2-ylcarbonyl-3-methyl-sulfonyl-propyl) -2R-methylsulfonylamino-3-benzylsulfonylpropionamide (Compound 160); 1H? MR (DMSO-d6) 7.9498 (m, 2H), 7.6577 (m, 1H), 7.5556 (m, 1H), 7.3870 (m, 5H), 5.4016 (m, 1H), 4.5444 (m, 3H), 3.32 (m, 2H), 2.9784 (s, 1H), 2.9326 (s, 1H), 2.49 (m, 1H), 2.20 (m, 1H); MS: (M +) 586.0, (M ") 584.0;
methyl IR- (15-benzoxazol-2-ylcarbonyl-3-phenylpropyl carbamoyl) -2 -pyrid-2-ilmetilsulfoniletilcarbamato (Compound 161); MS: m / e (+1) = 564.6; methyl IR- (15-benzooxazol-2-ylcarbonyl-3-methylsulfonylpropylcarbamoyl) -2 -benzylsulfonylethylcarbamate (Compound 162); XH NMR (DMSO); 9.03 (d, J = 7.2Hz, 1H), 7.97 (d, J = 7.9Hz, 1H), 7.90 (d, J = 8.2Hz, 1H), 7.65 (td, J = 7.2, 1.2Hz, 1H), 7.55 (t, J = 7.9Hz, 1H), 7.37 (m, 5H), 5.32 (m, 1H), 4.65 (m, 1H), 4.50 (m, 2H), 3.53 (m, IH), 3.49 (s) , 3H), 3.33 (s, 2H), 3.24 (m, 1H), 2.98 (s, 3H), 2.41 (m, 1H), 2.18 (m, 1H); MS; m / e 653.2; N- (15-benzooxazol-2-ylcarbonyl) -2R- [3, 3-di (2-methoxyethyl) ureido] -3-pyrid-2-ylmethylsulfonylpropionamide (Compound 163); MS; m / e + 1 = 615.6; N- [IR- (15-benzooxazol-2-ylcarbonylbutylcarbamoyl) -2- (2-methoxybenzylsulfonyl) ethyl] morfoime-4 -carboxamide (Compound 164); XH? MR (DMSO): 8.66 (d, J = 6Hz, 1H), 8.03 ((d, J = 9Hz, 1H), 7.93 ((d, J = 9Hz, 1H), 7.68 (t, J = 8Hz, 1H), 7.58 (t, J = 9Hz, 1H), 7.36 (m, 2H), 7.0 (m, 3H), 5.29 (m, 1H), 4.77 (m, 1H), 4.54 ((d, J = 14Hz , 1H), 4.43 (d, J = 14Hz, 1H), 3.84 (s, 3H), 3.5-3.3 (m, 10H), 1.95 (m, 1H), 1.74 (m, 1H), 1.46 (m, 2H) ), 0.93 (t, J = 8Hz, 3H); MS; m / e = 587.31;? - (15-benzooxazol-2-ylcarbonylbutylcarbamoyl) -2R- (3,3-dimethylureido) -3- (2-methoxybenzylsulfonyl); propionamide (Compound 165);? MR 300mHz (DMSO-d6), 8.63 (d, J = 6.9H3, 1H), 8.03 (d, J = 8.8H, 1H), 7.92 (d, J = 9.1, 1H) , 7.70 (t, J = 8.8H3, 1H), 7.58 (t, J = 8.2H3, 1H), 7.37 (m, 2H), 7.08 (d, J = 9.1H3, 1H), 6.98 (t, J = 8.2H3, 1H), 6.71 (d, J = 9.1H3, 1H), 5.27 (m, 1H), 4.77 (m, 1H), 4.55 (d, J = 15.1H3, 1H), 4.43 (d, J = 15.1H3, 1H), 3.79 (s, 3H), 3.47 (d, J = 6.9H3, 2H), 2.83 (6H), 1.93 (m, 1H), 1.75 (m, 1H), 1.43 ( m, 2H), 0.93 (t, J = 8H3, 3H); N- (15-benzoxazol-2-ilcarbonilbutil) -2-methylsulfonyl amino-3 - (2-metoxibe n-sulphonylpropionamide (Compound 166); XH? MR (DMSO): 9.0 ((d, J = 6Hz, 1H), 8.01 ((d, J = 8Hz, 1H), 7.91 (d, J = 8Hz, 1H), 7.67 (t, J = 7Hz, 1H), 7.57 (t, J = 8Hz, 1H), 7.36 (t, J = 8Hz, 2H), 7.07 (d, J = 8Hz, 1H), 6.97 (dt, J = 2.7Hz, 1H), 7.85 (m, 1H), 5.33 (m, 4H), 4.5 (m, 3H), 3.8 (s, 3H), 3.35 (m, 2H), 2.92 (s, 3H), 1.93 (m, 1H), 1.72 ( m, 1H), 1.44 (m, 2H), 0.91 (t, J = 7Hz, 3H); MS: m / e = 552.l9; 3-cyclohexyl-N- (2-hydroxy-2- (5-nitrobenzooxazole -2-yl) -15-f-eethylethyl] propionamide (Compound 167); MS (ESI) m / z = 466 (M + 1); ^ -? MR (300 MHz, CDC13,): d 5 0.95 (m, 2H), d 1.22 (m, 4H), d 1.51 (m, 2H), d 1.65 (m, 6H), d 2.15 (m, 2H), d 2.65 (m, 2H), d 4.15 (m, 1H) , d 4.50 (m, 1H), d 5.08 (m, 1H), d 5.80 (d, J = 6 Hz, 1H), d 6.09 (m, 1H), d 7-00 - 7.35
(, 5H), d 7.60 (m, 1H), d 8.40 (m, 1H), d 8.55 (m, 1H), (C26H3 ?? 305); Methyl 2- [25-r-3-cyclohexylpropionylamino) -1-hydroxy-4-phenylbutyl] benzooxazole-6-carboxylate (Compound 168); MS (ESI) m / z = 478 (M + 1); XH-? MR (300 MHz, CDCl 3): d 0.84 (, 2H), d 1.22 (m, 4H), d 1.51 (m, 7H), d 1.90 (m, 1H), d 2.11 (m, 2H), d 2.65 (m, 2H), d 3.95 (s, 3H), d 4.19 (m, 1H), d 4.50 (m, 1H), d 5.09 (s, 1H), d 6.09 (m, 1H), d 6.49 (m, 1H), 7.01 d - 7.35 (m, 5H), d 7.65 (m, 1H), 8.01 d (m, 1H), 8.17 d (m, 1H), (C28H34N205); N- [2- (5-chlorobenzooxazol-2-yl) -2-hydroxy-15-phenethyl ethyl] -3-cyclohexylpropionamide (Compound 169); MS (ESI) m / z = 455 (M + 1); ? -? MR (300 MHz, CDC13): d 0.84 (m, 2H), d 1.12 (m, 4H), d 1.20 (m, 2H), d 1.51 (m, 6H), d 2.00 (m, 3H) , d 2.65 (m, 2H), d 4.21 (m, 1H), d 4.50 (m, 1H), d 5.02 (s, 1H), d 6.44 (m, 1H), d 7.01 - 7.47 (m, 7H) , d 7.65 (s, 1H), (C26H3? Cl? 203); benzyl 15- (2 -benzooxazol -i1-2 -2 -hydroxy-is-phenethyl etilsulfamoilmetil) -3 -metilbutilcarbamato (Compound 170); 1H? MR 300 MHz, CDCl3): 7.71 (m, 1H), 7.52 m, 1H), 7.20-10 7.40 (m, 12H), 5.9 (m, 0.5H), 5.6 (m, 0.5H), 4.80- 5.20 (m, 5H), 4.1-4.3 (m, 2H), 2.7-2.9 (m, 4H), 1.7-2.0 (m, 2H), 0.90 (m, 3H), 0.79 (m, 3H), 3.30 ( m, 1H); N- [15- (2-Benzooxazol-2-yl-2-hydroxy-15-phenethylethyl sulfamoylmethyl) -3-methylbutylacetamide (Compound 171); Benzyl 15- (2-benzooxazol-2-yl-2-hydroxy-15-phenethyl ethylsulfamoylmethyl) -3-methylbutylcarbamate (Compound 172); '' "H? MR (DMSO): 7.71 (m, 1H), 7.5 (m, 1H), 7.0-7.4 (m, 12H), 4.9-6.2 (m, 6H), 4.0-4.35 (m, 2H) , 3.75 (m, 1H), 3.20-3.60 (m, 2H), 2.5-3.0 (m, 2H), 1.15-2.15 (m, 3H), 0.6-1.05 (m, 6H); MS: m / e 580.1; N- [IR- (2-benzooxazol-2-yl-2-hydroxy-15-phenethyl ethylsulfamoylmethyl) -3-methylbutylacetamide (Compound 173); 2-acetylamino-N- (2-benzooxazol-2-yl-2- hydroxy-15-phenethylethyl-3-cyclohexylpropionamide (Compound 174); tert-butyl 15- (2-benzooxazol-2-yl-2-hydroxy-15-phenethylethyl] -2-cyclohexylethyl) carbamate (Compound 175); 2-acetylamino -N-2-yl-l, l-dimethyl-2-oxoethyl) -3-cyclohexylpropionamide (Compound 176); benzyl 15- [2- (5-phenylbenzooxazol-2-yl) -2-hydroxyethyl carbamoyl] -3 methylbuty1carbamate (Compound 177); N- (2-benzooxazol-2-yl-2-hydroxy-15-phenethylethyl) -3-cyclopentylpropionamide (Compound 178); XH? MR (CDC13): 7.72 (m, 1H), 7.53 (m, 1H), 7.08-7.19 (m, 8H), 5.98 (m, 1H), 5.05 (m, 2H), 4.51 (m, 1H), 2.6-2.8 (m, 4H), 2.17-2.29 (m , 1H), 1.95-2 .15 (m, 2H), 1.8-1.95 (m, 1H), 1.68-1.78 (m, 1H), 1.3-1.7 (m, 6H), 1.0-1.12 (m, 1H), 0.85-1.0 (m, 1 HOUR); N- (2-benzooxazol-2-yl-2-hydroxy-15-phenethylethyl) -2-bicyclo [2.2.1] hept-2-ylacetamide (Compound 179); N- (2-benzooxazol-2-yl-2-hydroxy-15-phenethylethyl) -2-naphthalen-1-ylacetamide (Compound 180); N- (2-benzooxazol-2-yl-2-hydroxy-15-phenethylethyl) -3-phenylpropionamide (Compound 181); 1U? MR (CDC13): 7.69 (m, 1H), 7.53 (m, 1H), 7.37 (m, 2H), 7.03-7.35 (m, 10H), 5.9 (m, 1H), 4.98 (m, 1H) , 4.40-4.55 (m, 1H), 3.0 (m, 1H), 2.80 (t, J = 7.7Hz, 2H), 2.55 (m, 2H), 2.38 (t, J = 7.5Hz, 2H); Methyl 2- [25- (3-cyclohexylpropionylamino) -l-hydroxy-4-phenylbutyl] -4,5-dihydrooxazole-4S-carboxylate (Compound 182);
MS (ESI) m / z = 431 (M + I); XH-NMR (300 MHz, CDCl 3): d 0.89
(m, 2H), d 1.20 (m, 4H), d 1.48 (m, 2H), d 1.65 (m, 6H), d
2. 00 (m, 2H), d 2.15 (m, 2H), d 2.73 (t, J = 4 Hz, 2H), d
3. 76 (s, 3H), d 4.30-4.65 (m, 5H) d 6.00 (d, J = 6Hz, 1H), d 7.13-7.35 (m, 5H), (C24H34N203); methyl 2- [25- (3-cyclohexylpropionylamino) -l-hydroxy-4-phenylbutyloxazole -4-carboxylate (Compound 183); N- (2-benzooxazol-2-yl-2-hydroxy-15-phenethyl) -4-cyclohexylbutyramide (Compound 184); XH? MR (CDC13): 7.62-7.73 (m, 1H), 7.46-7.59 (m, 1H), 7.05-7.43 (m, 2H), 6.22-6.38 (m, 1H), 5.11 (s, 1H), 4.50-4.69 (m, 1H), 2.58-2.82 (m, 2H), 2.14-2.24 (m, 1H), 2.0. 2.14 (m, 1H), 1.50-1.76 (m, 6H), 1.31-1.50 (m, 1H), 0.94-1.31 (m, 7H), 0.63-0.93 (m, 2H); MS: m / e = 435.1; methyl 2- [25- (3-cyclohexylpropionylamine) -l-hydroxy-4-phenylbutyl] -4,5-dihydrooxazole-4R-carboxylate (Compound 185); MS (ESI) m / z = 431 (M + 1); ^ -? MR (300 MHz, CDC13): d 0.89 (m, 2H), d 1.20 (m, 4H), d 1.48 (m, 2H), d 1.65 (m, 6H), d 2.00 (m, 2H) , d 2.15 (m, 2H), d 2.73 (t, J = 4 Hz, 2H), d 3.76 (s, 3H), d 4.35 - 4.72 (m, 5H), d 5.75 (, 1H), d 7.13 - 7.35 (m, 5H), (C 24 H 34 N 0 O 5); 3-cyclohexyl-N- [2-hydroxy-2- (5-trifluoromethyl-benzo-oxazol-2-yl) -15-phenethylethyl] -propionamide (Compound 186); MS (ESI) m / z = 489 (M + 1); XH-? MR (300 MHz, CDC13): d 0.77 (m, 2H), d 1.22 (m, 4H), d 1.51 (m, 2H), d 1.60 (m, 6H), d 2.15 (m, 4H) , d 2.70 (m, 2H), d 4.51 (m, 1H), d 5.11 (s, 1H), d 6.10 (d, J = 6 Hz, 1H), d 7.00 - 7.35 (m, 5H), d 7.56 (s, 2H), d 7.99 (s, 1H), (C27H31F3? 203); 25-acetylamino-N- (2-benzooxazol-2-yl-2-hydroxy-15-phenethylethyl) -3- (2-trifluoromethylphenyl) propionamide (Compound 187); methyl 1- (1-benzooxazol-2-ylcarbonyl-3-phenylpropyl carbamoyl) -2-cyclohexylethylcarbamate (Compound 188); 1H? MR (CDC13): 7.89 (d, J = 7.4Hz, 1H), 7.62 (M, 1HO, 7.54 (m, 1H), 7.46 (m, 1H), 7.13-7.30 (m, 1H), 6.87 ( d, J = 7.9Hz, 1H), 5.68 (m, 1H), 5.04 (d, J = 9.6Hz, 1H), 4.24 (m, 1H), 3.66 (s, 3H), 2.75 (5, J = 8.3 Hz, 2H), 2.45 (m, 1H), 2.19 (m, 1H), 2.00 (M, 1H), 1.52-1.80 (m = 5H), 1.44 (m, 1H), 1.12-1.27 (m, 4H), 0.89 (m, 2H); MS: m / e = 492.04; N- (1-benzooxazol-2-ylcarbonyl-3-phenylpropyl) -3-cyclohexyl-2-methylsulfonylaminopropionamide (Compound 189); XH? MR ( CDCI3): 7.87 (m, 1H), 7.62 (m, 1H), 7.55 (m, 1H), 7.46 (m, 1H), 7.13-7.28 (m, 5H), 6.79 (d, J = 7.9Hz, 1H ), 5.71 (m, 1H), 4.92 (m, 1H), 4.00 (m, 1H), 2.95 (2, 3H), 2.75 (m, 2H), 2.48 (m, 1H), 2.21 (m, 1H) , 1.78 (m, 1H), 1.61 (m, 5H), 1.45
(m, 1H), 1.16 (m, 4H), 0.89 (m, 2H); cyclohexylmethyl 1-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamate (Compound 190); 1 H NMR (CDC13); 7.88 (m, 1H), 7.62 (m, 1H),
7. 52 (m, 1H), 7.49 (m, 1H), 7.13-7.23 (m, 5H), 5.57 (m, 1H),
3. 89 (d, J = 6.5Hz, 2H), 2.79 (m, 2H), 2.42 (m, 1H), 2.12 (m,
1H), 1.50-1.73 (m, 6H), 1.24 (m, 6H), 0.89 (m, 2H); MS: m / e = 421.0; benzyl 1- (1-benzooxazol-2-ylcarbonyl-3-phenylpropyl sulfamoimethyl) -2-methylbutylcarbamate (Compound 191); 1H NMR
(CDC13): 7.88 (d, J = 7.7Hz, 1H), 7.62 (m, 1H), 7.55 (m, 1H),
7. 47 (m, 1H), 7.33 (m, 5H), 7.19 (m, 5H), 6.35 (d, J = 7.7Hz,
1H), 5.45 (m, 1H), 5.13 (s, 2H), 5.0 (m, 1H), 4.43 (m, 1H), 3.06 (m, iH), 2.87 (m, 1H), 2.45 (m, 1H) ), 2.15 (m, 1H), 1.41
(m, 1H), 1.07 (m, 1H), 0.88 (m, 6H); MS: m / e = 5.78.1; N- [IR- (15-benzooxazol-2-ylcarbonyl-3-phenylpropyl carbamoyl) -2- (6-methylpyrid-2-ylmethylsulfonyl) ethyl] thiophen-3-carboxamide (Compound 192); N- [IR- (15-benzooxazol-2-ylcarbonyl) -3-phenylpropyl carbamoyl) -2- (2-methylpyrid-3-ylmethylsulfonyl) ethyl] nicotinamide (Compound 193); N- [IR- (15-benzooxazol-2-ylcarbonyl-3-phenylpropyl carbamoyl) -2- (2-cyanobenzylsulfonyl) ethyl] azetidine-3-carboxamide (Compound 194);
tert-butyl IR- (l-benzooxazol-2-ylcarbonylcyclobutylcarbamoyl) -2- (2-difluoromethoxybenzylsulfonyl) ethylcarbamate (Compound 195); erc-butyl IR- (15-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl) -2- (4-trifluoromethylpyrid-3-ylmethylsulfonyl) ethylcarbamate (Compound 196); N- [IR- (L-benzooxazol-2-ylcarbonylcyclobutylcarbamoyl) -2- (2-difluoromethoxybenzylsulfonyl) ethylmorpholine-4-carboxamide (Compound 197); N- [IR- (15-benzooxazol-2-ylcarbonylpentylcarbamoyl) -2-pyrid-3-ylmethylsulfonylethyl] isonicotinamide (Compound 198); methyl IR- (15-benzooxazol-2-ylcarbonyl butylcarbamoyl) -2- (2-methoxybenzylsulfonyl) ethylcarbamate (Compound 199); N- [IR- (1-benzooxazol-2-ylcarbonylpropylcarbamoyl) -2-benzylsulfonylethyl] morpholine-4-carboxamide (Compound 200); ? MR 300mHz (DMSO-d6), 8.65 (d, J = 7.1H3, 1H), 8.01 (d, J = 8.2H3, 1H), 7.91 (d, J = 8.8H3, 1H), 7.66 (t, J) = 8H3, 1H), 7.55 (t., J = 7.7H3, 1H), 7.38 (s, 5H), 7.05 (d, J = 9.4H, IH), 5.21 (m, 1H), 4.75 (m, 1H), 4.49 (s, 2H), 3.53 < m, 4H), 3.45 (m, 2H), 3.32 (m, 4H), 2.02 (m, 1H), 1.77 (m, 1H), 0.96 (t, J = 8H3, 3H); M = 543.24 M + = 542.61; N- (LR-benzooxazol-2-ylcarbonylpropyl) -2- (3,3-dimethyl ureido) -3- (2-methoxybenzylsulfonyl) propionamide (Compound
201); MR 300mHz (DMSO-d6), 8.61 (d, J = 7.4H3, 1H), 8.01 (d, J = .8.5H3, 1H), 7.90 (d, J = 7.1H3, 1H), 7.65 (t, J = 8H3, 1H), 7.55 (t, J = 8H3, 1H), 7.33 (m, 2H), 7.05 (d, J = 8.8H3, 1H), 6.96 (t, J = 8.2H3, 1H), 6.70 (d, J = 9.1H3, 1H), 5.20 (m, 1H), 4.53 (d, J = 15.4H3, 1H), 4.41 (d, J = 15.4H3, 1H), 3.77 (s, 3H), 3.45 (d, J = 7.1H3, 2H), 2.81 (s, 6H), 2.0 (m, 1H), 1.7 (m, 1H), 0.96 (t, J = 8H3, 3H); MS = 651.33 M + = 650.59; methyl IR- (15-benzooxazol-2-ylcarbonylpropyl carbamoyl) -2- (2-methoxybenzylsulfonylethyl) carbamate (Compound 202); N- (1-benzooxazol-2-ylcarbonylpentyl) -2 - [3, 3-bis (2-methoxy-ethyl-ureido] -3-pyrid-3-ylmethylsulfonyl-propionamide (Compound 203); N- (15-benzooxazol-2-ylcarbonylpentyl) - 2R- [3, 3-bis (2-methoxyethyl) ureido] -3- (3,5-dimethylisoxazol-4-ylmethylsulfonyl) propionamide (Compound 204); N- (15-benzooxazol-2-ylcarbonylpropyl) -3- ( 3, 5-dimethyl isoxazole-4-ylmethylsulfonyl) -2R-methylsulfonylaminopropionamide (Compound 205): 1H? MR: (DMSO) 9.04 (d, J = 6.6Hz, 1H), 8.00-7.87 (m, 3H), 7.63 ( t, J = 8Hz, 1H), 7.53 (t, J = 8Hz, 1H), 5.25 (m, 1H), 4.61-4.36 (m, 3H), 3.56-3.31 (m, 2H), 2.91 (s, 3H) ), 2.36 (s, 3H), 2.17 (s, 3H), 2.02 (m, 1H), 1.74 (m, 1H), 0.96 (t, J = 7Hz, 3H); MS: (M ++ l) 527 Methyl IR- (15-benzooxazol-2-ylcarbonylpropylcarbamoyl) -2- (3, 5-dimethylisoxazol-4-ylmethylsulfonyl) ethylcarbamate (Compound 206); XH? MR: (DMSO) 8.78 (d, J = 5.8Hz, 1H ), 7.99 (d, J = 8Hz, 1H), 7.87 (d, J = 8Hz, 1H), 7.69 (d, J = 8.5Hz, 1H), 7.62 (t, J = 8Hz, 1H), 7.52 (t J = 8Hz, 1H), 5.20 (m, 1H ), 4.68 (m, 1H), 4.39 (d, J = 14Hz, 1H), 4.29 (d, J = 14Hz, 1H), 3.52 (s, 3H), 3.60-3.28 (m, 2H), 2.37 (s) , 3H), 2.15 (s, 3H), 2.02 (m, 1H), 1.74 (m, 1H), 0.95 (t, J = 7Hz, 3H); MS: (M ++ 1) 507; N- (1R-benzooxazol-2-ylcarbonylpentylcarbamoyl) -2-pyrid-2-ylmethylsulfonylethyl] isonicotinamide (Compound 207); ? MR 1H: 9.15-9.30 (m, 1H), 8.4-8.9 (m, 4 H), 7.32-8.05 (m, 9H), 5.28 (m, 1H), 5.10 (m, ffl), 4.75 (m, 2H), 3.75 (m, 1H), 3.62 (m, 1H), 1.95 (m, 1H), 1.75 (m, 1H), 1.05-1.45 (m, 4H), 0.87 (m, 3H); MS: M + l = 564.0; And 1-oxide of 4- [IR- (15-benzooxazol-2-ylcarbonylpentyl carbamoyl) -2-pyrid-2-ylmethylsulfonyl-ethylcarbamoylpyridine (Compound 208). REFERENCE 13 Bencil 15- (N-methoxy-N-methylcarbamoyl) -3-phenylpropylcarbamate
A solution of 2-benzyloxycarbonylamino-4-phenylbutyric acid (5.05 g, 16.1 mmol) in methylene chloride (70 mL) was cooled to 0 ° C and treated with diisopropylethylamine (2.82 mL, 16.2 mmol) added as drops and after PyBOP®
(8.53 g, 16.4 mmol) added in one portion. The mixture was stirred for 5 minutes and then treated with N, O-dimethylhydroxylamine hydrochloride (1.73 g, 17.71 mmol) added in one portion. The mixture was neutralized with diisopropylethyl amine (4.6 mL, 26.44 mmol) added as a drop, stirred for 2 hours at room temperature and then diluted with methylene chloride (70 mL). The dilution was washed with IN of aqueous hydrochloric acid (3x 40 mL), saturated sodium bicarbonate (3x 40 mL) and brine (40 mL) and then concentrated. The product was purified from the residue by column chromatography eluting with 2: 3 ethyl acetate / hexane to give benzyl 15- (N-methoxy-N-methylcarbamoyl) -3-phenylpropicarbamate (5.48 g, 15.4 mmol) as oil . MS (PCI) m / z = 357 (M + 1). Continue as in Reference 13 providing tert-butyl 15- (N-methoxy-N-methylcarbamoyl) -3-phenylpropylcarbamate; 1H? MR (CDCl3): d 1.35 (s, 9H), d 1-64 -1.72 (m, 2H), d 2.40-2.54 (m, 1H), d 2.60-2.77 (m, 1H), d 3.00 (d, s, 3H) 3.52 (s, 3H), d 4.23 (m, 1H), d 7.10-7.37 (m, 5H). REFERENCE 14 Salt of 25-amino-N-methoxy-N-methyl-4-phenylbutyramide trifluoroacetic acid A solution of tert-butyl 1- (N-methoxy-N-methyl carbamoyl) -3-phenylpropylcarbamate (9.32 g, 29 mmol ), provided as in Reference 13, in methylene chloride (100 mL) was cooled to 0 ° C and then treated with anisole (5 mL, 46.5 mmol) and trifluoroacetic acid (50 mL, 296 mmol). The mixture was stirred for 30 minutes, allowing it to warm to room temperature, and then concentrated.
The residue was dissolved in toluene (100 mL) and the solution was concentrated. The residue was redissolved in toluene (100 ml) and concentrated to provide acid salt of 25-amino-N-methoxy-N-methyl-4-phenylbutyramide trifluoroacetic acid (9.74 g, 29 mmol) as crude product. MS (PCI) m / z = 223 (M + 1). REFERENCE 15 Benzyl-1- [1- (N-methoxy-N-methylcarbamoyl) -35-phenylpropyl carbamoyl] -3-methylbutylcarbamate A solution formed by the salt of 25-amino-N-methoxy-N-methyl-4-phenylbutyramide trifluoroacetic (9.74 g, 29 mmol), provided as in Reference 2, in DMF (75 mL) was cooled to 0 ° C and then neutralized with diisopropylethyl amine added as drops. A solution formed by 2,5-dioxopyrrolidin-1-yl-2-benzyloxycarbonylamino-4-methyl valerate (10.50 g, 29 mmol) in DMF (75 mL) and an additional amount of diisopropylethylamine (10.10 mL, 58 mmol) was added. to the cooled butyramide solution. The mixture was stirred for 2 hours, allowing it to warm to room temperature, and then it was emptied into water with ice (300 mL). The mixture was allowed to stand for 1 hour to provide a white precipitate. The precipitate was collected by filtration and dried (P205) under vacuum to give benzyl-1- [1- (N-methoxy-N-methylcarbamoyl) -35-phenylpropylcarbamoyl] -3-methylbutylcarbamate (12.24 g, 26.1 mmol). XH? MR (CDC13): d 0.91 (d, J = 5-88 Hz, 6H), d 1.45-1.55 (m, 1H), d 1.45-1.55 (m, 2H), d 1.77-2.00 (m, 1H) ), d 2.11 -2.22 (m, 1H), d 2.70 (m, 2H), d 3.20 (s, 3H) 3.60 (s, 3H) 4.25 (m, 1H), d 5.00 (m, 1H), d 5.15 (s, 2H), d 6.6 (d.J = 8.15 Hz, 1H), d 7.15-7.45 (m, 10H). REFERENCE 16 Ethyl 35-benzyloxycarbonylamino-2-hydroxy-5-phenylpentanimidate
A suspension formed by lithium aluminum hydride
(0.885 g, 23.3 mmol) in anhydrous diethyl ether was cooled to -45 ° C under nitrogen and then treated with a benzyl 15- (N-methoxy-N-methylcarbamoyl) -3-phenylpropylcarbamate solution.
(5.53 g, 15.53 mmol), provided as in the
Reference 13, in ether (75 mL) and THF (25 mL) was added in the form of drops over a period of 30 minutes such that the temperature of the mixture was maintained at -40 to -45 ° C. The mixture was allowed to warm to 5 ° C and then cooled again to -35 ° C. A saturated solution of sodium bicarbonate (7 mL, 0.5 M) was added dropwise and the mixture allowed to warm to 0 ° C. The mixture was allowed to warm to room temperature and was stirred for 1 hour to provide a precipitate. The precipitate was collected by filtration and washed with ether (100 mL). The filtrate and the washings were combined and washed with 1? of cold hydrochloric acid on ice (2x 50 mL), saturated sodium bicarbonate (2 x 50 mL) and brine (50 mL), dried (? a2S04) and concentrated in vacuo to give benzyl 15-formyl-3-phenylpropylcarbamate (4.01 g, 13.5 mmol) as a colorless oil. MS (PCI) m / z = 298 (M + 1). A solution of benzyl 15-formyl-3-phenylpropyl carbamate (4.557 g, 15.3 mmol) in anhydrous methylene chloride (50 mL) was stirred while treated sequentially with 2-hydroxy-2-methylpropionitrile (4.25 mL, 46.2 mmol) and triethylamine (1.28 ml, 9.20 mmol). The mixture was stirred for 4 hours at room temperature and concentrated in vacuo. The residue was dissolved in ether (100 mL) and the solution was washed with water (5 x 20 mL) and brine (20 mL), dried (MgSO 4) and concentrated to give benzyl 2-cyano-2-hydroxy-1S. -phenethyl ethylcarbamate (4,957 g, 15.3 mmol) as a yellow oil. 1NMR (CDC13): d 1.75 - 2.01 (m, 2H), d 2.08 - 2.24 (m, 1H), d 2.51 - 2.80 (m, 2H), d 3.70 - 4.02 (m, 1H), d 5.07, d 5.33 (m, 3H), d 7.10 - 7.47 (m, 10H). A solution formed by chloroform (30 mL) and anhydrous ethanol (30 mL, 510 mmol) was cooled to 0 ° C and then treated with acetyl chloride (32.6 mL, 459 mmol) added as drops over a period of 30 minutes. minutes The mixture was cooled with crude benzyl 2-cyano-2-hydroxy-l-phenethylethyl carbamate solution (4,957 g., 15.3 mmol) in chloroform (30 mL). The mixture was stirred for 2 hours at 0 ° C and then at 6 hours at room temperature and concentrated in vacuo to give ethyl 35-benzyloxycarbonylamino-2-hydroxy-5-phenyl pentanimidate (6.212 g 15.3 mmol) as yellow oil. MS (PCI) m / z = 371 (M + 1). REFERENCE 17 25-amino-4-phenyl-1- (45-phenyl-4,5-dihydrooxazol-2-yl) butan-l-ol A mixture formed by ethyl 35-benzyloxycarbonylamine -2-hydroxy-5-phenylpentanimidate (0.78 g, 1.92 mmol), provided as in Reference 16, diisopropylethylamine (0.218 μL, 1.26 mmol) and 25-amino-2-phenylethanol (0.260 g, 1.9 mmol) in chloroform (25 mL) was heated under reflux for 3 hours. hours and then stirred for approximately 12 hours, while allowing it to cool to room temperature. The mixture was concentrated and the residue was dissolved in ethyl acetate (50 ml). The solution was washed with 0.5N sodium hydroxide (40 mL) and brine (40 mL), dried (MgSO4) and then concentrated. The product was purified from the residue by flash chromatography eluting with 1: 3 hexanes / ethyl acetate to give benzyl 2-hydroxy-2- (4,5-dihydro-45-phenyloxazol-2-yl) -15-phenylethylcarbamate ( 0.475 g, 1.1 mmol) as an oily mixture of diastereoisomers. MS (PCI) m / z = 445 (M + 1). (C27H28H204). A solution formed by benzyl 2-hydroxy-2- (4,5-dihydro-45-phenyloxazol-2-yl) -15-phenylethylcarbamate (100 mg, 0.22 mmol) in methanol (10 mL) was placed under a nitrogen atmosphere and stirred while the Pearlman catalyst (20 mg) was added. The mixture was stirred vigorously under a hydrogen atmosphere until the reaction was completed and then filtered. The filter was washed with methanol (2 x 25 mL). The combined filtrates were concentrated to provide 25-amino-4-phenyl-1- (45-phenyl-4,5-dihydrooxazol-2-yl) butan-1-ol (51 mg, 0.16 mmol) as a clear oil. MS (PCI) m / z = 311 (M + 1). (C? 9H22N202). REFERENCE 18 25-amino-l-oxazol-2-yl-4-phenylbutan-l-ol A solution formed by oxazole (0.25 g, 3.62 mmol) in THF (20 mL) was treated with borane tetrahydrofuran complex (3.62 mL , 3.62 mmol) under nitrogen and the mixture was stirred for 30 minutes and then cooled to -78 ° C. A solution formed of sec-butyllithium (2.78 ml, 3.62 mmol) in cyclohexane was added dropwise and the mixture was stirred for 30 minutes. A solution consisting of tert-butyl (5) -1-formyl-3-phenylpropylcarbamate (0.476 g, 1.81 mmol) in THF (25 mL) was added and the mixture was stirred and allowed to warm while the reaction continued to its termination. The mixture was subsequently cooled to -78 ° C, cooled by gradually adding 5% acetic acid in ethanol
(20 mL), allowed to warm to room temperature and stirred for 18 hours. The mixture was concentrated to dryness and the residue was extracted with ether (2x25 mL). The combined extracts were washed with brine, dried (MgSO4) and concentrated to dryness to give tert-butyl-2-hydroxy-2-oxazol-2-yl-15-phenethylethylcarbamate (0.125 g, 0.376 mmol) as an oil. yellow. MS (PCI) m / z = 333 (M + 1). A mixture formed by tert-butyl 2-hydroxy-2-oxazol-2-yl-lS-phenethylethylcarbamate (0.125 g, 0.376 mmol), anisole (0.2 mL) and trifluoroacetic acid (0.6 mL) in methylene chloride (20 mL) it was stirred at room temperature for 2 hours and then concentrated to provide 25-amino-1-oxazol-2-yl-4-phenylbutan-1-ol trifluoroacetic acid salt (0.08 g, 0.229 mmol) as a yellow oil. MS (PCI) m / z = 233 (M + 1). REFERENCE 19 Methyl 2- (25-amino-l-hydroxy-4-phenylbutyl) oxazole-4-carboxylate A solution formed by methyl 2- (25-benzyloxycarbonylamino-l-hydroxy-4-phenylbutyl) -4,5-dihydrooxazole -4-carboxylate (0.100 g, 0.235 mmol) in methylene chloride (3 mL) was cooled to 0 ° C and then treated with DBU (39 mL, 0.26 mmol) and bromotrichloromethane (26 mL, 0.26 mmol). The mixture was stirred for 6 hours at 0 ° C, washed with ammonium chloride (10 mL) and concentrated. The residue was dried (MgSO4) to give methyl 2- (25-benzyloxycarbonylamino-l-hidoxy-4-phenylbutyl) oxazole-4-carboxylate. MS (PCI) m / z = 425 (M + 1).
Perform deprotection affording methyl 2- (25-amino-1-hydroxy-4-phenylbutyl) oxazole-4-carboxylate EXAMPLE 19 Benzyl 15- [2- (4,5-dihydrooxazol-2-yl) -2-hydroxy-15 - phenethylethylcarbamoyl] -3-methylbutylcarbamate (Compound 210)
A mixture formed by ethyl 3- (2-benzyloxycarbonyl amino-4-methy1valerylamino) -2-hydroxy-5-phenylpentanimidate
(0.327 g, 0.63 mmol), diisopropylethylamine (0.218 mL, 1.26 mmol) and ethanolamine (38.4 mg, 0.63 mmol) in chloroform (20 mL) was heated (reflux temperature) for 3 hours and then stirred at room temperature for approximately 12 hours. The mixture was concentrated and the residue was dissolved in ethyl acetate (50 mL). The solution was washed with 0.5 M sodium hydroxide (40 mL) and brine (40 mL), dried (MgSO4) and concentrated in vacuo. The product was purified from the residue by flash chromatography eluting with 3: 1 ethyl acetate / hexane to give benzyl 15- [2- (4,5-dihydrooxazol-2-yl) -2-hydroxy-15-phenethylethylcarbamoyl ] 3-methylbutylcarbamate (38 mg, 0.079 mmol) as a white solid. MS (PCI) m / z = 482 (M + 1). (C27H35 3? 5). Cotinuate the same as in Example 19 to give benzyl 15- [2- (1-benzoimidazol-2-yl) -2-hydroxy-15-phenylethyl ethylcarbamoyl] -3-methylbutylcarbamate (Compound 211); EXAMPLE 20 Benzyl 15- [2- (4,5-dihydro-45-phenyloxazol-2-yl) -2-hydroxy-15-phenylethylethylcarbamoyl] -3-methylbutylcarbamate (Compound 212)
A solution formed by 25-amino-4-phenyl-1- (45-phenyl-4,5-dihydrooxazol-2-yl) butan-1-ol (51 mg, 0.165 mmol), provided as in Example 18, in DMF (2 mL) was cooled to 0 ° C and a second solution formed by 2,5-dioxo pyrrolidin-1-yl-2S-benzyloxycarbonylamino-4-methylvalerate (0.063 g, 0.174 mmol) and diisopropylethylamine (30.3 μL, 0.174). mmol) in DMF (3 mL) was added. The mixture was stirred for 2 hours, while allowing to warm to room temperature, and then concentrated. The product was purified from the residue by column chromatography eluting with 1: 1 ethyl acetate / hexane to provide benzyl 15- [2- (4,5-dihydro-45-phenyloxazol-2-yl) -2-hydroxy -15-phenylethyl-ethylcarbamoyl] -3-methylbutylcarbamate (34 mg, 0.061 mmol) as a clear oil. MS (PCI) m / z = 558 (M + 1). (C33H39N305). Continue as in Example 20 to provide the following compounds of Formula I: benzyl 15- (2-benzooxazol-2-yl-2-hydroxy-15-phenethyl ethylcarbamoyl) -3-methylbutylcarbamate (Compound 213); MS
(ESI) m / z = 530 (M + 1); XH-NMR (300 MHz. CDCl 3,): d 0.65 - 0.7 (dd, 6H), d 0.98 (d, J = 6 Hz 2H), d 1.10 - 1.55 (m, 3H), d 1.65 - 1.85 (m, 1H), 2.08 (m, 1H), d 2.70 (m, 2H), d 3.99 - 4.13 (m, 1H), d 4.50 (m, 1H), d 4.90 - 5.21 (m, 3H), d 6.40 -6.70 (dd, 1H), d 7.05-7.35 (m, 10H), d 7.47 (d, J = 4 Hz,
2H), d 7. 51 (d, J = 2 Hz, 2H), (C31N35N305); benzyl -1- [2- (4, 5-dihydro-5-phenyloxazol-2-yl) -2-hydroxy-1-phenethyl-1-carbamoyl-3-methylbutylcarbamate (Compound 214, benzyl 1- [2- (4,5-dihydro) -45-methyl-55-phenyloxazol-2-yl) -2-hydroxy-1-phenylethylcarbamoyl] -3-methylbutylcarbamate (Compound 215); benzyl 3-methyl-1- (2-hydroxy-2-naphtho [2, 3 -d] oxazol-2-yl-1-phenethylethylcarbamoyl-jbutylcarbamate (Compound 216); MS (ESI) m / z = 580 (M + 1); -NMR (300 MHz, CDC13): d 0.65-0.95 (m, 6H), d 1.25 (m, 3H), d 1.54 (m, 3H), d 2.20 (m, 1H), d 2.82 (t, J = 4 Hz, 2H), d 4.00 - 4.20 (m, 1H), d 4.35 - 4.55 (m, 1H), d 4.90 - 5.09 (m, 3H), d 6.60 (m, 1H), d 7.23 (m, 10H), d 7.56 (m, 2H), d 7.96 (m, 3H) ), d 8.18 (s, 1H), (C 35 H 37 N 305), benzyl 15- (2-benzooxazol-2-yl-2-hydroxy-15-phenethyl ethylcarbamoyl) -2-methylpropylcarbamate (Compound 217); benzyl 15- (2 - benzooxazol-2-yl-2-hydroxy-15-phenethyl ethylcarbamoyl) -3-methylbutylcarbamate (Compound 218); benzyl 1 5- [2- (4,5-dihydro-4,4-dimethyloxazol-2-yl) -2 -hydroxy -15-phenethylethylcarbamoyl] -3-methylbutylcarbamate (Compound 219); MS (PCI) m / z = 510 (M + 1); XH NMR (CDC13): d 0.8-0.99 (d, J = 6 Hz, 6H), 1.11 - 1.35 (m, 6H). d 1.4 -1.78 (m, 3H), d 1.82-2.01 (m, 2H), d 2.55-2.72 (m, 2H), d 3.95 (m, -lH), d 4.0-4.25 (m, 3H), d 4.30 (s, 1H), d 5.10 (s, 2H), d 5.35 (s, 1H), d 6.58 (m, 1H) 7.1-7.37 (m, 10H); (C29H39N305); methyl 2- [2- (2-benzyloxycarbonylamino-4-methylvaleryl amino) -1-hydroxy-4-phenylbutyl] -4,5-dihydroxazole-4-carboxylate (Compound 220), MS (PCI) m / z = 540 ( M +1); XH NMR (CDC13): d 0.8-0.99 (d, J == 6 Hz, 6H), 1.25 (m, 1H), d 1.47 (m, 1H) 1.65 (m, 2H), d 1.99 (m, 2H) , d 2.15 (s, 1H), d 2.65 (t, J = 4Hz, 2H), d 3.70 (s, 3H) 4.18 (m, 1H), d 4.25-4.50 (m, 3H), d 4.51-4.64 ( m, 2H), d 5.17 (m, 2H), d 5.35 (d, J = 5Hz, 1H)
6. 65 (d, J == 6Hz, 1H), d 7.17-7.45 (m, 10H); (C29H37N307). methyl 2 [2- (2, 2-dimethylpropionylamino) -4-f-enylbutyryl] oxazole -4-carboxylate (Compound 221); MS (ESI) m / z = 373 (M + XH-NMR (300 MHz, CDC13): d 1.25 (s, 9H), d 2.20 (m, 1H), d 2.46 (m, 1H), d 2.77 (t , J = 4 Hz, 2H), d 3.99 (s, 3H), d 5.55 (m, 1H), d
6. 41 (d, J = 4 Hz, 1H), d 7.20 - 7.38 (m, 5H), d 8.41 (s,
1H), (C20H24N2O5); tert-butyl 4-. { 15 [2- (5- tert -Butylbenzooxazol-2-yl) -2-hydroxy-15-phenethylethylcarbamoyl] -3-methylbutylcarbamoyl} piperidine-1-carboxylate (Compound 222); tert-butyl 4-. { l5- [2-hydroxy-15-phenethyl-2- (5-sulfamoyl benzooxazol-2-yl) ethylcarbamoyl] -3-methylbutylcarbamoyl} piperidine-1-carboxylate (Compound 223); tert-butyl 4- [15- (2-hydroxy-2-naphtho [1,2-d] oxazol-2-yl-15-phenethylethylcarbamoyl) -3-methylbutylcarbamoyl] piperidine-1-carboxylate (Compound 224); tert-butyl 4- [15- (2-hydroxy-2-naphtho [2, 1-d] oxazol-2-yl-15-phenethylethylcarbamoyl) -3-methylbutylcarbamoyl] piperidine-1-carboxylate (Compound 225);
tert-butyl 4-. { l5- [2-Hydroxy-15-phenethyl -2- (5-phenylbenzooxazol-2-yl) ethylcarbamoyl] -3-methylbutylcarbamoyl} piperidine-1-carboxylate (Compound 226); tert-butyl 4- [15- (2-benzooxazol-2-yl) -2-hydroxy-15-phenethylethylcarbamoyl) -2-methylbutylcarbamoyl] piperidine-1-carboxylate (Compound 227); MS (ESI) m / z = 607 (M + 1); XH-NMR (300 MHz, CDC13): d 0.50-0.61 (m, 1H), d 0.75-0.98 (m, 6H), d 1.22 (m, 1H), d 1.41 (s, 9H), d 1.81 - 1.85 (m, 1H), d 1.99 - 2.06 (m, 1H), d 2.70 (m, 2H), 4.24 (d, J = 2 Hz 2H), d 4.50 - 4.70 (m, 1H), d 4.99 - 5.14 ( m, 2H), d 6.96 -7.81 (m, 15H), (C3H46N406); tert-butyl 3- [15- (2-benzooxazol-2-yl) -2-hydroxy-15-phenethylethylcarbamoyl) -2-methylbutylcarbamoyl] benzylcarbamate (Compound 228); tert-butyl 4- [15- (2-benzooxazol-2-yl) -2-hydroxy-15-phenethylethylcarbamoyl) -2-cyclohexylethylcarbamoyl] piperidine-1-carboxylate (Compound 229); benzyl 3-methyl-15- [2-hydroxy-15-phenethyl-2- (5-phenyl-oxazol-2-yl) ethylcarbamoyl] butylcarbamate (Compound 230); MS (ESI) m / z = 556 (M + 1); XH-NMR (300 MHz, CDC13): d 0.75 -0.95 (m, 6H), d 1.25-1.80 (m, 5H), d 2.00 (m, 2H), d 2.67 (m, 2H), d 4.15 (m , 1H), d 4.55 (m, 1H), d 4.85 - 5.20 (m, 2H), d 5.50 (m, 1H), d 6.80 (d, J = 6Hz, 1H), d 7.12-748 (m, 14H), d 7. 62 (d, J = 2 Hz, 2H), (C33H37N3? 5): pyrid-3-yl-3-methyl-lS- [2-hydroxy-lS-f-eethyl-2- (5 phenyloxazol-2-yl) ethylcarbamoyl] butylcarbamate (Compound 231); MS (ESI) m / z = 527 (M + 1); XH-NMR (300 MHz, CDC13): d 0.75 -0.95 (m, 6H), d 1.45 -1.75 (m, 5H), d 2.00 (m, 2H), d 2.67 (m, 2H), d 4.40 - 5.10 (m, 3H), d 5.60 (s, 1H), d 7.00 - 7.47 (m, 10H), d 7.62 (m, 2H), d 8.15 (m, 1H), d 8.65 (m, 1H), d 9.15 (m, 1H), (C3? H34N404); and benzyl IS- [2-hydroxy-15-phenethyl-2- (5-f-enyloxazol-2-yl) ethylsulfamoylmethyl] -2R-methylbutylcarbamate (Compound
232); MS (ESI) m / z = 606 (M + 1); ^ -NMR (300 MHz, CDCl 3): d 0.75-0.95 (m, 6H), d 1.30 -1.50 (m, 5H), d 1.98 (m, 2H), d 2.77 (m, 3H), d 3.55 (m , 2H) d 4.90-5.10 (m, 3H), d 5.60 (m, IH), d 7.02-7.47 (m, 14H), d 7.62 (m, 2H), (C33H39N3? 6S). EXAMPLE 21 Benzyl 3-methyl-l5- (15-pyrid-2-ylcarbonyl-3-f-enylpropylcarbamoyl] butylcarbamate (Compound 233)
A solution formed by 2-bromopyridine (0.291 mL, 3.06 mmol) in dry THF (2 mL) was cooled to -78 ° C and then a solution of n-butyllithium (1.6 mL, 2.72 mmol) in pentane was added in Drops form for 2 minutes. The mixture was stirred at -78 ° C for 10 minutes and then a solution of benzyl 1- [1- (N-methoxy-N-methylcarbamoyl) -3-phenylpropylcarbamoyl] -3-methylbutylcarbamate (0.3 g, 0.64 mmol) in THF (2 mL). The mixture was stirred while allowing it to gradually warm to room temperature, and then it was emptied into a solution containing acetic acid (0.163 mL) in diethyl ether (50 mL). The organic phase was washed with brine (40 mL), dried (MgSO 4) and concentrated in vacuo. The product was purified from the residue by flash chromatography on silica gel eluting with 1: 2 ethyl acetate: hexanes to give benzyl-3-methyl-1- (l-pyrid-2-ylcarbonyl-3-phenylpropylcarbamoyl) ) butylcarbamate (82 mg, 0.17 mmol) as a white solid. MS (ESI) m / z = 488 (M + 1); XH ™ MR (CDC13): d 0.8-1.05 (d.J = 4 Hz, 6H). 1.5 (m, 1H), d 1.6 - 1.78 (t, 2H), d 1.99 - 2.20 (m, 1H), d 2.6 - 2.9 (m, 1H), d 2.55 -2.85 (m, 2H), d 4.25 ( m, 1H), d 5.17 (s, 2H), d 5.25 (m, 1H), d 6.00 (m, 1H), d 6.85-6.95 (d, J = 10Hz, 1H), d 7.1 - 7.4 (m, 10H) 7.50 (t, J = 4Hz, 1H), d 7.85 (t, J == 6Hz, 1H) 8.01 (d, J == 8 hz, 1H), d 8.69 (m, 1H). Anal (C29H33? 304).
Continue as in Example 21 to provide the following compounds of Formula I: benzyl 1- [l-pyrid-3-ylcarbonyl) -3-phenylpropylcarbamoyl-3-methylbutylcarbamate (Compound 234), MS (PCI) m / z = 488 (M +1); XH NMR (CDCl 3): d 0.8 - 1.05 (d, J = 4 Hz, 6H), 1.5 (m, 1H), d 1.6 - 1.78 (t, 2H), d 1.80 - 2.01 (m, 2H), d 2.25 (m, 1H) 2.6 - 2.9 (t, J = 3 Hz, 1H), d 2.55 - 2.85 (m, 2H), d 4.30 (m, 1H), d 5.17 (s, 2H), d 5.35 (d, J = 6Hz, 1H), d 5-55 (m, 1H), d 7.02 (d, J = 8Hz, 1H), d 7.1 - 7.4 (m, 10H) 8.05 (d, J = 5 Hz, 1H), d 8.78 (d, J = 4Hz, 1H), d 9.10 (s, 1H); (C29H33N304); and benzyl 1- [1- (guiñol-3-ylcarbonyl) -3-phenylpropyl carbamoyl] -3-methylbutylcarbamate (Compound 235), MS (PCI) m / z = 538 (M + 1); XH NMR (CDC13): d 0.8 - 1.05 (d, J = 4 Hz, 6H), 1.5 (m, 1H), d 1.6 - 1.78 (m, 2H), d 1.99 - 2.20 (m, 1H), d 2.6 - 2.9 (m, 1H), d 2.55 -2.85 (m, 2H), d 4.35 (m, 1H), d 5.17 - 5.25 (m, 3H), d 5.70 (m, 1H), d 6.75 - 6.85 (d , J = 10Hz, 1H), 8 d 7.20 - 7.45 (m, 10H), d 7.65 (t, J = 6Hz, 1H), d 7.77 - 7.90 (m, 2H), d 8.22 (d, J = 7, 1H), d 8.46 (s, 1H), d 9.4 (s, 1H); (C33H35N304).
EXAMPLE 22 Benzyl 1- [1- (lH-indol-5-ylcarbonyl) -3-f-enylpropylcarbamoyl] -3-methylbutylcarbamate (Compound 236)
A mixture formed by potassium hydride (0.29 g, 2.56 mmol, 67% in mineral oil) in anhydrous ether (5 mL) was cooled to 0 ° C and then a solution formed by 5-bromo-ltf-indole (0.5 was added). g, 2.56 mmol) in ahydrous ether (5 mL). The mixture was stirred for 15 minutes and then cooled to -78 ° C under nitrogen. A solution consisting of tert-butyl lithium (3 mL in pentane, 5.08 mmol) in anhydrous ether (5 mL) was cooled to -78 ° C and added to the indole mixture for 2 minutes. The mixture was stirred for 10 minutes and then a solution consisting of benzyl 1- [1- (N-methoxy-N-methyl carbamoyl) -3-phenylpropylcarbamoyl] -3-methylbutylcarbamate (0.3 g, 0.64 mM) in ether was added ( 10 mL). The mixture was allowed to warm to room temperature and then was poured into a cold solution at 0 ° C of phosphoric acid (25 mL, 1 M in water). The aqueous layer was separated and extracted with ethyl acetate (25 mL). The organic layers were combined and washed with saturated sodium bicarbonate (25 mL), dried (MgSO 4) and concentrated. The product was purified from the residue by flash chromatography on silica gel eluting with 1: 2 ethyl acetate / hexane to give benzyl 1- [1- (1-lido-indol-2-ylcarbonyl) -3-phenylpropylcarbamoyl] - 3-methylbutylcarbamate (112 mg, 0.21 mmol) as a white solid. MS (ESI) m / z = 526 (M + 1); XH NMR
(CDC13): d 0.8 - 1.05 (d, J = 4 Hz, 6H), 1.5 (s, 1H), S 1.5 -1.78 (m, 3H), d 2.00 (m, 1H), d 2.4 (, 1H) , d 2.65 (m, 2H), d 4.35 (m, 1H), d 5.17 (s, 2H), d 5.25 (d, J = 6 Hz, 1H), d 5.75 (m, 1H), d 6.55 (s) , 1H) 7.05 (d, J = 4Hz, 1H), d 7.1-7.45 (m, 10H) 7.7 (d, J = 4Hz, 1H), d 8.15 (d, J = 4Hz, 1H) d.78 (m , 1H), (C32H35N304). EXAMPLE 23 Benzyl 1- [1- (benzofur-2-ylcarbonyl) -3-phenylpropylcarbamoyl] -3-methylbutylcarbamate (Compound 237)
A solution formed by benzofuran (0.302 g, 2.56 mmol) in anhydrous ether (5 mL) was cooled to -15 ° C under a nitrogen atmosphere and then a solution of n-butyllithium (1.6 mL in hexanes) was added in Drops form for 2 minutes. The mixture was stirred for 1 hour and then a solution formed by benzyl 1- [1- (N-methoxy-N-methyl carbamoyl) -3-phenylpropylcarbamoyl] -3-methylbutylcarbamate (0.3 g, 0.64 mmol) in diethyl ether was added. . The mixture was stirred at -15 ° C until the reaction was complete. The mixture was cooled with a solution of acetic acid (0.153 mL) in diethyl ether
(50 mL). The organic phase was washed with brine (40 mL), dried (MgSO 4) and concentrated in vacuo. The product was purified from the residue by flash chromatography eluting with 2: 3 ethyl acetate / hexanes to give benzyl 1- [1- (benzofur-2-ylcarbonyl) -3-phenylpropylcarbamoyl-3-methylbutylcarbamate (70mg , 0.13 mmol) as a white solid. 1H? MR (CDC13): d 0.8 - 0.99 (d, J = 4 Hz, 6H), 1.5 (m, 1H), d 1.6 - 1.72 (m, 2H), d 1.99 - 2.18 (m, 1H), d 2.22 - 2.41 (m, 1H), d 2.6 - 2.75 (m, 2H), d 4.21 (, 1H), d 5.01 (m, 1H), d 5.17 (s, 2H), d 5.50 (m, 1H), d 6.75 -6.81 (d, J = 7 Hz, 1H), d 7.10 - 7.37 (m, 11H) 7.4 - 7.59 (m,, 3H), d 7.64 (d, J = 7 Hz, 1H). (C32H34? 205). Continue as in Example 23 to provide the following compounds of Formula I: benzyl 1- [1- (benzothiazol-2-ylcarbonyl) -3-phenylpropyl carbamoyl-3-methylbutylcarbamate (Compound 238), XH NMR
(CDC13): d 0.91 (d, J = 5.88 Hz, 6H), d 1.39 -1.54 (m, 1H), d
1. 60 - 1.72 (m, 2H), d 2.11 - 2.25 (m, 1H), d 2.40 - 2.54 (m, 1H), d 2.72 (m, 2H), d 4.21 (m, 1H), d 5.10 (s, 3H), d 5.84
(m, 1H), d 6.87 (d, J = 8.15 Hz, 1H), d 7.10 - 7.40 (m, 10H), d 7.54 (dt, J = 1.62, 8.10 Hz, 1H), d 7.58 (dt, J = 1.46,
7. 80 Hz, 1H), d 7.97 (dd, J = 1.80, 8.15 Hz, 1H), d 8.17 (dd,
J = 1.66, 7.67 Hz, 1H); benzyl 3-methyl-15- (3-pheny1-15-thiazole-2-ylcarbonylpropylcarbamoyl) butylcarbamate (Compound 239); N- [3-methyl-15-3-phenyl-15-thiazole-2-ylcarbonylpropyl carbamoyl) butyl] -4-methylpiperazine-l-carboxamide (Compound 240); tert-butyl 4- [3-methyl-lS- (3-phenyl-lS-thiazol-2-yl carbonylpropylcarbamoyl) butylcarbamoyl] piperazine-1-carboxylate (Compound 241); benzyl 3-methyl-15- (3-phenyl-15-thien-2-ylcarbonylpropyl carbamoyl) butylcarbamate (Compound 242); benzyl 15- [15- (l-methyl-lff-imidazol-2-ylcarbonyl-3-phenylpropylcarbamoyl] -3-methylbutylcarbamate (Compound 243); benzyl 15- (15- (l-thiazol-2-ylcarbonyl-3-phenylpropylcarbamoyl) ) -2-methylpropylcarbamate (Compound 244); N- [3-methyl-15-3-phenyl-15-thiazole-2-ylcarbonylpropyl carbamoyl) butyl] piperazine-1 -carboxamide (Compound 245);
benzyl 15- [15- (4-methylthiazol-2-ylcarbonyl) -3-phenylpropylcarbamoyl] -3-methylbutylcarbamate (Compound 246); benzyl 15- (15-furyl-2-ylcarbonyl-3-phenylpropyl carbamoyl) -3-methylbutylcarbamate (Compound 247), "" "H NMR (CDC13): d 0.91 (d, J = 6.18 Hz, 6H), 1.42 - 1.70 (m, 3H), d 1.98 - 2.13 (m, 1H), d 2.19 - 2.37 (m, 1H), d 2.69 (t, J = 7.60 Hz, 2H), d 4.22 (m, 1H), d 5.10 ( d, J = 7.76 Hz, 1H), d 5.12 (s, 2H), d 5.54 (m, 1H), d 6.76 (d, J = 8.15 Hz, 1H), d 7.16 - 7.36 (m, 10H), d 7.39 (dt, J = 1.82, 7.86 Hz, 1H), d 7.47 (dt, J = 1.63, 7.79 Hz, 1H), d 7.69 (s, 1H), d 7.80 (d, J = 7.15 Hz, 1H), d 7.85 (d, J = 8.18 Hz, 1H); benzyl 15- [15- (l-benzyl-lH-imidazol-2-ylcarbonyl-3-phenylpropylcarbamoyl] -3-methylbutylcarbamate (Compound 248); benzyl 3-phenyl- 1- (4,5-dihydro-45-phenyloxazol-2-yl carbonyl) propyl] carbamate (Compound 249); benzyl 3-pheny1-1- (4,5-dihydro-5-phenyloxazol-2-yl carbonyl) propyl] carbamate (Compound 250); benzyl [1- (4,5-dihydro-45-methyl-55-phenyloxazol-2-ylcarbonyl) -3-phenylpropyl] carbamate (Compound 251); and ethyl 2- [2- (2-benzyloxycarbonylamino-4-methylvaleryl amino) -4-phenylbutyryl] thiazole-4-carboxylate (Compound 252). EXAMPLE 24 Methyl 2- [2- (2-benzyloxycarbonylamino-4-methyl valerylamino) -! -hydroxy-4-phenylbutyl] oxazole-4-carboxylate (Compound 253)
A solution formed by methyl 2- [2- (2-benzyloxycarbonylamino-4-methylvalerylamino) -l-hydroxy-4-phenylbutyl] -4,5-dihydrooxazole -4-carboxylate (0.036 g, 0.067 mmol) in methylene chloride (3 mL) was cooled to 0 ° C and then DBU (11.2 mg, 72.7 μmol) and bromotrichloromethane (14.6 mg, 73.7 μmol) were added. The mixture was stirred for 6 hours at room temperature and concentrated. The residue was dissolved in ethyl acetate (20 mL) and the solution was dried (MgSO 4) and concentrated. The product was purified from the residue by flash chromatography eluting with 1: 3 hexanes / ethyl acetate to provide methyl 2- [2- (2-benzyloxycarbonylamino-4-methyl valerylamino) -! -hydroxy-4-phenylbutyl] oxazole-4-carboxylate (12 mg, 0.022 mmol) as a white solid. MS (PCI) m / z 538 (M + 1) H NMR (CDC13): d 0.8 -1.05 (d, J = 4 Hz, 6H), d 1.55-1.70 (m, 3H), d 2.00 (m, 1H ), d 2.40 (m, 1H), d 2.69 (m, 2H), d 3.99 (m, 3H) 4.45 (m, 1H), d 5.17 (s, 2H), d 5.78 (m, 1H), d 7.01 (d, J = 4Hz 1H), d 7.14-7.47 (m, 10H) 7.72 (d, J = 4Hz, 1H), d 8.40 (s, 1H), (C29H35N307). EXAMPLE 25 2- [2- (2-Benzyloxycarbonylamino-4-methylvalerylamino) -1-hydroxy-4-phenylbutyl] oxazole-4-carboxylic acid (Compound 254)
A mixture formed by methyl 2- [2- (2-benzyloxycarbonylamino-4-methylvalerylamino) -1-hydroxy-4-phenylbutyl] oxazole-4-carboxylate (2.16 g, 4.02 mmol), provided as in Example 18, and sodium hydroxide (0.815 mL, 1.63 M in water) in methanol (10 mL) was stirred for approximately 12 hours at room temperature, acidified with 1 M hydrochloric acid and concentrated. The residue was dissolved in ethyl acetate (50 mL) and the solution was dried (MgSO4). The product was recrystallized from methanol and ether to give 2- [2- (2-benzyloxycarbonylamino-4-methyl valerylamino) -l-hydroxy-4-phenylbuitol] oxazole-4-carboxylic acid (1.77 g, 3.38 mmol) as a whitish solid. EXAMPLE 26 Benzyl 3-methyl-l- [2-hydroxy-l-phenethyl-2- (4-phenyl carbamoyloxazol-2-yl) ethylcarbamoyl] butylcarbamate (Compound 255)
A solution formed by 2- [2- (2-benzyloxycarbonylamino-4-methylvalerylamino) -1-hydroxy-4-phenylbutyl] oxazole-4-carboxylic acid (0.05 g, 0.096 mmol), provided as in Example 7, DMF (5 mL) was stirred while adding PyBOP® (0.05 g, 0.096 mmol) and aniline (9 mg, 0.096 mmol). The mixture was stirred for an additional 2 minutes and diisopropylethylamine (12.4 mg, 0.096 mmol) was added. The mixture was stirred 2 hours at room temperature, emptied in cold water at 0 ° C and extracted with ethyl acetate (4 x 30 mL). The extracts were combined, dried (MgSO4) and then concentrated. The product was purified from the residue by flash chromatography eluting with 1: 2 hexanes / ethyl acetate to provide benzyl 3-methyl-l- [2-hydroxy-l-phenethyl-2- (4-phenyl carbamoyloxazole-2 -yl) ethyl carbamoyl] butylcarbamate (30 mg, 0.05 mmol) as a white solid. MS (ESI)) m / z = 599 (M + 1); 1H NMR (CDCL3): d 0.8-1.05 (d, J = 4 Hz, 6H), 1.35 (m, 1H), d 1.55 (m, 1H), d 2.00-2.15 (m, 2H), d 2.62 (m , 2H), 5 d 2.80 (m, 2H), d 3.65 (m,
2H), d 4.11 (m, 1H), or d 4.30 (m, 1H), d 4.45 (m, 1H), d 4.95
(s, 1H) 5.17 (s, 2H), d 5.2 (d, J = 4Hz, 1H), d 6.70 (d, J =
5Hz 1H) d 7.1 - 7.45 (m, 15H) 7.7 (d, J = 4Hz, 1H), d 8.19
(s, 1H), d 8.99 (s, 1H), (C34H38N4? 6). Continue the same as in Example 26 to provide the following compounds of Formula I: Benzyl 1- [2- (4-benzylcarbamoyloxazol-2-yl) -2-hydroxy-1-phenethylethylcarbamoyl] -3-methylbutylcarbamate (Compound 256), MS , (ESI)) m / z = 613 (M + 1); XH NMR (CDC13): d 0.8 - 1.05 (d, J = 4 Hz, 6H), d 1.25 -1-75 (m, 3H), d 2.00-2.20 (m, 2H), d 2.69 (m, 2H) , d 3.85 (m, 1H), d 3.95 (m, 1H), d 4.25 (m, 1H), d 4.60 (m, 2H), d 4.80 (s, 1H), d 5.17 (s, 2H); d 5.59 (m, 1H), d 6.59 (d, J = 4Hz 1H), d 7.05-7.47 (m, 15H), d 8.20 (s, 1H); (C35H40N4? 6); and Benzyl 3-methyl-l- [2-hydroxy-1-phenethyl-2- (4-phenethylcarbamoyloxazol-2-yl) ethylcarbamoyl] butylcarbamate (Compound 257), MS (ESI)) m / z = 627 (M + 1); XH NMR (CDC13): d 0.8 -1.05 (d, J = 4 Hz, 6H), d 5 1.25-1.75 (m, 4H), d 2.00 (m, 2H), d 2.59 (m, 2H) 2.88 (m , 2H), d 3.65 (m, 2H), d 4.02 (m, 1H), d 4.25 (m, 1H), d 4.80 (s, 1H), d 5.17 (s, 2H), d 6.59 (d, J = 4 Hz, 1H), d 7.00-7:42 (m, 15H), d 8.20 (s, 1H); EXAMPLE 27 Benzyl 1- [1- (4,5-dihydro-45-phenoxyoxazole-2-ylcarbonyl) -3- phenylpropylcarbamoyl] -3-methylbutylcarbamate (Compound 258)
A solution formed by benzyl 15- [2- (4,5-dihydro-4S-phenyloxazol-2-yl) -2-hydroxy-15-phenethylethylcarbamoyl] -3-methylbutylcarbamate (0.038 g, 0.078 mmol), provided as in Example 14, and Dess-Martin Periodinano (0.031 g, 0.072 mmol) in methylene chloride (5 mL) was stirred while a mixture of 0.001: 1 methylene chloride / water (2 mL) was added little by little. The mixture was stirred until the reaction was completed and then concentrated. The residue was dissolved in ethyl acetate (50 mL) and the solution was washed with saturated sodium bicarbonate (40 mL), sodium thiosulfate (40 mL, 10% w / w), water (40 mL) and brine (40 mL). mL), dried (MgSO 4) and then concentrated. The product was purified from the residue by flash chromatography eluting with 3: 1 ethyl acetate / hexanes to give benzyl 1- [1-4, 5-dihydro-4S-phenyloxazol-2-ylcarbonyl) -3-phenylpropylcarbamoyl] -3-methylbutylcarbamate
(0.014 g, 4S-phenyloxazol-2-ylcarbonyl) -3-phenylpropyl carbamoyl] -3-methylbutylcarbamate (0.014g, 37.5%) as a white solid. MS (PCI) m / z = 556 (M + 1) X H NMR (CDC 13): d 0-8 - 1.05 (d, J = 6 Hz, 6 H), d 1.4 -1.78 (m, 3 H), d 1.87 - 2.12 (m, 1H), d 2.40 (m, 1H), d 2.65 (t, J = 4Hz, 2H), d 4.25 (t, J = 3Hz, 2H), d 4.75 (t, J = 4 Hz, 1H ), d 5.10 (s, 2H), d 5-40 (d J = 3Hz, 1H), d 5.50 (t, J = 4 Hz, 1H), d 6.97 (d, J = 3Hz, 1H) 7.1 - 7.49 (m, 15H). (C33H37N305). Continue as in Example 27 to provide the following compounds of Formula I: benzyl 15- (15-benzooxazol-2-ylcarbonyl-3-phenylpropyl carbamoyl) -3-methylbutylcarbamate (Compound 259);
benzyl 15- [15- (4,5-dihydrooxazol-2-ylcarbonyl) -3-phenylpropylcarbamoyl-3-methylbutylcarbamate (Compound 260), MS (PCI) m / z = 480 (M + 1) XH NMR (CDC13): d 0.8 - 1.05 (d, J = 6 Hz, 6H), d 3.4 - 1.78 (m, 3H), d 1.82 - 2.01 (m, 2H), d 2.65 (t, J = 5 Hz 2H), d 2.99 ( t, J = 4Hz, 1H), d 3.75 (d, J = 3Hz, 1H), d 4.10 - 4.35 (m, 3H), d 4.50 (m, 1H), d 5.17 (s, 3H), d 6.85 ( s, 1H), d 7.1-7.49 (m, 10H), (C27H33N3O5); N- [3-methyl-15- (3-phenyl-15-benzooxazol-2-ylcarbonylpropylcarbamoyl) butyl] piperidine-4-carboxamide (Compound 261) H NMR (DMSO-dg): d 0.83 (d, J = 6.91 Hz, 6H), d 1.34 - 1.87 (m, 7H), d 1.92 - 2.07 (m, 1H), d 2.20 - 2.33 (m, 1H), d 2.41 - 2.54 (m, 1H), d 2.62 - 2.92 ( m, 4H), d 3-26 (bd, J = 12.12 2H), d 4.39 (m, 1H), d 5.18 (, 1H), d 7.16 - 7.33 (m, 5H), d 7.54 (t, J = 7.64 Hz, 1H), d 7.64 (t, 7.82 Hz, 1H), d 7.87 (d, J = 8.40 Hz, 1H), d 7.96 (d, J = 7.67 Hz, 1H), d 8.07 (d, J = 8.15 Hz, 1H), d 8.29 (bs, 1H), d 8.60 (bs, 1H), d 8.76 (d, J = 6.45 Hz, 1H); benzyl 1- [1- (4,5-dihydro-5-phenyloxazol-2-ylcarbonyl) -3-phenylpropylcarbamoyl] -3-methylbutylcarbamate (Compound 262) benzyl 1- [1- (4,5-dihydro-55-phenyl- 45-methyloxazol-2-ylcarbonyl) -3-phenylpropylcarbamoyl) -3-methylbutylcarbamate (Compound 263); benzyl 15- (15-phenethyl-2-benzimidazol-2-yl-l-oxoethylcarbamoyl) -3-methylbutylcarbamate (Compound 264), 1H NMR (CDC13): d 0.82-0.96 (m, 6H), d 1.44-1.75 (, 3H), d 2.17 - 2.32 (m, 1H), d 2.43 - 2.56 (m, 1H), d 2.61 - 2.80 (m, 2H), d 4. 55 (m, 1H), d 5.13 (m, 2H), d 5.35 (d, J = 8.67 Hz, 1H), d 5.70-5.88 (m, IH), d 7.00-7.42 (m, 14H), d 7.50-7.83 (m, 2H); benzyl 1- [1- (naphtho [2,3-d] oxazol-2-ylcarbonyl) -3-phenylpropylcarbamoyl] -3-methylbutylcarbamate (Compound 265); methyl 2- [2- (2-benzyloxycarbonylamino-4-methylvaleryl amino) -4-phenylbutyryl] -4,5-dihydrooxazole-4-carboxylate (Compound 266), MS (PCI) m / z = 538 (M + 1); XH NMR (CDC13): d 0.8-0.99 (d, J = 6 Hz, 6H), 1.25 (m, 1H), d 1.47 (m, 1H) 1.65 (m, 3H), d 1.99 (m, 1H), d 2.35 (m, 1H), d 2.65 (m, 2H), d 3.70 (m, 3H) 4.18 (m, 2H), d 4.55 (m, 1H), d 5.17 (s, 2H), d 5.35 (m , 1H) 6.75 (m, 1H), d 7.17-7.45 (m, 10H), (C29H35N307); benzyl 15- [15- (4,5-dihydro-4,4-dimethyloxazol-2-ylcarbonyl) -3-phenylpropylcarbamoyl] -3-methylbutylcarbamate (Compound 267), MS (PCI) m / z = 508 (M + 1 ); H NMR (CDC13): d 0.8 - 0.99 (d.J = 6 Hz, 6H), d 1.36 (s, 6H), d 1.5 (m, 1H), d 1.65 (m, 2H) 1.82 - 2.01 (m, 1H), d 2.35 (m, 1H), 5 d 2.6 (t J = 6 Hz, 2H), d 4.05 (s, 2H), d 4.25 (m, 2H), d 5.10 (s, 2H), d 5.4 (m, 1H), d 6.75 (d J = 8Hz, 1H) 7.1-7.38 (m, 10H); (C29H37N305); benzyl 15- (15-benzooxazol-2-ylcarbonyl-3-phenylpropyl carbamoyl) -2-methylpropylcarbamate (Compound 268). 1H NMR (CDC13): d 0.90 (d, J = 6.91 Hz, 3H), d 0.97 (d, J = 6.94 Hz, 3H), d 2.06-2.25 (m, 2H), d 2.38-2.55 (m, 1H) ), d 2.74 (m, 2H), d 4.03 (dd, J = 1.73, 6.45 Hz, 1H), d 5.10 (s, 2H), d 5.29 (d, J = 8.67 Hz, 1H), d 5.73 (m , 1H), d 6.66 (d, J = 7.42 Hz, 1H), d 7.09 - 7.40 (m, 10H), d 7.46 (dt, J = 1.62, 8.10 Hz, 1H), d 7.55 (dt, J = 1 -83, 7.76 Hz, 1H), d 7.64 (d.J = 8.06 Hz, 1H), d 7.89 (d, J = 7.46 Hz, 1H); benzyl 15- (15-benzooxazol-2-ylcarbonyl-3-phenylpropyl carbamoyl) -2-methylpropylcarbamate (Compound 269), "" "H NMR (CDC13); d 0.88 (t, J = 7.43 Hz, 3H), d 0.91 (d.J = 6.67 Hz. 3H), d 1.04-1.21 (m, 1H), d 1.40 -1.55 (m, 1H), d 1.78 -1.93 (m, 1H), d 2.10-2.24 (m, 1H) , d 2.40 - 2.54 (m, 1H), d 2.74 (t, J = 7.60 Hz, 2H), d 4.06 (t, J = 6.21 Hz, 1H), d 5.09 (s, 2H), 6 5.29 (d, J = 8.67 Hz, 1H), d 5.72 (m, 1H), d
6. 66 (d, J = 8.00 Hz, 1H), d 7.09 - 7.39 (m, 10H), d 7.46 (dt, J = 1.68, 7.80 Hz, 1H), d 7.55 (dt, J = 1.44, 7.56 Hz,
1H), d 7.63 (d.J = 8.04 Hz, 1H), d 7.89 (d, J = 7.82 Hz, 1H); benzyl 15- [15- (5-chlorobenzooxazol-2-ylcarbonyl) -3-f-enylpropylcarbamoyl] -3-methylbutylcarbamate (Compound 270); 1 H NMR (CDCl 3); d 0.90 (m, 6H), d 1.39 -1.53 (m, 1H), d 1.59
-1.70 (m, 2H), d 2.07 - 2.21 (m, 1H), d 2.37 - 2.52 (m, 1H), d 2.73 (t, J = 7.91 Hz, 2H), d 4.20 (m, 1H), d 5.06 (d, J = 7.91 Hz. 1H), d 5.10 (s, 2H), d 5.64 (m, 1H), d 6.77 (d.
7. 67 Hz, 1H), d 7.09 - 7.37 (m, 10H), d 7.53 (dq, J = 1.86, 8.91 Hz, 2H), d 7.89 (d.J = 1.73 Hz, 1H);
N-. { 3-methyl-15- [3-phenyl-15- (5-chlorobenzooxazol-2-ylcarbonyl) propylcarbamoyl] butyl} piperidine-4-carboxamide (Compound 271); N- [2-cyclohexyl-15-. { 3-phenyl-15-benzooxazol-2-ylcarbonylpropylcarbamoyl) ethyl] piperidine-4-carboxamide (Compound 272); MS (ESI) m / z == 545 (M + 1); ^ -IJMR (300 MHz, CDC13, (CD3OD): d 0.85 (m, 2H), d 1.02-1.58 (m, 4H), d 1.40-1.71 (m, 7H), d 1.75-2.21 (m, 5H) , d 2.38 (m, 1H), d 2.51 (m, 1H), d 2.69 (t, J = 4 Hz, 2H), d 3.32 (m, 2H), d 4.39 (q, J = 6 Hz 1H), d 5.53 (q, J = 3 Hz 1H), d 7.11 - 7.21 (m, 5H), d 7.24 (s, 1H), d 7.38 - 7.61 (m, 3H), d 7.73 (d.J = 6 Hz, 1H), d 7.82 (d, J = 6Hz, lH), (C32H40? 4O4), methyl 2- (2-benzyloxycarbonylamino-4-methylvaleryl amino) -4-phenylbutyryloxazole-4-carboxylate (Compound 273), benzyl 1- [- (4-phenylcarbamoyloxazol-2-ylcarbonyl) -3-phenylpropylcarbamoyl] -3-methylbutylcarbamate (Compound 274), MS (ESI) m / z = 597 (M + 1); XH? MR (CDC13); d 0.8 - 1.05 (d, J = 4 Hz, 6H), d 1.55 (m, 1H), d 1.70 (s, 2H), d 2.00 - 2.20 (m, 1H), d 2.40 (m, 1H), d 2.69 (m , 2H), d 2.97 (t, J = 4 Hz, 2H), d 3.70 (q, J = 3 Hz, 2H) 4.25 (m, 1H), d 5.17 (s, 2H), d 5.59 (m, 1H) ), d 6.99 (d, J = 4Hz 1H), d 7.14 - 7.47 (m, 15H) 7.72 (d.J = 4Hz, 1H), d 8.47 (s, 1H), d 8.65 (s, 1H), ( C34H36? 406); benzyl 1- [- (4-benzylcarbamoyloxazol-2-ylcarbonyl) -3-phenylpropylcarbamoyl] -3-methylbutylcarbamate (Compound 275), MS (ESI)) m / z = 611 (M + 1); XH NMR (CDC13). d 0.8 - 1.05 (d, J = 4 Hz, 6H), d 1.45 - 1.70 (m, 4H), d 2.00 - 2.20 (m, 1H), d 2.40 (m, 1H), d 2.69 (m, 2H) , d 4.25 (m, 1H), d 4.67 (t, J = 3 Hz, 2H), d 5.17 (m, 3H), d 5.59 (in, 1H), d 6.85 (d, J = 4Hz 1H), d 7.10 - 7.47 (m, 15H), d 8.47 (s, 1H), (C35H38N40β); erc-butyl 4-. { 15- [15- (5- erc-Butylbenzooxazol-2-yl carbonyl) -3-phenylpropylcarbamoyl] -3-methylbutylcarbarmoyl} piperidine-1-carboxylate (Compound 276), 1 H NMR (CDC13); d 0.86 - 0.97 (m, 6H), d 1.34 - 1.85 (m, 7H), d 1.38 (s, 9H), d 1.43 (s, 9H), d 2.09 - 2.30 (m, EH), d 2.37 - 2.52 (m, 1H), d 2.72 (m, 4H), d 4.11 (bd, J = 12.85, 2H), d 4.49 (m, 1H), d
. 66 (m, 1H), d 5.97 (d, J = 7.91 Hz. 1H), d 6.89 (d, J =
7. 67 Hz. 1H), d 7.11 - 7.27 (m, 5H), d 7.50 - 7.64 (m, 2H), d 7.86 (d, J = 1.56 Hz. 1H); tert-butyl 4-. { 15- [15- (5-sulfamoylbenzooxazol-2-ylcarbonyl) -3-phenylpropylcarbamoyl] -3-methylbutylcarbamoyl} piperidine-1-carboxylate (Compound 277), XH NMR (CDC13): d 0.85-0.96 (m, 6H), d 1.37-1.82 (m, 7H), d 1.42 (s, 9H), d 2.08-2.46 (m , 3H), d 2.71 (m, 4H), d 4.02 (bs, 2H), d 4.56 (m, 1H), d 5.38 (bs, 1H), d 5.78 (bs, 2H), d 6.38 (d, J = 8.42 Hz, 1H), d 7.07 -7.25 (m, 5H), d 7.70 (dd, J = 3.48, 8.64 Hz, 1H), d 8.08 (dd, J = 1.73, 8.67 Hz, 1H), d 8.41 (dd, J = 1.49, 3.96 Hz, 1H); N-. { 3-Methyl-lS- [3-phenyl-15- (5- erc-butylbenzooxazol-2-ylcarbonyl) propylcarbamoyl] butyl} piperidine-4-carboxamide (Compound 278),? U NMR (DMSO-d6): d 0.82 (t, J = 6.18 Hz, 6H), d 1.36 (s, 9H), d 1.33-3.8 (m, 7H), d 1.91 - 2.06 (m, 1H), d 2.19 - 2.34 (, 1H), d 2.42 - 2.54 (m, 1H), d 2.61 -2.92 (m, 4H), d 3.27 (bd, J = 12.02 2H), d 4.39 (m, 1H), d 5.19 (m, 1H), d 7.15 - 7.33 (m, 5H), d 7.74 (d J =, 1.97, 7.91 Hz, 2H), d 7.90 (d, J = 1.83 Hz , 1H), d 8.07 (d, J = 8.15 Hz. 1H), d 8.27 (bs. 1H), d 8.56 (bs, 1H), d 8.72 (d, J = 6.43 Hz, 1H); N-. { 3-methyl -IS- [3-phenyl-lS- (5-sulfamoylbenzooxazol-2-ylcarbonyl) propylcarbamoyl] butyl} piperidine-4-carboxamide
(Compound 279), XH? MR (DMSO-d6): d 0.80-0.88 (m, 6H), d 1.31-1.86 (m, 7H), d 1.92 - 2.05 (m, 1H), d 2.22 - 2.33 (m , 1H), d 2.41-2.52 (m, 1H), d 2.63-2.89 (m, 4H), d 3.26 (bd, J = 11.88 2H), d 4.40 (m, 1H), d 5.13 (m, 1H) , d 7.16 -7.31 (m, 5H), d 7.57 (s, 2H), d 8.05 (m, 3H), d 8.25 (bs, 1H), d 8.32 (s, 1H), d 8.55 (bs, 1H) , d 8.82 (d.J = 6.18 Hz, 1H), d 8.88 (d, J = 6.84 Hz, 1H); tert-butyl 4- [15- (1-naphtho [1,2-d] oxazole-2-ylcarbonyl-3-phenylpropylcarbamoyl) -3-methylbutylcarbamoyl] piperidine-1-carboxylate (Compound 280),? MR (CDC13); d 0.87 - 0.95
(m, 6H), d 1.39 -1.85 (m, 7H), d 1.44 (s, 9H), d 2.13 - 2.32
(m, 2H), d 2.45 - 2.60 (m, 1H), d 2.65 - 2.81 (m, 4H), d 4.12
(m, 2H), d 4.53 (m, 1H), d 5.79 (m, 1H), d 6.00 (d, 'j = 7.94
Hz, 1H), d 6.90 (d, J = 7.67 Hz, 1H), d 7.12 - 7.26 (m, 5H), d 7.56 - 7.80 (m, 3H), d 7.93 - 8.00 (m, 2H), d 8.52 (dd, J == 1.97, 8.00 Hz, 1H); tert-butyl 4- [15- (l-naphtho [2, l-d] oxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl) -3-methylbutylcarbamoyl] piperidine-1-carboxylate (Compound 281), XH NMR (CDC13); d 0.88 - 0.97
(m, 6H), d 1.38 - 1.86 (m, 7H), d 1.43 (s, 9H), d 2.15 - 2.31
(m, 2H). d 2.43 - 2.57 [m, 1H), d 2.67 - 2.79 (m, 4H), d 4.11
(m, 2H), d 4.52 (m, 1H), d 5-73 (m, 1H), d 5.96 (d.I = 7.94
Hz, 1H), d 6.90 (d, J = 7.91 Hz. 1H), d 7.12 - 7.26 (m, 5H), d 7.66 (m, 2H), d 7.85 (s, 1H), d 7.99 (dd, J = 1.85, 7.80
Hz, 1H), d 8.33 (dd, J = 1.97, 7.94 Hz. 1H); tert-butyl 4-. { l5- [15- (5-Pentylbenzooxazol-2-yl carbonyl) -3-phenylpropylcarbamoyl] -3-methylbutylcarbamoyl} piperidine-1-carboxylate (Compound 282); MS (ESI) m / z = 681 (M + 1); XH-NMR (300 MHz. (CDC13): d 0.85-0.98 (m, 6H), d 1.43 (s, 9H), d 1.60-1.85 (m, 5H), d 2.14-2.30 (m, 2H), d 2.56 (m, 1H), d 2.75 (m, 4H), d 4.12 (m, 2H), d 4.52 (m, 1H), d 5.69 (m, 1H), d 5.92 (d, J = 6 Hz, 1H d 6.85 (d.J = 6 Hz, 1H), d 7.13 - 7.26 (m, 7H) d 7.36 - 7.80 (m, 7H), d 8.05 (s, 1H), (C40H48N4O6); N-. {3-methyl-15- [3-phenyl-15- (naphtho [1,2-d] oxazole -2-yl carbonyl) propylcarbamoyl] butyl}. Piperidine-4-carboxamide (Compound 283), X? MR (DMSO- < d6): d 0.81 (m, 6H), d 1.35 -1.86 (m, 7H), d 1.96 - 2.11 (m, 1H), d 2.26 - 2.53 (m, 2H), d 2.64 - 2.91 (m, 4H), d 3.26 (bd, J = 11.63 2H), d 4.42 (m, 1H), d 5.27 (m, 1H), d 7.19-7.36 (m, 5H), d 7.70 (t, J = 7.91 Hz, 1H), d 7.83 (t, J = 7.43 Hz, 1H), d 8.01 (d, J = 8.91 Hz. 1H), d 8.08 (m, 1H), d 8.18 (d, J = 8.91 Hz, 2H), d 8.27 (bs, 1H), d 8.39 (d, J = 7.91 Hz, 1H), d 8.56 (bs, 1H), d 8.75 (d.J = 6.45 Hz, 1H); - { 3 -methyl-15- [3-phenyl-15- (naphtho [2, 1-d] oxaz. ol-2-carbonyl) propylcarbamoyl] butyl} piperidine-4-carboxamide (Compound 284), X? MR (DMS0-d6): d 0.81 (t, J = 6.43 Hz, 6H), d 1.34-1.87 (m, 7H), d 1.97-2.12 (m, 1H ), d 2.24 - 2.38 (m, 1H), d 2.42 - 2.53 (m, 1H), d 2.66 - 2.93 (m, 4H), d 3.26 (bd, J = 10.12 2H), d 4.41 (m, 1H) , d 5-26 (m, 1H), d 7.16 -7.34 (m, 5H), d 7.77 (m, 2H), d 7.97 (d, J = 8.91 Hz, 1H), d 8.05 (d, J = 8.86 Hz, 1H), d 8.07 (d.J = 8.64 Hz, 1H), d 8.19 (d.J = 7.91 Hz, 1H), d 8.26 (bs, 1H), d 8.28 (d, J = 7.67 Hz. ), d 8.56 (bs, 1H), d 8.78 (d, J = 6.43 Hz, 1H); N-. { 3-methyl-l- [3-phenyl-1- (5-phenylbenzooxazol-2-yl carbonyl) propylcarbamoyl] butyl} piperidine-4-carboxamide (Compound 285); Benzyl 1- [1- (4-phenylethylcarbamoyloxazol-2-ylcarbonyl) -3-phenylpropylcarbamoyl] -3-methylbutylcarbamate (Compound 286) MS (ESI)) m / z = 625 (M + 1); XH ™ MR (CDCl3); d 0.8 - 1.05 (d, J = 4 Hz, 6H), d 1.50 (m, 3H), d 1.65 (m, 3H), d 2.00 - 2.20 (m, 1H), d 2.35 (m, 1H), d 2.60 (m, 2H), d 2.99 (t, J = 4Hz, 2H), d 3.67 (q, J = 3 Hz, 2H), 4.19 (m, 1H), d 5.17 (s, 2H), d 5.59 ( m, 1H), d 6.85-6.98 (m, 2H), d 7.10-7.47 (m, 15H), d 8.43 (s, 1H); (C36H4o 406); bencil l-. { l- [4- (3-Phenylpropylcarbamoyl) oxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl} -3-methylbutylcarbamate (Compound 287); MS (ESI) m / z = 639 (M + 1); XH-NMR (300 MHz. CDC13): d 0.95 (d, J = 6 Hz, 6H), d 1.50 (m, 1H), d 1.65 (m, 3H), 12.00 (m, 4H), d 2.35 (m , 1H), d 2.67 (m, 4H), d 3.49 (m, 2H), d 4.20 (m, 1H), d 5.09 (s, 2H), d 5.50 (m, 1H). d 6.85 (m, 1H), d 7.23 (m, 15H), d 8.35 (s, 1H), d (C37H42N406); tert-butyl 4- [15- (15-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl) -2-methylbutylcarbamoylpiperidine-1-carboxylate (Compound 288); tert-butyl 3- [15- (15-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl) -2-methylbutylcarbamoylbenzylcarbamate (Compound 289); N- [2-methyl-lS- (3-phenyl-15-benzooxazol-2-yl carbonylpropylcarbamoyl) butyl] piperidine-4-carboxamide (Compound 290); N- [2-methyl-15- (3-phenyl-15-benzooxazol-2-ylcarbonylpropylcarbamoyl) butyl] -3-aminomethylbenzamide (Compound 291); bencil l-. { l-l- [4- (2-indol-3-yl-ethylcarbamoyl) -oxazol-2-ylcarbonyl] -3-phenylpropylcarbamoyl-3-methylbutylcarbamate (Compound 292); MS (ESI) m / z = 664 (M + 1); 1H-? MR (300 MHz,
CDCI3): 5 0.94 (d, J = 6 Hz, 6H), d 1.40-1.70 (m, 6H), d 2.00 (m, 1H), d 2.25 (m, 1H), d 2.67 (m, 2H), d 3.09 (m, 2H), d 3.52 - 3.85 (m, 2H), d 4.20 (m, 1H), d 5.09 (s.2H), d 5.50 (m, 1H), d5 6.80 (d.J = 6 Hz, 1H), d 6.99 - 7.41 (m, 14H), d 7.65 (d, J = 6 Hz. 1H), d 8.35 (s, 1H), d 8.39 (s, 1H), (C38H4? 506); benzyl 1- [1- (4-methylcarbamoyloxazol-2-ylcarbonyl) -3-phenylpropylcarbamoyl] -3-methylbutylcarbamate (Compound 293); MS (ESI) m / z = 535 (M + 1); XH-NMR (300 MHz, CDC? 3): 0.95 (d, J = 6 Hz, 6H), d 1.33-1.70 (m, 5H), d 2.00 (m, 1H), d 2.28 (m, 1H), d 2.67 (m, 2H), d 2.99 (d, J = 2 Hz, 3H), d 4.15 (m, 1H), d 5.09 (m, 2H), d 5.50 (m, 1H), d 6.88 (, 1H) ), d 7.09 -7.38 (m, 10H), d 8.35 (s, 1H), (C29H34N406); benzyl 2- { 2- [2- (2-Benzyloxycarbonylamino-4-methyl valerylamino) -4-phenylbutyryl] oxazol-2-ylcarbonylamino} valerate (Compound 294); bencil 15-. { 15- [4- (4-Benzylpiperidin-1-ylcarbonyl) oxazol-2-ylcarbonyl] -3-phenylpropylcarbamoyl} -3-methylbutyl carbamate (Compound 295); MS (ESI) m / z == 679 (M + 1) 1 H-NMR (300 MHZ CDL3): d 0.92 (m, 6H), d 1.25 (m, 1H), d 1.48 (q, J = 4Hz, 1H ), d 1.52 - 1.85 (m, 6H), d 2.0 (m, 1H), d 2.36 (m, 1H), d 2.53 - 2.77 (m, 3H), d .03 (t, J = 8 Hz, 1H ), d 4.19 (m, 1H), d 4.65 (m, 1H), d 5.02 - 5.13 (m, 3H), d 5.53 (m, 1H), d 6.68 (d, J = 6 Hz, 1H), d 7.08-7.39 (m, 15H), d 8.28 benzyl 15- [15- (4-fur-2-ylmethylcarbamoyloxazol-2-ylcarbonyl) -3-phenylpropylcarbamoyl-3-methylbutylcarbamate (Compound 296); MS (ESI) m / z = 601 (M + 1); XH-NMR (300 MHz, CDC13): d 0.98 (d, J = 6 Hz 6H), d 1.58 (q, J = 6 Hz 1H), 1.62 (m, H), d 2.00 (m, 1H), d 2.27 (m, 1H), d 2.76 (m, 2H), d 4.20 (m, 1H), d 4.70 (d, J = 4 Hz, 2H), d 4.98 - 5.18 (m, 2H), d 5.56 (m , 1H), d 6.82 (m, 1H), d 7.05-7.42 (m, 13H), d 8-32 (d, J = 4 Hz, 1H), (C33H36N407); benzyl 3-methyl-15- [15- (4-pyrid-2-ylmethylcarbamoyl oxazol-2-ylcarbonyl) -3-f-enylpropylcarbamoyl] butylcarbamate (Compound 297); MS (ESI) m / z = 612 (M + 1); XH-NMR (300 MHz, CDCl 3): d 0.98 (d, J = 6 Hz 6H), d 1.4 - 2.15 (m, 5H), d 2.32
(m, 1H), d 2.71 (m, 2H), d 4.21 (m, 1H), d 4.75 (d, J = 2 Hz, 2H), d 5.09 (, 2H), d 5.15 - 5.5 (m, 1H ), d 7.10 - 7.38 (m, 13H), d 7.7 (t, J = 4 Hz, 1H), d 7.95 (m, 1H), d 8.32 (d, J = 4 Hz, 1H), d 8.59 (s) , 1 H), (C 34 H 37 N 5? 6); benzyl 3-methyl-15- [15- (4-pyrid-3-ylmethylcarbamoyl-oxazol-2-ylcarbonyl) -3-phenylpropylcarbamoyl] butylcarbamate (Compound 298); MS (ESI) m / z = 612 (M + 1); XH-NMR (300 MHz, CDCL3); d 0.98 (d.J = 6 Hz 6H), d 1.5 (q, J = 4 Hz, 1H), d 1.65 (m, 2H), d 1.95 (m, 3H), d.25 5 (m, 1H) , d 2.68 (m, 2H), d 4.19 (, 1H), d 4.72 (d, J = 2 Hz, 2H), d 5.09 (s, 2H), d
. 41 (m, 1H), d 6.90 (t, J = 2 Hz, 1H), d 7.05-7.35 (m, 10H), d 7.46 (m, 1H), d 7.72 (d, J = 6 Hz, 1H) , d 8.31 (d, J = 4 Hz, 1H), d 8.62 (d, J = 4 Hz 1H), d 8-73 (s, 1H), (C34H37N506);
benzyl 3-methyl-15- [15- (4-pyrid-4-ylmethylcarbamoyl-oxazol-2-ylcarbonyl) -3-phenylpropylcarbamoyl] butylcarbamate (Compound 299); MS (ESI) m / z = 612 (M + 1); XH-NMR (300 MHz, CDC13): d 0.98 (d.J = 6 Hz, 6H), d 1.5 (q, J = 4 Hz, 1H), 1.65 (m, 2H), 1.95 (m, 3H), 2.25 (m, 1H), 2.68 (m, 2H), 4.19 (m, 1H), 4.72 (t, J = 2 Hz, 2H), 5.11 (d, J = 4 Hz. 2H), 5.43 (m, 1H) ), 6.92 (d, J = 6 Hz, 1H), 7.05-7.35 (m, 11H), 7.46 (m, 1H), 8.33 (d, J = 4 Hz, 1H), 8.58 (m, 2H), ( C34H37N50ß); bencil 15-. { 15- [4- (2-Chlorobenzylcarbamoyl) oxazol-2-ylcarbonyl] -3-phenylpropylcarbamoyl} -3-methylbutylcarbamate (Compound 300); MS (ESI) m / z = 646 (M + 1); XH-NMR (300 MHz, CDCl 3): d 0.98 (d, J = 6 Hz, 6H), d 1.5 (q, J == 4 Hz. 1H), d 1.62 (m, 4H), 1.95 d (m, 1H), d 2.30 (m, 1H), d 2.65 (m, 2H), d 4.19 (m, 1H), d 4.70 (d, J = 2 Hz, 2H), d 5.09 (m, 2H), d 5.47 (m, 1H), d 6.82 (m, 1H) d 7.05-7.45 (m, 14H), d 8.33 (d, J = 4 Hz, 1H), (C35H37ClN40e); bencil 15-. { 15- [4- (3-Chlorobenzylcarbamoyl) oxazol-2-ylcarbonyl] -3-phenylpropylcarbamoyl} -3-methylbutylcarbamate (Compound 301); MS (ESI) m / z = 646 (M + 1); XH-NMR (300 MHz, CDCl 3): d 0.98 (d, J = 6 Hz, 6H), d 1.5 (q, J = 4 Hz, 1H), d 1.62 (m, 4H), d 2.00 (m, 1H ), d 2.25 (m, 1 H), d 2.65 (m, 2H), d 4.20 (m, 1H), d 4.68 (d, J = 2 Hz, 2H), d 5.09 (m, 2H), d 5.43 (m, 1H), d 6.85 (d, J = 6 Hz, 1H), d 7.05-7.45 (m, 14H), d 8.33 (d, J = 4 Hz, 1H), (C35H37C1N406);
bencil 15-. { 15- [4- (4-Chlorobenzylcarbamoyl) oxazol-2-ylcarbonyl] -3-phenylpropylcarbamoyl} -3-methylbutylcarbamate (Compound 302); MS (ESI) m / z = 646 (M + 1); ^ -NMR (300 MHz, CDC13): d 0.98 (d, J = 6 Hz, 6H), d 1.5 (q, J = 4 Hz, 1H), d 1.62 (m, 4H), d 2.00 (m, 1H ), d 2.25 (m, 1H), d 2.65 (m, 2H), d 4.20 (m, 1H), d 4.68 (d, J = 2 Hz, 2H), d 5.09 (m, 2H), d 5.43 ( m, 1H), d 6.85 (m, 1H), d 7.05-7.45 (m, 14H), d 8.33 (d, J = 4 Hz, 1H), (C35H37C1N40S); benzyl 3-methyl-lS-. { 15- [4- (25-phenylcycloprop-15-ylcarbamoyl) oxazol-2-ylcarbonyl] -3-phenylpropylcarbamoyl} -3-methylbutylcarbamate (Compound 303); MS (ESI) m / z = 637 (M + 1); ^ -NMR (300 MHz, CDC13): d 0.92 (d, J = 6 Hz, 6H), d 1.46-1.78 (m, 6H), d 2.00 (m, 3H), d 2.31 (m, 1H), d 2.67 (m, 2H), d 2.99 - 3.22 (m, 1H), d 4.20 (m, 1H), d 5.04 (d, J = 6 Hz, 1H), d 5.11 (s, 2H), d 5.54 (m , 1H), d 6.87 (m, 1H), d 7.08-7.47 (m, 15H), d 8.30 (d, J = 2 Hz, 1H), (C37H40N4O6); benzyl 3-methyl-15- [15- (4-diphenylmethylmethylcarbarmoyl oxazol-2-ylcarbonyl) -3-phenylpropylcarbamoyl] -3-methylbutyl carbamate (Compound 304); MS (ESI) m / z = 687 (M + 1); XH-NMR (300 MHz, CDCl 3): d 0.98 (d, J = 6 Hz, 6H), d 1.48 (q, J = 4 Hz, 1H), d 1.62 (m, 2H), d 2.00 (m, 1H ), d 2.30 (m, 1H), d 2.67 (ra, 2H), d 4.18 (m, 1H), d 5.09 (ra, 3H), d 5.43 (m, 1H), d 6.42 (d, J = 6 Hz, 1H), d 6.80 (d, J = 6Hz, 1H), d 7.02 -7.72 (m, 20H), d 7.79 (d, J = 6 Hz, 1H), 8.33 (d, J = 4 Hz, 1H), (C39H48N406);
benzyl-S- (4-adamantan-l-ylmethylcarbamoyloxazol-2-ylcarbonyl) -3-phenylpropylcarbamoyl] -3-methylbutylcarbamate (Compound 305); MS (ESI) m / z = 670 (M + 1); ^ -NMR (300 MHz, CDC13): d 0.92 (m, 8H), d 1.18 - 1.78 (m, 16H), d 2.00 (m, 1H), d 2.31 (m, 1H), d 2.67 (m, 2H ), d 2.99 - 3.09 (m, 2H), d 4.21 (m, 1H), d 5.11 (m, 3H), d 5.51 (m, 1H), d 6.87 (m, 1H), d 7.02 (m, 1H) ), d 7.08-7.47 (m, 10H), d 8.31 (d, J = 2 Hz, 1H), (C39H48N406); bencil 1-. { l- [4- (1-Methylethylcarbamoyl) oxazol-2-ylcarbonyl] -3-phenylpropylcarbamoyl} -3-methylbutylcarbamate (Compound 306); bencil 1-. { l- [4- (15-phenylethylcarbamoyl) oxazol-2-ylcarbonyl] -3-phenylpropylcarbamoyl} -3-methylbutylcarbamate (Compound 307); MS (ESI) m / z = 625 (M + 1); XH-NMR (300 MHz, CDC13): d 0.92 (d, J = 6 Hz, 6H), d 1.54-1.65 (m, 7H), d 2.00 (m, 1H), d 2.25 (m, 1H), d 2.65 (m, 2H), d 4.15 (m, 1H), d 4.99 (d, J = 2 Hz, 1H), d 5.09 (s, 2H), d 5.32 (m, 1H), d 5.43 (m, 1H) ), d 6.79 (d, J = 6 Hz, 1H), d 7.05-7.45 (m, 15H), d 8.31 (s, 1H), (C36H4oN4Oβ); bencil 1-. { 1- [4- (1R-phenylethylcarbamoyl) oxazol-2-ylcarbonyl] -3-phenylpropylcarbamoyl} -3-methylbutylcarbamate (Compound 308); MS (ESI) m / z = 625 (M + 1); ^ -NMR (300 MHz, CDCl 3): d 0.92 (d, J = 6 Hz, 6H), d 1.45-1.68 (m, 7H), d 2.00 (m, 1H), d 2.25 (m, 1H), d 2.65 (m, 2H), d 4.15 (m, 1H), d 4.99 (d, J = 2 Hz, 1H), d 5.09 (s, 2H), d 5.32 (m, 1H), d 5.43 (m, 1H) ), d 6.79 (d, J = 6 Hz, 5 1 H), d 7.05-7.45 (m, 15H), d 8.31 (s, 1H), (C36H4oN406); bencil l-. { 1- [4- (N-Benzyl-N-methylcarbamoyl) oxazol-2-ylcarbonyl] -3-phenylpropylcarbamoyl} -3-methylbutylcarbamate (Compound 309); MS (ESI) m / z = 625 (M + 1); ^ -? MR (300 MHz, CDC13): d 0.90 (d, J = 6 Hz, 6H), d 1.27 -1.68 (m, 4H), d 2.00 (m, 1H), d 2.25 (m, lH ), d 2.65 (m, 2H), d 3.10 (s, 1H), d 4.19 (m, 1H), d 4.71 (s, 2H), d 5.09 (s, 2H), d 5.22 (m, 1H), d 5.43 (m, 1H), d 6.99 (d, J = 6 Hz, 1H), d 7.05-7.45 (m, 15H), d 7.60 (m, 1H), 58.31 (s, 1H), (C36H40? 4O6) ); benzyl 1- [1- (4-pyrrolidin-1-ylcarbonyloxazol-2-ylcarbonyl) -3-phenylpropylcarbamoyl] -3-methylbutylcarbamate (Compound 310); MS (ESI) m / z = 575 (M + 1); 1H-? MR (300 MHz, CDCl 3): d 0.93 (d, J = 6 Hz, 6H), d 1.45 -1.73 (m, 3H), d 1.85-2.12 (m, 5H), d 2.34 (m, 1H ), d 2.64 (m, 2H), d 3.62
(t, J = 4 Hz, 2H), d 3.82 (m, 2H), d 4.21 (m, 1H), 4.99 - 5.11 (m, 2H), d 5.55 (m, 1H), d 5.43 (m, 1H) ), d 6.79 (m, 1H), d 7.05 - 7.45 (m, 10H), d 8.31 (d, J = 2Hz, 1H), (C36H38? 406); benzyl 1- [1- (4-piperidin-1-ylcarbonyloxazol-2-ylcarbonyl) -3-phenylpropylcarbamoyl] -3-methylbutylcarbamate (Compound 311); MS (ESI) m / z = 589 (M + 1); XH-? MR (300 MHz, CDCI3): d 0.90 (d, J = 6 Hz, 6H), d 1-25 (m, 2H), d 1.49-1.66 (m, 6H), d 2.12 (m, 1H ), d 2.34 (m, 1H), d 2.64 (m, 2H), d 3.65 (m, 2H), d 3.85 (m, 2H), d 4.17 (m, 1H), d 4.99 - 5.11 (m, 3H) ), d 5.55 (m, 1H), d 6.67 (m, 1H), d 7.08-7.39 (m, 11H), d 8.27 (s, 1H), (C33H40N4O6); Benzyl 1- (1- [4- (2,3-dihydroindol-1-ylcarbonyl) oxazole-2-ylcarbonyl] -3-phenylpropylcarbamoyl} -3-methylbutylcarbamate (Compound 312); benzyl-; [4- (3, 4-dihydro-lJJ-isoquinol-2-yl carbonyl) oxazole-2-ylcarbonyl] -3-phenylpropylcarbamoyl} -3-methylbutylcarbamate (Compound 313); MS (ESI) m / z = 637 (M + 1); XH-NMR (300 MHz, CDCl 3): d 0.90 (d, J = 6 Hz, 6H), d 1.25 (m, 2H), d 1.45 -1.79 (m, 4H), d 2.11 ( m, 1H), d 2.40 (m, 1H), d 2.68 (m, 2H), d 2.95 (t J = 4 Hz, 2H), d 3.96 (t, J = 4 Hz, 1H), d 4.15 ( m, 2H), d 4.86 (d, J = 6 Hz, 1H), d 4.99 -5.11 (m, 3H), d 5.59 (m, 1H), d 6.70 (m, 1H), d 7.05-7.45 (m , 12H), d 8.35 (s, 1H), (C37H40N4O6); benzyl 1-. {L- [4- (3, 4-dihydro-2H-quinol-l-ylcarbonyl) oxazol-2-ylcarbonyl] -3 -phenylpropylcarbamoyl.} - 3-methylbutyl carbamate (Compound 314); MS (ESI) m / z = 637 (M + 1); ^ -NMR (300 MHz, CDC13): d 0.90 (d, J = 6 Hz, 6H), d 1.25 (m, 2H), d 1.40 - 1.69 (m, 3H), d 2.05 (m, 2H), d 2.52 (t, J = 6 H) z, 2H), d 2.82 (t, J = 4 Hz, 2H), d 3.80 - 4.21 (ra, 4H), d 4.86 (d, J = 6 Hz, 1H), d 5.09 (s, 2H), d 5.21 (m, 1H), d 6.62 (m, 1H), d 6.85-7.31 (m, 11H), d 7.51 (m, 1H), d 7.67 (m, 1H), d 8.31 (s, 1H), ( C 37 H 40 N 4 O 6); Benzyl 1- [1- (4-naphth-1-ylmethylcarbamoyloxazol-2-ylcarbonyl) -3-phenylpropylcarbamoyl] -3-methylbutylcarbamate (Compound 315); MS (ESI) m / z = 661 (M + 1); XH-NMR (300 MHz, CDC13): d 0.90 (d, J = 6 Hz, 6H), d 1.25 (m, 2H), d 1.54 (m, 3H), d 2.05 (m, 1H), d 2.59 ( t, J = 6 Hz, lH), d 2.82 (t, J = 4 Hz, 2H), d 4.12 (m, 1H), d 4.90 - 5.09 (m, 4H), d 5.34 (m, 1H), 6 6.71 (m, 1H), d 6.95-7.12 (m, 3H), d 7.27 (m, 10H), d 7.51 (m, 2H), d 7.88 (t, J = 6 Hz, 1H), d 8.06 (d , J = 6 Hz, 1H), d 8.35 (s, 1H), (C39H40 4? 6); tert -butyl 4- [15- (15-benzooxazol-2-ylcarbonyl) -3-phenylpropylcarbamoyl) -2-cyclohexylethylcarbamoyl] piperidine-1-carboxylate (Compound 316); fifteen-. { l5- [4- (3, 4-dihydro-2H-quinol-l-ylcarbonyl) oxazole-2-ylcarbonyl] -ethylcarbamoyl} -3-methylbutylcarbarmate (Compound 317); benzyl 3-methyl-15 [15- (5-phenyloxazol-2-ylcarbonyl) -3-phenylpropylcarbamoyl] butylcarbamate (Compound 318); MS
(ESI) m / z. = 554 (M + 1); XH-NMR (300 MHz, CDCl 3): d 0.97
(d, J = 4 Hz, 6H), d 1.50 (t, J = 4 Hz, 1H), d 1.65 -1.82
(m, 3H), d 2.20 (m, 1H), d 2.48 (m, 1H), d 2.75 (t, J = 4
Hz. 2H), d 4.27 (m, 1H), d 5.09 (s, 2H), d 5.65 (m, 1H), d 6.85 (d, J = 6Hz, 1H), d 7.12 - 7.62 (m, 14H) , d 7. 77
(d., J = 2 Hz, 2H), (C33H35N3O5); pyrid-3-lyl-3-methyl-15- [15- (5-phenyloxazol-2-ylcarbonyl) -3-phenylpropylcarbamoyl] butylcarbamate (Compound
319); MS (ESI) m / z = 525 (M + 1); ^ -NMR (300 MHz, CDC13) d 0.80 - 1.05 (m, 6H), d 1.27 (m, 3H), d 1.72 (m, 3H), d 2.15 (m, 1H), d 2.46 (m, 1H) , d 2.77 (t, J == 4 Hz, 2H), d 4.75 (m, 1H), d 5.65 (m, 1H), d 6.95 (d, J = 4Hz, 1H), d 7.02 (d, J = 4Hz, 1H), d 7.09 - 7.35 (m, 5H), d 7.37 - 7.62 (m, 3H), d 7.80 (d, J = 4 Hz, 1H), d 8.15 (d, J = 6Hz, 1H), d 8.75 (m, 1H), d 9.09 (s, 1H), (C3? H32N404); benzyl 15- [15- (5-f-enyloxazol-2-ylcarbonyl) -3-phenyl-propylsulfamoylmethyl] -2R-me t -butyl-1-carbamate (Compound 320);
MS (ESI) m / z = 604 (M + 1); XH-NMR (300 MHz, CDCl 3): d 0.95
(m, 6H), d 1.25 (m, 1H), d 1.49 (m, 1H), d 1.65 (m, 1H), S 2.15 (m, 1H), d 2.48 (m, 1H), d 2-85 (m, 211), d 3.12 (m,
2H), d 4.46 (m, 1H), d 4.99 (d, J = 8Hz, 1H), d 5.12 (m, 3H), d 6.32 (d, J = 6Hz, 1H), d 7.19 - 7.55 (m, 14H), d 7.76 (m, 2H), (C33H37N43? 6S); benzyl 3-methyl-l-. { 2-hydroxy-1-phenethyl-2- [4- (3-phenylpropylcarbamoyl) oxazol-2-yl] ethylcarbamoyl} Butylcarbamate (Compound 321); bencil 1-. { 2-hydroxy-2- [4- (2-indol-3-yl-ethylcarbamoyl) -oxazol-2-yl] -1-phenethylethylcarbamoyl} -3-methylbutylcarbamate (Compound 322); MS (ESI) m / z = 666 (M + 1); XH-NMR (300 MHz, CDC13): d 0.90 (d, J = 6 Hz, 6H), d 1.40 -1.80 (m, 6H), d 2.00 (m, 1H); d 2.67 (m, 2H), d 3.09 (m, 2H), d 3.52 - 3.85 (m, 2H), d 3.99 - 4.20 (m, 2H), d 4.26 - 4.44 (m, 1H), d 4.81 (s) , 1H), d 5.09 (s, 2H), d 5.50 (m, 1H), d 6.72 (d, J = 6 Hz, 1H), d 6.99 - 7.41 (m, 14H), d 8.18 (s.1H) , d 8.39 (s.1H), (C38H43N506);
benzyl 3-methyl-l- [2-hydroxy-2- (4-methylcarbamoyloxazol-2-yl) -1-phenethylethylcarbamoyl] butylcarbamate (Compound 323); MS (ESI) m / z = 537 (M + 1); XH-NMR (300 MHz, CDC13): d 0.90 (d, J = 6 Hz, 6H), d 1.33-1.80 (m, 6H), d 2.00 (m, 1H), d 2.67 (m, 2H), 2.89 (m, 3H), d 4.10 (m, 1H), d 4.25 (m, 1H), d 4.81 (s, 1H), d 5.09 (m, 3H), d 6.68 (d, J = 4 Hz, 1H) , d 7.09-7.38 (m, 10H), d 8.18 (s, 1H), (C29H3βN406); benzyl 2- { 2- [2- (2-Benzyloxycarbonylamino-4-methyl valerylamino) -l-hydroxy-4-phenylbutyl] oxazol-2-ylcarbonylamino} valerate (Compound 324); MS (ESI) m / z = 727 (M + 1); XH-NMR (300 MHz, CDC13): d 0.95 (m, 12H), d 1.45 -1.80 (m, 9H), d 2.00 (m, 1H), d 2.67 (m, 2H), d 3.99 d 4.15 (m, 2H), d 4.85 (m, 2H), d 5.09 (m, 4H), d 5.50 (m, 1H), d 6.88 (m, 1H), d 7.12-7.45 (m, 15H), d 8.18 (s, 1H), (C4? H50N4O8); bencil 15-. { 2- [4- (4-benzylpiperidino-l-ylcarbonyl) oxazol-2-yl] -2-hydroxy-15-phenethylethylcarbamoyl} -3-methylbutyl carbamate (Compound 325); benzyl 15 [2- (4-fur-2-ylmethylcarbamoyloxazol-2-yl) -2-hydroxy-15-phenethylethylcarbamoyl] -3-methylbutylcarbamate (Compound 326); benzyl 3-methyl-lS- [2-hydroxy-15-phenethyl-2- (4-pyrid-2-ylmethylcarbamoyloxazol-2-yl) ethylcarbamoyl] butylcarbamate (Compound 327);
benzyl 3-methyl-lS- [2-hydroxy-15-phenethyl-2- (4-pyrid-3-ylmethylcarbamoyloxazol-2-yl) ethylcarbamoyl] butylcarbamate (Compound 328); benzyl 3-methyl-lS- [2-hydroxy-15-phenethyl-2- (4-pyrid-4-ylmethylcarbamoyloxazol-2-yl) ethylcarbamoyl] butylcarbamate (Compound 329); benzyl 3-methyl-15-. { 2- [4- (2-Chlorobenzylcarbamoyl) oxazol-2-yl] -2-hydroxy-15-phenethylethylcarbamoyl} Butylcarbamate (Compound 330); benzyl 3-methyl-15-. { 2- [4- (3-Chlorobenzylcarbamoyl) oxazol-2-yl] -2-hydroxy-15-phenethylethylcarbamoyl} butyl carbamate (Compound 331); benzyl 3-methyl-15-. { 2- [4- (4-chlorobenzylcarbamoyl) oxazol-2-yl] -2-hydroxy-15-phenethylethylcarbamoyl} buti1 carbamate (Compound 332); benzyl 3-methyl-15-. { 2-Hydroxy-15-phenethyl-2- [4- (2R-phenylecycloprop-15-i1carbamoyl) oxazol-2-yl] ethylcarbamoyl} Butylcarbamate (Compound 333); benzyl 15- [2- (4-adamantan-1-ylmethylearbamoyl oxazol-2-yl) -2-hydroxymethyl) -l-phenethylethylcarbamoyl] -3-methylbutylcarbamate (Compound 334); benzyl 3-methyl-lg- [2-hydroxy-phenethyl-2- (4-diphenylmethylcarbamoyloxazol-2-yl) ethylcarbamoyl] butylcarbamate (Compound 335);
benzyl 3-methyl-l-. { 2-hydroxy-2- [4- (1-methylethyl carbamoyl) oxazol-2-yl] -1-phenethylethylcarbamoyl} Butylcarbamate (Compound 336); benzyl 3-methyl-l-. { 2-hydroxy-l-phenethyl-2- [4- (15-phenylethylcarbamoyl) oxazol-2-yl] ethylcarbamoyl} Butylcarbamate (Compound 337); benzyl 3 -methyl-1. { 2-hydroxy-1-phenethyl-2- [4- (1R-phenylethylcarbamoyl) oxazol-2-yl] ethylcarbamoyl} Butylcarbamate (Compound 338); benzyl 3-methyl-l-. { 2- [4- (N-Benzyl-N-methylcarbamoyl) oxazol-2-yl] -2-hydroxy-1-phenethylethylcarbamoyl} Butylcarbamate (Compound 339); benzyl 3-methyl-l. { 2-hydroxy-l-phenethyl-2- (4-pyrrolidin-1-ylcarbonyloxazol-2-yl) ethylcarbamoyl] butylcarbamate (Compound 340); benzyl 3-methyl-l [2-hydroxy-l-phenethyl-2- (4-piperidin-1-ylcarbonyloxazol-2-yl) ethylcarbamoyl] butylcarbamate (Compound 341); benzyl 3-methyl-l-. { 2- [4- (2,3-dihydroindol-1-ylcarbonyl) oxazol-2-yl] -2-hydroxy-1-phenethylethylcarbamoyl} Butylcarbamate (Compound 342); benzyl 3-methyl-l-. { 2- [4- (3, 4-dihydro-lH-isoquinol-2-ylcarbonyl) oxazol-2-yl] -2-hydroxy-1-phenethylethylcarbamoyl} Butylcarbamate (Compound 343);
benzyl 3-methyl-l-. { 2- [4- (3, 4-dihydro-lH-quinol-1-ylcarbonyl) oxazol-2-yl] -2-hydroxy-1-phenethylethylcarbamoyl} Butyl Carbamate (Compound 344); benzyl 3-methyl-l- [2-hydroxy-2- (4-naphth-1-ylmethylcarbonyloxazol-2-yl) -1-phenethylethylcarbamoyl] butylcarbamate (Compound 345); and bencil 15-. { 2- [4- (3, 4-Dihydro-2H-quinol-1-ylcarbonyl) oxazol-2-yl] -2-hydroxy-15-methylethylcarbamoyl} 3-methylbutyl carbamate (Compound 346). Continue through the analogous methods to those described above to provide the following compounds of Formula I: N- [3-methyl-15- (15-thiazol-2-ylcarbonylethylcarbamoyl) butyl] -4-morpholine-4-ylbenzamide (Compound 347); and N- [15- (2-benzooxazol-2-yl-l, l-dimethyl-2-oxoethylcarbamoyl) -3-methylbutyl] -4- (4-methylpiperazin-1-yl) benzamide (Compound 348). Continuing through methods analogous to those specified in this Application, the compounds of Formula I are provided which are formed by elements A, B, C and D listed in the following Table 1. TABLE 1
Although any combination of the elements A, B and C may include the compounds of the invention, certain combinations are preferred. For example, the following combinations A11-B5-C4-D1 A17-B5-C4-D1 A66-B5-C4-D1 A75-B5-C4-D1
A128-B5-C4-D1 A11-B6-C4-D1 A17-B6-C4-D1 A66-B6-C4-D1
A75-B6-C4-D1 A128-B6-C4-D1 A11-B8-C4-11 A17-B8-C4-D1
A66-B8-C4-D1 A75-B8-C4-D1 A128-B8-C4-D1 A11-B12-C4-D1
A17-B12-C4-D1 A66-B12-C4-D1 A75-B12-C4-D1 A128-B12-C4-D1
A11-B11-C4-D1 A17-B11-C4-D1 A66-B11-C4-D1 A75-B11-C4-D1
A128-B11-C4-D1 A11-B14-C4-D1 A17-B14-C4-D1 A66-B14-C4-D1
A75-B14-C4-D1 A128-B14-C4-D1 A11-B5-C4-D2 A17-B5-C4-D2
A66-B5-C4-D2 A75-B5-C4-D2 A128-B5-C4-D2 A11-B6-C4-D2
AI7-B6-C4-D2 A66-B6-C4-D2 A75-B6-C4-D2 A128-B6-C4-D2
A11-B8-C4-D2 A17-B8-C4-D2 A66-B8-C4-D2 A75-B8-C4-D2 A128-B8-C4-D2 A11-B12-C4-D2 A17-B12-C4-D2 A66 -B12-C4-D2 A75-B12-C4-D2 A128-B12-C4-D2 A11-B11-C4-D2 A17-B11-C4-D2 A66-B11-C4-D2 A75-B11-C4-D2 A128- B11-C4-D2 A11-B14-C4-D2 A17-B14-C4-D2 A66-B14-C4-D2 A75-B14-C4-D2 A128-B14-C4-D2
A61-B5-C4-D1 A64-B5-C4-D1 A37-B5-C4-D1 A38-B5-C4-D1
A90-B5-C4-D1 A92-B5-C4-D1 A133-B5-C4-D1 A61-B6-C4-D1
A64-B6-C4-D1 A37-B6-C4-D1 A38-B6-C4-D1 A90-B6-C4-D1
A92-B6-C4-D1 A133-B6-C4-D1 A61-B12-C4-D1 A64-B12-C4-D1
A37-B12-C4-D1 A38-B12-C4-D1 A90-B12-C4-D1 A92-B12-C4-D1
A133-B12-C4-D1
A11-B31-C4-D1 A75-B31-C4-D1 A128-B31-C4-D1 A11-B13-C4-D1
A75-B13-C4-D1 A128-B13-C4-D1 A11-B21-C4-D1 A75-B21-C4-D1
A128-B21-C4-D1 AU-B46-C4-D1 A75-B46-C4-D1 A128-B46-C4-D1
A 1-B49-C4-D1 A75-B49-C4-D1 A128-B49-C4-D1 AH-B50-C4-D1
A75-B50-C4-D1 A128-B50-C4-D1 A11-B51-C4-D1 A75-B51-C4-D1
A128-B51-C4-D1 A11-B52-C4-D1 A75-B52-C4-D1 A128-B52-C4-D1
A11-B53-C4-D1 A75-B53-C4-D1 A128-B53-C4-D1
A11-B5-C36-D1 A75-B5-C36-D1 A128-B5-C36-D1 A11-B6-C36-D1
A75-B6-C36-D1 A128-B6-C36-D1 A11-B12-C36-D1 A75-B12-C36-D1
A128-B12-C36-D1 A11-B5-C11-D1 A75-B5-C11-D1 A128-B5-C11-D1
A11-B6-C11-D1 A75-B6-C11-D1 A128-B6-C11-D1 A11-B12-C11-D1
A75-B12-C11-D1 A128-B12-C11-D1 A11-B5-C10-D1 A75-B5-C10-D1
A128-B5-C10-D1 A11-B6-C1 &-D1 A75-B6-C10-D1 A128-B6-C10-D1
A11-B12-C10-D1 A75-B12-C10-D1 A128-B12-C10-D1 A11-B5-C35-D1
A75-B5-C35-D1 A128-B5-C35-D1 A11-B6-C35-D1 A75-B6-C35-D1
A128-B6-C35-D1 A11-B12-C35-D1 A75-B12-C35-D1 A128-B12-C35-D1
A11-B5-C4-D33 A75-B5-C4-D33 A128-B5-C4-D33 A11-B6-C4-D33
A75-B6-C4-D33 A128-B6-C4-D33 A11-B12-C4-D33 A75-B12-C4-D33
A128-B12-C4-D33 A11-B5-C4-D83 A75-B5-C4-D83 A128-B5-C4-D83
A11-B6-C4-D83 A75-B6-C4-D83 A128-B6-C4-D83 AI 1-B12-C4-D83
A75-B12-C4-D83 A128-B12-C4-D83 A11-B5-C4-D86 A75-B5-C4-D86
A128-B5-C4-D86 A11-B6-C4-D86 A75-B6-C4-D86 A128-B6-C4-D86 A11-B12-C4-D86 A75-B12-C4-D86 A128-B12-C4-D86 A11 -B5-C4-D123
A75-B5-C4-D123 A128-B5-C4-D123 A11-B6-C4-D123 A75-B6-C4-D123
A128-B6-C4-D123 A11-B12-C4-D123 A75-B12-C4-D123 A128-B12-C4-D123
EXAMPLE 28 Assay of Cathepsin B Solutions of the test compounds were prepared in various concentrations in 10 μL of dimethyl sulfoxide.
(DMSO) and then diluted into the assay buffer (40 μL, consisting of: N, N-bis (2-hydroxyethyl) -2-aminoethano-phophonic acid (BES), 50 mM (pH 6); polyoxyethylene sorbitan monolaurate; 0.05% and dithiothreitol
(DTT), 2.5 mM). Human cathepsin B was added (0.025 pMoles in
μL of the assay buffer) at the dilutions. The assay solutions were mixed for 5-10 seconds on a stir plate, covered and incubated for 30 minutes at room temperature. Z-FR-.AMC (20 nMole in 25 μL of the assay buffer) was added to the assay solutions and the hydrolysis was followed spectrophotometrically at (? 460 nm) for 5 minutes. Apparent inhibition constants (Ki) were calculated from the progress curves of the enzyme using standard mathematical models. The compounds of the invention were tested by the assay described above and observed to exhibit the inhibitory activity of cathepsin B with a Ki less than or equal to 10 μM. EXAMPLE 29 Assay of Cathepsin K Solutions of the test compounds were prepared in various concentrations in 10 μL of dimethyl sulfoxide (DMSO) and then diluted into the assay buffer (40 μL, formed by: MES, 50 mM ( pH 5.5), EDTA, 2.5 mM, and DTT, 2.5 mM). Human cathepsin K (0.0906 pMoles in 25 μL of the assay buffer) was added to the dilutions. The assay solutions were mixed for 5-10 seconds on a shaker plate, 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 assay solutions and the hydrolysis was followed spectrophotometrically at (? 460 nm) for 5 minutes. Apparent inhibition constants (Ki) were calculated from the progress curves of the enzyme using standard mathematical models. The compounds of the invention were tested by the assay described above and observed to exhibit the inhibitory activity of cathepsin K with a Ki less than or equal to 10 μM. EXAMPLE 30 Assay of Cathepsin L Solutions of the test compounds were prepared in various concentrations in 10 μL of dimethyl sulfoxide (DMSO) and then diluted into the assay buffer (40 μL, formed by: MES, 50 mM ( pH 5.5), EDTA, 2.5 mM, and DTT, 2.5 mM). Human cathepsin L (0.05 pMoles in 25 μL of the assay buffer) was added to the dilutions. The assay solutions were mixed for 5-10 seconds on a shaker plate, covered and incubated for 30 minutes at room temperature. Z-Phe-Arg-AMC (1 nMoles in 25 μL of the assay buffer) was added to the assay solutions and hydrolysis it was followed spectrophotometrically at (? 460 nm) for 5 minutes. Apparent inhibition constants (Ki) were calculated from the progress curves of the enzyme using standard mathematical models. The compounds of the invention were tested by the assay described above and observed to exhibit the inhibitory activity of cathepsin L with a Ki less than or equal to 10 μM. EXAMPLE 31 Assay of Cathepsin S Solutions of the test compounds were prepared in various concentrations in 10 μL of dimethyl sulfoxide (DMSO) and then diluted into the assay buffer (40 μL)., consisting of: MES, 50 mM (pH 6.5); EDTA, 2.5 mM; and NaCl, 100 mM). Human cathepsin S (0.158 pMoles in 25 μL of the assay buffer) was added to the dilutions. The assay solutions were mixed for 5-10 seconds on a shaker plate, covered and incubated for 30 minutes at room temperature. Z-Val-Val-Arg-AMC (9 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 progress curves of the enzyme using standard mathematical models. The compounds of the invention were tested by the assay described above and observed to exhibit the inhibitory activity of cathepsin S with a Ki less than or equal to 10 μM. EXAMPLE 32 Rat Ovalbumin Test Mouse C57 (females) 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 in each day 22, 23 or 24 by an exposure for 60 minutes to an ovalbumin aerosol (10 g / 1) twice, with 4 hours of separation. The mice are dosed p.o. with any vehicle 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 euthanized 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 euthanasia. The lungs were insufflated with 10% neutral buffered formalin (NBF) at 30 cm of water pressure. The lungs were removed and placed in 10% NBF stacks. After fixation in 10% of NBF for a minimum of 24 hours the lungs were processed through graduated alcohols to wax. Lungs were blocked longitudinally and a 2 μm section of each animal was cut at the level of the main bronchus. Subsequently, the sections were stained with hematoxylin and eosin. The pathological assessment of the sections was carried out and a rating was assigned. The histopathological evaluation of lung tissue demonstrates a dose-dependent anti-inflammatory effect in vascular and mucosal beds after treatment with compounds of the invention between 0.03 and 30 mg / kg. EXAMPLE 32 Representative Pharmaceutical Formulas Containing a Compound of Formula I ORAL FORMULA Compound of Formula I 10-100 mg Citric Acid Monohydrate 105 mg Sodium Hydroxide 18 mg Flavoring Water c. s. for 100 mL INTRAVENOUS FORMULA Compound of Formula I 0.1-10 mg Dextrose Monohydrate c.s. to make it isotonic Citric Acid Monohydrate 1.05 mg Sodium Hydroxide 0.18 mg Water for Injection c.s. for 1.0 mL TABLET FORMULA Compound of Formula I 1% Microcrystalline Cellulose 73% Stearic Acid 25% Colloidal Silica 1% The resulting tablets are useful for administration in accordance with the methods of this invention for treating or preventing a mediated disease state with cathepsin, such as osteoporosis, juvenile onset diabetes, multiple sclerosis, pemphigus vulgaris, Graves' disease, myasthenia gravis, systemic lupus erythematosus, rheumatoid arthritis, Hashimoto's thyroiditis, asthma, rejection of organ transplants or tissue grafts, chronic obstructive pulmonary disease, bronchiolitis, excessive elastolysis of the respiratory tract in asthma and bronchitis, pneumonias, plaque rupture, atheroma and systemic amyloidosis.
Claims (6)
1-ylcarbonyl, piperidin-4-ylcarbonyl, pyrazin-2-ylcarbonyl, pyrid-3-ylcarbonyl, pyrid-4-ylcarbonyl, pyrid-3-ylaminocarbonyl, tetrahydro-pyran-4-ylcarbonyl and tetrahydropyran-4-yloxycarbonyl; R3 is selected from hydrogen, (C1-4) alkyl, phenyl (C2-3) alkyl or (C4-4) alkylsulfonyl (C2-) alkyl or R3 and R4 taken together with the carbon atom to which R3 is attached and R4 form (C? -4) cycloalkylene; R4 is hydrogen or as defined above; and R34 is (C6-i2) aryl or hetero (C5-12) aryl, each optionally substituted by 1 to 5 radicals selected from a group consisting of (C1-4) alkyl, cyano, halo, (C1-4) alkyl substituted by halo, nitro, -X5NR14R14, -X5OR14, -X5SR14, -X5C (0) NR14R14, -X5C (0) OR14, -X5S (0) R15, -X5S (O) 2R15 and -X5C (0) R15, where X5, R14 and R15 are according to the above defined; and N-oxide derivatives, derivatives of prodrugs, protected derivatives, individual isomers and mixtures of isomers; and the pharmaceutically acceptable salts thereof. 11. The compound of Claim 10, wherein q is 0, 1 or 2, R1 represents especially morpholin-4-ylcarbonyl, methoxycarbonyl, methylsulfonyl, piperidin-4-ylcarbonyl, pyrazin-2-ylcarbonyl., pyrid-3-ylcarbonyl, pyrid-4-ylcarbonyl, tetrahydropyran-4-ylcarbonyl or tetrahydropyran-4-yloxycarbonyl, R3 is ethyl, butyl, 2-methylsulfonylethyl, phenethyl or propyl -X?: LS (O) 2R32 is X8S ( 0) 2R32 represents benzylsulfonylmethyl, 2-chlorobenzyl sulfonylmethyl, 2-cyanobenzyl sulfonylmethyl, 2-difluoro methoxybenzylsulfonylmethyl, 3,5-dimethyl-isooxazol-4-ylmethyl sulfonylmethyl, 2-methoxybenzyl sulfonylmethyl, 6-methylpyrid-2-ylmethylsulfonylmethyl, 2 -nitrobenzylsulfonylmethyl, pyrid-2-ylmethylsulfonylmethyl, o-tolylmethyl-sulfonylmethyl or 2-trifluoromethylbenzyl sulfonylmethyl; and the N-oxide derivatives and prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers; and the pharmaceutically acceptable salts thereof. 12. The compound of claim 11 selected from the group consisting of: N- [1.R- (lS-benzooxazol-2-ylcarbonylbutylcarbamoyl-2-benzylsulfonylethyl] morpholine-4-carboxamide; methyl IR- (lS-benzooxazole-2) -carbonylobutylcarbamoyl) -2-benzylsulfonylethylcarbamate; N- (lS-benzooxazol-2-ylcarbonylbutyl) - 2? -methylsulfonylamino-3-benzylsulfonylpropionamide; N- (lS-benzooxazol-2-ylcarbonylbutylcarbamoyl) -2 / R- (3, 3-dimethylureido) -3- (2-methoxybenzylsulfonyl) propionamide; N- [1.R- (lS-benzooxazol-2-ylcarbonylbutylcarbamoyl) -2- (2-difluoromethoxybenzylsulfonyl) ethyl] morpholine-4-carboxamide; N- [IR- (lS-benzooxazol-2-ylcarbonylbutylcarbamoyl) -2- (2-methoxybenzylsulfonyl) ethyl] morpholine-4-carboxamide; N- [1.R- (lS-benzooxazol-2-ylcarbonylpentylcarbamoyl) -2-benzylsulphonylethyl] morpholine-4-carboxamide; N- [IR- (lS-benzooxazol-2-ylcarbonylpentylcarbamoyl) -2- (2-chlorobenzylsulfonyl) ethyl] morpholine-4-carboxamide; IR- (lS-benzooxazol-2-ylcarbonylpentylcarbamoyl) 2- (2-difluoromethoxybenzylsulfonyl) ethylcarbamate; N- [IR- (lS-benzooxazol-2-ylcarbonylpentylcarbamoyl) -
2- (2-difluoromethoxybenzylsulfonyl) ethyl] morpholine-4-carboxyamide; N- [IR- (lS-benzooxazol-2-ylcarbonylpentylcarbamoyl) -2- (3,5-dimethylisoxazol-4-ylmethylsulfonylthyl] isonicotinamide; N- [IR- (lS-benzooxazol-2-ylcarbonylpentylcarbamoyl) -2- (2-nitrobenzylsulfonyl) ethyl] morpholine-4-carboxamide; N- [IR- (lS-benzooxazol-2-ylcarbonylpentylcarbamoyl) -2-pyridin-2-ylmethylsulfonylethyl] morpholine-4-carboxamide; N- [IR- (lS-benzooxazol-2-ylcarbonylpentylcarbamoyl; ) - 2-o-tolylmethylsulfonylethyl] morpholine-4-carboxamide; N- [IR- (lS-benzooxazol-2-ylcarbonylpentylcarbamoyl) -2- (2-trifluoromethylbenzylsulfonyl) ethyl] morpholine-4-carboxamide; N- [IR- ( lS-benzooxazol-2-ylcarbonyl-
3-phenylpropyl carbamoyl) -2-benzylsulfonylethyl] nicotinamide; N- [IR- (lS-benzooxazol-2-ylcarbonyl-3-phenylpropyl carbamoyl) -2-benzylsulfonylethyl] pyrazine-2-carboxamide; N- [IR- (lS-benzooxazol-2-ylcarbonyl-3-phenylpropyl-carbamoyl) -2- (2-chlorobenzylsulfonyl) ethy] 3-morpholine-
4-carboxamide; N- [IR- (l __? -benzooxazol-2-ylcarbonyl-3-phenylpropyl carbamoyl) -2- (2-cyanobenzylsulfonyl) ethyl] isonicotinamide; N- [IR- (L _? -benzooxazol-2-ylcarbonyl-3-methyl-cylfonyl carbamoyl) -2- (2-difluoromethoxybenzylsulfonyl) ethyl] morpholine-4-carboxamide; N- [IR- (lS-benzooxazol-2-ylcarbonylpentylcarbamoyl) -2- (2-difluoromethoxybenzylsulfonyl) ethy] isonicotinamide; N- [IR- (lS-benzooxazol-2-ylcarbonyl-3-enylpropyl carbamoyl) -2-benzylsulfonylethylmorpholine-4-carboxamide; N- [IR- (lS-benzooxazol-2-ylcarbonyl-3-phenylpropyl carbamoyl) -2- (6-methylpyrid-2-ylmethylsulfonyl) ethyl] isonicotinamide; N- [IR- (lS-benzooxazol-2-ylcarbonyl-3-phenylpropyl carbamoyl) -2- (2-nitrobenzylsulfonyl) ethyl] morpholine-4-carboxamide; N- [IR- (lS-benzooxazol-2-ylcarbonyl-3-phenylpropyl carbamoyl) -2-pyrid-2-ylmethylsulfonylethyl] morpholine-4-carboxamide; N- [IR- (lS-benzooxazol-2-ylcarbonyl-3-phenylpropyl carbamoyl) -2-o-tolylmethylsulfonylethyl] morpholine-4-carboxamide; N- [IR- (lS-benzooxazol-2-ylcarbonyl-3-phenylpropyl carbamoyl) -2- (2-trifluoromethylbenzylsulfonyl) ethyl] tetrahydropyran-4-carboxamide; tetrahydropyran-4-yl 1- (lS-benzooxasol-2-ylcarbonyl-3-phenylpropylcarbamoyl) -2-benzylsulfonyl-ethylcarbamate; and N- [IR- (lS-benzooxazol-2-ylcarbonyl-3-phenylpropylcarbamoyl) -2- (2-cyanobenzylsulfonyl) ethyl] piperidine-4-carboxamide; and N-oxide derivatives, derivatives of prodrugs, protected derivatives, individual isomers and mixtures of isomers; and the pharmaceutically acceptable salts thereof. A pharmaceutical composition which includes a compound of Claim 1, or an N-oxide derivative, prodrug derivative, single isomer, mixture of isomers, or a pharmaceutically acceptable salt thereof in a mixture with one or more suitable excipients. 14. A method for treating a disease in an animal wherein the activity of the cysteine protease contributes to the pathology and / or symptomatology of the disease, and this method includes administering to the animal a therapeutically effective amount of the compound of the Formula I: wherein: A includes a heteromonocyclic ring containing 5 to 6 ring member atoms or a fused heteropolycyclic ring system containing 8 to 14 ring member atoms, where each ring contains 5 to 7 ring member atoms, X 1 is a carbon atom ring member and each atom ring member other than X1 is a carbon atom or a heteroatom, with the proviso that (i) at least one atom member of the ring is a heteroatom and (ii) when A is a heteromonocyclic radical containing 5 ring member atoms, not more than two of the ring member atoms including A are heteroatoms; n is 0, 1, 2 or 3; X1 is = C-or-CH-; X2 is a bond of a divalent group of Formula (a) or (b): (a) (b) X3 and X4 are independently -C (0) - or -CH2S (0) 2; - R9 and R10 are independently hydrogen, (Ci-β) alkyl or as defined below; R11 in each occurrence is independently hydrogen or (C-i-β) alkyl; R12 and R13 are independently (i) (C-? -6) alkyl optionally substituted with cyano, halo, nitro, -NR14-R14, -NR14C (0) OR14, -NR14C (0) NR14R14, -NR14C (NR14) NR14R14 , -OR14, -SR14, -C (0) OR14, -C (0) NR14R14, -S (0) 2NR14R14, -P (0) (OR14) OR14, 0P (0) (0R14) 0R14, -NR14C (0) R15, -S (0) R15, -S (0) 2R15, -C (0) R15, -OR16, -SR16, -S (0) R16, -S (0) 2R16, -C (0) R16, -C (0) 0R16, -0C (0) R1S, -NR16R17, -NR17C (0) R16, -NR17C (0) OR16, -C (O) NR16R17, -S (O) 2NR16R17, -NR17C (0) NR16R17 or -NR17C (NR17) NR16R17, wherein R14 in each occurrence is independently hydrogen, (C? -6) alkyl or (C? -3) alkyl substituted by halo R15 is (C -? - 6) alkyl or (C? -3) alkyl substituted by halo, halo, (C-? - 6) alkyl or R16 is (C-3-12) cycloalkyl (C-0-b) ) alkyl, (C-6-? 2) aryl (C-0-ß) alkyl, hetero (C-
5-? 2) aryl (C-0-ß) alkyl, (C-9_12) pylcycloaryl (C-0) -β) alkyl or hetero (C-8-?) polycycloaryl (C-0-β) alkyl and R17 is hydrogen or (C-? -6) alkyl, and wherein within R16 the aforementioned ring of cycloalkyl, heterocycloalkyl, aryl , heteroaryl, polycycloaryl or heteropolycycloaryl is optionally substituted by a group selected from -R18, -X5OR18, -X5SR18, -X5S (0) R18, -X5S (0) 2R18, -X5S (0) 2R18, -X5C (0) R18 , -X5C (0) OR18, -X5OC (0) R18 X5NR18R19, -X5NR19C (0) R18, -X5NR19C (O) OR18, -X5NR19C (0) OR18, -X5C (0) NR18R19, -X5S (O) 2NR18R19, -X5NR19C (0) NR18R19 or -X5NR19C (NR19) NR18R19, in where X5 is a bond or (C -? _6) alkylene, R18 is hydrogen or (C -? - 6) alkyl and R19 is (C-3_? 2) cycloalkyl (Co-β) alkyl, hetero (C-3) 2) cycloalkyl (C-0-β) alkyl, (C-
6-12) aryl (C-0-β) alkyl, hetero (C-5-12) aryl (Coe) alkyl, (C-9-? 2) polycycloaryl (Coe) alkyl or hetero (C-8.12) polycycloaryl (Co-β) alkyl, or (ii) a group selected from (C-3-12) cycloalkyl (C-0-β) alkyl, hetero (C) -3-12) cycloalkyl (Co-β) alkyl, (C-0-e) aryl, (C-6-12) alkyl, (Ce-? 2) aryl (C-0-S) alkyl, hetero (C -5-12) aryl, (C-9-? 2) polycycloaryl (Co-β) polycycloaryl and hetero (C-8-? 2) polycycloaryl (C-0-β) alkyl, where the aforementioned ring of cycloalkyl, heterocycloalkyl , aryl, heteroaryl, polycycloaryl or heteropolycycloaryl is optionally substituted by a group selected from -R18, -X5OR18, -X5SR18, -X5S (0) R18, -X5S (0) 2R18, - X5C (0) R18, -X5C (0) OR18, -X5OC (0) R18, -X5NR18R19, -X5NR19C (O) R18, -X5NR19C (0) OR18, -X5C (0) NR18R19, -X5S (O) 2NR18R19 , -X5NR19C (O) NR18R19 -X5NR19C (NR19) NR18R19, wherein X5, R18 and R19 are as defined above; wherein within R12 and / or R13 any present alicyclic or aromatic ring system can be subsequently substituted by 1 to 5 radicals independently selected from (C -? - 6) alkyl, (C -? - 6) alkylidene, cyano, halo, (C-1-4) alkyl substituted by halo, nitro, -XGNR14R14, -X6NR14C (0) OR14, -X6NR14C (O) NR14R14, X6NR1C (NR14) NR14R14, -X6OR14, -X6SR14, -X6C (0) OR14, X6C (O) NR14R14, -X6S (0) 2NR14R14, -X6S (0) 2NR14R14, -X6P (0) (OR14) OR14, X6OP (0) (OR14) OR14, -X6NR14C (0) R15, -X6S (0 ) R15, -X6S (O) 2R15 and -X6C (0) R15, wherein X6, R14 and R15 are as defined above; or R12 together with R9 and / or R13 together with R10 form trimethylene, tetramethylene or phenylene-1,2-dimethylene, optionally substituted with hydroxy or oxo; and R1 is -X7X8R20, where X7 is -C (0) -, -C (0) C (0) -ó-S (0) 2-, X8 is a bond, -0- or -NR21-, where R21 is hydrogen or (C? -6) alkyl, and R20 is (i) (d-6) alkyl optionally substituted by cyano, halo, nitro, -NR14R14, -NR14C (O) O14, NR14C (0) NR14R14, - NR14C (NR14) NR1 R14, -0R14, -SR14, -C (0) 014, -C (0) NR14R14, -S (0) 2NR14R14, -P (0) (0140) 14, -0P (0) ( 0] 4) 014, - NR14C (0) R15, -S (0) R15, -C (0) R15, -C (0) R15, -OR22, -SR22, -S (0) R22, -S ( 0) 2R22, -C (0) R22, -C (0) OR22, -C (0) NR22R23, -NR22R23, NR23C (0) R22, -NR23C (0) 0R22, -NR23C (O) NR22R23 or -NR23C (NR23) NR22R23, where R14 and R15 are as defined above, R22 is (C3_? 2) cycloalkyl (C0-) ß) alkyl, hetero (C3-y2) cycloalkyl (Co-e) alkyl, (C6-? 2) aryl (C0-ß) alkyl, hetero (C5-? 2) aryl (C0-e) alkyl (C9-i2) ) bicycloaryl (C0-ß) alkyl or hetero (C8-? 2) bicycloaryl (C0-ß) alkyl and R23 in each in each occurrence is independently hydrogen or (C? -6) alkyl, or (ii) (C3-12) ) (C0-β) cycloalkyl, hetero (C3-? 2) cycloalkyl (C0-ß) alkyl, (CS-i2) aryl (C0-6) alkyl, hetero (C5-? 2) aryl (C0-ß) alkyl, (C9-? 2) bicycloaryl (Co-ß) alkyl or hetero (C8-? 2) bicycloaryl (Co-ß) alkyl or hetero (C5-6) aryl or (iii) (C3-6) cycloalkyl (C0) -β) alkyl, hetero (C3_6) cycloalkyl (C0-β) alkyl, phenyl (C0-β) alkyl or hetero (C5-6) aryl (C0-6) alkyl, wherein said cycloalkyl, heterocycloalkyl, phenyl or heteroaryl is replaced by -X9OR24, -X9SR24, -X9S (0) R24, -X9S (O) 2 -X9C (0) R24, -X9C (0) OR24, -X9C (0) NR24R25, -X9NR24R25, X9NR25C (0) R24, -X9NR25C (0) OR24, -X9NR25C (O) NR24R25 or -X9NR25C (NR25) NR24R25, where X9 is a bond or (C? -6) alkylene, R24 is (C3_ß) cycloalkyl (C0-?) Alkyl, hetero (C3-6) cycloalkyl (C0-?) Alkyl, phenyl (C0-?) Alkyl) or hetero (C5-6) aryl (C0-e) alkyl and R25 in each occurrence is independently hydrogen or (Cx-β) alkyl; wherein within R1 any present alicyclic or aromatic ring system can be further substituted by 1 to 5 radicals independently selected from (C? -6) alkyl, (C? -6) alkylidene, cyano, halo, (C? -4) alkyl substituted by halo, nitro, -X6NR14R14, X6NR14C (0) OR14, -X6NR14C (0) NR14R14, -X6NR14C (NR14) NR14R14, -X6OR14, -X6SR14, -N6C (0) OR14, -X6NR14C (0) NR14R14, -X6NR14C (NR14) NR14R1, -X6OR14, -X6SR14, -X6C (0) OR14, -X6C (O) NR14R14, -X6S (O) 2NR14R14, -X6P (0) (OR) 14, -X6OP (0) ( OR14) OR14, -X6NR14C (O) R15, -X6S (0) R15, -X6S (0) 2R15 and -X6C (0) R15, wherein X6, R14 and R15 are as defined above; or when X 2 is a divalent group of the formula (a) or (b), then R 1 may also represent hydrogen, carboxy, oxalo or carbamoyl; R2 is hydrogen or (C? -6) alkyl; R3 is (i) (C? -6) alkyl optionally substituted with cyano, halo, nitro, -SR26, -C (0) OR26, -C (O) NR26N26, -P (O) (OR26) OR26, -S (0) R27. { or -C (0) R27, wherein R26 in each occurrence is independently hydrogen, (C? -6) alkyl or (C? _3) alkyl substituted by halo and R27 is (C? -6) alkyl substituted by halo, ( C? -3) alkyl and R27 is (C? -6) alkyl or (C? -3) alkyl substituted by halo, or (ii) (C5-6) cycloalkyl (C2-3) alkyl, hetero (C3.6) ) (C2-3) cycloalkyl alkyl, (C6-i2) aryl (C2-3) alkyl or hetero (C5-6) aryl (C2-3) alkyl, wherein said cycloalkyl, heterocycloalkyl, aryl or heteroaryl is substituted optionally with 1 to 5 radicals independently selected from (C? -6) alkyl, (Ci-e) alkylidene, cyano, halo, (C? -4) alkyl substituted by halo, nitro, -X6NR14C (0) OR14, - X6NR14C (O) NR14R14, -X6NR14C (NR14) NR14R14, -X6OR14, -X6SR14, -X6C (0) OR14, -X6C (O) NR14R14, -X6S (O) 2NR14R14, -X6P (0) (OR14) OR14 , -X60P (0) (OR14) OR14, -X6NR14C (O) R15, -X6S (0) R15, -X6S (0) 2R15 and -X6C (0) R15, wherein -X6, R14 and R15 are in accordance with the previously defined, with the condition that when where R3 is (C1-5) unsubstituted alkyl and R4 is hydrogen or (C1-5) unsubstituted alkyl, then X2 might not represent (i) a bond when R1 is -C (0) R20, -C (0) 2R20 or -S (O) 2R20 wherein R20 is (Ci-β) alkyl, phenyl (C? -4) alkyl, phenyl, (C3. ) cycloalkyl, canfan-10-yl, naphth-1-yl, naphth-2-yl, phenyl substituted by one or more of (C? -4) alkyl, perfluoro (C? -4) alkyl, (C? -) alkoxy, hydroxy, halo, amido, nitro, amino, (C 1-4) alkylamino, (C 1-4) dialkylamino, carboxy or (C? -) alkoxycarbonyl or naphth-1-yl or naphth-2-yl substituted by one or more than (C? -4) alkyl, perfluoro (C? -4) alkyl, (C? -6) alkoxy, hydroxy, halo, amido, nitro, amino, carboxy or (C? -6) alkoxycarbonyl or (ii) a divalent group of the formula (a) or (b) in which the R 12 moiety is methyl, isopropyl, n-butyl, sec-butyl, tert-butyl, 1-methylpropyl, benzyl, naphth-1-ylmethyl, naphthyl 2-ylmethyl, thien-2-ylmethyl, thien-3-ylmethyl, or where R 9 and R 12 form ethylene, trimethylene, trimethylene substituted by hydroxy, tetramethylene or phenylene-1,2-dimethylene; or R3 and R4 taken together with the carbon atom to which both R3 and R4 are attached form (C3.8) cycloalkylene or (C3-8) heterocycloalkylene, wherein said cycloalkylene or heterocycloalkylene is optionally substituted by 1 to 3 radicals independently selected from (C? _6) alkyl, (C? _6) alkylidene, cyano, halo, (C? -4) alkyl substituted by halo, nitro, X5NR14C (O) OR14, -X5NR14C (0) NR14R14, -X5NR14C ( NR14) NR14R14, -X5OR14, -X5SR14, X5C (0) OR14, -X5C (0) NR14R14, -X5S (O) 2NR14R14, -X5P (O) (OR14) OR14, and -X5OP (0) (OR14) OR14 , -X5NR14C (0) R15, -X5S (0) R15, -X5S (O) 2R15 and -X5C (0) R15, wherein X5, R14 and R15 are according to the above defined; R4 is hydrogen, (C? -6) alkyl or as defined above; R5 is hydrogen and R6 is hydroxy or R5 and R6 together form oxo; R7 is a group selected from cyano, halo, nitro, -R29, -X10NR 9R30, -X10NR30C (O) OR29, -X10NR30C (O) NR2 R30, -X10NR30C (NR30) NR29R30, -X10OR29, -X10SR29, X10C (O ) OR29, -X10C (O) NR29R30, -X10S (O) 2 NR29R30, -X10P (O) (OR30) OR29, -X10OP (0) (OR29) OR29, X10NR30C (O) R31, -X10S (O) R31 and -X10C (O) R31, where X10 is a bond or (C? _6) alkylidene, R29 is hydrogen or -R31, R30 in each occurrence is hydrogen or (C? -6) alkyl and R31 is (C? -6) ) alkyl, (C3-12) cycloalkyl (C0-ß) alkyl, hetero (C3-12) cycloalkyl (Co-e) alkyl, (C6-? 2) aryl (Co-ß) alkyl or hetero (C5-? 2) ) aryl (C0-ß) alkyl, where within R7 any present alicyclic or aromatic ring system can be further substituted by 1 to 5 radicals independently selected from (C? -6) alkyl, (C? -6) alkylidene, cyano , halo, (C? -4) alkyl substituted by halo, nitro, -X6NR14R14, X6NR14C (0) OR14, -X6NR14C (0) NR14R14, -X6NR14C (NR14) NR14R14, -X6OR14, -X6SR14, -X6C (0) OR14, -X6C (0) NR14R14, -X5S (O) 2NR14R14, -X 6P (O) (OR14) OR14, -X60P (0) (0R14) 0R14, -X6NR14C (0) R15, -X6S (0) R15, -X6S (0) 2R15 and -X6C (0) R15, where X6, R14 and R15 are in accordance with the above defined; and R8 in each occurrence is independently selected from (C? -6) alkyl, (C? -6) alkylidene, cyano, halo, (C? -4) alkyl substituted by halo, nitro, -X6NR14R14, -X6NR14C (0) NR14R14, -X6NR14C (NR14) NR14R14, -X6OR14, -X6SR14, -X6C (O) OR14, -X6C (0) NR14R14, -X6S (0) 2NR14R14, -X60P (O) (OR14) OR14, and X6C (0 ) R15, where X6, R14 and R15 are according to the above defined; or a derivative of N-oxide, derivatives of prodrugs, protected derivatives, individual isomers and mixtures of isomers; or the pharmaceutically acceptable salts thereof. 15. The method of Claim 14 wherein the cysteine protease is cathepsin S. 16. The method of Claim 15, wherein the disease is an autoimmune disorder, allergic disorder, allogeneic immune response, a disorder involving excessive elastolysis. , cardiovascular disorders or a disorder that involves the formation of fibrils. The method of Claim 16, wherein the disorder is selected from juvenile onset diabetes, multiple sclerosis, pemphigus vulgaris, Graves' disease, myasthenia gravis, systemic lupus erythematosus, rheumatoid arthritis, Hashimoto's thyroiditis, asthma, transplant rejections of organs or tissue grafts, chronic obstructive pulmonary disease, bronchiolitis, excessive elastolysis of airways in asthma and bronchitis, pneumonias, plaque rupture, atheroma and systemic amyloidosis. 18. A method for treating a disease in an animal wherein the activity of the cysteine protease contributes to the pathology and / or symptomatology of the disease, and this method includes administering to the animal a therapeutically effective amount of the compound of the claim. 8; or an N-oxide derivative, prodrug derivative, protected derivative, single isomer or a mixture of isomers; or a pharmaceutically acceptable salt thereof. 19. The method of Claim 18 wherein the cysteine protease is cathepsin S. 20. The method of claim 19 wherein the cysteine protease is cathepsin S. The method of claim 19, wherein the disease is an autoimmune disorder, allergic disorder, allogenic immune response, a disorder involving excessive elastolysis, cardiovascular disorders or a disorder involving the formation of fibrils. 22. A compound according to any one of Claims 1-8 wherein R5 and R6 together form oxo. 23. A compound according to Claim 1 or Claim 22 wherein ring A is selected from 4,5-dihydrooxazol-2-yl, benzooxazol-2-yl, benzothiazol-2-yl and oxazol-2-yl. 24. A compound according to Claim 23 wherein ring A is benzooxazol-2-yl or oxazol-2-yl. 25. A compound according to Claim 23 or 24 wherein ring A is substituted by R7 wherein R7 is hydrogen, halo (C? -4) alkyl, (C? 4) alkoxycarbonyl, nitro or phenyl. 26. A compound according to any one of Claims 1-8 or 22-25 wherein R3 is (C? -4) alkyl optionally substituted by phenyl or (C -4) alkylsulfonyl and R4 is hydrogen or methyl or R3 and R4 taken at joint form with the carbon atom to which they are attached form (C2-5) direct, saturated alkylene, where within the mentioned alkylene any of one or two carbon atoms is optionally replaced by a heteroatom selected from -0-, -S- or -NR28- wherein R28 is hydrogen or (C? -β) alkyl. 27. A compound according to Claim 26 wherein R3 is (C? -4) alkyl and R4 is hydrogen or methyl. 28. A compound with any of Claims 9-11 or 26 wherein R3 is (C? -4) alkyl and R4 is hydrogen. 29. A compound according to Claim 28 wherein R3 is n-propyl. 30. A compound according to any preceding claim for use in therapy. 31. A compound or pharmaceutical composition according to any preceding Claim for use in the treatment of a disease in an animal wherein the activity of the cysteine protease contributes to the pathology and / or symptomatology of the disease. 32. A compound or pharmaceutical composition for use according to claim 31 wherein the cysteine protease is cathepsin S. 33. A compound or pharmaceutical composition for use according to claim 32 for treating asthma. 34. Use of a compound according to any preceding Claim for the manufacture of a medicament for the treatment of a disease in an animal wherein the activity of the cysteine protease contributes to the pathology and / or symptomatology of the disease. 35. Use according to claim 34 for the treatment of a disease in an animal wherein the activity of cathepsin S contributes to the pathology and / or symptomatology of the disease. 36. Use according to Claim 35 for the treatment of asthma. 37. A compound or pharmaceutical composition according to any preceding Claim and an anti-inflammatory agent as a combined preparation for simultaneous, separate or sequential use in the treatment of asthma. 38. A compound, pharmaceutical composition or use thereof, substantially as described herein, with reference to the Examples. 39. A compound of Formula I I wherein: A includes a heteromonocyclic ring containing from 5 to 6 ring member atoms or a fused heteropolycyclic ring system containing from 8 to 14 ring member atoms, wherein each ring contains from 5 to 7 ring member atoms, X1 is a ring member carbon atom and each ring member atom other than X1 is a carbon atom or a heteroatom, with the proviso that (i) at least one ring member atom is a hetero atom and (ii) ) when A is a heteromonocyclic radical containing 5 ring member atoms, not more than two of the ring member atoms including A are heteroatoms; n is 0, 1, 2 or 3; X1 is = C-OR-CH-; X2 is a bond of a divalent group of Formula (a) or (b): (a) (b) wherein: A includes a heteromonocyclic ring containing 5 to 6 ring member atoms or a fused heteropolycyclic ring system containing 8 to 14 ring member atoms, where each ring contains 5 to 7 ring member atoms, X 1 is a carbon atom ring member and each atom ring member other than X1 is a carbon atom or a heteroatom, with the proviso that (i) at least one atom member of the ring is a heteroatom and (ii) when A is a heteromonocyclic radical containing 5 ring member atoms, not more than two of the ring member atoms including A are heteroatoms; n is 0, 1, 2 or 3; X1 is = C-or-CH-; X2 is a bond of a divalent group of the Formula (a) (b) where: X3 and X4 are independently -C (0) - or -CH2S (0) 2; - R9 and R10 are independently hydrogen, (C? _?) alkyl or as defined below; R11 in each occurrence is independently hydrogen or (C-i-β) alkyl; R12 and R13 are independently (i) (C-? -6) alkyl optionally substituted with cyano, halo, nitro, -NR14-R14, -NR14C (0) OR14, -NR14C (0) NR14R14, -NR14C (NR14) NR14R14 , -OR14, -SR14, -C (0) OR14, -C (0) NR14R14, -S (O) 2NR14R14, -P (O) (OR14) OR14, OP (O) (OR14) OR14, -NR14C (0) R15, -S (0) R15, -S (0) 2R15, -C (0) R15, -OR16, -SR16, -S (0) R16, -S (0) 2R16, -C (0) R16, -C (0) OR16, -OC (0) R16, -NR16R17, -NR17C (0) R16, -NR17C (O) OR16, -C (O) NR16R17, -S (0) 2NR16R17, -NR17C (0) NR16R17 or -NR17C (NR17) NR16R17, wherein R14 in each occurrence is independently hydrogen, (C -? - 6) alkyl or (C -? _ 3) alkyl substituted by halo, R15 is (C -? - 6) alkyl or (C-! _3) alkyl substituted by halo, halo, (C -? - 6) alkyl or R16 is (C-3-? 2) (C-0-6) alkylcycloalkyl, (C-6-12) aryl (C-0-6) alkyl, hetero (C-5? 2) aryl (C-0-6) ß) alkyl, (C-9-12) pylcycloaryl (C-0-6) alkyl or hetero (C-8-? 2) polycycloaryl (C-0-6) alkyl and R17 is hydrogen or (C -? - 6) ) alkyl, and wherein within R16 the aforementioned cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or heteropolycycloaryl ring is optionally substituted by a group selected from -R18, -X5OR18, -X5SR18, -X5S (0) R18, -X5S ( 0) 2R18, -X5S (0) 2R18, -X5C (0) R18, -X5C (0) OR18, -X50C (0) R18 X5NR18R19, -X5NR19C (O) R18, -X5NR19C (O) OR18, -X5NR19C ( 0) OR18, -X5C (0) NR18R19, -X5S (O) 2NR18R19, -X5NR19C (O) NR18R19 or -X5 (NR19) C (NR19) NR18R19), wherein X5 is a bond or (C -? - 6) ) alkylene, R18 is hydrogen or (C- .6) alkyl and R19 is (C-3-12) cycloalkyl (Coe) alkyl, hetero (C-3? 2) cycloalkyl (C-0-6) alkyl, ( C-6-? 2) aryl (Coe) alkyl, hetero (C-5? 2) aryl (C-0-e) alkyl, (C-9_? 2) polycycloaryl (Coe) alkyl or hetero (C-8) -12) polycycloaryl (Co- e) alkyl, or (ii) a group selected from (C-3? 2) cycloalkyl (Co-β) alkyl, hetero (C-3? 2) cycloalkyl (Co-β) alkyl, (C-0-) e) aryl, (C-6-12) alkyl, (C-6-12) aryl (Coe) alkyl, hetero (C-5-12) aryl, (C-9-? 2) polycycloaryl (C-0- e) polycycloaryl and hetero (C-8-? 2) polycycloaryl (C-0-β) alkyl, wherein said ring of cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or heteropolycycloaryl is optionally substituted by a group selected from -R18, -X5OR18, -X5SR18, -X5S (0) R18, -X5S (0) 2R18, -X5C (0) R18, -X5C (0) OR18, -X5OC (0) R18, -X5NR18R19, -X5NR19C (O) R18 , -X5NR19C (0) OR18, -X5C (0) NR18R19, -X5S (O) 2NR18R19, -X5NR19C (O) NR18R19-X5NR19C (NR19) NR18R19, wherein X5, R18 and R19 are as defined above; wherein within R12 and / or R13 any present alicyclic or aromatic ring system can be subsequently substituted by 1 to 5 radicals independently selected from (C -? - 6) alkyl, (C -? - 6) alkylidene, cyano, halo, (C -? _ 4) alkyl substituted by halo, nitro, -X5NR14R14, -X5NR14C (O) OR14, -X5NR14C (O) NR14R14, X5NR14C (NR1) NR14R14, -X5OR14, -X5SR14, -X5C (0) OR14, X5C (O) NR1 R14, -X5S (0) 2NR14R14, -X5S (0) 2NR14R14, -X5P (0) (OR14) OR14, -X5OP (O) (OR14) OR14, -X5NR14C (0) R15, -X5S ( 0) R15, -X5S (O) 2R15 and -X5C (0) R15, wherein X5, R14 and R15 are as defined above; or R12 together with R9 and / or R13 together with R10 form trimethylene, tetramethylene of enylene-1,2-dimethylene, optionally substituted by 1 to 3 radicals independently selected from (C? _) alkyl, (C? -6) alkylidene, cyano, halo, (C? -4) alkyl substituted by halo, nitro, oxo, X5NR14C (0) OR14, -X5NR14C (0) NR14R14, -X5NR14C (NR14) NR1 R14, -X5OR14, -X5SR14, -X5C (0) OR14, -X5C (0) NR14R14, -X5S (O) 2NR14R14, X5P (0) (OR14) OR14, -X5OP (0) (OR1) OR14, -X5NR14C (O) R15, -X5S (0) R15, -X5S (0) 2R15 and -X5C (0) R15, wherein X5 , R14 and R15 are according to the above defined; and R1 is -X6X7R20, where X6 is -C (O) -, -C (O) C (O) -ó-S (O) 2-, X7 is a bond, -O- or -NR21-, wherein R21 is hydrogen or (C? -6) alkyl, and R20 is (i) (C? -6) alkyl optionally substituted by cyano, halo, nitro, -NR14R14, -NR14C (0) O14, NR14C (0) NR14R14, -NR14C (NR14) NR14R14, -O14, -SR14, -C (0) O14, -C (0) NR14R14, -S (0) 2NR14R14, -P (O) (014014, -OP (0) (0) 4) O14, NR14C (0) R15, -S (0) R15, -S (0) R15, -C (0) R15, -O22, -SR22, -S (0) R22, -S (0) 2R22, -C ( 0) R22, -C (0) O22, -C (0) NR22R23, -NR22R23, NR23C (0) R22, -NR23C (0) O22, -NR23C (0) NR22R23 or -NR23C (NR23) NR22R23, where R14 and R15 are as defined above, R22 is (C3_2) cycloalkyl (C0-ß) alkyl, hetero (C3-? 2) cycloalkyl (C0-ß) alkyl, (C6-i2) aryl (C0-e) alkyl, hetero (C5-? 2) ) aryl (C0-ß) alkyl (C9_2) bicycloaryl (Co-e) alkyl or hetero (C8-? 2) bicycloaryl (C0-e) alkyl and R23 in each in each occurrence is independently hydrogen or (C? -6) alkyl, or (ii) (C3.12) cycloalkyl (C0-ß) alkyl, hetero (C3-? 2) cycloalkyl (C0-ß) alkyl, (C6-i2) aryl (C0-ß) alkyl, hetero (C5) -? 2) aryl (C0-6) alkyl, (C9-? 2) bicycloaryl (C0-ß) alkyl or hetero (C8-12) bicycloaryl (Co-ß) alkyl or hetero (C5-6) aryl or (iii) ) (C3-6) cycloalkyl (C0-β) alkyl, hetero (C3-6) cycloalkyl (Co-β) alkyl, phenyl (Co-e) alkyl or hetero (C5-6) aryl (C0-β) alkyl, wherein said cycloalkyl, heterocycloalkyl, phenyl or heteroaryl is substituted by -R24. -X5OR24, -X5SR24, -X5S (0) R24, -X5S (0) 2 R24, -X5C (0) R24, -X5C (0) OR24, -X5C (0) NR24R25, -X5NR24R25, -X5NR25C (0) R24, -X5NR25C (0) OR24, -X5NR 5C (O) NR24R25 or -X5NR25C (NR25) NR24R25, where X5 as defined above, R24 is (C3-6) cycloalkyl (Co-β) alkyl, hetero (C3.6) cycloalkyl (C0-ß) alkyl, phenyl (C0-β) alkyl) or hetero (C5-6) aryl (Co-e) alkyl and R25 in each occurrence is independently hydrogen or (C6-6) alkyl; wherein within R1 any present alicyclic or aromatic ring system can be further substituted by 1 to 5 radicals independently selected from (C? -6) alkyl, (C? -6) alkylidene, cyano, halo, (C? _4) alkyl substituted by halo, nitro, -X5NR14R14, X5NR1 C (0) OR14, -X5NR14C (O) NR14R14, -X5NR14C (NR14) NR14R14, -X5OR14, -X5SR14, -N5C (0) OR14, -X5NR1 C (0) NR14R14 , -X5NR14C (NR14) NR14R14, -X5OR14, -X5SR14, -X5C (0) OR14, -X5C (O) NR14R14, -X5S (O) 2NR14R14, -X5P (0) (OR) 14, -X5OP (0) (OR14) OR14, -X5NR14C (O) R15, -X5S (0) R15, -X5S (0) 2R15 and -X5C (0) R15, wherein X5, R14 and R15 are as defined above; or when X 2 is a divalent group of the formula (a) or (b), then R 1 may also represent hydrogen, carboxy, oxalo or carbamoyl; R2 is hydrogen or (C6-6) alkyl; R3 is (i) (Ci-β) alkyl optionally substituted with cyano, halo, nitro, -SR24, -C (0) OR24, -C (0) NR24N24, -P (O) (OR24) OR24, -S ( 0) R25. { or -C (0) R25, wherein R24 in each occurrence is independently hydrogen, (C? -6) alkyl or (C? -3) alkyl substituted by halo and R25 is (C? -6) alkyl substituted by halo, (C? -3) alkyl and R25 is (C? -6) alkyl or (C? -3) alkyl substituted by halo, or (ii) (C5-6) cycloalkyl (C2-3) alkyl, hetero (C3. ß) (C2-3) cycloalkyl alkyl, (C6-i2) aryl (C2-3) alkyl or hetero (C5-ß) aryl (C2-3) alkyl, wherein said cycloalkyl, heterocycloalkyl, aryl or heteroaryl is substituted for optionally subsequently with 1 to 5 radicals independently selected from (Cx-ß) alkyl, (C? -6) alkylidene, cyano, halo, (C? -4) alkyl substituted by halo, nitro, -X5NR14C (0) 0R14, -X5NR14C (0) NR14R14, -XSNR14C (NR14) NR14R14, -5OR14, -X5SR14, -X5C (0) OR14, -X5C (0) NR14R14, -X5S (O) 2NR14R14, -X5P (0) (OR14) OR14 , -X5OP (0) (OR14) OR14, -X5NR14C (O) R15, -X5S (0) R15, -X5S (0) 2R15 and -X5C (0) R15, wherein -X5, R14 and R15 are in accordance as defined above, with the condition that when R3 is (C? _5) unsubstituted alkyl and R4 is hydrogen or (C? _5) unsubstituted alkyl, then X2 might not represent (i) a bond when R1 is -C (0) R20, -C (0) 2R2 ° or -S (O) 2R20 wherein R20 is (C? -6) alkyl, phenyl (C? -4) alkyl, phenyl, (C3_7) cycloalkyl, canfan-10-yl, naphth-1-yl, naphth- 2-yl, phenyl substituted by one or more of (C? -) alkyl, perfluoro (C? -4) alkyl, (C? -) alkoxy, hydroxy, halo, amido, nitro, amino, (C? -4) alkylamino, (C? -4) dialkylamino, carboxy or (C? -4) alkoxycarbonyl or naphth-1-yl or naphth-2-yl substituted by one or more of (C? _4) alkyl, perfluoro (C? _4) alkyl, (C? -6) alkoxy, hydroxy, halo, amido, nitro, amino, carboxy or (C?) alkoxycarbonyl or (ii) a divalent group of the formula (a) or (b) in which half R12 is methyl, isopropyl, n-butyl, sec-butyl, tert-butyl, 1-methylpropyl, benzyl, naphth-1-ylmethyl, naphth-2-ylmethyl, thien-2-ylmethyl, thien-3-ylmethyl, or where R9 and R12 form ethylene, trimethylene, trimethylene substituted by hydroxy , tetramethylene or phenylene-1,2-dimethylene; or R3 and R4 taken together with the carbon atom to which both R3 and R4 are attached form (C3.8) cycloalkylene or (C3-8) heterocycloalkylene, wherein said cycloalkylene or heterocycloalkylene is optionally substituted by 1 to 3 radicals independently selected from (C? -6) alkyl, (C? -6) alkylidene, cyano, halo, (C? -4) alkyl substituted by halo, nitro, -X SR, X5C (0) 0R14, -X5C (0 ) NR14R14, -X5S (0) 2NR1 R14, -X5P (O) (OR14) OR14, -X50P (0) (0R14) 0R14, -X5NR14C (0) R15, -X5S (0) R15, -X5S (0) 2R15 and -X5C (0) R15, wherein X5, R14 and R15 are as defined above; R4 is hydrogen, (C? -6) alkyl or as defined above; R5 is hydrogen and R6 is hydroxy or R5 and R6 together form oxo; R7 is a group selected from cyano, halo, nitro, -R29, -X5NR29R30, -X5NR30C (O) OR29, -X5NR30C (O) NR29R30, -X5NR30C (NR30) NR29R30, -X5OR29, -X5SR29, X5C (0) OR29 , -X5C (0) NR29R30, -X5S (O) 2 NR29R30, -X5P (0) (OR30) OR29, -X50P (0) (OR29) OR29, -X5NR30C (0) R31, -X5S (0) R31 and -X5C (0) R31, where X5 is as defined above, R29 is hydrogen or -R31, R30 at each occurrence is hydrogen or (C? -6) alkyl and R31 is (C? -6) alkyl, ( C3-? 2) cycloalkyl (C0-ß) alkyl, hetero (C3-? 2) cycloalkyl (C0-ß) alkyl, (C6-12) aryl (Co-e) alkyl or hetero (C5-? 2) aryl ( C0-6) alkyl, wherein within R7 any present alicyclic or aromatic ring system can be further substituted by 1 to 5 radicals independently selected from (C? -6) alkyl, (C? -6) alkylidene, cyano, halo, (C? -4) alkyl substituted by halo, nitro, -NR14R14, -NR14C (O) 0R14, NR14C (0) NR14R14, -NR14C (NR14) NR14R14, -OR14, -SR14, -C (0) 0R14, - C (0) NR14R14, -S (0) 2NR14R14, -P (O) (OR14) OR14, -OP (O) (OR14) OR14, - NR14C (0) R15, -S (0) R15, -S (0) 2R15, -C (0) R15, -OR16, -R16, -S (0) R16, - S (0) 2R16, -C (0) R16, -C (0) R16, -OC (0) R16, NR16R17, -NR17C (O) R16, -NR17C (0) OR16, -C (0) NR16R17, -S (O) 2NR16R17, -NR17C (O) NR16R17 or -NR17C (NR17) NR16R17 or (ii) a group selected from (C3_? 2) cycloalkyl (Co-e) alkyl, hetero (C3-? 2) cycloalkyl ( C0-β) alkyl, (C6-? 2) aryl (C0-6) alkyl, hetero (C5-? 2) aryl (C0-6) alkyl, (C9_12) polycycloaryl (Co-β) alkyl and hetero (C8-) 2) polycycloaryl (Co-e) alkyl, wherein said ring of cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or heteropolycycloaryl is optionally substituted by a group selected from R18, -X5OR18, X5CR18, -X5S (0) R18, - X5S (0) 2R18, -X5C (0) R18, X5C (0) OR18, X5OC (0) R18, -X5NR18R19, -X5NR19C (0) R18, -X5NR19C (O) OR18, X5C (0) NR18R19, -X5S (0) 2NR18R19, -X5NR19C (O) NR18R19 or X5NR19C (NR19) NR18R19, wherein X5, R14, R15, R17, R18 and R19 are as defined above; wherein within R7 any present alicyclic or aromatic ring system can be further substituted by 1 to 5 radicals independently selected from (C? -6) alkyl, (C? -6) alkylidene, cyano, halo, (C? -) alkyl substituted by halo, nitro, -X5NR14R14, -X5NR14C (O) OR14, -X5NR14C (O) NR1 R14, X5NR14C (NR1) NR14R14, -X5OR14, -X5SR14, -X5C (0) 0R14, -X5C (O) NR14R14, -X5S (0) 2NR14R14, -X5P (0) (OR14) OR14, -X5OP (O) (OR14 ) OR14, X5NR14C (0) R15, -X5S (0) R15, -X5S (O) 2R15 and -X5C (0) R15, wherein X5, R14 and R15 are according to the above defined; and R8 in each occurrence is independently selected from (C? -6) alkyl, (C? -6) alkylidene, cyano, halo, (C? _) alkyl substituted by halo, nitro, -X5NR14R14, -X5NR14C (0) NR14R14 , -X5NR14C (NR14) NR14R14, -X5OR14, -X5SR14, X5C (0) OR14, -X5C (0) NR14R14, -X5S (O) 2NR14R14, -X5OP (O) (OR14) OR14, and X5C (0) R15 , wherein X5, R14 and R15 are according to the above defined; and N-oxide derivatives, derivatives of prodrugs, protected derivatives, individual isomers and mixtures of isomers; and the pharmaceutically acceptable salts thereof. 40. The compound of Claim 39 wherein: A is selected from thien-2-yl, oxazol-2-yl, 4,5-dihydrooxazol-2-yl, fur-2-yl, lH-indol-5-yl , pyrid-2-yl, pyrid-3-yl, thiazol-2-yl, 1-methyl-1H-imidazol-2-yl, 1-benzyl-lH-imidazol-2-yl, benzooxazol-2-yl, benzofur -2-yl, benzothiazol-2-yl, lH-benzoimidazol-2-yl, 1, 1-dioxo-lH-l6-benzo [b] thien-2-yl, quinol-3-yl, [1, 3 ] dioxolan-2-yl, naphtho [2,3-d] oxazol-2-yl, naphtho [1,2-d] oxazol-2-yl and naphtho [2, 1-d] oxazol-2-yl, each one substituted by a group R7 and optionally substituted with a group R8, particularly where R7 is halo, nitro, -R29, -O29, -C (0) R20, -C (0) 029, -SC02? R29R30, -C ( 0)? R29R30 or -C (O)? HCHR43C (O) OR29, where R20 is (C? _?) Alkyl, (C3_? 2) cycloalkyl (0-?) Alkyl, hetero (C3.? 2) cycloalkyl ( Co-e) alkyl, (C6-? 2) aryl (Co-β) alkyl, diphenyl (Co-e) alkyl, hetero (C5-? 2) aryl (C0-β) alkyl or hetero (C8-? 2) polycycloaryl (C0-β) alkyl and R29 is hydrogen or -R20, where R20 is defined as previously, where the aforementioned heterocycloalkyl can be substituted with (C6-i2) aryl (C0-3) alkyl, R30 at each occurrence is hydrogen or (C.6) alkyl and R43 is (C6-6) alkyl, and R8 in each occurrence is independently hydrogen, (C? -6) alkyl or (C? _4) alkyl substituted by halo; wherein within R7 any present alicyclic or aromatic ring system can be further substituted by 1 to 5 radicals independently selected from (C? _6) alkyl, (C? -6) alkylidene, cyano, halo, (C? -) substituted alkyl by halo, nitro, -X5NR14R14, -X5NR14C (O) OR14, X5NR14-C (0) NR14R14, -X5NR14C (NR14) NR14R14, -X5OR14, -X5SR14, X5C (0) OR14, -X5C (0) NR14R14, - X5S (O) 2NR14R14, -X5P (O) (OR14) OR14, -X5OP (0) (OR14) OR14, -X5NR14C (0) R15, -X5S (0) R15, -X5S (O) 2R15 and -X5C ( 0) R15, where X5 is a bond or (C? -6) alkylene, R14 in each occurrence is independently hydrogen, (Ci-β) alkyl or (C? -3) alkyl substituted by halo and R15 is (C? - 6) alkyl or (C 1-3) alkyl substituted by halo. X2 is a bond or a divalent group of Formula (a) or (b), wherein within Formula (a) X3 is -C (O) -, R9 is hydrogen, R11 is hydrogen or methyl, and R12 is ( C? -6) alkyl; R1 is hydrogen or -X6X7X20, where X6 is -C (O) -ó-S (O) 2-, X7 is a bond or -O- and R20 is (C? -6) alkyl, (C3-12) cycloalkyl (C0-ß) alkyl, hetero (C3-12) cycloalkyl (Co-e) alkyl, (C6_? 2) aryl (Co-e) alkyl or hetero (C5_? 2) aryl (Co-β) alkyl; wherein within R1 any present alicyclic or aromatic ring system can be further substituted by 1 to 5 radicals independently selected from (C? -6) alkyl, -C (0) OR14, -X5NR14R14 and -X5NR14C (0) OR14, in where X5 is a bond or (Ci-e) alkylene, R14 in each occurrence independently is hydrogen, (C? -6) alkyl or (C? -3) alkyl substituted by halo and R15 is (C? -6) alkyl or (C? -6) alkyl substituted by halo; R2 is hydrogen; R3 is (C? -6) alkyl or (C6-? 0) aryl (C? -3) alkyl or R3 and R4 taken together form (C? -6) straight, saturated alkylene; R4 is hydrogen or (C? -6) alkyl or as defined above; and R5 and R6 preferably form oxo; and N-oxide derivatives, derivatives of prodrugs, protected derivatives, individual isomers and mixtures of isomers; or the pharmaceutically acceptable salts thereof. 41. The compound of Claim 40 wherein: A is oxazol-2-yl, 4,5-dihydrooxazol-2-yl, benzo-oxazol-2-yl, naphtho [2,3-d] oxazol-2-yl, Naphtho [1,2-d] oxazol-2-yl or naphtho [2, 1-d] oxazol-2-yl, each substituted by a group R7 and optionally substituted with a group R8, particularly where R7 is halo, - R29, -C (0) R20. -C (0) 029, -C (0)? R29R30 or -S (0) 2? R29R3 ° where R20 is (C? -6) alkyl, (C3- X2) cycloalkyl (C0-?) Alkyl, (C6) -i2) aryl (C0-ß) alkyl, hetero (C5-12) aryl (C0-β) alkyl or hetero (C8-? 2) polycycloaryl (C0-e) alkyl. X2 is a divalent group of Formula (a), wherein within Formula (a) X3 is -C (0) -, R9 and R11 are each hydrogen and R12 is isobutyl, sec-butyl or isopropyl; R1 is selected from acetyl, benzoyl, benzyloxycarbonyl, benzylsulfonyl, bicyclo [2.2.2] hept-2-ylcarbonyl, tert-butoxycarbonyl, tert -butyryl, 4- tert -butoxycarbonyl piperazin-1-ylcarbonyl, 1- tert -butoxycarbonylpiperidine- 4-ylcarbonyl, 2-cyclohexylacetyl, 4-cyclohexylbutyryl, 2-cyclohexylethylsulfonyl, 3-cyclohexylpropionyl, 2-pentylethylsulfonyl, hydrogen, 4-methylpiperazin-1-ylcarbonyl, methylsulfonyl, 4-methylvaleryl, 3-morpholin-4-yl-propionyl , naphth-2-ylmethyl, 3-phenylpropionyl, piperazin-1-ylcarbonyl, piperidin-4-ylcarbonyl and pyrid-3-ylcarbonyl, wherein within R1 any present alicyclic or aromatic ring system may be further substituted by 1 to 3 radicals independently selected from 3-amino-methyl and 3- erc-butoxycarbonylaminomethyl; R3 is phenethyl or R3 and R4 taken together form ethylene; and R 4 is hydrogen or methyl or as defined above; and N-oxide derivatives, derivatives of prodrugs, protected derivatives, individual isomers and mixtures of isomers; and the pharmaceutically acceptable salts thereof. 42. The compound of Claim 41 wherein A is selected from oxazol-2-yl, 4,5-dihydrooxazol-2-yl, benzooxazol-2-yl or naphtho [1,2-d] oxazol-2-yl, each substituted by a group R7 and optionally substituted with a group R8, particularly where R7 is adamantan-1-ylmethylcarbamoyl, benzyl, benzyl carbamoyl, benzyl (methyl) carbamoyl, l-benzyloxycarbonyl-3-methylbutyl carbamoyl, 4-benzylpiperidin-1 -carbonyl, tert-butyl, chloro, 2,3-dihydroindol-1-ylcarbonyl, 3,4-dihydro-1-yl-isoquinol-2-ylcarbonyl, 3,4-dihydro-lH-quinol-1-ylcarbonyl, diphenyl-methylcarbamoyl, fur-2-ylmethylcarbamoyl, hydrogen, 2- (1H-indol-3-yl) ethylcarbamoyl, methoxy, methoxycarbonyl, methyl, 3-methylbutylcarbamoyl, methylcarbamoyl, 1-methylethylcarbamoyl, naphth-1-ylmethylcarbonyl, nitro, phenyl, phenylcarbamoyl, 2-phenylcyclopropylcarbamoyl, 1-phenylethylcarbamoyl, sulfamoyl, trifluoromethyl, phenethyl carbamoyl, 3-phenylpropylcarbamoyl, piperid-1-ylcarbonyl, pyrid-2-ylmethiicarbamo ilo, pyrid-3-ylmethylcarbamoyl, pyrid-4-ylmethylcarbamoyl or pyrrolidin-1-ylcarbonyl and R8 is methyl X2 is a divalent group of the formula (a), wherein within the formula R12 is isopropyl; R3 is phenethyl; and R4 is hydrogen; and N-oxide derivatives, derivatives of prodrugs, protected derivatives, individual isomers and mixtures of isomers; and the pharmaceutically acceptable salts thereof. 43. A pharmaceutical composition that includes a therapeutically effective amount of a compound of Claim 39 in combination with one or more pharmaceutically acceptable excipients. 44. The composition of Claim 43 which further includes one or more active ingredients selected from the group consisting of (i) a therapeutically effective amount of a bisphosphonic acid or acid ester thereof or a pharmaceutically acceptable salt thereof and (ii) a Therapeutically effective amount of an estrogen receptor agonist or a pharmaceutically acceptable salt thereof. 45. The composition of Claim 44 wherein the bisphosphonic acid is selected from the group consisting of acid 1., 1-dichloromethylene-1, 1-diphosphonic acid, l-hydroxy-3-pyrrolidin-1-ylpropylidene-1, 1-bisphosphonic acid, 1-hydroxyethylidene-1,1-diphosphonic acid, 1-hydroxy-3 acid ( N-methyl-N-pentylamino) propylidene-1,1-bisphosphonic acid, 6-amino-l-hydroxyhexylidene-1,1-bisphosphonic acid, 3- (dimethylamino) -1-hydroxypropylidene-1,1-bisphosphonic acid, -amino- 1-hydroxypropylidene-1,1-bisphosphonic acid, 2-pyrid-2-ylethylidene-1, 1-bisphosphonic acid, l-hydroxy-2-pyrid-3-ylethylidene-l, 1-bisphosphonic acid, acid 4-chlorophenylthiomethylenebisphosphonic acid and 1-hydroxy-2- (1H-imidazol-1-yl) ethylidene-1,1-bisphosphonic acid or acid ester thereof or a pharmaceutically acceptable salt thereof. 46. The composition of Claim 45 wherein the bisphosphonic acid is 1,1-dichloromethylene-1,1-diphosphonic acid or a pharmaceutically acceptable salt thereof. 47. The composition of Claim 46 which includes 1,1-dichloromethylene-1,1-diphosphonate monosodium trihydrate. 48. A method for treating a disease in an animal wherein the activity of the cysteine protease contributes to the pathology and / or symptomatology of the disease, and this method includes administering to the animal a therapeutically effective amount of the compound of the Formula I: I wherein: A includes a heteromonocyclic ring containing 5 to 6 ring member atoms or a fused heteropolycyclic ring system containing 8 to 14 ring member atoms, where each ring contains 5 to 7 ring member atoms, X 1 is a carbon atom ring member and each atom ring member other than X1 is a carbon atom or a heteroatom, with the proviso that (i) at least one ring member atom is a heteroatom and (ii) when A is a heteromonocyclic radical containing 5 member atoms of the ring, not more than two of the ring members of the ring including A are heteroatoms; n is 0, 1, 2 or 3; X1 is = C-or-CH-; X2 is a bond of a divalent group of the Formula (a) or (b): (a) (b) wherein: X3 and X4 are independently -C (0) - or -CH2S (0) 2; - R9 and R10 are independently hydrogen, (C? _?) alkyl or as defined below; R11 in each occurrence is independently hydrogen or (C -? - 6) alkyl; R12 and R13 are independently (i) (C-? -6) alkyl optionally substituted with cyano, halo, nitro, -NR1-R14, -NR14C (0) OR14, -NR14C (0) NR14R14, -NR14C (NR14) NR14R14 , -OR14, -SR14, -C (0) OR14, -C (0) NR14R14, -S (0) 2NR14R14, -P (O) (OR14) OR14, OP (O) (OR14) OR14, -NR14C ( 0) R15, -S (0) R15, -S (0) 2R15, -C (0) R15, -OR16, -SR16, -S (0) R16, -S (0) 2R16, -C (0) R16, -C (0) OR16, -OC (0) R16, -NR16R17, -NR17C (0) R16, -NR17C (O) OR16, -C (O) NR16R17, -S (O) 2NR16R17, -NR17C ( 0) NR16R17 or -NR17C (NR17) NR16R17, wherein R14 in each occurrence is independently hydrogen, (C -? - 6) alkyl or (C -? _ 3) alkyl substituted by halo, R15 is (C -? - 6) alkyl or (C-? _ 3) alkyl substituted by halo, halo, (C-? 6) alkyl or R16 is (C-3-12) cycloalkyl (Co-β) alkyl, (C-6-12) aryl ( C-0-β) alkyl, hetero (C-5_?) Aryl (C-0-β) alkyl, (C-9-? 2) phenylcycloaryl (C-0-6) alkyl or hetero (C-8-i2) ) polycycloaryl (C-0-6) alkyl and R17 is hydrogen or (C -? - 6) alkyl, and wherein within R16 the aforementioned cycloalkyl ring, h ethocycloalkyl, aryl, heteroaryl, polycycloaryl or heteropolycycloaryl is optionally substituted by a group selected from -R18, -X5OR18, -X5SR18, -X5S (0) R18, -X5S (0) 2R18, -X5S (0) 2R18, -X5C ( 0) R18, -X5C (0) OR18, -X5OC (0) R18 X5NR18R19, -X5NR19C (O) R18, -X5NR19C (O) OR18, -X5NR19C (0) OR18, -X5C (0) NR18R19, -X5S ( O) 2NR18R19, -X5NR19C (O) NR18R19 or -X5 (NR19) C (NR19) NR18R19), wherein X5 is a bond or (C -? - 6) alkylene, R18 is hydrogen or (C-? 6) alkyl and R19 is (C-3-12) cycloalkyl (C-0-β) alkyl, hetero (C-3? 2) cycloalkyl (Co-β) alkyl, (C-6-12) aryl (C-0- ß) alkyl, hetero (C-5? 2) aryl (Co-β) alkyl, (C-9_? ) polycycloaryl (C-0-β) alkyl or hetero (C-8-12) polycycloaryl (C-0-β) alkyl, or (ii) a group selected from (C-3? 2) cycloalkyl (Coe) alkyl , hetero (C-3? 2) cycloalkyl (Coe) alkyl, (C-0-e) aryl, (C-6-12) alkyl, (C-6-12) aryl (Co-β) alkyl, hetero (C-5_? 2) aryl, (C-9-i2) polycycloaryl (Coe) polycycloaryl and hetero (C-8-? 2) polycycloaryl (C-0-e) alkyl, where the aforementioned ring of cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or heteropolycycloaryl is optionally substituted by a group selected from -R18, -X5OR18, -X5SR18, -X5S (0) R18, -X5S (0) 2R18, -X5C (0) R18, -X5C (0) OR18, -X5OC (0) R18, -X5NR18R19, -X5NR19C (O) R18, -X5NR19C (0) OR18, -X5C (0) NR18R19, -X5S (O) 2NR18R19, -X5NR19C (O) NR18R19-XSNR19C (NR19 ) NR18R19, wherein X5, R18 and R19 are as defined above; wherein within R12 and / or R13 any present alicyclic or aromatic ring system can be subsequently substituted by 1 to 5 radicals independently selected from (C -? - 6) alkyl, (C-? 6) alkylidene, cyano, halo, (C -? - 4) alkyl substituted by halo, nitro, -X6NR14R14, -X6NR14C (O) OR14, -X6NR14C (O) NR14R14, -X6NR14C (NR14) NR14R14, -X6OR14, -X6SR14, -X6C (0) OR14 , X6C (O) NR14R14, -X6S (0) 2NR14R14, -X6S (0) 2NR14R14, -X6P (0) (OR14) OR14, X6OP (0) (OR14) OR14, -X6NR14C (0) R15, -X6S ( 0) R15, -X6S (O) 2R15 and -X6C (0) R15, wherein X6 is a bond or (C? -6) alkylene and R14 and R15 are as defined above; or R12 together with R9 and / or R13 together with R10 form trimethylene, tetramethylene or phenylene-1,2-dimethylene, optionally substituted with hydroxy or oxo; and R1 is -X7X8R20, where X7 is -C (0) -, -C (O) C (0) -ó-S (0) 2-, X8 is a bond, -O- or -NR21-, wherein R21 is hydrogen or (Ci-e) alkyl, and R20 is (i) (C6-6) alkyl optionally substituted by cyano, halo, nitro, -NR14R14, -NR14C (O) O14, NR14C (0) NR14R14, - NR14C (NR14) NR14R14, -OR14, -SR14, -C (0) 014, -C (0) NR14R14, -S (0) 2NR14R14, -P (O) (O14) O14, -OP (0) (O14 ) OR14, -NR14C (0) R15, -S (0) R15, -S (0) R15, -C (0) R15, -OR22, -SR22, -S (0) R22, -S (0) 2R22 , -C (0) R22, -C (0) 022, -C (0) NR22R23, -NR22R23, NR23C (0) R22, -NR23C (0) 022, -NR23C (0) NR22R23 or -NR23C (NR23) NR22R23, where R14 and R15 are as defined above, R22 is (C3-12) cycloalkyl (Co-ß) alkyl, hetero (C3-? 2) cycloalkyl (C0-ß) alkyl, (C6-? 2) aryl (Co-ß) alkyl, hetero (C5-? 2) aryl (Co-e) alkyl (C9-? 2) bicycloaryl (Co-e) alkyl or hetero (C8-? 2) bicycloaryl (Co-e) alkyl and R23 in each in each occurrence is independently hydrogen or (C? -6) alkyl, or (ii) (C3-? 2) cycloalkyl (C0-e) alkyl, hetero (C3-? 2) cycloalkyl (C0-?) Alkyl, (C6-? 2) aryl (C0-6) alkyl, hetero (C5-? 2) aryl (C0-6) alkyl, (C9-? 2) bicycloaryl (Co-e) alkyl or hetero (C8-? 2) bicycloaryl (Co-e) alkyl or hetero (C5-6) aryl or (iii) (C3.6) cycloalkyl (Co-e) alkyl, hetero (C3-) S) cycloalkyl (C0-β) alkyl, phenyl (Co-e) alkyl or hetero (C5_6) aryl (C0-6) alkyl, wherein said cycloalkyl, heterocycloalkyl, phenyl or heteroaryl is substituted by -X9OR24, -X9SR24, - X9S (0) R24, -X9S (0) 2R24, -X9C (0) R24, -X9C (0) OR24, -X9C (0) NR24R25, -X9NR24R25, X9NR25C (0) R24, -X9NR25C (0) OR24, -X9NR25C (O) NR24R25 or -X9NR25C (NR25) NR24R25, where X9 is a bond or (C? -6) alkylene, R24 is (C3-X2) cycloalkyl (C0-?) Alkyl, hetero (C3_? 2) cycloalkyl (C0-ß) alkyl, (C6-12) aryl (C0-e) alkyl, or hetero (C5-? 2) aryl (C0-ß) alkyl, (C9-12) bicycloaryl (C0-ß) alkyl or hetero (C8-? 2) bicycloaryl (C0-β) alkyl and R25 in each occurrence is independently hydrogen or (Ci-β) alkyl; wherein within R1 any present alicyclic or aromatic ring system can be further substituted by 1 to 5 radicals independently selected from (C? -6) alkyl, (C? -6) alkylidene, cyano, halo, (C? -4) alkyl substituted by halo, nitro, -X6NR14R14, X6NR14C (0) OR14, -X6NR14C (0) NR14R14, -X6NR14C (NR14) NR14R14, -X6OR14, -X6SR14, -X6C (0) OR14, -X6C (0) NR14R14, -X6S (O) 2NR14R14, -X6P ( O) (OR) 14, -X6OP (0) (OR14) OR14, -X6NR14C (0) R15, -X6S (0) R15, -X6S (O) 2R15 and -X6C (0) R15, wherein X6, is a bond or (C0-β) alkylene and R14 and R15 are as defined above; or when X 2 is a divalent group of the formula (a) or (b), then R 1 may also represent hydrogen, carboxy, oxalo or carbamoyl; R2 is hydrogen or (C? -6) alkyl; R3 is (i) (Ci-β) alkyl optionally substituted with cyano, halo, nitro, -SR24, -C (0) 0R24, -C (O) NR24N24, -P (O) (OR24) OR24, -S ( 0) R25. { or -C (0) R25, wherein R24 in each occurrence is independently hydrogen, (C? -6) alkyl or (C? -3) alkyl substituted by halo and R25 is (C? -6) alkyl substituted by halo, (C? -3) alkyl and R25 is (C? -6) alkyl or (C1-3) alkyl substituted by halo, or (ii) (C5-6) cycloalkyl (C2-3) alkyl, hetero (C3.6) ) (C2-3) cycloalkyl, (C6-? 2) aryl (C2-3) alkyl or hetero (C5-6) aryl (C2-3) alkyl, wherein said cycloalkyl, heterocycloalkyl, aryl or heteroaryl is substituted for optionally subsequently with 1 to 5 radicals independently selected from (C? -6) alkyl, (C? _6) alkylidene, cyano, halo, (C? -4) alkyl substituted by halo, nitro, -X6NR14C (0) OR14, -X6NR14C (0) NR14R14, -X6NR14C (NR14) NR14R14, -X6OR14, -X6SR14, -X6C (0) 0R14, -X6C (O) NR14R14, -X6S (O) 2NR14R14, -X6P (0) (OR14) OR14 , -X60P (0) (0R14) 0R14, -X6NR14C (0) R15, -X6S (0) R15, -X6S (0) 2R15 and -X6C (0) R15, where -X6, R14 and R15 are in accordance as defined above, or R3 and R4 taken as njunta form (C2.5) direct, saturated alkylene, where within the mentioned alkylene any of 1 to 2 carbon atoms is optionally replaced by a heteroatom selected from -0-, -S- or -NR28- where R28 is hydrogen or ( C0-β) alkyl; R4 is hydrogen, (C? -6) alkyl or as defined above; R5 is hydrogen and R6 is hydroxy or R5 and R6 together form oxo; R7 is a group selected from cyano, halo, nitro, -R29, -X10NR29R30, -X10NR30C (O) OR29, -X10NR30C (O) NR29R30, X10NR30C (NR30) NR29R30, -X10OR29, -X10SR29, X10C (O) OR29, X10C (O) NR29R30, -X10S (O) 2NR29R30, -X10P (0) (OR30) OR29, X10OP (0) (OR29) OR29, -X10NR30C (O) R20, -X10S (O) R20 and -X10C (O ) R20 and -C (0) NR42CHR43C (0) OR29, where X10 is a bond or (C? -6) alkylene, where R20 is as defined above, R29 is hydrogen or -R20, where R20 is defined as above, R30 at each occurrence is hydrogen or (C? -6) alkyl, R42 is hydrogen, (C? -6) alkyl or together with R43 forms trimethylene, tetramethylene or phenylene-1,2-dimethylene, optionally substituted with hydroxy or oxo, and R43 is as defined above or is (i) (C? -6) alkyl optionally substituted by cyano, halo, nitro, -NR14R14, -NR14C (0) OR14, -NR14C (0) NR14R14, - NR14C (NR14) NR14R14, -OR14, -SR14, -C (0) 0R14, -C (0) NR14R14, -S (0) 2NR14R14, -P (O) (OR14) OR14, -OP (0) (OR14 ) OR14, -NR14C (0) R15, -S (0) R15, -S ( 0) 2R15, -C (0) R15, -OR16, -R16, -S (0) R16, -S (0) 2R16, -C (0) R16, -0C (0) R16, -0C (0) R16, NR16R17, -NR17C (O) R16, -NR17C (0) OR16, -C (0) NR16R17, -S (0) 2NR16R17, -NR17C (0) NR16R17 or -NR17C (NR17) NR16R17 or (ii) a selected group of (C3_? 2) cycloalkyl (Co-e) alkyl, hetero (C3-? 2) cycloalkyl (Co-ß) alkyl, (C6-i2) aryl (Co-e) alkyl, hetero (C5-? 2) ) aryl (C0-ß) alkyl, (C9-? 2) polycycloaryl (C0-ß) alkyl and hetero (C8_? 2) polycycloaryl (Co-ß) alkyl, where the aforementioned ring of cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or heteropolycycloaryl is optionally substituted by a group selected from R18, -X5OR18, X5SR18, -X5S (0) R18, -X5S (0) 2R18, -X5C (0) R18, X5C (0) OR18, X5OC (0) R18 , -X5NR18R19, -X5NR19C (O) R18, -X5NR19C (O) OR18, X5C (0) NR18R19, -X5S (0) 2NR18R19, -X5NR19C (O) NR18R19 or X5NR19C (NR19) NR18R19, wherein X5, R14, R15, R17, R18 and R19 are as defined above; wherein within R7 any present alicyclic or aromatic ring system can be further substituted by 1 to 5 radicals independently selected from (C? -6) alkyl, (Ci-6) alkylidene, cyano, halo, (C? _4) substituted alkyl by halo, nitro, -X6NR14R14, -X6NR14C (O) OR14, -X6NR14C (O) NR14R14,X6NR14C (NR14) NR14R14, -X6OR14, -X6SR14, -X6C (0) OR14, -X6C (O) NR14R14, -X6S (0) 2NR14R14, -X6P (0) (OR14) OR14, -X6OP (O) (OR14 ) OR14, X6NR14C (0) R15, -X6S (0) R15, -X6S (O) 2R15 and -X6C (0) R15, wherein X6, R14 and R15 are according to the above defined; and R8 in each occurrence is independently selected from (C? -6) alkyl, (C? -4) alkyl substituted by halo, (C? _6) alkylidene, cyano, halo, (C? -4) alkyl substituted by halo, Nitro, -X6NR14R14, -X6NR14C (O) NR14R14, -X6NR14C (NR14) NR14R14, -X6NR14C (NR14) NR14R14, -X6OR14, -X6SR14, -X6C (0) OR14, -X6C (0) NR14R14, -X6S (O ) 2NR14R14, -X6OP (O) (OR14) OR14OR14, -X6OP (0) (OR1) OR14, -X6NR14C (0) R15, -X6S (0) R15, -X6S (O) 2R15 and X6C (0) R15, where X6 is a bond or (C? -6) alkylene, R14 in each occurrence is independently hydrogen, (C? -6) alkyl or (C? _3) alkyl substituted by halo and R15 (C? -6) alkyl or (C1-3) alkyl substituted by halo; and N-oxide derivatives, derivatives of prodrugs, protected derivatives, individual isomers and mixtures of isomers; and the pharmaceutically acceptable salts thereof. 49. The method of Claim 48 wherein the disease is osteoporosis. 50. The method of Claim 49 where the animal is a human. 51. The method of Claim 50 where the human is a woman in the post-menopause stage. 52. The method of Claim 51 wherein the cysteine protease is cathepsin K. 53. A process for making a compound of Formula I: I wherein: A includes a heteromonocyclic ring containing from 5 to 6 ring member atoms or a fused heteropolycyclic ring system containing from 8 to 14 ring member atoms, wherein each ring contains from 5 to 7 ring member atoms, X1 is a ring-member carbon atom and each ring member atom other than X1 is a carbon atom or a heteroatom, with the proviso that (i) at least one ring member atom is a heteroatom and (ii) when A is a heteromonocyclic radical containing 5 ring member atoms, not more than two of the ring member atoms including A are heteroatoms; n is 0, 1, 2 or 3; X1 is = C-or-CH-; X2 is a bond of a divalent group of Formula (a) or (b): (a) (b) wherein: X3 and X4 are independently -C (0) - or -CH2S (0) 2; - R9 and R10 are independently hydrogen, (Ci-s) alkyl or as defined below; R11 in each occurrence is independently hydrogen or (C -? - 6) alkyl; R12 and R13 are independently (i) (C-? -6) alkyl optionally substituted with cyano, halo, nitro, -NR14-R14, -NR14C (0) OR14, -NR14C (0) NR14R14, -NR14C (NR14) NR14R14 , -OR14, -SR14, -C (0) OR14, -C (0) NR1 R14, -S (0) 2NR14R14, -P (O) (OR14) OR14, OP (O) (OR14) OR14, -NR1 C (0) R15, -S (0) R15, -S (0) 2R15, -C (0) R15, -OR16, -SR16, -S (0) R16, -S (0) 2R16, -C ( 0) R16, -C (0) OR16, -OC (0) R16, -NR16R17, -NR17C (0) R16, -NR17C (O) OR16, -C (O) NR16R17, -S (0) 2NR16R17, - NR17C (0) NR16R17 or -NR17C (NR17) NR16R17, wherein R14 in each occurrence is independently hydrogen, (C -? - 6) alkyl or (C -? - 3) alkyl substituted by halo, R15 is (C-? -6) alkyl or (C -? - 3) alkyl substituted by halo, halo, (C -? - 6) alkyl or R16 is (C-3-12) cycloalkyl (C-0-β) alkyl, (C-) 6-12) aryl (C-0-ß) alkyl, hetero (C-5? 2) aryl (Co-β) alkyl, (C-9-i2) phenylcycloaryl (Co-β) alkyl or hetero (C-) 8-? 2) polycycloaryl (C-0-e) alkyl and R17 is hydrogen or (C -? - 6) alkyl, and wherein within R16 the aforementioned cycloalkyl ring it, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or heteropolycycloaryl is optionally substituted by a group selected from -R18, -X5OR18, -X5SR18, -X5S (0) R18, -X5S (0) 2R18, -X5S (0) 2R18, - X5C (0) R18, -X5C (0) OR18, -X5OC (0) R18 X5NR18R19, -X5NR19C (O) R18, -X5NR19C (O) OR18, -X5NR19C (0) OR18, -X5C (0) NR18R19, - X5S (O) 2NR18R19, -X5NR19C (0) NR18R19 or -X5 (NR19) C (NR19) NR18R19), wherein X5 is a bond or (C-? 6) alkylene, R18 is hydrogen or (Ci-β) alkyl and R19 is (C-3? 2) cycloalkyl (Coe) alkyl, hetero (C-3_? 2) cycloalkyl (Co-β) alkyl, (C-6-12) aryl (C-0-e) alkyl, hetero (C-5-? 2) aryl (C-0-β) alkyl, (C-9-12) polycycloaryl (Co-β) alkyl or hetero (C-8-12) polycycloaryl (Co-β) alkyl, or (ii) a selected group of (C-3-12) cycloalkyl (C-0-ß) alkyl, hetero (C-3-12) cycloalkyl (Co-ß) alkyl, (C-0-ß) aryl, (C-6-12) alkyl, (C-6-? 2) aryl (C-0-6) alkyl, hetero (C-5? 2) aryl, (C-9-12) polycycloaryl (C-0-β) polycycloaryl and hetero (C-8-? 2) polycycloaryl (C-0-6) alkyl, where the aforementioned ring of cycloalkyl, heterocycloalkyl, aryl , heteroaryl, polycycloaryl or heteropolycycloaryl is optionally substituted by a group selected from -R18, -X5OR18, -X5SR18, -X5S (0) R18, -X5S (0) 2R18, -X5C (0) R18, -X5C (0) 0R18 , -X5OC (0) R18, -X5NR18R19, -X5NR19C (O) R18, -X5NR19C (0) OR18, -X5C (0) NR18R19, -X5S (O) 2NR18R19, -X5NR19C (O) NR18R19-X5NR19C (NR19) NR18R19, wherein X5, R18 and R19 are as defined above; wherein within R12 and / or R13 any present alicyclic or aromatic ring system can be subsequently substituted by 1 to 5 radicals independently selected from (C -? - 6) alkyl, (C -? _?) alkylidene, cyano, halo, (C -? - 4) alkyl substituted by halo, nitro, -X5NR14R14, -X5NR14C (O) OR14, -X5NR1C (0) NR14R14, -X5NR14C (NR14) NR14R14, -X5OR14, -X5SR14, -X5C (0) OR14 , X5C (O) NR14R14, -X5S (0) 2NR14R14, -X5S (0) 2NR14R14, -X5P (0) (OR14) OR14, X5OP (0) (OR14) OR14, -X5NR14C (0) R15, -X5S ( 0) R15, -X5S (O) 2R15 and -X5C (0) R15, wherein X5, R14 and R15 are as defined above; or R12 together with R9 and / or R13 together with R10 form trimethylene, tetramethylene or phenylene-1,2-dimethylene, optionally substituted by 1 to 3 radicals independently selected from (C? -6) alkyl, (C? -6) alkylidene , cyano, halo, (C? -4) alkyl substituted by halo, nitro, oxo, X5NR1 C (0) OR14, -X5NR14C (O) NR14R14, -X5NR14C (NR14) NR14R14, -X5OR14, -X5SR14, -X5C ( 0) OR14, -X5C (0) NR14R14, -X5S (O) 2NR14R14, X5P (0) (OR14) OR14, -X5OP (0) (OR14) OR14, -X5NR14C (O) R15, -X5S (0) R15, -X5S (0) 2R15 and -X5C (0) R15, wherein X5 , R14 and R15 are according to the above defined; and R1 is -X6X7R20, where X6 is -C (O) -, -C (O) C (O) -ó-S (O) 2-, X7 is a bond, -0- or -NR21-, wherein R21 is hydrogen or (C? -6) alkyl, and R20 is (i) (C? -6) alkyl optionally substituted by cyano, halo, nitro, - NR14R14, -NR14C (0) O14, NR14C (0) NR14R14, -NR14C (NR14) NR1 R14, -O14, -SR14, -C (0) O14, -C (0) NR14R14, -S (0) 2NR14R14, -P (0) (014014, -OP (0) (0] 4) O14, NR14C (0) R15, -S (0) R15, -S (0) R15, -C (0) R15, -O22, -SR22, -S (0) R22, -S (0) 2R22, -C ( 0) R22, -C (0) O22, -C (0) NR22R23, -NR22R23, NR23C (0) R22, -NR23C (0) O22, -NR23C (0) NR2R23 or -NR3C (NR23) NR22R23, where R14 and R15 are as defined above, R22 is (C3-12) cycloalkyl (Co-e) alkyl, hetero (C3-12) cycloalkyl (C0-e) alkyl, (C6-? 2) aryl (C0-6) alkyl, hetero (C5-12) aryl (C0-6) alkyl (C9-? 2) bicycloaryl (C0-6) alkyl or hetero ( C8-? 2) bicycloaryl (C0-ß) alkyl and R23 in each in each occurrence is independently hydrogen or (C? -6) alkyl, or (ii) (C3-12) cycloalkyl (C0-?) Alkyl, hetero ( C3-? 2) cycloalkyl (C0-ß) alkyl, (C6-i2) aryl (C0-ß) alkyl, hetero (C5-? 2) aryl (C0-ß) alkyl, (C9-? 2) bicycloaryl (C0) -β) alkyl or hetero (C8-? 2) bicycloaryl (Co-e) alkyl or hetero (C5-6) aryl or (iii) (C3-6) cycloalkyl (C0-ß) alkyl, hetero (C3-6) cycloalkyl (Co-e) alkyl, phenyl (Co-β) alkyl or hetero (C5-6) aryl (C0-β) alkyl, wherein said cycloalkyl, heterocycloalkyl, phenyl or heteroaryl is substituted by -R24, -X5OR24, - X5SR24, -X5S (0) R24, -X5S (O) 2 R24, -X5C (0) R24, -X5C (0) OR24, -X5C (0) NR24R25, -X5NR24R25, -X5NR25C (0) R24, -X5NR25C (0) OR24, -X5NR25C (O) NR24R25 OR -X5NR25C (NR25) NR2R25, where X5 as defined above, R24 is (C3-6) cycloalkyl (Co-e) alkyl, hetero (C3-6) cycloalkyl (Co-ß) alkyl, phenyl (C0-ß) alkyl or hetero (C5-6) aryl (C0-ß) alkyl and R25 in each occurrence is independently hydrogen or (C? -6) alkyl; wherein within R1 any present alicyclic or aromatic ring system can be further substituted by 1 to 5 radicals independently selected from (C? -6) alkyl, (C? -6) alkylidene, cyano, halo, (C? -4) alkyl substituted by halo, nitro, -X5NR14R14, X5NR14C (0) OR14, -X5NR14C (0) NR14R14, -X5NR14C (NR14) NR14R14, -X5OR14, -X5SR14, -N5C (0) OR14, -X5NR14C (0) NR14R14, -X5NR14C (NR14) NR14R14, -X50R14, -X5SR14, -X5C (0) OR14, -X5C (O) NR14R14, -X5S (O) 2NR14R14, -X5P (0) (OR) 14, -X5OP (0) ( OR14) OR14, -X5NR14C (O) R15, -X5S (0) R15, -X5S (0) 2R15 and -X5C (0) R15, wherein X5, R14 and R15 are as defined above; or when X 2 is a divalent group of the formula (a) or (b), then R 1 may also represent hydrogen, carboxy, oxalo or carbamoyl; R2 is hydrogen or (C? -6) alkyl; R3 is (i) (Ci-β) alkyl optionally substituted with cyano, halo, nitro, -SR26, -C (0) OR26, -C (0) NR26N26, -P (O) (OR26) OR26, -S ( 0) R27. { or -C (0) R27, wherein R2S in each occurrence is independently hydrogen, (C? -6) alkyl or (C? _3) alkyl substituted by halo and R27 is (C? -6) alkyl substituted by halo, ( C? -3) alkyl and R27 is (C? -6) alkyl or (C1-3) alkyl substituted by halo, or (ii) (C5-6) cycloalkyl (C2-3) alkyl, hetero (C3-b) (C2-3) cycloalkyl alkyl, (C6-i2) aryl (C2-3) alkyl or hetero (C5-6) aryl (C2-3) alkyl, wherein said cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted subsequently with 1 to 5 radicals independently selected from (C? _6) alkyl, (Ci-e) alkylidene, cyano, halo, (C? -4) alkyl substituted by halo, nitro, -X5NR14C (0) 0R14, -X5NR1C ( O) NR14R14, -X5NR14C (NR14) NR14R14, -5OR14, -X5SR14, -X5C (0) OR14, -X5C (0) NR14R14, -X5S (O) 2NR14R14, -X5P (0) (OR14) OR14, -X5OP (0) (OR14) OR14, -X5NR14C (O) R15, -X5S (0) R15, -X5S (0) 2R15 and -X5C (0) R15, wherein -X5, R14 and R15 are as defined previously, with the condition that when R3 is (C1-5) unsubstituted alkyl and R4 is hydrogen or (C1-5) unsubstituted alkyl, then X2 might not represent (i) a bond when R1 is -C (0) R20, -C (0) 2R2 ° or -S (O) 2R20 wherein R20 is - (C? -6) alkyl, phenyl (C1-4) alkyl, phenyl, (C3-7) cycloalkyl, canfan-10-yl, naphth-1-yl, naphth-2-yl, phenyl substituted by one or more of (C? _4) alkyl, perfluoro (C? -4) alkyl, (CX-) alkoxy, hydroxy, halo, amido, nitro, amino, (C1-4) alkylamino, (C 1-4) dialkylamino, carboxy or (C 1-4) alkoxycarbonyl or naphth-1-yl or naphth-2-yl substituted by one or more of (CX-) alkyl, perfluoro (C? _4) alkyl, ( C? -6) alkoxy, hydroxy, halo, amido, nitro, amino, carboxy or (C? -6) alkoxycarbonyl or (ii) a divalent group of the formula (a) or (b) in which the half R12 is methyl, isopropyl, n-butyl, sec-butyl, tert-butyl, 1-methylpropyl, benzyl, naphth-1-ylmethyl, naphth-2-ylmethyl, thien-2-ylmethyl, thien-3-ylmethyl, or where R9 and R12 form ethylene, trimethylene, trimethylene substituted by hydroxy , tetramethylene or phenylene-1,2-dimethylene; or R3 and R4 taken together with the carbon atom to which both R3 and R4 are attached form (C3-8) cycloalkylene or (C3-8) heterocycloalkylene, wherein said cycloalkylene or heterocycloalkylene is optionally substituted by 1 to 3 radicals independently selected from (C? -6) alkyl, (C? -6) alkylidene, cyano, halo, (C? -4) alkyl substituted by halo, nitro, X5NR14C (0) OR14, -X5NR14C (0) NR14R14, -X5NR14C (NR14) NR14R14, -X5OR14, -X5SR14, -X5C (0) OR14, -X5C (0) NR14R14, -X5S (O) 2NR1R14, X5P (0) ) (OR14) OR14, -X5OP (0) (OR14) OR14, -X5NR14C (O) R15, -X5S (0) R15, -X5S (0) 2R15 and -X5C (0) R15, where X5, R14 and R15 they are in accordance with the previously defined; R4 is hydrogen, (C? -6) alkyl or as defined above; R5 is hydrogen and R6 is hydroxy or R5 and R6 together form oxo; R7 is a group selected from cyano, halo, nitro, -R29, -X5NR29R30, -X5NR30C (O) OR29. -X5NR30C (0) NR29R30, -X5NR30C (NR30) NR29R30, -X5OR29, -X5SR29, X5C (0) OR29, -X5C (0) NR29R30, -X5S (O) 2 NR29R30, -X5P (0) (OR30) OR29 , -X50P (0) (OR29) OR29, -X5NR30C (0) R31, -X5S (0) R31 and -X5C (0) R31, where X5 is as defined above, R29 is hydrogen or -R31, R30 in each occurrence it is hydrogen or (Ci-β) alkyl and R 31 is (C 6 -6) alkyl, (C 3 - 2) cycloalkyl (Co-e) alkyl, hetero (C 3 - 2) cycloalkyl (C 0 -) alkyl, (C6-12) aryl (C0-ß) alkyl or hetero (C5-? 2) aryl (C0-ß) alkyl, wherein within R7 any present alicyclic or aromatic ring system can be further substituted by 1 to 5 radicals independently selected from (Ci-ß) alkyl, (C? -6) alkylidene, cyano, halo, (CX-4) alkyl substituted by halo, nitro, -X5NR14R14, -X5NR14C (O) OR14, X5NR14C (0) NR14R14 , -X5NR14C (NR14) NR14R14, -X5OR14, -X5SR14, X5C (0) OR14, -X5C (0) NR14R14, -X5S (O) 2NR14R14, -X5P (O) (OR14) OR14, -X50P (0) (OR14) OR14, -X5NR14C (0) R15, -X5S ( 0) R15, -X5S (0) 2R15 and -X5C (0) R15, wherein X5, R14 and R15 are as defined above; and R8 in each occurrence is independently selected from (C? -6) alkyl, (C? -6) alkylidene, cyano, halo, (C? -4) alkyl substituted by halo, nitro, -X5NR1 R14, -X5NR14C (0 ) NR14R14, -X5NR14C (NR14) NR14R14, -X5OR14, -X5SR14, X5C (0) OR14, -X5C (0) NR14R14, -X5S (O) 2NR14R14, -X50P (O) (OR14) OR14, and X5C (0) R15, where X5, R14 and R15 are as defined above; and N-oxide derivatives, derivatives of prodrugs, protected derivatives, individual isomers and mixtures of isomers; and the pharmaceutically acceptable salts thereof; and this process includes: (A) reacting an organometallic compound of Formula 2: with a compound of Formula 3: where n, A, X ^ X2, R1, R2, R3, R4, R7 and R8 are according to the above, to provide a compound of Formula I wherein R5 and R6 together form oxo; or (B) reacting a compound of Formula 4: with a compound of Formula 5 (a) or 5 (b) wherein the dashed line represents an optional bond and B is a monocyclic radical containing from 5 to 6 ring member atoms or a fused polycyclic radical containing from 8 to 11 ring members, where each ring contains from 5 to 7 atoms members of the ring and each ring member atom is a carbon atom or a heteroatom and n, R ^ R ^ R ^ R ^ R7 and R8 are as defined above to provide a compound of Formula I wherein the ring formed by X 1 is a 4,5-tetrahydroozaxol-2-yl or oxazol-2-yl or its half, respectively, R 5 is hydrogen and R 6 is hydroxy or (C) reacting a compound of Formula 6: with a compound of the formula R X OY, where Y is hydrogen or an activation group and n, A,? , X2, R ^ R2, R3, R4, R7 and R8 are as defined above to provide a compound of Formula I wherein R5 is hydrogen and R6 is hydroxy; or (D) reacting a compound of Formula 7: or a protected derivative thereof, with R39OH, wherein R39 is -X6X7R20 and n, A, x. X2, x. X, R2, R3, R4, R7 and R20 are as defined above, and deprotection if necessary, to provide a compound of Formula I wherein R1 is -X6X7R20, (E) optionally oxidizing a compound of the Formula I wherein R5 is hydrogen and R6 is hydroxy to provide a compound of Formula I wherein R5 and R6 together form oxo; (F) optionally oxidizing a compound of Formula I wherein A is 4,5-dihydroxyoxazol-2-yl optionally substituted to provide a compound of Formula I wherein A is optionally substituted oxazole-2-yl; (G) optionally converted to a compound of Formula I wherein R7 is -C (0) OH to a compound of Formula I wherein R7 is methoxycarbonyl; (H) optionally converted to a pharmaceutically acceptable salt of a compound of Formula I, - (I) optionally converted to a salt form of a compound of Formula I to a non-salt form; (J) optionally converted to a non-oxidized form of a compound of Formula I to a pharmaceutically acceptable N-oxide; (K) optionally converted to an N-oxide form of a compound of Formula I to its non-oxidized form; (L) optionally converted a non-derivative compound of Formula I to a pharmaceutically prodrug derivative; and (M) optionally converted to 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 |
|---|---|---|---|
| US60/124,421 | 1999-03-15 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| MXPA01009240A true MXPA01009240A (en) | 2002-05-09 |
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