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US 2003/0119788 A1Published application
Novel compounds and compositions as protease inhibitors
AssigneeAxys Pharmaceuticals, Inc.
InventorsClifford M. Bryant, James T. Palmer, Robert M. Rydzewski, Eduardo L. Setti, Zong-Qiang Tian, Shankar Venkatraman, Dan-Xiong Wang
Life of this patent
Estimating the term…
Abstract
The present invention relates to novel N-cyanomethyl amides which are cysteine protease inhibitors, the pharmaceutically acceptable salts and N-oxides thereof, their uses as therapeutic agents and the methods of their making.
Claims28
A compound of Formula I:
- 98
- in which:
- R1 is a group of Formula (a) or (b):
- 99
- wherein:
- X1 and X2 independently are —C(O)— or —CH2S(O)2—;
- R5 and R6 independently are hydrogen, (C1-6)alkyl or as defined below;
- R7 and R8 independently are hydrogen or (C1-6)alkyl or as defined below;
- R9 and R10 independently are (i) (C1-6)alkyl optionally substituted with cyano, halo, halo-substituted (C1-3)alkyl, nitro, —NR12R12, —NR12C(O)OR12, —NR12C(O)NR12R12, —NR12C(NR12)NR12R12, —OR12, —SR12, —C(O)OR12, —OC(O)R12, —C(O)NR12R12, —S(O)2NR12R12, —P(O)(OR12)OR12, —OP(O)(OR12)OR12, —NR12C(O)R13, —S(O)R13, —S(O)2R13, —C(O)R13, —14, —SR14, —S(O)R14, —S(O)2R14, —C(O)R14, —C(O)OR14, —OC(O)R14, —NR14R15, —NR15C(O)R14, —NR15C(O)R14, —C(O)NR14R15, —S(O)2NR14R15, —NR15C(O)NR14R15 or —NR15C(NR15)NR14R15, wherein R12 at each occurrence independently is hydrogen, (C1-6)alkyl or halo-substituted (C1-3)alkyl, R13 is (C1-6)alkyl or halo-substituted (C1-3)alkyl, R14 is (C3-12)cycloalkyl(C0-6)alkyl, hetero(C3-12)cycloalkyl(C0-6)alkyl, (C6-12)aryl(C0-6)alkyl, hetero(C5-12)aryl(C0-6)alkyl, (C9-12)polycycloaryl(C0-6)alkyl or hetero(C8-12)polycycloaryl(C0-6)alkyl and R15 is hydrogen or (C1-6)alkyl, and wherein within R14 said cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or heterpolycycloaryl ring optionally is substituted by a group selected from —R16, —X3OR16, —X3SR16, —X3S(O)R16, —X3S(O)2R16, —X3C(O)R16, —X3C(O)OR16, —X3OC(O)R16, —X3NR16R17, —X3NR17C(O)R16, —X3NR17C(O)OR16, X3C(O)NR16R17, —X3S(O)2NR16R17, —X3NR17C(O)NR16R17 or —X3NR17C(NR17)NR16R17, wherein X3 is a bond or (C1-6)alkylene, R16 is hydrogen or (C1-6)alkyl and R17 is (C3-12)cycloalkyl(C0-6)alkyl, hetero(C3-12)cycloalkyl(C0-6)alkyl, (C6-12)aryl(C0-6)alkyl, hetero(C5-12)aryl(C0-6)alkyl, (C9-12)polycycloaryl(C0-6)alkyl or hetero(C8-12)polycycloaryl(C0-6)alkyl, or (ii) a group selected from (C3-12)cycloalkyl(C0-6)alkyl, hetero(C3-12)Cycloalkyl(C0-6)alkyl, (C6-12)aryl(C0-6)alkyl, hetero(C5-12)aryl(C0-6)alkyl, (C9-12)polycycloaryl(C0-6)alkyl and hetero(C8-12)polycycloaryl(C0-6)alkyl, wherein said cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or heterpolycycloaryl ring optionally is substituted by a group selected from —R16, —X3OR16, —X3SR16, —X3S(O)R16, —X3S(O)2R16, —X3C(O)R16, —X3C(O)OR16, —X3OC(O)R16, —X3NR16R17, —X3NR17C(O)R16, —X3NR17C(O)OR16, —X3C(O)NR16R17, —X3S(O)2NR16R17, —X3NR17C(O)NR16R17 or —X3NR17C(NR17)NR16R17, wherein X3, R16 and R17 are as defined above;
- wherein within R9 and/or R10 any alicyclic or aromatic ring system present may be substituted further by 1 to 5 radicals independently selected from (C1-6)alkyl, (C1-6)alkylidene, cyano, halo, halo-substituted (C1-4)alkyl, nitro, —X3NR12R12, —X3NR12C(O)OR12, —X3NR12C(O)NR12R12, —X3NR12C(NR12)NR12R12, —X3OR12, —X13SR12, —X3C(O)OR2, —X3C(O)NR12R12, —X3S(O)2NR12R12, —X3P(O)(OR3)OR12, —X3OP(O)(OR3)OR12, —X3NR12C(O)R13, —X3S(O)R13, —X13S(O)2R13 and —X3C(O)R13, wherein X3, R12 and R13 are as defined above;
- or
- R9 together with R7 and/or R10 together with R8 form trimethylene, tetramethylene or phenylene-1,2-dimethylene, optionally substituted with hydroxy, oxo, (C1-4)alkyl or methylene;
- or
- R9 and R5 together with the carbon atom to which both R9 and R5 are attached and/or R10 and R6 together with the carbon atom to which both R10 and R6 are attached form (C3-8)cycloalkylene or (C3-8)heterocycloalkylene;
- and
- R11 is —X4X5R18, wherein X4is —C(O)—, —C(O)C(O)— or —S(O)2—, X5 is a bond, —O— or —NR19—, wherein R19 is hydrogen or (C1-6)alkyl, and R18 is (i) (C1-6)alkyl optionally substituted by cyano, halo, halo-substituted (C1-3)alkyl, nitro, —NR14R14, —NR14C(O)OR14, —NR14C(o)NR14R14, —NR14C(NR14)NR14R14, —OR14, —SR14, —C(O)OR14, —C(O)NR14R14, —S(O)2NR14R14, —P(O)(OR14)OR14, —OP(O)(OR14)OR14, —NR14C(O)R15, —S(O)R15, —S(O)2R15, —C(O)R15, —OR20, —SR20, —S(O)R20, —S(O)2R20, —C(O)R20, —C(O)OR20, —C(O)NR20R2, —20R21, —NR21 C(O)R20, NR21C(O)OR20, —NR21C(O)NR20R21 or —NR21C(NR21)NR20R21, wherein R14 and R15 are as defined above, R20 is (C3-12)cycloalkyl(C0-6)alkyl, hetero(C3-12)cycloalkyl(C0-6)alkyl, (C6-12)aryl(C0-6)alkyl, hetero(C5-12)aryl(C0-6)alkyl, (C9-12)polycycloaryl(C0-6)alkyl or hetero(C8-12)polycycloaryl(C0-6)alkyl and R21 at each occurrence independently is hydrogen or (C1-6)alkyl, or (ii) (C3-12)cycloalkyl(C0-6)alkyl, hetero(C3-12)cycloalkyl(C0-6)alkyl, (C6-12)aryl(C0-6)alkyl, diphenyl(C0-6)alkyl, hetero(C5-12)aryl(C0-6)alkyl, dihetero(C5-6)aryl(C0-6)alkyl, (C9-2)polycycloaryl(C0-6)alkyl or hetero(C8-12)polycycloaryl(C0-6)alkyl wherein said cycloalkyl, heterocycloalkyl, aryl, diphenyl, heteroaryl, diheteroaryl, polycycloaryl or heterpolycycloaryl ring may be substituted by —R22, —X3OR22, —X3SR22, —X3S(O)R22, —X3S(O)2R22, —X3C(O)R22, —X3C(O)OR22, —X3C(O)NR22R23, —X3NR22R23, —X3NR23C(O)R22, —X3NR23C(O)OR22, —X3NR23S(O)2R22, —X3NR23C(O)NR22R23 or —X3NR23C(NR23)NR22R23, wherein X3 is as defined above, R22 is (C3-12)cycloalkyl(C0-6)alkyl, hetero(C3-12)cycloalkyl(C0-6)alkyl, (C6-12)aryl(C0-6)alkyl, hetero(C5-12)aryl(C0-6)alkyl, (C9-12)polycycloaryl(C0-6)alkyl or hetero(C8-12)polycycloaryl(C0-6)alkyl and R23 at each occurrence independently is hydrogen or (C1-6)alkyl;
- wherein within R11 any alicyclic or aromatic ring system present may be substituted further by 1 to 5 radicals independently selected from (C1-6)alkyl, (C1-6)alkylidene, cyano, halo, halo-substituted (C1-4)alkyl, nitro, —X3NR12R12, —X3NR12C(O)OR12, —X3NR12C(O)NR12R12, —X3NR12C(NR12)NR12R12, —X3OR12, —X3SR12, —X3C(O)OR12, —X3C(O)NR12R12, —X3S(O)2NR12R12, —X3P(O)(OR3)OR12, —X3OP(O)(OR3)OR12, —X3NR12C(O)R13, —X3S(O)R13, X3S(O)2R13 and —X3C(O)R13, wherein X3, R12 and R13 are as defined above;
- R2 is hydrogen or (C1-6)alkyl;
- R3is hydrogen, (C1-6)alkyl or as defined below;
- R4 is (i) cyano, —C(O)OR12 or (C1-6)alkyl, wherein said alkyl optionally is substituted with cyano, halo, halo-substituted (C1-3)alkyl, nitro, —NR12R12, —NR12C(O)OR12, —NR12C(O)NR12R12, —NR12C(NR12)NR12R12, —OR12, —SR12, —C(O)OR12, —OC(O)R12, —C(O)NR12R12, —S(O)2NR12R12, —P(O)(OR12)OR12, —OP(O)(OR12)OR12, —NR12C(O)R13, —S(O)R13, —S(O)2R13, —C(O)R13, —OR14, —SR14, —S(O)R14, —S(O)2RR14, —C(O)R14, —C(O)OR14, —OC(O)R14, —NR14R15, —NR15C(O)R14, —NR15C(O)OR14, —C(O)NR14R15, —S(O)2NR14R15, —NR15C(O)NR14R15 or —NR15C(NR15)NR14R15, wherein R12, R13 and R14 are as defined above, or (ii) a group selected from (C3-12)cycloalkyl(C0-6)alkyl, hetero(C3-12)cycloalkyl(C0-6)alkyl, (C6-12)aryl(C0-6)alkyl, hetero(C5-12)aryl(C0-6)alkyl, (C9-12)polycycloaryl(C0-6)alkyl and hetero(C8-12)polycycloaryl(C0-6)alkyl, wherein said cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or heterpolycycloaryl ring optionally is substituted by a group selected from —R16, —X3OR16, —X3SR16, —X3S(O)R16, —X3S(O)2R16, —X3C(O)R16, —X3C(O)OR16, —X3OC(O)R16, —X3NR16R17, —X3NR17C(O)R16, —X3NR17C(O)OR16, —X3C(O)NR16R17, —X3S(O)2NR16R17, —X3NR17C(O)NR16R17 or —X3NR17C(NR17)NR16R17, wherein X3, R16 and R17 are as defined above;
- wherein within R4 any alicyclic or aromatic ring system present may be substituted further by 1 to 5 radicals independently selected from (C1-6)alkyl, (C1-6)alkylidene, cyano, halo, halo-substituted (C1-4)alkyl, nitro, —X3NR12R12, —X3NR12C(O)OR12, —X3NR12R12, —X3NR12C(NR12)NR12R12, —X3OR12, —X3SR12, —X3C(O)OR12, —X3C(O)NR12R12, —X3S(O)2NR12R12, —X3P(O)(OR3)OR12, —X3OP(O)(OR3)OR12, —X3NR12C(O)R13, —X3S(O)R13, —X3S(O)2R13 and X3, R12 and R13 are as defined above;
- or
- R4 taken together with R2 forms trimethylene, tetramethylene or phenylene-1,2-dimethylene, optionally substituted with hydroxy, oxo, (C1-4)alkyl or methylene;
- or
- R4 and R3 taken together with the carbon atom to which both R4 and R3 are attached form (C3-8)cycloalkylene or (C3-8)heterocycloalkylene, wherein said cycloalkylene or heterocycloalkylene is optionally substituted 1 to 3 radicals independently selected from (C1-6)alkyl, (C1-6)alkylidene, cyano, halo, halo-substituted (C1-4)alkyl, nitro, —X3NR12R12, —X3NR12C(O)OR12, —X3NR12C(O)NR12R12, —X3NR12C(NR12)NR12R12, —X3OR12, —X3SR12, —X3C(O)OR12, —X3C(O)NR12R12, —X3S(O)2NR12R12, —X3P(O)(OR3)OR12, —X3OP(O)(OR3)OR12, —X3NR12C(O)R13, —X3S(O)R13, —X3S(O)2R13 and —X3C(O)R13, wherein X3, R12 and R13 are as defined above;
- and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers;
- and the pharmaceutically acceptable salts thereof.
24 more elements
A compound of Formula II:
- 100
- in which:
- X1 is selected from —C(O)—, —S(O)—, —C(S), —S(O)2— and —P(O)2—;
- R1 and R2 independently are hydrogen or (C1-6)alkyl;
- R3 and R4 independently are hydrogen or (C1-6)alkyl or R3 and R4 taken together with the carbon atom to which both R3 and R4 are attached form (C3-8)cycloalkylene;
- R5 and R6 independently are hydrogen or (C1-6)alkyl or R5 and R6 taken together with the carbon atom to which both R5 and R6 are attached form (C3-8)cycloalkylene or (C3-8)heterocycloalkylene;
- and
- R7 is —X2X3R9, wherein X2 is —C(O)—, —S(O)—, —C(S)—, —S(O)2— or —P(O)2—, X3 is a bond, —O— or —NR10—, wherein R10 is hydrogen or (C1-6)alkyl, and R9 is (C3-6)cycloalkyl(C0-6)alkyl, hetero(C3-6)cycloalkyl(C0-6)alkyl, phenyl(C0-6)alkyl or hetero(C5-6)aryl(C0-6)alkyl, wherein within R9 said cycloalkyl, heterocycloalkyl, phenyl or heteroaryl is substituted by —R2, —X4NR11R12, —X4NR11C(O)R12, —X4NR11C(O)OR12, —X4NR11C(O)NR11R12, —X4NR11C(NR11)NR11R12, —X4OR12, —X4SR12, —X4S(O)R12, —X4S(O)2R12, —X4C(O)R12, —X4C(O)OR12, —X4OC(O)R12, —X4C(O)NR11R12, —X4OC(O)NR11R12, —X4S(O)2NR11R12, —X4P(O)(OR11)OR12 or —X4OP(O)(OR11)OR12, wherein X4 is a bond or (C1-6)alkylene, R11 at each occurrence is hydrogen or (C1-6)alkyl and R12 is (C3-6)cycloalkyl(C0-6)alkyl, hetero(C3-6)cycloalkyl(C0-6)alkyl, phenyl(C0-6)alkyl or hetero(C5-6)aryl(C0-6)alkyl, wherein within R12 said cycloalkyl, heterocycloalkyl, phenyl or heteroaryl is substituted by —R13, —X4NR11R13, —X4NR11C(O)R13, —X4NR11C(O)OR13, —X4NR11C(O)NR11R13, —X4NR11C(NR11)NR11R13, —X4OR13, —X4SR13, —X4S(O)R13, —X4S(O)2R13, —X4C(O)R13, —X4C(O)OR13, —X4OC(O)R13, —X4C(O)NR11R13, —X4OC(O)NR11R13, —X4S(O)2NR11R13, —X4P(O)(OR11)OR13 or —X4OP(O)(OR11)OR13, wherein X4 and R11 are as defined above and R13 is (C3-6)cycloalkyl(C0-6)alkyl, hetero(C3-6)cycloalkyl(C0-6)alkyl, phenyl(C0-6)alkyl or hetero(C5-6)aryl(C0-6)alkyl, wherein within R7 any alicyclic and aromatic rings present may be substituted further by 1 to 5 radicals independently selected from (C1-6)alkyl, (C1-6)alkylidene, cyano, halo, halo-substituted (C1-4)alkyl, nitro, —X5NR14R14, —X5NR14C(O)OR14, —X5NR14C(O)NR14R14, —X5NR14C(NR14)NR14R14, —X5OR14, —X5SR14, —X5C(O)OR14, —X5C(O)NR14R14, —X5S(O)2NR14R14, —X5P(O)(OR5)OR14, —X5OP(O)(OR5)OR14, —X5NR14C(O)R15, —X5S(O)R15, —X5S(O)2R15 and —X5C(O)R15, wherein X5 is a bond or (C1-6)alkylene, R14 at each occurrence independently is hydrogen, (C1-6)alkyl or halo-substituted (C1-3)alkyl and R15 is (C1-6)alkyl or halo-substituted (C1-3)alkyl;
- and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers;
- and the pharrmaceutically acceptable salts thereof.
7 more elements
Dependencies are inferred from the claim text.