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US 2003/0144274 A1Published application
Alkyne matrix metalloproteinase inhibitors
AssigneeWarner-Lambert Company
InventorsAmy Mae Bunker, William Glen Harter, James Lester Hicks, Patrick Michael O'Brien, Ly Pham, Joseph Armand Picard, William Howard Roark
Life of this patent
Estimating the term…
Abstract
A compound of Formula I 1 or a pharmaceutically acceptable salt thereof, or a tautomer thereof, wherein G1, G2, and B are as defined in the application, are selective inhibitors of MMP-13. The compounds are useful for treating diseases mediated by MMP-13, including cancer and arthritis.
Claims41
A compound of Formula I
- 87
- or a pharmaceutically acceptable salt thereof, or a tautomer thereof,
- wherein:
- G1 and G2 independently are
- 88
- wherein
- E is independently O or S;
- A is OR1 or NR1R2;
- R1 and R2 independently are hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, (CH2)naryl, or (CH2)ncycloalkyl, (CH2)nheteroaryl, or R1 and R2 are taken together with the nitrogen atom to which they are attached to complete a 3- to 8-membered ring having carbon atoms, the nitrogen atom bearing R1 and R2, and 0 or 1 heteroatom selected from N(H), N(CH3), O, and S, and which ring is optionally unsubstituted or substituted with ═O, halo, or methyl, wherein n is an integer of from 0 to 6;
- or
- G1 and G2 independently are hydrogen, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, (CH2)mOH, (CH2)mOR3, (CH2)mcycloalkyl, (CH2)maryl, (CH2)msubstituted aryl, (CH2)mheteroaryl, (CH2)msubstituted heteroaryl, CH(OH)(CH2)maryl, CHOH(CH2)msubstituted aryl, CH(OH)(CH2)mheteroaryl, CH(OH)(CH2)msubstituted heteroaryl, (CO2)q(CH2)maryl, (CO2)q(CH2)msubstituted aryl, (CO2)q(CH2)mheteroaryl, (CO2)q(CH2)msubstituted heteroaryl, (CO2)q(CH2)mcarbocycle, (CO2)q(CH2)mheterocycle, (CO2)q(CH2)mNR3R4, (CH2)mC(O)R3, (CH2)mC(O)OR3, (CH2)mC(O)NR3R4, (CH2)mC(S)NR3R4, or (CH2)mC(NH)NR3R4;
- m is an integer of from 0 to 6;
- q is an integer of 0 or 1;
- R3 and R4 independently are hydrogen, C1-C6 alkyl, (CH2)maryl, or (CH2)mheteroaryl, or R3 and R4 are taken together with the nitrogen atom to which they are attached to complete a 3- to 7-membered ring having carbon atoms, the nitrogen atom bearing R3 and R4, and 0 or 1 heteroatoms selected from N(H), N(CH3), O, and S;
- B is:
- 89 90
- wherein:
- each Y is independently O or S;
- R5, R6, and R7 independently are hydrogen, halo, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, NO2, NR9R10, CN, or CF3, wherein R9 and R10 independently are hydrogen, C1-C6 alkyl, C3-C7 cycloalkyl, phenyl, or benzyl, or R9 and R10 are taken together with the nitrogen atom to which they are attached to form a 3- to 7-membered ring having carbon atoms, the nitrogen atom bearing R9 and R10, and 0 or 1 atoms selected from O, S, N(H), and N(CH3);
- R8 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, CH2CO2H, OH, NH2, or C1-C6 alkanoyl;
- X is S, S(O), S(O)2, O, N(R8), wherein R8 is as defined above, C(═O), or CH2;
- and
- — is a bond or is absent.
20 more elements
A compound of Formula II
- 91
- or a pharmaceutically acceptable salt thereof, or a tautomer thereof,
- wherein:
- G1 and G2 independently are
- 92
- wherein
- E is independently O or S;
- A is OR1 or NR1R2;
- R1 and R2 independently are hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, (CH2)naryl, (CH2)ncycloalkyl, or (CH2)nheteroaryl, or R1 and R2 are taken together with the nitrogen atom to which they are attached to complete a 3- to 8-membered ring having carbon atoms, the nitrogen atom bearing R1 and R2, and 0 or 1 heteroatom selected from N(H), N(CH3), O, and S, and which ring is optionally unsubstituted or substituted with ═O, halo, or methyl, wherein
- n is an integer of from 0 to 6;
- or
- G1 and G2 independently are hydrogen, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, (CH2)mOH, (CH2)mOR3, (CH2)mcycloalkyl, (CH2)maryl, (CH2)msubstituted aryl, (CH2)mheteroaryl, (CH2)msubstituted heteroaryl, CH(OH)(CH2)maryl, CHOH(CH2)msubstituted aryl, CH(OH)(CH2)mheteroaryl, CH(OH)(CH2)msubstituted heteroaryl, (CO2)q(CH2)maryl, (CO2)q(CH2)msubstituted aryl, (CO2)q(CH2)mheteroaryl, (CO2)q(CH2)msubstituted heteroaryl, (CO2)q(CH2)mcarbocycle, (CO2)q(CH2)mheterocycle, (CO2)q(CH2)mNR3R4, (CH2)mC(O)R3, (CH2)mC(O)OR3, (CH2)mC(O)NR3R4, (CH2)mC(S)NR3R4, or (CH2)mC(NH)NR3R4;
- m is an integer of from 0 to 6;
- q is an integer of 0 or 1;
- R3 and R4 independently are hydrogen, C1-C6 alkyl, (CH2)maryl, or (CH2)mheteroaryl, or R3 and R4 are taken together with the nitrogen atom to which they are attached to complete a 3- to 7-membered ring having carbon atoms, the nitrogen atom bearing R3 and R4, and 0 or 1 heteroatoms selected from N(H), N(CH3), O, and S;
- and
- R5, R6, and R7 independently are hydrogen, halo, hydroxy, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, NO2, CN, CF3, or NR9R10, wherein R9 and R10 independently are hydrogen, C1-C6 alkyl, C3-C7 cycloalkyl, phenyl, or benzyl, or R9 and R10 are taken together with the nitrogen atom to which they are attached to complete a 3- to 7-membered ring having carbon atoms, the nitrogen atom bearing R9 and R10, and 0 or 1 heteroatoms selected from N(H), N(CH3), O, and S.
14 more elements
A compound of Formula III
- 93
- or a pharmaceutically acceptable salt thereof, or a tautomer thereof,
- wherein:
- G1 and G2 independently are
- 94
- wherein
- E is independently O or S;
- A is OR1 or NR1R2;
- R1 and R2 independently are hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, (CH2)naryl, (CH2)ncycloalkyl, or (CH2)nheteroaryl, or R1 and R2 are taken together with the nitrogen atom to which they are attached to complete a 3- to 8-membered ring having carbon atoms, the nitrogen atom bearing R1 and R2, and 0 or 1 heteroatom selected from N(H), N(CH3), O, and S, and which ring is optionally unsubstituted or substituted with ═O, halo, or methyl, wherein:
- n is an integer of from 0 to 6;
- or
- G1 and G2 independently are hydrogen, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, (CH2)mOH, (CH2)mOR3, (CH2)mcycloalkyl, (CH2)maryl, (CH2)msubstituted aryl, (CH2)mheteroaryl, (CH2)msubstituted heteroaryl, CH(OH)(CH2)maryl, CHOH(CH2)msubstituted aryl, CH(OH)(CH2)mheteroaryl, CH(OH)(CH2)msubstituted heteroaryl, (CO2)q(CH2)maryl, (CO2)q(CH2)msubstituted aryl, (CO2)q(CH2)mheteroaryl, (CO2)q(CH2)msubstituted heteroaryl, (CO2)q(CH2)mcarbocycle, (CO2)q(CH2)mheterocycle, (CO2)q(CH2)mNR3R4, (CH2)mC(O)R3, (CH2)mC(O)OR3, (CH2)mC(O)NR3R4, (CH2)mC(S)NR3R4, or (CH2)mC(NH)NR3R4;
- m is an integer of from 0 to 6;
- q is an integer of 0 or 1;
- R3 and R4 independently are hydrogen, C1-C6 alkyl, (CH2)maryl, or (CH2)mheteroaryl, or R3 and R4 are taken together with the nitrogen atom to which they are attached to complete a 3- to 7-membered ring having carbon atoms, the nitrogen atom bearing R3 and R4, and 0 or 1 heteroatoms selected from N(H), N(CH3), O, and S;
- and
- R5 and R6 independently are hydrogen, halo, hydroxy, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, NO2, CN, CF3, or NR9R10, wherein R9 and R10 independently are hydrogen, C1-C6 alkyl, C3-C7 cycloalkyl, phenyl, or benzyl, or R9 and R10 are taken together with the nitrogen atom to which they are attached to complete a 3- to 7-membered ring having carbon atoms, the nitrogen atom bearing R9 and R10, and 0 or 1 atoms selected from N(H), N(CH3), O, and S.
14 more elements
A compound of Formula IV
- 95
- or a pharmaceutically acceptable salt thereof, or a tautomer thereof,
- wherein:
- G1 and G2 independently are
- 96
- wherein
- E is independently O or S;
- A is OR1 or NR1R2;
- R1 and R2 independently are hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, (CH2)naryl, (CH2)ncycloalkyl, or (CH2)nheteroaryl, or R1 and R2 are taken together with the nitrogen atom to which they are attached to complete a 3- to 8-membered ring having carbon atoms, the nitrogen atom bearing R1 and R2, and 0 or 1 heteroatom selected from N(H), N(CH3), O, and S, and which ring is optionally unsubstituted or substituted with ═O, halo, or methyl, wherein n is an integer of from 0 to 6;
- or
- G1 and G2 independently are hydrogen, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, (CH2)mOH, (CH2)mOR3, (CH2)mcycloalkyl, (CH2)maryl, (CH2)msubstituted aryl, (CH2)mheteroaryl, (CH2)msubstituted heteroaryl, CH(OH)(CH2)maryl, CHOH(CH2)msubstituted aryl, CH(OH)(CH2)mheteroaryl, CH(OH)(CH2)msubstituted heteroaryl, (CO2)q(CH2)maryl, (CO2)q(CH2)msubstituted aryl, (CO2)q(CH2)mheteroaryl, (CO2)q(CH2)msubstituted heteroaryl, (CO2)q(CH2)mcarbocycle, (CO2)q(CH2)mheterocycle, (CO2)q(CH2)mNR3R4, (CH2)mC(O)R3, (CH2)mC(O)OR3, (CH2)mC(O)NR3R4, (CH2)mC(S)NR3R4, or (CH2)mC(NH)NR3R4;
- m is an integer of from 0 to 6;
- q is an integer of 0 or 1;
- R3 and R4 independently are hydrogen, C1-C6 alkyl, (CH2)maryl, or (CH2)mheteroaryl, or R3 and R4 are taken together with the nitrogen atom to which they are attached to complete a 3- to 7-membered ring having carbon atoms, the nitrogen atom bearing R3 and R4, and 0 or 1 heteroatoms selected from N(H), N(CH3), O, and S;
- Y is independently O or S;
- R5, R6, and R7 independently are hydrogen, halo, hydroxy, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, NO2, CN, CF3, or NR9R10, wherein R9 and R10 independently are hydrogen, C1-C6 alkyl, C3-C7 cycloalkyl, phenyl, or benzyl, or R9 and R10 are taken together with the nitrogen atom to which they are attached to complete a 3- to 7-membered ring having carbon atoms, the nitrogen atom bearing R9 and R10, and 0 or 1 heteroatoms selected from N(H), N(CH3), O, and S;
- and
- R8 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkanoyl, CH2CO2H, NH2, or OH.
15 more elements
A compound of Formula V
- 97
- or a pharmaceutically acceptable salt thereof, or a tautomer thereof,
- wherein:
- G1 and G2 independently are
- 98
- wherein
- E is independently O or S;
- A is OR1 or NR1R2;
- R1 and R2 independently are hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, (CH2)naryl, (CH2)ncycloalkyl, or (CH2)nheteroaryl, or R1 and R2 are taken together with the nitrogen atom to which they are attached to complete a 3- to 8-membered ring having carbon atoms, the nitrogen atom bearing R1 and R2, and 0 or 1 heteroatom selected from N(H), N(CH3), O, and S, and which ring is optionally unsubstituted or substituted with ═O, halo, or methyl, wherein n is an integer of from 0 to 6;
- or
- G1 and G2 independently are hydrogen, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, (CH2)mOH, (CH2)mOR3, (CH2)mcycloalkyl, (CH2)maryl, (CH2)msubstituted aryl, (CH2)mheteroaryl, (CH2)msubstituted heteroaryl, CH(OH)(CH2)maryl, CHOH(CH2)msubstituted aryl, CH(OH)(CH2)mheteroaryl, CH(OH)(CH2)msubstituted heteroaryl, (CO2)q(CH2)maryl, (CO2)q(CH2)msubstituted aryl, (CO2)q(CH2)mheteroaryl, (CO2)q(CH2)msubstituted heteroaryl, (CO2)q(CH2)mcarbocycle, (CO2)q(CH2)mheterocycle, (CO2)q(CH2)mNR3R4, (CH2)mC(O)R3, (CH2)mC(O)OR3, (CH2)mC(O)NR3R4, (CH2)mC(S)NR3R4, or (CH2)mC(NH)NR3R4;
- m is an integer of from 0 to 6;
- q is an integer of 0 or 1;
- R3 and R4 independently are hydrogen, C1-C6 alkyl, (CH2)maryl, or (CH2)mheteroaryl, or R3 and R4 are taken together with the nitrogen atom to which they are attached to complete a 3- to 7-membered ring having carbon atoms, the nitrogen atom bearing R3 and R4, and 0 or 1 heteroatoms selected from N(H), N(CH3), O, and S;
- Y is O or S;
- R5, R6, and R7 independently are hydrogen, halo, hydroxy, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, NO2, CN, CF3, or NR9R10, wherein R9 and R10 independently are hydrogen, C1-C6 alkyl, C3-C7 cycloalkyl, phenyl, or benzyl, or R9 and R10 are taken together with the nitrogen atom to which they are attached to complete a 3- to 7-membered ring having carbon atoms, the nitrogen atom bearing R9 and R10, and 0 or 1 heteroatoms selected from N(H), N(CH3), O, and S;
- R8 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkanoyl, CH2CO2H, NH2, or OH;
- and
- — is a bond or is absent.
16 more elements
A compound of Formula VI
- 99
- or a pharmaceutically acceptable salt thereof, or a tautomer thereof,
- wherein:
- G1 and G2 independently are
- 100
- wherein
- E is independently O or S;
- A is OR1 or NR1R2;
- R1 and R2 independently are hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, (CH2)naryl, (CH2)ncycloalkyl, or (CH2)nheteroaryl, or R1 and R2 are taken together with the nitrogen atom to which they are attached to complete a 3- to 8-membered ring having carbon atoms, the nitrogen atom bearing R1 and R2, and 0 or 1 heteroatom selected from N(H), N(CH3), O, and S, and which ring is optionally unsubstituted or substituted with ═O, halo, or methyl, wherein n is an integer of from 0 to 6;
- or
- G1 and G2 independently are hydrogen, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, (CH2)mOH, (CH2)mOR3, (CH2)mcycloalkyl, (CH2)maryl, (CH2)msubstituted aryl, (CH2)mheteroaryl, (CH2)msubstituted heteroaryl, CH(OH)(CH2)maryl, CHOH(CH2)msubstituted aryl, CH(OH)(CH2)mheteroaryl, CH(OH)(CH2)msubstituted heteroaryl, (CO2)q(CH2)maryl, (CO2)q(CH2)msubstituted aryl, (CO2)q(CH2)mheteroaryl, (CO2)q(CH2)msubstituted heteroaryl, (CO2)q(CH2)mcarbocycle, (CO2)q(CH2)mheterocycle, (CO2)q(CH2)mNR3R4, (CH2)mC(O)R3, (CH2)mC(O)OR3, (CH2)mC(O)NR3R4, (CH2)mC(S)NR3R4, or (CH2)mC(NH)NR3R4;
- m is an integer of from 0 to 6;
- q is an integer of 0 or 1;
- R3 and R4 independently are hydrogen, C1-C6 alkyl, (CH2)maryl, or (CH2)mheteroaryl, or R3 and R4 are taken together with the nitrogen atom to which they are attached to complete a 3- to 7-membered ring having carbon atoms, the nitrogen atom bearing R3 and R4, and 0 or 1 heteroatoms selected from N(H), N(CH3), O, and S;
- Y is O or S:
- R5, R6, and R7 independently are hydrogen, halo, hydroxy, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, NO2, CN, CF3, or NR9R10, wherein R9 and R10 independently are hydrogen, C1-C6 alkyl, C3-C7 cycloalkyl, phenyl, or benzyl, or R9 and R10 are taken together with the nitrogen atom to which they are attached to complete a 3- to 7-membered ring having carbon atoms, the nitrogen atom bearing R9 and R10, and 0 or 1 heteroatoms selected from N(H), N(CH3), O, and S;
- and
- X is S, (SO), S(O)2, O, N(R8), wherein R8 is as defined above, C(O), or CH2.
15 more elements
A compound of Formula VII
- 101
- or a pharmaceutically acceptable salt thereof, or a tautomer thereof,
- wherein:
- G1 and G2 independently are
- 102
- wherein
- E is independently O or S;
- A is OR1 or NR1R2;
- R1 and R2 independently are hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, (CH2)naryl, (CH2)ncycloalkyl, or (CH2)nheteroaryl, or R1 and R2 are taken together with the nitrogen atom to which they are attached to complete a 3- to 8-membered ring having carbon atoms, the nitrogen atom bearing R1 and R2, and 0 or 1 heteroatom selected from N(H), N(CH3), O, and S, and which ring is optionally unsubstituted or substituted with ═O, halo, or methyl, wherein n is an integer of from 0 to 6;
- or
- G1 and G2 independently are hydrogen, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, (CH2)mOH, (CH2)mOR3, (CH2)mcycloalkyl, (CH2)maryl, (CH2)msubstituted aryl, (CH2)mheteroaryl, (CH2)msubstituted heteroaryl, CH(OH)(CH2)maryl, CHOH(CH2)msubstituted aryl, CH(OH)(CH2)mheteroaryl, CH(OH)(CH2)msubstituted heteroaryl, (CO2)q(CH2)maryl, (CO2)q(CH2)msubstituted aryl, (CO2)q(CH2)mheteroaryl, (CO2)q(CH2)msubstituted heteroaryl, (CO2)q(CH2)mcarbocycle, (CO2)q(CH2)mheterocycle, (CO2)q(CH2)mNR3R4, (CH2)mC(O)R3, (CH2)mC(O)OR3, (CH2)mC(O)NR3R4, (CH2)mC(S)NR3R4, or (CH2)mC(NH)NR3R4;
- m is an integer of from 0 to 6;
- q is an integer of 0 or 1;
- R3 and R4 independently are hydrogen, C1-C6 alkyl, (CH2)maryl, or (CH2)mheteroaryl, or R3 and R4 are taken together with the nitrogen atom to which they are attached to complete a 3- to 7-membered ring having carbon atoms, the nitrogen atom bearing R3 and R4, and 0 or 1 heteroatoms selected from N(H), N(CH3), O, and S;
- Y is O or S:
- R5, R6, and R7 independently are hydrogen, halo, hydroxy, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, NO2, CN, CF3, or NR9R10, wherein R9 and R10 independently are hydrogen, C1-C6 alkyl, C3-C7 cycloalkyl, phenyl, or benzyl, or R9 and R10 are taken together with the nitrogen atom to which they are attached to complete a 3- to 7-membered ring having carbon atoms, the nitrogen atom bearing R9 and R10, and 0 or 1 heteroatoms selected from N(H), N(CH3), O, and S;
- and
- X is S, (SO), S(O)2, O, N(R8), wherein R8 is as defined above, C(O), or CH2.
15 more elements
Dependencies are inferred from the claim text.