US2023174519A1PendingUtilityA1
Inhibitors of Rho Associated Coiled-Coil Containing Protein Kinase
Est. expirySep 1, 2037(~11.1 yrs left)· nominal 20-yr term from priority
C07D 417/12C07D 491/052C07D 498/10C07D 519/00C07D 495/04A61P 11/00C07D 401/12C07D 401/14C07D 403/14C07D 487/08C07D 487/10C07D 498/08C07D 403/12C07D 413/14C07D 471/04C07D 471/10C07D 487/04C07D 491/048A61P 1/16C07D 413/12
66
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Claims
Abstract
The invention relates to inhibitors of ROCK1 and/or ROCK2. Also provided are methods of inhibiting ROCK1 and/or ROCK2 that are useful for the treatment of disease.
Claims
exact text as granted — not AI-modified1 . A compound having the formula I:
wherein:
R 1 is a selected from the group consisting of the following structures:
R 5 is selected from H, halo, hydroxy, —NRR′, —(CH 2 ) f NRR′, —O—(CH 2 ) g NRR′, —C(═O)—NRR′, cyano, lower alkyl, C 3 -C 6 cyclic alkyl, lower alkoxy, C 1 -C 3 perfluoro alkyl, C 1 -C 3 perfluoro alkoxy and carboxyl;
each of A 1 , A 2 , A 3 and A 4 are independently selected from N, C—R a and CH, wherein the maximum number of N among A 1 , A 2 , A 3 and A 4 is 3;
B is selected from group consisting of NH, O and S;
each of D 1 , D 2 , D 3 , D 4 and D 5 are independently selected from N, C—R a and CH; wherein the maximum number of N among D 1 , D 2 , D 3 , D 4 and D 5 is 3;
each of E 1 , E 2 , E 3 and E 4 are independently selected from N, C—R a and CH, wherein the maximum number of N among E 1 , E 2 , E 3 and E 4 is 2;
each of G 1 and G 2 are independently selected from NH, CH—R a and CH 2 ;
each of J 1 and J 2 are independently selected from N and CH,
each of L 1 and L 2 are independently selected from N and CH,
each R a is independently selected from the group consisting of lower alkyl, halo and amino;
R 2 is selected from the group consisting of H, halo, hydroxy, —NRR′, —(CH 2 ) f NRR′, —O—(CH 2 ) g NRR′, —C(═O)—NRR′, cyano, lower alkyl, C 3 -C 6 cyclic alkyl, lower alkoxy, C 1 -C 3 perfluoro alkyl, C 1 -C 3 perfluoro alkoxy and carboxyl;
R 3 is selected from the group consisting of H, halo, hydroxy, —NRR′, —(CH 2 ) f NRR′, —O—(CH 2 ) g NRR′, —C(═O)—NRR′, cyano, lower alkyl, C 3 -C 6 cyclic alkyl, lower alkoxy, C 1 -C 3 perfluoro alkyl, C 1 -C 3 perfluoro alkoxy and carboxyl;
alternatively R 2 and R 3 are taken together to form a 4- to 7-membered fused ring having from 0 to 3 ring heteroatoms, and is unsubstituted or is substituted with halo, hydroxy, amino, —C(═O)-lower alkyl, lower alkyl, and lower alkoxy;
R 4 is a selected from the group consisting of the following structures:
X 1 is selected from the group consisting of O, NH, and CHR 6 ;
each R 6 is independently selected from the group consisting of H, halo, hydroxy, lower alkyl, substituted lower alkyl, lower alkoxy, aryl, substituted aryl, aralkyl, substituted aralkyl, heterocycle, substituted heterocycle, —NRR′, —(CH 2 ) f NRR′, —O—(CH 2 ) g NRR′, —C(═O)—NRR′, —C(═O)—OR, cyano, lower alkyl, C 3 -C 6 cyclic alkyl, C 1 -C 3 perfluoro alkyl, C 1 -C 3 perfluoro alkoxy and carboxyl;
additionally or alternatively, two R 6 substituents attached to the same ring carbon may be taken together to form an oxo group (i.e., ═O), or a C 3 to C 7 spiro cyclic group; and
additionally or alternatively, two R 6 substituents attached to different ring carbons may be taken together to form a ring, wherein the ring formed when taking the two R 6 groups together has from 4 to 7 ring atoms including from 0 to 3 ring heteroatoms.
each R 7 is independently selected from the group consisting of H, halo, hydroxy, lower alkyl, substituted lower alkyl, lower alkoxy, —NRR′, —C(═O)—NRR′, —C(═O)—OR, cyano, oxo, C 1 -C 3 perfluoro alkyl, and C 1 -C 3 perfluoro alkoxy;
each R 8 is independently selected from the group consisting of H, halo, hydroxy, lower alkyl, substituted lower alkyl, lower alkoxy, —NRR′, —C(═O)—NRR′, —C(═O)—OR, cyano, oxo, C 1 -C 3 perfluoro alkyl, and C 1 -C 3 perfluoro alkoxy;
each R 9 is independently selected from the group consisting of H, halo, hydroxy, lower alkyl, substituted lower alkyl, lower alkoxy, —NRR′, —C(═O)—NRR′, —C(═O)—OR, cyano, oxo, C 1 -C 3 perfluoro alkyl, and C 1 -C 3 perfluoro alkoxy;
each R 10 is independently selected from the group consisting of H, halo, hydroxy, lower alkyl, substituted lower alkyl, lower alkoxy, —NRR′, —C(═O)—NRR′, —C(═O)—OR, cyano, oxo, C 1 -C 3 perfluoro alkyl, and C 1 -C 3 perfluoro alkoxy;
X 2 is selected from CH 2 , CHR 8 , O, NH and N-(lower alkyl);
X 3 is selected from CH, CR 9 and N;
each R is independently selected from H and lower alkyl;
each R′ is independently selected from H, lower alkyl, aryl, substituted aryl, aralkyl, and substituted aralkyl;
a is selected from 0 to 3;
b is selected from 0 to 2;
c is selected from 0 to 2;
d is selected from 0 to 2;
e is selected from 0 to 2;
each f is independently 1 to 3;
each g is independently 2 or 3;
n is selected from 0 to 4;
m is selected from 1 to 3;
p is selected from 1 to 3;
q is selected from 0 to 3;
r is selected from 0 to 3;
wherein q and r are not simultaneously selected to be 0;
s is selected from 0 to 3;
t is selected from 0 to 3;
wherein s and t are not simultaneously selected to be 0;
v is selected from 0 to 3; and
w is selected from 0 to 3.
2 . The compound according to claim 1 , having the formula Ia:
R 1 is a selected from the group consisting of the following structures:
R 5 is selected from H, halo, hydroxy, —NRR′, —(CH 2 ) f NRR′, —O—(CH 2 ) g NRR′, —C(═O)—NRR′, cyano, lower alkyl, C 3 -C 6 cyclic alkyl, lower alkoxy, C 1 -C 3 perfluoro alkyl, C 1 -C 3 perfluoro alkoxy and carboxyl;
each of A 1 and A 3 are independently selected from N and CH;
each of D 1 , D 2 , D 3 , D 4 and D 5 are independently selected from N and CH; wherein the maximum number of N among D 1 , D 2 , D 3 , D 4 and D 5 is 3;
R 2 is selected from the group consisting of H, halo, hydroxy, —NRR′, —(CH 2 ) f NRR′, —O—(CH 2 ) g NRR′, —C(═O)—NRR′, cyano, lower alkyl, C 3 -C 6 cyclic alkyl, lower alkoxy, C 1 -C 3 perfluoro alkyl, C 1 -C 3 perfluoro alkoxy and carboxyl;
R 3 is selected from the group consisting of H, halo, hydroxy, —NRR′, —(CH 2 ) f NRR′, —O—(CH 2 ) g NRR′, —C(═O)—NRR′, cyano, lower alkyl, C 3 -C 6 cyclic alkyl, lower alkoxy, C 1 -C 3 perfluoro alkyl, C 1 -C 3 perfluoro alkoxy and carboxyl;
alternatively R 2 and R 3 are taken together to form a 4- to 7-membered fused ring having from 0 to 3 ring heteroatoms, and is unsubstituted or is substituted with halo, hydroxyl, amino, —C(═O)-lower alkyl, lower alkyl, and lower alkoxy;
R 4 is a selected from the group consisting of the following structures:
X 1 is selected from the group consisting of O, NH, and CHR 6 ;
each R 6 is independently selected from the group consisting of H, halo, hydroxy, lower alkyl, substituted lower alkyl, lower alkoxy, aryl, substituted aryl, aralkyl, substituted aralkyl, heterocycle, substituted heterocycle, —NRR′, —(CH 2 ) f NRR′, —O—(CH 2 ) g NRR′, —C(═O)—NRR′, —C(═O)—OR, cyano, lower alkyl, C 3 -C 6 cyclic alkyl, C 1 -C 3 perfluoro alkyl, C 1 -C 3 perfluoro alkoxy and carboxyl;
additionally or alternatively, two R 6 substituents attached to the same ring carbon may be taken together to form an oxo group (i.e., ═O), or a C 3 to C 7 spiro cyclic group; and
additionally or alternatively, two R 6 substituents attached to different ring carbons may be taken together to form a ring, wherein the ring formed when taking the two R 6 groups together has from 4 to 7 ring atoms including from 0 to 3 ring heteroatoms.
each R 7 is independently selected from the group consisting of H, halo, hydroxy, lower alkyl, substituted lower alkyl, lower alkoxy, —NRR′, —C(═O)—NRR′, —C(═O)—OR, cyano, oxo, C 1 -C 3 perfluoro alkyl, and C 1 -C 3 perfluoro alkoxy;
each R 8 is independently selected from the group consisting of H, halo, hydroxy, lower alkyl, substituted lower alkyl, lower alkoxy, —NRR′, —C(═O)—NRR′, —C(═O)—OR, cyano, oxo, C 1 -C 3 perfluoro alkyl, and C 1 -C 3 perfluoro alkoxy;
each R 9 is independently selected from the group consisting of H, halo, hydroxy, lower alkyl, substituted lower alkyl, lower alkoxy, —NRR′, —C(═O)—NRR′, —C(═O)—OR, cyano, oxo, C 1 -C 3 perfluoro alkyl, and C 1 -C 3 perfluoro alkoxy;
each R 10 is independently selected from the group consisting of H, halo, hydroxy, lower alkyl, substituted lower alkyl, lower alkoxy, —NRR′, —C(═O)—NRR′, —C(═O)—OR, cyano, oxo, C 1 -C 3 perfluoro alkyl, and C 1 -C 3 perfluoro alkoxy;
X 2 is selected from CH 2 , CHR 8 , O, NH and N-(lower alkyl);
X 3 is selected from CH and N;
each R is independently selected from H and lower alkyl;
each R′ is independently selected from H, lower alkyl, aryl, substituted aryl, aralkyl, and substituted aralkyl;
a is selected from 0 to 3;
b is selected from 0 to 2;
c is selected from 0 to 2;
d is selected from 0 to 2;
e is selected from 0 to 2;
each f is independently 1 to 3;
each g is independently 2 or 3;
n is selected from 0 to 4;
m is selected from 1 to 3;
p is selected from 1 to 3;
q is selected from 0 to 3;
r is selected from 0 to 3;
wherein q and r are not simultaneously selected to be 0;
s is selected from 0 to 3;
t is selected from 0 to 3;
wherein s and t are not simultaneously selected to be 0;
v is selected from 0 to 3; and
w is selected from 0 to 3.
3 . The compound according to claim 1 , having the formula Ib:
wherein:
R 1 is a selected from the group consisting of the following structures:
wherein
R 5 is selected from H, halo, hydroxy, —(CH 2 ) f NRR′, —O—(CH 2 ) g NRR′, —C(═O)—NRR′, cyano, lower alkyl, C 3 -C 6 cyclic alkyl, lower alkoxy, C 1 -C 3 perfluoro alkyl, C 1 -C 3 perfluoro alkoxy and carboxyl;
each of A 1 and A 3 are independently selected from N and CH;
each of D 2 and D 3 are independently selected from N and CH; wherein at least one of D 2 and D 3 is N;
R 2 is selected from the group consisting of H, halo, hydroxy, —NRR′, —(CH 2 ) f NRR′, —O—(CH 2 ) g NRR′, —C(═O)—NRR′, cyano, lower alkyl, C 3 -C 6 cyclic alkyl, lower alkoxy, C 1 -C 3 perfluoro alkyl, C 1 -C 3 perfluoro alkoxy and carboxyl;
R 3 is selected from the group consisting of H, halo, hydroxy, —(CH 2 ) f NRR′, —O—(CH 2 ) g NRR′, —C(═O)—NRR′, cyano, lower alkyl, C 3 -C 6 cyclic alkyl, lower alkoxy, C 1 -C 3 perfluoro alkyl, C 1 -C 3 perfluoro alkoxy and carboxyl;
alternatively R 2 and R 3 are taken together to form a 4- to 7-membered fused ring having from 0 to 3 ring heteroatoms, and is unsubstituted or is substituted with halo, hydroxyl, amino, —C(═O)-lower alkyl, lower alkyl, and lower alkoxy;
R 4 is a selected from the group consisting of the following structures:
X 1 is selected from the group consisting of O, NH, and CHR 6 ;
each R 6 is independently selected from the group consisting of H, halo, hydroxy, lower alkyl, substituted lower alkyl, lower alkoxy, aryl, substituted aryl, aralkyl, substituted aralkyl, heterocycle, substituted heterocycle, —NRR′, —(CH 2 ) f NRR′, —O—(CH 2 ) g NRR′, —C(═O)—NRR′, —C(═O)—OR, cyano, lower alkyl, C 3 -C 6 cyclic alkyl, C 1 -C 3 perfluoro alkyl, C 1 -C 3 perfluoro alkoxy and carboxyl;
additionally or alternatively, two R 6 substituents attached to the same ring carbon may be taken together to form an oxo group (i.e., ═O), or a C 3 to C 7 spiro cyclic group; and
additionally or alternatively, two R 6 substituents attached to different ring carbons may be taken together to form a ring, wherein the ring formed when taking the two R 6 groups together has from 4 to 7 ring atoms including from 0 to 3 ring heteroatoms.
each R 7 is independently selected from the group consisting of H, halo, hydroxy, lower alkyl, substituted lower alkyl, lower alkoxy, —NRR′, —C(═O)—NRR′, —C(═O)—OR, cyano, oxo, C 1 -C 3 perfluoro alkyl, and C 1 -C 3 perfluoro alkoxy;
each R 8 is independently selected from the group consisting of H, halo, hydroxy, lower alkyl, substituted lower alkyl, lower alkoxy, —NRR′, —C(═O)—NRR′, —C(═O)—OR, cyano, oxo, C 1 -C 3 perfluoro alkyl, and C 1 -C 3 perfluoro alkoxy;
each R 9 is independently selected from the group consisting of H, halo, hydroxy, lower alkyl, substituted lower alkyl, lower alkoxy, —NRR′, —C(═O)—NRR′, —C(═O)—OR, cyano, oxo, C 1 -C 3 perfluoro alkyl, and C 1 -C 3 perfluoro alkoxy;
each R 10 is independently selected from the group consisting of H, halo, hydroxy, lower alkyl, substituted lower alkyl, lower alkoxy, —NRR′, —C(═O)—NRR′, —C(═O)—OR, cyano, oxo, C 1 -C 3 perfluoro alkyl, and C 1 -C 3 perfluoro alkoxy;
X 2 is selected from CH 2 , CHR 8 , O, NH and N-(lower alkyl);
X 3 is selected from CH and N;
each R is independently selected from H and lower alkyl;
each R′ is independently selected from H, lower alkyl, aryl, substituted aryl, aralkyl, and substituted aralkyl;
a is selected from 0 to 3;
b is selected from 0 to 2;
d is selected from 0 to 2;
e is selected from 0 to 2;
each f is independently 1 to 3;
each g is independently 2 or 3;
n is selected from 0 to 4;
m is selected from 1 to 3;
p is selected from 1 to 3;
q is selected from 0 to 3;
r is selected from 0 to 3;
wherein q and r are not simultaneously selected to be 0;
s is selected from 0 to 3;
t is selected from 0 to 3;
wherein s and t are not simultaneously selected to be 0;
v is selected from 0 to 3; and
w is selected from 0 to 3.
4 . The compound according to claim 1 , having the formula II:
R 5 is selected from H, halo, hydroxy, —NRR′, —(CH 2 ) f NRR′, —O—(CH 2 ) g NRR′, —C(═O)—NRR′, cyano, lower alkyl, C 3 -C 6 cyclic alkyl, lower alkoxy, C 1 -C 3 perfluoro alkyl, C 1 -C 3 perfluoro alkoxy and carboxyl;
each of L 1 and L 2 are independently selected from N and CH;
R 2 is selected from the group consisting of H, halo, hydroxy, —NRR′, —(CH 2 ) f NRR′, —O—(CH 2 ) g NRR′, —C(═O)—NRR′, cyano, lower alkyl, C 3 -C 6 cyclic alkyl, lower alkoxy, C 1 -C 3 perfluoro alkyl, C 1 -C 3 perfluoro alkoxy and carboxyl;
R 3 is selected from the group consisting of H, halo, hydroxy, —NRR′, —(CH 2 ) f NRR′, —O—(CH 2 ) g NRR′, —C(═O)—NRR′, cyano, lower alkyl, C 3 -C 6 cyclic alkyl, lower alkoxy, C 1 -C 3 perfluoro alkyl, C 1 -C 3 perfluoro alkoxy and carboxyl;
alternatively R 2 and R 3 are taken together to form a 4- to 7-membered fused ring having from 0 to 3 ring heteroatoms, and is unsubstituted or is substituted with halo, hydroxy, amino, —C(═O)-lower alkyl, lower alkyl, and lower alkoxy;
R 4 is a selected from the group consisting of the following structures:
X 1 is selected from the group consisting of O, NH, and CHR 6 ;
each R 6 is independently selected from the group consisting of H, halo, hydroxy, lower alkyl, substituted lower alkyl, lower alkoxy, aryl, substituted aryl, aralkyl, substituted aralkyl, heterocycle, substituted heterocycle, —NRR′, —(CH 2 ) f NRR′, —O—(CH 2 ) g NRR′, —C(═O)—NRR′, —C(═O)—OR, cyano, lower alkyl, C 3 -C 6 cyclic alkyl, C 1 -C 3 perfluoro alkyl, C 1 -C 3 perfluoro alkoxy and carboxyl;
additionally or alternatively, two R 6 substituents attached to the same ring carbon may be taken together to form an oxo group (i.e., ═O), or a C 3 to C 7 spiro cyclic group; and
additionally or alternatively, two R 6 substituents attached to different ring carbons may be taken together to form a ring, wherein the ring formed when taking the two R 6 groups together has from 4 to 7 ring atoms including from 0 to 3 ring heteroatoms.
each R 7 is independently selected from the group consisting of H, halo, hydroxy, lower alkyl, substituted lower alkyl, lower alkoxy, —NRR′, —C(═O)—NRR′, —C(═O)—OR, cyano, oxo, C 1 -C 3 perfluoro alkyl, and C 1 -C 3 perfluoro alkoxy;
each R 8 is independently selected from the group consisting of H, halo, hydroxy, lower alkyl, substituted lower alkyl, lower alkoxy, —NRR′, —C(═O)—NRR′, —C(═O)—OR, cyano, oxo, C 1 -C 3 perfluoro alkyl, and C 1 -C 3 perfluoro alkoxy;
each R 9 is independently selected from the group consisting of H, halo, hydroxy, lower alkyl, substituted lower alkyl, lower alkoxy, —NRR′, —C(═O)—NRR′, —C(═O)—OR, cyano, oxo, C 1 -C 3 perfluoro alkyl, and C 1 -C 3 perfluoro alkoxy;
each R 10 is independently selected from the group consisting of H, halo, hydroxy, lower alkyl, substituted lower alkyl, lower alkoxy, —NRR′, —C(═O)—NRR′, —C(═O)—OR, cyano, oxo, C 1 -C 3 perfluoro alkyl, and C 1 -C 3 perfluoro alkoxy;
X 2 is selected from CH 2 , CHR 8 , O, NH and N-(lower alkyl);
X 3 is selected from CH, CR 9 and N;
each R is independently selected from H and lower alkyl;
each R′ is independently selected from H, lower alkyl, aryl, substituted aryl, aralkyl, and substituted aralkyl;
a is selected from 0 to 3;
b is selected from 0 to 2;
c is selected from 0 to 2;
d is selected from 0 to 2;
e is selected from 0 to 2;
each f is independently 1 to 3;
each g is independently 2 or 3;
n is selected from 0 to 4;
m is selected from 1 to 3;
p is selected from 1 to 3;
q is selected from 0 to 3;
r is selected from 0 to 3;
wherein q and r are not simultaneously selected to be 0;
s is selected from 0 to 3;
t is selected from 0 to 3;
wherein s and t are not simultaneously selected to be 0;
v is selected from 0 to 3; and
w is selected from 0 to 3.
5 . The compound according to claim 1 , having the formula Ha:
wherein:
R 2 is selected from the group consisting of H, halo, hydroxy, —NRR′, —(CH 2 ) f NRR′, —O—(CH 2 ) g NRR′, —C(═O)—NRR′, cyano, lower alkyl, C 3 -C 6 cyclic alkyl, lower alkoxy, C 1 -C 3 perfluoro alkyl, C 1 -C 3 perfluoro alkoxy and carboxyl;
R 3 is selected from the group consisting of H, halo, hydroxy, —NRR′, —(CH 2 ) f NRR′, —O—(CH 2 ) g NRR′, —C(═O)—NRR′, cyano, lower alkyl, C 3 -C 6 cyclic alkyl, lower alkoxy, C 1 -C 3 perfluoro alkyl, C 1 -C 3 perfluoro alkoxy and carboxyl;
alternatively R 2 and R 3 are taken together to form a 4- to 7-membered fused ring having from 0 to 3 ring heteroatoms, and is unsubstituted or is substituted with halo, hydroxyl, amino, —C(═O)-lower alkyl, lower alkyl, and lower alkoxy;
R 4 is a selected from the group consisting of the following structures:
X 1 is selected from the group consisting of O, NH, and CHR 6 ;
R 5 is selected from H, halo, hydroxy, —NRR′, —(CH 2 ) f NRR′, —O—(CH 2 ) g NRR′, —C(═O)—NRR′, cyano, lower alkyl, C 3 -C 6 cyclic alkyl, lower alkoxy, C 1 -C 3 perfluoro alkyl, C 1 -C 3 perfluoro alkoxy and carboxyl;
each R 6 is independently selected from the group consisting of H, halo, hydroxy, lower alkyl, substituted lower alkyl, lower alkoxy, aryl, substituted aryl, aralkyl, substituted aralkyl, heterocycle, substituted heterocycle, —NRR′, —(CH 2 ) f NRR′, —O—(CH 2 ) g NRR′, —C(═O)—NRR′, —C(═O)—OR, cyano, lower alkyl, C 3 -C 6 cyclic alkyl, C 1 -C 3 perfluoro alkyl, C 1 -C 3 perfluoro alkoxy and carboxyl;
additionally or alternatively, two R 6 substituents attached to the same ring carbon may be taken together to form an oxo group (i.e., ═O), or a C 3 to C 7 spiro cyclic group; and
additionally or alternatively, two R 6 substituents attached to different ring carbons may be taken together to form a ring, wherein the ring formed when taking the two R 6 groups together has from 4 to 7 ring atoms including from 0 to 3 ring heteroatoms;
each R 7 is independently selected from the group consisting of H, halo, hydroxy, lower alkyl, substituted lower alkyl, lower alkoxy, —NRR′, —C(═O)—NRR′, —C(═O)—OR, cyano, oxo, C 1 -C 3 perfluoro alkyl, and C 1 -C 3 perfluoro alkoxy;
each R 8 is independently selected from the group consisting of H, halo, hydroxy, lower alkyl, substituted lower alkyl, lower alkoxy, —NRR′, —C(═O)—NRR′, —C(═O)—OR, cyano, oxo, C 1 -C 3 perfluoro alkyl, and C 1 -C 3 perfluoro alkoxy;
each R 9 is independently selected from the group consisting of H, halo, hydroxy, lower alkyl, substituted lower alkyl, lower alkoxy, —NRR′, —C(═O)—NRR′, —C(═O)—OR, cyano, oxo, C 1 -C 3 perfluoro alkyl, and C 1 -C 3 perfluoro alkoxy;
each R 10 is independently selected from the group consisting of H, halo, hydroxy, lower alkyl, substituted lower alkyl, lower alkoxy, —NRR′, —C(═O)—NRR′, —C(═O)—OR, cyano, oxo, C 1 -C 3 perfluoro alkyl, and C 1 -C 3 perfluoro alkoxy;
X 2 is selected from CH 2 , CHR 8 , O, NH and N-(lower alkyl);
X 3 is selected from CH and N;
each R is independently selected from H and lower alkyl;
each R′ is independently selected from H, lower alkyl, aryl, substituted aryl, aralkyl, and substituted aralkyl;
a is selected from 0 to 3;
b is selected from 0 to 2;
c is selected from 0 to 2;
d is selected from 0 to 2;
e is selected from 0 to 2;
each f is independently 1 to 3;
each g is independently 2 or 3;
n is selected from 0 to 4;
m is selected from 1 to 3;
p is selected from 1 to 3;
q is selected from 0 to 3;
r is selected from 0 to 3;
wherein q and r are not simultaneously selected to be 0;
s is selected from 0 to 3;
t is selected from 0 to 3;
wherein s and t are not simultaneously selected to be 0;
v is selected from 0 to 3; and
w is selected from 0 to 3.
6 . The compound according to claim 1 , having the formula IIj;
wherein
each of L 1 and L 2 are independently selected from N and CH;
R 2 is selected from the group consisting of H, halo, hydroxy, —NRR′, —(CH 2 ) f NRR′, —O—(CH 2 ) g NRR′, —C(═O)—NRR′, cyano, lower alkyl, C 3 -C 6 cyclic alkyl, lower alkoxy, C 1 -C 3 perfluoro alkyl, C 1 -C 3 perfluoro alkoxy and carboxyl;
R 3 is selected from the group consisting of H, halo, hydroxy, —NRR′, —(CH 2 ) f NRR′, —O—(CH 2 ) g NRR′, —C(═O)—NRR′, cyano, lower alkyl, C 3 -C 6 cyclic alkyl, lower alkoxy, C 1 -C 3 perfluoro alkyl, C 1 -C 3 perfluoro alkoxy and carboxyl;
alternatively R 2 and R 3 are taken together to form a 4- to 7-membered fused ring having from 0 to 3 ring heteroatoms, and is unsubstituted or is substituted with halo, hydroxyl, amino, —C(═O)-lower alkyl, lower alkyl, and lower alkoxy;
R 5 is selected from H, halo, hydroxy, —NRR′, —(CH 2 ) f NRR′, —O—(CH 2 ) g NRR′, —C(═O)—NRR′, cyano, lower alkyl, C 3 -C 6 cyclic alkyl, lower alkoxy, C 1 -C 3 perfluoro alkyl, C 1 -C 3 perfluoro alkoxy and carboxyl;
each R 61 is independently selected from the group consisting of H, halo, hydroxy, lower alkyl, substituted lower alkyl, lower alkoxy, aryl, aralkyl, heterocycle, —NRR′, —(CH 2 ) f NRR′, —O—(CH 2 ) g NRR′, —C(═O)—NRR′, —C(═O)—OR, cyano, lower alkyl, C 3 -C 6 cyclic alkyl, C 1 -C 3 perfluoro alkyl, C 1 -C 3 perfluoro alkoxy and carboxyl;
each R is independently selected from H and lower alkyl;
each R′ is independently selected from H, lower alkyl, aryl, substituted aryl, aralkyl, and substituted aralkyl;
a is selected from 0 to 3;
each f is independently 1 to 3;
each g is independently 2 or 3; and
x is selected from 1 to 3.
7 . The compound according to claim 1 , having the formula IIk:
wherein:
R 2 is selected from the group consisting of H, halo, hydroxy, —NRR′, —(CH 2 ) f NRR′, —O—(CH 2 ) g NRR′, —C(═O)—NRR′, cyano, lower alkyl, C 3 -C 6 cyclic alkyl, lower alkoxy, C 1 -C 3 perfluoro alkyl, C 1 -C 3 perfluoro alkoxy and carboxyl;
R 3 is selected from the group consisting of H, halo, hydroxy, —NRR′, —(CH 2 ) f NRR′, —O—(CH 2 ) g NRR′, —C(═O)—NRR′, cyano, lower alkyl, C 3 -C 6 cyclic alkyl, lower alkoxy, C 1 -C 3 perfluoro alkyl, C 1 -C 3 perfluoro alkoxy and carboxyl;
alternatively R 2 and R 3 are taken together to form a 4- to 7-membered fused ring having from 0 to 3 ring heteroatoms, and is unsubstituted or is substituted with halo, hydroxyl, amino, —C(═O)-lower alkyl, lower alkyl, and lower alkoxy;
R 5 is selected from H, halo, hydroxy, —NRR′, —(CH 2 ) f NRR′, —O—(CH 2 ) g NRR′, —C(═O)—NRR′, cyano, lower alkyl, C 3 -C 6 cyclic alkyl, lower alkoxy, C 1 -C 3 perfluoro alkyl, C 1 -C 3 perfluoro alkoxy and carboxyl;
each R 61 is independently selected from the group consisting of H, halo, hydroxy, lower alkyl, substituted lower alkyl, lower alkoxy, aryl, aralkyl, heterocycle, —NRR′, —(CH 2 ) f NRR′, —O—(CH 2 ) g NRR′, —C(═O)—NRR′, —C(═O)—OR, cyano, lower alkyl, C 3 -C 6 cyclic alkyl, C 1 -C 3 perfluoro alkyl, C 1 -C 3 perfluoro alkoxy and carboxyl;
each R is independently selected from H and lower alkyl;
each R′ is independently selected from H, lower alkyl, aryl, substituted aryl, aralkyl, and substituted aralkyl;
a is selected from 0 to 3;
each f is independently 1 to 3;
each g is independently 2 or 3; and
x is selected from 1 to 3.
8 . The compound according to claim 1 , having the formula III:
each of A 1 , A 3 and A 4 are independently selected from N, C—R a and CH, wherein the maximum number of N among A 1 , A 3 and A 4 is 3;
B is selected from group consisting of NH, O and S;
each R a is independently selected from the group consisting of lower alkyl, halo and amino;
R 2 is selected from the group consisting of H, halo, hydroxy, —NRR′, —(CH 2 ) f NRR′, —O—(CH 2 ) g NRR′, —C(═O)—NRR′, cyano, lower alkyl, C 3 -C 6 cyclic alkyl, lower alkoxy, C 1 -C 3 perfluoro alkyl, C 1 -C 3 perfluoro alkoxy and carboxyl;
R 3 is selected from the group consisting of H, halo, hydroxy, —NRR′, —(CH 2 ) f NRR′, —O—(CH 2 ) g NRR′, —C(═O)—NRR′, cyano, lower alkyl, C 3 -C 6 cyclic alkyl, lower alkoxy, C 1 -C 3 perfluoro alkyl, C 1 -C 3 perfluoro alkoxy and carboxyl;
alternatively R 2 and R 3 are taken together to form a 4- to 7-membered fused ring having from 0 to 3 ring heteroatoms, and is unsubstituted or is substituted with halo, hydroxyl, amino, —C(═O)-lower alkyl, lower alkyl, and lower alkoxy;
R 4 is a selected from the group consisting of the following structures:
X 1 is selected from the group consisting of O, NH, and CHR 6 ;
R 5 is selected from H, halo, hydroxy, —NRR′, —(CH 2 ) f NRR′, —O—(CH 2 ) g NRR′, —C(═O)—NRR′, cyano, lower alkyl, C 3 -C 6 cyclic alkyl, lower alkoxy, C 1 -C 3 perfluoro alkyl, C 1 -C 3 perfluoro alkoxy and carboxyl;
each R 6 is independently selected from the group consisting of H, halo, hydroxy, lower alkyl, substituted lower alkyl, lower alkoxy, aryl, substituted aryl, aralkyl, substituted aralkyl, heterocycle, substituted heterocycle, —NRR′, —(CH 2 ) f NRR′, —O—(CH 2 ) g NRR′, —C(═O)—NRR′, —C(═O)—OR, cyano, lower alkyl, C 3 -C 6 cyclic alkyl, C 1 -C 3 perfluoro alkyl, C 1 -C 3 perfluoro alkoxy and carboxyl;
additionally or alternatively, two R b substituents attached to the same ring carbon may be taken together to form an oxo group (i.e., ═O), or a C 3 to C 7 spiro cyclic group; and
additionally or alternatively, two R 6 substituents attached to different ring carbons may be taken together to form a ring, wherein the ring formed when taking the two R 6 groups together has from 4 to 7 ring atoms including from 0 to 3 ring heteroatoms;
each R 7 is independently selected from the group consisting of H, halo, hydroxy, lower alkyl, substituted lower alkyl, lower alkoxy, —NRR′, —C(═O)—NRR′, —C(═O)—OR, cyano, oxo, C 1 -C 3 perfluoro alkyl, and C 1 -C 3 perfluoro alkoxy;
each R 8 is independently selected from the group consisting of H, halo, hydroxy, lower alkyl, substituted lower alkyl, lower alkoxy, —NRR′, —C(═O)—NRR′, —C(═O)—OR, cyano, oxo, C 1 -C 3 perfluoro alkyl, and C 1 -C 3 perfluoro alkoxy;
each R 9 is independently selected from the group consisting of H, halo, hydroxy, lower alkyl, substituted lower alkyl, lower alkoxy, —NRR′, —C(═O)—NRR′, —C(═O)—OR, cyano, oxo, C 1 -C 3 perfluoro alkyl, and C 1 -C 3 perfluoro alkoxy;
each R 10 is independently selected from the group consisting of H, halo, hydroxy, lower alkyl, substituted lower alkyl, lower alkoxy, —NRR′, —C(═O)—NRR′, —C(═O)—OR, cyano, oxo, C 1 -C 3 perfluoro alkyl, and C 1 -C 3 perfluoro alkoxy;
X 2 is selected from CH 2 , CHR 8 , O, NH and N-(lower alkyl);
X 3 is selected from CH and N;
each R is independently selected from H and lower alkyl;
each R′ is independently selected from H, lower alkyl, aryl, substituted aryl, aralkyl, and substituted aralkyl;
a is selected from 0 to 3;
b is selected from 0 to 2;
c is selected from 0 to 2;
d is selected from 0 to 2;
e is selected from 0 to 2;
each f is independently 1 to 3;
each g is independently 2 or 3;
n is selected from 0 to 4;
m is selected from 1 to 3;
p is selected from 1 to 3;
q is selected from 0 to 3;
r is selected from 0 to 3;
wherein q and r are not simultaneously selected to be 0;
s is selected from 0 to 3;
t is selected from 0 to 3;
wherein s and t are not simultaneously selected to be 0;
v is selected from 0 to 3; and
w is selected from 0 to 3.
9 . The compound according to claim 1 , having the formula IIIa:
wherein:
R 2 is selected from the group consisting of H, halo, hydroxy, —NRR′, —(CH 2 ) f NRR′, —O—(CH 2 ) g NRR′, —C(═O)—NRR′, cyano, lower alkyl, C 3 -C 6 cyclic alkyl, lower alkoxy, C 1 -C 3 perfluoro alkyl, C 1 -C 3 perfluoro alkoxy and carboxyl;
R 3 is selected from the group consisting of H, halo, hydroxy, —NRR′, —(CH 2 ) f NRR′, —O—(CH 2 ) g NRR′, —C(═O)—NRR′, cyano, lower alkyl, C 3 -C 6 cyclic alkyl, lower alkoxy, C 1 -C 3 perfluoro alkyl, C 1 -C 3 perfluoro alkoxy and carboxyl;
alternatively R 2 and R 3 are taken together to form a 4- to 7-membered fused ring having from 0 to 3 ring heteroatoms, and is unsubstituted or is substituted with halo, hydroxyl, amino, —C(═O)-lower alkyl, lower alkyl, and lower alkoxy;
R 4 is a selected from the group consisting of the following structures:
X 1 is selected from the group consisting of O, NH, and CHR 6 ;
R 5 is selected from H, halo, hydroxy, —(CH 2 ) f NRR′, —O—(CH 2 ) g NRR′, —C(═O)—NRR′, cyano, lower alkyl, C 3 -C 6 cyclic alkyl, lower alkoxy, C 1 -C 3 perfluoro alkyl, C 1 -C 3 perfluoro alkoxy and carboxyl;
each R 6 is independently selected from the group consisting of H, halo, hydroxy, lower alkyl, substituted lower alkyl, lower alkoxy, aryl, substituted aryl, aralkyl, substituted aralkyl, heterocycle, substituted heterocycle, —NRR′, —(CH 2 ) f NRR′, —O—(CH 2 ) g NRR′, —C(═O)—NRR′, —C(═O)—OR, cyano, lower alkyl, C 3 -C 6 cyclic alkyl, C 1 -C 3 perfluoro alkyl, C 1 -C 3 perfluoro alkoxy and carboxyl;
additionally or alternatively, two R b substituents attached to the same ring carbon may be taken together to form an oxo group (i.e., ═O), or a C 3 to C 7 spiro cyclic group; and
additionally or alternatively, two R 6 substituents attached to different ring carbons may be taken together to form a ring, wherein the ring formed when taking the two R 6 groups together has from 4 to 7 ring atoms including from 0 to 3 ring heteroatoms;
each R 7 is independently selected from the group consisting of H, halo, hydroxy, lower alkyl, substituted lower alkyl, lower alkoxy, —NRR′, —C(═O)—NRR′, —C(═O)—OR, cyano, oxo, C 1 -C 3 perfluoro alkyl, and C 1 -C 3 perfluoro alkoxy;
each R 8 is independently selected from the group consisting of H, halo, hydroxy, lower alkyl, substituted lower alkyl, lower alkoxy, —NRR′, —C(═O)—NRR′, —C(═O)—OR, cyano, oxo, C 1 -C 3 perfluoro alkyl, and C 1 -C 3 perfluoro alkoxy;
each R 9 is independently selected from the group consisting of H, halo, hydroxy, lower alkyl, substituted lower alkyl, lower alkoxy, —NRR′, —C(═O)—NRR′, —C(═O)—OR, cyano, oxo, C 1 -C 3 perfluoro alkyl, and C 1 -C 3 perfluoro alkoxy;
each R 10 is independently selected from the group consisting of H, halo, hydroxy, lower alkyl, substituted lower alkyl, lower alkoxy, —NRR′, —C(═O)—NRR′, —C(═O)—OR, cyano, oxo, C 1 -C 3 perfluoro alkyl, and C 1 -C 3 perfluoro alkoxy;
X 2 is selected from CH 2 , CHR 8 , O, NH and N-(lower alkyl);
X 3 is selected from CH and N;
each R is independently selected from H and lower alkyl;
each R′ is independently selected from H, lower alkyl, aryl, substituted aryl, aralkyl, and substituted aralkyl;
a is selected from 0 to 3;
b is selected from 0 to 2;
c is selected from 0 to 2;
d is selected from 0 to 2;
e is selected from 0 to 2;
each f is independently 1 to 3;
each g is independently 2 or 3;
n is selected from 0 to 4;
m is selected from 1 to 3;
p is selected from 1 to 3;
q is selected from 0 to 3;
r is selected from 0 to 3;
wherein q and r are not simultaneously selected to be 0;
s is selected from 0 to 3;
t is selected from 0 to 3;
wherein s and t are not simultaneously selected to be 0;
v is selected from 0 to 3; and
w is selected from 0 to 3.
10 . The compound according to claim 1 , having the formula:
11 . A method of treating a fibrotic disorder in a subject comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 10 .
12 . The method of claim 11 , wherein fibrotic disorder is selected from the group consisting of pulmonary fibrosis including cystic and idiopathic pulmonary fibrosis, radiation induced lung injury, liver fibrosis including cirrhosis, cardiac fibrosis including arterial fibrosis, endomyocardial fibrosis, old myocardial infraction, arterial stiffness, atherosclerosis, restenosis, arthrofibrosis, Crohn's disease, myelofibrosis, Peyronie's diseases, nephrogenic systemic fibrosis, progressive massive fibrosis, retroperitoneal cavity fibrosis, schleroderma/systemic sclerosis, mediastinal fibrosis, Keloids and hypertrophic scars, glial scaring, or renal fibrosis.
13 . A method of treating a central nervous system disorder in a subject comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 10 .
14 . The method of claim 13 , wherein the central nervous system disorder is selected from the group consisting of Huntington's disease, Parkinson's Disease, Alzheimer's, Amyotrophic lateral sclerosis (ALS), Batten disease, dementia, spinal muscular atrophy, motor neurone diseases, spinocerebellar ataxia, acute or chronic pain, dementia, neuronal degeneration, spinal cord injury, cerebral vasospasm or multiple sclerosis.
15 . A method of treating glaucoma in a subject comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 10 .
16 . A method of treating inflammation in a subject comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 10 .
17 . A method of treating an autoimmune disorder in a subject comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 10 .Join the waitlist — get patent alerts
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