US2021087167A1PendingUtilityA1
Ask1 inhibitor compounds and uses thereof
Est. expiryApr 5, 2037(~10.7 yrs left)· nominal 20-yr term from priority
Inventors:Samuel David Brown
C07D 498/08C07D 491/08C07D 487/04C07D 417/14C07D 405/14C07D 403/14C07D 401/14A61P 1/16A61K 31/4439
53
PatentIndex Score
0
Cited by
0
References
0
Claims
Abstract
Described herein are compounds, including pharmaceutically acceptable salts, solvates, metabolites, prodrugs thereof, methods of making such compounds, pharmaceutical compositions comprising such compounds, and methods of using such compounds to treat non-alcoholic steatohepatitis and other diseases characterized by dysfunctional tissue healing and fibrosis.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A compound that has the structure of Formula III, or a pharmaceutically acceptable salt or solvate thereof:
wherein
is
R 1 is
Z is O, S, C(═O), N(R 8 ), or C(R 9 ) 2 ;
X is O or S;
R 2 is C 3-6 cycloalkyl;
R 3 is selected from a group consisting of hydrogen, C 1-6 alkyl, and C 3-6 cycloalkyl;
each R 4 is independently selected from a group consisting of hydrogen, halo, C 1-6 alkyl, and C 3-6 cycloalkyl;
or one R 4 and another R 2 , R 3 , or R 4 , together with the atoms to which they are attached, form a 5- or 6-membered ring that is optionally containing one or two heteroatoms selected from O, N, and S; wherein the 5- or 6-membered ring is saturated, unsaturated, or aromatic; and wherein the 5- or 6-membered ring is optionally substituted with one, two, or three substituents selected from the group consisting of halo, —CN, C 1-6 alkyl, —C 1-6 alkyl-OH, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 2-9 heterocycle, C 6-10 aryl, C 1-9 heteroaryl, —C(═O)R 14 , —C(═O)OR 13 , —C(═O)N(R 13 ) 2 , —S(═O)R 14 , —S(═O) 2 R 13 , —S(═O) 2 —N(R 13 ) 2 , —N(R 13 ) 2 , —N(R 13 )C(═O)R 14 , and —N(R 13 )S(═O) 2 R 13 ;
each R 5 is independently selected from a group consisting of halogen and C 1-6 alkyl;
R 5a is selected from the group consisting of hydrogen and C 1 -C 6 alkyl;
each R 25 is independently selected from a group consisting of halogen, —CN, —OH, —OR 6 , —SR 6 , —S(═O)R 7 , —NO 2 , —N(R 6 ) 2 , —S(═O) 2 R 7 , —NHS(═O) 2 R 7 , —S(═O) 2 N(R 6 ) 2 , —C(═O)R 7 , —C(═O)OR 6 , —OC(═O)R 7 , —C(═O)N(R 6 ) 2 , —OC(═O)N(R 6 ) 2 , —NR 6 C(═O)N(R 6 ) 2 , —NR 6 C(═O)R 7 , —NR 6 C(═O)OR 6 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 2-9 heterocycle, C 6-10 aryl, C 1-9 heteroaryl, and a fused C 5-9 heteroaryl-cycloalkyl; wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 2-9 heterocycle, C 6-10 aryl, C 1-9 heteroaryl, and fused C 5-9 heteroaryl-cycloalkyl are optionally substituted with one, two, or three substituents selected from the group consisting of halo, —CN, C 1-6 alkyl, —C 1-6 alkyl-OH, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 2-9 heterocycle, C 6-10 aryl, C 1-9 heteroaryl, —C(═O)R 14 , —C(═O)OR 13 , —C(═O)N(R 13 ) 2 , —S(═O)R 14 , —S(═O) 2 R 13 , —S(═O) 2 —N(R 13 ) 2 , —N(R 13 ) 2 , —N(R 13 )C(═O)R 14 , and —N(R 13 )S(═O) 2 R 13 ;
each R 6 is independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, —C 1 -C 6 alkyl-O—C 1 -C 6 alkyl, —C 1 -C 6 alkyl-C 2-9 heterocycle, —C 1 -C 6 alkyl-C 2-9 heteroaryl, C 3 -C 8 cycloalkyl, —C 3 -C 8 cycloalkyl-phenyl, and C 2-9 heterocycle, wherein C 1 -C 6 alkyl, —C 1 -C 6 alkyl-O—C 1 -C 6 alkyl, —C 1 -C 6 alkyl-C 2-9 heterocycle, —C 1 -C 6 alkyl-C 2-9 heteroaryl, C 3 -C 8 cycloalkyl, —C 3 -C 8 cycloalkyl-phenyl, and C 2-9 heterocycle are optionally substituted with one, two, or three substituents selected from the group consisting of halo, —OR 8 , —SR 8 , —N(R 8 ) 2 , —C 1-6 alkyl, —O—C 1-6 alkyl, —C(═O)R 14 , —C(═O)OR 13 , and —N(R 13 )C(═O)R 14 ; or two R 6 on the same heteroatom are taken together with that heteroatom to which they are attached to form a C 2-9 heterocycle or a C 2-9 heteroaryl, wherein C 2-9 heterocycle or C 2-9 heteroaryl are optionally substituted with one, two, or three substituents selected from the group consisting of halo, —OR 8 , —SR 8 , —N(R 8 ) 2 , —C 1-6 alkyl, —O—C 1-6 alkyl, —C(═O)R 14 , —C(═O)OR 13 , and —N(R 13 )C(═O)R 14 ;
each R 7 is independently selected from the group consisting of C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, and C 2-9 heterocycle, wherein C 3 -C 8 cycloalkyl and C 2-9 heterocycle are optionally substituted with one, two, or three substituents selected from the group consisting of halo, oxo, —OR 8 , —SR 8 , —N(R 8 ) 2 , —C 1-6 alkyl, —O—C 1-6 alkyl, —C(═O)R 14 , —C(═O)OR 13 , and —N(R 13 )C(═O)R 14 ;
each R 8 is independently selected from the group consisting of hydrogen and C 1 -C 6 alkyl;
each R 9 is independently selected from the group consisting of hydrogen, halogen, and C 1 -C 6 alkyl;
each R 13 is independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and C 3 -C 8 cycloalkyl; or two R 13 on the same heteroatom are taken together with that heteroatom to which they are attached to form a C 2-9 heterocycle;
each R 14 is independently selected from the group consisting of C 1 -C 6 alkyl and C 3 -C 8 cycloalkyl;
n is 0, 1, 2, 3, or 4;
p is 0, 1, 2, or 3; and
q is 0, 1, or 2.
2 . A compound that has the structure of Formula II, or a pharmaceutically acceptable salt or solvate thereof:
wherein
is
R 1 is
Z is O, S, C(═O), N(R 8 ), or C(R 9 ) 2 ;
X is O or S;
R 2 is C 3-6 cycloalkyl;
R 3 is selected from a group consisting of hydrogen, C 1-6 alkyl, and C 3-6 cycloalkyl;
each R 4 is independently selected from a group consisting of hydrogen, halo, C 1-6 alkyl, and C 3-6 cycloalkyl;
or one R 4 and another R 2 , R 3 , or R 4 , together with the atoms to which they are attached, form a 5- or 6-membered ring that is optionally containing one or two heteroatoms selected from O, N, and S; wherein the 5- or 6-membered ring is saturated, unsaturated, or aromatic; and wherein the 5- or 6-membered ring is optionally substituted with one, two, or three substituents selected from the group consisting of halo, —CN, C 1-6 alkyl, —C 1-6 alkyl-OH, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 2-9 heterocycle, C 6-10 aryl, C 1-9 heteroaryl, —C(═O)R 14 , —C(═O)OR 13 , —C(═O)N(R 13 ) 2 , —S(═O)R 14 , —S(═O) 2 R 13 , —S(═O) 2 —N(R 13 ) 2 , —N(R 13 ) 2 , —N(R 13 )C(═O)R 14 , and —N(R 13 )S(═O) 2 R 13 ;
each R 5 is independently selected from a group consisting of halogen and C 1-6 alkyl;
R 5a is selected from the group consisting of hydrogen and C 1 -C 6 alkyl;
R 2 is selected from a group consisting of halogen, —CN, —OH, —OR 6 , —SR 6 , —S(═O)R 7 , —NO 2 , —N(R 6 ) 2 , —S(═O) 2 R 7 , —NHS(═O) 2 R 7 , —S(═O) 2 N(R 6 ) 2 , —C(═O)R 7 , —C(═O)OR 6 , —OC(═O)R 7 , —C(═O)N(R 6 ) 2 , —OC(═O)N(R 6 ) 2 , —NR 6 C(═O)N(R 6 ) 2 , —NR 6 C(═O)R 7 , —NR 6 C(═O)OR 6 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 2-9 heterocycle, C 6-10 aryl, C 1-9 heteroaryl, and a fused C 5-9 heteroaryl-cycloalkyl; wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 2-9 heterocycle, C 6-10 aryl, C 1-9 heteroaryl, and fused C 5-9 heteroaryl-cycloalkyl are optionally substituted with one, two, or three substituents selected from the group consisting of halo, —CN, C 1-6 alkyl, —C 1-6 alkyl-OH, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 2-9 heterocycle, C 6-10 aryl, C 1-9 heteroaryl, —C(═O)R 14 , —C(═O)OR 13 , —C(═O)N(R 13 ) 2 , —S(═O)R 14 , —S(═O) 2 R 13 , —S(═O) 2 —N(R 13 ) 2 , —N(R 13 ) 2 , —N(R 13 )C(═O)R 14 , and —N(R 13 )S(═O) 2 R 13 ;
each R 6 is independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, —C 1 -C 6 alkyl-O—C 1 -C 6 alkyl, —C 1 -C 6 alkyl-C 2-9 heterocycle, —C 1 -C 6 alkyl-C 2-9 heteroaryl, C 3 -C 8 cycloalkyl, and C 2-9 heterocycle; or two R 6 on the same heteroatom are taken together with that heteroatom to which they are attached to form a C 2-9 heterocycle or a C 2-9 heteroaryl;
each R 7 is independently selected from the group consisting of C 1 -C 6 alkyl and C 3 -C 8 cycloalkyl;
R 8 is selected from the group consisting of hydrogen and C 1 -C 6 alkyl;
each R 9 is independently selected from the group consisting of hydrogen, halogen, and C 1 -C 6 alkyl;
each R 13 is independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and C 3 -C 8 cycloalkyl; or two R 13 on the same heteroatom are taken together with that heteroatom to which they are attached to form a C 2-9 heterocycle;
each R 14 is independently selected from the group consisting of C 1 -C 6 alkyl and C 3 -C 8 cycloalkyl;
n is 0, 1, 2, 3, or 4;
p is 0, 1, 2, or 3; and
q is 0, 1, or 2.
3 . The compound of claim 1 or 2 , or a pharmaceutically acceptable salt or solvate thereof, wherein
R 25 is selected from a group consisting of C 3-8 cycloalkyl, C 2-9 heterocycle, C 6-10 aryl, C 1-9 heteroaryl, and a fused C 5-9 heteroaryl-cycloalkyl; wherein C 3-8 cycloalkyl, C 2-9 heterocycle, C 6-10 aryl, C 1-9 heteroaryl, and fused C 5-9 heteroaryl-cycloalkyl, wherein C 3-8 cycloalkyl, C 2-9 heterocycle, C 6-10 aryl, C 1-9 heteroaryl, and fused C 5-9 heteroaryl-cycloalkyl are optionally substituted with one, two, or three substituents selected from the group consisting of halo, —CN, C 1-6 alkyl, —C 1-6 alkyl-OH, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 2-9 heterocycle, C 6-10 aryl, C 1-9 heteroaryl, —C(═O)R 14 , —C(═O)OR 13 , —C(═O)N(R 13 ) 2 , —S(═O)R 14 , —S(═O) 2 R 13 , —S(═O) 2 —N(R 13 ) 2 , —N(R 13 ) 2 , —N(R 13 )C(═O)R 14 , and —N(R 13 )S(═O) 2 R 13 .
4 . The compound of claim 1 or 2 , or a pharmaceutically acceptable salt or solvate thereof, wherein
R 25 is selected from a group consisting of C 2-9 heterocycle and C 1-9 heteroaryl; wherein C 2-9 heterocycle and C 1-9 heteroaryl are optionally substituted with one, two, or three substituents selected from the group consisting of halo, —CN, C 1-6 alkyl, —C 1-6 alkyl-OH, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 2-9 heterocycle, C 6-10 aryl, C 1-9 heteroaryl, —C(═O)R 14 , —C(═O)OR 13 , —C(═O)N(R 13 ) 2 , —S(═O)R 14 , —S(═O) 2 R 13 , —S(═O) 2 —N(R 13 ) 2 , —N(R 13 ) 2 , —N(R 13 )C(═O)R 14 , and —N(R 13 )S(═O) 2 R 13 .
5 . The compound of claim 1 or 2 , or a pharmaceutically acceptable salt or solvate thereof, wherein
R 25 is selected from a group consisting of C 2-9 heterocycle and C 1-9 heteroaryl; wherein C 2-9 heterocycle and C 1-9 heteroaryl are optionally substituted with one or two substituents selected from the group consisting of halo, —CN, C 1-6 alkyl, —C 1-6 alkyl-OH, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 2-9 heterocycle, C 6-10 aryl, C 1-9 heteroaryl, —C(═O)R 14 , —C(═O)OR 13 , —C(═O)N(R 13 ) 2 , —S(═O)R 14 , —S(═O) 2 R 13 , —S(═O) 2 —N(R 13 ) 2 , —N(R 13 ) 2 , —N(R 13 )C(═O)R 14 , and —N(R 13 )S(═O) 2 R 13 .
6 . The compound of claim 1 or 2 , or a pharmaceutically acceptable salt or solvate thereof, wherein
R 25 is selected from a group consisting of pyrazole, imidazole, thiazole, and pyridine; wherein pyrazole, imidazole, thiazole, and pyridine are optionally substituted with one or two substituents selected from the group consisting of halo, —CN, C 1-6 alkyl, —C 1-6 alkyl-OH, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 2-9 heterocycle, C 6-10 aryl, C 1-9 heteroaryl, —C(═O)R 14 , —C(═O)OR 13 , —C(═O)N(R 13 ) 2 , —S(═O)R 14 , —S(═O) 2 R 13 , —S(═O) 2 —N(R 13 ) 2 , —N(R 13 ) 2 , —N(R 13 )C(═O)R 14 , and —N(R 13 )S(═O) 2 R 13 .
7 . The compound of claim 6 , or a pharmaceutically acceptable salt or solvate thereof, wherein
R 25 is selected from a group consisting of pyrazole, imidazole, thiazole, and pyridine; wherein pyrazole, imidazole, thiazole, and pyridine are optionally substituted with one or two substituents selected from the group consisting of halo, C 1-6 alkyl, and C 3-8 cycloalkyl.
8 . The compound of claim 7 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 25 is
wherein each R 11 is independently C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl.
9 . The compound of claim 7 , or a pharmaceutically acceptable salt or solvate thereof, wherein
R 25 is
wherein each R 12 is independently hydrogen, halo, C 1 -C 6 alkyl, or C 3 -C 6 cycloalkyl; and
m is 1 or 2.
10 . The compound of claim 7 , or a pharmaceutically acceptable salt or solvate thereof, wherein
R 25 is selected from a group consisting of unsubstituted pyrazole, unsubstituted imidazole, unsubstituted thiazole, and unsubstituted pyridine.
11 . The compound of claim 1 or 2 , or a pharmaceutically acceptable salt or solvate thereof, wherein
R 25 is selected from a group consisting of pyrimidine, pyrazine, and pyridazine; wherein pyrimidine, pyrazine, and pyridazine are optionally substituted with one or two substituents selected from the group consisting of halo, C 1-6 alkyl, and C 3-8 cycloalkyl.
12 . The compound of claim 1 or 2 , or a pharmaceutically acceptable salt or solvate thereof, wherein
R 25 is selected from a group consisting of halogen, —OR 6 , —N(R 6 ) 2 , C 1-6 alkyl, pyrazole, imidazole, thiazole, and pyridine; wherein pyrazole, imidazole, thiazole, and pyridine are optionally substituted with one or two substituents selected from the group consisting of halo, C 1-6 alkyl, and C 3-8 cycloalkyl.
13 . The compound of claim 12 , or a pharmaceutically acceptable salt or solvate thereof, wherein
R 25 is selected from a group consisting of halogen, —OR 6 , —N(R 6 ) 2 , C 1-6 alkyl, and unsubstituted pyridine.
14 . The compound of claim 1 or 2 , or a pharmaceutically acceptable salt or solvate thereof, wherein
R 25 is —C(═O)N(R 6 ) 2 and each R 6 is independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, —C 1 -C 6 alkyl-O—C 1 -C 6 alkyl, —C 1 -C 6 alkyl-C 2-9 heterocycle, —C 1 -C 6 alkyl-C 2-9 heteroaryl, C 3 -C 8 cycloalkyl, and C 2-9 heterocycle.
15 . The compound of claim 14 , or a pharmaceutically acceptable salt or solvate thereof wherein
R 25 is
16 . The compound of claim 14 , or a pharmaceutically acceptable salt or solvate thereof, wherein
R 23 is
wherein R 10 is a C 2-9 heteroaryl.
17 . The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein
R 25 is —C(═O)N(R 6 ) 2 and two R 6 on the same heteroatom are taken together with that heteroatom to which they are attached to form a C 2-9 heterocycle or a C 2-9 heteroaryl, wherein C 2-9 heterocycle or C 2-9 heteroaryl are optionally substituted with one, two, or three substituents selected from the group consisting of halo, —OR 8 , —SR 8 , —N(R 8 ) 2 , —C 1-6 alkyl, —O—C 1-6 alkyl, —C(═O)R 14 , —C(═O)OR 13 , and —N(R 13 )C(═O)R 14 .
18 . The compound of claim 17 , or a pharmaceutically acceptable salt or solvate thereof, wherein
R 25 is
19 . The compound of claim 2 , or a pharmaceutically acceptable salt or solvate thereof, wherein
R 25 is —C(═O)N(R 6 ) 2 and two R 6 are taken together with that heteroatom to which they are attached to form a C 2-9 heterocycle or a C 2-9 heteroaryl.
20 . The compound of claim 18 or 19 , or a pharmaceutically acceptable salt or solvate thereof, wherein
R 25 is
21 . The compound of claim 1 or 2 , or a pharmaceutically acceptable salt or solvate thereof, wherein
R 25 is —OR 6 and R 6 is selected from the group consisting of C 1 -C 6 alkyl, —C 1 -C 6 alkyl-O—C 1 -C 6 alkyl, and —C 1 -C 6 alkyl-C 2-9 heterocycle.
22 . The compound of any one of claims 1 - 21 , or a pharmaceutically acceptable salt or solvate thereof, wherein
R 1 is
23 . The compound of any one of claims 1 - 22 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is
24 . The compound of any one of claims 1 - 23 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is
25 . The compound of any one of claims 1 - 23 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is
26 . The compound of any one of claims 1 - 21 , or a pharmaceutically acceptable salt or solvate thereof, wherein
R 1 is
27 . A compound that has the structure of Formula I, or a pharmaceutically acceptable salt or solvate thereof:
wherein
is
Z is O, S, C(═O), N(R 8 ), or C(R 9 ) 2 ;
R 1 and R 3 are each independently selected from a group consisting of hydrogen, halogen, —CN, —OH, —OR 6 , —SR 6 , —S(═O)R 7 , —NO 2 , —N(R 6 ) 2 , —S(═O) 2 R 7 , —NHS(═O) 2 R 7 , —S(═O) 2 N(R 6 ) 2 , —C(═O)R 7 , —C(═O)OR 6 , —OC(═O)R 7 , —C(═O)N(R 6 ) 2 , —OC(═O)N(R 6 ) 2 , —WC(═O)N(R 6 ) 2 , —NR 6 C(═O)R 7 , —NR 6 C(═O)OR 7 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 2-9 heterocycle, C 6-10 aryl, C 1-9 heteroaryl, and a fused C 5-9 heteroaryl-cycloalkyl; wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 2-9 heterocycle, C 6-10 aryl, C 1-9 heteroaryl, and fused C 5-9 heteroaryl-cycloalkyl are optionally substituted with one, two, or three substituents selected from the group consisting of halo, —CN, C 1-6 alkyl, —C 1-6 alkyl-OH, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 2-9 heterocycle, C 6-10 aryl, C 1-9 heteroaryl, —C(═O)R 14 , —C(═O)OR 13 , —C(═O)N(R 13 ) 2 , —S(═O)R 14 , —S(═O) 2 R 13 , —S(═O) 2 —N(R 13 ) 2 , —N(R 13 ) 2 , —N(R 13 )C(═O)R 14 , and —N(R 13 )S(═O) 2 R 13 ;
R 2 is selected from a group consisting of hydrogen, halogen, —CN, —OH, —SR 6 , —S(═O)R 7 , —NO 2 , —N(R 6 ) 2 , —S(═O) 2 R 7 , —NHS(═O) 2 R 7 , —S(═O) 2 N(R 6 ) 2 , —C(═O)R 7 , —C(═O)OR 6 , —OC(═O)R 7 , —C(═O)N(R 6 ) 2 , —OC(═O)N(R 6 ) 2 , —NR 6 C(═O)N(R 6 ) 2 , —WC(═O)R 7 , —NR 6 C(═O)OR 7 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 2-9 heterocycle, C 6-10 aryl, C 1-9 heteroaryl, and a fused C 5-9 heteroaryl-cycloalkyl; wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 2-9 heterocycle, C 6-10 aryl, C 1-9 heteroaryl, and fused C 5-9 heteroaryl-cycloalkyl are optionally substituted with one, two, or three substituents selected from the group consisting of halo, —CN, C 1-6 alkyl, —C 1-6 alkyl-OH, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 2-9 heterocycle, C 6-10 aryl, C 1-9 heteroaryl, —C(═O)R 14 , —C(═O)OR 13 , —C(═O)N(R 13 ) 2 , —S(═O)R 14 , —S(═O) 2 R 13 , —S(═O) 2 —N(R 13 ) 2 , —N(R 13 ) 2 , —N(R 13 )C(═O)R 14 , and —N(R 13 )S(═O) 2 R 13 ; wherein R 2 and R 3 are not both hydrogen;
each R 4 and each R 5 are independently selected from a group consisting of halogen, —CN, and C 1-6 alkyl;
R 5a is selected from the group consisting of hydrogen and C 1 -C 6 alkyl;
each R 6 is independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, —C 1 -C 6 alkyl-O—C 1 -C 6 alkyl, —C 1 -C 6 alkyl-C 2-9 heterocycle, —C 1 -C 6 alkyl-C 2-9 heteroaryl, C 3 -C 8 cycloalkyl, and C 2-9 heterocycle; or two R 6 on the same heteroatom are taken together with that heteroatom to which they are attached to form a C 2-9 heterocycle or a C 2-9 heteroaryl;
each R 7 is independently selected from the group consisting of C 1 -C 6 alkyl and C 3 -C 8 cycloalkyl;
R 8 is selected from the group consisting of hydrogen and C 1 -C 6 alkyl;
each R 9 is independently selected from the group consisting of hydrogen, halogen, and C 1 -C 6 alkyl;
each R 13 is independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and C 3 -C 8 cycloalkyl; or two R 13 on the same heteroatom are taken together with that heteroatom to which they are attached to form a C 2-9 heterocycle;
each R 14 is independently selected from the group consisting of C 1 -C 6 alkyl and C 3 -C 8 cycloalkyl;
n is 0, 1, or 2;
p is 0, 1, 2, or 3; and
q is 0, 1, or 2.
28 . The compound of claim 27 , or a pharmaceutically acceptable salt or solvate thereof, wherein
R 2 is selected from a group consisting of C 3-8 cycloalkyl, C 2-9 heterocycle, C 6-10 aryl, C 1-9 heteroaryl, and a fused C 5-9 heteroaryl-cycloalkyl; wherein C 3-8 cycloalkyl, C 2-9 heterocycle, C 6-10 aryl, C 1-9 heteroaryl, and fused C 5-9 heteroaryl-cycloalkyl are optionally substituted with one, two, or three substituents selected from the group consisting of halo, —CN, C 1-6 alkyl, —C 1-6 alkyl-OH, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 2-9 heterocycle, C 6-10 aryl, C 1-9 heteroaryl, —C(═O)R 14 , —C(═O)OR 13 , —C(═O)N(R 13 ) 2 , —S(═O)R 14 , —S(═O) 2 R 13 , —S(═O) 2 —N(R 13 ) 2 , —N(R 13 ) 2 , —N(R 13 )C(═O)R 14 , and —N(R 13 )S(═O) 2 R 13 .
29 . The compound of claim 27 , or a pharmaceutically acceptable salt or solvate thereof, wherein
R 2 is selected from a group consisting of C 2-9 heterocycle and C 1-9 heteroaryl; wherein C 2-9 heterocycle and C 1-9 heteroaryl are optionally substituted with one, two, or three substituents selected from the group consisting of halo, —CN, C 1-6 alkyl, —C 1-6 alkyl-OH, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 2-9 heterocycle, C 6-10 aryl, C 1-9 heteroaryl, —C(═O)R 14 , —C(═O)OR 13 , —C(═O)N(R 13 ) 2 , —S(═O)R 14 , —S(═O) 2 R 13 , —S(═O) 2 —N(R 13 ) 2 , —N(R 13 ) 2 , —N(R 13 )C(═O)R 14 , and —N(R 13 )S(═O) 2 R 13 .
30 . The compound of claim 27 , or a pharmaceutically acceptable salt or solvate thereof, wherein
R 2 is selected from a group consisting of C 2-9 heterocycle and C 1-9 heteroaryl; wherein C 2-9 heterocycle and C 1-9 heteroaryl are optionally substituted with one or two substituents selected from the group consisting of halo, —CN, C 1-6 alkyl, —C 1-6 alkyl-OH, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 2-9 heterocycle, C 6-10 aryl, C 1-9 heteroaryl, —C(═O)R 14 , —C(═O)OR 13 , —C(═O)N(R 13 ) 2 , —S(═O)R 14 , —S(═O) 2 R 13 , —S(═O) 2 —N(R 13 ) 2 , —N(R 13 ) 2 , —N(R 13 )C(═O)R 14 , and —N(R 13 )S(═O) 2 R 13 .
31 . The compound of claim 27 , or a pharmaceutically acceptable salt or solvate thereof, wherein
R 2 is selected from a group consisting of pyrazole, imidazole, thiazole, and pyridine; wherein pyrazole, imidazole, thiazole, and pyridine are optionally substituted with one or two substituents selected from the group consisting of halo, —CN, C 1-6 alkyl, —C 1-6 alkyl-OH, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 2-9 heterocycle, C 6-10 aryl, C 1-9 heteroaryl, —C(═O)R 14 , —C(═O)OR 13 , —C(═O)N(R 13 ) 2 , —S(═O)R 14 , —S(═O) 2 R 13 , —S(═O) 2 —N(R 13 ) 2 , —N(R 13 ) 2 , —N(R 13 )C(═O)R 14 , and —N(R 13 )S(═O) 2 R 13 .
32 . The compound of claim 27 , or a pharmaceutically acceptable salt or solvate thereof, wherein
R 2 is selected from a group consisting of pyrazole, imidazole, thiazole, and pyridine; wherein pyrazole, imidazole, thiazole, and pyridine are optionally substituted with one or two substituents selected from the group consisting of halo, C 1-6 alkyl, and C 3-8 cycloalkyl.
33 . The compound of claim 32 , or a pharmaceutically acceptable salt or solvate thereof, wherein
R 2 is
wherein R 11 is C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl.
34 . The compound of claim 32 , or a pharmaceutically acceptable salt or solvate thereof, wherein
R 2 is
wherein each R 12 is independently halo, C 1 -C 6 alkyl, or C 3 -C 6 cycloalkyl; and
m is 1 or 2.
35 . The compound of claim 32 , or a pharmaceutically acceptable salt or solvate thereof, wherein
R 2 is selected from a group consisting of unsubstituted pyrazole, unsubstituted imidazole, unsubstituted thiazole, and unsubstituted pyridine.
36 . The compound of claim 27 , or a pharmaceutically acceptable salt or solvate thereof, wherein
R 2 is —C(═O)N(R 6 ) 2 and each R 6 is independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, —C 1 -C 6 alkyl-O—C 1 -C 6 alkyl, —C 1 -C 6 alkyl-C 2-9 heterocycle, —C 1 -C 6 alkyl-C 2-9 heteroaryl, C 3 -C 8 cycloalkyl, and C 2-9 heterocycle.
37 . The compound of claim 36 , or a pharmaceutically acceptable salt or solvate thereof wherein
R 2 is
38 . The compound of claim 36 , or a pharmaceutically acceptable salt or solvate thereof wherein
R 2 is
wherein R 10 is a heteroaryl.
39 . The compound of any one of the claims 27 - 38 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is hydrogen.
40 . The compound of any one of claims 27 - 38 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is C 1 -C 6 alkyl.
41 . The compound of claim 27 , or a pharmaceutically acceptable salt or solvate thereof, wherein
R 3 is selected from a group consisting of C 3-8 cycloalkyl, C 2-9 heterocycle, C 6-10 aryl, C 1-9 heteroaryl, and a fused C 5-9 heteroaryl-cycloalkyl; wherein C 3-8 cycloalkyl, C 2-9 heterocycle, C 6-10 aryl, C 1-9 heteroaryl, and fused C 5-9 heteroaryl-cycloalkyl, wherein C 3-8 cycloalkyl, C 2-9 heterocycle, C 6-10 aryl, C 1-9 heteroaryl, and fused C 5-9 heteroaryl-cycloalkyl are optionally substituted with one, two, or three substituents selected from the group consisting of halo, —CN, C 1-6 alkyl, —C 1-6 alkyl-OH, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 2-9 heterocycle, C 6-10 aryl, C 1-9 heteroaryl, —C(═O)R 14 , —C(═O)OR 13 , —C(═O)N(R 13 ) 2 , —S(═O)R 14 , —S(═O) 2 R 13 , —S(═O) 2 —N(R 13 ) 2 , —N(R 13 ) 2 , —N(R 13 )C(═O)R 14 , and —N(R 13 )S(═O) 2 R 13 .
42 . The compound of claim 27 , or a pharmaceutically acceptable salt or solvate thereof, wherein
R 3 is selected from a group consisting of C 2-9 heterocycle and C 1-9 heteroaryl; wherein C 2-9 heterocycle and C 1-9 heteroaryl are optionally substituted with one, two, or three substituents selected from the group consisting of halo, —CN, C 1-6 alkyl, —C 1-6 alkyl-OH, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 2-9 heterocycle, C 6-10 aryl, C 1-9 heteroaryl, —C(═O)R 14 , —C(═O)OR 13 , —C(═O)N(R 13 ) 2 , —S(═O)R 14 , —S(═O) 2 R 13 , —S(═O) 2 —N(R 13 ) 2 , —N(R 13 ) 2 , —N(R 13 )C(═O)R 14 , and —N(R 13 )S(═O) 2 R 13 .
43 . The compound of claim 27 , or a pharmaceutically acceptable salt or solvate thereof, wherein
R 3 is selected from a group consisting of C 2-9 heterocycle and C 1-9 heteroaryl; wherein C 2-9 heterocycle and C 1-9 heteroaryl are optionally substituted with one or two substituents selected from the group consisting of halo, —CN, C 1-6 alkyl, —C 1-6 alkyl-OH, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 2-9 heterocycle, C 6-10 aryl, C 1-9 heteroaryl, —C(═O)R 14 , —C(═O)OR 13 , —C(═O)N(R 13 ) 2 , —S(═O)R 14 , —S(═O) 2 R 13 , —S(═O) 2 —N(R 13 ) 2 , —N(R 13 ) 2 , —N(R 13 )C(═O)R 14 , and —N(R 13 )S(═O) 2 R 13 .
44 . The compound of claim 27 , or a pharmaceutically acceptable salt or solvate thereof, wherein
R 3 is selected from a group consisting of pyrazole, imidazole, thiazole, and pyridine; wherein pyrazole, imidazole, thiazole, and pyridine are optionally substituted with one or two substituents selected from the group consisting of halo, —CN, C 1-6 alkyl, —C 1-6 alkyl-OH, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 2-9 heterocycle, C 6-10 aryl, C 1-9 heteroaryl, —C(═O)R 14 , —C(═O)OR 13 , —C(═O)N(R 13 ) 2 , —S(═O)R 14 , —S(═O) 2 R 13 , —S(═O) 2 —N(R 13 ) 2 , —N(R 13 ) 2 , —N(R 13 )C(═O)R 14 , and —N(R 13 )S(═O) 2 R 13 .
45 . The compound of claim 27 , or a pharmaceutically acceptable salt or solvate thereof, wherein
R 3 is selected from a group consisting of pyrazole, imidazole, thiazole, and pyridine; wherein pyrazole, imidazole, thiazole, and pyridine are optionally substituted with one or two substituents selected from the group consisting of halo, C 1-6 alkyl, and C 3-8 cycloalkyl.
46 . The compound of claim 45 , or a pharmaceutically acceptable salt or solvate thereof, wherein
R 3 is
wherein R 11 is C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl.
47 . The compound of claim 43 , or a pharmaceutically acceptable salt or solvate thereof, wherein
R 3 is
wherein each R 12 is independently halo, C 1 -C 6 alkyl, or C 3 -C 6 cycloalkyl; and
m is 1 or 2.
48 . The compound of claim 43 , or a pharmaceutically acceptable salt or solvate thereof, wherein
R 3 is selected from a group consisting of unsubstituted pyrazole, unsubstituted imidazole, unsubstituted thiazole, and unsubstituted pyridine.
49 . The compound of claim 27 , or a pharmaceutically acceptable salt or solvate thereof, wherein
R 3 is —C(═O)N(R 6 ) 2 and each R 6 is independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, —C 1 -C 6 alkyl-O—C 1 -C 6 alkyl, —C 1 -C 6 alkyl-C 2-9 heterocycle, —C 1 -C 6 alkyl-C 2-9 heteroaryl, C 3 -C 8 cycloalkyl, and C 2-9 heterocycle.
50 . The compound of claim 49 , or a pharmaceutically acceptable salt or solvate thereof wherein
R 3 is
51 . The compound of claim 49 , or a pharmaceutically acceptable salt or solvate thereof wherein
R 3 is
wherein R 10 is a heteroaryl.
52 . The compound of claim 27 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is —OR 6 and R 6 is selected from the group consisting of C 1 -C 6 alkyl, —C 1 -C 6 alkyl-O—C 1 -C 6 alkyl, and —C 1 -C 6 alkyl-C 2-9 heterocycle.
53 . The compound of any one of claims 41 - 52 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is hydrogen.
54 . The compound of any one of claims 41 - 52 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is C 1 -C 6 alkyl.
55 . The compound of any one of claims 27 - 54 , or a pharmaceutically acceptable salt or solvate thereof, wherein
R 1 is selected from a group consisting of C 3-8 cycloalkyl, C 2-9 heterocycle, C 6-10 aryl, C 1-9 heteroaryl, and a fused C 5-9 heteroaryl-cycloalkyl; wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 2-9 heterocycle, C 6-10 aryl, C 1-9 heteroaryl, and fused C 5-9 heteroaryl-cycloalkyl are optionally substituted with one, two, or three substituents selected from the group consisting of halo, —CN, C 1-6 alkyl, —C 1-6 alkyl-OH, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 2-9 heterocycle, C 6-10 aryl, C 1-9 heteroaryl, —C(═O)R 14 , —C(═O)OR 13 , —C(═O)N(R 13 ) 2 , —S(═O)R 14 , —S(═O) 2 R 13 , —S(═O) 2 —N(R 13 ) 2 , —N(R 13 ) 2 , —N(R 13 )C(═O)R 14 , and —N(R 13 )S(═O) 2 R 13 .
56 . The compound of claim 55 , or a pharmaceutically acceptable salt or solvate thereof, wherein
R 1 is selected from a group consisting of a C 1-9 heteroaryl and a fused C 5-9 heteroaryl-cycloalkyl; wherein the C 1-9 heteroaryl and fused C 5-9 heteroaryl-cycloalkyl are optionally substituted with one, two, or three substituents selected from the group consisting of halo, —CN, C 1-6 alkyl, —C 1-6 alkyl-OH, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 2-9 heterocycle, C 6-10 aryl, C 1-9 heteroaryl, —C(═O)R 14 , —C(═O)OR 13 , —C(═O)N(R 13 ) 2 , —S(═O)R 14 , —S(═O) 2 R 13 , —S(═O) 2 —N(R 13 ) 2 , —N(R 13 ) 2 , —N(R 13 )C(═O)R 14 , and —N(R 13 )S(═O) 2 R 13 .
57 . The compound of claim 55 , or a pharmaceutically acceptable salt or solvate thereof, wherein
R 1 is selected from a group consisting of a C 1-9 heteroaryl and a fused C 5-9 heteroaryl-cycloalkyl; wherein the C 1-9 heteroaryl and fused C 5-9 heteroaryl-cycloalkyl are optionally substituted with one or two substituents selected from the group consisting of halo, —CN, C 1-6 alkyl, —C 1-6 alkyl-OH, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 2-9 heterocycle, C 6-10 aryl, C 1-9 heteroaryl, —C(═O)R 14 , —C(═O)OR 13 , —C(═O)N(R 13 ) 2 , —S(═O)R 14 , —S(═O) 2 R 13 , —S(═O) 2 —N(R 13 ) 2 , —N(R 13 ) 2 , —N(R 13 )C(═O)R 14 , and —N(R 13 )S(═O) 2 R 13 .
58 . The compound of claim 57 , or a pharmaceutically acceptable salt or solvate thereof, wherein
R 1 is selected from a group consisting of triazole, imidazole, oxazole, isoxazole, oxadiazole, and tetrazole; wherein triazole, imidazole, oxazole, isoxazole, oxadiazole, and tetrazole are optionally substituted with one or two substituents selected from the group consisting of halo, —CN, C 1-6 alkyl, —C 1-6 alkyl-OH, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 2-9 heterocycle, C 6-10 aryl, C 1-9 heteroaryl, —C(═O)R 14 , —C(═O)OR 13 , —C(═O)N(R 13 ) 2 , —S(═O)R 14 , —S(═O) 2 R 13 , —S(═O) 2 —N(R 13 ) 2 , —N(R 13 ) 2 , —N(R 13 )C(═O)R 14 , and —N(R 13 )S(═O) 2 R 13 .
59 . The compound of claim 58 , or a pharmaceutically acceptable salt or solvate thereof, wherein
R 1 is selected from a group consisting of triazole, imidazole, oxazole, isoxazole, oxadiazole, and tetrazole; wherein triazole, imidazole, oxazole, isoxazole, oxadiazole, and tetrazole are optionally substituted with one or two substituents selected from the group consisting of halo, C 1-6 alkyl, and C 3-8 cycloalkyl.
60 . The compound of claim 59 , or a pharmaceutically acceptable salt or solvate thereof, wherein
R 1 is
61 . The compound of claim 60 , or a pharmaceutically acceptable salt or solvate thereof, wherein
R 1 is
62 . The compound of claim 57 , or a pharmaceutically acceptable salt or solvate thereof, wherein
R 1 is
63 . The compound of any one of claims 1 - 62 , or a pharmaceutically acceptable salt or solvate thereof, wherein
is
64 . The compound of any one of claims 1 - 63 , or a pharmaceutically acceptable salt or solvate thereof, wherein p is 0.
65 . The compound of any one of claims 1 - 62 , or a pharmaceutically acceptable salt or solvate thereof, wherein
is
66 . The compound of any one of claims 1 - 62 , or a pharmaceutically acceptable salt or solvate thereof, wherein
is
67 . The compound of claims 65 or 66 , or a pharmaceutically acceptable salt or solvate thereof, wherein q is 0.
68 . The compound of any one of claims 1 - 67 , or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0.
69 . The compound of any one of claims 1 - 67 , or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1.
70 . The compound of any one of claims 1 - 67 , or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2.
71 . The compound of any one of claims 1 - 70 , or a pharmaceutically acceptable salt or solvate thereof, wherein Z is C(R 9 ) 2 .
72 . The compound of any one of claims 1 - 71 , or a pharmaceutically acceptable salt or solvate thereof, wherein each R 9 is H.
73 . The compound of claim 27 , or a pharmaceutically acceptable salt or solvate thereof, wherein the compound has one of the following structures:
74 . The compound of claim 1 , 2 , or 27 , or a pharmaceutically acceptable salt or solvate thereof, wherein the compound has one of the following structures:
75 . The compound of claim 1 , 2 , or 27 , or a pharmaceutically acceptable salt or solvate thereof, wherein the compound has one of the following structures:
76 . A pharmaceutical composition comprising a compound of any one of claims 1 - 75 , or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.
77 . A method of treating non-alcoholic steatohepatitis in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1 - 75 , or a pharmaceutically acceptable salt or solvate thereof.Join the waitlist — get patent alerts
Track US2021087167A1 — get alerts on status changes and closely related new filings.
We store only your email — no account needed. See our privacy policy.