Cyclohexyl acid triazole azoles as LPA antagonists
The present invention provides compounds of Formula (I): Formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof, wherein all the variables are as defined herein. These compounds are selective LPA receptor inhibitors.
1. The compound of Formula (IIa) or (IIb):
or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof, wherein X 1 , X 2 , X 3 , and X 4 are each independently CR 5 or N; provided that no more than two of X 1 , X 2 , X 3 , or X 4 are N;
the moiety is
the moiety is
R 1 is (—CH 2 ) a R 9 ;
a is an integer of 0 or 1;
R 2 is each independently halo, cyano, hydroxyl, amino, C 1-6 alkyl, C 3-6 cycloalkyl, 4- to 6-membered heterocyclyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxy, alkoxyalkyl, haloalkoxyalkyl, or haloalkoxy;
R 3 is halo, cyano, hydroxyl, amino, —OR a , —SR a , —NR c R c , C 1-6 alkyl, C 1-6 heteroalkyl, 6- to 10-membered aryl, arylalkyl, 5- to 10-membered heteroaryl, heteroarylalkyl, 3- to 8-membered carbocyclyl, carbocyclylalkyl, 4- to 8-membered heterocyclyl, or heterocyclylalkyl; wherein the alkyl, heteroalkyl, aryl, heteroaryl, carbocyclyl, heterocyclyl, and R a , by themselves or as part of another group, are each independently substituted with 0 to 5 R d ;
R 4 is methyl, Cl, or F;
R 5 is hydrogen, halo, cyano, hydroxyl, amino, C 1-6 alkyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy, or haloalkoxy;
R 7a is each independently hydrogen, halo, cyano, hydroxyl, amino, C 1-6 alkyl, C 3-6 cycloalkyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy, or haloalkoxy;
f is an integer of 0, 1, or 2;
Z is CH 2 or NR 8b ; with the proviso that when Z is NR 8b , Y 1 is C;
n is 0 or 1;
R 6 is C 1-4 alkyl;
R 8b is hydrogen or C 1-4 alkyl;
R 9 is selected from —CN, —C(O)OR 10 , —C(O)NR 11a R 11b ,
R e is C 1-6 alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, or haloalkoxyalkyl;
R 10 is hydrogen or C 1-10 alkyl;
R 11a and R 1lb are each independently hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, 4- to 6-membered heterocyclyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy, or haloalkoxy;
R a is selected from C 1-6 alkyl, C 1-6 deuterated alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, carbocyclyl, carbocyclylalkyl, heterocyclyl, and heterocyclylalkyl;
R b is each independently hydrogen or R a ;
R c is each independently R b ; or alternatively, two R c , taken together with the nitrogen atom to which they are attached, form a 4- to 7-membered heterocyclyl; and
R d is each independently selected from R a , alkoxy, haloalkoxy, alkylamino, cycloalkylamino, heterocyclylamino, haloalkyl, hydroxyalkyl, aminoalkyl, cycloalkoxy, heterocyclyloxy, haloalkoxy, alkoxyalkoxy, haloalkylamino, alkoxyalkylamino, haloalkoxyalkylamino, arylamino, aralkylamino, aryloxy, aralkyloxy, heteroaryloxy, heteroarylalkyloxy, alkylthio, halo, cyano, hydroxyl, amino, oxo, —OR a , —SR a , —NR c R c ; or alternatively one or two R d on alkyl, heteroalkyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl, taken together with the atoms to which the R d is attached, form a cyclic or bridge moiety.
2. The compound according to claim 1 , wherein X 1 is CR 5 , where R 5 is hydrogen or C 1-4 alkyl.
3. The compound according to claim 2 , wherein X 3 is N.
4. The compound according to claim 2 , wherein
the moiety is selected from
R 5a is each independently halo, cyano, hydroxyl, amino, C 1-6 alkyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy, or haloalkoxy; and
d is an integer of 0, 1, or 2.
5. The compound according to claim 4 , wherein
the moiety is
6. The compound according to claim 5 , wherein R 7a is hydrogen.
7. The compound according to claim 6 , wherein R 1 is CO 2 H.
8. The compound according to claim 1 , which is represented by Formula (IIa) or (IIIb):
Y 1 and Y 3a are each independently selected from C or N;
Y 2 , Y 4 , and Y 5 are each independently selected from C, CR 4a , N, S, or O; with the proviso that at least one of Y 1 , Y 2 , Y 3a , Y 4 , and Y 5 is N or NR 4b ; and the dashed circle denotes optional bonds forming an aromatic ring;
R 2a is hydrogen, chloro, fluoro, or C 1-4 alkyl;
R 4a is each independently hydrogen, halo, hydroxyl, cyano, —C(O)NH 2 , —C(O)NHR, C(O)OR, C 1-4 alkyl, C 1-4 haloalkyl, C 2-6 alkoxyalkyl, or C 1-4 alkoxy;
R 4b is each independently hydrogen or C 1-4 alkyl;
R 5 is hydrogen or C 1-4 alkyl; and
R 6 is C 1-4 alkyl.
9. The compound according to claim 8 , wherein the
moiety is selected from
10. The compound according to claim 9 , wherein R 1 is CO 2 H.
11. The compound according to claim 10 , wherein
the moiety is
and
R 5 is hydrogen, methyl, or ethyl.
12. The compound according to claim 1 , wherein
the moiety is
13. The compound according to claim 12 , wherein
R 3 is halo, cyano, hydroxyl, amino, —OR a , —SR a , —NR c R c , C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 heteroalkyl, 6- to 10-membered aryl, arylalkyl, 5- to 10-membered heteroaryl, heteroarylalkyl, 3- to 8-membered carbocyclyl, carbocyclylalkyl, 4- to 8-membered heterocyclyl, or heterocyclylalkyl; wherein the alkyl, heteroalkyl, aryl, heteroaryl, carbocyclyl, heterocyclyl, and R a , by themselves or as part of another group, are each independently substituted with 0 to 5 R d ;
R a is selected from C 1-6 alkyl, C 1-6 deuterated alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, carbocyclyl, carbocyclylalkyl, heterocyclyl, and heterocyclylalkyl;
R b is each independently hydrogen or R a ;
R c is each independently R b ; or alternatively, two R c , taken together with the nitrogen atom to which they are attached, form a 4- to 7-membered heterocyclyl; and
R d is each independently selected from R a , alkoxy, haloalkoxy, alkylamino, cycloalkylamino, heterocyclylamino, haloalkyl, hydroxyalkyl, aminoalkyl, cycloalkoxy, heterocyclyloxy, haloalkoxy, alkoxyalkoxy, haloalkylamino, alkoxyalkylamino, haloalkoxyalkylamino, arylamino, aralkylamino, aryloxy, aralkyloxy, heteroaryloxy, heteroarylalkyloxy, alkylthio, halo, cyano, hydroxyl, amino, oxo, —OR a , —SR a , and —NR c R c ; or alternatively one or two R d on alkyl, heteroalkyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl, taken together with the atoms to which the R d is attached, form a cyclic or bridge moiety.
14. The compound according to claim 13 , wherein
R 3 is C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, —S-(C 1-6 alkyl), C 3-6 cycloalkyl, 4- to 6-membered heterocyclyl, phenyl,
(a 5 or 6-membered heteroaryl containing 1 to 3 heteroatoms each of which is independently selected from N, O, and S), -(C 1-3 alkylene)-(C 3-6 cycloalkyl),
-(C 1-3 alkylene)-(phenyl), -(C 1-3 alkylene)-(4 to 6-membered heterocyclyl),
—O-(C 3-6 cycloalkyl), —O-(4 to 6-membered heterocyclyl), —O-phenyl, —O-(5 or 6-membered heteroaryl containing 1 to 3 heteroatoms each of which is independently selected from N, O, and S), —O-(C 1-3 alkylene)-(phenyl),
—O-(C 1-3 alkylene)-(C 3-6 cycloalkyl), —NH-(C 1-3 alkylene)-(phenyl),
—NH-(C 1-6 alkyl), —NH-(C 1-6 haloalkyl), —NH-phenyl, —NH-(C 3-6 cycloalkyl),
—NH-(C 1-3 alkylene)-(C 3-6 cycloalkyl), and —N(C 1-6 alkyl) 2 ; and the alkyl, alkylene, cycloalkyl, phenyl, heterocyclyl, and heteroaryl, by themselves or as part of another group, are each independently substituted with 0 to 3 R d ; and
R d is halo, cyano, hydroxyl, amino, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, or 4- to 6-membered heterocyclyl;
R 4a is hydrogen, fluoro, chloro, C 1-4 alkyl, C 1-4 haloalkyl, C 2-6 alkoxyalkyl, or C 1-4 alkoxy; and
R 4b is hydrogen.
15. A pharmaceutical composition comprising one or more compounds according to claim 1 , or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof; and a pharmaceutically acceptable carrier or diluent.
16. A method of relieving the disease-state and/or reducing the risk of a disease, disorder, or condition selected from idiopathic pulmonary fibrosis (IPF), non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), chronic kidney disease, diabetic kidney disease, and systemic sclerosis, in a patient having the disease, disorder, or condition, comprising administering a therapeutically effective amount of a compound or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt or solvate thereof according to claim 1 .
17. A pharmaceutical composition comprising one or more compounds according to claim 1 , or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof; and a pharmaceutically acceptable carrier or diluent.
18. A pharmaceutical composition comprising one or more compounds according to claim 2 , or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof; and a pharmaceutically acceptable carrier or diluent.
19. A pharmaceutical composition comprising one or more compounds according to claim 3 , or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof; and a pharmaceutically acceptable carrier or diluent.
20. A pharmaceutical composition comprising one or more compounds according to claim 4 , or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof; and a pharmaceutically acceptable carrier or diluent.
21. A pharmaceutical composition comprising one or more compounds according to claim 5 , or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof; and a pharmaceutically acceptable carrier or diluent.
22. A pharmaceutical composition comprising one or more compounds according to claim 6 , or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof; and a pharmaceutically acceptable carrier or diluent.
23. A pharmaceutical composition comprising one or more compounds according to claim 7 , or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof; and a pharmaceutically acceptable carrier or diluent.
24. A pharmaceutical composition comprising one or more compounds according to claim 8 , or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof; and a pharmaceutically acceptable carrier or diluent.
25. A pharmaceutical composition comprising one or more compounds according to claim 9 , or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof; and a pharmaceutically acceptable carrier or diluent.
26. A pharmaceutical composition comprising one or more compounds according to claim 10 , or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof; and a pharmaceutically acceptable carrier or diluent.
27. A pharmaceutical composition comprising one or more compounds according to claim 11 , or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof; and a pharmaceutically acceptable carrier or diluent.
28. A pharmaceutical composition comprising one or more compounds according to claim 12 , or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof; and a pharmaceutically acceptable carrier or diluent.
29. A pharmaceutical composition comprising one or more compounds according to claim 13 , or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof; and a pharmaceutically acceptable carrier or diluent.
30. A pharmaceutical composition comprising one or more compounds according to claim 14 , or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof; and a pharmaceutically acceptable carrier or diluent.