Cyclopentyl acids as LPA antagonists
The present invention provides compounds of 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. A compound of Formula (I):
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 6 or N; provided that no more than two of X 1 , X 2 , X 3 , or X 4 are N;
Q 1 , Q 2 , and Q 3 are independently N, O, NR 5a , or CR 5b , and the dashed circle denotes bonds forming an aromatic ring; provided that at least one of Q 1 , Q 2 , and Q 3 is not CR 5b ,
L is independently a covalent bond or C 1-4 alkylene substituted with 0 to 4 R 9 ;
W is independently O, —OCH 2 — or —CH 2 O—;
Y 1 is independently O or NR 7 ;
Y 2 is independently
Y 3 is independently OR 4 , NR 9 R 4 or
with the proviso that when Y 1 is O, then Y 3 is not OR 4 ;
Y 5 independently is O or NH;
alternatively, —Y 2 —Y 3 is R 4b ,
R 1 is independently cyano, —C(O)OR 11 , —C(O)NR 12a R 12b ,
R 2 is each independently halo, cyano, hydroxyl, amino, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 1-4 alkylamino, —(CH 2 ) 0-1 —(C 3-6 cycloalkyl), —(CH 2 ) 0-1 -phenyl, or C 1-6 alkyl substituted with 0 to 3 R c ;
R 3a is independently hydrogen, halo, hydroxyl, or C 1-4 alkyl;
R 3b is independently hydrogen, halo, cyano, hydroxyl, amino, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy or C 1-6 alkyl substituted with 0 to 2 R a ;
or alternatively, R 3a and R 3b together, with the carbon atom they are attached to, form a C 3-4 carbocyclyl;
R 4 is -L 1 -R 4a ;
L 1 is independently a covalent bond or C 1-4 alkylene substituted with 0 to 4 R 9 ;
R 4a is independently C 1-10 alkyl, C 1-10 haloalkyl, C 1-10 alkenyl, C 3-8 cycloalkyl, C 6-10 aryl, 3 to 8-membered heterocyclyl, 5 to 6-membered heteroaryl; wherein each of the alkyl, alkenyl, alkylene, cycloalkyl, aryl, heterocyclyl, and heteroaryl, by itself or as part of other moiety, is independently substituted with 0 to 3 R 10 ;
R 4b is independently C 1-10 alkyl, C 1-10 haloalkyl, C 1-10 alkenyl, C 3-8 cycloalkyl, C 6-10 aryl, 3 to 8-membered heterocyclyl, 5 to 6-membered heteroaryl; wherein each of the alkyl, alkenyl, alkylene, cycloalkyl, aryl, heterocyclyl, and heteroaryl, by itself or as part of other moiety, is independently substituted with 0 to 3 R 10a ;
R 5a is independently hydrogen, C 1-4 haloalkyl, —(CH 2 ) 0-1 —(C 3-6 cycloalkyl), (CH 2 ) 0-1 -phenyl, or C 1-6 alkyl substituted with 0 to 3 R a ;
R 5b is independently hydrogen, halo, cyano, hydroxyl, amino, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 1-4 alkylamino, —(CH 2 ) 0-1 —(C 3-6 cycloalkyl), —(CH 2 ) 0-1 -phenyl, or C 1-6 alkyl substituted with 0 to 3 R b ;
R 6 is each independently hydrogen, halo, cyano, hydroxyl, amino, C 1-4 alkylamino, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy or C 1-6 alkyl substituted with 0 to 1 R b ;
R 7 and R 8 are each independently hydrogen, C 1-6 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl or C 1-6 alkyl substituted with 0 to 1 R c ;
R 9 is each independently halo, oxo, cyano, hydroxyl, amino, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 3-6 cycloalkyl, or C 1-6 alkyl substituted with 0 to 3 R a ;
R 10 and R 10a are each independently halo, hydroxyl, amino, cyano, C 2-6 alkenyl, C 2-6 alkynyl, C 1-4 alkylamino, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, phenyl, or 5 to 6 membered heteroaryl, C 1-6 alkyl substituted with 0 to 3 R b ;
R 11 , R 12a and R 12b are each independently hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl or benzyl;
R a is independently halo, cyano, hydroxyl, C 1-4 alkoxy, C 1-4 haloalkyl, or C 1-4 haloalkoxy;
R b is independently halo, cyano, hydroxyl, amino, C 1-4 alkoxy, C 1-4 haloalkyl, or C 1-4 haloalkoxy;
R e is independently C 1-4 haloalkyl, C 3-6 cycloalkyl, or C 1-6 alkyl substituted with 0 to 3 R a ;
m is an integer of 0, 1, or 2; and
q is an integer of 0, 1, or 2.
2. The compound according to claim 1 , wherein:
the
moiety is independently
* denotes the attachment point to L; and
R 5a and R 5b are the same as defined in claim 1 .
3. The compound according to claim 2 , wherein:
the
moiety is independently —OR 4b , —NR 7 R 4b ,
4. The compound according to claim 3 , wherein L is a covalent bond or C 1-2 alkylene.
5. The compound according to claim 4 , wherein:
R 3a and R 3b are independently hydrogen or C 1-4 alkyl;
or alternatively, R 3a and R 3b together, with the carbon atom they are attached to, form C 3-4 cycloalkyl.
6. The compound according to claim 5 , wherein R 1 is CO 2 H.
7. The compound according to claim 6 , wherein:
X 1 , X 2 , X 3 , and X 4 are independently CR 6 ; or X 1 , X 2 and X 3 are CR 6 and X 4 is N; or X 2 and X 3 are CR 6 and X 1 and X 4 are N; or X 1 and X 2 are CR 6 and X 3 and X 4 are N; and R 6 is independently hydrogen, halo, hydroxyl, C 1-6 alkyl, C 1-4 haloalkyl, or C 1-4 alkoxy.
8. The compound according to claim 7 , wherein:
X 1 , X 2 , X 3 , and X 4 are independently CR 6 ; or X 1 , X 2 and X 3 are CR 6 and X 4 is N; or X 2 and X 3 are CR 6 and X 1 and X 4 are N;
the
moiety is independently
* denotes the attachment point to L;
L is independently a covalent bond or —CH 2 —;
W is independently O or —OCH 2 —;
the
moiety is independently —NR 7 R 4b ,
R 2 is each independently halo, cyano, hydroxyl, C 1-4 alkoxy, C 1-4 haloalkyl or C 1-4 haloalkoxy;
R 4 is independently C 3-6 alkyl, —(CH 2 ) 0-1 —C 3-6 cycloalkyl, —(CH (C 1-2 alkyl))-C 3-6 cycloalkyl, —(CH 2 ) 0-1 -phenyl or —(CH (C 1-2 alkyl))-phenyl, wherein each of said cycloalkyl and phenyl is independently substituted with 0 to 3 R 10 ;
R 4b is independently 5 to 6-membered heteroaryl substituted with 0 to 2 R 10a ;
R 5a is independently C 1-6 alkyl, or —(CH 2 ) 0-1 —(C 3-6 cycloalkyl);
R 5b is independently hydrogen, halo, cyano, hydroxyl, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, or —(CH 2 ) 0-1 —(C 3-6 cycloalkyl);
R 6 is each independently hydrogen, halo, hydroxyl, C 1-6 alkyl, C 1-4 haloalkyl, or C 1-4 alkoxy;
R 7 and R 8 are each independently hydrogen or C 1-2 alkyl;
R 10 is each independently halo, cyano, hydroxyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or C 1 -6 haloalkoxy;
R 10a is each independently halo, cyano, hydroxyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, —(CH 2 ) 0-3 —C 3-6 cycloalkyl, phenyl or 5 to 6 membered heteroaryl;
m is 0 or 1; and
q is 0 or 1.
9. The compound according to claim 8 , wherein:
the
moiety is independently
* denotes the attachment point to L;
L is independently a covalent bond or —CH 2 —;
W is independently O or —OCH 2 —;
the
moiety is independently —NR 7 R 4b ,
R 3a and R 3b are each independently hydrogen or C 1-4 alkyl;
or alternatively, R 3a and R 3b together, with the carbon atom they are attached to, form C 3-4 cycloalkyl;
R 4 is independently C 3-6 alkyl, —(CH 2 ) 0-1 —C 3-6 cycloalkyl, —(CH 2 )-phenyl, or —(CH(CH 3 ))-phenyl; wherein each of said alkyl, cycloalkyl and phenyl is independently substituted with 0 to 2 R 10 ;
R 4b is independently
R 6 is independently hydrogen, halo or C 1-4 alkyl;
R 7 and R 8 are each independently hydrogen or C 1-2 alkyl;
R 10 is each independently halo or C 1-4 alkyl; and
R 10a is independently C 1-4 alkyl, —(CH 2 ) 1-3 —C 3-6 cycloalkyl, phenyl or pyridyl.
10. A compound of Formula (II):
or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof,
wherein:
X 4 is CH or N;
the
moiety is independently
* denotes the attachment point to L;
L is independently a covalent bond or —CH 2 —;
W is independently O or —OCH 2 —;
the
moiety is independently-NR 7 R 4b ,
R 3a and R 3b are each independently hydrogen or methyl;
or alternatively, R 3a and R 3b together, with the carbon atom they are attached to, form cyclopropyl;
R 4 is independently C 3-6 alkyl, —(CH 2 ) 0-1 —C 3-6 cycloalkyl, —(CH 2 )-phenyl, or —(CH(CH 3 ))-phenyl;
R 4b is independently
R 6 is independently hydrogen, halo or C 1-4 alkyl;
R 7 and R 8 are each independently hydrogen or methyl;
R 10a is independently C 1-4 alkyl, phenyl or pyridyl; and
m is 0 or 1.
11. The compound according to claim 1 , which is selected from:
or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt or solvate thereof.
12. 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.
13. A method of treating a disease, disorder, or condition associated with dysregulation of lysophosphatidic acid receptor 1 (LPA 1 ) in a patient having the disease, disorder, or condition, comprising administering a therapeutically effective amount of a compound or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof according to claim 1 .
14. The method according to claim 13 , wherein the disease, disorder, or condition is related to pathological fibrosis, transplant rejection, cancer, osteoporosis, or inflammatory disorders.
15. The method according to claim 14 , wherein the pathological fibrosis is pulmonary, liver, renal, cardiac, dernal, ocular, or pancreatic fibrosis.
16. The method according to claim 13 , wherein the disease, disorder, or condition is idiopathic pulmonary fibrosis (IPF), non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), chronic kidney disease, diabetic kidney disease, and systemic sclerosis.
17. The method according to claim 14 , wherein the cancer is of the bladder, blood, bone, brain, breast, central nervous system, cervix, colon, endometrium, esophagus, gall bladder, genitalia, genitourinary tract, head, kidney, larynx, liver, lung, muscle tissue, neck, oral or nasal mucosa, ovary, pancreas, prostate, skin, spleen, small intestine, large intestine, stomach, testicle, or thyroid.
18. A method of treating fibrosis in a mammal having fibrosis, comprising administering a therapeutically effective amount of a compound or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof according to claim 1 .
19. The method according to claim 18 , wherein the fibrosis is idiopathic pulmonary fibrosis (IPF), nonalcoholic steatohepatitis (NASH), chronic kidney disease, diabetic kidney disease, and systemic sclerosis.
20. A method of treating a disease, disorder, or condition selected from: lung fibrosis, asthma, chronic obstructive pulmonary disease (COPD), renal fibrosis, acute kidney injury, chronic kidney disease, liver fibrosis, skin fibrosis, fibrosis of the gut, breast cancer, pancreatic cancer, ovarian cancer, prostate cancer, glioblastoma, bone cancer, colon cancer, bowel cancer, head and neck cancer, melanoma, multiple myeloma, chronic lymphocytic leukemia, cancer pain, tumor metastasis, transplant organ rejection, scleroderma, ocular fibrosis, age related macular degeneration (AMD), diabetic retinopathy, collagen vascular disease, atherosclerosis, Raynaud's phenomenon, or neuropathic pain in a mammal 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 , to the mammal.