Triazole N-linked carbamoyl cyclohexyl acids as LPA antagonists

Patent metadata

Field	Value
Publication number	US-11697646-B2
Application number	US-202117224161-A
Country	US
Kind code	B2
Filing date	Apr 7, 2021
Priority date	Dec 19, 2017
Publication date	Jul 11, 2023
Grant date	Jul 11, 2023

Abstract

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.

First claim

What is claimed is:

1. A compound of Formula (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 6 or N; provided that no more than two of X 1 , X 2 , X 3 , or X 4 are N;
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, C 4-6 heterocyclyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxy, alkoxyalkyl, haloalkoxyalkyl, or haloalkoxy;
R 3 is independently hydrogen or C 1-4 alkyl;
R 4 is C 1-10 alkyl, C 3-8 cycloalkyl, 6 to 10-membered aryl, —(C 1-6 alkylene)-(C 3-8 cycloalkyl), or —(C 1-6 alkylene)-(6 to 10-membered aryl); wherein each of the alkyl, alkenyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl, by itself or as part of other moiety, is independently substituted with 0 to 3 R 8 ; or alternatively, R 3 and R 4 , taken together with the N and O to which they are attached, form a 4- to 6-membered heterocyclic ring moiety which is substituted with 0 to 3 R 8 ;
R 5 is hydrogen, C 1-6 alkyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy, or haloalkoxy;
R 6 is hydrogen, halo, cyano, hydroxyl, amino, C 1-6 alkyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy, or haloalkoxy;
R 7a is independently hydrogen, halo, oxo, cyano, hydroxyl, amino, C 1-6 alkyl, C 3-6 cycloalkyl, C 4-6 heterocyclyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy, or haloalkoxy;
R 8 is each independently deuterium, halo, hydroxyl, amino, cyano, C 1-6 alkyl, C 1-6 deuterated alkyl, C 2-6 alkenyl, C 2-6 alkynyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy, haloalkoxy, —CHO, phenyl, or 5 to 6 membered heteroaryl; or alternatively, two R 8 , taken together with the atoms to which they are attached, form a 3 to 6-membered carbocyclic ring or a 3 to 6-membered heterocyclic ring each of which is independently substituted with 0 to 3 R 12 ;
R 9 is selected from —CN, —C(O)OR 10 , —C(O)NR 11a R 11b ,

R e is C 1-6 alkyl, C 3-6 cycloalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, or haloalkoxyalkyl;
R 10 is hydrogen or C 1-10 alkyl;
R 11a and R 11b are each independently hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, C 4-6 heterocyclyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy, or haloalkoxy;
R 12 is halo, cyano, hydroxyl, amino, C 1-6 alkyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy, haloalkoxy, phenyl, or 5 to 6 membered heteroaryl;
f is an integer of 0, 1, or 2; and
n is 0 or 1.

2. The compound according to claim 1 , wherein R 1 is CO 2 H.

3. The compound according to claim 1 , wherein
R 4 is C 1-10 alkyl, C 1-10 haloalkyl, C 3-6 cycloalkyl, —(C 1-4 alkylene)-(C 3-6 cycloalkyl), —(C 1-4 alkylene)-(C 1-6 alkoxy), or —(C 1-4 alkylene)-phenyl; wherein each of the alkyl, alkylene, cycloalkyl, and phenyl, by itself or as part of another group, is independently substituted with 0 to 3 R 8 ; and
R 8 is each independently halo, hydroxyl, amino, cyano, C 1-6 alkyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy, or haloalkoxy; or alternatively, two R 8 , taken together with the atom(s) to which they are attached, form a 3 to 6-membered carbocyclic ring.

4. The compound according to claim 1 , wherein X 1 is CR 6 , where R 6 is hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, or C 1-4 alkoxyalkyl.

5. The compound according to claim 1 , wherein X 3 is N.

6. The compound according to claim 1 , wherein
the

moiety is selected from

R 6a 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.

7. The compound according to claim 6 , wherein
the

moiety is selected from

and
R 6 is each independently hydrogen, halo, cyano, hydroxyl, amino, C 1-6 alkyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy, or haloalkoxy.

8. The compound according to claim 1 , wherein f is 0 or 1.

9. 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.

10. 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.

11. 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.

12. 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.

13. A method of treating a disease, disorder, or condition associated with dysregulation of lysophosphatidic acid receptor 1 (LPA1) in a patient having the disease, disorder, or condition, comprising administering a therapeutically effective amount of a compound according to claim 1 , or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt or solvate thereof, to the patient.

14. The method according to claim 13 , wherein the disease, disorder, or condition is 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, dermal, ocular, or pancreatic fibrosis.

16. The method according to claim 14 , 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 according to claim 1 , or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt or solvate

Assignees

• Bristol Myers Squibb Co

Inventors

• Shi Yan
• Cheng Peter Tai Wah
• Wang Ying
• Shi Jun
• Tao Shiwei
• Li Jun
• Kennedy Lawrence J
• Kaltenbach Iii Robert F
• Zhang Hao
• Corte James R

Classifications

• A61P1/16

  for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics · CPC title

• A61P11/00

  Drugs for disorders of the respiratory system · CPC title

• A61P19/10

  for osteoporosis · CPC title

• C07C249/06

  by nitrosation of hydrocarbons or substituted hydrocarbons · CPC title

• C07D403/04

  directly linked by a ring-member-to-ring-member bond · CPC title