Triazole n-linked carbamoyl cyclohexyl acids as LPA antagonists

Patent metadata

Field	Value
Publication number	US-11008300-B2
Application number	US-202016744303-A
Country	US
Kind code	B2
Filing date	Jan 16, 2020
Priority date	Dec 19, 2017
Publication date	May 18, 2021
Grant date	May 18, 2021

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 (IIa):

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 compound of Formula (IIIb):

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 2a is hydrogen, chloro, fluoro, or C 1-4 alkyl;
R 3 is hydrogen or C 1-6 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 6 is hydrogen, halo, cyano, hydroxyl, amino, C 1-6 alkyl, 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; and
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.

10. The compound according to claim 9 , wherein the

moiety is selected from

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

• C07D403/04

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

• C07D401/04 Primary

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

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P35/04

  specific for metastasis · CPC title

• A61P35/02

  specific for leukemia · CPC title