Cyclohexyl acid triazole azines as lpa antagonists

Patent metadata

Field	Value
Publication number	US-2021230143-A1
Application number	US-201816772825-A
Country	US
Kind code	A1
Filing date	Dec 18, 2018
Priority date	Dec 19, 2017
Publication date	Jul 29, 2021
Grant date	—

Abstract

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.

First claim

1 . A compound according to 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 5 or N; provided that no more than two of X 1 , X 2 , X 3 , or X 4 are N;
one of Q 1 , Q 2 , and Q 3 is NR 6 , and the other two are N; and the dashed circle denotes optional bonds forming an aromatic ring;
L is a covalent bond or C 1-4 alkylene substituted with 0 to 4 R 7 ;
Z is CHR 8a , NR 8b or O;
the Y ring is phenyl or an azine moiety;
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;
n is an integer of 0, 1, or 2;
R 3 is halo, cyano, hydroxyl, amino, oxo, —OR a , —SR a , ═S, —NR c R c , ═NH, ═N—OH, ═NR a , ═N—OR a , —NO 2 , —S(O) 2 R a , —S(O) 2 NHR b , —S(O) 2 NR c R c , —S(O) 2 OR b , —OS(O) 2 R b , —OS(O) 2 OR b , —P(O)(OR b )(OR b ), —C(O)R b , C(NR b )R b , —C(O)OR b , —C(O)NR c R c , —C(NR b )NR c R c , —OC(O)R b , —NR b C(O)R b , —OC(O)OR b , —NR b C(O)OR b , —OC(O)NR c R c , NR b C(O)NR c R c , —NR b C(NR b )R b , —NR b C(NR b )NR c R c , —NH—(C 1-3 alkylene)-O-(aryl), C 1-6 alkyl, C 1-6 deuterated alkyl, C 2-6 alkenyl, 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 the group consisting of 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;
R d is each independently selected from the group consisting of 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 , ═S, —NR c R c , —NH, ═N—OH, ═NR a , ═N—OR a , —NO 2 , —S(O) 2 R a , —S(O) 2 NHR b , —S(O) 2 NR c R c , —S(O) 2 OR b , —OS(O) 2 R b , —OS(O) 2 OR b , —P(O)(OR b )(OR b ), —C(O)R b , —C(NR b )R b , —C(O)OR b , —C(O)NR c R c , —C(N)NR c R c , —OC(O)R b , —NR b C(O)R b , —OC(O)OR b , —NR b C(O)OR b , —NR b C(O)NR c R c , —NR b C(NR b )R b , and —NR b C(NR b )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;
R 4 is each independently halo, cyano, hydroxyl, amino, C 1-6 alkyl, C 3-6 cycloalkyl,
4- to 6-membered heterocyclyl, 5 or 6-membered heteroaryl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxy, alkoxyalkyl, haloalkoxyalkyl, or haloalkoxy; or R 3 and R 4 , taken together with the atoms to which they are attached, form a monocyclic or bicyclic ring moiety;
m is an integer of 0, 1, or 2;
R 5 is hydrogen, halo, cyano, hydroxyl, amino, C 1-6 alkyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy, or haloalkoxy;
R 6 is hydrogen, C 1-6 alkyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy, or haloalkoxy;
R 7 is halo, oxo, cyano, hydroxyl, amino, C 1-6 alkyl, C 3-6 cycloalkyl, 4- to 6-membered heterocyclyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy, or haloalkoxy;
R 8a is hydrogen, halo, hydroxyl, cyano, or C 1-4 alkyl;
R 8b is hydrogen or C 1-4 alkyl;
R 9 is selected from the group consisting of —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; and
R 11a and R 11b 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.

2 . The compound according to claim 1 , wherein
the

moiety is

3 . The compound according to claim 2 , wherein
the

moiety is

Y 1 , Y 2 , Y 3 , and Y 4 are each independently N or CH with the proviso that at least one of Y 1 , Y 2 , Y 3 , and Y 4 is CH.

4 . The compound according to claim 3 , 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 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 the group consisting of 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 the group consisting of 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.

5 . The compound according to claim 1 , which is represented by Formula (IIa), (IIb), (IIc), or (IId):

Y 1 , Y 2 , Y 3 , and Y 4 are each independently N or CH;
R 7a is hydrogen, halo, oxo, cyano, hydroxyl, amino, C 1-6 alkyl, C 3-6 cycloalkyl, 4- to 6-membered

Assignees

• Bristol Myers Squibb Co

Inventors

• Shi Yan
• Wang Ying
• Cheng Peter Tai Wah
• Shi Jun
• Tao Shiwei
• Corte James R
• Fang Tianan
• Li Jun
• Kennedy Lawrence J
• Kaltenbach Iii Robert F
• Jusuf Sutjano

Classifications

• A61P35/00 Primary

  Antineoplastic agents · CPC title

• C07D401/14 Primary

  containing three or more hetero rings · CPC title

• C07D409/14

  containing three or more hetero rings · CPC title

• C07D403/14

  containing three or more hetero rings · CPC title

• A61K31/506

  not condensed and containing further heterocyclic rings · CPC title