Indazole derivatives as alpha v integrin antagonists

Patent metadata

Field	Value
Publication number	US-11028071-B2
Application number	US-202016924346-A
Country	US
Kind code	B2
Filing date	Jul 9, 2020
Priority date	Nov 8, 2016
Publication date	Jun 8, 2021
Grant date	Jun 8, 2021

Abstract

The present invention provides compounds of Formula (Ia) or (Ib):or stereoisomers, tautomers, or pharmaceutically acceptable salts or solvates thereof, wherein all the variables are as defined herein. These compounds are antagonists to αV-containing integrins. This invention also relates to pharmaceutical compositions comprising these compounds and methods of treating a disease, disorder, or condition associated with dysregulation of αV-containing integrins, such as pathological fibrosis, transplant rejection, cancer, osteoporosis, and inflammatory disorders, by using the compounds and pharmaceutical compositions.

First claim

What is claimed is:

1. A compound of Formula (Ia) or (Ib):

wherein:
A, E, G, and J are independently N, C, or CH with the provisos that one of A, E, G, and J is N and one of A, E, G, and J is C attached to Y;
X is a C 1-4 alkylene substituted with 0, 1, or 2 R 8a ;
Y is a covalent bond or O;
R 1 is:

R 2 is hydrogen, halo, or C 1-6 alkyl;
R 3 is hydrogen, C 1-6 alkyl, 3- to 10-membered carbocyclyl, carbocyclylalkyl, 6- to 10-membered aryl, arylalkyl, 3- to 14-membered heterocyclyl, heterocyclylalkyl, 5- to 14-membered heteroaryl, or heteroarylalkyl, wherein the alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl, by themselves or as part of another group, are each independently substituted with 0, 1, 2, or 3 R 6 ;
R 3a is hydrogen;
R 4 is hydrogen, C 1-6 alkyl, 3- to 10-membered carbocyclyl, carbocyclylalkyl, 3- to 10-membered heterocyclyl, heterocyclylalkyl, 6- to 10-membered aryl, arylalkyl, 5- to 14-membered heteroaryl, heteroarylalkyl, —S(O) m R 7 , —C(O)NR a R b , —NHC(O)OR a , —NHC(O)NR a R b , —OC(O)NR a R b , —OC(O)R 7 , —NHS(O) m NR a R b , or —NHS(O) m R 7 ; wherein the alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl, by themselves or as part of another group, are each independently substituted with 0, 1, 2, or 3 R 9 ;
R 5 is hydrogen, R 5a , or a structural moiety selected from

L 1 and L 2 are each independently C 1-4 alkylene;
R 5a and R 5b are each independently C 1-6 alkyl, phenyl, benzyl, or 5- to 7-membered heterocyclyl; wherein the alkyl, phenyl, and heterocyclyl are each independently substituted with 0 to 3 R5′;
R 5c is C 1-6 alkyl or 5- to 7-membered carbocyclyl; wherein the C 1-6 alkyl, and heterocyclyl are each independently substituted with 0 to 3 R 5d ;
R 5d , at each occurrence, is independently halo, OH, alkoxy, oxo, or alkyl; or alternatively, two adjacent R 5d , together with the atoms to which they are attached, form a carbocyclyl moiety;
R 6 is halo, cyano, hydroxyl, amino, oxo, nitro, —S(O) m R 12 , C 1-6 alkyl, alkoxy, haloalkyl, haloalkoxy, haloaminoalkyl, hydroxyalkyl, aminoalkyl, alkoxycarbonyl, 6- to 10-membered aryl, aryloxy, arylalkoxy, 5- to 10-membered heteroaryl, 3- to 6-membered carbocyclyl, or 3- to 7-membered heterocyclyl; wherein the alkyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl, by themselves or as part of another group, are each independently substituted with 0, 1, or 2 R 10 ;
R 7 is each independently C 1-6 alkyl, C 1-6 alkoxy, C 1-6 aminoalkyl, C 1-6 haloalkyl, 6- to 10-membered aryl, arylalkyl, 5- to 10-membered heteroaryl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, by themselves or as part of another group, are each independently substituted with 0, 1, 2, or 3 R 11 ;
R 9 is each independently halo, cyano, hydroxyl, amino, oxo, nitro, C 1-6 alkyl, alkoxy, haloalkyl, haloalkoxy, haloaminoalkyl, hydroxyalkyl, aminoalkyl, alkoxycarbonyl, 6- to 10-membered aryl, aryloxy, arylalkoxy, 5- to 10-membered heteroaryl, 3- to 6-membered carbocyclyl, or 3- to 7-membered heterocyclyl; wherein the alkyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl, by themselves or as part of another group, are each independently substituted with 0, 1, or 2 R 13 ;
R 10 is halo, cyano, hydroxyl, amino, oxo, C 1-6 alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxy, haloalkoxy, amido, carbamate, or sulfonamide;
R 11 , at each occurrence, is independently halo, cyano, hydroxyl, amino, oxo, C 1-6 alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxy, or haloalkoxy;
R 12 is —N(R x R y )C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, or C 1-6 aminoalkyl;
R 13 is halo, cyano, hydroxyl, amino, oxo, C 1-6 alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxy, haloalkoxy, amido, carbamate, or sulfonamide;
R a and R b , at each occurrence, are independently hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, cycloalkylalkyl, arylalkyl, heteroarylalkyl, or alkoxyalkyl; or alternatively, R a and R b , taken together with the atoms to which they are attached, form a 3- to 8-membered carbocyclic or heterocyclic ring; wherein the aryl and heteroaryl, by themselves or as part of another group, are each independently substituted with one or more groups independently selected from halo, cyano, hydroxyl, amino, C 1-6 alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxy, haloalkoxy, amido, carbamate, and sulfonamide; and the carbocyclyl and heterocyclyl, by themselves or as part of another group, are each independently substituted with one or more groups independently selected from halo, cyano, hydroxyl, amino, oxo, C 1-6 alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxy, haloalkoxy, amido, carbamate, and sulfonamide;
R e is OH, amino, amido, carbamate, sulfonamide, C 1-4 alkyl, halo, C 1-4 haloalkyl, or C 3-6 cycloalkyl;
R x and R y are each independently hydrogen or C 1-6 alkyl;
m is an integer of 1 or 2;
r is an integer of 0, 1, 2, or 3; and
or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1 having a structure selected from:

3. The compound according to claim 1 having a structure selected from:

4. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein:
Y is a covalent bond or O;
X is a C 1-3 alkylene;
R 1 is:

R 2 is hydrogen or methyl;
R 3 is:

R 4 is hydrogen; and
R 5 is hydrogen.

5. The compound of claim 1 or a pharmaceutically acceptable salt thereof, having a structure selected from:

wherein:
Y is a covalent bond or O;
X is a C 1-3 alkylene;
R 1 is:

R 2 is hydrogen or methyl;
R 3 is:

R 4 is hydrogen; and
R 5 is hydrogen.

6. The compound of claim 5 or a pharmaceutically acceptable salt thereof, having the structure:

7. The compound of claim 5 or a pharmaceutically acceptable salt thereof, having the structure:

8. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein said compound is:
3-(6-methoxypyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) ethoxy)pyrazolo[4,3-b]pyridin-1-yl)propanoic acid (11); or
3-(6-methoxypyridin-3-yl)-3-(5-(3-(5,6,7

Assignees

• Bristol Myers Squibb Co

Inventors

• Ye Xiang-Yang
• Morales Christian L
• Higgins Mendi A
• Mull Eric

Classifications

• A61P11/00

  Drugs for disorders of the respiratory system · CPC title

• A61P37/06

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

• A61P19/10

  for osteoporosis · CPC title

• C07D498/04

  Ortho-condensed systems · CPC title

• A61K31/498

  Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine · CPC title