Indazole derivatives as αv integrin antagonists

Patent metadata

Field	Value
Publication number	US-10745384-B2
Application number	US-201716347831-A
Country	US
Kind code	B2
Filing date	Nov 7, 2017
Priority date	Nov 8, 2016
Publication date	Aug 18, 2020
Grant date	Aug 18, 2020

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 C or CH with the proviso that only one of A, E, G, and J is C attached to Y;
L 1 and L 2 are each independently C 1-4 alkylene;
X is a C 1-4 alkylene substituted with 0, 1, or 2 R 8a ;
Y is a covalent bond;
m is an integer of 1 or 2;
r is an integer of 0, 1, 2, or 3;
R 1 is an Arginine mimetic moiety selected from the group consisting of

wherein one of the asterisks in each of the arginine mimetics moiety is an attachment point to X and the other two asterisks are hydrogen;
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

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 R 5d ;
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 ; and
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 8a and R 8b , at each occurrence, are independently halo, cyano, hydroxyl, amino, oxo, C 1-6 alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxy, or haloalkoxy;
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 f is hydrogen, CH 3 , CH 2 CH 3 , or C(O)OCH 2 CH 3 ;
R g is selected from CH 3 , CH 2 CCl 3 , phenyl, 4-fluorophenyl, 4-methoxyphenyl, benzyl,

and
R x and R y are each independently hydrogen or C 1-6 alkyl;
or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (Ia) or Formula (Ib) is represented by structural Formula (IIa), Formula (IIb), Formula (IIc), or Formula (IId):

3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (Ia) or Formula (Ib) is represented by structural Formula (IIIa), Formula (IIIb), Formula (IIIc), or Formula (IIId):

4. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group consisting of

5. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 3 is hydrogen or a structural moiety selected from the group consisting of

Assignees

• Bristol Myers Squibb Co

Inventors

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

Classifications

• C07D498/04

  Ortho-condensed systems · CPC title

• C07D487/04

  Ortho-condensed systems · CPC title

• A61K31/5383

  ortho- or peri-condensed with heterocyclic ring systems · CPC title

• A61K31/5355

  Non-condensed oxazines and containing further heterocyclic rings · CPC title

• A61K31/4985

  Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems · CPC title