Azole amides and amines as alpha v integrin inhibitors

Patent metadata

Field	Value
Publication number	US-10851098-B2
Application number	US-201716347829-A
Country	US
Kind code	B2
Filing date	Nov 7, 2017
Priority date	Nov 8, 2016
Publication date	Dec 1, 2020
Grant date	Dec 1, 2020

Abstract

The present invention provides compounds of Formula (I): (Formula (I)), or stereoisomers, tautomers, or pharmaceutically acceptable salts or solvates thereof, wherein all the variables are as defined herein. These compounds are inhibitors 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 (I):

wherein:
A, E, and G are independently N or CR 6 ;
L 1 and L 2 are each independently C 1-4 alkylene;
X is a C 1-6 alkylene substituted with 0, 1, or 2 R 7b ;
Y is C(O) or CH 2 ;
Z is a covalent bond, O, S, NH, —O—(C 1-3 alkylene)-, —S—(C 1-3 alkylene)-, or —NH—(C 1-3 alkylene)-, wherein the C 1-3 alkylene is each independently substituted with 0, 1, or 2 R 7a ;
g is an integer of 1 or 2;
n is an integer of 1 or 2;
r is an integer of 0, 1, 2, or 3;
t is an integer of 0, 1, 2, or 3;
R 1 is an Arginine mimetic moiety selected from the group consisting of

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 or C 1-6 alkyl;
R 3 is hydrogen, 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 8 ;
R 3X is hydrogen; or alternatively, R 3 and R 3X , together with the atom to which they are attached, form a carbocyclyl or a heterocyclyl, and the carbocyclyl and heterocyclyl are each independently substituted with 0, 1, 2, or 3 R 12 ;
R 4 is hydrogen, C 1-10 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, NR a R b , OH, OR a , S(O) n R 10 , C(O)NR a R b , NHC(O)OR a , NHC(O)NR a R b , NHC(O)R 10 , OC(O)NR a R b , OC(O)R 10 , NHS(O) n NR a R b , or NHS(O) n R 10 ; 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 15 ;
R 5 is H, R 5a , or a structural moiety selected from

R 5a and R 5b are each independently C 1-6 alkyl, phenyl, 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 alkyl and carbocyclyl 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, forma carbocyclyl moiety;
R 6 is hydrogen, C 1-6 alkyl, C 3-5 cycloalkyl, heteroalkyl, cycloheteroalkyl, aryl, or heteroaryl, wherein the alkyl, cycloalkyl, heteroalkyl, cycloheteroalkyl, aryl, and heteroaryl are each independently substituted with 0, 1, 2, or 3 R 9 ;
R 7a and R 7b are each independently halo, cyano, hydroxyl, oxo, NR a R b , C 1-6 alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxy, haloalkoxy, heteroalkyl, aryl, cycloalkyl, heteroaryl, cycloheteroalkyl, amido, carbamate, or sulfonamide; 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 cycloalkyl and cycloheteroalkyl, 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 8 at each occurrence is independently halo, cyano, nitro, OH, NR a R b , C 1-6 alkyl, alkoxy, alkylamino, haloalkyl, haloalkoxy, haloalkylamino, hydroxyalkyl, aminoalkyl, alkylsulfonyl, sulfonamide, 3 to 6 membered carbocyclyl, 3 to 6 membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl; or alternatively, two R 8 at adjacent positions, together with the atoms to which they are attached, form a carbocyclyl or heterocyclyl; 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 9 at each occurrence is independently halo, cyano, nitro, OH, alkoxy, NR a R b , C 1-6 alkyl, heteroalkyl, aryl, cycloalkyl, heteroaryl, or cycloheteroalkyl; 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 cycloalkyl and cycloheteroalkyl, 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 10 is C 1-6 alkyl, 3 to 10 membered carbocyclyl, or 3 to 10 membered heterocyclyl, wherein the alkyl, carbocyclyl, and heterocyclyl are each independently substituted with 0, 1, 2, or 3 R 11 ;
R 11 is halo, cyano, nitro, OH, alkoxy, NR a R b , alkyl, aryl, cycloalkyl, heteroaryl, cycloheteroalkyl, or S(O) g (aryl); wherein the aryl, alkyl, cycloalkyl, heteroaryl, and cycloheteroalkyl are each independently substituted with 0, 1, 2, or 3 R 13 ;
R 12 at each occurrence is independently halo, cyano, nitro, OH, alkoxy, NR a R b , alkyl, heteroalkyl, aryl, cycloalkyl, heteroaryl, or cycloheteroalkyl; or alternatively, two R 12 at adjacent positions, together with the atoms to which they are attached, form a carbocyclyl or heterocyclyl; 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 cycloalkyl and cycloheteroalkyl, 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 13 and R 14 , at each occurrence, are independently halo, cyano, nitro, OH, alkoxy, NR a R b , alkyl, heteroalkyl, aryl, cycloalkyl, heteroaryl, or cycloheteroalkyl; 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 cycloalky

Assignees

• Bristol Myers Squibb Co

Inventors

• Devasthale Pratik
• Wang Wei

Classifications

• C07D401/12

  linked by a chain containing hetero atoms as chain links · CPC title

• A61K31/437

  the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline · CPC title

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• A61P37/06

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

• A61P35/00 Primary

  Antineoplastic agents · CPC title