3-substituted propionic acids as αV integrin inhibitors

Patent metadata

Field	Value
Publication number	US-10968219-B2
Application number	US-201716347844-A
Country	US
Kind code	B2
Filing date	Nov 7, 2017
Priority date	Nov 8, 2016
Publication date	Apr 6, 2021
Grant date	Apr 6, 2021

Abstract

The present invention provides compounds of Formula (I): or stereoisomers, tautomers, or pharmaceutically acceptable salts or solvates thereof, wherein all the variables are as defined herein. These compounds are antagonists to α v -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 ay-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, O, S, NR 6a , CHR 6b or CR 6b ;
L 1 and L 2 are each independently C 1-4 alkylene;
M and L are independently N or C with the proviso that M and L are not both N;
wherein A, L, E, G, and L form a ring moiety selected from pyrazole, pyrrole, thiazole, imidazole, oxazole, and pyrrolidine;
X is a C 1-6 alkylene substituted with 0, 1, or 2 R 7b ;
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 ;
n 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

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, 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 8 ;
or R 2 and R 3 taken together with the atom to which they are attached form a carbocyclyl or a heterocyclyl, wherein 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 , 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 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, 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, form a carbocyclyl moiety;
R 6a is each independently hydrogen, C 1-6 alkyl, haloalkyl, alkoxy, amino, haloalkoxy, hydroxyalkyl, aminoalkyl, or C 3-5 cycloalkyl, wherein the cycloalkyl is substituted with 0, 1, 2, or 3 halo, cyano, nitro, amino, or OH;
R 6b is each independently hydrogen, halo, cyano, nitro, amino, OH, C 1-6 alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, aminoalkyl, or C 3-5 cycloalkyl, wherein the cycloalkyl is substituted with 0, 1, 2, or 3 halo, cyano, nitro, amino, or OH;
R 7a and R 7b are each independently halo, cyano, hydroxyl, amino, C 1-6 alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxy, haloalkoxy, amido, carbamate, or sulfonamide;
R 8 is each independently halo, cyano, oxo, nitro, OH, NR a R b , C 1-6 alkyl, alkoxy, alkylamino, haloalkyl, haloalkoxy, haloaminoalkyl, 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, NR a R b , C 1-6 alkyl, alkoxy, alkylamino, haloalkyl, haloalkoxy, haloaminoalkyl, 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 9 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 10 is C 1-6 alkyl, 3- to 10-membered carbocyclyl, 3- to 10-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl; wherein the alkyl, carbocyclyl, heterocyclyl are each independently substituted with 0, 1, 2, or 3 R 11 ;
R 11 is halo, cyano, nitro, OH, amino, C 1-6 alkyl, alkoxy, 3- to 10-membered carbocyclyl, 3- to 10-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl; wherein the aryl, alkyl, and heteroaryl are each independently substituted with 0, 1, 2, or 3 R 13 ;
R 12 , R 13 and R 14 , at each occurrence, are independently halo, cyano, nitro, OH, amino, C 1-6 alkyl, alkoxy, aminoalkyl, haloalkyl, haloalkoxy, haloaminoalkyl, 3 to 6 membered carbocyclyl, 3 to 6 membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl; 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 a and R b , at each occurrence, are independently hydrogen, C 1-10 alkyl, 3- to 10-membered carbocyclyl, or 3- to 10-membered heterocyclyl; wherein the alkyl, carbocyclyl, heterocyclyl are each independently substituted with 0, 1, 2, or 3 R 14 ;
R e is OH, C 1-4 alkyl, halo, haloalkyl, C 1-4 cycloalkyl, amino, amido, carbamate, or sulfonamide;
R f is hydrogen, CH 3 , CH 2 CH 3 , or COOCH 2 CH 3 ; and
R g is selected from CH 3 , CH 2 CH 3 , CH 2 CCl 3 , phenyl, 4-fluorophenyl, 4-methoxyphenyl, benzyl,

Assignees

• Bristol Myers Squibb Co

Inventors

• Zhao Guohua
• Devasthale Pratik
• Ye Xiang-Yang
• Selvakumar Kumaravel
• Dhanusu Suresh
• Balasubramanian Palanikumar
• Guernon Leatte R
• Civiello Rita
• Han Xiaojun
• Parker Michael Frederick
• Jacutin-Porte Swanee E

Classifications

• C07D519/00

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• C07D491/04

  Ortho-condensed systems · CPC title

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• A61K31/55

  having seven-membered rings, e.g. azelastine, pentylenetetrazole · CPC title

• A61K31/4375

  the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine · CPC title