Cyclobutanes- and azetidine-containing mono and spirocyclic compounds as αV integrin inhibitors

Patent metadata

Field	Value
Publication number	US-11639353-B2
Application number	US-202117212210-A
Country	US
Kind code	B2
Filing date	Mar 25, 2021
Priority date	Nov 8, 2016
Publication date	May 2, 2023
Grant date	May 2, 2023

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 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 is a covalent bond, —C(O)—, —O—, —O—C 1-3 alkyl-, —C(R a R b )—, —C(O)—N(R 6 )—, or —N(R 6 )—C(O)—;
E ring is:

L 1 and L 2 are each independently C 1-4 alkylene;
X is C 1-5 linear alkylene or phenylene substituted with 0, 1, 2, or 3 R 9 ;
Z is N or CH;
Y is a covalent bond, —C(O)—, —O—, —N(R 6 )—, —C(R a R b )—, —C(O)—N(R 6 )—, —N(R 6 )—C(O)—, —C(O)—C(R a R b )—, —C(R a R b )—O—, or —O—C(R a R b )—;
m is each independently an integer of 1 or 2;
n is each independently 0, 1, or 2;
r is an integer of 0, 1, 2, or 3;
w is each independently 0, 1, or 2;
R 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 each independently halo, oxo, C 1-4 alkyl, or C 1-4 alkoxy;
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, 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 10 ;
R 4 is hydrogen, halo, 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, NR c R d , OR h , S(O) m R 7 , C(O)NR c R d , NHC(O)OR h , NHC(O)NR c R d , NHC(O)R 7 , OC(O)NR c R d , OC(O)R 7 , NHS(O) m NR c R d , 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 17 ;
R 4a is hydrogen, halo, or C 1-6 alkyl;
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 5e is C 1-6 alkyl or 5- to 7-membered carbocyclyl; wherein the alkyl is 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 , at each occurrence, is hydrogen, C 1-6 alkyl, arylalkyl, heteroarylalkyl, —C(O)R 6a , or —C(O)OR 6a ;
R 6a is C 1-6 alkyl, aryl, or arylalkyl;
R 7 is C 1-6 alkyl, 3- to 10-membered carbocyclyl, carbocyclylalkyl, 4- to 10-membered heterocyclyl, heterocyclylalkyl, 6- to 10-membered aryl, arylalkyl, 5- to 10-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 12 ;
R 8 is each independently halo, oxo, C 1-4 alkyl, or C 1-4 alkoxy;
R 9 is halo, hydroxyl, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, 3- to 6-membered carbocyclyl, carbocyclylalkyl, 4- to 6-membered heterocyclyl, heterocyclylalkyl, 6- to 10-membered aryl, arylalkyl, 5- to 10-membered heteroaryl, or heteroarylalkyl; 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 each independently halo, hydroxyl, cyano, oxo, amino, S(O) m R 15 , C 1-6 alkyl, C 1-6 alkoxy, 3- to 6-membered carbocyclyl, 4- to 7-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, carbocyclyl, heterocyclyl, aryl, and heteroaryl are each independently substituted with 0, 1, 2, or 3 R 16 ;
R 11 is C 1-6 alkyl, 6- to 10-membered aryl, or 5- to 10-membered heterocyclyl, wherein the alkyl and aryl are each independently substituted with 0, 1, 2, or 3 R 13 ; and
R 12 , R 13 and R 14 are each independently halo, cyano, hydroxyl, amino, oxo, C 1-6 alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxy, haloalkoxy, amido, carbamate, or sulfonamide;
R 15 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 16 is each independently halo, cyano, hydroxyl, amino, oxo, C 1-6 alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxy, haloalkoxy, amido, carbamate, or sulfonamide;
R 17 is each independently halo, hydroxyl, cyano, oxo, amino, C 1-6 alkyl, C 1-6 alkoxy, 3- to 6-membered carbocyclyl, 4- to 7-membered heterocyclyl, 6- to 10-membered aryl, or 5-to 10-membered heteroaryl, wherein the alkyl, alkoxy, carbocyclyl, heterocyclyl, aryl, and heteroaryl are each independently substituted with 0, 1, 2, or 3 R 18 ;
R 18 is each independently 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 3-6 cycloalkyl, C 1-6 alkoxy, NHC(O)R 11 , NHS(O) m R 11 , halo, cyano, hydroxyl, amino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxy, haloalkoxy, amido, carbamate, or sulfonamide;
R c and R d , at each occurrence, are independently hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, aryl, heteroaryl, cycloalkylalkyl, arylalkyl, heteroarylalkyl, or alkoxyalkyl; 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, by itself or as part of another group, is 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 h , at each occurrence, is independently C 1-6 alkyl, C 3-6 cycloalkyl, cycloalkylalkyl, 6- to 10-membered aryl, arylalkyl, 5- to 10-membered heteroaryl, or heteroarylalkyl, wherein the alkyl, cycloalkyl, aryl, and heteroaryl, by themselves or as part of another group, are each independently substituted with 0, 1, 2, or 3 R 14 ;
R e is OH, 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 CH 3 , CH 2 CH 3 , CH 2 CCl 3 , phenyl, 4-fluorophenyl, 4-methoxyphenyl, benzyl,

Assignees

• Bristol Myers Squibb Co

Inventors

• Devasthale Pratik
• Moore Fang
• Zhao Guohua
• Pieniazek Susan Nicole
• Selvakumar Kumaravel
• Dhanusu Suresh
• Panda Manoranjan
• Marcin Lawrence R

Classifications

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• A61P11/00

  Drugs for disorders of the respiratory system · CPC title

• A61P13/12

  of the kidneys · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61P37/06

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