WO 2018/089360 A1 - Pyrrole Amides As Alpha V Integrin Inhibitors - The Lens

Pyrrole Amides As Alpha V Integrin Inhibitors

Published: May 17, 2018
Earliest Priority: Nov 08 2016
Family: 10
Cited Works: 41
Cited by: 0
Cites: 13
Additional Info: Cited Works Full text

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 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.

Claims

A compound of Formula I)
wherein:
A is a covalent bond, O, S, NH, -0-(C1 3 alkylene)-, -S-CC^ alkylene)-, or
-NH-(C1_3 alkylene)-, wherein the Cj_3 alkylene is each independently substituted with 0,
1, or 2 R7a;
X is absent or a C1-5 linear alkylene substituted with 0, 1, 2, or 3 R7b; Y is C(O) or C(R6aR6b);
L1 and L2 are each independently C^ alkylene; n is an integer of 1 or 2; r is an integer of 0, 1, 2, or 3;
R1 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; R2 is hydrogen or Ο 6 alkyl;
R3 is hydrogen, C^g 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 R8;
R A is hydrogen; or alternatively, R A and R3, together with the atom or atoms to which they are attached, form a 3- to 6-membered carbocyclic or heterocyclic ring which is optionally substituted with one or more groups independently selected from halo, cyano, hydroxyl, amino, oxo, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxy, haloalkoxy, amido, carbamate, and sulfonamide;
R4 is hydrogen, C^Q 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, NRARB, ORA, S(0)NR10, C(0)NRARB, NHC(0)ORA, NHC(0)NRARB, NHC(0)R10, OC(0)NRARB, OC(0)R10, NHS(0)NNRARB, or NHS(0)NR10; 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 R9;
R5 is hydrogen, R5A, or a structural moiety selected from
R5A and R5B are each independently Ο 6 alkyl, phenyl, benzyl, or 5- to 7-membered heterocyclyl; wherein the alkyl, phenyl, and heterocyclyl are each independently substituted with 0 to 3 R5D;
R5C is alkyl or 5- to 7-membered carbocyclyl; wherein the alkyl, phenyl, and heterocyclyl are each independently substituted with 0 to 3 R5D; R5d, at each occurrence, is independently halo, OH, alkoxy, oxo, or alkyl; or alternatively, two adjacent R5d, together with the atoms to which they are attached, form a carbocyclyl moiety;
R6a and R6b are each independently hydrogen or Ci-6 alkyl;
R7a and are each independently halo, cyano, hydroxyl, amino, Ο 6 alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxy, haloalkoxy, amido, carbamate, or sulfonamide;
R8 is each independently halo, cyano, OH, NRaRb, C^g 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 R8 at adjacent positions, together with the atoms to which they are attached, form a carbocyclyl or heterocyclyl; wherein the aryl and heteroaryl are each independently substituted with one or more groups independently selected from halo, cyano, hydroxyl, amino, C^g alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxy, haloalkoxy, amido, carbamate, and sulfonamide; and the carbocyclyl and heterocyclyl are each independently substituted with one or more groups independently selected from halo, cyano, hydroxyl, amino, oxo, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxy, haloalkoxy, amido, carbamate, and sulfonamide;
R9 at each occurrence is independently halo, cyano, OH, NRaRb, C ^g 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 R9 at adj acent positions, together with the atoms to which they are attached, form a carbocyclyl or heterocyclyl; wherein the aryl and heteroaryl are each independently substituted with one or more groups independently selected from halo, cyano, hydroxyl, amino, C ^g alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxy, haloalkoxy, amido, carbamate, and sulfonamide; and the carbocyclyl and heterocyclyl are each independently substituted with one or more groups independently selected from halo, cyano, hydroxyl, amino, oxo, C^g alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxy, haloalkoxy, amido, carbamate, and sulfonamide;
R10 is Cy.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 R11;
R11 is halo, cyano, hydroxyl, amino, amino, amido, carbamate, sulfonamide, C^g 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, cycloalkyl, heteroaryl, and cycloheteroalkyl are each independently substituted with 0, 1, 2, or 3 R12;
R12 and R13, at each occurrence, are independently halo, cyano, OH, amino, Ο 6 alkyl, alkoxy, alkylamino, haloalkyl, haloalkoxy, haloaminoalkyl, 3 to 6 membered carbocyclyl, or 3 to 6 membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl; wherein wherein the aryl and heteroaryl are each independently substituted with one or more groups independently selected from halo, cyano, hydroxyl, amino, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxy, haloalkoxy, amido, carbamate, and sulfonamide; and the carbocyclyl and heterocyclyl are each independently substituted with one or more groups independently selected from halo, cyano, hydroxyl, amino, oxo, C^g alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxy, haloalkoxy, amido, carbamate, and sulfonamide;
Ra, Rb, and Rc, at each occurrence, are independently hydrogen, C^Q 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 R13;
Re is OH, amino, amido, carbamate, sulfonamide, Cj_4 alkyl, halo, C haloalkyl, or C3.6 cycloalkyl; Rf is H, CH3, CH2CH3, C(0)OCH2CH3; and g is CH3, CH2CH3, CH2CCI3, phenyl, 4-fluorophenyl, 4-methoxyphenyl, benzyl, or a pharmaceutically acceptable salt thereof,.
A compound of claim 1 wherein Y is C(O).
A compound claim 1 wherein X is C2-4 linear alkylene.
A compound of claim 1 wherein R1 is selected from a structural formula selected from the group consisting of
A compound of claim 1 wherein R4 is hydrogen and R3 is 3- to 10-membered carbocyclyl, 6- to 10-membered aryl, 3- to 14-membered heterocyclyl, 5- to 14- membered heteroaryl, wherein the carbocyclyl, heterocyclyl, aryl, and heteroaryl are each independently substituted with 0, 1 , 2, or 3 R8.
A compound of claim 5 wherein R3 is selected from the group consisting of hydrogen,
A compound of claim 1 wherein R3 is hydrogen and R4 is NRaRb, ORa, S(0)nR10, C(0)NRaRb, NHC(0)ORa, NHC(0)NRaRb, NHC(0)R10, OC(0)NRaRb, OC(0)R10, NHS(0)nNRaRb, or NHS(0)nR10.
A compound of claim 7 wherein R4 is selected from hydrogen and the following structural moieties:
A compound of claim 1 wherein R5 is H or R5a; and R5a is methyl, ethyl, isopropyl -butyl, isopentyl, or a structural moiety selected from
A compound of claim 1 wherein R2 is H; and R5 is H.
1 1. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
A method of treating pathological fibrosis, transplant rejection, cancer, osteoporosis, or inflammatory disorders comprising administering a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof, to a patient in need thereof.
The method of claim 12 wherein the pathological fibrosis is pulmonary, liver, renal, cardiac, dernal, ocular, or pancreatic fibrosis.
The method of claim 12 wherein the pathological fibrosis is idiopathic pulmonary fibrosis (IPF), nonalcoholic steatohepatitis (NASH), chronic kidney disease, diabetic kidney disease, or systemic sclerosis.
-I l l-
The method of claim 12 wherein the cancer is of the bladder, blood, bone, brain, breast, central nervous system, cervix, colon, endometrium, esophagus, gall bladder, genitalia, genitourinary tract, head, kidney, larynx, liver, lung, muscle tissue, neck, oral or nasal mucosa, ovary, pancreas, prostate, skin, spleen, small intestine, large intestine, stomach, testicle, or thyroid.