# US 11,028,071 B2 · Indazole derivatives as alpha v integrin antagonists

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- Number: US 11,028,071 B2
- Document ID: US11028071B2
- Status: Granted
- Kind: B2
- Application number: 16/924,346
- Filed: 2020-07-09
- Published: 2020-10-29
- Granted: 2021-06-08
- Earliest claimed: 2016-11-08
- Assignees: Bristol-Myers Squibb Company
- Applicants: Bristol-Myers Squibb Company
- Inventors: Xiang-Yang Ye; Christian L. Morales; Mendi A. Higgins; Eric Mull
- Web page: https://patentgrep.com/patent/US11028071B2

## CPC

- C07D 401/14: containing three or more hetero rings
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 19/10: for osteoporosis
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 35/00: Antineoplastic agents
- A61P 37/02: Immunomodulators
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 471/04: Ortho-condensed systems
- C07D 498/04: Ortho-condensed systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## 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.

## Claims

### Claim 1

A compound of Formula (Ia) or (Ib):
wherein:
A, E, G, and J are independently N, C, or CH with the provisos that one of A, E, G, and J is N and one of A, E, G, and J is C attached to Y;
X is a C1-4 alkylene substituted with 0, 1, or 2 R8a;
Y is a covalent bond or O;
R1 is:
R2 is hydrogen, halo, or C1-6 alkyl;
R3 is hydrogen, C1-6 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 R6;
R3a is hydrogen;
R4 is hydrogen, C1-6 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)mR7, —C(O)NRaRb, —NHC(O)ORa, —NHC(O)NRaRb, —OC(O)NRaRb, —OC(O)R7, —NHS(O)mNRaRb, or —NHS(O)mR7; 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
L1 and L2 are each independently C1-4 alkylene;
R5a and R5b are each independently C1-6 alkyl, phenyl, benzyl, or 5- to 7-membered heterocyclyl; wherein the alkyl, phenyl, and heterocyclyl are each independently substituted with 0 to 3 R5′;
R5c is C1-6 alkyl or 5- to 7-membered carbocyclyl; wherein the C1-6 alkyl, 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;
R6 is halo, cyano, hydroxyl, amino, oxo, nitro, —S(O)mR12, C1-6 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 R10;
R7 is each independently C1-6 alkyl, C1-6 alkoxy, C1-6 aminoalkyl, C1-6 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 R11;
R9 is each independently halo, cyano, hydroxyl, amino, oxo, nitro, C1-6 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 R13;
R10 is halo, cyano, hydroxyl, amino, oxo, C1-6 alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxy, haloalkoxy, amido, carbamate, or sulfonamide;
R11, at each occurrence, is independently halo, cyano, hydroxyl, amino, oxo, C1-6 alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxy, or haloalkoxy;
R12 is —N(RxRy)C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, or C1-6 aminoalkyl;
R13 is halo, cyano, hydroxyl, amino, oxo, C1-6 alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxy, haloalkoxy, amido, carbamate, or sulfonamide;
Ra and Rb, at each occurrence, are independently hydrogen, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, cycloalkylalkyl, arylalkyl, heteroarylalkyl, or alkoxyalkyl; or alternatively, Ra and Rb, 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, C1-6 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, C1-6 alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxy, haloalkoxy, amido, carbamate, and sulfonamide;
Re is OH, amino, amido, carbamate, sulfonamide, C1-4 alkyl, halo, C1-4 haloalkyl, or C3-6 cycloalkyl;
Rx and Ry are each independently hydrogen or C1-6 alkyl;
m is an integer of 1 or 2;
r is an integer of 0, 1, 2, or 3; and
or a pharmaceutically acceptable salt thereof.

### Claim 2 (depends on 1)

The compound according to claim 1 having a structure selected from:

### Claim 3 (depends on 1)

The compound according to claim 1 having a structure selected from:

### Claim 4 (depends on 1)

The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein:
Y is a covalent bond or O;
X is a C1-3 alkylene;
R1 is:
R2 is hydrogen or methyl;
R3 is:
R4 is hydrogen; and
R5 is hydrogen.

### Claim 5 (depends on 1)

The compound of claim 1 or a pharmaceutically acceptable salt thereof, having a structure selected from:
wherein:
Y is a covalent bond or O;
X is a C1-3 alkylene;
R1 is:
R2 is hydrogen or methyl;
R3 is:
R4 is hydrogen; and
R5 is hydrogen.

### Claim 6 (depends on 5)

The compound of claim 5 or a pharmaceutically acceptable salt thereof, having the structure:

### Claim 7 (depends on 5)

The compound of claim 5 or a pharmaceutically acceptable salt thereof, having the structure:

### Claim 8 (depends on 1)

The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein said compound is:
3-(6-methoxypyridin-3-yl)-3-(5-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) ethoxy)pyrazolo[4,3-b]pyridin-1-yl)propanoic acid (11); or
3-(6-methoxypyridin-3-yl)-3-(5-(3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)propanoic acid (113).

### Claim 9 (depends on 1)

A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, and a carrier.

### Claim 10 (depends on 1)

A method of treating a disease, disorder, or condition selected from pathological fibrosis, transplant rejection, cancer, osteoporosis, and 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.

### Claim 11 (depends on 1)

The method of claim 1 wherein the pathological fibrosis is pulmonary, liver, renal, cardiac, dermal, ocular, or pancreatic fibrosis.

### Claim 12 (depends on 1)

The method of claim 1 wherein the disease, disorder, or condition is idiopathic pulmonary fibrosis (IPF), nonalcoholic steatohepatitis (NASH), chronic kidney disease, diabetic kidney disease, or systemic sclerosis.