# US 12,110,290 B2 · Triazolopyridinyl compounds as kinase inhibitors

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- Number: US 12,110,290 B2
- Document ID: US12110290B2
- Status: Granted
- Kind: B2
- Application number: 18/347,703
- Filed: 2023-07-06
- Published: 2024-04-04
- Granted: 2024-10-08
- Earliest claimed: 2020-10-19
- Assignees: Bristol-Myers Squibb Company
- Applicants: Bristol-Myers Squibb Company
- Inventors: Guanglin Luo; Jie Chen; Carolyn Diane Dzierba; David B. Frennesson; Junqing Guo; Amy C. Hart; Xirui Hu; Michael E. Mertzman; Matthew Reiser Patton; Jianliang Shi; Steven H. Spergel; Brian Lee Venables; Yong-Jin Wu; Zili Xiao; Michael G. Yang
- Web page: https://patentgrep.com/patent/US12110290B2

## CPC

- C07D 471/04: Ortho-condensed systems
- A61P 9/04: Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
- A61P 17/06: Antipsoriatics
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Compounds having formula (I), and enantiomers, and diastereomers, stereoisomers, pharmaceutically-acceptable salts thereof, are useful as kinase modulators, including RIPK1 modulation. All the variables are as defined herein.

## Claims

### Claim 1

A compound having formula (I), or salt thereof,
wherein
R1 is H, C1-3 alkyl, C1-3 alkoxy, C1-3 haloalkyl, C1-3 haloalkoxy, C1-3 deuteroalkyl, C1-3 deuteroalkoxy, halo, or cyclopropyl;
R2 is H, or halo;
R3 is H, halo, C1-3 alkyl or C1-3 deuteroalkyl;
R4 is H or F;
R5a and R5b are each H;
one of R6a and R6b is H and the other is F;
R7a and R7b are each, independently, H, deuterium, OH, F, C1-2 alkyl, or C1-2 haloalkyl;
R8 is H, F, Cl, C1-3 alkyl, C1-3 alkoxy, C1-3 deuteroalkyl, or C1-3 deuteroalkoxy;
R9 is H or CH3;
ring Z is phenyl;
Y is F, Cl, C1-3 alkyl, C1-3 alkoxy, CN, C1-3 haloalkyl, C1-3 haloalkoxy, C1-3 deuteroalkyl, C1-3 deuteroalkoxy, C(O)OCH3, or C═CH; and
n is 0, 1, 2, or 3.

### Claim 2 (depends on 1)

A compound of claim 1, wherein the compound has formula (II), or salt thereof,
wherein
R1 is H, C1-3 alkyl, C1-3 alkoxy, C1-3 haloalkyl, C1-3 deuteroalkyl, halo, or cyclopropyl;
R2 is H, or halo;
R3 is H, halo, C1-3 alkyl, or C1-3 deuteroalkyl;
R4 is H or F;
R5a and R5b are each H;
one of R6a and R6b is H and the other is F;
R7a and R7b are each, independently, H, deuterium, OH, F, C1-2 alkyl or C1-2 haloalkyl;
ring Z is phenyl;
Y is F, Cl, C1-3 alkyl, C1-3 alkoxy, CN, or C1-3 haloalkyl;
n is 0, 1, or 2.

### Claim 3 (depends on 2)

A compound of claim 2, or salt thereof, wherein
R1 is H, C1-2 alkyl, C1-2 alkoxy, CD3, halo, or cyclopropyl;
R2 is H, or halo;
R3 is H, halo, or C1-2 alkyl;
R4 is H or F;
R5a and R5b are each H;
one R6a and R6b is H and the other is F;
R7a and R7b are each, independently, H, deuterium, OH, F, C1-2 alkyl or C1-2 haloalkyl;
Y is F, Cl, C1-2 alkyl, C1-2 alkoxy, CN, or C1-2 haloalkyl; and
n is 0, 1, or 2.

### Claim 4 (depends on 2)

A compound of claim 2, or salt thereof, wherein
R1 is C1-2 alkyl, C1-2 deuteroalkyl, C1-2 haloalkyl, or halo;
R2 is H, or halo;
R3 is H, halo, or C1-2 alkyl;
R4 is H or F;
R5a and R5b are each H;
one of R6a and R6b is H and the other is F;
R7a and R7b are each, independently, H, deuterium, OH, F, C1-2 alkyl or C1-2 haloalkyl;
Y is F, Cl, C1-2 alkyl, CN, or C1-2 haloalkyl; and
n is 0, 1, or 2.

### Claim 5 (depends on 3)

A compound of claim 3, or salt thereof, wherein
R1 is Cl or CH3;
R2 is H, or F;
R3 is H, or F;
R4 is H;
R5a and R5b are each H;
R6a and R6b are each, independently, H, or F;
R7a and R7b are each, independently, H, methyl, or OH;
Y is F or Cl; and
n is 0, 1, or 2.

### Claim 6 (depends on 3)

A compound of claim 3, or salt thereof,
wherein

### Claim 7 (depends on 1)

A compound of claim 1, or salt thereof, wherein the compound of Formula (I) is a compound of Formula (Ie), (If), or (Ig),

### Claim 8 (depends on 1)

A compound of claim 1, or salt thereof, wherein the compound of Formula (I) is a compound of Formula (Ii), (Ij), (Ik), (II), or (Im)

### Claim 9

A compound, or salt thereof, wherein the compound is selected from
3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-6-chloro-N-(3-(4-chlorophenyl)-2-fluoro-3-hydroxypropyl)-2-fluorobenzamide;
3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-6-chloro-2-fluoro-N-((2S,3S)-2-fluoro-3-(4-fluorophenyl)-3-hydroxybutyl)benzamide;
3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-6-chloro-2-fluoro-N-((2R,3R)-2-fluoro-3-(4-fluorophenyl)-3-hydroxybutyl)benzamide;
3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-6-chloro-2-fluoro-N-((2S,3R)-2-fluoro-3-(4-fluorophenyl)-3-hydroxybutyl)benzamide;
3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-6-chloro-2-fluoro-N-((2R,3S)-2-fluoro-3-(4-fluorophenyl)-3-hydroxybutyl)benzamide;
3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-fluoro-N-((2S,3S)-2-fluoro-3-(4-fluorophenyl)-3-hydroxybutyl)-6-(methyl-d3)benzamide;
3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-fluoro-N-((2R,3R)-2-fluoro-3-(4-fluorophenyl)-3-hydroxybutyl)-6-(methyl-d3)benzamide;
3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-fluoro-N-((2S,3R)-2-fluoro-3-(4-fluorophenyl)-3-hydroxybutyl)-6-(methyl-d3)benzamide;
3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-fluoro-N-((2R,3S)-2-fluoro-3-(4-fluorophenyl)-3-hydroxybutyl)-6-(methyl-d3)benzamide;
3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-6-chloro-2-fluoro-N-((2S,3S)-2-fluoro-3-(4-fluorophenyl)-3-hydroxypropyl)benzamide;
3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-6-chloro-2-fluoro-N-((2R,3R)-2-fluoro-3-(4-fluorophenyl)-3-hydroxypropyl)benzamide;
3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-6-chloro-2-fluoro-N-((2R,3S)-2-fluoro-3-(4-fluorophenyl)-3-hydroxypropyl)benzamide;
3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-6-chloro-2-fluoro-N-((2S,3R)-2-fluoro-3-(4-fluorophenyl)-3-hydroxypropyl)benzamide;
3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-((2R,3S)-3-(4-chlorophenyl)-2-fluoro-3-hydroxypropyl)-2-fluoro-6-methylbenzamide;
3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-((2S,3R)-3-(4-chlorophenyl)-2-fluoro-3-hydroxypropyl)-2-fluoro-6-methylbenzamide;
3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-((2S,3S)-3-(4-chlorophenyl)-2-fluoro-3-hydroxypropyl)-2-fluoro-6-methylbenzamide; and
3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-((2R,3R)-3-(4-chlorophenyl)-2-fluoro-3-hydroxypropyl)-2-fluoro-6-methylbenzamide.

### Claim 10 (depends on 1)

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

### Claim 11 (depends on 1)

A method of inhibiting casein kinase RIPK1 activity in a patient, comprising administering to the patient in need thereof, a therapeutically effective amount of one or more compounds according to claim 1.

### Claim 12 (depends on 1)

A method for treating a disease comprising the administration to a subject in need thereof a therapeutically-effective amount of at least one compound of claim 1, wherein the disease is selected from inflammatory bowel disease, ulcerative colitis, Crohn's disease, psoriasis, rheumatoid arthritis (RA), NASH, and heart failure.

### Claim 13 (depends on 1)

A method for treating a disease comprising the administration to a subject in need thereof a therapeutically-effective amount of at least one compound of claim 1, wherein the disease is selected from multiple sclerosis, amyotrophic lateral sclerosis, or alzheimers.

### Claim 14 (depends on 1)

A method for treating a disease comprising the administration to a subject in need thereof a therapeutically-effective amount of at least one compound of claim 1, wherein the disease is selected from inflammatory bowel disease, ulcerative colitis, and Crohn's disease.