# US 12,760,019 B2 · SIK inhibitors

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- Number: US 12,760,019 B2
- Document ID: US12760019B2
- Status: Granted
- Kind: B2
- Application number: 18/466,034
- Filed: 2023-09-13
- Published: 2024-04-18
- Granted: 2026-10-13
- Earliest claimed: 2022-09-21
- Assignees: Pfizer Inc.
- Applicants: Pfizer Inc.
- Inventors: Andrea Nicole Bootsma; David Christopher Ebner; Daniel Wei-Shung Kung; Matthew Alexander Perry; Daniel Copley Schmitt; Joseph Walter Strohbach; Atli Thorarensen
- Web page: https://patentgrep.com/patent/US12760019B2

## CPC

- C07D 471/04: Ortho-condensed systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

A compound of formula I having the structure: or a pharmaceutically acceptable salt thereof, wherein A1 and A2 are independently O or S; X is selected from CH2, CD2, NR3, O, and S, where R3 is selected from hydrogen, C1-C4 linear or branched chain alkyl, halo(C1-C4)linear or branched chain alkyl, and hydroxyl(C1-C4)linear or branched chain alkyl; Y and Z are selected from C and N, where when Y is C, then Z is N, and when Y is N, then Z is C; R1 and R2 are independently selected from hydrogen, deuterium, C1-C4 linear or branched chain alkyl, etc.; or a C1-C2 alkyl substituted with a C3-C5 cycloalkyl ring; or taken together to form a C3-C6 cycloalkyl ring; or where X is CH2 or CD2, then R1 and R2 are independently selected from hydrogen, deuterium, halogen, hydroxyl, C1-C4 linear or branched chain alkyl, etc.; R4 is selected from hydrogen, deuterium, cyano, halogen, (C1-C3) alkoxy, etc.; R5 is selected from hydrogen, deuterium, halogen, C1-C3 alkoxy, amino, (C1-C4 linear or branched chain alkyl)amino, etc.; R6 is selected from hydrogen, deuterium, halogen, CO2R7 where R7 is selected from H and C1-C4 linear or branched chain alkyl, etc.; R8 is selected from hydrogen, deuterium, and C1-C3 linear or branched chain alkyl; R9 is selected from C1-C3 linear or branched chain alkyl, and a halo(C1-C3)linear or branched chain alkyl; and, n and m are independently selected from 0, 1 and 2. The invention also relates to pharmaceutical compositions thereof and therapeutic methods of use therewith.

## Claims

### Claim 1

A compound of formula IA having the structure:
or a pharmaceutically acceptable salt thereof, wherein
A1 and A2 are independently O or S;
X is selected from CH2, CD2, NR3, O, and S, where R3 is selected from hydrogen, C1-C4 linear or branched chain alkyl, halo(C1-C4) linear or branched chain alkyl, and hydroxyl(C1-C4) linear or branched chain alkyl;
R1 and R2 are independently selected from hydrogen, deuterium, C1-C4 linear or branched chain alkyl, halo(C1-C4) linear or branched chain alkyl, hydroxyl(C1-C4) linear or branched chain alkyl, cyano (C1-C4) linear or branched chain alkyl, and C1-C3 alkoxy (C1-C4) linear or branched chain alkyl; or a C1-C2 alkyl substituted with a C3-C5 cycloalkyl ring; or taken together to form a C3-C6 cycloalkyl ring; or where X is CH2 or CD2, then R1 and R2 are independently selected from hydrogen, deuterium, halogen, hydroxyl, C1-C4 linear or branched chain alkyl, halo(C1-C4) linear or branched chain alkyl, hydroxyl(C1-C4) linear or branched chain alkyl, cyano (C1-C4) linear or branched chain alkyl, and C1-C3 alkoxy (C1-C4) linear or branched chain alkyl, and a C1-C2 alkyl substituted with a C3-C5 cycloalkyl ring;
R4 is selected from hydrogen, deuterium, cyano, halogen, (C1-C3) alkoxy, halo(C1-C3) alkoxy, C1-C3 alkyl-substituted thiol, C1-C4 linear or branched chain alkyl, halo(C1-C4) linear or branched chain alkyl, and a hydroxyl(C1-C4) linear or branched chain alkyl;
R5 is selected from hydrogen, deuterium, halogen, C1-C3 alkoxy, amino, (C1-C4 linear or branched chain alkyl)amino, di(C1-C4 linear or branched chain alkyl)amino, (4-6 membered) heterocyclic, C1-C4 linear or branched chain alkyl, halo(C1-C4) linear or branched chain alkyl, and a hydroxyl(C1-C4) linear or branched chain alkyl;
R6 is selected from hydrogen, deuterium, halogen, C1-C4 linear or branched chain alkoxy, CONH2, C1-C4 linear or branched chain alkyl, halo(C1-C4) linear or branched chain alkyl, hydroxyl(C1-C4) linear or branched chain alkyl, and CO2R7 where R7 is selected from H and C1-C4 linear or branched chain alkyl;
R8 is selected from hydrogen, deuterium, and C1-C3 linear or branched chain alkyl;
R9 is selected from C1-C3 linear or branched chain alkyl, and a halo(C1-C3) linear or branched chain alkyl; and,
n and m are independently selected from 0, 1 and 2.

### Claim 2 (depends on 1)

The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein A1 is O.

### Claim 3 (depends on 1)

The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein A2 is O or S.

### Claim 4 (depends on 1)

The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R1 and R2 are independently selected from ethyl, methyl, and H.

### Claim 5 (depends on 1)

The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R4 is cyano or methoxy.

### Claim 6 (depends on 1)

The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R5 is H.

### Claim 7 (depends on 1)

The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R5 is azetidine, pyrrolidine, or dimethylamino.

### Claim 8 (depends on 1)

The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R6 is H.

### Claim 9 (depends on 1)

The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R8 is H.

### Claim 10 (depends on 1)

The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R9 is methyl.

### Claim 11 (depends on 1)

The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein X is CH2.

### Claim 12 (depends on 1)

The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein X is O.

### Claim 13 (depends on 1)

The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein m is 0 and n is 1.

### Claim 14 (depends on 1)

The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein m is 1 and n is 1.

### Claim 15 (depends on 1)

The compound of claim 1 selected from the group consisting of:
2-((1-Aminocyclopentyl) methoxy)-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)-6-(methylthio)benzonitrile;
2-(((1S,2R)-1-Amino-2-ethylcyclopentyl) methoxy)-6-methoxy-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)benzonitrile;
2-(((1R,2S)-1-Amino-2-ethylcyclopentyl) methoxy)-6-methoxy-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)benzonitrile;
2-((1-Amino-3-ethylcyclopentyl) methoxy)-6-methoxy-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)benzonitrile;
2-(((1R,3R)-1-Amino-3-ethylcyclopentyl) methoxy)-6-methoxy-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)benzonitrile;
2-(((1S,3S)-1-Amino-3-ethylcyclopentyl) methoxy)-6-methoxy-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)benzonitrile;
2-(((1R,3S)-1-Amino-3-ethylcyclopentyl) methoxy)-6-methoxy-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)benzonitrile;
2-(((1S,3R)-1-Amino-3-ethylcyclopentyl) methoxy)-6-methoxy-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)benzonitrile;
2-(((1S,2S)-1-Amino-2-ethylcyclopentyl) methoxy)-6-methoxy-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)benzonitrile;
2-(((1R,2R)-1-Amino-2-ethylcyclopentyl) methoxy)-6-methoxy-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)benzonitrile;
3-(3-(((1S,2R)-1-Amino-2-ethylcyclopentyl) methoxy)-4-cyano-5-(methylthio)phenyl) imidazo[1,2-a]pyridine-5-carbonitrile;
3-(3-(((1R,2S)-1-Amino-2-ethylcyclopentyl) methoxy)-4-cyano-5-(methylthio)phenyl) imidazo[1,2-a]pyridine-5-carbonitrile;
2-((1-Amino-2-ethylcyclopentyl) methoxy)-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)-6-(methylthio)benzonitrile;
2-(((1S,2R)-1-Amino-2-ethylcyclopentyl) methoxy)-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)-6-(methylthio)benzonitrile;
2-(((1R,2S)-1-amino-2-ethylcyclopentyl) methoxy)-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)-6-(methylthio)benzonitrile;
2-(((2S,3R)-3-Amino-2-ethyltetrahydrofuran-3-yl) methoxy)-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)-6-(methylthio)benzonitrile;
2-(((2R,3R)-3-Amino-2-ethyltetrahydrofuran-3-yl) methoxy)-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)-6-(methylthio)benzonitrile;
2-(((2R,3S)-3-Amino-2-ethyltetrahydrofuran-3-yl) methoxy)-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)-6-(methylthio)-benzonitrile;
2-(((2S,3S)-3-Amino-2-ethyltetrahydrofuran-3-yl) methoxy)-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)-6-(methylthio)benzonitrile;
(R)-3-(3-((1-Amino-3,3-difluorocyclopentyl) methoxy)-4-cyano-5-(methylthio)phenyl) imidazo[1,2-a]pyridine-5-carbonitrile;
(S)-3-(3-((1-amino-3,3-difluorocyclopentyl) methoxy)-4-cyano-5-(methylthio)phenyl) imidazo[1,2-a]pyridine-5-carbonitrile;
(R)-2-((1-Amino-3,3-difluorocyclopentyl) methoxy)-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)-6-(methylthio)benzonitrile;
(S)-2-((1-Amino-3,3-difluorocyclopentyl) methoxy)-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)-6-(methylthio)benzonitrile;
(R)-3-(3-((1-Amino-3,3-dimethylcyclohexyl) methoxy)-4-cyano-5-(methylthio)phenyl) imidazo[1,2-a]pyridine-5-carbonitrile;
(S)-3-(3-((1-amino-3,3-dimethylcyclohexyl) methoxy)-4-cyano-5-(methylthio)phenyl) imidazo[1,2-a]pyridine-5-carbonitrile;
2-(((1R,3R)-1-Amino-3-ethylcyclohexyl) methoxy)-6-methoxy-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)benzonitrile;
2-(((1S,3S)-1-Amino-3-ethylcyclohexyl) methoxy)-6-methoxy-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)benzonitrile;
3-(3-(((1S,3S)-1-Amino-3-ethylcyclohexyl) methoxy)-4-cyano-5-(methylthio)phenyl) imidazo[1,2-a]pyridine-5-carbonitrile;
3-(3-(((1R,3R)-1-Amino-3-ethylcyclohexyl) methoxy)-4-cyano-5-(methylthio)phenyl) imidazo[1,2-a]pyridine-5-carbonitrile;
(S)-2-((1-Aminospiro [4.4]nonan-1-yl) methoxy)-6-methoxy-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)benzonitrile;
(R)-2-((1-Aminospiro[4.4]nonan-1-yl) methoxy)-6-methoxy-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)benzonitrile;
(S)-2-((3-Amino-1-(2,2,2-trifluoroethyl) piperidin-3-yl) methoxy)-6-methoxy-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)benzonitrile;
(R)-2-((3-Amino-1-(2,2,2-trifluoroethyl) piperidin-3-yl) methoxy)-6-methoxy-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)benzonitrile;
(R)-2-((3-Aminotetrahydrothiophen-3-yl) methoxy)-4-(imidazo[1,2-a]pyridin-3-yl)-6-(methylthio)benzonitrile;
(S)-2-((3-Aminotetrahydrothiophen-3-yl) methoxy)-4-(imidazo[1,2-a]pyridin-3-yl)-6-(methylthio)benzonitrile;
(R)-2-((3-Aminotetrahydrofuran-3-yl) methoxy)-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)-6-(methylthio)benzonitrile;
(S)-2-((3-Aminotetrahydrofuran-3-yl) methoxy)-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)-6-(methylthio)benzonitrile;
(R)-2-((1-Amino-3,3-difluorocyclopentyl) methoxy)-4-(imidazo[1,2-a]pyridin-3-yl)-6-(methylthio)benzonitrile;
(S)-2-((1-Amino-3,3-difluorocyclopentyl) methoxy)-4-(imidazo[1,2-a]pyridin-3-yl)-6-(methylthio)benzonitrile;
(R)-3-(3-((3-Aminotetrahydrothiophen-3-yl) methoxy)-4-cyano-5-(methylthio)phenyl) imidazo[1,2-a]pyridine-5-carbonitrile;
(S)-3-(3-((3-Aminotetrahydrothiophen-3-yl) methoxy)-4-cyano-5-(methylthio)phenyl) imidazo[1,2-a]pyridine-5-carbonitrile;
2-((1-Aminocyclohexyl) methoxy)-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)-6-(methylthio)benzonitrile;
(R)-2-((3-Aminotetrahydrothiophen-3-yl) methoxy)-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)-6-(methylthio)benzonitrile;
(S)-2-((3-Aminotetrahydrothiophen-3-yl) methoxy)-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)-6-(methylthio)benzonitrile;
2-(((1S)-1-Amino-3-(methoxymethyl)cyclohexyl) methoxy)-4-(imidazo[1,2-a]pyridin-3-yl)-6-(methylthio)benzonitrile;
2-(((1R)-1-Amino-3-(methoxymethyl)-cyclohexyl) methoxy)-4-(imidazo[1,2-a]pyridin-3-yl)-6-(methylthio)benzonitrile;
2-(((1S,2S)-1-Amino-2-(cyclopropylmethyl)cyclopentyl) methoxy)-6-methoxy-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)benzonitrile;
2-(((1R,2R)-1-Amino-2-(cyclopropylmethyl)cyclopentyl) methoxy)-6-methoxy-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)benzonitrile;
2-(((1S,2R)-1-Amino-2-(cyclopropylmethyl)cyclopentyl) methoxy)-6-methoxy-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)benzonitrile;
2-(((1R,2S)-1-Amino-2-(cyclopropylmethyl)cyclopentyl) methoxy)-6-methoxy-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)benzonitrile;
2-(((1S,3S)-1-Amino-3-(trifluoromethyl)cyclohexyl) methoxy)-4-(imidazo[1,2-a]pyridin-3-yl)-6-(methylthio)benzonitrile;
2-(((1R,3R)-1-Amino-3-(trifluoromethyl)cyclohexyl) methoxy)-4-(imidazo[1,2-a]pyridin-3-yl)-6-(methylthio)benzonitrile;
2-(((1R,3S)-1-Amino-3-(trifluoromethyl)cyclohexyl) methoxy)-4-(imidazo[1,2-a]pyridin-3-yl)-6-(methylthio)benzonitrile;
2-(((1S,3R)-1-Amino-3-(trifluoromethyl)cyclohexyl) methoxy)-4-(imidazo[1,2-a]pyridin-3-yl)-6-(methylthio)benzonitrile;
3-(3-((1-Aminocyclohexyl) methoxy)-4-cyano-5-(methylthio)phenyl) imidazo[1,2-a]pyridine-5-carbonitrile;
3-(3-((1-Aminocyclopentyl) methoxy)-4-cyano-5-(methylthio)phenyl) imidazo[1,2-a]pyridine-5-carbonitrile;
3-(3-((1-Aminocyclopentyl) methoxy)-4-cyano-5-(methylthio)phenyl) pyrazolo[1,5-a]pyridine-4-carbonitrile;
Ethyl 3-(3-((1-aminocyclopentyl) methoxy)-4-cyano-5-(methylthio)phenyl)-5-cyanoimidazo[1,2-a]pyridine-7-carboxylate;
3-(3-((1-Aminocyclopentyl) methoxy)-4-cyano-5-(methylthio)phenyl)-6-methoxyimidazo[1,2-a]pyridine-5-carbonitrile;
3-(3-((1-Aminocyclopentyl) methoxy)-4-cyano-5-(methylthio)phenyl)-7-methylimidazo[1,2-a]pyridine-5-carbonitrile;
3-(3-((1-Aminocyclopentyl) methoxy)-4-cyano-5-(methylthio)phenyl)-6-(dimethylamino) imidazo[1,2-a]pyridine-5-carbonitrile;
3-(3-((1-Aminocyclopentyl) methoxy)-4-cyano-5-(methylthio)phenyl)-6-ethylimidazo[1,2-a]pyridine-5-carbonitrile;
3-(3-((1-Aminocyclopentyl) methoxy)-4-cyano-5-(methylthio)phenyl)-6-methylimidazo[1,2-a]pyridine-5-carbonitrile;
3-(3-((1-Aminocyclopentyl) methoxy)-4-cyano-5-(methylthio)phenyl)-7-chloroimidazo[1,2-a]pyridine-5-carbonitrile;
3-(3-((1-Aminocyclohexyl) methoxy)-4-cyano-5-(methylthio)phenyl) pyrazolo[1,5-a]pyridine-4-carbonitrile;
6-Amino-3-(3-((1-aminocyclopentyl) methoxy)-4-cyano-5-(methylthio)phenyl) imidazo[1,2-a]pyridine-5-carbonitrile;
3-(3-((1-Aminocyclopentyl) methoxy)-4-cyano-5-(methylthio)phenyl)-6-(azetidin-1-yl) imidazo[1,2-a]pyridine-5-carbonitrile;
3-(3-((1-Aminocyclopentyl) methoxy)-4-cyano-5-(methylthio)phenyl)-6-(pyrrolidin-1-yl) imidazo[1,2-a]pyridine-5-carbonitrile;
3-(3-((1-Aminocyclopentyl) methoxy)-4-cyano-5-methoxyphenyl)-6-(dimethylamino) imidazo[1,2-a]pyridine-5-carbonitrile;
3-(3-((1-Aminocyclohexyl) methoxy)-4-cyano-5-(methylthio)phenyl)-6-methoxyimidazo[1,2-a]pyridine-5-carbonitrile;
3-(3-((1-Aminocyclopentyl) methoxy)-4-cyano-5-(methylthio)phenyl)-7-methoxyimidazo[1,2-a]pyridine-5-carbonitrile;
3-(3-((1-Aminocyclohexyl) methoxy)-4-cyano-5-(methylthio)phenyl)-7-methoxyimidazo[1,2-a]pyridine-5-carbonitrile;
3-(3-((1-Aminocyclohexyl) methoxy)-4-cyano-5-methoxyphenyl)-7-methoxyimidazo[1,2-a]pyridine-5-carbonitrile; and
3-(3-((1-Aminocyclopentyl) methoxy)-4-cyano-5-(methylthio)phenyl)-6-(methylamino) imidazo[1,2-a]pyridine-5-carbonitrile
or, a pharmaceutically acceptable salt thereof.

### Claim 16 (depends on 1)

The compound of claim 1 selected from the group consisting of:
3-(3-((1-Aminocyclohexyl) methoxy)-4-cyano-5-(methylthio)phenyl) imidazo[1,2-a]pyridine-5-carbonitrile;
2-(((1S,2R)-1-Amino-2-ethylcyclopentyl) methoxy)-6-methoxy-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)benzonitrile;
2-(((2S,3R)-3-Amino-2-ethyltetrahydrofuran-3-yl) methoxy)-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)-6-(methylthio)benzonitrile;
3-(3-(((1S,2R)-1-Amino-2-ethylcyclopentyl) methoxy)-4-cyano-5-(methylthio)phenyl) imidazo[1,2-a]pyridine-5-carbonitrile; and
3-(3-((1-aminocyclopentyl) methoxy)-4-cyano-5-(methylthio)phenyl)-6-(dimethylamino) imidazo[1,2-a]pyridine-5-carbonitrile;
or, a pharmaceutically acceptable salt thereof.

### Claim 17

3-(3-((1-Aminocyclohexyl) methoxy)-4-cyano-5-(methylthio)phenyl) imidazo[1,2-a]pyridine-5-carbonitrile; or, a pharmaceutically acceptable salt thereof.

### Claim 18

2-(((1S,2R)-1-Amino-2-ethylcyclopentyl) methoxy)-6-methoxy-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)benzonitrile; or, a pharmaceutically acceptable salt thereof.

### Claim 19

2-(((2S,3R)-3-Amino-2-ethyltetrahydrofuran-3-yl) methoxy)-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)-6-(methylthio)benzonitrile; or, a pharmaceutically acceptable salt thereof.

### Claim 20

3-(3-(((1S,2R)-1-Amino-2-ethylcyclopentyl) methoxy)-4-cyano-5-(methylthio)phenyl) imidazo[1,2-a]pyridine-5-carbonitrile; or, a pharmaceutically acceptable salt thereof.

### Claim 21

3-(3-((1-Aminocyclopentyl) methoxy)-4-cyano-5-(methylthio)phenyl)-6-(dimethylamino) imidazo[1,2-a]pyridine-5-carbonitrile; or, a pharmaceutically acceptable salt thereof.

### Claim 22 (depends on 1)

A pharmaceutical composition comprising a compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or salt, and a pharmaceutically acceptable excipient.