# US 9,518,055 B2 · Imidazopyridyl compounds as aldosterone synthase inhibitors

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- Number: US 9,518,055 B2
- Document ID: US9518055B2
- Status: Granted
- Kind: B2
- Application number: 14/885,187
- Filed: 2015-10-16
- Published: 2016-02-04
- Granted: 2016-12-13
- Earliest claimed: 2011-09-22
- Assignees: Merck Sharp & Dohme Corp.
- Applicants: Merck Sharp & Dohme Corp.
- Inventors: Amjad Ali; D. Jonathan Bennett; Jaiqiang Cai; Emma Carswell; Andrew Cooke; Scott B. Hoyt; Michael Lo; Clare London; John MacLean; Min K. Park; Paul Ratcliffe; Jerry Andrew Taylor; Brent Whitehead; Yusheng Xiong
- Web page: https://patentgrep.com/patent/US9518055B2

## CPC

- C07D 471/04: Ortho-condensed systems
- A61K 31/437: the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
- A61P 9/00: Drugs for disorders of the cardiovascular system
- C07D 487/04: Ortho-condensed systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

This invention relates to imidazopyridyl compounds of the structural formula: or their pharmaceutically acceptable salts, wherein the variable are defined herein. The inventive compounds selectively inhibit aldosterone synthase. This invention also provides for pharmaceutical compositions comprising the compounds of Formula I or their salts as well as potentially to methods for the treatment, amelioration or prevention of conditions that could be treated by inhibiting aldosterone synthase.

## Claims

### Claim 1

A compound of the structural formula
or a pharmaceutically acceptable salt thereof
wherein:
Ring A is attached to Ring B via positions D and E and is:
D is C;
E is N;
R1 is H or alkyl;
R2 is H; halogen; —CN; —OR7; —N(R10)C(O)R7; —NR11R12; —C(O)R7; —C(O)N(R11)(R12); —C(O)OR7; —S(O)m—R7; alkyl optionally substituted one or more times by halogen, —OR7, NR8R9, —CN, —N(R10)C(O)R7, —C(O)N(R8)(R9), —C(O)OR7, or —S(O)m—R7; cycloalkyl optionally substituted one or more times by halogen, alkyl, haloalkyl, —OR7, —NR8R9, —CN, —N(R10)C(O)R7, —C(O)N(R8)(R9), —C(O)OR7 or —S(O)m—R7; heterocycloalkyl optionally substituted one or more times by halogen, alkyl, haloalkyl, —OR7, —CN, —NR8R9—N(R10)C(O)R7, —C(O)N(R8)(R9), —C(O)OR7 or —S(O)m—R7; aryl optionally substituted one or more times by halogen, alkyl, haloalkyl, cycloalkyl, —OR7, —CN, —NR8R9—N(R10)C(O)R7, —C(O)N(R8)(R9), —C(O)OR7, or —S(O)m—R7; or heteroaryl optionally substituted one or more times by halogen, alkyl, haloalkyl, cycloalkyl, —OR7, —CN, —NR8R9, —N(R10)C(O)R7, —C(O)N(R8)(R9), —C(O)OR7 or —S(O)m—R7;
R3 is cycloalkyl optionally substituted once or twice by alkyl or halogen;
R4 is H; halogen; —CN; —OR7; —NR8R9; —N(R10)C(O)R7; —C(O)R7; —C(O)N(R8)(R9); —C(O)OR7; —N(R10)S(O)2—R7; —S(O)n—R7; alkyl optionally substituted one or more times by halogen, —OR7, —NR8R9, —CN, —N(R10)C(O)R7, —C(O)N(R8)(R9), —C(O)OR7, —N(R10)S(O)2—R7 or —S(O)nR7; cycloalkyl optionally substituted one or more times by halogen, alkyl, haloalkyl, —OR7, —NR8R9, —CN, —N(R10)C(O)R7, —C(O)N(R8)(R9), —C(O)OR7 or —S(O)m—R7; aryl optionally substituted one or more times by halogen, alkyl, haloalkyl, cycloalkyl, —OR7, —CN, —NR8R9—N(R10)C(O)R7, —C(O)N(R8)(R9), —C(O)OR7 or —S(O)m—R7; heterocycloalkyl optionally substituted one or more times by halogen, alkyl, haloalkyl, —OR7, —CN, —NR8R9—N(R10)C(O)R7, —C(O)N(R8)(R9), —C(O)OR7 or —S(O)m—R7; or heteroaryl optionally substituted one or more times by halogen, alkyl, haloalkyl, cycloalkyl, —OR7, —CN, —NR8R9, —N(R10)C(O)R7, —C(O)N(R8)(R9), —C(O)OR7 or —S(O)m—R7;
R5 is H; halogen; —CN; —OR7; —NR8R9; —N(R10)C(O)R7; —C(O)N(R8)(R9); —C(O)R7; —C(O)OR7; —N(R10)S(O)2—R7; —S(O)n—R7; alkyl optionally substituted one or more times by halogen, —OR7, —NR8R9, —CN, —N(R11)C(O)R7, —C(O)N(R8)(R9), —C(O)OR7, —N(R10)S(O)2—R7, or —S(O)n—R7; cycloalkyl optionally substituted one or more times by halogen, alkyl, haloalkyl, —OR7, —NR8R9, —CN, —N(R10)C(O)R7, —C(O)N(R8)(R9), —C(O)OR7 or —S(O)m—R7; aryl optionally substituted one or more times by halogen, alkyl, haloalkyl, cycloalkyl, —OR7, —CN, —NR8R9—N(R10)C(O)(R7), —C(O)N(R8)(R9), —C(O)OR7 or —S(O)m—R7; heterocycloalkyl optionally substituted one or more times by halogen, alkyl, haloalkyl, cycloalkyl, —OR7, —CN, —NR8R9—N(R10)C(O)R7, —C(O)N(R8)(R9), —C(O)OR7 or —S(O)m—R7; or heteroaryl optionally substituted one or more times by halogen, alkyl, haloalkyl, cycloalkyl, —OR7, —CN, —NR8R9, —N(R10)C(O)R7, —C(O)N(R8)(R9), —C(O)OR7 or —S(O)m—R7;
or R4 and R5 are joined together to form a 5- to 7-membered carbocyclic or heterocyclic ring that is fused to the pyridyl ring to which R4 and R5 are attached, wherein the ring formed by R4 and R5 is optionally substituted by 1 to 3 R6;
R6 is independently H; halogen; —CN; —OR7; —NR8R9; —N(R10)C(O)R7; —C(O)N(R7)(R8); —C(O)N(R8)(R9); —C(O)OR7; —S(O)m—R7; alkyl optionally substituted one or more times by halogen, —OR7, —NR8R9, —CN, —N(R10)C(O)R7, —C(O)N(R8)(R9), —C(O)OR7 or —S(O)m—R7; cycloalkyl optionally substituted one or more times by halogen, alkyl, haloalkyl, —OR7, —NR8R9, —CN, —N(R10)C(O)R7, —C(O)N(R8)(R9), —C(O)OR7 or —S(O)m—R7; aryl optionally substituted one or more times by halogen, alkyl, haloalkyl, cycloalkyl, —OR7, —CN, —NR8R9—N(R10)C(O)(R7), —C(O)N(R7)(R8), —C(O)OR7 or —S(O)m—R7; heterocycloalkyl optionally substituted one or more times by halogen, alkyl, haloalkyl, —OR7, —CN, —NR8R9—N(R10)C(O)R7, —C(O)N(R8)(R9), —C(O)OR7 or —S(O)m—R7; or heteroaryl optionally substituted one or more times by halogen, alkyl, haloalkyl, cycloalkyl, —OR7, —CN, —NR8R9, —N(R10)C(O)R7, —C(O)N(R8)(R9), —C(O)OR7 or —S(O)m—R7;
R7 is independently H; alkyl optionally substituted one or more times by halogen, —OR10, —NR8R9, —CN, —N(R10)C(O)R10, —C(O)N(R8)(R9), —C(O)OR10 or —S(O)m—R10; cycloalkyl optionally substituted one or more times by halogen, alkyl, haloalkyl, —OR10, —NR8R9, —CN, —N(R10)C(O)R10, —C(O)N(R8)(R9), —C(O)OR10 or —S(O)m—R10; aryl optionally substituted one or more times by halogen, alkyl, haloalkyl, cycloalkyl, —OH, —OR10, —NR8R9, —CN, —N(R10)C(O)R10, —C(O)N(R8)(R9), —C(O)OR10 or —S(O)m—R10; or heteroaryl optionally substituted one or more times by halogen, alkyl, haloalkyl, cycloalkyl, —OR10, —NR8R9, —CN, —N(R9)C(O)R10, —C(O)N(R8)(R9), —C(O)OR10 or —S(O)m—R10;
R8 is independently H or alkyl;
R9 is independently H or alkyl;
or R8 and R9 are joined together with the nitrogen to which they are attached to form a saturated 5- to 7-membered heterocyclic ring;
R10 is independently H or alkyl;
R11 is independently H; alkyl optionally substituted one or more times by halogen, —OR7, —NR8R9, —CN, —N(R10)C(O)R7, —C(O)N(R8)(R9), —C(O)OR7 or —S(O)m—R7; cycloalkyl optionally substituted one or more times by halogen, alkyl, haloalkyl, —OR7, —NR8R9, —CN, —N(R10)C(O)R7, —C(O)N(R8)(R9), —C(O)OR8 or —S(O)m—R8; aryl optionally substituted one or more times by halogen, alkyl, haloalkyl, cycloalkyl, —OR7, —CN, —NR8R9—N(R10)C(O)(R7), —C(O)N(R7)(R8), —C(O)OR7 or —S(O)m—R7; heterocycloalkyl optionally substituted one or more times by halogen, alkyl, haloalkyl, —OR7, —CN, —NR8R9—N(R10)C(O)R7, —C(O)N(R8)(R9), —C(O)OR7 or —S(O)m—R7; or heteroaryl optionally substituted one or more times by halogen, alkyl, haloalkyl, cycloalkyl, —OR7, —CN, —NR8R9, —N(R10)C(O)R7, —C(O)N(R8)(R9), —C(O)OR7 or —S(O)m—R7;
R12 is independently H; alkyl optionally substituted one or more times by halogen, —OR7, —NR8R9, —CN, —N(R10)C(O)R7, —C(O)N(R8)(R9), —C(O)OR7 or —S(O)m—R7; cycloalkyl optionally substituted one or more times by halogen, alkyl, haloalkyl, —OR7, —NR8R9, —CN, —N(R10)C(O)R7, —C(O)N(R8)(R9), —C(O)OR8 or —S(O)m—R8; aryl optionally substituted one or more times by halogen, alkyl, haloalkyl, cycloalkyl, —OR7, —CN, —NR8R9—N(R10)C(O)(R7), —C(O)N(R7)(R8), —C(O)OR7 or —S(O)m—R7; heterocycloalkyl optionally substituted one or more times by halogen, alkyl, haloalkyl, —OR7, —CN, —NR8R9—N(R10)C(O)R7, —C(O)N(R8)(R9), —C(O)OR7 or —S(O)m—R7; or heteroaryl optionally substituted one or more times by halogen, alkyl, haloalkyl, cycloalkyl, —OR7, —CN, —NR8R9, —N(R10)C(O)R7, —C(O)N(R8)(R9), —C(O)OR7 or —S(O)m—R7;
a is 0, 1, 2, 3 or 4;
n is 1 or 2; and
m is 0, 1 or 2.

### Claim 2 (depends on 1)

The compound as defined in claim 1 or a pharmaceutically acceptable salt thereof, which has the structural formula Formula II
wherein:
R2 is independently halogen, —CN, alkyl, haloalkyl, cycloalkyl, OR7 or phenyl optionally substituted by halogen;
R3 is cycloalkyl;
R4 is H, halogen, —CN, alkyl or cycloalkyl;
R5 is:
i.) H, halogen, —CN, alkyl, —OR7, haloalkyl or phenyl optionally substituted by halogen or haloalkyl;
ii.) —C(O)OR7; or
iii.) a group of the formula:
where:
Ra is H, OH, or —C1-C3-alkyl optionally substituted with 1 to 3 —F;
Rb is H, —OH, or —C1-C3-alkyl optionally substituted with 1 to 3 —F;
Rc is —C1-C3-alkyl optionally substituted with 1 to 3 —F; —OC1-C3-alkyl; —N(H)S(O)2—C1-C3-alkyl; optionally substituted with 1 to 3 —F; or —N(H)C(O)C1-C3-alkyl, optionally substituted with 1 to 3 —F;
R7 is H, alkyl, haloalkyl, cycloalkyl, or phenyl optionally substituted by halogen; and
a is 0, 1 or 2.

### Claim 3 (depends on 1)

The compound as defined in claim 1 or a pharmaceutically acceptable salt thereof, which has the structural formula
wherein:
R1 is independently H or alkyl;
R2 is independently halogen, —CN, alkyl, haloalkyl, cycloalkyl, OR7 or phenyl optionally substituted by halogen;
R3 is cycloalkyl;
R4 is H, halogen, —CN, alkyl or cycloalkyl;
R5 is:
i.) H, halogen, —CN, alkyl, —OR7, —C(O)OR7, haloalkyl or phenyl optionally substituted by halogen or haloalkyl; or
ii.) a group of the formula:
where:
Ra is H, OH, or —C1-C3-alkyl optionally substituted with 1 to 3 —F;
Rb is H, —OH, or —C1-C3-alkyl optionally substituted with 1 to 3 —F;
Rc is —C1-C3-alkyl optionally substituted with 1 to 3 —F; —OC1-C3-alkyl; —N(H)S(O)2—C1-C3-alkyl, optionally substituted with 1 to 3 —F; or —N(H)C(O)C1-C3-alkyl, optionally substituted with 1 to 3 —F;
R7 is H, alkyl, haloalkyl, cycloalkyl, or phenyl optionally substituted by halogen; and
a is 0, 1 or 2.

### Claim 4 (depends on 1)

The compound as defined in claim 1 or a pharmaceutically acceptable salt thereof, which has the structural formula
wherein:
R2 is independently halogen, —CN, alkyl, haloalkyl, cycloalkyl, OR7 or phenyl optionally substituted by halogen;
R3 is cycloalkyl;
R6 is alkyl or halo;
a is 0, 1 or 2; and
b is 0, 1 or 2.

### Claim 5 (depends on 1)

The compound as defined in claim 1 or a pharmaceutically acceptable salt thereof, which has the structural formula
wherein:
R2 is independently halogen, —CN, alkyl, haloalkyl, cycloalkyl, OR7 or phenyl optionally substituted by halogen;
R3 is cycloalkyl;
R6 is alkyl or halo;
a is 0, 1 or 2; and
b is 0, 1 or 2.

### Claim 6 (depends on 1)

The compound as defined in claim 1 which is
3-cyclopropyl-6-methyl-2-(4-methylpyridin-3-yl)imidazo[1,2-a]pyridine;
3-cyclopropyl-6-fluoro-2-(pyridin-3-yl)imidazo[1,2-a]pyridine;
3-cyclopropyl-6-fluoro-2-(5-methylpyridin-3-yl)imidazo[1,2-a]pyridine;
3-cyclopropyl-6-fluoro-2-(6-methylpyridin-3-yl)imidazo[1,2-a]pyridine;
3-cyclopropyl-6-fluoro-2-(5-fluoropyridin-3-yl)imidazo[1,2-a]pyridine;
3-cyclopropyl-6-fluoro-2-(5-fluoro-4-methylpyridin-3-yl)imidazo[1,2-a]pyridine;
3-cyclopropyl-2-(4-ethyl-5-fluoropyridin-3-yl)-6-fluoroimidazo[1,2-a]pyridine;
3-cyclopropyl-6-fluoro-2-(5-methoxypyridin-3-yl)imidazo[1,2-a]pyridine;
3-cyclopropyl-6-fluoro-2-(5-(trifluoromethyl)pyridin-3-yl)imidazo[1,2-a]pyridine;
5-(3-cyclopropyl-6-fluoroimidazo[1,2-a]pyridin-2-yl)nicotinonitrile;
2-(5-(3-cyclopropyl-6-fluoroimidazo[1,2-a]pyridin-2-yl)pyridin-3-yl)propan-2-ol;
2-(5-(3-cyclopropyl-6-fluoroimidazo[1,2-a]pyridin-2-yl)pyridin-3-yl)-1,1,1-trifluoropropan-2-ol;
3-cyclopropyl-6-fluoro-2-(5-phenylpyridin-3-yl)imidazo[1,2-a]pyridine;
methyl 5-(3-cyclopropyl-6-fluoroimidazo[1,2-a]pyridin-2-yl)nicotinate;
4-(3-cyclopropyl-6-fluoroimidazo[1,2-a]pyridin-2-yl)isoquinoline;
6-chloro-3-cyclopropyl-2-(5-fluoropyridin-3-yl)imidazo[1,2-a]pyridine;
6-chloro-3-cyclopropyl-7-fluoro-2-(5-fluoropyridin-3-yl)imidazo[1,2-a]pyridine;
4-(3-cyclopropyl-8-fluoroimidazo[1,2-a]pyridin-2-yl)isoquinoline;
2-{5-[3-cyclopropyl-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl]pyridin-3-yl}-1,1,1-trifluoropropan-2-ol; or
3-cyclopropyl-2-[5-(1,1,1-trifluoro-2-hydroxypropan-2-yl)pyridin-3-yl]imidazo[1,2-a]pyridine-6-carbonitrile;
or a pharmaceutically acceptable salt thereof.

### Claim 7

A compound selected from the group consisting of:
6-Fluoro-2-(pyridin-3-yl)imidazo[1,2-a]pyridine;
2-(5-(3-Chloro-6-fluoroimidazo[1,2-a]pyridin-2-yl)pyridin-3-yl)propan-2-ol;
2-(5-(6-Fluoro-3-methylimidazo[1,2-a]pyridin-2-yl)pyridin-3-yl)propan-2-ol;
6-fluoro-2-(5-(2-hydroxypropan-2-yl)pyridin-3-yl)imidazo[1,2-a]pyridine-3-carbonitrile;
6-fluoro-2-(pyridin-3-yl)imidazo[1,2-a]pyridine;
6-fluoro-2-(4-methylpyridin-3-yl)imidazo[1,2-a]pyridine;
6-fluoro-2-(5-methylpyridin-3-yl)imidazo[1,2-a]pyridine;
2-(5-(6-fluoroimidazo[1,2-a]pyridin-2-yl)pyridin-3-yl)propan-2-ol;
1,1,1-trifluoro-2-(5-(6-fluoroimidazo[1,2-a]pyridin-2-yl)pyridin-3-yl)propan-2-ol;
8-fluoro-2-(5-methylpyridin-3-yl)imidazo[1,2-a]pyridine;
6-chloro-2-(5-fluoropyridin-3-yl)imidazo[1,2-a]pyridine;
6-chloro-7-fluoro-2-(5-fluoropyridin-3-yl)imidazo[1,2-a]pyridine;
2-(isoquinolin-4-yl)imidazo[1,2-a]pyridine-7-carbonitrile;
6-methyl-2-(6-methylpyridin-3-yl)-3-methylimidazo[1,2-a]pyridine;
8-methyl-2-(6-methylpyridin-3-yl)-3-methylimidazo[1,2-a]pyridine;
7-methyl-2-(6-methylpyridin-3-yl)-3-methylimidazo[1,2-a]pyridine;
6-fluoro-3-methyl-2-(pyridin-3-yl)imidazo[1,2-a]pyridine;
6-fluoro-3-methyl-2-(5-methoxypyridin-3-yl)imidazo[1,2-a]pyridine;
6-fluoro-3-methyl-2-(5-methylpyridin-3-yl)imidazo[1,2-a]pyridine;
6-fluoro-3-methyl-2-(4-methylpyridin-3-yl)imidazo[1,2-a]pyridine;
5-(6-fluoro-3-methylimidazo[1,2-a]pyridin-2-yl)nicotinonitrile;
3-methyl-6-fluoro-2-(5-(trifluoromethyl)pyridin-3-yl)imidazo[1,2-a]pyridine;
2-(5-(6-fluoro-3-methylimidazo[1,2-a]pyridin-2-yl)pyridin-3-yl)propan-2-ol;
1,1,1-trifluoro-2-(5-(6-fluoro-3-methylimidazo[1,2-a]pyridin-2-yl)pyridin-3-yl)propan-2-ol;
4-(6-fluoro-3-ethylimidazo[1,2-a]pyridin-2-yl)isoquinoline; and
7-fluoro-2-(5-fluoropyridin-3-yl)-3-methylimidazo[1,2-a]pyridine,
or a pharmaceutically acceptable salt thereof.

### Claim 8 (depends on 1)

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

### Claim 9 (depends on 1)

A pharmaceutical composition comprising a therapeutically effective amount of at least one compound of any one of claim 1, or a pharmaceutically acceptable salt thereof, a therapeutically effective amount of at least one additional therapeutic agent and a pharmaceutically acceptable carrier.

### Claim 10 (depends on 1)

A compound of any one claim 1, or a pharmaceutically acceptable salt thereof for use in therapy.

### Claim 11 (depends on 1)

A compound of claim 1, or a pharmaceutically acceptable salt thereof for use in the treatment, amelioration or prevention of one or more conditions selected from hypertension, heart failure such as congestive heart failure, diastolic dysfunction, left ventricular diastolic dysfunction, heart failure, diastolic dysfunction, left ventricular diastolic dysfunction, diastolic heart failure, systolic dysfunction, hypokalemia, renal failure, restenosis, syndrome X, nephropathy, post-myocardial infarction, coronary heart diseases, increased formation of collagen, fibrosis and remodeling following hypertension and endothelial dysfunction, cardiovascular diseases, renal dysfunction, liver diseases, vascular diseases, cerebrovascular diseases, retinopathy, neuropathy, insulinopathy, endothelial dysfunction, ischemia, myocardial and vascular fibrosis, myocardial necrotic lesions, vascular damage, myocardial necrotic lesions, vascular damage, myocardial infarction, left ventricular hypertrophy, cardiac lesions, vascular wall hypertrophy, endothelial thickening and fibrinoid necrosis of coronary arteries.

### Claim 12 (depends on 1)

A combination comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof and one or more additional pharmacologically active agents.