Spirodiamine derivatives as aldosterone synthase inhibitors

1. Compounds of formula (I)

wherein

R 1 , R 2 , R 3 and R 4 are independently selected from H, alkyl and cycloalkyl;

or R 1 and R 2 together form —CH 2 —CH 2 —;

R 5 and R 6 are independently selected from H or alkyl;

A 1 is —CH— or —N—;

A 2 is —C(O)— or —S(O) 2 —;

R 12 is heteroaryl or substituted heteroaryl, wherein substituted heteroaryl is substituted with one to three substituent independently selected from alkyl, cycloalkyl, haloalkyl, hydroxy, alkoxy, cyano and halogen;

R 13 is halogen, cyano, alkoxy or haloalkoxy;

R 15 is H, alkyl, cycloalkyl or halogen;

m is zero or 1; and

R 14 and (i) R 9 together are —CH 2 —, R 10 and R 11 together are —CH 2 —, n is 1 and p is zero; or (ii) R 9 together are —CH 2 —CH 2 —, R 10 and R 11 together are —CH 2 —, n is 1 and p is 1 and R 7 and R 8 are independently selected from H or alkyl; or (iii) R 7 together are —CH 2 —, R 8 and R 11 together are —CH 2 —CH 2 —, n is 1, p is 1 and R 9 and R 10 are independently selected from H or alkyl;

or, a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1 , wherein R 1 and R 2 are alkyl or R 1 and R 2 together form —CH 2 —CH 2 —.

3. The compound according to claim 1 wherein R 1 and R 2 are alkyl.

4. The compound according to claim 1 wherein R 3 and R 4 are H.

5. The compound according to claim 1 wherein R 13 is halogen.

6. The compound according to claim 1 wherein R 15 is H.

7. The compound according to claim 1 wherein A 1 is —CH—.

8. The compound according to claim 1 wherein A 2 is —C(O)—.

9. The compound according to claim 1 wherein R 9 and R 14 together form —CH 2 —, R 10 and R 11 together form —CH 2 —, n is 1 and p is zero.

10. The compound according to claim 1 wherein R 12 is a heteroaryl group selected from the group consisting of imidazolyl, isoxazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl and pyrimidinyl.

11. The compound of claim 1 wherein A 1 is —CH 2 — and A 2 is —C(O)—.

12. The compound of claim 11 wherein R 12 is a heteroaryl group selected from the group consisting of imidazolyl, isoxazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl and pyrimidinyl.

13. The compound according to claim 1 wherein R 12 is pyrazolyl substituted by alkyl or is pyridinyl substituted by alkyl.

14. The compound according to claim 11 , wherein R 12 is pyrazolyl substituted by alkyl.

15. The compound according to claim 1 which compound is selected from the group consisting of:

5-Chloro-3,3-dimethyl-2-[5-[2-(1-methylpyrazole-4-carbonyl)-2,6-diazaspiro[3.3]heptan-6-yl]-3-pyridyl]isoindolin-1-one;

5-Chloro-2-[5-[2-(1-ethylpyrazole-4-carbonyl)-2,6-diazaspiro[3.3]heptan-6-yl]-3-pyridyl]-3,3-dimethyl-isoindolin-1-one;

5-Chloro-2-[5-[2-(1-isopropylpyrazole-4-carbonyl)-2,6-diazaspiro[3.3]heptan-6-yl]-3-pyridyl]-3,3-dimethyl-isoindolin-1-one;

5-Chloro-3,3-dimethyl-2-[5-[2-(1-methylimidazole-2-carbonyl)-2,6-diazaspiro[3.3]heptan-6-yl]-3-pyridyl]isoindolin-1-one;

5-Chloro-3,3-dimethyl-2-[5-[2-(2-methylpyrazole-3-carbonyl)-2,6-diazaspiro[3.3]heptan-6-yl]-3-pyridyl]isoindolin-1-one;

5-Chloro-3,3-dimethyl-2-[5-[2-(3-methylimidazole-4-carbonyl)-2,6-diazaspiro[3.3]heptan-6-yl]-3-pyridyl]isoindolin-1-one;

5-Chloro-3,3-dimethyl-2-[5-[2-(4-methylpyridine-3-carbonyl)-2,6-diazaspiro[3.3]heptan-6-yl]-3-pyridyl]isoindolin-1-one;

3,3-Dimethyl-2-[5-[2-(1-methylpyrazole-4-carbonyl)-2,6-diazaspiro[3.3]heptan-6-yl]-3-pyridyl]-1-oxo-isoindoline-5-carbonitrile;

2-[5-[2-(1-Ethylpyrazole-4-carbonyl)-2,6-diazaspiro[3.3]heptan-6-yl]-3-pyridyl]-3,3-dimethyl-1-oxo-isoindoline-5-carbonitrile;

2-[5-[2-(1-Isopropylpyrazole-4-carbonyl)-2,6-diazaspiro[3.3]heptan-6-yl]-3-pyridyl]-3,3-dimethyl-1-oxo-isoindoline-5-carbonitrile;

3,3-Dimethyl-2-[5-[2-(1-methylimidazole-2-carbonyl)-2,6-diazaspiro[3.3]heptan-6-yl]-3-pyridyl]-1-oxo-isoindoline-5-carbonitrile;

3,3-Dimethyl-2-[5-[2-(2-methylpyrazole-3-carbonyl)-2,6-diazaspiro[3.3]heptan-6-yl]-3-pyridyl]-1-oxo-isoindoline-5-carbonitrile;

3,3-Dimethyl-2-[5-[2-(3-methylimidazole-4-carbonyl)-2,6-diazaspiro[3.3]heptan-6-yl]-3-pyridyl]-1-oxo-isoindoline-5-carbonitrile;

3,3-Dimethyl-2-[5-[2-(4-methylpyridine-3-carbonyl)-2,6-diazaspiro[3.3]heptan-6-yl]-3-pyridyl]-1-oxo-isoindoline-5-carbonitrile;

2-Methoxy-7,7-dimethyl-6-[5-[2-(1-methylpyrazole-4-carbonyl)-2,6-diazaspiro[3.3]heptan-6-yl]-3-pyridyl]pyrrolo[3,4-b]pyridin-5-one;

2-Methoxy-7,7-dimethyl-6-[5-[2-(4-methylpyridine-3-carbonyl)-2,6-diazaspiro[3.3]heptan-6-yl]-3-pyridyl]pyrrolo[3,4-b]pyridin-5-one;

2-Methoxy-7,7-dimethyl-6-[5-[2-(2-methylpyrazole-3-carbonyl)-2,6-diazaspiro[3.3]heptan-6-yl]-3-pyridyl]pyrrolo[3,4-b]pyridin-5-one;

5-Chloro-3-methyl-2-[5-[2-(1-methylpyrazole-4-carbonyl)-2,6-diazaspiro[3.3]heptan-6-yl]-3-pyridyl]isoindolin-1-one;

5′-Chloro-2′-[5-[2-(1-methylpyrazole-4-carbonyl)-2,6-diazaspiro[3.3]heptan-6-yl]-3-pyridyl]spiro[cyclopropane-1,3′-isoindoline]-1′-one;

5′-Chloro-2′-[5-[2-(4-methylpyridine-3-carbonyl)-2,6-diazaspiro[3.3]heptan-6-yl]-3-pyridyl]spiro[cyclopropane-1,3′-isoindoline]-1′-one;

5′-Chloro-2′-[5-[2-(2-methylpyrazole-3-carbonyl)-2,6-diazaspiro[3.3]heptan-6-yl]-3-pyridyl]spiro[cyclopropane-1,3′-isoindoline]-1′-one;

(3R or 3S)-5-Chloro-3-methyl-2-[5-[2-(1-methylpyrazole-4-carbonyl)-2,6-diazaspiro[3.3]heptan-6-yl]-3-pyridyl]isoindolin-1-one;

(3S or 3R)-5-Chloro-3-methyl-2-[5-[2-(1-methylpyrazole-4-carbonyl)-2,6-diazaspiro[3.3]heptan-6-yl]-3-pyridyl]isoindolin-1-one;

5-Chloro-2-[5-[2-(4-methoxypyridine-3-carbonyl)-2,6-diazaspiro[3.3]heptan-6-yl]-3-pyridyl]-3,3-dimethyl-isoindolin-1-one;

5-Chloro-2-[5-[2-(3,6-dimethylpyrazine-2-carbonyl)-2,6-diazaspiro[3.3]heptan-6-yl]-3-pyridyl]-3,3-dimethyl-isoindolin-1-one;

5-Chloro-2-[5-[2-(1,5-dimethylpyrazole-4-carbonyl)-2,6-diazaspiro[3.3]heptan-6-yl]-3-pyridyl]-3,3-dimethyl-isoindolin-1-one;

5-Chloro-3,3-dimethyl-2-[5-[2-(3-methylisoxazole-4-carbonyl)-2,6-diazaspiro[3.3]heptan-6-yl]-3-pyridyl]isoindolin-1-one;

5-Chloro-3,3-dimethyl-2-[5-[2-(6-methylpyrazine-2-carbonyl)-2,6-diazaspiro[3.3]heptan-6-yl]-3-pyridyl]isoindolin-1-one;

5-Chloro-3,3-dimethyl-2-[5-[2-(4-methylpyrimidine-5-carbonyl)-2,6-diazaspiro[3.3]heptan-6-yl]-3-pyridyl]isoindolin-1-one;

5-Chloro-3,3-dimethyl-2-[5-[2-(5-methylpyrazine-2-carbonyl)-2,6-diazaspiro[3.3]heptan-6-yl]-3-pyridyl]isoindolin-1-one;

5-Chloro-2-[5-[2-(2,5-dimethylpyrazole-3-carbonyl)-2,6-diazaspiro[3.3]heptan-6-yl]-3-pyridyl]-3,3-dimethyl-isoindolin-1-one;

5-Chloro-3,3-dimethyl-2-[5-[2-(5-methyloxazole-4-carbonyl)-2,6-diazaspiro[3.3]heptan-6-yl]-3-pyridyl]isoindolin-1-one;

5-Chloro-3,3-dimethyl-2-[5-[2-(pyrimidine-2-carbonyl)-2,6-diazaspiro[3.3]heptan-6-yl]-3-pyridyl]isoindolin-1-one;

5-Chloro-3,3-dimethyl-2-[5-[2-(5-methylpyrimidine-2-carbonyl)-2,6-diazaspiro[3.3]heptan-6-yl]-3-pyridyl]isoindolin-1-one;

5-Chloro-2-[5-[2-[3-(difluoromethyl)-1-methyl-pyrazole-4-carbonyl]-2,6-diazaspiro[3.3]heptan-6-yl]-3-pyridyl]-3,3-dimethyl-isoindolin-1-one;

5-[6-[5-(6-Chloro-1,1-dimethyl-3-oxo-isoindolin-2-yl)-3-pyridyl]-2,6-diazaspiro[3.3]heptane-2-carbonyl]pyridine-3-carbonitrile;

5-Chloro-2-[5-[2-(3-methoxypyrazine-2-carbonyl)-2,6-diazaspiro[3.3]heptan-6-yl]-3-pyridyl]-3,3-dimethyl-isoindolin-1-one;

5-Chloro-3,3-dimethyl-2-[5-[2-(pyrazine-2-carbonyl)-2,6-diazaspiro[3.3]heptan-6-yl]-3-pyridyl]isoindolin-1-one;

5-Chloro-3,3-dimethyl-2-[5-[2-(5-methylisoxazole-4-carbonyl)-2,6-diazaspiro[3.3]heptan-6-yl]-3-pyridyl]isoindolin-1-one;

5-Chloro-3,3-dimethyl-2-[5-[2-(pyrimidine-5-carbonyl)-2,6-diazaspiro[3.3]heptan-6-yl]-3-pyridyl]isoindolin-1-one;

5-Chloro-3,3-dimethyl-2-[5-[2-(4-methyloxazole-5-carbonyl)-2,6-diazaspiro[3.3]heptan-6-yl]-3-pyridyl]isoindolin-1-one;

5-Chloro-3,3-dimethyl-2-[5-[2-(oxazole-4-carbonyl)-2,6-diazaspiro[3.3]heptan-6-yl]-3-pyridyl]isoindolin-1-one;

5-Chloro-3,3-dimethyl-2-[5-[2-(2-methyloxazole-5-carbonyl)-2,6-diazaspiro[3.3]heptan-6-yl]-3-pyridyl]isoindolin-1-one;

5-Chloro-2-[5-[2-(2,4-dimethyloxazole-5-carbonyl)-2,6-diazaspiro[3.3]heptan-6-yl]-3-pyridyl]-3,3-dimethyl-isoindolin-1-one;

5-Chloro-3,3-dimethyl-2-[5-[2-(2-methyloxazole-4-carbonyl)-2,6-diazaspiro[3.3]heptan-6-yl]-3-pyridyl]isoindolin-1-one;

2-[6-[5-(6-Chloro-1,1-dimethyl-3-oxo-isoindolin-2-yl)-3-pyridyl]-2,6-diazaspiro[3.3]heptane-2-carbonyl]pyridine-3-carbonitrile;

5-Chloro-2-[5-[2-(5-chloro-2-methyl-pyrimidine-4-carbonyl)-2,6-diazaspiro[3.3]heptan-6-yl]-3-pyridyl]-3,3-dimethyl-isoindolin-1-one;

5-Chloro-2-[5-[2-(4,6-dimethylpyrimidine-5-carbonyl)-2,6-diazaspiro[3.3]heptan-6-yl]-3-pyridyl]-3,3-dimethyl-isoindolin-1-one;

5-Chloro-2-[5-[2-(2,4-dimethylpyridine-3-carbonyl)-2,6-diazaspiro[3.3]heptan-6-yl]-3-pyridyl]-3,3-dimethyl-isoindolin-1-one;

3-[6-[5-(6-Chloro-1,1-dimethyl-3-oxo-isoindolin-2-yl)-3-pyridyl]-2,6-diazaspiro[3.3]heptane-2-carbonyl]pyridine-4-carbonitrile;

(3S or 3R)-5-Chloro-2-[5-[2-(1-ethylpyrazole-4-carbonyl)-2,6-diazaspiro[3.3]heptan-6-yl]-3-pyridyl]-3-methyl-isoindolin-1-one;

(3R or 3S)-5-Chloro-2-[5-[2-(1-ethylpyrazole-4-carbonyl)-2,6-diazaspiro[3.3]heptan-6-yl]-3-pyridyl]-3-methyl-isoindolin-1-one;

6-Chloro-2-[5-[2-(1-methylpyrazole-4-carbonyl)-2,6-diazaspiro[3.3]heptan-6-yl]-3-pyridyl]-3,4-dihydroisoquinolin-1-one;

(3R or 3S)-5-Chloro-3-methyl-2-[4-methyl-5-[2-(1-methylpyrazole-4-carbonyl)-2,6-diazaspiro[3.3]heptan-6-yl]-3-pyridyl]isoindolin-1-one;

(3S or 3R)-5-Chloro-3-methyl-2-[4-methyl-5-[2-(1-methylpyrazole-4-carbonyl)-2,6-diazaspiro[3.3]heptan-6-yl]-3-pyridyl]isoindolin-1-one;

5-Chloro-3,3-dimethyl-2-[5-[7-(1-methylpyrazole-4-carbonyl)-2,7-diazaspiro[3.5]nonan-2-yl]-3-pyridyl]isoindolin-1-one;

5-Chloro-3,3-dimethyl-2-[5-[7-(4-methylpyridine-3-carbonyl)-2,7-diazaspiro[3.5]nonan-2-yl]-3-pyridyl]isoindolin-1-one;

5-Chloro-2-[5-[7-(1-ethylpyrazole-4-carbonyl)-2,7-diazaspiro[3.5]nonan-2-yl]-3-pyridyl]-3,3-dimethyl-isoindolin-1-one;

5-Chloro-3,3-dimethyl-2-[5-[2-(1-methylpyrazole-4-carbonyl)-2,7-diazaspiro[3.5]nonan-7-yl]-3-pyridyl]isoindolin-1-one;

5-Chloro-2-[5-[2-(1-ethylpyrazole-4-carbonyl)-2,7-diazaspiro[3.5]nonan-7-yl]-3-pyridyl]-3,3-dimethyl-isoindolin-1-one; and,

5-Chloro-3,3-dimethyl-2-[5-[2-(4-methylpyridine-3-carbonyl)-2,7-diazaspiro[3.5]nonan-7-yl]-3-pyridyl]isoindolin-1-one; or,

a pharmaceutically acceptable salt thereof.

16. The compound according to claim 1 which compound is selected from the group consisting of:

5-Chloro-3,3-dimethyl-2-[5-[2-(1-methylpyrazole-4-carbonyl)-2,6-diazaspiro[3.3]heptan-6-yl]-3-pyridyl]isoindolin-1-one;

5-Chloro-2-[5-[2-(1-ethylpyrazole-4-carbonyl)-2,6-diazaspiro[3.3]heptan-6-yl]-3-pyridyl]-3,3-dimethyl-isoindolin-1-one;

5-Chloro-3,3-dimethyl-2-[5-[2-(4-methylpyridine-3-carbonyl)-2,6-diazaspiro[3.3]heptan-6-yl]-3-pyridyl]isoindolin-1-one;

2-[5-[2-(1-Ethylpyrazole-4-carbonyl)-2,6-diazaspiro[3.3]heptan-6-yl]-3-pyridyl]-3,3-dimethyl-1-oxo-isoindoline-5-carbonitrile;

2-Methoxy-7,7-dimethyl-6-[5-[2-(1-methylpyrazole-4-carbonyl)-2,6-diazaspiro[3.3]heptan-6-yl]-3-pyridyl]pyrrolo[3,4-b]pyridin-5-one;

5′-Chloro-2′-[5-[2-(1-methylpyrazole-4-carbonyl)-2,6-diazaspiro[3.3]heptan-6-yl]-3-pyridyl]spiro[cyclopropane-1,3′-isoindoline]-1′-one;

5-Chloro-3,3-dimethyl-2-[5-[7-(1-methylpyrazole-4-carbonyl)-2,7-diazaspiro[3.5]nonan-2-yl]-3-pyridyl]isoindolin-1-one;

5-Chloro-2-[5-[7-(1-ethylpyrazole-4-carbonyl)-2,7-diazaspiro[3.5]nonan-2-yl]-3-pyridyl]-3,3-dimethyl-isoindolin-1-one; and,

5-Chloro-3,3-dimethyl-2-[5-[2-(1-methylpyrazole-4-carbonyl)-2,7-diazaspiro[3.5]nonan-7-yl]-3-pyridyl]isoindolin-1-one; or,

or a pharmaceutically acceptable salt thereof.

17. A process to prepare a compound according to claim 1 comprising reacting a compound of formula (II) with a compound of formula (III) to afford compound I wherein R 1 , R 2 , R 3 ,

R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , A 1 , A 2 m, n and p are as described in claim 1 and X is halogen or triflate.

18. A process to prepare a compound according to claim 1 comprising reacting a compound of formula (IV) with a compound of formula (V) to afford a compound of formula (I)

wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , A 1 , A 2 m, n and p are as described in claim 1 and X is halogen.

19. A pharmaceutical composition comprising a compound according to claim 1 and at least one therapeutically acceptable carrier, diluent or excipient.

20. A method for the treatment of chronic kidney disease, congestive heart failure, hypertension, primary aldosteronism and Cushing syndrome, which method comprises administering to a patient in need thereof, a therapeutically effective amount of a compound according to claim 1 .