Heterocyclic compounds containing a pyrrolopyridine or benzimidazole core

1. A compound of formula (I):

wherein:

X is N or C;

Y is C or N;

wherein when X═N then Y═C and when X═C then Y═N;

R 1 is aryl or heteroaryl selected from the group consisting of phenyl, isoxazolyl, oxazolyl, imidazolyl, pyrazolyl, thiazolyl, furanyl, thienyl, pyrrolyl, pyridinyl, pyrimidinyl, pyridazinyl, benzimidazolyl, benzopyrazolyl, pyrazolopyridinyl, imidazopyridinyl, indolyl, and quinolinyl; wherein each of the foregoing R 1 groups is optionally substituted with 1 to 3 substituents selected from R 6 ;

R 2 and R 3 are each independently H or C 1 -C 5 alkyl; or

R 2 and R 3 together with the carbon atom to which they are attached, form a C 3 -C 8 cycloalkyl ring;

R 4 and R 5 are each independently H or C 1 -C 5 alkyl; or

R 4 and R 5 together with the carbon atom to which they are attached, form a C 3 -C 8 cycloalkyl ring;

each R 6 is independently C 1 -C 5 alkyl, —C 1 -C 5 alkylamino, —C 1 -C 5 alkyl-NH—C 1 -C 3 alkyl, —C 1 -C 5 alkyl-N(C 1 -C 3 alkyl) 2 , —C 1 -C 5 alkyl-aryl, —C 1 -C 5 alkyl-heteroaryl, —C 1 -C 5 alkyl-heterocyclyl, C 1 -C 5 alkoxyl, C 3 -C 8 cycloalkyl, —C(O)NH 2 , —C(O)NH—C 1 -C 5 alkyl, —C(O)N(C 1 -C 5 alky) 2 , —C(O)NH—C 3 -C 8 cycloalkyl, —C(O)OC 1 -C 5 alkyl, halogen, cyano, heterocyclyl, aryl or heteroaryl; wherein each aryl and heteroaryl of said R 6 is optionally independently substituted with 1 to 2 of C 1 -C 5 alkyl;

n is 0 or 1;

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , wherein:

X is C;

Y is N;

R 1 is aryl or heteroaryl; wherein each of the foregoing R 1 groups is optionally substituted with 1 to 3 substituents selected from R 6 ;

R 2 and R 3 are each independently H or C 1 -C 5 alkyl; or

R 2 and R 3 together with the carbon atom to which they are attached, form a C 3 -C 8 cycloalkyl ring;

R 4 and R 5 are each independently H or C 1 -C 5 alkyl; or

R 4 and R 5 together with the carbon atom to which they are attached, form a C 3 -C 8 cycloalkyl ring; and

each R 6 is independently C 1 -C 5 alkyl, —C 1 -C 5 alkylamino, —C 1 -C 5 alkyl-NH—C 1 -C 3 alkyl, —C 1 -C 5 alkyl-N(C 1 -C 3 alkyl) 2 , —C 1 -C 5 alkyl-aryl, —C 1 -C 5 alkyl-heteroaryl, —C 1 -C 5 alkyl-heterocyclyl, C 1 -C 5 alkoxyl, C 3 -C 8 cycloalkyl, —C(O)NH 2 , —C(O)NH—C 1 -C 5 alkyl, —C(O)N(C 1 -C 5 alky) 2 , —C(O)NH—C 3 -C 8 cycloalkyl, —C(O)OC 1 -C 5 alkyl, halogen, cyano, heterocyclyl, aryl or heteroaryl; wherein each aryl and heteroaryl of said R 6 is optionally independently substituted with 1 to 2 of C 1 -C 5 alkyl; and

n is 0 or 1;

or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 wherein:

R 1 is phenyl, isoxazolyl, oxazolyl, imidazolyl, pyrazolyl, thiazolyl, furanyl, thienyl, pyrrolyl, pyridinyl, pyrimidinyl, pyridazinyl, benzimidazolyl, benzopyrazolyl, pyrazolopyridinyl, imidazopyridinyl, indolyl, or quinolinyl; wherein each of the foregoing R 1 groups is optionally substituted with 1 to 3 substituents selected from R 6 ;

R 2 and R 3 are each independently H or C 1 -C 3 alkyl; or

R 2 and R 3 together with the carbon atom to which they are attached, form a C 3 -C 6 cycloalkyl ring;

R 4 and R 5 are each independently H or C 1 -C 3 alkyl; or

R 4 and R 5 together with the carbon atom to which they are attached, form a C 3 -C 6 cycloalkyl ring; and

each R 6 is independently C 1 -C 5 alkyl, —C 1 -C 5 alkylamino, —C 1 -C 5 alkyl-NH—C 1 -C 3 alkyl, —C 1 -C 5 alkyl-N(C 1 -C 3 alkyl) 2 , —C 1 -C 5 alkyl-phenyl, C 1 -C 3 alkoxyl, C 3 -C 6 cycloalkyl, —C(O)NH 2 , —C(O)NH—C 1 -C 3 alkyl, —C(O)N(C 1 -C 3 alkyl) 2 , —C(O)NH—C 3 -C 6 cycloalkyl, halogen, cyano or heteroaryl; wherein each heteroaryl of said R 6 is optionally independently substituted with 1 to 2 of C 1 -C 3 alkyl;

or a pharmaceutically acceptable salt thereof.

4. The compound of claim 3 , wherein:

R 1 is phenyl, isoxazolyl, imidazolyl, pyrazolyl, pyridinyl, benzimidazolyl, pyrazolopyridinyl, imidazopyridinyl or quinolinyl; wherein each of the foregoing R 1 groups is optionally substituted with 1 to 3 substituents selected from R 6 ;

R 2 and R 3 are each independently H or C 1 -C 3 alkyl;

R 4 and R 5 are each independently H or C 1 -C 3 alkyl;

each R 6 is independently C 1 -C 5 alkyl, —C 1 -C 5 alkyl-N(C 1 -C 2 alkyl) 2 , —CH 2 -phenyl, —C(O)NH 2 , —C(O)NH—C 3 -C 6 cycloalkyl, halogen or heteroaryl; wherein each heteroaryl of said R 6 is optionally independently substituted with 1 to 2 of C 1 -C 3 alkyl; and

n is 1;

or a pharmaceutically acceptable salt thereof.

5. The compound of claim 4 wherein:

R 1 is benzimidazolyl substituted with 1 to 2 substituents selected from R 6 ;

R 2 and R 3 are each independently H or methyl;

R 4 and R 5 are H; and

R 6 is C 1 -C 3 alkyl;

or a pharmaceutically acceptable salt thereof.

6. The compound of claim 1 wherein:

X is N;

Y is C;

R 1 is aryl or heteroaryl, each optionally substituted with 1 to 3 substituents selected from R 6 ;

R 2 and R 3 are each independently H or C 1 -C 5 alkyl; or

R 2 and R 3 together with the carbon atom to which they are attached, form a C 3 -C 8 cycloalkyl ring;

R 4 and R 5 are each independently H or C 1 -C 5 alkyl; or

R 4 and R 5 together with the carbon atom to which they are attached, form a C 3 -C 8 cycloalkyl ring;

each R 6 is independently C 1 -C 5 alkyl, —C 1 -C 5 alkylamino, —C 1 -C 5 alkyl-NH—C 1 -C 3 alkyl, —C 1 -C 5 alkyl-N(C 1 -C 3 alkyl) 2 , —C 1 -C 5 alkyl-aryl, —C 1 -C 5 alkyl-heteroaryl, —C 1 -C 5 alkyl-heterocyclyl, C 1 -C 5 alkoxyl, C 3 -C 8 cycloalkyl, —C(O)NH 2 , —C(O)NH—C 1 -C 5 alkyl, —C(O)N(C 1 -C 5 alky) 2 , —C(O)NH—C 3 -C 8 cycloalkyl, —C(O)OC 1 -C 5 alkyl, halogen, cyano, heterocyclyl, aryl or heteroaryl; wherein each aryl and heteroaryl of said R 6 is optionally independently substituted with 1 to 2 of C 1 -C 5 alkyl; and

n is 0 or 1;

or a pharmaceutically acceptable salt thereof.

7. The compound of claim 3 wherein:

R 1 is phenyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, pyridinyl, benzimidazolyl, pyrazolopyridinyl or quinolinyl; wherein each of the foregoing R1 groups optionally substituted with 1 to 3 substituents selected from R 6 ;

R 2 and R 3 are each independently H or C 1 -C 3 alkyl;

R 4 and R 5 are each independently H or C 1 -C 3 alkyl; and

each R 6 is independently C 1 -C 5 alkyl, —C 1 -C 5 alkyl-N(C 1 -C 2 alkyl) 2 , —C 1 -C 3 alkyl-phenyl, —C 1 -C 3 alkyl-pyridinyl, —C 1 -C 3 alkyl-tetrahydrofuranyl, —C 1 -C 3 alkyl-morpholinyl, C 3 -C 6 cycloalkyl, —C(O)NH 2 , —C(O)NH—C 1 -C 3 alkyl, —C(O)NH—C 3 -C 6 cycloalkyl, —C(O)OC 1 -C 3 alkyl, halogen or heteroaryl; wherein each heteroaryl group of said R 6 is optionally independently substituted with 1 to 2 of C 1 -C 3 alkyl;

or a pharmaceutically acceptable salt thereof.

8. The compound of claim 3 wherein:

R 1 is phenyl, isoxazolyl, imidazolyl, pyrazolyl, pyridinyl, pyrazolopyridinyl or quinolinyl; wherein each of the foregoing R 1 groups is optionally substituted with 1 to 3 substituents selected from R 6 ; and

each R 6 is independently C 1 -C 5 alkyl, —C 1 -C 3 alkyl-phenyl, —C 1 -C 3 alkyl-pyridinyl, —C 1 -C 3 alkyl-tetrahydrofuranyl, —C 1 -C 3 alkyl-morpholinyl, —C(O)NH 2 , —C(O)NH—C 3 -C 6 cycloalkyl or;

or a pharmaceutically acceptable salt thereof.

9. A compound of claim 1 selected from the group consisting of:

10-methyl-6-oxo-N-[1-(pyridin-4-ylmethyl)-1H-pyrazol-4-yl]-7,8,9,10-tetrahydro-6H-pyrido[3′,2′:4,5]pyrrolo[1,2-a][1,4]diazepine-2-carboxamide;

N-(1-benzyl-1H-pyrazol-4-yl)-trans-8,9-dimethyl-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxamide;

(9R)—N-(1-benzyl-1H-pyrazol-4-yl)-9-methyl-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxamide;

N-(1-benzyl-1H-pyrazol-4-yl)-10-methyl-6-oxo-7,8,9,10-tetrahydro-6H-pyrido[3′,2′:4,5]pyrrolo[1,2-a][1,4]diazepine-2-carboxamide;

(9S)—N-(1-benzyl-1H-pyrazol-4-yl)-9-methyl-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxamide;

(9R)-9-methyl-N-(5-methyl-1,2-oxazol-3-yl)-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxamide;

(9R)-9-methyl-6-oxo-N-[1-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxamide;

(9R)-9-methyl-6-oxo-N-(quinolin-3-yl)-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxamide;

N-(2-carbamoylphenyl)-6-oxo-7,8,9,10-tetrahydro-6H-pyrido[3′,2′:4,5]pyrrolo[1,2-a][1,4]diazepine-2-carboxamide;

N-[2-(cyclopentylcarbamoyl)-1-methyl-1H-imidazol-4-yl]-6-oxo-7,8,9,10-tetrahydro-6H-pyrido[3′,2′:4,5]pyrrolo[1,2-a][1,4]diazepine-2-carboxamide;

N-(1-benzyl-1H-pyrazol-4-yl)-6-oxo-7,8,9,10-tetrahydro-6H-pyrido[3′,2′:4,5]pyrrolo[1,2-a][1,4]diazepine-2-carboxamide;

10-methyl-N-(1-methyl-1H-pyrazol-4-yl)-6-oxo-7,8,9,10-tetrahydro-6H-pyrido[3′,2′:4,5]pyrrolo[1,2-a][1,4]diazepine-2-carboxamide;

N-(1-tert-butyl-1H-pyrazol-4-yl)-6-oxo-7,8,9,10-tetrahydro-6H-pyrido[3′,2′:4,5]pyrrolo[1,2-a][1,4]diazepine-2-carboxamide;

N-(1-methyl-1H-pyrazol-4-yl)-6-oxo-7,8,9,10-tetrahydro-6H-pyrido[3′,2′:4,5]pyrrolo[1,2-a][1,4]diazepine-2-carboxamide;

N-(1-tert-butyl-1H-pyrazol-4-yl)-10-methyl-6-oxo-7, 8,9,10-tetrahydro-6H-pyrido[3′,2′:4,5]pyrrolo[1,2-a][1,4]diazepine-2-carboxamide;

N-[5-chloro-7-(morpholin-4-ylmethyl)-1H-benzimidazol-2-yl]-6-oxo-7,8,9,10-tetrahydro-6H-pyrido[3′,2′:4,5]pyrrolo[1,2-a][1,4]diazepine-2-carboxamide;

N-(5-benzyl-1,2-oxazol-3-yl)-cis-8,9-dimethyl-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxamide;

6-oxo-N-[1-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-7,8,9,10-tetrahydro-6H-pyrido[3′,2′:4,5]pyrrolo[1,2-a][1,4]diazepine-2-carboxamide;

6-oxo-N-(quinolin-3-yl)-7,8,9,10-tetrahydro-6H-pyrido[3′,2′:4,5]pyrrolo[1,2-a][1,4]diazepine-2-carboxamide;

10-methyl-6-oxo-N-[1-(tetrahydrofuran-3-ylmethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-7,8,9,10-tetrahydro-6H-pyrido[3′,2′:4,5]pyrrolo[1,2-a][1,4]diazepine-2-carboxamide;

(9N)—N-(5-benzyl-1,2-oxazol-3-yl)-9-methyl-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxamide;

N-(4-methylpyridin-2-yl)-6-oxo-7,8,9,10-tetrahydro-6H-pyrido[3′,2′:4,5]pyrrolo[1,2-a][1,4]diazepine-2-carboxamide;

N-(1-ethyl-1H-benzimidazol-2-yl)-1-oxo-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]benzimidazole-8-carboxamide;

N-(3-benzyl-1,2-oxazol-5-yl)-6-oxo-7,8,9,10-tetrahydro-6H-pyrido[3′,2′:4,5]pyrrolo[1,2-a][1,4]diazepine-2-carboxamide; or

a pharmaceutically acceptable salt thereof.

10. A compound of claim 1 selected from the group consisting of:

N-(5-benzyl-1,2-oxazol-3-yl)-10-methyl-6-oxo-7,8,9,10-tetrahydro-6H-pyrido[3′,2′:4,5]pyrrolo[1,2-a][1,4]diazepine-2-carboxamide;

10-methyl-6-oxo-N-[1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-7,8,9,10-tetrahydro-6H-pyrido[3′,2′:4,5]pyrrolo[1,2-a][1,4]diazepine-2-carboxamide;

10-methyl-6-oxo-N-[1-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-7,8,9,10-tetrahydro-6H-pyrido[3′,2′:4,5]pyrrolo[1,2-a][1,4]diazepine-2-carboxamide;

N-(1-benzyl-1H-pyrazol-4-yl)-cis-8,9-dimethyl-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxamide;

N-(3-benzyl-1,2-oxazol-5-yl)-10-methyl-6-oxo-7,8,9,10-tetrahydro-6H-pyrido[3′,2′:4,5]pyrrolo[1,2-a][1,4]diazepine-2-carboxamide;

10-methyl-N-(5-methyl-1,2-oxazol-3-yl)-6-oxo-7,8,9,10-tetrahydro-6H-pyrido[3′,2′:4,5]pyrrolo[1,2-a][1,4]diazepine-2-carboxamide;

Cis-8,9-dimethyl-N-(5-methyl-1,2-oxazol-3-yl)-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxamide;

N-(5-methyl-1,2-oxazol-3-yl)-6-oxo-7,8,9,10-tetrahydro-6H-pyrido[3′,2′:4,5]pyrrolo[1,2-a][1,4]diazepine-2-carboxamide;

N-(3-fluorophenyl)-6-oxo-7,8,9,10-tetrahydro-6H-pyrido[3′,2′:4,5]pyrrolo[1,2-a][1,4]diazepine-2-carboxamide;

5,5-dimethyl-1-oxo-N-[1-(propan-2-yl)-1H-benzimidazol-2-yl]-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]benzimidazole-8-carboxamide;

6-oxo-N-[1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-7,8,9,10-tetrahydro-6H-pyrido[3′,2′:4,5]pyrrolo[1,2-a][1,4]diazepine-2-carboxamide;

6-oxo-N-[1-(tetrahydrofuran-3-ylmethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-7,8,9,10-tetrahydro-6H-pyrido[3′,2′:4,5]pyrrolo[1,2-a][1,4]diazepine-2-carboxamide;

N-(1-ethyl-1H-benzimidazol-2-yl)-cis-8,9-dimethyl-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxamide;

1-oxo-N-[1-(propan-2-yl)-1H-benzimidazol-2-yl]-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]benzimidazole-8-carboxamide;

N-(1-benzyl-1H-pyrazol-4-yl)-9,9-dimethyl-6-oxo-7,8,9,10-tetrahydro-6H-pyrido[3′,2′:4,5]pyrrolo[1,2-a][1,4]diazepine-2-carboxamide;

9-methyl-6-oxo-N-(pyridin-3-yl)-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxamide;

N-(1-ethyl-1H-benzimidazol-2-yl)-10-methyl-6-oxo-7,8,9,10-tetrahydro-6H-pyrido[3′,2′:4,5]pyrrolo[1,2-a][1,4]diazepine-2-carboxamide;

9,9-dimethyl-N-(1-methyl-1H-pyrazol-4-yl)-6-oxo-7,8,9,10-tetrahydro-6H-pyrido[3′,2′:4,5]pyrrolo[1,2-a][1,4]diazepine-2-carboxamide; or

a pharmaceutically acceptable salt thereof.

11. A pharmaceutical composition comprising one or more compounds of claim 1 , or the pharmaceutically acceptable salts thereof, optionally combined with one or more excipients and/or carriers.

12. A method treating a ribosomal S6 kinase2 (RSK2) regulated disorder comprising administering to a patient in need thereof a pharmaceutically effective amount of one or more compounds of claim 1 , or the pharmaceutically acceptable salts thereof.

13. The method of claim 12 , wherein the RSK2 regulated disorder is selected from the group consisting of cardiovascular disease, inflammatory disease, allergic disease, pulmonary disease, fibrotic disease, renal disease and cancer.