Pyrazine substituted pyrrolopyridines as inhibitors of JAK and PDK1

1. A compound of formula (I):

wherein:

a is 0, 1 or 2;

each of R 1 and R 2 is independently hydroxy, cyano, halogen, C 1-6 alkyl, C 2-10 alkenyl, haloC 1-6 alkyl, hydroxyC 1-6 alkyl, C 1-6 alkylcarbonyl, C 1-6 alkoxy, haloC 1-6 alkoxy, C 1-6 alkoxycarbonyl, carboxy, nitro, NR x R y , CONR x R y , NR x (CONR x R y ), S(O) r NR x R y or a ring which is: C 6-10 aryl, C 6-10 aryloxy, C 6-10 arylC 1-6 alkyl, C 6-10 arylcarbonyl, C 3-10 cycloalkyl, azetidinyl, a 5 or 6 membered saturated or partially saturated heterocyclic ring containing 1, 2 or 3 atoms independently selected from N, O and S, a 5 membered heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, not more than one heteroatom of which is O or S, a 6 membered heteroaromatic ring containing 1, 2 or 3 N atoms or a 7-15 membered unsaturated, partially saturated or saturated heterocyclic ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S; optionally substituted by one or more groups independently selected from R a ;

R 3 is hydrogen or C 1-6 alkyl;

R 4 is hydrogen, -L-R b or -M-R c ;

each of R 5 , R 6 and R 7 is independently selected from hydrogen, hydroxy, cyano, halogen, C 1-6 alkyl, C 2-10 alkenyl, haloC 1-6 alkyl, hydroxyC 1-6 alkyl, C 1-6 alkylcarbonyl, C 1-6 alkoxy, haloC 1-6 alkoxy, C 1-6 alkoxycarbonyl, carboxy, nitro, NR x R y or a ring which is: C 6-10 aryl, C 6-10 arylC 1-6 alkyl, C 3-10 cycloalkyl, azetidinyl, a 5 or 6 membered saturated or partially saturated heterocyclic ring containing 1, 2 or 3 atoms independently selected from N, O and S, a 5 membered heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, not more than one heteroatom of which is O or S, a 6 membered heteroaromatic ring containing 1, 2 or 3 nitrogen atoms or a 7-15 membered unsaturated, partially saturated or saturated heterocyclic ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S; any of which rings being optionally substituted by one or more groups independently selected from hydroxy, cyano, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 2-10 alkenyl, haloC 1-6 alkyl, amino, C 1-6 alkylamino and di(C 1-6 alkyl)amino;

each of L and M is a direct bond, —O(CR v R w ) b [N(R z )] c — or —N(R z )(CR v R w ) b —;

b is 0, 1, 2, 3 or 4;

c is 0 or 1;

r is 0, 1 or 2;

each R a is independently selected from hydroxy, oxo, cyano, halogen, C 1-6 alkyl, C 2-10 alkenyl, haloC 1-6 alkyl, C 1-6 alkylcarbonyl, C 1-6 alkoxy, haloC 1-6 alkoxy, hydroxyC 1-6 alkyl, C 1-6 alkoxycarbonyl, carboxy, NR x R y or a ring which is: C 6-10 aryl, C 6-10 arylC 1-6 alkyl, C 3-10 cycloalkyl, azetidinyl, a 5 or 6 membered saturated or partially saturated heterocyclic ring containing 1, 2 or 3 atoms independently selected from N, O and S, a 5 membered heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, not more than one heteroatom of which is O or S, a 6 membered heteroaromatic ring containing 1, 2 or 3 nitrogen atoms or a 7-15 membered unsaturated, partially saturated or saturated heterocyclic ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S; any of which rings being optionally substituted by one or more groups independently selected from hydroxy, cyano, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 2-10 alkenyl, haloC 1-6 alkyl, amino, C 1-6 alkylamino and di(C 1-6 alkyl)amino;

R b is hydroxy, cyano, halogen, C 1-6 alkyl, C 2-10 alkenyl, haloC 1-6 alkyl, hydroxyC 1-6 alkyl, C 1-6 alkylcarbonyl, C 1-6 alkoxy, haloC 1-6 alkoxy, C 1-6 alkoxycarbonyl, carboxy, nitro or NR x R y ;

R c is C 3-10 cycloalkyl, azetidinyl, a 5 or 6 membered saturated or partially saturated heterocyclic ring containing 1, 2 or 3 atoms independently selected from N, O and S, a 5 membered heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, O, and S, not more than one heteroatom of which is O or S, a 6 membered heteroaromatic ring containing 1, 2 or 3 N atoms or a 7-15 membered unsaturated, partially saturated or saturated heterocyclic ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S; optionally substituted by one or more groups independently selected from R d ;

each R d is independently selected from hydroxy, oxo, cyano, halogen, C 1-6 alkyl, C 2-10 alkenyl, haloC 1-6 alkyl, C 1-6 alkylcarbonyl, C 1-6 alkoxy, haloC 1-6 alkoxy, hydroxyC 1-6 alkyl, C 1-6 alkoxycarbonyl, carboxy, NR x R y or a ring which is: C 6-10 aryl, C 6-10 arylC 1-6 alkyl, C 3-10 cycloalkyl, azetidinyl, a 5 or 6 membered saturated or partially saturated heterocyclic ring containing 1, 2 or 3 atoms independently selected from N, O and S, a 5 membered heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, not more than one heteroatom of which is O or S, a 6 membered heteroaromatic ring containing 1, 2 or 3 nitrogen atoms or a 7-15 membered unsaturated, partially saturated or saturated heterocyclic ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S; any of which rings being optionally substituted by one or more groups independently selected from hydroxy, cyano, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 2-10 alkenyl, haloC 1-6 alkyl, amino, C 1-6 alkylamino and di(C 1-6 alkyl)amino;

each of R v and R w is independently hydrogen, C 1-6 alkyl, halogen, hydroxy or haloC 1-6 alkyl;

each of R x and R y is independently hydrogen, C 1-6 alkyl, C 1-6 alkylcarbonyl, haloC 1-6 alkyl or hydroxyC 1-6 alkyl;

R z is hydrogen or C 1-6 alkyl;

or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof.

2. A compound of claim 1 of formula (II):

wherein:

R 1 is azetidinyl, a 5 or 6 membered saturated or partially saturated heterocyclic ring containing 1, 2 or 3 atoms independently selected from N, O and S, a 5 membered heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, and S, not more than one heteroatom of which is O or S, a 6 membered heteroaromatic ring containing 1, 2 or 3 N atoms or a 7-15 membered unsaturated, partially saturated or saturated heterocyclic ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S; optionally substituted by one or more groups independently selected from R a ;

or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof.

3. A compound of claim 1 of formula (III):

wherein:

L is —O(CR v R w ) b — or —N(R z )(CR v R w ) b —;

R l is azetidinyl, a 5 or 6 membered saturated or partially saturated heterocyclic ring containing 1, 2 or 3 atoms independently selected from N, O and S, a 5 membered heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, not more than one heteroatom of which is O or S, a 6 membered heteroaromatic ring containing 1, 2 or 3 N atoms or a 7-15 membered unsaturated, partially saturated or saturated heterocyclic ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S; optionally substituted by one or more groups independently selected from R a ;

or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof.

4. A compound of claim 1 of formula (IV):

wherein:

M is a direct bond, —O—, —N(R z )— or —O(CR v R w ) b N(R z )—;

R 1 is azetidinyl, a 5 or 6 membered saturated or partially saturated heterocyclic ring containing 1, 2 or 3 atoms independently selected from N, O and S, a 5 membered heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, not more than one heteroatom of which is O or S, a 6 membered heteroaromatic ring containing 1, 2 or 3 N atoms or a 7-15 membered unsaturated, partially saturated or saturated heterocyclic ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S; optionally substituted by one or more groups independently selected from R a ;

or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof.

5. A compound of claim 1 wherein R 7 is hydrogen, C 1-6 alkyl or haloC 1-6 alkyl.

6. A compound of claim 1 wherein each of R 5 and R 6 is independently hydrogen or C 1-6 alkyl.

7. A compound of claim 1 selected from:

5-(1-methyl-1H-pyrazol-4-yl)-3-(6-piperazin-1-ylpyrazin-2-yl)-1H-pyrrolo[2,3-b]pyridine;

5-(1-methyl-1H-pyrazol-4-yl)-3-[6-(piperidin-4-yloxy)pyrazin-2-yl]-1H-pyrrolo[2,3-b]pyridine;

3-[6-(cyclohexyloxy)pyrazin-2-yl]-5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine;

N-methyl-6-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-N-piperidin-4-ylpyrazin-2-amine;

3-[6-(piperidin-4-yloxy)pyrazin-2-yl]-5-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine;

3-{6-[(3R)-piperdin-3-yloxy]pyrazin-2-yl}-5-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine;

3-{6-[(3S)-piperdin-3-yloxy]pyrazin-2-yl}-5-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine;

trans-3-{6-[(3-fluoropiperdin-4-yl)oxy]pyrazin-2-yl}-5-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine;

cis-3-{6-[(3-fluoropiperdin-4-yl)oxy]pyrazin-2-yl}-5-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine;

3-[6-(azetidine-3-yloxy)pyrazin-2-yl]-5-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine;

5-(1H-pyrazol-4-yl)-3-{6-[(3S)-pyrrolidin-3-yloxy]pyrazin-2-yl-1H-pyrrolo[2,3-b]pyridine;

(2S)-1-({6-[5-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]pyrazin-2-yl}oxy)propan-2-amine;

(2S)-2-({6-[5-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]pyrazin-2-yl}oxy)propan-1-amine;

5-(1H-pyrazol-4-yl)-3-{6-[(3R)-pyrrolidin-3-yloxy]pyrazin-2-yl-1H-pyrrolo[2,3-b]pyridine;

(2R)-1-({6-[5-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]pyrazin-2-yl}oxy)propan-2-amine;

(2R)-2-({6-[5-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]pyrazin-2-yl}oxy)propan-1-amine;

Trans-4-({6-[5-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]pyrazin-2-yl)}amino)cyclohexanol;

6-[5-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl-N-(tetrahydro-2H-pyran-5-yl)pyrazin-2-amine;

1-{6-[5-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]pyrazin-2-yl}piperdin-4-ol;

2-({6-[5-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]pyrazin-2-yl}amino)ehthanol;

1-{6-[5-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]pyrazin-2-yl}azetidin-3-ol;

3-({6-[5-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]pyrazin-2-yl}amino)propan-1-ol;

4-({6-[5-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]pyrazin-2-yl}oxy)cyclohexanol;

5-(1-ethyl-1H-pyrazol-4-yl)-3-[6-(piperidin-4-yloxy)pyrazin-2-yl]-1H-pyrrolo[2,3-b]pyridine;

5-[1-(cyclopropylmethyl)-1H-pyrazol-4-yl]-3-[6-(piperidin-4-yloxy)pyrazin-2-yl]-1H-pyrrolo[2,3-b]pyridine;

2-(4-{3-[6-(piperidin-4-yloxy)pyrazin-2-yl]-1H-pyrrolo[2,3-b]pyridine-5-yl}-1H-pyrazol-1-yl)ethanol;

3-[6-(piperidin-4-yloxy)pyrazin-2-yl]-5-[1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl]-1H-pyrrolo[2,3-b]pyridine;

3-[6-(piperidin-4-yloxy)pyrazin-2-yl]-1-(2,2,2-trifluoroethyl)-5-[1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl]-1H-pyrrolo[2,3-b]pyridine;

5-(1H-pyrazol-4-yl)-3-(6-{[3-(trifluoromethyl)azetidin-3-yl]oxy}pyrazin-2-yl]-1H-pyrrolo[2,3-b]pyridine;

3,3,3-trifluoro-2-({6-[5-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]pyrazin-2-yl}oxy)propan-1-amine;

N-ethyl-N-piperidin-4-yl-6-[5-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]pyrazin-2-amine;

N-piperidin-4-yl-N-propyl-6-[5(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]pyrazin-2-amine;

3-[5-methyl-6-(piperidin-4-yloxy)pyrazin-2-yl]-5-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine;

N-[2-({6-[5-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]pyrazin-2-yl}oxy)ethyl]cyclohexanamine;

and pharmaceutically acceptable salts, stereoisomers and tautomers thereof.

8. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt or tautomer thereof in association with a pharmaceutically acceptable carrier.