IP Library › Granted Patent US 8,101,613

Granted Patent B2

US 8,101,613 · App. 12/540,047 · Granted Jan 24, 2012

6,6-bicyclic ring substituted heterobicyclic protein kinase inhibitors

Assignee: OSI Pharmaceuticals, LLC

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Quick Facts

Patent No.: US 8,101,613
App. No.: 12/540,047
Granted: Jan 24, 2012
Kind: B2

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Abstract

Compounds of the formula and pharmaceutically acceptable salts thereof, wherein X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , R 1 , and Q 1 are defined herein, inhibit the IGF-1R enzyme and are useful for the treatment and/or prevention of hyperproliferative diseases such as cancer, inflammation, psoriasis, allergy/asthma, disease and conditions of the immune system, disease and conditions of the central nervous system.

Claims (3174)

1. A compound represented by Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

X 1 and X 2 are each CH;

X 3 and X 5 are each N;

X 4 , X 6 , and X 7 are each C;

Q 1 is

X 11 is C-E 11 wherein E 11 is H or halogen;

X 12 , X 13 , and X 15 , are all CH;

X 14 is C-E 11 wherein E 11 is H halogen, C 1-10 alkyl, —OH or —OC 1-10 alkyl;

X 16 is N;

R 1 is C 0-10 alkyl, cycloC 3-10 alkyl, bicycloC 5-10 alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, heterocyclyl, heterobicycloC 5-10 alkyl, spiroalkyl, or heterospiroalkyl, any of which is optionally substituted by one or more independent G 11 substituents;

G 1 is phenyl or pyridyl, either of which is optionally substituted with one or more independent halo, —CF 3 , —OCF 3 , —OR 222 , —NR 222 R 333 (R 222a ) j2a , —C(O)R 222 , —CO 2 R 222 , —C(═O)NR 222 R 333 , —NO 2 , —CN, —S(O) j2a R 222 , —SO 2 NR 222 R 333 , —NR 222 C(═O)R 333 , —NR 222 C(═O)OR 333 , —NR 222 C(═O)NR 333 R 222a , —NR 222 S(O) j2a R 333 , —C(═S)OR 222 , —C(═O)SR 222 , —NR 222 C(═NR 333 )NR 222a R 333a , —NR 222 C(═NR 333 )OR 222a , —NR 222 C(═NR 333 )SR 222a , —OC(═O)OR 222 , —OC(═O)NR 222 R 333 , —OC(═O)SR 222 , —SC(═O)OR 222 , or —SC(═O)NR 222 R 333 substituents;

G 11 is halo, oxo, —CF 3 , —OCF 3 , —OR 21 , —NR 21 R 31 (R 2a1 ) j4 , —C(O)R 21 , —CO 2 R 21 , —C(═O)NR 21 R 31 , —NO 2 , —CN, —S(O) j4 R 21 , —SO 2 NR 21 R 31 , NR 21 (C═O)R 31 , NR 21 C(═O)OR 31 , NR 21 C(═O)NR 31 R 2a1 , NR 21 S(O) j4 R 31 , —C(═S)OR 21 , —C(═O)SR 21 , NR 21 C(═NR 31 )NR 2a1 R 3a1 , —NR 21 C(═NR 31 )OR 2a1 , —NR 21 C(═NR 31 )SR 2a1 , —OC(═O)OR 21 , —OC(═O)NR 21 R 31 , —OC(═O)SR 21 , —SC(═O)OR 21 , —SC(═O)NR 21 R 31 , —P(O)OR 21 OR 31 , C 1-10 alkylidene, C 0-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxyC 1-10 alkyl, C 1-10 alkoxyC 2-10 alkenyl, C 1-10 alkoxyC 2-10 alkynyl, C 1-10 alkylthioC 1-10 alkyl, C 1-10 alkylthioC 2-10 alkenyl, C 1-10 alkylthioC 2-10 alkynyl, cycloC 3-8 alkyl, cycloC 3-8 alkenyl, cycloC 3-8 alkylC 1-10 alkyl, cycloC 3-8 alkenylC 1-10 alkyl, cycloC 3-8 alkylC 2-10 alkenyl, cycloC 3-8 alkenylC 2-10 alkenyl, cycloC 3-8 alkylC 2-10 alkynyl, cycloC 3-8 alkenylC 2-10 alkynyl, heterocyclyl-C 0-10 alkyl, heterocyclyl-C 2-10 alkenyl, or heterocyclyl-C 2-10 alkynyl, any of which is optionally substituted with one or more independent halo, oxo, —CF 3 , —OCF 3 , —OR 2221 , —NR 2221 R 3331 (R 222a1 ) j4a , —C(O)R 2221 , —CO 2 R 2221 , —C(═O)NR 2221 R 3331 , —NO 2 , —CN, —S(O) j4a R 2221 , —SO 2 NR 2221 R 3331 , —NR 2221 C(═O)R 3331 , —NR 2221 C(═O)OR 3331 , —NR 2221 C(═O)NR 3331 R 222a1 , —NR 2221 S(O) j4a R 3331 , —C(═S)OR 2221 , —C(═O)SR 2221 , —NR 2221 C(═NR 3331 )NR 222a1 R 333a1 , —NR 2221 C(═NR 3331 )OR 222a1 , —NR 2221 C(═NR 3331 )SR 222a1 , —OC(═O)OR 2221 , —OC(═O)NR 2221 R 3331 , —OC(═O)SR 2221 , —SC(═O)OR 2221 , —P(O)OR 2221 OR 3331 , or —SC(═O)NR 2221 R 3331 substituents;

or G 11 is aryl-C 0-10 alkyl, aryl-C 2-10 alkenyl, aryl-C 2-10 alkynyl, hetaryl-C 0-10 alkyl, hetaryl-C 2-10 alkenyl, or hetaryl-C 2-10 alkynyl, any of which is optionally substituted with one or more independent halo, —CF 3 , —OCF 3 , —OR 2221 , —NR 2221 R 3331 (R 222a1 ) j5a , —C(O)R 2221 , —CO 2 R 2221 , —C(═O)NR 2221 R 3331 , —NO 2 , —CN, —S(O) j5a R 2221 , —SO 2 NR 2221 R 3331 , —NR 2221 C(═O)R 3331 , —NR 2221 C(═O)OR 3331 , —NR 2221 C(═O)NR 3331 R 222a1 , —NR 2221 S(O) j5a R 3331 , —C(═S)OR 2221 , —C(═O)SR 2221 , —NR 2221 C(═NR 3331 )NR 222a1 R 333a1 , —NR 2221 C(═NR 3331 )OR 222a1 , —NR 2221 C(═NR 3331 )SR 222a1 , —OC(═O)OR 2221 , —OC(═O)NR 2221 R 3331 , —OC(═O)SR 2221 , —SC(═O)OR 2221 , —P(O)OR 2221 OR 3331 , or —SC(═O)NR 2221 R 3331 substituents;

or G 11 is C, taken together with the carbon to which it is attached forms a C═C double bond which is substituted with R 5 and G 111 ;

R 2 , R 2a , R 3 , R 3a , —R 222 , R 222a , R 333 , R 333a , R 21 , R 2a1 , R 31 , R 3a1 , R 2221 , R 222a1 , R 3331 , and R 333a1 are each independently C 0-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxyC 1-10 alkyl, C 1-10 alkoxyC 2-10 alkenyl, C 1-10 alkoxyC 2-10 alkynyl, C 1-10 alkylthioC 1-10 alkyl, C 1-10 alkylthioC 2-10 alkenyl, C 1-10 alkylthioC 2-10 alkynyl, cycloC 3-8 alkyl, cycloC 3-8 alkenyl, cycloC 3-8 alkylC 1-10 alkyl, cycloC 3-8 alkenylC 1-10 alkyl, cycloC 3-8 alkylC 2-10 alkenyl, cycloC 3-8 alkenylC 2-10 alkenyl, cycloC 3-8 alkylC 2-10 alkynyl, cycloC 3-8 alkenylC 2-10 alkynyl, heterocyclyl-C 0-10 alkyl, heterocyclyl-C 2-10 alkenyl, heterocyclyl-C 2-10 alkynyl, aryl-C 0-10 alkyl, aryl-C 2-10 alkenyl, or aryl-C 2-10 alkynyl, hetaryl-C 0-10 alkyl, hetaryl-C 2-10 alkenyl, or hetaryl-C 2-10 alkynyl, any of which is optionally substituted by one or more independent G 111 substituents;

or in the case of —NR 222 R 333 (R 222a ) j2a or —NR 2221 R 3331 (R 222a1 ) j4a or —NR 2221 R 3331 (R 222a1 ) j5a , then R 222 and R 333 , or R 2221 and R 3331 , respectfully, are optionally taken together with the nitrogen atom to which they are attached to form a 3-10 membered saturated or unsaturated ring, wherein said ring is optionally substituted by one or more independent G 1111 substituents and wherein said ring optionally includes one or more heteroatoms other than the nitrogen to which R 222 and R 333 , or R 2221 and R 3331 are attached;

R 5 , G 111 , and G 1111 are each independently C 0-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxyC 1-10 alkyl, C 1-10 alkoxyC 2-10 alkenyl, C 1-10 alkoxyC 2-10 alkynyl, C 1-10 alkylthioC 1-10 alkyl, C 1-10 alkylthioC 2-10 alkenyl, C 1-10 alkylthioC 2-10 alkynyl, cycloC 3-8 alkyl, cycloC 3-8 alkenyl, cycloC 3-8 alkylC 1-10 alkyl, cycloC 3-8 alkenylC 1-10 alkyl, cycloC 3-8 alkylC 2-10 alkenyl, cycloC 3-8 alkenylC 2-10 alkenyl, cycloC 3-8 alkylC 2-10 alkynyl, cycloC 3-8 alkenylC 2-10 alkynyl, heterocyclyl-C 0-10 alkyl, heterocyclyl-C 2-10 alkenyl, heterocyclyl-C 2-10 alkynyl, aryl-C 0-10 alkyl, aryl-C 2-10 alkenyl, aryl-C 2-10 alkynyl, hetaryl-C 0-10 alkyl, hetaryl-C 2-10 alkenyl, or hetaryl-C 2-10 alkynyl, any of which is optionally substituted with one or more independent halo, —CF 3 , OCF 3 , —OR 77 , —NR 77 R 87 , —C(O)R 77 , —CO 2 R 77 , —CONR 77 R 87 , —NO 2 , —CN, —S(O) j5a R 77 , —SO 2 NR 77 R 87 , —NR 77 C(═O)R 87 , —NR 77 C(═O)OR 87 , —NR 77 C(═O)NR 78 R 87 , —NR 77 S(O) j5a R 87 , —C(═S)OR 77 , —C(═O)SR 77 , —NR 77 C(═NR 87 )NR 78 R 88 , —NR 77 C(═NR 87 )OR 78 , NR 77 C(═NR 87 )SR 78 , —OC(═O)OR 77 , —OC(═O)NR 77 R 87 , —OC(═O)SR 77 , —SC(═O)OR 77 , —P(O)OR 77 OR 87 , or —SC(═O)NR 77 R 87 substituents;

R 77 , R 78 , R 87 , R 88 are each independently C 0-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxyC 1-10 alkyl, C 1-10 alkoxyC 2-10 alkenyl, C 1-10 alkoxyC 2-10 alkynyl, C 1-10 alkylthioC 1-10 alkyl, C 1-10 alkylthioC 2-10 alkenyl, C 1-10 alkylthioC 2-10 alkynyl, cycloC 3-8 alkyl, cycloC 3-8 alkenyl, cycloC 3-8 alkylC 1-10 alkyl, cycloC 3-8 alkenylC 1-10 alkyl, cycloC 3-8 alkylC 2-10 alkenyl, cycloC 3-8 alkenylC 2-10 alkenyl, cycloC 3-8 alkylC 2-10 alkynyl, cycloC 3-8 alkenylC 2-10 alkynyl, heterocyclyl-C 0-10 alkyl, heterocyclyl-C 2-10 alkenyl, heterocyclyl-C 2-10 alkynyl, C 1-10 alkylcarbonyl, C 2-10 alkenylcarbonyl, C 2-10 alkynylcarbonyl, C 1-10 alkoxycarbonyl, C 1-10 alkoxycarbonylC 1-10 alkyl, monoC 1-6 alkylaminocarbonyl, diC 1-6 alkylaminocarbonyl, mono(aryl)aminocarbonyl, di(aryl)aminocarbonyl, or C 1-10 alkyl(aryl)aminocarbonyl, any of which is optionally substituted with one or more independent halo, cyano, hydroxy, nitro, C 1-10 alkoxy, —SO 2 N(C 0-4 alkyl)(C 0-4 alkyl), or —N(C 0-4 alkyl)(C 0-4 alkyl) substituents;

or R 77 , R 78 , R 87 , R 88 are each independently aryl-C 0-10 alkyl, aryl-C 2-10 alkenyl, aryl-C 2-10 alkynyl, hetaryl-C 0-10 alkyl, hetaryl-C 2-10 alkenyl, hetaryl-C 2-10 alkynyl, mono(C 1-6 alkyl)aminoC 1-6 alkyl, di(C 1-6 alkyl)aminoC 1-6 alkyl, mono(aryl)aminoC 1-6 alkyl, di(aryl)aminoC 1-6 alkyl, or —N(C 1-6 alkyl)-C 1-6 alkyl-aryl, any of which is optionally substituted with one or more independent halo, cyano, nitro, —O(C 0-4 alkyl), C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, haloC 1-10 alkyl, haloC 2-10 alkenyl, haloC 2-10 alkynyl, —COOH, C 1-4 alkoxycarbonyl, —CON(C 0-4 alkyl)(C 0-10 alkyl), —SO 2 N(C 0-4 alkyl)(C 0-4 alkyl), or —N(C 0-4 alkyl)(C 0-4 alkyl) substituents;

j2a, j4, j4a, j5a are each independently 0, 1, or 2.

2. The compound of claim 1 , wherein:

X 11 , X 12 , X 13 , X 14 , and X 15 are each CH.

3. The compound of claim 1 wherein R 1 is cycloC 3-10 alkyl, bicycloC 5-10 alkyl, aryl, heteroaralkyl, heterocyclyl, heterobicycloC 5-10 alkyl, spiroalkyl, or heterospiroalkyl any of which is optionally substituted by one or more independent G 11 substituents.

4. The compound of claim 1 wherein R 1 is C 0-10 alkyl, heteroaralkyl, or aralkyl, any of which is optionally substituted by one or more independent G 11 substituents.

5. The compound of claim 1 wherein R 1 is cycloC 3-10 alkyl, bicycloC 5-10 alkyl, spiroalkyl, or heterospiroalkyl any of which is optionally substituted by one or more independent G 11 substituents.

6. The compound of claim 1 wherein R 1 is heterocyclyl or heterobicycloC 5-10 alkyl, either of which is optionally substituted by one or more independent G 11 substituents.

7. The compound of claim 1 wherein R 1 is aryl or heteroaryl, either of which is optionally substituted by one or more independent G 11 substituents.

8. The compound of claim 1 wherein R 1 is C 0-10 alkyl, cycloC 3-10 alkyl, bicycloC 5-10 alkyl, aralkyl, heteroaralkyl, heterocyclyl, heterobicycloC 5-10 alkyl, spiroalkyl, or heterospiroalkyl any of which is optionally substituted by one or more independent G 11 substituents.

9. The compound of claim 3 wherein G 11 is oxo, —OR 21 , NR 21 R 31 (R 2a1 ) j4 , —CO 2 R 21 , —C(═O)NR 21 R 31 , C 0-10 alkyl, heterocyclyl-C 0-10 alkyl, any of which is optionally substituted with one or more independent halo, oxo, —CF 3 , —OCF 3 , —OR 2221 , —NR 2221 R 3331 (R 222a1 ) j4a , —C(O)R 2221 , —CO 2 R 2221 , —C(═O)NR 2221 R 3331 , —NO 2 , —CN, —S(O) j4a R 2221 , —SO 2 NR 2221 R 3331 , —NR 2221 C(═O)R 3331 , —NR 2221 C(═O)OR 3331 , —NR 2221 C(═O)NR 3331 R 222a1 , —NR 2221 S(O) j4a R 3331 , —C(═S)OR 2221 , —C(═O)SR 2221 , —NR 2221 C(═NR 3331 )NR 222a1 R 333a1 , —NR 2221 C(═NR 3331 )OR 222a1 , —NR 2221 C(═NR 3331 )SR 222a1 , —OC(═O)OR 2221 , —OC(═O) NR 2221 R 3331 , —OC(═O)SR 2221 , —SC(═O)OR 2221 , —P(O)OR 2221 OR 3331 , or —SC(═O)NR 2221 R 3331 substituents;

or G 11 is hetaryl-C 0-10 alkyl, any of which is optionally substituted with one or more independent halo, —CF 3 , —OCF 3 , —OR 2221 , —NR 2221 R 3331 (R 222a1 ) j5a , —C(O)R 2221 , —CO 2 R 2221 , —C(═O)NR 2221 R 3331 , —NO 2 , —CN, —S(O) j5a R 2221 , —SO 2 NR 2221 R 3331 , —NR 2221 C(═O)R 3331 , —NR 2221 C(═O)OR 3331 , —NR 2221 C(═O)NR 3331 R 222a1 , —NR 2221 S(O) j5a R 3331 , —C(═S)OR 2221 , —C(═O)SR 2221 , —NR 2221 C(═NR 3331 )NR 222a1 R 333a1 , —NR 2221 C(═NR 3331 )OR 222a1 , —NR 2221 C(═NR 3331 )SR 222a1 , —OC(═O)OR 2221 , —OC(═O)NR 2221 R 3331 , —OC(═O)SR 2221 , —SC(═O)OR 2221 , —P(O)OR 2221 OR 3331 , or —SC(═O)NR 2221 R 3331 substituents.

10. The compound of claim 3 wherein G 11 is oxo, —OR 21 , NR 21 R 31 (R 2a1 ) j4 , —CO 2 R 21 , —C(═O)NR 21 R 31 , C 0-10 alkyl, heterocyclyl-C 0-10 alkyl, any of which is optionally substituted with one or more independent halo, oxo, —OR 2221 , or —NR 2221 R 3331 (R 222a1 ) j4a substituents;

or G 11 is hetaryl-C 0-10 alkyl, any of which is optionally substituted with one or more independent halo, —CF 3 , —OCF 3 , —OR 2221 , —NR 2221 R 3331 (R 222a1 ) j5a , —C(O)R 2221 , —CO 2 R 2221 , —C(═O)NR 2221 R 3331 , —NO 2 , —CN, —S(O) j5aR 2221 , —SO 2 NR 2221 R 3331 , —NR 2221 C(═O)R 3331 , —NR 2221 C(═O)OR 3331 , —NR 2221 C(═O)NR 3331 R 222a1 , —NR 2221 S(O) j5a R 3331 , —(═S)OR 2221 , —C(═O)SR 2221 , —NR 2221 C(═NR 3331 )NR 222a1 R 333a1 , —NR 2221 C(═NR)OR 222a1 , —NR 2221 C(═NR 3331 )SR 222a1 , —OC(═O)OR 2221 , —OC(═O)NR 2221 R 3331 , —OC(═O)SR 2221 , —SC(═O)OR 2221 , —P(O)OR 2221 OR 3331 , or —SC(═O)NR 2221 R 3331 substituents.

11. The compound of claim 1 selected from:

3-Cyclobutyl-1-(2-pyridin-2-ylquinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine;

3-Cyclobutyl-1-(2-thiophen-2-ylquinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine;

3-Cyclobutyl-1-(2-phenoxyquinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine;

[7-(8-Amino-3-cyclobutylimidazo[1,5-a]pyrazin-1-yl)-quinolin-2-yl]-phenylamine;

1-(6-Chloro-2-phenylquinolin-7-yl)-3-cyclobutylimidazo[1,5-a]pyrazin-8-ylamine;

1-(6-Chloro-2-pyridin-2-ylquinolin-7-yl)-3-cyclobutylimidazo[1,5-a]pyrazin-8-ylamine;

1-(6-Chloro-2-thiophen-2-ylquinolin-7-yl)-3-cyclobutylimidazo[1,5-a]pyrazin-8-ylamine;

1-(6-Chloro-2-phenoxyquinolin-7-yl)-3-cyclobutylimidazo[1,5-a]pyrazin-8-ylamine;

[7-(8-Amino-3-cyclobutylimidazo[1,5-a]pyrazin-1-yl)-6-chloroquinolin-2-yl]-phenyl-amine;

3-Cyclobutyl-1-(8-fluoro-2-phenylquinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine;

3-Cyclobutyl-1-(8-fluoro-2-pyridin-2-ylquinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine;

3-Cyclobutyl-1-(8-fluoro-2-thiophen-2-ylquinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine;

3-Cyclobutyl-1-(8-fluoro-2-phenoxyquinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine;

[7-(8-Amino-3-cyclobutylimidazo[1,5-a]pyrazin-1-yl)-8-fluoroquinolin-2-yl]-phenyl-amine;

3-Cyclobutyl-1-(4-methyl-2-phenylquinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine;

3-Cyclobutyl-1-(4-methyl-2-pyridin-2-ylquinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine;

3-Cyclobutyl-1-(4-methyl-2-thiophen-2-ylquinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine;

[7-(8-Amino-3-cyclobutylimidazo[1,5-a]pyrazin-1-yl)-4-methylquinolin-2-yl]-phenylamine;

3′-Cyclobutyl-1-(4-methyl-2-phenoxyquinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine;

[7-(8-Amino-3-cyclobutylimidazo[1,5-a]pyrazin-1-yl)-2-phenylquinolin-4-yl]-methylamine;

[7-(8-Amino-3-cyclobutylimidazo[1,5-a]pyrazin-1-yl)-2-pyridin-2-ylquinolin-4-yl]-methylamine;

[7-(8-Amino-3-cyclobutylimidazo[1,5-a]pyrazin-1-yl)-2-thiophen-2-ylquinolin-4-yl]-methylamine;

[7-(8-Amino-3-cyclobutylimidazo[1,5-a]pyrazin-1-yl)-2-phenoxyquinolin-4-yl]-methylamine;

7-(8-Amino-3-cyclobutylimidazo[1,5-a]pyrazin-1-yl)-N 4 -methyl-N 2 -phenylquinoline-2,4-diamine;

3-[8-Amino-1-(2-phenylquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclobutanol;

3-[8-Amino-1-(2-pyridin-2-ylquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclobutanol;

3-[8-Amino-1-(2-thiophen-2-ylquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclobutanol;

3-[8-Amino-1-(2-phenoxyquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclobutanol;

3-[8-Amino-1-(2-phenylaminoquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclobutanol;

3-[8-Amino-1-(6-chloro-2-phenylquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclobutanol;

3-[8-Amino-1-(6-chloro-2-pyridin-2-ylquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclobutanol;

3-[8-Amino-1-(6-chloro-2-thiophen-2-ylquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclobutanol;

3-[8-Amino-1-(6-chloro-2-phenylaminoquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclobutanol;

3-[8-Amino-1-(6-chloro-2-phenoxyquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclobutanol;

3-[8-Amino-1-(8-fluoro-2-pyridin-2-ylquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclobutanol;

3-[8-Amino-1-(8-fluoro-2-thiophen-2-ylquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclobutanol;

3-[8-Amino-1-(8-fluoro-2-phenoxyquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclobutanol;

3-[8-Amino-1-(8-fluoro-2-phenylaminoquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclobutanol;

3-[8-Amino-1-(8-fluoro-2-phenylquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclobutanol;

3-[8-Amino-1-(8-fluoro-4-methyl-2-phenylquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclobutanol;

3-[8-Amino-1-(8-fluoro-4-methyl-2-thiophen-2-yl-quinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclobutanol;

3-[8-Amino-1-(8-fluoro-4-methyl-2-pyridin-2-ylquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclobutanol;

3-[8-Amino-1-(8-fluoro-4-methyl-2-phenylaminoquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclobutanol;

3-[8-Amino-1-(8-fluoro-4-methyl-2-phenoxyquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclobutanol;

3-(3-Azetidin-1-ylmethylcyclobutyl)-1-(2-pyridin-2-ylquinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine;

3-(3-Azetidin-1-ylmethylcyclobutyl)-1-(2-thiophen-2-ylquinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine;

3-(3-Azetidin-1-ylmethylcyclobutyl)-1-(2-phenoxyquinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine;

{7-[8-Amino-3-(3-azetidin-1-ylmethylcyclobutyl)-imidazo[1,5-a]pyrazin-1-yl]-quinolin-2-yl}-phenylamine;

3-(3-Azetidin-1-ylmethylcyclobutyl)-1-(6-chloro-2-phenylquinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine;

3-(3-Azetidin-1-ylmethylcyclobutyl)-1-(6-chloro-2-pyridin-2-yl-quinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine;

3-(3-Azetidin-1-ylmethylcyclobutyl)-1-(6-chloro-2-thiophen-2-yl-quinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine;

{7-[8-Amino-3-(3-azetidin-1-ylmethylcyclobutyl)-imidazo[1,5-a]pyrazin-1-yl]-6-chloro-quinolin-2-yl}-phenylamine;

3-(3-Azetidin-1-ylmethylcyclobutyl)-1-(6-chloro-2-phenoxyquinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine;

3-(3-Azetidin-1-ylmethylcyclobutyl)-1-(4-methyl-2-phenylquinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine;

3-(3-Azetidin-1-ylmethylcyclobutyl)-1-(4-methyl-2-pyridin-2-ylquinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine;

3-(3-Azetidin-1-ylmethylcyclobutyl)-1-(4-methyl-2-thiophen-2-ylquinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine;

3-(3-Azetidin-1-ylmethylcyclobutyl)-1-(4-methyl-2-phenoxyquinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine;

{7-[8-Amino-3-(3-azetidin-1-ylmethylcyclobutyl)-imidazo[1,5-a]pyrazin-1-yl]-4-methyl-quinolin-2-yl}-phenyl-amine;

3-(3-Dimethylaminomethylcyclobutyl)-1-(2-phenylquinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine;

3-(3-Dimethylaminomethylcyclobutyl)-1-(2-pyridin-2-ylquinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine;

3-(3-Dimethylaminomethylcyclobutyl)-1-(2-thiophen-2-ylquinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine;

{7-[8-Amino-3-(3-dimethylaminomethylcyclobutyl)-imidazo[1,5-a]pyrazin-1-yl]-quinolin-2-yl}-phenylamine;

3-(3-Dimethylaminomethylcyclobutyl)-1-(2-phenoxyquinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine;

1-(6-Chloro-2-phenylquinolin-7-yl)-3-(3-dimethylaminomethylcyclobutyl)-imidazo[1,5-a]pyrazin-8-ylamine;

1-(6-Chloro-2-pyridin-2-ylquinolin-7-yl)-3-(3-dimethylaminomethylcyclobutyl)-imidazo[1,5-a]pyrazin-8-ylamine;

1-(6-Chloro-2-thiophen-2-ylquinolin-7-yl)-3-(3-dimethylaminomethylcyclobutyl)-imidazo[1,5-a]pyrazin-8-ylamine;

1-(6-Chloro-2-phenoxyquinolin-7-yl)-3-(3-dimethylaminomethylcyclobutyl)-imidazo[1,5-a]pyrazin-8-ylamine;

{7-[8-Amino-3-(3-dimethylaminomethylcyclobutyl)-imidazo[1,5-a]pyrazin-1-yl]-6-chloroquinolin-2-yl}-phenylamine;

3-(3-Dimethylaminomethylcyclobutyl)-1-(4-methyl-2-phenylquinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine;

3-(3-Dimethylaminomethylcyclobutyl)-1-(4-methyl-2-pyridin-2-ylquinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine;

3-(3-Dimethylaminomethylcyclobutyl)-1-(4-methyl-2-thiophen-2-ylquinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine;

{7-[8-Amino-3-(3-dimethylaminomethylcyclobutyl)-imidazo[1,5-a]pyrazin-1-yl]-4-methylquinolin-2-yl}-phenylamine;

3-(3-Dimethylaminomethylcyclobutyl)-1-(4-methyl-2-phenoxyquinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine;

4-[8-Amino-1-(2-pyridin-2-ylquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclohexanecarboxylic acid amide;

4-[8-Amino-1-(2-thiophen-2-ylquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclohexanecarboxylic acid amide;

4-[8-Amino-1-(2-phenoxyquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclohexanecarboxylic acid amide;

4-[8-Amino-1-(2-phenylaminoquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclohexanecarboxylic acid amide;

4-[8-Amino-1-(6-chloro-2-phenylquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclohexanecarboxylic acid amide;

4-[8-Amino-1-(6-chloro-2-pyridin-2-ylquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclohexanecarboxylic acid amide;

4-[8-Amino-1-(6-chloro-2-thiophen-2-ylquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclohexanecarboxylic acid amide;

4-[8-Amino-1-(6-chloro-2-phenylaminoquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclohexanecarboxylic acid amide;

4-[8-Amino-1-(6-chloro-2-phenoxyquinolin-7-yl)-imidazo[1,5-a]pyrazin-yl]-cyclohexanecarboxylic acid amide;

4-[8-Amino-1-(4-methyl-2-phenylquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclohexanecarboxylic acid amide;

4-[8-Amino-1-(4-methyl-2-pyridin-2-ylquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclohexanecarboxylic acid amide;

4-[8-Amino-1-(4-methyl-2-thiophen-2-ylquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclohexanecarboxylic acid amide;

4-[8-Amino-1-(4-methyl-2-phenoxyquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclohexanecarboxylic acid amide;

4-[8-Amino-1-(4-methyl-2-phenylaminoquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclohexanecarboxylic acid amide;

4-[8-Amino-1-(2-pyridin-2-ylquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclohexanecarboxylic acid methylamide;

4-[8-Amino-1-(2-thiophen-2-ylquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclohexanecarboxylic acid methylamide;

4-[8-Amino-1-(2-phenylaminoquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclohexanecarboxylic acid methylamide;

4-[8-Amino-1-(2-phenoxyquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclohexanecarboxylic acid methylamide;

3-(4-Aminomethylcyclohexyl)-1-(2-pyridin-2-ylquinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine;

3-(4-Aminomethylcyclohexyl)-1-(2-thiophen-2-ylquinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine;

3-(4-Aminomethylcyclohexyl)-1-(2-phenoxyquinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine;

{7-[8-Amino-3-(4-aminomethylcyclohexyl)-imidazo[1,5-a]pyrazin-1-yl]-quinolin-2-yl}-phenylamine;

3-Isopropyl-1-(2-phenylquinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine;

3-tert-Butyl-1-(2-phenylquinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine;

5-[8-Amino-1-(2-phenylquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-pyrrolidin-3-ol;

3-Cyclobutyl-1-(2-phenylquinolin-7-yl)-2H-imidazo[1,5-a]pyrazin-8-ylamine;

trans-4-[8-Amino-1-(2-phenylquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclohexanecarboxylic acid amide;

trans-4-[8-Amino-1-(2-phenylquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclohexanecarboxylic acid methyl ester;

trans-4-[8-Amino-1-(2-phenylquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclohexanecarboxylic acid;

trans-4-[8-Amino-1-(2-phenylquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclohexanecarboxylic acid methylamide;

trans-{4-[8-Amino-1-(2-phenylquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclohexyl}-methanol;

trans-2-{4-[8-Amino-1-(2-phenylquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclohexylmethyl}-isoindole-1,3-dione;

trans-3-(4-Aminomethylcyclohexyl)-1-(2-phenylquinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine;

3-(3-Azetidin-1-ylmethylcyclobutyl)-1-(2-phenylquinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine;

{3-[8-Amino-1-(2-phenylquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclobutyl}-methanol.

3-Cyclobutyl-1-(2-phenylquinolin-7-yl)-2H-imidazol[1,5-a]pyrazin-8-ylamine;

trans-4-[8-Amino-1-(2-phenylquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclohexanecarboxylic acid amide;

trans-4-[8-Amino-1-(2-phenylquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclohexanecarboxylic acid methyl ester;

trans-4-[8-Amino-1-(2-phenylquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclohexanecarboxylic acid;

trans-4-[8-Amino-1-(2-phenylquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]cyclohexanecarboxylic acid methylamide;

trans-{4-[8-Amino-1-(2-phenylquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclohexyl}-methanol;

trans-2-{4-[8-Amino-1-(2-phenylquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclohexylmethyl}-isoindole-1,3-dione;

trans-3-(4-Aminomethylcyclohexyl)-1-(2-phenylquinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine;

3-(3-Azetidin-1-ylmethylcyclobutyl)-1-(2-phenylquinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine;

{3-[8-Amino-1-(2-phenylquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclobutyl}-methanol;

or a pharmaceutically acceptable salt thereof.

12. The compound of claim 1 selected from