8-METHYL-1-PHENYL-IMIDAZOL[1,5-A]PYRAZINE COMPOUNDS

• US 20120309966A1
• Filed: 02/03/2011
• Published: 12/06/2012
• Est. Priority Date: 02/08/2010
• Status: Active Grant

• Current Assignee: Merck Sharp & Dohme LLC (Merck & Co., Inc.)
• Original Assignee: N.V. Organon (Merck & Co., Inc.)
• Inventors: Wijkmans, Jacobus Cornelis Henricus Maria, de Man, Adrianus Petrus Antonius, Rewinkel, Johannes Bernardus Maria, Jans, Christian Gerardus Johannes Maria, Raajimakers, Hans Cornelis Andreas
• Granted Patent: US 8,658,794 B2
• Time in Patent Office: Days
• US Class Current: 544/117
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 37/08 Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07D 487/04 Ortho-condensed systems
• CPC Class Codes: C07D 519/00 Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Abstract

The present invention provides 8-methyl-1-phenyl-imidazo[1,5-a]pyrazine deriva-tives according to formula I or pharmaceutically acceptable salts thereof. The compounds of the current invention show inhibitory activity against Lck and can be used for the treatment of Lck-mediated diseases or Lck-mediated conditions such as inflammatory disorders.

Claims

1. An 8-methyl-1-phenyl-imidazo[1,5-a]pyrazine compound according to formula I

2. The compound according to claim 1 wherein

R3 is (R31)(R32)CH—

O;

or

R3 is (3-7C)cycloalkoxy which is optionally substituted with one or more fluoro or hydroxy;

or

R3 is heteroaryl, which is optionally substituted with one or more groups from R34, R35, R36, halogen, hydroxy or cyano;

R31 is H or (1-5C)alkyl optionally substituted with one or more fluoro, hydroxy or (1-6C)alkoxy;

R32 is (1-5C)alkyl optionally substituted with one or more fluoro;

R34 is (1-6C)alkyl optionally substituted with one or more fluoro;

R35 is (1-6C)alkoxy optionally substituted with one or more fluoro;

R36 is hydrogen or (1-6C)alkyl optionally substituted with one or more fluoro;

R4 is

3. The compound according to claim 2 wherein R1 is one or two groups independently selected from hydrogen, hydroxyl, (1-3C)alkoxy or halogen.

4. The compound according to claim 3 wherein

R3 is (R31)(R32)CH—

O;

R31 is (1-5C)alkyl optionally substituted with OH;

R32 is (1-5C)alkyl.

5. The compound according to claim 3 wherein

R3 is heteroaryl, which is optionally substituted with one or more groups selected from R34,

R35, R36, fluoro, chloro and OH;

R34 is (1-6C)alkyl;

R35 is (1-6C)alkoxy.

R36 is hydrogen or (1-6C)alkyl.

6. The compound according to claim 5 wherein

the heteroaryl group in R3 is

7. The compound according to claim 6 wherein

R4 is

8. The compound according to claim 7 wherein

R4 is

9. The compound according to claim 6 wherein

R4 is

10. The compound according to claim 9 wherein

R4 is

11. The compound according to claim 6 wherein R4 is (1-4C)alkyl, optionally substituted independently by one or more substituents from R8, hydroxyl wherein R8 is heteroaryl.

12. The Compound according to claim 1 selected from a group consisting of

N-[2-Methoxy-4-[8-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazine]phenyl]-1-methyl-1H-indole-2-carboxamide,

N-(4-(3-((Trans)-4-(4-acetylpiperazin-1-yl)cyclohexyl)-8-methylimidazo[1,5-a]pyrazin-1-yl)-2-methoxyphenyl)-4-methoxy-1-methyl-1H-indole-2-carboxamide,

(S)-pentan-2-yl 4-(3-(azetidin-1-yl)-8-methylimidazo[1,5-a]pyrazin-1-yl)-2-methoxyphenylcarbamate,

(S)-pentan-2-yl 4-(3-((R)-1-(2-(dimethylamino)acetyl)pyrrolidin-3-yl)-8-methylimidazo[1,5-a]pyrazin-1-yl)-2-methoxyphenylcarbamate,

(Trans)-4-(1-(3-methoxy-4-(4-methoxy-1-methyl-1H-indole-2-carboxamido)phenyl)-8-methylimidazo[1,5-a]pyrazin-3-yl)cyclohexyl acetate,

N-(4-(3-((trans)-4-hydroxycyclohexyl)-8-methylimidazo[1,5-a]pyrazin-1-yl)-2-methoxyphenyl)-4-methoxy-1-methyl-1H-indole-2-carboxamide,

4-Methoxy-N-(2-methoxy-4-(8-methyl-3-((trans)-4-(4-methylpiperazin-1-yl)cyclohexyl)imidazo[1,5-a]pyrazin-1-yl)phenyl)-1-methyl-1H-indole-2-carboxamide,

4-Methoxy-N-(2-methoxy-4-(8-methyl-3-((cis)-4-(4-methylpiperazin-1-yl)cyclohexyl)imidazo[1,5-a]pyrazin-1-yl)phenyl)-1-methyl-1H-indole-2-carboxamide,

N-(4-(3-((trans)-4-(3,3-difluoroazetidin-1-yl)cyclohexyl)-8-methylimidazo[1,5-a]pyrazin-1-yl)-2-methoxyphenyl)-4-methoxy-1-methyl-1H-indole-2-carboxamide,

N-(4-(3-((cis)-4-(3,3-difluoroazetidin-1-yl)cyclohexyl)-8-methylimidazo[1,5-a]pyrazin-1-yl)-2-methoxyphenyl)-4-methoxy-1-methyl-1H-indole-2-carboxamide,

(S)-Pentan-2-yl 2-methoxy-4-(3-((trans)-4-(2-methoxyethylamino)cyclohexyl)-8-methyl-imidazo[1,5-a]pyrazin-1-yl)phenylcarbamate,

N-(2-methoxy-4-(8-methyl-3-((trans)-4-morpholinocyclohexyl)imidazo[1,5-a]pyrazin-1-yl)phenyl)-1-methyl-1H-indole-2-carboxamide,

4-Methoxy-N-(2-methoxy-4-(8-methyl-3-(3-methyloxetan-3-yl)imidazo[1,5-a]pyrazin-1-yl)phenyl)-1-methyl-1H-indole-2-carboxamide,

N-(4-(3-(hydroxymethyl)-8-methylimidazo[1,5-a]pyrazin-1-yl)-2-methoxyphenyl)-4-methoxy-1-methyl-1H-indole-2-carboxamide,

N-(4-(3-((1H-imidazol-1-yl)methyl)-8-methylimidazo[1,5-a]pyrazin-1-yl)-2-methoxyphenyl)-4-methoxy-1-methyl-1H-indole-2-carboxamide,

4-Methoxy-N-(2-methoxy-4-(8-methyl-3-(1-(tetrahydro-2H-pyran-4-yl)azetidin-3-yl)imidazo[1,5-a]pyrazin-1-yl)phenyl)-1-methyl-1H-indole-2-carboxamide,

4-Methoxy-N-(2-methoxy-4-(8-methyl-3-(piperidin-4-yl)imidazo[1,5-a]pyrazin-1-yl)phenyl)-1-methyl-1H-indole-2-carboxamide,

N-(4-(3-(1-(2-(dimethylamino)-2-oxoethyl)piperidin-4-yl)-8-methylimidazo[1,5-a]pyrazin-1-yl)-2-methoxyphenyl)-1-methyl-1H-indole-2-carboxamide,

N-(4-(3-(1-(2-(dimethylamino)acetyl)piperidin-4-yl)-8-methylimidazo[1,5-a]pyrazin-1-yl)-2-methoxyphenyl)-1-methyl-1H-indole-2-carboxamide,

N-(4-(3-(1-(2-Aminoacetyl)piperidin-4-yl)-8-methylimidazo[1,5-a]pyrazin-1-yl)-2-methoxyphenyl)-1-methyl-1H-indole-2-carboxamide,

N-(4-(3-(1-carbamoylpiperidin-4-yl)-8-methylimidazo[1,5-a]pyrazin-1-yl)-2-methoxyphenyl)-4-methoxy-1-methyl-1H-indole-2-carboxamide,

Methyl 4-(1-(3-methoxy-4-(4-methoxy-1-methyl-1H-indole-2-carboxamido)phenyl)-8-methylimidazo[1,5-a]pyrazin-3-yl)piperidine-1-carboxylate,

N-(2-methoxy-4-(8-methyl-3-(4-methylpiperazin-1-yl)imidazo[1,5-a]pyrazin-1-yl)phenyl)-1-methyl-1H-indole-2-carboxamide,

N-(2-methoxy-4-(8-methyl-3-(morholin-4-yl)imidazo[1,5-a]pyrazin-1-yl)phenyl)-1-methyl-1H-indole-2-carboxamide,

Isopropyl 2-methoxy-4-(8-methyl-3-(4-morpholinopiperidin-1-yl)imidazo[1,5-a]pyrazin-1-yl)phenylcarbamate,

(S)-Pentan-2-yl 2-methoxy-4-(3-((trans)-4-((2-methoxyethyl)(methyl)amino)cyclohexyl)-8-methylimidazo[1,5-a]pyrazin-1-yl)phenylcarbamate,

N-(4-(3-((Trans)-4-(dimethylamino)cyclohexyl)-8-methylimidazo[1,5-a]pyrazin-1-yl)-2-methoxyphenyl)-4-methoxy-1-methyl-1H-indole-2-carboxamide,

4-Methoxy-N-(2-methoxy-4-(3-((cis)-4-((2-Methoxyethyl)(methyl)amino)cyclohexyl)-8-methylimidazo[1,5-a]pyrazin-1-yl)phenyl)-1-methyl-1H-indole-2-carboxamide,

4-Methoxy-N-(2-methoxy-4-(8-methyl-3-((cis)-4-morpholinocyclohexyl)imidazo[1,5-a]pyrazin-1-yl)phenyl)-1-methyl-1H-indole-2-carboxamide,

N-(4-(3-((Cis)-4-(dimethylamino)cyclohexyl)-8-methylimidazo[1,5-a]pyrazin-1-yl)-2-methoxyphenyl)-4-methoxy-1-methyl-1H-indole-2-carboxamide,

(S)-Pentan-2-yl 4-(3-((cis)-4-(4-acetylpiperazin-1-yl)cyclohexyl)-8-methylimidazo[1,5-a]pyrazin-1-yl)-2-methoxyphenylcarbamate,

(S)-Pentan-2-yl 4-(3-((cis)-4-(3,3-difluoroazetidin-1-yl)cyclohexyl)-8-methylimidazo[1,5-a]pyrazin-1-yl)-2-methoxyphenylcarbamate,

(S)-Pentan-2-yl 2-methoxy-4-(8-methyl-3-((1r,3r)-3-(4-methylpiperazin-1-yl)cyclobutyl)imidazo[1,5-a]pyrazin-1-yl)phenylcarbamate,

(S)-Pentan-2-yl 2-methoxy-4-(8-methyl-3-(3-(4-methylpiperazin-1-yl)cyclopentyl)imidazo[1,5-a]pyrazin-1-yl)phenylcarbamate,

(S)-Pentan-2-yl 2-methoxy-4-(3-((trans)-4-(N-(2-methoxyethyl)acetamido)cyclohexyl)-8-methylimidazo[1,5-a]pyrazin-1-yl)phenylcarbamate,

4-Methoxy-N-(2-methoxy-4-(8-methyl-3-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)imidazo[1,5-a]pyrazin-1-yl)phenyl)-1-methyl-1H-indole-2-carboxamide,

(S)-Pentan-2-yl 4-(3-(4-acetylpiperazin-1-yl)-8-methylimidazo[1,5-a]pyrazin-1-yl)-2-methoxyphenylcarbamate,

N-(4-(3-(4-(1-Acetylpiperidin-4-yl)piperazin-1-yl)-8-methylimidazo[1,5-a]pyrazin-1-yl)-2-methoxyphenyl)-4-methoxy-1-methyl-1H-indole-2-carboxamide,

(S)-Pentan-2-yl 2-methoxy-4-(8-methyl-3-((trans)-4-(4-methylpiperazin-1-yl)cyclohexyl)imidazo[1,5-a]pyrazin-1-yl)phenylcarbamate,

N-(2-Methoxy-4-(8-methyl-3-((trans)-4-(4-methylpiperazin-1-yl)cyclohexyl)imidazo[1,5-a]pyrazin-1-yl)phenyl)-1-methyl-1H-indole-2-carboxamide 2,2,2-trifluoroacetate,

N-(4-(3-((Trans)-4-(4-acetylpiperazin-1-yl)cyclohexyl)-8-methylimidazo[1,5-a]pyrazin-1-yl)-2-methoxyphenyl)-1-methyl-1H-indole-2-carboxamide,

(S)-Pentan-2-yl 4-(3-((trans)-4-(4-acetylpiperazin-1-yl)cyclohexyl)-8-methylimidazo[1,5-a]pyrazin-1-yl)-2-methoxyphenylcarbamate,

(R)—

N-(4-(3-(1-(2-(Dimethylamino)acetyl)pyrrolidin-3-yl)-8-methylimidazo[1,5-a]pyrazin-1-yl)-2-methoxyphenyl)-4-methoxy-1-methyl-1H-indole-2-carboxamide,

(S)-Pentan-2-yl 2-methoxy-4-(8-methyl-3-((cis)-4-(4-methylpiperazin-1-yl)cyclohexyl)imidazo[1,5-a]pyrazin-1-yl)phenylcarbamate,

N-(4-(3-(4-Acetylpiperazin-1-yl)-8-methylimidazo[1,5-a]pyrazin-1-yl)-2-methoxyphenyl)-4-methoxy-1-methyl-1H-indole-2-carboxamide,

4-Methoxy-N-(2-methoxy-4-(8-methyl-3-(4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)imidazo[1,5-a]pyrazin-1-yl)phenyl)-1-methyl-1H-indole-2-carboxamide,

(R)-4-methoxy-N-(2-methoxy-4-(8-methyl-3-(1-(tetrahydro-2H-pyran-4-yl)pyrrolidin-3-yl)imidazo[1,5-a]pyrazin-1-yl)phenyl)-1-methyl-1H-indole-2-carboxamide,

(S)-4-Methoxy-N-(2-methoxy-4-(8-methyl-3-(1-(tetrahydro-2H-pyran-4-yl)pyrrolidin-3-yl)imidazo[1,5-a]pyrazin-1-yl)phenyl)-1-methyl-1H-indole-2-carboxamide,

4-Methoxy-N-(2-methoxy-4-(8-methyl-3-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)imidazo[1,5-a]pyrazin-1-yl)phenyl)-1-methyl-1H-indole-2-carboxamide,

4-Methoxy-N-(2-methoxy-4-(8-methyl-3-(1-methyl-2-oxopiperidin-4-yl)imidazo[1,5-a]pyrazin-1-yl)phenyl)-1-methyl-1H-indole-2-carboxamide,

N-(4-(3-((trans)-4-aminocyclohexyl)-8-methylimidazo[1,5-a]pyrazin-1-yl)-2-methoxyphenyl)-4-methoxy-1-methyl-1H-indole-2-carboxamide,

N-(4-(3-((trans)-4-(2,2-Difluoroethylamino)cyclohexyl)-8-methylimidazo[1,5-a]pyrazin-1-yl)-2-methoxyphenyl)-4-methoxy-1-methyl-1H-indole-2-carboxamide,

Isopropyl 4-(3-((trans)-4-(3,3-difluoroazetidin-1-yl)cyclohexyl)-8-methylimidazo[1,5-a]pyrazin-1-yl)-2-methoxyphenyl(methyl)carbamate,

5-Methoxy-N-(2-methoxy-4-(8-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-1-yl)phenyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide,

N-(2-Methoxy-4-(8-methyl-3-(1-methylpiperidin-4-yl)imidazo[1,5-a]pyrazin-1-yl)phenyl)-1-methyl-1H-indole-2-carboxamide,

(S)-4-Hydroxybutan-2-yl 2-methoxy-4-(8-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-1-yl)phenylcarbamate,

4-Fluoro-N-(2-methoxy-4-(8-methyl-3-(1-methylpiperidin-4-yl)imidazo[1,5-a]pyrazin-1-yl)phenyl)-1-methyl-1H-indole-2-carboxamide,

N-(5-Fluoro-2-methoxy-4-(8-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-1-yl)phenyl)-4-methoxy-1-methyl-1H-indole-2-carboxamide,

5-Hydroxypentan-2-yl 5-fluoro-2-methoxy-4-(8-methyl-3-(tetrahydro-2h-pyran-4-yl)imidazo[1,5-a]pyrazin-1-yl)phenylcarbamate,

(S)-sec-Butyl 2-methoxy-4-(8-methyl-3-((trans)-4-(4-methylpiperazin-1-yl)cyclohexyl)imidazo[1,5-a]pyrazin-1-yl)phenylcarbamate,

N-(4-(3-(1′

-acetyl-1,4′

-bipiperidin-4-yl)-8-methylimidazo[1,5-a]pyrazin-1-yl)-2-methoxyphenyl)-4-methoxy-1-methyl-1H-indole-2-carboxamide,

(S)-pentan-2-yl 2-methoxy-4-(3-((S)-1-(2-methoxyacetyl)pyrrolidin-3-yl)-8-methylimidazo[1,5-a]pyrazin-1-yl)phenylcarbamate,

(trans)-4-(1-(3-Methoxy-4-(4-methoxy-1-methyl-1H-indole-2-carboxamido)phenyl)-8-methylimidazo[1,5-a]pyrazin-3-yl)cyclohexyl cyclopentylcarbamate,

(R)—

N-(4-(3-(1-(2-(dimethylamino)-2-oxoethyl)pyrrolidin-3-yl)-8-methylimidazo[1,5-a]pyrazin-1-yl)-2-methoxyphenyl)-4-methoxy-1-methyl-1H-indole-2-carboxamide,

(R)—

N-(4-(3-(1-(2-hydroxyacetyl)pyrrolidin-3-yl)-8-methylimidazo[1,5-a]pyrazin-1-yl)-2-methoxyphenyl)-4-methoxy-1-methyl-1H-indole-2-carboxamide,

4-Methoxy-N-(2-methoxy-4-(8-methyl-3-((trans)-4-(piperazin-1-yl)cyclohexyl)imidazo[1,5-a]pyrazin-1-yl)phenyl)-1-methyl-1H-indole-2-carboxamide,

4-Chloro-N-(2-methoxy-4-(8-methyl-3-((trans)-4-(4-methylpiperazin-1-yl)cyclohexyl)imidazo[1,5-a]pyrazin-1-yl)phenyl)-1-methyl-1H-pyrrole-2-carboxamide,

N-(2-methoxy-4-(8-methyl-3-((trans)-4-(4-methylpiperazin-1-yl)cyclohexyl)imidazo[1,5-a]pyrazin-1-yl)phenyl)-6-methyl-6H-thieno[2,3-b]pyrrole-5-carboxamide,

N-(2-Methoxy-4-(8-methyl-3-((trans)-4-(4-methylpiperazin-1-yl)cyclohexyl)imidazo[1,5-a]pyrazin-1-yl)phenyl)-6H-thieno[2,3-b]pyrrole-5-carboxamide,

4-Methoxy-N-(2-methoxy-4-(8-methyl-3-((trans)-4-(4-methylpiperazin-1-yl)cyclohexyl)imidazo[1,5-a]pyrazin-1-yl)phenyl)-1H-indole-2-carboxamide,

4-Hydroxy-N-(2-methoxy-4-(8-methyl-3-((trans)-4-(4-methylpiperazin-1-yl)cyclohexyl)imidazo[1,5-a]pyrazin-1-yl)phenyl)-1-methyl-1H-indole-2-carboxamide,

(S)-Pentan-2-yl 4-(3-((trans)-4-(aminomethyl)cyclohexyl)-8-methylimidazo[1,5-a]pyrazin-1-yl)-2-methoxyphenylcarbamate,

1-Methyl-N-(4-(8-methyl-3-((trans)-4-(4-methylpiperazin-1-yl)cyclohexyl)imidazo[1,5-a]pyrazin-1-yl)phenyl)-1H-indole-2-carboxamide,

N-(2-hydroxy-4-(8-methyl-3-((trans)-4-(4-methylpiperazin-1-yl)cyclohexyl)imidazo[1,5-a]pyrazin-1-yl)phenyl)-4-methoxy-1-methyl-1H-indole-2-carboxamide,

4-Methoxy-N-(2-methoxy-4-(8-methyl-3-((trans)-4-((methylamino)methyl)cyclohexyl)imidazo[1,5-a]pyrazin-1-yl)phenyl)-1-methyl-1H-indole-2-carboxamide,

N-(4-(3-((trans)-4-((dimethylamino)methyl)cyclohexyl)-8-methylimidazo[1,5-a]pyrazin-1-yl)-2-methoxyphenyl)-4-methoxy-1-methyl-1H-indole-2-carboxamide,

(S)-Pentan-2-yl 4-(3-((trans)-4-((dimethylamino)methyl)cyclohexyl)-8-methylimidazo[1,5-a]pyrazin-1-yl)-2-methoxyphenylcarbamate,

6-Methoxy-N-(2-methoxy-4-(8-methyl-3-((trans)-4-(4-methylpiperazin-1-yl)cyclohexyl)imidazo[1,5-a]pyrazin-1-yl)phenyl)-1H-indazole-3-carboxamide,

5-Chloro-N-(2-methoxy-4-(8-methyl-3-((trans)-4-(4-methylpiperazin-1-yl)cyclohexyl)imidazo[1,5-a]pyrazin-1-yl)phenyl)-1-methyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamide,

N-(4-(3-((trans)-4-(acetamidomethyl)cyclohexyl)-8-methylimidazo[1,5-a]pyrazin-1-yl)-2-methoxyphenyl)-4-methoxy-1-methyl-1H-indole-2-carboxamide,

(S)-pentan-2-yl 4-(3-((trans)-4-(acetamidomethyl)cyclohexyl)-8-methylimidazo[1,5-a]pyrazin-1-yl)-2-methoxyphenylcarbamate,

(S)-pentan-2-yl 4-(3-((trans)-4-(methoxycarbonylmethyl)cyclohexyl)-8-methylimidazo[1,5-a]pyrazin-1-yl)-2-methoxyphenylcarbamate,

4-Methoxy-N-(2-methoxy-4-(8-methyl-3-(4-oxocyclohexyl)imidazo[1,5-a]pyrazin-1-yl)phenyl)-1-methyl-1H-indole-2-carboxamide,

N-(4-(3-((trans)-4-hydroxy-4-((methylamino)methyl)cyclohexyl)-8-methylimidazo[1,5-a]pyrazin-1-yl)-2-methoxyphenyl)-4-methoxy-1-methyl-1H-indole-2-carboxamide,

4-Methoxy-N-(2-methoxy-4-(8-methyl-3-(1-methyl-5-oxopyrrolidin-3-yl)imidazo[1,5-a]pyrazin-1-yl)phenyl)-1-methyl-1H-indole-2-carboxamide,

4-Methoxy-N-(2-methoxy-4-(8-methyl-3-((trans)-4-(4-methyl-3-oxopiperazin-1-yl)cyclohexyl)imidazo[1,5-a]pyrazin-1-yl)phenyl)-1-methyl-1H-indole-2-carboxamide,

5-Methoxy-N-(2-methoxy-4-(8-methyl-3-((trans)-4-(4-methylpiperazin-1-yl)cyclohexyl)imidazo[1,5-a]pyrazin-1-yl)phenyl)-1-methyl-1H-pyrrolo[2,3-c]pyridine-2-carboxamide,

4-methoxy-N-(2-methoxy-4-(8-methyl-3-((trans)-4-morpholinocyclohexyl)imidazo[1,5-a]pyrazin-1-yl)phenyl)-1-methyl-1H-indole-2-carboxamide,

S)-pentan-2-yl 2-methoxy-4-(8-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-1-yl)phenylcarbamate,

(S)-pentan-2-yl 2-methoxy-4-(8-methyl-3-((trans)-4-morpholinocyclohexyl)imidazo[1,5-a]pyrazin-1-yl)phenylcarbamate,

(S)-pentan-2-yl 4-(3-(1-(2-(dimethylamino)acetyl)piperidin-4-yl)-8-methylimidazo[1,5-a]pyrazin-1-yl)-2-methoxyphenylcarbamate,

(S)-pentan-2-yl 4-(3-(1-(2-(dimethylamino)-2-oxoethyl)piperidin-4-yl)-8-methylimidazo[1,5-a]pyrazin-1-yl)-2-methoxyphenylcarbamate,

(S)-pentan-2-yl 2-methoxy-4-(8-methyl-3-morpholinoimidazo[1,5-a]pyrazin-1-yl)phenylcarbamate,

isopropyl 2-methoxy-4-(8-methyl-3-((trans)-4-(4-methylpiperazin-1-yl)cyclohexyl)imidazo[1,5-a]pyrazin-1-yl)phenylcarbamate,

4-fluoro-N-(2-methoxy-4-(8-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-1-yl)phenyl)-1-methyl-1H-indole-2-carboxamide,

tert-butyl 2-methoxy-4-(8-methyl-3-((trans)-4-(4-methylpiperazin-1-yl)cyclohexyl)imidazo[1,5-a]pyrazin-1-yl)phenylcarbamate,

N-(4-(3-(1-(2-(dimethylamino)-2-oxoethyl)piperidin-4-yl)-8-methylimidazo[1,5-a]pyrazin-1-yl)-2-methoxyphenyl)-4-methoxy-1-methyl-1H-indole-2-carboxamide,

N-(4-(3-(azetidin-1-yl)-8-methylimidazo[1,5-a]pyrazin-1-yl)-2-methoxyphenyl)-1-methyl-1H-indole-2-carboxamide,

5-hydroxypentan-2-yl 2-methoxy-4-(8-methyl-3-((trans)-4-(4-methylpiperazin-1-yl)cyclohexyl)imidazo[1,5-a]pyrazin-1-yl)phenylcarbamate,

(S)-pentan-2-yl 4-(3-(1-(2-aminoacetyl)piperidin-4-yl)-8-methylimidazo[1,5-a]pyrazin-1-yl)-2-methoxyphenylcarbamate,

N-(4-(3-(1-(2-aminoacetyl)piperidin-4-yl)-8-methylimidazo[1,5-a]pyrazin-1-yl)-2-methoxyphenyl)-4-methoxy-1-methyl-1H-indole-2-carboxamide,

N-(4-(3-((trans)-4-(aminomethyl)cyclohexyl)-8-methylimidazo[1,5-a]pyrazin-1-yl)-2-methoxyphenyl)-4-methoxy-1-methyl-1H-indole-2-carboxamide,

(S)-pentan-2-yl 2-methoxy-4-(8-methyl-3-((cis)-4-morpholinocyclohexyl)imidazo[1,5-a]pyrazin-1-yl)phenylcarbamate,

(S)-pentan-2-yl 2-methoxy-4-(8-methyl-3-(4-morpholinopiperidin-1-yl)imidazo[1,5-a]pyrazin-1-yl)phenylcarbamate,

4-methoxy-N-(2-methoxy-4-(8-methyl-3-(4-morpholinopiperidin-1-yl)imidazo[1,5-a]pyrazin-1-yl)phenyl)-1-methyl-1H-indole-2-carboxamide,

4-methoxy-N-(2-methoxy-4-(8-methyl-3-((trans)-3-(4-methylpiperazin-1-yl)cyclobutyl)imidazo[1,5-a]pyrazin-1-yl)phenyl)-1-methyl-1H-indole-2-carboxamide,

4-methoxy-N-(2-methoxy-4-(3-((trans)-4-(2-methoxyethylamino)cyclohexyl)-8-methylimidazo[1,5-a]pyrazin-1-yl)phenyl)-1-methyl-1H-indole-2-carboxamide,

4-methoxy-N-(2-methoxy-4-(3-((trans)-4-(N-(2-methoxyethyl)acetamido)cyclohexyl)-8-methylimidazo[1,5-a]pyrazin-1-yl)phenyl)-1-methyl-1H-indole-2-carboxamide,

4-methoxy-N-(2-methoxy-4-(8-methyl-3-morpholinoimidazo[1,5-a]pyrazin-1-yl)phenyl)-1-methyl-1H-indole-2-carboxamide,

4-methoxy-N-(2-methoxy-4-(3-((trans)-4-((2-methoxyethyl)(methyl)amino)cyclohexyl)-8-methylimidazo[1,5-a]pyrazin-1-yl)phenyl)-1-methyl-1H-indole-2-carboxamide,

N-(4-(3-(1-(2-(dimethylamino)acetyl)piperidin-4-yl)-8-methylimidazo[1,5-a]pyrazin-1-yl)-2-methoxyphenyl)-4-methoxy-1-methyl-1H-indole-2-carboxamide,

(S)-pentan-2-yl 4-(3-((trans)-4-(3,3-difluoroazetidin-1-yl)cyclohexyl)-8-methylimidazo[1,5-a]pyrazin-1-yl)-2-methoxyphenylcarbamate,

(S)-pentan-2-yl 2-methoxy-4-(8-methyl-3-(4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)imidazo[1,5-a]pyrazin-1-yl)phenylcarbamate, and

N-(4-(3-((trans)-4-(3,3-difluoroazetidin-1-yl)cyclohexyl)-8-methylimidazo[1,5-a]pyrazin-1-yl)-2-methoxyphenyl)-1-methyl-1H-indole-2-carboxamide.

13. The compound of claim 12 for use in therapy.

14. The compound of claim 12 for use in the treatment of a Lck-mediated disease or a Lck-mediated condition.

15. (canceled)