BTK INHIBITORS

• US 20140206681A1
• Filed: 01/22/2014
• Published: 07/24/2014
• Est. Priority Date: 01/23/2013
• Status: Abandoned Application

• Current Assignee: Merck Sharp & Dohme Corporation (Merck & Co., Inc.)
• Original Assignee: Ronald M. Kim
• Inventors: KIM, RONALD M., Liu, Jian, Gao, Xiaolei, Boga, Sobhana Babu, Guiadeen, Deodialsingh, Yu, Wensheng, Anand, Rajan, Yu, Younong, Selyutin, Oleg B., Wu, Hao, Liu, Shilan, Kozlowski, Joseph A., Gao, Ying-Duo, Yang, Chundao, Wang, Hongjian
• Application Number:
  US14/160,587
• Publication Number:
  US 20140206681A1
• Time in Patent Office: Days
• US Class Current: 514/230.5
• CPC Class Codes: A61K 31/497 containing further heterocyclic rings
• CPC Class Codes: A61K 31/4985 Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
• CPC Class Codes: A61K 31/506 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61K 31/5365 ortho- or peri-condensed with heterocyclic ring systems
• CPC Class Codes: A61K 31/5383 ortho- or peri-condensed with heterocyclic ring systems
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• 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 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: C07D 455/02 containing not further condensed quinolizine ring systems
• CPC Class Codes: C07D 471/04 Ortho-condensed systems
• CPC Class Codes: C07D 487/04 Ortho-condensed systems
• CPC Class Codes: C07D 491/048 the oxygen-containing ring being five-membered
• CPC Class Codes: C07D 498/04 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
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The present invention provides Bruton'"'"'s Tyrosine Kinase (Btk) inhibitor compounds according to Formula I

or a pharmaceutically acceptable salt thereof or to pharmaceutical compositions comprising these compounds and to their use in therapy. In particular, the present invention relates to the use of Btk inhibitor compounds in the treatment of Btk mediated disorders.

Claims

1. A compound according to Formula I, or a pharmaceutically acceptable salt, thereof

3. The compound of claim 1, wherein ring K is defined as:

B₁ is C(R⁷), B₂ is C(R⁸), B₃ is C(R⁹), and B₄ is C(R¹⁰);

or

B₁ is N, B₂ is N, B₃ is C(R⁹), and B₄ is C(R¹⁰);

or

B₁ is N, B₂ is C(R⁸), B₃ is N, and B₄ is C(R¹⁰);

or

B₁ is N, B₂ is C(R⁸), B₃ is C(R⁹), and B₄ is N;

or

B₁ is C(R⁷), B₂ is C(R⁸), B₃ is N, and B₄ is N;

or

B₁ is C(R⁷), B₂ is N, B₃ is C(R⁹), and B₄ is N.

4. The compound of claim 3, wherein ring K is defined as:

B₁ is C(R⁷), B₂ is C(R⁸), B₃ is C(R⁹), and B₄ is C(R¹⁰), and wherein R⁷, R⁸, R⁹ and R¹⁰ each are H, halogen, (1-3C)alkyl, (1-3C)alkoxy or halo(1-3C)alkyl;

any alkoxy may optionally be substituted with one, two or three halogen.

5. The compound of claim 1, wherein ring L is selected from the group consisting of phenyl, pyridyl, pyrimidyl, pyridazyl, triazinyl, thiazolyl, oxazolyl, isoxazolyl, pyrazolyl, imidazolyl, thiadiazolyl, and isothiazolyl.

6. The compound of claim 5, wherein the ring system L is selected from the group consisting of:

7. The compound of claim 5, wherein ring L is pyridyl.

8. The compound of claim 1, wherein R⁵ is selected from the group consisting of hydrogen, fluorine, chlorine, CN, cyclopropyl, cyclobutyl, oxetanyl, (1-3C)alkyl, (1-5C) alkoxy, and (1-5C)cycloalkoxy;

the alkyl, alkoxy, cycloalkyl and cycloalkoxy of which are optionally substituted with one or more halogen.

9. The compound of claim 8, wherein R⁵ is selected from the group consisting of hydrogen, fluorine, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopropoxyl, and trifluoromethyl.

10. The compound of claim 1, wherein R¹¹ is selected from the group consisting of H, ²H, F, Cl, Br, methyl, C²H₃, ethyl, cyclopropyl and vinyl.

11. The compound of claim 10, wherein R¹¹ is H, F or Cl.

12. The compound of claim 1, wherein bicyclic ring system E-G is selected from the group consisting of:

13. The compound of claim 12, wherein bicyclic ring system E-G is

14. The compound of claim 1 selected from the group consisting of:

4-{8-amino-3-[(6S,8aS)-3-oxohexahydro[1,3]oxazolo[3,4-a]pyridin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(6R,8aR)-3-oxohexahydro[1,3]oxazolo[3,4-a]pyridin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(6R,8aS)-2-methyl-3-oxooctahydroimidazo[1,5-a]pyridin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-N-[4-(cyclopropyloxy)pyridin-2-yl]benzamide;

4-{8-amino-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-N-pyridin-2-ylbenzamide;

4-{8-amino-3-[(6S,8aR)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-N-(4-cyclobutylpyridin-2-yl)benzamide;

4-{8-amino-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-N-(5-methyl-1,3-thiazol-2-yl)benzamide;

4-{8-amino-3-[(6S,8aR)-3-oxooetahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-N-pyridin-2-ylbenzamide;

4-{8-amino-3-[(6S,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(6R,8aR)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(6R,8aS)-3-oxohexahydro[1,3]oxazolo[3,4-a]pyridin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(6S,8aR)-3-oxohexahydro[1,3]oxazolo[3,4-a]pyridin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-N-[4-(difluoromethyl)pyridin-2-yl]-3-fluorobenzamide;

4-{8-amino-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-N-(4-cyanopyridin-2-yl)-3-fluorobenzamide;

4-{8-amino-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-N-(4-cyclopropylpyridin-2-yl)-3-fluorobenzamide;

4-{8-amino-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-N-[4-(difluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-N-(4-ethylpyridin-2-yl)benzamide;

4-{8-amino-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-N-(4-cyclopropylpyridin-2-yl)benzamide;

4-{8-amino-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-N-[4-(trifluoromethyl)pyrimidin-2-yl]benzamide;

4-{8-amino-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-N-[4-(1,1-difluoroethyl)pyridin-2-yl]-3-fluorobenzamide;

4-{8-amino-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-2-methyl-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-3-fluoro-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-2-fluoro-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-N-[4-(1,1-difluoroethyl)pyridin-2-yl]-2-fluorobenzamide;

4-{8-amino-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-N-[4-(difluoromethyl)pyridin-2-yl]-2-fluorobenzamide;

4-{8-amino-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-N-(4-cyclopropylpyridin-2-yl)-2-fluorobenzamide;

4-{8-amino-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-N-(4-cyclopropylpyridin-2-yl)-2-methylbenzamide;

4-{8-amino-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-N-[4-(3-fluorooxetan-3-yl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-N-[4-(1-fluoro-1-methylethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(1R,6R,8aS)-1-methyl-3-oxohexahydro[1,3]oxazolo[3,4-a]pyridin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-3-fluoro-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(1R,6R,8aS)-1-methyl-3-oxohexahydro[1,3]oxazolo[3,4-a]pyridin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-N-(4-cyclopropylpyridin-2-yl)-3-fluorobenzamide;

4-{8-amino-3-[(1S,6R,8aS)-1-methyl-3-oxohexahydro[1,3]oxazolo[3,4-a]pyridin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-3-fluoro-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-N-(4-cyanopyridin-2-yl), 2-fluorobenzamide;

4-{8-amino-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-N-(4-cyanopyridin-2-yl)-3-methoxybenzamide;

4-{8-amino-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-N-(4-cyanopyridin-2-yl)-2-methylbenzamide;

4-{8-amino-3-[(1S,6R,8aS)-1-methyl-3-oxohexahydro[1,3]oxazolo[3,4-a]pyridin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-N-(4-cyclopropylpyridin-2-yl)-3-fluorobenzamide;

4-{8-amino-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-N-(4-cyclopropylpyridin-2-yl)-3-methoxybenzamide;

4-{8-amino-3-[(7R,9aS)-4-oxooctahydropyrido[2,1-c][1,4]oxazin-7-yl]imidazo[1,5-a]pyrazin-1-yl}-3-fluoro-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(7R,9aS)-4-oxooctahydro-2H-pyrido[1,2-a]pyrazin-7-yl]imidazo[1,5-a]pyrazin-1-yl}-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(7S,9aR)-4-oxooctahydro-2H-pyrido[1,2-a]pyrazin-7-yl]imidazo[1,5-a]pyrazin-1-yl}-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-2-chloro-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-N-[4-(cyclopropyloxy)pyridin-2-yl]-3-fluorobenzamide;

4-{8-amino-3-[(3S,9aS)-6-oxooctahydro-2H-quinolizin-3-yl]imidazo[1,5-a]pyrazin-1-yl}-3-fluoro-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(3R,9aR)-6-oxooctahydro-2H-quinolizin-3-yl]imidazo[1,5-a]pyrazin-1-yl}-3-fluoro-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(1S,6R,8aS)-1-methyl-3-oxohexahydro[1,3]oxazolo[3,4-a]pyridin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-N-(4-cyclopropylpyridin-2-yl)benzamide;

4-{8-amino-3-[(1R,6R,8aS)-1-methyl-3-oxohexahydro[1,3]oxazolo[3,4-a]pyridin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-N-(4-cyclopropylpyridin-2-yl)benzamide;

4-{8-amino-3-[(1S,6R,8aS)-1-methyl-3-oxohexahydro[1,3]oxazolo[3,4-a]pyridin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(1R,6R,8aS)-1-methyl-3-oxohexahydro[1,3]oxazolo[3,4-a]pyridin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(7R,9aS)-2-methyl-4-oxooctahydro-2H-pyrido[1,2-a]pyrazin-7-yl]imidazo[1,5-a]pyrazin-1-yl}-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(7S,9aR)-2-methyl-4-oxooctahydro-2H-pyrido[1,2-a]pyrazin-7-yl]imidazo[1,5-a]pyrazin-1-yl}-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(6R,8aS)-1,1-dimethyl-3-oxohexahydro[1,3]oxazolo[3,4-a]pyridin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(1R,6R,8aS)-1-methyl-3-oxohexahydro[1,3]oxazolo[3,4-a]pyridin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-N-(4-cyclopropylpyridin-2-yl)-3-methoxybenzamide;

4-{8-amino-3-[(7R,9aR)-4-oxooctahydro-2H-pyrido[1,2-a]pyrazin-7-yl]imidazo[1,5-a]pyrazin-1-yl}-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(7R,9aS)-octahydropyrido[2,1-c][1,4]oxazin-7-yl]imidazo[1,5-a]pyrazin-1-yl}-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(7S,9aR)-octahydropyrido[2,1-c][1,4]oxazin-7-yl]imidazo[1,5-a]pyrazin-1-yl}-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(7S,9aS)-4-oxooctahydro-2H-pyrido[1,2-a]pyrazin-7-yl]imidazo[1,5-a]pyrazin-1-yl}-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(2S,6S,8aR)-2-hydroxy-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(2R,6R,8aS)-2-hydroxy-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-(methylamino)-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-[(ethylcarbamoyl)amino]-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(1R,6R,8aS)-1-methyl-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(1S,6R,8aR)-1-methyl-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(1S,6R,8aR)-1-methyl-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(1R,6R,8aS)-1-methyl-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(7R,9aS)-2-(2-hydroxyethyl)-4-oxooctahydro-2H-pyrido[1,2-a]pyrazin-7-yl]imidazo[1,5-a]pyrazin-1-yl}-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(2R,6S,8aR)-2-hydroxy-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(2S,6R,8aS)-2-hydroxy-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-3-ethoxy-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-3-(benzyloxy)-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-3-(difluoromethoxy)-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(2S,6R,8aR)-2-hydroxy-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(2R,6S,8aS)-2-hydroxy-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(2R,6S,8aS)-2-hydroxy-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(2S,6R,8aR)-2-hydroxy-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(6R,8aR)-3-oxotetrahydro-1H-[1,3]oxazolo[4,3-c][1,4]oxazin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(3R,7R,9aS)-3-methyl-4-oxooctahydropyrido[2,1-c][1,4]oxazin-7-yl]imidazo[1,5-a]pyrazin-1-yl}-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(3E,6R,8aS)-3-(cyanoimino)octahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

methyl {3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]-1-(4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl)imidazo[1,5-a]pyrazin-8-yl}carbamate;

4-{8-amino-3-[(7R,9aS)-2-ethyl-4-oxooctahydro-2H-pyrido[1,2-a]pyrazin-7-yl]imidazo[1,5-a]pyrazin-1-yl}-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(7R,9aS)-2-(1-methylethyl)-4-oxooctahydro-2H-pyrido[1,2-a]pyrazin-7-yl]imidazo[1,5-a]pyrazin-1-yl}-N-[4-(trifluoromethyl)pyridin-2-ylbenzamide;

methyl {(7R,9aS)-7-[8-amino-1-(4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]-4-oxooctahydro-2H-pyrido[1,2-a]pyrazin-2-yl}acetate;

4-{8-amino-3-[(4aS,7R)-2-methyl-1-oxooctahydro-1H-pyrido[1,2-c]pyrimidin-7-yl]imidazo[1,5-a]pyrazin-1-yl}-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(4aR,7S)-2-methyl-1-oxooctahydro-1H-pyrido[1,2-c]pyrimidin-7-yl]imidazo[1,5-a]pyrazin-1-yl}-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(7R,9aS)-4-oxo-2-(pyridin-4-ylcarbonyl)octahydro-2H-pyrido[1,2-a]pyrazin-7-yl]imidazo[1,5-a]pyrazin-1-yl}-3-methoxy-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

2-{(7R,9aS)-7-[8-amino-1-(4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]-4-oxooctahydro-2H-pyrido[1,2-a]pyrazin-2-yl}-2-methylpropanoic acid;

4-{8-amino-3-[(6R,8aS)-octahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-3-methoxy-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(1R,6R,8aS)-1-methyl-3-oxohexahydro[1,3]oxazolo[3,4-a]pyridin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-3-methoxy-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(6R,8aS)-1,1-dimethyl-3-oxohexahydro[1,3]oxazolo[3,4-a]pyridin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-3-methoxy-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(3R,8aR)-6-oxohexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-3-yl]imidazo[1,5-a]pyrazin-1-yl}-3-methoxy-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(4aS,7R)-1-oxohexahydro-3H-pyrido[1,2-c][1,3]oxazin-7-yl]imidazo[1,5-a]pyrazin-1-yl}-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(4aR,7S)-1-oxohexahydro-3H-pyrido[1,2-c][1,3]oxazin-7-yl]imidazo[1,5-a]pyrazin-1-yl}-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(6S,8aR)-2,2-dimethyl-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(6R,8aS)-2,2-dimethyl-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(1S,6R,8aS)-3-imino-1-methylhexahydro[1,3]oxazolo[3,4-a]pyridin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-N-[4-(1-hydroxyethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-N-[4-(1-hydroxy-1-methylethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-N-[4-(1-methoxyethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(6R,8aS)-2,2-dimethyl-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-3-methoxy-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(6S,8aR)-2,2-dimethyl-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-3-methoxy-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(7R,9aS)-4-oxo-2-(pyridin-4-ylcarbonyl)octahydro-2H-pyrido[1,2-a]pyrazin-7-yl]imidazo[1,5-a]pyrazin-1-yl}-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

methyl 2-{[(4-{8-amino-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}phenyl)carbonyl]amino}pyridine-4-carboxylate;

4-{8-amino-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-N-[5-(trifluoromethyl)pyridazin-3-yl]benzamide;

4-{8-amino-3-[(7R,9aS)-4-oxo-2-(phenylcarbonyl)octahydro-2H-pyrido[1,2-a]pyrazin-7-yl]imidazo[1,5-a]pyrazin-1-yl}-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-N-isoquinolin-3-ylbenzamide;

4-{8-amino-3-[(3R,8aR)-6-oxohexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-3-yl]imidazo[1,5-a]pyrazin-1-yl}-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

{(7R,9aS)-7-[8-amino-1-(4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]-4-oxooctahydro-2H-pyrido[1,2-a]pyrazin-2-yl}acetic acid;

4-{8-amino-3-[(1S,6R,8aS)-1-ethenyl-3-oxohexahydro[1,3]oxazolo[3,4-a]pyridin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(1R,6R,8aS)-1-ethenyl-3-oxohexahydro[1,3]oxazolo[3,4-a]pyridin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(4aR,7R)-2-methyl-1-oxooctahydro-1H-pyrido[1,2-c]pyrimidin-7-yl]imidazo[1,5-a]pyrazin-1-yl}-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-3-chloro-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(6R,8aS)-2,2-dimethyl-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-3-ethoxy-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-3-(1,1-difluoroethyl)-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-5-chloro-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-5-ethoxy-2-fluoro-N-[1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]benzamide;

4-{8-amino-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-3-[(˜

2˜

H_—

3_)methyloxy]-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-N-[5-cyano-4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-3-hydroxy-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

5-{8-amino-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-N-[4-(trifluoromethyl)pyridin-2-yl]pyridine-2-carboxamide;

4-{8-amino-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-N-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-3-(cyclopropyloxy)-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-N-[3-methyl-4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-3-cyano-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-N˜

1˜

-[4-(trifluoromethyl)pyridin-2-yl]benzene-1,3-dicarboxamide;

4-{8-amino-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-N-[6-(1-methylethyl)-4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-N-[6-cyclobutyl-4-(trifluoromethyl)pyridin-2-yl]benzamide;

2-{8-amino-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl)-5-[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}benzoic acid;

4-{8-amino-5-chloro-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-3-ethoxy-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-N-(6-methoxypyridin-2-yl)benzamide;

4-{8-amino-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-2-fluoro-5-methoxy-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-3-ethoxy-N-[1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]benzamide;

4-{8-amino-5-chloro-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-2-fluoro-5-methoxy-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-5-chloro-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-5-ethoxy-2-fluoro-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-3-fluoro-5-methoxy-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-5-chloro-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-3-ethoxy-N-[1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]benzamide;

4-{8-amino-5-chloro-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-N-(4-cyclopropylpyridin-2-yl)-5-ethoxy-2-fluorobenzamide;

4-{8-amino-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-N-(4-cyclopropylpyridin-2-yl)-5-ethoxy-2-fluorobenzamide;

4-{8-amino-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-3-(cyclohexyloxy)-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-3-(1-methylethoxy)-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo pyrazin-1-yl}-3-(cyclobutyloxy)-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-3-(cyclopentyloxy)-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-3-(2,2-dimethylpropoxy)-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-5-chloro-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-3-methoxy-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-5-chloro-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-3-(cyclopropyloxy)-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-5-chloro-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-3-(cyclopropyloxy)-N-[1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]benzamide;

4-{8-amino-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-3-(cyclopropyloxy)-N-[1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]benzamide;

4-{8-amino-5-chloro-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-3-(cyclopropyloxy)-N-(4-cyclopropylpyridin-2-yl)benzamide;

4-{8-amino-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-3-(cyclopropyloxy)-N-(4-cyclopropylpyridin-2-yl)benzamide;

4-{8-amino-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-3-(azetidin-3-yloxy)-N-[1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]benzamide;

4-{8-amino-5-chloro-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-5-(cyclopropyloxy)-2-fluoro-N-[1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]benzamide;

4-{8-amino-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-5-ethoxy-2-fluoro-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-5-ethoxy-2-fluoro-N-[1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]benzamide;

4-{8-amino-5-chloro-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-5-chloro-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-N-(5-methyl-1,3-thiazol-2-yl)benzamide;

2-{8-amino-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-5-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl acetate;

4-{8-(acetylamino)-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-3-hydroxy-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-3-hydroxy-N-(2-methoxyethyl)-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-5-chloro-3-[(6R,8aS)-3-oxoodahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-3-ethoxy-N-(5-methyl-1,3-thiazol-2-yl)benzamide;

4-{8-amino-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-3-ethoxy-N-(5-methyl-1,3-thiazol-2-yl)benzamide;

4-{8-amino-5-fluoro-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-5-fluoro-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-3-ethoxy-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-5-fluoro-3-[(6R,8aS)-3-oxooetahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-3-methoxy-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-5-fluoro-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-3-ethoxy-N-[1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]benzamide;

4-{8-amino-5-fluoro-3-[(6R,8aS)-3-oxooetahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-3-ethoxy-N-(5-methyl-1,3-thiazol-2-yl)benzamide;

4-{8-amino-5-fluoro-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-3-hydroxy-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-5-fluoro-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-3-fluoro-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-5-fluoro-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-N-(4-cyclopropylpyridin-2-yl)-3-fluorobenzamide;

4-{8-amino-5-fluoro-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-N-(4-cyclopropylpyridin-2-yl)benzamide;

4-{8-amino-5-fluoro-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-5-ethoxy-2-fluoro-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-N-[3-(trifluoromethyl)-1H-pyrazol-5-yl]benzamide;

4-{8-amino-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-N-[1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]benzamide;

4-{8-amino-3-[(6R,8aS)-3-oxooetahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-N-1 H-imidazol-2-ylbenzamide;

4-{8-amino-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-N-[5-(trifluoromethyl)isoxazol-3-yl]benzamide;

4-{8-amino-3-[(6R,8aS)-3-oxooetahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-N-[3-(trifluoromethyl)isoxazol-5-yl]benzamide;

4-{8-amino-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-N-(1,5-dimethyl-1H-pyrazol-3-yl)benzamide;

4-{8-amino-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-N-(3-methyl-1,2,4-thiadiazol-5-yl)benzamide;

4-{8-amino-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-N-[4-(trifluoromethyl)-1H-imidazol-2-yl]benzamide;

4-{8-amino-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-N-(3-ethyl-1,2,4-thiadiazol-5-yl)benzamide;

4-{8-amino-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-N-[3-(1-methylethyl)-1,2,4-thiadiazol-5-yl]benzamide;

4-{8-amino-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-N-[1-cyclopentyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]benzamide;

4-{8-amino-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-N-(5-cyclopropyl-1-methyl-1H-pyrazol-3-yl)benzamide;

4-{8-amino-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-N-(5-methyl-1,3,4-thiadiazol-2-yl)benzamide;

4-{8-amino-5-chloro-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-N-[1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]benzamide;

ethyl 2-{[(4-{8-amino-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}phenyl)carbonyl]amino}-4-(trifluoromethyl)-1,3-oxazole-5-carboxylate;

4-{8-amino-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-N-[1-ethyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]benzamide;

4-{8-amino-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-3-methyl-N-[1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]benzamide;

4-{8-amino-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-3-methyl-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-3-methoxy-N-[1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]benzamide;

4-{8-amino-5-chloro-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-3-methoxy-N-[1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]benzamide;

4-{8-amino-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-3-chloro-N-[1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]benzamide;

4-{8-amino-5-chloro-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-3-chloro-N-[1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]benzamide;

4-{8-amino-5-chloro-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-5-chloro-2-fluoro-N-[1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]benzamide;

4-{8-amino-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-5-chloro-2-fluoro-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-5-chloro-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-3-chloro-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(6R,8aS)-3-oxooetahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-3-chloro-N-(5-methyl-1,3-thiazol-2-yl)benzamide;

4-{8-amino-5-chloro-3-[(6R,8aS)-3-oxooetahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-3-chloro-N-(5-methyl-1,3-thiazol-2-yl)benzamide;

4-{8-amino-5-chloro-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-2-fluoro-5-methyl-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-2-fluoro-5-methyl-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-(8-amino-3-[(6R,8aS)-3-oxooetahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl)-3-(2-methoxyethoxy)-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-3-(2-hydroxyethoxy)-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-3-(2-ethoxyethoxy)-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(6R,8aS)-3-oxooetahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-3-methoxy-N-(5-methyl-1,3-thiazol-2-yl)benzamide;

4-{8-amino-5-chloro-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-3-methoxy-N-(5-methyl-1,3-thiazol-2-yl)benzamide;

4-{8-amino-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-3-(but-3-yn-1-yloxy)-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-5-methyl-3-[(6R,8aS)-3-oxooetahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-3-ethoxy-N-[1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]benzamide;

4-{8-amino-3-[(6R,8aS)-3-oxooetahydroindolizin-6-yl]-5-(trifluoromethyl)imidazo[1,5-a]pyrazin-1-yl}-3-ethoxy-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-5-chloro-3-[(6R,8aS)-3-oxooetahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-N-(4-ethylpyridin-2-yl)-3-methoxybenzamide;

4-{8-amino-5-chloro-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-3-methoxy-N-(4-methoxypyridin-2-yl)benzamide;

4-{8-amino-5-chloro-3-[(6R,8aS)-3-oxooetahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-N-(4-cyclobutylpyridin-2-yl)-3-methoxybenzamide;

4-{8-amino-5-chloro-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-3-methoxy-N-(5-methylpyridin-2-yl)benzamide;

4-{8-amino-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]-5-(trifluoromethyl)imidazo[1,5-a]pyrazin-1-yl}-3-chloro-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]-5-(trifluoromethyl)imidazo[1,5-a]pyrazin-1-yl}-N-(4-cyclopropylpyridin-2-yl)-3-fluorobenzamide;

4-{8-amino-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]-5-(trifluoromethyl)imidazo[1,5-a]pyrazin-1-yl}-3-methoxy-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-3-fluoro-5-methyl-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]-5-(trifluoromethyl)imidazo[1,5-a]pyrazin-1-yl}-3-ethoxy-N-[1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]benzamide;

4-{8-amino-5-chloro-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-3-(1,1-difluoroethoxy)-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-5-chloro-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-3-fluoro-5-methoxy-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-5-chloro-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-2-chloro-5-methoxy-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(6R,8aS)-2,2-dimethyl-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-3-fluoro-5-methoxy-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-5-fluoro-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-3-fluoro-5-methoxy-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-(8-amino-5-fluoro-3-((6R,8aS)-3-oxooctahydroindolizin-6-yl)imidazo[1,5-a]pyrazin-1-yl)-3-ethoxy-5-fluoro-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide;

4-(8-amino-3-((6R,8aS)-1,1-dimethyl-3-oxooctahydroindolizin-6-yl)imidazo[1,5-a]pyrazin-1-yl)-3-ethoxy-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide; and

4-(8-amino-3-((6R,8aS)-1,1-dimethyl-3-oxooctahydroindolizin-6-yl)imidazo[1,5-a]pyrazin-1-yl)-3-ethoxy-5-fluoro-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide.

15. The compound of claim 1 selected from the group consisting of:

4-{8-amino-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-3-ethoxy-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(6R,8aS)-1,1-dimethyl-3-oxohexahydro[1,3]oxazolo[3,4-a]pyridin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-3-methoxy-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(6S,8aR)-2,2-dimethyl-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(6R,8aS)-2,2-dimethyl-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-3-methoxy-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-3-methoxy-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(6R,8aS)-2,2-dimethyl-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-3-ethoxy-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-5-chloro-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-5-ethoxy-2-fluoro-N-[1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]benzamide;

4-{8-amino-5-chloro-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-3-ethoxy-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-3-fluoro-5-methoxy-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-5-chloro-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-3-ethoxy-N-[1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]benzamide;

4-{8-amino-5-chloro-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-3-methoxy-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-5-fluoro-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-3-ethoxy-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]-5-(trifluoromethyl)imidazo[1,5-a]pyrazin-1-yl}-3-ethoxy-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide; and

4-(8-amino-5-fluoro-3-((6R,8aS)-3-oxooctahydroindolizin-6-yl)imidazo[1,5-a]pyrazin-1-yl)-3-ethoxy-5-fluoro-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide.

16. The compound of claim 1 having Formula 1e

17. The compound of claim 16, or a pharmaceutically acceptable salt thereof, wherein

R⁷, R⁸, R⁹, and R¹⁰ are independently selected from H, halogen, or (1-3C)alkoxy;

R¹¹ is H, halogen or (1-3C)alkyl, wherein the alkyl is optionally substituted with one, two or three halogen;

R^c is H or CH₃; and

R^d is H or CH₃.

18. The compound of claim 1, or a pharmaceutically acceptable salt thereof, for use in the treatment of Bruton'"'"'s Tyrosine Kinase (Btk) mediated disorders.

19. Use of the compound of Formula I according to claim 1, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of Bruton'"'"'s Tyrosine Kinase (Btk) mediated disorders.

20. A pharmaceutical composition which comprises the compound of claim 1, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

21. The pharmaceutical composition of claim 20, which further comprises at least one additional therapeutically active agent.

22. The pharmaceutical composition of claim 21, wherein the additional therapeutically active agent is an anti-inflammatory agent, an immunosuppressant agent, or a chemotherapeutic agent.

23. A method for treating a subject suffering with a Bruton'"'"'s Tyrosine Kinase (Btk) mediated disorder comprising administering to the subject the compound of claim 1, or a pharmaceutically acceptable salt thereof, in an amount effective to treat the Btk mediated disorder.

24. The method of claim 23, wherein the Btk mediated disorder is selected from the group consisting of rheumatoid arthritis, psoriatic arthritis, infectious arthritis, progressive chronic arthritis, deforming arthritis, osteoarthritis, traumatic arthritis, gouty arthritis, Reiter'"'"'s syndrome, polychondritis, acute synovitis and spondylitis, glomerulonephritis (with or without nephrotic syndrome), autoimmune hematologic disorders, hemolytic anemia, aplasic anemia, idiopathic thrombocytopenia, and neutropenia, autoimmune gastritis, and autoimmune inflammatory bowel diseases, ulcerative colitis, Crohn'"'"'s disease, host versus graft disease, allograft rejection, chronic thyroiditis, Graves'"'"' disease, scleroderma, diabetes (type and type II), active hepatitis (acute and chronic), pancreatitis, primary billiary cirrhosis, myasthenia gravis, multiple sclerosis, systemic lupus erythematosis, psoriasis, atopic dermatitis, contact dermatitis, eczema, skin sunburns, vasculitis (e.g. Behcet'"'"'s disease) chronic renal insufficiency, Stevens-Johnson syndrome, inflammatory pain, idiopathic sprue, cachexia, sarcoidosis, Guillain-Barré

syndrome, uveitis, conjunctivitis, kerato conjunctivitis, otitis media, periodontal disease, pulmonary interstitial fibrosis, asthma, bronchitis, rhinitis, sinusitis, pneumoconiosis, pulmonary insufficiency syndrome, pulmonary emphysema, pulmonary fibrosis, silicosis, chronic inflammatory pulmonary disease, and chronic obstructive pulmonary disease.

25. The method of claim 24, wherein the Btk mediated disorder is rheumatoid arthritis, psoriatic arthritis, or osteoarthritis.

2. A compound according to Formula II, or a pharmaceutically acceptable salt thereof,