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Btk inhibitors

a technology of btk inhibitors and inhibitors, which is applied in the direction of biocide, drug composition, immunological disorders, etc., can solve the problems of serious adverse effects, fyn-deficient mice also show pronounced neurological defects, and are prohibitive for the development of btk inhibitors

Inactive Publication Date: 2014-07-24
MERCK SHARP & DOHME CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

This patent describes compounds that can stop the activity of Btk, which is a protein involved in autoimmune and inflammatory diseases. These compounds can be used to treat these diseases, and pharmaceutical compositions are being developed to do so.

Problems solved by technology

With dramatic adverse effects reported for knockouts of Src-family kinases, especially for double and triple knockouts, this is seen as prohibitive for the development of Btk inhibitors that are not selective over the Src-family kinases.
In addition, Fyn-deficient mice also show pronounced neurological defects.
Hence, an inhibitor that inhibits multiple or all kinases of the Src-family kinases simultaneously may cause serious adverse effects.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

example 1

[1018]

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

(a) 4-(8-((2,4-dimethoxybenzyl)amino)-3-((3S,6S)-6-(hydroxymethyl)piperidin-3-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide

[1019]To a solution of ((2S,5S)-5-(8-((2,4-dimethoxybenzyl)amino)-1-(4-((4-(trifluoromethyl) pyridin-2-yl)carbamoyl)phenyl)imidazo[1,5-a]pyrazin-3-yl)piperidin-2-yl)methyl acetate (120 mg, 0.17 mmol) in 3 mL of MeOH was added NaOMe (46 mg, to 0.85 mmol). The reaction mixture was stirred at room temperature for 3 h under N2.

[1020]The mixture was poured into aq. NH4Cl, extracted with DCM. The organic layer was dried over Na2SO4, and concentrated in vacuo to give 110 mg of crude 4-(8-((2,4-dimethoxybenzyl)amino)-3-((3S,6S)-6-(hydroxymethyl)piperidin-3-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide, which was used in the next step directly. MS-ESI (m / z): 662.0 (M+...

example 2

[1023]

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

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

[1024]To a mixture of (2R,5R)-benzyl 5-(8-((2,4-dimethoxybenzyl)amino)-1-(44(4-(trifluoromethyl)pyridin-2-yl)carbamoyl)phenyl)imidazo[1,5-a]pyrazin-3-yl)-2-(hydroxymethyl)piperidine-1-carboxylate (40 mg) in 3 mL of MeOH was added NaOMe (54 mg, 1 mmol). The reaction mixture was stirred at room temperature for 24 h, and then at 40° C. for 6 hours under N2. The mixture was poured into aq. NH4Cl, extracted with DCM (20 mL). The organic layer was dried over Na2SO4, and concentrated in vacuo to give 40 mg crude of 4-(8-((2,4-dimethoxybenzyl)amino)-3-((6R,8aR)-3-oxohexahydro-1H-oxazolo[3,4-a]pyridin-6-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide, which...

example 3

[1026]

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

(a) (2S,5R)-benzyl5-(8-amino-1-(4-((4-(trifluoromethyl)pyridin-2-yl)carbamoyl)phenyl)imidazo[1,5-a]pyrazin-3-yl)-2-(methoxymethyl)piperidine-1-carboxylate

[1027]To a degassed mixture of (2S,5R)-benzyl 5-(8-amino-1-bromoimidazo[1,5-a]pyrazin-3-yl)-2-(methoxymethyl)piperidine-1-carboxylate (50 mg, 0.105 mmol), 4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-N-(4-trifluoromethyl-pyridin-2-yl)-benzamide (41 mg, 0.105 mmol) and K2CO3 (44 mg, 0.316 mmol) in dioxane / H2O (6 mL, 3:1) was added Pd(dppf)Cl2 under N2. The mixture was heated to 100° C. for 1 hour. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated, and the residue was purified on silica gel column chromatograph (PE:EA=100%˜70%) to give (2S,5R)-benzyl 5-(8-amino-1-(4-((4-(trifluoromethyl)pyridin-2-yl)carbamoyl)phenyl)imidazo[1,5-a]pyrazi...

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Abstract

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

Description

FIELD OF THE INVENTION[0001]The present invention relates to Btk inhibitor compounds, 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 Bruton's Tyrosine Kinase (Btk) mediated disorders.BACKGROUND OF THE INVENTION[0002]B lymphocyte activation is key in the generation of adaptive immune responses. Derailed B lymphocyte activation is a hallmark of many autoimmune diseases and modulation of this immune response is therefore of therapeutic interest. Recently the success of B cell therapies in autoimmune diseases has been established. Treatment of rheumatoid arthritis (RA) patients with Rituximab (anti-CD20 therapy) is an accepted clinical therapy. More recent clinical trial studies show that treatment with Rituximab also ameliorates disease symptoms in relapsing remitting multiple sclerosis (RRMS) and systemic lupus erythematosus (SLE) patients. Thi...

Claims

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Application Information

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IPC IPC(8): C07D471/04A61K31/4985A61K31/506C07D487/04A61K31/5383A61K31/519A61K31/5365A61K45/06C07D498/04C07D455/02
CPCC07D471/04C07D498/04A61K31/4985A61K31/506C07D455/02A61K31/5383A61K31/519A61K31/5365A61K45/06C07D487/04C07D519/00C07D491/048A61K31/497A61P19/02A61P29/00A61P37/00Y02A50/30
Inventor KIM, RONALD M.LIU, JIANGAO, XIAOLEIBOGA, SOBHANA BABUGUIADEEN, DEODIALSINGHKOZLOWSKI, JOSEPH A.YU, WENSHENGANAND, RAJANYU, YOUNONGSELYUTIN, OLEG B.GAO, YING-DUOWULIU, SHILANYANG, CHUNDAOWANG, HONGJIAN
Owner MERCK SHARP & DOHME CORP
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