Imidazopyrazine analogs with 3-tertiary carbon substitutions as btk inhibitors

Patent metadata

Field	Value
Publication number	US-2018009828-A1
Application number	US-201515538957-A
Country	US
Kind code	A1
Filing date	Dec 17, 2015
Priority date	Dec 31, 2014
Publication date	Jan 11, 2018
Grant date	—

Abstract

The present invention provides Bruton's Tyrosine Kinase (Btk) inhibitor compounds according to Formula (I), or pharmaceutically acceptable salts thereof, Formula (I) 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 of Formula I in the treatment of Btk mediated disorders.

First claim

What is claimed is:

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

wherein
Ring A is selected from the group consisting of:

R 1 is (1-6C)alkyl, (1-6C)haloalkyl or cyclopropyl;
R 2 is (1-3C)alkoxy or halogen;
R 3 is (1-3C)alkyl;
x is 0, 1 or 2;
T is C(R a ) 2 , NR c or a bond;
U is C(R b ) 2 , O or NR d ;
R a , R b , R c , and R d are each independently selected from H and (1-3C)alkyl.

2 . The compound of claim 1 having Formula Ia

or a pharmaceutically acceptable salt thereof.

3 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
R 1 is CF 3 ; R 3 is methyl; and x is 1.

4 . The compound of claim 1 selected from the group consisting of:
(6S,8aR)-6-(8-amino-1-bromoimidazo[1,5-a]pyrazin-3-yl)-6-methyltetrahydro-1H-oxazolo[3,4-a]pyridin-3(5H)-one;
4-(8-amino-3-((6S,8aR)-6-methyl-3-oxohexahydro-1H-oxazolo[3,4-a]pyridin-6-yl)imidazo[1,5-a]pyrazin-1-yl)-3-ethoxy-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide;
4-(8-amino-3-((6S,8aR)-6-methyl-3-oxohexahydro-1H-oxazolo[3,4-a]pyridin-6-yl)imidazo[1,5-a]pyrazin-1-yl)-3-ethoxy-N-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)benzamide;
(7S,9aR)-7-(8-amino-1-bromoimidazo[1,5-a]pyrazin-3-yl)-2-isopropyl-7-methylhexahydro-1H-pyrido[1,2-a]pyrazin-4(6H)-one;
4-(8-amino-3-((7S,9aR)-2-isopropyl-7-methyl-4-oxooctahydro-1H-pyrido[1,2-a]pyrazin-7-yl)imidazo[1,5-a]pyrazin-1-yl)-3-ethoxy-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide bis(2,2,2-trifluoroacetate);
4-(8-amino-3-((7S,9aR)-2-isopropyl-7-methyl-4-oxooctahydro-1H-pyrido[1,2-a]pyrazin-7-yl)imidazo[1,5-a]pyrazin-1-yl)-3-ethoxy-N-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)benzamide bis(2,2,2-trifluoroacetate);
6R,8aS)-6-(8-amino-1-bromoimidazo[1,5-a]pyrazin-3-yl)-6-methyltetrahydro-1H-oxazolo[3,4-a]pyridin-3(5H)-one;
(7R,9aS)-7-(8-amino-1-bromoimidazo[1,5-a]pyrazin-3-yl)-2-isopropyl-7-methylhexahydro-1H-pyrido[1,2-a]pyrazin-4(6H)-one;
4-(8-amino-3-((6R,8aS)-6-methyl-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)-6-methyl-3-oxooctahydroindolizin-6-yl)imidazo[1,5-a]pyrazin-1-yl)-3-methoxy-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide;
7-(8-amino-1-bromoimidazo[1,5-a]pyrazin-3-yl)-2,7-diethyloctahydro-1H-pyrido[1,2-c]pyrimidin-1-one;
7-(8-amino-1-bromoimidazo[1,5-a]pyrazin-3-yl)-2,7-diethyloctahydro-1H-pyrido[1,2-c]pyrimidin-1-one;
7-(8-amino-1-bromoimidazo[1,5-a]pyrazin-3-yl)-2,7-dimethyloctahydro-1H-pyrido[1,2-c]pyrimidin-1-one; and
7-(8-amino-1-bromoimidazo[1,5-a]pyrazin-3-yl)-2,7-dimethyloctahydro-1H-pyrido[1,2-c]pyrimidin-1-one;
or a pharmaceutically acceptable salt thereof

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

6 . The pharmaceutical composition of claim 5 , which further comprises at least one additional therapeutically active agent.

7 . The compound of claim 1 or a pharmaceutically acceptable salt thereof for use in therapy.

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

9 . 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.

10 . 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 in an amount effective to treat the Btk mediated disorder, thereby treating the subject.

11 . The method of claim 10 , 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, schleroderma, diabetes (type I 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.

12 . The method of claim 11 , wherein the Btk mediated disorder is rheumatoid arthritis, psoriatic arthritis, or osteoarthritis.

Assignees

• Liu Jian
• Kozlowski Joseph A
• Gao Xiaolei
• Guiadeen Deodial Guy
• Liu Shilan
• Wang Dahai
• Merck Sharp & Dohme

Inventors

• Liu Jian
• Kozlowski Joseph A
• Gao Xiaolei
• Guiadeen Deodial Guy
• Liu Shilan
• Wang Dahai

Classifications

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P37/08

  Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14) · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title