IP Library › Granted Patent US 9,834,554
Granted Patent B2
US 9,834,554 · App. 15/105,354 · Granted Dec 5, 2017

BTK inhibitors

Inventors: Jian Liu (Edison, NJ); Ronald M. Kim (Summit, NJ); Joseph Kozlowski (Princeton, NJ); Deodialsingh Guiadeen (Chesterfield, NJ); Arto D. Krikorian (Astoria, NY); Younong Yu (East Brunswick, NJ)
Assignee: Merck Sharp & Dohme Corp.
C07D471/04A61K45/06C07D519/00
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Quick Facts
Patent No.
US 9,834,554
App. No.
15/105,354
Granted
Dec 5, 2017
Kind
B2
Abstract

The present invention provides Bruton's Tyrosine Kinase (Btk) inhibitor compounds according to Formula I or pharmaceutically acceptable salts thereof. 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 (71)

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

wherein:

X is CH 2 or O;

R 1 is (1-4C)alkyl, (1-5C)alkoxy, (3-6C)cycloalkyl, or (3-6C)cycloalkoxy; any alkyl or alkoxy group of R 1 may optionally be substituted with one, two or three halogen;

R 2 is H, or —C(O)(CH 2 ) y —O—(1-6C)alkyl;

R 3 is selected from the group consisting of

a) OH;

b) (1-6C)alkyl;

c) (3-6C)cycloalkyl;

d) (1-6C)alkoxy;

e) (1-3C)heterocycloalkyl;

f) (1-3C)heteroaryl; and

g) (3-6C)cycloalkyl(1-3C)alkyl; and

h) —(CH 2 ) y —O—(CH 2 ) y —(1-6C)alkoxy;

wherein b)-h) are optionally substituted with one, two or three groups selected from:

halogen, (1-6C)alkyl, (1-6C)alkoxy, (3-6C)cycloalkyl, hydroxyl or cyano;

R 4 is H or (1-3C)alkyl;

R 3 and R 4 together can form a saturated heterocyclic 5- or 6-membered ring;

R 5 is H, (1-3C)alkoxy, or (3-6C)cycloalkoxy; and

y is 1, 2, or 3.

2. The compound of claim 1 , wherein R 2 is H.

3. The compound of claim 1 , wherein R 4 is CH 3 .

4. The compound of claim 2 , wherein X is O.

5. The compound of claim 2 , wherein X is CH 2 .

6. The compound of claim 1 having Formula Ia

or a pharmaceutically acceptable salt thereof.

7. The compound of claim 1 having Formula Ib

or a pharmaceutically acceptable salt thereof.

8. A compound selected from the group consisting of:

4-(7-amino-3-{(2R)-4-[(3-methyloxetan-3-yl)carbonyl]morpholin-2-yl}-1H-pyrazolo[3,4-c]pyridin-1-yl)-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{3-[(2R)-4-acetylmorpholin-2-yl]-7-amino-1H-pyrazolo[3,4-c]pyridin-1-yl}-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{7-amino-3-[(2R)-4-propanoylmorpholin-2-yl]-1H-pyrazolo[3,4-c]pyridin-1-yl}-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{7-[(methoxyacetyl)amino]-3-[(2R)-4-(methoxyacetyl)morpholin-2-yl]-1H-pyrazolo[3,4-c]pyridin-1-yl}-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{7-amino-3-[(2R)-4-(methoxyacetyl)morpholin-2-yl]-1H-pyrazolo[3,4-c]pyridin-1-yl}-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{3-[(2R)-4-acetylmorpholin-2-yl]-7-amino-1H-pyrazolo[3,4-c]pyridin-1-yl}-N-(4-methoxypyridin-2-yl)benzamide;

4-{7-amino-3-[(2R)-4-(methoxyacetyl)morpholin-2-yl]-1H-pyrazolo[3,4-c]pyridin-1-yl}-N-(4-methoxypyridin-2-yl)benzamide;

4-(7-amino-3-{(2R)-4-[(3-methyloxetan-3-yl)carbonyl]morpholin-2-yl}-1H-pyrazolo[3,4-c]pyridin-1-yl)-N-(4-methoxypyridin-2-yl)benzamide;

4-(7-amino-3-{(3R)-1-[(3-methyloxetan-3-yl)carbonyl]piperidin-3-yl}-1H-pyrazolo[3,4-c]pyridin-1-yl)-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-(7-amino-3-{(3R)-1-[(3-methyl-1H-pyrazol-4-yl)carbonyl]piperidin-3-yl}-1H-pyrazolo[3,4-c]pyridin-1-yl)-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{7-amino-3-[(3R)-1-propanoylpiperidin-3-yl]-1H-pyrazolo[3,4-c]pyridin-1-yl}-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-(7-amino-3-{(3R)-1-[(2,2-difluorocyclopropyl)carbonyl]piperidin-3-yl}-1H-pyrazolo[3,4-c]pyridin-1-yl)-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{7-amino-3-[(3R)-1-(1,2,5-oxadiazol-3-ylcarbonyl)piperidin-3-yl]-1H-pyrazolo[3,4-c]pyridin-1-yl}-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{7-amino-3-[(3R)-1-(cyclobutylacetyl)piperidin-3-yl]-1H-pyrazolo[3,4-c]pyridin-1-yl}-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-(7-amino-3-{(3R)-1-[(3,5-dimethylisoxazol-4-yl)carbonyl]piperidin-3-yl}-1H-pyrazolo[3,4-c]pyridin-1-yl)-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{7-amino-3-[(3R)-1-(3-methoxypropanoyl)piperidin-3-yl]-1H-pyrazolo[3,4-c]pyridin-1-yl}-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-(7-amino-3-{(3R)-1-[(3,3-difluorocyclobutyl)carbonyl]piperidin-3-yl}-1H-pyrazolo[3,4-c]pyridin-1-yl)-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{7-amino-3-[(3R)-1-(methoxyacetyl)piperidin-3-yl]-1H-pyrazolo[3,4-c]pyridin-1-yl}-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{7-amino-3-[(3R)-1-(2-methylpropanoyl)piperidin-3-yl]-1H-pyrazolo[3,4-c]pyridin-1-yl}-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{7-amino-3-[(3R)-1-(cyclobutylcarbonyl)piperidin-3-yl]-1H-pyrazolo[3,4-c]pyridin-1-yl}-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{3-[(3R)-1-acetylpiperidin-3-yl]-7-amino-1H-pyrazolo[3,4-c]pyridin-1-yl}-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{7-amino-3-[(3R)-1-(ethoxyacetyl)piperidin-3-yl]-1H-pyrazolo[3,4-c]pyridin-1-yl}-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-(7-amino-3-{(3R)-1-[(2-methoxyethoxy)acetyl]piperidin-3-yl}-1H-pyrazolo[3,4-c]pyridin-1-yl)-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{7-amino-3-[(3R)-1-(cyclopropylcarbonyl)piperidin-3-yl]-1H-pyrazolo[3,4-c]pyridin-1-yl}-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-(7-amino-3-{(3R)-1-[(1-hydroxycyclopropyl)carbonyl]piperidin-3-yl}-1H-pyrazolo[3,4-c]pyridin-1-yl)-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-(7-amino-3-{(3R)-1-[(1-methylcyclopropyl)carbonyl]piperidin-3-yl}-1H-pyrazolo[3,4-c]pyridin-1-yl)-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-(7-amino-3-{(3R)-1-[(1-cyanocyclopropyl)carbonyl]piperidin-3-yl}-1H-pyrazolo[3,4-c]pyridin-1-yl)-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-(7-amino-3-{(3R)-1-[(3-methyloxetan-3-yl)carbonyl]piperidin-3-yl}-1H-pyrazolo[3,4-c]pyridin-1-yl)-N-(4-methoxypyridin-2-yl)benzamide;

4-(7-amino-3-{(3R)-1-[3-hydroxy-2-(hydroxymethyl)-2-methylpropanoyl]piperidin-3-yl}-1H-pyrazolo[3,4-c]pyridin-1-yl)-N-(4-methoxypyridin-2-yl)benzamide;

4-(7-amino-3-{(3R,6S)-6-methyl-1-[(3-methyloxetan-3-yl)carbonyl]piperidin-3-yl}-1H-pyrazolo[3,4-c]pyridin-1-yl)-N-(4-cyclopropylpyridin-2-yl)benzamide;

4-{7-amino-3-[(3R,6S)-1-(cyclopropylcarbonyl)-6-methylpiperidin-3-yl]-1H-pyrazolo[3,4-c]pyridin-1-yl}-N-(4-cyclopropylpyridin-2-yl)benzamide;

4-(7-amino-3-{(3R,6S)-1-[(2S)-2-hydroxypropanoyl]-6-methylpiperidin-3-yl}-1H-pyrazolo[3,4-c]pyridin-1-yl)-N-(4-cyclopropylpyridin-2-yl)benzamide;

4-(7-amino-3-{(3R,6S)-1-[(2S)-2-methoxypropanoyl]-6-methylpiperidin-3-yl}-1H-pyrazolo[3,4-c]pyridin-1-yl)-N-(4-cyclopropylpyridin-2-yl)benzamide;

4-{7-amino-3-[(3R,6S)-1-(cyclopropylcarbonyl)-6-methylpiperidin-3-yl]-1H-pyrazolo[3,4-c]pyridin-1-yl}-N-[4-(cyclopropyloxy)pyridin-2-yl]benzamide;

4-(7-amino-3-{(3R,6S)-6-methyl-1-[(3-methyloxetan-3-yl)carbonyl]piperidin-3-yl}-1H-pyrazolo[3,4-c]pyridin-1-yl)-N-[4-(cyclopropyloxy)pyridin-2-yl]benzamide;

4-(7-amino-3-{(3R,6S)-1-[(2R)-2-hydroxypropanoyl]-6-methylpiperidin-3-yl}-1H-pyrazolo[3,4-c]pyridin-1-yl)-N-[4-(cyclopropyloxy)pyridin-2-yl]benzamide;

4-{7-amino-3-[(3R,6S)-1-(cyclopropylcarbonyl)-6-methylpiperidin-3-yl]-1H-pyrazolo[3,4-c]pyridin-1-yl}-3-methoxy-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{7-amino-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]-1H-pyrazolo[3,4-c]pyridin-1-yl}-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{7-amino-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]-1H-pyrazolo[3,4-c]pyridin-1-yl}-3-(cyclopropyloxy)-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{7-amino-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]-1H-pyrazolo[3,4-c]pyridin-1-yl}-3-methoxy-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide; and

4-{7-amino-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]-1H-pyrazolo[3,4-c]pyridin-1-yl}-3-ethoxy-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

or a pharmaceutically acceptable salt thereof.

Assignments (2)
MERGER Recorded Aug 8, 2022
From: MERCK SHARP & DOHME CORP.
To: MERCK SHARP & DOHME LLC
Reel/Frame 061102/0145 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 16, 2016
From: LIU, JIAN; KIM, RONALD M.; KOZLOWSKI, JOSEPH; GUIADEEN, DEODIALSINGH; KRIKORIAN, ARTO D.; YU, YOUNONG
To: MERCK SHARP & DOHME CORP.
Reel/Frame 038934/0652 →
Continuity (2)
Provisional Application 61919471 · Dec 20, 2013
Related Publication 20160326164A1 · Nov 10, 2016