Pyrimidine compounds as JAK kinase inhibitors

Patent metadata

Field	Value
Publication number	US-10028960-B2
Application number	US-201715498803-A
Country	US
Kind code	B2
Filing date	Apr 27, 2017
Priority date	Apr 28, 2016
Publication date	Jul 24, 2018
Grant date	Jul 24, 2018

Abstract

The invention provides compounds of formula (I):

wherein the variables are defined in the specification, or a pharmaceutically-acceptable salt thereof, that are inhibitors of JAK kinases. The invention also provides pharmaceutical compositions comprising such compounds, methods of using such compounds to treat gastrointestinal and other inflammatory diseases, and processes and intermediates useful for preparing such compounds.

First claim

What is claimed is:

1. A compound of formula (I):

wherein
R 1 is selected from:
(a) —S(O) 2 R 4 , wherein R 4 is selected from:
C 1-4 alkyl, wherein C 1-4 alkyl is optionally substituted with —CN, —OC 1-3 alkyl, or C 3-6 cycloalkyl,
heterocyclyl containing 4 to 6 ring atoms including one nitrogen atom, wherein any heterocyclyl is optionally substituted with —CN, C 3-6 cycloalkyl,
pyridinyl, wherein pyridinyl is optionally substituted with fluoro, and phenyl;

(b) C 1-4 alkyl, wherein C 1-4 alkyl is optionally substituted with —CN,

 or pyridinyl, wherein pyridinyl is optionally substituted with —CN; and
(c) —C(O)R 5 , wherein R 5 is selected from:
C 1-4 alkyl, wherein C 1-4 alkyl is optionally substituted with C 3-6 cycloalkyl, or with one or two fluoro,
—OC 1-4 alkyl,
C 3-6 cycloalkyl, and
morpholinyl;

R 2 is hydrogen or methyl;
R 3 is C 1-3 alkyl; and
n is 1 or 2;
or a pharmaceutically-acceptable salt or stereoisomer thereof.

2. The compound of claim 1 , wherein R 3 is methyl.

3. The compound of claim 1 , wherein R 2 is methyl.

4. The compound of claim 1 , wherein n is 2.

5. The compound of claim 1 , wherein R 1 is selected from:
(a) S(O) 2 R 4 , wherein R 4 is selected from:
C 1-2 alkyl, wherein C 1-2 alkyl is optionally substituted with —CN, —OCH 3 , or cyclopropyl,
azetidinyl or pyrrolidinyl, wherein azetidinyl is optionally substituted with —CN,
cyclopropyl,
pyridinyl, wherein pyridinyl is optionally substituted with fluoro, and phenyl;

(b) C 1-4 alkyl, wherein C 1-4 alkyl is optionally substituted with —CN,

 or pyridinyl, wherein pyridinyl is optionally substituted with —CN; and
(c) C(O)R 5 , wherein R 5 is selected from:
C 1-2 alkyl, wherein C 1-2 alkyl is optionally substituted with cyclopropyl, or with one or two fluoro,
—OC 1-4 alkyl,
C 3-6 cycloalkyl, and
morpholinyl.

6. The compound of claim 1 , wherein the compound is selected from:
1-(((1R,3s,5S)-3-((4-((5-(hydroxymethyl)-1H-pyrazol-3-yl)amino)-6-methoxypyrimidin-2-yl)(methyl)amino)-8-azabicyclo[3.2.1]octan-8-yl)sulfonyl)azetidine-3-carbonitrile,
1-(((1R,3s,5S)-3-((4-((5-(hydroxymethyl)-1H-pyrazol-3-yl)amino)-6-methoxypyrimidin-2-yl)(methyl)amino)-9-azabicyclo[3.3.1]nonan-9-yl)sulfonyl)azetidine-3-carbonitrile,
(3-((6-methoxy-2-(methyl((1R,3s,5S)-9-(methylsulfonyl)-9-azabicyclo[3.3.1]nonan-3-yl)amino)pyrimidin-4-yl)amino)-1H-pyrazol-5-yl)methanol,
(3-((6-methoxy-2-(((1R,3s,5S)-9-((2-methoxyethyl)sulfonyl)-9-azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)pyrimidin-4-yl)amino)-1H-pyrazol-5-yl)methanol,
(3-((1R,3s,5S)-3-((4-((5-(hydroxymethyl)-1H-pyrazol-3-yl)amino)-6-methoxypyrimidin-2-yl)(methyl)amino)-8-azabicyclo[3.2.1]octan-8-yl)propanenitrile,
5-(((1R,3s,5S)-3-((4-((5-(hydroxymethyl)-1H-pyrazol-3-yl)amino)-6-methoxypyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonan-9-yl)methyl)picolinonitrile,
5-(((1R,3s,5S)-3-((4-((5-(hydroxymethyl)-1H-pyrazol-3-yl)amino)-6-methoxypyrimidin-2-yl)(methyl)amino)-9-azabicyclo[3.3.1]nonan-9-yl)methyl)nicotinonitrile,
isobutyl (1R,3s,5S)-3-((4-((5-(hydroxymethyl)-1H-pyrazol-3-yl)amino)-6-methoxypyrimidin-2-yl)(methyl)amino)-9-azabicyclo[3.3.1]nonane-9-carboxylate,
2,2-difluoro-1-((1R,3s,5S)-3-((4-((5-(hydroxymethyl)-1H-pyrazol-3-yl)amino)-6-methoxypyrimidin-2-yl)(methyl)amino)-9-azabicyclo[3.3.1]nonan-9-yl)ethan-1-one,
(3-((2-(((1R,3s,5S)-9-(azetidin-1-ylsulfonyl)-9-azabicyclo[3.3.1]nonan-3-yl)amino)-6-methoxypyrimidin-4-yl)amino)-1H-pyrazol-5-yl)methanol,
1-(((1R,3s,5S)-3-((4-((5-(hydroxymethyl)-1H-pyrazol-3-yl)amino)-6-methoxypyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonan-9-yl)sulfonyl)azetidine-3-carbonitrile,
(3-((2-(((1R,3s,5S)-9-((5-fluoropyridin-3-yl)sulfonyl)-9-azabicyclo[3.3.1]nonan-3-yl)amino)-6-methoxypyrimidin-4-yl)amino)-1H-pyrazol-5-yl)methanol,
(3-((6-methoxy-2-(((1R,3s,5S)-9-(phenylsulfonyl)-9-azabicyclo[3.3.1]nonan-3-yl)amino)pyrimidin-4-yl)amino)-1H-pyrazol-5-yl)methanol,
(3-((2-(((1R,3s,5S)-9-(ethylsulfonyl)-9-azabicyclo[3.3.1]nonan-3-yl)amino)-6-methoxypyrimidin-4-yl)amino)-1H-pyrazol-5-yl)methanol,
(3-((2-(((1R,3s,5S)-9-((cyclopropylmethyl)sulfonyl)-9-azabicyclo[3.3.1]nonan-3-yl)amino)-6-methoxypyrimidin-4-yl)amino)-1H-pyrazol-5-yl)methanol,
(3-((6-methoxy-2-(((1R,3s,5S)-9-(pyridin-3-ylsulfonyl)-9-azabicyclo[3.3.1]nonan-3-yl)amino)pyrimidin-4-yl)amino)-1H-pyrazol-5-yl)methanol,
3-(((1R,3s,5S)-3-((4-((5-(hydroxymethyl)-1H-pyrazol-3-yl)amino)-6-methoxypyrimidin-2-yl)(methyl)amino)-9-azabicyclo[3.3.1]nonan-9-yl)-sulfonyl)propanenitrile,
(3-((6-methoxy-2-(methyl((1R,3s,5S)-9-(pyrrolidin-1-ylsulfonyl)-9-azabicyclo[3.3.1]nonan-3-yl)amino)pyrimidin-4-yl)amino)-1H-pyrazol-5-yl)methanol,
(3-((2-(((1R,3s,5S)-9-(cyclopropylsulfonyl)-9-azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)-6-methoxypyrimidin-4-yl)amino)-1H-pyrazol-5-yl)methanol,
(3-((6-methoxy-2-(methyl((1R,3s,5S)-9-(pyridin-3-ylsulfonyl)-9-azabicyclo[3.3.1]nonan-3-yl)amino)pyrimidin-4-yl)amino)-1H-pyrazol-5-yl)methanol,
(3-((6-methoxy-2-(methyl((1R,3s,5S)-9-(phenylsulfonyl)-9-azabicyclo[3.3.1]nonan-3-yl)amino)pyrimidin-4-yl)amino)-1H-pyrazol-5-yl)methanol,
(3-((2-(((1R,3s,5S)-9-(azetidin-1-ylsulfonyl)-9-azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)-6-methoxypyrimidin-4-yl)amino)-1H-pyrazol-5-yl)methanol,
(3-((2-(((1R,3s,5S)-9-((cyclopropylmethyl)sulfonyl)-9-azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)-6-methoxypyrimidin-4-yl)amino)-1H-pyrazol-5-yl)methanol,
(3-((2-(((1R,3s,5S)-9-((5-fluoropyridin-3-yl)sulfonyl)-9-azabicyclo[3.3.1]nonan-3-yl)(methyl)amino)-6-methoxypyrimidin-4-yl)amino)-1H-pyrazol-5-yl)methanol,
4-(((1R,3s,5S)-3-((4-((5-(hydroxymethyl)-1H-pyrazol-3-yl)amino)-6-methoxypyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonan-9-yl)methyl)picolinonitrile,
(3-((6-methoxy-2-(((1R,3s,5S)-9-(pyridin-3-ylmethyl)-9-azabicyclo[3.3.1]nonan-3-yl)amino)pyrimidin-4-yl)amino)-1H-pyrazol-5-yl)methanol,
3-((1R,3s,5S)-3-((4-((5-(hydroxymethyl)-1H-pyrazol-3-yl)amino)-6-methoxypyrimidin-2-yl)(methyl)amino)-9-azabicyclo[3.3.1]nonan-9-yl)propanenitrile,
1-(((1R,3s,5S)-3-((4-((5-(hydroxymethyl)-1H-pyrazol-3-yl)amino)-6-methoxypyrimidin-2-yl)(methyl)amino)-9-azabicyclo[3.3.1]nonan-9-yl)methyl)cyclopropane-1-carbonitrile,
(3-((6-methoxy-2-(methyl((1R,3s,5S)-9-(pyridin-4-ylmethyl)-9-azabicyclo[3.3.1]nonan-3-yl)amino)pyrimidin-4-yl)amino)-1H-pyrazol-5-yl)methanol,
4-(((1R,3s,5S)-3-((4-((5-(hydroxymethyl)-1H-pyrazol-3-yl)amino)-6-methoxypyrimidin-2-yl)(methyl)amino)-9-azabicyclo[3.3.1]nonan-9-yl)methyl)picolinonitrile,
2,2-difluoro-1-((1R,3s,5S)-3-((4-((5-(hydroxymethyl)-1H-pyrazol-3-yl)amino)-6-methoxypyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonan-9-yl)ethan-1-one,
isobutyl (1R,3s,5S)-3-((4-((5-(hydroxymethyl)-1H-pyrazol-3-yl)amino)-6-methoxypyrimidin-2-yl)(methyl)amino)-9-azabicyclo[3.3.1]nonane-9-carboxylate,
methyl (1R,3s,5S)-3-((4-((5-(hydroxymethyl)-1H-pyrazol-3-yl)amino)-6-methoxypyrimidin-2-yl)(methyl)amino)-9-azabicyclo[3.3.1]nonane-9-carboxylate,
((1R,3s,5S)-3-((4-((5-(hydroxymethyl)-1H-pyrazol-3-yl)amino)-6-methoxy-pyrimidin-2-yl)(methyl)amino)-9-azabicyclo[3.3.1]nonan-9-yl)(morpholino)methanone,
2-cyclopropyl-1-((1R,3s,5S)-3-((4-((5-(hydroxymethyl)-1H-pyrazol-3-yl)amino)-6-methoxypyrimidin-2-yl)(methyl)amino)-9-azabicyclo[3.3.1]nonan-9-yl)ethan-1-one,
cyclopentyl((1R,3s,5S)-3-((4-((5-(hydroxymethyl)-1H-pyrazol-3-yl)amino)-6-methoxypyrimidin-2-yl)(methyl)amino)-9-azabicyclo[3.3.1]nonan-9-yl)methanone, and
cyclobutyl((1R,3s,5S)-3-((4-((5-(hydroxymethyl)-1

Assignees

• Theravance Biopharma R&D Ip Llc

Inventors

• Hudson Ryan
• Kozak Jennifer
• Fleury Melissa
• Fatheree Paul R
• Beausoleil Anne-Marie
• Podesto Dante D

Classifications

• A61P43/00

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

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• A61P17/06

  Antipsoriatics · CPC title

• A61P17/00

  Drugs for dermatological disorders · CPC title

• A61P1/04

  for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants · CPC title