Substituted naphthyridines as JAK kinase inhibitors

Patent metadata

Field	Value
Publication number	US-9725470-B2
Application number	US-201615165126-A
Country	US
Kind code	B2
Filing date	May 26, 2016
Priority date	May 28, 2015
Publication date	Aug 8, 2017
Grant date	Aug 8, 2017

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 inflammatory bowel 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) C 1-4 alkyl, wherein C 1-4 alkyl is optionally substituted with one, two, or three fluoro or with a substituent selected from:
(i) —CN,
(ii) —OC 1-3 alkyl,
(iii) —C(O)OC 1-4 alkyl,
(iv) phenyl, wherein phenyl is optionally substituted with —OH,
(v) pyridinyl, wherein pyridinyl is optionally substituted with —CN,
(vi) tetrahydropyranyl,
(vii) —C(O)NR a R b , wherein R a and R b are independently hydrogen or C 1-3 alkyl or R a is hydrogen and R b is

 and
(viii) a group selected from

(b) a group selected from
(i)
(ii)
(iii)

 wherein m is 1 or 2;

(c) —C(O)R 6 , wherein R 6 is selected from
(i) C 1-4 alkyl, wherein C 1-4 alkyl is optionally substituted with one, two, or three fluoro or with a substituent selected from —OH, —CN, —OC 1-4 alkyl, phenyl, and —NR e R f , wherein R e and R f are independently hydrogen or C 1-3 alkyl;
(ii) C 3-6 cycloalkyl, wherein C 3-6 cycloalkyl is optionally substituted with C 1-3 alkyl;
(iii) pyridinyl, wherein pyridinyl is optionally substituted with —CN; and
(iv)

 wherein R 7 is —CN, —CF 3 , or —OCH 3 ;

(d) —C(O)OR 8 , wherein R 8 is selected from
(i) C 1-4 alkyl, wherein C 1-4 alkyl is optionally substituted with —CN, C 3-6 cycloalkyl, tetrahydrofuranyl, or —OR m , wherein R m is hydrogen or C 1-3 alkyl; and
(ii) C 2-4 alkenyl; and

(e) —S(O) 2 R 9 , wherein R 9 is selected from
(i) C 1-4 alkyl, wherein C 1-4 alkyl is optionally substituted with —CN, —OC 1-3 alkyl, phenyl, pyridinyl, or C 3-6 cycloalkyl,
(ii) C 2-4 alkenyl,
(iii) C 3-6 cycloalkyl, wherein C 3-6 cycloalkyl is optionally substituted with C 1-3 alkyl,
(iv) phenyl,
(v) pyridinyl, wherein pyridinyl is optionally substituted with fluoro,
(vi) heterocyclyl containing 4 to 6 ring atoms including one nitrogen atom, wherein the heterocyclyl is optionally substituted with —CN or C 1-3 alkyl, wherein C 1-3 alkyl is optionally substituted with —CN or —OC 1-3 alkyl; and
(vii)

R 2 is selected from hydrogen, —OC 1-3 alkyl, and —CH 2 —R 10 , wherein R 10 is selected from —OH, morpholinyl, piperidinyl, wherein piperidinyl is optionally substituted with two fluoro, and piperazinyl, wherein piperazinyl is optionally substituted with methyl;
R 3 is selected from hydrogen, C 1-3 alkyl, —OC 1-3 alkyl, —C(O)OC 1-3 alkyl, —S(O) 2 C 1-3 alkyl, and —CH 2 S(O) 2 C 1-3 alkyl;
R 4 is hydrogen or —OC 1-3 alkyl;
R 5 is hydrogen or fluoro; and
n is 1 or 2;
provided that
(i) when R 3 is —OC 1-3 alkyl and R 2 , R 4 , and R 5 are each hydrogen, R 9 is not phenyl;
(ii) when R 5 is fluoro, n is 1, and R 2 , R 3 , and R 4 are each hydrogen, R 9 is not phenyl; and
(iii) when R 5 is fluoro, R 3 is methyl, and R 2 and R 4 are each hydrogen, R 1 is not —C(O)OR 8 ;
or a pharmaceutically-acceptable salt or stereoisomer thereof.

2. The compound of claim 1 , wherein:
R 1 is selected from:
(a) C 1-4 alkyl, wherein C 1-4 alkyl is optionally substituted with one, two, or three fluoro or with a substituent selected from
—CN;
(ii) —OC 1-3 alkyl;
(iv) phenyl, wherein phenyl is optionally substituted with —OH;
(v) pyridinyl, wherein pyridinyl is optionally substituted with —CN;
(vi) tetrahydropyranyl;
(vii) —C(O)NHCH 3 ; and
(viii)

(b) a group selected from
(i)
(ii)
(iii)

 wherein m is 1;

(c) —C(O)R 6 , wherein R 6 is selected from
(i) C 1-4 alkyl, wherein C 1-4 alkyl is optionally substituted with one, two, or three fluoro or with a substituent selected from —OH and phenyl;
(ii) C 3-6 cycloalkyl, wherein C 3-6 cycloalkyl is optionally substituted with C 1-3 alkyl; and
(iv)

 wherein R 7 is —CN or —CF 3 ;

(d) —C(O)OR 8 , wherein R 8 is selected from
(i) C 1-4 alkyl, wherein C 1-4 alkyl is optionally substituted with —CN, C 3-6 cycloalkyl, tetrahydrofuranyl, or —OR m , wherein R m is hydrogen or C 1-3 alkyl; and
(ii) C 2-4 alkenyl; and

(e) —S(O) 2 R 9 , wherein R 9 is selected from
(i) C 1-4 alkyl, wherein C 1-4 alkyl is optionally substituted with —CN, —OC 1-3 alkyl, phenyl, pyridinyl, or C 3-6 cycloalkyl;
(ii) C 2-4 alkenyl;
(iii) C 3-6 cycloalkyl, wherein C 3-6 cycloalkyl is optionally substituted with C 1-3 alkyl;
(v) pyridinyl, wherein pyridinyl is optionally substituted with fluoro;
(vi) heterocyclyl containing 4 or 5 ring atoms including one nitrogen atom, wherein the heterocyclyl is bonded to sulfur through the nitrogen atom and the heterocycle is optionally substituted with —CN or —CH 2 OCH 3 ; and
(vii)

R 2 is selected from hydrogen, —OCH 3 , and —CH 2 —R 10 , wherein R 10 is selected from —OH, morpholinyl, piperidinyl, wherein piperidinyl is substituted with two fluoro at the 4-position, and piperazinyl, wherein piperazinyl is substituted with methyl at the 4-position;
R 3 is selected from hydrogen, —CH 3 , —OCH 3 , and —C(O)OCH 3 ; and
R 4 is hydrogen or —OCH 3 ;

provided that when R 5 is fluoro, R 3 is hydrogen.

3. The compound of claim 2 , wherein R 1 is C 1-4 alkyl, wherein C 1-4 alkyl is optionally substituted with one, two, or three fluoro or with a substituent selected from
(i) —CN;
(ii) —OC 1-3 alkyl;
(iv) phenyl, wherein phenyl is optionally substituted with —OH;
(v) pyridinyl, wherein pyridinyl is optionally substituted with —CN;
(vi) tetrahydropyranyl,
(vii) —C(O)NHCH 3 , and
(viii)

4. The compound of claim 2 , wherein R 1 is —C(O)R 6 , wherein R 6 is selected from
(i) C 1-4 alkyl, wherein C 1-4 alkyl is optionally substituted with one, two, or three fluoro or with a substituent selected from —OH and phenyl;
(ii) C 3-6 cycloalkyl, wherein C 3-6 cycloalkyl is optionally substituted with C 1-3 alkyl; and
(iv)

 wherein R 7 is —CN or —CF 3 .

5. The compound of claim 2 , wherein R 1 is —S(O) 2 R 9 , wherein R 9 is selected from
(i) C 1-4 alkyl, wherein C 1-4 alkyl is optionally substituted with —CN, —OC 1-3 alkyl, phenyl, pyridinyl, or C 3-6 cycloalkyl;
(ii) C 2-4 alkenyl;
(iii) C 3-6 cycloalkyl, wherein C 3-6 cycloalkyl is optionally substituted with C 1-3 alkyl;
(v) pyridinyl, wherein pyridinyl is optionally substituted with fluoro;
(vi) heterocyclyl containing 4 or 5 ring atoms including one nitrogen atom

Assignees

• Theravance Biopharma R&D Ip Llc

Inventors

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

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

• A61P1/00

  Drugs for disorders of the alimentary tract or the digestive system · CPC title

• A61P1/04

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

• C07D519/00 Primary

  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 title