Therapeutic compounds, compositions and methods of use thereof

Patent metadata

Field	Value
Publication number	US-10189836-B2
Application number	US-201816009596-A
Country	US
Kind code	B2
Filing date	Jun 15, 2018
Priority date	Dec 18, 2015
Publication date	Jan 29, 2019
Grant date	Jan 29, 2019

Abstract

Compounds of Formula (I) and methods of use as Janus kinase inhibitors are described herein.

First claim

What is claimed is:

1. A compound of Formula (I):

or a salt or stereoisomer thereof, wherein:
R 1 is a 3-11 membered heterocyclyl that is optionally substituted with one or more R a ;
R 2 is selected from the group consisting of:

each R a is independently selected from the group consisting of OH, halo, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, 6-10 membered aryl, 3-11 membered heterocyclyl, C(O)NR c R d , NR c R d , and C 1 -C 6 alkanoyl, wherein said alkyl, cycloalkyl, alkanoyl, 6-10 membered aryl, and 3-11 membered heterocyclyl are optionally substituted with one or more groups independently selected from the group consisting of halo, C 1 -C 6 alkoxy, (C 1 -C 6 alkyl)S—, C 3 -C 8 cycloalkyl, 3-11 membered heterocyclyl that is optionally substituted with one or more groups independently selected from the group consisting of —C(O)—NR c R d , —C(O)—OR k , —(C 1 -C 6 alkyl)-C(O)—NR c R d , and —(C 1 -C 6 alkyl)-C(O)—OR k , and C 1 -C 6 alkyl that is optionally substituted with one or more groups independently selected from the group consisting of halo, C 1 -C 6 alkoxy, and C 3 -C 8 cycloalkyl;
R b is selected from the group consisting of hydrogen, —OR k , —CN, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, 6-10 membered aryl, 3-11 membered heterocyclyl, —NR s R t , —C(O)NR f R g , —S(O) n R e , —S(O) 2 NR f R g , —NR c C(O)R m , and —C(O)R m , wherein said C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 6 alkanoyl, 6-10 membered aryl, and 3-11 membered heterocyclyl are each independently optionally substituted with one or more groups independently selected from R h ; and R x is selected from the group consisting of hydrogen and C 1 -C 6 alkyl that is optionally substituted with one or more groups independently selected from halo, cyano, and C 1 -C 6 alkoxy; or R b and R x taken together form a C 1 -C 6 alkenylene that is optionally substituted with one or more groups independently selected from halo, cyano, and C 1 -C 6 alkoxy;
R c and R d , independently at each occurrence, are selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, 6-10 membered aryl, and 3-11 membered heterocyclyl, wherein each C 1 -C 6 alkyl is independently optionally substituted with one or more groups independently selected from the group consisting of halo, cyano, C 3 -C 8 cycloalkyl, 6-10 membered aryl, and 3-11 membered heterocyclyl; or alternatively R c and R d may be joined together with the nitrogen atom to which they are attached to form an optionally substituted 3-11 membered heterocyclyl that is optionally substituted with one or more groups independently selected from the group consisting of halo, C 3 -C 8 cycloalkyl, 6-10 membered aryl, and C 1 -C 6 alkyl that is optionally substituted with one or more groups independently selected from the group consisting of halo, C 1 -C 6 alkoxy, and C 3 -C 8 cycloalkyl;
each R e is independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, 6-10 membered aryl, and 3-11 membered heterocyclyl, wherein any C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, 6-10 membered aryl, and 3-11 membered heterocyclyl is optionally substituted with one or more groups independently selected from halo, cyano, hydroxy, C 1 -C 6 alkoxy, —SH, (C 1 -C 6 alkyl)S—, C 3 -C 8 cycloalkyl, 6-10 membered aryl, and C 1 -C 6 alkyl that is optionally substituted with one or more groups independently selected from the group consisting of halo, C 1 -C 6 alkoxy, R p , and C 3 -C 8 cycloalkyl;
R f and R g , independently at each occurrence, are selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, 6-10 membered aryl, and 3-11 membered heterocyclyl, wherein each C 1 -C 6 alkyl is independently optionally substituted with one or more groups independently selected from the group consisting of halo, C 3 -C 8 cycloalkyl, 6-10 membered aryl, and 3-11 membered heterocyclyl; or alternatively R f and R g may be joined together with the nitrogen atom to which they are attached to form an optionally substituted 3-11 membered heterocyclyl that is optionally substituted with one or more groups independently selected from the group consisting of halo, C 3 -C 8 cycloalkyl, 6-10 membered aryl, (C 1 -C 6 alkyl)S—, cyano, and C 1 -C 6 alkyl that is optionally substituted with one or more groups independently selected from the group consisting of halo, C 1 -C 6 alkoxy, and C 3 -C 8 cycloalkyl;
each R h is independently selected from the group consisting of halo, cyano, S(O) 2 NR f R g , C 1 -C 6 alkoxy, C 1 -C 6 alkanoyl, C 3 -C 8 cycloalkyl, 6-10 membered aryl, and 3-11 membered heterocyclyl, wherein any C 1 -C 6 alkoxy, C 1 -C 6 alkanoyl, C 3 -C 8 cycloalkyl, 6-10 membered aryl, and 3-11 membered heterocyclyl is optionally substituted with one or more groups independently selected from the group consisting of halo, cyano, and C 1 -C 6 alkyl that is optionally substituted with one or more groups independently selected from the group consisting of halo, —S(O) 2 (C 1 -C 6 alkyl), C 1 -C 6 alkoxy, cyano, and C 3 -C 8 cycloalkyl;
each R k is independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, 6-10 membered aryl, and 3-11 membered heterocyclyl, wherein any C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, 6-10 membered aryl, and 3-11 membered heterocyclyl is optionally substituted with one or more groups independently selected from the group consisting of halo, cyano, 6-10 membered aryl and 3-11 membered heterocyclyl, wherein any said 6-10 aryl and 3-11 membered heterocyclyl is optionally substituted with halo, cyano, (C 1 -C 6 alkyl) 2 NC(O)—, or C 1 -C 6 alkyl that is optionally substituted with one or more groups independently selected from the group consisting of halo, C 1 -C 6 alkoxy, cyano, hydroxy, and C 3 -C 8 cycloalkyl;
R m is selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 8 cycloalkyl, (C 3 -C 8 cycloalkyl)oxy, 6-10 membered aryl, and 3-11 membered heterocyclyl, wherein any C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 8 cycloalkyl, (C 3 -C 8 cycloalkyl)oxy, 6-10 membered aryl, and 3-11 membered heterocyclyl is optionally substituted with one or more groups R n ;
each R n is independently selected from the group consisting of halo, cyano, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 8 cycloalkyl, —SH, —NR u R v , C 1 -C 6 alkylthio, 6-10 membered aryl, and 3-11 membered heterocyclyl, wherein any C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 8 cycloalkyl, C 1 -C 6 alkylthio, 6-10 membered aryl, and 3-11 membered heterocyclyl is optionally substituted with one or more groups independently selected from the group consisting of halo, cyano, and C 1 -C 6 alkyl that is optionally substituted with one or more groups independently selected from the group consisting of halo and cyano;
each R p is independently selected from the group consisting of C 3 -C 8 cycloalkyl, 6-10 membered aryl, and 3-11 membered heterocyclyl, wherein any C 3 -C 8 cycloalkyl, 6-10 membered aryl, and 3-11 membered heterocyclyl is optionally substituted with one or more groups independently selected from the group consisting of halo, cyano, hydroxy, C 1 -C 6 alkoxy, C 3 -C 8 cycloalkyl, —SH, (C 1 -C 6 alkyl)S—, and C 1 -C 6 alkyl that is optionally substituted with one or more groups independently selected from the group consisting of halo, hydroxy, C 1 -C 6 alkoxy, cyano, and C 3 -C 8 cycloalkyl;
R s and R t , independently at each occurrence, are selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, 6-10 membered aryl, a

Assignees

• Genentech Inc

Inventors

• Cheng Yun-Xing
• Hua Rongbao
• Kellar Terry
• Li Wei
• Gibbons Paul
• Zak Mark Edward

Classifications

• C07D519/00

  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

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• A61P11/06

  Antiasthmatics · CPC title