5-chloro-2-difluoromethoxyphenyl pyrazolopyrimidine compounds, compositions and methods of use thereof

Patent metadata

Field	Value
Publication number	US-9604984-B2
Application number	US-201615139164-A
Country	US
Kind code	B2
Filing date	Apr 26, 2016
Priority date	May 23, 2014
Publication date	Mar 28, 2017
Grant date	Mar 28, 2017

Abstract

Compounds of Formula (00A) and methods of use as Janus kinase inhibitors are described herein.

First claim

What is claimed is:

1. A compound of Formula (00A):

or a stereoisomer or salt thereof, wherein: R 00 is H or CH 3 ; R 01 is H or NH 2 ; R 0 is H or NH 2 ; and Ring Q is (ii):

wherein: t 2 is 0 or 1; X B is selected from the group consisting of H, C 1 -C 6 alkyl, C 2 -C 4 alkenyl, —NR a R b , C 2 -C 5 alkynyl, 3-6-membered cycloalkyl, 6-10 membered aryl, 3-11 membered heterocycloalkyl, 5-6 membered heterocycloalkenyl, and 5-10 membered heteroaryl; wherein when X B is C 1 -C 6 alkyl, C 2 -C 4 alkenyl, C 2 -C 5 alkynyl, 3-6-membered cycloalkyl, 6-10 membered aryl, 3-11 membered heterocycloalkyl, 5-6 membered heterocycloalkenyl, or 5-10 membered heteroaryl, X B is optionally substituted by Y 1 , wherein Y 1 is selected from:
(a) C 1 -C 6 alkyl optionally substituted by T 1 , wherein T 1 is selected from the group consisting of OH, halo, CN, imino, 3-6 membered cycloalkyl, 3-11 membered heterocycloalkyl, 3-11 membered heterocycloalkenyl, 5-10 membered heteroaryl, —O—(C 1 -C 6 alkyl), C(O)OH, oxetan-3-ylmethyl, —C(O)O—(C 1 -C 6 alkyl), —S—(C 1 -C 6 alkyl), —SO 2 —(C 1 -C 6 alkyl), —NR a R b , —C(O)NR a R b , -(2-oxoindolin-1-yl), —OC(O)-3-6 membered cycloalkyl, and phenyl, wherein each alkyl, cycloalkyl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, and phenyl of T 1 is optionally substituted by OH, —C(O)O—(C 1 -C 6 alkyl), C 1 -C 6 alkyl, halo, CN, oxo, —(C 1 -C 6 alkyl)CONR a R b , —NR a R b , phenyl, or —O—(C 1 -C 6 alkyl) optionally substituted by OH;
(b) 3-11 membered heterocycloalkyl, —(C 1 -C 6 alkylene)-3-11 membered heterocycloalkyl, —C(O)-3-11 membered heterocycloalkyl, —(C 1 -C 6 alkylene)C(O)-3-11 membered heterocycloalkyl, or —OC(O)-4-6 membered heterocycloalkyl; wherein the heterocycloalkyl is optionally substituted by OH, halo, CN, C 1 -C 6 alkyl, —(C 1 -C 6 alkylene)-CF 3 , oxo, —C(O)—(C 1 -C 6 alkyl), —C(O)O—(C 1 -C 6 alkyl), —C(O)O—(C 1 -C 6 alkylene)-phenyl, —SO 2 —(C 1 -C 6 alkyl), —C(O)NR a R b , —NR a R b , (C 1 -C 6 alkylene)-phenyl, or —C(O)-4-6 membered heterocycloalkyl optionally substituted by —NR a R b ;
(c) N(+)(AA) 3 , wherein each AA is independently C 1 -C 6 alkyl optionally substituted by phenyl;
(d) 3-6 membered cycloalkyl optionally substituted by OH, halo, NR a R b , or CN;
(e) CN, halo, or oxo;
(f) —C(O)—(C 1 -C 6 alkyl), —C(O)OH, —C(O)O—(C 1 -C 6 alkylene)-phenyl, —SO 2 —(C 1 -C 6 alkyl), —C(O)NR a R b , or —C(O)-4-6 membered heterocycloalkyl optionally substituted by —(C 1 -C 6 alkyl) or —NR a R b , or —C(O)O—(C 1 -C 6 alkyl) optionally substituted by OH, NR a R b , or 3-11 membered heterocycloalkyl wherein said heterocycloalkyl is optionally substituted by C 1 -C 6 alkyl;
(g) OH, —O-phenyl, or —O—(C 1 -C 6 alkyl), wherein the alkyl is optionally substituted by OH or —NR a R b ;
(h) phenyl optionally substituted by OH, halo, C 1 -C 6 alkyl, CF 3 , or CN;
(i) 5-6 membered heteroaryl optionally substituted by OH, halo, C 1 -C 6 alkyl, CF 3 , CN, or 3-11 membered heterocycloalkyl optionally substituted by C 1 -C 6 alkyl or 3-11 membered heterocycloalkyl;
(j) isoindolin-2-yl optionally substituted by halo;
(k) —NR a R b , and
(l) —O—CH 2 C(O)-3-11 membered heterocycloalkyl;

wherein R a and R b are independently selected from:
(a) H,
(b) C 1 -C 6 alkyl optionally substituted by OH, halo, CN, —C(O)OH, —C(O)O—(C 1 -C 6 alkyl), —C(O)O-(3-11 membered heterocycloalkyl), —C(O)O—(C 1 -C 6 alkyl)-S—(C 1 -C 6 alkyl), —S—(C 1 -C 6 alkyl), naphthylenyl, —NR az R bz , —C(O)NR az R bz , oxo, —O—(C 1 -C 6 alkyl), 5-6 membered heteroaryl optionally substituted by C 1 -C 6 alkyl or halo, or benzo[1,3]dioxol-2-yl, or 3-11 membered heterocycloalkenyl optionally substituted by oxo;
(c) —(C 1 -C 6 alkylene)-3-6 membered cycloalkyl wherein the alkylene is optionally substituted by OH, halo, or CN;
(d) —(C 1 -C 6 alkylene)-phenyl wherein alkylene is optionally substituted by halo and the phenyl is optionally substituted by OH, halo, CF 3 , C 1 -C 6 alkyl, —O—(C 1 -C 6 alkyl), —S—(C 1 -C 6 alkyl, or —O-phenyl;
(e) —(C 1 -C 6 alkylene)-4-6 membered heterocycloalkyl wherein the heterocycloalkyl is optionally substituted by halo, oxo, or C 1 -C 6 alkyl;
(f) —(C 1 -C 6 alkylene)-O-phenyl wherein the phenyl is optionally substituted by halo, C 1 -C 6 alkyl, or —O-phenyl;
(g) —(C 1 -C 6 alkyl)3-6 membered cycloalkyl optionally substituted by OH, halo, CN, or C 1 -C 6 alkyl optionally substituted by OH or CN;
(h) C 2 -C 5 alkenyl;
(i) 4-6 membered heterocycloalkyl optionally substituted by halo,
(j) —(C 1 -C 6 alkylene)-3-6 membered cycloalkyl substituted by hydroxymethyl,
(k) phenyl,
(l) —C(O)(C 1 -C 6 alkyl),
(m) —C(O)O(C 1 -C 6 alkyl),
(n) —C(O)O(3-6 membered cycloalkyl), and
(o) —C(O)-phenyl,

wherein R az and R bz are each independently selected from
(a) H,
(b) C 1 -C 6 alkyl optionally substituted by OH, halo, CN, —C(O)OH, —C(O)O—(C 1 -C 6 alkyl), —C(O)O-(3-11 membered heterocycloalkyl), —C(O)O—(C 1 -C 6 alkyl)-S—(C 1 -C 6 alkyl), —S—(C 1 -C 6 alkyl), naphthylenyl, -oxo, —O—(C 1 -C 6 alkyl), 5-6 membered heteroaryl optionally substituted by C 1 -C 6 alkyl or halo, or benzo[1,3]dioxol-2-yl, or 3-11 membered heterocycloalkenyl optionally substituted by oxo;
(c) —(C 1 -C 6 alkylene)-3-6 membered cycloalkyl wherein the alkylene is optionally substituted by OH, halo, or CN;
(d) —(C 1 -C 6 alkylene)-phenyl wherein alkylene is optionally substituted by halo and the phenyl is optionally substituted by OH, halo, CF 3 , C 1 -C 6 alkyl, —O—(C 1 -C 6 alkyl), —S—(C 1 -C 6 alkyl, or —O-phenyl;
(e) —(C 1 -C 6 alkylene)-4-6 membered heterocycloalkyl wherein the heterocycloalkyl is optionally substituted by halo, oxo, or C 1 -C 6 alkyl;
(f) —(C 1 -C 6 alkylene)-O-phenyl wherein the phenyl is optionally substituted by halo, C 1 -C 6 alkyl, or —O-phenyl;
(g) —(C 1 -C 6 alkyl)3-6 membered cycloalkyl optionally substituted by OH, halo, CN, or C 1 -C 6 alkyl optionally substituted by OH or CN;
(h) C 2 -C 5 alkenyl;
(i) 4-6 membered heterocycloalkyl optionally substituted by halo,
(j) —(C 1 -C 6 alkylene)-3-6 membered cycloalkyl substituted by hydroxymethyl,
(k) phenyl,
(l) —C(O)(C 1 -C 6 alkyl),
(m) —C(O)O(C 1 -C 6 alkyl),
(n) —C(O)O(3-6 membered cycloalkyl), and
(o) —C(O)-phenyl.

2. The compound of claim 1 , further defined as a compound of Formula (IV):

wherein:
R 0d is H or NH 2 ;
R 1d is 3-11 membered heterocycloalkyl or —C(O)-3-11 membered heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted C 1 -C 6 alkyl, CF 3 , or fluoro, or R 1d is —(C 1 -C 6 alkylene)-NR v R w , wherein R v and R w are independently H or C 1 -C 6 alkyl optionally substituted by halo.

3. The compound of claim 1 , further defined as a compound of Formula (V):

wherein:
R 0e is H or NH 2 ;
R 1e is selected from the group consisting of

a. H,
b. C 1 -C 6 alkyl optionally substituted by halo, CN, or phenyl,
c. —(C 1 -C 6 alkylene)-3-6 membered cycloalkyl wherein the cycloalkyl is optionally substituted by CN,
d. —(C 1 -C 6 alkylene)-4-6 membered heterocycloalkyl wherein the heterocycloalkyl is optionally substituted by C 1 -C 6 alkyl;
R 2e is H or C 1 -C 6 alkyl;
or R 1e and R 2e together form a 3-11 membered heterocycloalkyl optionally substituted by halo or —NR v R w , wherein R v and R w are in

Assignees

• Genentech Inc

Inventors

• Zak Mark Edward
• Ray Nicholas Charles
• Goodacre Simon Charles
• Mendonca Rohan
• Kellar Terry
• Cheng Yun-Xing
• Li Wei
• YUEN Po-Wei

Classifications

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• A61P11/06

  Antiasthmatics · CPC title

• 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

• A61K31/519 Primary

  ortho- or peri-condensed with heterocyclic rings · CPC title

• C07D487/04 Primary

  Ortho-condensed systems · CPC title