Anti-proliferative agents for treating pah

Patent metadata

Field	Value
Publication number	US-2020331909-A1
Application number	US-202016849329-A
Country	US
Kind code	A1
Filing date	Apr 15, 2020
Priority date	Apr 19, 2019
Publication date	Oct 22, 2020
Grant date	—

Abstract

in which A, R1, R2, R3 and R4 are as defined herein, and the pharmaceutically acceptable salts thereof; to pharmaceutical compositions comprising such compounds and salts; to methods of using such compounds, salts and compositions for treating pulmonary hypertension and related diseases, like pulmonary arterial hypertension; to methods of using such compounds, salts and compositions for treating abnormal cell growth, such as cancer; and to processes to make such compounds, salts and compositions.

First claim

What is claimed is:

1 . A compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:
A is CH or N;
R 1 is C 1 -C 2 alkyl or C 1 -C 2 fluoroalkyl;
R 2 is C 1 -C 4 alkyl optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of —OH, C 1 -C 2 alkoxy, and F;
R 3 is 4- to 8-membered heterocyclyl, C 3 -C 8 cycloalkyl, (4- to 8-membered heterocyclyl)-C 1 -C 4 alkyl-, or (C 3 -C 8 cycloalkyl)-C 1 -C 4 alkyl-,
wherein each of the 4- to 8-membered heterocyclyl and the 4- to 8-membered heterocyclyl moiety in (4- to 8-membered heterocyclyl)-C 1 -C 4 alkyl- is optionally substituted with 1 or 2 R 5 ,
wherein each of the C 3 -C 8 cycloalkyl and the C 3 -C 8 cycloalkyl moiety in (C 3 -C 8 cycloalkyl)-C 1 -C 4 alkyl- is optionally substituted with 1 or 2 R 5 and further optionally substituted with 1 —N(R 6 ) 2 , and
wherein each of the C 1 -C 4 alkyl moieties in (4- to 8-membered heterocyclyl)-C 1 -C 4 alkyl- and (C 3 -C 8 cycloalkyl)-C 1 -C 4 alkyl- is optionally substituted with 1, 2, or 3 R 5 ;
R 4 is a moiety having the structure of

each R 5 is independently selected from the group consisting of —F, —OH, —CN, C 1 -C 4 alkyl, C 1 -C 4 fluoroalkyl, C 1 -C 4 alkoxy, C 1 -C 4 fluoroalkoxy, C 1 -C 4 alkoxy-C 1 -C 4 alkyl-, C 1 -C 4 fluoroalkoxy-C 1 -C 4 alkyl-, C 1 -C 4 alkoxy-C 1 -C 4 fluoroalkyl, and C 1 -C 4 fluoroalkoxy-C 1 -C 4 fluoroalkyl-;
each R 6 is independently selected from the group consisting of H and C 1 -C 2 alkyl;
each R 7 is independently H or C 1 -C 2 alkyl; and
each R 8 is independently H, F, or C 1 -C 2 alkyl.

2 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
A is CH or N; R 1 is CH 3 or C 1 fluoroalkyl; R 2 is CH 3 ; R 3 is 5- to 7-membered heterocyclyl, C 3 -C 6 cycloalkyl, (5- to 7-membered heterocyclyl)-C 1 -C 4 alkyl-, or (C 3 -C 6 cycloalkyl)-C 1 -C 4 alkyl-,
wherein each of the 5- to 7-membered heterocyclyl and the 5- to 7-membered heterocyclyl moiety in (5- to 7-membered heterocyclyl)-C 1 -C 4 alkyl- is optionally substituted with 1 R 5 ,
wherein each of the C 3 -C 6 cycloalkyl and the C 3 -C 6 cycloalkyl moiety in (C 3 -C 6 cycloalkyl)-C 1 -C 4 alkyl- is optionally substituted with 1 or 2 R 5 and further optionally substituted with 1 —N(R 6 ) 2 , and
wherein each of the C 1 -C 4 alkyl moieties in (5- to 7-membered heterocyclyl)-C 1 -C 4 alkyl- and (C 3 -C 6 cycloalkyl)-C 1 -C 4 alkyl- is optionally substituted with 1, 2, or 3 R 5 ;
R 4 is a moiety having the structure of

each R 5 is independently selected from the group consisting of —F, —OH, —CN, C 1 -C 2 alkyl, C 1 -C 2 fluoroalkyl, C 1 -C 2 alkoxy, C 1 -C 2 fluoroalkoxy, C 1 -C 2 alkoxy-C 1 -C 2 alkyl-, C 1 -C 2 fluoroalkoxy-C 1 -C 2 alkyl-, C 1 -C 2 alkoxy-C 1 -C 2 fluoroalkyl-, and C 1 -C 2 fluoroalkoxy-C 1 -C 2 fluoroalkyl-;
each R 6 is independently selected from the group consisting of H and C 1 -C 2 alkyl; and
each R 7 is independently H or CH 3 , provided that no more than two R 7 are CH 3 .

3 . The compound of claim 1 , wherein the compound is a compound of Formula II:

or a pharmaceutically acceptable salt thereof.

4 . The compound of claim 3 , or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula III:

5 . The compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein:
A is CH or N; R 3 is 5- to 7-membered heterocyclyl optionally substituted with 1 R 5 ; and R 5 is selected from the group consisting of F, OH, —CN, C 1 -C 2 alkyl, C 1 -C 2 fluoroalkyl, C 1 -C 2 alkoxy, C 1 -C 2 fluoroalkoxy, C 1 -C 2 alkoxy-C 1 -C 2 alkyl-, C 1 -C 2 fluoroalkoxy-C 1 -C 2 alkyl-, C 1 -C 2 alkoxy-C 1 -C 2 fluoroalkyl-, and C 1 -C 2 fluoroalkoxy-C 1 -C 2 fluoroalkyl-.

6 . The compound of claim 5 , or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from the group consisting of 2-azaspiro[3.3]heptanyl, tetrahydrofuranyl, pyrrolidinyl, and piperidinyl, wherein each of the heterocyclyl selections is optionally substituted with 1 R 5 ; and R 5 is selected from the group consisting of F, OH, —CN, C 1 -C 2 alkyl, C 1 -C 2 fluoroalkyl, C 1 -C 2 alkoxy, C 1 -C 2 fluoroalkoxy, C 1 -C 2 alkoxy-C 1 -C 2 alkyl-, C 1 -C 2 fluoroalkoxy-C 1 -C 2 alkyl-, C 1 -C 2 alkoxy-C 1 -C 2 fluoroalkyl-, and C 1 -C 2 fluoroalkoxy-C 1 -C 2 fluoroalkyl-.

7 . The compound of claim 5 , or a pharmaceutically acceptable salt thereof, wherein R 3 is 2-azaspiro[3.3]heptan-6-yl optionally substituted with 1 R 5 that is selected from the group consisting of C 1 -C 2 alkyl, C 1 -C 2 fluoroalkyl, C 1 -C 2 alkoxy-C 1 -C 2 alkyl-, and C 1 -C 2 fluoroalkoxy-C 1 -C 2 alkyl-.

8 . The compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein:
A is CH or N; R 3 is C 3 -C 6 cycloalkyl optionally substituted with 1 or 2 R 5 and further optionally substituted with 1 —N(R 6 ) 2 ; each R 5 is independently selected from the group consisting of F, OH, —CN, C 1 -C 2 alkyl, C 1 -C 2 fluoroalkyl, C 1 -C 2 alkoxy, C 1 -C 2 fluoroalkoxy, C 1 -C 2 alkoxy-C 1 -C 2 alkyl-, C 1 -C 2 fluoroalkoxy-C 1 -C 2 alkyl-, C 1 -C 2 alkoxy-C 1 -C 2 fluoroalkyl, and C 1 -C 2 fluoroalkoxy-C 1 -C 2 fluoroalkyl-; and each R 6 is independently selected from the group consisting of H and C 1 -C 2 alkyl.

9 . The compound of claim 8 , or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and bicyclo[3.1.0]hexanyl, wherein each of the selections is optionally substituted with 1 or 2 R 5 and further optionally substituted with 1 —N(R 6 ) 2 .

10 . The compound of claim 8 , or a pharmaceutically acceptable salt thereof, wherein R 3 is cyclobutyl optionally substituted with 1 or 2 R 5 ; and each R 5 is independently selected from the group consisting of F, OH, C 1 -C 2 alkyl, C 1 -C 2 fluoroalkyl, C 1 -C 2 alkoxy, C 1 -C 2 fluoroalkoxy, C 1 -C 2 alkoxy-C 1 -C 2 alkyl-, C 1 -C 2 fluoroalkoxy-C 1 -C 2 alkyl-, C 1 -C 2 alkoxy-C 1 -C 2 fluoroalkyl, and C 1 -C 2 fluoroalkoxy-C 1 -C 2 fluoroalkyl-.

11 . The compound of claim 8 , or a pharmaceutically acceptable salt thereof, wherein R 3 is cyclopentyl optionally substituted with 1 or 2 R 5 ; and each R 5 is independently selected from the group consisting of F, OH, C 1 -C 2 alkyl, C 1 -C 2 fluoroalkyl, C 1 -C 2 alkoxy, C 1 -C 2 fluoroalkoxy, C 1 -C 2 alkoxy-C 1 -C 2 alkyl-, C 1 -C 2 fluoroalkoxy-C 1 -C 2 alkyl-, C 1 -C 2 alkoxy-C 1 -C 2 fluoroalkyl, and C 1 -C 2 fluoroalkoxy-C 1 -C 2 fluoroalkyl-.

12 . The compound of claim 8 , or a pharmaceutically acceptable salt thereof, wherein R 3 is cyclopentyl.

13 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is CH.

14 . The compound of any claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is N.

15 . A com

Assignees

• Pfizer

Inventors

• Bhattacharya Samit Kumar
• Behenna Douglas Carl
• Cameron Kimberly O
• Chen Ping
• Curto John M
• Freeman-Cook Kevin Daniel
• Jalaie Mehran
• Kania Robert Steven
• Lian Yajing
• Nair Sajiv Krishnan
• Palmer Cynthia Louise
• Pettersson Martin Youngjin
• Rui Eugene Yuanjin
• Sammons Matthew
• Yang Qingyi
• Zhang Liying

Classifications

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• C07B2200/13

  Crystalline forms, e.g. polymorphs · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P9/12

  Antihypertensives · CPC title

• A61K31/519

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