Anti-proliferative agents for treating PAH

Patent metadata

Field	Value
Publication number	US-11203594-B2
Application number	US-202016849329-A
Country	US
Kind code	B2
Filing date	Apr 15, 2020
Priority date	Apr 19, 2019
Publication date	Dec 21, 2021
Grant date	Dec 21, 2021

Abstract

This invention relates to compounds of general Formula Iin 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 compound selected fro

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