Inhibitors of tyrosine kinase 2 mediated signaling

Patent metadata

Field	Value
Publication number	US-10508113-B2
Application number	US-201916299485-A
Country	US
Kind code	B2
Filing date	Mar 12, 2019
Priority date	Mar 12, 2018
Publication date	Dec 17, 2019
Grant date	Dec 17, 2019

Abstract

Disclosed herein are compounds of Formula (I), and pharmaceutically acceptable salts thereof, wherein R 1 , R2, R 3 , R 4a , R 4b , X 1 , X 2 , X 3 , X 4 , X 5 , nad n are as defined herein, pharmaeceutical compositions 2C X 5 , and n are as defined herein, pharmaceutical compositions comprising same, and methods of preparation and use.

First claim

What is claimed is:

1. A compound of Formula (II-a):

or a pharmaceutically acceptable salt thereof;
wherein:
R 1 is unsubstituted or substituted C 1-3 alkyl, unsubstituted or substituted C 3-4 carbocyclyl, or unsubstituted or substituted 4- to 5-membered heterocyclyl;
R 2 is -NH 2 , -NHR 2a , unsubstituted or substituted C 1-3 alkyl, and R 2a is unsubstituted or substituted C 1-3 alkyl;
R 3 is -(C 1-3 alkylene) m -OR 3a , -(C 1-3 alkylene) m -N(R 3a ) 2 , C 1-3 alkyl, or C 1-3 haloalkyl, wherein m is 0 or 1, and each instance of R 3a is independently hydrogen, C 1-3 alkyl, or C 1-3 haloalkyl;
each instance of R 4a and R 4ab is hydrogen;
R 5 is hydrogen, -CN, -OR 5a , -NHR 5a , or unsubstituted or substituted C 1-6 alkyl, wherein R 5a is unsubstituted or substituted C 1-6 alkyl, unsubstituted or substituted C 3-6 carbocyclyl, unsubstituted or substituted C 3-6 carbocyclylC 1-3 alkyl, unsubstituted or substituted 4- to 6-membered heterocyclyl, or unsubstituted or substituted 4- to 6-membered heterocyclylC 1-3 alkyl;
n is 1; and
each instance of substituted is independent substitution with 1, 2, or 3 substituents selected from the group consisting of halogen, -CN, -OH, C 1-3 alkyl, C 1-3 haloalkyl, -OC 1-3 alkyl, and -OC 1-3 haloalkyl.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is -CH 3 , - CH 2 F, -CHF 2 , -CF 3

3. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein R 2 is -NH 2 , - NHCH 3 , -CH 3 , or -CH 2 OH.

4. The compound of claim 3 , or a pharmaceutically acceptable salt thereof, wherein R 3 is -OH, - OCH 3 , -CH 2 OH, -CH 2 NH 2 , -CH(OH)CH 3 , -CH 3 , or CH 2 CH 3 .

5. The compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein R 5 is hydrogen, -CN, -CH 3 , -CH 2 F, -CHF 2 , -CF 3 , -CH 2 OCH 3 , -OCH 3 , -OCH 2 CH 3 , -OCH(CH 3 ) 2 , -OCH 2 CH 2 OH, -

OCH 2 CH 2 OCH 3 , -OCHF 2 , -OCH 2 CN.

6. The compound of claim 1 , wherein the compound is of Formula (III-a):

or a pharmaceutically acceptable salt thereof.

7. The compound of claim 6 , or a pharmaceutically acceptable salt thereof, wherein R 1 is -CH 3 , - CH 2 F, -CHF 2 , -CF 3 .

8. The compound of claim 7 , or a pharmaceutically acceptable salt thereof, wherein R 2 is -NH 2 , - NHCH 3 , -CH 3 , or -CH 2 OH.

9. The compound of claim 8 , or a pharmaceutically acceptable salt thereof, wherein R 3a is hydrogen or -CH 3 .

10. The compound of claim 9 , or a pharmaceutically acceptable salt thereof, wherein m is 1.

11. The compound of claim 10 , or a pharmaceutically acceptable salt thereof, wherein R 5 is hydrogen, -CN, -CH 3 , -CH 2 F, -CHF 2 , -CF 3 , -CH 2 OCH 3 , -OCH 3 , -OCH 2 CH 3 , -OCH(CH 3 ) 2 , -

OCH 2 CH 2 OH, -OCH 2 CH 2 OCH 3 , -OCHF 2 , -OCH 2 CN.

12. The compound of claim 1 , wherein the compound is of Formula (IV-a):

or a pharmaceutically acceptable salt thereof.

13. The compound of claim 12 , or a pharmaceutically acceptable salt thereof, wherein R 1 is -CH 3 , - CH 2 F, -CHF 2 , -CF 3 .

14. The compound of claim 13 , or a pharmaceutically acceptable salt thereof, wherein R 2 is -NH 2 , - NHCH 3 , -CH 3 , or -CH 2 OH.

15. The compound of claim 14 , or a pharmaceutically acceptable salt thereof, wherein R 3a is hydrogen or -CH 3 .

16. The compound of claim 15 , or a pharmaceutically acceptable salt thereof, wherein R 5 is hydrogen, -CN, -CH 3 , -CH 2 F, -CHF 2 , -CF 3 , -CH 2 OCH 3 , -OCH 3 , -OCH 2 CH 3 , -OCH(CH 3 ) 2 , - OCH 2 CH 2 OH, -OCH 2 CH 2 OCH 3 , -OCHF 2 , -OCH 2 CN.

17. The compound of claim 1 , wherein the compound is of Formula (I-ii-Il-a):

or a pharmaceutically acceptable salt thereof, wherein each of R 1a and R 1b is independently hydrogen or - CH 3 .

18. The compound of claim 17 , or a pharmaceutically acceptable salt thereof, wherein R 2 is - NH 2 , - NHCH 3 , -CH 3 , or -CH 2 OH.

19. The compound of claim 18 , or a pharmaceutically acceptable salt thereof, wherein R 3 is -OH, - OCH 3 , -CH 2 OH, -CH 2 NH 2 , -CH(OH)CH 3 , -CH 3 , or CH 2 CH 3 .

20. The compound of claim 19 , or a pharmaceutically acceptable salt thereof, wherein R 5 is hydrogen, -CN, -CH 3 , -CH 2 F, -CF 3 , -CH 2 OCH 3 , -OCH 3 , -OCH 2 CH 3 , -OCH(CH 3 ) 2 , - OCH 2 CH 2 OH, -OCH 2 CH 2 OCH 3 , -OCHF 2 , -OCH 2 CN.

21. The compound of claim 1 selected from the group consisting of:

and pharmaceutically acceptable salts thereof.

22. A compound of formula:

or a pharmaceutically acceptable salt thereof.

23. The compound of claim 22 :

24. The pharmaceutically acceptable salt of the compound of claim 22 :

Assignees

• Abbvie Inc

Inventors

• Argiriadi Maria A
• Breinlinger Eric C
• Chien Ellen Yulin Tsai
• Cowart Marlon D
• Frank Kristine E
• Friedman Michael M
• Hardee David J
• Herold J Martin
• Liu Huaqing
• Qiu Wei
• Scanio Marc J
• Schrimpf Michael R
• Vargo Thomas R
• Van Epps Stacy A
• Webster Matthew P
• Little Andrew J
• Katcher Matthew H

Classifications

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• C07D471/04 Primary

  Ortho-condensed systems · CPC title