KRas G12C inhibitors

Patent metadata

Field	Value
Publication number	US-10689377-B2
Application number	US-201816191190-A
Country	US
Kind code	B2
Filing date	Nov 14, 2018
Priority date	Nov 15, 2017
Publication date	Jun 23, 2020
Grant date	Jun 23, 2020

Abstract

The present invention relates to compounds that inhibit KRas G12C. In particular, the present invention relates to compounds that irreversibly inhibit the activity of KRas G12C, pharmaceutical compositions comprising the compounds and methods of use therefor.

First claim

We claim:

1. A compound of formula (II):

or a pharmaceutically acceptable salt thereof:
wherein:
X is selected from the group consisting of a piperazine, a bridged piperazine, a 7-membered spirocyclic ring and a diazepane, wherein X is optionally substituted with one or more R 8 ;
Y is a bond, O, S or NR 5 ;
R 1 is —C(O)C(R A ) C(R B ) p or —SO 2 C(R A ) C(R B ) p ;
R 2 is hydrogen, alkyl, hydroxyalkyl, dihydroxyalkyl, alkylaminylalkyl, dialkylaminylalkyl, —Z—NR 5 R 10 , heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, or heteroarylalkyl, wherein each of the Z, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, and heteroarylalkyl may be optionally substituted with one or more R 9 ;
each Z is C1-C4 alkylene;
each R 3 is independently C1-C3 alkyl, oxo, haloalkyl, hydroxyl or halogen;
L is a bond, —C(O)—, or C1-C3 alkylene;
R 4 is hydrogen, cycloalkyl, heterocyclyl, aryl, aralkyl or heteroaryl, wherein each of the cycloalkyl, heterocyclyl, aryl, aralkyl and heteroaryl may be optionally substituted with one or more R 6 , R 7 or R 8 ;
each R 5 is independently hydrogen or C1-C3 alkyl;
R 6 is cycloalkyl, heterocyclyl, heterocyclylalkyl, aryl, or heteroaryl, wherein each of the cycloalkyl, heterocyclyl, aryl, or heteroaryl may be optionally substituted with one or more R 7 ;
each R 7 is independently halogen, hydroxyl, C1-C6 alkyl, cycloalkyl, alkoxy, haloalkyl, amino, cyano, heteroalkyl, hydroxyalkyl or Q-haloalkyl, wherein Q is O or S;
R 8 is oxo, C1-C3 alkyl, C2-C4 alkynyl, heteroalkyl, cyano, —C(O)OR 5 , —C(O)N(R 5 ) 2 , —N(R 5 ) 2 , wherein the C1-C3 alkyl may be optionally substituted with cyano, halogen, —OR 5 , —N(R 5 ) 2 , or heteroaryl;
each R 9 is independently hydrogen, oxo, acyl, hydroxyl, hydroxyalkyl, cyano, halogen, C1-C6 alkyl, aralkyl, haloalkyl, heteroalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, alkoxy, dialkylaminyl, dialkylamidoalkyl, or dialkylaminylalkyl, wherein the C1-C6 alkyl may be optionally substituted with cycloalkyl;
each R 10 is independently hydrogen, acyl, C1-C3 alkyl, heteroalkyl or hydroxyalkyl;
R 11 is haloalkyl;
R A is absent, hydrogen, deuterium, cyano, halogen, C1-C-3 alkyl, haloalkyl, heteroalkyl, —C(O)N(R 5 ) 2 , or hydroxyalkyl;
each R B is independently hydrogen, deuterium, cyano, C1-C3 alkyl, hydroxyalkyl, heteroalkyl, C1-C3 alkoxy, halogen, haloalkyl, —ZNR 5 R 11 , —C(O)N(R 5 ) 2 , —NHC(O)C1-C3 alkyl, —CH 2 NHC(O)C1-C3 alkyl, -CH 2 N(CH 3 )C(O)C1-C3 alkyl, heteroaryl, heteroarylalkyl, dialkylaminylalkyl, or heterocyclylalkyl wherein the heterocyclyl portion is substituted with one or more substituents independently selected from halogen, hydroxyl, alkoxy and C1-C3 alkyl, wherein the heteroaryl or the heteroaryl portion of the heteroarylalkyl is optionally substituted with one or more R 7 ;
or when is a double bond and p is two, one R B is hydrogen and R A and one R B and the carbon atoms to which they are attached form a 4-8 membered partially saturated cycloalkyl substituted with oxo;
m is zero or an integer between 1 and 2;
p is one or two; and wherein,
when is a triple bond then R A is absent, p equals one and R B is hydroxyalkyl,
or when is a double bond then R A is present, R B is present and p equals two, wherein when R A is hydrogen or C1-C3 alkyl, at least one R B is deuterium, cyano, halogen, haloalkyl, hydroxyalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, —ZNR 5 R 11 , —C(O)N(R 5 ) 2 , —NHC(O)C1-C3 alkyl, -CH 2 NHC(O)C1-C3 alkyl, —NHC(O)C1-C3 alkyl or heterocyclylalkyl, wherein the heterocyclyl portion is substituted with one or more substituents independently selected from halogen, hydroxyl, alkoxy and C1-C3 alkyl; or when each R B is hydrogen, then R A is deuterium, cyano, halogen, haloalkyl, —C(O)N(R 5 ) 2 , hydroxyalkyl or heteroalkyl.

2. The compound of claim 1 , wherein R 1 —X is:

wherein the piperazinyl ring is optionally substituted with R 8 .

3. The compound of claim 2 , wherein R 1 is —C(O)C(R A ) C(R B ) p .

4. The compound of claim 3 , wherein is a triple bond and R A is absent, p is one and R B is hydroxyalkyl or C1-C3 alkoxy.

5. The compound of claim 3 , wherein is a double bond and R A is hydrogen, p is two and at least one R B is independently deuterium, cyano, halogen, haloalkyl, hydroxyalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, —ZNR 5 R 11 , —C(O)N(R 5 ) 2 , —NHC(O)C1-C3 alkyl, —NHC(O)C1-C3 alkyl or heterocyclylalkyl wherein the heterocyclyl portion is substituted with one or more substituents independently selected from halogen, hydroxyl, alkoxy or C1-C3 alkyl.

6. The compound of claim 5 , wherein the at least one R B is halogen.

7. The compound of claim 5 , wherein the at least one R B is haloalkyl.

8. The compound of claim 5 , wherein the at least one R B is —ZNR 5 R 11 .

9. The compound of claim 5 , wherein the at least one R B is cyano.

10. The compound of claim 5 , wherein the at least one R B is hydroxyalkyl.

11. The compound of claim 5 , wherein the at least one R B is heteroalkyl.

12. The compound of claim 5 , wherein the at least one R B is —C(O)N(R 5 ) 2 , wherein each R 5 is hydrogen.

13. The compound of claim 5 , wherein the at least one R B is —C(O)N(R 5 ) 2 , wherein each R 5 is C1-C3 alkyl.

14. The compound of claim 5 , wherein the at least one R B is heteroaryl optionally substituted with one or more R 7 .

15. The compound of claim 5 , wherein the at least one R B is heteroarylalkyl optionally substituted with one or more R 7 .

16. The compound of claim 5 , wherein the at least one R B is heterocyclylalkyl substituted with one or more R 7 .

17. The compound of claim 3 , wherein is a double bond and p is two, each R B is hydrogen, and R A is deuterium, cyano, halogen, haloalkyl, heteroalkyl, —C(O)N(R 5 ) 2 , or hydroxyalkyl.

18. The compound of claim 17 , wherein R A is halogen.

19. The compound of claim 17 , wherein R A is haloalkyl.

20. The compound of claim 17 , wherein R A is cyano.

21. The compound of claim 17 , wherein R A is heteroalkyl.

22. The compound of claim 17 , wherein R A is —C(O)N(R 5 ) 2 , wherein each R 5 is hydrogen.

23. The compound of claim 17 , wherein R A is hydroxyalkyl.

24. The compound of claim 2 , wherein is a double bond and p is two, one R B is hydrogen, the second R B is dialkylaminylalkyl, and R A is halogen.

25. The compound of claim 2 , wherein is a double bond and p is two, each R B is deuterium, and R A is deuterium.

26. The compound of claim 2 , wherein Y is O.

27. The compound of claim 2 , wherein R 2 is selected from the group consisting of hydroxyalkyl, alkylaminylalkyl, dialkylaminylalkyl, —ZNR 5 R 10 , heterocyclyl and heterocyclylalkyl, wherein each of the Z, heterocyclyl or heterocyclylalkyl are independently optionally substituted with R 9 .

28. The compound of claim 27 , wherein R 2 is heterocyclylalkyl optionally substituted with one or more R 9 .

29. The compound of claim 28 , wherein the

Assignees

• Mirati Therapeutics Inc
• Array Biopharma Inc

Inventors

• Blake James F
• Burgess Laurence E
• Chicarelli Mark Joseph
• Christensen James Gail
• Cook Adam
• Fell Jay Bradford
• Fischer John P
• Marx Matthew Arnold
• Mejia Macedonio J
• Savechenkov Pavel
• Vigers Guy P A
• Smith Christopher Ronald
• Rodriguez Martha E

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

• A61P35/02

  specific for leukemia · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• C07D491/08

  Bridged systems · CPC title