Combination therapies

Patent metadata

Field	Value
Publication number	US-2022040181-A1
Application number	US-201917275175-A
Country	US
Kind code	A1
Filing date	Sep 9, 2019
Priority date	Sep 10, 2018
Publication date	Feb 10, 2022
Grant date	—

Abstract

The present invention relates to combination therapies for treating KRas G12C cancers. In particular, the present invention relates to methods of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of a Src-family kinase inhibitor and a KRAS G12C inhibitor of Formula (I), Formula I-A or Formula I-B, pharmaceutical compositions comprising a therapeutically effective amounts of the inhibitors, kits comprising the compositions and methods of use therefor.

First claim

1 . A method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of a Src-family kinase inhibitor and a KRAS G12C inhibitor of formula (I):

or a pharmaceutically acceptable salt thereof:
wherein:
X is a 4-12 membered saturated or partially saturated monocyclic, bridged or spirocyclic ring, wherein the saturated or partially saturated monocyclic ring 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, 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, 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 ;
when is a triple bond then R A is absent, R B is present and p equals one,
or when

is a double bond then R A is present, R B is present and p equals two, or R A , R B and the carbon atoms to which they are attached form a 5-8 membered partially saturated cycloalkyl optionally substituted with one or more R 7 ;
m is zero or an integer between 1 and 2; and
p is one or two.

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

wherein the piperazinyl ring is optionally substituted with R 8 .

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

4 . (canceled)

5 . (canceled)

6 . The method of claim 3 , wherein is a double bond and, 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 or heterocyclylalkyl wherein the heterocyclyl portion is substituted with one or more substituents independently selected from halogen, hydroxyl, alkoxy or C1-C3 alkyl.

7 . (canceled)

8 . (canceled)

9 . (canceled)

10 . (canceled)

11 . (canceled)

12 . (canceled)

13 . (canceled)

14 . (canceled)

15 . (canceled)

16 . (canceled)

17 . (canceled)

18 . (canceled)

19 . (canceled)

20 . (canceled)

21 . (canceled)

22 . (canceled)

23 . (canceled)

24 . (canceled)

25 . The method of claim 6 , 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.

26 . The method of claim 25 , wherein R A is halogen.

27 . (canceled)

28 . (canceled)

29 . (canceled)

30 . (canceled)

31 . (canceled)

32 . (canceled)

33 . (canceled)

34 . The method 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.

35 . (canceled)

36 . (canceled)

37 . The method of according to claim 2 , wherein Y is O.

38 . The method according to 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 .

39 . The method of claim 38 , wherein R 2 is heterocyclylalkyl optionally substituted with one or more R 9 .

40 . The method of claim 39 , wherein the heterocyclyl of the heterocyclylalkyl is independently azetidinyl, methylazetidinyl, difluoroazetidinyl, tetrahydropyran, pyrrolidinyl, methylpyrrolidinyl, diemethylpyrrolidinyl, isopropylpyrrolidinyl, cycloalkylalkylpyrrolidinyl, hydroxypyrrolindinyl, fluoropyrrolidinyl, difluoropyrrolidinyl, (N-methyl)fluoropyrrolidinyl, (N-methyl)difluoropyrrolidinyl, methoxyethylpyrrolidinyl, (N-methyl)methoxypyrrolidinyl, piperazinyl, dimethylaminylpyrrolidinyl, morpholinyl, methylmorpholinyl, 1,4-oxazepanyl, piperdinyl, methylpiperidinyl acylpiperdinyl, cyanopiperdinyl, cycloalkylpiperdinyl, halopiperdinyl, dihalopiperdinyl, fluoropiperdinyl, difluoropiperdinyl, alkoxypiperdinyl, pyrrolidonyl, piperidinonyl, thiomorpholinyl-1,1-dioxide, 3-azabicyclo[3.1.0]hexanyl, oxa-5-azabicyclo[2.2.1]heptan-5-yl, or azabicyclo[2.2.1]heptan-2-yl.

41 . The method of claim 40 , wherein the (N-methyl)difluoropyrrolidinyl is 3,3-difluoro-1-methylpyrrolidinyl.

42 . The method of claim 40 , wherein the heterocyclyl is N-methylpyrrolidinyl.

43 . (canceled)

44 . The method according to claim 2 , wherein R 4 is aryl optionally substituted with one or more R 7 .

45 . The method of claim 44 , wherein the aryl is selected from the group consisting of

Assignees

• Mirati Therapeutics Inc

Inventors

• Engstrom Lars Daniel
• Aranda Ruth Wei
• Olson Peter
• Christensen James Gail

Classifications

• A61K31/5377

  not condensed and containing further heterocyclic rings, e.g. timolol · CPC title

• A61K31/553

  having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61K31/541

  Non-condensed thiazines containing further heterocyclic rings · CPC title

• A61P35/00 Primary

  Antineoplastic agents · CPC title