INHIBITORS OF KRAS G12C

• US 20150239900A1
• Filed: 10/10/2014
• Published: 08/27/2015
• Est. Priority Date: 10/10/2013
• Status: Active Grant

• Current Assignee: Araxes Pharma LLC
• Original Assignee: Araxes Pharma LLC
• Inventors: Li, Liansheng, Feng, Jun, Wu, Tao, Ren, Pingda, Liu, Yi, Long, Yun Oliver, Liu, Yuan
• Granted Patent: US 9,840,516 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07D 215/46 with hydrocarbon radicals, substituted by nitrogen atoms, attached to said nitrogen atoms
• CPC Class Codes: C07D 215/54 attached in position 3
• CPC Class Codes: C07D 217/22 with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
• CPC Class Codes: C07D 239/84 Nitrogen atoms
• CPC Class Codes: C07D 239/94 Nitrogen atoms
• CPC Class Codes: C07D 239/95 with hetero atoms directly attached in positions 2 and 4
• CPC Class Codes: C07D 241/44 with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
• CPC Class Codes: C07D 401/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 403/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 409/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 487/04 Ortho-condensed systems
• CPC Class Codes: C07D 495/04 Ortho-condensed systems

Abstract

Compounds having activity as inhibitors of G12C mutant KRAS protein are provided. The compounds have the following structure (I):

or a pharmaceutically acceptable salt, tautomer, prodrug or stereoisomer thereof, wherein R¹, R^2a, R^3a, R^3b, R^4a, R^4b, G¹, G², L¹, L², m¹, m², A, B, W, X, Y, Z and E are as defined herein. Methods associated with preparation and use of such compounds, pharmaceutical compositions comprising such compounds and methods to modulate the activity of G12C mutant KRAS protein for treatment of disorders, such as cancer, are also provided.

Claims

1. A compound having the following structure (I):

2. The compound of claim 1, wherein the compound has the following structure (I′

);

3. The compound of claim 1, wherein the compound has the following structure (I′

a);

4. The compound of claim 3, wherein the compound has one of the following structures (I′

b), (I′

c), (I′

d) or (I′

e);

5. The compound of claim 4, wherein the compound has one of the following structures (I′

f), (I′

g), (I′

h) or (I′

i);

6. The compound of claim 4, wherein the compound has one of the following structures (I′

j), (I′

k), (I′

l), or (I′

m);

7. The compound of claim 1, wherein the compound has the following structure (I″

);

12. The compound of claim 1, wherein the compound has the following structure (I′

″

);

16. The compound claim 1, wherein R¹ is aryl.

17. The compound of claim 16, wherein R¹ is phenyl.

20. The compound of claim 16, wherein R¹ is substituted with one or more substituents.

21. The compound of claim 20, wherein the substituents are selected from halo, cyano, cyanoC₁-C₆alkyl, cyanoC₃-C₈cycloalkyl, hydroxyl, C₁-C₆alkyl, C₁-C₆alkylcycloalky, C₂-C₆alkynyl, C₁-C₆alkoxy, C₁-C₆haloalkoxy, C₁-C₆alkylaminyl, C₁-C₆alkylcarbonylaminyl, C₁-C₆hydroxylalkyl, C₁-C₆halo alkyl, C₁-C₆alkoxyalkyl, aminylsulfone, aminylcarbonyl, aminylcarbonylC₁-C₆alkyl, aminylcarbonylC₃-C₈cycloalkyl, C₁-C₆alkylaminylcarbonyl, C₃-C₈cycloalkylaminylcarbonyl, C₃-C₈cycloalkylalkyl and C₃-C₈cycloalkyl, C₃-C₈fusedcycloalkyl and heteroaryl.

22. The compound of claim 21, wherein the substituents are selected from fluoro, chloro, bromo, cyano, hydroxyl, hydroxylmethyl, methoxy, methoxymethyl, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, aminylcarbonyl and cyclopropyl.

23. The compound of claim 16, wherein R¹ has one of the following structures:

24. The compound of claim 1, wherein R¹ is heteroaryl.

26. The compound of claim 24, wherein R¹ is thiophenyl, pyridinyl, pyridinonyl, pyrimidinyl, benzooxazolyl, benzoisoxazolyl, benzodioxazolyl, benzoimidazolyl, quinolinyl, quinolinonyl, dihydroquinolinonyl, tetrahydroquinolinyl, quinazolinyl, indazolyl, indolinonyl, benzothiophenyl or dihydrobenzodioxinyl.

28. The compound of claim 24, wherein R¹ is substituted with one or more substituents.

29. The compound of claim 28, wherein the substituents are selected from halo, C₁-C₆alkyl, C₁-C₆alkoxy, or C₂-C₆alkenylcarbonylaminyl.

30. The compound of claim 29, wherein the substituents are selected from fluoro, chloro, amino and methyl.

31. The compound of claim 24, wherein R¹ has one of the following structures:

33. The compound of claim 1, wherein R^2a is halo.

34. The compound of claim 33, wherein R^2a is chloro or fluoro.

40. The compound of claim 1, wherein R^2b, when present, is halo.

42. The compounds of claim 40, wherein halo is chloro or fluoro.

43. The compound of claim 3, wherein Q is —

C(═

O)—

.

50. The compound of claim 3, wherein at least one of R⁹ or R¹⁰ is H.

51. The compound of claim 50, wherein each of R⁹ and R¹⁰ are H.

58. The compound of claim 1, wherein E has one of the following structures:

59. The compound of claim 1, wherein L¹ is a bond.

62. The compound of claim 1, wherein L² is a bond.

65. The compound of claim 1, wherein R^3a, R^3b, R^4a and R^4b are H.

69. The compound of claim 1 wherein Z is N.

70. The compound of claim 69, wherein X is N.

72. The compound of claim 70, wherein Y is CR⁶, wherein R⁶ is H and W is CR⁶, wherein R⁶ is a bond to L¹.

81. The compound of claim 1, wherein the compound is any one of compounds 1-376.

82. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

85. A method for treatment of cancer, the method comprising administering an effective amount of the pharmaceutical composition of claim 82 to a subject in need thereof.

88. A method for regulating activity of a KRAS, HRAS or NRAS G12C mutant protein, the method comprising reacting the KRAS G12C mutant protein with the compound of claim 1.

89. A method for inhibiting proliferation of a cell population, the method comprising contacting the cell population with the compound of claim 1.

91. A method for treating a disorder mediated by a KRAS G12C, HRAS G12C or NRAS G12C mutation in a subject in need thereof, the method comprising:

determining if the subject has a KRAS, HRAS or NRAS G12C mutation; and

if the subject is determined to have the KRAS, HRAS or NRAS G12C mutation, then administering to the subject a therapeutically effective amount of the pharmaceutical composition of claim 82.

94. A method for preparing a labeled KRAS, HRAS or NRAS G12C mutant protein, the method comprising reacting the KRAS, HRAS or NRAS G12C mutant with a compound of claim 1, to result in the labeled KRAS, HRAS or NRAS G12C protein.

95. A method for inhibiting tumor metastasis, the method comprising administering an effective amount of the pharmaceutical composition of claim 82 to a subject in need thereof.

96. The compound of claim 1, wherein Y is CR⁶, and R⁶ is H, oxo, cyano, cyanoalkyl, amino, aminylalkyl, aminylalkylaminyl, aminylcarbonyl, aminylsulfonyl, —

CO₂NR^aR^b, wherein R^a and R^b, are each independently H or C1-C6 alkyl or R^a and R^b join to form a carbocyclic or heterocyclic ring, alkylaminyl, haloalkylaminyl, hydroxylalkyaminyl, amindinylalkyl, amidinylalkoxy, amindinylalkylaminyl, guanidinylalkyl, guanidinylalkoxy, guanidinylalkylaminyl, C₁-C₆ alkoxy, aminylalkoxy, alkylaminylalkoxy, alkylcarbonylaminylalkoxy, C₁-C₆ alkyl, heterocyclyl, heterocyclyloxy, heterocyclylalkyloxy, heterocyclylaminyl, heterocyclylalkylaminyl, heteroaryl, heteroaryloxy, heteroarylalkyloxy, heteroarylaminyl, heteroarylalkylaminyl, aryl, aryloxy, arylaminyl, arylalkylaminyl or arylalkyloxy.

97. The compound of claim 96, wherein R⁶ is heterocyclylaminyl.

98. The compound of claim 96, wherein R⁶ is H.

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