Compositions and methods of targeting mutant k-ras

Patent metadata

Field	Value
Publication number	US-2018201610-A1
Application number	US-201815874485-A
Country	US
Kind code	A1
Filing date	Jan 18, 2018
Priority date	Jan 18, 2017
Publication date	Jul 19, 2018
Grant date	—

Abstract

Compounds and compositions are presented that inhibit K-Ras, and especially mutant K-Ras. Certain compounds preferentially or even selectively inhibit specific forms of mutant K-Ras, and particularly the G12D mutant form.

First claim

What we claim is:

1 . A compound having a structure according to Formula I

wherein R 6 has the structure according to either Formula II or Formula III

wherein:
V represents C(R 5 ) or N;
W represents C(R 1 ) or N;
X represents C(R 2 ) or N;
Y represents C(R 3 ) or N;
Z represents O, S, C(R 4a )(R 4b ) or N(R 4a );
wherein R 1 is selected from the group consisting of H, alkyl, and cycloalkyl;
wherein R 2 is selected from the group consisting of H, halo, alkyl, substituted alkyl, fluoroalkyl, cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, aralkyl, polycycloalkyl, hetero-polycycloalkyl, polycycloaryl, hetero-polycycloaryl, acyloxy, alkyloxycarbonyl, amino, amido, sulfonamido, pyrazolyl, and substituted pyrazolyl;
wherein R 3 and R 7 are independently H or halo;
wherein R 4a is independently selected from the group consisting of H, alkyl, substituted alkyl, fluoroalkyl, and aryl;
wherein R 4b are independently selected from the group consisting of H, alkyl, substituted alkyl, fluoroalkyl, aryl, and alkyloxy;
wherein R 5 is H or alkyl; and
wherein R 8 is selected from the group consisting of H, substituted alkyl, aminoalkyl, alkyl amido, cycloalkyl, aralkyl, substituted aralkyl, heteroaralkyl, substituted heteroaralkyl, alkyl cycloalkyl, alkyl heterocycloalkyl, polycycloaryl, alkyloxy, acyloxy, alkyloxycarbonyl, and amino.

2 . A compound having a structure according to Formula I

wherein R 9 has the structure according to one of Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, Formula XI, Formula XII, Formula XIII and Formula XIV

wherein R 1 is selected from the group consisting of H, alkyl, and cycloalkyl;
wherein R 2 is selected from the group consisting of H, halo, alkyl, substituted alkyl, fluoroalkyl, cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, aralkyl, polycycloalkyl, hetero-polycycloalkyl, polycycloaryl, hetero-polycycloaryl, acyloxy, alkyloxycarbonyl, amino, amido, sulfonamido, pyrazolyl, and substituted pyrazolyl;
wherein R 3 and R 7 are independently H or halo;
wherein R 4a is independently selected from the group consisting of H, alkyl, substituted alkyl, fluoroalkyl, and aryl;
wherein R 4b are independently selected from the group consisting of H, alkyl, substituted alkyl, fluoroalkyl, aryl, and alkyloxy;
wherein R 5 is H or alkyl; and
wherein R 8 is selected from the group consisting of H, substituted alkyl, aminoalkyl, alkyl amido, cycloalkyl, aralkyl, substituted aralkyl, heteroaralkyl, substituted heteroaralkyl, alkyl cycloalkyl, alkyl heterocycloalkyl, polycycloaryl, alkyloxy, acyloxy, alkyloxycarbonyl, and amino.

3 . The compound of claim 1 wherein R 6 has the structure according to Formula II.

4 . The compound of claim 3 wherein R 7 is a halogen.

5 . The compound of claim 3 wherein R 9 comprises a structure selected from the group consisting of pyrazolyl, thiazolyl, oxazolyl, and thiophenyl.

6 . The compound of claim 2 , wherein R 9 has the structure according to Formula V or Formula XI.

7 . The compound of claim 6 , wherein R 4a of Formula V is H, CF 3 , CHF 2 , CH 2 F, CH 3 , and R 4b of Formula XI is H, CF 3 , CHF 2 , CH 2 F, CH 3 , or alkyloxy.

8 . The compound of claim 6 , wherein R 4a of Formula V and R 4b of Formula XI are methyl, and R 1 is methyl.

9 . The compound of claim 8 , wherein R 2 is alkyl, aryl, or aralkyl.

10 . The compound of claim 6 , wherein one of R 2 or R 4a of Formula V or R 4b of Formula XI is H and R 1 is cycloalkyl.

11 . The compound of claim 1 , wherein R 2 is alkyl, R 4a is methyl, and R 4b is H or methyl.

12 . The compound of claim 2 , wherein R 9 has the structure according to Formula VI or Formula XI.

13 . The compound of claim 12 , wherein R 1 and R 2 form a five or six member aromatic ring.

14 . The compound of claim 12 , wherein R 4a is methyl and R 2 is alkyl.

15 . The compound of claim 2 , wherein R 9 has the structure according to Formula VII or Formula XII, wherein R 3 of Formula VII and R 2 of Formula XII are alkyl.

16 . The compound of claim 2 , wherein R 9 has the structure according to Formula VIII or Formula XIII, wherein R 3 of Formula VIII and R 2 of Formula XIII are alkyl or cycloalkyl.

17 . The compound of claim 2 , wherein R 8 is H, optionally substituted benzyl, heterobenzyl, aminoalkyl, alkyl amido, alkyloxy, acyloxy, or alkyloxycarbonyl.

18 . The compound of claim 2 , wherein R 8 has a structure selected from the group consisting of

and n is 1-3.

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

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

21 . A method of inhibiting mutant K-Ras, comprising contacting a mutant K-Ras with a compound of claim 1 , at a concentration effective to inhibit the mutant K-Ras, wherein the mutant K-Ras is in a GTP-bound, or active state before the contacting step.

22 . A method of inhibiting mutant K-Ras, comprising contacting a mutant K-Ras with a compound of claim 1 , at a concentration effective to inhibit the mutant K-Ras, wherein the mutant K-Ras is in a GTP-bound, or active state before the contacting step.

23 . A method of treating a neoplastic disease in a mammal in need thereof, comprising a step of administering to the mammal an effective amount of a compound of claim 1 .

24 . The method of claim 23 , wherein the neoplastic disease comprises a mutant K-Ras with a, mutation at glycine-12 (Gly12), Gly13, and/or glutamine-61 (Gln61).

Assignees

• Nantbio Inc

Inventors

• Tao Chunlin
• Nallan Laxman
• Ho David G
• Wang Qinwei
• Weingarten Paul
• Juncker-Jensen Anna B

Classifications

• C07D417/14 Primary

  containing three or more hetero rings · CPC title

• A61P35/00

  Antineoplastic agents · CPC title