Compositions and methods for treating cancer

Patent metadata

Field	Value
Publication number	US-11718630-B2
Application number	US-202218050269-A
Country	US
Kind code	B2
Filing date	Oct 27, 2022
Priority date	Apr 10, 2012
Publication date	Aug 8, 2023
Grant date	Aug 8, 2023

Abstract

K-Ras is the most frequently mutated oncogene in human cancer. Disclosed herein are compositions and methods for modulating K-Ras and treating cancer.

First claim

What is claimed is:

1. A human K-Ras protein having a cysteine at residue 12, wherein said cysteine is covalently bonded to a compound, wherein said compound has the formula
R 1 -L 1 -L 2 -L 3 -E,
wherein
R 1 is substituted or unsubstituted fused ring aryl or substituted or unsubstituted fused ring heteroaryl;
L 1 is substituted or unsubstituted heteroarylene;
L 2 is a bond;
L 3 is

wherein
f8 is an integer from 0 to 8; each R 2C is independently oxo, halogen, —CX c 3 , —CN, —SO 2 Cl, —SO n3 R 10c , —SO v3 NR 7c R 8c , —NHNH 2 , —ONR 7c R 8c , —NHC═(O)NHNH 2 , —NHC═(O)NR 7 R 8c , —N(O) m3 , —NR 7c R 8c , —C(O)R 9c , —C(O)—OR 9c , —C(O)NR 7c R 8c , —OR 10c , —NR 7c SO 2 R 10c , —NR 7c C═(O)R 9c , —NR 7c C(O)—OR 9c , —NR 7c OR 9c , —OCX c 3 , —OCHX c 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; wherein two adjacent R 2C substituents are optionally joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
each R 7c , R 8c , R 9c and R 10c is independently hydrogen, halogen, —CF 3 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 2 Cl, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC═(O)NHNH 2 , —NHC═(O)NH 2 , —NHSO 2 H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF 3 , —OCHF 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R 7c and R 8c are optionally joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
m3 and v3 are independently an integer from 1 to 2;
n3 is independently an integer from 0 to 4;
X c is independently —Cl, —Br, —I, or —F; and,

prior to covalently bonding to the cysteine 12,

E is,
wherein R 13 is hydrogen, halogen, —CX b 3 , —CN, —SO 2 Cl, —SO r R 17 , —SO p NR 14 R 15 , —NHNH 2 , —ONR 14 R 15 , —NHC═(O)NHNH 2 , —NHC(O)NR 14 R 15 , —N(O) q , —NR 14 R 15 , —C(O)R 16 , —C(O)—OR 16 , —C(O)NR 14 R 15 , —OR 17 , —NR 14 SO 2 R 17 , —NR 14 C═(O)R 16 , —NR 14 C(O)—R 16 , —NR 14 OR 16 , —OCX b 3 , —OCHX b 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
wherein R 14 , R 15 , R 16 , and R 17 are independently hydrogen, halogen, —CF 3 , —CN, —OH, —NH 2 , —COH, —CONH 2 , —NO 2 , —SH, —SO 2 Cl, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC═(O)NHNH 2 , —NHC═(O)NH 2 , —NHSO 2 H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF 3 , —OCHF 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
wherein R 14 and R 15 substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
wherein p is 1 or 2;
wherein q is an integer from 1 to 2;
wherein r is an integer from 0 to 4;
wherein X b is independently Cl, Br, I, or F; and
wherein each substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted heteroaryl, and substituted aryl is independently substituted with a substituent group.

2. The human K-Ras protein of claim 1 , wherein R 13 is hydrogen, —F, —Cl, —Br, —I, —CX b 3 , or —CN, and X b is —Cl, —Br, —I, or —F.

3. The human K-Ras protein of claim 1 , wherein R 13 is —F, —Cl, —Br, or —I.

4. The human K-Ras protein of claim 1 , wherein R 13 is —F.

5. The human K-Ras protein of claim 2 , wherein R 1 is substituted fused ring aryl.

6. The human K-Ras protein of claim 2 , wherein R 1 is

wherein
e7 is an integer from 0 to 7;
R 3 is independently halogen, —CX 3 , —CN, —SO 2 Cl, —SO n R 10 , —SO v NR 7 R 8 , —NHNH 2 , —ONR 7 R 8 , —NHC═(O)NHNH 2 , —NHC═(O)NR 7 R 8 , —N(O) m , —NR 7 R 8 , —C(O)R 9 , —C(O)—OR 9 , —C(O)NR 7 R 8 , —NR 7 SO 2 R 10 , —NR 7 C═(O)R 9 , —NR 7 C(O)—OR 9 , —NR 7 OR 9 , —OCX 3 , —OCHX 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R 7 , R 8 , R 9 , and R 10 are independently hydrogen, halogen, —CF 3 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 2 Cl, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC═(O)NHNH 2 , —NHC═(O)NH 2 , —NHSO 2 H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF 3 , —OCHF 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
m and v are independently 1 or 2;
n is independently an integer from 0 to 4; and
each X is independently —Cl, —Br, —I, or —F.

7. The human K-Ras protein of claim 2 , wherein R 1 is

wherein e7 is 1, and R 3 is halogen, —OH, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl.

8. The human K-Ras protein of claim 2 , wherein R 1 is

wherein e7 is 1, and R 3 is halogen.

9. The human K-Ras protein of claim 7 , wherein at least one R 2C is a substituted alkyl.

10. The human K-Ras protein of claim 7 , wherein at least one R 2C is an alkyl substituted with —CN.

11. The human K-Ras protein of claim 3 , wherein R 1 is substituted fused ring aryl.

12. The human K-Ras protein of claim 3 , wherein R 1 is

wherein
e7 is an integer from 0 to 7;
R 3 is independently halogen, —CX 3 , —CN, —SO 2 Cl, —SO n R 10 , —SO v NR 7 R 8 , —NHNH 2 , —ONR 7 R 8 , —NHC═(O)NHNH 2 , —NHC═(O)NR 7 R 8 , —N(O) m , —NR 7 R 8 , —C(O)R 9 , —C(O)—OR 9 , —C(O)NR 7 R 8 , —NR 7 SO 2 R 10 , —NR 7 C═(O)R 9 , —NR 7 C(O)—OR 9 , —NR 7 OR 9 , —OCX 3 , —OCHX 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R 7 , R 8 , R 9 , and R 10 are independently hydrogen, halogen, —CF 3 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 2 Cl, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC═(O)NHNH 2 , —NHC═(O)NH 2 , —NHSO 2 H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF 3 , —OCHF 2 , substituted or unsubstituted alkyl, su

Assignees

• Univ California

Inventors

• Ostrem Jonathan
• Peters Ulf
• Shokat Kevan M

Classifications

• C07D495/04 Primary

  Ortho-condensed systems · CPC title

• A61K38/1709

  from mammals · CPC title

• C07C235/20

  having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms · CPC title

• C07C317/08

  of an acyclic unsaturated carbon skeleton · CPC title

• C07D207/14

  Nitrogen atoms not forming part of a nitro radical · CPC title