Granted Patent B2

US 12,116,375 · App. 18/490,700 · Granted Oct 15, 2024

Inventors: Jonathan Ostrem (San Francisco, CA); Ulf Peters (San Francisco, CA); Kevan M. Shokat (San Francisco, CA)

Assignee: The Regents of the University of California

C07D495/04A61K38/1709C07C235/20C07C317/08C07D207/14C07D211/58C07D211/62C07D231/40C07D295/185C07D295/26C07D401/04C07D401/06C07D401/12C07D405/12C07D409/04C07D413/12C07D417/12C07D471/10C07D487/04C07D487/10C12N9/14C12Q1/6886C12Q2600/156C12Q2600/158C12Y306/05002G01N2500/04

Abstract

Claims (69)

1. A method of treating colorectal cancer in a human subject with a K-Ras G12C-mutated colorectal cancer,

the method comprising administering to said human subject with said K-Ras G12C-mutated colorectal cancer a therapeutically effective amount of a pharmaceutical composition for the treatment of said K-Ras G12C-mutated colorectal cancer, wherein the pharmaceutical composition comprises a pharmaceutically acceptable carrier and a compound having the formula:

R 1 -L 1 -L 2 -L 3 -E,

or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein

R 1 is a substituted phenyl having the formula

wherein

e5 is an integer from 1 to 4;

each R 3 is independently halogen, —CX 3 , —CN, —SO 2 NR 7 R 8 , —N(O) 2 , —NR 7 C(═O)R 9 , —NR 7 R 8 , —C(O)R 9 , —C(O)—OR 9 , —C(O)NR 7 R 8 , —OR 10 , substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, wherein

two adjacent R 3 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 7 , R 8 , R 9 , and R 10 is independently hydrogen, or substituted or unsubstituted alkyl; R 7 and R 8 are optionally joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; and

X is —F;

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 2 C is independently oxo, halogen, —CX 3 , —CN, —SO 2 Cl, —SO n3 R 10c , —SO v3 NR 7c R 8c , —NHNH 2 , —ONR 7 CR 8c , —NHC═(O)NHNH 2 , —NHC═(O)NR 7c 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 an integer from 0 to 4;

X c is independently —Cl, —Br, —I, or—F; and

E is

wherein each substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted heteroaryl, substituted aryl is independently substituted with a substituent group.

2. The method of claim 1 , wherein each R 3 is independently —Cl, —Br, —I, —F, —CF 3 , —OH, —OCH 3 , —OCH 2 CH 2 NH 2 , —OCH 2 CH 2 OH, OCH 2 CCH, —CH 3 , —CH 2 CH 3 , —CH 2 NH 2 , —CH 2 OH, —CH 2 CH 2 OH, —CHCH 3 OH, C(OH)(CH 3 ) 2 , —C(CH 3 ) 3 , —CH 2 N(CH 3 ) 2 , —CCH, —CN, —C(O)H, —C(O)CH 3 , —C(O)NH 2 , —NHC(O)CH 3 , —NHS(O) 2 CH 3 , —C(O)OCH 3 , —C(O)OH, —C(O)N(CH 3 ) 2 , —CH 2 NHC(O)CH 3 , —C(O)NHCH 2 CH 2 OH, —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —NHC(O)OC(CH 3 ) 3 , —S(O) 2 NH 2 , phenyl, pyrrolidinyl, tetrazolyl, imidazolyl, isoxazolyl, or

and when two adjacent R 3 substituents are joined, the two adjacent R 3 substituents form 2,2-dimethyl-1,3-dioxolane, 1,2,5-thiadiazole, 1,2,5-oxadiazolyl, or pyridyl.

3. The method of claim 2 , wherein the substituted phenyl ring of R 1 is substituted with:

at least one halogen atom; and

at least one —OR 10 group, wherein R 10 is H or CH 3 .

4. The method of claim 3 , wherein

f8 is 1 and R 2C is methyl, trifluoromethyl, phenyl, or oxo; or

f8 is 2 and R 2C is methyl.

5. The method of claim 4 , wherein f8 is 1 and R 2C is methyl.

6. The method of claim 5 , wherein L 1 is 6,6-fused ring heteroarylene.

7. A method for covalently binding a compound to a K-Ras G12C protein in a human subject with a K-Ras G12C-mutated cancer, the method comprising administering to said human subject a pharmaceutical composition comprising a pharmaceutically acceptable carrier and said compound having the formula:

R 1 -L 1 -L 2 -L 3 -E,

or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein

R 1 is a substituted phenyl having the formula

wherein

e5 is an integer from 1 to 4;

each R 3 is independently halogen, —CX 3 , —CN, —SO 2 NR 7 R 8 , —N(O) 2 , —NR 7 C(═O)R 9 , —NR 7 R 8 , —C(O)R 9 , —C(O)—OR 9 , —C(O)NR 7 R 8 , —OR 10 , substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, wherein

two adjacent R 3 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 7 , R 8 , R 9 , and R 10 is independently hydrogen, or substituted or unsubstituted alkyl; R 7 and R 8 are optionally joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; and

X is —F;

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 7 CR 8c , —NHC═(O)NHNH 2 , —NHC═(O)NR 7c 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 ═(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 2 C 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 an integer from 0 to 4;

X c is independently —Cl, —Br, —I, or —F; and

E is

wherein each substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted heteroaryl, substituted aryl is independently substituted with a substituent group.

8. The method of claim 7 , wherein each R 3 is independently —Cl, —Br, —I, —F, —CF 3 , —OH, —OCH 3 , —OCH 2 CH 2 NH 2 , —OCH 2 CH 2 OH, OCH 2 CCH, —CH 3 , —CH 2 CH 3 , —CH 2 NH 2 , —CH 2 OH, —CH 2 CH 2 OH, —CHCH 3 OH, —C(OH)(CH 3 ) 2 , —C(CH 3 ) 3 , —CH 2 N(CH 3 ) 2 , —CCH, —CN, —C(O)H, —C(O)CH 3 , —C(O)NH 2 , —NHC(O)CH 3 , —NHS(O) 2 CH 3 , —C(O)OCH 3 , —C(O)OH, —C(O)N(CH 3 ) 2 , —CH 2 NHC(O)CH 3 , —C(O)NHCH 2 CH 2 OH, —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —NHC(O)OC(CH 3 ) 3 , —S(O) 2 NH 2 , phenyl, pyrrolidinyl, tetrazolyl, imidazolyl, isoxazolyl, or

and when two adjacent R 3 substituents are joined, the two adjacent R 3 substituents form 2,2-dimethyl-1,3-dioxolane, 1,2,5-thiadiazole, 1,2,5-oxadiazolyl, or pyridyl.

9. The method of claim 8 , wherein the substituted phenyl ring of R 1 is substituted with:

at least one halogen atom; and

at least one-OR 10 group, wherein R 10 is H or CH 3 .

10. The method of claim 9 , wherein

f8 is 1 and R 2C is methyl, trifluoromethyl, phenyl, or oxo; or

f8 is 2 and R 2C is methyl.

11. The method of claim 10 , wherein f8 is 1 and R 2C is methyl.

12. The method of claim 11 , wherein L 1 is 6,6-fused ring heteroarylene.

Assignments (1)

Continuity (10)

Cited By (1)

US 12,528,818