K-Ras modulators

Patent metadata

Field	Value
Publication number	US-10857140-B2
Application number	US-201615571475-A
Country	US
Kind code	B2
Filing date	May 6, 2016
Priority date	May 6, 2015
Publication date	Dec 8, 2020
Grant date	Dec 8, 2020

Abstract

Provided herein, inter alia, are methods and compounds of formula (I) for inhibiting K-Ras and for treating cancer.

First claim

What is claimed is:

1. A compound having the formula:

or a pharmaceutically acceptable salt thereof, wherein:
E is:

wherein:
R 16 is hydrogen; R 17 is hydrogen; R 18 is hydrogen; Y is N or CH; Ring A is a C 3 -C 7 cycloalkyl or 3 to 7 membered heterocycloalkyl; R 1 is independently halogen, —CX 1 3 , —CHX 1 2 , —CH 2 X 1 , —CN, —SO 2 Cl, —SO n1 R 10 , —SO v1 NR 7 R 8 , —NHNR 7 R 8 , —ONR 7 R 8 , —NHC═(O)NHNR 7 R 8 , —NHC(O)NR 7 R 8 , —N(O) m1 , —NR 7 R 8 , —C(O)R 9 , —C(O)—OR 9 , —C(O)NR 7 R 8 , —OR 10 , —NR 7 SO 2 R 10 , —NR 7 C(O)R 9 , —NR 7 C(O)OR 9 , —NR 7 OR 9 , —OCX 1 3 , —OCHX 1 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; and two adjacent R 1 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2 is independently oxo, halogen, —CX 2 3 , —CHX 2 2 , —CH 2 X 2 , —CN, —SO 2 Cl, —SO n2 R 14 , —SO v2 NR 11 R 12 , —NHNR 11 R 12 , —NHC═(O)NHNR 11 R 12 , —NHC(O)NR 11 R 12 , —N(O) m2 , —NR 11 R 12 , —C(O) 14 , —C(O)—OR 14 , -c(O)NR 11 R 12 , —OR 15 , —NR 11 SO 2 R 15 , —NR 11 C(O)R 14 , —NR 11 C(O)OR 14 , —NR 11 OR 14 , —OCX 2 3 , —OCHX 2 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, and two adjacent R 2 substituents or two R 2 substituents bonded to the same atom may optionally be joined to form a substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycloalkyl; L 1 is a bond; L 2 is —NR 7B ; R 7B is hydrogen; L 4 is unsubstituted C 1 -C 3 alkylene, or unsubstituted 2 to 3 membered heteroalkylene; R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 14 , and R 15 are independently hydrogen, halogen, —CX 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, —OCX 3 , —OCHX 2 , —CHX 2 , —CH 2 X, 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 and R 8 substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; each X, X 1 , and X 2 is independently —F, —Cl, —Br, or —I; n1, n2, v1, and v2 are independently an integer from 0 to 4; m1 and m2 are independently 1 or 2; z1 is independently an integer from 0 to 5; and z2 is 0.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Y is N.

3. The compound of claim 1 , having the formula:

or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1 , having the formula:

or a pharmaceutically acceptable salt thereof.

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
each R 1 is independently halogen, —CX 1 3 , —CHX 1 2 , —CH 2 X 1 , —CN, —SO v1 NR 7 R 8 , —NO 2 , —NR 7 R 8 , —C(O)R 9 , —C(O)—OR 9 , —C(O)NR 7 R 8 , —NR 7 C(O)R 9 , —NR 7 C(O)OR 9 , —OCX 1 3 , —OCHX 1 2 , substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted C 6 -C 10 aryl, or substituted or unsubstituted 5 to 10 membered heteroaryl;
R 7 is hydrogen, C 1 -C 8 alkyl unsubstituted or substituted with R 48 , C 3 -C 8 cycloalkyl unsubstituted or substituted with R 48 , 3 to 8 membered heterocycloalkyl unsubstituted or substituted with R 48 , C 6 -C 10 aryl unsubstituted or substituted with R 48 , or 5 to 10 membered heteroaryl unsubstituted or substituted with R 48 , wherein R 48 is halogen, —CX 48 3 , —CHX 48 2 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHC(O)—OH, —OCX 48 3 , —OCHX 48 2 , or —OCH 2 X 48 , wherein X 48 is halogen;
R 8 is hydrogen, C 1 -C 8 alkyl unsubstituted or substituted with R 51 , C 3 -C 8 cycloalkyl unsubstituted or substituted with R 51 , 3 to 8 membered heterocycloalkyl unsubstituted or substituted with R 51 , C 6 -C 10 aryl unsubstituted or substituted with R 51 , or 5 to 10 membered heteroaryl unsubstituted or substituted with R 51 , wherein R 51 is halogen, —CX 51 3 , —CHX 51 2 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHC(O)—OH, —OCX 51 3 , —OCHX 51 2 , or —OCH 2 X 51 , wherein X 51 is halogen;
R 9 is hydrogen, C 1 -C 8 alkyl unsubstituted or substituted with R 54 , C 3 -C 8 cycloalkyl unsubstituted or substituted with R 54 , 3 to 8 membered heterocycloalkyl unsubstituted or substituted with R 54 , C 6 -C 10 aryl unsubstituted or substituted with R 54 , or 5 to 10 membered heteroaryl unsubstituted or substituted with R 54 , wherein R 54 is halogen, —CX 54 3 , —CHX 54 2 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHC(O)—OH, —OCX 54 3 , —OCHX 54 2 , or —OCH 2 X 54 , wherein X 54 is halogen; and
R 10 is hydrogen, C 1 -C 8 alkyl unsubstituted or substituted with R 57 , C 3 -C 8 cycloalkyl unsubstituted or substituted with R 57 , 3 to 8 membered heterocycloalkyl unsubstituted or substituted with R 57 , C 6 -C 10 aryl unsubstituted or substituted with R 57 , or 5 to 10 membered heteroaryl unsubstituted or substituted with R 57 , wherein R 57 is halogen, —CX 57 3 , —CHX 57 2 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHC(O)—OH, —OCX 57 3 , —OCHX 57 2 , or —OCH 2 X 57 , wherein X 57 is halogen.

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R 1 is independently halogen, —CX 1 3 , —CHX 1 2 , —CH 2 X 1 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —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, —OCX 1 3 , —OCHX 1 2 , substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted C 3 -Cg cycloalkyl, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted C 6 aryl, or substituted or unsubstituted 5 to 6 membered heteroaryl.

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is independently halogen, —CX 1 3 , —CHX 1 2 , —CH 2 X 1 , —OH, —SH, —COOH, —OCX 1 3 , —OCHX 1 2 , —CH 3 , —CH 2 CH 3 , —OCH 3 , —OCH 2 CH 3 , —SCH 3 , or —SCH 2 CH 3 .

8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein z1 is 2 or 3.

9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein L 4 is —CH 2 —.

10. The compound of claim 1 , wherein the compound is:

Assignees

• Univ California
• Leidos Biomedical Res Inc

Inventors

• Mccormick Frank
• Renslo Adam R
• Turner David
• Gysin Stephan
• Maciag Anna E
• Chertov Oleg

Classifications

• C07D211/28

  to which a second hetero atom is attached · CPC title

• C07D207/16

  Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals · CPC title

• A61K47/545

  Heterocyclic compounds (A61K47/558 takes precedence) · CPC title

• A61K31/445 Primary

  Non condensed piperidines, e.g. piperocaine · CPC title

• C07D211/60

  Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals · CPC title