MAP4K4 (HGK) inhibitors

Patent metadata

Field	Value
Publication number	US-10000451-B2
Application number	US-201715650902-A
Country	US
Kind code	B2
Filing date	Jul 15, 2017
Priority date	Jan 18, 2015
Publication date	Jun 19, 2018
Grant date	Jun 19, 2018

Abstract

The invention provides mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4) inhibitors, and pharmaceutically acceptable salts, hydrides and stereoisomers thereof. The compounds are employed in pharmaceutical compositions, and methods of making and use, including treating a person in need thereof with an effective amount of the compound or composition, and detecting a resultant diminution of tumor cell growth, cancer or metastasis.

First claim

What is claimed is:

1. A compound having the structure:

wherein:
R1-R5 and R10 are independently H, halo, OH, C1-C9 alkyl, C1-C9 alkyl amine, or C1-C9 alkyl ether, and each of C1-C9 alkyl, C1-C9 alkyl amine, and C1-C9 alkyl ether is substituted with 0-3 groups selected from OR′, ═O, ═NR′, ═N—OR′, NR′R″, —SR′, halogen, —SiR′R″R′″, —OC(O)R′, —C(O)R′, —CO 2 R′, —CONR′R″, —OC(O)NR′R″, NR″ C(O)R′, —NR′ C(O)NR″R′″, —NR′ SO 2 NR′″, —NR″ CO 2 R′, —NHC(NH 2 )═NH, —NR′C(NH 2 )═NH, —NHC(NH 2 )═NR′, —S(O)R′, —SO 2 R′, —SO 2 NR′R″, —NR″SO 2 R, —CN, and NO 2 and comprises 0-3 heteroatoms selected from N, O, S, and P;
R6-R7 are independently N or CR10;
R8 is H or Me;
R9 is H;
R′, R″, and R′″ are each independently hydrogen, unsubstituted (C1-C8)alkyl, unsubstituted (C1-C8)heteroalkyl, unsubstituted aryl, aryl substituted with 1-3 halogens, unsubstituted alkyl, unsubstituted alkoxy, unsubstituted thioalkoxy, or aryl-(C1-C4)alkyl, or
a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , wherein R1, R2, R4, and R5 are H, or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 , wherein R3 is OH or C1-C6 alkyl ether, or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1 , wherein R7 is CR10, or a pharmaceutically acceptable salt thereof.

5. The compound of claim 1 , wherein R8 or R9 are H, or a pharmaceutically acceptable salt thereof.

6. The compound of claim 1 , wherein R1, R2, R4, and R5 are H; and R3 is OH or C1-C6 alkyl ether, or a pharmaceutically acceptable salt thereof.

7. The compound of claim 1 , wherein R1, R2, R4, and R5 are H; and R7 is CR10, or a pharmaceutically acceptable salt thereof.

8. The compound of claim 1 , wherein R1, R2, R4, and R5 are H; and R8 and R9 are H, or a pharmaceutically acceptable salt thereof.

9. The compound of claim 1 , wherein R3 is OH or C1-C6 alkyl ether; and R7 is CR10, or a pharmaceutically acceptable salt thereof.

10. The compound of claim 1 , wherein R3 is OH or C1-C6 alkyl ether; and R8 and R9 are H, or a pharmaceutically acceptable salt thereof.

11. The compound of claim 1 , wherein R7 is CR10; and R8 and R9 are H, or a pharmaceutically acceptable salt thereof.

12. The compound of claim 1 , wherein R1, R2, R4, and R4 are H; R3 is OH, or C1-C6 alkyl ether; and R7 is CR10, or a pharmaceutically acceptable salt thereof.

13. The compound of claim 1 , wherein R1, R2, R4, and R4 are H; R3 is OH or C1-C6 alkyl ether; R8 and R9 are H, or a pharmaceutically acceptable salt thereof.

14. The compound of claim 1 , wherein R3 is OH or C1-C6 alkyl ether; R7 is CR10; and R8 and R9 are H, or a pharmaceutically acceptable salt thereof.

15. The compound of claim 1 , wherein R1, R2, R4, and R4 are H; R3 is OH or C1-C6 alkyl ether; R7 is CR10; and R8 and R9 are H, or a pharmaceutically acceptable salt thereof.

16. The compound of claim 1 , wherein the compound is a diindolylmethanone or indol-2-yl, indol-6-yl-methanone, or a pharmaceutically acceptable salt thereof.

17. The compound of claim 1 , wherein the compound has a structure selected from:

#
Structure

 1

 4

 5

 6

 7

 8

 9

10a

10b

11

12

13

14

15

16

Assignees

• Stanford Res Inst Int

Inventors

• Jong Ling
• Chang Chih-Tsung
• Park Jaehyeon

Classifications

• C07D209/14 Primary

  Radicals substituted by nitrogen atoms, not forming part of a nitro radical · CPC title

• C07D209/12

  Radicals substituted by oxygen atoms · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K31/404

  Indoles, e.g. pindolol · CPC title

• C07D403/02

  containing two hetero rings · CPC title