Heterocyclic inhibitors of ERK1 and ERK2 and their use in the treatment of cancer

Patent metadata

Field	Value
Publication number	US-9896445-B2
Application number	US-201615183486-A
Country	US
Kind code	B2
Filing date	Jun 15, 2016
Priority date	Jun 15, 2015
Publication date	Feb 20, 2018
Grant date	Feb 20, 2018

Abstract

The present application provides novel heterocyclic compounds and pharmaceutically acceptable salts thereof. Also provided are methods for preparing these compounds. These compounds are useful for inhibiting ERK1/2. By administering to a patient in need a therapeutically effective amount of one or more of the compounds of formula (I), wherein X, Y, Z, J, M, and R 1 to R 8 are defined herein, these compounds are effective in treating conditions associated with dysregulation of the RAS/RAF/MEK/ERK pathway. A variety of conditions can be treated using these compounds and include diseases which are characterized by abnormal cellular proliferation. In one embodiment, the disease is cancer.

First claim

What is claimed is:

1. A compound of formula (II),

or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or stereoisomer thereof, wherein:
R 1 is C 6-12 aryl or 5- to 10-membered heteroaryl, which is unsubstituted or substituted with 1-3 substituents selected from halogen, C 1-6 alkyl, CN, hydroxyC 1-6 alkyl, aminoC 1-6 alkyl, —C 1-6 alkyl-O—C 1-6 alkyl, —C 1-6 alkyl-NH—C 1-6 alkyl, —C 1-6 alkyl-N—(C 1-6 alkyl) 2 , —C 1-6 alkyl-NH—C 1-6 alkyl-OH, —C 1-6 alkyl-NH—C 1-6 alkyl-C 3-10 cycloalkyl, —C 1-6 alkyl-NH—C 1-6 alkyl-NH—C 1-6 alkyl, —C 1-6 alkyl-NH—C(O)—C 1-6 alkyl, —C 1-6 alkyl-O—C(O)—C 1-6 alkyl, —C 1-6 alkyl-NH—C 0-6 alkyl-(4- to 6-membered heterocyclyl), or —C 1-6 alkyl-NH—C 0-6 alkyl-(5- to 6-membered heteroaryl), wherein the C 1-6 alkyl, cycloalkyl, heterocyclyl, and/or heteroaryl is unsubstituted or substituted with 1-3 substituents selected from halogen, C 1-6 alkyl, NH 2 , hydroxyC 1-6 alkyl, or aminoC 1-6 alkyl;
n is 0 to 6;
R 2 is C 1-6 alkyl, hydroxyC 1-6 alkyl, aminoC 1-6 alkyl, —C 1-6 alkyl-O—C 1-6 alkyl, —C 1-6 alkyl-NH—C 1-6 alkyl, —C 1-6 alkyl-N—(C 1-6 alkyl) 2 , —C 1-6 alkyl-NH—C 1-6 alkyl-OH, —C 1-6 alkyl-NH—C 1-6 alkyl-C 3-10 cycloalkyl, —C 1-6 alkyl-NH—C 1-6 alkyl-NH—C 1-6 alkyl, —C 1-6 alkyl-NH—C(O)—C 1-6 alkyl, —C 1-6 alkyl-O—C(O)—C 1-6 alkyl, —C 1-6 alkyl-NH—C 0-6 alkyl-(4- to 6-membered heterocyclyl), —C(O)—NH 2 , —C(O)—NH—C 1-6 alkyl, —C(O)—N(C 1-6 alkyl) 2 , or —C 1-6 alkyl-NH—C 0-6 alkyl-(5- to 6-membered heteroaryl), wherein the C 1-6 alkyl, heterocyclyl, or heteroaryl is unsubstituted or substituted with 1-3 substituents selected from halogen, C 1-6 alkyl, cycloalkyl, NH 2 , hydroxyC 1-6 alkyl, or aminoC 1-6 alkyl; and
R 8 is H or C 1-6 alkyl;
alternatively, R 2 , R 8 , and the C atom that both R 2 and R 8 are attached join together to form a 3- to 10- membered cycloalkyl or 4- to 10-membered heterocyclyl ring, wherein the cycloalkyl or heterocyclyl is unsubstituted or substituted with 1-3 substituents selected from hydroxyl, halogen, or C 1-6 alkyl;
R 3 is H or C 1-6 alkyl, wherein the C 1-6 alkyl is unsubstituted or substituted with 1-5 halogens;
M is a bond or NH;
X and Y are each independently CH, C—R 7 , or N;
Z is CH or N,
R 5 is H, halogen, C 1-6 alkyl, or O—C 1-6 alkyl, wherein C 1-6 alkyl is unsubstituted or substituted with 1-5 halogens;
R 6 is H or C 1-6 alkyl, wherein the C 1-6 alkyl is unsubstituted or substituted with 1-5 halogens;
R 7 is C 1-6 alkyl, wherein the C 1-6 alkyl is unsubstituted or substituted with 1-5 halogens; and
R 4 is C 1-6 alkyl, C 3-10 cycloalkyl, C 4-10 cycloalkenyl, —C 1-6 alkyl-phenyl, —C 1-6 alkyl-(5 to 6-membered heteroaryl), —C 1-6 alkyl-(4 to 6-membered heterocyclyl), 4- or 10-membered heterocyclyl, phenyl, or 5- to 10-membered heteroaryl, wherein the alkyl, cycloalkyl, cycloalkenyl, phenyl, heteroaryl, or heterocyclyl is unsubstituted or substituted with 1-3 substituents selected from halogen, CN, —C(O)—NH 2 , —C(O)—NH—C 1-6 alkyl, —C(O)—N—(C 1-6 alkyl) 2 , —O—C 1-6 alkyl-NH 2 , —O—C 1-6 alkyl-NH—(C 1-6 alkyl), —O—C 1-6 alkyl-N(C 1-6 alkyl) 2 , 4- to 6-membered heterocyclyl, —C(O)-(4- to 6-membered heterocyclyl), —O-phenyl, —O—C 1-6 alkyl-(4- to 6-membered heterocyclyl), C 1-6 alkyl, C 2-6 alknyl, hydroxyl, C 1-6 alkoxyl, or hydroxyC 1-6 alkyl, and the heterocyclyl or heteroaryl is unsubstituted or substituted with 1-3 substituents selected from halogen, C 1-6 alkyl, —C(O)—C 1-6 alkyl, or 4- to 6-membered heterocyclyl.

2. The compound of claim 1 , or a pharmaceutically acceptable salt, prodrug, solvate,
hydrate, or stereoisomer thereof, wherein:
R 1 is phenyl, or 5- or 6-membered heteroaryl, which is unsubstituted or substituted with 1-3 substituents selected from halogen, C 1-6 alkyl, CN, hydroxyC 1-6 alkyl, or aminoC 1-6 alkyl, wherein the C 1-6 alkyl is unsubstituted or substituted with 1-3 substituents selected from halogen.

3. The compound of claim 1 , or a pharmaceutically acceptable salt, prodrug, solvate,
hydrate, or stereoisomer thereof, wherein:
R 1 is phenyl, pyridyl, thienyl, or thiazolyl, which is unsubstituted or substituted with 1-3 substituents selected from halogen, C 1-6 alkyl, CN, hydroxyC 1-6 alkyl, or aminoC 1-6 alkyl, wherein the C 1-6 alkyl is unsubstituted or substituted with 1-3 substituents selected from halogen.

4. The compound of claim 1 , or a pharmaceutically acceptable salt, prodrug, solvate,
hydrate, or stereoisomer thereof, wherein:
n is 0 or 1.

5. The compound of claim 1 , or a pharmaceutically acceptable salt, prodrug, solvate,
hydrate, or stereoisomer thereof, wherein:
R 2 is C 1-6 alkyl, hydroxyC 1-6 alkyl, aminoC 1-6 alkyl, —C 1-6 alkyl-NH—C 1-6 alkyl, —C 1-6 alkyl-NH—C 0-6 alkyl-(4- to 6-membered heterocyclyl), —C(O)—NH 2 , —C(O)—NH—C 1-6 alkyl, —C(O)—N(C 1-6 alkyl) 2 , —C 1-6 alkyl-NH—C 1-6 alkyl-OH, or —C 1-6 alkyl-NH—C 0-6 alkyl-(5- to 6-membered heteroaryl), wherein the C 1-6 alkyl, heterocyclyl, or heteroaryl is unsubstituted or substituted with 1-3 substituents selected from halogen, C 1-6 alkyl, NH 2 , hydroxyC 1-6 alkyl, or aminoC 1-6 alkyl, and
R 8 is H.

6. The compound of claim 1 , or a pharmaceutically acceptable salt, prodrug, solvate,
hydrate, or stereoisomer thereof, wherein:
R 2 is CH 3 , CH 2 OH, CH 2 NH 2 , —CH 2 NH(CH 3 ), —CH 2 NHCH 2 CH 2 OH, —CH 2 NH-(tetrahydro-2H-pyran), or —CH 2 NH—CH 2 -(1H-pyrrole), and
R 8 is H.

7. The compound of claim 1 , or a pharmaceutically acceptable salt, prodrug, solvate,
hydrate, or stereoisomer thereof, wherein:
R 3 is H or CH 3 .

8. The compound of claim 1 , or a pharmaceutically acceptable salt, prodrug, solvate,
hydrate, or stereoisomer thereof, wherein:
M is a bond.

9. The compound of claim 1 , or a pharmaceutically acceptable salt, prodrug, solvate,
hydrate, or stereoisomer thereof, wherein:
X and Y are each independently CH, C—R 7 , or N; and
R 7 is CH 3 .

10. The compound of claim 1 , or a pharmaceutically acceptable salt, prodrug, solvate,
hydrate, or stereoisomer thereof, wherein:
Z is N.

11. The compound of claim 1 , or a pharmaceutically acceptable salt, prodrug, solvate,
hydrate, or stereoisomer thereof, wherein:
R 5 is H, halogen, or C 1-6 alkyl.

12. The compound of claim 1 , or a pharmaceutically acceptable salt, prodrug, solvate,
hydrate, or stereoisomer thereof, wherein:
R 6 is H.

13. The compound of claim 2 , or a pharmaceutically acceptable salt, prodrug, solvate,
hydrate, or stereoisomer thereof, wherein:
R 4 is

which can be unsubstituted or substituted with 1-3 substituents selected from halogen or C 1-6 alkoxy.

14. The compound of claim 1 , or a pharmaceutically acceptable salt, prodrug, solvate,
hydrate, or stereoisomer thereof, wherein:
R 1 is phenyl, pyridyl, thienyl, or thiazolyl, which is unsubstituted or substituted with 1-3 substituents selected from halogen, C 1-6 alkyl, CN, hydroxyC 1-6 alkyl, or aminoC 1-6 alkyl, wherein the C 1-6 alkyl is unsubstituted or substituted with 1-3 substituents selected from halogen;
n is 0 or 1;
R 2 is C 1-6 alkyl, hydroxyC 1-6 alkyl, aminoC 1-6 alkyl, —C 1-6 alkyl-O—C 1-6 alkyl, —C 1-6 alkyl-NH—C 1-6 alkyl, —C 1-6 alkyl-N—(C 1-6 alkyl) 2 , —C 1-6 alkyl-NH—C 1-6 alkyl-OH, —C 1-6 alkyl-NH—C 1-6 alkyl-C 3-10 cycloalkyl, —C 1-6 alkyl-NH—C 1-6 alkyl-NH—C 1-6 alkyl, —C 1-6 alkyl-NH—C(O)—C 1-6 alkyl, —C 1-6 alkyl-O—

Assignees

• Asana Biosciences Llc
• Ansana Biosciences Llc

Inventors

• Venkatesan Aranapakam M
• Thompson Scott K
• Smith Roger A
• Reddy Sanjeeva P
• Kethiri Raghava Reddy
• Dewang Purushottam M
• Hallur Gurulingappa
• Mulakala Chandrika
• Mullangi Ramesh
• Zainuddin Mohd

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• C07D409/14

  containing three or more hetero rings · CPC title

• A61K31/506 Primary

  not condensed and containing further heterocyclic rings · CPC title

• C07D403/04 Primary

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D403/14

  containing three or more hetero rings · CPC title