Inhibitors of erk and methods of use

Patent metadata

Field	Value
Publication number	US-2017226110-A1
Application number	US-201715439719-A
Country	US
Kind code	A1
Filing date	Feb 22, 2017
Priority date	Oct 3, 2013
Publication date	Aug 10, 2017
Grant date	—

Abstract

The present invention provides chemical entities or compounds and pharmaceutical compositions thereof that are capable of modulating certain protein kinases such as ERK (MAPK). Also provided are methods of using such compounds or compositions, and methods of using these compositions to modulate the activities of one or more of these kinases, especially for therapeutic applications such as the treatment disorders such as cancer.

First claim

What is claimed is:

1 - 64 . (canceled)

65 . A compound of Formula II-E:

or a pharmaceutically acceptable salt or prodrug thereof, wherein:
R 1 is 3- to 6-membered heterocyclyl, —C 1-10 alkyl-(3- to 6-membered heterocyclyl), -(3- to 6-membered heterocyclyl)-C 1-10 alkyl, -(3- to 6-membered heterocyclyl)-C 3-10 aryl, or -(3- to 6-membered heterocyclyl)-C 1-10 hetaryl, each of which is unsubstituted or substituted by one or more independent R 10 or R 11 substituents;
R 21 is halogen, -L-C 1-10 heteroalkyl, -L-C 3-10 aryl, -L-C 1-10 hetaryl, -L-C 3-10 cycloalkyl, -L-C 1-10 heterocyclyl, -L-C 1-10 alkyl-C 3-10 aryl, -L-C 1-10 alkyl-C 1-10 hetaryl, -L-C 1-10 alkyl-C 3-10 cycloalkyl, -L-C 1-10 alkyl-C 1-10 heterocyclyl, -L-C 2-10 alkenyl-C 3-10 aryl, -L-C 2-10 alkenyl-C 1-10 hetaryl, -L-C 2-10 alkenyl-C 3-10 cycloalkyl, -L-C 2-10 alkenyl-C 1-10 heterocyclyl, -L-C 2-10 alkynyl-C 3-10 aryl, -L-C 1-10 heteroalkyl-C 3-10 aryl, -L-C 1-10 heteroalkyl-C 1-10 hetaryl, -L-C 1-10 heteroalkyl-C 3-10 cycloalkyl, or -L-C 1-10 heteroalkyl-C 1-10 heterocyclyl, each of which is substituted by one or more independent R 12 substituents;
L is a bond, —O—, —N(R 31 )—, —S(O) 0-2 —, —C(═O)—, —C(═O)O—, —OC(═O)—, —C(═O)N(R 31 )—, —N(R 31 )C(═O)—, —NR 31 C(═O)O—, —NR 31 C(═O)NR 32 —, —NR 31 S(O) 0-2 —, —S(O) 0-2 N(R 31 )—, —C(═S)O—, —C(═O)S—, —NR 31 C(═NR 32 )NR 32 —, —NR 31 C(═NR 32 )O—, —NR 31 C(═NR 32 )S—, —OC(═O)O—, —OC(═O)NR 31 —, —OC(═O)S—, —SC(═O)S—, —P(O)OR 31 O—, or —SC(═O)NR 31 —;
R 72 is hydrogen, —C 1-10 alkyl, —C 2-10 alkenyl, —C 2-10 alkynyl, —C 1-10 heteroalkyl, —C 3-10 aryl, —C 1-10 hetaryl, —C 3-10 cycloalkyl, —C 1-10 heterocyclyl, —OH, —CF 3 , —C(O)R 31 , —CO 2 R 31 , —C(═O)NR 31 , —S(O) 0-2 R 31 , —C(═S)OR 31 , or —C(═O)SR 31 ;
R 10 is —C 1-10 alkyl, —C 2-10 alkenyl, —C 2-10 alkynyl, —C 1-10 heteroalkyl, —C 3-10 aryl, —C 1-10 hetaryl, —C 3-10 cycloalkyl, or —C 1-10 heterocyclyl, each of which is optionally substituted by one or more independent R 11 substituents;
R 11 and R 12 are independently hydrogen, halogen, —C 1-10 alkyl, —C 2-10 alkenyl, —C 2-10 alkynyl, —C 1-10 heteroalkyl, —C 3-10 aryl, —C 1-10 hetaryl, —C 3-10 cycloalkyl, —C 1-10 heterocyclyl, —OH, —CF 3 , —OCF 3 , —OR 31 , —NR 31 R 32 , —C(O)R 31 , —CO 2 R 31 , —C(═O)NR 31 , —NO 2 , —CN, —S(O) 0-2 R 31 , —SO 2 NR 31 R 32 , —NR 31 C(═O)R 32 , —NR 31 C(═O)OR 32 , —NR 31 C(═O)NR 32 R 33 , —NR 31 S(O) 0-2 R 32 , —C(═S)OR 31 , —C(═O)SR 31 , —NR 31 C(═NR 32 )NR 32 R 33 , —NR 31 C(═NR 32 )OR 33 , —NR 31 C(═NR 32 )SR 33 , —OC(═O)OR 33 , —OC(═O)NR 31 R 32 , —OC(═O)SR 31 , —SC(═O)SR 31 , —P(O)OR 31 OR 32 , or —SC(═O)NR 31 NR 32 ; and
each of R 3 , R 32 , and R 33 is independently hydrogen, halogen, —C 1-10 alkyl, —C 2-10 alkenyl, —C 2-10 alkynyl, —C 1-10 heteroalkyl, —C 3-10 aryl, —C 1-10 hetaryl, —C 3-10 cycloalkyl, or —C 1-10 heterocyclyl, or —R 31 together with R 32 form a heterocyclic ring.

66 . The compound of claim 65 , wherein R 21 is halogen, -L-C 1-10 heteroalkyl, -L-C 3-10 aryl, -L-C 1-10 hetaryl, -L-C 3-10 cycloalkyl, or -L-C 1-10 heterocyclyl, each of which is substituted by one or more independent R 12 substituents.

67 . The compound of claim 65 , wherein L is a bond, —O—, —N(R 31 )—, —S(O) 0-2 —, —C(═O)—, —C(═O)O—, —OC(═O)—, —C(═O)N(R 31 )—, or —N(R 3 )C(═O)—.

68 . The compound of claim 65 , wherein L is a bond.

69 . The compound of claim 65 , wherein R 21 is -L-C 1-10 hetaryl substituted by one or more independent R 12 substituents; and wherein L is a bond.

70 . The compound of claim 69 , wherein the C 1-10 hetaryl of R 21 is selected from the group consisting of pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, and pyridazinyl.

71 . The compound of claim 69 , wherein each R 12 substituent is independently selected from the group consisting of —C 1-10 alkyl, —C 2-10 alkenyl, —C 2-10 alkynyl, —C 1-10 heteroalkyl, —C 3-10 aryl, —C 1-10 hetaryl, —C 3-10 cycloalkyl, —C 1-10 heterocyclyl, —OH, —CF 3 , —OCF 3 , and —OR 31 ; wherein each R 31 is independently hydrogen or —C 1-10 alkyl.

72 . The compound of claim 71 , wherein each R 12 substituent is independently selected from the group consisting -Me, -Et, -i-Pr, -n-Pr, OH, —OMe, —OEt, and —OPr.

73 . The compound of claim 65 , wherein R 1 is 3- to 6-membered heterocyclyl, unsubstituted or substituted by one or more independent R 10 or R 11 substituents.

74 . The compound of claim 65 , wherein R 1 is -(3- to 6-membered heterocyclyl)-C 1-10 alkyl, unsubstituted or substituted by one or more independent R 10 or R 11 substituents.

75 . The compound of claim 65 , wherein R 1 is -(3- to 6-membered heterocyclyl)-C 3-10 aryl, unsubstituted or substituted by one or more independent R 10 or R 11 substituents.

76 . The compound of claim 65 , wherein R 1 is

unsubstituted or substituted by one or more independent R 10 or R 11 substituents.

77 . The compound of claim 65 , wherein R 1 is substituted with one or more R 10 substituents.

78 . The compound of claim 77 , wherein each R 10 is independently —C 1-10 alkyl, —C 3-10 aryl, —C 1-10 hetaryl, —C 3-10 cycloalkyl, or —C 1-10 heterocyclyl.

79 . The compound of claim 65 , wherein R 72 is H.

80 . A pharmaceutical composition comprising the compound of claim 65 and a pharmaceutically acceptable excipient.

81 . The pharmaceutical composition of claim 80 , wherein the composition is formulated in an oral dosage.

82 . A method of inhibiting activity of a protein kinase, comprising contacting the protein kinase with the compound of claim 65 .

83 . The method of claim 82 , wherein the protein kinase is ERK.

84 . A method of treating cancer in a subject in need thereof, comprising administering to the subject an effect amount of the compound of claim 65 , wherein the cancer is selected from the group consisting of breast cancer, pancreatic cancer, non-small cell lung cancer (NSCLC), thyroid cancer, seminomas, melanoma, bladder cancer, liver cancer, kidney cancer, myelodysplastic syndrome (MDS), acute myelogenous leukemia (AML), and colorectal cancer.

85 . A compound of Formula II-E:

or a pharmaceutically acceptable salt or prodrug thereof, wherein:
R 1 is —C 2-10 alkenyl, —C 2-10 alkynyl, —C 3-10 aryl, —C 1-10 hetaryl, —C 3-10 cycloalkyl, —C 1-10 heterocyclyl, —C 1-10 alkyl-C 3-10 cycloalkyl, —C 1-10 alkyl-C 1-10 heterocyclyl, —C 2-10 alkenyl-C 3-10 aryl, —C 2-10 alkenyl-C 1-10 hetaryl, —C 2-10 alkenyl-C 3-10 cycloalkyl, —C 2-10 alkenyl-C 1-10 heterocyclyl, —C 2-10 alkynyl-C 3-10 aryl, —C 2-10 alkynyl-C 1-10 hetaryl, —C 2-10 alkynyl-C 3-10 cycloalkyl, —C 2-10 alkynyl-C 1-10 heterocyclyl, —C 1-10 alkoxy-C 1-10 hetaryl, —C 1-10 alkoxy-C 3-10 cycloalkyl, —C 1-10 alkoxy-C 1-10 heterocyclyl, —C 1-10 heteroalkyl-C 1-10 hetaryl, —C 1-10 heteroalkyl-C 3-10 cycloalkyl, —C 1-10 heteroalkyl-C 1-10 heterocyclyl, —C 3-10 aryl-C 1-10 alkyl, —C 3-10 aryl-C 2-10 alkenyl, —C 3-10 aryl-C 2-10 alkynyl, —C 3-10 aryl-C 3-10 hetaryl, —C 3-10 aryl-C 3-10 cycloalkyl, —C 3-10 aryl-C 1-10 heterocyclyl, —C 1-10 hetaryl-C 1-10 alkyl, —C 1-10 hetaryl-C 2-10 alkenyl, —C 1-10 hetaryl-C 2-10 alkynyl, —C 3-10 hetaryl-C 3-10 aryl

Assignees

• Kura Oncology Inc

Inventors

• Li Liansheng
• Wu Tao
• Feng Jun
• Ren Pingda
• Liu Yi

Classifications

• C07D519/00

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• A61K31/4745

  condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines (yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48) · CPC title

• A61K31/4439 Primary

  containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465) · CPC title

• A61K31/513

  having oxo groups directly attached to the heterocyclic ring, e.g. cytosine · CPC title

• A61K31/5517

  condensed with five-membered rings having nitrogen as a ring hetero atom, e.g. imidazobenzodiazepines, triazolam · CPC title