Thiazole derivatives useful as mutant IDH1 inhibitors for treating cancer

Patent metadata

Field	Value
Publication number	US-10836759-B2
Application number	US-201716312206-A
Country	US
Kind code	B2
Filing date	Jun 21, 2017
Priority date	Jun 22, 2016
Publication date	Nov 17, 2020
Grant date	Nov 17, 2020

Abstract

A compound of Formula II or a pharmaceutically acceptable salt thereof, wherein CyN is a cyclic amine group bound via a nitrogen atom; X is C or N; R 1 and R 2 are each independently a halogen, CN, CF 3 , CHF 2 , CH 2 F, a C 1 -C10alkyl group, a C1-C 10 alkoxy group, a di(C 1 -C 5 alkyl)amino; m and n are each independently 1, 2, or 3, and represents either a single bond or a double bond, wherein the racemic mixture of 3-(4-(4-chlorophenyl)thiazol-2-yl)-1-(2-ethyl-5-methoxyphenyl)-6-(2-methylprop-1-en-1-yl)-5-(piperazine-1-carbonyl)pyridin-2(1H)-one atropisomers is excluded.

First claim

What is claimed is:

1. A compound of Formula II:

or a pharmaceutically acceptable salt thereof, wherein
CyN is a cyclic amine group bound via a nitrogen atom that is optionally substituted with one or more substituents independently chosen from halogen, C 1 -C 2 alkyl, and C 1 -C 2 alkoxy;
X is C or N;
R 1 and R 2 are each independently a halogen, CN, CF 3 , CHF 2 , CH 2 F, a C 1 -C 10 alkyl group, a C 1 -C 10 alkoxy group, a di(C 1 -C 5 alkyl)amino;
m and n are each independently 1, 2, or 3; and
represents either a single bond or a double bond,
wherein the racemic mixture of 3-(4-(4-chlorophenyl)thiazol-2-yl)-1-(2-ethyl-5-methoxyphenyl)-6-(2-methylprop-1-en-1-yl)-5-(piperazine-1-carbonyl)pyridin-2(1H)-one atropisomers is excluded.

2. The compound or salt of claim 1 , wherein the compound is an atropisomer of Formula II-A:

wherein at least one R 1 group is an ortho substituent and the atropisomer of Formula II-A is present in excess of its corresponding enantiomer.

3. The compound or salt of claim 1 , wherein the compound is an atropisomer compound of Formula II-B:

wherein at least on R 1 group is an ortho substituent and the atropisomer of Formula II-B is present in excess of its corresponding enantiomer.

4. The compound or salt of claim 1 , wherein the compound is an atropisomer of Formula II-C:

wherein at least one R 1 group is an ortho substituent and the atropisomer of Formula II-C is present in excess of its corresponding enantiomer.

5. The compound or salt of claim 1 , wherein the compound is an atropisomer compound of Formula II-D:

wherein at least on R 1 group is an ortho substituent and the atropisomer of Formula II-D is present in excess of its corresponding enantiomer.

6. The compound or salt of claim 1 , wherein m is 1 and R 2 is a 4-substituent.

7. The compound or salt of claim 1 , wherein R 2 is 4-Cl, 4-CF 3 , 4-CHF 2 , 4-CH 3 O, or 4-CN.

8. The compound or salt of claim 1 , wherein X is C and R 2 is 4-Cl, 4-CF 3 , 4-CHF 2 , or 4-NC; or.
X is N and R 2 is 4-CF 3 , 4-CHF 2 , or 4-CH 3 O.

9. The compound or salt of claim 1 wherein n is 2 and R 1 is 2-C 2 H 5 , 5-CH 3 O; or 2-C 2 H 5 , 5-Cl; or 2-Cl, 5-(CH 3 ) 2 N; or 2-C 2 H 5 O, 5-C 2 H 50 ; or 2-C 2 H 5 O, 5-Cl; or 3-C 2 H 5 O, 5-NC, or di-2,6-C 2 H 5 .

10. The compound or salt of claim 1 , wherein CyN— is:

11. The atropisomer compound or salt thereof, of claim 2 , wherein the atropisomer compound is one of the following compounds:

12. The atropisomer compound or salt of claim 3 , wherein the atropisomer compound is one of the following compounds:

13. The atropisomer compound or salt thereof, of claim 4 , wherein the atropisomer compound is one of the following compounds:

14. The atropisomer compound or salt thereof, of claim 5 , wherein the atropisomer compound is one of the following compounds:

15. A pharmaceutical composition comprising a compound or salt of claim 1 , together with a pharmaceutically acceptable carrier.

16. A method of treating a cancer characterized by the presence of an IDH1 mutation, wherein the IDH1 mutation results in a new ability of the enzyme to catalyze the NADPH-dependent reduction of α-ketoglutarate to R(−)-2-hydroxyglutarate in a patient, comprising the step of providing to a patient in need thereof a therapeutic agent, wherein the therapeutic agent is a compound or salt thereof of claim 1 .

17. The method of claim 16 , wherein the IDH1 mutation is an IDH1 R132H or IDH1 R132C mutation.

18. The method of claim 16 , wherein the cancer is selected from glioma (glioblastoma), acute myelogenous leukemia, acute myeloid leukemia, myelodysplastic/myeloproliferative neoplasms, sarcoma, chronic myelomonocytic leukemia, non-Hodgkin lymphoma, astrocytoma, melanoma, non-small cell lung cancer, cholangiocarcinomas, chondrosarcoma, or colon cancer.

19. A method of treating Ollier disease or Maffuci syndrome, comprising providing a therapeutic agent to a patient in need thereof, wherein the therapeutic agent is a compound or salt thereof of claim 1 .

20. The method of claim 16 , further comprising administering to the patient in need thereof at least one additional therapeutic agent.

Assignees

• Us Health
• Univ North Carolina Chapel Hill

Inventors

• Boxer Matthew Brian
• Wang Xiaodong
• Brimacombe Kyle Ryan
• Davis Mindy Irene Emily
• Fang Yuhong
• Hall Matthew
• Jadhav Ajit
• Karavadhi Surendra
• Liu Li
• Martinez Natalia
• Mciver Andrew Louis
• Pragani Rajan
• Rohde Jason Matthew
• Simeonov Anton
• Zhao Wei
• Shen Min

Classifications

• C07D417/04

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

• A61K31/4995

  Pyrazines or piperazines forming part of bridged ring systems · CPC title

• A61P35/02

  specific for leukemia · CPC title

• C07D487/08

  Bridged systems · CPC title

• A61K31/496

  Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin · CPC title