Fused 2-aminothiazole compounds

Patent metadata

Field	Value
Publication number	US-9505784-B2
Application number	US-201414321242-A
Country	US
Kind code	B2
Filing date	Jul 1, 2014
Priority date	Jun 12, 2009
Publication date	Nov 29, 2016
Grant date	Nov 29, 2016

Abstract

The present application relates to therapeutic organic compounds, compositions comprising an effective amount of a therapeutic organic compound; and methods for treating and preventing disease comprising administering and effective amount of a therapeutic organic compound to a subject in need thereof.

First claim

The invention claimed is:

1. A compound of the Formula I:

or a pharmaceutically acceptable salt, enantiomer, stereoisomer, rotamer, tautomer, diastereomer, or racemate thereof;
wherein
Q is CH or N;
R 1 is H, C(O)—C 3-6 -cycloalkyl, aryl, heteroaryl, C(O)N(H)-heteroaryl, C(O)-heteroaryl, C(O)-heterocycle, C(O)-aryl, CO 2 —C 1-6 -alkyl, C 3-6 -cycloalkyl, or C(O)—C 1-6 -alkyl-heterocycle, wherein the aryl or heteroaryl groups can be substituted or unsubstituted;
R 2 is H, C 1-6 -alkyl, C 1-6 -alkoxy, or halogen;
R 3 is H, C(O)—N(H)-aryl, C(O)—N(H)—C 1-6 -alkyl-heterocycle, C(O)—N(H)—C 1-6 -alkyl-heteroaryl, wherein the aryl, heteroaryl or heterocyclic groups can be substituted or unsubstituted; and
R 4 is C(O)N(H)—C 1-6 -alkoxy or NH 2 .

2. The compound of claim 1 , wherein the aryl, heteroaryl and heterocyclic groups of R 1 and R 3 can optionally be independently substituted one or more times with OH, C 1-6 -alkyl, C 1-6 -alkoxy, C 1-6 -alkyl-heterocycle, C(O)—C 1-6 -alkyl, CO 2 —C 1-6 -alkyl, aryl, heteroaryl, heterocycle, SO 2 -heterocycle, SO 2 -aryl, SO 2 -heteroaryl, C 1-6 -alkyl-aryl, C 1-6 -alkyl-heteroaryl, CF 3 , or halogen;
wherein the substituent aryl, heteroaryl and heterocyclic groups can be further independently substituted one or more times with OH, C 1-6 -alkyl, C 1-6 -alkoxy, C(O)—C 1-6 -alkyl, CO 2 —C 1-6 -alkyl, aryl, heteroaryl, heterocycle, SO 2 -heterocycle, SO 2 -aryl, SO 2 -heteroaryl, C 1-6 -alkyl-heterocycle, C 1-6 -alkyl-aryl, C 1-6 -alkyl-heteroaryl, CF 3 , or halogen.

3. The compound of claim 1 , wherein the aryl, heteroaryl and heterocyclic groups of R 1 and R 3 can optionally be independently substituted one or more times with C 1-6 -alkyl, C 1-6 -alkoxy, SO 2 -heterocycle, C 1-6 -alkyl-heterocycle, heterocycle, CF 3 , or heteroaryl;
wherein the substituent heterocyclic and heteroaryl groups can be optionally further independently substituted one or more times with OH, C 1-6 -alkyl, C 1-6 -alkoxy, C 1-6 -alkyl-OH, or C(O)—C 1-6 -alkyl.

4. The compound of claim 1 , wherein
R 1 is H, C(O)—C 3-6 -cycloalkyl, pyrimidine, C(O)-piperidine, C 3-6 -cycloalkyl, pyridine, phenyl, C(O)-phenyl, C(O)—C 1-6 -alkyl-piperazine, or C(O)-oxazolidinone;
wherein the pyrimidine, piperidine, pyridine, and phenyl groups of R 1 can be optionally independently substituted one or more times with OH, C 1-6 -alkyl, C 1-6 -alkoxy, C(O)—C 1-6 -alkyl, CO 2 —C 1-6 -alkyl, aryl, heteroaryl, heterocycle, SO 2 -heterocycle, SO 2 -aryl, SO 2 -heteroaryl, C 1-6 -alkyl-heterocycle, C 1-6 -alkyl-aryl, C 1-6 -alkyl-heteroaryl, CF 3 , or halogen; and
wherein the substituent aryl, heteroaryl and heterocyclic groups can optionally be further independently substituted one or more times with OH, C 1-6 -alkyl, C 1-6 -alkoxy, C 1-6 -alkyl-OH, or C(O)—C 1-6 -alkyl.

5. The compound of claim 1 , wherein
R 3 is H, C(O)—N(H)-phenyl, C(O)—N(H)—(CH 2 ) 2 -morpholino, C(O)—N(H)—C 1-6 -alkyl-morpholino, or C(O)—N(H)—C 1-6 -alkyl-imidazole;
wherein the morpholino, imidazole, and phenyl groups of R 3 can optionally be independently substituted one or more times with OH, C 1-6 -alkyl, C 1-6 -alkoxy, C(O)—C 1-6 -alkyl, CO 2 —C 1-6 -alkyl, aryl, heteroaryl, heterocycle, SO 2 -heterocycle, SO 2 -aryl, SO 2 -heteroaryl, C 1-6 -alkyl-heterocycle, C 1-6 -alkyl-aryl, C 1-6 -alkyl-heteroaryl, CF 3 , or halogen; and
wherein the substituent aryl, heteroaryl and heterocyclic groups can optionally be further independently substituted one or more times with OH, C 1-6 -alkyl, C 1-6 -alkoxy, C 1-6 -alkyl-OH, or C(O)—C 1-6 -alkyl.

6. The compound of claim 1 , wherein
R 1 is C(O)—C 3-6 -cycloalkyl, pyrimidine, C(O)-piperidine, H, C 3-6 -cycloalkyl, pyridine, Ph-SO 2 -piperazine, C(O)-PhCH 2 -piperazine-C 1-6 -alkyl, C(O)—C 1-6 -alkyl-piperazine, Ph-piperazine-C 1-6 -alkyl, C(O)-oxazolidinone-C 1-6 -alkyl-morpholino, wherein the pyrimidine group is optionally independently substituted one or more times with C 1-6 -alkyl or piperazine, wherein the piperazine of the pyrimidine group is optionally substituted with C 1-6 -alkyl-OH; and wherein the C(O)—C 1-6 -alkyl-piperazine is optionally substituted with C(O)C 1-6 -alkyl.

7. The compound of claim 1 , wherein R 3 is H, C(O)—N(H)-Ph, C(O)—N(H)—C 1-6 -alkyl-morpholino, or C(O)—N(H)—C 1-6 -alkyl-imidazole, wherein Ph is optionally substituted one or more times with CF 3 , C 1-6 -alkyl-piperazine-C 1-6 -alkyl, or imidazole-C 1-6 -alkyl.

8. The compound of claim 1 , wherein
R 1 is C(O)-cyclopropyl, pyrimidine, C(O)-piperidine, H, cyclopropyl, pyridine, Ph-SO 2 -piperazine, C(O)-PhCH 2 -piperazine-CH 2 CH 3 , C(O)—(CH 2 ) 2 -piperazine, Ph-piperazine-CH 3 , or C(O)-oxazolidinone-(CH 2 ) 3 -morpholino, wherein the pyrimidine is substituted with CH 3 and piperazine, wherein the piperazine of the pyrimidine is optionally substituted with (CH 2 ) 2 OH, and wherein the piperazine of the C(O)—(CH 2 ) 2 -piperazine group is optionally substituted with C(O)CH 3 ;
R 2 is H, CH 3 , F or Cl;
R 3 is H, C(O)—N(H)-Ph, C(O)—N(H)—(CH 2 ) 2 -morpholino, C(O)—N(H)—(CH 2 ) 3 -morpholino, or C(O)—N(H)—(CH 2 ) 3 -imidazole, wherein Ph is substituted with CF 3 and CH 2 -piperazine-CH 2 CH 3 , or CF 3 and imidazole-CH 3 ; and
R 4 is C(O)N(H)OCH 3 or NH 2 .

9. The compound of claim 1 , wherein Formula I is represented by the Formula II:

or a pharmaceutically acceptable salt, enantiomer, stereoisomer, rotamer, tautomer, diastereomer, or racemate thereof, wherein
Q is CH;
R 1 is C(O)—C 3-6 -cycloalkyl, C(O)N(H)-heteroaryl, C(O)-heteroaryl, C(O)-aryl, CO 2 —C 1-6 -alkyl, C 3-6 -cycloalkyl, or C(O)—C 1-6 -alkyl-heteroaryl;
R 2 and R 3 are H; and
R 4 is C(O)N(H)—C 1-6 -alkoxy or NH 2 ;
wherein each of the aryl and heteroaryl groups is substituted or unsubstituted.

10. The compound of claim 9 , wherein
R 1 is C(O)—C 3-6 -cycloalkyl;
Q is C(H); and
R 2 and R 3 are H.

11. The compound of claim 1 , wherein the compound is of Formula:

or a pharmaceutically acceptable salt, enantiomer, stereoisomer, rotamer, tautomer, diastereomer, or racemate thereof.

12. A method of treating cancer, comprising administering to a subject in need thereof a compound of claim 1 , wherein the cancer is selected from the group consisting of multiple myeloma, chronic myelogenous leukemia, pancreatic cancer, non-small cell lung cancer, lung cancer, breast cancer, colon cancer, ovarian cancer, prostate cancer, malignant melanoma, non-melanoma skin cancers, gastrointestinal stromal tumors, hematologic tumors, hematologic malignancies, childhood leukemia, childhood lymphomas, Hodgkin's disease, lymphomas of lymphocytic origin, lymphomas of cutaneous origin, acute leukemia, chronic leukemia, acute lymphoblastic leukemia, acute myelocytic leukemia, chronic myelocytic leukemia, plasma cell neoplasm, lymphoid neoplasm and cancers associated with AIDS.

13. The method of claim 12 , wherein the cancer is pancreatic cancer or non-small cell lung cancer.

14. The method of claim 12 , wherein the cancer is gastrointestinal stromal tumor or chronic myelogenous leukemia.

15. The method of claim 12 , wherein the cancer is resistant to treatment with Gleevec (Imatinib mesylate) or Imatinib.

16. The method of claim 15 , wherein treatment

Assignees

• Dana Farber Cancer Inst Inc

Inventors

• Choi Hwan Geun
• Sim Taebo
• Gray Nathanael
• Zhou Wenjun
• Chang Jae Won
• Zhang Jianming
• Weisberg Ellen

Classifications

• A61P37/02

  Immunomodulators · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P35/04

  specific for metastasis · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title