Triazole compounds that modulate HSP90 activity

Patent metadata

Field	Value
Publication number	US-9539243-B2
Application number	US-201514591092-A
Country	US
Kind code	B2
Filing date	Jan 7, 2015
Priority date	Aug 8, 2008
Publication date	Jan 10, 2017
Grant date	Jan 10, 2017

Abstract

The present invention relates to substituted triazole compounds and compositions comprising substituted triazole compounds. The invention further relates to methods of inhibiting the activity of Hsp90 in a subject in need thereof and methods for treating hyperproliferative disorders, such as cancer, in a subject in need thereof comprising administering to the subject a substituted triazole compound of the invention, or a pharmaceutical composition comprising such a compound.

First claim

What is claimed is:

1. A method of treating cancer in a subject in need thereof, wherein the cancer is selected the group consisting of myeloid leukemia, T cell leukemia, B cell leukemia, chronic myeloid leukemia, acute myelocytic leukemia, non-Hodgkin's lymphoma, multiple myeloma, non-small cell lung cancer, small cell lung cancer, melanoma, gastrointestinal stromal tumors, gastric cancer, breast cancer, renal cell carcinoma, prostate cancer, colon carcinoma, mesothelioma, pancreatic cancer and ovarian cancer, comprising administering to the subject an effective amount of a compound according to the structural formula:

or a pharmaceutically acceptable salt thereof; wherein:
R 1 is H, OR 12 or C 1 -C 3 alkyl;
R 2 is OR 12 or halo;
R 3 is H, C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl;
m is 0 or 1;
R 7 is phenyl, S(O) p R 10 , OR 10 , N(R 10 ) 2 or ═NN(R 10 ) 2 ;
R 5 and R 6 are individually hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, 5-7 membered heterocyclyl, phenyl, benzyl, 5-7 membered heteroaryl, —N(R 12 ) 2 , —C(O)R 12 , —C(O)OR 12 , —S(O) p R 12 , or —S(O) p N(R 12 ) 2 , wherein each R 5 and R 6 that is not hydrogen is optionally and independently substituted with one or more R 20 ; or R 5 and R 6 , taken together with the nitrogen to which they are attached, form a 5-7 membered heterocyclyl which is optionally substituted with one or more R 20 ;
each R 10 is independently selected from H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, 5-14 membered heterocyclyl, C 6 -C 20 aryl, 5-14 membered heteroaryl, —OR 12 , —N(R 12 ) 2 , —C(O)R 12 , —C(O)OR 12 , —C(S)R 12 , —C(O)SR 12 , —C(O)N(R 12 ) 2 , —C(S)N(R 12 ) 2 , —C(NR 12 )OR 12 , —C(NR 12 )R 12 , —C(NR 12 )N(R 12 ) 2 , —C(NR 12 )SR 12 , —S(O) p R 12 , —S(O) p OR 12 or —S(O) p N(R 12 ) 2 , wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl represented by R 10 are independently and optionally substituted by one or more R 20 ; or two R 10 moieties attached to the same nitrogen atom are taken together to form a 5-14 membered heterocyclyl or a 5-14 membered heteroaryl, each of which are optionally and independently substituted with one or more R 20 ;
each R 12 is independently H, C 1 -C 3 alkyl, C 2 -C 3 alkenyl, C 1 -C 3 haloalkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy, C 3 -C 7 cycloalkyl, phenyl, or benzyl, wherein each R 12 with at least one hydrogen atom is optionally substituted with one or more R 20 ; or two R 12 substituents that are attached to the same atom or adjacent atoms, taken together with the atom(s) to which they are attached, form a 5-7 membered heterocyclyl or C 3 -C 7 cycloalkyl which are each optionally and independently substituted with one or more R 20 ; and
each R 20 is independently selected from the group consisting of C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, 5-14 membered heterocyclyl, C 6 -C 20 aryl, 5-14 membered heteroaryl, C 3 -C 7 cycloalkyl-(C 1 -C 3 )alkyl, 5-14 membered heterocyclyl-(C 1 -C 3 )alkyl, C 6 -C 20 aryl-(C 1 -C 3 )alkyl, 5-14 membered heteroaryl-(C 1 -C 3 )alkyl, halo, cyano, nitro, azido, —N(R 12 ) 2 , —OR 12 , —C(O)R 12 , —C(O)OR 12 , —C(S)R 12 , —C(O)SR 12 , —C(S)SR 12 , —C(S)OR 12 , —C(O)N(R 12 ) 2 , —C(S)N(R 12 ) 2 , —C(NR 12 )OR 12 , —C(NR 12 )R 12 , —C(NR 12 )N(R 12 ) 2 , —C(NR 12 )SR 12 , —OC(O)N(R 12 ) 2 , —OC(O)R 12 , —OC(O)OR 12 , —OC(S)OR 12 , —OC(NR 12 )OR 12 , —SC(O)R 12 , —SC(O)OR 12 , —SC(NR 12 )OR 12 , —OC(S)R 12 , —SC(S)R 12 , —SC(S)OR 12 , —OC(O)N(R 12 ) 2 , —OC(S)N(R 12 ) 2 , —OC(NR 12 )NR 12 ) 2 , —SC(O)N(R 12 ) 2 , —SC(NR 12 )N(R 12 ) 2 , —SC(S)N(R 12 ) 2 , —OC(NR 12 )R 12 , —SC(NR 12 )R 12 , —NR 12 C(O)R 12 , —NR 12 C(S)R 12 , —NR 12 C(S)OR 12 , —NR 12 C(NR 12 )R 12 , —NR 12 C(O)OR 12 , —NR 12 C(NR 12 )OR 12 , —NR 12 C(O)N(R 12 ) 2 , —NR 12 C(S)N(R 12 ) 2 , —NR 12 C(NR 12 )N(R 12 ) 2 , —S(O) p R 12 , —OS(O) p R 12 , —OS(O) p OR 12 , —OS(O) p N(R 12 ) 2 , —S(O) p OR 12 , —NR 12 S(O) p R 12 , —NR 12 S(O) p N(R 12 ) 2 , —NR 12 S(O) p OR 12 , —S(O) p N(R 12 ) 2 , —SS(O) p R 12 , —SS(O) p OR 12 , —SS(O) p N(R 12 ) 2 , —OP(O)(OR 12 ) 2 , or —SP(O)(OR 12 ) 2 , wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, and heteroaralkyl represented by R 20 are each optionally and independently substituted with one to three groups from halo, C 1 -C 3 alkyl, phenyl, benzyl, C 1 -C 3 haloalkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy, nitro, cyano, azido, amino and C 1 -C 5 carbamoyl; or two R 20 moieties attached to the same atom form an oxo (═O), thioxo (═S) or imino (═NR 12 );
provided that one of R 1 and R 3 is hydrogen.

2. A method of treating cancer in a subject in need thereof, wherein the cancer is selected the group consisting of myeloid leukemia, T cell leukemia, B cell leukemia, chronic myeloid leukemia, acute myelocytic leukemia, non-Hodgkin's lymphoma, multiple myeloma, non-small cell lung cancer, small cell lung cancer, melanoma, gastrointestinal stromal tumors, gastric cancer, breast cancer, renal cell carcinoma, prostate cancer, colon carcinoma, mesothelioma, pancreatic cancer and ovarian cancer, comprising administering to the subject an effective amount of a compound according to the structural formula:

or a pharmaceutically acceptable salt thereof; wherein:
m is 0 or 1;
r is 0, 1 or 2;
R 8 is C 1 -C 3 alkyl or C 1 -C 3 haloalkyl;
R 3 is H, C 1 -C 4 alkyl or C 3 -C 6 cycloalkyl;
R 7 is phenyl, S(O) p R 31 , OR 31 , N(R 31 ) 2 or ═NN(R 31 ) 2 ;
R 13 and R 14 are individually hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, 5-7 membered heterocyclyl, phenyl, benzyl, 5-7 membered heteroaryl, —N(R 32 ) 2 , —C(O)R 32 , —C(O)OR 32 , —S(O) p R 32 , or —S(O) p N(R 32 ) 2 , wherein each R 13 and R 14 that is not hydrogen is optionally and independently substituted with one or more R 21 ; or R 13 and R 14 , taken together with the nitrogen to which they are attached, form a 5-7 membered heterocyclyl which is optionally substituted with one or more R 21 ;
each R 31 is independently selected from H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, 5-14 membered heterocyclyl, C 6 -C 20 aryl, 5-14 membered heteroaryl, —OR 32 , —C(O)R 32 , —C(O)OR 32 , —C(S)R 32 , —C(O)SR 32 , —C(O)N(R 32 ) 2 , —C(S)N(R 32 ) 2 , —C(NR 32 )OR 32 , —C(NR 32 )R 32 , —C(NR 32 )N(R 32 ) 2 , —C(NR 32 )SR 32 , —S(O) p R 32 , —S(O) p OR 32 or —S(O) p N(R 32 ) 2 , wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl represented by R 31 are independently and optionally substituted by one or more R 21 ; or two R 31 moieties attached to the same nitrogen atom are taken together to form a 5-14 membered heterocyclyl or a 5-14 membered heteroaryl, each of which are optionally and independently substituted with one or more R 21 ;
each R 32 is independently H, C 1 -C 3 alkyl, C 2 -C 3 alkenyl, C 1 -C 3 haloalkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy, C 3 -C 7 cycloalkyl, phenyl, or benzyl, wherein each R 32 with at least one hydrogen atom is optionally substituted with one or more R 21 ; or two R 32 substituents that are attached to the same atom or adjacent atoms, taken together with the atom(s) to which they are attached, form a 5-7 membered heterocyclyl or C 3 -C 7 cycloalkyl which are each optionally and independently substituted with one or more R 21 ; and
each R 21 is independently selected from the group

Assignees

• Synta Pharmaceuticals Corp

Inventors

• Burlison Joseph
• Zhang Shijie
• Ying Weiwen
• Chimmanamada Dinesh U
• Song Minghu
• Chae Junghyun
• Schweizer Stefan M

Classifications

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61K31/5377

  not condensed and containing further heterocyclic rings, e.g. timolol · CPC title

• A61K31/635

  having a heterocyclic ring, e.g. sulfadiazine · CPC title

• C07D405/04

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

• C07D401/14

  containing three or more hetero rings · CPC title