Compounds and methods for treating cancer

Patent metadata

Field	Value
Publication number	US-9725425-B1
Application number	US-201514631632-A
Country	US
Kind code	B1
Filing date	Feb 25, 2015
Priority date	Feb 25, 2014
Publication date	Aug 8, 2017
Grant date	Aug 8, 2017

Abstract

Provided are small molecule inhibitors of ubiquitin specific protease 2, 8 and 12 (USP2 and USP8 and USP12) activity and methods for their use in treating cancers. The small molecule inhibitors of the invention are particularly useful in the treatment of non-small cell lung cancers that are resistant to tyrosine kinase inhibitors and in the treatment of prostate cancer that is resistant to AR inhibitor therapy.

First claim

What is claimed is:

1. A method for treating non-small cell lung cancer, the method comprising:
administering to a subject in need thereof a compound according to Formula A:

or pharmaceutically acceptable salt thereof,
wherein
n is 0, 1, 2, 3, or 4;
each occurrence of R 1 is independently hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; —OR A1 ; —C(═O)R A1 ; —C(═O)N(R A1 ) 2 ; —CO 2 R A1 ; —CN; —SCN; —SR A1 ; —SOR A1 ; —SO 2 R A1 ; —NO 2 ; —N 3 ; —N(R A1 ) 2 ; —NHC(═O)R A1 ; —NR A1 C(═O)N(R A1 ) 2 ; —OC(═O)OR A1 ; —OC(═O)R A1 ; —OC(═O)N(R A1 ) 2 ; —NR A1 C(═O)OR A1 ; or —C(R A1 ) 3 ;
each occurrence of R A1 is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR A2 , —N(R A2 ) 2 , —SR A2 , —CN, —SCN, —C(═NR A2 )R A2 , —C(═NR A2 )OR A2 , —C(═NR A2 )N(R A2 ) 2 , —C(═O)R A2 , —C(═O)OR A2 , —C(═O)N(R A2 ) 2 , —NO 2 , —NR A2 C(═O)R A2 , —NR A2 C(═O)OR A2 , —NR A2 C(═O)N(R A2 ) 2 , —OC(═O)R A2 , —OC(═O)OR A2 , or —OC(═O)N(R A2 ) 2 ;
each instance of R A2 is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two R A2 groups are joined to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring;
R 2 is cyclic or acyclic, branched or unbranched aliphatic; cyclic or acyclic, branched or unbranched heteroaliphatic; aryl; or heteroaryl; optionally substituted with m instances of R 4 ;
each instance of R 4 is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR B , —N(R B ) 2 , —SR B , —CN, —SCN, —C(═NR B )R B , —C(═NR B )OR B , —C(═NR B )N(R B ) 2 , —C(═O)R B , —C(═O)OR B , —C(═O)N(R B ) 2 , —NO 2 , —NR B C(═O)R B , —NR B C(═O)OR B , —NR B C(═O)N(R B ) 2 , —OC(═O)R B , —OC(═O)OR B , or —OC(═O)N(R B ) 2 ;
each instance of R B is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two R B groups are joined to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring; and
m is 0, 1, 2, 3, 4, or 5,
in an amount effective to treat the non-small cell lung cancer.

2. A method for treating prostate cancer, the method comprising: administering to a subject in need thereof a compound according to Formula A:

or pharmaceutically acceptable salt thereof,
wherein
n is 0, 1, 2, 3, or 4;
each occurrence of R 1 is independently hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; —OR A1 ; —C(═O)R A1 ; —C(═O)N(R A1 ) 2 ; —CO 2 R A1 ; —CN; —SCN; —SR A1 ; —SOR A1 ; —SO 2 R A1 ; —NO 2 ; —N 3 ; —N(R A1 ) 2 ; —NHC(═O)R A1 ; —NR A1 C(═O)N(R A1 ) 2 ; —OC(═O)OR A1 ; —OC(═O)R A1 ; —OC(═O)N(R A1 ) 2 ; —NR A1 C(═O)OR A1 ; or —C(R A1 ) 3 ;
each occurrence of R A1 is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR A2 , —N(R A2 ) 2 , —SR A2 , —CN, —SCN, —C(═NR A2 )R A2 , —C(═NR A2 )OR A2 , —C(═NR A2 )N(R A2 ) 2 , —C(═O)R A2 , —C(═O)OR A2 , —C(═O)N(R A2 ) 2 , —NO 2 , —NR A2 C(═O)R A2 , —NR A2 C(═O)OR A2 , —NR A2 C(═O)N(R A2 ) 2 , —OC(═O)R A2 , —OC(═O)OR A2 , or —OC(═O)N(R A2 ) 2 ;
each instance of R A2 is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two R A2 groups are joined to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring;
R 2 is cyclic or acyclic, branched or unbranched aliphatic; cyclic or acyclic, branched or unbranched heteroaliphatic; aryl; or heteroaryl; optionally substituted with m instances of R 4 ;
each instance of R 4 is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR B , —N(R B ) 2 , —SR B , —CN, —SCN, —C(═NR B )R B , —C(═NR B )OR B , —C(═NR B )N(R B ) 2 , —C(═O)R B , —C(═O)OR B , —C(═O)N(R B ) 2 , —NO 2 , —NR B C(═O)R B , —NR B C(═O)OR B , —NR B C(═O)N(R B ) 2 , —OC(═O)R B , —OC(═O)OR B , or —OC(═O)N(R B ) 2 ;
each instance of R B is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two R B groups are joined to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring; and
m is 0, 1, 2, 3, 4, or 5
in an amount effective to treat the prostate cancer.

3. The method of claim 1 , wherein the compound according to Formula A is a compound having a formula of Formula An-1:

wherein
A is N or C—R 4 , wherein no more than two A groups can be N;
n is 0, 1, 2, 3, or 4;
each occurrence of R 1 is independently

Assignees

• Dana Farber Cancer Inst Inc

Inventors

• D'Andrea Alan D
• Gray Nathanael
• Buhrlage Sara Jean
• Parmar Kalindi

Classifications

• C07D263/60 Primary

  Naphthoxazoles; Hydrogenated naphthoxazoles · CPC title

• C07D413/04

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