Compounds and methods for treating synovial sarcomas

Patent metadata

Field	Value
Publication number	US-10752628-B2
Application number	US-201615774530-A
Country	US
Kind code	B2
Filing date	Nov 16, 2016
Priority date	Nov 16, 2015
Publication date	Aug 25, 2020
Grant date	Aug 25, 2020

Abstract

The present invention includes compound and methods that are useful in treating certain cancers, such as synovial sarcomas.

First claim

What is claimed:

1. A compound having the structure of formula I:

wherein n is 1, 2, 3, or 4;
o and p are independently 0, 1, or 2;
R 1 and R 6 are, independently, selected from the group consisting of H and C 1 -C 6 alkyl, wherein the alkyl group is optionally substituted with at least one independently selected from the group consisting of C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, halo, —OH, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, —NH 2 , —NHC(═O)(C 1 -C 6 alkyl), —NH(C 1 -C 6 alkyl) and —N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl);
R 2 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 perfluoroalkyl, C 6 -C 10 aryl C 1 -C 6 alkyl, C 1 -C 6 heteroaryl C 1 -C 6 alkyl, C 2 -C 9 heterocyclyl C 1 -C 6 alkyl, or C 3 -C 10 carbocyclyl C 1 -C 6 alkyl, wherein the alkyl group is optionally substituted with at least one independently selected from the group consisting of C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, halo, —OH, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, —NH 2 , —NHC(═O)(C 1 -C 6 alkyl), —NH(C 1 -C 6 alkyl) and —N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl) and the aryl, heteroaryl, heterocyclyl, or carbocyclyl group is optionally substituted with at least one independently selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, halo, —OH, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl), —NO 2 , —C(═O)OH, —C(═O)OR, and —NHC(═O)(C 1 -C 6 alkyl);
R 3 is selected from the group consisting of —C(═O)R C , and —C(═O)N(R A ) 2 ; and
each occurrence of R 4 is independently selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, halo, —OH, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl), —NO 2 , —C(═O)OH, —C(═O)OR, and —NHC(═O)(C 1 -C 6 alkyl); where
R A is independently selected at each occurrence from hydrogen or a C 1 -C 6 linear or branched alkyl;
R C is a saturated C 3 -C 8 cycloalkyl; and
each R is, independently, selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 heteroaryl, C 6 -C 10 aryl, C 3 -C 8 cycloalkyl, C 2 -C 9 heterocyclyl, C 6 -C 10 aryl C 1 -C 6 alkyl, C 1 -C 6 heteroaryl C 1 -C 6 alkyl, wherein the alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl group is optionally substituted with at least one independently selected from the group consisting of C 1 -C 6 alkyl, —OH, —(C 1 -C 6 alkoxy), halo, —NH 2 , —NHC(═O)(C 1 -C 6 alkyl), —NH(C 1 -C 6 alkyl) and —N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl);
with the proviso that said compound is not:

2. The compound according to claim 1 , wherein
R 1 and R 6 are independently selected from hydrogen, hydroxymethyl, hydroxyethyl, or hydroxypropyl;
R 2 is optionally substituted benzyl;
R 3 is —C(═O)R C and R C is a C 4 -C 5 cycloalkyl or wherein R 3 is —C(═O)NHR A ;
each occurrence of R 4 is independently selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, halo, —OH, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl), —NO 2 , —C(═O)OH, —C(═O)OR, and —NHC(═O)(C 1 -C 6 alkyl.

3. The compound according to claim 2 , wherein R 2 is fluorobenzyl.

4. The compound according to claim 2 , wherein R 1 and R 6 are independently selected from hydrogen or hydroxymethyl.

5. The compound according to claim 1 , wherein R 1 is —(CH 2 ) q XR 7 , wherein q is 1, 2, 3, 4, 5, or 6, X is absent, O, or NR 8 ,
R 7 is hydrogen or C 1 -C 6 alkyl, and
R 8 is hydrogen or C 1 -C 6 alkyl.

6. The compound according to claim 1 , wherein R 1 is selected from the group consisting of H and C 1 -C 6 alkyl, wherein the alkyl group is optionally substituted with at least one independently selected from the group consisting of C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, halo, —OH, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, —NH 2 , —NHC(═O)(C 1 -C 6 alkyl), —NH(C 1 -C 6 alkyl) and —N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl) and R 6 is hydrogen.

7. The compound according to claim 1 , wherein R 2 is (CH 2 ) m R 5 , wherein m is 1, 2 or 3, and wherein R 5 is selected from the group consisting of aryl and heteroaryl, wherein the aryl or heteroaryl group is optionally substituted with at least one independently selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, halo, —OH, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl), —NO 2 , —C(═O)OH, —C(═O)OR, and —NHC(═O)(C 1 -C 6 alkyl).

8. The compound according to claim 1 , wherein o and p are 1.

9. The compound according to claim 1 , wherein the compound has the structure of Formula IA and/or Formula IB:

10. A compound of formula (II), or a salt, solvate or stereoisomer thereof:

wherein R 1 is selected from the group consisting of H and C 1 -C 6 alkyl, wherein the alkyl group is optionally substituted with at least one independently selected from the group consisting of C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, halo, —OH, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, —NH 2 , —NHC(═O)(C 1 -C 6 alkyl), —NH(C 1 -C 6 alkyl) and —N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl);
R 2 is (CH 2 ) m R 5 , wherein m is 1, 2 or 3, and wherein R 5 is selected from the group consisting of aryl and heteroaryl, wherein the aryl or heteroaryl group is optionally substituted with at least one independently selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, halo, —OH, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl), —NO 2 , —C(═O)OH, —C(═O)OR, and —NHC(═O)(C 1 -C 6 alkyl);
R 3 is selected from the group consisting of H, —S(═O) 2 R, —C(═O)R, —S(═O) 2 NHR and —C(═O)NHR, wherein R is selected from the group consisting of C 1 -C 6 alkyl and saturated C 3 -C 8 cycloalkyl, wherein the alkyl or cycloalkyl group is optionally substituted with at least one moiety independently selected from the group consisting of C 1 -C 6 alkyl, —OH, —(C 1 -C 6 alkoxy), halo, —NH 2 , —NHC(═O)(C 1 -C 6 alkyl), —NH(C 1 -C 6 alkyl) and —N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl);
each occurrence of R 4 is independently selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, halo, —OH, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl), —NO 2 , —C(═O)OH, —C(═O)OR, and —NHC(═O)(C 1 -C 6 alkyl); and
n is 0, 1, 2, 3 or 4;
with the proviso that said compound is not:

11. The compound of claim 10 , which is a compound of formula (IIA), or a salt or solvate thereof:

or
a compound of formula (IIB), or a salt or solvate thereof:

12. The compound of claim 10 , wherein R 1 is selected from the group consisting of H and C 1 -C 6 alkyl,

Assignees

• Broad Inst Inc
• Harvard College
• Dana-Farber Cancer Institute Inc

Inventors

• Kadoch Cigall
• Garcia-Rivera Enrique
• Maetani Micah
• Schreiber Stuart L

Classifications

• C07D471/20 Primary

  Spiro-condensed systems · CPC title

• A61P35/00

  Antineoplastic agents · CPC title