Compounds and methods for treating synovial sarcomas

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, wherein the alkyl group is optionally substituted with at least one independently selected from the group consisting of C 1 -C 6 alkyl, halo, —OH, C 1 -C 6 alkoxy, and C 1 -C 6 haloalkoxy;

wherein R 2 is CH 2 R 5 ;

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 linear or branched C 1 -C 6 alkyl or C 3 -C 8 alicyclic cycloalkyl;

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 and C 1 -C 6 haloalkoxy

wherein R 5 is aryl 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).

13. The compound of claim 10 , wherein n is 1, and R 4 is at the 7′ position of (II).

14. The compound of claim 10 , which is at least one selected from the group consisting of:

cyclobutyl(2′-(2-fluorobenzyl)-7′-methoxy-1′,2′,3′,9′-tetrahydrospiro[piperidine-4,4′-pyrido[3,4-b]indol]-1-yl)methanone:

(S)-(2′-benzyl-1′-(hydroxymethyl)-7′-methoxy-1′,2′,3′,9′-tetrahydrospiro[piperidine-4,4′-pyrido[3,4-b]indol]-1-yl)(cyclobutyl):

(S)-cyclobutyl(2′-(3-fluorobenzyl)-1′-(hydroxymethyl)-7′-methoxy-1′,2′,3,9′-tetrahydrospiro[piperidine-4,4′-pyrido[3,4-b]indol]-1-yl)methanone:

(S)-cyclobutyl(2′-(4-fluorobenzyl)-1′-(hydroxymethyl)-7′-methoxy-1′,2′,3′,9′-tetrahydrospiro[piperidine-4,4′-pyrido[3,4-b]indol]-1-yl)methanone:

(S)-(2′-(2-chlorobenzyl)-1′-(hydroxymethyl)-7′-methoxy-1′,2′,3′,9′-tetrahydrospiro[piperidine-4,4′-pyrido[3,4-b]indol]-1-yl)(cyclobutyl)methanone:

(R)-2′-benzyl-1′-(hydroxymethyl)-7′-methoxy-N-propyl-1′,2′,3′,9′-tetrahydrospiro[piperidine-4,4′-pyrido[3,4-b]indole]-1-carboxamide:

(S)-2′-benzyl-1′-(hydroxymethyl)-7′-methoxy-N-propyl-1′,2′,3′,9′-tetrahydrospiro[piperidine-4,4′-pyrido[3,4-b]indole]-1-carboxamide:

(S)-cyclopentyl(2′-(2-fluorobenzyl)-1′-(hydroxymethyl)-7′-methoxy-1′,2′,3′,9′-tetrahydrospiro[piperidine-4,4′-pyrido[3,4-b]indol]-1-yl)methanone:

(R)-cyclopentyl(2′-(2-fluorobenzyl)-1′-(hydroxymethyl)-7′-methoxy-1′,2′,3′,9′-tetrahydrospiro[piperidine-4,4′-pyrido[3,4-b]indol]-1-yl)methanone:

or a salt, solvate, and/or stereoisomer thereof.

15. A pharmaceutical composition comprising at least one compound of claim 1 and a pharmaceutically acceptable carrier.

16. The pharmaceutical composition of claim 15 , further comprising at least one additional anticancer agent selected from the group consisting of doxorubicin and ifosfamide.

17. A method of treating or preventing a synovial sarcoma in a subject in need thereof comprising administering to the subject in need thereof a therapeutically effective amount of at least one compound of claim 1 .

18. The method of claim 17 , wherein the subject further receives radiotherapy to treat or prevent the synovial sarcoma.

19. The method of claim 17 , wherein the at least one compound is administered to the subject by at least one route selected from the group consisting of nasal, inhalational, topical, oral, buccal, rectal, pleural, peritoneal, vaginal, intramuscular, subcutaneous, transdermal, epidural, intrathecal and intravenous routes.

20. The method of claim 17 , wherein the subject is human.