Heterocyclic constrained tricyclic sulfonamides as anti-cancer agents

Patent metadata

Field	Value
Publication number	US-10759790-B2
Application number	US-201615758045-A
Country	US
Kind code	B2
Filing date	Sep 8, 2016
Priority date	Sep 9, 2015
Publication date	Sep 1, 2020
Grant date	Sep 1, 2020

Abstract

A genus of arylsulfonamide derivatives of heterocyclic constrained tricyclic compounds is disclosed. The compounds are of the following genus:

The compounds induce FOXO1 transcription factor translocation to the nucleus by modulating PP2A and, as a consequence, exhibit anti-proliferative effects. They are useful in the treatment of a variety of disorders, including as a therapy in cancer treatment, or used in combination with other drugs to restore sensitivity to chemotherapy where resistance has developed.

First claim

We claim:

1. A compound of formula I:

wherein:
D is selected from a direct bond, —O—, —CH 2 O—, —OCH 2 —, —C(═O)NR D —, and —N(R D )C(═O)—;
R D is selected from hydrogen and (C 1 -C 6 )alkyl;
T is a benzene ring or a five- or six-membered heteroaromatic ring;
U is a benzene ring or a five- or six-membered heteroaromatic ring;
X 1 , X 2 , X 3 , and X 4 are independently selected in each instance from hydrogen, halogen, nitro, cyano, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )haloalkylthio, —NR 1 R 2 , —C(O)R 1 , —OC(O)R 1 , —C(O)NR 1 R 2 , —C(O)OR 1 , —SR 1 , SO 2 R 1 , and —SO 2 NR 1 R 2 ;
R 1 and R 2 are independently selected in each instance from the group consisting of hydrogen and (C 1 -C 6 )alkyl;
Q is selected from —O—, S(O) n —, and —NR—;
n is zero, 1 or 2;
R is selected from hydrogen, optionally substituted (C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl, aryl, or heteroaryl; —SO 2 R 3 ; —SO 2 N(R 3 R 4 ); —C(═O)R 5 ; —C(═O)OR 5 ; or —C(═O)N(R 3 R 4 ); wherein said substituents on the (C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl, aryl, or heteroaryl are selected from the group consisting of hydroxy, halogen, cyano, nitro, amino, (C 1 -C 4 )alkylamino, (C 1 -C 4 )dialkylamino, (C 1 -C 4 )acylamino, (C 1 -C 4 )alkylsulfonyl, (C 1 -C 4 )alkylthio, (C 1 -C 4 )alkyl, (C 3 -C 7 )cycloalkyl, (C 1 -C 4 )haloalkyl, (C 1 -C 4 )haloalkoxy, and (C 1 -C 4 )alkoxy;
R 3 and R 4 are independently selected in each instance from hydrogen, (C 1 -C 6 )alkyl, aryl, and arylalkyl, wherein said aryl or the aryl of the arylalkyl is optionally substituted with hydroxy, halogen, cyano, nitro, amino, (C 1 -C 4 )alkylamino, (C 1 -C 4 )dialkylamino, (C 1 -C 4 )acylamino, (C 1 -C 4 )alkylsulfonyl, (C 1 -C 4 )alkylthio, (C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl, (C 1 -C 4 )haloalkoxy, or (C 1 -C 4 )alkoxy;
R 5 is selected from hydrogen, optionally substituted (C 1 -C 4 )alkyl, or optionally substituted aryl, wherein said optional substituents are selected from the group consisting of (C 1 -C 3 )alkyl, OR 1 , NH 2 , NHMe, N(Me) 2 , and heterocycle;
Y is selected from hydrogen or hydroxyl;
V is selected from phenyl, a six-membered heteroaromatic ring, furan, and thiophene;
Z 1 and Z 2 are independently selected in each instance from the group consisting of hydrogen, halogen, nitro, cyano, azide, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )haloalkoxy, —(C 1 -C 6 )haloalkylthio, —NR 1 R 2 , —NR 1 C(O)R 2 , —NR 1 C(O)OR 6 , —C(O)R′, —OC(O)R′, —C(O)NR 1 R 2 , —C(O)OR 1 , —SO 2 R′, and —SO 2 NR 1 R 2 ; and
R 6 is (C 1 -C 8 )hydrocarbon.

2. A compound according to claim 1 wherein D is a direct bond.

3. A compound according to claim 1 wherein D is —O—.

4. A compound according to claim 1 wherein D is chosen from —OCH 2 —, —C(═O)NR D — or —N(R D )C(═O)—.

5. A compound according to claim 1 wherein T and U are each independently selected from the group consisting of a benzene ring and pyridine.

6. A compound according to claim 1 wherein Y is hydroxyl.

7. A compound according claim 1 wherein Q is —O—.

8. A compound according claim 1 wherein Q is —NR—.

9. A compound according to claim 1 wherein R is selected from hydrogen; (C 1 -C 3 )alkyl optionally substituted with one or more of hydroxy, methoxy, fluoro, or phenyl; phenyl optionally substituted with one or more of hydroxy, fluoro, methoxy, nitro, amino, or methyl; or a nitrogen-containing heteroaryl optionally substituted with one or two methyl groups.

10. A compound according to claim 1 wherein zero, one or two of X 1 , X 2 , X 3 , and X 4 are independently selected in each instance from halogen, (C 1 -C 6 )alkyl, and halo(C 1 -C 6 )alkyl, and the remainder are hydrogen.

11. A compound according to claim 1 wherein the relative stereochemistry is of formula IIa or formula IIb:

12. A compound according to claim 1 of formula:

13. A compound according to claim 1 of formula:

14. A compound according to claim 1 of formula:

15. A compound according to claim 1 of formula:

16. A compound according to claim 1 , wherein Z 1 is hydrogen, and Z 2 is hydrogen, fluoro, chloro, trifluoromethyl, —NHBoc, methoxy, or trifluoromethoxy.

17. A compound according to claim 1 , wherein V is phenyl.

18. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound according to claim 1 .

19. A compound according to claim 1 selected from:

20. A compound according to claim 19 selected from:

Assignees

• Icahn School Med Mount Sinai
• Ichan School Of Medicine At Mount Sinai

Inventors

• Ohlmeyer Michael
• Zaware Nilesh

Classifications

• C07D403/04

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

• C07D498/04

  Ortho-condensed systems · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P43/00

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

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title