Tricyclic heterocycles as anticancer agents

Patent metadata

Field	Value
Publication number	US-9796717-B2
Application number	US-201414768632-A
Country	US
Kind code	B2
Filing date	Feb 19, 2014
Priority date	Feb 19, 2013
Publication date	Oct 24, 2017
Grant date	Oct 24, 2017

Abstract

Tricyclic chemical modulators of FOXO transcription factor proteins are disclosed. The compounds are useful to treat cancer, age-onset proteotoxicity, stress-induced depression, inflammation, and acne. The compounds are of the following and similar genera:

in which Het is an aromatic heterocyclic ring and Y is a point of attachment of various side chains and rings. An example of such a compound is 4-chloro-N-(3-(10,11-dihydro-5H-benzo[b]pyrido[2,3-f]azepin-5-yl)propyl)benzenesulfonamide:

First claim

The invention claimed is:

1. A compound of formula (I):

R 1 , R 2 , R 3 , and R 4 are independently selected from the group consisting of: H, halo, —N 3 , —NR 6 R 7 , (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, —OR 6 , —C(O)R 6 , —OC(O)R 6 , —C(O)NR 6 R 7 , —C(O)OR 6 , —SR 6 , —SO 2 R 6 , and —SO 2 NR 6 R 7 ;
R 5 is —(CR 15 R 16 ) p -Q q -(CR 15 R 16 ) n-p —Z or

Q is chosen from —O—, —NR 14 — and

each R 6 and R 7 is independently selected from the group consisting of: H and (C 1 -C 6 )alkyl;
R 14 is H or (C 1 -C 3 )alkyl;
R 15 and R 16 , in each occurrence are chosen independently from H, OH, cyano, amino, (C 1 -C 3 )alkylamino, (C 1 -C 3 )dialkylamino, (C 1 -C 3 )alkyl, (C 1 -C 3 )haloalkyl, (C 1 -C 3 )haloalkoxy, and (C 1 -C 3 )alkoxy, or, taken together, two of R 15 and R 16 may form a three to seven membered heterocycle or non-aromatic carbocycle, wherein said three to seven membered carbocycle or heterocycle may be additionally substituted with one or two substituents chosen from OH, F, cyano, amino, (C 1 -C 3 )alkylamino, (C 1 -C 3 )dialkylamino, (C 1 -C 3 )alkyl, (C 1 -C 3 )haloalkyl, (C 1 -C 3 )haloalkoxy, and (C 1 -C 3 )alkoxy;
n is an integer from 2 to 4;
p is zero, 1 or 2;
q is zero or 1;
t is zero, 1 or 2;
u is zero, 1 or 2, that when Y is

is 2;
v is 1, 2 or 3;
Z is selected from the group consisting of: —NHSO 2 R 17 , —NHC(O)NR 8 R 9 , —NHC(O)OR 8 , —S(O) 2 NR 8 R 9 , substituted or unsubstituted cyclic carbamate; substituted or unsubstituted cyclic urea, cyclic imide and cyanoguanidine;
R 8 and R 9 are independently selected from H, substituted or unsubstituted (C 1 -C 6 )alkyl, substituted or unsubstituted (C 3 -C 7 ) cycloalkyl and substituted or unsubstituted (C 5 -C 14 )aryl; and
R 17 is chosen from phenyl and monocyclic heteroaryl, said phenyl and monocyclic heteroaryl optionally substituted with one or two substituents chosen from OH, halogen, cyano, nitro, (C 1 -C 3 )alkylamino, (C 1 -C 3 )dialkylamino, (C 1 -C 3 )acylamino, (C 1 -C 3 )alkylsulfonyl, (C 1 -C 3 )alkylthio, (C 1 -C 3 )alkyl, (C 1 -C 3 )haloalkyl, (C 1 -C 3 )haloalkoxy, and (C 1 -C 3 )alkoxy.

2. A compound according to claim 1 , wherein Z is selected from the group consisting of: —NHSO 2 R 7 , —NHC(O)NR 8 R 9 , and —NHC(O)OR 8 .

3. A compound according to claim 2 wherein Z is —NHSO 2 R 17 .

4. A compound according to claim of formula:

wherein Ar is a substituted or unsubstituted phenyl, thienyl, furanyl or pyrrolyl.

5. A compound according to claim 4 wherein p and q are both zero, R 1 is H and R 16 is chosen from H and OH.

6. A compound according to claim 5 of formula:

wherein:
R 1 is independently selected from the group consisting of: H and halo; and
R 2 and R 4 are H.

7. A compound according to claim 4 wherein two R 15 or R 16 taken together form a three to seven membered carbocycle or heterocycle B, wherein said three to seven membered carbocycle or heterocycle B may be additionally substituted with one or two substituents chosen from OH, F, cyano, amino, (C 1 -C 3 )alkylamino, (C 1 -C 3 )dialkylamino, (C 1 -C 3 )alkyl, (C 1 -C 3 )haloalkyl, (C 1 -C 3 )haloalkoxy, and (C 1 -C 3 )alkoxy, said compound being of formula:

wherein
t is zero, 1 or 2; and
Ar is a substituted or unsubstituted phenyl, thienyl, furanyl or pyrrolyl.

8. A compound according to claim 7 wherein
(a) B is a five-membered ring of formula:

wherein, in the five-membered ring:
W 1 and W 2 are both —CH 2 —; or
one of W 1 and W 2 is —O— and the other is —CH 2 —; or
one of W 1 and W 2 is —CH(OH)— and the other is —CH 2 — and the arylsulfonamide replaces one hydrogen on one CH 2 group; or
(b) B is a six-membered ring of formula:

wherein, in the six-membered ring:
all of W 1 W 2 and W 3 are —CH 2 —; or
one of W 1 W 2 and W 3 is —O— and the other two are —CH 2 —; or
one of W 1 W 2 and W 3 is —CH(OH)— and the other two are —CH 2 —
and the arylsulfonamide replaces one hydrogen on one CH 2 group.

9. A compound according to claim 4 wherein two R 15 or R 16 taken together form a three to seven membered carbocycle or heterocycle B, wherein said three to seven membered carbocycle or heterocycle B may be additionally substituted with one or two substituents chosen from OH, F, cyano, amino, (C 1 -C 3 )alkylamino, (C 1 -C 3 )dialkylamino, (C 1 -C 3 )alkyl, (C 1 -C 3 )haloalkyl, (C 1 -C 3 )haloalkoxy, and (C 1 -C 3 )alkoxy, said compound being of formula:

wherein
t is zero, 1 or 2; and
Ar is a substituted or unsubstituted phenyl, thienyl, furanyl or pyrrolyl.

10. A compound according to claim 9 , wherein
(a) B is a five-membered ring of formula:

wherein, in the five-membered ring:
W 1 and W 2 are both —CH 2 —; or
one of W 1 and W 2 is —O— and the other is —CH 2 —; or
one of W 1 and W 2 is —CH(OH)— and the other is —CH 2 —
and the arylsulfonamide replaces one hydrogen on one CH 2 group; or
(b) B is a six-membered ring of formula:

wherein, in the six-membered ring:
all of W 1 W 2 and W 3 are —CH 2 —; or
one of W 1 W 2 and W 3 is —O— and the other two are —CH 2 —; or
one of W 1 W 2 and W 3 is —CH(OH)— and the other two are —CH 2 —
and the arylsulfonamide replaces one hydrogen on one CH 2 group.

11. A compound according to claim 4 wherein Ar is phenyl or thienyl, optionally substituted with one or two substituents chosen from (C 1 -C 3 )alkyl, halogen, cyano, nitro, (C 1 -C 3 )haloalkyl, (C 1 -C 3 )alkylsulfonyl, (C 1 -C 3 )haloalkoxy, and acetylamino.

12. A compound according to claim 1 wherein t is zero.

13. A compound according to claim 4 wherein
Ar is phenyl, optionally substituted at the 3, 4 or 5 positions with one or two substituents chosen from methyl, halogen, cyano, trifluoromethyl and trifluoromethoxy;
R 1 and R 3 are independently selected from the group consisting of H and halo; and
R 2 and R 4 are H.

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

Assignees

• Icahn School Med Mount Sinai

Inventors

• Ohlmeyer Michael
• Kastrinsky David

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · 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

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title