Tricyclic compounds as anticancer agents

Patent metadata

Field	Value
Publication number	US-9540358-B2
Application number	US-201214238511-A
Country	US
Kind code	B2
Filing date	Aug 16, 2012
Priority date	Aug 16, 2011
Publication date	Jan 10, 2017
Grant date	Jan 10, 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 phenothiazine, dibenzoazepine and annulene and similar genera:

First claim

The invention claimed is:

1. A compound of formula (I):

wherein:
X is selected from the group consisting of: —(CH 2 —CH 2 )—, and —CH═CH—;
Y is

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 14 , R 15 and R 16 may form a three to seven membered non-aromatic carbocycle or heterocycle 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 2;
v is 1, 2 or 3;
with the proviso that when q is zero and R 15 and R 16 , in all of their occurrences are H, n is not 4;
Z is selected from the group consisting of: —NHSO 2 R 17 , —NHC(O)NR 8 R 9 , —S(O) 2 NR 8 R 9 , substituted or unsubstituted cyclic carbamate; substituted or unsubstituted cyclic urea, cyanoguanidine;
R 8 and R 9 are independently selected from H, substituted or unsubstituted (C 1 -C 6 )alkyl, and substituted or unsubstituted (C 3 -C 7 ) cycloalkyl; 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 17 and —NHC(O)NR 8 R 9 .

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

4. A compound according to claim 3 of formula:

wherein Ar is a substituted or unsubstituted phenyl, thienyl, furanyl or pyrrolyl, and the dotted line represents an optional double bond.

5. A compound according to claim 4 wherein p and q are both zero, R 15 is H and R 16 is chosen from H and OH.

6. A compound according to claim 5 of formula (ID) or (ID′):

wherein:
R 1 and R 3 are independently selected from the group consisting of: H and halo; and
R 2 and R 4 are H.

7. A compound according to claim 6 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.

8. A compound according to claim 4 wherein two R 15 or R 16 taken together form a three to seven membered non-aromatic 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
p is zero, 1 or 2; and
Ar is a substituted or unsubstituted phenyl, thienyl, furanyl or pyrrolyl.

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

wherein:
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 —; or
(b) B is a six-membered ring of formula:

wherein:
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 —.

10. A compound according to claim 4 wherein two R 15 or R 16 taken together form a three to seven membered non-aromatic 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
k is zero, 1 or 2; and
Ar is a substituted or unsubstituted phenyl, thienyl, furanyl or pyrrolyl.

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

wherein:
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 —; or
(b) B is a six-membered ring of formula:

wherein:
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 —.

12. A compound according to claim 9 wherein p is zero.

13. A compound according to claim 4 wherein Ar is phenyl or thienyl, optionally substituted with one or two substituents chosen from methyl, halogen, cyano, nitro, trifluoromethyl, methyl sulfonyl, trifluoromethoxy, and acetyl amino.

14. A compound according to claim 13 wherein said one or two substituents are located at positions that are not adjacent to the point of attachment of Ar to the sulfonamide.

15. 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 indepen

Assignees

• Ohlmeyer Michael
• Narla Goutham
• Dhawan Neil
• Kastrinsky David
• Icahn School Med Mount Sinai

Inventors

• Ohlmeyer Michael
• Narla Goutham
• Dhawan Neil
• Kastrinsky David

Classifications

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P37/02

  Immunomodulators · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title