Pyrimidyl cyclopentanes as Akt protein kinase inhibitors

Patent metadata

Field	Value
Publication number	US-9346805-B2
Application number	US-201213676963-A
Country	US
Kind code	B2
Filing date	Nov 14, 2012
Priority date	Jan 9, 2008
Publication date	May 24, 2016
Grant date	May 24, 2016

Abstract

The present invention provides compounds of Formula I including tautomers, resolved enantiomers, resolved diastereomers, solvates, metabolites, salts and pharmaceutically acceptable prodrugs thereof.

Also provided are methods of using the compounds of this invention as Akt protein kinase inhibitors and for the treatment of Akt-mediated diseases, for example, hyperproliferative diseases such as cancer.

First claim

What is claimed is:

1. A method of inhibiting Akt-1 protein kinase for treating or lessening the severity of a cancer in a patient, comprising administering to said patient a therapeutically effective amount of a compound of Formula I:

and tautomers, resolved enantiomers, resolved diastereomers, metabolites, salts and pharmaceutically acceptable prodrugs thereof, wherein:
R 1 is H, CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , CH═CH 2 , CH 2 OH, CF 3 , CHF 2 , CH 2 F, or C 3 -C 6 cycloalkyl;
R 2 is H, OH, OCH 3 or F;
R 3 is H, F or CH 3 ;
each R 4 is independently selected from H, F, Cl, Br, I, CN, (CH 2 ) t NR 10 R 10 , (CH 2 ) t OR 10 , (CH 2 ) t C(O)R 10 , (CH 2 ) 1 C(O)OR 10 , (CH 2 ) t C(O)NR 10 R 10 , (CH 2 ) t NR 10 C(O)R 10 , (CH 2 ) t NR 10 C(O)OR 10 , (CH 2 ) t NR 10 C(O)NR 10 R 10 , C 1 -C 6 alkyl, (CR 10 R 10 ) t C 3 -C 8 cycloalkyl, (CR 10 R 10 ) t C 3 -C 6 heterocyclyl, (CR 10 R 10 ) t C 6 -C 8 aryl, O(CR 10 R 10 ) t C 6 -C 8 aryl, (CR 10 R 10 ) t C 3 - C 6 heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted by one or more F, Cl, Br, I, CN, C 1 -C 3 alkyl, CF 3 , OH or O(C 1 -C 3 alkyl);
R 5 is H, C 1 -C 6 alkyl, (CR 10 R 10 ) t OR 10 , (CR 10 R 10 ) t NR 10 R 10 , (CH 2 ) t C 3 -C 8 cycloalkyl, (CH 2 ) t C 6 -C 8 aryl, wherein said aryl is optionally substituted by F, Cl, Br or I;
R 6 , R 7 , R 8 and R 9 are independently selected from H, C 1 -C 6 alkyl, (CR 10 R 10 ) t OR 10 , (CR 10 R 10 ) t C 6 -C 8 aryl; wherein said aryl is optionally substituted by F, Cl, Br or I;
R 10 is independently selected from H, OH, O(C 1 -C 3 alkyl), (CH 2 ) t NR 11 R 11 , (CH 2 ) t C(O)NR 11 R 11 , (CH 2 ) t S(O)NR 11 R 11 , (CH 2 ) 3 S(O) 2 NR 11 R 11 , C 3 -C 6 alkyl, (CH 2 ) t C 3 -C 8 cycloalkyl, (CH 2 ) t C 3 -C 6 heterocyclyl, (CH 2 ) 1 C 6 -C 8 aryl and (CH 2 ) 1 C 3 -C 6 heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted by one or more F, Cl, Br, I, CN, C 1 -C 3 alkyl, CF 3 , OH, O(C 1 -C 3 alkyl); or
two R 10 are taken together to form oxo or a C 3 -C 6 heterocyclyl;
R 11 is independently selected from H, C 1 -C 3 alkyl, OH, OC 1 -C 3 alkyl, NH 2 , N(C 1 -C 3 alkyl) 2 ; or
two R 11 are taken together to form a C 3 -C 6 heterocyclyl, optionally substituted by methyl or ethyl;
m and n are independently 1, 2 or 3, provided that m and n taken together are 3, 4 or 5;
p is 0, 1, 2 or 3; and
each t is independently 0, 1, 2, 3 or 4.

2. The method of claim 1 , wherein R 1 is H, CH 3 , CH 2 CH 3 , CH═CH 2 , CH 2 OH, CF 3 , CHF 2 or CH 2 F.

3. The method of claim 1 , wherein m is 2 and n is 1.

4. The method of claim 1 , wherein m is 2 and n is 2.

5. The method of claim 1 , wherein m is 3 and n is 1.

6. The method of claim 1 , wherein m is 3 and n is 2.

7. The method of claim 1 , wherein m is 4 and n is 1.

8. The method of claim 1 , wherein m and n are independently 1 or 2, provided that m and n taken together are 3.

9. The method of claim 1 , wherein m and n are independently 1, 2 or 3, provided that m and n taken together are 4.

10. The method of claim 1 , wherein p is 1 or 2 and R 4 is F, Cl, Br, I, CN, (CH 2 ) t NR 10 R 10 or (CH 2 ) t OR 10 .

11. The method of claim 10 , wherein the residue of Formula I having the structure

is selected from:

wherein the wavy lines represent points of attachment of the residue in Formula I.

12. The method of claim 10 , wherein the residue of Formula I having the structure:

is selected from:

wherein the wavy line represents points of attachment for the residue in Formula I.

13. The method of claim 10 , wherein the residue of Formula I having the structure

is selected from:

wherein the wavy lines represent points of attachment of the residue in Formula I.

14. The method of claim 10 , wherein the residue of Formula I having the structure

is selected from:

15. The method of claim 1 , wherein R 4 is (CR 10 R 10 ) t C 6 -C 8 aryl, wherein said aryl is optionally substituted by F, Cl, Br or I.

16. The method of claim 15 , wherein R 4 is selected from:

wherein the wavy line represents the point of attachment of R 4 in Formula I;
R 12 is F, Cl, Br or I;
q is 0, 1, 2, 3, 4 or 5; and
R 10 is independently selected from H, OH, O(C 1 -C 3 alkyl), (CH 2 ) t NR 11 R 11 , C 1 -C 6 alkyl, (CH 2 ) t C 3 -C 8 cycloalkyl or (CH 2 ) t C 3 -C 6 heterocyclyl, wherein said cycloalkyl and heterocyclyl are optionally substituted by one or more C 1 -C 3 alkyl; or
two R 10 are taken together to form oxo.

17. The method of claim 16 , wherein R 4 is selected from

18. The method of claim 1 , wherein R 4 is O(CR 10 R 10 ) t C 6 -C 8 aryl, wherein said aryl is optionally substituted by F, Cl, Br or I.

19. The method of claim 18 , wherein t is 0, 1, 2 or 3; R 10 is independently selected from H, OH, O(C 1 -C 3 alkyl) or (CH 2 ) t NR 11 R 11 , or two R 10 are taken together to form oxo; and R 11 is independently selected from H or C 1 -C 3 alkyl, or two R 11 are taken together to form a C 3 -C 6 heterocyclyl, optionally substituted by methyl or ethyl.

20. T

Assignees

• Array Biopharma Inc

Inventors

• Banka Anna
• Bencsik Josef R
• Blake James F
• Fong Kin Chiu
• Hentemann Martin F
• Mitchell Ian S
• Sammond Douglas Mccord
• Tang Tony P
• Wallace Eli M
• Xu Rui
• Graham James

Classifications

• A61P35/04

  specific for metastasis · CPC title

• A61P37/08

  Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14) · CPC title

• A61P43/00

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

• A61P5/00

  Drugs for disorders of the endocrine system · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title