Substituted piperazines as AKT inhibitors

Patent metadata

Field	Value
Publication number	US-9303040-B2
Application number	US-30752607-A
Country	US
Kind code	B2
Filing date	Jul 5, 2007
Priority date	Jul 6, 2006
Publication date	Apr 5, 2016
Grant date	Apr 5, 2016

Abstract

The present invention provides compounds, including resolved enantiomers, diastereomers, solvates and pharmaceutically acceptable salts thereof, comprising the Formula:

Also provided are methods of using the compounds of this invention as AKT protein kinase inhibitors and for the treatment of hyperproliferative diseases such as cancer.

First claim

What is claimed is:

1. A compound of the Formula:

and enantiomers and salts thereof, wherein:
X is S, SO or SO 2 ;
R 1 is H, Me, Et, CF 3 , CHF 2 or CH 2 F;
R 2 is H or Me;
R 5 is H, Me, Et, or CF 3 ;
A is

wherein
G is phenyl optionally substituted independently with one to four R 9 groups;
R 6 and R 7 are independently H, (C 3 -C 6 cycloalkyl)-(CH 2 ), (C 3 -C 6 cycloalkyl)-(CH 2 CH 2 ), V—(CH 2 ) 0-1 wherein V is a 5-6 membered heteroaryl, W—(CH 2 ) 1-2 wherein W is phenyl optionally substituted with F, Cl, Br, I, OMe, CF 3 or Me, C 3 -C 6 -cycloalkyl, hydroxy-(C 3 -C 6 -cycloalkyl), fluoro-(C 3 -C 6 -cycloalkyl), CH(CH 3 )CH(OH)phenyl, 4-6 membered heterocycle optionally substituted with F, OH, cyclopropylmethyl, C 1 -C 3 alkyl or C(═O)(C 1 -C 3 alkyl), or C 1 -C 6 -alkyl optionally substituted with one or more groups independently selected from OH, O(C 1 -C 6 -alkyl), CN, F, NH 2 , NH(C 1 -C 6 -alkyl), N(C 1 -C 6 -alkyl) 2 , tetrahydropyranyl, tetrahydrofuranyl, morpholinyl, oxetanyl, piperidinyl, and pyrrolidinyl,
or R 6 and R 7 together with the nitrogen to which they are attached form a 3-6 membered heterocyclic ring optionally substituted with one or more groups independently selected from OH, halogen, oxo, CF 3 , CH 2 CF 3 , and (C 1 -C 3 )alkyl;
R a and R b are H,
or R a is H, and R b and R 6 together with the atoms to which they are attached form a 5-6 membered heterocyclic ring having one or two ring nitrogen atoms;
R c and R d are H or Me,
or R c and R d together with the atom to which they are attached form a cyclopropyl ring;
R 8 is H, Me, or OH,
or R 8 and R 6 together with the atoms to which they are attached form a 5-6 membered heterocyclic ring having one or two ring nitrogen atoms;
each R 9 is independently halogen, C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, O—(C 1 -C 6 -alkyl), CF 3 , OCF 3 , S(C 1 -C 6 -alkyl), CN, OCH 2 -phenyl, NH 2 , NH—(C 1 -C 6 -alkyl), N—(C 1 -C 6 -alkyl) 2 , piperidine, pyrrolidine, CH 2 F, CHF 2 , OCH 2 F, OCHF 2 , OH, SO 2 (C 1 -C 6 -alkyl), C(O)NH 2 , C(O)NH(C 1 -C 6 -alkyl), and C(O)N(C 1 -C 6 -alkyl) 2 ; and
m, n and p are independently 0 or 1.

2. The compound of claim 1 , having the Formula:

and enantiomers and salts thereof, wherein:
R 1 is H, Me, Et, CF 3 , CHF 2 or CH 2 F;
R 2 is H or Me;
R 5 is H, Me, Et, or CF 3 ;
A is

wherein
G is phenyl optionally substituted independently with one to four R 9 groups;
R 6 and R 7 are independently H, (C 3 -C 6 cycloalkyl)-(CH 2 ), (C 3 -C 6 cycloalkyl)-(CH 2 CH 2 ), V—(CH 2 ) 0-1 wherein V is a 5-6 membered heteroaryl, W—(CH 2 ) 1-2 wherein W is phenyl optionally substituted with F, CI or Me, C 3 -C 6 -cycloalkyl, hydroxy-(C 3 -C 6 -cycloalkyl), fluoro-(C 3 -C 6 -cycloalkyl), CH(CH 3 )CH(OH)phenyl, or C 1 -C 6 -alkyl optionally substituted with one or more groups independently selected from OH, O(C 1 -C 6 -alkyl), CN, F, NH 2 , NH(C 1 -C 6 -alkyl), N(C 1 -C 6 -alkyl) 2 , piperidinyl, and pyrrolidinyl,
or R 6 and R 7 together with the nitrogen to which they are attached form a 4-6 membered heterocyclic ring optionally substituted with one or more groups independently selected from OH, halogen, oxo, CF 3 , CH 2 CF 6 , and (C 1 -C 3 )alkyl;
R a and R b are H,
or R a is H, and R b and R 6 together with the atoms to which they are attached form a 5-6 membered heterocyclic ring having one or two ring nitrogen atoms;
R c and R d are H or Me,
or R c and R d together with the atom to which they are attached form a cyclopropyl ring;
R 8 is H, Me, or OH,
or R 8 and R 6 together with the atoms to which they are attached form a 5-6 membered heterocyclic ring having one or two ring nitrogen atoms;
each R 9 is independently halogen, C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, O—(C 1 -C 6 -alkyl), CF 3 , OCF 3 , S(C 1 -C 6 -alkyl), CN, OCH 2 -phenyl, NH 2 , NH—(C 1 -C 6 -alkyl), N—(C 1 -C 6 -alkyl) 2 , piperidine, pyrrolidine, CH 2 F, CHF 2 , OCH 2 F, OCHF 2 , OH, SO 2 (C 1 -C 6 -alkyl), C(O)NH 2 , C(O)NH(C 1 -C 6 -alkyl), and C(O)N(C 1 -C 6 -alkyl) 2 ; and
m, n and p are independently 0 or 1.

3. The compound of claim 1 , wherein R 2 is H.

4. The compound of claim 3 , wherein R 5 is H or (S)-methyl.

5. The compound of claim 4 , wherein G is phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 4-fluorophenyl, 4-bromophenyl, 4-methylphenyl, 4-ethylphenyl, 4-isopropylphenyl, 4-trifluoromethylphenyl, 4-cyanophenyl, 4-methoxyphenyl, 4-ethoxyphenyl, 4-thiomethylphenyl, 4-trifluoromethoxyphenyl, 4-cyclopropylphenyl, 4-chloro-3-fluorophenyl, 3,4-difluorophenyl, 4-bromo-3-fluorophenyl, 3-fluoro-4-methylphenyl, 3-fluoro-4-methoxyphenyl, 3-fluoro-4-trifluoromethylphenyl, 4-cyano-3-fluorophenyl, 3,4-dichlorophenyl, 2,4-dichlorophenyl, 2,4-difluorophenyl, 2-chloro-4-fluorophenyl, 2-fluoro-4-chlorophenyl, 3,5-dichlorophenyl, 3,5-difluorophenyl, 3-chloro-5-fluorophenyl, 3-chloro-4-fluorophenyl, 3-bromo-4-fluorophenyl, 3,5-difluoro-4-chlorophenyl, 2,3-difluoro-4-chlorophenyl, 2,5-difluoro-4-chlorophenyl, 3,5-difluoro-4-bromophenyl, 2,3-difluoro-4-bromophenyl, 2,5-difluoro-4-bromophenyl or 4-(OCH 2 Ph)-phenyl.

6. The compound of claim 5 , wherein m is 0, n is 1 and p is 0, such that A is represented by the formula:

7. The compound of claim 6 , wherein R 8 is H.

8. The compound of claim 7 , wherein R c and R d are H.

9. The compound of claim 7 , wherein R c and R d together with the atom to which they are attached form a cyclopropyl ring.

10. The compound of claim 7 , wherein R 6 and R 7 are independently H, methyl, ethyl, isopropyl, isobutyl, tert-butyl, 3-pentyl, CH(isopropyl) 2 , CH 2 CH 2 OH, CH 2 CH 2 CH 2 OH, CH(CH 2 CH 2 OH) 2 , CH 2 CH 2 OMe, CH(CH 2 CH 2 OMe) 2 , CH 2 CH 2 CH 2 OMe, CH 2 CN, CH 2 -cyclopropyl, CH 2 -cyclobutyl, cyclopentyl, cyclohexyl, CH 2 -phenyl, CH 2 -(pyrid-2-yl), CH 2 -(pyrid-3-yl), CH 2 -(pyrid-4-yl), 4-hydroxycyclohex-1-yl, or CH(CH 3 )CH(OH)phenyl.

11. The compound of claim 7 , wherein R 6 and R 7 together with the nitrogen to which they are attached form a pyrrolidinyl, piperidinyl, azetidinyl, morpholinyl or piperazinyl ring, wherein said pyrrolidinyl, piperidinyl, azetidinyl, morpholinyl and piperazinyl rings are optionally substituted with one or two groups independently selected from OH, F methyl, CH 2 CF 3 , and oxo.

12. The compound of claim 6 , wherein A is selected from:

13. The compound of claim 5 , wherein m is 1, n is 1 and p is 0, such that A is represented by the formula:

14. The compound of claim 13 , wherein A is selected from:

Assignees

• Mitchell Ian S
• Blake James F
• Xu Rui
• Kallan Nicholas C
• Xiao Dengming
• Spencer Keith Lee
• Bencsik Josef R
• Array Biopharma Inc

Inventors

• Mitchell Ian S
• Blake James F
• Xu Rui
• Kallan Nicholas C
• Xiao Dengming
• Spencer Keith Lee
• Bencsik Josef R

Classifications

• 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

• A61P35/00

  Antineoplastic agents · CPC title

• A61P43/00

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

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title