Hydroxylated and methoxylated pyrimidyl cyclopentanes as akt protein kinase inhibitors

Patent metadata

Field	Value
Publication number	US-2016152606-A9
Application number	US-201414458062-A
Country	US
Kind code	A9
Filing date	Aug 12, 2014
Priority date	Jul 6, 2006
Publication date	Jun 2, 2016
Grant date	—

Abstract

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

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 Formula I:

and tautomers, resolved enantiomers, resolved diastereomers, solvates, metabolites, and salts thereof, wherein:
R 1 is H, Me, Et, vinyl, 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

G is phenyl optionally substituted by one to four R 9 groups or a 5-6 membered heteroaryl optionally substituted by a halogen;
R 6 and R 7 are independently H, OCH 3 , (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 optionally substituted with C 1 -C 3 alkyl or O(C 1 -C 3 alkyl), 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, C 1 -C 3 alkyl, cyclopropylmethyl 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, oxo, O(C 1 -C 6 -alkyl), CN, F, NH 2 , NH(C 1 -C 6 -alkyl), N(C 1 -C 6 -alkyl) 2 , cyclopropyl, phenyl, imidazolyl, piperidinyl, pyrrolidinyl, morpholinyl, tetrahydrofuranyl, oxetanyl or tetrahydropyranyl,
or R 6 and R 7 together with the nitrogen to which they are attached form a 4-7 membered heterocyclic ring optionally substituted with one or more groups independently selected from OH, halogen, oxo, CF 3 , CH 2 CF 3 , CH 2 CH 2 OH, O(C 1 -C 3 alkyl), C(═O)CH 3 , NH 2 , NHMe, N(Me) 2 , S(O) 2 CH 3 , cyclopropylmethyl 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 from a cyclopropyl ring;
R 8 is H, Me, F 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, CH 2 O-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 ;
R 10 is H or Me; and
m, n and p are independently 0 or 1.

2 . The compound of claim 1 , wherein R 10 is H.

3 . The compound of claim 1 , wherein R 10 is methyl.

4 . The compound of claim 1 , wherein OR 2 is in the (S) or (R) configuration.

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

6 . The compound of claim 1 , wherein R 2 is methyl.

7 . The compound of claim 1 , wherein R 5 is H.

8 . The compound of claim 1 , wherein R 5 is methyl.

9 . The compound of claim 8 , wherein R 5 is in the (S) configuration.

10 . The compound of claim 1 , wherein R 1 is methyl.

11 . The compound of claim 10 , wherein R 1 is in the (R) configuration.

12 . The compound of claim 1 , wherein R 1 is H.

13 . The compound of claim 1 , wherein G is phenyl optionally substituted with one or more groups independently selected from F, Cl, Br, I, Me, ethyl, isopropyl, CN, CF 3 , OCF 3 , SMe, OMe and OCH 2 Ph.

14 . The compound of claim 13 , wherein G is 4-chlorophenyl, 2,4-dichlorophenyl, 3-chloro-4-fluorophenyl, 3,4-difluorophenyl, 4-chloro-3-fluorophenyl, 3-fluoro-4-bromophenyl, 3,4-dichlorophenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-bromophenyl, 4-cyanophenyl, 4-trifluoromethylphenyl, 4-thiomethylpyhenyl, or 4-methylphenyl.

15 . The compound of claim 13 , wherein G is 4-iodophenyl, 4-trifluoromethoxyphenyl, 3,5-difluorophenyl, 4-bromo-3-fluorophenyl, 3-fluoro-4-methoxyphenyl, 3-fluoro-4-trifluoromethylphenyl, 3-trifluoromethoxy-4-chlorophenyl, 3-fluoro-4-trifluoromethoxyphenyl, 3-trifluoromethyl-4-chlorophenyl, 3-trifluoromethoxy-4-fluorophenyl, 3,5-bis(trifluoromethyl)phenyl, 3-chloro-5-fluorophenyl, 3-bromo-4-methoxyphenyl, 2-fluoro-4-chlorophenyl, 2-fluoro-4-bromophenyl, 2-fluoro-4-trifluoromethylphenyl, or 3-trifluoromethyl-4-fluorophenyl.

16 . The compound of claim 1 , wherein G is a 5-6 membered heteroaryl optionally substituted by a halogen.

17 . The compound of claim 16 , wherein G is a thiophene or pyridine optionally substituted by a halogen.

18 . The compound of claim 17 , wherein G is selected from the structures:

19 . The compound of claim 1 , wherein R 6 and R 7 are independently selected from H, OCH 3 , (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 having from one to two ring heteroatoms independently selected from N, O and S, W—(CH 2 ) 1-2 wherein W is phenyl optionally substituted with F, Cl or Me, C 3 -C 6 -cycloalkyl optionally substituted with OCH 3 , hydroxy-(C 3 -C 6 -cycloalkyl), fluoro-(C 3 -C 6 -cycloalkyl), CH(CH 3 )CH(OH)phenyl, 5-6 membered heterocycle optionally substituted with CH 3 or C(═O)CH 3 , or C 1 -C 6 -alkyl optionally substituted with one or more groups independently selected from OH, oxo, O(C 1 -C 6 -alkyl), CN, F, NH 2 , NH(C 1 -C 6 -alkyl), N(C 1 -C 6 -alkyl) 2 , phenyl, imidazolyl, piperidinyl, pyrrolidinyl, morpholinyl, and tetrahydropyranyl.

20 . The compound of claim 19 , wherein R 6 and R 7 are independently selected from H, methyl, ethyl, isopropyl, isobutyl, tert-butyl, 3-pentyl, OCH 3 , CH 2 CH 2 OH, CH 2 CH 2 OMe, CH 2 CH 2 CF 3 , CH 2 CH(CH 3 )OH, CH 2 CH(CF 3 )OH, CH 2 CF 3 , CH 2 CH 2 F, CH 2 C(═O)NH 2 , CH 2 C(═O)NH(CH 3 ), CH 2 C(═O)N(CH 3 ) 2 , CH 2 C(═O)NH(iPr), CH 2 CH 2 C(═O)NH 2 , CH 2 -cyclopropyl, CH 2 -cyclopentyl, CH 2 -tBu (neopentyl), cyclopropyl, cyclopentyl, cyclohexyl, 4-methoxycyclohexyl, 4,4-dimethylcyclohexyl, 3,3-dimethylcyclohexyl, CH 2 -(pyrid-3-yl), 4-hydroxycyclohex-1-yl, CH(CH 3 )CH(OH)phenyl, CH(phenyl)CH 2 OH, CH(tetrahydropyranyl)CH 2 OH, CH 2 CH 2 CH 2 (imidazolyl), CH 2 CH 2 (morpholinyl), CH 2 (tetrahydropyranyl), CH 2 CH 2 (tetrahydropyranyl), pyrrolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrofuranyl,

21 . The compound of claim 1 , wherein R 6 and R 7 together with the nitrogen to which they are attached form a 4-7 membered heterocyclic ring, wherein said heterocyclic ring is optionally substituted with one or more groups independently selected from OH, halogen, oxo, CF 3 , CH 2 CF 3 , CH 2 CH 2 OH, OCH 3 , C(═O)CH 3 , NH 2 , NHMe, N(Me) 2 , S(O) 2 CH 3 , and (C 1 -C 3 )alkyl.

22 . The compound of claim 21 , wherein NR 6 R 7 is selected from the structures:

23 . The compound of claim 1 , wherein R 8 and R 6 together with th

Assignees

• Array Biopharma Inc
• Genentech Inc

Inventors

• Mitchell Ian S
• Blake James F
• Xu Rui
• Kallan Nicholas C
• Xiao Dengming
• Spencer Keith Lee
• Bencsik Josef R
• Wallace Eli M
• Schlachter Stephen T
• Leivers Anna L
• Liang Jun
• Safina Brian
• Zhang Birong
• Chabot Christine
• Do Steven

Classifications

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P35/00

  Antineoplastic agents · 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

• A61P29/00

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

• C07D401/12

  linked by a chain containing hetero atoms as chain links · CPC title