Hydroxylated and methoxylated pyrimidyl cyclopentanes as Akt protein kinase inhibitors

Patent metadata

Field	Value
Publication number	US-9359340-B2
Application number	US-201414458062-A
Country	US
Kind code	B2
Filing date	Aug 12, 2014
Priority date	Jul 6, 2006
Publication date	Jun 7, 2016
Grant date	Jun 7, 2016

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 method of preparing a compound of Formula I:

or a tautomer, resolved enantiomer, resolved diastereomer, or salt 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) 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 form 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
said method comprising:
reacting a corresponding compound having the formula:

with a corresponding compound having the formula

to provide the compound of formula I, the tautomer, the resolved enantiomer, the resolved diastereomer, or the salt thereof.

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

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

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

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

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

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

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

9. The method of claim 1 , wherein R 5 is in the (S) configuration.

10. The method of claim 1 , wherein R 5 is methyl.

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

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

13. The method of claim 1 , wherein each R 9 group is independently selected from F, Cl, Br, I, Me, ethyl, isopropyl, CN, CF 3 , OCF 3 , SMe, OMe and OCH 2 Ph.

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

17. The method of claim 1 , wherein G is a thiophene or pyridine optionally substituted by a halogen.

18. The method of claim 1 , wherein G is selected from the structures:

19. The method 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 method of claim 1 , 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 method 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 method of claim 21 , where

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

• A61P35/00

  Antineoplastic agents · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · 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

• C07D403/12

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