US2014315887A1PendingUtilityA1
Pyrimidyl cyclopentanes as akt protein kinase inhibitors
Est. expiryJul 5, 2027(~1 yrs left)· nominal 20-yr term from priority
Inventors:Josef R. BencsikJames F. BlakeNicholas C. KallanIan S. MitchellKeith L. SpencerDengming XiaoRui XuChristine ChabotJun LiangBrian Safina
C07D 403/12C07D 401/12C07D 239/70C07D 409/12A61P 35/00A61K 31/506
64
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Claims
Abstract
The present invention provides compounds of Formula I, including tautomers, resolved enantiomers, 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 hyperproliferative diseases such as cancer.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A method of treating an AKT-mediated disease or disorder in a mammal, said method comprising administering to said mammal an effective amount of a compound of Formula I:
or an enantiomer or salt thereof, wherein:
R 1 and R 1a are independently selected from H, Me, Et, vinyl, CF 3 , CHF 2 or CH 2 F;
R 2 is H, OH, OMe or F;
R 2a is H, Me or F;
R 3 is H, Me, Et, or CF 3 ;
A is
G is phenyl optionally substituted by one to four R e groups or a 5-6 membered heteroaryl optionally substituted by a halogen;
R 5 and R 6 are independently H, OCH 3 , C 3 -C 6 -cycloalkyl optionally substituted with F, OH, C 1 -C 3 alkyl or O(C 1 -C 3 alkyl), 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 5 and R 6 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, or
R c is hydrogen and R d and R 6 together with the atoms to which they are attached form a 4 to 6 membered heterocyclic ring having one nitrogen atom;
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;
each R e is independently halogen, C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, CF 3 , OCF 3 , S(C 1 -C 6 -alkyl), CN, OCH 2 -phenyl, NH 2 , NO 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 ;
m and n are independently 0, 1, 2 or 3 with the proviso that (m+n) must equal 2, 3 or 4; and
p is 0 or 1.
2 . The method of claim 1 wherein:
R 1 and R 1a are independently selected from H, Me, Et, vinyl, CF 3 , CHF 2 or CH 2 F;
R 2 is H, OH, OMe or F;
R 2a is H, Me or F;
R 3 is H, Me, Et, or CF 3 ;
A is
G is phenyl optionally substituted by one to four R e groups or a 5-6 membered heteroaryl optionally substituted by a halogen;
R 5 and R 6 are independently H, OCH 3 , C 3 -C 6 -cycloalkyl optionally substituted with F, OH, C 1 -C 3 alkyl or O(C 1 -C 3 alkyl), 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 5 and R 6 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;
each R e 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 , NO 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 ;
m and n are independently 0, 1 or 2, with the proviso that (m+n) must equal 2, 3 or 4; and
p is 0 or 1.
3 . The method of claim 1 wherein R 3 is H.
4 . The method of claim 1 wherein R 3 is methyl.
5 . The method of claim 4 , wherein said methyl is optionally in the (S) configuration.
6 . The method of claim 1 wherein R 3 is ethyl.
7 . The method of claim 1 wherein R 1 is methyl.
8 . The method of claim 7 , wherein said methyl is optionally in the (R) configuration.
9 . The method of claim 1 wherein R 1 is hydrogen.
10 . The method of claim 1 wherein R 1a is hydrogen.
11 . The method of claim 1 wherein R 1a is methyl.
12 . The method of claim 1 wherein R 2 is H.
13 . The method of claim 1 wherein R 2 is F.
14 . The method of claim 1 wherein R 2 is OH.
15 . The method of claim 1 wherein R 2a is H.
16 . The method of claim 1 wherein R 2a is F.
17 . The method of claim 1 wherein G is phenyl optionally substituted with one to four R e groups.
18 . The method of claim 17 , wherein G is phenyl optionally substituted with one to four groups independently selected from F, Cl, Br, I, methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, CN, CF 3 , OMe, OEt, OCF 3 , NO 2 , SMe and OCH 2 Ph.
19 . The method of claim 18 , wherein G is 4-chlorophenyl, 4-fluorophenyl, 4-bromophenyl, 4-iodophenyl, 4-trifluoromethylphenyl, 4-trifluormethoxyphenyl, 4-thiomethylphenyl, 3-fluoro-4-chlorophenyl, 2,4-dichlorophenyl or 3,4-dichlorophenyl.
20 . The method of claim 1 , wherein G is a 5-6 membered monocyclic heteroaryl optionally substituted by one or more halogens.
21 . The method of claim 20 , wherein G is:
22 . The method of claim 1 wherein R a is H.
23 . The method of claim 1 wherein R b is H.
24 . The method of claim 1 wherein R c is H.
25 . The method of claim 1 wherein R d is H.
26 . The method of claim 1 wherein R 5 is H or ethyl.
27 . The method of claim 1 wherein R 6 is H or ethyl.
28 . The method of claim 1 wherein m is 1 and n is 1.
29 . The method of claim 1 wherein p is 0.
30 . The method of claims 29 , wherein A is:
31 . The method of claim 1 wherein p is 1.
32 . The method of claim 31 , wherein A is:
33 . The method of claim 31 , wherein A is:
34 . The method of claim 1 , wherein m is 0, R c is hydrogen, and R d and R 6 together with the atoms to which they are attached form a 4 to 6 membered heterocyclic ring having one nitrogen atom.
35 . The method of claim 34 , wherein n is 1 and q is 1, n is 1 and q is 2, or n is 2 and q is 2.
36 . The method of claim 1 wherein said disease or disorder is inflammatory, hyperproliferative, cardiovascular, neurodegenerative, gynecological, or dermatological disease.
37 . A method of inhibiting the production of AKT protein kinase in a mammal, which comprises administering to said mammal an effective amount of a compound as described in claim 1 .Join the waitlist — get patent alerts
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