US2007293494A1PendingUtilityA1
2-Anilino-4-(Heterocyclic) Amino-Pyrimidines
Individually held — no corporate assignee on recordPriority: Jun 15, 2006Filed: Jun 13, 2007Published: Dec 20, 2007
Est. expiryJun 15, 2026(expired)· nominal 20-yr term from priority
A61P 7/02A61P 9/12A61P 3/10A61P 35/00A61P 9/06A61P 9/14A61P 3/06A61P 9/04A61P 9/00A61P 43/00A61P 9/10A61P 9/08A61P 3/00A61P 27/02A61P 25/00A61P 29/00C07D 403/14A61P 1/02C07D 239/48C07D 413/12C07D 417/12C07D 403/12A61P 13/12A61P 13/02C07D 401/12C07D 401/14A61K 31/505
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Claims
Abstract
The present invention relates to 2-arylamino-4-(heterocyclic)aminopyrimidines inhibitors which are inhibitors and therefore inhibit Protein Kinase C-alpha (PKC-α). The PKC-α inhibitors of the present invention are important for improving myocardial intracellular calcium cycling, resulting in improved myocardial contraction and relaxation performance and thereby slowing the progression of heart failure. The present invention further relates to compositions comprising said 2-arylamino-4-(heterocyclic)amino-pyrimidines and to methods for controlling, abating, or otherwise slowing the progression of heart failure.
Claims
exact text as granted — not AI-modified1 . A compound having the formula:
wherein R is a substituted or unsubstituted heterocyclic unit containing from 3 to 7 atoms;
L is a linking group having the formula:
—[C(R 4a R 4b )] n —
each R 4a and R 4b is independently chosen from:
i) hydrogen; or
ii) C 1 -C 4 linear, branched, or cyclic alkyl;
the index n is from 0 to 4; and
R 1 is phenyl having the formula:
R 5 is hydrogen or one or more independently chosen substitutes for hydrogen.
2 . A compound according to claim 1 wherein R is a unit having the formula:
R 2 and R 3 are taken together to form a ring containing from 3 to 7 atoms optionally substituted with one or more substituents.
3 . A compound according to claim 2 wherein R is chosen from pyrrolidin-1-yl, pyrrolin-1-yl, imidazolidin-1-yl, imidazolin-1-yl, pyrazolidin-1-yl, pyrazolin-1-yl, piperidin-1-yl, piperazin-1-yl, 4-methylpiperazin-1-yl, morpholin-4-yl, 4-acetylpiperazin-1-yl, and 4-methanesulfonyl-piperazin-1-yl.
4 . A compound according to claim 3 wherein R is pyrrolidin-1-yl or morpholin-4-yl.
5 . A compound according to claim 1 wherein R is a unit having the formula:
R 2 and R 3 are taken together to form a ring containing from 3 to 7 atoms optionally substituted with one or more substituents; R 10 is methyl, ethyl, 1-propyl, 2-propyl, or phenyl.
6 . A compound according to claim 5 wherein R is chosen from pyrrolidin-2-yl, N-methyl-pyrrolidin-2-yl, N-methylpyrrolidin-2-on-5-yl, pyrrolin-2-yl, imidazolidin-2-yl, imidazolin-2-yl, pyrazolidin-2-yl, pyrazolin-2-yl, piperidin-2-yl, N-methyl-piperidin-2-yl, piperazin-2-yl, 1-methylpiperazin-2-yl, 4-methylpiperazin-2-yl, 1,4-dimethylpiperazin-2-yl, morpholin-3-yl, and N-methylmorpholin-3-yl.
7 . A compound according to claim 1 wherein R is a unit having the formula:
wherein R 2 and R 3 are taken together to form a heterocycle having from 3 to 7 atoms optionally substituted with one or more substituents; R 10 is methyl, ethyl, 1-propyl, 2-propyl, or phenyl.
8 . A compound according to claim 7 wherein R is chosen from piperidin-3-yl, pyrrolidin-3-yl, and morpholin-2-yl.
9 . A compound according to claim 7 wherein R 1 is chosen from N-methyl-pyrrolidin-3-yl, N-methylpiperidin-3-yl, N-(2-propyl)-piperidin-3-yl and N-methylmorpholin-3-yl.
10 . A compound according to claim 1 wherein R is a unit having the formula:
wherein R 2 and R 3 are taken together to form a heterocycle having from 3 to 7 atoms optionally substituted with one or more substituents; R 10 is methyl, ethyl, 1-propyl, 2-propyl, or phenyl.
11 . A compound according to claim 10 wherein R is chosen from piperidin-4-yl, N-methyl-piperidin-4-yl, 2,2,6,6-tetramethyl-piperidin-4-yl, N-methyl-2,2,6,6-tetramethyl-piperidin-4-yl, 8-azabicyclo[3.2.1]oct-3-yl or N-methyl-8-azabicyclo[3.2.1]oct-3-yl.
12 . A compound according to claim 1 wherein L is a unit chosen from —CH 2 CH 2 —, —CH 2 CH 2 CH 22 —, and —CH 2 CH 2 CH 2 CH 2 —.
13 . A compound according to claim 1 wherein R 5 represent one of more independently chosen substitutions for hydrogen, R 5 having the formula:
-(L 1 ) y -R 6 R 6 is a unit chosen from: i) hydrogen; ii) halogen; iii) nitro; iv) hydroxy; v) amino, mono- or di-substituted (C 1 -C 4 linear or branched alkyl)amino; vi) substituted or unsubstituted C 1 -C 4 linear or branched alkyl; vii) substituted or unsubstituted C 1 -C 4 linear or branched alkoxy; viii) substituted or unsubstituted phenyl; ix) substituted or unsubstituted C 2 -C 5 heterocyclic; x) substituted or unsubstituted C 3 -C 8 heteroaryl; xi) cyano; or xii) CH m X 3-m wherein X is halogen and m is from 0 to 2; L 1 is a linking unit chosen from: i) —[C(R 7a R 7b )] j —; ii) —[C(R 7a R 7b )] j O[C(R 8a R 8b )] k —; iii) —[C(R 7a R 7b )] j NR 9 SO 2 [C(R 8a R 8b )] k —; iv) —[C(R 7a R 7b )] j SO 2 NR 9 [C(R 8a R 8b )] k —; v) —[C(R 7a R 7b )]NR 9 C(O)[C(R 8a R 8b )] k —; vi) —[C(R 7a R 7b )] j C(O)NR 9 [C(R 8a R 8b )] k —; or vii) —[C(R 7a R 7b )] j SO 2 [C(R 8a R 8b )] k —; R 7a , R 7b , R 8a , R 8b , and R 9 are each independently hydrogen, methyl, or ethyl; the indices j and k are each independently from 0 to 3; the index y is 0 or 1.
14 . A compound according to claim 13 wherein R 1 is chosen from 3-chlorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 3-chloro-4-methylphenyl, 3-chloro-4-fluorophenyl, 3,4-difluorophenyl, 3-trifluoromethylphenyl, 3-trifluoromethyl-4-chlorophenyl, 3-methoxyphenyl, 3-methylphenyl, 3-ethylphenyl, or 3-isopropylphenyl.
15 . A compound according to claim 13 wherein R 1 is chosen from 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,3-difluorophenyl, 2,4-difluorophenyl, 2,5-difluorophenyl, 2,6-difluorophenyl, 2,3,4-trifluorophenyl, 2,3,5-trifluorophenyl, 2,3,6-trifluorophenyl, 2,4,5-trifluorophenyl, 2,4,6-trifluorophenyl, 2-chlorophenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl, 2,6-dichlorophenyl, 2,3,4-trichlorophenyl, 2,3,5-trichlorophenyl, 2,3,6-trichlorophenyl, 2,4,5-trichlorophenyl, or 2,4,6-trichlorophenyl.
16 . A compound according to claim 13 wherein R 1 is chosen from 2-methylphenyl, 4-methylphenyl, 2,3-dimethylphenyl, 2,4-dimethylphenyl, 2,5-dimethylphenyl, 2,6-dimethylphenyl, 3,4-dimethyl-phenyl, 2,3,4-trimethylphenyl, 2,3,5-trimethyl-phenyl, 2,3,6-trimethylphenyl, 2,4,5-trimethylphenyl, 2,4,6-trimethylphenyl, 2-ethylphenyl, 4-ethylphenyl, 2,3-diethylphenyl, 2,4-diethylphenyl, 2,5-diethylphenyl, 2,6-diethylphenyl, 3,4-diethylphenyl, 2,3,4-triethylphenyl, 2,3,5-triethylphenyl, 2,3,6-triethylphenyl, 2,4,5-triethylphenyl, or 2,4,6-triethylphenyl.
17 . A compound according to claim 13 wherein R 1 is chosen from 2-methoxyphenyl, 4-methoxyphenyl, 2,3-dimethoxyphenyl, 2,4-dimethoxyphenyl, 2,5-dimethoxyphenyl, 2,6-dimethoxyphenyl, 3,4-dimethoxyphenyl, 2,3,4-trimethoxyphenyl, 2,3,5-trimethoxyphenyl, 2,3,6-trimethoxy-phenyl, 2,4,5-trimethoxyphenyl, 2,4,6-trimethoxyphenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 2,3-dihydroxyphenyl, 2,4-dihydroxyphenyl, 2,5-dihydroxyphenyl, 2,6-dihydroxyphenyl, 3,4-dihydroxy-phenyl, 2,3,4-trihydroxyphenyl, 2,3,5-trihydroxy-phenyl, 2,3,6-trihydroxyphenyl, 2,4,5-trihydroxyphenyl, or 2,4,6-trihydroxyphenyl.
18 . A compound according to claim 13 wherein L 1 has the formula:
—[CH 2 ] j — the index j is 0, 1, or 2; and R 6 is chosen from phenyl, piperidin-1-yl, pyridin-2-yl, pyridin-3-yl, or pyridin-4-yl.
19 . A compound according to claim 18 wherein R 1 is chosen from 3-(pyridin-2-yl)phenyl, 3-(pyridin-3-yl)phenyl, 3-(pyridin-4-yl)phenyl, 3-(pyridin-2-yl)phenyl, biphenyl-3-yl, or 3-(piperidin-1-ylmethyl)phenyl.
20 . A compound according to claim 13 wherein L 1 has the formula:
—O[CH 2 ] k — the index k is 1 or 2; and R 6 is chosen from phenyl, piperidin-1-yl, pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl.
21 . A compound according to claim 13 wherein L 1 has the formula:
—SO 2 NH[CH 2 ] k — the index k is 0, 1, or 2; and R 6 is chosen from: i) hydrogen; ii) substituted or unsubstituted C 1 -C 4 linear or branched alkyl; iii) substituted or unsubstituted phenyl; and iv) substituted or unsubstituted C 3 -C 9 heteroaryl.
22 . A compound according to claim 21 wherein R 1 is chosen from benzene-sulfonamide, N-methyl-benzenesulfonamide, N-ethyl-benzenesulfonamide, N-(n-propyl)-benzenesulfonamide, N-(iso-propyl)-benzenesulfonamide, N-(n-butyl)-benzenesulfonamide, N-(sec-butyl)-benzenesulfonamide, N-(iso-butyl)-benzene-sulfonamide, and N-(tert-butyl)-benzenesulfonamide.
23 . A compound according to claim 21 wherein R 1 is chosen from N-phenyl-benzene-sulfonamide, N-(pyrimidin-2-yl)-benzenesulfonamide, N-(pyrimidin-4-yl)-benzenesulfonamide, N-(pyrimidin-5-yl)-benzenesulfonamide, N-(pyridin-2-yl)-benzenesulfonamide, N-(pyridin-3-yl)-benzenesulfonamide, and N-(pyridin-4-yl)-benzenesulfonamide.
24 . A compound according to claim 13 wherein L 1 has the formula:
—NHC(O)—; R 5 is chosen from: i) hydrogen; ii) substituted or unsubstituted C 1 -C 4 linear or branched alkyl; iii) substituted or unsubstituted phenyl; or iv) substituted or unsubstituted C 3 -C 9 heteroaryl.
25 . A compound according to claim 24 wherein R 5 is chosen from phenyl, piperidin-1-yl, pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl.
26 . A compound having the formula:
wherein R 5 has the formula: R 6 is a unit chosen from: i) hydrogen; ii) halogen; iii) nitro; iv) hydroxy; v) amino or mono- or di-substituted (C 1 -C 4 linear or branched alkyl)amino; vi) substituted or unsubstituted C 1 -C 4 linear or branched alkyl; vii) substituted or unsubstituted C 1 -C 4 linear or branched alkoxy; viii) substituted or unsubstituted phenyl; ix) substituted or unsubstituted C 2 -C 5 heterocyclic; and x) substituted or unsubstituted C 3 -C 9 heteroaryl; xi) cyano; or xii) CH m X 3-m wherein X is halogen and m is from 0 to 2; L 1 is a linking unit chosen from: i) [CH 2 ] j —; ii) —O[CH 2 ] k —; iii) —SO 2 NH—; iv) —NHC(O)—; or v) —C(O)NH—; the index j is 0, 1 or 2 the index k is 0 or 1.
27 . A compound having the formula:
wherein R is a unit having the formula:
R 2 and R 3 are taken together to form a ring containing from 3 to 7 atoms optionally substituted with one or more substituents;
R 5 has the formula:
-(L 1 ) y -R 6
R 6 is a unit chosen from:
i) hydrogen;
ii) halogen;
iii) nitro;
iv) hydroxy;
v) amino or mono- or di-substituted (C 1 -C 4 linear or branched alkyl)amino;
vi) substituted or unsubstituted C 1 -C 4 linear or branched alkyl;
vii) substituted or unsubstituted C 1 -C 4 linear or branched alkoxy;
viii) substituted or unsubstituted phenyl;
ix) substituted or unsubstituted C 2 -C 5 heterocyclic;
x) substituted or unsubstituted C 3 -C 9 heteroaryl;
xi) cyano; or
xii) CH m X 3-m wherein X is halogen and m is from 0 to 2;
L 1 is a linking unit chosen from:
i) —[CH 2 ] j —;
ii) —O[CH 2 ] k —;
iii) —SO 2 NH—;
iv) —NHC(O)—; or
v) —C(O)NH—;
the index j is 0, 1 or 2, the index k is 0 or 1.
28 . A compound having the formula:
wherein R is a unit having the formula:
R 2 and R 3 are taken together to form a ring containing from 3 to 7 atoms optionally substituted with one or more substituents;
R 5 has the formula:
-(L 1 ) y -R 6
R 6 is a unit chosen from:
i) hydrogen;
ii) halogen;
iii) nitro;
iv) hydroxy;
v) amino or mono- or di-substituted (C 1 -C 4 linear or branched alkyl)amino;
vi) substituted or unsubstituted C 1 -C 4 linear or branched alkyl;
vii) substituted or unsubstituted C 1 -C 4 linear or branched alkoxy;
viii) substituted or unsubstituted phenyl;
ix) substituted or unsubstituted C 2 -C 5 heterocyclic; and
x) substituted or unsubstituted C 3 -C 9 heteroaryl;
xi) cyano; or
xii) CH m X 3-m wherein X is halogen and m is from 0 to 2;
L 1 is a linking unit chosen from:
i) —[CH 2 ] j —;
ii) —O[CH 2 ] k —;
iii) —SO 2 NH—;
iv) —NHC(O)—; or
v) —C(O)NH—;
the index j is 0, 1 or 2, the index k is 0 or 1.
29 . A compound having the formula:
wherein R is a heterocyclic unit chosen from:
i)
ii)
iii)
R 2 and R 3 are taken together to form a ring containing from 3 to 7 atoms optionally substituted with one or more substituents;
R 5 has the formula:
-(L 1 ) y -R 6
R 6 is a unit chosen from:
i) hydrogen;
ii) halogen;
iii) nitro;
iv) hydroxy;
v) amino or mono- or di-substituted (C 1 -C 4 linear or branched alkyl)amino;
vi) substituted or unsubstituted C 1 -C 4 linear or branched alkyl;
vii) substituted or unsubstituted C 1 -C 4 linear or branched alkoxy;
viii) substituted or unsubstituted phenyl;
ix) substituted or unsubstituted C 2 -C 5 heterocyclic;
x) substituted or unsubstituted C 3 -C 9 heteroaryl;
xi) cyano; or
xii) CH m X 3-m wherein X is halogen and m is from 0 to 2;
L 1 is a linking unit chosen from:
i) —[CH 2 ] j —;
ii) —O[CH 2 ] r ;
iii) —SO 2 NH—;
iv) —NHC(O)—; or
v) —C(O)NH—;
the index j is 0, 1 or 2, the index k is 0 or 1;
R 10 is methyl, ethyl, 1-propyl, 2-propyl, or phenyl.
30 . A compound chosen from:
N 2 -(3-Chlorophenyl)-N 4 -(3-morpholin-4-yl-propyl)-pyrimidine-2,4-diamine; N 2 -(3-Fluorophenyl)-N 4 -(3-morpholin-4-yl-propyl)-pyrimidine-2,4-diamine; N 2 -(3-Nitrophenyl)-N 4 -(3-morpholin-4-ylpropyl)-pyrimidine-2,4-diamine; N 2 -(3-Bromophenyl)-N 4 -(3-morpholin-4-yl-propyl)-pyrimidine-2,4-diamine; N 2 -(3-Aminophenyl)-N 4 -(3-morpholin-4-yl-propyl)-pyrimidine-2,4-diamine; {3-[4-(3-Morpholin-4-yl-propylamino)-pyrimidin-2-ylamino]-phenyl}-methanol; N 2 -(3-Phenoxyphenyl)-N 4 -(3-morpholin-4-yl-propyl)-pyrimidine-2,4-diamine; N 2 -(3-Chlorophenyl)-N 4 -[3-(4-methylpiperazin-1-yl)-propyl]-pyrimidine-2,4-diamine; N 2 -(4-(Benzyloxy)-3-chlorophenyl)-N 4 -(3-pyrrolidin-1-yl-propyl)-pyrimidine-2,4-diamine; N 2 -(3-Nitrophenyl)-N 4 -(3-pyrrolidin-1-yl-propyl)-pyrimidine-2,4-diamine; N 2 -(3-Chlorophenyl)-N 4 -(3-pyrrolidin-1-yl-propyl)-pyrimidine-2,4-diamine; N 2 -(3-Methylphenyl)-N 4 -(3-pyrrolidin-1-yl-propyl)-pyrimidine-2,4-diamine; N 2 -[3-Methoxyphenyl]-N 4 -(3-pyrrolidin-1-yl-propyl)-pyrimidine-2,4-diamine; N 2 -[3-Trifluoromethyl-phenyl]-N 4 -(3-pyrrolidin-1-yl-propyl)-pyrimidine-2,4-diamine; N 2 -(3-Isopropylphenyl)-N 4 -(3-morpholin-4-yl-propyl)-pyrimidine-2,4-diamine; N 2 -(3,5-Bis-trifluoromethyl-phenyl)-N 4 -(3-morpholin-4-yl-propyl)-pyrimidine-2,4-diamine; N 2 -[3-(Pyridin-3-yl)-phenyl]-N 4 -(3-morpholin-4-yl-propyl)-pyrimidine-2,4-diamine; N 2 -[3-(Benzo[d]thiazol-2-yl)-phenyl]-N 4 -(3-morpholin-4-yl-propyl)-pyrimidine-2,4-diamine; N 2 -[3-(1H-Indol-2-yl)-phenyl]-N 4 -(3-morpholin-4-yl-propyl)-pyrimidine-2,4-diamine; N 2 -[3-(1H-Indol-4-yl)-phenyl]-N 4 -(3-morpholin-4-yl-propyl)-pyrimidine-2,4-diamine; N 2 -Biphenyl-3-yl-N 4 -(3-morpholin-4-yl-propyl)-pyrimidine-2,4-diamine; N 2 -(3′-Nitro-biphenyl-3-yl)-N 4 -(3-morpholin-4-yl-propyl)-pyrimidine-2,4-diamine; N-{3-[4-(3-Morpholin-4-yl-propylamino)-pyrimidin-2-ylamino]-phenyl}-benzene-sulfonamide; N 2 -[3-(1H-Imidazol-1-ylmethyl)-phenyl]-N 4 -(3-morpholin-4-yl-propyl)-pyrimidine-2, 4-diamine; 3-[4-(3-Morpholin-4-yl-propylamino)-pyrimidin-2-ylamino]-N-(pyridin-3-ylmethyl)-benzenesulfonamide; 3-[4-(3-Morpholin-4-yl-propylamino)-pyrimidin-2-ylamino]-benzenesulfonamide; N-{3-[4-(3-Morpholin-4-yl-propylamino)-pyrimidin-2-ylamino]-phenyl}-benzamide; N-Isopropyl-3-[4-(3-pyrrolidin-1-yl-propylamino)-pyrimidin-2-ylamino]-benzamide; N 2 -[3-(4-Methyl-piperazine-1-sulfonyl)phenyl]-N 4 -(3-morpholin-4-ylpropyl)-pyrimidine-2, 4-diamine; N-{3-[4-(3-Morpholin-4-yl-propylamino)-pyrimidin-2-ylamino]-phenyl}-nicotinamide; N 2 -(3-Chlorophenyl)-N 4 -piperidin-2-ylmethyl-pyrimidine-2,4-diamine; N 2 -(3-Chlorophenyl)-N 4 -(1-methylpiperidin-2-ylmethyl)-pyrimidine-2,4-diamine; N 2 -(3-Chlorophenyl)-N 4 -piperidin-3-ylmethyl-pyrimidine-2,4-diamine; N 2 -(3-Chlorophenyl)-N 4 -(1-methylpiperidin-3-ylmethyl)-pyrimidine-2,4-diamine: N 2 -(3-Chlorophenyl)-N 4 -(1-methylpiperidin-4-ylmethyl)-pyrimidine-2,4-diamine; N 2 -(3-Chlorophenyl)-N 4 -[2-(1-methylpyrrolidin-2-yl)-ethyl]-pyrimidine-2,4-diamine; N 2 -(3-Chlorophenyl)-N 4 -morpholin-2-ylmethyl-pyrimidine-2,4-diamine; and N 2 -(3-Chlorophenyl)-N 4 -(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-pyrimidine-2,4-diamine; N 2 -(3-Chloro-phenyl)-N 4 -(2,2,6,6-tetramethyl-piperidin-4-yl)-pyrimidine-2,4-diamine; N-Benzyl-3-[4-(3-pyrrolidin-1-yl-propylamino)-pyrimidin-2-ylamino]-benzamide; 3-[4-(3-Morpholin-4-yl-propylamino)-pyrimidin-2-ylamino]-N-phenyl-benzenesulfonamide; 3-[4-(3-Morpholin-4-yl-propylamino)-pyrimidin-2-ylamino]-N-(2-pyridin-3-yl-ethyl)-benzenesulfonamide; N 2 -(3-Chloro-phenyl)-N 4 -piperidin-4-ylmethyl-pyrimidine-2,4-diamine; N 4 -(3-Morpholin-4-yl-propyl)-N 2 -(3-pyridin-4-yl-phenyl)-pyrimidine-2,4-diamine; N 2 -(3-Chloro-phenyl)-N 4 -(1-methyl-pyrrolidin-3-ylmethyl)-pyrimidine-2,4-diamine; N 2 -(3-Chloro-phenyl)-N 4 -(1-isopropyl-piperidin-3-ylmethyl)-pyrimidine-2,4-diamine; N-{3-[4-(3-Morpholin-4-yl-propylamino)-pyrimidin-2-ylamino]-phenyl}-isonicotinamide; N 2 -[3-(Morpholine-4-sulfonyl)-phenyl]-N 4 -(3-morpholin-4-yl-propyl)-pyrimidine-2,4-diamine; 1-(4-{3-[2-(3-Chloro-phenylamino)-pyrimidin-4-ylamino]-propyl}-piperazin-1-yl)-ethanone; N 2 -[3-(1H-Indol-6-yl)-phenyl]-N 4 -(3-morpholin-4-yl-propyl)-pyrimidine-2,4-diamine; N 2 -(3-Chloro-phenyl)-N 4 -[3-(4-methanesulfonyl-piperazin-1-yl)-propyl]-pyrimidine-2,4-diamine; N 4 -(3-Morpholin-4-yl-propyl)-N 2 -(3-trifluoromethoxy-phenyl)-pyrimidine-2,4-diamine; N 4 -(3-Morpholin-4-yl-propyl)-N 2 -[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-pyrimidine-2,4-diamine; 4-Dimethylamino-N-{3-[4-(3-morpholin-4-yl-propylamino)-pyrimidin-2-ylamino]-phenyl}-benzamide; N-(3-Chloro-phenyl)-3-[4-(3-pyrrolidin-1-yl-propylamino)-pyrimidin-2-ylamino]-benzamide.
31 . A compound chosen from
N 2 -(3-Chlorophenyl)-N 4 -(3-pyrrolidin-1-yl-propyl)-pyrimidine-2,4-diamine; N 2 -(3-Chlorophenyl)-N 4 -(3-pyrrolin-1-yl-propyl)-pyrimidine-2,4-diamine; N 2 -(3-Chlorophenyl)-N 4 -(3-imidazolidin-1-yl-propyl)-pyrimidine-2,4-diamine; N 2 -(3-Chlorophenyl)-N 4 -(3-imidazolin-1-yl-propyl)-pyrimidine-2,4-diamine; N 2 -(3-Chlorophenyl)-N 4 -(3-pyrazolidin-1-yl-propyl)-pyrimidine-2,4-diamine; N 2 -(3-Fluorophenyl)-N 4 -(3-pyrrolidin-1-yl-propyl)-pyrimidine-2,4-diamine; N 2 -(3-Fluorophenyl)-N 4 -(3-pyrrolin-1-yl-propyl)-pyrimidine-2,4-diamine; N 2 -(3-Fluorophenyl)-N 4 -(3-imidazolidin-1-yl-propyl)-pyrimidine-2,4-diamine; N 2 -(3-Fluorophenyl)-N 4 -(3-imidazolin-1-yl-propyl)-pyrimidine-2,4-diamine; N 2 -(3-Fluorophenyl)-N 4 -(3-piperidin-1-yl-propyl)-pyrimidine-2,4-diamine; N 2 -(3-Fluorophenyl)-N 4 -(3-piperazin-1-yl-propyl)-pyrimidine-2,4-diamine; N 2 -(3-Fluorophenyl)-N 4 -(3-pyrazolidin-1-yl-propyl)-pyrimidine-2,4-diamine; N 2 -(3-Methylphenyl)-N 4 -(3-pyrrolidin-1-yl-propyl)-pyrimidine-2,4-diamine; N 2 -(3-Methylphenyl)-N 4 -(3-pyrrolin-1-yl-propyl)-pyrimidine-2,4-diamine N 2 -(3-Methylphenyl)-N 4 -(3-imidazolidin-1-yl-propyl)-pyrimidine-2,4-diamine; N 2 -(3-Methylphenyl)-N 4 -(3-imidazolin-1-yl-propyl)-pyrimidine-2,4-diamine; N 2 -(3-Methylphenyl)-N 4 -(3-pyrazolidin-1-yl-propyl)-pyrimidine-2,4-diamine; N 2 -(3-Methylphenyl)-N 4 -(3-piperidin-1-yl-propyl)-pyrimidine-2,4-diamine; N 2 -(3-Methylphenyl)-N 4 -(3-piperazin-1-yl-propyl)-pyrimidine-2,4-diamine; N 2 -(3-Methoxyphenyl)-N 4 -(3-pyrrolidin-1-yl-propyl)-pyrimidine-2,4-diamine; N 2 -(3-Methoxyphenyl)-N 4 -(3-pyrrolin-1-yl-propyl)-pyrimidine-2,4-diamine; N 2 -(3-Methoxyphenyl)-N 4 -(3-imidazolidin-1-yl-propyl)-pyrimidine-2,4-diamine; N 2 -(3-Methoxyphenyl)-N 4 -(3-imidazolin-1-yl-propyl)-pyrimidine-2,4-diamine; N 2 -(3-Methoxyphenyl)-N 4 -(3-pyrazolidin-1-yl-propyl)-pyrimidine-2,4-diamine; N 2 -(3-Methoxyphenyl)-N 4 -(3-piperidin-1-yl-propyl)-pyrimidine-2,4-diamine; N 2 -(3-Methoxyphenyl)-N 4 -(3-piperazin-1-yl-propyl)-pyrimidine-2,4-diamine; N 2 -(3-Trifluoromethylphenyl)-N 4 -(3-pyrrolidin-1-yl-propyl)-pyrimidine-2,4-diamine; N 2 -(3-Trifluoromethylphenyl)-N 4 -(3-pyrrolin-1-yl-propyl)-pyrimidine-2,4-diamine; N 2 -(3-Trifluoromethylphenyl)-N 4 -(3-imidazolidin-1-yl-propyl)-pyrimidine-2,4-diamine; N 2 -(3-Trifluoromethylphenyl)-N 4 -(3-imidazolin-1-yl-propyl)-pyrimidine-2,4-diamine; N 2 -(3-Trifluoromethylphenyl)-N 4 -(3-pyrazolidin-1-yl-propyl)-pyrimidine-2,4-diamine; N 2 -(3-Trifluoromethylphenyl)-N 4 -(3-piperidin-1-yl-propyl)-pyrimidine-2,4-diamine; and N 2 -(3-Trifluoromethylphenyl)-N 4 -(3-piperazin-1-yl-propyl)-pyrimidine-2,4-diamine.
32 . A compound chosen from:
N 2 -[3-(Pyridin-2-yl)-phenyl]-N 4 -(3-morpholin-4-yl-propyl)-pyrimidine-2,4-diamine; N 2 -[3-(1-Indol-3-yl)-phenyl]-N 4 -(3-morpholin-4-yl-propyl)-pyrimidine-2,4-diamine; N 2 -[3-(Pyridin-4-yl)-phenyl]-N 4 -(3-morpholin-4-yl-propyl)-pyrimidine-2,4-diamine; N 2 -[3-(1H-Indol-2-yl)-phenyl]-N 4 -(3-pyrrolidin-1-yl-propyl)-pyrimidine-2,4-diamine; N 2 -[3-(1H-Indol-3-yl)-phenyl]-N 4 -(3-pyrrolidin-1-yl-propyl)-pyrimidine-2,4-diamine; N 2 -[3-(Benzo[d]thiazol-2-yl)-phenyl]1-N 4 -(3-pyrrolidin-1-yl-propyl)-pyrimidine-2,4-diamine; N 2 -[3-(Pyridin-2-yl)-phenyl]-N 4 -(3-pyrrolin-1-yl-propyl)-pyrimidine-2,4-diamine; N 2 -[3-(Pyridin-4-yl)-phenyl]-N 4 -(3-pyrrolin-1-yl-propyl)-pyrimidine-2,4-diamine; N 2 -[3-(1H-Indol-2-yl)-phenyl]-N 4 -(3-pyrrolin-1-yl-propyl)-pyrimidine-2,4-diamine; N 2 -[3-(1H-Indol-3-yl)-phenyl]-N 4 -(3-pyrrolin-1-yl-propyl)-pyrimidine-2,4-diamine; N 2 -[3-(Benzo[d]thiazol-2-yl)-phenyl]-N 4 -(3-pyrrolin-1-yl-propyl)-pyrimidine-2,4-diamine; N 2 -[3-(Pyridin-2-yl)-phenyl]-N 4 -(3-imidazolidin-1-yl-propyl)-pyrimidine-2,4-diamine; N 2 -[3-(Pyridin-4-yl)-phenyl]-N 4 -(3-imidazolidin-1-yl-propyl)-pyrimidine-2,4-diamine; N 2 -[3-(1H-Indol-2-yl)-phenyl]-N 4 -(3-imidazolidin-1-yl-propyl)-pyrimidine-2,4-diamine; N 2 -[3-(1H-Indol-3-yl)-phenyl]-N 4 -(3-imidazolidin-1-yl-propyl)-pyrimidine-2,4-diamine; N 2 -[3-(Benzo[d]thiazol-2-yl)-phenyl]-N 4 -(3-imidazolidin-1-yl-propyl)-pyrimidine-2,4-diamine; N 2 -[3-(Pyridin-2-yl)-phenyl]-N 4 -(3-imidazolin-1-yl-propyl)-pyrimidine-2,4-diamine; N 2 -[3-(Pyridin-4-yl)-phenyl]-N 4 -(3-imidazolin-1-yl-propyl)-pyrimidine-2,4-diamine; N 2 -[3-(1H-Indol-2-yl)-phenyl]-N 4 -(3-imidazolin-1-yl-propyl)-pyrimidine-2,4-diamine; 2-[3-(1H-Indol-3-yl)-phenyl]-N 4 -(3-imidazolin-1-yl-propyl)-pyrimidine-2,4-diamine; N 2 -[3-(Benzo[d]thiazol-2-yl)-phenyl]-N 4 -(3-imidazolin-1-yl-propyl)-pyrimidine-2,4-diamine; N 2 -[3-(Pyridin-2-yl)-phenyl]-N 4 -(3-pyrazolidin-1-yl-propyl)-pyrimidine-2,4-diamine; N 2 -[3-(Pyridin-4-yl)-phenyl]-N 4 -(3-pyrazolidin-1-yl-propyl)-pyrimidine-2,4-diamine; N 2 -[3-(1H-Indol-2-yl)-phenyl]-N 4 -(3-pyrazolidin-1-yl-propyl)-pyrimidine-2,4-diamine; N 2 -[3-(1H-Indol-3-yl)-phenyl]-N 4 -(3-pyrazolidin-1-yl-propyl)-pyrimidine-2,4-diamine; N 2 -[3-(Benzo[d]thiazol-2-yl)-phenyl]-N 4 -(3-pyrazolidin-1-yl-propyl)-pyrimidine-2,4-diamine; N 2 -[3-(Pyridin-2-yl)-phenyl]-N 4 -(3-pyrazolin-1-yl-propyl)-pyrimidine-2,4-diamine; N 2 -[3-(Pyridin-4-yl)-phenyl]-N 4 -(3-pyrazolin-1-yl-propyl)-pyrimidine-2,4-diamine; N 2 -[3-(1H-Indol-2-yl)-phenyl]-N 4 -(3-pyrazolin-1-yl-propyl)-pyrimidine-2,4-diamine; N 2 -[3-(1H-Indol-3-yl)-phenyl]-N 4 -(3-pyrazolin-1-yl-propyl)-pyrimidine-2,4-diamine; N 2 -[3-(Benzo[d]thiazol-2-yl)-phenyl]-N 4 -(3-pyrazolin-1-yl-propyl)-pyrimidine-2,4-diamine; N 2 -[3-(Pyridin-2-yl)-phenyl]-4-(3-piperidin-1-yl-propyl)-pyrimidine-2,4-diamine; N 2 -[3-(Pyridin-4-yl)-phenyl]-N 4 -(3-piperidin-1-yl-propyl)-pyrimidine-2,4-diamine; N 2 -[3-(1H-Indol-2-yl)-phenyl]-N 4 -(3-piperidin-1-yl-propyl)-pyrimidine-2,4-diamine; N 2 -[3-(1H-Indol-3-yl)-phenyl]-N 4 -(3-piperidin-1-yl-propyl)-pyrimidine-2,4-diamine; N 2 -[3-(Benzo[d]thiazol-2-yl)-phenyl]-N 4 -(3-piperidin-1-yl-propyl)-pyrimidine-2,4-diamine; N 2 -[3-(Pyridin-2-yl)-phenyl]-N 4 -(3-piperazin-1-yl-propyl)-pyrimidine-2,4-diamine; N 2 -[3-(Pyridin-4-yl)-phenyl]-N 4 -(3-piperazin-1-yl-propyl)-pyrimidine-2,4-diamine; N 2 -[3-(1H-indol-2-yl)-phenyl]-N 4 -(3-piperazin-1-yl-propyl)-pyrimidine-2,4-diamine; N 2 -[3-(1H-Indol-3-yl)-phenyl]-N 4 -(3-piperazin-1-yl-propyl)-pyrimidine-2,4-diamine; N 2 -[3-(Benzo[d]thiazol-2-yl)-phenyl]-N 4 -(3-piperazin-1-yl-propyl)-pyrimidine-2,4-diamine; N 2 -[3-(Pyridin-2-yl)-phenyl]-N 4 -[3-(4-methylpiperazin-1-yl)-propyl]-pyrimidine-2,4-diamine; N 2 -[3-(Pyridin-4-yl)-phenyl]-N 4 -[3-(4-methylpiperazin-1-yl)-propyl]-pyrimidine-2,4-diamine; N 2 -[3-(1H-Indol-2-yl)-phenyl]-N 4 -[3-(4-methylpiperazin-1-yl)-propyl]-pyrimidine-2,4-diamine; N 2 -[3-(1H-Indol-3-yl)-phenyl]-N 4 -[3-(4-methylpiperazin-1-yl)-propyl]-pyrimidine-2,4-diamine; and N 2 -[3-(Benzo[d]thiazol-2-yl)-phenyl]-N 4 -[3-(4-methylpiperazin-1-yl)-propyl]-pyrimidine-2,4-diamine.
33 . A compound chosen from:
N 2 -(3′-Nitro-biphenyl-3-yl)-N 4 -(3-pyrrolidin-1-yl-propyl)-pyrimidine-2,4-diamine; N 2 -(3′-Nitro-biphenyl-3-yl)-N 4 -(3-pyrrolin-1-yl-propyl)-pyrimidine-2,4-diamine; N 2 -(3′-Nitro-biphenyl-3-yl)-N 4 -(3-imidazolidin-1-yl-propyl)-pyrimidine-2,4-diamine; N 2 -(3′-Nitro-biphenyl-3-yl)-N 4 -(3-imidazolin-1-yl-propyl)-pyrimidine-2,4-diamine; N 2 -(3′-Nitro-biphenyl-3-yl)-N 4 -(3-pyrazolidin-1-yl-propyl)-pyrimidine-2,4-diamine; N 2 -(3′-Nitro-biphenyl-3-yl)-N 4 -(3-piperidin-1-yl-propyl)-pyrimidine-2,4-diamine; N 2 -(3′-Nitro-biphenyl-3-yl)-N 4 -(3-piperazin-1-yl-propyl)-pyrimidine-2,4-diamine, N 2 -(3′-Nitro-biphenyl-3-yl)-N 4 -(3-pyrazolidin-1-yl-propyl)-pyrimidine-2,4-diamine; N 2 -(3′-Chloro-biphenyl-3-yl)-N 4 -(3-pyrrolidin-1-yl-propyl)-pyrimidine-2,4-diamine; N 2 -(3′-Chloro-biphenyl-3-yl)-N 4 -(3-pyrrolin-1-yl-propyl)-pyrimidine-2,4-diamine; N 2 -(3′-Chloro-biphenyl-3-yl)-N 4 -(3-imidazolidin-1-yl-propyl)-pyrimidine-2,4-diamine; N 2 -(3′-Chloro-biphenyl-3-yl)-N 4 -(3-imidazolin-1-yl-propyl)-pyrimidine-2,4-diamine; N 2 -(3′-Chloro-biphenyl-3-yl)-N 4 -(3-pyrazolidin-1-yl-propyl)-pyrimidine-2,4-diamine; N 2 -(3′-Chloro-biphenyl-3-yl)-N 4 -(3-piperidin-1-yl-propyl)-pyrimidine-2,4-diamine; N 2 -(3′-Chloro-biphenyl-3-yl)-N 4 -(3-piperazin-1-yl-propyl)-pyrimidine-2,4-diamine; N 2 -(3′-Chloro-biphenyl-3-yl)-N 4 -(3-pyrazolidin-1-yl-propyl)-pyrimidine-2,4-diamine; N 2 -(3′-Chloro-biphenyl-3-yl)-N 4 -(3-morpholin-4-yl-propyl)-pyrimidine-2,4-diamine; N 2 -(3′-Fluoro-biphenyl-3-yl)-N 4 -(3-pyrrolidin-1-yl-propyl)-pyrimidine-2,4-diamine; N 2 -(3′-Fluoro-biphenyl-3-yl)-N 4 -(3-pyrrolin-1-yl-propyl)-pyrimidine-2,4-diamine; N 2 -(3′-Fluoro-biphenyl-3-yl)-N 4 -(3-imidazolidin-1-yl-propyl)-pyrimidine-2,4-diamine; N-(3′-Fluoro-biphenyl-3-yl)-N 4 -(3-imidazolin-1-yl-propyl)-pyrimidine-2,4-diamine; N 2 -(3′-Fluoro-biphenyl-3-yl)-N 4 -(3-pyrazolidin-1-yl-propyl)-pyrimidine-2,4-diamine; N 2 -(3′-Fluoro-biphenyl-3-yl)-N 4 -(3-piperidin-1-yl-propyl)-pyrimidine-2,4-diamine; N 2 -(3′-Fluoro-biphenyl-3-yl)-N 4 -(3-piperazin-1-yl-propyl)-pyrimidine-2,4-diamine; N 2 -(3′-Fluoro-biphenyl-3-yl)-N 4 -(3-pyrazolidin-1-yl-propyl)-pyrimidine-2,4-diamine; N 2 -(3′-Fluoro-biphenyl-3-yl)-N 4 -(3-morpholin-4-yl-propyl)-pyrimidine-2,4-diamine; N 2 -(3′-Methyl-biphenyl-3-yl)-N 4 -(3-pyrrolidin-1-yl-propyl)-pyrimidine-2,4-diamine; N 2 -(3′-Methyl-biphenyl-3-yl)-N 4 -(3-pyrrolin-1-yl-propyl)-pyrimidine-2,4-diamine; N 2 -(3′-Methyl-biphenyl-3-yl)-N 4 -(3-imidazolidin-1-yl-propyl)-pyrimidine-2,4-diamine; N 2 -(3′-Methyl-biphenyl-3-yl)-N 4 -(3-imidazolin-1-yl-propyl)-pyrimidine-2,4-diamine; N 2 -(3′-Methyl-biphenyl-3-yl)-N 4 -(3-pyrazolidin-1-yl-propyl)-pyrimidine-2,4-diamine; N 2 -(3′-Methyl-biphenyl-3-yl)-N 4 -(3-piperidin-1-yl-propyl)-pyrimidine-2,4-diamine; N 2 -(3′-Methyl-biphenyl-3-yl)-N 4 -(3-piperazin-1-yl-propyl)-pyrimidine-2,4-diamine; N 2 -(3′-Methyl-biphenyl-3-yl)-N 4 -(3-pyrazolidin-1-yl-propyl)-pyrimidine-2,4-diamine; N 2 -(3′-Methyl-biphenyl-3-yl)-N 4 -(3-morpholin-4-yl-propyl)-pyrimidine-2,4-diamine; N 2 -(3′-Methoxy-biphenyl-3-yl)-N 4 -(3-pyrrolidin-1-yl-propyl)-pyrimidine-2,4-diamine; N 2 -(3′-Methoxy-biphenyl-3-yl)-N 4 -(3-pyrrolin-1-yl-propyl)-pyrimidine-2,4-diamine; N 2 -(3′-Methoxy-biphenyl-3-yl)-N 4 -(3-imidazolidin-1-yl-propyl)-pyrimidine-2,4-diamine; N 2 -(3′-Methoxy-biphenyl-3-yl)-N 4 -(3-imidazolin-1-yl-propyl)-pyrimidine-2,4-diamine; N 2 -(3′-Methoxy-biphenyl-3-yl)-N 4 -(3-pyrazolidin-1-yl-propyl)-pyrimidine-2,4-diamine; N 2 -(3′-Methoxy-biphenyl-3-yl)-N 4 -(3-piperidin-1-yl-propyl)-pyrimidine-2,4-diamine; N 2 -(3′-Methoxy-biphenyl-3-yl)-N 4 -(3-piperazin-1-yl-propyl)-pyrimidine-2,4-diamine; N 2 -(3′-Methoxy-biphenyl-3-yl)-N 4 -(3-pyrazolidin-1-yl-propyl)-pyrimidine-2,4-diamine; N 2 -(3′-Methoxy-biphenyl-3-yl)-N 4 -(3-morpholin-4-yl-propyl)-pyrimidine-2,4-diamine; N 2 -(3′-Dimethylamino-biphenyl-3-yl)-N 4 -(3-pyrrolidin-1-yl-propyl)-pyrimidine-2,4-diamine; N 2 -(3′-Dimethylamino-biphenyl-3-yl)-N 4 -(3-pyrrolin-1-yl-propyl)-pyrimidine-2,4-diamine; N 2 -(3′-Dimethylamino-biphenyl-3-yl)-N 4 -(3-imidazolidin-1-yl-propyl)-pyrimidine-2,4-diamine; N 2 -(3′-Dimethylamino-biphenyl-3-yl)-N 4 -(3-imidazolin-1-yl-propyl)-pyrimidine-2,4-diamine; N 2 -(3′-Dimethylamino-biphenyl-3-yl)-N 4 -(3-pyrazolidin-1-yl-propyl)-pyrimidine-2,4-diamine; N 2 -(3′-Dimethylamino-biphenyl-3-yl)-N 4 -(3-piperidin-1-yl-propyl)-pyrimidine-2,4-diamine; N 2 -[(-(3′-Dimethylamino-biphenyl-3-yl)-N 4 -(3-piperazin-1-yl-propyl)-pyrimidine-2,4-diamine; N 2 -(3′-Dimethylamino-biphenyl-3-yl)-N 4 -(3-pyrazolidin-1-yl-propyl)-pyrimidine-2,4-diamine; and N 2 -(3′-Dimethylamino-biphenyl-3-yl)-N 4 -(3-morpholin-4-yl-propyl)-pyrimidine-2,4-diamine.
34 . A composition comprising:
A) a compound according to claim 1; and B) the balance carriers and excipients.
35 . A method for improving cardiac contraction/relaxation parameters in heart failure patients comprising administering to a human suffering from acute heart failure a composition comprising a compound according to claim 1 .
36 . A method for treating or preventing a disease or medical condition selected from diabetes, numerous forms of cancer, microalbinuria, endothelial dysfunction, cerebrovascular disease, stroke, coronary heart disease, cardiovascular disease and sequela (e.g. arrhythmia, sudden death, increased infarct size, congestive heart failure, angina), myocardial ischemic states, hypertension, lipid disorders, ischemia-reperfusion injury, atherosclerosis, peripheral artery/vascular disease, microvascular complications of diabetes (neuropathy, nephropathy, retinopathy), restenosis, renal disease, blood coagulation disorders, inflammatory diseases, cardiac hypertrophy, dilated cardiomyopathy, ischemic injury and suboptimal mitogen stimulation said method comprised of the steps of administering to a patient in need thereof a therapeutic amount of a compound according to claim 1 .
37 . A method for treating acute heart failure comprising administering to a human an effective amount of a composition comprising one or more of the PKC-α inhibitors according to claim 1 .
38 . A method for chronic heart failure comprising administering to a human an effective amount of a composition comprising one or more of the PKC-α inhibitors according to claim 1 .
39 . A method of treating or preventing acute or chronic heart failure said method comprised of the step of administering to a patient in need thereof a pharmaceutically acceptable amount of a compound according to claim 1 or a therapeutically acceptable salt thereof in combination with a drug selected that acts on the renin-angiotensin-aldosterone system, a diuretic digoxin or β-adrenergic receptor blockers, natriuretic peptides and inotropic agents.
40 . The method of claim 37 wherein the drug used in combination with a compound according to claim 1 is a renin-angiotensin-aldosterone system selected from an ACEI, ARB, or aldosterone inhibitor.
41 . The use of a compound according to claim 1 in the manufacture of a medicament.Join the waitlist — get patent alerts
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