METHOD OF USING AMINOCYANOPYRIDINE COMPOUNDS AS MITOGEN ACTIVATED PROTEIN KINASE-ACTIVATED PROTEIN KINASE-2 INHIBITORS

PROCEDE D'UTILISATION DE COMPOSES D'AMINOCYANOPYRIDINE EN TANT QU'INHIBITEURS DE LA PROTEINE MAPKAP KINASE-2

English Abstract

A method is described for inhibiting mitogen activated protein kinase-
activated protein kinase-2 in a subject in need of such inhibition, where the
method involves administering to the subject an anminocyanopyridine MK-2
inhibiting compound, or a pharmaceutically acceptable salt thereof.

French Abstract

La présente invention a trait à un procédé permettant l'inhibition de la protéine MAPKKK chez un sujet qui en a besoin, qui comprend l'administration au sujet d'un composé d'aminocyanopyridine MK-2, ou un de ses sels pharmaceutiquement acceptables.

Claims

WHAT IS CLAIMED IS:
1. A method of inhibiting mitogen activated protein kinase-
activated protein kinase-2 in a subject in need of such inhibition, the
method comprising administering to the subject an anminocyanopyridine
MK-2 inhibiting compound, or a pharmaceutically acceptable salt thereof,
the compound having the structure:
<IMG>
wherein:
R1 is selected from the group consisting of -H, C1-C6 alkyl, C2-C6
alkenyl, C2-C6 alkynyl, carboxy C1-C4 alkyl, aryl C1-C4 alkyl, amino, amino
C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino, C1-C4 alkyl, di-( C1-C4
alkyl)amino C1-C4 alkyl, C1-C4 alkyl-C1-C4 alkyl, hydroxy C1-C4 alkyl, and
aryl C1-C4 alkylcarbonyl;
R2 is selected from the group consisting of -H, C1-C6 alkyl, C2-C6
alkenyl, C2-C6 alkynyl, amino, amino C1-C4 alkyl, C1-C4 alkylamino, aryl,
heteroaryl, heterocyclyl, carboxy, carboxy C1-C4 alkyl, C1-C4 alkoxy,
hydroxy, hydroxy C1-C4 alkyl, hydroxy C1-C4 alkylamino, hydroxy C1-C4
alkoxy, C1-C4 alkoxy C1-C4 alkyl, C1-C4 alkoxy C1-C4 alkylamino, amino C1-
C4 alkylamino, aryl C1-C4 alkyl, C1-C4 alkylamino C1-C4 alkyl, di C1-C4
alkylamino C1-C4 alkyl, C1-C4 alkyl C1-C4 alkyl, carboxy C1-C4 alkyl, aryl
C1-C4 alkylcarbonyl, phthaloamino C1-C4 alkyl, halo, carbamyl, C1-C4
alkylthio, C1-C4 alkoxyarylamino, C1-C10 mono- and bicyclic cycloalkyl,
wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl can be
optionally substituted with one or more of the groups selected from
235

halogen, hydroxy, C1-C4 alkoxy, aryloxy, C2-C4 alkenyloxy, C2-C4
alkynyloxy, C1-C4 alkyl, carboxy, carbamyl, C1-C4. alkoxycarbonyl, C1-C4
alkoxycarbonyl C1-C4 alkoxy, carboxy C1-C4 alkoxy amino, C1-C4
alkylamino, di-C1-C4 alkylamino, N-C1-C4 alkyl-N-cyano C1-C4 alkylamino,
nitro, C1-C4 alkylcarbonylamino, cyano, halo C1-C4 alkyl, di-halo C1-C4
alkyl, tri-halo C1-C4 alkyl, hydroxy C1-C4 alkoxy, halo C1-C4 alkoxy, tri-halo
C1-C4 alkoxy,
<IMG>
R3 is selected from the group consisting of -H, C1-C6 alkyl, C2-C6
alkenyl, C2-C6 alkynyl, cyano, amino C1-C4 alkyl, amino, aryl, wherein the
aryl group optionally can be substituted with one or more group selected
from halogen, hydroxy, C1-C4 alkoxy, C1-C4 alkyl, carboxy, C1-C4
alkoxycarbonyl, carboxy C1-C4 alkoxy, amino, di- C1-C4 alkylamino, N-C1-
C4 alkyl-N-cyano C1-C4 alkylamino, nitro, C1-C4 alkylcarbonylamino, cyano,
halo C1-C4 alkyl, di-halo C1-C4 alkyl, tri-halo C1-C4 alkyl, halo C1-C4
alkoxy,
di-halo C1-C4 alkoxy, tri-halo C1-C4 alkoxy, and
where the R2 and R3 groups are such that they optionally join to
form a ring system selected from:
<IMG>
236

R4 is selected from the group consisting of -H, C1-C6 alkyl, C2-C6
alkenyl, C2-C6 alkynyl, hydroxy, C1-C4 alkylthio, C1-C4 alkoxy, C1-C4
alkoxycarbonyl, mercapto, N-imidazoylphenyl, , C1-C4 isoalkyl,
aminofluorobenzhydryl, aryl and heteroaryl, wherein the aryl and
heteroaryl groups optionally can be substituted with one or more groups
selected from halogen, hydroxy, C1-C4 alkoxy, C1-C4 alkyl, C1-C4 alkylthio,
C1-C4 alkylsulfonyl, C1-C4 alkylsulfinyl, cartoxy, carbamyl, C1-C4
alkoxycarbonyl, carboxy C1-C4 alkyl, carboxy C1-C4 alkoxy, amino, di- C1-
C4 alkylamino, N-C1-C4 alkyl-N-cyano C1-C4 alkylamino, nitro, C1-C4
alkylcarbonylamino, cyano, halo C1-C4 alkyl, di-halo C1-C4 alkyl, tri-halo
C1-C4 alkyl, halo C1-C4 alkoxy, di-halo C1-C4 alkoxy, tri-halo C1-C4 alkoxy
<IMG>
wherein the R3 and R4 groups are such that they optionally join to
form a ring system selected from:
237

<IMG>
238

D, E and G are each independently selected from carbon, oxygen,
sulfur, and nitrogen;
R5 is selected from the group consisting of -H, and C1-C5 alkyl; and
wherein the R1 and R5 groups optionally join to form a piperidyl ring
or an oxazinyl ring;
R6 R7 R8 R9 R10 R11 R12 R13 R14 R15 R16 R17 R18 R19 R20
R21 R22 R23 R24 R25 R26 R27 R28 R29 R30 R31 R32 R33 R34 R35 R36
R37 R38 R39 R40 R41 R42 R43 R44 R45 R46 R47 R48 R49 R50 R51 R52
R53 R54 R55 R56 R57 R58 R59 R60 R61 R62 R63 R64 R65 R66 R67 R68
R69, R70, R71, R72, R73, R74, R75, and R76 are each optionally present and
are each independently selected from the group consisting of -H, C1-C4
alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 isoalkyl, amino, nitro, hydroxy,
C1-C4 alkoxy, C1-C4 alkenoxy, oxo, carboxy, halo, halo C1-C4 alkyl, dihalo
C1-C4 alkyl, trihalo C1-C4 alkyl, cyano, cyano C1-C4 alkyl, dicyano C1-C4
alkyl, halophenyl, hydroxy C1-C4 alkoxy, C1-C4 alkoxy C1-C4 alkoxy, -
(CH2)-O-(C6H4)-O-(CH3), carboxy C1-C4 alkoxy, C1-C4 alkylcarboxy C1-C4
alkoxy, C1-C4 alkoxyamino, C1-C4 alkylamino, di C1-C4 alkylamino, tri C1-
C4 alkylamino, amino C1-C4 alkoxy, diamino C1-C4 alkoxy, C1-C4
alkylamino C1-C4 alkoxy, di C1-C4 alkylamino C1-C4 alkoxy, cyano C1-C4
alkoxy C1-C4 alkyl, -(CH2)-O-(CF2)-CHF2, tetra C1-C4 alkoxy C1-C4 alkyl,
phenyl, benzyl, benzoyl, aryl, N-morpholinyl, morpholinyl C1-C4 alkoxy,
pyrrolidyl C1-C4 alkoxy, N pyrrolidyl C1-C4 alkoxy, C1-C4 alkylcarboxy,
carboxy C1-C4 alkyl - ethyl ester, pyridyl C1-C4 alkyl, pyridyl C1-C4 alkoxy,
COO-CH2-CH3; and
wherein R38 and R39 are such that they optionally join to form a ring
system of the type selected from:
<IMG>
239

2. The method according to claim 1, wherein the
aminocyanopyridine MK-2 inhibiting compound is one having the structure:
<IMG>
wherein:
R1 is selected from the group consisting of -H, methyl, ethyl, propyl,
butyl, -(CH2)COOH, phenyl, pyridyl, dimethylaminoethyl, methoxyethyl,
tetramethylaminoethyl, carboxymethyl, and phenylacetyl;
R2 is selected from the group consisting of -H, methyl, ethyl, propyl,
butyl, amino, phenyl, methoxy, carboxy, carboxymethyl,
hydroxyethylamino, propylamino, ethylamino, methylamino, methoxyethyl,
ethoxyethylamino, aminoethylamino, benzylamino,
dimethylaminoethylamino, phthaloaminoethyl, fluorophenyl, difluorophenyl,
chlorophenyl, bromophenyl, furyl, carbamylpyrryl, methyl-1,3-isodiazoyl,
1,3-isodiazoyl, 1,3,4-triazoyl, methoxyphenyl, -S(CH3),
tetramethylaminoethyl, acetylaminophenyl, methoxyphenylamino,
carboxyphenyl, carboxy-3-isopyrryl, cyanophenyl, cyclopropyl,
phenoxyphenyl, pyridyl, dihydroxybromophenyl, difluoromethoxyphenyl,
trifluoromethylphenyl, trifluoromethylfluorophenyl, hydroxyphenyl,
methylaminomethyl, methylaminoethyl, thiophyl, pyrryl, aminomethyl,
<IMG>
240

R3 is selected from the group consisting of -H, methyl, ethyl, propyl,
isopropyl, cyano, aminomethyl, phenyl, fluorophenyl, and amino;
wherein the R2 and R3 groups are such that they optionally join to
form a ring system selected from:
<IMG>
R4 is selected from the group consisting of -H, methyl, ethyl, propyl,
hydroxy, furyl, methylfuryl, methylimidazolyl, phenyl, hydroxyphenyl,
carboxyphenyl, pyrazolyl, hydroxy, dihydroxyphenyl, methoxyphenyl,
chlorophenyl, bromophenyl, fluorophenyl, dichlorophenyl,
dihydroxyborophenyl, thienyl, pyrryl, N-methylpyrryl, pyridyl, methylthio,
methylsulfonylphenyl, carboethoxyphenyl, methoxy, carbamylphenyl,
mercapto, N-isoimidazoylphenyl, isopropyl, amino, hydroxynaphthyl,
thiazoyl, carboxymethylphenyl, trifluoromethylphenyl, methylphenyl,
cyanophenyl, dimethylphenyl, fluorobenzhydryl, methoxyfuryl,
aminosulfonylphenyl,
<IMG>
241

wherein the R3 and R4 groups are such that they optionally join to
form a ring system selected from:
242

<IMG>
243

D, E and G are each independently selected from the group
consisting of carbon, oxygen, sulfur, and nitrogen;
R5 is selected from the group consisting of -H, and C1-C5 alkyl; and
wherein the R1 and R5 groups can join to form a piperidyl ring;
R6 R7 R8 R9 R10 R11 R12 R13 R14 R15 R16 R17 R18 R19 R20
R21 R22 R23 R24 R25 R26 R27 R28 R29 R30 R31 R32 R33 R34 R35 R36
R37 R38 R39 R40 R41 R42 R43 R44 R45 R46 R47 R48 R49 R50 R51 R52
R53 R54 R55 R56 R57 R58 R59 R60 R61 R62 R63 R64 R65 R66 R67 R68
R69, R70 R71, R72, R73, R74, R75, and R76 are each optionally present and
are each independently selected from the group consisting of - H, methyl,
ethyl, propyl, butyl, isobutyl, amino, nitro, hydroxy, methoxy, ethoxy,
propoxy, 2-propenoxy, oxo, carboxy, bromo, chloro, fluoro, trifluoromethyl,
chloromethyl, hydroxymethyl, dicyanomethyl, 2-fluorophenyl, 3-
fluorophenyl, hydroxyethoxy, ethoxyethoxy, -(CH2)-O-(C6H4)-O-(CH3),
carboxymethoxy, isopropylcarboxymethoxy, isobutylcarboxymethoxy,
methylamino, dimethylamino, aminoethoxy, diaminoethoxy,
dimethylaminoethoxy, cyanomethoxymethyl, 2-propenoxymethyl,
methoxymethyl, isopropoxymethyl, ethoxymethyl, -(CH2)-O-(CF2)-CHF2,
isobutoxymethyl, benzoyl, phenyl, N-morpholinyl, morpholinylethoxy,
pyrrolidylethoxy, N pyrrolidylethoxy, oxo, ethylcarboxy, carboxymethyl -
ethyl ester, pyridylmethyl, 4-pyridylmethoxy, 2-pyridylmethyl, and -COO-
CH2-CH3; and
wherein R38 and R39 are such that they can join to form a ring
system of the type selected from:
<IMG>
3. The method according to claim 2, wherein the
aminocyanopyridine MK-2 inhibiting compound is one wherein:
244

R1 is selected from the group consisting of -H, methyl, ethyl, -
(CH2)COOH, and phenyl;
R2 is selected from the group consisting of -H, methyl, ethyl, amino,
phenyl, methoxy, carboxy, hydroxyethylamino, propylamino, ethylamino,
methylamino, methoxyethyl, ethoxyethylamino, aminoethylamino,
benzylamino, dimethylaminoethylamino, fluorophenyl, difluorophenyl,
chlorophenyl, bromophenyl, furyl, carbamylpyrryl, methyl-1,3-isodiazoyl,
1,3-isodiazoyl, 1,3,4-triazoyl, methoxyphenyl, -S(CH3), acetylaminophenyl,
methoxyphenylamino, carboxyphenyl, cyanophenyl, cyclopropyl,
phenoxyphenyl, pyridyl, dihydroxybromophenyl, difluoromethoxyphenyl,
trifluoromethylphenyl, trifluoromethylfluorophenyl, hydroxyphenyl,
<IMG>
R3 is selected from the group consisting of -H, methyl, ethyl, propyl,
isopropyl, cyano, and aminomethyl;
wherein the R2 and R3 groups are such that they optionally join to
form a ring system selected from:
<IMG>
R4 is selected from the group consisting of -H, methyl, ethyl, propyl,
hydroxy, furyl, indolyl, methylfuryl, methyiimidazolyl, phenyl,
hydroxyphenyl, carboxyphenyl, pyrazolyl, hydroxy, dihydroxyphenyl,
methoxyphenyl, chlorophenyi, dichlorophenyl, dihydroxyborophenyl,
245

thienyl, pyrryl, N-methylpyrryl, pyridyl, methylthio, methylsulfonylphenyl,
carboethoxyphenyl, methoxy, carbamylphenyl, N isoimidazoylphenyl,
amino, hydroxynaphthyl, thiazoyl, carboxymethylphenyl,
aminosulfonylphenyl, and
<IMG>
wherein the R3 and R4 groups are such that they optionally join to
form a ring system selected from:
<IMG>
246

D, E and G are each independently selected from the group
consisting of carbon, oxygen, sulfur, and nitrogen;
R5 is selected from the group consisting of -H, and C1-C5 alkyl;
R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20,
R31, R32, R33, R34, R35, R36, R37, R38, R39, R40, R41, R42, R43, R44, R45,
R46,
R71, R72, R73, R74, R75, and R76 are each optionally present and are each
independently selected from the group consisting of - H, methyl, ethyl,
butyl, amino, nitro, hydroxy, methoxy, ethoxy, oxo, 2-propenoxy, carboxy,
bromo, chloro, fluoro, trifluoromethyl, chloromethyl, hydroxymethyl,
dicyanomethyl, hydroxyethoxy, ethoxyethoxy, -(CH2)-O-(C6H4)-O-(CH3),
carboxymethoxy, isopropylcarboxymethoxy, methylamino, dimethylamino,
aminoethoxy, diaminoethoxy, cyanomethoxymethyl, methoxymethyl,
isopropoxymethyl, ethoxymethyl, -(CH2)-O-(CF2)-CHF2, isobutoxymethyl,
phenyl, morpholinylethoxy, pyrrolidylethoxy, N-pyrrolidylethoxy, and
pyridylmethyl, and
wherein R38 and R39 are such that they optionally join to form a ring
system of the type selected from:
<IMG>
4. The method according to claim 2, wherein the
aminocyanopyridine MK-2 inhibiting compound is one wherein:
R1 is selected from the group consisting of -H, methyl, and ethyl;
R2 is selected from the group consisting of -H, methyl, amino,
phenyl, methoxy, hydroxyethylamino, propylamino, ethylamino,
methylamino, methoxyethyl, ethoxyethylamino, aminoethylamino,
benzylamino, dimethylaminoethylamino, fluorophenyl, difluorophenyl,
chlorophenyl, bromophenyl, furyl, carbamylpyrryl, methyl-1,3-isodiazoyl,
1,3-isodiazoyl, 1,3,4-triazoyl, methoxyphenyl, -S(CH3), acetylaminophenyl,
methoxyphenylamino, carboxyphenyl, cyanophenyl, cyclopropyl,
247

phenoxyphenyl, pyridyl, dihydroxybromophenyl, difluoromethoxyphenyl,
and
<IMG>
R3 is selected from the group consisting of -H, methyl, ethyl, propyl,
isopropyl, and cyano;
wherein the R2 and R3 groups are such that they optionally join to
form a ring system selected from:
<IMG>
R4 is selected from the group consisting of -H, methyl, ethyl, propyl,
hydroxy, furyl, indolyl, methylfuryl, methylimidazolyl, phenyl,
hydroxyphenyl, carboxyphenyl, pyrazolyl, hydroxy, dihydroxyphenyl,
methoxyphenyl, chlorophenyl, dichlorophenyl, dihydroxyborophenyl,
thienyl, pyrryl, N-methylpyrryl, pyridyl, methylthio, methylsulfonylphenyl,
carboethoxyphenyl, methoxy, carbamylphenyl, amino, and
aminosulfonylphenyl;
wherein the R3 and R4 groups are such that they optionally join to
form a ring system selected from:
248

<IMG>
D, E and G are each independently selected from the group
consisting of carbon, oxygen, sulfur, and nitrogen;
R5 is -H;
R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20,
R35, R36, R37, R38, R39, R40, R41, R42, R71, R72, R73, R74, R75, and R76 are
each optionally present and are each independently selected from the
group consisting of - H, methyl, ethyl, butyl, amino, nitro, hydroxy,
methoxy, ethoxy, oxo, 2-propenoxy, carboxy, bromo, fluoro,
trifluoromethyl, chloromethyl, dicyanomethyl, hydroxyethoxy,
ethoxyethoxy, -(CH2)-O-(C6H4)-O-(CH3), carboxymethoxy,
isopropylcarboxymethoxy, methylamino, dimethylamino, aminoethoxy,
diaminoethoxy, phenyl, morpholinylethoxy, pyrrolidylethoxy, N-
pyrrolidylethoxy, and pyridylmethyl, and
wherein R38 and R39 are such that they optionally join to form a ring
system consisting of:
<IMG>
249

5. The method according to claim 2, wherein the
aminocyanopyridine MK-2 inhibiting compound is one wherein:
R1 is selected from the group consisting of -H, methyl, and ethyl;
R2 is selected from the group consisting of -H, methyl, amino,
phenyl, methoxy, hydroxyethylamino, propylamino, ethylamino,
methylamino, methoxyethyl, ethoxyethylamino, aminoethylamino,
benzylamino, dimethylaminoethylamino, fluorophenyl, difluorophenyl,
chlorophenyl, bromophenyl, furyl, carbamylpyrryl, methyl-1,3-isodiazoyl,
1,3-isodiazoyl, 1,3,4-triazoyl, methoxyphenyl, -S(CH3), acetylaminophenyl,
methoxyphenylamino, carboxyphenyl, and
<IMG>
R3 is selected from the group consisting of -H, methyl, ethyl, propyl,
and isopropyl;
wherein the R2 and R3 groups are such that they optionally join to
form a ring system selected from:
<IMG>
R4 is selected from the group consisting of -H, methyl, ethyl, propyl,
furyl, indolyl, methylfuryl, methylimidazolyl, phenyl, hydroxyphenyl,
carboxyphenyl, pyrazolyl, hydroxy, dihydroxyphenyl, methoxyphenyl,
chlorophenyl, dichlorophenyl, dihydroxyborophenyl, thienyl, pyrryl, N-
methylpyrryl, pyridyl, methylthio, methylsulfonylphenyl, carboethoxyphenyl,
and aminosulfonylphenyl;
250

wherein the R3 and R4 groups are such that they optionally join to
form a ring system selected from:
<IMG>
D, E and G are each independently selected from the group
consisting of carbon, oxygen, sulfur, and nitrogen;
R5 is -H;
R6, R7, R8, R9, R10, R11, R12, R35, R36, R37, R38, R39, R40, R41, R42,
R71, R72, R73, R74, R75, and R76 are each optionally present and are each
independently selected from the group consisting of - H, methyl, ethyl,
butyl, amino, nitro, hydroxy, methoxy, ethoxy, oxo, 2-propenoxy, carboxy,
bromo, fluoro, trifluoromethyl, chloromethyl, dicyanomethyl,
hydroxyethoxy, ethoxyethoxy, carboxymethoxy, isopropylcarboxymethoxy,
methylamino, dimethylamino, aminoethoxy, diaminoethoxy,
morpholinylethoxy, pyrrolidylethoxy, N pyrrolidylethoxy, and pyridylmethyl,
and
wherein R38 and R39 are such that they optionally join to form a ring
system consisting of:
<IMG>
251

6. The method according to claim 2, wherein the
aminocyanopyridine MK-2 inhibiting compound is one wherein:
R1 is -H;
R2 is selected from the group consisting of amino, phenyl,
fluorophenyl, difluorophenyl, furyl, carbamylpyrryl, methyl-1,3-isodiazoyl,
1,3-isodiazoyl, 1,3,4-triazoyl, methoxyphenyl, acetylaminophenyl,
methoxyphenylamino, and carboxyphenyl;
R3 is selected from the group consisting of -H, methyl, ethyl, and
propyl;
R4 is selected from the group consisting of methyl, ethyl, propyl,
furyl, phenyl, hydroxyphenyl, carboxyphenyl, pyrazolyl, hydroxy,
dihydroxyphenyl, methoxyphenyl, chlorophenyl, dihydroxyborophenyl, and
aminosulfonylphenyl;
wherein the R3 and R4 groups are such that they optionally join to
form a ring system selected from:
<IMG>
252

D, E and G are each independently selected from the group
consisting of carbon, oxygen, sulfur, and nitrogen;
R5 is -H;
R6, R7, R8, R9, R10, R11, R12, R35, R36, R37, R38, R39, R40, R41, R42,
R71, R72, R73, R74, R75, and R76 are each optionally present and are each
independently selected from the group consisting of - H, amino, nitro,
hydroxy, methoxy, ethoxy, oxo, 2-propenoxy, carboxy, bromo, fluoro,
trifluoromethyi, chloromethyl, dicyanomethyl, hydroxyethoxy,
ethoxyethoxy, carboxymethoxy, isopropylcarboxymethoxy, methylamino,
dimethylamino, aminoethoxy, diaminoethoxy, morpholinylethoxy,
pyrrolidylethoxy, and pyridylmethyl, and
wherein R38 and R39 are such that they optionally join to form a ring
system consisting of:
<IMG>
7. The method according to claim 2, wherein the
aminocyanopyridine MK-2 inhibiting compound comprises at least one
compound that is selected from the group consisting of:
2-amino-4-(2-fluorophenyl)-6,8-dihydro-5H-pyrazolo[3,4-h]quinoline-3-
carbonitrile,
2-amino-4-(2-furyl)-6,7-dihydro-5H-pyrazolo[3,4-h]quinoline-3-carbonitrile,
2-amino-4-(2,3-difluorophenyl)-6,7-dihydro-5H-pyrazolo[3,4-h]quinoline-3-
carbonitrile,
8-amino-6-(2-furyl)-4,5-dihydro-1H-pyrazolo[4,3-h]quinoline-7-carbonitrile,
2-amino-3-cyano-4-(2-furyl)-5,6-dihydrobenzo[h]quinoline-8-carboxylic
acid,
4-[2-amino-3-cyano-6-(2-furyl)pyridin-4-yl]-1H-pyrrole-2-carboxamide,
2-amino-4-phenyl-6,8-dihydro-5H-pyrazolo[3,4-h]quinoline-3-carbonitrile,
2-amino-6-(2-furyl)-4-(1-methyl-1H-imidazol-4-yl)nicotinonitrile,
253

8-amino-6-(2-furyl)-4,5-dihydro-1H-pyrazolo[4,3-h]quinoline-7-carbonitrile,
2-amino-4-(2-furyl)-8-hydroxy-5,6-dihydrobenzo[h]quinoline-3-carbonitrile,
2-amino-4-(2,6-difluorophenyl)-6,7-dihydro-5H-pyrazolo[3,4-h]quinoline-3-
carbonitrile,
2-amino-6-(4-hydroxyphenyl)-4-(1H-imidazol-5-yl)nicotinonitrile,
2-amino-4-(2-fluorophenyl)-6-(2-furyl)nicotinonitrile, 2-amino-4-(2-
fluorophenyl)-6-(2-furyl)nicotinonitrile,
2-amino-4-(2-fluorophenyl)-5,6-dihydrobenzo[h]quinoline-3-carbonitrile,
4-[6-amino-5-cyano-4-(2-furyl)pyridin-2-yl]benzoic acid,
2-amino-6-(2-furyl)-4-(1H-imidazol-5-yl)nicotinonitrile,
2-amino-4-(2-furyl)-6-(1H-pyrazol-3-yl)nicotinonitrile,
2-amino-3-cyano-4-(4H-1,2,4-triazol-3-yl)-5,6-dihydrobenzo[h]quinoline-8-
carboxylic acid,
2-amino-6-(3-hydroxyphenyl)-4-(1H-imidazol-5-yl)nicotinonitrile,
2-amino-6-(2-furyl)-4-(1H-imidazol-4-yl)nicotinonitrile,
2-amino-4-(2,4-difluorophenyl)-6,7-dihydro-5H-pyrazolo[3,4-h]quinoline-3-
carbonitrile,
4,6-diamino-2-(trifluoromethyl)-2,3-dihydrofuro[2,3-b]pyridine-5-
carbonitrile,
2-amino-4-(2-furyl)-6,8-dihydro-5H-pyrrolo[3,4-h]quinoline-3-carbonitrile,
4-[6-amino-5-cyano-4-(2-fluorophenyl)pyridin-2-yl]benzoic acid,
2-amino-4-(2-furyl)-5,6-dihydro-1,8-phenanthroline-3-carbonitrile,
2-amino-6-(3,4-dihydroxyphenyl)-4-(2-fluorophenyl)nicotinonitrile,
2-amino-4-(1-methyl-1H-imidazol-4-yl)-6-phenylnicotinonitrile,
2-amino-4-(2-furyl)-6-(1H-pyrazol-3-yl)nicotinonitrile,
4-[6-amino-5-cyano-4-(1H-imidazol-5-yl)pyridin-2-yl]benzoic acid,
2-amino-4-(3-fluorophenyl)-6,8-dihydro-5H-pyrazolo[3,4-h]quinoline-3-
carbonitrile,
2-amino-6-(3,4-dihydroxyphenyl)-4-(2-fluorophenyl)nicotinonitrile,
N (4-[6-amino-5-cyano-4-(2-furyl)pyridin-2-yl]phenyl)methanesulfonamide,
2-amino-4-(2-furyl)-6,7-dihydro-5H-pyrrolo[2,3-h]quinoline-3-carbonitrile,
2-amino-4-(1H-imidazol-5-yl)-6-phenylnicotinonitrile,
254

2-amino-4-(2-furyl)-5,6-dihydrobenzo[h]quinoline-3-carbonitrile,
2-amino-4-(1H-imidazol-5-yl)-6-(4-methoxyphenyl)nicotinonitrile,
2-amino-6-(3-chlorophenyl)-4-(1H-imidazol-5-yl)nicotinonitrile,
2-amino-4-(2-furyl)-6-(1H-pyrazol-4-yl)nicotinonitrile,
2-amino-4-(4-methoxyphenyl)-6,7-dihydro-5H-pyrazolo[3,4-h]quinoline-3-
carbonitrile,
2-amino-4-(2,5-difluorophenyl)-6,7-dihydro-5H-pyrazolo[3,4-h]quinoline-3-
carbonitrile,
2-amino-4-(4-fluorophenyl)-6,8-dihydro-5H-pyrazolo[3,4-h]quinoline-3-
carbonitrile,
2-amino-4-(4H-1,2,4-triazol-3-yl)-5,6-dihydrobenzo[h]quinoline-3-
carbonitrile,
4,6-diamino-2-(chloromethyl)-2,3-dihydrofuro[2,3-b]pyridine-5-carbonitrile,
2-amino-4-(1H-imidazol-4-yl)-6-phenylnicotinonitrile,
4-[6-amino-5-cyano-4-(2-furyl)pyridin-2-yl]benzenesulfonamide,
4-[6-amino-5-cyano-4-(2-furyl)pyridin-2-yl]phenylboronic acid,
2-amino-6-(4-methoxyphenyl)-4-(4H-1,2,4-triazol-3-yl)nicotinonitrile,
2-amino-4-(2-fluorophenyl)-6-(3-furyl)nicotinonitrile,
2-amino-6-(2-furyl)-4-(methylthio)nicotinonitrile,
2-amino-4-(2-fluorophenyl)-6-(3-hydroxyphenyl)nicotinonitrile,
8-amino-6-(2-furyl)-4,5-dihydro-2H-pyrazolo[4,3-h]quinoline-7-carbonitrile,
2-amino-4-(2-bromophenyl)-6-(2-furyl)nicotinonitrile,
2-amino-4-(2-fluorophenyl)-6-(4-hydroxyphenyl)nicotinonitrile,
2-amino-4-phenyl-6-thien-2-ylnicotinonitrile,
2-amino-4-(3-methoxyphenyl)-6,7-dihydro-5H-pyrazolo[3,4-h]quinoline-3-
carbonitrile,
2-amino-4-(2-furyl)-7-methyl-6,7-dihydro-5H-pyrazolo[3,4-h]quinoline-3-
carbonitrile,
2-amino-4-(2-fluorophenyl)-6-(1H-pyrrol-2-yl)nicotinonitrile,
2-amino-4-(2-furyl)-5-methyl-6,8-dihydro-5H-pyrazolo[3,4-h]quinoline-3-
carbonitrile,
2-amino-4-(2-furyl)-6-(1-methyl-1H-pyrrol-3-yl)nicotinonitrile,
255

3-amino-5,6,7,8-tetrahydroisoquinoline-4-carbonitrile,
N-[4-(2-amino-3-cyano-6,7-dihydro-5H-pyrazolo[3,4-h]quinolin-4-
yl)phenyl]acetamide,
6-amino-4-[(4-methoxyphenyl)amino]-2-(trifluoromethyl)-2,3-
dihydrofuro[2,3-b]pyridine-5-carbonitrile,
4-[6-amino-5-cyano-4-(2-furyl)pyridin-2-yl]-N-(tert-
butyl)benzenesulfonamide,
4,6-diamino-2-ethyl-2,3-dihydrofuro[2,3-b]pyridine-5-carbonitrile,
6-amino-4-(2-furyl)-2,4'-bipyridine-5-carbonitrile, 2,4-diamino-6-
(methylthio)nicotinonitrile,
3-(2-amino-3-cyano-6,7-dihydro-5H-pyrazolo[3,4-h]quinolin-4-yl)benzoic
acid,
2-amino-6-(4-chlorophenyl)-4-(1H-imidazol-5-yl)nicotinonitrile,
2-amino-4-(1,3-benzodioxol-4-yl)-6,7-dihydro-5H-pyrazolo[3,4-h]quinoline-
3-carbonitrile,
4,6-diamino-2-methyl-2,3-dihydrofuro[2,3-b]pyridine-5-carbonitrile,
2-amino-4-(1H-imidazol-5-yl)-6-[4-(methylsulfonyl)phenyl]nicotinonitrile,
2,4-diaminoquinoline-3-carbonitrile,
2,8-diamino-4-(2-furyl)-5,6-dihydrobenzo[h]quinoline-3-carbonitrile,
2-amino-4,6-di(2-furyl)nicotinonitrile,
4,6-diamino-2-butyl-2,3-dihydrofuro[2,3-b]pyridine-5-carbonitrile,
ethyl 4-[6-amino-5-cyano-4-(1H-imidazol-5-yl)pyridin-2-yl]benzoate,
2,4-diamino-6-methoxynicotinonitrile,
2-amino-4-methylnicotinonitrile,
2-amino-4-(4-cyanophenyl)-6,7-dihydro-5H-pyrazolo[3,4-h]quinoline-3-
carbonitrile,
2-amino-4-cyclopropyl-6-methylnicotinonitrile,
2-amino-4-(2-furyl)-6-(1-methyl-1H-pyrrol-2-yl)nicotinonitrile,
2-amino-4-(2-chlorophenyl)-6,7-dihydro-5H-pyrazolo[3,4-h]quinoline-3-
carbonitrile,
2-amino-6-(2-furyl)-4-(4-phenoxyphenyl)nicotinonitrile,
256

2-amino-4-pyridin-3-yl-6,8-dihydro-5H-pyrazolo[3,4-h]quinoline-3-
carbonitrile,
2-amino-6-{[2-(4-chlorophenyl)-2-oxoethyl]thio}-4-(2-furyl)pyridine-3,5-
dicarbonitrile,
4-[2-amino-3-cyano-6-(2-furyl)pyridin-4-yl]phenylboronic acid,
2-amino-6-(3-chlorophenyl)-4-(1H-imidazol-4-yl)nicotinonitrile,
4-(6-amino-5-cyano-4-phenylpyridin-2-yl)-N-(tert-
butyl)benzenesulfonamide,
2-amino-4-methoxynicotinonitrile,
4-[2-amino-3-cyano-6-(2-furyl)pyridin-4-yl]benzoic acid,
4,6-diamino-2-[(4-methoxyphenoxy)methyl]-2,3-dihydrofuro[2,3-b]pyridine-
5-carbonitrile,
2-amino-4-(2-fluorophenyl)-6-(4-methoxyphenyl)nicotinonitrile,
4-[6-amino-5-cyano-4-(2-fluorophenyl)pyridin-2-yl]-N-(tert-
butyl)benzenesulfonamide,
(2,4-diamino-3-cyano-5H-chromeno[2,3-b]pyridin-9-yl)oxy]acetic acid,
3-pyridinecarbonitrile,
2-amino-4-methylm-2-amino-6-(2-furyl)nicotinonitrile,
2-amino-4-(2-furyl)-6-(3-hydroxyphenyl)nicotinonitrile,
4-[6-amino-5-cyano-4-(2-furyl)pyridin-2-yl]benzamide,
2-amino-4-(2-furyl)-7-hydroxy-5,6-dihydrobenzo[h]quinoline-3-carbonitrile,
2-amino-4-(2-furyl)-6-(1H-indol-3-yl)nicotinonitrile,
2-amino-4-pyridin-4-yl-6,8-dihydro-5H-pyrazolo[3,4-h]quinoline-3-
carbonitrile,
2-amino-4-(3-fluorophenyl)-6-(4-hydroxyphenyl)nicotinonitrile,
2-amino-4-[2-(difluoromethoxy)phenyl]-6,7-dihydro-5H-pyrazolo[3,4-
h]quinoline-3-carbonitrile,
2-amino-4-(2-furyl)-6-thien-3-ylnicotinonitrile,
2-amino-4-(3-fluorophenyl)-6-(4-methoxyphenyl)nicotinonitrile,
2-[2-amino-3-cyano-6-(2-furyl)pyridin-4-yl]phenylboronic acid,
2,4-diamino-6-propylpyridine-3,5-dicarbonitrile,
257

4,6-diamino-2-[(prop-2-ynyloxy)methyl]-2,3-dihydrofuro[2,3-b]pyridine-5-
carbonitrile,
4,6-diamino-2-(hydroxymethyl)-2,3-dihydrofuro[2,3-b]pyridine-5-
carbonitrile,
2-amino-6-(2-furyl)-4-[4-(trifluoromethyl)phenyl]nicotinonitrile,
5-amino-7-methylthieno[3,2-b]pyridine-6-carbonitrile,
2-amino-4-(2-furyl)-5,5-dimethyl-6,8-dihydro-5H-pyrazolo[3,4-h]quinoline-
3-carbonitrile,
N-[3-cyano-4-(2-fluorophenyl)-6-(2-furyl)pyridin-2-yl]glycine,
2-[(allyloxy)methyl]-4,6-diamino-2,3-dihydrofuro[2,3-b]pyridine-5-
carbonitrile,
2-amino-4-(2-furyl)-6-methyl-5,6-dihydrobenzo[h]quinoline-3-carbonitrile,
4,6-diamino-2-(methoxymethyl)-2,3-dihydrofuro[2,3-b]pyridine-5-
carbonitrile,
2-amino-4-(2-furyl)-6-(1H-indol-3-yl)nicotinonitrile,
2-amino-4-(2-furyl)-6-[4-(1H-imidazol-1-yl)phenyl]nicotinonitrile,
2-amino-4-(2-furyl)-6-(4-hydroxyphenyl)nicotinonitrile,
2-amino-4-(2-furyl)-5,6,7,8-tetrahydro-5,8-methanoquinoline-3-carbonitrile,
4,6-diamino-2-(isopropoxymethyl)-2,3-dihydrofuro[2,3-b]pyridine-5-
carbonitrile,
3-[6-amino-5-cyano-4-(2-furyl)pyridin-2-yl]phenylboronic acid,
4,6-diamino-2-(ethoxymethyl)-2,3-dihydrofuro[2,3-b]pyridine-5-carbonitrile,
2-amino-4-(4-bromophenyl)-6-(2-furyl)nicotinonitrile,
4,6-diamino-2-[(1,1,2,2-tetrafluoroethoxy)methyl]-2,3-dihydrofuro[2,3-
b]pyridine-5-carbonitrile,
2-amino-4-[2-fluoro-4-(trifluoromethyl)phenyl]-6-(2-furyl)nicotinonitrile,
2-amino-4-(2-methoxyphenyl)-6,8-dihydro-5H-pyrazolo[3,4-h]quinoline-3-
carbonitrile,
2-amino-4-(2-fluorophenyl)-5-methyl-6,8-dihydro-5H-pyrazolo[3,4-
h]quinoline-3-carbonitrile,
3,6-diamino-4-ethyl-1 H-pyrazolo[3,4-b]pyridine-5-carbonitrile,
6-amino-4-(2-furyl)-2,2'-bipyridine-5-carbonitrile,
258

2-amino-4-(2-furyl)-6-(8-hydroxy-1-naphthyl)nicotinonitrile,
4-(2-amino-3-cyano-6,7-dihydro-5H-pyrazolo[3,4-h]quinolin-4-yl)benzoic
acid,
2-amino-6-(3,4-dichlorophenyl)-4-(2-furyl)nicotinonitrile,
2-amino-4-(2-furyl)-6-(10H-phenothiazin-2-yl)nicotinonitrile,
sodium 2-amino-3-cyano-4-quinolinecarboxylate,
2-anilino-4-(2-fluorophenyl)-6-(2-furyl)nicotinonitrile,
2-amino-4-(3-fluorophenyl)-6-(2-furyl)nicotinonitrile,
2-amino-4-(4-fluorophenyl)-6-(2-furyl)nicotinonitrile,
4,6-diamino-2-(tert-butoxymethyl)-2,3-dihydrofuro[2,3-b]pyridine-5-
carbonitrile,
2-amino-4-(2-furyl)-6-(1,3-thiazol-2-yl)nicotinonitrile,
4-(2-fluorophenyl)-6-(2-furyl)-2-piperidin-1-ylnicotinonitrile,
2-amino-6-(4-chlorophenyl)-4-(2-furyl)nicotinonitrile,
2-amino-6-(4-hydroxyphenyl)-4-(2-methoxyphenyl)nicotinonitrile,
2-amino-6-(2-furyl)-4-(2-hydroxyphenyl)nicotinonitrile,
methyl 3-(2-amino-3-cyano-6,7-dihydro-5H-pyrazolo[3,4-h]quinolin-4-
yl)benzoate,
2-amino-4-(2-chlorophenyl)-6-(5-methyl-2-furyl)nicotinonitrile,
3,6-diamino-2-benzoylthieno[2,3-b]pyridine-5-carbonitrile,
methyl 4-[6-amino-5-cyano-4-(2-furyl)pyridin-2-yl]benzoate,
2-aminonicotinonitrile,
2-amino-4-(2-furyl)-8-{[2-(trimethylsilyl)ethoxy]methyl}-6,8-dihydro-5H-
pyrazolo[3,4-h]quinoline-3-carbonitrile,
3-amino-5H-pyrido[4,3-b]indole-4-carbonitrile,
2-(2-amino-3-cyano-6,7-dihydro-5H-pyrazolo[3,4-h]quinolin-4-yl)benzoic
acid,
2-amino-6-(4-methoxyphenyl)-4-phenylnicotinonitrile,
2-amino-4-(2-furyl)-5,6,7,8-tetrahydroquinoline-3-carbonitrile,
2-amino-4-(2-furyl)-6-isobutylnicotinonitrile,
2-amino-6-benzyl-4-(2-furyl)nicotinonitrile,
2-amino-4-(2-furyl)-6-methyl-5-phenylnicotinonitrile,
259

2-amino-4-(2-furyl)-6-[4-(trifluoromethoxy)phenyl]nicotinonitrile,
2-amino-4-(2-furyl)-6-propyl-5,6,7,8-tetrahydro-1,6-naphthyridine-3-
carbonitrile,
2-amino-4-(2-furyl)benzo[h]quinoline-3-carbonitrile,
2-amino-6-(4-methoxyphenyl)-4-thien-2-ylnicotinonitrile,
2-amino-4-(2-fluorophenyl)-6-tetrahydrofuran-2-ylnicotinonitrile,
ethyl 6-amino-5-cyano-4-(2-furyl)pyridine-2-carboxylate,
2-amino-4-(2-furyl)-9-methoxy-5,6-dihydrobenzo[h]quinoline-3-carbonitrile,
2-amino-4-(2-furyl)-8-methoxy-5,6-dihydrobenzo[h]quinoline-3-carbonitrile,
2-amino-4-(2-furyl)-8,9-dimethoxy-5,6-dihydrobenzo[h]quinoline-3-
carbonitrile,
2-amino-4-(2-furyl)-7-methoxy-5,6-dihydrobenzo[h]quinoline-3-carbonitrile,
2-amino-4-(2-furyl)-7,9-dimethyl-5,6-dihydrobenzo[h]quinoline-3-
carbonitrile,
ethyl 4-[6-amino-5-cyano-4-(2-furyl)pyridin-2-yl]benzoate,
2-amino-6-(3-bromophenyl)-4-(2-furyl)nicotinonitrile,
2-amino-4-(2-furyl)-6-[4-(trifluoromethyl)phenyl]nicotinonitrile,
2-amino-4-(2-furyl)-6-[3-(trifluoromethyl)phenyl]nicotinonitrile,
2-amino-4-(2-furyl)-6-[4-(methylsulfonyl)phenyl]nicotinonitrile,
4,6-diamino-2-(phenoxymethyl)-2,3-dihydrofuro[2,3-b]pyridine-5-
carbonitrile,
4,6-diamino-3-phenyl-2,3-dihydrofuro[2,3-b]pyridine-5-carbonitrile,
4,6-diamino-3-vinyl-2,3-dihydrofuro[2,3-b]pyridine-5-carbonitrile,
2-amino-4-(2-fluorophenyl)-5-methyl-6,8-dihydro-5H-pyrazolo[3,4-
h]quinoline-3-carbonitrile,
3-amino-1-methyl-5,6,7,8-tetrahydroisoquinoline-4-carbonitrile,
2-amino-4-(2-fluorophenyl)-5,5-dimethyl-6,8-dihydro-5H-pyrazolo[3,4-
h]quinoline-3-carbonitrile,
2-amino-4-(2-fluorophenyl)-6-(3-hydroxyphenyl)nicotinonitrile,
2-amino-4-[2-(difluoromethoxy)phenyl]-6,7-dihydro-5H-pyrazolo[3,4-
h]quinoline-3-carbonitrile,
2-(benzylamino)-4-(2-fluorophenyl)-6-(2-furyl)nicotinonitrile,
260

2-amino-4-(2-furyl)-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-b]pyridine-3-
carbonitrile,
2-amino-4-(2-furyl)-5H-indeno[1,2-b]pyridine-3-carbonitrile,
3-amino-1-methyl-5,6,7,8-tetrahydroisoquinoline-4-carbonitrile,
2-amino-4-(2-fluorophenyl)-6-(3-hydroxyphenyl)nicotinonitrile,
2-amino-4-(2-thienyl)-5,6,7,8-tetrahydro-3-quinolinecarbonitrile,
2-amino-4-(3-fluorophenyl)-5,6,7,8-tetrahydro-3-quinolinecarbonitrile,
2-(1-piperidinyl)-6-(2-thienyl)-4-(trifluoromethyl)nicotinonitrile,
2-(dimethylamino)-6-(2-thienyl)-4-(trifluoromethyl)nicotinonitrile,
3-Quinolinecarbonitrile,
2-amino-4-methyl- or 2-amino-4-methyl-3-quinolinecarbonitrile,
2-amino-4-(4-methoxyphenyl)-6-(2-thienyl)nicotinonitrile,
2-amino-6-cyclopropyl-4-(2-methoxyphenyl)nicotinonitrile,
2-amino-4-(2-fluorophenyl)-6-phenylnicotinonitrile,
(4bS,8aR)-2,4-diamino-4b,5,6,7,8,8a-hexahydro[1]benzofuro[2,3-
b]pyridine-3-carbonitrile,
2-amino-4-(2-fluorophenyl)-5,5-dimethyl-6,8-dihydro-5H-pyrazolo[3,4-
h]quinoline-3-carbonitrile,
2-amino-4-(2-furyl)-5-phenyl-6,8-dihydro-5H-pyrazolo[3,4-h]quinoline-3-
carbonitrile,
3-amino-1,6-dimethyl-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile,
3-amino-1,7-dimethyl-5,6,7,8-tetrahydro-2,7-naphthyridine-4-carbonitrile,
2-amino-4-(2-fluorophenyl)-5-phenyl-6,8-dihydro-5H-pyrazolo[3,4-
h]quinoline-3-carbonitrile,
2-amino-4-(2-fluorophenyl)-5-phenyl-6,8-dihydro-5H-pyrazolo[3,4-
h]quinoline-3-carbonitrile,
4,6-diamino-2-(morpholin-4-ylmethyl)-2,3-dihydrofuro[2,3-b]pyridine-5-
carbonitrile,
ethyl (4,6-diamino-5-cyano-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-
yl)acetate,
2-amino-4-(2-methoxyphenyl)-6-(5-methyl-2-furyl)nicotinonitrile,
2-amino-6-methyl-4-(4-nitrophenyl)nicotinonitrile,
261

2-amino-4-(3,4-dimethoxyphenyl)-6-(5-methyl-2-furyl)nicotinonitrile,
2,4-diamino-6-[(4-methoxyphenyl)thio]nicotinonitrile,
4,6-diamino-2-(phenoxymethyl)-2,3-dihydrofuro[2,3-b]pyridine-5-
carbonitrile,
4,6-diamino-3-phenyl-2,3-dihydrofuro[2,3-b]pyridine-5-carbonitrile,
4,6-diamino-2-[(2-methylphenoxy)methyl]-2,3-dihydrofuro[2,3-b]pyridine-5-
carbonitrile,
2-amino-4-(2-furyl)-6-(4-methoxyphenyl)nicotinonitrile,
2-amino-4-(3-fluorophenyl)-5,6-dihydrobenzo[h]quinoline-3-carbonitrile,
2-amino-4-(4-methoxyphenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine-3-
carbonitrile,
2-amino-9-ethyl-9H-pyrido[2,3-b]indole-3-carbonitrile,
2-amino-6-isobutyl-4-(4-methylphenyl)nicotinonitrile,
1-(2-furyl)-3-[(3-hydroxypropyl)amino]-5,6,7,8-tetrahydroisoquinoline-4-
carbonitrile,
2-azepan-1-yl-6-(4-fluorophenyl)-4-phenylnicotinonitrile,
2-amino-6-tert-butyl-4-(4-methylphenyl)nicotinonitrile,
2-amino-4-(4-bromophenyl)-6-methylnicotinonitrile,
2-amino-4-thien-2-yl-5,6,7,8,9,10-hexahydrocycloocta[b]pyridine-3-
carbonitrile,
2-amino-4-(4-chlorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine-3-
carbonitrile,
2-(allylamino)-5-amino-7-(4-bromophenyl)thieno[3,2-b]pyridine-3,6-
dicarbonitrile,
2-amino-4-pyridin-3-yl-5,8,7,8,9,10-hexahydrocycloocta[b]pyridine-3-
carbonitrile,
2-amino-4-(4-bromophenyl)-6-tert-butylnicotinonitrile,
1-(2-furyl)-3-morpholin-4-yl-5,6,7,8-tetrahydroisoquinoline-4-carbonitrile,
2-amino-4-(4-methylphenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine-3-
carbonitrile,
2-amino-7,7-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridine-3-carbonitrile,
2-amino-6-isobutyl-4-(4-methoxyphenyl)nicotinonitrile,
262

4,6-diamino-2-oxo-1-phenyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-5-
carbonitrile,
2-amino-4-(2-methoxyphenyl)-5,6-dimethylnicotinonitrile,
2-(dimethylamino)-4-(2-fluorophenyl)-6-(2-furyl)nicotinonitrile,
2-(dimethylamino)-4-(2-fluorophenyl)-6-(2-furyl)nicotinonitrile,
4-(2-fluorophenyl)-6-(2-furyl)-2-(methylamino)nicotinonitrile,
4-(2-fluorophenyl)-6-(2-furyl)-2-morpholin-4-ylnicotinonitrile,
tert-butyl N-[3-cyano-4-(2-fluorophenyl)-6-(2-furyl)pyridin-2-yl]glycinate,
2-(ethylamino)-4-(2-fluorophenyl)-6-(2-furyl)nicotinonitrile,
ethyl 4-[6-amino-5-cyano-4-(2-fluorophenyl)pyridin-2-yl]benzoate,
2-amino-6-(2-fluorophenyl)-4-(3-furyl)nicotinonitrile,
6-amino-4-(2-fluorophenyl)-2,2'-bipyridine-5-carbonitrile,
2-amino-4-(2-fluorophenyl)-6-thien-2-ylnicotinonitrile,
ethyl 6-amino-5-cyano-4-(2-fluorophenyl)pyridine-2-carboxylate,
2-amino-6-(2-furyl)-4-phenylnicotinonitrile,
ethyl 2-amino-3-cyano-4-(2-furyl)-5,6,7,8-tetrahydroquinoline-6-
carboxylate,
2-amino-4-(2-furyl)-6-(4-hydroxyphenyl)-5-methylnicotinonitrile,
2-amino-4-(2-furyl)-6-(4-methoxyphenyl)-5-methylnicotinonitrile,
2-amino-6-(4-fluorophenyl)-4-(2-furyl)-5-methylnicotinonitrile,
2-amino-4-(2-furyl)-5,6-diphenylnicotinonitrile,
2-amino-4-(2-furyl)-5-methyl-6-phenylnicotinonitrile,
2-amino-6-(3,4-dimethylphenyl)-4-(2-furyl)nicotinonitrile,
2-amino-6-(4-fluorophenyl)-4-(2-furyl)nicotinonitrile,
2-amino-4-(3-fluorophenyl)-6-(3-hydroxyphenyl)nicotinonitrile,
6-amino-4-(3-fluorophenyl)-2,4'-bipyridine-5-carbonitrile,
6-amino-4-(2-fluorophenyl)-2,4'-bipyridine-5-carbonitrile,
2-amino-4-butyl-6-methylnicotinonitrile,
2-amino-6-methyl-4-propylnicotinonitrile,
2-amino-4-ethyl-6-methylnicotinonitrile, 2-amino-4,6-dimethylnicotinonitrile,
2-amino-4-[2-(hexyloxy)phenyl]-6,7-dihydro-5H-pyrazolo[3,4-h]quinoline-3-
carbonitrile,
263

2-amino-4-(2-(beta-D-glucopyranosyloxy)phenyl]-6,7-dihydro-5H-
pyrazolo[3,4-h]quinoline-3-carbonitrile,
4-[2-(allyloxy)phenyl]-2-amino-6,7-dihydro-5H-pyrazolo[3,4-h]quinoline-3-~
carbonitrile,
methyl [2-(2-amino-3-cyano-6,7-dihydro-5H-pyrazolo[3,4-h]quinolin-4-
yl)phenoxy]acetate,
2-amino-4-(2-ethoxyphenyl)-6,7-dihydro-5H-pyrazolo[3,4-h]quinoline-3-
carbonitrile,
ethyl 4-[2-amino-3-cyano-6-(2-furyl)pyridin-4-yl]-1H-pyrrole-2-carboxylate,
2-amino-6-methylnicotinonitrile,
2-amino-6-(4-cyanophenyl)-4-(2-furyl)nicotinonitrile,
2-amino-6-(4-fluorobenzyl)-4-(2-furyl)nicotinonitrile,
2-amino-5-(4-fluorophenyl)-4-(2-furyl)-6-methylnicotinonitrile,
2-amino-4-(2-furyl)-6-(4-methoxyphenyl)nicotinonitrile,
2-amino-4-(2-methylphenyl)-5,6,7,8-tetrahydroquinoline-3-carbonitrile,
2-amino-4-(4-methoxyphenyl)-5,6,7,8-tetrahydroquinoline-3-carbonitrile,
2-amino-4-phenyl-5,6,7,8-tetrahydroquinoline-3-carbonitrile,
2-amino-6-(4-methoxyphenyl)-4-(2-methylphenyl)nicotinonitrile,
2-amino-4,6-bis(4-methoxyphenyl)nicotinonitrile,
2-amino-4-(3-chlorophenyl)-6-(4-methoxyphenyl)nicotinonitrile,
2-amino-4-(2-chlorophenyl)-6-(4-methoxyphenyl)nicotinonitrile,
2-amino-4-(2-furyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-3-carbonitrile,
2-amino-4-(2-furyl)-6-(4-methylphenyl)nicotinonitrile,
2-amino-4-(2-furyl)-6-phenylnicotinonitrile,
6-amino-4-(2-furyl)-2,3'-bipyridine-5-carbonitrile,
2-amino-6-(1,3-benzodioxol-5-yl)-4-(2-furyl)nicotinonitrile,
2-amino-4-isoquinolin-4-yl-6-(4-methoxyphenyl)nicotinonitrile,
2-amino-4-(1-benzothien-3-yl)-6-(4-methoxyphenyl)nicotinonitrile,
2-amino-6-(4-methoxyphenyl)-4-thien-3-ylnicotinonitrile,
2-amino-4-(3-furyl)-6-(4-methoxyphenyl)nicotinonitrile,
2-amino-6-(4-methoxyphenyl)-4-(1H-pyrrol-2-yl)nicotinonitrile,
2-amino-4-(2-furyl)-6-(1H-pyrrol-2-yl)nicotinonitrile,
264

2'-amino-6'-(4-methoxyphenyl)-3,4'-bipyridine-3'-carbonitrile,
2-amino-4-[2-(trifluoromethoxy)phenyl]-6,7-dihydro-5H-pyrazolo[3,4-
h]quinoline-3-carbonitrile,
2-amino-4-(2-furyl)-5H-thiochromeno[4,3-b]pyridine-3-carbonitrile,
2-amino-4-{4-[(2-cyanoethyl)(methyl)amino]phenyl}-6,7-dihydro-5H-
pyrazolo[3,4-h]quinoline-3-carbonitrile,
2-amino-4-[2-(2-hydroxyethoxy)phenyl]-6,7-dihydro-5H-pyrazolo[3,4-
h]quinoline-3-carbonitrile,
2-amino-4-(2-methylphenyl)-6,7-dihydro-5H-pyrazolo[3,4-h]quinoline-3-
carbonitrile,
2-amino-4-[4-(dimethylamino)phenyl]-6,7-dihydro-5H-pyrazolo[3,4-
h]quinoline-3-carbonitrile,
2-amino-4-(1H-indol-7-yl)-6,7-dihydro-5H-pyrazolo[3,4-h]quinoline-3-
carbonitrile,
methyl 4-(2-amino-3-cyano-6,7-dihydro-5H-pyrazolo[3,4-h]quinolin-4-
yl)benzoate,
methyl 2-(2-amino-3-cyano-6,7-dihydro-5H-pyrazolo[3,4-h]quinolin-4-
yl)benzoate,
[2-(2-amino-3-cyano-6,7-dihydro-5H-pyrazolo[3,4-h]quinolin-4-
yl)phenoxy]acetic acid,
2-amino-6-phenylnicotinonitrile,
2-amino-6-cyclohexylnicotinonitrile,
2-amino-4-(2-furyl)-6-(1-trityl-1H-pyrazol-4-yl)nicotinonitrile,
2-amino-4-(2-fluorophenyl)-6-(4-hydroxyphenyl)nicotinonitrile,
2,4-diamino-7,8-dihydroxy-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
2,4-diamino-8-hydroxy-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
2-amino-7,8-dihydroxy-4-[(2-hydroxyethyl)amino]-5H-chromeno[2,3-
b]pyridine-3-carbonitrile,
2,4-diamino-7,8-dimethoxy-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
2-amino-7,8-dihydroxy-4-(propylamino)-5H-chromeno[2,3-b]pyridine-3-
carbonitrile,
265

2-amino-4-(ethylamino)-7,8-dihydroxy-5H-chromeno[2,3-b]pyridine-3-
carbonitrile,
2,4-diamino-9-hydroxy-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
2,4-diamino-9-fluoro-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
2,4-diamino-7-hydroxy-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
2,4-diamino-8-(2-hydroxyethoxy)-5H-chromeno[2,3-b]pyridine-3-
carbonitrile,
8,10-diamino-2,3-dihydro-11H-[1,4]dioxino[2',3':6,7]chromeno[2,3-
b]pyridine-9-carbonitrile,
2,4,7-triamino-5H-chromeno[2,3-b]pyridine-3-carbonitrile
2,4-diamino-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
2,4-diamino-8-(2-ethoxyethoxy)-7-hydroxy-5H-chromeno[2,3-b]pyridine-3-
carbonitrile,
2,4-diamino-9-hydroxy-8-methoxy-5H-chromeno[2,3-b]pyridine-3-
carbonitrile,
2,4-diamino-6,8-dihydroxy-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
2,4-diamino-8-ethoxy-7-hydroxy-5H-chromeno[2,3-b]pyridine-3-
carbonitrile,
2,4-diamino-8-(2-ethoxyethoxy)-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
2,4-diamino-8-(2-aminoethoxy)-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
2,4-diamino-3-cyano-5H-chromeno[2,3-b]pyridine-7-carboxylic acid,
2,4-diamino-8,9-dihydroxy-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
2,4-diamino-8-(2-morpholin-4-ylethoxy)-5H-chromeno[2,3-b]pyridine-3-
carbonitrile,
[(2,4-diamino-3-cyano-5H-chromeno[2,3-b]pyridin-8-yl)oxy]acetic acid,
2,4-diamino-9-methoxy-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
2,4-diamino-8-(2-pyrrolidin-1-ylethoxy)-5H-chromeno[2,3-b]pyridine-3-
carbonitrile,
2-amino-7,8-dimethoxy-4-(methylamino)-5H-chromeno[2,3-b]pyridine-3-
carbonitrile,
2,4-diamino-8-methoxy-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
266

2,4-diamino-8-[2-(dimethylamino)ethoxy]-5H-chromeno[2,3-b]pyridine-3-
carbonitrile,
2,4,7-triamino-9-methoxy-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
2(2,4-diamino-3-cyano-8-methoxy-5H-chromeno[2,3-b]pyridin-5-
yl)malononitrile,
2,4-diamino-7,8-di[2-(amino)ethoxy]-5H-chromeno[2,3-b]pyridine-3-
carbonitrile,
2,4-diamino-9-nitro-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
2-amino-7,8-dimethoxy-4-[(4-methoxyphenyl)amino]-5H-chromeno[2,3-
b]pyridine-3-carbonitrile,
2,4-diamino-8-methoxy-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
2(2,4-diamino-3-cyano-7-hydroxy-5H-chromeno[2,3-b]pyridin-5-
yl)malononitrile,
2(2,4-diamino-3-cyano-7-bromo-5H-chromeno[2,3-b]pyridin-5-
yl)malononitrile,
2-amino-8-ethoxy-4-(ethylamino)-5H-chromeno[2,3-b]pyridine-3-
carbonitrile,
2,4,9-triamino-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
2,4,7-triamino-5H-thiochromeno[2,3-b]pyridine-3-carbonitrile,
2-amino-7,8-dimethoxy-4-[(4-methoxyphenyl)amino]-5H-chromeno[2,3-
b]pyridine-3-carbonitrile,
2(2,4-diamino-3-cyano-7-methoxy-5H-chromeno[2,3-b]pyridin-5-
yl)malononitrile,
2,4-diamino-9-hydroxy-8-(piperidin-1-ylmethyl)-5H-chromeno[2,3-
b]pyridine-3-carbonitrile,
7,8-bis(allyloxy)-2,4-diamino-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
2-amino-8-(2-ethoxyethoxy)-4-[(2-ethoxyethyl)amino]-5H-chromeno[2,3-
b]pyridine-3-carbonitrile,
tert-butyl {[2,4-diamino-7-(2-tert-butoxy-2-oxoethoxy)-3-cyano-5H-
chromeno[2,3-b]pyridin-8-yl]oxy}acetate,
2-amino-4-[(2-aminoethyl)amino]-7,8-dimethoxy-5H-chromeno[2,3-
b]pyridine-3-carbonitrile,
267

2(2,4-diamino-3-cyano-8-hydroxy-5H-chromeno[2,3-b]pyridin-5-
yl)malononitrile,
2,4,7-triamino-5H-thiochromeno[2,3-b]pyridine-3-carbonitrile 10,10-
dioxide,
2,4-diamino-7-bromo-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
2-amino-7,8-dimethoxy-4-(propylamino)-5H-chromeno[2,3-b]pyridine-3-
carbonitrile,
2,4-diamino-7-hydroxy-5H-thiochromeno[2,3-b]pyridine-3-carbonitrile,
2,4-diamino-7-(dimethylamino)-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
2,4-diamino-7-methoxy-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
2(2,4-diamino-3-cyano-9-methoxy-5H-chromeno[2,3-b]pyridin-5-
yl)malononitrile,
2-amino-4-(benzylamino)-7,8-dimethoxy-5H-chromeno[2,3-b]pyridine-3-
carbonitrile,
8-(allyloxy)-2,4-diamino-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
2,4-diamino-9-fluoro-5H-thiochromeno[2,3-b]pyridine-3-carbonitrile,
2,4-diamino-7-methoxy-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
2,4-diamino-9-(2-pyrrolidin-1-ylethoxy)-5H-chromeno[2,3-b]pyridine-3-
carbonitrile,
2,4-diamino-7-nitro-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
2,4-diamino-10-methyl-5,10-dihydrobenzo[b]-1,8-naphthyridine-3-
carbonitrile,
[(2,4-diamino-3-cyano-5H-chromeno[2,3-b]pyridin-9-yl)oxy]acetic acid,
2-amino-4-{[2-(dimethylamino)ethyl]amino}-7,8-dimethoxy-5H-
chromeno[2,3-b]pyridine-3-carbonitrile,
2,4-diamino-7-nitro-5H-thiochromeno[2,3-b]pyridine-3-carbonitrile 10,10-
dioxide,
2,4-diamino-7-phenyl-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
2,4-diamino-7-chloro-9-methyl-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
2,4-diamino-7-fluoro-5H-thiochromeno[2,3-b]pyridine-3-carbonitrile 10,10-
dioxide,
8-ethoxy-2,4-bis(ethylamino)-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
268

2,4-diamino-5-(2-fluoro-phenyl)-8-methoxy-5H-chromeno[2,3-b]pyridine-3-
carbonitrile,
2,4-diamino-9-(2-hydroxyethoxy)-5H-chromeno[2,3-b]pyridine-3-
carbonitrile,
2,4-diamino-9-(2-aminoethoxy)-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
2(2,4-diamino-3-cyano-7-chloro-5H-chromeno[2,3-b]pyridin-5-
yl)malononitrile,
2,4-bis{[2-(dimethylamino)ethyl]amino}-7,8-dimethoxy-5H-chromeno[2,3-
b]pyridine-3-carbonitrile,
2-amino-4-{[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]amino}-7,8-
dimethoxy-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
2,4-diamino-7-fluoro-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
2,4-diamino-7-bromo-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
2,4-diamino-9-(pyridin-4-ylmethoxy)-5H-chromeno[2,3-b]pyridine-3-
carbonitrile,
2,4-diamino-7-chloro-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
2,4-diamino-9-tert-butyl-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
ethyl 2,4-diamino-3-cyano-5H-chromeno[2,3-b]pyridine-9-carboxylate,
2,4-diamino-9-[2-(dimethylamino)ethoxy]-5H-chromeno[2,3-b]pyridine-3-
carbonitrile,
2,4-bis(butylamino)-7,8-dimethoxy-5H-chromeno[2,3-b]pyridine-3-
carbonitrile,
2-amino-4-(butylamino)-7,8-dimethoxy-5H-chromeno[2,3-b]pyridine-3-
carbonitrile,
7,8-dimethoxy-2,4-bis(propylamino)-5H-chromeno[2,3-b]pyridine-3-
carbonitrile,
2,4-bis(ethylamino)-7,8-dimethoxy-5H-chromeno[2,3-b]pyridine-3-
carbonitrile,
2-amino-4-(ethylamino)-7,8-dimethoxy-5H-chromeno[2,3-b]pyridine-3-
carbonitrile,
2,4-diamino-6,8-dimethoxy-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
269

2,4-diamino-7-(trifluoromethoxy)-5H-chromeno[2,3-b]pyridine-3-
carbonitrile,
2,4-diamino-7-bromo-9-methoxy-5H-chromeno[2,3-b]pyridine-3-
carbonitrile,
2,4-diamino-9-methoxy-7-nitro-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
7,9-diamino-10H-[1,3]dioxolo[8,7]chromeno[2,3-b]pyridine-8-carbonitrile,
7,9-diamino-10H-[1,3]dioxolo[8,7]chromeno[2,3-b]pyridine-8-carbonitrile,
2,4-diamino-8-methyl-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
7,8-dimethoxy-2,4-bis[(2-methoxyethyl)amino]-5H-chromeno[2,3-
b]pyridine-3-carbonitrile,
2-amino-7,8-dimethoxy-4-[(2-methoxyethyl)amino]-5H-chromeno[2,3-
b]pyridine-3-carbonitrile,
2-amino-7,8-dimethoxy-4-[(2-pyrrolidin-1-ylethyl)amino]-5H-chromeno[2,3-
b]pyridine-3-carbonitrile,
7,8-dimethoxy-2,4-bis[(2-pyrrolidin-1-ylethyl)amino]-5H-chromeno[2,3-
b]pyridine-3-carbonitrile,
2,4-bis(glycinyl)-7,8-dimethoxy-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
N (2-amino-3-cyano-7,8-dimethoxy-5H-chromeno[2,3-b]pyridin-4-
yl)glycine,
2,4-diamino-3-cyano-5H-chromeno[2,3-b]pyridine-9-carboxylic acid,
2,4-diamino-6-methoxy-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
2,4-diamino-9-bromo-7-chloro-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
2,4-bis(ethylamino)-7,8-dihydroxy-5H-chromeno[2,3-b]pyridine-3-
carbonitrile,
2,4-diamino-6-bromo-9-methoxy-5H-chromeno[2,3-b]pyridine-3-
carbonitrile,
2,4-diamino-8-hydroxy-7,9-bis(piperidin-1-ylmethyl)-5H-chromeno[2,3-
b]pyridine-3-carbonitrile,
2,4-diamino-5-phenyl-8-hydroxy-5H-chromeno[2,3-b]pyridine-3-
carbonitrile,
2,4-diamino-5-(3-fluoro-phenyl)-8-methoxy-5H-chromeno[2,3-b]pyridine-3-
carbonitrile,
270

2,4-diamino-9-hydroxy-6,8-bis(piperidin-1-ylmethyl)-5H-chromeno[2,3-
b]pyridine-3-carbonitrile,
2,4-diamino-7-bromo-8-methoxy-5H-chromeno[2,3-b]pyridine-3-
carbonitrile,
2,4-diamino-5-phenyl-8-methoxy-5H-chromeno[2,3-b]pyridine-3-
carbonitrile,
2,4-diamino-9-fluoro-5H-thiochromeno[2,3-b]pyridine-3-carbonitrile 10,10-
dioxide,
2,4-diamino-7-nitro-5H-thiochromeno[2,3-b]pyridine-3-carbonitrile,
2,4-diamino-7-methoxy-5H-thiochromeno[2,3-b]pyridine-3-carbonitrile
10,10-dioxide,
2,4-diamino-7-methoxy-5H-thiochromeno[2,3-b]pyridine-3-carbonitrile,
2,4-diamino-5H-thiochromeno[2,3-b]pyridine-3-carbonitrile 10,10-dioxide,
2,4-diamino-5H-thiochromeno[2,3-b]pyridine-3-carbonitrile,
2,4-diamino-7-fluoro-5H-thiochromeno[2,3-b]pyridine-3-carbonitrile,
2-amino-7,9-dimethyl-5-oxo-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
2-amino-7-isopropyl-5-oxo-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
2-amino-7-ethyl-5-oxo-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
2-amino-7-methyl-5-oxo-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
2-amino-7-chloro-5-oxo-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
2-amino-7-bromo-5-oxo-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
2-amino-5-oxo-5H-chromeno[2,3-b]pyridine-3-carbonitrile, and
3-amino-5H-pyrido[3,4-b][1,4]benzothiazine-4-carbonitrile.
8. A method of inhibiting mitogen activated protein kinase-
activated protein kinase-2 in a subject in need of such inhibition, the
method comprising administering to the subject a compound, or a
pharmaceutically acceptable salt thereof, the compound having the
structure:
271

<IMG>
wherein:
G is selected from the group consisting of - O -, - S -, and -N-;
when G is -O-, R41 and R42 are absent;
when G is -S-, R41 and R42 are optionally absent, or are oxo;
when G is -N-, R41 is absent, and R42 is -H or C1-C4-alkyl;
R1, R2, R35, R36, R37, R38, R39, and R40 each is independently
selected from the group consisting of
hydrogen, hydroxy, amino, halo, nitro,
branched or unbranched C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl,
C1-C6 alkoxy, hydroxy C1-C6 alkyl, hydroxy C1-C6 alkoxy, C1-C6 alkoxy C1-
C6 alkoxy, C1-C6 alkoxy C1-C6 alkyl, C2-C6 alkenoxy,
branched or unbranched amino C1-C6 alkyl, diamino C2-C6 alkyl, C1-
C6 alkylamino C1-C6 alkyl, C1-C6 alkylamino, di-(C1-C6 alkyl)amino, C1-C4
alkoxyarylamino, C1-C4 alkoxyalkylamino, amino C1-C6 alkoxy, di-(C1-C4
alkylamino, C2-C6 alkoxy, di-(C1-C6 alkyl)amino C1-C6 alkyl, C1-C6
alkylamino C1-C6 alkoxy, halo C1-C6 alkoxy, dihalo C1-C6 alkoxy, trihalo C1-
C6 alkoxy, cyano C1-C6 alkyl, dicyano C1-C6 alkyl, cyano C1-C6 alkoxy,
dicyano C1-C6 alkoxy, carbamyl C1-C4 alkoxy, heterocyclyl C1-C4 alkoxy,
heteroaryl C1-C4 alkoxy, sulfo, sulfamyl, C1-C4 alkylaminosulfonyl, hydroxy
C1-C4 alkylaminosulfonyl, di-(C1-C4 alkyl)aminosulfonyl, C1-C4 alkylthio, C1-
C4 alkylsulfonyl, C1-C4 alkylsulfinyl,
aryl, aryl C1-C6 alkyl, heterocyclyl C1-C6 alkyl, heteroaryl C1-C6 alkyl,
heterocyclyl C1-C6 alkoxl, heteroaryl C1-C6 alkoxy, aryl C1-C6 alkoxy,
where the aryl ring can be substituted or unsubstituted, and, if substituted,
272

the substituent group is selected from one or more of the group consisting
of C1-C6 alkyl, halo, amino, and C1-C6 alkoxy,
substituted or unsubstituted C3-C6 cyclyl, C3-C6 heterocyclyl, and, if
substituted, the substituent group is selected from one or more of the
group consisting of C1-C6 alkyl, C1-C6 alkoxy, halo, amino, and where the
C3-C6 heterocyclyl ring contains O, S, or N,
branched or unbranched C1-C6 alkoxycarbonyl C1-C6 alkoxy, and
carboxy, carboxy C1-C6 alkoxy, carboxy C1-C6 alkyl, hydroxy C1-C4
alkoxycarbonyl, C1-C4 alkoxycarbonyl,
where R38 and R39 are such that they optionally join to form a ring
system of the type selected from
<IMG>
9. The method according to claim 3, wherein the compound is
one having the structure:
<IMG>
wherein:
G is selected from the group consisting of - O -, - S -, and -N-;
when G is -O-, R41 and R42 are absent;
when G is -S-, R41 and R42 are optionally absent, or are oxo;
when G is -N-, R41 is absent, and R42 is -H or C1-C4-alkyl;
273

R1 is selected from the group consisting of hydrogen, branched or
unbranched alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, arylalkyl, carboxy,
carboxyalkyl, hydroxyalkyl, alkylcarboxy, aryl, amino, aminoalkyl,
alkylamino, halo, alkylaminoalkyl, alkoxy, alkoxyalkyl, monocyclyl, bicyclyl,
polycyclyl, and heterocyclyl;
R2 is selected from the group consisting of hydrogen, alkyl, alkenyl,
alkynyl, alkoxy, hydroxyalkyl, alkylaryl, arylalkyl, alkoxyaryl, aminoalkyl,
alkylaminoalkyl, arylaminoalkyl, alkoxyalkyl, alkylcarboxy, and
carboxyalkyl;
R35 is selected from the group consisting of hydrogen, dicyanoalkyl,
and substituted or unsubstituted heterocyclyl and cyclyl, where
substituents, if any, comprise halo moieties;
R36 is selected from the group consisting of hydrogen, dicyanoalkyl,
and substituted or unsubstituted heterocyclyl and cyclyl, where
substituents, if any, comprise halo moieties;
R37 is selected from the group consisting of hydrogen, alkoxy, halo,
alkyl, alkenyl, alkylyl, arylalkyl, or alkylaryl;
R38 is selected from the group consisting of hydrogen, hydroxy,
alkoxy, alkyl, alkenyl, alkynyl, amino, alkylamino, arylamino,
alkylaminoalkyl, carboxy, aminoalkoxy, halo, alkylcarboxyalkyl, alkylamino,
aminoalkyl, nitro, aryl, arylalkyl, alkylaryl, or arylamino;
R39 is selected from the group consisting of hydrogen, hydroxy,
alkoxy, alkenoxy, hydroxyalkoxy, alkoxyalkoxy, aminoalkoxy,
heterocyclylalkyl, heterocyclylalkoxy, carboxyalkoxy, alkylaminoalkoxy,
and alkylcarboxyalkoxy;
where the R38 and R39 groups optionally join to form a six
membered heterocyclic ring; and
R40 is selected from the group consisting of hydrogen, hydroxy,
halo, nitro, amino, alkyl, alkoxy, heterocyclylalkoxy, carboxyalkoxy,
pyrrolidylethoxy, carboxymethoxy, hydroxyalkoxy, aminoalkoxy,
alkylcarboxy, alkylaminoalkyl, carboxy, and heterocyclylalkyl.
274

10. A method of inhibiting mitogen activated protein kinase-
activated protein kinase-2 in a subject in need of such inhibition, the
method comprising administering to the subject a compound, or a
pharmaceutically acceptable salt thereof, the compound having the
structure:
<IMG>
wherein:
G is selected from the group consisting of -O-, -S-, and -N-;
when G is -O-, R41 and R42 are absent;
when G is -S-, R41 and R42 are optionally absent, or are oxo;
when G is -N-, R41 is absent, and R42 is -H or -CH3;
R1 is selected from the group consisting of hydrogen, ethyl,
dimethylaminoethyl, butyl, propyl, methoxyethyl, tetramethylaminoethyl,
and carboxymethyl;
R2 is selected from the group consisting of hydrogen, hydroxyethyl,
propyl, ethyl, methyl, 4-methoxyphenyl, ethoxyethyl, aminoethyl,
phenylmethyl, dimethylaminoethyl, phthaloaminoethyl, butyl, methoxyethyl,
tetramethylaminoethyl, and carboxymethyl;
R35 is selected from the group consisting of hydrogen,
dicyanomethyl, 2-fluorophenyl, phenyl, and 3-fluorophenyl.
R36 is selected from the group consisting of hydrogen,
dicyanomethyl, 2-fluorophenyl, phenyl, and 3-fluorophenyl;
R37 is selected from the group consisting of hydrogen, hydroxy,
methoxy, bromo, and 2-pyridomethyl;
R38 is selected from the group consisting of hydrogen, hydroxy,
methoxy, amino, carboxy, diaminoethoxy, bromo, propoxy,
275

isobutylcarboxymethoxy, dimethylamino, nitro, phenyl, chloro,
pyridylmethyl, and fluoro;
R39 is selected from the group consisting of hydrogen, hydroxy,
methoxy, hydroxyethoxy, ethoxyethoxy, ethoxy, aminoethoxy,
morpholinoethoxy, carboxymethoxy, N-pyrrolidylethoxy,
dimethylaminoethoxy, pyridylmethyl, 2-propenoxy, and
isobutylcarboxymethoxy, where the R38 and R39 groups optionally join to
form a six membered heterocyclic ring; and
R40 is selected from the group consisting of hydrogen, hydroxy,
fluoro, methoxy, nitro, amino, pyrrolidylethoxy, carboxymethoxy, methyl,
hydroxyethoxy, aminoethoxy, 4-pyridylmethoxy, isobutyl, ethylcarboxy,
dimethylaminoethoxy, carboxy, bromo, and pyrridylmethyl.
11. The method according to claim 9, wherein the compound is
one wherein:
G is selected from the group consisting of -O- and -S-;
when G is -O-, R41 and R42 are absent;
when G is -S-, R41 and R42 are optionally absent, or are oxo;
R1 is selected from the group consisting of hydrogen, and C1-C2
alky;
R2 is selected from the group consisting of hydrogen, C1-C3 alkyl,
hydroxy C1-C2 alkyl, C1-C2 alkoxyphenyl, C1-C2 alkoxy C1-C2 alkyl, amino
C1-C2 alkyl, phenyl C1-C2 alkyl, and di C1-C2 alkylamino C1-C2 alkyl;
R35 and R36 are each independently selected from the group
consisting of hydrogen, dicyano C1-C2 alkyl, and halophenyl;
R37 is selected from the group consisting of hydrogen, and hydroxy;
R38 is selected from the group consisting of hydrogen, hydroxy, C1 -
C3 alkoxy, amino, nitro, carboxy, diamino C1 - C2 alkoxy, halo, propenoxy,
iso C3 - C4 alkylcarboxy C1 - C2 alkoxy, di C1 - C2 alkylamino, and phenyl;
R39 is selected from the group consisting of hydrogen, hydroxy, C1 -
C3 alkoxy, hydroxy C1 - C2 alkoxy, C1 - C2 alkoxy C1 - C2 alkoxy, amino C1
- C2 alkoxy, morpholino C1 - C2 alkoxy, carboxyl C1 - C2 alkoxy, pyrrolidyl
276

C1 - C2 alkoxy, di C1 - C2 alkylamino C1 - C2 alkoxy, pyrrolidyl C1 - C2
alkyl,
iso C3 - C4 alkylcarboxy C1 - C2 alkoxy, and 2-propenoxy,
where the R38 and R39 groups can join to form a six membered
heterocyclic ring; and
R40 is selected from the group consisting of hydrogen, hydroxy,
halo, C1-C2 alkyl, C1-C2 alkoxy, nitro, amino, pyrrolidyl C1-C2 alkoxy,
carboxy C1-C2 alkoxy, hydroxy C1-C2 alkoxy, and amino C1-C2 alkoxy.
12. The method according to claim 10, wherein the compound is
one wherein:
G is selected from the group consisting of -O- and -S-;
when G is -O-, R41 and R42 are absent;
when G is -S-, R41 and R42 are optionally absent, or are oxo;
R1 is hydrogen;
R2 is selected from the group consisting of hydrogen, C1 - C3 alkyl,
hydroxy C1 - C2 alkyl, C1 - C2 alkoxyphenyl, C1 - C2 alkoxy C1 - C2 alkyl,
amino C1 - C2 alkyl, phenyl C1 - C2 alkyl, and di C1 - C2 alkylamino C1 - C2
alkyl;
R35 and R36 are each independently selected from the group
consisting of hydrogen, and dicyano C1 - C2 alkyl.
R37 is selected from the group consisting of hydrogen, and hydroxy;
R38 is selected from the group consisting of hydrogen, hydroxy, C1-
C2 alkoxy, amino, nitro, carboxy, diamino C1-C2 alkoxy, halo, 2-propenoxy,
iso C3-C4 alkylcarboxy C1-C2 alkoxy, di C1-C2 alkylamino, and phenyl;
R39 is selected from the group consisting of hydrogen, hydroxy, C1 -
C2 alkoxy, hydroxy C1-C2 alkoxy, C1-C2 alkoxy C1-C2 alkoxy, amino C1-C2
alkoxy, morpholino C1-C2 alkoxy, carboxyl C1-C2 alkoxy, pyrrolidyl C1-C2
alkoxy, di C1-C2 alkylamino C1-C2 alkoxy, pyrrolidyl C1-C2 alkyl, iso C3-C4
alkylcarboxy C1-C2 alkoxy, and 2-propenoxy;
wherein the R38 and R39 groups optionally join to form a six
membered heterocyclic ring; and
277

R40 is selected from the group consisting of hydrogen, hydroxy,
halo, C1-C2 alkoxy, nitro, amino, pyrrolidyl C1-C2 alkoxy, and carboxy C1-
C2 alkoxy.
13. The method according to claim 10, wherein the compound is
one wherein:
G is selected from the group consisting of -O- and -S-;
when G is -O-, R41 and R42 are absent;
when G is -S-, R41 and R42 are optionally absent, or are oxo;
R1 is hydrogen;
R2 is selected from the group consisting of hydrogen, C1-C3 alkyl,
hydroxy C1-C2 alkyl, C1-C2 alkoxyphenyl, C1-C2 alkoxy C1-C2 alkyl, amino
C1-C2 alkyl, and phenyl C1-C2 alkyl;
R35 and R36 are each independently selected from the group
consisting of hydrogen, and dicyano C1-C2 alkyl.
R37 is selected from the group consisting of hydrogen, and hydroxy;
R38 is selected from the group consisting of hydrogen, hydroxy, C1-
C2 alkoxy, amino, carboxy, diamino C1-C2 alkoxy, halo, 2-propenoxy, iso
C3-C4 alkylcarboxy C1-C2 alkoxy, and di C1-C2 alkylamino;
R39 is selected from the group consisting of hydrogen, hydroxy, C1-
C2 alkoxy, hydroxy C1-C2 alkoxy, C1-C2 alkoxy C1-C2 alkoxy, amino C1-C2
alkoxy, morpholino C1-C2 alkoxy, carboxyl C1-C2 alkoxy, pyrrolidyl C1-C2
alkoxy, di C1-C2 alkylamino C1-C2 alkoxy, pyrrolidyl C1-C2 alkyl, iso C3-C4
alkylcarboxy C1-C2 alkoxy, and 2-propenoxy;
where the R38 and R39 groups optionally join to form a six
membered heterocyclic ring; and
R40 is selected from the group consisting of hydrogen, hydroxy,
halo, C1-C2 alkoxy, nitro, amino, and pyrrolidyl C1-C2 alkoxy.
14. The method according to claim 10, wherein the compound is
one wherein:
G is selected from the group consisting of -O- and -S-;
when G is -O-, R41 and R42 are absent;
when G is -S-, R41 and R42 are optionally absent, or are oxo;
278

R1 is hydrogen;
R2 is selected from the group consisting of hydrogen, C1-C3 alkyl,
hydroxy C1-C2 alkyl, C1-C2 alkoxyphenyl, C1-C2 alkoxy C1-C2 alkyl, and
amino C1-C2 alkyl;
R35 and R36 are each independently selected from the group
consisting of hydrogen, and dicyanoethyl;
R37 is selected from the group consisting of hydrogen, and hydroxy;
R38 is selected from the group consisting of hydrogen, hydroxy, C1-
C2 alkoxy, amino, carboxy, diamino C1-C2 alkoxy, halo, 2-propenoxy, iso
C3-C4 alkylcarboxy C1-C2 alkoxy, and di C1-C2 alkylamino;
R39 is selected from the group consisting of hydrogen, hydroxy, C1-
C2 alkoxy, hydroxy C1-C2 alkoxy, C1-C2 alkoxy C1-C2 alkoxy, amino C1-C2
alkoxy, morpholino C1-C2 alkoxy, carboxyl C1-C2 alkoxy, pyrrolidyl C1-C2
alkoxy, di C1-C2 alkylamino C1-C2 alkoxy, pyrrolidyl C1-C2 alkyl, iso C3-C4
alkylcarboxy C1-C2 alkoxy, and 2-propenoxy;
where the R38 and R39 groups optionally join to form a six
membered heterocyclic ring; and
R40 is selected from the group consisting of hydrogen, hydroxy,
halo, methoxy, nitro, and amino.
15. The method according to claim 1, wherein the
aminocyanopyridine MK-2 inhibiting compound comprises at least one
compound that is selected from the group consisting of:
2-amino-4-(2-fluorophenyl)-6,8-dihydro-5H-pyrazolo[3,4-h]quinoline-3-
carbonitrile,
2-amino-4-(2-furyl)-6,7-dihydro-5H-pyrazolo[3,4-h]quinoline-3-carbonitrile,
2-amino-4-(2,3-difluorophenyl)-6,7-dihydro-5H-pyrazolo[3,4-h]quinoline-3-
carbonitrile,
8-amino-6-(2-furyl)-4,5-dihydro-1H-pyrazolo[4,3-h]quinoline-7-carbonitrile,
2-amino-3-cyano-4-(2-furyl)-5,6-dihydrobenzo[h]quinoline-8-carboxylic
acid,
4-[2-amino-3-cyano-6-(2-furyl)pyridin-4-yl]-1H-pyrrole-2-carboxamide,
2-amino-4-phenyl-6,8-dihydro-5H-pyrazolo[3,4-h]quinoline-3-carbonitrile,
279

2-amino-6-(2-furyl)-4-(1-methyl-1H-imidazol-4-yl)nicotinonitrile,
8-amino-6-(2-furyl)-4,5-dihydro-1H-pyrazolo[4,3-h]quinoline-7-carbonitrile,
2-amino-4-(2-furyl)-8-hydroxy-5,6-dihydrobenzo[h]quinoline-3-carbonitrile,
2-amino-4-(2,6-difluorophenyl)-6,7-dihydro-5H-pyrazolo[3,4-h]quinoline-3-
carbonitrile,
2-amino-6-(4-hydroxyphenyl)-4-(1H-imidazol-5-yl)nicotinonitrile,
2-amino-4-(2-fluorophenyl)-6-(2-furyl)nicotinonitrile, 2-amino-4-(2-
fluorophenyl)-6-(2-furyl)nicotinonitrile,
2-amino-4-(2-fluorophenyl)-5,6-dihydrobenzo[h]quinoline-3-carbonitrile,
4-[6-amino-5-cyano-4-(2-furyl)pyridin-2-yl]benzoic acid,
2-amino-6-(2-furyl)-4-(1H-imidazol-5-yl)nicotinonitrile,
2-amino-4-(2-furyl)-6-(1H-pyrazol-3-yl)nicotinonitrile,
2-amino-3-cyano-4-(4H-1,2,4-triazol-3-yl)-5,6-dihydrobenzo[h]quinoline-8-
carboxylic acid,
2-amino-6-(3-hydroxyphenyl)-4-(1H-imidazol-5-yl)nicotinonitrile,
2-amino-6-(2-furyl)-4-(1H-imidazol-4-yl)nicotinonitrile,
2-amino-4-(2,4-difluorophenyl)-6,7-dihydro-5H-pyrazolo[3,4-h]quinoline-3-
carbonitrile, 4,6-diamino-2-(trifluoromethyl)-2,3-dihydrofuro[2,3-b]pyridine-
5-carbonitrile,
2-amino-4-(2-furyl)-6,8-dihydro-5H-pyrrolo[3,4-h]quinoline-3-carbonitrile,
4-[6-amino-5-cyano-4-(2-fluorophenyl)pyridin-2-yl]benzoic acid,
2-amino-4-(2-furyl)-5,6-dihydro-1,8-phenanthroline-3-carbonitrile,
2-amino-6-(3,4-dihydroxyphenyl)-4-(2-fluorophenyl)nicotinonitrile,
2-amino-4-(1-methyl-1H-imidazol-4-yl)-6-phenylnicotinonitrile,
2-amino-4-(2-furyl)-6-(1H-pyrazol-3-yl)nicotinonitrile,
4-[6-amino-5-cyano-4-(1H-imidazol-5-yl)pyridin-2-yl]benzoic acid,
2-amino-4-(3-fluorophenyl)-6,8-dihydro-5H-pyrazolo[3,4-h]quinoline-3-
carbonitrile,
2-amino-6-(3,4-dihydroxyphenyl)-4-(2-fluorophenyl)nicotinonitrile,
N-{4-[6-amino-5-cyano-4-(2-furyl)pyridin-2-yl]phenyl}methanesulfonamide,
2-amino-4-(2-furyl)-6,7-dihydro-5H-pyrrolo[2,3-h]quinoline-3-carbonitrile,
2-amino-4-(1H-imidazol-5-yl)-6-phenylnicotinonitrile,
280

2-amino-4-(2-furyl)-5,6-dihydrobenzo[h]quinoline-3-carbonitrile,
2-amino-4-(1H-imidazol-5-yl)-6-(4-methoxyphenyl)nicotinonitrile,
2-amino-6-(3-chlorophenyl)-4-(1H-imidazol-5-yl)nicotinonitrile,
2-amino-4-(2-furyl)-6-(1H-pyrazol-4-yl)nicotinonitrile,
2-amino-4-(4-methoxyphenyl)-6,7-dihydro-5H-pyrazolo[3,4-h]quinoline-3-
carbonitrile,
2-amino-4-(2,5-difluorophenyl)-6,7-dihydro-5H-pyrazolo[3,4-h]quinoline-3-
carbonitrile,
2-amino-4-(4-fluorophenyl)-6,8-dihydro-5H-pyrazolo[3,4-h]quinoline-3-
carbonitrile,
2-amino-4-(4H-1,2,4-triazol-3-yl)-5,6-dihydrobenzo[h]quinoline-3-
carbonitrile,
4,6-diamino-2-(chloromethyl)-2,3-dihydrofuro[2,3-b]pyridine-5-carbonitrile,
2-amino-4-(1H-imidazol-4-yl)-6-phenylnicotinonitrile,
4-[6-amino-5-cyano-4-(2-furyl)pyridin-2-yl]benzenesulfonamide,
4-[6-amino-5-cyano-4-(2-furyl)pyridin-2-yl]phenylboronic acid,
2-amino-6-(4-methoxyphenyl)-4-(4H-1,2,4-triazol-3-yl)nicotinonitrile,
2-amino-4-(2-fluorophenyl)-6-(3-furyl)nicotinonitrile,
2-amino-6-(2-furyl)-4-(methylthio)nicotinonitrile,
2-amino-4-(2-fluorophenyl)-6-(3-hydroxyphenyl)nicotinonitrile,
8-amino-6-(2-furyl)-4,5-dihydro-2H-pyrazolo[4,3-h]quinoline-7-carbonitrile,
2-amino-4-(2-bromophenyl)-6-(2-furyl)nicotinonitrile,
2-amino-4-(2-fluorophenyl)-6-(4-hydroxyphenyl)nicotinonitrile,
2-amino-4-phenyl-6-thien-2-ylnicotinonitrile,
2-amino-4-(3-methoxyphenyl)-6,7-dihydro-5H-pyrazolo[3,4-h]quinoline-3-
carbonitrile,
2-amino-4-(2-furyl)-7-methyl-6,7-dihydro-5H-pyrazolo[3,4-h]quinoline-3-
carbonitrile,
2-amino-4-(2-fluorophenyl)-6-(1H-pyrrol-2-yl)nicotinonitrile,
2-amino-4-(2-furyl)-5-methyl-6,8-dihydro-5H-pyrazolo[3,4-h]quinoline-3-
carbonitrile,
2-amino-4-(2-furyl)-6-(1-methyl-1H-pyrrol-3-yl)nicotinonitrile,
281

3-amino-5,6,7,8-tetrahydroisoquinoline-4-carbonitrile,
N-[4-(2-amino-3-cyano-6,7-dihydro-5H-pyrazolo[3,4-h]quinolin-4-
yl)phenyl]acetamide,
6-amino-4-[(4-methoxyphenyl)amino]-2-(trifluoromethyl)-2,3-
dihydrofuro[2,3-b]pyridine-5-carbonitrile,
4-[6-amino-5-cyano-4-(2-furyl)pyridin-2-yl]-N-(tert-
butyl)benzenesulfonamide,
4,6-diamino-2-ethyl-2,3-dihydrofuro[2,3-b]pyridine-5-carbonitrile,
6-amino-4-(2-furyl)-2,4'-bipyridine-5-carbonitrile, 2,4-diamino-6-
(methylthio)nicotinonitrile,
3-(2-amino-3-cyano-6,7-dihydro-5H-pyrazolo[3,4-h]quinolin-4-yl)benzoic
acid,
2-amino-6-(4-chlorophenyl)-4-(1H-imidazol-5-yl)nicotinonitrile,
2-amino-4-(1,3-benzodioxol-4-yl)-6,7-dihydro-5H-pyrazolo[3,4-h]quinoline-
3-carbonitrile, 4,6-diamino-2-methyl-2,3-dihydrofuro[2,3-b]pyridine-5-
carbonitrile,
2-amino-4-(1H-imidazol-5-yl)-6-[4-(methylsulfonyl)phenyl]nicotinonitrile,
2,4-diaminoquinoline-3-carbonitrile,
2,8-diamino-4-(2-furyl)-5,6-dihydrobenzo[h]quinoline-3-carbonitrile,
2-amino-4,6-di(2-furyl)nicotinonitrile,
4,6-diamino-2-butyl-2,3-dihydrofuro[2,3-b]pyridine-5-carbonitrile,
ethyl 4-[6-amino-5-cyano-4-(1H-imidazol-5-yl)pyridin-2-yl]benzoate,
2,4-diamino-6-methoxynicotinonitrile,
2-amino-4-methylnicotinonitrile,
2-amino-4-(4-cyanophenyl)-6,7-dihydro-5H-pyrazolo[3,4-h]quinoline-3-
carbonitrile,
2-amino-4-cyclopropyl-6-methylnicotinonitrile,
2-amino-4-(2-furyl)-6-(1-methyl-1H-pyrrol-2-yl)nicotinonitrile,
2-amino-4-(2-chlorophenyl)-6,7-dihydro-5H-pyrazolo[3,4-h]quinoline-3-
carbonitrile,
2-amino-6-(2-furyl)-4-(4-phenoxyphenyl)nicotinonitrile,
282

2-amino-4-pyridin-3-yl-6,8-dihydro-5H-pyrazolo[3,4-h]quinoline-3-
carbonitrile,
2-amino-6-{[2-(4-chlorophenyl)-2-oxoethyl]thio}-4-(2-furyl)pyridine-3,5-
dicarbonitrile,
4-[2-amino-3-cyano-6-(2-furyl)pyridin-4-yl]phenylboronic acid,
2-amino-6-(3-chlorophenyl)-4-(1H-imidazol-4-yl)nicotinonitrile,
4-(6-amino-5-cyano-4-phenylpyridin-2-yl)-N-(tert-
butyl)benzenesulfonamide,
2-amino-4-methoxynicotinonitrile,
4-[2-amino-3-cyano-6-(2-furyl)pyridin-4-yl]benzoic acid,
4,6-diamino-2-[(4-methoxyphenoxy)methyl]-2,3-dihydrofuro[2,3-b]pyridine-
5-carbonitrile, 2-amino-4-(2-fluorophenyl)-6-(4-
methoxyphenyl)nicotinonitrile,
4-[6-amino-5-cyano-4-(2-fluorophenyl)pyridin-2-yl]-N-(tert-
butyl)benzenesulfonamide, (2,4-diamino-3-cyano-5H-chromeno[2,3-
b]pyridin-9-yl)oxy]acetic acid,
3-Pyridinecarbonitrile, 2-Amino-4-Methylm
2-amino-6-(2-furyl)nicotinonitrile,
2-amino-4-(2-furyl)-6-(3-hydroxyphenyl)nicotinonitrile,
4-[6-amino-5-cyano-4-(2-furyl)pyridin-2-yl]benzamide,
2-amino-4-(2-furyl)-7-hydroxy-5,6-dihydrobenzo[h]quinoline-3-carbonitrile,
2-amino-4-(2-furyl)-6-(1H-indol-3-yl)nicotinonitrile,
2-amino-4-pyridin-4-yl-6,8-dihydro-5H-pyrazolo[3,4-h]quinoline-3-
carbonitrile,
2-amino-4-(3-fluorophenyl)-6-(4-hydroxyphenyl)nicotinonitrile,
2-amino-4-[2-(difluoromethoxy)phenyl]-6,7-dihydro-5H-pyrazolo[3,4-
h]quinoline-3-carbonitrile,
2-amino-4-(2-furyl)-6-thien-3-ylnicotinonitrile,
2-amino-4-(3-fluorophenyl)-6-(4-methoxyphenyl)nicotinonitrile,
2-[2-amino-3-cyano-6-(2-furyl)pyridin-4-yl]phenylboronic acid,
2,4-diamino-6-propylpyridine-3,5-dicarbonitrile,
2,4-diamino-7,8-dihydroxy-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
283

2,4-diamino-8-hydroxy-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
2-amino-7,8-dihydroxy-4-[(2-hydroxyethyl)amino]-5H-chromeno[2,3-
b]pyridine-3-carbonitrile,
2,4-diamino-7,8-dimethoxy-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
2-amino-7,8-dihydroxy-4-(propylamino)-5H-chromeno[2,3-b]pyridine-3-
carbonitrile,
2-amino-4-(ethylamino)-7,8-dihydroxy-5H-chromeno[2,3-b]pyridine-3-
carbonitrile,
2,4-diamino-9-hydroxy-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
2,4-diamino-9-fluoro-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
2,4-diamino-7-hydroxy-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
2,4-diamino-8-(2-hydroxyethoxy)-5H-chromeno[2,3-b]pyridine-3-
carbonitrile,
8,10-diamino-2,3-dihydro-11H-[1,4]dioxino[2',3':6,7]chromeno[2,3-
b]pyridine-9-carbonitrile,
2,4,7-triamino-5H-chromeno[2,3-b]pyridine-3-carbonitrile
2,4-diamino-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
2,4-diamino-8-(2-ethoxyethoxy)-7-hydroxy-5H-chromeno[2,3-b]pyridine-3-
carbonitrile, 2,4-diamino-9-hydroxy-8-methoxy-5H-chromeno[2,3-
b]pyridine-3-carbonitrile,
2,4-diamino-6,8-dihydroxy-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
2,4-diamino-8-ethoxy-7-hydroxy-5H-chromeno[2,3-b]pyridine-3-
carbonitrile,
2,4-diamino-8-(2-ethoxyethoxy)-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
2,4-diamino-8-(2-aminoethoxy)-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
2,4-diamino-3-cyano-5H-chromeno[2,3-b]pyridine-7-carboxylic acid,
2,4-diamino-8,9-dihydroxy-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
2,4-diamino-8-(2-morpholin-4-ylethoxy)-5H-chromeno[2,3-b]pyridine-3-
carbonitrile, [(2,4-diamino-3-cyano-5H-chromeno[2,3-b]pyridin-8-
yl)oxy]acetic acid,
2,4-diamino-9-methoxy-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
284

2,4-diamino-8-(2-pyrrolidin-1-ylethoxy)-5H-chromeno[2,3-b]pyridine-3-
carbonitrile,
2-amino-7,8-dimethoxy-4-(methylamino)-5H-chromeno[2,3-b]pyridine-3-
carbonitrile,
2,4-diamino-8-methoxy-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
2,4-diamino-8-[2-(dimethylamino)ethoxy]-5H-chromeno[2,3-b]pyridine-3-
carbonitrile, 2,4,7-triamino-9-methoxy-5H-chromeno[2,3-b]pyridine-3-
carbonitrile,
2(2,4-diamino-3-cyano-8-methoxy-5H-chromeno[2,3-b]pyridin-5-
yl)malononitrile,
2,4-diamino-7,8-di[2-(amino)ethoxy]-5H-chromeno[2,3-b]pyridine-3-
carbonitrile,
2,4-diamino-9-nitro-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
2-amino-7,8-dimethoxy-4-[(4-methoxyphenyl)amino]-5H-chromeno[2,3-
b]pyridine-3-carbonitrile,
2,4-diamino-8-methoxy-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
2(2,4-diamino-3-cyano-7-hydroxy-5H-chromeno[2,3-b]pyridin-5-
yl)malononitrile,
2(2,4-diamino-3-cyano-7-bromo-5H-chromeno[2,3-b]pyridin-5-
yl)malononitrile,
2-amino-8-ethoxy-4-(ethylamino)-5H-chromeno[2,3-b]pyridine-3-
carbonitrile,
2,4,9-triamino-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
2,4,7-triamino-5H-thiochromeno[2,3-b]pyridine-3-carbonitrile,
2-amino-7,8-dimethoxy-4-[(4-methoxyphenyl)amino]-5H-chromeno[2,3-
b]pyridine-3-carbonitrile,
2(2,4-diamino-3-cyano-7-methoxy-5H-chromeno[2,3-b]pyridin-5-
yl)malononitrile,
2,4-diamino-9-hydroxy-8-(piperidin-1-ylmethyl)-5H-chromeno[2,3-
b]pyridine-3-carbonitrile,
7,8-bis(allyloxy)-2,4-diamino-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
285

2-amino-8-(2-ethoxyethoxy)-4-[(2-ethoxyethyl)amino]-5H-chromeno[2,3-
b]pyridine-3-carbonitrile,
tert-butyl {[2,4-diamino-7-(2-tert-butoxy-2-oxoethoxy)-3-cyano-5H-
chromeno[2,3-b]pyridin-8-yl]oxy)acetate,
2-amino-4-[(2-aminoethyl)amino]-7,8-dimethoxy-5H-chromeno[2,3-
b]pyridine-3-carbonitrile,
2(2,4-diamino-3-cyano-8-hydroxy-5H-chromeno[2,3-b]pyridin-5-
yl)malononitrile,
2,4,7-triamino-5H-thiochromeno[2,3-b]pyridine-3-carbonitrile 10,10-
dioxide,
2,4-diamino-7-bromo-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
2-amino-7,8-dimethoxy-4-(propylamino)-5H-chromeno[2,3-b]pyridine-3-
carbonitrile,
2,4-diamino-7-hydroxy-5H-thiochromeno[2,3-b]pyridine-3-carbonitrile,
2,4-diamino-7-(dimethylamino)-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
2,4-diamino-7-methoxy-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
2(2,4-diamino-3-cyano-9-methoxy-5H-chromeno[2,3-b]pyridin-5-
yl)malononitrile,
2-amino-4-(benzylamino)-7,8-dimethoxy-5H-chromeno[2,3-b]pyridine-3-
carbonitrile,
8-(allyloxy)-2,4-diamino-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
2,4-diamino-9-fluoro-5H-thiochromeno(2,3-b]pyridine-3-carbonitrile,
2,4-diamino-7-methoxy-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
2,4-diamino-9-(2-pyrrolidin-1-ylethoxy)-5H-chromeno[2,3-b]pyridine-3-
carbonitrile,
2,4-diamino-7-nitro-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
2,4-diamino-10-methyl-5,10-dihydrobenzo[b]-1,8-naphthyridine-3-
carbonitrile,
[(2,4-diamino-3-cyano-5H-chromeno[2,3-b]pyridin-9-yl)oxy]acetic acid,
2-amino-4-{[2-(dimethylamino)ethyl]amino}-7,8-dimethoxy-5H-
chromeno[2,3-b]pyridine-3-carbonitrile,
286

2,4-diamino-7-nitro-5H-thiochromeno[2,3-b]pyridine-3-carbonitrile 10,10-
dioxide,
2,4-diamino-7-phenyl-5H-chromeno[2,3-b]pyridine-3-carbonitrile, and
prodrugs, salts, tautomers, and combinations thereof.
16. The method according to claim 1, wherein the
aminocyanopyridine MK-2 inhibiting compound comprises at least one
compound that is selected from the group consisting of:
2-amino-4-(2-fluorophenyl)-6,8-dihydro-5H-pyrazolo[3,4-h]quinoline-3-
carbonitrile,
2-amino-4-(2-furyl)-6,7-dihydro-5H-pyrazolo[3,4-h]quinoline-3-carbonitrile,
2-amino-4-(2,3-difluorophenyl)-6,7-dihydro-5H-pyrazolo[3,4-h]quinoline-3-
carbonitrile,
8-amino-6-(2-furyl)-4,5-dihydro-1H-pyrazolo[4,3-h]quinoline-7-carbonitrile,
2-amino-3-cyano-4-(2-furyl)-5,6-dihydrobenzo[h]quinoline-8-carboxylic
acid,
4-[2-amino-3-cyano-6-(2-furyl)pyridin-4-yl]-1H-pyrrole-2-carboxamide,
2-amino-4-phenyl-6,8-dihydro-5H-pyrazolo[3,4-h]quinoline-3-carbonitrile,
2-amino-6-(2-furyl)-4-(1-methyl-1H-imidazol-4-yl)nicotinonitrile,
8-amino-6-(2-furyl)-4,5-dihydro-1H-pyrazolo[4,3-h]quinoline-7-carbonitrile,
2-amino-4-(2-furyl)-8-hydroxy-5,6-dihydrobenzo[h]quinoline-3-carbonitrile,
2-amino-4-(2,6-difluorophenyl)-6,7-dihydro-5H-pyrazolo[3,4-h]quinoline-3-
carbonitrile,
2-amino-6-(4-hydroxyphenyl)-4-(1H-imidazol-5-yl)nicotinonitrile,
2-amino-4-(2-fluorophenyl)-6-(2-furyl)nicotinonitrile, 2-amino-4-(2-
fluorophenyl)-6-(2-furyl)nicotinonitrile,
2-amino-4-(2-fluorophenyl)-5,6-dihydrobenzo[h]quinoline-3-carbonitrile,
4-[6-amino-5-cyano-4-(2-furyl)pyridin-2-yl]benzoic acid,
2-amino-6-(2-furyl)-4-(1H-imidazol-5-yl)nicotinonitrile,
2-amino-4-(2-furyl)-6-(1H-pyrazol-3-yl)nicotinonitrile,
2-amino-3-cyano-4-(4H-1,2,4-triazol-3-yl)-5,6-dihydrobenzo[h]quinoline-8-
carboxylic acid,
2-amino-6-(3-hydroxyphenyl)-4-(1H-imidazol-5-yl)nicotinonitrile,
287

2-amino-6-(2-furyl)-4-(1H-imidazol-4-yl)nicotinonitrile,
2-amino-4-(2,4-difluorophenyl)-6,7-dihydro-5H-pyrazolo[3,4-h]quinoline-3-
carbonitrile, 4,6-diamino-2-(trifluoromethyl)-2,3-dihydrofuro[2,3-b]pyridine-
5-carbonitrile,
2-amino-4-(2-furyl)-6,8-dihydro-5H-pyrrolo[3,4-h]quinoline-3-carbonitrile,
4-[6-amino-5-cyano-4-(2-fluorophenyl)pyridin-2-yl]benzoic acid,
2-amino-4-(2-furyl)-5,6-dihydro-1,8-phenanthroline-3-carbonitrile,
2-amino-6-(3,4-dihydroxyphenyl)-4-(2-fluorophenyl)nicotinonitrile,
2-amino-4-(1-methyl-1H-imidazol-4-yl)-6-phenylnicotinonitrile,
2-amino-4-(2-furyl)-6-(1H-pyrazol-3-yl)nicotinonitrile,
4-[6-amino-5-cyano-4-(1H-imidazol-5-yl)pyridin-2-yl]benzoic acid,
2-amino-4-(3-fluorophenyl)-6,8-dihydro-5H-pyrazolo[3,4-h]quinoline-3-
carbonitrile,
2-amino-6-(3,4-dihydroxyphenyl)-4-(2-fluorophenyl)nicotinonitrile,
N-{4-[6-amino-5-cyano-4-(2-furyl)pyridin-2-yl]phenyl}methanesulfonamide,
2-amino-4-(2-furyl)-6,7-dihydro-5H-pyrrolo[2,3-h]quinoline-3-carbonitrile,
2-amino-4-(1H-imidazol-5-yl)-6-phenylnicotinonitrile,
2-amino-4-(2-furyl)-5,6-dihydrobenzo[h]quinoline-3-carbonitrile,
2-amino-4-(1H-imidazol-5-yl)-6-(4-methoxyphenyl)nicotinonitrile,
2,4-diamino-7,8-dihydroxy-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
2,4-diamino-8-hydroxy-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
2-amino-7,8-dihydroxy-4-[(2-hydroxyethyl)amino]-5H-chromeno[2,3-
b]pyridine-3-carbonitrile,
2,4-diamino-7,8-dimethoxy-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
2-amino-7,8-dihydroxy-4-(propylamino)-5H-chromeno[2,3-b]pyridine-3-
carbonitrile,
2-amino-4-(ethylamino)-7,8-dihydroxy-5H-chromeno[2,3-b]pyridine-3-
carbonitrile,
2,4-diamino-9-hydroxy-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
2,4-diamino-9-fluoro-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
2,4-diamino-7-hydroxy-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
288

2,4-diamino-8-(2-hydroxyethoxy)-5H-chromeno[2,3-b]pyridine-3-
carbonitrile,
8,10-diamino-2,3-dihydro-11H-[1,4]dioxino[2',3':6,7]chromeno[2,3-
b]pyridine-9-carbonitrile,
2,4,7-triamino-5H-chromeno[2,3-b]pyridine-3-carbonitrile
2,4-diamino-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
2,4-diamino-8-(2-ethoxyethoxy)-7-hydroxy-5H-chromeno[2,3-b]pyridine-3-
carbonitrile, 2,4-diamino-9-hydroxy-8-methoxy-5H-chromeno[2,3-
b]pyridine-3-carbonitrile,
2,4-diamino-6,8-dihydroxy-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
2,4-diamino-8-ethoxy-7-hydroxy-5H-chromeno[2,3-b]pyridine-3-
carbonitrile,
2,4-diamino-8-(2-ethoxyethoxy)-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
2,4-diamino-8-(2-aminoethoxy)-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
2,4-diamino-3-cyano-5H-chromeno[2,3-b]pyridine-7-carboxylic acid,
2,4-diamino-8,9-dihydroxy-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
2,4-diamino-8-(2-morpholin-4-ylethoxy)-5H-chromeno[2,3-b]pyridine-3-
carbonitrile, [(2,4-diamino-3-cyano-5H-chromeno[2,3-b]pyridin-8-
yl)oxy]acetic acid,
2,4-diamino-9-methoxy-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
2,4-diamino-8-(2-pyrrolidin-1-ylethoxy)-5H-chromeno[2,3-b]pyridine-3-
carbonitrile,
2-amino-7,8-dimethoxy-4-(methylamino)-5H-chromeno[2,3-b]pyridine-3-
carbonitrile,
2,4-diamino-8-methoxy-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
2,4-diamino-8-[2-(dimethylamino)ethoxy]-5H-chromeno[2,3-b]pyridine-3-
carbonitrile, 2,4,7-triamino-9-methoxy-5H-chromeno[2,3-b]pyridine-3-
carbonitrile,
2(2,4-diamino-3-cyano-8-methoxy-5H-chromeno[2,3-b]pyridin-5-
yl)malononitrile,
2,4-diamino-7,8-di[2-(amino)ethoxy]-5H-chromeno[2,3-b]pyridine-3-
carbonitrile,
289

2,4-diamino-9-nitro-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
2-amino-7,8-dimethoxy-4-[(4-methoxyphenyl)amino]-5H-chromeno[2,3-
b]pyridine-3-carbonitrile,
2,4-diamino-8-methoxy-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
2(2,4-diamino-3-cyano-7-hydroxy-5H-chromeno[2,3-b]pyridin-5-
yl)malononitrile,
2(2,4-diamino-3-cyano-7-bromo-5H-chromeno[2,3-b]pyridin-5-
yl)malononitrile,
2-amino-8-ethoxy-4-(ethylamino)-5H-chromeno[2,3-b]pyridine-3-
carbonitrile,
2,4,9-triamino-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
2,4,7-triamino-5H-thiochromeno[2,3-b]pyridine-3-carbonitrile,
2-amino-7,8-dimethoxy-4-[(4-methoxyphenyl)amino]-5H-chromeno[2,3-
b]pyridine-3-carbonitrile,
2(2,4-diamino-3-cyano-7-methoxy-5H-chromeno[2,3-b]pyridin-5-
yl)malononitrile,
2,4-diamino-9-hydroxy-8-(piperidin-1-ylmethyl)-5H-chromeno[2,3-
b]pyridine-3-carbonitrile,
7,8-bis(allyloxy)-2,4-diamino-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
2-amino-8-(2-ethoxyethoxy)-4-[(2-ethoxyethyl)amino]-5H-chromeno[2,3-
b]pyridine-3-carbonitrile, and
prodrugs, salts, tautomers, and combinations thereof.
17. The method according to claim 1, wherein the
aminocyanopyridine MK-2 inhibiting compound is selected from the group
consisting of:
2-amino-4-(2-fluorophenyl)-6,8-dihydro-5H-pyrazolo[3,4-h]quinoline-3-
carbonitrile,
2-amino-4-(2-furyl)-6,7-dihydro-5H-pyrazolo[3,4-h]quinoline-3-carbonitrile,
2-amino-4-(2,3-difluorophenyl)-6,7-dihydro-5H-pyrazolo[3,4-h]quinoline-3-
carbonitrile,
8-amino-6-(2-furyl)-4,5-dihydro-1 H-pyrazolo[4,3-h]quinoline-7-carbonitrile,
2,4-diamino-7,8-dihydroxy-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
290

2,4-diamino-8-hydroxy-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
2-amino-7,8-dihydroxy-4-[(2-hydroxyethyl)amino]-5H-chromeno[2,3-
b]pyridine-3-carbonitrile,
2,4-diamino-7,8-dimethoxy-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
2-amino-7,8-dihydroxy-4-(propylamino)-5H-chromeno[2,3-b]pyridine-3-
carbonitrile,
2-amino-4-(ethylamino)-7,8-dihydroxy-5H-chromeno[2,3-b]pyridine-3-
carbonitrile,
2,4-diamino-9-hydroxy-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
2,4-diamino-9-fluoro-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
2,4-diamino-7-hydroxy-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
2,4-diamino-8-(2-hydroxyethoxy)-5H-chromeno[2,3-b]pyridine-3-
carbonitrile,
8,10-diamino-2,3-dihydro-11H-[1,4]dioxino[2',3':6,7]chromeno[2,3-
b]pyridine-9-carbonitrile,
2,4,7-triamino-5H-chromeno[2,3-b]pyridine-3-carbonitrile
2,4-diamino-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
2,4-diamino-8-(2-ethoxyethoxy)-7-hydroxy-5H-chromeno[2,3-b]pyridine-3-
carbonitrile, 2,4-diamino-9-hydroxy-8-methoxy-5H-chromeno[2,3-
b]pyridine-3-carbonitrile,
2,4-diamino-6,8-dihydroxy-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
2,4-diamino-8-ethoxy-7-hydroxy-5H-chromeno[2,3-b]pyridine-3-
carbonitrile,
2,4-diamino-8-(2-ethoxyethoxy)-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
2,4-diamino-8-(2-aminoethoxy)-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
2,4-diamino-3-cyano-5H-chromeno[2,3-b]pyridine-7-carboxylic acid,
2,4-diamino-8,9-dihydroxy-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
2,4-diamino-8-(2-morpholin-4-ylethoxy)-5H-chromeno[2,3-b]pyridine-3-
carbonitrile, [(2,4-diamino-3-cyano-5H-chromeno[2,3-b]pyridin-8-
yl)oxy]acetic acid,
2,4-diamino-9-methoxy-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
291

2,4-diamino-8-(2-pyrrolidin-1-ylethoxy)-5H-chromeno[2,3-b]pyridine-3-
carbonitrile,
2-amino-7,8-dimethoxy-4-(methylamino)-5H-chromeno[2,3-b]pyridine-3-
carbonitrile,
2,4-diamino-8-methoxy-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
2,4-diamino-8-[2-(dimethylamino)ethoxy]-5H-chromeno[2,3-b]pyridine-3-
carbonitrile, 2,4,7-triamino-9-methoxy-5H-chromeno[2,3-b]pyridine-3-
carbonitrile,
2(2,4-diamino-3-cyano-8-methoxy-5H-chromeno[2,3-b]pyridin-5-
yl)malononitrile, and
prodrugs, salts, tautomers, and combinations thereof.
18. A method of preventing or treating a TNF.alpha. mediated disease
or disorder in a subject in need of such prevention or treatment, the
method comprising administering to the subject an effective amount of an
aminocyanopyridine MK-2 inhibiting compound.
19. The method according to claim 18, wherein the
aminocyanopyridine MK-2 inhibiting compound is one having the formula:
<IMG>
wherein:
R1 is selected from the group consisting of -H, methyl, ethyl, propyl,
butyl, -(CH2)COOH, phenyl, pyridyl, dimethylaminoethyl, methoxyethyl,
tetramethylaminoethyl, carboxymethyl, and phenylacetyl;
R2 is selected from the group consisting of -H, methyl, ethyl, propyl,
butyl, amino, phenyl, methoxy, carboxy, carboxymethyl,
hydroxyethylamino, propylamino, ethylamino, methylamino, methoxyethyl,
292

ethoxyethylamino, aminoethylamino, benzylamino,
dimethylaminoethylamino, phthaloaminoethyl, fluorophenyl, difluorophenyl,
chlorophenyl, bromophenyl, furyl, carbamylpyrryl, methyl-1,3-isodiazoyl,
1,3-isodiazoyl, 1,3,4-triazoyl, methoxyphenyl, -S(CH3),
tetramethylaminoethyl, acetylaminophenyl, methoxyphenylamino,
carboxyphenyl, carboxy-3-isopyrryl, cyanophenyl, cyclopropyl,
phenoxyphenyl, pyridyl, dihydroxybromophenyl, difluoromethoxyphenyl,
trifluoromethylphenyl, trifluoromethylfluorophenyl, hydroxyphenyl,
methylaminomethyl, methylaminoethyl, thiophyl, pyrryl, aminomethyl,
<IMG>
R3 is selected from the group consisting of -H, methyl, ethyl, propyl,
isopropyl, cyano, aminomethyl, phenyl, fluorophenyl, and amino;
wherein the R2 and R3 groups are such that they optionally join to
form a ring system selected from:
<IMG>
R4 is selected from the group consisting of -H, methyl, ethyl, propyl,
hydroxy, furyl, methylfuryl, methylimidazolyl, phenyl, hydroxyphenyl,
carboxyphenyl, pyrazolyl, hydroxy, dihydroxyphenyl, methoxyphenyl,
293

chlorophenyl, bromophenyl, fluorophenyl, dichlorophenyl,
dihydroxyborophenyl, thienyl, pyrryl, N-methylpyrryl, pyridyl, methylthio,
methylsulfonylphenyl, carboethoxyphenyl, methoxy,
carbamylphenyl, mercapto, N-isoimidazoylphenyl, isopropyl, amino,
hydroxynaphthyl, thiazoyl, carboxymethylphenyl, trifluoromethylphenyl,
methylphenyl, cyanophenyl, dimethylphenyl, fluorobenzhydryl,
methoxyfuryl, aminosulfonylphenyl,
<IMG>
wherein the R3 and R4 groups are such that they optionally join to
form a ring system selected from:
294

<IMG>
295

D, E and G are each independently selected from the group
consisting of carbon, oxygen, sulfur, and nitrogen;
R5 is selected from the group consisting of -H, and C1-C5 alkyl; and
wherein the R1 and R5 groups can join to form a pyridylidene ring;
R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20,
R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32, R33, R34, R35,
R36,
R37, R38, R39, R40, R41, R42, R43, R44, R45, R46, R47, R48, R49, R50, R51,
R52,
R53, R54, R55, R56, R57, R58, R59, R60, R61, R62, R63, R64, R65, R66, R67,
R68,
R69, R70, R71, R72, R73, R74, R75, and R76 are each optionally present and
are each independently selected from the group consisting of - H, methyl,
ethyl, propyl, butyl, isobutyl, amino, nitro, hydroxy, methoxy, ethoxy,
propoxy, 2-propenoxy, oxo, carboxy, bromo, chloro, fluoro, trifluoromethyl,
chloromethyl, hydroxymethyl, dicyanomethyl, 2-fluorophenyl, 3-
fluorophenyl, hydroxyethoxy, ethoxyethoxy, -(CH2)-O-(C6H4)-O-(CH3),
carboxymethoxy, isopropylcarboxymethoxy, isobutylcarboxymethoxy,
methylamino, dimethylamino, aminoethoxy, diaminoethoxy,
dimethylaminoethoxy, cyanomethoxymethyl, 2-propenoxymethyl,
methoxymethyl, isopropoxymethyl, ethoxymethyl, -(CH2)-O-(CF2)-CHF2,
isobutoxymethyl, benzoyl, phenyl, N-morpholinyl, morpholinylethoxy,
pyrrolidylethoxy, N-pyrrolidylethoxy, oxo, ethylcarboxy, carboxymethyl -
ethyl ester, pyridylmethyl, 4-pyridylmethoxy, 2-pyridylmethyl, and -COO-
CH2-CH3; and
wherein R38 and R39 are such that they optionally join to form a ring
system of the type selected from:
<IMG>
20. The method according to claim 18, wherein the
aminocyanopyridine MK-2 inhibiting compound is one having the structure:
296

<IMG>
wherein:
G is selected from the group consisting of - O -, - S -, and -N-;
when G is -O-, R41 and R42 are absent;
when G is -S-, R41 and R42 are optionally absent, or are oxo;
when G is -N-, R41 is absent, and R42 is -H or C1-C4-alkyl;
R1 is selected from the group consisting of hydrogen, branched or
unbranched alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, arylalkyl, carboxy,
carboxyalkyl, hydroxyalkyl, alkylcarboxy, aryl, amino, aminoalkyl,
alkylamino, halo, alkylaminoalkyl, alkoxy, alkoxyalkyl, monocyclyl, bicyclyl,
polycyclyl, and heterocyclyl;
R2 is selected from the group consisting of hydrogen, alkyl, alkenyl,
alkynyl, alkoxy, hydroxyalkyl, alkylaryl, arylalkyl, alkoxyaryl, aminoalkyl,
alkylaminoalkyl, arylaminoalkyl, alkoxyalkyl, alkylcarboxy, and
carboxyalkyl;
R35 is selected from the group consisting of hydrogen, dicyanoalkyl,
and substituted or unsubstituted heterocyclyl and cyclyl, where
substituents, if any, comprise halo moieties;
R36 is selected from the group consisting of hydrogen, dicyanoalkyl,
and substituted or unsubstituted heterocyclyl and cyclyl, where
substituents, if any, comprise halo moieties;
R37 is selected from the group consisting of hydrogen, alkoxy, halo,
alkyl, alkenyl, alkylyl, arylalkyl, or alkylaryl;
R38 is selected from the group consisting of hydrogen, hydroxy,
alkoxy, alkyl, alkenyl, alkynyl, amino, alkylamino, arylamino,
297

alkylaminoalkyl, carboxy, aminoalkoxy, halo, alkylcarboxyalkyl, alkylamino,
aminoalkyl, nitro, aryl, arylalkyl, alkylaryl, or arylamino;
R39 is selected from the group consisting of hydrogen, hydroxy,
alkoxy, alkenoxy, hydroxyalkoxy, alkoxyalkoxy, aminoalkoxy,
heterocyclylalkyl, heterocyclylalkoxy, carboxyalkoxy, alkylaminoalkoxy,
and alkylcarboxyalkoxy;
where the R38 and R39 groups optionally join to form a six
membered heterocyclic ring; and
R40 is selected from the group consisting of hydrogen, hydroxy,
halo, nitro, amino, alkyl, alkoxy, heterocyclylalkoxy, carboxyalkoxy,
pyrrolidylethoxy, carboxymethoxy, hydroxyalkoxy, aminoalkoxy,
alkylcarboxy, alkylaminoalkyl, carboxy, and heterocyclylalkyl.
21. The method according to claim 18, wherein the subject is a
mammal.
22. The method according to claim 21, wherein the subject is a
human.
23. The method according to claim 22, wherein the TNF.alpha.
mediated disease or disorder is selected from the group consisting of:
arthritis, rheumatoid arthritis, spondyloarthopathies, gouty arthritis,
osteoarthritis, systemic lupus erythematosus, juvenile arthritis, asthma,
bronchitis, menstrual cramps, tendinitis, bursitis, connective tissue injuries
or disorders, skin related conditions, psoriasis, eczema, burns, dermatitis,
gastrointestinal conditions, inflammatory bowel disease, gastric ulcer,
gastric varices, Crohn's disease, gastritis, irritable bowel syndrome,
ulcerative colitis, cancer, colorectal cancer, herpes simplex infections, HIV,
pulmonary edema, kidney stones, minor injuries, wound healing, vaginitis,
candidiasis, lumbar spondylanhrosis, lumbar spondylarthrosis, vascular
diseases, migraine headaches, sinus headaches, tension headaches,
dental pain, periarteritis nodosa, thyroiditis, aplastic anemia, Hodgkin's
disease, sclerodoma, rheumatic fever, type I diabetes, myasthenia gravis,
multiple sclerosis, sarcoidosis, nephrotic syndrome, Behcet's syndrome,
polymyositis, gingivitis, hypersensitivity, swelling occurring after injury,
298

myocardial ischemia, ophthalmic diseases, retinitis, retinopathies,
conjunctivitis, uveitis, ocular photophobia, acute injury to the eye tissue,
pulmonary inflammation, viral infections, cystic fibrosis, central nervous
system disorders, cortical dementias, and Alzheimer's disease.
24. The method according to claim 18, wherein the subject is
administered an effective amount of the aminocyanopyridine MK-2
inhibiting compound.
25. The method according to claim 24, wherein the effective
amount comprises an amount within a range of from about 0.1 mg/kg/day
to about 150 mg/kg/day.
26. The method according to claim 25, wherein the effective
amount comprises an amount within a range of from about 0.1 mg/kg/day
to about 10 mg/kg/day.
27. The method according to claim 18, wherein the
aminocyanopyridine MK-2 inhibiting compound provides a TNF.alpha. release
IC50 values of below 200 µM in an in vitro cell assay.
28. The method according to claim 18, wherein the
aminocyanopyridine MK-2 inhibiting compound provides a TNF.alpha. release
IC50 values of below 1 µM in an in vitro cell assay.
29. The method according to claim 18, wherein the
aminocyanopyridine MK-2 inhibiting compound provides a degree of
inhibition of TNF.alpha. in a rat LPS assay of at least about 25%.
30. The method according to claim 18, wherein the
aminocyanopyridine MK-2 inhibiting compound provides a degree of
inhibition of TNF.alpha. in a rat LPS assay of above 80%.
31. The method according to claim 18, wherein the
aminocyanopyridine MK-2 inhibiting compound provides an MK-2 inhibition
IC50 value of below 200 µM.
32. The method according to claim 18, wherein the
aminocyanopyridine MK-2 inhibiting compound provides an MK-2 inhibition
IC50 value of below 1 µM.
299

Description

CA 02508780 2005-06-09
WO 2004/054505 PCT/US2003/039166
METHOD OF USING AMINOCYANOPYRIDINE
COMPOUNDS AS MITOGEN ACTIVATED PROTEIN
KINASE-ACTIVATED PROTEIN KINASE-2 INHIBITORS
CROSS REFERENCE TO RELATED PATENTS AND PATENT
APPLICATIONS
[000'1] This application claims the benefit of U.S. Provisional
Application No. 60/432,807, filed December 12, 2002, which is
incorporated herein by reference in its entirety. This application is related
to commonly assigned and copending applications having the titles
"Method of making tricyclic aminocyanopyridine compounds" (and having
Provisional Application Serial No. 60/432,783), "Tricyclic
aminocyanopyridine inhibitors of mitogen activated protein kinase-
activated protein kinase-2" (and having Provisional Application Serial No.
60/432,844), and "Aminocyanopyridine inhibitors of mitogen activated
protein kinase-activated protein kinase-2" (and having Provisional
Application Serial No. 60/432,843), each of which was filed on the same
date as the present application.
BACKGROUND OF THE INVENTION
(1 ) Field of the Invention:
[0002] The present invention relates to a method of inhibiting mitogen-
activated protein kinase-activated protein kinase-2 (MAPKAP kinase-2, or
MK-2) in a subject in need of such inhibition, and also to the prevention
and treatment of TNFa mediated diseases or disorders by the
administration of an MK-2 inhibitor.
(2) Description of the Related Art:
[0003] Mitogen-activated protein kinases (MAPKs) are members of
conserved signal transduction pathways that activate transcription factors,
translation factors and other target molecules in response to a variety of
extracellular signals. MAPKs are activated by phosphorylation at a dual
phosphorylation motif with the sequence Thr-X-Tyr by mitogen-activated
protein kinase kinases (MAPKKs). In higher eukaryotes, the physiological
role of MAPK signaling has been correlated with cellular events such as
1

CA 02508780 2005-06-09
WO 2004/054505 PCT/US2003/039166
proliferation, oncogenesis, development and differentiation. Accordingly,
the ability to regulate signal transduction via these pathways could lead to
the development of treatments and preventive therapies for human
diseases associated with MAPK signaling, such as inflammatory diseases,
autoimmune diseases and cancer.
[0004] In mammalian cells, three parallel MAPK pathways have been
described. The best characterized pathway leads to the activation of the
extraceliular-signal-regulated kinase (ERK). Less well understood are the
signal transduction pathways leading to the activation of the cJun N-
terminal kinase (JNK) and the p38 MAPK. See, e.g., Davis, Trends
Biochem. Sci. y9:470-473 (1994); Cano, et al., Trends Biochem. Sci.
20:117-122(1995).
[0005] The p38 MAPK pathway is potentially activated by a wide
variety of stresses and cellular insults. These stresses and cellular insults
include heat shock, UV irradiation, inflammatory cytokines (such as TNF
and IL-1 ), tunicamycin, chemotherapeutic drugs (i.e., cisplatinum),
anisomycin, sorbitol/hyperosmolarity, gamma irradiation, sodium arsenite,
and ischaemia. See, Ono, K., et aI, Cellular Signalling i2, 1 - 13 (2000).
Activation of the p38 pathway is involved in (1 ) production of
proinflammatory cytokines, such as TNF-a; (2) induction of enzymes, such
as Cox-2; (3) expression of an intracellular enzyme, such as iNOS, which
plays an important role in the regulation of oxidation; (4) induction of
adherent proteins, such as VCAM-1 and many other inflammatory-related
molecules. Furthermore, the p38 pathway functions as a regulator in the
proliferation and differentiation of cells of the immune system. See, Ono,
K., et al., Id. at 7.
[0006] The p38 kinase is an upstream kinase of mitogen-activated
protein kinase-activated protein kinase-2 (MAPKAP kinase-2 or MK-2).
(See, Freshney, N. W., efi al., J. Cell, 78:1039-1049 (1994)). MK-2 is a
protein that appears to be predominantly regulated by p38 in cells.
Indeed, MK-2 was the first substrate of p38a to be identified. For
example, in vitro phosphorylation of MK-2 by p38a activates MK-2. The
2

CA 02508780 2005-06-09
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substrates that MK-2 acts upon, in turn, include heat shock protein 27,
lymphocyte-specific protein 1 (LAP1), cAMP response element-binding
protein (CREB), ATF1, serum response factor (SRF), and tyrosine
hydroxylase. The substrate of MK-2 that has been best characterized is
small heat shock protein 27 (hsp27).
[0007] The role of the p38 pathway in inflammatory-related diseases
has been studied in several animal models. The pyridinyl imidazole
compound SB203580 has been shown to be a specific inhibitor of p38 in
vivo, and also has been shown to inhibit activation of MK-2, (See, Rouse,
J., et al, Cell, 78:1027-1037 (1994); Cuenda, A., et al, Biochem. J.,
333:11-15 (1998)), as well as a MAP kinase homologue termed
reactivating kinase (RK). (See, Cuenda, A., et al., FEBS Lett., 364(2):229 -
233 (1995)). Inhibition of p38 by SB203580 can reduce mortality in a
murine model of endotoxin-induced shock and inhibit the development of
mouse collagen-induced arthritis and rat adjuvant arthritis. See, e.g.,
Badger, A. M., et al., J. Pharmacol Exp. Ther., 279:1453 - 1461 (1996).
Another p38 inhibitor that has been utilized in an animal model that is
believed to be more potent than SB203580 in its inhibitory effect on p38 is
SB 220025. A recent animal study has demonstrated that SB 220025
caused a significant dose-dependent decrease in vascular density of
granulomas in laboratory rats. (See Jackson, J. R., et al, J. Pharmacol.
Exp. Ther., 284:687 - 692 (1998)). The results of these animal studies
indicated that p38, or the components of the p38 pathway, can be useful
therapeutic targets for the prevention or treatment of inflammatory
disease.
[0008] Due to its integral role in the p38 signaling pathway, MK-2 has
been used as a monitor for measuring the level of activation in the
pathway. Because of its downstream location in the pathway, relative to
p38, MK-2 has been measured as a more convenient, albeit indirect,
method of assessing p38 activation. However, so far, research efforts
exploring therapeutic strategies associated with the modulation of this
pathway have focused mainly on the inhibition of p38 kinase.
3

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[0009] Several compounds that inhibit the activity of p38 kinase have
been described in U.S. Patent Nos. 6,046,208, 6,251,914, and 6,335,340.
These compounds have been suggested to be useful for the treatment of
CSBP/RK/p38 kinase mediated disease. Commercial efforts to apply p38
inhibitors have centered around two p38 inhibitors, the pyridinylimidazole
inhibitor SKF 86002, and the 2,4,5 triaryl imidazole inhibitor SB203580.
See, Lee, J. C., et al, Immunopharmacology 47, 185-192 (2000).
Compounds possessing a similar structure have also been investigated as
potential p38 inhibitors. Indeed, p38 MSP kinase's role in various disease
states has been elucidated through the use of inhibitors.
[00010] Kotlyarov, A. et al, in Nat. Cell Biol., 1(2):94 - 97 (1999)
introduced a targeted mutation into a mouse MK-2 gene, resulting in MK-
2-deficient mice. It was shown that mice lacking MK-2 possessed
increased stress resistance and survived LPS-induced endotoxic shock
better than MK-2+ mice. The authors concluded that MK-2 was an
essential component in the inflammatory response that regulates
biosynthesis of TNFa at a post-transcriptional level. More recently,
Lehner, M.D., et al, in J, lmmunol., 168(9):4667-4673 (2002), reported that
MK-2-deficient mice showed increased susceptibility to Listeria
monocytogenes infection, and concluded that MK-2 had an essential role
in host defense against intracellular bacteria, probably via regulation of
TNF and IFN-gamma production required for activation of antibacterial
effector mechanisms.
[00011] The location of MK-2 in the p38 signaling pathway at a point
that is downstream of p38 offers the potential that MK-2 could act as a
focal point for modulating the pathway without affecting as many
substrates as would the regulation of an enzyme further upstream in the
signaling cascade -- such as p38 MAP kinase.
(00012] Accordingly, it would be useful to provide compounds and
methods that could serve to modulate the activity of MK-2 -- in particular,
to act as inhibitors of MK-2 activity. Such compounds and methods would
be useful for the provision of benefits similar to p38 MAP kinase inhibitors,
4

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which benefits include the prevention and treatment of diseases and
disorders that are mediated by TNFa. It would be even more useful to
provide MK-2 inhibitors having improved potency and reduced undesirable
side effects, relative to p38 inhibitors.
SUMMARY OF THE INVENTION
(000'13] Briefly, therefore the present invention is directed to a novel
method of inhibiting mitogen activated protein kinase-activated protein
kinase-2 in a subject in need of such inhibition, the method comprising
administering to the subject an anminocyanopyridine MK-2 inhibiting
compound, or a pharmaceutically acceptable salt thereof, the compound
having the structure:
R'
Rq
'5
R
wherein:
Ri is selected from the group consisting of -H, Ci-C6 alkyl, C2-C6
alkenyl, C2-C6 alkynyf, carboxy C1-C4 alkyl, aryl Ci-C4 alkyl, amino, amino
C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino, Ci-C4 alkyl, di-( C1-C4
alkyl)amino C1-C4 alkyl, C1-C4 alkyl-C1-C4 alkyl, hydroxy C1-C4 alkyl, and
aryl C1-C~ alkylcarbonyl;
R~ is selected from the group consisting of -H, C1-C6 alkyl, C2-C6
alkenyl, C2-C6 alkynyl, amino, amino C1-C4 alkyl, C~-C4 alkylamino, aryl,
heteroaryl, heterocyclyl, carboxy, carboxy Ci-C4 alkyl, C1-C4 alkoxy,
hydroxy, hydroxy C1-C4 alkyl, hydroxy C1-C4 alkylamino, hydroxy C1-C4
alkoxy, C1-C4 alkoxy C1-C4 alkyl, C1-C4 alkoxy C~-C4 alkylamino, amino C1-
C4 alkylamino, aryl C1-C4 alkyl, C1-C4 alkylamino C1-C~. alkyl, di C1-C4

CA 02508780 2005-06-09
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alkylamino C1-C4 alkyl, C1-C4 alkyl C1-C4 alkyl, carboxy C1-C4 alkyl, aryl
C1-C4 alkylcarbonyl, phthaloamino C1-C4 alkyl, halo, carbamyl, C1-C4
alkylthio, Cj-C4 alkoxyarylamino, C1-C1o mono- and bicyclic cycloalkyl,
wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl can be
optionally substituted with one or more of the groups selected from
halogen, hydroxy, C~-C4 alkoxy, aryloxy, C2-C4 alkenyloxy, C2-Cø
alkynyloxy, C1-C4 alkyl, carboxy, carbamyl, C1-C4 alkoxycarbonyl, C1-C4
alkoxycarbonyl C1-C4 alkoxy, carboxy C1-Ca alkoxy amino, C1-C4
alkylamino, di-C1-C4 alkylamino, N-C1-C4 alkyl-N-cyano Ci-C4 alkylamino,
nitro, C1-C4 alkylcarbonylamino, cyano, halo Ci-C4 alkyl, di-halo C1-C4
alkyl, tri-halo Cj-C4 alkyl, hydroxy C1-C4 alkoxy, halo Ci-C4 alkoxy, tri-halo
C1-C4 alkoxy,
0
o \ o \
and
CN3
R3 is selected from the group consisting of -H, C1-C6 alkyl, C2-Cs
alkenyl, C2-C6 alkynyl, cyano, amino C1-C4 alkyl, amino, aryl, wherein the
aryl group optionally can be substituted with one or more group selected
from halogen, hydroxy, C1-C~ alkoxy, C1-C4 alkyl, carboxy, C1-C4
alkoxycarbonyl, carboxy C1-C4 alkoxy, amino, di- C~-C~ alkylamino, N-C1-
C4 alkyl-N-cyano C1-C4 alkylamino, nitro, C1-C4 alkylcarbonylamino, cyano;
halo C1-C4 alkyl, di-halo C1-C4 alkyl, tri-halo Cy-C4 alkyl, halo C1-C4
alkoxy,
di-halo C1-C4 alkoxy, tri-halo Cy-C4 alkoxy, and
where the R2 and R3 groups are such that they optionally join to
form a ring system selected from:
6

CA 02508780 2005-06-09
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H31
'C\ N N
and
~ \ mnr v~nr
~w ~ r
R4 is selected from the group consisting of -H, C1-C6 alkyl, C2-C6
alkenyl, G2-C6 alkynyl, hydroxy, C1-C4 alkylthio, C1-C~ alkoxy, Ci-C4
alkoxycarbonyl, mercapto, N imidazoylphenyl, , C1-C4 isoalkyl,
aminofluorobenzhydryl, aryl and heteroaryl, wherein the aryl and
heteroaryl groups optionally can be substituted with one or more groups
selected from halogen, hydroxy, C1-C4 alkoxy, C1-C4 alkyl, C1-C4 alkylthio,
C~-C4 alkylsulfonyl, C1-C4 alkylsulfinyl, cartoxy, carbamyl, C1-C4
alkoxycarbonyl, carboxy C1-C4 alkyl, carboxy C1-C4 alkoxy, amino, di- C1-
C4 alkylamino, N C1-C4 alkyl-N cyano C1-C4 alkylamino, nitro, C1-C4
alkylcarbonylamino, cyano, halo Ci-C4 alkyl, di-halo C1-C4 alkyl, tri-halo
C1-C4 alkyl, halo C1-C4 alkoxy, di-halo Cj-C4 alkoxy, tri-halo C1-C4 alkoxy
s ~ °
and
p
H
7

CA 02508780 2005-06-09
WO 2004/054505 PCT/US2003/039166
wherein the R3 and R4 groups are such that they optionally join to
form a ring system selected from:
8

CA 02508780 2005-06-09
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R7 ..,a
r
1
R
R i 0'~.-... v s , z
R
Ri i R-E
Rm
R22 R2i
R23
R\ ~ r
8251
a s
R26 \
/G
27
R R2$ R2s ~R3fl R;s~
> >
R5G
R57 R55
R58,' ~ /
E
RSS~~ ~'''G ~~'
RGO , ~' R62
R61
~/ R72 71
1 jR -~.-
~, , ~~a ~~ /
\ R f
R~~ \
~~ R76
R75
Rno

CA 02508780 2005-06-09
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D, E and G are each independently selected from the group
consisting of carbon, oxygen, sulfur, and nitrogen;
R5 is selected from the group consisting of -H, and C1-C5 alkyl; and
wherein the R1 and R5 groups optionally join to form a piperidyl ring
or oxazinyl ring;
R6 R7 R8 R9 R10 R11 R12 R13 R14 R15 R16 R17 R18 R19 R20
s s s ~ s ~ s > > s s ~ s r r
R21 R22 R23 R24 R25 R26 R27 R28 R29 R30 R31 R32 R33 R34 R35 R36
r r r > > s > > > s s ~ r a > >
R37 R38 R39 R40 R41 R42 R43 R44 R45 R46 R47 R48 R49 R50 R51 R52
r s s > > > s s s ~ s s r > > >
R53 R54 R55 R56 R57 R58 R59 R60 R61 R62 R63 R64 R65 R66 R67 R68
r s s s s s s s a s s s s s r s
~ R69, R7°, R71, R72, R73, R74, R75; and R76 are each optionally
present and
are each independently selected from the group consisting of -H, C1-C4
alkyl, C2-C4 alkenyi, C2-C4 alkynyl, C1-C4 isoalkyl, amino, nitro, hydroxy,
C1-C4 alkoxy, C1-C4 alkenoxy, oxo, carboxy, halo, halo C1-C4 alkyl, dihalo
C1-C4 alkyl, trihalo C1-C4 alkyl, cyano, cyano C1-C4 alkyl, dicyano C1-C4
alkyl, halophenyl, hydroxy C1-C4 alkoxy, C1-C4 alkoxy C1-C4 alkoxy, -
(CH2)-O-(C6H4)-O-(CH3), carboxy C1-C4 alkoxy, C1-C4 alkylcarboxy C1-C4
alkoxy, C1-C4 alkoxyamino, C1-C4 alkylamino, di C1-C4 alkylamino, tri C1-
C4 alkylamino, amino C1-C4 alkoxy, diamino C1-C4 alkoxy, C1-Ca.
alkylamino C1-C4 alkoxy, di C1-C4 alkylamino C1-C4 alkoxy, cyano C1-C4
aikoxy C1-C4 alkyl, -(CH2)-O-(CF2)-CHF2, tetra C1-C4 alkoxy C1-C4 alkyl,
phenyl, benzyl, benzoyl, aryl, N-morpholinyl, morpholinyl C1-C4 alkoxy,
pyrrolidyl C1-C4 alkoxy, N pyrrolidyl C1-C4 alkoxy, C1-C4 alkylcarboxy,
carboxy C1-C4 alkyl - ethyl ester, pyridyl C1-C4 alkyl, pyridyl C1-C4 alkoxy, -
COO-CH2-CH3; and
wherein R38 and R39 are such that they optionally join to form a ring
system of the type selected from:
o ~~. o
and
o ~~ o

CA 02508780 2005-06-09
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[000'14] The invention is also direct to a novel method of inhibiting
mitogen activated protein kinase-activated protein kinase-2 in a subject in
need of such inhibition, the method comprising administering to the subject
a compound, or a pharmaceutically acceptable salt thereof, the compound
having the structure:
R3~ R36 R35 NH-R2
R38
R39i ~ ~Gi ~N~ ~NH-R1
41 ~R42
wherein:
G is selected from the group consisting of - O -, - S -, and -N-;
when G is -O-, R41 and R42 are absent;
when G is -S-, R41 and R42 are optionally absent, or are oxo;
when G is -N-, R41 is absent, and R42 is -H or C1-C4-alkyl;
Ri, Rz, R3~, R36, R3', R38, R39, and R4° each is independently
selected from the group consisting of
hydrogen, hydroxy, amino, halo, nitro,
branched or unbranched C~-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl,
C1-C6 alkoxy, hydroxy C1-C6 alkyl, hydroxy C1-C6 alkoxy, C1-C6 alkoxy Ci-
C6 alkoxy, C1-C6 alkoxy C1-C6 alkyl, C2-C6 alkenoxy,
branched or unbranched amino C1-C6 alkyl, diamino C2-C6 alkyl, C1-
C6 alkylamino C1-C6 alkyl, C1-C6 alkylamino, di-( C1-C6 alkyl)amino, Cy-C4
alkoxyarylamino, C1-C4 alkoxyalkylamino, amino C1-C6 alkoxy, di-(C1-C4
alkylamino, C2-C6 alkoxy, di-(C1-C6 alkyl)amino C1-C6 alkyl, C1-C6
..alkylamino C1-C6 alkoxy, halo C1-C6 alkoxy, dihalo Ci-C6 alkoxy, trihalo C1-
C6alkoxy, cyano Cf-C6 alkyl, dicyano Cj-C6 alkyl, cyano C1-C6 alkoxy,
dicyano C1-C6 alkoxy, carbamyl C1-C4 alkoxy, heterocyclyl C1-C4 alkoxy,
heteroaryl Ci-C4 alkoxy, sulfo, sulfamyl, C1-C4 alkylaminosulfonyl, hydroxy
11

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C1-C4 alkylaminosulfonyl, di-(C1-C4 alkyl)aminosulfonyl, C1-C4 alkylthio, C1-
C4 alkylsulfonyl, C1-C4 alkylsulfinyl,
aryl, aryl C1-C6 alkyl, heterocyclyl Ci-Cs alkyl, heteroaryl C1-C6 alkyl,
heterocyclyl C1-C6 alkoxy, heteroaryl C1-C6 alkoxy, aryl Ci-C6 alkoxy,
where the aryl ring can be substituted or unsubstituted, and, if substituted,
the substituent group is selected from one or more of the group consisting
of C1-C6 alkyl, halo, amino, and C1-C6 alkoxy,
substituted or unsubstituted C~-C6 cyclyl, C3-C6 heterocyclyl, and, if
substituted, the substituent group is selected from one or more of the
group consisting of C1-C6 alkyl, C1-C6 alkoxy, halo, amino, and where the
C3-C6 heterocyclyl ring contains O, S, or N,
branched or unbranched C1-C6 alkoxycarbonyl Ci-C6 alkoxy, and
carboxy, carboxy C1-C6 alkoxy, carboxy Cy-C6 alkyl, hydroxy C1-C4
alkoxycarbonyl, C1-C4 aikoxycarbonyl,
where R38 and R39 are such that they optionally join to form a ring
system of the type selected from
o ~~ o
and
o ~~ ~ w
[00015] In preferred embodiments, R3$ is other than cyano.
[00016] The present invention is also directed to a novel method of
inhibiting mitogen activated protein kinase-activated protein kinase-2 in a
subject in need of such inhibition, the method comprising administering to
the subject a compound, or a pharmaceutically acceptable salt thereof, the
compound having the structure:
12

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Rse Rs5 NH_R2
R38 . ~
R39~ ~ ~G~ ~N~ ~NH-Rj
Rq,1 R42
wherein:
G is selected from the group consisting of -O-, -S-, and -N-;
when G is -O-, R41 and R42 are absent;
when G is -S-, R4~ and R42 are optionally absent, or are oxo;
when G is -N-, R41 is absent , and R42 is -H or -CH3;
Ri is selected from the group consisting of hydrogen, ethyl,
dimethylaminoethyl, butyl, propyl, methoxyethyl, tetramethylaminoethyl,
and carboxymethyl;
R2 is selected from the group consisting of hydrogen, hydroxyethyl,
propyl, ethyl, methyl, 4-methoxyphenyl, ethoxyethyl, aminoethyl,
phenylmethyl, dimethylaminoethyl, phthaloaminoethyl, butyl, methoxyethyl,
tetramethylaminoethyl, and carboxymethyl;
R35 is selected from the group consisting of hydrogen,
dicyanomethyl, 2-fluorophenyl, phenyl, and 3-fluorophenyl.
R36 is selected from the group consisting of hydrogen,
dicyanomethyl, 2-fluorophenyl, phenyl, and 3-fluorophenyl;
R37 is selected from the group consisting of hydrogen, hydroxy,
methoxy, bromo, and 2-pyridomethyl;
R38 is selected from the group consisting of hydrogen, hydroxy,
methoxy, amino, carboxy, diaminoethoxy, bromo, propoxy,
isobutylcarboxymethoxy, dimethylamino, vitro, phenyl, chloro,
pyridylmethyl, and fluoro;
R39 is selected from the group consisting of hydrogen, hydroxy,
methoxy, hydroxyethoxy, ethoxyethoxy, ethoxy, aminoethoxy,
morpholinoethoxy, carboxymethoxy, N-pyrrolidylethoxy,
dimethylaminoethoxy, pyridylmethyl, 2-propenoxy, and ,
13

CA 02508780 2005-06-09
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isobutylcarboxymethoxy, where the R3$ and R~9 groups can join to form a
six membered heterocyclic ring; and
R4° is selected from the group consisting of hydrogen, hydroxy,
fluoro, methoxy, nitro, amino, pyrrolidylethoxy, carboxymethoxy, methyl,
hydroxyethoxy, aminoethoxy, 4-pyridylmethoxy, isobutyl, ethylcarboxy,
dimethylaminoethoxy, carboxy, bromo, and pyrridylmethyl.
[00017] The present invention is also directed to a novel method of
preventing or treating a TNFa mediated disease or disorder in a subject in
need of such prevention or treatment, the method comprising
administering to the subject an effective amount of an aminocyanopyridine
MK-1 inhibiting compound.
[00018] Among the several advantages found to be achieved by the
present invention, therefore, may be noted the provision of a method that
could serve to modulate the activity of MK-2 -- in particular, to inhibit MK-2
activity, and the provision of a method for the prevention and treatment of
diseases and disorders that are mediated by TNFa.
BRIEF DESCRIPTION OF THE DRAWINGS
[00019] Figure 1 is a graph showing paw thickness as a function of time
from day 0 to day 7 for MK2 (+/+) and MK2 (-/-) mice, which have received
serum injection; and
[00020] Figure 2 is a bar chart showing paw thickness at seven days
after injection for normal mice, MK2 (+/+) mice receiving serum, MK2 (-/-)
mice receiving serum, and MK2 (+/+) mice receiving serum and anti-TNF
antibody.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[00021] In accordance with the present invention, it has been
discovered that certain aminocyanopyridine compounds can inhibit the
activity of MAPKAP kinase-2. Many of these compounds exhibit their
inhibitory effect at low concentrations -- having in vitro MK-2 inhibition
ICSo
values of under 1.0 p,M, and with some having ICSO values of under about
0.5 ~M, and even as low as about 0.2 p,M. Accordingly, these compounds
can be potent and effective drugs for use in methods to prevent or treat
14

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diseases and disorders that are mediated by TNFa. For example, they
can be used for the prevention or treatment of arthritis.
[00022] Aminocyanopyridine compounds that are useful in the present
method include those having the structure shown in formula I:
~N
R1
rs n N ~
R
5
wherein:
R1 is selected from the group consisting of -H, C1-Cs alkyl, C2-Cs
alkenyl, C2-Cs alkynyl, carboxy C1-C4 alkyl, aryl Ci-C4 alkyl, amino, amino
C1-C~ alkyl, C1-C4 alkoxy, Cj-C4 alkylamino, C1-C4 alkyl, di-( C1-C4
10 alkyl)amino C1-C4 alkyl, C1-C4 alkyl-C1-C4 alkyl, hydroxy Cj-C4 alkyl, and
aryl C1-C4 alkylcarbonyl;
R2 is selected from the group consisting of -H, C1-Cs alkyl, C2-Cs
alkenyl, C2-Cs alkynyl, amino, amino C1-C4 alkyl, C1-C4 alkylamino, aryl,
heteroaryl, heterocyclyl, carboxy, carboxy C1-C4 alkyl, Ci-C4 alkoxy,
15 hydroxy, hydroxy Cj-C4 alkyl, hydroxy C1-C4 alkylamino, hydroxy C1-C4
alkoxy, C1-C4 alkoxy C1-C4 alkyl, C1-C4 alkoxy C1-C4 alkylamino, amino C1-
C4 alkylamino, aryl C1-C4 alkyl, C1-C4 alkylamino C1-C4 alkyl, di C1-C4
alkylamino C1-C4 alkyl, C1-C4 alkyl C1-C4 alkyl, carboxy Ci-C4 alkyl, aryl
C1-C4 alkylcarbonyl, phthaloamino C1-C4 alkyl, halo, carbamyl, C1-C4
alkylthio, C1-C4 alkoxyarylamino, C1-C1o mono- and bicyclic cycloalkyl,
wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl can be
optionally substituted with one or more of the groups selected from
halogen, hydroxy, Ci-C4 alkoxy, aryloxy, C2-C4 alkenyloxy, C2-C4
alkynyfoxy, C1-C4 alkyl, carboxy, carbamyl, Ci-C4 alkoxycarbonyl, C1-C4

CA 02508780 2005-06-09
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alkoxycarbonyl C1-C4 alkoxy, carboxy C1-C4 alkoxy amino, C1-C4
alkylamino, di-C1-C4 alkylamino, N C1-C4 alkyl-N cyano C1-Cø alkylamino,
nitro, C1-C4 alkylcarbonylamino, cyano, halo C1-C4 alkyl, di-halo C1-C4
alkyl, tri-halo C1-C4 alkyl, hydroxy C1-C4 alkoxy, halo C1-C4 alkoxy, tri-halo
C1-C4 alkoxy,
0
o \ o \
and
CH3
R3 is selected from the group consisting of -H, C1-C6 alkyl, C2-C6
alkenyl, C2-C6 alkynyl, cyano, amino C1-C4 alkyl, amino, aryl, wherein the
aryl group optionally can be substituted with one or more group selected
from halogen, hydroxy, C1-C4 alkoxy, Ci-C4 alkyl, carboxy, C1-C4
alkoxycarbonyl, carboxy C1-C4 alkoxy, amino,, di- C1-C4 alkylamino, N C1-
C4 alkyl-N cyano C1-C4 alkylamino, nitro, Ci-C4 alkylcarbonylamino, cyano,
halo C1-C4 alkyl, di-halo C1-C4 alkyl, tri-halo C1-C4 alkyl, halo C1-C4
alkoxy,
di-halo C1-C~ alkoxy, tri-halo C1-C4 alkoxy, and
where the R2 and R3 groups are such that they optionally join to
form a ring system selected from:
his l
''\ N
N
and.
a ~~ ~~ ~
[00023] As shown above, ring substituent groups that join to form
additional ring structures adjacent the substituted ring can be described
with reference to chemical formulas that show wavy lines to indicate that a
16

CA 02508780 2005-06-09
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partial molecule is shown. In these formulas, the wavy lines cut through
the ring to which the substituents are joined (in this case, the pyridine ring
of formula I), rather than across the bond joining the substituent group to
the ring. Accordingly, the partial ring that is shown is the ring to which the
substituent groups are shown as being bonded in the general formula.
R4 is selected from the group consisting of -H, Ci-C6 alkyl, C2-Cs
alkenyl, C2-C6 alkynyl, hydroxy, C1-C4 alkylthio, Ci-C4 alkoxy, C1-C4
alkoxycarbonyl, mercapto, N imidazoylphenyl, , Cj-C4 isoalkyl,
aminofluorobenzhydryl, aryl and heteroaryl, wherein the aryl and
heteroaryl groups optionally can be substituted with one or more groups
selected from halogen, hydroxy, C1-C4 alkoxy, Cy-C4 alkyl, C1-C4 alkylthio,
C1-C4 alkylsulfonyl, C1-C4 alkyisulfinyl, cartoxy, carbamyl, C1-C4
alkoxycarbonyl, carboxy C1-Ca. alkyl, carboxy C1-C4 alkoxy, amino, di- C7-
C4 alkylamino, N Ci-C4 alkyl-N cyano C~-Ca. alkylamino, vitro, C1-C4
alkylcarbonylamino, cyano, halo C1-C4 alkyl, di-halo C1-C4 alkyl, tri-halo
Ci-C4 alkyl, halo C1-C4 alkoxy, di-halo C1-C4 alkoxy, tri-halo C1-C4 alkoxy
ci
\ s \ ° \
and
°
H
wherein the R3 and R4 groups are such that they optionally join to
form a ring system selected from:
17

CA 02508780 2005-06-09
WO 2004/054505 PCT/US2003/039166
R7 ..,a
R
,
Rio
i
~E-- R
Rii ~R12
R22 R21
R23
R\
R25!
~E
R2s ,
~G
27 \\
R R2s R2s 'R3o R''"
X37 R36 R35
R3$ /
> >
R3s~ D~ E G
I4o R41 \R42 R4n
R50 H._ R4a R57 . R55
47
R5i R R5 ~ I /
R52 ~ > >
Ilun~,. R59~~ ~G
R53 ~ 54 50 ~ \ R62
R D ., \ R Rsi
~2~ R71
~D
and R73-
w / ~
R7 ~ \
I~ R7s
R75
R""
18

CA 02508780 2005-06-09
WO 2004/054505 PCT/US2003/039166
D, E and G are each independently selected from the group
consisting of carbon, oxygen, sulfur, and nitrogen;
R5 is selected from the group consisting of -H, and C1-C5 alkyl; and
wherein the Ri and R5 groups can join to form a piperidyl ring or an
oxazinyl ring;
R6 R7 R8 R9 R10 R11 R12 R13 R14 R15 R16 R17 R18 R19 R20
J f 1 J J J J 7 1 1 1 1 J 1 J
R21 R22 R23 R24 R25 R26 R27 R28 R29 R30 R31 R32 R33 R34 R35 R36
J J f J J J J 1 1 1 J J 1 J J J
R37 R38 R39 R40 R41 R42 R43 R44 R45 R46 R47 R48 R49 R50 R51 R52
1 J f f f J 1 f 1 1 f J J f J J
R53 R54 R55 R56 R57 R58 R59 R60 R61 R62 R63 R64 R65 R66 R67 R68
J J J 1 1 J J 7 1 J 7 1 J 1 J 1
R69, R7°, R71, R72, R73, R74, R75, and R76 are each optionally
present and
are each independently selected from the group consisting of -H, C1-C4
alkyl, G2-C4 alkenyl, C2-C4 alkynyl, C1-C4 isoalkyl, amino, nitro, hydroxy,
C1-C4 alkoxy, C1-C4 alkenoxy, oxo, carboxy, halo, halo C1-C4 alkyl, dihalo
C1-C4 alkyl, trihalo C1-C4 alkyl, cyano, cyano C1-C4 alkyl, dicyano C1-C4
alkyl, halophenyl, hydroxy C1-C4 alkoxy, C1-C4 alkoxy C1-C4 alkoxy, -
(CH2)-O-(C6H4)-O-(CH3), carboxy Ci-C4 alkoxy, Ci-C4 alkylcarboxy C1-C4
alkoxy, C1-C4 alkoxyamino, G1-C4 alkylamino, di C1-C4 alkylamino, tri C1-
C4 a(kylamino, amino Ci-C4 alkoxy, diamino Ci-G4 alkoxy, C1-C4
alkylamino C1-C4 alkoxy, di C1-C4 alkylamino C1-C4 alkoxy, cyano C1-C4
alkoxy C1-C4 alkyl, -(CH2)-O-(CF2)-CHF2, tetra C1-C4 alkoxy C1-C4 alkyl,
phenyl, benzyl, benzoyl, aryl, N-morpholinyl, morpholinyl C1-C4 alkoxy,
pyrrolidyl C1-C4 alkoxy, N pyrrolidyl C1-C4 alkoxy, C1-C4 alkylcarboxy,
carboxy C1-C4 alkyl - ethyl ester, pyridyl C1-C4 alkyl, pyridyl C1-C4 aikoxy, -
COO-CH2-CH3; and
wherein R3a and R39 are such that they optionally join to form a ring
system of the type selected from:
o ~~- o ~i
an ~~d
o ~~ o
19

CA 02508780 2005-06-09
WO 2004/054505 PCT/US2003/039166
[00024] In a preferred embodiment, when R2 is heteroaryl, R3 is other
than cyano.
[00025] It is also preferred that at least one of R1, R2, R3, R4, and R5 is
other than hydrogen.
[00026] In another embodiment, when R', R3 and R5 are hydrogen:
R2 is other than alkenyl, alkyl, alkynyi, aryl, arylalkyl, cycloalkyl,
cycloalkylalkyl, heterocycle, heterocyclealkyl, heterocyclealkylcarbonyl,
(NZ1Z2)alkyl, or -RARg;
where Zi and Z2 are each independently selected from the group
consisting of hydrogen, alkoxycarbonyl, alkyl, alkylcarbonyl, benzyl,
benzyloxycarbonyl, and formyl;
RA is selected from the group consisting of aryl and arylalkyl;
RB is selected from the group consisting of aryl, arylalkoxy,
arylalkyl, aryloxy, heterocycle, and heterocyclealkyl; and
R4 is other than alkenyl, alkoxyalkynyl, alkyl, alkynyl, cycloalkyl,
aryl, arylalkyl, heterocycls, heterocyclealkyl, or -RcRpRE;
where Rc is selected from the group consisting of aryl, arylalkyl,
heterocycle and heterocyclealkyl;
Ro is selected from the group consisting of aryl, arylalkoxy,
arylalkoxyimino, arylalkyl, aryloxy, heterocycle, heterocyclealkoxy,
heterocyclealkyl, heterocyclecarbonyl, heterocycleimino, heterocycleoxy,
heterocycleoxyalkyl, heterocycleoxyimino, heterocycleoxyiminoalkyl, and
heterocyclesulfonyl; and
RE is absent or selected from the group consisting of aryl,
arylalkoxy, arylalkoxyimino, arylalkyl, aryloxy, heterocycle,
heterocyclealkoxy, heterocyclealkyl, heterocyclecarbonyl,
heterocycleimino, heterocycleoxy, heterocycleoxyalkyl,
heterocycleoxyimino, heterocycleoxyiminoalkyl, and heterocyciesulfonyl.
[00027] As used herein, the term "alkyl", alone or in combination,
means an acyclic alkyl radical, linear or branched, which, unless otherwise
noted, preferably contains from 1 to about 10 carbon atoms and more
preferably contains from 1 to about 6 carbon atoms. "Alkyl" also

CA 02508780 2005-06-09
WO 2004/054505 PCT/US2003/039166
encompasses cyclic alkyl radicals containing from 3 to about 7 carbon
atoms, preferably from 3 to 5 carbon atoms. The alkyl radicals can be
optionally substituted with groups as defined below, Examples of such
alkyl radicals include methyl, ethyl, chloroethyl, hydroxyethyl, n-propyl,
isopropyl, n-butyl, cyanobutyl, isobutyl, sec-butyl, tert-butyl, pentyl,
aminopentyl, iso-amyl, hexyl, octyl, and the like.
[00028] The term "alkenyl" refers to an unsaturated, acyclic
hydrocarbon radical, linear or branched, in so much as it contains at least
one double bond. Unless otherwise noted, such radicals preferably
contain from 2 to about 6 carbon atoms, preferably from 2 to about 4
carbon atoms, more preferably from 2 to about 3 carbon atoms. The
alkenyl radicals may be optionally substituted with groups as defined
below. Examples of suitable alkenyl radicals include propenyl, 2-
chloropropylenyl, buten-1 yl, isobutenyl, penten-1 yl, 2-methylbuten-1-yl, 3-
methylbuten-1-yl, hexen-1-yl, 3-hydroxyhexen-1-yl, hepten-1-yl, octen-1-yl,
and the like.
[00029] The term "alkynyl" refers to an unsaturated, acyclic
hydrocarbon radical, linear or branched, in so much as it contains one or
more triple bonds, such radicals preferably containing 2 to about 6 carbon
atoms, more preferably from 2 to about 3 carbon atoms. The alkynyl
radicals may be optionally substituted with groups as described below.
Examples of suitable alkynyl radicals include ethynyl, proynyl,
hydroxypropynyl, butyn-1-yl, butyn-2-yl, pentyn-1-yl, pentyn-2-yl, 4-
methoxypentyn-2-yl, 3-methylbutyn-1-yl, hexyl-1-yl, hexyn-2-yl, hexyn-3-yl,
3,3-dimethylbutyn-1-yl radicals, and the like.
[00030] The term "alkoxy" includes linear or branched oxy-containing
radicals, each of which has, unless otherwise noted, alkyl portions of 1 to
about 6 carbon atoms, preferably 1 to about 4 carbon atoms, such as
methoxy, ethoxy, propoxy, isopropoxy, isobutoxy radicals, and the like.
[00031 ] The term "alkoxyalkyl" also embraces alkyl radicals having one
or more alkoxy radicals attached to the alkyl radical, that is, to form
monoalkoxyalkyl and dialkoxyalkyl radicals. Examples of such radicals
21

CA 02508780 2005-06-09
WO 2004/054505 PCT/US2003/039166
include methoxyalkyls, ethoxyalkyls, propoxyalkyls, isopropoxyalkyls,
butoxyalkyls, tert-butoxyalkyls, and the like. The "alkoxy" radicals may be
further substituted with one or more halo atoms, such as fluoro, chloro, or
bromo, to provide "haloalkoxy" radicals. Examples of such radicals includ
fluoromethoxy, chloromethoxy, trifluoromethoxy, difluoromethoxy,
trifluoroethoxy, fluoroethoxy, tetrafluoroethoxy, pentafluoroethoxy,
fluoropropoxy, and the like.
[00032] The term "alkylthio" embraces radicals containing a linear or
branched alkyl radical, preferably, unless otherwise noted, of from 1 to
about 6 carbon atoms, attached to a divalent sulfur atom. An example of
"lower alkylthio", is methylthio (CH3-S-).
[00033] The term "alkylthioalkyl" embraces alkylthio radicals, attached
to an alkyl group. An example of such radicals is methylthiomethyl.
[00034] The term "halo" means radicals comprising halogens, such as
fluorine, chlorine, bromine, or iodine.
[00035] The term "heterocyclyl" means a saturated or unsaturated
mono- or multi-ring carbocycle wherein one or more carbon atoms is
replaced by N, S, P, or O. This includes, for example, structures such as:
z3
\z3 ,or I I2
zi Z z~ zi, z
where Z, Z1, Z2, or Z3 is C, S, P, O, or N, with the proviso that one
of Z, Zi, Z2, or Z3 is other than carbon, but is not O or S when attached to
another Z atom by a double bond or when attached to another O or S
atom. Furthermore, the optional substituents are understood to be
attached to Z, Z1, Z2, or Z3 only when each is C. The term "heterocycle"
also includes fully saturated ring structures, such as piperazinyl, dioxanyl,
tetrahydrofuranyl, oxiranyl, aziridinyl, morpholinyl, pyrrolidinyl,
piperidinyl,
thiazolidinyl, and others.
22

CA 02508780 2005-06-09
WO 2004/054505 PCT/US2003/039166
[00036] The term "heteroaryl" means a fully unsaturated heterocycle,
which can include, but is not limited to, furyl, thenyl, pyrryl, imidazolyl,
pyrazolyl, pyridyl, thiazolyl, quinolinyl, isoquinolinyl, benzothienyl, and
indolyl.
[00037] In either, "heterocyclyl" or "heteroaryl", the point of attachment
to the molecule of interest can be at the heteroatom or elsewhere within
the ring.
[00038] The term "cycloalkyl" means a mono- or multi-ringed carbocycle
wherein each ring contains three to about seven carbon atoms, preferably
three to about six carbon atoms, and more preferably three to about five
carbon atoms. Examples include radicals, such as cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, cycloalkenyl, and cycloheptyl. The term
"cycloalkyl" additionally encompasses spiro systems wherein the cycloalkyl
ring has a carbon ring atom in common with the seven-membered
heterocyclic ring of the benzothiepine.
[00039] The term "oxo" means a doubly-bonded oxygen.
[00040] The term "aryl" means a fully unsaturated mono- or multi-ring
carbocycle, including, but not limited to, substituted or unsubstituted
phenyl, naphthyl, or anthracenyl.
[00041] The present aminocyanopyridine compounds inhibit the activity
of the MK-2 enzyme. When it is said that a subject compound inhibits MK-
2, it is meant that the MK-2 enzymatic activity is lower in the presence of
the compound than it is under the same conditions in the absence of such
compound.
[00042] One method of expressing the potency of a compound as an
MK-2 inhibitor is to measure the "ICSO" value of the compound. The lCSo
value of an MK-2 inhibitor is the concentration of the compound that is
required to decrease the MK-2 enzymatic activity by one-half.
Accordingly, a compound having a lower ICSO value is considered to be a
more potent inhibitor than a compound having a higher ICSO value. As
used herein, aminocyanopyridine compounds that inhibit MK-2 can be
23

CA 02508780 2005-06-09
WO 2004/054505 PCT/US2003/039166
referred to as aminocyanopyridine MK-2 inhibitors, or aminocyanopyridine
MK-2 inhibiting compounds or MK-2 inhibiting agents.
[00043] Examples of aminocyanopyridine compounds that are suitable
for use as MK-2 inhibitors in the present invention are shown in Table I.
Table I: Aminocyanopyridine MK-2 Inhibitors
24

CA 02508780 2005-06-09
WO 2004/054505 PCT/US2003/039166
M
K-2
Avg.
IC50
No.Structures Compound Name s)b (uM)
1 , 2-amino-4-(2-fluorophenyl)-6,8-1.22
dihydro-5H-pyrazolo[3,4-h]quinoline-3
F ~ carbonitrile bis(trifluoroacetate)
=N
Ni ~N~NH2
I
H F
O F O
F~OH F----r -OH
2 2-amino-4-(2-fury!)-6,7-dihydro-5H-1.36
O i pyrazolo[3,4-h]quinoline-3-carbonitrile
bis(trifluoroacetate)
-N F O
HN ~ \N~NHZ F-~OH
F
~N-.
F
F-~OH
F
3 F ~ 2-amino-4-(2,3-difluorophenyl)-6,7-1.95
dihydro-5H-pyrazolo[3,4-h]quinoline-3
F ~ carbonitrile bis(trifluoroacetate)
~N
~
NH2
HN \ N
N'
O
F
2 F--~OH
F
4 8-amino-6-(2-fury!)-4,5-dihydro-11.96
H-
O , pyrazolo[4,3-h]quinoline-7-carbonitrile
~\N
~NJ~ N H2
N-NH
O
F
2 F-~ O H
F
2-amino-3-cyano-4-(2-fury!)-5,6-2.35
O , dihydrobenzo[h]quinoline-8-carboxylic
acid trifluoroacetate
=N
\N~ NH2
I
HO
~ O
F
O F--~OH
F

CA 02508780 2005-06-09
WO 2004/054505 PCT/US2003/039166
MK-2
Avg.
IC50
No.Structures Com ound Name(s)b (uM
NHz 4-[2-amino-3-cyano-6-(2-furyl)pyridin-2.41
N~ =N 4-yl]-iH-pyrrole-2-carboxamide
\ o
C I H NHz
7 / 2-amino-4-phenyl-6,8-dihydro-5H-2.73
pyrazolo[3,4-h]quinoline-3-carbonitrile
bis(trifiuoroacetate)
/ -N
N/ \N' _NHz
l
N
H
F O O
F
F OH F~OH
-
F
IF
8 / 2-amino-6-(2-furyl)-4-(1-methyl-iH-2.88
N imidazol-4-yl)nicotinonitrile
N / ~ F bis(trifluoroacetate)
,
N HO~
~
F
F
N"NHz O
~
F
O Hp~
I'F
F
26

CA 02508780 2005-06-09
WO 2004/054505 PCT/US2003/039166
- - MI<-2
Avg.
IC50
No.Structures Compound Name(s)b (uM)
9 8-amino-6-(2-furyl)-4,5-dihydro-13.23
H-
o / pyrazolo[4,3-h]quinoiine-7-carbonitrile
~N trifluoroacetate
~
I
/ / N" N H2
N-N
H O
+2.6 F OH
F
2-amino-4-(2-furyl)-8-hydroxy-5,6-3.48
o ,, dihydrobenzo[h]quinoline-3-
N carbonitrile trifluoroacetate'
i I
\NO _NH2
I
HO ~
F
F--~ O H
F
11 ~ ~ 2-amino-4-(2,6-difiuorophenyl)-6,7-3.59
I dihydro-5H-pyrazolo[3,4-h]quinofine-3
F ~ F carbonitriie bis(trifluoroacetate)
~,N
I
HN \ N~NH2
N
O O
F---~OH F-~OH
F F
12 ~N 2-amino-6-(4-hydroxyphenyl)-4-(13.62
HN , ~ N-
imidazol-5-yl)nicotinonitrile
Ho'~F trifluoroacetate
\ F
( \ Nr NHZ O
HO ~ HO~F
F
F
13 ~ 2-amino-4-(2-fluorophenyl)-6-(2-4.06
I furyl)nicotinonitrife
\
F
~N
~I
~N~NH2
I
O
14 r 2-amino-4-(2-fluorophenyl)-6-(2-4.41
I furyl)nicotinonitrile
trifluoroacetate
F
-N F O
\N- _NH I OH
2
F
O
27

CA 02508780 2005-06-09
WO 2004/054505 PCT/US2003/039166
- M
K-2
Avg.
IC50
No.Structures Compound Name(s)b (uM)
15 / 2-amino-4-(2-fluorophenyi)-5,6-4.47
dihydrobenzo[h]quinoline-3-
F ~ carbonitrile trifluoroacetate
/ =N
\ \N~NH2
O
F
F--~OH
F
16 4-[6-amino-5-cyano-4-(2-furyl)pyridin-4.63
O 2-yl]benzoic acid trifluoroacetate
=N
F O
~N NHz F---~OH
HO \ F
O
17 ~ N 2-amino-6-(2-furyl)-4-(i4.94
H-imidazol-5-
HN O yl)nicotinonitrile
trifluoroacetate
/
N 2 HO~
~
F
\ F
\ N" N Hz
O
18 _ 2-amino-4-(2-furyl)-6-(15.46
H-pyrazol-3-
O , yl)nicotinonitrile
i~,N
/ N' _ N H2
//
N- N
H
19 ~-N 2-amino-3-cyano-4-(4H-1,2,4-triazol-35.74
HN ~. N yl)-5,6-dihydrobenzo[h]quinoline-8-
carboxylic acid bis(trifluoroacetate)
=N
\ \N_ _NH2
I
HO
/
O
F F O
O F~OH ~~
F--r -OH
F ~F
20 ~ N 2-amino-6-(3-hydroxyphenyl)-4-(15.81
H-
HN / imidazol-5-yl)nicotinonitrile
~ N O trifluoroacetate
i II
2 Ho~F
'
~
\ N~NH2
F
F
OH
28

CA 02508780 2005-06-09
WO 2004/054505 PCT/US2003/039166
- - MiC-2
Avg.
IC50
No.Structures Compound Names b (uM)
21 N~NH 2-amino-6-(2-furyl)-4-(15.95
H-imidazol-4-
yl)nicotinonitrile
trifluoroacetate
F off hydrate
F
=N
~ ~N~iJHa
O OH2
22 F 2-amino-4-(2,4-difluorophenyl)-6,7-6
\ dihydro-5H-pyrazolo[3,4-h]quinoline-3
carbonitrile bis(trifluoroacetate)
F
i,N
~
NH2
HN \ N
v _-
N
F O O
F' ''
F OHF~OH
F F
23 NH2 4,6-diamino-2-(trifluoromethyl)-2,3-6.14
F ,~ =N dihydrofuro[2,3-b]pyridine-5-
carbonitrile or 6N009
O \
N NNz
F
24 2-amino-4-(2-furyl)-6,8-dihydro-5H-6.2
O ,r pyrrolo[3,4-h]quinoline-3-carbonitrile
trifluoroacetate
/ =N
I ~N~NHz
H F O
~~OH
F
25 , 4-[6-amino-5-cyano-4-(2-6.4
fluorophenyi)pyridin-2-yl]benzoic
acid
F ~ trifluoroacetate
/ -N
~N~ NHZ
I
HO \
O
O
+0.65 F ON
F
26 2-amino-4-(2-furyl)-5,6-dihydro-1,8-6.48
O / phenanthroline-3-carbonitrile
bis(trifluoroacetate)
/ .= N
1
\ ~N~NH2
NJ o
F F O
F--~OH F~OH
F F
29

CA 02508780 2005-06-09
WO 2004/054505 PCT/US2003/039166
M
K-2
Avg.
IC50
No.Structures Compound Name s)b (uM)
27 / 2-amino-6-(3,4-dihydroxyphenyl)-4-(2-7.54
fluorophenyl)nicotinonitrile
F ~ trifluoroacetate
=N
\N_ _NHz
~
F O
HO ~
OH .23 F--~OH
F
28 / 2-amino-4-(1-methyl-1 7.63
N H-imidazol-4-yl)
6-phenylnicotinonitrile
N / ~F bis(trifluoroacetate)
,~N H I\O
F
F
N- _ N H2 O
/ HO~F
F
F
29 2-amino-4-(2-furyl)-6-(17.72
H-pyrazol-3-
O / yl)nicotinonitrile
trifluoroacetate
/ =N
\N~ NHZ
I~
N~ N O
H F
F--~ O H
F
30 ~-N 4-[6-amino-5-cyano-4-(18.37
H-imidazol-5-
HN ~. yl)pyridin-2-yl]benzoic
acid
hydrochloride
/ =N
CI H
\N NH2
HO
O
31 F / 2-amino-4-(3-fluorophenyl)-6,8-8.5
( dihydro-5H-pyrazolo[3,4-h]quinoline-3
carbonitrile bis(trifluoroacetate)
/ -N
N i ~N~ NHz
!
O F O
\H F
F--~O H F--~O H
F F

CA 02508780 2005-06-09
WO 2004/054505 PCT/US2003/039166
- M
K-2
Avg.
IC50
No.Structures Compound Name(s)b (uM)
32 / 2-amino-6-(3,4-dihydroxyphenyl)-4-(2-9.2
fluorophenyl)nicotinonitrile
F \
,. = N
i \N_ _ NHz
HO
OH
33 N-{4-[6-amino-5-cyano-4-(2-9.27
furyl)pyridin-2-
~N yl]phenyl}methanesuifonamide
trifluoroacetate
N~NHz
HN ~ F O
S=O F--~OH
O F
34 2-amino-4-(2-furyl)-6,7-dihydro-5H-9.4
O ~ pyrrolo[2,3-h]quinoiine-3-carbonitrile
trifluoroacetate
=N
HN \ \N~NHz
O
~~OH
F
35 ~ N 2-amino-4-(1 H-imidazol-5-yl)-6-9.4
HN / O phenylnicotinonitrile
trifluoroacetate
//N 2 HO~F
F
F
I
N- _ N Hz
\
/
36 2-amino-4-(2-furyl)-5,6-9.42
o dihydrobenzo[h}quinoline-3-
carbonitrile trifluoroacetate
N
\ \N' -NHz
O
F~OH
F
37 NN~N 2-amino-4-(iH-imidazol-5-yl)-6-(4-9.43
methoxyphenyl)nicotinonitriie
trifluoroacetate
-N F O
\N"NHz F--~OH
~
F
\
31

CA 02508780 2005-06-09
WO 2004/054505 PCT/US2003/039166
M
K-2
Avg.
IC50
No.Structures Compound Name(s)b (uM)
38 ~ N p 2-amino-6-(3-chlorophenyl)-4-(110
H-
HN / imidazol-5-yl)nicotinonitrile
F
~ trifluoroacetate
~. N 2 H~ I 'F
F
N_ _NHZ
CI
39 _ 2-amino-4-(2-furyl)-6-(111.6
o F off H-pyrazol-4-
yi)nicotinonitrile
bis(trifluoroacetate)
F
/ -N O
I F
F'-~OH
i
~
~NH
2
N
I
N
~N
H
40 ~O 2-amino-4-(4-methoxyphenyl)-6,7-12
dihydro-5H-pyrazolo[3,4-h]quinoline-3
I w carbonitrile bis(trifluoroacetate)
/
i~N
I
HN \ N~NH2
N-
F O O
F
F--~OH F~OH
F F
41 ~ F 2-amino-4-(2,5-difluorophenyl)-6,7-12.8
~ dihydro-5H-pyrazolo[3,4-h]quinoline-3
F / carbonitrile bis(trifluoroacetate)
~N
I
HN \ N~NHZ
~
N'-
F O O
F1 ~J
F OHF~OH
F IF
42 F 2-amino-4-(4-fluorophenyl)-6,8-12.9
dihydro-5H-pyrazolo[3,4-h]quinoline-3
/
~ carbonitrile bis(trifluoroacetate)
/ =N
N ~ ~N~ N HZ
HF O F O
F--~OH F--~OH
F F
32

CA 02508780 2005-06-09
WO 2004/054505 PCT/US2003/039166
MK-2
Avg.
IC50
No.Structures Compound Name(s)~' (uM)
43 ~=N 2-amino-4-(4H-1,2,4-triazol-3-yl)-5,6-13.1
HN ~. N dihydrobenzo[h]quinoline-3-
carbonitrile bis(trifluoroacetate)
/ - N
\N~ N H2
/ F O F O
F--~OH F--~OH
F F
44 NHz 4,6-diamino-2-(chloromethyl)-2,3-13.4
a ~ =N dihydrofuro[2,3-b]pyridine-5-
I carbonitrile
~N NHZ
45 O 2-amino-4-(1 H-imidazol-4-yl)-6-14.2
~ phenylnicotinonitrile
trifiuoroacetate
~ F-- hydrate
oH
F
=N
~N,~ NHz
OH2
46 4-[6-amino-5-cyano-4-(2-furyl)pyridin-16.1
O O / 2-yl]benzenesulfonamide
HO~F ~ N trifluoroacetate
F
F
N' _NH2
I
HaN~
S,
00
47 4-[6-amino-5-cyano-4-(2-furyt)pyridin-16.7
--
0 2-yl]phenyiboronic
acid
~ N trifluoroacetate
I ~
N" 'NH2
I
HOB
F O
OH
F-~OH
F
48 ~ N 2-amino-6-(4-methoxyphenyl)-4-(4H-17.3
HN ~ N 1,2,4-triazol-3-yi)nicotinonitrile
bis(trifluoroacetate)
-N
~N~ NHz
O
F F O
F-~'~OH F~OH
F F
33

CA 02508780 2005-06-09
WO 2004/054505 PCT/US2003/039166
M
fC-2
Avg.
IC50
No.Structures Compound Name(s)b (uM)
49 ~ 2-amino-4-(2-fluorophenyl)-6-(3-17.9
furyl)nicotinonitrile
trifluoroacetate
F
,N
~
/' N
NH2
~
O
O
F
~
F---
OH
F
50 O 2-amino-6-(2-furyl)-4-22.5
F \ (methyithio)nicotinonitrile
~
HO trifluoroacetate
F S ~ N
F \ r
I
\\
N"NH2
O
51 / 2-amino-4-(2-fluorophenyl)-6-(3-24.2
hydroxyphenyl)nicotinonitrile
F ~ trifluoroacetate
/ -N F O
\N"NH ~OH
2 F
OH
52 8-amino-6-(2-furyl)-4,5-dihydro-2H-25.3
O / pyrazolo[4,3-h]quinoline-7-carbonitrile
~
N
~
/ N~~N HZ
//
N-N
H
53 , 2-amino-4-(2-bromophenyl)-6-(2-26.1
furyl)nicotinonitrile
trifluoroacetate
Br
/ -N O
\N' -NH2F OH
O F
54 / 2-amino-4-(2-fluorophenyl)-6-(4-26.8
hydroxyphenyl)nicotinonitrile
F ~ trifluoroacetate
/ =N F O
/ \N" NH I OH
2 F
HO \
34

CA 02508780 2005-06-09
WO 2004/054505 PCT/US2003/039166
- M
K-2
Avg.
IC50
No.Structures Compound Name(s)b (uM
55 ~ 2-amino-4-phenyl-6-thien-2-26.9
ylnicotinonitrile
N
\N" NHz
56 ~o ~ 2-amino-4-(3-methoxyphenyi)-6,7-27.8
dihydro-5H-pyrazolo[3,4-h]quinoline-3
carbonitrile bis(trifluoroacetate)
~~N
HN \ N~NHz
N-
F O O
F
F--~OH F~OH
F F
57 2-amino-4-(2-furyl)-7-methyl-6,7-28.3
o , dihydro-5H-pyrazolo[3,4-h]quinoline-3
carbonitrile bis(trifluoroacetate)
N
~N ~ \N' _NHz
N
F O F O
F~OH F--~OH
~F F
58 , 2-amino-4-(2-fluorophenyl)-6-(129.3
H-
pyrrol-2-yl)nicotinonitrile
F trifluoroacetate hydrate
=N
OH
\N N~0.1 z
z
NH
+0.4 F OH
F
59 ~ 2-amino-4-(2-furyl)-5-methyl-6,8-31.3
dihydro-5H-pyrazolo[3,4-h]quinoline-3
carbonitrile trifluoroacetate
=N
N~ \N~NHz O
F
H F--~ O H
F

CA 02508780 2005-06-09
WO 2004/054505 PCT/US2003/039166
M
fC-2
Avg.
IC50
No.Structures Compound Name(s)b (uM)
60 2-amino-4-(2-furyl)-6-(1-methyl-1H-32.1
pyrrol-3-yl)nicotinonitrile
.
~N
~
I
~N \ \N
NH2
61 N NH2 3-amino-5,6,7,8- 33.4
t etrahydroisoquinoline-4-carbonitril2
W
N
62 O N-[4-(2-amino-3-cyano-6,7-dihydro-35.9
5H-pyrazolo[3,4-h]quinolin-4-
NH yl)phenyl]acetamide
\ bis(trifluoroacetate)
N
i
NN N~ NHz
N
O O
F--~'~OH F~OH
F F
63 r O~ 6-amino-4-[(4-methoxyphenyi)amino]-36.4
I 2-(trifluoromethyl)-2,3-dihydrofuro[2,3-
HN b]pyridine-5-carbonitrile
F ~N
F ~
F O N" N H2
64 4-[6-amino-5-cyano-4-(2-furyl)pyridin-36.4
O O / 2-yi]-N-(tert-
~F N butyl)benzenesulfonamide
HO
~~
F \ trifluoroacetate
F
I
\
N_ _NH2
H
N~ I /
S,
0
0
65 NH2 4,6-diamino-2-ethyi-2,3-37.9
~iN dihydrofuro[2,3-b]pyridine-5-
carbonitrile trifluoroacetate
O ~~ O NHz
F-~OH
F
36

CA 02508780 2005-06-09
WO 2004/054505 PCT/US2003/039166
M -2
Avg.
IC50
No. Structures Compound Name(s)b (uM)
66 ~ 6-amino-4-(2-furyl)-2,4'-bipyridine-5- 39.9
F o ~ ~ carbonitrile bis(trifluoroacetate)
F--~OH / -N
F ~ F O
\N NHZ F~OH
N~ ~F
67 NH 2 4-diamino-6- 41.6
~.~N F O (methylthio)nicotinonitrile
~OH bis(trifluoroacetate)
~S ~ N NH2 F F
O
F
~OH
F F
68 OH 3-(2-amino-3-cyano-6,7-dihydro-5H- 41.7
o ~ pyrazolo[3,4-h]quinolin-4-yl)benzoic
I acid bis(trifiuoroacetate)
/
i~N
I
HN \ N~NHZ
N O O
F--~O R~O H
F F
69 ~N 2-amino-6-(4-chlorophenyl)-4-(1 H- 42.9
HN ~- O imidazol-5-yl)nicotinonitrile
~N ~~F trifluoroacetate
~[2
F
N- 'NHZ
CI
70 O ~ 2-amino-4-(1,3-benzodioxol-4-yl)-6,7- 43.2
dihydro-5H-pyrazolo[3,4-h]quinoline-3
o / carbonitrile bis(trifluoroacetate)
i~N
I
HN \ N~NHZ
N
O O
F~OH F~OH
F F
71 NHz 4,6-diamino-2-methyl-2,3- 44.1
/ '~.~N dihydrofuro[2,3-b]pyridine-5
I carbonitrile trifluoroacetate
F---~OH
F
37

CA 02508780 2005-06-09
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M
K-2
Avg.
ICS
No.Structures Com ound Names b (uM)
72 ~-N 2-amino-4-(1 H-imidazol-5-yl)-6-[4-45.3
HN / O (methylsulfonyl)phenyl]nicotinonitrile
N 2 HO~F trifluoroacetate
i
~
F
\ F
I
\
N- _ N Hz
I
\S
/
~
~~
~
O
O
73 NHz ~ N 2,4-diaminoquinoline-3-carbonitrile45.5
\ \
N NH2
74 2,8-diamino-4-(2-furyl)-5,6-46.8
o , dihydrobenzo[h]quinoline-3-
N carbonitrile trifluoroacetate
/
I
/ \NO -NHz
I
F
HzN \
F--~ O H
F
75 2-amino-4,6-di(2-furyl)nicotinonitril247.6
w
O
~N
/
I
O ~N~NHz
I
76 NHz sodium 4-[2-amino-3-cyano-6-(2-48.7
N,. =N furyl)pyridin-4-yl]-1
H-pyrrole-2-
carboxylate
\ o ~ ~ off
N
H
77 NHz 4,6-diamino-2-butyl-2,3-49.1
~iN dihydrofuro[2,3-b]pyridine-5-
I carbonitrile trifluoroacetate
O \N NHz
O
F
F--~ O H
F
78 o ethyl 4-[6-amino-5-cyano-4-(149.1
H-
N imidazol-5-yl)pyridin-2-yl]benzoate
F
H j
~
F--- trifluoroacetate
oH
F
=N
\N" N Hz
I
~O \
O
38

CA 02508780 2005-06-09
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M
K-2
Avg.
IC50
No.Structures Compound Name(s)b (uM)
79 NH2 2,4-diamino-6-methoxynicotinonitrile50.9
,
N
/
~O N' _NH2
80 N 2-amino-4-methylnicotinonitrile51.9
~
\ trifluoroacetate
i
N NH2
O
HO~F
F
81 i~N 2-amino-4-(4-cyanophenyl)-6,7-52.1
dihydro-5H-pyrazolo[3,4-h]quinoline-3
carbonitrile bis(trifluoroacetate)
,,N
~
NHZ
HN \ N
~ N-
O O
F--~O H F-~O H
F F
82 2-amino-4-cyclopropyl-6-53.7
~ methyinicotinonitrile
N trifluoroacetate
\ .
/
O
HO~F
N NH2 F
F
83 2-amino-4-(2-furyl)-6-(1-methyl-1H-54.4
o pyrrol-2-yl)nicotinonitrile
~~N
~N
'N NH2
84 \ 2-amino-4-(2-chlorophenyl)-6,7-58.4
dihydro-5H-pyrazolo[3,4-h]quinoline-3
a ~ carbonitrile bis(trifluoroacetate)
~/N
i\
~
NHZ
HN N
N-
O O
F--~OH F--~OH
F F
39

CA 02508780 2005-06-09
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M fC-2
Avg.
IC50
No. Structures Compound Names}b uM
85 \ 2-amino-6-(2-furyl)-4-(4- 59.3
phenoxyphenyl)nicotinonitrile
o / trifluoroacetate
/ =N F O
\ \N~NH F~OH
O z F
86 N, 2-amino-4-pyridin-3-yl-6,8-dihydro-5H- 62.5
pyrazolo[3,4-h]quinoline-3-carbonitrile
tris(trifluoroacetate)
/ = N
N ~ wN~ NHz
~N I
H
F O F O
F OH F~OFf~OH
F -IF ~F
87 2-amino-6-{[2-(4-chlorophenyl)-2- 63.3
p oxoethyl]thio}-4-(2-furyl)pyridine-3,5-
N\~ //N dicarbonitriie
~ O
H2N N"S
CI
88 HO ,OH 4-[2-amino-3-cyano-6-(2-furyi)pyridin- 64.6
.B
4-yl]phenylboronic acid
trifluoroacetate
/ -N O
\N- _NH2F OH
O F
89 O 2-amino-6-(3-chlorophenyl)-4-(1 H- 64.9
F-~OH imidazol-4-yl)nicotinonitrile
trifluoroacetate hydrate
F
/ =N
wN~NH2
\ OH2
a

CA 02508780 2005-06-09
WO 2004/054505 PCT/US2003/039166
M
K-2
Avg.
IC50
No.Structures Compound Name s)b (uM)
0 \ 4-(6-amino-5-cyano-4-phenylpyridin-268
O I yl)-N-(tent-butyl)benzenesulfonamide
/ trifluoroacetate
HO~F /N
F I\
\ N_ _ NH2
H
~N~ /
S,,
0
0
91 O/ 2-amino-4-methoxynicotinonitrile69.6
N
N NHZ
92 OH 4-[2-amino-3-cyano-6-(2-furyi)pyridin-69.8
O 4-yl]benzoic acid trifluoroacetate
=N O
I
~
\N- _NHZF OH
'O F
93 ~ _ NHZ 4,6-diamino-2-[(4- 69.8
o ~ ~ o ,. =N methoxyphenoxy)methyl]-2,3-
dihydrofuro[2,3-b]pyridine-5-
~
carbonitrile
N NHZ
94 / 2-amino-4-(2-fluorophenyl)-6-(4-70.4
methoxyphenyl)nicotinonitrile
F ~ trifluoroacetate
=N
O
~ ~ F
N NH2 F-~OH
~O \ F
95 \ 4-[6-amino-5-cyano-4-(2-71.5
O I fluorophenyl)pyridin-2-yl]-N-(tert-
/ F butyl)benzenesulfonamide
HO~F /~N trifluoroacetate
I\
\ N"NH2
H I
N. S /
~ O
~
41

CA 02508780 2005-06-09
WO 2004/054505 PCT/US2003/039166
Avg.
IC50
No. Structures Compound Name(s)b (uM)
g6 NHz [(2,4-diamino-3-cyano-5N- 72.2
N chromeno[2,3-b]pyridin-9-yl)oxy]acefic
acid trifluoroacetate
O / O~N~NHz
HO~O
O
F
~OH
1.56 F F
g7 _ 3-Pyridinecarbonitrile, 2-Amino-4- 77
N Methyl-
N NHa
g8 ~ -N 2-amino-6-(2-furyl)nicotinonitrile 77.5
hydrochloride
I O N H_H
CI H
gg 2-amino-4-(2-furyl)-6-(3- 77,g
hydroxyphenyl)nicotinonitrile
trifluoroacetate
F-~OH
F
'100 4-[6-amino-5-cyano-4-(2-furyl)pyridin- 78.5
2-yl]benzamide trifiuoroacetate
~N
w
O 2
F
F---~OH
F
101 2-amino-4-(2-furyl)-7-hydroxy-5,6- 82.6
dihydrobenzo[h]quinoline-3-
carbonitrile trifluoroacetate
2
F-~OH
F
42

CA 02508780 2005-06-09
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M
K-2
Avg.
tC50
No.Structures Compound Name(s)b (uM)
102,~ 2-amino-4-(2-furyl)-6-(187.1
H-indol-3-
yl)nicotinonitrile
trifluoroacetate
,~N
N- _NHz
O
F
F-~OH
F
103~N 2-amino-4-pyridin-4-yi-6,8-dihydro-5N-94.3
pyrazolo[3,4-h]quinoline-3-carbonitrile
tris(trifluoroaoetate)
/. - N
N / wN~ NHz
I
'N
H
F O F O
F OH F~OI-F--~OH
F F F
104F / 2-amino-4-(3-fluorophenyl)-6-(4-96
hydroxyphenyl)nicotinonitrile
trifluoroacetate
-N F O
\N~NH ~OH
z F
HO
105F ~ 2-amino-4-[2-(difluoromethoxy)phenyi]96.1
6,7-dihydro-5H-pyrazolo[3,4-
~ h
~ i
li
3
b
il
it
F ]qu
o no
ne-
-car
on
r
e
~iN bis(trifluoroacetate)
HN \ I N~NHz
~ N'
O p
F--~OH F-~OH
F F
106 2-amino-4-(2-furyl)-6-thien-3-97.3
w
ylnicotinonitrile
i~N
\N' _NHz
J
S
43

CA 02508780 2005-06-09
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M
f(-2
Avg.
IC50
No.Structures Compound Name s)b (uM
107F / 2-amino-4-(3-fluorophenyl)-6-(4-97.3
methoxyphenyl)nicotinonitrile
trifluoroacetate
-N O
~~OH
~
~
/
N
NH
F
~O
108~ 2-[2-amino-3-cyano-6-(2-furyl)pyridin-99.6
~ i 4-yl]phenylboronic
Ho acid
, trifluoroacetate
a
i
HO / - N O
F
\N NH F~OH
F
109N\ NH2 ~ N 2,4-diamino-6-propylpyridine-3,5-99.8
dicarbonitrile
N NHz
110\~ NH 4,6-diamino-2-[(prop-2-105
2 n
N lox
)meth
l]-2
3-dih
drofuro[2
3-
/~ y
y
y
y
,
y
,
O ~ b]pyridine-5-carbonitrile
~
~ trifluoroacetate
O
NO NH2
F
F~OH
~
F
111NHZ 4,6-diamino-2-(hydroxymethyl)-2,3-106
Ho , =N dihydrofuro[2,3-b]pyridine-5-
carbonitrile
~
O
N NHz
112F F F 2-amino-6-(2-furyl)-4-[4-107
(trifluoromethyl)phenyl]nicotinonitrile
trifluoroacetate
/ -N O
\N~NHzF off
O F
113N NH2 5-amino-7-methylthieno[3,2-b]pyridine109
6-carbonitrile or GK02302
N
114/ ~ 2-amino-4-(2-furyl)-5,5-dimethyl-6,8-109
dihydro-5H-pyrazolo(3,4-h]quinoline-3
carbonitrile
=N
N ~ ~N~ N H2
N
H
44

CA 02508780 2005-06-09
WO 2004/054505 PCT/US2003/039166
M
If-2
Avg.
IC50
No.Structures Compound Name(s)b (uM)
115, N-[3-cyano-4-(2-fluorophenyl)-6-(2-114
furyl)pyridin-2-yl]glycine
F ~ trifluoroacetate
=N
O
N
Nv _OH
O
F
F--~OH
F
116NH2 N 2-[(allyloxy)methyl]-4,6-diamino-2,3-118
dihydrofuro[2,3-b]pyridine-5-
carbonitrile trifluoroacetate
FNO NH2
F--~OH
F
117 2-amino-4-(2-furyl)-6-methyl-5,6-119
o / dihydrobenzo[h]quinoline-3-
A N carbonitrile trifluoroacetate
\N_ _NH2
~
\ ,
F O
F--~OH
F
118NH2 4,6-diamino-2-(methoxymethyl)-2,3-119
-.O , i dihydrofuro[2,3-b]pyridine-5-
carbonitrile trifluoroacetate
\N NHZ
F I
F-~OH
F
119 2-amino-4-(2-furyl)-6-(1120
w H-indol-3-
\ yl)nicotinonitrile
~N
w /
/ \N NH2
N
H
120 2-amino-4-(2-furyl)-6-[4-(iN-imidazol-121
w
1-yl)phenyl]nicotinonitrile
,~N
\N- 'NH2
~J \

CA 02508780 2005-06-09
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M
K-2
Avg.
IC50
No. Structures Compound Name s)b (uM)
121 2-amino-4-(2-furyl)-6-(4-122
"._ \
o hydroxyphenyl)nicotinonitrile
trifluoroacetate
~~N
\N' 'NHz
I
O
HO ~
F~OH
F
122 2-amino-4-(2-furyl)-5,6,7,8-tetrahydro-122
---
0 5,8-methanoquinoline-3-carbonitriie
trifluoroacetate
~N
wN~N Hz
O
F-~OH
F
123 NH2 4,6-diamino-2-(isopropoxymethyl)-2,3-125
o , '~~N dihydrofuro[2,3-6]pyridine-5-
carbonitrile trifluoroacetate
O \N NHz
O
F~ ~
F~OH
~F
124 3-[6-amino-5-cyano-4-(2-furyl)pyridin-126
o r 2-yl]phenylboronic
acid
=N
\N' _ NHz
NO' B'O H
125 NHZ 4,6-diamino-2-(ethoxymethyl)-2,3-127
o ~ '~.~N dihydrofuro[2,3-b]pyridine-5-
carbonitrile trifluoroacetate
O ~~ O NHz
F--~ O H
F
126 Br 2-amino-4-(4-bromophenyi)-6-(2-130
furyl)nicotinonitrile
trifluoroacetate
-N F O
\N~NH F~OH
O z F
46

CA 02508780 2005-06-09
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M
-2
Avg.
iC50
No.Structures Compound Name(s)b uM)
127F F NH2 4,6-diamino-2-[(11,2,2-131
'~iN tetrafiuoroethoxy)methyl]-2
3-
,
F F ~ dihydrofuro[2,3-b]pyridine-5-
O N N H2
carbonitrile
128F F F 2-amino-4-[2-fluoro-4-133
(trifluoromethyi)phenyl]-6-(2-
furyl)nicotinonitrile
trifluoroacetate
F
=N O
F
\N~ NH F~OH
z F
O
129/ 2-amino-4-(2-methoxyphenyl)-6,8-136
dihydro-5H-pyrazoi0[3,4-h]quinoline-3
carbonitrife bis(trifiuoroacetate)
=N
N wN~ NHz
HF O F O
F~OH F---~OH
~
F F
130/ 2-amino-4-(2-fluorophenyi)-5-methyl-142
6,8-dihydro-5H-pyrazolo[3,4-
h]quinoline-3-carbonitrile
-N trifiuoroacetate
~
N \N
N Hz O
F
H F--~ O H
F
131 3,6-diamino-4-ethyl-1 146
H-pyrazolo[3,4-
~\ NH b]pYridine-5-carbonitrile
Z
~N
H2N N
132 6-amino-4-(2-furyl)-2,2'-bipyridine-5-149
F O ~ O carbonitriie bis(trifluoroacetate)
F--~OH ~ N
F ~
O
F
~'N I ~N NHz F-~OH
F
47

CA 02508780 2005-06-09
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M K-2
Avg.
IC50
No. Structures Compound Name s)b (uM)
133 2-amino-4-(2-furyl)-6-(8-hydroxy-1- 153
naphthyl)nicotinonitrile trifluoroacetate
,N
OH
~N NHz
\ O
F-~OH
F
134 O off 4-(2-amino-3-cyano-6,7-dihydro-5H- 155
pyrazolo[3,4-h]quinolin-4-yl)benzoic
I \ acid bis(trifiuoroacetate)
i
~N
I\
HN \ N~NHz
~NF O F O
F-~OH F--~OH
F F
135 2-amino-6-(3,4-dichlorophenyl)-4-(2- 156
\ ~ furyi)nicotinonitrile
/ N
/
Cf \ \
~N NHz
CI /
136 2-amino-4-(2-furyl)-6-(10H- 158
o / phenothiazin-2-yl)nicotinonitrile
=N
\N~ NHz
\ I
NH
\ I
137 ~ ~- Na+ sodium 2-amino-3-cyano-4- 161
quinolinecarboxylate
/ N
/ /~
\ \
N NHz
48

CA 02508780 2005-06-09
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M K-2
Avg.
IC50
No. Structures Compound Name(s)b (uM
138 \ 2-anilino-4-(2-fluorophenyl)-6-(2- 162
I furyl)nicotinonitrile
F ~ N
I~ IN~H \
O O
HO~ F
F F
139 F , 2-amino-4-(3-fluorophenyl)-6-(2- 164
furyl)nicotinonitrile trifluoroacetate
-N F O
\ \N_ 'NH ~OH
z
O
140 F 2-amino-4-(4-fluorophenyl)-6-(2- 165
furyl)nicotinonitriie trifiuoroacetate
-N F O
\N_ _NH F~ON
F
141 NH2 4,6-diamino-2-(tert-butoxymethyl)-2,3- 167
O I ~ ~iN dihydrofuro[2,3-b]pyridine-5-
carbonitrile
O~N~NH2
142 2-amino-4-(2-fury!)-6-(1,3-thiazol-2- 167
F O ~ o yl)nicotinonitrile bis(trifluoroacetate)
F--~OH / -N
F ~ F O
\N NH2 F~OH
~~N ~F
143 , 4-(2-fluorophenyl)-6-(2-fury!)-2- 176
I piperidin-1-ylnicotinonitrile
F ~ trifluoroacetate
=N
I
\N~ N
O O
F
F-~OH
F
49

CA 02508780 2005-06-09
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- M
K-2
Avg.
IC50
No.Structures Compound Name(s)b (uM)
144 2-amino-6-(4-chlorophenyl)-4-(2-182
o i furyl)nicotinonitrile
=N
\N~ NH2
I
~
145, 2-amino-6-(4-hydroxyphenyl)-4-(2-183
methoxyphenyl)nicotinonitrile
0
/,,N
N- _NHZ
HO
146~ 2-amino-6-(2-furyl)-4-(2-185
hydroxyphenyl)nicotinonitrile
HO
~N
N" N H2
l
O
K+ +0.3 ~ HZ
+0
2
.
147O methyl3-(2-amino-3-cyano-6,7-191
o ~ dihydro-5H-pyrazolo[3,4-h]quinolin-4-
yl)benzoate bis(trifluoroacetate)
i
,N
HN \ N~NHz
N
O O
F--~OH F--~OH
F F
148/ ~ 2-amino-4-(2-chlorophenyl)-6-(5-192
N NH methyi-2-furyl)nicotinonitrile
2
O
i
~
N
CI
149~ ~ 3,6-diamino-2-benzoylthieno[2,3-199
NHZ b]pyridine-5-carbonitrile
HZN ~N S O

CA 02508780 2005-06-09
WO 2004/054505 PCT/US2003/039166
- - MIC-2
Avg,
IC50
No,Structures Compound Name(s)b (uM)
150 methyi 4-[6-amino-5-cyano-4-(2-199
o / furyl)pyridin-2-yl]benzoate
trifluoroacetate
=N
O ~ I \N~NHZ
F
O ~ ~
\ F~OH
~F
151//N 2-aminonicotinonitrile200
O trifluoroacetate
F
HO~F
N
NH2
F
152 2-amino-4-(2-furyl)-8-{[2-200
(trimethylsilyl)ethoxy]methyl}-6,8-
dihydro-5H-pyrazolo[3,4-h]quinoline-3
CN carbonitrile
I
N~ NHa
N i
TMS~O~ N
153N 3-amino-5H-pyrido[4,3-b]indole-4-200
/ carbonitrile
~ NHz
N
154~ 2-(2-amino-3-cyano-6,7-dihydro-5H-200
Ho I - pyrazolo[3,4-h]quinolin-4-yl)benzoic
acid bis(trifluoroacetate)
,N
~
NH2
HN \ N
N
p O
F
F OHF~OH
F F
155~ 2-amino-6-(4-methoxyphenyl)-4-200
I phenylnicotinonitrile
trifluoroacetate
~N
\N~ N HZ
O
F
~OH
F F
156N NHz 2-amino-4-(2-furyl)-5,6,7,8-200
tetrahydroquinoline-3-carbonitrile
N
/'o
51

CA 02508780 2005-06-09
WO 2004/054505 PCT/US2003/039166
M
K-2
Avg.
IC50
No.Structures Compound Name(s)b (uM)
157 2-amino-4-(2-furyl)-6-200
\ o isobutylnicotinonitrile
=N
N NHz
158 2-amino-6-benzyl-4-(2-200
\ o furyl)nicotinonitrile
trifluoroacetate
I \ =N F O
F~OH
/ N
NH
z
F
159 2-amino-4-(2-furyl)-6-methyl-5-200
\ o phenylnicotinonitrile
trifluoroacetate
I / ~ -N F O
F--~OH
~
~
N
NHz
F
160 2-amino-4-(2-furyl)-6-[4-200
o
\ (trifluoromethoxy)phenyl]nicotinonitrile
trifluoroacetate
=N F O
F~OH
/ I
"
F
N
NI-i
\ I 2 F
F
O
F
161F O 2-amino-4-(2-furyl)-6-propyl-5,6,7,8-200
- tetrahydro-1,6-naphthyridine-3-
~
F-- carbonitrile bis(trifluoroacetate)
OH
\ O
F
~N ~ \ =N
i
N N HZ
O
F~~
F~OH
~F
162 2-amino-4-(2-furyl)benzo[h]quinoline-200
w
O 3-carbonitrile trifluoroacetate
/ =N
F O
N NHz F~OH
'F
163~ 2-amino-6-(4-methoxyphenyl)-4-thien-200
2-ylnicotinonitrile
trifluoroacetate
=N F O
/ \N- _ NHz F--~OH
I
w0 \
F
52

CA 02508780 2005-06-09
WO 2004/054505 PCT/US2003/039166
M
-2
Avg.
tC50
No.Structures Compound Name(s)b uM)
164~ 2-amino-4-(2-fluorophenyl)-6-200
I tetrahydrofuran-2-ylnicotinonitrile
F
- N
I
N"NHZ
O
165 ethyl6-amino-5-cyano-4-(2-200
w
furyl)pyridine-2-carboxylate
=N
~O ~
~
N
NHZ
O
166 2-amino-4-(2-furyl)-9-methoxy-5,6-200
o ~ dihydrobenzo[h]quinoiine-3-
~ N carbonitrile trifluoroacetate
~I
\NO -NHZ
I
F
F--~OH
F
167 2-amino-4-(2-furyl)-8-methoxy-5,6-200
O , dihydrobenzo[h]quinoline-3-
~ N carbonitrile trifluoroacetate
I
\N~NH2
I
\ ~
F~ ~
F~OH
~
F
168 2-amino-4-(2-furyl)-8,9-dimethoxy-5,6-200
O ~ dihydrobenzo[h]quinoline-3-
~ N carbonitrile trifiuoroacetate
~
I
\N" NH2
F O
O ' ~
O F~OH
f
F
169 2-amino-4-(2-furyl)-7-methoxy-5,6-200
o , dihydrobenzo[h]quinoline-3-
N carbonitrile trifluoroacetate
i
i
\N' _ N H2
F O
F--~ O H
F
53

CA 02508780 2005-06-09
WO 2004/054505 PCT/US2003/039166
M
K-2
Avg.
IC50
No.Structures Compound Name(s)b (uM)
170 2-amino-4-(2-furyl)-7,9-dimethyl-5,6-200
dihydrobenzo[h]quinoline-3-
~ N carbonitrile trifluoroacetate
~
I
\N' _NH2
F O
F--~OH
F
171 ethyl4-[6-amino-5-cyano-4-(2-200
o / furyl)pyridin-2-yl]benzoate
=N
\N- _NHZ
O I
O
172 2-amino-6-(3-bromophenyl)-4-(2-200
o / furyl)nicotinonitrile
=N
\N~ N HZ
I
Br
173 2-amino-4-(2-furyl)-6-[4-200
o i (trifluoromethyl)phenyl]nicotinonitrile
=N
\N- -NHZ
F
F
F
174 2-amino-4-(2-furyl)-6-[3-200
o ~ (trifluoromethyl)phenyl]nicotinonitrile
=N
~N~ NH2
I
F F
F
175 2-amino-4-(2-furyl)-6-[4-200
o / (methylsulfonyl)phenyl]nicotinonitrile
=N
\N_ _ NHZ
O
O
54

CA 02508780 2005-06-09
WO 2004/054505 PCT/US2003/039166
M
K-2
Avg.
IC50
No.Structures Compound Name(s)b (uM)
176_ NHZ N 4,6-diamino-2-(phenoxymethyl)-2,3-200
dihydrofuro[2,3-b]pyridine-5-
carbonitrile trifluoroacetate
O \NO NH2
F
F~--~OH
F
177~ 4,6-diamino-3-phenyl-2,3-200
/ dihydrofuro[2,3-b]pyridine-5-
NH
z carbonitrile trifiuoroacetate
~N
O ~
O NHZ
~
F~OH
~
F
178NH2 4,6-diamino-3-vinyl-2,3-200
~~N dihydrofuro[2,3-b]pyridine-5-
carbonitrile trifluoroacetate
O \N NHz
O
F
F--~OH
F
179/ 2-amino-4-(2-fluorophenyl)-5-methyl-200
6,8-dihydro-5H-pyrazoio[3,4-
h]quinoline-3-carbonitrile
-N trifluoroacetate
~
N ~ \N
N H2 O
F
F-~OH
F
180 3-amino-1-methyl-5,6,7,8-200
tetrahydroisoquinoline-4-carbonitrile
CN
N NHZ
181/ 2-amino-4-(2-fluorophenyl)-5,5-200
dimethyl-6,8-dihydro-5H-pyrazolo[3,4-
F ~ h]quinoline-3-carbonitrile
/ =N
N/ \N_ _NH2
N
H

CA 02508780 2005-06-09
WO 2004/054505 PCT/US2003/039166
M
K-2
Avg.
IC50
No. Structures Compound Name(s)b (uM)
182 / 2-amino-4-(2-fluorophenyl)-6-(3-200
hydroxyphenyl)nicotinonitrile
F \ trifluoroacetate
/ -N F O
w ~ F--r -OH
-N NH
F
OH
183 F \ 2-amino-4-[2-(difluoromethoxy)phenyl]200
6,7-dihydro-5N-pyrazolo[3,4-
~
/
F h]quinoline-3-carbonitrile
O
,N
HN \ N~NHZ
~N-
184 / 2-(benzylamino)-4-(2-fluorophenyl)-6-200
(2-furyl)nicotinonitrile
trifluoroacetate
F \
/ =N
\ \ ~N /
O \
O
F
F--~OH
F
185 2-amino-4-(2-fury!)-6,7-dihydro-5H-200
O / benzo[6,7]cyclohepta[1,2-b]pyridine-3
carbonitrile trifluoroacetate
/ -N F O
\N- _NH F I OH
F
186 2-amino-4-(2-furyl)-5H-indeno[1,2-200
O / bjpyridine-3-carbonitrile
trifluoroacetate
/ =N
~N~ NHZ
O
F
F-~OH
F
187 3-amino-1-methyl-5,6,7,8-200
tetrahydroisoquinoline-4-carbonitrile
\ CN trifluoroacetate
N N H2
O
F
1
~
!
O H
F
F
56

CA 02508780 2005-06-09
WO 2004/054505 PCT/US2003/039166
M
K-2
Avg.
IC50
No. Structures Compound Names b (uM)
188 , 2-amino-4-(2-fluorophenyl)-6-(3-200
hydroxyphenyl)nicotinonitrile
F
=N
\N " N Hz
OH
189 2-amino-4-(2-thienyl)-5,6,7,8-200
tetrahydro-3-quinolinecarbonitrile
/ \~
. ~
N
\N ~\ NHz
190 / F 2-amino-4-(3-fluorophenyl)-5,6,7,8-200
tetrahydro-3-quinolinecarbonitrile
/ ~ ~\N
\N' ~ N Hz
191 F 2-(1-piperidinyl)-6-(2-thienyl)-4-200
F F (trifluoromethyl)nicotinonitrile
/ N
S ~ N N
192 F 2-(dimethylamino)-6-(2-thienyl)-4-200
F F (trifluoromethyl)nicotinonitrile
/ N
/
\
S ~ /
~
N
193r 3-Quinolinecarbonitrile,200
\ 2-amino-4-
NHz
methyl- or 2-amino-4-methyl-3-
\ / -N quinolinecarbonitrile
57

CA 02508780 2005-06-09
WO 2004/054505 PCT/US2003/039166
M -2
Avg.
(C50
No. Structures Gompound Name(s)b (uM)
194 O/ 2-amino-4-(4-methoxyphenyl)-6-(2- 200
thienyl)nicotinonitrile
/ N
S i
N NHz
195 NHz 2-amino-6-cyclopropyl-4-(2- 200
methoxyphenyl)nicotinonitriie
- N
O
196 , 2-amino-4-(2-fluorophenyl)-6- 200
phenylnicotinonitrile
'F
=N
/ ~ ~N~NHz ,
197 N (4bS,8aR)-2,4-diamino-4b,5,6,7,8,8a- 200
H N /~ hexahydro[1]benzofuro[2,3-b]pyridine-
z 3-carbonitrile
-- N Hz
,,,~0 N
198 ~ 2-amino-4-(2-fluorophenyl)-5,5- 200
dimethyl-6,8-dihydro-5H-pyrazolo[3,4-
F h]quinoline-3-carbonitrile
=N bis(trifluoroacetate)
N~ l \N~NHz
'N F
H F O
F
F O~H
F O
F
O,- H
58

CA 02508780 2005-06-09
WO 2004/054505 PCT/US2003/039166
MK-2
Avg.
IC50
No.Structures Compound Name(s)b (uM)
199~ 2-amino-4-(2-furyl)-5-phenyl-6,8-200
dihydro-5H-pyrazolo[3,4-h]quinoline-3
carbonitrile trifluoroacetate
,, = N
N ~
\N~ NH2
l
O
H F
1.25 F--~OH
F
200I 3-amino-1,6-dimethyl-5,6,7,8-200
N tetrahydro-2,6-naphthyridine-4-
carbonitrile
CN
i
N NH2
201~N 3-amino-1,7-dimethyl-5,6,7,8-200
tetrahydro-2,7-naphthyridine-4-
CN carbonitrile
N N Hz
202, 2-amino-4-(2-fluorophenyl)-5-phenyl-200
\ 6,8-dihydro-5H-pyrazolo[3,4-
~
\ h]quinoline-3-carbonitrile
- N trifluoroacetate
N~ ~N~NH2
~N
H O
F~ ~
F~OH
~
F
203, 2-amino-4-(2-fluorophenyl)-5-phenyl-200
\ 6,8-dihydro-5H-pyrazolo[3,4-
~
\ h]quinoline-3-carbonitrile
- N trifluoroacetate
N/ \N- _NH2
N
H O
F
F--~O H
F
204O~ NH 4,6-diamino-2-(morpholin-4-ylmethyl)-200
2 ~ N 2,3-dihydrofuro[2,3-b]pyridine-5-
N W '~ carbonitrile
N NHZ
O
F
F--~ O H
F
59

CA 02508780 2005-06-09
WO 2004/054505 PCT/US2003/039166
M K-2
Avg.
IC50
No. Structures Compound Name(s)b (uM)
205 NHZ ethyl (4,6-diamino-5-cyano-2-oxo-2,3- 200
//N dihydro-1 H-pyrrolo[2,3-b]pyridin-1
O ~ yl)acetate
O N~N~NH2 '
~O
206 / ~ 2-amino-4-(2-methoxyphenyl)-6-(5- 200
methyl-2-furyl)nicotinonitrile
0
I ~N
O N"NHZ ,
207 NH2 ~ N 2-amino-6-methyl-4-(4- 200
nitrophenyl)nicotinonitrile
N
/
I / N.:O
I_
O
208 ~O 2-amino-4-(3,4-dimethoxyphenyl)-6-(5 200
methyl-2-furyl)nicotinonitrile
~i
/N
/
O N~ N H2
209 I NHZ 2,4-diamino-6-[(4- 200
/ =N methoxyphenyl)thin]nicotinonitrile
I
S N NHZ
210 NH2 _ 4,6-diamino-2-(phenoxymethyl)-2,3- 200
\ O ~ / dihydrofuro[2,3-b]pyridine-5
~/ carbonitrile
HZN N O
211 4,6-diamino-3-phenyl-2,3- 200
dihydrofuro[2,3-b]pyridine-5-
N\ NH2 ~ carbonitrile
HaN ~ N O
212 4,6-diamino-2-[(2- 200
N NHa methylphenoxy)methyl]-2,3-
dihydrofuro[2,3-b]pyridine-5-
O
carbonitrile
/ O
HzN N

CA 02508780 2005-06-09
WO 2004/054505 PCT/US2003/039166
M
K-2
Avg.
tC50
No. Structures Compound Name(s)b (uM)
213 2-amino-4-(2-furyl)-6-(4-200
methoxyphenyl)nicotinonitrile
N
i
N" N HZ
~
O
/
214 F / 2-amino-4-(3-fluorophenyl)-5,6-200
dihydrobenzo[h]quinoline-3-
carbonitrile trifluoroacetate
/ - N
~N~ N Hz
O
F
F--~OH
F
215 N NH2 2-amino-4-(4-methoxyphenyl)-6,7-200
dihydro-5H-cyclopenta[b]pyridine-3-
carbonitrile
N
i
,o
216 - ~ N 2-amino-9-ethyl-9H-pyrido[2,3-200
\ / I ~ ~ b]indole-3-carbonitrile
N N NH2
217 ~N NHZ 2-amino-6-isobutyl-4-(4-200
methylphenyl)nicotinonitrile
~N
218 N 1-(2-furyl)-3-[(3-hydroxypropyl)amino]-200
5,6,7,8-tetrahydroisoquinoline-4-
H carbonitrile
N~OH
~N
O
61

CA 02508780 2005-06-09
WO 2004/054505 PCT/US2003/039166
M
IC-2
Avg.
IC50
No.Structures Compound Name(s)b (uM
219 2-azepan-1-yl-6-(4-fluorophenyl)-4-200
/ phenylnicotinonitrile
/ N
/ ~N~N
F
220 2-ami no-6-to rt-butyl-4-(4-200
~N NHZ methylphenyl)nicotinonitrile
w
~
N
221~N NH2 2-amino-4-(4-bromophenyl)-6-200
methylnicotinonitrile
~N
Br
222 2-amino-4-thien-2-yl-5,6,7,8,9,10-200
hexahydrocycloocta[b]pyridine-3-
i N carbonitrile
N" NHz
223 2-amino-4-(4-chlorophenyl)-6,7,8,9-200
tetrahydro-5H-cyclohepta[b]pyridine-3
carbonitrile
~\N
NHZ
N
224N \ 2-(allylamino)-5-amino-7-(4-200
\ \ NH2 bromophenyl)thieno[3,2-b]pyridine-3,6
dicarbonitrile
S \\
~
N
Br
225N NH2 2-amino-4-pyridin-3-yl-5,6,7,8,9,10-200
hexahydrocycloocta[b]pyridine-3-
carbonitrile
~
N
N
62

CA 02508780 2005-06-09
WO 2004/054505 PCT/US2003/039166
M K-2
Avg.
IC50
No. Structures Compound Name(s)b uM)
226 2-amino-4-(4-bromophenyl)-6-tert- 200
~N NHz butylnicotinonitrile
W
N
Br
227 N 1-(2-furyl)-3-morpholin-4-yl-5,6,7,8- 200
O tetrahydroisoquinoline-4-carbonitrile
N
N
O
228 N NN2 2-amino-4-(4-methylphenyl)-6,7- 200
dihydro-5H-cyclopenta[b]pyridine-3-
N carbonitrile
i
229 ~N 2-amino-7,7-dimethyl-7,8-dihydro-5H- 200
o I ~ pyrano[4,3-b]pyridine-3-carbonitrile
N NH2
230 ~N NH2 2-amino-6-isobutyl-4-(4- 200
methoxyphenyl)nicotinonitrile
W
N
/
0
231 N NH2 ' 4,6-diamino-2-oxo-1-phenyl-2,3- 200
dihydro-1 H-pyrrolo[2,3-b]pyridine-5-
carbonitrile
o
H N \N~~
s
232 ~ 2-amino-4-(2-methoxyphenyl)-5,6- 200
dimethylnicotinonitrile
O N
\N NH2
63

CA 02508780 2005-06-09
WO 2004/054505 PCT/US2003/039166
- M
fC-2
Avg.
IC50
No.Structures Compound Name(s)b (uM)
233~ 2-(dimethylamino)-4-(2-fluorophenyl)-200
6-(2-furyl)nicotinonitrile
F / N
II
N~N/
O
234~ 2-(dimethylamino)-4-(2-fluorophenyl)-200
6-(2-furyl)nicotinonitrile
F Il
N~N~
O O
F
NO~F
F
23~~ 4-(2-fluorophenyl)-6-(2-furyl)-2-200
(methylamino)nicotinonitrile
F '~ N
II
N~N~
O H
236/ 4-(2-fluorophenyi)-6-(2-furyl)-2-200
I morphoiin-4-ylnicotinonitrile
F
/ =N
\N' _ N \
O ~O
237~ tert-butyl N-[3-cyano-4-(2-200
I fluorophenyl)-6-(2-furyl)pyridin-2-
F yl]glycinate
-N
\N~ I-I
O
O
238~ 2-(ethylamino)-4-(2-fluorophenyl)-6-(2200
I furyl)nicofinonitrile
F
-N
~N~ H~
O
64

CA 02508780 2005-06-09
WO 2004/054505 PCT/US2003/039166
M
K-2
Avg.
IC50
No. Structures Compound Name(s)b (uM)
239 / ethyl4-[6-amino-5-cyano-4-(2-200
fluorophenyl)pyridin-2-yl]benzoate
F
=N
i' ~N~NH2
\I
O
O
240 2-amino-6-(2-fluorophenyl)-4-(3-200
o furyl)nicotinonitrile
trifluoroacetate
=N
~N~ NH2
I
\
F O
+0.35 F OH
F
241 / 6-amino-4-(2-fluorophenyl)-2,2'-200
bipyridine-5-carbonitriie
F ~ trifluoroacetate
=N
\N' _NHZ
\ N _ O
+0.8 F OH
F
24.2~ 2-amino-4-(2-fluorophenyl)-6-thien-2-200
ylnicotinonitrile
hydrate
F
- N
\N_ 'NHZ
I
S
+0.y OH2
243 ~ ethyl6-amino-5-cyano-4-(2-200
fluorophenyl)pyridine-2-carboxylate
F
~N
O ~N~NH2
O
244 \ 2-amino-6-(2-furyl)-4-200
phenylnicotinonitrile
~~N
N" N H2
1
O

CA 02508780 2005-06-09
WO 2004/054505 PCT/US2003/039166
M
K-2
Avg.
IC50
No.Structures Compound Name(s)b uM)
245 ethyl2-amino-3-cyano-4-(2-furyl)-200
O 5,6,7,8-tetrahydroquinoiine-6-
O carboxylate trifluoroacetate
~,N
~
~
N
NH
z
O
F~OH
F
246 2-amino-4-(2-furyl)-6-(4-200
hydroxyphenyl)-5-methylnicotinonitrile
trifluoroacetate
-~N
/ ~N~NHz
I
O
HO \
F-~OH
F
247 2-amino-4-(2-furyl)-6-(4-200
o methoxyphenyl)-5-
methylnicotinonitrile
trifluoroacetate
N
\N" NHz
O
F~OH
F
248 2-amino-6-(4-fluorophenyl)-4-(2-furyl)-200
0 5-methylnicotinonitriie
trifluoroacetate
N
/
\N- - N Nz
~
O
F \
F~OH
F
249~ 2-amino-4-(2-furyl)-5,6-200
o diphenylnicotinonitrile
trifluoroacetate
//N
/ /
\N- -NHz
I
\
O
F~OH
F
66

CA 02508780 2005-06-09
WO 2004/054505 PCT/US2003/039166
M
-2
Avg.
IC50
No.Structures Com ound Names b uM)
250 2-amino-4-(2-furyl)-5-methyl-6-200
o phenylnicotinonitrile
trifluoroacetate
iiN
/ \N' _NHZ
O
F-~OH
F
251 2-amino-6-(3,4-dimethylphenyi)-4-(2-200
- \
furyl)nicotinonitrile
trifluoroacetate
/N
/
/ \N~NHZ
O
F~OH
F
252 2-amino-6-(4-fluorophenyl)-4-(2-200
furyljnicotinonitrile
trifluoroacetate
,N
\N~ N H2
I
F
/ O
F~OH
F
253F / 2-amino-4-(3-fluorophenyl)-6-(3-200
hydroxyphenyl)nicotinonitrile
trifluoroacetate
-N F O
/ \N' _NH I OH
2 F
ON
254F , 6-amino-4-(3-fluorophenyl)-2,4'-200
bipyridine-5-carbonitrile
trifluoroacetate
/ -N F O
/ \N" 'NH ~OH
N 2 F
67

CA 02508780 2005-06-09
WO 2004/054505 PCT/US2003/039166
M
K-2
Avg.
(C50
No.Structures Compound Name(s)b uM)
255, 6-amino-4-(2-fluorophenyl)-2,4'-200
I bipyridine-5-carbonitrile
F ~ trifluoroacetate
~N F O
\N" NH I OH
N\ J 2 F
255 2-amino-4-butyl-6-methylnicotinonitrile200
trifluoroacetate
//N O
F
HO~
F
N_ _NHZ
F
257 2-amino-6-methyl-4- 200
propyinicotinonitrile
trifluoroacetate
~iN O
~ F
HO~
F
N- 'NH2
258 2-amino-4-ethyl-6-methylnicotinonitrile200
~~N O trifluoroacetate
F
I ~
HO ~
F
N_ _NH2
F
259 2-amino-4,6-dimethylnicotinonitrile200
'
N
O trifluoroacetate
'
i
I ~ HO~F
N N H2 F
F
260~ 2-amino-4-[2-(hexyloxy)phenyl]-6,7-200
~ I dihydro-5H-pyrazolo[3,4-h]quinoline-3
~
\ 'o carbonitrile bis(trifluoroacetate)
N
/
I
~
NHZ
HN \ N
~
N-'
O O
F--~OH F-~OH
F F
68

CA 02508780 2005-06-09
WO 2004/054505 PCT/US2003/039166
~.., i ~ ~ ~." ~ ,
MK_2
Avg.
IC50
No. Structures Compound Name(s)b uM)
261 OH 2-amino-4-[2-(beta-D-200
glucopyranosyl0xy)phenyl]-6,7-
HO",u, O dihydro-5H-pyrazolo[3,4-h]quinoline-3
~
I carbonitrile bis(trifluoroacetate)
HO ~ O ,/N
OH
I
N NH2
HN \
N
O O
F--~OH F-~OH
F F
262 ~ 4-[2-(allyloxy)phenyl]-2-amino-6,7-200
I dihydro-5H-pyrazolo[3,4-h]quinoline-3
O ~ carbonitrile bis(trifluoroacetate)
i~N
I
HN \ N~NH2
N
O
F F~ ~
F OHF~OH
F ~F
263 methyl [2-(2-amino-3-cyano-6,7-200
~ dihydro-5H-pyrazolo[3,4-h]quinoiin-4-
I
O ~ yl)phenoxy]acetate
N
O i~ bis(trifluoroacetate)
I
~
NHZ
HN \ N
N
O
F' ~]
F OHF~OH
F IF
264 ~ 2-amino-4-(2-ethoxyphenyl)-6,7-200
dihydro-5H-pyrazolo[3,4-h]quinoiine-3
/~O ~ carbonitrile bis(trifluoroacetate)
~~N
I
HN \ N~NH2
\N-
O O
F' ~]
F OH F~OH
F IF
265 NH2 ethyl4-[2-amino-3-cyano-6-(2-200
~ -N furyl)pyridin-4-yl]-1H-pyrrole-2-
N carboxylate
\ o
O I H O
69

CA 02508780 2005-06-09
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M
IC-2
Avg.
iC50
No.Structures Compound Name(s)b (uM)
266~ =N 2-amino-6-methylnicotinonitrile200
hydrochloride
N NHZ
GH
267 2-amino-6-(4-cyanophenyl)-4-(2-200
o furyl)nicotinonitrile
trifluoroacetate
,N
\N~NH
z
O
N~
F~OH
F
268 2-amino-6-(4-fluorobenzyl)-4-(2-200
o furyl)nicotinonitrile
trifluoroacetate
~N
F
\ /
~
NH2
\N
O
F~OH
F
269 2-amino-5-(4-fluorophenyi)-4-(2-200
w
F furyl)-6-methylnicotinonitrile
~ o
\ trifluoroacetate
~ N
i
N NH2
O
F~ ~
F-I" 'OH
~F
270, 2-amino-4-(2-furyl)-6-(4-200
\ o methoxyphenyl)nicotinonitrile
trifluoroacetate
=N
\N' _NHz
F O
F---~OH
F
271/ 2-amino-4-(2-methylphenyl)-5,6,7,8-200
tetrahydroquinoline-3-carbonitrile
o trifluoroacetate
- N F
HO~ F
\N NHZ F
7~

CA 02508780 2005-06-09
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M
K-2
Avg.
IC50
No. Structures Compound Name(s)b uM)
272 O~ 2-amino-4-(4-methoxyphenyl)-5,6,7,8200
tetrahydroquinoline-3-carbonitrile
trifluoroacetate
0
/ =N F
HO~F
~N NHZ F
273 , 2-amino-4-phenyl-5,6,7,8-200
tetrahydroquinoline-3-carbonitrile
/ =N
N NH2
274 ~ 2-amino-6-(4-methoxyphenyl)-4-(2-200
~ methylphenyl)nicotinonitrile
\ trifluoroacetate
=N
/ \N~NHz
O
F
~OH
F F
275 ~O 2-amino-4,6-bis(4- 200
methoxyphenyl)nicotinonitrile
trifluoroacetate
/ =N
\N- _NHZ
O
F
~OH
F F
276 G , 2-amino-4-(3-chlorophenyl)-6-(4-200
methoxyphenyl)nicotinonitrile
trifluoroacetate
=N O
F
~
/ \N' _NHZ Fw-~OH
l
F
\
277 ~. 2-amino-4-(2-chlorophenyl)-6-(4-200
methoxyphenyl)nicotinonitrile
G \ trifluoroacetate
=N F O
/ \N' _NH2 F-~OH
I
F
\
71

CA 02508780 2005-06-09
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M
-2
Avg.
IC50
No. Structures Compound Name(s)b (uM)
278 2-amino-4-(2-furyl)-5,6,7,8-200
w
O tetrahydro-1 6-naphthyridine-3-
F ~ O
F--~OH ~ N carbonitrile bis(trifluoroacetate)
F HN / i
F
~II
'
\N NH~~OH
F
279 2-amino-4-(2-fury()-6-(4-200
\ o methylphenyl)nicotinonitrile
,,N
\N' _ NH2
280 NHZ 2-amino-4-(2-furyl)-6-200
phenylnicotinonitrile
0
i
281 6-amino-4-(2-furyl)-2,3'-bipyridine-5-200
O carbonitriie
/~N
~
N'' ~N
NHZ
282 2-amino-6-(1,3-benzodioxol-5-yl)-4-(2200
w
\ o furyl)nicotinonitrile
i~N
~
O ~ ~N
NHZ
O \
283 N ~ \ 2-amino-4-isoquinolin-4-yl-6-(4-200
methoxyphenyl)nicotinonitrile
trifluoroacetate
-N F O
\N"NHZ F--~OH
I
F
\
284 ~ 2-amino-4-(1-benzothien-3-yl)-6-(4-200
methoxyphenyl)nicotinonitrile
trifluoroacetate
~N F O
\N- _NH2 F--r 'OH
~ ~
w0 \
F
72

CA 02508780 2005-06-09
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M
K-2
Avg.
IC50
No.Structures Com ound Name(s)b (uM
285~ S 2-amino-6-(4-methoxyphenyl)-4-thien-200
3-ylnicotinonitrile
trifluoroacetate
-N F O
\N' _NHz F--~ON
I
F
\
286~ O 2-amino-4-(3-furyl)-6-(4-200
methoxyphenyl)nicotinonitrile
trifluoroacetate
-N F O
\N" NH2 F-~OH
I
w0 \
F
287~ 2-amino-6-(4-methoxyphenyl)-4-(1200
H-
pyrrol-2-yl)nicotinonitrile
trifluoroacetate
-N F O
\N' _NHz F--~OH
~
F
\
288 2-amino-4-(2-furyl)-6-(1200
H-pyrrol-2-
\ o yl)nicotinonitrile
iN
N
~N NHZ
289N,. 2'-amino-6'-(4-methoxyphenyl)-8,4'-200
bipyridine-3'-carbonitrile
trifluoroacetate
N.
O
F
\N NHZ F--~OH
~O \ F
290\ 2-amino-4-[2- 200
F F ~ (trifluoromethoxy)phenyl]-6,7-dihydro-
5H-pyrazolo[3,4-h]quinoline-3-
iN carbonitrile bis(trifluoroacetate)
\
HN \ I N- _NHz
N-
O O
F--~OH F--~OH
F F
73

CA 02508780 2005-06-09
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M
K-2
Avg.
IC50
No. Structures Compound Name(s)b (uM)
291 _ 2-amino-4-(2-furyl)-5H-200
o thiochromeno[4,3-b]pyridine-3-
~ N carbonitrile trifluoroacetate
s
N- ' N Hz
O
F
F~OH
F
292 i N 2-amino-4-{4-[(2- 200
~
~ N cyanoethyl)(methyl)amino]phenyl}-6,7-
dihydro-5H-pyrazolo[3,4-h]quinoline-3
carbonitrile bis(trifluoroacetate)
N
HN \ N~NHz
~ N-
O O
F F
F--~OH F-~OH
F F
293 ~ 2-amino-4-[2-(2- 200
hydroxyethoxy)phenyl]-6,7-dihydro-5H
Ho~O ~ pyrazolo[3,4-h]quinoline-3-carbonitrile
i~N bis(trifluoroacetate)
HN \ N~NHZ
F p F O
F-~OH F--~OH
F F
294 2-amino-4-(2-methylphenyl)-6,7-200
~ dihydro-5H-pyrazolo[3,4-h]quinoline-3
carbonitrile bis(trifluoroacetate)
~~N
HN \ N~NH2
N
O O
F--~OH F--~OH
F F
74

CA 02508780 2005-06-09
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M
K-2
Avg.
iC50
No.Structures Compound Name(s)b uM)
295wNi 2-amino-4-[4-(dimethylamino)phenyl]-200
6,7-dihydro-5H-pyrazolo[3,4-
h]quinoline-3-carbonitrile
bis(trifluoroacetate)
N
I
HN \
N~NHZ
N
O O
F--~ON F-~OH
F F
296~ \ 2-amino-4-(1 H-indol-7-yl)-6,7-dihydro-200
5H-pyrazoio[3,4-h]quinoline-3-
~
N carbonitrile bis(trifluoroacetate)
H i
N
i
HN \ N"NHZ
~-
O
F
F
F--~OH F~OH
F F
297~O O methyl4-(2-amino-3-cyano-6,7-200
dihydro-5H-pyrazolo[3,4-h]quinolin-4-
yi)benzoate bis(trifluoroacetate)
i
/,N
HN \ N~NH2
~N-
O O
F--r -OH F~OH
~F IF
298\ methyl2-(2-amino-3-cyano-6,7-200
dihydro-5H-pyrazolo[3,4-h]quinolin-4-
yl)benzoate bis(trifluoroacetate)
O .%N
HN \ N~NHz
~
N-'
O O
F
F-~OHF~OH
F

CA 02508780 2005-06-09
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M K-2
Avg.
IC50
No. Structures Compound Name(s)b (uM)
299 ~ [2-(2-amino-3-cyano-6,7-dihydro-5H- 200
pyrazolo[3,4-h]quinolin-4
Ho~o i' yl)phenoxy]acetic acid
'oI ~ iN bis(trifluoroacetate)
HN \ ~ N~NHZ
ON-
F F O
F-I'~OH F~OH
F F
300 , =N 2-amino-6-phenylnicotinonitrile 200
~ hydrochloride
~N N-H
W
CI H
301 , =N 2-amino-6-cyclohexylnicotinonitrile 200
hydrochloride
'N N-H
I
H
CI H
302 2-amino-4-(2-furyl)-6-(1-trityl-1H- 200
pyrazol-4-yl)nicotinonitrile
=N
i ~
\N- _NH2
303
/ 2-amino-4-(2-fluorophenyl)-6-(4- 200
hydroxyphenyl)nicotinonitrile
F
=N
\N- _NH2
HO
Notes:
a: The aminocyanopyridine compound may be shown with a solvent, such as, for
example, trifluoroacetate, with which it can form a salt. Both the salt and
acid forms of the
aminocyanopyridine compound are included in the present invention.
b: Compound names generated by ACDIName software.
76

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[00044] In another embodiment, the method of the present invention
comprises the administering to the subject an aminocyanopyridine
compound having the structure shown in formula I, where:
R1 is selected from the group consisting of -H, methyl, ethyl, propyl,
butyl, -(CH2)COOH, phenyl, pyridyl, dimethylaminoethyl, methoxyethyl,
tetramethylaminoethyl, carboxymethyl, and phenylacetyl;
R2 is selected from the group consisting of -H, methyl, ethyl, propyl,
butyl, amino, phenyl, methoxy, carboxy, carboxymethyl,
hydroxyethylamino, propylamino, ethylamino, methylamino, methoxyethyl,
ethoxyethylamino, aminoethylamino, benzylamino,
dimethylaminoethylamino, phthaloaminoethyl, fluorophenyl, difluorophenyl,
chlorophenyl, bromophenyl, furyl, carbamylpyrryl, methyl-1,3-isodiazoyl,
1,3-isodiazoyl, 1,3,4-triazoyl, methoxyphenyl, -S(CH3),
tetramethylaminoethyl, acetylaminophenyl, methoxyphenylamino,
carboxyphenyl, carboxy-3-isopyrryl, cyanophenyl, cyclopropyl,
phenoxyphenyl, pyridyl, dihydroxybromophenyl, difluoromethoxyphenyl,
trifluoromethylphenyl, trifluoromethylfluorophenyl, hydroxyphenyl,
methylaminomethyl, methylaminoethyl, thiophyl, pyrryl, aminomethyl,
0
~ o \
and
° ~ CH3
R3 is selected from the group consisting of -H, methyl, ethyl, propyl,
isopropyl, cyano, aminomethyl, phenyl, fluorophenyl, and amino;
wherein the R2 and R3 groups are such that they optionally join to
form a ring system selected from the group consisting of:
77

CA 02508780 2005-06-09
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H31
J\ N
N
and
s w
R4 is selected from the group consisting of -H, methyl, ethyl, propyl,
hydroxy, furyl, methylfuryl, methylimidazolyl, phenyl, hydroxyphenyl,
carboxyphenyl, pyrazolyl, hydroxy, dihydroxyphenyl, methoxyphenyl,
chlorophenyl, bromophenyl, fluorophenyl, dichiorophenyl,
dihydroxyborophenyl, thienyl, pyrryl, N-methylpyrryl, pyridyl, methylthio,
methylsulfonylphenyl, carboethoxyphenyl, methoxy, carbamylphenyl,
mercapto, N-isoimidazoylphenyl, isopropyl, amino, hydroxynaphthyl,
thiazoyl, carboxymethylphenyl, trifluoromethylphenyl, methylphenyl,
cyanophenyl, dimethylphenyl, fluorobenzhydryl, methoxyfuryl,
aminosulfonylphenyl,
\ s \ ° \
,and ~ ,
/ N / °
H
wherein the R~ and R4 groups are such that they optionally join to
form a ring system selected from the group consisting of:
78

CA 02508780 2005-06-09
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ft14
ft13
ft15 \'
ft16
X17
w a
ft10.--. ~ ,
ft1g-- ~ ~ Rav
~~~12
Fil1 19
R23
r
~fl
ft25~--...
,
R2s G
ft27
R25 R2s ftao ft~'
,
R~+d
R56
ft57 ft55
ft5 ftss~\, r
ft5; . , ,
R5~/~ ~G
ft60 ~ ~ ft62
ft81
7 ,/
ft72 ft71
~ / -~r
and
\ ft73 ~
~, ,
~~ ft76
ft75
H"'"

CA 02508780 2005-06-09
WO 2004/054505 PCT/US2003/039166
D, E and G are each independently selected from the group
consisting of carbon, oxygen, sulfur, and nitrogen;
R5 is selected from the group consisting of -H, and C1-C5 alkyl; and
wherein the R1 and R5 groups can join to form a piperidyl ring;
R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, Ri9, R20,
R21 R22 R23 R24 R25 R26 R27 R28 R29 R30 R31 R32 R33 R34 R35 R36
s s s s a s ~ s a a a ~ s o r ,
R37~ R38~ R39~ R40~ R41 ~ R42s R43~ R44~ R45~ R46~ R47~ R48~ R49, R50, R51,
R52.
R53 R54 R55 R56 R57 R58 R59 R60 R61 R62 R63 R64 R65 R66 R67 R68
s ~ r s s ~ r > > s s s s ~ r ,
R6s, R7o R71, R72, R73, R74, R75, and R76 are each optionally present (for
example, they can be present when required to balance the valence of the
atom to which they are shown as being bound) and are each
independently selected from the group consisting of -H, methyl, ethyl,
propyl, butyl, isobutyl, amino, nitro, hydroxy, methoxy, ethoxy, propoxy, 2-
propenoxy, oxo, carboxy, bromo, chloro, fluoro, trifluoromethyl,
chloromethyl, hydroxymethyl, dicyanomethyl, 2-fluorophenyl, 3-
fluorophenyl, hydroxyethoxy, ethoxyethoxy, -(CH2)-O-(C6H4)-O-(CH3),
carboxymethoxy, isopropylcarboxymethoxy, isobutylcarboxymethoxy,
methylamino, dimethylamino, aminoethoxy, diaminoethoxy,
dimethylaminoethoxy, cyanomethoxymethyl, 2-propenoxymethyl,
methoxymethyl, isopropoxymethyl, ethoxymethyl, -(CH2)-O-(CF2)-CHF2,
isobutoxymethyl, benzoyl, phenyl, N-morpholinyl, morpholinylethoxy,
pyrrolidylethoxy, N pyrroiidyiethoxy, oxo, ethylcarboxy, carboxymethyl
ethyl ester, pyridylmethyl, 4-pyridylmethoxy, 2-pyridylmethyl, and -COO
CH2-CH3; and
wherein R38 and R39 are such that they optionally join to form a ring
system of the type selected from the group consisting of:
o ~~ o
and
o ~~ o

CA 02508780 2005-06-09
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[00045] In another embodiment, the present method can be practiced
by the administration of an aminocyanopyridine compound that provides
an ICSO of less than about 200 ~,M, in an in vitro assay of MK-2 inhibitory
activity. Examples of such compounds comprise the compound shown in
formula I, where:
R1 is selected from the group consisting of -H, methyl, ethyl, -
(CH2)COOH, and phenyl;
R2 is selected from the group consisting of -H, methyl, ethyl, amino,
phenyl, methoxy, carboxy, hydroxyethylamino, propylamino, ethylamino,
methylamino, methoxyethyl, ethoxyethylamino, aminoethylamino,
benzylamino, dimethylaminoethylamino, fluorophenyl, difluorophenyl,
chlorophenyl, bromophenyl, furyl, carbamylpyrryl, methyl-1,3-isodiazoyl,
1,3-isodiazoyl, 1,3,4-triazoyl, methoxyphenyl, -S(CH3), acetylaminophenyl,
methoxyphenylamino, carboxyphenyl, cyanophenyl, cyclopropyl,
phenoxyphenyl, pyridyl, dihydroxybromophenyl, difluoromethoxyphenyl,
trifluoromethylphenyl, trifluoromethylfluorophenyl, hydroxyphenyl,
0
O \ O
and
O ~ CH3
R3 is selected from the group consisting of -H, methyl, ethyl, propyl,
isopropyl, cyano, and aminomethyl;
wherein the R2 and R3 groups are such that they optionally join to
form a ring system selected from the group consisting of:
81

CA 02508780 2005-06-09
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. _. . ,
NH
and
R4 is selected from the group consisting of -H, methyl, ethyl, propyl,
hydroxy, furyl, indolyl, methylfuryl, methylimidazolyl, phenyl,
hydroxyphenyl, carboxyphenyl, pyrazolyl, hydroxy, dihydroxyphenyl,
methoxyphenyl, chlorophenyl, dichlorophenyl, dihydroxyborophenyl,
thienyl, pyrryl, N-methylpyrryl, pyridyl, methylthio, methylsulfonylphenyl,
carboethoxyphenyl, methoxy, carbamylphenyl, N-isoimidazoylphenyl,
amino, hydroxynaphthyl, thiazoyl, carboxymethylphenyl,
aminosulfonylphenyl, and
S
N I /
wherein the R3 and R4 groups are such that they optionally join to
form a ring system selected from the group consisting of:
82

CA 02508780 2005-06-09
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R
Rip_ , >
E R
R1~ R12
R~~
7~
~p R ~/
and
R~3 E
~~ R7s
R75
D, E and G are each independently selected from the group
consisting of carbon, oxygen, sulfur, and nitrogen;
R5 is selected from the group consisting of -H, and Ci-C5 alkyl;
R6 R7 R8 R9 R10 R11 R12 R13 R14 R15 R16 R17 R18 R19 R20
a s s s ~ s ~ i s ~ s s r s a
R31 R32 R33 R34 R35 R36 R37 R38 R39 R40 R41 R42 R43 R44 R45 R46
s ~ s s ~ s s ~ s s s ~ s > > ,
R71, R72, R73y R74, R75, and R76 are each optionally present (such as when
required to balance the valence of the atom to which they are shown as
being bound) and are each independently selected from the group
consisting of - H, methyl, ethyl, butyl, amino, nitro, hydroxy, methoxy,
ethoxy, oxo, 2-propenoxy, carboxy, bromo, chloro, fluoro, trifluoromethyl,
83
R-., H._

CA 02508780 2005-06-09
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chloromethyl, hydroxymethyl, dicyanomethyl, hydroxyethoxy,
ethoxyethoxy, -(CH2)-O-(C6H4)-O-(CH3), carboxymethoxy,
isopropylcarboxymethoxy, methylamino, dimethylamino, aminoethoxy,
diaminoethoxy, cyanomethoxymethyl, methoxymethyl, isopropoxymethyl,
ethoxymethyl, -(CH2)-O-(CF2)-CHFz, isobutoxymethyl, phenyl,
morpholinylethoxy, pyrrolidylethoxy, N pyrrolidylethoxy, and pyridylmethyl,
and
wherein R3$ and R39 are such that they optionally join to form a ring
system of the type selected from the group consisting of:
o ~~ o
, and
o ~~ o
[00046 In another embodiment, the present method can be practiced
by the administration of an aminocyanopyridine compound that provides
an ICSO of less than about 100 p.M, in an in vitro assay of MK-2 inhibitory
activity. Examples of such compounds comprise the compound shown in
formula I, where:
R1 is selected from the group consisting of -H, methyl, and ethyl;
R2 is selected from the group consisting of -H, methyl, amino,
phenyl, methoxy, hydroxyethylamino, propylamino, ethylamino,
methylamino, methoxyethyl, ethoxyethylamino, aminoethylamino,
benzylamino, dimethylaminoethylamino, fluorophenyl, difluorophenyl,
chlorophenyl, bromophenyl, furyl, carbamylpyrryl, methyl-1,3-isodiazoyl,
1,3-isodiazoyl, 1,3,4-triazoyl, methoxyphenyl, -S(CH3), acetylaminophenyl,
methoxyphenylamino, carboxyphenyl, cyanophenyl, cyclopropyl,
phenoxyphenyl, pyridyl, dihydroxybromophenyl, difluoromethoxyphenyl,
and
84

CA 02508780 2005-06-09
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<r
R3 is selected from the group consisting of -H, methyl, ethyl, propyl,
isopropyl, and cyano;
wherein the R2 and R3 groups are such that they optionally join to
form a ring system selected from the group consisting of
-~._
NH
and
R4 is selected from the group consisting of -H, methyl, ethyl, propyl,
hydroxy, furyl, indolyl, methylfuryi, methylimidazolyl, phenyl,
hydroxyphenyl, carboxyphenyl, pyrazolyl, hydroxy, dihydroxyphenyl,
methoxyphenyl, chlorophenyi, dichiorophenyl, dihydroxyborophenyl,
thienyl, pyrryl, N-methylpyrryl, pyridyl, methylthio, methylsulfonylphenyl,
carboethoxyphenyl, methoxy, carbamylphenyl, amino, and
aminosulfonylphenyl;
wherein the R3 and R4 groups are such that they optionally join to
form a ring system selected from:
85

CA 02508780 2005-06-09
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R7 ~a
R1
Rio_ \ ,
~E-.-\ Ri
Rii R12
Rna
R72
R71
D
and R73 E
/\
R74
~~ R76
R~~ R-., n._ R7s
D, E and G are each independently selected from the group
consisting of carbon, oxygen, sulfur, and nitrogen;
R5 is -H;
'rJ R6 R7 R8 R9 R10~ Rii~ R12 R13 R14 R15 R16 R17 Ri8 R19~ R20~
s > > > > s s a s s
R , R 6, R , R ~ R39~ R40~ R41 ~ R42~ R71 s R7 ~ R 3~ R74~ R7b~ and R76 are
each optionally present (such as when required to balance the valence of
the atom to which they are shown as being bound) and are each
independently selected from the group consisting of - H, methyl, ethyl,
butyl, amino, nitro, hydroxy, methoxy, ethoxy, oxo, 2-propenoxy, carboxy,
bromo, fluoro, trifluoromethyl, chloromethyl, dicyanomethyl,
hydroxyethoxy, ethoxyethoxy, -(CH2)-O-(C6H4)-O-(CH3), carboxymethoxy,
isopropylcarboxymethoxy, methylamino, dimethylamino, aminoethoxy,
diaminoethoxy, phenyl, morpholinylethoxy, pyrrolidylethoxy, N
pyrrolidylethoxy, and pyridylmethyl, and
wherein R3$ and R39 are such that they optionally join to form a ring
system consisting of:
C
86

CA 02508780 2005-06-09
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[00047] In another embodiment, the present method can be practiced
by the administration of an aminocyanopyridine compound that provides
an 1C5Q of less than about 50 p.M, in an in vitro assay of MhC-2 inhibitory
activity. Examples of such compounds comprise the compound shown in
formula I, where:
R1 is selected from the group consisting of -H, methyl, and ethyl;
R2 is selected from the group consisting of -H, methyl, amino,
phenyl, methoxy, hydroxyethylamino, propylamino, ethylamino,
methylamino, methoxyethyl, ethoxyethylamino, aminoethylamino,
benzylamino, dimethylaminoethylamino, fluorophenyi, difiuorophenyl,
chlorophenyl, bromophenyl, furyl, carbamylpyrryl, methyl-1,3-isodiazoyl,
1,3-isodiazoyl, 1,3,4-triazoyl, methoxyphenyl, -S(CH3), acetylaminophenyl,
methoxyphenylamino, carboxyphenyl, and
<~,~
R3 is selected from the group consisting of -H, methyl, ethyl, propyl,
and isopropyl;
wherein the R2 and R3 groups are such that they optionally join to
form a ring system consisting of
y
R4 is selected from the group consisting of -H, methyl, ethyl, propyl,
furyl, indolyl, methylfuryl, methylimidazolyl, phenyl, hydroxyphenyl,
carboxyphenyl, pyrazolyl, hydroxy, dihydroxyphenyl, methoxyphenyl,
87

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chlorophenyl, dichlorophenyl, dihydroxyborophenyl, thienyl, pyrryl, N-
methylpyrryl, pyridyl, methylthio, methylsulfonylphenyl, carboethoxyphenyl,
and aminosulfonylphenyl;
wherein the R3 and R4 groups are such that they optionally join to
form a ring system selected from:
Rio_ \ , and
~E-'
Rii R12
R72
R71
D
R73-
R~ \
~~ R7s
R7s
D, E and G are each independently selected from the group
consisting of carbon, oxygen, sulfur, and nitrogen;
R5 is -H;
R6 R7 R8 R9 R10 R11 R12 R35 R36 R37 R38 R39 R40 R41 R42
~ s s s s ~ s ~ s s s ~ s ~ s
R71, R72, R7s, R74, R75, and R76 are each optionally present (such as when
required to balance the valence of the atom to which they are shown as
being bound) and are each independently selected from the group
consisting of - H, methyl, ethyl, butyl, amino, nitro, hydroxy, methoxy,
ethoxy, oxo, 2-propenoxy, carboxy, bromo, fluoro, trifluoromethyl,
chloromethyl, dicyanomethyl, hydroxyethoxy, ethoxyethoxy,
carboxymethoxy, isopropylcarboxymethoxy, methylamino, dimethylamino,
88

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aminoethoxy, diaminoethoxy, morpholinylethoxy, pyrrolidylethoxy, N
pyrrolidylethoxy, and pyridylmethyl, and
wherein R3$ and R39 are such that they optionally join to form a ring
system consisting of:
cod,
[00048] In another embodiment, the present method can be practiced
by the administration of an aminocyanopyridine compound that provides
an ICSO of less than about 20 p.M, in an in vitro assay of MK-2 inhibitory
activity. Examples of such compounds comprise the compound shown in
formula I, where:
Ri is -H;
R2 is selected from the group consisting of amino, phenyl,
fluorophenyl, difluorophenyl, furyl, carbamylpyrryl, methyl-1,3-isodiazoyl,
1,3-isodiazoyl, 1,3,4-triazoyl, methoxyphenyl, acetylaminophenyl,
methoxyphenylamino, and carboxyphenyl;
R3 is selected from the group consisting of -H, methyl, ethyl, and
propyl;
R4 is selected from the group consisting of methyl, ethyl, propyl,
furyl, phenyl, hydroxyphenyl, carboxyphenyl, pyrazolyl, hydroxy,
dihydroxyphenyl, methoxyphenyl, chlorophenyl, dihydroxyborophenyl, and
aminosulfonylphenyl;
89

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wherein the R3 and R4 groups are such that they optionally join to
form a ring system selected from the group consisting of:
R36 R35
R3$
f
and
R1~~ ' ' D
39'/
R E .G
E ~ 40 R41 \R42
R~ ~R12 R
R72
R71
D
R73
l ~ '
R7 ~ \
~~ R76
R75
D, E and G are each independently selected from the group
consisting of carbon, oxygen, sulfur, and nitrogen;
R5 is -H;
R6 R7 R8 R9 R10 Ri 1 R12 R35 R36 R37 R33 R39 R40 R41 R42
~ s s ~ s s ~ s r s r > > s s
R71, R72, R73, R74, R75, and R76 are each optionally present (such as when
required to balance the valence of the atom to which they are shown as
being bound) and are each independently selected from the group
consisting of - H, amino, nitro, hydroxy, methoxy, ethoxy, oxo, 2-
propenoxy, carboxy, bromo, fluoro, trifluoromethyl, chloromethyl,
dicyanomethyl, hydroxyethoxy, ethoxyethoxy, carboxymethoxy,
isopropylcarboxymethoxy, methylamino, dimethylamino, aminoethoxy,
diamlnoethoxy, morpholinylethoxy, pyrrolidylethoxy, and pyridyfmethyl,
and
wherein R38 and R39 are such that they optionally join to form a ring
system consisting of:

CA 02508780 2005-06-09
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[00049] In an embodiment of this invention, the present method can be
practiced by the administration of an aminocyanopyridine tricyclic
compound having the structure shown in formula II:
R37 R36 R35 N[-i-R2
R3s
R39i ~ wG~ wN,~ wNH_Ri
R40 R41
wherein:
G is selected from the group consisting of - O -, - S -, and -N-;
when G is -O-, R41 and R4z are absent;
when G is -S-, R41 and R42 are optionally absent, or are oxo;
when G is -N-, R41 is absent, and R42 is -H or C1-C4-alkyl;
each of R1, R2, R35, R36, R3', R38, R39, and R4° is independently
selected from the group consisting of
hydrogen, hydroxy, amino, halo, nitro,
branched or unbranched C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl,
C1-C6 alkoxy, hydroxy C1-C6 alkyl, hydroxy C1-C6 alkoxy, C1-C6 alkoxy C1-
C6 alkoxy, C1-C6 alkoxy C1-C6 alkyl, C1-C6 alkenoxy,
branched or unbranched amino C1-C6 alkyl, diamino C2-C6 alkyl, C1-
C6 alkylamino Ci-C6 alkyl, C1-C6 alkylamino, di-( Ci-C6 alkyl)amino, C1-C4
alkoxyarylamino, C1-C4 alkoxyalkylamino, amino C1-C6 alkoxy, di-(C1-C4
alkylamino, C2-C6 alkoxy, di-(C1-C6 alkyl)amino C~-C6 alkyl, C1-C6
alkylamino C1-C6 alkoxy, halo C1-C6 alkoxy, dihalo C1-C6 alkoxy, trihalo C1-
91

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C6 alkoxy, cyano C1-C6 alkyl, dicyano Ci-C6 alkyl, cyano C1-C6 alkoxy,
dicyano C1-C6 alkoxy, carbamyl C1-C4 alkoxy, heterocyclyl C1-C4 alkoxy,
heteroaryl C1-C4 alkoxy, sulfo, sulfamyl, C1-C4 alkylaminosulfonyl, hydroxy
C1-C4 alkylaminosulfonyi, di-(C1-C4 aikyl)aminosulfonyl, C1-C4 alkylthio, C~-
C4 alkylsulfonyl, C1-C4 alkylsulfinyl,
aryl, aryl C1-Cs alkyl, heterocyclyl C1-C6 alkyl, heteroaryl Ci-C6 alkyl,
heterocyclyl C1-C6 alkoxy, heteroaryl Cj-C6 alkoxy, aryl C1-C6 alkoxy,
where the aryl ring can be substituted or unsubstituted, and, if substituted,
the substituent group is selected from one or more of the group consisting
of C1-C6 alkyl, halo, amino, and C1-C6 alkoxy,
substituted or unsubstituted Cs-C6 cyclyl, Cs-C6 heterocyclyl, and, if
substituted, the substituent group is selected from one or more of the
group consisting of C1-C6 alkyl, Ci-C6 alkoxy, halo, amino, and where the
C~-C6 heterocyclyl ring contains O, S, or N,
branched or unbranched C1-C6 alkoxycarbonyl C1-C6 alkoxy, and
carboxy, carboxy C1-C6 aikoxy, carboxy C1-C6 alkyl, hydroxy Ci-C4
alkoxycarbonyl, C1-C4 alkoxycarbonyl,
where R38 and R39 are such that they optionally join to form a ring
system of the type selected from
O ~.~ o z, i
an ''~d
O ~~ o
[00050] And where the terms "alkyl, alkenyl, alkynyl, alkoxy, a(koxyalkyl,
haloalkoxy, halo, alkylthio, alkylthioalkyl, heterocyclyl, cyclyl, aryl,
heteroaryl, cycloaryl, and oxo" have the same meanings as described
above.
[00051] The tricyclic aminocyanopyridine compounds that are useful in
the present invention include benzonapthyridines, pyridochromanes, and
pyridothiochromanes.
92

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[00052] Examples of tricyclic arriinocyanopyridine compounds that are
useful as MK-2 inhibitors in the present method are shown in Table II:
TABLE 2: Tricyclic Aminocyanopyridine MK-2 Inhibitors
93

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MK-2
Avg.
IC50
No. Structures Compound Name(s)b (uM)
1 NH2 2,4-diamino-7,8-dihydroxy-5H-0.125
Ho , , -N chromeno[2,3-b]pyridine-3-
carbonitrile trifluoroacetate
HO ~ O ~N NHZ
O
F
F--~OH
F
2 . NH2 2,4-diamino-8-hydroxy-5H-0.187
=N chromeno[2,3-b]pyridine-3-
carbonitrile hydrochloride
HO O N NHZ
Cl H
3 HN~OH 2-amino-7,8-dihydroxy-4-[(2-0.237
hydroxyethyl)amino]-5H-
HO ~ ~ CN chromeno[2,3-b]pyridine-3-
carbonitrile trifluoroacetate
' ~
I,
HO
O
N N HZ
O
C' -OH
03 F
1
3
.
4 I NH2 2,4-diamino-7,8-dimethoxy-5H-0.335
O ~ ~ =N chromeno[2,3-b]pyridine-3-
carbonitrile
I O N NHz
HN~ 2-amino-7,8-dihydroxy-4-0.403
(propylamino)-5H-chromeno[2,3-
HO ~ ~ CN b]pyridine-3-carbonitrile
trifluoroacetate
HO ~ O N N H2
O
F
~OH
0
79
.
F F
6 HN~ 2-amino-4-(ethylamino)-7,8-0.419
dihydroxy-5H-chromeno[2,3-
HO ~ ~ cN b]pyridine-3-carbonitrile
trifluoroacetate
~
~
HO
~ O
N NH2
O
.99
F3C~0 N
7 NH2 2,4-diamino-9-hydroxy-5H-0.459
CN chromeno[2,3-b]pyridine-3-
carbonitrile trifluoroacetate
O"N' _NN2
OH
CF3 COOH
94

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8 NH2 2,4-diamino-9-fluoro-5H- 0.471
CN chromeno[2,3-b]pyridine-3-
~ ~ carbonitrile
O- _N_ _NH2
F CF3C02H
9 NH2 2,4-diamino-7-hydroxy-5H- 0.473
HO ~ N chromeno[2,3-b]pyridine-3-
carbonitrile trifluoroacetate
0' _ N' _ NH2
O
F'~
1.5 F~OH
'F
NH2 2,4-diamino-8-(2-hydroxyethoxy)-5H- 0.483
~~N chromeno[2,3-b]pyridine-3-
carbonitrile trifluoroacetate
~O I ~ O I N NH2
HO O
C 3r 'OH
11 NH2 8,10-diamino-2,3-dihydro-11H- 0.488
o / , =N [1,4]dioxino[2',3':6,7]chromeno[2,3-
b]pyridine-9-carbonitrile
Co ~ O ~N NHZ trifluoroacetate
O
F
F--~OH
F
12 NH2 2,4,7-triamino-5H-chromeno[2,3- 0.514
H2N I ~ I ~ CN b]pyridine-3-carbonitrile
O N NH2
13 NH2 2,4-diamino-5H-chromeno[2,3- 0.563
-N b]pyridine-3-carbonitrile
trifiuoroacetate
O"N' _NH2
O
F
2 F--~ O H
F
14 F OH 2,4-diamino-8-(2-ethoxyethoxy)-7- 0.62
o~~ F~O NHz hydroxy-5H-chromeno[2,3-b]pyridine
Ho ~ ~ CN 3-carbonitrile trifluoroacetate
~O~O I ~ O ~ N~ NH2
NH2 2,4-diamino-9-hydroxy-8-methoxy- 0.682
'N 5H-chromeno[2,3-b]pyridine-3-
carbonitrile trifluoroacetate
O ~ I O~N~NH2
OH F O
F--~ O H
F

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16 OH NH2 2,4-diamino-6,8-dihydroxy-5H-0.694
=N chromeno[2,3-b]pyridine-3-
carbonitrile trifluoroacetate
I
~
~
HO ~
NH2
N
O
0
C 3~OH
17 F OH 2,4-diamino-8-ethoxy-7-hydroxy-5H-0.773
0 3-b
8 F~' idi
-3
h
2
. ]pyr
O NH ne
c
romeno[
,
-
HO I ~ I ~ ON carbonitrile trifluoroacetate
~O ~ O~N~NHZ
18 NHZ 2,4-diamino-8-(2-ethoxyethoxy)-5H-0.817
=N chromeno[2,3-b]pyridine-3-
carbonitrile
O N O NHZ
F
O F---~OH
F
19 NH2 2,4-diamino-8-(2-aminoethoxy)-5H-0.82
=N chromeno[2,3-b]pyridine-3-
carbonitrile hydrochloride
H2N~0 O N NH2
CI H
20 O NH2 2,4-diamino-3-cyano-5H-0.857
CN chromeno[2,3-b]pyridine-7-
Ho I ~ I ~ carboxylic acid trifluoroacetate
O N NH2
O
F
~OH
F F
21 NHZ 2,4-diamino-8,9-dihydroxy-5H-0.857
-N chromeno[2,3-b]pyridine-3-
carbonitrile trifluoroacetate
~
~
~
NH2
HO ~
N
O
OH O
F
F-~OH
F
22 NHZ 2,4-diamino-8-(2-morpholin-4-0.91
~~ ylethoxy)-5H-chromeno[2,3-
N b]pyridine-3-carbonitrile
I
I
~ O trifluoroacetate
~O
N NH
~
a
N
'
O
3 C a~OH
1
.6
23 NH2 [(2,4-diamino-3-cyano-5H-0.916
chromeno[2,3-b]pyridin-8-
N yl)oxy]acetic acid
trifluoroacetate
HO~O .~ O N NH2
O
96

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24 NHz 2,4-diamino-9-methoxy-5H- 1.37
~, =N chromeno[2,3-b]pyridine-3
carbonitrile trifluoroacetate
O~ N~ NH2
~O F~ O
2 F~pH
~F
=N ylethoxy)-5H-chromeno[2,3-
b]pyridine-3-carbonitrile
~N ~ NHz
F~~
F~OH
~F
- I 1.68
26 ~NH 2-amino-7,8-dimethoxy-4- 1.69
O ~N (methylamino)-5H-chromeno[2,3-
b]pyridine-3-carbonitrile
bis(trifluoroacetate)
~O ~ O N NH2
O O
F F
HO ~F HO F
,F F
27 H H 2,4-diamino-8-methoxy-5H- 1.72
N _ chromeno[2,3-b]pyridine-3-
i -N carbonitrile
\N ~ N-H
H
28 NHz 2,4-diamino-8-[2- 1.75
(dimethylamino)ethoxy]-5H-
chromeno[2,3-b]pyridine-3-
O N NHz carbonitrile trifluoroacetate
O
2.3 C 3~ON
29 NHz 2,4,7-triamino-9-methoxy-5H- 1.79
HzN I ~ I ~ CN chromeno[2,3-b]pyridine-3-
~ ~ carbonitrile trifluoroacetate
O_ 'N_ 'NH2
,O
1.25 CF3 COOH
N= = H 2(2,4-diamino-3-cyano-8-methoxy- 1.94
-N 5H-chromeno[2,3-b]pyridin-5-
yl)malononitrile
O- 'N- _NHZ
31 NHz 2,4-diamino-7,8-di[2-(amino)ethoxy]- 2.55
CIH HZN~.O , ~ =N 5H-chromeno[2,3-b]pyridine-3-
\ ~ \ ~ carbonitriie trifiuoroacetake
aHH2N-~-O O N NH2
97

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32 NHZ 2,4-diamino-9-nitro-5H- 2.58
ON chromeno[2,3-b]pyridine-3-
~ ~ carbonitrile
O- _N- _NHz
NOz
0.125 CF3C02H
33 ~O , 2-amino-7,8-dimethoxy-4-[(4- 2.98
methoxyphenyl)amino]-5H-
NH chromeno[2,3-b]pyridine-3-
i~N carbonitrile bis(trifluoroacetate)
~O [ ~ O"N"NH2
O O
F F
HO F HO F
F ~ F
34 H H 2,4-diamino-8-methoxy-5H- 3.24
N chromeno[2,3-b]pyridine-3-
=N carbonitrile
O N N-H
O H
F
2.3 HO
F
F
35 N= = H 2(2,4-diamino-3-cyano-7-hydroxy-5H 3.8
Ho ~. ~ -N chromeno[2,3-b]pyridin-5-
yl)malononitrile
I p"N"NHz
36 N- NH 2(2,4-diamino-3-cyano-7-bromo-5H- 4.22
sr ~ ~ -N chromeno[2,3-b]pyridin-5-
yl)malononitrile
I p"N"NHz
37 2-amino-8-ethoxy-4-(ethylamino)-5N 4.76
H N chromeno[2, 3-b]pyridine-3-
carbonitrile
~N
O ~ O N ~ ONHZ
F
F--~OH
F
38 NH2 2,4,9-triamino-5H-chromeno[2,3- 5.01
ON b]pyridine-3-carbonitrile
trifluoroacetate
O" N" N H2
NH2
O
F
F~OH
98

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39 NHZ 2,4,7-triamino-5H-thiochromeno[2,3-5.6
H2N b]pyridine-3-carbonitrile
-N
I \ I trifluoroacetate
S N NHZ
F OH
F
~IF
O
40 ~O ~ 2-amino-7,8-dimethoxy-4-[(4-6.11
( methoxyphenyl)amino]-5H-
NH chromeno[2,3-b]pyridine-3-
!~N carbonitrile
NH .
41 N- -NH 2(2,4-diamino-3-cyano-7-methoxy-6.18
= N
,O 5H-chromeno[2,3-b]pyridin-5-
\ I \ I yi)malononitrile
O N NHZ
42 NH2 2,4-diamino-9-hydroxy-8-(piperidin-18.28
CN ylmethyl)-5H-chromeno[2,3-
b]pyridine-3-carbonitrile
I
~
N trifluoroacetate
~ O
N NH
z
OH
2.0 TFA
43 NH2 7,8-biS(allyloxy)-2,4-diamino-5H-9.6
~O ~ ~ CN chromeno[2,3-b]pyridine-3-
carbonitrile trifluoroacetate
I
~O
~ O"N_ 'NHZ
O
F
0.8 F~OH
F
44 O~ 2-amino-8-(2-ethoxyethoxy)-4-[(2-9.66
ethoxyethyi)aminoj-5H-
HN chromeno[2,3-b]pyridine-3-
=N carbonitrile
O F O NHZ
O F--~O H
F
99

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45 O NHZ tert-butyl {[2,4-diamino-7-(2-tert- 10.3
\/ butoxy-2-oxoethoxy)-3-cyano-5H-
~o~o ~ ~ cN chromeno[2,3-b]pyridin-8-
o~o I ~ o' \N' \NH YI]oxy}acetate trifluoroacetate
z
0
F
F OH
1.6
F
46 HN~NH2 2-amino-4-[(2-aminoethyl)amino]-7,8 11.5
dimethoxy-5H-chromeno[2,3-
,O ~ ~ CN b]pyridine-3-carbonitrile
~ tritluoroacetate
~O ~ O N NHz
O
1.72 ~
F3C' _OH
47 N= = H 2(2,4-diamino-3-cyano-8-hydroxy-5H 12.8
=N chromeno[2,3-b]pyridin-5-
yl)malononitrile
HO ~ ~ O"N' -NHZ
48 NH2 2,4,7-triamino-5H-thiochromeno[2,3- 14.4
HZN ~ ~ CN b]pyridine-3-carbonitrile 10,10-
dioxide
SOZI N NHZ
49 NHz 2,4-diamino-7-bromo-5H- 15.1
sr ~ ~ =N chromeno[2,3-b]pyridine-3-
carbonitrile
O N NHZ
50 HN~ 2-amino-7,8-dimethoxy-4- 15.6
(propylamino)-5H-chromeno[2,3-
,o ~ ~ CN b]pyridine-3-carbonitrile
~O ~ ~ O I N NH2
O
0.32 F3C~OH
51 NH2 2,4-diamino-7-hydroxy-5H- 17.4
Ho I ~ ~ ~ CN thiochromeno[2,3-b]pyridine-3-
carbonitrile
S N NHZ
52 ~ NH2 2,4-diamino-7-(dimethylamino)-5H- 17.6
N CN chromeno[2,3-b]pyridine-3-
carbonitrile
O N NH2
53 I NN2 2,4-diamino-7-methoxy-5H- 19.7
o ~ ~ =N chromeno[2,3-b]pyridine-3-
carbonitrile
O N NHZ
100

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54 N- -NH 2(2,4-diamino-3-cyano-9-methoxy- 21.2
-N 5H-chromeno[2,3-b]pyridin-5-
yl)malononitrile
I O"N- _NH2
~,O
55 O 2-amino-4-(benzylamino)-7,8- 27,4
F~ dimethoxy-5H-chromeno[2,3-
\ / 1.22 F- 'F OH b]pyridine-3-carbonitrile
NH trifluoroacetate
,O / ~ / ~ -N
~O ~ O ~N NH2
56 NH2 8-(allyloxy)-2,4-diamino-5H- 33.8
=N chromeno[2,3-b]pyridine-3-
carbonitrile trifluoroacetate
O ~ O \N NHZ
F~ O
F--Y"OH
~F
57 NH2 2,4-diamino-9-fluoro-5H- 42.2
CN thiochromeno[2,3-b]pyridine-3-
carbonitriie trifluoroacetate
S" N" N H2
F Fo%~O
F-
F OH
58 NH2 2,4-diamino-7-methoxy-5H- 43
,O ~ / -N chromeno[2,3-b]pyridine-3-
carbonitrile trifluoroacetate
O N NH2
O
+2.3 F OH
F
59 NH2 2,4-diamino-9-(2-pyrrolidin-1- 45.2
CN ylethoxy)-5H-chromeno[2,3-
b]pyridine-3-carbonitrile
O"N"NH trifluoroacetate
a
~O
N
O
F
~OH
1.94 F F
60 NH2 2,4-diamino-7-nitro-5H- 62.2
Noz \ I _ , I =N chromeno[2,3-b]pyridine-3-
carbonitrile
O \N NHz
101

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61 NHz ~ N 2,4-diamino-10-methyl-5,10- 70.1
I ~ I ~ ~ dihydrobenzo[b]-1,8-naphthyridine-3
carbonitrile trifluoroacetate
N NHz
2.0 TFA
62 NH2 [(2,4-diamino-3-cyano-5H- 72,
CN chromeno[2,3-b]pyridin-9-
yl)oxy]acetic acid trifluoroacetate
O I / O NH
HO_ v0
O
F
~OH
1.56 F F
6 3 I 2-amino-4-{[2- ~g.1
HN~N~ (dimethylamino)ethylJamino}-7,8-
dimethoxy-5H-chromeno[2,3-
0
CN
i b]pyridine-3-carbonitrile
~ ~
trifluoroacetate
O O N NNz
O
2.01
/ \
F3C
OH
64NHz 2,4-diamino-7-nitro-5H-
80.8
_ lne-3-
NOz / / '~--'N l
il
l
I ca
rbo ,'t
e 10,10-d
oxide
S~ \N
NHz
~
00
65 / NH 2,4-diamino-7-phenyl-5H- g3,g
I z i~N chromeno[2,3-b]pyridine-3-
carbonitrile trifluoroacetate
/ O~ ~NHz
O
F
0.58 F~OH
F
56 NHz 2,4-diamino-7-chioro-9-methyl-5H- 136
CI I ~ I ~ CN chromeno[2,3-b]pyridine-3-
~ ~ carbonitrile
/ O"N"NHz
NHz 2,4-diamino-7-fluoro-5H- 142
ca'rbonitr le 10,10-dfoxide'ne-3-
I
0;0 N NHz
102

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68 ~ 8-ethoxy-2,4-bis(ethylamino)-5H-148
HN chromeno[2,3-b]pyridine-3-
=N carbonitrile
\ I O N O H~
F
F--~OH
F
9 ~ 2,4-diamino-5-(2-fluoro-phenyl)-8-151
I methoxy-5H-chromeno[2,3-
\
F NHz b]pyridine-3-carbonitrile
= N
O
I O N NHz
70 NHz 2,4-diamino-9-(2-hydroxyethoxy)-5H-154
N chromeno[2,3-b]pyridine-3-
carbonitrile trifluoroacetate
~
~
N~
O
N H2
O
HO~
O
F~~ O H
0.89 F F
71 NHz 2,4-diamino-9-(2-aminoethoxy)-5H-161
N chromeno[2,3-b]pyridine-3-
carbonitrile trifluoroacetate
O- _N_ _NHz
HzN~O
O
F~
~OH
3
61
F
.
72 N= =NH 2(2,4-diamino-3-cyano-7-chloro-5H-200
_ chromeno[2,3-b]pyridin-5-
a
N
I I yl)malononitrile
O N NHz
73 ( 2,4-bis{[2- 200
~N~ (dimethylamino)ethyl]amino}-7,8-
HN dimethoxy-5H-chromeno[2,3-
,O ~ ~ CN b]pyridine-3-carbonitrile
I trifluoroacetate
~O '~ O N~ N~N~
O H
2.37 ~
F3G' _OH
74 O 2-amino-4-{[2-(1,3-dioxo-1,3-dihydro200
2H-isoindol-2-yl)ethyl]amino}-7,8-
HN~'N~ dimethoxy-5H-chromeno[2,3-
b]pyridine-3-carbonitrile
,O ~ ~ CN O trifluoroacetate
I
~O
~ O I N NHz
O
1.28 F
C~
3
OH
103

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75 NHz 2,4-diamino-7-fluoro-5H-200
F chromeno[2,3-b]pyridine-3-
CN
I ~ I ~ carbonitrile trifluoroacetate
O N~ NHz
0.75 CF3 COOH
76 NH2 2,4-diamino-7-bromo-5H-200
ar ~ ~ -N chromeno[2,3-b]pyridine-3-
carbonitrile trifluoroacetate
O N NH2
O ,
+2.3 F OH
F
77 NHz 2,4-diamino-9-(pyridin-4-ylmethoxy)-200
CN 5H-chromeno[2,3-b]pyridine-3-
carbonitrile trifluoroacetate
I
N~
~ O"N_ _NHz
O
O
F
1
~
~OH
.
F
78 NHz 2,4-diamino-7-chloro-5H-200
G chromeno[2,3-b]pyridine-3-
~
~ CN
I carbonitrile
I
O N NHZ
1.75 CF3C02H
79 NHz 2,4-diamino-9-tert-butyl-5H-200
CN chromeno[2,3-b]pyridine-3-
~ ~ carbonitrile
O" N" N HZ
1.25 CF3CO2H
80 NHz ethyl2,4-diamino-3-cyano-5H-200
CN chromeno[2,3-b]pyridine-9-
carboxylate
~
~
~ O
N~
NHz
O O~
81 N Hz 2,4-diami no-9-[2- 200
CN (dimethyiamino)ethoxy]-5H-
chromeno[2,3-b]pyridine-3-
~ carbonitrile trifluoroacetate
"
I
O
N
' NH
z
w N~'~/O
O
F
~OH
F
1
2.
F
1
104

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82 HN~ 2,4-bis(butylamino)-7,8-dimethoxy- 200
5H-chromeno[2,3-bjpyridine-3-
O \ \ CN carbonitrile
~ O ~ N N'~
H
O
0.21 FaC~OH
83 HN~ 2-amino-4-(butyiamino)-7,8- 200
dimethoxy-5H-chromeno[2,3-
CN b]pyridine-3-carbonitrile
O N NHZ
O
0.16 F3C~OH
84 HN~ 7 8-dimethoxy-2,4-bis(propylamino)- 200
5H-chromeno[2,3-b]pyridine-3-
O I \ I \ CN carbonitriie
O N N'~
H
O
0.31 FsC~OH
85 HN~ 2 4-bis(ethylamino)-7,8-dimethoxy- 200
5H-ciromeno[2,3-b]pyridine-3-
\ CN carbonitrile
O / O N N'~
H
O
0.21 F3C~OH
86 HN-'\ 2-amino-4-(ethylamino)-7,8-
dimethoxy-5H-chromeno[2,3-
\ CN b]pyridine-3-carbonitrile
O / O N~ N Hz
O
0.24 F3e~OH
O' NH2 2 4-diamino-6,8-dimethoxy-
-N chromeno[2,3-b]pyridine-3-
carbonitrife trifiuoroacetate
O \ ~ O~N~NH2
O
F
F--~OH
F
105

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88 F 2,4-diamino-7-(trifluoromethoxy)-5H-200
~F NH2 chromeno[2,3-b]pyridine-3-
O F -N carbonitrile trifluoroacetate
O~N~NH2
O
F~~
1.25 F--r -OH
~F
89 NH2 2,4-diamino-7-bromo-9-methoxy-5H-200
Br -N chromeno[2,3-b]pyridine-3-
carbonitrile trifluoroacetate
~
~
N H2
N
O
O O
F
1.75 F~OH
F
90 NH2 2,4-diamino-9-methoxy-7-nitro-5H-200
=N chromeno[2,3-b]pyridine-3-
/
N02 /
I carbonitrile trifluoroacetate
I
O" N- - N H2
O
~p F
~
2 F--r -O H
~F
91 N~k 7,9-diamino-10H- 200
o i ~. =N [1,3]dioxolo[6,7]chromeno[2,3-
b]pyridine-8-carbonitrile
O N NHz
92 NHZ 7,9-diamino-10N- 200
=N [1,3]dioxolo[6,7]chromenoj2,3-
b]pyridine-8-carbonitrile
O ~ O ~N NH2 trifluoroacetate
O
F~ ~
F~OH
~F
93 NH2 2,4-diamino-8-methyl-5H-200
-N chromeno[2,3-b]pyridine-3-
carbonitrile trifluoroacetate
O N NHz
O
F
1.75 F-~O H
F
94 HN~O~ 7,8-dimethoxy-2,4-bis[(2-200
methoxyethyl)amino]-5H-
~ CN chromeno[2,3-b]pyridine-3-
carbonitrile
~O ~ O N N~O~
H
O
C~OH
44 F
0
.
s
106

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95 HN.~O~ 2-amino-7,8-dimethoxy-4-[(2-200
methoxyethyi)amino]-5H-
~O chromeno[2,3-b]pyridine-3-
~
~ CN
I carbonitriie
I
~O ~ O N NHz
O
C' _OH
0
36 F
.
3
2-amino-7,8-dimethoxy-4-[(2-200
N pyrroiidin-1-ylethyl)amino]-5H-
'~
HN chromeno[2,3-b]pyridine-3-
~O ~ ~ CN carbonitrile
~O I ~ O I N NH2
O
2.1 ~
F3C' _OH
97 7,8-dimethoxy-2,4-bis[(2-pyrrolidin-1-200
~ ylethyl)amino]-5H-chromeno[2,3-
N
~
H N b]pyridine-3-carbonitrile
~'O w ~ cN
~
I ~
I N
ON
O
O
N
O H
5.s F3C~ H
98 ~ 2,4-bis(glycinyl)-7,8-dimethoxy-5H-200
HN COOH
chromeno[2,3-b]pyridine-3-
~O ~ ~ CN carbonitrile trifluoroacetate
~O I ~ O I N~ N~COOH
H
O
0.41 ~
F3C' _OH
99 ~ N-(2-amino-3-cyano-7,8-dimethoxy-200
HN COOH
5H-chromeno[2,3-b]pyridin-4-
/O I ~ I ~ CN yl)glycine
~O ~ O N~ NHz
O
0.32 F3C' _OH
107

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7 NHZ 2,4-diamino-3-cyano-5H-200
00
=N chromeno[2,3-b]pyridine-9-
carboxylic acid bis(trifluoroacetate)
O- ' N- _ N HZ
O F, OII
OH F~OH
F
O
FI ~
F~OH
'F
101 Oi NH 2,4-diamino-6-methoxy-5H-200
chromeno[2,3-b]pyridine-3-
_ carbonitrile bis(trifluoroacetate)
O \N NH2
O
F~ ~
F~OH
~F
O
F
F-~OH
F
102 NH2 2,4-diamino-9-bromo-7-chloro-5H-200
-N chromeno[2,3-b]pyridine-3-
carbonitrile trifluoroacetate
O- _ N' _ NH2
gr F O
F~OH
~F
103 HN~ 2,4-bis(ethylamino)-7,8-dihydroxy-200
5H-chromeno[2,3-b]pyridine-3-
HO I ~ carb0nitrile trifluoroacetate
~ CN
I
H~ '~ o N N~
H
O
1.07
F3C~OH
104 Br NH2 2,4-diamino-6-bromo-9-methoxy-5H-200
-N chromeno[2,3-b]pyridine-3-
carbonitrile trifluoroacetate
~
~
NH2
O
N
~O F O
F---~ O H
F
108

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105 3.76 TFA 2,4-diamino-8-hydroxy-7,9-200
bis(piperidin-1-ylmethyl)-5H-
NHZ chromeno[2,3-b]pyridine-3-
~N I ~ I ~ CN carbonitrile trifluoroacetate
I
'
~
HO ~ O'~N~NHz
106 , 2,4-diamino-5-phenyl-8-hydroxy-5H-200
chromeno[2,3-b]pyridine-3-
NHz carbonitrile
-N
J
O N I NHz
HO ~
107 F , 2,4-diamino-5-(3-fluoro-phenyl)-8-200
methoxy-5H-chromeno[2,3-
NHz b]pyridine-3-carbonitrile
=N
I
I
O ~
O N
NHz
I
108 3.71 TFA 2,4-diamino-9-hydroxy-6,8-200
bis(piperidin-1-ylmethyl)-5H-
~
N chromeno[2,3-b]pyridine-3-
NHz carbonitrile trifluoroacetate
~ CN
N ~ O N~ NH
z
ON
109 NHz 2,4-diamino-7-bromo-8-methoxy-5H-200
-N chromeno[2,3-b]pyridine-3-
I I ~ carbonitrile
~ O N NHz
110 , 2,4-diamino-5-phenyl-8-methoxy-5H-200
chromeno[2,3-b]pyridine-3-
NHZ carbonitrile
=N
I O N NHz
111 N Hz 2,4-diamino-9-fl 200
uoro-5H-
thiochromeno[2,3-b]pyridine-3-
carbonitrile 10,10-dioxide
~
~
r
S02 ' N- _ N Hz
F
112 NHz 2,4-diamino-7-nitro-5H-200
NO2 hiochromeno[2,3-b]pyridine-3-
~
CN t
I carbonitrile
I ~
S N NHz
109

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113~ NHz 2,4-diamino-7-methoxy-5H-200
-N thiochromeno[2,3-b]pyridine-3-
carbonitrile 10,10-dioxide
I
~
~
\
NHz
N
S
I
0 0
114NHz 2,4-diamino-7-methoxy-5H-200
-N thiochromeno[2,3-b]pyridine-3-
carbonitrile bis(trifluoroacetate)
I
\
S"N' _NHz
O
F
F-~OH
F O
F
F--~OH
F
i15NHz 2,4-diamino-5H-thiochromeno[2,3-200
~N b]pyridine-3-carbonitrile
10,10-
~ ~ dioxide
I
~
~
\
S
N
NHz
p0
116NHz 2,4-diamino-5H-thiochromeno[2,3-200
-N b]pyridine-3-carbonitrife
trifluoroacetate
I
~
~
\
NHz
S
N
O
F
2 F--~ O H
F
117NHz 2,4-diamino-7-fluoro-5H-200
! N thiochromeno[2,3-b]pyridine-3-
F carbonitrile bis(trifluoroacetate)
I
~
~
NHz
\
S
\i~l
O
F_ ;~
F
F OH
F
O
-J~
F
OH
1180 2-amino-7,9-dimethyl-5-oxo-5H-200
-N chromeno[2,3-b]pyridine-3-
~ ~ carbonitrile
I
O" N- -NHZ
1190 2-amino-7-isopropyl-5-oxo-5H-200
=N chromeno[2,3-b]pyridine-3-
carbonitrile
O N NHz
110

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120 0 2-amino-7-ethyl-5-oxo-5H- 200
i ,, =N chromeno[2,3-b]pyridine-3-
carbonitrile
O N NH2
121 0 2-amino-7-methyl-5-oxo-5N- 200
i ~ =N chromeno[2,3-b]pyridine-3-
carbonitrile
O N NH2
122 0 2-amino-7-chloro-5-oxo-5H= 200
=N chromeno[2,3-b]pyridine-3-
carbonitrile
O N NHz
123 O 2-amino-7-bromo-5-oxo-5H- 200
_ chromeno[2,3-b]pyridine-3-
Br ~ \ ~ \ N carbonitrile
O~N NH2
124 0 2-amino-5-oxo-5H-chromeno[2,3- 200
i =N b]pyridine-3-carbonitrile
I O \N I NHZ
125 S ~ N 3-amino-5H-pyrido[3,4- 200
~ i NH b][1,4]benzothiazine-4-carbonitrile
N
Notes;
a: The aminocyanopyridine compound may be shown with a solvent, such as, for
example, trifluoroacetate, with which it can form a salt. Both the salt and
acid forms of the
aminocyanopyridine compound are included in the present invention.
b: Compound names generated by ACDIName software.
111

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[00053] In another embodiment, the present method can be practiced
by administering aminocyanopyridine compounds comprising the
compound shown in formula II, where:
G is selected from the group consisting of - O -, - S -, and -N-;
when G is -O-, R41 and R42 are absent;
when G is -S-, R41 and R42 are optionally absent, or are oxo;
when G is -N-, R41 is absent, and R42 is -H or C1-C4-alkyl;
R1 is selected from the group consisting of hydrogen, branched or
unbranched alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, arylalkyl, carboxy,
carboxyalkyl, hydroxyalkyl, alkylcarboxy, aryl, amino, aminoalkyl,
alkylamino, halo, alkylaminoalkyl, alkoxy, alkoxyalkyl, monocyclyl, bicyclyl,
polycyclyl, and heterocyclyl;
R2 is selected from the group consisting of hydrogen, alkyl, alkenyl,
alkynyl, alkoxy, hydroxyalkyl, alkylaryl, arylalkyl, alkoxyaryl, aminoalkyl,
alkylaminoalkyl, arylaminoalkyl, alkoxyalkyl, alkylcarboxy, and
carboxyalkyl;
R35 is selected from the group consisting of hydrogen, dicyanoalkyl,
and substituted or unsubstituted heterocyclyl and cyclyl, where
substituents, if any, comprise halo moieties;
R36 is selected from the group consisting of hydrogen, dicyanoalkyl,
and substituted or unsubstituted heterocyclyl and cyclyl, where
substituents, if any, comprise halo moieties;
R3' is selected from the group consisting of hydrogen, alkoxy, halo,
alkyl, alkenyl, alkylyl, arylalkyl, or alkylaryl;
R38 is selected from the group consisting of hydrogen, hydroxy,
alkoxy, alkyl, alkenyl, alkynyl, amino, alkylamino, arylamino,
alkylaminoalkyl, carboxy, aminoalkoxy, halo, alkylcarboxyalkyl, alkylamino,
aminoalkyl, nitro, aryl, arylalkyl, alkylaryl, or arylamino;
R39 is selected from the group consisting of hydrogen, hydroxy,
alkoxy, alkenoxy, hydroxyalkoxy, alkoxyalkoxy, aminoalkoxy,
heterocyclylalkyl, heterocyclylalkoxy, carboxyalkoxy, alkylaminoalkoxy,
and alkylcarboxyalkoxy;
112

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_,
where the R38 and R39 groups can join to form a six membered
heterocyclic ring; and
R4° is selected from the group consisting of hydrogen, hydroxy,
halo, nitro, amino, alkyl, alkoxy, heterocyclylalkoxy, carboxyalkoxy,
pyrrolidylethoxy, carboxymethoxy, hydroxyalkoxy, aminoalkoxy,
alkylcarboxy, alkylaminoalkyl, carboxy, and heterocyclylalkyl.
[00054] In another embodiment, the present method can be practiced
by the administration of an aminocyanopyridine compound comprising the
compound shown in formula II, where:
G is selected from the group consisting of -O-, -S-, and -N-;
when G is -O-, R41 and R42 are absent;
when G is -S-, R41 and R42 are optionally absent, or are oxo;
when G is -N-, R4' is absent, and R42 is -H or -CH3;
R1 is selected from the group consisting of hydrogen, ethyl,
dimethylaminoethyl, butyl, propyl, methoxyethyl, tetramethylaminoethyl,
and carboxymethyl;
R2 is selected from the group consisting of hydrogen, hydroxyethyl,
propyl, ethyl, methyl, 4-methoxyphenyl, ethoxyethyl, aminoethyl,
phenylmethyl, dimethylaminoethyl, phthaloaminoethyl, butyl, methoxyethyl,
tetramethylaminoethyl, and carboxymethyl;
R35 is selected from the group consisting of hydrogen,
dicyanomethyl, 2-fluorophenyl, phenyl, and 3-fluorophenyl.
R36 is selected from the group consisting of hydrogen,
dicyanomethyl, 2-fluorophenyl, phenyl, and 3-fluorophenyl;
R3' is selected from the group consisting of hydrogen, hydroxy,
methoxy, bromo, and 2-pyridomethyl;
R38 is selected from the group consisting of hydrogen, hydroxy,
methoxy, amino, carboxy, diaminoethoxy, bromo, propoxy,
isobutylcarboxymethoxy, dimethylamino, nitro, phenyl, chloro,
pyridylmethyl, and fluoro;
R39 is selected from the group consisting of hydrogen, hydroxy,
methoxy, hydroxyethoxy, ethoxyethoxy, ethoxy, aminoethoxy,
113

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. . _. _,
morpholinoethoxy, carboxymethoxy, N-pyrrolidylethoxy,
dimethylaminoethoxy, pyridylmethyl, 2-propenoxy, and
isobutylcarboxymethoxy, where the R38 and R39 groups optionally join to
form a six membered heterocyclic ring; and
Rao is selected from the group consisting of hydrogen, hydroxy,
fluoro, methoxy, nitro, amino, pyrrolidylethoxy, carboxymethoxy, methyl,
hydroxyethoxy, aminoethoxy, 4-pyridylmethoxy, isobutyl, ethylcarboxy,
dimethylaminoethoxy, carboxy, bromo, and pyrridylmethyl.
[00055] In another embodiment, the present method can be practiced
by the administration of an aminocyanopyridine compound that provides
an ICSO of less than about 200 ~.M, in an in vitro assay of MIC-2 inhibitory
activity. Examples of such compounds comprise the compound shown in
formula II, where:
G is selected from the group consisting of -O- and -S-;
when G is -S-, R41 and R42 are optionally absent, or are oxo;
when G is -O-, R41 and R42 are absent;
Ri is selected from the group consisting of hydrogen, and C1-C2
alky;
R2 is selected from the group consisting of hydrogen, C1-Cs alkyl,
hydroxy C1-C2 alkyl, C1-C~ alkoxyphenyl, C1-C2 alkoxy C1-C2 alkyl, amino
C1-C2 alkyl, phenyl C1-C2 alkyl, and di C1-C2 alkylamino C1-C2 alkyl;
R35 and R36 are each independently selected from the group
consisting of hydrogen, dicyano C1-C2 alkyl, and halophenyl;
R37 is selected from the group consisting of hydrogen, and hydroxy;
R3a is selected from the group consisting of hydrogen, hydroxy, C1 -
Cs alkoxy, amino, nitro, carboxy, diamino C1 - C2 alkoxy, halo, propenoxy,
iso C3 - C4 alkylcarboxy C1 - C2 alkoxy, di C1 - C2 alkylamino, and phenyl;
R39 is selected from the group consisting of hydrogen, hydroxy, C1 -
Cs alkoxy, hydroxy C1 - C2 alkoxy, C1 - C2 alkoxy C1 - C2 alkoxy, amino C1
- C2 alkoxy, morpholino C1 - C2 alkoxy, carboxyl C1 - C2 alkoxy, pyrrolidyl
C1 - C2 alkoxy, di C1 - C2 alkylamino C1 - C2 alkoxy, pyrrolidyl C1 - C2
alkyl,
iso C3 - C4 alkylcarboxy C1 - C2 alkoxy, and 2-propenoxy,
114

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where the R38 and R39 groups optionally join to form a six
membered heterocyclic ring; and
R4° is selected from the group consisting of hydrogen, hydroxy,
halo, C1-C2 alkyl, Ci-C2 alkoxy, nitro, amino, pyrrolidyl C1-C2 alkoxy,
carboxy C1-C2 alkoxy, hydroxy Cy-C2 alkoxy, and amino C1-C2 alkoxy.
[00056] In another embodiment, the present method can be practiced
by the administration of an aminocyanopyridine compound that provides
an IC5° of less than about 100 ~.M, in an in vitro assay of MK-2
inhibitory
activity. Examples of such compounds comprise the compound shown in
formula II, where:
G is selected from the group consisting of -O- and -S-;
when G is sulfur, R41 and R42 are optionally absent, or are oxo;
when G is -O-, R4' and R42 are absent;
R1 is hydrogen;
R2 is selected from the group consisting of hydrogen, C1 - C3 alkyl,
hydroxy C1 - C2 alkyl, C1 - C2 alkoxyphenyl, C1 - C2 alkoxy C1 - C2 alkyl,
amino C1 - C2 alkyl, phenyl C1 - C2 alkyl, and di C1 - C2 alkylamino C1 - C2
alkyl;
R35 and R36 are each independently selected from the group
consisting of hydrogen, and dicyano C1 - C2 alkyl.
R37 is selected from the group consisting of hydrogen, and hydroxy;
R~$ is selected from the group consisting of hydrogen, hydroxy, Ci-
C2 alkoxy, amino, carboxy, nitro, diamino C1-C2 alkoxy, halo, 2-propenoxy,
iso C3-C4 alkylcarboxy C1-C2 alkoxy, di C1-C2 alkylamino, and phenyl;
R39 is selected from the group consisting of hydrogen, hydroxy, C1 -
C2 alkoxy, hydroxy Ci-C2 alkoxy, C1-C2 alkoxy C1-C2 alkoxy, amino C1-C2
alkoxy, morpholino C1-C2 alkoxy, carboxyl Ci-C2 alkoxy, pyrrolidyl C1-C2
alkoxy, di C1-C2 alkylamino C1-C2 alkoxy, pyrrolidyi Ci-C2 alkyl, iso C3-C4
alkylcarboxy C1-C2 alkoxy, and 2-propenoxy;
wherein the R38 and R39 groups optionally join to form a six
membered heterocyclic ring; and
115

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R4° is selected from the group consisting of hydrogen, hydroxy,
halo, C1-C2 alkoxy, nitro, amino, pyrroiidyl C1-C2 alkoxy, and carboxy Ci-
C2 alkoxy.
(00057] In another embodiment, the present method can be practiced
by the administration of an aminocyanopyridine compound that provides
an ICSO of less than about 50 ~,M, in an in vitro assay of MK-2 inhibitory
activity. Examples of such compounds comprise the compound shown in
formula II, where:
G is selected from the group consisting of -O- and -S-;
when G is sulfur, R41 and R42 are optionally absent, or are oxo;
when G is -O-, R4' and R42 are absent;
Ri is hydrogen;
R2 is selected from the group consisting of hydrogen, C1-C3 alkyl,
hydroxy C1-C2 alkyl, C1-C2 alkoxyphenyi, C1-C2 alkoxy Ci-C2 alkyl, amino
C1-C2 alkyl, and phenyl C j-C2 alkyl;
R35 and R36 are each independently selected from the group
consisting of hydrogen, and dicyano Cj-C2 alkyl.
R3' is selected from the group consisting of hydrogen, and hydroxy;
R3$ is selected from the group consisting of hydrogen, hydroxy, C1-
C2 alkoxy, amino, carboxy, diamino C1-C2 alkoxy, halo, 2-propenoxy, iso
C3-C~ alkylcarboxy C~-C2 alkoxy, and di C1-C2 alkylamino;
R39 is selected from the group consisting of hydrogen, hydroxy, C1-
C2 alkoxy, hydroxy C1-C2 alkoxy, Cj-C2 alkoxy C1-C2 alkoxy, amino C1-C2
alkoxy, morpholino C1-C2 alkoxy, carboxyl C1-C2 alkoxy, pyrrolidyl C1-C2
alkoxy, di C1-C2 alkylamino C~-C2 alkoxy, pyrrolidyl C1-C2 alkyl, iso C3-C4
alkylcarboxy C1-C2 alkoxy, and 2-propenoxy;
where the R38 and R39 groups optionally join to form a six
membered heterocyclic ring; and
R4° is selected from the group consisting of hydrogen, hydroxy,
halo, C1-C2 alkoxy, nitro, amino, and pyrrolidyl C1-C2 alkoxy.
[00058 In another embodiment, the present method can be practiced
by the administration of an aminocyanopyridine compound that provides
116

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an ICSO of less than about 20 ~.M, in an in vitro assay of MK-2 inhibitory
activity. Examples of such compounds comprise the compound shown in
formula II, where:
G is selected from the group consisting of -O- and -S-;
when G is sulfur, R41 and R42 are optionally absent, or are oxo;
when G is -O-, R41 and R42 are absent;
R1 is hydrogen;
R2 is selected from the group consisting of hydrogen, C1-C3 alkyl,
hydroxy C1-C2 alkyl, C1-C2 alkoxyphenyl, C1-C2 alkoxy C1-C2 alkyl, and
amino C1-C2 alkyl;
R°5 and R36 are each independently selected from the group
consisting of hydrogen, and dicyanoethyl;
R37 is selected from the group consisting of hydrogen, and hydroxy;
R38 is selected from the group consisting of hydrogen, hydroxy, C1-
C2 alkoxy, amino, carboxy, diamino C1-C2 alkoxy, halo, 2-propenoxy, iso
C3-C4 alkylcarboxy C1-C2 alkoxy, and di C1-C2 alkylamino;
R39 is selected from the group consisting of hydrogen, hydroxy, C1-
C2 alkoxy, hydroxy C1-C2 alkoxy, C1-C2 alkoxy C1-C2 alkoxy, amino C1-C2
alkoxy, morpholino C1-C2 alkoxy, carboxyl C1-C2 alkoxy, pyrrolidyl C1-C2
alkoxy, di C1-C2 alkylamino Ci-C2 alkoxy, pyrrolidyl C1-C2 alkyl, iso C3-C4
alkylcarboxy C1-C2 alkoxy, and 2-propenoxy;
where the R3g and R39 groups optionally join to form a six
membered heterocyclic ring; and
R4° is selected from the group consisting of hydrogen, hydroxy,
halo, methoxy, nitro, and amino.
[00059] Examples of aminocyanopyridine MK-2 inhibitor compounds
that can be used in the present method include, without limitation, the
following:
2-amino-4-(2-fluorophenyl)-6,8-dihydro-5H-pyrazolo[3,4-h]quinoline-3-
carbonitrile,
2-amino-4-(2-furyl)-6,7-dihydro-5H-pyrazolo[3,4-h]quinoline-3-carbonitrile,
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2-amino-4-(2,3-difluorophenyl)-6,7-dihydro-5H-pyrazolo[3,4-h]quinoline-3-
carbonitrile,
8-amino-6-(2-furyl)-4,5-dihydro-1 H-pyrazolo[4,3-h]quinoline-7-carbonitrile,
2-amino-3-cyano-4-(2-furyl)-5,6-dihydrobenzo[h]quinaline-8-carboxylic
acid,
4-[2-amino-3-cyano-6-(2-furyl)pyridin-4-yl]-1 H-pyrroie-2-carboxamide,
2-amino-4-phenyl-6,8-dihydro-5H-pyrazolo[3,4-h]quinoline-3-carbonitrile,
2-amino-6-(2-furyl)-4-(1-methyl-1 H-imidazol-4-yl)nicotinonitrile,
8-amino-6-(2-furyl)-4,5-dihydro-1 H-pyrazolo[4,3-h]quinoline-7-carbonitrile,
2-amino-4-(2-furyl)-8-hydroxy-5,6-dihydrobenzo[h]quinoline-3-carbonitrile,
2-amino-4-(2,6-difluorophenyl)-6,7-dihydro-5H-pyrazolo[3,4-h]quinoline-3-
carbonitrile,
2-amino-6-(4-hydroxyphenyl)-4-(1 H-imidazol-5-yl)nicotinonitrile,
2-amino-4-(2-fluorophenyl)-6-(2-furyl)nicotinonitrile, 2-amino-4-(2-
fluorophenyl)-6-(2-furyl)nicotinonitrile,
2-amino-4-(2-fluorophenyi)-5,6-dihydrobenzo[h]quinoline-3-carbonitrile,
4-[6-amino-5-cyano-4-(2-furyl)pyridin-2-yl]benzoic acid,
2-amino-6-(2-furyl)-4-(1 H-imidazol-5-yl)nicotinonitrile,
2-amino-4-(2-furyl)-6-(1 H-pyrazol-3-yl)nicotinonitrile,
2-amino-3-cyano-4-(4H-1,2,4-triazol-3-yl)-5,6-dihydrobenzo[h]quinoline-8-
carboxylic acid,
2-amino-6-(3-hydroxyphenyl)-4-(1 H-imidazol-5-yl)nicotinonitrile,
2-amino-6-(2-furyl)-4-(1 H-imidazol-4-yl)nicotinonitrile,
2-amino-4-(2,4-difluorophenyl)-6,7-dihydro-5H-pyrazolo[3,4-h]quinoline-3-
carbonitrile,
4,6-diamino-2-(trifluoromethyl)-2,3-dihydrofuro[2,3-b]pyridine-5-
carbonitrile,
2-amino-4-(2-furyl)-6,8-dihydro-5H-pyrrolo[3,4-h]quinoline-3-carbonitrile,
4-[6-amino-5-cyano-4-(2-fluorophenyl)pyridin-2-yl]benzoic acid,
2-amino-4-(2-furyl)-5,6-dihydro-1,8-phenanthroline-3-carbonitrile,
2-amino-6-(3,4-dihydroxyphenyl)-4-(2-fluorophenyl)nicotinonitrile,
2-amino-4-(1-methyl-1 H-imidazol-4-yl)-6-phenylnicotinonitrile,
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2-amino-4-(2-furyl)-6-(1 H-pyrazol-3-yl)nicotinonitrile,
4-[6-amino-5-cyano-4-(1 H-imidazol-5-yl)pyridin-2-yl]benzoic acid,
2-amino-4-(3-fluorophenyl)-6,8-dihydro-5H-pyrazolo[3,4-h]quinoline-3-
carbonitrile,
2-amino-6-(3,4-dihydroxyphenyl)-4-(2-fluorophenyl)nicotinonitrile,
N {4-[6-amino-5-cyano-4-(2-furyl)pyridin-2-yl]phenyl]methanesuifonamide,
2-amino-4-(2-furyl)-6,7-dihydro-5H-pyrroloj2,3-h]quinoline-3-carbonitrile,
2-amino-4-(1 H-imidazol-5-yl)-6-phenylnicotinonitrile,
2-amino-4-(2-furyl)-5,6-dihydrobenzo[h]quinoline-3-carbonitrile,
2-amino-4-(1 H-imidazol-5-yl)-6-(4-methoxyphenyl)nicotinonitrile,
2-amino-6-(3-chlorophenyl)-4-(1 H-imidazol-5-yl)nicotinonitrile,
2-amino-4-(2-furyl)-6-(1 H-pyrazol-4-yl)nicotinonitrile,
2-amino-4-(4-methoxyphenyl)-6,7-dihydro-5H-pyrazolo[3,4-h]quinoline-3-
carbonitrile,
2-amino-4-(2,5-difluorophenyl)-6,7-dihydro-5H-pyrazolo[3,4-h]quinoline-3-
carbonitrile,
2-amino-4-(4-fluorophenyl)-6,8-dihydro-5H-pyrazolo[3,4-h]quinoline-3-
carbonitrile,
2-amino-4-(4H-1,2,4-triazol-3-yl)-5,6-dihydrobenzo[h]quinoline-3-
carbonitrile,
4,6-diamino-2-(chloromethyl)-2,3-dihydrofuro[2,3-b]pyridine-5-carbonitrile,
2-amino-4-(1 H-imidazol-4-yl)-6-phenylnicotinonitrile,
4-j6-amino-5-cyano-4-(2-furyl)pyridin-2-yl]benzenesulfonamide,
4-j6-amino-5-cyano-4-(2-furyl)pyridin-2-yl]phenylboronic acid,
2-amino-6-(4-methoxyphenyl)-4-(4H-1,2,4-triazol-3-yl)nicotinonitrile,
2-amino-4-(2-fluorophenyl)-6-(3-furyl)nicotinonitrile,
2-amino-6-(2-furyl)-4-(methylthio)nicotinonitrile,
2-amino-4-(2-fluorophenyl)-6-(3-hydroxyphenyl)nicotinonitrile,
8-amino-6-(2-furyl)-4,5-dihydro-2H-pyrazolo[4,3-h]quinoline-7-carbonitrile,
2-amino-4-(2-bromophenyl)-6-(2-furyl)nicotinonitrile,
2-amino-4-(2-fluorophenyl)-6-(4-hydroxyphenyl)nicotinonitrile,
2-amino-4-phenyl-6-thien-2-ylnicotinonitrile,
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2-amino-4-(3-methoxyphenyl)-6,7-dihydro-5H-pyrazolo[3,4-h]quinoline-3-
carbonitrile,
2-amino-4-(2-furyl)-7-methyl-8,7-dihydro-5H-pyrazolo[3,4-h]quinoline-3-
carbonitrile,
2-amino-4-(2-fluorophenyl)-6-(1 H-pyrrol-2-yl)nicotinonitrile,
2-amino-4-(2-furyl)-5-methyl-8,8-dihydro-5H-pyrazalo[3,4-h]quinoline-3-
carbonitrile,
2-amino-4-(2-furyl)-6-(1-methyl-1 H-pyrrol-3-yl)nicotinonitrile,
3-amino-5,6,7,8-tetrahydroisoquinoline-4-carbonitrile,
N-[4-(2-amino-3-cyano-6,7-dihydro-5H-pyrazolo[3,4-h]quinolin-4-
yl)phenyl]acetamide,
6-amino-4-[(4-methoxyphenyl)amino]-2-(trifluoromethyl)-2,3-
dihydrofuro[2,3-b]pyridine-5-carbonitrile,
4-[6-amino-5-cyano-4-(2-furyl)pyridin-2-yl]-N (tert-
butyl)benzenesulfonamide,
4,6-diamino-2-ethyl-2,3-dihydrofuro[2,3-b]pyridine-5-carbonitrile,
6-amino-4-(2-furyl)-2,4'-bipyridine-5-carbonitrile, 2,4-diamino-6-
(methylthio)nicotinonitrile,
3-(2-amino-3-cyano-6,7-dihydro-5H-pyrazolo[3,4-h]quinolin-4-yl)benzoic
acid,
2-amino-6-(4-chlorophenyl)-4-(1 H-imidazol-5-yl)nicotinonitrile,
2-amino-4-(1,3-benzodioxol-4-yl)-6,7-dihydro-5H-pyrazolo[3,4-h]quinoline-
3-carbonitrile,
4,6-diamino-2-methyl-2,3-dihydrofuro[2,3-b]pyridine-5-carbonitrile,
2-amino-4-(1 H-imidazol-5-yl)-6-[4-(methylsulfonyl)phenyl]nicotinonitrile,
2,4-diaminoquinoline-3-carbonitrile,
2,8-diamino-4-(2-furyl)-5,6-dihydrobenzo[h]quinoline-3-carbonitrile,
2-amino-4,6-di(2-furyl)nicotinonitrile,
4,6-diamino-2-butyl-2,3-dihydrofuro[2,3-b]pyridine-5-carbonitrile,
ethyl 4-[8-amino-5-cyano-4-(1 H-imidazol-5-yl)pyridin-2-yl]benzoate,
2,4-diamino-6-methoxynicotinonitrile,
2-amino-4-methylnicotinonitrile,
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2-amino-4-(4-cyanophenyl)-6,7-dihydro-5H-pyrazolo[3,4-h]quinoline-3-
carbonitrile,
2-amino-4-cyclopropyl-6-methylnicotinonitrile,
2-amino-4-(2-furyl)-6-(1-methyl-1 H-pyrrol-2-yl)nicotinonitrile,
2-amino-4-(2-chlorophenyl)-6,7-dihydro-5H-pyrazolo[3,4-h]quinoline-3-
carbonitriie,
2-amino-6-(2-furyl)-4-(4-phenoxyphenyl)nicotinonitrile,
2-amino-4-pyridin-3-yl-6,8-dihydro-5H-pyrazolo[3,4-h]quinoline-3-
carbonitrile,
2-amino-6-{[2-(4-chlorophenyl)-2-oxoethyl]thio}-4-(2-furyl)pyridine-3,5-
dicarbonitrile,
4-[2-amino-3-cyano-6-(2-furyl)pyridin-4-yl]phenylboronic acid,
2-amino-6-(3-chlorophenyl)-4-(1 H-imidazol-4-yl)nicotinonitrile,
4-(6-amino-5-cyano-4-phenylpyridin-2-yl)-N (tert-
butyl)benzenesulfonamide,
2-amino-4-methoxynicotinonitrile,
4-[2-amino-3-cyano-6-(2-furyl)pyridin-4-yl]benzoic acid,
4,6-diamino-2-[(4-methoxyphenoxy)methyl]-2,3-dihydrofuro[2,3-b]pyridine-
5-carbonitrile,
2-amino-4-(2-fluorophenyl)-6-(4-methoxyphenyl)nicotinonitrile,
4-[6-amino-5-cyano-4-(2-fluorophenyl)pyridin-2-yl]-N-(tert-
butyl)benzenesulfonamide,
(2,4-diamino-3-cyano-5H-chromeno[2,3-b]pyridin-9-yl)oxy]acetic acid,
3-Pyridinecarbonitrile, 2-Amino-4-Methylm
2-amino-6-(2-furyl)nicotinonitrile,
2-amino-4-(2-furyl)-6-(3-hydroxyphenyl)nicotinonitrile,
4-[6-amino-5-cyano-4-(2-furyl)pyridin-2-yl]benzamide,
2-amino-4-(2-furyl)-7-hydroxy-5,6-dihydrobenzo[h]quinoline-3-carbonitrile,
2-amino-4-(2-furyl)-6-(1 H-indol-3-yl)nicotinonitrile,
2-amino-4-pyridin-4-yl-6,8-dihydro-5H-pyrazolo[3,4-h]quinoline-3-
carbonitrile,
2-amino-4-(3-fluorophenyl)-6-(4-hydroxyphenyl)nicotinonitriie,
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2-amino-4-[2-(difluoromethoxy)phenyl]-6,7-dihydro-5H-pyrazolo[3,4-
hjquinoline-3-carbonitrile,
2-amino-4-(2-furyl)-6-thien-3-ylnicotinonitrile,
2-amino-4-(3-fluorophenyl)-6-(4-methoxyphenyl)nicotinonitrile,
2-[2-amino-3-cyano-6-(2-furyl)pyridin-4-yl]phenylboronic acid,
2,4-diamino-6-propylpyridine-3,5-dicarbonitrile,
4,6-diamino-2-[(prop-2-ynyloxy)methyl]-2,3-dihydrofuro[2,3-b]pyridine-5-
carbonitrile,
4,6-diamino-2-(hydroxymethyl)-2,3-dihydrofuro[2,3-bjpyridine-5-
carbonitrile,
2-amino-6-(2-furyl)-4-[4-(trifluoromethyl)phenyljnicotinonitrile,
5-amino-7-methylthieno[3,2-b]pyridine-6-carbonitrile,
2-amino-4-(2-furyl)-5,5-dimethyl-6,8-dihydro-5H-pyrazolo[3,4-h]quinoline-
3-carbonitrile,
N-[3-cyano-4-(2-fluorophenyl)-6-(2-furyl)pyridin-2-yl]glycine,
2-[(allyloxy)methyl]-4,6-diamino-2,3-dihydrofuro[2,3-b]pyridine-5-
carbonitrile,
2-amino-4-(2-furyl)-6-methyl-5,6-dihydrobenzo[h]quinoline-3-carbonitrile,
4,6-diamino-2-(methoxymethyl)-2,3-dihydrofuro[2,3-b]pyridine-5-
carbonitrile,
2-amino-4-(2-furyl)-6-(1 H-indol-3-yl)nicotinonitrile,
2-amino-4-(2-furyl)-6-[4-(1 H-imidazol-1-yl)phenyl]nicotinonitrile,
2-amino-4-(2-furyl)-6-(4-hydroxyphenyl)nicotinonitrile,
2-amino-4-(2-furyl)-5,6,7,8-tetrahydro-5,8-methanoquinoline-3-carbonitrile,
4,6-diamino-2-(isopropoxymethyl)-2,3-dihydrofuro[2,3-b]pyridine-5-
carbonitrile,
3-[6-amino-5-cyano-4-(2-furyl)pyridin-2-yl]phenylboronic acid,
4,6-diamino-2-(ethoxymethyl)-2,3-dihydrofuro[2,3-b]pyridine-5-carbonitrile,
2-amino-4-(4-bromophenyl)-6-(2-furyl)nicotinonitrile,
4,6-diamino-2-[(1,1,2,2-tetrafluoroethoxy)methyl]-2,3-dihydrofuro[2,3-
b]pyridine-5-carbonitrile,
2-amino-4-[2-fluoro-4-(trifluoromethyl)phenyl]-6-(2-furyl)nicotinonitrile,
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2-amino-4-(2-methoxyphenyl)-6,8-dihydro-5H-pyrazolo[3,4-h]quinoline-3-
. carbonitrile,
2-amino-4-(2-fluorophenyl)-5-methyl-6,8-dihydro-5H-pyrazolo[3,4-
h]quinoiine-3-carbonitrile,
3,6-diamino-4-ethyl-1 H-pyrazolo[3,4-b]pyridine-5-carbonitrile,
6-amino-4-{2-furyl)-2,2'-bipyridine-5-carbonitriie,
2-amino-4-(2-furyl)-6-(8-hydroxy-1-naphthyl)nicotinonitrile,
4-(2-amino-3-cyano-6,7-dihydro-5H-pyrazolo[3,4-h]quinolin-4-yl)benzoic
acid,
2-amino-6-(3,4-dichlorophenyi)-4-(2-furyl)nicotinonitrile,
2-amino-4-(2-furyl)-6-(1 OH-phenothiazin-2-yl)nicotinonitrile,
sodium 2-amino-3-cyano-4-quinolinecarboxylate,
2-anilino-4-(2-fluorophenyl)-6-(2-furyl)nicotinonitrile,
2-amino-4-(3-fluorophenyl)-6-(2-furyl)nicotinonitrile,
2-amino-4-(4-fluorophenyl)-6-(2-furyl)nicotinonitrile,
4,6-diamino-2-(tent-butoxymethyl)-2,3-dihydrofuro[2,3-b]pyridine-5-
carbonitrile,
2-amino-4-(2-furyl)-6-(1,3-thiazol-2-yl)nicotinonitrile,
4-(2-fluorophenyl)-6-(2-furyl)-2-piperidin-1-ylnicotinonitrile,
2-amino-6-(4-chlorophenyl)-4-(2-furyl)nicotinonitrile,
2-amino-6-(4-hydroxyphenyl)-4-{2-methoxyphenyl)nicotinonitrile,
2-amino-6-(2-furyl)-4-(2-hydroxyphenyl)nicotinonitrile,
methyl 3-(2-amino-3-cyano-6,7-dihydro-5H-pyrazolo[3,4-h]quinolin-4-
yi)benzoate,
2-amino-4-(2-chlorophenyl)-6-(5-methyl-2-furyl)nicotinonitrile,
3,6-diamino-2-benzoylthieno[2,3-b]pyridine-5-carbonitrile,
methyl 4-[6-amino-5-cyano-4-(2-furyl)pyridin-2-yl]benzoate,
2-aminonicotinonitriie,
2-amino-4-(2-furyl)-8-{[2-(trimethylsilyl)ethoxy]methyl}-6,8-dihydro-5H-
pyrazolo[3,4-h]quinoline-3-carbonitrile,
3-amino-5H-pyrido[4,3-b]indole-4-carbonitrile,
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2-(2-amino-3-cyano-6,7-dihydro-5H-pyrazolo[3,4-h]quinolin-4-yl)benzoic
acid,
2-amino-6-(4-methoxyphenyl)-4-phenylnicotinonitrile,
2-amino-4-(2-furyl)-5,6,7,8-tetrahydroquinoline-3-carbonitrile,
2-amino-4-(2-furyl)-6-isobutylnicotinonitrile,
2-amino-6-benzyl-4-(2-furyl)nicotinonitrile,
2-amino-4-(2-furyl)-6-methyl-5-phenylnicotinonitrile,
2-amino-4-(2-furyl)-6-[4-(trifluoromethoxy)phenyl]nicotinonitrile,
2-amino-4-(2-furyl)-6-propyl-5,6,7,8-tetrahydro-1,6-naphthyridine-3-
carbonitrile,
2-amino-4-(2-furyl)benzo[h]quinoline-3-carbonitrile,
2-amino-6-(4-methoxyphenyl)-4-thien-2-ylnicotinonitrile,
2-amino-4-(2-fluorophenyl)-6-tetrahydrofuran-2-ylnicotinonitrile,
ethyl 6-amino-5-cyano-4-(2-furyl)pyridine-2-carboxylate,
2-amino-4-(2-furyl)-9-methoxy-5,6-dihydrobenzo[h]quinoline-3-carbonitrile,
2-amino-4-(2-furyl)-8-methoxy-5,6-dihydrobenzo[h]quinoline-3-carbonitrile,
2-amino-4-(2-furyl)-8,9-dimethoxy-5,6-dihydrobenzo[h]quinoline-3-
carbonitrile,
2-amino-4-(2-furyl)-7-methoxy-5,6-dihydrobenzo[h]quinoline-3-carbonitrile,
2-amino-4-(2-furyl)-7,9-dimethyl-5,6-dihydrobenzo[h]quinoline-3-
carbonitrile,
ethyl 4-[6-amino-5-cyano-4-(2-furyl)pyridin-2-yl]benzoate,
2-amino-6-(3-bromophenyl)-4-(2-furyl)nicotinonitrile,
2-amino-4-(2-furyl)-6-[4-(trifluoromethyl)phenyl]nicotinonitrile,
2-amino-4-(2-furyl)-6-[3-(trifluoromethyl)phenyl]nicotinonitrile,
2-amino-4-(2-furyl)-6-[4-(methylsulfonyl)phenyl]nicotinonitrile,
4,6-diamino-2-(phenoxymethyl)-2,3-dihydrofuro[2,3-b]pyridine-5-
carbonitrile,
4,6-diamino-3-phenyl-2,3-dihydrofuro[2,3-b]pyridine-5-carbonitrile,
4,6-diamino-3-vinyl-2,3-dihydrofuro[2,3-b]pyridine-5-carbonitrile,
2-amino-4-(2-fluorophenyl)-5-methyl-6,8-dihydro-5H-pyrazolo[3,4-
h]quinoline-3-carbonitrile,
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3-amino-1-methyl-5,6,7,8-tetrahydroisoquinoline-4-carbonitrile,
2-amino-4-(2-fluorophenyl)-5,5-dimethyl-6,8-dihydro-5H-pyrazolo[3,4-
h]quinoline-3-carbonitrile,
2-amino-4-(2-fluorophenyl)-6-(3-hydroxyphenyl)nicotinonitrile,
2-amino-4-[2-(difluoromethoxy)phenyl]-6,7-dihydro-5H-pyrazolo[3,4-
h]quinoline-3-carbonitrile,
2-(benzylamino)-4-(2-fluorophenyl)-6-(2-furyl)nicotinonitrile,
2-amino-4-(2-furyl)-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-b]pyridine-3-
carbonitrile,
2-amino-4-(2-furyl)-5H-indeno[1,2-b]pyridine-3-carbonitrile,
3-amino-1-methyl-5,6,7,8-tetrahydroisoquinoline-4-carbonitrile,
2-amino-4-(2-fluorophenyl)-6-(3-hydroxyphenyl)nicotinonitrile,
2-amino-4-(2-thienyl)-5,6,7,8-tetrahydro-3-quinolinecarbonitrile,
2-amino-4-(3-fluorophenyl)-5,6,7,8-tetrahydro-3-quinolinecarbonitrile,
2-(1-piperidinyl)-6-(2-thienyl)-4-(trifluoromethyl)nicotinonitrile,
2-(dimethyiamino)-6-(2-thienyl)-4-(trifluoromethyl)nicotinonitrile,
3-Quinolinecarbonitrile,
2-amino-4-methyl- or 2-amino-4-methyl-3-quinolinecarbonitrile,
2-amino-4-(4-methoxyphenyl)-6-(2-thienyl)nicotinonitrile,
2-amino-6-cyciopropyl-4-(2-methoxyphenyl)nicotinonitrile,
2-amino-4-(2-fluorophenyl)-6-phenylnicotinonitrile,
(4bS,8aR)-2,4-diamino-4b,5,6,7,8,8a-hexahydro[1 ]benzofuro[2,3-
b]pyridine-3-carbonitrile,
2-amino-4-(2-fluorophenyl)-5,5-dimethyl-6,8-dihydro-5H-pyrazolo[3,4-
h]quinoline-3-carbonitrile,
2-amino-4-(2-furyl)-5-phenyl-6,8-dihydro-5H-pyrazolo[3,4-h]quinoline-3-
carbonitrile,
3-amino-1,6-dimethyl-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile,
3-amino-1,7-dimethyl-5,6,7,8-tetrahydro-2,7-naphthyridine-4-carbonitrile,
2-amino-4-(2-fluorophenyl)-5-phenyl-6,8-dihydro-5H-pyrazolo[3,4-
h]quinoline-3-carbonitrile,
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2-amino-4-(2-fluorophenyl)-5-phenyl-6,8-dihydro-5H-pyrazolo[3,4-
h]quinoiine-3-carbonitrile,
4,6-diamino-2-(morpholin-4-ylmethyl)-2,3-dihydrofuro[2,3-b]pyridine-5-
carbonitrile,
ethyl (4,6-diamino-5-cyano-2-oxo-2,3-dihydro-1 H-pyrrolo[2,3-b]pyridin-1-
yl)acetate,
2-amino-4-(2-methoxyphenyl)-6-(5-methyl-2-furyl)nicotinonitrile,
2-amino-6-methyl-4-(4-nitrophenyl)nicotinonitrile,
2-amino-4-(3,4-dimethoxyphenyl)-6-(5-methyl-2-furyl)nicotinonitrile,
2,4-diamino-6-[(4-methoxyphenyl)thio]nicotinonitrile,
4,6-diamino-2-(phenoxymethyl)-2,3-dihydrofuro[2,3-b]pyridine-5-
carbonitrile,
4,6-diamino-3-phenyl-2,3-dihydrofuro[2,3-b]pyridine-5-carbonitrile,
4,6-diamino-2-[(2-methylphenoxy)methyl]-2,3-dihydrofuro[2,3-b]pyridine-5-
carbonitrile,
2-amino-4-(2-furyl)-6-(4-methoxyphenyl)nicotinonitrile,
2-amino-4-(3-fluorophenyl)-5,6-dihydrobenzo[h]quinoline-3-carbonitrile,
2-amino-4-(4-methoxyphenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine-3-
carbonitrile,
2-amino-9-ethyl-9H-pyrido[2,3-b]indole-3-carbonitrile,
2-amino-6-isobutyl-4-(4-methylphenyl)nicotinonitrile,
1-(2-furyl)-3-[(3-hydroxypropyl)amino]-5,6,7,8-tetrahydroisoquinoline-4-
carbonitrile,
2-azepan-1-yl-6-(4-fiuorophenyl)-4-phenylnicotinonitrile,
2-amino-6-tert-butyl-4-(4-methylphenyl)nicotinonitrile,
2-amino-4-(4-bromophenyl)-6-methylnicotinonitrile,
2-amino-4-thien-2-yl-5,6,7,8,9,10-hexahydrocycloocta[b]pyridine-3-
carbonitrile,
2-amino-4-(4-chlorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine-3-
carbonitrile,
2-(allylamino)-5-amino-7-(4-bromophenyl)thieno[3,2-b]pyridine-3,6-
dicarbonitrile,
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2-amino-4-pyridin-3-yl-5,6,7,8,9,10-hexahydrocycloocta[b]pyridine-3-
carbonitrile,
2-amino-4-(4-bromophenyl)-6-tert-butylnicotinonitrile,
1-(2-furyl)-3-morpholin-4-yl-5,6,7,8-tetrahydroisoquinoline-4-carbonitrile,
2-amino-4-(4-methylphenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine-3-
carbonitrile,
2-amino-7,7-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridine-3-carbonitrile,
2-amino-6-isobutyl-4-(4-methoxyphenyl)nicotinonitrile,
4,6-diamino-2-oxo-1-phenyl-2,3-dihydro-1 H-pyrrolo[2,3-b]pyridine-5-
carbonitrile,
2-amino-4-(2-methoxyphenyf)-5,6-dimethylnicotinonitrile,
2-(dimethylamino)-4-(2-fluorophenyl)-6-(2-furyl)nicotinonitrile,
2-(dimethylamino)-4-(2-fluorophenyl)-6-(2-furyl)nicotinonitrile,
4-(2-fluorophenyl)-6-(2-furyl)-2-(methylamino)nicotinonitrile,
4-(2-fluorophenyl)-6-(2-furyl)-2-morpholin-4-ylnicotinonitrile,
tent-butyl N [3-cyano-4-(2-fluorophenyl)-6-(2-furyl)pyridin-2-yl]glycinate,
2-(ethylamino)-4-(2-fluorophenyl)-6-(2-furyl)nicotinonitrile,
ethyl 4-[6-amino-5-cyano-4-(2-fluorophenyl)pyridin-2-yl]benzoate,
2-amino-6-(2-fluorophenyl)-4-(3-furyl)nicotinonitrile,
6-amino-4-(2-fluorophenyl)-2,2'-bipyridine-5-carbonitrile,
2-amino-4-(2-fluorophenyl)-6-thien-2-ylnicotinonitrile,
ethyl 6-amino-5-cyano-4-(2-fluorophenyl)pyridine-2-carboxylate,
2-amino-6-(2-furyl)-4-phenylnicotinonitrile,
ethyl 2-amino-3-cyano-4-(2-furyl)-5,6,7,8-tetrahydroquinoline-6-
carboxylate,
2-amino-4-(2-furyl)-6-(4-hydroxyphenyl)-5-methylnicotinonitrile,
2-amino-4-(2-furyl)-6-(4-methoxyphenyl)-5-methylnicotinonitrile,
2-amino-6-(4-fluorophenyl)-4-(2-furyl)-5-methylnicotinonitrile,
2-amino-4-(2-furyl)-5,6-diphenylnicotinonitrile,
2-amino-4-(2-furyl)-5-methyl-6-phenylnicotinonitrile,
2-amino-6-(3,4-dimethylphenyl)-4-(2-furyl)nicotinonitrile,
2-amino-6-(4-fluorophenyl)-4-(2-furyl)nicotinonitrile,
127

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2-amino-4-(3-fluorophenyl)-6-(3-hydroxyphenyl)nicotinonitrile,
6-amino-4-(3-fluorophenyl)-2,4'-bipyridine-5-carbonitrile,
6-amino-4-(2-fluorophenyl)-2,4'-bipyridine-5-carbonitrile,
2-amino-4-butyl-6-methylnicotinonitrile,
2-amino-6-methyl-4-propylnicotinonitrile,
2-amino-4-ethyl-6-methylnicotinonitrile, 2-amino-4,6-dimethylnicotinonitrile,
2-amino-4-[2-(hexyloxy)phenyl]-6,7-dihydro-5H-pyrazolo[3,4-h]quinoline-3-
carbonitrile,
2-amino-4-[2-(beta-D-glucopyranosyloxy)phenyl]-6,7-dihydro-5H-
pyrazolo[3,4-h]quinoline-3-carbonitrile,
4-[2-(allyloxy)phenyl]-2-amino-6,7-dihydro-5H-pyrazolo[3,4-h]quinoline-3-
carbonitrile,
methyl [2-(2-amino-3-cyano-6,7-dihydro-5H-pyrazolo[3,4-h]quinolin-4-
yl)phenoxy]acetate,
2-amino-4-(2-ethoxyphenyl)-6,7-dihydro-5H-pyrazolo[3,4-h]quinoline-3-
carbonitrile,
ethyl 4-[2-amino-3-cyano-6-(2-furyl)pyridin-4-yl]-1 H-pyrrole-2-carboxylate,
2-amino-6-methylnicotinonitrile,
2-amino-6-(4-cyanophenyl)-4-(2-furyl)nicotinonitrile,
2-amino-6-(4-fluorobenzyl)-4-(2-furyl)nicotinonitrile,
2-amino-5-(4-fluorophenyl)-4-(2-furyl)-6-methylnicotinonitrile,
2-amino-4-(2-furyl)-6-(4-methoxyphenyl)nicotinonitrile,
2-amino-4-(2-methylphenyl)-5,6,7,8-tetrahydroquinoline-3-carbonitrile,
2-amino-4-(4-methoxyphenyl)-5,6,7,8-tetrahydroquinoline-3-carbonitrile,
2-amino-4-phenyl-5,6,7,8-tetrahydroquinoline-3-carbonitrile,
2-amino-6-(4-methoxyphenyl)-4-(2-methylphenyl)nicotinonitrile,
2-amino-4,6-bis(4-methoxyphenyl)nicotinonitrile,
2-amino-4-(3-chlorophenyl)-6-(4-methoxyphenyl)nicotinonitrile,
2-amino-4-(2-chlorophenyl)-6-(4-methoxyphenyl)nicotinonitrile,
2-amino-4-(2-furyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-3-carbonitrile,
2-amino-4-(2-furyl)-6-(4-methylphenyl)nicotinonitrile,
2-amino-4-(2-furyl)-6-phenylnicotinonitrile,
128

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6-amino-4-(2-furyl)-2,3'-bipyridine-5-carbonitrile,
2-amino-6-(1,3-benzodioxol-5-yl)-4-(2-furyl)nicotinonitrile,
2-amino-4-isoquinolin-4-yl-6-(4-methoxyphenyl)nicotinonitrile,
2-amino-4-(1-benzothien-3-yl)-6-(4-methoxyphenyl)nicotinonitrile,
2-amino-6-(4-methoxyphenyl)-4-thien-3-ylnicotinonitrile,
2-amino-4-(3-furyl)-6-(4-methoxyphenyl)nicotinonitrile,
2-amino-6-(4-methoxyphenyl)-4-(1 H-pyrrol-2-yl)nicotinonitrile,
2-amino-4-(2-furyl)-6-(1 H-pyrrol-2-yl)nicotinonitrile,
2'-amino-6'-(4-methoxyphenyl)-3,4'-bipyridine-3'-carbonitrile,
2-amino-4-[2-(trifluoromethoxy)phenyl]-6,7-dihydro-5H-py.razolo[3,4-
h]quinoline-3-carbonitrile,
2-amino-4-(2-furyl)-5H-thiochromeno[4,3-b]pyridine-3-carbonitrile,
2-amino-4-~4-[(2-cyanoethyl)(methyl)amino]phenyl}-6,7-dihydro-5H-
pyrazolo[3,4-h]quinoline-3-carbonitrile,
2-amino-4-[2-(2-hydroxyethoxy)phenyl]-6,7-dihydro-5H-pyrazolo[3,4-
h]quinoline-3-carbonitrile,
2-amino-4-(2-methylphenyl)-6,7-dihydro-5H-pyrazolo[3,4-h]quinoline-3-
carbonitrile,
2-amino-4-[4-(dimethylamino)phenyl]-6,7-dihydro-5H-pyrazolo[3,4-
h]quinoline-3-carbonitrile,
2-amino-4-(1 H-indol-7-yl)-6,7-dihydro-5H-pyrazolo[3,4-h]quinoline-3-
carbonitrile,
methyl 4-(2-amino-3-cyano-6,7-dihydro-5H-pyrazolo[3,4-h]quinolin-4-
yl)benzoate,
methyl2-(2-amino-3-cyano-6,7-dihydro-5H-pyrazolo[3,4-h]quinolin-4-
yl)benzoate,
[2-(2-amino-3-cyano-6,7-dihydro-5H-pyrazolo[3,4-h]quinolin-4-
yl)phenoxy]acetic acid,
2-amino-6- phenylnicotinonitrile,
2-amino-6-cyclohexylnicotinonitrile,
2-amino-4-(2-furyl)-6-(1-trityl-1 H-pyrazol-4-yl)nicotinonitrile,
2-amino-4-(2-fluorophenyl)-6-(4-hydroxyphenyl)nicotinonitrile,
129

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2,4-diamino-7,8-dihydroxy-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
2,4-diamino-8-hydroxy-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
2-amino-7,8-dihydroxy-4-[(2-hydroxyethyl)amino]-5H-chromeno[2,3-
b]pyridine-3-carbonitrile,
2,4-diamino-7,8-dimethoxy-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
2-amino-7,8-dihydroxy-4-(propylamino)-5H-chromeno[2,3-b]pyridine-3-
carbonitrile,
2-amino-4-(ethylamino)-7,8-dihydroxy-5H-chromeno[2,3-b]pyridine-3-
carbonitrile,
2,4-diamino-9-hydroxy-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
2,4-diamino-9-fluoro-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
2,4-diamino-7-hydroxy-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
2,4-diamino-8-(2-hydroxyethoxy)-5H-chromeno[2,3-b]pyridine-3-
carbonitrile,
8,10-diamino-2,3-dihydro-11H-[1,4]dioxino[2',3':6,7]chromeno[2,3-
b]pyridine-9-carbonitrile,
2,4,7-triamino-5H-chromeno[2,3-b]pyridine-3-carbonitrile
2,4-diamino-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
2,4-diamino-8-(2-ethoxyethoxy)-7-hydroxy-5H-chromeno[2,3-b]pyridine-3-
carbonitrile,
2,4-diamino-9-hydroxy-8-methoxy-5H-chromeno[2,3-b]pyridine-3-
carbonitrile,
2,4-diamino-6,8-dihydroxy-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
2,4-diamino-8-ethoxy-7-hydroxy-5H-chromeno[2,3-b]pyridine-3-
carbonitrile,
2,4-diamino-8-(2-ethoxyethoxy)-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
2,4-diamino-8-(2-aminoethoxy)-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
2,4-diamino-3-cyano-5H-chromeno[2,3-b]pyridine-7-carboxylic acid,
2,4-diamino-8,9-dihydroxy-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
2,4-diamino-8-(2-morpholin-4-ylethoxy)-5H-chromeno[2,3-b]pyridine-3-
carbonitrile,
[(2,4-diamino-3-cyano-5H-chromeno[2,3-b]pyridin-8-yl)oxy]acetic acid,
130

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2,4-diamino-9-methoxy-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
2,4-diamino-8-(2-pyrrolidin-1-ylethoxy)-5H-chromeno[2,3-b]pyridine-3-
carbonitrile,
2-amino-7,8-dimethoxy-4-(methylamino)-5H-chromeno[2,3-b]pyridine-3-
carbonitrile,
2,4-diamino-8-methoxy-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
2,4-diamino-8-[2-(dimethylamino)ethoxy]-5H-chromeno[2,3-b]pyridine-3-
carbonitrile,
2,4,7-triamino-9-methoxy-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
2(2,4-diamino-3-cyano-8-methoxy-5H-chromeno[2,3-b]pyridin-5-
yl)malononitrile,
2,4-diamino-7,8-di[2-(amino)ethoxy]-5H-chromeno[2,3-b]pyridine-3-
carbonitrile,
2,4-diamino-9-nitro-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
2-amino-7,8-dimethoxy-4-[(4-methoxyphenyl)amino]-5H-chromeno[2,3-
b]pyridine-3-carbonitrile,
2,4-diamino-8-methoxy-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
2(2,4-diamino-3-cyano-7-hydroxy-5H-chromeno[2,3-b]pyridin-5-
yl)malononitrile,
2(2,4-diamino-3-cyano-7-bromo-5H-chromeno[2,3-b]pyridin-5-
yl)malononitrile,
2-amino-8-ethoxy-4-(ethylamino)-5H-chromeno[2,3-b]pyridine-3-
carbonitrile,
2,4,9-triamino-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
2,4,7-triamino-5H-thiochromeno[2,3-b]pyridine-3-carbonitrile,
2-amino-7,8-dimethoxy-4-[(4-methoxypheny!)amino]-5H-chromeno[2,3-
b]pyridine-3-carbonitrile,
2(2,4-diamino-3-cyano-7-methoxy-5H-chromeno[2,3-b]pyridin-5-
yl)malononitrile,
2,4-diamino-9-hydroxy-8-(piperidin-1-ylmethyl)-5H-chromeno[2,3-
b]pyridine-3-carbonitrile,
7,8-bis(allyloxy)-2,4-diamino-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
131

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2-amino-8-(2-ethoxyethoxy)-4-[(2-ethoxyethyl)amino]-5H-chromeno[2,3-
b]pyridine-3-carbonitrile,
tent-butyl [[2,4-diamino-7-(2-tert~butoxy-2-oxoethoxy)-3-cyano-5H-
chromeno[2,3-b]pyridin-8-yl]oxy}acetate,
2-amino-4-[(2-aminoethyl)amino]-7,8-dimethoxy-5H-chromeno[2,3-
b]pyridine-3-carbonitrile,
2(2,4-diamino-3-cyano-8-hydroxy-5H-chromeno[2,3-b]pyridin-5-
yl)malononitrile,
2,4,7-triamino-5H-thiochromeno[2,3-b]pyridine-3-carbonitrile 10,10-
dioxide,
2,4-diamino-7-bromo-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
2-amino-7,8-dimethoxy-4-(propylamino)-5H-chromeno[2,3-b]pyridine-3-
carbonitrile,
2,4-diamino-7-hydroxy-5H-thiochromeno[2,3-b]pyridine-3-carbonitrile,
2,4-diamino-7-(dimethylamino)-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
2,4-diamino-7-methoxy-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
2(2,4-diamino-3-cyano-9-methoxy-5H-chromeno[2,3-b]pyridin-5-
yi)maiononitrile,
2-amino-4-(benzylamino)-7,8-dimethoxy-5H-chromeno[2,3-b]pyridine-3-
carbonitrile,
8-(allyloxy)-2,4-diamino-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
2,4-diamino-9-fluoro-5H-thiochromeno[2,3-b]pyridine-3-carbonitrile,
2,4-diamino-7-methoxy-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
2,4-diamino-9-(2-pyrrolidin-1-ylethoxy)-5H-chromeno[2,3-b]pyridine-3-
carbonitrile,
2,4-diamino-7-nitro-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
2,4-diamino-10-methyl-5,10-dihydrobenzo[b]-1,8-naphthyridine-3-
carbonitriie,
[(2,4-diamino-3-cyano-5H-chromeno[2,3-b]pyridin-9-yl)oxy]acetic acid,
2-amino-4-~[2-(dimethylamino)ethyl]amino}-7,8-dimethoxy-5H-
chromeno[2,3-b]pyridine-3-carbonitrile,
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2,4-diamino-7-nitro-5H-thiochromeno[2,3-b]pyridine-3-carbonitrile 10,10-
dioxide, .
2,4-diamino-7-phenyl-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
2,4-diamino-7-chloro-9-methyl-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
2,4-diamino-7-fluoro-5H-thiochromeno[2,3-b]pyridine-3-carbonitrile 10,10-
dioxide,
8-ethoxy-2,4-bis(ethylamino)-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
2,4-diamino-5-(2-fluoro-phenyl)-8-methoxy-5H-chromeno[2,3-b]pyridine-3-
carbonitrile,
2,4-diamino-9-(2-hydroxyethoxy)-5H-chromeno[2,3-b]pyridine-3-
carbonitrile,
2,4-diamino-9-(2-aminoethoxy)-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
2(2,4-diamino-3-cyano-7-chloro-5H-chromeno[2,3-b]pyridin-5-
yl)malononitrile,
2,4-bis{[2-(dimethylamino)ethyl]amino}-7,8-dimethoxy-5H-chromeno[2,3-
b]pyridine-3-carbonitrile,
2-amino-4-~[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]amino}-7,8-
dimethoxy-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
2,4-diamino-7-fluoro-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
2,4-diamino-7-bromo-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
2,4-diamino-9-(pyridin-4-ylmethoxy)-5H-chromeno[2,3-b]pyridine-3-
carbonitrile,
2,4-diamino-7-chloro-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
2,4-diamino-9-tert-butyl-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
ethyl2,4-diamino-3-cyano-5H-chromeno[2,3-b]pyridine-9-carboxylate,
2,4-diamino-9-[2-(dimethylamino)ethoxy]-5H-chromeno[2,3-b]pyridine-3-
carbonitrile,
2,4-bis(butylamino)-7,8-dimethoxy-5H-chromeno[2,3-b]pyridine-3-
carbonitrile,
2-amino-4-(butylamino)-7,8-dimethoxy-5H-chromeno[2,3-b]pyridine-3-
carbonitrile,
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.._..,
7,8-dimethoxy-2,4-bis(propylamino)-5H-chromeno[2,3-b]pyridine-3-
carbonitrile,
2,4-bis(ethylamino)-7,8-dimethoxy-5H-chromeno[2,3-b]pyridine-3-
carbonitrile,
~ 2-amino-4-(ethylamino)-7,8-dimethoxy-5H-chromeno[2,3-b]pyridine-3-
carbonitrile,
2,4-diamino-6,8-dimethoxy-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
2,4-diamino-7-(trifluoromethoxy)-5H-chromeno[2,3-b]pyridine-3-
carbonitrile,
2,4-diamino-7-bromo-9-methoxy-5H-chromeno[2,3-b]pyridine-3-
carbonitrile,
2,4-diamino-9-methoxy-7-nitro-5H-chromeno(2,3-b]pyridine-3-carbonitrile,
7,9-diamino-10H-[1,3]dioxolo[6,7]chromeno[2,3-b]pyridine-8-carbonitrile,
7,9-diamino-1 OH-[1,3]dioxolo[6,7]chromeno[2,3-b]pyridine-8-carbonitrile,
2,4-diamino-8-methyl-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
7,8-dimethoxy-2,4-bis[(2-methoxyethyl)amino]-5H-chromeno[2,3-
b]pyridine-3-carbonitrile,
2-amino-7,8-dimethoxy-4-[(2-methoxyethyl)amino]-5H-chromeno[2,3-
b]pyridine-3-carbonitrile,
2-amino-7,8-dimethoxy-4-[(2-pyrrolidin-1-ylethyl)amino]-5H-chromeno[2,3-
b]pyridine-3-carbonitrile,
7,8-dimethoxy-2,4-bis[(2-pyrrolidin-1-ylethyl)amino]-5H-chromeno[2,3-
b]pyridine-3-carbonitrile,
2,4-bis(glycinyl)-7,8-dimethoxy-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
N-(2-amino-3-cyano-7,8-dimethoxy-5H-chromeno[2,3-b]pyridin-4-
yl)glycine,
2,4-diamino-3-cyano-5H-chromeno[2,3-b]pyridine-9-carboxylic acid,
2,4-diamino-6-methoxy-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
2,4-diamino-9-bromo-7-chloro-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
2,4-bis(ethylamino)-7,8-dihydroxy-5H-chromeno[2,3-b]pyridine-3-
carbonitrile,
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2,4-diamino-6-bromo-9-methoxy-5H-chromeno[2,3-b]pyridine-3-
carbonitrile,
2,4-diamino-8-hydroxy-7,9-bis(piperidin-1-ylmethyl)-5H-chromeno[2,3-
b]pyridine-3-carbonitrile,
2,4-diamino-5-phenyl-8-hydroxy-5H-chromeno[2,3-b]pyridine-3-
carbonitrile,
2,4-diamino-5-(3-fluoro-phenyl)-8-methoxy-5H-chromeno[2,3-b]pyridine-3-
carbonitrile,
2,4-diamino-9-hydroxy-6,8-bis(piperidin-1-ylmethyl)-5H-chromeno[2,3-
b]pyridine-3-carbonitrile,
2,4-diamino-7-bromo-8-methoxy-5H-chromeno[2,3-b]pyridine-3-
carbonitrile,
2,4-diamino-5-phenyl-8-methoxy-5H-chromeno[2,3-b]pyridine-3-
carbonitrile,
2,4-diamino-9-fluoro-5H-thiochromeno[2,3-b]pyridine-3-carbonitrile 10,10-
dioxide,
2,4-diamino-7-nitro-5H-thiochromeno[2,3-b]pyridine-3-carbonitrile,
2,4-diamino-7-methoxy-5H-thiochromeno[2,3-b]pyridine-3-carbonitrile
10,10-dioxide,
2,4-diamino-7-methoxy-5H-thiochromeno[2,3-b]pyridine-3-carbonitrile,
2,4-diamino-5H-thiochromeno[2,3-b]pyridine-3-carbonitrile 10,10-dioxide,
2,4-diamino-5H-thiochromeno[2,3-b]pyridine-3-carbonitrile,
2,4-diamino-7-fluoro-5H-thiochromeno[2,3-b]pyridine-3-carbonitrile,
2-amino-7,9-dimethyl-5-oxo-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
2-amino-7-isopropyl-5-oxo-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
2-amino-7-ethyl-5-oxo-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
2-amino-7-methyl-5-oxo-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
2-amino-7-chloro-5-oxo-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
2-amino-7-bromo-5-oxo-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
2-amino-5-oxo-5H-chromeno[2,3-b]pyridine-3-carbonitrile, and
3-amino-5H-pyrido[3,4-b][1,4]benzothiazine-4-carbonitrile.
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[00060] It should be understood that salts and prodrugs of the
aminocyanopyridine compounds that are described herein, as well as
isomeric forms, tautomers, racemic mixtures of the compounds, and the
like, which have the same or similar activity as the compounds that are
described, are to be considered to be included within the description of the
compound.
[00061 ] Aminocyanopyridine MK-2 inhibiting compounds of the type
shown in formula II, above, include tricyclic aminocyanopyridine MK-2
inhibiting compounds, such as benzonapthyridines, pyridochromanes, and
pyridothiochromanes. A general method for the synthesis of these tricyclic
aminocyanopyridines is shown in Scheme 1, below:
Scheme 1:
O CN NH2
H H2N ~ CN 1 ) EtOH, AcOH, D ~ ~ CN
2) Et3SiH, TFA ~
R Z CN R ~G N NH
2
Z = OH, SH, NRaY G = O, S, NRa
[00062] In this method, a substituted benzaldehyde is reacted with a
tricarbonitrile, preferably 2-amino-1-propane-1,1,3-tricarbonitrile. The
reaction can be carried out by heating the reactants to reflux in a solution
of acetic acid and ethanol. The reaction product can be concentrated in
vacuo and dissolved in trifluoroacetic acid. Triethylsilane is added and the
mixture is stirred. In a preferred method, the mixture is stirred for about 1
hour at 0°C. Dichloromethane is then added and solids are collected.
The
solids can be collected by filtration, and can be washed with
dichloromethane and ether. The solids comprise the desired tricyclic
aminocyanopiyridine MK-2 inhibiting compound of the type including
benzonapthyridines, pyridochromanes, and pyridothiochromanes.
[00063] Referring to the reactants and products shown above in
Scheme I:
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Z can be OH, SH, or NRaY, where Y is a protecting group for
nitrogen. The Y group can be benzyl, allyl, an alkyl carbamate, or a benzyl
carbamate. Other nitrogen protecting groups are know to persons having
skill in the art of organic synthesis. A perferred protecting group is tert-
butylcarbamate. Ra can be an alkyl group, an aryl group, or a heteroaryl
group. The benzene ring of the benzaldehyde can be further substituted
by one, two, three, or four additional R groups at carbons 3, 4, 5, or 6.
Each R can independently be hydrogen; alkyl; aryl; a heteroatom, such as
O, N, or S, substituted with hydrogen, C1-C6 alkyl, C1-C6 branched alkyl,
aryl, heteroaryl (wherein the heteroaryl can include, but is not limited to,
pyrazolyl, inidizolyl, pyrryl, pyridyl, thiophyl, furyl and pyrimidyl), ester
and
amido.
[00064] Advantages of this method include that it is a general method
that can be used to produce various types of the tricyclic compounds of
formula II depending upon the types of reactants used. It is also an easy
and straightforward synthesis method that can be carried out in a single
vessel.
[00065] In an embodiment of this method of synthesis, a tricyclic
aminocyanopyridine MK-2 inhibiting compound can be prepared by
reacting a substituted benzaldehyde having the structure:
H
with a tricarbonitrile having the structure:
~N
C
Rb / C~ N
C
III
N
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to form an aminocyanopyridine compound having the structure:
R5 Rs Ra Rb
R6 \ \ C~ N
G~N~NH
R ~ 2
R8
wherein:
Z is selected from the group consisting of -OH, -SH, and -NRaY;
Ra is selected from the group consisting of alkyl, aryl, and
heteroaryl;
Y is a protecting group for nitrogen. Examples of such nitrogen
protecting groups include benzyl, allyl, alkyl carbamates and benzyl
carbamates.
G is selected from the group consisting of -O-, -S-, and -NRX ;
RX is alkyl;
Rb is selected from the group consisting of furyl and -NH-R2;
R2 is selected from the group consisting of hydrogen, alkyl, alkenyl,
alkynyl, alkoxy, hydroxyalkyl, alkylaryl, arylalkyl, alkoxyaryl, aminoalkyl,
alkylaminoalkyl, arylaminoalkyl, alkoxyalkyl, alkylcarboxy, and
carboxyalkyl;
R3 and R4 are each independently selected from the group
consisting of hydrogen, dicyanoalkyl, and substituted or unsubstituted
heterocyclyl and cyclyl, where substituents, if any, comprise halo moieties;
and
R5, R6, R' and R8 are each independently selected from the group
consisting of hydrogen, hydroxy, alkoxy, halo, alkyl, alkenyl, alkylyl,
arylalkyl, alkylaryl, amino, alkylamino, arylamino, alkylaminoalkyl, carboxy,
aminoalkoxy, alkylcarboxyalkyl, alkylamino, aminoalkyl, nitro, aryl,
arylamino, alkenoxy, hydroxyalkoxy, alkoxyalkoxy, heterocyclylalkyl,
heterocyclylalkoxy, carboxyalkoxy, alkylaminoalkoxy, alkylcarboxyalkoxy,
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pyrrolidylethoxy, hydroxyalkoxy, and alkylcarboxy, where R6 and R' are
such that they optionally join to form a six membered heterocyclic ring.
[00066] In an embodiment of the general method described above,
R~ is selected from the group consisting of hydrogen, alkyl, alkenyl,
alkynyl, alkoxy, hydroxyalkyl, alkylaryl, arylalkyl, alkoxyaryl, aminoalkyl,
alkylaminoalkyl, arylaminoalkyl, alkoxyalkyl, alkylcarboxy, and
carboxyalkyl;
R3 and R4 are each independently selected from the group
consisting of hydrogen, dicyanoalkyl, and substituted or unsubstituted
heterocyclyl and cyclyl, where substituents, if any, comprise halo moieties;
R5 is selected from the group consisting of hydrogen, alkoxy, halo,
alkyl, alkenyl, alkylyl, arylalkyl, or alkylaryl;
R6 is selected from the group consisting of hydrogen, hydroxy,
alkoxy, alkyl, alkenyl, alkynyl, amino, alkylamino, arylamino,
alkylaminoalkyl, carboxy, aminoalkoxy, halo, alkylcarboxyalkyl, alkylamino,
aminoalkyl, nitro, aryl, arylalkyl, alkylaryl, or arylamino;
R' is selected from the group consisting of hydrogen, hydroxy,
alkoxy, alkenoxy, hydroxyalkoxy, alkoxyalkoxy, aminoalkoxy,
heterocyclylalkyl, heterocyclylalkoxy, carboxyalkoxy, alkylaminoalkoxy,
and alkylcarboxyalkoxy;
where the R6 and R7 groups can join to form a six membered
heterocyclic ring; and
Ra is selected from the group consisting of hydrogen, hydroxy, halo,
nitro, amino, alkyl, alkoxy, heterocyclylalkoxy, carboxyalkoxy,
pyrrolidylethoxy, carboxymethoxy, hydroxyalkoxy, aminoalkoxy,
alkylcarboxy, alkylaminoalkyl, carboxy, and heterocyclylalkyl.
[00067] In a preferred embodiment of this method, the substituted
benzaldehyde comprises salicaldehyde and the tricarbonitrile comprises 2-
amino-1-propene-1,1,3-tricarbonitrile. It is also preferred that the nitrogen
protecting group "Y", comprises tert-butylcarbamate.
[00068] In an embodiment of the present method,
Z is selected from the group consisting of -OH, -SH, and -NRaY;
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Ra is selected from the group consisting of alkyl, aryl, and
heteroaryl;
Y is a protecting group for nitrogen that is selected from the group
consisting of benzyl, ailyl, alkyl carbamates and benzyl carbamate;
G is selected from the group consisting of -O-, -S-, and -NRX ;
RX is C1-C6 alkyl;
Rb is selected from the group consisting of furyl and -NH-R2;
R2 is selected from the group consisting of hydrogen, alkyl, alkenyl,
alkynyl, alkoxy, hydroxyalkyl, alkylaryl, arylalkyl, alkoxyaryl, aminoalkyl,
alkylaminoalkyl, arylaminoalkyl, alkoxyalkyl, alkylcarboxy, and
carboxyalkyl;
R3 and R4 are each independently selected from the group
consisting of hydrogen, dicyanoalkyl, and substituted or unsubstituted
heterocyclyl and cyclyi, where substituents, if any, comprise halo moieties;
and
R5, R6, R' and R$ are each independently selected from the group
consisting of:
hydrogen, hydroxy, amino, halo, vitro,
branched or unbranched C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl,
C1-C6 alkoxy, hydroxy C1-C6 alkyl, hydroxy C1-C6 alkoxy, Ci-C6 alkoxy Gi-
C6 alkoxy, C1-C6 alkoxy C1-C6 alkyl, C2-C6 alkenoxy,
branched or unbranched amino C1-C6 alkyl, diamino C2-C6 alkyl, C1-
Cs alkylamino C1-C6 alkyl, C1-C6 alkylamino, di-( C1-C6 alkyl)amino, C1-C4.
alkoxyarylamino, C1-C4 alkoxyalkylamino, amino C1-C6 alkoxy, di-(C1-C~.
alkylamino, C2-C6 alkoxy, di-(C1-C6 alkyl)amino C1-C6 alkyl, C1-C6
alkylamino C1-C6 alkoxy, halo C1-C6 alkoxy, dihalo Ci-C6 alkoxy, trihalo C1-
C6 alkoxy, cyano C1-C6 alkyl, dicyano Cj-C6 alkyl, cyano C1-C6 alkoxy,
dicyano C1-C6 alkoxy, carbamyl C1-C4 alkoxy, heterocyclyl C1-C~ alkoxy,
heteroaryl C1-C4 alkoxy, sulfo, sulfamyl, Cj-C4 alkylaminosulfonyl, hydroxy
C1-C4 alkylaminosulfonyl, di-(C1-C4 alkyl)aminosulfonyl, C1-C4 alkylthio, C1-
C4 alkylsulfonyl, G~-C4 alkylsulfinyl,
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aryl, aryl C1-C6 alkyl, heterocyclyl C1-C6 alkyl, heteroaryl C1-C6 alkyl,
heterocyclyl C1-C6 alkoxy, heteroaryl C1-Cs alkoxy, aryl C~-C6 alkoxy,
where the aryl ring can be substituted or unsubstituted, and, if substituted,
the substituent group is selected from one or more of the group consisting
of C~-C6 alkyl, halo, amino, and C1-C6 alkoxy,
substituted or unsubstituted C3-C6 cyclyl, Ca-C6 heterocyclyl, and, if
substituted, the substituent group is selected from one or more of the
group consisting of C1-C6 alkyl, C1-C6 alkoxy, halo, amino, and where the
C3-C6 heterocyclyl ring contains O, S, or N,
branched or unbranched C1-C6 alkoxycarbonyl C1-C6 alkoxy, and
carboxy, carboxy C1-C6 alkoxy, carboxy C1-C6 alkyl, hydroxy C1-C4
alkoxycarbonyl, C1-C4 alkoxycarbonyl.
[00069] And where the terms "alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl,
haloalkoxy, halo, alkylthio, alkylthioalkyl, heterocyclyl, cyclyl, aryl,
heteroaryl, cycloaryl, and oxo" have the same meanings as described
above.
[00070] A general method for the synthesis of aminocyanopyridine MK-
2 inhibitors that are not tricyclic benzonapthyridines, pyridochromanes,
and pyridothiochromanes can be found in Kambe, S. et al., Synthesis
5:366 - 368 (1980). Further details of the synthesis of
aminocyanopyridines are provided in the examples.
[00071] The MK-2 inhibiting activity of an aminocyanopyridine
compound can be determined by any one of several methods that are well
known to those having skill in the art of enzyme activity testing. One such
method is described in detail in the general methods section of the
examples. In addition, the efficacy of an aminocyanopyridine MK-2
inhibiting compound in therapeutic applications can be determined by
testing for inhibition of TNFa production in cell culture and in animal model
assays. In general, it is preferred that the aminocyanopyridine MK-2
inhibiting compounds of the present invention be capable of inhibiting the
production andlor the release of TNFa in cell cultures and in animal
models.
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[00072] In the present method, the aminocyanopyridine MK-2 inhibitor
compounds that are described herein can be used as inhibitors of
MAPKAP kinase-2. When this inhibition is for a therapeutic purpose, one
or more of the present compounds can be administered to a subject that is
in need of MK-2 inhibition. As used herein, a "subject in need of MK-2
inhibition" is a subject who has, or who is at risk of contracting a TNFa
mediated disease or disorder. TNFa mediated diseases and disorders are
described in more detail below.
[00073] In an embodiment of the present method, a subject in need of
prevention or treatment of a TNFa mediated disease or disorder is treated
with one or more of the present aminocyanopyridine compounds. In one
embodiment, the subject is treated with an effective amount of the
aminocyanopyridine MK-2 inhibitor compound. The effective amount can
be an amount that is sufficient for preventing or treating the TNFa
mediated disease or disorder.
[00074] The aminocyanopyridine compound that is used in the subject
method can be any aminocyanopyridine compound that is described
above.
[00075] In the subject method, the aminocyanopyridine MK-2 inhibitor
compound can be used in any amount that is an effective amount. It is
preferred, however, that the amount of the aminocyanopyridine compound
that is administered is within a range of about 0.1 mg/day per kilogram of
the subject to about 150 mg/day/kg. It is more preferred that the amount
of the aminocyanopyridine compound is within a range of about 0.1
mg/day/kg to about 20 mg/day/kg. An amount that is within a range of
about 0.1 mg/day/kg to about 10 mg/day/kg, is even more preferred.
[00076] When the term "about" is used herein in relation to a dosage
amount of the aminocyanopyridine compound, it is to be understood to
mean an amount that is within ~ 0.05 mg. By way of example, "about 0.1 -
10 mglday" includes all dosages within 0.05 to 10.05 mg/day.
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[00077] In another embodiment of the present invention, a
pharmaceutical composition that contains one or more of the
aminocyanopyridine MK-2 inhibitors can be administered to a subject for
the prevention or treatment of a TNFa mediated disease or disorder. The
pharmaceutical composition includes a aminocyanopyridine MK-2 inhibitor
of the present invention and a pharmaceutically acceptable carrier.
[00078] In another embodiment, a kit can be produced that is suitable
for use in the prevention or treatment of a TNFa mediated disease or
disorder. The kit comprises a dosage form comprising an
aminocyanopyridine MK-2 inhibitor in an amount which comprises a
therapeutically effective amount.
[00079] As used herein, an "effective amount" means the dose or
effective amount to be administered to a patient and the frequency of
administration to the subject which is readily determined by one of ordinary
skill in the art, by the use of known techniques and by observing results
obtained under analogous circumstances. The dose or effective amount
to be administered to a patient and the frequency of administration to the
subject can be readily determined by one of ordinary skill in the art by the
use of known techniques and by observing results obtained under
analogous circumstances. In determining the effective amount or dose, a
number of factors are considered by the attending diagnostician, including
but not limited to, the potency and duration of action of the compounds
used, the nature and severity of the illness to be treated, as well as the
sex, age, weight, general health and individual responsiveness of the
patient to be treated, and other relevant circumstances.
[00080] The phrase "therapeutically-effective" indicates the capability of
an agent to prevent, or improve the severity of, the disorder, while avoiding
adverse side effects typically associated with alternative therapies. The
phrase "therapeutically-effective" is to be understood to be equivalent to
the phrase "effective for the treatment, prevention, or inhibition", and both
are intended to qualify the amount of an agent for use in therapy which will
achieve the goal of improvement in the severity of pain and inflammation
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and the frequency of incidence, while avoiding adverse side effects
typically associated with alternative therapies.
[00081 ] Those skilled in the art will appreciate that dosages may also be
determined with guidance from Goodman & Goldman's The
Pharmacological Basis of Therapeutics, Ninth Edition (1996), Appendix II,
pp. 1707-1711.
[00082] The frequency of dose will depend upon the half-life of the
active components of the composition. If the active molecules have a
short half life (e.g. from about 2 to 10 hours) it may be necessary to give
one or more doses per day. Alternatively, if the active molecules have a
long half-life (e.g. from about 2 to about 15 days) it may only be necessary
to give a dosage once per day, per week, or even once every 1 or 2
months. A preferred dosage rate is to administer the dosage amounts
described above to a subject once per day,
[00083] For the purposes of calculating and expressing a dosage rate,
all dosages that are expressed herein are calculated on an average
amount-per-day basis irrespective of the dosage rate. For example, one
100 mg dosage of an aminocyanopyridine MIC-2 inhibitor taken once every
two days would be expressed as a dosage rate of 50 mg/day. Similarly,
the dosage rate of an ingredient where 50 mg is taken twice per day would
be expressed as a dosage rate of 100 mg/day.
[00084] For purposes of calculation of dosage amounts, the weight of a
normal adult human will be assumed to be 70 kg.
[00085] When the aminocyanopyridine MK-2 inhibitor is supplied along
with a pharmaceutically acceptable carrier, the pharmaceutical
compositions that are described above can be formed. Pharmaceutically
acceptable carriers include, but are not limited to, physiological saline,
Ringer's, phosphate solution or butter, buffered saline, and other carriers
known in the art. Pharmaceutical compositions may also include
stabilizers, anti-oxidants, colorants, and diluents. Pharmaceutically
acceptable carriers and additives are chosen such that side effects from
the pharmaceutical compound are minimized and the performance of the
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compound is not canceled or inhibited to such an extent that treatment is
ineffective.
(00086] The term "pharmacologically effective amount" shall mean that
amount of a drug or pharmaceutical agent that will elicit the biological or
medical response of a tissue, system, animal or human that is being
sought by a researcher or clinician. This amount can be a therapeutically
effective amount.
[00087] The term "pharmaceutically acceptable" is used herein to mean
that the modified noun is appropriate for use in a pharmaceutical product.
Pharmaceutically acceptable cations include metallic ions and organic
ions. More preferred metallic ions include, but are not limited to,
appropriate alkali metal salts, alkaline earth metal salts and other
physiological acceptable metal ions. Exemplary ions include aluminum,
calcium, lithium, magnesium, potassium, sodium and zinc in their usual
valences. Preferred organic ions include protonated tertiary amines and
quaternary ammonium cations, including in part, trimethylamine,
diethylamine, N,N'-dibenzylethylenediamine, chloroprocaine, choline,
diethanolamine, ethylenediamine, meglumine (N methylglucamine) and
procaine. Exemplary pharmaceutically acceptable acids include, without
limitation, hydrochloric acid, hydroiodic acid, hydrobromic acid, phosphoric
acid, sulfuric acid, methanesulfonic acid, acetic acid, formic acid, tartaric
acid, malefic acid, malic acid, citric acid, isocitric acid, succinic acid,
lactic
acid, gluconic acid, glucuronic acid, pyruvic acid oxalacetic acid, fumaric
acid, propionic acid, aspartic acid, glutamic acid, benzoic acid, and the
like.
[00088] Also included in the invention are the isomeric forms and
tautomers and the pharmaceutically-acceptable salts of the
aminocyanopyridine MK-2 inhibitors, Illustrative pharmaceutically
acceptable salts are prepared from formic, acetic, propionic, succinic,
glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic,
malefic,
fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, stearic,
salicylic, p-hydroxybenzoic, phenylacetic, mandeiic, embonic (pamoic),
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methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic,
toluenesulfonic, 2-hydroxyethanesulfonic, sulfanilic,
cyclohexylaminosulfonic, algenic, ~i-hydroxybutyric, galactaric and
galacturonic acids.
[00089] Suitable pharmaceutically-acceptable base addition salts of
compounds of the present invention include metallic ion salts and organic
ion salts. More preferred metallic ion salts include, but are not limited to,
appropriate alkali metal (Group la) salts, alkaline earth metal (Group Ila)
salts and other physiological acceptable metal ions. Such salts can be
made from the ions of aluminum, calcium, lithium, magnesium, potassium,
sodium and zinc. Preferred organic salts can be made from tertiary
amines and quaternary ammonium salts, including in part, trifluoroacetate,
trimethylamine, diethylamine, N,N'-dibenzylethylenediamine,
chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N
methylglucamine) and procaine. All of the above salts can be prepared by
those skilled in the art by conventional means from the corresponding
compound of the present invention.
[00090] The method of the present invention is useful for, but not limited
to, the prevention and treatment of diseases and disorders that are
mediated by TNFa. For example, the aminocyanopyridine MK-2 inhibitors
of the invention would be useful to treat arthritis, including, but not
limited
to, rheumatoid arthritis, spondyloarthopathies, gouty arthritis,
osteoarthritis, systemic lupus erythematosus and juvenile arthritis. Such
aminocyanopyridine MK-2 inhibitor compounds of the invention would be
useful in the treatment of asthma, bronchitis, menstrual cramps, tendinitis,
bursitis, connective tissue injuries or disorders, and skin related conditions
such as psoriasis, eczema, burns and dermatitis.
[00091] The aminocyanopyridine MK-2 inhibitor compounds that are
useful in the method of the invention also would be useful to treat
gastrointestinal conditions such as inflammatory bowel disease, gastric
ulcer, gastric varices, Crohn's disease, gastritis, irritable bowel syndrome
and ulcerative colitis and for the prevention or treatment of cancer, such as
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colorectal cancer. Such aminocyanopyridine MK-2 inhibiting compounds
would be useful in treating inflammation in diseases and conditions such
as herpes simplex infections, HIV, pulmonary edema, kidney stones, minor
injuries, wound healing, vaginitis, candidiasis, lumbar spondylanhrosis,
lumbar spondylarthrosis, vascular diseases, migraine headaches, sinus
headaches, tension headaches, dental pain, periarteritis nodosa,
thyroiditis, aplastic anemia, Hodgkin's disease, sclerodoma, rheumatic
fever, type I diabetes, myasthenia gravis, multiple sclerosis, sarcoidosis,
nephrotic syndrome, Behcet's syndrome, polymyositis, gingivitis,
hypersensitivity, swelling occurring after injury, myocardial ischemia, and
the like.
[00092] The aminocyanopyridine MK-2 inhibitors would also be useful in
the treatment of ophthalmic diseases, such as retinitis, retinopathies,
conjunctivitis, uveitis, ocular photophobia, and of acute injury to the eye
tissue. These compounds would also be useful in the treatment of
pulmonary inflammation, such as that associated with viral infections and
cystic fibrosis. The compounds would also be useful for the treatment of
certain central nervous system disorders such as cortical dementias
including Alzheimer's disease.
[00093] As used herein, the terms "TNFa mediated disease or disorder"
are meant to include, without limitation, each of the symptoms or diseases
that is mentioned above.
[00094] The terms "treating" or "to treat" mean to alleviate symptoms,
eliminate the causation either on a temporary or permanent basis, or to
prevent or slow the appearance of symptoms. The term "treatment"
includes alleviation, elimination of causation of or prevention of pain and/or
inflammation associated with, but not limited to, any of the diseases or
disorders described herein. Besides being useful for human treatment, the
subject compounds are also useful for treatment of mammals, including
horses, dogs, cats, rats, mice, sheep, pigs, etc.
[00095] The term "subject" for purposes of treatment includes any
human or animal subject who is in need of the prevention of or treatment
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of any one of the TNFa mediated diseases or disorders. The subject is
typically a mammal. "Mammal", as that term is used herein, refers to any
animal classified as a mammal, including humans, domestic and farm
animals, and zoo, sports, or pet animals, such as dogs, horses, cats,
cattle, etc., Preferably, the mammal is a human.
[00096] For methods of prevention, the subject is any human or animal
subject, and preferably is a subject that is in need of prevention and/or
treatment of a TNFa mediated disease or disorder. The subject may be a
human subject who is at risk of obtaining a TNFa mediated disease or
disorder, such as those described above. The subject may be at risk due
to genetic predisposition, sedentary lifestyle, diet, exposure to disorder-
causing agents, exposure to pathogenic agents and the like.
[00097] The subject pharmaceutical compositions may be administered
enterally and parenterally. Parenteral administration includes
subcutaneous, intramuscular, intradermal, intramammary, intravenous,
and other administrative methods known in the art. Enteral administration
includes solution, tablets, sustained release capsules, enteric coated
capsules, and syrups. When administered, the pharmaceutical
composition may be at or near body temperature.
(00098] In particular, the pharmaceutical compositions of the present
invention can be administered orally, for example, as tablets, coated
tablets, dragees, troches, lozenges, aqueous or oily suspensions,
dispersible powders or granules, emulsions, hard or soft capsules, or
syrups or elixirs. Compositions intended for oral use may be prepared
according to any method known in the art for the manufacture of
pharmaceutical compositions and such compositions may contain one or
more agents selected from the group consisting of sweetening agents,
flavoring agents, coloring agents and preserving agents in order to provide
pharmaceutically elegant and palatable preparations. Tablets contain the
active ingredient in admixture with non-toxic pharmaceutically acceptable
excipients which are suitable for the manufacture of tablets. These
excipients may be, for example, inert diluents, such as calcium carbonate,
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sodium carbonate, lactose, calcium phosphate or sodium phosphate;
granulating and disintegrating agents, for example, maize starch, or alginic
acid; binding agents, for example starch, gelatin or acacia, and lubricating
agents, for example magnesium stearate, stearic acid or talc. The tablets
may be uncoated or they may be coated by known techniques to delay
disintegration and adsorption in the gastrointestinal tract and thereby
provide a sustained action over a longer period. For example, a time
delay material such as glyceryl monostearate or glyceryl distearate may be
employed.
[00099] Formulations for oral use may also be presented as hard gelatin
capsules wherein the active ingredients are mixed with an inert solid
diluent, for example, calcium carbonate, calcium phosphate or kaolin, or
as soft gelatin capsules wherein the active ingredients are present as
such, or mixed with water or an oil medium, for example, peanut oil, liquid
paraffin, or olive oil.
[000100] Aqueous suspensions can be produced that contain the
aminocyanopyridine MK-2 inhibitors in admixture with excipients suitable
for the manufacture of aqueous suspensions. Such excipients are
suspending agents, for example, sodium carboxymethylcellulose,
methylcellulose, hydroxypropylmethyl-cellulose, sodium alginate,
polyvinylpyrrolidone gum tragacanth and gum acacia; dispersing or wetting
agents may be naturally-occurring phosphatides, for example lecithin, or
condensation products of an alkylene oxide with fatty acids, for example
polyoxyethylene stearate, or condensation products of ethylene oxide with
long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol,
or condensation products of ethylene oxide with partial esters derived from
fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or
condensation products of ethylene oxide with partial esters derived from
fatty acids and hexitol anhydrides, for example polyoxyethylene sorbitan
monooleate.
[000101] The aqueous suspensions may also contain one or more
preservatives, for example, ethyl or n-propyl p-hydroxybenzoate, one or
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more coloring agents, one or more flavoring agents, or one or more
sweetening agents, such as sucrose or saccharin.
[000102] Oily suspensions may be formulated by suspending the active
ingredients in an omega-3 fatty acid, a vegetable oil, for example arachis
oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid
paraffin. The oily suspensions may contain a thickening agent, for
example beeswax, hard paraffin or cetyl alcohol.
[000103] Sweetening agents, such as those set forth above, and
flavoring agents may be added to provide a palatable oral preparation.
These compositions may be preserved by the addition,of an antioxidant
such as ascorbic acid.
[000104] Dispersible powders and granules suitable for preparation of an
aqueous suspension by the addition of water provide the active ingredient
in admixture with a dispersing or wetting agent, a suspending agent and
one or more preservatives. Suitable dispersing or wetting agents and
suspending agents are exemplified by those already mentioned above.
Additional excipients, for example sweetening, flavoring and coloring
agents, may also be present.
[000105] Syrups and elixirs containing the novel compounds may be
formulated with sweetening agents, for example glycerol, sorbitol or
sucrose. Such formulations may also contain a demulcent, a preservative
and flavoring and coloring agents.
[000106] The subject compositions can also be administered
parenterally, either subcutaneously, or intravenously, or intramuscularly, or
intrasternally, or by infusion techniques, in the form of sterile injectable
aqueous or olagenous suspensions. Such suspensions may be
formulated according to the known art using those suitable dispersing of
wetting agents and suspending agents which have been mentioned above,
or other acceptable agents. The sterile injectable preparation may also be
a sterile injectable solution or suspension in a non-toxic parenterally-
acceptable diluent or solvent, for example as a solution in 1,3-butanediol.
Among the acceptable vehicles and solvents that may be employed are
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water, Ringer's solution and isotonic sodium chloride solution. In addition,
sterile, fixed oils are conventionally employed as a solvent or suspending
medium. For this purpose, any bland fixed oil may be employed including
synthetic mono-, or di-, glycerides. In addition, n-3 polyunsaturated fatty
acids may find use in the preparation of injectables.
[000107] The subject compositions can also be administered by
inhalation, in the form of aerosols or solutions for nebulizers, or rectally,
in
the form of suppositories prepared by mixing the drug with a suitable non-
irritating excipient which is solid at ordinary temperature but liquid at the
rectal temperature and will therefore melt in the rectum to release the
drug. Such materials are cocoa butter and poly-ethylene glycols.
[000108] The novel compositions can also be administered topically, in
the form of creams, ointments, jellies, collyriums, solutions or suspensions.
[000109] Daily dosages can vary within wide limits and will be adjusted to
the individual requirements in each particular case. In general, for
administration to adults, an appropriate daily dosage has been described
above, although the limits that were identified as being preferred may be
exceeded if expedient. The daily dosage can be administered as a single
dosage or in divided dosages.
[000110] Various delivery systems include capsules, tablets, and gelatin
capsules, for example.
[000111 ] The following examples describe preferred embodiments of the
invention. Other embodiments within the scope of the claims herein will be
apparent to one skilled in the art from consideration of the specification or
practice of the invention as disclosed herein. It is intended that the
specification, together with the examples, be considered to be exemplary
only, with the scope and spirit of the invention being indicated by the
claims which follow the examples. In the examples all percentages are
given on a weight basis unless otherwise indicated.
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GENERAL INFORMATION FOR PREPARATION METHODS:
[000112] Unless otherwise noted, reagents and solvents were used as
received from commercial suppliers.
[000113] NMR anal sis:
[000114] Proton nuclear magnetic resonance spectra were obtained on a
Varian Unity Innova 400, a Varian Unity Innova 300 a Varian Unity 300, a
Bruker AMX 500 or a Bruker AV-300 spectrometer. Chemical shifts are
given in ppm (8) and coupling constants, J, are reported in Hertz.
Tetramethylsilane was used as an internal standard for proton spectra and
the solvent peak was used as the reference peak for carbon spectra.
Mass spectra were obtained on a Perkin Elmer Sciex 100 atmospheric
pressure ionization (APCI) mass spectrometer, a Finnigan LCQ Duo
LCMS ion trap electrospray ionization (ESI) mass spectrometer, a
PerSeptive Biosystems Mariner TOF HPLC-MS (ESI), or a Waters ZQ
mass spectrometer (ESI).
[000115] Determination of MK-2 ICSO;
[000116] Recombinant MAPKAPK2 was phosphorylated at a
concentration of 42-78 ~.M by incubation with
0.23 ~.M of active p38a in 50 mM HEPES, 0.1 mM EDTA, 10 mM
magnesium acetate, and 0.25 mM ATP, pH 7.5 for one hour at 30°C.
[000117] The phosphorylation of HSP-peptide (KKKALSRQLSVAA) by
MAPKAPK2 was measured using an anion exchange resin capture assay
method. The reaction was carried out in 50 mM ~-glycerolphosphate, 0.04
BSA, 10 mM magnesium acetate, 2% DMSO and 0.8 mM dithiotheritol,
pH 7.5 in the presence of the HSP-peptide with 0.2 ~,Ci [y33P]ATP and
0.03mM ATP. The reaction was initiated by the addition of 15 nM
MAPKAPK2 and was allowed to incubate at 30°-C for 30 min. The
reaction
was terminated and [y33P]ATP was removed from solution by the addition
of 150 p,l of AG 1 X8 ion exchange resin in 900 mM sodium formate pH 3Ø
A 50 SCI aliquot of head volume was removed from the quenched reaction
mixture and added to a 96-well plate, 150 ~,I of Microscint-40 (Packard)
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was added and the amount of phosphorylated-peptide was determined.
Allow the Microscint to sit in the plates for 60 minutes prior to counting.
[000118] Compounds are evaluated as potential inhibitors of the MK2
kinase by measuring their effects on MK2 phosphorylation of the peptide
substrate. Compounds may be screened initially at two concentrations
prior to determination of ICSO values. Screening results are expressed as
percent inhibition at the concentrations of compound tested. For ICSO value
determinations, compounds are tested at six concentrations in ten-fold
serial dilutions with each concentration tested in triplicate. Results are
expressed as iCSO values in micromolar. The assay is performed at a final
concentration of 2% DMSO.
[000119] Preferred aminocyanopyridine MK-2 inhibiting compounds of
the present invention provide ICSO values for MK-2 inhibition of below 200
~,M. One method that can be used for determining the MK-2 inhibition ICSo
value is that described just above. More preferred aminocyanopyridine
MK-2 inhibiting compounds have the capability of providing MK-2 inhibition
ICSO values of below 100 p,M, yet more preferred of below 50 p.M, even
more preferred of below 20 p.M, yet more preferred of below 10 p,M, and
even more preferred of below 1 p.M.
[000120] 0937 Cell TNFa release assay
[000121 ] The human monocyte-like cell line, 0937 (ATCC #CRL-1593,2),
is cultured in RPM11640 media with 10% heat-inactivated fetal calf serum
(GIBCO), glutamine and pen/strep at 37°C and 5% C02. Differentiation of
U937 to monocytic/macrophage-like cells is induced by the addition of
phorboll2-myristate 13-acetate (Sigma) at final concentration of 20 ng/ml
to a culture of U937 cells at ~0.5 million cells/ml and incubated for 24 hrs.
The cells are centrifuged, washed with PBS and resuspended in fresh
media without PMA and incubated for 24 hrs. Cells adherent to the culture
flask are harvested by scraping, centrifugation, and resuspended in fresh
media to 2 million cells/ml, and 0.2 ml is aliquoted to each of 96 wells in
flat-bottom plate. Cells are then incubated for an additional 24 hrs to allow
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for recovery. The media is removed from the cells, and 0.1 ml of fresh
media is added per well. 0.05 ml of serially diluted compound or control
vehicle (Media with DMSO) is added to the cells. The final DMSO
concentration does not exceed 1 %. After 1 hr incubation, 0.05 ml of
400ng/ml LPS (E Coli serotype 0111:B4, Sigma) in media is added for final
concentration of 100 ng/ml. Cells are incubated at 37°C for 4 hrs.
After
4hrs incubation, supernatants are harvest and assayed by ELISA for the
presence of TNFa. '
[000122] U937 cell TNFa ELISA
[000123] ELISA plates (NUNC-ImmunoT"" Plate MaxisorbTM Surface)
were coated with purified mouse monoclonal IgG1 anti-human TNFa
antibody (R&D Systems #MAB610; 1.25 ug/ml in sodium bicarbonate pH
8.0, 0.1 ml/well) and incubated at 4°C. Coating solution was aspirated
the
following day and wells were blocked with 1 mg/ml gelatin in PBS (plus 1 x
thimerasol) for 2 days at 4°C. Prior to using, wells were washed 3x
with
wash buffer (PBS with 0.05% Tween). Cultured media samples were
diluted in EIA buffer (5 mg/ml bovine y globulin, 1 mg/ml gelatin, 1 ml/I
Tween-20, 1 mg/ml thimerasol in PBS), added to wells (0.1 mllwell) in
triplicate and allowed to incubate for 1.5 hr at 37°C in a humidified
chamber. Plates were again washed and 0.1 ml/well of a mixture of rabbit
anti-human TNFoc polyclonal antibodies in EIA buffer (1:400 dilution of
Sigma #T8300, and 1:400 dilution of Calbiochem #654250) was added for
1 hr at 37°C. Plates were washed as before and peroxidase-conjugated
goat anti-rabbit IgG (H+L) antibody (Jackson ImmunoResearch #111-035-
144, 1 ug/ml in EIA buffer, 0.1 ml/well) was added for 45 min. After final
washing, plates were developed with peroxidase-ABTS solution
(ICirkegaard/Perry #50-66-01, 0.1 ml/well). Enzymatic conversion of ABTS
to colored product was measured after 5-30 minutes using a SpectroMax
340 spectrophotometer (Molecular Devices) at 405 nm. TNF levels were
quantitated from a recombinant human TNFa (R&D Systems #210-TA-
010) standard curve using a quadratic parameter fit generated by
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SoftMaxPRO software. ELISA sensitivity was approximately 30 pg
TNF/ml. ICSO values for compounds were generated using BioAssay
Solver.
[000124] Preferred aminocyanopyridine MK-2 inhibiting compounds of
the present invention provide TNFa release ICSO values of below 200 ~.M
in an in vitro cell assay. One method that can be used for determining
TNFa release ICSO in an in vitro cell assay is that described just above.
More preferred aminocyanopyridine MK-2 inhibiting compounds have the
capability of providing TNFoc release ICSO values of below 50 ~.M, yet more
preferred of below 10, and even more preferred of below 1.0 p.M.
[000125] Lipopolysaccharide (LPS)-Induced TNFa Production.
[000126] Adult male 225-250 gram Lewis rats (Harlan Sprague-Dawley)
were used. Rats were fasted 18 hr prior to oral dosing, and allowed free
access to water throughout the experiment. Each treatment group
consisted of 5 animals.
[000127] Compounds were prepared as a suspension in a vehicle
consisting of 0.5% methylcellulose, 0.025% Tween-20 in PBS.
Compounds or vehicle were orally administered in a volume of 1 ml using
an 18 gauge gavage needle. LPS (E, coli serotype 0111:B4, Lot
#39H4103, Cat. # L-2630, Sigma) was administered 1-4 hr later by
injection into the penile vein at a dose of 1 mg/kg in 0.5 ml sterile saline.
Blood was collected in serum separator tubes via cardiac puncture 1.5 hr
after LPS injection, a time point corresponding to maximal TNFoc
production. After clotting, serum was withdrawn and stored at -20°C
until
assay by ELISA (described below).
[000128] Rat LPS TNFa ELISA
[000129] ELISA plates (NUNC-ImmunoTM Plate MaxisorbTM Surface)
were coated with 0.1 ml per well of an Protein G purified fraction of a 2.5
ug/ml of hamster anti-mouse/rat TNFcc monoclonal antibody TN19.12 (2.5
ug/ml in PBS, 0.1 ml/well). The hybridoma cell line was kindly provided by
Dr. Robert Schreiber, Washington University. Wells were blocked the
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following day with 1 mg/ml gelatin in PBS. Serum samples were diluted in
a buffer consisting of 5 mg/ml .bovine y-globulin, 1 mg/ml gelatin, 1 ml/I
Tween-20, 1 mg/ml thimerasol in PBS, and 0.1 ml of diluted serum was
added wells in duplicate and allowed to incubate for 2 hr at 37°C.
Plates
were washed with PBS-Tween, and 0.1 ml per well of a 1:300 dilution of
rabbit anti-mouse/rat TNFa antibody (BioSource International, Cat.
#AMC3012) was added for 1.5 hr at 37°C. Plates were washed, and a
1:1000 fold dilution of peroxidase-conjugated donkey anti-rabbit IgG
antibody (Jackson ImmunoResearch, Cat. #711-035-152) was added for
45 min. After washing, plates were developed with 0.1 ml of ABTS-
peroxide solution (Kirkegaard/Perry, Cat. #50-66-01 ). Enzymatic
conversion of ABTS to colored product was measured after ~30 minutes
using a SpectroMax 340 spectrophotometer (Molecular Devices Corp.) at
405 nm. TNF levels in serum were quantitated from a recombinant rat
TNFa (BioSource International, Cat. #PRC3014.) standard curve using a
quadratic parameter fit generated by SoftMaxPRO software. ELISA
sensitivity was approximately 30 pg TNF/ml. Results are expressed in
percent inhibition of the production of TNFa as compared to blood
collected from control animals dosed only with vehicle.
[000130] Preferred aminocyanopyridine MK-2 inhibiting compounds of
the present invention are capable of providing some degree of inhibition of
TNFa in animals. That is, the degree of inhibition of TNFoc in animals is
over 0%. One method for determining the degree of inhibition of TNFa is
the rat LPS assay that is described just above. More preferred
aminocyanopyridine MK-2 inhibiting compounds have the capability of
providing rat LPS TNFa inhibition values of at least about 25%, even more
preferred of above 50%, yet more preferred of above 70%, and even more
preferred of above 80%.
[000131 ] Synthesis of aminoc anopyridine compounds:
[000132] A general method for the synthesis of aminocyanopyridines
described in Examples 1 - 213 can be found in Kambe, S. et al., "A simple
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method for the preparation of 2-amino-4-aryl-3-cyanopyridines by the
condensation of malononitrile with aromatic aldehydes and alkyl ketones in
the presence of ammonium acetate", Synthesis 5:366 - 368 (1980).
Further details of the synthesis of aminocyanopyridines of the present
invention are provided below.
EXAMPLE 1
[000133] This example illustrates the production of 2-amino-6-(3,4-
dihydroxyphenyl)-4-(2-fluorophenyl)nicotinonitrile trifluoroacetate.
[000134] 2-Fluorobenzaledhyde (5 mmol, 1.0 equiv., 530p.L), 3,4-
dihydroxyacetophenone (5 mmol, 1.0 equiv., 760mg) malononitrile (5
mmol, 1.0 equiv., 290p.L) and ammonium acetate (7.5 mmol, 1.5 equiv.,
578mg) were combined in dichloroethane (10 mL) and heated to reflux for
4 hours. Dichloroethane was evaporated and the residue was purified by
reverse phase chromatography. The product was isolated as ari orange
solid (145mg, 8% yield).
1 H NMR (400 MHz, DMSO) ~ 7.70 (d, 1 H), 7.59-7.53 (m, 3H), 7.37 (d, 1 H),
7.32 (t, 1 H), 7.18 (s, 1 H), 6.90 (d, 1 H), 6.34 (bs, 1 H) 3.21 (bs, 4H): m/z
322 (M+H).
EXAMPLE 2
[000135] This example illustrates the production of 2-amino-4-(2-
fluorophenyl)-6-(2-furyl)nicotinonitrile trifluoroacetate.
[000136] 2-Fluorobenzaledhyde (2 mmol, 1.0 equiv., 210p.L), and
malononitrile (2 mmol, 1.0 equiv., 126~.L) were combined in toluene (3 mL)
and heated to 50°C for 0.5 hours. 2-acetyl furan (2 mmol, 1.0 equiv.,
146mg) and ammonium acetate (3 mmol, 1.5 equiv., 230mg) were added
and the reaction stirred at 55°C overnight. Amberlyst resin (1 g) was
added and the reaction was diluted with dichloromethane. After shaking
overnight, the resin was isolated by filtration and washed with
dichloromethane and methanol. The resin was treated with 2M ammonia
in methanol. After shaking overnight, the resin was removed by filtration
and the filtrate concentrated under a stream of nitrogen. The residue was
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purified by reverse phase chromatography and the product was isolated as
a brown solid (50mg, 9%). i H NMR (300 MHz, DMSO) 8 7.78 (s, 1 H),
7.65-7.75 (m, 2H), 7.43-7.35 (m, 2H), 7.22 (d, 1 H), 7.14 (s, 1 H), 6.67 (s,
1 H) 6.48 (bs, 2H): m/z 280 (M+H).
EXAMPLE 3
[000137] This example illustrates the production of 2-amino-6-(4-
hydroxyphenyl)-4-(1 H-imidazol-5-yl)nicotinonitrile trifluoroacetate.
[000138] Step 1: Production of 2-(1 H-imidazol-5-
ylmethylene)malononitrile.
[000139] 1 H-imidazole-5-carbaldehyde (20 mmol, 1.0 equiv., 1.92g), and
malononitrile (20 mmol, 1.0 equiv., 1.26mL) were combined in
trimethylorthoformate (30 mL) and triethylamine (7mL). After stirring at
room temperature overnight, the solvents were evaporated and the
residue partitioned between 1 M hydrochloric acid (HCI) and
dichloromethane. The aqueous layer was neutralized with sodium
bicarbonate and extracted with ethyl acetate (3 x 100 mL). The combined
organic extracts were dried over magnesium sulfate (MgS04~, filtered and
evaporated to give the product as a yellow solid (2.58g, 90%). 1H NMR
(400 MHz, Acetone) 8 12.11 (bs, 1 H), 8.07 (s, 1 H), 8.04 (s, 1 H), 7.95 (s,
1 H): m/z 143 (M-H).
[000140] Step 2: Production of 2-[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1 H-
inidazol-5-yl)methylene)malononitrile;
[000141] 2-(1 H-imidazol-5-ylmethylene)malononitrile, (2 mmol, 1.0
equiv., 288mg), prepared as described in Step 1, was added to a cool
(0°C) suspension of sodium hydride (60% in mineral oil, 1.1 equiv., 50
mg)
in tetrahydrofuran (THF) (15 mL). After 20 minutes, [2-
(chloromethoxy)ethyl](trimethyl)silane (2.2 mmol, 1.1 equiv., 390p,L) was
added and the solution warmed to room temperature overnight. The
reaction was treated with water (5mL) and concentrated the residue was
extracted with ethyl acetate (25 mL) and the layers separated. Dried
organic extract with MgS04, filtered and evaporated to give a brown solid.
The product was purified by silica gel chromatography. The product was
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isolated as a yellow solid, (277mg, 50%). 1H NMR (400 MHz, CDC13) 7.98
(s, 1 H), 7.76 (s, 1 H), 5.34 (s, 2H) 3.52 (dd, 2H), 0.92 (dd, 2H), -0.01 (s,
9H): m/z 275 (M+H).
[000142] Step 3: Production of 2-amino-6-(4-hydroxyphenyl)-4-(1 H-
imidazol-5-yl)nicotinonitrile trifluoroacetate.
[000143] 2-[(1-{[2-(trimethylsilyl)ethoxy]methyl-1 H-inidazol-5-
yl)methylene)malononitrile (0.8 mmol, 1.0 equiv., 220mg), prepared as
described in Step 2, above, 4-hydroxyacetophenone (0.8mmol, 1.0 equiv.,
109mg) and ammonium acetate (1.2 mmol, 1.5 equiv., 95mg) were
combined in toluene (3 mL) and benzene (1mL) heated to 80°C overnight.
After cooling, Amberlyst resin (1 g) was added and the mixture heated to
50°C overnight. The resin was isolated by filtration and washed with
dichloromethane and methanol. The resin was treated with 2M ammonia
in methanol. The resin was removed by filtration and the filtrate
concentrated under a stream of nitrogen. The residue was purified by
reverse phase chromatography and the product was isolated as a solid
(25mg, 11 %). 1 H NMR (300 MHz, Acetone) b 8.59 (s, 1 H), 8.32 (s, 1 H),
8.12 (d, 2H), 7.87 (s, 1 H), 6.97 (d, 2H), 6.73 (bs, 1 H): m/z 278 (M+H).
EXAMPLE 4
[000144] This illustrates the production of 2-amiho-6-(3-hydroxyphenyl)-
4-(1 H-imidazol-5-yl)nicotinonitrile trifluoroacetate.
[000145] 2-amino-6-(3-hydroxyphenyi)-4-(1 H-imidazol-5-yl)nicotinonitrile
trifluoroacetate was prepared in the same manner as 2-amino-6-(4-
hydroxyphenyl)-4-(1 H-imidazol-5-yl)nicotinonitrile trifluoroacetate, as
described in Example 3. The amount produced was 25mg, at a yield of
11 %. 1 H NMR (300 MHz, Acetone) 8 8.51 (s, 1 H), 8.32 (s, 1 H), 7.93 (s,
1 H), 7.76 (t, 1 H) 7.66 (d, 2H), 7.34 (t, 1 H), 6.98 (dd, 1 H), 6.59 (bs, 1
H):
m/z 278 (M+H). TNFa release assay IC50: 7.0 ~M; Rat LPS assay: 41
inhibition of TNFa production at 20 mpk (IG).
EXAMPLE 5
[000'146] This illustrates the production of 2-amino-6-(2-furyl)-4-(1 H-
imidazol-5-yl)nicotinonitrile trifluoroacetate.
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[000147] 2-amino-6-(2-furyl)-4-(1 H-imidazol-5-yl)nicotinonitrile
trifluoroacetate was prepared in the same manner as 2-amino-6-(4-
hydroxyphenyl)-4-(1 H-imidazol-5-yl)nicotinonitrile trifluoroacetate, as
described in Example 3. The amount produced was 20mg, at a yield of
10%. ~ H NMR (300 MHz, Acetone) ~ 8.40 (s, 1 H), 8.29 (s, 1 H), 7.81 (m,
2H), 7.27 (d, 1 H), 6.70-6.68 (m, 2H): m/z 252 (M+H).
EXAMPLE 6
[000148] This illustrates the production of intermediate 2-[1-(1-methyl-
1 H-imidazol-4-yl)ethylidene]malononitrile.
[000149] 2-(1 H-imidazol-5-yimethylene)malononitrile (3.92 mmol, 1.0
equiv., 565mg), prepared as described in Step 1 of Example 3, was
dissolved in THF and cooled to 0°C. Sodium hydride (60% in mineral oil,
1.1 equiv., 103 mg) as added followed by dimethylsulfate (4.31 mmol, 1.1
equiv., 410~,L). The solution warmed to room temperature overnight. The
reaction was treated with water and extracted with ethyl acetate. The
organic extract was dried with MgS04, filtered and evaporated to give a
solid. The product was isolated as a white solid, (500mg, 80%). iH NMR
(300 MHz, Acetone) 8.01 (s, 2H), 7.85 (s, 1 H), 3.92: m/z 159 (M+H). The
material can be used as an intermediate as shown next, for the
preparation of an aminocyanopyridine compound.
EXAMPLE 7
[000150] This illustrates the production of 2-amino-6-(2-furyl)-4-(1-
methyl-1 H-imidazol-4-yl)nicotinonitrile bis(trifluoroacetate).
[000151] 2-[1-(1-methyl-1H-imidazol-4-yl)ethylidene]malononitrile (1.0
mmol, 1.0 equiv., 158mg), 2-acetylfuran (1.0 mmol, 1.0 equiv., 100~,L) and
ammonium acetate (1.5 mmol, 1.5 equiv., 115mg) were combined in
toluene (2 mL) and benzene (1 mL) heated to 70°C overnight. After
cooling, Amberlyst resin (1 g) was added and the mixture shaken
overnight. The resin was isolated by filtration and washed with
dichloromethane and methanol. The resin was treated with 2M ammonia
in methanol. The resin was removed by filtration and the filtrate
concentrated under a stream of nitrogen. The residue was purified by
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reverse phase chromatography and the product was isolated as a solid
(35mg, 13%). 1 H NMR (400 MHz, Acetone) 8 8.08 (s, 1 H), 7.91 (s, 1 H),
7.81 (s, 1 H), 7.76 (s, 1 H), 7.19 (d, 1 H), 6.64 (d, 1 H) 6.46 (bs, 2H), 3.94
(s,
3H): m/z 266 (M+H).
EXAMPLE 8
[000152] This illustrates the production of 2-amino-4-(1-methyl-1 H-
imidazol-4-yl)-6-phenylnicotinonitrile bis(trifluoroacetate).
[000153] 2-amino-4-(1-methyl-1 H-imidazol-4-yl)-6-phenylnicotinonitrile
bis(trifluoroacetate) was prepared in the same manner as 2-amino-6-(2-
furyl)-4-(1-methyl-1 H-imidazol-4-yl)nicotinonitrile bis(trifluoroacetate), as
described in Example 7, with the production of 40mg of solid material and
with a yield of 13%. 1H NMR (400 MHz, Acetone) 8 8.15 (bs, 4H), 7.91 (s,
1 H), 7.48 (s, 3H), 4.00 (s, 3H): m/z 276 (M+H).
EXAMPLES 9 - 58
[000'154] This illustrates the production of aminocyanopyridine
compounds of the present invention.
[000155] The compounds listed in the table below were prepared by the
methods described in Kambe, S. et al., "A simple method for the
preparation of 2-amino-4-aryl-3-cyanopyridines by the condensation of
malononitrile with aromatic aldehydes and alkyl ketones in the presence of
ammonium acetate", Synthesis 5:366 - 368 (1980). NMR analysis was
carried out for each compound and selected data is presented for each
compound as shown in the table.
Ex. Compound name m/z
No.
(M+H)
9 4-[6-amino-5-cyano-4-(1 H-imidazol-5-yl)pyridin-2-yl]benzoic306
acid hydrochloride
10 2-amino-6-(3,4-dihydroxyphenyl)-4-(2- 322
fluorophenyi)nicotinonitrile
11 2-amino-4-(1 H-imidazol-5-yl)-6-phenylnicotinonitrile262
trifluoroacetate
12 2-amino-4-(1 H-imidazol-5-yl)-6-(4- 292
methoxyphenyl)nicotinonitrile trifluoroacetate
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Ex, Compound name m/z
No.
(M+H)
13 8-ethoxy-2,4-bis(ethylamino)-5H-chromeno[2,3-b]pyridine-3-339
carbonitrile
14 2-amino-6-(3-chlorophenyl)-4-(1 H-imidazol-5-296
yl)nicotinonitrile trifluoroacetate
15 4-[6-amino-5-cyano-4-(2-furyi)pyridin-2-341
yl]benzenesulfonamide trifluoroacetate
16 2-amino-4-(2-fluorophenyl)-6-(3-hydroxyphenyl)nicotinonitrile306
trifluoroacetate
17 2-amino-4-(2-bromophenyl)-6-(2-furyl)nicotinonitrile340
trifluoroacetate
18 2-amino-4-(2-fluorophenyl)-6-(4-hydroxyphenyl)nicotinonitrile306
trifiuoroacetate
19 2-amino-6-(4-chlorophenyl)-4-(1 H-imidazof-5-296
yl)nicotinonitrile trifluoroacetate
20 2-amino-4-(1 H-imidazol-5-yl)-6-[4- 340
(methylsulfonyl)phenyl]nicotinonitrile
trifluoroacetate
21 ethyl 4-[6-amino-5-cyano-4-(1 H-imidazol-5-yl)pyridin-2-334
yl]benzoate trifluoroacetate
22 2-amino-4-cyclopropyl-6-methylnicotinonitrile174
trifluoroacetate
23 2-amino-6-(2-furyl)-4-(4-phenoxyphenyl)nicotinonitrile354
trifluoroacetate
24 4-[2-amino-3-cyano-6-(2-furyl)pyridin-4-yl]phenylboronic306
acid
trifluoroacetate
25 4-[2-amino-3-cyano-6-(2-furyl)pyridin-4-yl]benzoic306
acid
trifluoroacetate
26 2-amino-4-(2-fluorophenyl)-6-(4- 320
methoxyphenyl)nicotinonitrile trifluoroacetate
27 2-amino-4-(3-fluorophenyl)-6-(4-hydroxyphenyl)nicotinonitril2306
trifluoroacetate
28 2-amino-4-(3-fluorophenyl)-6-(4- 320
methoxyphenyl)nicotinonitrile trifluoroacetate
29 2-[2-amino-3-cyano-6-(2-furyl)pyridin-4-yl]phenylboronic306
acid
trifluoroacetate
30 2-amino-6-(2-furyl)-4-[4-(trifluoromethyl)phenyl]nicotinonitrile330
trifluoroacetate
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Ex. Compound name m/z
No.
(M+H)
31 2-amino-4-(4-bromophenyl)-6-(2-furyl)nicotinonitrile340
trifluoroacetate
32 2-amino-4-[2-fluoro-4-(trifluoromethyl)phenyl]-6-(2-348
furyl)nicotinonitrile trifluoroacetate
33 2-amino-4-(3-fluorophenyl)-6-(2-furyl)nicotinonitriie280
trifluoroacetate
34 2-amino-4-(4-fluorophenyl)-6-(2-furyl)nicotinonitrile280
trifluoroacetate
35 2-amino-6-(4-methoxyphenyl)-4-thien-3-ylnicotinonitrile308
trifluoroacetate
36 2-amino-4-(3-furyl)-6-(4-methoxyphenyl)nicotinonitrile292
trifluoroacetate
37 2-amino-6-(4-methoxyphenyl)-4-(1 H-pyrrol-2-yl)nicotinonitrile291
trifluoroacetate
38 2-amino-6-(4-methoxyphenyl)-4-thien-2-ylnicotinonitrile308
trifluoroacetate
39 2-amino-4-(3-chlorophenyl)-6-(4- 336
methoxyphenyl)nicotinonitrile trifluoroacetate
40 2-amino-4-(2-chloropheny!)-6-(4-methoxyphenyl)336
nicotinonitrile trifluoroacetate
41 2'-amino-6'-(4-methoxyphenyl)-3,4'-bipyridine-3'-carbonitrile303
trifluoroacetate
42 2-amino-4-isoquinolin-4-yl-6-(4-methoxyphenyl)nicotinonitrile353
trifluoroacetate
43 2-amino-4-(1-benzothien-3-yl)-6-(4- 358
methoxyphenyl)nicotinonitrile trifluoroacetate
44 2-amino-4-(2-furyl)-6-(4-methoxyphenyl)nicotinonitrile292
trifluoroacetate
45 2-amino-4-(2-methylphenyl)-5,6,7,8-tetrahydroquinoline-3-263
carbonitrile trifluoroacetate
46 2-amino-4-(4-methoxyphenyl)-5,6,7,8-tetrahydroquinoline-3-280
carbonitrile trifluoroacetate
47 2-amino-4-phenyl-5,6,7,8-tetrahydroquinoline-3-carbonitrile250
48 2-amino-6-(4-methoxyphenyl)-4-(2- 316
methylphenyl)nicotinonitrile trifluoroacetate
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Ex. Compound name m/z
No. (M+H)
49 2-amino-4,6-bis(4-methoxyphenyl)nicotinonitrile332
trifluoroacetate
50 2-amino-6-(4-methoxyphenyl)-4-phenylnicotinonitrile302
trifluoroacetate
51 2-amino-4-butyl-6-methylnicotinonitrile190
trifluoroacetate
52 2-amino-6-methyl-4-propylnicotinonitrile176
trifluoroacetate
53 2-amino-4-ethyl-6-methylnicotinonitrile162
trifluoroacetate
54 2-amino-4,6-dimethylnicotinonitrile 148
trifluoroacetate
55 6-amino-4-(3-fluorophenyl)-2,4'-bipyridine-5-carbonitrile291
trifluoroacetate
56 2-amino-4-(3-fluorophenyl)-6-(3-hydroxyphenyl)nicotinonitrile306
trifluoroacetate
57 2-amino-4-(3-fluorophenyl)-6-(3-hydroxyphenyl)nicotinonitrile306
trifluoroacetate
58 6-amino-4-(2-fluorophenyl)-2,4'-bipyridine-5-carbonitrile291
trifluoroacetate
EXAMPLE 59
[000156] This illustrates the production of 4-[2-amino-3-cyano-6-(2-
furyl)pyridin-4-yl]-1 H-pyrrole-2-carboxamide.
[000157] A mixture of malononitrile (20mmol, 1.32g), ethyl 4-
formylpyrrole-2-carboxylate (20mmol, 3.34g), 2-acetylfuran (20 mmol,
2.2g) and ammonium acetate (30 mmol, 2.32g) in toluene (25mL) was
heated under reflux for 24 hours with azeotropic removal of water. After
cooling to room temperature, the reaction mixture was evaporated under
reduced pressure to dryness and the residue was stirred with ethanol
(15ml) for 4 hours. The resultant precipitate was collected by filtration,
washed with aqueous ethanol and air-dried. Recrystallization of the solid
from tetrahydrofuran gave a yellow-brown powder (2.25 g, 35% yield); iH
NMR (400 MHZ, DMSO) 8 12.42 (s, 1 H), 7.836 (s, 1 H), 7.776 (d, 1 H),
7.404 (d, 1 H), 7.220 (s, 1 H), 7.195 (d, 1 H), 6.797 (s, 2H), 6.642(dd, 1 H),
4.257 (q, 2H), 1.277 (t, 3H).
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[000158] To a suspension of the above solid (5mmol, 1.6g) in ethanol
(50mL) was added aqueous sodium hydroxide(10% wt/volume, l5mmol,
6ml) and the mixture was warmed at 60°C for 5 hours. The resultant
solution was kept at room temperature overnight and then evaporated
under reduced pressure. The residue was dissolved in warm water (50
ml), then acidified with 5% HCf solution to pH = 3. The resultant
precipitate was collected by filtration, washed with water and dried under
vacuum to give a greyish powder. To a solution of the above solid
(lmmol, 0.294g) in dry dimethylformamide (l2ml) was added 1,1'-
carbonyldiimidazole (1.2mmol, 0.195g) in one portion and the mixture was
stirred at 50°C for 2 hours. After cooling to room temperature, ammonia
was bubbled into the reaction mixture for 30 minutes and then kept at
room temperature for 48 hours. The mixture was evaporated in vacuo to
dryness and the residue was stirred with water (l0ml), The resultant
precipitate was collected by filtration, washed successively with water and
ether and recrystallized from methanol to give the product as a gray
powder (0.182g, 62% yield): iH NMR (400 MHz, DMSO) b 7.812 (s, 1 H),
7.459 (d, 1 H), 7.147 (s, 1 H), 7.128 (d, 1 H), 6.915 (d, 1 H), 6.620 (m, 3H);
m/z 294 (M+H).
EXAMPLES 60 - 75
[000159] This illustrates the production of aminocyanopyridine
compounds of the present invention.
[000160] The compounds listed in the table below were prepared by the
methods described in Kambe, S. et al., "A simple method for the
preparation of 2-amino-4-aryl-3-cyanopyridines by the condensation of
malononitrile with aromatic aldehydes and alkyl ketones in the presence of
ammonium acetate", Synthesis 5:366 - 368 (1980). NMR analysis was
carried out for each compound and selected data is presented for each
compound as shown in the table.
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j000161 ]
Ex. No. Compound name m/z (M+H)
60 4,6-diamino-2-(trifluoromethyl)-2,3-245
dihydrofuro[2,3-b]pyridine-5-carbonitrile
or
6N009
61 4,6-diamino-2-(chloromethyl)-2,3- 225
dihydrofuro[2,3-b]pyridine-5-carbonitrile
62 4-[2-amino-3-cyano-6-(2-furyl)pyridin-4-yl]-295
1 H-pyrrole-2-carboxylate
63 4,6-diamino-2-[(4- 313
methoxyphenoxy)methyl]-2,3-
dihydrofuro[2,3-b]pyridine-5-carbonitrile
64 4,6-diamino-2-(hydroxymethyl)-2,3-207
dihydrofuro[2,3-b]pyridine-5-carbonitrile
65 2,4-diamino-6-[(4- 273
methoxyphenyl)thio]nicotinonitrile
66 4,6-diamino-2-(phenoxymethyl)-2,3-283
dihydrofuro[2,3-b]pyridine-5-carbonitrile
67 4,6-diamino-2-[(2-methylphenoxy)methyl]-297
2,3-dihydrofuro[2,3-b]pyridine-5-carbonitrile
68 2-amino-7,9-dimethyl-5-oxo-5H- 266
chromeno[2,3-b]pyridine-3-carbonitrile
69 2-amino-7-isopropyl-5-oxo-5H- 280
chromeno[2,3-b]pyridine-3-carbonitrile
70 2-amino-7-ethyl-5-oxo-5H-chromeno[2,3-266
b]pyridine-3-carbonitrile
71 2-amino-7-methyl-5-oxo-5H-chromeno[2,3-252
b]pyridine-3-carbonitrile
72 2-amino-7-chloro-5-oxo-5H-chromeno[2,3-272
b]pyridine-3-carbonitrile
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. _. . ,
Ex. No. Compound name m/z (M+H)
73 2-amino-7-bromo-5-oxo-5H-chromeno[2,3-316, 318
b]pyridine-3-carbonitrile
74 2-amino-5-oxo-5H-chromeno[2,3- 238
b]pyridine-3-carbonitrile
75 ethyl4-[2-amino-3-cyano-6-(2-furyl)pyridin-323
4-yl]-1 H-pyrrole-2-carboxylate
EXAMPLE 76
[000162] This illustrates the production of 2-amino-6-(2-furyl)-4-(1 H-
imidazol-5-yl)nicotinonitrile trifluoroacetate.
[000163] Step 1: Production of 2-amino-6-(2-furyl)-4-(1-{[2-
(trimethylsilyl)ethoxy]methyl}-1 H-imidazol-4-yl)nicotinonitrile.
[000164] To a solution of 2-Acetylfuran (0.96 g, 8.71 mmol) and 2-[(1-([2-
(trimethylsilyl)ethoxy]methyl]-1 H-imidazol-5-yl)methylene]malononitrile (2.0
g, 7.3 mmol) in benzene (15 mL) at room temperature was added
ammonium acetate (1.08 g, 14.1 mmol). After heating to reflux for 10 hrs
the reaction was cooled to room temperature and diluted with ethyl acetate
and water. The layers were separated and the organic layer washed with
brine and dried sodium sulfate (Na2S04). The solvent was removed to
give a solid, which after chromatography (silica, 30% ethyl
acetate/hexane) gave the desired product (0.78 g, 38%). iH NMR (300
MHz, d6-DMSO) 8 8.14 (s, 1 H), 8.02 (s, 1 H), 7.88 (s, 1 H), 7.57 (s, 1 H),
7.10 (d, J = 3.3 Hz, 1 H), 6.81 (bm, 2H), 6.67 (m, 1 H), 5.44 (s, 2H), 3.53
(t,
J = 7.5 Hz, 2H), 0.86 (t, J = 7.5 Hz, 2H), 0.05 (s, 9H): m/z 382 (M+H).
[000165] Step 2: Production of 2-amino-6-(2-furyl)-4-(1 H-imidazol-5-
yl)nicotinonitrile trifluoroacetate.
[000166] To a round bottom flask containing 2-amino-6-(2-furyl)-4-(1-([2-
(trimethylsilyl)ethoxy]methyl}-1 H-imidazol-4-yl)nicotinonitrile (0.42 g, 1.10
mmol), prepared as described in Step 1, above, was added 0.5 M
HCI/ethyl alcohol (EtOH) (15 mL) at room temperature. The reaction was
heated to reflux for 5 hrs and then allowed to cool. A precipitate formed
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upon cooling and was filtered. The solid was collected and purified by
reverse phase high pressure liquid chromatography (RP-HPLC)
(H20:CH3CN+j0.05%TFA) to give the desired product after lypholization
(0.22 g, 61 % yield). 1H NMR (300 MHz, d6-DMSO) 8 8.46 (bs, 1 H), 8.11
(s, 1 H), 7.91 (d, J = 1.2 Hz, 1 H), 7.48 (s, 1 H), 7.13 (d, J = 3.6 Hz, 1 H),
6.69 (dd, J = 1.8, 3.3 Hz, 1 H), 3.7 (bm, 3H): m/z 252 (M+H).
EXAMPLE 77
[000167] This illustrates the production of ethyl 4-[6-amino-5-cyano-4-(2-
fluorophenyl)pyridin-2-yl]benzoate.
[000168] To a solution of ethyl 4-acetylbenzoate (1.12 g, 5.83 mmol) and
2-(2-fluorobenzylidene)malononitrile (1.0 g, 5.81 mmol) in benzene at
room temperature was added ammonium acetate (0.67 g, 8.69 mmol).
The reaction mixture was heated to reflux for 4 hrs and then allowed to
cool to room temperature. The reaction mixture was poured into ethanol
and the precipitate filtered to give a light yellow solid (0.30 g, 14% yield).
iH NMR (300 MHz, d6-DMSO) b 8.24 (d, J = 8.1 Hz, 2H), 8.04 (d, J = 8.1
Hz, 2H), 7.60-7.58 (bm, 2H), 7.40-7.34 (bm, 4H), 7.17 (bs, 1 H), 4.34 (q,
2H), 1.32 (t, 3H): m/z 362 (M+H).
EXAMPLE 78
[000169] This illustrates the production of 4-[6-amino-5-cyano-4-(2-
fluorophenyl)pyridin-2-yl]benzoic acid trifluoroacetate.
[000170] To a solution of ethyl-4-[6-amino-5-cyano-4-(2-
fluorophenyl)pyridin-2-yl]benzoate (0.20 g, 0.55 mmol) in THF/H~O (9:1 )
was added aqueous lithium hydroxide (LiOH~H20) at room temperature.
The reaction was heated to reflux for 4 hrs and the solvent removed in
vacuo to give a solid, which was purified by RP-HPLC to give the desired
product (0.091 g, 50% yield). iH NMR (300 MHz, d6-DMSO) ~ 8.27(d, J =
8.4 Hz, 2H), 8.08 (d, J = 8.4 Hz, 2H), 7.66-7.62 (bm, 2H), 7.52-7.40 (bm,
3H), 7.21 (bs, 1 H), 4.81 (bs, 2H): m/z 334 (M+H).
EXAMPLE 79
[000171] This illustrates the production of 2-amino-4-(2-furyl)-6-(1 H-
pyrazol-3-yl)nicotinonitrile trifluoroacetate.
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[000172] Step 1; Production of 1-(1H-pyrazol-5-yl)-1-ethanone.
[000173] To a solution of KOH (18 g, in 50 mL of water) was added
diethyl ether. The solution was cooled to 0 °C and 1-Methyl-3-1-
nitrosoguanidine (MNNG), (4.0 g) was added slowly to generate
diazomethane (CH2N2). After this addition was complete the CH2N2 in
diethyl ether was transferred to a solution of 3-Butyn-2-one (4.0 g, 0.058
mol) in ether via pipet. The reaction was stirred at room temperature for 4
hrs and the solvent removed in vacuo to give an oil, which on high vacuum
turned to a solid (1.71 g, 26% yield). 'H NMR (300 MHz, CDC13) 8 7.68 (d,
J = 2.1 Hz, 1 H), 6.84 (d, J = 2.1 Hz, 1 H), 2.60 (s, 3H).
[000174] Step 2: Production of 2-amino-4-(2-furyl)-6-(1 H-pyrazol-3-
yl)nicotinonitrile trifluoroacetate.
[000175] To a solution of 1-(1H-pyrazol-5-yl)-1-ethanone (0.64 g, 5.80
mmol), prepared as described above in Step 1, furaldehyde (0.48 mL, 5.80
mmol), and malononitrile (0.38 g, 5.80 mmol) in benzene (15 mL) at room
temperature was added ammonium acetate (1.11 g, 14.5 mmol). The
reaction was heated to reflux for 10 hrs and then allowed to cool to room
temperature. The mixture was diluted with water and ethyl acetate. The
layers were separated and the organic layer washed with brine and dried,
using Na2S04. The solvent was removed to give a brown solid, which
after RP-HPLC (H20:CH3CN+0.05%TFA) gave the desired product (185
mg, 12% yield). iH NMR (300 MHz, CD30D) 8 8.0 (d, J = 1.2 Hz, 1 H),
7.81 (d, J = 2.1 Hz, 1 H), 7.61 (s, 1 H), 7.46 (d, J = 3.6 Hz, 1 H), 6.84 (d,
J =
2.1 Hz, 1 H), 6.78-6.76 (m, 1 H); m/z 252 (M+H).
EXAMPLES 80 - 91
[000176] This illustrates the production of aminocyanopyridine
compounds of the present invention.
[000177] The compounds fisted in the table below were prepared by the
methods described in Kambe, S. et al., "A simple method for the
preparation of 2-amino-4-aryl-3-cyanopyridines by the condensation of
malononitrile with aromatic aldehydes and alkyl ketones in the presence of
ammonium acetate", Synthesis 5:366 - 368 (1980). NMR analysis was
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carried out for each compound and selected data is presented for each
compound as shown in the table.
Ex. No. Compound name m/z (M+H)
80 2-amino-4-(1 H-imidazol-4-yl)-6- 262
phenylnicotinonitrile trifluoroacetate
hydrate
81 2-amino-4-(2-fluorophenyl)-6-(1 H-pyrrol-2-279
yl)nicotinonitrile trifluoroacetate
hydrate
82 2-amino-6-(3-chlorophenyl)-4-(1 H-imidazol-4-296
yl)nicotinonitrile trifluoroacetate
hydrate
83 2-amino-4-(2-fluorophenyl)-6-phenylnicotinonitrile290
84 ethyl4-[6-amino-5-cyano-4-(2- 334
fluorophenyl)pyridin-2-yl]benzoate
85 2-amino-6-(2-fluorophenyl)-4-(3- 280
furyl)nicotinonitrile trifluoroacetate
86 2-amino-4-(2-fluorophenyl)-6-thien-2- 296
ylnicotinonitrile hydrate
87 6-amino-4-(2-fluorophenyl)-2,2'-bipyridine-5-291
carbonitrile trifluoroacetate
88 2-amino-4-(2-furyl)-6-(1 H-pyrazol-4- 252
yl)nicotinonitrile bis(trifluoroacetate)
89 2-amino-4-(2-furyl)-6-(1-trityl-1 H-pyrazol-4-494
yl)nicotinonitrile
90 2-amino-4-(2-fluorophenyl)-6-tetrahydrofuran-2-284
ylnicotinonitrile
91 ethyl6-amino-5-cyano-4-(2-fluorophenyl)pyridine-286
2-carboxylate
EXAMPLE 92
[000178] This illustrates the production of 2-amino-4-(2-furyl)-8-hydroxy-
5,6-dihydrobenzo[h]quinoline-3-carbonitrile trifluoroacetate.
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[000'179] A glass vial was charged with 6-hydroxy-2-tetralone (0.49 g, 3
mmol), malononitrile, (0. g, 3 mmol), ammonium acetate (0. g, 6 mmol),
furaldehyde (0. g, 3 mmol) and a magnetic stirring bar. Benzene (6 mL)
was added to the vial, which was capped and heated to 80 degrees
Celsius for 18 hours. The vial was then cooled to room temperature, and
a 1:2 mixture of methanol and dichloromethane (15 mL) was added
followed by 8 g of Amberlyst resin. The mixture was agitated for 24 h,
then the resin was filtered and washed with dichloromethane (3X15 mL).
A 2 M solution of ammonia in methanol (15 mL) was added to the resin,
and the mixture was agitated overnight at room temperature. The resin
was filtered and the filtrate collected in a tared flask. The resin was
washed sequentially with a 1:1 mixture of methanol and dichloromethane
(2X15 mL), 2 M ammonia in methanol (2X15 mL), and a 1:1 mixture of
methanol and dichloromethane (2X15 mL). The combined filtrates were
concentrated in vacuo, and the residue was purified by reverse phase
chromatography. The product was isolated as a tan solid (10.4 mg, 1
yield). 1H NMR (400 MHz, DMSO) ~ 2.70 (m, 4H), 6.63 (d, 1 H), 6.70 (dd,
1 H), 6.73 (d, 1 H), 6.87 (d, 1 H), 7.91 (d, 1 H), 7.96 (d, 1 H); m/z 304
(M+H);
HRMS (M+H) calculated for CigH~4NgO2: 304.1086, found 304.1086.
. EXAMPLE 93
[000180] This illustrates the production of 2-amino-4-(2-furyl)-6,8-
dihydro-5H-pyrrolo[3,4-h]quinoline-3-carbonitrile trifluoroacetate.
[000181 ] This material was prepared in a manner similar to that used to
produce 2-amino-4-(2-furyi)-8-hydroxy-5,6-dihydrobenzo[h]quinoline-3-
carbonitrile trifluoroacetate, as described in Example 92. The product was
isolated as a tan solid (171.9 mg, 17% yield). 1H NMR (400 MHz, DMSO)
8 2.60 (m, 2H), 2.74 (m, 2H), 6.65 (s, 1 H), 6.73 (dd, 1 H), 6.90 (d, 1 H),
7.30
(s, 1 H), 7.95 (s, 1 H), 11.9 (br s, 1 H); m/z 277 (M+H); HRMS (M+H)
calculated for C16H~3N4O: 277.1089, found 277.1078.
EXAMPLE 94
[000182] This illustrates the production of 2-amino-4-(2-furyl)-6,7-
dihydro-5H-pyrazolo[3,4-h]quinoline-3-carbonitrile bis(trifluoroacetate).
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[000183] This material was prepared in a manner similar to that used to
produce 2-amino-4-(2-furyi)-8-hydroxy-5,6-dihydrobenzo[h]quinoline-3-
carbonitrile trifluoroacetate, as described in Example 92. The product was
isolated as a tan solid (248 mg, 17% yield). 'H NMR (400 MHz, DMSO) 8
2.75-2.90 (m, 4H), 6.73 (dd, 1 H), 6.88 (d, 1 H), 7.92 (s, 1 H), 7.95 (d, 1
H);
m/z 278 (M+H); HRMS (M+H) calculated for C15H12N5O~ 278.1042, found
278.1058.
EXAMPLE 95
[000184] This illustrates the production of 2-amino-4-(2-fluorophenyl)-5,6-
dihydrobenzo[h]quinofine-3-carbonitrile trifluoroacetate.
[000185] This material was prepared in a manner similar to that used to
produce 2-amino-4-(2-furyl)-8-hydroxy-5,6-dihydrobenzo[h]quinoline-3-
carbonitrile trifluoroacetate, as described in Example 92. The product was
isolated as a tan solid (49.1 mg, 4% yield). iH NMR (400 MHz, DMSO) 8
2.38-2.48 (m, 2H), 2.75-2.82 (m, 2H), 7.25-7.30 (m, 2H), 7.35-7.47 (m,
5H), 7.55-7.64 (m, 1 H), 8.16-8.22 (m, 1 H); m/z 316 (M+H); ); HRMS (M+H)
calculated for C2oH~5FN3: 316.1250, found 316.1248.
EXAMPLE 96
[000186] This illustrates the production of 2-amino-3-cyano-4-(2-furyl)-
5,6-dihydrobenzo[h]quinoline-8-carboxylic acid trifluoroacetate. ,
[000187] This material was prepared in a manner similar to that used to
produce 2-amino-4-(2-furyl)-8-hydroxy-5,6-dihydrobenzo[h]quinoline-3-
carbonitrile trifluoroacetate, as described in Example 92. The product was
isolated as a tan solid (30.1 mg, 5% yield). iH NMR (400 MHz, DMSO) 8
2.80-2.93 (m, 4H), 6.77 (dd, 1 H), 6.98 (dd, 7.87 (dd, 1 H), 7.92 (d, 1 H),
7.95 (d, 1 H), 7.99 (dd, 1 H), 8.23 (d, 1 H) ); mlz 332 (M+H); HRMS (M+H)
calculated for Ci9H14N3O3: 332.1035, found 332.1032.
EXAMPLE 97
[000188] This illustrates the production of 2-amino-3-cyano-4-(4H-1,2,4-
triazol-3-yl)-5,6-dihydrobenzo[h]quinoline-8-carboxylic acid
bis(trifiuoroacetate).
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[000189] This material was prepared in a manner similar to that used to
produce 2-amino-4-(2-furyl)-8-hydroxy-5,6-dihydrobenzo[h]quinoline-3-
carbonitrile trifluoroacetate, as described in Example 92. The product was
isolated as a tan solid (29.4 mg, 4% yield). iH NMR (400 MHz, DMSO) 8
2.72-2.92 (m, 4H), 7.86 (s, 1 H), 7.94 (d, 1 H), 8.27 (d, 1 H), 8.78 (br s, 1
H);
m/z 333 (M+H); HRMS (M+H) calculated for C17H13N6O2: 333.1100, found '
333.1083.
EXAMPLE 98
[000190] This illustrates the production of 2-amino-4-(2-furyl)-5,6-
dihydro-1,8-phenanthroline-3-carbonitrile bis(trifluoroacetate).
[000191] 2-amino-4-(2-furyl)-5,6-dihydro-1,8-phenanthroline-3-
carbonitrile bis(trifluoroacetate) was prepared in a manner similar to that
used to produce 2-amino-4-(2-furyl)-8-hydroxy-5,6-
dihydrobenzo[h]quinoline-3-carbonitrile trifluoroacetate, as described in
Example 92. The product was isolated as a tan solid (205 mg, 12%
yield). 1 H NMR (400 MHz, DMSO) 8 2.85-2.98 (m, 4H), 6.79 (dd, 1 H),
7.04 (dd, 1 H), 8.02 (dd, 1 H), 8.19 (1 H), 8.76 (d, 1 H), 8.77 (s, 1 H); m/z
289
(M+H); HRMS (M+H) calculated for C17H13N4O: 289.1089, found 289.1069.
EXAMPLE 99
[000192] This illustrates the production of 2-amino-4-(2-fluorophenyl)-6,8-
dihydro-5H-pyrazolo[3,4-h]quinoline-3-carbonitrile bis(trifluoroacetate).
[000193] 2-amino-4-(2-fluorophenyl)-6,8-dihydro-5H-pyrazolo[3,4-
h]quinoline-3-carbonitrile bis(trifluoroacetate) was prepared in a manner
similar to that used to produce 2-amino-4-(2-furyl)-8-hydroxy-5,6-
dihydrobenzo[h]quinoline-3-carbonitrile trifluoroacetate, as described in
Example 92. The product was isolated as a yellow solid (173.7 mg, 17%
yield). 1H NMR (400 MHz, DMSO) 8 2.50-2.60 (m, 2H), 2.72-2.78 (m, 2H),
7.36-7.48 (m, 3H), 7.55-7.63 (m, 1 H), 7.97 (s, 1 H); m/z 306 (M+H); HRMS
(M+H) calculated for C1~H13FN5: 306.1150, found 306.1178.
EXAMPLE 100
[000194] This illustrates the production of 2-amino-4-phenyl-6,8-dihydro-
5H-pyrazolo[3,4-h]quinoline-3-carbonitrile bis(trifluoroacetate).
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[000195] This material was prepared in a manner similar to that used to
produce 2-amino-4-(2-furyl)-8-hydroxy-5,6-dihydrobenzo[h]quinoline-3-
carbonitrile trifluoroacetate, as described in Example 92. The product was
isolated as a yellow solid (242 mg, 24% yield). iH NMR (400 MHz,
DMSO) 8 2.50-2.62 (m, 2H), 2.69-2.76 (m, 2H), 7.36-7.46 (m, 2H), 7.50-
7.59 m, 3H), 7.96 (s, 1 H); m/z 288 (M+H); HRMS (M+H) calculated for
C17H14N5: 288.1244, found 288.1253. TNFa release assay ICSO = 17.7 p,M.
EXAMPLE 101
[000196] This illustrates the production of 2-amino-3-cyano-4-(2-furyl)-
5,6-dihydrobenzo[h]quinoline-8-carboxylic acid trifluoroacetate.
[000197] Step- 1: (Preparation of 5-oxo-5,6,7,8-tetrahydronaphthalene-2-
yl-trifluoromethanesulfonate) - A round bottomed flask was charged with
6-hydroxy-1-tetralone (7.87 g, 48.5 mmol), pyridine (97 mL) and a
magnetic stirring bar. The flask was sealed under nitrogen, and triflic
anhydride (8.24 mL, 49 mmol) was added dropwise over 30 minutes. The
mixture was stirred at room temperature for 7 days, then the mixture was
diluted with diethyl ether. The organic layer was washed with water
(1 X100 ml), 5% aqueous hydrogen chloride (2X100 mL), and brine (1 X100
mL). The organic layer was then dried over magnesium sulfate and
concentrated in vacuo. The product was purified via flash column
chromatography (0-20% ethyl acetate/hexane) to give 11.72 g of product
as a white solid (81% yield). iH NMR (400 MHz, DMSO) 8 2.22 (quintet,
2H), 2.72 (t, 2H), 3.06 (t, 2H), 7.22 (s, 1 H), 7.24 (d, 1 H), 8.17 (d, 1 H);
HRMS (M+H) calculated for C17H1oF3O5S: 295.0246, found 295.0285.
[000198] Step 2: (Preparation of methyl 5-oxo-5,6,7,8-
tetrahydronaphthalene-2-carboxylate) - A three-necked round bottomed
flask was charged with 5-oxo-5,6,7,8-tetrahydronaphthalene-2-yl-
trifluoromethanesulfonate, prepared as described in Step 1, (9.98 g, 33.9
mmol), bis(diphenylphosphony!)propane (0.42 4, 1 mmol), palladium
acetate (0.23 g, 1 mmol), methanol (34 mL), dimethylformamide (68 mL),
triethylamine (9.5 mL, 68.3 mmol) and a magnetic stirring bar. The flask
was fitted with a condenser and septa, then carbon monoxide was bubbled
174

CA 02508780 2005-06-09
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through the solution for 15 minutes. The flask was placed under a
nitrogen atmosphere and heated to 70.degrees Celsius for 8 hours. The
mixture was diluted with ethyl acetate (200 mL) and washed with water
(1 X100 mL), 5% aqueous hydrogen chloride (2X200 mL) and brine (1 X100
mL). The organic layer was dried over magnesium sulfate and
concentrated in vacuo. The residue was purified by flash column
chromatography (0-30% ethyl acetate/hexane) to give 4.08 g of product as
a yellow solid (59% yield). 1 H NMR (400 MHz, DMSO) 8 2.21 (quintet,
2H), 2.74 (t, 2H), 3.06 (t, 2H), 3.98 (S, 3h), 7.30 (s, 1 H), 7.97 (d, 1 H),
7.99
(s, 1 H), 8.12 (d, 1 H); m/z 205 (M+H); HRMS (M+H) calculated for
Ci2H13~3~ 205.0859, found 205.0882.
[000199] Step 3: (Preparation of 2-amino-3-cyano-4-(2-furyl)-5,6-
dihydrobenzo[h]quinoline-8-carboxylic acid trifluoroacetate) - A glass vial
was charged with methyl 5-oxo-5,6,7,8-tetrahydronaphthalene-2-
carboxylate, as prepared in Step 2, above, (1.03 g, 5.06 mmol),
malononitrile (0.363, 5.5 mmol), 2-furaldehyde (0.42 mL, 5.07 mmol),
ammonium acetate (0.794 g, 10.3 mmol), toluene (10 mL) and a magnetic
stirring bar. The vial was capped and heated to 80 degrees Celsius for 24
hours. The vial was cooled to room temperature, then the reaction mixture
was diluted with a 1:1 mixture of dichloromethane/methanol (20 mL), and
amberlyst resin (20 g) was added to the flask. The slurry was agitated for
72 hours at room temperature, then the resin was collected by vacuum
filtration and washed with dichloromethane (3x30 mL). The resin was then
combined with 2 M ammonia in methanol and agitated for 4 hours at room
temperature. The resin was filtered and washed with a 1:1 mixture of
dichloromethane/2M ammonia in methanol (6X30 mL). The combined
filtrates were concentrated in vacuo. The residue was treated with ethanol
(6 mL) and 2 M aqueous lithium hydroxide (6 mL), at 50 degrees Celsius
for 1 hour. The mixture was concentrated in vacuo, and the residue
purified by preparative RP-HPLC giving 0.3 g of product as a white solid
(18% yield). iH NMR (300 MHz, DMSO) b 2.80-2.96 (m, 4H), 6.79 (m,
1 H), 7.00 (d, 1 H), 7.89 (s, 1 H), 7.95 (d, 1 H), 8.01 (s, 1 H), 8.26 (s, 1
H); m/z
175

CA 02508780 2005-06-09
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332 (M+H); HRMS (M+H) calculated for Ci9H1aN3O3: 332.1030, found
332.1039.
EXAMPLE 102
[000200] This illustrates the preparation of 2-amino-4-(2,3-
difluorophenyl)-6,7-dihydro-5H-pyrazolo[3,4-h]quinoline-3-carbonitrile
bis(trifluoroacetate).
[00020'1] 2-amino-4-(2,3-difluorophenyl)-6,7-dihydro-5H-pyrazolo[3,4-
h]quinoline-3-carbonitrile bis(trifluoroacetate) was prepared in a manner
similar to that used to produce 2-amino-4-(2-furyl)-8-hydroxy-5,6-
dihydrobenzo[h]quinoline-3-carbonitrile trifluoroacetate, as described in
Example 106. The product was isolated as a yellow solid (205.7 mg, 17%
yield). 'H NMR (400 MHz, DMSO) ~ 2.55-2.60 (m, 2H), 2.72-2.80 (m, 2H),
6.81 (br s, 1 H), 7.25-7.32 (m, 1 H), 7.38-7.46 (m, 1 H), 7.58-7.68 (m, 1 H),
7.97 (s, 1 H); m/z 324 (M+H); HRMS (M+H) calculated for Cl7HizF2N5:
324.1055, found 324.1030. TNFa release assay ICSO = 4.0 p.M; Rat LPS
Assay 83% inhibition at 20 mpl< (IG).
EXAMPLE 103
[000202] This illustrates the preparation of 2-amino-4-(2,4-
difluorophenyl)-6,7-dihydro-5H-pyrazolo[3,4-h]quinoline-3-carbonitrile
bis(trifluoroacetate).
[000203] 2-amino-4-(2,4-difluorophenyl)-6,7-dihydro-5H-pyrazolo[3,4-
h]quinoline-3-carbonitrile bis(trifluoroacetate) was prepared in a manner
similar to that used to produce 2-amino-4-(2-furyl)-8-hydroxy-5,6-
dihydrobenzo[h]quinoline-3-carbonitrile trifluoroacetate, as described in
Example 92. The product was isolated as a yellow solid (149.1 mg, 13%
yield). 1H NMR (400 MHz, DMSO) ~ 2.55-2.60 (m, 2H), 2.72-2.80 (m, 2H),
6.78 (br s, 1 H), 7.31 (td, 1 H), 7.47-7.58 (m, 2H), 7.96 (s, 1 H); m/z 324
(M+H); HRMS (M+H) calculated for C17H12F2N5: 324.1055, found
324.1074.
176

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EXAMPLE 104
[000204] This illustrates the preparation of 2-amino-4-(2,6-
difluorophenyl)-6,7-dihydro-5H-pyrazolo[3,4-h]quinoline-3-carbonitrile
bis(trifluoroacetate).
[000205] 2-amino-4-(2,6-difluorophenyl)-6,7-dihydro-5H-pyrazolo[3,4-
h]quinoline-3-carbonitrile bis(trifluoroacetate) was prepared in a manner
similar to that used to produce 2-amino-4-(2-furyl)-8-hydroxy-5,6-
dihydrobenzo[h]quinoline-3-carbonitrile trifluoroacetate, as described in
Example 92. The product was isolated as a white solid (137.7 mg, 12%
yield). 1 H NMR (400 MHz, DMSO) 8 2.55-2.60 (m, 2H), 2.72-2.80 (m, 2H),
6.85 (br s, 1 H), 7.33-7.40 (m, 2H), 7.62-7.73 (m, 1 H), 7.98 (s, 1 H); m/z
324
(M+H); HRMS (M+H) calculated for C17H12F2N5~ 324.1055, found
324.1098.
EXAMPLE 105
[000206] This illustrates the preparation of 8-amino-6-(2-furyl)-4,5-
dihydro-1 H-pyrazolo[4,3-h]quinoline-7-carbonitrile.
[000207] 8-amino-6-(2-furyl)-4,5-dihydro-1 H-pyrazolo[4,3-h]quinoline-7-
carbonitrile was prepared in a manner similar to that used to produce 2-
amino-4-(2-furyl)-8-hydroxy-5,6-dihydrobenzo[h]quinoline-3-carbonitrile
trifluoroacetate, as described in Example 92. The product was isolated as
a yellow solid (51 mg, 8% yield), iH NMR (400 MHz, DMSO) 8 2.67 (t,
2H), 2.83 (t, 2H), 6.76 (dd, 1 H), 6.93 (d, 1 H), 7.57 (s, 1 H), 7.98 (d, 1
H);
m/z 278 (M+H); HRMS (M+H) calculated for C157H12N50: 278.101036,
found 278.1051. TNFa release assay ICSO = 0.9 p,M.
EXAMPLE 106
[000208] This illustrates the preparation of 2-amino-4-(2-furyl)-6-(1 H-
pyrazol-3-yl)nicotinonitrile trifluoroacetate.
[000209] 2-amino-4-(2-furyl)-6-(1 H-pyrazol-3-yl)nicotinonitriie
trifluoroacetate was prepared in a manner similar to that used to produce
2-amino-4-(2-furyl)-8-hydroxy-5,6-dihydrobenzo[h]quinoline-3-carbonitrile
trifluoroacetate, as described in Example 92. The product was isolated as
a brown solid (110 mg, 6% yield). iH NMR (300 MHz, DMSO) ~ 6.76 (dd,
177

CA 02508780 2005-06-09
WO 2004/054505 PCT/US2003/039166
1 H), 6.84 (br s, 1 H), 6.95 (s, 1 H), 7.46 (d, 1 H), 7.64 (s, 1 H), 7.86 (s,
1 H),
8.03 (s, 1 H); m/z 253 (M+H); HRMS (M+H) calculated for C13H1oN50~
252.0880, found 252.0855. TNFa release assay ICSO = 4.0 ~,M.
EXAMPLE 107
[000210] This illustrates the preparation of 8-amino-6-(2-furyl)-4,5-
dihydro-1 H-pyrazolo[4,3-h]quinoline-7-carbonitrile trifluoroacetate.
[000211] 8-amino-6-(2-furyl)-4,5-dihydro-1 H-pyrazolo[4,3-h]quinoline-7-
carbonitrile trifluoroacetate was prepared in a manner similar to that used
to produce 2-amino-4-(2-furyl)-8-hydroxy-5,6-dihydrobenzo[h]quinoline-3-
carbonitrile trifluoroacetate, as described in Example 92. The product was
isolated as a tan solid (379 mg, 38% yield). iH NMR (300 MHz, DMSO) 8
2.69 (t, 2H), 2.84 (t, 2H), 6.76 (dd, 1 H), 6.94 dd, 1 H), 7.58 (s, 1 H), 7.99
(dd, 1 H); m/z 278 (M+H); HRMS (M+H) calculated for C15H12N50~
278.1036, found 278.1054.
EXAMPLES 108 - 174
[000212] This illustrates the production of aminocyanopyridine
compounds of the present invention.
[000213] The compounds listed in the table below were prepared by the
methods described in I<ambe, S. et al., "A simple method for the
preparation of 2-amino-4-aryl-3-cyanopyridines by the condensation of
malononitrile with aromatic aldehydes and alkyl ketones in the presence of
ammonium acetate", Synthesis 5:366 - 368 (1980). NMR analysis was
carried out for each compound and selected data is presented for each
compound as shown in the table.
178

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Ex. m/z HRMS HRMS Calculated
Compound Name
No. (M+H) Theor. Found Formula
2-amino-4-(3-
fluorophenyl)-6,8-
dihydro-5H-
108 pyrazolo[3,4- 306 306.115 306.1168 C1~H13FN5
h]quinoline-3-
carbonitrile
bis(trifluoroacetate)
N-(4-[6-amino-5-
cyano-4-(2-
furyl)pyridin-2-
109 355 355.0859 355.0853 C17H15N403S
yl]phenyl)methanes
ulfonamide
trifluoroacetate
2-amino-4-(2-furyl)-
6,7-dihydro-5H-
pyrrolo[2,3-
110 377 277.1089 277.1063 C~6H13N40
h]quinoline-3-
carbonitrile
trifluoroacetate
2-amino-4-(4-
methoxypheny!)-
6,7-dihydro-5H-
111 pyrazolo[3,4- 318 318.1349 318.1349 C1sH16N50
h]quinoline-3-
carbonitrile
bis(trlfluoroacetate)
179

CA 02508780 2005-06-09
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Ex. m/z HRMS HRMS Calculated
Compound Name
No. (M+H) Theor. Found Formula
2-amino-4-(2,5-
difluorophenyl)-6,7-
dihydro-5H-
112 pyrazolo[3,4- 324 324.1055 324.1098 C1~H12F2N5
h]quinoline-3-
carbonitrile
bis(trifluoroacetate)
2-amino-4-(4-
fluorophenyl)-6,8-
dihydro-5H-
113 pyrazolo[3,4- 306 306.115 306.1155 C1~H13FN5
h]quinoline-3-
carbonitrile
bis(trifluoroacetate)
2-amino-4-(4H-
1,2,4-triazol-3-yl)-
5,6-
114 289 289.1202 289.1173 Cl6HisNs
dihydrobenzo[h]qui
noline-3-carbonitrile
bis(trifluoroacetate)
2-amino-6-(4-
methoxyphenyl)-4-
115 (4H-1,2,4-triazol-3-293 293.1151 293.'1137C15H13N60
yl)nicotinonitrile
bis(trifluoroacetate)
2-amino-4-(2-
fluorophenyl)-6-(3-
116 280 280.0881 280.0916 C16H11 FNsO
furyl)nicotinonitrile
trifluoroacetate
180

CA 02508780 2005-06-09
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Ex. m/z HRMS HRMS Calculated
Compound Name
No. (M+H) Theor. Found Formula
8-amino-6-(2-furyl)-
4,5-dihydro-2H-
117 pyrazolo[4,3- 278 278.1036 278.1018 C15H~2N50
h]quinoline-7-
carbonitrile
2-amino-4-(3-
methoxyphenyl)-
6,7-dihydro-5H-
118 pyrazolo[3,4- 318 318.1349 318.1361 Ci$H16N50
h]quinoline-3-
carbonitrile
bis(trifluoroacetate)
2-amino-4-(2-furyl)-
7-methyl-6,7-
dihydro-5H-
119 pyrazolo[3,4- 292 292.1198 292.1201 C16H14N50
h]quinoline-3-
carbonitrile
bis(trifluoroacetate)
N-[4-(2-amino-3-
cyano-6,7-dihydro-
5H-pyrazolo[3,4-
120 h]quinolin-4- 303 303.1353 303.1399 CisH17N60
yl)phenyl]acetamid
a
bis(trifluoroacetate)
181

CA 02508780 2005-06-09
WO 2004/054505 PCT/US2003/039166
Ex. m/z HRMS HRMS Calculated
Compound Name
No. (M+H) Theor. Found Formula
6-amino-4-[(4-
methoxyphenyl)ami
no]-2-
C16H14F3N4~
121 (trifluoromethyl)-351 351.1063 351.1078
2
2,3-dihydrofuro[2,3-
b]pyridine-5-
carbonitrile
4,6-diamino-2-
ethyl-2,3-
dihydrofuro[2,3-
122 205 205.1089 205.1056 C1oH13N40
b]pyridine-5-
carbonitrile
trifluoroacetate
3-(2-amino-3-
cyano-6,7-dihydro-
5H-pyrazolo[3,4-
123 332 332.1142 332.1148 C1sH14Ns02
h]quinoiin-4-
yl)benzoic acid
bis(trifluoroacetate)
2-amino-4-(1,3-
benzodioxol-4-yl)-
6,7-dihydro-5H-
124 pyrazolo[3,4- 332 332.1142 332.1124 C1aH14N542
h]quinoline-3-
carbonitriie
bis(trifluoroacetate)
182

CA 02508780 2005-06-09
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Ex. m/z HRMS HRMS Calculated
Compound Name
No. (M+H) Theor. Found Formula
4,6-dlamino-2-
methyl-2,3-
dihydrofuro[2,3-
125 191 191.0933 191.0896 C~H1yN40
b]pyridine-5-
carbonitrile
trifluoroacetate
2,8-diamino-4-(2-
furyl)-5,6-
126 dihydrobenzo[h]qui303 303.1246 303.1237 C1aH15N40
noline-3-carbonitrile
trifluoroacetate
4,6-diamino-2-
butyl-2,3-
dihydrofuro[2,3-
127 233 233.1402 233.1378 C12H1~N40
b]pyridine-5-
carbonitrile
trifluoroacetate
2-amino-4-(4-
cyanophenyl)-6,7-
dihydro-5H-
128 pyrazolo[3,4- 313 313.1196 313.1244 C18H13Ns
h]quinoline-3-
carbonitrile
bis(trifluoroacetate)
183

CA 02508780 2005-06-09
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Ex. m/z HRMS HRMS Calculated
Compound Name
No. (M+H) Theor. Found Formula
2-amino-4-(2-
chlorophenyl)-6,7-
dihydro-5H-
129 pyrazolo[3,4- 322 322.0854 322.089 C17H13CIN5
h]quinoline-3-
carbonitrile
bis(trifiluoroacetate)
2-amino-4-pyridin-
3-yl-6,8-dihydro-
5H-pyrazolo[3,4-
130 289 289.1196 289.1209 CisHisN6
h]quinoline-3-
carbonitrile
tris(trifiluoroacetate)
2-amino-4-(2-fiuryl)-
7-hydroxy-5,6-
131 dihydrobenzo[h]qui304 304.1086 304.1076 C18H14N302
noline-3-carbonitrile
trifluoroacetate
2-amino-4-(2-fiuryl)-
6-(1 H-indol-3-
132 301 301.1084 301.1078 Ci$H13N4O
yl)nicotinonitrile
trifluoroacetate
2-amino-4-pyridin-
4-yl-6,8-dihydro-
5H-pyrazolo[3,4-
133 289 289.1196 289.1218 C16H1sNs
h]quinoline-3-
carbonitrile
tris(trifluoroacetate)
184

CA 02508780 2005-06-09
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Ex. m/z HRMS HRMS Calculated
Compound Name
No. (M+H) Theor. Found Formula
2-amino-4-[2-
(difluoromethoxy)ph
enyl]-6,7-dihydro-
134 5H-pyrazolo[3,4- 354 354.1161 354.1162 C18H14F2N50
h]quinoline-3-
carbonitrile
bis(trifluoroacetate)
4,6-diamino-2-
[(prop-2-
ynyloxy)methyl]-
135 2,3-dihydrofuro[2,3-245 245.1039 245.1019 C12H1sNa.42
b]pyridine-5-
carbonitrile
trifluoroacetate
2-[(allyloxy)methyl]-
4,6-diamino-2,3-
dihydrofuro[2,3-
136 247 247.1195 247.1179 C12H151V402
b]pyridine-5-
carbonitrile
trifluoroacetate
4,6-diamino-2-
(methoxymethyl)-
2,3-dihydrofuro[2,3-
137 221 221.1039 221.1015 C1pH13N4~2
b]pyridine-5-
carbonitrile
trifluoroacetate
185

CA 02508780 2005-06-09
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Ex. m/z HRMS HRMS Calculated
Compound Name
No. (M+H) Theor. Found Formula
2-amino-4-(2-furyl)-
6-methyl-5,6-
138 dihydrobenzo[h]qui302 302.1293 302.1269 C19Hy6N30
noline-3-carbonitrile
trifluoroacetate
4,6-diamino-2-
(isopropoxymethyl)-
2,3-dihydrofuro[2,3-
139 249 249.1352 249.1336 C12H1~N~02
b]pyridine-5-
carbonitrile
trifluoroacetate
4,6-diamino-2-
(ethoxymethyl)-2,3-
dihydrofuro[2,3-
140 235 235.1195 235.118 C11H1~N~02
b]pyridine-5-
carbonitrile
trifluoroacetate
4,6-diamino-2-
[(1,1,2,2-
tetrafluoroethoxy)m
C~ 1 Hi 1
F4N4O
141 ethyl]-2,3- 307 307.0813 307.0819
dihydrofuro[2,3-
z
b]pyridine-5-
carbonitrile
186

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Ex. m/z HRMS HRMS Calculated
Compound Name
No. (M+H) Theor. Found Formula
2-amino-4-(2-
methoxyphenyl)-
6,8-dihydro-5H-
142 pyrazolo[3,4- 318 318.1349 318.1357 C18Hy6N50
h]quinoline-3-
carbonitrile
bis(trifluoroacetate)
4-(2-amino-3-
cyano-6,7-dihydro-
5H-pyrazolo[3,4-
143 332 332.1142 332.1153 Ci$Hy4N502
h]quinolin-4-
yl)benzoic acid
bis(trifluoroacetate)
4,6-diamino-2-(tert-
butoxymethyl)-2,3-
144 dihydrofuro[2,3-263 263.1503 263.1506 C13H19N402
b]pyridine-5-
carbonitrile
methyl 3-(2-amino-
3-cyano-6,7-
dihydro-5H-
145 pyrazolo[3,4- 346 346.1299 346.1318 Ci9H16N502
h]quinolin-4-
yl)benzoate
bis(trifluoroacetate)
187

CA 02508780 2005-06-09
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Ex. m/z HRMS HRMS Calculated
Compound Name
No. (M+H) Theor. Found Formula
4,6-diamino-3-
phenyl-2,3-
dihydrofuro[2,3-
146 253 253.1038 253.1082 C14H13N40
b]pyridine-5-
carbonitrile
trifluoroacetate
4,6-diamino-3-vinyl-
2,3-dihydrofuro[2,3-
147 b]pyridine-5- 203 203.0933 203.0904 C1oH11N40
carbonitrile
trifluoroacetate
4,6-diamino-2-
(phenoxymethyl)-
2,3-dihydrofuro[2,3-
148 283 283.1167 283.1195 C15H~~N402
b)pyridine-5-
carbonitrile
trifluoroacetate
2-amino-4-(2-furyl)-
7,9-dimethyl-5,6-
149 dihydrobenzo[h]qui316 316.145 316.1441 C2oHi8N30
noline-3-carbonitrile
trifluoroacetate
2-amino-4-(2-furyl)-
7-methoxy-5,6-
150 dihydrobenzo[h]qui318 318.1243 318.124 Cj9Hj6N302
noline-3-carbonitrile
trifluoroacetate
188

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Ex. m/z HRMS HRMS Calculated
Compound Name
No. (M+H) Theor. Found Formula
2-amino-4-(2-furyl)-
8,9-dimethoxy-5,6-
151 dihydrobenzo[h]qui348 348.1348 348.1351 C2oH1$N303
noline-3-carbonitrile
trifluoroacetate
2-amino-4-(2-furyl)-
8-methoxy-5,6-
152 dihydrobenzo[h]qui318 318.1243 318.1232 C19Hy6N302
noline-3-carbonitrile
trifluoroacetate
2-amino-4-(2-furyl)-
9-methoxy-5,6-
153 dihydrobenzo[h]qui318 318.1243 318.1243 Ci9H16N302
noline-3-carbonitrile
trifluoroacetate
2-amino-4-(2-furyl)-
5H-indeno[1,2-
154 b]pyridine-3- 274 274.098 274.1051 C17H12N30
carbonitriie
trifluoroacetate
2-amino-4-(2-furyl)-
6,7-dihydro-5H-
benzo[6,7]cyclohep
155 302 302.1293 302.1285 Ci9H16N30
to[1,2-b]pyridine-3-
carbonitrile
trifluoroacetate
189

CA 02508780 2005-06-09
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Ex. m/z HRMS HRMS Calculated
Compound Name
No. (M+H) Theor. Found Formula
2-amino-4-(3-
fluorophenyl)-5,6-
156 dihydrobenzo[h]qui316 316.125 316.149 C2oH15FNs
noline-3-carbonitrife
trifluoroacetate
2-amino-4-(2-
ethoxyphenyl)-6,7-
dihydro-5H-
157 pyrazolo[3,4- 332 332.1506 332.1507 Ci9Hi8N50
h]quinoline-3-
carbonitrile
bis(trifluoroacetate)
methyl [2-(2-amino-
3-cyano-6,7-
dihydro-5H-
158 pyrazolo[3,4- 376 376.1404 376.1403 C2oH1gN503
h]quinolin-4-
yl)phenoxy]acetate
bis(trifluoroacetate)
4-[2-
(aliyloxy)phenyl]-2-
amino-6,7-dihydro-
159 5H-pyrazolo[3,4-344 344.1506 344.1507 C2oHi$N50
h]quinoline-3-
carbonitrile
bis(trifluoroacetate)
190

CA 02508780 2005-06-09
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Ex. m/z HRMS HRMS Calculated
Compound Name
No. (M+H) Theor. Found Formula
2-amino-4-[2-(beta-
D-
glucopyranosyloxy)
phenyl]-6,7-
160 dihydro-5H- 466 466.1721 466.1742 C23H24N50s
pyrazolo[3,4-
h]quinoline-3-
carbonitrile
bis(trifluoroacetate)
2-amino-4-[2-
(hexyloxy)phenyl]-
6,7-dihydro-5H-
161 pyrazolo[3,4- 388 388.2132 388.2136 C23H26N50
h]quinoline-3-
carbonitrile
bis(trifluoroacetate)
methyl 2-(2-amino-
3-cyano-6,7-
dihydro-5H-
162 pyrazolo[3,4- 346 346.1299 346.1345 C1gH16N5O2
h]quinolin-4-
yl)benzoate
bis(trifluoroacetate)
191

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Ex. m/z HRMS HRMS Calculated
Compound Name
No. (M+H) Theor. Found Formula
2-amino-4-(1
H-
indol-7-yl)-6,7-
dihydro-5H-
163 pyrazolo[3,4- 327 327.1353 327.164 C19H15Ns
h]quinoline-3-
carbonitrile
bis(trifluoroacetate)
methyl 4-(2-amino-
3-cyano-6,7-
dihydro-5H-
164 pyrazolo[3,4- 346 346.1299 346.1329 C19H1sN542
h]quinolin-4-
yl)benzoate
bis(trifluoroacetate)
2-amino-4-[4-
(dimethylamino)phe
nyl]-6,7-dihydro-5H-
165 pyrazolo[3,4- 331 331.1666 331.1684 C19Hi9N~
h]quinoline-3-
carbonitrile
bis(trifluoroacetate)
2-amino-4-(2-
methylphenyl)-6,7-
dihydro-5H-
166 pyrazolo[3,4- 302 302.14 302.1408 ClsHlsNS
h]quinoline-3-
carbonitrile
bis(trifluoroacetate)
192

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Ex. m/z HRMS HRMS Calculated
Compound Name
No. (M+H) Theor. Found Formula
2-amino-4-[2-(2-
hydroxyethoxy)phe
nyl]-6,7-dihydro-5H-
167 pyrazolo[3,4- 348 348.1455 348.149 C19H18N502
h]quinoline-3-
carbonitrile
bis(trifluoroacetate)
2-amino-4-{4-[(2-
cyanoethyl)(methyl)
amino]phenyl}-6,7-
dihydro-5H-
168 370 370.1775 370.1754 C21 H2oN7
pyrazolo[3,4-
h]quinoline-3-
carbonitrile
bis(trifluoroacetate)
2-amino-4-(2-furyl)-
5H-
thiochromeno[4,3-
169 306 306.0696 306.07 C~~H12N30S
b]pyridine-3-
carbonitrile
trifluoroacetate
2-amino-4-[2-
(trifluoromethoxy)p
henyl]-6,7-dihydro-
170 5H-pyrazolo[3,4- 372 372.1067 372.1095 ClaHlsFsN50
h]quinoline-3-
carbonitrile
bis(trifluoroacetate)
193

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Ex. m/z HRMS HRMS Calculated
Compound Name
No. (M+H) Theor. Found Formula
[2-(2-amino-3-
cyano-6,7-dihydro-
5H-pyrazolo[3,4-
171 h]quinolin-4- 362 362.1248362.1233 C19H16N503
yl)phenoxy]acetic
acid
bis(trifluoroacetate)
2-(2-amino-3-
cyano-6,7-dihydro-
5H-pyrazolo[3,4-
172 332 332.1142332.1131 CisH14N502
h]quinolin-4-
yl)benzoic acid
bis(trifluoroacetate)
2-amino-4-[2-
(difluoromethoxy)ph
r
173 enyl]-6,7-dihydro-354 354.1161354.1163 Cial-I14F2N5~
5H-pyrazolo[3,4-
h]quinoline-3-
carbonitrile
4,6-diamino-2-
(morpholin-4-
ylmethyl)-2,3-
174 276 276.1455276.1455 CisH18N502
dihydrofuro[2,3-
b]pyridine-5-
carbonitrile
EXAMPLE 175
[000214] This illustrates the preparation of 4-[6-amino-5-cyano-4-(2-
furyl)pyridin-2-yl]benzoic acid trifluoroacetate.
194

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[000215] A glass vial was charged with 4-acetylbenzoic acid (0.33 g, 2
mmol), malononitrile, (0.12 g, 3 mmol), ammonium acetate (0.23 g, 6
mmol), furaldehyde (0.19 g, 3 mmol) and a magnetic stirring bar. Toluene
(3 mL) was added to the vial, which was capped and heated to 80 degrees
Celsius for 18 hours. The vial was then cooled to room temperature, and
a 1:2 mixture of methanol and dichloromethane (15 mL) was added
followed by 8 g of Amberlyst resin. The mixture was agitated for 24 h,
then the resin was filtered and washed with dichloromethane (3X15 mL).
A 2 M solution of ammonia in methanol (15 mL) was added to the resin,
and the mixture was agitated overnight at room temperature. The resin
was filtered and the filtrate collected in a tared flask. The resin was
washed sequentially with a 1:1 mixture of methanol and dichloromethane
(2X15 mL), 2 M ammonia in methanol (2X15 mL), and a 1:1 mixture of
methanol and dichloromethane (2X15 mL). The combined filtrates were
concentrated in vacuo, and the residue was purified by reverse phase
chromatography. The product was isolated as a tan solid (9.1 mg, 1
yield). 1 H NMR (300 MHz, CDCI3-CD30D) $ 6.60 (dd, 1 H), 7.49 (d, 1 H),
7.54 (s, 1 H), 7.663 (d, 1 H), 8.02 (d, 2H), 8.12 (d, 2H); m/z 306 (M+H);
HRMS (M+H) calculated for C17H13N3O3: 306.0879, found 306.0874.
EXAMPLES 176 - 213 ,
[000216] This illustrates the production of aminocyanopyridine
compounds of the present invention.
[000217] The compounds listed in the table below were prepared by the
methods described in Kambe, S. et aL, "A simple method for the
preparation of 2-amino-4-aryl-3-cyanopyridines by the condensation of
malononitrile with aromatic aldehydes and alkyl ketones in the presence of
ammonium acetate", Synthesis 5:366 - 368 (1980). NMR analysis was
carried out for each compound and selected data is presented for each
compound as shown in the table.
195

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Ex. m/z HRMS HRMS Formula
Compound name
No. (M+H) Theor. Found Calcd for
2-amino-4-(2-furyl)-
6-propyl-5,6,7,8-
tetrahydro-1,6-
176 283 283.1559 283.1577 C16H79N40
naphthyridine-3-
carbonitrile
bis(trifluoroacetate)
2-amino-4-(2-furyl)-
6-[4-
177 (trifluoromethoxy)p346 346.0803 346.0831 C1~H11 F3N302
henyl]nicotinonitrile
trifluoroacetate
2-amino-4-(2-furyl)-
6-methyl-5-
178 276 276.1137 276.116 C1~H1~N30
phenylnicotinonitrife
trifluoroacetate
2-amino-6-benzyl-
4-(2-
179 276 276.1137 276.117 C17H14N30
furyl)nicotinonitrile
trifluoroacetate
2-amino-4-(2-furyl)-
180 6-isobutyl- 242 242.1293 242.1319 C14H16N30
nicotinonitrile
2-amino-4-(2-furyl)-
5,6,7,8-tetrahydro-
181 240 240.1137 240.1154 C14H14N30
quinoline-3-
carbonitrile
196

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Ex. m/z HRMS HRMS Formula
Compound name
No. (M+H) Theor. Found Calcd for
2-amino-5-(4-
fluorophenyl)-4-(2-
182 fury!)-6- 294 294.1043 294.1053 Cl7HisFNsO
methylnicotinonitrile
trifluoroacetate
2-amino-6-(4-
fluorobenzyl)-4-(2-
183 294 294.1043 294.1063 C1~H13FN30
furyl)nicotinonitrile
trifluoroacetate
2-amino-6-(4-
fluorophenyl)-4-(2-
184 280 280.0886 280.0904 C16H11FNs0
furyl)nicotinonitrile
trifluoroacetate
2-amino-4-(2-furyl)-
5,6,7,8-tetrahydro-
5,8-
185 252 252.1137 252.1136 C15H1~.N3C
methanoquinoline-
3-carbonitrile
trifluoroacetate
2-amino-6-(3,4-
dimethylphenyl)-4-
186 (2- 290 290.1293 290.1292 C18H16N30
furyl)nicotinonitrile
trifluoroacetate
2-amino-4-(2-furyl)-
5,6-
187 dihydrobenzo[h]qui288 288.1137 288.1139 CigH14N30
noline-3-carbonitrile
trifluoroacetate
197

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Ex. m/z HRMS HRMS Formula
Compound name
No. (M+H) Theor. Found Calcd for
2-amino-4-(2-furyl)-
5-methyl-6-
188 276 276.1137 276.1143 Cl~Hy4N30
phenylnicotinonitrile
trifluoroacetate
2-amino-4-(2-furyl)-
5,6-
189 338 338.1293 338.1294 C~2H~6N30
diphenylnicotinonitri
le trifluoroacetate
2-amino-6-(4-
fluorophenyl)-4-(2-
190 furyl)-5- 294 294.1043 294.1044 Cl7HisFNsO
methylnicotinonitrile
trifluoroacetate
2-amino-4-(2-furyl)-
6-(4-
191 methoxyphenyl)-5-306 306.1243 306.1235 ClsHisNa42
methylnicotinonitrile
trifluoroacetate
2-amino-4-(2-furyl)-
6-(3-
192 hydroxyphenyl)nico278 278.093 278.093 C16H12N302
tinonitrile
trifluoroacetate
2-amino-4-(2-furyl)-
6-(4-
193 hydroxyphenyl)-5-292 292.1086 292.1086 C17H14N302
methylnicotinonitrile
trifluoroacetate
198

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Ex. m/z HRMS HRMS Formula
Compound name
No. (M+H) Theor. Found Calcd for
2-amino-4-(2-furyl)-
6-(4-
194 hydroxyphenyl)nico278 278.093 278.0934 C16H12N302
tinonitrile
trifluoroacetate
2-amino-4-(2-furyl)-
5,6,7,8-tetrahydro-
195 1,6-naphthyridine-241 241.1089 241.1 C13H~3N4O2
O76
3-carbonitrile
bis(trifluoroacetate)
2-amino-4-(2-furyl)-
5 (8-hydroxy-1-
196 328
naphthyl)nicotinonit
rile trifluoroacetate 328.1086 328.1095 C2oH14N302
ethyl 2-amino-3-
cyano-4-(2-furyl)-
5'6,7,8
197 312
tetrahydroquinoline-
6-carboxylate
trifluoroacetate 312.1348 312.1342 C17Hi8N302
2-amino-6-(4-
cyanophenyl)-4-(2-
198 287
furyl)nicotinonitrile
trifluoroacetate 287.0933 287.0941 C1~H11 N40
2-amino-4-(2-furyl)-
6-(1-methyl-1H-
199 265
pyrrol-2-
yl)nicotinonitrile 265.1089 265.1123 C15H13N40
199

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Ex. m/z HRMS HRMS Formula
Compound name
No. (M+H) Theor. Found Calcd for
2-amino-4,6-di(2-
200 252
furyl)nicotinonitrile 252.0773 252.0751 C14H1oNsos
2-amino-4-(2-furyl)-
201 6-(1 H-pyrrol-2- 251
yl)nicotinonitrile 251.0933 251.0928 C14H11 N4~
2-amino-4-(2-furyl)-
6-[4-(1 H-imidazol-
202 1- 328
yl)phenyl]nicotinonit
rile 328.1198 328.1194 C19Hy4N50
2-amino-4-(2-furyl)-
6-(1,3-thiazol-2-
203 269
yl)nicotinonitrile
bis(trifluoroacetate) 269.0497 269.0479 C13H9N40
2-amino-4-(2-furyl)-
204 6-thien-3- 268
ylnicotinonitrile 268.0545 268.0545 C14H1oN30
2-amino-6-(1,3-
benzodioxol-5-yl)-4-
205 306
(2-
furyl)nicotinonitrile 306.0879 306.0888 Cj~H72N303
6-amino-4-(2-furyl)-
2,2'-bipyridine-5-
206 326
carbonitrile
bis(trifluoroacetate) 263.0933 263.0945 C15H j 1
N40
6-amino-4-(2-furyl)-
207 2,3'-bipyridine-5-263
carbonitrile 263.0933 263.0935 C15H11N44
200

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Ex. m/z HRMS HRMS Formula
Compound name
No. (M+H) Theor. Found Calcd for
6-amino-4-(2-furyl)-
2~4~-bipyridine-5-
208 263
carbonitrile
bis(trifluoroacetate) 263.0933 263.0928 C15H11 N40
2-amino-4-(2-furyl)-
209 6- 262
phenylnicotinonitrile 262.098 262.0971 C16H12N30
2-amino-4-(2-furyl)-
6 (4
210 276
methylphenyl)nicoti
nonitrile 276.1137 276.1121 C1~H14N30
2-amino-4-(2-furyl)-
6-(1-methyl-1
H-
211 265
pyrrol-3-
yl)nicotinonitrile 265.1089 265.1088 C15H13N40
2-amino-4-(2-furyl)-
212 6-(1 H-indol-3- 301
yl)nicotinonitrile 301.1089 301.1107 CigH13N4O
2-amino-4-(2-
furyl)benzo[h]quinol
213 286
ine-3-carbonitrile
trifluoroacetate ---- ---- C1gH12N3O
EXAMPLE 214
[000218] This illustrates the production of 2-amino-4-(2-furyl)-5H-
chromeno[2,3-b]pyridine-3-carbonitrile.
201

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O
H O ~
NC
O + NC CN Pyridine I O / CN OH I ~ I ~ CN
CN ~ EtOH, AcOH'
CN 2) TFA, Et3SiH O N NH2
[000219] 3-(2-furyl)-3-oxopropanenitrile (10 mmol, 1.0 equiv., 1.35g) and
malononitrile (10 mmol, 1.0 equiv., 600~.L) were combined in pridine
(lOmL). The mixture was heated to 100 °C for 1 hour. The reaction
mixture was diluted with 150 mL dichloromethane and washed with 1 M
HCI (3 x 50 mL). The organic layer was dried and evaporated to give a
dark oil (GDS-13695-130). The oil was dissolved in EtOH (30 mL) and
treated with salicaldehyde (10 mmol, 1.0 equiv., 1.0 mL) and acetic acid
(AcOH) (10 mL). The resulting mixture was heated to reflux for 2 hours.
The solvents were evaporated and the in vacuo and the residue was
dissolved in trifluoroacetic acid (l5mL). Triethylsilane (10 mL) was added
and the solution was stirred overnight. The solvents were evaporated and
the residue purified by reverse phase chromatography. The product was
isolated as a solid (370mg, 13%). 1H NMR (400 MHz, DMSO) b 7.99 (s,
1 H), 7.24-7.20 (m, 2H), 7.08-7.04 (m, 3H), 6.94 (bs, 2H), 6.76 (s, 1 H), 3.96
(s, 2H): m/z 290 (M+H).
EXAMPLE 215
[000220] This illustrates the production of 2,4-diamino-10-methyl-5,10-
dihydrobenzo[b]-1,8-naphthyridine-3-carbonitrile trifluoroacetate.
202

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1) NaH O
Br 2) Boc-o-Boc ~ Br 1 n-BuLi
) i ~ H
/ 3) NaH I ~ .Boc
NH2 4) Mel N 2) DMF / N.Boc
CN
H2N ~ CN
1 ) CN
EtOH, AcOH
2) TFA, Et3SiH
NH2
CN
N N NHz
[00022'1] Step 1: (synthesis of t Butyl 2-bromophenyl(methyl)carbamate)
[000222] 2-bromoaniline (25 mmol, 1.0 equiv. 4.3g) was dissolved in THF
(150 mL). Sodium hydride (60% in mineral oil, 1.1 g) was added and the
mixture heated to reflux for 1 hour. After cooling to room temperature, a
solution of di-t butyl-dicarbonate in THF (1.OM, 30 mmol, 1.2 equiv., 30
mL) was added followed by sodium hydride (1.1 g). The resulting mixture
was heated to reflux for 14 hours. After cooling to room temperature,
lodomethane (28 mmol, 1.12 equiv., 1.75 mL) was added and the mixture
heated to refiux for 3 hours. After cooling to room temperature, the
reaction was quenched with water and diluted with ether. The organic
layer was washed with saturated aqueous ammonium chloride (NH4C1),
saturated aqueous sodium bicarbonate (NaHCO~), and saturated aqueous
sodium chloride (NaCI). The organic layer was dried over MgS04, filtered
and evaporated to give a yellow oil. Purification by silica gel
chromatography gave the product as a yellow oil (5.9g, 82%). 1H NMR
(400 MHz, CDC13) 8 7.58 (d, 1 H), 7.29 (t, 1 H), 7.21 (d, 1 H), 7.12 (t, 1 H),
3.13 (s, 3H), 1.33 (s, 9H): m/z 271 (M+H).
[000223] Step 2: (synthesis of 2,4-diamino-10-methyl-5,10-
dihydrobenzo[b]-1,8-naphthyridine-3-carbonitrile trifluoroacetate)
203

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[000224] t Butyl 2-bromophenyl(methyl)carbamate (2.65 mmol, 1.0
equiv., 759 mg) was dissolved in THF (20 mL). The solution was cooled in
a dry ice acetone bath and a solution of n-BuLi in hexane (1.6M, 1.1 equiv.
1.8 mL) was added dropwise. After 15 minutes, dimethylformamide (DMF)
(1 mL) was added and the reaction allowed to warm to room temperature.
The reaction mixture was quenched with sat, aq. NH4C1, and partitioned
between ether and water. The organic layer was washed with water and
dried over MgS04, filtered and evaporated to get 820 mg of a yellow oil.
This oil was carried on immediately without purification or characterization.
The resulting oil was treated with 2-amino-1-propene-1,1,3-tricarbonitrile
(2 mmol, 265mg), acetic acid (2.OmL), and ethanol (lOmL) and the
resulting solution was heated to reflex overnight. The reaction slurry was
concentrated in vacuo and then dissolved in trifluoroacetic acid (7mL) at
0°C. Triethylsi(ane (S,OmL) was added via syringe. The reaction stirred
for 2 hours before evaporating solvents to get a brown solid. The solid
was washed with dichloromethane and dried to give the product as a light
brown solid. (90mg, 9%). 1H NMR (400 MHz, DMSO) 8 7.16 (t, 1 H), 7.03
(d, 1 H), 6.97-6.91 (m, 2H), 3.70 (s, 2H), 3.34 (s, 3H): m/z 252 (M+H).
EXAMPLE 216
[000225] This illustrates the production of 2,4-diamino-8-ethoxy-7-
hydroxy-5H-chromeno[2,3-b]pyridine-3-carbonitrile.
NH2 NHS
HO ~ ~ CN ~ HO ~ ~ CN
8~--
NaOH, DMSO
HO O N NH2 ~O ~ O N NH2
[000226] 2,4-diamino-7,8-dihydroxy-5H-chromeno[2,3-b]pyridine-3-
carbonitrile (400 mg, 1.0 mmol) and NaOH (166 mg, 4,2 mmol) were
suspended in dimethylsulfoxide (DMSO) (5 mL) and warmed until
dissolved. Ethyl bromide was added to the reaction mixture, which was
heated to 85°C until disappearance of starting material (HPCL
monitoring).
After neutralizing with NH4C1, the crude reaction mixture was purified by
204

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reverse phase column chromatography. Evaporation of the solvent on a
lyophilizer gave an orange solid as a TFA salt 2,4-diamino-8-ethoxy-7-
hydroxy-5H-chromeno[2,3-b]pyridine-3-carbonitrile, which was confirmed
by 2D NMR analysis. 1H-NMR (300 MHz, CD30D): 8 1.47 (t, 3H), 3.63 (s,
2H), 4.12 (quartet, 2H), 6.59-6.81 (m, 2H). HRMS calcd for C15H14N4O3
(M+H): 299.11. Found:299.1132.
EXAMPLE 217
[000227] This illustrates the production of 2,4-diamino-8-(2-
ethoxyethoxy)-7-hydroxy-5H-chromeno[2,3-b]pyridine-3-carbonitrile.
[000228] 2,4-diamino-8-(2-ethoxyethoxy)-7-hydroxy-5H-chromeno[2,3-
b]pyridine-3-carbonitrile was prepared from 2,4-diamino-8-hydroxy-5H-
chromeno[2,3-b]pyridine-3-carbonitrile in the same method as described
above in Example 216, using 2-bromoethyl-ethylether in lieu of 2-
bromoethyl-ethylether. 1H-NMR (300 MHz, CD30D): 8 1.28 (t, 3H), 3.60
(s, 2H), 3.67 (quartet, 2H), 3.86 (s, 2H), 4.19 (s, 2H), 6.58-6.82 (m, 2H).
HRMS calcd for C17H18N4O4 (M+H): 343.13. Found: 343.1418.
EXAMPLES 218 - 219
[000229] This illustrates the production of aminocyanopyridine
compounds of the present invention.
[000230] The aminocyanopyridine compounds shown in the table below
were prepared according to the general method described in Example
216. NMR analysis was carried out according to the method described
above, and resulting data for each of the compounds is provided in the
table.
205

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Ex. Compound HRMS calcd HRMS found
No, name
218 tert-butyl f [2,4-diamino-7-(2-tert-499.21 499.2204
butoxy-2-oxoethoxy)-3-cyano-5H-
chromeno[2,3-b]pyridin-8-
yl]oxy}acetate trifluoroacetate
219 7,8-bis(allyloxy)-2,4-diamino-5H-351.14 351.1445
chromeno[2,3-b]pyridine-3-
carbonitrile trifluoroacetate
EXAMPLE 220
[000231] This illustrates the production of 2,4-diamino-7,8-dihydroxy-5H-
chromeno[2,3-b]pyridine-3-carbonitrile.
[000232] To a cooled (0 °C) solution of 2,4-diamino-7,8-dimethoxy-5H-
chromeno[2,3-b]pyridine-3-carbonitrile (1.34mmol, 400mg) and
dichloromethane (4.OmL) was slowly added boron tribromide (1 M,
dichloromethane, 8.04mmol, 8.04mL). The suspension was stirred at 0 °C
for 15 minutes, then the ice bath was removed and the reaction warmed to
23 °C overnight. After 16h at 23 °C the reaction was cooled to
0°C and
carefully neutralized with 2.5N sodium hydroxide to pH = 7. The product
was collected by filtration, dissolved in dimethyl sulfoxide (1.0 mL) and
purified by reverse phase chromatography. The product was isolated as a
pale orange solid (62mg, 17% yield). iH NMR (400 MHz, DMSO) 8
9.071 (s, 1 H), 8.795 (s, 1 H), 6.520 (s, 1 H), 6.410 (bs, 2H), 6.405(s, 1 H),
6.244 (bs, 2H), 3.48 (s, 2H): m/z 271 (M+); HRMS (M+H) calculated for
C13H11 N4~3 271.0753, found 271.0721.
EXAMPLE 221
[000233] This illustrates the production of 2,4-diamino-8-hydroxy-5H-
chromeno[2,3-b]pyridine-3-carbonitrile.
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[000234] 2,4-Dihydroxy-benzaldehyde (43.4mmol, 6.Og), 2-amino-1-
propene-1,1,3-tricarbonitrile (43.4mmol, 5.74g), acetic acid (l3.OmL), and
ethanol (125.OmL) were combined and heated to reflux for 2 hours. The
reaction slurry was concentrated in vacuo and then dissolved in
trifluoroacetic acid (160.OmL) at 0°C. Triethylsilane (0.28mo1, 32.76g,
45.OmL) was added via syringe. The reaction was stirred for 1 hour at
0°C. 300mL of dichloromethane was added to the reaction and the solid
was collected via filtration and washed (2x75mL) with dichloromethane
and ether. The product was isolated as a pale orange solid (13.10g, 63%
yield). ~H NMR (400 MHz, DMSO) 8 6.958(d, 1 H), 6.537 (dd, 1 H), 6.390
(d, 1 H), 3.510(s, 2H): m/z 255 (M+); HRMS (M+H) calculated for
C13H11 N4~2 255.0804, found 255.0894.
EXAMPLE 222
[000235] This illustrates the production of 8,10-diamino-2,3-dihydro-11 H-
[1,4]dioxino[2',3':6,7]chromeno[2,3-b]pyridine-9-carbonitrile.
[000236] 2,4-diamino-7,8-dihydroxy-5H-chromeno[2,3-b]pyridine-3-
carbonitrile (0.56mmol, 150mg) was dissolved in DMSO (3.OmL) and
sodium hydroxide (2.24mmol, 90mg) was added followed by
dibromoethane (0.56mmol, 105.20mg, 48.26p.L). The dark homogeneous
solution was heated to 70°C for 16 hours. The crude reaction mixture
was
cooled to 23°C, neutralized with trifluoroacetic acid and directly
purified via
reverse phase chromatography. The product was isolated as a pale
orange solid (30mg, 18% yield). iH NMR (400 MHz, CD30D) 8 6.715(s,
1 H), 6.553 (s, 1 H), 4.215 (bs, 4H), 3.575(s, 2H): m/z 298 (M+H).
EXAMPLE 223
[000237] This illustrates the production of 2,4-diamino-8-(2-
ethoxyethoxy)-5H-chromeno[2,3-b]pyridine-3-carbonitrile.
[000238] 2,4-diamino-8-hydroxy-5H-chromeno[2,3-b]pyridine-3-
carbonitrile (0.62mmol, 300mg) was dissolved in DMSO (4.OmL) and solid
sodium hydroxide (2.79mmol, 111.6mg) was added followed by 2-
bromoethyl-ethylether (0.62mmol, 69.9p.L). The reaction was heated to
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80°C with stirring for 9 hours. The crude reaction was filtered and
diluted
with DMSO (4.OmL) and purified via reverse phase chromatography. The
product was isolated as a tan solid (80mg, 40% yield). iH NMR (400 MHz,
CD30D) ~ 7.180(d, 1 H), 6.795 (d, 1 H), 6.46 (d, 1 H), 4.090 (t, 2H), 3.766(t,
2H), 3.607 (s, 2H), 3.572 (t, 2H), 1.200 (t, 2H); m/z 327 (M+H).
EXAMPLE 224
[000239] This illustrates the production of 2,4-diamino-8-(2-pyrrolidin-1-
ylethoxy)-5H-chromeno[2,3-b]pyridine-3-carbonitrile .
[000240] 2,4-diamino-8-(2-pyrrolidin-1-ylethoxy)-5H-chromeno[2,3-
b]pyridine-3-carbonitrile was prepared from 2,4-diamino-8-hydroxy-5H-
chromeno[2,3-b]pyridine-3-carbonitrilein the same manner as described in
Example 223, using 1-(2-chloroethyl)pyridine in lieu of 2-bromoethyl-
ethylether. The product was isolated as a tan solid (100mg, 46% yield).
iH NMR (400 MHz, CD~OD) ~ 7.199 (d, 1 H), 6.680 (d, 1 H), 6.668 (d, 1 H),
4.290 (t, 2H), 3.618 (s, 2H), 3.562 (t, 2H), 3.375 (bs, 4H), 2.077(bs, 4H);
m/z 352 (M+H). TNFa release assay ICSO: 2.9~.M; Rat LPS Assay 60%
inhibition at 20 mpk (IP).
EXAMPLE 225
[000241] This illustrates the production of 2,4-diamino-8-(2-
aminoethoxy)-5H-chromeno[2,3-b]pyridine-3-carbonitrile.
[000242] 2,4-diamino-8-(2-aminoethoxy)-5H-chromeno[2,3-b]pyridine-3-
carbonitrile was prepared from 2,4-diamino-8-hydroxy-5H-'chromeno[2,3-
b]pyridine-3-carbonitrile in the same manner as described in Example 223
using 2-bromoethylamine in lieu of 2-bromoethyl-ethylether. The product
was isolated as a tan solid (167mg, 51% yield). iH NMR (400 MHz,
DMSO) 8 8.180 (bs, 2H), 7.100 (d, 1 H), 6.762 (d, 1 H), 6.646 (bs, 1 H),
4.154 (t, 2H), 3.573 (s, 2H), 3.155 (t, 2H); m/z 398 (M+H). TNFo~ release
assay ICSO: 6.9p.M; Rat LPS Assay 88% inhibition at 20 mpk (IP)
EXAMPLE 226
[000243] This illustrates the production of [(2,4-diamino-3-cyano-5H-
chromeno[2,3-b]pyridin-8-yl)oxy]acetic acid.
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[000244] [(2,4-diamino-3-cyano-5H-chromeno[2,3-b]pyridin-8-
yl)oxy]acetic acid was prepared from 2,4-diamino-8-hydroxy-5H-
chromeno[2,3-b]pyridine-3-carbonitrile in the same manner as described in
Example 223 using bromoacetic acid in lieu of 2-bromoethyl-ethylether.
The product was isolated as a tan solid (110.6mg, 31% yield). iH NMR
(400 MHz, DMSO) ~ 7.030 (d, 1 H), 6.640 (d, 1 H), 6.516 (d, 1 H), 6.474 (bs,
2H), 6.278 (bs, 2H), 4.633 (s, 2H), 3.543 (s, 2H); m/z 427 (M+H).
EXAMPLE 227
[000245] This illustrates the production of 2,4-diamino-8-(2-
hydroxyethoxy)-5H-chromeno[2,3-b]pyridine-3-carbonitrile.
[000246] 2,4-diamino-8-(2-hydroxyethoxy)-5H-chromeno[2,3-b]pyridine-
3-carbonitrile was prepared from 2,4-diamino-8-hydroxy-5H-chromeno[2,3-
b]pyridine-3-carbonitrile in the same manner as described in Example 223
using 2-bromoethanol in lieu of 2-bromoethyl-ethylether. The product was
isolated as a tan solid (120mg, 35% yield). iH NMR (400 MHz, DMSO) 8
7.025 (d, 1 H), 6.670 (d, 1 H), 6.550 (d, 1 H), 3.931 (t, 2H), 3.662 (t, 2H),
3.546 (s, 2H); m/z 413 (M+H).
EXAMPLE 228
[000247] This illustrates the production of 2,4-diamino-8-(2-morpholin-4-
ylethoxy)-5H-chromeno[2,3-b]pyridine-3-carbonitrile.
[000248] 2,4-diamino-8-(2-morpholin-4-ylethoxy)-5H-chromeno[2,3-
b]pyridine-3-carbonitrile was prepared from 2,4-diamino-8-hydroxy-5H-
chromeno[2,3-b]pyridine-3-carbonitrile in the same manner as described in
Example 223 using 1-(2-chloroethyl)morpholine in lieu of 2-bromoethyl-
ethylether. The product was isolated as a tan solid (80mg, 17% yield). 1 H
NMR (400 MHz, DMSO) 8 7.071 (d, 1 H), 6.714 (d, 1 H), 6.654 (d, 1 H),
6.527 (bs, 2H), 6.323 (bs, 2H), 4.311 (t, 2H), 3.938 (m, 2H), 3.664 (t, 2H),
3.558 (s, 2H), 3.534 (m, 2H), 3.451 (m, 2H), 3.158 (m, 2H); m/z 482
(M+H).
EXAMPLES 229 - 235
[000249] This illustrates the production of aminocyanopyridine
compounds of the present invention.
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[000250] The aminocyanopyridine compounds shown in the table below
were prepared according to the general method described in Example
223. NMR analysis was carried out according to the method described
above, and resulting data for each of the compounds is provided in the
table,
Ex. Compound name m/z
No. (M+H)
229 2,4-diamino-8-methoxy-5H-chromeno[2,3-b]pyridine-3-carbonitrile269
230 7,9-diamino-10H-[1,3]dioxolo[6,7]chromeno[2,3-b]pyridine-8-283
carbonitrile
231 8-(allyloxy)-2,4-diamino-5H-chromeno[2,3-b]pyridine-3-carbonitrile295
trifluoroacetate
232 2-amino-8-ethoxy-4-(ethylamino)-5H-chromeno[2,3-b]pyridine-3-311
carbonitriie
233 8-ethoxy-2,4-bis(ethylamino)-5H-chromeno[2,3-b]pyridine-3-339
carbonitrile
234 2-amino-8-(2-ethoxyethoxy)-4-[(2-ethoxyethyl)amino]-5H-399
chromeno[2,3-b]pyridine-3-carbonitrile
235 2,4-diamino-8-[2-(dimethylamino)ethoxy]-5H-chromeno[2,3-326
b]pyridine-3-carbonitrile trifluoroacetate
EXAMPLE 236
[000251 ] This illustrates the production of 2,4-diamino-9-methoxy-5H-
chromeno[2,3-b]pyridine-3-carbonitrile bis(trifluoroacetate).
[000252] 3-Methoxysalicyaldehyde (10 mmol, 1.52 g), 2-amino-1-
propene-1,1,3-tricarbonitrile (10 mmol, 1.32 g) acetic acid (2.5 mL), and
ethanol (40 mL) were combined and heated to reflux overnight. The
reaction slurry was concentrated in vacuo and then dissolved in
trifluoroacetic acid (15 mL) at 0°C. Triethylsilane (62 mmol, 7.2 g, 10
mL)
was added via syringe. The reaction stirred for one hour at room
temperature. Dichloromethane (100 mL) was added to the reaction and
the solid formed was collected via filtration and washed with
dichloromethane (2x). The product was isolated as a white solid (2.5 g,
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50% yield). 1 H NMR (300 MHz, DMSO-d6): b 7.08 (t, J = 8Hz,1 H), 7.00-
6.80 (m, 2H), 6.73 (d, J= 7.4 Hz, 2H), 3.83(s, 3H), 3.68 (s, 2H); m/z 269
(M+H); Anal. calculated for C14H12Na.02-2CF3CO2H: C, 43.56; H, 2.84; N,
11.29, found: C, 43.40; H, 2.98; N, 11.32.
EXAMPLE 237
[000253] This illustrates the production of 2,4-diamino-7-hydroxy-5H-
chromeno[2,3-b]pyridine-3-carbonitrile trifluoroacetate.
[000254] 2,4-diamino-7-hydroxy-5H-chromeno[2,3-b]pyridine-3-
carbonitrile was prepared in the same manner as described in Example
236, except that 5-hydroxysalicyaldehyde was used in place of
methoxysalicyaldehyde. The product was isolated as a pink solid (951
mg, 30% yield). iH NMR (300 MHz, DMSO-d6): 8 6.88 (d, J= 8.8 Hz, 1 H),
6.63 (d, J-8.7 Hz, 1 H), 6.55(s, 1 H), 3.6 (s, 2H): m/z 255 (M+H); Anal.
calculated for C13H10N4~2-1 .5CF3C02H -0.5H20: C, 44.25; H, 2.90; N,
12.90, found: C, 44.04; H, 3.05; N, 12.84.
EXAMPLE 238
[000255] This illustrates the production of 2,4-diamino-5H-chromeno[2,3-
b]pyridine-3-carbonitrile Bis(trifluoroacetate).
[000256] 2,4-diamino-5H-chromeno[2,3-b]pyridine-3-carbonitrile was
prepared in the same manner as described in Example 236 except that
salicyaldehyde was used in place of methoxysalicyaldehyde. The product
was isolated as a light tan solid (1.26 g, 33% yield). 'H NMR (300 MHz,
DMSO-d6), 8 7.30-6.90 (m, 6H), 3.7 (s, 2H); mlz 239 (M+H); Anal. Calcd
for C13H1oN4O-2CF3CO2H -0.25H20: C, 43.37; H, 2.68; N, 11.90, found: C,
43.07; H, 2.81; N, 11.79.
EXAMPLE 239
[000257] This illustrates the production of 2,4-diamino-8,9-dihydroxy-5H-
chromeno[2,3-b]pyridine-3-carbonitrile trifluoroacetate.
[000258] 2,4-diamino-8,9-dihydroxy-5H-chromeno[2,3-b]pyridine-3-
carbonitrile was prepared in the same manner as described in Example
236, except that 2,3,4-trihydroxybenzaldehyde was used in place of
methoxysalicyaldehyde. The product was isolated as a white solid (3.6 g,
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82% yield). 1H NMR (500 MHz, DMSO-d6): 8 7.1 (bs, 3H), 6.58 (d, J = 8
Hz, 1 H), 6.47 (d, J = 8 Hz, 1 H), 3.75 (s, 2H); m/z 271 (M+H).
EXAMPLE 240
[000259] This illustrates the production of 2,4-diamino-9-hydroxy-8-
methoxy-5H-chromeno[2,3-b]pyridine-3-carbonitrile trifluoroacetate.
[000260] 2,3-dihydroxy-4-methoxybenzaldehyde (3 mmol, 506 mg), 2-
amino-1-propene-1,1,3-tricarbonitrile (3 mmol, 398 mg), acetic acid (1 mL),
and ethanol (15 mL) were combined and heated to reflux overnight. The
reaction slurry was concentrated in vacuo and then dissolved in
trifluoroacetic acid (10 mL) at 0°C. Triethylsilane (25 mmol, 2.88 g, 4
mL)
was added via syringe. The reaction stirred for overnight at room
temperature to give a yellow slurry. Dichloromethane (50 mL) was added
to the reaction and the solid formed was collected via filtration and washed
with dichloromethane (2x). The product was isolated as a yellow solid
(482 mg, 35% yield). 1H NMR (300 MHz, DMSO-d6): ~ 6.73 (d, J=8.5 Hz,
1 H), 6.57 (d, J=8.5 Hz,1 H), 3.77(s, 3H), 3.57 (s, 2H); m/z 285 (M+H); Anal.
calculated for Ciq.H12N4~3-1 .25CF3C02H -1.5H20: C, 43.58; H, 3.62; N,
12.32, found: C, 43.80; H, 3.22; N, 12.65.
EXAMPLE 241
[000261] This illustrates the production of 2,4-diamino-9-hydroxy-5H-
chromeno[2,3-b]pyridine-3-carbonitrile trifluoroacetate.
[000262] 2,3-dihydroxybenzaldehyde (5 mmol, 691 mg), 2-amino-1-
propene-1,1,3-tricarbonitrile (5 mmol, 661 mg), acetic acid (1.2 mL), and
ethanol (20 mL) were combined and heated to reflux overnight. The
reaction slurry was concentrated in vacuo and then dissolved in
trifluoroacetic acid (20 mL) at 0°C. Triethylsiiane (62 mmol, 7.2 g, 10
mL)
was added via syringe. The reaction stirred for two and one-half days at
room temperature to give a solution, which was concentrated in vacuo.
The residue was stirred in methanol and the slurry was filtered. The
product was obtained as a brown solid by concentrating the filtrate (167
mg, 9% yield). 1 H NMR (300 MHz, DMSO-d6): 8 6.91 (t, J = 7.7 Hz, 1 H),
6.86-6.70 (m, 2H), 6.59 (d, J = 7.3 Hz 1 H), 3.61 (s, 2H); m/z 255 (M+H).
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EXAMPLE 242
[000263] This illustrates the production of 2,4,7-triamino-5H-
chromeno[2,3-b]pyridine-3-carbonitrile.
(000264] Step 1: Preparation of 2,4-diamino-7-nitro-5H-chromeno[2,3-
b]pyridine-3-carbonitrile: 5-nitrosalicylaldehyde (132 mmol, 22.00 g), 2-
amino-1-propene-1,1,3-tricarbonitrile (132 mmol, 17.39 g), acetic acid (31
mL), and ethanol (500 mL) were combined and heated to reflux overnight.
The resulting slurry was concentrated in vacuo and then dissolved in
trifluoroacetic acid (350 mL) at 0°C. Triethylsilane (1.40 mol, 162 g,
225
mL) was added. The mixture was heated overnight at 66 °C. The mixture
was cooled and concentrated in vacuo. Triturating with methanol gave
2,4-diamino-7-nitro-5H-chromeno[2,3-b]pyridine-3-carbonitrile as a yellow
solid (22.48 g, 60%yield). 1 H NMR (300 MHz, DMSO-d6): 8 8.13 (d, J =
9.0 Hz, 1 H), 8.00 (s, 1 H), 7.25 (d, J = 9.0 Hz, 1 H ), 6.70 (br s, 2H), 6.50
(bs, 2H), 3.82 (s, 2H); m/z 284 (M+H); Anal. Calcd for C13H9N5O3-O.5H2O:
C, 53.43; H, 3.45; N, 23.96, found: C, 53.41; H, 3.17; N, 23.71.
[000265] Step 2: A mixture of 2,4-diamino-7-nitro-5H-chromeno[2,3-
b]pyridine-3-carbonitrile, produced as described above, (0.55 mmol, 155
mg) and palladium on carbon (Pd/C) (35 mg, 10% on activated carbon) in
DMF (15 mL) was stirred under an atmosphere of hydrogen (balloon) for
3.5 hours. The catalyst was removed by filtration using a plug of celite.
The filtrated was concentrated in vacuo and the residue was triturated with
methanol to give 2,4,7-triamino-5H-chromeno[2,3-b]pyridine-3-carbonitrile
as a grey solid (109 mg, 79% yield). 1H NMR (300 MHz, DMSO-d6): 8
6.72 (d, J= 8.0 Hz, 1 H), 6.39-6.5(m, 4H), 6.25 (s, 2H), 3.52 (s, 2H); m/z
254 (M+H).
EXAMPLE 243
(000266] This illustrates the production of 2,4-diamino-9-fluoro-5H-
chromeno[2,3-b]pyridine-3-carbonitrile trifluoroacetate.
[000267] 3-Fluoro-2-hydroxybenzaldehyde (3.45 mmol, 484 mg), 2-
amino-1-propene-1,1,3-tricarbonitrile (3.50 mmol, 463 mg), acetic acid (0.9
mL) and ethanol (27 mL) were combined and heated to reflux for 14 hours.
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The reaction slurry was concentrated in vacuo and then dissolved in
trifluoroacetic acid (10.5 mL). Triethylsilane (43mmol, 4.97 g, 6.9 mL) was
added via syringe. The reaction was heated to reflux for 5 hours.
Dichloromethane (50 mL) was added to the reaction and the solid formed
was collected via filtration and washed with methanol. The product was
isolated as a white solid (377 mg, 30% yield). iH NMR (500 MHz, DMSO-
d6): 8 7.25-7.19 (m, 1 H), 7.15-7.08 (m, 1 H), 7.00-6.96 (m, 1 H), 6.70 (bs,
2H), 6.51 (bs, 2H), 3.75 (S, 2H); m/z 257 (M+H).
EXAMPLE 244.
[000268] This illustrates the production of 2,4-diamino-3-cyano-5H-
chromeno[2,3-b]pyridine-7-carboxylic acid Bis(trifluoroacetate).
[000269] 5-Carboxysalicyaldehyde (3 mmol, 500 mg), 2-amino-1-
propene-1,1,3-tricarbonitrile (3 mmol, 396 mg) acetic acid (1.2 mL), and
ethanol (15 mL) were combined and heated to reflux for 2.5days. The
reaction slurry was concentrated in vacuo and then dissolved in
trifluoroacetic acid (10 mL). Triethylsilane (62 mmol, 7.2g, 10 mL) was
added via syringe. The reaction was stirred for 4 hours at 50 °C and
then
was stirred overnight at room temperature. Dichloromethane (20 mL) was
added to the reaction and the solid formed was collected via filtration and
washed with dichloromethane (2x). The product was isolated as a yellow
solid (560 mg, 36% yield). iH NMR (500 MHz, DMSO-d6): 8 7.86 (d, J=
7.4 Hz, 1 H), 7.85 (s, 1 H), 7.31 (d, J= 7.4 Hz, 1 H), 6.80 (br s, 2H), 3.85
(s,
2H); m/z 283 (M+H); anal. Calculated for C14H1oNa.Os-2CF3C02H-0.25H20:
C, 42.00; H, 2.45; N, 10.88, found: C, 42.30; H, 2.31; N, 10.51.
EXAMPLE 245
[000270] This illustrates the production of 2,4-diamino-6,8-dihydroxy-5H-
chromeno[2,3-b]pyridine-3-carbonitrile trifluoroacetate.
[000271] 2,4-diamino-6,8-dihydroxy-5H-chromeno[2,3-b]pyridine-3-
carbonitrile was prepared in the same manner as described in Example
244, except that 2,4,6-trihydroxybenzaldehyde was used in place of 5-
carboxysalicyaldehyde. The product was isolated as an orange solid (106
mg, 9% yield). 1H NMR (free base, 300 MHz, DMSO-d6): 8 9.65 (s, 1 H),
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9.40 (s, 1 H), 6.41 (s, 2H), 6.35 (s, 2H), 6.10 (s, 1 H), 5.85 (s, 1 H), 3.31
(s,
2H); m/z 271 (M+H).
EXAMPLES 246 - 264
[000272] This illustrates the production of aminocyanopyridine
compounds of the present invention.
[000273] The aminocyanopyridine compounds shown in the table below
were prepared according to the general method described in Example
242. NMR analysis was carried out according to the method described
above, and resulting data for each of the compounds is provided in the
table.
Ex,
Compound name M+H
No.
2,4-diamino-7-(dimethylamino)-5H-chromeno[2,3-
246 282
b]pyridine-3-carbonitrile
2,4-diamino-7-nitro-5H-chromeno[2,3-b]pyridine-3-
247 284
carbonitrile
2,4-diamino-7-chloro-9-methyl-5H-chromeno[2,3-
248 287
bjpyridine-3-carbonitrile
2,4-diamino-6,8-dimethoxy-5H-chromeno[2,3-
249 299
b]pyridine-3-carbonitrile trifluoroacetate
2,4-diamino-7-(trifluoromethoxy)-5H-chromeno[2,3-
250 323
b]pyridine-3-carbonitrile trifluoroacetate
2,4-diamino-7-bromo-9-methoxy-5H-chromeno[2,3-
251 347
b]pyridine-3-carbonitrile trifluoroacetate
2,4-diamino-9-methoxy-7-nitro-5H-chromeno[2,3-
252 314
b]pyridine-3-carbonitrile trifluoroacetate
2~4-diamino-8-methyl-5H-chromeno[2,3-b]pyridine-
253 253
3-carbonitrile trifluoroacetate
2,4-diamino-3-cyano-5H-chromeno[2,3-b]pyridine-9-
254 283
carboxylic acid bis(trifluoroacetate)
2,4-diamino-6-methoxy-5H-chromeno[2,3-
255 269
b]pyridine-3-carbonitrile bis(trifluoroacetate)
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Ex.
Compound name M+H
No.
2,4-diamino-9-bromo-7-chloro-5H-chromeno[2,3-
256 357
b]pyridine-3-carbonitrile trlfluoroacetate
2~4-diamino-6-bromo-9-methoxy-5H-chromeno[2,3-
257 347
b]pyridine-3-carbonitrile trifluoroacetate
2,4,7-triamino-9-methoxy-5H-chromeno[2,3-
258 284
b]pyridine-3-carbonitrile trifluoroacetate
2,4-diamino-9-vitro-5H-chromeno[2,3-b]pyridine-3-
259 284
carbonitrile
2,4,9-triamino-5H-chromeno[2,3-b]pyridine-3-
260 254
carbonitrile trifluoroacetate
2,4-diamino-7-fluoro-5H-chromeno[2,3-b]pyridine-3-
261 257
carbonitrile trifluoroacetate
2,4-diamino-7-chloro-5H-chromeno[2,3-b]pyridine-3-
262 273
carbonltrile
2~4-diamino-9-tert-butyl-5H-chromeno[2,3-
263 2g5
b]pyridine-3-carbonitrile
ethyl2,4-diamino-3-cyano-5H-chromeno[2,3-
264 311
b]pyridine-9-carboxylate
EXAMPLE 265
[000274] This illustrates the production of 2,4-diamino-7-vitro-5H-
thiochromeno[2,3-b]pyridine-3-carbonitrile.
[000275] Step 1:, Production of 5-Nitrothiosalicylaldehyde: A mixture of 2-
chloro-5-nitrobenzaldehyde (2g, 11 mmol) and lithium sulfide (0.54 g, 11.7
mmol) in 30 mL of anhydrous DMSO was stirred under nitrogen at room
temperature overnight. The solution was then added to a mixture of ice-
water, acidified with 2N HCI and extracted with ether three times. The
combined ether layers were washed with water, brine, dried, filtered and
concentrated to give the crude 5-vitro-2-thiosalicylaldehyde as an orange
solid (1.3g, 65% yield)
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[000276] Step 2: A solution of the crude 5-nitro-2-thiosalicylaldehyde
(1.3g, 7.1 mmol), 2-amino-1-propene-1,1,3-tricarbonitrile (7.6 mmol, 1 g),
acetic acid (2.5 mL) in 70 mL of ethanol was heated at 76°C under
nitrogen overnight. The reaction mixture was cooled to room temperature
and filtered. The solid was washed with ethanol to give the desired tricyclic
intermediate as a light brown solid (1.5g, 71.4% yield).
[000277] Step 3: A reaction mixture of the aforementioned tricyclic
intermediate (1.2 g, 4 mmol) and triethylsilane (15 mL) in 100 mL of
trifluoroacetic acid was heated at between 60-65°C under nitrogen for 2
hours. After that, the solution was cooled to room temperature and
concentrated in vacuo. Ether was added to the residue. The solid was
filtered, washed with additional ether to give 2,4-diamino-7-nitro-5H-
thiochromeno[2,3-b]pyridine-3-carbonitrile as an orange powder (0.9 g,
75% yield). iH NMR (400 MHz, CDsCN + D20) b 8.089 (d, 1 H), 8.046 (dd,
1 H), 7.609 (d, 1 H), 3.898 (s, 2H); m/z 300 (M+H).
EXAMPLE 266
[000278] This illustrates the production of 2,4,7-triamino-5H-
thiochromeno[2,3-b]pyridine-3-carbonitrile trifluoroacetate.
[000279] To 2,4-diamino-7-nitro-5H-thiochromeno[2,3-b]pyridine-3-
carbonitrile (produced as described above in Example 265; 0.8 g, 2.7
mmol) in 9 mL of 50% (by weight) of ethanol-water was added iron powder
(0.55 g, 10 mmol). The mixture was heated to 60°C and then 0.5 mL of
HCI/ethanol (prepared from 5.2 mL of conc. HCI and 25 mL of 50% of
ethanol-water) was added. The resulting mixture was heated at 76°C for
2.5 hours and filtered hot. The solid was washed with 50% ethanol-water.
The filtrates were combined and concentrated in vacuo to give a brownish
yellow solid. The solid was then dissolved in acetonitrile, filtered to
remove a small amount of insoluble solid and concentrated in vacuo. The
resulting solid was then washed with methanol and trifluoroacetic acid.
The trifluoroacetic acid filtrate was concentrated in vacuo to give an amber
oil. Ether was added and the solid was filtered, washed with ether, air-
dried overnight and then dried in a vacuum oven at 44°C for 2 hours to
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give the product as a grayish solid (0.53 g, 71% yield). ~H NMR (400 MHz,
CD3CN + D20) 8 7.153 (d, 1 H), 6.792 (s, 1 H), 6.698 (d, 1 H), 3.628 (s, 2H);
m/z 270 (M+H).
EXAMPLE 267
[000280] This illustrates the production of 2,4-diamino-7-nitro-5H-
thiochromeno[2,3-b]pyridine-3-carbonitrile 10,10-dioxide.
(000281 ] To a solution of 2,4-diamino-7-nitro-5H-thiochromeno[2,3-
b]pyridine-3-carbonitrile, produced as described in Example 265, (3 g, 10
mmol) in 125 mL of trifluoroacetic acid cooled with a water bath was added
dropwise 30% hydrogen peroxide (8 g). After addition was completed, the
water bath was removed. After 4 hours, additional 30% hydrogen
peroxide (2 g) was added and stirring at room temperature was continued
for additional 2 hours. After that, water (20 mL) was added and the
resulting solution was concentrated to about 70 mL. Then more water was
added and the yellow suspension was stirred at room temperature
overnight. The suspension was filtered and washed with water to give the
desired product as a yellow solid (2 g, 60.4% yield). iH NMR(400MHz,
DMSO + D20) 8 8.350 (dd, 1 H), 8.265 (d, 1 H), 8.220 (d, 1 H), 4.160 (s,
2H); m/z 332 (M+H).
EXAMPLE 268
[000282] This illustrates the production of 2,4,7-triamino-5H-
thiochromeno[2,3-b]pyridine-3-carbonitrile 10,10-dioxide.
[000283] A mixture of 2,4-diamino-7-nitro-5H-thiochromeno[2,3-
b]pyridine-3-carbonitrile 10,10-dioxide, produced as described in Example
267, (0.8 g, 2.4 mmol) and iron powder (0.58 g, 10 mmol) in 50% of
ethanol-water (10 mL) was heated to 70°C, then 1 mL of HCI/ethanol
(prepared from 5.2 mL of conc. HCI and 25 mL of 50% of ethanol-water)
was added. The resulting mixture was heated at 76°C for 3 hours and
filtered hot. The solid was washed with methanol and trifluoroacetic acid.
The trifluoroacetic acid filtrate was concentrated in vacuo and ether was
added to the viscous oil. The solid was filtered and washed with ether to
give the desired product as a beige solid (0.42 g, 57.5% yield). ~H NMR
218

CA 02508780 2005-06-09
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(400 MHz, DMSO + D20) 8 7.521 (d, 1 H), 6.60 (dd, 1 H), 6.529 (s, 1 H),
3.753 (s, 2H); m/z 302 (M+H).
EXAMPLE 269
[000284] This illustrates the production of 2,4-diamino-7-fluoro-5H-
thiochromeno[2,3-b]pyridine-3-carbonitrile.
[000285] 2,4-diamino-7-fluoro-5H-thiochromeno[2,3-b]pyridine-3-
carbonitrile was prepared as a bis-trifluoroacetate in the same manner as
described in Example 265, except that 2,5-difluorobenzaldehyde was used
as the starting material in place of 2-chloro-5-nitrobenzaldehyde. The
product was isolated as a beige solid (0.35 g, 35% yield). 'H NMR (400
MHz, CD3CN + D20) 8 7.425 (dd, 1 H), 7.153 (dd, 1 H), 7.088 (dt, 1 H)
3.743 (s, 2H); m/z 273 (M+H)
EXAMPLE 270
[000286] This illustrates the production of 2,4-diamino-5H-
thiochromeno[2,3-b]pyridine-3-carbonitrile Bis(trifluoroacetate).
[000287] 2,4-diamino-5H-thiochromeno[2,3-b]pyridine-3-carbonitrile was
prepared in the same manner as described in Example 265, except that 2-
fluorobenzaldehyde was used as the starting material in place of 2-chloro-
5-nitrobenzaldehyde. The product was isolated as a beige solid (1.8 g,
47.4% yield). iH NMR (400 MHz, CD3CN + DSO) 8 7.271-7.435 (m, 4H),
3.785 (s, 2 H); m/z 255 (M+H).
EXAMPLE 271
[000288] This illustrates the production of 2,4-diamino-7-methoxy-5H-
thiochromeno[2,3-b]pyridine-3-carbonitrile.
[000289] 2,4-diamino-7-methoxy-5H-thiochromeno[2,3-b]pyridine-3-
carbonitrile was prepared in the same manner as described in Example
265, except that 2-fluoro-5-methoxybenzaldehyde was used as the starting
material. The product was isolated as a beige solid (0.5 g, 49% yield). jH
NMR (400 MHz, CD3CN + D20) 8 7.329 (d, 1 H), 6.938 (d, 1 H), 6.885 (dd,
1 H), 3.795 (s, 3H), 3.710 (s, 2H); m/z 285 (M+H)
219

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EXAMPLE 272
[000290] This illustrates the production of 2,4-diamino-7-hydroxy-5H-
thiochromeno[2,3-b]pyridine-3-carbonitrile.
[000291] A mixture of 2,4-diamino-7-methoxy-5H-thiochromeno[2,3-
b]pyridine-3-carbonitrile (0.3 g, 0.59 mmol), produced as described in
Example 271, and 0.6 mL of boron tribromide (6.4 mmol) in 30 mL of
methylene chloride was stirred at room temperature for 18 h. After that,
the solid was filtered, washed with methylene chloride, water and
methanol. The methanol filtrate was concentrated to give a solid, which
was washed with water, acetonitrile and ether to give the desired product
as a red solid (54 mg, 33.6% yield). iH NMR (400 MHz, DMSO + D20) ~
9.520 (s, 1 H), 8.111 (d, 1 H), 7.561 (d, 1 H), 7.522 (s, 2H); m/z 271 (M+H).
EXAMPLE 273
[000292] This illustrates the production of 2,4-diamino-7-nitro-5H-
thiochromeno[2,3-b]pyridine-3-carbonitrile 10,10-dioxide (an alternative
procedure).
[000293] A mixture of 2,4,7-triamino-5H-thiochromeno[2,3-b]pyridine-3-
carbonitrile (0.1 g, 0.26 mmol), produced as described in Example 268,
and 30% hydrogen peroxide (1.5 mL) in 3 mL of trifluoroacetic acid was
stirred at room temperature overnight. Water (30 mL) was then added and
the resulting suspension was stirred at ambient temperature for 2 hours.
The solid was filtered to give the desired product as a yellow solid (18 mg,
8.6% yield): 1H NMR (400 MHz, DMSO + D20) ~ 8.353 (dd, 1 H), 8.263 (d,
1 H), 8.228 (d, 1 H), 4.163 (s, 2H); m/z 332 (M+H).
EXAMPLE 274
[000294] This illustrates the production of 2,4-diamino-7-fluoro-5H-
thiochromeno[2,3-b]pyridine-3-carbonitrile 10,10-dioxide.
[000295] 2,4-diamino-7-fluoro-5H-thiochromeno[2,3-b]pyridine-3-
carbonitrile 10,10-dioxide was prepared in the same manner as 2,4-
diamino-7-nitro-5H-thiochromeno[2,3-b]pyridine-3-carbonitrile 10,10-
dioxide, as described in Example 273. The product was isolated as a
yellow solid (51 mg, 32.7% yield). 1H NMR (400 MHz, DMSO) 8 8.028 (q,
220

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1 H), 7.433 (dt, 1 H), 7.253 (d, 1 H), 7.162 (bs, 1 H), 6.917 (bs, 1 H), 4.024
(s,
2H); m/z 305 (M+H).
EXAMPLE 275.
[000296] This illustrates the production of 2,4-diamino-5H-
thiochromeno[2,3-b]pyridine-3-carbonitrile 10,10-dioxide.
[000297] 2,4-diamino-5H-thiochromeno[2,3-b]pyridine-3-carbonitrile
10,10-dioxide was prepared in the same manner as 2,4-diamino-7-nitro-
5H-thiochromeno[2,3-b]pyridine-3-carbonitrile 10,10-dioxide, as described
in Example 273. The product was isolated as a yellow solid (73 mg,
42.9% yield), iH NMR (400 MHz, DMSO) 8 7.945 (dd, 1 H), 7.762 (dt, 1 H),
7.568 (t, 1 H), 7.467 (d, 2H), 7.179 (bs, 2H), 6.886 (bs, 1 H), 4.009 (s, 2H);
m/z 287 (M+H).
EXAMPLE 276.
[000298] This illustrates the production of 2,4-diamino-7-methoxy-5H-
thiochromeno[2,3-b]pyridine-3-carbonitrile 10,10-dioxide.
[000299] 2,4-diamino-7-methoxy-5H-thiochromeno[2,3-b]pyridine-3-
carbonitrile 10,10-dioxide was prepared in the same manner as 2,4-
diamino-7-nitro-5H-thiochromeno[2,3-b]pyridine-3-carbonitrile 10,10-
dioxide, as described in Example 273. The product was isolated as a light
brown solid (110 mg, 34.2% yield). iH NMR (400 MHz, DMSO + D20) 8
7.858 (d, 1 H), 7.107 (dd, 1 H), 6.972 (d, 1 H), 3.942 (2, 2H), 3.833 (s, 3H);
m/z 316 (M+H).
EXAMPLES 277 - 278
[000300] This illustrates the production of aminocyanopyridine
compounds of the present invention.
[000301] The aminocyanopyridine compounds shown in the table below
were prepared according to the general method described in Example
273. NMR analysis was carried out according to the method described
above, and resulting data for each of the compounds is provided in the
table.
221

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Ex. Compound name m/z (M+H)
No.
2,4-diamino-9-fluoro-5H-thiochromeno[2,3-b]pyridine-3-
277
carbonitrile trifluoroacetate 273
2,4-diamino-9-fluoro-5H-thiochromeno[2,3-b]pyridine-3-
278
carbonitrile 10,10-dioxide 305
EXAMPLES 279 - 294
[000302] This illustrates the production of certain aminocyanopyridine
compounds of the present invention.
[000303] General procedure for the N-alkylation:
[000304] To a solution of 2,4-diamino-7,8-dimethoxy-5H-chromeno[2,3-
b]pyridine-3-carbonitrile (1.34 mmol) and the corresponding halide (2.01
mmol) in dimethylformamide ( 5 mL) is added sodium hydride (80 mg, 2.01
mmol). The reaction mixture is stirred at room temperature or heated to
40°C until completion. The mixture is quenched with saturated aqueous
ammonium chloride and directly purified by purified by reverse phase
chromatography. Both the mono alkylated and dialkylated product were
isolated.
[000305] The following compounds were prepared using the procedure
described above:
Example 279: 2-amino-4-{[2-(dimethylamino)ethyl]amino}-7,8-dimethoxy-
5H-chromeno[2,3-b]pyridine-3-carbonitrile,
Example 280: 2,4-bisf[2-(dimethylamino)ethyl]amino}-7,8-dimethoxy-5H-
chromeno[2,3-b]pyridine-3-carbonitrile,
Example 281: 2-amino-4-[(2-aminoethy!)amino]-7,8-dimethoxy-5H-
chromeno[2,3-b]pyridine-3-carbonitrile,
Example 282: 2-amino-4-~[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-
yl)ethyl]amino}-7,8-dimethoxy-5H-chromeno[2,3-b]pyridine-3-carbonitrile,
Example 283: 2-amino-7,8-dimethoxy-4-[(2-pyrrolidin-1-ylethyl)amino]-5H-
chromeno[2,3-b]pyridine-3-carbonitrile,
Example 284: 7,8-dimethoxy-2,4-bis[(2-pyrrolidin-1-ylethyl)amino]-5H-
chromeno[2,3-b]pyridine-3-carbonitrile,
222

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Example 285: 2,4-bis(glycinyl)-7,,8-dimethoxy-5H-chromeno[2,3-b]pyridine-
3-carbonitrile trifluoroacetate,
Example 286: N-(2-amino-3-cyano-7,8-dimethoxy-5H-chromeno[2,3-
b]pyridin-4-yl)glycine,
Example 287: 7,8-dimethoxy-2,4-bis[(2-methoxyethyl)amino]-5H-
chromeno[2,3-b]pyridine-3-carbonitrile,
Example 288: 2-amino-7,8-dimethoxy-4-[(2-methoxyethyl)amino]-5H-
chromeno[2,3-b]pyridine-3-carbonitrile,
Example 289: 2,4-bis(butylamino)-7,8-dimethoxy-5H-chromeno[2,3-
b]pyridine-3-carbonitrile
Example 290: 2-amino-4-(butylamino)-7,8-dimethoxy-5H-chromeno[2,3-
b]pyridine-3-carbonitrile,
Example 291: 7,8-dimethoxy-2,4-bis(propylamino)-5H-chromeno[2,3-
b]pyridine-3-carbonitrile,
Example 292: 2-amino-7,8-dimethoxy-4-(propylamino)-5H-chromeno[2,3-
b]pyridine-3-carbonitrile,
Example 293: 2,4-bis(ethylamino)-7,8-dimethoxy-5H-chromeno[2,3-
b]pyridine-3-carbonitrile, and
Example 294: 2-amino-4-(ethylamino)-7,8-dimethoxy-5H-chromeno[2,3-
b]pyridine-3-carbonitrile.
[000306] Genera~rocedure for the demethylation:
[000307] To a solution of the corresponding dimethoxy aryl analog (0.68
mmol) in dichloromethane (2mL) is slowly added boron tribromide (1 M,
dichloromethane, 3.38mmol, 3.38mL). The reaction mixture is stirred at
room temperature for 4 hours, quenched with 5% aqueous sodium
hydroxide, then neutralized with 5% aqueous HCI. The resulting solid is
collected and the aqueous layer is extracted with dichloromethane. The
organic layer is concentrated under vacuum and combined with the solid.
The residue is purified by reverse phase chromatography.
EXAMPLE 295
[000308] This illustrates the production of 2-amino-4-(ethylamino)-7,8-
dihydroxy-5H-chromeno[2,3-b]pyridine-3-carbonitrile.
223

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[000309] 2-amino-4-(ethylamino)-7,8-dihydroxy-5H-chromeno[2,3-
b]pyridine-3-carbonitrile was prepared using the demethylation procedure
described above starting with 2-amino-4-(ethylamino)-7,8-dimethoxy-5H-
chromeno[2,3-b]pyridine-3-carbonitrile. iH NMR (400 MHz, DMSO) ~
6.5(s, 1 H), 6.4 (s, 1 H), 3.65(q, 2H), 2.5 (s, 2H), 1.25 (t, 3H); m/z 299.15
(M+H); HRMS (M+H) calculated for C15H15N403 299.1139, found
299.1113.
EXAMPLE 296
[000310] This illustrates the production of 2-amino-7,8-dihydroxy-4-
(propylamino)-5H-chromeno[2,3-b]pyridine-3-carbonitrile.
[000311] 2-amino-7,8-dihydroxy-4-(propylamino)-5H-chromeno[2,3-
b]pyridine-3-carbonitrile is prepared using the demethylation procedure
described above for Examples 279 - 294 starting with 2-amino-7,8-
dimethoxy-4-(propylamino)-5H-chromeno[2,3-b]pyridine-3-carbonitrile. 1 H
NMR (400 MHz, DMSO) ~ 6.5(s, 1 H), 6.4 (s, 1 H), 3.55(m, 2H), 2.5 (s, 2H),
1.6(m, 2H), 1.35 (t, 3H); m/z 313.16 (M+H); HRMS (M+H) calculated for
C1 gH17N403 313.1295, found 313.1325.
EXAMPLE 297
[000312] This illustrates the production of 2-amino-7,8-dihydroxy-4-[(2-
hydroxyethyl)amino]-5H-chromeno[2,3-b]pyridine-3-carbonitrile.
[000313] 2-amino-7,8-dihydroxy-4-[(2-hydroxyethyl)amino]-5H-
chromeno[2,3-b]pyridine-3-carbonitrile was prepared using the
demethylation procedure described above for Examples 279 - 294, starting
with 2-amino-7,8-dimethoxy-4-[(2-methoxyethyl)amino]-5H-chromeno[2,3-
b]pyridine-3-carbonitrile. 1H NMR (400 MHz, DMSO) 8 6.5(s, 1 H), 6.4 (s,
1 H), 3.65(m, 2H), 3.55(m, 2H), 2.5 (s, 2H); m/z 315.13 (M+H).
EXAMPLE 298
[000314] This illustrates the production of 2,4-bis(ethylamino)-7,8-
dihydroxy-5H-chromeno[2,3-b]pyridine-3-carbonitrile.
224

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[000315) 2,4-bis(ethylamino)-7,8-dihydroxy-5H-chromeno[2,3-b]pyridine-
3-carbonitrile. was prepared by using the procedure described in~ Examples
279 - 294.
EXAMPLES 299 - 304
[000316] This illustrates the production of certain aminocyanopyridine
compounds of the present invention.
[000317] General procedure for the O-alkylation of phenol 2,4-diamino-9-
hydroxy-5H-chromenof2,3-blwridine-3-carbonitrile:
[000318] A solution of 2,4-diamino-9-hydroxy-5H-chromeno[2,3-
b]pyridine-3-carbonitrile (0.73 mmol), and powdered sodium hydroxide
(117 mg, 2.93 mmol)) in dimethyl sulfoxide (4 mL) is heated to 50°C for
five minutes. The corresponding halide is added and the reaction mixture
is stirred at 50°C or 75°C until completion. The mixture is
quenched with
saturated aqueous ammonium chloride and directly purified by purified by
reverse phase chromatography.
[000319] The following compounds were prepared using the above
procedure:
Example 299: 2,4-diamino-9-(2-aminoethoxy)-5H-chromeno[2,3-
b]pyridine-3-carbonitrile,
Example 300: (2,4-diamino-3-cyano-5H-chromeno[2,3-b]pyridin-9-
yl)oxy]acetic acid, '
Example 301: 2,4-diamino-9-(2-hydroxyethoxy)-5H-chromeno[2,3-
b]pyridine-3-carbonitrile,
Example 302: 2,4-diamino-9-[2-(dimethylamino)ethoxy]-5H-chromeno[2,3-
b]pyridine-3-carbonitrile,
Example 303: 2,4-diamino-9-(pyridin-4-ylmethoxy)-5H-chromeno[2,3-
b]pyridine-3-carbonitrile, and
Example 304: 2,4-diamino-9-(2-pyrrolidin-1-ylethoxy)-5H-chromeno[2,3-
b]pyridine-3-carbonitrile.
225

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EXAMPLES 305 - 333
[000320] This illustrates the production of certain aminocyanopyridine
compounds of the present invention.
[00032'i] General procedure for the Mannich condensation:
[000322] To a solution of the corresponding phenol (0.92 mmol) in
ethanol (5 mL) is added formic acid (37% solution, 76 p.L, 1.01 mmol) and
piperidine (100 ~.L, 1.01 mmol). The reaction mixture is stirred at
75°C until
completion. The mixture is quenched with saturated aqueous ammonium
chloride and directly purified by purified by reverse phase chromatography
and each regioisomer isolated.
[000323] The following compounds were prepared using the above
procedure:
Example 305: 2,4-diamino-9-hydroxy-6,8-bis(piperidin-1-ylmethyl)-5H-
chromeno[2,3-b]pyridine-3-carbonitrile, and
Example 306: 2,4-diamino-9-hydroxy-8-(piperidin-1-ylmethyl)-5H-
chromeno[2,3-b]pyridine-3-carbonitrile, were produced starting with 2,4-
diamino-9-hydroxy-5H-chromeno[2,3-b]pyridine-3-carbonitrile, produced
as described in Examples 299 - 304, and
Example 307: 2,4-diamino-8-hydroxy-7,9-bis(piperidin-1-ylmethyl)-5H-
chromeno[2,3-b]pyridine-3-carbonitrile, was produced starting with 2,4-
diamino-8-hydroxy-5H-chromeno[2,3-bJpyridine-3-carbonitrile, produced
as described in Example 221.
[000324] Other aminocyanopyridine compounds of the present invention
can be produced by the same general method, and are shown in the table
below along with NMR parameters, which were determined as described
above.
226

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Ex. m/z HRMS HRMS
Compound name Formula Calcd
for
No. (M+H) Theor. Found
2,4-diamino-9-hydroxy-8-(piperidin-
1-ylmethyl)-5H-chromenoj2,3-
308 352.26352.1768352.1778C1 gH21 N5~2
b]pyridine-3-carbonitrile
trifluoroacetate
2,4-diamino-8-hydroxy-7,9-
bis(piperidin-1-ylmethyl)-5H-
309 449.33449.266 449.2637C25H32N602
chromeno[2,3-b]pyridine-3-
carbonitrile trifluoroacetate
2, 4-d i am i no-9-hyd
roxy-6, 8-
bis(piperidin-1-ylmethyl)-5H-
310 449.32449.266 449.2629C25H32N6~2
chromeno[2,3-b]pyridine-3-
carbonitrile trifluoroacetate
2,4-diamino-9-(2-pyrrolidin-1-
ylethoxy)-5H-chromeno[2,3-
311 352.26352.1768352.1777C1 gH21 N502
b]pyridine-3-carbonitrile
trifluoroacetate
2,4-diamino-9-(pyridin-4-
ylmethoxy)-5H-chromeno[2,3-
312 346.16346.1299346.1344CigH15N5~2
b]pyridine-3-carbonitrile
trifluoroacetate
2,4-diamino-9-[2- ,
(dimethylamino)ethoxy]-5H-
313 326.24326.1612326.1607C17H1 gN5~2
chromeno[2,3-b]pyridine-3-
carbonitrile trifluoroacetate
2,4-diamino-9-(2-hydroxyethoxy)-
314 5H-chromeno[2,3-b]pyridine-3-299.19299.1139299.1153C15H14N4~3
carbonitrile trifluoroacetate
[(2,4-diamino-3-cyano-5H-
315 chromeno[2,3-b]pyridin-9-313.14313.0931313.0972C15H12N4~4
yl)oxy]acetic acid trifluoroacetate
2,4-diamino-9-(2-aminoethoxy)-5H-
316 chromeno[2,3-b]pyridine-3-298.18298.1299298.1303C15H15N5~2
carbonitrile trifluoroacetate
227

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Ex. m/z HRMS HRMS
Compound name Formula Calcd
for
No. (M-rH) Theor. Found
2,4-bis(ethylamino)-7,8-dihydroxy-
317 5H-chromeno[2,3-b]pyridine-3-327.2 327.1452327.1493C17H1 gN4~3
carbonitrile trifluoroacetate
2-amino-4-([2-
(dimethylamino)ethyl]amino]-7,8-
318 dimethoxy-5H-chromeno[2,3-370.27 370.1874370.1869C1 gH23N5~3
b]pyridine-3-carbonitrile
trifluoroacetate
2,4-bis{[2-
(dimethylamino)ethyl]amino]-7,8-
319 dimethoxy-5H-chromeno[2,3-441.31 441.2609411.2629C23H32N6~3
b]pyridine-3-carbonitrile
trifluoroacetate
2-amino-4-[(2-aminoethyl)amino]-
7,8-dimethoxy-5H-chromeno[2,3-
320 342.22 342.1561342.1546C17H19N5~3
b]pyridine-3-carbonitrile
trifluoroacetate
2-amino-4-{[2-(1,3-dioxo-1,3-
dihydro-2H-isoindol-2-
321 yl)ethyl]amino]-7,8-dimethoxy-5H-472,21 C25H21 N5~5
chromeno[2,3-b]pyridine-3-
carbonitrile trifluoroacetate
2-amino-7,8-dimethoxy-4-[(2-
pyrrolidin-1-ylethyl)amino]-5H-
322 396.32 396.203396.2061C21 H25N503
chromeno[2,3-b]pyridine-3-
carbonitrile
7,8-dimethoxy-2,4-bis[(2-pyrrolidin-
323 1-ylethyl)amino]-5H-chromeno[2,3-493.44 C27H36N6~3
b]pyridine-3-carbonitrile
2,4-bis(glycinyl)-7,8-dimethoxy-5H-
324 chromeno[2,3-b]pyridine-3-415.33 C1 gH18N4~7
carbonitrile trifluoroacetate
N-(2-amino-3-cyano-7,8-dimethoxy-
325 5H-chromeno[2,3-b]pyridin-4-357.26 357.1193357.1818C17H16N4~5
yl)glycine
228

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Ex. m/z HRMS HRMS
Compound name Formula Calcd
for
No. (M+H) Theor, Found
7,8-dimethoxy-2,4-bis[(2-
methoxyethyl)amino]-5H-
326 415.3 415.1976415.1972C21 H26N4~5
chromeno[2,3-b]pyridine-3-
carbonitrile
2-amino-7,8-dimethoxy-4-[(2-
methoxyethyl)amino]-5H-
327 357.25357.1557357.2538C1 gH2pN404
chromeno[2,3-b]pyridine-3-
carbonitrile
2,4-bis(butylamino)-7,8-dimethoxy-
328 5H-chromeno[2,3-b]pyridine-3-411.35411.2391411.2391C23H30N4~3
carbonitrile
2-amino-4-(butylamino)-7,8-
329 dimethoxy-5H-chromeno[2,3-355.26355.1765355.1763C1 gH22N4~3
b]pyridine-3-carbonitrile
7,8-dimethoxy-2,4-
330 bis(propylamino)-5H-chromeno[2,3-383.31383.2078383.2085C21 H26N4~3
b]pyridine-3-carbonitrile
2-amino-7,8-dimethoxy-4-
331 (propylamino)-5H-chromeno[2,3-341.25341.1608341.1623C1 gH2pN40g
b]pyridine-3-carbonitrile
2,4-bis(ethylamino)-7,8-dimethoxy-
332 5H-chromeno[2,3-b]pyridine-3-355.27355.1765355.1784C1 gH22N403
carbonitrile
2-amino-4-(ethylamino)-7,8-
333 dimethoxy-5H-chromeno[2,3-327.21327.1452327.142C17H18N403
b]pyridine-3-carbonitrile
EXAMPLE 334
[000325] This illustrates the production of 2,4-diamino-7,3-dimethoxy-5H-
chromeno[2,3-b]pyridine-3-carbonitrile.
[000326] To a stirred solution of 3,4-dimethoxyphenol (35.7mmol, 5.5g)
and piperidine (40mmoi, 3.4g) in ethanol (50mL) was slowly added
formaldehyde (37%, water, 39.5mmol, 3.2g). The mixture was stirred at
room temperature for 4 hours and then evaporated in vacuo and the
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resultant residue was partitioned between ethyl acetate (100mL) and water
(100 mL). The organic layer was washed with water, dried (MgSO~) and
evaporated to give a colorless oily residue. To a solution of the above oily
product in acetone was added methyl iodide (100mmol, 14.2g) and the
mixture was stirred at room temperature overnight. The resultant white
precipitate was collected by filtration, washed with ether and air-dried to
give 8.14 g of a white solid.
[000327] To a slurry of the above solid (1 mmol, 390mg) and 2-amino-1-
propene-1,1,3-tricarbonitrile (lmmol, 132mg) in ethanol (lOmL) was added
triethylamine (0.5mL) and the resultant solution was heated at reflux for 30
minutes. After cooling to room temperature, the precipitate was collected
by filtration, washed with ethanol and air-dried to give the product as a
white solid (178mg, 60% yield). 'H NMR (400 MHZ, DMSO) b 6.582 (s,
1 H), 6.574 (s, 1 H), 6.406 (s, 2H), 6.241 (s, 2H), 3.686 (s, 3H), 3.671 (s,
3H), 3.524 (s, 2H); m/z 299 (M+H).
EXAMPLE 335
[000328] This illustrates the production of 2(2,4-diamino-3-cyano-8-
methoxy-5H-chromeno[2,3-b]pyridin-5-yl)malononitrile.
[000329] To a solution of 2-hydroxy-4-methoxybenzaldehyde (l0mmol,
1.52g) and malononitrile (40mmol, 2.64g) in ethanol (250mL) was added
six drops of piperidine. The mixture was heated at 50°C for 10 minutes
and then stirred at room temperature for 5 hours. The resultant precipitate
was collected by filtration and recrystallized from methanol to give the
product as a pale yellow solid (1.19g, 36% yield). iH NMR (400 MHz,
DMSO) b 7.274(d, 1 H), 6.999 (s, 2H), 6.817 (dd, 1 H), 6.733 (d, 1 H), 6.619
(s, 2H), 4.804 (d, 1 H), 4.734 (d, 1 H), 3.757 (s, 3H); m/z 333 (M+H).
EXAMPLE 336
j000330] This illustrates the production of 2(2,4-diamino-3-cyano-7-
bromo-5H-chromeno[2,3-b]pyridin-5-yl)malononitrile.
[000331] To a solution of 5-bromo-2-hydroxybenzaldehyde (l0mmol, 2g)
and malononitrile (35mmol, 2.31 g) in ethanol (200mL) was added six
drops of piperidine and the mixture was stirred at room temperature for 30
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hours. The resultant precipitate was collected by filtration and
recrystallized from methanol to give the product as a white solid (1.68g,
44% yield). 1H NMR (400 MHz, DMSO) 8 7.489 (dd, 1 H), 7.344 (d, 1 H),
7.230 (d, 1 H), 7.063 (s, 2H), 6.686 (s, 2H), 4.876 (d, 1 H), 4.850 (d, 1 H);
m/z 381, 383 (M+H).
EXAMPLE 337
[000332] This illustrates the production of 2(2,4-diamino-3-cyano-7-
methoxy-5H-chromeno[2,3-b]pyridin-5-yl)malononitrile.
[000333] To a solution of 2-hydroxy-5-methoxybenzaldehyde (l0mmol,
1.52g) and malononitrile (40mmol, 2.64g) in ethanol (350mL) was added
six drops of piperidine and the mixture was stirred at room temperature for
18 hours. The resultant precipitate was collected by filtration, successively
washed with ethanol and ether and and air-dried to give the product as a
grey solid (1.42g, 43% yield). 1H NMR (400 MHz, DMSO) 8 7.107(d, 1 H),
6.990 (m, 3H), 6.865 (d, 1 H), 6.603 (s, 2H), 4.850 (d, 1 H), 4.794 (d, 1 H),
3.724 (s, 3H); m/z 333 (M+H).
EXAMPLE 338
[000334] This illustrates the production of 2(2,4-diamino-3-cyano-8-
hydroxy-5H-chromeno[2,3-b]pyridin-5-yl)malononitrile.
[000335] To a solution of 2,4-dihydroxybenzaldehyde (l0mmol, 1.38g)
and malononitrile (40mmol, 2.64g) in ethanol (350mL) was added six
drops of piperidine and the mixture was stirred at room temperature for 5
hours. The resultant precipitate was collected by filtration, washed
successively with ethanol and ether and air-dried to give the product as a
yellow solid (1.62g, 51% yield). 1H NMR (400 MHz, DMSO) 8 9.887 (s,
1 H), 7.162 (d, 1 H), 6.971 (s, 2H), 6.613 (dd, 1 H), 6.597 (s, 2H), 6.497 (d,
1 H), 4.743 (d, 1 H), 4.687 (d, 1 H); m/z 319 (M+H).
EXAMPLE 339 - 348
[000336] This illustrates the production of certain aminocyanopyridine
compounds of the present invention.
[000337] The aminocyanopyridine compounds listed in the table below
were produced according to the general method described in Example
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336. NMR analysis was carried out for each material according to the
method described above. The names and NMR data for each compound
is provided in the table.
Ex. Compound name m/z
No.
(M+H)
339 2,4-diamino-7-methoxy-5H-chromeno[2,3-b]pyridine-3-carbonitrile269
340 2(2,4-diamino-3-cyano-7-hydroxy-5H-chromeno[2,3-b]pyridin-5-319
yl)malononitrile
341 2,4-diamino-7-bromo-5H-chromeno[2,3-b]pyridine-3-carbonitrile317, 319
342 2(2,4-diamino-3-cyano-9-methoxy-5H-chromeno[2,3-b]pyridin-5-333
yl)malononitrile
343 2,4-diamino-5-(2-fluoro-phenyl)-8-methoxy-5H-chromeno[2,3-363
b]pyridine-3-carbonitrile
344 2(2,4-diamino-3-cyano-7-chloro-5H-chromeno[2,3-b]pyridin-5-337
yl)malononitrile
345 2,4-diamino-5-phenyl-8-hydroxy-5H-chromeno[2,3-b]pyridine-3-331
carbonitrile
346 2,4-diamino-5-(3-fluoro-phenyl)-8-methoxy-5H-chromeno[2,3-363
b]pyridine-3-carbonitrile
347 2,4-diamino-7-bromo-8-methoxy-5H-chromeno[2,3-b]pyridine-3-347, 349
carbonitrile
348 2,4-diamino-5-phenyl-8-methoxy-5H-chromeno[2,3-b]pyridine-3-345
carbonitrile
EXAMPLE 349
[000338] This example illustrates that MK2 knock-out mice (MK2 (-/-))
are resistant to the formation of K/BN serum-induced arthritis.
[000339] A strain of mice has been reported that develops symptoms
similar to human rheumatoid arthritis. The mice were designated K/BxN
mice. See, Wipke, B. T. and P. M. Allen, J. of Immunology, ~67.~1601 -
1608 (2001 ). Serum from the mice can be injected into host animals to
provoke a typical RA response. The progression of the RA symptoms in
the mice is measured by measuring paw thickness as a function of time.
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[000340] In the present example, host mice having normal MK-2
production (MK2 (+/+)) were genetically altered by disabling the gene
encoding MK-2 to produce mice having no capability of endogenous
synthesis of active MK-2 (MK2 (-/-)). Normal host mice (MK2 (+/+)) and
MK-2 knock-out mice (MK2 (-/-), were separated into four groups with
each group containing both male and female mice. All groups of mice
were treated similarly, except that one group (Normal), composed of MK2
(+/+) mice that served as the control group, was not injected with serum
from K/BxN mice, while the other three groups were injected with K/BxN
serum at day 0. The other three groups of mice were MK2 (+/+),
MK2 (-/-), and Anti-TNF. The Anti-TNF group was composed of MK2 (+/+)
mice which were also injected at day ) with anti-TNF antibody. The paw
thickness of all mice was measured immediately after the injections on day
0, and then on each successive day thereafter for 7 days.
[00034'1] Figure 1 is a graph that shows paw thickness as a function of
time from day 0 to day 7 for MK2 (+/+) and MK2 (-/-) mice, which have
received serum injection. It can be seen that paw thickness increased
significantly for MK2(+l+) mice, whereas there was substantially no
increase in paw thickness for MK2 knock-out mice. This indicated the
requirement for a functioning MK2 regulatory system to the inflammatory
response caused by the serum challenge. When anti-TNF antibody was
administered to the MK2 (+/+) mice along with the serum injection, the
swelling response was significantly reduced. This can be seen in Figure 2,
which is a bar chart showing paw thickness at seven days after injection
for normal mice, MK2 (+/+) mice receiving serum, MK2 (-l-) mice receiving
serum, and MK2 (+/+) mice receiving serum and anti-TNF antibody.
[000342] This data shows that the MK2 knock-out mice show no arthritic
response to a serum challenge, whereas MK2 (+/+) mice show a normal
response. Treatment of MK2 (+/+) mice that receive a serum challenge
with anti-TNF antibody reduces the response back to near-normal levels.
This illustrates the utility of the MK2 regulatory system as a potential
control point for the modulation of TNF production, and indicates that
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such regulation could serve as a treatment for inflammation -- such as that
caused by arthritis, for example. It further shows that MK2 inhibition can
have a beneficial effect on inflammation, and indicates that administration
of an MK2 inhibitor can be an effective method of preventing or treating
TNF modulated diseases or disorders.
[000343] All references cited in this specification, including without
limitation all papers, publications, patents, patent applications,
presentations, texts, reports, manuscripts, brochures, books, Internet
postings, journal articles, periodicals, and the like, are hereby incorporated
by reference into this specification in their entireties. The discussion of
the
references herein is intended merely to summarize the assertions made by
their authors and no admission is made that any reference constitutes
prior art. Applicants reserve the right to challenge the accuracy and
pertinency of the cited references.
[000344] In view of the above, it will be seen that the several advantages
of the invention are achieved and other advantageous results obtained.
[000345] As various changes could be made in the above methods and
compositions without departing from the scope of the invention, it is
intended that all matter contained in the above description shall be
interpreted as illustrative and not in a limiting sense.
234