Ureas having antiangiogenic activity

1. A compound of formula (I)

or a therapeutically acceptable salt thereof, wherein

A is selected from the group consisting of pyridazinyl, pyridinyl, pyridine N-oxide, pyrimidinyl, indol-3-yl, pyrazol-4-yl, pyrazinyl, isoxazol-4-yl, and triazinyl;

R 1 and R 2 are independently selected from the group consisting of hydrogen, alkenyl, alkoxy, alkoxyalkyl, alkyl, alkynyl, aryl, arylalkyl, cyanoalkyl, cycloalkyl, (cycloalkyl)alkyl, haloalkyl, heterocyclyl, heterocyclylalkyl, hydroxyalkyl, (NR A R B )alkyl, and (NR A R B )carbonyl; or

R 1 and R 2 , together with the nitrogen atom to which they are attached, form a five- to seven-membered ring containing zero or one additional heteroatom selected from the group consisting of nitrogen, oxygen, and sulfur, wherein the remaining atoms are carbon; wherein the ring can be optionally substituted with one, two, three, or four substituents independently selected from the group consisting of alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylene, alkylcarbonyl, alkylsulfanylalkyl, aryl, arylalkyl, arylcarbonyl, arylcarbonylalkyl, cycloalkyl, (cycloalkyl)alkyl, (cycloalkyl)carbonyl, (cycloalkyl)carbonylalkyl, ethylenedioxy, haloalkoxy, haloalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl, heterocyclylcarbonylalkyl, hydroxy, hydroxyalkyl, NR A R B , (NR A R B )alkyl, and (NR A R B )carbonyl;

R 3 at each occurance is independently selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylsulfanyl, aryl, arylalkyl, aryloxy, cyano, cyanoalkyl, cycloalkyl, (cycloalkyl)alkyl, halo, haloalkyl, heterocycle, hydroxy, hydroxyalkyl, and nitro;

X is selected from the group consisting of O and S;

m is 0-4; and

R A and R B are independently selected from the group consisting of hydrogen, alkenyl, alkoxyalkyl, alkyl, alkynyl, alkylcarbonyl, aryl, arylalkyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, heterocyclylalkyl, and hydroxyalkyl.

2. The compound of claim 1 wherein A is pyridinyl.

3. The compound of claim 2 wherein R 3 is alkyl; X is O; and m is 1.

4. The compound of claim 3 wherein R 1 is selected from the group consisting of hydrogen and alkyl; and R 2 is heterocyclylalkyl.

5. A compound of claim 1 selected from the group consisting of

N-benzyl-N′-{(3R)-1-[(6-methylpyridin-3-yl)carbonyl]pyrrolidin-3-yl}urea;

N-{(3R)-1-[(6-methyl-3-pyridinyl)carbonyl]-3-pyrrolidinyl}-1-pyrrolidinecarboxamide;

N-{(3R)-1-[(6-methyl-3-pyridinyl)carbonyl]-3-pyrrolidinyl}-N′-[3-(4-morpholinyl)propyl]urea;

N-[2-(1H-imidazol-4-yl)ethyl]-N′-{(3R)-1-[(6-methyl-3-pyridinyl)carbonyl]-3-pyrrolidinyl}urea;

N-[2-(1H-indol-3-yl)ethyl]-N′-{(3R)-1-[(6-methyl-3-pyridinyl)carbonyl]-3-pyrrolidinyl}urea;

N-ethyl-N′-{(3R)-1-[(6-methyl-3-pyridinyl)carbonyl]-3-pyrrolidinyl}urea;

N-isobutyl-N′-{(3R)-1-[(6-methyl-3-pyridinyl)carbonyl]-3-pyrrolidinyl}urea;

N-(1-methylbutyl)-N′-{(3R)-1-[(6-methyl-3-pyridinyl)carbonyl]-3-pyrrolidinyl}urea;

N-{(3R)-1-[(6-methyl-3-pyridinyl)carbonyl]-3-pyrrolidinyl}-N′-neopentylurea;

N-(3,3-dimethylbutyl)-N′-{(3R)-1-[(6-methyl-3-pyridinyl)carbonyl]-3-pyrrolidinyl}urea;

N-{(3R)-1-[(6-methyl-3-pyridinyl)carbonyl]-3-pyrrolidinyl}-N′-(2,2,2-trifluoroethyl)urea;

N-(2-methoxy-1-methylethyl)-N′-{(3R)-1-[(6-methyl-3-pyridinyl)carbonyl]-3-pyrrolidinyl}urea;

N-(2-ethoxyethyl)-N′-{(3R)-1-[(6-methyl-3-pyridinyl)carbonyl]-3-pyrrolidinyl}urea;

N-{(3R)-1-[(6-methyl-3-pyridinyl)carbonyl]-3-pyrrolidinyl}-N′-(tetrahydro-3-furanylmethyl)urea;

N-(cyanomethyl)-N′-{(3R)-1-[(6-methyl-3-pyridinyl)carbonyl]-3-pyrrolidinyl}urea;

N-{(3R)-1-[(6-methyl-3-pyridinyl)carbonyl]-3-pyrrolidinyl}-N′-2-propynylurea;

N-(cyclopropylmethyl)-N′-{(3R)-1-[(6-methyl-3-pyridinyl)carbonyl]-3-pyrrolidinyl}urea;

N-cyclobutyl-N′-{(3R)-1-[(6-methyl-3-pyridinyl)carbonyl]-3-pyrrolidinyl}urea;

N-cyclohexyl-N′-{(3R)-1-[(6-methyl-3-pyridinyl)carbonyl]-3-pyrrolidinyl}urea;

N-(4-methylcyclohexyl)-N′-{(3R)-1-[(6-methyl-3-pyridinyl)carbonyl]-3-pyrrolidinyl}urea;

N-(cyclohexylmethyl)-N′-{(3R)-1-[(6-methyl-3-pyridinyl)carbonyl]-3-pyrrolidinyl}urea;

N-cycloheptyl-N′-{(3R)-1-[(6-methyl-3-pyridinyl)carbonyl]-3-pyrrolidinyl}urea;

N-[(1S)-1-(hydroxymethyl)-3-methylbutyl]-N′-{(3R)-1-[(6-methyl-3-pyridinyl)carbonyl]-3-pyrrolidinyl}urea;

N-[(1R)-1-(hydroxymethyl)-3-methylbutyl]-N′-{(3R)-1-[(6-methyl-3-pyridinyl)carbonyl]-3-pyrrolidinyl}urea;

N-[(1S)-2-hydroxy-1-phenylethyl]-N′-{(3R)-1-[(6-methyl-3-pyridinyl)carbonyl]-3-pyrrolidinyl}urea;

N-(3-isopropoxypropyl)-N′-{(3R)-1-[(6-methyl-3-pyridinyl)carbonyl]-3-pyrrolidinyl}urea;

N-(2,3-dihydroxypropyl)-N′-{(3R)-1-[(6-methyl-3-pyridinyl)carbonyl]-3-pyrrolidinyl}urea;

N-{(3R)-1-[(6-methyl-3-pyridinyl)carbonyl]-3-pyrrolidinyl}-N′-[2-(2-thienyl)ethyl]urea;

N-[2-(5-methoxy-1H-indol-3-yl)ethyl]-N′-{(3R)-1-[(6-methyl-3-pyridinyl)carbonyl]-3-pyrrolidinyl}urea;

N-(2,4-difluorobenzyl)-N′-{(3R)-1-[(6-methyl-3-pyridinyl)carbonyl]-3-pyrrolidinyl}urea;

N-(3,3-diphenylpropyl)-N′-{(3R)-1-[(6-methyl-3-pyridinyl)carbonyl]-3-pyrrolidinyl}urea;

N-[(1R)-2-hydroxy-1-phenylethyl]-N′-{(3R)-1-[(6-methyl-3-pyridinyl)carbonyl]-3-pyrrolidinyl}urea;

N-{(3R)-1-[(6-methylpyridin-3-yl)carbonyl]pyrrolidin-3-yl}-N′-[(1S)-1-phenylethyl]urea;

N,N-dibutyl-N′-{(3R)-1-[(2-chloro-6-methylpyridin-3-yl)carbonyl]pyrrolidin-3-yl}urea;

N′-{(3R)-1-[(2-chloro-6-methylpyridin-3-yl)carbonyl]pyrrolidin-3-yl}-N-isopropyl-N-(2-methoxyethyl)urea;

N-{(3R)-1-[(2-chloro-6-methylpyridin-3-yl)carbonyl]pyrrolidin-3-yl}-1,3,3-trimethyl-6-azabicyclo[3.2.1]octane-6-carboxamide;

N-{(3R)-1-[(2-chloro-6-methylpyridin-3-yl)carbonyl]pyrrolidin-3-yl}-N′-[(1R)-2-hydroxy-1-phenylethyl]urea;

N-{(3R)-1-[(2-chloro-6-methylpyridin-3-yl)carbonyl]pyrrolidin-3-yl}-N′-(3-ethoxypropyl)urea;

N-{(3R)-1-[(2-chloro-6-methylpyridin-3-yl)carbonyl]pyrrolidin-3-yl}-N′-(3-isopropoxypropyl)urea;

N-{(3R)-1-[(2-chloro-6-methylpyridin-3-yl)carbonyl]pyrrolidin-3-yl}-N′-(3-isobutoxypropyl)urea;

N-{(3R)-1-[(2-chloro-6-methylpyridin-3-yl)carbonyl]pyrrolidin-3-yl}-N′-[3-(methylthio)propyl]urea;

N-benzyl-N′-{(3R)-1-[(2-chloro-6-methylpyridin-3-yl)carbonyl]pyrrolidin-3-yl}-N-ethylurea;

N,N-dibenzyl-N′-{(3R)-1-[(2-chloro-6-methylpyridin-3-yl)carbonyl]pyrrolidin-3-yl}urea;

N′-{(3R)-1-[(2-chloro-6-methylpyridin-3-yl)carbonyl]pyrrolidin-3-yl}-N-methyl-N-(2-phenylethyl)urea;

N′-{(3R)-1-[(2-chloro-6-methylpyridin-3-yl)carbonyl]pyrrolidin-3-yl}-N-[2-(3,4-dimethoxyphenyl)ethyl]-N-methylurea;

4-benzyl-N-{(3R)-1-[(2-chloro-6-methylpyridin-3-yl)carbonyl]pyrrolidin-3-yl}piperidine-1-carboxamide;

N-{(3R)-1-[(2-chloro-6-methylpyridin-3-yl)carbonyl]pyrrolidin-3-yl}-4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidine-1-carboxamide;

N-{(3R)-1-[(2-chloro-6-methylpyridin-3-yl)carbonyl]pyrrolidin-3-yl}-4-phenylpiperazine-1-carboxamide;

N-[2-(diethylamino)ethyl]-N-methyl-N′-{(3R)-1-[(6-methylpyridin-3-yl)carbonyl]pyrrolidin-3-yl}urea;

N-benzyl-N-ethyl-N′-{(3R)-1-[(6-methylpyridin-3-yl)carbonyl]pyrrolidin-3-yl}urea;

N-benzyl-N-isopropyl-N′-{(3R)-1-[(6-methylpyridin-3-yl)carbonyl]pyrrolidin-3-yl}urea;

N-benzyl-N-butyl-N′-{(3R)-1-[(6-methylpyridin-3-yl)carbonyl]pyrrolidin-3-yl}urea;

N,N-dibenzyl-N′-{(3R)-1-[(6-methylpyridin-3-yl)carbonyl]pyrrolidin-3-yl}urea;

N-benzyl-N′-{(3R)-1-[(6-methylpyridin-3-yl)carbonyl]pyrrolidin-3-yl}-N-(2-phenylethyl)urea;

N 3 ,N 3 -diethyl-N 1 -{(3R)-1-[(6-methylpyridin-3-yl)carbonyl]pyrrolidin-3-yl}piperidine-1,3-dicarboxamide;

N-{(3R)-1-[(6-methylpyridin-3-yl)carbonyl]pyrrolidin-3-yl}-4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidine-1-carboxamide;

4-ethyl-N-{(3R)-1-[(6-methylpyridin-3-yl)carbonyl]pyrrolidin-3-yl}piperazine-1-carboxamide;

4-benzyl-N-{(3R)-1-[(6-methylpyridin-3-yl)carbonyl]pyrrolidin-3-yl}piperazine-1-carboxamide;

N-methyl-N′-{(3R)-1-[(6-methylpyridin-3-yl)carbonyl]pyrrolidin-3-yl}-N-propylurea;

N-isobutyl-N-methyl-N′-{(3R)-1-[(6-methylpyridin-3-yl)carbonyl]pyrrolidin-3-yl}urea;

N-methyl-N-(3-methylbutyl)-N′-{(3R)-1-[(6-methylpyridin-3-yl)carbonyl]pyrrolidin-3-yl}urea;

N-methyl-N′-{(3R)-1-[(6-methylpyridin-3-yl)carbonyl]pyrrolidin-3-yl}-N-prop-2-ynylurea;

N-ethyl-N′-{(3R)-1-[(6-methylpyridin-3-yl)carbonyl]pyrrolidin-3-yl}-N-propylurea;

N-isopropyl-N′-{(3R)-1-[(6-methylpyridin-3-yl)carbonyl]pyrrolidin-3-yl}-N-propylurea;

N-(sec-butyl)-N′-{(3R)-1-[(6-methylpyridin-3-yl)carbonyl]pyrrolidin-3-yl}-N-propylurea;

N,N-dibutyl-N′-{(3R)-1-[(6-methylpyridin-3-yl)carbonyl]pyrrolidin-3-yl}urea;

N-(2-cyanoethyl)-N-cyclopropyl-N′-{(3R)-1-[(6-methylpyridin-3-yl)carbonyl]pyrrolidin-3-yl}urea;

2-ethyl-N-{(3R)-1-[(6-methylpyridin-3-yl)carbonyl]pyrrolidin-3-yl}piperidine-1-carboxamide;

N-{(3R)-1-[(6-methylpyridin-3-yl)carbonyl]pyrrolidin-3-yl}-4-propylpiperidine-1-carboxamide;

N-{(3R)-1-[(6-methylpyridin-3-yl)carbonyl]pyrrolidin-3-yl}azepane-1-carboxamide;

N-ethyl-N-(2-methoxyethyl)-N′-{(3R)-1-[(6-methylpyridin-3-yl)carbonyl]pyrrolidin-3-yl}urea;

N-(2-methoxyethyl)-N′-{(3R)-1-[(6-methylpyridin-3-yl)carbonyl]pyrrolidin-3-yl}-N-propylurea;

N,N-bis(2-methoxyethyl)-N′-{(3R)-1-[(6-methylpyridin-3-yl)carbonyl]pyrrolidin-3-yl}urea;

1,3,3-trimethyl-N-{(3R)-1-[(6-methylpyridin-3-yl)carbonyl]pyrrolidin-3-yl}-6-azabicyclo[3.2.1]octane-6-carboxamide;

N-methyl-N′-{(3R)-1-[(6-methylpyridin-3-yl)carbonyl]pyrrolidin-3-yl}-N-(2-phenylethyl)urea;

4-sec-butyl-N-{(3R)-1-[(6-methylpyridin-3-yl)carbonyl]pyrrolidin-3-yl}piperazine-1-carboxamide;

4-(2-ethoxyethyl)-N-{(3R)-1-[(6-methylpyridin-3-yl)carbonyl]pyrrolidin-3-yl}piperazine-1-carboxamide;

4-cyclohexyl-N-{(3R)-1-[(6-methylpyridin-3-yl)carbonyl]pyrrolidin-3-yl}piperazine-1-carboxamide;

N-{(3R)-1-[(6-methylpyridin-3-yl)carbonyl]pyrrolidin-3-yl}-4-(2-thien-2-ylethyl)piperazine-1-carboxamide;

N-{(3R)-1-[(6-methylpyridin-3-yl)carbonyl]pyrrolidin-3-yl}-4-(2-oxo-2-piperidin-1-ylethyl)piperazine-1-carboxamide;

4-(cyclohexylcarbonyl)-N-{(3R)-1-[(6-methylpyridin-3-yl)carbonyl]pyrrolidin-3-yl}piperazine-1-carboxamide;

N-benzyl-N-(2-hydroxyethyl)-N′-{(3R)-1-[(6-methylpyridin-3-yl)carbonyl]pyrrolidin-3-yl}urea;

N-(2-hydroxy-2-phenylethyl)-N-methyl-N′-{1-[(6-methylpyridin-3-yl)carbonyl]pyrrolidin-3-yl}urea;

N-methyl-N′-{(3R)-1-[(6-methylpyridin-3-yl)carbonyl]pyrrolidin-3-yl}-N-(2-pyridin-2-ylethyl)urea;

4-hydroxy-N-{(3R)-1-[(6-methylpyridin-3-yl)carbonyl]pyrrolidin-3-yl}piperidine-1-carboxamide;

N 1 -{(3R)-1-[(6-methylpyridin-3-yl)carbonyl]pyrrolidin-3-yl}piperidine-1,4-dicarboxamide;

N-{(3R)-1-[(6-methylpyridin-3-yl)carbonyl]pyrrolidin-3-yl}-1,4-dioxa-8-azaspiro[4.5]decane-8-carboxamide;

2,6-dimethyl-N-{(3R)-1-[(6-methylpyridin-3-yl)carbonyl]pyrrolidin-3-yl}morpholine-4-carboxamide;

N-{(3R)-1-[(6-methylpyridin-3-yl)carbonyl]pyrrolidin-3-yl}-4-phenylpiperazine-1-carboxamide;

N-{(3R)-1-[(6-methylpyridin-3-yl)carbonyl]pyrrolidin-3-yl}-4-pyridin-2-ylpiperazine-1-carboxamide;

4-(2-fluorophenyl)-N-{(3R)-1-[(6-methylpyridin-3-yl)carbonyl]pyrrolidin-3-yl}piperazine-1-carboxamide;

4-(4-fluorophenyl)-N-{(3R)-1-[(6-methylpyridin-3-yl)carbonyl]pyrrolidin-3-yl}piperazine-1-carboxamide;

4-(2-methoxyphenyl)-N-{(3R)-1-[(6-methylpyridin-3-yl)carbonyl]pyrrolidin-3-yl}piperazine-1-carboxamide;

4-methyl-N-{(3R)-1-[(6-methylpyridin-3-yl)carbonyl]pyrrolidin-3-yl}-1,4-diazepane-1-carboxamide;

ethyl {4-[({(3R)-1-[(6-methylpyridin-3-yl)carbonyl]pyrrolidin-3-yl}amino)carbonyl]piperazin-1-yl}acetate;

N-{(3R)-1-[(6-methylpyridin-3-yl)carbonyl]pyrrolidin-3-yl}-4-(4-nitrophenyl)piperazine-1-carboxamide; and

3-(methoxymethyl)-N-{(3R)-1-[(6-methylpyridin-3-yl)carbonyl]pyrrolidin-3-yl}piperidine-1-carboxamide.

6. A pharmaceutical composition comprising a compound of claim 1 or a therapeutically acceptable salt thereof, in combination with a therapeutically acceptable carrier.