US 2013/0274255 A1Published application

Heterocyclic pyrazole compounds, method for preparing the same and use thereof

AssigneeDevelopment Center for Biotechnology

InventorsChu-Bin LIAO, Chao-Cheng CHIANG, Huei-Ru YANG, Yuan-Chun LIAO, Paonien CHEN

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Abstract

The present invention relates to a compound of formula (I): or hydrates, solvates, prodrugs, or pharmaceutically acceptable salts thereof, wherein R1, R2, X, Y, ring A, R3 and R4 are as defined in the detailed description and claims. The compound of formula (I) are receptor tyrosine kinase (RTK) inhibitors and have efficacy for the treatment, prevention, or amelioration of RTK-related diseases.

Claims18

Dependent claims

A compound of formula (I):

wherein:
R1 and R2 independently represent hydrogen, halo, cyano, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, —(CH2)mORa, —(CH2)mNRaRb, —NRaRb, —ORaSRb, —CO2Ra, —NRaCO—(CH2)nmNRaRb, —CONRaRb, —CONRa—(CH2)mNRaRb, aryl, heteroaryl or heterocyclyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, ORa, SRb, aryl, heteroaryl, and heterocyclyl groups are optionally substituted by one or more substituents, preferably one to three substituents, or more preferably one or two substitutents, selected from halo, hydroxyl, alkyl, haloalkyl, alkoxy, amino, cycloalkyl, aralkyl, aryl, heteroaryl, heterocyclyl, heterocyclyl-alkyl, and —CONH-heteroaryl;
X represents alkylene, alkenylene, alkyl-carbonyl, alkenyl-carbonyl, carbonyl, oxygen, —C═NORc;
Y represents a direct bond, alkylene, alkenylene, or —NH—;
ring A represents aryl, heteroaryl, or heterocyclyl;
R3 and R4 independently represent hydroxyl, hydrogen, halo, nitro, cyano, amino, oxo, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenylene, aryl, alkylaryl, NRaRb, —NH-aryl, heteroaryl, alkenylene-aryl, S(O)n-heterocyclyl, —NH-heterocyclyl, or heterocyclyl, wherein the alkyl, haloalkyl, alkoxy, haloalkoxy, alkenylene, aryl, aralkyl, —NH-aryl, heteroaryl, alkenylene-aryl, S(O)n-heterocyclyl, —NH-heterocyclyl, and heterocyclyl groups are optionally substituted by one or more substituents, preferably one to three or more preferably one or two substitutents, selected from amino, cyano, halo, haloalkyl, hydroxyl, alkyl, alkoxy, and haloalkoxy;
Ra and Rb are independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, aryl, heteroaryl, or heterocyclyl, or Ra and Rb, together with the oxygen, nitrogen or sulfur atom to which they are bonded, form a heteroaryl or heterocyclyl group;
Rc represents hydrogen or alkyl,
m is 0, 1, 2, or 3;
and
n is 0, 1 or 2,
Y represents a direct bond, alkylene, alkenylene, or —NH—;
ring A represents aryl, heteroaryl, or heterocyclyl;
R3 and R4 independently represent hydroxyl, hydrogen, halo, nitro, cyano, amino, oxo, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenylene, aryl, alkylaryl, NRaRb, —NH-aryl, heteroaryl, alkenylene-aryl, S(O)n-heterocyclyl, —NH-heterocyclyl, or heterocyclyl, wherein the alkyl, haloalkyl, alkoxy, haloalkoxy, alkenylene, aryl, aralkyl, —NH-aryl, heteroaryl, alkenylene-aryl, S(O)n-heterocyclyl, —NH-heterocyclyl, and heterocyclyl groups are optionally substituted by one or more substituents, preferably one to three or more preferably one or two substitutents, selected from amino, cyano, halo, haloalkyl, hydroxyl, alkyl, alkoxy, and haloalkoxy;
Ra and Rb are independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, aryl, heteroaryl, or heterocyclyl, or Ra and Rb, together with the oxygen, nitrogen or sulfur atom to which they are bonded, form a heteroaryl or heterocyclyl group;
Rc represents hydrogen or alkyl,
m is 0, 1, 2, or 3;
and
n is 0, 1 or 2,
or hydrates, solvates, prodrugs, or pharmaceutically acceptable salts thereof.

17 more elements

The compound selected from:

6-(4-Bromo-phenyl)-5,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene,
4-(4,7-Dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-6-yl)-phenylamine hydrochloride,
6-(3-Methoxy-phenyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene,
6-(2,4-Dimethoxy-phenyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene,
6-(4-Nitro-phenyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene,
6-Phenyl-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene,
[4-(4,7-Dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-6-yl)-phenyl]-(4-fluoro-phenyl)-amine,
[4-(4,7-Dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-6-yl)-phenyl]-(4-methoxy-phenyl)-amine,
4′-(4,7-Dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-6-yl)-3-methoxy-biphenyl-4-ol,
3-[4-(4,7-Dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-6-yl)-phenylamino]-phenol,
4′-(4,7-Dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-6-yl)-biphenyl-4-ol,
6-(4-Styryl-phenyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene,
N-[4-(4,7-Dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-6-yl)-phenyl]-benzene-1,4-diamine,
6-(3′,4′-Dimethoxy-biphenyl-4-yl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]-pentalene,
4′-(4,7-Dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-6-yl)-biphenyl-4-carbonitrile,
6-Pyridin-3-yl-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene,
6-Furan-3-yl-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene,
4,7-Dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene,
6-(3′,5′-Dichloro-biphenyl-4-yl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene,
6-(4′-Trifluoromethyl-biphenyl-4-yl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]-pentalene,
2-Bromo-6-phenyl-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene,
6-(1-Oxy-pyridin-3-yl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene,
2-Bromo-6-(4-bromo-phenyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene,
2-Bromo-6-(4-methoxy-phenyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene,
6-(3-Fluoro-phenyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene,
6-(3-Chloro-phenyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene,
6-(4-Fluoro-phenyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene,
6-(2-Fluoro-phenyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene,
6-(3,5-Bis-trifluoromethyl-phenyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]-pentalene,
6-(2-Bromo-phenyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene,
6-(3-Bromo-phenyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene,
6-(3-Chloro-phenyl)-4H-1-thia-4,5-diaza-cyclopenta[a]pentalen-7-one,
6-(2-Methoxy-phenyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene,
6-(4-Amino-phenyl)-4H-1-thia-4,5-diaza-cyclopenta[a]pentalen-7-one,
6-(3,5-Dichloro-phenyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene,
6-Pyridin-2-yl-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene hydrochloride,
3-(4,7-Dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-6-yl)-phenylamine hydrochloride,
6-Pyridin-4-yl-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene hydrochloride,
6-(1-Oxy-pyridin-4-yl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene,
6-(6-Bromo-pyridin-3-yl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene,
6-(4-Methoxy-phenyl)-2-phenyl-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene,
5-(4,7-Dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-6-yl)-pyridin-2-ylamine hydrochloride,
2-Bromo-6-(6-bromo-pyridin-3-yl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]-pentalene,
6-(4-Amino-phenyl)-4H-1-thia-4,5-diaza-cyclopenta[a]pentalen-7-one,
6-(6-Bromo-pyridin-3-yl)-4H-1-thia-4,5-diaza-cyclopenta[a]pentalen-7-one,
6-(4-Methoxy-phenyl)-2-pyridin-4-yl-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]-pentalene,
6-(4-Methoxy-phenyl)-2-pyridin-3-yl-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]-pentalene,
2-(4-Fluoro-phenyl)-6-(4-methoxy-phenyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene,
2-(3,4-Difluoro-phenyl)-6-(4-methoxy-phenyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene,
2,6-Bis-(4-methoxy-phenyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene,
2-(3,4-Dimethoxy-phenyl)-6-(4-methoxy-phenyl)-4,7-dihydro-1-thia-4,5-diaza-1-cyclopenta[a]pentalene,
2-Methoxy-4-[6-(4-methoxy-phenyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-2-yl]-phenol,
6-(4-Methoxy-phenyl)-2-(6-methoxy-pyridin-3-yl)-4,7-dihydro-1-thia-4,5-diaza-1-cyclopenta[a]pentalene,
2-Furan-3-yl-6-(4-methoxy-phenyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]-pentalene,
5-[6-(4-Methoxy-phenyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-2-yl]-pyridin-2-ylamine,
5-[6-(4-Methoxy-phenyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-2-yl]-pyrimidin-2-ylamine,
6-(4-Methoxy-phenyl)-2-pyridin-3-yl-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]-pentalene,
6-[4-(4-Methyl-piperazin-1-yl)-phenyl]-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene,
5-[6-(4-Methoxy-phenyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-2-yl]-pyridin-2-ylamine,
6-(4-Methoxy-phenyl)-2-[6-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene,
5-[6-(4-Methoxy-phenyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-2-yl]-pyridin-2-ylamine,
N-{5-[6-(4-Methoxy-phenyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-2-yl]-pyridin-2-yl}-2-pyrrolidin-1-yl-acetamide,
2-(3-Fluoro-4-methoxy-phenyl)-6-(4-methoxy-phenyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene,
6-(4-Pyrrolidin-1-yl-phenyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene,
6-(4-Morpholin-4-yl-phenyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene,
3-[6-(4-Methoxy-phenyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-2-yl]-phenylamine,
2-(6-Amino-pyridin-3-yl)-6-(4-methoxy-phenyl)-4H-1-thia-4,5-diaza-cyclopenta[a]pentalen-7-one,
N-{5-[6-(4-Methoxy-phenyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-2-yl]-pyridin-2-yl}-2-pyrrolidin-1-yl-acetamide hydrochloride,
5-{6-(4-Morpholin-4-yl-phenyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]-pentalen-2-yl}-pyridin-2-Ylamine hydrochloride,
5-{6-[4-(4-Methyl-piperazin-1-yl)-phenyl]-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]-pentalen-2-yl}-pyridin-2-ylamine hydrochloride,
6-[4-(4-Methyl-piperazin-1-yl)-phenyl]-2-pyridin-3-yl-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene hydrochloride,
5-[6-(4-Methoxy-phenyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-2-yl]-pyridin-3-ylamine hydrochloride,
4-[2-(6-Amino-pyridin-3-yl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-6-yl]-phenol,
4-(4,7-Dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-6-yl)-phenol,
[4-(4,7-Dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-6-yl)-phenyl]-(4-fluorophenyl)amine,
[4-(4,7-Dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-6-yl)-phenyl]-(4-methoxy-phenyl)-amine,
(4-Bromo-phenyl)-(4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-6-yl)-amine,
(2,4-Dichloro-phenyl)-(4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-6-yl)-amine,
(4,7-Dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-6-yl)-(4-iodo-phenyl)-amine,
(4,7-Dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-6-yl)-(4-methoxy-phenyl)-amine,
(4,7-Dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-6-yl)-(3,4-dimethoxy-phenyl)-amine,
(3-Chloro-phenyl)-(4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-6-yl)-amine,
(4,7-Dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-6-yl)-(3-methoxy-phenyl)-amine,
(4,7-Dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-6-yl)-(3-trifluoromethyl-phenyl)-amine,
(4,7-Dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-6-yl)-(3-fluoro-phenyl)-amine,
(2-Chloro-phenyl)-(4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-6-yl)-amine,
(4-Chloro-phenyl)-(4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-6-yl)-amine,
(4,7-Dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-6-yl)-(4-trifluoromethyl-phenyl)-amine,
(3-Bromo-phenyl)-(4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-6-yl)-amine,
(4,7-Dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-6-yl)-(2-trifluoromethyl-phenyl)-amine,
(4,7-Dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-6-yl)-(2-methoxy-phenyl)-amine,
(4,7-Dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-6-yl)-(4-trifluoromethoxy-phenyl)-amine,
(4,7-Dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-6-yl)-(2-trifluoromethoxy-phenyl)-amine,
(3,5-Dichloro-phenyl)-(4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-6-yl)-amine,
(2,4-Dichloro-phenyl)-(4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-6-yl)-amine,
(3,4-Dichloro-phenyl)-(4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-6-yl)-amine,
(2,3-Dichloro-phenyl)-(4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-6-yl)-amine, and
(4,7-Dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-6-yl)-[4-(piperidine-1-sulfonyl)-phenyl]-amine,
or hydrates, solvates, prodrugs, or pharmaceutically acceptable salts thereof.

96 more elements

Dependencies are inferred from the claim text.

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Abstract

A compound of formula (I):

wherein:
R1 and R2 independently represent hydrogen, halo, cyano, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, —(CH2)mORa, —(CH2)mNRaRb, —NRaRb, —ORaSRb, —CO2Ra, —NRaCO—(CH2)nmNRaRb, —CONRaRb, —CONRa—(CH2)mNRaRb, aryl, heteroaryl or heterocyclyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, ORa, SRb, aryl, heteroaryl, and heterocyclyl groups are optionally substituted by one or more substituents, preferably one to three substituents, or more preferably one or two substitutents, selected from halo, hydroxyl, alkyl, haloalkyl, alkoxy, amino, cycloalkyl, aralkyl, aryl, heteroaryl, heterocyclyl, heterocyclyl-alkyl, and —CONH-heteroaryl;
X represents alkylene, alkenylene, alkyl-carbonyl, alkenyl-carbonyl, carbonyl, oxygen, —C═NORc;
Y represents a direct bond, alkylene, alkenylene, or —NH—;
ring A represents aryl, heteroaryl, or heterocyclyl;
R3 and R4 independently represent hydroxyl, hydrogen, halo, nitro, cyano, amino, oxo, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenylene, aryl, alkylaryl, NRaRb, —NH-aryl, heteroaryl, alkenylene-aryl, S(O)n-heterocyclyl, —NH-heterocyclyl, or heterocyclyl, wherein the alkyl, haloalkyl, alkoxy, haloalkoxy, alkenylene, aryl, aralkyl, —NH-aryl, heteroaryl, alkenylene-aryl, S(O)n-heterocyclyl, —NH-heterocyclyl, and heterocyclyl groups are optionally substituted by one or more substituents, preferably one to three or more preferably one or two substitutents, selected from amino, cyano, halo, haloalkyl, hydroxyl, alkyl, alkoxy, and haloalkoxy;
Ra and Rb are independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, aryl, heteroaryl, or heterocyclyl, or Ra and Rb, together with the oxygen, nitrogen or sulfur atom to which they are bonded, form a heteroaryl or heterocyclyl group;
Rc represents hydrogen or alkyl,
m is 0, 1, 2, or 3;
and
n is 0, 1 or 2,
Y represents a direct bond, alkylene, alkenylene, or —NH—;
ring A represents aryl, heteroaryl, or heterocyclyl;
R3 and R4 independently represent hydroxyl, hydrogen, halo, nitro, cyano, amino, oxo, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenylene, aryl, alkylaryl, NRaRb, —NH-aryl, heteroaryl, alkenylene-aryl, S(O)n-heterocyclyl, —NH-heterocyclyl, or heterocyclyl, wherein the alkyl, haloalkyl, alkoxy, haloalkoxy, alkenylene, aryl, aralkyl, —NH-aryl, heteroaryl, alkenylene-aryl, S(O)n-heterocyclyl, —NH-heterocyclyl, and heterocyclyl groups are optionally substituted by one or more substituents, preferably one to three or more preferably one or two substitutents, selected from amino, cyano, halo, haloalkyl, hydroxyl, alkyl, alkoxy, and haloalkoxy;
Ra and Rb are independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, aryl, heteroaryl, or heterocyclyl, or Ra and Rb, together with the oxygen, nitrogen or sulfur atom to which they are bonded, form a heteroaryl or heterocyclyl group;
Rc represents hydrogen or alkyl,
m is 0, 1, 2, or 3;
and
n is 0, 1 or 2,
or hydrates, solvates, prodrugs, or pharmaceutically acceptable salts thereof.

17 more elements