IP Library Granted Patent US 8,138,217
Granted Patent B2
US 8,138,217 · App. 11/050,360 · Granted Mar 20, 2012

1H-thieno[2,3-c]pyrazole derivatives useful as kinase inhibitors

Assignee: Nerviano Medical Sciences S.R.L.
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Quick Facts
Patent No.
US 8,138,217
App. No.
11/050,360
Granted
Mar 20, 2012
Kind
B2
Abstract

Thieno[2,3-c]pyrazole derivatives of formula (I) and pharmaceutically acceptable salts thereof, as defined in the specification, process for their preparation and pharmaceutical compositions comprising them are disclosed; the compounds of the invention may be useful, in therapy, in the treatment of diseases associated with a disregulated protein kinase activity, like cancer.

Claims (214)

1. A compound of formula (I)

wherein

R is an optionally substituted aryl or heteroaryl group;

R 1 and R 2 represent, the same or different and independently from each other, a hydrogen atom, a straight or branched C 1 -C 3 alkyl or a group —CONH 2 or —CH 2 NR′R″ or, taken together with the carbon atom to which they are bonded, R 1 and R 2 may form a C 3 -C 6 cycloalkyl group; with the proviso that at least one of R 1 and R 2 is other than a hydrogen atom; R′ and R″ represent, the same or different and independently from each other, a hydrogen atom or a straight or branched C 1 -C 3 alkyl group or, taken together with the nitrogen atom to which they are bonded, R′ and R″ may form a heterocyclic ring of formula

wherein R′″ is a hydrogen atom or a straight or branched C 1 -C 3 alkyl group;

R 3 is a hydrogen or halogen atom or a group selected from hydroxy, cyano, straight or branched C 1 -C 3 alkyl or C 1 -C 3 alkoxy;

or stereoisomers, tautomers, and pharmaceutically acceptable salts thereof with the proviso that the compound not have one of R 1 and R 2 be a hydrogen atom, the other one of R 1 and R 2 be a C 1 -C 3 alkyl and R be a 4-(1-methyl-piperazin-4-yl)phenyl.

2. A compound of formula (I) according to claim 1 wherein R is a group, optionally further substituted, selected from thienyl, furyl, pyrrolyl and phenyl.

3. A compound of formula (I) according to claim 2 wherein R is thienyl, furyl, pyrrolyl, N-methyl-pyrrolyl, phenyl and phenyl substituted by halogen atoms, heterocycles, heterocylyloxy or heterocyclylalkyl groups.

4. A compound of formula (I) according to claim 3 wherein R is selected from 2-thienyl, 2-furyl, 1-methyl-pyrrolyl-2-yl, phenyl, 4-fluorophenyl, 4-(1-methyl-piperidyl-4-yloxy)phenyl, 4-(1-methyl-piperazinyl-4-yl)phenyl, 4-(1-methyl-piperazinyl-4-yl-methyl)phenyl, 4-(pyrrolidin-1-yl)methyl-phenyl, 4-(piperidin-1-yl)methyl-phenyl, 4-(1-methyl-piperazin-4-yl)methyl-phenyl, 4-(morpholino-1-yl)methyl-phenyl, 4-(alkylamino)methyl-phenyl, 4-(dialkylamino)methyl-phenyl or 4-(morpholino-4-yl)phenyl.

5. A compound of formula (I) according to claim 1 wherein one of R 1 and R 2 is a hydrogen atom or a methyl group and the remaining one of R 1 and R 2 is methyl, ethyl or a group —CH 2 NR′R″ wherein R′ and R″ are defined in claim 1 .

6. A compound of formula (I) according to claim 1 wherein R 1 and R 2 , together with the carbon atom to which they are attached, form a C 3 -C 6 cycloalkyl group.

7. A compound of formula (I) according to claim 6 wherein R 1 and R 2 , together with the carbon atom to which they are attached, form a cyclopropyl or cyclopentyl group.

8. A compound of formula (I) according to claim 1 wherein R, R 1 and R 2 are as set defined in claim 1 and R 3 represents a hydrogen, fluorine or chlorine atom, or a group selected from hydroxy, methoxy or cyano.

9. A compound of formula (I) according to claim 1 wherein R is optionally substituted, in any of its free positions, by from 1 to 6 groups, selected from: halogen, nitro, carboxy, cyano, alkyl, polyfluorinated alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl; aryl, heterocyclyl, alkyl-heterocyclyl, heterocyclyl-alkyl, amino-alkyl, amino groups and alkylamino, dialkylamino, arylamino, diarylamino, ureido, alkylureido or arylureido; carbonylamino groups and formylamino, alkylcarbonylamino, alkenylcarbonylamino, arylcarbonylamino, alkoxycarbonylamino; hydroxy groups and alkoxy, polyfluorinated alkoxy, aryloxy, heterocylyloxy, alkylcarbonyloxy, arylcarbonyloxy, cycloalkenyloxy or alkylideneaminoxy; carbonyl groups and alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, cycloalkyloxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl; alkylthio, arylthio, alkylsulfonyl, arylsulfonyl, alkylsulfinyl, arylsulfonyl, arylsulfonyloxy, aminosulfonyl, alkylaminosulfonyl or dialkylaminosulfonyl.

10. A compound of formula (I) according to claim 1 , optionally in the form of a pharmaceutically acceptable salt thereof, selected from the group consisting of:

1) N-(1-methyl-1-phenylethyl)-3-[(4-morpholin-4-ylbenzoyl)amino]-1H-thieno[2,3-c]pyrazole-5-carboxamide;

2) 3-[(4-morpholin-4-ylbenzoyl)amino]-N-(1-phenylcyclopropyl)-1H-thieno[2,3-c]pyrazole-5-carboxamide;

3) N-[(1R)-1-(4-fluorophenyl)ethyl]-3-[(4-morpholin-4-ylbenzoyl)amino]-1H-thieno[2,3-c]pyrazole-5-carboxamide;

4) 3-[(4-morpholin-4-ylbenzoyl)amino]-N-[(1R)-1-phenylpropyl]-1H-thieno[2,3-c]pyrazole-5-carboxamide;

5) 3-[(4-morpholin-4-ylbenzoyl)amino]-N-(1S)-1-phenyl-2-pyrrolidin-1-ylethyl]-1H-thieno[2,3-c]pyrazole-5-carboxamide;

6) 3-[(4-morpholin-4-ylbenzoyl)amino]-N-[(1S)-2-morpholin-4-yl-1-phenylethyl]-1H-thieno[2,3-c]pyrazole-5-carboxamide;

7) 3-[(4-fluorobenzoyl)amino]-N-(1-phenylcyclopropyl)-1H-thieno[2,3-c]pyrazole-5-carboxamide;

8) 3-[(4-fluorobenzoyl)amino]-N-(1-methyl-1-phenylethyl)-1H-thieno[2,3-c]pyrazole-5-carboxamide;

9) 3-[(4-fluorobenzoyl)amino]-N-[(1R)-1-phenylpropyl]-1H-thieno[2,3-c]pyrazole-5-carboxamide;

10) 3-[(4-fluorobenzoyl)amino]-N-[(1S)-1-phenyl-2-pyrrolidin-1-ylethyl]-1H-thieno[2,3-c]pyrazole-5-carboxamide;

11) 3-[(4-fluorobenzoyl)amino]-N-[(1R)-1-(4-fluorophenyl)ethyl]-1H-thieno[2,3-c]pyrazole-5-carboxamide;

12) 3-[(4-fluorobenzoyl)amino]-N-[(1S)-2-morpholin-4-yl-1-phenylethyl]-1H-thieno[2,3-c]pyrazole-5-carboxamide;

13) N-(1-ethyl-1-phenylpropyl)-3-[(4-fluorobenzoyl)amino]-1H-thieno[2,3-c]pyrazole-5-carboxamide;

14) 3-[(4-fluorobenzoyl)amino]-N-(1-phenylcyclopentyl)-1H-thieno[2,3-c]pyrazole-5-carboxamide;

15) N-[(1S)-2-morpholin-4-yl-1-phenylethyl]-3-[(thien-2-ylcarbonyl)amino]-1H-thieno[2,3-c]pyrazole-5-carboxamide;

16) N-(1-methyl-1-phenylethyl)-3-[(thien-2-ylcarbonyl)amino]-1H-thieno[2,3-c]pyrazole-5-carboxamide;

17) N-[(1R)-1-(4-fluorophenyl)ethyl]-3-[(thien-2-ylcarbonyl)amino]-1H-thieno[2,3-c]pyrazole-5-carboxamide;

18) N-(1-phenylcyclopropyl)-3-[(thien-2-ylcarbonyl)amino]-1H-thieno[2,3-c]pyrazole-5-carboxamide;

19) N-[(1S)-1-phenyl-2-pyrrolidin-1-ylethyl]-3-[(thien-2-ylcarbonyl)amino]-1H-thieno[2,3-c]pyrazole-5-carboxamide;

20) N-[(1R)-1-phenylpropyl]-3-[(thien-2-ylcarbonyl)amino]-1H-thieno[2,3-c]pyrazole-5-carboxamide;

21) N-(1-methyl-1-phenylethyl)-3-{[(1-methyl-1H-pyrrol-2-yl)carbonyl]amino}-1H-thieno[2,3-c]pyrazole-5-carboxamide;

22) 3-{[(1-methyl-1H-pyrrol-2-yl)carbonyl]amino}-N-(1-phenylcyclopropyl)-1H-thieno[2,3-c]pyrazole-5-carboxamide;

23) 3-(2-furoylamino)-N-(1-phenylcyclopropyl)-1H-thieno[2,3-c]pyrazole-5-carboxamide;

24) 3-(2-furoylamino)-N-(1-methyl-1-phenylethyl)-1H-thieno[2,3-c]pyrazole-5-carboxamide;

25) N-(1-methyl-1-phenylethyl)-3-({4-[(1-methylpiperidin-4-yl)oxy]benzoyl}amino)-1H-thieno[2,3-c]pyrazole-5-carboxamide;

26) 3-({4-[(1-methylpiperidin-4-yl)oxy]benzoyl}amino)-N-(1-phenylcyclopropyl)-1H-thieno[2,3-c]pyrazole-5-carboxamide;

27) N-(1-methyl-1-phenylethyl)-3-({4-[(4-methylpiperazin-1-yl)methyl]benzoyl}amino)-1H-thieno[2,3-c]pyrazole-5-carboxamide;

28) 3-({4-[(4-methylpiperazin-1-yl)methyl]benzoyl}amino)-N-(1-phenylcyclopropyl)-1H-thieno[2,3-c]pyrazole-5-carboxamide:

29) N-(1-methyl-1-phenylethyl)-3-{[4-(4-methylpiperazin-1-yl)benzoyl]amino}-1H-thieno[2,3-c]pyrazole-5-carboxamide;

30) 3-{[4-(4-methylpiperazin-1-yl)benzoyl]amino}-N-[(1R)-1-phenylpropyl]-1H-thieno[2,3-c]pyrazole-5-carboxamide;

31) 3-{[4-(4-methylpiperazin-1-yl)benzoyl]amino}-N-[(1S)-2-morpholin-4-yl-1-phenylethyl]-1H-thieno[2,3-c]pyrazole-5-carboxamide;

32) 3-{[4-(4-methylpiperazin-1-yl)benzoyl]amino}-N-[(1S)-1-phenyl-2-pyrrolidin-1-ylethyl]-1H-thieno[2,3-c]pyrazole-5-carboxamide;

33) N-(1-ethyl-1-phenylpropyl)-3-{[4-(4-methylpiperazin-1-yl)benzoyl]amino}-1H-thieno[2,3-c]pyrazole-5-carboxamide;

34) 3-{[4-(4-methylpiperazin-1-yl)benzoyl]amino}-N-(1-phenylcyclopentyl)-1H-thieno[2,3-c]pyrazole-5-carboxamide;

35) 3-{[4-(4-methylpiperazin-1-yl)benzoyl]amino}-N-(1-phenylcyclopropyl)-1H-thieno[2,3-c]pyrazole-5-carboxamide;

36) 3-(4-Pyrrolidin-1-ylmethyl-benzoylamino)-1H-thieno[2,3-c]pyrazole-5-carboxylic acid (1-methyl-1-phenyl-ethyl)-amide;

37) 3-(4-Morpholin-4-ylmethyl-benzoylamino)-1H-thieno[2,3-c]pyrazole-5-carboxylic acid(1-methyl-1-phenyl-ethyl)-amide;

38) 3-(4-Piperidin-1-ylmethyl-benzoylamino)-1H-thieno[2,3-c]pyrazole-5-carboxylic acid(1-methyl-1-phenyl-ethyl)-amide;

39) 3-[4-(Isopropylamino-methyl)-benzoylamino]-1H-thieno[2,3-c]pyrazole-5-carboxylic acid(1-methyl-1-phenyl-ethyl)-amide;

40) 3-[4-(1,1-Dioxo-1-thiomorpholin-4-ylmethyl)-benzoylamino]-1H-thieno[2,3-c]pyrazole-5-carboxylic acid(1-methyl-1-phenyl-ethyl)-amide;

41) 3-(4-Morpholin-4-ylmethyl-benzoylamino)-1H-thieno[2,3-c]pyrazole-5-carboxylic acid[1-(1-fluoro-phenyl)-1-methyl-ethyl]-amide;

42) 3-(4-Morpholin-4-ylmethyl-benzoylamino)-1H-thieno[2,3-c]pyrazole-5-carboxylic acid[1-(2-fluoro-phenyl)-1-methyl-ethyl]-amide;

43) 3-(4-Morpholin-4-ylmethyl-benzoylamino)-1H-thieno[2,3-c]pyrazole-5-carboxylic acid[1-(4-fluoro-phenyl)-1-methyl-ethyl]-amide;

44) 4-{4-[5-(1-Methyl-1-phenyl-ethylcarbamoyl)-1H-thieno[2,3-c]pyrazol-3-ylcarbamoyl]-benzyl}-piperazine-1-carboxylic acid tert-butyl ester;

45) 3-[4-(4-Fluoro-piperidin-1-ylmethyl)-benzoylamino]-1H-thieno[2,3-c]pyrazole-5-carboxylic acid(1-methyl-1-phenyl-ethyl)-amide;

46) 3-(4-piperazin-1-ylmethyl-benzoylamino)-1H-thieno[2,3-c]pyrazole-5-carboxylic acid(1-methyl-1-phenyl-ethyl)-amide;

47) 3-(4-Imidazol-1-ylmethyl-benzoylamino)-1H-thieno[2,3-c]pyrazole-5-carboxylic acid (1-methyl-1-phenyl-ethyl)-amide;

48) 3-(4-Thiazolidin-3-ylmethyl-benzoylamino)-1H-thieno[2,3-c]pyrazole-5-carboxylic acid(1-methyl-1-phenyl-ethyl)-amide;

49) 3-(4-Pyrrolidin-1-ylmethyl-benzoylamino)-1H-thieno[2,3-c]pyrazole-5-carboxylic acid[1-(3-fluoro-phenyl)-1-methyl-ethyl]-amide;

50) 3-(4-Piperidin-1-ylmethyl-benzoylamino)-1H-thieno[2,3-c]pyrazole-5-carboxylic acid[1-(3-fluoro-phenyl)-1-methyl-ethyl]-amide;

51) 3-(4-Piperidin-1-ylmethyl-benzoylamino)-1H-thieno[2,3-c]pyrazole-5-carboxylic acid[1-(2-fluoro-phenyl)-1-methyl-ethyl]-amide;

52) 3-(4-Azetidin-1-ylmethyl-benzoylamino)-1H-thieno[2,3-c]pyrazole-5-carboxylic acid (1-methyl-1-phenyl-ethyl)-amide;

53) 3-(4-Azetidin-1-ylmethyl-benzoylamino)-1H-thieno[2,3-c]pyrazole-5-carboxylic acid[1-(2-fluoro-phenyl)-1-methyl-ethyl]-amide;

54) 3-(4-Azetidin-1-ylmethyl-benzoylamino)-1H-thieno[2,3-c]pyrazole-5-carboxylic acid[1-(3-fluoro-phenyl)-1-methyl-ethyl]amide;

55) 3-(4-Azetidin-1-ylmethyl-benzoylamino)-1H-thieno[2,3-c]pyrazole-5-carboxylic acid[1-(4-fluoro-phenyl)-1-methyl-ethyl]-amide;

56) 3-[4-(4-tert-Butyl-piperazin-1-ylmethyl)-benzoylamino]-1H-thieno[2,3-c]pyrazole-5-carboxylic acid(1-methyl-1-phenyl-ethyl)-amide;

57) 3-(4-Pyrrolidin-1-ylmethyl-benzoylamino)-1H-thieno[2,3-c]pyrazole-5-carboxylic acid[1-(4-fluoro-phenyl)-1-methyl-ethyl]-amide;

58) 3-(4-Piperidin-1-ylmethyl-benzoylamino)-1H-thieno[2,3-c]pyrazole-5-carboxylic acid[1-(4-fluoro-phenyl)-1-methyl-ethyl]-amide;

59) 3-Phenylacetylamino-1H-thieno pyrazole-5-carboxylic acid(1-methyl-1-phenyl-ethyl)-amide;

60) 3-(4-Dimethylaminomethyl-benzoylamino)-1H-thieno[2,3-c]pyrazole-5-carboxylic acid(1-methyl-1-phenyl-ethyl)-amide;

61) 3-(4-Cyclopropylaminomethyl-benzoylamino)-1H-thieno[2,3-c]pyrazole-5-carboxylic acid(1-methyl-1-phenyl-ethyl)-amide;

62) 3-(4-Cyclobutylaminomethyl-benzoylamino)-1H-thieno[2,3-c]pyrazole-5-carboxylic acid(1-methyl-1-phenyl-ethyl)-amide;

63) 3-{4-[(Isopropyl-methyl-amino)-methyl]-benzoylamino}-1H-thieno[2,3-c]pyrazole-5-carboxylic acid(1-methyl-1-phenyl-ethyl)-amide;

64) 3-(4-Cyclopentylaminomethyl-benzoylamino)-1H-thieno[2,3-c]pyrazole-5-carboxylic acid(1-methyl-1-phenyl-ethyl)-amide;

65) 3-{4-[(Diisopropylamino)-methyl]-benzoylamino}-1H-thieno[2,3-c]pyrazole-5-carboxylic acid(1-methyl-1-phenyl-ethyl)-amide;

66) 3-(4-Aminomethyl-benzoylamino)-1H-thieno[2,3-c]pyrazole-5-carboxylic acid (1-methyl-1-phenyl-ethyl)-amide;

67) 3-(4-Pyrrolidin-1-ylmethyl-benzoylamino)-1H-thieno[2,3-c]pyrazole-5-carboxylic acid [1-(2-fluoro-phenyl)-1-methyl-ethyl]-amide;

68) 3-(4-Pyrrolidin-1-ylmethyl-benzoylamino)-1H-thieno[2,3-c]pyrazole-5-carboxylic acid[1-(2-methoxy-phenyl)-1-methyl-ethyl]-amide;

69) 3-(4-Pyrrolidin-1-ylmethyl-benzoylamino)-1H-thieno[2,3-c]pyrazole-5-carboxylic acid[1-(3-methoxy-phenyl)-1-methyl-ethyl]-amide;

70) 3-(4-Pyrrolidin-1-ylmethyl-benzoylamino)-1H-thieno[2,3-c]pyrazole-5-carboxylic acid[1-(4-methoxy-phenyl)-1-methyl-ethyl]-amide;

71) 3-(4-Piperidin-1-ylmethyl-benzoylamino)-1H-thieno[2,3-c]pyrazole-5-carboxylic acid[1-(4-methoxy-phenyl)-1-methyl-ethyl]-amide;

72) 3-(4-Piperidin-1-ylmethyl-benzoylamino)-1H-thieno[2,3-c]pyrazole-5-carboxylic acid[1-(3-methoxy-phenyl)-1-methyl-ethyl]-amide;

73) 3-(4-Piperidin-1-ylmethyl-benzoylamino)-1H-thieno[2,3-c]pyrazole-5-carboxylic acid[1-(2-methoxy-phenyl)-1-methyl-ethyl]-amide;

74) 3-(4-Azetidin-1-ylmethyl-benzoylamino)-1H-thieno[2,3-c]pyrazole-5-carboxylic acid[1-(2-methoxy-phenyl)-1-methyl-ethyl]-amide;

75) 3-(4-Azetidin-1-ylmethyl-benzoylamino)-1H-thieno[2,3-c]pyrazole-5-carboxylic acid[1-(3-methoxy-phenyl)-1-methyl-ethyl]-amide;

76) 3-(4-Azetidin-1-ylmethyl-benzoylamino)-1H-thieno[2,3-c]pyrazole-5-carboxylic acid[1-(4-methoxy-phenyl)-1-methyl-ethyl]-amide;

77) 3-(4-Morpholin-4-ylmethyl-benzoylamino)-1H-thieno[2,3-c]pyrazole-5-carboxylic acid[1-(4-methoxy-phenyl)-1-methyl-ethyl]-amide;

78) 3-(4-Morpholin-4-ylmethyl-benzoylamino)-1H-thieno[2,3-c]pyrazole-5-carboxylic acid[1-(3-methoxy-phenyl)-1-methyl-ethyl]-amide;

79) 3-(4-Morpholin-4-ylmethyl-benzoylamino)-1H-thieno[2,3-c]pyrazole-5-carboxylic acid[1-(2-methoxy-phenyl)-1-methyl-ethyl]-amide;

80) 3-[4-(4-Methyl-piperazin-1-yl)-benzoylamino]-1H-thieno[2,3-c]pyrazole-5-carboxylic acid[1-methyl-1-(2-methoxy-phenyl)-ethyl]-amide;

81) 3-[4-(4-Methyl-piperazin-1-yl)-benzoylamino]-1H-thieno[2,3-c]pyrazole-5-carboxylic acid[1-methyl-1-(3-methoxy-phenyl)-ethyl]-amide;

82) 3-[4-(4-Methyl-piperazin-1-yl)-benzoylamino]-1H-thieno[2,3-c]pyrazole-5-carboxylic acid[1-methyl-1-(4-methoxy-phenyl)-ethyl]-amide;

83) 3-[4-(4-Methyl-piperazin-1-yl)-benzoylamino]-1H-thieno[2,3-c]pyrazole-5-carboxylic acid[1-methyl-1-(2-fluoro-phenyl)-ethyl]-amide;

84) 3-[4-(4-Methyl-piperazin-1-yl)-benzoylamino]-1H-thieno[2,3-c]pyrazole-5-carboxylic acid[1-methyl-]-(3-fluoro-phenyl)-ethyl]-amide;

85) 3-[4-(4-Methyl-piperazin-1-yl)-benzoylamino]-1H-thieno[2,3-c]pyrazole-5-carboxylic acid[1-methyl-1-(4-fluoro-phenyl)-ethyl]-amide;

86) 3-({4-[(1-methylpiperidin-4-yl)oxy]benzoyl}amino)-1H-thieno[2,3-c]pyrazole-5-carboxylic acid[1-methyl-1-(2-fluoro-phenyl)-ethyl]-amide;

87) 3-({4-[(1-methylpiperidin-4-yl)oxy]benzoyl}amino)-1H-thieno[2,3-c]pyrazole-5-carboxylic acid[1-methyl-1-(3-fluoro-phenyl)-ethyl]-amide;

88) 3-({4-[(1-methylpiperidin-4-yl)oxy]benzoyl}amino)-1H-thieno[2,3-c]pyrazole-5-carboxylic acid[1-methyl-1-(4-fluoro-phenyl)-ethyl]-amide;

89) 3-({4-[(1-methylpiperidin-4-yl)oxy]benzoyl}amino)-1H-thieno[2,3-c]pyrazole-5-carboxylic acid[1-methyl-1-(4-methoxy-phenyl)-ethyl]-amide;

90) 3-({4-[(1-methylpiperidin-4-yl)oxy]benzoyl}amino)-1H-thieno[2,3-c]pyrazole-5-carboxylic acid[1-methyl-]-(3-methoxy-phenyl)-ethyl]-amide;

91) 3-({4-[(1-methylpiperidin-4-yl)oxy]benzoyl}amino)-1H-thieno[2,3-c]pyrazole-5-carboxylic acid[1-methyl-1-(2-methoxy-phenyl)-ethyl]-amide;

92) 3-(4-Cyclopropylaminomethyl-benzoylamino)-1H-thieno[2,3-c]pyrazole-5-carboxylic acid 1-(2-fluoro-phenyl)-1-methyl-ethyl]-amide;

93) 3-(4-Cyclopropylaminomethyl-benzoylamino)-1H-thieno[2,3-c]pyrazole-5-carboxylic acid 1-(2-methoxy-phenyl)-1-methyl-ethyl]-amide;

94) 3-[4-(Isopropylamino-methyl)-benzoylamino]-1H-thieno[2,3-c]pyrazole-5-carboxylic acid 1-(2-fluoro-phenyl)-1-methyl-ethyl]-amide;

95) 3-[4-(Isopropylamino-methyl)-benzoylamino]-1H-thieno[2,3-c]pyrazole-5-carboxylic acid 1-(2-methoxy-phenyl)-1-methyl-ethyl]-amide;

96) 3-(4-Azepan-1-ylmethyl-benzoylamino)-1H-thieno[2,3-c]pyrazole-5-carboxylic acid (1-methyl-1-phenyl-ethyl)-amide;

97) 3-(4-Azepan-1-ylmethyl-benzoylamino)-1H-thieno[2,3-c]pyrazole-5-carboxylic acid[1-(2-fluoro-phenyl)-1-methyl-ethyl]-amide;

98) 3-(4-Pyrazol-1-ylmethyl-benzoylamino)-1H-thieno[2,3-c]pyrazole-5-carboxylic acid (1-methyl-1-phenyl-ethyl)-amide;

99) 3-(4-methoxy-benzoylamino)-1H-thieno[2,3-c]pyrazole-5-carboxylic acid(1-methyl-1-phenyl-ethyl)-amide;

100) 3-(3-methoxy-benzoylamino)-1H-thieno[2,3-c]pyrazole-5-carboxylic acid(1-methyl-1-phenyl-ethyl)-amide;

101) 3-(2-methoxy-benzoylamino)-1H-thieno[2,3-c]pyrazole-5-carboxylic acid(1-methyl-1-phenyl-ethyl)-amide;

102) 3-(3-Morpholin-4-yl-benzoylamino)-1H-thieno[2,3-c]pyrazole-5-carboxylic acid (1-methyl-1-phenyl-ethyl)-amide;

103) 3-[4-(4-Methyl-piperazin-1-yl)-benzoylamino]-1H-thieno[2,3-c]pyrazole-5-carboxylic acid(1-methyl-1-phenyl-ethyl)-amide;

104) 3-(4-Dimethylamino-benzoylamino)-1H-thieno[2,3-c]pyrazole-5-carboxylic acid(1-methyl-1-phenyl-ethyl)-amide);

105) 3-[(Furan-3-carbonyl)-amino]-1H-thieno[2,3-c]pyrazole-5-carboxylic acid(1-methyl-1-phenyl-ethyl)-amide;

106) 3-[(Thiophene-3-carbonyl)-amino]-1H-thieno[2,3-c]pyrazole-5-carboxylic acid (1-methyl-1-phenyl-ethyl)-amide;

107) 3-[(1-Methyl-1H-pyrrole-3-carbonyl)-amino]-1H-thieno[2,3-c]pyrazole-5-carboxylic acid(1-methyl-1-phenyl-ethyl)-amide;

108) 3-[(1-Methyl-1H-pyrazole-3-carbonyl)-amino]-1H-thieno[2,3-c]pyrazole-5-carboxylic acid(1-methyl-1-phenyl-ethyl)-amide;

109) 3-[(1-Methyl-1H-pyrazole-5-carbonyl)-amino]-1H-thieno[2,3-c]pyrazole-5-carboxylic acid(1-methyl-1-phenyl-ethyl)-amide;

110) 3-[(Pyridine-2-carbonyl)-amino]-1H-thieno[2,3-c]pyrazole-5-carboxylic acid(1-methyl-1-phenyl-ethyl)-amide;

111) 3-[(Pyridine-3-carbonyl)-amino]-1H-thieno[2,3-c]pyrazole-5-carboxylic acid(1-methyl-1-phenyl-ethyl)-amide;

112) 3-[(Pyridine-4-carbonyl)-amino]-1H-thieno[2,3-c]pyrazole-5-carboxylic acid(1-methyl-1-phenyl-ethyl)-amide;

113) 3-(4-Chloro-benzoylamino)-1H-thieno[2,3-c]pyrazole-5-carboxylic acid(1-methyl-1-phenyl-ethyl)-amide;

114) 3-(4-Phenoxy-benzoylamino)-1H-thieno[2,3-c]pyrazole-5-carboxylic acid(1-methyl-1-phenyl-ethyl)-amide;

115) 3-(4-Morpholin-4-yl-benzoylamino)-1H-thieno[2,3-c]pyrazole-5-carboxylic acid[1-(2-methoxy-phenyl)-1-methyl-ethyl]-amide;

116) 3-(4-Morpholin-4-yl-benzoylamino)-1H-thieno[2,3-c]pyrazole-5-carboxylic acid[1-(4-methoxy-phenyl)-1-methyl-ethyl]-amide;

117) 3-[4-(4-Methyl-piperazin-1-yl)-benzoylamino]-1H-thieno[2,3-c]pyrazole-5-carboxylic acid[1-(2-methoxy-phenyl)-1-methyl-ethyl]-amide;

118) 3-[4-(4-Methyl-piperazin-1-yl)-benzoylamino]-1H-thieno[2,3-c]pyrazole-5-carboxylic acid[1-(3-methoxy-phenyl)-1-methyl-ethyl]-amide;

119) 3-[4-(4-Methyl-piperazin-1-yl)-benzoylamino]-1H-thieno[2,3-c]pyrazole-5-carboxylic acid[1-(4-methoxy-phenyl)-1-methyl-ethyl]-amide;

120) 3-[(Thiophene-2-carbonyl)-amino]-1H-thieno[2,3-c]pyrazole-5-carboxylic acid(1-ethyl-1-phenyl-propyl)-amide;

121) 3-[(Thiophene-2-carbonyl)-amino]-1H-thieno[2,3-c]pyrazole-5-carboxylic acid (1-phenyl-cyclopentyl)-amide;

122) 3-[(Thiophene-2-carbonyl)-amino]-1H-thieno[2,3-c]pyrazole-5-carboxylic acid[142-fluoro-phenyl)-1-methyl-ethyl]-amide;

123) 3-[(Thiophene-2-carbonyl)-amino]-1H-thieno[2,3-c]pyrazole-5-carboxylic acid[1-(3-fluoro-phenyl)-1-methyl-ethyl]-amide;

124) 3-(4-Trifluoromethoxy-benzoylamino)-1H-thieno[2,3-c]pyrazole-5-carboxylic acid((S)-2-morpholin-4-yl-1-phenyl-ethyl)-amide;

125) 3-[4-(2-Dimethylamino-ethoxy)-benzoylamino]-1H-thieno[2,3-c]pyrazole-5-carboxylic acid[1-(2-fluoro-phenyl)-1-methyl-ethyl]-amide;

126) 3-[4-(2-Dimethylamino-ethoxy)-benzoylamino]-1H-thieno[2,3-c]pyrazole-5-carboxylic acid(1-methyl-1-phenyl-ethyl)-amide;

127) 3-(4-Fluoro-benzoylamino)-1H-thieno[2,3-c]pyrazole-5-carboxylic acid((S)-1-phenyl-2-piperidin-1-yl-ethyl)-amide;

128) 3-(4-Morpholin-4-yl-benzoylamino)-1H-thieno[2,3-c]pyrazole-5-carboxylic acid(1-ethyl-1-phenyl-propyl)-amide;

129) 3-[(Thiophene-2-carbonyl)-amino]-1H-thieno[2,3-c]pyrazole-5-carboxylic acid((S)-1-phenyl-2-piperidin-1-yl-ethyl)-amide;

130) 3-(4-Morpholin-4-yl-benzoylamino)-1H-thieno[2,3-c]pyrazole-5-carboxylic acid(1-phenyl-cyclopentyl)-amide;

131) 3-[4-(4-Methyl-piperazin-1-yl)-benzoylamino]-1H-thieno[2,3-c]pyrazole-5-carboxylic acid[1-(3-chloro-phenyl)-1-methyl-ethyl]-amide;

132) 3-(4-Fluoro-benzoyl amino)-1H-thieno[2,3-c]pyrazole-5-carboxylic acid[1-(1-chloro-phenyl)-1-methyl-ethyl]-amide;

133) 3-(4-Methoxy-benzoylamino)-1H-thieno[2,3-c]pyrazole-5-carboxylic acid(1-phenyl-cyclopropyl)-amide;

134) 3-(4-Trifluoromethoxy-benzoylamino)-1H-thieno[2,3-c]pyrazole-5-carboxylic acid(1-phenyl)-cyclopropyl)-amide;

135) 3-[(6-Morpholin-4-yl-pyridine-3-carbonyl)-amino]-1H-thieno[2,3-c]pyrazole-5-carboxylic acid(1-methyl-1-phenyl-ethyl)-amide;

136) 3-(4-Morpholin-4-yl-benzoylamino)-1H-thieno[2,3-c]pyrazole-5-carboxylic acid((S)-1-methyl-2-morpholin-4-yl-1-phenyl-ethyl)-amide;

137) 3-(4-Morpholin-4-yl-benzoylamino)-1H-thieno[2,3-c]pyrazole-5-carboxyli c acid (1-methyl-1-pyridin-4-yl-ethyl)-amide;

138) 3-[4-(4-Methyl-piperazin-1-yl)-benzoylamino]-1H-thieno[2,3-c]pyrazole-5-carboxylic acid[1-(4-fluoro-phenyl)-1-methyl-ethyl]-amide;

139) 3-(4-Morpholin-4-yl-benzoylamino)-1H-thieno[2,3-c]pyrazole-5-carboxylic acid[1-(3-methoxy-phenyl)-1-methyl-ethyl]-amide;

140) 3-[4-(4-Methyl-piperazin-1-yl)-benzoylamino]-1H-thieno[2,3-c]pyrazole-5-carboxylic acid[1-(2-fluoro-phenyl)-1-methyl-ethyl]-amide;

141) 3-[4-(4-Methyl-piperazin-1-yl)-benzoylamino]-1H-thieno[2,3-c]pyrazole-5-carboxylic acid[1-(3-fluoro-phenyl)-1-methyl-ethyl]-amide

142) 3-(4-Methane sulfonyl-benzoylamino)-1H-thieno[2,3-c]pyrazole-5-carboxylic acid(1-methyl-1-phenyl-ethyl)-amide

143) 3-[4-(1,1-Dioxo-thiomorpholin-4-yl)-benzoylamino]-1H-thieno[2,3-c]pyrazole-5-carboxylic acid(1-methyl-1-phenyl-ethyl)-amide;

144) 3-(4-Morpholin-4-yl-benzoylamino)-1H-thieno[2,3-c]pyrazole-5-carboxylic acid[1-methyl-1-(3-pyrrolidin-1-yl-phenyl)-ethyl]-amide;

145) 3-[4-(4-Methyl-piperazin-1-yl)-benzoylamino]-1H-thieno[2,3-c]pyrazole-5-carboxylic acid[1-methyl-1-(3-pyrrolidin-1-yl-phenyl)-ethyl]-amide;

146) 3-(4-Morpholin-4-yl-benzoylamino)-1H-thieno[2,3-c]pyrazole-5-carboxylic acid[1-(3-methanesulfonyl-phenyl)-1-methyl-ethyl]-amide;

147) 3-(4-Morpholin-4-yl-benzoylamino)-1H-thieno[2,3-c]pyrazole-5-carboxylic acid[1-(2-fluoro-phenyl)-1-methyl-ethyl]-amide;

148) 3-(4-Morpholin-4-yl-benzoylamino)-1H-thieno[2,3-c]pyrazole-5-carboxylic acid[1-(3-fluoro-phenyl)-1-methyl-ethyl]-amide;

149) 3-(4-Morpholin-4-yl-benzoylamino)-1H-thieno[2,3-c]pyrazole-5-carboxylic acid[1-(4-fluoro-phenyl)-1-methyl-ethyl]-amide;

150) 3-[(Thiophene-2-carbonyl)-amino]-1H-thieno[2,3-c]pyrazole-5-carboxylic acid[1-(4-fluoro-phenyl)-1-methyl-ethyl]-amide;

151) 3-[(Thiophene-2-carbonyl)-amino]-1H-thieno[2,3-c]pyrazole-5-carboxylic acid[1-(2-methoxy-phenyl)-1-methyl-ethyl]-amide;

152) 3-[(Thiophene-2-carbonyl)-amino]-1H-thieno[2,3-c]pyrazole-5-carboxylic acid[1-(3-methoxy-phenyl)-1-methyl-ethyl]-amide;

153) 3-[(Thiophene-2-carbonyl)-amino]-1H-thieno[2,3-c]pyrazole-5-carboxylic acid[1-(4-methoxy-phenyl)-1-methyl-ethyl]-amide;

154) 3-[(Furan-2-carbonyl)-amino]-1H-thieno[2,3-c]pyrazole-5-carboxylic acid 1-(2-fluoro-phenyl)-1-methyl-ethyl]-amide;

155) 3-[(Furan-2-carbonyl)-amino]-1H-thieno[2,3-c]pyrazole-5-carboxylic acid 1-(3-fluoro-phenyl)-1-methyl-ethyl]-amide;

156) 3-[(Furan-2-carbonyl)-amino]-1H-thieno[2,3-c]pyrazole-5-carboxylic acid 1-(4-fluoro-phenyl)-1-methyl-ethyl]-amide;

157) 3-[(Furan-2-carbonyl)-amino]-1H-thieno[2,3-c]pyrazole-5-carboxylic acid 1-(2-methoxy-phenyl)-1-methyl-ethyl]-amide;

158) 3-[(1-Methyl-1H-pyrazole-5-carbonyl)-amino]-1H-thieno[2,3-c]pyrazole-5-carboxylic acid 1-(2-fluoro-phenyl)-1-methyl-ethyl]-amide;

159) 3-[(1-Methyl-1H-pyrazole-5-carbonyl)-amino]-1H-thieno[2,3-c]pyrazole-5-carboxylic acid 1-(2-methoxy-phenyl)-1-methyl-ethyl]-amide;

160) 3-[(1-Methyl-1H-pyrazole-5-carbonyl)-amino]-1H-thieno[2,3-c]pyrazole-5-carboxylic acid 1-(4-fluoro-phenyl)-1-methyl-ethyl]-amide;

161) 3-[(1-Methyl-1H-pyrazole-2-carbonyl)-amino]-1H-thieno[2,3-c]pyrazole-5-carboxylic acid 1-(2-fluoro-phenyl)-1-methyl-ethyl]-amide;

162) 3-[(1-Methyl-1H-pyrazole-2-carbonyl)-amino]-1H-thieno[2,3-c]pyrazole-5-carboxylic acid 1-(2-fluoro-phenyl)-1-methyl-ethyl]-amide;

163) 3-[(1-Methyl-1H-pyrazole-2-carbonyl)-amino]-1H-thieno[2,3-c]pyrazole-5-carboxylic acid 1-(2-methoxy-phenyl)-1-methyl-ethyl]-amide;

164) 3-(4-Morpholin-4-yl-benzoylamino)-1H-thieno[2,3-c]pyrazole-5-carboxylic acid((R)-1-phenyl-ethyl)-amide;

165) 3-(4-Morpholin-4-yl-benzoylamino)-1H-thieno[2,3-c]pyrazole-5-carboxylic acid((S)-1-phenyl-ethyl)-amide;

166) 3-Benzoylamino-1H-thieno[2,3-c]pyrazole-5-carboxylic acid(1-methyl-1-phenyl-ethyl)-amide

167) 3-(3-Fluoro-benzoylamino)-1H-thieno[2,3-c]pyrazole-5-carboxylic acid(1-methyl-1-phenyl-ethyl)-amide; and

168) 3-(2-Fluoro-benzoylamino)-1H-thieno[2,3-c]pyrazole-5-carboxylic acid(1-methyl-1-phenyl-ethyl)-amide.

11. A process for preparing the compounds of formula (I) and the pharmaceutically acceptable salts thereof, according to claim 1 , which process comprises:

a) reacting a compound of formula (II), wherein Alk stands for a lower alkyl group, with hydrazine or a hydrazine salt and reacting the thus obtained intermediate compound under acidic conditions so as to obtain a compound of formula (III)

(b) reacting the compound of formula (III) with any suitable pyrazole nitrogen atom protecting agent, so as to obtain a compound of formula (IV), in any one of its tautomeric forms (IVa) or (IVb)

and wherein Q represents the said protecting group;

c) acylating the compound of formula (IV) with a compound of formula (V), wherein R is as defined in claim 1 and Z represents a suitable leaving group, so as to obtain a compound of formula (VI)

d) selectively hydrolyzing the tert-butyl carboxyester group so as to obtain a compound of formula (VII)

e) reacting the compound of formula (VII) with a compound of formula (VIII) wherein R 1 , R 2 and R 3 are as defined in claim 1 , in the presence of any suitable condensing agent, so as to obtain a compound of formula (IX)

f) deprotecting the compound of formula (IX) from the Q pyrazole nitrogen atom protecting group so as to obtain the compound of formula (I) and, whenever desired, converting the compound of formula (I) into a pharmaceutically acceptable salt or converting the salt thereof into the free compound of formula (I).

12. The process according to claim 11 wherein, within the compounds of formula (II), Alk represents ethyl.

13. The process according to claim 11 wherein, within the compounds of formula (IV), Q represents the group ethoxycarbonyl (—COOEt).

14. A process for preparing the compounds of formula (I) and the pharmaceutically acceptable salts thereof, according to claim 1 , which process comprises:

a′) reacting the compound of a formula (III) being obtained from a reaction of a compound of formula (II), wherein Alk stands for a lower alkyl group, with hydrazine or a hydrazine salt and reacting the thus obtained intermediate compound under acidic conditions

with an excess of a compound of formula (V), wherein R is as defined in claim 1 and Z represents a suitable leaving group, so as to obtain a compound of formula (X)

b′) deprotecting the compound of formula (X) at the pyrazole nitrogen atom and further reacting the resultant compound by

selectively hydrolyzing the tert-butyl carboxyester group so as to obtain a compound of formula (VII)

reacting the compound of formula (VII) with a compound of formula (VIII) wherein R 1 , R 2 and R 3 are as defined in claim 1 , in the presence of any suitable condensing agent, so as to obtain a compound of formula (IX)

and deprotecting the compound of formula (IX) from the Q pyrazole nitrogen atom protecting group so as to obtain the compound of formula (I) and, whenever desired, converting the compound of formula (I) into a pharmaceutically acceptable salt or converting the salt thereof into the free compound of formula (I).

15. The process according to any one of claim 11 or 14 wherein, within the compounds of formula (V), Z represents a chlorine or bromine atom.

16. A process for preparing the compounds of formula (I) and the pharmaceutically acceptable salts thereof, according to claim 1 , which process comprises:

a) reacting a compound of formula (II), wherein Alk stands for a lower alkyl group, with hydrazine or a hydrazine salt and reacting the thus obtained intermediate compound under acidic conditions so as to obtain a compound of formula (III)

(b) reacting the compound of formula (III) with any suitable pyrazole nitrogen atom protecting agent, so as to obtain a compound of formula (IV), in any one of its tautomeric forms (IVa) or (IVb)

and wherein Q represents the said protecting group;

c) acylating the compound of formula (IV) with a compound of formula (V), wherein R is as defined in claim 1 and Z represents a suitable leaving group, so as to obtain a compound of formula (VI)

d) selectively hydrolyzing the tert-butyl carboxyester group so as to obtain a compound of formula (VII)

e) reacting the compound of formula (VII) with a compound of formula (VIII) wherein R 1 , R 2 and R 3 are as defined in claim 1 , in the presence of any suitable condensing agent, so as to obtain a compound of formula (IX)

f′) treating the compound of formula IX, wherein R is a phenyl group substituted at position 4′ with a chloromethyl group with ammonia or a primary or secondary amine to deprotect and converting them into a compound of formula I, wherein R is an optionally substituted 4′-(amino-methyl)phenyl group:

17. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined in claim 1 , and at least one pharmaceutically acceptable excipient, carrier and/or diluent.

18. A pharmaceutical composition according to claim 17 further comprising one or more chemotherapeutic agents.

19. A product or kit comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined in claim 1 , or a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined in claim 1 , and at least one pharmaceutically acceptable excipient, carrier and/or diluents, and one or more chemotherapeutic agent, as a combined preparation for simultaneous, separate or sequential use in anticancer therapy wherein the cancer is ovarian carcinoma or colon carcinoma.

20. A compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined in claim 1 , for use as a medicament in anticancer therapy wherein the cancer is ovarian carcinoma or colon carcinoma.

Assignments (3)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Apr 14, 2011
From: PFIZER ITALIA S.R.L.
To: NERVIANO MEDICAL SCIENCES S.R.L.
Reel/Frame 026124/0787 →
MERGER Recorded May 17, 2007
From: PHARMACIA ITALIA S.P.A.
To: PFIZER ITALIA S.R.L.
Reel/Frame 019310/0512 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 5, 2005
From: FANCELLI, DANIELE; VIANELLO, PAOLA; VARASI, MARIO; BINDI, SIMONA; VIOGLIO, SERGIO; TESEI, DANIA
To: PHARMACIA ITALIA S.P.A.
Reel/Frame 016523/0458 →
Continuity (2)
Provisional Application 60541452 · Feb 3, 2004
Related Publication 20050187209A1 · Aug 25, 2005