公开(公告)号：US07803829B2

公开(公告)日：2010-09-28

申请号：US12295447

申请日：2007-03-29

申请人： Daniele Fancelli ,  Antonella Isacchi ,  Michele Modugno ,  Jurgen Moll ,  Luisa Rusconi ,  Chiara Soncini ,  Rosita Lupi

发明人： Daniele Fancelli ,  Antonella Isacchi ,  Michele Modugno ,  Jurgen Moll ,  Luisa Rusconi ,  Chiara Soncini ,  Rosita Lupi

IPC分类号： A61K31/415

CPC分类号： A61K31/4162 ,  A61K31/44

摘要： The invention provides low molecular weight compounds, namely 1H-thieno[2,3-c]pyrazoles, showing a high affinity for the ATP pocket of ABL tyrosine kinase. These compounds are thus ATP-competitive tyrosine kinase inhibitors displaying a significant inhibitory potency also, and in particular, towards BCR-ABL inhibitor-resistant T315I ABL mutants. The compounds of the invention find a useful application in the treatment of BCR-ABL inhibitor-resistant ABL-mediated diseases, such as Imatinib-resistant chronic myelogenous leukemia. Moreover, the invention provides a screening method for the identification of compounds capable of binding the ATP pocket of a kinase protein, in particular of the T315I mutant ABL kinase.

摘要翻译： 本发明提供了低分子量化合物，即1H-噻吩并[2,3-c]吡唑，显示出对ABL酪氨酸激酶的ATP口袋的高亲和力。 因此，这些化合物也是ATP竞争性酪氨酸激酶抑制剂，也显示出显着的抑制效力，特别是对抗BCR-ABL抑制剂抗性的T315I ABL突变体。 本发明的化合物可用于治疗BCR-ABL抑制剂抗性ABL介导的疾病，例如伊马替尼耐药性慢性骨髓性白血病。 此外，本发明提供了用于鉴定能够结合激酶蛋白质的ATP口袋，特别是T315I突变体ABL激酶的化合物的筛选方法。

公开(公告)号：US20100022532A1

公开(公告)日：2010-01-28

申请号：US12295447

申请日：2007-03-29

申请人： Daniele Fancelli ,  Antonella Isacchi ,  Michele Modugno ,  Jurgen Moll ,  Luisa Rusconi ,  Chiara Soncini ,  Rosita Lupi

发明人： Daniele Fancelli ,  Antonella Isacchi ,  Michele Modugno ,  Jurgen Moll ,  Luisa Rusconi ,  Chiara Soncini ,  Rosita Lupi

IPC分类号： A61K31/4162 ,  A61K31/5377 ,  A61K31/454 ,  A61K31/496

CPC分类号： A61K31/4162 ,  A61K31/44

摘要： The invention provides low molecular weight compounds, namely 1H-thieno[2,3-c]pyrazoles, showing a high affinity for the ATP pocket of ABL tyrosine kinase. These compounds are thus ATP-competitive tyrosine kinase inhibitors displaying a significant inhibitory potency also, and in particular, towards BCR-ABL inhibitor-resistant T315I ABL mutants. The compounds of the invention find a useful application in the treatment of BCR-ABL inhibitor-resistant ABL-mediated diseases, such as Imatinib-resistant chronic myelogenous leukemia. Moreover, the invention provides a screening method for the identification of compounds capable of binding the ATP pocket of a kinase protein, in particular of the T315I mutant ABL kinase.

摘要翻译： 本发明提供了低分子量化合物，即1H-噻吩并[2,3-c]吡唑，显示出对ABL酪氨酸激酶的ATP口袋的高亲和力。 因此，这些化合物也是ATP竞争性酪氨酸激酶抑制剂，也显示出显着的抑制效力，特别是对抗BCR-ABL抑制剂抗性的T315I ABL突变体。 本发明的化合物可用于治疗BCR-ABL抑制剂抗性ABL介导的疾病，例如伊马替尼耐药性慢性骨髓性白血病。 此外，本发明提供了用于鉴定能够结合激酶蛋白质的ATP口袋，特别是T315I突变体ABL激酶的化合物的筛选方法。

公开(公告)号：US08084455B2

公开(公告)日：2011-12-27

申请号：US12293985

申请日：2007-03-29

申请人： Daniele Fancelli ,  Antonella Isacchi ,  Michele Modugno ,  Juergen Moll ,  Luisa Rusconi ,  Chiara Soncini ,  Rosita Lupi

发明人： Daniele Fancelli ,  Antonella Isacchi ,  Michele Modugno ,  Juergen Moll ,  Luisa Rusconi ,  Chiara Soncini ,  Rosita Lupi

IPC分类号： A61K31/497

CPC分类号： A61K31/4162 ,  A61K31/454 ,  A61K31/496 ,  A61K31/5377

摘要： The invention provides low molecular weight compounds, namely tetrahydropyrrolo[3,4-c]pyrazoles, showing a high affinity for the ATP pocket of ABL tyrosine kinase. These compounds are thus ATP-competitive tyrosine kinase inhibitors displaying a significant inhibitory potency also, and in particular, towards BCR-ABL inhibitor-resistant T315I ABL mutants. The compounds of the invention find a useful application in the treatment of BCR-ABL inhibitor-resistant ABL-mediated diseases, such as Imatinib-resistant chronic myelogenous leukemia. Moreover, the invention provides a screening method for the identification of compounds capable of binding the ATP pocket of a kinase protein, in particular of the T315I mutant ABL kinase.

摘要翻译： 本发明提供了低分子量化合物，即四氢吡咯并[3,4-c]吡唑，显示出对ABL酪氨酸激酶的ATP口袋的高亲和力。 因此，这些化合物也是ATP竞争性酪氨酸激酶抑制剂，也显示出显着的抑制效力，特别是对抗BCR-ABL抑制剂抗性的T315I ABL突变体。 本发明的化合物可用于治疗BCR-ABL抑制剂抗性ABL介导的疾病，例如伊马替尼耐药性慢性骨髓性白血病。 此外，本发明提供了用于鉴定能够结合激酶蛋白质的ATP口袋，特别是T315I突变体ABL激酶的化合物的筛选方法。

公开(公告)号：US20100035876A1

公开(公告)日：2010-02-11

申请号：US12293985

申请日：2007-03-29

申请人： Daniele Fancelli ,  Antonella Isacchi ,  Michele Modugno ,  Juergen Moll ,  Luisa Rusconi ,  Chiara Soncini ,  Rosita Lupi

发明人： Daniele Fancelli ,  Antonella Isacchi ,  Michele Modugno ,  Juergen Moll ,  Luisa Rusconi ,  Chiara Soncini ,  Rosita Lupi

IPC分类号： A61K31/5377 ,  C12N5/00 ,  A61K31/496 ,  A61K31/454 ,  G01N33/53

CPC分类号： A61K31/4162 ,  A61K31/454 ,  A61K31/496 ,  A61K31/5377

摘要： The invention provides low molecular weight compounds, namely tetrahydropyrrolo[3,4-c]pyrazoles, showing a high affinity for the ATP pocket of ABL tyrosine kinase. These compounds are thus ATP-competitive tyrosine kinase inhibitors displaying a significant inhibitory potency also, and in particular, towards BCR-ABL inhibitor-resistant T315I ABL mutants. The compounds of the invention find a useful application in the treatment of BCR-ABL inhibitor-resistant ABL-mediated diseases, such as Imatinib-resistant chronic myelogenous leukemia. Moreover, the invention provides a screening method for the identification of compounds capable of binding the ATP pocket of a kinase protein, in particular of the T315I mutant ABL kinase.

摘要翻译： 本发明提供了低分子量化合物，即四氢吡咯并[3,4-c]吡唑，显示出对ABL酪氨酸激酶的ATP口袋的高亲和力。 因此，这些化合物也是ATP竞争性酪氨酸激酶抑制剂，也显示出显着的抑制效力，特别是对抗BCR-ABL抑制剂抗性的T315I ABL突变体。 本发明的化合物可用于治疗BCR-ABL抑制剂抗性ABL介导的疾病，例如伊马替尼耐药性慢性骨髓性白血病。 此外，本发明提供了用于鉴定能够结合激酶蛋白质的ATP口袋，特别是T315I突变体ABL激酶的化合物的筛选方法。

公开(公告)号：US07943654B2

公开(公告)日：2011-05-17

申请号：US11988528

申请日：2006-07-10

申请人： Daniele Fancelli ,  Jurgen Moll ,  Maurizio Pulici ,  Francesca Quartieri ,  Tizizno Bandiera

发明人： Daniele Fancelli ,  Jurgen Moll ,  Maurizio Pulici ,  Francesca Quartieri ,  Tizizno Bandiera

IPC分类号： A01N43/56 ,  A01N43/06 ,  A61K31/415 ,  A61K31/38 ,  C07D487/02 ,  C07D231/54 ,  C07D333/00

CPC分类号： C07D495/04

摘要： There are provided thieno[2,3-c]pyrazole derivatives of formula (I), wherein A is an aryl or heteroaryl ring, on which the substituent-NHZR5 is at the ortho position to the CONH linker; R1 and R2 are the same or different and, independently from each other, represent a hydrogen atom or an organic group; R4 is a hydrogen or halogen atom or an organic group; Z is direct bond, >C═O, or —C(═O)NH—; R5 is hydrogen or an organic group; or isomers, tautomers, carriers, metabolites, prodrugs, and pharamaceutically acceptable salts thereof. A process for their preparation and pharamaceutical compositions comprising them are also disclosed; the compounds of the invention may be useful, in theraphy, in the treatment of diseases associated with a disregulated protein kinase activity, like cancer.

摘要翻译： 提供式（I）的噻吩并[2,3-c]吡唑衍生物，其中A是芳基或杂芳基环，取代基-NHZR5在其上与CONH连接体的邻位; R1和R2相同或不同，彼此独立地表示氢原子或有机基团; R4是氢或卤素原子或有机基团; Z是直接键合，> C = O或-C（= O）NH-; R5是氢或有机基团; 或异构体，互变异构体，载体，代谢物，前药和药物上可接受的盐。 还公开了其制备方法和包含它们的药用组合物; 本发明的化合物在治疗与失调的蛋白激酶活性相关的疾病（例如癌症）中可能是有用的。

公开(公告)号：US20090149457A1

公开(公告)日：2009-06-11

申请号：US11988528

申请日：2006-07-10

申请人： Daniele Fancelli ,  Jurgen Moll ,  Maurizio Pulici ,  Francesca Quartieri ,  Tiziano Bandiera

发明人： Daniele Fancelli ,  Jurgen Moll ,  Maurizio Pulici ,  Francesca Quartieri ,  Tiziano Bandiera

IPC分类号： A61K31/5377 ,  C07D231/54 ,  A61K31/4162 ,  C12N9/99 ,  A61P35/00 ,  A61P37/00 ,  A61P25/00 ,  C07D409/14 ,  A61K31/496 ,  C07D413/14

CPC分类号： C07D495/04

摘要： There are provided thieno[2,3-c]pyrazole derivatives of formula (I), wherein A is an aryl or heteroaryl ring, on which the substituent-NHZR5 is at the ortho position to the CONH linker; R1 and R2 are the same or different and, independently from each other, represent a hydrogen atom or an organic group; R4 is a hydrogen or halogen atom or an organic group; Z is direct bond, >C═O, or —C(═O)NH—; R5 is hydrogen or an organic group; or isomers, tautomers, carriers, metabolites, prodrugs, and pharamaceutically acceptable salts thereof. A process for their preparation and pharamaceutical compositions comprising them are also disclosed; the compounds of the invention may be useful, in theraphy, in the treatment of diseases associated with a disregulated protein kinase activity, like cancer.

摘要翻译： 提供式（I）的噻吩并[2,3-c]吡唑衍生物，其中A是芳基或杂芳基环，取代基-NHZR5在其上与CONH连接体的邻位; R1和R2相同或不同，彼此独立地表示氢原子或有机基团; R4是氢或卤素原子或有机基团; Z是直接键合，> C-O或-C（-O）NH-; R5是氢或有机基团; 或异构体，互变异构体，载体，代谢物，前药和药物上可接受的盐。 还公开了其制备方法和包含它们的药用组合物; 本发明的化合物在治疗与失调的蛋白激酶活性相关的疾病（例如癌症）中可能是有用的。

公开(公告)号：US20050032839A1

公开(公告)日：2005-02-10

申请号：US10882493

申请日：2004-07-01

申请人： Daniele Fancelli ,  Barbara Forte ,  Jurgen Moll ,  Mario Varasi ,  Paola Vianello

发明人： Daniele Fancelli ,  Barbara Forte ,  Jurgen Moll ,  Mario Varasi ,  Paola Vianello

IPC分类号： A61K31/4162 ,  A61P35/00 ,  C07D487/04 ,  A61K31/454

CPC分类号： C07D487/04

摘要： Pyrrolo[3,4-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.

摘要翻译： 公开了本说明书中定义的式（I）的吡咯并[3,4-c]吡唑衍生物及其药学上可接受的盐，其制备方法和包含它们的药物组合物; 本发明的化合物在治疗中可用于治疗与失调的蛋白激酶活性相关的疾病，如癌症。

公开(公告)号：US20090239924A1

公开(公告)日：2009-09-24

申请号：US12302569

申请日：2007-05-25

申请人： Daniele Fancelli ,  Maurizio Pulici ,  Jurgen Moll ,  Tiziano Bandiera

发明人： Daniele Fancelli ,  Maurizio Pulici ,  Jurgen Moll ,  Tiziano Bandiera

IPC分类号： A61K31/4162 ,  C07D491/048 ,  A61P35/00 ,  A61P35/04

CPC分类号： C07D491/048

摘要： Furo[3,2-c]pyrazole derivatives of formula (I) as defined in the description, and pharmaceutically acceptable salts thereof, wherein A is an aryl or heteroaryl ring, —NHZR5 is at the ortho position to the CONH linker; —R1 and R2 are the same or different and, independently from each other, represent a hydrogen atom, or an organic residue; R3 is a hydrogen or halogen atom or an organic group; R4 is a hydrogen or halogen atom or an organic group; Z is direct bond, >C═O, or —C(═O)NH—; —R5 is hydrogen or an optionally substituted organic group or isomers, tautomers, carriers, metabolites, prodrugs, and pharmaceutically acceptable salts thereof. A 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, in particular Aurora kinases activity or IGF-1R activity, like cancer.

摘要翻译： 如描述中定义的式（I）的呋喃并[3,2-c]吡唑衍生物及其药学上可接受的盐，其中A是芳基或杂芳基环，-NHZR5位于与CONH接头的邻位; -R 1和R 2相同或不同，彼此独立地表示氢原子或有机残基; R3是氢或卤素原子或有机基团; R4是氢或卤素原子或有机基团; Z是直接键合，> C-O或-C（-O）NH-; -R5是氢或任选取代的有机基团或其异构体，互变异构体，载体，代谢物，前药及其药学上可接受的盐。 公开了其制备方法和包含它们的药物组合物; 本发明的化合物在治疗中可用于治疗与失调的蛋白激酶活性，特别是Aurora激酶活性或IGF-1R活性相关的疾病，如癌症。

公开(公告)号：US20060276471A1

公开(公告)日：2006-12-07

申请号：US11503256

申请日：2006-08-11

申请人： Daniele Fancelli ,  Barbara Forte ,  Jurgen Moll ,  Mario Varasi ,  Paola Vianello

发明人： Daniele Fancelli ,  Barbara Forte ,  Jurgen Moll ,  Mario Varasi ,  Paola Vianello

IPC分类号： A61K31/5377 ,  A61K31/496 ,  A61K31/454 ,  C07D487/02

CPC分类号： C07D487/04

摘要： Pyrrolo[3,4-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.

公开(公告)号：US20130344031A1

公开(公告)日：2013-12-26

申请号：US14010819

申请日：2013-08-27

申请人： Maria Gabriella Brasca ,  Raffaella Amici ,  Daniele Fancelli ,  Marcella Nesi ,  Paolo Orsini ,  Fabrizio Orzi ,  Patrick Roussel ,  Anna Vulpetti ,  Paolo Pevarello

发明人： Maria Gabriella Brasca ,  Raffaella Amici ,  Daniele Fancelli ,  Marcella Nesi ,  Paolo Orsini ,  Fabrizio Orzi ,  Patrick Roussel ,  Anna Vulpetti ,  Paolo Pevarello

IPC分类号： C07D487/04 ,  A61K31/454 ,  A61N5/10 ,  A61K31/4162 ,  A61K45/06 ,  A61K31/5377 ,  A61K31/496

CPC分类号： C07D487/04 ,  A61K31/4162 ,  A61K31/454 ,  A61K31/496 ,  A61K31/5377 ,  A61K45/06 ,  A61N5/10

摘要： Compounds represented by formula (Ia) or (Ib) and wherein R and R1 are as defined in the description, and pharmaceutically acceptable salts thereof, are disclosed; the said compounds are useful in the treatment of cell cycle proliferative disorders, e.g. cancer, associated with an altered cell cycle dependent kinase activity.