HK1066538A - Amino-phthalazinone derivatives actives as kinase inhibitors, process for their preparation and pharmaceutical compositions containing them - Google Patents
Amino-phthalazinone derivatives actives as kinase inhibitors, process for their preparation and pharmaceutical compositions containing them Download PDFInfo
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Description
The present invention relates to amino-2, 3-naphthyridinone derivatives as kinase inhibitors, more particularly to 7-amino-2, 3-naphthyridin-1-one derivatives, to processes for their preparation, to pharmaceutical compositions containing them and to their use as therapeutic agents, particularly in the treatment of disorders associated with dysregulated protein kinases.
The malfunction of Protein Kinases (PKs) is a marker for a variety of diseases. Oncogenes and proto-oncogenes encoding PKs involved in human malignancies have great homology. Increased PKs activity is also implicated in a number of non-malignant lesions such as benign prostate hyperplasia, familial adenomatosis, polyposis, neurofibromatosis, psoriasis, vascular smooth cell proliferation associated with atherosclerosis, pulmonary fibrosis, arthritis glomerulonephritis and post-surgical stenosis and restenosis.
PKs are also involved in inflammatory conditions and in viral and parasitic proliferation. PKs also play a major role in the onset and progression of neurodegenerative diseases.
For general reference to PKs dysfunction or dysregulation see, for example, CurrentOption in Chemical Biology 1999, 3, 459-465.
It is an object of the present invention to provide compounds for use in therapy as medicaments for the treatment of patients suffering from diseases caused by dysregulated protein kinase activity and/or related diseases.
It is another object of the present invention to provide compounds endowed with multiple protein kinase inhibitory activities.
The present inventors have now found that certain 7-amino-2, 3-naphthyridin-1-one derivatives, hereinafter simply referred to as amino-2, 3-naphthyridine ketone derivatives or amino-2, 3-naphthyridine ketones, impart a variety of protein kinase inhibitory activities and are therefore useful in therapeutic methods for treating diseases associated with dysregulated protein kinases.
More specifically, the amino-2, 3-naphthyridones of the invention are useful in the treatment of various cancers, including but not limited to: cancers, such as bladder cancer, breast cancer, colon cancer, kidney cancer, liver cancer, lung cancer, including small cell lung cancer, esophageal cancer, biliary-bladder cancer, ovarian cancer, pancreatic cancer, stomach cancer, cervical cancer, thyroid cancer, prostate cancer, and skin cancer, including squamous cell carcinoma; hematopoietic tumors of lymphoid lineage, including leukemia, acute cell leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma and Burkettt's lymphoma; myeloblastic hemangiomas, including acute and chronic myelogenous leukemias, myelodysplastic syndrome and promyelocytic leukemia; tumors of mesenchymal origin, including fibrosarcoma and rhabdomyosarcoma; tumors of the central and peripheral nervous system, including astrocytomas, neuroblastoma, glioma and schwannoma; other tumors, including melanoma, seminoma, malignant teratoma, osteosarcoma, xeroderma pigmentosum (Pimentosum), keratoacanthoma, thyroid follicular carcinoma and Kaposi's sarcoma.
Due to the role of PKs in the regulation of cell proliferation, these amino-2, 3-naphthyridinones are also useful in the treatment of a wide variety of cell proliferative disorders, such as benign prostate hyperplasia, familial adenomatosis, polyposis, neurofibromatosis, psoriasis, vascular smooth cell proliferation associated with atherosclerosis, pulmonary fibrosis, arthritis glomerulonephritis and post-surgical stenosis and restenosis.
The compounds of the invention are useful in the treatment of Alzheimer's disease, as suggested by the fact that cdk5 is involved in the phosphorylation of tau protein (J.biochem., 117, 741-749, 1995).
The compounds of the invention are useful as modulators of apoptosis in the treatment of cancer, viral infections, prevention of AIDS in HIV-infected individuals, prevention of autoimmune diseases and neurodegenerative diseases.
The compounds of the invention are also useful for inhibiting tumor angiogenesis and metastasis.
The compounds of the invention are useful as inhibitors of cyclin-dependent kinases (cdks) and also as inhibitors of other protein kinases such as the different isomeric forms of protein kinase C, Met, PAK-4, PAK-5, ZC-1, STLK-2, DDR-2, Aurora 1, Aurora2, Bub-1, PLK, Chk1, Chk2, HER2, rafl, MEK1, MAPK, EGF-R, PDGF-R, FGF-R, IGF-R, VEGF-R, PI3K, weel kinase, Src, Abl, t, ILK, MK-2, IKK-2, Cdc7, Nek and are therefore useful in the treatment of diseases associated with other protein kinases.
Some amino-2, 3-naphthyridinone and amino-2, 3-naphthyridinedione derivatives are known in the art as chemical intermediates, therapeutic agents, and even protein kinase inhibitors.
By way of example, Heisei in JP-A-09061961 discloses that the compounds N- [3- [2, 4-bis (1, 1-dimethylpropyl) phenoxy ] propyl ] -N' - (3, 4-dihydro-4-oxo-6-2, 3-naphthyridinyl) -ureｃA and 2- [2, 4-bis (1, 1-dimethylpropyl) phenoxy ] -N- (3, 4-dihydro-4-oxo-6-2, 3-naphthyridinyl) -butyramide are contrast agents for cardiac imaging.
JP-A-10287658 to Heisei discloses that the compound N- [3, 4-dihydro-3- [4- [4- (1-naphthyl) -1-piperazinyl ] butyl ] -4-oxo-6-2, 3-naphthyridinyl ] -acetamide is ｃA 5-hydroxytryptamine/dopaminergic substance.
Novartis in WO 98/35958 discloses that the compounds N- [3, 4-dihydro-4-oxo-1- (4-pyridylmethyl) -6-2, 3-naphthyridinyl ] -acetamide and N- [3, 4-dihydro-4-oxo-1- (4-pyridylmethyl) -6-2, 3-naphthyridinyl ] -2, 2, 2-trifluoro-acetamide are synthetic intermediates for the preparation of the VEGF receptor tyrosine kinase inhibitor anilino-2, 3-naphthyridine.
In addition to the above, 2, 3-naphthyridinedione or 2, 3-naphthyridinone derivatives bearing substituted amino groups at both the 6 and 7 positions of the ring, such as 7- (cyclohexylamino) -6-phenylamino-1 (2H) -2, 3-naphthyridinone and 6, 7-bis (phenylamino) -1(2H) -2, 3-naphthyridinone, are disclosed by CibｃA-Geigy in EP-A-600831 as protein kinase inhibitors.
Accordingly, the present invention provides a method for treating diseases caused by and/or associated with altered protein kinase activity by administering to a mammal in need thereof an effective amount of an amino-2, 3-naphthyridone derivative represented by formula (I):
wherein
Ra and Rb are each independently a hydrogen atom or optionally further substituted group selected from: straight or branched C1-C6Alkyl radical, C3-C6Cycloalkyl or cycloalkyl C1-C6Alkyl, aryl C1-C6Alkyl, 5-to 7-membered heterocyclyl or heterocyclyl C having 1-3 heteroatoms selected from nitrogen, oxygen or sulfur1-C6An alkyl group; or one of Ra or Rb is hydrogen or optionally substituted straight or branched C1-C6Alkyl and the other is selected from-COR ', -CONHR ', -COOR ' or-SO2R 'wherein R' is hydrogen or optionally substitutedA group selected from the above alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclic group or heterocyclylalkyl group;
R1is of the formula-CHR4R5Group, wherein R4And R5Each independently hydrogen or optionally substituted C selected from linear or branched1-C6Alkyl radical, C3-C6Cycloalkyl or cycloalkyl C1-C6Alkyl, aryl C1-C6Alkyl, 5-to 7-membered heterocyclyl or heterocyclyl C having 1-3 heteroatoms selected from nitrogen, oxygen or sulfur1-C6A group of alkyl groups; or R1Is of the formula-NHR ', -NR ' COR ', -NR ' CONHR "or-NR ' SO2R ', wherein R' has a definition other than the above-mentioned hydrogen, R 'is hydrogen or has the above-mentioned definition for R';
R2is a hydrogen atom or optionally further substituted group selected from: straight or branched C1-C6Alkyl radical, C3-C6Cycloalkyl or cycloalkyl C1-C6Alkyl, aryl C1-C6Alkyl, 5-to 7-membered heterocyclyl or heterocyclyl C having 1-3 heteroatoms selected from nitrogen, oxygen or sulfur1-C6An alkyl group;
any R at one or more of the free positions 5, 6 and 8 on the 2, 3-naphthyridone ring3Each independently is a halogen atom, nitro, carboxyl, cyano or optionally further substituted group selected from: straight or branched C1-C6Alkyl radical, C3-C6Cycloalkyl or cycloalkyl C1-C6Alkyl, aryl C1-C6Alkyl, 5-to 7-membered heterocyclyl or heterocyclyl C having 1-3 heteroatoms selected from nitrogen, oxygen or sulfur1-C6An alkyl group; or R3Is selected from-COR ', -CONHR', -SO2R ', -NR' COR ', -NR' CONHR 'or-NR' SO2R ' wherein R ' and R ' are the same or different, are hydrogen or the above-mentioned groups; m is0 or an integer of 1 to 3; or a pharmaceutically acceptable salt thereof.
In a preferred embodiment of the above method, the disease caused by and/or associated with altered protein kinase activity is selected from the group consisting of cancer, cell proliferative disorders, Alzheimer's disease, viral infections, autoimmune diseases and neurodegenerative disorders.
Specific types of cancer that can be treated include carcinoma, squamous cell carcinoma, hematopoietic tumors of myeloid or lymphoid lineage, tumors of mesenchymal origin, tumors of the central and peripheral nervous system, seminoma, teratoma, osteosarcoma, xeroderma pigmentosum, keratoacanthoma, lymphadenoid carcinoma and Kaposi's sarcoma.
In another preferred embodiment of the above method, the cell proliferative disorder is selected from the group consisting of benign prostate hyperplasia, familial adenomatosis, polyposis, neuro-fibromatosis, psoriasis, vascular smooth cell proliferation associated with atherosclerosis, pulmonary fibrosis, arthritis glomerulonephritis and post-surgical stenosis and restenosis.
In addition, the method of the present invention aims to provide tumor angiogenesis and metastasis inhibition.
The present invention further provides an amino-2, 3-phthalazinone derivative represented by formula (I):
wherein
Ra and Rb are each independently a hydrogen atom or optionally further substituted group selected from: straight or branched C1-C6Alkyl radical, C3-C6Cycloalkyl or cycloalkyl C1-C6Alkyl, aryl C1-C6Alkyl, 5-to 7-membered heterocyclyl or heterocyclyl C having 1-3 heteroatoms selected from nitrogen, oxygen or sulfur1-C6An alkyl group; or one of Ra or Rb is hydrogen or optionally substitutedStraight or branched chain C of1-C6Alkyl and the other is selected from-COR ', -CONHR ', -COOR ' or-SO2R 'wherein R' is hydrogen or an optionally substituted group selected from the above alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl or heterocyclylalkyl groups;
R1is of the formula-CHR4R5Group, wherein R4And R5Each independently hydrogen or optionally substituted C selected from linear or branched1-C6Alkyl radical, C3-C6Cycloalkyl or cycloalkyl C1-C6Alkyl, aryl C1-C6Alkyl, 5-to 7-membered heterocyclyl or heterocyclyl C having 1-3 heteroatoms selected from nitrogen, oxygen or sulfur1-C6A group of alkyl groups; or R1Is of the formula-NHR ', -NR ' COR ', -NR ' CONHR "or-NR ' SO2R ', wherein R' has a definition other than the above-mentioned hydrogen, R 'is hydrogen or has the above-mentioned definition for R';
R2is a hydrogen atom or optionally further substituted group selected from: straight or branched C1-C6Alkyl radical, C3-C6Cycloalkyl or cycloalkyl C1-C6Alkyl, aryl C1-C6Alkyl, 5-to 7-membered heterocyclyl or heterocyclyl C having 1-3 heteroatoms selected from nitrogen, oxygen or sulfur1-C6An alkyl group;
any R at one or more of the free positions 5, 6 and 8 on the 2, 3-naphthyridone ring3Each independently is a halogen atom, nitro, carboxyl, cyano or optionally further substituted group selected from: straight or branched C1-C6Alkyl radical, C3-C6Cycloalkyl or cycloalkyl C1-C6Alkyl, aryl C1-C6Alkyl, 5-to 7-membered heterocyclyl or heterocyclyl C having 1-3 heteroatoms selected from nitrogen, oxygen or sulfur1-C6An alkyl group; or R3Is selected from-COR ', -CONHR', -SO2R ', -NR' COR ', -NR' CONHR 'or-NR' SO2R ' wherein R ' and R ' are the same or different, are hydrogen or the above-mentioned groups; m is 0 or an integer of 1 to 3; or a pharmaceutically acceptable salt thereof;
the compounds N- [3, 4-dihydro-4-oxo-1- (4-pyridylmethyl) -6-2, 3-naphthyridinyl ] -acetamide and N- [3, 4-dihydro-4-oxo-1- (4-pyridylmethyl) -6-2, 3-naphthyridinyl ] -2, 2, 2-trifluoro-acetamide are excluded.
The compounds of formula (I), object of the present invention, have asymmetric carbon atoms and can therefore exist as racemic mixtures or as individual optical isomers.
Thus, all possible isomers and mixtures thereof and all possible isomers of both metabolites and pharmaceutically acceptable biological precursors (otherwise known as prodrugs) of the compounds of formula (I) and mixtures thereof, as well as any treatment methods comprising the same, are also within the scope of the present invention.
As used herein, unless otherwise specified, the term halogen atom means a chlorine, bromine, fluorine or iodine atom.
With respect to the term straight or branched C1-C6By alkyl we mean such groups as, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl and the like.
With respect to the term C3-C6By cycloalkyl we mean groups such as, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
By the term aryl we mean mono-, di-or poly-carbocyclic and heterocyclic hydrocarbons having from 1 to 4 ring moieties, either fused to each other or connected by single bonds, wherein at least one of the carbocyclic or heterocyclic rings is aromatic.
Non-limiting examples of aryl groups are, for example, phenyl, 2, 3-indanyl, biphenyl, alpha-or beta-naphthyl, fluorenyl, 9, 10-dihydroanthracenyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, imidazolyl, imidazopyridinyl, 1, 2-methylenedioxyphenyl, thiazolyl, isothiazolyl, pyrrolyl-phenyl, furyl, phenyl-furyl, benzotetrahydrofuryl, oxazolyl, isoxazolyl, pyrazolyl, benzopyranyl, thienyl, benzothienyl, isoindolinyl, benzimidazolyl, isoindolinyl-phenyl, quinolyl, isoquinolyl, 2, 6-diphenyl-pyridyl, quinoxalinyl, pyrazinyl, phenyl-quinolyl, benzofurazanyl, 1, 2, 3-triazolyl, 1-phenyl-1, 2, 3-triazolyl and the like.
By the term 5-7 membered heterocyclyl thus includes aromatic heterocyclyl groups also known as aryl groups, we further mean saturated or partially saturated 5-7 membered carbocyclic rings in which one or more carbon atoms are replaced by 1-3 heteroatoms such as nitrogen, oxygen and sulfur.
Further examples of the optionally benzo-fused or further substituted 5-7 membered heterocyclic group other than the above-mentioned heteroaryl group are 1, 3-dioxolane, pyran, pyrrolidine, pyrroline, imidazolidine, pyrazolidine, pyrazoline, piperidine, piperazine, morpholine, tetrahydrofuran, azepine (azepine), diaza and the like.
According to formula (I) of the invention, it is clear to the skilled person that when m is 0, no R is present3The radicals, or in other words the 5, 6 and 8 positions of the 2, 3-naphthyridone ring of the numbering system below, being unsubstituted or hydrogen-substituted
Similarly, when m is 1 or 2, one or two R are present at one or two of the 5, 6 or 8 positions3Substituents, which are the same or different from each other; finally, when m is 3, all possible 5, 6 and 8 positions are R as described above3Groups, which are the same or different.
According to the above for Ra, Rb, R', R2，R3，R4And R5Definitions of substituents, any of the above definitions of groups being optionally substituted in any free position by one or more, e.g. 1 to 6, groups selected from: halogen atoms, nitro groups, oxy groups (═ O), carboxyl groups, cyano groups, alkyl groups, perfluorinated alkyl groups, alkenyl groups, alkynyl groups, cycloalkyl groups, aryl groups, heterocyclic groups, amino groups and derivatives thereof, for example, alkylamino groups, dialkylamino groups, arylamino groups, diarylamino groups, ureido groups, alkylureido groups or arylureido groups; carbonylamino and derivatives thereof, for example, formylamino, alkylcarbonylamino, alkenylcarbonylamino, arylcarbonylamino, alkoxycarbonylamino; hydroxy and its derivatives, for example, alkoxy, aryloxy, alkylcarbonyloxy, arylcarbonyloxy, cycloalkenyloxy or alkyleneaminooxy; carbonyl and derivatives thereof, for example, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, cycloalkyloxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl; examples of sulfur-containing derivatives are alkylthio, arylthio, alkylsulfonyl, arylsulfonyl, alkylsulfinyl, arylsulfinyl, arylsulfonyloxy, aminosulfonyl, alkylaminosulfonyl or dialkylaminosulfonyl.
Next, each of the above substituents may be further substituted with one or more of the above groups, as appropriate.
In these latter groups, unless specified in the specification, by the term perfluorinated alkyl we mean a straight or branched chain C as defined above1-C6An alkyl group in which one or more hydrogen atoms are replaced with fluorine atoms. Examples of perfluorinated alkyl groups are, for example, trifluoromethyl, 2, 2, 2-trifluoroethyl, 1, 2-difluoroethyl, 1,1, 1, 3, 3, 3-hexafluoropropyl-2-yl and the like.
By the term alkenyl or alkynyl we mean straight or branched chain C2-C6Alkenyl or alkynyl radicals are, for example, vinyl, allyl, isopropenyl, 1-, 2-or 3-butenyl, isobutenyl, hexenyl, ethynyl, 1-or 2-propynyl, butynyl and the like.
As noted above, it will be clear to the skilled artisan that any group whose name is identified as a composite name, such as, for example, cycloalkylalkyl, arylalkyl, heterocyclylalkyl, alkoxy, alkylthio, aryloxy, arylalkoxy, heterocyclyloxy, heterocyclylalkoxy, alkylcarbonyloxy, and the like, means that the moiety from which it is derived is conventionally made.
As an example, the term heterocyclyl-alkoxy refers to an alkoxy group (e.g., alkyl-oxy) further substituted with a heterocyclyl group.
Pharmaceutically acceptable salts of the compounds of formula (I) are acid addition salts with inorganic or organic acids, for example nitric acid, hydrochloric acid, hydrobromic acid, sulfuric acid, perchloric acid, phosphoric acid, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, lactic acid, oxalic acid, malonic acid, malic acid, maleic acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, isethionic acid (isethionic acid) and salicylic acid, and salts with inorganic or organic bases, for example alkali or alkaline earth metals, in particular sodium, potassium, calcium or magnesium hydroxide, carbonates or bicarbonates, acyclic or cyclic amines, preferably methylamine, ethylamine, diethylamine, triethylamine or piperidine.
Compounds of formula (I) represent a preferred class of compounds of the invention, wherein one of Ra or Rb is a hydrogen atom or an optionally substituted straight or branched chain C1-C6The other is a group-COR ', wherein R' is an optionally substituted group as mentioned above selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl or heterocyclylalkyl, and R1，R2，R3And m is as defined above.
Among such compounds, more preferred are compounds of formula (I) wherein R is1Is a radical-CHR4R5Wherein R is4And R5As defined above, R2Is hydrogen and m is 0.
Compounds of formula (I) represent another preferred class of compounds according to the invention, wherein one of Ra or Rb is a hydrogen atom orOptionally substituted straight or branched C1-C6Alkyl and the other is a group-CONHR 'wherein R' is a hydrogen atom or an optionally substituted group mentioned above selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl or heterocyclylalkyl, and R1，R2，R3And m is as defined above.
Among such compounds, more preferred are compounds of formula (I) wherein R is1Is a radical-CHR4R5Wherein R is4And R5As defined above, R2Is hydrogen and m is 0.
Compounds of formula (I) represent another preferred class of compounds according to the invention, wherein one of Ra or Rb is a hydrogen atom or an optionally substituted, linear or branched C1-C6The other is a group-COOR 'in which R' is a hydrogen atom or an optionally substituted group mentioned above selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl or heterocyclylalkyl, and R1，R2，R3And m is as defined above.
Among such compounds, more preferred are compounds of formula (I) wherein R is1Is a radical-CHR4R5Wherein R is4And R5As defined above, R2Is hydrogen and m is 0.
Compounds of formula (I) represent another preferred class of compounds according to the invention, wherein one of Ra or Rb is a hydrogen atom or an optionally substituted, linear or branched C1-C6Alkyl radical, the other being a radical-SO2R 'wherein R' is an optionally substituted group as mentioned above selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl or heterocyclylalkyl, and R1，R2，R3And m is as defined above.
Among such compounds, more preferred are compounds of formula (I) wherein R is1Is a radical-CHR4R5Wherein R is4And R5As defined above, R2Is hydrogen and m is 0.
Compounds of formula (I) represent another preferred class of compounds of the invention, wherein Ra and Rb are both hydrogen atoms, and R1，R2，R3And m is as defined above.
Among such compounds, more preferred are compounds of formula (I) wherein R is1Is a radical-CHR4R5Wherein R is4And R5As defined above, R2Is hydrogen and m is 0.
Compounds of formula (I) represent another preferred class of compounds according to the invention, wherein one of Ra or Rb is a hydrogen atom or an optionally substituted, linear or branched C1-C6Alkyl, the other being an optionally substituted radical as mentioned above from the group consisting of alkyl, cycloalkylalkyl, arylalkyl, or heterocyclylalkyl, and R1，R2，R3And m is as defined above.
Among such compounds, more preferred are compounds of formula (I) wherein R is1Is a radical-CHR4R5Wherein R is4And R5As defined above, R2Is hydrogen and m is 0.
Specific examples of preferred compounds of formula (I) according to the invention, optionally in the form of pharmaceutically acceptable salts, are:
4- (4-oxo-6-propionylamino-3, 4-dihydro-2, 3-naphthyridin-1-ylmethyl) -benzoic acid methyl ester;
4- (4-oxo-6- (4-trifluoromethyl-benzoylamino) -3, 4-dihydro-2, 3-naphthyridin-1-ylmethyl) -benzoic acid methyl ester;
4- {6- [ (furan-2-carbonyl) -amino ] -4-oxo-3, 4-dihydro-2, 3-naphthyridin-1-ylmethyl } -benzoic acid methyl ester;
4- (6- (3, 4-dimethoxy-benzoylamino) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-1-ylmethyl) -benzoic acid methyl ester;
4- (6- (3-cyclopentyl-propionylamino) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-1-ylmethyl) -benzoic acid methyl ester;
4- [ 4-oxo-6- (2-propyl-pentanoylamino) -3, 4-dihydro-2, 3-naphthyridin-1-ylmethyl ] -benzoic acid methyl ester;
4- { 4-oxo-6- [3- (3-trifluoromethyl-phenyl) -ureido ] -3, 4-dihydro-2, 3-naphthyridin-1-ylmethyl } -benzoic acid methyl ester;
4- {6- [3- (3-methoxy-phenyl) -ureido ] -4-oxo-3, 4-dihydro-2, 3-naphthyridin-1-ylmethyl } -benzoic acid methyl ester;
4- [ 4-oxo-6- (3-p-tolyl-ureido) -3, 4-dihydro-2, 3-naphthyridin-1-ylmethyl ] -benzoic acid methyl ester;
4- {6- [3- (2, 4-difluoro-phenyl) -ureido ] -4-oxo-3, 4-dihydro-2, 3-naphthyridin-1-ylmethyl } -benzoic acid methyl ester;
4- {6- [3- (3, 4-dichloro-phenyl) -ureido ] -4-oxo-3, 4-dihydro-2, 3-naphthyridin-1-ylmethyl } -benzoic acid methyl ester;
4- [ 4-oxo-6- (3-pyridin-3-yl-ureido) -3, 4-dihydro-2, 3-naphthyridin-1-ylmethyl ] -benzoic acid methyl ester;
4- (6-amino-4-oxo-3, 4-dihydro-2, 3-naphthyridin-1-ylmethyl) -benzoic acid methyl ester;
n- [1- (4-chloro-3-fluoro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -propionamide;
n- [1- (4-chloro-3-fluoro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -4-trifluoromethyl-benzamide;
16. furan-2-carboxylic acid [1- (4-chloro-3-fluoro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -amide;
n- [1- (4-chloro-3-fluoro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3, 4-dimethoxy-benzamide;
n- [1- (4-chloro-3-fluoro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3-cyclopentyl-propionamide;
2-propyl-pentanoic acid [1- (4-chloro-3-fluoro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] amide;
20.1- [1- (4-chloro-3-fluoro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3- (3-trifluoromethyl-phenyl) -urea;
1- [1- (4-chloro-3-fluoro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3- (3-methoxy-phenyl) -urea;
1- [1- (4-chloro-3-fluoro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3-p-tolyl-urea;
1- [1- (4-chloro-3-fluoro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3- (2, 4-difluoro-phenyl) -urea;
24.1- [1- (4-chloro-3-fluoro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3- (3, 4-dichloro-phenyl) -urea;
25.1- [1- (4-chloro-3-fluoro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3-pyridin-3-yl-urea;
7-amino-4- (4-chloro-3-fluoro-benzyl) -2H-2, 3-naphthyridin-1-one;
27. n- {1- [ (E) -3- (4-nitro-phenyl) -allyl ] -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl } -propionamide;
n- {1- [ (E) -3- (4-nitro-phenyl) -allyl ] -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl } -4-trifluoromethyl-benzamide;
29. furan-2-carboxylic acid {1- [ (E) -3- (4-nitro-phenyl) -allyl ] -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl } -amide;
n- {1- [ (E) -3- (4-nitro-phenyl) -allyl ] -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl } -3, 4-dimethoxy-benzamide;
n- {1- [ (E) -3- (4-nitro-phenyl) -allyl ] -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl } -3-cyclopentyl-propionamide;
2-propyl-pentanoic acid {1- [ (E) -3- (4-nitro-phenyl) -allyl ] -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl } -amide;
33.1- {1- [ (E) -3- (4-nitro-phenyl) -allyl ] -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl } -3- (3-trifluoromethyl-phenyl) -urea;
34.1- {1- [ (E) -3- (4-nitro-phenyl) -allyl ] -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl } -3- (3-methoxy-phenyl) -urea;
35.1- {1- [ (E) -3- (4-nitro-phenyl) -allyl ] -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl } -3-p-tolyl-urea;
1- {1- [ (E) -3- (4-nitro-phenyl) -allyl ] -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl } -3- (2, 4-difluoro-phenyl) -urea;
1- {1- [ (E) -3- (4-nitro-phenyl) -allyl ] -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl } -3- (3, 4-dichloro-phenyl) -urea;
1- {1- [ (E) -3- (4-nitro-phenyl) -allyl ] -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl } -3-pyridin-3-yl-urea;
7-amino-4- [ (E) -3- (4-nitro-phenyl) -allyl ] -2H-2, 3-naphthyridin-1-one;
40. n- (4-oxo-1-thiophen-3-ylmethyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) -propionamide;
n- (4-oxo-1-thiophen-3-ylmethyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) -4-trifluoromethyl-benzamide;
42. furan-2-carboxylic acid (4-oxo-1-thiophen-3-ylmethyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) -amide;
n- (4-oxo-1-thiophen-3-ylmethyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) -3, 4-dimethoxy-benzamide;
n- (4-oxo-1-thiophen-3-ylmethyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) -3-cyclopentyl-propionamide;
45.2-propyl-pentanoic acid (4-oxo-1-thiophen-3-ylmethyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) -amide;
1- (4-oxo-1-thiophen-3-ylmethyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) -3- (3-trifluoromethyl-phenyl) -urea;
1- (4-oxo-1-thiophen-3-ylmethyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) - (3-methoxy-phenyl) -urea;
48.1- (4-oxo-1-thiophen-3-ylmethyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) -3-p-tolyl-urea;
1- (4-oxo-1-thiophen-3-ylmethyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) -3- (2, 4-difluoro-phenyl) -urea;
50.1- (4-oxo-1-thiophen-3-ylmethyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) -3- (3, 4-dichloro-phenyl) -urea;
51.1- (4-oxo-1-thiophen-3-ylmethyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) -3-pyridin-3-yl-urea;
52.7-amino-4-thiophen-3-ylmethyl-2H-2, 3-naphthyridin-1-one;
53.N- [1- (3-methoxy-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -propionamide;
n- [1- (3-methoxy-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -4-trifluoromethyl-benzoyl;
55. furan-2-carboxylic acid [1- (3-methoxy-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -amide;
56.N- [1- (3-methoxy-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3, 4-dimethoxy-benzamide;
n- [1- (3-methoxy-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3-cyclopentyl-propionamide;
58.2-propyl-pentanoic acid [1- (3-methoxy-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -amide;
59.1- [1- (3-methoxy-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3- (3-trifluoromethyl-phenyl) -urea;
60.1- [1- (3-methoxy-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] - (3-methoxy-phenyl) -urea;
61.1- [1- (3-methoxy-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3-p-tolyl-urea;
62.1- [1- (3-methoxy-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3- (2, 4-difluoro-phenyl) -urea;
63.1- [1- (3-methoxy-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3- (3, 4-dichloro-phenyl) -urea;
64.1- [1- (3-methoxy-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3-pyridin-3-yl-urea;
65.7-amino-4- (3-methoxy-benzyl) -2H-2, 3-naphthyridin-1-one;
66.N- (4-oxo-1-propyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) propanamide;
n- (4-oxo-1-propyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) -4-trifluoromethyl-benzamide;
68. furan-2-carboxylic acid (4-oxo-1-propyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) -amide;
n- (4-oxo-1-propyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) -3, 4-dimethoxy-benzamide;
n- (4-oxo-1-propyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) -3-cyclopentyl-propionamide;
71.2-propyl-pentanoic acid (4-oxo-1-propyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) -amide;
72.1- (4-oxo-1-propyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) -3- (3-trifluoromethyl-phenyl) -urea;
73.1- (4-oxo-1-propyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) - (3-methoxy-phenyl) -urea;
74.1- (4-oxo-1-propyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) -3-p-tolyl-urea;
1- (4-oxo-1-propyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) -3- (2, 4-difluoro-phenyl) -urea;
1- (4-oxo-1-propyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) -3- (3, 4-dichloro-phenyl) -urea;
77.1- (4-oxo-1-propyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) -3-pyridin-3-yl-urea;
78.7-amino-4-propyl-2H-2, 3-naphthyridin-1-one;
79.N- [1- (3, 3-dimethyl-butyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -propionamide;
80.N- [1- (3, 3-dimethyl-butyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -4-trifluoromethyl-benzamide;
81. furan-2-carboxylic acid [1- (3, 3-dimethyl-butyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -amide;
82.N- [1- (3, 3-dimethyl-butyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3, 4-dimethoxy-benzamide;
n- [1- (3, 3-dimethyl-butyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3-cyclopentyl-propionamide;
84.2-propyl-pentanoic acid [1- (3, 3-dimethyl-butyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -amide;
85.1- [1- (3, 3-dimethyl-butyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3- (3-trifluoromethyl-phenyl) -urea;
86.1- [1- (3, 3-dimethyl-butyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] - (3-methoxy-phenyl) -urea;
87.1- [1- (3, 3-dimethyl-butyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3-p-tolyl-urea;
88.1- [1- (3, 3-dimethyl-butyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3- (2, 4-difluoro-phenyl) -urea;
89.1- [1- (3, 3-dimethyl-butyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3- (3, 4-dichloro-phenyl) -urea;
90.1- [1- (3, 3-dimethyl-butyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3-pyridin-3-yl-urea;
91.7-amino-4- (3, 3-dimethyl-butyl) -2H-2, 3-naphthyridin-1-one;
92.N- [ 4-oxo-1- (3-phenyl-propyl) -3, 4-dihydro-2, 3-naphthyridin-6-yl ] -propionamide;
93.N- [ 4-oxo-1- (3-phenyl-propyl) -3, 4-dihydro-2, 3-naphthyridin-6-yl ] -4-trifluoromethyl-benzamide;
94. furan-2-carboxylic acid [ 4-oxo-1- (3-phenyl-propyl) -3, 4-dihydro-2, 3-naphthyridin-6-yl ] -amide;
95.N- [ 4-oxo-1- (3-phenyl-propyl) -3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3, 4-dimethoxy-benzamide;
96.N- [ 4-oxo-1- (3-phenyl-propyl) -3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3-cyclopentyl-propionamide;
97.2-propyl-pentanoic acid [ 4-oxo-1- (3-phenyl-propyl) -3, 4-dihydro-2, 3-naphthyridin-6-yl ] -amide;
98.1- [ 4-oxo-1- (3-phenyl-propyl) -3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3- (3-trifluoromethyl-phenyl) -urea;
99.1- [ 4-oxo-1- (3-phenyl-propyl) -3, 4-dihydro-2, 3-naphthyridin-6-yl ] - (3-methoxy-phenyl) -urea;
1- [ 4-oxo-1- (3-phenyl-propyl) -3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3-p-tolyl-urea;
101.1- [ 4-oxo-1- (3-phenyl-propyl) -3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3- (2, 4-difluoro-phenyl) -urea;
102.1- [ 4-oxo-1- (3-phenyl-propyl) -3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3- (3, 4-dichloro-phenyl) -urea;
103.1- [ 4-oxo-1- (3-phenyl-propyl) -3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3-pyridin-3-yl-urea;
104.7-amino-4- (3-phenyl-propyl) -2H-2, 3-naphthyridin-1-one;
n- (4-oxo-1-pyridin-3-ylmethyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) -propionamide;
n- (4-oxo-1-pyridin-3-ylmethyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) -4-trifluoromethyl-benzamide;
107. furan-2-carboxylic acid (4-oxo-1-pyridin-3-ylmethyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) -amide;
ethyl N- (4-oxo-1-pyridin-3-ylmethyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) -succinamate;
n- (4-oxo-1-pyridin-3-ylmethyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) -3-cyclopentyl-propionamide;
110.2-propyl-pentanoic acid (4-oxo-1-pyridin-3-ylmethyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) -amide;
1- (4-oxo-1-pyridin-3-ylmethyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) -3- (3-trifluoromethyl-phenyl) -urea;
112.1- (3-methoxy-phenyl) -3- (4-oxo-1-pyridin-3-ylmethyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) -urea;
113.1- (4-oxo-1-pyridin-3-ylmethyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) -3-p-tolyl) -urea;
114.1- (2, 4-difluoro-phenyl) -3- (4-oxo-1-pyridin-3-ylmethyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) -urea;
115.1- (3, 4-dichloro-phenyl) -3- (4-oxo-1-pyridin-3-ylmethyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) -urea;
1- (4-oxo-1-pyridin-3-ylmethyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) -3-pyridin-3-yl-urea;
117.7-amino-4-pyridin-3-ylmethyl-2H-2, 3-naphthyridin-1-one;
n- (4-oxo-1-pyridin-3-ylmethyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) -benzamide;
n- [1- (4-chloro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -propionamide;
n- [1- (4-chloro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -4-trifluoromethyl-benzamide;
121. furan-2-carboxylic acid [1- (4-chloro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -amide;
ethyl N- [1- (4-chloro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -succinamate;
n- [1- (4-chloro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3-cyclopentyl-propionamide;
124.2-propyl-pentanoic acid [1- (4-chloro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -amide;
125.1- [1- (4-chloro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3- (3-trifluoromethyl-phenyl) -urea;
126.1- [1- (4-chloro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3- (3-methoxy-phenyl) -urea;
127.1- [1- (4-chloro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3-p-tolyl-urea;
128.1- [1- (4-chloro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3- (2, 4-difluoro-phenyl) -urea;
129.1- [1- (4-chloro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3- (3, 4-dichloro-phenyl) -urea;
130.1- [1- (4-chloro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3-pyridin-3-yl-urea;
131.7-amino-4- (4-chloro-benzyl) -2H-2, 3-naphthyridin-1-one;
n- [1- (4-cyano-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -propionamide;
n- [1- (4-cyano-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -4-trifluoromethyl-benzamide;
134. furan-2-carboxylic acid [1- (4-cyano-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -amide;
n- [1- (4-cyano-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -succinamic acid ethyl ester;
n- [1- (4-cyano-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3-cyclopentyl-propionamide;
2-propyl-pentanoic acid [1- (4-cyano-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -amide;
138.1- [1- (4-cyano-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3- (3-trifluoromethyl-phenyl) -urea;
139.1- [1- (4-cyano-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3- (3-methoxy-phenyl) -urea;
140.1- [1- (4-cyano-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3-p-tolyl) -urea;
141.1- [1- (4-cyano-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3- (2, 4-difluoro-phenyl) -urea;
142.1- [1- (4-cyano-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3- (3, 4-dichloro-phenyl) -urea;
143.1- [1- (4-cyano-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3-pyridin-3-yl) -urea;
144.7-amino-4- (4-cyano-benzyl) -2H-2, 3-naphthyridin-1-one;
n- [1- (3-fluoro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -propionamide;
n- [1- (3-fluoro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -4-trifluoromethyl-benzamide;
147. furan-2-carboxylic acid [1- (3-fluoro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -amide;
n- [1- (3-fluoro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -succinamic acid ethyl ester;
n- [1- (3-fluoro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3-cyclopentyl-propionamide;
150.2-propyl-pentanoic acid [1- (3-fluoro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -amide;
151.1- [1- (3-fluoro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3- (3-trifluoromethyl-phenyl) -urea;
152.1- [1- (3-fluoro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3- (3-methoxy-phenyl) -urea;
153.1- [1- (3-fluoro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3-p-tolyl) -urea;
154.1- [1- (3-fluoro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3- (2, 4-difluoro-phenyl) -urea;
155.1- [1- (3-fluoro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3- (3, 4-dichloro-phenyl) -urea;
156.1- [1- (3-fluoro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3-pyridin-3-yl-urea;
157.7-amino-4- (3-fluoro-benzyl) -2H-2, 3-naphthyridin-1-one;
n- [1- (3-methyl-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -propionamide;
159.N- [1- (3-methyl-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -4-trifluoromethyl-benzamide;
160. furan-2-carboxylic acid [1- (3-methyl-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -amide;
n- [1- (3-methyl-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -succinamic acid ethyl ester;
n- [1- (3-methyl-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3-cyclopentyl-propionamide;
163.2-propyl-pentanoic acid [1- (3-methyl-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -amide;
164.1- [1- (3-methyl-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3- (3-trifluoromethyl-phenyl) -urea;
165.1- [1- (3-methyl-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3- (3-methoxy-phenyl) -urea;
166.1- [1- (3-methyl-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3-p-tolyl-urea;
167.1- [1- (3-methyl-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3- (2, 4-difluoro-phenyl) -urea;
168.1- [1- (3-methyl-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3- (3, 4-dichloro-phenyl) -urea;
169.1- [1- (3-methyl-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3-pyridin-3-yl-urea;
170.7-amino-4- (3-methyl-benzyl) -2H-2, 3-naphthyridin-1-one;
n- [1- (2, 4-dichloro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -propionamide;
n- [1- (2, 4-dichloro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -4-trifluoromethyl-benzamide;
173. furan-2-carboxylic acid [1- (2, 4-dichloro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -amide;
ethyl N- [1- (2, 4-dichloro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -succinamic acid;
n- [1- (2, 4-dichloro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3-cyclopentyl-propionamide;
176.2-propyl-pentanoic acid [1- (2, 4-dichloro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -amide;
177.1- [1- (2, 4-dichloro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3- (3-trifluoromethyl-phenyl) -urea;
178.1- [1- (2, 4-dichloro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3- (3-methoxy-phenyl) -urea;
179.1- [1- (2, 4-dichloro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3-p-tolyl-urea;
180.1- [1- (2, 4-dichloro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3- (2, 4-difluoro-phenyl) -urea;
181.1- [1- (2, 4-dichloro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3- (3, 4-dichloro-phenyl) -urea;
182.1- [1- (2, 4-dichloro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3-pyridin-3-yl) -urea;
183.7-amino-4- (2, 4-dichloro-benzyl) -2H-2, 3-naphthyridin-1-one;
n- (4-oxo-1-quinolin-3-ylmethyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) -propionamide;
n- (4-oxo-1-quinolin-3-ylmethyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) -4-trifluoromethyl-benzamide;
186. furan-2-carboxylic acid (4-oxo-1-quinolin-3-ylmethyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) -amide;
n- (4-oxo-1-quinolin-3-ylmethyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) -succinamic acid ethyl ester;
n- (4-oxo-1-quinolin-3-ylmethyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) -3-cyclopentyl-propionamide;
189.2-propyl-pentanoic acid (4-oxo-1-quinolin-3-ylmethyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) -amide;
190.1- (4-oxo-1-quinolin-3-ylmethyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) -3- (3-trifluoromethyl-phenyl) -urea;
191.1- (4-oxo-1-quinolin-3-ylmethyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) -3- (3-methoxy-phenyl) -urea;
192.1- (4-oxo-1-quinolin-3-ylmethyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) -3-p-tolyl-urea;
193.1- (4-oxo-1-quinolin-3-ylmethyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) -3- (2, 4-difluoro-phenyl) -urea;
194.1- (4-oxo-1-quinolin-3-ylmethyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) -3- (3, 4-difluoro-phenyl) -urea;
195.1- (4-oxo-1-quinolin-3-ylmethyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) -3-pyridin-3-yl-urea;
196.7-amino-4-quinolin-3-ylmethyl-2H-3, 4-dihydro-2, 3-naphthyridin-1-one;
n- [ 4-oxo-1- (2-trifluoromethyl-benzyl) -3, 4-dihydro-2, 3-naphthyridin-6-yl ] -propionamide;
n- [ 4-oxo-1- (2-trifluoromethyl-benzyl) -3, 4-dihydro-2, 3-naphthyridin-6-yl ] -4-trifluoromethyl-benzamide;
199. furan-2-carboxylic acid [ 4-oxo-1- (2-trifluoromethyl-benzyl) -3, 4-dihydro-2, 3-naphthyridin-6-yl ] -amide;
n- [ 4-oxo-1- (2-trifluoromethyl-benzyl) -3, 4-dihydro-2, 3-naphthyridin-6-yl ] -succinamic acid ethyl ester;
n- [ 4-oxo-1- (2-trifluoromethyl-benzyl) -3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3-cyclopentyl-propionamide;
202.2-propyl-pentanoic acid [ 4-oxo-1- (2-trifluoromethyl-benzyl) -3, 4-dihydro-2, 3-naphthyridin-6-yl ] -amide;
203.1- [ 4-oxo-1- (2-trifluoromethyl-benzyl) -3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3- (3-trifluoromethyl-phenyl) -urea;
204.1- [ 4-oxo-1- (2-trifluoromethyl-benzyl) -3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3- (3-methoxy-phenyl) -urea;
205.1- [ 4-oxo-1- (2-trifluoromethyl-benzyl) -3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3-p-tolyl-urea;
206.1- [ 4-oxo-1- (2-trifluoromethyl-benzyl) -3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3- (2, 4-difluoro-phenyl) -urea;
207.1- [ 4-oxo-1- (2-trifluoromethyl-benzyl) -3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3- (3, 4-dichloro-phenyl) -urea;
208.1- [ 4-oxo-1- (2-trifluoromethyl-benzyl) -3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3-pyridin-3-yl) -urea
209.7-amino-4- (2-trifluoromethyl-benzyl) -2H-2, 3-naphthyridin-1-one.
As mentioned above, the preparation of the amino-2, 3-naphthyridinone derivatives of formula (I) represents a further object of the invention.
The compounds of formula (I) and pharmaceutically acceptable salts thereof may thus be obtained by the following processes, including:
a) under optional reducing conditions, reacting the compound of formula (II)
Wherein R is3And m has the meaning indicated above and Hal represents a halogen atom,
with suitable phosphine derivatives (PL)3) Reaction to obtain a compound of formula (III)
Wherein P is a phosphorus atom and L is a phosphine ligand;
b) reacting the compound of formula (III) with an aldehyde resin-CHO in the presence of a suitable reducing agent to obtain a resin-supported compound of formula (IV)
Wherein R is3M, P, L, Hal and the resin are as defined above;
c) reacting a compound of formula (IV) with a carbonyl derivative of formula (V) or a nitroso derivative of formula (VI)
R4-CO-R5 (V) R’-NO(VI)
Wherein R is4，R5And R' is as defined above; to obtain a compound of formula (VII)
Wherein each A is a group ═ CR4R5Or ═ NR'; and optionally reacting a compound of formula (VII) according to any of the following steps d.1) or d.2)
d.1) with one of the derivatives of the formula (VIII), (IX), (X) or (XI) under any basic conditions,
R’COZ (VIII)，R’NCO(IX)，R’OCOZ (X)，R’SO2Z(XI)
wherein Z is a halogen atom or a suitable leaving group and R' is as defined above, to obtain a compound of formula (XII)
Wherein Rb is-COR ', -CONHR ', -COOR ' or-SO, respectively2R'; or
d.2) reaction with a compound of the formula (XIII)
Rb-Z (XIII)
Wherein Z is a halogen atom and Rb is an alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl or heterocyclylalkyl group as defined above, to obtain the corresponding compounds of formula (XII) above;
e) reacting the compound of formula (VII) or (XII) thus obtained with a hydrazine derivative of formula (XIV)
R2-NH-NH2 (XIV)
Wherein R is2As defined above, to obtain a compound of formula (XV) or (XVI), respectively,
wherein Rb, R2，R3M and resin are as defined above and R1Is of the formula-CHR4R5or-NHR' wherein R4，R5And R' is as defined above;
f) reacting a compound of formula (XV) or (XVI) under acidic conditions to obtain a compound of formula (I), which is converted, when necessary, into another compound of formula (I) and/or a pharmaceutically acceptable salt thereof.
The above method is a similar method that can be carried out according to a known method.
It is clear to the skilled person that if the compounds of formula (I) are prepared according to the above described methods to obtain a mixture of isomers, it is within the scope of the present invention to separate them into the single isomers of formula (I) carried out according to conventional techniques.
Likewise, it is within the scope of the invention to convert the corresponding salts thereof to the free compound (I) according to methods well known in the art.
According to step a) of the process, a compound of formula (II) wherein Hal represents a halogen atom, preferably bromine, is reacted with a suitable phosphine derivative PL3Such as, for example, triphenylphosphine, tri-n-butylphosphine, tri-tert-butylphosphine or 1, 4-bis (diphenylphosphino) butane.
Preferably, the phosphine derivative is triphenylphosphine PPh3。
The reaction may be carried out in any solvent, for example, including ethyl acetate, ethyl propionate and the like, dimethylformamide, dimethylacetamide and the like, dichloromethane, chloroform and the like, acetone or acetonitrile; preferably, ethyl propionate is used. The temperature may vary from about 20 ℃ to about 100 ℃.
The reaction can be carried out by adding the phosphine to a solution of the compound of formula (II) or by adding a solution of (II) to the phosphine.
When triphenylphosphine is used, the compounds of the formula (II) are directly converted into the corresponding derivatives of the formula (III) which bear an amino group in the original nitro position. Alternatively, when PL is used3Instead of triphenylphosphine, the compounds of the formula (II) can first be converted into intermediate derivatives of the formula (IIa)
Wherein R is3M, P and L are as defined above, which has to be suitably reduced to a compound of formula (III).
The reducing conditions to be used are those conventionally used for reducing the aromatic nitro derivative to an amino derivative, and include the use of a chemical reducing agent, for example, tin dichloride, iron and acetic acid, zinc and hydrochloric acid, or titanium trichloride.
Alternatively, the reduction step may occur under catalytic hydrogenation conditions in the presence of a suitable catalyst, typically platinum, palladium or palladium on carbon.
Preferably, the compound of formula (II) is converted to the compound of formula (III) conventionally by using triphenylphosphine.
According to step b) of the process, the compound of formula (III) is reacted with a suitable aldehyde RCHO resin, such as a polystyrene or polyethylene glycol resin, in the presence of a reducing agent such as, for example, pyridine-borane complex, sodium cyanoborohydride, sodium triacetoxyborohydride, dimethylthioborane, and the like.
Preferably, the resin is 4- (4-formyl-3-methoxyphenoxy) butyrylaminomethylation resin or 4- (4-formyl-3-methoxyphenoxy) butyryl (NOVAGEL)TM)。
The reaction is carried out in the presence of a suitable solvent, preferably dichloromethane, 2, 2, 2-trifluoroethanol and acetic acid, by directly adding an excess of reducing agent, optionally dissolved in the same solvent, to the mixture of resin and compound of formula (III) and by stirring at a temperature in the range of about 0 ℃ to about 40 ℃ for a suitable time. By way of example, this may be carried out at about 20 ℃ for about 15 hours.
According to step c) of the process, the compound of formula (IV) is then reacted with a compound of formula (V) or with a compound of formula (VI) to obtain the corresponding derivative of formula (VII).
The reaction is carried out in the presence of a suitable base, optionally in the presence of a suitable phase transfer catalyst, such as triethylamine, diisopropylethylamine, piperidine, sodium carbonate, cesium carbonate, potassium tert-butoxide, sodium methoxide, diazabicycloundecene, potassium hydroxide, and the like.
To a suspension of a compound of formula (IV) in a suitable solvent, e.g. dichloromethane, dimethylformamide, tetrahydrofuran, etc., is added a compound of formula (V) or a compound of formula (VI). The temperature is adjusted to a suitable value, for example, from about-70 ℃ to about 40 ℃ depending on the electrophile (V) or (VI), and a base is added. Stirring is continued for a suitable time, for example from about 2 to about 15 hours.
The further reaction of the product of the formula (VII) thus obtained is carried out directly according to one of steps d.1) or d.2), or according to step e).
According to step d.1) of the process, in particular, the compound of formula (VII) is reacted with a carboxylic acid derivative of formula (VIII), with an isocyanate of formula (IX), with a chloroformate derivative of formula (X) or with a sulfonyl derivative of formula (XI) to obtain the corresponding compound of formula (XII), wherein Rb is respectively of formula-COR ', -CONHR ', -COOR ' or-SO2The radical of R'.
When a compound of formula (VIII), (X) or (XI) is used, Z is preferably a halogen atom, more preferably a chlorine atom. In this case, the compound of formula (VII) is suspended in a suitable solvent, such as dichloromethane, dimethylformamide, tetrahydrofuran, dioxane, etc., and then a suitable base, such as triethylamine, diisopropylethylamine, sodium carbonate, etc., is added. An electrophile of formula (VIII), (X), or (XI) is then added and the mixture is stirred at a temperature in the range of about 20 ℃ to about 80 ℃ for about 2 to 15 hours. When an isocyanate of the formula (IX) is used, the reaction conditions are the same as described above, except that a base is not necessary.
In the latter case, a catalyst such as dimethylaminopyridine may optionally be used.
Basically similar considerations apply when considering step d.2) of the process, wherein the compound of formula (VII) is further converted into the corresponding functionalized amino derivative of formula (XII) according to well known methods.
By way of example, a compound of formula (VII) may be reacted with a derivative of formula (XIII) wherein Z is a halogen atom, e.g. bromine, Rb is arylalkyl, e.g. benzyl, according to conventional methods.
According to step e) of the process, the compound of formula (VII) obtained from step c), or the compound of formula (XII) obtained from one of steps d.1) or d.2), is reacted with hydrazine or a hydrazine derivative of formula (XIV) to obtain the corresponding compound of formula (XV) or (XVI).
The compound of formula (XII) is suspended in a suitable solvent, preferably dimethylformamide, in the presence of hydrazine hydrate of general formula (XIV) or another hydrazine and stirred at a suitable temperature, e.g. 20 ℃, for about 2 to about 20 hours.
According to step f) of the process, the compound of formula (XV) or (XVI) is reacted under acidic conditions, preferably in the presence of trifluoroacetic acid, to give the desired compound of formula (I). The compound of formula (XV) or (XVI) is thus suspended in a solution of 5-95% trifluoroacetic acid in dichloromethane and the mixture is stirred at a temperature ranging from about 20 ℃ to reflux temperature for about 5 minutes to about 3 hours.
As mentioned above, it is clear to the skilled person that by cleaving the compound of formula (XV) from the resin, the corresponding derivative will be obtained in which Ra and Rb are both hydrogen atoms.
Likewise, when starting from the compound of formula (XVI), the corresponding derivative of formula (I) will be obtained for which one of Ra or Rb, for example Ra, is a hydrogen atom and the other, for example Rb, is a group as defined in step d.1) or d.2).
In addition, it is clear to the skilled person that any of the compounds of formula (I) above may be further converted into other compounds of formula (I) as set forth in step f), if desired, by treatment according to conventional methods.
By way of example, compounds of formula (I) wherein both Ra and Rb are not hydrogen atoms may be prepared according to well known methods by reacting any compound of formula (I) wherein one of Ra or Rb is a hydrogen atom, into another compound of formula (I) wherein the same hydrogen atom is replaced by a suitable group.
When the compounds of formula (I) are prepared according to various different methods, these are all considered to be within the scope of the present invention, any functional group in the starting materials or intermediates thereof, which can cause undesired side reactions, needs to be suitably protected according to conventional techniques.
Likewise, the latter can be converted into the free deprotected compound according to known methods.
Pharmaceutically acceptable salts of the compounds of formula (I) may be obtained according to conventional methods, or their free compounds may be obtained from a salt thereof.
The compounds of formula (II) are well known or can be readily prepared according to well known methods [ see, e.g., j. org. chem. (1985), 50, 4120-; J.chem.Soc. (1961), 5275-5284 ].
Alternatively, it is reported from the working examples that compounds of formula (II) wherein Hal represents a bromine atom can be prepared by reacting commercially available 6-nitro 2-benzo [ c ] furanones, for example in the presence of aqueous hydrogen peroxide, with bromine under bromination conditions in a suitable solvent, for example in dichloromethane, dichloromethane/water or hexane/water mixtures, at temperatures of about 20 ℃ to reflux.
The compounds of the formulae (V), (VI), (VIII), (IX), (X), (XI), (XIII) and (XIV) are known or can be prepared readily by known methods.
Likewise, aldehyde resin R-CHO, phosphine derivative PL3And other suitable reagents for this process are known compounds which are either commercially available or readily prepared according to known methods.
The compounds of formula (I) according to the invention are advantageously prepared by carrying out the above reactions between several intermediates in a serial manner according to combinatorial chemistry techniques well known in the art.
Thus, all preferred compounds of the invention, where appropriate in the form of pharmaceutically acceptable salts, are conveniently indicated herein and are defined by the process definition product, e.g. a product of formula (I) obtainable by the defined process.
Thus, there is provided any specific compound of formula (I) obtainable, for example, by combinatorial chemistry techniques according to the process of the invention by first reacting a compound of formula (IV) with one of the aldehyde derivatives of formula (V) as shown in table I
By reacting any of the resulting compounds of formula (VII) with one of the acid chloride derivatives of formula (VIII) as shown in Table II; by reacting any resulting compound of formula (XII) with hydrazine; and by processing according to step f) of the method.
Also provided are any specific compounds of formula (I) obtainable by combinatorial chemistry techniques according to the methods of the invention by first reacting a compound of formula (IV) with one of the aldehyde derivatives of formula (V) as shown in table I
By reacting any of the resulting compounds of formula (VII) with one of the isocyanate derivatives of formula (IX) as shown in Table III; by reacting any resulting compound of formula (XII) with hydrazine; and by processing according to step f) of the method.
TABLE I
Aldehyde derivatives R of formula (V)4-CO-R5(R5＝H)
| 1. | 3, 5-diiodo-4-hydroxybenzaldehyde |
| 2. | 3-iodobenzaldehyde |
| 3. | 3, 5-dibromobenzaldehyde |
| 4. | 4-bromothiophene-2-carbaldehyde |
| 5. | 2-naphthaldehyde |
| 6. | N-ethyl-carbazole-3-aldehyde |
| 7. | 4-chloro-1-methylpyrazole-3-carbaldehyde |
| 8. | Acetic acid (3-formyl-1-phenyl-1H-pyrazol-5-yl) methyl ester |
| 9. | 1-acetyl-3-indolecarboxaldehyde |
| 10. | 4-formyl-1-methylpyrrole-2-carboxylic acid methyl ester |
| 11. | 3, 5-di-tert-butyl-4-hydroxybenzaldehyde |
| 12. | 5- (methylthio) -2-thiophenecarboxaldehyde |
| 13. | 4- (methylthio) benzaldehyde |
| 14. | 3-nitro-4- (2-pyridylthio) benzaldehyde |
| 15. | 5-methyl-2-thiophenecarboxaldehyde |
| 16. | 3-acetoxybenzaldehyde |
| 17. | 4-dimethyl benzaldehyde |
| 18. | 4-pyridinecarboxaldehyde n-oxide |
| 19. | 4-fluoro-3-methylbenzaldehyde |
| 20. | 2, 6-dichloroisonicotinaldehyde (nicotinaldehyde) |
| 21. | 5- (2, 4-difluorophenyl) -2-furfural |
| 22. | 2- (4-bromobenzoyl) -1-benzofuran-5-carbaldehyde |
| 23. | 2-benzoyl-1-benzofuran-5-carbaldehyde |
| 24. | 2-butyl-4-formylimidazole |
| 25. | 5-benzyloxy-1H-pyrrolo [2, 3-c)]Pyridine-3-carbaldehyde |
| 26. | 6-methyl-2-pyridinecarboxaldehyde |
| 27. | 4- [4- (tert-butyl) thiazol-2-yl]Benzaldehyde |
| 28. | 5-formyl-2, 4-dimethoxy-pyrimidine |
| 29. | 2- [ (4-chlorobenzyl) thio]Pyrimidine-4-carbaldehyde |
| 30. | 3-fluoro-2-hydroxybenzaldehydes |
| 31. | 3-hydroxybenzaldehydes |
| 32. | 3-carboxybenzaldehyde |
| 33. | 4-vinyl benzaldehyde |
| 34. | 5- (2, 5-dichlorophenyl) -2-furfural |
| 35. | 2-fluoro-5-nitrobenzaldehyde |
| 36. | 5- (4-nitrophenyl) -2-furfural |
| 37. | 4-dimethylaminobenzaldehyde |
| 38. | 4- [3- (dimethylamino) propoxy group]Benzaldehyde |
| 39. | 4-n-butylbenzaldehyde |
| 40. | 4- (4-benzylpiperazino) benzaldehyde |
| 41. | 2, 2' -bithiophene-5-carbaldehyde |
| 42. | 4- [4- (1-adamantyl) -1, 3-thiazol-2-yl]Benzaldehyde |
| 43. | 4-formyl-trans-stilbene compounds |
| 44. | 6-chloroimidazo [2, 1-b][1，3]Thiazole-5-carbaldehyde |
| 45. | 4- (Phenylethynyl) benzaldehyde |
| 46. | 3, 3' - (4-formylphenylimino) dipropionitrile |
| 47. | 6-formyl-2- (methylthio) nicotinonitrile |
| 48. | 4-cyanobenzaldehyde |
| 49. | 3- [ (4-Formylphenoxy) methyl group]Thiophene-2-carbonitriles |
| 50. | 2- (3-formyl-1H-indol-1-yl) benzyl |
| 51. | 2, 6-Difluorobenzoic acid 2-formyl-6-methoxyphenyl ester |
| 52. | 4-formyl-2-methoxyphenyl carbonic acid tert-butyl ester |
| 53. | 4- (difluoromethoxy) benzaldehyde |
| 54. | 2- [ 1-methyl-5- (trifluoromethyl) pyrazol-3-yl]Thiophene-5-carbaldehyde |
| 55. | 5- (3-trifluoromethylphenyl) furan-2-carbaldehyde |
| 56. | 2, 3-difluoro-4-methylbenzaldehyde |
| 57. | 3-chloro-5- (trifluoromethyl) pyridine-2-carbaldehyde |
| 58. | 4- (trifluoromethoxy) benzaldehyde |
| 59. | 3- [ (2, 4-difluorophenyl) thio]-5- (trifluoromethyl) pyridine-2-carbaldehyde |
| 60. | 3, 5-bis (trifluoromethyl) benzaldehyde |
| 61. | 2, 3, 5, 6-tetrafluorobenzaldehyde |
| 62. | 4- (methylsulfonyl) benzaldehyde |
| 63. | 1- [ (4-methylphenyl) sulfonyl]-1H-indole-3-carbaldehyde |
| 64. | 2, 4, 5-Trichlorobenzenesulfonic acid 4-formyl-2-methoxyphenyl ester |
| 65. | 2, 3, 4, 5, 6-pentamethylbenzenesulfonic acid 4-formylphenyl ester |
| 66. | 3- (4-formylphenyl) -2- (pyridin-2-ylsulfonyl) acrylonitrile |
| 67. | 4-acetamide benzaldehyde |
| 68. | 4- [ [ 5-chloro-2-oxopyrimidin-1 (2H) -yl]Methoxy radical]Benzaldehyde |
| 69. | 4- (5-formyl-2-furyl) benzene-1-sulfonamide |
| 70. | 3-benzo [1, 3 ]]Dioxol-5-yl-2-methyl-propanal |
| 71. | 3- (Phenylthio) butanal |
| 72. | 3-chloro-4, 4, 4-trifluoro-2-phenylbutanal |
| 73. | 2-cyano-2-phenylacetaldehyde |
| 74. | 3-Methoxyphenylacetaldehyde |
| 75. | Pyridine-3-carbaldehyde |
| 76. | 4-chlorobenzaldehyde |
| 77. | 4-cyanobenzaldehyde |
| 78. | 3-fluorobenzaldehyde |
| 79. | M-tolualdehyde |
| 80. | 2, 4-Dichlorobenzaldehyde |
| 81. | Quinoline-3-carbaldehyde |
| 82. | 2- (trifluoromethyl) benzaldehyde |
| 83. | 4-formylbenzoic acid methyl ester |
| 84. | 4-chloro-3-fluorobenzaldehyde |
| 85. | 4-Nitrocinnamic aldehyde |
| 86. | 3-thiophenecarboxaldehyde |
| 87. | 3-methoxybenzaldehyde |
| 88. | Propionaldehyde |
| 89. | 3, 3-dimethylbutyraldehyde |
| 90. | 3-Phenylpropanal |
TABLE II
Acyl chloride derivatives of formula (VIII) R' COZ (Z ═ Cl)
| 1. | 3, 5-bis (trifluoromethyl) benzoyl chloride |
| 2. | Benzoyl chloride |
| 3. | 2-bromobenzoyl chloride |
| 4. | 2-fluorobenzoyl chloride |
| 5. | 2, 4-difluorobenzoyl chloride |
| 6. | 2, 6-difluorobenzoyl chloride |
| 7. | 2-chlorobenzoyl chloride |
| 8. | 2, 4-Dichlorobenzoyl chloride |
| 9. | 2-methoxybenzoyl chloride |
| 10. | 2- (trifluoromethyl) benzoyl chloride |
| 11. | O-toluyl chloride |
| 12. | 3-bromobenzoyl chloride |
| 13. | 3-fluorobenzoyl chloride |
| 14. | 3-chlorobenzoyl chloride |
| 15. | 3, 4-DichlorobenzylAcyl chloride |
| 16. | M-methoxybenzoyl chloride |
| 17. | 3, 4-Dimethoxybenzoyl chloride |
| 18. | 3, 4, 5-trimethoxybenzoyl chloride |
| 19. | 3, 5-Dimethoxybenzoyl chloride |
| 20. | 3- (trifluoromethyl) benzoyl chloride |
| 21. | M-toluoyl chloride |
| 22. | 4-bromobenzoyl chloride |
| 23. | 4-fluorobenzoyl chloride |
| 24. | 4-chlorobenzoyl chloride |
| 25. | P-methoxybenzoyl chloride |
| 26. | 4-Ethoxybenzoyl chloride |
| 27. | 4-n-butoxy benzoyl chloride |
| 28. | 4-Biphenylcarbonyl chloride |
| 29. | 4- (trifluoromethyl) benzoyl chloride |
| 30. | 4-tert-butylbenzoyl chloride |
| 31. | Para-toluoyl chloride |
| 32. | 4-Ethylbenzoyl chloride |
| 33. | 4-n-propylbenzoyl chloride |
| 34. | 4-n-butylbenzoyl chloride |
| 35. | Pivaloyl chloride |
| 36. | Isobutyryl chloride |
| 37. | 2-ethylhexanoyl chloride |
| 38. | Acetyl chloride |
| 39. | Phenoxyacetyl chloride |
| 40. | 4-chlorophenoxyacetyl chloride |
| 41. | Methoxy acetyl chloride |
| 42. | Phenylacetyl chloride |
| 43. | Tert-butyl acetyl chloride |
| 44. | Isovaleryl chloride |
| 45. | Propionyl chloride |
| 46. | Hydrocinnamoyl chloride |
| 47. | Butyryl chloride |
| 48. | Valeryl chloride |
| 49. | 4-iodobenzoyl chloride |
| 50. | Cyclopropanecarbonyl chloride |
| 51. | Cyclobutanecarbonyl chloride |
| 52. | Cyclopentane carbonyl chloride |
| 53. | 3-Cyclopentylpropionyl chloride |
| 54. | Cyclohexane carbonyl chloride |
| 55. | 4-Cyanobenzoyl chloride |
| 56. | 2-furoyl chloride |
| 57. | 1-naphthoyl chloride |
| 58. | 2-naphthoyl chloride |
| 59. | Thiophene-2-carbonyl chloride |
| 60. | Thiophene-2-acetyl chloride |
| 61. | (3, 4-Dimethoxyphenyl) acetyl chloride |
| 62. | 3, 5-Dichlorobenzoyl chloride |
| 63. | 2, 5-Dichlorobenzoyl chloride |
| 64. | 3, 4-difluorobenzoyl chloride |
| 65. | 9-fluorenone-4-carbonyl chloride |
| 66. | 3, 5-difluorobenzoyl chloride |
| 67. | Benzyloxy acetyl chloride |
| 68. | 3-cyanobenzoyl chloride |
| 69. | (2, 5-Dimethoxyphenyl) acetyl chloride |
| 70. | 3-Methoxybenzene acetyl chloride |
| 71. | Nicotinoyl chloride hydrochloride |
| 72. | Isonicotinoyl chloride hydrochloride |
| 73. | 2, 4, 6-trimethylbenzoyl chloride |
| 74. | Diphenylacetyl chloride |
| 75. | 2-methyl valeryl chloride |
| 76. | 3, 4-methylenedioxybenzoyl chloride |
| 77. | 2, 4-Dimethoxybenzoyl chloride |
| 78. | 2-phenoxypropionyl chloride |
| 79. | 2-phenylbutyryl chloride |
| 80. | 2-BButyryl chloride |
| 81. | 2, 3-Dichlorobenzoyl chloride |
| 82. | 4-chlorophenyl acetyl chloride |
| 83. | dl-2-methylbutyryl chloride |
| 84. | 2, 3-difluorobenzoyl chloride |
| 85. | 1- (4-chlorophenyl) -1-cyclopentanecarbonyl chloride |
| 86. | 2-ethoxy-1-naphthoyl chloride |
| 87. | Benzo [ b ]]Thiophene-2-carbonyl chloride |
| 88. | 4- (trifluoromethoxy) benzoyl chloride |
| 89. | 2- (trifluoromethoxy) benzoyl chloride |
| 90. | 3-chlorobenzo [ b]Thiophene-2-carbonyl chloride |
| 91. | 2-fluoro-3-(trifluoromethyl) benzoyl chloride |
| 92. | 2-fluoro-4- (trifluoromethyl) benzoyl chloride |
| 93. | 2-fluoro-5- (trifluoromethyl) benzoyl chloride |
| 94. | 3-fluoro-5- (trifluoromethyl) benzoyl chloride |
| 95. | 4-fluoro-2- (trifluoromethyl) benzoyl chloride |
| 96. | 4-fluoro-3- (trifluoromethyl) benzoyl chloride |
| 97. | 2-fluoro-6- (trifluoromethyl) benzoyl chloride |
| 98. | 2, 3, 6-trifluorobenzoyl chloride |
| 99. | 2, 4, 5-trifluorobenzoyl chloride |
| 100. | 3- (trifluoromethoxy) benzoyl chloride |
| 101 | Isoxazole-5-carbonyl chloride |
| 102 | 2, 4, 6-trifluorobenzoyl chloride |
| 103 | 2, 5-bis (trifluoromethyl) benzoyl chloride |
| 104 | 2, 3, 4-trifluorobenzoyl chloride |
| 105 | 2, 4, 6-trichlorobenzoyl chloride |
| 106 | 2, 4-dichloro-5-fluorobenzoyl chloride |
| 107 | 4-Methoxyphenylacetyl chloride |
| 108 | 5-fluoro-2- (trifluoromethyl) benzoyl chloride |
| 109 | 2-chloro-6-fluorobenzoyl chloride |
| 110 | 2-bromo-5-methoxybenzoyl chloride |
| 111 | Cyclopentyl acetyl chloride |
| 112 | 3-chloro-4-fluorobenzoyl chloride |
| 113 | 3-fluoro-4- (trifluoromethyl) benzoyl chloride |
| 114 | 4-fluorophenyl acetyl chloride |
| 115 | 4-tert-butylphenoxyacetyl chloride |
| 116 | 7-imidazol-1-yl-5, 6-dihydro-naphthalene-2-carbonyl chloride |
| 117 | 4-imidazol-1-ylmethyl-benzoyl chloride |
| 118 | 4-bromo-3-methylbenzoyl chloride |
TABLE III
Isocyanate derivatives R' NCO of the formula (IX)
| 1. | Phenyl isocyanate |
| 2. | Isocyanates of 2-bromobenzene |
| 3. | 2-fluorophenyl isocyanate |
| 4. | 2, 4-difluorophenyl isocyanate |
| 5. | 2, 6-difluorophenyl isocyanate |
| 6. | 2-chlorophenyl isocyanate |
| 7. | 2, 3-Dichlorophenyl isocyanate |
| 8. | 2, 4-Dichlorophenyl isocyanate |
| 9. | 2, 5-Dichlorophenyl isocyanate |
| 10. | 2, 6-Dichlorophenyl isocyanate |
| 11. | 2-methoxyphenyl isocyanate |
| 12. | 2, 4-Dimethoxyphenyl isocyanate |
| 13. | 2, 5-Dimethoxyphenyl isocyanate |
| 14. | 2-ethoxyphenyl isocyanate |
| 15 | 2- (trifluoromethyl) phenyl isocyanate |
| 16. | O-tolyl isocyanate |
| 17. | 2, 6-dimethylphenyl isocyanate |
| 18. | 2-Ethylphenyl isocyanate |
| 19. | 3-bromophenyl isocyanate |
| 20. | 3-fluorophenyl isocyanate |
| 21. | 3-chlorophenyl isocyanate |
| 22. | 3, 4-Dichlorophenyl isocyanate |
| 23. | 3-methoxyphenyl isocyanate |
| 24. | 3- (trifluoromethyl) phenyl isocyanate |
| 25. | M-tolyl isocyanate |
| 26. | 4-bromophenyl isocyanate |
| 27. | 4-fluorophenyl isocyanate |
| 28. | 4-chlorophenyl isocyanate |
| 29. | 4-methoxyphenyl isocyanate |
| 30. | 4- (trifluoromethyl) phenyl isocyanate |
| 31. | P-tolyl isocyanate |
| 32. | Benzoyl isocyanate |
| 33. | 1-naphthyl isocyanate |
| 34. | Isocyanato benzyl ester |
| 35. | 3, 5-bis (trifluoromethyl) phenyl isocyanate |
| 36. | 2, 5-difluorophenyl isocyanate |
| 37. | 2, 4, 5-trichlorophenyl isocyanate |
| 38. | 2, 4, 6-trichlorophenyl isocyanate |
| 39. | 2-isopropylphenyl isocyanate |
| 40. | 2, 3-dimethylphenyl isocyanate |
| 41. | 4-methoxy-2-methylphenyl isocyanate |
| 42. | 2, 4-dimethylphenyl isocyanate |
| 43. | 2, 5-dimethylphenyl isocyanate |
| 44. | 2-Ethyl-6-methylphenyl isocyanate |
| 45. | 3-Cyanophenyl isocyanate |
| 46. | 5-chloro-2, 4-dimethoxyphenyl isocyanate |
| 47. | 3-chloro-4-methylphenyl isocyanate |
| 48. | 3, 5-Dichlorophenyl isocyanate |
| 49. | Isocyanic acid 5-chloro-2-methoxyphenyl ester |
| 50. | 3, 4, 5-trimethoxyphenyl isocyanate |
| 51. | 3, 5-Dimethoxyphenyl isocyanate |
| 52. | 3- (methylthio) phenyl isocyanate |
| 53. | 3-Acetylphenyl isocyanate |
| 54. | 3, 4-dimethylphenyl isocyanate |
| 55. | Isocyanic acid 35-Dimethylphenyl ester |
| 56. | 2-methoxy-5-methylphenyl isocyanate |
| 57. | 3-Ethylphenyl isocyanate |
| 58. | 4-bromo-2- (trifluoromethyl) phenyl isocyanate |
| 59. | 4-chloro-2- (trifluoromethyl) phenyl isocyanate |
| 60. | 4-chloro-3- (trifluoromethyl) phenyl isocyanate |
| 61. | 4-iodophenyl isocyanate |
| 62. | 4-Phenoxyphenyl isocyanate |
| 63. | 4-ethoxyphenyl isocyanate |
| 64. | 4-Acetylphenyl isocyanate |
| 65. | 4-isopropylphenyl isocyanate |
| 66. | 4-Ethylphenyl isocyanate |
| 67. | 4-n-butylphenyl isocyanate |
| 68. | 2, 4, 6-trimethylphenyl isocyanate |
| 69. | 2-isopropyl-6-methylphenyl isocyanate |
| 70. | 2, 6-Diethylphenylisocyanate |
| 71. | 5-chloro-2-methylphenyl isocyanate |
| 72. | 4-chloro-2-methylphenyl isocyanate |
| 73. | 4- (trifluoromethoxy) phenyl isocyanate |
| 74. | 2-chloro-5- (trifluoromethyl) phenyl isocyanate |
| 75. | 2-chloro-6-methylphenyl isocyanate |
| 76. | 2, 4, 5-trimethylphenyl isocyanate |
| 77. | 3-chloro-2-methoxyphenyl isocyanate |
| 78. | 3-chloro-2-methylphenyl isocyanate |
| 79. | 3-chloro-4-fluorophenyl isocyanate |
| 80. | 4-bromo-2-methylphenyl isocyanate |
| 81. | 4-bromo-2, 6-dimethylphenyl isocyanate |
| 82. | 2, 6-dibromo-4-fluorophenyl isocyanate |
| 83. | 4-Butoxyphenyl isocyanate |
| 84. | 3-fluoro-4-methylphenyl isocyanate |
| 85. | 5-fluoro-2-methylphenyl isocyanate |
| 86. | 2-Biphenyl isocyanate |
| 87. | 4-Biphenyl isocyanate |
| 88. | 2-bromo-4, 6-difluorophenyl isocyanate |
| 89. | (r) - (+) -1-phenylethyl isocyanate |
| 90. | 1- (1-naphthyl) ethyl isocyanate |
| 91. | (s) - (+) -1- (1-naphthyl) ethyl isocyanate |
| 92. | 3, 4-difluorophenyl isocyanate |
| 93. | 2- (trifluoromethoxy) phenyl isocyanate |
| 94. | 4-Benzyloxyphenyl isocyanate |
| 95. | 4-bromo-2-chlorophenyl isocyanate |
| 96. | 4-bromo-2-fluorophenyl isocyanate |
| 97. | 2-fluoro-5-methylphenyl isocyanate |
| 98. | 2, 3, 4-Trifluorophenyl isocyanate |
| 99. | 2- (difluoromethoxy) phenyl isocyanate |
| 100. | 4- (difluoromethoxy) phenyl isocyanate |
| 101. | 2-methylbenzyl isocyanate |
| 102. | 2-chlorobenzyl isocyanate |
| 103. | 4-Fluorobenzyl isocyanate |
| 104. | Isocyanic acid 4-methoxybenzyl ester |
| 105. | 2, 6-difluorobenzoyl isocyanate |
| 106. | 4-fluorobenzoyl isocyanate |
| 107. | 2-fluoro-3- (trifluoromethyl) phenyl isocyanate |
| 108. | 2-fluoro-5- (trifluoromethyl) phenyl isocyanate |
| 109. | 2-fluoro-6- (trifluoromethyl) phenyl isocyanate |
| 110. | 4-fluoro-2- (trifluoromethyl) phenyl isocyanate |
| 111. | 2- (tert-butyl) phenyl isocyanate |
| 112. | 3-pyridyl isocyanate |
Accordingly, another object of the present invention is a library of two or more amino-2, 3-phthalazinone derivatives of formula (I)
Wherein
Ra and Rb are each independently a hydrogen atom or optionally further substituted group selected from: straight or branched C1-C6Alkyl radical, C3-C6Cycloalkyl or cycloalkyl C1-C6Alkyl, aryl C1-C6Alkyl, 5-to 7-membered heterocyclyl or heterocyclyl C having 1-3 heteroatoms selected from nitrogen, oxygen or sulfur1-C6An alkyl group; or one of Ra or Rb is hydrogen or optionally substituted straight or branched C1-C6Alkyl, the other is selected from-COR',-CONHR ', -COOR' or-SO2R 'wherein R' is hydrogen or an optionally substituted group selected from the above alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl or heterocyclylalkyl groups;
R1is of the formula-CHR4R5Group, wherein R4And R5Each independently hydrogen or optionally substituted C selected from linear or branched1-C6Alkyl radical, C3-C6Cycloalkyl or cycloalkyl C1-C6Alkyl, aryl C1-C6Alkyl, 5-to 7-membered heterocyclyl or heterocyclyl C having 1-3 heteroatoms selected from nitrogen, oxygen or sulfur1-C6A group of alkyl groups; or R1Is of the formula-NHR ', -NR ' COR ', -NR ' CONHR "or-NR ' SO2R ', wherein R' has a definition other than the above-mentioned hydrogen, R 'is hydrogen or has the above-mentioned definition for R';
R2is a hydrogen atom or optionally further substituted group selected from: straight or branched C1-C6Alkyl radical, C3-C6Cycloalkyl or cycloalkyl C1-C6Alkyl, aryl C1-C6Alkyl, 5-to 7-membered heterocyclyl or heterocyclyl C having 1-3 heteroatoms selected from nitrogen, oxygen or sulfur1-C6An alkyl group;
any R at one or more of the free positions 5, 6 and 8 on the 2, 3-naphthyridone ring3Each independently is a halogen atom, nitro, carboxyl, cyano or optionally further substituted group selected from: straight or branched C1-C6Alkyl radical, C3-C6Cycloalkyl or cycloalkyl C1-C6Alkyl, aryl C1-C6Alkyl, 5-to 7-membered heterocyclyl or heterocyclyl C having 1-3 heteroatoms selected from nitrogen, oxygen or sulfur1-C6An alkyl group; or R3Is selected from-COR ', -CONHR', -SO2R ', -NR' COR ', -NR' CONHR 'or-NR' SO2R ' wherein R ' and R ' are the same or different, are hydrogen or the above-mentioned groups; m is 0 or an integer of 1 to 3;
or a pharmaceutically acceptable salt thereof.
As mentioned above, it is clear to the skilled person that once a library of amino-2, 3-naphthyridinone derivatives consisting of several thousand compounds of formula (I) has been prepared, said library is very advantageous for screening against a given target kinase as described above.
For general references to libraries of compounds and their use as screens for biological activity see, j.med.chem.1999, 42, 2373-; and bioorg.med.chem.lett.10(2000), 223- > 226.
Pharmacology of
The compounds of formula (I) have activity as protein kinase inhibitors and are therefore useful, for example, for limiting the unregulated proliferation of tumor cells.
In therapy, these compounds may be used in the treatment of various tumours, such as for example carcinomas, e.g. breast cancer, lung cancer, bladder cancer, colon cancer, ovarian cancer, endometrial cancer, sarcomas, e.g. soft tissue sarcomas and osteosarcomas, and haematological malignancies, such as e.g. leukaemia.
In addition, the compounds of formula (I) are also useful in the treatment of other cell proliferative disorders, such as psoriasis, vascular smooth cell proliferation associated with atherosclerosis, and post-operative stenosis and restenosis, for the treatment of Alzheimer's disease.
The putative protein kinase inhibitory activity and potency of the selected compounds were determined by an assay based on the use of MultiScreen-PH 96-well plates (Millipore) in which a phosphofiber filter paper was placed at the bottom of each well and the positively charged substrate was allowed to bind after the washing/filtration step.
When the serine/threonine kinase transfers the radiolabeled phosphate moiety to the filter-bound histone, the emitted light is measured on a scintillation counter.
Inhibition assay for cdk 2/cyclin A Activity
Kinase reaction: to each well of a 96U bottom well plate was added a final volume of 100. mu.l buffer (TRIS HCl 10mM pH7.5, MgCl)210mM, 7.5mM DTT) 1.5. mu.M histone H1 substrate, 25. mu.M ATP (0.2. mu. CiP)33γ -ATP), 30ng of baculovirus co-expressed cdk 2/cyclin a, 10 μ M inhibitor. After incubation at 37 ℃ for 10 minutes, the reaction was stopped with 20. mu.l of 120mM EDTA.
Capturing: 100 microliters were transferred from each well to a MultiScreen plate and the substrate was bound to the phosphocellulose filter paper. Then using a catalyst without Ca++/Mg++The plate was washed 3 times with 150 μ l/well PBS and filtered through a MultiScreen filtration system.
And (3) detection: the filter paper was allowed to dry at 37 ℃ and then 100. mu.l/well of scintillator was added and detected by radioactive counting in a Top-Count instrument33P-labeled histone H1.
And (4) conclusion: data were analyzed with reference to total enzyme activity (═ 100%) and expressed as% inhibition.
To study and determine the potency (IC50) and kinetic profile of the inhibitor calculated by Ki, all compounds exhibiting > 50% inhibition were further analyzed.
IC50 determination: the method used was the same as above, with inhibitors analyzed at different concentrations ranging from 0.0045 to 10 μ M. The experimental data were analyzed by the computer program GraphPad Prizm using the four parametric logarithm equations:
lower base + (upper base-lower base)/(1 +10^ ((logIC50-x) × slope))
Wherein x is the logarithm of the inhibitor concentration and y is the response value; y starts from the lower bottom and progresses in an S-shape towards the upper bottom.
Ki meterCalculating out: varying concentrations of ATP and histone H1: ATP was 4, 8, 12, 24, 48. mu.M (containing proportionally diluted P)33γ -ATP), histone is 0.4, 0.8, 1.2, 2.4, 4.8 μ M, which are used in the absence and presence of two different, suitably selected inhibitor concentrations.
For Ki determination, experimental data were analyzed by the computer program "SigmaPlot" using the random double reaction system equation:
wherein a ═ ATP and B ═ histone H1.
In addition, selected compounds were characterized for a panel of serine/threonine kinases that are strictly cell cycle related (cdk 2/cyclin E, cdk 1/cyclin B1, cdk 4/cyclin D1) and for specificity for MAPK, PKA, EGFR, IGF1-R, Cdc7/dbf4 and aurora-2.
Inhibition assay for cdk 2/cyclin E activity
Kinase reaction: to each well of a 96U bottom well plate was added a final volume of 100. mu.l buffer (TRIS HCl 10mM pH7.5, MgCl)210mM, 7.5mM DTT +0.2mg/ml BSA) 1.5. mu.M histone H1(Sigma # H-5505) substrate, 25. mu.M ATP (0.2. mu.CiP)33gamma-ATP), 15ng baculovirus co-expressionCdk 2/cyclin E, inhibitor at appropriate concentration. After incubation at 37 ℃ for 10 minutes, the reaction was stopped with 20. mu.l of 120mM EDTA.
Capturing: 100 microliters were transferred from each well to a MultiScreen plate and the substrate was bound to the phosphocellulose filter paper. Then using a catalyst without Ca++/Mg++The plate was washed 3 times with 150 μ l/well PBS and filtered through a MultiScreen filtration system.
And (3) detection: the filter paper was allowed to dry at 37 ℃ and then 100. mu.l/well of scintillator was added and detected by radioactive counting in a Top-Count instrument33P-labeled histone H1.
Inhibition assay for cdk 1/cyclin B1 Activity
Kinase reaction: to each well of a 96U bottom well plate was added a final volume of 100. mu.l buffer (TRIS HCl 10mM pH7.5, MgCl)210mM, 7.5mM DTT +0.2mg/ml BSA) 1.5. mu.M histone H1(Sigma # H-5505) substrate, 25. mu.M ATP (0.2. mu.CiP)33γ -ATP), 30ng of baculovirus co-expressed cdk 2/cyclin B1, appropriate concentration of inhibitor. After incubation at 37 ℃ for 10 minutes, the reaction was stopped with 20. mu.l of 120mM EDTA.
Capturing: 100 microliters were transferred from each well to a MultiScreen plate and the substrate was bound to the phosphocellulose filter paper. Then using a catalyst without Ca++/Mg++The plate was washed 3 times with 150 μ l/well PBS and filtered through a MultiScreen filtration system.
And (3) detection: the filter paper was allowed to dry at 37 ℃ and then 100. mu.l/well of scintillator was added and detected by radioactive counting in a Top-Count instrument33P-labeled histone H1.
Inhibition assay for cdk 4/cyclin D1 Activity
Kinase reaction: to each well of a 96U bottom well plate was added a final volume of 50. mu.l buffer (TRIS HCl 10mM pH7.5, MgCl)2 10mM，7.5mM DTT+0.4. mu.M mouse GST-Rb (769- & 921) (# sc-4112, from Santa Cruz) substrate, 10. mu.M ATP (0.5. mu. CiP) in 0.2mg/ml BSA)33γ -ATP), 100ng of baculovirus-expressed GST-cdk 4/GST-cyclin D1, appropriate concentrations of inhibitors. After incubation at 37 ℃ for 40 minutes, the reaction was stopped with 20. mu.l of 120mM EDTA.
Capturing: 60 microliters from each well was transferred to a MultiScreen plate and the substrate was bound to the phosphocellulose filter paper. Then using a catalyst without Ca++/Mg++The plate was washed 3 times with 150 μ l/well PBS and filtered through a MultiScreen filtration system.
And (3) detection: the filter paper was allowed to dry at 37 ℃ and then 100. mu.l/well of scintillator was added and detected by radioactive counting in a Top-Count instrument33P-labeled Rb fragment.
Inhibition assay for MAPK activity
Kinase reaction: to each well of a 96U bottom well plate was added a final volume of 100. mu.l buffer (TRIS HCl 10mM pH7.5, MgCl)210 μ M MBP (Sigma # M-1891), 25 μ M ATP (0.2 μ CiP) in 10mM, 7.5mM DTT +0.1mg/ml BSA)33γ -ATP), 25ng of GST-MAPK expressed by the bacteria (Upstate Biotechnology #14-173), appropriate concentrations of inhibitors. After incubation at 37 ℃ for 15 minutes, the reaction was stopped with 20. mu.l of 120mM EDTA.
Capturing: 100 microliters were transferred from each well to a MultiScreen plate and the substrate was bound to the phosphocellulose filter paper. Then using a catalyst without Ca++/Mg++The plate was washed 3 times with 150 μ l/well PBS and filtered through a MultiScreen filtration system.
And (3) detection: the filter paper was allowed to dry at 37 ℃ and then 100. mu.l/well of scintillator was added and detected by radioactive counting in a Top-Count instrument33P marks MBP.
Inhibition assay for PKA activity
Kinase reaction: adding to each well of a 96U bottom well plateThe final volume is 100. mu.l buffer (TRIS HCl 10mM pH7.5, MgCl)210 μ M Histone H1(Sigma # H-5505) substrate, 10 μ M ATP (0.2 μ CiP) in 10mM, 7.5mM DTT +0.2mg/ml BSA)33γ -ATP), 1U bovine heart PKA (Sigma #2645), appropriate concentrations of inhibitors. After 5 minutes incubation at 37 ℃ the reaction was stopped with 20. mu.l 120mM EDTA.
Capturing: 100 microliters were transferred from each well to a MultiScreen plate and the substrate was bound to the phosphocellulose filter paper. Then using a catalyst without Ca++/Mg++The plate was washed 3 times with 150 μ l/well PBS and filtered through a MultiScreen filtration system.
And (3) detection: the filter paper was allowed to dry at 37 ℃ and then 100. mu.l/well of scintillator was added and detected by radioactive counting in a Top-Count instrument33P-labeled histone H1.
Inhibition assay for EGFR Activity
Kinase reaction: to each well of a 96U bottom plate was added a final volume of 100. mu.l buffer (Hepes 50mM pH7.5, MnCl)2-MgCl2 3mM，1mM DTT+3μM NaVO30.1mg/ml BSA) 25nM home-made (in house) biotinylated PolyGluTyr (Sigma #0275) substrate, 2.5. mu.M ATP (0.3. mu. CiP)33gamma-ATP), 80ng of baculovirus-expressed GST-EGFR, appropriate concentration of inhibitor. After 5 minutes incubation at 37 ℃ the reaction was stopped with 20. mu.l 120mM EDTA.
Capturing: 100 microliters were transferred from each well to streptavidin-Flashplate and biotinylated substrate was bound to the plate. Then using a catalyst without Ca++/Mg++The plate was washed 3 times with 150 μ l/well PBS.
And (3) detection: radioactivity was counted in a Top-Count instrument.
Inhibition assay for IGF1-R Activity
Inhibition assay of IGF1-R activity was performed according to the following method.
Kinase reaction: to each well of a 96U bottom plate was added a final volume of 30. mu.l buffer (50mM Hepes pH7.9, 3mM MnCl)2，1mM DTT，3μM NaVO3) 10 μ M biotinylated MBP (Sigma cat. # M-1891) substrate, 0-20 μ M inhibitor, 6 μ M cold ATP, 2nM33P-labeled ATP, and 22.5ng IGF1-R (preincubated with cold 60 μ MATP for 30 minutes at room temperature). After incubation for 35 minutes at room temperature, the reaction was stopped by adding 100 microliters of PBS buffer containing 32mM EDTA, 500. mu.M cold ATP, 0.1% Triton X100, and 10mg/ml streptavidin-coated SPA beads. After 15 min incubation, 110. mu.l of the suspension was withdrawn and transferred to 96-well optiplatates containing 100. mu.l of 5M CsCl. After 4 hours, the plate was read for 2 minutes on a Packard TOP-Count radioactive reader.
And (4) conclusion: experimental data were analyzed using GraphPad Prizm program.
In addition, the putative protein kinase inhibitory activity and potency of selected compounds were also determined by assay methods based on the use of SPA (scintillation proximity assay) 96 well plate assays. The assay is based on the ability of streptavidin-coated SPA beads to capture biotinylated peptides derived from the phosphorylation sites of histones.
When the serine/threonine kinase transfers the radiolabeled phosphate moiety to the biotinylated histone peptide, the emitted light is measured on a scintillation counter.
Inhibition assay for cdk5/p25 Activity
Inhibition assays for cdk5/p25 activity were performed according to the following methods.
Kinase reaction: to each well of a 96U bottom well plate was added a final volume of 100. mu.l buffer (Hepes 20mM pH7.5, MgCl)215mM, 1mM DTT), 0.25uCi P33g-ATP, 4nM cdk5/P25 complex, 0-100. mu.M inhibitor. After incubation at 37 ℃ for 20 min, the cells were incubated by adding phosphate buffer containing 0.1% TritonX100, 50. mu.M ATP and 5mM EDTAThe reaction was stopped with 500. mu.g of SPA beads in water. The beads were allowed to settle and assayed on a TOP-Count scintillation reader33P-labelling the radioactivity in the peptide.
And (4) conclusion: data were analyzed using the following formula and expressed as% inhibition:
100X (1- (unknown-BKgd)/(control enzyme-BKgd))
IC50 values were calculated using the difference of the four parameter log equations:
y is 100/(1+10^ ((logEC50-x) ×) slope)
Wherein X ═ log (μ M) and Y ═ inhibition.
Cdc7/dbf4 activity inhibition assay
Inhibition assay of Cdc7/dbf4 activity was performed according to the following method.
At gamma33The biotin-MCM 2 substrate was reverse-phosphorylated with the Cdc7/Dbf4 complex in the presence of ATP labelled ATP. The phosphorylated biotin-MCM 2 substrate was then captured with streptavidin-coated SPA beads and the degree of phosphorylation was assessed by beta counting.
Inhibition assays for Cdc7/dbf4 activity were performed in 96-well plates according to the following method.
To each well of the plate was added:
10 microliter substrate (biotinylated MCM2, 6. mu.M final concentration)
10 microliter of enzyme (Cdc7/Dbf4, 12.5nM final concentration)
10 microliter of test compound (12 increasing concentrations in the nM to. mu.M range produce a dose-response curve)
10 microliters of a mixture of cold ATP (10. mu.M final concentration) and radioactive ATP (1/2500 molar ratio to cold ATP),
and then used to start the reaction taking place at 37 ℃.
In the presence of 15mM MgCl2，2mM DTT，3μM NaVO3Substrate, enzyme and ATP were diluted in 50mM HEPES pH7.9 with 2mM glycerophosphate and 0.2mg/ml BSA. The solvent used for the test compounds also contained 10% DMSO.
After 20 minutes of incubation, the reaction was stopped by adding 100 microliters of PBS pH7.4 containing 50mM EDTA, 1mM cold ATP, 0.1% Triton X100 and 10mg/ml streptavidin-coated SPA beads to each well.
Incubation at room temperature after 15 minutes of biotinylated MCM 2-streptavidin SPA bead interaction, a Packard Cell Harvester (Filtermate) was used in 96-well filter plates (Unifilter)RGF/BTM) The beads were captured, washed with distilled water and read with TopCount (packard).
Analytical experimental data (triplicate for each spot) were determined for IC50 using nonlinear regression analysis after subtracting the blank background from the readings (Sigma Plot).
Inhibition assay for aurora-2 Activity
The inhibitory activity and potency of selected compounds were determined by an assay based on the use of streptavidin scintillation proximity assay beads (amersham pharmacia biotech) performed on 96-well plates. At the end of the reaction, the biotinylated peptide substrate was captured with a bead followed by CsCl2Layering it.
When the kinase transfers the radiolabeled phosphate moiety to the peptide bound to the beads, the emitted light is measured on a scintillation counter.
Inhibition assay of aurora-2 activity was performed in 96-well plates according to the following method.
Kinase reaction: to each well of a 96U bottom well plate was added a final volume of 60. mu.l buffer (Hepes 50mM pH7.0, MgCl)28 μ M biotinylated peptide (four replicates LRRWSSG), 10 μ M ATP (0.5 uCiP) in 10mM, 1mM DTT, 0.125mg/ml BSA, 3 μ M orthovanadate33g-ATP), 10nM Aurora2, 10 μ M inhibinAnd (4) preparing the preparation. After incubation for 30 minutes at room temperature, the reaction was terminated and the biotinylated peptide was captured by adding 100 microliters of bead suspension.
Layering: 100 microliter CsCl27.5M was added to each well and left for 1 hour before radioactivity was measured on a TOP-Count scintillation reader.
And (4) conclusion: data were analyzed with reference to total enzyme activity (═ 100%) and expressed as% inhibition.
To investigate the efficacy of the inhibitors calculated by IC50, all compounds showing an inhibition of > 60% were further analyzed.
The method used was the same as above except that a dilution series of the inhibitor was used. The experimental data was processed by non-linear regression using the following equation:
wherein v isbIs the reference velocity, v is the observed reaction velocity, v is the0Is the velocity in the absence of inhibitor, and]is the inhibitor concentration.
The compounds of formula (I) of the present invention, suitable for administration to a mammal, such as a human, can be administered by conventional routes and dosage levels, depending on the age, weight, condition and route of administration of the patient.
For example, a suitable dose of a compound of formula (I) for oral administration may range from about 10 to about 500mg per dose, 1 to 5 times per day.
The compounds of the invention may be administered in a variety of dosage forms, for example orally in the form of tablets, capsules, sugar or film coated tablets, solutions or suspensions; rectal administration in the form of suppositories; parenteral administration, for example intramuscular administration, or by intravenous and/or intrathecal and/or intraspinal injection or infusion.
In addition, the compounds of the present invention may be administered as a single agent or, alternatively, in combination with known anti-cancer treatments, such as radiation therapy or chemotherapy administered in combination with: cytostatic or cytotoxic agents, antibiotic-type agents, alkylating agents, antimetabolite agents, hormonal agents, immunological agents, interferon-type agents, cyclooxygenase inhibitors (e.g., COX-2 inhibitors), metallomatrix protease inhibitors, telomerase inhibitors, tyrosine kinase inhibitors, anti-growth factor receptor agents, anti-HER agents, anti-EGFR agents, anti-angiogenic agents, farnesyl transferase inhibitors, rasraf signal transduction pathway inhibitors, cell cycle inhibitors, other cdks inhibitors, tubulin binding agents, topoisomerase I inhibitors, topoisomerase II inhibitors, and the like.
By way of example, the compounds of the invention may be administered in combination with one or more chemotherapeutic agents, such as, for example, exemestane, formestane, anastrozole, letrozole, fadrozole, taxane (taxane), taxane derivatives, encapsulated taxane, CPT-11, camptothecin derivatives, anthracyclines, for example, doxorubicin, idarubicin, epirubicin, etoposide, navelbine, vinblastine, carboplatin, cisplatin, estramustine, celecoxib, tamoxifen, raloxifene, Sugen SU-5416, Sugen SU6668, monoclonal antibodies (Herceptin), and the like, optionally in liposomal form.
If formulated in fixed doses, such combination products employ the compounds of the present invention within the dosage ranges described above and the other pharmaceutically active agents within approved dosage ranges.
When the combination formulation is inappropriate, the compound of formula (I) may be used sequentially with known anticancer drugs.
The invention also includes pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, which may be a carrier or diluent.
Pharmaceutical compositions containing the compounds of the present invention are generally prepared according to conventional methods and administered in pharmaceutically suitable dosage forms.
For example, solid oral dosage forms may contain the active compound in a pharmaceutical formulation, and, optionally, a diluent, such as lactose, glucose, sucrose, saccharose, cellulose, corn starch or potato starch; lubricants, for example silicon dioxide, talc, magnesium or calcium stearate, and/or polyethylene glycol; binding agents, for example starches, gum arabic, gelatin, methylcellulose, carboxymethylcellulose or polyvinylpyrrolidone; disintegrating agents, such as starch, alginic acid, alginates or sodium starch glycolate; an effervescent mixture; a dye; a sweetener; wetting agents such as lecithin, polysorbates, lauryl sulfate; and, in general, no toxic and no pharmaceutically active substances. The pharmaceutical formulations may be prepared in a known manner, for example, by mixing, granulating, tableting, sugar-coating, or film-coating processes.
Liquid dispersions for oral administration may be, for example, syrups, emulsions and suspensions.
The syrup may contain as carriers, for example, sucrose or sucrose and glycerol and/or mannitol and/or sorbitol.
Suspensions and emulsions may contain as carrier, for example, a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl alcohol.
Suspensions or solutions for intramuscular injections may contain the active compound in association with a pharmaceutically acceptable carrier, for example sterile water, olive oil, ethyl oleate, glycols, for example propylene glycol, and, if desired, the appropriate amount of lidocaine hydrochloride. Solutions for intravenous injection or infusion may contain as carrier, for example, sterile water, or preferably, they may be sterile, aqueous, isotonic saline solutions, or they may contain as carrier propylene glycol.
Suppositories may contain the active compound and a pharmaceutically acceptable carrier, for example coconut oil, polyethylene glycol, polyoxyethylene sorbitan fatty ester surfactant or lecithin.
The following examples illustrate the invention in detail, but do not limit it.
General procedure
Flash chromatography was performed on silica gel (Merck grade 9385, 60 angstroms). HPLC/MS was performed on a Waters X TerrarP 18 (4.6X 50mm, 3.5 μm) column using a Waters 2790 HPLC system equipped with a 996Waters PDA detector and a Micromass mode ZQ single quadrupole mass spectrometer equipped with an Electrospray (ESI) ion source. Mobile phase A was ammonium acetate 5mM buffer (pH5.5, acetic acid/acetonitrile 95: 5) and mobile phase B was H2O/acetonitrile (5: 95). The gradient was 10 to 90% B within 8 min, holding 90% B for 2 min. Detection was performed at 220nm and 254 nm. Flow rate 1 ml/min. The injection volume was 10 microliters. Full scan, mass range 100 to 800 amu. The capillary voltage was 2.5 KV; the source temperature was 120 ℃; the cone is 10V. Retention times in minutes at 220nm or 254nm are given (HPLC r.t.). The mass is given in m/z ratio.
When required, compounds were purified by preparative HPLC using a Waters preparative HPLC600 equipped with a 996Waters PDA detector on a Waters Symmetry C18(19 x 50mm, 5um) column, Micromass mode ZMD single quadrupole mass spectrometer, electrospray ionization, positive mode. Mobile phase a was water 0.01% TFA and mobile phase B was acetonitrile. The gradient was 10 to 90% B within 8 min, holding 90% B for 2 min. The flow rate was 20 ml/min.
At 400.45 MHz on Mercury VX 400 equipped with a 5mm dual resonance probe (1H {15N-31P) ID-PFG Varian)To carry out1H-NMR spectroscopic analysis.
Example 1
6-Nitro-3-bromo-3H-isobenzofuran-1-one (II)
To 125 ml of 6-nitro-2-benzo [ c ]]A solution of furanone (8.0 g, 0.047 mol) in dichloromethane was added bromine (8.25 g, 0.052 mol, 1.15 equivalents) and hydrogen peroxide (5.07 g of a 35% aqueous solution, 1.77 equivalents of hydrogen peroxide, 0.052 mol, 1,15 equivalents). The mixture was gently refluxed for 11 hours, then cooled and concentrated by evaporation of the solvent. The aqueous layer was separated, the organic phase washed with water and then dried (Na)2SO4)。
After evaporation of the solvent, the crude residue was purified by flash chromatography over silica gel (hexane-ethyl acetate 8-2 to 7-3). 8.18g of the title compound are obtained. [ M-1 ]]-＝257；HPLC r.t.5.37；1H-NMR(CDCl3) Characteristic signal (ppm): 7.47(s, 1H), 7.86(d, 1H), 8.67(dd, 1H), 8.74(d, 1H).
Example 2
(5-amino-3-oxo-1, 3-dihydro-isobenzofuran-1-yl) -triphenylphosphonium bromide
(III)
A solution of 6-nitro-3-bromo-3H-isobenzofuran-1-one (8.7 g, 0.034 mol) in ethyl propionate (464 ml) was heated to 70-75 deg.C and 313 ml of an ethyl propionate solution of triphenylphosphine (36 g, 0.137 mol, 4 eq) was added dropwise with stirring over 7 hours. Heat and stir overnight, then cool the mixture to room temperature. The precipitate was collected, dried in vacuo and purified by flash chromatography on silica gel. A gradient from 97-3-0 to 93-5-2 dichloromethane-methanol-acetic acid was used as eluent to give 6.2 g of the title compound. [ M ] A]+＝410；HPLC r.t.4.72；1H-NMR(DMSO-d6) Characteristic signal (ppm): 6.01(br.s, 2H, interchangeable with heavy water), 6.49(dd, 1H), 6.80(d,1H)，6.87(d，1H)，7.62-8.00(m，15H)，8.17(s，1H)。
example 3
(5- { 2-methoxy-4- [3- (4-resinbenzylcarbamoyl) -propoxy [ ] -propyl ] -amide]-benzyl radical
Amino } -3-oxo-1, 3-dihydro-isobenzofuran-1-yl) triphenyl-phosphonium bromide
The compound of example 2 (252 mg, 0.514 mmol) was dissolved in 15.25 ml of a solvent mixture made up of dichloromethane (13.5 ml), trifluoroethanol (1.5 ml) and acetic acid (0.25 ml). Novabiochem4- (4-formyl-3-methoxyphenoxy) butyrylaminomethylation resin (326 mg, nominal substitution 0.94 mmol/g, 0.6 eq.) was poured into the solution, the resulting suspension was gently stirred for 9 hours, and then pyridine-borane complex (250. mu.l, about 6 mmol, 10 eq.) was added dropwise. After 40 hours the resin was filtered, washed with dichloromethane, methanol and then dichloromethane and dried in vacuo (518 mg calculated fill: 0.78 mmol/g; IR: 1787 cm)-1Lactone developing band).
Example 4
4- [3- (methoxy-4- ({ 3-oxo-1- [ 1-pyridin-3-yl-methano-l)]-1, 3-dihydro
-isobenzofuran-5-ylamino } -methyl) -phenoxy) -N- (4-resin-benzyl) -butyramide
(5- { 2-methoxy-4- [3- (4-resinBenzylcarbamoyl) -propoxy ] of example 3]-benzylamino } -3-oxo-1, 3-dihydro-isobenzofuran-1-yl) triphenyl-phosphonium bromide (100 mg, 0.078 meq) suspended in dry dichloromethane (3 ml); pyridine-3-carbaldehyde (50 μ l, ca. 6 eq) was added followed by TEA (50 μ l). After stirring at room temperature for 20 hours, the resin was filtered off and washed with dichloromethane, methanol and then dichloromethane, and then dried under vacuum (IR: 1776 cm)-1)。
Example 5
N- { 2-methoxy-4- [3- (4-resinbenzylcarbamoyl) -propoxy [ ]]-benzyl
-1- [ 1-pyridin-3-yl-3-ylmethylene-3-oxo-3-yl } -N-methyl-)]-1, 3-dihydro-isobenzofuran-5-
Phenyl-benzamide
4- [3- (methoxy-4- ({ 3-oxo-1- [ 1-pyridin-3-yl-Methylidene) example 4]-1, 3-dihydro-isobenzofuran-5-ylamino } -methyl) -phenoxy) -N- (4-resin-benzyl) -butyramide in anhydrous dichloromethane (3 ml); diisopropylethylamine (200. mu.l) and benzoyl chloride (100. mu.l, ca. 10 equivalents) were added sequentially. After stirring at room temperature for 20 hours, the resin was filtered off and washed with dichloromethane, methanol and dichloromethane, and then dried in vacuo (IR: 1786 cm)-1)。
Example 6
4- [3- (methoxy-4- (1- { 3-oxo-1- [ 1-pyridin-3-yl-methano-l)]-1, 3-bis
Hydro-isobenzofuran-5-yl } -3-p-tolyl-adenoylmethyl) phenoxy]-N- (4-resin-
Benzyl) -butyramide
4- [3- (methoxy-4- ({ 3-oxo-1- [ 1-pyridin-3-yl-methylene ] -1, 3-dihydro-isobenzofuran-5-ylamino } -methyl) -phenoxy) -N- (4-resinbenzyl) -butyramide of example 4 was suspended in dry dichloromethane (3 ml); and p-toluyl isocyanate (100. mu.l, about 10 equivalents) was added. After stirring at room temperature for 20 hours the resin was filtered off and washed with dichloromethane, methanol and then dichloromethane, and then dried in vacuo.
Example 7
N- { 2-methoxy-4- [3- (4-resinbenzylcarbamoyl) -propoxy [ ]]-benzyl
-1-pyridin-3-ylmethyl-4-oxo-3-methyl-3,4-dihydro-2, 3-diazanaphthalene-6-
Phenyl) -benzamides
N- { 2-methoxy-4- [3- (4-resin-benzylcarbamoyl) -propoxy ] -benzyl } -N- { 3-oxo-1- [ 1-pyridin-3-yl-methylene ] -1, 3-dihydro-isobenzofuran-5-yl } -benzamide of example 5 was suspended in dimethylformamide (3 ml) and aqueous hydrazine solution (approximately 25% solution) (400 μ l, approximately 40 eq) was added. After stirring at room temperature for 20 hours the resin was filtered off and washed with dimethylformamide, methanol and dichloromethane and then dried in vacuo (IR: disappearance of the lactone developing band).
Example 8
4- { 3-methoxy-4- [1- (4-oxo-1-pyridin-3-ylmethyl-3, 4-dihydro-2, 3-
Triazanaphthalenone-6-yl) -3-p-tolyl-ureidomethyl]-phenoxy } -N- (4-resin)
Benzyl) -butyramide
4- [3- (methoxy-4- (1- { 3-oxo-1- [ 1-pyridin-3-yl-methylene ] -1, 3-dihydro-isobenzofuran-5-yl } -3-p-tolyl-ureidomethyl) -phenoxy) -N- (4-resin-benzyl) -butyramide of example 6 was suspended in dimethylformamide (3 ml) and aqueous hydrazine solution (ca 25% solution) (400. mu.l, ca 40 eq) was added. After stirring at room temperature for 20 hours the resin was filtered off and washed with dimethylformamide, methanol and dichloromethane, then dried in vacuo.
Example 9
N- (4-oxo-1-pyridin-3-ylmethyl-3, 4-dihydro-2, 3-phthalazinone-6-yl)
-benzamides
N- { 2-methoxy-4- [3- (4-resin-benzylcarbamoyl) -propoxy ] group of example 7]-benzyl } -N- (4-oxo-1-pyridin-3-ylmethyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) -benzamide was suspended in 20% TFA in DCM (3 ml) and stirred at room temperature for 2 hours.The resin was filtered off and the solution was collected and dried to yield 15 mg of the title compound. [ M +1 ]]+＝357；HPLC r.t.4.02；1H-NMR (DMSO-d6), characteristic signal (ppm): 4.39(s, 2H), 7.47-7.62(m, 3H), 7.93-8.05(m, 3H), 8.26(dd, 1H), 8.54(m, 1H), 8.65(br.S, 1H), 8.76(d, 1H), 10.73(s, 1H, interchangeable with water), 12.45(s, 1H, interchangeable with water).
Example 10
1- (4-oxo-1-pyridin-3-ylmethyl-3, 4-dihydro-2, 3-phthalazinone-6-yl)
-3-p-tolyl-urea
Example 8 4- { 3-methoxy-4- [1- (4-oxo-1-pyridin-3-ylmethyl-3, 4-dihydro-2, 3-phthalazin-6-yl) -3-p-tolyl-ureidomethyl]-phenoxy } -N- (4-resin-benzyl) -butyramide was suspended in 20% TFA in DCM (3 ml) and stirred at room temperature for 2 hours. The resin was filtered off and the solution was collected and dried to yield 11 mg of the title compound. [ M +1 ]]+＝386；HPLC r.t.4.72；1H-NMR (DMSO-d6), characteristic signal (ppm): 2.23(s, 3H), 4.26(s, 2H), 7.10(d, 2H), 7.29(m, 1H), 7.33(d, 2H), 7.64(m, 1H), 7.83(dd, 1H), 7.89(d, 1H), 8.40(m, 2H), 8.56(d, 1H), 8.70(br.S, 1H), 9.22(br.s, 1H), 12.38(br.s, 1H).
By similar procedure and by reacting a compound of formula (III) with a suitable aldehyde of formula (V) and then with a suitable acid chloride derivative of formula (VIII) or an isocyanate of formula (IX), the following compounds are prepared:
7-amino-4- (4-chloro-benzyl) -2H-2, 3-naphthyridin-1-one
[M+1]+＝286；HPLC r.t.4.62；1H-NMR (DMSO-d6), characteristic signal (ppm): 4.11(s, 2H), 6.97(dd, 1H), 7.24-7.32(m, 5H), 7.56(d, 1H), 12.05(s, 1H, interchangeable with heavy water).
7-amino-4- (4-methoxy-benzyl) -2H-2, 3-naphthyridin-1-one
[M+1]+＝282；HPLC r.t.3.83；1H-NMR (DMSO-d6), characteristic signal (ppm): 3.68(s, 3H)4.04(s, 2H), 6.10(s, 2H, interchangeable with heavy water), 6.82(d, 2H), 6.97(dd, 1H), 7.17(d, 2H), 7.23(d, 1H), 7.57(d, 1H).
7-amino-4- (4-nitro-benzyl) -2H-2, 3-naphthyridin-1-one
[M+1]+＝297；1H-NMR (DMSO-d6), characteristic signal (ppm): 4.29(s, 2H), 6.18(s, 2H, interchangeable with heavy water), 7.00(dd, 1H), 7.26(d, 1H), 7.57(m, 3H), 8.14(d, 2H).
N- (4-oxo-1-pyridin-3-ylmethyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) -propionamide;
[M+H]+＝309；HPLC r.t.2.88。
n- (4-oxo-1-pyridin-3-ylmethyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) -4-trifluoromethyl-benzamide;
[M+H]+＝425；HPLC r.t.5.1。
furan-2-carboxylic acid (4-oxo-1-pyridin-3-ylmethyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) -amide; [ M + H ]]+＝346；HPLC r.t.3.37。
N- (4-oxo-1-pyridin-3-ylmethyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) -3-cyclopentyl-propionamide; [ M + H ]]+＝377；HPLC r.t.4.99。
2-propyl-pentanoic acid (4-oxo-1-pyridin-3-ylmethyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) -amide; [ M + H ]]+＝379；HPLC r.t.5.09。
1- (4-oxo-1-pyridin-3-ylmethyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) -3- (3-trifluoromethyl-phenyl) -urea; [ M + H ]]+＝440；HPLC r.t.5.29。
1- (3-methoxy-phenyl) -3- (4-oxo-1-pyridin-3-ylMethyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) -urea; [ M + H ]]+＝402；HPLC r.t.4.33。
1- (4-oxo-1-pyridin-3-ylmethyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) -3-p-tolyl-urea; [ M + H ]]+＝386；HPLC r.t.4.62。
1- (2, 4-difluoro-phenyl) -3- (4-oxo-1-pyridin-3-ylmethyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) -urea; [ M + H ]]+＝408；HPLC r.t.4.58。
1- (3, 4-dichloro-phenyl) -3- (4-oxo-1-pyridin-3-ylmethyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) -urea [ M + H]+＝440；HPLC r.t.5.59。
N- [1- (4-chloro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl]-propionamide; [ M + H ]]+＝342；HPLC r.t.5.18。
N- [1- (4-chloro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl]-4-trifluoromethyl-benzamide; [ M + H ]]+＝458；HPLC r.t.7.13。
Furan-2-carboxylic acid [1- (4-chloro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ester]-an amide; [ M + H ]]+＝380；HPLC r.t.5.66。
N- [1- (4-chloro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl]-3-cyclopentyl-propionamide; [ M + H ]]+＝410；HPLC r.t.7.22。
2-propyl-pentanoic acid [1- (4-chloro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl]-an amide; [ M + H ]]+＝412；HPLC r.t.7.33。
1- [1- (4-chloro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl]-3- (3-trifluoromethyl-phenyl) -urea; [ M + H ]]+＝473；HPLC r.t.7.26。
1- [1- (4-chloro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl]-3- (3-methoxy-phenyl) -urea; [ M + H ]]+＝435；HPLC r.t.6.43。
1- [1- (4-chloro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl]-3-p-tolyl-urea; [ M + H ]]+＝419；HPLC r.t.6.74。
1- [1- (4-chloro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl]-3- (2, 4-difluoro-phenyl) -urea; [ M + H ]]+＝441；HPLC r.t.6.71。
N- [1- (4-cyano-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl]-propionamide; [ M + H ]]+＝333；HPLC r.t.4.26。
N- [1- (4-cyano-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl]-4-trifluoromethyl-benzamide; [ M + H ]]+＝449；HPLC r.t.6.3。
Furan-2-carboxylic acid [1- (4-cyano-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl]-an amide; [ M + H ]]+＝371；HPLC r.t.4.72。
N- [1- (4-cyano-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl]-3-cyclopentyl-propionamide; [ M + H ]]+＝401；HPLC r.t.6.3。
2-propyl-pentanoic acid [1- (4-cyano-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl]-an amide; [ M + H ]]+＝403；HPLC r.t.6.42。
1- [1- (4-cyano-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl]-3- (3-trifluoromethyl-phenyl) -urea; [ M + H ]]+＝464；HPLC r.t.6.46；1H-NMR (DMSO-d6), characteristic signal (ppm): 4.34(s, 2H), 7.34(d, 1H), 7.47-7.55(m, 3H), 7.59(d, 1H), 7.73(d, 2H), 7.80-7-88(m, 2H), 8.00(s, 1H), 8.43(d, 1H), 9.20(s, 1H), 9.40(s, 1H), 12.44(br.s, 1H).
1- [1- (4-cyano-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl]-3- (3-methoxy-phenyl) -urea; [ M + H ]]+＝426；HPLC r.t.5.59。
1- [1- (4-cyano-benzyl) -4-oxo-3, 4-diHydrogen-2, 3-naphthyridin-6-yl]-3-p-tolyl-urea; [ M + H ]]+＝410；HPLC r.t.5.89。
1- [1- (4-cyano-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl]-3- (2, 4-fluoro-phenyl) -urea; [ M + H ]]+＝432；HPLC r.t.6。
N- [1- (3-fluoro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl]-propionamide; [ M + H ]]+＝326；HPLC r.t.4.69；1H-NMR (DMSO-d6), characteristic signal (ppm): 1.08(t, 3H), 2.35(q, 2H), 4.24(s, 2H), 7.00(m, 1H), 7.11(m, 2H), 7.29(m, 1H), 7.90(d, 1H), 7.95(dd, 1H), 8.53(d, 1H), 10.35(br.s, 1H), 12.42(br.S, 1H).
N- [1- (3-fluoro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl]-4-trifluoromethyl-benzamide; [ M + H ]]+＝442；HPLC r.t.6.68。
Furan-2-carboxylic acid [1- (3-fluoro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ester]-an amide; [ M + H ]]+＝364；HPLC r.t.5.16.
N- [1- (3-fluoro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl]-3-cyclopentyl-propionamide; [ M + H ]]+＝394；HPLC r.t.6.73。
2-propyl-pentanoic acid [1- (3-fluoro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl]-an amide; [ M + H ]]+＝396；HPLC r.t.6.85。
1- [1- (3-fluoro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl]-3- (3-trifluoromethyl-phenyl) -urea; [ M + H ]]+＝457；HPLC r.t.6.86。
1- [1- (3-fluoro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl]-3- (3-methoxy-phenyl) -urea; [ M + H ]]+＝419；HPLC r.t.5.98。
N- [1- (3-methyl-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl]-propionamide; [ M + H ]]+＝322；HPLC r.t.4.92。
N- [1- (3-methyl-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl]-4-trifluoromethyl-benzamide; [ M + H ]]+＝438；HPLC r.t.6.93。
Furan-2-carboxylic acid [1- (3-methyl-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl]-an amide; [ M + H ]]+＝360；HPLC r.t.5.38。
N- [1- (3-methyl-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl]-3-cyclopentyl-propionamide; [ M + H ]]+＝390；HPLC r.t.6.95。
2-propyl-pentanoic acid [1- (3-methyl-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl]-an amide; [ M + H ]]+＝392；HPLC r.t.7.08。
1- [1- (3-methyl-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl]-3- (3-trifluoromethyl-phenyl) -urea; [ M + H ]]+＝453；HPLC r.t.7.04。
1- [1- (3-methyl-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl]-3- (3-methoxy-phenyl) -urea; [ M + H ]]+＝415；HPLC r.t.6.18。
1- [1- (3-methyl-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl]-3-p-tolyl-urea; [ M + H ]]+＝399；HPLC r.t.6.48。
1- [1- (3-methyl-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl]-3- (2, 4-difluoro-phenyl) -urea; [ M + H ]]+＝421；HPLC r.t6.5。
N- [1- (2, 4-dichloro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl]-propionamide; [ M + H ]]+＝376；HPLC r.t.5.83；1H-NMR (DMSO-d6), characteristic signal (ppm): 1.09(t, 3H), 2.37(q, 2H), 4.33(s, 2H), 7.30(d, 1H), 7.32(dd, 1H), 7.60(d, 1H), 7.93(d, 1H), 8.02(dd, 1H), 8.56(d, 1H), 10.39(s, 1H), 12.33(s, 1H).
N- [1- (2, 4-dichloro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl]-4-trifluoromethyl-benzamide; [ M + H ]]+＝492；HPLC r.t.7.68；1H-NMR (DMSO-d6), characteristic signal (ppm): 4.37(s, 2H), 7.30-7.37(m, 2H), 7.62(d, 1H), 7.94(d, 2H), 8.02(d, 1H), 8.19(d, 2H), 8.27(dd, 1H), 8.77(d, 1H), 10.96(br.S, 1H), 12.41(br.S, 1H).
Furan-2-carboxylic acid [1- (2, 4-dichloro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl]-an amide; [ M + H ]]+＝414；HPLC r.t.6.26。
N- [1- (2, 4-dichloro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl]-ethyl succinamic acid; [ M + H ]]+＝HPLC r.t.6.11。
N- [1- (2, 4-dichloro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl]-3-cyclopentyl-propionamide; [ M + H ]]+＝444；HPLC r.t.7.82；1H-NMR (DMSO-d6), characteristic signal (ppm): 1.00-1.85(m, 11H), 2.37(t, 2H), 4.33(s, 2H), 7.30(d, 1H), 7.32(dd, 1H), 7.60(dd, 1H), 7.92(d, 1H), 8.00(dd, 1H), 8.56(dd, 1H), 10.40(br.s., 1H), 12.33(br.s., 1H).
2-propyl-pentanoic acid [1- (2, 4-dichloro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl]-an amide; [ M + H ]]+＝446；HPLC r.t.7.94；1H-NMR (DMSO-d6), characteristic signal (ppm): 1.001.85(m, 9H), 1.58-1.66(m, 2H), 2.37(m, 2H), 4.33(s, 2H), 7.30(d, 1H), 7.32(dd, 1H), 7.60(d, 1H), 7.92(d, 1H), 8.00(dd, 1H), 8.56(dd, 1H), 10.40(br.S, 1H), 12.33(br.S, 1H).
1- [1- (2, 4-dichloro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl]-3- (3-trifluoromethyl-phenyl) -urea; [ M + H ]]+＝507；HPLC r.t.7.83。
1- [1- (2, 4-dichloro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl]-3- (3-methoxy-phenyl) -urea; [ M + H ]]+＝469；HPLC r.t.7.02；1H-NMR (DMSO-d6), characteristic signal (ppm):3.73(s，3H)，4.33(s，2H)，6.58(m，1H)，6.96(m，1H)，7.15-7.22(m，2H)，7.28-7.36(m，2H)，7.61(d，1H)，7.827.90(m，2H)，8.44(d，1H)，8.91(br.S，1H)，9.35(br.S，1H)，12.31(br.s，1H)。
1- [1- (2, 4-dichloro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl]-3-p-tolyl-urea; [ M + H ]]+＝453；HPLC r.t.7.35。
1- [1- (2, 4-dichloro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl]-3- (2, 4-difluoro-phenyl) -urea; [ M + H ]]+＝475；HPLC r.t.7.38；1H-NMR (DMSO-d6), characteristic signal (ppm): 4.33(s, 2H), 7.06(m, 1H), 7.25-7.36(m, 3H), 7.61(d, 1H), 7.85(dd, 1H), 7.88(d, 1H), 8.03(m, 1H), 8.45(d, 1H), 8.75(s, 1H), 9.71(s, 1H), 12.33(s, 1H).
N- (4-oxo-1-quinolin-3-ylmethyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) -propionamide; [ M + H ]]+＝359；HPLC r.t.4.01。
N- (4-oxo-1-quinolin-3-ylmethyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) -4-trifluoromethyl-benzamide; [ M + H ]]+＝475；HPLC r.t.6；1H-NMR (DMSO-d6), characteristic signal (ppm): 4.51(s, 2H), 7.57(dt, 1H), 7.69(dt, 1H), 7.87-8.00(m, 4H), 8.09(d, 1H), 8.15-8.20(m, 3H), 8.23(dd, 1H), 8.76(d, 1H), 8.92(d, 1H), 10.92(s, 1H), 12.49(s, 1H).
N- (4-oxo-1-quinolin-3-ylmethyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) -succinamic acid ethyl ester; [ M + H ]]+＝＝431；HPLC r.t.4.37。
N- (4-oxo-1-quinolin-3-ylmethyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) -3-cyclopentyl-propionamide; [ M + H ]]+＝427；HPLC r.t.5.97。
2-propyl-pentanoic acid (4-oxo-1-quinolin-3-ylmethyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) -amide; [ M + H ]]+＝429；HPLC r.t.6.08。1H-NMR (DMSO-d6), TecSign signal (ppm): 0.80-0.88(m, 6H), 1.18-1.29(m, 4H), 1.29-1.64(m, 4H), 2.37-2.48(m, 1H), 4.48(s, 2H), 7.55(m, 1H), 7.70(m, 1H), 7.88(dd, 1H), 7.95-8.01(m, 3H), 8.17(d, 1H), 8.58(d, 1H), 8.91(d, 1H), 10.36(br.s, 1H), 12.42(br.S, 1H).
1- (4-oxo-1-quinolin-3-ylmethyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) -3- (3-trifluoromethyl-phenyl) -urea; [ M + H ]]+＝490；HPLC r.t.6.16。
1- (4-oxo-1-quinolin-3-ylmethyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) -3- (3-methoxy-phenyl) -urea; [ M + H ]]+＝452；HPLC r.t.5.27；1H-NMR (DMSO-d6), characteristic signal (ppm): 3.72(s, 3H), 4.47(s, 2H), 6.57(m, 1H), 6.94(m, 1H), 7.19(m, 2H), 7.55(dd, 1H), 7.69(dd, 1H), 7.81(dd, 1H), 7.88(dd, 1H), 7.96(m, 2H), 8.16(d, 1H), 8.44(d, 1H), 8.82(br.s, 1H), 8.91(d, 1H), 9.25(br.s, 1H), 12.40(br.s, 1H).
1- (4-oxo-1-quinolin-3-ylmethyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) -3-p-tolyl-urea; [ M + H ]]+＝436；HPLC r.t.5.56。
1- (4-oxo-1-quinolin-3-ylmethyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) -3- (2, 4-difluoro-phenyl) -urea; [ M + H ]]+＝458；HPLC r.t.5.55；1H-NMR (DMSO-d6), characteristic signal (ppm): 4.48(s, 2H), 7.05(m, 1H), 7.30(m, 1H), 7.54(dt, 1H), 7.69(dt, 1H), 7.79(dd, 1H), 7.87(d, 1H), 7.95-8.07(m, 2H), 8.16(d, 1H), 8.44(d, 1H), 8.61(d, 1H), 8.90(s, 1H), 9.56(s, 1H)12.41(s, 1H).
1- (4-oxo-1-quinolin-3-ylmethyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) -3- (3, 4-dichloro-phenyl) -urea; [ M + H ]]+＝491；HPLC r.t.6.51。
N- [ 4-oxo-1- (2-trifluoromethyl-benzyl) -3, 4-dihydro-2, 3-naphthyridin-6-yl]-propionamide; [ M + H ]]+＝376；HPLC r.t.5.41。
N- [ 4-oxo-1- (2-trifluoromethyl-benzyl) -3, 4-dihydro-2, 3-naphthyridin-6-yl]-4-trifluoromethyl-benzamide; [ M + H ]]+＝492；HPLC r.t.7.23。
Furan-2-carboxylic acid [ 4-oxo-1- (2-trifluoromethyl-benzyl) -3, 4-dihydro-2, 3-naphthyridin-6-yl]-an amide; [ M + H ]]+＝414；HPLC r.t.5.82。
N- [ 4-oxo-1- (2-trifluoromethyl-benzyl) -3, 4-dihydro-2, 3-naphthyridin-6-yl]-3-cyclopentyl-propionamide; [ M + H ]]+＝444；HPLC r.t.7.33。
2-propyl-pentanoic acid [ 4-oxo-1- (2-trifluoromethyl-benzyl) -3, 4-dihydro-2, 3-naphthyridin-6-yl]-an amide; [ M + H ]]+＝446；HPLC r.t.7.43。
1- [ 4-oxo-1- (2-trifluoromethyl-benzyl) -3, 4-dihydro-2, 3-naphthyridin-6-yl]-3- (3-trifluoromethyl-phenyl) -urea; [ M + H ]]+＝507；HPLC r.t.7.36。
1- [ 4-oxo-1- (2-trifluoromethyl-benzyl) -3, 4-dihydro-2, 3-naphthyridin-6-yl]-3-p-tolyl) -urea; [ M + H ]]+＝453；HPLC r.t.6.88。
1- [ 4-oxo-1- (2-trifluoromethyl-benzyl) -3, 4-dihydro-2, 3-naphthyridin-6-yl]-3- (2, 4-difluoro-phenyl) -urea; [ M + H ]]+＝475；HPLC r.t.6.88。
4- (4-oxo-6-propionylamino-3, 4-dihydro-2, 3-naphthyridin-1-ylmethyl) -benzoic acid methyl ester; [ M + H ]]+＝366；HPLC r.t.2.61。
4- (4-oxo-6- (4-trifluoromethyl-benzoylamino) -3, 4-dihydro-2, 3-naphthyridin-1-ylmethyl) -benzoic acid methyl ester; [ M + H ]]+＝482；HPLC r.t.6.47。
4- {6- [ (furan-2-carbonyl) -amino]-4-oxo-3, 4-dihydro-2, 3-naphthyridin-1-ylmethyl } -benzoic acid methyl ester; [ M + H ]]+＝404；HPLC r.t.4.91。
4-[6- (3, 4-dimethoxy-benzoylamino) -3, 4-dihydro-2, 3-naphthyridin-1-ylmethyl]-methyl benzoate; [ M + H ]]+＝474；HPLC r.t.5.27。
4- [6- (3-cyclopentyl-propionylamino) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-1-ylmethyl]-methyl benzoate; [ M + H ]]+＝434；HPLC r.t.6.48。
4- [ 4-oxo-6- (2-propyl-pentanoylamino) -3, 4-dihydro-2, 3-naphthyridin-1-ylmethyl]-methyl benzoate; [ M + H ]]+＝436；HPLC r.t.6.61。
4- {6- [3- (3-methoxy-phenyl) -ureido]-4-oxo-3, 4-dihydro-2, 3-naphthyridin-1-ylmethyl } -benzoic acid methyl ester; [ M + H ]]+＝459；HPLC r.t.5.74。
4- [ 4-oxo-6- (3-p-tolyl-ureido) -3, 4-dihydro-2, 3-naphthyridin-1-ylmethyl]-methyl benzoate; [ M + H ]]+＝443；HPLC r.t.6.03。
4- {6- [3- (2, 4-difluoro-phenyl) -ureido ] -urea]-4-oxo-3, 4-dihydro-2, 3-naphthyridin-1-ylmethyl } -benzoic acid methyl ester; [ M + H ]]+＝465；HPLC r.t.6.04。
N- [1- (4-chloro-3-fluoro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl]-propionamide; [ M + H ]]+＝360；HPLC r.t.4.04。
N- [1- (4-chloro-3-fluoro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl]-4-trifluoromethyl-benzamide; [ M + H ]]+＝476；HPLC r.t.6.3。
Furan-2-carboxylic acid [1- (4-chloro-3-fluoro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl]-an amide; [ M + H ]]+＝398；HPLC r.t.4.58。
N- [1- (4-chloro-3-fluoro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl]-3, 4-dimethoxy-benzamide; [ M + H ]]+＝468；HPLC r.t.4.97。
N- [1- (4-chloro-3-fluoro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl]-3-cyclopentyl-propionamide; [ M + H ]]+＝428；HPLC r.t.7.3。
2-propyl-pentanoic acid [1- (4-chloro-3-fluoro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl]-an amide; [ M + H ]]+＝430；HPLC r.t.7.41。
1- [1- (4-chloro-3-fluoro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl]-3- (3-trifluoromethyl-phenyl) -urea; [ M + H ]]+＝491；HPLC r.t.6.54。
1- [1- (4-chloro-3-fluoro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl]-3-p-tolyl-urea; [ M + H ]]+＝437；HPLC r.t.5.91。
N- {1- [ (E) -3- (4-Nitro-phenyl) -allyl]-4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl } -3, 4-dimethoxy-benzamide [ M + H [ ]]+＝；HPLC r.t.4.96。
N- (4-oxo-1-thiophen-3-ylmethyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) -propionamide;
[M+H]+＝314；HPLC r.t.4.26。
n- (4-oxo-1-thiophen-3-ylmethyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) -4-trifluoromethyl-benzamide; [ M + H ]]+＝430；HPLC r.t.6.43。
Furan-2-carboxylic acid (4-oxo-1-thiophen-3-ylmethyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) -amide; [ M + H ]]+＝352；HPLC r.t.4.76。
N- (4-oxo-1-thiophen-3-ylmethyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) -3, 4-dimethoxy-benzamide; [ M + H ]]+＝422；HPLC r.t.5.16。
2-propyl-pentanoic acid (4-oxo-1-thiophen-3-ylmethyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) -amide; [ M + H ]]+＝384；HPLC r.t.6.54。
1- (4-oxo-1-thiophen-3-ylmethyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) -3- (3-trifluoromethyl-phenyl) -urea; [ M + H ]]+＝445；HPLC r.t.6.57。
1- (4-oxo-1-thiophen-3-ylmethyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) -3- (3-methoxy-phenyl) -urea; [ M + H ]]+＝407；HPLC r.t.5.66。
1- (4-oxo-1-thiophen-3-ylmethyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) -3-p-tolyl-urea; [ M + H ]]+＝391；HPLC r.t.5.98。
1- (4-oxo-1-thiophen-3-ylmethyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) -3- (2, 4-difluoro-phenyl) -urea; [ M + H ]]+＝413；HPLC r.t.5.96。
N- [1- (3-methoxy-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl]-propionamide; [ M + H ]]+＝338；HPLC r.t.4.48。
N- [1- (3-methoxy-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl]-4-trifluoromethyl-benzamide; [ M + H ]]+＝454；HPLC r.t.6.52。
Furan-2-carboxylic acid [1- (3-methoxy-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ester]-an amide; [ M + H ]]+＝376；HPLC r.t.4.95。
N- [1- (3-methoxy-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl]-3, 4-dimethoxy-benzamide; [ M + H ]]+＝446；HPLC r.t.5.32。
N- [1- (3-methoxy-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl]-3-cyclopentyl-propionamide; [ M + H ]]+＝406；HPLC r.t.6.53。
2-propionic acid-pentanoic acid [1- (3-methoxy-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl]-an amide; [ M + H ]]+＝408；HPLC r.t.6.65；1H-NMR (DMSO-d6), characteristic signal (ppm): 0.84(q, 6H), 1.15-1.62(m, 8H), 2.41(m, 1H), 3.68(s, 3H), 4.18(s, 2H), 6.75(ddd, 1H), 6.82(dt, 1H), 6.86(t，1H)，7.16(t，1H)，7.89(d，1H)，7.95(dd，1H)，8.55(d，1H)，10.34(s，1H)，12.41(s，1H)。
1- [1- (3-methoxy-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl]-3- (3-trifluoromethyl-phenyl) -urea; [ M + H ]]+＝469；HPLC r.t.6.67。
1- [1- (3-methoxy-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl]-3- (3-methoxy-phenyl) -urea; [ M + H ]]+＝431；HPLC r.t.5.79。
1- [1- (3-methoxy-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl]-3-p-tolyl-urea; [ M + H ]]+＝415；HPLC r.t.6.08。
1- [1- (3-methoxy-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl]-3- (2, 4-difluoro-phenyl) -urea; [ M + H ]]+＝437；HPLC r.t.6.08。
N- (4-oxo-1-propyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) -propionamide; [ M + H ]]+＝260；HPLC r.t.3.78。
Furan-2-carboxylic acid (4-oxo-1-propyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) -amide; [ M + H ]]+＝298；HPLC r.t.4.35。
1- (4-oxo-1-propyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) -3-p-tolyl-urea; [ M + H ]]+＝；HPLC r.t.5.69。
1- (4-oxo-1-propyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) -3- (2, 4-difluoro-phenyl) -urea; [ M + H ]]+＝359；HPLC r.t.5.68。
N- [ 4-oxo-1- (3-phenyl-propyl) -3, 4-dihydro-2, 3-naphthyridin-6-yl]-propionamide; [ M + H ]]+＝336；HPLC r.t.5.35。
N- [ 4-oxo-1- (3-phenyl-propyl) -3, 4-dihydro-2, 3-naphthyridin-6-yl]-4-trifluoromethyl-benzamide; [ M + H ]]+＝452；HPLC r.t.7.26。
Furan-2-carboxylic acid [ 4-oxo-1- (3-phenyl-propyl) -3, 4-dihydro-2, 3-naphthyridin-6-yl]-an amide; [ M + H ]]+＝374；HPLC r.t.5.78。
N- [ 4-oxo-1- (3-phenyl-propyl) -3, 4-dihydro-2, 3-naphthyridin-6-yl]-3, 4-dimethoxy-benzamide; [ M + H ]]+＝444；HPLC r.t.6.11。
N- [ 4-oxo-1- (3-phenyl-propyl) -3, 4-dihydro-2, 3-naphthyridin-6-yl]-3-cyclopentyl-propionamide; [ M + H ]]+＝404；HPLC r.t.7.31。
2-propyl-pentanoic acid [ 4-oxo-1- (3-phenyl-propyl) -3, 4-dihydro-2, 3-naphthyridin-6-yl]-an amide; [ M + H ]]+＝406；HPLC r.t.7.43。
1- [ 4-oxo-1- (3-phenyl-propyl) -3, 4-dihydro-2, 3-naphthyridin-6-yl]-3- (3-trifluoromethyl-phenyl) -urea; [ M + H ]]+＝467；HPLC r.t.7.41。
1- [ 4-oxo-1- (3-phenyl-propyl) -3, 4-dihydro-2, 3-naphthyridin-6-yl]-3- (3-methoxy-phenyl) -urea; [ M + H ]]+＝429；HPLC r.t.6.56。
1- [ 4-oxo-1- (3-phenyl-propyl) -3, 4-dihydro-2, 3-naphthyridin-6-yl]-3-p-tolyl-urea; [ M + H ]]+＝413；HPLC r.t.6.88。
1- [ 4-oxo-1- (3-phenyl-propyl) -3, 4-dihydro-2, 3-naphthyridin-6-yl]-3- (2, 4-difluoro-phenyl) -urea; [ M + H ]]+＝435；HPLC r.t.6.88。
1- [1- (3-fluoro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl]-3- (2, 4-difluoro-phenyl) -urea; [ M + H ]]+＝425；1H-HMR (DMSO-d6), characteristic Signal (ppm): 4.25(s, 2H), 6.977.08(m, 2H), 7.09-7.15(m, 2H), 7.27-7.35(m, 2H), 7.77(dd, 1H), 7.86(d, 1H), 7.98-8.08(m, 1H), 8.42(d, 1H), 8.61(d, 1H), 9.55(s, 1H), 12.42(s, 1H).
1- [1- (3-fluoro-benzyl) -4-oxo-3, 4-diHydrogen-2, 3-naphthyridin-6-yl]-3-p-tolyl-urea; [ M + H ]]+＝403；1H-NMR (DMSO-d6), characteristic signal (ppm): 2.23(s, 3H), 4.24(s, 2H), 7.00(m, 1H), 7.05-7.16(m, 4H), 7.27-7.35(m, 3H), 7.79(dd, 1H), 7.84(d, 1H), 8.39(d, 1H), 8.70(br.S, 1H), 9.20(br.S, 1H), 12.39(s, 1H).
Claims (38)
1. A method for treating a disease caused by and/or associated with an altered protein kinase activity, comprising administering to a mammal in need thereof an effective amount of an amino-2, 3-naphthyridone derivative represented by formula (I):
wherein
Ra and Rb are each independently a hydrogen atom or optionally further substituted group selected from: straight or branched chainC1-C6Alkyl radical, C3-C6Cycloalkyl or cycloalkyl C1-C6Alkyl, aryl C1-C6Alkyl, 5-to 7-membered heterocyclyl or heterocyclyl C having 1-3 heteroatoms selected from nitrogen, oxygen or sulfur1-C6An alkyl group; or one of Ra or Rb is hydrogen or optionally substituted straight or branched C1-C6Alkyl and the other is selected from-COR ', -CONHR ', -COOR ' or-SO2R 'wherein R' is hydrogen or an optionally substituted group selected from the above alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl or heterocyclylalkyl groups;
R1is of the formula-CHR4R5Group, wherein R4And R5Each independently hydrogen or optionally substituted C selected from linear or branched1-C6Alkyl radical, C3-C6Cycloalkyl or cycloalkyl C1-C6Alkyl, aryl C1-C6Alkyl, 5-to 7-membered heterocyclyl or heterocyclyl C having 1-3 heteroatoms selected from nitrogen, oxygen or sulfur1-C6A group of alkyl groups; or R1Is of the formula-NHR ', -NR ' COR ', -NR ' CONHR "or-NR ' SO2R ', wherein R' has a definition other than the above-mentioned hydrogen, R 'is hydrogen or has the above-mentioned definition for R';
R2is a hydrogen atom or optionally further substituted group selected from: straight or branched C1-C6Alkyl radical, C3-C6Cycloalkyl or cycloalkyl C1-C6Alkyl, aryl C1-C6Alkyl, 5-to 7-membered heterocyclyl or heterocyclyl C having 1-3 heteroatoms selected from nitrogen, oxygen or sulfur1-C6An alkyl group;
any R at one or more of the free positions 5, 6 and 8 on the 2, 3-naphthyridone ring3Each independently is a halogen atom, nitro, carboxyl, cyano or optionally further substituted group selected from: straight or branched C1-C6Alkyl radical, C3-C6Cycloalkyl or cycloalkaneRadical C1-C6Alkyl, aryl C1-C6Alkyl, 5-to 7-membered heterocyclyl or heterocyclyl C having 1-3 heteroatoms selected from nitrogen, oxygen or sulfur1-C6An alkyl group; or R3Is selected from-COR ', -CONHR', -SO2R ', -NR' COR ', -NR' CONHR 'or-NR' SO2R ' wherein R ' and R ' are the same or different, are hydrogen or the above-mentioned groups;
m is 0 or an integer of 1 to 3;
or a pharmaceutically acceptable salt thereof.
2. The method of claim 1, wherein the disease caused by and/or associated with altered protein kinase activity is a cell proliferative disease selected from cancer, alzheimer's disease, viral infection, autoimmune disease or neurodegenerative disease.
3. The method of claim 2, wherein the cancer is selected from the group consisting of carcinoma, squamous cell carcinoma, hematopoietic tumors of lymphoid or myeloid lineage, tumors of mesenchymal origin, tumors of the central and peripheral nervous system, melanoma, seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosum, keratoacanthoma, thyroid follicular cancer and Kaposi's sarcoma.
4. The method of claim 1, wherein said cell proliferative disorder is selected from the group consisting of benign prostate hyperplasia, familial epithelial hyperplasia, polyposis, neuro-fibromatosis, psoriasis, vascular smooth cell proliferation associated with atherosclerosis, pulmonary fibrosis, arthritis glomerulonephritis and post-surgical stenosis and restenosis.
5. The method of claim 1 which provides tumor angiogenesis and metastasis inhibition.
6. The method of claim 1, further comprising administering to the mammal in need of treatment radiation therapy or chemotherapy in combination with at least one cytostatic or cytotoxic agent.
7. The method of claim 1, wherein the mammal in need of treatment is a human.
8. The process of claim 1, wherein in the compound of formula (I), one of Ra and Rb is a hydrogen atom and the other is-COR ', -CONHR ', -COOR ' or-SO2R ', wherein R' is as defined in claim 1.
9. The process of claim 1, wherein in the compound of formula (I), one of Ra and Rb is a hydrogen atom and the other is-COR ', -CONHR ', -COOR ' or-SO2R’，R2Is hydrogen, m is 0 and R1And R' is as defined in claim 1.
10. A method of inhibiting the activity of a protein kinase comprising contacting the kinase with an effective amount of a compound as defined in claim 1.
11. An amino-2, 3-phthalazinone derivative represented by formula (I):
wherein
Ra and Rb are each independently a hydrogen atom or optionally further substituted group selected from: straight or branched C1-C6Alkyl radical, C3-C6Cycloalkyl or cycloalkyl C1-C6Alkyl, aryl C1-C6Alkyl, 5-to 7-membered heterocyclyl or heterocyclyl C having 1-3 heteroatoms selected from nitrogen, oxygen or sulfur1-C6An alkyl group; or one of Ra or Rb is hydrogen or optionally substituted straight or branched C1-C6Alkyl and the other is selected from-COR ', -CONHR ', -COOR ' or-SO2The radical of R ', wherein R' is hydrogen orOptionally substituted groups selected from the above alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl or heterocyclylalkyl groups;
R1is of the formula-CHR4R5Group, wherein R4And R5Each independently hydrogen or optionally substituted C selected from linear or branched1-C6Alkyl radical, C3-C6Cycloalkyl or cycloalkyl C1-C6Alkyl, aryl C1-C6Alkyl, 5-to 7-membered heterocyclyl or heterocyclyl C having 1-3 heteroatoms selected from nitrogen, oxygen or sulfur1-C6A group of alkyl groups; or R1Is of the formula-NHR ', -NR ' COR ', -NR ' CONHR "or-NR ' SO2R ', wherein R' has a definition other than the above-mentioned hydrogen, R 'is hydrogen or has the above-mentioned definition for R';
R2is a hydrogen atom or optionally further substituted group selected from: straight or branched C1-C6Alkyl radical, C3-C6Cycloalkyl or cycloalkyl C1-C6Alkyl, aryl C1-C6Alkyl, 5-to 7-membered heterocyclyl or heterocyclyl C having 1-3 heteroatoms selected from nitrogen, oxygen or sulfur1-C6An alkyl group;
any R at one or more of the free positions 5, 6 and 8 on the 2, 3-naphthyridone ring3Each independently is a halogen atom, nitro, carboxyl, cyano or optionally further substituted group selected from: straight or branched C1-C6Alkyl radical, C3-C6Cycloalkyl or cycloalkyl C1-C6Alkyl, aryl C1-C6Alkyl, 5-to 7-membered heterocyclyl or heterocyclyl C having 1-3 heteroatoms selected from nitrogen, oxygen or sulfur1-C6An alkyl group; or R3Is selected from-COR ', -CONHR', -SO2R ', -NR' COR ', -NR' CONHR 'or-NR' SO2R ' wherein R ' and R ' are the same or different, are hydrogen or the above-mentioned groups;
m is 0 or an integer of 1 to 3;
or a pharmaceutically acceptable salt thereof;
the compounds N- [3, 4-dihydro-4-oxo-1- (4-pyridylmethyl) -6-2, 3-naphthyridinyl ] -acetamide and N- [3, 4-dihydro-4-oxo-1- (4-pyridylmethyl) -6-2, 3-naphthyridinyl ] -2, 2, 2-trifluoro-acetamide are excluded.
12. A compound of formula (I) according to claim 11, wherein one of Ra or Rb is a hydrogen atom or an optionally substituted straight or branched C1-C6The other is a group-COR ', wherein R' is an optionally substituted group selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl or heterocyclylalkyl as defined in claim 11, and R1，R2，R3And m is as defined in claim 11.
13. A compound of formula (I) according to claim 12, wherein R1Is a radical-CHR4R5Wherein R is4And R5As defined in claim 11, R2Is hydrogen and m is 0.
14. A compound of formula (I) according to claim 11, wherein one of Ra or Rb is a hydrogen atom or an optionally substituted straight or branched C1-C6Alkyl and the other is a group-CONHR ', wherein R' is a hydrogen atom or an optionally substituted group selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl or heterocyclylalkyl as defined in claim 11, and R1，R2，R3And m is as defined in claim 11.
15. A compound of formula (I) according to claim 14, wherein R1Is a radical-CHR4R5Wherein R is4And R5As defined in claim 11, R2Is hydrogen and m is 0.
16. A compound of formula (I) according to claim 11, wherein one of Ra or Rb is a hydrogen atom or an optionally substituted straight or branched C1-C6The other is a group-COOR ', wherein R' is a hydrogen atom or an optionally substituted group selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl or heterocyclylalkyl as defined in claim 11, and R1，R2，R3And m is as defined in claim 11.
17. A compound of formula (I) according to claim 16, wherein R1Is a radical-CHR4R5Wherein R is4And R5As defined in claim 11, R2Is hydrogen and m is 0.
18. A compound of formula (I) according to claim 11, wherein one of Ra or Rb is a hydrogen atom or an optionally substituted straight or branched C1-C6Alkyl radical, the other being a radical-SO2R ', wherein R' is an optionally substituted group selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl or heterocyclylalkyl as defined in claim 11, and R1，R2，R3And m is as defined in claim 11.
19. A compound of formula (I) according to claim 18, wherein R1Is a radical-CHR4R5Wherein R is4And R5As defined in claim 11, R2Is hydrogen and m is 0.
20. A compound of formula (I) according to claim 11, wherein Ra and Rb are both hydrogen atoms and R is1，R2，R3And m is as defined in claim 11.
21. A compound of formula (I) according to claim 20, wherein R1Is a radical-CHR4R5Wherein R is4And R5As defined in claim 11, R2Is hydrogen and m is 0.
22. A compound of formula (I) according to claim 11, wherein one of Ra or Rb is a hydrogen atom or an optionally substituted straight or branched C1-C6The other is an optionally substituted group selected from alkyl, cycloalkyl, cycloalkylalkyl, arylalkyl or heterocyclylalkyl as defined in claim 11, and R is1，R2，R3And m is as defined in claim 11.
23. A compound of formula (I) according to claim 22, wherein R1Is a radical-CHR4R5Wherein R is4And R5As defined above, R2Is hydrogen and m is 0.
24. A compound of formula (I) as defined in claim 11, optionally in the form of a pharmaceutically acceptable salt, selected from:
1)4- (4-oxo-6-propionylamino-3, 4-dihydro-2, 3-naphthyridin-1-ylmethyl) -benzoic acid methyl ester;
2)4- (4-oxo-6- (4-trifluoromethyl-benzoylamino) -3, 4-dihydro-2, 3-naphthyridin-1-ylmethyl) -benzoic acid methyl ester;
3)4- {6- [ (furan-2-carbonyl) -amino ] -4-oxo-3, 4-dihydro-2, 3-naphthyridin-1-ylmethyl } -benzoic acid methyl ester;
4)4- (6- (3, 4-dimethoxy-benzoylamino) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-1-ylmethyl) -benzoic acid methyl ester;
5)4- (6- (3-cyclopentyl-propionylamino) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-1-ylmethyl) -benzoic acid methyl ester;
6)4- [ 4-oxo-6- (2-propyl-pentanoylamino) -3, 4-dihydro-2, 3-naphthyridin-1-ylmethyl ] -benzoic acid methyl ester;
7)4- { 4-oxo-6- [3- (3-trifluoromethyl-phenyl) -ureido ] -3, 4-dihydro-2, 3-naphthyridin-1-ylmethyl } -benzoic acid methyl ester;
8)4- {6- [3- (3-methoxy-phenyl) -ureido ] -4-oxo-3, 4-dihydro-2, 3-naphthyridin-1-ylmethyl } -benzoic acid methyl ester;
9)4- [ 4-oxo-6- (3-p-tolyl-ureido) -3, 4-dihydro-2, 3-naphthyridin-1-ylmethyl ] -benzoic acid methyl ester;
10)4- {6- [3- (2, 4-difluoro-phenyl) -ureido ] -4-oxo-3, 4-dihydro-2, 3-naphthyridin-1-ylmethyl } -benzoic acid methyl ester;
11)4- {6- [3- (3, 4-dichloro-phenyl) -ureido ] -4-oxo-3, 4-dihydro-2, 3-naphthyridin-1-ylmethyl } -benzoic acid methyl ester;
12)4- [ 4-oxo-6- (3-pyridin-3-yl-ureido) -3, 4-dihydro-2, 3-naphthyridin-1-ylmethyl ] -benzoic acid methyl ester;
13)4- (6-amino-4-oxo-3, 4-dihydro-2, 3-naphthyridin-1-ylmethyl) -benzoic acid methyl ester;
14) n- [1- (4-chloro-3-fluoro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -propionamide;
15) 4-trifluoromethyl-benzamide, N- [1- (4-chloro-3-fluoro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -amide;
16) furan-2-carboxylic acid [1- (4-chloro-3-fluoro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -amide;
17) n- [1- (4-chloro-3-fluoro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3, 4-dimethoxy-benzamide;
18) n- [1- (4-chloro-3-fluoro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3-cyclopentyl-propionamide;
19) 2-propyl-pentanoic acid [1- (4-chloro-3-fluoro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] amide;
20)1- [1- (4-chloro-3-fluoro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3- (3-trifluoromethyl-phenyl) -urea;
21)1- [1- (4-chloro-3-fluoro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3- (3-methoxy-phenyl) -urea;
22)1- [1- (4-chloro-3-fluoro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3-p-tolyl-urea;
23)1- [1- (4-chloro-3-fluoro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3- (2, 4-difluoro-phenyl) -urea;
24)1- [1- (4-chloro-3-fluoro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3- (3, 4-dichloro-phenyl) -urea;
25)1- [1- (4-chloro-3-fluoro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3-pyridin-3-yl-urea;
26) 7-amino-4- (4-chloro-3-fluoro-benzyl) -2H-2, 3-naphthyridin-1-one;
27) n- {1- [ (E) -3- (4-nitro-phenyl) -allyl ] -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl } -propionamide;
28) n- {1- [ (E) -3- (4-nitro-phenyl) -allyl ] -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl } -4-trifluoromethyl-benzamide;
29) furan-2-carboxylic acid {1- [ (E) -3- (4-nitro-phenyl) -allyl ] -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl } -amide;
30) n- {1- [ (E) -3- (4-nitro-phenyl) -allyl ] -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl } -3, 4-dimethoxy-benzamide;
31) n- {1- [ (E) -3- (4-nitro-phenyl) -allyl ] -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl } -3-cyclopentyl-propionamide;
32) 2-propyl-pentanoic acid {1- [ (E) -3- (4-nitro-phenyl) -allyl ] -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl } -amide;
33)1- {1- [ (E) -3- (4-nitro-phenyl) -allyl ] -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl } -3- (3-trifluoromethyl-phenyl) -urea;
34)1- {1- [ (E) -3- (4-nitro-phenyl) -allyl ] -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl } -3- (3-methoxy-phenyl) -urea;
35)1- {1- [ (E) -3- (4-nitro-phenyl) -allyl ] -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl } -3-p-tolyl-urea;
36)1- {1- [ (E) -3- (4-nitro-phenyl) -allyl ] -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl } -3- (2, 4-difluoro-phenyl) -urea;
37)1- {1- [ (E) -3- (4-nitro-phenyl) -allyl ] -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl } -3- (3, 4-dichloro-phenyl) -urea;
38)1- {1- [ (E) -3- (4-nitro-phenyl) -allyl ] -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl } -3-pyridin-3-yl-urea;
39) 7-amino-4- [ (E) -3- (4-nitro-phenyl) -allyl ] -2H-2, 3-naphthyridin-1-one;
40) n- (4-oxo-1-thiophen-3-ylmethyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) -propionamide;
41) n- (4-oxo-1-thiophen-3-ylmethyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) -4-trifluoromethyl-benzamide;
42) furan-2-carboxylic acid (4-oxo-1-thiophen-3-ylmethyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) -amide;
43) n- (4-oxo-1-thiophen-3-ylmethyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) -3, 4-dimethoxy-benzamide;
44) n- (4-oxo-1-thiophen-3-ylmethyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) -3-cyclopentyl-propionamide;
45) 2-propyl-pentanoic acid (4-oxo-1-thiophen-3-ylmethyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) -amide;
46)1- (4-oxo-1-thiophen-3-ylmethyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) -3- (3-trifluoromethyl-phenyl) -urea;
47)1- (4-oxo-1-thiophen-3-ylmethyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) - (3-methoxy-phenyl) -urea;
48)1- (4-oxo-1-thiophen-3-ylmethyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) -3-p-tolyl-urea;
49)1- (4-oxo-1-thiophen-3-ylmethyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) -3- (2, 4-difluoro-phenyl) -urea;
50)1- (4-oxo-1-thiophen-3-ylmethyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) -3- (3, 4-dichloro-phenyl) -urea;
51)1- (4-oxo-1-thiophen-3-ylmethyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) -3-pyridin-3-yl-urea;
52) 7-amino-4-thiophen-3-ylmethyl-2H-2, 3-naphthyridin-1-one;
53) n- [1- (3-methoxy-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -propionamide;
54) n- [1- (3-methoxy-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -4-trifluoromethyl-benzoyl;
55) furan-2-carboxylic acid [1- (3-methoxy-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -amide;
56) n- [1- (3-methoxy-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3, 4-dimethoxy-benzamide;
57) n- [1- (3-methoxy-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3-cyclopentyl-propionamide;
58) 2-propyl-pentanoic acid [1- (3-methoxy-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -amide;
59)1- [1- (3-methoxy-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3- (3-trifluoromethyl-phenyl) -urea;
60)1- [1- (3-methoxy-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] - (3-methoxy-phenyl) -urea;
61)1- [1- (3-methoxy-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3-p-tolyl-urea;
62)1- [1- (3-methoxy-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3- (2, 4-difluoro-phenyl) -urea;
63)1- [1- (3-methoxy-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3- (3, 4-dichloro-phenyl) -urea;
64)1- [1- (3-methoxy-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3-pyridin-3-yl-urea;
65) 7-amino-4- (3-methoxy-benzyl) -2H-2, 3-naphthyridin-1-one;
66) n- (4-oxo-1-propyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) propanamide;
67) n- (4-oxo-1-propyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) -4-trifluoromethyl-benzamide;
68) furan-2-carboxylic acid (4-oxo-1-propyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) -amide;
69) n- (4-oxo-1-propyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) -3, 4-dimethoxy-benzamide;
70) n- (4-oxo-1-propyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) -3-cyclopentyl-propionamide;
71) 2-propyl-pentanoic acid (4-oxo-1-propyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) -amide;
72)1- (4-oxo-1-propyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) -3- (3-trifluoromethyl-phenyl) -urea;
73)1- (4-oxo-1-propyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) - (3-methoxy-phenyl) -urea;
74) 1-4-oxo-1-propyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) -3-p-tolyl-urea;
75)1- (4-oxo-1-propyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) -3- (2, 4-difluoro-phenyl) -urea;
76)1- (4-oxo-1-propyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) -3- (3, 4-dichloro-phenyl) -urea;
77)1- (4-oxo-1-propyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) -3-pyridin-3-yl-urea;
78) 7-amino-4-propyl-2H-2, 3-naphthyridin-1-one;
79) n- [1- (3, 3-dimethyl-butyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -propionamide;
80) n- [1- (3, 3-dimethyl-butyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -4-trifluoromethyl-benzamide;
81) furan-2-carboxylic acid [1- (3, 3-dimethyl-butyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -amide;
82) n- [1- (3, 3-dimethyl-butyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3, 4-dimethoxy-benzamide;
83) n- [1- (3, 3-dimethyl-butyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3-cyclopentyl-propionamide;
84) 2-propyl-pentanoic acid [1- (3, 3-dimethyl-butyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -amide;
85)1- [1- (3, 3-dimethyl-butyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3- (3-trifluoromethyl-phenyl) -urea;
86)1- [1- (3, 3-dimethyl-butyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] - (3-methoxy-phenyl) -urea;
87)1- [1- (3, 3-dimethyl-butyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3-p-tolyl-urea;
88)1- [1- (3, 3-dimethyl-butyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3- (2, 4-difluoro-phenyl) -urea;
89)1- [1- (3, 3-dimethyl-butyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3- (3, 4-dichloro-phenyl) -urea;
90)1- [1- (3, 3-dimethyl-butyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3-pyridin-3-yl-urea;
91) 7-amino-4- (3, 3-dimethyl-butyl) -2H-2, 3-naphthyridin-1-one;
92) n- [ 4-oxo-1- (3-phenyl-propyl) -3, 4-dihydro-2, 3-naphthyridin-6-yl ] -propionamide;
93) n- [ 4-oxo-1- (3-phenyl-propyl) -3, 4-dihydro-2, 3-naphthyridin-6-yl ] -4-trifluoromethyl-benzamide;
94) furan-2-carboxylic acid [ 4-oxo-1- (3-phenyl-propyl) -3, 4-dihydro-2, 3-naphthyridin-6-yl ] -amide;
95) n- [ 4-oxo-1- (3-phenyl-propyl) -3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3, 4-dimethoxy-benzamide;
96) n- [ 4-oxo-1- (3-phenyl-propyl) -3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3-cyclopentyl-propionamide;
97) 2-propyl-pentanoic acid [ 4-oxo-1- (3-phenyl-propyl) -3, 4-dihydro-2, 3-naphthyridin-6-yl ] -amide;
98)1- [ 4-oxo-1- (3-phenyl-propyl) -3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3- (3-trifluoromethyl-phenyl) -urea;
99)1- [ 4-oxo-1- (3-phenyl-propyl) -3, 4-dihydro-2, 3-naphthyridin-6-yl ] - (3-methoxy-phenyl) -urea;
100)1- [ 4-oxo-1- (3-phenyl-propyl) -3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3-p-tolyl-urea;
101)1- [ 4-oxo-1- (3-phenyl-propyl) -3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3- (2, 4-difluoro-phenyl) -urea;
102)1- [ 4-oxo-1- (3-phenyl-propyl) -3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3- (3, 4-dichloro-phenyl) -urea;
103)1- [ 4-oxo-1- (3-phenyl-propyl) -3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3-pyridin-3-yl-urea;
104) 7-amino-4- (3-phenyl-propyl) -2H-2, 3-naphthyridin-1-one;
105) n- (4-oxo-1-pyridin-3-ylmethyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) -propionamide;
106) n- (4-oxo-1-pyridin-3-ylmethyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) -4-trifluoromethyl-benzamide;
107) furan-2-carboxylic acid (4-oxo-1-pyridin-3-ylmethyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) -amide;
108) n- (4-oxo-1-pyridin-3-ylmethyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) -succinamic acid ethyl ester;
109) n- (4-oxo-1-pyridin-3-ylmethyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) -3-cyclopentyl-propionamide;
110) 2-propyl-pentanoic acid (4-oxo-1-pyridin-3-ylmethyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) -amide;
111)1- (4-oxo-1-pyridin-3-ylmethyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) -3- (3-trifluoromethyl-phenyl) -urea;
112)1- (3-methoxy-phenyl) -3- (4-oxo-1-pyridin-3-ylmethyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) -urea;
113)1- (4-oxo-1-pyridin-3-ylmethyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) -3-p-tolyl) -urea;
114)1- (2, 4-difluoro-phenyl) -3- (4-oxo-1-pyridin-3-ylmethyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) -urea;
115)1- (3, 4-dichloro-phenyl) -3- (4-oxo-1-pyridin-3-ylmethyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) -urea;
116)1- (4-oxo-1-pyridin-3-ylmethyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) -3-pyridin-3-yl-urea;
117) 7-amino-4-pyridin-3-ylmethyl-2H-2, 3-naphthyridin-1-one
118) N- (4-oxo-1-pyridin-3-ylmethyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) -benzamide;
119) n- [1- (4-chloro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -propionamide;
120) n- [1- (4-chloro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -4-trifluoromethyl-benzamide;
121) furan-2-carboxylic acid [1- (4-chloro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -amide;
122) n- [1- (4-chloro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -succinamic acid ethyl ester;
123) n- [1- (4-chloro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3-cyclopentyl-propionamide;
124) 2-propyl-pentanoic acid [1- (4-chloro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -amide;
125)1- [1- (4-chloro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3- (3-trifluoromethyl-phenyl) -urea;
126)1- [1- (4-chloro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3- (3-methoxy-phenyl) -urea;
127)1- [1- (4-chloro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3-p-tolyl-urea;
128)1- [1- (4-chloro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3- (2, 4-difluoro-phenyl) -urea;
129)1- [1- (4-chloro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3- (3, 4-dichloro-phenyl) -urea;
130)1- [1- (4-chloro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3-pyridin-3-yl-urea;
131) 7-amino-4- (4-chloro-benzyl) -2H-2, 3-naphthyridin-1-one;
132) n- [1- (4-cyano-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -propionamide;
133) 4-trifluoromethyl-benzamide, N- [1- (4-cyano-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -4-dihydro-benzamide;
134) furan-2-carboxylic acid [1- (4-cyano-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -amide;
135) n- [1- (4-cyano-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -succinamic acid ethyl ester;
136) n- [1- (4-cyano-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3-cyclopentyl-propionamide;
137) 2-propyl-pentanoic acid [1- (4-cyano-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -amide;
138)1- [1- (4-cyano-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3- (3-trifluoromethyl-phenyl) -urea;
139)1- [1- (4-cyano-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3- (3-methoxy-phenyl) -urea;
140)1- [1- (4-cyano-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3-p-tolyl) -urea;
141)1- [1- (4-cyano-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3- (2, 4-difluoro-phenyl) -urea;
142)1- [1- (4-cyano-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3- (3, 4-dichloro-phenyl) -urea;
143)1- [1- (4-cyano-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3-pyridin-3-yl) -urea;
144) 7-amino-4- (4-cyano-benzyl) -2H-2, 3-naphthyridin-1-one;
145) n- [1- (3-fluoro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -propionamide;
146) n- [1- (3-fluoro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -4-trifluoromethyl-benzamide;
147) furan-2-carboxylic acid [1- (3-fluoro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -amide;
148) n- [1- (3-fluoro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -succinamic acid ethyl ester;
149) n- [1- (3-fluoro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3-cyclopentyl-propionamide;
150) 2-propyl-pentanoic acid [1- (3-fluoro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -amide;
151)1- [1- (3-fluoro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3- (3-trifluoromethyl-phenyl) -urea;
152)1- [1- (3-fluoro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3- (3-methoxy-phenyl) -urea;
153)1- [1- (3-fluoro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3-p-tolyl) -urea;
154)1- [1- (3-fluoro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3- (2, 4-difluoro-phenyl) -urea;
155)1- [1- (3-fluoro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3- (3, 4-dichloro-phenyl) -urea;
156)1- [1- (3-fluoro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3-pyridin-3-yl-urea;
157) 7-amino-4- (3-fluoro-benzyl) -2H-2, 3-naphthyridin-1-one;
158) n- [1- (3-methyl-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -propionamide;
159) n- [1- (3-methyl-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -4-trifluoromethyl-benzamide;
160) furan-2-carboxylic acid [1- (3-methyl-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -amide;
161) n- [1- (3-methyl-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -succinamic acid ethyl ester;
162) n- [1- (3-methyl-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3-cyclopentyl-propionamide;
163) 2-propyl-pentanoic acid [1- (3-methyl-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -amide;
164)1- [1- (3-methyl-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3- (3-trifluoromethyl-phenyl) -urea;
165)1- [1- (3-methyl-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3- (3-methoxy-phenyl) -urea;
166)1- [1- (3-methyl-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3-p-tolyl-urea;
167)1- [1- (3-methyl-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3- (2, 4-difluoro-phenyl) -urea;
168)1- [1- (3-methyl-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3- (3, 4-dichloro-phenyl) -urea;
169)1- [1- (3-methyl-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3-pyridin-3-yl-urea;
170) 7-amino-4- (3-methyl-benzyl) -2H-2, 3-naphthyridin-1-one;
171) n- [ (2, 4-dichloro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -propionamide;
172) n- [1- (2, 4-dichloro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -4-trifluoromethyl-benzamide;
173) furan-2-carboxylic acid [1- (2, 4-dichloro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -amide;
174) n- [1- (2, 4-dichloro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -succinamic acid ethyl ester;
175) n- [1- (2, 4-dichloro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3-cyclopentyl-propionamide;
176) 2-propyl-pentanoic acid [1- (2, 4-dichloro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -amide;
177)1- [1- (2, 4-dichloro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3- (3-trifluoromethyl-phenyl) -urea;
178)1- [1- (2, 4-dichloro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3- (3-methoxy-phenyl) -urea;
179)1- [1- (2, 4-dichloro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3-p-tolyl-urea;
180)1- [1- (2, 4-dichloro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3- (2, 4-difluoro-phenyl) -urea;
181)1- [1- (2, 4-dichloro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3- (3, 4-dichloro-phenyl) -urea;
182)1- [1- (2, 4-dichloro-benzyl) -4-oxo-3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3-pyridin-3-yl) -urea;
183) 7-amino-4- (2, 4-dichloro-benzyl) -2H-2, 3-naphthyridin-1-one;
184) n- (4-oxo-1-quinolin-3-ylmethyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) -propionamide;
185) n- (4-oxo-1-quinolin-3-ylmethyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) -4-trifluoromethyl-benzamide;
186) furan-2-carboxylic acid (4-oxo-1-quinolin-3-ylmethyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) -amide;
187) n- (4-oxo-1-quinolin-3-ylmethyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) -succinamic acid ethyl ester;
188) n- (4-oxo-1-quinolin-3-ylmethyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) -3-cyclopentyl-propionamide;
189) 2-propyl-pentanoic acid (4-oxo-1-quinolin-3-ylmethyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) -amide;
190)1- (4-oxo-1-quinolin-3-ylmethyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) -3- (3-trifluoromethyl-phenyl) -urea;
191)1- (4-oxo-1-quinolin-3-ylmethyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) -3- (3-methoxy-phenyl) -urea;
192)1- (4-oxo-1-quinolin-3-ylmethyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) -3-p-tolyl-urea;
193)1- (4-oxo-1-quinolin-3-ylmethyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) -3- (2, 4-difluoro-phenyl) -urea;
194)1- (4-oxo-1-quinolin-3-ylmethyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) -3- (3, 4-difluoro-phenyl) -urea;
195)1- (4-oxo-1-quinolin-3-ylmethyl-3, 4-dihydro-2, 3-naphthyridin-6-yl) -3-pyridin-3-yl-urea;
196) 7-amino-4-quinolin-3-ylmethyl-2H-3, 4-dihydro-2, 3-naphthyridin-1-one;
197) n- [ 4-oxo-1- (2-trifluoromethyl-benzyl) -3, 4-dihydro-2, 3-naphthyridin-6-yl ] -propionamide;
198) n- [ 4-oxo-1- (2-trifluoromethyl-benzyl) -3, 4-dihydro-2, 3-naphthyridin-6-yl ] -4-trifluoromethyl-benzamide;
199) furan-2-carboxylic acid [ 4-oxo-1- (2-trifluoromethyl-benzyl) -3, 4-dihydro-2, 3-naphthyridin-6-yl ] -amide;
200) n- [ 4-oxo-1- (2-trifluoromethyl-benzyl) -3, 4-dihydro-2, 3-naphthyridin-6-yl ] -succinamic acid ethyl ester;
201) n- [ 4-oxo-1- (2-trifluoromethyl-benzyl) -3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3-cyclopentyl-propionamide;
202) 2-propyl-pentanoic acid [ 4-oxo-1- (2-trifluoromethyl-benzyl) -3, 4-dihydro-2, 3-naphthyridin-6-yl ] -amide;
203)1- [ 4-oxo-1- (2-trifluoromethyl-benzyl) -3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3- (3-trifluoromethyl-phenyl) -urea;
204)1- [ 4-oxo-1- (2-trifluoromethyl-benzyl) -3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3- (3-methoxy-phenyl) -urea;
205)1- [ 4-oxo-1- (2-trifluoromethyl-benzyl) -3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3-p-tolyl-urea;
206)1- [ 4-oxo-1- (2-trifluoromethyl-benzyl) -3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3- (2, 4-difluoro-phenyl) -urea;
207)1- [ 4-oxo-1- (2-trifluoromethyl-benzyl) -3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3- (3, 4-dichloro-phenyl) -urea;
208)1- [ 4-oxo-1- (2-trifluoromethyl-benzyl) -3, 4-dihydro-2, 3-naphthyridin-6-yl ] -3-pyridin-3-yl) -urea
209) 7-amino-4- (2-trifluoromethyl-benzyl) -2H-2, 3-naphthyridin-1-one.
25. A process for the preparation of a compound of formula (I) according to claim 11, and pharmaceutically acceptable salts thereof, which process comprises:
a) under optional reducing conditions, reacting the compound of formula (II)
Wherein R is3And m has the meaning of claim 11 and Hal represents a halogen atom, with suitable phosphine derivatives (PL)3) Reaction to obtain a compound of formula (III)
Wherein P is a phosphorus atom and L is a phosphine ligand;
b) reacting the compound of formula (III) with an aldehyde resin-CHO in the presence of a suitable reducing agent to obtain a resin-supported compound of formula (IV)
Wherein R is3M, P, L, Hal and the resin are as defined above;
c) reacting a compound of formula (IV) with a carbonyl derivative of formula (V) or a nitroso derivative of formula (VI)
R4-CO-R5 (V) R’-NO(VI)
Wherein R is4，R5And R' is as defined in claim 11; to obtain a compound of formula (VII)
Wherein each A is a group ═ CR4R5Or ═ NR'; and optionally reacting the compound of formula (VII) according to any of the following steps d.1) or d.2)
d.1) with one of the derivatives of the formula (VIII), (IX), (X) or (XI) under any basic conditions,
R’COZ(VIII)，R’NCO(IX)，R’OCOZ(X)，R’SO2Z(XI)
wherein Z is a halogen atom or a suitable leaving group and R' is as defined in claim 11, to obtain a compound of formula (XII)
Wherein Rb is-COR ', -CONHR ', -COOR ' or-SO, respectively2R'; or
d.2) reaction with a compound of the formula (XIII)
Rb-Z(XIII)
Wherein Z is a halogen atom and Rb is alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl or heterocyclylalkyl as defined in claim 11, to obtain the corresponding compounds of formula (XII) above;
e) reacting the compound of formula (VII) or (XII) thus obtained with a hydrazine derivative of formula (XIV)
R2-NH-NH2 (XIV)
Wherein R is2As defined in claim 11, to obtain a compound of formula (XV) or (XVI), respectively,
wherein Rb, R2，R3M and resin are as defined above and R1Is of the formula-CHR4R5or-NHR' wherein R4，R5And R' is as defined above;
f) reacting a compound of formula (XV) or (XVI) under acidic conditions to obtain a compound of formula (I), which is converted, when necessary, into another compound of formula (I) and/or a pharmaceutically acceptable salt thereof.
26. The process of claim 25, wherein in step a) the phosphine derivative is triphenylphosphine PPh 3.
27. The process of claim 25, wherein in step b) the reducing agent is selected from pyridine-borane complex, sodium cyanoborohydride, sodium triacetoxyborohydride, or dimethylsulfoborane.
28. The process of claim 25, wherein in step d.1), compounds of the formula (VIII), (X) or (XI) are used in which Z is a chlorine atom.
29. The process of claim 25 wherein in step f), acidic conditions are achieved by using trifluoroacetic acid.
30. Any specific compound of formula (I) as defined in claim 11, which may be obtained, for example, by combinatorial chemistry techniques according to the method set out in claim 25, by first reacting a compound of formula (IV) with one of the aldehyde derivatives of formula (V) as shown in table I;
by reacting any of the resulting compounds of formula (VII) with one of the acid chloride derivatives of formula (VIII) as shown in table II; by reacting any resulting compound of formula (XII) with hydrazine; and processed by step f) of the method according to claim 25.
31. Any specific compound of formula (I) as defined in claim 11, which may be obtained, for example, by combinatorial chemistry techniques according to the method set out in claim 25, by first reacting a compound of formula (IV) with one of the aldehyde derivatives of formula (V) as shown in table I;
by reacting any of the resulting compounds of formula (VII) with one of the isocyanate derivatives of formula (IX) as shown in Table III; by reacting any resulting compound of formula (XII) with hydrazine; and reacting by step f) of the method according to claim 25.
32. Two or more libraries of amino-2, 3-phthalazinone derivatives of formula (I):
wherein
Ra and Rb are each independently a hydrogen atom or optionally further substituted group selected from: straight or branched C1-C6Alkyl radical, C3-C6Cycloalkyl or cycloalkyl C1-C6Alkyl, aryl C1-C6Alkyl, 5-to 7-membered heterocyclyl or heterocyclyl C having 1-3 heteroatoms selected from nitrogen, oxygen or sulfur1-C6An alkyl group; or one of Ra or Rb is hydrogen or optionally substituted straight or branched C1-C6Alkyl and the other is selected from-COR ', -CONHR ', -COOR ' or-SO2R 'wherein R' is hydrogen or an optionally substituted group selected from the above alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl or heterocyclylalkyl groups;
R1is of the formula-CHR4R5Group, wherein R4And R5Each independently hydrogen or optionally substituted C selected from linear or branched1-C6Alkyl radical, C3-C6Cycloalkyl or cycloalkyl C1-C6Alkyl, aryl C1-C6Alkyl, 5-to 7-membered heterocyclyl or heterocyclyl C having 1-3 heteroatoms selected from nitrogen, oxygen or sulfur1-C6A group of alkyl groups; or R1Is of the formula-NHR ', -NR ' COR ', -NR ' CONHR "or-NR ' SO2R ', wherein R' has a definition other than the above-mentioned hydrogen, R 'is hydrogen or has the above-mentioned definition for R';
R2is a hydrogen atom or optionally further substituted group selected from: straight or branched C1-C6Alkyl radical, C3-C6Cycloalkyl or cycloalkyl C1-C6Alkyl, aryl C1-C6Alkyl, 5-to 7-membered heterocyclyl or having 1-3 substituentsHeterocyclic radicals C containing hetero atoms from nitrogen, oxygen or sulfur1-C6An alkyl group;
any R at one or more of the free positions 5, 6 and 8 on the 2, 3-naphthyridone ring3Each independently is a halogen atom, nitro, carboxyl, cyano or optionally further substituted group selected from: straight or branched C1-C6Alkyl radical, C3-C6Cycloalkyl or cycloalkyl C1-C6Alkyl, aryl C1-C6Alkyl, 5-to 7-membered heterocyclyl or heterocyclyl C having 1-3 heteroatoms selected from nitrogen, oxygen or sulfur1-C6An alkyl group; or R3Is selected from-COR ', -CONHR', -SO2R ', -NR' COR ', -NR' CONHR 'or-NR' SO2R ' wherein R ' and R ' are the same or different, are hydrogen or the above-mentioned groups;
m is 0 or an integer of 1 to 3;
or a pharmaceutically acceptable salt thereof.
33. A pharmaceutical composition comprising an effective amount of a compound of formula (I) as defined in claim 11, and at least one pharmaceutically acceptable excipient, carrier or diluent.
34. The pharmaceutical composition according to claim 33, further comprising one or more chemotherapeutic agents as a combined preparation for simultaneous, separate or sequential use in anticancer therapy.
35. A product or kit comprising a compound according to claim 11 or a pharmaceutical composition thereof as defined in claim 33, and one or more chemotherapeutic agents, as a combined preparation for simultaneous, separate or sequential use in anticancer therapy.
36. Use of a compound of formula (I) as defined in claim 11, or a pharmaceutically acceptable salt thereof, as a medicament.
37. Use of a compound of formula (I) as defined in claim 11, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a disease caused by and/or associated with altered protein kinase activity.
38. The use according to claim 37 for the treatment of tumors.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US09/922,729 | 2001-08-07 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| HK1066538A true HK1066538A (en) | 2005-03-24 |
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