CN100354275C - Pyrazolopyridine derivates - Google Patents

Pyrazolopyridine derivates Download PDF

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CN100354275C
CN100354275C CNB2004800053906A CN200480005390A CN100354275C CN 100354275 C CN100354275 C CN 100354275C CN B2004800053906 A CNB2004800053906 A CN B2004800053906A CN 200480005390 A CN200480005390 A CN 200480005390A CN 100354275 C CN100354275 C CN 100354275C
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pyrazolo
fluorophenyl
pyridyl
pyridine
pyridines
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CN1753894A (en
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C·阿曼萨罗萨勒斯
M·沃基利比尔纳多
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Palau Pharma SA
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Palau Pharma SA
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Abstract

New compounds of formula (I) and the salts, solvates and prodrugs thereof, wherein the meanings for the various substituents are as disclosed in the description. These compounds are useful as p38 kinase inhibitors.

Description

Pyrazolo pyridine derivatives
Technical field
The present invention relates to a series of new pyrazolo pyridine derivatives, the method for preparing them, the pharmaceutical composition that contains these compounds and their application in medicine.
Background technology
Kinases is to participate in the protein of replying of different cells to external signal.In the nineties, found new kinases family, be called as MAPK (mitogen activated protein kinase).MAPK is by their substrate of the activation of the phosphorylation in Serine and the threonine residues.
MAPK is in response to signal is by other kinase activations widely, and described signal comprises somatomedin, pro-inflammatory cytokine, UV radiation, intracellular toxin and seepage water pressure.In case they are activated, MAPK activates other kinases or protein by phosphorylation, and transcription factor is for example finally induced the increase or the minimizing of specific gene or genomic expression.
MAPK family comprises p38, ERK (extracellular regulated protein kinase) and JNK kinases such as (the terminal kinases of C-Jun N-).
The p38 kinases cell to stress reaction reply and a large amount of cytokine synthetic activated channels in play the part of pivotal player, described cytokine is tumour necrosis factor (TNF-α), il-1 (IL-1), interleukin-6 (IL-6) and interleukin-8 (IL-8) etc. particularly.
IL-1 and TNF-α are produced by scavenger cell and monocyte, participate in mediation and other physiopathology illnesss of process of immune regulation.For example, the rising of TNF-alpha levels is relevant with inflammatory diseases and autoimmune disorders, and relevant with the process that causes the degeneration of reticular tissue and osseous tissue, for example rheumatoid arthritis, osteoarthritis, diabetes, inflammatory bowel disease and sepsis.
Thereby the p38 kinase inhibitor can be used in treatment or prevents by cytokine mediated diseases such as IL-1 and TNF-α, as noted earlier.
On the other hand, have been found that the p38 inhibitor suppresses other short inflammatory protein matter, for example IL-6, IL-8, interferon-and GM-CSF (granulocyte-macrophage colony-stimulating factor).And, have been found that in nearest research the p38 inhibitor not only blocks cytokine and synthesizes, and block these inductive signal cascades, for example the inducing action of cyclooxygenase-2 (COX-2).
Summary of the invention
An aspect of of the present present invention relates to new compound of Formula I
Figure C20048000539000321
Wherein:
A represents N or N +O -
R 1Represent phenyl or Het, alternatively by one or more R that are selected from aAnd R bSubstituting group replace;
R 2Represent Het, alternatively by one or more R that are selected from aAnd R bSubstituting group replace;
R 3Represent H, Cy, described Cy is alternatively by one or more R that are selected from aAnd R bSubstituting group replace perhaps R 3Represent C 1-6Alkyl is alternatively by one or more R that are selected from bReplace with the substituting group of Cy*, wherein Cy* can be alternatively by one or more R that are selected from bAnd R cSubstituting group replace;
R 4Represent H, R a, halogen ,-OR a' ,-OCOR a,-OSO 2R a,-OCONR aR a' ,-NO 2,-CN ,-COR a' ,-CO 2R a' ,-CONR a' R a' ,-NR a' R a' ,-NR a' COR a' ,-NR a' CONR a' R a' ,-NR a' CO 2R a,-NR a' SO 2R a,-SR a' ,-SOR a,-SO 2R aOr-SO 2NR a' R a';
R 52 N that can be positioned at formula I pyrazoles ring represent H or R on any f
Each R aRepresent C independently 1-6Alkyl, C 2-6Thiazolinyl, C 2-6Alkynyl or Cy, wherein this C 1-6Alkyl, C 2-6Thiazolinyl or C 2-6Alkynyl can be alternatively by one or more R that are selected from bReplace with the substituting group of Cy*, wherein any of group Cy or Cy* can be alternatively by one or more R that are selected from bAnd R cSubstituting group replace;
Each R a' represent H or R independently a
Each R bRepresent independently halogen ,-OR c' ,-OCOR c,-OSO 2R c,-OCONR cR c' ,-NO 2,-CN ,-COR c' ,-CO 2R c' ,-CONR c' R c' ,-CONR c' NR c' R c' ,-NR c' R c' ,-NR c' COR c' ,-NR c' CONR c' R c' ,-NR c' CO 2R c,-NR c' SO 2R c,-SR c' ,-SOR c,-SO 2R c,-SO 2NR c' R c' ,-C (NR c') NR c' R c' ,-C (NSO 2NR c' R c') NR c' R c' ,-C (NOR c') R c' ,-C (NNR c' R c') R c' ,-NR c' C (NR c') NR c' R c' or-NR c' C (NCN) NR c' R c';
Each R cRepresent C independently 1-6Alkyl, C 2-6Thiazolinyl, C 2-6Alkynyl or Cy, wherein all these groups can be alternatively by one or more substituent R dReplace;
Each R c' represent H or R independently c
Each R dRepresent halogen, R independently e,-OR e' ,-OCOR e,-OSO 2R e,-OCONR eR e' ,-NO 2,-CN ,-COR e' ,-CO 2R e' ,-CONR e' R e' ,-CONR e' NR e' R e' ,-NR e' R e' ,-NR e' COR e' ,-NR e' CONR e' R e' ,-NR e' CO 2R e,-NR e' SO 2R e,-SR e' ,-SOR e,-SO 2R e,-SO 2NR e' R e' ,-C (NR e') NR e' R e' ,-C (NSO 2NR e' R e') NR e' R e' ,-C (NOR e') R e' ,-C (NNR e' R e') R e' ,-NR e' C (NR e') NR e' R e' ,-NR e' C (NCN) NR e' R e' or Cy, described Cy is replaced by one or more substituting groups alternatively, and substituting group is selected from halogen, R e,-OR e' ,-OCOR e,-OSO 2R e,-OCONR eR e' ,-NO 2,-CN ,-COR e' ,-CO 2R e' ,-CONR e' R e' ,-CONR e' NR e' R e' ,-NR e' R e' ,-NR e' COR e' ,-NR e' CONR e' R e' ,-NR e' CO 2R e,-NR e' SO 2R e,-SR e' ,-SOR e,-SO 2R e,-SO 2NR e' R e' ,-C (NR e') NR e' R e' ,-C (NSO 2NR e' R e') NR e' R e' ,-C (NOR e') R e' ,-C (NNR e' R e') R e' ,-NR e' C (NR e') NR e' R e' and-NR e' C (NCN) NR e' R e';
Each R eRepresent C independently 1-6Alkyl or halo C 1-6Alkyl;
Each R e' represent H or R independently e
R fRepresent C 1-6Alkyl, C 2-6Thiazolinyl, C 2-6Alkynyl or Cy, wherein this C 1-6Alkyl, C 2-6Thiazolinyl or C 2-6Alkynyl can be alternatively by one or more R that are selected from gReplace with the substituting group of Cy*, wherein any of group Cy or Cy* can be alternatively by one or more R that are selected from gAnd R aSubstituting group replace;
Each R gRepresent independently halogen ,-OR a' ,-OCOR a,-OSO 2R a,-OCONR aR a' ,-NO 2,-CN ,-COR a' ,-CO 2R a' ,-CONR a' R a' ,-CONR a' NR a' R a' ,-NR a' R a' ,-NR a' COR a' ,-NR a' CONR a' R a' ,-NR a' CO 2R a,-NR a' SO 2R a,-SR a' ,-SOR a,-SO 2R a,-SO 2NR a' R a' ,-C (NR a') NR a' R a' ,-C (NSO 2NR a' R a') NR a' R a' ,-C (NOR a') R a' ,-C (NNR a' R a') R a' ,-NR a' C (NR a') NR a' R a' or-NR a' C (NCN) NR a' R a';
Het in the above-mentioned definition represents pyridine, pyrazine, pyrimidine, pyridazine, 2 (1H)-pyridone, 2 (1H)-pyrazine ketone, 2 (1H)-pyrimidone or 2 (1H)-pyridazinone;
On behalf of part 3-to 7-unit's monocycle or 8-to 12-unit two unsaturated, saturated or aromatics, Cy in the above-mentioned definition or Cy* encircle carbocyclic rings, it contains 1 to 4 heteroatoms that is selected from N, S and O alternatively, when ring is saturated or part when unsaturated, it can contain 1 or 2 oxo group alternatively, and wherein said one or more ring can be by carbon or nitrogen atom bonding in the rest part of molecule.
The invention still further relates to additive salt and their solvate and the prodrug of The compounds of this invention.Prodrug is defined as being converted in can body any formula I compound precursor of formula I compound.
Some formula I compound may have chiral centre, may form various steric isomers.The present invention relates to every kind of these steric isomers and composition thereof.And some The compounds of this invention may show the cis/trans isomer.The present invention relates to every kind of geometrical isomer and composition thereof.
Formula I compound is a selectivity p38 kinase inhibitor.
Thereby another aspect of the present invention relates to pharmaceutical composition, and it comprises formula I compound or its pharmacy acceptable salt, solvate or prodrug and one or more pharmaceutically acceptable vehicle of significant quantity.
Another aspect of the present invention relates to formula I compound or its pharmacy acceptable salt, solvate or prodrug and is used for the treatment of or prevents by the purposes in the medicine of the disease of p38 mediation in preparation.
Another aspect of the present invention relates to formula I compound or its pharmacy acceptable salt, solvate or prodrug and is used for the treatment of or prevents by the purposes in the medicine of cytokine mediated disease in preparation.
Another aspect of the present invention relates to formula I compound or its pharmacy acceptable salt, solvate or prodrug and is used for the treatment of or prevents by the purposes in the medicine of the disease of TNF-α, IL-1, IL-6 and/or IL-8 mediation in preparation.
Another aspect of the present invention relates to formula I compound or its pharmacy acceptable salt, solvate or prodrug and is used for the treatment of or prevents to be selected from purposes in the medicine of disease of immunity, autoimmunity and inflammatory diseases, cardiovascular disorder, infectious diseases, bone resorption disease, neurodegenerative disease, proliferative disease and the process relevant with inducing of cyclooxygenase-2 in preparation.
Another aspect of the present invention relates to formula I compound or its pharmacy acceptable salt, solvate or prodrug and is used for the treatment of or prevents purposes by the disease of p38 mediation.
Another aspect of the present invention relates to formula I compound or its pharmacy acceptable salt, solvate or prodrug and is used for the treatment of or prevents purposes by cytokine mediated disease.
Another aspect of the present invention relates to formula I compound or its pharmacy acceptable salt, solvate or prodrug and is used for the treatment of or prevents purposes by the disease of TNF-α, IL-1, IL-6 and/or IL-8 mediation.
Another aspect of the present invention relates to the purposes that formula I compound or its pharmacy acceptable salt, solvate or prodrug are used for the treatment of or prevent to be selected from the disease of immunity, autoimmunity and inflammatory diseases, cardiovascular disorder, infectious diseases, bone resorption disease, neurodegenerative disease, proliferative disease and the process relevant with inducing of cyclooxygenase-2.
Another aspect of the present invention relates to the method for the treatment of or preventing the curee of these needs, especially human disease by the p38 mediation, and it comprises the formula I compound of described curee's administering therapeutic significant quantity or its pharmacy acceptable salt, solvate or prodrug.
Another aspect of the present invention relates to treats or prevents the curee of these needs, especially human method by cytokine mediated disease, and it comprises the formula I compound of described curee's administering therapeutic significant quantity or its pharmacy acceptable salt, solvate or prodrug.
Another aspect of the present invention relates to the method for the treatment of or preventing the curee of these needs, especially human disease by TNF-α, IL-1, IL-6 and/or IL-8 mediation, and it comprises the formula I compound of described curee's administering therapeutic significant quantity or its pharmacy acceptable salt, solvate or prodrug.
Another aspect of the present invention relates to the method for the treatment of or preventing the curee of these needs, especially human a kind of like this disease, described disease is selected from immunity, autoimmunity and inflammatory diseases, cardiovascular disorder, infectious diseases, bone resorption disease, neurodegenerative disease, proliferative disease and the process relevant with inducing of cyclooxygenase-2, and it comprises the formula I compound of described curee's administering therapeutic significant quantity or its pharmacy acceptable salt, solvate or prodrug.
Another aspect of the present invention relates to the preparation method of formula I compound, and it comprises:
(a) make formula IV ketone
Figure C20048000539000361
R wherein 1And R 2Have above-mentioned implication,
With formula V amino-pyrazol and formula VI aldehyde reaction,
Figure C20048000539000362
R wherein 3, R 4And R 5Has above-mentioned implication; Perhaps
(b) if in formula I compound, R 5Represent H, R 3Have and R 1Identical implication makes formula IV ketone or formula VII enolate
Figure C20048000539000363
R wherein 1And R 2Have above-mentioned implication,
With the reaction of formula Va amino-pyrazol,
Figure C20048000539000364
R wherein 4Has above-mentioned implication; Perhaps
(c) if in formula I compound, R 4Represent NH 2, with formula XIX compound
Figure C20048000539000371
R wherein 1, R 2And R 3Have above-mentioned implication,
Handle with formula VIIIa hydrazine,
NH 2-NHR 5
VIIIa
R wherein 5Has above-mentioned implication; Perhaps
(d) divide one or more steps that formula I compound is converted into another kind of formula I compound; And
(e) if necessary, after the step in front, make formula I compound and alkali or acid-respons, obtain corresponding salt.
In the definition in front, term C 1-6Alkyl is represented the straight or branched alkyl chain as the part of a group or group, and it contains 1 to 6 carbon atom.Example comprises methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, isopentyl, neo-pentyl and hexyl etc.
Halo C 1-6Alkyl is represented C 1-6One or more hydrogen atoms of alkyl are substituted the gained group by one or more halogen atoms (being fluorine, chlorine, bromine or iodine), and halogen atom can be identical or different.Example comprises trifluoromethyl, methyl fluoride, 1-chloroethyl, 2-chloroethyl, 1-fluoro ethyl, 2-fluoro ethyl, 2-bromotrifluoromethane, 2-iodine ethyl, 2,2,2-trifluoroethyl, pentafluoroethyl group, 3-fluoropropyl, 3-chloropropyl, 2,2,3,3-tetrafluoro propyl group, 2,2,3,3,3-five fluoropropyls, seven fluoropropyls, 4-fluorine butyl, nine fluorine butyl, 5-fluorine amyl group and 6-fluorine hexyl etc.
Term C 2-6Thiazolinyl is represented the straight or branched hydrocarbyl chain as the part of a group or group, and it contains 2 to 6 carbon atoms, also contains one or more pair of key.Example comprises vinyl, 1-propenyl, 2-propenyl, pseudoallyl, 1-butylene base, crotyl, 3-butenyl, 1,3-butadiene base, 1-pentenyl, pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl and 5-hexenyl etc.
Term C 2-6Alkynyl is represented the straight or branched hydrocarbyl chain as the part of a group or group, and it contains 2 to 6 carbon atoms, also contains one or more triple bond.Example comprises ethynyl, 1-proyl, 2-propynyl, ethyl acetylene base, 2-butyne base, 3-butynyl, 1,3-diacetylene base, 1-pentynyl, valerylene base, 3-pentynyl, 4-pentynyl, 1-hexin base, 2-hexin base, 3-hexin base, 4-hexin base and 5-hexin base etc.
Oxo group represents that carbonyl (CO-).
Halogen atom group's expression fluorine, chlorine, bromine or iodine.
R 1And R 2Het in the definition represents pyridine, pyrazine, pyrimidine, pyridazine, 2 (1H)-pyridone, 2 (1H)-pyrazine ketone, 2 (1H)-pyrimidone or 2 (1H)-pyridazinone.As noted earlier, these groups can be alternatively by one or more R that are selected from aAnd R bSubstituting group replace, they can be positioned at any available position of Het group, and can be via any available carbon or nitrogen atom bonding in the rest part of molecule.
Term Cy or Cy* are as the part of a group or group, expression 3-to 7-unit's monocycle carbon ring group or 8-to 12-unit two ring carbon ring groups, it can be unsaturated, the saturated or aromatics of part, and can contain 1 to 4 heteroatoms that is selected from N, S and O alternatively.When Cy or Cy* group are saturated or part when undersaturated, it can contain 1 or 2 oxo group alternatively.Cy or Cy* ring can be substituted as described in defining as general formula I, and these substituting groups are positioned at any available position, and can be by any available carbon or nitrogen atom bonding in the rest part of molecule.Cy or Cy* examples of groups comprise cyclopropane, tetramethylene, pentamethylene, hexanaphthene, suberane, azacyclopropane, oxyethane, trimethylene oxide, imidazolidine, isothiazolidine, different  azoles alkane,  azoles alkane, pyrazolidine, tetramethyleneimine, thiazolidine, two  alkane, morpholine, piperazine, piperidines, pyrans, tetrahydropyrans, azepine , the  piperazine,  azoles quinoline, pyrroline, thiazoline, pyrazoline, tetrahydroglyoxaline, different  azoles quinoline, isothiazoline, phenyl, naphthyl, 1,2,4- diazole, 1,2, the 4-thiadiazoles, 1,3,4- diazole, 1,3, the 4-thiadiazoles, furans, imidazoles, different  azoles, isothiazole, the  azoles, pyrazoles, the pyrroles, thiazole, thiophene, 1,2, the 3-triazole, 1,2, the 4-triazole, pyrazine, pyridazine, pyridine, pyrimidine, benzoglyoxaline, cumarone, benzothiazole, thionaphthene, Imidazopyrazines, Imidazopyridazine, imidazopyridine, imidazopyrimidine, indazole, indoles, isoindole, isoquinoline 99.9, tetrahydroisoquinoline, naphthyridines, the pyrazolo pyrazine, Pyrazolopyridine, pyrazolopyrimidine, purine, quinazoline, quinoline, quinoxaline, cyclobutanone, cyclopentanone, pimelinketone, suberone, pyrrolidin-2-one, piperidines-2-ketone, piperidin-4-one-, 2 (1H)-pyridones, 2 (1H)-pyrazine ketone, 2 (1H)-pyrimidones, 2 (1H)-pyridazinones and phthalimide etc.
The term heteroaryl is as the part of a group or group, expression aromatics 5-or 6-unit's monocycle or 8-to 1 2-unit two rings, it contains 1 to 4 heteroatoms that is selected from N, S and O, and can be substituted alternatively, disclosed when using this term, wherein said substituting group can be positioned at any available position.Heteroaryl can be by any available carbon or nitrogen atom bonding in the rest part of molecule.The example of heteroaryl comprises 1,2,4- diazole, 1,2, the 4-thiadiazoles, 1,3,4- diazole, 1,3, the 4-thiadiazoles, furans, imidazoles, different  azoles, isothiazole, the  azoles, pyrazoles, the pyrroles, thiazole, thiophene, 1,2,3-triazoles, 1,2, the 4-triazole, pyrazine, pyridazine, pyridine, pyrimidine, benzoglyoxaline, cumarone, benzothiazole, thionaphthene, Imidazopyrazines, Imidazopyridazine, imidazopyridine, imidazopyrimidine, indazole, indoles, isoindole, isoquinoline 99.9, naphthyridines, the pyrazolo pyrazine, Pyrazolopyridine, pyrazolopyrimidine, purine, quinazoline, quinoline and quinoxaline etc.
In the definition of Het, heteroaryl, Cy and Cy*, the ring deutero-group from correspondence represented in this term in front.
In front in the definition of heteroaryl, Cy and Cy*, when in general sense two rings of specified case representation, comprise that all possible atom arranges.For example, the term Pyrazolopyridine is appreciated that groups such as comprising 1H-pyrazolo [3,4-b] pyridine, pyrazolo [1,5-a] pyridine, 1H-pyrazolo [3,4-c] pyridine, 1H-pyrazolo [4,3-c] pyridine and 1H-pyrazolo [4,3-b] pyridine; The term Imidazopyrazines is appreciated that groups such as comprising 1H-imidazo [4,5-b] pyrazine, imidazo [1,2-a] pyrazine and imidazo [1,5-a] pyrazine; The term pyrazolopyrimidine is appreciated that groups such as comprising 1H-pyrazolo [3,4-d] pyrimidine, 1H-pyrazolo [4,3-d] pyrimidine, pyrazolo [1,5-a] pyrimidine and pyrazolo [1,5-c] pyrimidine.
Phraseology " is replaced by one or more substituting groups alternatively " and means that a group can be replaced by one or more, preferred 1,2,3 or 4 substituting group, as long as this group has 1,2,3 or 4 easy substituted position.
In the definition in front, mentioning R 52 N that can be positioned at the pyrazoles ring this means R on any the time 51 N that can be positioned at this ring go up or 2 N on.Thereby formula I compound comprises following two types compound:
Figure C20048000539000401
A kind of embodiment of the present invention is those formulas I compound as defined above, and wherein A represents N.
Another embodiment of the present invention is such formula I compound, and wherein A represents N, R 52 N that can be positioned at formula I pyrazoles ring represent H or R on any a
If another embodiment of the present invention is such formula I compound, wherein R 3And R 5All represent H, R 2Represent Het, described Het is replaced by one or more substituting groups alternatively, substituting group be selected from halogen ,-CN ,-CF 3,-OH ,-NO 2,-OR 6,-NR 6R 6,-OCF 3, C 1-6Alkyl, C 2-6Thiazolinyl, C 2-6Alkynyl and Cy, wherein Cy can be alternatively by one or more R that are selected from bAnd R cSubstituting group replace R wherein 6Represent C 1-6Alkyl, then R 4Be not-NR a' COR a,-NHCONHR aOr-NHCO 2R a
If another embodiment of the present invention is such formula I compound, wherein R 3And R 5All represent H, then R 4Be not-NR a' COR a,-NHCONHR aOr-NHCO 2R a
Another embodiment of the present invention is such formula I compound, and wherein A represents N; R 4Represent H, R a, halogen ,-OR a,-OCOR a,-OSO 2R a,-OCONR aR a' ,-NO 2,-CN ,-COR a' ,-CO 2R a' ,-CONR a' R a' ,-NR a' R a' ,-NR a' SO 2R a,-SR a' ,-SOR a,-SO 2R aOr-SO 2NR a' R a'; R 52 N that can be positioned at formula I pyrazoles ring represent H or R on any a
Another embodiment of the present invention is such formula I compound, wherein R 1Represent pyridine or phenyl, wherein all these groups can be alternatively by one or more R that are selected from aAnd R bSubstituting group replace.
Another embodiment of the present invention is such formula I compound, wherein R 1Represent phenyl, alternatively by one or more R that are selected from aAnd R bSubstituting group replace.
Another embodiment of the present invention is such formula I compound, wherein R 1Represent phenyl, replaced by one or more substituting groups alternatively, substituting group be selected from halogen ,-OR c' ,-NO 2,-CN ,-CONR c' R c' ,-NR c' R c' and C 1-6Alkyl, this alkyl is replaced by one or more substituting groups alternatively, substituting group be selected from halogen ,-OR c' ,-COR c' ,-NR c' R c' and-NR c' COR c'.
Another embodiment of the present invention is such formula I compound, wherein R 1Represent phenyl, alternatively by one or more halogen and halo C of being selected from 1-6The substituting group of alkyl replaces.
Another embodiment of the present invention is such formula I compound, wherein R 2Represent pyridine or pyrimidine, wherein all these groups can be alternatively by one or more R that are selected from aAnd R bSubstituting group replace.
Another embodiment of the present invention is such formula I compound, wherein R 2Represent 4-pyridine or 4-pyrimidine, wherein all these groups can be alternatively by one or more R that are selected from aAnd R bSubstituting group replace.
Another embodiment of the present invention is such formula I compound, wherein R 2Represent 4-pyridine or 4-pyrimidine, wherein all these groups can be replaced by one or more substituting groups alternatively, substituting group be selected from halogen ,-OR c' ,-NR c' R c' ,-SR c' and-SO 2R c
Another embodiment of the present invention is such formula I compound, wherein R 2Represent the 4-pyridine.
Another embodiment of the present invention is such formula I compound, wherein R 2Represent quilt-NR c' R c' the 4-pyrimidine that replaces; Wherein at R 2In:
Each R c' represent H or R independently c
Each R cRepresent C independently 1-6Alkyl, alternatively by one or more be selected from Cy and-OR e' substituting group replace;
Each R e' represent H or R independently e
Another embodiment of the present invention is such formula I compound, wherein R 3Represent H or Cy, alternatively by one or more R that are selected from aAnd R bSubstituting group replace.
Another embodiment of the present invention is such formula I compound, wherein R 3Represent H, heteroaryl or phenyl, wherein all these groups can be alternatively by one or more R that are selected from aAnd R bSubstituting group replace.
Another embodiment of the present invention is such formula I compound, wherein R 3Represent heteroaryl or phenyl, wherein all these groups can be alternatively by one or more R that are selected from aAnd R bSubstituting group replace.
Another embodiment of the present invention is such formula I compound, wherein R 3Represent bicyclic heteroaryl or phenyl, wherein all these groups can be replaced by one or more substituting groups alternatively, substituting group be selected from halogen ,-NO 2,-OR c', C 1-6Alkyl and Cy, wherein C 1-6Alkyl can be alternatively by one or more R that are selected from bReplace with the substituting group of Cy*, any of group Cy or Cy* can be alternatively by one or more R that are selected from bAnd R cSubstituting group replace.
Another embodiment of the present invention is such formula I compound, wherein R 3Represent bicyclic heteroaryl or phenyl, wherein all these groups can be replaced by one or more substituting groups alternatively, substituting group be selected from halogen ,-NO 2,-OR c', C 1-6Alkyl, halo C 1-6Alkyl and Cy; Wherein at R 3In:
Each R c' represent H or R independently c
Each R cRepresent C independently 1-6Alkyl is alternatively by one or more substituent R dReplace;
Each R dRepresent Cy independently.
Another embodiment of the present invention is such formula I compound, wherein R 4Represent H, R a, halogen ,-OR a' ,-CN ,-CONR a' R a,-NR a' R a' or-NR a' COR a'.
Another embodiment of the present invention is such formula I compound, wherein R 4Represent H.
Another embodiment of the present invention is such formula I compound, wherein R 5Represent H, perhaps R 5Represent R f, be positioned on 2 N of pyrazoles ring.
Another embodiment of the present invention is such formula I compound, wherein R 5Represent R f, be positioned on 2 N of pyrazoles ring.
Another embodiment of the present invention is such formula I compound, wherein R fRepresent C 1-6Alkyl, C 2-6Thiazolinyl or Cy, wherein C 1-6Alkyl or C 2-6Thiazolinyl can be alternatively by one or more R that are selected from gReplace with the substituting group of Cy*, wherein any of group Cy or Cy* can be alternatively by one or more R that are selected from gAnd R aSubstituting group replace.
Another embodiment of the present invention is such formula I compound, wherein R fRepresent C 1-6Alkyl, C 2-6Thiazolinyl or Cy, wherein C 1-6Alkyl or C 2-6Thiazolinyl can be alternatively by one or more R that are selected from gReplace with the substituting group of Cy*, wherein any of group Cy or Cy* can be alternatively by one or more R that are selected from gAnd R aSubstituting group replace each R wherein gRepresent independently halogen ,-OR a' ,-COR a' ,-CO 2R a' ,-CONR a' R a' ,-NR a' R a' ,-NR a' COR a' ,-NR a' CONR a' R a' ,-NR a' SO 2R a' ,-SR a' ,-SOR a' or-SO 2R a'.
Another embodiment of the present invention is such formula I compound, wherein R fRepresent C 1-6Alkyl, C 2-6Thiazolinyl or Cy, wherein C 1-6Alkyl or C 2-6Thiazolinyl can be alternatively by one or more R that are selected from gReplace with the substituting group of Cy*, wherein any of group Cy or Cy* can be alternatively by one or more R that are selected from gAnd R aSubstituting group replace, wherein at R fIn:
Each R gRepresentative-OR independently a' ,-COR a' ,-CONR a' R a' ,-NR a' R a' ,-NR a' COR a' ,-NR a' CONR a' R a' ,-NR a' SO 2R a' ,-SOR a' or-SO 2R a';
Each R a' represent H or R independently a
Each R aRepresent Cy or C independently 1-6Alkyl, wherein C 1-6Alkyl can be alternatively by one or
A plurality of R that are selected from bReplace with the substituting group of Cy*, any of group Cy or Cy* can be alternatively
By one or more R that are selected from bAnd R cSubstituting group replace;
Each R bRepresentative-OR independently c' ,-NR c' R c' ,-CN ,-COR c' ,-SR c' or-SOR c';
Each R c' represent H or R independently c
Each R cRepresent C independently 1-6Alkyl or Cy, wherein all these groups can be alternatively by one or more R dReplace.
Another embodiment of the present invention is such formula I compound, wherein R 5Be positioned on 2 N of pyrazoles ring, represent R f, R wherein fRepresent C 1-6Alkyl is replaced by one or more substituting groups alternatively, and substituting group is selected from-OR a' ,-COR a' ,-CONR a' R a' ,-NR a' R a' ,-NR a' COR a' ,-NR aCONR a' R a' ,-NR a' SO 2R a' and Cy*, this Cy* is alternatively by one or more R that are selected from aSubstituting group replace; Wherein at R fIn:
Each R a' represent H or R independently a
Each R aRepresent Cy or C independently 1-6Alkyl, wherein C 1-6Alkyl can be alternatively by one or
A plurality of R that are selected from bReplace with the substituting group of Cy*, any of group Cy or Cy* can be alternatively by one or more R that are selected from bAnd R cSubstituting group replace;
Each R bRepresentative-OR independently c' ,-NR c' R c' ,-CN ,-COR c' ,-SR c' or-SOR c';
Each R c' represent H or R independently c
Each R cRepresent C independently 1-6Alkyl or Cy, wherein all these groups can be alternatively by one or more R dReplace;
Each R dRepresentative-OR independently e'.
Another embodiment of the present invention is such formula I compound, wherein R 5Represent H, perhaps R 5Represent R a, be positioned on 2 N of pyrazoles ring.
Another embodiment of the present invention is such formula I compound, wherein R 5Represent R a, be positioned on 2 N of pyrazoles ring.
Another embodiment of the present invention is such formula I compound, wherein R 5In R aRepresent C 1-6Alkyl, C 2-6Thiazolinyl or Cy, wherein C 1-6Alkyl or C 2-6Thiazolinyl can be alternatively by one or more R that are selected from bReplace with the substituting group of Cy*, wherein any of group Cy or Cy* can be alternatively by one or more R that are selected from bAnd R cSubstituting group replace.
Another embodiment of the present invention is such formula I compound, wherein R 5In R aRepresent C 1-6Alkyl, C 2-6Thiazolinyl or Cy, wherein C 1-6Alkyl or C 2-6Thiazolinyl can be alternatively by one or more R that are selected from bReplace with the substituting group of Cy*, wherein any of group Cy or Cy* can be alternatively by one or more R that are selected from bAnd R cSubstituting group replace R wherein 5In each R bRepresent independently halogen ,-OR c' ,-COR c' ,-CO 2R c' ,-CONR c' R c' ,-NR c' R c' ,-NR c' COR c' ,-NR c' CONR c' R c' ,-NR c' SO 2R c' ,-SR c' ,-SOR c' or-SO 2R c'.
Another embodiment of the present invention is such formula I compound, wherein R 5In R aRepresent C 1-6Alkyl, C 2-6Thiazolinyl or Cy, wherein C 1-6Alkyl or C 2-6Thiazolinyl can be alternatively by one or more R that are selected from bReplace with the substituting group of Cy*, wherein any of group Cy or Cy* can be alternatively by one or more R that are selected from bAnd R cSubstituting group replace; Wherein at R 5In: each R bRepresentative-OR independently c' ,-COR c' ,-CONR c' R c' ,-NR c' R c' ,-NR c' COR c' ,-NR c' CONR c' R c' ,-NR c' SO 2R c' ,-SOR c' or-SO 2R c';
Each R c' represent H or R independently c
Each R cRepresent Cy or C independently 1-6Alkyl, wherein all these groups can be alternatively by one or more R that are selected from dSubstituting group replace;
Each R dRepresent R independently e,-OR e' ,-NR e' R e' ,-CN ,-COR e' ,-SR e' ,-SOR e' or Cy.
Another embodiment of the present invention is such formula I compound, wherein R 5Be positioned on 2 N of pyrazoles ring, represent R a, R wherein 5In R aRepresent C 1-6Alkyl is replaced by one or more substituting groups alternatively, and substituting group is selected from-OR c' ,-COR c' ,-CONR c' R c' ,-NR c' R c' ,-NR c' COR c' ,-NR c' CONR c' R c' ,-NR c' SO 2R c' and Cy*, this Cy* is alternatively by one or more R that are selected from cSubstituting group replace; Wherein at R 5In:
Each R c' represent H or R independently c
Each R cRepresent Cy or C independently 1-6Alkyl, wherein all these groups can be alternatively by one or more R that are selected from dSubstituting group replace;
Each R dRepresentative-OR independently e' ,-NR e' R e' ,-CN ,-COR e' ,-SR e' ,-SOR e' or Cy;
Each R e' represent H or R independently e
Each R eRepresent C independently 1-6Alkyl.
In addition, all possible combination of above-mentioned embodiment also constitutes a part of the present invention.
The compounds of this invention can contain one or more basic nitrogens, therefore can generate salt with organic or inorganic acid, and this also constitutes a part of the present invention.The example of these salt comprises: with the salt of mineral acid, described mineral acid is hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, nitric acid, perchloric acid, sulfuric acid or phosphoric acid for example; With organic acid salt, described organic acid is methylsulfonic acid, trifluoromethanesulfonic acid, ethyl sulfonic acid, Phenylsulfonic acid, right-toluenesulphonic acids, fumaric acid, oxalic acid, acetate or oxysuccinic acid or the like for example.The compounds of this invention can contain one or more acid protons, so they can also generate salt with alkali, and this also constitutes a part of the present invention.The example of these salt comprises: with the salt of inorganic cation, positively charged ion is sodium, potassium, calcium, magnesium, lithium, aluminium, zinc etc. for example; With the salt that pharmaceutically acceptable amine forms, amine is ammonia, alkylamine, hydroxyalkyl amine, Methionin, arginine, N-methylglucosamine, PROCAINE HCL, PHARMA GRADE etc. for example.For the type of operable salt without limits, as long as be pharmaceutically acceptable when they are used for the treatment of purpose.Salt can prepare like this, in a conventional manner, formula I compound with required acid or the alkaline purification of capacity, is obtained salt.Formula I compound and their salt are different on some physical propertiess, but they are equal to for purposes of the present invention.
Can there be the solvation form in some The compounds of this invention, comprises hydrated form.Generally speaking, for purposes of the present invention, be equal to not solvation form with the solvation form of pharmaceutically acceptable solvent, for example water, ethanol etc.
Some The compounds of this invention can exist some diastereomers and/or some optically active isomers.Diastereomer can be separated by routine techniques, for example chromatogram or fractional crystallization.Optically active isomer can be split by conventional optical resolution technology, obtains optically pure isomer.This fractionation can be carried out at any chirality synthetic intermediate or general formula I product.Optically pure isomer also can utilize the synthetic acquisition separately of mapping specificity.No matter synthetic all isomer and composition thereof (for example racemic mixture) are contained in the present invention, still physical mixed and getting.
And can there be the cis/trans isomer in some The compounds of this invention.The present invention includes every kind of geometrical isomer and composition thereof.
Formula I compound can obtain according to following process.Just as the skilled person will be apparent, blanking method can be different because of its chemical structure really to be used to prepare set compound.And, in some following process, may be necessity or desirable with GPF (General Protection False radical protection reactivity or unstable group.The attribute of these blocking groups and introducing or the technology of removing them are all known, a part that constitutes prior art is (for example referring to Greene T.W.and WutsP.G.M, " Protective Groups in Organic Synthesis ", John Wiley﹠amp; Sons, 3rd edition, 1999).Blocking group with amino-functional is an example, can use tertbutyloxycarbonyl (Boc) or benzyl (Bn).Carboxyl for example can protected one-tenth C 1-6The form of alkyl ester or alkyl aryl, benzyl for example, and hydroxyl for example can protect with THP trtrahydropyranyl (THP).No matter when have blocking group, what all will need the back goes to protect step, and this can carry out under standard organic synthesis condition, for example above-mentioned reference described those.
Formula I compound generally can obtain by the reaction of formula IV compound and formula V amino-pyrazol and formula VI aldehyde, shown in the following flow process:
Figure C20048000539000461
R wherein 1, R 2, R 3, R 4And R 5Have the implication identical with general formula I.This reaction preferably is performed such, in the presence of mineral acid, and hydrochloric acid for example, in the polar solvent that is fit to, for example 2-methyl cellosolve or ethanol, heating is preferably to refluxing.
R wherein 5Represent R 5*Formula I compound (being formula Ia and Ib compound) generally be by R wherein 5Represent the formula I compound (being formula Ic compound) and formula R of H 5*The reaction of-X (II) alkylating agent obtains, shown in the following flow process:
Figure C20048000539000471
R wherein 5*Represent R aOr R fR 1, R 2, R 3, R 4, R aAnd R fHave the described implication of general formula I, X represents leavings group, for example alkyl sulfonic ester or aromatic yl sulphonate, for example methanesulfonates or tosylate, perhaps halogen, for example Cl, Br or I.This reaction is performed such, in the presence of alkali, and for example KOH, K 2CO 3Or NaH, in the solvent that is fit to, for example acetone, toluene, dimethyl formamide, 1,2-glycol dimethyl ether or diglyme, heating is preferably to refluxing.Using under the situation of non-polar solvent, toluene for example, this reaction is performed such, in the presence of cation chelating agent, crown ether 18-C-6 for example, perhaps in the presence of consisting of phase-transferring agent, tetraalkylammonium salt for example.
R wherein aRepresentative-CH 2The formula Ia of OH and Ib compound can be by the prepared in reaction of formula Ic compound and formaldehyde, and reaction conditions is in the polar solvent that is fit to, and for example water heats, preferably to refluxing.
R wherein aRepresent the formula Ia and the Ib compound of optional substituted phenyl or optional substituted heteroaryl can be by formula Ic compound and formula R a-B (OH) 2(III) prepared in reaction of boric acid, wherein R aRepresent optional substituted phenyl or heteroaryl, reaction conditions is in the presence of alkali, for example pyridine and/or triethylamine, and in the presence of catalyzer, venus crystals (II) for example, in the solvent that is fit to, for example aprotic solvent, for example methylene dichloride.
Formula II and III compound be commercial available, be to have broadly described in the literature or can be by the preparation of described similarity method, and suitablely protected as required.
R wherein 5Represent H, R 3Have and R 1The formula I compound of identical meanings (being Compound I d) also can be by the prepared in reaction of formula IV compound and formula Va amino-pyrazol, shown in the following flow process:
Figure C20048000539000481
Perhaps select as an alternative, by the prepared in reaction of formula VII compound and formula Va compound:
Figure C20048000539000482
R wherein 1, R 2And R 4Has the described implication of general formula I.This reaction preferably is performed such, in the presence of mineral acid, and hydrochloric acid for example, in the polar solvent that is fit to, for example 2-methyl cellosolve or ethanol, heating is preferably to refluxing.
Formula V and Va amino-pyrazol and formula VI aldehyde are commercial available, and can be protected aptly.Select as an alternative, formula Va compound can be aptly by the prepared in reaction of formula VIII compound and formula IX compound, shown in the following flow process:
Figure C20048000539000483
R wherein 4Has the described implication of general formula I.This reaction is performed such, and in the polar solvent that is fit to, for example ethanol heats, preferably to refluxing.Formula V compound also can obtain by this method, from formula IX compound and formula NH 2-NHR 5(VIIIa) compound begins.
Formula IX compound is commercial available, and can be protected aptly, perhaps can be aptly by formula X compound
Figure C20048000539000484
With the prepared in reaction of acetonitrile, reaction conditions is in the presence of alkali, butyllithium for example, and in the solvent that is fit to, tetrahydrofuran (THF) for example, under the temperature that is fit to, preferred-78 ℃.
Formula X ester is commercial available, perhaps can be by the preparation of broadly described method be arranged in the literature, and can be protected aptly.
Formula VII enol ether can be aptly by formula IV ketone and formula R 1The prepared in reaction of-COY (XI) compound, wherein Y represents halogen, preferred Cl, reaction conditions be in the presence of alkali, NaH for example, in suitable polar solvent, dimethyl formamide for example.
Formula XI compound is commercial available, perhaps can be by the formula R of popular response from correspondence 1-CO 2The preparation of H (XII) carboxylic acid.
Formula XII compound is commercial available, perhaps can be by the preparation of broadly described method be arranged in the literature, and can be protected aptly.
Formula IV compound can be by formula R 1The prepared in reaction of-H (XIII) compound and formula XIV compound:
R wherein 1And R 2Have the described implication of general formula I, reaction conditions is in the presence of lewis acidic, for example AlCl 3, in the halogenated solvent that is fit to, methylene dichloride for example.
Formula XIV compound is commercial available, perhaps can be easily according to the carboxylic acid preparation of common process from correspondence.
Select as an alternative, formula IV compound can be aptly by formula R 2-CH 3(XV) compound and formula R 1The prepared in reaction of-CN (XVI) compound, wherein R 1And R 2Have the described implication of general formula I, reaction conditions is in the presence of alkali, diisopropylamino lithium for example, and it is from butyllithium and N, N '-diisopropylamine generates, in proton-inert polar solvent, tetrahydrofuran (THF) for example, cooling is preferably to-78 ℃.
Select as an alternative, formula IV compound can be aptly by formula R 2-CH 3(XV) compound and formula R 1-CO 2R 6(XVII) prepared in reaction of compound, wherein R 1And R 2Has the described implication of general formula I, R 6Represent C 1-6Alkyl, reaction conditions are in the presence of alkali, for example two (trimethylsilyl) sodium amides or sodium hydride, and in proton-inert polar solvent, for example tetrahydrofuran (THF) or dimethyl formamide, under the temperature that is fit to, preferred room temperature.
Formula XIII, XV, XVI and XVII compound are commercial available, perhaps can be by broadly described method preparation is arranged in the literature.
Select as an alternative, formula IV compound can be aptly by formula R 2-CH 3(XV) prepared in reaction of compound and formula XVIII compound, described those are identical about the reaction of formula XV compound and formula XVI compound for reaction conditions and front.
Formula XVIII compound can be aptly by formula XI compound and N, the prepared in reaction of O-dimethyl hydroxylamine hydrochloride, and reaction conditions is in the presence of alkali, triethylamine for example, in the halogenated solvent that is fit to, methylene dichloride for example, cooling is preferably to 0 ℃.
Select as an alternative, formula XVIII compound can be by formula XII compound and N, the prepared in reaction of O-dimethyl hydroxylamine hydrochloride, reaction conditions is in the presence of the condensing agent that is fit to, and N-(3-dimethylamino-propyl)-N '-ethyl carbodiimide or dicyclohexylcarbodiimide for example is alternatively in the presence of I-hydroxybenzotriazole, perhaps in the presence of the alkali that is fit to, pyridine for example, in the solvent that is fit to, dimethyl formamide for example.
Formula I compound also can obtain from formula XIX compound, shown in the following flow process.
Figure C20048000539000502
Figure C20048000539000511
R wherein 1, R 2, R 3, R 4And R 5Has the described implication of general formula I.The reaction of XIX and formula VIIIa compound generates wherein R 4=NH 2Formula I compound (Ie).This reaction is performed such, and in the solvent that is fit to, for example ethanol heats, preferably to refluxing.From these R wherein 4=NH 2Formula I compound begin, can generate wherein R by mutual conversion reaction 4Not NH 2Formula I compound, this has detailed explanation in addition.This method can be used for preparing such formula I compound, wherein R 3Represent H, optional substituted C 1-6Alkyl or Cy are different from R 1
Formula VIIIa compound is commercial available, and can be protected aptly.
Formula XIX compound can be aptly by formula XX compound
Figure C20048000539000512
R wherein 1, R 2And R 3Have the described implication of general formula I,
With chlorizating agent, POCl for example 3Or PCl 3Prepared in reaction, reaction need not solvent or in the solvent that is fit to, dimethyl formamide for example, heating is preferably to refluxing.
Formula XX compound generally is to obtain by the reaction of formula XXI compound and 2-malonamide nitrile, shown in the following flow process:
R wherein 1, R 2And R 3Has the described implication of general formula I, each R 6Represent C independently 1-6Alkyl.This reaction is performed such, in the presence of alkali, and sodium methylate for example, in the solvent that is fit to, dimethyl formamide for example, heating is preferably to refluxing.
Formula XXI compound can be aptly by the prepared in reaction of formula IV compound and formula XXII compound:
Figure C20048000539000521
R wherein 3And R 6Have aforementioned implication, reaction conditions is in the solvent that is fit to, for example tetrahydrofuran (THF).
Formula XXII compound is commercial available, perhaps can for example make formula XXIII acid amides by the described method preparation of document
Figure C20048000539000522
With triethyl oxygen  Tetrafluoroboric acid reactant salt, reaction conditions is in the presence of alkali, sodium ethylate for example, and in the solvent that is fit to, for example ethanol or ethanol-diethyl ether mixture.
Select as an alternative, The compounds of this invention also can obtain by the mutual conversion of another kind of formula I compound, under the standard test condition of being reported, in one or several steps, adopts the organic chemical reactions of knowing.
Thereby, R 4Can be converted into another kind of R 4, generate new formula I compound.For example, R 4=H can by with suitable bromizating agent, for example Br 2Reaction be converted into R 4=Br, reaction conditions are in the solvent that is fit to, and chloroform for example is under suitable temperature, between the boiling point of room temperature and solvent;
Perhaps R 4=H can be by being converted into R with suitable chlorizating agent, the reaction of for example N-chloro-succinimide 4=Cl, reaction conditions are in the solvent that is fit to, and dimethyl formamide for example is under suitable temperature, between the boiling point of room temperature and solvent;
Perhaps R 4=NH 2Can by with NaNO 2Generate diazonium salt, be converted into R succeeded by reaction with copper halide, for example CuBr or CuCl 4=halogen, reaction conditions are in the presence of acid, for example HBr or HCl;
Perhaps R 4=NH 2Can by with NaNO 2Generate diazonium salt, succeeded by with H 3PO 2Reaction be converted into R 4=H, reaction conditions are in the solvent that is fit to, for example water;
Perhaps R 4=halogen can be converted into R by the reaction with cyanide salt, for example CuCN 4=CN, reaction conditions are in the solvent that is fit to, and for example N-Methyl pyrrolidone heats, preferably to refluxing.
Other R 4Transform and also can be applied to R 5And R 1, R 2With R 3The substituting group of group generates other formulas I compound, for example comprises:
CN is to CONH 2Conversion be to use basic hydrolysis, KOH for example, reaction conditions are in the solvent that is fit to, the trimethyl carbinol for example, heating is preferably to refluxing;
CN is to CH 2NH 2Conversion be and reductive agent reaction LiAlH for example 4, reaction conditions is in the solvent that is fit to, for example diethyl ether;
Hydroxy-acid group to the conversion of ester or acid amides be respectively with alcohol or amine reaction, reaction conditions be in the presence of activator, N for example, N '-dicyclohexylcarbodiimide and 4-Dimethylamino pyridine, in suitable solvent, diethyl ether for example;
Ester group is hydrolysis in the presence of alkali to the conversion of carboxyl, and KOH for example, reaction conditions are in the solvent that is fit to, for example ethanol;
OH, SH or NH 2Conversion to OR, SR and NHR or NRR is to react with alkylating agent R-X respectively, and wherein R represents R a, R c, R eOr R fX represents halogen, preferred chlorine or bromine, reaction conditions is in the presence of alkali, for example triethylamine, sodium hydroxide, yellow soda ash, salt of wormwood or sodium hydride, in the solvent that is fit to, for example methylene dichloride, chloroform, dimethyl formamide, ethanol or butanols are under the temperature between room temperature and the solvent boiling point;
Select as an alternative, NHR can be converted into NCH by the reaction with formaldehyde 3R, wherein R represents R a, R c, R eOr R f, reaction conditions is in acid medium, for example formic acid heats, preferably to refluxing;
Amine to the conversion of acid amides is and carboxylic acid reaction, reaction conditions is in the presence of suitable condensing agent, N-(3-dimethylamino-propyl)-N '-ethyl carbodiimide or dicyclohexylcarbodiimide for example, alternatively in the presence of I-hydroxybenzotriazole, perhaps in the presence of suitable alkali, pyridine for example, in the solvent that is fit to, dimethyl formamide for example; Perhaps select as an alternative, amine can be converted into acid amides by the reaction with acyl chlorides, and reaction conditions be in pyridine, perhaps in the presence of alkali, and triethylamine for example, in the solvent that is fit to, for example methylene dichloride cools off, preferably to 0 ℃;
Amine transforms to involve to two steps of urea or carbamate and makes amine and activator reaction, triphosgene for example, reaction conditions is in the presence of alkali, for example diisopropylethylamine, triethylamine or N-methylmorpholine, in the solvent that is fit to, for example acetonitrile or halon, for example chloroform or methylene dichloride, make gained compound and second kind of amine (under the situation of urea) or alcohol (under the situation of carbamate) reaction then, reaction conditions is in the solvent that is fit to, and for example is used in the solvent in the first step; Perhaps select as an alternative, amine can be by being converted into urea or carbamate with the reaction of isocyanic ester or chloro-formic ester respectively, and reaction conditions be in the solvent that is fit to, dimethyl formamide for example, and under the temperature that is fit to, preferred room temperature;
Amine to the conversion of sulphonamide is and the sulfonic acid halide reaction, SULPHURYL CHLORIDE for example, and reaction conditions be alternatively in the presence of alkali, 4-Dimethylamino pyridine for example, in suitable solvent, for example two  alkane, chloroform, methylene dichloride or pyridine;
Hydroxyl is and carboxylic acid reaction that reaction conditions is above-mentioned standard conditions to the conversion of ester group;
The conversion of sulfane basal orientation sulfinyl or alkylsulfonyl be respectively with the suitable oxidant reaction of 1 or 2 equivalents, for example between-the chlorine peroxybenzoic acid, reaction conditions is in the solvent that is fit to, for example methylene dichloride;
Uncle or secondary hydroxyl are to react with sulfonic acid halide to the conversion of leavings group, for example alkyl sulfonic ester or aromatic yl sulphonate, for example methanesulfonates or tosylate or halogen, for example Cl, Br or I, methylsulfonyl chloride for example, reaction conditions is in the presence of alkali, for example pyridine or triethylamine, in the solvent that is fit to, for example methylene dichloride or chloroform perhaps react with halogenating agent, for example SOCl 2, reaction conditions is in the solvent that is fit to, for example tetrahydrofuran (THF);
The replacement of described leavings group is and alcohol, amine or thiol reactant, and reaction conditions is alternatively in the presence of alkali, for example K 2CO 3, in the solvent that is fit to, dimethyl formamide, 1 for example, 2-glycol dimethyl ether or acetonitrile;
The elimination that is bonded to the leavings group of alkyl obtains thiazolinyl and is and alkali reaction, and KOH for example, reaction conditions are in the solvent that is fit to, toluene for example, and heating is preferably to refluxing;
Primary amide to the conversion of secondary amide is and alkylation reactions, and reaction conditions is in the presence of alkaline, and sodium hydride for example is in the solvent that is fit to, under the temperature between room temperature and the solvent boiling point;
CHO to the conversion of amine is and the amine reaction, and reaction conditions is in the presence of reductive agent, sodium triacetoxy borohydride for example, and in the solvent that is fit to, for example 1, the 2-ethylene dichloride;
Acetal groups is to react in acid medium to the conversion of aldehyde, HCl for example, and reaction conditions is under suitable temperature, preferably to refluxing;
Ester group to the conversion of alcohol groups is and reductive agent reaction, for example LiAlH 4, reaction conditions is in the solvent that is fit to, for example tetrahydrofuran (THF);
The alkylsulfonyl that is bonded to aromatic ring to the conversion of aminoderivative is and the reaction of corresponding amine, reaction conditions is in the solvent that is fit to, tetrahydrofuran (THF) for example, perhaps use this amine as solvent, heating, preferably in the temperature between room temperature and 100 ℃, and preferably the encloses container depressed of atmosphere in react;
The conversion that is bonded to the alkylsulfonyl of aromatic ring is to obtain corresponding alkoxy derivative with the alcoholate displacement, reaction conditions is in the solvent that is fit to, tetrahydrofuran (THF) for example, perhaps use corresponding alcohol as solvent, heating, preferably to the temperature between room temperature and 100 ℃, and preferably the encloses container depressed of atmosphere in react;
Olefinic or aromatic halogen are to NHR, wherein R represents R a, R c, R eOr R fConversion be and formula H 2The reaction of NR amine, preferably heating;
Select as an alternative, olefinic or aromatic halogen can by with formula H 2The reaction of NR amine is converted into NHR, and reaction conditions is in the presence of alkali, for example Cs 2CO 3Or sodium tert-butoxide, in the presence of palladium catalyst, acid chloride (II) and in the presence of phosphine for example, 2,2 '-two (diphenyl phosphine)-1 for example, 1 '-dinaphthalene, in solvent, for example toluene, preferably heating;
Olefinic or aromatic halogen to the conversion of phenyl or heteroaryl be with phenyl-or heteroaryl-boric acid handle, reaction conditions is in the presence of catalyzer, palladium catalyst for example, for example acid chloride (II) or four (triphenyl phosphine) palladium (0) and in the presence of alkali, for example Na 2CO 3, K 2CO 3Or CsF, in the polar solvent that is fit to, for example 1,2-glycol dimethyl ether or toluene-water mixture, preferably heating;
Aromatic halogen is to carry out halogen with reductive agent to decompose to the conversion of H, Zn for example, and reaction conditions be in the solvent that is fit to, acetate for example, heating is preferably to backflow;
The oxidation of 7 N of pyrazolo [3,4-b] pyridine ring obtains corresponding N-oxide compound, for example between-the chlorine peroxybenzoic acid, reaction conditions be in suitable solvent, for example methylene dichloride.
Equally, any aromatic ring of The compounds of this invention can experience close electric aromatics substitution reaction, and this has extensive description in the literature.
A lot of these mutual conversion reactions have more detailed explanation in an embodiment.
As will be conspicuous by those skilled in the art, these mutual conversion reactions also can be carried out at the synthetic intermediate of formula I compound.
The present invention also comprises the salt of formula I compound.These salt can prepare by ordinary method, formula I compound are handled with appropriate amount of acid, for example hydrochloric acid, sulfuric acid, nitric acid, oxalic acid or methylsulfonic acid.Contain under the situation of acid proton at formula I compound, also can obtain salt, for example sodium hydroxide, potassium hydroxide, calcium hydroxide or lime carbonate with alkaline purification.The salt of formula I compound can be converted into the salt of other formulas I compound then, utilizes ion exchange resin to carry out ion-exchange.
As noted earlier, The compounds of this invention serves as the p38 kinase inhibitor, induces the minimizing of pro-inflammatory cytokine.Therefore, the expection of these compounds can be used for the disease for the treatment of or preventing the p38 kinases to work therein.This comprises the disease that excessive generation caused by cytokines such as TNF-α, IL-1, IL-6 or IL-8.These diseases include but not limited to immunity, autoimmunity and inflammatory diseases, cardiovascular disorder, infectious diseases, bone resorption disease, neurodegenerative disease, proliferative disease and induce relevant process with cyclooxygenase-2.
As an example, can be with the immunity of The compounds of this invention treatment or prevention, autoimmunity and inflammatory diseases comprise rheumatism (rheumatoid arthritis for example, arthritic psoriasis, infective arthritis, carrying out property chronic arthritis, arthritis deformans, osteoarthritis, traumatic arthritis, urarthritis, conjunctivo-urethro-synovial syndrome, polychondritis, acute synovitis and spondylitis), glomerulonephritis (with or do not have a nephrotic syndrome), autoimmune blood disease (hemolytic anemia for example, congenital anemia, spontaneous thrombopenia and neutrophilic leukocyte reduce), autoimmune gastritis and autoimmune inflammatory bowel disease (for example ulcerative colitis and Crohn disease), the host is to the disease of graft, homograft rejection, chronic thyroiditis, the Ge Leifushi disease, scleroderma, diabetes (I type and II type), active hepatitis (acute and chronic), the sclerosis of primary courage, myasthenia gravis, multiple sclerosis, systemic lupus erythematous, psoriasis, atopic dermatitis, contact dermatitis, eczema, the skin sunburn, chronic renal insufficiency, ectodermosis pluriorificialis, spontaneous sprue, sarcoidosis, guillain-Barre syndrome, uveitis, conjunctivitis, keratoconjunctivitis, otitis media, periodontopathy, the interstitial lung fibrosis, asthma, bronchitis, rhinitis, sinusitis paranasal sinusitis, pneumoconiosis, PI syndrome, pulmonary emphysema, pnemnofibrosis, silicosis, chronic inflammatory lung disease (for example chronic obstructive pulmonary disease) and other respiratory tract inflammatory or occlusive disease.
The cardiovascular disorder that can treat or prevent comprises platelet aggregation, acute coronary syndrome, atherosclerosis and the cerebrovascular accident etc. that myocardial infarction, megalocardia, cardiac insufficiency, ischemia-reperfusion disease, thrombosis, zymoplasm bring out.
The infectious diseases that can treat or prevent comprises sepsis, septic shock, endotoxin shock, the sepsis that gram negative bacterium causes, shigellosis, meningitis, cerebral malaria, pneumonia, pulmonary tuberculosis, viral myocarditis, viral hepatitis (hepatitis A, hepatitis B and hepatitis C), HIV infects, by the retinitis that cytomegalovirus caused, influenza, bleb, the infection relevant with third-degree burn disposed, by infecting the myalgia that is caused, be secondary to the emaciation of infection and Veterinarian virus infection etc., for example lentivirus, the goat arthritis virus, visna virus, feline immunodeficiency virus, bovine immunodeficiency virus or dog immunodeficiency virus.
The bone resorption disease that can treat or prevent comprises osteoporosis, osteoarthritis, traumatic arthritis, urarthritis and osteopathia relevant with multiple myeloma etc.
The neurodegenerative disease that can treat or prevent comprises Alzheimer, Parkinson's disease, cerebral ischemia and traumatic neurodegenerative disease etc.
The proliferative disease that can treat or prevent comprises endometriosis, noumenal tumour, acute and chronic lymphocytic leukemia, Kaposi, multiple myeloma, metastatic melanoma and vasculogenesis disease, for example eye neovascularization and infantile hemangioma.
The p38 kinase inhibitor also suppresses the expression of short inflammatory protein matter, cyclooxygenase-2 (COX-2) for example, and this enzyme is responsible for the generation of prostaglandin(PG).Therefore, The compounds of this invention can also be used for the treatment of or prevent the disease by the COX-2 mediation, especially treats the process with inflammation, heating and neuromuscular pain, for example headache, the pain by cancer caused, toothache and arthritis ache.
Activity according to product described herein the invention still further relates to composition, and it contains The compounds of this invention and vehicle or other auxiliarys, if necessary.The compounds of this invention can be with the form administration of any pharmaceutical preparation, and its attribute will depend on attribute and its route of administration of active compound as known.Can use any route of administration, for example oral, parenteral, nose, eye, rectum and topical.
According to the present invention, the solids composition of oral administration comprises tablet, granule and capsule.In any case, manufacture method based on active compound and vehicle simple mix, non-slurry pelletizing or wet granulation.These vehicle for example can be thinner, for example lactose, Microcrystalline Cellulose, mannitol or secondary calcium phosphate; Tackiness agent, for example starch, gelatin or polyvidone; Disintegrating agent, for example sodium starch glycolate or croscarmellose sodium; And lubricant, for example Magnesium Stearate, stearic acid or talcum.Tablet can utilize known technology to be surrounded by suitable vehicle in addition, and purpose is to postpone their disintegration and absorptions in gi tract, and the continuous action of longer time is provided thus, perhaps only improves their sensory qualities or their stability.Also can utilize natural or the synthetic membrane-forming agent is coated in active compound on the inert particle.Gelseal also is possible, and active compound mixes with water or oil medium therein, for example peanut oil, mineral oil or sweet oil.
Active compound is mixed with dispersion or wetting agent, suspension agent and sanitas, can obtain pulvis and granule, prepare oral suspension for adding entry.Can also add other vehicle, for example sweeting agent, correctives and tinting material.
The liquid dosage form of oral administration comprises emulsion, solution, suspension, syrup and elixir, wherein contains inert diluent commonly used, for example purified water, ethanol, Sorbitol Powder, glycerine, polyoxyethylene glycol (macrogols) and propylene glycol.Described composition can also contain auxiliary agent, for example wetting agent, suspension agent, sweeting agent, correctives, sanitas and buffer reagent.
According to the present invention, the injectable prepared product of administered parenterally is included in sterile solution, suspension or the emulsion in water-based or the non-aqueous solvent, and solvent is propylene glycol, polyoxyethylene glycol or vegetables oil for example.These compositions can also contain auxiliary agent, for example wetting agent, emulsifying agent, dispersion agent and sanitas.They can be sterilized by any known process, perhaps are made into aseptic solid composite, water-soluble soon before use or other sterile injectable medium arbitrarily.From sterilizable material, and maintenance also is possible under these conditions in whole manufacturing process.
With regard to rectal administration, active compound can preferably be formulated on oleaginous base, the semi-synthetic glyceryl ester of vegetables oil or solid for example, and perhaps on hydrophilic matrix, the suppository of polyoxyethylene glycol (macrogol) for example.
Compound can also be formulated into for its topical application, is used for the treatment of that occur in can be by approaching zone of this approach or the pathology in the organ, for example, skin and enteron aisle.Preparation comprises creme, lotion, gelifying agent, pulvis, solution and patch, and wherein compound is dispersed or dissolved in the suitable vehicle.
The compounds of this invention can also be formulated into solid dosage, dissolves or is dispersed in the suitable carrier, is used for sucking in single agent or multi-agent container.Prepared product as aerosol (solid or the liquid particle dispersion in gas) administration adopts the device that is fit to, for example spraying gun, pressurised metered dose inhaler or Diskus.Depend on this, compound and vehicle (for example are responsible for forming the propelling agent of suitable pressure in container, to force content to come out by the opening of valve), solvent, emulsifying agent, viscosity increasing agent, sanitas, stablizer and lubricant prepare together, to avoid valve blockage.
Dosage and frequency will depend on factors such as the specific compound of the attribute of the disease for the treatment of and seriousness, patient's age, general situation and body weight and institute's administration and route of administration.The representative example that is fit to dosage range is from about 0.01mg/kg about 100mg/kg every day extremely, the dosed administration that this can be used as single agent or separates.But, dosage generally depends on doctor's judgement.
Embodiment
The activity of The compounds of this invention can be utilized following test assessment:
Test 1: to the restraining effect that discharges by LPS inductive TNF-α among human tissue cell's property lymphoma cell U-937
The keeping of U-937 cell and differentiation: U-937 cell (ATCC N ° CRL-159.2) is cultivated in RPMI 1640 substratum that are supplemented with 10% inactivation foetal calf serum (Gibco).In the presence of 20ng/ml PMA (phorbol 12-myristinate 13-acetic ester), will amount to 0.5 * 10 6Cell incubation 24 hours reaches unicellular completely differentiation.All incubations all are at 37 ℃ and contain 5%CO 2Atmosphere under carry out.With cell centrifugation (200 * g, 5 minutes), be suspended in again in RPMI 1640 substratum that are supplemented with 2% inactivation foetal calf serum, density is 2 * 10 6Cell/ml.
Inhibition to TNF-α release: with 100 μ L U-937 cells (2 * 10 6Cell/ml) and 100 μ L are for test manufacture things (ultimate density 0.001-10 μ M) incubation 30 minutes in 96 hole flat boards.(10mM DMSO) is diluted in the substratum, and final DMSO concentration is equal to or less than 0.1% with the product mother liquor.(intestinal bacteria 055B5, Sigma) to ultimate density 100ng/ml, incubation utilized commercialization ELISA test kit (BiosourceInternational) to quantize the TNF-α amount that is discharged in the supernatant liquor after 4 hours to add total 20 μ L LPS.
Test 2: to the restraining effect that discharges by LPS inductive TNF-α in the human peripheral liquid monocyte
Obtain monocyte: will not have the phosphate buffered saline (PBS) dilution of calcium or magnesium with equal-volume from the heparinization venous blood that the healthy volunteer obtains.30ml mixture aliquots containig is transferred to the 50ml centrifuge tube that contains 15ml Ficoll-Hypaque (1.077g/ml).With test tube under 1200 * g and room temperature centrifugal 20 minutes, need not braking.Remove about 2/3rds of the thrombocyte band that is positioned at monocyte top with volumetric pipette.Monocyte is transferred to the 50ml test tube carefully, uses the phosphate buffered saline (PBS) washed twice, under 300 * g and room temperature centrifugal 10 minutes, be suspended in again among the RPMI that is supplemented with 1% inactivation foetal calf serum, cell density is 2 * 10 6Cell/ml.
Inhibition to TNF-α release: on 96 hole flat boards, with 100 μ L monocytes (2 * 10 6Cell/ml) and 50 μ L for test manufacture thing (ultimate density 0.001-10 μ M) and 50 μ L LPS (intestinal bacteria 055B5, Sigma) (ultimate density 400ng/ml) 37 ℃ with contain 5%CO 2Atmosphere under incubation 19 hours.Utilize commercialization ELISA test kit (BiosourceInternational) to quantize the TNF-α amount that is discharged in the supernatant liquor.
Test 3: to the restraining effect of p38-alpha kinase
At damping fluid Tris 25mM pH 7.5, among the EGTA 0.02mM incubation final volume be 25 μ L, amount to 5 μ L for test manufacture thing (ultimate density 0.001-10 μ M), contain 5-10mU p38-α, the Mg of 0.33mg/ml myelin basic protein 2+Acetate (10mM) and [γ 33P-ATP] (100 μ M, specific activity 500cpm/pmol).Add Mg 2+ [γ 33P-ATP] begin to react.At room temperature incubation added 5 μ L, 3% phosphoric acid solution quencher reaction after 40 minutes.Make reaction mixture (10 μ L) pass filter (P30), reach 5 minutes three times with 75mM phosphoric acid solution washing, with methanol wash once dry then, by liquid scintillation counting(LSC) it.
Following table is presented in the test 2 with representative The compounds of this invention gained result:
Embodiment Inhibition % under 0.1 μ M
1 57.5
4 68.4
6 81.4
8 66.3
18 82.6
22 56.5
30 83.6
36 92.0
39 51.1
41 90.6
43 61.2
56 58.7
59 60.0
63 53.2
68 50.0
72 52.7
78 73.3
80 69.3
82 59.9
90 86.3
102 67.9
106 69.3
121 52.1
128 82.0
136 67.0
137 61.4
183 66.7
184 71.2
188 73.2
196 70.2
208 67.7
209 84.2
210 57.3
211 70.6
212 67.5
213 68.1
214 71.1
217 53.8
232 67.9
237 53.4
240 58.4
248 53.2
250 67.0
268 69.1
272 65.6
279 100.0
282 65.2
283 52.4
287 71.2
289 51.3
290 65.8
The following example is set forth the present invention, but does not limit the scope of the invention.
Use following abbreviation in an embodiment:
AcOH: acetate
EtOAc: ethyl acetate
NH 4OAc: ammonium acetate
BuLi: butyllithium
tBuOH: the trimethyl carbinol
Conc.: dense
DMAP:4-(N, N-dimethylamino) pyridine
DMF: dimethyl formamide
EtOH: ethanol
MeOH: methyl alcohol
THF: tetrahydrofuran (THF)
t R: retention time
LC-MS: liquid chromatography-mass spectrography
H AThe HA of from an AB system:AB system
H BThe H of from an AB system:AB system B
Complex signal: sophisticated signal
Broad s: wide is unimodal
Ketone: ketone
Enol: enol
Utilize following chromatographic process to carry out LC-MS:
Method 1: pillar: Tracer Excel 120, and ODSB 5 μ m (10mm * 0.21mm), temperature: 30 ℃, flow velocity: 0.35ml/ minute, eluent: A=acetonitrile, B=0.1%HCOOH, gradient: 0 minute 10%A-10 minute 90%A.
Method 2: pillar: X-Terra MS C18 5 μ m (150mm * 2.1mm), temperature: 30 ℃, flow velocity: 0.40ml/ minute, eluent: A=acetonitrile, B=10mM NH 4OAc (pH=6.80), gradient: 0 minute 25%A-6 minute 80%A-7.5 minute 25%A.
Reference example 1
1-(4-fluorophenyl)-2-(4-pyridyl) ethyl ketone
A) 4-fluoro-N-methoxyl group-N-methyl-benzamide
In volumetric flask, under 0 ℃ of argon atmospher, introduce N, the O-dimethyl hydroxylamine hydrochloride (25.54g, 261.8mmol) and CH 2Cl 2(443ml).Add the 4-fluorobenzoyl chloride (34.59g, 218.2mmol), succeeded by slow adding triethylamine (48.13g, 475.6mmol). reactant was stirred 30 minutes down at 5 ℃, makes it to reach room temperature.With 5% aqueous citric acid solution (180ml) and 5%NaHCO 3The aqueous solution (180ml) washing.Water CH 2Cl 2Extraction.With organic phase through Na 2SO 4Drying is concentrated into driedly, obtains 20.23g required compound (yield: 88%).
B) title compound
Under argon atmospher, to be cooled to-78 ℃, Diisopropylamine (23.4ml, drip in THF 165.7mmol) (250ml) solution BuLi (103.5ml 1.6M hexane solution, 165.7mmol).After 5 minutes, go through 20 minutes adding 4-picoline (10.28g, THF 110.4mmol) (85ml) solution.Mixture was stirred 15 minutes down at 0 ℃, go through THF (85ml) solution that added 4-fluoro-N-methoxyl group-N-methyl-benzamide (in a joint, obtaining) in 30 minutes.Make reactant reach room temperature.Add entry (100ml) and EtOAc (100ml), mixture was stirred 30 minutes.Separate organic phase, through Na 2SO 4Drying is concentrated into driedly, obtains 24.32g required compound (yield: 100%).
1H NMR (300MHz, CDCl 3) δ (TMS): 4.29 (s, 2H), 7.14-7.23 (sophisticated signal, 4H), 8.05 (m, 2H), 8.59 (dd, J o=1.6Hz, J m=4.4Hz, 2H).
Reference example 2
2-(4-pyridyl)-1-[3-(trifluoromethyl) phenyl] ethyl ketone
A) N-methoxyl group-N-methyl-3-(trifluoromethyl) benzamide
According to saving described similar technology, but be to use 3-(trifluoromethyl) Benzoyl chloride to replace the 4-fluorobenzoyl chloride, obtain required product (yield: 86%) to reference example 1 a.
B) title compound
According to saving described similar technology to reference example 1b, still replace 4-fluoro-N-methoxyl group-N-methyl-benzamide with N-methoxyl group-N-methyl-3-(trifluoromethyl) benzamide (in this routine a joint, obtaining), obtain title compound (yield: 22%).
1H NMR(300MHz，CDCl 3)δ(TMS)：4.31(s，2H)，7.20(d，J＝5.8Hz，2H)，7.63(t，J＝7.8Hz，1H)，7.84(d，J＝7.8Hz，1H)，8.16(d，J＝7.9Hz，1H)，8.24(s，1H)，8.56(d，J＝5.8Hz，2H).
Reference example 3
1-phenyl-2-(4-pyridyl) ethyl ketone
Under argon atmospher, (22ml, THF 15.03mmol) (200ml) solution is cooled to-78 ℃ with Diisopropylamine.Dropping BuLi (96ml 1.6M hexane solution, 153.0mmol).After 1 hour, (15.00g, THF 161.1mmol) (75ml) solution is warmed to 0 ℃ to add the 4-picoline.Under this temperature, stirred 30 minutes.Be cooled to-78 ℃, (18.27g, THF 177.2mmol) (75ml) solution stirred 2 hours down at-78 ℃ to add benzonitrile.At room temperature stir and spend the night.Add entry (225ml), water-ice bath cooling transfers to pH 1 with 48%HBr.Separate organic phase.Water is heated to backflow reaches 2 hours, cooling extracts with diethyl ether.Water is transferred to neutral pH with 1N NaOH, extract with EtOAc.With organic phase through Na 2SO 4Drying is concentrated into driedly, obtains 28.53g title compound (yield: 90%).
1H NMR(300MHz，CDCl 3)δ(TMS)：4.29(s，2H)，7.20(dd，J o＝1.6Hz，J m＝4.4Hz，2H)，7.49(m，2H)，7.58(m，1H)，8.00(d，J＝8.2Hz，2H)，8.56(dd，J o＝1.6Hz，J m＝4.4Hz，2H).
Reference example 4
1-(4-fluorophenyl)-2-(4-pyridyl) vinyl 4-fluorobenzoic acid ester
Under argon atmospher, (0.81g adds 1-(4-fluorophenyl)-2-(4-pyridyl) ethyl ketone (2.00g, 9.3mmol in DMF 18.6mmol) (30ml) suspension to the HaH that is cooled to 0 ℃, in reference example 1, obtain) DMF (15ml) solution, be stirred to room temperature and reach 30 minutes.Be cooled to 0 ℃ then, add 4-fluorobenzoyl chloride (2.95g, DMF 1.9mmol) (10ml) solution.At room temperature stir and spend the night.Add entry, evaporation removes and desolvates.Resistates is dissolved in CHCl 3With the mixture of water, separate each phase.Water CHCl 3Extraction (x3).Wash organic phase with water (x2), through Na 2SO 4Drying is concentrated into dried.The gained crude product uses to increase progressively polar hexane-EtOAc mixture as eluent through the silica gel chromatography purifying, obtains the 0.98g required compound, is yellow solid (yield: 31%).
1H NMR(300MHz，CDCl 3)δ(TMS)：6.68(s，1H)，7.11(t，J＝8.6Hz，2H)，7.29(t，J＝8.6Hz，2H)，7.39(d，J＝6.0Hz，2H)，7.60(dd，J o＝5.2Hz，J m＝8.8Hz，2H)，8.27(dd，J o＝5.4Hz，J m＝8.8Hz，2H)，8.58(d，J＝6.0Hz，2H)
Reference example 5
1-phenyl-2-(4-pyridyl) vinyl benzoic acid ester
According to reference example 4 described similar technologies, but be to use 1-phenyl-2-(4-pyridyl) ethyl ketone (in reference example 3, obtaining) to replace 1-(4-fluorophenyl)-2-(4-pyridyl) ethyl ketone, Benzoyl chloride replaces the 4-fluorobenzoyl chloride, obtains title compound (yield: 62%).
1H NMR (300MHz, CDCl 3) δ (TMS): 6.72 (s, 1H), 7.38-7.42 (sophisticated signal, 5H), 7.60-7.63 (sophisticated signal, 4H), 7.71 (t, J=7.4,1H), 8.23 (d, J=7.1Hz, 2H), 8.51 (dd, J o=1.5Hz, J m=4.6Hz, 2H).
Reference example 6
2-[2-(methylthio group) pyrimidine-4-yl]-1-[3-(trifluoromethyl) phenyl] ethyl ketone
A) 4-methyl-2-(methylthio group) pyrimidine
To NaOH (7.46g, add in water 186.4mmol) (120ml) solution 4-methylpyrimidine-2-thiolate hydrochlorate (13.78g, 84.7mmol), under argon atmospher, drip subsequently methyl iodide (13.23g, 93.2mmol).At room temperature stirred 2 hours.Use CH 2Cl 2Extraction (x2).With organic phase through Na 2SO 4Drying is concentrated into dried.The gained crude product uses to increase progressively polar hexane-EtOAc mixture as eluent through the silica gel chromatography purifying, obtains 10.26g required compound (yield: 86%).
B) title compound
According to saving described similar technology to reference example 1b, but be to use N-methoxyl group-N-methyl-3-(trifluoromethyl) benzamide (in reference example 2a joint, obtaining) to replace 4-fluoro-N-methoxyl group-N-methyl-benzamide, 4-methyl-2-(methylthio group) pyrimidine (obtaining in this routine a joint) replaces the 4-picoline, obtain title compound, be crude product, be directly used in following reaction (yield: quantitatively).
Reference example 7
3-(dimethylamino)-1-(4-fluorophenyl)-2-(4-pyridyl) third-2-alkene-1-ketone
Under argon atmospher, in anhydrous THF (5ml) solution of 1-(4-fluorophenyl)-2-(4-pyridyl) ethyl ketone (0.30g, 1.4mmol obtain in reference example 1), add dimethylformamide dimethyl acetal (0.27g, 3.2mmol).At room temperature stir and spend the night.Evaporating solvent obtains 0.39g title compound (yield: quantitatively).
1H NMR(300MHz，CDCl 3)δ(TMS)：2.79(s，6H)，6.97(t，J＝8.7Hz，2H)，7.05(dd，J o＝1.5Hz，J m＝4.5Hz，2H)，7.38(s，1H)，7.45(m，2H)，8.48(dd，J o＝1.5Hz，J m＝4.5Hz，2H).
Reference example 8
3-(dimethylamino)-2-[2-(methylthio group) pyrimidine-4-yl]-1-[3-(trifluoromethyl) phenyl] third-2-alkene-1-ketone
According to reference example 7 described similar technologies, but be to use 2-[2-(methylthio group) pyrimidine-4-yl]-1-[3-(trifluoromethyl) phenyl] ethyl ketone (in reference example 6, obtaining) replacement 1-(4-fluorophenyl)-2-(4-pyridyl) ethyl ketone, obtain required compound, be the form of crude product, be directly used in following reaction.
Reference example 9
1-(6-chloropyridine-3-yl)-2-(4-pyridyl) ethyl ketone
A) 6-chloronicotinoyl chloride hydrochloride
With 6-chlorine apellagrin (10.00g, SOCl 63.5mmol) 2(37ml) solution is heated to reflux and reaches 2 hours.With SOCl 2Be evaporated to driedly, obtain the required product of 12.56g (yield: 93%).
B) 6-chloro-N-methoxyl group-N-methylnicotinamide
According to saving described similar technology, but be to use 6-chloronicotinoyl chloride hydrochloride (in this routine a joint, obtaining) to replace the 4-fluorobenzoyl chloride, obtain required compound (yield: 71%) to reference example 1a.
C) title compound
According to saving described similar technology, but be to use 6-chloro-N-methoxyl group-N-methylnicotinamide (in this routine b joint, obtaining) to replace 4-fluoro-N-methoxyl group-N-methyl-benzamide, obtain title compound (yield: quantitatively) to reference example 1b.
1H NMR(300MHz，CDCl 3)δ(TMS)：4.27(s，2H)，7.18(dd，J o＝1.5Hz，J m＝4.5Hz，2H)，7.45(dd，J o＝0.6Hz，J m＝8.4Hz，1H)，8.20(dd，J o＝2.5Hz，J m＝8.3Hz，2Hs，1H)，8.56(18(dd，J o＝1.6Hz，J m＝4.4Hz，2H)，8.98(d，J＝2.4Hz，1H).
Reference example 10
2-(4-fluorophenyl)-6-hydroxyl-3,4 '-dipyridyl-5-nitrile
Under argon atmospher, and adding 2-malonamide nitrile in DMF (175ml) solution of 3-(dimethylamino)-1-(4-fluorophenyl)-2-(4-pyridyl) third-2-alkene-1-ketone (12.77g, 47.2mmol obtain in reference example 7) (4.41g, 52.0mmol).(5.35g, 99.2mmol), being heated to refluxes reaches 1 hour to add sodium methylate then.Make the mixture cooling, concentrate dilute with water.Regulate pH to 4 with 1N HCl.Obtain precipitation, filter, drying obtains the 6.57g required compound, is solid (yield: 48%).
1H NMR(300MHz，CDCl 3+CD 3OD)δ(TMS)：4.20(s，OH+NH+CD 3OD)，6.96(dd，J o＝1.6Hz，J m＝4.5Hz，2H)，7.05(t，J＝8.7Hz，2H)，7.23(m，2H)，7.96(s，1H)，8.39(dd，J o＝1.4Hz，J m＝4.6Hz，2H).
Reference example 11
2-hydroxyl-5-[2-(methylthio group) pyridin-4-yl]-6-[3-(trifluoromethyl) phenyl] pyridine-3-nitrile
According to reference example 10 described similar technologies, but be to use 3-(dimethylamino)-2-[2-(methylthio group) pyrimidine-4-yl]-1-[3-(trifluoromethyl) phenyl] third-2-alkene-1-ketone (in reference example 8, obtaining) replacement 3-(dimethylamino)-1-(4-fluorophenyl)-2-(4-pyridyl) third-2-alkene-1-ketone, obtain title compound (yield: 20%).
1H NMR(300MHz，CDCl 3+CD 3OD)δ(TMS)：3.28(s，3H)，3.84(s，OH+CD 3OD)，6.38(d，J＝5.4Hz，1H)，7.42(d，J＝7.8Hz，1H)，7.53(t，J＝7.8Hz，1H)，7.61(s，1H)，7.73(d，J＝7.8Hz，1H)，8.18(d，J＝5.1Hz，1H)，8.35(s，1H).
Reference example 12
6-chloro-2-(4-fluorophenyl)-3,4 '-dipyridyl-5-nitrile
With 2-(4-fluorophenyl)-6-hydroxyl-3,4 '-dipyridyl-5-nitrile (6.57g, 22.5mmol obtain in reference example 10), POCl 3(26.3ml 287.5mmol) is heated to reflux under argon atmospher with the mixture of DMF (0.37ml) and reaches 2 hours.With the ice bath cooling, add the alkalization of 30% ammoniacal liquor.Filtration gained precipitation washes with water.Product uses to increase progressively polar hexane-EtOAc mixture as eluent through the silica gel chromatography purifying, obtains the required product of 3.86g, is yellow solid (yield: 55%).
1H NMR(300MHz，CDCl 3)δ(TMS)：7.00(t，J＝8.6Hz，2H)，7.11(dd，J o＝1.6Hz，J m＝4.4Hz，2H)，7.37(m，2H)，7.98(s，1H)，8.62(dd，J o＝1.5Hz，J m＝4.5Hz，2H).
Reference example 13
1-(6-picoline-3-yl)-2-(4-pyridyl) ethyl ketone
A) N-methoxyl group-6, the N-dimethyl nicotinamide
Under argon atmospher, to 6-methylnicotinic acid (5.00g, 36.5mmol) DMF (150ml) solution in add I-hydroxybenzotriazole (4.92g, 36.5mmol), N-ethyl-N-(3-dimethylamino-propyl) carbodiimide hydrochloride (8.38g, 45.7mmol) and the 4-methylmorpholine (16.0ml, 145.8mmol).Mixture was at room temperature stirred 30 minutes, add N then, and the O-dimethyl hydroxylamine hydrochloride (3.55g, 36.5mmol).Reaction mixture at room temperature stirred spend the night.Evaporation removes and desolvates.Resistates is dissolved in CHCl 3With 0.2N NaHCO 3Mixture.Separate each phase, water CHCl 3Extraction.With organic phase through Na 2SO 4Drying is concentrated into dried.Product uses to increase progressively polar hexane-EtOAc mixture as eluent through the silica gel chromatography purifying, obtains the required product of 1.11g (yield: 29%).
B) title compound
According to saving described similar technology to reference example 1b, but be to use N-methoxyl group-6, N-dimethyl nicotinamide (obtaining in this routine a joint) replaces 4-fluoro-N-methoxyl group-N-methyl-benzamide, obtains title compound (yield: 87%).
1H NMR(300MHz，CDCl 3)δ(TMS)：2.64(s，3H)，4.28(s，2H)，7.20(dd，J o＝1.4Hz，J m＝4.6Hz，2H)，7.28(d，J＝8.1Hz，1H)，8.15(dd，J o＝2.4Hz，J m＝8.1Hz，1H)，8.57(dd，J o＝1.8Hz，J m＝4.5Hz，2H)，9.10(d，J＝2.4Hz，1H).
Reference example 14
2-chloro-5-[2-(methylthio group) pyrimidine-4-yl]-6-[3-(trifluoromethyl) phenyl] pyridine-3-nitrile
According to reference example 12 described similar technologies, but be to use 2-hydroxyl-5-[2-(methylthio group) pyrimidine-4-yl]-6-[3-(trifluoromethyl) phenyl] pyridine-3-nitrile (in reference example 11, obtaining) replacement 2-(4-fluorophenyl)-6-hydroxyl-3,4 '-dipyridyl-5-nitrile, obtain title compound (yield: 44%).
1H NMR(300MHz，CDCl 3)δ(TMS)：2.48(s，3H)，6.62(d，J＝5.1Hz，1H)，7.51(m，2H)，7.71(d，J＝7.2Hz，1H)，7.82(s，1H)，8.39(d，J＝5.1Hz，1H)，8.42(s，1H)，8.42(s，1H).
Reference example 15
3-amino-5-(1-benzyl piepridine-4-yl)-2H-pyrazoles
A) 1-benzyl piepridine-4-carboxylic acid methyl ester
Under argon atmospher, (10.00g is 6.4mmol) with triethylamine (10.32g, CHCl 10.2mmol) to piperidines-4-carboxylic acid methyl ester 3(14.69g, 8.6mml), water and ice bath cool off simultaneously (100ml) to add bromotoluene in the solution.Mixture at room temperature stirred spend the night.Add CHCl 3And water, separate two-phase.Water CHCl 3Extraction.With organic phase through Na 2SO 4Drying is concentrated into driedly, obtains the 13.80g required compound, is orange solids (yield: 88%).
B) 3-(1-benzyl piepridine-4-yl)-3-oxypropionitrile
Under argon atmospher, (12.4ml 1.6M hexane solution drips acetonitrile (1ml) in THF 19.8mmol) (25ml) solution to the BuLi that is cooled to-78 ℃.Stirring is after 5 minutes down at-78 ℃ with the gained suspension, and THF (5ml) solution of dropping 1-benzyl piepridine-4-carboxylic acid methyl ester (2.0g, 8.1mmol obtain in prosthomere) stirred 30 minutes down at-78 ℃.Make it to reach room temperature, under this temperature, stir and spend the night.Add 1N HCl and regulate pH to 7, water CHCl 3Extraction.With organic phase through Na 2SO 4Drying is concentrated into driedly, obtains the 1.92g required compound, is orange solids (yield: 98%).
C) title compound
Under argon atmospher, and adding-hydrazine hydrate in EtOH (77ml) solution of 3-(1-benzyl piepridine-4-yl)-3-oxypropionitrile (1.85g, 7.6mmol obtain in prosthomere) (0.74ml, 15.3mmol).Mixture heating up is spent the night to refluxing.Evaporating solvent, with resistates water-soluble-CHCl 3Mixture.Water CHCl 3Extraction.With organic phase through Na 2SO 4Drying is concentrated into dried.The gained crude product uses to increase progressively polar hexane-EtOAc mixture as eluent through the silica gel chromatography purifying, obtains 0.46g required compound (yield: 23%).
1H NMR (300MHz, CD 3OD) δ (TMS): 1.72 (m, 2H), 1.90 (m, 2H), 2.15 (m, 2H), 2.56 (m, 1H), 2.97 (m, 2H), 3.57 (s, 2H), 4.89 (wide s, NH+NH 2+ H 2O), 5.43 (s, 1H), 7.27-7.34 (sophisticated signal, 5H).
Reference example 16
3-(dimethylamino)-1-(4-fluorophenyl)-2-(4-pyridyl) but-2-ene-1-ketone
According to reference example 7 described similar technologies, but be to use the N,N-DIMETHYLACETAMIDE dimethyl-acetal to replace dimethylformamide dimethyl acetal, obtain required compound, be the form of crude product, be directly used in following reaction.
1H NMR(300MHz，CDCl 3)δ(TMS)：2.15(s，3H)，3.00(s，6H)，6.80(m，4H)，7.45(m，2H)，8.30(d，J＝8.0Hz，2H).
Reference example 17
2-(4-fluorophenyl)-6-hydroxy-4-methyl-3,4 '-dipyridyl-5-nitrile
According to reference example 10 described similar technologies, but be to use 3-(dimethylamino)-1-(4-fluorophenyl)-2-(4-pyridyl) but-2-ene-1-ketone (in reference example 16, obtaining) to replace 3-dimethylamino-1-(4-fluorophenyl)-2-(4-pyridyl) third-2-alkene-1-ketone, obtain title compound (yield: 21%).
1H NMR (300MHz, CDCl 3) δ (TMS): 1.55 (wide s, OH+H 2O), 2.30 (s, 3H), 6.97 (m, 4H), 7.25 (m, 2H), 8.52 (m, 2H).
Reference example 18
6-chloro-2-(4-fluorophenyl)-4-methyl-3,4 '-dipyridyl-5-nitrile
According to reference example 12 described similar technologies, but be to use 2-(4-fluorophenyl)-6-hydroxy-4-methyl-3,4 '-dipyridyl-5-nitrile (in reference example 17, obtaining) replacement 2-(4-fluorophenyl)-6-hydroxyl-3,4 '-dipyridyl-5-nitrile, obtain title compound (yield: 52%).
1H NMR(300MHz，CDCl 3)δ(TMS)：2.41(s，3H)，6.90(m，2H)，7.09(d，J＝9.0Hz，2H)，7.25(m，2H)，8.62(m，J＝4.0Hz，2H).
Reference example 19
1-(4-fluorophenyl)-2-[2-(methylthio group) pyrimidine-4-yl] ethyl ketone
Under argon atmospher, to 4-methyl-2-(methylthio group) pyrimidine (21.00g, 150.0mmol, in reference example 6a joint, obtain) and 4-fluorobenzoic acid ethyl ester (25.14g, 150.0mmol) THF (300ml) solution in drip two (trimethylsilyl) sodium amide (150ml 2M THF solution, THF 300mmol) (150ml) solution cools off with ice bath simultaneously.At room temperature stirred 2 hours.Add saturated NH 4Cl, evaporating solvent.Resistates is dissolved in the mixture of EtOAc and water, separates each phase.Water is stripped with EtOAc.Merge organic phase, use the salt water washing, through Na 2SO 4Drying is concentrated into driedly, obtains 36.36g title compound (yield: 93%).
1H NMR(300MHz，CDCl 3)δ(TMS)：2.52(ketone：s，3H)，2.61(enol：s，3H)，4.35(ketone：s，2H)，5.92(enol：s，1H)，6.64(enol：d，J＝5.7Hz，1H)，6.95(ketone：d，J＝5.1Hz，1H)，7.08-7.19(m，2H)，7.83(enol：m，2H)，8.07(ketone：m，2H)，8.31(enol：d，J＝5.7Hz，1H)，8.56(ketone：d，J＝5.1Hz，1H).
Reference example 20
3-(dimethylamino)-1-(4-fluorophenyl)-2-[2-(methylthio group) pyrimidine-4-yl] third-2-alkene-1-ketone
According to reference example 7 described similar technologies, but be to use 1-(4-fluorophenyl)-2-[2-(methylthio group) pyrimidine-4-yl] ethyl ketone (obtaining in reference example 19) replaces 1-(4-fluorophenyl)-2-(4-pyridyl) ethyl ketone, obtains title compound.
1H NMR (300MHz, CDCl 3) δ (TMS): 2.50 (s, 3H), 2.96 (s, 6H), 6.20-8.20 (sophisticated signal, 7H).
Reference example 21
6-(4-fluorophenyl)-2-(hydroxyl)-5-(2-methylthiopyrimidine-4-yl) pyridine-3-nitrile
According to reference example 10 described similar technologies, but be to use 3-(dimethylamino)-1-(4-fluorophenyl)-2-[2-(methylthio group) pyrimidine-4-yl] third-2-alkene-1-ketone (in reference example 20, obtaining) replacement 3-(dimethylamino)-1-(4-fluorophenyl)-2-(4-pyridyl) third-2-alkene-1-ketone, obtain title compound (yield: 91%).
LU-MS (method 1): t R=7.09 minutes; M/z=338.9[M+H] +
Reference example 22
2-chloro-6-(4-fluorophenyl)-5-(2-methylthiopyrimidine-4-yl) pyridine-3-nitrile
With 6-(4-fluorophenyl)-2-(hydroxyl)-5-(2-methylthiopyrimidine-4-yl) pyridine-3-nitrile (48.84g, 144.6mmol obtain in reference example 21), POCl 3(166ml 1.8mol) ℃ reaches 2 hours with the mixture heating up to 100 of DMF (2.2ml).Be cooled to room temperature, concentrate.With acetone-CO 2Bathe cooling, add EtOAc and ice subsequently.The decantation organic phase is used saturated NaHCO 3Washing is through Na 2SO 4Drying is concentrated into dried.The gained crude product uses to increase progressively polar hexane-EtOAc mixture wash-out through the silica gel chromatography purifying, obtains 31.00g title compound (yield: 60%).
1H NMR(300MHz，CDCl 3)δ(TMS)：2.54(s，3H)，6.60(d，J＝5.1Hz，1H)，7.08(t，J＝8.5Hz，2H)，7.44(m，2H)，8.37(d，J＝5.1Hz，1H)，8.39(s，1H).
Reference example 23
2-(2-chloropyridine-4-yl)-1-(4-fluorophenyl) ethyl ketone
According to reference example 19 described similar technologies, but from 2-chloro-4-picoline and 4-fluorobenzoic acid ethyl ester, obtain title compound.
LC-MS (method 1): t R=7.96 minutes; M/z=250.0,252.0[M+H] +
Reference example 24
2-[2-(methylthio group) pyrimidine-4-yl]-1-phenyl ethyl ketone
According to reference example 19 described similar technologies, but begin from 4-methyl-2-(methylthio group) pyrimidine (reference example 6a joint, obtaining) and phenylformic acid ethyl ester, obtain title compound.
1H NMR(300MHz，CDCl 3)δ(TMS)：2.52(ketone：s，3H)，2.62(enol：s，3H)，4.39(ketone：s，2H)，5.99(enol：s，1H)，6.65(enol：d，J＝5.7Hz，1H)，6.98(ketone：d，J＝5.1Hz，1H)，7.40-7.51(m，3H)，7.85(enol：m，2H)，8.03(ketone：m，2H)，8.32(enol：d，J＝5.7Hz，1H)，8.46(ketone：d，J＝5.1Hz，1H).
Reference example 25
3-(dimethylamino)-2-[2-(methylthio group) pyrimidine-4-yl]-1-phenyl third-2-alkene-1-ketone
According to reference example 7 described similar technologies, but from 2-[2-(methylthio group) pyrimidine-4-yl]-1-phenyl ethyl ketone (obtaining) at reference example 24, obtain title compound.
1H NMR (300MHz, CDCl 3) δ (TMS): 2.50 (s, 3H), 2.90 (s, 6H), 6.20-8.00 (sophisticated signal, 8H).
Reference example 26
2-hydroxyl-5-(2-methylthiopyrimidine-4-yl)-6-phenylpyridine-3-nitrile
According to reference example 10 described similar technologies, but be to use 3-(dimethylamino)-2-[2-(methylthio group) pyrimidine-4-yl]-1-phenyl third-2-alkene-1-ketone (in reference example 25, obtaining) replacement 3-dimethylamino-1-(4-fluorophenyl)-2-(4-pyridyl) third-2-alkene-1-ketone, obtain title compound.
LC-MS (method 1): t R=6.90 minutes; M/z=320.9[M+H] +
Reference example 27
1-[6-(4-fluorophenyl)-2-hydroxyl-5-(2-methylthiopyrimidine-4-yl) pyridin-3-yl] ethyl ketone
According to reference example 10 described similar technologies, but from 3-(dimethylamino)-1-(4-fluorophenyl)-2-[2-(methylthio group) pyrimidine-4-yl] third-2-alkene-1-ketone (obtaining reference example 20) and 3-oxo butyramide begin, and obtains title compound.
1H NMR(300MHz，CDCl 3)δ(TMS)：2.43(s，3H)，2.66(enol：s，3H)，6.53(d，J＝5.1Hz，1H)，7.12(t，J＝8.4Hz，2H)，7.42(m，2H)，8.29(d，J＝5.1Hz，1H)，8.63(s，1H).
Reference example 28-29
According to reference example 12 described similar technologies, but in each case from suitable compound, obtain the following table compound:
Reference example The compound title Initial compounds LC-MS
Method t R(minute) m/z[M+H] +
28 2-chloro-5-(2-methylthiopyrimidine-4-yl)-6-phenylpyridine-3-nitrile Reference example 26 1 10.18 338.9
29 4-[6-chloro-5-(1-chlorovinyl)-2-(4-fluorophenyl) pyridin-3-yl]-the 2-methylthiopyrimidine Reference example 27 1 11.62 391.9 393.9 395.9
Reference example 30
1-(4-fluorophenyl)-2-pyrimidine-4-base ethyl ketone
Under argon atmospher, to be cooled to 0 ℃ NaH (2.26g, 50%, slowly add in DMF 47.7mmol) (92ml) suspension 4-methylpyrimidine (3.00g, 31.9mmol).(6.40g 38.2mmol), at room temperature stirs and spends the night to add 4-fluorobenzoic acid ethyl ester then.Add entry, evaporating solvent.Resistates is dissolved in EtOAc and brinish mixture.Separate each phase, water extracts with EtOAc.Merge organic phase, through Na 2SO 4Drying is concentrated into dried.The gained crude product uses to increase progressively polar hexane-EtOAc mixture as eluent through the silica gel chromatography purifying, obtains 3.30g required compound (yield: 48%).
1H NMR(300MHz，CDCl 3)δ(TMS)：4.11(ketone：s，2H)，5.94(enol：s，1H)，6.94(enol：d，J＝5.4Hz，1H)，7.08-7.16(m，2H)，7.37(ketone：d，J＝5.1Hz，1H)，7.89(enol：m，2H)，8.08(ketone：m，2H)，8.42(enol：d，J＝5.4Hz，1H)，8.69(ketone：d，J＝5.1Hz，1H)，8.81(enol：s，1H)，9.17(ketone：s，1H).
Embodiment 1
4, two (4-the fluorophenyl)-5-(4-pyridyl) of 6--1H-pyrazolo [3,4-b] pyridine
Method A
In volumetric flask, introduce 1-(4-fluorophenyl)-2-(4-pyridyl) ethyl ketone (23.56g, 109.4mmol obtain) and 2-methyl cellosolve (150ml) in reference example 1.Adding 3-amino-2H-pyrazoles under argon atmospher (10.00g, and (170ml) solution of 2-methyl cellosolve 120.3mmol) and 37%HCl (3.23g, 32.8mmol).Being heated to refluxes reaches 3 days.Make its cooling, concentrate.The gained solid is dissolved in CHCl 3(400ml) and MeOH (50ml), wash with 0.1N HCl (300ml) and 1N NaOH (300ml).With organic phase through Na 2SO 4Drying is concentrated into driedly, obtains the required product of 9.93g, is cream-colored solid (yield: 47%).
Method B
Under argon atmospher, (60mg adds 1-(4-fluorophenyl)-2-(4-pyridyl) vinyl 4-fluorobenzoic acid ester (0.22g, 65.0mmol obtain) in EtOH 71.8mmol) (2ml) and 1 37%HCl solution in reference example 4 to 3-amino-2H-pyrazoles.Being heated to refluxes reaches 3 days.Mixture CHCl 3Dilute with MeOH.Use saturated NaHCO 3Washing.Water CHCl 3Extraction (x2).With organic phase through Na 2SO 4Drying is concentrated into dried.The gained crude product uses to increase progressively polar hexane-EtOAc mixture as eluent through the silica gel chromatography purifying, obtains the required product of 58mg, is white solid (yield: 23%).
1H NMR (300MHz, CDCl 3+ CD 3OD) δ (TMS): 4.08 (s, NH+CD 3OD), 6.80-7.01 (sophisticated signal, 6H), 7.21 (m, 2H), 7.28 (m, 2H), 7.95 (s, 1H), 8.27 (dd, J o=1.4Hz, J m=4.6Hz, 2H).
Embodiment 2
4,6-phenylbenzene-5-(4-pyridyl)-1H-pyrazolo [3,4-b] pyridine
According to the described similar technology of embodiment 1 method B, but be to use 1-phenyl-2-(4-pyridyl) vinyl benzoic acid ester (in reference example 5, obtaining) to replace 1-(4-fluorophenyl)-2-(4-pyridyl) vinyl 4-fluorobenzoic acid ester, obtain title compound, be white solid (yield: 37%).
1H NMR (300MHz, CDCl 3) δ (TMS): 4.08 (s, NH+H 2O), 6.85 (d, J=6.0Hz, 2H), 7.12-7.31 (sophisticated signal,, 10H), 7.98 (s, 1H), 8.29 (d, J=5.8Hz, 2H).
Embodiment 3
5-(4-pyridyl)-4, two [3-(trifluoromethyl) phenyl]-1H-pyrazolo [3, the 4-b] pyridines of 6-
According to the described similar technology of embodiment 1 method A, but be to use 2-(4-pyridyl)-1-[3-(trifluoromethyl) phenyl] ethyl ketone (in reference example 2, obtaining) replacement 1-(4-fluorophenyl)-2-(4-pyridyl) ethyl ketone, obtain title compound (yield: 10%).
1H NMR (300MHz, CDCl 3) δ (TMS): 1.57 (s, NH+H 2O), 6.86 (wide s, 2H), 7.30-7.60 (sophisticated signal, 8H), 7.99 (s, 1H), 8.35 (wide s, 2H).
Embodiment 4
4, two (4-the fluorophenyl)-3-methyl-5-(4-pyridyl) of 6--1H-pyrazolo [3,4-b] pyridine
According to the described similar technology of embodiment 1 method B, but be to use 3-amino-5-methyl-2H-pyrazoles to replace 3-amino-2H-pyrazoles, obtain title compound, be white solid (yield: 19%).
1H NMR (300MHz, CDCl 3+ CD 3OD) δ (TMS): 2.03 (wide s, 3H), 4.08 (s, NH+CD 3OD), 6.81 (m, 2H), 6.96 (m, 2H), 7.01 (m, 2H), 7.04 (m, 2H), 7.29 (m, 2H), 8.23 (m, 2H).
Embodiment 5
4,6-phenylbenzene-3-methyl-5-(4-pyridyl)-1H-pyrazolo [3,4-b] pyridine
According to the described similar technology of embodiment 1 method B, but be to use 3-amino-5-methyl-2H-pyrazoles to replace 3-amino-2H-pyrazoles, 1-phenyl-2-(4-pyridyl) vinyl benzoic acid ester (obtaining in reference example 5) replaces 1-(4-fluorophenyl)-2-(4-pyridyl) vinyl 4-fluorobenzoic acid ester, obtain title compound, be white solid (yield: 16%).
1H NMR (300MHz, CDCl 3) δ (TMS): 2.02 (s, 3H), 2.02 (s, NH+H 2O), 6.83 (dd, J o=1.5Hz, J m=4.5Hz, 2H), 7.13 (m, 2H), 7.23-7.33 (sophisticated signal, 6H), 8.25 (83 (dd, J o=1.5Hz, J m=4.5Hz, 2H).
Embodiment 6
2-ethyl-4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6-
Embodiment 7
1-ethyl-4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6-
With 4, two (4-the fluorophenyl)-5-(4-pyridyl) of 6--1H-pyrazolo [3,4-b] pyridine (0.39g, 0.8mmol, in embodiment 1, obtain), (0.05g, 0.8mmol) (0.01g, toluene 0.03mmol) (3ml) suspension is heated to 100 ℃ and reaches 2 hours KOH with crown ether 18-C-6.(0.18g, toluene 1.2mmol) (1ml) solution stirred 2 days down at 100 ℃ to add iodic ether.Make its cooling, add entry and EtOAc, separate each phase.Water extracts with EtOAc.With organic phase through Na 2SO 4Drying is concentrated into dried.The gained crude product is through the silica gel chromatography purifying, use increases progressively polar hexane-EtOAc mixture as eluent, obtain 0.20g 2-ethyl-4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolos [3 of 6-, 4-b] 61%) and 28mg 1-ethyl-4 pyridine (yield:, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridine (yields: 9%) of 6-.
Embodiment 6: 1H NMR (300MHz, CDCl 3) δ (TMS): 1.68 (t, J=7.4Hz, 3H), 4.51 (c, J=7.2Hz, 2H), 6.82 (dd, J o=1.6Hz, J m=4.4Hz, 2H), 6.89 (t, J=8.7Hz, 2H), 7.00 (t, J=8.7Hz, 2H), 7.15 (m, 2H), 7.30 (m, 2H), 7.78 (s, 1H), 8.31 (dd, J o=1.6Hz, J m=4.5Hz, 2H).
Embodiment 7: 1H NMR (300MHz, CDCl 3) δ (TMS): 1.61 (t, J=7.4Hz, 3H), 4.67 (c, J=7.2Hz, 2H), 6.81 (dd, J o=1.6Hz, J m=4.4Hz, 2H), 6.96 (t, J=8.7Hz, 2H), 7.01 (t, J=8.7Hz, 2H), 7.13 (m, 2H), 7.29 (m, 2H), 7.86 (s, 1H), 8.32 (dd, J o=1.5Hz, J m=4.5Hz, 2H).
Embodiment 8
4, two (4-fluorophenyl)-2-methyl-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6-
Embodiment 9
4, two (4-fluorophenyl)-1-methyl-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6-
According to embodiment 6 and 7 described similar technologies, but be to use methyl iodide to replace iodic ether, obtain title compound.
Embodiment 8: productive rate: 52%; 1H NMR (300MHz, CDCl 3) δ (TMS): 4.25 (s, 3H), 6.81 (d, J=5.3Hz, 2H), 6.95 (t, J=8.6Hz, 2H), 6.98 (t, J=8.5Hz, 2H), 7.12 (m, 2H), 7.28 (m, 2H), 7.77 (s, 1H), 8.29 (d, J=5.2Hz, 2H).
Embodiment 9: productive rate: 5%; 1H NMR (300MHz, CDCl 3) δ (TMS): 4.20 (s, 3H), 6.81 (dd, J o=1.5Hz, J m=4.5Hz, 2H), 6.90 (t, J=8.7Hz, 2H), 6.98 (t, J=8.6Hz, 2H), 7.12 (m, 2H), 7.26 (m, 2H), 7.84 (s, 1H), 8.29 (dd, J o=1.5Hz, J m=4.5Hz, 2H).
Embodiment 10
4, two (the 4-fluorophenyls)-2 of 6-, 3-dimethyl-5-(4-pyridyl) pyrazolo [3,4-b] pyridine
Embodiment 11
4, two (the 4-fluorophenyls)-1 of 6-, 3-dimethyl-5-(4-pyridyl) pyrazolo [3,4-b] pyridine
According to embodiment 6 and 7 described similar technologies, but be to use 4, two (4-fluorophenyl)-3-methyl-5-(4-pyridyl)-1 H-pyrazolos [3 of 6-, 4-b] pyridine (in embodiment 4, obtaining) replacement 4, two (4-the fluorophenyl)-5-(4-pyridyl) of 6--1H-pyrazolo [3,4-b] pyridine, methyl iodide replaces iodic ether, obtains title compound.
Embodiment 10: productive rate: 53%; 1H NMR (300MHz, CDCl 3) δ (TMS): 2.03 (s, 3H), 4.13 (s, 3H), 6.79 (dd, J o=1.5Hz, J m=4.5Hz, 2H), 6.88 (t, J=8.8Hz, 2H), 6.98-7.11 (sophisticated signal; , 4H), 7.30 (m, 2H), 8.26 (dd, J o=1.6Hz, J m=4.4Hz, 2H).
Embodiment 11: productive rate: 30%; 1H NMR (300MHz, CDCl 3+ CD 3OD) δ (TMS): 2.01 (wide s, 3H), 4.15 (wide s, 3H), 6.81 (m, 2H), 6.93 (m, 2H), 7.00 (m, 2H), 7.07 (m, 2H), 7.30 (m, 2H), 8.23 (m, 2H).
Embodiment 12
2-[2-[1-(tertbutyloxycarbonyl) piperidin-4-yl] ethyl]-4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6-
Embodiment 13
1-[2-[1-(tertbutyloxycarbonyl) piperidin-4-yl] ethyl]-4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6-
A) 2-[1-(tertbutyloxycarbonyl) piperidin-4-yl] ethanol
To 0 ℃ 2-(4-piperidyl) ethanol (9.63g, slowly add in DMF 74.5mmol) (100ml) solution tert-Butyl dicarbonate (16.26g, 5mol).Mixture at room temperature stirred spend the night.Concentrated solvent is dissolved in resistates in the mixture of EtOAc and water.Separate each phase.With organic phase through Na 2SO 4Drying is concentrated into driedly, obtains the required product of 15.09g (yield: 88%).
B) 2-[1-(tertbutyloxycarbonyl) piperidin-4-yl] the ethyl methane sulfonate ester
Under argon atmospher, to 2-[1-(tertbutyloxycarbonyl) piperidin-4-yl] CHCl of ethanol (7.50g, 32.7mmol obtain in a joint) 3(180ml) add triethylamine (4.6ml) and be cooled to 0 ℃ in the solution.Drip then methylsulfonyl chloride (2.6ml, 32.7mmol).Mixture at room temperature stirred spend the night.Add entry, separate each phase.Water CHCl 3Extraction (x3).With organic phase through Na 2SO 4Drying is concentrated into driedly, obtains 11.18g required compound (yield: quantitatively).
C) title compound
According to embodiment 6 and 7 described similar technologies, but be to use 2-[1-(tertbutyloxycarbonyl) piperidin-4-yl] ethyl methane sulfonate ester (obtaining in b joint) replaces iodic ether, obtains title compound.
Embodiment 12: productive rate: 14%; 1H NMR (300MHz, GDCl 3) δ (TMS): 1.00-1.40 (sophisticated signal; 3H), 1.45 (s, 9H), 1.70 (m, 2H), 2.66 (m, 2H), 2.05 (m, 2H), 4.09 (m, 2H), 4.90 (t, J=7.4Hz, 2H), 6.83 (dd, J o=1.6Hz, J m=4.4Hz, 2H), 6.90 (t, J=8.7Hz, 2H), 7.00 (t, J=8.7Hz, 2H), 7.14 (m, 2H), 7.28 (m, 2H), 7.77 (s, 1H), 8.31 (dd, J o=1.6Hz, J m=4.4Hz, 2H).
Embodiment 13: productive rate: 29%; 1H NMR (300MHz, CDCl 3) δ (TMS) :): 1.00-1.40 (sophisticated signal, 3H), 1.46 (s, 9H), 1.82 (m, 2H), 1.98 (m, 2H), 2.67 (m, 2H), 4.08 (m, 2H), 4.65 (t, J=7.0Hz Hz, 2H), 6.82 (dd, J o=1.6Hz, J m=4.5Hz, 2H), 6.93 (t, J=8.7Hz, 2H), 7.01 (t, J=8.7Hz, 2H), 7.25 (m, 2H), 7.28 (m, 2H), 7.86 (s, 1H), 8.32 (dd, J o=1.5Hz, J m=4.5Hz, 2H).
Embodiment 14
2-[1-(tertbutyloxycarbonyl) piperidin-4-yl]-4, two (4-fluorophenyl)-3-methyl-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6-
Embodiment 15
1-[1-(tertbutyloxycarbonyl) piperidin-4-yl]-4, two (4-fluorophenyl)-3-methyl-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6-
A) 1-(tertbutyloxycarbonyl) piperidin-4-yl methanesulfonates
According to saving described similar technology, but be to use (1-tertbutyloxycarbonyl) piperidines-4-alcohol to replace 2-[1-(tertbutyloxycarbonyl) piperidin-4-yl to embodiment 12 and 13b] ethanol, obtain required compound (yield: 97%).
B) title compound
According to embodiment 6 and 7 described similar technologies, but be to use 4, two (4-fluorophenyl)-3-methyl-5-(4-pyridyl)-1 H-pyrazolos [3 of 6-, 4-b] pyridine (in embodiment 4, obtaining) replacement 4, two (4-the fluorophenyl)-5-(4-pyridyl) of 6--1H-pyrazolo [3,4-b] pyridine, 1-(tertbutyloxycarbonyl) piperidin-4-yl methanesulfonates (obtaining in a joint) replaces iodic ether, obtains title compound.
Embodiment 14: productive rate: 13%; 1H NMR (300MHz, CDCl 3) δ (TMS): 1.51 (s, 9H), 1.97 (m, 2H), 2.06 (s, 3H), 2.45 (m, 2H), 2.94 (m, 2H), 4.35 (m, 3H), 6.78 (d, J=6.0Hz, 2H), 6.87 (t, J=8.7Hz, 2H), 7.01 (t, J=8.6Hz, 2H), 7.10 (m, 2H), 7.33 (m, 2H), 8.26 (d, J=6.0Hz, 2H).
Embodiment 15: productive rate 52%; 1H NMR (300MHz, CDCl 3) δ (TMS): 1.54 (s, 9H), 2.00 (s, 3H), 2.00 (m, 2H), 2.31 (m, 2H), 2.99 (m, 2H), 4.33 (m, 2H), 5.10 (m, 1H), 6.78 (dd, J o=1.8Hz, J m=4.5Hz, 2H), 6.92 (t, J=8.7Hz, 2H), 6.99 (t, J=8.7Hz, 2H), 7.08 (m, 2H), 7.30 (m, 2H), 8.27 (dd, J o=1.5Hz, J m=4.5Hz, 2H).
Embodiment 16
2-(3-chloropropyl)-4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6-
Embodiment 17
1-(3-chloropropyl)-4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6-
According to embodiment 6 and 7 described similar technologies, but be to use 1-bromo-3-chloropropane to replace iodic ether, obtain title compound.
Embodiment 16: productive rate: 28%; 1H NMR (300MHz, CDCl 3) δ (TMS): 2.54 (m, 2H), 3.52 (t, J=6.0Hz, 2H), 4.61 (t, J=6.0Hz, 2H), 6.81 (dd, J o=1.6Hz, J m=4.4Hz, 2H), 6.86 (t, J=8.8Hz, 2H), 6.98 (t, J=8.7Hz, 2H), 7.13 (m, 2H), 7.28 (m, 2H), 7.83 (s, 1H), 8.29 (dd, J o=1.5Hz, J m=4.5Hz, 2H).
Embodiment 17: productive rate: 19%; 1H NMR (300MHz, CDCl 3) δ (TMS): 2.51 (m, 2H), 3.61 (t, J=6.3Hz, 2H), 4.78 (t, J=6.4Hz, 2H), 6.82 (dd, J o=1.6Hz, J m=4.4Hz, 2H), 6.92 (t, J=8.7Hz, 2H), 7.01 (t, J=8.7Hz, 2H), 7.14 (m, 2H), 7.26 (m, 2H), 7.86 (s, 1H), 8.32 (dd, J o=1.6Hz, J m=4.4Hz, 2H).
Embodiment 18
3-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--2-yl] third-1-alcohol
Method A
A) 4, two (4-the fluorophenyl)-5-(4-pyridyl) of 6--2-[3-(tetrahydropyrans-2-base oxygen base) propyl group] pyrazolo [3,4-b] pyridine
With 4, two (4-fluorophenyl)-5-(4-pyridyl)-1 H-pyrazolo [3, the 4-b] pyridine (0.30g of 6-, 0.8mmol, in embodiment 1, obtain), (0.05g, 0.8mmol) (0.01g, toluene 0.03mmol) (10ml) suspension is heated to 100 ℃ and reaches 1 hour KOH with crown ether 18-C-6.(0.17g 0.8mmol), stirred 24 hours down at 100 ℃ to add 2-(3-bromine propoxy-) tetrahydropyrans.Make its cooling, add entry and EtOAc, separate each phase.Water extracts with EtOAc.With organic phase through Na 2SO 4Drying is concentrated into dried.The gained crude product uses to increase progressively polar hexane-EtOAc mixture as eluent through the silica gel chromatography purifying, obtains 0.22g required compound (yield: 54%).
LC-MS (method 1): t R=7.60 minutes; M/z=527.2[M+H] +.
B) title compound
With 4, two (4-the fluorophenyl)-5-(4-pyridyl) of 6--2-[3-(tetrahydropyrans-2-base oxygen base) propyl group] pyrazolo [3,4-b] pyridine (0.22g, 0.42mmol obtain in a joint) is at 4: 2: 1AcOH: THF: H 2Solution in the O mixture (9ml) is heated to 55 ℃ and reaches 3 hours.Make its cooling, concentrate.In resistates, add saturated NaHCO 3With 1N NaOH, extract with EtOAc.With organic phase through Na 2SO 4Drying is concentrated into driedly, obtains 0.15g title compound (yield: 83%).
LC-MS (method 1): t R=5.37 minutes; M/z=443.1[M+H] +.
Embodiment 18
3-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--2-yl] third-1-alcohol
Embodiment 19
3-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--1-yl] third-1-alcohol
Method B
According to embodiment 6 and 7 described similar technologies, but be to use 3-iodine propyl alcohol to replace iodic ether, obtain title compound.
Embodiment 18: productive rate: 33%; 1H NMR (300MHz, CDCl 3) δ (TMS): 1.58 (s, OH+H 2O), 2.17 (m, 2H), 3.71 (m, 2H), 4.63 (t, J=6.4Hz, 2H), 6.83 (dd, J o=1.6Hz, J m=4.4Hz, 2H), 6.90 (t, J=8.7Hz, 2H), 7.00 (t, J=8.7Hz, 2H), 7.15 (m, 2H), 7.29 (m, 2H), 7.82 (s, 1H), 8.33 (dd, J o=1.5Hz, J m=4.5Hz, 2H).
Embodiment 19: productive rate: 21%; 1H NMR (300MHz, CDCl 3) δ (TMS): 1.57 (s, OH+H 2O), 2.17 (m, J=5.9Hz, 2H), 3.58 (m, 2H), 4.78 (t, J=6.0Hz, 2H), 6.82 (dd, J o=1.5Hz, J m=4.5Hz, 2H), 6.94 (t, J=8.7Hz, 2H), 7.02 (t, J=8.7Hz, 2H), 7.15 (m, 2H), 7.27 (m, 2H), 7.90 (s, 1H), 8.34 (dd, J o=1.5Hz, J m=4.5Hz, 2H).
Embodiment 20
2-[1-(tertbutyloxycarbonyl) piperidin-4-yl]-4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6-
Embodiment 21
1-[1-(tertbutyloxycarbonyl) piperidin-4-yl]-4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6-
According to embodiment 6 and 7 described similar technologies, but be to use 1-(tertbutyloxycarbonyl) piperidin-4-yl methanesulfonates (in embodiment 14a joint, obtaining) to replace iodic ether, obtain title compound.
Embodiment 20: productive rate 30%; 1H NMR (300MHz, CDCl 3) δ (TMS): 1.48 (s, 9H), 2.00-2.20 (m, 4H), 2.87 (m, 2H), 4.21 (m, 2H), 4.50 (m, 1H), 6.73 (dd, J o=1.5Hz, J m=4.5Hz, 2H), 6.81 (t, J=8.7Hz, 2H), 6.92 (t, J=8.7Hz, 2H), 7.03 (m, 2H), 7.20 (m, 2H), 7.73 (s, 1H), 8.23 (dd, J o=1.4Hz, J m=4.4Hz, 2H).
Embodiment 21: productive rate: 28%; 1H NMR (300MHz, CDCl 3) δ (TMS): 1.46 (s, 9H), 2.10-2.30 (sophisticated signal, 4H), 2.96 (m, 2H), 4.30 (m, 2H), 4.60 (m, 1H), 6.82 (dd, J o=1.5Hz, J m=4.5Hz, 2H), 6.89 (t, J=8.7Hz, 2H), 7.00 (t, J=8.7Hz, 2H), 7.14 (m, 2H), 7.31 (m, 2H), 7.82 (s, 1H), 8.31 (dd, J o=1.5Hz, J m=4.5Hz, 2H).
Embodiment 22
2-methyl-4,6-phenylbenzene-5-(4-pyridyl) pyrazolo [3,4-b] pyridine
Embodiment 23
1-methyl-4,6-phenylbenzene-5-(4-pyridyl) pyrazolo [3,4-b] pyridine
Under argon atmospher, to 4, add in acetone (1ml) suspension of 6-phenylbenzene-5-(4-pyridyl)-1H-pyrazolo [3,4-b] pyridine (0.10g, 0.3mmol obtain in embodiment 2) KOH (21mg, 0.4mmol).(47mg, acetone 0.3mmol) (0.1ml) solution at room temperature stir and spend the night to add methyl iodide then.Add entry, use CHCl 3Extraction.With organic phase through Na 2SO 4Drying is concentrated into dried.The gained crude product is through the silica gel chromatography purifying, use increases progressively polar hexane-EtOAc mixture as eluent, obtain 47mg 2-methyl-4,6-phenylbenzene-5-(4-pyridyl) pyrazolo [3,4-b] 47%) and 38mg 1-methyl-4 pyridine (yield:, 6-phenylbenzene-5-(4-pyridyl) pyrazolo [3,4-b] pyridine (yield: 38%).
Embodiment 22: 1H NMR (300MHz, CDCl 3) δ (TMS): 4.24 (s, 3H), 6.83 (dd, J o=1.5Hz, J m=4.5Hz, 2H), 7.16-7.21 (sophisticated signal, 4H), 7.26-7.31 (sophisticated signal, 6H), 7.77 (s, 1H), 8.24 (dd, J o=1.5Hz, J m=4.5Hz, 2H).
Embodiment 23: 1H NMR (300MHz, CDCl 3) δ (TMS): 4.23 (s, 3H), 6.81 (dd, J o=1.6Hz, J m=4.4Hz, 2H), 7.17 (m, 2H), 7.22-7.32 (sophisticated signal, 8H), 7.89 (s, 1H), 8.26 (dd, J o=1.5Hz, J m=4.5Hz, 2H).
Embodiment 24
4, two (4-the fluorophenyl)-5-(4-pyridyl) of 6--2-[2-(tetrahydropyrans-2-base oxygen base) ethyl] pyrazolo [3,4-b] pyridine
According to embodiment 6 and 7 described similar technologies, but be to use 2-(2-bromine oxethyl) tetrahydropyrans to replace iodic ether, obtain title compound (yield: 50%).
1H NMR (300MHz, CDCl 3) δ (TMS): 1.48-1.63 (sophisticated signal, 6H), 3.47 (m, 1H), 3.67 (m, 1H), 4.02 (m, 1H), 4.22 (m, 1H), 4.57 (m, 1H), 4.65 (m, 2H), 6.83 (dd, J o=1.5Hz, J m=4.5Hz, 2H), 6.90 (t, J=8.7Hz, 2H), 7.00 (t, J=8.6Hz, 2H), 7.14 (m, 2H), 7.31 (m, 2H), 7.92 (s, 1H), 8.32 (dd, J o=1.5Hz, J m=4.5Hz, 2H).
Embodiment 25
2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--1-yl] ethanol
According to embodiment 22 and 23 described similar technologies, but be to use 4, two (4-the fluorophenyl)-5-(4-pyridyl) of 6--1H-pyrazolo [3,4-b] pyridine (in embodiment 1, obtaining) replacement 4,6-phenylbenzene-5-(4-pyridyl)-1H-pyrazolo [3,4-b] pyridine, ethylene bromohyrin replaces methyl iodide, obtains title compound.
1H NMR(300MHz，CDCl 3)δ(TMS)：4.19(m，2H)，4.32(m，OH)，4.77(t，J＝4.7Hz，2H)，6.82(dd，J o＝1.5Hz，J m＝4.5Hz，2H)，6.95(t，J＝8.7Hz，2H)，7.02(t，J＝8.6Hz，2H)，7.15(m，2H)，7.26(m，2H)，7.89(s，1H)，8.34(dd，J o＝1.6Hz，J m＝4.5Hz，2H).
Embodiment 26
4, two (4-the fluorophenyl)-2-(4-methylthio group benzyl) of 6--5-(4-pyridyl) pyrazolo [3,4-b] pyridine
Embodiment 27
4, two (4-the fluorophenyl)-1-(4-methylthio group benzyl) of 6--5-(4-pyridyl) pyrazolo [3,4-b] pyridine
A) 1-chloromethyl-4-(methylthio group) benzene
Under argon atmospher, with thionyl chloride (0.2ml, THF 3.2mmol) (9ml) solution slowly join 4-(methylthio group phenyl) methyl alcohol (0.346g, 2.2mmol) in.Mixture was at room temperature stirred 2 days.Add salt solution (9ml), separate each phase.With organic phase through Na 2SO 4Drying is concentrated into driedly, obtains 0.37g required compound (yield: 95%).
B) title compound
In volumetric flask, under argon atmospher, introduce 4, two (4-the fluorophenyl)-5-(4-pyridyl) of 6--1H-pyrazolo [3,4-b] pyridine (0.30g, 78.0mmol obtain) and DMF (3.5ml) in embodiment 1.(0.06g 1.1mmol), adds DMF (0.4ml) solution of 1-chloromethyl-4-(methylthio group) benzene (0.15g, 0.9mmol obtain) subsequently in a joint to add KOH.Being heated to 60 ℃ spends the night.Make its cooling, concentrate.The mixture of resistates is water-soluble and EtOAc.Separate two-phase.With organic phase through Na 2SO 4Drying is concentrated into dried.The gained crude product is through the silica gel chromatography purifying, use increases progressively polar hexane-EtOAc mixture as eluent, obtain 0.10g 4, two (4-the fluorophenyl)-2-(4-methylthio group benzyl) of 6--5-(4-pyridyl) pyrazolo [3,4-b] 25%) and 0.19g 4 pyridine (yield:, two (4-the fluorophenyl)-1-(4-methylthio group benzyl) of 6--5-(4-pyridyl) pyrazolo [3,4-b] pyridine (yield: 47%).
Embodiment 26: 1H NMR (300MHz, CDCl 3) δ (TMS): 2.50 (s, 3H), 5.60 (s, 2H), 6.84 (dd, J o=1.5Hz, J m=4.5Hz, 2H), 6.92 (t, J=8.8Hz, 2H), 7.00 (t, J=8.7Hz, 2H), 7.05 (m, 2H), 7.24-7.37 (sophisticated signal, 6H), 7.76 (s, 1H), 8.34 (dd, J o=1.5Hz, J m=4.5Hz, 2H).
Embodiment 27: 1H NMR (300MHz, CDCl 3) δ (TMS): 2.49 (s, 3H), 5.77 (s, 2H), 6.85 (dd, J o=1.6Hz, J m=4.4Hz, 2H), 6.97 (t, J=8.8Hz, 2H), 7.03 (t, J=8.7Hz, 2H), 7.15 (m, 2H), 7.24-7.33 (sophisticated signal, 4H), 7.42 (d, J=8.1Hz, 2H), 7.89 (s, 1H), 8.36 (dd, J o=1.5Hz, J m=4.5Hz, 2H).
Embodiment 28
2-[1-(tertbutyloxycarbonyl) piperidin-4-yl methyl]-4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6-
Embodiment 29
1-[1-(tertbutyloxycarbonyl) piperidin-4-yl methyl]-4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6-
A) (4-piperidyl) methyl alcohol
Under 0 ℃, to LiAlH 4(10.10g slowly adds piperidines-4-carboxylic acid ethyl ester (18.13g, THF 0.120mol) (300ml) solution in THF 0.266mol) (150ml) suspension.At room temperature stir and spend the night.With the ice bath cooling, slowly add the mixture of entry (14ml) and THF (28ml).Add the mixture of the 15%NaOH aqueous solution (14ml) and water (37ml) then, at room temperature stirred subsequently 30 minutes.Filtration gained precipitation, concentrated filtrate obtains 17.88g required compound (yield: quantitatively).
B) [1-(tertbutyloxycarbonyl) piperidin-4-yl] methyl alcohol
According to saving described similar technology, but be to use (4-piperidyl) methyl alcohol (in this routine a joint, obtaining) to replace 2-(4-piperidyl) ethanol, obtain title compound (yield: 77%) to embodiment 12a.
C) [1-(tertbutyloxycarbonyl) piperidin-4-yl] methylmethanesulfonate ester
According to saving described similar technology, but be to use [1-(tertbutyloxycarbonyl) piperidin-4-yl] methyl alcohol (in this routine b joint, obtaining) to replace 2-[1-(tertbutyloxycarbonyl) piperidin-4-yl to embodiment 12b] ethanol, obtain title compound (yield: 71%).
D) title compound
According to embodiment 26 and 27 described similar technologies, but be to use [1-(tertbutyloxycarbonyl) piperidin-4-yl] methylmethanesulfonate ester (in c joint, obtaining) to replace 1-chloromethyl-4-(methylthio group) benzene, obtain title compound.
Embodiment 28: productive rate: 22%; 1H NMR (300MHz, CDCl 3) δ (TMS): 1.47 (s, 9H), 1.63 (m, 2H), 2.43 (m, 1H), 2.72 (m, 2H), 4.15 (m, 2H), 4.33 (d, J=7.2Hz, 2H), 6.86 (dd, J o=1.5Hz, J m=4.5Hz, 2H), 6.93 (t, J=8.7Hz, 2H), 7.04 (t, J=8.7Hz, 2H), 7.17 (m, 2H), 7.33 (m, 2H), 7.77 (s, 1H), 8.35 (dd, J o=1.6Hz, J m=4.4Hz, 2H).
Embodiment 29: productive rate: 71%; 1H NMR (300MHz, CDCl 3) δ (TMS): 1.20-1.8 (sophisticated signal, 5H), 1.49 (s, 9H), 2.35 (m, 1H), 2.74 (m, 2H), 4.15 (m, 2H), 4.54 (d, J=7.2Hz, 2H), 6.86 (dd, J o=1.5Hz, J m=4.5Hz, 2H), 6.97 (t, J=8.7Hz, 2H), 7.04 (t, J=8.7Hz, 2H), 7.18 (m, 2H), 7.28 (m, 2H), 7.90 (s, 1H), 8.36 (dd, J o=1.6Hz, J m=4.5Hz, 2H).
Embodiment 30
4, two (4-fluorophenyl)-2-[2-(morpholine-4-yl) ethyls of 6-]-5-(4-pyridyl) pyrazolo [3,4-b] pyridine
Embodiment 31
4, two (4-fluorophenyl)-1-[2-(morpholine-4-yl) ethyls of 6-]-5-(4-pyridyl) pyrazolo [3,4-b] pyridine
According to embodiment 26 and 27 described similar technologies, but be to use 4-(2-chloroethyl) morpholine hydrochloride to replace 1-chloromethyl-4-(methylthio group) benzene and 2 equivalent KOH, obtain title compound.
Embodiment 30: productive rate: 10%; 1H NMR (300MHz, CDCl 3) δ (TMS): 2.55 (m, 4H), 3.06 (t, J=6.4Hz, 2H), 3.70 (m, 4H), 4.58 (t, J=6.4Hz, 2H), 6.86 (dd, J o=1.6Hz, J m=4.4Hz, 2H), 6.93 (t, J=8.9Hz, 2H), 7.04 (t, J=8.7Hz, 2H), 7.16 (m, 2H), 7.31 (m, 2H), 7.88 (s, 1H), 8.35 (dd, J o=1.5Hz, J m=4.5Hz, 2H).
Embodiment 31: productive rate: 24%; 1H NMR (300MHz, CDCl 3) δ (TMS): 2.63 (m, 4H), 3.04 (t, J=6.9Hz, 2H), 3.69 (m, 4H), 4.77 (t, J=6.8Hz, 2H), 6.86 (dd, J o=1.5Hz, J m=4.5Hz, 2H), 6.96 (t, J=8.7Hz, 2H), 7.05 (t, J=8.7Hz, 2H), 7.18 (m, 2H), 7.28 (m, 2H), 7.90 (s, 1H), 8.36 (dd, J o=1.5Hz, J m=4.5Hz, 2H).
Embodiment 32
2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--2-yl] the acetate ethyl ester
Embodiment 33
2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--1-yl] the acetate ethyl ester
According to embodiment 26 and 27 described similar technologies, but be to use the bromoacetic acid ethyl ester to replace 1-chloromethyl-4-(methylthio group) benzene, obtain title compound.
Embodiment 32: productive rate: 6%; 1H NMR (300MHz, CDCl 3) δ (TMS): 1.32 (t, J=7.2Hz, 3H), 4.32 (c, J=7.2Hz, 2H), 5.27 (s, 2H), 6.86 (dd, J o=1.6Hz, J m=4.4Hz, 2H), 6.93 (t, J=8.7Hz, 2H), 7.03 (t, J=8.6Hz, 2H), 7.18 (m, 2H), 7.32 (m, 2H), 7.93 (s, 1H), 8.35 (dd, J o=1.5Hz, J m=4.5Hz, 2H).
Embodiment 33: productive rate: 21%; 1H NMR (300MHz, CDCl 3) δ (TMS): 1.32 (t, J=7Hz, 3H), 4.31 (c, J=6.9Hz, 2H), 5.42 (s, 2H), 6.84 (dd, J o=1.6Hz, J m=4.5Hz, 2H), 6.95 (t, J=8.7Hz, 2H), 7.05 (t, J=8.7Hz, 2H), 7.19 (m, 2H), 7.28 (m, 2H), 7.98 (s, 1H), 8.36 (dd, J o=1.5Hz, J m=4.5Hz, 2H).
Embodiment 34
3-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--2-yl] the propionic acid ethyl ester
Embodiment 35
3-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--1-yl] the propionic acid ethyl ester
According to embodiment 26 and 27 described similar technologies, but be to use 3-bromo-propionic acid ethyl ester to replace 1-chloromethyl-4-(methylthio group) benzene, obtain title compound.
Embodiment 34: productive rate: 5%; 1H NMR (300MHz, CDCl 3) δ (TMS): 1.26 (t, J=7.2Hz, 3H), 3.20 (t, J=6.3Hz, 2H), 4.31 (c, J=7.2Hz, 2H), 4.76 (t, J=6.3Hz, 2H), 6.85 (dd, J o=1.6Hz, J m=4.4Hz, 2H), 6.93 (t, J=8.8Hz, 2H), 7.03 (t, J=8.5Hz, 2H), 7.16 (m, 2H), 7.32 (m, 2H), 7.92 (s, 1H), 8.34 (dd, J o=1.5Hz, J m=4.5Hz, 2H).
Embodiment 35: productive rate: 3%; 1H NMR (300MHz, CDCl 3) 6 (TMS): 1.25 (t, J=7.2Hz, 3H), 3.10 (t, J=7.2Hz, 2H), 4.17 (c, J=7.1Hz, 2H), 4.94 (t, J=7.0Hz, 2H), 6.85 (dd, J o=1.6Hz, J m=4.6Hz, 2H), 6.96 (t, J=8.6Hz, 2H), 7.04 (t, J=8.6Hz, 2H), 7.18 (m, 2H), 7.31 (m, 2H), 7.89 (s, 1H), 8.36 (dd, J o=1.5Hz, J m=4.5Hz, 2H).
Embodiment 36
4, two (4-the fluorophenyl)-2-(4-piperidyl) of 6--5-(4-pyridyl) pyrazolo [3,4-b] pyridine
Under argon atmospher, to 2-[1-(tertbutyloxycarbonyl) piperidin-4-yl that is cooled to 0 ℃]-4, the CH of two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines (0.62g, 1.1mmol obtain in embodiment 20) of 6- 2Cl 2(19ml) add trifluoroacetic acid (1.8ml) in the solution.At room temperature stirred 2.5 hours.Evaporating solvent.Resistates is dissolved in CHCl 3, with 1N NaOH and salt water washing.With organic phase through Na 2SO 4Drying is concentrated into driedly, obtains 319mg title compound (yield: 62%).
1H NMR (300MHz, CDCl 3) δ (TMS): 1.71 (wide s, NH+H 2O), 2.21 (m, 2H), 2.34 (m, 2H), 2.88 (m, 2H), 3.35 (m, 2H), 4.54 (m, 1H), 6.87 (dd, J o=1.5Hz, J m=4.5Hz, 2H), 6.95 (t, J=8.7Hz, 2H), 7.06 (t, J=8.6Hz, 2H), 7.18 (m, 2H), 7.34 (m, 2H), 7.88 (s, 1H), 8.36 (dd, J o=1.6Hz, J m=4.4Hz, 2H).
Embodiment 37
4, two (4-the fluorophenyl)-1-(4-piperidyl) of 6--5-(4-pyridyl) pyrazolo [3,4-b] pyridine
According to embodiment 36 described similar technologies, but be to use 1-[1-(tertbutyloxycarbonyl) piperidin-4-yl]-4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolos [3 of 6-, 4-b] pyridine (in embodiment 21, obtaining) replacement 2-[1-(tertbutyloxycarbonyl) piperidin-4-yl]-4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolos [3 of 6-, 4-b] pyridine, obtain title compound (yield: 29%).
1H NMR (300MHz, CDCl 3) δ (TMS): 1.62 (wide s, NH+H 2O), 2.13 (m, 2H), 2.32 (m, 2H), 2.92 (m, 2H), 3.33 (m, 2H), 4.52 (m, 1H), 6.81 (dd, J o=1.5Hz, J m=4.5Hz, 2H), 6.94 (t, J=8.7Hz, 2H), 7.01 (t, J=8.6Hz, 2H), 7.14 (m, 2H), 7.27 (m, 2H), 7.86 (s, 1H), 8.32 (dd, J o=1.4Hz, J m=4.4Hz, 2H).
Embodiment 38
4, two (4-the fluorophenyl)-2-(4-piperidino methyl) of 6--5-(4-pyridyl) pyrazolo [3,4-b] pyridine
According to embodiment 36 described similar technologies, but be to use 2-[1-(tertbutyloxycarbonyl) piperidin-4-yl methyl]-4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolos [3 of 6-, 4-b] pyridine (in embodiment 28, obtaining) replacement 2-[1-(tertbutyloxycarbonyl) piperidin-4-yl]-4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolos [3 of 6-, 4-b] pyridine, obtain title compound (yield: 13%).
1H NMR (300MHz, CDCl 3) δ (TMS): 1.30-1.80 (sophisticated signal, 4H), 1.63 (wide s, NH+H 2O), 2.38 (m, 1H), 2.64 (m, 2H), 3.14 (m, 2H), 4.32 (d, J=7.2H), 6.86 (dd, J o=1.6Hz, J m=4.4Hz, 2H), 6.93 (t, J=8.8Hz, 2H), 7.04 (t, J=8.6Hz, 2H), 7.18 (m, 2H), 7.33 (m, 2H), 7.78 (s, 1H), 8.35 (dd, J o=1.8Hz, J m=4.5Hz, 2H).
Embodiment 39
4, two (4-the fluorophenyl)-1-(4-piperidino methyl) of 6--5-(4-pyridyl) pyrazolo [3,4-b] pyridine
According to embodiment 36 described similar technologies, but be to use 1-[1-(tertbutyloxycarbonyl) piperidin-4-yl methyl]-4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolos [3 of 6-, 4-b] pyridine (in embodiment 29, obtaining) replacement 2-[1-(tertbutyloxycarbonyl) piperidin-4-yl]-4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolos [3 of 6-, 4-b] pyridine, obtain title compound (yield: 12%).
1H NMR (300MHz, CDCl 3) δ (TMS): 1.80-2.10 (sophisticated signal, 4H), 2.47 (m, 1H), 3.0 (m, 3H), 3.50 (m, 2H), 4.63 (d, J=6.6,2H), 7.04 (t, J=8.4Hz, 2H), and 7.12-7.16 (sophisticated signal, 4H), 7.22 (m, 2H), 7.31 (m, 2H), 7.95 (s, 1H), 8.58 (d, J=6.6,2H).
Embodiment 40
4, two (6-chloropyridine-3-the yl)-5-(4-pyridyl) of 6--1H-pyrazolo [3,4-b] pyridine
According to the described similar technology of embodiment 1 method A, but be to use 1-(6-chloropyridine-3-yl)-2-(4-pyridyl) ethyl ketone (in reference example 9, obtaining) to replace 1-(4-fluorophenyl)-2-(4-pyridyl) ethyl ketone, obtain title compound (yield: 17%).
1H NMR (300MHz, CDCl 3) δ (TMS): 6.90 (dd, J o=1.5Hz, J m=4.5Hz, 2H), 7.21 (d, J=8.4Hz, 1H), 7.30 (d, J=8.4Hz, 1H), 7.38 (dd, J o=2.5Hz, J m=8.3Hz, 1H), 7.49 (dd, J o=2.4Hz, J m=8.4Hz, 1H), 8.00 (s, 1H), 8.36 (d, J=2.4Hz, 1H), 8.46-8.48 (sophisticated signal, 3H), 11.34 (wide s, 1H).
Embodiment 41
4, two (4-the fluorophenyl)-3-methyl-2-(4-piperidyl) of 6--5-(4-pyridyl) pyrazolo [3,4-b] pyridine
According to embodiment 36 described similar technologies, but be to use 2-[1-(tertbutyloxycarbonyl) piperidin-4-yl]-4, two (4-fluorophenyl)-3-methyl-5-(4-pyridyl) pyrazolos [3 of 6-, 4-b] pyridine (in embodiment 14, obtaining) replacement 2-[1-(tertbutyloxycarbonyl) piperidin-4-yl]-4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolos [3 of 6-, 4-b] pyridine, obtain title compound (yield: 73%).
1H NMR (300MHz, CDCl 3) δ (TMS): 1.55 (wide s, NH+H 2O), (s, 3H), 2.35 (m, 2H), 3.34 (m, 2H), 3.85 (m, 2H), 4.73 (m, 2H), 4.75 (m, 1H), 6.78 (d, J=6.3Hz, 2H), 6.89 (t, J=8.6Hz, 2H), 7.03-7.19 (sophisticated signal, 4H), 7.29 (m, 2H), 8.27 (d, J=6.0Hz, 2H).
Embodiment 42
4, two (4-the fluorophenyl)-3-methyl isophthalic acids of 6--(4-piperidyl)-5-(4-pyridyl) pyrazolo [3,4-b] pyridine
According to embodiment 36 described similar technologies, but be to use 1-[1-(tertbutyloxycarbonyl) piperidin-4-yl]-4, two (4-fluorophenyl)-3-methyl-5-(4-pyridyl) pyrazolos [3 of 6-, 4-b] pyridine (in embodiment 15, obtaining) replacement 2-[1-(tertbutyloxycarbonyl) piperidin-4-yl]-4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolos [3 of 6-, 4-b] pyridine, obtain title compound (yield: 59%).
1H NMR (300MHz, CDCl 3) δ (TMS): 1.55 (wide s, NH+H 2O), 2.01 (s, 3H), 2.07 (m, 2H), 2.29 (m, 2H), 2.90 (m, 2H), 3.32 (m, 2H), 4.75 (m, 1H), 6.78 (dd, J o=1.6Hz, J m=4.4Hz, 2H), 6.93 (t, J=8.7Hz, 2H), 6.99 (t, J=8.7Hz, 2H), 7.08 (m, 2H), 7.30 (m, 2H), 8.27 (dd, J o=1.6Hz, J m=4.4Hz, 2H).
Embodiment 43
4, two (4-fluorophenyl)-2-[2-(4-piperidyl) ethyls of 6-]-5-(4-pyridyl) pyrazolo [3,4-b] pyridine
According to embodiment 36 described similar technologies, but be to use 2-[2-[1-(tertbutyloxycarbonyl) piperidin-4-yl] ethyl]-4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolos [3 of 6-, 4-b] pyridine (in embodiment 12, obtaining) replacement 2-[1-(tertbutyloxycarbonyl) piperidin-4-yl]-4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolos [3 of 6-, 4-b] pyridine, obtain title compound (yield: 88%).
1H NMR (300MHz, CDCl 3) δ (TMS): 1.00-1.60 (sophisticated signal, 3H), 1.66 (s, NH+H 2O), 1.74 (m, 2H), 2.03 (m, 2H), 2.60 (m, 2H), 3.10 (m, 2H), 4.85 (t, J=7.2Hz, 2H), 6.82 (dd, J o=1.5Hz, J m=4.5Hz, 2H), 6.89 (t, J=8.7Hz, 2H), 7.00 (t, J=8.7Hz, 2H), 7.13 (m, 2H), 7.30 (m, 2H), 7.76 (s, 1H), 8.31 (dd, J o=1.5Hz, J m=4.5Hz, 2H).
Embodiment 44
2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--2-yl] acetate
To 2-(4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--2-yl] acetate ethyl ester (0.09g, 0.2mmol, in embodiment 32, obtain) EtOH (4.2ml) solution in add KOH (0.09g, water 2.5mmol) (0.5ml) solution.Being heated to refluxes reaches 1 hour.Make its cooling, concentrate.Resistates is dissolved in the mixture of EtOAc and water.Separate each phase.With aqueous phase as acidified, extract with EtOAc.Merge organic phase, through Na 2SO 4Drying is concentrated into driedly, obtains 57mg title compound (yield: 66%).
1H NMR (300MHz, CDCl 3+ CD 3OD) δ (TMS): 4.00 (wide s, 1H+CD 3OD), 5.28 (wide s, 2H), 6.92-7.05 (sophisticated signal, 6H), 7.15-7.30 (sophisticated signal, 4H), 8.02 (wide s, 1H), 8.26 (m, 2H).
Embodiment 45
2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--1-yl] acetate
According to embodiment 44 described similar technologies, but be to use 2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolos [3 of 6-, 4-b] pyridine-1-yl] acetate ethyl ester (in embodiment 33, obtaining) replacement 2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolos [3 of 6-, 4-b] pyridine-2-yl] the acetate ethyl ester, obtain title compound (yield: 96%).
1H NMR (300MHz, CDCl 3+ CD 3OD) δ (TMS): 3.88 (wide s, 1H+CD 3OD), 5.32 (s, 2H), 6.83 (dd, J o=1.5Hz, J m=4.5Hz, 2H), 6.88 (t, J=8.7Hz, 2H), 6.98 (t, J=8.6Hz, 2H), 7.11 (m, 2H), 7.20 (m, 2H), 7.90 (s, 1H), 8.21 (dd, J o=1.5Hz, J m=4.5Hz, 2H).
Embodiment 46
3-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--2-yl] propionic acid
According to embodiment 44 described similar technologies, but be to use 3-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolos [3 of 6-, 4-b] pyridine-2-yl] propionic acid ethyl ester (in embodiment 34, obtaining) replacement 2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolos [3 of 6-, 4-b] pyridine-2-yl] the acetate ethyl ester, obtain title compound (yield: 69%).
1H NMR (300MHz, CDCl 3+ CD 3OD) δ (TMS): 3.08 (t, J=6.3Hz, 2H), 4.50 (wide s, 1H+CD 3OD), 4.72 (t, J=6.3Hz, 2H), 6.88 (dd, J o=1.6Hz, J m=4.6Hz, 2H), 6.90 (t, J=8.7Hz, 2H), 6.99 (t, J=8.7Hz, 2H), 7.15 (m, 2H), 7.23 (m, 2H), 8.03 (s, 1H), 8.21 (dd, J o=1.5Hz, J m=4.5Hz, 2H).
Embodiment 47
3-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--1-yl] propionic acid
According to embodiment 44 described similar technologies, but be to use 3-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolos [3 of 6-, 4-b] pyridine-1-yl] propionic acid ethyl ester (in embodiment 35, obtaining) replacement 2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolos [3 of 6-, 4-b] pyridine-2-yl] the acetate ethyl ester, obtain title compound (yield: 88%).
1H NMR (300MHz, CDCl 3+ CD 3OD) δ (TMS): 3.02 (t, J=7.2Hz, 2H), 4.50 (wide s, 1H+CD 3OD), 4.86 (t, J=7.3Hz, 2H), 6.87 (dd, J o=1.5Hz, J m=4.5Hz, 2H), 6.91 (t, J=8.7Hz, 2H), 7.00 (t, J=8.7Hz, 2H), 7.12 (m, 2H), 7.24 (m, 2H), 7.84 (s, 1H), 8.21 (dd, J o=1.5Hz, J m=4.5Hz, 2H).
Embodiment 48
2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--2-yl]-1-(morpholine-4-yl) ethyl ketone
Under argon atmospher, to 2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolos [3 of 6-, 4-b] pyridine-2-yl] acetate (0.05g, 0.1mmol, in embodiment 44, obtain) DMF (1ml) solution in add N, N '-dicyclohexylcarbodiimide (0.02g, 0.1mmol) and I-hydroxybenzotriazole (0.02g, 0.1mmol).Mixture was stirred 15 minutes, and the adding morpholine (0.01g, 0.1mmol).At room temperature stirred 2 days.Add EtOAc, filtering mixt.Filtrate is used saturated NaHCO 3Washing.With organic phase through Na 2SO 4Drying is concentrated into dried.The gained crude product uses to increase progressively polar EtOAc-MeOH mixture as eluent through the silica gel chromatography purifying, obtains 18mg title compound (yield: 35%).
1H NMR (300MHz, CDCl 3) δ (TMS): 3.66-3.76 (sophisticated signal, 8H), 5.30 (s, 2H), 6.82 (d, J=5.7Hz, 2H), 6.91 (t, J=8.8Hz, 2H), 6.99 (t, J=8.7Hz, 2H), 7.14 (m, 2H), 7.28 (m, 2H), 7.99 (s, 1H), 8.32 (d, J=6.0Hz, 2H).
Embodiment 49
2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--1-yl] ethanamide
According to embodiment 48 described similar technologies, but be to use 2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolos [3 of 6-, 4-b] pyridine-1-yl] acetate (in embodiment 45, obtaining) replacement 2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolos [3 of 6-, 4-b] pyridine-2-yl] acetate, the aqueous ammonia to replace morpholine obtains title compound (yield: 36%).
1H NMR (300MHz, CDCl 3) δ (TMS): 5.35 (s, 2H), 5.56 (wide s, 1H), 6.15 (wide s, 1H), 6.85 (d, J=5.4Hz, 2H), 6.96 (t, J=8.6Hz, 2H), 7.06 (t, J=8.6Hz, 2H), 7.17 (m, 2H), 7.29 (m, 2H), 8.01 (s, 1H), 8.38 (d, J=5.4Hz, 2H).
Embodiment 50
2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--1-yl]-1-(morpholine-4-yl) ethyl ketone
According to embodiment 48 described similar technologies, but be to use 2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolos [3 of 6-, 4-b] pyridine-1-yl] acetate (in embodiment 45, obtaining) replacement 2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolos [3 of 6-, 4-b] pyridine-2-yl] acetate, obtain title compound (yield: 60%).
1H NMR (300MHz, CDCl 3) δ (TMS): 3.67-3.70 (sophisticated signal, 4H), 3.75-3.81 (sophisticated signal, 4H), 5.50 (s, 2H), 6.83 (dd, J o=1.6Hz, J m=4.4Hz, 2H), 6.95 (t, J=8.7Hz, 2H), 7.04 (t, J=8.7Hz, 2H), 7.17 (m, 2H), 7.27 (m, 2H), 7.99 (s, 1H), 8.35 (dd, J o=1.6Hz, J m=4.4Hz, 2H)
Embodiment 51
3-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--2-yl]-1-(morpholine-4-yl) propane-1-ketone
According to embodiment 48 described similar technologies, but be to use 3-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolos [3 of 6-, 4-b] pyridine-2-yl] propionic acid (in embodiment 46, obtaining) replacement 2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolos [3 of 6-, 4-b] pyridine-2-yl] acetate, obtain title compound (yield: 64%).
1H NMR (300MHz, CDCl 3) δ (TMS): 3.20 (t, J=6.0Hz, 2H), 3.45 (m, 2H), 3.55-3.63 (sophisticated signal, 6H), 4.79 (t, J=6.1Hz, 2H), 6.81 (dd, J o=1.6Hz, J m=4.4Hz, 2H), 6.90 (t, J=8.7Hz, 2H), 6.99 (t, J=8.7Hz, 2H), 7.13 (m, 2H), 7.30 (m, 2H), 7.94 (s, 1H), 8.31 (dd, J o=1.6Hz, J m=4.4Hz, 2H)
Embodiment 52
3-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--1-yl]-N-propyl group propionic acid amide
According to embodiment 48 described similar technologies, but be to use 3-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolos [3 of 6-, 4-b] pyridine-1-yl] propionic acid (in embodiment 47, obtaining) replacement 2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolos [3 of 6-, 4-b] pyridine-2-yl] acetate, propylamine replaces morpholine, obtains title compound (yield: 76%).
1H NMR(300MHz，CDCl 3)δ(TMS)：0.84(t，J＝7.3Hz，3H)，1.42(m，2H)，2.98(t，J＝6.7Hz，2H)，3.18(m，2H)，4.95(t，J＝6.7Hz，2H)，6.05(m，NH)，6.84(dd，J o＝1.5Hz，J m＝4.5Hz，2H)，6.96(t，J＝8.7Hz，2H)，7.04(t，J＝8.7Hz，2H)，7.16(m，2H)，7.32(m，2H)，7.89(s，1H)，8.36(dd，J o＝1.5Hz，J m＝4.5Hz，2H).
Embodiment 53
3-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--1-yl]-1-(morpholine-4-yl) propane-1-ketone
According to embodiment 48 described similar technologies, but be to use 3-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolos [3 of 6-, 4-b] pyridine-1-yl] propionic acid (in embodiment 47, obtaining) replacement 2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolos [3 of 6-, 4-b] pyridine-2-yl] acetate, obtain title compound (yield: 72%).
1H NMR (300MHz, CDCl 3) δ (TMS): 3.13 (t, J=7.3Hz, 2H), 3.49 (m, 2H), 3.63-3.67 (sophisticated signal, 6H), 4.99 (t, J=7.3Hz, 2H), 6.84 (dd, J o=1.4Hz, J m=4.4Hz, 2H), 6.96 (t, J=8.7Hz, 2H), 7.04 (t, J=8.7Hz, 2H), 7.16 (m, 2H), 7.30 (m, 2H), 7.89 (s, 1H), 8.36 (dd, J o=1.6Hz, J m=4.4Hz, 2H)
Embodiment 54
4, two (4-the fluorophenyl)-2-(4-methylthio group phenyl) of 6--5-(4-pyridyl) pyrazolo [3,4-b] pyridine
Embodiment 55
4, two (4-the fluorophenyl)-1-(4-methylthio group phenyl) of 6--5-(4-pyridyl) pyrazolo [3,4-b] pyridine
In volumetric flask, under argon atmospher, introduce 4  molecular sieve (1g, in advance under 200 ℃ of vacuum dry 3 hours), 4, two (4-the fluorophenyl)-5-(4-pyridyl) of 6--1H-pyrazolo [3,4-b] pyridine (0.30g, 0.8mmol, in embodiment 1, obtain), (4-methylthio group phenyl) boric acid (0.26g, 1.6mmol), venus crystals (II) (0.28g, 1.6mmol), pyridine (0.12g, 1.6mmol), triethylamine (0.16g, 1.6mmol) and CH 2Cl 2(22ml).At room temperature stirred 2 days.By diatomite filtration, concentrate.The gained crude product is through the silica gel chromatography purifying, use increases progressively polar hexane-EtOAc mixture as eluent, obtain 40mg 4, two (4-the fluorophenyl)-2-(4-methylthio group phenyl) of 6--5-(4-pyridyl) pyrazolo [3,4-b] 10%) and 90mg 4 pyridine (yield:, two (4-the fluorophenyl)-1-(4-methylthio group phenyl) of 6--5-(4-pyridyl) pyrazolo [3,4-b] pyridine (yield: 23%).
Embodiment 54: 1H NMR (300MHz, CDCl 3) δ (TMS): 2.46 (s, 3H), 6.76 (dd, J o=1.6Hz, J m=4.4Hz, 2H), 6.83 (t, J=8.7Hz, 2H), 6.95 (t, J=8.6Hz, 2H), 7.11 (m, 2H), 7.26 (m, 2H), 7.29 (d, J=8.7Hz, 2H), 7.83 (d, J=8.7Hz, 2H), 8.16 (s, 1H), 8.26 (dd, J o=1.6Hz, J m=4.4Hz, 2H).
Embodiment 55: 1H NMR (300MHz, CDCl 3) δ (TMS): 2.46 (s, 3H), 6.76 (dd, J o=1.5Hz, J m=4.5Hz, 2H), 6.86 (t, J=8.7Hz, 2H), 6.96 (t, J=8.7Hz, 2H), 7.08 (m, 2H), 7.22 (m, 2H), 7.34 (d, J=9.0Hz, 2H), 7.94 (s, 1H), 8.23 (d, J=8.7Hz, 2H), 8.26 (dd, J o=1.5Hz, J m=4.5Hz, 2H).
Embodiment 56
4, two (4-the fluorophenyl)-2-(4-methanesulfinyl phenyl) of 6--5-(4-pyridyl) pyrazolo [3,4-b] pyridine
Embodiment 57
4, two (4-the fluorophenyl)-2-(4-methylsulfonyl phenyl) of 6--5-(4-pyridyl) pyrazolo [3,4-b] pyridine
Under argon atmospher, to 4, the CH of two (4-the fluorophenyl)-2-(4-methylthio group phenyl) of 6--5-(4-pyridyl) pyrazolo [3,4-b] pyridine (0.09g, 0.2mmol obtain in embodiment 54) 2Cl 2(0.04g 0.2mmol), at room temperature stirred 2 hours (3.5ml) to add 3-chlorine peroxybenzoic acid in the solution.Add CHCl 3, use saturated NaHCO 3Washing.With organic phase through Na 2SO 4Drying is concentrated into dried.The gained crude product is through the silica gel chromatography purifying; use increases progressively polar hexane-EtOAc mixture as eluent; obtain 15mg 4; two (4-the fluorophenyl)-2-(4-methanesulfinyl phenyl) of 6--5-(4-pyridyl) pyrazolo [3; 4-b] 16%) and 10mg4 pyridine (yield:; two (4-the fluorophenyl)-2-(4-methylsulfonyl phenyl) of 6--5-(4-pyridyl) pyrazolo [3,4-b] pyridine (yield: 11%).
Embodiment 56: 1H NMR (300MHz, CDCl 3) δ (TMS): 2.83 (s, 3H), 6.90 (dd, J o=1.5Hz, J m=4.5Hz, 2H), 6.96 (t, J=8.7Hz, 2H), 7.08 (t, J=8.7Hz, 2H), 7.24 (m, 2H), 7.36 (m, 2H), 7.75 (H AFrom an AB system, J=8.9Hz, 2H), 8.32 (H BFrom anAB system, J=8.9Hz, 2H), 8.38 (s, 1H), 8.39 (dd, J o=1.5Hz, J m=4.5Hz, 2H).
Embodiment 57: 1H NMR (300MHz, CDCl 3) δ (TMS): 3.16 (s, 3H), 6.89 (dd, J o=1.6Hz, J m=4.4Hz, 2H), 6.97 (t, J=8.7Hz, 2H), 7.09 (t, J=8.7Hz, 2H), 7.24 (m, 2H), 7.36 (m, 2H), 8.05 (H AFrom an AB system, J=9.0Hz, 2H), 8.38 (H BFrom anAB system, J=9.0Hz, 2H), 8.39 (dd, J o=1.6Hz, J m=4.6Hz, 2H), 8.41 (s, 1H).
Embodiment 58
4, two (4-the fluorophenyl)-1-(4-methanesulfinyl phenyl) of 6--5-(4-pyridyl) pyrazolo [3,4-b] pyridine
According to embodiment 56 described similar technologies, but be to use 4, two (4-the fluorophenyl)-1-(4-methylthio group phenyl) of 6--5-(4-pyridyl) pyrazolo [3,4-b] pyridine (in embodiment 55, obtaining) replacement 4, two (4-the fluorophenyl)-2-(4-methylthio group phenyl) of 6--5-(4-pyridyl) pyrazolo [3,4-b] pyridine, obtain title compound (yield: 70%).
1H NMR(300MHz，CDCl 3)δ(TMS)：2.82(s，3H)，6.90(dd，J o＝1.8Hz，J m＝4.5Hz，2H)，7.00(t，J＝8.7Hz，2H)，7.09(t，J＝8.6Hz，2H)，7.20(m，2H)，7.35(m，2H)，7.86(dd，J o＝2.1Hz，J m＝6.9Hz，2H)，8.10(s，1H)，8.41(dd，J o＝1.5Hz，J m＝4.5Hz，2H)，8.69(dd，J o＝1.8Hz，J m＝6.9Hz，2H).
Embodiment 59
4, two (4-the fluorophenyl)-2-(4-methanesulfinyl benzyl) of 6--5-(4-pyridyl) pyrazolo [3,4-b] pyridine
Embodiment 60
4, two (4-the fluorophenyl)-2-(4-methylsulfonyl benzyl) of 6--5-(4-pyridyl) pyrazolo [3,4-b] pyridine
According to embodiment 56 described similar technologies, but be to use 4, two (4-the fluorophenyl)-2-(4-methylthio group benzyl) of 6--5-(4-pyridyl) pyrazolo [3,4-b] pyridine (in embodiment 26, obtaining) replacement 4, two (4-the fluorophenyl)-2-(4-methylthio group phenyl) of 6--5-(4-pyridyl) pyrazolo [3,4-b] pyridine, obtain title compound.
Embodiment 59: productive rate: 48%; 1H NMR (300MHz, CDCl 3) δ (TMS): 2.74 (s, 3H), 5.70 (s, 2H), 6.85 (dd, J o=1.5Hz, J m=4.5Hz, 2H), 6.93 (t, J=8.8Hz, 2H), 7.02 (t, J=8.7Hz, 2H), 7.16 (m, 2H), 7.32 (m, 2H), 7.59 (H AFrom an AB system, J=8.2Hz, 2H), 7.68 (H BFrom an AB system, J=8.2Hz, 2H), 7.87 (s, 1H), 8.39 (dd, J o=1.5Hz, J m=4.5Hz, 2H).
Embodiment 60: productive rate: 16%; 1H NMR (300MHz, CDCl 3) δ (TMS): 3.07 (s, 3H), 5.73 (s, 2H), 6.85 (dd, J o=1.6Hz, J m=4.4Hz, 2 H), 6.93 (t, J=8.7Hz, 2H), 7.03 (t, J=8.8Hz, 2H), 7.16 (m, 2H), 7.32 (m, 2H), 7.61 (H AFrom an AB system, J=8.7Hz, 2H), 7.89 (s, 1H), 7.97 (H BFrom an AB system, J=8.7Hz, 2H), 8.36 (dd, J o=1.8Hz, J m=4.5Hz, 2H).
Embodiment 61
4, two (4-the fluorophenyl)-1-(4-methanesulfinyl benzyl) of 6--5-(4-pyridyl) pyrazolo [3,4-b] pyridine
Embodiment 62
4, two (4-the fluorophenyl)-1-(4-methylsulfonyl benzyl) of 6--5-(4-pyridyl) pyrazolo [3,4-b] pyridine
According to embodiment 56 described similar technologies, but be to use 4, two (4-the fluorophenyl)-1-(4-methylthio group benzyl) of 6--5-(4-pyridyl) pyrazolo [3,4-b] pyridine (in embodiment 27, obtaining) replacement 4, two (4-the fluorophenyl)-2-(4-methylthio group phenyl) of 6--5-(4-pyridyl) pyrazolo [3,4-6] pyridine, obtain title compound.
Embodiment 61: productive rate: 69%; 1H NMR (300MHz, CDCl 3) δ (TMS): 2.71 (s, 3H), 5.84 (s, 2H), 6.83 (dd, J o=1.5Hz, J m=4.5Hz, 2H), 6.94 (t, J=8.7Hz, 2H), 7.01 (t, J=8.6Hz, 2H), 7.13 (m, 2H), 7.25 (m, 2H), 7.61 (H AFrom an AB system, J=8.4Hz, 2H), 7.92 (H BFrom an AB system, J=8.4Hz, 2H), 7.91 (s, 1H), 8.34 (dd, J o=1.5Hz, J m=4.5Hz, 2H).
Embodiment 62: productive rate: 4%: 1H NMR (300MHz, CDCl 3) δ (TMS): 3.03 (s, 3H), 5.87 (s, 2H), 6.83 (d, J=6.0Hz, 2H), 6.94 (t, J=8.8Hz, 2H), 7.02 (t, J=8.7Hz, 2H), 7.14 (m, 2H), 7.26 (m, 2H), 7.60 (H AFrom an AB system, J=8.2Hz, 2H), 7.91 (s, 1H), 7.93 (H BFrom an AB system, J=8.2Hz, 2H), 8.34 (d, J=6.3Hz, 2H).
Embodiment 63
3-chloro-4, two (4-the fluorophenyl)-5-(4-pyridyl) of 6--1H-pyrazolo [3,4-b] pyridine
Under argon atmospher, to 4, two (4-the fluorophenyl)-5-(4-pyridyl) of 6--1H-pyrazolo [3,4-b] add N-chloro-succinimide (0.10g in DMF (5ml) solution of pyridine (0.20g, 0.5mmol obtain) in embodiment 1,0.8mmol), mixture heating up to 60 ℃ is reached 5 hours.With 1N NaOH washing, use CHCl 3Extract with EtOAc.Merge organic phase, through Na 2SO 4Drying is concentrated into dried.The gained crude product uses to increase progressively polar hexane-EtOAc mixture as eluent through the silica gel chromatography purifying, obtains 171mg title compound (yield: 79%).
1H NMR (300MHz, CDCl 3) δ (TMS): 1.61 (wide s, NH+H 2O), 6.82 (dd, J o=1.6Hz, J m=4.4Hz, 2H), 6.98 (t, J=8.7Hz, 2H), 7.03 (t, J=8.7Hz, 2H), 7.13 (m, 2H), 7.29 (m, 2H), 8.35 (dd, J o=1.5Hz, J m=4.5Hz, 2H).
Embodiment 64
3-bromo-4, two (4-the fluorophenyl)-5-(4-pyridyl) of 6--1H-pyrazolo [3,4-b] pyridine
Under argon atmospher, to 4, the CHCl of two (4-the fluorophenyl)-5-(4-pyridyl) of 6--1H-pyrazolo [3,4-b] pyridine (1.00g, 2.6mmol obtain in embodiment 1) 3(10ml) add Br in the suspension 2(0.69g, CHCl 4.3mmol) 3(3ml) solution.Add acetonitrile (4ml), mixture was at room temperature stirred 2 days.Resistates is concentrated, be dissolved in CHCl 3, with 1N NaOH washing.Generate precipitation, filter it, dissolve with MeOH.With solution concentration, wash with 1NNaOH.With the EtOAc extraction, through Na 2SO 4Drying concentrates.Handle with diethyl ether, the decantation solvent, dry products therefrom obtains 1.16g title compound (yield: 97%).
1H NMR (300MHz, CD 3OD) δ (TMS): 4.78 (wide s, NH+CD 3OD), 6.89 (t, J=8.8Hz, 2H), 6.93-6.99 (sophisticated signal, 4H), 7.14 (m, 2H), 7.27 (m, 2H), 8.12 (dd, J o=1.5Hz, J m=4.5Hz, 2H).
Embodiment 65
4, two (4-the fluorophenyl)-5-(4-pyridyl) of 6--1H-pyrazolo [3,4-b] pyridine-3-nitrile
In volumetric flask, under argon atmospher, introduce 3-bromo-4, two (4-the fluorophenyl)-5-(4-pyridyl) of 6--1H-pyrazolo [3,4-b] pyridine (0.20g, 0.4mmol, in embodiment 64, obtain), (0.05g, 0.6mmol) and anhydrous 1-Methyl-2-Pyrrolidone (1ml), being heated to refluxes reaches 2 hours to cupric cyanide (I).Pour in 10% ethylenediamine solution (4ml), use CHCl 3Extraction.Add salt solution to aqueous phase, extract with EtOAc.Merge organic phase, through Na 2SO 4Drying is concentrated into dried.The gained crude product uses to increase progressively polar hexane-EtOAc mixture as eluent through the silica gel chromatography purifying, obtains title compound, is solid form (yield: quantitatively).
1H NMR (300MHz, CDCl 3+ CD 3OD) δ (TMS): 4.00 (wide s, NH+CD 3OD), 6.80-7.40 (sophisticated signal, 12H), 8.25 (m, 2H).
Embodiment 66
3-bromo-4, two (4-fluorophenyl)-1-methyl-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6-
According to embodiment 64 described similar technologies, but be to use 4, two (4-fluorophenyl)-1-methyl-5-(4-pyridyl) pyrazolos [3 of 6-, 4-b] pyridine (in embodiment 9, obtaining) replacement 4, two (4-the fluorophenyl)-5-(4-pyridyl) of 6--1H-pyrazolo [3,4-b] pyridine, obtain title compound (yield: 15%).
1H NMR (300MHz, CDCl 3) δ (TMS): 4.21 (s, 3H), 6.78 (d, J=6.0Hz, 2H), 6.93-7.02 (sophisticated signal, 4H), 7.08 (m, 2H), 7.27 (m, 2H), 8.29 (d, J=6.0Hz, 2H).
Embodiment 67
4, two (4-the fluorophenyl)-5-(4-pyridyl) of 6--1H-pyrazolo [3,4-b] pyridine-3-carboxamide
Under argon atmospher, with KOH (0.07g, tBuOH 1.3mmol) (2.5ml) solution joins 4, two (4-the fluorophenyl)-5-(4-pyridyl) of 6--1H-pyrazolo [3,4-b] pyridine-3-nitrile (0.05g, 0.1mmol, in embodiment 65, obtain) in, being heated to refluxes spends the night.Add entry and EtOAc, separate each phase.Water extracts with EtOAc.Merge organic phase, through Na 2SO 4Drying is concentrated into dried.The gained crude product uses to increase progressively polar hexane-EtOAc mixture as eluent through the silica gel chromatography purifying, obtains the 15mg title compound, is solid form (yield: 28%).
1H NMR (300MHz, CDCl 3) δ (TMS): 1.56 (wide s, NH 2+ H 2O), 6.80 (d, J=4.5Hz, 2H), 6.90-7.10 (sophisticated signal, 6H), 7.30 (m, 2H), 8.30 (d, J=4.5Hz, 2H).
Embodiment 68
3-amino methyl-4, two (4-the fluorophenyl)-5-(4-pyridyl) of 6--1H-pyrazolo [3,4-b] pyridine
With LiAlH 4(0.06g, 1.5mmol) and anhydrous diethyl ether (2ml) be incorporated in the volumetric flask.Mixture is cooled off with ice bath, drip 4, diethyl ether (1ml) solution of two (4-the fluorophenyl)-5-(4-pyridyl) of 6--1H-pyrazolo [3,4-b] pyridine-3-nitrile (0.15g, 0.4mmol obtain in embodiment 65).Add THF (2ml), mixture is at room temperature stirred spend the night.With the ice bath cooling, add entry (0.1ml), THF (0.2ml), the 15%NaOH aqueous solution (0.1ml) and water (0.3ml) continuously.Filtration gained precipitation is washed with THF.The solvent of evaporated filtrate.The gained resistates uses to increase progressively polar hexane-EtOAc mixture as eluent through the silica gel chromatography purifying, obtains the 71mg title compound, is solid form (yield: 47%).
1H NMR (300MHz, CDCl 3) δ (TMS): 2.10 (wide s, NH 2+ H 2O) 3.62 (s, 2H), 6.80 (dd, J o=1.5Hz, J m=4.5Hz, 2H), 6.93 (t, J=8.7Hz, 2H), 7.03 (t, J=8.6Hz, 2H), 7.11 (m, 2H), 7.25 (m, 2H), 8.30 (dd, J o=1.5Hz, J m=4.5Hz, 2H).
Embodiment 69
4, two (4-fluoro-3-the nitrophenyl)-5-(4-pyridyl) of 6--1H-pyrazolo [3,4-b] pyridine
Under argon atmospher, to 4, the dense H of two (4-the fluorophenyl)-5-(4-pyridyl) of 6--1H-pyrazolo [3,4-b] pyridine (0.20g, 0.5mmol obtain in embodiment 1) 2SO 4(3ml) add 65%HNO in the solution 3(0.1ml, 0.2mmol).Be heated to 90 ℃ and reach 30 minutes.With the ice bath cooling, transfer to pH=8 with 1N NaOH.Extract with EtOAc.With organic phase through Na 2SO 4Drying is concentrated into dried.The gained crude product uses to increase progressively polar hexane-EtOAc mixture as eluent through the silica gel chromatography purifying, obtains the 69mg title compound, is solid form (yield: 28%).
1H NMR (300MHz, CDCl 3+ CD 3OD) δ (TMS): 4.28 (s, NH+CD 3OD), 7.03 (dd, J o=1.5Hz, J m=4.5Hz, 2H), 7.22 (dd, J o=2.7Hz, J m=10.5Hz, 1H), 7.36 (dd, J o=2.6Hz, J m=10.4Hz, 1H), 7.53 (m, 2H), 7.99-8.01 (sophisticated signal, 2H), 8.13 (m, 1H), 8.41 (dd, J o=1.5Hz, J m=4.5Hz, 2H).
Embodiment 70
3-amino-6-(4-fluorophenyl)-5-(4-pyridyl)-1H-pyrazolo [3,4-b] pyridine
According to saving described similar technology to reference example 15c, but be to use 6-chloro-2-(4-fluorophenyl)-3,4 '-dipyridyl-5-nitrile (in reference example 12, obtaining) replacement 3-(1-benzyl piepridine-4-yl)-3-oxypropionitrile, obtain title compound (yield: 41%).
1H NMR(300MHz，CD 3OD)δ(TMS)：4.38(s，NH 2+CD 3OD)，7.05(t，J＝8.8Hz，2H)，7.26(dd，J o＝1.6Hz，J m＝4.6Hz，2H)，7.39(m，2H)，8.27(s，1H)，8.42(dd，J o＝1.4Hz，J m＝4.6Hz，2H).
Embodiment 71
3-amino-6-(4-fluorophenyl)-1-methyl-5-(4-pyridyl) pyrazolo [3,4-b] pyridine
According to saving described similar technology to reference example 15c, but be to use 6-chloro-2-(4-fluorophenyl)-3,4 '-dipyridyl-5-nitrile (in reference example 12, obtaining) replacement 3-(1-benzyl piepridine-4-yl)-3-oxypropionitrile, methyl hydrazine replaces a hydrazine hydrate, obtains title compound (yield: 70%).
1H NMR (300MHz, CDCl 3) δ (TMS): 4.00 (s, 3H), 4.17 (broad s, and 2 wide .98 (t, J=8.7Hz, 2H), 7.09 (dd, J o=1.5Hz, J m=4.5Hz, 2H), 7.37 (m, 2H), 7.90 (s, 1H), 8.50 (dd, J o=1.5Hz, J m=4.5Hz, 2H).
Embodiment 72
4-[6-(4-fluorophenyl)-5-(4-pyridyl)-1H-pyrazolo [3,4-b] pyridin-4-yl] phenol
Under argon atmospher, to 1-(4-fluorophenyl)-2-(4-pyridyl) ethyl ketone (0.30g, 1.4mmol, in reference example 1, obtain) 2-methyl cellosolve (2ml) solution in add 3-amino-2H-pyrazoles (0.13g, 1.5mmol), 4-hydroxy benzaldehyde (0.17g, 1.4mmol), 2-methyl cellosolve (2ml) and 37%HCl (0.04g, 0.4mmol).Mixture heating up is spent the night to refluxing.Make its cooling, concentrate.The gained solid is dissolved in CHCl 3With several MeOH.Add saturated NaHCO 3, water CHCl 3Extract three times.Merge organic phase, through Na 2SO 4Drying is concentrated into dried.Crude product uses to increase progressively polar hexane-EtOAc mixture as eluent through the silica gel chromatography purifying, obtains 0.22g required compound (yield: 41%).
LC-MS (method 1): t R=5.56 minutes; M/z=383.0[M+H] +.
Embodiment 73
2-(2,2-diethoxy ethyl)-4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6-
Embodiment 74
1-(2,2-diethoxy ethyl)-4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6-
In volumetric flask, under argon atmospher, introduce 4, two (4-the fluorophenyl)-5-(4-pyridyl) of 6--1H-pyrazolo [3,4-b] pyridine (0.20g, 0.5mmol, in embodiment 1, obtain), KOH (0.03g, 0.5mmol), 2-bromo-1, (0.10g is 0.5mmol) with 1-methoxyl group-2-(2-methoxy ethoxy) ethane (2ml) for the 1-diethoxyethane.With mixture heating up to 100 ℃, under this temperature, stir and spend the night.Make its cooling, add H 2The O-EtOAc mixture.Separate each phase, water extracts with EtOAc.Merge organic phase, through Na 2SO 4Drying is concentrated into dried.The gained crude product is through the silica gel chromatography purifying, use increases progressively polar hexane-EtOAc mixture as eluent, obtain 139mg 2-(2,2-diethoxy ethyl)-4,53%) and 60mg 1-(2,2-diethoxy ethyl)-4 two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6-(yield:, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridine (yields: 24%) of 6-.
Embodiment 73: 1H NMR (300MHz, CDCl 3) δ (TMS): 1.15 (t, J=7.0Hz, 6H), 3.50 (m, 2H), 3.73 (m, 2H), 4.49 (d, J=5.4Hz, 2H), 5.06 (t, J=5.4Hz, 1H), 6.83 (dd, J o=1.4Hz, J m=4.4Hz, 2H), 6.90 (t, J=8.7Hz, 2H), 7.00 (t, J=8.6Hz, 2H), 7.14 (m, 2H), 7.29 (m, 2H), 7.85 (s, 1H), 8.32 (dd, J o=1.5Hz, J m=4.5Hz, 2H).
Embodiment 74: 1H NMR (300 MHz, CDCl 3) δ (TMS): 1.21 (t, J=6.9Hz, 6H), 3.58 (m, 2H), 3.82 (m, 2H), 4.74 (d, J=5.7Hz, 2H), 5.19 (t, J=5.7Hz, 1H), 6.81 (dd, J o=1.5Hz, J m=4.5Hz, 2H), 6.92 (t, J=8.7Hz, 2H), 7.01 (t, J=8.7Hz, 2H), 7.13 (m, 2H), 7.25 (m, 2H), 7.87 (s, 1H), 8.32 (dd, J o=1.5Hz, J m=4.5Hz, 2H).
Embodiment 75
4, two (4-fluorophenyl)-1-methyl-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--3-nitrile
According to embodiment 65 described similar technologies, but be to use 3-bromo-4, two (4-fluorophenyl)-1-methyl-5-(4-pyridyl) pyrazolos [3 of 6-, 4-b] pyridine (in embodiment 66, obtaining) replacement 3-bromo-4, two (4-the fluorophenyl)-5-(4-pyridyl) of 6--1H-pyrazolo [3,4-b] pyridine, obtain title compound (yield: 48%).
1H NMR(300MHz，CDCl 3)δ(TMS)：4.32(s，3H)，6.81(dd，J o＝1.5Hz，J m＝4.5Hz，2H)，6.96(t，J＝8.4Hz，2H)，7.05(t，J＝8.4Hz，2H)，7.13(m，2H)，7.29(m，2H)，8.35(dd，J o＝1.5Hz，J m＝4.5Hz，2H).
Embodiment 76
3-bromo-6-(4-fluorophenyl)-5-(4-pyridyl)-1H-pyrazolo [3,4-b] pyridine
In 48%HBr (1ml) solution of 3-amino-6-of 0 ℃ (4-fluorophenyl)-5-(4-pyridyl)-1H-pyrazolo [3,4-b] pyridine (0.20g, 0.7mmol obtain in embodiment 70), go through and dripped NaNO in 15 minutes 2(holding temperature is at 0-5 ℃ simultaneously for 0.05g, water 0.7mmol) (0.1ml) solution.Mixture was stirred 15 minutes under this temperature.Slowly add CuBr (0.24g, 48%HBr 1.7mmol) (1ml) solution down at 0 ℃ then.Gained solution was stirred 3 hours down at 0 ℃.Make it reach room temperature, be neutralized to pH=7 with saturated sodium bicarbonate and 30% ammoniacal liquor.Filter solid CH 2Cl 2Mixture washing with water.Organic phase is washed with 1NNaOH, and water extracts with EtOAc.Merge organic phase, through Na 2SO 4Drying is concentrated into dried.The gained crude product uses to increase progressively polar CHCl through the silica gel chromatography purifying 3-MeOH mixture obtains 50mg title compound (yield: 21%) as eluent.
1H NMR(300MHz，CDCl 3+CD 3OD)δ(TMS)：4.24(s，NH+CD 3OD)，6.92(m，2H)，7.15(m，2H)，7.29(m，2H)，7.95(s，1H)，8.39(d，J＝6.0Hz，2H).
Embodiment 77
6-fluorophenyl-5-(4-pyridyl)-1H-pyrazolo [3,4-b] pyridine
With 3-amino-6-(4-fluorophenyl)-5-(4-pyridyl)-1H-pyrazolo [3,4-b] pyridine (0.20g, 0.7mmol obtain in embodiment 70) and H 3PO 2(0.2ml, water 2.0mmol) (2ml) solution mixes, and is cooled to 5 ℃.Drip NaNO 2(0.10g, water 1.4mmol) (0.4ml) solution.Stirred 30 minutes down at 5 ℃, make it to reach room temperature, at room temperature stirred 4 hours.With 1N NaOH neutralization, use CHCl 3Extraction.Merge organic phase, through Na 2SO 4Drying is concentrated into dried.The gained crude product uses to increase progressively polar hexane-EtOAc mixture as eluent through the silica gel chromatography purifying, obtains 63mg title compound (yield: 33%).
1H NMR(300MHz，MeOH+CDCl 3)δ(TMS)：3.46(s，NH+CD 3OD)，6.92(t，J＝8.6Hz，2H)，7.07(dd，J o＝1.6Hz，J m＝4.4Hz，2H)，7.26(m，2H)，8.08(s，1H)，8.09(s，1H)，8.37(dd，J o＝1.5Hz，J m＝4.5Hz，2H).
Embodiment 78
N-methyl-[3-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--2-yl] propyl group] amine
Under argon atmospher, to 2-(3-chloropropyl)-4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolos [3 of 6-, 4-b] pyridine (0.07g, 0.1mmol, in embodiment 16, obtain) acetonitrile (0.3ml) solution in add methylamine (1.8ml 33%EtOH solution, 14.6mmol).Be heated to 60 ℃ and reach 3 days, after 24 and 48 hours, add methylamine (0.9ml and 3.6ml 33%EtOH solution) respectively.With organic phase through Na 2SO 4Drying is concentrated into dried.The gained crude product uses to increase progressively polar EtOAc-MeOH mixture as eluent through the silica gel chromatography purifying, obtains the 24mg title compound, is solid form (yield: 29%).
1H NMR (300MHz, CDCl 3) δ (TMS): 2.00 (wide s, NH+H 2O), 2.53 (m, 2H), 2.61 (s, 3H), 2.99 (t, J=6.7Hz, 2H), 4.67 (t, J=6.4Hz, 2H), 6.82 (dd, J o=1.5Hz, J m=4.5Hz, 2H), 6.90 (t, J=8.7Hz, 2H), 7.00 (t, J=8.6Hz, 2H), 7.13 (m, 2H), 7.27 (m, 2H), 7.90 (s, 1H), 8.32 (dd, J o=1.5Hz, J m=4.5Hz, 2H).
Embodiment 79
[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--2-yl] methyl alcohol
With 4, two (4-the fluorophenyl)-5-(4-pyridyl) of the 6--suspension of 1H-pyrazolo [3,4-b] pyridine (0.20g, 0.5mmol obtain in embodiment 1) in 30-40% formalin (0.9ml) stirred 4 hours under 130 ℃ of argon atmosphers.Concentrated solvent is dissolved in CHCl with resistates 3With the mixture of water, separate each phase.With organic phase through Na 2SO 4Drying is concentrated into dried.The gained crude product uses to increase progressively polar hexane-EtOAc mixture as eluent through the silica gel chromatography purifying, obtains the 140mg title compound, is solid form (yield: 65%).
1H NMR(300MHz，CDCl 3)δ(TMS)：3.5(t，1H，OH)，6.11(d，J＝7.8Hz，2H)，6.85(dd，J o＝1.8Hz，J m＝4.5Hz，2H)，6.97(t，J＝8.7Hz，1H)，7.08(t，J＝8.7Hz，1H)，7.16(m，2H)，7.31(m，2H)，7.97(s，1H)，8.37(dd，J o＝1.6Hz，J m＝4.3Hz，2H).
Embodiment 80
2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--2-yl]-N,N-dimethylacetamide
Embodiment 81
2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--1-yl]-N,N-dimethylacetamide
According to embodiment 73 and 74 described similar technologies, but be to use 2-chloro-N,N-dimethylacetamide to replace 2-bromo-1, the 1-diethoxyethane obtains title compound.
Embodiment 80: yield: 10%
Embodiment 81: yield: 32%;
1H NMR(300MHz，CDCl 3)δ(TMS)：3.01(s，3H)，3.18(s，3H)，5.47(s，2H)，6.79(dd，J o＝1.5Hz，J m＝4.5Hz，2H)，6.91(t，J＝8.7Hz，1H)，7.01(t，J＝8.6Hz，1H)，7.15(m，2H)，7.23(m，2H)，7.95(s，1H)，8.31(dd，J o＝1.6Hz，J m＝4.3Hz，2H).
Embodiment 82
4, two (4-fluorophenyl)-2-[2-(2-methoxy ethoxy) ethyls of 6-]-5-(4-pyridyl) pyrazolo [3,4-b] pyridine
Embodiment 83
4, two (4-fluorophenyl)-1-[2-(2-methoxy ethoxy) ethyls of 6-]-5-(4-pyridyl) pyrazolo [3,4-b] pyridine
According to embodiment 6 and 7 described similar technologies, but be to use 1-bromo-2-(2-methoxy ethoxy) ethane to replace iodic ether, obtain title compound.
Embodiment 82: productive rate: 27%; 1H NMR (300MHz, CDCl 3) δ (TMS): 3.28 (s, 3H), 3.45 (m, 2H), 3.57 (m, 2H), 4.05 (t, J=5.1Hz, 2H), 4.63 (t, J=5.1Hz, 2H), 6.82 (dd, J o=1.5Hz, J m=4.5Hz, 2H), 6.89 (t, J=8.7Hz, 2H), 6.99 (t, J=8.7Hz, 2H), 7.14 (m, 2H), 7.29 (m, 2H), 7.93 (s, 1H), 8.31 (dd, J o=1.6Hz, J m=4.4Hz, 2H).
Embodiment 83: productive rate: 19%; 1H NMR (300MHz, CDCl 3) δ (TMS): 3.32 (s, 3H), 3.50 (m, 2H), 3.68 (m, 2H), 4.08 (t, J=6.0Hz, 2H), 4.81 (t, J=6.0Hz, 2H), 6.81 (dd, J o=1.4Hz, J m=4.4Hz, 2H), 6.92 (t, J=8.7Hz, 2H), 7.01 (t, J=8.6Hz, 2H), 7.13 (m, 2H), 7.26 (m, 2H), 7.86 (s, 1H), 8.32 (dd, J o=1.5Hz, J m=4.5Hz, 2H).
Embodiment 84
4, two (4-fluorophenyl)-2-[3-(morpholine-4-yl) propyl group of 6-]-5-(4-pyridyl) pyrazolo [3,4-b] pyridine
A) 3-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--2-yl] the propyl group methanesulfonates
According to saving described similar technology to embodiment 12b, but be to use 3-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolos [3 of 6-, 4-b] pyridine-2-yl] third-1-alcohol (in embodiment 18, obtaining) replacement 2-[1-(tertbutyloxycarbonyl) piperidin-4-yl] ethanol, obtain required compound (yield: quantitatively).
B) title compound
In volumetric flask, under argon atmospher, introduce 3-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolos [3 of 6-, 4-b] pyridine-2-yl] propyl group methanesulfonates (0.10g, 0.2mmol, in a joint, obtain), NaI (0.003g, 0.02mmol), morpholine (0.03g, 0.4mmol) and 1,2-glycol dimethyl ether (2ml).With mixture heating up to 90 ℃, under this temperature, stir and spend the night.The mixture that adds entry and EtOAc.Separate each phase.Water extracts with EtOAc.With organic phase through Na 2SO 4Drying is concentrated into dried.The gained crude product uses to increase progressively polar EtoAc-MeOH mixture as eluent through the silica gel chromatography purifying, obtains 37mg title compound (yield: 36%).
1H NMR (300MHz, GDCl 3) δ (TMS): 2.27 (m, 2H), 2.30-2.43 (sophisticated signal, 6H), 3.69 (m, 4H), 4.53 (t, J=6.6Hz, 2H), 6.83 (dd, J o=1.6Hz, J m=4.4Hz, 2H), 6.89 (t, J=8.7Hz, 2H), 7.00 (t, J=8.6Hz, 2H), 7.14 (m, 2H), 7.31 (m, 2H), 7.81 (s, 1H), 8.32 (dd, J o=1.6Hz, J m=4.4Hz, 2H).
Embodiment 85
4, two (6-chloropyridine-3-yl)-2-methyl-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6-
Embodiment 86
4, two (6-chloropyridine-3-yl)-1-methyl-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6-
According to embodiment 73 and 74 described similar technologies, but be to use 4, two (6-chloropyridine-3-the yl)-5-(4-pyridyl) of 6--1H-pyrazolo [3,4-b] pyridine (in embodiment 40, obtaining) replacement 4, two (4-the fluorophenyl)-5-(4-pyridyl) of 6--1H-pyrazolo [3,4-b] pyridine, methyl iodide replaces 2-bromo-1, the 1-diethoxyethane obtains title compound.
Embodiment 85: productive rate 26%; 1H NMR (300MHz, CDCl 3) δ (TMS): 1.56 (s, NH+H 2O), 4.32 (s, 3H), 6.88 (dd, J o=1.5Hz, J m=4.5Hz, 2H), 7.19 (d, J=8.4Hz, 1H), 7.31 (m, 2H), 7.58 (dd, J o=2.4Hz, J m=8.4Hz, 1H), 7.84 (s, 1H), 8.37 (dd, J o=2.4Hz, J m=6.9Hz, 2H), 8.43 (dd, J o=1.6Hz, J m=4.4Hz, 2H).
Embodiment 86: productive rate: 27%; 1H NMR (300MHz, CDCl 3) δ (TMS): 1.57 (s, NH+H 2O), 4.26 (s, 3H), 6.88 (dd, J o=1.8Hz, J m=4.5Hz, 2H), 7.20 (d, J=8.4Hz, 1H), 7.29 (d, J=8.1Hz, 1H), 7.35 (dd, J o=2.4Hz, J m=8.1Hz, 1H), 7.50 (dd, J o=2.6Hz, J m=8.2Hz, 1H), 7.91 (s, 1H), 8.34 (d, J=2.1Hz, 1H), 8.43-8.45 (sophisticated signal, 3H)
Embodiment 87
4, two (6-chloropyridine-3-the yl)-3-methyl-5-(4-pyridyl) of 6--1H-pyrazolo [3,4-b] pyridine
According to the described similar technology of embodiment 1 method A, but be to use 1-(6-chloropyridine-3-yl)-2-(4-pyridyl) ethyl ketone (in reference example 9, obtaining) to replace 1-(4-fluorophenyl)-2-(4-pyridyl) ethyl ketone, 3-amino-5-methyl-2H-pyrazoles replaces 3-amino-2H-pyrazoles, obtains title compound (yield: 9%).
1H NMR (300MHz, CDCl 3+ CD 3OD) δ (TMS): 2.09 (s, 3H), 3.51 (s, NH+H 2O), 6.92 (m, 2H), 7.23 (d, J=8.4Hz, 1H), 7.32 (m, 1H), 7.51 (m, 1H), 7.54 (dd, J o=2.4Hz, J m=8.4Hz, 1H), 8.26 (wide s, 1H), 8.35-8.38 (sophisticated signal, 3H).
Embodiment 88
4, two (6-picoline-3-the yl)-5-(4-pyridyl) of 6--1H-pyrazolo [3,4-b] pyridine
According to the described similar technology of embodiment 1 method A, but be to use 1-(6-picoline-3-yl)-2-(4-pyridyl) ethyl ketone (in reference example 13, obtaining) to replace 1-(4-fluorophenyl)-2-(4-pyridyl) ethyl ketone, obtain title compound (yield: 23%).
1H NMR (300MHz, CDCl 3) δ (TMS): 1.59 (s, NH+H 2O), 2.59 (s, 6H), 6.90 (dd, J o=1.5Hz, J m=4.5Hz, 2H), 6.99 (d, J=8.1Hz, 1H), 7.09 (d, J=7.8Hz, 1H), 7.33 (m, 2H), 7.99 (s, 1H), 8.39 (dd, J o=1.5Hz, J m=4.5Hz, 2H), 8.47 (d, J=2.1Hz, 1H), 8.80 (wide s, 1H).
Embodiment 89
4, two (4-the fluorophenyl)-2-(2-phthaloyl imino-ethyl) of 6--5-(4-pyridyl) pyrazolo [3,4-b] pyridine
According to embodiment 6 and 7 described similar technologies, but be to use N-(2-bromotrifluoromethane) phthalimide to replace methyl iodide, obtain title compound (yield: 29%).
1H NMR(300MHz，CDCl 3)δ(TMS)：4.32(t，J＝6.1Hz，2H)，4.76(t，J＝6.0Hz，2H)，6.81(dd，J o＝1.6Hz，J m＝4.4Hz，2H)，6.88(t，J＝8.7Hz，2H)，6.95(t，J＝8.6Hz，2H)，7.07(m，2H)，7.25(m，2H)，7.50(m，2H)，7.61(s，1H)，7.71(m，2H)，8.32(dd，J o＝1.6Hz，J m＝4.4Hz，2H).
Embodiment 90
2-(2-amino-ethyl)-4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6-
To 4, two (4-the fluorophenyl)-2-(2-phthaloyl imino-ethyl) of 6--5-(4-pyridyl) pyrazolo [3,4-b] pyridine (0.09g, 0.2mmol, in embodiment 89, obtain) EtOH (2ml) solution in add a hydrazine hydrate (0.02g 0.3mmol), reach mixture heating up at 3 hours to refluxing.The mixture that adds entry and EtOAc.Separate each phase.Water extracts with EtOAc.With organic phase through Na 2SO 4Drying is concentrated into dried.The gained crude product uses to increase progressively polar CHCl through the silica gel chromatography purifying 3-MeOH mixture obtains 57mg title compound (yield: 83%) as eluent.
1H NMR(300MHz，CDCl 3)δ(TMS)：1.57(s，NH 2+H 2O)，3.38(t，J＝5.7Hz，2H)，4.49(t，J＝5.5Hz，2H)，6.83(dd，J o＝1.5Hz，J m＝4.5Hz，2H)，6.90(t，J＝8.8Hz，2H)，7.00(t，J＝8.7Hz，2H)，7.15(m，2H)，7.31(m，2H)，7.85(s，1H)，8.32(dd，J o＝1.6Hz，J m＝4.6Hz，2H).
Embodiment 91
2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--2-yl] ethanol
With 4, two (4-the fluorophenyl)-5-(4-pyridyl) of 6--2-[2-(tetrahydropyrans-2-base oxygen base) ethyl] pyrazolo [3,4-b] pyridine (1.08g, 2.09mmol obtain in embodiment 24) is at 4: 2: 1 AcOH: THF: H 2Solution in the O mixture (42ml) is heated to 55 ℃ and spends the night.Make the mixture cooling, use saturated NaHCO 3Alkalization extracts with EtOAc.With organic phase through Na 2SO 4Drying is concentrated into dried.The gained crude product uses to increase progressively polar hexane-EtOAc mixture as eluent through the silica gel chromatography purifying, obtains 0.78g title compound (yield: 87%).
1H NMR (300MHz, CDCl 3) δ (TMS): 1.61 (wide s, OH+H 2O), 4.21 (t, J=4.7Hz, 2H), 4.58 (t, J=4.7Hz, 2H), 6.83 (dd, J o=1.6Hz, J m=4.4Hz, 2H), 6.91 (t, J=8.7Hz, 2H), 7.01 (t, J=8.6Hz, 2H), 7.14 (m, 2H), 7.27 (m, 2H), 7.87 (s, 1H), 8.33 (dd, J o=1.6Hz, J m=4.5Hz, 2H).
Embodiment 92
6-(4-fluorophenyl)-2-methyl-5-(4-pyridyl) pyrazolo [3,4-b] pyridine
According to embodiment 6 and 7 described similar technologies, but be to use 6-fluorophenyl-5-(4-pyridyl)-1H-pyrazolo [3,4-b] pyridine (in embodiment 77, obtaining) replacement 4, two (4-the fluorophenyl)-5-(4-pyridyl) of 6--1H-pyrazolo [3,4-b] pyridine, methyl iodide replaces iodic ether, obtains title compound (yield: 35%).
1H NMR (300MHz, CDCl 3) δ (TMS): 1.56 (wide s, NH+H 2O), 4.31 (s, 3H), 6.95 (t, J=8.7Hz, 2H), 7.11 (d, J=6.0Hz, 2H), 7.41 (m, 2H), 8.01 (s, 1H), 8.06 (s, 1H), 8.51 (d, J=6.0Hz, 2H).
Embodiment 93
4, two (4-the fluorophenyl)-2-(3-phthaloyl imino-propyl group) of 6--5-(4-pyridyl) pyrazolo [3,4-b] pyridine
According to embodiment 6 and 7 described similar technologies, but be to use N-(3-bromopropyl) phthalimide to replace iodic ether, obtain title compound (yield: 31%).
1H NMR(300MHz，CDCl 3)δ(TMS)：2.54(q，J＝6.4Hz，2H)，3.79(t，J＝6.2Hz，2H)，4.50(t，J＝6.6Hz，2H)，6.82(dd，J o＝1.5Hz，J m＝4.5Hz，2H)，6.89(t，J＝8.7Hz，2H)，7.02(t，J＝8.7Hz，2H)，7.17(m，2H)，7.28(m，2H)，7.71(m，2H)，7.83(m，2 H)，7.93(s，1H)，8.32(dd，J o＝1.6Hz，J m＝4.5Hz，2H).
Embodiment 94
2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--2-yl] acetaldehyde
In volumetric flask, introduce 2-(2,2-diethoxy ethyl)-4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3,4-b] pyridines (0.31g, 0.6mmol obtain) of 6-and 1N HCl (2.6ml) in embodiment 73.Mixture heating up to 100 ℃ is reached 1 hour.Make its cooling, transfer to pH=7, extract with EtOAc.With organic phase through Na 2SO 4Drying is concentrated into dried.The gained crude product uses to increase progressively polar hexane-EtOAc mixture as eluent through the silica gel chromatography purifying, obtains 166mg title compound (yield: 65%).
1H NMR(300MHz，CDCl 3)δ(TMS)：5.26(s，2H)，6.83(dd，J o＝1.4Hz，J m＝4.4Hz，2H)，6.91(t，J＝8.5Hz，2H)，7.00(t，J＝8.8Hz，2H)，7.15(m，2H)，7.30(m，2H)，7.88(s，1H)，8.31(m，2H)，9.85(s，1H).
Embodiment 95
2-(3-aminopropyl)-4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6-
According to embodiment 90 described similar technologies, but be to use 4, two (4-the fluorophenyl)-2-(3-phthaloyl imino-propyl group) of 6--5-(4-pyridyl) pyrazolo [3,4-b] pyridine (in embodiment 93, obtaining) replacement 4, two (4-the fluorophenyl)-2-(2-phthaloyl imino-ethyl) of 6--5-(4-pyridyl) pyrazolo [3,4-b] pyridine, obtain title compound (yield: 49%).
1H NMR(300MHz，CDCl 3)δ(TMS)：1.54(s，NH 2+H 2O)，2.19(m，2H)，2.76(t，J＝6.7Hz，2H)，4.57(t，J＝6.7Hz，2H)，6.83(dd，J o＝1.6Hz，J m＝4.4Hz，2H)，6.90(t，J＝8.7Hz，2H)，7.00(t，J＝8.7Hz，2H)，7.13(m，2H)，7.30(m，2H)，7.81(s，1H)，8.32(dd，J o＝1.5Hz，J m＝4.5Hz，2H).
Embodiment 96
N-[4, two (4-the fluorophenyl)-5-(4-pyridyl) of 6--1H-pyrazolo [3,4-b] pyridin-3-yl methyl]-1-(tertbutyloxycarbonyl) piperidines-4-methane amide
According to embodiment 48 described similar technologies, but be to use 1-(tertbutyloxycarbonyl) piperidines-4-carboxylic acid to replace 2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolos [3 of 6-, 4-b] pyridine-2-yl] acetate, 3-amino methyl-4, two (4-the fluorophenyl)-5-(4-pyridyl) of 6--1H-pyrazolo [3,4-b] pyridine (obtaining in embodiment 6 8) replaces morpholine, obtains title compound (yield: 26%).
Embodiment 97
N-[4, two (4-the fluorophenyl)-5-(4-pyridyl) of 6--1H-pyrazolo [3,4-b] pyridin-3-yl methyl] piperidines-4-methane amide
According to embodiment 36 described similar technologies, but be to use N-[4, two (4-the fluorophenyl)-5-(4-pyridyl) of 6--1H-pyrazolo [3,4-b] the pyridin-3-yl methyl]-1-(tertbutyloxycarbonyl) piperidines-4-methane amide (in embodiment 96, obtaining) replacement 2-[1-(tertbutyloxycarbonyl) piperidin-4-yl]-4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolos [3 of 6-, 4-b] pyridine, obtain title compound (yield: 63%).
1H NMR (300MHz, CDCl 3) δ (TMS): 1.40-1.90 (sophisticated signal, 3H+H 2O), 2.18 (m, 2H), 2.63 (m, 2H), 3.13 (m, 2H), 4.15 (d, J=5.1Hz, 2H), 5.20 (wide s, 1H, NH), 6.20 (wide s, 1H, NH), 6.78 (dd, J o=1.5Hz, J m=4.5Hz, 2H), 6.94 (t, J=8.7Hz, 2H), 7.03 (t, J=8.7Hz, 2H), 7.08-7.14 (sophisticated signal, 4H), 8.30 (dd, J o=1.6Hz, J m=4.4Hz, 2H).
Embodiment 98
2-(3-benzyloxy propyl group)-4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6-
Embodiment 99
1-(3-benzyloxy propyl group)-4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6-
According to embodiment 6 and 7 described similar technologies, but be to use 3-bromopropyl alcohol benzylic ether to replace iodic ether, obtain title compound.
Embodiment 98: productive rate: 43%; 1H NMR (300MHz, CDCl 3) δ (TMS): 2.38 (m, 2H), 3.48 (t, J=5.6Hz, 2H), 4.44 (s, 2H), 4.57 (t, J=6.7Hz, 2H), 6.82 (dd, J o=1.5Hz, J m=4.5Hz, 2H), 6.89 (t, J=8.7Hz, 2H), 6.99 (t, J=8.7Hz, 2H), 7.10 (m, 2H), 7.26-7.32 (sophisticated signal, 7H), 7.73 (s, 1H), 8.32 (dd, J o=1.8Hz, J m=4.5Hz, 2H).
Embodiment 99: productive rate: 20%; 1H NMR (300MHz, CDCl 3) δ (TMS): 2.19 (m, 2H), 3.58 (t, J=6.1Hz, 2H), 4.48 (s, 2H), 4.75 (t, J=6.9Hz, 2H), 6.81 (dd, J o=1.5Hz, J m=4.5Hz, 2H), 6.90 (t, J=8.7Hz, 2H), 7.01 (t, J=8.6Hz, 2H), 7.12 (m, 2H), 7.24-7.33 (sophisticated signal, 7H), 7.86 (s, 1H), 8.32 (dd, J o=1.6Hz, J m=4.4Hz, 2H).
Embodiment 100
N, N-diethyl-[2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--2-yl] ethyl] amine
Embodiment 101
N, N-diethyl-[2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--1-yl] ethyl] amine
According to embodiment 6 and 7 described similar technologies, but be to use N-(2-chloroethyl) diethylamide hydrochloride to replace iodic ether and 2 equivalent KOH, obtain title compound.
Embodiment 100: productive rate: 5%; 1H NMR (300MHz, CDCl 3) δ (TMS): 0.99 (t, J=7.2Hz, 6H), 2.56 (c, J=7.1Hz, 4H), 3.08 (t, J=6.5Hz, 2H), 4.48 (t, J=6.5Hz, 2H), 6.82 (dd, J o=1.5Hz, J m=4.5Hz, 2H), 6.89 (t, J=8.8Hz, 2H), 7.00 (t, J=8.6Hz, 2H), 7.14 (m, 2H), 7.29 (m, 2H), 7.85 (s, 1H), 8.32 (dd, J o=1.5Hz, J m=4.5Hz, 2H).
Embodiment 101: productive rate: 73%; 1H NMR (300MHz, CDCl 3) δ (TMS): 1.05 (t, J=7.2Hz, 6H), 2.66 (c, J=7.2Hz, 4H), 3.09 (t, J=7.2Hz, 2H), 4.69 (t, J=7.2Hz, 2H), 6.82 (dd, J o=1.5Hz, J m=4.5Hz, 2H), 6.92 (t, J=8.7Hz, 2H), 6.98 (t, J=8.7Hz, 2H), 7.14 (m, 2H), 7.26 (m, 2H), 7.85 (s, 1H), 8.32 (dd, J o=1.5Hz, J m=4.5Hz, 2H).
Embodiment 102
4, two (4-the fluorophenyl)-5-(4-pyridyl) of 6--2-(3-pyridylmethyl) pyrazolo [3,4-b] pyridine
Embodiment 103
4, two (4-the fluorophenyl)-5-(4-pyridyl) of 6--1-(3-pyridylmethyl) pyrazolo [3,4-b] pyridine
According to embodiment 6 and 7 described similar technologies, but be to use the 3-chloromethyl pyridine hydrochloride to replace iodic ether, obtain title compound.
Embodiment 102: productive rate: 16%; 1H NMR (300MHz, CDCl 3) δ (TMS): 5.63 (s, 2H), 6.81 (dd, J o=1.8Hz, J m=4.5Hz, 2H), 6.90 (t, J=8.8Hz, 2H), 6.99 (t, J=8.7Hz, 2H), 7.10 (m, 2H), 7.31 (m, 2H), 7.82 (m, 2H), 8.32 (dd, J o=1.5Hz, J m=4.5Hz, 2H), 8.61 (dd, J o=1.5Hz, J m=4.8Hz, 2H), 8.68 (s, 1H).
Embodiment 103: productive rate: 22%; 1H NMR (300MHz, CDCl 3) δ (TMS): 5.80 (s, 2H), 6.81 (dd, J o=1.5Hz, J m=4.5Hz, 2H), 6.94 (t, J=8.6Hz, 2H), 7.01 (t, J=8.7Hz, 2H), 7.13 (m, 2H), 7.27 (m, 2H), 7.79 (m, 1H), 7.88 (s, 1H), 8.32 (dd, J o=1.4Hz, J m=4.4Hz, 2H), 8.56 (d, J=5.0Hz, 2H), 8.75 (s, 1H).
Embodiment 104
N, N-dimethyl-[3-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--2-yl] propyl group] amine
Embodiment 105
N, N-dimethyl-[3-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--1-yl] propyl group] amine
According to embodiment 6 and 7 described similar technologies, but be to use N-(3-chloropropyl) dimethyl amine hydrochloride to replace iodic ether, obtain title compound.
Embodiment 104:22%; 1H NMR (300MHz, CDCl 3) δ (TMS): 2.21-2.29 (sophisticated signal, 10H), 4.51 (t, J=6.6Hz, 2H), 6.82 (dd, J o=1.6Hz, J m=4.4Hz, 2H), 6.89 (t, J=8.8Hz, 2H), 7.00 (t, J=8.7Hz, 2H), 7.14 (m, 2H), 7.30 (m, 2H), 7.81 (s, 1H), 8.31 (dd, J o=1.6Hz, J m=4.4Hz, 2H).
Embodiment 105: productive rate: 19%; 1H NMR (300MHz, CDCl 3) δ (TMS): 2.18-2.27 (sophisticated signal, 8H), 2.43 (t, J=7.2Hz, 2H), 4.65 (t, J=7.1Hz, 2H), 6.82 (dd, J o=1.5Hz, J m=4.5Hz, 2H), 6.93 (t, J=8.8Hz, 2H), 7.01 (t, J=8.7Hz, 2H), 7.14 (m, 2H), 7.27 (m, 2H), 7.86 (s, 1H), 8.32 (dd, J o=1.5Hz, J m=4.5Hz, 2H).
Embodiment 106
1-[2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--2-yl] ethyl] piperidines-4-alcohol
In volumetric flask, under argon atmospher, introduce 2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolos [3 of 6-, 4-b] pyridine-2-yl] acetaldehyde (0.08g, 0.2mmol, in embodiment 94, obtain), sodium triacetoxy borohydride (0.08g, 0.4mmol), 4-hydroxy piperidine (0.02g, 0.2mmol) and 1,2-ethylene dichloride (3ml).Mixture at room temperature stirred spend the night.Concentrate, add the mixture of entry and EtOAc.Separate each phase.Water extracts with EtOAc.With organic phase through Na 2SO 4Drying is concentrated into dried.The gained crude product uses to increase progressively polar EtOAc-MeOH mixture as eluent through the silica gel chromatography purifying, obtains 19mg title compound (yield: 20%).
1H NMR (300MHz, CDCl 3) δ (TMS): 1.57 (wide s1H+OH+H 2O), 1.85 (m, 2H), 2.05 (m, 2H), 2.30 (m, 2H), 2.80 (m, 2H), 3.01 (m, 2H), 4.54 (m, 2H), 6.83 (dd, J o=1.5Hz, J m=4.5Hz, 2H), 6.90 (t, J=8.6Hz, 2H), 7.01 (t, J=8.6Hz, 2H), 7.14 (m, 2H), 7.29 (m, 2H), 7.85 (s, 1H), 8.34 (dd, J o=1.6Hz, J m=4.4Hz, 2H).
Embodiment 107
3-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--2-yl]-2-hydroxyl third-1-alcohol
Embodiment 108
3-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--1-yl]-2-hydroxyl third-1-alcohol
According to embodiment 6 and 7 described similar technologies, but be to use 3-N-PROPYLE BROMIDE-1, the 2-glycol replaces iodic ether, obtains title compound.
Embodiment 107: productive rate 17%; 1H NMR (300MHz, CDCl 3) δ (TMS): 3.49 (s, 1H, OH), 3.72 (m, 2H), 4.32 (m, 1H), 4.60 (m, 2H), 5.30 (s, 1H, OH), 6.83 (dd, J o=1.6Hz, J m=4.4Hz, 2H), 6.91 (t, J=8.7Hz, 2H), 7.01 (t, J=8.6Hz, 2H), 7.14 (m, 2H), 7.28 (m, 2H), 7.88 (s, 1H), 8.32 (dd, J o=1.6Hz, J m=4.4Hz, 2H).
Embodiment 108: productive rate: 26%; 1H NMR (300MHz, CDCl 3) δ (TMS): 3.65 (m, 2H), 4.26 (m, 1H), 4.78 (m, 2H), 5.30 (s, 2H, OH), 6.82 (dd, J o=1.5Hz, J m=4.5Hz, 2H), 6.94 (t, J=8.6Hz, 2H), 7.03 (t, J=8.7Hz, 2H), 7.14 (m, 2H), 7.28 (m, 2H), 7.91 (s, 1H), 8.34 (dd, J o=1.5Hz, J m=4.5Hz, 2H).
Embodiment 109
4, two (4-the fluorophenyl)-5-(4-pyridyl) of 6--2-(4-pyridylmethyl) pyrazolo [3,4-b] pyridine
Embodiment 110
4, two (4-the fluorophenyl)-5-(4-pyridyl) of 6--1-(4-pyridylmethyl) pyrazolo [3,4-b] pyridine
According to embodiment 6 and 7 described similar technologies, but be to use the 4-chloromethyl pyridine hydrochloride to replace iodic ether, obtain title compound.
Embodiment 109: productive rate: 29%; 1H NMR (300MHz, CDCl 3) δ (TMS): 5.63 (s, 2H), 6.83 (dd, J o=1.5Hz, J m=4.5Hz, 2H), 6.90 (t, J=8.7Hz, 2H), 6.99 (t, J=8.7Hz, 2H), 7.12 (m, 2H), 7.23-7.33 (sophisticated signal, 4H), 7.84 (s, 1H), 8.32 (dd, J o=1.5Hz, J m=4.5Hz, 2H), 8.61 (dd, J o=1.5Hz, J m=4.8Hz, 2H).
Embodiment 110: productive rate: 15%; 5.80 (s, 2H), 6.82 (dd, J o=1.5Hz, J m=4.5Hz, 2H), 6.93 (t, J=8.7Hz, 2H), 7.00 (t, J=8.7Hz, 2H), 7.14 (m, 2H), 7.20-7.26 (sophisticated signal, 4H), 7.93 (s, 1H), 8.34 (dd, J o=1.5Hz, J m=4.5Hz, 2H), 8.61 (dd, J o=1.5Hz, J m=4.8Hz, 2H).
Embodiment 111
N-(tertbutyloxycarbonyl)-[1-[3-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--2-yl] propyl group] piperidin-4-yl] amine
Under argon atmospher, to 3-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolos [3 of 6-, 4-b] pyridine-2-yl] propyl group methanesulfonates (0.15g, 0.3mmol, in embodiment 84a joint, obtain) acetonitrile (2ml) solution in add N-(tertbutyloxycarbonyl)-N-(4-piperidyl) amine (0.12g 0.6mmol), be heated to 60 ℃ and spend the night.Add CHCl 3With saturated NaHCO 3Mixture.Separate each phase.Water CHCl 3Extraction.With organic phase through Na 2SO 4Drying is concentrated into dried.The gained crude product uses to increase progressively polar EtOAc-MeOH mixture as eluent through the silica gel chromatography purifying, obtains 40mg title compound (yield: 22%).
1H NMR (300MHz, CDCl 3) δ (TMS): 1.44 (wide s, 2H+NH 2+ H 2O), 1.95 (m, 2H), 2.06 (m, 2H), 2.25 (m, 2H), 2.35 (m, 2H), 3.46 (m, 2H), 4.40 (m, 1H), 4.51 (t, 2H), 6.83 (d, J=6.0Hz, 2H), 6.90 (t, J=8.7Hz, 2H), 7.00 (t, J=8.7Hz, 2H), 7.14 (m, 2H), 7.29 (m, 2H), 7.80 (s, 1H), 8.32 (d, J=6.0Hz, 2H).
Embodiment 112
2-[1-(tertbutyloxycarbonyl) piperidin-4-yl]-6-(4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3,4-b] pyridine
Embodiment 113
1-[1-(tertbutyloxycarbonyl) piperidin-4-yl]-6-(4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3,4-b] pyridine
According to embodiment 6 and 7 described similar technologies, but be to use 6-fluorophenyl-5-(4-pyridyl)-1H-pyrazolo [3,4-b] pyridine (in embodiment 77, obtaining) replacement 4, two (4-the fluorophenyl)-5-(4-pyridyl) of 6--1H-pyrazolo [3,4-b] pyridine, 1-(tertbutyloxycarbonyl) piperidin-4-yl methanesulfonates (obtaining in embodiment 14 a joint) replaces iodic ether, obtains title compound.
Embodiment 112: productive rate: 26%; 1H NMR (300MHz, CDCl 3) δ (TMS): 1.50 (s, 9H), 2.17-2.32 (sophisticated signal, 2H), 2.99 (m, 2H), 4.33 (m, 2H), 4.60 (m, 1H), 6.95 (t, J=8.7Hz, 2H), 7.11 (dd, J o=1.5Hz, J m=4.5Hz, 2H), 7.41 (m, 2H), 8.06 (s, 1H), 8.07 (s, 1H), 8.52 (dd, J o=1.6Hz, J m=4.4Hz, 2H).
Embodiment 113: productive rate: 55%; 1H NMR (300MHz, CDCl 3) δ (TMS): 1.50 (s, 9H), 2.04 (m, 2H), 2.30 (m, 2H), 3.00 (m, 2H), 4.42 (m, 2H), 5.10 (m, 1H), 7.00 (t, J=8.6Hz, 2H), 7.10 (dd, J o=1.6Hz, J m=4.5Hz, 2H), 7.37 (m, 2H), 8.07 (s, 1H), 8.10 (s, 1H), 8.52 (dd, J o=1.8Hz, J m=4.5Hz, 2H).
Embodiment 114
3-methyl-4, two (6-picoline-3-the yl)-5-(4-pyridyl) of 6--1H-pyrazolo [3,4-b] pyridine
According to the described similar technology of embodiment 1 method A, but be to use 1-(6-picoline-3-yl)-2-(4-pyridyl) ethyl ketone (in reference example 13, obtaining) to replace 1-(4-fluorophenyl)-2-(4-pyridyl) ethyl ketone, 3-amino-5-methyl-2H-pyrazoles replaces 3-amino-2H-pyrazoles, obtains title compound (yield: 24%).
1H NMR (300MHz, CDCl 3) δ (TMS): 2.07 (s, 3H), 2.54 (s, 3H), 2.57 (s, 3H), 6.85 (m, 2H), 6.99 (d, J=8.1Hz, 1H), 7.08 (d, J=8.1Hz, 1H), 7.30 (m, 1H), 8.10 (dd, J o=2.4Hz, J m=8.1Hz, 1H), 8.32 (dd, J o=1.5Hz, J m=4.5Hz, 2H), 8.38 (s, 1H), 8.57 (s, 1H), 10.74 (wide s, NH).
Embodiment 115
1-[3-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--2-yl] propyl group] piperidin-4-one-
In volumetric flask, under argon atmospher, introduce 3-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolos [3 of 6-, 4-b] pyridine-2-yl] propyl group methanesulfonates (0.15g, 0.3mmol, in embodiment 84 a joint, obtain), NaI (0.008g, 0.06mmol), 4-piperidone monohydrate hydrochloride (0.04g, 0.3mmol), K 2CO 3(0.07g, 0.5mmol) and DMF (2ml).Mixture heating up to 60 ℃ is reached 24 hours.Make its cooling, add the mixture of entry and EtOAc.Separate each phase.Water extracts with EtOAc.With organic phase through Na 2SO 4Drying is concentrated into dried.The gained crude product uses to increase progressively polar EtOAc-MeOH mixture as eluent through the silica gel chromatography purifying, obtains 16mg title compound (yield: 10%).
1H NMR (300MHz, CDCl 3) δ (TMS): 1.57 (wide s, 4H+H 2O), 2.30 (m, 2H), 2.42 (m, 2H), 2.48 (m, 2H), 2.73 (t, 2H), 4.55 (t, 2H), 6.83 (d, J=6.0Hz, 2H), 6.90 (t, J=8.7Hz, 2H), 7.00 (t, J=8.6Hz, 2H), 7.18 (m, 2H), 7.27 (m, 2H), 7.82 (s, 1H), 8.32 (d, J=6.0Hz, 2H).
Embodiment 116
N-(tertbutyloxycarbonyl)-[1-[2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--2-yl] ethyl] piperidin-4-yl] amine
A) 2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--2-yl] the ethyl methane sulfonate ester
According to saving described similar technology to embodiment 12b, but be to use 2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolos [3 of 6-, 4-b] pyridine-2-yl] ethanol (in embodiment 91, obtaining) replacement 2-[1-(tertbutyloxycarbonyl) piperidin-4-yl] ethanol, obtain required compound (yield: quantitatively).
B) title compound
According to embodiment 111 described similar technologies, but be to use 2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolos [3 of 6-, 4-b] pyridine-2-yl] ethyl methane sulfonate ester (in a joint, obtaining) replacement 3-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolos [3 of 6-, 4-b] pyridine-2-yl] the propyl group methanesulfonates, obtain required compound (yield: 66%).
1H NMR (300MHz, CDCl 3) δ (TMS): 1.44 (s, 9H), 1.57 (wide s, 1H+NH+H 2O), 1.90 (m, 2H), 2.22 (m, 2H), 2.82 (m, 2H), 3.01 (t, J=6.6Hz, 2H), 3.45 (m, 1H), 4.40 (m, 1H), 4.52 (t, J=6.5Hz, 2H), 6.82 (d, J=5.7Hz, 2H), 6.89 (t, J=8.7Hz, 2H), 7.01 (t, J=8.6Hz, 2H), 7.14 (m, 2H), 7.29 (m, 2H), 7.82 (s, 1H), 8.31 (dd, J o=1.5Hz, J m=4.5Hz, 2H).
Embodiment 117
N-methyl-[1-[2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--2-yl] ethyl] piperidin-4-yl] amine
According to embodiment 111 described similar technologies, but be to use 2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolos [3 of 6-, 4-b] pyridine-2-yl] ethyl methane sulfonate ester (in embodiment 116a joint, obtaining) replacement 3-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolos [3 of 6-, 4-b] pyridine-2-yl] the propyl group methanesulfonates, N-methyl-N-(piperidin-4-yl) amine replaces N-(tertbutyloxycarbonyl)-N-(4-piperidyl) amine, obtains required compound (yield: 50%).
1H NMR (300MHz, CDCl 3) δ (TMS): 1.61 (wide s, 1H+NH+H 2O), 2.28 (s, 3H), 2.41 (m, 4H), 2.57 (m, 4H), 3.03 (t, J=6.5Hz, 2H), 4.55 (t, J=6.5Hz, 2H), 6.83 (dd, J o=1.5Hz, J m=4.5Hz, 2H), 6.90 (t, J=8.7Hz, 2H), 7.01 (t, J=8.7Hz, 2H), 7.14 (m, 2H), 7.29 (m, 2H), 7.85 (s, 1H), 8.32 (dd, J o=1.5Hz, J m=4.5Hz, 2H).
Embodiment 118
[1-[3-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--2-yl] propyl group] piperidin-4-yl] amine
According to embodiment 36 described similar technologies, but be to use N-(tertbutyloxycarbonyl)-[1-[3-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolos [3 of 6-, 4-b] pyridine-2-yl] propyl group] piperidin-4-yl] amine (in embodiment 111, obtaining) replacement 2-[1-(tertbutyloxycarbonyl) piperidin-4-yl]-4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolos [3 of 6-, 4-b] pyridine, obtain title compound (yield: 89%).
1H NMR (300MHz, CDCl 3) δ (TMS): 1.35 (m, 2H), 1.62 (wide s NH 2+ H 2O), 1.85 (m, 2H), 2.03 (m, 2H), 2.25 (m, 2H), 2.36 (m, 2H), 2.70 (m, 1H), 2.82 (m, 2H), 4.52 (d, J=6.6Hz, 2H), 6.83 (dd, J o=1.5Hz, J m=4.5Hz, 2H), 6.90 (t, J=8.7Hz, 2H), 7.00 (t, J=8.6Hz, 2H), 7.13 (m, 2H), 7.29 (m, 2H), 7.81 (s, 1H), 8.31 (dd, J o=1.6Hz, J m=4.4Hz, 2H).
Embodiment 119
2-[1-[2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--2-yl] ethyl] piperidin-4-yl] ethanol
According to embodiment 111 described similar technologies, but be to use 2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolos [3 of 6-, 4-b] pyridine-2-yl] ethyl methane sulfonate ester (in embodiment 116a joint, obtaining) replacement 3-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolos [3 of 6-, 4-b] pyridine-2-yl] the propyl group methanesulfonates, 2-(4-piperidyl) ethanol replaces N-(tertbutyloxycarbonyl)-N-(4-piperidyl) amine, obtains required compound (yield: 50%).
1H NMR (300MHz, CDCl 3) δ (TMS): 1.48-1.53 (sophisticated signal, 5H), 2.11 (m, 2H), 2.88 (m, 2H), 2.99 (m, 2H), 3.70 (t, J=6.5Hz, 2H), 4.55 (t, J=6.5Hz, 2H), 6.83 (dd, J o=1.5Hz, J m=4.5Hz, 2H), 6.89 (t, J=8.7Hz, 2H), 7.00 (t, J=8.6Hz, 2H), 7.14 (m, 2H), 7.29 (m, 2H), 7.86 (s, 1H), 8.32 (dd, J o=1.5Hz, J m=4.5Hz, 2H).
Embodiment 120
[1-[2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--2-yl] ethyl] piperidin-4-yl] amine
According to embodiment 36 described similar technologies, but be to use N-(tertbutyloxycarbonyl)-[1-[2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolos [3 of 6-, 4-b] pyridine-2-yl] ethyl] piperidin-4-yl] amine (in embodiment 116, obtaining) replacement 2-[1-(tertbutyloxycarbonyl) piperidin-4-yl]-4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolos [3 of 6-, 4-b] pyridine, obtain title compound (yield: 77%).
1H NMR (300MHz, CDCl 3) δ (TMS): 1.38 (m, 2H), 1.78 (wide s, 2H+NH 2+ H 2O), 2.18 (m, 2H), 2.75 (m, 1H), 2.84 (m, 2H), 3.02 (t, J=6.3Hz, 2H), 4.54 (t, J=6.5Hz, 2H), 6.82 (d, J=5.7Hz, 2H), 6.89 (t, J=8.7Hz, 2H), 7.00 (t, J=8.6Hz, 2H), 7.14 (m, 2H), 7.29 (m, 2H), 7.84 (s, 1H), 8.31 (d, J=6.0Hz, 2H).
Embodiment 121
6-(4-fluorophenyl)-2-(4-piperidyl)-5-(4-pyridyl) pyrazolo [3,4-b] pyridine
According to embodiment 36 described similar technologies, but be to use 2-[1-(tertbutyloxycarbonyl) piperidin-4-yl]-6-(4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3,4-b] pyridine (in embodiment 11 2, obtaining) replacement 2-[1-(tertbutyloxycarbonyl) piperidin-4-yl]-4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolos [3 of 6-, 4-b] pyridine, obtain title compound (yield: 77%).
1H NMR(300MHz，CDCl 3)δ(TMS)：1.89(m，NH+H 2O)，2.25(m，2H)，2.30(m，2H)，2.89(m，2H)，3.34(m，2H)，4.60(m，1H)，6.95(t，J＝8.7Hz，2H)，7.11(dd，J o＝1.5Hz，J m＝4.5Hz，2H)，7.40(m，2H)，8.07(s，1H)，8.08(s，1H)，8.51(dd，J o＝1.6Hz，J m＝4.4Hz，2H).
Embodiment 122
6-(4-fluorophenyl)-1-(4-piperidyl)-5-(4-pyridyl) pyrazolo [3,4-b] pyridine
According to embodiment 36 described similar technologies, but be to use 1-[1-(tertbutyloxycarbonyl) piperidin-4-yl]-6-(4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3,4-b] pyridine (in embodiment 113, obtaining) replacement 2-[1-(tertbutyloxycarbonyl) piperidin-4-yl]-4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolos [3 of 6-, 4-b] pyridine, obtain title compound (yield: quantitatively).
1H NMR(300MHz，CDCl 3)δ(TMS)：1.60(m，NH+H 2O)，2.42(m，2 H)，2.67(m 2H)，3.28(m，2H)，3.72(m，2H)，5.28(m，1H)，7.00(t，J＝8.7Hz，2H)，7.11(dd，J o＝1.5Hz，J m＝4.5Hz，2H)，7.37(m，2H)，8.10(s，1H)，8.12(s，1H)，8.54(dd，J o＝1.6Hz，J m＝4.4Hz，2H).
Embodiment 123
3-amino-5-[2-(methylthio group) pyrimidine-4-yl]-6-[3-(trifluoromethyl) phenyl]-1H-pyrazolo [3,4-b] pyridine
According to saving described similar technology to reference example 15c, but be to use 2-chloro-5-[2-(methylthio group) pyrimidine-4-yl]-6-[3-(trifluoromethyl) phenyl] pyridine-3-nitrile (in reference example 14, obtaining) replacement 3-(1-benzyl piepridine-4-yl)-3-oxypropionitrile, obtain title compound (yield: 78%).
1H NMR (300MHz, CDCl 3) δ (TMS): 2.44 (s, 3H), 4.32 (wide s, NH 2), 6.61 (d, J=5.1Hz, 1H), 7.44-7.84 (sophisticated signal, 2H), 7.65 (d, J=7.2Hz, 1H), 7.84 (s, 1H), 8.30 (d, J=5.1Hz, 1H), 8.40 (s, 1H), 9.55 (wide s, NH).
Embodiment 124
4, two (4-fluorophenyl)-2-[3-[1-(tertbutyloxycarbonyl) piperazines of 6--4-yl] propyl group]-5-(4-pyridyl) pyrazolo [3,4-b] pyridine
According to saving described similar technology, but be to use 1-(tertbutyloxycarbonyl) piperazine to replace morpholine, add triethylamine (1.5 equivalent) to embodiment 84b, obtain required compound (yield: 14%).
1H NMR (300MHz, CDCl 3) δ (TMS): 2.66 (m, 2H), 2.98 (m, 4H), 3.10 (m, 2H), 3.66-3.74 (sophisticated signal, 4H), 4.66 (m, 2H), 6.85 (dd, J o=1.5Hz, J m=4.5Hz, 2H), 6.91 (t, J=8.7Hz, 2H), 7.00 (t, J=8.7Hz, 2H), 7.14 (m, 2H), 7.28 (m, 2H), 7.98 (s, 1H), 8.32 (dd, J o=1.5Hz, J m=4.5Hz, 2H).
Embodiment 125
4, two (4-fluorophenyl)-2-[3-(piperazine-1-yl) propyl group of 6-]-5-(4-pyridyl) pyrazolo [3,4-b] pyridine
According to embodiment 36 described similar technologies, but be to use 4, two (4-fluorophenyl)-2-[3-[1-(tertbutyloxycarbonyl) piperazines of 6--4-yl] propyl group]-5-(4-pyridyl) pyrazolo [3,4-b] pyridine (in embodiment 124, obtaining) replacement 2-[1-(tertbutyloxycarbonyl) piperidin-4-yl]-4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolos [3 of 6-, 4-b] pyridine, obtain title compound (yield: quantitatively).
1H NMR (300MHz, CDCl 3) δ (TMS): 1.78 (wide s, 2H+NH+H 2O), 2.26 (m, 2H), 2.40-2.59 (sophisticated signal, 6H), 3.04 (m, 2H), 4.52 (m, 2H), 6.83 (dd, J o=1.5Hz, J m=4.5Hz, 2H), 6.90 (t, J=8.7Hz, 2H), 7.00 (t, J=8.7Hz, 2H), 7.14 (m, 2H), 7.29 (m, 2H), 7.80 (s, 1H), 8.31 (dd, J o=1.5Hz, J m=4.5Hz, 2H).
Embodiment 126
5-[2-(methylthio group) pyrimidine-4-yl]-6-[3-(trifluoromethyl) phenyl]-1H-pyrazolo [3,4-b] pyridine
According to embodiment 77 described similar technologies, but be to use 3-amino-5-[2-(methylthio group) pyrimidine-4-yl]-6-[3-(trifluoromethyl) phenyl]-1H-pyrazolo [3,4-b] pyridine (in embodiment 123, obtaining) replacement 3-amino-6-(4-fluorophenyl)-5-(4-pyridyl)-1H-pyrazolo [3,4-b] pyridine, obtain title compound (yield: 34%).
1H NMR (300MHz, CDCl 3) δ (TMS): 1.55 (wide s, NH+H 2O), 6.70 (d, J=5.1Hz, 1H), 7.50 (m, 2H), 7.72 (m, 1H), 7.86 (s, 1H), 8.24 (s, 1H), 8.35 (d, J=5.1Hz, 1H), 8.54 (s, 1H).
Embodiment 127
5-[2-(methylsulfonyl) pyrimidine-4-base-6-[3-(trifluoromethyl) phenyl]-1H-pyrazolo [3,4-b] pyridine
According to embodiment 56 described similar technologies, but be to use 5-[2-(methylthio group) pyrimidine-4-yl]-6-[3-(trifluoromethyl) phenyl]-1H-pyrazolo [3,4-b] pyridine (in embodiment 126, obtaining) replacement 4, two (4-the fluorophenyl)-2-(4-methylthio group phenyl) of 6--5-(4-pyridyl) pyrazolo [3,4-b] between pyridine and 2 equivalents-the chlorine peroxybenzoic acid, obtain title compound (yield: quantitatively).
1H NMR (300MHz, CDCl 3) δ (TMS): 1.56 (wide s, NH+H 2O), 3.22 (s, 3H), 7.21 (d, J=5.1Hz, 1H), 7.49 (d, J=4.8Hz, 2H), 7.71 (m, 1H), 7.84 (s, 1H), 8.30 (s, 1H), 8.71 (m, 2H).
Embodiment 128
(1S)-and N-(1-phenylethyl)-[4-[6-[3-(trifluoromethyl) phenyl]-1H-pyrazolo [3,4-b] pyridine-5-yl] pyrimidine-2-base] amine
With 5-[2-(methylsulfonyl) pyrimidine-4-yl]-6-[3-(trifluoromethyl) phenyl]-1H-pyrazolo [3; 4-b] pyridine (0.55g; 0.13mmol, in embodiment 127, obtain) with (1S)-(0.16g, mixture heating up to 100 1.3mmol) ℃ reaches 1 hour to the 1-phenyl ethyl amine.Make its cooling, the gained crude product uses to increase progressively polar EtOAc-hexanes mixtures as eluent through the silica gel chromatography purifying, obtains 10mg title compound (yield: 16%).
1H NMR (300MHz, CDCl 3+ CD 3OD) δ (TMS): 1.50 (d, 3H), 3.80 (wide s, 2NH+H 2O), 6.30 (d, 1H), 7.20-7.40 (sophisticated signal, 6H), 7.50 (d, 1H), 7.68 (d, 1H), 7.76 (d, 1H), 7.83 (s, 1H), 8.08 (d, 1H), 8.15 (s, 1H), 8.24 (wide s, 1H).
Embodiment 129
1-[3-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--2-yl] propyl group] piperidines-4-alcohol
According to embodiment 111 described similar technologies, but be to use piperidines-4-alcohol to replace N-(tertbutyloxycarbonyl)-N-(4-piperidyl) amine, obtain required compound (yield: 39%).
1H NMR (300MHz, CDCl 3) δ (TMS): 1.57 (m, 2H), 1.88-2.50 (sophisticated signal, 5H+OH+H 2O), 2.75 (m, 2H), 3.44-3.51 (sophisticated signal, 4H), 4.52 (t, J=6.6Hz, 2H), 6.83 (dd, J o=1.6Hz, J m=4.4Hz, 2H), 6.89 (t, J=8.7Hz, 2H), 7.00 (t, J=8.6Hz, 2H), 7.14 (m, 2H), 7.34 (m, 2H), 7.82 (s, 1H), 8.32 (dd, J o=1.5Hz, J m=4.5Hz, 2H).
Embodiment 130
2-[1-[3-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--2-yl] propyl group] piperidin-4-yl] ethanol
According to embodiment 111 described similar technologies, but be to use 2-(4-piperidyl) ethanol to replace N-(tertbutyloxycarbonyl)-N-(4-piperidyl) amine, obtain required compound (yield: 44%).
1H NMR (300MHz, CDCl 3) δ (TMS): 1.20-2.00 (wide s, 8 H+OH+H 2O), 2.50 (m, 1H), 2.85 (m, 1H), 3.50 (m, 1H), 3.70 (m, 4H), 4.59 (m, 2H), 6.83 (d, J=6.0Hz, 2H), 6.90 (t, J=8.7Hz, 2H), 7.00 (t, J=8.6Hz, 2H), 7.14 (m, 2H), 7.30 (m, 2H), 7.89 (s, 1H), 8.32 (d, J=6.0Hz, 2H).
Embodiment 131
4, two (4-the fluorophenyl)-3-(4-piperidyl) of 6--5-(4-pyridyl)-1H-pyrazolo [3,4-b] pyridine
A) 3-(1-benzyl piepridine-4-yl)-4, two (4-the fluorophenyl)-5-(4-pyridyl) of 6--1H-pyrazolo [3,4-b] pyridine
According to the described similar technology of embodiment 1 method A, but be to use 3-amino-5-(1-benzyl piepridine-4-yl)-2H-pyrazoles (in reference example 15, obtaining) to replace 3-amino-2H-pyrazoles, obtain title compound (yield: 6%).
B) title compound
Under argon atmospher,, add Pd/C and HCOONH in MeOH (1ml) solution of two (4-the fluorophenyl)-5-(4-pyridyl) of 6--1H-pyrazolo [3,4-b] pyridine (23mg, 0.04mmol obtain) in prosthomere to 3-(1-benzyl piepridine-4-yl)-4 4(0.01g, water 0.2mmol) (0.06ml) solution.Mixture heating up is reached 5 hours to refluxing.By diatomite filtration, concentrate.Resistates is dissolved in CHCl 3, use saturated NaHCO 3Washing obtains 2mg title compound (yield: 10%).
1H NMR (300MHz, CDCl 3) δ (TMS): 1.10-1.90 (wide s, 7H), 2.23 (m, 2H), 2.99 (m, 2H), 6.80 (dd, J o=1.6Hz, J m=4.4Hz, 2H), 6.92 (t, J=8.7Hz, 2H), 7.02 (t, J=8.7Hz, 2H), 7.12 (m, 2H), 7.28 (m, 2H), 8.28 (dd, J o=1.5Hz, J m=4.5Hz, 2H).
Embodiment 132
6-(4-fluorophenyl)-5-(4-pyridyl)-1H-pyrazolo [3,4-b] pyridine-3-nitrile
According to embodiment 65 described similar technologies, but be to use 3-bromo-6-(4-fluorophenyl)-5-(4-pyridyl)-1H-pyrazolo [3,4-b] pyridine (in embodiment 76, obtaining) replacement 3-bromo-4, two (4-the fluorophenyl)-5-(4-pyridyl) of 6--1H-pyrazolo [3,4-b] pyridine, obtain title compound (yield: 38%).
Embodiment 133
2-[2-[[1-(tertbutyloxycarbonyl) piperidin-4-yl] amino] ethyl]-4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6-
According to embodiment 111 described similar technologies, but be to use 2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolos [3 of 6-, 4-b] pyridine-2-yl] ethyl methane sulfonate ester (in embodiment 116a joint, obtaining) replacement 3-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolos [3 of 6-, 4-b] pyridine-2-yl] the propyl group methanesulfonates, [N-(tertbutyloxycarbonyl) piperidin-4-yl] amine replaces N-(tertbutyloxycarbonyl)-N-(4-piperidyl) amine, obtains required compound (yield: 40%).
1H NMR (300MHz, CDCl 3) δ (TMS): 1.20 (m, 2H), 1.45 (s, 9H), 1.55 (wide s NH+H 2O), 1.83 (m, 2H), 2.65 (m, 1H), 2.77 (m, 2H), 3.31 (t, 2H), 4.02 (m, 2H), 4.53 (t, 2H), 6.82 (dd, J o=1.5Hz, J m=4.5Hz, 2H), 6.90 (t, J=8.8Hz, 2H), 7.00 (t, J=8.7Hz, 2 H), 7.13 (m, 2H), 7.28 (m, 2H), 7.84 (s, 1H), 8.32 (dd, J o=1.5Hz, J m=4.5Hz, 2H).
Embodiment 134
4, two (4-the fluorophenyl)-2-[2-[(4-piperidyls of 6-) amino] ethyl]-5-(4-pyridyl) pyrazolo [3,4-b] pyridine
According to embodiment 36 described similar technologies, but be to use 2-[2-[[1-(tertbutyloxycarbonyl) piperidin-4-yl] amino] ethyl]-4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolos [3 of 6-, 4-b] pyridine (in embodiment 133, obtaining) replacement 2-[1-(tertbutyloxycarbonyl) piperidin-4-yl]-4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolos [3 of 6-, 4-b] pyridine, obtain title compound (yield: 97%).
1H NMR (300MHz, CDCl 3) δ (TMS): 1.30 (m, 2H), 1.70 (wide s, 2 NH+H 2O), 1.85 (m, 2H), 2.61 (m, 3H), 3.09 (m, 2H), 3.31 (t, J=5.7Hz, 2H), 4.53 (t, J=5.7Hz, 2H), 6.82 (dd, J o=1.6Hz, J m=4.4Hz, 2H), 6.90 (t, J=8.8Hz, 2H), 7.00 (t, J=8.7Hz, 2H), 7.14 (m, 2H), 7.29 (m, 2H), 7.85 (s, 1H), 8.32 (dd, J o=1.6Hz, J m=4.4Hz, 2H).
Embodiment 135
N-(2-methoxy ethyl)-[2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--2-yl] ethyl] amine
According to embodiment 111 described similar technologies, but be to use 2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolos [3 of 6-, 4-b] pyridine-2-yl] ethyl methane sulfonate ester (in embodiment 116a joint, obtaining) replacement 3-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolos [3 of 6-, 4-b] pyridine-2-yl] the propyl group methanesulfonates, 2-methoxy ethyl amine replaces N-(tertbutyloxycarbonyl)-N-(4-piperidyl) amine, obtains required compound (yield: 63%).
1H NMR (300MHz, CDCl 3) δ (TMS): 1.57 (wide s, NH+H 2O), 2.81 (t, J=5.1Hz, 2H), 3.30 (t, J=5.8Hz, 2H), 3.31 (s, 3H), 3.45 (t, J=5.1Hz, 2H), 4.55 (t, J=5.7Hz, 2H), 6.82 (dd, J o=1.8Hz, J m=4.5Hz, 2H), 6.89 (t, J=8.7Hz, 2H), 7.00 (t, J=8.7Hz, 2H), 7.14 (m, 2H), 7.29 (m, 2H), 7.85 (s, 1H), 8.32 (dd, J o=1.5Hz, J m=4.5Hz, 2H).
Embodiment 136
1-[4-[2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--2-yl] ethyl] piperazine-1-yl] ethyl ketone
According to embodiment 111 described similar technologies, but be to use 2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolos [3 of 6-, 4-b] pyridine-2-yl] ethyl methane sulfonate ester (in embodiment 116a joint, obtaining) replacement 3-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolos [3 of 6-, 4-b] pyridine-2-yl] the propyl group methanesulfonates, 1-(piperazine-1-yl) ethyl ketone replaces N-(tertbutyloxycarbonyl)-N-(4-piperidyl) amine, obtains required compound (yield: 50%).
1H NMR(300MHz，CDCl 3)δ(TMS)：2.07(s，3H)，2.50(m，4H)，3.07(t，J＝6.3Hz，2H)，3.41(t，J＝4.9Hz，2H)，3.57(t，J＝4.9Hz，2H)，4.55(t，J＝6.3Hz，2H)，6.82(dd，J o＝1.5Hz，J m＝4.5Hz，2H)，6.90(t，J＝8.7Hz，2H)，7.00(t，J＝8.6Hz，2H)，7.14(m，2H)，7.29(m，2H)，7.82(s，1H)，8.32(dd，J o＝1.5Hz，J m＝4.5Hz，2H).
Embodiment 137
3-[4,6-phenylbenzene-5-(4-pyridyl) pyrazolo [3,4-b] pyridine-2-yl] third-1-alcohol
Embodiment 138
3-[4,6-phenylbenzene-5-(4-pyridyl) pyrazolo [3,4-b] pyridine-1-yl] third-1-alcohol
According to embodiment 6 and 7 described similar technologies, but be to use 4,6-phenylbenzene-5-(4-pyridyl)-1H-pyrazolo [3,4-b] pyridine (in embodiment 2, obtaining) replacement 4, two (4-the fluorophenyl)-5-(4-pyridyl) of 6--1H-pyrazolo [3,4-b] pyridine, 3-iodine propyl alcohol replaces iodic ether, obtains title compound.
Embodiment 137: productive rate: 44%; 1H NMR (300MHz, CDCl 3) δ (TMS): 1.56 (s, OH+H 2O), 2.25 (m, 2H), 3.70 (m, 2H), 4.62 (t, J=6.3Hz, 2H), 6.83 (dd, J o=1.6Hz, J m=4.6Hz, 2H), 7.17-7.34 (sophisticated signal, 10H), 7.84 (s, 1H), 8.26 (dd, J o=1.5Hz, J m=4.5Hz, 2H).
Embodiment 138: productive rate: 27%; 1H NMR (300MHz, CDCl 3) δ (TMS): 1.58 (s, OH+H 2O), 2.15 (m, 2H), 3.59 (m, 2H), 4.79 (t, J=6.0Hz, 2H), 6.83 (dd, J o=1.6Hz, J m=4.4Hz, 2H), 7.17 (m, 2H), 7.21-7.33 (sophisticated signal, 8H) t 7.91 (s, 1H), 8.27 (dd, J o=1.5Hz, J m=4.5Hz, 2H).
Embodiment 139
2-ethyl-4,6-phenylbenzene-5-(4-pyridyl) pyrazolo [3,4-b] pyridine
Embodiment 140
1-ethyl-4,6-phenylbenzene-5-(4-pyridyl) pyrazolo [3,4-b] pyridine
According to embodiment 6 and 7 described similar technologies, but be to use 4,6-phenylbenzene-5-(4-pyridyl)-1H-pyrazolo [3,4-b] pyridine (in embodiment 2, obtaining) replacement 4, two (4-the fluorophenyl)-5-(4-pyridyl) of 6--1H-pyrazolo [3,4-b] pyridine obtain title compound.
Embodiment 139: productive rate 12%; 1H NMR (300MHz, CDCl 3) δ (TMS): 1.67 (t, J=7.3Hz, 3H), 4.50 (c, J=7.3Hz, 2H), 6.83 (dd, J o=1.5Hz, J m=4.5Hz, 2H), 7.15-7.34 (sophisticated signal, 10H), 7.80 (s, 1H), 8.25 (dd, J o=1.5Hz, J m=4.5Hz, 2H).
Embodiment 140: productive rate 21%; 1H NMR (300MHz, CDCl 3) δ (TMS): 1.61 (t, J=7.2Hz, 3H), 4.68 (c, J=7.2Hz, 2H), 6.82 (dd, J o=1.5Hz, J m=4.5Hz, 2H), 7.17 (m, 2H), 7.23-7.32 (sophisticated signal, 8H), 7.88 (s, 1H), 8.26 (dd, J o=1.5Hz, J m=4.5Hz, 2H).
Embodiment 141
4,6-phenylbenzene-2-(2-phthaloyl imino-ethyl)-5-(4-pyridyl) pyrazolo [3,4-b] pyridine
According to embodiment 6 and 7 described similar technologies, but be to use 4,6-phenylbenzene-5-(4-pyridyl)-1 H-pyrazolo [3,4-b] pyridine (in embodiment 2, obtaining) replacement 4, two (4-the fluorophenyl)-5-(4-pyridyl) of 6--1H-pyrazolo [3,4-b] pyridine, N-(2-bromotrifluoromethane) phthalimide replaces iodic ether, obtains title compound (yield: 31%).
1H NMR (30DMHz, CDCl 3) δ (TMS): 4.32 (t, J=6.1Hz, 2H), 4.75 (t, J=6.1Hz, 2H), 6.82 (dd, J o=1.5Hz, J m=4.5Hz, 2H), 7.11 (m, 2H), 7.18-7.32 (sophisticated signal, 7H), 7.73 (m, 2H), 7.80 (s, 1H), 7.83 (m, 2H), 8.25 (dd, J o=1.5Hz, J m=4.5Hz, 2H).
Embodiment 142
2-(2-amino-ethyl)-4,6-phenylbenzene-5-(4-pyridyl) pyrazolo [3,4-b] pyridine
According to embodiment 90 described similar technologies, but be to use 2-(2-phthaloyl imino-ethyl)-4,6-phenylbenzene-5-(4-pyridyl) pyrazolo [3,4-b] pyridine (in embodiment 141, obtaining) replacement 4, two (4-the fluorophenyl)-2-(2-phthaloyl imino-ethyl) of 6--5-(4-pyridyl) pyrazolo [3,4-b] pyridine, obtain title compound (yield: 51%).
1H NMR (300MHz, CDCl 3) δ (TMS): 1.50 (s, NH 2+ H 2O), 3.37 (t, J=5.5Hz, 2H), 4.48 (t, J=5.4Hz, 2H), 6.83 (dd, J o=1.5Hz, J m=4.5Hz, 2H), 7.17-7.34 (sophisticated signal, 10H), 7.86 (s, 1H), 8.25 (dd, J o=1.5Hz, J m=4.5Hz, 2H).
Embodiment 143
2-allyl group-4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6-
Embodiment 144
1-allyl group-4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6-
According to embodiment 6 and 7 described similar technologies, but be to use allyl bromide 98 to replace iodic ether, obtain title compound.
Embodiment 143: productive rate: 33%; 1H NMR (300MHz, CDCl 3) δ (TMS): 5.08 (d, J=6.3Hz, 2H), 5.40 (m, 2H), 6.16 (m, 1H), 6.82 (dd, J o=1.5Hz, J m=4.5Hz, 2H), 6.89 (t, J=8.7Hz, 2H), 7.00 (t, J=8.6Hz, 2H), 7.13 (m, 2H), 7.30 (m, 2H), 7.78 (s, 1H), 8.34 (dd, J o=1.5Hz, J m=4.5Hz, 2H).
Embodiment 144: productive rate: 10%; 1H NMR (300MHz, CDCl 3) δ (TMS): 5.22-5.34 (sophisticated signal, 4H), 6.14 (m, 1H), 6.81 (dd, J o=1.5Hz, J m=4.5Hz, 2H), 6.93 (t, J=8.7Hz, 2H), 7.01 (t, J=8.6Hz, 2H), 7.14 (m, 2H), 7.29 (m, 2H), 7.87 (s, 1H), 8.32 (dd, J o=1.5Hz, J m=4.5Hz, 2H).
Embodiment 145
1-[2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--2-yl] ethyl] piperidin-4-one-
According to embodiment 111 described similar technologies, but be to use 2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolos [3 of 6-, 4-b] pyridine-2-yl] ethyl methane sulfonate ester (in embodiment 116a joint, obtaining) replacement 3-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolos [3 of 6-, 4-b] pyridine-2-yl] the propyl group methanesulfonates, 4-piperidone monohydrate hydrochloride replaces N-(tertbutyloxycarbonyl)-N-(4-piperidyl) amine, and add triethylamine (3 equivalent), obtain required product (yield: 18%).
1H NMR(300MHz，CDCl 3)δ(TMS)：2.41(t，J＝6.0Hz，4H)，2.84(t，J＝6.0Hz，4H)，3.20(t，J＝6.4Hz，2H)，4.58(t，J＝6.4Hz，2H)，6.83(d，J＝6.0Hz，2H)，6.90(t，J＝8.7Hz，2H)，7.00(t，J＝8.6Hz，2H)，7.14(m，2H)，7.30(m，2H)，7.85(s，1H)，8.32(d，J＝6.0Hz，2H).
Embodiment 146
3-amino methyl-6-(4-fluorophenyl)-5-(4-pyridyl)-1H-pyrazolo [3,4-b] pyridine
According to embodiment 68 described similar technologies, but be to use 6-(4-fluorophenyl)-5-(4-pyridyl)-1H-pyrazolo [3,4-b] pyridine-3-nitrile (in embodiment 132, obtaining) replacement 4, two (4-the fluorophenyl)-5-(4-pyridyl) of 6--1H-pyrazolo [3,4-b] pyridine-3-nitrile, obtain title compound (yield: 22%).
1H NMR (300MHz, CDCl 3+ CD 3OD) δ (TMS): 4.24 (s, 2H), 4.25 (wide s, NH+NH 2+ CD 3OD), 6.95 (m, 2H), 7.16 (m, 2H), 7.29 (m, 2H), 8.25 (wide s, 1H), 8.38 (wide s, 2H).
Embodiment 147
3-amino-6-(4-fluorophenyl)-4-methyl-5-(4-pyridyl)-1H-pyrazolo [3,4-b] pyridine
According to saving described similar technology to reference example 15c, but be to use 6-chloro-2-(4-fluorophenyl)-4-methyl-3,4 '-dipyridyl-5-nitrile (in reference example 18, obtaining) replacement 3-(1-benzyl piepridine-4-yl)-3-oxypropionitrile, obtain title compound (yield: 27%).
1H NMR (300MHz, CDCl 3) δ (TMS): 1.56 (wide s, NH+NH 2+ H 2O), 2.51 (s, 3H), 6.80-7.20 (sophisticated signal, 4H), 7.22 (m, 2H), 8.55 (d, J=8.0Hz, 2H).
Embodiment 148
3-[N-[2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--2-yl] ethyl] amino] third-1-alcohol
According to embodiment 111 described similar technologies, but be to use 2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolos [3 of 6-, 4-b] pyridine-2-yl] ethyl methane sulfonate ester (in embodiment 116a joint, obtaining) replacement 3-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolos [3 of 6-, 4-b] pyridine-2-yl] the propyl group methanesulfonates, 3-amino-1-propyl alcohol replaces N-(tertbutyloxycarbonyl)-N-(4-piperidyl) amine, obtains required compound (yield: 57%).
1H NMR (300MHz, CDCl 3) δ (TMS): 1.50-1.80 (sophisticated signal, 2H+NH+OH+H 2O), 2.91 (t, J=5.7Hz, 2H), 3.31 (t, J=5.4Hz, 2H), 3.77 (t, J=5.4Hz, 2H), 4.54 (t, J=5.4Hz, 2H), 6.82 (dd, J o=1.5Hz, J m=4.5Hz, 2H), 6.90 (t, J=8.7Hz, 2H), 7.00 (t, J=8,7Hz, 2H), 7.15 (m, 2H), 7.29 (m, 2H), 7.82 (s, 1H), 8.31 (dd, J o=1.8Hz, J m=4.5Hz, 2H).
Embodiment 149
N-ethyl-[2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--2-yl] ethyl] amine
According to embodiment 111 described similar technologies, but be to use 2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolos [3 of 6-, 4-b] pyridine-2-yl] ethyl methane sulfonate ester (in embodiment 116 of a joint, obtaining) replacement 3-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolos [3 of 6-, 4-b] pyridine-2-yl] the propyl group methanesulfonates, ethylamine replaces N-(tertbutyloxycarbonyl)-N-(4-piperidyl) amine, obtains required compound (yield: 58%).
1H NMR (300MHz, CDCl 3) δ (TMS): 1.09 (t, J=7.0Hz, 3H), 1.71 (wide s, NH+H 2O), 2.70 (c, J=7.1Hz, 2H), 3.29 (t, J=5.7Hz, 2H), 4.56 (t, J=5.7Hz, 2H), 6.82 (dd, J o=1.5Hz, J m=4.5Hz, 2H), 6.90 (t, J=8.7Hz, 2H), 7.00 (t, J=8.7Hz, 2H), 7.14 (m, 2H), 7.29 (m, 2H), 7.84 (s, 1H), 8.32 (dd, J o=1.5Hz, J m=4.5Hz, 2H).
Embodiment 150
2-[N-[2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--2-yl] ethyl] amino] ethanol
According to embodiment 111 described similar technologies, but be to use 2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolos [3 of 6-, 4-b] pyridine-2-yl] ethyl methane sulfonate ester (in embodiment 116a joint, obtaining) replacement 3-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolos [3 of 6-, 4-b] pyridine-2-yl] the propyl group methanesulfonates, the 2-monoethanolamine replaces N-(tertbutyloxycarbonyl)-N-(4-piperidyl) amine, obtains required compound (yield: 54%).
1H NMR (300MHz, CDCl 3) δ (TMS): 1.70 (wide s, NH+OH+H 2O), 2.82 (t, J=5.3Hz, 2H), 3.32 (t, J=5.6Hz, 2H), 3.62 (t, J=5.3Hz, 2H), 4.55 (t, J=5.6Hz, 2H), 6.83 (dd, J o=1.5Hz, J m=4.5Hz, 2H), 6.90 (t, J=8.7Hz, 2H), 7.00 (t, J=8.6Hz, 2H), 7.14 (m, 2H), 7.29 (m, 2H), 7.83 (s, 1H), 8.31 (dd, J o=1.8Hz, J m=4.5Hz, 2H).
Embodiment 151
The N-[(2-pyridyl) methyl]-[2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--2-yl] ethyl] amine
According to embodiment 111 described similar technologies, but be to use 2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolos [3 of 6-, 4-b] pyridine-2-yl] ethyl methane sulfonate ester (in embodiment 116a joint, obtaining) replacement 3-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolos [3 of 6-, 4-b] pyridine-2-yl] the propyl group methanesulfonates, (2-pyridyl) methylamine replaces N-(tertbutyloxycarbonyl)-N-(4-piperidyl) amine, obtains required compound (yield: 52%).
1H NMR (300MHz, CDCl 3) δ (TMS): 1.62 (wide s, NH+H 2O), 3.33 (t, J=5.7Hz, 2H), 3.92 (s, 2H), 4.58 (t, J=5.7Hz, 2H), 6.83 (dd, J o=1.8Hz, J m=4.5Hz, 2H), 6.90 (t, J=8.7Hz, 2H), 6.99 (t, J=8.6Hz, 2H), 7.14 (m, 4H), 7.29 (m, 2H), 7.60 (m, 1H), 7.86 (s, 1H), 8.31 (dd, J o=1.5Hz, J m=4.5Hz, 2H), 8.51 (m, 1H).
Embodiment 152
The N-[(2-thienyl) methyl]-[2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--2-yl] ethyl] amine
According to embodiment 111 described similar technologies, but be to use 2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolos [3 of 6-, 4-b] pyridine-2-yl] ethyl methane sulfonate ester (in embodiment 116a joint, obtaining) replacement 3-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolos [3 of 6-, 4-b] pyridine-2-yl] the propyl group methanesulfonates, (2-thienyl) methylamine replaces N-(tertbutyloxycarbonyl)-N-(4-piperidyl) amine, obtains required compound (yield: 25%).
1H NMR (300MHz, CDCl 3) 6 (TMS): 1.55 (wide s, NH+H 2O) 3.32 (t, J=5.6Hz, 2H), 4.00 (s, 2H), 4.54 (t, J=5.6Hz, 2H), 6.83 (dd, J o=1.5Hz, J m=4.5Hz, 2H), 6.90 (t, J=8.7Hz, 2H), 6.91 (m, 1H), 7.00 (t, J=8.6Hz, 2H), 7.16 (m, 3H), 7.29 (m, 3H), 7.86 (s, 1H), 8.32 (dd, J o=1.5Hz, J m=4.5Hz, 2H).
Embodiment 153
1-[2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--2-yl] ethyl] piperidines-4-methane amide
According to embodiment 111 described similar technologies, but be to use 2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolos [3 of 6-, 4-b] pyridine-2-yl] ethyl methane sulfonate ester (in embodiment 116a joint, obtaining) replacement 3-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolos [3 of 6-, 4-b] pyridine-2-yl] the propyl group methanesulfonates, piperidines-4-methane amide replaces N-(tertbutyloxycarbonyl)-N-(4-piperidyl) amine, obtains required compound (yield: 75%).
1H NMR (300MHz, CDCl 3) δ (TMS): 1.61-1.76 (sophisticated signal, 5H), 1.84 (m, 2H), 2.91 (m, 2H), 3.01 (t, J=6.3Hz, 2H), 4.52 (t, J=6.3Hz, 2H), 5.27 (wide s, NH), 5.41 (wide s, NH), 6.83 (dd, J o=1.5Hz, J m=4.5Hz, 2H), 6.89 (t, J=8.7Hz, 2H), 7.02 (t, J=8.6Hz, 2H), 7.14 (m, 2H), 7.30 (m, 2H), 7.83 (s, 1H), 8.32 (dd, J o=1.4Hz, J m=4.6Hz, 2H).
Embodiment 154
4, two (4-fluorophenyl)-2-[2-(tetramethyleneimine-1-yl) ethyls of 6-]-5-(4-pyridyl) pyrazolo [3,4-b] pyridine
According to embodiment 111 described similar technologies, but be to use 2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolos [3 of 6-, 4-b] pyridine-2-yl] ethyl methane sulfonate ester (in embodiment 116a joint, obtaining) replacement 3-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolos [3 of 6-, 4-b] pyridine-2-yl] the propyl group methanesulfonates, tetramethyleneimine replaces N-(tertbutyloxycarbonyl)-N-(4-piperidyl) amine, obtains required compound (yield: 75%).
1H NMR(300MHz，CDCl 3)δ(TMS)：1.77(m，4H)，2.55(m，4H)，3.17(t，J＝6.6Hz，2H)，4.58(t，J＝6.6Hz，2H)，6.82(dd，J o＝1.5Hz，J m＝4.5Hz，2H)，6.89(t，J＝8.7Hz，2H)，7.00(t，J＝8.7Hz，2H)，7.14(m，2H)，7.29(m，2H)，7.84(s，1H)，8.31(dd，J o＝1.5Hz，J m＝4.5Hz，2H).
Embodiment 155
(3R)-and 1-[2-(4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--2-yl] ethyl] tetramethyleneimine-3-alcohol
According to embodiment 111 described similar technologies, but be to use 2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolos [3 of 6-, 4-b] pyridine-2-yl] ethyl methane sulfonate ester (in embodiment 116a joint, obtaining) replacement 3-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolos [3 of 6-, 4-b] pyridine-2-yl] the propyl group methanesulfonates, (3R)-and 3-pyrrolidinol replacement N-(tertbutyloxycarbonyl)-N-(4-piperidyl) amine, obtain required compound (yield: 52%).
1H NMR (300MHz, CDCl 3) δ (TMS): 1.69 (wide s, 1H+OH+H 2O), 2.14 (m, 1H), 2.40 (m, 1H), 2.58 (m, 1H), 2.69 (m, 1H), 2.94 (m, 1H), 3.20 (t, J=6.4Hz, 2H), 4.32 (m, 1H), 4.57 (t, J=6.4Hz, 2H), 6.83 (dd, J o=1.5Hz, J m=4.5Hz, 2H), 6.89 (t, J=8.7Hz, 2H), 7.00 (t, J=8.6Hz, 2H), 7.14 (m, 2H), 7.29 (m, 2H), 7.82 (s, 1H), 8.32 (dd, J o=1.5Hz, J m=4.5Hz, 2H).
Embodiment 156
2-[N-[2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--2-yl] ethyl]-the N-methylamino] ethanol
According to embodiment 111 described similar technologies, but be to use 2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolos [3 of 6-, 4-b] pyridine-2-yl] ethyl methane sulfonate ester (in embodiment 116a joint, obtaining) replacement 3-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolos [3 of 6-, 4-b] pyridine-2-yl] the propyl group methanesulfonates, 2-(methylamino) ethanol replaces N-(tertbutyloxycarbonyl)-N-(4-piperidyl) amine, obtains required compound (yield: 71%).
1H NMR (300MHz, CDCl 3) δ (TMS): 1.56 (wide s, OH+H 2O), 2.34 (s, 3H), 2.60 (t, J=5.2Hz, 2H), 3.14 (t, J=6.0Hz, 2H), 3.53 (t, J=5.2Hz, 2H), 4.53 (t, J=6.0Hz, 2H), 6.83 (dd, J o=1.8Hz, J m=4.5Hz, 2H), 6.89 (t, J=8.7Hz, 2H), 7.00 (t, J=8.6Hz, 2H), 7.14 (m, 2H), 7.29 (m, 2H), 7.81 (s, 1H), 8.31 (dd, J o=1.5Hz, J m=4.5Hz, 2H).
Embodiment 157
4, and two (4-the fluorophenyl)-5-(4-pyridyl) of 6--2-[2-(1,2,3,4-tetrahydroisoquinoline-2-base ethyl pyrazolo [3,4-b] pyridine
According to embodiment 111 described similar technologies, but be to use 2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--2-yl] ethyl methane sulfonate ester (in embodiment 116a joint, obtaining) replacement 3-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolos [3 of 6-, 4-b] pyridine-2-yl] the propyl group methanesulfonates, 1,2,3, the 4-tetrahydroisoquinoline replaces N-(tertbutyloxycarbonyl)-N-(4-piperidyl) amine, obtains required compound (yield: 57%).
1H NMR (300MHz, CDCl 3) δ (TMS): 2.78-2.85 (sophisticated signal, 4H), 3.20 (t, J=6.3Hz, 2H), 3.72 (s, 2 H), 4.63 (t, J=6.3Hz, 2H), 6.81 (dd, J o=1.5Hz, J m=4.5Hz, 2H), 6.86-7.17 (sophisticated signal, 10H), 7.30 (m, 2H), 7.86 (s, 1H), 8.31 (dd, J o=1.5Hz, J m=4.5Hz, 2H).
Embodiment 158
4, two (4-fluorophenyl)-2-[2-(4-phenylpiperazine-1-yl) ethyls of 6-]-5-(4-pyridyl) pyrazolo [3,4-b] pyridine
According to embodiment 111 described similar technologies, but be to use 2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolos [3 of 6-, 4-b] pyridine-2-yl] ethyl methane sulfonate ester (in embodiment 116a joint, obtaining) replacement 3-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolos [3 of 6-, 4-b] pyridine-2-yl] the propyl group methanesulfonates, the 1-phenylpiperazine replaces N-(tertbutyloxycarbonyl)-N-(4-piperidyl) amine, obtains required compound (yield: 71%).
1H NMR (300MHz, CDCl 3) δ (TMS): 2.69 (m, 4H), 3.10 (t, J=6.4Hz, 2H), 3.16 (m, 4H), 4.59 (t, J=6.4Hz, 2H), 6.82 (dd, J o=1.8Hz, J m=4.5Hz, 2H), 6.86-7.02 (sophisticated signal, 9H), 7.14 (m, 2H), 7.29 (m, 2H), 7.86 (s, 1H), 8.32 (dd, J o=1.5Hz, J m=4.5Hz, 2H).
Embodiment 159
4, two (4-fluorophenyl)-2-[2-[4-(piperidino) piperidines of 6--1-yl] ethyl]-5-(4-pyridyl) pyrazolo [3,4-b] pyridine
According to embodiment 111 described similar technologies, but be to use 2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolos [3 of 6-, 4-b] pyridine-2-yl] ethyl methane sulfonate ester (in embodiment 116a joint, obtaining) replacement 3-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolos [3 of 6-, 4-b] pyridine-2-yl] the propyl group methanesulfonates, 4-piperidino-(1-position only) piperidines replaces N-(tertbutyloxycarbonyl)-N-(4-piperidyl) amine, obtains required compound (yield: 51%).
1H NMR (300MHz, CDCl 3) δ (TMS): 1.40-1.60 (sophisticated signal, 8H), 1.78 (m, 2H), 2.04-2.22 (sophisticated signal, 3H), 2.48 (m, 4H), 2.96 (m, 4H), 4.52 (t, J=6.4Hz, 2H), 6.82 (dd, J o=1.5Hz, J m=4.5Hz, 2H), 6.89 (t, J=8.7Hz, 2H), 7.00 (t, J=8.6Hz, 2H), 7.13 (m, 2H), 7.29 (m, 2H), 7.85 (s, 1H), 8.31 (dd, J o=1.5Hz, J m=4.5Hz, 2H).
Embodiment 160
3-[N-[2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--2-yl] ethyl]-the N-methylamino] propionitrile
According to embodiment 111 described similar technologies, but be to use 2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolos [3 of 6-, 4-b] pyridine-2-yl] ethyl methane sulfonate ester (in embodiment 116a joint, obtaining) replacement 3-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolos [3 of 6-, 4-b] pyridine-2-yl] the propyl group methanesulfonates, 3-(methylamino) propionitrile replaces N-(tertbutyloxycarbonyl)-N-(4-piperidyl) amine, obtains required compound (yield: 50%).
1H NMR (300MHz, CDCl 3) δ (TMS): 2.35 (sophisticated signal, 5H), 2.71 (t, J=6.4Hz, 4H), 3.13 (t, J=5.9Hz, 2H), 4.50 (t, J=5.9Hz, 2H), 6.83 (dd, J o=1.6Hz, J m=4.4Hz, 2H), 6.90 (t, J=8.7Hz, 2H), 6.99 (t, J=8.7Hz, 2H), 7.17 (m, 2H), 7.31 (m, 2H), 7.87 (s, 1H), 8.32 (dd, J o=1.5Hz, J m=4.5Hz, 2H).
Embodiment 161
N-methyl-[2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--2-yl] ethyl] amine
According to embodiment 111 described similar technologies, but be to use 2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolos [3 of 6-, 4-b] pyridine-2-yl] ethyl methane sulfonate ester (in embodiment 116a joint, obtaining) replacement 3-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolos [3 of 6-, 4-b] pyridine-2-yl] the propyl group methanesulfonates, methylamine replaces N-(tertbutyloxycarbonyl)-N-(4-piperidyl) amine, obtains required compound (yield: 51%).
1H NMR (300MHz, CDCl 3) δ (TMS): 1.61 (wide s, NH+H 2O), 3.25 (t, J=5.6Hz, 2H), 4.57 (t, J=5.6Hz, 2H), 6.82 (dd, J o=1.5Hz, J m=4.5Hz, 2H), 6.90 (t, J=8.7Hz, 2H), 7.00 (t, J=8.6Hz, 2H), 7.14 (m, 2H), 7.29 (m, 2H), 7.84 (s, 1H), 8.31 (dd, J o=1.5Hz, J m=4.5Hz, 2H).
Embodiment 162
2-[2-[4-(tertbutyloxycarbonyl) piperazine-1-yl] ethyl]-4,6-(4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3,4-b] pyridine
According to embodiment 111 described similar technologies, but be to use 2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolos [3 of 6-, 4-b] pyridine-2-yl] ethyl methane sulfonate ester (in embodiment 116a joint, obtaining) replacement 3-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolos [3 of 6-, 4-b] pyridine-2-yl] the propyl group methanesulfonates, 1-(tertbutyloxycarbonyl) piperazine replaces N-(tertbutyloxycarbonyl)-N-(4-piperidyl) amine, obtains required compound (yield: 63%).
1H NMR(300MHz，CDCl 3)δ(TMS)：1.45(s，9H)，2.46(m，4H)，3.05(t，J＝6.4Hz，2H)，3.40(m，4H)，4.54(t，J＝6.4Hz，2H)，6.82(dd，J o＝1.6Hz，J m＝4.4Hz，2H)，6.89(t，J＝8.7Hz，2H)，7.00(t，J＝8.6Hz，2H)，7.15(m，2H)，7.30(m，2H)，7.86(s，1H)，8.33(dd，J o＝1.5Hz，J m＝4.5Hz，2H).
Embodiment 163
4, two (4-fluorophenyl)-2-[2-(piperazine-1-yl) ethyls of 6-]-5-(4-pyridyl) pyrazolo [3,4-b] pyridine
According to embodiment 36 described similar technologies, but be to use 2-[2-[4-(tertbutyloxycarbonyl) piperazine-1-yl] ethyl]-4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolos [3 of 6-, 4-b] pyridine (in embodiment 162, obtaining) replacement 2-[1-(tertbutyloxycarbonyl) piperidin-4-yl]-4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolos [3 of 6-, 4-b] pyridine, obtain title compound (yield: 62%).
1H NMR (300MHz, CDCl 3) δ (TMS): 1.56 (wide s, NH+H 2O), 2.45 (m, 4H), 2.85 (m, 4H), 3.00 (t, J=6.4Hz, 2H), 4.55 (t, J=6.4Hz, 2H), 6.82 (dd, J o=1.6Hz, J m=4.4Hz, 2H), 6.89 (t, J=8.7Hz, 2H), 7.03 (t, J=8.7Hz, 2H), 7.14 (m, 2H), 7.30 (m, 2H), 7.86 (s, 1H), 8.32 (dd, J o=1.5Hz, J m=4.5Hz, 2H).
Embodiment 164
4, two (4-the fluorophenyl)-5-(4-pyridyl) of 6--2-vinyl pyrazoles is [3,4-b] pyridine also
With 2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--2-yl] ethyl methane sulfonate ester (0.15g, 0.3mmol, in embodiment 116a joint, obtain) (0.02g, toluene 0.3mmol) (4ml) solution are heated to 100 ℃ of backflows and spend the night with KOH.Add entry and EtOAc, separate each phase.Water is saturated with NaCl (solid), extract with EtOAc.Merge organic phase, through Na 2SO 4Drying is concentrated into dried.The gained crude product uses to increase progressively polar hexane-EtOAc mixture as eluent through the silica gel chromatography purifying, obtains 110mg title compound (yield: 90%).
1H NMR (300MHz, CDCl 3) δ (TMS): 5.27 (dd, J Gem=1.8 Hz, J Vec=8.7Hz, 1H), 6.22 (dd, J Gem=1.4Hz, J Vec=15.4Hz, 1H), 6.83 (dd, J o=1.5Hz, J m=4.5Hz, 2H), 6.91 (t, J=8.7Hz, 2H), 7.01 (t, J=8.6Hz, 2H), 7.15 (m, 2H), 7.17-7.34 (sophisticated signal, 3H), 7.90 (s, 1H), 8.33 (dd, J o=1.5Hz, J m=4.5Hz, 2H).
Embodiment 165
2-[N-[2-[4,6-pair-(4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3,4-b] pyridine-2-yl] ethyl]-N-(2-hydroxyethyl) amino] ethanol
According to embodiment 111 described similar technologies, but be to use 2-[4,6-pair-(4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3,4-b] pyridine-2-yl] ethyl methane sulfonate ester (in embodiment 116a joint, obtaining) replacement 3-[4,6-pair-(4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3,4-b] pyridine-2-yl] the propyl group methanesulfonates, 2-(2-hydroxyethyl amino) ethanol replaces N-(tertbutyloxycarbonyl)-N-(4-piperidyl) amine, obtains required compound (yield: 51%).
1H NMR (300MHz, CDCl 3) δ (TMS): 1.50 (wide s, 2OH+H 2O), 2.73 (t, J=5.0Hz, 4H), 3.21 (t, J=5.6Hz, 2H), 3.52 (t, J=5.0Hz, 4H), 4.54 (t, J=5.4Hz, 2H), 6.82 (dd, J o=1.5Hz, J m=4.5Hz, 2H), 6.89 (t, J=8.7Hz, 2H), 6.99 (t, J=8.7Hz, 2H), 7.13 (m, 2H), 7.29 (m, 2H), 7.89 (s, 1H), 8.32 (dd, J o=1.8Hz, J m=4.5Hz, 2H).
Embodiment 166
N-cyclopropyl-[2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--2-yl] ethyl] amine
According to embodiment 111 described similar technologies, but be to use 2-[4,6-pair-(4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3,4-6] pyridine-2-yl] ethyl methane sulfonate ester (in embodiment 116a joint, obtaining) replacement 3-[4,6-pair-(4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3,4-b] pyridine-2-yl] the propyl group methanesulfonates, cyclopropylamine replaces N-(tertbutyloxycarbonyl)-N-(4-piperidyl) amine, obtains required compound (yield: 47%).
1H NMR (300MHz, CDCl 3) δ (TMS): 0.30 (m, 2H), 0.45 (m, 2H), 1.60 (wide s, NH+H 2O), 2.20 (m, 1H), 3.36 (t, J=5.7Hz, 2H), 4.55 (t, J=5.7Hz, 2H), 6.82 (dd, J o=1.5Hz, J m=4.5Hz, 2H), 6.90 (t, J=8.7Hz, 2H), 7.00 (t, J=8.6Hz, 2H), 7.14 (m, 2H), 7.30 (m, 2H), 7.82 (s, 1H), 8.32 (dd, J o=1.5Hz, J m=4.5Hz, 2H).
Embodiment 167
N-[2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--2-yl] ethyl] ethanamide
According to saving described similar technology to reference example 1a, but be to use Acetyl Chloride 98Min. to replace the 4-fluorobenzoyl chloride, 2-(2-amino-ethyl)-4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolos [3 of 6-, 4-b] pyridine (in embodiment 90, obtaining) replacement N, the O-dimethyl hydroxylamine obtains required compound (yield: 48%).
1H NMR(300MHz，CDCl 3)δ(TMS)：1.98(s，3H)，3.95(m，2H)，4.58(t，J＝5.4Hz，2H)，6.47(m，NH)，6.83(d，J＝9.0Hz，2H)，6.91(t，J＝8.7Hz，2H)，7.01(t，J＝8.6Hz，2H)，7.14(m，2H)，7.28(m，2H)，7.82(s，1H)，8.33(d，J＝9.0Hz，2H).
Embodiment 168
N-[2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--2-yl] ethyl]-N '-sec.-propyl urea
Under argon atmospher, to 2-(2-amino-ethyl)-4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolos [3 of 6-, 4-b] pyridine (0.06g, 0.15mmol, in embodiment 90, obtain) DMF (1ml) solution in add isopropyl isocyanate (0.02g, 0.18mmol).At room temperature stirred 2 days.Concentrated solvent adds diethyl ether in the gained resistates once more.Concentrated solvent obtains the 38mg title compound, is solid form (yield: 50%).
1H NMR(300MHz，CDCl 3)δ(TMS)：1.05(d，J＝6.3Hz，6H)，3.84(m，3H)，4.22(m，NH)，4.58(t，J＝5.4Hz，2H)，5.30(m，NH)，6.82(dd，J o＝1.4Hz，J m＝4.6Hz，2H)，6.91(t，J＝8.7Hz，2H)，7.00(t，J＝8.6Hz，2H)，7.13(m，2H)，7.28(m，2H)，7.84(s，1H)，8.32(dd，J o＝1.5Hz，J m＝4.5Hz，2H).
Embodiment 169
N-[2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--2-yl] ethyl] Toluidrin
Under argon atmospher, to 2-(2-amino-ethyl)-4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolos [3 of 6-, 4-b] pyridine (0.06g, 0.15mmol obtain in embodiment 90) and DMAP (0.001g, 0.0058mmol) pyridine (0.6ml) solution in add methylsulfonyl chloride (0.017ml, 0.22mmol), with ice bath cooling (0.017ml, 0.22mmol).At room temperature stir and spend the night.Concentrated solvent.Resistates is dissolved in CHCl 3, add saturated NaHCO 3Separate each phase.With organic phase through Na 2SO 4Drying concentrates.The gained crude product uses EtOAc as solvent through the silica gel chromatography purifying, obtains 70mg title compound (yield: 95%).
1H NMR(300MHz，CDCl 3)δ(TMS)：2.99(s，3H)，3.86(m，2H)，4.64(t，J＝5.3Hz，2H)，5.33(m，NH)，6.83(dd，J o＝1.5Hz，J m＝4.5Hz，2H)，6.91(t，J＝8.7Hz，2H)，7.01(t，J＝8.7Hz，2H)，7.14(m，2H)，7.29(m，2H)，7.88(s，1H)，8.33(dd，J o＝1.5Hz，J m＝4.5Hz，2H).
Embodiment 170-178
According to embodiment 72 described similar technologies, but in each case from suitable compound, obtain the following table compound:
Embodiment The compound title Initial compounds LC-MS
Method t R(minute) m/z [M+H] +
170 6-(4-fluorophenyl)-4-(4-piperidyl)-5-(4-pyridyl)-1H-pyrazolo [3,4-b] pyridine Reference example 1,3-amino-2H-pyrazoles and 1-(tertbutyloxycarbonyl) piperidines-4-formaldehyde 1 3.34 374.1
171 6-(4-fluorophenyl)-4-(2-furyl)-5-(4-pyridyl)-1H-pyrazolo [3,4-b] pyridine Reference example 1,3-amino-2H-pyrazoles and furans-2-formaldehyde 1 5.72 357.1
172 6-(4-fluorophenyl)-4-(1H-imidazol-4 yl)-5-(4-pyridyl)-1H-pyrazolo [3,4-b] pyridine Reference example 1,3-amino-2H-pyrazoles and 2H-pyrazoles-3-formaldehyde 1 3.25 357.1
173 4-(5-bromothiophene-2-yl)-6-(4-fluorophenyl)-5-(4-pyridyl)-1H-pyrazolo [3,4-b] pyridine Reference example 1,3-amino-2H-pyrazoles and 5-bromothiophene-2-formaldehyde 1 7.46 450.9 452.9
174 4, two (4-the fluorophenyl)-5-(2-methylthiopyrimidine-4-yl) of 6--1H-pyrazolo [3,4-b] pyridine Reference example 19,3-amino-2H-pyrazoles and 4-fluorobenzaldehyde 1 9.11 432.2
175 5-(2-chloropyridine-4-yl)-4, two (4-fluorophenyl)-1H-pyrazolo [3, the 4-b] pyridines of 6- Reference example 23,3-amino-2H-pyrazoles and 4-fluorobenzaldehyde 1 8.99 419.0 421.0
176 6-(4-fluorophenyl)-4-(2-phenylethyl)-5-(4-pyridyl)-1H-pyrazolo [3,4-b] pyridine Reference example 1,3-amino-2H-pyrazoles and 3-phenylpropionaldehyde 1 6.52 395.0
177 4-(6-chloropyridine-3-yl)-6-(4-fluorophenyl)-5-(4-pyridyl)-1H-pyrazolo [3,4-b] pyridine Reference example 1,6-chloropyridine-3-formaldehyde and amino-2H-pyrazoles 1 5.50 402.0 404.0
178 4-(3, the 4-dichlorophenyl)-1-ethyl-6-(4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3,4-b] pyridine Reference example 1,3,4-difluorobenzaldehyde and 3-amino-2-ethyl pyrazoles 1 10.56 462.9 464.9
Embodiment 179
6-(4-fluorophenyl)-4-(1-methyl piperidine-4-yl)-5-(4-pyridyl)-1H-pyrazolo [3,4-b] pyridine
In formic acid (0.64ml) solution of 6-(4-fluorophenyl)-4-(4-piperidyl)-5-(4-pyridyl)-1H-pyrazolo [3,4-b] pyridine (0.24g, 0.6mmol obtain), add 35-40% formalin (0.96ml) in embodiment 170.Be heated to 70-80 ℃ and reach 24 hours.Make its cooling, add 1N NaOH.Use CHCl 3Extraction merges organic phase, through Na 2SO 4Drying is concentrated into dried.The gained crude product uses to increase progressively polar CHCl through the silica gel chromatography purifying 3-MeOH-NH 3Mixture obtains 47mg required compound (yield: 19%) as eluent.
LC-MS (method 1): t R=3.28 minutes; M/z=388.1[M+H] +.
Embodiment 180
3-amino-6-(4-fluorophenyl)-5-(2-methylthiopyrimidine-4-yl)-1H-pyrazolo [3,4-b] pyridine
According to saving described similar technology to reference example 15c, but be to use 2-chloro-6-(4-fluorophenyl)-5-(2-methylthiopyrimidine-4-yl) pyridine-3-nitrile (in reference example 22, obtaining) to replace 3-(1-benzyl piepridine-4-yl)-3-oxypropionitrile, obtain title compound.
LC-MS (method 1): t R=6.70 minutes; M/z=353.0[M+H] +.
Embodiment 181
6-(4-fluorophenyl)-5-(2-methylthiopyrimidine-4-yl)-1H-pyrazolo [3,4-b] pyridine
To be cooled to 0 ℃, 3-amino-6-(4-fluorophenyl)-5-(2-methylthiopyrimidine-4-yl)-1H-pyrazolo [3,4-b] pyridine (10.00g, 28.4mmol, in embodiment 180, obtain) AcOH (52ml), water (22ml) and dense HCl (5.7ml) solution in drip NaNO 2(2.30g, water 33.4mmol) (7.5ml) solution.Stirred 30 minutes down at 0 ℃, slowly add H 3PO 2(50% aqueous solution, 56.8ml).Stirred 6 hours down at 0 ℃.Be cooled to room temperature, slowly add 6N NaOH down at 0 ℃ and alkalize, extract with EtOAc to pH=8.Merge organic phase, through Na 2SO 4Drying is concentrated into dried.The gained crude product uses to increase progressively polar hexane-EtOAc mixture as eluent through the silica gel chromatography purifying, obtains 4.00g title compound (yield: 42%).
LC-MS (method 1): t R=7.80 minutes; M/z=338.0[M+H] +.
Embodiment 182-193
According to embodiment 6 and 7 described similar technologies, but in each case from suitable compound, obtain the following table compound:
Embodiment The compound title Initial compounds LC-MS
Method t R(minute) m/z[M+H] +
182 4,6-phenylbenzene-5-(4-pyridyl)-2-[2-(tetrahydropyrans-2-base oxygen base) ethyl] pyrazolo [3,4-b] pyridine Embodiment 2 and 2-(2-bromine oxethyl) tetrahydropyrans 1 6.70 477.1
183 6-(4-fluorophenyl)-4-(2-furyl)-2-methyl-5-(4-pyridyl) pyrazolo [3,4-b] pyridine Embodiment 171 and methyl iodide 1 5.32 371.1
184 6-(4-fluorophenyl)-2-methyl-4-(1-methyl isophthalic acid H-imidazol-4 yl)-5-(4-pyridyl) pyrazolo [3,4-b] pyridine Embodiment 172 and methyl iodide (2 equivalent) 1 3.66 385.2
185 6-(4-fluorophenyl)-5-(2-methylthiopyrimidine-4-yl)-2-[2-(tetrahydropyrans-2-base oxygen base) ethyl] pyrazolo [3,4-b] pyridine Embodiment 181 and 2-(2-bromine oxethyl) tetrahydropyrans 1 8.79 466.1
186 6-(4-fluorophenyl)-5-(2-methylthiopyrimidine-4-yl)-2-[3-(tetrahydropyrans-2-base oxygen base) propyl group] pyrazolo [3,4-b] pyridine Embodiment 181 and 2-(3-bromine propoxy-) tetrahydropyrans 1 9.11 480.2
187 4, two (4-the fluorophenyl)-5-(2-methylthiopyrimidine-4-yl) of 6--2-[3-(tetrahydropyrans-2-base oxygen base) propyl group] pyrazolo [3,4-b] pyridine Embodiment 174 and 2-(3-bromine propoxy-) tetrahydropyrans 1 10.26 574.2
188 4-(5-bromothiophene-2-yl)-6-(4-fluorophenyl)-2-methyl-5-(4-pyridyl)-1H-pyrazolo [3,4-b] pyridine Embodiment 173 and methyl iodide 1 6.94 464.9 466.9
189 6-(4-fluorophenyl)-2-methyl-5-(2-methylthiopyrimidine-4-yl) pyrazolo [3,4-b] pyridine Embodiment 181 and methyl iodide 1 7.29 352.0
190 5-(2-chloropyridine-4-yl)-4, two (4-the fluorophenyl)-2-methylpyrazoles of 6-are [3,4-b] pyridine also Embodiment 175 and methyl iodide 1 8.55 433.0 435.0
191 6-(4-fluorophenyl)-4-(2-phenylethyl)-5-(4-pyridyl)-2-[3-(tetrahydropyrans-2-base oxygen base) propyl group] pyrazolo [3,4-b] pyridine Embodiment 176 and 2-(3-bromine propoxy-) tetrahydropyrans 1 7.74 537.0
192 4-(6-chloropyridine-3-yl)-6-(4-fluorophenyl)-5-(4-pyridyl)-2-[3-(tetrahydropyrans-2-base oxygen base) propyl group] pyrazolo [3,4-b] pyridine Embodiment 177 and 2-(3-bromine propoxy-) tetrahydropyrans 1 9.05 544.2 546.2
193 4-(6-fluorine pyridin-3-yl)-6-(4-fluorophenyl)-2-methyl-5-(4-pyridyl) pyrazolo [3,4-b] pyridine Embodiment 177 and methyl iodide 1 5.34 416.1 418.1
Embodiment 194
5-(2-methylthiopyrimidine-4-yl)-2-[3-(tetrahydropyrans-2-base oxygen base) propyl group]-6-(3-trifluoromethyl) pyrazolo [3,4-b] pyridine
According to embodiment 6 and 7 described similar technologies, but from 5-[2-(methylthio group) pyrimidine-4-yl]-6-[3-(trifluoromethyl) phenyl]-1H-pyrazolo [3,4-b] pyridine (obtaining in embodiment 126) and 2-(3-bromine propoxy-) tetrahydropyrans begin, and obtains title compound.
1H NMR (300MHz, CDCl 3) δ (TMS): 1.50-1.90 (m, 4H), 2.40 (sophisticated signal, 5H), 3.37-3.50 (m, 4H), 3.85 (m, 2H), 4.53 (m, 1H), 4.65 (m, 2H), 6.68 (d, J=5.1Hz, 1H), 7.40 (t, J=7.8Hz, 1H), 7.52 (d, J=7.6Hz, 1H), 7.61 (d, J=7.5Hz, 1H), 7.93 (s, 1H), 8.13 (s, 1H), 8.32 (d, J=5.1Hz, 1H), 8.49 (s, 1H).
Embodiment 195
6-(4-fluorophenyl)-2-methyl-5-(4-pyridyl)-4-[5-(3-pyridyl) thiophene-2-yl] pyrazolo [3,4-b] pyridine
With 4-(5-bromothiophene-2-yl)-6-(4-fluorophenyl)-2-methyl-5-(4-pyridyl)-1H-pyrazolo [3,4-b] pyridine (0.10g, 0.2mmol obtain in embodiment 188), 3-pyridyl boric acid (0.04g, 0.3mmol), K 2CO 3(0.06g, 0.4mmol), Pd (PPh 3) 4(0.017g, 0.01mmol), 1, suspension heated overnight under 80 ℃ of argon atmosphers of 2-glycol dimethyl ether (1.31ml) and water (0.04ml).Make its cooling, use CHCl 3Dilute with water.Merge organic phase, through Na 2SO 4Drying is concentrated into dried.The gained crude product uses to increase progressively polar hexane-EtOAc mixture as eluent through the silica gel chromatography purifying, obtains 35mg required compound (yield: 50%).
LC-MS (method 1): t R=5.42 minutes; M/z=464.0[M+H] +.
Embodiment 196-202
According to embodiment 91 described similar technologies, but use suitable initial compounds in each case, obtain the following table compound:
LC-MS
Embodiment The compound title Initial compounds Method t R(minute) m/z [M+H] +
196 2-[4,6-phenylbenzene-5-(4-pyridyl) pyrazolo [3,4-b] pyridine-2-yl] ethanol Embodiment 182 1 4.67 393.0
197 3-[5-(2-methylthiopyrimidine-4-yl)-6-(3-trifluoromethyl) pyrazolo [3,4-b] pyridine-2-yl] third-1-alcohol Embodiment 194 1 7.67 446.0
198 2-[6-(4-fluorophenyl)-5-(2-methylthiopyrimidine-4-yl) pyrazolo [3,4-b] pyridine-2-yl] ethanol Embodiment 185 1 6.58 382.0
199 3-[6-(4-fluorophenyl)-5-(2-methylthiopyrimidine-4-yl) pyrazolo [3,4-b] pyridine-2-yl] third-1-alcohol Embodiment 186 1 6.79 396.1
200 3-[4, two (4-fluorophenyl)-5-(2-methylthiopyrimidine-4-yl) pyrazolo [3, the 4-b] pyridines of 6--2-yl] third-1-alcohol Embodiment 187 1 8.10 490.2
201 3-[6-(4-fluorophenyl)-4-(2-phenylethyl)-5-(4-pyridyl) pyrazolo [3,4-b] pyridine-2-yl] third-1-alcohol Embodiment 191 1 5.80 453.2
202 3-[4-(6-chloropyridine-3-yl)-6-(4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3,4-b] pyridine-2-yl] third-1-alcohol Embodiment 192 1 5.88 460.2 462.2
Embodiment 203-207
According to embodiment 56 described similar technologies, but use suitable initial compounds in each case, obtain the following table compound:
LC-MS
Embodiment The compound title Initial compounds Method t R(minute) m/z [M+H] +
203 6-(4-fluorophenyl)-2-methyl-5-(2-methanesulfonyl pyrimidine-4-yl) pyrazolo [3,4-b] pyridine Embodiment 189 1 5.76 384.0
204 3-[5-(2-methanesulfonyl pyrimidine-4-yl)-6-(3-trifluoromethyl) pyrazolo [3,4-b] pyridine-2-yl] third-1-alcohol Embodiment 197 1 6.39 478.0
205 2-[6-(4-fluorophenyl)-5-(2-methanesulfonyl pyrimidine-4-yl) pyrazolo [3,4-b] pyridine-2-yl] ethanol Embodiment 198 1 5.28 414.0
206 3-[6-(4-fluorophenyl)-5-(2-methanesulfonyl pyrimidine-4-yl) pyrazolo [3,4-b] pyridine-2-yl] third-1-alcohol Embodiment 199 1 5.46 428.0
207 3-[4, two (4-fluorophenyl)-5-(2-methanesulfonyl pyrimidine-4-yl) pyrazolo [3, the 4-b] pyridines of 6--2-yl] third-1-alcohol Embodiment 200 1 6.76 522.2
Embodiment 208
N-cyclopropyl methyl-[4-[6-[3-(trifluoromethyl) phenyl]-1H-pyrazolo [3,4-b] pyridine-5-yl] pyrimidine-2-base] amine
With 5-[2-(methylsulfonyl) pyrimidine-4-yl]-6-[3-(trifluoromethyl) phenyl]-1H-pyrazolo [3; 4-b] pyridine (90mg; 0.2mmol, in embodiment 127, obtain) and (cyclopropyl methyl) amine (75mg, THF 1.0mmol) (2ml) solution heated overnight in 60 ℃ of encloses containers.Make its cooling, concentrate.The gained crude product uses to increase progressively polar hexane-EtOAc mixture as eluent through the silica gel chromatography purifying, obtains 57mg required compound (yield: 67%).
LC-MS (method 1): t R=8.12 minutes; M/z=411.0[M+H] +.
Embodiment 209-213
According to embodiment 208 described similar technologies, but use suitable initial compounds in each case, obtain the following table compound:
LC-MS
Embodiment The compound title Initial compounds Method t R(minute) m/z [M+H] +
209 (1S)-3-[5-[2-(1-phenylethyl amino) pyrimidine-4-yl]-6-(3-trifluoromethyl) pyrazolo [3,4-b] pyridine-2-yl] third-1-alcohol Embodiment 204 and (1S)-1-phenylethyl-1-amine 1 9.11 519.1
210 N-cyclopropyl methyl-[4-[6-(4-fluorophenyl)-2-methylpyrazole is [3,4-b] pyridine-5-yl also] pyrimidine-2-base] amine Embodiment 203 and (cyclopropyl methyl) amine 1 6.43 375.1
211 2-[5-[2-[(cyclopropyl methyl) amino] pyrimidine-4-yl]-6-(4-fluorophenyl) pyrazolo [3,4-b] pyridine-2-yl] ethanol Embodiment 205 and (cyclopropyl methyl) amine 1 5.85 405.1
212 3-[5-[2-[(cyclopropyl methyl) amino] pyrimidine-4-yl]-6-(4-fluorophenyl) pyrazolo [3,4-b] pyridine-2-yl] third-1-alcohol Embodiment 206 and (cyclopropyl methyl) amine 1 6.06 419.1
213 3-[5-[2-[(cyclopropyl methyl) amino] pyrimidine-4-yl]-4, two (4-fluorophenyl) pyrazolo [3, the 4-b] pyridines of 6--2-yl] third-1-alcohol Embodiment 207 and (cyclopropyl methyl) amine 1 7.63 513.3
Embodiment 214
4-[4-[4, two (4-the fluorophenyl)-2-methylpyrazoles of 6-are [3,4-b] pyridine-5-yl also] pyridine-2-base amino] benzsulfamide
With 5-(2-chloropyridine-4-yl)-4, two (4-the fluorophenyl)-2-methylpyrazoles of 6-also [3,4-b] pyridine (100mg, 0.23mmol obtain in embodiment 190) (46mg, mixture 0.27mmol) is 190 ℃ of following heated overnight with the 4-aminobenzene sulfonamide.Make its cooling, the gained crude product uses EtOAc as eluent through the silica gel chromatography purifying, obtains 23mg required compound (yield: 17%).
LC-MS (method 1): t R=6.91 minutes; M/z=569.0[M+H] +.
Embodiment 215-230
According to embodiment 72 described similar technologies, but use suitable initial compounds in each case, obtain the following table compound:
LC-MS
Embodiment The compound title Initial compounds Method t R(minute) m/z[M+H] +
215 4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--3-alcohol Reference example 1, the pure and mild 4-fluorobenzaldehyde of 5-amino-1H-pyrazoles-3- 1 5.02 401.1
216 6-(4-fluorophenyl)-4-(3H-imidazoles-4-yl)-5-(4-pyridyl)-1H-pyrazolo [3,4-b] pyridine Reference example 1,3-amino-2H-pyrazoles and 3H-imidazoles-4-formaldehyde 1 3.23 357.1
217 6-(4-fluorophenyl)-4-(1H-pyrazoles-3-yl)-5-(4-pyridyl)-1H-pyrazolo [3,4-b] pyridine Reference example 1,3-amino-2H-pyrazoles and 2H-pyrazoles-3-formaldehyde 1 4.24 357.1
218 3-[6-(4-fluorophenyl)-5-(4-pyridyl)-1H-pyrazolo [3,4-b] pyridine-4-yl] phenol Reference example 1,3-amino-2H-pyrazoles and 3-hydroxy benzaldehyde 1 4.99 383.1
219 4-cyclopropyl-6-(4-fluorophenyl)-5-(4-pyridyl)-1H-pyrazolo [3,4-b] pyridine Reference example 1,3-amino-2H-pyrazoles and cyclopanecarboxaldehyde 1 4.99 331.1
220 6-(4-fluorophenyl)-4-(5-methyl furan-2-yl)-5-(4-pyridyl)-1H-pyrazolo [3,4-b] pyridine Reference example 1,3-amino-2H-pyrazoles and 5-methyl furan-2-formaldehyde 1 8.45 445
221 4-(5-bromine furans-2-yl)-6-(4-fluorophenyl)-5-(4-pyridyl)-1H-pyrazolo [3,4-b] pyridine Reference example 1,3-amino-2H-pyrazoles and 5-methyl furan-2-formaldehyde 1 7.02 435.0 437.0
222 4-(4-benzyloxy phenyl)-6-(4-fluorophenyl)-2-methyl-5-pyrimidine-4-base-1H-pyrazolo [3,4-b] pyridine Reference example 30,3-amino-2H-pyrazoles and 4-benzyloxy phenyl aldehyde 1 9.05 474.1
223 4-(4-benzyloxy phenyl)-6-(4-fluorophenyl)-5-(2-methylthiopyrimidine-4- Reference example 19,3-amino-2H-pyrazoles and 4-benzyloxy phenyl aldehyde 1 10.52 520.1
Base)-1H-pyrazolo [3,4-b] pyridine
224 6-(4-fluorophenyl)-4-propyl group-5-(4-pyridyl)-1H-pyrazolo [3,4-b] pyridine Reference example 1,3-amino-2H-pyrazoles and butyraldehyde 1 5.42 333.0
225 4-(3-benzyloxy phenyl)-6-(4-fluorophenyl)-5-(4-pyridyl)-1H-pyrazolo [3,4-b] pyridine Reference example 1,3-amino-2H-pyrazoles and 3-benzyloxy phenyl aldehyde 1 8.00 473.2
226 5-(2-chloropyridine-4-yl)-6-(4-fluorophenyl)-1H-pyrazolo [3,4-b] pyridine Reference example 23,3-amino-2H-pyrazoles and paraformaldehyde 1 7.73 325.2 327.2
227 4-[6-(4-fluorophenyl)-5-(4-pyridyl)-1H-pyrazolo [3,4-b] pyridine-4-yl] fourth-1-alcohol Reference example 1,3-amino-2H-pyrazoles and 5-hydrogenation of hydroxypentylaldehyd, 1 4.23 363.2
228 4-benzyl-6-(4-fluorophenyl)-5-(4-pyridyl)-1H-pyrazolo [3,4-b] pyridine Reference example 1,3-amino-2H-pyrazoles and phenyl acetaldehyde 1 6.37 381.2
229 4-(4-benzyloxy phenyl)-6-(4-fluorophenyl)-2-methyl-5-(4-pyridyl)-1H-pyrazolo [3,4-b] pyridine Reference example 1,3-amino-2H-pyrazoles and 4-benzyloxy phenyl aldehyde 5,06(s，2H)，6.85(dd，J o＝1.5Hz， J m＝4.5Hz，2H)，6.91(m，4H)， 6.95(m，2H)，7.23-7.40(m，7H)， 8.01(s，1H)，8.35(dd，J o＝1.5Hz， J m=4.5Hz, 2H), 10.62 (wide s, 1 H, NH).
230 4, two (4-the fluorophenyl)-5-pyrimidines of 6--4-base-1H-pyrazolo [3,4-b] pyridine Reference example 30,3-amino-2H-pyrazoles and 4-fluorobenzaldehyde 6.92-7.08 (complicated unimodal, 5H), 7.23 (m, 2H), 7.32 (m, 2H), 7.99 (s, 1H), 8.45 (d, J=5.1Hz, 1H), 9.03 (s, 1H), 11.40 (wide s, 1H, NH).
Embodiment 231
[(2S)-and 2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--2-yl] ethyl] tetramethyleneimine-2-methane amide
A) [(2S)-and 2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--2-yl] ethyl]-1-(carbobenzoxy-(Cbz)) tetramethyleneimine-2-methane amide
According to embodiment 48 described similar technologies, but from 2-(2-amino-ethyl)-4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3,4-b] pyridines (obtaining in embodiment 90) of 6-and (2S)-1-(carbobenzoxy-(Cbz)) tetramethyleneimine-2-carboxylic acid begins, and obtains required compound.
LC-MS (method 1): t R=7.13 minutes; M/z=659.3[M+H] +.
B) title compound
According to embodiment 269 described similar technologies, but from [2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--2-yl] ethyl]-1-(carbobenzoxy-(Cbz)) tetramethyleneimine-2-methane amide (in a joint, obtaining) beginning, obtain title compound.
LC-MS (method 1): t R=4.35 minutes; M/z=525.2[M+H] +.
Embodiment 232
2-[2-(4,6-phenylbenzene-5-(4-pyridyl) pyrazolo [3,4-b] pyridine-2-yl) ethylamino] ethanol
A) 2-[4,6-phenylbenzene-5-(4-pyridyl) pyrazolo [3,4-b] pyridine-2-yl] the ethyl methane sulfonate ester
According to saving described similar technology to embodiment 12b, still from 2-[4,6-phenylbenzene-5-(4-pyridyl) pyrazolo [3,4-b] pyridine-2-yl] ethanol (in embodiment 196, obtaining) beginning, obtain required compound.
1H NMR (300MHz, CDCl 3) δ (TMS): 2.94 (s, 3H), 4.76 (m, 2H), 4.85 (m, 2H), 6.88 (d, J o=1.5Hz, J m=4.5Hz, 2H), 7.15-7.90 (sophisticated signal, 10H), 8.27 (s, 1H), 8.28 (dd, J o=1.5Hz, J m=4.5Hz, 2H).
B) title compound
According to embodiment 111 described similar technologies, but from 2-[4,6-phenylbenzene-5-(4-pyridyl) pyrazolo [3,4-b] pyridine-2-yl] ethyl methane sulfonate ester (obtaining in a joint) and 2-amino-1-ethanol begins, and obtains required compound.
LC-MS (method 1): t R=3.89 minutes; M/z=436.1[M+H] +.
Embodiment 233
6-(4-fluorophenyl)-2-methyl-4-(3-pyridyl)-5-(4-pyridyl) pyrazolo [3,4-b] pyridine
Under argon atmospher, to 4-(6-chloropyridine-3-yl)-6-(4-fluorophenyl)-2-methyl-5-(4-pyridyl) pyrazolo [3,4-b] pyridine (74mg, 0.2mmol, in embodiment 193, obtain) AcOH (1ml) solution in add Zn (72mg, 1.1mmol), mixture heating up is spent the night to refluxing.Make its cooling, concentrate.With the saturated NaHCO of resistates 3Handle, use CHCl 3Extraction.With organic phase through Na 2SO 4Drying is concentrated into dried.The gained crude product uses to increase progressively polar hexane-EtOAc-MeOH mixture as eluent through the silica gel chromatography purifying, obtains 2.4mg title compound (yield: 4%).
LC-MS (method 1): t R=4.02 minutes; M/z=382.2[M+H] +.
Embodiment 234-235
According to saving described similar technology to reference example 15c, still use suitable initial compounds in each case, obtain the following table compound:
LC-MS
Embodiment The compound title Initial compounds Method t R(minute) m/z [M+H] +
234 6-(4-fluorophenyl)-3-methyl-5-(2-methylthiopyrimidine-4-yl)-1H-pyrazolo [3,4-b] pyridine A reference example 29 and a hydrazine hydrate 1 8.57 352.0
235 3-amino-5-(2-methylthiopyrimidine-4-yl)-6-phenyl-1H-pyrazolo [3,4-b] pyridine A reference example 28 and a hydrazine hydrate 1 6.55 335.0
Embodiment 236-237
According to embodiment 77 described similar technologies, but use suitable initial compounds in each case, obtain the following table compound:
LC-MS
Embodiment The compound title Initial compounds Method t R(minute) m/z [M+H] +
236 5-(2-methylthiopyrimidine-4-yl)-6-phenyl-1H-pyrazolo [3,4-b] pyridine Embodiment 235 1 7.54 320.0
237 6-(4-fluorophenyl)-4-methyl-5-(2-methylthiopyrimidine-4-yl)-1H-pyrazolo [3,4-b] pyridine Embodiment 147 1 4.42 305.0
Embodiment 238
5-(2-methoxy pyrimidine-4-yl)-6-(3-trifluoromethyl)-1H-pyrazolo [3,4-b] pyridine
In encloses container; to 5-[2-(methylsulfonyl) pyrimidine-4-yl]-6-[3-(trifluoromethyl) phenyl]-1H-pyrazolo [3; 4-b] pyridine (90mg; 0.2mmol; in embodiment 127, obtain) MeOH (5ml) solution in add sodium methylate (11mg; 0.2mmol), be heated to 60 ℃ and reach 24 hours.(11mg 0.2mmol), stirred other 2 hours down at 60 ℃ to add sodium methylate then.Make its cooling, concentrate.Add EtOAc and damping fluid (pH=5.3).Separate each phase, organic phase is washed with water, through Na 2SO 4Drying is concentrated into dried.The gained crude product uses 50% hexane-EtOAc mixture wash-out through the silica gel chromatography purifying, obtains 38mg title compound (yield: 47%).
LC-MS (method 1): t R=7.71 minutes; M/z=372.0[M+H] +.
Embodiment 239-242
According to saving described similar technology to reference example 1a, still use suitable initial compounds in each case, obtain the following table compound:
LC-MS
Embodiment The compound title Initial compounds Method t R(minute) m/z [M+H] +
239 N-[2-[4,6-phenylbenzene-5-(4-pyridyl) pyrazolo [3,4-b] pyridine-2-yl] ethyl] ethanamide Embodiment 142 and Acetyl Chloride 98Min. 1 5.34 434.1
240 N-[3-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--2-yl] propyl group] ethanamide Embodiment 95 and Acetyl Chloride 98Min. 1 5.31 484.1
241 N-[2-[4,6-phenylbenzene-5-(4-pyridyl) pyrazolo [3,4-b] pyridine-2-yl] ethyl]-N-(2-hydroxyethyl) ethanamide Embodiment 232 and Acetyl Chloride 98Min. 1 5.27 478.1
242 N-[2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--2-yl] ethyl] propionic acid amide Embodiment 90 and propionyl fluoride 1 5.39 484.1
Embodiment 243
N-[3-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--2-yl] propyl group] Toluidrin
According to embodiment 169 described similar technologies, but from 2-(3-aminopropyl)-4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3,4-b] pyridines (obtaining in the embodiment 95) beginnings of 6-obtain required compound.
LC-MS (method 1): t R-5.79 minutes; M/z=520.1[M+H] +.
Embodiment 244
5-(2-aminopyrimidine-4-yl)-6-(3-trifluoromethyl)-1H-pyrazolo [3,4-b] pyridine
In encloses container, will under-20 ℃, use NH 3(g) saturated THF (20ml) solution joins 5-[2-(methylsulfonyl) pyrimidine-4-yl]-6-[3-(trifluoromethyl) phenyl]-1H-pyrazolo [3,4-b] pyridine (90mg, 0.2mmol obtain in embodiment 127).At room temperature stirred 2 days, and concentrated.The gained crude product uses to increase progressively polar hexane-EtOAc mixture as eluent through the silica gel chromatography purifying, obtains 7mg title compound (yield: 9%).
LC-MS (method 1): t R=6.01 minutes; M/z=357.0[M+H] +.
Embodiment 245
N-[5-(2-methylthiopyrimidine-4-yl)-6-(3-trifluoromethyl)-1H-pyrazolo [3,4-b] pyridin-3-yl] ethanamide
With 3-amino-5-[2-(methylthio group) pyrimidine-4-yl]-6-[3-(trifluoromethyl) phenyl]-1H-pyrazolo [3,4-b] pyridine (200mg, 0.5mmol, in embodiment 123, obtain) and (39mg, pyridine 0.5mmol) (10ml) solution at room temperature stirred 3 hours with Acetyl Chloride 98Min..Concentrate, resistates is dissolved in the mixture of EtOAc and 1N NaOH.With organic phase through Na 2SO 4Drying is concentrated into dried.The gained crude product uses to increase progressively polar hexane-EtOAc mixture as eluent through the silica gel chromatography purifying, obtains 78mg title compound (yield: 37%).
LC-MS (method 1): t R=8.55 minutes; M/z=445.0[M+H] +.
Embodiment 246
N-cyclopropyl methyl-[4-[3-benzyloxycarbonyl amino-6-(3-trifluoromethyl)-1H-pyrazolo [3,4-b] pyridine-5-yl] pyrimidine-2-base] amine
A) N-carbobenzoxy-(Cbz)-[5-(2-methylthiopyrimidine-4-yl)-6-(3-trifluoromethyl)-1H-pyrazolo [3,4-b] pyridin-3-yl] amine
According to embodiment 245 described similar technologies, but from 3-amino-5-[2-(methylthio group) pyrimidine-4-yl]-6-[3-(trifluoromethyl) phenyl]-1H-pyrazolo [3,4-b] pyridine (obtaining in embodiment 123) and benzyl chloroformate begin, and obtains required compound.
LC-MS (method 1): t R=10.00 minutes; M/z=537.1[M+H] +.
B) N-carbobenzoxy-(Cbz)-[5-(2-methanesulfonyl pyrimidine-4-yl)-6-(3-trifluoromethyl)-1H-pyrazolo [3,4-b] pyridin-3-yl] amine
According to embodiment 56 described similar technologies, but from N-carbobenzoxy-(Cbz)-[5-(2-methylthiopyrimidine-4-yl)-6-(3-trifluoromethyl)-1H-pyrazolo [3,4-b] pyridin-3-yl] amine (in a joint, obtaining) beginning, obtain required compound.
LC-MS (method 1): t R=8.47 minutes; M/z=567.1[M+H] +.
C) title compound
According to embodiment 208 described similar technologies; but from N-carbobenzoxy-(Cbz)-[5-(2-methanesulfonyl pyrimidine-4-yl)-6-(3-trifluoromethyl)-1H-pyrazolo [3; 4-b] pyridin-3-yl] amine (obtaining in b joint) and (cyclopropyl methyl) amine begins, and obtains required compound.
LC-MS (method 1): t R=9.44 minutes; M/z=560.3[M+H] +.
Embodiment 247
N-[2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--2-yl] ethyl]-the 2-hydroxyl acetamide
According to embodiment 48 described similar technologies, but from 2-(2-amino-ethyl)-4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3,4-b] pyridines (obtaining in embodiment 90) of 6-and oxyacetic acid begin, and obtain title compound.
LC-MS (method 1): t R=4.84 minutes; M/z=486.1[M+H] +.
Embodiment 248
N-[2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--2-yl] ethyl] piperidines-4-methane amide
A) N-[2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--2-yl] ethyl]-1-(tertbutyloxycarbonyl) piperidines-4-methane amide
According to embodiment 48 described similar technologies, but from 2-(2-amino-ethyl)-4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines (obtaining in embodiment 90) of 6-and 1-(tertbutyloxycarbonyl) piperidines-4-carboxylic acid begin, and obtain required compound.
B) title compound
According to embodiment 36 described similar technologies, but from N-[2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--2-yl] ethyl]-1-(tertbutyloxycarbonyl) piperidines-4-methane amide (in a joint, obtaining) beginning, obtain title compound.
LC-MS (method 1): t R=4.29 minutes; M/z=539.2[M+H] +.
Embodiment 249
N-(2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--2-yl] ethyl]-2-(methylamino) ethanamide
A) N-[2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--2-yl] ethyl]-the 2-chlor(o)acetamide
According to saving described similar technology to reference example 1a, still from 2-(2-amino-ethyl)-4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3,4-b] pyridines (obtaining in embodiment 90) of 6-and chloroacetyl chloride begin, and obtain title compound.
LC-MS (method 1): t R=5.72 minutes; M/z=504.1,506.1[M+H] +.
B) title compound
According to embodiment 78 described similar technologies, but from N-[2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--2-yl] ethyl]-2-chlor(o)acetamide (obtaining in a joint) and methylamine begin, and obtains title compound.
LC-MS (method 1): t R=4.28 minutes; M/z=499.2[M+H] +.
Embodiment 250
N-[2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--2-yl] ethyl]-2-(2-hydroxyethyl amino) ethanamide
According to embodiment 78 described similar technologies, but from N-[2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--2-yl] ethyl]-2-chlor(o)acetamide (obtaining in embodiment 249a joint) and 2-monoethanolamine begin, and obtains title compound.
LC-MS (method 1): t R=4.29 minutes; M/z=529.2[M+H] +.
Embodiment 251
N-[2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--2-yl] ethyl] niacinamide
A) nicotinoyl chlorine hydrochloride
With nicotinic acid (0.50g, 4.0mmol) and POCl 3Solution (5ml) heated 1.5 hours under refluxing, and concentrated.Products therefrom is directly used in following reaction.
B) title compound
According to embodiment 245 described similar technologies, but from 2-(2-amino-ethyl)-4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3,4-b] pyridines (obtaining in embodiment 90) of 6-and nicotinoyl chlorine hydrochloride (obtaining in a joint) beginning obtains title compound.
LC-MS (method 1): t R=5.25 minutes; M/z=533.1[M+H] +.
Embodiment 252-265
According to embodiment 6 and 7 described similar technologies, but in each case from suitable compound, obtain the following table compound:
Embodiment The compound title Initial compounds LC-MS
Method t R(minute) m/z[M+H] +
252 4-(4-benzyloxy phenyl)-6-(4-fluorophenyl)-2-methyl-5-(4-pyridyl) pyrazolo [3,4-b] pyridine Embodiment 229 and methyl iodide 1 7.53 487.1
253 6-(4-fluorophenyl)-5-(2-methylthiopyrimidine-4-yl)-2-methylpyrazole is [3,4-b] pyridine also Embodiment 181 and methyl iodide 1 7.13 352.1
254 6-(4-fluorophenyl)-2,4-dimethyl-5-(4-pyridyl) pyrazolo [3,4-b] pyridine Embodiment 237 and methyl iodide 1 4.11 319.00
255 4-(4-benzyloxy phenyl)-6-(4-fluorophenyl)-2-methyl-5-(2-methylthiopyrimidine-4-yl) pyrazolo [3,4-b] pyridine Embodiment 223 and methyl iodide 1 10.16 534.2
256 2-(1-benzyl-pyrrole alkane-2-ylmethyl)-4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6- Embodiment 1 and 1-benzyl-2-chloromethyl tetramethyleneimine 1 6.10 558.2
257 4-(4-benzyloxy phenyl)-6-(4-fluorophenyl)-2- Embodiment 222 and iodo first 1 8.72 488.2
Methyl-5-pyrimidine-4-base pyrazolo [3,4-b] pyridine Alkane
258 6-(4-fluorophenyl)-2-methyl-4-(5-methyl furan-2-yl)-5-(4-pyridyl) pyrazolo [3,4-b] pyridine Embodiment 220 and methyl iodide 1 5.85 385.0
259 4-(5-bromine furans-2-yl)-6-(4-fluorophenyl)-2-methyl-5-(4-pyridyl) pyrazolo [3,4-b] pyridine Embodiment 221 and methyl iodide 1 6.48 449.1 451.1
260 6-(4-fluorophenyl)-2-methyl-4-propyl group-5-(4-pyridyl) pyrazolo [3,4-b] pyridine Embodiment 224 and methyl iodide 1 4.88 347.0
261 4-(3-benzyloxy phenyl)-6-(4-fluorophenyl)-2-methyl-5-(4-pyridyl) pyrazolo [3,4-b] pyridine Embodiment 225 and methyl iodide 1 7.79 487.0
262 6-(4-fluorophenyl)-4-(2-phenylethyl)-2-methyl-5-(4-pyridyl) pyrazolo [3,4-b] pyridine Embodiment 176 and methyl iodide 1 5.94 409.0
263 5-(2-chloropyridine-4-yl)-6-(4-fluorophenyl)-2-methylpyrazole is [3,4-b] pyridine also Embodiment 226 and methyl iodide 1 7.30 339.2 341.2
264 4-benzyl-6-(4-fluorophenyl)-2-methyl-5-(4-pyridyl) pyrazolo [3,4-b] pyridine Embodiment 228 and methyl iodide 1 5.95 395.2
265 4-[6-(4-fluorophenyl)-2-methyl-5-(4-pyridyl) pyrazolo [3,4-b] pyridin-4-yl] fourth-1-alcohol Embodiment 227 and methyl iodide 1 3.69 377.2
Embodiment 266
4-[6-(4-fluorophenyl)-2-methyl-5-(4-pyridyl) pyrazolo [3,4-b] pyridin-4-yl] phenol
To 4-(4-benzyloxy phenyl)-6-(4-fluorophenyl)-2-methyl-5-(4-pyridyl) pyrazolo [3,4-b] pyridine (112mg, 0.2mmol, in embodiment 252, obtain) EtOH (13ml) solution in add 10%Pd/C (20mg), depressed hydrogenation 2 days in the atmosphere of room temperature.By diatomite filtration,, concentrate with the EtOH washing.The gained crude product uses to increase progressively polar hexane-EtOAc-MeOH mixture as eluent through the silica gel chromatography purifying, obtains 61mg title compound (yield: 67%).
LC-MS (method 1): t R=4.65 minutes; M/z=397.1[M+H] +.
Embodiment 267
N-[6-(4-fluorophenyl)-5-(2-methylthiopyrimidine-4-yl)-1H-pyrazolo [3,4-b] pyridin-3-yl] ethanamide
According to embodiment 245 described similar technologies, but begin from 3-amino-6-(4-fluorophenyl)-5-(2-methylthiopyrimidine-4-yl) pyrazolo [3,4-b] pyridine (in embodiment 180, obtaining) and Acetyl Chloride 98Min., obtain title compound.
LC-MS (method 1): t R=7.01 minutes; M/z=395.1[M+H] +.
Embodiment 268
N-[5-[2-[(cyclopropyl methyl) amino] pyrimidine-4-yl]-6-(4-fluorophenyl)-1H-pyrazolo [3,4-b] pyridin-3-yl] ethanamide
A) N-[6-(4-fluorophenyl)-5-(2-methanesulfonyl pyrimidine-4-yl)-1 H-pyrazolo [3; 4-b] pyridin-3-yl] ethanamide and N-[6-(4-fluorophenyl)-5-(2-methanesulfonyl pyrimidine-4-yl)-1H-pyrazolo [3,4-b] pyridin-3-yl] ethanamide 7-oxide compound
According to embodiment 56 described similar technologies, but from N-[6-(4-fluorophenyl)-5-(2-methylthiopyrimidine-4-yl)-1H-pyrazolo [3,4-b] pyridin-3-yl] ethanamide (in embodiment 267, obtaining) beginning, and use between 2 equivalents-the chlorine peroxybenzoic acid, obtain title compound.
N-[6-(4-fluorophenyl)-5-(2-methanesulfonyl pyrimidine-4-yl)-1H-pyrazolo [3,4-b] pyridin-3-yl] ethanamide: LC-MS (method 1): t R=5.64 minutes; M/z=427.1[M+H] +.
N-[6-(4-fluorophenyl)-5-(2-methanesulfonyl pyrimidine-4-yl)-1H-pyrazolo [3,4-b] pyridin-3-yl] ethanamide 7-oxide compound: LC-MS (method 1): t R=4.44 minutes; M/z=443.0[M+H] +.
B) title compound
According to embodiment 208 described similar technologies; but from N-[6-(4-fluorophenyl)-5-(2-methanesulfonyl pyrimidine-4-yl)-1H-pyrazolo [3; 4-b] pyridin-3-yl] ethanamide (obtaining in a joint) and (cyclopropyl methyl) amine begins, and obtains title compound.
LC-MS (method 1): t R=6.19 minutes; M/z=418.1[M+H] +.
Embodiment 269
3-[6-(4-fluorophenyl)-4-(2-furyl)-5-(4-pyridyl) pyrazolo [3,4-b] pyridine-2-yl] third-1-alcohol
A) 6-(4-fluorophenyl)-4-(2-furyl)-5-(4-pyridyl)-2-[3-(tetrahydropyrans-2-base oxygen base) propyl group] pyrazolo [3,4-b] pyridine
According to embodiment 6 and 7 described similar technologies, but from 6-(4-fluorophenyl)-4-(2-furyl)-5-(4-pyridyl)-1H-pyrazolo [3,4-b] pyridine (obtaining in embodiment 171) and 2-(3-bromine propoxy-) tetrahydropyrans begin, and obtains required compound.
LC-MS (method 1): t R=7.19 minutes; M/z=499.2[M+H] +.
B) title compound
According to embodiment 91 described similar technologies, but from 6-(4-fluorophenyl)-4-(2-furyl)-5-(4-pyridyl)-2-[3-(tetrahydropyrans-2-base oxygen base) propyl group] pyrazolo [3,4-b] pyridine (in a joint, obtaining) beginning, obtain title compound.
LC-MS (method 1): t R=5.05 minutes; M/z=415.1[M+H] +.
Embodiment 270-278
According to embodiment 269 described similar technologies, but in each case from suitable compound, obtain the following table compound:
Embodiment The compound title Initial compounds LC-MS
Method t R(minute) m/z [M+H] +
270 2-[4-(4-benzyloxy phenyl)-6-(4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3,4-b] pyridine-2-yl] ethanol Embodiment 229 and 2-(2-bromine oxethyl) tetrahydropyrans 1 6.76 517.2
271 3-[4-(4-benzyloxy phenyl)-6-(4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3,4-b] pyridine-2-yl] third-1-alcohol Embodiment 229 and 2-(3-bromine propoxy-) tetrahydropyrans 1 6.91 531.2
272 3-[6-(4-fluorophenyl)-4-(5-methyl furan-2-yl)-5-(4-pyridyl) pyrazolo [3,4-b] pyridine-2-yl] third-1-alcohol Embodiment 220 and 2-(3-bromine propoxy-) tetrahydropyrans 1 5.42 429.1
273 3-[4-cyclopropyl-6-(4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3,4-b] pyridine-2-yl] third-1-alcohol Embodiment 219 and 2-(3-bromine propoxy-) tetrahydropyrans 1 4.40 389.1
274 3-[4-(5-bromothiophene-2-yl)-6-(4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3,4-b] pyridine-2-yl] third-1-alcohol Embodiment 173 and 2-(3-bromine propoxy-) tetrahydropyrans 1 6.25 508.9 510.9
275 3-[6-(4-fluorophenyl)-4-propyl group-5-(4-pyridyl) pyrazolo [3,4-b] pyridine-2-yl] third-1-alcohol Embodiment 224 and 2-(3-bromine propoxy-) tetrahydropyrans 1 4.90 391.2
276 3-[4, two (4-the fluorophenyl)-5-pyrimidines of 6--4-base pyrazolo [3,4-b] pyridine-2-yl] third-1-alcohol Embodiment 230 and 2-(3-bromine propoxy-) tetrahydropyrans 1 6.56 444.2
277 3-[4-(3-benzyloxy phenyl)-6-(4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3,4-b] pyridine-2-yl] third-1-alcohol Embodiment 225 and 2-(3-bromine propoxy-) tetrahydropyrans 1 7.03 531.3
278 3-[4-benzyl-6-(4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3,4-b] pyridine-2-yl] third-1-alcohol Embodiment 228 and 2-(3-bromine propoxy-) tetrahydropyrans 1 5.27 439.2
Embodiment 279-285
According to embodiment 268 described similar technologies, but in each case from suitable compound and the amine that is fit to, obtain the following table compound:
Embodiment The compound title Initial compounds Amine LC-MS
Method t R(minute) m/z [M+H] +
279 (1S)-and N-(1-phenylethyl)-[4-[6-(4-fluorophenyl)-3-methyl isophthalic acid H-pyrazolo [3,4-b] pyridine-5-yl] pyrimidine-2-base] amine Embodiment 234 (1S)-the 1-phenyl ethyl amine 1 9.32 425.1
280 N-cyclopropyl methyl-[4-[6-(4-fluorobenzene Embodiment (cyclopropyl 2 5.54 373.2
Base)-and 3-methyl isophthalic acid H-pyrazolo [3,4-b] pyridine-5-yl] pyrimidine-2-base] amine 234 Methyl) amine
281 1-[4-[6-(4-fluorophenyl)-2-methylpyrazole is [3,4-b] pyridine-5-yl also] pyrimidine-2--amino] propane-2-alcohol Embodiment 253 1-aminopropane-2-alcohol 1 4.73 379.2
282 N-cyclopropyl methyl-4-[6-[phenyl-1H-pyrazolo [3,4-b] pyridine-5-yl] pyrimidine-2-base] amine Embodiment 236 (cyclopropyl methyl) amine 1 7.53 343.1
283 2-[4-[6-(4-fluorophenyl)-2-methylpyrazole is [3,4-b] pyridine-5-yl also] pyrimidine-2--amino] third-1-alcohol Embodiment 253 2-amino third-1-alcohol 1 4.74 379.1
284 4-[4-[6-(4-fluorophenyl)-2-methylpyrazole is [3,4-b] pyridine-5-yl also] pyrimidine-2--amino] fourth-1-alcohol Embodiment 253 The amino fourth of 4--1-alcohol 1 4.61 393.2
285 (1S)-and N-(1-phenylethyl)-[4-[6-phenyl-1 H-pyrazolo [3,4-b] pyridine-5-yl] pyrimidine-2-base] amine Embodiment 236 (1S)-the 1-phenyl ethyl amine 1 8.10 393.1
Embodiment 286-290
According to embodiment 208 described similar technologies, but in each case from suitable compound, obtain the following table compound:
Embodiment The compound title Initial compounds LC-MS
Method t R(minute) m/z [M+H] +
286 N-(3-methoxy-propyl)-[4-[6-(3-trifluoromethyl)-1H-pyrazolo [3,4-b] pyridine-5-yl] pyrimidine-2-base] amine Embodiment 127 and 3-METHOXY PROPYL AMINE 1 7.14 429.1
287 3-[4-[6-(3-trifluoromethyl)-1H-pyrazolo [3,4-b] pyridine-5-yl] pyrimidine-2--amino] third-1-alcohol Embodiment 127 and 3-amino third-1-alcohol 1 5.91 415.1
288 3-[4-[6-(4-fluorophenyl)-2-(3-hydroxypropyl) pyrazolo [3,4-b] pyridine-5-yl] pyrimidine-2--amino] third-1-alcohol Embodiment 206 and 3-amino third-1-alcohol 1 4.55 423.1
289 N-ethyl-[4-[6-(3-trifluoromethyl)-1H-pyrazolo [3,4-b] pyridine-5-yl] pyrimidine-2-base] amine Embodiment 127 and ethamine 1 7.21 385.0
290 N-benzyl-[4-[6-(3-trifluoromethyl)-1H-pyrazolo [3,4-b] pyridine-5-yl] pyrimidine-2-base] amine Embodiment 127 and benzylamine 1 8.86 447.1
Embodiment 291
4-[5-[2-[(cyclopropyl methyl) amino] pyrimidine-4-yl]-6-(4-fluorophenyl)-2-methylpyrazole [3,4-b] pyridin-4-yl also] phenol
A) 4-(4-benzyloxy phenyl)-6-(4-fluorophenyl)-5-(2-methanesulfonyl pyrimidine-4-yl)-2-methylpyrazole [3,4-b] pyridine also
According to embodiment 56 described similar technologies, but from 4-(4-benzyloxy phenyl)-6-(4-fluorophenyl)-2-methyl-5-(2-methylthiopyrimidine-4-yl) pyrazolo [3,4-b] pyridine (in embodiment 255, obtaining) beginning, obtain required compound.
LC-MS (method 1): t R=8.77 minutes; M/z=566.2[M+H] +.
B) 4-[6-(4-fluorophenyl)-5-(2-methanesulfonyl pyrimidine-4-yl)-2-methylpyrazole [3,4-b] pyridin-4-yl also] phenol
According to embodiment 266 described similar technologies, but from 4-(4-benzyloxy phenyl)-6-(4-fluorophenyl)-2-methyl-5-(2-methanesulfonyl pyrimidine-4-yl) pyrazolo [3,4-b] pyridine (in a joint, obtaining) beginning, obtain required compound.
LC-MS (method 1): t R=6.17 minutes; M/z=476.1[M+H] +.
C) title compound
According to embodiment 128 described similar technologies; but from 4-[6-(4-fluorophenyl)-5-(2-methanesulfonyl pyrimidine-4-yl)-2-methylpyrazole also [3; 4-b] pyridin-4-yl] phenol (obtaining in b joint) and (cyclopropyl methyl) amine begins, and obtains title compound.
LC-MS (method 1): t R=6.62 minutes; M/z=467.2[M+H] +.
Embodiment 292-295
According to embodiment 266 described similar technologies, but in each case from suitable compound, obtain the following table compound:
Embodiment The compound title Initial compounds LC-MS
Method t R(minute) m/z [M+H] +
292 4-[6-(4-fluorophenyl)-2-(3-hydroxypropyl)-5-(4-pyridyl) pyrazolo [3,4-b] pyridin-4-yl] phenol Embodiment 271 1 4.41 441.1
293 4-[6-(4-fluorophenyl)-2-methyl-5-(pyrimidine-4-yl) pyrazolo [3,4-b] pyridin-4-yl] phenol Embodiment 257 1 5.71 398.1
294 3-[6-(4-fluorophenyl)-2-(3-hydroxypropyl)-5-(4-pyridyl) pyrazolo [3,4-b] pyridin-4-yl] phenol Embodiment 277 1 4.54 441.2
295 3-[6-(4-fluorophenyl)-2-methyl-5-(4-pyridyl) pyrazolo [3,4-b] pyridin-4-yl] phenol Embodiment 261 1 4.74 397.0
Embodiment 296
4, two (4-the fluorophenyl)-5-(4-pyridyl) of 6--2-(tetramethyleneimine-2-ylmethyl) pyrazolo [3,4-b] pyridine
To 2-(1-benzyl-pyrrole alkane-2-ylmethyl)-4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolos [3 of 6-, 4-b] pyridine (83mg, 0.1mmol, in embodiment 259, obtain) EtOH (6.9ml) solution in add 10%Pd/C (8mg) and formic acid (0.34ml), heating is 2 hours under refluxing.Make its cooling,,, concentrate with the EtOH washing by diatomite filtration.The gained crude product uses to increase progressively polar hexane-EtOAc-MeOH-NH through the silica gel chromatography purifying 3Mixture obtains 40mg title compound (yield: 57%) as eluent.
LC-MS (method 1): t R=4.98 minutes; M/z=468.1[M+H] +.
Embodiment 297
4-[4-[6-(4-fluorophenyl)-2-methylpyrazole is [3,4-b] pyridine-5-yl also] pyridine-2-base aminobenzene sulfonamide
According to embodiment 214 described similar technologies, but from 5-(2-chloropyridine-4-yl)-6-(4-fluorophenyl)-2-methylpyrazole also [3,4-b] pyridine (in embodiment 263, obtaining) and 4-aminobenzene sulfonamide begin, obtain title compound.
LC-MS (method 1): t R=5.36 minutes; M/z=475.3[M+H] +.
Embodiment 298
N-[5-[2-[(cyclopropyl methyl) amino] pyrimidine-4-yl]-6-(4-fluorophenyl)-1H-pyrazolo [3,4-b] pyridin-3-yl] ethanamide 7-oxide compound
According to embodiment 208 described similar technologies; but from N-[6-(4-fluorophenyl)-5-(2-methanesulfonyl pyrimidine-4-yl)-1H-pyrazolo [3; 4-b] pyridin-3-yl] ethanamide 7-oxide compound (obtaining in embodiment 268a joint) and (cyclopropyl methyl) amine begins, and obtains title compound.
LC-MS (method 1): t R=5.45 minutes; M/z=434.2[M+H] +.
Embodiment 299
N-[6-(4-fluorophenyl)-5-(4-pyridyl)-1H-pyrazolo [3,4-b] pyridin-3-yl] Isonicotinamide
A) different nicotinoyl chlorine hydrochloride
(0.10g 0.8mmol) is heated to reflux with the solution of thionyl chloride (1ml) and reaches 2 hours, concentrates with Yi Yansuan.Products therefrom is used for next step immediately.
B) title compound
In volumetric flask, under argon atmospher, introduce 3-amino-6-(4-fluorophenyl)-5-(4-pyridyl)-1H-pyrazolo [3,4-b] pyridine (0.20g, 0.7mmol, in embodiment 70, obtain), different nicotinoyl chlorine hydrochloride (0.12g, 0.7mmol obtain in a joint) and pyridine (1ml).At room temperature stirred 2 days.Concentrate, resistates is dissolved in CHCl 3Mixture with 1N HCl.Separate each phase, water CHCl 3Extraction (x2).Slowly add 1N NaOH alkalization to aqueous phase.Add salt solution, use CHCl 3Extract with EtOAc.With organic phase through Na 2SO 4Drying is concentrated into dried.The gained crude product uses to increase progressively polar CHCl through the silica gel chromatography purifying 3-MeOH mixture obtains 98mg title compound (yield: 68%) as eluent.
LC-MS (method 1): t R=4.21 minutes; M/z=411.1[M+H] +.

Claims (37)

1, compound of Formula I
Figure C2004800053900002C1
Wherein:
A represents N or N +O -
R 1Represent phenyl or Het, alternatively by one or more R that are selected from aAnd R bSubstituting group replace;
R 2Represent Het, alternatively by one or more R that are selected from aAnd R bSubstituting group replace;
R 3Represent H, Cy, described Cy is alternatively by one or more R that are selected from aAnd R bSubstituting group replace perhaps R 3Represent C 1-6Alkyl is alternatively by one or more R that are selected from bReplace with the substituting group of Cy*, wherein Cy* can be alternatively by one or more R that are selected from bAnd R cSubstituting group replace;
R 4Represent H, R a, halogen ,-OR a' ,-OCOR a,-OSO 2R a,-OCONR aR a' ,-NO 2,-CN ,-COR a' ,-CO 2R a' ,-CONR a' R a' ,-NR a' R a' ,-NR a' COR a' ,-NR a' CONR a' R a' ,-NR a' CO 2R a,-NR a' SO 2R a,-SR a', SOR a,-SO 2R aOr-SO 2NR a' R a';
R 52 N that can be positioned at formula I pyrazoles ring represent H or R on any f
Each R aRepresent C independently 1-6Alkyl, C 2-6Thiazolinyl, C 2-6Alkynyl or Cy, wherein this C 1-6Alkyl, C 2-6Thiazolinyl or C 2-6Alkynyl can be alternatively by one or more R that are selected from bReplace with the substituting group of Cy*, wherein any of group Cy or Cy* can be alternatively by one or more R that are selected from bAnd R cSubstituting group replace;
Each R a' represent H or R independently a
Each R bRepresent independently halogen ,-OR c' ,-OCOR c,-OSO 2R c,-OCONR cR c' ,-NO 2,-CN ,-COR c' ,-CO 2R c' ,-CONR c' R c' ,-CONR c' NR c' R c' ,-NR c' R c' ,-NR c' COR c' ,-NR c' CONR c' R c' ,-NR c' CO 2R c,-NR c' SO 2R c,-SR c' ,-SOR c,-SO 2R c,-SO 2NR c' R c' ,-C (NR c') NR c' R c' ,-C (NSO 2NR c' R c') NR c' R c' ,-C (NOR c') R c' ,-C (NNR c' R c') R c' ,-NR c' C (NR c') NR c' R c' or-NR c' C (NCN) NR c' R c';
Each R cRepresent C independently 1-6Alkyl, C 2-6Thiazolinyl, C 2-6Alkynyl or Cy, wherein all these groups can be alternatively by one or more substituent R dReplace;
Each R c' represent H or R independently c
Each R dRepresent halogen, R independently e,-OR e' ,-OCOR e,-OSO 2R e,-OCONR eR e' ,-NO 2,-CN ,-COR e' ,-CO 2R e' ,-CONR e' R e' ,-CONR e' NR e' R e' ,-NR e' R e' ,-NR e' COR e' ,-NR e' CONR e' R e' ,-NR e' CO 2R e,-NR e' SO 2R e,-SR e' ,-SOR e,-SO 2R e,-SO 2NR e' R e' ,-C (NR e') NR e' R e' ,-C (NSO 2NR e' R e') NR e' R e' ,-C (NOR e') R e' ,-C (NNR e' R e') R e' ,-NR e' C (NR e') NR e' R e' ,-NR e' C (NCN) NR e' R e' or Cy, described Cy is replaced by one or more substituting groups alternatively, and substituting group is selected from halogen, R e,-OR e' ,-OCOR e,-OSO 2R e,-OCONR eR e' ,-NO 2,-CN ,-COR e' ,-CO 2R e' ,-CONR e' R e' ,-CONR e' NR e' R e' ,-NR e' R e' ,-NR e' COR e' ,-NR e' CONR e' R e' ,-NR e' CO 2R e,-NR e' SO 2R e,-SR e' ,-SOR e,-SO 2R e,-SO 2NR e' R e' ,-C (NR e') NR e' R e' ,-C (NSO 2NR e' R e') NR e' R e' ,-C (NOR e') R e' ,-C (NNR e' R e') R e' ,-NR e' C (NR e') NR e' R e' and-NR e' C (NCN) NR e' R e';
Each R eRepresent C independently 1-6Alkyl or halo C 1-6Alkyl;
Each R e' represent H or R independently e
R fRepresent C 1-6Alkyl, C 2-6Thiazolinyl, C 2-6Alkynyl or Cy, wherein this C 1-6Alkyl, C 2-6Thiazolinyl or C 2-6Alkynyl can be alternatively by one or more R that are selected from gReplace with the substituting group of Cy*, wherein any of group Cy or Cy* can be alternatively by one or more R that are selected from 8And R aSubstituting group replace;
Each R gRepresent independently halogen ,-OR a' ,-OCOR a,-OSO 2R a,-OCONR aR a' ,-NO 2,-CN ,-COR a' ,-CO 2R a' ,-CONR a' R a' ,-CONR a' NR a' R a' ,-NR a' R a' ,-NR a' COR a' ,-NR a' CONR a' R a' ,-NR a' CO 2R a,-NR a' SO 2R a,-SR a' ,-SOR a,-SO 2R a,-SO 2NR a' R a' ,-C (NR a') NR a' R a' ,-C (NSO 2NR a' R a') NR a' R a' ,-C (NOR a') R a' ,-C (NNR a' R a') R a' ,-NR a' C (NR a') NR a' R a' or-NR a' C (NCN) NR a' R a';
Het in the above-mentioned definition represents pyridine, pyrazine, pyrimidine, pyridazine, 2 (1H)-pyridone, 2 (1H)-pyrazine ketone, 2 (1H)-pyrimidone or 2 (1H)-pyridazinone;
On behalf of part 3-to 7-unit's monocycle or 8-to 12-unit two unsaturated, saturated or aromatics, Cy in the above-mentioned definition or Cy* encircle carbocyclic rings, it contains 1 to 4 heteroatoms that is selected from N, S and O alternatively, when ring is saturated or part when unsaturated, it can contain 1 or 2 oxo group alternatively, and wherein said one or more ring can be by carbon or nitrogen atom bonding in the rest part of molecule;
Or its salt and solvate.
2, according to the compound of claim 1, wherein A represents N.
3, according to the compound of claim 2, R wherein 52 N that can be positioned at formula I pyrazoles ring represent R on any f
4, according to each compound of claim 1 to 3, if its condition is R 3And R 5All represent H, R 2Represent Het, described Her is replaced by one or more substituting groups alternatively, substituting group be selected from halogen ,-CN ,-CF 3,-OH ,-NO 2,-OR 6,-NR 6R 6,-OCF 3, C 1-6Alkyl, C 2-6Thiazolinyl, C 2-6Alkynyl and Cy, wherein Cy can be alternatively by one or more R that are selected from bAnd R cSubstituting group replace R wherein 6Represent C 1-6Alkyl, then R 4Be not-NR a' COR a,-NHCONHR aOr-NHCO 2R a
5, according to each compound of claim 1 to 3, wherein R 1Represent pyridine or phenyl, wherein all these groups can be alternatively by one or more R that are selected from aAnd R bSubstituting group replace.
6, according to the compound of claim 5, R wherein 1Represent phenyl, alternatively by one or more R that are selected from aAnd R bSubstituting group replace.
7, according to the compound of claim 6, R wherein 1Represent phenyl, replaced by one or more substituting groups alternatively, substituting group be selected from halogen ,-OR c' ,-NO 2,-CN ,-CONR c' R c' ,-NR c' R c' and C 1-6Alkyl, this alkyl is replaced by one or more substituting groups alternatively, substituting group be selected from halogen ,-OR c' ,-COR c' ,-NR C' R c' and-NR c' COR c'.
8, according to the compound of claim 7, R wherein 1Represent phenyl, alternatively by one or more halogen and halo C of being selected from 1-6The substituting group of alkyl replaces.
9, according to each compound of claim 1 to 3, wherein R 2Represent pyridine or pyrimidine, wherein all these groups can be alternatively by one or more R that are selected from aAnd R bSubstituting group replace.
10, according to the compound of claim 9, R wherein 2Represent 4-pyridine or 4-pyrimidine, wherein all these groups can be alternatively by one or more R that are selected from aAnd R bSubstituting group replace.
11, according to the compound of claim 10, R wherein 2Represent 4-pyridine or 4-pyrimidine, wherein all these groups can be replaced by one or more substituting groups alternatively, substituting group be selected from halogen ,-OR c' ,-NR c' R c' ,-SR c' and-SO 2R c
12, according to the compound of claim 11, R wherein 2Represent the 4-pyridine.
13, according to the compound of claim 11, R wherein 2Represent quilt-NR c' R c' the 4-pyrimidine that replaces; Wherein at R 2In:
Each R c' represent H or R independently c
Each R cRepresent C independently 1-6Alkyl, alternatively by one or more be selected from Cy and-OR e' substituting group replace;
Each R e' represent H or R independently e
14, according to each compound of claim 1 to 3, wherein R 3Represent H or Cy, described Cy is alternatively by one or more R that are selected from aAnd R bSubstituting group replace.
15, according to the compound of claim 14, R wherein 3Represent H, heteroaryl or phenyl, wherein all these groups can be alternatively by one or more R that are selected from aAnd R bSubstituting group replace, and wherein heteroaryl represent 5-or the 6-unit's monocycle or 8-to 12-unit two rings of fragrance, this ring contain 1 to 4 be selected from the heteroatoms of N, S and O and can pass through carbon or nitrogen atom bonding in the rest part of molecule.
16, according to the compound of claim 15, R wherein 3Represent heteroaryl or phenyl, wherein all these groups can be alternatively by one or more R that are selected from aAnd R bSubstituting group replace.
17, according to the compound of claim 16, R wherein 3Represent bicyclic heteroaryl or phenyl, wherein all these groups can be replaced by one or more substituting groups alternatively, substituting group be selected from halogen ,-NO 2,-OR c', C 1-6Alkyl and Cy, wherein C 1-6Alkyl can be alternatively by one or more R that are selected from bReplace with the substituting group of Cy*, any of group Cy or Cy* can be alternatively by one or more R that are selected from bAnd R cSubstituting group replace.
18, according to the compound of claim 17, R wherein 3Represent bicyclic heteroaryl or phenyl, wherein all these groups can be replaced by one or more substituting groups alternatively, substituting group be selected from halogen ,-NO 2,-OR c', C 1-6Alkyl, halo C 1-6Alkyl and Cy; Wherein at R 3In:
Each R c' represent H or R independently c
Each R cRepresent C independently 1-6Alkyl is alternatively by one or more substituent R dReplace; Each R dRepresent Cy independently.
19, according to each compound of claim 1 to 3, wherein R 4Represent H, R a, halogen ,-OR a' ,-CN ,-CONR a' R a,-NR a' R a' or-NR a' COR a'.
20, according to the compound of claim 19, R wherein 4Represent H.
21, according to each compound of claim 1 to 3, wherein R 5Represent H, perhaps R 5Represent R a, be positioned on 2 N of pyrazoles ring.
22, according to the compound of claim 21, R wherein 5Represent R a
23, according to the compound of claim 21, R wherein 5In R aRepresent C 1-6Alkyl, C 2-6Thiazolinyl or Cy, wherein C 1-6Alkyl or C 2-6Thiazolinyl can be replaced by one or more substituting groups that are selected from Rb and Cy* alternatively, and wherein any of group Cy or Cy* can be alternatively by one or more R that are selected from bAnd R cSubstituting group replace.
24, according to the compound of claim 23, R wherein 5In each R bRepresent independently halogen ,-OR c' ,-COR c' ,-CO 2R c' ,-CONR c' R c' ,-NR c' R c' ,-NR c' COR c' ,-NR c' CONR c' R c' ,-NR c' SO 2R c' ,-SR c' ,-SOR c' or-SO 2R c'.
25, according to the compound of claim 24, wherein at R 5In:
Each R bRepresentative-OR independently c' ,-COR c' ,-CONR c' R c' ,-NR c' R c' ,-NR c' COR c' ,-NR c' CONR c' R c' ,-NR c' SO 2R c' ,-SOR c' or-SO 2R c';
Each R c' represent H or R independently c
Each R cRepresent Cy or C independently 1-6Alkyl, wherein all these groups can be alternatively by one or more R that are selected from dSubstituting group replace;
Each R dRepresent R independently e,-OR e' ,-NR e' R e' ,-CN ,-COR e' ,-SR e' ,-SOR e' or Cy.
26, according to the compound of claim 22, R wherein 5In R aRepresent C 1-6Alkyl is replaced by one or more substituting groups alternatively, and substituting group is selected from-OR c' ,-COR c' ,-CONR c' R c' ,-NR c' R c' ,-NR c' COR c' ,-NR c' CONR c' R c' ,-NR c' SO 2R c' and Cy*, this Cy* is alternatively by-individual or a plurality of R that are selected from cSubstituting group replace; Wherein at R 5In:
Each R c' represent H or R independently c
Each R cRepresent Cy or C independently 1-6Alkyl, wherein all these groups can be alternatively by one or more R that are selected from dSubstituting group replace;
Each R dRepresentative-OR independently e' ,-NR e' R e' ,-CN ,-COR e' ,-SR e' ,-SOR e' or Cy;
Each R e' represent H or R independently e
Each R eRepresent C independently 1-6Alkyl.
27, according to the compound of claim 1, be selected from:
4, two (4-the fluorophenyl)-5-(4-pyridyl) of 6--1H-pyrazolo [3,4-b] pyridine;
4,6-phenylbenzene-5-(4-pyridyl)-1H-pyrazolo [3,4-b] pyridine;
5-(4-pyridyl)-4, two [3-(trifluoromethyl) phenyl]-1H-pyrazolo [3, the 4-b] pyridines of 6-;
4, two (4-the fluorophenyl)-3-methyl-5-(4-pyridyl) of 6--1H-pyrazolo [3,4-b] pyridine;
3-methyl-4,6-phenylbenzene-5-(4-pyridyl)-1H-pyrazolo [3,4-b] pyridine;
2-ethyl-4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6-;
1-ethyl-4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6-;
4, two (4-fluorophenyl)-2-methyl-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6-;
4, two (4-fluorophenyl)-1-methyl-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6-;
4, two (the 4-fluorophenyls)-2 of 6-, 3-dimethyl-5-(4-pyridyl) pyrazolo [3,4-b] pyridine;
4, two (the 4-fluorophenyls)-1 of 6-, 3-dimethyl-5-(4-pyridyl) pyrazolo [3,4-b] pyridine;
2-[2-[1-(tertbutyloxycarbonyl) piperidin-4-yl] ethyl]-4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6-;
1-[2-[1-(tertbutyloxycarbonyl) piperidin-4-yl] ethyl]-4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6-;
2-[1-(tertbutyloxycarbonyl) piperidin-4-yl]-4, two (4-fluorophenyl)-3-methyl-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6-;
1-[1-(tertbutyloxycarbonyl) piperidin-4-yl]-4, two (4-fluorophenyl)-3-methyl-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6-;
2-(3-chloropropyl)-4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6-;
1-(3-chloropropyl)-4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6-;
3-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--2-yl] third-1-alcohol;
3-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--1-yl] third-1-alcohol;
2-[1-(tertbutyloxycarbonyl) piperidin-4-yl]-4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6-;
1-[1-(tertbutyloxycarbonyl) piperidin-4-yl]-4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6-;
2-methyl-4,6-phenylbenzene-5-(4-pyridyl) pyrazolo [3,4-b] pyridine;
1-methyl-4,6-phenylbenzene-5-(4-pyridyl) pyrazolo [3,4-b] pyridine;
4, two (4-the fluorophenyl)-5-(4-pyridyl) of 6--2-[2-(tetrahydropyrans-2-base oxygen base) ethyl]-pyrazolo [3,4-b] pyridine;
2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--1-yl] ethanol;
4, two (4-the fluorophenyl)-2-(4-methylthio group benzyl) of 6--5-(4-pyridyl) pyrazolo [3,4-b] pyridine;
4, two (4-the fluorophenyl)-1-(4-methylthio group benzyl) of 6--5-(4-pyridyl) pyrazolo [3,4-b] pyridine;
2-[1-(tertbutyloxycarbonyl) piperidin-4-yl methyl]-4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6-;
1-[1-(tertbutyloxycarbonyl) piperidin-4-yl methyl]-4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6-;
4, two (4-fluorophenyl)-2-[2-(morpholine-4-yl) ethyls of 6-]-5-(4-pyridyl) pyrazolo [3,4-b] pyridine;
4, two (4-fluorophenyl)-1-[2-(morpholine-4-yl) ethyls of 6-]-5-(4-pyridyl) pyrazolo [3,4-b] pyridine;
2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--2-yl] the acetate ethyl ester;
2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--1-yl] the acetate ethyl ester;
3-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--2-yl] the propionic acid ethyl ester;
3-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--1-yl] the propionic acid ethyl ester;
4, two (4-the fluorophenyl)-2-(4-piperidyl) of 6--5-(4-pyridyl) pyrazolo [3,4-b] pyridine;
4, two (4-the fluorophenyl)-1-(4-piperidyl) of 6--5-(4-pyridyl) pyrazolo [3,4-b] pyridine;
4, two (4-the fluorophenyl)-2-(4-piperidino methyl) of 6--5-(4-pyridyl) pyrazolo [3,4-b] pyridine;
4, two (4-the fluorophenyl)-1-(4-piperidino methyl) of 6--5-(4-pyridyl) pyrazolo [3,4-b] pyridine;
4, two (6-chloropyridine-3-the yl)-5-(4-pyridyl) of 6--1H-pyrazolo [3,4-b] pyridine;
4, two (4-the fluorophenyl)-3-methyl-2-(4-piperidyl) of 6--5-(4-pyridyl) pyrazolo [3,4-b] pyridine;
4, two (4-the fluorophenyl)-3-methyl isophthalic acids of 6--(4-piperidyl)-5-(4-pyridyl) pyrazolo [3,4-b] pyridine;
4, two (4-fluorophenyl)-2-[2-(4-piperidyl) ethyls of 6-]-5-(4-pyridyl) pyrazolo [3,4-b] pyridine;
2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--2-yl] acetate;
2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--1-yl] acetate;
3-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--2-yl] propionic acid;
3-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--1-yl] propionic acid;
2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--2-yl]-1-(morpholine-4-yl) ethyl ketone;
2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--1-yl] ethanamide;
2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--1-yl]-1-(morpholine-4-yl) ethyl ketone;
3-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--2-yl]-1-(morpholine-4-yl) third-1-ketone;
3-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--1-yl]-N-propyl group propionic acid amide;
3-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--1-yl]-1-(morpholine-4-yl) third-1-ketone;
4, two (4-the fluorophenyl)-2-(4-methylthio group phenyl) of 6--5-(4-pyridyl) pyrazolo [3,4-b] pyridine;
4, two (4-the fluorophenyl)-1-(4-methylthio group phenyl) of 6--5-(4-pyridyl) pyrazolo [3,4-b] pyridine;
4, two (4-the fluorophenyl)-2-(4-methanesulfinyl phenyl) of 6--5-(4-pyridyl) pyrazolo [3,4-b] pyridine;
4, two (4-the fluorophenyl)-2-(4-methylsulfonyl phenyl) of 6--5-(4-pyridyl) pyrazolo [3,4-b] pyridine;
4, two (4-the fluorophenyl)-1-(4-methanesulfinyl phenyl) of 6--5-(4-pyridyl) pyrazolo [3,4-b] pyridine;
4, two (4-the fluorophenyl)-2-(4-methanesulfinyl benzyl) of 6--5-(4-pyridyl) pyrazolo [3,4-b] pyridine;
4, two (4-the fluorophenyl)-2-(4-methylsulfonyl benzyl) of 6--5-(4-pyridyl) pyrazolo [3,4-b] pyridine;
4, two (4-the fluorophenyl)-1-(4-methanesulfinyl benzyl) of 6--5-(4-pyridyl) pyrazolo [3,4-b] pyridine;
4, two (4-the fluorophenyl)-1-(4-methylsulfonyl benzyl) of 6--5-(4-pyridyl) pyrazolo [3,4-b] pyridine;
3-chloro-4, two (4-the fluorophenyl)-5-(4-pyridyl) of 6--1H-pyrazolo [3,4-b] pyridine;
3-bromo-4, two (4-the fluorophenyl)-5-(4-pyridyl) of 6--1H-pyrazolo [3,4-b] pyridine;
4, two (4-the fluorophenyl)-5-(4-pyridyl) of 6--1H-pyrazolo [3,4-b] pyridine-3-nitrile;
3-bromo-4, two (4-fluorophenyl)-1-methyl-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6-;
4, two (4-the fluorophenyl)-5-(4-pyridyl) of 6--1H-pyrazolo [3,4-b] pyridine-3-carboxamide;
3-amino methyl-4, two (4-the fluorophenyl)-5-(4-pyridyl) of 6--1H-pyrazolo [3,4-b] pyridine;
4, two (4-fluoro-3-the nitrophenyl)-5-(4-pyridyl) of 6--1H-pyrazolo [3,4-b] pyridine;
3-amino-6-(4-fluorophenyl)-5-(4-pyridyl)-1H-pyrazolo [3,4-b] pyridine;
3-amino-6-(4-fluorophenyl)-1-methyl-5-(4-pyridyl) pyrazolo [3,4-b] pyridine;
4-[6-(4-fluorophenyl)-5-(4-pyridyl)-1H-pyrazolo [3,4-b] pyridin-4-yl] phenol;
2-(2,2-diethoxy ethyl)-4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6-;
1-(2,2-diethoxy ethyl)-4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6-;
4, two (4-fluorophenyl)-1-methyl-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--3-nitrile;
3-bromo-6-(4-fluorophenyl)-5-(4-pyridyl)-1H-pyrazolo [3,4-b] pyridine;
6-fluorophenyl-5-(4-pyridyl)-1H-pyrazolo [3,4-b] pyridine;
N-methyl-[3-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--2-yl] propyl group] amine;
[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--2-yl] methyl alcohol;
2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--2-yl]-N,N-dimethylacetamide;
2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--1-yl]-N,N-dimethylacetamide;
4, two (4-fluorophenyl)-2-[2-(2-methoxy ethoxy) ethyls of 6-]-5-(4-pyridyl) pyrazolo [3,4-b] pyridine;
4, two (4-fluorophenyl)-1-[2-(2-methoxy ethoxy) ethyls of 6-]-5-(4-pyridyl) pyrazolo [3,4-b] pyridine;
4, two (4-fluorophenyl)-2-[3-(morpholine-4-yl) propyl group of 6-]-5-(4-pyridyl) pyrazolo [3,4-b] pyridine;
4, two (6-chloropyridine-3-yl)-2-methyl-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6-;
4, two (6-chloropyridine-3-yl)-1-methyl-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6-;
4, two (6-chloropyridine-3-the yl)-3-methyl-5-(4-pyridyl) of 6--1H-pyrazolo [3,4-b] pyridine;
4, two (6-picoline-3-the yl)-5-(4-pyridyl) of 6--1H-pyrazolo [3,4-b] pyridine;
4, two (4-the fluorophenyl)-2-(2-phthaloyl imino-ethyl) of 6--5-(4-pyridyl) pyrazolo [3,4-b] pyridine;
2-(2-amino-ethyl)-4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6-;
2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--2-yl] ethanol;
6-(4-fluorophenyl)-2-methyl-5-(4-pyridyl) pyrazolo [3,4-b] pyridine;
4, two (4-the fluorophenyl)-2-(3-phthaloyl imino-propyl group) of 6--5-(4-pyridyl) pyrazolo [3,4-b] pyridine;
2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--2-yl] acetaldehyde;
2-(3-aminopropyl)-4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6-;
N-[4, two (4-the fluorophenyl)-5-(4-pyridyl) of 6--1H-pyrazolo [3,4-b] pyridin-3-yl methyl]-1-(tertbutyloxycarbonyl) piperidines-4-methane amide;
N-[4, two (4-the fluorophenyl)-5-(4-pyridyl) of 6--1H-pyrazolo [3,4-b] pyridin-3-yl methyl]-1H-piperidines-4-methane amide;
2-(3-benzyloxy propyl group)-4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6-;
1-(3-benzyloxy propyl group)-4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6-;
N, N-diethyl-[2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--2-yl] ethyl] amine;
N, N-diethyl-[2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--1-yl] ethyl] amine;
4, two (4-the fluorophenyl)-5-(4-pyridyl) of 6--2-(3-pyridylmethyl) pyrazolo [3,4-b] pyridine;
4, two (4-the fluorophenyl)-5-(4-pyridyl) of 6--1-(3-pyridylmethyl) pyrazolo [3,4-b] pyridine;
N, N-dimethyl-[3-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--2-yl] propyl group] amine;
N, N-dimethyl-[3-[4, two (4-the fluorophenyl)-5-(4-pyridyl) of 6--pyrazolo [3,4-b] pyridine-1-yl] propyl group] amine;
1-[2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--2-yl] ethyl] piperidines-4-alcohol;
3-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--2-yl]-2-hydroxyl third-1-alcohol;
3-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--1-yl]-2-hydroxyl third-1-alcohol;
4, two (4-the fluorophenyl)-5-(4-pyridyl) of 6--2-(4-pyridylmethyl) pyrazolo [3,4-b] pyridine;
4, two (4-the fluorophenyl)-5-(4-pyridyl) of 6--1-(4-pyridylmethyl) pyrazolo [3,4-b] pyridine;
N-(tertbutyloxycarbonyl)-[1-[3-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--2-yl] propyl group] piperidin-4-yl] amine;
2-[1-(tertbutyloxycarbonyl) piperidin-4-yl]-6-(4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3,4-b] pyridine;
1-[1-(tertbutyloxycarbonyl) piperidin-4-yl]-6-(4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3,4-b] pyridine;
3-methyl-4, two (6-picoline-3-the yl)-5-(4-pyridyl) of 6--1H-pyrazolo [3,4-b] pyridine;
1-[3-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--2-yl]-propyl group] piperidin-4-one-;
N-(tertbutyloxycarbonyl)-[1-[2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--2-yl] ethyl] piperidin-4-yl] amine;
N-methyl-[1-[2-[4, two (4-the fluorophenyl)-5-(4-pyridyl) of 6--pyrazolo [3,4-b] pyridine-2-yl] ethyl] piperidin-4-yl] amine;
[1-[3-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--2-yl] propyl group] piperidin-4-yl] amine;
2-[1-[2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--2-yl] ethyl] piperidin-4-yl] ethanol;
[1-[2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--2-yl] ethyl] piperidin-4-yl] amine;
6-(4-fluorophenyl)-2-(4-piperidyl)-5-(4-pyridyl)-pyrazolo [3,4-b] pyridine;
6-(4-fluorophenyl)-1-(4-piperidyl)-5-(4-pyridyl)-pyrazolo [3,4-b] pyridine;
3-amino-5-[2-(methylthio group) pyrimidine-4-yl]-6-[3-(trifluoromethyl) phenyl]-1H-pyrazolo [3,4-b] pyridine;
2-[3-[1-(4-tertbutyloxycarbonyl) piperazine-1-yl] propyl group]-4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6-;
4, two (4-fluorophenyl)-2-[3-(1-piperazine-1-yl) propyl group of 6-]-5-(4-pyridyl) pyrazolo [3,4-b] pyridine;
5-[2-(methylthio group) pyrimidine-4-yl]-6-[3-(trifluoromethyl) phenyl]-1H-pyrazolo [3,4-b] pyridine;
5-[2-(methylsulfonyl) pyrimidine-4-yl]-6-[3-(trifluoromethyl) phenyl]-1H-pyrazolo [3,4-b] pyridine;
(1S)-and N-(1-phenylethyl)-[4-[6-[3-(trifluoromethyl) phenyl]-1H-pyrazolo [3,4-b] pyridine-5-yl] pyrimidine-2-base] amine;
1-[3-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--2-yl] propyl group] piperidines-4-alcohol;
2-[1-[3-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--2-yl] propyl group] piperidin-4-yl] ethanol;
4, two (4-the fluorophenyl)-3-(4-piperidyl) of 6--5-(4-pyridyl)-1H-pyrazolo [3,4-b] pyridine;
6-(4-fluorophenyl)-5-(4-pyridyl)-1H-pyrazolo [3,4-b] pyridine-3-nitrile;
2-[2-[[1-(tertbutyloxycarbonyl) piperidin-4-yl] amino] ethyl]-4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6-;
4, two (4-the fluorophenyl)-2-[2-[(4-piperidyls of 6-) amino] ethyl]-5-(4-pyridyl) pyrazolo [3,4-b] pyridine;
N-(2-methoxy ethyl)-[2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--2-yl] ethyl] amine;
1-[4-[2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--2-yl] ethyl] piperazine-1-yl] ethyl ketone;
3-[4,6-phenylbenzene-5-(4-pyridyl) pyrazolo [3,4-b] pyridine-2-yl] third-1-alcohol;
3-[4,6-phenylbenzene-5-(4-pyridyl) pyrazolo [3,4-b] pyridine-1-yl] third-1-alcohol;
2-ethyl-4,6-phenylbenzene-5-(4-pyridyl) pyrazolo [3,4-b] pyridine;
1-ethyl-4,6-phenylbenzene-5-(4-pyridyl) pyrazolo [3,4-b] pyridine;
4,6-phenylbenzene-2-(2-phthaloyl imino-ethyl)-5-(4-pyridyl) pyrazolo [3,4-b] pyridine;
2-(2-amino-ethyl)-4,6-phenylbenzene-5-(4-pyridyl) pyrazolo [3,4-b] pyridine;
2-allyl group-4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6-;
1-allyl group-4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6-;
1-[2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--2-yl] ethyl] piperidin-4-one-;
3-amino methyl-6-(4-fluorophenyl)-5-(4-pyridyl)-1H-pyrazolo [3,4-b] pyridine;
3-amino-6-(4-fluorophenyl)-4-methyl-5-(4-pyridyl)-1H-pyrazolo [3,4-b] pyridine;
3-[N-[2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--2-yl] ethyl] amino] third-1-alcohol;
N-ethyl-[2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--2-yl] ethyl] amine;
2-[N-[2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--2-yl] ethyl] amino] ethanol;
The N-[(2-pyridyl) methyl]-[2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--2-yl] ethyl] amine;
The N-[(2-thienyl) methyl]-[2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--2-yl] ethyl] amine;
1-[2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--2-yl] ethyl] piperidines-4-methane amide;
4, two (4-fluorophenyl)-2-[2-(tetramethyleneimine-1-yl) ethyls of 6-]-5-(4-pyridyl) pyrazolo [3,4-b] pyridine;
(3R)-and 1-[2-(4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--2-yl] ethyl] tetramethyleneimine-3-alcohol;
2-[N-[2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--2-yl] ethyl]-the N-methylamino] ethanol;
4, two (4-the fluorophenyl)-5-(4-pyridyl) of 6--2-[2-(1,2,3,4-tetrahydroisoquinoline-2-yl) ethyl] pyrazolo [3,4-b] pyridine;
4, two (4-fluorophenyl)-2-[2-(4-phenylpiperazine-1-yl) ethyls of 6-]-5-(4-pyridyl) pyrazolo [3,4-b] pyridine;
4, two (4-fluorophenyl)-2-[2-[4-(piperidino) piperidines of 6--1-yl] ethyl]-5-(4-pyridyl) pyrazolo [3,4-b] pyridine;
3-[N-[2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--2-yl] ethyl]-the N-methylamino] propionitrile;
N-methyl-[2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--2-yl] ethyl] amine;
2-[2-[4-(tertbutyloxycarbonyl) piperazine-1-yl] ethyl]-4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6-;
4, two (4-fluorophenyl)-2-[2-(piperazine-1-yl) ethyls of 6-]-5-(4-pyridyl) pyrazolo [3,4-b] pyridine;
4, two (4-the fluorophenyl)-5-(4-pyridyl) of 6--2-vinyl pyrazoles is [3,4-b] pyridine also;
2-[N-[2-[4,6-pair-(4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3,4-b] pyridine-2-yl] ethyl]-N-(2-hydroxyethyl) amino] ethanol;
N-cyclopropyl-[2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--2-yl] ethyl] amine;
N-[2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--2-yl] ethyl] ethanamide;
N-[2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--2-yl] ethyl]-N '-sec.-propyl urea;
N-[2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--2-yl] ethyl] Toluidrin;
6-(4-fluorophenyl)-4-(4-piperidyl)-5-(4-pyridyl)-1H-pyrazolo [3,4-b] pyridine;
6-(4-fluorophenyl)-4-(2-furyl)-5-(4-pyridyl)-1H-pyrazolo [3,4-b] pyridine;
6-(4-fluorophenyl)-4-(1H-imidazol-4 yl)-5-(4-pyridyl)-1H-pyrazolo [3,4-b] pyridine;
4-(5-bromothiophene-2-yl)-6-(4-fluorophenyl)-5-(4-pyridyl)-1H-pyrazolo [3,4-b] pyridine;
4, two (4-the fluorophenyl)-5-(2-methylthiopyrimidine-4-yl) of 6--1H-pyrazolo [3,4-b] pyridine;
5-(2-chloropyridine-4-yl)-4, two (4-fluorophenyl)-1H-pyrazolo [3, the 4-b] pyridines of 6-;
6-(4-fluorophenyl)-4-(2-phenylethyl)-5-(4-pyridyl)-1H-pyrazolo [3,4-b] pyridine;
4-(6-chloropyridine-3-yl)-6-(4-fluorophenyl)-5-(4-pyridyl)-1H-pyrazolo [3,4-b] pyridine;
4-(3, the 4-dichlorophenyl)-1-ethyl-6-(4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3,4-b] pyridine;
6-(4-fluorophenyl)-4-(1-methyl piperidine-4-yl)-5-(4-pyridyl)-1H-pyrazolo [3,4-b] pyridine;
3-amino-6-(4-fluorophenyl)-5-(2-methylthiopyrimidine-4-yl)-1H-pyrazolo [3,4-b] pyridine;
6-(4-fluorophenyl)-5-(2-methylthiopyrimidine-4-yl)-1H-pyrazolo [3,4-b] pyridine;
4,6-phenylbenzene-5-(4-pyridyl)-2-[2-(tetrahydropyrans-2-base oxygen base) ethyl] pyrazolo [3,4-b] pyridine;
6-(4-fluorophenyl)-4-(2-furyl)-2-methyl-5-(4-pyridyl) pyrazolo [3,4-b] pyridine;
6-(4-fluorophenyl)-2-methyl-4-(1-methyl isophthalic acid H-imidazol-4 yl)-5-(4-pyridyl) pyrazolo [3,4-b] pyridine;
6-(4-fluorophenyl)-5-(2-methylthiopyrimidine-4-yl)-2-[2-(tetrahydropyrans-2-base oxygen base) ethyl] pyrazolo [3,4-b] pyridine;
6-(4-fluorophenyl)-5-(2-methylthiopyrimidine-4-yl)-2-[3-(tetrahydropyrans-2-base oxygen base) propyl group] pyrazolo [3,4-b] pyridine;
4, two (4-the fluorophenyl)-5-(2-methylthiopyrimidine-4-yl) of 6--2-[3-(tetrahydropyrans-2-base oxygen base) propyl group] pyrazolo [3,4-b] pyridine;
4-(5-bromothiophene-2-yl)-6-(4-fluorophenyl)-2-methyl-5-(4-pyridyl)-1H-pyrazolo [3,4-b] pyridine;
6-(4-fluorophenyl)-2-methyl-5-(2-methylthiopyrimidine-4-yl) pyrazolo [3,4-b] pyridine;
5-(2-chloropyridine-4-yl)-4, two (4-the fluorophenyl)-2-methylpyrazoles of 6-are [3,4-b] pyridine also;
6-(4-fluorophenyl)-4-(2-phenylethyl)-5-(4-pyridyl)-2-[3-(tetrahydropyrans-2-base oxygen base) propyl group] pyrazolo [3,4-b] pyridine;
4-(6-chloropyridine-3-yl)-6-(4-fluorophenyl)-5-(4-pyridyl)-2-[3-(tetrahydropyrans-2-base oxygen base) propyl group] pyrazolo [3,4-b] pyridine;
4-(6-chloropyridine-3-yl)-6-(4-fluorophenyl)-2-methyl-5-(4-pyridyl) pyrazolo [3,4-b] pyridine;
5-(2-methylthiopyrimidine-4-yl)-2-[3-(tetrahydropyrans-2-base oxygen base) propyl group]-6-(3-trifluoromethyl) pyrazolo [3,4-b] pyridine;
6-(4-fluorophenyl)-2-methyl-5-(4-pyridyl)-4-[5-(3-pyridyl) thiophene-2-yl] pyrazolo [3,4-b] pyridine;
2-[4,6-phenylbenzene-5-(4-pyridyl) pyrazolo [3,4-b] pyridine-2-yl] ethanol;
3-[5-(2-methylthiopyrimidine-4-yl)-6-(3-trifluoromethyl) pyrazolo [3,4-b] pyridine-2-yl] third-1-alcohol;
2-[6-(4-fluorophenyl)-5-(2-methylthiopyrimidine-4-yl) pyrazolo [3,4-b] pyridine-2-yl] ethanol;
3-[6-(4-fluorophenyl)-5-(2-methylthiopyrimidine-4-yl) pyrazolo [3,4-b] pyridine-2-yl] third-1-alcohol;
3-[4, two (4-fluorophenyl)-5-(2-methylthiopyrimidine-4-yl) pyrazolo [3, the 4-b] pyridines of 6--2-yl] third-1-alcohol;
3-[6-(4-fluorophenyl)-4-(2-phenylethyl)-5-(4-pyridyl) pyrazolo [3,4-b] pyridine-2-yl] third-1-alcohol;
3-[4-(6-chloropyridine-3-yl)-6-(4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3,4-b] pyridine-2-yl] third-1-alcohol;
6-(4-fluorophenyl)-2-methyl-5-(2-methanesulfonyl pyrimidine-4-yl) pyrazolo [3,4-b] pyridine;
3-[5-(2-methanesulfonyl pyrimidine-4-yl)-6-(3-trifluoromethyl) pyrazolo [3,4-b] pyridine-2-yl] third-1-alcohol;
2-[6-(4-fluorophenyl)-5-(2-methanesulfonyl pyrimidine-4-yl) pyrazolo [3,4-b] pyridine-2-yl] ethanol;
3-[6-(4-fluorophenyl)-5-(2-methanesulfonyl pyrimidine-4-yl) pyrazolo [3,4-b] pyridine-2-yl] third-1-alcohol;
3-[4, two (4-fluorophenyl)-5-(2-methanesulfonyl pyrimidine-4-yl) pyrazolo [3, the 4-b] pyridines of 6--2-yl] third-1-alcohol;
N-cyclopropyl methyl-[4-[6-[3-(trifluoromethyl) phenyl]-1H-pyrazolo [3,4-b] pyridine-5-yl] pyrimidine-2-base] amine;
(1S)-3-[5-[2-(1-phenylethyl amino) pyrimidine-4-yl]-6-(3-trifluoromethyl) pyrazolo [3,4-b] pyridine-2-yl] third-1-alcohol;
N-cyclopropyl methyl-[4-[6-(4-fluorophenyl)-2-methylpyrazole is [3,4-b] pyridine-5-yl also] pyrimidine-2-base] amine;
2-[5-[2-[(cyclopropyl methyl) amino] pyrimidine-4-yl]-6-(4-fluorophenyl) pyrazolo [3,4-b] pyridine-2-yl] ethanol;
3-[5-[2-[(cyclopropyl methyl) amino] pyrimidine-4-yl]-6-(4-fluorophenyl) pyrazolo [3,4-b] pyridine-2-yl] third-1-alcohol;
3-[5-[2-[(cyclopropyl methyl) amino] pyrimidine-4-yl]-4, two (4-fluorophenyl) pyrazolo [3, the 4-b] pyridines of 6--2-yl] third-1-alcohol;
4-[4-[4, two (4-the fluorophenyl)-2-methylpyrazoles of 6-are [3,4-b] pyridine-5-yl also] pyridine-2-base amino] benzsulfamide;
4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--3-alcohol;
6-(4-fluorophenyl)-4-(3H-imidazol-4 yl)-5-(4-pyridyl)-1H-pyrazolo [3,4-b] pyridine;
6-(4-fluorophenyl)-4-(1H-pyrazole-3-yl)-5-(4-pyridyl)-1H-pyrazolo [3,4-b] pyridine;
3-[6-(4-fluorophenyl)-5-(4-pyridyl)-1H-pyrazolo [3,4-b] pyridin-4-yl] phenol;
4-cyclopropyl-6-(4-fluorophenyl)-5-(4-pyridyl)-1H-pyrazolo [3,4-b] pyridine;
6-(4-fluorophenyl)-4-(5-methyl furan-2-yl)-5-(4-pyridyl)-1H-pyrazolo [3,4-b] pyridine;
4-(5-bromine furans-2-yl)-6-(4-fluorophenyl)-5-(4-pyridyl)-1H-pyrazolo [3,4-b] pyridine;
4-(4-benzyloxy phenyl)-6-(4-fluorophenyl)-5-pyrimidine-4-base-1H-pyrazolo [3,4-b] pyridine;
4-(4-benzyloxy phenyl)-6-(4-fluorophenyl)-5-(2-methylthiopyrimidine-4-yl)-1H-pyrazolo [3,4-b] pyridine;
6-(4-fluorophenyl)-4-propyl group-5-(4-pyridyl)-1H-pyrazolo [3,4-b] pyridine;
4-(3-benzyloxy phenyl)-6-(4-fluorophenyl)-5-(4-pyridyl)-1H-pyrazolo [3,4-b] pyridine;
5-(2-chloropyridine-4-yl)-6-(4-fluorophenyl)-1H-pyrazolo [3,4-b] pyridine;
4-[6-(4-fluorophenyl)-5-(4-pyridyl)-1H-pyrazolo [3,4-b] pyridin-4-yl] fourth-1-alcohol;
4-benzyl-6-(4-fluorophenyl)-5-(4-pyridyl)-1H-pyrazolo [3,4-b] pyridine;
4-(4-benzyloxy phenyl)-6-(4-fluorophenyl)-5-(4-pyridyl)-1H-pyrazolo [3,4-b] pyridine;
4, two (4-the fluorophenyl)-5-pyrimidines of 6--4-base-1H-pyrazolo [3,4-b] pyridine;
[(2S)-and 2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--2-yl] ethyl] tetramethyleneimine-2-methane amide;
2-[2-(4,6-phenylbenzene-5-(4-pyridyl) pyrazolo [3,4-b] pyridine-2-yl) ethylamino] ethanol;
6-(4-fluorophenyl)-2-methyl-4-(3-pyridyl)-5-(4-pyridyl) pyrazolo [3,4-b] pyridine;
6-(4-fluorophenyl)-3-methyl-5-(2-methylthiopyrimidine-4-yl)-1H-pyrazolo [3,4-b] pyridine;
3-amino-5-(2-methylthiopyrimidine-4-yl)-6-phenyl-1H-pyrazolo [3,4-b] pyridine;
5-(2-methylthiopyrimidine-4-yl)-6-phenyl-1H-pyrazolo [3,4-b] pyridine;
6-(4-fluorophenyl)-4-methyl-5-(2-methylthiopyrimidine-4-yl)-1H-pyrazolo [3,4-b] pyridine;
5-(2-methoxy pyrimidine-4-yl)-6-(3-trifluoromethyl)-1H-pyrazolo [3,4-b] pyridine;
N-[2-[4,6-(phenylbenzene)-5-(4-pyridyl) pyrazolo [3,4-b] pyridine-2-yl] ethyl] ethanamide;
N-[3-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--2-yl] propyl group] ethanamide;
N-[2-[4,6-phenylbenzene-5-(4-pyridyl) pyrazolo [3,4-b] pyridine-2-yl] ethyl]-N-(2-hydroxyethyl) ethanamide;
N-[2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--2-yl] ethyl] propionic acid amide;
N-[3-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--2-yl] propyl group] Toluidrin;
5-(2-aminopyrimidine-4-yl)-6-(3-trifluoromethyl)-1H-pyrazolo [3,4-b] pyridine;
N-[5-(2-methylthiopyrimidine-4-yl)-6-(3-trifluoromethyl)-1H-pyrazolo [3,4-b] pyridin-3-yl] ethanamide;
N-cyclopropyl methyl-[4-[3-benzyloxycarbonyl amino-6-(3-trifluoromethyl)-1H-pyrazolo [3,4-b] pyridine-5-yl] pyrimidine-2-base] amine;
N-[2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--2-yl] ethyl]-the 2-hydroxyl acetamide;
N-[2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--2-yl] ethyl] piperidines-4-methane amide;
N-(2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--2-yl] ethyl]-2-(methylamino) ethanamide;
N-[2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--2-yl] ethyl]-2-(2-hydroxyethyl amino) ethanamide;
N-[2-[4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6--2-yl] ethyl] niacinamide;
4-(4-benzyloxy phenyl)-6-(4-fluorophenyl)-2-methyl-5-(4-pyridyl) pyrazolo [3,4-b] pyridine;
6-(4-fluorophenyl)-5-(2-methylthiopyrimidine-4-yl)-2-methylpyrazole is [3,4-b] pyridine also;
6-(4-fluorophenyl)-2,4-dimethyl-5-(4-pyridyl) pyrazolo [3,4-b] pyridine;
4-(4-benzyloxy phenyl)-6-(4-fluorophenyl)-2-methyl-5-(2-methylthiopyrimidine-4-yl) pyrazolo [3,4-b] pyridine;
2-(1-benzyl-pyrrole alkane-2-ylmethyl)-4, two (4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3, the 4-b] pyridines of 6-;
4-(4-benzyloxy phenyl)-6-(4-fluorophenyl)-2-methyl-5-pyrimidine-4-base pyrazolo [3,4-b] pyridine;
6-(4-fluorophenyl)-2-methyl-4-(5-methyl furan-2-yl)-5-(4-pyridyl) pyrazolo [3,4-b] pyridine;
4-(5-bromine furans-2-yl)-6-(4-fluorophenyl)-2-methyl-5-(4-pyridyl) pyrazolo [3,4-b] pyridine;
6-(4-fluorophenyl)-2-methyl-4-propyl group-5-(4-pyridyl) pyrazolo [3,4-b] pyridine;
4-(3-benzyloxy phenyl)-6-(4-fluorophenyl)-2-methyl-5-(4-pyridyl) pyrazolo [3,4-b] pyridine;
6-(4-fluorophenyl)-2-methyl-4-(2-phenylethyl)-5-(4-pyridyl) pyrazolo [3,4-b] pyridine;
5-(2-chloropyridine-4-yl)-6-(4-fluorophenyl)-2-methylpyrazole is [3,4-b] pyridine also;
4-benzyl-6-(4-fluorophenyl)-2-methyl-5-(4-pyridyl) pyrazolo [3,4-b] pyridine;
4-[6-(4-fluorophenyl)-2-methyl-5-(4-pyridyl) pyrazolo [3,4-b] pyridin-4-yl] fourth-1-alcohol;
4-[6-(4-fluorophenyl)-2-methyl-5-(4-pyridyl) pyrazolo [3,4-b] pyridin-4-yl] phenol;
N-[6-(4-fluorophenyl)-5-(2-methylthiopyrimidine-4-yl)-1H-pyrazolo [3,4-b] pyridin-3-yl] ethanamide;
N-[5-[2-[(cyclopropyl methyl) amino] pyrimidine-4-yl]-6-(4-fluorophenyl)-1H-pyrazolo [3,4-b] pyridin-3-yl] ethanamide;
3-[6-(4-fluorophenyl)-4-(2-furyl)-5-(4-pyridyl) pyrazolo [3,4-b] pyridine-2-yl] third-1-alcohol;
2-[4-(4-benzyloxy phenyl)-6-(4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3,4-b] pyridine-2-yl] ethanol;
3-[4-(4-benzyloxy phenyl)-6-(4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3,4-b] pyridine-2-yl] third-1-alcohol;
3-[6-(4-fluorophenyl)-4-(5-methyl furan-2-yl)-5-(4-pyridyl) pyrazolo [3,4-b] pyridine-2-yl] third-1-alcohol;
3-[4-cyclopropyl-6-(4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3,4-b] pyridine-2-yl] third-1-alcohol;
3-[4-(5-bromothiophene-2-yl)-6-(4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3,4-b] pyridine-2-yl] third-1-alcohol;
3-[6-(4-fluorophenyl)-4-propyl group-5-(4-pyridyl) pyrazolo [3,4-b] pyridine-2-yl] third-1-alcohol;
3-[4, two (4-the fluorophenyl)-5-pyrimidines of 6--4-base pyrazolo [3,4-b] pyridine-2-yl] third-1-alcohol;
3-[4-(3-benzyloxy phenyl)-6-(4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3,4-b] pyridine-2-yl] third-1-alcohol;
3-[4-benzyl-6-(4-fluorophenyl)-5-(4-pyridyl) pyrazolo [3,4-b] pyridine-2-yl] third-1-alcohol;
(1S)-and N-(1-phenylethyl)-[4-[6-(4-fluorophenyl)-3-methyl isophthalic acid H-pyrazolo [3,4-b] pyridine-5-yl] pyrimidine-2-base] amine;
N-cyclopropyl methyl-[4-[6-(4-fluorophenyl)-3-methyl isophthalic acid H-pyrazolo [3,4-b] pyridine-5-yl] pyrimidine-2-base] amine;
1-[4-[6-(4-fluorophenyl)-2-methylpyrazole is [3,4-b] pyridine-5-yl also] pyrimidine-2--amino] propan-2-ol;
N-cyclopropyl methyl-4-[6-[phenyl-1H-pyrazolo [3,4-b] pyridine-5-yl] pyrimidine-2-base] amine;
2-[4-[6-(4-fluorophenyl)-2-methylpyrazole is [3,4-b] pyridine-5-yl also] pyrimidine-2--amino] third-1-alcohol;
4-[4-[6-(4-fluorophenyl)-2-methylpyrazole is [3,4-b] pyridine-5-yl also] pyrimidine-2--amino] fourth-1-alcohol;
(1S)-and N-(1-phenylethyl)-[4-[6-phenyl-1H-pyrazolo [3,4-b] pyridine-5-yl] pyrimidine-2-base] amine;
N-(3-methoxy-propyl)-[4-[6-(3-trifluoromethyl)-1H-pyrazolo [3,4-b] pyridine-5-yl] pyrimidine-2-base] amine;
3-[4-[6-(3-trifluoromethyl)-1H-pyrazolo [3,4-b] pyridine-5-yl] pyrimidine-2--amino] third-1-alcohol;
3-[4-[6-(4-fluorophenyl)-2-(3-hydroxypropyl) pyrazolo [3,4-b] pyridine-5-yl] pyrimidine-2--amino] third-1-alcohol;
N-ethyl-[4-[6-(3-trifluoromethyl)-1H-pyrazolo [3,4-b] pyridine-5-yl] pyrimidine-2-base] amine;
N-benzyl-[4-[6-(3-trifluoromethyl)-1H-pyrazolo [3,4-b] pyridine-5-yl] pyrimidine-2-base] amine;
4-[5-[2-[(cyclopropyl methyl) amino] pyrimidine-4-yl]-6-(4-fluorophenyl)-2-methylpyrazole [3,4-b] pyridin-4-yl also] phenol;
4-[6-(4-fluorophenyl)-2-(3-hydroxypropyl)-5-(4-pyridyl) pyrazolo [3,4-b] pyridin-4-yl] phenol;
4-[6-(4-fluorophenyl)-2-methyl-5-pyrimidine-4-base pyrazolo [3,4-b] pyridin-4-yl] phenol;
3-[6-(4-fluorophenyl)-2-(3-hydroxypropyl)-5-(4-pyridyl) pyrazolo [3,4-b] pyridin-4-yl] phenol;
3-[6-(4-fluorophenyl)-2-methyl-5-(4-pyridyl) pyrazolo [3,4-b] pyridin-4-yl] phenol;
4, two (4-the fluorophenyl)-5-(4-pyridyl) of 6--2-(tetramethyleneimine-2-ylmethyl) pyrazolo [3,4-b] pyridine;
4-[4-[6-(4-fluorophenyl)-2-methylpyrazole is [3,4-b] pyridine-5-yl also] pyridine-2-base amino] benzsulfamide;
N-[5-[2-[(cyclopropyl methyl) amino] pyrimidine-4-yl]-6-(4-fluorophenyl)-1H-pyrazolo [3,4-b] pyridin-3-yl] ethanamide 7-oxide compound; With
N-[6-(4-fluorophenyl)-5-(4-pyridyl)-1H-pyrazolo [3,4-b] pyridin-3-yl] Isonicotinamide;
Perhaps its salt, solvate or prodrug.
28, preparation is according to the method for the formula I compound of claim 1, and it comprises:
(a) make formula IV ketone
Figure C2004800053900027C1
R wherein 1And R 2Have and implication identical described in the claim 1,
With formula V amino-pyrazol and formula VI aldehyde reaction,
Figure C2004800053900027C2
R 3-CHO
V VI
R wherein 3, R 4And R 5Have and implication identical described in the claim 1; Perhaps
(b) if in formula I compound, R 5Represent H, R 3Have and R 1Identical implication makes formula IV ketone or formula VII enolate
Figure C2004800053900027C3
R wherein 1And R 2Have and implication identical described in the claim 1,
With the reaction of formula Va amino-pyrazol,
Figure C2004800053900028C1
R wherein 4Have and implication identical described in the claim 1; Perhaps
(c) if in formula I compound, R 4Represent NH 2, with formula XIX compound
R wherein 1, R 2And R 3Have and implication identical described in the claim 1,
Handle with formula VIIIa hydrazine,
NH 2-NHR 5
VIIIa
R wherein 5Have and implication identical described in the claim 1; Perhaps
(d) divide one or more steps that formula I compound is converted into another kind of formula I compound; And
(e) if necessary, after the step in front, make formula I compound and alkali or acid-respons, obtain corresponding salt.
29, pharmaceutical composition, it comprise significant quantity according to each formula I compound or its pharmacy acceptable salt or solvate and one or more pharmaceutically acceptable vehicle of claim 1 to 27.
30, be used for the treatment of or prevent in preparation according to each formula I compound or its pharmacy acceptable salt or solvate of claim 1 to 27 by the purposes in the medicine of the disease of p38 mediation.
31, be used for the treatment of or prevent in preparation according to each formula I compound or its pharmacy acceptable salt or solvate of claim 1 to 27 by the purposes in the medicine of cytokine mediated disease.
32, be used for the treatment of or prevent in preparation according to each formula I compound or its pharmacy acceptable salt or solvate of claim 1 to 27 by the purposes in the medicine of the disease of TNF-α, IL-1, IL-6 and/or IL-8 mediation.
33, be used for the treatment of or prevent to be selected from immunity, autoimmunity and inflammatory diseases, cardiovascular disorder, infectious diseases, bone resorption disease, neurodegenerative disease, proliferative disease and induce purposes in the medicine of disease of relevant process in preparation according to each formula I compound or its pharmacy acceptable salt or solvate of claim 1 to 27 with cyclooxygenase-2.
34, according to the compound of claim 1, wherein
A represents N;
R 1Represent phenyl, replaced by one or more substituting groups alternatively, substituting group be selected from halogen ,-OR c' ,-NO 2,-CN ,-CONR c' R c' ,-NR c' R c' and C 1-6Alkyl, this alkyl is replaced by one or more substituting groups alternatively, substituting group be selected from halogen ,-OR c' ,-COR c' ,-NR C' R c' and-NR c' COR c';
R 2Represent 4-pyridine or 4-pyrimidine, wherein all these groups can be replaced by one or more substituting groups alternatively, substituting group be selected from halogen ,-OR c' ,-NR c' R c' ,-SR c' and-SO 2R c
R 3Represent H, heteroaryl or phenyl, wherein all these groups can be alternatively by one or more R that are selected from aAnd R bSubstituting group replace, and wherein heteroaryl represent 5-or the 6-unit's monocycle or 8-to 12-unit two rings of fragrance, this ring contain 1 to 4 be selected from the heteroatoms of N, S and O and can pass through carbon or nitrogen atom bonding in the rest part of molecule.
35, according to the compound of claim 34, R wherein 2Represent the 4-pyridine.
36, according to the compound of claim 35, R wherein 3Represent bicyclic heteroaryl or phenyl, wherein all these groups can be replaced by one or more substituting groups alternatively, substituting group be selected from halogen ,-NO 2,-OR c', C 1-6Alkyl and Cy, wherein C 1-6Alkyl can be alternatively by one or more R that are selected from bReplace with the substituting group of Cy*, any of group Cy or Cy* can be alternatively by one or more R that are selected from bAnd R cSubstituting group replace.
37, according to the compound of claim 34, R wherein 2Represent quilt-NR c' R c' the 4-pyrimidine that replaces; Wherein at R 2In:
Each R c' represent H or R independently c
Each R cRepresent C independently 1-6Alkyl, alternatively by one or more be selected from Cy and-substituting group of ORe ' replaces;
Each R e' represent H or R independently e
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