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CN101790526A - 5-heteroaryl substituted indazoles as kinase inhibitors - Google Patents

5-heteroaryl substituted indazoles as kinase inhibitors Download PDF

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Publication number
CN101790526A
CN101790526A CN200880102038A CN200880102038A CN101790526A CN 101790526 A CN101790526 A CN 101790526A CN 200880102038 A CN200880102038 A CN 200880102038A CN 200880102038 A CN200880102038 A CN 200880102038A CN 101790526 A CN101790526 A CN 101790526A
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China
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indazole
triazole
benzyl
alkyl
isoxazole
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CN200880102038A
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I·阿克里托普罗-赞泽
B·D·沃克菲尔德
H·马克
S·C·特纳
A·F·加西基
V·J·格拉恰斯
K·萨里斯
D·M·卡尔文
M·J·米奇默惠岑
Q·帅
J·R·帕特尔
M·巴克
N·托伊施
P·J·科瓦
S·W·久里克
A·J·龙
A·瓦苏德文
A·霍布森
N·圣约翰穆尔
L·王
D·乔治
B·李
K·弗兰克
E·F·约翰逊
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Abert & Co KG GmbH
Abbott GmbH and Co KG
Abbott Laboratories
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Abert & Co KG GmbH
Abbott GmbH and Co KG
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Abstract

The present invention relates to compounds of formula (I) or pharmaceutical acceptable salts, wherein A, R1, R2, R3 and m, are defined in the description. The present invention relates also to methods of making said compounds, and compositions containing said compounds which are useful for inhibiting kinases such as Glycogen Synthase kinase 3 (GSK-3), Rho kinase (ROCK), Janus Kinases (JAK), AKT, PAK4, PLK, CK2, KDR, MK2, JNK1, aurora, pim 1 and nek 2.

Description

Be used as the indazole compound of the 5-heteroaryl replacement of kinase inhibitor
Technical field
The present invention relates to comprise the compound of 5-substituted indazole, the method for preparing described compound, comprise described compound compositions, described compound can effectively suppress kinases such as Glycogen Synthase kinase 3 (GSK-3), Rho kinases (ROCK), Janus kinases (JAK), AKT, PAK4, PLK, CK2, KDR, MK2, JNK1, aurora, pim 1 and nek 2.
Background of invention
Protein kinase is a class catalysis phosphate group is transferred to the tyrosine, Serine, Threonine or the histidine residues that are positioned on the protein substrate from ATP a enzyme.Very clear and definite, protein kinase plays an important role in normal cell growth.Many growth factor receptor proteins have all had the intramolecularly zone of protein kinase effect, and it is by this function effect signal conduction.The interaction of somatomedin and its acceptor is the essential incident of cell growth normal regulating, and the phosphorylation state of substrate protein is relevant with cell growth modulating action usually.
As everyone knows, protein phosphorylation is unusual direct relevant with some morbid state or be the factor that works of these disease incidences.Therefore, protein kinase has become new study of pharmacy target (Cohen, p.Nature Reviews Drug Discovery, 1:309-315,2002).Clinically, use various kinases inhibitors and treated multiple disorders such as cancers, chronic inflammatory disease, diabetes and apoplexy.
Protein kinase is the many gang's enzymes of the big kind of the quantity of catalytic protein phosphorylation, plays a crucial role in cell signaling.According to its target protein, protein kinase can play the plus or minus regulating effect.Protein kinase is relevant with the specific signals pathway of regulating cell function, described cell function as but be not limited to metabolism, cell cycle progression, cell adhesion, vascular function, apoptosis and blood vessel and take place.Therefore, the cell signaling dysfunction is relevant with numerous disease, and the disease of tool feature comprises cancer and diabetes.Getting in touch between the signal transduction that cytokine is regulated and signaling molecule and proto-oncogene and the tumor suppressor gene clearly proved.Equally, diabetes, virus infection are also relevant with the regulating effect of protein kinase with the relation between its related symptoms.
Because protein kinase is almost regulated each cell processes, comprise metabolism, cell proliferation, cytodifferentiation and cell survival, so protein kinase is the noticeable target of interventional therapy various disease states.For example, wherein the cell cycle control that plays a crucial role of protein kinase occurs as the cell processes relevant with numerous disease with blood vessel, described disease as but be not limited to cancer, inflammatory diseases, blood vessel and take place unusually and relative disease, atherosclerosis, macular degeneration, diabetes, obesity and pain.
To what the explanation of relation between protein kinase complicacy and various protein kinase and the kinase pathways and interactional complicacy had given prominence to that exploitation can be used as protein kinase modulator, conditioning agent or inhibitor multiple kinases or multiple kinase pathways had the importance of useful active medicine.
Therefore, the someone advises that because the complicacy that signal cascade amplifies in the protein kinase approach cell, the medicine that may need to influence number of ways simultaneously reaches significant clinical activity.To the greatest extent possessor's suggestion provides the single medicine of combined effect to be very attractive notion, but needs to identify and use the single medicine of tool clinical effectiveness in specified disease background (setting) of the correct combination of target number of ways.
Glycogen synthase kinase-3 (GSK-3) is that these two kinds of isoforms are GSK-3 α and GSK-3 β by the Serine/Tyrosylprotein kinase of two kinds of isoforms coding, and molecular weight is respectively 51 and 47kDa.They share 97% sequence similarity in its kinase catalytic district.GSK-3 α isoform has the terminal tail of rich glycine N-of prolongation.The little splice variant of GSK-3 β (with total amount～15% express) identified and had 13 aminoacid insertion fragments in the kinases district.This variant reduces τ (albumen) is active.GSK-3 high conservative all in whole evolutionary process finds that so far it is present in all Mammalss, and the district has high homology at kinases.Two kinds of isoform expression in mammalian tissues are ubiquitous, comprise brain.Pharmacology GSK-3 inhibitor can not optionally suppress wherein a kind of isoform.
GSK-3 β plays an important role in the control of metabolism, differentiation and survival.It is accredited as the enzyme that can carry out phosphorylation at first, and therefore suppresses Glycogensynthase.Afterwards, everybody generally acknowledged that GSK-3 β and tau protein kinases 1 (TPK1) were identical, and this is a kind of enzyme at epi-position phosphorylation tau protein, finds that also it is by hyperphosphorylation in alzheimer's disease and several tau protein abnormal deposition neurodegeneration.
What is interesting is that the protein kinase B of GSK-3 β (AKT) phosphorylation can cause the kinase activity forfeiture, therefore has the people to propose some effects that this inhibition may mediate neurotrophic factor.In addition, the phosphorylation of the beta-catenin that is caused by GSK-3 β (a kind of albumen relevant with cell survival) can cause its degraded by ubiquitination (ubiquitinilation) dependence protein enzyme body approach.
Therefore, as if the activity of inhibition GSK-3 β can cause neurotrophic activity.Prove on evidence, lithium is as the noncompetitive inhibitor of GSK-3 β, can in some models, strengthen spinous process and take place, also can increase neuron survival rate, and can suppress of the expression of short apoptosis factor (proapoptotic factors) as P53 and Bax by inducing survival factors such as Bcl-2.
The additional studies amyloid beta can increase GSK-3 'beta ' activity and tau protein phosphorylation.And the neurotoxic effect of this hyperphosphorylation and amyloid beta can be chlorinated lithium and the retardance of GSK-3 β antisense mRNA.These researchs show that together GSK-3 β may process unusually and the contact thing between the tau protein hyperphosphorylation for two kinds of main pathological process: the APP (amyloid precursor protein) in the alzheimer's disease.
These experimental observations show that GSK-3 β can be effective to prevent and treat the neuropathology consequence reach cognition and the attention deficit relevant with alzheimer's disease, and other acute and chronic neurodegenerative disease.These diseases include but not limited to: Parkinson's disease, tau protein abnormal deposition neurodegeneration (as volume temporo top dementia, cortical degeneration, Pick's disease, stein-leventhal syndrome) and other dementia comprise vascular dementia; Acute apoplexy and other wound; Cerebrovascular accident (as relevant macular degeneration of age); Brain and spinal cord injuries receptor; Peripheral neuropathy; Retinopathy and glaucoma.
GSK-3 β also can be used for treating other disease, as: non-insulin-dependent diabetes mellitus (NIDDM) and obesity; Manic depressive illness; Schizophrenia; Bald; Inflammation; Cancer such as mammary cancer, nonsmall-cell lung cancer, thyroid carcinoma, T or B cell leukemia and several viral-induced tumour.
Rho kinases (ROCKs) as the first Rho effector that is described, is a serine/threonine kinase, and it is extremely important in the primary process of cell migration, cell proliferation and cell survival.In various illnesss, all observed the abnormal activation of Rho/ROCK approach.Because the example of the morbid state that the vasospasm activity of The compounds of this invention can effectively be treated comprises cardiovascular disorder such as hypertension, chronic and congestive heart failure, cardiac hypertrophy, restenosis, chronic renal failure, subarachnoid hemorrhage cerebral vasospasm, pulmonary hypertension and atherosclerosis.Its characteristic of flaccid muscles also can be of value to treatment asthma, male erectile dysfunction, Female sexual dysfunction and bladder excessive activities syndrome.Adult vertebrate brain of damage and spinal cord can activate ROCKs, thereby suppress axon growth and sprouting.Suppress ROCKs and can induce that new axon growth, aixs cylinder stride across damage rewiring (axonalrewiring across lesions within the CNS) among the CNS, the functional rehabilitation (Spinal injury, cerebral trauma) after adding rapid regeneration and strengthening the acute neuronal damage of Mammals.Suppress the Rho/ROCK approach and also be proved to be effective, described neurodegenerative disease such as apoplexy, inflammation and demyelination, alzheimer's disease the animal model and the treatment pain of other neurodegenerative disease.Therefore the Rho/ROCK approach restrainer can effectively prevent neurodegenerative disease, in the neurotization of various neuropathy moderate stimulation, described neuropathy comprises Spinal injury, alzheimer's disease, apoplexy, multiple sclerosis, amyotrophic lateral sclerosis (spinal cord) lateral sclerosis, also can treat pain.The ROCK inhibitor has shown to have anti-inflammatory property.Therefore, compound of the present invention can be used for treating neural inflammatory diseases such as apoplexy, multiple sclerosis, alzheimer's disease, Huntington Chorea, Parkinson's disease, amyotrophic lateral sclerosis (spinal cord) lateral sclerosis and inflammatory pain, and other inflammatory diseases such as rheumatoid arthritis, osteoarthritis, asthma, irritable bowel syndrome, Crohn's disease, psoriasis, ulcerative colitis, lupus and inflammatory bowel.Because the ROCK inhibitor can reduce cell proliferation and cell migration, so they can be used for treating cancer and metastases.In addition, evidence suggests that ROCK inhibitor support capable of inhibiting cell when poisoning intrusion resets, so they also have a potential therapeutic value in antiviral and antibacterial applications.The ROCK inhibitor also can be used for treating insulin resistant and diabetes.In addition, the ROCK inhibitor has shown the process (Abstract S02.3,8th World Congress onInflammation, Copenhagen, Denmark, June 16-20,2007) that can improve cystic fibrosis.
In addition, Rho-dependency coiled coil formation protein kinase (ROCK)-1 and-2 has shown and can strengthen myosin light chain (MLC) phosphorylation by suppressing MLC Phosphoric acid esterase and phosphorylation MLC.The adjusting that this causes Actin muscle-myosin to shrink.Nearest report proves, in the pneumonia model relevant with asthma, suppresses ROCK and can cause the inflammatory cell chemotaxis to be disintegrated, and suppress smooth muscle contraction.Therefore, the Rho/ROCK approach restrainer should can be used for treating asthma.
Janus kinases (JAKs) is important gang's intracellular protein Tyrosylprotein kinase (PTKs), has 4 kinds of Mammals member: JAK1, JAK2, JAK3 and TYK2, and the homologue in chicken, fish and fruit bat.JAKs plays a crucial role in the signal transduction path in several important cells, and described approach comprises (eponymous) JAK/STAT approach that adopts name to name, and the mediation of pair cell factor signal conduction is very important.Notion below this just vital role in cytokine signaling conduction has been supported: cause at cytokine activity can adopting specificity JAK inhibitor for treating under the situation of disease.The important example of this disease comprises autoimmune disease such as rheumatoid arthritis and psoriasis, myeloproliferative syndrome such as leukemia, lymphoma and cardiovascular disorder.
JAK2 as a member in the Janus kinases (JAK) of protein tyrosine kinase (PTKs) family, is the intramolecularly mediators of important cytokine signal conduction.The sudden change of JAK2 gene is relevant with leukemia, and the JAK activity is unusually also relevant with the panimmunity disease, comprises rheumatoid arthritis.
The Aurora kinases is gang's polygene mitotic division serine-threonine kinase, as the novel oncogene of a class.These kinases comprise aurora-A, aurora-B and aurora-B member.They are over-activity and/or overexpression in several solid tumors, and described solid tumor includes but not limited to mammary cancer, ovarian cancer, prostate cancer, carcinoma of the pancreas and colorectal carcinoma.Especially, aurora-A is the centrosome kinases, and the cell cycle is depended in its location, plays an important role in cell cycle progression and cell proliferation.Aurora-A is positioned at the 20ql3 chromosomal region, in several dissimilar malignant tumours, increase usually, described malignant tumour as but be not limited to colorectal carcinoma, mammary cancer and bladder cancer.Suppress the kinase whose activity of aurora and can help to reduce cell proliferation, tumor growth and the generation of potential tumour.
Therefore, but still need to develop the using method of the single medicine of the specificity set (specific sets) that comprises target kinases or kinase pathways.Thereby the correct combination that particularly influences many targets reaches the method for clinical effectiveness.
The invention summary
In main embodiment, the invention provides formula (I) compound or its pharmaceutically acceptable salt,
Figure GPA00001018010700061
Wherein
A is
Figure GPA00001018010700071
R 1Be hydrogen, alkyl, aryl, heterocycle, heteroaryl, R aR bN-, R cR dN-C (O)-or R cR dN-S (O) 2-;
R 2Be hydrogen, alkoxy carbonyl, alkyl, alkyl-carbonyl, aryl carbonyl, heterocycle carbonyl or R eR fN-alkyl-C (O)-;
R 3Be alkyl, alkoxyl group, aryl, cyano group, cycloalkyl, halogen, haloalkyl, heteroaryl, nitro or R gR hN-;
R 4Be alkyl, alkoxyalkyl, aryl, cycloalkyl, heteroaryl, heterocycle, Heterocyclylalkyl, R jR kN-or R jR kThe N-alkyl-;
R 5Be alkyl, aryl or heteroaryl;
R 6Be alkyl, alkoxyalkyl, R jR kThe N-alkyl-, aryl, cycloalkyl or heteroaryl;
R 7Be alkyl, aryl or heteroaryl;
R aAnd R bIndependent separately is hydrogen, alkyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroarylalkyl, R 4-C (O)-or R 5-S (O) 2-;
R cAnd R dIndependent separately is hydrogen, alkyl or heteroaryl;
R eAnd R fIndependent separately is hydrogen, alkyl, arylalkyl, heteroarylalkyl, R 6-C (O)-or R 7-S (O) 2-;
R gAnd R hIndependent separately is hydrogen, alkyl or alkyl-carbonyl;
R jAnd R kIndependent separately is hydrogen, alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl or heterocycle;
R i, R Ii, R Iii, R Iv, R v, R Vi, R Vii, R Viii, R Ix, R x, R Xi, R Xii, R Xiii, R Xiv, R Xv, R Xvi, R Xvii, R Xviii, R Xix, R Xx, R Xxi, R XxiiAnd R XxiiiIndependent separately is alkyl, alkoxyl group, alkoxyalkyl, alkoxy carbonyl, alkoxy carbonyl alkyl, aryl, arylalkyl, aryl (hydroxyl) alkyl, aromatic yloxy yl alkyl, aryl carbonyl, artyl sulfo alkyl, carboxyl, carboxyalkyl, cyano group alkyl, cycloalkyl, cycloalkylalkyl, naphthene base carbonyl, halogen, heteroaryl, heteroarylalkyl, heterocycle, Heterocyclylalkyl, heterocycle carbonyl, hydroxyalkyl, trialkylsilkl alkyl, H 2NC (O)-alkyl, Z aZ bN-, Z aZ bN alkyl, Z cZ dNC (O)-or Z cZ dNS (O) 2-, R wherein Xiv, R Xv, R Xvi, and R XviiAt compound (xiv), (xv), (xvi) or (xvii) go up any unappropriated valency (open valence) and locate to occur;
Z aAnd Z bIndependent separately is hydrogen, alkyl, alkoxy carbonyl alkyl, aryl, arylalkyl, cycloalkyl, H 2NC (O)-, H 2N alkyl C (O)-, H 2NC (O)-alkyl, dialkyl group NC (O)-or dialkyl group NC (O)-alkyl-;
Z cAnd Z dIndependent separately is hydrogen, alkyl, alkoxyalkyl, aryl, arylalkyl, aryl (hydroxyl) alkyl, cycloalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycle, Heterocyclylalkyl, hydroxyalkyl, H 2NC (O)-alkyl-, dialkyl group NC (O)-alkyl-, dialkyl group N-alkyl-or CHZ eZ f
Z eBe aryl or heteroaryl;
Z fBe heteroarylalkyl, Heterocyclylalkyl or Z 1Z 2The N-alkyl-;
M is 0,1 or 2;
A is 0 or 1;
B is 0,1 or 2;
C is 0,1,2 or 3; With
D is 0,1,2,3 or 4.
The present invention also provides pharmacy can accept composition, and described composition comprises formula (I) compound and the suitable pharmaceutical carrier for the treatment of significant quantity.
The objective of the invention is to can be used for preventing or treating the disease that causes unusually by protein kinase activity in order to provide.In addition, the present invention also provides the pharmacy compositions useful that can be used for preventing or treating the The compounds of this invention of described disease.
The invention still further relates to the medicinal compositions of the 5-substituted indazole compound that comprises at least one formula (I), it can be its pharmaceutically acceptable salt or prodrug forms, and described medicinal compositions can comprise or not comprise pharmaceutical acceptable carrier, coated tablet (dragees), assistant agent or other auxiliary substance.
The compounds of this invention has GSK-3, ROCK-1, ROCK-2, JAK2 and other kinase whose activity of inhibition, can be used for suppressing these kinases.Some compound of the present invention, can be used for selectivity and suppresses these kinases for optionally one or more kinases.Therefore, compound of the present invention can be used as preparation can prevent and/or treat the disease that is caused unusually by the FSK-3 activity, is more particularly the activeconstituents of the composition of neurodegenerative disease such as alzheimer's disease.In addition, compound of the present invention also can be used as the activeconstituents that preparation is used to prevent and/or treat the composition of following disease: neurodegenerative disease such as Parkinson's disease, tau protein abnormal deposition neurodegeneration (as volume temporo top dementia, cortical degeneration, Pick's disease, stein-leventhal syndrome) and other dementia comprise vascular dementia; Acute apoplexy and other wound; Cerebrovascular accident (as relevant macular degeneration of age); Brain and Spinal injury; Peripheral neuropathy; Retinopathy and glaucoma; And other disease such as non-insulin-dependent diabetes mellitus (NIDDM) (as type ii diabetes) and obesity; Manic depressive illness; Schizophrenia; Bald; Cancer such as mammary cancer, nonsmall-cell lung cancer, thyroid carcinoma, T or B cell leukemia and several viral-induced tumour.
Detailed Description Of The Invention
The compounds of this invention has above-mentioned formula (I).More particularly, formula (I) compound can include but not limited to wherein A for (ii), (iii), (iv), (vii), (x), (xiv), (xv), (xvi), (xvii), (xviii), (xix), (xx), (xxi), (xxii) or compound (xxiii).
In another embodiment of the present invention, formula (I) compound is disclosed, wherein A is for (ii),
Figure GPA00001018010700101
R 1Be hydrogen, aryl, heteroaryl, heterocycle, R aR bN-or R cR dN-C (O)-; R 2Be hydrogen, alkoxy carbonyl, heterocycle carbonyl, alkyl-carbonyl or R eR fN-alkyl-C (O)-; R 4Be alkyl, alkoxyalkyl, aryl, cycloalkyl, heterocycle, Heterocyclylalkyl, R jR kN-or R jR kThe N-alkyl-; R 5Be alkyl, aryl or heteroaryl; R aAnd R bIndependent separately is hydrogen, arylalkyl, cycloalkylalkyl, R 4-C (O)-or R 5-S (O) 2-; R cAnd R dIndependently be hydrogen or heteroaryl, R separately eAnd R fIndependent separately is hydrogen or alkyl, R jAnd R kIndependent separately is hydrogen, alkyl, aryl, cycloalkyl or heterocycle; R IiBe alkyl, alkoxyalkyl, alkoxy carbonyl, aryl, arylalkyl, aryl (hydroxyl) alkyl, aromatic yloxy yl alkyl, aryl carbonyl, alkoxy carbonyl alkyl, artyl sulfo alkyl, carboxyl, carboxyalkyl, cycloalkyl, cycloalkylalkyl, naphthene base carbonyl, halogen, heteroaryl, heteroarylalkyl, heterocycle, Heterocyclylalkyl, heterocycle carbonyl, hydroxyalkyl, trialkylsilkl alkyl, Z aZ bN-, Z aZ bThe N alkyl-or Z cZ dNC (O)-; Z aAnd Z bIndependent separately is hydrogen, alkyl or H 2N alkyl C (O)-; Z cAnd Z dIndependent separately be hydrogen, alkyl, alkoxyalkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroarylalkyl, Heterocyclylalkyl, hydroxyalkyl or dialkyl group N-alkyl-; M is 0; B is 0,1 or 2.
In another embodiment of the present invention, formula (I) compound is disclosed, wherein A is for (iii),
Figure GPA00001018010700111
R 1Be hydrogen or R aR bN-; R 2Be hydrogen; R 4Be R jR kThe N-alkyl-; R aAnd R bIndependent separately is hydrogen or R 4-C (O)-; R jAnd R kThe alkyl of respectively doing for oneself; R IiiBe alkoxy carbonyl alkyl, alkyl, arylalkyl, cyano group alkyl, Heterocyclylalkyl or H 2NC (O)-alkyl-; C is 0,1 or 2; M is 0.
In another embodiment of the present invention, formula (I) compound is disclosed, wherein A is for (iv),
Figure GPA00001018010700112
R 1Be hydrogen or R aR bN-; R 2Be hydrogen; R aAnd R bThe hydrogen of respectively doing for oneself; R IvBe aryl, arylalkyl, heterocycle, Heterocyclylalkyl, Z aZ bN alkyl or Z cZ dNS (O) 2-; Z aAnd Z bIndependent separately is hydrogen or alkyl; Z cAnd Z dThe alkyl of respectively doing for oneself; C is 0,1 or 2; M is 0.
In another embodiment of the present invention, formula (I) compound is disclosed, wherein A is (vii),
Figure GPA00001018010700113
R 1Be hydrogen, alkyl or R aR bN; R 2Be hydrogen; R aAnd R bThe hydrogen of respectively doing for oneself; R ViiBe alkyl, alkoxy carbonyl, aryl, arylalkyl, cycloalkyl, Heterocyclylalkyl, heterocycle carbonyl, hydroxyalkyl or Z cZ dNC (O)-; Z cAnd Z dIndependent separately is hydrogen, alkyl, alkoxyalkyl, aryl, arylalkyl, aryl (hydroxyl) alkyl, cycloalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycle, Heterocyclylalkyl, hydroxyalkyl or CHZ eZ fZ eBe aryl or heteroaryl, Z fBe heteroarylalkyl, Heterocyclylalkyl or Z 1Z 2The N-alkyl-; B is 1; M is 0.
In another embodiment of the present invention, formula (I) compound is disclosed, wherein A is (x),
Figure GPA00001018010700121
R 1Be hydrogen; R 2Be hydrogen; R xBe alkyl, aryl or Z aZ bN-; Z aAnd Z bIndependent separately is hydrogen, alkyl, aryl or arylalkyl; B is 1 or 2; M is 0.
In another embodiment of the present invention, formula (I) compound is disclosed, wherein A is (xiv),
Figure GPA00001018010700122
R 1Be hydrogen; R 2Be hydrogen; R XivBe Z aZ bN-; Z aAnd Z bIndependent separately is hydrogen or cycloalkyl; C is 1; M is 0.
In another embodiment of the present invention, formula (I) compound is disclosed, wherein A is (xv),
R 1Be hydrogen or R aR bN-; R 2Be hydrogen; R aAnd R bThe hydrogen of respectively doing for oneself; R XvBe Z aZ bN-; Z aAnd Z bIndependent separately is hydrogen, alkoxy carbonyl alkyl, aryl, arylalkyl or cycloalkyl; D is 0 or 1; M is 0.
In another embodiment of the present invention, formula (I) compound is disclosed, wherein A is (xvi),
Figure GPA00001018010700124
R 1Be hydrogen; R 2Be hydrogen; R XviBe Z aZ bN-; Z aAnd Z bIndependent separately is hydrogen or cycloalkyl; D is 1; M is 0.
In another embodiment of the present invention, formula (I) compound is disclosed, wherein A is (xvii),
Figure GPA00001018010700131
R 1Be hydrogen; R 2Be hydrogen; R XviiBe aryl or Z aZ bN-; Z aAnd Z bIndependent separately is hydrogen, alkyl, alkoxy carbonyl alkyl, aryl, arylalkyl, cycloalkyl or H 2NC (O)-alkyl-; D is 0 or 1; M is 0.
In another embodiment of the present invention, formula (I) compound is disclosed, wherein A is (xviii),
Figure GPA00001018010700132
R 1Be R aR bN-; R 2Be hydrogen; R aAnd R bThe hydrogen of respectively doing for oneself; C is 0; M is 0.
In another embodiment of the present invention, formula (I) compound is disclosed, wherein A is (xix),
Figure GPA00001018010700133
R 1Be R aR bN-; R 2Be hydrogen; R aAnd R bIndependent separately is hydrogen; C is 0; M is 0.
In another embodiment of the present invention, formula (I) compound is disclosed, wherein A is (xx),
Figure GPA00001018010700134
(xx)
R 1Be R aR bN-; R 2Be hydrogen; R 4Be R jR kThe N-alkyl-; R aAnd R bHydrogen or R respectively do for oneself 4-C (O)-; R jAnd R kIndependent is alkyl; R XxBe Z aZ bN-or heterocycle; Z aAnd Z bIndependent is hydrogen or alkyl; C is 0 or 1; M is 0.
In another embodiment of the present invention, formula (I) compound is disclosed, wherein A is (xxi),
Figure GPA00001018010700141
R 1Be R aR bN-; R 2Be hydrogen; R aAnd R bThe hydrogen of respectively doing for oneself; R XxiBe alkoxyl group; D is 1; M is 0.
In another embodiment of the present invention, formula (I) compound is disclosed, wherein A is (xxii),
Figure GPA00001018010700142
R 1Be R aR bN-; R 2Be hydrogen; R 4Be R jR kThe N-alkyl-; R aAnd R bIndependent separately is hydrogen or R 4-C (O)-; R jAnd R kThe alkyl of respectively doing for oneself; C is 0, and m is 0.
In another embodiment of the present invention, formula (I) compound is disclosed, wherein A is (xxiii),
Figure GPA00001018010700143
R 1Be R aR bN-; R 2Be hydrogen; R aAnd R bThe hydrogen of respectively doing for oneself; C is 0; M is 0.
Specific embodiment is a part of the present invention, and it includes but not limited to the compound as shown in the formula (I):
The mixture of 5-(1-benzyl-1H-1,2,3-triazole-4-yl)-1H-indazole and 5-(1-benzyl-1H-1,2,3-triazole-5-yl)-1H-indazole;
5-(1H-1,2,3-triazole-5-yl)-1H-indazole;
5-(1-benzyl-1H-1,2,3-triazole-4-yl)-1H-indazole;
5-[1-(2-methyl-benzyl)-1H-1,2,3-triazole-4-yl]-the 1H-indazole;
5-[1-(3-methyl-benzyl)-1H-1,2,3-triazole-4-yl]-the 1H-indazole;
5-[1-(4-methyl-benzyl)-1H-1,2,3-triazole-4-yl]-the 1H-indazole;
5-[1-(3-methoxy-benzyl)-1H-1,2,3-triazole-4-yl]-the 1H-indazole;
5-[1-(2-luorobenzyl)-1H-1,2,3-triazole-4-yl]-the 1H-indazole;
5-[1-(3-luorobenzyl)-1H-1,2,3-triazole-4-yl]-the 1H-indazole;
5-[1-(4-luorobenzyl)-1H-1,2,3-triazole-4-yl]-the 1H-indazole;
5-[1-(2-benzyl chloride base)-1H-1,2,3-triazole-4-yl]-the 1H-indazole;
5-[1-(3-benzyl chloride base)-1H-1,2,3-triazole-4-yl]-the 1H-indazole;
5-[1-(4-benzyl chloride base)-1H-1,2,3-triazole-4-yl]-the 1H-indazole;
5-[1-(2-bromobenzyl)-1H-1,2,3-triazole-4-yl]-the 1H-indazole;
5-[1-(2-nitrobenzyl)-1H-1,2,3-triazole-4-yl]-the 1H-indazole;
5-[1-(3-nitrobenzyl)-1H-1,2,3-triazole-4-yl]-the 1H-indazole;
5-[1-(4-nitrobenzyl)-1H-1,2,3-triazole-4-yl]-the 1H-indazole;
2-{[4-(1H-indazole-5-yl)-1H-1,2, the 3-triazol-1-yl] methyl } cyanobenzene;
3-{[4-(1H-indazole-5-yl)-1H-1,2, the 3-triazol-1-yl] methyl } cyanobenzene;
4-{[4-(1H-indazole-5-yl)-1H-1,2, the 3-triazol-1-yl] methyl } cyanobenzene;
5-{1-[2-(trifluoromethyl) benzyl]-1H-1,2,3-triazole-4-yl }-the 1H-indazole;
5-{1-[3-(trifluoromethyl) benzyl]-1H-1,2,3-triazole-4-yl }-the 1H-indazole;
5-{1-[4-(trifluoromethyl) benzyl]-1H-1,2,3-triazole-4-yl }-the 1H-indazole;
5-{1-[3-(trifluoromethoxy) benzyl]-1H-1,2,3-triazole-4-yl }-the 1H-indazole;
5-{1-[4-(trifluoromethoxy) benzyl]-1H-1,2,3-triazole-4-yl }-the 1H-indazole;
5-[1-(4-tertiary butyl benzyl)-1H-1,2,3-triazole-4-yl]-the 1H-indazole;
3-{[4-(1H-indazole-5-yl)-1H-1,2, the 3-triazol-1-yl] methyl } methyl benzoate;
4-{[4-(1H-indazole-5-yl)-1H-1,2, the 3-triazol-1-yl] methyl } methyl benzoate;
5-[1-(2, the 4-dimethyl benzyl)-1H-1,2,3-triazole-4-yl]-the 1H-indazole;
5-[1-(3, the 5-dimethyl benzyl)-1H-1,2,3-triazole-4-yl]-the 1H-indazole;
5-[1-(2, the 3-dichloro benzyl)-1H-1,2,3-triazole-4-yl]-the 1H-indazole;
5-[1-(2, the 4-dichloro benzyl)-1H-1,2,3-triazole-4-yl]-the 1H-indazole;
5-[1-(2, the 5-dichloro benzyl)-1H-1,2,3-triazole-4-yl]-the 1H-indazole;
5-[1-(3, the 5-dichloro benzyl)-1H-1,2,3-triazole-4-yl]-the 1H-indazole;
5-{1-[2, two (trifluoromethyl) benzyls of 4-]-1H-1,2,3-triazole-4-yl }-the 1H-indazole;
N-cyclohexyl-6-(1H-indazole-5-yl) imidazo [2,1-b] [1,3] thiazole-5-amine;
N-cyclohexyl-2-(1H-indazole-5-yl) imidazo [1,2-a] pyridine-3-amine;
N-cyclohexyl-2-(1H-indazole-5-yl) imidazo [1,2-a] pyrazine-3-amine;
5-[1-benzyl-4-(4-fluorophenyl)-1H-imidazoles-5-yl]-the 1H-indazole;
N-{3-[4-(4-fluorophenyl)-5-(1H-indazole-5-yl)-1H-imidazoles-1-yl] propyl group }-N, the N-dimethyl amine;
N-cyclohexyl-2-(1H-indazole-5-yl) imidazo [1,2-a] pyrimidine-3-amine;
5-[4-(4-fluorophenyl)-1-(1-phenylethyl)-1H-imidazoles-5-yl]-the 1H-indazole;
2-(1H-indazole-5-yl)-N-isopropylimdazole is [1,2-a] pyrimidine-3-amine also;
4-(1H-indazole-5-yl)-N-phenyl-1,3-thiazoles-2-amine;
5-(2-methyl isophthalic acid, 3-thiazole-4-yl)-1H-indazole;
N-ethyl-4-(1H-indazole-5-yl)-1,3-thiazoles-2-amine;
N-benzyl-4-(1H-indazole-5-yl)-1,3-thiazoles-2-amine;
4-(1H-indazole-5-yl)-1,3-thiazoles-2-amine;
4-(1H-indazole-5-yl)-N-(2-phenylethyl)-1,3-thiazoles-2-amine;
N-benzyl-2-(1H-indazole-5-yl) imidazo [1,2-a] pyrimidine-3-amine;
N-butyl-2-(1H-indazole-5-yl) imidazo [1,2-a] pyrimidine-3-amine;
N-(4-chloro-phenyl-)-2-(1H-indazole-5-yl) imidazo [1,2-a] pyrimidine-3-amine;
2-(1H-indazole-5-yl)-N-(4-p-methoxy-phenyl) imidazo [1,2-a] pyrimidine-3-amine;
2-(1H-indazole-5-yl) imidazo [1,2-a] pyrimidine;
N-[2-(1H-indazole-5-yl) imidazo [1,2-a] pyridin-3-yl] glycine methyl ester;
N-benzyl-2-(1H-indazole-5-yl) imidazo [1,2-a] pyridine-3-amine;
N-(4-chloro-phenyl-)-2-(1H-indazole-5-yl) imidazo [1,2-a] pyridine-3-amine;
2-(1H-indazole-5-yl)-N-(4-p-methoxy-phenyl) imidazo [1,2-a] pyridine-3-amine;
4-[4-(4-fluorophenyl)-5-(1H-indazole-5-yl)-1H-imidazoles-1-yl] piperidines-1-formic acid tertiary butyl ester;
3, two (1-benzyl-1H-1,2,3-triazole-4-the yl)-1H-indazoles of 5-;
5-(1-benzyl-1H-1,2,3-triazole-4-yl)-3-phenyl-1H-indazole;
5-(1-benzyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-amine;
5-(1-benzyl-1H-1,2,3-triazole-4-yl)-1-[(1-methyl piperidine-4-yl) carbonyl]-1H-indazole-3-amine;
N-[5-(1-benzyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-2-methoxyl group ethanamide;
N 1-[5-(1-benzyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-N 2, N 2-dimethyl G-NH2;
N-[5-(1-benzyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl] butyramide;
5-[4-(4-fluorophenyl)-1-piperidin-4-yl-1H-imidazoles-5-yl]-the 1H-indazole;
5-{4-(4-fluorophenyl)-1-[2-(1-methylpyrrolidin-2-yl) ethyl]-1H-imidazoles-5-yl }-the 1H-indazole;
5-{4-(4-fluorophenyl)-1-[3-(4-methylpiperazine-1-yl) propyl group]-1H-imidazoles-5-yl }-the 1H-indazole;
5-(1H-indazole-5-base) isoxazole-3-ethyl formate;
5-(1H-indazole-5-yl)-N-methyl-isoxazole-3-methane amide;
5-(3-Bian isoxazole-5-yl)-1H-indazole;
N-[5-(1-benzyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl] benzamide;
5-(3-propyl group isoxazole-5-base)-1H-indazole;
N-benzyl-4-(1H-indazole-5-yl)-5-phenyl-1,3-thiazoles-2-amine;
4-(1H-indazole-5-yl)-N, 5-phenylbenzene-1,3-thiazoles-2-amine;
5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazole-4-yl)-1H-indazole;
5-(1-benzyl-4-cyclopropyl-1H-1,2,3-triazole-5-yl)-1H-indazole;
2-(1H-indazole-5-yl)-3-phenylimidazole is [1,2-a] pyrimidine also;
5-[1-(tetrahydrochysene-2H-pyrans-4-ylmethyl)-1H-1,2,3-triazole-4-yl]-the 1H-indazole;
5-[3-(piperidines-1-base carbonyl) isoxazole-5-base]-the 1H-indazole;
5-(1H-indazole-5-yl)-N-phenyl-isoxazole azoles-3-methane amide;
N-cyclohexyl-5-(1H-indazole-5-base) isoxazole-3-methane amide;
5-[3-(piperidines-1-ylmethyl) isoxazole-5-base]-the 1H-indazole;
[5-(1H-indazole-5-base) isoxazole-3-base] methyl alcohol;
5-(1H-indazole-5-yl)-N-(2-methoxy ethyl) isoxazole-3-methane amide;
5-(1-benzyl-5-phenyl-1H-1,2,3-triazole-4-yl)-1H-indazole;
5-(4-benzyl-1H-1,2,3-triazol-1-yl)-1H-indazole;
5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-amine;
5-(1-benzyl-4-cyclopropyl-1H-1,2,3-triazole-5-yl)-1H-indazole-3-amine;
5-(3-isobutyl-isoxazole-5-base)-1H-indazole-3-amine;
5-(3-Bian isoxazole-5-yl)-1H-indazole-3-amine;
N-{2-[4-(4-fluorophenyl)-5-(1H-indazole-5-yl)-1H-imidazoles-1-yl] ethyl }-N, the N-dimethyl amine;
5-[4-(4-fluorophenyl)-1-(3-morpholine-4-base propyl group)-1H-imidazoles-5-yl]-the 1H-indazole;
5-[4-(4-fluorophenyl)-1-(3-tetramethyleneimine-1-base propyl group)-1H-imidazoles-5-yl]-the 1H-indazole;
5-{4-(4-fluorophenyl)-1-[2-(4-methyl piperidine-1-yl) ethyl]-1H-imidazoles-5-yl }-the 1H-indazole;
5-[1-(1-benzyl piepridine-4-yl)-4-(4-fluorophenyl)-1H-imidazoles-5-yl]-the 1H-indazole;
5-[4-(4-fluorophenyl)-1-(2-morpholine-4-base ethyl)-1H-imidazoles-5-yl]-the 1H-indazole;
5-[1-(1-benzyl-pyrrole alkane-3-yl)-4-(4-fluorophenyl)-1H-imidazoles-5-yl]-the 1H-indazole;
2-{4-[4-(4-fluorophenyl)-5-(1H-indazole-5-yl)-1H-imidazoles-1-yl] piperidines-1-yl }-2-oxo ethanol;
5-(1-benzyl-5-phenyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-amine;
2-[1-(1H-indazole-5-yl)-1H-1,2,3-triazole-4-yl] propan-2-ol;
5-[4-(methoxymethyl)-1H-1,2, the 3-triazol-1-yl]-the 1H-indazole;
1-[1-(1H-indazole-5-yl)-1H-1,2,3-triazole-4-yl]-the 1-phenylethyl alcohol;
5-(4-propyl group-1H-1,2,3-triazol-1-yl)-1H-indazole;
1-[1-(1H-indazole-5-yl)-1H-1,2,3-triazole-4-yl] propan-2-ol;
3-[1-(1H-indazole-5-yl)-1H-1,2,3-triazole-4-yl] third-1-alcohol;
1-{[1-(1H-indazole-5-yl)-1H-1,2,3-triazole-4-yl] methyl }-1H-1,2, the 3-benzotriazole;
5-{4-[(phenyl sulfenyl) methyl]-1H-1,2, the 3-triazol-1-yl }-the 1H-indazole;
5-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-1H-indazole;
5-[4-(2-phenylethyl)-1H-1,2, the 3-triazol-1-yl]-the 1H-indazole;
5-[4-(cyclohexyl methyl)-1H-1,2, the 3-triazol-1-yl]-the 1H-indazole;
5-(4-cyclopentyl-1H-1,2,3-triazol-1-yl)-1H-indazole;
1-[1-(1H-indazole-5-yl)-1H-1,2,3-triazole-4-yl] hexalin;
5-[4-(phenoxymethyl)-1H-1,2, the 3-triazol-1-yl]-the 1H-indazole;
5-{4-[(1,1-dioxo thiomorpholine-4-yl) methyl]-1H-1,2, the 3-triazol-1-yl }-the 1H-indazole;
5-[4-(3-phenyl propyl)-1H-1,2, the 3-triazol-1-yl]-the 1H-indazole;
[1-benzyl-4-(1H-indazole-5-yl)-1H-1,2,3-triazole-5-yl] (phenyl) ketone;
N, N-diethyl-N-{[1-(1H-indazole-5-yl)-1H-1,2,3-triazole-4-yl] methyl } amine;
N-[2-(1H-indazole-5-yl) imidazo [1,2-a] pyrimidin-3-yl]-the Beta-alanine ethyl ester;
5-(1-benzyl-5-methyl isophthalic acid H-1,2,3-triazole-4-yl)-1H-indazole;
5-(1-benzyl-5-methyl isophthalic acid H-1,2,3-triazole-4-yl)-1H-indazole-3-amine;
N 3-[2-(1H-indazole-5-yl) imidazo [1,2-a] pyrimidin-3-yl]-β-alanimamides;
5-(1-benzyl-5-iodo-1H-1,2,3-triazole-4-yl)-1H-indazole-3-amine;
N-{3-[4-(3-amino-1H-indazole-5-yl)-1-benzyl-1H-1,2,3-triazole-5-yl] phenyl }-N '-(3-aminomethyl phenyl) urea;
5-(1H-indazole-5-yl)-N-(2-isopropoxy ethyl) isoxazole-3-methane amide;
5-[3-(morpholine-4-base carbonyl) isoxazole-5-base]-the 1H-indazole;
5-(1H-indazole-5-yl)-N-(3-morpholine-4-base propyl group) isoxazole-3-methane amide;
N-[2-(1H-imidazol-4 yl) ethyl]-5-(1H-indazole-5-base) isoxazole-3-methane amide;
(3R)-and 1-{[5-(1H-indazole-5-base) isoxazole-3-base] carbonyl } piperidines-3-alcohol;
1-{[5-(1H-indazole-5-base) isoxazole-3-base] carbonyl } piperidines-3-methane amide;
2-[2-(4-{[5-(1H-indazole-5-base) isoxazole-3-base] carbonyl } piperazine-1-yl) oxyethyl group] ethanol;
The 5-{3-[(4-methyl isophthalic acid, 4-Diazesuberane-1-yl) carbonyl] isoxazole-5-base }-the 1H-indazole;
N-(3-hydroxypropyl)-5-(1H-indazole-5-base) isoxazole-3-methane amide;
N-[(1R)-2-hydroxyl-1-phenylethyl]-5-(1H-indazole-5-base) isoxazole-3-methane amide;
N-[3-(1H-imidazoles-1-yl) propyl group]-5-(1H-indazole-5-base) isoxazole-3-methane amide;
5-(1H-indazole-5-yl)-N-[3-(2-oxo-pyrrolidine-1-yl) propyl group] isoxazole-3-methane amide;
N-{2-[4-(amino-sulfonyl) phenyl] ethyl }-5-(1H-indazole-5-base) isoxazole-3-methane amide;
[1-benzyl-4-(1H-indazole-5-yl)-1H-1,2,3-triazole-5-yl] (3-chloro-phenyl-) ketone;
[1-benzyl-4-(1H-indazole-5-yl)-1H-1,2,3-triazole-5-yl] (cyclopropyl) ketone;
5-[5-cyclopropyl-1-(tetrahydrochysene-2H-pyrans-4-ylmethyl)-1H-1,2,3-triazole-4-yl]-the 1H-indazole;
N 1-{ [1-benzyl-4-(1H-indazole-5-yl)-1H-1,2,3-triazole-5-yl] methyl } G-NH2;
(4-fluorophenyl) [4-(1H-indazole-5-yl)-1-(tetrahydrochysene-2H-pyrans-4-ylmethyl)-1H-1,2,3-triazole-5-yl] ketone;
(4-chloro-phenyl-) [4-(1H-indazole-5-yl)-1-(tetrahydrochysene-2H-pyrans-4-ylmethyl)-1H-1,2,3-triazole-5-yl] ketone;
(3-chloro-phenyl-) [4-(1H-indazole-5-yl)-1-(tetrahydrochysene-2H-pyrans-4-ylmethyl)-1H-1,2,3-triazole-5-yl] ketone;
(2-chloro-phenyl-) [4-(1H-indazole-5-yl)-1-(tetrahydrochysene-2H-pyrans-4-ylmethyl)-1H-1,2,3-triazole-5-yl] ketone;
Cyclopentyl [4-(1H-indazole-5-yl)-1-(tetrahydrochysene-2H-pyrans-4-ylmethyl)-1H-1,2,3-triazole-5-yl] ketone;
1-benzyl-4-(1H-indazole-5-yl)-1H-1,2,3-triazole-5-formic acid;
5-{5-(4-fluorophenyl)-1-[4-(trifluoromethyl) benzyl]-1H-1,2,3-triazole-4-yl }-1H-indazole-3-amine;
5-[1-benzyl-5-(4-fluorophenyl)-1H-1,2,3-triazole-4-yl]-1H-indazole-3-amine;
[4-(1H-indazole-5-yl)-1-(tetrahydrochysene-2H-pyrans-4-ylmethyl)-1H-1,2,3-triazole-5-yl] (tetrahydrochysene-2H-pyrans-4-yl) ketone;
5-[1-benzyl-5-(2-aminomethyl phenyl)-1H-1,2,3-triazole-4-yl]-the 1H-indazole;
5-{1-benzyl-5-[(4-methylpiperazine-1-yl) carbonyl]-1H-1,2,3-triazole-4-yl }-the 1H-indazole;
1-{[1-benzyl-4-(1H-indazole-5-yl)-1H-1,2,3-triazole-5-yl] carbonyl } piperidines-4-alcohol;
1-ethanoyl-5-[5-(4-fluorophenyl)-1-(tetrahydrochysene-2H-pyrans-4-ylmethyl)-1H-1,2,3-triazole-4-yl]-the 1H-indazole;
1-benzyl-4-(1H-indazole-5-yl)-N, N-dimethyl-1H-1,2,3-triazole-5-methane amide;
N, 1-dibenzyl-4-(1H-indazole-5-yl)-1H-1,2,3-triazole-5-methane amide;
N-(2-hydroxyl-2-phenylethyl)-5-(1H-indazole-5-yl)-N-methyl-isoxazole-3-methane amide;
N-[(1S)-2-hydroxyl-1-phenylethyl]-5-(1H-indazole-5-base) isoxazole-3-methane amide;
N-benzyl-N-(2-hydroxyethyl)-5-(1H-indazole-5-base) isoxazole-3-methane amide;
5-[1-benzyl-5-(2-aminomethyl phenyl)-1H-1,2,3-triazole-4-yl]-3-methyl isophthalic acid H-indazole;
5-[1-benzyl-5-(2-aminomethyl phenyl)-1H-1,2,3-triazole-4-yl]-1H-indazole-3-amine;
2-{2-[1-(1H-indazole-5-yl)-1H-1,2,3-triazole-4-yl] ethyl }-1H-isoindole-1,3 (2H)-diketone;
5-{4-[(2, the 4-dichlorophenoxy) methyl]-1H-1,2, the 3-triazol-1-yl }-the 1H-indazole;
5-{4-[(2, the 6-dichlorophenoxy) methyl]-1H-1,2, the 3-triazol-1-yl }-the 1H-indazole;
5-[5-(4-fluorophenyl)-1-(tetrahydrochysene-2H-pyrans-4-ylmethyl)-1H-1,2,3-triazole-4-yl]-the 1H-indazole;
1-{[1-(1H-indazole-5-yl)-1H-1,2,3-triazole-4-yl] methyl }-the 1H-indazole;
5-[1-benzyl-5-(piperidines-1-base carbonyl)-1H-1,2,3-triazole-4-yl]-the 1H-indazole;
5-[5-(2-aminomethyl phenyl)-1-(tetrahydrochysene-2H-pyrans-4-ylmethyl)-1H-1,2,3-triazole-4-yl]-the 1H-indazole;
5-[5-(2-aminomethyl phenyl)-1-(tetrahydrochysene-2H-pyrans-4-ylmethyl)-1H-1,2,3-triazole-4-yl]-1H-indazole-3-amine;
5-[1-benzyl-5-(morpholine-4-base carbonyl)-1H-1,2,3-triazole-4-yl]-the 1H-indazole;
5-[1-benzyl-5-(4-p-methoxy-phenyl)-1H-1,2,3-triazole-4-yl]-1H-indazole-3-amine;
N-[(1S)-1-benzyl-2-hydroxyethyl]-5-(1H-indazole-5-base) isoxazole-3-methane amide;
N-[(1S, 2R)-2-hydroxyl-2,3-dihydro-1H-indenes-1-yl]-5-(1H-indazole-5-base) isoxazole-3-methane amide;
5-{3-[(3-phenylmorpholine-4-yl) carbonyl] isoxazole-5-base }-the 1H-indazole;
N-benzyl-5-(1H-indazole-5-base) isoxazole-3-methane amide;
((1S)-2-{[5-(1H-indazole-5-base) isoxazole-3-base] carbonyl }-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-1-yl) methyl alcohol;
N-[(1R)-3-hydroxyl-1-phenyl propyl]-5-(1H-indazole-5-base) isoxazole-3-methane amide;
N-[(1S)-3-hydroxyl-1-phenyl propyl]-5-(1H-indazole-5-base) isoxazole-3-methane amide;
N-2,3-dihydro-1H-indenes-1-base-5-(1H-indazole-5-base) isoxazole-3-methane amide;
N-2,3-dihydro-1H-indenes-2-base-5-(1H-indazole-5-base) isoxazole-3-methane amide;
5-(1H-indazole-5-yl)-N-(1-phenyl propyl) isoxazole-3-methane amide;
5-{1-benzyl-5-[3-(dimethylamino) phenyl]-1H-1,2,3-triazole-4-yl }-1H-indazole-3-amine;
5-{1-benzyl-5-[4-(dimethylamino) phenyl]-1H-1,2,3-triazole-4-yl }-1H-indazole-3-amine;
N-{3-[4-(3-amino-1H-indazole-5-yl)-1-benzyl-1H-1,2,3-triazole-5-yl] phenyl } ethanamide;
N-{4-[4-(3-amino-1H-indazole-5-yl)-1-benzyl-1H-1,2,3-triazole-5-yl] phenyl } ethanamide;
5-{1-benzyl-5-[3-(1H-pyrazol-1-yl) phenyl]-1H-1,2,3-triazole-4-yl }-1H-indazole-3-amine;
5-[1-benzyl-5-(1-methyl isophthalic acid H-pyrazoles-4-yl)-1H-1,2,3-triazole-4-yl]-1H-indazole-3-amine;
3-[4-(3-amino-1H-indazole-5-yl)-1-benzyl-1H-1,2,3-triazole-5-yl]-the N-phenylbenzamaide;
3-[4-(3-amino-1H-indazole-5-yl)-1-benzyl-1H-1,2,3-triazole-5-yl]-N-benzyl benzamide;
5-[1-benzyl-5-(1-Methyl-1H-indole-5-yl)-1H-1,2,3-triazole-4-yl]-1H-indazole-3-amine;
5-[1-benzyl-5-(3-p-methoxy-phenyl)-1H-1,2,3-triazole-4-yl]-1H-indazole-3-amine;
5-[1-benzyl-5-(3-morpholine-4-base phenyl)-1H-1,2,3-triazole-4-yl]-1H-indazole-3-amine;
5-[3-(1,3-dihydro-2H-isoindole-2-base carbonyl) isoxazole-5-base]-the 1H-indazole;
5-{3-[(4-methyl-2-phenylpiperazine-1-yl) carbonyl] isoxazole-5-base }-the 1H-indazole;
1-{[1-benzyl-4-(1H-indazole-5-yl)-1H-1,2,3-triazole-5-yl] carbonyl } piperidines-4-amine;
N-[5-(1-benzyl-5-phenyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl] benzamide;
N-[5-(1-benzyl-5-phenyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl] benzsulfamide;
N-[5-(1-benzyl-5-phenyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-N '-(4-p-methoxy-phenyl) urea;
N-[5-(1-benzyl-5-phenyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl] butyramide;
N-[5-(1-benzyl-5-phenyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-the 2-methyl propanamide;
N-[5-(1-benzyl-5-phenyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl] cyclopropane carboxamide;
N-[1-benzoyl-5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl] benzamide;
N-[5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-the 3-fluorobenzamide;
N-[5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl] benzamide;
N-benzyl-5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-amine;
N-[(1R)-1-benzyl-2-hydroxyethyl]-5-(1H-indazole-5-base) isoxazole-3-methane amide;
5-(1-benzyl-1H-pyrazoles-4-yl)-1H-indazole;
N-[(1R)-3-hydroxyl-1-phenyl propyl]-5-(3-methyl isophthalic acid H-indazole-5-base) isoxazole-3-methane amide;
3-[4-(3-amino-1H-indazole-5-yl)-1-benzyl-1H-1,2,3-triazole-5-yl] phenol;
3-[4-(3-amino-1H-indazole-5-yl)-1-benzyl-1H-1,2,3-triazole-5-yl] benzamide;
5-{1-benzyl-5-[4-(methyl sulphonyl) phenyl]-1H-1,2,3-triazole-4-yl }-1H-indazole-3-amine;
N-[5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-the 2-chlorobenzamide;
N-[5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-the 4-chlorobenzamide;
N-[5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl] ethyl sulfonamide;
N-[5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl] benzsulfamide;
N-[5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-the 2-chlorobenzene sulfonamide;
N-[5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-the 3-chlorobenzene sulfonamide;
N-[5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-the 4-chlorobenzene sulfonamide;
N-[5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-2,5-dimethyl furan-3-sulphonamide;
5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazole-4-yl)-N-(2-benzyl chloride base)-1H-indazole-3-amine;
5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazole-4-yl)-N-(3-benzyl chloride base)-1H-indazole-3-amine;
N-[5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-the 3-chlorobenzamide;
N-[5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-the 2-furoamide;
5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazole-4-yl)-N-ethyl-1H-indazole-3-amine;
5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazole-4-yl)-N-(4-benzyl chloride base)-1H-indazole-3-amine;
5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazole-4-yl)-N-(3-furyl methyl)-1H-indazole-3-amine;
N-[5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-N '-[5-methyl-2-(trifluoromethyl)-3-furyl] urea;
N-[5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-the 3-furoamide;
5-(1H-indazole-5-yl)-N-[(1S)-1-phenyl propyl] isoxazole-3-methane amide;
5-(1H-indazole-5-yl)-N-[(1R)-1-phenyl propyl] isoxazole-3-methane amide;
5-(1-benzyl-1H-pyrazoles-4-yl)-1H-indazole-3-amine;
1-benzyl-4-(1H-indazole-5-yl)-N-[(2S)-tetrahydrofuran (THF)-2-ylmethyl]-1H-1,2,3-triazole-5-methane amide;
1-benzyl-4-(1H-indazole-5-yl)-N-(2-isopropoxy ethyl)-1H-1,2,3-triazole-5-methane amide;
1-benzyl-4-(1H-indazole-5-yl)-N-[(2R)-tetrahydrofuran (THF)-2-ylmethyl]-1H-1,2,3-triazole-5-methane amide;
1-benzyl-4-(1H-indazole-5-yl)-N-(tetrahydrofuran (THF)-3-ylmethyl)-1H-1,2,3-triazole-5-methane amide;
1-benzyl-N-cyclopentyl-4-(1H-indazole-5-yl)-1H-1,2,3-triazole-5-methane amide;
1-benzyl-N-(cyclopentyl-methyl)-4-(1H-indazole-5-yl)-1H-1,2,3-triazole-5-methane amide;
1-benzyl-N-ethyl-4-(1H-indazole-5-yl)-N-methyl isophthalic acid H-1,2,3-triazole-5-methane amide;
1-benzyl-4-(1H-indazole-5-yl)-N-sec.-propyl-N-methyl isophthalic acid H-1,2,3-triazole-5-methane amide;
1-benzyl-4-(1H-indazole-5-yl)-N-(2-methoxy ethyl)-N-methyl isophthalic acid H-1,2,3-triazole-5-methane amide;
1-benzyl-4-(1H-indazole-5-yl)-N-phenyl-1H-1,2,3-triazole-5-methane amide;
1-benzyl-N-(4-chloro-phenyl-)-4-(1H-indazole-5-yl)-1H-1,2,3-triazole-5-methane amide;
1-benzyl-4-(1H-indazole-5-yl)-N-(2-morpholine-4-base ethyl)-1H-1,2,3-triazole-5-methane amide;
1-benzyl-N-[2-(dimethylamino) ethyl]-4-(1H-indazole-5-yl)-N-methyl isophthalic acid H-1,2,3-triazole-5-methane amide;
1-benzyl-N-(2-hydroxyethyl)-4-(1H-indazole-5-yl)-N-propyl group-1H-1,2,3-triazole-5-methane amide;
1-benzyl-N-[3-(dimethylamino) propyl group]-4-(1H-indazole-5-yl)-N-methyl isophthalic acid H-1,2,3-triazole-5-methane amide;
1-benzyl-N-[2-(diethylamino) ethyl]-4-(1H-indazole-5-yl)-N-methyl isophthalic acid H-1,2,3-triazole-5-methane amide;
N, 1-dibenzyl-N-ethyl-4-(1H-indazole-5-yl)-1H-1,2,3-triazole-5-methane amide;
N, 1-dibenzyl-N-(2-hydroxyethyl)-4-(1H-indazole-5-yl)-1H-1,2,3-triazole-5-methane amide;
(3R)-and 1-{[1-benzyl-4-(1H-indazole-5-yl)-1H-1,2,3-triazole-5-yl] carbonyl } piperidines-3-alcohol;
1-{[1-benzyl-4-(1H-indazole-5-yl)-1H-1,2,3-triazole-5-yl] carbonyl } piperidines-4-methane amide;
5-{1-benzyl-5-[(2,6-thebaine-4-yl) carbonyl]-1H-1,2,3-triazole-4-yl }-the 1H-indazole;
5-{5-[(4-ethanoyl piperazine-1-yl) carbonyl]-1-benzyl-1H-1,2,3-triazole-4-yl }-the 1H-indazole;
5-{1-benzyl-5-[(4-phenylpiperazine-1-yl) carbonyl]-1H-1,2,3-triazole-4-yl }-the 1H-indazole;
The 1-benzyl-N-[(1R)-1-(hydroxymethyl)-2-methyl-propyl]-4-(1H-indazole-5-yl)-1H-1,2,3-triazole-5-methane amide;
The 1-benzyl-N-[(1S)-1-(hydroxymethyl)-2-methyl-propyl]-4-(1H-indazole-5-yl)-1H-1,2,3-triazole-5-methane amide;
1-benzyl-N-[3-(1H-imidazoles-1-yl) propyl group]-4-(1H-indazole-5-yl)-1H-1,2,3-triazole-5-methane amide;
N-[5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-N '-ethyl carbamide;
N-[5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-N '-phenylurea;
N-benzyl-N '-[5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl] urea;
N-[5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-N '-(2-chloro-phenyl-) urea;
N-[5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-N '-(3-chloro-phenyl-) urea;
N-[5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-N '-(4-chloro-phenyl-) urea;
N-[5-(1-benzyl-5-iodo-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl] benzamide;
3-[4-(3-amino-1H-indazole-5-yl)-1H-pyrazol-1-yl] propionitrile;
2-[4-(3-amino-1H-indazole-5-yl)-1H-pyrazol-1-yl] ethanamide;
3-[4-(3-amino-1H-indazole-5-yl)-1H-pyrazol-1-yl] methyl propionate;
3-[4-(3-amino-1H-indazole-5-yl)-1H-pyrazol-1-yl] propionic acid amide;
[4-(3-amino-1H-indazole-5-yl)-1H-pyrazol-1-yl] acetonitrile;
4-(3-amino-1H-indazole-5-yl)-N, N-dimethyl-1H-imidazoles-1-sulphonamide;
5-pyrazine-2-base-1H-indazole-3-amine;
5-thiophene-2-base-1H-indazole-3-amine;
5-(2-aminopyrimidine-4-yl)-1H-indazole-3-amine;
5-(2-methoxypyridine-3-yl)-1H-indazole-3-amine;
5-imidazo [1,2-a] pyridin-3-yl-1H-indazole-3-amine;
N 2, N 2-dimethyl-N 1-[5-(1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl] G-NH2;
5-(1H-pyrazoles-5-yl)-1H-indazole-3-amine;
5-(4-methyl isophthalic acid H-imidazoles-5-yl)-1H-indazole-3-amine;
5-(1H-imidazol-4 yl)-1H-indazole-3-amine;
N 2, N 2-dimethyl-N 1-5-[1-(3-methyl-benzyl)-1H-1,2,3-triazole-4-yl]-1H-indazole-3-yl } G-NH2;
5-(1-benzyl-1H-imidazol-4 yl)-1H-indazole-3-amine;
N 1-5-[1-(4-tertiary butyl benzyl)-1H-1,2,3-triazole-4-yl]-1H-indazole-3-yl }-N 2, N 2-dimethyl G-NH2;
N 2, N 2-dimethyl-N 1-5-[1-(2-piperidines-1-base ethyl)-1H-1,2,3-triazole-4-yl]-1H-indazole-3-yl } G-NH2;
N 2, N 2-dimethyl-N 1-5-[1-(2-morpholine-4-base ethyl)-1H-1,2,3-triazole-4-yl]-1H-indazole-3-yl } G-NH2;
N 1-(5-{1-[2-(3,5-dimethyl isoxazole-4-yl) ethyl]-1H-1,2,3-triazole-4-yl }-1H-indazole-3-yl)-N 2, N 2-dimethyl G-NH2;
N 1-(5-{1-[2-(3,5-dimethyl-1H-pyrazoles-4-yl) ethyl]-1H-1,2,3-triazole-4-yl }-1H-indazole-3-yl)-N 2, N 2-dimethyl G-NH2;
2-(4-{3-[(N, N-dimethyl glycyl) amino]-1H-indazole-5-yl }-1H-1,2, the 3-triazol-1-yl)-2 Methylpropionic acid;
(4-{3-[(N, N-dimethyl glycyl) amino]-1H-indazole-5-yl }-1H-1,2, the 3-triazol-1-yl) ethyl acetate;
N 2, N 2-dimethyl-N 1-(5-{1-[(trimethyl silyl) methyl]-1H-1,2,3-triazole-4-yl }-1H-indazole-3-yl) G-NH2;
N 1-[5-(3-furyl)-1H-indazole-3-yl]-N 2, N 2-dimethyl G-NH2;
N 2, N 2-dimethyl-N 1-[5-(1H-pyrazoles-5-yl)-1H-indazole-3-yl] G-NH2;
N 2, N 2-dimethyl-N 1-(5-pyrimidine-5-base-1H-indazole-3-yl) G-NH2;
N 1-[5-(2,1,3-Ben Bing oxadiazole-5-yl)-1H-indazole-3-yl]-N 2, N 2-dimethyl G-NH2;
N 2, N 2-dimethyl-N 1-[5-(1H-pyrazoles-4-yl)-1H-indazole-3-yl] G-NH2;
N 2, N 2-dimethyl-N 1-[5-(1-methyl isophthalic acid H-pyrazoles-4-yl)-1H-indazole-3-yl] G-NH2;
N 1-[5-(3,5-dimethyl-1H-pyrazoles-4-yl)-1H-indazole-3-yl]-N 2, N 2-dimethyl G-NH2;
N 1-5-[2-(dimethylamino) pyrimidine-5-yl]-1H-indazole-3-yl }-N 2, N 2-dimethyl G-NH2;
N 2, N 2-dimethyl-N 1-[5-(2-morpholine-4-yl pyrimidines-5-yl)-1H-indazole-3-yl] G-NH2;
N 2, N 2-dimethyl-N 1-5-[1-(2-morpholine-4-base ethyl)-1H-pyrazoles-4-yl]-1H-indazole-3-yl } G-NH2;
N 1-[5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-N 2, N 2-dimethyl G-NH2;
N 1-[5-(1-benzyl-1H-pyrazoles-4-yl)-1H-indazole-3-yl]-N 2, N 2-dimethyl G-NH2;
N 1-[5-(1-benzyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-N 2-methyl G-NH2;
N-[5-(1-benzyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-2-tetramethyleneimine-1-yl acetamide;
N 1-[5-(1-benzyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-N 2-cyclopentyl G-NH2;
N 1-[5-(1-benzyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-N 2-cyclopropyl G-NH2;
N 1-[5-(1-benzyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-N 2-tetrahydrochysene-2H-pyrans-4-base G-NH2;
N-[5-(1-benzyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-2-(3-hydroxyl pyrrolidine-1-yl) ethanamide;
N-[5-(1-benzyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-2-(3-hydroxy piperidine-1-yl) ethanamide;
N 1-[5-(1-benzyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-N 3, N 3-dimethyl-β-alanimamides;
N-[5-(1-benzyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-2-morpholine-4-yl acetamide;
N-[5-(1-benzyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-2-(4-methylpiperazine-1-yl) ethanamide;
N-[5-(1-benzyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-2-(3-oxo piperazine-1-yl) ethanamide;
N 1-[5-(1-benzyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-N 2-sec.-propyl G-NH2;
N 1-[5-(1-benzyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-N 2-cyclohexyl G-NH2;
N-[5-(1-benzyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl] ethanamide;
N 1-[5-(1-benzyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-N 2-cyclobutyl G-NH2;
N-[5-(1-benzyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-N '-propyl group urea;
N-[5-(1-benzyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl] ethyl sulfonamide;
5-(1-benzyl-1H-1,2,3-triazole-4-yl)-N-(cyclopropyl methyl)-1H-indazole-3-amine;
N-[5-(1-benzyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-N '-ethyl carbamide;
1-[5-(1-benzyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl] pyrrolidin-2-one;
N-[5-(1-benzyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-4-(dimethylamino) butyramide;
N-3, the heterochromatic alkene of 4-dihydro-1H-(isochromen)-4-base-5-(1H-indazole-5-base) isoxazole-3-methane amide;
N-(cyclohexyl methyl)-5-(1H-indazole-5-base) isoxazole-3-methane amide;
N-(3-benzyl chloride base)-5-(1H-indazole-5-base) isoxazole-3-methane amide;
5-(1H-indazole-5-yl)-N-(2-methoxy-benzyl) isoxazole-3-methane amide;
5-(1H-indazole-5-yl)-N-[2-(trifluoromethyl) benzyl] isoxazole-3-methane amide;
5-(1H-indazole-5-yl)-N-[3-(trifluoromethyl) benzyl] isoxazole-3-methane amide;
5-(1H-indazole-5-yl)-N-[4-(trifluoromethyl) benzyl] isoxazole-3-methane amide;
5-(1H-indazole-5-yl)-N-(pyridine-2-ylmethyl) isoxazole-3-methane amide;
5-(1H-indazole-5-yl)-N-(pyridin-3-yl methyl) isoxazole-3-methane amide;
5-(1H-indazole-5-yl)-N-(pyridin-4-yl methyl) isoxazole-3-methane amide;
N-(2-benzyl chloride base)-5-(1H-indazole-5-base) isoxazole-3-methane amide;
N-(4-benzyl chloride base)-5-(1H-indazole-5-base) isoxazole-3-methane amide;
5-(1H-indazole-5-yl)-N-(1-phenyl-2-piperidines-1-base ethyl) isoxazole-3-methane amide;
N-[2-(1H-imidazoles-1-yl)-1-phenylethyl]-5-(1H-indazole-5-base) isoxazole-3-methane amide;
5-(1H-indazole-5-yl)-N-(2-morpholine-4-base-1-phenylethyl) isoxazole-3-methane amide;
5-(1H-indazole-5-yl)-N-[2-(4-methylpiperazine-1-yl)-1-phenylethyl] isoxazole-3-methane amide;
5-(1H-indazole-5-yl)-N-(1-phenyl-2-tetramethyleneimine-1-base ethyl) isoxazole-3-methane amide;
2-([5-(1H-indazole-5-base) isoxazole-3-base] carbonyl } amino)-2-phenylethyl carboxylamine tertiary butyl ester;
5-(1H-indazole-5-yl)-N-(1-naphthyl methyl) isoxazole-3-methane amide;
5-(1H-indazole-5-yl)-N-(2-phenylethyl) isoxazole-3-methane amide;
5-(1H-indazole-5-yl)-N-(2-pyridine-2-base ethyl) isoxazole-3-methane amide;
5-(1H-indazole-5-yl)-N-(2-pyridin-3-yl ethyl) isoxazole-3-methane amide;
5-(1H-indazole-5-yl)-N-(2-pyridin-4-yl ethyl) isoxazole-3-methane amide;
N-[2-(2-chloro-phenyl-) ethyl]-5-(1H-indazole-5-base) isoxazole-3-methane amide;
N-[2-(3-chloro-phenyl-) ethyl]-5-(1H-indazole-5-base) isoxazole-3-methane amide;
N-[2-(4-chloro-phenyl-) ethyl]-5-(1H-indazole-5-base) isoxazole-3-methane amide;
N-benzyl-N-ethyl-5-(1H-indazole-5-base) isoxazole-3-methane amide;
5-(1H-indazole-5-yl)-N-methyl-N-(1-naphthyl methyl) isoxazole-3-methane amide;
5-(1H-indazole-5-yl)-N-methyl-N-(2-phenylethyl) isoxazole-3-methane amide;
5-(1H-indazole-5-yl)-N-methyl-N-(2-pyridine-2-base ethyl) isoxazole-3-methane amide;
5-(1H-indazole-5-yl)-N-[(1R)-1-phenylethyl] isoxazole-3-methane amide;
5-(1H-indazole-5-yl)-N-1,2,3,4-naphthane-1-isoxazole-3-methane amide;
5-(1H-indazole-5-yl)-N-[(1S)-1-(1-naphthyl) ethyl] isoxazole-3-methane amide;
5-(1H-indazole-5-yl)-N-[(1R)-1-(1-naphthyl) ethyl] isoxazole-3-methane amide;
N-[3-(dimethylamino)-1-phenyl propyl]-5-(1H-indazole-5-base) isoxazole-3-methane amide;
N-(2,3-dihydro-1,4-Ben Bing dioxin-5-ylmethyl)-5-(1H-indazole-5-base) isoxazole-3-methane amide;
N-(3,4-dihydro-2H-1,5-benzo two oxa-s
Figure GPA00001018010700331
(benzodioxepin)-the 6-ylmethyl)-5-(1H-indazole-5-base) isoxazole-3-methane amide;
5-(1H-indazole-5-yl)-N-[(1-Methyl-1H-indole-4-yl) methyl] isoxazole-3-methane amide;
5-{3-[(3-Phenylpyrrolidine-1-yl) carbonyl] isoxazole-5-base }-the 1H-indazole;
5-{3-[(2-Phenylpyrrolidine-1-yl) carbonyl] isoxazole-5-base }-the 1H-indazole;
5-{3-[(2-Phenylpiperidine-1-yl) carbonyl] isoxazole-5-base }-the 1H-indazole;
5-(1H-indazole-5-yl)-N-[(1S)-1-phenylethyl] isoxazole-3-methane amide;
5-(1H-indazole-5-yl)-N-[(1R)-1-(4-aminomethyl phenyl) ethyl] isoxazole-3-methane amide;
5-(1H-indazole-5-yl)-N-[(1S)-1-(4-aminomethyl phenyl) ethyl] isoxazole-3-methane amide;
N-[(1R, 2S)-2-hydroxyl-2,3-dihydro-1H-indenes-1-yl]-5-(1H-indazole-5-base) isoxazole-3-methane amide;
N-[(1R, 2R)-2-hydroxyl-2,3-dihydro-1H-indenes-1-yl]-5-(1H-indazole-5-base) isoxazole-3-methane amide;
N-[(1R)-1-(4-bromophenyl) ethyl]-5-(1H-indazole-5-base) isoxazole-3-methane amide;
N-[(1S)-1-(4-bromophenyl) ethyl]-5-(1H-indazole-5-base) isoxazole-3-methane amide;
N-[(1R)-1-(4-chloro-phenyl-) ethyl]-5-(1H-indazole-5-base) isoxazole-3-methane amide;
N-[(1S)-1-(4-chloro-phenyl-) ethyl]-5-(1H-indazole-5-base) isoxazole-3-methane amide;
5-(1H-indazole-5-yl)-N-[(1S)-1-(2-naphthyl) ethyl] isoxazole-3-methane amide;
N-[1-(4-ethoxyl phenenyl)-2-hydroxyethyl]-5-(1H-indazole-5-base) isoxazole-3-methane amide;
N-[2-hydroxyl-1-(4-isopropyl phenyl) ethyl]-5-(1H-indazole-5-base) isoxazole-3-methane amide;
N-[1-(3, the 4-3,5-dimethylphenyl)-2-hydroxyethyl]-5-(1H-indazole-5-base) isoxazole-3-methane amide;
N-[2-hydroxyl-1-(2-p-methoxy-phenyl) ethyl]-5-(1H-indazole-5-base) isoxazole-3-methane amide;
N-[2-hydroxyl-1-(4-aminomethyl phenyl) ethyl]-5-(1H-indazole-5-base) isoxazole-3-methane amide;
5-(1H-indazole-5-yl)-N-[(1R)-1-(2-p-methoxy-phenyl) ethyl] isoxazole-3-methane amide;
N-[(1S)-1-(3, the 4-difluorophenyl) ethyl]-5-(1H-indazole-5-base) isoxazole-3-methane amide;
5-(1H-indazole-5-yl)-N-[(1R)-1-(3-p-methoxy-phenyl) ethyl] isoxazole-3-methane amide;
5-(1H-indazole-5-yl)-N-{ (1R)-1-[3-(trifluoromethyl) phenyl] ethyl } isoxazole-3-methane amide;
N-[1-(2,3-dihydro-1,4-Ben Bing dioxin-6-yl) ethyl]-5-(1H-indazole-5-base) isoxazole-3-methane amide;
N-[1-(3, the 5-dichlorophenyl)-2-hydroxyethyl]-5-(1H-indazole-5-base) isoxazole-3-methane amide;
5-(1-benzyl-1H-1,2,3-triazole-4-yl)-3-[({[6-(trifluoromethyl) pyridine-2-yl] amino } carbonyl) amino]-1H-indazole-1-formic acid tertiary butyl ester;
5-(1-benzyl-1H-1,2,3-triazole-4-yl)-1-[(1-methyl piperidine-2-yl) carbonyl]-1H-indazole-3-amine;
5-(1-benzyl-1H-1,2,3-triazole-4-yl)-1-[(dimethylamino) ethanoyl]-1H-indazole-3-amine;
3-amino-5-(1-benzyl-1H-1,2,3-triazole-4-yl)-1H-indazole-1-formic acid tertiary butyl ester;
N-[5-(1-benzyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-2-piperidines-1-yl acetamide;
N-[5-(1-benzyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-2-morpholine-4-yl acetamide; With
N-[5-(1-benzyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-1-methyl piperidine-2-methane amide.
All patents, patent application and the reference quoted in the specification sheets are all incorporated this paper into its integral body.Under inconsistent situation, comprise that with of the present invention disclosure in being defined in is as the criterion.
The following term that uses in the whole text in this specification sheets and the claims has following meaning:
Term used herein " thiazolinyl " is meant and comprises 2-10 carbon atom and comprise at least one straight or branched alkyl by the carbon-to-carbon double bond removing two hydrogen and form.The representative example of thiazolinyl includes but not limited to vinyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl isophthalic acid-heptenyl and 3-decene base.
Term used herein " alkoxyl group " is meant that the alkyl that this paper defines is connected with parent molecular moiety by Sauerstoffatom.The representative example of alkoxyl group includes but not limited to methoxyl group, oxyethyl group, propoxy-, 2-propoxy-, butoxy, tert.-butoxy, pentyloxy and hexyloxy.
Term used herein " alkoxyl group alkoxyl group " is meant that the alkoxyl group that this paper defines is connected with parent molecular moiety by the alkoxyl group that another this paper defines.The representative example of alkoxyl group alkoxyl group includes but not limited to tert.-butoxy methoxyl group, 2-ethoxy ethoxy, 2-methoxy ethoxy and methoxymethoxy.
Term used herein " alkoxy alkoxy alkyl " is meant that the alkoxyl group alkoxyl group that this paper defines is connected with parent molecular moiety by the alkylidene group that this paper defines.The representative example of alkoxy alkoxy alkyl includes but not limited to tert.-butoxy methoxymethyl, oxyethyl group methoxy ylmethyl, (2-methoxy ethoxy) methyl and 2-(2-methoxy ethoxy) ethyl.
Term used herein " alkoxyalkyl " is meant that the alkoxyl group that this paper defines is connected with parent molecular moiety by the alkylidene group that this paper defines.The representative example of alkoxyalkyl includes but not limited to tert.-butoxy methyl, 2-ethoxyethyl group, 2-methoxy ethyl and methoxymethyl.
Term used herein " alkoxy carbonyl " is meant that the alkoxyl group that this paper defines is connected with parent molecular moiety by the carbonyl that this paper defines.The representative example of alkoxy carbonyl includes but not limited to methoxycarbonyl, ethoxy carbonyl and tert-butoxycarbonyl.
Term used herein " alkoxy carbonyl alkyl " is meant that the alkoxy carbonyl that this paper defines is connected with parent molecular moiety by the alkylidene group that this paper defines.The representative example of alkoxy carbonyl alkyl includes but not limited to 3-methoxycarbonyl propyl group, 4-ethoxy carbonyl butyl and 2-tert-butoxycarbonyl ethyl.
Term used herein " alkyl " is meant the straight or branched alkyl that comprises 1-10 carbon atom.The representative example of alkyl includes but not limited to methyl, ethyl, n-propyl, different-propyl group, normal-butyl, sec-butyl, isobutyl-, the tertiary butyl, n-pentyl, isopentyl, neo-pentyl, n-hexyl, 3-methyl hexyl, 2,2-dimethyl amyl group, 2,3-dimethyl amyl group, n-heptyl, n-octyl, n-nonyl and positive decyl.
Term used herein " alkyl-carbonyl " is meant that the alkyl that this paper defines is connected with parent molecular moiety by the carbonyl that this paper defines.The representative example of alkyl-carbonyl includes but not limited to ethanoyl, 1-oxopropyl, 2,2-dimethyl-1-oxopropyl, 1-oxo butyl and 1-oxo amyl group.
Term used herein " alkyl-carbonyl alkyl " is meant that the alkyl-carbonyl that this paper defines is connected with parent molecular moiety by the alkylidene group that this paper defines.The representative example of alkyl-carbonyl alkyl includes but not limited to 2-oxopropyl, 3,3-dimethyl-2-oxopropyl, 3-oxo butyl and 3-oxo amyl group.
Term used herein " alkyl-carbonyl oxygen base " is meant that the alkyl-carbonyl that this paper defines is connected with parent molecular moiety by Sauerstoffatom.The representative example of alkyl-carbonyl oxygen base includes but not limited to ethanoyl oxygen base, ethyl ketonic oxygen base and tertiary butyl ketonic oxygen base.
Term used herein " alkylidene group " is meant the divalent group derived from the straight or branched alkyl of 1-10 carbon atom.The representative example of alkylidene group includes but not limited to-CH 2-,-CH (CH 3)-,-C (CH 3) 2-,-CH 2CH 2-,-CH 2CH 2CH 2-,-CH 2CH 2CH 2CH 2-and-CH 2CH (CH 3) CH 2-.
Term " alkylidene group-NR used herein g-" be meant alkylidene group that this paper defines by this paper definition-NR g-group is connected with parent molecular moiety.
Term used herein " alkyl sulphinyl " is meant that the alkyl that this paper defines is connected with parent molecular moiety by the sulfinyl that this paper defines.The representative example of alkyl sulphinyl includes but not limited to methylsulfinyl and ethyl sulfinyl.
Term used herein " alkyl sulphinyl alkyl " is meant that the alkyl sulphinyl that this paper defines is connected with parent molecular moiety by the alkylidene group that this paper defines.Representational alkyl sulphinyl alkyl includes but not limited to methylsulfinyl methyl and ethyl sulfinyl methyl.
Term used herein " alkyl sulphonyl " is meant that the alkyl that this paper defines is connected with parent molecular moiety by the alkylsulfonyl that this paper defines.The representative example of alkyl sulphonyl includes but not limited to methyl sulphonyl and ethylsulfonyl.
Term used herein " alkyl sulphonyl alkyl " is meant that the alkyl sulphonyl that this paper defines is connected with parent molecular moiety by the alkylidene group that this paper defines.The representative example of alkyl sulphonyl alkyl includes but not limited to sulfonyloxy methyl ylmethyl and ethylsulfonyl methyl.
Term used herein " alkyl sulfenyl " is meant that the alkyl that this paper defines is connected with parent molecular moiety by sulphur atom.The alkyl sulfenyl includes but not limited to methyl sulfenyl, ethyl sulfenyl, tertiary butyl sulfenyl and hexyl sulfenyl.
Term used herein " alkyl sulfenyl alkyl " is meant that the alkyl sulfenyl that this paper defines is connected with parent molecular moiety by the alkylidene group that this paper defines.The representative example of alkyl sulfenyl alkyl includes but not limited to methyl sulfenyl methyl and 2-(ethyl sulfenyl) ethyl.
Term used herein " alkynyl " is meant the straight or branched alkyl that comprises 2-10 carbon atom and comprise at least one carbon-to-carbon triple bond.The representative example of alkynyl includes but not limited to ethynyl, 1-proyl, 2-propynyl, 3-butynyl, valerylene base and ethyl acetylene base.
Term used herein " aryl " is meant phenyl, aryl bicyclic or three cyclophane bases.Aryl bicyclic be naphthyl or with Cycloalkylfused phenyl with cycloalkenyl group condensed phenyl or with the bicyclic heteroaryl ring condensed phenyl of this paper definition or with the monocyclic heterocycles condensed phenyl of this paper definition.Aryl bicyclic of the present invention must be connected with parent molecular moiety by any carbon atom that utilizes on the phenyl ring.The representative example of aryl bicyclic includes but not limited to 2,3-dihydro-1,4-benzene and dioxin-5-base, 2,3-dihydro-1,4-benzene and dioxin-6-base, 3,4-dihydro-2H-1,5-benzo two oxa-s
Figure GPA00001018010700381
-6-base, dihydro indenyl, indenyl, indoles-4-base, naphthyl, dihydro naphthyl and tetralyl.Three cyclophane bases be anthracene luxuriant and rich with fragrance or with Cycloalkylfused aryl bicyclic or with cycloalkenyl group condensed aryl bicyclic or with phenyl condensed aryl bicyclic.Three cyclophane bases are connected with parent molecular moiety by any carbon atom on the three cyclophane bases.The representative example of three cyclophane basic rings includes but not limited to Azulene base, dihydro anthryl, fluorenyl and tetrahydrochysene phenanthryl.
Aryl of the present invention is optional by 1; 2; 3; 4 or 5 independently are selected from following substituting group and replace: thiazolinyl; alkoxyl group; the alkoxyl group alkoxyl group; alkoxy alkoxy alkyl; alkoxyalkyl; alkoxy carbonyl; alkoxy carbonyl alkyl; alkyl; alkyl-carbonyl; the alkyl-carbonyl alkyl; the alkyl-carbonyl oxygen base; alkyl sulphinyl; the alkyl sulphinyl alkyl; alkyl sulphonyl; the alkyl sulphonyl alkyl; the alkyl sulfenyl; alkyl sulfenyl alkyl; alkynyl; aryl * NC (O)-; aryl * NHC (O) NH-; carboxyl; carboxyalkyl; cyano group; the cyano group alkyl; formyl radical; the formyl radical alkyl; halogen; haloalkyl; heteroaryl; hydroxyl; hydroxyalkyl; sulfydryl; morpholino; nitro; Z 1Z 2N-or (Z 3Z 4N) carbonyl.Aryl * is optional independently to be selected from following substituting group replacement by 1,2 or 3: alkyl, halogen, cyano group or nitro.Z 1And Z 2Independently be selected from hydrogen, alkyl or alkyl-carbonyl separately.
Term used herein " aryloxy " is meant that the aryl that this paper defines is connected with parent molecular moiety by Sauerstoffatom.The representative example of aryloxy includes but not limited to phenoxy group, naphthyl oxygen base, 3-bromine phenoxy group, 4-chlorophenoxy, 4-methylphenoxy and 3,5-dimethoxy phenoxy group.
Term used herein " aromatic yloxy yl alkyl " is meant that the aryloxy that this paper defines is connected with parent molecular moiety by the alkyl that this paper defines.The representative example of aromatic yloxy yl alkyl includes but not limited to 2-phenoxy group ethyl, 3-naphthalene-2-base oxygen base propyl group and 3-bromobenzene oxygen ylmethyl.
Term used herein " arylalkyl " is meant that the aryl that this paper defines is connected with parent molecular moiety by the alkylidene group that this paper defines.The representative example of arylalkyl includes but not limited to benzyl, 2-phenylethyl, 3-phenyl propyl and 2-naphthalene-2-base ethyl.
Term used herein " aryl (hydroxyl) alkyl " is meant that the aryl that this paper defines is connected with parent molecular moiety by the alkylidene group that has a hydroxyl that this paper defines.The representative example of aryl (hydroxyl) alkyl includes but not limited to 2-phenylethyl alcohol-2-base and 2-hydroxyl-2-phenylethyl.
Term used herein " aryl carbonyl " is meant that the aryl that this paper defines is connected with parent molecular moiety by the carbonyl that this paper defines.The representative example of aryl carbonyl includes but not limited to benzoyl and naphthoyl.
Term used herein " artyl sulfo " is meant that the aryl that this paper defines is connected with parent molecular moiety by sulphur atom.The representative example of artyl sulfo includes but not limited to phenyl sulfenyl and 2-naphthyl sulfenyl.
Term used herein " artyl sulfo alkyl " is meant that the artyl sulfo that this paper defines is connected with parent molecular moiety by the alkylidene group that this paper defines.The representative example of artyl sulfo alkyl includes but not limited to phenyl sulfenyl methyl, 2-naphthalene-2-base sulfenyl ethyl and 5-phenyl sulfenyl methyl.
Term used herein " azido-" is meant-N 3Group.
Term used herein " azido-alkyl " is meant that the azido-that this paper defines is connected with parent molecular moiety by the alkylidene group that this paper defines.
Term used herein " carbonyl " is meant-C (O)-group.
Term used herein " carboxyl " is meant-CO 2The H group.
Term used herein " carboxyalkyl " is meant that the carboxyl that this paper defines is connected with parent molecular moiety by the alkylidene group that this paper defines.The representative example of carboxyalkyl includes but not limited to carboxyl methyl, 2-carboxy ethyl and 3-carboxyl propyl group.
Term used herein " cyano group " is meant-the CN group.
Term used herein " cyano group alkyl " is meant that the cyano group that this paper defines is connected with parent molecular moiety by the alkylidene group that this paper defines.The representative example of cyano group alkyl includes but not limited to cyano methyl, 2-cyano ethyl and 3-cyano group propyl group.
Term used herein " cycloalkenyl group " is meant and comprises 3-10 carbon atom and comprise at least one monocycle or dicyclo ring system by the carbon-to-carbon double bond removing two hydrogen and form.The representative example of monocycle ring system includes but not limited to 2-tetrahydrobenzene-1-base, 3-tetrahydrobenzene-1-base, 2,4-cyclohexadiene-1-base and 3-cyclopentenes-1-base.The dicyclo ring system by with the monocyclic cycloalkyl ring of another this paper definition, the monocyclic aryl ring of this paper definition, the monocyclic heterocycles of this paper definition or the bicyclic heteroaryl condensed monocycle cycloalkenyl group ring system example of this paper definition.Dicyclo ring system of the present invention must be connected with parent molecular moiety by the utilized carbon atom on the cyclenes basic ring.The representative example of dicyclo ring system includes but not limited to 4,5-dihydro-benzo [1,2,5] oxadiazoles, 3a, 4,5,6,7,7a-six hydrogen-1H-indenyl, 1,2,3,4,5,6-six hydrogen-pentalene base, 1,2,3,4,4a, 5,6,8a-octahydro-pentalene base.
Term used herein " cycloalkyl " is meant monocycle, two ring or volution ring systems.The monocycle ring system is by the saturated cyclic example that comprises 3-8 carbon atom.The example of monocycle ring system comprises cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl and ring octyl group.Bicyclic ring alkyl of the present invention by with another monocyclic cycloalkyl ring condensed monocyclic cycloalkyl ring or with cycloalkenyl group condensed monocyclic cycloalkyl ring with phenyl ring condensed monocyclic cycloalkyl ring or with the bicyclic heteroaryl ring condensed monocyclic cycloalkyl ring of this paper definition or with the monocyclic heterocycles condensed monocyclic cycloalkyl ring example of this paper definition.Bicyclic ring alkyl ring system of the present invention must be connected with parent molecular moiety by the utilized carbon atom on the mononaphthene basic ring.
Cycloalkyl of the present invention is optional to be selected from following substituting group replacement by 1,2,3 or 4: thiazolinyl, alkoxyl group, alkoxyl group alkoxyl group, alkoxyalkyl, alkoxy carbonyl, alkoxyl group alkylsulfonyl, alkyl, alkyl-carbonyl, alkyl-carbonyl oxygen base, alkyl sulphonyl, alkyl sulfenyl, alkyl sulfenyl alkyl, alkynyl, carboxyl, cyano group, formyl radical, halogenated alkoxy, haloalkyl, halogen, hydroxyl, hydroxyalkyl, sulfydryl, oxo, Z 1Z 2N-or (Z 3Z 4N) carbonyl.
Term used herein " cycloalkylalkyl " is meant that cycloalkyl is connected with parent molecular moiety by the alkyl of this paper definition.
Term used herein " naphthene base carbonyl " is meant that the cycloalkyl that this paper defines is connected with parent molecular moiety by the carbonyl that this paper defines.The representative example of naphthene base carbonyl includes but not limited to cyclopropyl carbonyl, 2-cyclobutyl carbonyl and cyclohexyl-carbonyl.
Term used herein " formyl radical " is meant-C (O) H group.
Term used herein " formyl radical alkyl " is meant that the formyl radical that this paper defines is connected with parent molecular moiety by the alkylidene group that this paper defines.The representative example of formyl radical alkyl includes but not limited to formyl radical methyl and 2-formyl radical ethyl.
Term used herein " halo " or " halogen " be meant-Cl ,-Br ,-I or-F.
Term used herein " halogenated alkoxy " is meant that the halogen of at least one this paper definition is connected with parent molecular moiety by the alkoxyl group that this paper defines.The representative example of halogenated alkoxy includes but not limited to chloro methoxyl group, 2-fluorine oxyethyl group, trifluoromethoxy and five fluorine oxyethyl groups.
Term used herein " haloalkyl " is meant that the halogen of at least one this paper definition is connected with parent molecular moiety by alkylidene group.The representative example of haloalkyl includes but not limited to chloro methyl, 2-fluoro ethyl, trifluoromethyl, pentafluoroethyl group and 2-chloro-3-fluorine amyl group.
Term used herein " heteroaryl " is meant bicyclic heteroaryl or bicyclic heteroaryl.Bicyclic heteroaryl is to comprise heteroatomic 5 or 6 yuan of rings that at least one independently is selected from O, N or S.5 yuan of rings comprise two two keys, can comprise 1,2,3 or 4 heteroatoms.6 yuan of rings comprise three two keys, can comprise 1,2,3 or 4 heteroatoms.5 or 6 yuan of heteroaryls are connected with parent molecular moiety with nitrogen-atoms by any carbon atom on the heteroaryl or as brain.The representative example of bicyclic heteroaryl includes but not limited to furyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazole Ji, oxazolyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, pyrazolyl, pyrryl, tetrazyl, thiadiazolyl group, thiazolyl, thienyl, triazolyl and triazinyl.Bicyclic heteroaryl comprises the monocyclic heterocycles condensed heteroaryl with monocycle cyclenes basic ring, another bicyclic heteroaryl or this paper definition of the monocyclic cycloalkyl ring of the monocyclic aromatic rings of this paper definition, this paper definition, this paper definition.Bicyclic heteroaryl ring system of the present invention must be connected with parent molecular moiety by the utilized carbon atom on the heteroaryl ring.Bicyclic heteroaryl is connected with parent molecular moiety by any carbon atom on the bicyclic heteroaryl or any nitrogen-atoms.The representative example of bicyclic heteroaryl includes but not limited to benzofuryl, Ben Bing oxadiazole base, 1,3-benzothiazolyl, benzimidazolyl-, benzodioxole base, benzothienyl, chromenyl, cinnolines base, furo pyridine, indyl, indazolyl, pseudoindoyl, isoquinolyl, naphthyridinyl, oxazole and pyridine, quinolyl, thienopyridine and thienopyridine base.
Heteroaryl of the present invention is optional by 1; 2; 3 or 4 independently are selected from following substituting group and replace: thiazolinyl; alkoxyl group; the alkoxyl group alkoxyl group; alkoxyalkyl; alkoxy carbonyl; alkoxy carbonyl alkyl; the alkoxyl group alkylsulfonyl; alkyl; alkyl-carbonyl; the alkyl-carbonyl alkyl; the alkyl-carbonyl oxygen base; the alkyl sulfenyl; alkyl sulfenyl alkyl; alkynyl; benzyl; carboxyl; carboxyalkyl; cyano group; the cyano group alkyl; formyl radical; halogenated alkoxy; haloalkyl; halogen; hydroxyl; hydroxyalkyl; sulfydryl; nitro; Z 1Z 2N-or (Z 3Z 4N) carbonyl.Substituted heteroaryl of the present invention can be tautomer.The present invention includes all tautomers, comprise non-aromaticity tautomer.
Term used herein " heteroarylalkyl " is meant that heteroaryl is connected with parent molecular moiety by the alkyl of this paper definition.
Term used herein " heterocycle " or " heterocyclic " are meant and comprise at least one heteroatomic monocycle, two ring or volution ring systems.Monocyclic heterocycles is to comprise heteroatomic 3,4,5,6 or 7 yuan of rings that at least one independently is selected from O, N and S.3 or 4 yuan of rings comprise 1 heteroatoms that is selected from O, N and S.5 yuan of rings comprise 0 or 1 two key and 1,2 or 3 heteroatoms that is selected from O, N and S.6 or 7 yuan of rings comprise 0,1 or 2 two key and 1,2 or 3 heteroatoms that is selected from O, N and S.Monocyclic heterocycles is connected with parent molecular moiety by any carbon atom on the monocyclic heterocycles or any nitrogen-atoms.The representative example of monocyclic heterocycles includes but not limited to azetidinyl, the azepan base, '-aziridino, the Diazesuberane base, 1, the 3-alkyl dioxin, 1, the 3-dioxolanyl, 1,3-dithiolane base, 1,3-dithiane base, imidazolinyl, imidazolidyl, the isothiazoline base, isothiazole alkyl; isoxazoline-3-yl; isoxazole alkyl, isoindoline-1, the 3-diketone, morpholinyl oxadiazole quinoline base oxadiazole alkyl (oxadiazolidinyl) oxazolinyl oxazolidinyl, piperazinyl, piperidyl, pyranyl, pyrazolinyl, pyrazolidyl, pyrrolinyl, pyrrolidyl, tetrahydrofuran base, tetrahydro-thienyl, the Thiadiazoline base, the thiadiazoles alkyl, thiazolinyl, thiazolidyl, thio-morpholinyl, 1,1-dioxo thio-morpholinyl (dioxidothiomorpholinyl) (thiomorpholine sulfone), sulfo-pyranyl and trithian base.Bicyclic heterocycles of the present invention is defined as and another monocyclic heterocycles of the cycloalkenyl group of the cycloalkyl of phenyl, this paper definition, this paper definition, this paper definition or the volution condensed monocyclic heterocycles of the two ends Cheng Qiao of carbon atom of monocyclic heterocycles and alkylidene chain wherein.Bicyclic heterocycles of the present invention is connected with parent molecular moiety by any carbon atom on the heterocycle or any nitrogen-atoms.The representative example of bicyclic heterocycles includes but not limited to 1,3-benzodioxole base, 1,3-benzo dithia cyclopentenyl, 2,3-dihydro-1,4-Ben Bing dioxin base, 2,3-dihydro-1-benzofuryl, 2,3-dihydro-1-benzothienyl, 3, the heterochromatic alkene of 4-dihydro-1H--4-base, 2,3-dihydro-1H-indyl, succinmimidyl and 1,2,3, the 4-tetrahydric quinoline group.Tricyclic heterocyclic be with phenyl condensed bicyclic heterocycles or with Cycloalkylfused bicyclic heterocycles with cycloalkenyl group condensed bicyclic heterocycles or with monocyclic heterocycles condensed bicyclic heterocycles.Tricyclic heterocyclic is connected with parent molecular moiety by any carbon atom on the tricyclic heterocyclic or any nitrogen-atoms.The representative example of tricyclic heterocyclic includes but not limited to 2,3,4,4a, and 9,9a-six hydrogen-1H-carbazyl, 5a, 6,7,8,9,9a-six diphenyl hydrogens are [b, d] furyl and 5a also, and 6,7,8,9,9a-six diphenyl hydrogens are [b, d] thienyl also.
Heterocycle of the present invention is optional by 1; 2 or 3 independently are selected from following substituting group and replace: thiazolinyl; alkoxyl group; the alkoxyl group alkoxyl group; alkoxyalkyl; alkoxy carbonyl; alkoxy carbonyl alkyl; the alkoxyl group alkylsulfonyl; alkyl; alkyl-carbonyl; the alkyl-carbonyl alkyl; the alkyl-carbonyl oxygen base; the alkyl sulfenyl; alkyl sulfenyl alkyl; alkynyl; aryl; benzyl; carboxyl; carboxyalkyl; cyano group; the cyano group alkyl; formyl radical; halogenated alkoxy; haloalkyl; halogen; hydroxyl; hydroxyalkyl; the hydroxyalkyl carbonyl; hydroxy alkoxy alkyl; sulfydryl; oxo; Z 1Z 2N-or (Z 3Z 4N) carbonyl.
Term used herein " Heterocyclylalkyl " is meant that heterocycle is connected with parent molecular moiety by the alkyl of this paper definition.
Term used herein " heterocycle carbonyl " is meant that the heterocycle that this paper defines is connected with parent molecular moiety by the carbonyl that this paper defines.
Term used herein " hydroxyl " is meant-the OH group.
Term used herein " hydroxyalkyl " is meant that at least one hydroxyl that this paper defines is connected with parent molecular moiety by the alkylidene group that this paper defines.The representative example of hydroxyalkyl includes but not limited to hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxyl amyl group and 2-ethyl-4-hydroxyl heptyl.
Term used herein " hydroxyalkyl carbonyl " is meant that the hydroxyalkyl that this paper defines is connected with parent molecular moiety by the carbonyl that this paper defines.Its representative example includes but not limited to 2-hydroxyacetyl and 4-maloyl group.
Term used herein " hydroxy alkoxy alkyl " is meant that the hydroxy alkoxy base that this paper defines is connected with parent molecular moiety by the alkylidene group that this paper defines.The representative example of hydroxy alkoxy alkyl includes but not limited to (2-hydroxyl-oxyethyl group)-ethyl and (3-hydroxyl 1-propoxy-)-ethyl.
During being meant, term used herein " hydroxyl-blocking group " or " O-blocking group " protect hydroxyl that the group of unwanted reaction does not take place in the building-up process.The example of hydroxyl-blocking group includes but not limited to the methyl ether that replaces, as methoxymethyl, benzyl oxygen ylmethyl, 2-methoxy ethoxy methyl, 2-(trimethyl silyl)-ethoxyl methyl, benzyl and trityl group; THP trtrahydropyranyl ether; The ethyl diethyldithiocarbamate ether that replaces, as 2,2,2-three chloroethyls and the tertiary butyl; Silyl ether is as trimethyl silyl, t-butyldimethylsilyl and t-butyldiphenylsilyl; Ring acetal and ketone are as methylene radical acetal, acetonide and benzylidene acetal; Cyclic ortho ester is as the methoxyl group methylene radical; Cyclic carbonate; With the ring-type boric acid ester.T.W.Greene and P.G.M.Wuts, the blocking group in the organic synthesis, the third edition, John Wiley﹠amp; Sons discloses hydroxyl-blocking group commonly used among the New York (1999).
Term used herein " sulfydryl " is meant-the SH group.
Term used herein " nitrogen-protecting group group " is meant amino those groups that unwanted reaction does not take place of protection in building-up process.Preferred nitrogen-protecting group is rolled into a ball and is ethanoyl, benzoyl, benzyl, benzyl oxygen base carbonyl (Cbz), formyl radical, phenyl sulfonyl, tert-butoxycarbonyl (Boc), tertiary butyl ethanoyl, trifluoroacetyl group and trityl group (trityl).
Term used herein " nitro " is meant-NO 2Group.
Term used herein " trialkylsilkl " is meant that the alkyl of three independent this paper definition of selecting is connected with parent molecular moiety by Siliciumatom.The representative example of trialkylsilkl includes but not limited to trimethyl silyl, triethylsilyl, t-butyldimethylsilyl and triisopropyl silyl.
Term used herein " trialkylsilkl alkyl " is meant that the trialkylsilkl that this paper defines is connected with parent molecular moiety by the alkylidene group that this paper defines.The representative example of trialkylsilkl alkyl includes but not limited to trimethyl silyl methyl, 2-trimethyl silyl ethyl and 2-t-butyldimethylsilyl ethyl.
Term " Z used herein 1Z 2N " is meant two groups, Z 1And Z 2, be connected with parent molecular moiety by nitrogen-atoms.Z 1And Z 2Independent separately is hydrogen, alkoxy carbonyl, alkyl, alkyl-carbonyl, aryl, arylalkyl and formyl radical.In some example of the present invention, Z 1And Z 2Form heterocycle with the nitrogen-atoms that connects them.Z 1Z 2The representative example of N includes but not limited to amino, methylamino, acetylamino, ethanoyl methylamino, phenyl amino, benzylamino, azetidinyl, pyrrolidyl and piperidyl.
Term " Z used herein 3Z 4N " is meant two groups, Z 3And Z 4, be connected with parent molecular moiety by nitrogen-atoms.Z 3And Z 4Independent separately is hydrogen, alkyl, aryl and arylalkyl.Z 3Z 4The representative example of N includes but not limited to amino, methylamino, phenyl amino and benzylamino.
Term " (Z used herein 3Z 4N) carbonyl " is meant the NZ that this paper defines 3Z 4Carbonyl by this paper definition is connected with parent molecular moiety.(Z 3Z 4N) representative example of carbonyl includes but not limited to aminocarboxyl, (methylamino) carbonyl, (dimethylamino) carbonyl and (ethylmethylamino) carbonyl.
Term used herein " oxo " is meant=the O part.
Term used herein " sulfinyl " is meant-S (O)-group.
Term used herein " alkylsulfonyl " is meant-SO 2-group.
Term used herein " sulphonamide " is meant-SO 2NH 2Group.
Term used herein " tautomer " is meant proton another atom from an atom transfer of compound to same compound, and wherein the compound that two or more structures are different balances each other.
Compound of the present invention can be steric isomer, wherein has asymmetric center or chiral centre.According to the substituting group configuration around the chiral atom, these steric isomers can be " R " or " S ".Term used herein " R " and " S " are IUPAC 1974 Recommendations forSection E, Fundamental Stereochemistry, Pure Appl.Chem., 1976, the configuration that defines among the 45:13-30.The present invention relates to various steric isomers and composition thereof, this is all within the scope of the present invention clear and definite.Steric isomer comprises the mixture of enantiomer and diastereomer and enantiomer or diastereomer.The single steric isomer of The compounds of this invention can be from buying the synthetic preparation of the starting raw material that comprises asymmetric or chiral centre that obtains, or by first its racemic mixture of preparation, and then split with the well-known method of those of ordinary skills and to prepare.These method for splitting examples are as follows: (1) is connected enantiomeric mixture with chiral auxiliary(reagent), and the mixture by recrystallization or the separating obtained diastereomer of chromatography discharges optically pure product from auxiliary agent then; Or (2) direct mixture of dissociated optical enantiomer on chiral chromatographic column.
Will be better understood Compounds and methods for of the present invention by the reference the following examples, the following examples are not in order to limit the scope of the invention for example just.In addition, this paper all references is all incorporated this paper into by reference.
The compound title is provided by the Name pro name software name that is provided by ACD/Labs.Perhaps, the AUTONOM name software name that the compound title adopts the MDL Information SystemsGmbH (being called Beilstein Informationssysteme in the past) of German Frankfurt to provide, it is
Figure GPA00001018010700461
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Figure GPA00001018010700471
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Abbreviation
Abbreviation used in the description of scheme and embodiment is as follows: DMF is N, and dinethylformamide, DMSO are that dimethyl sulfoxide (DMSO), EtOAc are ethyl acetate, CHCl 3Be chloroform, CH 2Cl 2Be methylene dichloride, CH 3CN is that acetonitrile, THF are that tetrahydrofuran (THF), HATU are O-(7-azepine benzo triazol-1-yl)-N, N, N ', N '-tetramethyl-urea hexafluorophosphate, EDC or EDCI are that 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride, LC/MS are liquid chromatography/mass spectrometry, NH 4OAC is ammonium acetate, NaBH (OAc) 3Be sodium triacetoxy borohydride, PBS is a bovine serum albumin, PBS is a phosphate buffered saline (PBS), TMS is a trimethyl silyl, MW is a microwave, DMAP is 4-(dimethylamino) pyridine, dppf is 1,1 '-two (diphenylphosphino) ferrocene, TFA is a trifluoroacetic acid, BINAP is 2,2 '-two (diphenylphosphino)-1,1 '-dinaphthalene (binaphyl), TBAF is a tetrabutyl ammonium fluoride, Tween is a polyoxyethylene sorbitan monolaurate, HPLC is a high pressure liquid chromatography, DME is 1, the 2-glycol dimethyl ether, Boc is a tert-butoxycarbonyl, BSA is a bovine serum albumin, DTT is a dithiothreitol (DTT), ATP is a Triphosaden, EDTA is an ethylenediamine tetraacetic acid (EDTA), HPMC is a HYDROXY PROPYL METHYLCELLULOSE, TMB is 3,3 ', 5,5 '-tetramethyl benzidine, HEPES is 4-(2-hydroxyethyl)-1-piperazine ethyl sulfonic acid.
The preparation of The compounds of this invention
Below synthetic schemes and the embodiment example preparation method of The compounds of this invention, get in touch these synthetic schemess and embodiment and can make everybody understand Compounds and methods for of the present invention better.
Scheme 1
Figure GPA00001018010700472
Shown in scheme 1, as the formula of formula (I) compounds represented 2Compound can prepare thus.Formula 1Compound, wherein R 1And R 2Suc as formula (I) define X 1Be iodine, bromine or chlorine, can buy and obtain or synthetic, when with reagent A-M according to known method in the document 1During processing, wherein A suc as formula (I) define M 1For-Sn (R z) 3Or-B (OR y) 2, R wherein zBe alkyl or aryl, R yBe hydrogen, alkyl, aryl, or two R yGroup forms 1 with the boron atom that connects them, and 3-two oxa-boron heterocycle pentanes (dioxoborolane) in the presence of palladium catalyst, obtain formula 2Compound.Formula 1Compound and formula A-Sn (R z) 3This reaction between the compound is commonly called the Stille coupled reaction, adopt palladium catalyst as but be not limited to tetrakis triphenylphosphine palladium (0), dichloro two (triphenylphosphine) palladium (II), three (dibenzylidene (dibenzylidine) acetone) two palladiums or palladium diacetate, be with or without part as three (2-furyl) phosphines or triphenylarsine in the presence of, in solvent such as toluene or DMF, under about 25 ℃-Yue 150 ℃ of temperature, react.In addition, can add Li (I), Cu (I) or Mn (II) salt improves reactivity or specificity.Formula 1Compound and formula A-B (OR y) 2Reaction between the compound is commonly called the Suzuki coupled reaction, adopt palladium catalyst as but be not limited to tetrakis triphenylphosphine palladium (0), dichloro two (triphenylphosphine) palladium (II), three (dibenzalacetones), two palladiums or palladium diacetate.Can add palladium part such as 2-(dicyclohexyl phosphino-) biphenyl, tri-butyl phosphine or three (2-furyl) phosphine and alkali as but be not limited to K 3PO 4The aqueous solution, cesium carbonate, salt of wormwood or Na 2CO 3, solvent such as toluene, glycol dimethyl ether, dioxane, water or DMF react under about 25 ℃-Yue 150 ℃ of temperature.This reaction also can be heated in microwave reactor and finished.
Although many organic stannanes can be bought and obtain or description arranged in the literature, also can by from A-halogenide or A-fluoroform sulphonate at Pd (Ph 3P) 4Exist down with formula ((R z) 3Sn) 2Six-alkyl, two stannanes (hexa-alkyldistannane) handle and to prepare other stannane.Equally, when buying less than organoboron reagent, A-B (OR y) 2Can carry out metal exchange with organolithium from corresponding halogenide or fluoroform sulphonate (A-halogen or A-fluoroform sulphonate), add the boron alkyl acid esters then and prepare.
Scheme 2
Formula 2Compound, wherein R 1And R 2Define suc as formula (I) compound, A is the heteroaryl ring that is connected with parent fraction by nitrogen-atoms, can prepare as 2 examples of scheme.Agent treated formula with formula A-H 1Compound, wherein H is the hydrogen on the nitrogen-atoms among the heteroaryl ring A, alkali as but be not limited in the presence of sodium tert-butoxide or the cesium carbonate and metal catalyst as but be not limited to copper metal, CuI or palladium diacetate, optional and part as but be not limited to BINAP or tri-tert phosphine reaction, obtain formula 2Compound.
Scheme 3
Figure GPA00001018010700491
Described in front scheme 1, can adopt as the Stille coupled reaction of describing in the scheme 3 and come synthesis type (I) compound.Formula 3Compound, wherein R IiDefine suc as formula (I) compound, when using formula 4During compound treatment, R wherein 1In formula (I), limit P 1For nitrogen-protecting group group as but be not limited to tert-butoxycarbonyl or ethanoyl, in the presence of dichloro two (triphenylphosphine) palladium (II) and (thiophene-2-ketonic oxygen base) copper, in toluene, under heating condition, react, obtain formula 5Compound.Handle formula with known condition of removing blocking group 5Compound, as when blocking group is tert-butoxycarbonyl, the processing formula in solvent such as acetate or dioxane with hydrochloric acid or trifluoroacetic acid 5Compound, or when blocking group during for ethanoyl with sodium hydroxide, lithium hydroxide or potassium hydroxide processing formula in the aqueous mixture of THF, Virahol or dioxane 5Compound obtains the formula as formula (I) representative compounds 6Compound, wherein A is for (ii).
Scheme 4
Can such as scheme 4 description by employed formula in the scheme 3 3Compound formula (I) compound.Formula 7Compound can be bought and obtains or can be according to the preparation of the known method of those of skill in the art in this area, and when with 1,1,1-tributyl-N during the processing of N-tin methide amine (stannamine) or methylethyl (tributyl stannyl) carbamate, can obtain formula 8Compound.Work as formula 8Alkynes in formula 9Compound exists when heating down, wherein R IiSuc as formula (I) define N 3Be azido-, can obtain formula 3Compound.
Scheme 5
Figure GPA00001018010700501
As described in scheme 5, as the formula of formula (I) representative compounds 12Compound, wherein A can prepare thus for (ii).Formula 10Compound, R wherein 1Suc as formula (I) definition, X 1Be iodine, bromine, chlorine or triflate, when in the presence of cuprous iodide, dichloro two (triphenylphosphine) palladium (II) and triethylamine, handling, and then during with tetrabutyl ammonium fluoride or potassium hydroxide treatment, can obtain formula with TMS acetylene 11Compound.This reaction can solvent as but be not limited among the DMF, under room temperature or heating condition, carry out.Formula 11Compound R Ii-Cl, sodiumazide, copper sulfate and metallic copper are handled in solvent such as dioxane under heating condition, can obtain formula 12Compound, it is formula (I) representative compounds, wherein A is for (ii).
Scheme 6
Figure GPA00001018010700511
Perhaps, formula 13Compound handle in the presence of cuprous iodide, dichloro two (triphenylphosphine) palladium (II) and triethylamine with TMS-acetylene, then with tetrabutyl ammonium fluoride or potassium hydroxide treatment, can obtain formula 14Compound.This be reflected at solvent as but be not limited under room temperature or heating condition, carry out among the DMF.Formula 14Compound, when using formula 9Compound treatment the time, R wherein IiDefine suc as formula (I), or when under heating condition, handling, can obtain formula with sodiumazide, copper sulfate and metallic copper 15Compound.Formula 15Compound, when heating in the presence of the ethanolic soln at hydrazine, can obtain formula 16Compound.Formula 16Compound, when the DMAP with two-tertiary butyl, two carbonic ethers and catalytic amount handles, can obtain formula in solvent such as THF or acetonitrile 17Compound.Formula 17Compound, when using formula 18Compound alkali as but be not limited in solvent such as methylene dichloride, handle in the presence of the pyridine, and then when handling, can obtain formula with trifluoroacetic acid 19Compound.Formula 16Compound, when adopting the known carboxylic acid of those skilled in the art-when amine coupling condition is handled with carboxylic acid, can obtain formula 19ACompound.The carboxylic acid of standard-amine coupling condition comprise add coupling reagent as but be not limited to 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDCI), 1,3 dicyclohexyl carbodiimides (DCC), two (2-oxo-3-oxazolidinyl) inferior phosphonyl chloride (BOPCl), O-(7-azepine benzo triazol-1-yl)-N, N, N ', N '-tetramethyl-urea hexafluorophosphate (HATU) or O-benzotriazole-1-base-N, N, N ', N '-tetramethyl-urea a tetrafluoro borate (TBTU), be with or without auxiliary agent as but be not limited to 1-hydroxyl-7-azepine benzotriazole (HOAT) or I-hydroxybenzotriazole hydrate (HOBT), solvent as but be not limited in the methylene dichloride.
Scheme 7
Formula for formula (I) representative compounds 24Compound can prepare thus.Formula 20Compound, X wherein 1Be halogen or triflate, when using formula 21Compound, diacetyl oxide and alkali as but be not limited to potassium acetate when under heating condition, handling, can obtain formula 22Compound.Formula 22Compound, when with sodiumazide, copper sulfate, alkali such as yellow soda ash and formula 23Compound treatment the time, R wherein IiSuch as (I) definition, can buy and obtain or, can obtain formula by those skilled in the art preparation 24Compound.
Scheme 8
Figure GPA00001018010700531
Such as scheme 8 description, as the formula of formula (I) representative compounds 29With 30Compound can prepare thus.Formula 25Compound, R wherein 1Suc as formula (I) define X 1Be halogen or triflate, when using formula 23Compound, cuprous iodide, dichloro two (triphenylphosphine) palladium (II) and triethylamine when in DMF, under room temperature or heating condition, handling, can obtain formula 27Compound.Formula 27Compound, when using formula 9Compound under heating condition, without solvent or solvent as but when being not limited to handle in the dioxane, can obtain formula 29With 30Compound.
Scheme 9
Figure GPA00001018010700532
Formula as formula (I) representative compounds 32Compound, wherein A is (vii), R 1And R ViiSuc as formula (I) definition, can prepare thus.Formula 31Aldehyde, R wherein ViiSuc as formula (I) definition, can buy and obtain, when handling, can obtain the oxime intermediate with oxammonium hydrochloride and aqueous sodium hydroxide solution, when with this intermediate of chloramine-T trihydrate oxidation, and then with copper sulfate and copper wire and formula 11Compound treatment the time, can obtain formula 32Compound.
Scheme 10
Figure GPA00001018010700541
Formula as formula (I) representative compounds 38Compound, wherein A is (x), can prepare thus.Formula 33Compound, R wherein 1Define suc as formula (I), can buy and obtain or,, during the processing of O-dimethyl hydroxyl amine, can obtain formula when adopting the known sour coupling condition of those skilled in the art N by those skilled in the art preparation 34Compound.The carboxylic acid of standard-amine coupling condition comprise add coupling reagent as but be not limited to 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDCI), 1,3-dicyclohexyl carbodiimide (DCC), two (2-oxo-3-oxazolidinyl) inferior phosphonyl chloride (BOPCl), O-(7-azepine benzo triazol-1-yl)-N, N, N ', N '-tetramethyl-urea hexafluorophosphate (HATU) or O-benzotriazole-1-base-N, N, N ', N '-tetramethyl-urea a tetrafluoro borate (TBTU), be with or without auxiliary agent as but be not limited to 1-hydroxyl-7-azepine benzotriazole (HOAT) or I-hydroxybenzotriazole hydrate (HOBT), solvent as but be not limited in the methylene dichloride.Formula 34Compound, when in solvent such as tetrahydrofuran (THF), at room temperature handling, can obtain the compound of formula 35 with Grignard reagent such as benzyl magnesium bromide.The compound of formula 35, when with blocking group reagent as but the DMAP that is not limited to two-tertiary butyl, two carbonic ethers and catalytic amount when handling in solvent such as THF or acetonitrile can obtain the compound of formula 36.The compound of formula 36, when with the tribromide pyridine solvent as but be not limited among the THF heating or do not heat under when handling, can obtain formula 36ACompound.Formula 36ACompound, when using formula 37Compound heating or heat treated not, handle product with the condition of sloughing nitrogen-protecting group group then, can obtain formula 38Compound.T.W.Greene and P.G.M.Wuts, Protective Groups in Organic Synthesis (blocking group in the organic synthesis), the third edition, John Wiley﹠amp; Sons, New York (1999) disclose common used nitrogen-protecting group group and the method for removing them.
Scheme 11
Figure GPA00001018010700551
Formula 36Compound, R wherein 1Such as (I) definition, P 1Be nitrogen-protecting group group, when using formula 39Compound under heating condition, handle, and then the nitrogen-protecting group the sloughed group condition of describing in the known or document with those skilled in the art can obtain the formula as formula (I) representative compounds when handling product 40Compound, wherein A is (xvii).
Scheme 12
Figure GPA00001018010700552
Such as scheme 12 description, as the formula of formula (I) representative compounds 47Compound, wherein A is (x), can prepare thus.Formula 41Compound, R wherein 1Define suc as formula (I), when the DMAP with two-tertiary butyl, two carbonic ethers and catalytic amount handles, can obtain formula in solvent such as THF or acetonitrile 42Compound.Formula 42Compound handle with tributyl (1-vinyl ethyl ether base) stannane and dichloro two (triphenylphosphine) palladium (II) and can obtain formula 44Compound.Formula 44Compound, when with the THF solution-treated of tribromide pyridine, can obtain formula 45Compound.Formula 45Compound, when using formula 46Compound solvent as but when being not limited to handle in the ethanol, R wherein xDefine suc as formula (I), can obtain formula 47Compound.
Scheme 13
Figure GPA00001018010700561
Shown in scheme 13, as the formula of formula (I) representative compounds 51Compound, wherein A can prepare thus for (iv).Formula 48Compound, R wherein 1Define suc as formula (I), can buy and obtain or, when in formula by the preparation of literature method or method described herein 49Compound and formula 50When there was heating down in compound, both all can buy and obtain or adopt the method preparation of describing in the document by those skilled in the art, can obtain formula 51Compound.
Scheme 14
Figure GPA00001018010700562
X＝CH，N，S
Y=CH, N, key
Such as scheme 14 description, as the formula of formula (I) representative compounds 55Compound, wherein A is (xiv), (xv), (xvi) or (xvii), can prepare thus.Formula 52Compound, R wherein 1Define suc as formula (I),, handle with DMF then, and then carry out acid aftertreatment, can obtain formula when handling with butyllithium 48Compound.Formula 48Compound, when using formula 53Compound, wherein X be-CH-,-N-or-S-, Y for-CH-,-N-or key and three (trifluoromethanesulfonic acid) scandium handle, and then use formula 54Compound treatment the time, Z wherein aDefine suc as formula (I), can obtain formula 55Compound.
Scheme 15
Figure GPA00001018010700571
Such as scheme 15 description, as the formula of formula (I) representative compounds 56Compound, wherein A (vii), can prepare thus.The compound of formula (11), wherein R 1Define suc as formula (I), when with reagent as but be not limited to 2-chloro-2-(oxyimino) ethyl acetate when handling, can obtain formula 56Compound.This reaction can solvent as but be not limited to carry out in the toluene, may need the heating.
Scheme 16
Figure GPA00001018010700572
Such as scheme 16 description, as the formula of formula (I) representative compounds 29Compound, wherein A can prepare thus for (ii).The compound of formula (27), wherein R 1Define suc as formula (I), when using formula 9Compound, R IiC (O) Cl or ICl, CuI and triethylamine solvent as but when being not limited to handle in the tetrahydrofuran (THF), can obtain formula 29Compound.This reaction can be carried out in room temperature or heating.
Scheme 17
Figure GPA00001018010700573
Such as scheme 17 description, as the formula of formula (I) representative compounds 57Compound, wherein A (vi), can prepare thus.Formula 45Compound, R wherein 1Define suc as formula (I), when handling, can obtain formula with ammonium formiate and formic acid 57Compound.
Scheme 18
Figure GPA00001018010700581
Such as scheme 18 description, as the formula of formula (I) representative compounds 58Compound, wherein A (vii), can prepare thus.Formula 48Compound, R wherein 1Define suc as formula (I), when handling, can obtain formula with Nitromethane 99Min. 58Compound (Organicpreparations and procedures International, 2001,33,381-386).
Scheme 19
Figure GPA00001018010700582
Such as scheme 19 description, as the formula of formula (I) representative compounds 60Compound, wherein A (vi), can prepare thus.Formula 48Compound, R wherein 1By being defined, when using 1-(isocyano-methyl sulphonyl)-4-methylbenzene suc as formula (I) 59With suitable alkali as but be not limited to salt of wormwood and in solvent such as methyl alcohol or tetrahydrofuran (THF), handle, and then when handling, can obtain formula with suitable sour example hydrochloric acid 60Compound.
Scheme 20
Such as scheme 20 description, as the formula of formula (I) representative compounds 63Compound, wherein A (vi), can prepare thus.Formula 33Compound, R wherein 1Define suc as formula (I), when handling, can obtain formula with suitable chlorizating agent such as thionyl chloride 61Compound.Formula 61Compound, when with 2-(trimethyl silyl)-2H-1,2, the 3-triazole 62When in solvent such as tetramethylene sulfone, handling, can obtain formula 63Compound.
Scheme 21
Figure GPA00001018010700591
Such as scheme 21 description, as the formula of formula (I) representative compounds 66Compound, wherein A is (ix), can prepare thus.Formula 61Compound, R wherein 1Define suc as formula (I), when in suitable solvent such as tetrahydrofuran (THF), handling, obtain formula with hydrazine 64Compound.Formula 64Compound, when using tri-methyl ortho formate 65When in solvent such as tetrahydrofuran (THF), handling in the presence of the tosic acid of catalytic amount, can obtain formula 66Compound.
Scheme 22
Figure GPA00001018010700592
Such as scheme 22 description, as the formula of formula (I) representative compounds 69Compound, wherein A defines suc as formula (I), can prepare thus.Formula 67Compound, R wherein yBe hydrogen, alkyl, aryl or two R yGroup forms 1 with the boron atom that connects them, 3-two oxa-boron heterocycle pentanes, and the Suzuki reaction conditions of describing in the employing scheme 1 in the presence of palladium catalyst in the presence of heteroaryl iodide (A-I), obtains formula 68Compound.Formula 68Compound such as scheme 6 description handle with hydrazine and can be converted into formula 69Compound.
Scheme 23
Figure GPA00001018010700601
Such as scheme 23 description, as the formula of formula (I) representative compounds 74Compound, R wherein IiAnd R 4Define suc as formula (I), use formula 70Compound begin preparation, X wherein 1Be iodine, bromine or chlorine.Handle earlier the compound of formula 70 with hydrazine, then as scheme 6 description with the processing of two-tertiary butyl, two carbonic ethers, obtain formula 71Compound.Formula 71Compound and formula 18Acyl chlorides in the presence of alkali such as salt of wormwood, in tetrahydrofuran (THF), at room temperature reacted 2-8 hour, obtain formula 72Compound.Perhaps, formula 72Compound can be from formula 71Compound adopt the condition preparation of describing in the scheme 6.Formula 72Compound under the conditions that scheme 5 and 6 is described with (trimethyl silyl) acetylene reaction, obtain formula 73Compound.Formula 74Compound derive from formula 73Compound, use R Ii-N 3In the trimethyl carbinol aqueous solution at copper sulfate (II) and (R)-2-((S)-1,2-dihydroxy ethyl)-4-hydroxyl-5-oxo-2,5-dihydrofuran-3-sodium alkoxide exists down under 40-80 ℃ through 1-6 hour processing formula 73Compound, obtain formula 74Compound.
Scheme 24
Figure GPA00001018010700602
Such as scheme 24 description, as the formula of formula (I) representative compounds 76Compound, wherein A and R 4Define suc as formula (I), derive from formula 75Compound.Formula 75Compound can use A-B (OR y) 2Handle, wherein A suc as formula (I) define R yBe hydrogen, alkyl, aryl or two R yGroup forms 1 with the boron atom that connects them, 3-two oxa-boron heterocycle pentanes, and the Suzuki reaction conditions that employing scheme 1 is described in the presence of palladium catalyst obtains formula 76Compound.
Scheme 25
Figure GPA00001018010700611
Such as scheme 25 description, as the formula of formula (I) representative compounds 80Compound, R wherein IiAnd R 4Define suc as formula (I), can prepare thus.Formula 77With 78Compound under the Stille coupling condition that scheme 3 is described, react, obtain formula 79Compound.Formula 79Compound such as scheme 6 described in react, obtain formula 80Compound.
Scheme 26
Figure GPA00001018010700621
Such as scheme 26 description, as the formula of formula (I) representative compounds 82, 83, 84With 85Compound, wherein A, R 4, R 5, R aAnd R jDefine suc as formula (I), by formula 81Compound.Formula 81Compound can use acyl chlorides 18In solvent such as tetrahydrofuran (THF), in the presence of alkali such as salt of wormwood or triethylamine, handle, obtain formula 82Compound.Alternative solvent is a methylene dichloride, and alternative alkali is pyridine.Acyl chlorides can be by corresponding carboxylic acid by the N with oxalyl chloride and catalytic amount, and dinethylformamide is handled and prepared.Available R jNCO is the processing formula in hot pyridine 81Compound come preparation formula 83Compound.Available R 5SO 2Cl in pyridine or near processing formula under the room temperature 81Compound come preparation formula 84Compound.Formula 85Compound also from formula 81Compound begin, with R aCHO in the presence of reductive agent such as sodium triacetoxy borohydride or sodium cyanoborohydride and acetate at solvent as 1; in the 2-ethylene dichloride or near carrying out reduction amination under the room temperature, handle with the dichloromethane solution of trifluoroacetic acid then and slough the tert-butoxycarbonyl blocking group and prepare.
Scheme 27
Such as scheme 27 description, as the formula of formula (I) representative compounds 87Compound, wherein A, R jAnd R kDefine suc as formula (I), can be by formula 86Compound.Formula 86Compound according to preparation formula in the scheme 26 82The method of compound prepare.Then at amine, HNR jR kThere is heating-type in solvent such as acetonitrile down with alkali such as triethylamine 86Compound, obtain formula 87Compound.Perhaps, available heterocycle such as tetramethyleneimine, piperidines, piperazine and morpholino are for amine.
Scheme 28
Figure GPA00001018010700632
Such as scheme 28 description, as the formula of formula (I) representative compounds 89Compound, wherein A, R 1, R 2, R 3, m, Z cAnd Z dDefine suc as formula (I), can be by formula 88Compound.Formula 88Compound can according to scheme 1-4,7-9,22,24 and 26 the preparation.In preparation formula 88The process of compound in, the known method of those of skill in the art is ester with the protection of the carboxylic moiety on the A in the available organic synthesis field, hydrolysis exposes carboxylic acid then.Formula 88Compound, when adopting the known carboxylic acid of those skilled in the art-amine coupling condition with amine (HNZ cZ d) when handling, can obtain formula 89Compound.The carboxylic acid of standard-amine coupling condition comprise add coupling reagent as but be not limited to 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDCI), 1,3 dicyclohexyl carbodiimides (DCC), two (2-oxo-3-oxazolidinyl) inferior phosphonyl chloride (BOPCl), O-(7-azepine benzo triazol-1-yl)-N, N, N ', N '-tetramethyl-urea hexafluorophosphate (HATU) or O-benzotriazole-1-base-N, N, N ', N '-tetramethyl-urea a tetrafluoro borate (TBTU), choose wantonly in the presence of alkali such as triethylamine or diisopropyl ethyl amine add or do not add auxiliary agent as but be not limited to 1-hydroxyl-7-azepine benzotriazole (HOAT) or I-hydroxybenzotriazole hydrate (HOBT), solvent as but be not limited to methylene dichloride or N, in the dinethylformamide.
Embodiment
By the reference the following examples, will understand Compounds and methods for of the present invention better, the purpose of enumerating these embodiment is explanation the present invention and be not in order to limit the scope of the invention.
Embodiment 1
The mixture of 5-(1-benzyl-1H-1,2,3-triazole-4-yl)-1H-indazole and 5-(1-benzyl-1H-1,2,3-triazole-5-yl)-1H-indazole;
Embodiment 1A
5-iodo-1H-indazole-1-formic acid tertiary butyl ester
(20g dropwise adds diacetyl oxide (21.2g, chloroform 208.11mmol) (50mL) solution in chloroform 83.24mmol) (250mL) solution to ice bath refrigerative 4-iodo-2-aminotoluene.After adding, mixture was at room temperature stirred 1 hour.Add potassium acetate (2.5g, 24.97mmol) and Isopentyl nitrite (22.3mL 166.48mmol), heats mixture 20 hours down at 70 ℃.Cooling mixture is used saturated NaHCO 3Aqueous solution quencher is to pH 7.With this mixture of dichloromethane extraction, use the dried over sodium sulfate organic layer, filter.The pressure reducing and steaming solvent.With the thick solid of methanol wash, be dissolved in the tetrahydrofuran (THF) (200mL), with water (200mL) solution-treated of hot KOH (60g).The gained mixture stirred 15 minutes, handled to pH 1 with 6N HCl.Layering, the organic layer dried over sodium sulfate is filtered the pressure reducing and steaming solvent.Thick solid be dissolved in methylene dichloride (500mL) and triethylamine (23mL, 166.48mmol), add two-tertiary butyl, two carbonic ethers (23.6g, 108.2mmol) with the dimethyl aminopyridine of catalytic amount (～5mg).Mixture at room temperature stirred 2 hours, and dilute with water is used dichloromethane extraction, and dried over sodium sulfate is filtered.The pressure reducing and steaming solvent obtains title compound.MS(ESI+)m/z344.9(M+H) +。
Embodiment 1B
5-((trimethyl silyl) ethynyl)-1H-indazole-1-formic acid tertiary butyl ester
With embodiment 1A (10.81g, 31.4mmol), dichloro two (triphenylphosphine) palladium (II) (1.1g, 1.57mmol) and cuprous iodide (I) (365mg 1.92mmol) is mixing in triethylamine (70mL) under the rare gas element.(5.0mL, 36.0mmol), the gained mixture stirs down at 60 ℃ and spends the night to add trimethyl silyl acetylene.The pressure reducing and steaming solvent, the gained residue is dissolved in methylene dichloride, with 1N salt acid elution.The gained mixture is adsorbed on the silica gel, uses the silica gel chromatography purifying, and the hexane solution gradient elution with the 5-40% ethyl acetate obtains title compound.MS(ESI+)m/z?215.0(M-99) +。
Embodiment 1C
5-ethynyl-1H-indazole
(7.93g 25.2mmol) is dissolved in methyl alcohol (150mL) with embodiment 1B.Add 1N potassium hydroxide solution (50mL), mixture at room temperature stirred 1 hour.Removal of solvent under reduced pressure, the gained slurries are dissolved in ethyl acetate, water and salt water washing.The organic layer dried over sodium sulfate is filtered, and removal of solvent under reduced pressure obtains title compound. 1H?NMR(300MHz，DMSO-d 6)δppm?13.24(s，1H)8.10(s，1H)7.95(s，1H)7.55(d，J＝8.82Hz，1H)7.39(dd，J＝8.48，1.36Hz，1H)4.03(s，1H)。
Embodiment 1D
The mixture of 5-(1-benzyl-1H-1,2,3-triazole-4-yl)-1H-indazole and 5-(1-benzyl-1H-1,2,3-triazole-5-yl)-1H-indazole;
In the microwave phial, add 100.0mg (0.70mmol) embodiment 1C and 94mg (0.70mmol) benzyl azide.With microwave radiation (CEM-Discover, 100 watts, 1 minute slope time) mixture was heated 20 minutes down at 160 ℃.The gained mixture is dissolved in ethyl acetate, uses the silica gel chromatography purifying, and the hexane solution wash-out with 75% ethyl acetate obtains title compound. 1H?NMR(300MHz，DMSO-d 6)δppm?13.28(s，1H)13.12(s，1H)8.61(s，1H)8.23(s，1H)8.13(s，1H)8.11(s，1H)7.94(s，1H)7.82-7.89(m，2H)7.56-7.70(m，2H)7.20-7.44(m，9H)6.97-7.02(m，2H)5.69(s，2H)5.65(s，2H).MS(CI)m/z?276(M+H) +。
Embodiment 2
5-(1H-1,2,3-triazole-5-yl)-1H-indazole
In the microwave phial, add 100.0mg (0.70mmol) embodiment 1C, 81mg (0.7mmol) azido-trimethyl silyl, CuI (4mg) and dimethyl formamide/methyl alcohol (1mL, 9: 1).The gained mixture heated 20 minutes down for 160 ℃ with microwave radiation (CEM-Discover, 100 watts, 1 minute slope time).Mixture is dissolved in ethyl acetate, and organic layer washes with water.The anhydrous MgSO of organic layer 4Drying is filtered, and concentrating under reduced pressure is used the silica gel chromatography purifying, and the hexane solution wash-out with 80% ethyl acetate obtains title compound. 1H?NMR(300MHz，DMSO-d 6)δppm?13.16(s，1H)8.31(s，1H)8.25(s，1H)8.13(s，1H)7.87(d，J＝8.82Hz，1H)7.62(d，J＝8.82Hz，1H).MS(CI)m/z?186(M+H) +。
Embodiment 3
5-(1-benzyl-1H-1,2,3-triazole-4-yl)-1H-indazole
Embodiment 3A
5-iodo-1H-indazole-1-formic acid tertiary butyl ester
(20g dropwise adds diacetyl oxide (21.2g, chloroform 208.11mmol) (50mL) solution with adding funnel in chloroform 83.24mmol) (250mL) solution to ice bath refrigerative 4-iodo-2-aminotoluene.After adding, mixture was at room temperature stirred 1 hour.Add potassium acetate (2.5g, 24.97mmol) and Isopentyl nitrite (22.3mL, 166.48mmol), the gained mixture heated 20 hours down at 70 ℃.Cooling mixture is used saturated NaHCO then 3Aqueous solution quencher is to pH 7.Use the dichloromethane extraction mixture, dried over sodium sulfate is filtered the pressure reducing and steaming solvent.Thick solid methanol wash is dissolved in tetrahydrofuran (THF) (200mL), with water (200mL) solution-treated of hot KOH (60g).The gained mixture stirred 15 minutes, handled to pH 1 with 6N HCl.Layering, the organic layer dried over sodium sulfate is filtered the pressure reducing and steaming solvent.Thick material be dissolved in methylene dichloride (500mL) and triethylamine (23mL, 166.48mmol), add di-tert-butyl dicarbonic acid ester (23.6g, 108.2mmol) with the dimethyl aminopyridine of catalytic amount (～5mg).The gained mixture at room temperature stirred 2 hours, the water quencher, and dichloromethane extraction, dried over sodium sulfate is filtered.The pressure reducing and steaming solvent obtains title compound.MS(ESI+)m/z?344.9(M+H) +。
Embodiment 3B
5-((trimethyl silyl) ethynyl)-1H-indazole-1-formic acid tertiary butyl ester
With embodiment 3A (10.81g, 31.4mmol), dichloro two (triphenylphosphine) palladium (II) (1.1g, 1.57mmol) and cuprous iodide (I) (365mg 1.92mmol) is mixing in triethylamine (70mL) under the rare gas element.(5.0mL, 36.0mmol), the gained mixture stirs down at 60 ℃ and spends the night to add trimethyl silyl acetylene.Removal of solvent under reduced pressure, the gained residue is dissolved in methylene dichloride, with 1N salt acid elution.Mixture is adsorbed in silica gel, uses the silica gel chromatography purifying, the hexane solution gradient elution with the 5-40% ethyl acetate obtains title compound.MS(ESI+)m/z?215.0(M-99) +。
Embodiment 3C
5-ethynyl-1H-indazole
(7.93g 25.2mmol) is dissolved in the methyl alcohol (150mL) with embodiment 3B.Add 1N potassium hydroxide solution (50mL), the gained mixture at room temperature stirred 1 hour.Removal of solvent under reduced pressure, the gained slurries are dissolved in ethyl acetate, water and salt water washing.The organic layer dried over sodium sulfate is filtered, and removal of solvent under reduced pressure obtains title compound. 1H?NMR(300MHz，DMSO-d 6)δppm?13.24(s，1H)8.10(s，1H)7.95(s，1H)7.55(d，J＝8.82Hz，1H)7.39(dd，J＝8.48，1.36Hz，1H)4.03(s，1H)。
Embodiment 3D
5-(1-benzyl-1H-1,2,3-triazole-4-yl)-1H-indazole
Embodiment 3C (40mg, 0.28mmol), benzyl azide (37mg, 0.28mmol), CuSO 4(14mg 0.056mmol) mixes in the trimethyl carbinol (0.5mL) and water (0.5mL) with Cu silk (14mg), heats 10 minutes under 125 ℃ and 100 watts in the CEM-Discover microwave.Add 1M HCl and water in mixture, the products therefrom dichloromethane extraction with silica gel chromatography purifying (hexane solution of 50% ethyl acetate), obtains title compound. 1H?NMR(400MHz，DMSO-d 6)δppm?13.10(s，1H)8.60(s，1H)8.23(s，1H)8.11(s，1H)7.85(d，J＝8.59，1.53Hz，1H)7.59(d，J＝8.59Hz，1H)7.26-7.49(m，5H)5.65(s，2H).MS(ESI+)m/z?276.0(M+H) +。
Embodiment 4
5-[1-(2-methyl-benzyl)-1H-1,2,3-triazole-4-yl]-the 1H-indazole
In the 5mLCEM microwave reaction pipe that contains the miniature stirring rod (micro-flea stirring bar) that scribbles the Teflon coating, add the solution that 17.6mg (0.124mmol) embodiment 3C, 300 μ L comprise 7.80mg (0.118mmol) sodiumazide; Add 15.79 μ L (0.118mmol then; 21.80mg 2-methyl-bromotoluene 0.95 equivalent) (accurately adding (added neat)).In the gained suspension, add the 300 μ L trimethyl carbinols then; The 25mg copper wire; Add 50 μ L 1N copper sulfate pentahydrate solution at last.Cover microwave reactor then, 125 ℃ under 100 watts in the CEM-Discover microwave heated and stirred 10 minutes.After being chilled to room temperature, mixture is diluted with the 0.25N HCl aqueous solution; Gained aqueous suspension dichloromethane extraction.Organic layer distilled water, saturated NaCl solution washing; Use anhydrous sodium sulfate drying then, filter.With dilution in acetonitrile exsiccant solution; Filter dissolved organic matter matter by the glass wool plug (glass wool plug) that is coated with other anhydrous sodium sulphate then.Removing the filtrate of five equilibrium then analyzes with the LC/MS that carries out subsequently.The solution vaporising under vacuum that then those is contained required triazole product is dissolved in 1: the 1 DMSO/ methyl alcohol of 1.50mL once more.Then the thick triazole product of gained solution is passed through the reversed-phase HPLC purifying with acetonitrile/water 0.1%TFA linear gradient elution method, obtain title compound. 1H?NMR(500MHz，DMSO-d 6/D 2O)δppm?2.37(s，3H)5.66(s，2H)7.16-7.34(m，4H)7.63(d，J＝8.54Hz，1H)7.87(d，J＝8.70，1.37Hz，1H)8.14(s，1H)8.25(s，1H)8.49(s，1H).MS(ESI+)m/z?289.9(M+H) +。
Embodiment 5
5-[1-(3-methyl-benzyl)-1H-1,2,3-triazole-4-yl]-the 1H-indazole
Prepare title compound according to the method for describing among the embodiment 4, wherein replace 2-methyl-benzyl bromine with 3-methyl-bromotoluene. 1H?NMR(500MHz，DMSO-d 6/D 2O)δppm?8.58(s，1H)8.25(s，1H)8.14(s，1H)7.87(d，J＝8.85，1.53Hz，1H)7.64(d，J＝8.54Hz，1H)7.30(t，J＝7.63Hz，1H)7.14-7.24(m，3H)5.60(s，2H)2.31(s，3H).MS(ESI+)m/z?289.8(M+H) +。
Embodiment 6
5-[1-(4-methyl-benzyl)-1H-1,2,3-triazole-4-yl]-the 1H-indazole
Prepare title compound according to the method for describing among the embodiment 4, wherein replace 2-methyl-benzyl bromine with 4-methyl-bromotoluene. 1H?NMR(500MHz，DMSO-d 6/D 2O)δppm?8.55(s，1H)8.24(s，1H)8.14(s，1H)7.86(d，J＝8.54，1.53Hz，1H)7.63(d，J＝8.85Hz，1H)7.25-7.33(m，2H)7.18-7.24(m，2H)5.59(s，2H)2.29(s，3H).MS(ESI+)m/z?290.1(M+H) +。
Embodiment 7
5-[1-(3-methoxy-benzyl)-1H-1,2,3-triazole-4-yl]-the 1H-indazole
Prepare title compound according to the method for describing among the embodiment 4, wherein replace 2-methyl-benzyl bromine with 3-methoxyl group-bromotoluene. 1H?NMR(500MHz，DMSO-d 6/D 2O)δppm?8.59(s，1H)8.25(s，1H)8.14(s，1H)7.87(d，J＝8.54，1.53Hz，1H)7.64(d，J＝8.85Hz，1H)7.33(t，J＝7.93Hz，1H)6.89-7.00(m，3H)5.62(s，2H)3.76(s，3H).MS(ESI+)m/z?306.1(M+H) +。
Embodiment 8
5-[1-(2-luorobenzyl)-1H-1,2,3-triazole-4-yl]-the 1H-indazole
Prepare title compound according to the method for describing among the embodiment 4, wherein replace 2-methyl-benzyl bromine with the 2-fluoro benzyl bromide. 1H?NMR(500MHz，DMSO-d 6/D 2O)δppm?8.57(s，1H)8.25(s，1H)8.12-8.17(m，1H)7.87(d，J＝8.54，1.53Hz，1H)7.64(d，J＝8.54Hz，1H)7.41-7.49(m，J＝7.32，7.32Hz，2H)7.22-7.33(m，J＝7.02Hz，2H)5.71(s，2H).MS(ESI+)m/z?293.9(M+H) +。
Embodiment 9
5-[1-(3-luorobenzyl)-1H-1,2,3-triazole-4-yl]-the 1H-indazole
Prepare title compound according to the method for describing among the embodiment 4, wherein replace 2-methyl-benzyl bromine with the 3-fluoro benzyl bromide. 1H?NMR(500MHz，DMSO-d 6/D 2O)δppm?8.61(s，1H)8.25(s，1H)8.15(s，1H)7.87(d，J＝8.85，1.53Hz，1H)7.64(d，J＝8.54Hz，1H)7.41-7.51(m，1H)7.15-7.28(m，3H)5.68(s，2H).MS(ESI+)m/z?293.8(M+H) +。
Embodiment 10
5-[1-(4-luorobenzyl)-1H-1,2,3-triazole-4-yl]-the 1H-indazole
Prepare title compound according to the method for describing among the embodiment 4, wherein replace 2-methyl-benzyl bromine with the 4-fluoro benzyl bromide. 1H?NMR(500MHz，DMSO-d 6/D 2O)δppm?8.58(s，1H)8.24(s，1H)8.14(s，1H)7.86(d，J＝8.85，1.53Hz，1H)7.64(d，J＝8.85Hz，1H)7.46(d，J＝8.85，5.49Hz，2H)7.24(t，J＝9.00Hz，2H)5.64(s，2H).MS(ESI+)m/z?293.9(M+H) +。
Embodiment 11
5-[1-(2-benzyl chloride base)-1H-1,2,3-triazole-4-yl]-the 1H-indazole
Prepare title compound according to the method for describing among the embodiment 4, wherein replace 2-methyl-benzyl bromine with 2-benzyl chloride base bromo. 1H?NMR(500MHz，DMSO-d 6/D 2O)δppm?8.56(s，1H)8.26(s，1H)8.14(s，1H)7.88(d，J＝8.54，1.53Hz，1H)7.64(d，J＝8.54Hz，1H)7.55(d，J＝7.63，1.53Hz，1H)7.32-7.48(m，3H)5.76(s，2H).MS(ESI+)m/z?309.8(M+H) +。
Embodiment 12
5-[1-(3-benzyl chloride base)-1H-1,2,3-triazole-4-yl]-the 1H-indazole
Prepare title compound according to the method for describing among the embodiment 4, wherein replace 2-methyl-benzyl bromine with 3-benzyl chloride base bromo. 1H?NMR(500MHz，DMSO-d 6/D 2O)δppm?8.62(s，1H)8.26(s，1H)8.15(s，1H)7.87(d，J＝8.54，1.53Hz，1H)7.64(d，J＝8.54Hz，1H)7.40-7.49(m，J＝7.63Hz，3H)7.35(d，J＝6.41Hz，1H)5.67(s，2H).MS(ESI+)m/z?309.8(M+H) +。
Embodiment 13
5-[1-(4-benzyl chloride base)-1H-1,2,3-triazole-4-yl]-the 1H-indazole
Prepare title compound according to the method for describing among the embodiment 4, wherein replace 2-methyl-benzyl bromine with 4-benzyl chloride base bromo. 1H?NMR(500MHz，DMSO-d 6/D 2O)δppm?8.58(s，1H)8.24(s，1H)8.15(s，1H)7.86(d，J＝8.54，1.53Hz，1H)7.64(d，J＝8.85Hz，1H)7.45-7.52(m，2H)7.38-7.44(m，2H)5.65(s，2H).MS(ESI-)m/z?307.7(M-H) -。
Embodiment 14
5-[1-(2-bromobenzyl)-1H-1,2,3-triazole-4-yl]-the 1H-indazole
Prepare title compound according to the method for describing among the embodiment 4, wherein replace 2-methyl-benzyl bromine with the 2-bromo benzyl bromo. 1H?NMR(500MHz，DMSO-d 6/D 2O)δppm?8.55(s，1H)8.26(s，1H)8.14(s，1H)7.88(d，J＝8.54，1.53Hz，1H)7.72(d，J＝7.93Hz，1H)7.64(d，J＝8.54Hz，1H)7.41-7.50(m，1H)7.27-7.40(m，2H)5.74(s，2H).MS(ESI+)m/z?353.5(M+H) +。
Embodiment 15
5-[1-(2-nitrobenzyl)-1H-1,2,3-triazole-4-yl]-the 1H-indazole
Prepare title compound according to the method for describing among the embodiment 4, wherein replace 2-methyl-benzyl bromine with 2-nitrobenzyl bromo. 1H?NMR(500MHz，DMSO-d 6/D 2O)δppm?8.57(s，1H)8.27(s，1H)8.12-8.22(m，2H)7.88(d，J＝8.54，1.53Hz，1H)7.75-7.83(m，1H)7.60-7.72(m，2H)7.27(d，J＝7.63Hz，1H)6.02(s，2H).MS(ESI+)m/z?320.8(M+H) +。
Embodiment 16
5-[1-(3-nitrobenzyl)-1H-1,2,3-triazole-4-yl]-the 1H-indazole
Prepare title compound according to the method for describing among the embodiment 4, wherein replace 2-methyl-benzyl bromine with 3-nitrobenzyl bromo. 1H?NMR(500MHz，DMSO-d 6/D 2O)δppm?8.65(s，1H)8.21-8.28(m，3H)8.15(s，1H)7.80-7.91(m，2H)7.73(t，J＝7.78Hz，1H)7.65(d，J＝8.54Hz，1H)5.83(s，2H).MS(ESI+)m/z?320.8(M+H) +。
Embodiment 17
5-[1-(4-nitrobenzyl)-1H-1,2,3-triazole-4-yl]-the 1H-indazole
Prepare title compound according to the method for describing among the embodiment 4, wherein replace 2-methyl-benzyl bromine with 4-nitrobenzyl bromo. 1H?NMR(500MHz，DMSO-d 6/D 2O)δppm?8.64(s，1H)8.22-8.31(m，3H)8.15(s，1H)7.88(d，J＝8.70，1.37Hz，1H)7.57-7.68(m，3H)5.83(s，2H).MS(ESI+)m/z?320.7(M+H) +。
Embodiment 18
2-{[4-(1H-indazole-5-yl)-1H-1,2, the 3-triazol-1-yl] methyl } cyanobenzene
Prepare title compound according to the method for describing among the embodiment 4, wherein replace 2-methyl-benzyl bromine with the 2-cyano-benzyl bromide. 1H?NMR(500MHz，DMSO-d 6/D 2O)δppm?8.61(s，1H)8.26(s，1H)8.15(s，1H)7.93(d，J＝7.63Hz，1H)7.88(d，J＝8.54，1.53Hz，1H)7.72-7.80(m，1H)7.57-7.68(m，2H)7.53(d，J＝7.93Hz，1H)5.86(s，2H).MS(ESI+)m/z?300.9(M+H) +。
Embodiment 19
3-{[4-(1H-indazole-5-yl)-1H-1,2, the 3-triazol-1-yl] methyl } cyanobenzene
Prepare title compound according to the method for describing among the embodiment 4, wherein replace 2-methyl-benzyl bromine with the 3-cyano-benzyl bromide. 1H?NMR(500MHz，DMSO-d 6/D 2O)δppm?8.63(s，1H)8.26(s，1H)8.15(s，1H)7.85-7.93(m，2H)7.83(d，J＝7.63Hz，1H)7.72(d，J＝8.24Hz，1H)7.56-7.68(m，2H)5.74(s，2H).MS(ESI+)m/z?300.9(M+H) +。
Embodiment 20
4-{[4-(1H-indazole-5-yl)-1H-1,2, the 3-triazol-1-yl] methyl } cyanobenzene
Prepare title compound according to the method for describing among the embodiment 4, wherein replace 2-methyl-benzyl bromine with the 4-cyano-benzyl bromide. 1H?NMR(500MHz，DMSO-d 6/D 2O)δppm?8.62(s，1H)8.26(s，1H)8.15(s，1H)7.82-7.93(m，J＝8.24Hz，3H)7.65(d，J＝8.54Hz，1H)7.54(d，J＝8.24Hz，2H)5.78(s，2H).MS(ESI+)m/z?300.7(M+H) +。
Embodiment 21
5-{1-[2-(trifluoromethyl) benzyl]-1H-1,2,3-triazole-4-yl }-the 1H-indazole
Prepare title compound according to the method for describing among the embodiment 4, wherein replace 2-methyl-benzyl bromine with 2-trifluoromethyl benzyl bromo. 1H?NMR(500MHz，DMSO-d 6/D 2O)δppm?8.56(s，1H)8.27(s，1H)8.15(s，1H)7.89(d，J＝8.85，1.53Hz，1H)7.85(d，J＝7.93Hz，1H)7.72(t，J＝7.63Hz，1H)7.55-7.68(m，2H)7.33(d，J＝7.93Hz，1H)5.85(s，2H).MS(ESI+)m/z?300.7(M+H) +。
Embodiment 22
5-{1-[3-(trifluoromethyl) benzyl]-1H-1,2,3-triazole-4-yl }-the 1H-indazole
Prepare title compound according to the method for describing among the embodiment 4, wherein replace 2-methyl-benzyl bromine with 3-trifluoromethyl benzyl bromo. 1H?NMR(500MHz，DMSO-d 6/D 2O)δppm?8.65(s，1H)8.25(s，1H)8.14(s，1H)7.87(d，J＝8.70，1.37Hz，1H)7.77(s，1H)7.71-7.76(m，1H)7.61-7.69(m，3H)5.78(s，2H).MS(ESI+)m/z?344.0(M+H) +。
Embodiment 23
5-{1-[4-(trifluoromethyl) benzyl]-1H-1,2,3-triazole-4-yl }-the 1H-indazole
Prepare title compound according to the method for describing among the embodiment 4, wherein replace 2-methyl-benzyl bromine with 4-trifluoromethyl benzyl bromo. 1H?NMR(500MHz，DMSO-d 6/D 2O)δppm?8.63(s，1H)8.25(s，1H)8.14(s，1H)7.87(d，J＝8.54Hz，1H)7.78(d，J＝7.93Hz，2H)7.63(d，J＝8.54Hz，1H)7.58(d，J＝7.93Hz，2H)5.78(s，2H).MS(ESI+)m/z344.2(M+H) +。
Embodiment 24
5-{1-[3-(trifluoromethoxy) benzyl]-1H-1,2,3-triazole-4-yl }-the 1H-indazole
Prepare title compound according to the method for describing among the embodiment 4, wherein replace 2-methyl-benzyl bromine with 3-trifluoro-methoxybenzyl bromo. 1H?NMR(500MHz，DMSO-d 6/D 2O)δppm?8.64(s，1H)8.25(s，1H)8.14(s，1H)7.87(d，J＝8.54Hz，1H)7.64(d，J＝8.54Hz，1H)7.56(t，J＝8.24Hz，1H)7.31-7.45(m，3H)5.73(s，2H).MS(ESI+)m/z359.9(M+H) +。
Embodiment 25
5-{1-[4-(trifluoromethoxy) benzyl]-1H-1,2,3-triazole-4-yl }-the 1H-indazole
Prepare title compound according to the method for describing among the embodiment 4, wherein replace 2-methyl-benzyl bromine with 4-trifluoro-methoxybenzyl bromo. 1H?NMR(500MHz，DMSO-d 6/D 2O)δppm?8.61(s，1H)8.25(s，1H)8.14(s，1H)7.87(d，J＝8.70，1.37Hz，1H)7.63(d，J＝8.54Hz，1H)7.52(d，J＝8.85Hz，2H)7.40(d，J＝8.24Hz，2H)5.70(s，2H).MS(ESI+)m/z?359.9(M+H) +。
Embodiment 26
5-[1-(4-tertiary butyl benzyl)-1H-1,2,3-triazole-4-yl]-the 1H-indazole
Prepare title compound according to the method for describing among the embodiment 4, wherein replace 2-methyl-benzyl bromine with 4-tertiary butyl bromotoluene. 1H?NMR(500MHz，DMSO-d 6/D 2O)δppm?8.58(s，1H)8.24(s，1H)8.13(s，1H)7.86(d，J＝8.85，1.53Hz，1H)7.63(d，J＝8.54Hz，1H)7.42(d，J＝8.24Hz，2H)7.32(d，J＝8.24Hz，2H)5.60(s，2H)1.26(s，9H).MS(ESI+)m/z?332.1(M+H) +。
Embodiment 27
3-{[4-(1H-indazole-5-yl)-1H-1,2, the 3-triazol-1-yl] methyl } methyl benzoate
Prepare title compound according to the method for describing among the embodiment 4, wherein replace 2-methyl-benzyl bromine with 3-methoxycarbonyl bromotoluene. 1H?NMR(500MHz，DMSO-d 6/D 2O)δppm?8.62(s，1H)8.25(s，1H)8.14(s，1H)7.92-7.99(m，2H)7.87(d，J＝8.54，1.53Hz，1H)7.68(d，J＝7.63Hz，1H)7.63(d，J＝8.54Hz，1H)7.58(t，J＝7.63Hz，1H)5.75(s，2H)3.86(s，3H).MS(ESI+)m/z?333.9(M+H) +。
Embodiment 28
4-{[4-(1H-indazole-5-yl)-1H-1,2, the 3-triazol-1-yl] methyl } methyl benzoate
Prepare title compound according to the method for describing among the embodiment 4, wherein replace 2-methyl-benzyl bromine with 4-methoxycarbonyl bromotoluene. 1H?NMR(500MHz，DMSO-d 6/D 2O)δppm?8.62(s，1H)8.25(s，1H)8.14(s，1H)7.99(d，J＝8.24Hz，2H)7.87(d，J＝8.85Hz，1H)7.63(d，J＝8.54Hz，1H)7.49(d，J＝8.24Hz，2H)5.76(s，2H)3.85(s，3H).MS(ESI+)m/z?333.9(M+H) +。
Embodiment 29
5-[1-(2, the 4-dimethyl benzyl)-1H-1,2,3-triazole-4-yl]-the 1H-indazole
Prepare title compound according to the method for describing among the embodiment 4, wherein use 2,4-dimethyl benzyl chloro is for 2-methyl-benzyl bromine. 1H?NMR(500MHz，DMSO-d 6/D 2O)δppm?8.45(s，1H)8.24(s，1H)8.13(s，1H)7.86(d，J＝8.54Hz，1H)7.62(d，J＝8.54Hz，1H)7.12(d，J＝7.93Hz，1H)7.07(s，1H)7.04(d，J＝7.63Hz，1H)5.60(s，2H)2.32(s，3H)2.26(s，3H).MS(ESI+)m/z?304.0(M+H) +。
Embodiment 30
5-[1-(3, the 5-dimethyl benzyl)-1H-1,2,3-triazole-4-yl]-the 1H-indazole
Prepare title compound according to the method for describing among the embodiment 4, wherein use 3,5-dimethyl benzyl bromo is for 2-methyl-benzyl bromine. 1H?NMR(500MHz，DMSO-d 6/D 2O)δppm?8.56(s，1H)8.24(s，1H)8.13(s，1H)7.87(d，J＝8.54Hz，1H)7.63(d，J＝8.54Hz，1H)6.95-7.01(m，3H)5.55(s，2H)2.26(s，6H).MS(ESI+)m/z?304.2(M+H) +。
Embodiment 31
5-[1-(2, the 3-dichloro benzyl)-1H-1,2,3-triazole-4-yl]-the 1H-indazole
Prepare title compound according to the method for describing among the embodiment 4, wherein use 2, the 3-dichlorobenzyl chloride replaces 2-methyl-benzyl bromine. 1H?NMR(500MHz，DMSO-d 6/D 2O)δppm?8.59(s，1H)8.26(s，1H)8.14(s，1H)7.88(d，J＝8.70，1.37Hz，1H)7.69(d，J＝8.09，1.37Hz，1H)7.63(d，J＝8.54Hz，1H)7.44(t，J＝7.78Hz，1H)7.31(d，J＝7.78，1.07Hz，1H)5.81(s，2H).MS(ESI+)m/z?343.8(M+H) +。
Embodiment 32
5-[1-(2, the 4-dichloro benzyl)-1H-1,2,3-triazole-4-yl]-the 1H-indazole
Prepare title compound according to the method for describing among the embodiment 4, wherein use 2, the 4-dichlorobenzyl chloride replaces 2-methyl-benzyl bromine. 1H?NMR(500MHz，DMSO-d 6/D 2O)δppm?8.56(s，1H)8.25(s，1H)8.13(s，1H)7.87(d，J＝8.54Hz，1H)7.72(d，J＝2.14Hz，1H)7.63(d，J＝8.54Hz，1H)7.50(d，J＝8.39，1.98Hz，1H)7.40(d，J＝8.24Hz，1H)5.74(s，2H).MS(ESI-)m/z?341.8(M-H) -。
Embodiment 33
5-[1-(2, the 5-dichloro benzyl)-1H-1,2,3-triazole-4-yl]-the 1H-indazole
Prepare title compound according to the method for describing among the embodiment 4, wherein use 2, the 5-dichlorobenzyl chloride replaces 2-methyl-benzyl bromine. 1H?NMR(500MHz，DMSO-d 6/D 2O)δppm?8.59(s，1H)8.26(s，1H)8.14(s，1H)7.88(d，J＝8.85Hz，1H)7.63(d，J＝8.85Hz，1H)7.56-7.61(m，1H)7.49-7.55(m，1H)7.47(d，J＝2.44Hz，1H)5.75(s，2H).MS(ESI+)m/z?343.8(M+H) +。
Embodiment 34
5-[1-(3, the 5-dichloro benzyl)-1H-1,2,3-triazole-4-yl]-the 1H-indazole
Prepare title compound according to the method for describing among the embodiment 4, wherein use 3, the 5-dichlorobenzyl chloride replaces 2-methyl-benzyl bromine. 1H?NMR(500MHz，DMSO-d 6/D 2O)δppm?8.64(s，1H)8.26(s，1H)8.15(s，1H)7.87(d，J＝8.85Hz，1H)7.57-7.71(m，2H)7.44(d，J＝1.53Hz，2H)5.69(s，2H).MS(ESI+)m/z?344.1(M+H) +。
Embodiment 35
5-{1-[2, two (trifluoromethyl) benzyls of 4-]-1H-1,2,3-triazole-4-yl }-the 1H-indazole
Prepare title compound according to the method for describing among the embodiment 4, wherein use 2, two (trifluoromethyl) bromos of 4-are for 2-methyl-benzyl bromine. 1H?NMR(500MHz，DMSO-d 6/D 2O)δppm?8.62(s，1H)8.27(s，1H)8.07-8.18(m，3H)7.89(d，J＝8.70，1.37Hz，1H)7.64(d，J＝8.54Hz，1H)7.49(d，J＝7.93Hz，1H)5.96(s，2H).MS(ESI+)m/z?411.7(M+H) +。
Embodiment 36
N-cyclohexyl-6-(1H-indazole-5-yl) imidazo [2,1-b] [1,3] thiazole-5-amine
Embodiment 36A
1H-indazole-5-formaldehyde
Under argon gas to (5g dropwise adds hexane (40mL, 63.44mmol) solution of 1.6M n-Butyl Lithium in tetrahydrofuran (THF) 25.38mmol) (100mL) solution at-50 ℃ of refrigerative 5-bromo-indazoles.(3.9mL, 50.75mmol), the gained mixture heating up stirred 15 minutes to room temperature to add dimethyl formamide.Water quencher mixture is used ethyl acetate extraction then, with silica gel preadsorption (preabsorb), uses the silica gel chromatography purifying, and the hexane solution gradient elution with the 10-30% ethyl acetate obtains title compound. 1H?NMR(500MHz，DMSO-d 6)δppm?10.03(s，1H)8.45(s，1H)8.35(s，1H)7.85(dd，J＝8.70，1.37Hz，1H)7.69(d，J＝8.54Hz，1H)。
Embodiment 36B
N-cyclohexyl-6-(1H-indazole-5-yl) imidazo [2,1-b] [1,3] thiazole-5-amine
With embodiment 36A (50mg, 0.34mmol) and thiazolamine (28mg, 0.34mmol) (8mg, anhydrous methanol 0.017mmol) (1mL) solution mixes in the 4mL phial with the trifluoromethanesulfonic acid scandium.The sealing phial, jolting at room temperature 30 minutes.Adding isonitrile hexanaphthene (42mL, 0.34mmol), with mixture jolting at room temperature 2 days.By reversed-phase HPLC purifying gained mixture, obtain the tfa salt of title compound with acetonitrile/water 0.1%TFA linear gradient elution method. 1H?NMR(500MHz，DMSO-d 6)δppm?13.12(s，1H)8.32(s，1H)8.13(s，1H)8.05(d，J＝8.85，1.22Hz，1H)7.92(d，J＝4.27Hz，1H)7.60(d，J＝8.54Hz，1H)7.37(d，J＝3.66Hz，1H)4.89(s，1H)2.78-2.94(m，1H)1.73-1.83(m，2H)1.58-1.68(m，2H)1.45-1.53(m，1H)1.16-1.29(m，2H)1.04-1.14(m，3H).MS(ESI+)m/z?338.1(M+H) +。
Embodiment 37
N-cyclohexyl-2-(1H-indazole-5-yl) imidazo [1,2-a] pyridine-3-amine
Prepare title compound according to the method for describing among the embodiment 36B, wherein replace thiazolamine with the 2-aminopyridine. 1H?NMR(500MHz，DMSO-d 6)δppm?13.04(s，1H)8.57(s，1H)8.23-8.39(m，2H)8.11(s，1H)7.57(d，J＝8.54Hz，1H)7.46(d，J＝8.85Hz，1H)7.12-7.21(m，1H)6.88(t，J＝6.71Hz，1H)4.78(d，J＝5.80Hz，1H)2.78-2.91(m，1H)1.69-1.77(m，J＝10.98Hz，2H)1.57-1.67(m，2H)1.45-1.53(m，1H)1.21-1.34(m，2H)1.01-1.16(m，3H).MS(ESI+)m/z?332.1(M+H) +。
Embodiment 38
N-cyclohexyl-2-(1H-indazole-5-yl) imidazo [1,2-a] pyrazine-3-amine
Prepare title compound according to the method for describing among the embodiment 36B, wherein replace thiazolamine with the amino pyrazine of 2-. 1H?NMR(500MHz，DMSO-d 6)δppm?13.12(s，1H)8.90(d，J＝1.22Hz，1H)8.61(s，1H)8.37(d，J＝4.58，1.53Hz，1H)8.29(d，J＝8.70，1.37Hz，1H)8.15(s，1H)7.85(d，J＝4.58Hz，1H)7.62(d，J＝8.85Hz，1H)5.05(d，J＝6.71Hz，1H)2.81-2.99(m，1H)1.70-1.77(m，J＝10.68Hz，2H)1.58-1.67(m，2H)1.47(s，1H)1.24-1.38(m，2H)1.00-1.16(m，3H).MS(ESI+)m/z?333.1(M+H) +。
Embodiment 39
5-[1-benzyl-4-(4-fluorophenyl)-1H-imidazoles-5-yl]-the 1H-indazole
In the 20mL scintillation vial, add 50.0mg (0.34mmol) embodiment 36A.In this solid, add 2.0mL and contain 0.46mmol (49mg) benzyl amine and the Powdered activation of 50mg
Figure GPA00001018010700771
The dimethyl formamide solution of molecular sieve.Cover bottle then, on orbital shaker, heated 4 hours down at 60 ℃.Cool off reaction flask to room temperature, uncap.In the gained suspension, add 32mg (0.23mmol) Anhydrous potassium carbonate, add 66mg (0.23mmol) α-(p-toluenesulfonyl)-4-luorobenzyl isonitrile (isonitrile) then.And then cover bottle cap on vibrator 60 ℃ of following heated overnight.Remove reaction flask from vibrator, be chilled to room temperature, filter the gained suspension.On Savant Speed Vac with medium temperature reduction vaporization filtrate.Thick residue is dissolved in 1: 1 DMSO/ methyl alcohol again, by the reversed-phase HPLC purifying, obtains the tfa salt of title compound with acetonitrile/water TFA linear gradient elution method. 1H?NMR(300MHz，DMSO-d 6)δppm?9.01(s，1H)8.12(s，1H)7.76(s，1H)7.60(d，J＝8.48Hz，2H)7.32-7.45(m，2H)7.09-7.30(m，6H)6.96(d，J＝6.61，2.88Hz，2H)5.23(s，2H).MS(DCI)m/z?369(M+H) +。
Embodiment 40
N-{3-[4-(4-fluorophenyl)-5-(1H-indazole-5-yl)-1H-imidazoles-1-yl] propyl group }-N, the N-dimethyl amine
Prepare the tfa salt of title compound according to the method for describing among the embodiment 39, wherein use N 1, N 1-dimethylpropane-1, the 3-diamines replaces benzyl amine. 1H?NMR(300MHz，DMSO-d 6)δppm?9.49(s，1H)8.88(s，1H)8.19(s，1H)7.94(s，1H)7.73(d，J＝8.81Hz，1H)7.29-7.44(m，3H)7.17(t，J＝8.98Hz，2H)4.01(t，J＝7.12Hz，2H)2.89-3.04(m，J＝10.51Hz，2H)2.68(s，3H)2.67(s，3H)1.87-2.02(m，2H).MS(DCI)m/z?364(M+H) +。
Embodiment 41
N-cyclohexyl-2-(1H-indazole-5-yl) imidazo [1,2-a] pyrimidine-3-amine
Prepare the tfa salt of title compound with the method for describing among the embodiment 36B, wherein replace thiazole-2-amine with pyrimidine-2-amine. 1H?NMR(500MHz，DMSO-d 6)δppm?13.21-13.41(m，1H)9.07(d，J＝5.80Hz，1H)8.85(d，J＝3.05Hz，1H)8.51(s，1H)8.24(s，1H)8.14(d，J＝8.70，1.37Hz，1H)7.73(d，J＝8.85Hz，1H)7.47-7.56(m，1H)5.25-5.41(m，J＝2.75Hz，1H)2.81-2.91(m，J＝10.53，10.53Hz，1H)1.74-1.83(m，2H)1.56-1.66(m，2H)1.43-1.50(m，1H)1.24(q，J＝11.09Hz，2H)1.00-1.14(m，3H).MS(ESI+)m/z?333.1(M+H) +。
Embodiment 42
5-[4-(4-fluorophenyl)-1-(1-phenylethyl)-1H-imidazoles-5-yl]-the 1H-indazole
Prepare title compound with the method for describing among the embodiment 39, wherein replace benzyl amine with the 1-phenyl-ethyl amine. 1H?NMR(300MHz，CDCl 3)δppm?8.04(s，1H)7.75-7.84(m，1H)7.35-7.55(m，4H)7.20-7.31(m，5H)6.76-7.01(m，4H)5.09(q，J＝7.12Hz，1H)1.82(d，3H).MS(DCI)m/z?383(M+H) +。
Embodiment 43
2-(1H-indazole-5-yl)-N-isopropylimdazole is [1,2-a] pyrimidine-3-amine also
(42mg, 0.287mmol) (27mg, 0.284mmol) (7mg 0.014mmol) mixes in the 4mL phial in anhydrous methanol (2mL) embodiment 36A with the trifluoromethanesulfonic acid scandium with the 2-aminopyrimidine.The sealing phial, jolting at room temperature 30 minutes.(27mL 0.286mmol), spends the night mixture jolting at room temperature, then 40 ℃ of following joltings 2 hours to add the sec.-propyl isonitrile.Mixture is adsorbed on the silica gel, uses the silica gel chromatography purifying, the dichloromethane solution gradient elution with 0-5% methyl alcohol obtains title compound. 1H?NMR(300MHz，DMSO-d 6)δppm?13.08(s，1H)8.75(d，J＝6.95，1.86Hz，1H)8.60(s，1H)8.31(d，J＝8.82，1.36Hz，1H)8.20(d，J＝4.75Hz，1H)8.14(s，1H)7.60(d，J＝8.82Hz，1H)7.03(d，J＝6.78，4.07Hz，1H)6.54(d，J＝4.75Hz，1H)4.86(d，J＝5.09Hz，1H)1.05(d，J＝6.10Hz，6H).MS(ESI+)m/z?293.0(M+H) +。
Embodiment 44
4-(1H-indazole-5-yl)-N-phenyl-1,3-thiazoles-2-amine
Embodiment 44A
5-bromo-1H-indazole-1-formic acid tertiary butyl ester
With the 5-bromo-indazole (4.40g, 22.3mmol) and the dimethyl aminopyridine of catalytic amount (～50mg) be dissolved in the methylene dichloride (100mL).(5.43g 24.9mmol), at room temperature stirs mixture and to spend the night to add di-tert-butyl dicarbonic acid ester.Use the silica gel adsorption mixture, use the silica gel chromatography purifying, the hexane solution gradient elution with the 0-40% ethyl acetate obtains title compound.MS(ESI+)m/z297.2(M+H) +。
Embodiment 44B
5-ethanoyl-1H-indazole-1-formic acid tertiary butyl ester
With embodiment 44A (5.12g, 17.2mmol), tributyl (1-vinyl ethyl ether base) tin (7.0mL, 20.7mmol) and dichloro two (triphenylphosphine) palladium (II) (672mg, 0.957mmol) in toluene (85mL) the mixing.In mixture, fed nitrogen 5 minutes, and in sealed tube, mixture heating up to 100 ℃ was spent the night.Use the silica gel adsorption mixture, use the silica gel chromatography purifying, the hexane solution gradient elution with the 0-40% ethyl acetate obtains title compound.MS(ESI+)m/z?283.0(M+Na) +。
Embodiment 44C
5-(2-acetyl bromide)-1H-indazole-1-formic acid tertiary butyl ester
(1.60g, 6.15mmol) (1.98g 6.19mmol) mixes in tetrahydrofuran (THF), and is heated to 40 ℃ of reactions 2 hours with the tribromide pyridine with embodiment 44B.Use the silica gel adsorption mixture, use the silica gel chromatography purifying, the hexane solution gradient elution with the 0-40% ethyl acetate obtains title compound.MS(ESI+)m/z?360.9(M+Na) +。
Embodiment 44D
4-(1H-indazole-5-yl)-N-phenyl-1,3-thiazoles-2-amine
(71mg, 0.208mmol) (33mg 0.217mmol) mixes in the 4mL phial in ethanol (300mL) with 1-phenyl-2-thiocarbamide with embodiment 44C.Phial is spent the night 80 ℃ of following joltings.Use the silica gel adsorption mixture, use the silica gel chromatography purifying, dichloromethane solution (0-5%) gradient elution with methyl alcohol obtains title compound. 1H?NMR(400MHz，DMSO-d 6)δppm?13.08(s，1H)10.23(s，1H)8.32(s，1H)8.14(s，1H)7.93(d，J＝8.59，1.53Hz，1H)7.75(d，J＝8.75，1.07Hz，1H)7.58(d，J＝8.90Hz，1H)7.36(d，J＝8.59，7.36Hz，1H)7.25(s，1H)6.92-7.02(m，1H).MS(ESI+)m/z?292.9(M+H) +。
Embodiment 45
5-(2-methyl isophthalic acid, 3-thiazole-4-yl)-1H-indazole
Prepare title compound with the method for describing among the embodiment 44D, wherein replace 1-phenyl-2-thiocarbamide with thioacetamide. 1H?NMR(300MHz，DMSO-d 6)δppm?13.10(s，1H)8.34(s，1H)8.12(s，1H)7.94(d，J＝8.82，1.70Hz，1H)7.85(s，1H)7.57(d，J＝8.82Hz，1H)2.73(s，3H).MS(ESI+)m/z?215.9(M+H) +。
Embodiment 46
N-ethyl-4-(1H-indazole-5-yl)-1,3-thiazoles-2-amine
Prepare title compound with the method for describing among the embodiment 44D, wherein replace 1-phenyl-2-thiocarbamide with ethyl thiourea. 1H?NMR(300MHz，DMSO-d 6)δppm?13.04(s，1H)8.21(s，1H)8.09(s，1H)7.83(d，J＝8.65，1.53Hz，1H)7.58(t，J＝5.43Hz，1H)7.51(d，J＝8.82Hz，1H)6.96(s，1H)3.22-3.34(m，2H)1.21(t，J＝7.29Hz，3H).MS(ESI+)m/z?244.9(M+H) +。
Embodiment 47
N-benzyl-4-(1H-indazole-5-yl)-1,3-thiazoles-2-amine
Prepare title compound with the method for describing among the embodiment 44D, wherein replace 1-phenyl-2-thiocarbamide with 1-benzyl-2-thiocarbamide. 1H?NMR(400MHz，DMSO-d 6)δppm?13.02(s，1H)8.21(s，1H)8.12(t，J＝5.83Hz，1H)8.08(s，1H)7.83(d，J＝8.90，1.53Hz，1H)7.50(d，J＝8.90Hz，1H)7.39-7.45(m，2H)7.35(t，J＝7.52Hz，2H)7.26(t，J＝7.21Hz，1H)6.97(s，1H)4.54(d，J＝5.83Hz，1H).MS(ESI+)m/z?306.9(M+H) +。
Embodiment 48
4-(1H-indazole-5-yl)-1,3-thiazoles-2-amine
Prepare title compound with the method for describing among the embodiment 44D, wherein replace 1-phenyl-2-thiocarbamide with thiocarbamide. 1H?NMR(300MHz，DMSO-d 6)δppm?13.03(s，1H)8.17(s，1H)8.07(s，1H)7.81(d，J＝8.82，1.36Hz，1H)7.50(d，J＝8.82Hz，1H)7.01(s，2H)6.92(s，1H).MS(ESI+)m/z?216.9(M+H) +。
Embodiment 49
4-(1H-indazole-5-yl)-N-(2-phenylethyl)-1,3-thiazoles-2-amine
Prepare title compound with the method for describing among the embodiment 44D, wherein replace 1-phenyl-2-thiocarbamide with 1-styroyl thiocarbamide. 1H?NMR(300MHz，DMSO-d 6)δppm?13.03(s，1H)8.23(s，1H)8.09(s，1H)7.85(d，J＝8.65，1.53Hz，1H)7.71(t，J＝5.43Hz，1H)7.51(d，J＝8.82Hz，1H)7.26-7.36(m，4H)7.18-7.26(m，1H)6.97(s，1H)3.47-3.59(m，1H)2.94(t，J＝7.44Hz，1H).MS(ESI+)m/z?321.0(M+H) +。
Embodiment 50
N-benzyl-2-(1H-indazole-5-yl) imidazo [1,2-a] pyrimidine-3-amine
Prepare title compound with the method for describing among the embodiment 43, wherein replace the sec.-propyl isonitrile with the benzyl isonitrile. 1H?NMR(300MHz，DMSO-d 6)δppm?13.10(s，1H)8.50-8.58(m，2H)8.39(d，J＝4.07，2.03Hz，1H)8.25(d，J＝8.81，1.36Hz，1H)8.13(s，1H)7.61(d，J＝8.81Hz，1H)7.24(s，5H)6.92(d，J＝6.78，4.07Hz，1H)5.44(t，J＝6.27Hz，1H)4.13(d，J＝6.10Hz，2H).MS(ESI+)m/z?341.0(M+H) +。
Embodiment 51
N-butyl-2-(1H-indazole-5-yl) imidazo [1,2-a] pyrimidine-3-amine
Prepare title compound with the method for describing among the embodiment 43, wherein replace the sec.-propyl isonitrile with the butyl isonitrile. 1H?NMR(300MHz，DMSO-d 6)δppm?13.09(s，1H)8.70(d，J＝6.78，2.03Hz，1H)8.55(s，1H)8.44(d，J＝4.07，2.03Hz，1H)8.25(d，J＝8.82，1.36Hz，1H)8.14(s，1H)7.61(d，J＝8.82Hz，1H)7.03(d，J＝6.78，4.07Hz，1H)4.90(t，J＝5.93Hz，1H)2.96(s，2H)1.49(s，2H)1.34(s，2H)0.82(t，J＝7.29Hz，3H).MS(ESI+)m/z?307.0(M+H) +。
Embodiment 52
N-(4-chloro-phenyl-)-2-(1H-indazole-5-yl) imidazo [1,2-a] pyrimidine-3-amine
Prepare title compound with the method for describing among the embodiment 43, wherein replace the sec.-propyl isonitrile with 4-chloro-phenyl-isonitrile. 1H?NMR(500MHz，DMSO-d 6)δppm?13.12(s，1H)8.58(dd，J＝4.12，1.98Hz，1H)8.46(d，J＝15.87Hz，2H)8.40(dd，J＝6.71，1.83Hz，1H)8.06-8.16(m，2H)7.58(d，J＝8.85Hz，1H)7.18(d，J＝8.85Hz，2H)7.05(dd，J＝6.71，3.97Hz，1H)6.57(d，J＝8.85Hz，2H).MS(ESI+)m/z?361.0(M+H) +。
Embodiment 53
2-(1H-indazole-5-yl)-N-(4-p-methoxy-phenyl) imidazo [1,2-a] pyrimidine-3-amine
Prepare title compound with the method for describing among the embodiment 43, wherein replace the sec.-propyl isonitrile with 4-p-methoxy-phenyl isonitrile. 1H?NMR(500MHz，DMSO-d 6)δppm?13.10(s，1H)8.56(dd，J＝3.97，2.14Hz，1H)8.47(s，1H)8.36(dd，J＝6.56，1.98Hz，1H)8.15(dd，J＝8.70，1.37Hz，1H)8.10(s，1H)7.99(s，1H)7.57(d，J＝8.54Hz，1H)7.03(dd，J＝6.71，4.27Hz，1H)6.76(d，J＝8.85Hz，2H)6.50(d，J＝8.85Hz，2H)3.63(s，3H).MS(ESI+)m/z?357.4(M+H) +。
Embodiment 54
2-(1H-indazole-5-yl) imidazo [1,2-a] pyrimidine
Prepare title compound with the method for describing among the embodiment 44D, wherein replace 1-phenyl-2-thiocarbamide with the 2-aminopyrimidine. 1H?NMR(300MHz，DMSO-d 6)δppm?13.13(s，1H)8.96(dd，J＝6.78，2.03Hz，1H)8.51(dd，J＝4.41，2.03Hz，1H)8.42(s，1H)8.36(s，1H)8.15(s，1H)8.01(dd，J＝8.82，1.70Hz，1H)7.62(d，J＝8.48Hz，1H)7.04(dd，J＝6.61，4.24Hz，1H).MS(ESI+)m/z?236.1(M+H) +。
Embodiment 55
N-[2-(1H-indazole-5-yl) imidazo [1,2-a] pyridin-3-yl] glycine methyl ester
Prepare the tfa salt of title compound with the method for describing among the embodiment 36B, wherein replace thiazolamine with the 2-aminopyridine, and with 2-isocyano-methyl acetate replacement cyclohexyl isonitrile. 1HNMR(400MHz，DMSO-d 6)δppm?13.41(s，1H)8.90(d，J＝6.75Hz，1H)8.38(s，1H)8.27(s，1H)7.84-7.98(m，3H)7.77(d，J＝8.90Hz，1H)7.55(td，J＝6.75，1.23Hz，1H)5.95-6.06(m，1H)3.87(d，J＝4.60Hz，2H)3.51(s，3H).MS(ESI+)m/z?340.1(M+H) +。
Embodiment 56
N-benzyl-2-(1H-indazole-5-yl) imidazo [1,2-a] pyridine-3-amine
Prepare title compound with the method for describing among the embodiment 36B, wherein replace thiazolamine, and replace the cyclohexyl isonitrile with the benzyl isonitrile with the 2-aminopyridine.End product is precipitated out from solution, filters the back and separates. 1H?NMR(400MHz，DMSO-d 6)d?ppm?13.04(s，1H)8.49(s，1H)8.16-8.27(m，2H)8.09(s，1H)7.58(d，J＝8.90Hz，1H)7.44(d，J＝8.90Hz，1H)7.19-7.35(m，5H)7.13(ddd，J＝8.98，6.67，0.92Hz，1H)6.80(td，J＝6.75，0.92Hz，1H)5.32(t，J＝6.14Hz，1H)4.12(d，J＝6.14Hz，2H).MS(ESI+)m/z?322.1(M+H) +。
Embodiment 57
N-(4-chloro-phenyl-)-2-(1H-indazole-5-yl) imidazo [1,2-a] pyridine-3-amine
Prepare title compound with the method for describing among the embodiment 36B, wherein replace thiazolamine, and replace the cyclohexyl isonitrile with 1-chloro-4-isocyano-benzene with the 2-aminopyridine. 1H?NMR(400MHz，DMSO-d 6)δppm?13.06(s，1H)8.39(s，2H)8.05-8.14(m，2H)7.94(d，J＝6.75Hz，1H)7.62(d，J＝8.90Hz，1H)7.55(d，J＝8.59Hz，1H)7.28-7.34(m，1H)7.17(d，J＝8.90Hz，2H)6.88-6.96(m，J＝6.75，6.75Hz，1H)6.53(d，J＝8.59Hz，2H).MS(ESI+)m/z?360.0(M+H) +。
Embodiment 58
2-(1H-indazole-5-yl)-N-(4-p-methoxy-phenyl) imidazo [1,2-a] pyridine-3-amine
Prepare title compound with the method for describing among the embodiment 36B, wherein replace thiazolamine, and replace the cyclohexyl isonitrile with 1-isocyano--4-anisole with the 2-aminopyridine. 1H?NMR(400MHz，DMSO-d 6)δppm?13.04(s，1H)8.44(s，1H)8.14(d，J＝8.90，1.23Hz，1H)8.06(s，1H)7.87-7.96(m，2H)7.59(d，J＝8.90Hz，1H)7.54(d，J＝8.59Hz，1H)7.24-7.33(m，1H)6.86-6.93(m，J＝6.75，6.75Hz，1H)6.75(d，J＝9.21Hz，2H)6.47(d，J＝9.21Hz，2H)3.63(s，3H).MS(ESI+)m/z?356.1(M+H) +。
Embodiment 59
4-[4-(4-fluorophenyl)-5-(1H-indazole-5-yl)-1H-imidazoles-1-yl] piperidines-1-formic acid tertiary butyl ester
Prepare title compound with the method for describing among the embodiment 39, wherein replace benzyl amine with 4-amino piperidine-1-formic acid tertiary butyl ester. 1H?NMR(400MHz，DMSO-d 6)δppm?13.32(s，1H)8.14(s，1H)8.01(s，1H)7.79(s，1H)7.68(d，J＝8.59Hz，2H)7.24-7.39(m，2H)6.97(t，J＝8.90Hz，2H)3.91-4.05(m，2H)3.71-3.84(m，1H)2.53-2.69(m，2H)1.76-1.94(m，4H)1.35-1.40(m，9H).MS(DCI)m/z?462(M+H) +。
Embodiment 60
3, two (1-benzyl-1H-1,2,3-triazole-4-the yl)-1H-indazoles of 5-
Embodiment 60A
5-bromo-3-iodo-1H-indazole-1-formic acid tertiary butyl ester
To the 5-bromo-indazole (10g, add in dimethyl formamide 50.75mmol) (100mL) solution KOH (10g, 177.63mmol).After 2 hours, and adding iodine (20g, 78.80mmol).Mixture Na 2S 2O 5Water (20g) (200mL) solution-treated is used ethyl acetate extraction, the salt water washing, and dried over sodium sulfate is filtered removal of solvent under reduced pressure.The gained solid is dissolved in methylene dichloride (350mL), with di-tert-butyl dicarbonic acid ester (14.4g, 65.98mmol) and dimethyl aminopyridine (10mg, 0.08mmol) processing.Mixture at room temperature stirred 20 minutes, directly crossed silicagel column bed (bed), obtained title compound.MS(DCI/NH 3)m/z?422.9(M+H) +。
Embodiment 60B
5-bromo-3-phenyl-1H-indazole-1-formic acid tertiary butyl ester and 5-bromo-3-iodo-1H-indazole-1-formic acid tertiary butyl ester
(2.1g adds Pd (PPh in toluene 5mmol) (10mL) solution to embodiment 60A 3) 4(173mg, 0.15mmol), Na 2CO 3(1.1g, (5mL) solution of water 10mmol) and phenyl-boron dihydroxide (671mg, methyl alcohol 5.5mmol) (3mL) solution.Mixture at room temperature stirred 5 days, and ethyl acetate extraction is used in the water quencher, and the silica gel chromatography purifying with 5% ethyl acetate/hexane wash-out, obtains the title compound mixture. 1H?NMR(500MHz，DMSO-d 6)δppm?8.28(d，J＝1.53Hz，1H)8.12(d，J＝8.85Hz，1H)7.97-8.04(m，3H)7.80-7.86(m，2H)7.75(d，J＝1.83Hz，1H)7.54-7.63(m，3H)1.68(s，9H)1.64(s，9H).MS(ESI+)m/z373.9(M+H) +。
Embodiment 60C
3, two ((trimethyl silyl) the ethynyl)-1H-indazole-1-formic acid tertiary butyl ester of 5-and 5-bromo-3-((trimethyl silyl) ethynyl)-1H-indazole-1-formic acid tertiary butyl ester
With embodiment 60B (1g, 2.55mmol), dichloro two (triphenylphosphine) palladium (II) (89mg, 0.13mmol), triethylamine (1.78mL, 12.75mmol), trimethyl silyl acetylene (0.432mL, 3.06mmol) and CuI (24mg, 0.13mmol) in dimethyl formamide (10mL), mix, at room temperature stirred 20 hours.Mixture dilutes with ethyl acetate, washes with water, and the silica gel chromatography purifying obtains title compound. 1H?NMR(500MHz，DMSO-d 6)δppm?8.10(d，J＝8.85Hz，1H)8.07(d，J＝8.85Hz，1H)7.97(d，J＝1.83Hz，1H)7.84(s，1H)7.82(dd，J＝8.85，1.83Hz，1H)7.71(dd，J＝8.54，1.53Hz，1H)1.65(s，18H)0.33(d，J＝0.92Hz，18H)。
Embodiment 60D
3,5-diacetylene-1H-indazole-1-formic acid tertiary butyl ester and 5-bromo-3-ethynyl-1H-indazole-1-formic acid tertiary butyl ester
To embodiment 60C (350mg, add in tetrahydrofuran (THF) 0.85mmol) (5mL) solution 1MTBAF tetrahydrofuran solution (2mL, 2mmol).After 10 minutes, pressure reducing and steaming solvent, crude mixture silica gel chromatography purifying, the hexane solution wash-out with 5% ethyl acetate obtains title compound. 1H?NMR(500MHz，DMSO-d 6)δppm?8.12(d，J＝7.93Hz，1H)8.07(d，J＝8.85Hz，1H)8.01(d，J＝1.53Hz，1H)7.90(s，1H)7.83(dd，J＝8.85，1.83Hz，1H)7.74(dd，J＝8.85，1.53Hz，1H)4.91(s，1H)4.90(s，1H)4.29(s，1H)1.66(s，9H)1.65(s，9H)。
Embodiment 60E
3, two (1-benzyl-1H-1,2,3-triazole-4-the yl)-1H-indazoles of 5-
Prepare title compound with the method for describing among the embodiment 3D, wherein replace embodiment 3C with embodiment 60D. 1H?NMR(500MHz，DMSO-d 6)δppm?13.35(s，1H)8.76(s，1H)8.71(s，1H)8.70(s，1H)7.92(d，J＝8.61，1.28Hz，1H)7.64(d，J＝8.79Hz，1H)7.38-7.43(m，8H)7.33-7.37(m，2H)5.73(s，2H)5.66(s，2H).MS(ESI+)m/z?433.2(M+H) +。
Embodiment 61
5-(1-benzyl-1H-1,2,3-triazole-4-yl)-3-phenyl-1H-indazole
Embodiment 61A
3-phenyl-5-((trimethyl silyl) ethynyl)-1H-indazole-1-formic acid tertiary butyl ester and 5-bromo-3-phenyl-1H-indazole-1-formic acid tertiary butyl ester
With embodiment 60B (1g, 2.55mmol), dichloro two (triphenylphosphine) palladium (II) (89mg, 0.13mmol), triethylamine (1.78mL, 12.75mmol), trimethyl silyl acetylene (0.432mL, 3.06mmol) and CuI (24mg, 0.13mmol) in dimethyl formamide (10mL), mix, at room temperature stirred 20 minutes.Mixture dilutes with ethyl acetate, and the silica gel chromatography purifying obtains title compound. 1H?NMR(500MHz，DMSO-d 6)δppm?8.29(d，J＝1.53Hz，1H)8.09-8.19(m，3H)7.96-8.03(m，4H)7.83(dd，J＝8.85，1.83Hz，1H)7.72(dd，J＝8.85，1.53Hz，1H)7.50-7.65(m，6H)1.68(s，18H)0.26-0.27(m，9H)。
Embodiment 61B
5-ethynyl-3-phenyl-1H-indazole-1-formic acid tertiary butyl ester and 5-bromo-3-phenyl-1H-indazole-1-formic acid tertiary butyl ester
Prepare title compound with the method for describing among the embodiment 60D, wherein replace embodiment 60C with embodiment 61A. 1H?NMR(500MHz，DMSO-d 6)δppm?8.28(d，J＝1.53Hz，1H)8.21(s，1H)8.16(d，J＝8.54Hz，1H)8.12(d，J＝8.85Hz，1H)7.97-8.05(m，4H)7.83(dd，J＝8.85，1.83Hz，1H)7.75(dd，J＝8.85，1.53Hz，1H)7.53-7.64(m，6H)4.27(s，1H)1.68(s，9H)1.68(s，9H)。
Embodiment 61C
5-(1-benzyl-1H-1,2,3-triazole-4-yl)-3-phenyl-1H-indazole
Prepare title compound with the method for describing among the embodiment 3D, wherein replace embodiment 3C with embodiment 61B. 1H?NMR(500MHz，DMSO-d 6)δppm?13.38(s，1H)8.77(s，1H)8.52(s，1H)8.06(d，J＝7.33Hz，2H)7.98(d，J＝8.79Hz，1H)7.69(d，J＝8.79Hz，1H)7.53-7.61(m，J＝7.51，7.51Hz，2H)7.33-7.48(m，6H)5.68(s，2H).MS(ESI+)m/z?352.0(M+H) +。
Embodiment 62
5-(1-benzyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-amine
Embodiment 62A
2-fluoro-5-((trimethyl silyl) ethynyl) cyanobenzene
With 5-bromo-2-fluorobenzonitrile (5.01g, 25.0mmol), dichloro two (triphenylphosphine) palladium (II) (652mg, 0.929mmol) and cuprous iodide (I) (413mg 2.17mmol) is mixing in triethylamine (15mL) under the nitrogen.Add trimethyl silyl acetylene (4.2mL, 29.7mmol), with mixture heating up to 100 ℃.With mixture solidified, monitor with LC/MS.After reaction is finished, mixture is diluted with methylene dichloride, with 1N HCl washing.Organic layer is adsorbed on the silica gel, uses the silica gel chromatography purifying, hexane solution (5-45%) gradient elution with ethyl acetate obtains title compound. 1H?NMR(300MHz，DMSO-d 6)δppm?8.09(dd，J＝6.10，2.03Hz，1H)7.77-7.97(m，1H)7.54(t，J＝9.15Hz，1H)0.15-0.32(m，9H)。
Embodiment 62B
5-ethynyl-2-fluorobenzonitrile
(tetrahydrofuran solution of 1.0M, (5.05g in tetrahydrofuran (THF) 23.2mmol) (50mL) solution, stirred 20 minutes 70mL) to join embodiment 62A with tetrabutyl ammonium fluoride.Mixture is diluted with methylene dichloride, wash with water.Organic layer is adsorbed on the silica gel, uses the silica gel chromatography purifying, the hexane solution gradient elution with the 5-40% ethyl acetate obtains title compound. 1H?NMR(300MHz，DMSO-d 6)δppm?8.13(dd，J＝6.27，2.20Hz，1H)7.82-7.95(m，1H)7.56(t，J＝8.99Hz，1H)4.40(s，1H)。
Embodiment 62C
5-(1-benzyl-1H-1,2,3-triazole-4-yl)-2-fluorobenzonitrile
With embodiment 62B (1.68g, 11.6mmol) be dissolved in the trimethyl carbinol (14mL), add benzyl azide (2.14g, 15.8mmol), mixture is transferred in 14 microwave tubes (each 1.0mL), in each microwave tube, add entry (0.5mL), a bit of copper wire and 1M copper sulfate (II) solution (0.5mL), each microwave tube was heated 10 minutes down at 125 ℃ with 100 watts in the CEM-Discover microwave.Merge the reactant in the microwave tube, with ethyl acetate dilution, water and salt water washing.Organic materials is adsorbed on the silica gel, uses the silica gel chromatography purifying, the hexane solution gradient elution with the 5-50% ethyl acetate obtains title compound. 1H?NMR(300MHz，DMSO-d 6)δppm?8.73(s，1H)8.33-8.44(m，1H)8.19-8.32(m，1H)7.56-7.70(m，1H)7.28-7.47(m，5H)5.68(s，2H)。
Embodiment 62D
5-(1-benzyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-amine
Hydrazine hydrate (18mL) is joined embodiment 62C, and (1.93g is in ethanol 6.94mmoL) (10mL) solution.With mixture 95 ℃ of following heated overnight.Mixture dilutes with ethyl acetate, washes with water.Some products are settled out in separating funnel, filter to obtain title compound.The concentrating under reduced pressure ethyl acetate layer, the gained solid grinds with methyl alcohol, obtains other title compound. 1H?NMR(300MHz，DMSO-d 6)δppm?11.43(s，1H)8.42(s，1H)8.21(s，1H)7.67(d，J＝8.82，1.70Hz，1H)7.38(s，5H)7.26(d，J＝8.48Hz，1H)5.64(s，2H)5.38(s，2H).MS(ESI+)m/z?291.0(M+H) +。
Embodiment 63
5-(1-benzyl-1H-1,2,3-triazole-4-yl)-1-[(1-methyl piperidine-4-yl) carbonyl]-1H-indazole-3-amine
With embodiment 62D (44mg, 0.152mmol), 1-methyl piperidine-4-formate hydrochlorate (27mg, 0.150mmol) and HATU (61mg 0.160mmol) mixes in tetrahydrofuran (THF) (2mL).(110mL 0.631mmol), ℃ continues 30 minutes with mixture heating up to 90 to add diisopropyl ethyl amine.With methylene dichloride diluted mixture thing, with the washing of 1N sodium hydroxide.Organic layer is adsorbed on the silica gel, uses the silica gel chromatography purifying, the dichloromethane solution gradient elution with 5-15% methyl alcohol obtains title compound. 1H?NMR(300MHz，DMSO-d 6)δppm?8.58(s，1H)8.47(s，1H)8.26(d，J＝8.48Hz，1H)7.97(d，J＝8.48，1.70Hz，1H)7.38(s，5H)6.58(s，2H)5.67(s，2H)3.35-3.47(m，1H)2.95(d，J＝11.19Hz，2H)2.28(s，3H)2.03-2.20(m，2H)1.92(s，2H)1.77(s，2H).MS(ESI+)m/z?416.2(M+H) +。
Embodiment 64
N-[5-(1-benzyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-2-methoxyl group ethanamide
Embodiment 64A
3-amino-5-(1-benzyl-1H-1,2,3-triazole-4-yl)-1H-indazole-1-formic acid tertiary butyl ester
(1.80g 6.20mmol) is suspended in the methylene dichloride (100mL) of the dimethyl aminopyridine that contains catalytic amount with embodiment 62D.Dropwise added di-tert-butyl dicarbonic acid ester (1.36g, methylene dichloride 6.23mmol) (50mL) solution through 1 hour.Mixture is adsorbed on the silica gel, uses the silica gel chromatography purifying, the dichloromethane solution gradient elution with 0-5% methyl alcohol obtains title compound.MS(ESI+)m/z?391.1(M+H) +。
Embodiment 64B
N-[5-(1-benzyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-2-methoxyl group ethanamide
(45mg 0.115mmol) is dissolved in methylene dichloride (1.5mL) and pyridine (0.5mL) with embodiment 64A.(18uL, 0.197mmol), mixture at room temperature stirred 2 hours to add methoxyacetyl chloride.Remove with flow of warm nitrogen gas and to desolvate, mixture injects on the silicagel column, product silica gel chromatography purifying, dichloromethane solution gradient elution with 0-5% methyl alcohol, obtain 5-(1-benzyl-1H-1,2,3-triazole-4-yl)-3-(2-methoxyl group acetamido)-1H-indazole-1-formic acid tertiary butyl ester (58mg).This intermediate is dissolved in methylene dichloride (2mL) and trifluoroacetic acid (1mL), at room temperature stirs and spend the night.Removal of solvent under reduced pressure, mixture on the C8 post, is used the 10%-100% acetonitrile/water gradient elution that contains 0.1% trifluoroacetic acid with preparation HPLC purifying, obtains title compound. 1H?NMR(300MHz，DMSO-d 6)δppm?12.79(s，1H)10.16(s，1H)8.59(s，1H)8.20(s，1H)7.83(d，J＝8.65，1.53Hz，1H)7.51(d，J＝8.82Hz，1H)7.37(s，5H)5.64(s，2H)4.12(s，2H)3.42(s，3H).MS(ESI+)m/z?363.0(M+H) +。
Embodiment 65
N 1-[5-(1-benzyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-N 2, N 2-dimethyl G-NH2
(81mg 0.207mmol) is dissolved in methylene dichloride (2mL) and pyridine (0.5mL) with embodiment 64A.Divide three parts to add the dimethylamino acetyl chloride hydrochloride through 2 hours, 80% (120mg, 0.607mmol), mixture at room temperature stirs and spends the night.Add trifluoroacetic acid (2mL), mixture stirred 3 hours.With methylene dichloride diluted mixture thing, with the washing of 1N sodium hydroxide.Organic layer is adsorbed on the silica gel, uses the silica gel chromatography purifying, the dichloromethane solution gradient elution with 5-15% methyl alcohol obtains title compound. 1H?NMR(300MHz，DMSO-d 6)δppm?12.77(s，1H)10.05(s，1H)8.58(s，1H)8.24(s，1H)7.82(d，J＝8.65，1.53Hz，1H)7.50(d，J＝8.82Hz，1H)7.30-7.44(m，5H)5.64(s，2H)3.16-3.20(m，2H)2.34(s，6H).MS(ESI+)m/z?376.1(M+H) +。
Embodiment 66
N-[5-(1-benzyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl] butyramide
(76mg 0.195mmol) is dissolved in methylene dichloride (2mL) and pyridine (0.2mL) with embodiment 64A.(26uL 0.250mmol), at room temperature stirred mixture 2 hours to add butyryl chloride.Add trifluoroacetic acid (1mL), mixture stirred 3 hours.With methylene dichloride diluted mixture thing, wash with water.Organic layer is adsorbed on the silica gel, uses the silica gel chromatography purifying, the dichloromethane solution gradient elution with 1-8% methyl alcohol obtains title compound. 1H?NMR(300MHz，DMSO-d 6)δppm12.70(s，1H)10.30(s，1H)8.57(s，1H)8.23(s，1H)7.81(d，J＝8.82Hz，1H)7.49(d，J＝8.82Hz，1H)7.37(s，5H)5.64(s，2H)2.39(t，J＝7.29Hz，2H)1.67(s，2H)0.97(t，J＝7.46Hz，3H).MS(ESI+)m/z?361.1(M+H) +。
Embodiment 67
5-[4-(4-fluorophenyl)-1-piperidin-4-yl-1H-imidazoles-5-yl]-the 1H-indazole
Prepare title compound with the method for describing among the embodiment 39, wherein replace benzyl amine with piperidines-4-amine. 1H?NMR(300MHz，DMSO-d 6)δppm?13.28(s，1H)8.14(s，1H)7.94(s，1H)7.78(s，1H)7.63-7.72(m，2H)7.21-7.43(m，2H)6.90-7.04(m，2H)4.14(d，J＝5.59，1.86Hz，1H)3.53-3.74(m，J＝5.76Hz，1H)2.94(d，J＝12.21Hz，2H)2.21-2.35(m，2H)1.74-1.88(m，3H).MS(DCI)m/z?362(M+H) +。
Embodiment 68
5-{4-(4-fluorophenyl)-1-[2-(1-methylpyrrolidin-2-yl) ethyl]-1H-imidazoles-5-yl }-the 1H-indazole
Prepare title compound with the method for describing among the embodiment 39, wherein use 2-(1-methylpyrrolidin-2-yl) ethamine to replace benzyl amine. 1H?NMR(300MHz，DMSO-d 6)δppm?13.30(s，1H)8.14(s，1H)7.86(s，1H)7.82(s，1H)7.68(d，J＝8.48Hz，1H)7.24-7.47(m，3H)6.92-7.08(m，2H)3.83(t，J＝7.80Hz，2H)2.71-2.93(m，1H)1.88-2.01(m，3H)1.74-1.88(m，1H)1.00-1.83(m，7H).MS(DCI)m/z?390(M+H) +。
Embodiment 69
5-{4-(4-fluorophenyl)-1-[3-(4-methylpiperazine-1-yl) propyl group]-1H-imidazoles-5-yl }-the 1H-indazole
Prepare title compound with the method for describing among the embodiment 39, wherein use 3-(4-methylpiperazine-1-yl) propane-1-amine to replace benzyl amine. 1H?NMR(300MHz，DMSO-d 6)δppm?13.36(s，1H)8.13(s，1H)7.81(s，2H)7.67(d，J＝8.48Hz，1H)7.32-7.45(m，2H)7.27(d，J＝8.48，1.36Hz，1H)6.87-7.06(m，2H)3.72-3.91(m，2H)1.92-2.21(m，10H)1.91-2.20(s，3H)1.51-1.66(m，2H).MS(ESI+)m/z?419(M+H) +。
Embodiment 70
5-(1H-indazole-5-base) isoxazole-3-ethyl formate
(1.83g 12.9mmol) is dissolved in toluene (60mL) and triethylamine (2.2mL) and be heated to 90 ℃ with embodiment 3C.(1.89g 12.5mmol) is dissolved in toluene (15mL), dropwise adds through 30 minutes with 2-chloro-2-(hydroxyl imide base) ethyl acetate.After adding, with ethyl acetate diluted mixture thing, with 1N salt acid elution.The organic layer concentrating under reduced pressure, the gained residue grinds with methyl alcohol, obtains title compound. 1H?NMR(300MHz，DMSO-d 6)δppm?13.38(s，1H)8.43(s，1H)8.23(s，1H)7.92(d，J＝8.82，1.36Hz，1H)7.70(d，J＝8.82Hz，1H)7.44(s，1H)4.41(q，J＝7.12Hz，2H)1.35(t，J＝7.12Hz，3H).MS(ESI+)m/z?257.9(M+H) +。
Embodiment 71
5-(1H-indazole-5-yl)-N-methyl-isoxazole-3-methane amide
Embodiment 71A
5-(1H-indazole-5-base) isoxazole-3-formic acid
(1.50g 5.83mmol) is dissolved in tetrahydrofuran (THF) (100mL), methyl alcohol (10mL) and water (10mL) with embodiment 70.(680mg, 12.1mmol), mixture at room temperature stirred 2 hours to add potassium hydroxide.Removal of solvent under reduced pressure, the gained residue grinds with 1N hydrochloric acid and carbinol mixture, obtains solid, filters and obtains title compound. 1H?NMR(300MHz，DMSO-d 6)δppm?13.37(s，1H)8.39(s，1H)8.22(s，1H)7.90(dd，J＝8.81，1.36Hz，1H)7.69(d，J＝8.82Hz，1H)7.30(s，1H)。
Embodiment 71B
5-(1H-indazole-5-yl)-N-methyl-isoxazole-3-methane amide
With embodiment 71A (46mg, 0.201mmol), HATU (88mg, 0.231mmol) and diisopropyl ethyl amine (133uL 0.764mmol) mixes in tetrahydrofuran (THF) (2mL).Add monomethyl amine (40% the aqueous solution) (50uL), reactant stirred 2 hours down at 50 ℃.With methylene dichloride diluted mixture thing, with 1N sodium hydroxide, 1N hydrochloric acid and salt water washing.Organic layer is adsorbed on the silica gel, uses the silica gel chromatography purifying, the hexane solution gradient elution with the 10-50% ethyl acetate obtains title compound. 1H?NMR(300MHz，DMSO-d 6)δppm?13.36(s，1H)8.72(q，J＝4.30Hz，1H)8.39(s，1H)8.23(s，1H)7.89(d，J＝8.65，1.53Hz，1H)7.69(d，J＝8.82Hz，1H)7.28(s，1H)2.80(d，J＝4.75Hz，3H).MS(ESI+)m/z?243.0(M+H) +。
Embodiment 72
5-(3-Bian isoxazole-5-yl)-1H-indazole
(266mg 2.38mmol) is dissolved in the trimethyl carbinol (1mL) and water (1mL) with phenylacetic aldehyde (90+%).Add oxammonium hydrochloride (79mg, 1.14mmol), add then the 6N sodium hydroxide solution (19uL, 31.7mmol).Mixture stirred 30 minutes, and slowly added the chloramine-T trihydrate (308mg 1.09mmol), added copper sulfate (II) and segment copper wire then through 5 minutes.(154mg, 1.08mmol), mixture stirred 2 hours down at 50 ℃, at room temperature stirred then and spent the night to add embodiment 3C.With methylene dichloride diluted mixture thing, wash with water.Organic layer is adsorbed on the silica gel, uses the silica gel chromatography purifying, the hexane solution gradient elution with the 10-50% ethyl acetate obtains title compound. 1H?NMR(300MHz，DMSO-d 6)δppm?13.31(s，1H)8.28(s，1H)8.18(s，1H)7.79(dd，J＝8.65，1.53Hz，1H)7.64(d，J＝8.81Hz，1H)7.13-7.46(m，5H)6.83(s，1H)4.04(s，2H).MS(ESI+)m/z?275.7(M+H) +。
Embodiment 73
N-[5-(1-benzyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl] benzamide
(72mg 0.184mmol) is dissolved in methylene dichloride (2mL) and pyridine (0.2mL) with embodiment 64A.(36uL, 0.310mmol), mixture at room temperature stirred 2 hours to add Benzoyl chloride.Add trifluoroacetic acid (1mL), mixture stirred 3 hours.With methylene dichloride diluted mixture thing, wash with water.Organic layer is adsorbed on the silica gel, uses the silica gel chromatography purifying, the dichloromethane solution gradient elution with 1-8% methyl alcohol obtains title compound. 1H?NMR(300MHz，DMSO-d 6)δppm12.88(s，1H)10.81(s，1H)8.63(s，1H)8.16(s，1H)8.06-8.13(m，2H)7.88(d，J＝8.82，1.36Hz，1H)7.59-7.64(m，J＝7.12Hz，1H)7.51-7.59(m，3H)7.31-7.42(m，5H)5.63(s，2H).MS(ESI+)m/z?395.1(M+H) +。
Embodiment 74
5-(3-propyl group isoxazole-5-base)-1H-indazole
Prepare title compound with the method for describing among the embodiment 72, wherein replace phenylacetic aldehyde with butyraldehyde. 1H?NMR(300MHz，DMSO-d 6)δppm?13.31(s，1H)8.28(s，1H)8.20(s，1H)7.76-7.85(m，1H)7.63-7.70(m，1H)6.88(s，1H)2.63(t，J＝7.46Hz，2H)1.61-1.79(m，2H)0.96(t，J＝7.29Hz，3H).MS(ESI+)m/z?228.0(M+H) +。
Embodiment 75
N-benzyl-4-(1H-indazole-5-yl)-5-phenyl-1,3-thiazoles-2-amine
Embodiment 75A
1H-indazole-5-formic acid
Prepare title compound with the method for describing among the embodiment 3A, wherein replace 4-iodo-2-aminotoluene with 4-amino-3-methyl-toluate.In whole treating processes, add 6N HCl to pH6, cause solid to form, filter, wash twice with water, vacuum-drying obtains title compound. 1H?NMR(300MHz，DMSO-d 6)δppm?13.32(s，1H)12.83(s，1H)8.46(s，1H)8.24(s，1H)7.92(dd，J＝8.82，1.70Hz，1H)7.60(d，J＝8.82Hz，1H)。
Embodiment 75B
N-methoxyl group-N-methyl isophthalic acid H-indazole-5-methane amide
To embodiment 75A (1.6g, 10mmol) and N, O-dimethyl hydroxylamine (1.1g, 11mmol) in the suspension of methylene dichloride (40mL) and dimethyl formamide (10mL), add triethylamine (1.67mL, 12mmol) and EDC (2.1g, 11mmol), mixture at room temperature stirred 24 hours.The pressure reducing and steaming solvent, the gained residue dilutes with ethyl acetate, washes with water.The organic layer dried over sodium sulfate is used the silica gel column chromatography purifying in ethyl acetate, obtain title compound.MS(ESI+)m/z206.0(M+H) +。
Embodiment 75C
1-(1H-indazole-5-yl)-2-phenyl ethyl ketone
(900mg, tetrahydrofuran (THF) 4.39mmol) (10mL) solution with the ice bath cooling, use tetrahydrofuran solution (6.6mL, 13.16mmol) processing of 2M benzylmagnesium chloride under argon gas with embodiment 75B.Reactant at room temperature stirs and spends the night, and adds the benzylmagnesium chloride of another part equivalent then.Reactant after 90 minutes, is chilled to room temperature at 70 ℃ of following reheat.Add saturated aqueous ammonium chloride, the product ethyl acetate extraction is used the silica gel chromatography purifying, and the hexane gradient wash-out with 30% ethyl acetate obtains title compound.MS(ESI+)m/z?237.1(M+H) +。
Embodiment 75D
5-(2-phenyl acetyl)-1H-indazole-1-formic acid tertiary butyl ester
To embodiment 75C (236mg, add in methylene dichloride 1mmol) (2mL) suspension di-tert-butyl dicarbonic acid ester (327mg, 1.5mmol) and a small amount of dimethyl aminopyridine (～2mg).Mixture stirred 15 minutes, by the silicagel column bed, used the methylene dichloride wash-out.The pressure reducing and steaming solvent obtains title compound.MS(ESI+)m/z?337.0(M+H) +。
Embodiment 75E
2-bromo-1-(1H-indazole-5-yl)-2-phenyl ethyl ketone
(336mg dropwise added tribromide pyridine (352mg, tetrahydrofuran (THF) 1.1mmol) (20mL) solution in tetrahydrofuran (THF) 1mmol) (20mL) suspension with the embodiment 75D of 40 ℃ of oil baths heating through 10 fens clockwise with addition funnel.Reaction mixture reheat 2 hours, cooling is filtered, and evaporated filtrate obtains title compound.MS(ESI-)m/z?212.9(M-H) -。
Embodiment 75F
N-benzyl-4-(1H-indazole-5-yl)-5-phenyl-1,3-thiazoles-2-amine
Cover contain embodiment 75E (50mg, 0.16mmol) and the 1-benzylthiourea (26mg, the phial of ethanol 0.16mmol) (1mL) solution, on heating oscillator 80 ℃ the heating 2 hours.The solution of crude product by the reversed-phase HPLC purifying, obtains the tfa salt of title compound with acetonitrile/water 0.1%TFA linear gradient elution method. 1H?NMR(400MHz，DMSO-d 6)δppm?12.99(s，1H)8.33-8.37(m，1H)8.01(s，1H)7.92-7.99(m，1H)7.82(s，1H)7.60-7.67(m，J＝7.83，7.83Hz，1H)7.31-7.45(m，5H)7.17-7.30(m，5H)4.53(d，J＝4.60Hz，2H).MS(ESI+)m/z?383.0(M+H) +。
Embodiment 76
4-(1H-indazole-5-yl)-N, 5-phenylbenzene-1,3-thiazoles-2-amine
Prepare title compound with the method for describing among the embodiment 75F, wherein replace the 1-benzylthiourea with the 1-phenylthiourea. 1H?NMR(400MHz，DMSO-d 6)δppm?13.09(s，1H)10.29(s，1H)8.05(d，J＝0.92Hz，1H)7.89(d，J＝1.53，0.92Hz，1H)7.69(d，J＝8.59，1.23Hz，2H)7.47(dt，J＝8.59，0.92Hz，1H)7.40-7.44(m，1H)7.26-7.37(m，7H)6.94-7.02(m，J＝7.36，7.36Hz，1H).MS(ESI+)m/z?369.0(M+H) +。
Embodiment 77
5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazole-4-yl)-1H-indazole
Embodiment 77A
5-(cyclopropyl acethlene base)-1H-indazole-1-formic acid tertiary butyl ester
Under nitrogen with embodiment 44A (2.31g, 7.77mmol), cyclopropyl acethlene (620mg, 9.37mmol), dichloro two (triphenylphosphine) palladium (II) (170mg, 0.242mmol) and cuprous iodide (I) (92mg 0.483mmol) mixes in triethylamine (10mL).Mixture is heated to 100 ℃ of reactions 4 hours in sealed tube.With methylene dichloride diluted mixture thing, with 1N salt acid elution.Organic layer is adsorbed on the silica gel, uses the silica gel chromatography purifying, the hexane solution gradient elution with the 5-50% ethyl acetate obtains title compound.MS(ESI+)m/z?283.0(M+H) +。
Embodiment 77B
5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazole-4-yl)-1H-indazole
With embodiment 77A (145mg, 0.51mmol) and benzyl azide (82mg, 0.62mmol) accurately heating (heated neat) 10 minutes under 150 ℃ and 150 watts in the CEM-Discover microwave.Crude mixture is dissolved in methylene dichloride, as eluent, uses the silica gel column chromatography purifying with the hexane solution of 50% ethyl acetate. 1H?NMR(400MHz，DMSO-d 6)δppm?13.12(s，1H)8.11(d，J＝5.52Hz，2H)7.79(d，J＝8.59，1.53Hz，1H)7.60(d，J＝8.59Hz，1H)7.26-7.45(m，5H)5.69(s，2H)1.78-1.92(m，1H)0.98-1.09(m，2H)0.31-0.45(m，2H).MS(ESI+)m/z?316.0(M+H) +。
Embodiment 78
5-(1-benzyl-4-cyclopropyl-1H-1,2,3-triazole-5-yl)-1H-indazole
Separate title compound with the method for describing among the embodiment 77B. 1H?NMR(500MHz，DMSO-d 6)δppm?13.29(s，1H)8.14(s，1H)7.80(s，1H)7.65(d，J＝8.85Hz，1H)7.29(d，J＝8.54，1.53Hz，1H)7.21-7.27(m，3H)6.93(d，J＝7.48，1.98Hz，2H)5.49(s，2H)1.70-1.80(m，1H)0.81-0.92(m，4H).MS(ESI+)m/z316.0(M+H) +。
Embodiment 79
2-(1H-indazole-5-yl)-3-phenylimidazole is [1,2-a] pyrimidine also
Cover contain embodiment 75E (80mg, 0.25mmol) and pyrimidine-2-amine (23mg, the phial of ethanol 0.25mmol) (1mL) solution, in heating oscillator 80 ℃ of down heating 21 hours.The solution of crude product by the reversed-phase HPLC purifying, obtains title compound with acetonitrile/water 0.1%TFA linear gradient elution method. 1H?NMR(400MHz，DMSO-d 6)δppm?8.69(dd，J＝4.30，1.84Hz，1H)8.59(dd，J＝6.75，1.84Hz，1H)8.07(s，1H)8.02(s，1H)7.46-7.65(m，7H)7.16(dd，J＝6.75，3.99Hz，1H).MS(ESI+)m/z?312.0(M+H) +。
Embodiment 80
5-[1-(tetrahydrochysene-2H-pyrans-4-ylmethyl)-1H-1,2,3-triazole-4-yl]-the 1H-indazole
Embodiment 80A
4-(azido methyl) tetrahydrochysene-2H-pyrans
(4.76g 21.1mmol) is dissolved in dimethyl sulfoxide (DMSO) (25mL) with 4-(iodomethyl) tetrahydrochysene-2H-pyrans.(2.70g, 41.5mmol), mixture at room temperature stirs and spends the night to add sodiumazide.The gained slurries dilute with ether, wash with water.The organic layer concentrating under reduced pressure obtains title compound.This product is directly used in subsequent reaction without evaluation.
Embodiment 80B
5-[1-(tetrahydrochysene-2H-pyrans-4-ylmethyl)-1H-1,2,3-triazole-4-yl]-the 1H-indazole
(122mg, 0.864mmol) (150mg 0.619mmol) mixes with the trimethyl carbinol (1mL) and water (1mL) in microwave tube with embodiment 3C with embodiment 80A.Add a bit of copper wire, (5mg 0.02mmol), stirs phial 10 minutes at 100W under 125 ℃ in microwave (CEM-Discover) to add copper sulfate (II) then.With methylene dichloride diluted mixture thing, with 1N salt acid elution.Organic layer is adsorbed on the silica gel, uses the silica gel chromatography purifying, the dichloromethane solution gradient elution with 0-5% methyl alcohol obtains title compound. 1H?NMR(300MHz，DMSO-d 6)δppm?13.11(s，1H)8.53(s，1H)8.22(s，1H)8.12(s，1H)7.85(d，J＝8.48，1.36Hz，1H)7.60(d，J＝8.82Hz，1H)4.32(d，J＝7.12Hz，2H)3.85(d，J＝11.70，2.54Hz，2H)3.21-3.36(m，2H)2.14(s，1H)1.47(s，2H)1.30(s，2H).MS(ESI+)m/z284.0(M+H) +。
Embodiment 81
5-[3-(piperidines-1-base carbonyl) isoxazole-5-base]-the 1H-indazole
Embodiment 81A
5-(1H-indazole-5-base) isoxazole-3-formic acid
(1.50g 5.83mmol) is dissolved in tetrahydrofuran (THF) (100mL), methyl alcohol (10mL) and water (10mL) with embodiment 70.(680mg 12.1mmol), at room temperature stirred mixture 2 hours to add potassium hydroxide.Removal of solvent under reduced pressure, gained residue are ground with 1N hydrochloric acid and methyl alcohol and are obtained solid, filter and obtain title compound. 1H?NMR(300MHz，DMSO-d 6)δppm?13.36(s，1H)8.41(s，1H)8.23(s，1H)7.91(dd，J＝8.82，1.70Hz，1H)7.70(d，J＝8.82Hz，1H)7.36(s，1H)。
Embodiment 81B
5-[3-(piperidines-1-base carbonyl) isoxazole-5-base]-the 1H-indazole
With embodiment 81A (110mg, 0.480mmol), piperidines (55uL, 0.556mmol) and HATU (101mg 0.266mmol) mixes in dimethyl formamide (2mL).(133uL, 0.764mmol), reactant stirred 2 hours at 45 ℃ to add diisopropyl ethyl amine.With ethyl acetate diluted mixture thing, with 1N sodium hydroxide, 1N hydrochloric acid, water (3 times) and salt water washing.Organic layer is adsorbed on the silica gel, uses the silica gel chromatography purifying, the dichloromethane solution gradient elution with 0-5% methyl alcohol obtains title compound. 1H?NMR(300MHz，DMSO-d 6)δppm?13.37(s，1H)8.34-8.40(m，1H)8.21-8.25(m，1H)7.84-7.91(m，1H)7.66-7.72(m，1H)7.20(s，1H)3.59-3.69(m，2H)3.48-3.58(m，2H)1.47-1.72(m，6H).MS(ESI+)m/z?297.0(M+H) +。
Embodiment 82
5-(1H-indazole-5-yl)-N-phenyl-isoxazole azoles-3-methane amide
Prepare title compound with the method for describing among the embodiment 81B, wherein replace piperidines with aniline. 1H?NMR(500MHz，DMSO-d 6)δppm?13.40(s，1H)10.74(s，1H)8.44(s，1H)8.25(s，1H)7.93(d，J＝8.85，1.53Hz，1H)7.82(d，J＝7.63Hz，2H)7.72(d，J＝8.85Hz，1H)7.44(s，1H)7.35-7.42(m，2H)7.16(t，J＝7.32Hz，1H).MS(ESI+)m/z?304.9(M+H) +。
Embodiment 83
N-cyclohexyl-5-(1H-indazole-5-base) isoxazole-3-methane amide
With embodiment 81A (53mg, 0.231mmol), cyclo-hexylamine (29uL, 0.253mmol) and HATU (101mg 0.266mmol) mixes in dimethyl formamide (2mL).(133uL, 0.764mmol), reactant stirred 2 hours down at 45 ℃ to add diisopropyl ethyl amine.With ethyl acetate diluted mixture thing, with 1N sodium hydroxide, 1N hydrochloric acid, water (3 times) and salt water washing.Organic layer is adsorbed on the silica gel, uses the silica gel chromatography purifying, the dichloromethane solution gradient elution with 0-5% methyl alcohol obtains title compound. 1H?NMR(300MHz，DMSO-d 6)δppm?13.36(s，1H)8.58(d，J＝8.14Hz，1H)8.38(s，1H)8.22(s，1H)7.88(d，J＝8.81，1.70Hz，1H)7.69(d，J＝8.81Hz，1H)7.28(s，1H)3.69-3.86(m，1H)1.77(s，4H)1.60(d，J＝12.21Hz，1H)1.20-1.46(m，4H)1.06-1.20(m，1H).MS(ESI+)m/z311.0(M+H) +。
Embodiment 84
5-[3-(piperidines-1-ylmethyl) isoxazole-5-base]-the 1H-indazole
(22mg 0.0742mmol) is dissolved in tetrahydrofuran (THF) (2.5mL) with embodiment 81B under the nitrogen rare gas element.Add lithium aluminum hydride (tetrahydrofuran solution of 1.0M) (250uL), mixture heating up to 70 ℃ is continued 20 minutes.Add methyl alcohol, mixture is adsorbed on the silica gel, use the silica gel chromatography purifying, dichloromethane solution (0-7%) gradient elution with methyl alcohol obtains title compound. 1HNMR(400MHz，DMSO-d 6)δppm?13.30(s，1H)8.31(s，1H)8.20(s，1H)7.84(d，J＝8.59，1.53Hz，1H)7.66(d，J＝8.59Hz，1H)6.92(s，1H)3.54(s，2H)2.32-2.46(m，2H)1.47-1.59(m，4H)1.33-1.46(m，2H).MS(ESI+)m/z283.0(M+H) +。
Embodiment 85
[5-(1H-indazole-5-base) isoxazole-3-base] methyl alcohol
(84mg 0.366mmol) is dissolved in tetrahydrofuran (THF) (8mL) with embodiment 70.Added lithium aluminum hydride (1.0M tetrahydrofuran solution) (3.0mL) through 2 hours with every part of 1.0mL.After adding, with mixture restir 30 minutes.With methylene dichloride diluted mixture thing, wash with water, organic layer is adsorbed on the silica gel, use the silica gel chromatography purifying, the dichloromethane solution gradient elution with 0-20% methyl alcohol obtains title compound. 1H?NMR(400MHz，DMSO-d 6)δppm?13.31(s，1H)8.31(s，1H)8.21(s，1H)7.83(d，J＝8.59，1.53Hz，1H)7.67(d，J＝8.90Hz，1H)6.93(s，1H)5.51(s，1H)4.56(d，J＝2.45Hz，1H).MS(ESI+)m/z?215.9(M+H) +。
Embodiment 86
5-(1H-indazole-5-yl)-N-(2-methoxy ethyl) isoxazole-3-methane amide
Prepare title compound with the method for describing among the embodiment 81B, wherein replace piperidines with 2-methoxy ethyl amine. 1H?NMR(300MHz，DMSO-d 6)δppm?13.36(s，1H)8.74(t，J＝4.92Hz，1H)8.39(s，1H)8.23(s，1H)7.89(d，J＝8.65，1.53Hz，1H)7.69(d，J＝8.82Hz，1H)7.30(s，1H)3.38-3.53(m，4H)3.28(s，3H).MS(ESI+)m/z?287.0(M+H) +。
Embodiment 87
5-(1-benzyl-5-phenyl-1H-1,2,3-triazole-4-yl)-1H-indazole
Embodiment 87A
1-(5-iodo-1H-indazole-1-yl) ethyl ketone
(30.2g 130mmol) is dissolved in chloroform (300mL) and be chilled to 5 ℃ with 4-iodo-2-aminotoluene.Dropwise add diacetyl oxide (35mL, 343mmol), with mixture heat to room temperature.Add potassium acetate (4.21g, 42.9mmol) and Isopentyl nitrite (37mL, 277mmol), mixture heating up to 70 ℃ is spent the night.Use the saturated sodium bicarbonate aqueous solution neutralise mixt, use dichloromethane extraction.Removal of solvent under reduced pressure, the gained residue grinds with methyl alcohol, obtains title compound. 1H?NMR(300MHz，DMSO-d 6)δppm?8.41(s，1H)8.33(s，1H)8.05-8.21(m，1H)7.90(dd，J＝8.48，1.70Hz，1H)2.71(s，3H)。
Embodiment 87B
1-benzyl-5-phenyl-4-(tributyl stannyl)-1H-1,2, the 3-triazole
With phenylacetylene base tri-n-butyl tin (8.25g, 21.1mmol) and benzyl azide (2.3mL 18.4mmol) mixes and is heated to 150 ℃ and spends the night.Use the silica gel chromatography purified mixture, the hexane solution gradient elution with the 5-40% ethyl acetate obtains title compound.MS(ESI+)m/z?526.3(M+H) +。
Embodiment 87C
1-(5-(1-benzyl-5-phenyl-1H-1,2,3-triazole-4-yl)-1H-indazole-1-yl) ethyl ketone
In microwave tube under inert nitrogen gas with embodiment 87A (139mg, 0.486mmol), embodiment 87B (284mg, 0.542mmol), dichloro two (triphenylphosphine) palladium (II) (40mg, 0.057mmol) and thiophene-2-carboxylic acid copper (167mg, 0.876mmol) mixing in toluene (1.5mL).Microwave tube was heated 20 minutes at 125 watts at 150 ℃ in microwave (CEM-Discover).Mixture is adsorbed on the silica gel, uses the silica gel chromatography purifying, the hexane solution gradient elution with the 5-40% ethyl acetate obtains title compound.MS(ESI+)m/z?394.1(M+H) +。
Embodiment 87D
5-(1-benzyl-5-phenyl-1H-1,2,3-triazole-4-yl)-1H-indazole
With embodiment 87C (95mg 0.242mmol) is dissolved in tetrahydrofuran (THF) (2.0mL), methyl alcohol (1.0mL) and water (1.0mL), add potassium hydroxide (64mg, 1.14mmol).Mixture was stirred 2 hours,, wash with water with the ethyl acetate dilution.Organic layer is adsorbed on the silica gel, uses the silica gel chromatography purifying, the dichloromethane solution gradient elution with 0-5% methyl alcohol obtains title compound. 1H?NMR(300MHz，DMSO-d 6)δppm?13.08(s，1H)8.00(s，1H)7.79(s，1H)7.44-7.56(m，5H)7.24-7.36(m，5H)6.95-7.03(m，2H)5.49(s，2H).MS(ESI+)m/z?252.1(M+H) +。
Embodiment 88
5-(4-benzyl-1H-1,2,3-triazol-1-yl)-1H-indazole
With embodiment 87A (969mg, 3.39mmol), 3-phenyl-1-propine (392mg, 3.37mmol), sodiumazide (278mg, 4.28mmol), sodium ascorbate (68mg, 3.43mmol), yellow soda ash (75mg, 0.708mmol) and L-proline(Pro) (78mg, 8.98mmol) mixing in 1: 1 dimethyl sulfoxide (DMSO) and the mixture of water (10mL).(46mg, 0.184mmol), mixture stirred 3 hours down at 65 ℃ to add copper sulfate (II) pentahydrate.Add 6N sodium hydroxide (1mL), mixture stirred 30 minutes, the protecting group of sloughing indazole.With ethyl acetate diluted mixture thing, with 1N salt acid elution.The organic layer concentrating under reduced pressure, the gained residue grinds with methyl alcohol.Remaining solid absorption on silica gel, is used the silica gel chromatography purifying, and the dichloromethane solution gradient elution with 0-5% methyl alcohol obtains title compound. 1H?NMR(300MHz，DMSO-d 6)δppm?13.35(s，1H)8.58(s，1H)8.17-8.27(m，1H)7.86(d，J＝8.82，2.03Hz，1H)7.67-7.77(m，1H)7.27-7.36(m，2H)7.18-7.27(m，1H)4.10(s，1H).MS(ESI+)m/z?276.0(M+H) +。
Embodiment 89
5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-amine
Embodiment 89A
5-(cyclopropyl acethlene base)-2-fluorobenzonitrile
With 5-bromo-2-fluorobenzonitrile (3.06g, 15.3mmol), dichloro two (triphenylphosphine) palladium (II) (478mg, 0.681mmol) and cuprous iodide (I) (165mg 0.866mmol) mixes under the nitrogen rare gas element in triethylamine (15mL).Add cyclopropyl acethlene (1.8mL), mixture heating up to 60 ℃ becomes black solid until it.With methylene dichloride diluted mixture thing, with 1N salt acid elution.Organic layer is adsorbed on the silica gel, uses the silica gel chromatography purifying, the hexane solution gradient elution with the 5-40% ethyl acetate obtains title compound.MS(ESI+)m/z?319.0(M+H) +。
Embodiment 89B
5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-amine
With embodiment 89A (211mg, 1.14mmol) and benzyl azide (143uL 1.14mmol) mixes in microwave (CEM-Discover) pipe, with 100 watts be heated to 160 ℃ the reaction 26 minutes.Mixture is adsorbed on the silica gel, uses the silica gel chromatography purifying, the hexane solution gradient elution with the 20-60% ethyl acetate obtains inseparable triazole regional isomer (regiomer) mixture.Regional isomer intermixture is handled with hydrazine hydrate (3.0mL) and ethanol (3.0mL), and be heated to 90 ℃ of reactions 1 hour.With methylene dichloride diluted mixture thing, wash with water.Organic layer is adsorbed on the silica gel, uses the silica gel chromatography purifying, the dichloromethane solution gradient elution with 1-6% methyl alcohol obtains title compound. 1H?NMR(300MHz，DMSO-d 6)δppm?11.43(s，1H)8.07(s，1H)7.63(d，J＝8.65，1.53Hz，1H)7.32-7.45(m，3H)7.24-7.32(m，3H)5.68(s，2H)5.40(s，2H)1.69-1.83(m，1H)0.98-1.08(m，2H)0.32-0.42(m，2H).MS(ESI+)m/z?331.1(M+H) +。
Embodiment 90
5-(1-benzyl-4-cyclopropyl-1H-1,2,3-triazole-5-yl)-1H-indazole-3-amine
Separate title compound as by product with the method for describing among the embodiment 89B. 1H?NMR(300MHz，DMSO-d 6)δppm?11.62(s，1H)7.79(s，1H)7.32(d，J＝8.48Hz，1H)7.20-7.27(m，3H)7.15(d，J＝8.65，1.53Hz，1H)6.93(d，J＝7.12，2.37Hz，2H)5.49(s，2H)5.45(s，2H)1.71-1.82(m，1H)0.80-0.89(m，4H).MS(ESI+)m/z?331.1(M+H) +。
Embodiment 91
5-(3-isobutyl-isoxazole-5-base)-1H-indazole-3-amine
Embodiment 91A
2-fluoro-5-(3-isobutyl-isoxazole-5-base) cyanobenzene
Prepare title compound with the method for describing among the embodiment 72, wherein replace phenylacetic aldehyde, and replace embodiment 3C with embodiment 62B with isovaleric aldehyde. 1H?NMR(300MHz，DMSO-d 6)δppm8.47(dd，J＝6.10，2.03Hz，1H)8.19-8.29(m，1H)7.71(t，J＝8.99Hz，1H)7.08(s，1H)2.56(d，J＝7.12Hz，2H)1.86-2.10(m，1H)0.94(d，J＝6.78Hz，6H)。
Embodiment 91B
5-(3-isobutyl-isoxazole-5-base)-1H-indazole-3-amine
To embodiment 91A (75mg, 0.307mmol) middle ethanol (1.0mL) solution that adds hydrazine hydrate (1.5mL).In sealed tube, mixture heating up to 70 ℃ is spent the night.With methylene dichloride diluted mixture thing, wash with water.Organic layer is adsorbed on the silica gel, uses the silica gel chromatography purifying, the dichloromethane solution gradient elution with 0-5% methyl alcohol obtains title compound. 1H?NMR(300MHz，DMSO-d 6)δppm?11.67(s，1H)8.26(s，1H)7.66(dd，J＝8.82，1.70Hz，1H)7.32(d，J＝8.48Hz，1H)6.67(s，1H)5.56(s，2H)2.51-2.58(m，2H)1.89-2.11(m，1H)0.95(d，J＝6.44Hz，6H).MS(ESI+)m/z?257.0(M+H) +。
Embodiment 92
5-(3-Bian isoxazole-5-yl)-1H-indazole-3-amine
Embodiment 92A
5-(3-Bian isoxazole-5-yl)-2-fluorobenzonitrile
Prepare title compound with the method for describing among the embodiment 72, wherein replace embodiment 3C with embodiment 62B.Crude product is used for next step without being further purified or identifying.
Embodiment 92B
5-(3-Bian isoxazole-5-yl)-1H-indazole-3-amine
To embodiment 92A (65mg, 0.234mmol) middle ethanol (1.0mL) solution that adds hydrazine hydrate (1.5mL).In sealed tube, mixture heating up to 70 ℃ is spent the night.With methylene dichloride diluted mixture thing, wash with water.Organic layer is adsorbed on the silica gel, uses the silica gel chromatography purifying, the dichloromethane solution gradient elution with 0-20% methyl alcohol obtains title compound. 1H?NMR(300MHz，DMSO-d 6)δppm?11.67(s，1H)8.26(s，1H)7.66(d，J＝8.82，1.70Hz，1H)7.32(d，J＝8.48Hz，1H)6.67(s，1H)5.56(s，2H)2.45-2.57(m，2H)1.91-2.08(m，1H)0.95(d，J＝6.44Hz，6H).MS(ESI+)m/z?291.0(M+H) +。
Embodiment 93
N-{2-[4-(4-fluorophenyl)-5-(1H-indazole-5-yl)-1H-imidazoles-1-yl] ethyl }-N, the N-dimethyl amine
Prepare title compound with the method for describing among the embodiment 39, wherein replace benzyl amine with 2-dimethyl aminoethyl amine. 1H?NMR(500MHz，
Figure GPA00001018010701031
Figure GPA00001018010701032
ppm?13.28(s，1H)8.14(s，1H)7.78-7.87(m，2H)7.68(d，J＝8.54Hz，1H)7.33-7.41(m，2H)7.28(d，J＝8.54，1.53Hz，1H)6.95-7.05(m，2H)3.86(t，J＝6.56Hz，2H)2.31(t，J＝6.71Hz，2H)2.00(s，6H)。
Embodiment 94
5-[4-(4-fluorophenyl)-1-(3-morpholine-4-base propyl group)-1H-imidazoles-5-yl]-the 1H-indazole
Prepare title compound with the method for describing among the embodiment 39, wherein replace benzyl amine with 3-morpholino propyl group amine. 1H?NMR(500MHz，DMSO-d 6/D 2O)δppm?13.28(s，1H)8.14(s，1H)7.79-7.87(m，2H)7.68(d，J＝8.24Hz，1H)7.34-7.42(m，2H)7.28(d，J＝8.54，1.53Hz，1H)6.92-7.03(m，2H)3.77-3.89(m，2H)3.24-3.30(m，4H)2.10(t，J＝6.56Hz，2H)1.96-2.05(m，4H)1.54-1.66(m，2H).MS(ESI+)m/z?406.1(M+H) +。
Embodiment 95
5-[4-(4-fluorophenyl)-1-(3-tetramethyleneimine-1-base propyl group)-1H-imidazoles-5-yl]-the 1H-indazole
Prepare title compound with the method for describing among the embodiment 39, wherein replace benzyl amine with 3-tetramethyleneimine propyl group amine. 1H?NMR(500MHz，DMSO-d 6/D 2O)δppm?8.13(d，J＝0.92Hz，1H)7.79-7.85(m，2H)7.68(d，J＝8.54Hz，1H)7.38(d，J＝8.85，5.49Hz，2H)7.27(d，J＝8.54，1.53Hz，1H)6.99(t，J＝9.00Hz，2H)3.82-3.90(m，2H)2.21(t，J＝6.71Hz，2H)2.08-2.18(m，4H)1.56-1.65(m，2H)1.44-1.53(m，4H).MS(ESI+)m/z?390.2(M+H) +。
Embodiment 96
5-{4-(4-fluorophenyl)-1-[2-(4-methyl piperidine-1-yl) ethyl]-1H-imidazoles-5-yl }-the 1H-indazole
Prepare title compound with the method for describing among the embodiment 39, wherein use 2-(4-methyl piperidine-1-yl) ethamine to replace benzyl amine. 1H?NMR(500MHz，DMSO-d 6/D 2O)δppm?13.29(s，1H)8.14(s，1H)7.83(s，1H)7.81(s，1H)7.67(d，J＝8.54Hz，1H)7.32-7.40(m，2H)7.28(dd，J＝8.54，1.53Hz，1H)6.93-7.04(m，2H)3.85(t，J＝6.56Hz，2H)2.60(d，J＝11.60Hz，2H)2.37(t，J＝6.56Hz，2H)1.71-1.85(m，2H)1.45(d，J＝11.29Hz，2H)1.15-1.30(m，1H)0.95-1.07(m，2H)0.83(d，J＝6.71Hz，3H)MS(ESI+)m/z?404.1(M+H) +。
Embodiment 97
5-[1-(1-benzyl piepridine-4-yl)-4-(4-fluorophenyl)-1H-imidazoles-5-yl]-the 1H-indazole
Prepare title compound with the method for describing among the embodiment 39, wherein replace benzyl amine with 4-amino-N-benzyl piepridine. 1H?NMR(500MHz，DMSO-d 6/D 2O)δppm?13.32(s，1H)8.14(s，1H)8.02(s，1H)7.78(s，1H)7.69(d，J＝8.54Hz，1H)7.17-7.40(m，8H)6.97(t，J＝8.85Hz，2H)3.50-3.63(m，1H)3.40(s，2H)2.82(d，J＝11.90Hz，2H)1.90-2.05(m，2H)1.72-1.89(m，4H).MS(ESI+)m/z?452.2(M+H) +。
Embodiment 98
5-[4-(4-fluorophenyl)-1-(2-morpholine-4-base ethyl)-1H-imidazoles-5-yl]-the 1H-indazole
Prepare title compound with the method for describing among the embodiment 39, wherein replace benzyl amine with 2-morpholino ethylamine. 1H?NMR(500MHz，DMSO-d 6/D 2O)δppm?13.27(s，1H)8.14(s，1H)7.86(s，1H)7.81(s，1H)7.67(d，J＝8.54Hz，1H)7.33-7.42(m，2H)7.29(d，J＝8.54Hz，1H)6.95-7.06(m，2H)3.87(t，J＝6.41Hz，2H)3.42-3.51(m，4H)2.40(t，J＝6.56Hz，2H)2.21(d，J＝3.97Hz，4H).MS(ESI+)m/z392.1(M+H) +。
Embodiment 99
5-[1-(1-benzyl-pyrrole alkane-3-yl)-4-(4-fluorophenyl)-1H-imidazoles-5-yl]-the 1H-indazole
Prepare title compound with the method for describing among the embodiment 39, wherein replace benzyl amine with 3-tetramethyleneimine benzyl amine. 1H?NMR(500MHz，DMSO-d 6/D 2O)δppm?13.29(s，1H)8.13(s，1H)8.03(s，1H)7.76(s，1H)7.67(d，J＝8.54Hz，1H)7.29-7.38(m，6H)7.20-7.28(m，2H)6.98(t，J＝9.00Hz，2H)4.25-4.34(m，1H)3.53-3.69(m，2H)2.89-2.97(m，1H)2.84(d，J＝9.76，3.05Hz，1H)2.55(d，J＝10.07，6.71Hz，1H)2.17-2.34(m，2H)1.92-2.03(m，1H).MS(ESI+)m/z?438.1(M+H) +。
Embodiment 100
Having left out embodiment 100, no longer is the part of this document.
Embodiment 101
2-{4-[4-(4-fluorophenyl)-5-(1H-indazole-5-yl)-1H-imidazoles-1-yl] piperidines-1-yl }-2-oxo ethanol
Prepare title compound with the method for describing among the embodiment 39, wherein use 1-(4-amino piperidine-1-yl)-2-hydroxyl ethyl ketone to replace benzyl amine. 1H?NMR(300MHz，DMSO-d 6/D 2O)δppm13.27(s，1H)8.14(s，1H)7.99(s，1H)7.81(s，1H)7.69(d，J＝8.48Hz，1H)7.25-7.39(m，4H)6.91-7.03(m，2H)4.48(t，J＝5.43Hz，1H)4.34-4.44(m，1H)4.07(t，J＝5.59Hz，1H)3.79-3.91(m，1H)3.64-3.77(m，1H)2.85(m，1H)2.77-2.90(m，5H).MS(DCI)m/z?420(M+H) +。
Embodiment 102
5-(1-benzyl-5-phenyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-amine
Embodiment 102A
5-(1-benzyl-5-phenyl-1H-1,2,3-triazole-4-yl)-2-fluorobenzonitrile
In microwave tube under the nitrogen rare gas element with embodiment 87B (415mg, 0.792mmol), 5-bromo-2-fluorobenzonitrile (158mg, 0.790mmol), dichloro two (triphenylphosphine) palladium (II) (52mg, 0.074mmol) and thiophene-2-carboxylic acid copper (226mg, 1.19mmol) mixing in toluene (2mL).Microwave tube is heated to 150 ℃ of reactions 20 minutes at 125 watts in microwave (CEM-Discover).Use the silica gel adsorption mixture, use the silica gel chromatography purifying, the hexane solution gradient elution with (5-40%) ethyl acetate obtains title compound.MS(ESI+)m/z?355.1(M+H) +。
Embodiment 102B
5-(1-benzyl-5-phenyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-amine
(120mg 0.339mmol) with ethanol (1.0mL) solution-treated of hydrazine hydrate (1.0mL), is heated to 60 ℃ and spends the night with embodiment 102A.With methylene dichloride diluted mixture thing, wash with water.Organic layer is adsorbed on the silica gel, uses the silica gel chromatography purifying, the dichloromethane solution wash-out with 0-5% methyl alcohol obtains title compound. 1H?NMR(300MHz，DMSO-d 6)δppm?11.40(s，1H)8.06(s，1H)7.42-7.55(m，3H)7.23-7.33(m，5H)7.02-7.10(m，2H)6.94-7.02(m，2H)5.49(s，2H)5.34(s，2H).MS(ESI+)m/z?367.1(M+H) +。
Embodiment 103
2-[1-(1H-indazole-5-yl)-1H-1,2,3-triazole-4-yl] propan-2-ol
Prepare title compound according to the method for describing among the embodiment 88, wherein replace 3-phenyl-1-propine, only crude product mixture 2mL 1N NaOH aqueous solution quencher with 2-methyl-3-butyne-2-alcohol; And at room temperature stirred 1.5 hours.Then before extraction with suspension with hot pressing vaporized nitrogen drying. 1H?NMR(500MHz，DMSO-d 6/D 2O)δppm?8.51(s，1H)8.22-8.29(m，2H)7.88(d，J＝9.00，1.98Hz，1H)7.77(d，J＝8.85Hz，1H)1.57(s，6H).MS(ESI+)m/z?244.0(M+H) +。
Embodiment 104
5-[4-(methoxymethyl)-1H-1,2, the 3-triazol-1-yl]-the 1H-indazole
Prepare title compound according to the method for describing among the embodiment 88, wherein replace 3-phenyl-1-propine with the methyl propargyl ether. 1H?NMR(500MHz，DMSO-d 6/D 2O)δppm?8.73(s，1H)8.23-8.29(m，J＝1.83Hz，2H)7.88(d，J＝8.85，2.14Hz，1H)7.78(d，J＝9.15Hz，1H)4.57(s，2H)3.35(s，3H).MS(ESI+)m/z?230.0(M+H) +。
Embodiment 105
1-[1-(1H-indazole-5-yl)-1H-1,2,3-triazole-4-yl]-the 1-phenylethyl alcohol
Prepare title compound according to the method for describing among the embodiment 88, wherein replace 3-phenyl-1-propine with 2-phenyl-3-butyne-2-alcohol. 1H?NMR(500MHz，DMSO-d 6/D 2O)δppm?8.52(s，1H)8.21-8.28(m，2H)7.87(d，J＝8.85，2.14Hz，1H)7.76(d，J＝9.15Hz，1H)7.51-7.57(m，2H)7.34(t，J＝7.78Hz，2H)7.24(t，J＝7.32Hz，1H)1.92(s，3H).MS(ESI+)m/z?306.0(M+H) +。
Embodiment 106
5-(4-propyl group-1H-1,2,3-triazol-1-yl)-1H-indazole
Prepare title compound according to the method for describing among the embodiment 88, wherein replace 3-phenyl-1-propine with the 1-pentyne. 1H?NMR(500MHz，DMSO-d 6/D 2O)δppm?8.50(s，1H)8.20-8.30(m，2H)7.87(d，J＝9.00，1.98Hz，1H)7.77(d，J＝8.85Hz，1H)2.71(t，J＝7.48Hz，2H)1.64-1.78(m，2H)0.97(t，J＝7.32Hz，3H).MS(ESI+)m/z228.0(M+H) +。
Embodiment 107
1-[1-(1H-indazole-5-yl)-1H-1,2,3-triazole-4-yl] propan-2-ol
Prepare title compound according to the method for describing among the embodiment 88, wherein replace 3-phenyl-1-propine with penta-4-alkynes-2-alcohol. 1H?NMR(500MHz，DMSO-d 6/D 2O)δppm?8.49(s，1H)8.20-8.33(m，2H)7.88(dd，J＝9.00，1.98Hz，1H)7.74-7.82(m，1H)3.95-4.08(m，1H)2.74-2.89(m，2H)1.16(d，J＝6.10Hz，3H).MS(ESI+)m/z244.0(M+H) +。
Embodiment 108
3-[1-(1H-indazole-5-yl)-1H-1,2,3-triazole-4-yl] third-1-alcohol
Prepare title compound according to the method for describing among the embodiment 88, wherein replace 3-phenyl-1-propine with 4-pentyne-1-alcohol. 1H?NMR(500MHz，DMSO-d 6/D 2O)δppm?8.50(s，1H)8.28(s，1H)8.23(d，J＝1.83Hz，1H)7.83-7.91(m，1H)7.74-7.82(m，1H)4.50(t，J＝6.41Hz，1H)3.51(t，J＝6.41Hz，2H)2.77(t，J＝7.63Hz，2H)1.80-1.90(m，2H)MS(ESI+)m/z?244.0(M+H) +。
Embodiment 109
1-{[1-(1H-indazole-5-yl)-1H-1,2,3-triazole-4-yl] methyl }-1H-1,2, the 3-benzotriazole
Prepare title compound according to the method for describing among the embodiment 88, wherein replace 3-phenyl-1-propine with 1-propargyl-1H-benzotriazole. 1H?NMR(500MHz，DMSO-d 6/D 2O)δppm8.91(s，1H)8.21-8.29(m，2H)8.07(d，J＝8.54Hz，1H)7.99(d，J＝8.54Hz，1H)7.84(d，J＝9.00，1.98Hz，1H)7.72-7.81(m，1H)7.57-7.65(m，1H)7.41-7.52(m，1H)6.16(s，2H).MS(ESI-)m/z?315.0(M-H) -。
Embodiment 110
5-{4-[(phenyl sulfenyl) methyl]-1H-1,2, the 3-triazol-1-yl }-the 1H-indazole
Prepare title compound according to the method for describing among the embodiment 88, wherein replace 3-phenyl-1-propine with phenyl propargyl thioether. 1H?NMR(500MHz，DMSO-d 6/D 2O)δppm?8.59(s，1H)8.26(s，1H)8.21(d，J＝1.22Hz，1H)7.80-7.86(m，1H)7.72-7.79(m，1H)7.43(d，J＝8.39，1.37Hz，2H)7.35(t，J＝7.78Hz，2H)7.22(t，J＝7.32Hz，1H)4.38(s，2H).MS(ESI+)m/z?308.3(M+H) +。
Embodiment 111
5-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-1H-indazole
Prepare title compound according to the method for describing among the embodiment 88, wherein replace 3-phenyl-1-propine with cyclopropyl acethlene. 1H?NMR(500MHz，DMSO-d 6/D 2O)δppm?8.46(s，1H)8.25(s，1H)8.20(d，J＝1.53Hz，1H)7.84(d，J＝9.00，1.98Hz，1H)7.76(d，J＝8.85Hz，1H)1.97-2.14(m，1H)0.93-1.06(m，2H)0.77-0.91(m，2H).MS(ESI+)m/z?226.0(M+H) +。
Embodiment 112
5-[4-(2-phenylethyl)-1H-1,2, the 3-triazol-1-yl]-the 1H-indazole
Prepare title compound according to the method for describing among the embodiment 88, wherein replace 3-phenyl-1-propine with 1-phenyl-ethyl acetylene.Products therefrom is 1: 1 mixture of starting raw material and title compound. 1H?NMR(500MHz，DMSO-d 6/D 2O)δppm?8.48(s，1H)8.25(s，1H)8.21(d，J＝1.53Hz，1H)8.06(s，1H)7.81-7.89(m，1H)7.73-7.80(m，1H)7.61(dd，J＝8.85，1.53Hz，1H)7.45(d，J＝8.54Hz，1H)7.25-7.36(m，4H)7.17-7.25(m，1H)3.04(s，4H).MS(ESI+)m/z?290.1(M+H) +。
Embodiment 113
5-[4-(cyclohexyl methyl)-1H-1,2, the 3-triazol-1-yl]-the 1H-indazole
Prepare title compound according to the method for describing among the embodiment 88, wherein replace 3-phenyl-1-propine with 3-cyclohexyl-1-propine. 1H?NMR(500MHz，DMSO-d 6/D 2O)δppm?8.49(s，1H)8.21-8.29(m，2H)7.88(d，J＝9.00，1.98Hz，1H)7.77(d，J＝8.85Hz，1H)2.61(d，J＝6.71Hz，2H)1.54-1.77(m，6H)1.08-1.30(m，3H)0.91-1.05(m，2H).MS(ESI+)m/z?282.2(M+H) +。
Embodiment 114
5-(4-cyclopentyl-1H-1,2,3-triazol-1-yl)-1H-indazole
Prepare title compound according to the method for describing among the embodiment 88, wherein replace 3-phenyl-1-propine with cyclopentyl acetylene. 1H?NMR(500MHz，DMSO-d 6/D 2O)δppm?8.52(s，1H)8.19-8.30(m，2H)7.88(d，J＝9.00，1.98Hz，1H)7.77(d，J＝8.85Hz，1H)3.13-3.27(m，1H)1.98-2.15(m，2H)1.57-1.84(m，6H).MS(ESI+)m/z254.0(M+H) +。
Embodiment 115
1-[1-(1H-indazole-5-yl)-1H-1,2,3-triazole-4-yl] hexalin
Prepare title compound according to the method for describing among the embodiment 88, wherein replace 3-phenyl-1-propine with 1-ethynyl-1-hexalin. 1H?NMR(500MHz，DMSO-d 6/D 2O)δppm?8.52(s，1H)8.21-8.30(m，J＝1.53Hz，2H)7.89(dd，J＝9.00，1.98Hz，1H)7.77(d，J＝8.85Hz，1H)2.16-2.46(m，1H)1.92-2.05(m，2H)1.77-1.86(m，2H)1.61-1.77(m，2H)1.51-1.59(m，1H)1.42-1.51(m，2H)1.28-1.40(m，J＝9.92，2.90Hz，1H)MS(ESI+)m/z?284.0(M+H) +。
Embodiment 116
5-[4-(phenoxymethyl)-1H-1,2, the 3-triazol-1-yl]-the 1H-indazole
Prepare title compound according to the method for describing among the embodiment 88, wherein replace 3-phenyl-1-propine with the phenyl propargyl ether. 1H?NMR(500MHz，DMSO-d 6/ 2O)δppm?8.87(s，1H)8.22-8.34(m，2H)7.89(d，J＝8.85，1.83Hz，1H)7.79(d，J＝9.15Hz，1H)7.29-7.41(m，2H)7.09(d，J＝7.63Hz，2H)6.99(t，J＝7.32Hz，1H)5.25(s，2H).MS(ESI+)m/z?292.0(M+H) +。
Embodiment 117
5-{4-[(1,1-dioxo thiomorpholine-4-yl) methyl]-1H-1,2, the 3-triazol-1-yl }-the 1H-indazole
Prepare title compound according to the method for describing among the embodiment 88, wherein replace 3-phenyl-1-propine with N-propargyl thiomorpholine-sulfone. 1H?NMR(500MHz，DMSO-d 6/D 2O)δppm?8.81(s，1H)8.24-8.36(m，2H)7.89(d，J＝9.00，1.98Hz，1H)7.80(d，J＝9.15Hz，1H)4.38(s，2H)3.30-3.56(m，J＝39.36Hz，8H).MS(ESI+)m/z?332.9(M+H) +。
Embodiment 118
5-[4-(3-phenyl propyl)-1H-1,2, the 3-triazol-1-yl]-the 1H-indazole
Prepare title compound according to the method for describing among the embodiment 88, wherein replace 3-phenyl-1-propine with 1-phenyl-1-pentyne. 1H?NMR(500MHz，DMSO-d 6/D 2O)δppm?8.52(s，1H)8.26(s，1H)8.23(d，J＝1.53Hz，1H)7.87(d，J＝9.00，1.98Hz，1H)7.76(d，J＝9.15Hz，1H)7.31(t，J＝7.32Hz，2H)7.23-7.28(m，2H)7.20(t，J＝7.32Hz，1H)2.74(t，J＝7.63Hz，2H)2.65-2.72(m，2H)1.95-2.05(m，2H).MS(ESI+)m/z?304.2(M+H) +。
Embodiment 119
[1-benzyl-4-(1H-indazole-5-yl)-1H-1,2,3-triazole-5-yl] (phenyl) ketone
Embodiment 119A
5-ethynyl-1H-indazole-1-formic acid tertiary butyl ester
To embodiment 3C (230mg, add in methylene dichloride 1.62mmol) (10mL) solution di-tert-butyl dicarbonic acid ester (459mg, 2.1mmol) and a small amount of dimethyl aminopyridine (～3mg), mixture was at room temperature stirred 30 minutes.Add entry, the product dichloromethane extraction, dried over sodium sulfate is filtered, and the pressure reducing and steaming solvent obtains title compound.MS(ESI+)m/z?265.0(M+Na) +。
Embodiment 119B
[1-benzyl-4-(1H-indazole-5-yl)-1H-1,2,3-triazole-5-yl] (phenyl) ketone
Cover and under argon gas, contain embodiment 119A (90mg, 0.37mmol), benzyl azide (0.047mL, 0.37mmol), tetrahydrofuran (THF) (3mL), triethylamine (0.062mL, 0.44mmol), CuI (71mg, 0.37mmol) and Benzoyl chloride (0.059mL, phial 0.51mmol) and jolting 16 hours.Boil off solvent, product silica gel column chromatography purifying is with the hexane solution wash-out of 5-30% ethyl acetate.Thick material by the reversed-phase HPLC purifying, obtains title compound with acetonitrile/water 0.1% TFA linear gradient elution method with methylene dichloride (1mL) solution extraction of TFA (0.5mL). 1H?NMR(500MHz，DMSO-d 6/D 2O)δppm?13.08(s，1H)7.98(s，1H)7.77(s，1H)7.54(d，J＝8.24，1.22Hz，2H)7.43-7.48(m，1H)7.33-7.40(m，2H)7.22-7.30(m，5H)7.17-7.21(m，2H)5.74(s，2H).MS(ESI+)m/z?380.1(M+H) +。
Embodiment 120
N, N-diethyl-N-{[1-(1H-indazole-5-yl)-1H-1,2,3-triazole-4-yl] methyl } amine
Prepare title compound with the method for describing among the embodiment 88, wherein use 1,1-diethyl propargyl amine replaces 3-phenyl-1-propine. 1H?NMR(300MHz，DMSO-d 6)δppm?8.98(s，1H)8.30(d，J＝1.36Hz，1H)8.27(s，1H)7.85-7.93(m，1H)7.75-7.83(m，1H)4.53(d，J＝4.07Hz，2H)3.11-3.23(m，4H)1.31(t，J＝7.12Hz，6H).MS(ESI+)m/z?271.0(M+H) +。
Embodiment 121
N-[2-(1H-indazole-5-yl) imidazo [1,2-a] pyrimidin-3-yl]-the Beta-alanine ethyl ester
Prepare title compound with the method for describing among the embodiment 43, wherein replace the sec.-propyl isonitrile with the isocyano-ethyl propionate. 1H?NMR(300MHz，DMSO-d 6)δppm?13.09(s，1H)8.71(d，J＝6.78，2.03Hz，1H)8.54(s，1H)8.46(d，J＝4.24，1.87Hz，1H)8.23(d，J＝8.82，1.36Hz，1H)8.14(s，1H)7.61(d，J＝8.82Hz，1H)7.05(d，J＝6.78，4.07Hz，1H)5.03(t，J＝5.93Hz，1H)3.96(q，J＝7.12Hz，2H)3.23(q，J＝6.22Hz，2H)2.47-2.55(m，2H)1.08(t，J＝7.12Hz，3H).MS(ESI+)m/z?351.1(M+H) +。
Embodiment 122
5-(1-benzyl-5-methyl isophthalic acid H-1,2,3-triazole-4-yl)-1H-indazole
Embodiment 122A
1-benzyl-5-methyl-4-(tributyl stannyl)-1H-1,2, the 3-triazole
With tributyl (1-proyl) tin (3.87g, 11.8mmol) and benzyl azide (2.2mL 17.6mmol) mixes, and is heated to 150 ℃ and spends the night.Mixture silica gel chromatography purifying, the hexane solution gradient elution with the 5-40% ethyl acetate obtains title compound.MS(ESI+)?m/z?464.2(M+H) +。
Embodiment 122B
1-(5-(1-benzyl-5-methyl isophthalic acid H-1,2,3-triazole-4-yl)-1H-indazole-1-yl) ethyl ketone
With embodiment 87A (235mg, 0.821mmol), embodiment 122A (380mg, 0.822mmol), dichloro two (triphenylphosphine) palladium (II) (60mg, 0.085mmol) and thiophene-2-carboxylic acid copper (325mg 1.23mmol) mixes under the nitrogen rare gas element in microwave tube in toluene (2.0mL).Microwave tube is heated to 150 ℃ of reactions 20 minutes under 125 watts in microwave (CEM-Discover).Mixture is adsorbed on the silica gel, uses the silica gel chromatography purifying, the hexane solution gradient elution with the 5-40% ethyl acetate obtains title compound.MS(ESI+)m/z?332.2(M+H) +。
Embodiment 122C
5-(1-benzyl-5-methyl isophthalic acid H-1,2,3-triazole-4-yl)-1H-indazole
With embodiment 122B (109mg 0.329mmol) is dissolved in tetrahydrofuran (THF) (3.0mL) and water (0.5mL), add potassium hydroxide (53mg, 0.945mmol).Mixture stirred 2 hours, with the ethyl acetate dilution, washed with water.Organic layer is adsorbed on the silica gel, uses the silica gel chromatography purifying, the dichloromethane solution gradient elution with 0-5% methyl alcohol obtains title compound. 1H?NMR(300MHz，DMSO-d 6)δppm?13.13(s，1H)8.12(s，1H)8.01(s，1H)7.71-7.78(m，1H)7.59-7.66(m，1H)7.31-7.45(m，3H)7.23-7.29(m，2H)5.65(s，2H)2.43(s，3H).MS(ESI+)m/z?290.1(M+H) +。
Embodiment 123
5-(1-benzyl-5-methyl isophthalic acid H-1,2,3-triazole-4-yl)-1H-indazole-3-amine
Embodiment 123A
5-(1-benzyl-5-methyl isophthalic acid H-1,2,3-triazole-4-yl)-2-fluorobenzonitrile
With embodiment 122A (415mg, 0.792mmol), 5-bromo-2-fluorobenzonitrile (158mg, 0.790mmol), dichloro two (triphenylphosphine) palladium (II) (52mg, 0.074mmol) and thiophene-2-carboxylic acid copper (226mg 1.19mmol) mixes under the nitrogen rare gas element in microwave tube in toluene (2mL).Microwave tube was heated 20 minutes at 125 watts at 150 ℃ in microwave (CEM-Discover).Mixture is adsorbed on the silica gel, uses the silica gel chromatography purifying, the hexane solution gradient elution with the 5-40% ethyl acetate obtains title compound.MS(ESI+)m/z?293.0(M+H) +。
Embodiment 123B
5-(1-benzyl-5-methyl isophthalic acid H-1,2,3-triazole-4-yl)-1H-indazole-3-amine
(120mg 0.339mmol) with ethanol (1.0mL) solution-treated of hydrazine hydrate (1.0mL), and is heated to 60 ℃ and spends the night with embodiment 123A.With methylene dichloride diluted mixture thing, wash with water.Organic layer is adsorbed on the silica gel, uses the silica gel chromatography purifying, dichloromethane solution (0-5%) gradient elution with methyl alcohol obtains title compound. 1H?NMR(300MHz，DMSO-d 6)δppm?11.43(s，1H)7.98(s，1H)7.60(d，J＝8.65，1.53Hz，1H)7.27-7.44(m，4H)7.21-7.27(m，2H)5.65(s，2H)5.41(s，2H)2.41(s，3H).MS(ESI+)m/z?305.1(M+H) +。
Embodiment 124
N 3-[2-(1H-indazole-5-yl) imidazo [1,2-a] pyrimidin-3-yl]-β-alanimamides
(42mg, 0.120mmol) methyl alcohol (1.0mL) solution with 7N ammonia mixes, and is heated to 60 ℃ and spends the night with embodiment 121.Mixture is adsorbed on the silica gel, uses the silica gel chromatography purifying, dichloromethane solution (1-7%) gradient elution with methyl alcohol obtains title compound. 1H?NMR(300MHz，DMSO-d 6)δppm?13.09(s，1H)8.76(d，J＝6.78，2.03Hz，1H)8.56(s，1H)8.45(d，J＝4.07，2.03Hz，1H)8.24(d，J＝8.82，1.36Hz，1H)8.15(s，1H)7.61(d，J＝8.48Hz，1H)7.32(s，1H)7.03(d，J＝6.78，4.07Hz，1H)6.85(s，1H)4.93(t，J＝6.10Hz，1H)3.11-3.23(m，2H)2.32(t，J＝6.78Hz，2H).MS(ESI+)m/z?322.0(M+H) +。
Embodiment 125
5-(1-benzyl-5-iodo-1H-1,2,3-triazole-4-yl)-1H-indazole-3-amine
Embodiment 125A
5-(1-benzyl-5-iodo-1H-1,2,3-triazole-4-yl)-2-fluorobenzonitrile
With embodiment 62B (200mg, 1.38mmol), benzyl azide (0.176mL, 1.38mmol), tetrahydrofuran (THF) (12mL), triethylamine (0.230,1.56mmol), CuI (263mg, 1.38mmol) and ICl (0.069mL, mixture 1.38mmol) at room temperature stirred under argon gas 24 hours.Boil off solvent, crude mixture is dissolved in methylene dichloride, directly carries silicagel column, with ethyl acetate/hexane (10-20%) wash-out, obtains title compound.MS(ESI+)m/z?404.9(M+H) +。
Embodiment 125B
5-(1-benzyl-5-iodo-1H-1,2,3-triazole-4-yl)-1H-indazole-3-amine
With embodiment 125A (50mg, 0.12mmol) and ethanol (1mL) solution of hydrazine hydrate (1mL) 95 ℃ of down heating 2 hours.Add entry, solid collected by filtration is further purified by reversed-phase HPLC with acetonitrile/water 0.1%TFA linear gradient elution method, obtains the tfa salt of title compound. 1H?NMR(500MHz，DMSO-d 6)δppm?12.07(s，1H)8.30(s，1H)7.83(d，J＝8.85，1.53Hz，1H)7.44(d，J＝8.54Hz，1H)7.38-7.43(m，J＝7.32，7.32Hz，2H)7.32-7.37(m，1H)7.23-7.27(m，J＝7.02Hz，2H)5.74(s，2H)4.00(s，2H).MS(ESI+)m/z?417.0(M+H) +。
Embodiment 126
N-{3-[4-(3-amino-1H-indazole-5-yl)-1-benzyl-1H-1,2,3-triazole-5-yl] phenyl }-N '-(3-aminomethyl phenyl) urea
Embodiment 126A
Between 1-(3-(1-benzyl-4-(3-cyano group-4-fluorophenyl)-1H-1,2,3-triazole-5-yl) phenyl)-3--tolyl urea
Cover and under argon gas, contain embodiment 125A (94mg, 0.23mmol), (3-(4 for 1-, 4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycle pentane (dioxaborolan)-2-yls) phenyl)-3-between-tolyl urea (according to the method preparation of describing among the WO2004/113304) (990mg, 0.26mmol), PdCl 2The dppf methylene dichloride (19mg, 0.02mmol), salt of wormwood (64mg, 0.46mmol), the phial of DME (2mL) and water (0.2mL), on heating oscillator 80 ℃ of heating 90 minutes down.Boil off solvent, product extracts with ethanol/methylene.The silica gel chromatography purifying, the hexane solution wash-out with 10% ethyl acetate obtains title compound.MS(ESI+)m/z?503.2(M+H) +。
Embodiment 126B
N-{3-[4-(3-amino-1H-indazole-5-yl)-1-benzyl-1H-1,2,3-triazole-5-yl] phenyl }-N '-(3-aminomethyl phenyl) urea
(25mg, 0.05mmol) ethanol (2mL) solution with hydrazine monohydrate (0.5mL) heated 1 hour down at 80 ℃ with embodiment 126A.Crude mixture carries silica gel, and the dichloromethane solution gradient elution with 0-5% methyl alcohol obtains title compound. 1H?NMR(500MHz，DMSO-d 6)δppm11.40(s，1H)8.79(s，1H)8.63(s，1H)8.12(s，1H)7.57(d，J＝8.24，1.22Hz，1H)7.43(t，J＝1.83Hz，1H)7.38(t，J＝7.93Hz，1H)7.23-7.34(m，4H)7.08-7.22(m，4H)7.03(d，J＝6.71Hz，2H)6.88(d，J＝7.63Hz，1H)6.78(d，J＝7.32Hz，1H)5.50(s，2H)5.36(s，2H)2.26(s，3H).MS(ESI+)m/z?515.3(M+H) +。
Embodiment 127
5-(1H-indazole-5-yl)-N-(2-isopropoxy ethyl) isoxazole-3-methane amide
(37mg 0.18mmol) is dissolved in the solution of dimethyl formamide (0.8mL), and (61mg 0.18mmol) is dissolved in the solution of dimethyl formamide (0.8mL) to add HATU then to add 81A in the 20mL phial.(20mg 0.20mmol) is dissolved in the solution of dimethyl formamide (0.9mL), and (42mg 0.36mmol) is dissolved in the solution of dimethyl formamide (0.8mL) to add diisopropyl ethyl amine then to add 2-isopropoxy ethamine then.Then with mixture 40 ℃ of following joltings 3 hours.(6mL 2g), with the LC/MS check, is concentrated into dried by the carbonic acid silicon filter cylinder (Si-carbonate cartridge) by Silicycle Chemical Division supply to make the reaction mixture filtration with methyl alcohol.Residue is dissolved in 1: 1 DMSO/ methyl alcohol, with reversed-phase HPLC (Agilent, 5%-100% TFA/ water gradient elution, 8 minute working time) purifying. 1H?NMR(300MHz，DMSO-d 6/D 2O)δppm?8.38-8.43(m，1H)8.22-8.30(m，1H)7.90(d，1H)7.73(d，1H)7.21-7.29(m，1H)3.56-3.65(m，1H)3.52(t，2H)3.43(t，2H)1.10(d，6H).MS(ESI+)m/z?315(M+H) +。
Embodiment 128
5-[3-(morpholine-4-base carbonyl) isoxazole-5-base]-the 1H-indazole
Prepare title compound with the method for describing among the embodiment 127, wherein replace 2-isopropoxy ethamine with morpholino. 1H?NMR(300MHz，DMSO-d 6/D 2O)δppm?8.36-8.43(m，1H)8.22-8.29(m，1H)7.89(d，1H)7.72(d，1H)7.11-7.22(m，1H)3.68-3.72(m，4H)3.61-3.68(m，4H).MS(ESI+)m/z?299(M+H) +。
Embodiment 129
5-(1H-indazole-5-yl)-N-(3-morpholine-4-base propyl group) isoxazole-3-methane amide
Prepare the tfa salt of title compound with the method for describing among the embodiment 127, wherein replace 2-isopropoxy ethamine with 3-morpholino third-1-amine. 1H?NMR(300MHz，DMSO-d 6/D 2O)δppm?8.37-8.46(m，1H)8.20-8.31(m，1H)7.91(d，1H)7.73(d，1H)7.17-7.36(m，1H)3.98-4.08(m，2H)3.57-3.73(m，2H)3.42-3.51(m，2H)3.35-3.41(m，2H)3.14-3.22(m，2H)3.01-3.14(m，2H)1.88-2.06(m，2H).MS(ESI+)m/z?356(M+H) +。
Embodiment 130
N-[2-(1H-imidazol-4 yl) ethyl]-5-(1H-indazole-5-base) isoxazole-3-methane amide
Prepare title compound with the method for describing among the embodiment 127, wherein use 2-(1H-imidazol-4 yl) ethamine to replace 2-isopropoxy ethamine. 1H?NMR(300MHz，DMSO-d 6/D 2O)δppm?8.90-8.97(m，1H)8.34-8.46(m，1H)8.20-8.32(m，1H)7.90(d，1H)7.72(d，1H)7.38-7.49(m，1H)7.14-7.28(m，1H)3.57(t，2H)2.96(t，2H).MS(ESI+)m/z?323(M+H) +。
Embodiment 131
(3R)-and 1-{[5-(1H-indazole-5-base) isoxazole-3-base] carbonyl } piperidines-3-alcohol
Prepare title compound with the method for describing among the embodiment 127, wherein use (R)-piperidines-3-alcohol hydrochloride replacement 2-isopropoxy ethamine. 1H?NMR(300MHz，DMSO-d 6/D 2O)δppm?8.34-8.45(m，1H)8.19-8.30(m，1H)7.89(d，1H)7.72(d，1H)7.13(d，1H)4.03-4.19(m，1H)3.64-3.72(m，1H)3.54-3.62(m，1H)3.34-3.44(m，1H)3.20-3.32(m，1H)2.99-3.10(m，1H)1.67-2.03(m，2H)1.36-1.61(m，2H).MS(ESI+)m/z?313(M+H) +。
Embodiment 132
1-{[5-(1H-indazole-5-base) isoxazole-3-base] carbonyl } piperidines-3-methane amide
Prepare title compound with the method for describing among the embodiment 127, wherein replace 2-isopropoxy ethamine with piperidines-3-methane amide. 1H?NMR(300MHz，DMSO-d 6/D 2O)δppm?8.36-8.45(m，1H)8.22-8.32(m，1H)7.90(d，1H)7.72(d，1H)7.07-7.23(m，1H)4.27-4.56(m，1H)3.91-4.05(m，1H)3.09-3.37(m，1H)2.85-3.04(m，1H)2.31-2.45(m，1H)1.89-2.05(m，1H)1.73-1.86(m，1H)1.60-1.72(m，1H)1.36-1.55(m，1H).MS(ESI-)m/z?338(M-H) -。
Embodiment 133
2-[2-(4-{[5-(1H-indazole-5-base) isoxazole-3-base] carbonyl } piperazine-1-yl) oxyethyl group] ethanol
Prepare the tfa salt of title compound with the method for describing among the embodiment 127, wherein use 2-(2-(piperazine-1-yl) oxyethyl group) ethanol to replace 2-isopropoxy ethamine. 1H?NMR(300MHz，DMSO-d 6/D 2O)δppm?8.39-8.48(m，1H)8.19-8.32(m，1H)7.92(d，1H)7.74(d，1H)7.17-7.27(m，1H)4.49-4.60(m，1H)3.94-4.01(m，1H)3.76-3.81(m，4H)3.56-3.63(m，2H)3.51-3.56(m，2H)3.33-3.43(m，3H)3.13-3.23(m，1H)2.65-2.75(m，2H).MS(ESI+)m/z?386(M+H) +。
Embodiment 134
The 5-{3-[(4-methyl isophthalic acid, 4-Diazesuberane-1-yl) carbonyl] isoxazole-5-base }-the 1H-indazole
Prepare the tfa salt of title compound with the method for describing among the embodiment 127, wherein use the 1-methyl isophthalic acid, the 4-Diazesuberane replaces 2-isopropoxy ethamine. 1H?NMR(300MHz，DMSO-d 6/D 2O)δppm?8.38-8.46(m，1H)8.22-8.32(m，1H)7.85-7.98(m，1H)7.75(d，1H)7.22(d，1H)4.07-4.19(m，1H)3.69-3.77(m，2H)3.59-3.67(m，1H)3.44-3.59(m，1H)3.35-3.44(m，1H)3.24-3.35(m，2H)2.84-2.95(m，3H)2.66-2.74(m，1H)2.10-2.26(m，2H).MS(ESI+)m/z?326(M+H) +。
Embodiment 135
N-(3-hydroxypropyl)-5-(1H-indazole-5-base) isoxazole-3-methane amide
Prepare title compound with the method for describing among the embodiment 127, wherein replace 2-isopropoxy ethamine with 3-amino third-1-alcohol. 1H?NMR(300MHz，DMSO-d 6/D 2O)δppm?8.36-8.45(m，1H)8.20-8.30(m，1H)7.84-7.94(m，1H)7.71(d，1H)7.18-7.28(m，1H)3.48(t，2H)3.35(t，2H)1.64-1.78(m，2H).MS(ESI+)m/z?387(M+H) +。
Embodiment 136
N-[(1R)-2-hydroxyl-1-phenylethyl]-5-(1H-indazole-5-base) isoxazole-3-methane amide
Prepare title compound with the method for describing among the embodiment 127, wherein use (R)-2-amino-2-phenylethyl alcohol to replace 2-isopropoxy ethamine. 1H?NMR(300MHz，DMSO-d 6/D 2O)δppm9.11(d，1H)8.37-8.46(m，1H)8.23-8.28(m，1H)7.91(d，1H)7.73(d，1H)7.40-7.45(m，2H)7.32-7.39(m，2H)7.23-7.32(m，2H)5.05-5.13(m，1H)3.66-3.72(m，2H).MS(ESI+)m/z?349(M+H) +。
Embodiment 137
N-[3-(1H-imidazoles-1-yl) propyl group]-5-(1H-indazole-5-base) isoxazole-3-methane amide
Prepare title compound with the method for describing among the embodiment 127, wherein use 3-(1H-imidazoles-1-yl) third-1-amine to replace 2-isopropoxy ethamine. 1H?NMR(300MHz，DMSO-d 6/D 2O)δppm9.02-9.10(m，1H)8.40-8.44(m，1H)8.25-8.29(m，1H)7.87-7.95(m，1H)7.71-7.82(m，2H)7.61-7.69(m，1H)7.20-7.29(m，1H)4.28(t，2H)3.33(t，2H)2.06-2.19(m，2H).MS(ESI+)m/z?337(M+H) +。
Embodiment 138
5-(1H-indazole-5-yl)-N-[3-(2-oxo-pyrrolidine-1-yl) propyl group] isoxazole-3-methane amide
Prepare title compound with the method for describing among the embodiment 127, wherein use 1-(3-aminopropyl) pyrrolidin-2-one to replace 2-isopropoxy ethamine. 1H?NMR(300MHz，DMSO-d 6/D 2O)δppm?8.38-8.43(m，1H)8.24-8.30(m，1H)7.87-7.93(m，1H)7.73(d，1H)7.22-7.26(m，1H)3.39(t，2H)3.21-3.30(m，4H)2.26(t，2H)1.90-2.00(m，2H)1.70-1.79(m，2H).MS(ESI+)m/z?354(M+H) +。
Embodiment 139
N-{2-[4-(amino-sulfonyl) phenyl] ethyl }-5-(1H-indazole-5-base) isoxazole-3-methane amide
Prepare title compound with the method for describing among the embodiment 127, wherein use 4-(2-amino-ethyl) benzsulfamide to replace 2-isopropoxy ethamine. 1H?NMR(300MHz，DMSO-d 6/D 2O)δppm8.37-8.42(m，1H)8.24-8.29(m，1H)7.86-7.93(m，1H)7.70-7.80(m，3H)7.47(d，2H)7.20-7.24(m，1H)3.57(t，2H)2.96(t，2H).MS(ESI+)m/z412(M+H) +。
Embodiment 140
[1-benzyl-4-(1H-indazole-5-yl)-1H-1,2,3-triazole-5-yl] (3-chloro-phenyl-) ketone
Prepare title compound with the method for describing among the embodiment 119B, wherein replace Benzoyl chloride with the 3-chloro-benzoyl chloride. 1H?NMR(500MHz，DMSO-d 6)δppm?13.09(s，1H)7.99(s，1H)7.77(s，1H)7.38-7.51(m，4H)7.28-7.37(m，3H)7.20-7.27(m，4H)5.78(s，2H).MS(ESI+)m/z?414.1(M+H) +。
Embodiment 141
[1-benzyl-4-(1H-indazole-5-yl)-1H-1,2,3-triazole-5-yl] (cyclopropyl) ketone
Prepare title compound with the method for describing among the embodiment 119B, wherein replace Benzoyl chloride with the cyclopropyl formyl chloride. 1H?NMR(500MHz，DMSO-d 6)δppm?13.26(s，1H)8.18(s，1H)8.08(s，1H)7.61-7.70(m，2H)7.29-7.40(m，3H)7.24(d，J＝7.02Hz，2H)5.79(s，2H)1.86-2.00(m，1H)0.98-1.12(m，2H)0.77-0.93(m，2H).MS(ESI+)m/z?344.1(M+H) +。
Embodiment 142
5-[5-cyclopropyl-1-(tetrahydrochysene-2H-pyrans-4-ylmethyl)-1H-1,2,3-triazole-4-yl]-the 1H-indazole
Embodiment 142A
5-cyclopropyl-1-((tetrahydrochysene-2H-pyrans-4-yl) methyl)-4-(tributyl stannyl)-1H-1,2, the 3-triazole
With cyclopropyl acethlene (142mg 2.15mmol) joins 1,1,1-tributyl-N, (716mg, hexane 2.14mmol) (3.0mL) solution stirred 2 hours down at 70 ℃ in sealed tube N-tin methide amine (stannanamine).Mixture was chilled to room temperature, with the phial restir that goes to seal 10 minutes.(455mg 3.22mmol), reseals phial, is heated to 130 ℃ and spends the night to add embodiment 80A.Mixture silica gel chromatography purifying, hexane solution (5-50%) gradient elution with ethyl acetate obtains title compound.MS(ESI+)m/z?498.3(M+H) +。
Embodiment 142B
1-(5-(5-cyclopropyl-1-((tetrahydrochysene-2H-pyrans-4-yl) methyl)-1H-1,2,3-triazole-4-yl)-1H-indazole-1-yl) ethyl ketone
With embodiment 142A (220mg, 0.444mmol), embodiment 87A (128mg, 0.447mmol), dichloro two (triphenylphosphine) palladium (II) (33mg, 0.047mmol) and thiophene-2-carboxylic acid copper (127mg 0.666mmol) mixes under the nitrogen rare gas element in the 4mL phial in toluene (2.0mL).The sealing phial is heated to 150 ℃ of reactions 20 minutes.Mixture is adsorbed on the silica gel, uses the silica gel chromatography purifying, the hexane solution gradient elution with the 5-70% ethyl acetate obtains title compound.MS(ESI+)m/z?366.0(M+H) +。
Embodiment 142C
5-[5-cyclopropyl-1-(tetrahydrochysene-2H-pyrans-4-ylmethyl)-1H-1,2,3-triazole-4-yl]-the 1H-indazole
With embodiment 142B (46mg 0.126mmol) is dissolved in tetrahydrofuran (THF) (2.0mL) and water (0.5mL), add potassium hydroxide (80mg, 1.43mmol).Mixture was stirred 2 hours,, wash with water with the methylene dichloride dilution.Organic layer is adsorbed on the silica gel, uses the silica gel chromatography purifying, the dichloromethane solution gradient elution with 0-8% methyl alcohol obtains title compound. 1H?NMR(300MHz，CDCl 3)δppm?8.19(s，1H)7.96(d，J＝8.82Hz，1H)7.61(d，J＝7.80Hz，1H)7.25-7.28(m，1H)4.34(d，J＝6.44Hz，2H)4.02(d，J＝11.36，3.56Hz，2H)3.42(t，J＝11.53Hz，2H)2.33-2.46(m，1H)1.81-1.95(m，1H)1.59-1.70(m，2H)1.43-1.58(m，2H)1.23-1.28(m，1H)1.10-1.20(m，2H)0.47-0.62(m，2H).MS(ESI+)m/z?324.1(M+H) +。
Embodiment 143
N 1-{ [1-benzyl-4-(1H-indazole-5-yl)-1H-1,2,3-triazole-5-yl] methyl } G-NH2
Embodiment 143A
2-((1-benzyl-4-(tributyl stannyl)-1H-1,2,3-triazole-5-yl) methyl) isoindoline-1, the 3-diketone
With N-propargyl phthalic imidine (2.35g mg 12.7mmol) joins 1,1,1-tributyl-N, (4.23mg in hexane 12.7mmol) (3.0mL) solution, stirred 2 hours down at 70 ℃ in sealed tube N-tin methide amine.Mixture is chilled to room temperature, removes the phial restir that seals 10 minutes.(2.0mL 16.0mmol), reseals phial, is heated to 130 ℃ and spends the night to add benzyl azide.Mixture silica gel chromatography purifying, the hexane solution gradient elution with the 10-50% ethyl acetate obtains title compound.MS(ESI+)m/z?609.3(M+H) +。
Embodiment 143B
2-((4-(1-ethanoyl-1H-indazole-5-yl)-1-benzyl-1H-1,2,3-triazole-5-yl) methyl) isoindoline-1, the 3-diketone
With embodiment 143A (567mg, 0.934mmol), embodiment 87A (268mg, 0.934mmol), dichloro two (triphenylphosphine) palladium (II) (67mg, 0.095mmol) and thiophene-2-carboxylic acid copper (268mg 1.41mmol) mixes under the nitrogen rare gas element in microwave tube in toluene (2.5mL).Microwave tube is heated to 150 ℃ of reactions 20 minutes at microwave (CEM-Discover) at 125 watts.Mixture is adsorbed on the silica gel, uses the silica gel chromatography purifying, the hexane solution gradient elution with the 10-50% ethyl acetate obtains title compound.MS(ESI+)m/z?477.2(M+H) +。
Embodiment 143C
(1-benzyl-4-(1H-indazole-5-yl)-1H-1,2,3-triazole-5-yl) methylamine
(140mg 0.294mmol) with ethanol (0.7mL) solution-treated of hydrazine hydrate (0.7mL), at room temperature stirs and spends the night with embodiment 143B.Mixture is adsorbed on the silica gel, uses the silica gel chromatography purifying, the dichloromethane solution gradient elution with 1-6% methyl alcohol obtains title compound.MS(ESI+)m/z?305.0(M+H) +。
Embodiment 143D
N 1-{ [1-benzyl-4-(1H-indazole-5-yl)-1H-1,2,3-triazole-5-yl] methyl } G-NH2
With embodiment 143C (66mg, 0.217mmol), N-(tert-butoxycarbonyl)-glycine (39mg, 0.223mmol) and HATU (85mg 0.224mmol) mixes in methylene dichloride (2.5mL).(150uL, 0.865mmol), mixture at room temperature stirs and spends the night to add diisopropyl ethyl amine.Use the silica gel adsorption mixture, use the silica gel chromatography purifying, the dichloromethane solution gradient elution with 0-6% methyl alcohol obtains 2-((1-benzyl-4-(1H-indazole-5-yl)-1H-1,2,3-triazole-5-yl) methylamino)-2-oxoethyl t-butyl carbamate.This carbamate is dissolved in tetrahydrofuran (THF) (2mL), adds the diethyl ether solution of 0.5mL 1N hydrochloric acid, mixture was at room temperature stirred 20 minutes.Removal of solvent under reduced pressure adds ether in mixture, mixture at room temperature stirs and spends the night.Drain solvent, the gained residue is dry under nitrogen gas stream, obtains the hydrochloride of title compound. 1H?NMR(300MHz，DMSO-d 6)δppm?13.21(s，1H)9.02(t，J＝5.09Hz，1H)8.11-8.16(m，2H)8.06(s，2H)7.75-7.82(m，1H)7.64(d，J＝8.82Hz，1H)7.30-7.45(m，3H)7.23-7.31(m，2H)5.72(s，2H)4.57(d，J＝5.09Hz，2H)3.41(q，J＝5.76Hz，2H).MS(ESI+)m/z?362.1(M+H) +。
Embodiment 144
(4-fluorophenyl) [4-(1H-indazole-5-yl)-1-(tetrahydrochysene-2H-pyrans-4-ylmethyl)-1H-1,2,3-triazole-5-yl] ketone
Prepare title compound with the method for describing among the embodiment 119B, wherein replace Benzoyl chloride, replace benzyl azide with embodiment 80A with the 4-fluorobenzoyl chloride. 1H?NMR(300MHz，DMSO-d 6)δppm?13.10(s，1H)8.00(s，1H)7.72-7.80(m，3H)7.38-7.44(m，1H)7.30-7.36(m，1H)7.09-7.19(m，2H)4.41(d，J＝7.12Hz，2H)3.80(d，J＝11.36，2.54Hz，2H)3.14-3.26(m，2H)2.04-2.19(m，1H)1.38-1.49(m，2H)1.19-1.35(m，2H).MS(ESI+)m/z?406.1(M+H) +。
Embodiment 145
(4-chloro-phenyl-) [4-(1H-indazole-5-yl)-1-(tetrahydrochysene-2H-pyrans-4-ylmethyl)-1H-1,2,3-triazole-5-yl] ketone
Prepare title compound with the method for describing among the embodiment 119B, wherein replace Benzoyl chloride, replace benzyl azide with embodiment 80A with the 4-chloro-benzoyl chloride. 1H?NMR(300MHz，DMSO-d 6)δppm?13.10(s，1H)8.00(s，1H)7.77(s，1H)7.68(d，J＝8.48Hz，2H)7.29-7.45(m，4H)4.42(d，J＝7.12Hz，2H)3.81(d，J＝11.19，2.71Hz，2H)3.14-3.27(m，2H)2.03-2.19(m，1H)1.38-1.51(m，2H)1.22-1.36(m，2H).MS(ESI+)m/z?422.1(M+H) +。
Embodiment 146
(3-chloro-phenyl-) [4-(1H-indazole-5-yl)-1-(tetrahydrochysene-2H-pyrans-4-ylmethyl)-1H-1,2,3-triazole-5-yl] ketone
Prepare title compound with the method for describing among the embodiment 119B, wherein replace Benzoyl chloride, replace benzyl azide with embodiment 80A with the 3-chloro-benzoyl chloride. 1H?NMR(300MHz，DMSO-d 6)δppm?13.04(s，1H)7.95(s，1H)7.64(s，1H)7.48-7.54(m，1H)7.29-7.35(m，1H)7.22-7.28(m，1H)7.13-7.22(m，3H)4.58(d，J＝7.12Hz，2H)3.86(d，J＝11.53，2.37Hz，2H)3.20-3.30(m，2H)2.11-2.24(m，1H)1.45-1.54(m，2H)1.33-1.44(m，2H).MS(ESI+)m/z?422.1(M+H) +。
Embodiment 147
(2-chloro-phenyl-) [4-(1H-indazole-5-yl)-1-(tetrahydrochysene-2H-pyrans-4-ylmethyl)-1H-1,2,3-triazole-5-yl] ketone
Prepare title compound with the method for describing among the embodiment 119B, wherein replace Benzoyl chloride, replace benzyl azide with embodiment 80A with the 2-chloro-benzoyl chloride. 1H?NMR(300MHz，DMSO-d 6)δppm?13.08(s，1H)7.99(s，1H)7.75(s，1H)7.66(t，J＝1.86Hz，1H)7.56(d，J＝7.80Hz，1H)7.47-7.53(m，1H)7.36-7.42(m，1H)7.23-7.34(m，2H)4.45(d，J＝6.78Hz，2H)3.82(d，J＝11.19，2.37Hz，2H)3.18-3.29(m，2H)2.09-2.23(m，1H)1.41-1.53(m，2H)1.28-1.38(m，2H).MS(ESI+)m/z422.1(M+H) +。
Embodiment 148
Cyclopentyl [4-(1H-indazole-5-yl)-1-(tetrahydrochysene-2H-pyrans-4-ylmethyl)-1H-1,2,3-triazole-5-yl] ketone
Prepare title compound with the method for describing among the embodiment 119B, wherein replace Benzoyl chloride, replace benzyl azide with embodiment 80A with the pentamethylene formyl chloride. 1H?NMR(300MHz，DMSO-d 6)δppm?13.27(s，1H)8.18(s，1H)7.95(s，1H)7.68(d，J＝8.48Hz，1H)7.52(d，J＝8.48，1.70Hz，1H)4.47(d，J＝7.12Hz，2H)3.85(d，J＝11.53，2.37Hz，2H)3.18-3.30(m，2H)3.02-3.14(m，1H)2.00-2.17(m，1H)1.19-1.76(m，12H).MS(ESI+)m/z?380.1(M+H) +。
Embodiment 149
1-benzyl-4-(1H-indazole-5-yl)-1H-1,2,3-triazole-5-formic acid
Embodiment 149A
1-benzyl-4-(tributyl stannyl)-1H-1,2,3-triazole-5-methyl-formiate
(5.75g 68.4mmol) joins and fills ethyl (tributyl stannyl) Urethylane (26.9g is in large sealing pipe 68.6mmol) with the propynoic acid methyl esters.Mixture heating up to 70 ℃ is spent the night.Mixture is chilled to room temperature, and phial goes sealing, stirs 10 minutes.(10.2mL 81.6mmol), reseals phial, is heated to 130 ℃ and spends the night to add benzyl azide.Mixture silica gel chromatography purifying, the hexane solution gradient elution with the 5-40% ethyl acetate obtains title compound.MS(ESI+)m/z?508.3(M+H) +。
Embodiment 149B
4-(1-ethanoyl-1H-indazole-5-yl)-1-benzyl-1H-1,2,3-triazole-5-methyl-formiate
With embodiment 149A (7.17g, 14.1mmol), embodiment 87A (4.02g, 14.1mmol), dichloro two (triphenylphosphine) palladium (II) (1.01mg, 1.44mmol) and thiophene-2-carboxylic acid copper (4.07mg 21.3mmol) mixes under the nitrogen rare gas element in the large sealing pipe in toluene (55mL).With the seal of tube, heated 30 minutes down at 150 ℃.Mixture is adsorbed on the silica gel, uses the silica gel chromatography purifying, the hexane solution gradient elution with the 10-50% ethyl acetate obtains title compound.MS(ESI+)m/z?376.1(M+H) +。
Embodiment 149C
1-benzyl-4-(1H-indazole-5-yl)-1H-1,2,3-triazole-5-formic acid
With embodiment 149B (3.40mg 9.06mmol) is dissolved in tetrahydrofuran (THF) (100mL), methyl alcohol (10mL) and water (10mL), add potassium hydroxide (1.63g, 29.1mmol).Mixture stirred 3 hours, with the ethyl acetate dilution, with 1N salt acid elution, used the salt water washing, the organic layer dried over sodium sulfate of merging.After the filtration, removal of solvent under reduced pressure obtains title compound. 1H?NMR(300MHz，DMSO-d 6)δppm?13.16(s，1H)8.11-8.18(m，2H)7.66-7.76(m，1H)7.54-7.62(m，1H)7.31-7.43(m，3H)7.22-7.29(m，2H)5.93(s，2H).MS(ESI+)m/z?320.0(M+H) +。
Embodiment 150
5-{5-(4-fluorophenyl)-1-[4-(trifluoromethyl) benzyl]-1H-1,2,3-triazole-4-yl }-1H-indazole-3-amine
Embodiment 150A
1-(azido-methyl)-4-(trifluoromethyl) benzene
(2.30g, (4.26g 17.8mmol) is dissolved in the solution of dimethyl sulfoxide (DMSO) (15mL), at room temperature stirs and spends the night 35.4mmol) to join 4-(trifluoromethyl) bromotoluene with sodiumazide.Mixture dilutes with ethyl acetate, water and salt water washing, dried over sodium sulfate.After the filtration, removal of solvent under reduced pressure obtains title compound.Crude product is used for following step without further identifying.
Embodiment 150B
5-(4-fluorophenyl)-4-(tributyl stannyl)-1-(4-(trifluoromethyl) benzyl)-1H-1,2, the 3-triazole
With 4-fluorophenyl acetylene (524mg 4.36mmol) joins 1,1,1-tributyl-N, N-tin methide amine (1.46g, 4.37mmol) in, mixture stirred 30 minutes down at 50 ℃ in sealed tube.Mixture is chilled to room temperature, and phial goes sealing, stirs 10 minutes.(1.28g 6.30mmol), reseals phial, is heated to 130 ℃ and spends the night to add embodiment 150A.Use the silica gel chromatography purified mixture, the hexane solution gradient elution with the 5-35% ethyl acetate obtains title compound.MS(ESI+)m/z?612.3(M+H) +。
Embodiment 150C
2-fluoro-5-(5-(4-fluorophenyl)-1-(4-(trifluoromethyl) benzyl)-1H-1,2,3-triazole-4-yl) cyanobenzene
With embodiment 150B (485mg, 0.795mmol), 5-bromo-2-fluorobenzonitrile (143mg, 0.715mmol), dichloro two (triphenylphosphine) palladium (II) (49mg, 0.070mmol) and thiophene-2-carboxylic acid copper (205mg 1.08mmol) mixes under the nitrogen rare gas element in the 4mL phial in toluene (2.0mL).The sealing phial heated 30 minutes down at 150 ℃.Mixture is adsorbed on the silica gel, uses the silica gel chromatography purifying, the hexane solution gradient elution with the 10-50% ethyl acetate obtains title compound.MS(ESI+)m/z?441.2(M+H) +。
Embodiment 150D
5-{5-(4-fluorophenyl)-1-[4-(trifluoromethyl) benzyl]-1H-1,2,3-triazole-4-yl }-1H-indazole-3-amine
With ethanol (1.0mL) solution-treated of embodiment 150C, reaction mixture is heated to 65 ℃ stirred 3 hours with hydrazine hydrate (1.0mL).Mixture dilutes with methylene dichloride, washes with water.Organic layer is adsorbed on the silica gel, uses the silica gel chromatography purifying, the dichloromethane solution gradient elution with 0-6% methyl alcohol obtains title compound. 1H?NMR(300MHz，DMSO-d 6)δppm?11.42(s，1H)8.04(s，1H)7.67(d，J＝8.14Hz，2H)7.26-7.41(m，4H)7.22(d，J＝8.48Hz，2H)7.03-7.15(m，2H)5.62(s，2H)5.36(s，2H).MS(ESI+)m/z?453.1(M+H) +。
Embodiment 151
5-[1-benzyl-5-(4-fluorophenyl)-1H-1,2,3-triazole-4-yl]-1H-indazole-3-amine
Embodiment 151A
1-benzyl-5-(4-fluorophenyl)-4-(tributyl stannyl)-1H-1,2, the 3-triazole
With 4-fluorophenyl acetylene (525mg 4.37mmol) joins 1,1,1-tributyl-N, N-tin methide amine (1.46g, 4.37mmol) in, mixture stirred 2 hours down at 50 ℃ in the sealing phial.Mixture is chilled to room temperature, and phial goes sealing, stirs 10 minutes.(850uL 6.80mmol), reseals phial, is heated to 130 ℃ and spends the night to add benzyl azide.Mixture silica gel chromatography purifying, the hexane solution gradient elution with the 5-35% ethyl acetate obtains title compound.MS(ESI+)m/z?544.4(M+H) +。
Embodiment 151B
5-(1-benzyl-5-(4-fluorophenyl)-1H-1,2,3-triazole-4-yl)-2-fluorobenzonitrile
With embodiment 151A (361mg, 0.666mmol), 5-bromo-2-fluorobenzonitrile (119mg, 0.595mmol), dichloro two (triphenylphosphine) palladium (II) (45mg, 0.064mmol) and thiophene-2-carboxylic acid copper (193mg 1.01mmol) mixes under the nitrogen rare gas element in the 4mL phial in toluene (2.0mL).The sealing phial is heated to 150 ℃ of reactions 30 minutes.Mixture is adsorbed on the silica gel, uses the silica gel chromatography purifying, the hexane solution gradient elution with the 10-50% ethyl acetate obtains title compound.MS(ESI+)m/z?373.0(M+H) +。
Embodiment 151C
5-[1-benzyl-5-(4-fluorophenyl)-1H-1,2,3-triazole-4-yl]-1H-indazole-3-amine
(135mg 0.363mmol) with ethanol (1.0mL) solution-treated of hydrazine hydrate (1.0mL), is heated to 65 ℃ and stirred 3 hours with embodiment 151B.Mixture dilutes with methylene dichloride, washes with water.Organic layer is adsorbed on the silica gel, uses the silica gel chromatography purifying, the dichloromethane solution gradient elution with 0-6% methyl alcohol obtains title compound. 1H?NMR(300MHz，DMSO-d 6)δppm?11.40(s，1H)8.02(s，1H)7.24-7.38(m，7H)7.03-7.14(m，2H)6.98(d，J＝7.29，2.20Hz，2H)5.50(s，2H)5.35(s，2H).MS(ESI+)m/z?385.1(M+H) +。
Embodiment 152
[4-(1H-indazole-5-yl)-1-(tetrahydrochysene-2H-pyrans-4-ylmethyl)-1H-1,2,3-triazole-5-yl] (tetrahydrochysene-2H-pyrans-4-yl) ketone
Prepare title compound with the method for describing among the embodiment 119B, wherein replace benzyl azide, replace Benzoyl chloride with tetrahydrochysene-2H-pyrans-4-formyl chloride with embodiment 80A. 1H?NMR(300MHz，DMSO-d 6)δppm?13.30(s，1H)8.18(s，1H)8.00(s，1H)7.69(d，J＝8.48Hz，1H)7.53(d，J＝8.65，1.53Hz，1H)4.48(d，J＝7.12Hz，2H)3.79-3.90(m，2H)3.62-3.74(m，2H)3.18-3.30(m，2H)2.76-2.88(m，1H)2.64-2.76(m，2H)2.00-2.17(m，1H)1.20-1.58(m，8H).MS(ESI+)m/z?396.0(M+H) +。
Embodiment 153
5-[1-benzyl-5-(2-aminomethyl phenyl)-1H-1,2,3-triazole-4-yl]-the 1H-indazole
Embodiment 153A
1-benzyl-5-neighbour-tolyl-4-(tributyl stannyl)-1H-1,2, the 3-triazole
With 2-ethynyl toluene (456uL 3.62mmol) joins 1,1,1-tributyl-N, N-tin methide amine (1.21g, 3.62mmol) in, mixture was stirred 3 hours down at 70 ℃ in the sealing phial.Mixture is chilled to room temperature, and phial goes sealing, stirs 10 minutes.(678uL 5.42mmol), reseals phial, is heated to 130 ℃ and spends the night to add benzyl azide.Mixture silica gel chromatography purifying, the hexane solution gradient elution with the 5-45% ethyl acetate obtains title compound.MS(ESI+)m/z?539.8(M+H) +。
Embodiment 153B
1-(5-(1-benzyl-5-neighbour-tolyl-1H-1,2,3-triazole-4-yl)-1H-indazole-1-yl) ethyl ketone
With embodiment 153A (119mg, 0.221mmol), embodiment 87A (63mg, 0.221mmol), dichloro two (triphenylphosphine) palladium (II) (16mg, 0.023mmol) and thiophene-2-carboxylic acid copper (65mg 0.341mmol) mixes under the nitrogen rare gas element in the 4mL phial in toluene (2.0mL).The sealing phial heated 20 minutes down at 150 ℃.Mixture is adsorbed on the silica gel, uses the silica gel chromatography purifying, the hexane solution gradient elution with the 5-45% ethyl acetate obtains title compound.MS(ESI+)m/z?408.7(M+H) +。
Embodiment 153C
5-[1-benzyl-5-(2-aminomethyl phenyl)-1H-1,2,3-triazole-4-yl]-the 1H-indazole
With embodiment 153B (42mg 0.103mmol) is dissolved in tetrahydrofuran (THF) (2.0mL) and water (0.3mL), add potassium hydroxide (48mg, 0.856mmol).Mixture stirred 1 hour, with the methylene dichloride dilution, washed with water.Organic layer is adsorbed on the silica gel, uses the silica gel chromatography purifying, the dichloromethane solution gradient elution with 1-6% methyl alcohol obtains title compound. 1H?NMR(300MHz，DMSO-d 6)δppm?13.07(s，1H)7.97(s，1H)7.73(s，1H)7.44-7.53(m，3H)7.39(t，J＝6.95Hz，1H)7.28-7.35(m，2H)7.21-7.29(m，3H)6.86-6.95(m，2H)5.28-5.45(m，2H)1.59(s，3H).MS(ESI+)m/z?366.1(M+H) +。
Embodiment 154
5-{1-benzyl-5-[(4-methylpiperazine-1-yl) carbonyl]-1H-1,2,3-triazole-4-yl }-the 1H-indazole
Prepare title compound with the method for describing among the embodiment 81B, wherein replace embodiment 81A, replace piperidines, replace dimethyl formamide with tetrahydrofuran (THF) with the 1-methylpiperazine with embodiment 149C. 1H?NMR(300MHz，DMSO-d 6)δppm?13.20(s，1H)8.16(s，1H)7.96(s，1H)7.57-7.69(m，2H)7.31-7.44(m，3H)7.23-7.30(m，2H)5.36-5.83(m，2H)3.40-3.65(m，J＝4.75Hz，2H)2.38-2.49(m，2H)2.10-2.22(m，2H)1.89(s，3H)1.40(t，J＝4.92Hz，2H).MS(ESI+)m/z?402.2(M+H) +。
Embodiment 155
1-{[1-benzyl-4-(1H-indazole-5-yl)-1H-1,2,3-triazole-5-yl] carbonyl } piperidines-4-alcohol
Prepare title compound with the method for describing among the embodiment 81B, wherein replace embodiment 81A, replace piperidines, replace dimethyl formamide with tetrahydrofuran (THF) with the 4-hydroxy piperidine with embodiment 149C. 1H?NMR(300MHz，DMSO-d 6)δppm?13.15-13.24(m，1H)8.16(s，1H)7.97(s，1H)7.55-7.68(m，2H)7.32-7.43(m，3H)7.23-7.30(m，2H)5.41-5.83(m，J＝65.10Hz，2H)4.58(d，J＝3.39Hz，1H)3.74-3.91(m，1H)3.37-3.48(m，2H)2.66-2.79(m，1H)2.25-2.47(m，1H)1.54-1.68(m，1H)1.20-1.36(m，1H)0.74-0.90(m，1H)0.40-0.60(m，1H).MS(ESI+)m/z?403.1(M+H) +。
Embodiment 156
1-ethanoyl-5-[5-(4-fluorophenyl)-1-(tetrahydrochysene-2H-pyrans-4-ylmethyl)-1H-1,2,3-triazole-4-yl]-the 1H-indazole
Embodiment 156A
5-(4-fluorophenyl)-1-((tetrahydrochysene-2H-pyrans-4-yl) methyl)-4-(tributyl stannyl)-1H-1,2, the 3-triazole
With 4-fluorophenyl acetylene (440uL 3.88mmol) joins 1,1,1-tributyl-N, N-tin methide amine (1.30g, 3.89mmol) in, mixture was stirred 40 minutes down at 50 ℃ in sealed tube.Mixture is chilled to room temperature, and phial goes sealing, stirs 10 minutes.(710uL 5.68mmol), reseals phial, is heated to 130 ℃ of reactions and spends the night to add embodiment 80A.Mixture silica gel chromatography purifying, the hexane solution gradient elution with the 5-50% ethyl acetate obtains title compound.MS(ESI+)m/z?552.4(M+H) +。
Embodiment 156B
1-ethanoyl-5-[5-(4-fluorophenyl)-1-(tetrahydrochysene-2H-pyrans-4-ylmethyl)-1H-1,2,3-triazole-4-yl]-the 1H-indazole
With embodiment 156A (433mg, 0.787mmol), embodiment 87A (205mg, 0.717mmol), dichloro two (triphenylphosphine) palladium (II) (55mg, 0.078mmol) and thiophene-2-carboxylic acid copper (224mg 1.17mmol) mixes under the nitrogen rare gas element in the 4mL phial in toluene (2.0mL).The sealing phial is heated to 150 ℃ of reactions 20 minutes.Mixture is adsorbed on the silica gel, uses the silica gel chromatography purifying,, grind, obtain title compound with methyl alcohol with the hexane solution gradient elution of 5-45% ethyl acetate. 1H?NMR(300MHz，DMSO-d 6)δppm?8.40-8.48(m，J＝0.68Hz，1H)8.25(d，J＝8.82Hz，1H)7.82-7.91(m，1H)7.73(d，J＝8.48，1.70Hz，1H)7.50-7.60(m，2H)7.38-7.49(m，2H)4.13(d，J＝7.12Hz，2H)3.76(d，J＝11.36，2.54Hz，2H)3.10-3.25(m，2H)2.70(s，3H)1.86-2.08(m，1H)1.37(d，J＝12.55，1.70Hz，2H)1.03-1.23(m，2H).MS(ESI+)m/z?420.2(M+H) +。
Embodiment 157
1-benzyl-4-(1H-indazole-5-yl)-N, N-dimethyl-1H-1,2,3-triazole-5-methane amide
Prepare title compound with the method for describing among the embodiment 81B, wherein replace embodiment 81A, replace piperidines, replace dimethyl formamide with tetrahydrofuran (THF) with dimethyl amine with embodiment 149C. 1HNMR(300MHz，DMSO-d 6)δppm?13.19(s，1H)8.15(s，1H)7.96(t，J＝1.19Hz，1H)7.62(d，J＝1.36Hz，2H)7.33-7.44(m，3H)7.24-7.33(m，2H)5.59(s，2H)2.92(s，3H)2.21(s，3H).MS(ESI+)m/z?347.1(M+H) +。
Embodiment 158
N, 1-dibenzyl-4-(1H-indazole-5-yl)-1H-1,2,3-triazole-5-methane amide
Prepare title compound with the method for describing among the embodiment 81B, wherein replace embodiment 81A, replace piperidines, replace dimethyl formamide with tetrahydrofuran (THF) with benzyl amine with embodiment 149C. 1HNMR(300MHz，DMSO-d 6)δppm?13.15(s，1H)9.35(t，J＝6.10Hz，1H)8.01(d，J＝12.55Hz，2H)7.68(d，J＝8.82，1.36Hz，1H)7.53(d，J＝8.82Hz，1H)7.17-7.41(m，10H)5.66(s，2H)4.41(d，J＝6.10Hz，2H).MS(ESI+)m/z409.1(M+H) +。
Embodiment 159
N-(2-hydroxyl-2-phenylethyl)-5-(1H-indazole-5-yl)-N-methyl-isoxazole-3-methane amide
Prepare title compound with the method for describing among the embodiment 81B, wherein use DL-α-(methylamino methyl) benzyl alcohol to replace piperidines. 1H?NMR(300MHz，DMSO-d 6)δppm?13.01(s，1H)8.29(s，1H)8.17(s，1H)7.73-7.85(m，1H)7.62-7.72(m，1H)7.16-7.43(m，5H)6.86(s，1H)5.17(d，J＝4.39Hz，1H)4.89(s，1H)3.71(d，J＝5.49Hz，2H)3.10(s，3H).MS(ESI+)m/z?363.1(M+H) +。
Embodiment 160
N-[(1S)-2-hydroxyl-1-phenylethyl]-5-(1H-indazole-5-base) isoxazole-3-methane amide
Prepare title compound with the method for describing among the embodiment 81B, wherein use (S)-2-amino-2-phenylethyl alcohol to replace piperidines. 1H?NMR(300MHz，DMSO-d 6)δppm?13.37(s，1H)9.05(d，J＝8.14Hz，1H)8.40(s，1H)8.23(s，1H)7.89(d，J＝8.65，1.53Hz，1H)7.70(d，J＝8.82Hz，1H)7.20-7.46(m，6H)5.02-5.13(m，1H)4.98(t，J＝5.59Hz，1H)3.61-3.82(m，2H).MS(ESI+)m/z?349.0(M+H) +。
Embodiment 161
N-benzyl-N-(2-hydroxyethyl)-5-(1H-indazole-5-base) isoxazole-3-methane amide
Prepare title compound with the method for describing among the embodiment 81B, wherein use 2-(benzylamino) ethanol to replace piperidines. 1H?NMR(300MHz，DMSO-d 6)δppm?13.37(s，1H)9.05(d，J＝8.48Hz，1H)8.40(s，1H)8.23(s，1H)7.89(d，J＝8.65，1.53Hz，1H)7.70(d，J＝8.82Hz，1H)7.22-7.45(m，6H)5.02-5.14(m，1H)4.98(t，J＝5.76Hz，1H)3.61-3.81(m，2H).MS(ESI+)m/z?349.0(M+H) +。
Embodiment 162
5-[1-benzyl-5-(2-aminomethyl phenyl)-1H-1,2,3-triazole-4-yl]-3-methyl isophthalic acid H-indazole
Embodiment 162A
1-(5-bromo-3-methyl isophthalic acid H-indazole-1-yl) ethyl ketone
(838mg 3.97mmol) is dissolved in methylene dichloride (15mL) and diisopropyl ethyl amine (0.7mL) with 5-bromo-3-methyl isophthalic acid H-indazole.(500uL, 5.29mmol), mixture at room temperature stirs and spends the night to add diacetyl oxide.Mixture dilutes with ethyl acetate, uses 1N sodium hydroxide, uses 1N hydrochloric acid then, uses the salt water washing then.The organic layer dried over sodium sulfate, removal of solvent under reduced pressure obtains title compound.MS(ESI+)m/z?252.7(M+H) +。
Embodiment 162B
1-(5-(1-benzyl-5-neighbour-tolyl-1H-1,2,3-triazole-4-yl)-3-methyl isophthalic acid H-indazole-1-yl) ethyl ketone
With embodiment 153A (436mg, 0.808mmol), embodiment 162A (205mg, 0.810mmol), dichloro two (triphenylphosphine) palladium (II) (56mg, 0.080mmol) and thiophene-2-carboxylic acid copper (239mg 1.25mmol) mixes under the nitrogen rare gas element in the 4mL phial in toluene (2.0mL).The sealing phial heated 30 minutes down at 150 ℃.Mixture is adsorbed on the silica gel, uses the silica gel chromatography purifying, the hexane solution gradient elution with the 10-50% ethyl acetate obtains title compound.MS(ESI+)m/z?422.6(M+H) +。
Embodiment 162C
5-[1-benzyl-5-(2-aminomethyl phenyl)-1H-1,2,3-triazole-4-yl]-3-methyl isophthalic acid H-indazole
With embodiment 162B (202mg 0.548mmol) is dissolved in tetrahydrofuran (THF) (5.0mL), methyl alcohol (0.5mL) and water (0.5mL), add potassium hydroxide (133mg, 2.37mmol).Mixture stirred 1 hour, with the methylene dichloride dilution, washed with water then.Organic layer is adsorbed on the silica gel, uses the silica gel chromatography purifying, the hexane solution gradient elution with the 30-80% ethyl acetate obtains title compound. 1H?NMR(300MHz，DMSO-d 6)δppm?12.63(s，1H)7.70(s，1H)7.44-7.52(m，1H)7.38-7.43(m，1H)7.29-7.38(m，4H)7.22-7.29(m，3H)6.89-6.96(m，J＝6.44，3.05Hz，2H)5.30-5.48(m，2H)2.32(s，3H)1.58(s，3H).MS(ESI+)m/z?380.1(M+H) +。
Embodiment 163
5-[1-benzyl-5-(2-aminomethyl phenyl)-1H-1,2,3-triazole-4-yl]-1H-indazole-3-amine
Embodiment 163A
5-(1-benzyl-5-neighbour-tolyl-1H-1,2,3-triazole-4-yl)-2-fluorobenzonitrile
With embodiment 153A (450mg, 0.834mmol), 5-bromo-2-fluorobenzonitrile (167mg, 0.835mmol), dichloro two (triphenylphosphine) palladium (II) (56mg, 0.080mmol) and thiophene-2-carboxylic acid copper (242mg 1.27mmol) mixes under the nitrogen rare gas element in phial at 4mL at toluene (2.0mL).The sealing phial heated 30 minutes down at 150 ℃.Mixture is adsorbed on the silica gel, uses the silica gel chromatography purifying, the hexane solution gradient elution with the 10-50% ethyl acetate obtains title compound.MS(ESI+)m/z?369.2(M+H) +。
Embodiment 163B
5-[1-benzyl-5-(2-aminomethyl phenyl)-1H-1,2,3-triazole-4-yl]-1H-indazole-3-amine
(202mg 0.548mmol) with ethanol (1.0mL) solution-treated of hydrazine hydrate (1.0mL), is heated to 60 ℃ of stirrings and spends the night with embodiment 163A.Mixture dilutes with methylene dichloride, washes with water.Organic layer is adsorbed on the silica gel, uses the silica gel chromatography purifying, the hexane solution gradient elution with the 35-85% ethyl acetate obtains title compound. 1H?NMR(300MHz，DMSO-d 6)δppm11.38(s，1H)8.11(s，1H)7.41-7.49(m，1H)7.33-7.40(m，J＝6.95，6.95Hz，1H)7.28-7.32(m，2H)7.21-7.28(m，3H)7.00-7.06(m，1H)6.86-6.95(m，3H)5.27-5.44(m，4H)1.58(s，3H).MS(ESI+)m/z?381.1(M+H) +。
Embodiment 164
2-{2-[1-(1H-indazole-5-yl)-1H-1,2,3-triazole-4-yl] ethyl }-1H-isoindole-1,3 (2H)-diketone
Prepare title compound with the method for describing among the embodiment 88, wherein use 2-(fourth-3-alkynyl) isoindoline-1, the 3-diketone replaces 3-phenyl-1-propine.Crude product is handled with the 25%TFA/ methylene dichloride, by the reversed-phase HPLC purifying, obtained title compound with acetonitrile/water 0.1%TFA linear gradient elution method. 1H?NMR(400MHz，DMSO-d 6)δppm?13.33(s，1H)8.65(s，1H)8.22(s，1H)8.18(d，J＝1.53Hz，1H)7.78-7.90(m，5H)7.71-7.75(m，1H)3.92(t，J＝7.21Hz，2H)3.08(t，J＝7.21Hz，2H).MS(ESI+)m/z?359.0(M+H) +。
Embodiment 165
5-{4-[(2, the 4-dichlorophenoxy) methyl]-1H-1,2, the 3-triazol-1-yl }-the 1H-indazole
Prepare title compound with the method for describing among the embodiment 88, wherein use 2,4-two chloro-1-(Propargyl oxygen base) benzene replaces 3-phenyl-1-propine.Crude product is handled with the 25%TFA/ methylene dichloride, by the reversed-phase HPLC purifying, obtained title compound with acetonitrile/water 0.1%TFA linear gradient elution method. 1HNMR(400MHz，DMSO-d 6)δppm?13.38(s，1H)8.93(s，1H)8.28(d，J＝1.53Hz，1H)8.23(s，1H)7.88(d，J＝8.90，1.84Hz，1H)7.76(d，J＝8.90Hz，1H)7.59(d，J＝2.46Hz，1H)7.39-7.49(m，2H)5.37(s，2H).MS(ESI+)m/z359.9(M+H) +。
Embodiment 166
5-{4-[(2, the 6-dichlorophenoxy) methyl]-1H-1,2, the 3-triazol-1-yl }-the 1H-indazole
Prepare title compound with the method for describing among the embodiment 88, wherein use 1,3-two chloro-2-(Propargyl oxygen base) benzene replaces 3-phenyl-1-propine.Crude product is handled with the 25%TFA/ methylene dichloride, by the reversed-phase HPLC purifying, obtained title compound with acetonitrile/water 0.1%TFA linear gradient elution method. 1HNMR(500MHz，DMSO-d 6)δppm?13.39(s，1H)8.97(s，1H)8.29(d，J＝1.53Hz，1H)8.24(s，1H)7.89(d，J＝9.00，1.98Hz，1H)7.76(d，J＝8.85Hz，1H)7.51-7.55(m，2H)7.19-7.26(m，J＝8.24，8.24Hz，1H)5.23(s，2H).MS(ESI+)m/z?359.9(M+H) +。
Embodiment 167
5-[5-(4-fluorophenyl)-1-(tetrahydrochysene-2H-pyrans-4-ylmethyl)-1H-1,2,3-triazole-4-yl]-the 1H-indazole
With embodiment 156B (168mg 0.401mmol) is dissolved in tetrahydrofuran (THF) (5.0mL), methyl alcohol (0.5mL) and water (0.5mL), add potassium hydroxide (138mg, 2.46mmol).Mixture stirred 1 hour, with the methylene dichloride dilution, washed with water.Organic layer is adsorbed on the silica gel, uses the silica gel chromatography purifying, the dichloromethane solution gradient elution with 0-7% methyl alcohol obtains title compound. 1HNMR(300MHz，DMSO-d 6)δppm?13.08(s，1H)8.02(s，1H)7.77(s，1H)7.50-7.58(m，2H)7.37-7.49(m，4H)4.11(d，J＝7.12Hz，2H)3.76(d，J＝11.53，2.71Hz，2H)3.11-3.24(m，2H)1.88-2.03(m，1H)1.30-1.43(m，J＝12.72，1.86Hz，2H)1.04-1.22(m，2H).MS(ESI+)m/z?378.1(M+H) +。
Embodiment 168
1-{[1-(1H-indazole-5-yl)-1H-1,2,3-triazole-4-yl] methyl }-the 1H-indazole
Embodiment 168A
1-(Propargyl)-1H-indazole
(530mg 4.49mmol) is dissolved in dimethyl formamide (4mL) with indazole.(5.78mmol), mixture stirred 10 minutes for 60% suspension in mineral oil, 231mg slowly to add sodium hydride.(toluene solution of 80%wt, 5.0mL), mixture at room temperature stirs and spends the night to add propargyl bromide.Mixture dilutes with ethyl acetate, with excessive water washing, is adsorbed on the silica gel, uses the silica gel chromatography purifying, and the hexane solution gradient elution with the 5-30% ethyl acetate obtains title compound.MS(ESI+)m/z?157.1(M+H) +。
Embodiment 168B
1-{[1-(1H-indazole-5-yl)-1H-1,2,3-triazole-4-yl] methyl }-the 1H-indazole
Prepare title compound with the method for describing among the embodiment 88, wherein replace 3-phenyl-1-propine with embodiment 168A. 1H?NMR(300MHz，DMSO-d 6)δppm?13.36(s，1H)8.78(s，1H)8.22(d，J＝2.03，0.68Hz，1H)8.20(s，1H)8.10(d，J＝1.02Hz，1H)7.80-7.87(m，2H)7.75-7.80(m，1H)7.68-7.74(m，1H)7.39-7.46(m，1H)7.13-7.19(m，1H)5.81(s，2H).MS(ESI+)m/z?316.0(M+H) +。
Embodiment 169
5-[1-benzyl-5-(piperidines-1-base carbonyl)-1H-1,2,3-triazole-4-yl]-the 1H-indazole
Prepare title compound with the method for describing among the embodiment 81B, wherein replace embodiment 81A, replace dimethyl formamide with tetrahydrofuran (THF) with embodiment 149C. 1H?NMR(300MHz，DMSO-d 6)δppm?13.20(s，1H)8.16(s，1H)7.95-8.00(m，J＝1.02Hz，1H)7.62-7.68(m，1H)7.57-7.63(m，1H)7.31-7.44(m，3H)7.24-7.30(m，2H)5.36-5.84(m，J＝69.17Hz，2H)3.43-3.59(m，2H)2.43-2.59(m，2H)1.17-1.46(m，J＝39.67Hz，4H)0.49-0.65(m，2H).MS(ESI+)m/z?387.1(M+H) +。
Embodiment 170
5-[5-(2-aminomethyl phenyl)-1-(tetrahydrochysene-2H-pyrans-4-ylmethyl)-1H-1,2,3-triazole-4-yl]-the 1H-indazole
Embodiment 170A
1-((tetrahydrochysene-2H-pyrans-4-yl) methyl)-5-neighbour-tolyl-4-(tributyl stannyl)-1H-1,2, the 3-triazole
With 2-ethynyl toluene (576mg 4.57mmol) joins 1,1,1-tributyl-N, N-tin methide amine (1.53g, 4.58mmol) in, mixture stirred 2 hours down at 70 ℃ in sealed tube.Mixture is chilled to room temperature, and phial goes sealing, stirs 10 minutes.(648mg 4.59mmol), reseals phial, is heated to 130 ℃ and spends the night to add embodiment 80A.Mixture silica gel chromatography purifying, the hexane solution gradient elution with the 5-50% ethyl acetate obtains title compound.MS(ESI+)m/z?548.4(M+H) +。
Embodiment 170B
1-(5-(1-((tetrahydrochysene-2H-pyrans-4-yl) methyl)-5-neighbour-tolyl-1H-1,2,3-triazole-4-yl)-1H-indazole-1-yl) ethyl ketone
With embodiment 170A (432mg, 0.791mmol), embodiment 87A (222mg, 0.776mmol), dichloro two (triphenylphosphine) palladium (II) (58mg, 0.083mmol) and thiophene-2-carboxylic acid copper (231mg 1.21mmol) mixes under the nitrogen rare gas element in the 4mL phial in toluene (2.0mL).The sealing phial heated 20 minutes down at 150 ℃.Mixture is adsorbed on the silica gel, uses the silica gel chromatography purifying, the hexane solution gradient elution with the 20-70% ethyl acetate obtains title compound.MS(ESI+)m/z?416.2(M+H) +。
Embodiment 170C
5-[5-(2-aminomethyl phenyl)-1-(tetrahydrochysene-2H-pyrans-4-ylmethyl)-1H-1,2,3-triazole-4-yl]-the 1H-indazole
With embodiment 170B (184mg 0.443mmol) is dissolved in tetrahydrofuran (THF) (3.0mL), methyl alcohol (0.3mL) and water (0.3mL), add potassium hydroxide (140mg, 2.50mmol).Mixture stirred 3 hours, with the methylene dichloride dilution, washed with water.Organic layer is adsorbed on the silica gel, uses the silica gel chromatography purifying, the hexane solution gradient elution with the 35-100% ethyl acetate obtains title compound. 1HNMR(300MHz，DMSO-d 6)δppm?13.08(s，1H)7.98(s，1H)7.68-7.74(m，J＝1.02，1.02Hz，1H)7.49-7.56(m，1H)7.45-7.49(m，3H)7.41-7.45(m，J＝7.46Hz，2H)4.10(d，J＝13.73，6.95Hz，1H)3.89(d，J＝13.90，7.80Hz，1H)3.77(d，J＝10.51，2.71Hz，2H)3.10-3.24(m，2H)1.92(s，3H)1.88-1.98(m，1H)1.26-1.43(m，2H)1.04-1.21(m，2H).MS(ESI+)m/z?374.1(M+H) +。
Embodiment 171
5-[5-(2-aminomethyl phenyl)-1-(tetrahydrochysene-2H-pyrans-4-ylmethyl)-1H-1,2,3-triazole-4-yl]-1H-indazole-3-amine
Embodiment 171A
2-fluoro-5-(1-((tetrahydrochysene-2H-pyrans-4-yl) methyl)-5-neighbour-tolyl-1H-1,2,3-triazole-4-yl) cyanobenzene
With embodiment 170A (411mg, 0.752mmol), 5-bromo-2-fluorobenzonitrile (151mg, 0.755mmol), dichloro two (triphenylphosphine) palladium (II) (52mg, 0.074mmol) and thiophene-2-carboxylic acid copper (223mg 1.17mmol) mixes under the nitrogen rare gas element in the 4mL phial in toluene (2.0mL).The sealing phial is heated to 150 ℃ of reactions 30 minutes.Mixture is adsorbed on the silica gel, uses the silica gel chromatography purifying, the hexane solution gradient elution with the 10-50% ethyl acetate obtains title compound.MS(ESI+)m/z?377.6(M+H) +。
Embodiment 171B
5-[5-(2-aminomethyl phenyl)-1-(tetrahydrochysene-2H-pyrans-4-ylmethyl)-1H-1,2,3-triazole-4-yl]-1H-indazole-3-amine
With embodiment 171A (175mg, 0.465mmol) ethanol (2.0mL) solution-treated of usefulness hydrazine hydrate (2.0mL), mixture heating up to 65 ℃ stirring 2 hours.Mixture dilutes with methylene dichloride, washes with water.Organic layer is adsorbed on the silica gel, uses the silica gel chromatography purifying, the dichloromethane solution gradient elution with 1-8% methyl alcohol obtains title compound. 1H?NMR(300MHz，DMSO-d 6)δppm?11.39(s，1H)8.08(s，1H)7.45-7.55(m，1H)7.37-7.45(m，3H)7.01-7.08(m，J＝8.48Hz，1H)6.89-6.97(m，1H)5.34(s，2H)4.09(d，J＝13.73，6.95Hz，1H)3.89(d，J＝13.73，7.63Hz，1H)3.70-3.81(m，2H)3.08-3.24(m，2H)1.91(s，3H)1.84-1.99(m，1H)1.22-1.41(m，2H)1.04-1.20(m，2H).MS(ESI+)m/z?389.1(M+H) +。
Embodiment 172
5-[1-benzyl-5-(morpholine-4-base carbonyl)-1H-1,2,3-triazole-4-yl]-the 1H-indazole
Prepare title compound with the method for describing among the embodiment 81B, wherein replace embodiment 81A with embodiment 149C, the pyridine of morpholino TEPA, tetrahydrofuran (THF) replaces dimethyl formamide. 1H?NMR(300MHz，DMSO-d 6)δppm?13.22(s，1H)8.18(s，1H)7.95-8.03(m，1H)7.64-7.70(m，1H)7.57-7.64(m，1H)7.33-7.45(m，3H)7.24-7.31(m，2H)5.76(s，1H)5.52(s，1H)3.33-3.59(m，4H)2.61-2.74(m，2H)2.45-2.59(m，2H).MS(ESI+)m/z?389.1(M+H) +。
Embodiment 173
5-[1-benzyl-5-(4-p-methoxy-phenyl)-1H-1,2,3-triazole-4-yl]-1H-indazole-3-amine
Cover under argon gas, contain embodiment 125B (50mg, 0.12mmol), 4-anisole ylboronic acid (20mg, 0.13mmol), PdCl 2(dppf) methylene dichloride (10mg, 0.01mmol) and salt of wormwood (33mg, the phial of DME 0.24mmol) (2mL) and water (0.2mL) solution, in heating oscillator 80 ℃ of down heating 48 hours.The pressure reducing and steaming solvent, product by the reversed-phase HPLC purifying, obtains title compound with acetonitrile/water 0.1%TFA linear gradient elution method. 1H?NMR(400MHz，DMSO-d 6)δppm?11.85(s，1H)8.18(s，1H)7.26-7.34(m，3H)7.19-7.25(m，2H)7.16-7.19(m，2H)7.02(t，J＝8.13Hz，4H)5.47(s，2H)3.80(s，3H).MS(ESI+)m/z?397.1(M+H) +。
Embodiment 174
N-[(1S)-1-benzyl-2-hydroxyethyl]-5-(1H-indazole-5-base) isoxazole-3-methane amide
Prepare title compound with the method for describing among the embodiment 81B, wherein use (S)-(-)-2-amino-3-phenyl-1-propyl alcohol to replace piperidines. 1H?NMR(300MHz，DMSO-d 6)δppm?13.36(s，1H)8.47(d，J＝8.82Hz，1H)8.38(s，1H)8.22(s，1H)7.87(d，J＝8.82，1.70Hz，1H)7.69(d，J＝8.82Hz，1H)7.23-7.31(m，3H)7.22(s，1H)7.12-7.21(m，1H)4.90(t，J＝5.59Hz，1H)4.07-4.28(m，1H)3.40-3.58(m，2H)2.89-3.00(m，1H)2.75-2.86(m，1H).MS(ESI+)m/z?363.0(M+H) +。
Embodiment 175
N-[(1S, 2R)-2-hydroxyl-2,3-dihydro-1H-indenes-1-yl]-5-(1H-indazole-5-base) isoxazole-3-methane amide
Prepare title compound with the method for describing among the embodiment 81B, wherein use (1S, 2R)-(-)-cis-1-amino-2-indanol replacement piperidines. 1H?NMR(300MHz，DMSO-d 6)δppm?13.38(s，1H)8.42(s，1H)8.24(s，1H)8.16(d，J＝8.48Hz，1H)7.91(d，J＝8.82，1.70Hz，1H)7.71(d，J＝8.48Hz，1H)7.45(s，1H)7.16-7.32(m，4H)5.36-5.47(m，2H)4.50-4.61(m，1H)3.14(d，J＝15.43，5.26Hz，1H)2.90(d，J＝16.28，1.70Hz，1H).MS(ESI+)m/z?361.0(M+H) +。
Embodiment 176
5-{3-[(3-phenylmorpholine-4-yl) carbonyl] isoxazole-5-base }-the 1H-indazole
Prepare title compound with the method for describing among the embodiment 81B, wherein replace piperidines with 3-phenylmorpholine hydrochloride. 1H?NMR(300MHz，DMSO-d 6)δppm?13.38(s，1H)8.32-8.46(m，1H)8.24(s，1H)7.81-7.96(m，1H)7.70(d，J＝8.82Hz，1H)7.37-7.55(m，4H)7.26-7.37(m，2H)5.34-5.71(m，1H)4.51(d，J＝13.22Hz，1H)3.78-4.39(m，3H)3.59(t，J＝11.36Hz，1H)3.33-3.41(m，1H).MS(ESI+)m/z?375.0(M+H) +。
Embodiment 177
N-benzyl-5-(1H-indazole-5-base) isoxazole-3-methane amide
Prepare title compound with the method for describing among the embodiment 81B, wherein replace piperidines with benzyl amine. 1H?NMR(300MHz，DMSO-d 6)δppm?13.36(s，1H)9.35(t，J＝6.27Hz，1H)8.40(s，1H)8.23(s，1H)7.89(d，J＝8.82，1.70Hz，1H)7.69(d，J＝8.82Hz，1H)7.33-7.40(m，4H)7.32(s，1H)7.22-7.30(m，1H)4.48(d，J＝6.10Hz，2H).MS(ESI+)m/z?319.0(M+H) +。
Embodiment 178
((1S)-2-{[5-(1H-indazole-5-base) isoxazole-3-base] carbonyl }-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-1-yl) methyl alcohol
Prepare title compound with the method for describing among the embodiment 81B, wherein use (S)-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-1-yl) methyl alcohol replacement piperidines.MS(ESI+)m/z?435.1(M+H) +。
Embodiment 179
N-[(1R)-3-hydroxyl-1-phenyl propyl]-5-(1H-indazole-5-base) isoxazole-3-methane amide
Prepare title compound with the method for describing among the embodiment 81B, wherein use (R)-3-amino-3-phenyl propanol to replace piperidines. 1H?NMR(300MHz，DMSO-d 6)δppm?13.37(s，1H)9.24(d，J＝8.48Hz，1H)8.39(s，1H)8.23(s，1H)7.88(d，J＝8.82，1.70Hz，1H)7.69(d，J＝8.82Hz，1H)7.38-7.46(m，2H)7.34(t，J＝7.46Hz，2H)7.19-7.30(m，2H)5.09-5.27(m，1H)4.62(t，J＝4.92Hz，1H)3.37-3.52(m，2H)2.00-2.16(m，1H)1.84-2.00(m，1H).MS(ESI+)m/z?363.1(M+H) +。
Embodiment 180
N-[(1S)-3-hydroxyl-1-phenyl propyl]-5-(1H-indazole-5-base) isoxazole-3-methane amide
Prepare title compound with the method for describing among the embodiment 81B, wherein use (S)-3-amino-3-phenyl propanol to replace piperidines. 1H?NMR(300MHz，DMSO-d 6)δppm?13.36(s，1H)9.24(d，J＝8.14Hz，1H)8.39(s，1H)8.22(s，1H)7.88(d，J＝8.65，1.53Hz，1H)7.69(d，J＝8.81Hz，1H)7.37-7.45(m，2H)7.29-7.37(m，2H)7.19-7.29(m，2H)5.08-5.30(m，1H)4.55-4.68(m，1H)3.37-3.51(m，2H)2.00-2.14(m，1H)1.83-1.99(m，1H).MS(ESI+)m/z?363.0(M+H) +。
Embodiment 181
N-2,3-dihydro-1H-indenes-1-base-5-(1H-indazole-5-base) isoxazole-3-methane amide
Prepare title compound with the method for describing among the embodiment 81B, wherein replace piperidines with the 1-aminoidan. 1H?NMR(300MHz，DMSO-d 6)δppm?13.37(s，1H)9.13(d，J＝8.14Hz，1H)8.39(s，1H)8.23(s，1H)7.89(d，J＝8.82，1.36Hz，1H)7.70(d，J＝8.82Hz，1H)7.35(s，1H)7.15-7.32(m，4H)5.55(q，J＝7.91Hz，1H)2.95-3.08(m，1H)2.76-2.94(m，1H)2.37-2.49(m，1H)2.01-2.15(m，1H).MS(ESI+)m/z?345.0(M+H) +。
Embodiment 182
N-2,3-dihydro-1H-indenes-2-base-5-(1H-indazole-5-base) isoxazole-3-methane amide
Prepare title compound with the method for describing among the embodiment 81B, wherein replace piperidines with the 2-aminoidan. 1H?NMR(300MHz，DMSO-d 6)δppm?13.37(s，1H)9.08(d，J＝7.46Hz，1H)8.39(s，1H)8.23(s，1H)7.89(d，J＝8.82，1.70Hz，1H)7.69(d，J＝8.82Hz，1H)7.31(s，1H)7.10-7.28(m，4H)4.63-4.79(m，1H)3.24(d，J＝15.77，7.63Hz，2H)2.96-3.08(m，2H).MS(ESI+)m/z?345.0(M+H) +。
Embodiment 183
5-(1H-indazole-5-yl)-N-(1-phenyl propyl) isoxazole-3-methane amide
Prepare title compound with the method for describing among the embodiment 81B, wherein replace piperidines with α-Ethylbenzyl amine. 1H?NMR(300MHz，DMSO-d 6)δppm?13.36(s，1H)9.18(d，J＝8.82Hz，1H)8.38(s，1H)8.22(s，1H)7.88(d，J＝8.82，1.36Hz，1H)7.69(d，J＝8.48Hz，1H)7.39-7.48(m，2H)7.34(t，J＝7.29Hz，2H)7.19-7.29(m，2H)4.84-5.00(m，1H)1.69-2.04(m，2H)0.91(t，J＝7.29Hz，3H).MS(ESI+)m/z?347.1(M+H) +。
Embodiment 184
5-{1-benzyl-5-[3-(dimethylamino) phenyl]-1H-1,2,3-triazole-4-yl }-1H-indazole-3-amine
Prepare the tfa salt of title compound with the method for describing among the embodiment 173, wherein use 3-(dimethylamino) phenyl-boron dihydroxide to replace 4-anisole ylboronic acid. 1H?NMR(500MHz，DMSO-d 6)δppm?11.52(s，1H)8.17(s，1H)7.22-7.35(m，4H)7.08-7.15(m，2H)7.03(d，J＝6.71Hz，2H)6.82(d，J＝8.39，2.29Hz，1H)6.48-6.54(m，2H)5.47(s，2H)2.78(s，6H).MS(ESI+)m/z?410.2(M+H) +。
Embodiment 185
5-{1-benzyl-5-[4-(dimethylamino) phenyl]-1H-1,2,3-triazole-4-yl }-1H-indazole-3-amine
Prepare the tfa salt of title compound with the method for describing among the embodiment 173, wherein use 4-(dimethylamino) phenyl-boron dihydroxide to replace 4-anisole ylboronic acid. 1H?NMR(500MHz，DMSO-d 6)δppm?11.65(s，1H)8.17(s，1H)7.23-7.38(m，3H)7.12-7.16(m，2H)7.01-7.09(m，4H)6.74-6.78(m，2H)5.45(s，2H)2.95(s，6H).MS(ESI+)m/z410.2(M+H) +。
Embodiment 186
N-{3-[4-(3-amino-1H-indazole-5-yl)-1-benzyl-1H-1,2,3-triazole-5-yl] phenyl } ethanamide
Prepare title compound with the method for describing among the embodiment 173, wherein replace 4-anisole ylboronic acid with 3-acetyl amino phenyl ylboronic acid. 1H?NMR(500MHz，DMSO-d 6)δppm?10.05(s，1H)8.14(s，1H)7.69(d，J＝8.54Hz，1H)7.54(s，1H)7.41(t，J＝7.93Hz，1H)7.24-7.32(m，3H)7.08-7.16(m，2H)6.93-7.04(m，3H)5.48(s，2H)2.01(s，3H).MS(ESI+)m/z?424.2(M+H) +。
Embodiment 187
N-{4-[4-(3-amino-1H-indazole-5-yl)-1-benzyl-1H-1,2,3-triazole-5-yl] phenyl } ethanamide
Prepare title compound with the method for describing among the embodiment 173, wherein replace 4-anisole ylboronic acid with 4-acetyl amino phenyl ylboronic acid. 1H?NMR(500MHz，DMSO-d 6)δppm?10.14(s，1H)8.07(s，1H)7.66(d，J＝8.85Hz，2H)7.24-7.32(m，3H)7.18-7.22(m，2H)7.04-7.11(m，2H)6.98-7.02(m，2H)5.48(s，2H)5.35(s，2H)2.04-2.10(m，3H).MS(ESI+)m/z?424.1(M+H) +。
Embodiment 188
5-{1-benzyl-5-[3-(1H-pyrazol-1-yl) phenyl]-1H-1,2,3-triazole-4-yl }-1H-indazole-3-amine
Prepare title compound with the method for describing among the embodiment 173, wherein use 3-(1H-pyrazol-1-yl) phenyl-boron dihydroxide to replace 4-anisole ylboronic acid. 1H?NMR(500MHz，DMSO-d 6)δppm11.40(s，1H)8.45(d，J＝2.75Hz，1H)8.09(s，1H)7.99(d，J＝8.24，1.53Hz，1H)7.80-7.85(m，1H)7.74(d，J＝1.83Hz，1H)7.56(t，J＝7.93Hz，1H)7.20-7.30(m，3H)7.06-7.16(m，3H)6.98-7.04(m，2H)6.53-6.54(m，1H)5.55(s，2H)5.35(s，2H).MS(ESI+)m/z?433.2(M+H) +。
Embodiment 189
5-[1-benzyl-5-(1-methyl isophthalic acid H-pyrazoles-4-yl)-1H-1,2,3-triazole-4-yl]-1H-indazole-3-amine
Prepare title compound with the method for describing among the embodiment 173, wherein replace 4-anisole ylboronic acid with 1-methyl isophthalic acid H-pyrazoles-4-ylboronic acid. 1H?NMR(500MHz，DMSO-d 6)δppm11.78(s，1H)8.11(s，1H)7.87(s，1H)7.43(s，1H)7.27-7.41(m，4H)7.24(d，J＝8.54Hz，1H)7.05-7.11(m，J＝7.02Hz，2H)5.54(s，2H)3.86(s，3H).MS(ESI+)m/z?370.9(M+H) +。
Embodiment 190
3-[4-(3-amino-1H-indazole-5-yl)-1-benzyl-1H-1,2,3-triazole-5-yl]-the N-phenylbenzamaide
Prepare title compound with the method for describing among the embodiment 173, wherein use 3-(phenyl amino formyl radical) phenyl-boron dihydroxide to replace 4-anisole ylboronic acid. 1H?NMR(500MHz，DMSO-d 6)δppm?11.41(s，1H)10.22(s，1H)8.07-8.12(m，2H)7.95(s，1H)7.73(d，J＝7.63Hz，2H)7.60(t，J＝7.78Hz，1H)7.43(d，J＝7.63Hz，1H)7.32-7.39(m，2H)7.21-7.30(m，3H)7.05-7.15(m，3H)7.00(d，J＝6.71Hz，2H)5.54(s，2H)5.36(s，2H).MS(ESI+)m/z?486.2(M+H) +。
Embodiment 191
3-[4-(3-amino-1H-indazole-5-yl)-1-benzyl-1H-1,2,3-triazole-5-yl]-N-benzyl benzamide
Prepare title compound with the method for describing among the embodiment 173, wherein use 3-(benzylamino formyl radical) phenyl-boron dihydroxide to replace 4-anisole ylboronic acid. 1H?NMR(500MHz，DMSO-d 6)δppm?11.41(s，1H)9.04(t，J＝5.95Hz，1H)8.07(s，1H)8.01(d，J＝7.93Hz，1H)7.85(s，1H)7.56(t，J＝7.78Hz，1H)7.41(d，J＝7.63Hz，1H)7.21-7.35(m，8H)7.01-7.11(m，2H)6.96(d，J＝7.32，2.14Hz，2H)5.52(s，2H)5.35(s，2H)4.45(d，J＝5.80Hz，2H).MS(ESI+)m/z?500.2(M+H) +。
Embodiment 192
5-[1-benzyl-5-(1-Methyl-1H-indole-5-yl)-1H-1,2,3-triazole-4-yl]-1H-indazole-3-amine
Prepare the tfa salt of title compound with the method for describing among the embodiment 173, wherein replace 4-anisole ylboronic acid with 1-Methyl-1H-indole-5-ylboronic acid. 1H?NMR(500MHz，DMSO-d 6)δppm?11.35(s，1H)8.14(s，1H)7.54(d，J＝8.54Hz，1H)7.50(d，J＝1.53Hz，1H)7.42(d，J＝3.05Hz，1H)7.24-7.33(m，3H)6.97-7.05(m，5H)6.44(d，J＝2.75Hz，1H)5.46(s，2H)5.33(s，2H)3.83(s，3H).MS(ESI+)m/z420.1(M+H) +。
Embodiment 193
5-[1-benzyl-5-(3-p-methoxy-phenyl)-1H-1,2,3-triazole-4-yl]-1H-indazole-3-amine
Prepare title compound with the method for describing among the embodiment 173, wherein replace 4-anisole ylboronic acid with 3-anisole ylboronic acid. 1H?NMR(500MHz，DMSO-d 6)δppm?11.40(s，1H)8.08(s，1H)7.34-7.40(m，1H)7.24-7.32(m，3H)7.03-7.11(m，3H)6.98-7.02(m，2H)6.80-6.85(m，2H)5.49(s，2H)5.35(s，2H)3.66(s，3H).MS(ESI+)m/z?397.1(M+H) +。
Embodiment 194
5-[1-benzyl-5-(3-morpholine-4-base phenyl)-1H-1,2,3-triazole-4-yl]-1H-indazole-3-amine
Cover under argon gas, contain embodiment 125B (35mg, 0.09mmol), 3-morpholino phenyl-boron dihydroxide (21mg, 0.09mmol), PdCl 2(dppf) methylene dichloride (7mg, 0.009mmol) and salt of wormwood (24mg, the phial of DME 0.18mmol) (1mL) and water (0.1mL) solution, in heating oscillator 80 ℃ of down heating 3 days.The pressure reducing and steaming solvent, product by the reversed-phase HPLC purifying, obtains the tfa salt of title compound with acetonitrile/water 0.1%TFA linear gradient elution method. 1H?NMR(500MHz，DMSO-d 6)δppm?11.52(s，1H)8.14(s，1H)7.26-7.34(m，4H)6.98-7.12(m，5H)6.67-6.75(m，2H)5.47(s，2H)3.57-3.73(m，4H)2.91-3.03(m，4H).MS(ESI+)m/z?452.2(M+H) +。
Embodiment 195
5-[3-(1,3-dihydro-2H-isoindole-2-base carbonyl) isoxazole-5-base]-the 1H-indazole
Prepare title compound with the method for describing among the embodiment 81B, wherein replace piperidines with isoindoline. 1H?NMR(300MHz，DMSO-d 6)δppm?13.38(s，1H)8.43(s，1H)8.25(s，1H)7.93(d，J＝8.82，1.36Hz，1H)7.71(d，J＝8.48Hz，1H)7.30-7.47(m，5H)5.18(s，2H)4.92(s，2H).MS(ESI+)m/z?331.0(M+H) +。
Embodiment 196
5-{3-[(4-methyl-2-phenylpiperazine-1-yl) carbonyl] isoxazole-5-base }-the 1H-indazole
Prepare title compound with the method for describing among the embodiment 81B, wherein replace piperidines with the 1-methyl-3-phenyl piperazine. 1H?NMR(300MHz，DMSO-d 6)δppm?13.12(s，1H)8.28-8.36(m，1H)8.18(s，1H)7.83(d，J＝8.79，1.46Hz，1H)7.67(d，J＝8.79Hz，1H)7.48(d，J＝7.69Hz，2H)7.30-7.40(m，2H)7.21-7.29(m，1H)7.14(s，1H)5.56-5.73(m，J＝5.86Hz，1H)3.99-4.19(m，J＝8.42Hz，1H)3.38-3.47(m，1H)3.05-3.21(m，J＝7.69Hz，1H)2.80(d，J＝11.72Hz，1H)2.41(d，J＝12.08，4.39Hz，1H)2.24(s，3H)2.02-2.16(m，1H).MS(ESI+)m/z?388.1(M+H) +。
Embodiment 197
1-{[1-benzyl-4-(1H-indazole-5-yl)-1H-1,2,3-triazole-5-yl] carbonyl } piperidines-4-amine
Embodiment 197A
1-(1-benzyl-4-(1H-indazole-5-yl)-1H-1,2,3-triazole-5-carbonyl) piperidin-4-yl t-butyl carbamate
Prepare title compound with the method for describing among the embodiment 81B, wherein replace embodiment 81B, replace piperidines with the 4-Boc-amino piperidine with embodiment 149C.MS(ESI+)m/z?502.3(M+H) +。
Embodiment 197B
1-{[1-benzyl-4-(1H-indazole-5-yl)-1H-1,2,3-triazole-5-yl] carbonyl } piperidines-4-amine
(101mg 0.201mmol) is dissolved in the dioxane (4mL) and methyl alcohol (1mL) solution of 4M hydrochloric acid, at room temperature stirs 2 hours with embodiment 197A.Removal of solvent under reduced pressure obtains the HCl salt of title compound. 1H?NMR(300MHz，DMSO-d 6)δppm?8.18(s，1H)7.92-8.08(m，J＝1.36Hz，3H)7.53-7.70(m，2H)7.24-7.47(m，5H)5.40-5.73(m，J＝3.39Hz，2H)4.34-4.63(m，1H)3.44-3.53(m，J＝3.39Hz，1H)2.95-3.17(m，2H)2.76-2.94(m，J＝11.02，11.02Hz，1H)1.87-2.03(m，J＝11.87Hz，1H)1.30-1.52(m，J＝10.85Hz，2H)0.66-0.91(m，J＝10.17Hz，1H).MS(ESI+)m/z?402.2(M+H) +。
Embodiment 198
N-[5-(1-benzyl-5-phenyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl] benzamide
Embodiment 198A
3-amino-5-(1-benzyl-5-phenyl-1H-1,2,3-triazole-4-yl)-1H-indazole-1-t-butyl formate
(200mg, 0.55mmol) and N, (5mg 0.04mmol) is dissolved in methylene dichloride to N-lutidine-4-amine with embodiment 102B.Mixture at room temperature stirs, and dropwise adds two-tertiary butyl, two carbonic ethers (120mg, 0.55mmol) solution in the 5mL methylene dichloride simultaneously.Reaction mixture at room temperature stirred 8 hours, and vacuum concentration is dissolved in methylene dichloride (10mL), and (1N is 10mL) with saturated NaHCO with rare HCl aqueous solution 3The aqueous solution (10mL) washing.Concentrate organic layer, with reversed-phase HPLC (CH 3CN/H 2O/NH 4OAc) purifying obtains title compound. 1H?NMR(300MHz，DMSO-d 6)δppm?8.29(s，2H)，7.43-7.59(m，3H)，7.23-7.38(m，6H)，6.98(d，J＝7.17，2.39Hz，2H)，6.38(s，2H)，5.52(s，2H)，1.55(s，9H).MS(ESI+)m/z?467(M+H) +。
Embodiment 198B
N-[5-(1-benzyl-5-phenyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl] benzamide
With embodiment 198A (37.5mg, 0.08mmol) and pyridine (12.7mg 0.16mmol) is dissolved in methylene dichloride (2mL).Mixture at room temperature stirs.In mixture, add Benzoyl chloride (14mg, 0.1mmol).Reaction mixture at room temperature stirs and spends the night, and vacuum concentration is with reversed-phase HPLC (CH 3CN/H 2O/NH 4OAc) purifying obtains the precursor that Boc protects.With 1: 1 the TFA/ methylene dichloride (2mL) handled described precursor 1 hour, vacuum concentration obtains the tfa salt of title compound. 1H?NMR(300MHz，DMSO-d 6)δppm?12.84(s，1H)，10.70(s，1H)，8.01(d，J＝6.99Hz，2H)，7.87(s，1H)，7.50-7.69(m，3H)，7.36-7.48(m，5H)，7.18-7.35(m，5H)，6.92-7.03(m，2H)，5.48(s，2H).MS(ESI+)m/z?471(M+H) +。
Embodiment 199
N-[5-(1-benzyl-5-phenyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl] benzsulfamide
Prepare title compound with the method for describing among the embodiment 198B, wherein replace Benzoyl chloride with benzene sulfonyl chloride. 1H?NMR(300MHz，DMSO-d 6)δppm?12.69(s，1H)，10.61(s，1H)，7.99(s，1H)，7.70-7.76(m，2H)，7.45-7.62(m，6H)，7.24-7.36(m，7H)，6.99(d，J＝6.99，2.21Hz，2H)，5.50(s，2H).MS(ESI+)m/z?507(M+H) +。
Embodiment 200
N-[5-(1-benzyl-5-phenyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-N '-(4-p-methoxy-phenyl) urea
With embodiment 198A (25mg 0.54mmol) is dissolved in dioxane (2mL), in solution, add 1-isocyanato (isocyanato)-4-anisole (24mg, 0.16mmol).Reaction mixture stirred 12 hours down at 80 ℃, concentrated, with reversed-phase HPLC (CH 3CN/H 2O/NH 4OAc) purifying obtains the precursor that Boc protects.With 1: 1 the TFA/ methylene dichloride (2mL) handled described precursor 1 hour, vacuum concentration obtains the tfa salt of title compound. 1H?NMR(300MHz，DMSO-d 6)δppm?12.54(s，1H)，9.51(s，1H)，9.42(s，1H)，8.28(s，1H)，7.45-7.51(m，3H)，7.36-7.42(m，2H)，7.24-7.35(m，7H)，6.98(d，J＝7.17，2.39Hz，2H)，6.87-6.94(m，2H)，5.50(s，2H)，3.74(s，3H).MS(ESI+)m/z?516(M+H) +。
Embodiment 201
N-[5-(1-benzyl-5-phenyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl] butyramide
Prepare the tfa salt of title compound with the method for describing among the embodiment 198B, wherein replace Benzoyl chloride with butyryl chloride. 1H?NMR(300MHz，DMSO-d 6)δppm?10.77-10.84(m，1H)，8.07(s，1H)，7.97(d，J＝8.82Hz，1H)，7.64(d，J＝8.82，1.47Hz，1H)，7.43-7.57(m，3H)，7.22-7.38(m，5H)，6.91-7.06(m，2H)，5.50(s，2H)，2.33(t，J＝7.17Hz，2H)，1.54-1.60(m，2H)，0.91(t，J＝7.35Hz，3H).MS(ESI+)m/z437(M+H) +。
Embodiment 202
N-[5-(1-benzyl-5-phenyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-the 2-methyl propanamide
Prepare title compound with the method for describing among the embodiment 198B, wherein replace Benzoyl chloride with isobutyryl chloride. 1H?NMR(300MHz，DMSO-d 6)δppm?12.66(s，1H)，10.12(s，1H)，7.80(s，1H)，7.42-7.55(m，4H)，7.33-7.39(m，1H)，7.22-7.32(m，5H)，6.97(d，J＝6.99，2.57Hz，2H)，5.48(s，1H)，2.59-2.69(m，1H)，1.07(d，J＝6.99Hz，6H).MS(ESI+)m/z?437(M+H) +。
Embodiment 203
N-[5-(1-benzyl-5-phenyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl] cyclopropane carboxamide
Prepare title compound with the method for describing among the embodiment 198B, wherein replace Benzoyl chloride with the cyclopropyl formyl chloride. 1H?NMR(300MHz，DMSO-d 6)δppm?10.45-10.64(s，1H)，7.91(s，1H)，7.43-7.55(m，3H)，7.31-7.43(m，2H)，7.23-7.30(m，5H)，6.97(d，J＝7.17，2.39Hz，2H)，5.48(s，2H)，1.77-1.91(m，1H)，0.69-0.87(m，4H).MS(ESI+)m/z?435(M+H) +。
Embodiment 204
N-[1-benzoyl-5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl] benzamide
(33mg 0.1mmol) is dissolved in tetrahydrofuran (THF) (0.6mL) with embodiment 89B in the CEM microwave tube.(28mg, 0.2mmol), mixture heated 15 minutes down at 120 ℃ in the CEM-Discover microwave to add Benzoyl chloride.Reaction mixture is chilled to room temperature, concentrates.Residue reversed-phase HPLC (CH 3CN/H 2O/NH 4OAc) purifying obtains title compound. 1H?NMR(300MHz，DMSO-d 6)δppm?11.35(s，1H)，8.55(d，J＝8.82Hz，1H)，8.36(s，1H)，8.17(d，J＝8.64，1.65Hz，1H)，8.06(d，J＝7.54，2.39Hz，4H)，7.51-7.72(m，6H)，7.26-7.45(m，5H)，5.71(s，2H)，1.76-1.87(m，1H)，1.11(d，J＝6.62Hz，2H)，0.44(d，J＝4.41Hz，2H).MS(ESI+)m/z?539(M+H) +。
Embodiment 205
N-[5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-the 3-fluorobenzamide
Embodiment 205A
3-amino-5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazole-4-yl)-1H-indazole-1-t-butyl formate
Prepare title compound with the method for describing among the embodiment 198A, wherein replace embodiment 102A with embodiment 89B. 1H?NMR(300MHz，DMSO-d 6)δppm?8.26(s，1H)，7.96-8.07(m，1H)，7.86-7.95(m，1H)，7.35-7.46(m，3H)，7.28-7.35(m，2H)，6.35-6.47(m，2H)，5.70(s，2H)，1.72-1.84(m，1H)，1.60(s，9H)，0.99-1.10(d，J＝1.84Hz，2H)，0.38(d，J＝3.68Hz，2H).MS(ESI+)m/z?431(M+H) +。
Embodiment 205B
N-[5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-the 3-fluorobenzamide
With embodiment 205A (25mg, 0.058mmol) and pyridine (9.2mg 0.116mmol) is dissolved in methylene dichloride (1mL).Mixture at room temperature stirs, and adding 3-fluorobenzoyl chloride in mixture (11.1mg, 0.58mmol).Reaction mixture at room temperature stirs and spends the night, and concentrates, with reversed-phase HPLC (CH 3CN/H 2O/NH 4OAc) purifying obtains the precursor that Boc protects.With 1: 1 the TFA/ methylene dichloride (2mL) handled described precursor 1 hour, vacuum concentration obtains the tfa salt of title compound. 1HNMR(300MHz，DMSO-d 6)δppm?10.58(s，1H)，7.75(s，1H)，7.51-7.60(m，1H)，7.46(d，J＝8.82，1.47Hz，1H)，7.15-7.28(m，2H)，7.10(d，J＝2.21Hz，1H)，6.88-7.05(m，6H)，5.31(s，2H)，1.35-1.47(m，J＝5.15Hz，1H)，0.68(d，J＝8.27，1.65Hz，2H)，0.03(d，J＝5.52Hz，2H).MS(ESI+)m/z?453(M+H) +。
Embodiment 206
N-[5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl] benzamide
Prepare title compound with the method for describing among the embodiment 205B, wherein replace the 3-fluorobenzoyl chloride with Benzoyl chloride. 1H?NMR(300MHz，DMSO-d 6)δppm?12.89(s，1H)，10.83(s，1H)，8.02-8.15(m，3H)，7.83(d，J＝8.82，1.47Hz，1H)，7.50-7.66(m，4H)，7.24-7.43(m，5H)，5.67(s，2H)，1.77(m，1H)，0.99-1.10(m，2H)，0.39(m，2H).MS(ESI+)m/z?435(M+H) +。
Embodiment 207
N-benzyl-5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-amine
To embodiment 89B (18.3mg, add in dimethyl formamide 0.05mmol) (2mL) solution acetate (15mg, 0.25mmol) and phenyl aldehyde (6.4mg, 0.06mmol).Reaction mixture at room temperature stirs and spends the night.In reaction mixture, add sodium triacetoxy borohydride (NaBH (OAc) 3, 32mg, 0.15mmol).Reactant at room temperature stirred 3 hours, concentrated, with reversed-phase HPLC (CH 3CN/H 2O/NH 4OAc) purifying obtains title compound. 1H?NMR(300MHz，DMSO-d 6)δppm?13.09(s，1H)，9.24(s，1H)，8.02-8.10(m，3H)，7.84-7.90(m，1H)，7.49-7.67(m，4H)，7.25-7.45(m，5H)，5.70(s，2H)，3.30(s，2H)，1.88-1.95(m，1H)，1.01-1.09(m，2H)，0.43(d，J＝4.04Hz，2H).MS(ESI+)m/z?421(M+H) +。
Embodiment 208
N-[(1R)-1-benzyl-2-hydroxyethyl]-5-(1H-indazole-5-base) isoxazole-3-methane amide
Prepare title compound with the method for describing among the embodiment 81B, (37mg 0.245mmol) replaces piperidines wherein to use (R)-(+)-2-amino-3-phenyl-1-propyl alcohol. 1H?NMR(300MHz，DMSO-d 6)δppm?13.36(s，1H)8.46(d，J＝8.82Hz，1H)8.37(s，1H)8.22(s，1H)7.87(dd，J＝8.82，1.36Hz，1H)7.69(d，J＝8.82Hz，1H)7.12-7.35(m，6H)4.89(t，J＝5.59Hz，1H)4.13-4.25(m，1H)3.40-3.58(m，2H)2.90-2.99(m，1H)2.74-2.87(m，1H).MS(ESI+)m/z?363.0(M+H) +。
Embodiment 209
5-(1-benzyl-1H-pyrazoles-4-yl)-1H-indazole
Embodiment 209A
1-(5-bromo-1H-indazole-1-yl) ethyl ketone
(25.0g 134mmol) is dissolved in chloroform (250mL) to 4-bromo-2-aminotoluene, and mixture is chilled to 5 ℃.(35mL, 343mmol), mixture rises to room temperature dropwise to add diacetyl oxide.Add potassium acetate 3.97g, 40.4mmol) and Isopentyl nitrite (35mL, 262mmol), mixture is 70 ℃ of following heated overnight.Use the saturated sodium bicarbonate solution neutralise mixt, use dichloromethane extraction.The organic layer concentrating under reduced pressure that merges, the gained residue grinds with methyl alcohol, obtains title compound. 1H?NMR(300MHz，DMSO-d 6)δppm?8.45(s，1H)8.26(d，J＝8.82Hz，1H)8.17(d，J＝1.70Hz，1H)7.77(dd，J＝8.82，2.03Hz，1H)2.72(s，3H)。
Embodiment 209B
5-(1-benzyl-1H-pyrazoles-4-yl)-1H-indazole
With embodiment 209A (425mg, 1.78mmol), 1-benzyl-4-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycle pentane-2-yls)-the 1H-pyrazoles (508mg, 1.79mmol), dichloro two (triphenylphosphine) palladium (II) (133mg, 0.189mmol) and salt of wormwood (742mg, 5.37mmol) in sealed tube, mix under the nitrogen rare gas element with dioxane (10mL) and water (1mL), mixture heating up to 110 ℃ is spent the night.Mixture dilutes with methylene dichloride, washes with water.Organic layer is adsorbed on the silica gel, uses the silica gel chromatography purifying, the hexane solution gradient elution with ethyl acetate obtains title compound. 1HNMR(300MHz，DMSO-d 6)δppm?13.00(s，1H)8.25(s，1H)8.02(s，1H)7.92(s，2H)7.55-7.61(m，1H)7.48-7.54(m，1H)7.25-7.40(m，5H)5.35(s，2H).MS(ESI+)m/z?274.9(M+H) +。
Embodiment 210
N-[(1R)-3-hydroxyl-1-phenyl propyl]-5-(3-methyl isophthalic acid H-indazole-5-base) isoxazole-3-methane amide
Embodiment 210A
5-bromo-3-methyl isophthalic acid H-indazole-1-t-butyl formate
With 5-bromo-3-methyl isophthalic acid H-indazole (5.11g, 24.2mmol) and the dimethyl aminopyridine of catalytic amount (～30mg) be dissolved in methylene dichloride (100mL) and add two-tertiary butyl, two carbonic ethers (5.9g, 27.0mmol), mixture at room temperature stirred 3 hours.Removal of solvent under reduced pressure, the gained residue dilutes with ethyl acetate, with 1N sodium hydroxide (twice), 0.1N hydrochloric acid and salt water washing.The organic layer dried over sodium sulfate is filtered.Filtrate decompression concentrates, and obtains title compound.MS(ESI+)m/z?210.8(M-Boc) +。
Embodiment 210B
3-methyl-5-((trimethyl silyl) ethynyl)-1H-indazole-1-t-butyl formate
With embodiment 210A (7.55g, 24.3mmol), dichloro two (triphenylphosphine) palladium (II) (870mg, 1.24mmol) and cuprous iodide (I) (250mg 1.31mmol) mixes under the nitrogen rare gas element in triethylamine (60mL).(4.0mL, 28.9mmol), mixture is 60 ℃ of following heated overnight to add trimethyl silyl acetylene.Mixture dilutes with methylene dichloride, with 0.1M salt acid elution.Organic layer is adsorbed on the silica gel, uses the silica gel chromatography purifying, the hexane solution gradient elution with the 10-40% ethyl acetate obtains title compound.MS(ESI+)m/z?228.9(M-Boc) +。
Embodiment 210C
5-ethynyl-3-methyl isophthalic acid H-indazole
(7.26g 22.1mmol) is dissolved in methyl alcohol (170mL) with embodiment 210B.Add 1N potassium hydroxide (45mL) solution, mixture at room temperature stirs and spends the night.Removal of solvent under reduced pressure, the gained residue dilutes with ethyl acetate, water and salt water washing.The organic layer dried over sodium sulfate, concentrating under reduced pressure obtains title compound.MS(ESI+)m/z?157.1(M+H) +。
Embodiment 210D
5-(3-methyl isophthalic acid H-indazole-5-base) isoxazole-3-ethyl formate
(411mg 2.63mmol) is dissolved in toluene (15mL) and triethylamine (478uL), is warming up to 90 ℃ with embodiment 210C.Dropwise added chloro glyoxylic acid oxime ethyl ester (480mg 3.17mmol) was dissolved in the solution of toluene (15mL) through 30 minutes.After adding, mixture dilutes with ethyl acetate, with 1N salt acid elution.The organic layer concentrating under reduced pressure, the gained residue grinds with methyl alcohol, obtains title compound.MS(ESI+)m/z?271.9(M+H) +。
Embodiment 210E
5-(3-methyl isophthalic acid H-indazole-5-base) isoxazole-3-formic acid
With embodiment 210D (325mg 1.20mmol) is dissolved in tetrahydrofuran (THF) (10mL), methyl alcohol (1mL) and water (1mL), add potassium hydroxide (150mg, 2.67mmol).Mixture at room temperature stirred 3 hours.Mixture dilutes with ethyl acetate, with 1N salt acid elution.Product precipitates in separating funnel, filters, and obtains title compound.MS(ESI+)m/z?243.9(M+H) +。
Embodiment 210F
N-[(1R)-3-hydroxyl-1-phenyl propyl]-5-(3-methyl isophthalic acid H-indazole-5-base) isoxazole-3-methane amide
Prepare title compound with the method for describing among the embodiment 81B, wherein replace embodiment 81A, replace piperidines with (R)-3-amino-3-phenyl third-1-alcohol with embodiment 210E. 1H?NMR(300MHz，DMSO-d 6)δppm?12.93(s，1H)8.45(d，J＝8.82Hz，1H)8.33(s，1H)7.84(d，J＝8.82，1.70Hz，1H)7.59(d，J＝9.16Hz，1H)7.21-7.29(m，5H)7.13-7.21(m，1H)4.89(t，J＝5.59Hz，1H)4.10-4.26(m，1H)3.42-3.56(m，2H)2.88-3.00(m，1H)2.75-2.87(m，1H)2.55(s，3H).MS(ESI+)m/z377.1(M+H) +。
Embodiment 211
3-[4-(3-amino-1H-indazole-5-yl)-1-benzyl-1H-1,2,3-triazole-5-yl] phenol
Cover under argon gas, contain embodiment 125B (35mg, 0.09mmol), 3-hydroxy phenyl boric acid (12mg, 0.09mmol), PdCl 2(dppf) methylene dichloride (7mg, 0.009mmol) and salt of wormwood (24mg, the phial of DME 0.18mmol) (1mL) and water (0.1mL) solution, in heating oscillator 80 ℃ of down heating 3 days.Boil off solvent, product by the reversed-phase HPLC purifying, obtains title compound with acetonitrile/water 0.1%TFA linear gradient elution method. 1H?NMR(500MHz，DMSO-d 6)δppm?11.40(s，1H)9.68(s，1H)8.09(s，1H)7.24-7.35(m，5H)6.98-7.13(m，3H)6.88(d，J＝8.09，1.98Hz，1H)6.73(s，1H)6.60-6.66(m，1H)5.47(s，2H)5.35(s，2H).MS(ESI+)m/z?383.1(M+H) +。
Embodiment 212
3-[4-(3-amino-1H-indazole-5-yl)-1-benzyl-1H-1,2,3-triazole-5-yl] benzamide
Prepare title compound with the method for describing among the embodiment 173, wherein replace 4-anisole ylboronic acid with 3-formamyl phenyl-boron dihydroxide. 1H?NMR(500MHz，DMSO-d 6)δppm?11.41(s，1H)8.07(s，1H)7.97-8.03(m，2H)7.83-7.87(m，1H)7.53(t，J＝7.78Hz，1H)7.45(s，1H)7.38(d，J＝7.63Hz，1H)7.23-7.30(m，3H)7.00-7.10(m，2H)6.96(d，J＝7.48，1.98Hz，2H)5.51(s，2H)5.35(s，2H).MS(ESI+)m/z?410.1(M+H) +。
Embodiment 213
5-{1-benzyl-5-[4-(methyl sulphonyl) phenyl]-1H-1,2,3-triazole-4-yl }-1H-indazole-3-amine
Prepare title compound with the method for describing among the embodiment 173, wherein use 4-(methyl sulphonyl) phenyl-boron dihydroxide to replace 4-anisole ylboronic acid. 1H?NMR(500MHz，DMSO-d 6)δppm11.44(s，1H)7.94-8.01(m，3H)7.58(d，J＝8.54Hz，2H)7.22-7.30(m，3H)7.04-7.13(m，2H)6.98(d，J＝7.48，1.98Hz，2H)5.56(s，2H)5.37(s，2H)3.28(s，3H).MS(ESI+)m/z?445.2(M+H) +。
Embodiment 214
N-[5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-the 2-chlorobenzamide
Prepare title compound with the method for describing among the embodiment 205B, wherein replace the 3-fluorobenzoyl chloride with the 2-chloro-benzoyl chloride. 1H?NMR(300MHz，DMSO-d 6)δppm?10.94(s，1H)，8.24(s，1H)，7.85(d，J＝8.82，1.47Hz，1H)，7.65(d，J＝6.99，1.84Hz，1H)，7.43-7.61(m，4H)，7.26-7.42(m，5H)，5.68(s，2H)，1.71-1.83(m，1H)，1.04-1.12(m，2H)，0.37-0.45(m，2H).MS(ESI+)m/z?469(M+H) +。
Embodiment 215
N-[5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-the 4-chlorobenzamide
Prepare title compound with the method for describing among the embodiment 205B, wherein replace the 3-fluorobenzoyl chloride with the 4-chloro-benzoyl chloride. 1H?NMR(300MHz，DMSO-d 6)δppm?10.53(s，1H)，7.65-7.71(m，3H)，7.42(d，J＝8.82，1.47Hz，1H)，7.18-7.24(m，2H)，7.12-7.18(m，1H)，6.93-7.02(m，3H)，6.83-6.92(m，3H)，5.27(s，2H)，1.30-1.44(m，1H)，0.59-0.67(m，2H)，-0.07-0.04(m，2H).MS(ESI+)m/z?469(M+H) +。
Embodiment 216
N-[5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl] ethyl sulfonamide
Prepare title compound with the method for describing among the embodiment 205B, wherein replace the 3-fluorobenzoyl chloride with ethyl sulfonyl chloride. 1H?NMR(300MHz，DMSO-d 6)δppm?10.19(s，1H)，8.15(s，1H)，7.82(d，J＝8.64，1.65Hz，1H)，7.53(d，J＝8.82Hz，1H)，7.35-7.45(m，3H)，7.27-7.35(m，2H)，5.69(s，2H)，3.30(q，J＝7.35Hz，2H)，1.74-1.87(m，1H)，1.27-1.36(m，3H)，1.02-1.12(m，2H)，0.34-0.44(m，2H).MS(ESI+)m/z?423(M+H) +。
Embodiment 217
N-[5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl] benzsulfamide
Prepare title compound with the method for describing among the embodiment 205B, wherein replace the 3-fluorobenzoyl chloride with benzene sulfonyl chloride. 1H?NMR(300MHz，DMSO-d 6)δppm?12.75(s，1H)，10.69(s，1H)，8.02(s，1H)，7.71-7.83(m，3H)，7.43-7.60(m，4H)，7.34-7.43(m，3H)，7.27-7.34(m，2H)，5.69(s，2H)，1.69-1.83(m，1H)，0.99-1.11(m，2H)，0.31-0.45(m，2H).MS(ESI+)m/z?471(M+H) +。
Embodiment 218
N-[5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-the 2-chlorobenzene sulfonamide
Prepare title compound with the method for describing among the embodiment 205B, wherein replace the 3-fluorobenzoyl chloride with 2-chlorobenzene-1-SULPHURYL CHLORIDE. 1H?NMR(300MHz，DMSO-d 6)δppm?12.36(s，1H)，10.60(s，1H)，7.67(s，1H)，7.62(d，J＝7.91，1.65Hz，1H)，7.40(d，J＝8.82，1.47Hz，1H)，7.14-7.27(m，2H)，7.00-7.12(m，4H)，6.96-7.00(m，1H)，6.90-6.95(m，2H)，5.31(s，2H)，1.29-1.44(m，1H)，0.61-0.74(m，2H)，-0.05-0.05(m，2H).MS(ESI+)m/z?505(M+H) +。
Embodiment 219
N-[5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-the 3-chlorobenzene sulfonamide
Prepare the HCl salt of title compound with the method for describing among the embodiment 205B, wherein replace the 3-fluorobenzoyl chloride with 3-chlorobenzene-1-SULPHURYL CHLORIDE. 1H?NMR(300MHz，DMSO-d 6)δppm12.84(s，1H)，10.86(s，1H)，8.00(s，1H)，7.82(s，1H)，7.72(d，J＝7.72Hz，1H)，7.64(d，J＝1.84Hz，1H)，7.57(d，J＝7.72Hz，1H)，7.50(d，J＝8.82Hz，1H)，7.34-7.45(m，3H)，7.28-7.34(m，2H)，5.69(s，2H)，1.71-1.83(m，1H)，1.06(m，2H)，0.37(m，2H).MS(ESI+)m/z?505(M+H) +。
Embodiment 220
N-[5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-the 4-chlorobenzene sulfonamide
Prepare the HCl salt of title compound with the method for describing among the embodiment 205B, wherein replace the 3-fluorobenzoyl chloride with 4-chlorobenzene-1-SULPHURYL CHLORIDE. 1H?NMR(300MHz，DMSO-d 6)δppm12.80(s，1H)，10.79(s，1H)，8.00(s，1H)，7.73-7.83(m，3H)，7.56-7.64(m，2H)，7.49(d，J＝8.82Hz，1H)，7.34-7.45(m，3H)，7.28-7.34(m，2H)，5.69(s，2H)，1.71-1.86(m，1H)，0.99-1.12(m，2H)，0.31-0.43(m，2H).MS(ESI+)m/z?505(M+H) +。
Embodiment 221
N-[5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-2,5-dimethyl furan-3-sulphonamide
Prepare the HCl salt of title compound with the method for describing among the embodiment 205B, wherein use 2,5-dimethyl furan-3-SULPHURYL CHLORIDE replaces the 3-fluorobenzoyl chloride. 1H?NMR(300MHz，DMSO-d 6)δppm?12.82(s，1H)，10.48(s，1H)，8.00(s，1H)，7.78(d，J＝8.64，1.65Hz，1H)，7.50(d，J＝9.19Hz，1H)，7.34-7.45(m，3H)，7.28-7.33(m，2H)，6.20(s，1H)，5.69(s，2H)，2.11(s，6H)，1.71-1.84(m，1H)，1.01-1.11(m，2H)，0.32-0.41(m，2H).MS(ESI+)m/z?489(M+H) +。
Embodiment 222
5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazole-4-yl)-N-(2-benzyl chloride base)-1H-indazole-3-amine
Prepare title compound with the method for describing among the embodiment 207, wherein replace phenyl aldehyde with the 2-chlorobenzaldehyde. 1H?NMR(300MHz，DMSO-d 6)δppm?11.55(s，1H)，8.20(s，1H)，7.69(d，J＝8.46，1.47Hz，1H)，7.49(d，J＝8.82Hz，1H)，7.34-7.46(m，4H)，7.23-7.33(m，5H)，5.69(s，2H)，4.56(s，2H)，1.72-1.83(m，1H)，0.99-1.09(m，2H)，0.35-0.42(m，2H).MS(ESI+)m/z?455(M+H) +。
Embodiment 223
5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazole-4-yl)-N-(3-benzyl chloride base)-1H-indazole-3-amine
Prepare title compound with the method for describing among the embodiment 207, wherein replace phenyl aldehyde with the 3-chlorobenzaldehyde. 1H?NMR(300MHz，DMSO-d 6)δppm?11.53(s，1H)，8.15(s，1H)，7.59-7.77(m，1H)，7.25-7.48(m，10H)，5.68(s，2H)，4.49(s，2H)，1.71-1.80(m，1H)，1.04(s，2H)，0.38(s，2H)。
Embodiment 224
N-[5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-the 3-chlorobenzamide
Prepare title compound with the method for describing among the embodiment 205B, wherein replace the 3-fluorobenzoyl chloride with the 3-chloro-benzoyl chloride. 1H?NMR(300MHz，DMSO-d 6)δppm?10.99(s，1H)，8.12(s，2H)，8.03(d，J＝7.72Hz，1H)，7.83(d，J＝8.46Hz，1H)，7.68(s，1H)，7.58(t，J＝8.09Hz，2H)，7.33-7.44(m，3H)，7.25-7.33(m，2H)，5.68(s，2H)，1.72-1.86(m，1H)，0.99-1.12(m，2H)，0.34-0.45(m，2H).MS(ESI+)m/z470(M+H) +。
Embodiment 225
N-[5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-the 2-furoamide
Prepare title compound with the method for describing among the embodiment 205B, wherein replace the 3-fluorobenzoyl chloride with furans-2-formyl chloride. 1H?NMR(300MHz，DMSO-d 6)δppm?10.36(s，1H)，7.71(s，1H)，7.42(d，J＝8.82，1.47Hz，1H)，7.15(d，J＝8.82Hz，1H)，7.06(d，J＝3.31Hz，1H)，6.93-7.03(m，3H)，6.86-6.93(m，2H)，6.31(d，J＝3.49，1.65Hz，1H)，5.28(s，1H)，1.31-1.45(m，1H)，0.59-0.71(m，2H)，-0.05-0.05(m，2H).MS(ESI+)m/z?425(M+H) +。
Embodiment 226
5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazole-4-yl)-N-ethyl-1H-indazole-3-amine
Prepare title compound with the method for describing among the embodiment 207, wherein replace phenyl aldehyde with acetaldehyde. 1H?NMR(300MHz，DMSO-d 6)δppm?8.56(s，1H)，8.30-8.42(m，1H)，7.90-8.17(m，2H)，7.20-7.45(m，5H)，5.70(s，2H)，1.78-1.93(m，2H)，1.67(s，1H)，1.06(m，3H)，0.95(m，2H)，0.29-0.48(m，2H).MS(ESI+)m/z?359(M+H) +。
Embodiment 227
5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazole-4-yl)-N-(4-benzyl chloride base)-1H-indazole-3-amine
Prepare title compound with the method for describing among the embodiment 207, wherein replace phenyl aldehyde with the 4-chlorobenzaldehyde. 1H?NMR(300MHz，DMSO-d 6)δppm?10.01(s，1H)，9.25(s，1H)，8.25-8.33(m，1H)，8.09(d，J＝8.46Hz，1H)，7.84-7.97(m，2H)，7.57-7.73(m，2H)，7.26-7.51(m，6H)，5.70(s，2H)，1.71-1.84(m，1H)，0.97-1.15(m，2H)，0.36-0.47(m，2H).MS(ESI+)m/z?455(M+H) +。
Embodiment 228
5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazole-4-yl)-N-(3-furyl methyl)-1H-indazole-3-amine
Prepare title compound with the method for describing among the embodiment 207, wherein replace phenyl aldehyde with furans-3-formaldehyde. 1H?NMR(300MHz，DMSO-d 6)δppm?8.21(s，1H)，7.90(s，1H)，7.71-7.82(m，1H)，7.55-7.68(m，2H)，7.24-7.51(m，6H)，5.68(s，2H)，4.33(s，2H)，1.67-1.85(m，1H)，0.95-1.13(m，2H)，0.30-0.42(m，2H).MS(ESI+)m/z?411(M+H) +。
Embodiment 229
N-[5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-N '-[5-methyl-2-(trifluoromethyl)-3-furyl] urea
With embodiment 205A (30mg 0.07mmol) is dissolved in dioxane (2mL), in solution, add 3-isocyanato-5-methyl-2-(trifluoromethyl) furans (40mg, 0.21mmol).Reaction mixture stirred 12 hours down at 80 ℃, concentrated, with reversed-phase HPLC (CH 3CN/H 2O/NH 4OAc) purifying obtains the precursor that Boc protects.This precursor is dissolved in methyl alcohol, with dioxane solution (4M, 0.5mmol) processing of excessive HCl.To react and stir 5 hours, vacuum concentration obtains the HCl salt of title compound. 1H?NMR(300MHz，DMSO-d 6)δppm?12.73(s，1H)，10.19(s，1H)，8.40(s，1H)，7.83(d，J＝8.82，1.47Hz，1H)，7.64-7.75(m，1H)，7.49(d，J＝8.82Hz，1H)，7.35-7.45(m，3H)，7.27-7.35(m，2H)，5.69(s，2H)，2.33(s，3H)，1.73-1.84(m，1H)，1.02-1.11(m，2H)，0.35-0.43(m，2H).MS(ESI+)m/z?522(M+H) +。
Embodiment 230
N-[5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-the 3-furoamide
Prepare the HCl salt of title compound with the method for describing among the embodiment 205B, wherein replace the 3-fluorobenzoyl chloride with furans-3-formyl chloride. 1H?NMR(300MHz，DMSO-d 6)δppm?10.64(s，1H)，8.46(s，1H)，8.13(s，1H)，7.74-7.84(m，2H)，7.52-7.58(m，1H)，7.33-7.46(m，3H)，7.24-7.33(m，3H)，7.06(s，1H)，5.68(s，2H)，1.70-1.86(m，1H)，0.99-1.09(m，2H)，0.33-0.44(m，2H).MS(ESI+)m/z?425(M+H) +。
Embodiment 231
5-(1H-indazole-5-yl)-N-[(1S)-1-phenyl propyl] isoxazole-3-methane amide
Prepare title compound with the method for describing among the embodiment 81B, wherein use (S)-(-)-1-phenyl propyl amine to replace piperidines. 1H?NMR(300MHz，DMSO-d 6)δppm?13.37(s，1H)9.20(d，J＝8.48Hz，1H)8.39(s，1H)8.23(s，1H)7.88(d，J＝8.81，1.70Hz，1H)7.69(d，J＝8.81Hz，1H)7.38-7.49(m，2H)7.18-7.38(m，4H)4.83-5.02(m，1H)1.73-1.97(m，2H)0.86-0.97(m，3H).MS(ESI+)m/z?347.0(M+H) +。
Embodiment 232
5-(1H-indazole-5-yl)-N-[(1R)-1-phenyl propyl] isoxazole-3-methane amide
Prepare title compound with the method for describing among the embodiment 81B, wherein use (R)-(-)-1-phenyl propyl amine to replace piperidines. 1H?NMR(300MHz，DMSO-d 6)δppm?13.37(s，1H)9.20(d，J＝8.48Hz，1H)8.39(s，1H)8.23(s，1H)7.88(d，J＝8.65，1.53Hz，1H)7.69(d，J＝8.81Hz，1H)7.39-7.48(m，2H)7.18-7.38(m，4H)4.85-4.99(m，1H)1.74-1.97(m，2H)0.91(t，J＝7.29Hz，3H).MS(ESI+)m/z?347.0(M+H) +。
Embodiment 233
5-(1-benzyl-1H-pyrazoles-4-yl)-1H-indazole-3-amine
Embodiment 233A
5-(1-benzyl-1H-pyrazoles-4-yl)-2-fluorobenzonitrile
With 5-bromo-2-fluorobenzonitrile (484mg, 2.42mmol), 1-benzyl-4-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycle pentane-2-yls)-the 1H-pyrazoles (736mg, 2.59mmol), dichloro two (triphenylphosphine) palladium (II) (174mg, 0.248mmol) and salt of wormwood (1.36g, 9.84mmol) in sealed tube, mix under the nitrogen rare gas element with dioxane (10mL) and water (1mL), mixture heating up to 110 ℃ is spent the night.Mixture dilutes with methylene dichloride, washes with water.Organic layer is adsorbed on the silica gel, uses the silica gel chromatography purifying, the hexane solution gradient elution with the 10-50% ethyl acetate obtains title compound.MS(ESI+)m/z?290.0(M+H) +。
Embodiment 233B
5-(1-benzyl-1H-pyrazoles-4-yl)-1H-indazole-3-amine
(591mg 2.13mmol) with ethanol (3.0mL) solution-treated of hydrazine hydrate (4.0mL), is heated to 70 ℃ of stirrings and spends the night with embodiment 233A.Mixture dilutes with methylene dichloride, washes with water.The organic layer concentrating under reduced pressure, the gained residue grinds with methyl alcohol, obtains title compound. 1H?NMR(300MHz，DMSO-d 6)δppm?11.32(s，1H)8.10(s，1H)7.85(s，1H)7.80(s，1H)7.44(d，J＝8.48，1.70Hz，1H)7.25-7.41(m，5H)7.21(d，J＝8.82Hz，1H)5.35(s，2H)5.24-5.30(m，2H).MS(ESI+)m/z?290.0(M+H) +。
Embodiment 234
1-benzyl-4-(1H-indazole-5-yl)-N-[(2S)-tetrahydrofuran (THF)-2-ylmethyl]-1H-1,2,3-triazole-5-methane amide
In the 20mL phial, (51mg 0.16mmol) is dissolved in the solution of dimethyl formamide (0.5mL), and (18.2mg 0.18mmol) is dissolved in the solution of dimethyl formamide (0.9mL) to add (S)-(+)-tetrahydrofurfuryl amine then to add embodiment 149C.(68mg 0.18mmol) is dissolved in the solution of dimethyl formamide (0.5mL), and (0.087mL 0.5mmol) is dissolved in the solution of dimethyl formamide (0.5mL) to add diisopropyl ethyl amine then to add HATU.Mixture spends the night 50 ℃ of following joltings.By carbonic acid silicon filter cylinder (6mL-1g) the filtering reaction thing by Silicycle Chemical Division supply, filtrate is transferred in the 20mL phial.Use the LC/MS detecting reactant, be concentrated into dried.Residue is dissolved in 1: 1 DMSO/ methyl alcohol, with reversed-phase HPLC (Agilent, 5%-100%TFA/ water gradient elution, 8 minute working time). 1H?NMR(300MHz，DMSO-d 6/D 2O)δppm?1.35-1.54(m，1H)1.64-1.96(m，3H)3.17-3.26(m，1H)3.32-3.38(m，1H)3.50-3.77(m，2H)3.81-4.00(m，1H)5.58-5.74(m，2H)7.21-7.41(m，5H)7.54-7.66(m，1H)7.68-7.84(m，1H)8.01-8.19(m，2H).MS(ESI-)m/z?401(M-H) -。
Embodiment 235
1-benzyl-4-(1H-indazole-5-yl)-N-(2-isopropoxy ethyl)-1H-1,2,3-triazole-5-methane amide
Prepare title compound with the method for describing among the embodiment 234, wherein replace (S)-(+)-tetrahydrofurfuryl amine with 2-amino-ethyl isopropyl ether. 1H?NMR(300MHz，DMSO-d 6/D 2O)δppm?0.98(d，6H)3.31-3.45(m，4H)3.45-3.57(m，1H)5.61-5.74(m，2H)7.25-7.46(m，5H)7.57-7.65(m，1H)7.68-7.80(m，1H)8.04-8.13(m，2H).MS(ESI+)m/z?405(M+H) +。
Embodiment 236
1-benzyl-4-(1H-indazole-5-yl)-N-[(2R)-tetrahydrofuran (THF)-2-ylmethyl]-1H-1,2,3-triazole-5-methane amide
Prepare title compound with the method for describing among the embodiment 234, wherein use (R)-(-)-tetrahydrofurfuryl amine to replace (S)-(+)-tetrahydrofurfuryl amine. 1H?NMR(300MHz，DMSO-d 6/D 2O)δppm?1.34-1.60(m，1H)1.65-1.94(m，3H)3.16-3.26(m，1H)3.33-3.39(m，1H)3.51-3.77(m，2H)3.78-4.00(m，1H)5.60-5.73(m，2H)7.26-7.45(m，5H)7.56-7.68(m，1H)7.71-7.79(m，1H)8.01-8.15(m，2H).MS(ESI-)m/z401(M-H) -。
Embodiment 237
1-benzyl-4-(1H-indazole-5-yl)-N-(tetrahydrofuran (THF)-3-ylmethyl)-1H-1,2,3-triazole-5-methane amide
Prepare title compound with the method for describing among the embodiment 234, wherein replace (S)-(+)-tetrahydrofurfuryl amine with 3-amino methyl tetrahydrofuran (THF). 1H?NMR(300MHz，DMSO-d 6/D 2O)δppm?1.36-1.59(m，1H)1.67-2.00(m，1H)2.19-2.45(m，1H)3.11-3.23(m，2H)3.45-3.77(m，2H)5.45-6.14(m，2H)7.16-7.44(m，5H)7.50-7.84(m，2H)7.96-8.25(m，2H).MS(ESI+)m/z?403(M+H) +。
Embodiment 238
1-benzyl-N-cyclopentyl-4-(1H-indazole-5-yl)-1H-1,2,3-triazole-5-methane amide
Prepare title compound with the method for describing among the embodiment 234, wherein replace (S)-(+)-tetrahydrofurfuryl amine with cyclopentyl amine. 1H?NMR(300MHz，DMSO-d 6/D 2O)δppm?1.19-1.63(m，6H)1.71-1.99(m，2H)3.99-4.37(m，1H)5.52-5.77(m，2H)7.22-7.45(m，5H)7.55-7.83(m，2H)7.95-8.20(m，2H).MS(ESI-)m/z?385(M-H) -。
Embodiment 239
1-benzyl-N-(cyclopentyl-methyl)-4-(1H-indazole-5-yl)-1H-1,2,3-triazole-5-methane amide
Prepare title compound with the method for describing among the embodiment 234, wherein replace (S)-(+)-tetrahydrofurfuryl amine with the amino methyl pentamethylene. 1H?NMR(300MHz，DMSO-d 6/D 2O)δppm?1.02-1.28(m，2H)1.34-1.73(m，6H)1.83-2.17(m，1H)3.03-3.17(m，2H)5.51-5.80(m，2H)7.20-7.42(m，5H)7.52-7.81(m，2H)7.93-8.19(m，2H).MS(ESI+)m/z?401(M+H) +。
Embodiment 240
1-benzyl-N-ethyl-4-(1H-indazole-5-yl)-N-methyl isophthalic acid H-1,2,3-triazole-5-methane amide
Prepare title compound with the method for describing among the embodiment 234, wherein replace (S)-(+)-tetrahydrofurfuryl amine with N-methylethyl amine hydrochlorate. 1H?NMR(300MHz，DMSO-d 6/D 2O)δppm0.33-0.56(m，1H)0.90-1.14(m，2H)2.15-2.25(m，2H)2.58-2.69(m，1H)2.82-3.01(m，1H)3.35-3.52(m，1H)5.40-5.67(m，2H)7.14-7.48(m，5H)7.56-7.79(m，2H)7.90-8.24(m，2H).MS(ESI+)m/z?361(M+H) +。
Embodiment 241
1-benzyl-4-(1H-indazole-5-yl)-N-sec.-propyl-N-methyl isophthalic acid H-1,2,3-triazole-5-methane amide
Prepare title compound with the method for describing among the embodiment 234, wherein replace (S)-(+)-tetrahydrofurfuryl amine with isopropyl methyl amine. 1H?NMR(300MHz，DMSO-d 6/D 2O)δppm?0.22-0.51(m，2H)0.84-1.09(m，4H)1.96-2.13(m，2H)2.74-2.87(m，1H)4.44-4.92(m，1H)5.43-5.67(m，2H)7.20-7.44(m，5H)7.51-7.73(m，2H)7.84-8.14(m，2H).MS(ESI+)m/z?375(M+H) +。
Embodiment 242
1-benzyl-4-(1H-indazole-5-yl)-N-(2-methoxy ethyl)-N-methyl isophthalic acid H-1,2,3-triazole-5-methane amide
Prepare title compound with the method for describing among the embodiment 234, wherein use N-(2-methoxy ethyl) methylamine to replace (S)-(+)-tetrahydrofurfuryl amine. 1H?NMR(300MHz，DMSO-d 6/D 2O)δppm2.25-2.42(m，2H)2.74-3.06(m，4H)3.40-3.75(m，3H)5.38-5.73(m，2H)7.18-7.45(m，5H)7.53-7.74(m，2H)7.85-8.19(m，2H).MS(ESI+)m/z?391(M+H) +。
Embodiment 243
1-benzyl-4-(1H-indazole-5-yl)-N-phenyl-1H-1,2,3-triazole-5-methane amide
Prepare title compound with the method for describing among the embodiment 234, wherein replace (S)-(+)-tetrahydrofurfuryl amine with aniline. 1H?NMR(300MHz，DMSO-d 6/D 2O)δppm?5.65-5.79(m，2H)7.04-7.55(m，10H)7.54-7.84(m，2H)7.95-8.21(m，2H).MS(ESI+)m/z395(M+H) +。
Embodiment 244
1-benzyl-N-(4-chloro-phenyl-)-4-(1H-indazole-5-yl)-1H-1,2,3-triazole-5-methane amide
Prepare title compound with the method for describing among the embodiment 234, wherein replace (S)-(+)-tetrahydrofurfuryl amine with the 4-chloroaniline. 1H?NMR(300MHz，DMSO-d 6/D 2O)δppm?5.70-5.74(m，2H)7.25-7.42(m，7H)7.43-7.52(m，2H)7.54-7.66(m，1H)7.68-7.77(m，1H)8.03-8.15(m，2H).MS(ESI-)m/z?427(M-H) -。
Embodiment 245
1-benzyl-4-(1H-indazole-5-yl)-N-(2-morpholine-4-base ethyl)-1H-1,2,3-triazole-5-methane amide
Prepare title compound with the method for describing among the embodiment 234, wherein use N-(3-aminopropyl) morpholino for (S)-(+)-tetrahydrofurfuryl amine. 1H?NMR(300MHz，DMSO-d 6/D 2O)δppm?2.94-3.13(m，6H)3.46-3.61(m，2H)3.63-3.79(m，4H)5.61-5.88(m，2H)7.19-7.46(m，5H)7.56-7.88(m，2H)7.88-8.30(m，2H).MS(ESI-)m/z430(M-H) -。
Embodiment 246
1-benzyl-N-[2-(dimethylamino) ethyl]-4-(1H-indazole-5-yl)-N-methyl isophthalic acid H-1,2,3-triazole-5-methane amide
Prepare the tfa salt of title compound with the method for describing among the embodiment 234, wherein use N, N, N-trimethylammonium quadrol replaces (S)-(+)-tetrahydrofurfuryl amine. 1H?NMR(300MHz，DMSO-d 6/D 2O)δppm?2.28-2.42(m，3H)2.73-3.00(m，6H)3.07-3.19(m，2H)3.56-3.80(m，2H)5.55-5.68(m，2H)7.24-7.47(m，5H)7.56-7.78(m，2H)7.91-8.02(m，1H)8.10-8.17(m，1H).MS(ESI+)m/z?404(M+H) +。
Embodiment 247
1-benzyl-N-(2-hydroxyethyl)-4-(1H-indazole-5-yl)-N-propyl group-1H-1,2,3-triazole-5-methane amide
Prepare title compound with the method for describing among the embodiment 234, wherein use 2-(propyl group amino) ethanol to replace (S)-(+)-tetrahydrofurfuryl amine. 1H?NMR(300MHz，DMSO-d 6/D 2O)δppm?0.22-0.39(m，1H)0.80-1.06(m，3H)1.50-1.75(m，1H)2.65-2.78(m，1H)2.80-2.94(m，1H)2.97-3.09(m，1H)3.37-3.50(m，1H)3.51-3.63(m，1H)3.61-3.73(m，1H)5.39-5.74(m，2H)7.20-7.44(m，5H)7.50-7.85(m，2H)7.86-8.25(m，2H).MS(ESI+)m/z?405(M+H) +。
Embodiment 248
1-benzyl-N-[3-(dimethylamino) propyl group]-4-(1H-indazole-5-yl)-N-methyl isophthalic acid H-1,2,3-triazole-5-methane amide
Prepare the tfa salt of title compound with the method for describing among the embodiment 234, wherein use N, N, N-trimethylammonium-1, the 3-propylene diamine replaces (S)-(+)-tetrahydrofurfuryl amine. 1H?NMR(300MHz，DMSO-d 6/D 2O)δppm?8.06-8.23(m，1H)7.85-8.05(m，1H)7.57-7.73(m，2H)7.19-7.48(m，5H)5.41-5.74(m，2H)3.36-3.45(m，2H)2.88-3.10(m，3H)2.60-2.86(m，5H)2.24-2.42(m，4H)1.73-1.91(m，1H).MS(ESI+)m/z?418(M+H) +。
Embodiment 249
1-benzyl-N-[2-(diethylamino) ethyl]-4-(1H-indazole-5-yl)-N-methyl isophthalic acid H-1,2,3-triazole-5-methane amide
Prepare the tfa salt of title compound with the method for describing among the embodiment 234, wherein use N, N-diethyl-N-methyl ethylenediamine replaces (S)-(+)-tetrahydrofurfuryl amine. 1H?NMR(300MHz，DMSO-d 6/D 2O)δppm?7.82-8.24(m，2H)7.56-7.76(m，2H)7.15-7.49(m，5H)5.54-5.71(m，2H)3.60-3.77(m，2H)3.20-3.24(m，2H)3.13-3.18(m，2H)3.03-3.11(m，2H)2.32-2.44(m，3H)0.63-1.41(m，6H).MS(ESI+)m/z?432(M+H) +。
Embodiment 250
N, 1-dibenzyl-N-ethyl-4-(1H-indazole-5-yl)-1H-1,2,3-triazole-5-methane amide
Prepare title compound with the method for describing among the embodiment 234, wherein replace (S)-(+)-tetrahydrofurfuryl amine with N-Ethylbenzyl amine. 1H?NMR(300MHz，DMSO-d 6/D 2O)δppm?7.81-8.20(m，2H)7.49-7.71(m，2H)7.24-7.51(m，9H)6.39-7.18(m，2H)5.41-5.74(m，2H)4.53-4.84(m，1H)3.82-4.00(m，1H)3.37-3.54(m，1H)2.61-2.78(m，1H)0.91-1.08(m，1H)0.27-0.45(m，2H).MS(ESI+)m/z437(M+H) +。
Embodiment 251
N, 1-dibenzyl-N-(2-hydroxyethyl)-4-(1H-indazole-5-yl)-1H-1,2,3-triazole-5-methane amide
Prepare title compound with the method for describing among the embodiment 234, wherein replace (S)-(+)-tetrahydrofurfuryl amine with N-benzyl ethyl alcohol amine.MS(ESI+)m/z?453(M+H) +。
Embodiment 252
(3R)-and 1-{[1-benzyl-4-(1H-indazole-5-yl)-1H-1,2,3-triazole-5-yl] carbonyl } piperidines-3-alcohol
Prepare title compound with the method for describing among the embodiment 234, replace (S)-(+)-tetrahydrofurfuryl amine with (R)-(+)-3-hydroxyl piperidine hydrochloric acid salt. 1H?NMR(300MHz，DMSO-d 6/D 2O)δppm?7.83-8.22(m，2H)7.51-7.78(m，2H)7.23-7.45(m，5H)5.46-5.75(m，2H)3.80-4.31(m，1H)3.40-3.68(m，1H)2.58-3.15(m，2H)2.19-2.49(m，1H)0.31-2.14(m，4H).MS(ESI+)m/z?403(M+H) +。
Embodiment 253
1-{[1-benzyl-4-(1H-indazole-5-yl)-1H-1,2,3-triazole-5-yl] carbonyl } piperidines-4-methane amide
Prepare title compound with the method for describing among the embodiment 234, wherein use six hydrogen Isonicotinamides (isonipecotamide) to replace (S)-(+)-tetrahydrofurfuryl amine. 1H?NMR(300MHz，DMSO-d 6/D 2O)δppm?7.86-8.24(m，2H)7.53-7.70(m，2H)7.22-7.46(m，5H)5.42-5.77(m，2H)4.19-4.48(m，1H)2.65-3.10(m，2H)2.27-2.47(m，1H)2.05-2.24(m，1H)1.65-1.89(m，1H)1.29-1.55(m，1H)0.98-1.27(m，1H)0.52-0.87(m，1H).MS(ESI+)m/z?430(M+H) +。
Embodiment 254
5-{1-benzyl-5-[(2,6-thebaine-4-yl) carbonyl]-1H-1,2,3-triazole-4-yl }-the 1H-indazole
Prepare title compound with the method for describing among the embodiment 234, wherein use 2, the 6-thebaine replaces (S)-(+)-tetrahydrofurfuryl amine. 1H?NMR(300MHz，DMSO-d 6/D 2O)δppm?7.87-8.27(m，2H)7.50-7.76(m，2H)7.12-7.45(m，5H)5.46-5.68(m，2H)4.16-4.43(m，1H)2.61-2.98(m，1H)2.16-2.41(m，2H)1.77-2.13(m，1H)0.86-1.39(m，3H)0.38-0.83(m，3H).MS(ESI+)m/z?417(M+H) +。
Embodiment 255
5-{5-[(4-ethanoyl piperazine-1-yl) carbonyl]-1-benzyl-1H-1,2,3-triazole-4-yl }-the 1H-indazole
Prepare title compound with the method for describing among the embodiment 234, wherein replace (S)-(+)-tetrahydrofurfuryl amine with 1-ethanoyl piperazine. 1H?NMR(300MHz，DMSO-d 6/D 2O)δppm?7.89-8.41(m，2H)7.55-7.86(m，2H)7.07-7.51(m，5H)5.44-5.82(m，2H)3.46-3.70(m，3H)3.35-3.49(m，2H)2.57-2.93(m，3H)1.61-2.03(m，3H).MS(ESI+)m/z?430(M+H) +。
Embodiment 256
5-{1-benzyl-5-[(4-phenylpiperazine-1-yl) carbonyl]-1H-1,2,3-triazole-4-yl }-the 1H-indazole
Prepare title compound with the method for describing among the embodiment 234, wherein replace (S)-(+)-tetrahydrofurfuryl amine with the 1-phenylpiperazine. 1H?NMR(300MHz，DMSO-d 6/D 2O)δppm?7.79-8.38(m，2H)7.53-7.73(m，2H)7.22-7.46(m，5H)7.05-7.19(m，2H)6.64-6.79(m，3H)5.54-5.68(m，2H)3.50-3.90(m，2H)2.93-3.15(m，2H)2.62-2.89(m，2H)2.19-2.43(m，2H).MS(ESI-)m/z?462(M-H) -。
Embodiment 257
The 1-benzyl-N-[(1R)-1-(hydroxymethyl)-2-methyl-propyl]-4-(1H-indazole-5-yl)-1H-1,2,3-triazole-5-methane amide
Prepare title compound with the method for describing among the embodiment 234, wherein use (R)-(+)-2-amino-3-methyl isophthalic acid-butanols to replace (S)-(+)-tetrahydrofurfuryl amine. 1H?NMR(300MHz，DMSO-d 6/D 2O)δppm?7.95-8.31(m，2H)7.52-7.96(m，2H)7.18-7.46(m，5H)5.42-5.86(m，2H)3.68-3.94(m，1H)3.38-3.59(m，2H)1.49-2.08(m，1H)0.50-1.20(m，6H).MS(ESI+)m/z?405(M+H) +。
Embodiment 258
The 1-benzyl-N-[(1S)-1-(hydroxymethyl)-2-methyl-propyl]-4-(1H-indazole-5-yl)-1H-1,2,3-triazole-5-methane amide
Prepare title compound with the method for describing among the embodiment 234, wherein use (S)-(-)-2-amino-3-methyl isophthalic acid-butanols to replace (S)-(+)-tetrahydrofurfuryl amine. 1H?NMR(300MHz，DMSO-d 6/D 2O)δppm?7.94-8.36(m，2H)7.52-7.84(m，2H)7.18-7.51(m，5H)5.57-5.76(m，2H)3.75-3.94(m，1H)3.35-3.54(m，2H)1.70-1.94(m，1H)0.54-1.09(m，6H).MS(ESI+)m/z?405(M+H) +。
Embodiment 259
1-benzyl-N-[3-(1H-imidazoles-1-yl) propyl group]-4-(1H-indazole-5-yl)-1H-1,2,3-triazole-5-methane amide
Prepare title compound with the method for describing among the embodiment 234, wherein use 1-(3-aminopropyl) imidazoles to replace (S)-(+)-tetrahydrofurfuryl amine. 1H?NMR(300MHz，DMSO-d 6/D 2O)δppm?8.57-8.85(m，1H)7.92-8.16(m，2H)7.60-7.80(m，2H)7.47-7.55(m，2H)7.19-7.40(m，5H)5.54-5.75(m，2H)3.83-4.21(m，2H)3.19-3.26(m，2H)1.79-2.06(m，2H).MS(ESI+)m/z?427(M+H) +。
Embodiment 260
N-[5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-N '-ethyl carbamide
Prepare the hydrochloride of title compound with the method for describing among the embodiment 229, wherein replace 3-isocyanato-5-methyl-2-(trifluoromethyl) furans with isocyanato ethane. 1H?NMR(300MHz，DMSO-d 6)δppm?12.38(s，1H)，9.47(s，1H)，8.38(s，1H)，7.85-7.97(m，1H)，7.78(d，J＝8.82，1.47Hz，1H)，7.34-7.50(m，4H)，7.24-7.33(m，2H)，5.69(s，2H)，3.17-3.29(m，2H)，1.70-1.83(m，1H)，1.12(t，J＝7.17Hz，3H)，1.00-1.08(m，2H)，0.37(d，J＝3.68Hz，2H).MS(ESI+)m/z?402(M+H) +。
Embodiment 261
N-[5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-N '-phenylurea
Prepare the hydrochloride of title compound with the method for describing among the embodiment 229, wherein replace 3-isocyanato-5-methyl-2-(trifluoromethyl) furans with isocyanato benzene. 1H?NMR(300MHz，DMSO-d 6)δppm?12.47-12.78(m，1H)，9.64(s，1H)，8.39(s，1H)，7.70-7.95(m，1H)，7.45-7.60(m，3H)，7.27-7.45(m，7H)，7.02(m，1H)，5.69(s，2H)，1.79(m，1H)，1.07(m，2H)，0.40(m，2H).MS(ESI+)m/z?450(M+H) +。
Embodiment 262
N-benzyl-N '-[5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl] urea
Prepare the hydrochloride of title compound with the method for describing among the embodiment 229, wherein use (isocyanato methyl) benzene ((isocyanatomethyl) benzene) to replace 3-isocyanato-5-methyl-2-(trifluoromethyl) furans. 1H?NMR(300MHz，DMSO-d 6)δppm?12.42(s，1H)，9.61(s，1H)，8.37(s，1H)，8.23-8.33(m，1H)，7.79(d，J＝8.82，1.47Hz，1H)，7.36-7.50(m，4H)，7.28-7.36(m，6H)，7.21-7.27(m，1H)，5.69(s，2H)，4.45(d，J＝5.88Hz，2H)，1.65-1.79(t，J＝8.27，8.27Hz，1H)，0.99-1.08(m，2H)，0.30-0.43(m，2H).MS(ESI+)m/z?464(M+H) +。
Embodiment 263
N-[5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-N '-(2-chloro-phenyl-) urea
Prepare the hydrochloride of title compound with the method for describing among the embodiment 229, wherein replace 3-isocyanato-5-methyl-2-(trifluoromethyl) furans with 1-chloro-2-isocyanato benzene. 1H?NMR(300MHz，DMSO-d 6)δppm?12.74(s，1H)，10.23(s，1H)，8.44(s，1H)，8.34(d，J＝8.09Hz，1H)，7.83(d，J＝8.82，1.47Hz，1H)，7.46-7.55(m，2H)，7.35-7.45(m，3H)，7.28-7.35(m，3H)，7.03-7.12(m，1H)，5.70(s，2H)，1.70-1.86(m，1H)，1.00-1.12(m，2H)，0.33-0.45(m，2H).MS(ESI+)m/z?484(M+H) +。
Embodiment 264
N-[5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-N '-(3-chloro-phenyl-) urea
Prepare the hydrochloride of title compound with the method for describing among the embodiment 229, wherein replace 3-isocyanato-5-methyl-2-(trifluoromethyl) furans with 1-chloro-3-isocyanato benzene. 1H?NMR(300MHz，DMSO-d 6)δppm?12.66(s，1H)，10.02(s，1H)，9.71(s，1H)，8.22-8.48(m，1H)，7.71-7.91(m，2H)，7.51(d，J＝8.46Hz，1H)，7.37-7.46(m，2H)，7.26-7.37(m，5H)，7.02-7.11(m，1H)，5.69(s，2H)，1.73-1.89(m，1H)，0.99-1.11(m，2H)，0.33-0.48(m，2H).MS(ESI+)m/z?484(M+H) +。
Embodiment 265
N-[5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-N '-(4-chloro-phenyl-) urea
Prepare the hydrochloride of title compound with the method for describing among the embodiment 229, wherein replace 3-isocyanato-5-methyl-2-(trifluoromethyl) furans with 1-chloro-4-isocyanato benzene. 1H?NMR(300MHz，DMSO-d 6)δppm?12.65(s，1H)，9.96(s，1H)，9.68(s，1H)，8.37(s，1H)，7.81(d，J＝8.82，1.47Hz，1H)，7.53-7.60(m，2H)，7.50(d，J＝8.82Hz，1H)，7.39-7.44(m，1H)，7.33-7.40(m，4H)，7.27-7.32(m，2H)，5.69(s，2H)，1.71-1.87(m，1H)，1.00-1.12(m，2H)，0.34-0.44(m，2H).MS(ESI+)m/z?484(M+H) +。
Embodiment 266
N-[5-(1-benzyl-5-iodo-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl] benzamide
Embodiment 266A
3-amino-5-(1-benzyl-5-iodo-1H-1,2,3-triazole-4-yl)-1H-indazole-1-t-butyl formate
Prepare title compound with the method for describing among the embodiment 198A, wherein replace embodiment 102B with embodiment 125B.Products therefrom is directly used in subsequent reaction without evaluation.
Embodiment 266B
N-[5-(1-benzyl-5-iodo-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl] benzamide
Prepare the tfa salt of title compound with the method for describing among the embodiment 205B, wherein replace embodiment 205A with embodiment 266A. 1H?NMR(300MHz，DMSO-d 6)δppm?12.97(s，1H)，10.89(s，1H)，8.28(s，1H)，8.05-8.14(m，2H)，7.88(d，J＝8.82，1.47Hz，1H)，7.58-7.67(m，2H)，7.54(t，J＝7.35Hz，2H)，7.29-7.45(m，3H)，7.23(d，J＝6.99Hz，2H)，5.73(s，2H).MS(ESI+)m/z?521(M+H) +。
Embodiment 267
3-[4-(3-amino-1H-indazole-5-yl)-1H-pyrazol-1-yl] propionitrile
Embodiment 267A
3-(4-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycle pentane-2-yls)-1H-pyrazol-1-yl) propionitrile
To 4-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycle pentane-2-yls)-the 1H-pyrazoles (5.00g, add in acetonitrile 25.8mmol) (50mL) solution vinyl cyanide (3.4mL, 52mmol), add 1 then, and 8-diazabicylo [5.4.0] 11-7-alkene (1.94mL, 12.9mmol).After 2 hours, with the reaction mixture concentrating under reduced pressure.Crude product is dissolved in the methylene dichloride of minimum then, uses the silica gel chromatography purifying, the n-heptane solution gradient elution with the 10-50% ethyl acetate obtains title compound. 1H?NMR(400MHz，DMSO-d 6)δppm?8.03(s，1H)，7.64(s，1H)，4.40(t，J＝6.4Hz，2H)，3.06(t，J＝6.4Hz，2H)，1.26(s，12H).MS(ESI+)m/z?247.3(M+H) +。
Embodiment 267B
3-[4-(3-amino-1H-indazole-5-yl)-1H-pyrazol-1-yl] propionitrile
In microwave tube, add 5-bromo-1H-indazole-3-amine (0.14g, 0.66mmol), tetrakis triphenylphosphine palladium (0) (0.076g, 0.066mmol) and yellow soda ash (0.147g, 1.39mmol), add embodiment 267A (0.212g then, 0.858mmol) 1,2-glycol dimethyl ether (2.50mL) adds entry (1.25mL) then.Mixture reacts about 20 minutes (peak pressure 275psi, about 2 minutes slope time, 200 watts of peak powers) down at about 150 ℃ in the CEM microwave, then with the mixture concentrating under reduced pressure.Add methyl alcohol (20mL), the gained mixture stirred 1 hour.Remove by filter insoluble substance.Concentrating under reduced pressure filtrate is carried and is gone up silica gel, uses the silica gel chromatography purifying, with methylene chloride/ammoniacal liquor (990: 9: 1-985: to was 980: 18: 2 in 13.5: 1.5) substep gradient elution, obtains solid.With this solid be dissolved in minimum hot acetonitrile (～2mL) in, remove by filter a small amount of insolubles, with methyl alcohol (＜0.5mL) washing, leave standstill under the room temperature.Filter to collect the solid that spends the night and form, with other acetonitrile washing, under about 60 ℃ in vacuum drying oven about 2 hours of drying, obtain title compound. 1H?NMR(400MHz，DMSO-d 6)δppm?11.35(s，1H)，8.10(s，1H)，7.86(s，1H)，7.84(s，1H)，7.44(dd，J＝8.54，1.26Hz，1H)，7.23(d，J＝8.62Hz，1H)，5.32(s，2H)，4.42(t，J＝6.36Hz，2H)，3.10(t，J＝6.43Hz，2H).MS(ESI+)m/z?253.2(M+H) +。
Embodiment 268
2-[4-(3-amino-1H-indazole-5-yl)-1H-pyrazol-1-yl] ethanamide
Embodiment 268A
2-(4-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycle pentane-2-yls)-1H-pyrazol-1-yl) ethanamide
With 4-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycle pentane-2-yls)-1H-pyrazoles (2.00g, 10.3mmol), the 2-bromoacetamide (2.14g, 15.5mmol) and salt of wormwood (2.14g, 15.5mmol) suspension in acetone (60mL) is in about 50 ℃ of down about 3.5 days of heating.Then reaction mixture is chilled to room temperature, by diatomite filtration, with other washing with acetone, concentrating under reduced pressure then.Crude product is dissolved in the methylene dichloride of minimum then, uses the silica gel chromatography purifying, the n-heptane solution gradient elution with the 80-100% ethyl acetate obtains title compound. 1H?NMR(400MHz，DMSO-d 6)δppm?7.88(s，1H)，7.57(s，1H)，7.46(s，1H)，7.24(s，1H)，4.77(s，2H)，1.26(s，12H).MS(ESI+)m/z?252.2(M+H) +。
Embodiment 268B
2-[4-(3-amino-1H-indazole-5-yl)-1H-pyrazol-1-yl] ethanamide
Prepare title compound with the method for describing among the embodiment 267B, wherein replace embodiment 267A, heated about 10 minutes down at about 120 ℃ with embodiment 268A. 1H?NMR(400MHz，DMSO-d 6)δppm?11.32(s，1H)，7.98(s，1H)，7.87(s，1H)，7.77(s，1H)，7.48(s，1H)，7.45(d，J＝8.6Hz，1H)，7.26(s，1H)，7.22(d，J＝8.7Hz，1H)，5.28(s，2H)，4.78(s，2H).MS(ESI+)m/z?257.2(M+H) +。
Embodiment 269
3-[4-(3-amino-1H-indazole-5-yl)-1H-pyrazol-1-yl] methyl propionate
Embodiment 269A
3-(4-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycle pentane-2-yls)-1H-pyrazol-1-yl) propionic acid methyl ester
Prepare title compound with the method for describing among the embodiment 267A, wherein replace vinyl cyanide with methyl acrylate. 1H?NMR(400MHz，DMSO-d 6)δppm?7.91(s，1H)，7.57(s，1H)，4.35(t，J＝6.73Hz，2H)，2.87(t，J＝6.75Hz，2H)，3.59(s，3H)，1.24(s，12H).MS(ESI+)m/z?281.2(M+H) +。
Embodiment 269B
3-[4-(3-amino-1H-indazole-5-yl)-1H-pyrazol-1-yl] methyl propionate
Prepare title compound with the method for describing among the embodiment 267B, wherein replace embodiment 267A, heated about 20 minutes down at about 120 ℃ with embodiment 269A. 1H?NMR(400MHz，DMSO-d 6)δppm?11.32(s，1H)，8.00(s，1H)，7.85(s，1H)，7.76(s，1H)，7.42(d，J＝8.50Hz，1H)，7.21(d，J＝8.61Hz，1H)，5.28(s，2H)，4.37(t，J＝6.71Hz，2H)，3.61(s，3H)，2.92(t，J＝6.69Hz，2H).MS(ESI+)m/z?286.2(M+H) +。
Embodiment 270
3-[4-(3-amino-1H-indazole-5-yl)-1H-pyrazol-1-yl] propionic acid amide
Embodiment 270A
3-(4-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycle pentane-2-yls)-1H-pyrazol-1-yl) propionic acid amide
Prepare title compound with the method for describing among the embodiment 267A, wherein replace vinyl cyanide (0.72g, 53%) with acrylamide. 1H?NMR(400MHz，DMSO-d 6)δppm?7.84(s，1H)，7.56(s，1H)，7.37(s，1H)，6.88(s，1H)，4.30(t，J＝6.80Hz，2H)，2.60(t，J＝6.79Hz，2H)，1.24(s，12H).MS(ESI+)m/z?266.2(M+H) +。
Embodiment 270B
3-[4-(3-amino-1H-indazole-5-yl)-1H-pyrazol-1-yl] propionic acid amide
Prepare title compound with the method for describing among the embodiment 267B, wherein replace embodiment 267A, heat about 15 minutes (0.056g, 22%) down at about 120 ℃ with embodiment 270A. 1H?NMR(400MHz，DMSO-d 6)δppm?11.32(s，1H)，7.94(d，J＝0.53Hz，1H)，7.84(s，1H)，7.75(d，J＝0.54Hz，1H)，7.42(m，2H)，7.20(d，J＝8.26Hz，1H)，6.89(s，1H)，5.27(s，2H)，4.32(t，J＝6.89Hz，2H)，2.65(t，J＝6.89Hz，2H).MS(ESI+)m/z?271.0(M+H) +。
Embodiment 271
[4-(3-amino-1H-indazole-5-yl)-1H-pyrazol-1-yl] acetonitrile
Embodiment 271A
2-(4-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycle pentane-2-yls)-1H-pyrazol-1-yl) acetonitrile
Prepare title compound with the method for describing among the 268A, wherein replace the 2-bromoacetamide with the 2-bromoacetonitrile. 1H?NMR(400MHz，DMSO-d 6)δppm?7.99(s，1H)，7.66(s，1H)，5.45(s，2H)，1.25(s，12H)。
Embodiment 271B
3-(two (tert-butoxycarbonyl) amino)-5-bromo-1H-indazole-1-t-butyl formate
To 5-bromo-1H-indazole-3-amine (2.00g, add in tetrahydrofuran (THF) 9.43mmol) (20mL) solution 4-(dimethylamino) pyridine (0.230g, 1.886mmol) and two-tertiary butyl, two carbonic ethers (6.18g, 28.3mmol).Be reflected at 50 ℃ and heated about 2 hours down, be chilled to room temperature, concentrating under reduced pressure.Residue is dissolved in ether (100mL), uses 1N hydrochloric acid (2x 25mL), 1N sodium hydroxide (2x25mL) and salt solution (25mL) washing then successively.Use the dried over sodium sulfate organic layer then, filter, concentrating under reduced pressure, dry in vacuum drying oven under about 60 ℃, obtain title compound. 1H?NMR(400MHz，DMSO-d 6)8.05(d，J＝8.95Hz，1H)，7.99(d，J＝1.90Hz，1H)，7.81(dd，J＝8.94，1.89Hz，1H)，1.65(s，9H)，1.40(s，18H).MS(ESI+)m/z?512.2(M+H) +。
Embodiment 271C
3-(two (tert-butoxycarbonyl) amino)-5-(1-(cyano methyl)-1H-pyrazoles-4-yl)-1H-indazole-1-t-butyl formate
In phial, pack into embodiment 271A (0.682g, 2.93mmol), embodiment 271B (1.25g, 2.44mmol), cesium carbonate (1.99g, 6.10mmol), 1,4-dioxane (12.5mL) and water (2.50mL).After purifying with vacuum by barrier film (septa), (0.112g, 0.122mmol) (0.085g 0.29mmol), behind nitrogen wash, covers phial with tri-tert phosphorus a tetrafluoro borate to add three (dibenzalacetones), two palladiums (0).After at room temperature 6 hours, will be reflected between saturated sodium bicarbonate aqueous solution and the methylene dichloride (each 50mL) and distribute.Separate organic layer, water layer extracts with other methylene dichloride (2x50mL).The organic layer salt water washing that merges, dried over mgso is filtered concentrating under reduced pressure.Crude product oily matter is dissolved in the methylene dichloride of minimum, uses the silica gel chromatography purifying, the n-heptane solution gradient elution with the 20-60% ethyl acetate obtains title compound. 1H?NMR(400MHz，DMSO-d 6)δppm?8.43(s，1H)，8.19(s，1H)，8.08(d，J＝9.22Hz，1H)，7.93(m，2H)，5.53(s，2H)，1.67(s，9H)，1.39(s，18H).MS(ESI+)m/z?539.3(M+H) +。
Embodiment 271D
[4-(3-amino-1H-indazole-5-yl)-1H-pyrazol-1-yl] acetonitrile
To 3-(two (tert-butoxycarbonyl) amino)-(0.30g adds trifluoroacetic acid (2.0mL) in methylene dichloride 0.557mmol) (4.0mL) solution to 5-(1-(cyano methyl)-1H-pyrazoles-4-yl)-1H-indazole-1-t-butyl formate.After 45 minutes, will react and slowly use the saturated sodium bicarbonate solution quencher.The gained mixture extracts with methylene dichloride (3x25mL).The organic layer salt water washing that merges, dried over mgso is filtered, and concentrating under reduced pressure obtains thick solid.Filtration is suspended in the white depositions of initial water layer and brine layer, adds thick solid.The gained solid grinds with methylene chloride (19: 1).Remaining solid is collected in vacuum filtration, and is dry in vacuum drying oven under about 70 ℃, obtains title compound. 1HNMR(400MHz，DMSO-d 6)δppm?11.37(s，1H)，8.12(s，1H)，7.92(s，1H)，7.89(s，1H)7.49-7.41(m，1H)，7.24(d，J＝8.71Hz，1H)，5.52(s，2H)，5.31(s，2H).MS(ESI+)m/z?239.1(M+H) +。
Embodiment 272
4-(3-amino-1H-indazole-5-yl)-N, N-dimethyl-1H-imidazoles-1-sulphonamide
With 3-cyano group-4-fluorophenyl boric acid (0.083g, 0.503mmol), 4-iodo-N, N-dimethyl-1H-imidazoles-1-sulphonamide (0.167g, 0.554mmol), yellow soda ash (0.128g, 1.208mmol) and tetrakis triphenylphosphine palladium (0) (0.035g, 0.030mmol) mixing in glycol dimethyl ether (4mL) and water (1.5mL).Reaction mixture heated about 25 minutes down at about 150 ℃ in microwave (CEM-Discover).Separate organic layer, removal of solvent under reduced pressure.In residue, add ethanol (0.7mL) and hydrazine monohydrate (1mL).Reaction mixture was heated about 20 hours down at about 80 ℃.Reaction mixture is distributed between water (5mL) and methylene dichloride (100mL).Separate organic layer, concentrating under reduced pressure.Residue by the reversed-phase HPLC purifying, obtains title compound with acetonitrile/water (0.05M ammonium acetate) linear gradient elution method. 1HNMR(400MHz，DMSO-
Figure GPA00001018010701731
δδppm?11.42(s，1H)，8.25(s，1H)，8.21(d，J＝1.36Hz，1H)，7.92(d，J＝1.37Hz，1H)，7.74(dd，J＝8.66，1.58Hz，1H)，7.23(d，J＝8.68Hz，1H)，5.35(s，2H)，2.87(s，6H).MS(ESI+)m/z?307.2(M+H) +。
Embodiment 273
5-pyrazine-2-base-1H-indazole-3-amine
Prepare title compound with the method for describing among the embodiment 272, wherein replace 4-iodo-N, N-dimethyl-1H-imidazoles-1-sulphonamide with 2-iodine pyrazine. 1H?NMR(400MHz，DMSO-d 6)δppm11.61(s，1H)，9.18(d，1H，J＝1.6)，8.66(dd，1H，J＝1.7，2.4)，8.59(d，1H，J＝1.0)，8.51(d，1H，J＝2.5)，8.04(dd，1H，J＝1.8，8.8)，7.35(d，1H，J＝9.2)，5.54(s，2H).MS(ESI+)m/z?212.2(M+H) +。
Embodiment 274
5-thiophene-2-base-1H-indazole-3-amine
Prepare title compound with the method for describing among the embodiment 272, wherein replace 4-iodo-N, N-dimethyl-1H-imidazoles-1-sulphonamide with the 2-iodothiophen. 1H?NMR(400MHz，DMSO-d 6)δppm11.47(s，1H)，7.99(d，1H，J＝1.4)，7.55(dd，1H，J＝1.8，8.8)，7.43(dd，1H，J＝1.0，5.1)，7.35(dd，1H，J＝1.1，3.6)，7.26(d，1H，J＝8.6)，7.10(dd，1H，J＝3.5，5.1)，5.42(d，2H，J＝8.8).MS(ESI+)m/z?216.1(M+H) +。
Embodiment 275
5-(2-aminopyrimidine-4-yl)-1H-indazole-3-amine
Prepare title compound with the method for describing among the embodiment 272, wherein replace 4-iodo-N, N-dimethyl-1H-imidazoles-1-sulphonamide with 5-iodine pyrimidine-2-amine. 1H?NMR(400MHz，DMSO-d 6)δppm?11.40(s，1H)，8.53(s，2H)，7.91(dd，1H，J＝0.7，1.5)，7.47(dd，1H，J＝1.8，8.6)，7.28(dd，1H，J＝0.7，8.7)，6.64(s，2H)，5.36(s，2H).1H?NMR(400MHz，DMSO-d 6)δppm?11.41(s，1H)，8.53(s，2H)，7.92(m，1H)，7.47(dd，J＝8.66，1.74Hz，1H)，7.28(dd，J＝8.63，0.65Hz，1H)，6.64(s，2H)，5.36(s，2H).MS(ESI+)m/z?227.2(M+H) +。
Embodiment 276
5-(2-methoxypyridine-3-yl)-1H-indazole-3-amine
Prepare title compound with the method for describing among the embodiment 272, wherein replace 4 iodo-N, N-dimethyl-1H-imidazoles-1-sulphonamide with 3-iodo-2-methoxypyridine. 1H?NMR(400MHz，DMSO-d 6)δppm?11.43(s，1H)，8.14(dd，1H，J＝1.9，5.0)，7.86(s，1H)，7.71(dd，1H，J＝2.0，7.2)，7.42(dd，1H，J＝1.7，8.7)，7.26(d，1H，J＝8.6)，7.09(dd，1H，J＝5.0，7.3)，5.38(s，2H)，3.89(s，3H).MS(ESI+)m/z?241.2(M+H) +.
Embodiment 277
5-imidazo [1,2-a] pyridin-3-yl-1H-indazole-3-amine
Prepare title compound with the method for describing among the embodiment 272, wherein use 3-bromine imidazo [1,2-a] pyridine to replace 4-iodo-N, N-dimethyl-1H-imidazoles-1-sulphonamide. 1H?NMR(400MHz，DMSO-d 6)δppm?8.52(dt，1H，J＝1.2，7.0)，7.99(dd，1H，J＝0.7，1.7)，7.68(s，1H)，7.65(dt，2H，J＝1.2，9.0)，7.46(dd，1H，J＝1.8，8.6)，7.39(dd，1H，J＝0.8，8.6)，7.28(ddd，1H，J＝1.2，6.6，9.2)，6.96(td，1H，J＝1.3，6.7)，5.47(s，2H).MS(ESI+)m/z?250.2(M+H) +。
Embodiment 278
N 2, N 2-dimethyl-N 1-[5-(1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl] G-NH2
(257mg 0.685mmol) is dissolved in ethanol (15mL) with embodiment 65.Reaction mixture in the H-Cube instrument with palladium hydroxide (20%)/carbon in about 80 ℃ of down about 8 hours of hydrogenations under about 60psi.Removal of solvent under reduced pressure, residue by the reversed-phase HPLC purifying, obtains title compound with acetonitrile/water (0.05M ammonium acetate) linear gradient elution method. 1H?NMR(400MHz，DMSO-d 6)δppm?8.16-8.37(m，1H)，7.10-7.46(bs，2H)，7.00-7.34(bs，2H)，6.87-7.24(bs，2H)，3.33-3.34(m，2H).MS(ESI+)m/z?286.2(M+H) +。
Embodiment 279
5-(1H-pyrazoles-5-yl)-1H-indazole-3-amine
Prepare title compound with the method for describing among the embodiment 272, wherein replace 4-iodo-N, N-dimethyl-1H-imidazoles-1-sulphonamide with 5-iodo-1H-pyrazoles. 1H?NMR(400MHz，DMSO-d 6)δppm7.87-7.94(m，3H)，7.60-7.63(m，1H)，7.48(dd，J＝8.55，1.62Hz，1H)，7.19-7.32(m，2H)，5.25-5.28(m，2H).MS(ESI+)m/z?200.1(M+H) +。
Embodiment 280
5-(4-methyl isophthalic acid H-imidazoles-5-yl)-1H-indazole-3-amine
Prepare title compound with the method for describing among the embodiment 272, wherein replace 4-iodo-N, N-dimethyl-1H-imidazoles-1-sulphonamide with 5-iodo-4-methyl isophthalic acid H-imidazoles. 1H?NMR(400MHz，DMSO-d 6)δppm?7.85(s，1H)，7.52(d，2H，J＝6.6)，7.22(m，1H)，5.32(bs，2H).2.37(s，3H).MS(ESI+)m/z?214.1(M+H) +。
Embodiment 281
5-(1H-imidazol-4 yl)-1H-indazole-3-amine
Prepare title compound with the method for describing among the embodiment 272, wherein replace 4-iodo-N, N-dimethyl-1H-imidazoles-1-sulphonamide with 4-iodo-1H-imidazoles. 1H?NMR(400MHz，DMSO-d 6)δppm8.07(s，1H)，7.66(s，1H)，7.63(d，1H，J＝8.6)，7.37(s，1H)，7.20(d，1H，J＝8.8)，5.28(s，2H).MS(ESI+)m/z?200.1(M+H) +。
Embodiment 282
N 2, N 2-dimethyl-N 1-5-[1-(3-methyl-benzyl)-1H-1,2,3-triazole-4-yl]-1H-indazole-3-yl } G-NH2
Embodiment 282A
5-bromo-1H-indazole-3-amine
Prepare title compound with the method for describing among the embodiment 62D, wherein replace embodiment 62C with 5-bromo-2-fluorobenzonitrile. 1H?NMR(400MHz，DMSO-d 6)δppm?11.55(s，1H)，7.92(d，J＝1.87Hz，1H)，7.30(dd，J＝8.79，1.89Hz，1H)，7.19(d，J＝8.78Hz，1H)，5.41(s，2H)。
Embodiment 282B
3-amino-5-bromo-1H-indazole-1-t-butyl formate
Prepare title compound with the method for describing among the embodiment 64A, wherein replace embodiment 62D with embodiment 282A. 1H?NMR(400MHz，DMSO-d 6)δppm?8.12(d，J＝1.93Hz，1H)，7.95-7.81(m，1H)，7.65(dd，J＝8.85，1.96Hz，1H)，6.39(d，J＝4.44Hz，1H)，1.58(m，9H)
Embodiment 282C
5-bromo-3-(2-(dimethylamino) kharophen)-1H-indazole-1-t-butyl formate
To embodiment 282B (24.43g, 78mmol), salt of wormwood (81g, 587mmol) and 2-(dimethylamino) acetyl chloride hydrochloride (43.3g adds tetrahydrofuran (THF) (200mL) in mixture 274mmol).Reaction mixture is stir about 2 hours at room temperature.Filter reaction mixture, water (50mL) wash filtrate.Separate organic layer, water layer extracts with methylene dichloride (3x100mL).The organic extract liquid dried over mgso that merges is filtered concentrating under reduced pressure.Residue silica gel chromatography purifying, methylene dichloride (5%) eluant solution with methyl alcohol obtains title compound. 1H?NMR(400MHz，DMSO-d 6)δppm?10.72(s，1H)，8.19(d，1H，J＝1.6)，8.03(d，1H，J＝9.0)，7.76(dd，1H，J＝2.0，9.0)，3.22(s，2H)，2.32(s，6H)，1.63(s，9H)。
Embodiment 282D
3-(2-(dimethylamino) kharophen)-5-((trimethyl silyl) ethynyl)-1H-indazole-1-formic acid tertiary butyl ester
To embodiment 282C (2.56g, 6.44mmol), two (triphenylphosphine) palladium chloride (II) (0.225g, 0.321mmol) and cuprous iodide (I) (0.073g, 0.383mmol) mixture in add triethylamine (20mL, 144mmol), add then the ethynyl trimethyl silyl (0.760g, 7.73mmol).Reaction mixture was heated about 3 hours down at about 60 ℃.Reaction mixture dilutes with methylene dichloride (100mL), water (20mL) and salt solution (20mL) washing, and dried over mgso is filtered concentrating under reduced pressure.Residue silica gel chromatography purifying, dichloromethane solution (10%) wash-out with ethyl acetate obtains title compound. 1H?NMR(400MHz，DMSO-d 6)δppm?10.69(s，1H)，8.08(s，1H)，8.04(d，1H，J＝9.0)，7.62(d，1H，J＝8.8)，3.21(s，2H)，2.30(s，6H)，1.61(s，9H)，0.23(s，9H)。
Embodiment 282E
2-(dimethylamino)-N-(5-ethynyl-1H-indazole-3-yl) ethanamide
(0.303g adds potassium hydroxide aqueous solution (1.46mL, 1.46mmol, the solution of 1.0N) in methyl alcohol 0.731mmol) (5mL) solution to embodiment 282D.Reaction mixture is stir about 1 hour at room temperature.Removal of solvent under reduced pressure, residue are dissolved in ethyl acetate (80mL).Separate organic layer, water (10mL) and salt solution (10mL) washing, dried over mgso is filtered, and concentrating under reduced pressure obtains title compound. 1H?NMR(400MHz，DMSO-d 6)δppm?12.89(s，1H)，10.14(s，1H)，8.00(d，1H，J＝12.1)，7.44(s，2H)，7.38(d，1H，J＝8.6)，4.02(s，1H)，3.17(s，2H)，2.33(s，6H)。
Embodiment 282F
N 2, N 2-dimethyl-N 1-5-[1-(3-methyl-benzyl)-1H-1,2,3-triazole-4-yl]-1H-indazole-3-yl } G-NH2
(0.16g, (0.098g 0.667mmol), adds entry (1.2mL) then 0.660mmol) to add 1-(azido-methyl)-3-methylbenzene in the suspension in the trimethyl carbinol (1.2mL) to embodiment 282E.Add (R)-2-((S)-1,2-dihydroxy ethyl)-4-hydroxyl-5-oxo-2, and the 5-dihydrofuran-3-sodium alkoxide (0.057mL, 0.066mmol, the aqueous solution of 1.6M) and copper sulfate (II) the pentahydrate aqueous solution (0.019ml, 6.6 μ mol, 0.34M).Reaction mixture heated about 2 hours down at about 60 ℃.Removal of solvent under reduced pressure, residue by the reversed-phase HPLC purifying, obtains title compound with acetonitrile/water (0.05M ammonium acetate) linear gradient elution method. 1H?NMR(400MHz，DMSO-d 6)δppm?12.77(s，1H)，10.05(s，1H)，8.56(s，1H)，8.24(s，1H)，7.82(d，1H，J＝8.6)，7.50(d，1H，J＝8.8)，7.28(t，1H，J＝7.6)，7.16(m，4H)，5.59(s，2H)，3.18(s，2H)，2.34(s，6H)，2.30(s，3H).MS(ESI+)m/z?390.3(M+H) +。
Embodiment 283
5-(1-benzyl-1H-imidazol-4 yl)-1H-indazole-3-amine
Prepare title compound with the method for describing among the embodiment 272, wherein replace 4-iodo-N, N-dimethyl-1H-imidazoles-1-sulphonamide with 1-benzyl-4-iodo-1H-imidazoles. 1H?NMR(400MHz，DMSO-d 6)δppm?11.29(s，1H)，8.07(s，1H)，7.79(s，1H)，7.61(d，1H，J＝8.6)，7.46(s，1H)，7.36(m，5H)，7.17(d，1H，J＝8.8)，5.28(s，2H)，5.22(s，2H).MS(ESI+)m/z?290.2(M+H) +。
Embodiment 284
N 1-5-[1-(4-tertiary butyl benzyl)-1H-1,2,3-triazole-4-yl]-1H-indazole-3-yl }-N 2, N 2-dimethyl G-NH2
Prepare title compound with the method for describing among the embodiment 282F, wherein use 1-(azido-methyl)-4-tert.-butylbenzene to replace 1-(azido-methyl)-3-methylbenzene. 1H?NMR(400MHz，DMSO-d 6)δppm?12.88(s，1H)，10.05(s，1H)，8.57(s，1H)，8.23(s，1H)，7.81(d，1H，J＝8.8)，7.50(d，1H，J＝8.8)，7.41(d，2H，J＝8.2)，7.30(d，2H，J＝8.2)，3.18(s，2H)，2.34(s，6H)，1.26(s，9H).MS(ESI+)m/z?432.2(M+H) +。
Embodiment 285
N 2, N 2-dimethyl-N 1-5-[1-(2-piperidines-1-base ethyl)-1H-1,2,3-triazole-4-yl]-1H-indazole-3-yl } G-NH2
Prepare title compound with the method for describing among the embodiment 282F, wherein use 1-(2-azido-ethyl) piperidines to replace 1-(azido-methyl)-3-methylbenzene. 1H?NMR(400MHz，DMSO-d 6)δppm12.91(s，1H)，10.07(s，1H)，8.47(s，1H)，8.22(s，1H)，7.80(dd，1H，J＝1.2，8.7)，7.52(d，1H，J＝8.8)，4.49(t，2H，J＝6.4)，3.19(s，2H)，2.76(t，2H，J＝6.4)，2.41(s，4H)，2.35(s，6H)，1.69(s，3H)，1.47(m，4H)，1.37(dd，2H，J＝5.2，10.2).MS(ESI-)m/z?395.3(M-H) -。
Embodiment 286
N 2, N 2-dimethyl-N 1-5-[1-(2-morpholine-4-base ethyl)-1H-1,2,3-triazole-4-yl]-1H-indazole-3-yl } G-NH2
Prepare title compound with the method for describing among the embodiment 282F, wherein use 4-(2-azido-ethyl) morpholino for 1-(azido-methyl)-3-methylbenzene. 1H?NMR(400MHz，DMSO-d 6)δppm12.83(s，1H)，10.07(s，1H)，8.49(s，1H)，8.23(s，1H)，7.81(dd，1H，J＝1.3，8.7)，7.52(d，1H，J＝8.8)，4.53(t，2H，J＝6.3)，3.55(m，4H)，3.19(s，2H)，2.80(t，2H，J＝6.3)，2.45(m，4H)，2.35(s，6H).MS(ESI-)m/z?397.3(M-H) -。
Embodiment 287
N 1-(5-{1-[2-(3,5-dimethyl isoxazole-4-yl) ethyl]-1H-1,2,3-triazole-4-yl }-1H-indazole-3-yl)-N 2, N 2-dimethyl G-NH2
Prepare title compound with the method for describing among the embodiment 282F, wherein use 4-(2-azido-ethyl)-3, the 5-dimethyl isoxazole replaces 1-(azido-methyl)-3-methylbenzene. 1H?NMR(400MHz，DMSO-d 6)δppm?12.90(s，1H)，10.07(s，1H)，8.44(s，1H)，8.21(s，1H)，7.78(dd，1H，J＝1.3，8.7)，7.52(d，1H，J＝8.8)，4.51(t，2H，J＝6.7)，3.19(s，2H)，2.93(t，2H，J＝6.7)，2.35(s，6H)，2.08(d，6H，J＝4.3).MS(ESI-)m/z?407.2(M-H) -。
Embodiment 288
N 1-(5-{1-[2-(3,5-dimethyl-1H-pyrazoles-4-yl) ethyl]-1H-1,2,3-triazole-4-yl }-1H-indazole-3-yl)-N 2, N 2-dimethyl G-NH2
Prepare title compound with the method for describing among the embodiment 282F, wherein use 4-(2-azido-ethyl)-3,5-dimethyl-1H-pyrazoles replaces 1-(azido-methyl)-3-methylbenzene. 1H?NMR(400MHz，DMSO-d 6)δppm?12.85(s，1H)，10.06(s，1H)，8.37(s，1H)，8.21(s，1H)，7.78(d，1H，J＝8.8)，7.51(d，1H，J＝8.8)，4.42(t，2H，J＝6.9)，3.19(s，2H)，2.89(t，2H，J＝7.0)，2.35(s，6H)，1.97(s，6H).MS(ESI-)m/z?406.2(M-H) -。
Embodiment 289
2-(4-{3-[(N, N-dimethyl glycyl) amino]-1H-indazole-5-yl }-1H-1,2, the 3-triazol-1-yl)-2 Methylpropionic acid
Prepare title compound with the method for describing among the embodiment 282F, wherein replace 1-(azido-methyl)-3-methylbenzene with 2-azido--2 Methylpropionic acid. 1H?NMR(400MHz，DMSO-d 6)δppm12.77(s，1H)，10.03(s，1H)，8.47(s，1H)，8.22(s，1H)，7.85(dd，1H，J＝0.9，8.7)，7.49(d，1H，J＝8.6)，3.21(s，2H)，2.36(s，6H)，1.77(s，6H).MS(ESI-)m/z?370.2(M-H) -。
Embodiment 290
(4-{3-[(N, N-dimethyl glycyl) amino]-1H-indazole-5-yl }-1H-1,2, the 3-triazol-1-yl) ethyl acetate
Prepare title compound with the method for describing among the embodiment 282F, wherein replace 1-(azido-methyl)-3-methylbenzene with the 2-ethyl triazoacetate. 1H?NMR(400MHz，DMSO-d 6)δppm?12.87(s，1H)，10.08(s，1H)，8.51(s，1H)，8.26(s，1H)，7.82(dd，1H，J＝1.4，8.7)，7.53(d，1H，J＝8.8)，5.44(s，2H)，4.21(q，2H，J＝7.0)，3.19(s，2H)，2.35(s，6H)，1.24(t，3H，J＝7.1).MS(ESI+)m/z?372.2(M+H) +。
Embodiment 291
N 2, N 2-dimethyl-N 1-(5-{1-[(trimethyl silyl) methyl]-1H-1,2,3-triazole-4-yl }-1H-indazole-3-yl) G-NH2
Prepare title compound with the method for describing among the embodiment 282F, wherein use (azido-methyl) trimethyl silyl to replace 1-(azido-methyl)-3-methylbenzene. 1H?NMR(400MHz，DMSO-d 6)δppm?13.04(s，1H)，10.20(s，1H)，8.46(s，1H)，8.36(s，1H)，7.94(dd，1H，J＝1.3，8.7)，7.65(d，1H，J＝8.8)，4.18(s，2H)，3.33(s，2H)，2.49(s，6H)，0.25(m，9H).MS(ESI+)m/z?372.2(M+H) +。
Embodiment 292
N 1-[5-(3-furyl)-1H-indazole-3-yl]-N 2, N 2-dimethyl G-NH2
Prepare title compound with the method for describing among the embodiment 233A, wherein replace 5-bromo-2-fluorobenzonitrile, replace 1-benzyl-4-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycle pentane-2-yls)-1H-pyrazoles with furans-3-ylboronic acid with embodiment 282C. 1H?NMR(600MHz，DMSO-d 6)δppm12.70(s，1H)，9.98(s，1H)，8.08(s，1H)，7.90(s，1H)，7.72(t，1H，J＝1.6)，7.59(dd，1H，J＝1.4，8.7)，7.45(d，1H，J＝8.8)，6.87(s，1H)，3.17(s，2H)，2.33(s，6H).MS(ESI+)m/z?285.2(M+H) +。
Embodiment 293
N 2, N 2-dimethyl-N 1-[5-(1H-pyrazoles-5-yl)-1H-indazole-3-yl] G-NH2
Prepare title compound with the method for describing among the embodiment 233A, wherein replace 5-bromo-2-fluorobenzonitrile, replace 1-benzyl-4-(4 with 1H-pyrazoles-5-ylboronic acid with embodiment 282C, 4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycle pentane-2-yls)-the 1H-pyrazoles. 1H?NMR(400MHz，DMSO-d 6)δppm?12.68(s，1H)，10.01(s，1H)，8.12(s，1H)，7.80(d，1H，J＝9.0)，7.69(s，1H)，7.46(d，1H，J＝8.6)，6.60(d，1H，J＝2.0)，3.17(d，2H，J＝6.4)，2.34(s，6H).MS(ESI+)m/z?285.2(M+H) +。
Embodiment 294
N 2, N 2-dimethyl-N 1-(5-pyrimidine-5-base-1H-indazole-3-yl) G-NH2
Prepare title compound with the method for describing among the embodiment 233A, wherein replace 5-bromo-2-fluorobenzonitrile, replace 1-benzyl-4-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycle pentane-2-yls)-1H-pyrazoles with pyrimidine-5-ylboronic acid with embodiment 282C. 1H?NMR(600MHz，DMSO-d 6)δppm12.87(s，1H)，10.11(s，1H)，9.16(s，1H)，9.09(s，2H)，8.16(s，1H)，7.75(dd，1H，J＝1.5，8.8)，7.60(d，1H，J＝8.8)，3.18(s，2H)，2.33(s，6H).MS(ESI+)m/z?297.2(M+H) +。
Embodiment 295
N 1-[5-(2,1,3-Ben Bing oxadiazole-5-yl)-1H-indazole-3-yl]-N 2, N 2-dimethyl G-NH2
Prepare title compound with the method for describing among the embodiment 233A, wherein replace 5-bromo-2-fluorobenzonitrile, with benzo [c] [1,2 with embodiment 282C, 5] oxadiazole-5-ylboronic acid replaces 1-benzyl-4-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycle pentane-2-yls)-the 1H-pyrazoles. 1H?NMR(600MHz，DMSO-d 6)δppm?12.87(s，1H)，10.15(s，1H)，8.29(s，1H)，8.21(s，1H)，8.16(d，1H，J＝9.4)，7.99(dd，1H，J＝1.1，9.4)，7.85(m，1H)，7.59(d，1H，J＝8.8)，3.19(s，2H)，2.34(s，6H).MS(ESI+)m/z?337.2(M+H) +。
Embodiment 296
N 2, N 2-dimethyl-N 1-[5-(1H-pyrazoles-4-yl)-1H-indazole-3-yl] G-NH2
Prepare title compound with the method for describing among the embodiment 233A, wherein replace 5-bromo-2-fluorobenzonitrile, with 4-(4 with embodiment 282C, 4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycle pentane-2-yls)-1H-pyrazoles replacement 1-benzyl-4-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycle pentane-2-yls)-the 1H-pyrazoles. 1H?NMR(600MHz，DMSO-d 6)δppm?12.62(s，1H)，9.94(s，1H)，7.95(s，2H)，7.87(s，1H)，7.58(d，1H，J＝8.8)，7.42(d，1H，J＝8.8)，3.16(s，2H)，2.34(s，6H).MS(ESI+)m/z?285.2(M+H) +。
Embodiment 297
N 2, N 2-dimethyl-N 1-[5-(1-methyl isophthalic acid H-pyrazoles-4-yl)-1H-indazole-3-yl] G-NH2
Prepare title compound with the method for describing among the embodiment 233A, wherein replace 5-bromo-2-fluorobenzonitrile, with 1-methyl-4-(4 with embodiment 282C, 4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycle pentane-2-yls)-1H-pyrazoles replacement 1-benzyl-4-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycle pentane-2-yls)-the 1H-pyrazoles. 1H?NMR(600MHz，DMSO-d 6)δppm?12.64(s，1H)，9.98(s，1H)，8.04(s，1H)，7.86(s，1H)，7.76(s，1H)，7.55(dd，1H，J＝1.6，8.6)，7.43(d，1H，J＝8.8)，3.87(s，3H)，3.17(s，2H)，2.35(s，6H).MS(ESI+)m/z?299.2(M+H) +。
Embodiment 298
N 1-[5-(3,5-dimethyl-1H-pyrazoles-4-yl)-1H-indazole-3-yl]-N 2, N 2-dimethyl G-NH2
Prepare title compound with the method for describing among the embodiment 233A, wherein replace 5-bromo-2-fluorobenzonitrile, with 3 with embodiment 282C, 5-dimethyl-4-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycle pentane-2-yls)-1H-pyrazoles replacement 1-benzyl-4-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycle pentane-2-yls)-the 1H-pyrazoles. 1H?NMR(600MHz，DMSO-d 6)δppm?12.63(s，1H)，10.02(s，1H)，7.63(s，1H)，7.46(m，1H)，7.27(dd，1H，J＝1.6，8.6)，3.16(s，2H)，2.32(s，6H)，2.18(s，6H).MS(ESI+)m/z?323.2(M+H) +。
Embodiment 299
N 1-5-[2-(dimethylamino) pyrimidine-5-yl]-1H-indazole-3-yl }-N 2, N 2-dimethyl G-NH2
Prepare title compound with the method for describing among the embodiment 233A, wherein replace 5-bromo-2-fluorobenzonitrile, use N with embodiment 282C, N-dimethyl-5-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycle pentane-2-yls) pyrimidine-2-amine replacement 1-benzyl-4-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycle pentane-2-yls)-the 1H-pyrazoles. 1H?NMR(600MHz，DMSO-d 6)δppm?12.72(s，1H)，10.03(s，1H)，8.62(s，2H)，7.91(s，1H)，7.58(dd，1H，J＝1.6，8.6)，7.51(d，1H，J＝8.5)，3.16(s，8H)，2.33(s，6H).MS(ESI+)m/z?340.2(M+H) +。
Embodiment 300
N 2, N 2-dimethyl-N 1-[5-(2-morpholine-4-yl pyrimidines-5-yl)-1H-indazole-3-yl] G-NH2
Prepare title compound with the method for describing among the embodiment 233A, wherein replace 5-bromo-2-fluorobenzonitrile with embodiment 282C, (5-(4 with 4-, 4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycle pentane-2-yls) pyrimidine-2-base) morpholino is for 1-benzyl-4-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycle pentane-2-yls)-the 1H-pyrazoles. 1H?NMR(600MHz，DMSO-d 6)δppm?12.74(s，1H)，10.03(s，1H)，8.67(s，2H)，7.94(s，1H)，7.60(dd，1H，J＝1.8，8.8)，7.52(d，1H，J＝8.5)，3.74(m，4H)，3.67(m，4H)，3.17(s，2H)，2.33(s，6H).MS(ESI+)m/z?382.2(M+H) +。
Embodiment 301
N 2, N 2-dimethyl-N 1-5-[1-(2-morpholine-4-base ethyl)-1H-pyrazoles-4-yl]-1H-indazole-3-yl } G-NH2
Prepare title compound with the method for describing among the embodiment 233A, wherein replace 5-bromo-2-fluorobenzonitrile with embodiment 282C, ((4-(4 for 2-with 4-, 4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycle pentane-2-yls)-and the 1H-pyrazol-1-yl) ethyl) morpholino is for 1-benzyl-4-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycle pentane-2-yls)-the 1H-pyrazoles. 1H?NMR(600MHz，DMSO-d 6)δppm?12.63(s，1H)，9.96(s，1H)，8.09(s，1H)，7.85(s，1H)，7.77(s，1H)，7.54(dd，1H，J＝1.5，8.8)，7.43(d，1H，J＝8.5)，4.24(t，2H，J＝6.6)，3.54(m，4H)，3.16(s，2H)，2.73(t，2H，J＝6.6)，2.41(s，4H)，2.34(s，6H).MS(ESI+)m/z?398.3(M+H) +。
Embodiment 302
N 1-[5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-N 2, N 2-dimethyl G-NH2
Embodiment 302A
1-benzyl-5-cyclopropyl-4-(tributyl stannyl)-1H-1,2, the 3-triazole
Prepare title compound with the method for describing among the embodiment 142A, wherein replace hexane, replace embodiment 80A with (azido-methyl) benzene with toluene.Crude product is not purified to be used for following step.
Embodiment 302B
5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazole-4-yl)-2-fluorobenzonitrile
Prepare title compound with the method for describing among the embodiment 142B, wherein replace embodiment 142A, replace 87A with 2-fluoro-5-iodobenzene formonitrile HCN with embodiment 302A.MS(ESI+)m/z?319.2(M+H) +。
Embodiment 302C
5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-amine
Prepare title compound with the method for describing among the embodiment 62D, wherein replace embodiment 62C with embodiment 302B.MS(ESI-)m/z?299.2(M-H) -。
Embodiment 302D
3-amino-5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazole-4-yl)-1H-indazole-1-t-butyl formate
Prepare title compound with the method for describing among the embodiment 64A, wherein replace embodiment 62D with embodiment 302C.
Embodiment 302E
N 1-[5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-N 2, N 2-dimethyl G-NH2
Prepare title compound with the method for describing among the embodiment 64B, wherein replace embodiment 64A, replace methoxyacetyl chloride with the dimethylamino acetyl chloride hydrochloride with embodiment 302D. 1H?NMR(400MHz，DMSO-d 6)δppm?12.76(s，1H)，10.06(s，1H)，8.18(s，1H)，7.79(d，1H，J＝8.8)，7.50(d，1H，J＝8.8)，7.34(m，5H)，5.68(s，2H)，3.16(s，2H)，2.32(s，6H)，1.76(m，1H)，1.05(q，2H，J＝6.1)，0.39(q，2H，J＝5.4).MS(ESI+)m/z?416.3(M+H)+.MS(ESI+)m/z?416.3(M+H) +。
Embodiment 303
N 1-[5-(1-benzyl-1H-pyrazoles-4-yl)-1H-indazole-3-yl]-N 2, N 2-dimethyl G-NH2
Embodiment 303A
3-amino-5-(1-benzyl-1H-pyrazoles-4-yl)-indazole-1-formic acid tertiary butyl ester
Prepare title compound with the method for describing among the embodiment 64A, wherein replace embodiment 62D (0.925g, 100%) with embodiment 233B. 1H?NMR(400MHz，DMSO-d 6)δppm?8.19(s，1H)，8.04(s，1H)，7.90-7.95(m，1H)，7.87(s，1H)，7.74(d，J＝1.6Hz，1H)，7.28-7.36(m，5H)，6.27(s，2H)，5.37(s，2H)，1.58(s，9H).MS(ESI+)m/z?390(M+H) +。
Embodiment 303B
N 1-[5-(1-benzyl-1H-pyrazoles-4-yl)-1H-indazole-3-yl]-N 2, N 2-dimethyl G-NH2
With 2-(dimethylamino) acetate (32mg, 0.308mmol) and oxalyl chloride (0.31mL, the suspension of methylene dichloride 0.61mmol) (5mL) and dimethyl formamide (2) at room temperature stirred 1 hour, then concentrating under reduced pressure.Residue is suspended in tetrahydrofuran (THF) (3mL), join embodiment 303A (40mg, 0.103mmol) and salt of wormwood (43mg is in tetrahydrofuran (THF) 0.308mmol) (5mL) suspension.Reaction mixture is stir about 30 minutes at room temperature, adds trifluoroacetic acid (4mL) then, and reaction mixture is in about 60 ℃ of about 20 hours of heating down.Reaction mixture is chilled to room temperature, and concentrating under reduced pressure with methylene dichloride (20mL) dilution, washs with 15% sodium hydroxide solution (20mL).Separate organic extract liquid, dried over mgso is filtered concentrating under reduced pressure.Crude product by the reversed-phase HPLC purifying, obtains the acetate of title compound with acetonitrile/water (0.05M ammonium acetate) linear gradient elution method. 1H?NMR(400MHz，DMSO-d 6)δppm?9.97(s，1H)，8.21(s，1H)，7.83(s，1H)，7.82(s，1H)，7.56(d，J＝8.7Hz，1H)，7.43(d，J＝8.6Hz，1H)，7.32-7.40(m，2H)，7.25-7.32(m，3H)，5.35(s，2H)，3.16(s，2H)，2.33(s，6H)，1.91(s，3H).MS(ESI+)m/z?375(M+H) +。
Embodiment 304
N 1-[5-(1-benzyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-N 2-methyl G-NH2
Prepare title compound with the method for describing among the embodiment 303B, wherein use 2-(tert-butoxycarbonyl (methyl) amino) acetate to replace 2-(dimethylamino) acetate, replace embodiment 303A with embodiment 64A. 1H?NMR(400MHz，DMSO-d 6)δppm?8.56(s，1H)，8.28(s，1H)，7.78-7.88(m，1H)，7.45-7.56(m，1H)，7.28-7.45(5H，m)，5.64(2H，s)，2.37(s，2H)，1.89(s，3H).MS(ESI+)m/z?362(M+H) +。
Embodiment 305
N-[5-(1-benzyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-2-tetramethyleneimine-1-yl acetamide
Embodiment 305A
5-(1-benzyl-1H-1,2,3-triazole-4-yl)-3-(2-acetobrom amino)-1H-indazole-1-t-butyl formate
To embodiment 64A (500mg, add in tetrahydrofuran (THF) 1.28mmol) (12mL) suspension diisopropyl ethyl amine (0.22mL, 1.28mmol).Reaction mixture is stir about 15 minutes at room temperature, add then the 2-bromoacetyl chloride (0.11mL, 1.2mmol).Reaction mixture is stir about 16 hours at room temperature, and then add the 2-bromoacetyl chloride (0.11mL, 1.2mmol).Reaction mixture restir 15 minutes, concentrating under reduced pressure obtains title compound then, is brown solid.This material uses without being further purified.
Embodiment 305B
N-[5-(1-benzyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-2-tetramethyleneimine-1-yl acetamide
(44mg, 0.086mmol) (0.015mL, (0.021mL, 0.25mmol), reaction mixture heated about 15 minutes down at about 60 ℃ to add tetramethyleneimine in acetonitrile 0.086mmol) (1mL) solution with the sec.-propyl ethylamine to embodiment 305A.Reaction mixture is chilled to room temperature, adds trifluoroacetic acid (1mL).Reaction mixture was heated about 48 hours down at about 60 ℃.The concentrating under reduced pressure reaction mixture with methylene dichloride (20mL) dilution, washs with 15% aqueous sodium hydroxide solution (20mL).Separate organic layer, dried over mgso is filtered concentrating under reduced pressure.Crude product by the reversed-phase HPLC purifying, obtains title compound with acetonitrile/water (0.05M ammonium acetate) linear gradient elution method. 1H?NMR(400MHz，DMSO-d 6)δppm?8.58(s，1H)，8.24(s，1H)，7.81(d，J＝8.7Hz，1H)，7.50(d，J＝8.7Hz，1H)，7.27-7.45(m，5H)，5.64(s，2H)，3.35(s，2H)，2.65(s，4H)，1.76(s，4H).MS(ESI+)m/z?402(M+H) +。
Embodiment 306
N 1-[5-(1-benzyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-N 2-cyclopentyl G-NH2
Prepare title compound with the method for describing among the embodiment 305B, wherein replace tetramethyleneimine (0.004g, 12%) with cyclopentamine. 1H?NMR(400MHz，DMSO-d 6)δppm?8.56(s，1H)，8.31(s，1H)，7.73-7.86(d，J＝8.8Hz，1H)，7.49(d，J＝8.7Hz，1H)，7.29-7.45(m，5H)，5.64(s，2H)，3.37(s，2H)，2.99-3.14(m，1H)，1.60-1.80(m，4H)，1.30-1.50(m，4H).MS(ESI+)m/z?416(M+H) +。
Embodiment 307
N 1-[5-(1-benzyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-N 2-cyclopropyl G-NH2
To embodiment 305A (100mg, 0.196mmol) and diisopropyl ethyl amine (0.034mL, (11mg, 0.19mmol), reaction mixture is in about 60 ℃ of down about 1 hour of heating to add cyclopropylamine in acetonitrile 0.19mmol) (1mL) solution.Reaction mixture is chilled to room temperature, and adding hydrochloric acid (dioxane solution of 4N, 1mL).Reaction mixture is stir about 16 hours at room temperature.Concentrating under reduced pressure reaction mixture, crude product by the reversed-phase HPLC purifying, obtain the acetate of title compound with acetonitrile/water (0.05M ammonium acetate) linear gradient elution method. 1H?NMR(400MHz，DMSO-d 6)δppm?10.18(s，1H)，8.28(s，1H)，8.56(s，1H)，7.81(d，J＝8.6Hz，1H)，7.49(d，J＝8.7Hz，1H)，7.30-7.45(m，5H)，5.64(s，2H)，3.45(s，2H)，2.18-2.26(m，1H)，1.89(s，3H)，0.37-0.45(m，2H)，0.29-0.37(m，2H).MS(ESI+)m/z?388(M+H) +。
Embodiment 308
N 1-[5-(1-benzyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-N 2-tetrahydrochysene-2H-pyrans-4-base G-NH2
Prepare the acetate of title compound with the method for describing among the embodiment 307, wherein replace cyclopropylamine with tetrahydrochysene-2H-pyrans-4-amine. 1H?NMR(400MHz，DMSO-d 6)δppm?8.56(s，1H)，8.31(s，1H)，7.81(d，J＝8.7Hz，1H)，7.50(d，J＝8.7Hz，1H)，7.31-7.45(m，5H)，5.64(s，2H)，3.84(d，J＝11.2Hz，2H)，3.43(s，2H)，3.30(t，J＝10.8Hz，2H)，2.62-2.74(m，1H)，1.88(s，3H)，1.75-1.85(m，2H)，1.24-1.39(m，2H).MS(ESI+)m/z?432(M+H) +。
Embodiment 309
N-[5-(1-benzyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-2-(3-hydroxyl pyrrolidine-1-yl) ethanamide
Prepare the diacetin of title compound with the method for describing among the embodiment 307, wherein replace cyclopropylamine with tetramethyleneimine-3-alcohol. 1H?NMR(400MHz，DMSO-d 6)δppm?10.09(s，1H)，8.22(s，1H)，8.58(s，1H)，7.82(d，J＝8.7Hz，1H)，7.50(d，J＝8.7Hz，1H)，7.28-7.45(m，5H)，5.64(s，2H)，4.16-4.26(m，1H)，3.34(s，2H)，2.77-2.93(m，2H)，2.52-2.65(m，2H)，1.98-2.13(m，1H)，1.87(s，6H)，1.56-1.69(m，1H).MS(ESI+)m/z?418(M+H) +。
Embodiment 310
N-[5-(1-benzyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-2-(3-hydroxy piperidine-1-yl) ethanamide
Prepare the acetate of title compound with the method for describing among the embodiment 307, wherein replace cyclopropylamine with piperidines-3-alcohol. 1H?NMR(400MHz，DMSO-d 6)δppm?10.05(s，1H)，8.56(s，1H)，8.23(s，1H)，7.82(d，J＝8.7Hz，1H)，7.50(d，J＝8.7Hz，1H)，7.29-7.44(m，5H)，5.64(s，2H)，3.55-3.67(m，1H)，3.20(s，2H)，2.77-2.88(m，1H)，2.60-2.70(m，1H)，2.22-2.35(m，1H)，2.12-2.23(m，1H)，1.88(s，3H)，1.66-1.78(m，2H)，1.43-1.59(m，1H)，1.13-1.27(m，1H).MS(ESI+)m/z?432(M+H) +。
Embodiment 311
N 1-[5-(1-benzyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-N 3, N 3-dimethyl-β-alanimamides
Prepare the acetate of title compound with the method for describing among the embodiment 307, wherein replace cyclopropylamine with dimethyl amine. 1H?NMR(400MHz，DMSO-d 6)δppm?10.48(s，1H)，8.54(s，1H)，8.26(s，1H)，7.80(d，J＝8.7Hz，1H)，7.48(d，J＝8.7Hz，1H)，7.30-7.44(m，5H)，5.64(s，2H)，2.60(d，J＝6.1Hz，2H)，2.54(d，J＝6.3Hz，2H)，2.21(s，6H)，1.90(s，3H).MS(ESI+)m/z?390(M+H) +。
Embodiment 312
N-[5-(1-benzyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-2-morpholine-4-yl acetamide
Prepare title compound with the method for describing among the embodiment 307, wherein replace cyclopropylamine with morpholino. 1H?NMR(400MHz，DMSO-d 6)δppm?10.10(s，1H)，8.57(s，1H)，8.23(s，1H)，7.81(d，J＝8.7Hz，1H)，7.50(d，J＝8.7Hz，1H)，7.29-7.46(m，5H)，5.64(s，2H)，3.59-3.71(m，4H)，3.22-3.28(m，2H)，2.54-2.64(m，4H).MS(ESI+)m/z?418(M+H) +。
Embodiment 313
N-[5-(1-benzyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-2-(4-methylpiperazine-1-yl) ethanamide
Prepare the diacetin of title compound with the method for describing among the embodiment 307, wherein replace cyclopropylamine with the 1-methylpiperazine. 1H?NMR(400MHz，DMSO-d 6)δppm?8.57(s，1H)，8.25(s，1H)，7.81(d，J＝8.7Hz，1H)，7.50(d，J＝8.7Hz，1H)，7.32-7.43(m，5H)，5.64(s，2H)，3.22(s，2H)，2.53-2.65(m，4H)，2.31-2.45(m，4H)，2.17(s，3H)，1.85(s，6H).MS(ESI+)m/z?431(M+H) +。
Embodiment 314
N-[5-(1-benzyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-2-(3-oxo piperazine-1-yl) ethanamide
Prepare title compound with the method for describing among the embodiment 307, wherein replace cyclopropylamine with piperazine-2-ketone. 1H?NMR(400MHz，DMSO-d 6)δppm?10.21(s，1H)，8.57(s，1H)，8.22(s，1H)，7.81(d，J＝8.7Hz，1H)，7.50(d，J＝8.7Hz，1H)，7.31-7.46(m，5H)，5.64(s，2H)，3.36(s，2H)，3.24(s，2H)，3.17(s，2H)，2.78(s，2H).MS(ESI+)m/z?431(M+H) +。
Embodiment 315
N 1-[5-(1-benzyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-N 2-sec.-propyl G-NH2
Prepare the acetate of title compound with the method for describing among the embodiment 307, wherein with third-2-amine replacement cyclopropylamine. 1H?NMR(400MHz，DMSO-d 6)δppm?8.56(s?1H)，8.31(s，1H)，7.81(d，J＝8.7Hz，1H)，7.49(d，J＝8.7Hz，1H)，7.31-7.44(m，5H)，5.64(s，2H)，3.39(s，2H)，2.73-2.86(m，1H)，1.90(s，3H)，1.04(d，J＝6.1Hz，6H).MS(ESI+)m/z?390(M+H) +。
Embodiment 316
N 1-[5-(1-benzyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-N 2-cyclohexyl G-NH2
Prepare the acetate of title compound with the method for describing among the embodiment 307, wherein replace cyclopropylamine with hexahydroaniline. 1H?NMR(400MHz，DMSO-d 6)δppm?8.55(s，1H)，8.31(s，1H)，7.81(d，J＝8.7Hz，1H)，7.49(d，J＝8.7Hz，1H)，7.30-7.44(m，5H)，5.64(s，2H)，3.40(s，2H)，1.90(s，3H)，1.80-1.88(m，2H)，1.63-1.73(m，2H)，1.50-1.60(m，1H)，1.02-1.29(m，5H).MS(ESI+)m/z?430(M+H) +。
Embodiment 317
N-[5-(1-benzyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl] ethanamide
To embodiment 64A (20mg, 0.051mmol) and diisopropyl ethyl amine (0.063mL, (0.013mL, 0.17mmol), reaction mixture is stir about 1.5 hours at room temperature to add Acetyl Chloride 98Min. in tetrahydrofuran (THF) 0.35mmol) (1.5mL) mixture.Add hydrochloric acid (dioxane solution of 4N, 1.5mL) reaction mixture stir about 16 hours at room temperature.Removal of solvent under reduced pressure, crude product by the reversed-phase HPLC purifying, obtain the acetate of title compound with acetonitrile/water (0.05M ammonium acetate) linear gradient elution method. 1HNMR(400MHz，DMSO-d 6)δppm?10.35(s，1H)，8.57(s，1H)，8.22(s，1H)，7.81(d，J＝8.7Hz，1H)，7.48(d，J＝8.7Hz，1H)，7.33-7.42(m，5H)，5.64(s，2H)，2.13(s，3H).MS(ESI-)m/z?331(M-H) -。
Embodiment 318
N 1-[5-(1-benzyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-N 2-cyclobutyl G-NH2
Prepare title compound with the method for describing among the embodiment 307, wherein replace cyclopropylamine with the ring butylamine. 1H?NMR(400MHz，DMSO-d 6)δppm?8.56(s，1H)，8.29(s，1H)，7.81(d，J＝8.7Hz，1H)，7.49(d，J＝8.7Hz，1H)，7.31-7.45(m，5H)，5.64(s，2H)，3.31(s，2H)，2.01-2.20(m，2H)，1.48-1.83(m，5H).MS(ESI+)m/z?402(M+H) +。
Embodiment 319
N-[5-(1-benzyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-N '-propyl group urea
(75mg, (16mg, 0.19mmol), reaction mixture is stir about 3 hours at room temperature to add 1-isocyanato propane in pyridine 0.19mmol) (2mL) solution to embodiment 64A.Add isocyanic ester (0.1mL) again, reaction mixture heated about 16 hours down at about 80 ℃.Reaction mixture is chilled to room temperature, adds entry (5mL).Filter and collect the gained throw out, (dioxane solution of 4N 3mL) is handled, and at room temperature stir about is 4.5 hours to use hydrochloric acid then.Add ether (5mL), filter the collecting precipitation thing.Crude product by the reversed-phase HPLC purifying, obtains the acetate of title compound with acetonitrile/water (0.05M ammonium acetate) linear gradient elution method. 1H?NMR(400MHz，DMSO-d 6)δppm?9.34(s，1H)，8.50(s，1H)，8.42(s，1H)，7.80(d，J＝8.7Hz，1H)，7.38(d，J＝8.7Hz，1H)，7.31-7.48(m，5H)，5.65(s，2H)，3.18(dd，J＝6.6，12.7Hz，2H)，1.51(dd，J＝7.1，14.3Hz，2H)，0.91(t，J＝7.3Hz，3H).MS(ESI+)m/z?376(M+H) +。
Embodiment 320
N-[5-(1-benzyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl] ethyl sulfonamide
(75mg, (25mg, 0.19mmol), reaction mixture is stir about 3 hours at room temperature to add ethyl sulfonyl chloride in pyridine 0.19mmol) (2mL) solution to embodiment 64A.Add again SULPHURYL CHLORIDE (25mg, 0.19mmol), reaction mixture stir about 48 hours.Concentrating under reduced pressure reaction mixture, residue are dissolved in methylene dichloride (10mL), with 1N aqueous hydrochloric acid (10mL) washing.Isolate organic moiety, drying under reduced pressure, (dioxane solution of 4N 5mL) is handled, and at room temperature stir about is 12 hours with hydrochloric acid.Concentrating under reduced pressure reaction mixture, crude product by the reversed-phase HPLC purifying, obtain the acetate of title compound with acetonitrile/water (0.05M ammonium acetate) linear gradient elution method. 1H?NMR(400MHz，DMSO-d 6)δppm?10.12(s，1H)，8.61(s，1H)，8.24(s，1H)，7.83(d，J＝8.7Hz，1H)，7.52(d，J＝8.7Hz，1H)，7.29-7.48(m，5H)，5.64(s，2H)，3.29(d，J＝9.2Hz，2H)，1.31(t，J＝7.3Hz，3H).MS(ESI+)m/z?383(M+H) +。
Embodiment 321
5-(1-benzyl-1H-1,2,3-triazole-4-yl)-N-(cyclopropyl methyl)-1H-indazole-3-amine
With embodiment 64A (100mg, 0.256mmol), ring third formaldehyde (0.057mL, 0.76mmol), sodium triacetoxy borohydride (163mg, 0.76mmol) and acetate (0.044mL, 0.76mmol) 1, the mixture in the 2-ethylene dichloride (5mL) is stir about 2.5 hours at room temperature.Adding hydrochloric acid (dioxane solution of 4N, 4mL), reaction mixture stir about 16 hours.Filter the collecting precipitation thing, with ether (10mL) flushing.Solid is dissolved in methylene dichloride (10mL), handles with trifluoroacetic acid (0.1mL), and reaction mixture is stir about 2 hours at room temperature.Add 15% aqueous sodium hydroxide solution (about 15mL) neutralization reaction mixture, separate organic layer, dried over mgso is filtered concentrating under reduced pressure.Crude product by the reversed-phase HPLC purifying, obtains the acetate of title compound with acetonitrile/water (0.05M ammonium acetate) linear gradient elution method. 1H?NMR(400MHz，DMSO-d 6)δppm?11.43(s，1H)，8.41(s，1H)，8.28(s，1H)，7.68(d，J＝8.7Hz，1H)，7.32-7.45(m，5H)，7.26(d，J＝8.6Hz，1H)，6.08(t，J＝5.7Hz，1H)，5.64(s，2H)，3.12(t，J＝6.2Hz，2H)，1.04-1.22(m，1H)，0.35-0.53(m，2H)，0.17-0.32(m，2H).MS(ESI+)m/z?345(M+H) +。
Embodiment 322
N-[5-(1-benzyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-N '-ethyl carbamide
Prepare title compound with the method for describing among the embodiment 319, wherein replace 1-isocyanato propane with isocyanato ethane. 1H?NMR(400MHz，DMSO-d 6)δppm?9.32(s，1H)，8.49(s，1H)，8.42(s，1H)，7.81(d，J＝8.7Hz，1H)，7.70(d，J＝8.7Hz，1H)，7.31-7.49(m，5H)，5.65(s，2H)，3.23(d，J＝6.9Hz，2H)，1.12(t，J＝7.1Hz，3H).MS(ESI+)m/z?362(M+H) +。
Embodiment 323
1-[5-(1-benzyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl] pyrrolidin-2-one
With embodiment 64A (200mg, 0.51mmol) and diisopropyl ethyl amine (0.089mL, tetrahydrofuran (THF) 0.51mmol) (5mL) suspension be stir about 15 minutes at room temperature, add then the 4-bromobutanoylchloride (0.059mL, 0.51mmol).Reaction mixture stir about 16 hours.Remove by filter throw out, concentrating under reduced pressure filtrate.Residue absorbs with acetonitrile (5mL), and (0.089mL 0.51mmol) handles, and heating is about 16 hours under about 60 ℃ with diisopropyl ethyl amine.Reaction mixture is chilled to room temperature, concentrating under reduced pressure.(5mL) handle, and reaction mixture is stir about 2 hours at room temperature by the dioxane solution of 4N with hydrochloric acid for residue.Concentrating under reduced pressure reaction mixture, crude product by the reversed-phase HPLC purifying, obtain the acetate of title compound with acetonitrile/water (0.05M ammonium acetate) linear gradient elution method. 1H?NMR(400MHz，DMSO-d 6)δppm?12.84(s，1H)，8.56(s，1H)，8.49(s，1H)，7.84(d，J＝8.6Hz，1H)，7.51(d，J＝8.7Hz，1H)，7.29-7.46(m，5H)，5.64(s，2H)，3.96(t，J＝6.9Hz，2H)，2.56(t，J＝7.9Hz，2H)，2.25-2.12(m，2H).MS(ESI+)m/z359(M+H) +。
Embodiment 324
N-[5-(1-benzyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-4-(dimethylamino) butyramide
Prepare the diacetin of title compound with the method for describing among the embodiment 303B, wherein use 4-(dimethylamino) butyric acid to replace 2-(dimethylamino) acetate, replace embodiment 303A with embodiment 64A. 1H?NMR(400MHz，DMSO-d 6)δppm?10.34(s，1H)，8.53(s，1H)，8.22(s，1H)，7.78(d，J＝8.7Hz，1H)，7.47(d，J＝8.7Hz，1H)，7.30-7.41(m，5H)，5.62(s，2H)，2.41(t，J＝7.2Hz，2H)，2.28(t，J＝6.8Hz，2H)，2.14(s，6H)，1.84(s，6H)，1.74-1.77(m，2H).MS(ESI-)m/z?462(M-H) -。
Embodiment 325
N-3, the heterochromatic alkene of 4-dihydro-1H--4-base-5-(1H-indazole-5-base) isoxazole-3-methane amide
Prepare title compound with the method for describing among the embodiment 81B, wherein use 3, the heterochromatic alkene of 4-dihydro-1H--4-amine replaces piperidines. 1H?NMR(300MHz，DMSO-d 6)δppm?13.4(br?s，1H)，9.02(d，1H)，8.4(m，1H)，8.22(m，1H)，7.75(m，2H)，7.2-7.4(m，5H)，5.24(m，1H)，4.75(m，2H)，4.02(m，1H)，3.8(m，1H).MS?m/z(ESI+)361(M+H) +。
Embodiment 326
N-(cyclohexyl methyl)-5-(1H-indazole-5-base) isoxazole-3-methane amide
With 5-(1H-indazole-5-base) isoxazole-3-formic acid (35mg, 0.15mmol, embodiment 71A) is dissolved in N, dinethylformamide (0.8mL), (60mg 0.15mmol) is dissolved in N, the solution of dinethylformamide (0.8mL) to add HATU then.Add then 1-cyclohexyl methylamine (17mg 0.17mmol) is dissolved in N, the solution of dinethylformamide (0.8mL), (56 μ L 0..31mmol) are dissolved in N, the solution of dinethylformamide (0.8mL) to add diisopropyl ethyl amine then.The gained mixture was 40 ℃ of following joltings 3 hours.The filtering reaction thing detects with LC/MS, is concentrated into dried.Residue is dissolved in 1: 1 dimethyl sulfoxide (DMSO)/methyl alcohol, the usefulness reversed-phase HPLC ( C8 (2) 5 μ m AXIA TMPost (30mm * 75mm), 50mL/min, the aqueous solution of 10-100% acetonitrile/0.1% trifluoroacetic acid) purifying, obtain title compound. 1H?NMR(500MHz，DMSO-d 6/D 2O)δppm?0.91-0.97(m，2H)，1.12-1.27(m，4H)，1.61-1.75(m，5H)，3.08-3.16(m，2H)，7.22-7.24(m，1H)，7.71-7.75(m，1H)，7.87-7.92(m，1H)，8.23-8.27(m，1H)，8.38-8.41(m，1H).MS(ESI+)m/z?325(M+H) +；(ESI-)m/z323(M-H) -。
Embodiment 327
N-(3-benzyl chloride base)-5-(1H-indazole-5-base) isoxazole-3-methane amide
Prepare title compound with the method for describing among the embodiment 326, only use 1-(3-chloro-phenyl-) methylamine to replace 1-cyclohexyl methylamine. 1H?NMR(500MHz，DMSO-d 6/D 2O)δppm?4.47-4.52(m，2H)，7.27-7.29(m，1H)，7.30-7.42(m，4H)，7.72-7.75(m，1H)，7.89-7.93(m，1H)，8.25-8.28(m，1H)，8.41-8.42(m，1H).MS(ESI+)m/z353(M+H) +；(ESI-)m/z?351(M-H) -。
Embodiment 328
5-(1H-indazole-5-yl)-N-(2-methoxy-benzyl) isoxazole-3-methane amide
Prepare title compound with the method for describing among the embodiment 326, only use 1-(2-p-methoxy-phenyl) methylamine to replace 1-cyclohexyl methylamine. 1H?NMR(500MHz，DMSO-d 6/D 2O)δppm?3.82-3.86(m，3H)，4.45-4.50(m，2H)，6.92-6.97(m，1H)，7.01-7.04(m，1H)，7.19-7.24(m，1H)，7.26-7.31(m，2H)，7.69-7.77(m，1H)，7.88-7.93(m，1H)，8.24-8.28(m，1H)，8.38-8.44(m，1H).MS(ESI+)m/z?349(M+H) +；(ESI-)m/z?347(M-H) -。
Embodiment 329
5-(1H-indazole-5-yl)-N-[2-(trifluoromethyl) benzyl] isoxazole-3-methane amide
Prepare title compound with the method for describing among the embodiment 326, only use 1-[2-(trifluoromethyl) phenyl] methylamine replacement 1-cyclohexyl methylamine. 1H?NMR(500MHz，DMSO-d 6/D 2O)δppm?4.66-4.73(m，2H)，7.29-7.33(m，1H)，7.49-7.60(m，2H)，7.67-7.79(m，3H)，7.91-7.94(m，1H)，8.26-8.28(m，1H)，8.41-8.45(m，1H).MS(ESI+)m/z?387(M+H) +；(ESI-)m/z?385(M-H) -。
Embodiment 330
5-(1H-indazole-5-yl)-N-[3-(trifluoromethyl) benzyl] isoxazole-3-methane amide
Prepare title compound with the method for describing among the embodiment 326, only use 1-[3-(trifluoromethyl) phenyl] methylamine replacement 1-cyclohexyl methylamine. 1H?NMR(500MHz，DMSO-d 6/D 2O)δppm?4.57-4.61(m，2H)，7.28-7.31(m，1H)，7.59-7.77(m，5H)，7.90-7.94(m，1H)，8.27-8.28(m，1H)，8.40-8.43(m，1H).MS(ESI-)m/z?385(M-H) -
Embodiment 331
5-(1H-indazole-5-yl)-N-[4-(trifluoromethyl) benzyl] isoxazole-3-methane amide
Prepare title compound with the method for describing among the embodiment 326, only use 1-[4-(trifluoromethyl) phenyl] methylamine replacement 1-cyclohexyl methylamine. 1H?NMR(500MHz，DMSO-d 6/D 2O)δppm?4.55-4.60(s，2H)，7.27-7.30(m，1H)，7.54-7.59(m，2H)，7.70-7.76(m，3H)，7.88-7.94(m，1H)，8.24-8.28(m，1H)，8.40-8.44(m，1H).MS(ESI+)m/z?387(M+H) +；(ESI-)m/z?385(M-H) -。
Embodiment 332
5-(1H-indazole-5-yl)-N-(pyridine-2-ylmethyl) isoxazole-3-methane amide
Prepare title compound with the method for describing among the embodiment 326, only replace 1-cyclohexyl methylamine with 1-pyridine-2-base methylamine. 1H?NMR(500MHz，DMSO-d 6/D 2O)δppm?4.74-4.84(s，2H)，7.30-7.34(m，1H)，7.68-7.81(m，3H)，7.89-7.97(m，1H)，8.22-8.33(m，2H)，8.40-8.45(m，1H)，8.67-8.76(m，1H).MS(ESI+)m/z320(M+H) +；(ESI-)m/z?318(M-H) -。
Embodiment 333
5-(1H-indazole-5-yl)-N-(pyridin-3-yl methyl) isoxazole-3-methane amide
Prepare title compound with the method for describing among the embodiment 326, only replace 1-cyclohexyl methylamine with 1-pyridin-3-yl methylamine. 1H?NMR(500MHz，DMSO-d 6/D 2O)δppm?4.61-4.68(s，2H)，7.27-7.31(m，1H)，7.70-7.75(m，1H)，7.83-7.94(m，2H)，8.24-8.28(m，1H)，8.31-8.37(m，1H)，8.40-8.44(m，1H)，8.69-8.74(m，1H)，8.77-8.82(m，1H).MS(ESI+)m/z?320(M+H) +；(ESI-)m/z?318(M-H) -。
Embodiment 334
5-(1H-indazole-5-yl)-N-(pyridin-4-yl methyl) isoxazole-3-methane amide
Prepare title compound with the method for describing among the embodiment 326, only replace 1-cyclohexyl methylamine with 1-pyridin-4-yl methylamine. 1H?NMR(500MHz，DMSO-d 6/D 2O)δppm?4.73-4.80(s，2H)，7.30-7.33(m，1H)，7.73-7.78(m，1H)，7.89-7.97(m，3H)，8.25-8.30(m，1H)，8.40-8.46(m，1H)，8.76-8.83(m，2H).MS(ESI-)m/z318(M-H) -。
Embodiment 335
N-(2-benzyl chloride base)-5-(1H-indazole-5-base) isoxazole-3-methane amide
Prepare title compound with the method for describing among the embodiment 326, only use 1-(2-chloro-phenyl-) methylamine to replace 1-cyclohexyl methylamine. 1H?NMR(500MHz，DMSO-d 6/D 2O)δppm?4.54-4.58(s，2H)，7.27-7.32(m，1H)，7.33-7.42(m，3H)，7.47-7.49(m，1H)，7.71-7.77(m，1H)，7.88-7.98(m，1H)，8.24-8.27(m，1H)，8.41-8.44(m，1H).MS(ESI+)m/z?353(M+H) +；(ESI-)m/z?351(M-H) -。
Embodiment 336
N-(4-benzyl chloride base)-5-(1H-indazole-5-base) isoxazole-3-methane amide
Prepare title compound with the method for describing among the embodiment 326, only use 1-(4-chloro-phenyl-) methylamine to replace 1-cyclohexyl methylamine. 1H?NMR(500MHz，DMSO-d 6/D 2O)δppm?4.42-4.49(m，2H)，7.22-7.31(m，1H)，7.34-7.49(m，4H)，7.70-7.76(m，1H)，7.84-7.92(m，1H)，8.17-8.30(m，1H)，8.35-8.47(m，1H).MS(ESI-)m/z351(M-H) -。
Embodiment 337
5-(1H-indazole-5-yl)-N-(1-phenyl-2-piperidines-1-base ethyl) isoxazole-3-methane amide
Prepare title compound with the method for describing among the embodiment 81B, wherein replace piperidines with 1-phenyl-2-piperidines-1-base ethamine. 1H?NMR(300MHz，DMSO-d 6)δppm?13.4(br?s，1H)，9.12(d，1H)，8.4(s，1H)，8.22(s，1H)，7.9(d，1H)，7.7(d，1H)，7.2-7.4(m，6H)，5.2(m，1H)，3.2(m，2H)，2.3(m，4H)，1.2-1.4(m，6H).MS(ESI+)m/z416(M+H) +。
Embodiment 338
N-[2-(1H-imidazoles-1-yl)-1-phenylethyl]-5-(1H-indazole-5-base) isoxazole-3-methane amide
Prepare title compound with the method for describing among the embodiment 81B, wherein use 2-(1H-imidazoles-1-yl)-1-phenyl-ethyl amine to replace piperidines. 1H?NMR(300MHz，DMSO-d 6)δppm?13.4(br?s，1H)，9.5(d，1H)，8.4(s，1H)，8.22(s，1H)，7.78(m，1H)，7.52(d，2H)，7.72(d，2H)，7.2-7.4(m，5H)，6.85(s，1H)，5.44(m，1H)，4.44(m，2H).MS(ESI+)m/z?399(M+H) +。
Embodiment 339
5-(1H-indazole-5-yl)-N-(2-morpholine-4-base-1-phenylethyl) isoxazole-3-methane amide
Prepare title compound with the method for describing among the embodiment 81B, wherein replace piperidines with 2-morpholine-4-base-1-phenyl-ethyl amine. 1H?NMR(300MHz，DMSO-d 6)δppm?13.4(br?s，1H)，9.2(d，1H)，8.4(s，1H)，8.22(s，1H)，7.9(d，1H)，7.7(d，1H)，7.2-7.4(m，6H)，5.2(m，1H)，3.6(m，4H)，3.4(m，2H)，2.4(m，4H).MS(ESI+)m/z?418(M+H) +。
Embodiment 340
5-(1H-indazole-5-yl)-N-[2-(4-methylpiperazine-1-yl)-1-phenylethyl] isoxazole-3-methane amide
Prepare title compound with the method for describing among the embodiment 81B, wherein use 2-(4-methylpiperazine-1-yl)-1-phenyl-ethyl amine to replace piperidines. 1H?NMR(300MHz，DMSO-d 6)δppm?13.6(br?s，1H)，9.14(d，1H)，8.4(s，1H)，8.22(s，1H)，7.9(d，1H)，7.7(d，1H)，7.2-7.4(m，6H)，5.2(m，1H)，3.2(m，2H)，2.4(m，4H)，2.2(m，4H)，2.1(m，3H).MS(ESI+)m/z?432(M+H) +。
Embodiment 341
5-(1H-indazole-5-yl)-N-(1-phenyl-2-tetramethyleneimine-1-base ethyl) isoxazole-3-methane amide
Prepare title compound with the method for describing among the embodiment 81B, wherein replace piperidines with 1-phenyl-2-tetramethyleneimine-1-base ethamine. 1H?NMR(300MHz，DMSO-d 6)δppm?13.4(br?s，1H)，9.14(d，1H)，8.4(s，1H)，8.22(s，1H)，7.9(d，1H)，7.7(d，1H)，7.2-7.4(m，6H)，5.18(m，1H)，3.2(m，2H)，2.4(m，4H)，1.8(m，3H).MS(ESI+)m/z402.5(M+H) +。
Embodiment 342
2-([5-(1H-indazole-5-base) isoxazole-3-base] carbonyl } amino)-2-phenylethyl t-butyl carbamate
Prepare title compound with the method for describing among the embodiment 81B, wherein replace piperidines with 2-amino-2-phenylethyl t-butyl carbamate. 1H?NMR(300MHz，DMSO-d 6)δppm?13.4(br?s，1H)，9.14(d，1H)，8.4(s，1H)，8.22(s，1H)，7.9(d，1H)，7.7(d，1H)，7.2-7.4(m，6H)，7.00(t，1H)，5.18(m，1H)，3.2(m，2H)，1.4(s，9H).MS(ESI+)m/z?449(M+H) +。
Embodiment 343
5-(1H-indazole-5-yl)-N-(1-naphthyl methyl) isoxazole-3-methane amide
Prepare title compound with the method for describing among the embodiment 326, only use 1-(1-naphthyl) methylamine to replace 1-cyclohexyl methylamine. 1H?NMR(500MHz，DMSO-d 6/D 2O)δppm?4.93-4.99(m，2H)，7.28-7.32(m，1H)，7.48-7.66(m，4H)，7.70-7.76(m，1H)，7.86-7.92(m，2H)，7.96-8.00(m，1H)，8.18-8.23(m，1H)，8.24-8.27(m，1H)，8.38-8.44(m，1H)；).MS(ESI-)m/z?367(M-H) -。
Embodiment 344
5-(1H-indazole-5-yl)-N-(2-phenylethyl) isoxazole-3-methane amide
Prepare title compound with the method for describing among the embodiment 326, only replace 1-cyclohexyl methylamine with the 2-phenyl-ethyl amine. 1H?NMR(500MHz，DMSO-d 6/D 2O)δppm?2.84-2.92(t，2H)，3.47-3.57(t，2H)，7.18-7.35(m，6H)，7.69-7.77(m，1H)，7.86-7.91(m，1H)，8.22-8.29(m，1H)，8.37-8.44(m，1H).MS(ESI+)m/z?333(M+H) +；(ESI-)m/z?331(M-H) -。
Embodiment 345
5-(1H-indazole-5-yl)-N-(2-pyridine-2-base ethyl) isoxazole-3-methane amide
Prepare title compound with the method for describing among the embodiment 326, only replace 1-cyclohexyl methylamine with 2-pyridine-2-base ethamine. 1H?NMR(500MHz，DMSO-d 6/D 2O)δppm?3.22-3.29(t，2H)，3.71-3.75(t，2H)，7.14-7.26(m，1H)，7.70-7.75(m，1H)，7.81-7.94(m，3H)，8.23-8.29(m，1H)，8.35-8.44(m，2H)，8.71-8.83(m，1H).MS(ESI+)m/z?334(M+H) +；(ESI-)m/z?332(M-H) -。
Embodiment 346
5-(1H-indazole-5-yl)-N-(2-pyridin-3-yl ethyl) isoxazole-3-methane amide
Prepare title compound with the method for describing among the embodiment 326, only replace 1-cyclohexyl methylamine with 2-pyridin-3-yl ethamine. 1H?NMR(500MHz，DMSO-d 6/D 2O)δppm?3.01-3.13(t，2H)，3.55-3.70(t，2H)，7.14-7.26(m，1H)，7.70-7.77(m，1H)，7.84-7.95(m，2H)，8.25-8.29(m，1H)，8.36-8.45(m，2H)，8.69-8.75(m，1H)，8.77-8.84(m，1H).MS(ESI+)m/z?334(M+H) +；(ESI-)m/z?332(M-H) -。
Embodiment 347
5-(1H-indazole-5-yl)-N-(2-pyridin-4-yl ethyl) isoxazole-3-methane amide
Prepare title compound with the method for describing among the embodiment 326, only replace 1-cyclohexyl methylamine with 2-pyridin-4-yl ethamine. 1H?NMR(500MHz，DMSO-d 6/D 2O)δppm?3.12-3.23(t，2H)，3.67-3.71(t，2H)，7.20-7.21(m，1H)，7.69-7.76(m，1H)，7.86-7.91(m，3H)，8.25-8.27(m，1H)，8.38-8.41(m，1H)，8.70-8.77(m，2H).MS(ESI+)m/z?334(M+H) +；(ESI-)m/z?332(M-H) -。
Embodiment 348
N-[2-(2-chloro-phenyl-) ethyl]-5-(1H-indazole-5-base) isoxazole-3-methane amide
Prepare title compound with the method for describing among the embodiment 326, only use 2-(2-chloro-phenyl-) ethamine to replace 1-cyclohexyl methylamine. 1H?NMR(500MHz，DMSO-d 6/D 2O)δppm?2.99-3.05(t，2H)，3.54-3.61(t，2H)，7.21-7.23(m，1H)，7.26-7.33(m，2H)，7.35-7.40(m，1H)，7.41-7.47(m，1H)，7.70-7.75(m，1H)，7.87-7.93(m，1H)，8.23-8.31(m，1H)，8.37-8.44(m，1H).MS(ESI+)m/z?367(M+H) +；(ESI-)m/z?365(M-H) -。
Embodiment 349
N-[2-(3-chloro-phenyl-) ethyl]-5-(1H-indazole-5-base) isoxazole-3-methane amide
Prepare title compound with the method for describing among the embodiment 326, only use 2-(3-chloro-phenyl-) ethamine to replace 1-cyclohexyl methylamine. 1H?NMR(500MHz，DMSO-d 6/D 2O)δppm?2.89(t，2H)，3.54(t，2H)，7.19-7.42(m，5H)，7.69-7.77(m，1H)，7.86-7.94(m，1H)，8.22-8.29(m，1H)，8.38-8.42(m，1H).MS(ESI-)m/z?365(M-H) -。
Embodiment 350
N-[2-(4-chloro-phenyl-) ethyl]-5-(1H-indazole-5-base) isoxazole-3-methane amide
Prepare title compound with the method for describing among the embodiment 326, only use 2-(4-chloro-phenyl-) ethamine to replace 1-cyclohexyl methylamine. 1H?NMR(500MHz，DMSO-d 6/D 2O)δppm?2.86(t，2H)，3.50(t，2H)，7.17-7.24(m，1H)，7.27-7.41(m，4H)，7.71-7.76(m，1H)，7.85-7.91(m，1H)，8.21-8.29(m，1H)，8.34-8.44(m，1H).MS(ESI-)m/z?365(M-H) -。
Embodiment 351
N-benzyl-N-ethyl-5-(1H-indazole-5-base) isoxazole-3-methane amide
Prepare title compound with the method for describing among the embodiment 326, only replace 1-cyclohexyl methylamine with N-benzyl-N-ethylamine. 1H?NMR(500MHz，DMSO-d 6/D 2O)δppm?1.06-1.19(m，3H)，3.37-3.49(m，2H)，4.69-4.76(m，2H)，7.21-7.28(m，1H)，7.28-7.49(m，5H)，7.69-7.78(m，1H)，7.83-7.97(m，1H)，8.24-8.32(m，1H)，8.36-8.46(m，1H).MS(ESI+)m/z?347(M+H) +；(ESI-)m/z?345(M-H) -。
Embodiment 352
5-(1H-indazole-5-yl)-N-methyl-N-(1-naphthyl methyl) isoxazole-3-methane amide
Prepare title compound with the method for describing among the embodiment 326, only use N-methyl-N-(1-naphthyl methyl) amine to replace 1-cyclohexyl methylamine. 1H?NMR(500MHz，DMSO-d 6/D 2O)δppm3.04-3.11(m，3H)，5.20-5.35(m，2H)，7.20-7.31(m，1H)，7.33-7.66(m，4H)，7.66-7.77(m，1H)，7.81-8.18(m，4H)，8.20-8.28(m，1H)，8.31-8.45(m，1H).MS(ESI+)m/z?383(M+H) +；(ESI-)m/z?381(M-H) -。
Embodiment 353
5-(1H-indazole-5-yl)-N-methyl-N-(2-phenylethyl) isoxazole-3-methane amide
Prepare title compound with the method for describing among the embodiment 326, only use N-methyl-N-(2-phenylethyl) amine to replace 1-cyclohexyl methylamine. 1H?NMR(500MHz，DMSO-d 6/D 2O)δppm2.86-2.97(m，2H)，3.06-3.13(m，3H)，3.70-3.74(m，2H)，6.64-7.39(m，6H)，7.69-7.92(m，2H)，8.24-8.44(m，2H).MS(ESI+)m/z?347(M+H) +；(ESI-)m/z?345(M-H) -。
Embodiment 354
5-(1H-indazole-5-yl)-N-methyl-N-(2-pyridine-2-base ethyl) isoxazole-3-methane amide
Prepare title compound with the method for describing among the embodiment 326, only use N-methyl-N-(2-pyridine-2-base ethyl) amine to replace 1-cyclohexyl methylamine. 1H?NMR(500MHz，DMSO-d 6/D 2O)δppm?3.07-3.22(m，3H)，3.26-3.39(m，2H)，3.92-4.04(m，2H)，6.85-7.14(m，1H)，7.65-8.05(m，4H)，8.23-8.56(m，3H)，8.65-8.86(m，1H).MS(ESI+)m/z?348(M+H) +；(ESI-)m/z?346(M-H) -。
Embodiment 355
5-(1H-indazole-5-yl)-N-[(1R)-1-phenylethyl] isoxazole-3-methane amide
Prepare title compound with the method for describing among the embodiment 326, only use (1R)-1-phenyl-ethyl amine to replace 1-cyclohexyl methylamine. 1H?NMR(500MHz，DMSO-d 6/D 2O)δppm?1.49-1.54(m，3H)，5.12-5.20(m，1H)，7.23-7.29(m，2H)，7.33-7.46(m，4H)，7.71-7.75(m，1H)，7.87-7.91(m，1H)，8.22-8.28(m，1H)，8.37-8.42(m，1H).MS(ESI+)m/z?333(M+H) +；(ESI-)m/z?331(M-H) -。
Embodiment 356
5-(1H-indazole-5-yl)-N-1,2,3,4-naphthane-1-isoxazole-3-methane amide
Prepare title compound with the method for describing among the embodiment 326, only use 1,2,3,4-naphthane-1-amine replaces 1-cyclohexyl methylamine. 1H?NMR(500MHz，DMSO-d 6/D 2O)δppm?1.72-2.09(m，4H)，2.68-2.85(m，2H)，5.19-5.26(m，1H)，7.12-7.24(m，4H)，7.29-7.35(m，1H)，7.69-7.77(m，1H)，7.86-7.93(m，1H)，8.25-8.30(m，1H)，8.38-8.43(m，1H).MS(ESI-)m/z?357(M-H) -。
Embodiment 357
5-(1H-indazole-5-yl)-N-[(1S)-1-(1-naphthyl) ethyl] isoxazole-3-methane amide
Prepare title compound with the method for describing among the embodiment 81B, wherein use (1S)-1-(1-naphthyl) ethamine to replace piperidines. 1H?NMR(300MHz，DMSO-d 6)δppm?13.4(br?s，1H)，9.4(d，1H)，8.4(s，1H)，8.25(s，1H)，8.22(br?s，1H)，7.95(d，1H)，7.85(m，2H)，7.65(m，2H)，7.5(m，3H)，7.3(s，1H)，5.9(m，1H)，1.65(d，3H).MS(ESI+)m/z?382.9(M+H) +。
Embodiment 358
5-(1H-indazole-5-yl)-N-[(1R)-1-(1-naphthyl) ethyl] isoxazole-3-methane amide
Prepare title compound with the method for describing among the embodiment 81B, wherein use (1R)-1-(1-naphthyl) ethamine to replace piperidines. 1H?NMR(300MHz，DMSO-d 6)δppm?13.4(br?s，1H)，9.4(d，1H)，8.4(s，1H)，8.25(s，1H)，8.22(br?s，1H)，7.95(d，1H)，7.85(m，2H)，7.65(m，2H)，7.5(m，3H)，7.3(s，1H)，5.9(m，1H)，1.65(d，3H).MS(ESI+)m/z?382.9(M+H) +。
Embodiment 359
N-[3-(dimethylamino)-1-phenyl propyl]-5-(1H-indazole-5-base) isoxazole-3-methane amide
Prepare title compound with the method for describing among the embodiment 81B, wherein use N 3, N 3-dimethyl-1-phenyl the third-1, the 3-diamines replaces piperidines. 1H?NMR(300MHz，DMSO-d 6)δppm?13.4(br?s，1H)，9.4(d，1H)，8.4(s，1H)，8.25(s，1H)，7.92(m，1H)，7.7(m，1H)，7.3-7.5(m，6H)，5.15(m，1H)，3.2(m，2H)，7.75(s，6H)，2.35(m，1H)，2.15(m，1H).MS(ESI+)m/z?390(M+H) +。
Embodiment 360
N-(2,3-dihydro-1,4-Ben Bing dioxin-5-ylmethyl)-5-(1H-indazole-5-base) isoxazole-3-methane amide
Prepare title compound with the method for describing among the embodiment 81B, wherein use 1-(2,3-dihydro-1,4-Ben Bing dioxin-5-yl) methylamine to replace piperidines. 1H?NMR(300MHz，DMSO-d 6)δppm?13.4(br?s，1H)，9.24(t，1H)，8.4(s，1H)，8.25(s，1H)，7.92(d，1H)，7.7(d，1H)，7.24(s，1H)，6.9(m，3H)，4.4(d，2H)，4.3(d，2H)，4.25(d，2H).MS(ESI+)m/z?377(M+H) +。
Embodiment 361
N-(3,4-dihydro-2H-1,5-benzo two oxa-s
Figure GPA00001018010702021
-6-ylmethyl)-5-(1H-indazole-5-base) isoxazole-3-methane amide
Prepare title compound with the method for describing among the embodiment 81B, wherein use 1-(3,4-dihydro-2H-1,5-benzo two oxa-s
Figure GPA00001018010702022
-6-yl) methylamine replaces piperidines. 1H?NMR(300MHz，DMSO-d 6)δppm?13.4(br?s，1H)，9.2(t，1H)，8.4(s，1H)，8.25(s，1H)，7.92(d，1H)，7.7(d，1H)，7.24(s，1H)，6.9(m，3H)，4.42(d，2H)，4.15(m，4H)，2.2(m，2H).MS(ESI+)m/z?391(M+H) +。
Embodiment 362
5-(1H-indazole-5-yl)-N-[(1-Methyl-1H-indole-4-yl) methyl] isoxazole-3-methane amide
Prepare title compound with the method for describing among the embodiment 81B, wherein use (1-Methyl-1H-indole-4-yl) methylamine to replace piperidines. 1H?NMR(300MHz，DMSO-d 6)δppm?13.4(br?s，1H)，9.24(t，1H)，8.4(s，1H)，8.25(s，1H)，7.92(d，1H)，7.7(d，1H)，7.38(m，3H)，7.18(m，1H)，7.0(d，1H)，6.6(s，1H)，4.7(d，2H)，3.8(s，3H).MS(ESI+)m/z?372(M+H) +。
Embodiment 363
5-{3-[(3-Phenylpyrrolidine-1-yl) carbonyl] isoxazole-5-base }-the 1H-indazole
Prepare title compound with the method for describing among the embodiment 81B, wherein replace piperidines with the 3-Phenylpyrrolidine. 1H?NMR(300MHz，DMSO-d 6)δppm?13.4(br?s，1H)，8.4(m，1H)，8.25(s，1H)，7.92(d，1H)，7.8(d，1H)，7.24(m，6H)，4.4(m，1H)，3.4(m，2H)，2.4(m，2H)，2.0(m，2H).MS(ESI+)m/z?359(M+H) +。
Embodiment 364
5-{3-[(2-Phenylpyrrolidine-1-yl) carbonyl] isoxazole-5-base }-the 1H-indazole
Prepare title compound with the method for describing among the embodiment 81B, wherein replace piperidines with the 2-Phenylpyrrolidine. 1H?NMR(300MHz，DMSO-d 6)δppm?13.4(br?s，1H)，8.4(m，1H)，8.25(s，1H)，7.92(d，1H)，7.8(d，1H)，7.24(m，6H)，5.6(m，0.3H)，5.2(m，0.7H)，4.0(m，2H)，1.8-2.0(m，4H).MS(ESI+)m/z?390(M+H) +。
Embodiment 365
5-{3-[(2-Phenylpiperidine-1-yl) carbonyl] isoxazole-5-base }-the 1H-indazole
Prepare title compound with the method for describing among the embodiment 81B, wherein replace piperidines with the 2-Phenylpiperidine. 1H?NMR(300MHz，DMSO-d 6)δppm?13.4(br?s，1H)，8.4(m，1H)，8.25(s，1H)，7.92(d，1H)，7.8(d，1H)，7.24(m，6H)，5.6(m，0.3H)，5.2(m，0.7H)，4.0(m，2H)，1.8-2.0(m，6H).MS(ESI+)m/z?373(M+H) +。
Embodiment 366
5-(1H-indazole-5-yl)-N-[(1S)-1-phenylethyl] isoxazole-3-methane amide
With 5-(1H-indazole-5-base) isoxazole-3-formic acid (36mg, 0.16mmol, embodiment 71A) is dissolved in N, dinethylformamide (1.0mL), (60mg 0.16mmol) is dissolved in N, the solution of dinethylformamide (0.5mL) to add HATU then.Add then (S)-1-phenyl-ethyl amine (22mg 0.18mmol) is dissolved in N, the solution of dinethylformamide (0.6mL), (56 μ L 0.32mmol) are dissolved in N, the solution of dinethylformamide (0.2mL) to add diisopropyl ethyl amine then.The gained mixture was 40 ℃ of following joltings 3 hours.The filtering reaction thing detects with LC/MS, is concentrated into dried.Residue is dissolved in 1: 1 dimethyl sulfoxide (DMSO)/methyl alcohol, the usefulness reversed-phase HPLC (
Figure GPA00001018010702041
C8 (2) 5 μ m
Figure GPA00001018010702042
AXIA TMPost (30mm * 75mm), 50mL/min, the aqueous solution of 10-100% acetonitrile/0.1% trifluoroacetic acid) purifying, obtain title compound. 1H?NMR(500MHz，DMSO-d 6/D 2O)δppm?1.50(d，3H)，5.06-5.22(m，1H)，7.23-7.29(m，2H)，7.34-7.38(m，2H)，7.40-7.45(m，2H)，7.70-7.75(m，1H)，7.87-7.92(m，1H)，8.25-8.27(m，1H)，8.39-8.41(m，1H)，9.28(d，1H).MS(ESI+)m/z?333(M+H) +；(ESI-)m/z?331(M-H) -。
Embodiment 367
5-(1H-indazole-5-yl)-N-[(1R)-1-(4-aminomethyl phenyl) ethyl] isoxazole-3-methane amide
Prepare title compound with the method for describing among the embodiment 366, only use (1R)-1-(4-aminomethyl phenyl) ethamine to replace (S)-1-phenyl-ethyl amine. 1H?NMR(500MHz，DMSO-d 6/D2O)δppm1.49(d，3H)，2.25-2.31(m，3H)，5.09-5.18(m，1H)，7.14-7.18(m，2H)，7.23-7.24(m，1H)，7.28-7.32(m，2H)，7.70-7.75(m，1H)，7.86-7.92(m，1H)，8.22-8.29(m，1H)，8.37-8.42(m，1H)，9.19(d，1H).MS(ESI+)m/z347(M+H) +；(ESI-)345(M-H) -。
Embodiment 368
5-(1H-indazole-5-yl)-N-[(1S)-1-(4-aminomethyl phenyl) ethyl] isoxazole-3-methane amide
Prepare title compound with the method for describing among the embodiment 366, only use (1S)-1-(4-aminomethyl phenyl) ethamine to replace (S)-1-phenyl-ethyl amine. 1H?NMR(500MHz，DMSO-d 6/D2O)δppm1.48(d，3H)，2.26-2.30(m，3H)，5.05-5.23(m，1H)，7.15-7.17(m，2H)，7.22-7.25(m，1H)，7.28-7.32(m，2H)，7.67-7.79(m，1H)，7.86-7.93(m，1H)，8.22-8.30(m，1H)，8.38-8.41(m，1H)，9.21(d，1H).MS(ESI-)m/z345(M-H) -。
Embodiment 369
N-[(1R, 2S)-2-hydroxyl-2,3-dihydro-1H-indenes-1-yl]-5-(1H-indazole-5-base) isoxazole-3-methane amide
Prepare title compound with the method for describing among the embodiment 366, only use (1R, 2S)-1-aminoidan-2-alcohol replacement (S)-1-phenyl-ethyl amine. 1H?NMR(500MHz，DMSO-d 6/D2O)δppm2.89-2.96(m，1H)，3.13-3.21(m，1H)，4.55-4.61(m，1H)，5.40-5.47(m，1H)，7.21-7.34(m，4H)，7.39-7.42(m，1H)，7.72-7.77(m，1H)，7.91-7.95(m，1H)，8.25-8.29(m，1H)，8.42-8.45(m，1H).MS(ESI-)m/z?359(M-H) -。
Embodiment 370
N-[(1R, 2R)-2-hydroxyl-2,3-dihydro-1H-indenes-1-yl]-5-(1H-indazole-5-base) isoxazole-3-methane amide
Prepare title compound with the method for describing among the embodiment 366, only use (1R, 2R)-1-aminoidan-2-alcohol replacement (S)-1-phenyl-ethyl amine. 1H?NMR(500MHz，DMSO-d 6/D2O)δppm?2.72-2.83(m，1H)，3.13-3.30(m，1H)，4.44-4.53(m，1H)，5.24-5.32(m，1H)，7.10-7.18(m，1H)，7.20-7.27(m，3H)，7.30-7.33(m，1H)，7.72-7.78(m，1H)，7.91-7.93(m，1H)，8.24-8.29(m，1H)，8.41-8.45(m，1H)，9.17(d，1H).MS(ESI-)m/z?359(M-H) -。
Embodiment 371
N-[(1R)-1-(4-bromophenyl) ethyl]-5-(1H-indazole-5-base) isoxazole-3-methane amide
Prepare title compound with the method for describing among the embodiment 366, only use (1R)-1-(4-bromophenyl) ethamine to replace (S)-1-phenyl-ethyl amine. 1H?NMR(500MHz，DMSO-d 6/D2O)δppm1.50(d，3H)，5.08-5.18(m，1H)，7.21-7.27(m，1H)，7.36-7.41(m，2H)，7.50-7.59(m，2H)，7.70-7.76(m，1H)，7.86-7.93(m，1H)，8.23-8.29(m，1H)，8.38-8.41(m，1H)，9.32(d，1H).MS(ESI+)m/z?411(M+H) +。
Embodiment 372
N-[(1S)-1-(4-bromophenyl) ethyl]-5-(1H-indazole-5-base) isoxazole-3-methane amide
Prepare title compound with the method for describing among the embodiment 366, only use (1S)-1-(4-bromophenyl) ethamine to replace (S)-1-phenyl-ethyl amine. 1H NMR (500MHz, DMSO-d 6/ D2O) δ ppm1.49 (d, 3H), 5.09-5.19 (m, 1H), 7.23-7.25 (m, 1H), 7.37-7.40 (m, 2H), 7.53-7.57 (m, 2H), 7.71-7.75 (m, 1H), and 7.87-7.92 (m, 1H), 8.25-8.27 (m, 1H), 8.38-8.41 (m, 1H), 9.32 (d, 1H) .MS (ESI) negatively charged ion 409 (M-H) -
Embodiment 373
N-[(1R)-1-(4-chloro-phenyl-) ethyl]-5-(1H-indazole-5-base) isoxazole-3-methane amide
Prepare title compound with the method for describing among the embodiment 366, only use (1R)-1-(4-chloro-phenyl-) ethamine to replace (S)-1-phenyl-ethyl amine. 1H?NMR(500MHz，DMSO-d 6/D2O)δppm1.50(d，3H)，5.10-5.21(m，1H)，7.22-7.26(m，1H)，7.38-7.47(m，4H)，7.70-7.75(m，1H)，7.87-7.92(m，1H)，8.20-8.28(m，1H)，8.38-8.41(m，1H)，9.33(d，1H).MS(ESI-)m/z?365(M-H) -。
Embodiment 374
N-[(1S)-1-(4-chloro-phenyl-) ethyl]-5-(1H-indazole-5-base) isoxazole-3-methane amide
Prepare title compound with the method for describing among the embodiment 366, only use (1S)-1-(4-chloro-phenyl-) ethamine to replace (S)-1-phenyl-ethyl amine. 1H?NMR(500MHz，DMSO-d 6/D2O)δppm1.49(d，3H)，5.12-5.19(m，1H)，7.23-7.25(m，1H)，7.39-7.47(m，4H)，7.71-7.74(m，1H)，7.87-7.91(m，1H)，8.25-8.27(m，1H)，8.37-8.43(m，1H)，9.32(d，1H).MS(ESI-)m/z?365(M-H) -。
Embodiment 375
5-(1H-indazole-5-yl)-N-[(1S)-1-(2-naphthyl) ethyl] isoxazole-3-methane amide
Prepare title compound with the method for describing among the embodiment 366, only use (1S)-1-(2-naphthyl) ethamine to replace (S)-1-phenyl-ethyl amine. 1H?NMR(500MHz，DMSO-d 6/D2O)δppm?1.61(d，3H)，5.30-5.38(m，1H)，7.25-7.26(m，1H)，7.48-7.55(m，2H)，7.60-7.63(m，1H)，7.72-7.75(m，1H)，7.88-7.95(m，5H)，8.25-8.28(m，1H)，8.39-8.43(m，1H)，9.39(d，1H).MS(ESI-)m/z?381(M-H) -。
Embodiment 376
N-[1-(4-ethoxyl phenenyl)-2-hydroxyethyl]-5-(1H-indazole-5-base) isoxazole-3-methane amide
Prepare title compound with the method for describing among the embodiment 366, only use 2-amino-2-(4-ethoxyl phenenyl) ethanol to replace (S)-1-phenyl-ethyl amine. 1H?NMR(500MHz，DMSO-d 6/D2O)δppm?1.32(t，3H)，3.62-3.67(m，1H)，3.70-3.73(m，1H)，3.96-4.06(m，2H)，4.98-5.06(m，1H)，6.87-6.91(m，2H)，7.23-7.36(m，3H)，7.70-7.75(m，1H)，7.88-7.91(m，1H)，8.25-8.27(m，1H)，8.39-8.42(m，1H).MS(ESI-)m/z?391(M-H) -。
Embodiment 377
N-[2-hydroxyl-1-(4-isopropyl phenyl) ethyl]-5-(1H-indazole-5-base) isoxazole-3-methane amide
Prepare title compound with the method for describing among the embodiment 366, only use 2-amino-2-(4-isopropyl phenyl) ethanol to replace (S)-1-phenyl-ethyl amine. 1H?NMR(500MHz，DMSO-d 6/D2O)δppm?1.18(d，6H)，2.81-2.91(m，1H)，3.65-3.70(m，1H)，3.72-3.74(m，1H)，5.01-5.09(m，1H)，7.20-7.28(m，3H)，7.29-7.35(m，2H)，7.72-7.80(m，1H)，7.87-7.95(m，1H)，8.24-8.29(m，1H)，8.38-8.44(m，1H).MS(ESI-)m/z?389(M-H) -。
Embodiment 378
N-[1-(3, the 4-3,5-dimethylphenyl)-2-hydroxyethyl]-5-(1H-indazole-5-base) isoxazole-3-methane amide
Prepare title compound with the method for describing among the embodiment 366, only use 2-amino-2-(3, the 4-3,5-dimethylphenyl) ethanol to replace (S)-1-phenyl-ethyl amine. 1H?NMR(500MHz，DMSO-d 6/D2O)δppm?2.30(d，6H)，3.56-3.63(m，1H)，3.65-3.73(m，1H)，5.32-5.42(m，1H)，7.06-7.08(m，2H)，7.23-7.28(m，2H)，7.69-7.76(m，1H)，7.87-7.95(m，1H)，8.25-8.28(m，1H)，8.39-8.43(m，1H).MS(ESI-)m/z?375(M-H) -。
Embodiment 379
N-[2-hydroxyl-1-(2-p-methoxy-phenyl) ethyl]-5-(1H-indazole-5-base) isoxazole-3-methane amide
Prepare title compound with the method for describing among the embodiment 366, only use 2-amino-2-(2-p-methoxy-phenyl) ethanol to replace (S)-1-phenyl-ethyl amine. 1H NMR (500MHz, DMSO-d 6/ D2O) δ ppm 3.60-3.66 (m, 2H), 3.84-3.88 (m, 3H), 5.37-5.48 (m, 1H), 6.95 (t, 1H), 7.00-7.06 (m, 1H), 7.24-7.31 (m, 2H), 7.32-7.36 (m, 1H), 7.71-7.77 (m, 1H), 7.85-7.97 (m, 1H), 8.24-8.28 (m, 1H), 8.40-8.45 (m, 1H) .MS (ESI+) m/z 379 (M+H) +Negatively charged ion 377 (M-H) -
Embodiment 380
N-[2-hydroxyl-1-(4-aminomethyl phenyl) ethyl]-5-(1H-indazole-5-base) isoxazole-3-methane amide
Prepare title compound with the method for describing among the embodiment 366, only use 2-amino-2-(4-aminomethyl phenyl) ethanol to replace (S)-1-phenyl-ethyl amine. 1H?NMR(500MHz，DMSO-d 6/D2O)δppm?2.26-2.32(m，3H)，3.65-3.70(m，1H)，3.72-3.75(m，1H)，5.01-5.08(m，1H)，7.10-7.21(m，2H)，7.25-7.35(m，3H)，7.70-7.77(m，1H)，7.86-7.95(m，1H)，8.26-8.28(m，1H)，8.39-8.46(m，1H).MS(ESI+)m/z?363(M+H) +；(ESI-)m/z?361(M-H) -。
Embodiment 381
5-(1H-indazole-5-yl)-N-[(1R)-1-(2-p-methoxy-phenyl) ethyl] isoxazole-3-methane amide
Prepare title compound with the method for describing among the embodiment 366, only use (1R)-1-(2-p-methoxy-phenyl) ethamine to replace (S)-1-phenyl-ethyl amine. 1H?NMR(500MHz，DMSO-d 6/D2O)δppm?1.43(d，3H)，3.82-3.86(m，3H)，5.41-5.50(m，1H)，6.95(t，1H)，7.00-7.05(m，1H)，7.23-7.29(m，2H)，7.35-7.39(m，1H)，7.71-7.76(m，1H)，7.88-7.92(m，1H)，8.25-8.27(m，1H)，8.37-8.43(m，1H).MS(ESI+)m/z363(M+H) +；(ESI-)m/z?361(M-H) -。
Embodiment 382
N-[(1S)-1-(3, the 4-difluorophenyl) ethyl]-5-(1H-indazole-5-base) isoxazole-3-methane amide
Prepare title compound with the method for describing among the embodiment 366, only use (1S)-1-(3, the 4-difluorophenyl) ethamine to replace (S)-1-phenyl-ethyl amine. 1H?NMR(500MHz，DMSO-d 6/D2O)δppm?1.50(d，3H)，5.09-5.24(m，1H)，7.21-7.30(m，2H)，7.35-7.44(m，1H)，7.44-7.53(m，1H)，7.68-7.82(m，1H)，7.86-7.94(m，1H)，8.26-8.27(m，1H)，8.39-8.42(m，1H).MS(ESI-)m/z?367(M-H) -。
Embodiment 383
5-(1H-indazole-5-yl)-N-[(1R)-1-(3-p-methoxy-phenyl) ethyl] isoxazole-3-methane amide
Prepare title compound with the method for describing among the embodiment 366, only use (1R)-1-(3-p-methoxy-phenyl) ethamine to replace (S)-1-phenyl-ethyl amine. 1H?NMR(500MHz，DMSO-d 6/D2O)δppm?1.50(d，3H)，3.75-3.77(m，3H)，5.01-5.19(m，1H)，6.80-6.87(m，1H)，6.97-7.02(m，2H)，7.21-7.32(m，2H)，7.70-7.75(m，1H)，7.87-7.95(m，1H)，8.22-8.31(m，1H)，8.37-8.43(m，1H).MS(ESI-)m/z?361(M-H) -。
Embodiment 384
5-(1H-indazole-5-yl)-N-{ (1R)-1-[3-(trifluoromethyl) phenyl] ethyl } isoxazole-3-methane amide
Prepare title compound with the method for describing among the embodiment 366, only use (1R)-1-[3-(trifluoromethyl) phenyl] ethamine replacement (S)-1-phenyl-ethyl amine. 1H?NMR(500MHz，DMSO-d 6/D2O)δppm?1.54(d，3H)，5.22-5.29(m，1H)，7.23-7.27(m，1H)，7.58-7.69(m，2H)，7.71-7.75(m，2H)，7.77-7.83(m，1H)，7.87-7.92(m，1H)，8.24-8.29(m，1H)，8.38-8.42(m，1H).MS(ESI-)m/z?399(M-H) -。
Embodiment 385
N-[1-(2,3-dihydro-1,4-Ben Bing dioxin-6-yl) ethyl]-5-(1H-indazole-5-base) isoxazole-3-methane amide
Prepare title compound with the method for describing among the embodiment 366, only use 1-(2,3-dihydro-1,4-Ben Bing dioxin-6-yl) ethamine to replace (S)-1-phenyl-ethyl amine. 1H?NMR(500MHz，DMSO-d 6/D2O)δppm?1.46(d，3H)，4.18-4.25(m，4H)，5.01-5.10(m，1H)，6.80-6.95(m，3H)，7.22-7.24(m，1H)，7.70-7.74(m，1H)，7.87-7.91(m，1H)，8.26-8.27(m，1H)，8.39-8.41(m，1H).MS(ESI-)m/z?389(M-H) -。
Embodiment 386
N-[1-(3, the 5-dichlorophenyl)-2-hydroxyethyl]-5-(1H-indazole-5-base) isoxazole-3-methane amide
Prepare title compound with the method for describing among the embodiment 366, only use 2-amino-2-(3, the 5-dichlorophenyl) ethanol to replace (S)-1-phenyl-ethyl amine. 1H?NMR(500MHz，DMSO-d 6/D2O)δppm?3.68-3.72(m，1H)，3.76-3.78(m，1H)，5.02-5.10(m，1H)，7.26-7.29(m，1H)，7.47-7.52(m，3H)，7.72-7.75(m，1H)，7.89-7.93(m，1H)，8.25-8.28(m，1H)，8.39-8.44(m，1H).MS(ESI-)m/z?415(M-H) -。
Embodiment 387
5-(1-benzyl-1H-1,2,3-triazole-4-yl)-3-[({[6-(trifluoromethyl) pyridine-2-yl] amino } carbonyl) amino]-1H-indazole-1-t-butyl formate
The dichloromethane solution of triphosgene is chilled to 0 ℃ under nitrogen.(0.426mL is 3.07mmol) with embodiment 64A (150mg, methylene dichloride 0.384mmol) (2mL) mixture slowly dropwise to add triethylamine then.The gained mixture at room temperature stirred 1 hour.(62.3mg 0.384mmol), at room temperature stirs then and spends the night to add 6-(trifluoromethyl) pyridine-2-amine then.The filtering precipitation is with methylene dichloride and water washing.The vacuum-drying product obtains title compound.MS?m/z?579.3(M+H) +。
Embodiment 388
5-(1-benzyl-1H-1,2,3-triazole-4-yl)-1-[(1-methyl piperidine-2-yl) carbonyl]-1H-indazole-3-amine
1-methyl piperidine-3-formate hydrochlorate is mixed under nitrogen with the mixture of dimethyl formamide and methylene dichloride, stirred 15 minutes.Add carbonyl dimidazoles then in batches.Gained solution at room temperature stirred 1 hour.Add embodiment 62 then, stirred 2 hours down, at room temperature stir then and spend the night at 60 ℃.Reaction mixture is poured in the frozen water, added salt solution.Drain cold soln, residue absorbs with methylene dichloride, washes (2X) with water.The organic layer dried over mgso, volatile matter is removed in decompression.The solution that drains ethyl acetate extraction (3X).The organic layer that merges is used dried over mgso with salt water washing (2X), concentrates.Residue absorbs with small amount of acetone, is added drop-wise in the distilled water then.Filter collecting precipitation, wash with water, drying obtains title compound.MS?m/z?579.3(M+H) +。
Embodiment 389
5-(1-benzyl-1H-1,2,3-triazole-4-yl)-1-[(dimethylamino) ethanoyl]-1H-indazole-3-amine
Under nitrogen, through 15 minutes 2-(dimethylamino) acetate is dissolved in dimethyl formamide and pyridine in room temperature.Dropwise add carbonyl dimidazoles.The gained mixture at room temperature stirred 1 hour.Add embodiment 62 then, mixture at room temperature stirs and spends the night.Volatile matter is removed in decompression, and residuum joins in the frozen water.Add sodium-chlor, occur thickness oily matter in the cold soln.Drain solution.Residue washes (3X) with water, and is dry then.After spending the night, precipitation appears in the water from the solution that drains/dimethyl formamide mixture.This is proved to be and is starting raw material, filters and discards.The crystallization in methylene dichloride of product residue is filtered and is collected, with a small amount of dichloro hexane and ether flushing.Desciccate obtains title compound.MS?m/z?376.3(M+H) +。
Embodiment 390
3-amino-5-(1-benzyl-1H-1,2,3-triazole-4-yl)-1H-indazole-1-t-butyl formate
Embodiment 62 is suspended in the methylene dichloride that contains the catalytic amount dimethyl aminopyridine.Methylene dichloride (160mL) solution that added two-tertiary butyl, two carbonic ethers through 1 hour.Reaction mixture stir about 40 hours.Add silica gel, enriched mixture.This silica-gel mixture is joined on the silicagel column, use the methylene dichloride wash-out earlier, use 1% ethanol/methylene wash-out then, use 2% ethanol/methylene wash-out at last.Merge the flow point that contains required product, concentrate, obtain title compound.MS?m/z?391.3(M+H) +。
Embodiment 391
N-[5-(1-benzyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-2-piperidines-1-yl acetamide
2-(piperidines-1-yl) acetate is mixed with dimethyl formamide and pyridine.Mixture at room temperature stirred 15 minutes, added carbonyl dimidazoles then in batches.Continue at room temperature to stir 1 hour, add embodiment 64A then, continue to stir 24 hours.Reaction mixture is warming up to 69 ℃ of reactions 14 hours.Obtain a spot of title compound.MS?m/z?416.3(M+H) +。
Embodiment 392
N-[5-(1-benzyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-2-morpholine-4-yl acetamide
2-morpholino acetate is mixed with dimethyl formamide and pyridine.Mixture at room temperature stirred 15 minutes, added carbonyl dimidazoles then in batches.Continue at room temperature to stir 1 hour, add embodiment 64A then, continue to stir 28 hours.Reaction mixture is warming up to 60 ℃ of reactions 4 hours, continues then at room temperature to stir.Reaction mixture is warming up to 60 ℃ of reactions 7 hours once more.Obtain a small amount of title compound.MS?m/z?418.3(M+H) +。
Embodiment 393
N-[5-(1-benzyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-1-methyl piperidine-2-methane amide
1-methyl piperidine-3-formate hydrochlorate is mixed with dimethyl formamide and pyridine.Mixture at room temperature stirred 15 minutes, added carbonyl dimidazoles then in batches.Continue at room temperature to stir 1 hour, add embodiment 64A then, continue to stir 28 hours.Reaction mixture rises to 60 ℃ of reactions 4.25 hours, continues then at room temperature to stir to spend the night.Reaction mixture is warming up to 60 ℃ of reactions 7 hours once more.Obtain a spot of title compound.MS?m/z?416.3(M+H) +。
Biological data
ROCK-2 suppresses to measure
Tested formula (I) compound and suppressed the ability of the recombinant human ROCK-2 residue 11-552 of the N-end His6-mark of in Sf21 cell (Upstate), expressing by baculovirus.In polypropylene board (Axygen) at the bottom of the v-of 384-hole, the peptide substrates (vitamin H-Aha-KEAKEKRQEQIAKRRRLSSLRASTSKSGGSQK (SEQ ID NO:1)) that the recombinant human ROCK-2 residue 11-552 of the terminal His6-mark of reorganization N-that the 10ul of 1nM (final concentration) is expressed in Sf21 cell (Upstate) by baculovirus and the 10ul vitamin H (acyl) of 2uM (final concentration) are changed (Genemed) with the inhibitor (2%DMSO is final) of different concns at reaction buffer (25mMHEPES, pH 7.5,0.5mM DTT, 10mM MgCl 2, 100uM Na 3VO 4, 0.075mg/mlTriton X-100) and middle the mixing, add 5uM and contain 0.01uCi[ 33P]-the unlabelled ATP (Perkin Elmer) of ATP begins reaction.After 1 hour, add 50ul stop buffer (50mMEDTA, 2M NaCl final concentration) quencher reaction.80uL termination reaction thing is transferred among the FlashPlates (Perkin Elmer) of 384-hole streptavidin-Bao quilt, at room temperature hatched 10 minutes, with 0.05%Tween-20/PBS washing 3 times, go up counting with the automatic plate washing device of ELX-405 (BioTek) at TopCount flicker plate reader (Packard).
ROCK-1 suppresses to measure
Tested formula (I) compound and suppressed the ability of the recombinant human ROCK-1 amino acid/11 7-535 of the N-end His6-mark of in Sf21 cell (Upstate), expressing by baculovirus.In polypropylene board (Axygen) at the bottom of the v-of 384-hole, the peptide substrates (vitamin H-Aha-VRRLRRLTAREAA (SEQ ID NO:2)) that the recombinant human ROCK-1 amino acid/11 7-535 of the terminal His6-mark of reorganization N-that the 10ul of 2nM (final concentration) is expressed in Sf21 cell (Upstate) by baculovirus changes with 2uM (final concentration) vitamin H (acyl) in reaction buffer (Genemed) and the inhibitor (2%DMSO is final) of different concns at 10ul reaction buffer (25mM HEPES, pH 7.5,0.5mMDTT, 10mM MgCl 2, 100uM Na 3VO 4, 0.075mg/ml Triton X-100) and middle the mixing, add 5uM and contain 0.01uCi[ 33P]-the unlabelled AT (Perkin Elmer) of ATP begins reaction.After 1 hour, add 50ul stop buffer (50mM EDTA, 2M NaCl final concentration) quencher reaction.80uL termination reaction thing is transferred to the FlashPlatesPerkin Elmer of 384-hole streptavidin bag quilt) in, at room temperature hatched 10 minutes, with 0.05%Tween-20/PBS washing 3 times, go up counting with the automatic plate washing device of ELX-405 (BioTek) at TopCount flicker plate reader (Packard).
GSK suppresses to measure
Tested formula (I) compound and suppressed the ability of the GSK-3 of the N-end His6-mark of in Sf21 cell (Upstate), expressing by baculovirus.In polypropylene board (Axygen) at the bottom of the v-of 384-hole, the GSK3 of the terminal His-mark of reorganization N-that 10ul is expressed in Sf21 cell (Upstate) by baculovirus and the peptide substrates (vitamin H-ahx-YRRAAVPPSPSLSRHSSPHQS (p) EDEEE (SEQ ID NO:3)) of 10 μ l vitamin Hs (acyl) change, the inhibitor (2%DMSO is final) of 2 μ M final concentrations (Genemed) and different concns is at reaction buffer (20mMHEPES, pH 7.5,1mM DTT, 10mM MgCl 2100uM Na 3VO 4, 0.075mg/mlTriton X-100) and middle the mixing, add 20 μ l[ 33P]-ATP, 5 μ M final concentrations, 2mCi/umol (Perkin Elmer) begin reaction.After 1 hour, add 50ul stop buffer (50mM EDTA, 2M NaCl final concentration) quencher reaction.80 μ L termination reaction things are transferred among the FlashPlates (Perkin Elmer) of 384-hole streptavidin bag quilt, at room temperature hatched 10 minutes, with 0.05%Tween-20/PBS washing 3 times, go up counting with the automatic plate washing device of ELX-405 (BioTek) at TopCount flicker plate reader (Packard).
People GSK-3 β suppresses to measure
Tested the ability of compound inhibition people glycogen synthase kinase-3 β (hGSK-3 β) phosphorylation vitamin H-YRRAAVPPSPSLSRHSSPHQ (pS) EDEEE.With compound and 0.5 μ Ci 33P-ATP, 10 μ M ATP, 0.0125U hGSK-3 β (Upstate cell signaling solution) and 1 μ M substrate (vitamin H-YRRAAVPPSPSLSRHSSPHQ (pS) EDEEE (SEQ ID NO:3)) be at 50mM HEPES, 10mM MgCl 2, 100uM Na 3VO 4, 1mM DTT, 0.0075% Triton, 2%DMSO (cumulative volume 50 μ L) was at room temperature hatched 30 minutes.Add isopyknic 100mMEDTA, 4M NaCl 2Termination is hatched.80 these mixtures of μ L are joined among the Flashplates (PerkinElmer) of streptavidin bag quilt.Behind the washing step, it is right to go up at MicroBeta microplate liquid scintillation counter (PerkinElmer) 33P mixes and carries out quantitatively.The counting that obtains under S shape dose-response curve and the different concns is carried out match in GraphPad Prism, determine IC50s.
People GSK-3 α suppresses to measure
Tested the ability of compound inhibition people glycogen synthase kinase-3 α (hGSK-3 α) (0.5nM final concentration) phosphorylation vitamin H-RAAVPPSPSLSRHSSPHQ (pS) EDEEE (SEQ ID NO:3).With compound and 0.5Ci 33P-ATP, 10M ATP, 0.0125U hGSK-3 (Upstate cell signaling solution) and 2 μ M substrates (vitamin H-YRRAAVPPSPSLSRHSSPHQ (pS) EDEEE) are at 50mM HEPES, 10mM MgCl 2, 100uM Na 3VO 4, 1mM DTT, 0.0075%Triton was at room temperature hatched 30 minutes among the 2%DMSO (cumulative volume 50 μ L).Add isopyknic 100mM EDTA, 4M NaCl 2Termination is hatched.80 these mixtures of μ L are joined among the Flashplates (PerkinElmer) of streptavidin bag quilt.Behind the washing step, it is right to go up at MicroBeta microplate liquid scintillation counter (PerkinElmer) 33P mixes and carries out quantitatively.By the counting that obtains under S shape dose-response curve and the different concns is carried out match in GraphPad Prism, determine IC50.
JAK2 suppresses to measure
Adopt homogenizing time to differentiate fluorescence (HTRF) vitro kinase assay method and measure the kinase whose activity of Jak2 (Mathis, G., HTRF (R) Technology.J Biomol Screen, 1999.4 (6): p.309-314).Especially, the recombinant human JAK2 of the terminal His6-mark of C-that 10 μ L are expressed in Sf21 cell (Upstate) by baculovirus, terminal and the 10ul inhibitor (different concns of amino acid 808-, 2% final DMSO) and 10ul ATP (5 μ M final concentration) at reaction buffer (50mM HEPES, pH 7.5,10mM MgCl 2, 2mM MnCl 2, 0.1%BSA and 1mM DTT, 40 μ L final volume) mix.Add 10ul Bio-PDK peptide (vitamin H-Ahx-KTFCGTPEYLAPEVRREPRILSEEEQEMFRDFDYIADWC (SEQ IDNO:4), 0.5 μ M final concentration) and in black 384-orifice plate (Packard), begin reaction.After at room temperature hatching 60 minutes, add 60 μ L termination/exposure (revelation) damping fluid quenchers reactions obtain 30mM EDTA, 1 μ g/ml streptavidin-APC (Prozyme), 50ng/ml anti--Tyrosine O-phosphate mAb PT66-K europium cryptate compound, 30mM HEPES, pH 7.5,120mM KF, 0.005%Tween-20,0.05%BSA).The reaction of quencher was at room temperature left standstill 1 hour, and is middle simultaneously at 615nm and 665nm reading at time resolved fluorescence detector (Envision, Perkin Elmer) then.Ratio between 615nm and the 665nm signal is used to calculate IC 50
Method-beta-catenin reporter gene is measured
Test compound and in LEF/TCF (T-cytokine) reporter gene is measured, modulated the ability of beta-catenin-synthetic genetic transcription.With SY-SY5Y people neuroblast oncocyte with three copies of the TCF binding site that comprises two groups of thymidine kinase minimal promoter upstreams and the 80ng/ hole TOPFLASH plasmid of Photinus pyralis LUC open reading frame, (Upstate cell signaling solution) or with three copies of the mutation T CF binding site that comprises thymidine minimal promoter upstream and the 80ng/ hole FOPFLASH plasmid of Photinus pyralis LUC open reading frame, (Upstate cell signaling solution) transient transfection.In addition, with all cells 20ng/ hole pRL-TK plasmid (Promega) transient transfection that comprises hsv thymidine kinase promotor, obtain the Renilla luciferase expression of low-medium level.The transfection media transposing for to comprise the serum free medium of testing substrate, was hatched under 37 ℃ 24 hours.Termination is hatched, and is quantitative with Dual Glo luciferase assay method (Promega) by indication, goes up quantitatively at Pherastar reader (BMG).
With Photinus pyralis LUC to the Renilla uciferase activity stdn of every hole.Then, the FOPFLASH of standard of comparisonization replys with standardized FOPFLASH and replys, thereby provides the LEF/TCF specific signals.Maximum is replied and is the maximum rate between stdn TOPFLASH and the FOPFLASH signal.With Graphpad Prism match S shape dose-response curve.
The murine asthmatic model of acute asthma
Buy female Balb/c mouse from Taconic, support at Abbott biological study center.Adopt the 8-12 animal in age in week.All experimental designs (IACUC) are ratified by the management of laboratory animal and the use council (Institutional Animal Care and Use Committee).Dexamethasone (Dex) and Protalbinic acid (OVA) are available from Sigma.Remove intracellular toxin with DetoxiGel (Pierce) according to the scheme of manufacturers from Protalbinic acid, final material comprises the albumen less than 0.1EU/mg.Alum Imject is available from Pierce.
At the 0th day and the 7th day 2mg alum (alum) solution, make it to the OVA enhanced sensitivity with animal i.p. injection 8ug OVA.At the 14th and 16 day, to giving the aseptic PBS solution of 50 μ l of (challenge) 0.3 μ gOVA in the animals nose.With representative formula (I) compound (with the dissolving of the aqueous solution of 0.5%HMPC, 0.02%Tween 80) animals are carried out the i.p. administration when began afternoon in the 13rd day, every day twice, dosage is 3,10 and the 30mg/kg/ agent.Measure the preceding compound that gave whole dosage in 30 minutes at airway hyperreactivity (AHR).At 13-17 days orally give dexamethasone, once a day, dosage was 3mg/kg.After for the second time giving OVA24 hour, measured all terminal points at the 17th day.Adopt unconscious limited total body plethysmography (unconscious restrained whole bodyplethysmography) to estimate AHR.Briefly, induce the anesthesia on operation plane (surgical plane) with i.p. injection ketamine and xylazine.Trachea cannula is inserted in operation between third and fourth tracheal rings.Stop autonomous respiration by jugular vein intravenous injection (i.v.) pancuronium bromide.Animal is placed whole body plethysmography (Buxco), control ventilator (Harvard Apparatus) in the 0.2ml room air power ventilation of per minute 150 frequency of respiration with volume.With pressure in the transmodulator mensuration lung and the flow in the plethysmograph, adopt Biosystem Xa software pressing force/flow rate calculation lung resistance.Resistance behind the methacholine that establishment of base line resistance and giving is sent by ultrasonic atomizer in the line (3,10 or 30mg/ml).After finishing pulmonary function test (pft), with the lung aseptic PBS lavation of 0.5ml 4 times.Analyze IL-13, AMCase, Muc5ac and cellular infiltration liquid in the elutant.The effect of test experiments compound under twice each 3,10 of every day and 30mg/kg (6,20,60mg/kg/ days) dosage.Giving (Challenge) OVA makes lung resistance increase to 6.90cm H 2O/ml/ second, and the animal lung resistance that gives (challenged) PBS is 4.65cm H 2O/ml/ second.Handle mouse with experimental compound and can significantly suppress (p＜0.001) methacholine inductive Raw air way resistance, make it reduce to 4.55cmH 2O/ml/ second and 4.77cm H 2O/ml/ second, dosage range is 1 and 100mg/kg.Preferred compound need be less than the dosage of 50mg/kg to show described replying.Most preferred need be less than the dosage of 30mg/kg to show described replying.This restraining effect is equal to group (the 4.65cm H that gives (challenged) PBS 2O/ml/ second) and group (the 4.76cm H that handles with the 3mg/kg dexamethasone 2O/ml/ second) value of being measured.
IL-13 measures: with ELISA (R﹠amp; D Systems) according to the IL-13 concentration in the specification sheets mensuration bronchoalveolar lavage fluid (BAL) of manufacturers.Compare with the level that is lower than detection limit in giving the PBS group, the IL-13 concentration in giving the mouse of OVA in the BAL liquid significantly is induced to 102.5pg/ml.Behind the experimental compound that gives 30mg/kg dosage, this inducing action is significantly suppressed (p＜0.05) 60%.There is not significant inhibitory effect at 3mg/kg or 10mg/kg dosage group.
AMCase measures: acidic mammalian chitinase (AMCase) determination of activity is in 5.2 the BAL liquid at the contain 0.01%BSA, 30mM Trisodium Citrate, 60mM sodium phosphate, pH with dilution in 1: 10; at 80uM 4-methyl cymenyl (umbelliferyl) β-D-N, N '-diacetyl chitobiose glycosides (chitobioside) carries out under existing.At room temperature reactant is hatched 15 minutes, adding pH is 100uL 1M glycine/NaOH quencher reaction of 10.6.On Fluoskan Ascent photofluorometer, adopt at 385nm and excite by measuring the product generation in the fluorescent emission of 460nm.Compare with the AMCase activity value 2.17U of the animal that gives PBS, give that the AMCase activity is induced to 28.5U in the animal of OVA.After giving test compound, organize this inducing action at 30mg/kg and significantly suppressed (p＜0.01) 35%.
MUC5AC measures: with the concentration of the quantitative mucin gene MUC5AC of ELISA form.In brief, the BAL sample with dilution in damping fluid (the PBS solution of 2%BSA) in 1: 2, is contained in high protein in conjunction with on the 96-orifice plate (Costar), drying.Through after a series of washings, (Clone 45M, LabVision) reaction is 1 hour to add biotinylated MUC5AC antibody with dilution in 1: 100.Wash plate adds the streptavidin-HRP (SouthernBiotech) with dilution in 1: 3000 in plate, reacted 15 minutes.Use tmb substrate (Sigma) with plate colour developing 30 minutes then.Use 1M H 2SO 4Termination reaction, then in spectrophotometer at OD 450nm place reading.After giving experimental compound, the level of MUC5AC has been lowered more than 50%.
The mensuration of anti-nociception effect: neuropathic pain model
The spinal nerves of neuropathic pain (L5/L6) ligation model.As Kim and Chung (Kim S.H.; Chung J.M.An experimental model for peripheral neuropathy produced bysegmental spinal nerve ligation in the rat (by the peripheral neurophaty experimental model of segmentation ligation rat spinal nerves generation) .Pain 1992,50, described in detail 355-363), open the otch of 1.5cm at the lumbosacral plexus dorsal part.In anesthetized rat, separate juxtaspinal muscle (left side) from spinous process, separate L5 and L6 spinal nerves, with the tightly ligation of 3-0 silk thread.After the hemostasis, sew up a wound, coat antimicrobial ointment.Rat is recovered, before the behavior test that carries out at mechanicalness unusual pain (mechanical allodynia), be placed on then in the cage of soft bed 14 days.
The sciatic nerve ligation model of neuropathic pain.As Bennett and Xie (Bennett G.J.; Xie Y-K.A peripheral mononeuropathy in rat that produces disorders of painsensation like those seen in man (producing the peripheral neurophaty of rat of similar people's pain sensation disease) .Pain 1988,33, described in detail 87-107), in anesthetized rat, 0.5cm opens at the place otch of 1.5cm under pelvis, separately the gluteus (gluteous superficialis) (right side) on biceps muscle of thigh and surface.Expose sciatic nerve, separate, do the loose ligation (5-0 chromic catgut) of 4 spacing 1mm around it.Rat is recovered, before carrying out above-mentioned behavior test, be placed on then in the cage of soft bed 14 days at the unusual pain of mechanicalness.In addition, also carried out test by the cold unusual pain aspect that will produce in its rear solid end immersion cooling bath (4.5 ℃), and definite claw retraction waiting time.
Selected formula (I) compound analogue, i.p. or p.o. administration in the 1-150mg/kg dosage range can suppress sense of touch sexual abnormality pain more than 30% in Chung that all is proved to be in neuropathic pain described herein and the Bennett model.
Generally speaking, representative formula (I) compound can effectively suppress Raw air way resistance in the 1-100mg/kg dosage range in the mouse model of acute asthma.High dosage (30mg/kg) treatment also can suppress the active and MUC5AC level of AMCase in IL-13 inducing action and the BAL liquid.
Representative formula (I) compound is proved to be in the rat model of neuropathic pain and can effectively suppresses sense of touch sexual abnormality pain more than 30% in the 1-150mg/kg dosage range.
Formula (I) compound is found GSK-3 β, the people GSK-3 β that can suppress the terminal His-mark of people ROCK-2, N-, the recombinant human JAK2 and the Photinus pyralis LUC of His6-mark, the IC that shows 50Be the about 10 μ M of about 1.0 μ M-, the about 1.0 μ M of preferably about 100nM-.More preferably, formula (I) compound is found GSK-3 β, the people GSK-3 β that can suppress the terminal His-mark of people ROCK-2, N-, the recombinant human JAK2 and the Photinus pyralis LUC of His6-mark, the IC that shows 50For the about 100nM of about 10nM-, most preferably less than 10nM.
In addition, the inhibition selectivity that shows people ROCK-2 of some formula (I) compound is higher than more than 10 times of 50 kinase target groups.The inhibition selectivity that some formula (I) compound shows people GSK-3 β is higher than more than 10 times of 50 kinase target groups.The inhibition selectivity that some formula (I) compound shows the recombinant human JAK2 of His6-mark is higher than more than 10 times of 50 kinase target groups.
Administrated method
The present invention also provides the medicinal compositions that comprises The compounds of this invention.Described medicinal compositions comprises the The compounds of this invention with one or more nontoxic pharmaceutical acceptable carrier preparations.
Medicinal compositions of the present invention can be with administration in oral administration, rectal administration, parenteral admin, the brain pond, intravaginal administration, topical (with powder, ointment or drops form), suck administration or as oral cavity or nasal spray form of medication administration of human or other Mammals.Term used herein " parenteral admin " be meant comprise that intravenously, intramuscular, intraperitoneal, breastbone are interior, subcutaneous, intra-articular injection and infusion administering mode.
Term used herein " pharmaceutical acceptable carrier " is meant the formulation auxiliary agents of nontoxic inert solid, semisolid or liquid filling agent, thinner, coating material or any kind.Can be used as pharmaceutical acceptable carrier material some examples for sugar as but be not limited to lactose, dextrose plus saccharose; Starch as but be not limited to W-Gum and yam starch; Mierocrystalline cellulose and derivative thereof as but be not limited to Xylo-Mucine, ethyl cellulose and rhodia; Powdered tragacanth; Fructus Hordei Germinatus; Gelatin; Talcum powder; Vehicle as but be not limited to theobroma oil and suppository wax; Oils as but be not limited to peanut oil, Oleum Gossypii semen, Thistle oil, sesame oil, sweet oil, Semen Maydis oil and soya-bean oil; Glycols; As propylene glycol; The ester class as but be not limited to ethyl oleate and Laurate ethyl; Agar; Buffer reagent as but be not limited to magnesium hydroxide and aluminium hydroxide; Lalgine; Apirogen water; Isotonic saline solution; Ringer ' s solution; Ethanol and phosphate buffered saline buffer; And other compatible lubricant as but be not limited to Sulfuric acid,monododecyl ester, sodium salt and Magnesium Stearate, and tinting material, releasing agent, Drug coating, sweeting agent, seasonings and flavouring agent according to preparation scholar's judgement, also can exist sanitas and antioxidant in the composition.
The medicinal compositions that the present invention is used for parenteral injection comprise pharmacy can accept sterilized water or non-aqueous solution, dispersion, suspension or emulsion and use before just be made into the sterilized powder of aseptic injectable solution or dispersion again.Suitable water and nonaqueous carrier, thinner, solvent or carrier comprise water, ethanol, polyvalent alcohol (as glycerine, propylene glycol, polyoxyethylene glycol etc.), vegetables oil (as sweet oil), injection organosilane ester (as ethyl oleate) and suitable mixture thereof.Can under the dispersion situation, keep required particle diameter and use tensio-active agent to keep suitable flowability by as adopting coating material such as Yelkin TTS.
These compositions also can comprise assistant agent such as sanitas, wetting agent, emulsifying agent and dispersion agent.By adding various antibiotic and anti-mycotic agents such as Tegosept E, trichloro-butyl alcohol, phenol Sorbic Acid etc. to guarantee to prevent action of microorganisms.Also can comprise isotonic agent as sugar, sodium-chlor etc.The prolongation of injectable medicinal forms absorbs and can postpone the material that absorbs such as single stearic acid aluminium and gelatin and produce by including in.
In some cases, in order to prolong drug effect, need slow down from the absorption of subcutaneous or intramuscularly.This can finish by the liquid suspension of using weak water-soluble crystal or amorphous substance.The absorption rate of medicine depends on its dissolution rate then, and its dissolution rate can be depending on crystallographic dimension and crystalline form.Perhaps, absorb also can be by with medicine dissolution or be suspended in the oils carrier and finish in the delay of the formulation of parenteral admin.
Can prepare the long-acting injectable formulation by the microcapsule matrix that in biodegradable polymer such as polylactide/poly-glycollide, forms medicine.According to the character of medicine and polymer ratio and used particular polymers, may command drug releasing rate.The example of other biodegradable polymer comprises poly-(ortho ester) and poly-(acid anhydrides).Long acting injection also can by pharmaceutical pack is imbedded can be compatible with bodily tissue liposome or microemulsion in prepare.
Injection formulations can be sterilized, as filter or be added in the disinfectant that faces with before being dissolved or dispersed in the aseptic solid composite form of sterilized water or other aseptic injection medium through bacterium detention filter.
Oral dosage form comprises capsule, tablet, pill, powder and granule.In these solid dosages, active compound can with at least a inertia, pharmaceutical acceptable carrier or vehicle such as Trisodium Citrate or Lin Suanergai and/or a) weighting agent or extender such as starch, lactose, sucrose, glucose, N.F,USP MANNITOL and silicic acid; B) tackiness agent such as carboxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; C) wetting Agent for Printing Inks such as glycerine; D) disintegrating agent such as agar-agar, lime carbonate, potato or tapioca (flour), Lalgine, some silicate and yellow soda ash; E) solution retarding agent such as paraffin; F) absorption enhancer such as quaternary ammonium compounds; G) wetting agent such as hexadecanol or glyceryl monostearate; H) absorption agent such as kaolin and wilkinite and i) lubricant such as talcum powder, calcium stearate, Magnesium Stearate, solid polyethylene glycol, Sulfuric acid,monododecyl ester, sodium salt and composition thereof mix.Under capsule, tablet and pill situation, described formulation also can comprise buffer reagent.
The solids composition of similar type also can be used as weighting agent in the soft or hard filled capsules that adopts this carrier such as lactose or lactose (milk sugar) and high-molecular weight polyoxyethylene glycol etc.
Tablet, coated tablet, capsule, pill and granule solid dosage can be made into the form of dressing and shell such as enteric coating and the well-known dressing of other medicines formulation art.They can be chosen wantonly and comprise opalizer, also can have certain and form so that they only or preferentially optional with the delayed mode release of active ingredients in a part of enteron aisle.The example of available embedding composition comprises polymkeric substance and wax class.
If suitable, active compound also can be made microcapsule formulations with one or more above-mentioned carriers.
The liquid oral formulation comprises that pharmacy can accept emulsion, solution, suspension, syrup and elixir.Remove the active ingredient beyond the region of objective existence, liquid dosage form also can comprise the normally used inert diluent in this area such as water or other solvent, fatty acid ester of solubilizing agent and emulsifying agent such as ethanol, Virahol, ethyl-carbonate, ethyl acetate, benzyl alcohol, peruscabin, propylene glycol, 1,3 butylene glycol, dimethyl formamide, oils (particularly Oleum Gossypii semen, Peanut oil, Semen Maydis oil, germ oil, sweet oil, Viscotrol C and sesame oil), glycerine, tetrahydrofurfuryl alcohol, polyoxyethylene glycol and Sorbitan and composition thereof.
Except inert diluent, oral compositions also can comprise assistant agent such as wetting agent, emulsifying agent and suspending agent, sweeting agent, seasonings and flavouring agent.
Remove the active ingredient beyond the region of objective existence, suspension also can comprise isooctadecanol, polyoxyethylene sorbitol and sorbitan alcohol ester, the Microcrystalline Cellulose of suspending agent such as ethoxylation, aluminium hydroxide (aluminummetahydroxide), wilkinite, agar-agar, tragakanta and composition thereof partially.
The preferred suppository of the composition of rectum or vagina administration, it can be by mixing The compounds of this invention and suitable nonirritant carrier or at room temperature for solid but therefore can melt and discharge carrier such as theobroma oil, polyoxyethylene glycol or the suppository wax of active compound in rectum or vagina for liquid under body temperature.
Compound of the present invention can also the liposome form administration.As known in the art, liposome is usually derived from phosphatide or other Ester.Liposome is formed by the list or the multilayer hydrating fluid crystalline substance that are scattered in the aqueous medium.Any nontoxic, physiology that forms liposome can accept and but metabolism lipid all can adopt.Except that compound of the present invention, the composition of liposome form of the present invention can comprise stablizer, sanitas, vehicle etc.Preferred lipid is natural and synthetic phospholipid and phosphatidylcholine (Yelkin TTS), can use separately or together.
The method of formation liposome is known in the art.Referring to, as Prescott, Ed., Methodsin Cell Biology (method in the cytobiology), Volume XIV, Academic Press, NewYork, N.Y. (1976), p.33 and following or the like.
The topical formulation of The compounds of this invention comprises powder, sprays, ointment and inhalation.The propellant mixing that active compound can be under aseptic condition maybe may need with pharmaceutical acceptable carrier and any required sanitas, buffer reagent.Ophthalmic preparation, ophthalmic ointment, powder and solution are also contained in the scope of the present invention.
The actual dose level of activeconstituents can change to some extent in the medicinal compositions of the present invention, so that for specific patient, composition and administering mode, the amount of activeconstituents all can effectively reach required therapeutic response.Selected dosage level depend on specific compound activity, route of administration, sanatory seriousness and the patient's that treats illness and former with regard to Biography of Medical Figures.
When being used for above-mentioned or other when treatment, a kind of compound of the present invention of treatment significant quantity can be pure form use, if perhaps there are these forms, be that pharmaceutically acceptable salt, ester or prodrug forms use." the treatment significant quantity " of word The compounds of this invention is meant the enough amounts with the sanatory compound of rational benefit/risk ratio that is suitable for any therapeutic treatment.But, should be appreciated that total daily dosage portion Ying You doctor in charge of The compounds of this invention and composition is determining in the medical diagnosis scope reliably.Particular treatment effective dose level to any particular patient depends on various factors, comprises the illness of being treated and the seriousness of described illness; The activity of used specific compound; Used particular composition; Patient's age, body weight, general health situation, sex and diet; The drainage rate of administration time, route of administration and used specific compound; The time length of treatment; The medicine that is used in combination or uses simultaneously with used specific compound; And well-known similar factor in the medical field.
Term used herein " pharmaceutically acceptable salt " is meant derived from inorganic or organic acid salt.Described salt can be in the final separation and the purge process made acid-stable in situ of formula (I) compound, or separates preparation by the free alkali with formula (I) compound with inorganic or organic acid reaction.The representative example of acid salt includes but not limited to acetate, adipate, alginates, Citrate trianion, aspartate, benzoate, benzene sulfonate, bisulfate, butyrates, camphorate, camsilate, digluconate, glycerophosphate, Hemisulphate, enanthate, hexanoate, fumarate, hydrochloride, hydrobromate, 2-isethionate (isethionate), lactic acid salt, maleate, fumarate, mesylate, nicotinate, the 2-naphthalenesulfonate, oxalate, pamoate, pectate (pectinate), persulphate, 3-phenylpropionic acid salt, picrate, pivalate, propionic salt, succinate, vitriol, (L) tartrate, (D) tartrate, (DL) tartrate, thiocyanate-, phosphoric acid salt, glutaminate, supercarbonate, tosilate and undecylate.
Term used herein " pharmacy can be accepted prodrug " or " prodrug " are meant those prodrugs of no abnormal toxicity that being applicable in reliable medical diagnosis scope of The compounds of this invention contact with the lower animal tissue with the people, pungency, anaphylaxis etc.Prodrug of the present invention can be converted into formula (I) compound in vivo rapidly, as passing through hydrolysis in blood.
The present invention relates to by synthesis mode or formula (I) compound that forms by bio-transformation in the body.
Compound of the present invention can be non-solvent compound and solvate form thereof, comprises hydrate forms such as semihydrate.Usually, for the purposes of the present invention, described and pharmacy acceptable solvent are to be equal to as water and alcoholic acid equal solvent compound form and non-solvent compound form.
Total per daily dose scope of administration of human or zootic The compounds of this invention can be the about 30mg/kg/ of about 0.003-days.For oral purpose, the more preferred dose scope is the about 10mg/kg/ of about 0.01-days.If desired, for the administration purpose, effectively per daily dose can be divided into a plurality of dosage; Therefore, the single dose composition can comprise this amount or its approximate number that constitutes per daily dose.
Amino acid whose identity (serine/threonine, tyrosine, Methionin and Histidine) according to its target can be divided into protein kinase several big group.For example, Tyrosylprotein kinase comprises receptor tyrosine kinase (RTKs), as somatomedin, and nonreceptor tyrosine kinase, as src kinases family.Dual-the specificity protein kinase that also has target tyrosine and serine/threonine is as cyclin dependant kinase (CDKs) and mitogen-activated protein kinase (MAPKs).
Protein tyrosine kinase (PTKs) is formed adjusting and is related to kinases extended familys (Pearson, M. etc., the In Protein Tyrosinekinases of the cell of growth, differentiation, adhesion, mobility and death to cell signal; Fabbro, D., McCormick, F., Eds.; Humana Press Inc., 2006; Pp 1-29.).The member of Tyrosylprotein kinase includes but not limited to Yes, BMX, Syk, EphA1, FGFR3, RYK, MUSK, JAK1 and EGFR.Tyrosylprotein kinase is divided into two types, i.e. receptor type and non-receptor type Tyrosylprotein kinase.What is interesting is that the whole family of Tyrosylprotein kinase is made up of at least 90 certified kinases, wherein at least 58 is receptor type, and at least 32 is the non-receptor type kinases, comprises at least 30 kinds of subfamilies altogether.Tyrosylprotein kinase is relevant with multiple human diseases, comprises diabetes and cancer (Pearson, M. etc., In Protein Tyrosine Kinases; Fabbro, D., McCormick, F., Eds.; Humana Press Inc., 2006; Pp 1-29.).Tyrosylprotein kinase is relevant with the human malignancies of most of forms usually, also relevant with many congenital syndromes (Robertson etc., Trends Genet.16:265-271,2000).
The non-receptor type Tyrosylprotein kinase is one group of desmo enzyme that lacks the extracellular and stride the film sequence.At present, identified above 32 non-receptor type family tyrosine kinases (Robinson etc., Oncogene19,5548-5557,2000).Representative example comprises Src, Btk, Csk, ZAP70 and Kak family.Especially, the Src family of non-receptor type family tyrosine kinase is maximum family, is made up of Src, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr and Yrk protein tyrosine kinase.Kinase whose Src family is known relevant with tumour generation, cell proliferation and tumor progression.Many protein tyrosine kinases all are found and relate to various pathology illnesss and include but not limited to that the cell signaling approach of cancer and excessively proliferative disease and Immunological diseases is relevant.
Cyclin dependant kinase CDKs is the desmo enzyme of one group of control cell cycle progression, has vital role (Cohen, P.Nature Reviews DrugDiscovery 1,309-315,2002) in cell proliferation.The representative example of CDKs includes but not limited to that cyclin dependant kinase 2 (CDK2), cyclin dependant kinase 7 (CDK7), cyclin dependant kinase 6 (CDK6) and cell fission control 2 albumen (CDC2).CDKs relates to the regulating effect that changes between the cell cycle different steps, as process from resting stage of G1 (mitotic division in new cycle of cell fission and dna replication dna begin between gap) to S phase (active dna synthesis phase), or process from G2 to the M phase, active mitotic division and cell fission (Critical Reviews in Immunology 26 (3) such as Rowell wherein appears, 189-212,2006).Regulate cyclin subunit (as cyclin A, B1, B2, D1, D2, D3 and E) and the formation CDK of catalysis kinase subunit unit (as cdc2 (CDK1), CDK2, CDK4, CDK5 and CDK6) mixture by uniting.For their target substrate of phosphorylation, the CDKs cell cycle is regulated protein subunit and is demonstrated absolute dependency, and different paired kinases/cyclins are used for regulating the process of passing the cell cycle specific part.In addition, CDKs also relates to various disease states, include but not limited to those disease, various neoplastic disease and nervous system diseases that show cancerous phenotypes Current Medicinal Chemistry:CentralNervous System Agents 5 (2) such as (, 101-109,2005) Pallas.
Mitogen-activated protein(MAP) (MAP) kinases participates in nuclear signal transduction when the responsive cell external stimulus.The representative example of map kinase includes but not limited to mitogen-activated protein kinase 3 (MAPK3), mitogen-activated protein kinase 1 (ERK2), mitogen-activated protein kinase 7 (MAPK7), mitogen-activated protein kinase 8 (JNK1), mitogen-activated protein kinase 14 (p38 alpha), mitogen-activated protein kinase 10 (MAPK 10), JNK3 α protein kinase, stress activated protein kinase JNK2 and mitogen-activated protein kinase 14 (MAPK14).Map kinase is the serine/threonine kinase of proline(Pro) orientation, and it can mediate from the signal transduction of extracellular acceptor or heat-shocked or UV radiation (Barr etc., Trends in Pharmacological Sciences 27 (10), 525-530,2006).Dual-the specificity protein kinase of map kinase by comprising Tyrosylprotein kinase such as somatomedin activates the phosphorylation of Threonine and tyrosine.Prove that cell proliferation and differentiation are under the adjusting control of many map kinases cascade (Sridhar etc., Pharmaceutical Research, 17:11 1345-1353,2000).After this manner, the map kinase approach plays a crucial role in various disease states, as, the active shortage of map kinase has been proved to be and can have caused abnormal cell proliferation and oncogenesis (Qi etc., Journal of Cell Science 118 (16), 3569-3572,2005).In addition, the map kinase activity also relates to the insulin resistant relevant with diabetes B (Recent ResearchDevelopments in Physiology 1 (Pt.2) such as Fujishiro, 801-812,2003).
P90 ribosome S 6 kinases (Rsk) is Serine/Tyrosylprotein kinase, and it acts on mitogen-activated cell growth and propagation, differentiation and cell survival.Kinase whose Rsk family member's example includes but not limited to ribosomal protein S6 kinases, 90kDa, polypeptide 2 (Rsk3); Ribosomal protein S6 kinases, 90kDa, polypeptide 6 (Rsk4); Ribosomal protein S6 kinases, 90kDa, polypeptide 3 (Rsk2) and ribosomal protein S6 kinases, 90kDa, polypeptide 1 (Rsk1/p90Rsk).The Rsk family member is by extracellular signal correlation kinases and 1 activation (Frodin andGammeltoft, Mol.Cell.Endocrinol.151,65-77,1999) of phosphoinositide deopendent protein kinase.Under basic condition, the RSK kinases is positioned tenuigenin, and when being subjected to the mitogen stimulation, activatory (by extracellular dependency tyrosine phosphorylation) RSK temporarily transfers on the plasma membrane, activated fully there.The complete activatory RSK phosphorylation substrate relevant cancer Research 65 such as (, 3108-3116,2005) Clark with cell growth, propagation, differentiation and cell survival.RSK signal transduction path also relevant (Gross etc., J.Biol.Chem.276,46099-46103,2001) with the modulating action of cell cycle.Present data show that the small molecules that suppresses Rsk can be effective medicine of prevention and treatment cancer and inflammatory diseases.
Outpost of the tax office albumen (checkpoint protein) kinases family (CHK) is Serine/Tyrosylprotein kinase, plays an important role in cell cycle progression.The member's of outpost of the tax office family example includes but not limited to CHK1 and CHK2.Checkpoint kinase is for coordinating the Controlling System of cell cycle progression by formation, activation and the deactivation subsequently that influences the cyclin dependant kinase.Checkpoint kinase is at unsuitable time histocyte cycle progression, keeps the cellular metabolism balance when cell is stagnated, but when not satisfying cell death inducing (apoptosis) (Nurse, Cell, 91,865-867,1997 in some cases when requiring, the outpost of the tax office; Hartwell etc., Science, 266,1821-1828,1994).Kinase whose outpost of the tax office family member relates to cell breeding disease, cancerous phenotype and other and dna damage and repairs diseases associated (Kumagai and Dunphy Cell Cycle, 5,1265-1268 (2006); Xiao etc., Molecular cancer Therapeutics 5,1935-1943,2006).
The Aurora kinases is the mitotic Serine-family tyrosine kinase of polygene, as the novel oncogene of a class.These kinases comprise aurora-A and aurora-B member.The Aurora kinases is in several solid tumor camber activation and/or overexpression, and described solid tumor includes but not limited to mammary cancer, ovarian cancer, prostate cancer, carcinoma of the pancreas and colorectal carcinoma.Especially, aurora-A is the centrosome kinases, plays an important role in cell cycle progression and cell proliferation.Aurora-A is positioned the 20q13 chromosomal region, and this zone is amplified in several dissimilar malignant tumours such as colorectal carcinoma, mammary cancer and bladder cancer usually.Aurora-A also and height organize between the prognosis level dysploidy (high histo-prognostic grade aneuploidy) and have high correlation, make this kinases become potential prognosis carrier.Suppress the aurora kinase activity and can reduce cell proliferation, tumor growth and the generation of potential tumour.At Journal of Cell Science, 119,3664-3675, describing in detail the aurora kinase function in 2006.
Because it can be used as downstream effect of Rho/Rac family of the Small GTPases of cytokine and growth factor activation, so albumen Serine/Tyrosylprotein kinase ROCK-1 and ROCK-2 that the Rho-dependency contains coiled coil are considered to play an important role in cytoskeleton kinetics.But the various substrates of ROCKs phosphorylation include but not limited to MLCP, myosin light chain, ezrin-radicin-moesin albumen and LIM (Lin11, Isl1 and Mec3) kinases.ROCKs is mediation Actin muscle stress fiber and the formation of sticking together spot in various cell types also.Because ROCKs can strengthen cellular contraction, so it has vital role in cell migration, and for the tail contraction of monocyte and cancer cell essential.The ROCK inhibitor also can reduce tumour cell according to the show in vivo and propagate.Nearest experiment has defined the new function of ROCKs in cell, comprise centrosome location and cell size adjustment, it may facilitate various physiology and pathologic state (Mueller et al, Nature Reviews Drug Discovery 4,387-398,2005).The ROCK family member is the noticeable intervention target (intervention targets) that comprises the various symptom of cancer and cardiovascular disorder.The ROCK inhibitor can be effective medicine of hypertension, stenocardia and asthma.In addition, the Rho expection is worked in circulatory diseases, arteriosclerosis, inflammation and the autoimmune disease around, and therefore, it is effectively to treat target (Shimokawa et al, Arteriosclerosis, Thrombosis, and Vascular Biology, 25,1767-1775,2005).
The limited success of drug treatment when treatment Spinal injury is because the ability that the impaired nerve fiber in people's substantia alba medullae spinalis has lost regrowth and rebuild synaptic contact with the mating partner neurone that they are disconnected to a great extent.Caused the non-reversibility of this axon growth to stagnate with a large amount of molecule axon growth inhibitor in injury site, the hostile microenvironment that exists for feature in scar tissue and on the CNS myelin.In tissue culture, these axon growth inhibitor can be induced very violent replying usually, comprise aixs cylinder formation disintegrate shrinking back of (collapse) and aixs cylinder.Scar tissue in human brain and the spinal cord is the powerful and persistent obstacle of any reproducibility axon growth, and the ROCK inhibitor can help damaged fibers to cross these inhibition regenerated tissues and growth or rudiment.Many evidences show that brain and Spinal injury can cause the strong activation of RhoA-ROCK approach.Since the axon growth inhibitor or exist around damaged part and the persistence in the CNS myelin, this activation may continue the long period, make and suppress ROCK and become not only acute and subacute treatment, also to the target that has much magnetism of the chronic treatment of Spinal injury Spinal injury.Suppressing ROCK by two kinds of different small molecules ROCK inhibitor (Y-27632 and fasudil) can be in that part or whole body gives single dose or through different mouse and the Spinal Cord Injury in Rats model moderate stimulation or the acceleration functional rehabilitation (Dergham of several all administrations immediately after damage, P. wait Rho signaling pathway targeted to promotespinal cord repair (target promotes the Rho signal transduction path that spinal cord is repaired) .J.Neurosci.22,6570-6577,2002; Hara, M. wait Proteinkinase inhibition by fasudilhydrochloride promotes neurological recovery after spinal cord injury in rats (by nerve recovery after the fasudil hydrochloride arrestin kinases promotion Spinal Cord Injury in Rats) .J.Neurosurg.Spine 93,94-101,2000.; Fournier, ROCK inhibitionenhances axonal regeneration in the injured CNS such as A.E. (ROCK suppresses to strengthen axon regeneration among the impaired CNS) .J.Neurosci.23,1416-1423,2003; Sung, J.K. wait A possible roleof RhoA/Rho-kinase in experimental spinal cord injury in rat (RhoA/Rho kinases may act in rat experiment Spinal injury) .Brain Res.959,29-38,2003; Tanaka, H. wait Cytoplasmic p21 (Cip1/WAF1) enhances axonal regeneration andfunctional recovery after spinal cord injury in rats (kytoplasm p21 (Cip1/WAF1) can strengthen Spinal Cord Injury in Rats after axon regeneration and functional rehabilitation) .Neuroscience 127,155-164,2004).In these researchs, suppress ROCK and not only can strengthen nerve fiber and cross the damage location growth, also have a neuroprotective, and can reduce tissue injury and the hole forms.On the basis of these rodents research, having the patient that the active ROCK inhibitor of neuroprotective and stimulating neural regeneration can be vertebrae injry provides significant benefits.Because its vasodilator effect, they can make backbone blood flow normalizing, thereby further strengthen organization protection's effect.
The pathological characteristics of alzheimer's disease under microscopic level is neurofibrillary tangles thing and extracellular amyloid condensation product in the cell.Neuroneme twines the tau protein that the thing knot comprises unusual phosphorylation, a kind of microtubule dependency albumen, and the substrate of ROCK, and the amyloid condensation product is mainly formed by toxicity 42-amino acid long amyloid-β (A β) peptide.According to showing (Zhou recently, Y. wait Nonsteroidal anti-inflammatory drugs can lower amyloidogenic A β 42 byinhibiting Rho (NSAID (non-steroidal anti-inflammatory drug) can reduce amyloid formation property A β 42 by suppressing Rho) .Science 302,1215-1217,2003), in the cell of secretion A β 42 and in the transgenosis PDAPP mouse of a large amount of A β 42 of generation, some NSAIDs can reduce A β 42 by suppressing the RhoA-ROCK approach.ROCK inhibitor Y-27632 can effectively reduce A β 42 levels in cell cultures and in the PDAPP transgenic mice after the intracerebral ventricle injection.The activation of the Rho that is caused by tetra-sodium geranyl geraniol ester can increase A β 42 levels, and tetra-sodium geranyl geraniol ester is that the film of a kind of Rho adheres to required lipid; This increase can be suppressed fully by Y-27632.Be used for the amount that animal Alzheimer disease model ROCK inhibitor can effectively reduce toxicity A β 42 levels, but invalid to total A β level, this effect of Rho or ROCK inhibitor is at least a kind of mechanism that NSAIDs reduces A β 42 levels.Except many other treatments got involved, these inhibitor clearly had the advantage of the scorching regenerative growth that excites nerve, and therefore, suppressed the neural circuit that this approach may be repaired the amyloid damage.
Most importantly in the disease pathogenesis cross the brain endothelial tissue for white corpuscle and move to the inflammation cascade that CNS neutralization is caused by these cells, it finally causes CNS fibrous bundle demyelination and axonal injury and disappearance.The route that white corpuscle is crossed the brain endothelial tissue needs active RhoA and ROCK, because their endothelial migration of wearing is suppressed by ROCK inhibitor Y-2763294.
The neuroprotective activity of ROCK inhibitor fasudil and hydroxyl-fasudil not only is confined to spinal cord injury model, also existing report (Toshima Y, Satoh S, Ikegaki I, Asano T in gerbil jird and many infarct of rat brain model.A new model of cerebral microthrombosis in ratsand the neuroprotective effect of a Rho-kinase inhibitor (neuroprotective of a kind of novel rat brain microthrombus model and Rho kinase inhibitor) .Stroke 31,2245-2250,2000; Satoh, S. wait Pharmacological profile of hydroxy fasudil as a selective ROCKinhibitor on ischemic brain damage (Hydroxyfasudil is as the pharmacology spectrum of selectivity ROCK inhibitor to ischemic brain injury) .Life Sci.69,1441-1453,2001; Kitaoka; Y. wait Involvement of RhoA and possible neuroprotective effect of fasudil; a ROCKinhibitor; in NMDA-induced neurotoxicity in the rat retina (RhoA and the neurovirulent relation of NMDA inductive rat retina and fasudil are as ROCK inhibitor possible neuroprotective therein) .Brain Res.1018; 111-118,2004).In the rodent apoplexy model, several regeneration inhibitor, as activate the NgR1 mixture of ROCK and its one of them part, NOGO-A, big cerebral apoplexy inducing action 24 hours or even 1 week after be neutralized, and observe functional rehabilitation and improve (Lee, J.K., Kim, J.E., Sivula, M.﹠amp; Strittmatter, S.M.Nogoreceptor antagonism promotes Stroke recovery by enhancing axonalplasticity (the Nogo receptor antagonist promotes apoplexy to recover by increasing aixs cylinder plasticity) .J.Neurosci.24,6209-6217,2004; Wiessner, C. wait Anti-Nogo-A antibody infusion 24 hoursafter experimental Stroke improved behavioral outcome and corticospinalplasticity in normotensive and spontaneously hypertensive rats (anti-back 24 hours Nogo-A antibody of experimental apoplexy merges behavior outcome and the cortex spinal cord plasticity of improving the normal and spontaneous hypertensive rat of blood pressure) .J.Cereb.Blood FlowMetab.23,154-165,2003).Therefore, retardance ROCK is feasible neurotization strategy; In addition, this strategy also has an advantage, just is to use the treatment window of these inhibitor bigger than the option of thrombolytic agent or neuroprotective treatment apoplexy.
It is neuropathic pain that human peripheral nervous system or CNS neuronal damage can cause the chronic pain state.For replying inflammatory mediators such as the Ultrapole L (LPA) that damage produces, nearest relevant (the Inoue of neuropathic pain outbreak that studies show that in the rat model with peripheral nerve injury, M. wait Initiation of neuropathic pain requires lysophosphatidic acid receptorsignaling (the relevant lpa receptor signal that needs of neuropathic pain outbreak conducts) .Nature Med.10,712-718,2004).LPA is present in the damage location of PNS and CNS, plays a role by the LPA acceptor in conjunction with the G-albumen coupling, causes the RhoA-ROCK pathway activation.ROCK inhibitor Y-27632 can suppress the neuropathic pain outbreak after nerve injury or the LPA injection; and another ROCK inhibitor; H-1152; can be in L5 spinal nerves transection model alleviating neuropathic pain (Tatsumi; S. wait Involvement of Rho-kinase in inflammatory and neuropathic pain throughphosphorylation of myristoylated alanine-rich C-kinase substrate (MARCKS) (the Rho kinases is associated with inflammatory and neuropathic pain by the C kinase substrate that is rich in L-Ala of phosphorylation myristoylation) .Neuroscience 131; 491-498,2005).The result of these researchs shows that ROCK is a potential medicine target of inducing and keep lasting pain status.
In addition, (Abstract 1216 for Schueller etc., 8th World Congress on Inflammation, Copenhagen, Denmark, June 16-20,2007) prove the inhibitor of SLx-2119 as effective, the potent highly selective of the oral biology of ROCK 2, in 8 Apo E knock-out mice groups, in the presence of the lipid level that significantly raises, can reduce atherosclerosis and form, show that suppressing ROCK 2 has the atherosclerotic potentiality of restriction.
70kDa ribosome S 6 kinases (p70S6K) can be by many mitogens, somatomedin and hormone activation.Phosphorylation by many sites can make p70S6K activation occur, and the main target of activated protein kinase is 40S ribosomal protein S6, and it is the main component of synthesizing relevant mechanism with mammalian cell albumen.The adjusting of the activation of p70S6K and cell cycle control in addition,, neuronal cell differentiation, cell mobility and in metastases very important cell response, immunity and tissue repair relevant.Modulation p70S6 kinase activity also may be relevant with the treatment of disorders such as cancers, inflammation and various DPNs.At Prog.Cell Cycle Res., 1,21-32,1995, and Immunol.Cell Biol.78,447-51 can find the kinase whose detailed description to p70S6K in 2000.
Constitutive activity Serine/Tyrosylprotein kinase that Glycogen Synthase kinase 3 (GSK-3) is expressed for omnipresence, but its phosphorylation cell substrate, thereby regulate various cell functions, comprise that growth, metabolism, genetic transcription, protein translation, cytoskeleton are set up, cell cycle is regulated and apoptosis.GSK-3 is described to the key enzyme relevant with Glycogen Metabolism at the beginning, and it can regulate different a series of cell functions but it is now know that.Identified in the past this enzyme two types of GSK-3+f and
Figure GPA00001018010702301
The activity of GSK-3+f is by protein kinase B/Akt and the negative adjusting of Wnt signal transduction path.Therefore, the micromolecular inhibitor of GSK-3 may have several therepic use, comprise treatment and prevention neurodegenerative disease and stimulate (the J.Cell Science such as Gartner of neurotization in the various neuropathies, 2006,119,3927-3934.Zhou Deng Neuron, 2004,42,897-912), type ii diabetes, two-phase obstacle, apoplexy, cancer, osteoarthritis, osteoporosis, rheumatoid arthritis (Clinical Immunology such as Cuzzocrea, 2006,120,57-67) and chronic inflammatory disease.General review:Kockeritz etc., Current Drug Targets, 7,1377-1388,2006.Review ofneurological applications:Current Drug Targets, 7 (11), 1389-1397 and 1399-1409,2006.
Protein kinase has become noticeable target (Fabbro etc., Pharmacology﹠amp in the cancer therapy; Therapeutics 93:79-98,2002).Someone advises, protein kinase by following some show relevant with the development of human malignancies: (1) genome rearrangement (as the BCR-ABL in chronic granulocytic leukemia), (2) cause the sudden change of constitutive activity kinase activity, as acute myelocytic leukemia and gastroenteric tumor, (3) take off the adjusting kinase activity by activation oncogene or tumor suppressor gene disappearance, as in the cancer that has oncogene RAS, (4) take off the adjusting kinase activity by overexpression, as under the situation of EGFR, (5) ectopic expression of somatomedin can promote development and maintenance (Fabbro etc., the Pharmacology﹠amp of tumor phenotypes; Therapeutics 93:79-98,2002).
Some cancer takes place relevant with blood vessel.Blood vessel occur as new capillary vessel from before the vascular system growth (Risau, W., Nature 386:671-674,1997) of existence.Protein kinase can promote development and maintenance (Fabro etc., the Pharmacology﹠amp of tumor phenotypes according to the show; Therapeutics 93:79-98,2002).For example, VEGF A-D and four kinds of acceptors thereof relate to and neovascularization and the relevant phenotype of enhancing vascular permeability, take place and lymph vessels generation (Matter, A., DrugDiscov.Today 6:1005-1023,2001) as tumor vessel.
It has been recognized that owing to several reasons, the single medicine method of a kind of kinases of special target or a kind of kinase pathways may be not enough to treat disease and illness, particularly cancer.There is the essential sudden change of 5-7 kind in models show in normal cell becomes the process of harmful cell.In addition, people recognize that extensively cancer is the result that number of ways changes, particularly with process such as cell growth, propagation, apoptosis, mobility or intrusion proteins associated kinase pathways.In most of cancers, a universal characteristics is overexpression simultaneously and/or the activation of various protein kinase height, as acceptor and non-receptor type kinases, Serine/Tyrosylprotein kinase, PI3 kinases and cell cycle dependency kinases.In fact, several in these kinases, no matter be separately or with other kinases, all with manyly cause shifting, blood vessel takes place or the important process of cell survival, propagation, growth and vicious transformation, motility and the intrusion of relative inflammation and disease, illness and symptom is relevant.
Therefore, blocking a kind of target kinase may be not enough clinically, because there are the many target kinases that influence symptom, disease or illness process.In addition, blocking a kind of target kinase may be not enough clinically, because too much kinase mediated approach and other are carcinogenic or inflammation mechanism can compensate blocked target kinase.And, use single medicine also can increase the chemical sproof chance that this medicine forms.
Cardiovascular disorder is that the death that causes almost accounts for 1/4th of the annual total death toll in the whole world.Vascular disorder is to be flow to vitals and caused by vessel wall growth imbalance and limit blood as atherosclerosis and restenosis.Various kinase pathways activated the thorn activating signal activation of pulse atherosclerosis and regulate (Yang etc., Immunity9:575,1998) by the local cells factor and the somatomedin that produce in the vascular cell as JNK.Local asphyxia and local asphyxia add heart, kidney or brain again perfusion can cause death and cicatrization, it can finally cause congestive heart failure, renal failure or cerebral function obstacle.In organ transplantation, the perfusion again of previous local asphyxia donor organ can cause the tissue injury of acute white corpuscle mediation and portability function to postpone.Local asphyxia and perfusion approach again have various kinase mediated.As the tissue injury relevant (Li etc., Mol.Cell.Biol.16:5947-5954,1996) of, JNK approach with the white corpuscle mediation.At last, apoptotic enhancing also relevant (Pombo etc., J.Biol.Chem.269:26546-26551,1994) in the heart tissue with kinase activity.

Claims (156)

1. formula (I) compound or its pharmaceutically acceptable salt,
Figure FPA00001018010600011
Wherein
A is
Figure FPA00001018010600012
R 1Be hydrogen, alkyl, aryl, heterocycle, heteroaryl, R aR bN-, R cR dN-C (O)-or R cR dN-S (O) 2-;
R 2Be hydrogen, alkyl, alkoxy carbonyl, alkyl-carbonyl, aryl carbonyl, heterocycle carbonyl or R eR fN-alkyl-C (O)-;
R 3Be alkyl, alkoxyl group, aryl, cyano group, cycloalkyl, halogen, haloalkyl, heteroaryl, nitro, or R gR hN-;
R 4Be alkyl, alkoxyalkyl, aryl, cycloalkyl, heteroaryl, heterocycle, Heterocyclylalkyl, R jR kN-or R jR kThe N-alkyl-;
R 5Be alkyl, aryl, or heteroaryl;
R 6Be alkyl, alkoxyalkyl, R jR kThe N-alkyl-, aryl, cycloalkyl or heteroaryl;
R 7Be alkyl, aryl or heteroaryl;
R aAnd R bIndependent separately is hydrogen, alkyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroarylalkyl, R 4-C (O)-, or R 5-S (O) 2-;
R cAnd R dIndependent separately is hydrogen, alkyl or heteroaryl;
R eAnd R fIndependent separately is hydrogen, alkyl, arylalkyl, heteroarylalkyl, R 6-C (O)-, or R 7-S (O) 2-;
R gAnd R hIndependent separately is hydrogen, alkyl, or alkyl-carbonyl;
R jAnd R kIndependent separately is hydrogen, alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl, or heterocycle;
R i, R Ii, R Iii, R Iv, R v, R Vi, R Vii, R Viii, R Ix, R x, R Xi, R Xii, R Xiii, R Xiv, R Xv, R Xvi, R Xvii, R Xviii, R Xix, R Xx, R Xxi, R XxiiAnd R XxiiiIndependent separately is alkyl, alkoxyl group, alkoxyalkyl, alkoxy carbonyl, alkoxy carbonyl alkyl, aryl, arylalkyl, aryl (hydroxyl) alkyl, aromatic yloxy yl alkyl, aryl carbonyl, artyl sulfo alkyl, carboxyl, carboxyalkyl, cyano group alkyl, cycloalkyl, cycloalkylalkyl, naphthene base carbonyl, halogen, heteroaryl, heteroarylalkyl, heterocycle, Heterocyclylalkyl, heterocycle carbonyl, hydroxyalkyl, trialkylsilkl alkyl, H 2NC (O)-alkyl, Z aZ bN-, Z aZ bN alkyl, Z cZ dNC (O)-or Z cZ dNS (O) 2-, R wherein Xiv, R Xv, R XviAnd R XviiCan or (xvii) go up any unappropriated valency place at compound (xiv), (xv), (xvi) occurs;
Z aAnd Z bIndependent separately is hydrogen, alkyl, alkoxy carbonyl alkyl, aryl, arylalkyl, cycloalkyl, H 2NC (O)-, H 2N alkyl C (O)-, H 2NC (O)-alkyl, dialkyl group NC (O)-or dialkyl group NC (O)-alkyl-;
Z cAnd Z dIndependent separately is hydrogen, alkyl, alkoxyalkyl, aryl, arylalkyl, aryl (hydroxyl) alkyl, cycloalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycle, Heterocyclylalkyl, hydroxyalkyl, H 2NC (O)-alkyl-, dialkyl group NC (O)-alkyl-, dialkyl group N-alkyl-, or CHZ eZ f
Z eBe aryl or heteroaryl;
Z fBe heteroarylalkyl, Heterocyclylalkyl, or Z 1Z 2The N-alkyl-;
M is 0,1 or 2;
A is 0 or 1;
B is 0,1, or 2;
C is 0,1,2 or 3; And
D is 0,1,2,3 or 4.
2. the compound of claim 1, wherein
A for (ii), (iii), (iv), (vii), (x), (xiv), (xv), (xvi), (xvii), (xviii), (xix), (xx), (xxi), (xxii), or (xxiii).
3. the compound of claim 2, wherein A is for (ii)
Figure FPA00001018010600031
R 1Be hydrogen, aryl, heteroaryl, heterocycle, R aR bN-, or R cR dN-C (O)-;
R 2Be hydrogen, alkoxy carbonyl, heterocycle carbonyl, alkyl-carbonyl, or R eR fN-alkyl-C (O)-;
R 4Be alkyl, alkoxyalkyl, aryl, cycloalkyl, heterocycle, Heterocyclylalkyl, R jR kN-or R jR kThe N-alkyl-;
R 5Be alkyl, aryl or heteroaryl;
R aAnd R bIndependent separately is hydrogen, arylalkyl, cycloalkylalkyl, R 4-C (O)-or R 5-S (O) 2-;
R cAnd R dIndependent separately is hydrogen or heteroaryl;
R eAnd R fIndependent separately is hydrogen or alkyl;
R jAnd R kIndependent separately is hydrogen, alkyl, aryl, cycloalkyl, or heterocycle;
R IiBe alkyl, alkoxyalkyl, alkoxy carbonyl, aryl, arylalkyl, aryl (hydroxyl) alkyl, aromatic yloxy yl alkyl, aryl carbonyl, alkoxy carbonyl alkyl, artyl sulfo alkyl, carboxyl, carboxyalkyl, cycloalkyl, cycloalkylalkyl, naphthene base carbonyl, halogen, heteroaryl, heteroarylalkyl, heterocycle, Heterocyclylalkyl, heterocycle carbonyl, hydroxyalkyl, trialkylsilkl alkyl, Z aZ bN-, Z aZ bThe N alkyl-or Z cZ dNC (O)-;
Z aAnd Z bIndependent separately is hydrogen, alkyl or H 2N alkyl C (O)-;
Z cAnd Z dIndependent separately be hydrogen, alkyl, alkoxyalkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroarylalkyl, Heterocyclylalkyl, hydroxyalkyl or dialkyl group N-alkyl-;
M is 0; And
B is 0,1, or 2.
4. the compound of claim 3, wherein
R 1Be hydrogen, heterocycle, R aR bN-, or R cR dN-C (O)-;
R 2Be hydrogen, alkoxy carbonyl or R eR fN-alkyl-C (O)-;
R 4Be alkyl, alkoxyalkyl, aryl, cycloalkyl, heterocycle, Heterocyclylalkyl, R jR kN-or R jR kThe N-alkyl-;
R 5Be alkyl, aryl or heteroaryl;
R aAnd R bIndependent separately is hydrogen, arylalkyl, cycloalkylalkyl, R 4-C (O)-or R 5-S (O) 2-;
R jAnd R kIndependent separately is hydrogen, alkyl, aryl, cycloalkyl or heterocycle;
R IiBe alkyl, alkoxyalkyl, alkoxy carbonyl alkyl, aryl, arylalkyl, aromatic yloxy yl alkyl, aryl carbonyl, artyl sulfo alkyl, carboxyl, carboxyalkyl, cycloalkyl, cycloalkylalkyl, naphthene base carbonyl, halogen, heteroaryl, heteroarylalkyl, Heterocyclylalkyl, heterocycle carbonyl, hydroxyalkyl, trialkylsilkl alkyl, Z aZ bThe N alkyl-, or Z cZ dNC (O)-;
Z aAnd Z bIndependent separately is hydrogen or alkyl;
Z cAnd Z dIndependent separately is hydrogen, alkyl, alkoxyalkyl, aryl, arylalkyl, cycloalkylalkyl or Heterocyclylalkyl;
M is 0; And
B is 0,1 or 2.
5. the method for claim 3, wherein
R 1Be hydrogen or R aR bN-;
R 2Be hydrogen;
R 4Be alkyl, alkoxyalkyl or aryl;
R 5Be alkyl or aryl;
R aAnd R bIndependent separately is hydrogen, arylalkyl, R 4-C (O)-or R 5-S (O) 2-;
R IiBe alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl or halogen;
B is 1 or 2; And
M is 0.
6. the method for claim 3, wherein
R 1Be hydrogen, aryl, heteroaryl or R aR bN-, the triazole of wherein said heteroaryl for being replaced by arylalkyl;
R 4Be alkoxyalkyl, alkyl, aryl or R jR kN-;
R 5Be alkyl, aryl, or heteroaryl;
R aAnd R bIndependent separately is hydrogen, arylalkyl, R 4-C (O)-, or R 5-S (O) 2-;
R jAnd R kBe alkyl;
R IiBe alkyl, alkoxyalkyl, aryl, arylalkyl, aryl (hydroxyl) alkyl, aromatic yloxy yl alkyl, aryl carbonyl, artyl sulfo alkyl, carboxyl, cycloalkyl, cycloalkylalkyl, naphthene base carbonyl, halogen, heteroaryl, heteroarylalkyl, Heterocyclylalkyl, heterocycle carbonyl, hydroxyalkyl, Z aZ bN alkyl or Z cZ dNC (O)-;
Z aAnd Z bIndependent separately is hydrogen or H 2N alkyl-C (O)-;
Z cAnd Z dIndependent separately is hydrogen, alkoxyalkyl, alkyl, arylalkyl, cycloalkyl, cycloalkylalkyl, or Heterocyclylalkyl;
B is 1 or 2; And
M is 0.
7. the compound of claim 2, wherein A is for (iii)
R 1Be hydrogen or R aR bN-;
R 2Be hydrogen;
R aAnd R bThe hydrogen of respectively doing for oneself;
R IiiBe arylalkyl;
M is 0; And
C is 1.
8. the compound of claim 2, wherein A is for (iii)
Figure FPA00001018010600062
R 1Be hydrogen or R aR bN-;
R 2Be hydrogen;
R 4Be R jR kThe N-alkyl-;
R aAnd R bIndependent separately is hydrogen, or R 4-C (O)-;
R jAnd R kBe alkyl;
R IiiBe alkoxy carbonyl alkyl, alkyl, arylalkyl, cyano group alkyl, Heterocyclylalkyl, or H 2NC (O)-alkyl-;
C is 0,1 or 2; And
M is 0.
9. the compound of claim 2, wherein A is for (iv)
Figure FPA00001018010600071
R 1Be hydrogen or R aR bN-
R 2Be hydrogen;
R aAnd R bThe hydrogen of respectively doing for oneself;
R IvBe alkyl, aryl, arylalkyl, heterocycle, Heterocyclylalkyl or Z aZ bN alkyl or Z cZ dNS (O) 2-;
Z aAnd Z bIndependent separately is hydrogen or alkyl;
Z cAnd Z dThe alkyl of respectively doing for oneself;
C is 0, or 1; And
M is 0.
10. the compound of claim 2, wherein A is (vii)
Figure FPA00001018010600072
R 1For hydrogen ,-NR aR b, or alkyl;
R 2Be hydrogen;
R aAnd R bThe hydrogen of respectively doing for oneself;
R ViiBe alkyl, alkoxy carbonyl, aryl, arylalkyl, cycloalkyl, Heterocyclylalkyl, heterocycle carbonyl, hydroxyalkyl or Z cZ dNC (O)-;
Z cAnd Z dIndependent separately is hydrogen, alkyl, alkoxyalkyl, aryl, arylalkyl, aryl (hydroxyl) alkyl, cycloalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycle, Heterocyclylalkyl, hydroxyalkyl, or CHZ eZ f
Z eBe aryl or heteroaryl;
Z fBe heteroarylalkyl, Heterocyclylalkyl, or Z 1Z 2The N-alkyl-;
B is 1; And
M is 0.
11. the compound of claim 2, wherein A is (vii)
Figure FPA00001018010600081
R 1Be hydrogen, alkyl, or R aR bN-;
R 2Be hydrogen;
R aAnd R bThe hydrogen of respectively doing for oneself;
R ViiBe alkyl, alkoxy carbonyl, arylalkyl, cycloalkyl, Heterocyclylalkyl, heterocycle carbonyl, hydroxyalkyl or Z cZ dNC (O)-;
Z cAnd Z dIndependent separately is hydrogen, alkyl, alkoxyalkyl, aryl, arylalkyl, aryl (hydroxyl) alkyl, cycloalkyl, heteroarylalkyl, Heterocyclylalkyl or hydroxyalkyl;
B is 1; And
M is 0.
12. the method for claim 2, wherein A is (vii)
Figure FPA00001018010600082
R 1Be hydrogen or R aR bN-;
R 2Be hydrogen;
R aAnd R bBe hydrogen;
R ViiBe the alkyl or aryl alkyl;
B is 1; And
M is 0.
13. the compound of claim 2, wherein A is (x)
Figure FPA00001018010600083
R 1Be hydrogen;
R 2Be hydrogen;
R xBe alkyl, aryl or Z aZ bN-;
Z aAnd Z bIndependent separately is hydrogen, alkyl, aryl or arylalkyl;
B is 1 or 2; And
M is 0.
14. the compound of claim 2, wherein A is (xiv)
Figure FPA00001018010600091
R 1Be hydrogen;
R 2Be hydrogen;
R XivBe Z aZ bN-;
Z aAnd Z bIndependent separately is hydrogen or cycloalkyl;
C is 1; And
M is 0.
15. the compound of claim 2, wherein A is (xv)
Figure FPA00001018010600092
R 1Be hydrogen or R aR bN-;
R 2Be hydrogen;
R aAnd R bBe hydrogen;
R XvBe Z aZ bN-;
Z aAnd Z bIndependent separately is hydrogen, alkoxy carbonyl alkyl, aryl, arylalkyl or cycloalkyl;
D is 0 or 1; And
M is 0.
16. the compound of claim 2, wherein A is (xvi)
Figure FPA00001018010600101
R 1Be hydrogen;
R 2Be hydrogen;
R XviBe Z aZ bN-;
Z aAnd Z bIndependent separately is hydrogen or cycloalkyl;
D is 1; And
M is 0.
17. the compound of claim 2, wherein A is (xvii)
Figure FPA00001018010600102
R 1Be hydrogen;
R 2Be hydrogen;
R XviiBe Z aZ bN-or aryl;
Z aAnd Z bIndependent separately is hydrogen, alkyl, alkoxy carbonyl alkyl, aryl, arylalkyl, cycloalkyl, or H 2NC (O)-alkyl;
D is 0 or 1; And
M is 0.
18. the compound of claim 2, wherein A is (xviii)
Figure FPA00001018010600103
R 1Be R aR bN-;
R 2Be hydrogen;
R aAnd R bThe hydrogen of respectively doing for oneself;
C is 0; And
M is 0.
19. the compound of claim 2, wherein A is (xix)
Figure FPA00001018010600111
R 1Be R aR bN-;
R 2Be hydrogen;
R aAnd R bThe hydrogen of respectively doing for oneself;
C is 0; And
M is 0.
20. the compound of claim 2, wherein A is (xx)
Figure FPA00001018010600112
R 1Be R aR bN-;
R 2Be hydrogen;
R 4Be R jR kThe N-alkyl-;
R aAnd R bIndependent separately is hydrogen or R 4-C (O)-;
R jAnd R kIndependent is alkyl;
R XxBe Z aZ bN-or heterocycle;
Z aAnd Z bIndependent separately is hydrogen or alkyl;
C is 0 or 1; And
M is 0.
21. the compound of claim 2, wherein A is (xxi)
R 1Be R aR bN-;
R 2Be hydrogen;
R aAnd R bThe hydrogen of respectively doing for oneself;
R XxiBe alkoxyl group;
D is 1; And
M is 0.
22. the compound of claim 2, wherein A is (xxii)
Figure FPA00001018010600122
R 1Be R aR bN-;
R 2Be hydrogen;
R 4Be R jR kThe N-alkyl-;
R aAnd R bIndependent separately is hydrogen or R 4-C (O)-;
R jAnd R kIndependent separately is alkyl;
C is 0; And
M is 0.
23. the compound of claim 2, wherein A is (xxiii)
Figure FPA00001018010600123
R 1Be R aR bN-;
R 2Be hydrogen;
R aAnd R bThe hydrogen of respectively doing for oneself;
C is 0; And
M is 0.
24. the compound of claim 1, for
The mixture of 5-(1-benzyl-1H-1,2,3-triazole-4-yl)-1H-indazole and 5-(1-benzyl-1H-1,2,3-triazole-5-yl)-1H-indazole;
5-(1H-1,2,3-triazole-5-yl)-1H-indazole;
5-(1-benzyl-1H-1,2,3-triazole-4-yl)-1H-indazole;
5-[1-(2-methyl-benzyl)-1H-1,2,3-triazole-4-yl]-the 1H-indazole;
5-[1-(3-methyl-benzyl)-1H-1,2,3-triazole-4-yl]-the 1H-indazole;
5-[1-(4-methyl-benzyl)-1H-1,2,3-triazole-4-yl]-the 1H-indazole;
5-[1-(3-methoxy-benzyl)-1H-1,2,3-triazole-4-yl]-the 1H-indazole;
5-[1-(2-luorobenzyl)-1H-1,2,3-triazole-4-yl]-the 1H-indazole;
5-[1-(3-luorobenzyl)-1H-1,2,3-triazole-4-yl]-the 1H-indazole;
5-[1-(4-luorobenzyl)-1H-1,2,3-triazole-4-yl]-the 1H-indazole;
5-[1-(2-benzyl chloride base)-1H-1,2,3-triazole-4-yl]-the 1H-indazole;
5-[1-(3-benzyl chloride base)-1H-1,2,3-triazole-4-yl]-the 1H-indazole;
5-[1-(4-benzyl chloride base)-1H-1,2,3-triazole-4-yl]-the 1H-indazole;
5-[1-(2-bromobenzyl)-1H-1,2,3-triazole-4-yl]-the 1H-indazole;
5-[1-(2-nitrobenzyl)-1H-1,2,3-triazole-4-yl]-the 1H-indazole;
5-[1-(3-nitrobenzyl)-1H-1,2,3-triazole-4-yl]-the 1H-indazole;
5-[1-(4-nitrobenzyl)-1H-1,2,3-triazole-4-yl]-the 1H-indazole;
2-{[4-(1H-indazole-5-yl)-1H-1,2, the 3-triazol-1-yl] methyl } cyanobenzene;
3-{[4-(1H-indazole-5-yl)-1H-1,2, the 3-triazol-1-yl] methyl } cyanobenzene;
4-{[4-(1H-indazole-5-yl)-1H-1,2, the 3-triazol-1-yl] methyl } cyanobenzene;
5-{1-[2-(trifluoromethyl) benzyl]-1H-1,2,3-triazole-4-yl }-the 1H-indazole;
5-{1-[3-(trifluoromethyl) benzyl]-1H-1,2,3-triazole-4-yl }-the 1H-indazole;
5-{1-[4-(trifluoromethyl) benzyl]-1H-1,2,3-triazole-4-yl }-the 1H-indazole;
5-{1-[3-(trifluoromethoxy) benzyl]-1H-1,2,3-triazole-4-yl }-the 1H-indazole;
5-{1-[4-(trifluoromethoxy) benzyl]-1H-1,2,3-triazole-4-yl }-the 1H-indazole;
5-[1-(4-tertiary butyl benzyl)-1H-1,2,3-triazole-4-yl]-the 1H-indazole;
3-{[4-(1H-indazole-5-yl)-1H-1,2, the 3-triazol-1-yl] methyl } methyl benzoate;
4-{[4-(1H-indazole-5-yl)-1H-1,2, the 3-triazol-1-yl] methyl } methyl benzoate;
5-[1-(2, the 4-dimethyl benzyl)-1H-1,2,3-triazole-4-yl]-the 1H-indazole;
5-[1-(3, the 5-dimethyl benzyl)-1H-1,2,3-triazole-4-yl]-the 1H-indazole;
5-[1-(2, the 3-dichloro benzyl)-1H-1,2,3-triazole-4-yl]-the 1H-indazole;
5-[1-(2, the 4-dichloro benzyl)-1H-1,2,3-triazole-4-yl]-the 1H-indazole;
5-[1-(2, the 5-dichloro benzyl)-1H-1,2,3-triazole-4-yl]-the 1H-indazole;
5-[1-(3, the 5-dichloro benzyl)-1H-1,2,3-triazole-4-yl]-the 1H-indazole;
5-{1-[2, two (trifluoromethyl) benzyls of 4-]-1H-1,2,3-triazole-4-yl }-the 1H-indazole;
N-cyclohexyl-6-(1H-indazole-5-yl) imidazo [2,1-b] [1,3] thiazole-5-amine;
N-cyclohexyl-2-(1H-indazole-5-yl) imidazo [1,2-a] pyridine-3-amine;
N-cyclohexyl-2-(1H-indazole-5-yl) imidazo [1,2-a] pyrazine-3-amine;
5-[1-benzyl-4-(4-fluorophenyl)-1H-imidazoles-5-yl]-the 1H-indazole;
N-{3-[4-(4-fluorophenyl)-5-(1H-indazole-5-yl)-1H-imidazoles-1-yl] propyl group }-N, the N-dimethyl amine;
N-cyclohexyl-2-(1H-indazole-5-yl) imidazo [1,2-a] pyrimidine-3-amine;
5-[4-(4-fluorophenyl)-1-(1-phenylethyl)-1H-imidazoles-5-yl]-the 1H-indazole;
2-(1H-indazole-5-yl)-N-isopropylimdazole is [1,2-a] pyrimidine-3-amine also;
4-(1H-indazole-5-yl)-N-phenyl-1,3-thiazoles-2-amine;
5-(2-methyl isophthalic acid, 3-thiazole-4-yl)-1H-indazole;
N-ethyl-4-(1H-indazole-5-yl)-1,3-thiazoles-2-amine;
N-benzyl-4-(1H-indazole-5-yl)-1,3-thiazoles-2-amine;
4-(1H-indazole-5-yl)-1,3-thiazoles-2-amine;
4-(1H-indazole-5-yl)-N-(2-phenylethyl)-1,3-thiazoles-2-amine;
N-benzyl-2-(1H-indazole-5-yl) imidazo [1,2-a] pyrimidine-3-amine;
N-butyl-2-(1H-indazole-5-yl) imidazo [1,2-a] pyrimidine-3-amine;
N-(4-chloro-phenyl-)-2-(1H-indazole-5-yl) imidazo [1,2-a] pyrimidine-3-amine;
2-(1H-indazole-5-yl)-N-(4-p-methoxy-phenyl) imidazo [1,2-a] pyrimidine-3-amine;
2-(1H-indazole-5-yl) imidazo [1,2-a] pyrimidine;
N-[2-(1H-indazole-5-yl) imidazo [1,2-a] pyridin-3-yl] glycine methyl ester;
N-benzyl-2-(1H-indazole-5-yl) imidazo [1,2-a] pyridine-3-amine;
N-(4-chloro-phenyl-)-2-(1H-indazole-5-yl) imidazo [1,2-a] pyridine-3-amine;
2-(1H-indazole-5-yl)-N-(4-p-methoxy-phenyl) imidazo [1,2-a] pyridine-3-amine;
4-[4-(4-fluorophenyl)-5-(1H-indazole-5-yl)-1H-imidazoles-1-yl] piperidines-1-formic acid tertiary butyl ester;
3, two (1-benzyl-1H-1,2,3-triazole-4-the yl)-1H-indazoles of 5-;
5-(1-benzyl-1H-1,2,3-triazole-4-yl)-3-phenyl-1H-indazole;
5-(1-benzyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-amine;
5-(1-benzyl-1H-1,2,3-triazole-4-yl)-1-[(1-methyl piperidine-4-yl) carbonyl]-1H-indazole-3-amine;
N-[5-(1-benzyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-2-methoxyl group ethanamide;
N 1-[5-(1-benzyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-N 2, N 2-dimethyl G-NH2;
N-[5-(1-benzyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl] butyramide;
5-[4-(4-fluorophenyl)-1-piperidin-4-yl-1H-imidazoles-5-yl]-the 1H-indazole;
5-{4-(4-fluorophenyl)-1-[2-(1-methylpyrrolidin-2-yl) ethyl]-1H-imidazoles-5-yl }-the 1H-indazole;
5-{4-(4-fluorophenyl)-1-[3-(4-methylpiperazine-1-yl) propyl group]-1H-imidazoles-5-yl }-the 1H-indazole;
5-(1H-indazole-5-base) isoxazole-3-ethyl formate;
5-(1H-indazole-5-yl)-N-methyl-isoxazole-3-methane amide;
5-(3-Bian isoxazole-5-yl)-1H-indazole;
N-[5-(1-benzyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl] benzamide;
5-(3-propyl group isoxazole-5-base)-1H-indazole;
N-benzyl-4-(1H-indazole-5-yl)-5-phenyl-1,3-thiazoles-2-amine;
4-(1H-indazole-5-yl)-N, 5-phenylbenzene-1,3-thiazoles-2-amine;
5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazole-4-yl)-1H-indazole;
5-(1-benzyl-4-cyclopropyl-1H-1,2,3-triazole-5-yl)-1H-indazole;
2-(1H-indazole-5-yl)-3-phenylimidazole is [1,2-a] pyrimidine also;
5-[1-(tetrahydrochysene-2H-pyrans-4-ylmethyl)-1H-1,2,3-triazole-4-yl]-the 1H-indazole;
5-[3-(piperidines-1-base carbonyl) isoxazole-5-base]-the 1H-indazole;
5-(1H-indazole-5-yl)-N-phenyl-isoxazole azoles-3-methane amide;
N-cyclohexyl-5-(1H-indazole-5-base) isoxazole-3-methane amide;
5-[3-(piperidines-1-ylmethyl) isoxazole-5-base]-the 1H-indazole;
[5-(1H-indazole-5-base) isoxazole-3-base] methyl alcohol;
5-(1H-indazole-5-yl)-N-(2-methoxy ethyl) isoxazole-3-methane amide;
5-(1-benzyl-5-phenyl-1H-1,2,3-triazole-4-yl)-1H-indazole;
5-(4-benzyl-1H-1,2,3-triazol-1-yl)-1H-indazole;
5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-amine;
5-(1-benzyl-4-cyclopropyl-1H-1,2,3-triazole-5-yl)-1H-indazole-3-amine;
5-(3-isobutyl-isoxazole-5-base)-1H-indazole-3-amine;
5-(3-Bian isoxazole-5-yl)-1H-indazole-3-amine;
N-{2-[4-(4-fluorophenyl)-5-(1H-indazole-5-yl)-1H-imidazoles-1-yl] ethyl }-N, the N-dimethyl amine;
5-[4-(4-fluorophenyl)-1-(3-morpholine-4-base propyl group)-1H-imidazoles-5-yl]-the 1H-indazole;
5-[4-(4-fluorophenyl)-1-(3-tetramethyleneimine-1-base propyl group)-1H-imidazoles-5-yl]-the 1H-indazole;
5-{4-(4-fluorophenyl)-1-[2-(4-methyl piperidine-1-yl) ethyl]-1H-imidazoles-5-yl }-the 1H-indazole;
5-[1-(1-benzyl piepridine-4-yl)-4-(4-fluorophenyl)-1H-imidazoles-5-yl]-the 1H-indazole;
5-[4-(4-fluorophenyl)-1-(2-morpholine-4-base ethyl)-1H-imidazoles-5-yl]-the 1H-indazole;
5-[1-(1-benzyl-pyrrole alkane-3-yl)-4-(4-fluorophenyl)-1H-imidazoles-5-yl]-the 1H-indazole;
2-{4-[4-(4-fluorophenyl)-5-(1H-indazole-5-yl)-1H-imidazoles-1-yl] piperidines-1-yl }-2-oxo ethanol;
5-(1-benzyl-5-phenyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-amine;
2-[1-(1H-indazole-5-yl)-1H-1,2,3-triazole-4-yl] propan-2-ol;
5-[4-(methoxymethyl)-1H-1,2, the 3-triazol-1-yl]-the 1H-indazole;
1-[1-(1H-indazole-5-yl)-1H-1,2,3-triazole-4-yl]-the 1-phenylethyl alcohol;
5-(4-propyl group-1H-1,2,3-triazol-1-yl)-1H-indazole;
1-[1-(1H-indazole-5-yl)-1H-1,2,3-triazole-4-yl] propan-2-ol;
3-[1-(1H-indazole-5-yl)-1H-1,2,3-triazole-4-yl] third-1-alcohol;
1-{[1-(1H-indazole-5-yl)-1H-1,2,3-triazole-4-yl] methyl }-1H-1,2, the 3-benzotriazole;
5-{4-[(phenyl sulfenyl) methyl]-1H-1,2, the 3-triazol-1-yl }-the 1H-indazole;
5-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-1H-indazole;
5-[4-(2-phenylethyl)-1H-1,2, the 3-triazol-1-yl]-the 1H-indazole;
5-[4-(cyclohexyl methyl)-1H-1,2, the 3-triazol-1-yl]-the 1H-indazole;
5-(4-cyclopentyl-1H-1,2,3-triazol-1-yl)-1H-indazole;
1-[1-(1H-indazole-5-yl)-1H-1,2,3-triazole-4-yl] hexalin;
5-[4-(phenoxymethyl)-1H-1,2, the 3-triazol-1-yl]-the 1H-indazole;
5-{4-[(1,1-dioxo thiomorpholine-4-yl) methyl]-1H-1,2, the 3-triazol-1-yl }-the 1H-indazole;
5-[4-(3-phenyl propyl)-1H-1,2, the 3-triazol-1-yl]-the 1H-indazole;
[1-benzyl-4-(1H-indazole-5-yl)-1H-1,2,3-triazole-5-yl] (phenyl) ketone;
N, N-diethyl-N-{[1-(1H-indazole-5-yl)-1H-1,2,3-triazole-4-yl] methyl } amine;
N-[2-(1H-indazole-5-yl) imidazo [1,2-a] pyrimidin-3-yl]-the Beta-alanine ethyl ester;
5-(1-benzyl-5-methyl isophthalic acid H-1,2,3-triazole-4-yl)-1H-indazole;
5-(1-benzyl-5-methyl isophthalic acid H-1,2,3-triazole-4-yl)-1H-indazole-3-amine;
N3-[2-(1H-indazole-5-yl) imidazo [1,2-a] pyrimidin-3-yl]-β-alanimamides;
5-(1-benzyl-5-iodo-1H-1,2,3-triazole-4-yl)-1H-indazole-3-amine;
N-{3-[4-(3-amino-1H-indazole-5-yl)-1-benzyl-1H-1,2,3-triazole-5-yl] phenyl }-N '-(3-aminomethyl phenyl) urea;
5-(1H-indazole-5-yl)-N-(2-isopropoxy ethyl) isoxazole-3-methane amide;
5-[3-(morpholine-4-base carbonyl) isoxazole-5-base]-the 1H-indazole;
5-(1H-indazole-5-yl)-N-(3-morpholine-4-base propyl group) isoxazole-3-methane amide;
N-[2-(1H-imidazol-4 yl) ethyl]-5-(1H-indazole-5-base) isoxazole-3-methane amide;
(3R)-and 1-{[5-(1H-indazole-5-base) isoxazole-3-base] carbonyl } piperidines-3-alcohol;
1-{[5-(1H-indazole-5-base) isoxazole-3-base] carbonyl } piperidines-3-methane amide;
2-[2-(4-{[5-(1H-indazole-5-base) isoxazole-3-base] carbonyl } piperazine-1-yl) oxyethyl group] ethanol;
The 5-{3-[(4-methyl isophthalic acid, 4-Diazesuberane-1-yl) carbonyl] isoxazole-5-base }-the 1H-indazole;
N-(3-hydroxypropyl)-5-(1H-indazole-5-base) isoxazole-3-methane amide;
N-[(1R)-2-hydroxyl-1-phenylethyl]-5-(1H-indazole-5-base) isoxazole-3-methane amide;
N-[3-(1H-imidazoles-1-yl) propyl group]-5-(1H-indazole-5-base) isoxazole-3-methane amide;
5-(1H-indazole-5-yl)-N-[3-(2-oxo-pyrrolidine-1-yl) propyl group] isoxazole-3-methane amide;
N-{2-[4-(amino-sulfonyl) phenyl] ethyl }-5-(1H-indazole-5-base) isoxazole-3-methane amide;
[1-benzyl-4-(1H-indazole-5-yl)-1H-1,2,3-triazole-5-yl] (3-chloro-phenyl-) ketone;
[1-benzyl-4-(1H-indazole-5-yl)-1H-1,2,3-triazole-5-yl] (cyclopropyl) ketone;
5-[5-cyclopropyl-1-(tetrahydrochysene-2H-pyrans-4-ylmethyl)-1H-1,2,3-triazole-4-yl]-the 1H-indazole;
N 1-{ [1-benzyl-4-(1H-indazole-5-yl)-1H-1,2,3-triazole-5-yl] methyl } G-NH2;
(4-fluorophenyl) [4-(1H-indazole-5-yl)-1-(tetrahydrochysene-2H-pyrans-4-ylmethyl)-1H-1,2,3-triazole-5-yl] ketone;
(4-chloro-phenyl-) [4-(1H-indazole-5-yl)-1-(tetrahydrochysene-2H-pyrans-4-ylmethyl)-1H-1,2,3-triazole-5-yl] ketone;
(3-chloro-phenyl-) [4-(1H-indazole-5-yl)-1-(tetrahydrochysene-2H-pyrans-4-ylmethyl)-1H-1,2,3-triazole-5-yl] ketone;
(2-chloro-phenyl-) [4-(1H-indazole-5-yl)-1-(tetrahydrochysene-2H-pyrans-4-ylmethyl)-1H-1,2,3-triazole-5-yl] ketone;
Cyclopentyl [4-(1H-indazole-5-yl)-1-(tetrahydrochysene-2H-pyrans-4-ylmethyl)-1H-1,2,3-triazole-5-yl] ketone;
1-benzyl-4-(1H-indazole-5-yl)-1H-1,2,3-triazole-5-formic acid;
5-{5-(4-fluorophenyl)-1-[4-(trifluoromethyl) benzyl]-1H-1,2,3-triazole-4-yl }-1H-indazole-3-amine;
5-[1-benzyl-5-(4-fluorophenyl)-1H-1,2,3-triazole-4-yl]-1H-indazole-3-amine;
[4-(1H-indazole-5-yl)-1-(tetrahydrochysene-2H-pyrans-4-ylmethyl)-1H-1,2,3-triazole-5-yl] (tetrahydrochysene-2H-pyrans-4-yl) ketone;
5-[1-benzyl-5-(2-aminomethyl phenyl)-1H-1,2,3-triazole-4-yl]-the 1H-indazole;
5-{1-benzyl-5-[(4-methylpiperazine-1-yl) carbonyl]-1H-1,2,3-triazole-4-yl }-the 1H-indazole;
1-{[1-benzyl-4-(1H-indazole-5-yl)-1H-1,2,3-triazole-5-yl] carbonyl } piperidines-4-alcohol;
1-ethanoyl-5-[5-(4-fluorophenyl)-1-(tetrahydrochysene-2H-pyrans-4-ylmethyl)-1H-1,2,3-triazole-4-yl]-the 1H-indazole;
1-benzyl-4-(1H-indazole-5-yl)-N, N-dimethyl-1H-1,2,3-triazole-5-methane amide;
N, 1-dibenzyl-4-(1H-indazole-5-yl)-1H-1,2,3-triazole-5-methane amide;
N-(2-hydroxyl-2-phenylethyl)-5-(1H-indazole-5-yl)-N-methyl-isoxazole-3-methane amide;
N-[(1S)-2-hydroxyl-1-phenylethyl]-5-(1H-indazole-5-base) isoxazole-3-methane amide;
N-benzyl-N-(2-hydroxyethyl)-5-(1H-indazole-5-base) isoxazole-3-methane amide;
5-[1-benzyl-5-(2-aminomethyl phenyl)-1H-1,2,3-triazole-4-yl]-3-methyl isophthalic acid H-indazole;
5-[1-benzyl-5-(2-aminomethyl phenyl)-1H-1,2,3-triazole-4-yl]-1H-indazole-3-amine;
2-{2-[1-(1H-indazole-5-yl)-1H-1,2,3-triazole-4-yl] ethyl }-1H-isoindole-1,3 (2H)-diketone;
5-{4-[(2, the 4-dichlorophenoxy) methyl]-1H-1,2, the 3-triazol-1-yl }-the 1H-indazole;
5-{4-[(2, the 6-dichlorophenoxy) methyl]-1H-1,2, the 3-triazol-1-yl }-the 1H-indazole;
5-[5-(4-fluorophenyl)-1-(tetrahydrochysene-2H-pyrans-4-ylmethyl)-1H-1,2,3-triazole-4-yl]-the 1H-indazole;
1-{[1-(1H-indazole-5-yl)-1H-1,2,3-triazole-4-yl] methyl }-the 1H-indazole;
5-[1-benzyl-5-(piperidines-1-base carbonyl)-1H-1,2,3-triazole-4-yl]-the 1H-indazole;
5-[5-(2-aminomethyl phenyl)-1-(tetrahydrochysene-2H-pyrans-4-ylmethyl)-1H-1,2,3-triazole-4-yl]-the 1H-indazole;
5-[5-(2-aminomethyl phenyl)-1-(tetrahydrochysene-2H-pyrans-4-ylmethyl)-1H-1,2,3-triazole-4-yl]-1H-indazole-3-amine;
5-[1-benzyl-5-(morpholine-4-base carbonyl)-1H-1,2,3-triazole-4-yl]-the 1H-indazole;
5-[1-benzyl-5-(4-p-methoxy-phenyl)-1H-1,2,3-triazole-4-yl]-1H-indazole-3-amine;
N-[(1S)-1-benzyl-2-hydroxyethyl]-5-(1H-indazole-5-base) isoxazole-3-methane amide;
N-[(1S, 2R)-2-hydroxyl-2,3-dihydro-1H-indenes-1-yl]-5-(1H-indazole-5-base) isoxazole-3-methane amide;
5-{3-[(3-phenylmorpholine-4-yl) carbonyl] isoxazole-5-base }-the 1H-indazole;
N-benzyl-5-(1H-indazole-5-base) isoxazole-3-methane amide;
((1S)-2-{[5-(1H-indazole-5-base) isoxazole-3-base] carbonyl }-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-1-yl) methyl alcohol;
N-[(1R)-3-hydroxyl-1-phenyl propyl]-5-(1H-indazole-5-base) isoxazole-3-methane amide;
N-[(1S)-3-hydroxyl-1-phenyl propyl]-5-(1H-indazole-5-base) isoxazole-3-methane amide;
N-2,3-dihydro-1H-indenes-1-base-5-(1H-indazole-5-base) isoxazole-3-methane amide;
N-2,3-dihydro-1H-indenes-2-base-5-(1H-indazole-5-base) isoxazole-3-methane amide;
5-(1H-indazole-5-yl)-N-(1-phenyl propyl) isoxazole-3-methane amide;
5-{1-benzyl-5-[3-(dimethylamino) phenyl]-1H-1,2,3-triazole-4-yl }-1H-indazole-3-amine;
5-{1-benzyl-5-[4-(dimethylamino) phenyl]-1H-1,2,3-triazole-4-yl }-1H-indazole-3-amine;
N-{3-[4-(3-amino-1H-indazole-5-yl)-1-benzyl-1H-1,2,3-triazole-5-yl] phenyl } ethanamide;
N-{4-[4-(3-amino-1H-indazole-5-yl)-1-benzyl-1H-1,2,3-triazole-5-yl] phenyl } ethanamide;
5-{1-benzyl-5-[3-(1H-pyrazol-1-yl) phenyl]-1H-1,2,3-triazole-4-yl }-1H-indazole-3-amine;
5-[1-benzyl-5-(1-methyl isophthalic acid H-pyrazoles-4-yl)-1H-1,2,3-triazole-4-yl]-1H-indazole-3-amine;
3-[4-(3-amino-1H-indazole-5-yl)-1-benzyl-1H-1,2,3-triazole-5-yl]-the N-phenylbenzamaide;
3-[4-(3-amino-1H-indazole-5-yl)-1-benzyl-1H-1,2,3-triazole-5-yl]-N-benzyl benzamide;
5-[1-benzyl-5-(1-Methyl-1H-indole-5-yl)-1H-1,2,3-triazole-4-yl]-1H-indazole-3-amine;
5-[1-benzyl-5-(3-p-methoxy-phenyl)-1H-1,2,3-triazole-4-yl]-1H-indazole-3-amine;
5-[1-benzyl-5-(3-morpholine-4-base phenyl)-1H-1,2,3-triazole-4-yl]-1H-indazole-3-amine;
5-[3-(1,3-dihydro-2H-isoindole-2-base carbonyl) isoxazole-5-base]-the 1H-indazole;
5-{3-[(4-methyl-2-phenylpiperazine-1-yl) carbonyl] isoxazole-5-base }-the 1H-indazole;
1-{[1-benzyl-4-(1H-indazole-5-yl)-1H-1,2,3-triazole-5-yl] carbonyl } piperidines-4-amine;
N-[5-(1-benzyl-5-phenyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl] benzamide;
N-[5-(1-benzyl-5-phenyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl] benzsulfamide;
N-[5-(1-benzyl-5-phenyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-N '-(4-p-methoxy-phenyl) urea;
N-[5-(1-benzyl-5-phenyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl] butyramide;
N-[5-(1-benzyl-5-phenyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-the 2-methyl propanamide;
N-[5-(1-benzyl-5-phenyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl] cyclopropane carboxamide;
N-[1-benzoyl-5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl] benzamide;
N-[5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-the 3-fluorobenzamide;
N-[5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl] benzamide;
N-benzyl-5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-amine;
N-[(1R)-1-benzyl-2-hydroxyethyl]-5-(1H-indazole-5-base) isoxazole-3-methane amide;
5-(1-benzyl-1H-pyrazoles-4-yl)-1H-indazole;
N-[(1R)-3-hydroxyl-1-phenyl propyl]-5-(3-methyl isophthalic acid H-indazole-5-base) isoxazole-3-methane amide;
3-[4-(3-amino-1H-indazole-5-yl)-1-benzyl-1H-1,2,3-triazole-5-yl] phenol;
3-[4-(3-amino-1H-indazole-5-yl)-1-benzyl-1H-1,2,3-triazole-5-yl] benzamide;
5-{1-benzyl-5-[4-(methyl sulphonyl) phenyl]-1H-1,2,3-triazole-4-yl }-1H-indazole-3-amine;
N-[5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-the 2-chlorobenzamide;
N-[5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-the 4-chlorobenzamide;
N-[5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl] ethyl sulfonamide;
N-[5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl] benzsulfamide;
N-[5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-the 2-chlorobenzene sulfonamide;
N-[5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-the 3-chlorobenzene sulfonamide;
N-[5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-the 4-chlorobenzene sulfonamide;
N-[5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-2,5-dimethyl furan-3-sulphonamide;
5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazole-4-yl)-N-(2-benzyl chloride base)-1H-indazole-3-amine;
5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazole-4-yl)-N-(3-benzyl chloride base)-1H-indazole-3-amine;
N-[5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-the 3-chlorobenzamide;
N-[5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-the 2-furoamide;
5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazole-4-yl)-N-ethyl-1H-indazole-3-amine;
5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazole-4-yl)-N-(4-benzyl chloride base)-1H-indazole-3-amine;
5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazole-4-yl)-N-(3-furyl methyl)-1H-indazole-3-amine;
N-[5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-N '-[5-methyl-2-(trifluoromethyl)-3-furyl] urea;
N-[5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-the 3-furoamide;
5-(1H-indazole-5-yl)-N-[(1S)-1-phenyl propyl] isoxazole-3-methane amide;
5-(1H-indazole-5-yl)-N-[(1R)-1-phenyl propyl] isoxazole-3-methane amide;
5-(1-benzyl-1H-pyrazoles-4-yl)-1H-indazole-3-amine;
1-benzyl-4-(1H-indazole-5-yl)-N-[(2S)-tetrahydrofuran (THF)-2-ylmethyl]-1H-1,2,3-triazole-5-methane amide;
1-benzyl-4-(1H-indazole-5-yl)-N-(2-isopropoxy ethyl)-1H-1,2,3-triazole-5-methane amide;
1-benzyl 4-(1H-indazole-5-yl)-N-[(2R)-tetrahydrofuran (THF)-2-ylmethyl]-1H-1,2,3-triazole-5-methane amide;
1-benzyl-4-(1H-indazole-5-yl)-N-(tetrahydrofuran (THF)-3-ylmethyl)-1H-1,2,3-triazole-5-methane amide;
1-benzyl-N-cyclopentyl-4-(1H-indazole-5-yl)-1H-1,2,3-triazole-5-methane amide;
1-benzyl-N-(cyclopentyl-methyl)-4-(1H-indazole-5-yl)-1H-1,2,3-triazole-5-methane amide;
1-benzyl-N-ethyl-4-(1H-indazole-5-yl)-N-methyl isophthalic acid H-1,2,3-triazole-5-methane amide;
1-benzyl-4-(1H-indazole-5-yl)-N-sec.-propyl-N-methyl isophthalic acid H-1,2,3-triazole-5-methane amide;
1-benzyl-4-(1H-indazole-5-yl)-N-(2-methoxy ethyl)-N-methyl isophthalic acid H-1,2,3-triazole-5-methane amide;
1-benzyl-4-(1H-indazole-5-yl)-N-phenyl-1H-1,2,3-triazole-5-methane amide;
1-benzyl-N-(4-chloro-phenyl-)-4-(1H-indazole-5-yl)-1H-1,2,3-triazole-5-methane amide;
1-benzyl-4-(1H-indazole-5-yl)-N-(2-morpholine-4-base ethyl)-1H-1,2,3-triazole-5-methane amide;
1-benzyl-N-[2-(dimethylamino) ethyl]-4-(1H-indazole-5-yl)-N-methyl isophthalic acid H-1,2,3-triazole-5-methane amide;
1-benzyl-N-(2-hydroxyethyl)-4-(1H-indazole-5-yl)-N-propyl group-1H-1,2,3-triazole-5-methane amide;
1-benzyl-N-[3-(dimethylamino) propyl group]-4-(1H-indazole-5-yl)-N-methyl isophthalic acid H-1,2,3-triazole-5-methane amide;
1-benzyl-N-[2-(diethylamino) ethyl]-4-(1H-indazole-5-yl)-N-methyl isophthalic acid H-1,2,3-triazole-5-methane amide;
N, 1-dibenzyl-N-ethyl-4-(1H-indazole-5-yl)-1H-1,2,3-triazole-5-methane amide;
N, 1-dibenzyl-N-(2-hydroxyethyl)-4-(1H-indazole-5-yl)-1H-1,2,3-triazole-5-methane amide;
(3R)-and 1-{[1-benzyl-4-(1H-indazole-5-yl)-1H-1,2,3-triazole-5-yl] carbonyl } piperidines-3-alcohol;
1-{[1-benzyl-4-(1H-indazole-5-yl)-1H-1,2,3-triazole-5-yl] carbonyl } piperidines-4-methane amide;
5-{1-benzyl-5-[(2,6-thebaine-4-yl) carbonyl]-1H-1,2,3-triazole-4-yl }-the 1H-indazole;
5-{5-[(4-ethanoyl piperazine-1-yl) carbonyl]-1-benzyl-1H-1,2,3-triazole-4-yl }-the 1H-indazole;
5-{1-benzyl-5-[(4-phenylpiperazine-1-yl) carbonyl]-1H-1,2,3-triazole-4-yl }-the 1H-indazole;
The 1-benzyl-N-[(1R)-1-(hydroxymethyl)-2-methyl-propyl]-4-(1H-indazole-5-yl)-1H-1,2,3-triazole-5-methane amide;
The 1-benzyl-N-[(1S)-1-(hydroxymethyl)-2-methyl-propyl]-4-(1H-indazole-5-yl)-1H-1,2,3-triazole-5-methane amide;
1-benzyl-N-[3-(1H-imidazoles-1-yl) propyl group]-4-(1H-indazole-5-yl)-1H-1,2,3-triazole-5-methane amide;
N-[5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-N '-ethyl carbamide;
N-[5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-N '-phenylurea;
N-benzyl-N '-[5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl] urea;
N-[5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-N '-(2-chloro-phenyl-) urea;
N-[5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-N '-(3-chloro-phenyl-) urea;
N-[5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-N '-(4-chloro-phenyl-) urea;
N-[5-(1-benzyl-5-iodo-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl] benzamide;
3-[4-(3-amino-1H-indazole-5-yl)-1H-pyrazol-1-yl] propionitrile;
2-[4-(3-amino-1H-indazole-5-yl)-1H-pyrazol-1-yl] ethanamide;
3-[4-(3-amino-1H-indazole-5-yl)-1H-pyrazol-1-yl] methyl propionate;
3-[4-(3-amino-1H-indazole-5-yl)-1H-pyrazol-1-yl] propionic acid amide;
[4-(3-amino-1H-indazole-5-yl)-1H-pyrazol-1-yl] acetonitrile;
4-(3-amino-1H-indazole-5-yl)-N, N-dimethyl-1H-imidazoles-1-sulphonamide;
5-pyrazine-2-base-1H-indazole-3-amine;
5-thiophene-2-base-1H-indazole-3-amine;
5-(2-aminopyrimidine-4-yl)-1H-indazole-3-amine;
5-(2-methoxypyridine-3-yl)-1H-indazole-3-amine;
5-imidazo [1,2-a] pyridin-3-yl-1H-indazole-3-amine;
N 2, N 2-dimethyl-N 1-[5-(1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl] G-NH2;
5-(1H-pyrazoles-5-yl)-1H-indazole-3-amine;
5-(4-methyl isophthalic acid H-imidazoles-5-yl)-1H-indazole-3-amine;
5-(1H-imidazol-4 yl)-1H-indazole-3-amine;
N 2, N 2-dimethyl-N 1-5-[1-(3-methyl-benzyl)-1H-1,2,3-triazole-4-yl]-1H-indazole-3-yl } G-NH2;
5-(1-benzyl-1H-imidazol-4 yl)-1H-indazole-3-amine;
N 1-5-[1-(4-tertiary butyl benzyl)-1H-1,2,3-triazole-4-yl]-1H-indazole-3-yl }-N 2, N 2-dimethyl G-NH2;
N 2, N 2-dimethyl-N 1-5-[1-(2-piperidines-1-base ethyl)-1H-1,2,3-triazole-4-yl]-1H-indazole-3-yl } G-NH2;
N 2, N 2-dimethyl-N 1-5-[1-(2-morpholine-4-base ethyl)-1H-1,2,3-triazole-4-yl]-1H-indazole-3-yl } G-NH2;
N 1-(5-{1-[2-(3,5-dimethyl isoxazole-4-yl) ethyl]-1H-1,2,3-triazole-4-yl }-1H-indazole-3-yl)-N 2, N 2-dimethyl G-NH2;
N 1-(5-{1-[2-(3,5-dimethyl-1H-pyrazoles-4-yl) ethyl]-1H-1,2,3-triazole-4-yl }-1H-indazole-3-yl)-N 2, N 2-dimethyl G-NH2;
2-(4-{3-[(N, N-dimethyl glycyl) amino]-1H-indazole-5-yl }-1H-1,2, the 3-triazol-1-yl)-2 Methylpropionic acid;
(4-{3-[(N, N-dimethyl glycyl) amino]-1H-indazole-5-yl }-1H-1,2, the 3-triazol-1-yl) ethyl acetate;
N 2, N 2-dimethyl-N 1-(5-{1-[(trimethyl silyl) methyl]-1H-1,2,3-triazole-4-yl }-1H-indazole-3-yl) G-NH2;
N 1-[5-(3-furyl)-1H-indazole-3-yl]-N 2, N 2-dimethyl G-NH2;
N 2, N 2-dimethyl-N 1-[5-(1H-pyrazoles-5-yl)-1H-indazole-3-yl] G-NH2;
N 2, N 2-dimethyl-N 1-(5-pyrimidine-5-base-1H-indazole-3-yl) G-NH2;
N 1-[5-(2,1,3-Ben Bing oxadiazole-5-yl)-1H-indazole-3-yl]-N 2, N 2-dimethyl G-NH2;
N 2, N 2-dimethyl-N 1-[5-(1H-pyrazoles-4-yl)-1H-indazole-3-yl] G-NH2;
N 2, N 2-dimethyl-N 1-[5-(1-methyl isophthalic acid H-pyrazoles-4-yl)-1H-indazole-3-yl] G-NH2;
N 1-[5-(3,5-dimethyl-1H-pyrazoles-4-yl)-1H-indazole-3-yl]-N 2, N 2-dimethyl G-NH2;
N 1-5-[2-(dimethylamino) pyrimidine-5-yl]-1H-indazole-3-yl }-N 2, N 2-dimethyl G-NH2;
N 2, N 2-dimethyl-N 1-[5-(2-morpholine-4-yl pyrimidines-5-yl)-1H-indazole-3-yl] G-NH2;
N 2, N 2-dimethyl-N 1-5-[1-(2-morpholine-4-base ethyl)-1H-pyrazoles-4-yl]-1H-indazole-3-yl } G-NH2;
N 1-[5-(1-benzyl-5-cyclopropyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-N 2, N 2-dimethyl G-NH2;
N 1-[5-(1-benzyl-1H-pyrazoles-4-yl)-1H-indazole-3-yl]-N 2, N 2-dimethyl G-NH2;
N 1-[5-(1-benzyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-N 2-methyl G-NH2;
N-[5-(1-benzyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-2-tetramethyleneimine-1-yl acetamide;
N 1-[5-(1-benzyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-N 2-cyclopentyl G-NH2;
N 1-[5-(1-benzyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-N 2-cyclopropyl G-NH2;
N 1-[5-(1-benzyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-N 2-tetrahydrochysene-2H-pyrans-4-base G-NH2;
N-[5-(1-benzyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-2-(3-hydroxyl pyrrolidine-1-yl) ethanamide;
N-[5-(1-benzyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-2-(3-hydroxy piperidine-1-yl) ethanamide;
N 1-[5-(1-benzyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-N 3, N 3-dimethyl-β-alanimamides;
N-[5-(1-benzyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-2-morpholine-4-yl acetamide;
N-[5-(1-benzyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-2-(4-methylpiperazine-1-yl) ethanamide;
N-[5-(1-benzyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-2-(3-oxo piperazine-1-yl) ethanamide;
N 1-[5-(1-benzyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-N 2-sec.-propyl G-NH2;
N 1-[5-(1-benzyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-N 2-cyclohexyl G-NH2;
N-[5-(1-benzyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl] ethanamide;
N 1-[5-(1-benzyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-N 2-cyclobutyl G-NH2;
N-[5-(1-benzyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-N '-propyl group urea;
N-[5-(1-benzyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl] ethyl sulfonamide;
5-(1-benzyl-1H-1,2,3-triazole-4-yl)-N-(cyclopropyl methyl)-1H-indazole-3-amine;
N-[5-(1-benzyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-N '-ethyl carbamide;
1-[5-(1-benzyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl] pyrrolidin-2-one;
N-[5-(1-benzyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-4-(dimethylamino) butyramide;
N-3, the heterochromatic alkene of 4-dihydro-1H--4-base-5-(1H-indazole-5-base) isoxazole-3-methane amide;
N-(cyclohexyl methyl)-5-(1H-indazole-5-base) isoxazole-3-methane amide;
N-(3-benzyl chloride base)-5-(1H-indazole-5-base) isoxazole-3-methane amide;
5-(1H-indazole-5-yl)-N-(2-methoxy-benzyl) isoxazole-3-methane amide;
5-(1H-indazole-5-yl)-N-[2-(trifluoromethyl) benzyl] isoxazole-3-methane amide;
5-(1H-indazole-5-yl)-N-[3-(trifluoromethyl) benzyl] isoxazole-3-methane amide;
5-(1H-indazole-5-yl)-N-[4-(trifluoromethyl) benzyl] isoxazole-3-methane amide;
5-(1H-indazole-5-yl)-N-(pyridine-2-ylmethyl) isoxazole-3-methane amide;
5-(1H-indazole-5-yl)-N-(pyridin-3-yl methyl) isoxazole-3-methane amide;
5-(1H-indazole-5-yl)-N-(pyridin-4-yl methyl) isoxazole-3-methane amide;
N-(2-benzyl chloride base)-5-(1H-indazole-5-base) isoxazole-3-methane amide;
N-(4-benzyl chloride base)-5-(1H-indazole-5-base) isoxazole-3-methane amide;
5-(1H-indazole-5-yl)-N-(1-phenyl-2-piperidines-1-base ethyl) isoxazole-3-methane amide;
N-[2-(1H-imidazoles-1-yl)-1-phenylethyl]-5-(1H-indazole-5-base) isoxazole-3-methane amide;
5-(1H-indazole-5-yl)-N-(2-morpholine-4-base-1-phenylethyl) isoxazole-3-methane amide;
5-(1H-indazole-5-yl)-N-[2-(4-methylpiperazine-1-yl)-1-phenylethyl] isoxazole-3-methane amide;
5-(1H-indazole-5-yl)-N-(1-phenyl-2-tetramethyleneimine-1-base ethyl) isoxazole-3-methane amide;
2-([5-(1H-indazole-5-base) isoxazole-3-base] carbonyl } amino)-2-phenylethyl carboxylamine tertiary butyl ester;
5-(1H-indazole-5-yl)-N-(1-naphthyl methyl) isoxazole-3-methane amide;
5-(1H-indazole-5-yl)-N-(2-phenylethyl) isoxazole-3-methane amide;
5-(1H-indazole-5-yl)-N-(2-pyridine-2-base ethyl) isoxazole-3-methane amide;
5-(1H-indazole-5-yl)-N-(2-pyridin-3-yl ethyl) isoxazole-3-methane amide;
5-(1H-indazole-5-yl)-N-(2-pyridin-4-yl ethyl) isoxazole-3-methane amide;
N-[2-(2-chloro-phenyl-) ethyl]-5-(1H-indazole-5-base) isoxazole-3-methane amide;
N-[2-(3-chloro-phenyl-) ethyl]-5-(1H-indazole-5-base) isoxazole-3-methane amide;
N-[2-(4-chloro-phenyl-) ethyl]-5-(1H-indazole-5-base) isoxazole-3-methane amide;
N-benzyl-N-ethyl-5-(1H-indazole-5-base) isoxazole-3-methane amide;
5-(1H-indazole-5-yl)-N-methyl-N-(1-naphthyl methyl) isoxazole-3-methane amide;
5-(1H-indazole-5-yl)-N-methyl-N-(2-phenylethyl) isoxazole-3-methane amide;
5-(1H-indazole-5-yl)-N-methyl-N-(2-pyridine-2-base ethyl) isoxazole-3-methane amide;
5-(1H-indazole-5-yl)-N-[(1R)-1-phenylethyl] isoxazole-3-methane amide;
5-(1H-indazole-5-yl)-N-1,2,3,4-naphthane-1-isoxazole-3-methane amide;
5-(1H-indazole-5-yl)-N-[(1S)-1-(1-naphthyl) ethyl] isoxazole-3-methane amide;
5-(1H-indazole-5-yl)-N-[(1R)-1-(1-naphthyl) ethyl] isoxazole-3-methane amide;
N-[3-(dimethylamino)-1-phenyl propyl]-5-(1H-indazole-5-base) isoxazole-3-methane amide;
N-(2,3-dihydro-1,4-Ben Bing dioxin-5-ylmethyl)-5-(1H-indazole-5-base) isoxazole-3-methane amide;
N-(3,4-dihydro-2H-1,5-benzo two oxa-s
Figure FPA00001018010600311
-6-ylmethyl)-5-(1H-indazole-5-base) isoxazole-3-methane amide;
5-(1H-indazole-5-yl)-N-[(1-Methyl-1H-indole-4-yl) methyl] isoxazole-3-methane amide;
5-{3-[(3-Phenylpyrrolidine-1-yl) carbonyl] isoxazole-5-base }-the 1H-indazole;
5-{3-[(2-Phenylpyrrolidine-1-yl) carbonyl] isoxazole-5-base }-the 1H-indazole;
5-{3-[(2-Phenylpiperidine-1-yl) carbonyl] isoxazole-5-base }-the 1H-indazole;
5-(1H-indazole-5-yl)-N-[(1S)-1-phenylethyl] isoxazole-3-methane amide;
5-(1H-indazole-5-yl)-N-[(1R)-1-(4-aminomethyl phenyl) ethyl] isoxazole-3-methane amide;
5-(1H-indazole-5-yl)-N-[(1S)-1-(4-aminomethyl phenyl) ethyl] isoxazole-3-methane amide;
N-[(1R, 2S)-2-hydroxyl-2,3-dihydro-1H-indenes-1-yl]-5-(1H-indazole-5-base) isoxazole-3-methane amide;
N-[(1R, 2R)-2-hydroxyl-2,3-dihydro-1H-indenes-1-yl]-5-(1H-indazole-5-base) isoxazole-3-methane amide;
N-[(1R)-1-(4-bromophenyl) ethyl]-5-(1H-indazole-5-base) isoxazole-3-methane amide;
N-[(1S)-1-(4-bromophenyl) ethyl]-5-(1H-indazole-5-base) isoxazole-3-methane amide;
N-[(1R)-1-(4-chloro-phenyl-) ethyl]-5-(1H-indazole-5-base) isoxazole-3-methane amide;
N-[(1S)-1-(4-chloro-phenyl-) ethyl]-5-(1H-indazole-5-base) isoxazole-3-methane amide;
5-(1H-indazole-5-yl)-N-[(1S)-1-(2-naphthyl) ethyl] isoxazole-3-methane amide;
N-[1-(4-ethoxyl phenenyl)-2-hydroxyethyl]-5-(1H-indazole-5-base) isoxazole-3-methane amide;
N-[2-hydroxyl-1-(4-isopropyl phenyl) ethyl]-5-(1H-indazole-5-base) isoxazole-3-methane amide;
N-[1-(3, the 4-3,5-dimethylphenyl)-2-hydroxyethyl]-5-(1H-indazole-5-base) isoxazole-3-methane amide;
N-[2-hydroxyl-1-(2-p-methoxy-phenyl) ethyl]-5-(1H-indazole-5-base) isoxazole-3-methane amide;
N-[2-hydroxyl-1-(4-aminomethyl phenyl) ethyl]-5-(1H-indazole-5-base) isoxazole-3-methane amide;
5-(1H-indazole-5-yl)-N-[(1R)-1-(2-p-methoxy-phenyl) ethyl] isoxazole-3-methane amide;
N-[(1S)-1-(3, the 4-difluorophenyl) ethyl]-5-(1H-indazole-5-base) isoxazole-3-methane amide;
5-(1H-indazole-5-yl)-N-[(1R)-1-(3-p-methoxy-phenyl) ethyl] isoxazole-3-methane amide;
5-(1H-indazole-5-yl)-N-{ (1R)-1-[3-(trifluoromethyl) phenyl] ethyl } isoxazole-3-methane amide;
N-[1-(2,3-dihydro-1,4-Ben Bing dioxin-6-yl) ethyl]-5-(1H-indazole-5-base) isoxazole-3-methane amide;
N-[1-(3, the 5-dichlorophenyl)-2-hydroxyethyl]-5-(1H-indazole-5-base) isoxazole-3-methane amide;
5-(1-benzyl-1H-1,2,3-triazole-4-yl)-3-[({[6-(trifluoromethyl) pyridine-2-yl] amino } carbonyl) amino]-1H-indazole-1-formic acid tertiary butyl ester;
5-(1-benzyl-1H-1,2,3-triazole-4-yl)-1-[(1-methyl piperidine-2-yl) carbonyl]-1H-indazole-3-amine;
5-(1-benzyl-1H-1,2,3-triazole-4-yl)-1-[(dimethylamino) ethanoyl]-1H-indazole-3-amine;
3-amino-5-(1-benzyl-1H-1,2,3-triazole-4-yl)-1H-indazole-1-formic acid tertiary butyl ester;
N-[5-(1-benzyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-2-piperidines-1-yl acetamide;
N-[5-(1-benzyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-2-morpholine-4-yl acetamide; Or
N-[5-(1-benzyl-1H-1,2,3-triazole-4-yl)-1H-indazole-3-yl]-1-methyl piperidine-2-methane amide.
25. a medicinal compositions, described medicinal compositions comprise formula (I) compound and the suitable pharmaceutical carrier of the claim 1 for the treatment of significant quantity.
26. a method that suppresses Glycogen Synthase kinase 3 (GSK-3), Rho kinases (ROCK), Janus kinases (JAK), AKT, PAK4, PLK, CK2, KDR, MK2, JNK1, aurora, pim 1 and nek 2, described method comprises formula (I) compound of the claim 1 for the treatment of significant quantity.
27. one kind is suppressed the kinase whose method of GSK-3, described method comprises formula (I) compound of the claim 4 for the treatment of significant quantity, wherein suppresses the people of needs could effectively be treated or prevent to the GSK-3 kinases the disease or the illness that regulated by the GSK-3 kinases.
28. the method for claim 27, but wherein suppress GSK-3 kinases effective stimulus neurotization and treatment and prevention neurodegenerative disease, inflammation and demyelination, alzheimer's disease, apoplexy, multiple sclerosis, the cognition relevant and attention deficit, acute and chronic neurodegenerative disease, dementia, acute apoplexy and other wound, cerebrovascular accident, brain and Spinal injury, peripheral neuropathy, retinopathy and glaucoma with alzheimer's disease.
29. the method for claim 28, wherein said acute and chronic neurodegenerative disease is Parkinson's disease and tau protein abnormal deposition neurodegeneration.
30. the method for claim 29, wherein said tau protein abnormal deposition neurodegeneration is volume temporo top dementia, cortical degeneration, Pick's disease and stein-leventhal syndrome.
31. the method for claim 28, wherein said dementia are vascular dementia.
32. the method for claim 28, wherein said cerebrovascular accident are relevant macular degeneration of age.
33. the method for claim 27 wherein suppresses the GSK-3 kinases and can effectively treat non-insulin-dependent diabetes mellitus (NIDDM) and obesity, manic depressive illness, schizophrenia, bald, cancer, osteoarthritis, rheumatoid arthritis and osteoporosis.
34. the method for claim 33, wherein said cancer are mammary cancer, nonsmall-cell lung cancer, thyroid carcinoma, T or B cell leukemia and viral-induced tumour.
35. one kind is suppressed the kinase whose method of GSK-3, described method comprises formula (I) compound of the claim 8 for the treatment of significant quantity, wherein suppresses the people of needs could effectively be treated or prevent to the GSK-3 kinases the disease or the illness that regulated by the GSK-3 kinases.
36. the method for claim 35, but wherein suppress GSK-3 kinases effective stimulus neurotization and treatment and prevention neurodegenerative disease, inflammation and demyelination, alzheimer's disease, apoplexy, multiple sclerosis, the cognition relevant and attention deficit, acute and chronic neurodegenerative disease, dementia, acute apoplexy and other wound, cerebrovascular accident, brain and Spinal injury, peripheral neuropathy, retinopathy and glaucoma with alzheimer's disease.
37. the method for claim 36, wherein said acute and chronic neurodegenerative disease is Parkinson's disease and tau protein abnormal deposition neurodegeneration.
38. the method for claim 37, wherein said tau protein abnormal deposition neurodegeneration is volume temporo top dementia, cortical degeneration, Pick's disease and stein-leventhal syndrome.
39. the method for claim 36, wherein said dementia are vascular dementia.
40. the method for claim 36, wherein said cerebrovascular accident are relevant macular degeneration of age.
41. the method for claim 35 wherein suppresses the GSK-3 kinases and can effectively treat non-insulin-dependent diabetes mellitus (NIDDM) and obesity, manic depressive illness, schizophrenia, bald, cancer, osteoarthritis, rheumatoid arthritis and osteoporosis.
42. the method for claim 41, wherein said cancer are mammary cancer, nonsmall-cell lung cancer, thyroid carcinoma, T or B cell leukemia and viral-induced tumour.
43. one kind is suppressed the kinase whose method of GSK-3, described method comprises formula (I) compound of the claim 9 for the treatment of significant quantity, wherein suppresses the people of needs could effectively be treated or prevent to the GSK-3 kinases the disease or the illness that regulated by the GSK-3 kinases.
44. the method for claim 43, but wherein suppress GSK-3 kinases effective stimulus neurotization and treatment and prevention neurodegenerative disease, inflammation and demyelination, alzheimer's disease, apoplexy, multiple sclerosis, the cognition relevant and attention deficit, acute and chronic neurodegenerative disease, dementia, acute apoplexy and other wound, cerebrovascular accident, brain and Spinal injury, peripheral neuropathy, retinopathy and glaucoma with alzheimer's disease.
45. the method for claim 44, wherein said acute and chronic neurodegenerative disease is Parkinson's disease and tau protein abnormal deposition neurodegeneration.
46. the method for claim 43, wherein said tau protein abnormal deposition neurodegeneration is volume temporo top dementia, cortical degeneration, Pick's disease and stein-leventhal syndrome.
47. the method for claim 44, wherein said dementia are vascular dementia.
48. the method for claim 44, wherein said cerebrovascular accident are relevant macular degeneration of age.
49. the method for claim 43 wherein suppresses the GSK-3 kinases and can effectively treat non-insulin-dependent diabetes mellitus (NIDDM) and obesity, manic depressive illness, schizophrenia, bald, cancer, osteoarthritis, rheumatoid arthritis and osteoporosis.
50. the method for claim 49, wherein said cancer are mammary cancer, nonsmall-cell lung cancer, thyroid carcinoma, T or B cell leukemia and viral-induced tumour.
51. one kind is suppressed the kinase whose method of GSK-3, described method comprises formula (I) compound of the claim 11 for the treatment of significant quantity, wherein suppresses the people of needs could effectively be treated or prevent to the GSK-3 kinases the disease or the illness that regulated by the GSK-3 kinases.
52. the method for claim 51, but wherein suppress GSK-3 kinases effective stimulus neurotization and treatment and prevention neurodegenerative disease, inflammation and demyelination, alzheimer's disease, apoplexy, multiple sclerosis, the cognition relevant and attention deficit, acute and chronic neurodegenerative disease, dementia, acute apoplexy and other wound, cerebrovascular accident, brain and Spinal injury, peripheral neuropathy, retinopathy and glaucoma with alzheimer's disease.
53. the method for claim 52, wherein said acute and chronic neurodegenerative disease is Parkinson's disease and tau protein abnormal deposition neurodegeneration.
54. the method for claim 53, wherein said tau protein abnormal deposition neurodegeneration is volume temporo top dementia, cortical degeneration, Pick's disease and stein-leventhal syndrome.
55. the method for claim 52, wherein said dementia are vascular dementia.
56. the method for claim 52, wherein said cerebrovascular accident are relevant macular degeneration of age.
57. the method for claim 51 wherein suppresses the GSK-3 kinases and can effectively treat non-insulin-dependent diabetes mellitus (NIDDM) and obesity, manic depressive illness, schizophrenia, bald, cancer, osteoarthritis, rheumatoid arthritis and osteoporosis.
58. the method for claim 57, wherein said cancer are mammary cancer, nonsmall-cell lung cancer, thyroid carcinoma, T or B cell leukemia and viral-induced tumour.
59. one kind is suppressed the kinase whose method of GSK-3, described method comprises formula (I) compound of the claim 14 for the treatment of significant quantity, wherein suppresses the people of needs could effectively be treated or prevent to the GSK-3 kinases the disease or the illness that regulated by the GSK-3 kinases.
60. the method for claim 59, but wherein suppress GSK-3 kinases effective stimulus neurotization and treatment and prevention neurodegenerative disease, inflammation and demyelination, alzheimer's disease, apoplexy, multiple sclerosis, the cognition relevant and attention deficit, acute and chronic neurodegenerative disease, dementia, acute apoplexy and other wound, cerebrovascular accident, brain and Spinal injury, peripheral neuropathy, retinopathy and glaucoma with alzheimer's disease.
61. the method for claim 60, wherein said acute and chronic neurodegenerative disease is Parkinson's disease and tau protein abnormal deposition neurodegeneration.
62. the method for claim 61, wherein said tau protein abnormal deposition neurodegeneration is volume temporo top dementia, cortical degeneration, Pick's disease and stein-leventhal syndrome.
63. the method for claim 60, wherein said dementia are vascular dementia.
64. the method for claim 60, wherein said cerebrovascular accident are relevant macular degeneration of age.
65. the method for claim 59 wherein suppresses the GSK-3 kinases and can effectively treat non-insulin-dependent diabetes mellitus (NIDDM) and obesity, manic depressive illness, schizophrenia, bald, cancer, osteoarthritis, rheumatoid arthritis and osteoporosis.
66. the method for claim 65, wherein said cancer are mammary cancer, nonsmall-cell lung cancer, thyroid carcinoma, T or B cell leukemia and viral-induced tumour.
67. one kind is suppressed the kinase whose method of GSK-3, described method comprises formula (I) compound of the claim 15 for the treatment of significant quantity, wherein suppresses the people of needs could effectively be treated or prevent to the GSK-3 kinases the disease or the illness that regulated by the GSK-3 kinases.
68. the method for claim 67, but wherein suppress GSK-3 kinases effective stimulus neurotization and treatment and prevention neurodegenerative disease, inflammation and demyelination, alzheimer's disease, apoplexy, multiple sclerosis, the cognition relevant and attention deficit, acute and chronic neurodegenerative disease, dementia, acute apoplexy and other wound, cerebrovascular accident, brain and Spinal injury, peripheral neuropathy, retinopathy and glaucoma with alzheimer's disease.
69. the method for claim 68, wherein said acute and chronic neurodegenerative disease is Parkinson's disease and tau protein abnormal deposition neurodegeneration.
70. the method for claim 69, wherein said tau protein abnormal deposition neurodegeneration is volume temporo top dementia, cortical degeneration, Pick's disease and stein-leventhal syndrome.
71. the method for claim 68, wherein said dementia are vascular dementia.
72. the method for claim 68, wherein said cerebrovascular accident are relevant macular degeneration of age.
73. the method for claim 67 wherein suppresses the GSK-3 kinases and can effectively treat non-insulin-dependent diabetes mellitus (NIDDM) and obesity, manic depressive illness, schizophrenia, bald, cancer, osteoarthritis, rheumatoid arthritis and osteoporosis.
74. the method for claim 73, wherein said cancer are mammary cancer, nonsmall-cell lung cancer, thyroid carcinoma, T or B cell leukemia and viral-induced tumour.
75. one kind is suppressed the kinase whose method of GSK-3, described method comprises formula (I) compound of the claim 16 for the treatment of significant quantity, wherein suppresses the people of needs could effectively be treated or prevent to the GSK-3 kinases the disease or the illness that regulated by the GSK-3 kinases.
76. the method for claim 75, but wherein suppress GSK-3 kinases effective stimulus neurotization and treatment and prevention neurodegenerative disease, inflammation and demyelination, alzheimer's disease, apoplexy, multiple sclerosis, the cognition relevant and attention deficit, acute and chronic neurodegenerative disease, dementia, acute apoplexy and other wound, cerebrovascular accident, brain and Spinal injury, peripheral neuropathy, retinopathy and glaucoma with alzheimer's disease.
77. the method for claim 76, wherein said acute and chronic neurodegenerative disease is Parkinson's disease and tau protein abnormal deposition neurodegeneration.
78. the method for claim 77, wherein said tau protein abnormal deposition neurodegeneration is volume temporo top dementia, cortical degeneration, Pick's disease and stein-leventhal syndrome.
79. the method for claim 76, wherein said dementia are vascular dementia.
80. the method for claim 76, wherein said cerebrovascular accident are relevant macular degeneration of age.
81. the method for claim 75 wherein suppresses the GSK-3 kinases and can effectively treat non-insulin-dependent diabetes mellitus (NIDDM) and obesity, manic depressive illness, schizophrenia, bald, cancer, osteoarthritis, rheumatoid arthritis and osteoporosis.
82. the method for claim 81, wherein said cancer are mammary cancer, nonsmall-cell lung cancer, thyroid carcinoma, T or B cell leukemia and viral-induced tumour.
83. one kind is suppressed the kinase whose method of GSK-3, described method comprises formula (I) compound of the claim 17 for the treatment of significant quantity, wherein suppresses the people of needs could effectively be treated or prevent to the GSK-3 kinases the disease or the illness that regulated by the GSK-3 kinases.
84. the method for claim 83, but wherein suppress GSK-3 kinases effective stimulus neurotization and treatment and prevention neurodegenerative disease, inflammation and demyelination, alzheimer's disease, apoplexy, multiple sclerosis, the cognition relevant and attention deficit, acute and chronic neurodegenerative disease, dementia, acute apoplexy and other wound, cerebrovascular accident, brain and Spinal injury, peripheral neuropathy, retinopathy and glaucoma with alzheimer's disease.
85. the method for claim 84, wherein said acute and chronic neurodegenerative disease is Parkinson's disease and tau protein abnormal deposition neurodegeneration.
86. the method for claim 85, wherein said tau protein abnormal deposition neurodegeneration is volume temporo top dementia, cortical degeneration, Pick's disease and stein-leventhal syndrome.
87. the method for claim 84, wherein said dementia are vascular dementia.
88. the method for claim 84, wherein said cerebrovascular accident are relevant macular degeneration of age.
89. the method for claim 83 wherein suppresses the GSK-3 kinases and can effectively treat non-insulin-dependent diabetes mellitus (NIDDM) and obesity, manic depressive illness, schizophrenia, bald, cancer, osteoarthritis, rheumatoid arthritis and osteoporosis.
90. the method for claim 89, wherein said cancer are mammary cancer, nonsmall-cell lung cancer, thyroid carcinoma, T or B cell leukemia and viral-induced tumour.
91. one kind is suppressed the kinase whose method of GSK-3, described method comprises formula (I) compound of the claim 18 for the treatment of significant quantity, wherein suppresses the people of needs could effectively be treated or prevent to the GSK-3 kinases the disease or the illness that regulated by the GSK-3 kinases.
92. the method for claim 91, but wherein suppress GSK-3 kinases effective stimulus neurotization and treatment and prevention neurodegenerative disease, inflammation and demyelination, alzheimer's disease, apoplexy, multiple sclerosis, the cognition relevant and attention deficit, acute and chronic neurodegenerative disease, dementia, acute apoplexy and other wound, cerebrovascular accident, brain and Spinal injury, peripheral neuropathy, retinopathy and glaucoma with alzheimer's disease.
93. the method for claim 92, wherein said acute and chronic neurodegenerative disease is Parkinson's disease and tau protein abnormal deposition neurodegeneration.
94. the method for claim 93, wherein said tau protein abnormal deposition neurodegeneration is volume temporo top dementia, cortical degeneration, Pick's disease and stein-leventhal syndrome.
95. the method for claim 92, wherein said dementia are vascular dementia.
96. the method for claim 92, wherein said cerebrovascular accident are relevant macular degeneration of age.
97. the method for claim 91 wherein suppresses the GSK-3 kinases and can effectively treat non-insulin-dependent diabetes mellitus (NIDDM) and obesity, manic depressive illness, schizophrenia, bald, cancer, osteoarthritis, rheumatoid arthritis and osteoporosis.
98. the method for claim 97, wherein said cancer are mammary cancer, nonsmall-cell lung cancer, thyroid carcinoma, T or B cell leukemia and viral-induced tumour.
99. one kind is suppressed the kinase whose method of GSK-3, described method comprises formula (I) compound of the claim 19 for the treatment of significant quantity, wherein suppresses the people of needs could effectively be treated or prevent to the GSK-3 kinases the disease or the illness that regulated by the GSK-3 kinases.
100. the method for claim 99, but wherein suppress GSK-3 kinases effective stimulus neurotization and treatment and prevention neurodegenerative disease, inflammation and demyelination, alzheimer's disease, apoplexy, multiple sclerosis, the cognition relevant and attention deficit, acute and chronic neurodegenerative disease, dementia, acute apoplexy and other wound, cerebrovascular accident, brain and Spinal injury, peripheral neuropathy, retinopathy and glaucoma with alzheimer's disease.
101. the method for claim 100, wherein said acute and chronic neurodegenerative disease is Parkinson's disease and tau protein abnormal deposition neurodegeneration.
102. the method for claim 101, wherein said tau protein abnormal deposition neurodegeneration is volume temporo top dementia, cortical degeneration, Pick's disease and stein-leventhal syndrome.
103. the method for claim 100, wherein said dementia are vascular dementia.
104. the method for claim 100, wherein said cerebrovascular accident are relevant macular degeneration of age.
105. the method for claim 99 wherein suppresses the GSK-3 kinases and can effectively treat non-insulin-dependent diabetes mellitus (NIDDM) and obesity, manic depressive illness, schizophrenia, bald, cancer, osteoarthritis, rheumatoid arthritis and osteoporosis.
106. the method for claim 105, wherein said cancer are mammary cancer, nonsmall-cell lung cancer, thyroid carcinoma, T or B cell leukemia and viral-induced tumour.
107. one kind is suppressed the kinase whose method of GSK-3, described method comprises formula (I) compound of the claim 20 for the treatment of significant quantity, wherein suppresses the people of needs could effectively be treated or prevent to the GSK-3 kinases the disease or the illness that regulated by the GSK-3 kinases.
108. the method for claim 107, but wherein suppress GSK-3 kinases effective stimulus neurotization and treatment and prevention neurodegenerative disease, inflammation and demyelination, alzheimer's disease, apoplexy, multiple sclerosis, the cognition relevant and attention deficit, acute and chronic neurodegenerative disease, dementia, acute apoplexy and other wound, cerebrovascular accident, brain and Spinal injury, peripheral neuropathy, retinopathy and glaucoma with alzheimer's disease.
109. the method for claim 108, wherein said acute and chronic neurodegenerative disease is Parkinson's disease and tau protein abnormal deposition neurodegeneration.
110. the method for claim 109, wherein said tau protein abnormal deposition neurodegeneration is volume temporo top dementia, cortical degeneration, Pick's disease and stein-leventhal syndrome.
111. the method for claim 108, wherein said dementia are vascular dementia.
112. the method for claim 108, wherein said cerebrovascular accident are relevant macular degeneration of age.
113. the method for claim 107 wherein suppresses the GSK-3 kinases and can effectively treat non-insulin-dependent diabetes mellitus (NIDDM) and obesity, manic depressive illness, schizophrenia, bald, cancer, osteoarthritis, rheumatoid arthritis and osteoporosis.
114. the method for claim 113, wherein said cancer are mammary cancer, nonsmall-cell lung cancer, thyroid carcinoma, T or B cell leukemia and viral-induced tumour.
115. one kind is suppressed the kinase whose method of GSK-3, described method comprises formula (I) compound of the claim 21 for the treatment of significant quantity, wherein suppresses the people of needs could effectively be treated or prevent to the GSK-3 kinases the disease or the illness that regulated by the GSK-3 kinases.
116. the method for claim 115, but wherein suppress GSK-3 kinases effective stimulus neurotization and treatment and prevention neurodegenerative disease, inflammation and demyelination, alzheimer's disease, apoplexy, multiple sclerosis, the cognition relevant and attention deficit, acute and chronic neurodegenerative disease, dementia, acute apoplexy and other wound, cerebrovascular accident, brain and Spinal injury, peripheral neuropathy, retinopathy and glaucoma with alzheimer's disease.
117. the method for claim 116, wherein said acute and chronic neurodegenerative disease is Parkinson's disease and tau protein abnormal deposition neurodegeneration.
118. the method for claim 117, wherein said tau protein abnormal deposition neurodegeneration is volume temporo top dementia, cortical degeneration, Pick's disease and stein-leventhal syndrome.
119. the method for claim 116, wherein said dementia are vascular dementia.
120. the method for claim 116, wherein said cerebrovascular accident are relevant macular degeneration of age.
121. the method for claim 115 wherein suppresses the GSK-3 kinases and can effectively treat non-insulin-dependent diabetes mellitus (NIDDM) and obesity, manic depressive illness, schizophrenia, bald, cancer, osteoarthritis, rheumatoid arthritis and osteoporosis.
122. the method for claim 121, wherein said cancer are mammary cancer, nonsmall-cell lung cancer, thyroid carcinoma, T or B cell leukemia and viral-induced tumour.
123. one kind is suppressed the kinase whose method of GSK-3, described method comprises formula (I) compound of the claim 22 for the treatment of significant quantity, wherein suppresses the people of needs could effectively be treated or prevent to the GSK-3 kinases the disease or the illness that regulated by the GSK-3 kinases.
124. the method for claim 123, but wherein suppress GSK-3 kinases effective stimulus neurotization and treatment and prevention neurodegenerative disease, inflammation and demyelination, alzheimer's disease, apoplexy, multiple sclerosis, the cognition relevant and attention deficit, acute and chronic neurodegenerative disease, dementia, acute apoplexy and other wound, cerebrovascular accident, brain and Spinal injury, peripheral neuropathy, retinopathy and glaucoma with alzheimer's disease.
125. the method for claim 124, wherein said acute and chronic neurodegenerative disease is Parkinson's disease and tau protein abnormal deposition neurodegeneration.
126. the method for claim 125, wherein said tau protein abnormal deposition neurodegeneration is volume temporo top dementia, cortical degeneration, Pick's disease and stein-leventhal syndrome.
127. the method for claim 124, wherein said dementia are vascular dementia.
128. the method for claim 124, wherein said cerebrovascular accident are relevant macular degeneration of age.
129. the method for claim 123 wherein suppresses the GSK-3 kinases and can effectively treat non-insulin-dependent diabetes mellitus (NIDDM) and obesity, manic depressive illness, schizophrenia, bald, cancer, osteoarthritis, rheumatoid arthritis and osteoporosis.
130. the method for claim 129, wherein said cancer are mammary cancer, nonsmall-cell lung cancer, thyroid carcinoma, T or B cell leukemia and viral-induced tumour.
131. one kind is suppressed the kinase whose method of GSK-3, described method comprises formula (I) compound of the claim 23 for the treatment of significant quantity, wherein suppresses the people of needs could effectively be treated or prevent to the GSK-3 kinases the disease or the illness that regulated by the GSK-3 kinases.
132. the method for claim 131, but wherein suppress GSK-3 kinases effective stimulus neurotization and treatment and prevention neurodegenerative disease, inflammation and demyelination, alzheimer's disease, apoplexy, multiple sclerosis, the cognition relevant and attention deficit, acute and chronic neurodegenerative disease, dementia, acute apoplexy and other wound, cerebrovascular accident, brain and Spinal injury, peripheral neuropathy, retinopathy and glaucoma with alzheimer's disease.
133. the method for claim 132, wherein said acute and chronic neurodegenerative disease is Parkinson's disease and tau protein abnormal deposition neurodegeneration.
134. the method for claim 133, wherein said tau protein abnormal deposition neurodegeneration is volume temporo top dementia, cortical degeneration, Pick's disease and stein-leventhal syndrome.
135. the method for claim 132, wherein said dementia are vascular dementia.
136. the method for claim 132, wherein said cerebrovascular accident are relevant macular degeneration of age.
137. the method for claim 131 wherein suppresses the GSK-3 kinases and can effectively treat non-insulin-dependent diabetes mellitus (NIDDM) and obesity, manic depressive illness, schizophrenia, bald, cancer, osteoarthritis, rheumatoid arthritis and osteoporosis.
138. the method for claim 137, wherein said cancer are mammary cancer, nonsmall-cell lung cancer, thyroid carcinoma, T or B cell leukemia and viral-induced tumour.
139. a method that suppresses jak kinase, described method comprise formula (I) compound of the claim 1 for the treatment of significant quantity, wherein suppress the people of needs could effectively be treated or prevent to jak kinase disease or illness by the jak kinase adjusting.
140. the method for claim 139, wherein suppress jak kinase and can effectively treat and active unusual relevant autoimmune disease, myeloproliferative syndrome and the cardiovascular disorder of jak kinase, described method comprises the compound of the claim 5 that the Mammals of needs organism significant quantity is arranged.
141. the method for claim 140, wherein said myeloproliferative syndrome are leukemia, lymphoma or cancer.
142. the method for claim 141, wherein said cancer are leukemia.
143. the method for claim 140, wherein said autoimmune disease are rheumatoid arthritis and psoriasis.
144. the method for claim 139, wherein suppress jak kinase and can effectively treat and active unusual relevant autoimmune disease, myeloproliferative syndrome and the cardiovascular disorder of jak kinase, described method comprises the compound of the claim 8 that the Mammals of needs organism significant quantity is arranged.
145. the method for claim 144, wherein said myeloproliferative syndrome are leukemia, lymphoma or cancer.
146. the method for claim 145, wherein said cancer are leukemia.
147. the method for claim 144, wherein said autoimmune disease are rheumatoid arthritis and psoriasis.
148. the method for claim 139, wherein suppress jak kinase and can effectively treat and active unusual relevant autoimmune disease, myeloproliferative syndrome and the cardiovascular disorder of jak kinase, described method comprises the compound of the claim 12 that the Mammals of needs organism significant quantity is arranged.
149. the method for claim 148, wherein said myeloproliferative syndrome are leukemia, lymphoma or cancer.
150. the method for claim 149, wherein said cancer are leukemia.
151. the method for claim 148, wherein said autoimmune disease are rheumatoid arthritis and psoriasis.
152. one kind is suppressed the kinase whose method of ROCK, described method comprises formula (I) compound of the claim 3 for the treatment of significant quantity, wherein suppresses the ROCK kinases and can effectively treat neurodegenerative disease, inflammation and demyelination, alzheimer's disease, apoplexy, pneumonia, the asthma relevant with asthma; Promote regeneration after the Spinal injury and strengthen functional rehabilitation; Multiple sclerosis, pain, hypertension, chronic and congestive heart failure, cardiac hypertrophy, restenosis, chronic renal failure, the subarachnoid hemorrhage cerebral vasospasm, pulmonary hypertension, atherosclerosis, male erectile dysfunction, Female sexual dysfunction, bladder excessive activities syndrome, new axon growth inducing action, aixs cylinder strides across the damage rewiring among the CNS, amyotrophic lateral sclerosis (spinal cord) lateral sclerosis, Huntington Chorea, Parkinson's disease, rheumatoid arthritis, osteoarthritis, irritable bowel syndrome, Crohn's disease, psoriasis, ulcerative colitis, lupus, cancer and metastases, antiviral and antibacterial applications, insulin resistant, diabetes, cystic fibrosis, stenocardia and arteriosclerosis.
153. one kind is suppressed the kinase whose method of ROCK, described method comprises formula (I) compound of the claim 6 for the treatment of significant quantity, wherein suppresses the ROCK kinases and can effectively treat neurodegenerative disease, inflammation and demyelination, alzheimer's disease, apoplexy, pneumonia, the asthma relevant with asthma; Promote regeneration after the Spinal injury and strengthen functional rehabilitation; Multiple sclerosis, pain, hypertension, chronic and congestive heart failure, cardiac hypertrophy, restenosis, chronic renal failure, the subarachnoid hemorrhage cerebral vasospasm, pulmonary hypertension, atherosclerosis, male erectile dysfunction, Female sexual dysfunction, bladder excessive activities syndrome, new axon growth inducing action, aixs cylinder strides across the damage rewiring among the CNS, amyotrophic lateral sclerosis (spinal cord) lateral sclerosis, Huntington Chorea, Parkinson's disease, rheumatoid arthritis, osteoarthritis, irritable bowel syndrome, Crohn's disease, psoriasis, ulcerative colitis, lupus, cancer and metastases, antiviral and antibacterial applications, insulin resistant, diabetes, cystic fibrosis, stenocardia and arteriosclerosis.
154. one kind is suppressed the kinase whose method of ROCK, described method comprises formula (I) compound of the claim 7 for the treatment of significant quantity, wherein suppresses the ROCK kinases and can effectively treat neurodegenerative disease, inflammation and demyelination, alzheimer's disease, apoplexy, pneumonia, the asthma relevant with asthma; Promote regeneration after the Spinal injury and strengthen functional rehabilitation; Multiple sclerosis, pain, hypertension, chronic and congestive heart failure, cardiac hypertrophy, restenosis, chronic renal failure, the subarachnoid hemorrhage cerebral vasospasm, pulmonary hypertension, atherosclerosis, male erectile dysfunction, Female sexual dysfunction, bladder excessive activities syndrome, new axon growth inducing action, aixs cylinder strides across the damage rewiring among the CNS, amyotrophic lateral sclerosis (spinal cord) lateral sclerosis, Huntington Chorea, Parkinson's disease, rheumatoid arthritis, osteoarthritis, irritable bowel syndrome, Crohn's disease, psoriasis, ulcerative colitis, lupus, cancer and metastases, antiviral and antibacterial applications, insulin resistant, diabetes, cystic fibrosis, stenocardia and arteriosclerosis.
155. one kind is suppressed the kinase whose method of ROCK, described method comprises formula (I) compound of the claim 10 for the treatment of significant quantity, wherein suppresses the ROCK kinases and can effectively treat neurodegenerative disease, inflammation and demyelination, alzheimer's disease, apoplexy, pneumonia, the asthma relevant with asthma; Promote regeneration after the Spinal injury and strengthen functional rehabilitation; Multiple sclerosis, pain, hypertension, chronic and congestive heart failure, cardiac hypertrophy, restenosis, chronic renal failure, the subarachnoid hemorrhage cerebral vasospasm, pulmonary hypertension, atherosclerosis, male erectile dysfunction, Female sexual dysfunction, bladder excessive activities syndrome, new axon growth inducing action, aixs cylinder strides across the damage rewiring among the CNS, amyotrophic lateral sclerosis (spinal cord) lateral sclerosis, Huntington Chorea, Parkinson's disease, rheumatoid arthritis, osteoarthritis, irritable bowel syndrome, Crohn's disease, psoriasis, ulcerative colitis, lupus, cancer and metastases, antiviral and antibacterial applications, insulin resistant, diabetes, cystic fibrosis, stenocardia and arteriosclerosis.
156. one kind is suppressed the kinase whose method of ROCK, described method comprises formula (I) compound of the claim 13 for the treatment of significant quantity, wherein suppresses the ROCK kinases and can effectively treat neurodegenerative disease, inflammation and demyelination, alzheimer's disease, apoplexy, pneumonia, the asthma relevant with asthma; Promote regeneration after the Spinal injury and strengthen functional rehabilitation; Multiple sclerosis, pain, hypertension, chronic and congestive heart failure, cardiac hypertrophy, restenosis, chronic renal failure, the subarachnoid hemorrhage cerebral vasospasm, pulmonary hypertension, atherosclerosis, male erectile dysfunction, Female sexual dysfunction, bladder excessive activities syndrome, new axon growth inducing action, aixs cylinder strides across the damage rewiring among the CNS, amyotrophic lateral sclerosis (spinal cord) lateral sclerosis, Huntington Chorea, Parkinson's disease, rheumatoid arthritis, osteoarthritis, irritable bowel syndrome, Crohn's disease, psoriasis, ulcerative colitis, lupus, cancer and metastases, antiviral and antibacterial applications, insulin resistant, diabetes, cystic fibrosis, stenocardia and arteriosclerosis.
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