CN1104432C

CN1104432C - Pyrrole triazines and pyrimidines

Info

Publication number: CN1104432C
Application number: CN97196525A
Authority: CN
Inventors: A·G·阿范尼蒂斯; R·J·乔尔瓦特
Original assignee: DuPont Merck Pharmaceutical Co
Current assignee: Bristol Myers Squibb Pharma Co
Priority date: 1996-07-24
Filing date: 1997-07-23
Publication date: 2003-04-02
Anticipated expiration: 2017-07-23
Also published as: NZ333777A; CZ299451B6; EA004403B1; PL195762B1; SK9799A3; EE9900019A; IL164513A; CN1225637A; IL164513A0; JP4704521B2; PL331523A1; AR049583A2; CA2259583C; NO315610B3; SI9720045B; HRP970413A2; EE04316B1; CN1250223C; IL127871A; SI9720045A

Abstract

Corticotropin releasing factor (CRF) antagonists of formula (I) or (II) and their use in treating anxiety, depression, and other psychiatric, neurological disorders as well as treatment of immunological, cardiovascular or heart-related diseases and colonic hypersensitivity associated with psychopathological disturbance and stress.

Description

Pyrrolotriazine and pyrimidine compound

The field of the invention

The present invention relates to by give some [1,5-a]-pyrazolo-1,3,5-triazines, [1,5-a]-1,2,3-triazolo-1,3,5-triazines, [1,5-a]-pyrazolo-pyrimidine class and [1,5-a]-1,2,3-triazolo-pyrimidines treatment mental disorder and nervous system disease comprise severe depression, with anxiety relative disease, wound after stress disease, nuclear go up and benumb and eating disorder, and treat immune, cardiovascular or with cardiac-related diseases, the adaptive colitis relevant with stress with mental disorder.

Background of the present invention

Corticotropin releasing factor(CRF) (after this claiming CRF), for having 41 amino acid whose peptides, it is main physiological regulation agent [J.Rivier etc., Proc.Nat.Acad.Sci. (USA) 80:4851 (1983) of the peptide deutero-proopiomelanocortin of prepituitary gland glandular secretion; W.Vale etc., Science 213:1394 (1981)].Except that its internal secretion effect to pituitary gland, the immunohistochemistry of CRF location shows that this hormone has widely in central nervous system and distributes outside the hypothalamus, and generation widely spontaneous, electric physiology and behavior effect [W.Vale etc., the Rec.Prog.Horm.Res.39:245 (1983) consistent in brain with neurotransmitter or neuroregulator effect; G.F.Koob, Persp.Behav.Med.2:39 (1985); E.B.De Souza etc., J.Neurosci.5:3189 (1985)].Evidence suggests that also CRF plays remarkable effect [J.E.Blalock, PhysiologicalReviews 69:1 (1989) in the integration that immunity system is replied physiology, psychology and immunological stress thing; J.E.Morley, Life Sci.41:527 (1987)].

Clinical data be CRF at mental disorder and nervous system disease, comprise dysthymia disorders, with anxiety relative disease and eating disorder in have effect evidence be provided.Suppose also that CRF benumbs on AlzheimerShi disease, ParkinsonShi disease, HuntingtonShi disease, carrying out property nuclear and the nosetiology of amyotrophic lateral sclerosis and physiopathology in work, because they with central nervous system in CRF neurone imbalance relevant [seeing E.B.De Souza, Hosp.Practice23:59 (1988)].

In thymopathy or severe depression, refuse to obey that the middle CRF concentration of individual cerebrospinal fluid (CSF) of medicine significantly increases [C.B.Nemeroff etc., Science 226:1342 (1984); C.M.Banki etc., Am. J.Psychiatry 144:873 (1987); R.D.France etc., Biol.Psychiatry 28:86 (1988); M.Arato etc., Biol Psychiatry 25:355 (1989)].And the CRF Rd significantly reduces in the preceding cortex of suicide patient, and CRF supersecretion [C.B.Nemeroff etc., Arch.Gen.Psychiatry 45:577 (1988)].In addition, the thyroliberin of observing in the patient of depression the CRF passivation (ACTH) reacts (behind the intravenously administrable) [P.W.Gold etc., Am.J.Psychiatry 141:619 (1984); F.Holsboer etc., Psychoneuroendocrinology 9:147 (1984); P.W.Gold etc., New Eng.J.Med.314:1129 (1986)].The preclinical study that carries out in rat and inhuman Primates may the hypothesis relevant with the symptom of observing in people's dysthymia disorders provide other support [R.M.Sapolsky, Arch.Gen.Psychiatry 46:1047 (1989)] for the too much secretion of CRF.Prima Facie Evidence shows that tricyclic antidepressants can change the number [Grigoriadis etc., Neuropsychopharmacology 2:53 (1989)] that therefore the CRF level also regulates CRF acceptor in the brain.

Also to CRF with the nosetiology of anxiety relative disease in effect supposition has been proposed.CRF produces anxiety (anxiogenic) effect in animal, and interaction [D.R.Britton etc., Life Sci.31:363 (1982) between benzodiazepine /non--benzodiazepine anxiolytic and CRF in multiple behavior anxiety model, have been proved; C.W.Berridge and A.J.DunnRegul.Peptides 16:83 (1986)].The preliminary study of carrying out in multiple behavior example with the CRF receptor antagonist a-spiral sheep CRF (9-41) that supposes shows that described antagonist produces and " anxiety sample " effect [C.W.Berridge and A.J.Dunn Horm.Behav.21:393 (1987), Brain Research Reviews 15:71 (1990)] of benzodiazepine similar performance.Neurochemistry, internal secretion and receptors bind research all show the interaction between CRF and benzodiazepine anxiolytic, for the relation of CRF and these diseases provides other evidence.Zeisin can weaken conflict test [K.T.Britton etc., the Psychophamacology 86:170 (1985) of CRF rat; K.T.Britton etc., Psychopharmacology 94:306 (1988)] and " anxiety " in the sense of hearing startles test [N.R.Swerdlow etc., Psychopharmacology 88:147 (1986)] effect.The CRF effect of benzodiazepine receptor antagonist (Ro15-1788) (no behavior activity in operability the is conflicted test separately) dosage that can reverse-dependence mode, and the opposite agonist (FG7142) of benzodiazepine can strengthen CRF effect [K.T.Britton etc., Psychopharmacology94:306 (1988)].

Mechanism and action site that standard anxiolytic and thymoleptic produce its therapeutic action are still waiting to illustrate.Yet we suppose that the too much excretory of they and observed CRF in these diseases suppresses relevant.The preliminary study that our interest is in multiple behavior model to measure the effect of CRF receptor antagonist (alpha-helix CRF 9-41) shows that the CRF antagonist produces " anxiety sample " effect of being similar to benzodiazepine in nature and [sees G.F.Koob and K.T.Britton: corticotropin releasing factor(CRF): the basis of neuropeptide and clinical study, E.B.De Souza and C.B.Nemeroff edit, CRF Press the 221st page (1990)].

Several publications have been described Corticotropin releasing factor antagonists compound and their purposes in treatment mental disorder and nervous system disease.The example of this type of publication comprises the WO 95/33727 of WO 95/34563, Pfizer of WO 95/33750, Pfizer of PCT application US94/11050, Pfizer of DuPont Merck and the EP0778277A1 of Pfizer.

It is reported up to the present, also not with [1,5-a]-pyrazolo-1,3,5-triazines, [1,5-a]-1,2,3-triazolo-1,3,5-triazines class, [1,5-a]-pyrazolo-pyrimidine class and [1,5-a]-1,2,3-triazoles also-pyrimidines is used for the treatment of the report of mental disorder and nervous system disease as the Corticotropin releasing factor antagonists compound.Yet part of compounds is used for other purposes to have report to incite somebody to action wherein.

For example, the method for preparation of pyrazolotriazine compounds of the open following formula of EP 0269859 (Ostuka, 1988):

R wherein ¹Be OH or alkanoyl, R ²Be H, OH or SH, R ³Be the phenyl of undersaturated heterocyclic group, naphthyl or replacement, and think that these compounds have xanthine oxidase inhibitory activity and are used for the treatment of gout.

The method for preparation of pyrazolotriazine and the Pyrazolopyrimidine compound of the open following formula of EP 0594149 (Ostuka, 1994): Wherein A is CH or N, R ⁰And R ³Be H or alkyl, R ¹And R ²Be H, alkyl, alkoxyl group, alkylthio, nitro etc., and think that these compounds suppress male hormone, can be used for the treatment of benign prostatauxe and prostate cancer.

The method for preparation of pyrazolotriazine compounds of the open following formula of US 3910907 (ICI, 1975): R wherein ¹Be CH ₃, C ₂H ₅Or C ₆H ₅, X is H, C ₆H ₅, m-CH ₃C ₆H ₄, CN, COOEt, Cl, I or Br, Y is H, C ₆H ₅, o-CH ₃C ₆H ₄Or p-CH ₃C ₆H ₄, Z is OH, H, CH ₃, C ₂H ₅, C ₆H ₅, n-C ₃H ₇, i-C ₃H ₇, SH, SCH ₃, NHC ₄H ₉Or N (C ₂H ₅) ₂, and think that these compounds are the c-AMP phosphodiesterase inhibitor, as bronchodilator.

The method for preparation of pyrazolotriazine compounds of US 3995039 open following formulas:

R wherein ¹Be H or alkyl, R ²Be H or alkyl, R ³Be H, alkyl, alkanoyl, formamyl or elementary alkyl amido methanoyl, R is pyridyl, pyrimidyl or pyrazinyl, and thinks that these compounds can be used as bronchodilator.

The method for preparation of pyrazolotriazine compounds of US 5137887 open following formulas:

Wherein R is a lower alkoxy, and to propose these compounds be xanthine oxidase inhibitor, can be used for the treatment of gout.

The method for preparation of pyrazolotriazine compounds of US 4892576 open following formulas:

Wherein X is O or S, and Ar is phenyl, naphthyl, pyridyl or thienyl, R ₆-R ₈Be H, alkyl etc., R ₉Be H, alkyl and phenyl etc.This patent points out that these compounds can be used as sterilant and plant-growth regulator.

US 5484760 and WO 92/10098 openly contain the insect-killing composition of the Pesticidal compound of following formula:

Wherein A can be N, and B can be CR ₃, R ₃Can be phenyl of phenyl or replacement etc., R is-N (R ₄) SO ₂R ₅Or-SO ₂N (R ₆) R ₇, R ₁And R ₂Can form together:

Or Wherein X, Y and Z are H, alkyl, acyl group etc., and D is O or S.

US 3910907 and Senga etc. (J.Med.Chem., 1982,25,243-249) the triazolo triazine cAMP phosphodiesterase inhibitor of open following formula: Wherein Z is H, OH, CH ₃, C ₂H ₅, C ₆H ₅, n-C ₃H ₇, i-C ₃H ₇, SH, SCH ₃, NH (n-C ₄H ₉) or N (C ₂H ₅) ₂, R is H or CH ₃, R ₁Be CH ₃Or C ₂H ₅This reference is listed the treatment field that 8 cAMP phosphodiesterase inhibitors have operability: asthma, diabetes, female contraception, male infertility, psoriasis, thrombosis, anxiety disorder and hypertension.

The open Pyrazolopyrimidine compound of WO 95/35298 (Otsuka, 1995), and think and can be used as analgesic agent.These compounds can be represented by following formula:

Wherein Q is carbonyl or alkylsulfonyl, and n is 0 or 1, and A is singly-bound, alkylidene group, alkylene group, R ¹Be H, alkyl etc., R ²Be the phenyl or the phenoxy group of naphthyl, cycloalkyl, heteroaryl, replacement, R ³Be H, alkyl or phenyl, R ⁴Be H, alkyl, alkoxy carbonyl, phenylalkyl, phenyl or halogen that the optional benzene sulfenyl replaces, R ⁵And R ⁶Be H or alkyl.

The antiphlogistic use of the Pyrazolopyrimidine compound of the open following formula representative of EP 0591528 (Otsuka, 1991):

R wherein ₁, R ₂, R ₃And R ₄Be H, carboxyl, alkoxy carbonyl, optional alkyl, cycloalkyl or the phenyl that replaces, R ₅Be SR ₆Or NR ₇R ₈, R ₆Be pyridyl or the optional phenyl that replaces, R ₇And R ₈Be H or the optional phenyl that replaces.

Springer etc. (J.Med.Chem., 1976, vol.19, no.2,291-296) with the U.S. patent 4021556 of Springer and the Pyrazolopyrimidine compound of 3920652 open following formulas:

Wherein R can be the phenyl or the pyridyl of phenyl, replacement, can be used for the treatment of gout so suppress XOD based on them.

Joshi etc. (J.Prakt.Chemie, 321,2,1979, the 341-344) compound of open following formula: R wherein ¹Be CF ₃, C ₂F ₅Or C ₆H ₄F, R ²Be CH ₃, C ₂H ₅, CF ₃Or C ₆H ₄F.

Pyrazolo [1, the 5-a] pyrimidine compound of the open following formula of Mquestiau etc. (Bull.Soc.Belg., vol.101, no.2,1992, the 131-136 pages or leaves):

Open following formula pyrazolo [1, the 5-a] pyrimidine compound of Ibrahim etc. (Arch.Pharm. (weinheim) 320,487-491 (1987)):

Wherein R is NH ₂Or OH, Ar is 4-phenyl-3-cyano group-2-aminopyridine-2-base.Other reference of open azolopyrimidines comprises:

EP 0 511 528 (Otsuka, 1992), US4,997,940 (Dow, 1991), EP 0 374 448 (Nissan, 1990), US4,621,556 (ICN, 1997), EP 0 531 901 (Fujisawa, 1993), US4,567,263 (BASF, 1986), EP 0 662 477 (Isagro, 1995), DE4 243 279 (Bayer, 1994), US 5,397,774 (Upjohn, 1995), EP0 521 622 (Upjohn, 1993), WO 94/109017 (Upjohn, 1994), J.Med.Chem., 24,610-613 (1981), with J. Het. Chem., 22,601 (1985).

General introduction of the present invention

According to an aspect of the present invention, the invention provides new compound, medicinal compositions and can be used for the treatment of affective disorder, anxiety disorder, dysthymia disorders, irritable bowel syndrome, stress disease after the wound, paralysis on the nuclear, immunosuppression, the AlzheimerShi disease, gastrointestinal dysfunction, anorexia nervosa or other eating disorder, medicine or alcohol withdrawal symptom, drug habit, diseases associated with inflammation, growing barrier, disorderly, the disease that can work or help to treat by antagonism CRF includes but not limited to the disease that CRF induces or helps, or following diseases associated with inflammation: for example rheumatoid arthritis and osteoarthritis, pain, asthma, psoriasis and transformation reactions; General anxiety disease; Fear, fear, obsessional idea and behavior disorder; Stress disease after the wound; The somnopathy of bringing out by stress; The pain perception is fibromyalgia for example; Affective disorder is dysthymia disorders for example, comprises dysthymia disorders and post-natal depression that severe depression, disposable outbreak dysthymia disorders, recurrent major depression, children's drug abuse are brought out; Dispiritment (dysthemia); Two-way affective disorder; Cyclothymia; Fatigue syndrome; The headache that stress brings out; Cancer, human immunodeficiency virus (HIV) infects; Neurodegenerative disease is AlzheimerShi disease, ParkinsonShi disease and HuntingtonShi disease for example; Gastrointestinal dysfunction for example ulcer, irritable bowel syndrome, CrohnShi disease, spastic colon, diarrhoea, postoperative ilius with spiritual pathology disorder or the relevant adaptive colitis of stress; Eating disorder is anorexia and bulimia nervosa for example; Hemorrhage stress reaction; Stress reaction inductive psychic fit; Thyropathy syndrome; Inappropriate antidiarrheal (antidiarrhetic) hormone (ADH) syndrome; Obesity; Infertility; Wound; Spinal cord injuries receptor; Ischemic neuron infringement (as cerebral ischemia cerebral hippocampus ischemic for example); The infringement of exitotoxicity (excitotoxic) neurone; Epilepsy; Cardiovascular disorder and the disease relevant with heart comprise hypertension, tachycardia and congestive heart failure; Apoplexy; Immune disorder comprise pressure inducement immune disorder (the inductive imbalance of laying eggs of the fever of bringing out as pressure, pig pressure syndrome, ox shipment fever (bovine shipping), horse paroxysmal fibrillation and chicken, in pure pressure in the sheep or the dog with people-animal relevant pressure that interacts); Muscle spasm; The urinary incontinence; The senile dementia of Alzheimer type; Multi-infarct dementia; Amyotrophic lateral sclerosis; Chemical relies on and habituation (as alcohol, Cocaine, heroine, benzodiazepine or other medicines habituation); Medicine and alcohol withdrawal syndrome; Osteoporosis, the psychological nanism of Mammals and hypoglycemia.

The invention provides new combining, and therefore change the compound of CRF excretory anxiety effect with the corticotropin-releasing factor receptor body.Compound of the present invention can be used for the treatment of paralysis and eating disorder on stress disease after Mammals mental disorder and nervous system disease, the disease relevant with anxiety, the wound, the nuclear, and the treatment mammalian immune, cardiovascular or with cardiac-related diseases and with the adaptive colitis of spiritual pathology imbalance and pressure correlation.

According on the other hand, the invention provides new formula (1) and (2) (as following) compound, they can be as the antagonist of corticotropin releasing factor(CRF).As if compound of the present invention shows active as Corticotropin releasing factor antagonists, and suppress the CRF excessive secretion.The present invention also comprises the medicinal compositions that contains this formula (1) and (2) compound, and the method that suppresses CRF excessive secretion and/or treatment anxiety disorder with this compounds.

According to a further aspect in the invention, the invention provides also can be as the standard of the ability of measuring potential medicine and CRF receptors bind and the compound (The compounds of this invention that particularly marks) of reagent.

Detailed description of the present invention

[1] the present invention includes treatment Mammals affective disorder, anxiety disorder, dysthymia disorders, headache, irritable bowel syndrome, pressure disease after the wound, paralysis on the nuclear, immunosuppression, the AlzheimerShi disease, gastrointestinal dysfunction, anorexia nervosa or other eating disorder, drug habit, medicine or alcohol withdrawal symptom, diseases associated with inflammation, cardiovascular or and cardiac-related diseases, growing barrier, people's HIVvirus blood serum immunity infects, the hemorrhagic stress reaction, obesity, infertility, head and spinal cord injuries receptor, epilepsy, apoplexy, ulcer, amyotrophic lateral sclerosis, the disease that hypoglycemia maybe can work or help to treat by antagonism CRF, include but not limited to be induced or promoted disease by CRF, this method comprises formula (1) or (2) compound and its isomer that gives Mammals treatment significant quantity, the mixture of steric isomer or steric isomer with and pharmacy acceptable salt or prodrug: Wherein:

A is N or CR;

Z is N or CR ²

Ar is selected from phenyl, naphthyl, pyridyl, pyrimidyl, triazinyl, furyl, thienyl, benzothienyl, benzofuryl, 2,3-dihydro benzo furyl, 2,3-dihydrobenzo thienyl, 2,3-indanyl, 1,2-benzopyranyl, 3,4-dihydro-1,2-benzopyranyl, 1,2,3, the 4-tetrahydro naphthyl, each Ar is optional by 1-5 R ⁴Group replaces, and each Ar can link to each other with undersaturated carbon atom;

R independently is selected from H, C ₁-C ₄Alkyl, C ₂-C ₄Alkenyl, C ₂-C ₄Alkynyl, C ₃-C ₆Cycloalkyl, C ₄-C ₇Cycloalkylalkyl, halogen, CN, C ₁-C ₄Haloalkyl;

R ¹Independently be selected from H, C ₁-C ₄Alkyl, C ₂-C ₄Alkenyl, C ₂-C ₄Alkynyl, halogen, CN, C ₁-C ₄Haloalkyl, C ₁-C ₁₂Hydroxyalkyl, C ₂-C ₁₂Alkoxyalkyl, C ₂-C ₁₀Cyano group alkyl, C ₃-C ₆Cycloalkyl, C ₄-C ₁₀Cycloalkylalkyl, NR ⁹R ¹⁰, C ₁-C ₄Alkyl-NR ⁹R ¹⁰, NR ⁹COR ¹⁰, OR ¹¹, SH or S (O) _nR ¹²

R ²Be selected from H, C ₁-C ₄Alkyl, C ₂-C ₄Alkenyl, C ₂-C ₄Alkynyl, C ₃-C ₆Cycloalkyl, C ₄-C ₁₀Cycloalkylalkyl, C ₁-C ₄Hydroxyalkyl, halogen, CN ,-NR ⁶R ⁷, NR ⁹COR ¹⁰,-NR ⁶S (O) _nR ⁷, S (O) _nNR ⁶R ⁷, C ₁-C ₄Haloalkyl, OR ⁷, SH or S (O) _nR ¹²

R ³Be selected from

-H, OR ⁷, SH, S (O) _nR ¹³, COR ⁷, CO ₂R ⁷, OC (O) R ¹³, NR ⁸COR ⁷, N (COR ⁷) ₂, NR ⁸CONR ⁶R ⁷, NR ⁸CO ₂R ¹³, NR ⁶R ⁷, NR ^6aR ^7a, N (OR ⁷) R ⁶, CONR ⁶R ⁷, aryl, heteroaryl and heterocyclic radical, or

-C ₁-C ₁₀Alkyl, C ₂-C ₁₀Alkenyl, C ₂-C ₁₀Alkynyl, C ₃-C ₈Cycloalkyl, C ₅-C ₈Cycloalkenyl group, C ₄-C ₁₂Cycloalkylalkyl or C ₆-C ₁₀Cycloalkenyl alkyl, each is chosen wantonly by 1-3 and independently is selected from following substituting group replacement: C ₁-C ₆Alkyl, C ₃-C ₆Cycloalkyl, halogen, C ₁-C ₄Haloalkyl, cyano group, OR ¹⁵, SH, S (O) _nR ¹³, COR ¹⁵, CO ₂R ¹⁵, OC (O) R ¹³, NR ⁸COR ¹⁵, N (COR ¹⁵) ₂, NR ⁸CONR ¹⁶R ¹⁵, NR ⁸CO ₂R ¹³, NR ¹⁶R ¹⁵, CONR ¹⁶R ¹⁵, aryl, heteroaryl and heterocyclic radical;

R ⁴Independently be selected from: C ₁-C ₁₀Alkyl, C ₂-C ₁₀Alkenyl, C ₂-C ₁₀Alkynyl, C ₃-C ₆Cycloalkyl, C ₄-C ₁₂Cycloalkylalkyl, NO ₂, halogen, CN, C ₁-C ₄Haloalkyl, NR ⁶R ⁷, NR ⁸COR ⁷, NR ⁸CO ₂R ⁷, COR ⁷, OR ⁷, CONR ⁶R ⁷, CO (NOR ⁹) R ⁷, CO ₂R ⁷Or S (O) _nR ⁷, each C wherein ₁-C ₁₀Alkyl, C ₂-C ₁₀Alkenyl, C ₂-C ₁₀Alkynyl, C ₃-C ₆Cycloalkyl and C ₄-C ₁₂Cycloalkylalkyl is optional independently to be selected from following substituting group replacement: C by 1-3 ₁-C ₄Alkyl, NO ₂, halogen, CN, NR ⁶R ⁷, NR ⁸COR ⁷, NR ⁸CO ₂R ⁷, COR ⁷, OR ⁷, CONR ⁶R ⁷, CO ₂R ⁷, CO (NOR ⁹) R ⁷Or S (O) _nR ⁷

R ⁶And R ⁷, R ^6aAnd R ^7aIndependently be selected from:

-H，

-C ₁-C ₁₀Alkyl, C ₃-C ₁₀Alkenyl, C ₃-C ₁₀Alkynyl, has the C of 1-10 halogen atom ₁-C ₁₀Haloalkyl, C ₂-C ₈Alkoxyalkyl, C ₃-C ₆Cycloalkyl, C ₄-C ₁₂Cycloalkylalkyl, C ₅-C ₁₀Cycloalkenyl group or C ₆-C ₁₄Cycloalkenyl alkyl, each is chosen wantonly by 1-3 and independently is selected from following substituting group replacement: C ₁-C ₆Alkyl, C ₃-C ₆Cycloalkyl, halogen, C ₁-C ₄Haloalkyl, cyano group, OR ¹⁵, SH, S (O) _nR ¹³, COR ¹⁵, CO ₂R ¹⁵, OC (O) R ¹³, NR ⁸COR ¹⁵, N (COR ¹⁵) ₂, NR ⁸CONR ¹⁶R ¹⁵, NR ⁸CO ₂R ¹³, NR ¹⁶R ¹⁵, CONR ¹⁶R ¹⁵, aryl, heteroaryl or heterocyclic radical;

-aryl, aryl (C ₁-C ₄Alkyl), heteroaryl, heteroaryl (C ₁-C ₄Alkyl), heterocyclic radical or heterocyclic radical (C ₁-C ₄Alkyl);

Perhaps, NR ⁶R ⁷And NR ^6aR ^7aIndependent is piperidines, tetramethyleneimine, piperazine, N methyl piperazine, morpholine or thiomorpholine, and each is optional by 1-3 C ₁-C ₄Alkyl replaces;

R ⁸Independently be selected from H or C ₁-C ₄Alkyl;

R ⁹And R ¹⁰Independently be selected from H, C ₁-C ₄Alkyl or C ₃-C ₆Cycloalkyl;

R ¹¹Be selected from H, C ₁-C ₄Alkyl, C ₁-C ₄Haloalkyl or C ₃-C ₆Cycloalkyl;

R ¹²Be C ₁-C ₄Alkyl or C ₁-C ₄Haloalkyl;

R ¹³Be selected from C ₁-C ₄Alkyl, C ₁-C ₄Haloalkyl, C ₂-C ₈Alkoxyalkyl, C ₃-C ₆Cycloalkyl, C ₄-C ₁₂Cycloalkylalkyl, aryl, aryl (C ₁-C ₄Alkyl)-, heteroaryl or heteroaryl (C ₁-C ₄Alkyl)-;

R ¹⁴Be selected from C ₁-C ₁₀Alkyl, C ₃-C ₁₀Alkenyl, C ₃-C ₁₀Alkynyl, C ₃-C ₈Cycloalkyl or C ₄-C ₁₂Cycloalkylalkyl, each is chosen wantonly by 1-3 and independently is selected from following substituting group replacement: C ₁-C ₆Alkyl, C ₃-C ₆Cycloalkyl, halogen, C ₁-C ₄Haloalkyl, cyano group, OR ¹⁵, SH, S (O) _nR ¹⁵, COR ¹⁵, CO ₂R ¹⁵, OC (O) R ¹⁵, NR ⁸COR ¹⁵, N (COR ¹⁵) ₂, NR ⁸CONR ¹⁶R ¹⁵, NR ⁸CO ₂R ¹⁵, NR ¹⁶R ¹⁵, CONR ¹⁶R ¹⁵And C ₁-C ₆Alkylthio, C ₁-C ₆Alkyl sulphinyl and C ₁-C ₆Alkyl sulphonyl;

R ¹⁵And R ¹⁶Independently be selected from H, C ₁-C ₆Alkyl, C ₃-C ₁₀Cycloalkyl, C ₄-C ₁₆Cycloalkylalkyl, but when being S (O) _nR ¹⁵The time, R ¹⁵Can not be H;

Aryl is a phenyl or naphthyl, and each is chosen wantonly by 1-5 and independently is selected from following substituting group replacement: C ₁-C ₆Alkyl, C ₃-C ₆Cycloalkyl, halogen, C ₁-C ₄Haloalkyl, cyano group, OR ¹⁵, SH, S (O) _nR ¹⁵, COR ¹⁵, CO ₂R ¹⁵, OC (O) R ¹⁵, NR ⁸COR ¹⁵, N (COR ¹⁵) ₂, NR ⁸CONR ¹⁶R ¹⁵, NR ⁸CO ₂R ¹⁵, NR ¹⁶R ¹⁵And CONR ¹⁶R ¹⁵

Heteroaryl is pyridyl, pyrimidyl, triazinyl, furyl, pyranyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indyl, pyrryl, oxazolyl, benzofuryl, benzothienyl, benzothiazolyl, isoxazolyl, pyrazolyl, 2,3-dihydrobenzo thienyl or 2, the 3-dihydro benzo furyl, each is chosen wantonly by 1-5 and independently is selected from following substituting group replacement: C ₁-C ₆Alkyl, C ₃-C ₆Cycloalkyl, halogen, C ₁-C ₄Haloalkyl, cyano group, OR ¹⁵, SH, S (O) _nR ¹⁵, COR ¹⁵, CO ₂R ¹⁵, OC (O) R ¹⁵, NR ⁸COR ¹⁵, N (COR ¹⁵) ₂, NR ⁸CONR ¹⁶R ¹⁵, NR ⁸CO ₂R ¹⁵, NR ¹⁶R ¹⁵And CONR ¹⁶R ¹⁵

Heterocyclic radical is the heteroaryl of saturated or fractional saturation, chooses wantonly by 1-5 and independently is selected from following substituting group replacement: C ₁-C ₆Alkyl, C ₃-C ₆Cycloalkyl, halogen, C ₁-C ₄Haloalkyl, cyano group, OR ¹⁵, SH, S (O) _nR ¹⁵, COR ¹⁵, CO ₂R ¹⁵, OC (O) R ¹⁵, NR ⁸COR ¹⁵, N (COR ¹⁵) ₂, NR ⁸CONR ¹⁶R ¹⁵, NR ⁸CO ₂R ¹⁵, NR ¹⁶R ¹⁵And CONR ¹⁶R ¹⁵

N independently is 0,1 or 2.

[2] preferable methods of the present invention is such method, and wherein in formula (1) or (2) compound, Ar is phenyl, pyridyl or 2, the 3-dihydro benzo furyl, and each is optional by 1-4 R ⁴Substituting group replaces.

[3] the also preferred such method of the present invention, wherein in formula (1) or (2) compound, A is N, Z is CR ², Ar is a 2,4 dichloro benzene base, 2,4-3,5-dimethylphenyl or 2,4,6-trimethylphenyl, R ¹And R ²Be CH ₃, R ³Be NR ^6aR ^7a

[4] mixture that the present invention includes the compound of formula (1) or (2) and its isomer, steric isomer or steric isomer with and pharmacy acceptable salt or prodrug form:

Wherein:

A is N or CR;

Z is N or CR ²

R ²Be selected from H, C ₁-C ₄Alkyl, C ₂-C ₄Alkenyl, C ₂-C ₄Alkynyl, C ₃-C ₆Cycloalkyl, C ₄-C ₁₀Cycloalkylalkyl, C ₁-C ₄Hydroxyalkyl, halogen, CN ,-NR ⁶R ⁷, NR ⁹COR ¹⁰,-NR ⁶S (O) _nR ⁷, S (O) _nNR ⁶R ⁷, C ₁-C ₄Haloalkyl ,-OR ⁷, SH or S (O) _nR ¹²

R ³Be selected from

R ⁴Independently be selected from: C ₁-C ₁₀Alkyl, C ₂-C ₁₀Alkenyl, C ₂-C ₁₀Alkynyl, C ₃-C ₆Cycloalkyl, C ₄-C ₁₂Cycloalkylalkyl, NO ₂, halogen, CN, C ₁-C ₄Haloalkyl, NR ⁶R ⁷, NR ⁸COR ⁷, NR ⁸CO ₂R ⁷, COR ⁷, OR ⁷, CONR ⁶R ⁷, CO (NOR ⁹) R ⁷, CO ₂R ⁷Or S (O) _nR ⁷, each C wherein ₁-C ₁₀Alkyl, C ₂-C ₁₀Alkenyl, C ₂-C ₁₀Alkynyl, C ₃-C ₆Cycloalkyl and C ₄-C ₁₂Cycloalkylalkyl is optional independently to be selected from following substituting group replacement: C by 1-3 ₁-C ₄Alkyl, NO ₂, halogen, CN, NR ⁶R ⁷, NR ⁸COR ⁷, NR ⁸CO ₂R ⁷, OR ⁷, CONR ⁶R ⁷, CO ₂R ⁷, CO (NOR ⁹) R ⁷Or S (O) _nR ⁷

R ⁶And R ⁷, R ^6aAnd R ^7aIndependently be selected from:

-H，

R ⁸Independently be selected from H or C ₁-C ₄Alkyl;

R ¹²Be C ₁-C ₄Alkyl or C ₁-C ₄Haloalkyl;

Heteroaryl is pyridyl, pyrimidyl, triazinyl, furyl, pyranyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indyl, pyrryl, oxazolyl, benzofuryl, benzothienyl, benzothiazolyl, isoxazolyl, pyrazolyl, 2,3-dihydrobenzo thienyl or 2, the 3-dihydro benzo furyl, each is chosen wantonly by 1-5 and independently is selected from following substituting group replacement: C ₁-C ₆Alkyl, C ₃-C ₆Cycloalkyl, halogen, C ₁-C ₄Haloalkyl, cyano group, OR ¹⁵, SH, S (O) _nR ¹⁵,-COR ¹⁵, CO ₂R ¹⁵, OC (O) R ¹⁵, NR ⁸COR ¹⁵, N (COR ¹⁵) ₂, NR ⁸CONR ¹⁶R ¹⁵, NR ⁸CO ₂R ¹⁵, NR ¹⁶R ¹⁵And CONR ¹⁶R ¹⁵

Heterocyclic radical is the heteroaryl of saturated or fractional saturation, chooses wantonly by 1-5 and independently is selected from following substituting group replacement: C ₁-C ₆Alkyl, C ₃-C ₆Cycloalkyl, halogen, C ₁-C ₄Haloalkyl, cyano group, OR ¹⁵, SH, S (O) _nR ¹⁵, COR ¹⁵, CO ₂R ¹⁵, OC (O) R ¹⁵, NR ⁸COR ¹⁵, N (COR ¹⁵) ₂, NR ⁸CONR ¹⁶R ¹⁵, NR ⁸CO ₂R ¹⁵, NR ¹⁵R ¹⁶And CONR ¹⁶R ¹⁵

N independently is 0,1 or 2,

Prerequisite is:

(1) when A be N, Z is CR ², R ²Be H, R ³For-OR ⁷Or-OCOR ¹³And R ⁷During for H, R so ¹Can not be H, OH or SH;

(2) when A be N, Z is CR ², R ¹Be CH ₃Or C ₂H ₅, R ²Be H, R ³Be OH, H, CH ₃, C ₂H ₅, C ₆H ₅, n-C ₃H ₇, i-C ₃H ₇, SH, SCH ₃, NHC ₄H ₉Or N (C ₂H ₅) ₂The time, so Ar can not for phenyl or-CH ₃-phenyl;

(3) when A be N, Z is CR ², R ²Be H, Ar is pyridyl, pyrimidyl or pyrazinyl, R ³Be NR ^6aR ^7aThe time, R so ^6aAnd R ^7aCan not be H or alkyl;

(4) when A be N, Z is CR ², R ²Be SO ₂NR ⁶R ⁷The time, R so ³Can not be OH or SH;

(5) when A be CR, Z is CR ², R so ²Can not be-NR ⁶SO ₂R ⁷Or SO ₂NR ⁶R ⁷

(6) when A be N, Z is CR ², R ²Be NR ⁶SO ₂R ⁷Or-SO ₂NR ⁶R ⁷The time, R so ³Can not be OH or SH;

(7) when A be N, Z is CR ², R ¹Be methyl or ethyl, R ²Be H, R ³Be H, OH, CH ₃, C ₂H ₅, C ₆H ₅, n-C ₃H ₇, i-C ₃H ₇, SH, SCH ₃, NH (n-C ₄H ₉) or N (C ₂H ₅) ₂The time, so Ar can not for unsubstituted phenyl or-aminomethyl phenyl;

(8) when A be CR, Z is CR ², R ²Be H, phenyl or alkyl, R ³Be NR ⁸COR ⁷, when Ar is phenyl or the phenyl that replaced by thiophenyl, R so ⁷Can not be aryl, aryl (C ₁-C ₄Alkyl), heteroaryl, heteroaryl (C ₁-C ₄Alkyl), heterocyclic radical or heterocyclic radical (C ₁-C ₄Alkyl);

(9) when A be CR, Z is CR ², R ²Be H or alkyl, Ar is a phenyl, R ³Be SR ¹³Or NR ^6aR ^7aThe time, R so ¹³Can not be aryl or heteroaryl, R ^6aAnd R ^7aCan not be H or aryl; Or

(10) when A be CH, Z is CR ², R ¹Be OR ¹¹, R ²Be H, R ³Be OR ⁷, R ⁷And R ¹¹When all being H, Ar can not be phenyl, p-Br-phenyl, p-Cl-phenyl, p-NHCOCH so ₃-phenyl, p-CH ₃-phenyl, pyridyl or naphthyl;

(11) when A be CH, Z is CR ², R ²Be H, Ar is unsubstituted phenyl, R ³Be CH ₃, C ₂H ₅, CF ₃Or C ₆H ₄During F, R so ¹Can not be CF ₃Or C ₂F ₅

(12) when A be CR, R is H, Z is CR ², R ²Be OH, R ¹And R ³All be H, Ar can not be phenyl so;

(13) when A be CR, R is H, Z is CR ², R ²Be OH or NH ₂, R ¹And R ³All be CH ₃, Ar can not be 4-phenyl-3-cyano group-2-aminopyridine-2-base so.

[5] the preferred compound of the present invention be formula (1) and (2) compound and its isomer, steric isomer or steric isomer mixture with and pharmacy acceptable salt or prodrug, prerequisite is: (1) when A be N, R ¹Be H, C ₁-C ₄Alkyl, halogen, CN, C ₁-C ₁₂Hydroxyalkyl, C ₁-C ₄Alkoxyalkyl or SO ₂(C ₁-C ₄Alkyl), R ³Be NR ^6aR ^7a, R ^6aBe unsubstituted C ₁-C ₄During alkyl, R so ^7aCan not be phenyl, naphthyl, thienyl, benzothienyl, pyridyl, quinolyl, pyrazinyl, furyl, benzofuryl, benzothiazolyl, indyl or C ₃-C ₆Cycloalkyl; (2) A is N, R ¹Be H, C ₁-C ₄Alkyl, halogen, CN, C ₁-C ₁₂Hydroxyalkyl, C ₁-C ₄Alkoxyalkyl or SO ₂(C ₁-C ₄Alkyl), R ³Be NR ^6aR ^7a, R ^7aBe unsubstituted C ₁-C ₄During alkyl, R so ^6aCan not be phenyl, naphthyl, thienyl, benzothienyl, pyridyl, quinolyl, pyrazinyl, furyl, benzofuryl, benzothiazolyl, indyl or C ₃-C ₆Cycloalkyl.

[6] the preferred compound of the present invention also comprises the mixture of formula (1) and (2) compound and its isomer, steric isomer or steric isomer, with and pharmacy acceptable salt or prodrug, wherein Ar is phenyl, pyridyl or 2, the 3-dihydro benzo furyl, and each is optional by 1-4 R ⁴Substituting group replaces.

[7] the preferred compound of the present invention also comprises the mixture of formula (1) and (2) compound and its isomer, steric isomer or steric isomer, with and pharmacy acceptable salt or prodrug form, wherein A is N, Z is CR ², Ar is a 2,4 dichloro benzene base, 2,4-3,5-dimethylphenyl or 2,4,6-trimethylphenyl, R ¹And R ²Be CH ₃, R ³Be NR ^6aR ^7a

[11] the preferred compound of the present invention is the mixture of such compound and its isomer, steric isomer or steric isomer, with and pharmacy acceptable salt or prodrug form, wherein A is N.

[12] the preferred compound of the present invention mixture that also comprises such compound and its isomer, steric isomer or steric isomer with and pharmacy acceptable salt or prodrug form.

[13] the preferred compound of the present invention mixture that also comprises such compound and its isomer, steric isomer or steric isomer with and pharmacy acceptable salt or prodrug form, wherein Ar is phenyl, pyridyl or 2, the 3-dihydro benzo furyl, each Ar is optional by 1-4 R ⁴Substituting group replaces.

[14] the preferred compound of the present invention mixture that also comprises such compound and its isomer, steric isomer or steric isomer with and pharmacy acceptable salt or prodrug form, wherein R ³Be NR ^6aR ^7aOr OR ⁷

[15] the preferred compound of the present invention mixture that also comprises such compound and its isomer, steric isomer or steric isomer with and pharmacy acceptable salt or prodrug form, wherein Ar is phenyl, pyridyl or 2, the 3-dihydro benzo furyl, each Ar is optional by 1-4 R ⁴Substituting group replaces, R ³Be NR ^6aR ^7aOr OR ⁷

[16] the preferred compound of the present invention mixture that also comprises such compound and its isomer, steric isomer or steric isomer with and pharmacy acceptable salt or prodrug form, wherein Z is CR ²

[17] the preferred compound of the present invention mixture that also comprises such compound and its isomer, steric isomer or steric isomer with and pharmacy acceptable salt or prodrug, wherein Ar is phenyl, pyridyl or 2, the 3-dihydro benzo furyl, each Ar is optional by 1-4 R ⁴Substituting group replaces.

[18] the preferred compound of the present invention mixture that also comprises such compound and its isomer, steric isomer or steric isomer with and pharmacy acceptable salt or prodrug form, wherein R ³Be NR ^6aR ^7aOr OR ⁷

[19] the preferred compound of the present invention mixture that also comprises such compound and its isomer, steric isomer or steric isomer with and pharmacy acceptable salt or prodrug form, wherein R ^6aIndependently be selected from:

-H，

-aryl, aryl (C ₁-C ₄Alkyl)-, heteroaryl, heteroaryl (C ₁-C ₄Alkyl)-, heterocyclic radical or heterocyclic radical (C ₁-C ₄Alkyl)-; With

R ^7aIndependently be selected from:

-H，

-C ₅-C ₁₀Alkyl, C ₃-C ₁₀Alkenyl, C ₃-C ₁₀Alkynyl, has the C of 1-10 halogen atom ₁-C ₁₀Haloalkyl, C ₂-C ₈Alkoxyalkyl, C ₃-C ₆Cycloalkyl, C ₄-C ₁₂Cycloalkylalkyl, C ₅-C ₁₀Cycloalkenyl group or C ₆-C ₁₄Cycloalkenyl alkyl, each is chosen wantonly by 1-3 and independently is selected from following substituting group replacement: C ₁-C ₆Alkyl, C ₃-C ₆Cycloalkyl, halogen, C ₁-C ₄Haloalkyl, cyano group, OR ¹⁵, SH, S (O) _nR ¹³, COR ¹⁵, CO ₂R ¹⁵, OC (O) R ¹³, NR ⁸COR ¹⁵, N (COR ¹⁵) ₂, NR ⁸CONR ¹⁶R ¹⁵, NR ⁸CO ₂R ¹³, NR ¹⁶R ¹⁵, CONR ¹⁶R ¹⁵, aryl, heteroaryl or heterocyclic radical;

Perhaps, NR ⁶R ⁷And NR ^6aR ^7aIndependent is piperidines, tetramethyleneimine, piperazine, N methyl piperazine, morpholine or thiomorpholine, and each is optional by 1-3 C ₁-C ₄Alkyl replaces.

[20] the preferred compound of the present invention mixture that also comprises such compound and its isomer, steric isomer or steric isomer with and pharmacy acceptable salt or prodrug form, wherein R ^6aAnd R ^7aIdentical and be selected from:

-C ₁-C ₄Alkyl or C ₃-C ₆Cycloalkyl, each is chosen wantonly by 1-3 and independently is selected from following substituting group replacement: C ₁-C ₆Alkyl, C ₃-C ₆Cycloalkyl, halogen, C ₁-C ₄Haloalkyl, cyano group, OR ¹⁵, SH, S (O) _nR ¹³, COR ¹⁵, CO ₂R ¹⁵, OC (O) R ¹³, NR ⁸COR ¹⁵, N (COR ¹⁵) ₂, NR ⁸CONR ¹⁶R ¹⁵, NR ⁸CO ₂R ¹³, NR ¹⁶R ¹⁵, CONR ¹⁶R ¹⁵, aryl, heteroaryl or heterocyclic radical; With

-aryl or heteroaryl.

[21] the preferred compound of the present invention mixture that also comprises such compound and its isomer, steric isomer or steric isomer with and pharmacy acceptable salt or prodrug, wherein R ^6aBe selected from:

-H，

-C ₁-C ₁₀Alkyl, C ₃-C ₁₀Alkenyl, C ₃-C ₁₀Alkynyl, has the C of 1-10 halogen atom ₁-C ₁₀Haloalkyl, C ₂-C ₈Alkoxyalkyl, C ₃-C ₆Cycloalkyl, C ₄-C ₁₂Cycloalkylalkyl, C ₅-C ₁₀Cycloalkenyl group or C ₆-C ₁₄Cycloalkenyl alkyl, each is chosen wantonly by 1-3 and independently is selected from following substituting group replacement: C ₁-C ₆Alkyl, C ₃-C ₆Cycloalkyl, halogen, C ₁-C ₄Haloalkyl, cyano group, OR ¹⁵, SH, S (O) _nR ¹³, COR ¹⁵, CO ₂R ¹⁵, OC (O) R ¹⁵, NR ⁸COR ¹⁵, N (COR ¹⁵) ₂, NR ⁸CONR ¹⁶R ¹⁵, NR ⁸CO ₂R ¹³, NR ¹⁶R ¹⁵, CONR ¹⁶R ¹⁵, aryl, heteroaryl or heterocyclic radical;

R ^7aBe selected from:

-C ₁-C ₄Alkyl, each C ₁-C ₄Alkyl independently is selected from following substituting group by 1-3 and replaces: C ₁-C ₆Alkyl, C ₃-C ₆Cycloalkyl, halogen, C ₁-C ₄Haloalkyl, cyano group, OR ¹⁵, SH, S (O) _nR ¹³, COR ¹⁵, CO ₂R ¹⁵, OC (O) R ¹³, NR ⁸COR ¹⁵, N (COR ¹⁵) ₂, NR ⁸CONR ¹⁶R ¹⁵, NR ⁸CO ₂R ¹³, NR ¹⁶R ¹⁵, CONR ¹⁶R ¹⁵, aryl, heteroaryl or heterocyclic radical.

[22] the preferred compound of the present invention mixture that also comprises such compound and its isomer, steric isomer or steric isomer with and pharmacy acceptable salt or prodrug form, wherein R ^6aAnd R ^7aOne of be selected from:

-C ₃-C ₆Cycloalkyl, each C ₃-C ₆Cycloalkyl is optional independently to be selected from following substituting group replacement: C by 1-3 ₁-C ₆Alkyl, C ₃-C ₆Cycloalkyl, halogen, C ₁-C ₄Haloalkyl, cyano group, OR ¹⁵, SH, S (O) _nR ¹³, COR ¹⁵, CO ₂R ¹⁵, OC (O) R ¹³, NR ⁸COR ¹⁵, N (COR ¹⁵) ₂, NR ⁸CONR ¹⁶R ¹⁵, NR ⁸CO ₂R ¹³, NR ¹⁶R ¹⁵, CONR ¹⁶R ¹⁵, aryl, heteroaryl or heterocyclic radical;

-aryl,

-heteroaryl or

-heterocyclic radical, and R ^6aAnd R ^7aIn another be unsubstituted C ₁-C ₄Alkyl.

[23] the preferred compound of the present invention mixture that also comprises such compound and its isomer, steric isomer or steric isomer with and pharmacy acceptable salt or prodrug form, wherein R ^6aAnd R ^7aIndependent is H or C ₁-C ₁₀Alkyl, each C ₁-C ₁₀Alkyl is optional independently to be selected from following substituting group replacement: C by 1-3 ₁-C ₆Alkyl, C ₃-C ₆Cycloalkyl, halogen, C ₁-C ₄Haloalkyl, cyano group, OR ¹⁵, SH, S (O) _nR ¹³, COR ¹⁵, CO ₂R ¹⁵, OC (O) R ¹³, NR ⁸COR ¹⁵, N (COR ¹⁵) ₂, R ⁸CONR ¹⁶R ¹⁵, NR ⁸CO ₂R ¹³, NR ¹⁶R ¹⁵, CONR ¹⁶R ¹⁵, aryl, heteroaryl or heterocyclic radical.

[24] the preferred compound of the present invention mixture that also comprises such compound and its isomer, steric isomer or steric isomer with and pharmacy acceptable salt or prodrug form, wherein Ar is phenyl, pyridyl or 2, the 3-dihydro benzo furyl, each Ar is optional by 1-4 R ⁴Substituting group replaces, R ³Be NR ^6aR ^7aOr OR ⁷

[25] the preferred compound of the present invention mixture that also comprises such compound and its isomer, steric isomer or steric isomer with and pharmacy acceptable salt or prodrug form, wherein R ^6aIndependently be selected from:

-H，

-aryl, aryl (C ₁-C ₄Alkyl)-, heteroaryl, heteroaryl (C ₁-C ₄Alkyl), heterocyclic radical or heterocyclic radical (C ₁-C ₄Alkyl);

R ^7aIndependently be selected from:

-H，

[26] the preferred compound of the present invention mixture that also comprises such compound and its isomer, steric isomer or steric isomer with and pharmacy acceptable salt or prodrug form, wherein R ^6aAnd R ^7aIdentical and be selected from:

-C ₁-C ₄Alkyl or C ₃-C ₆Cycloalkyl, each is chosen wantonly by 1-3 and independently is selected from following substituting group replacement: C ₁-C ₆Alkyl, C ₃-C ₆Cycloalkyl, halogen, C ₁-C ₄Haloalkyl, cyano group, OR ¹⁵, SH, S (O) _nR ¹³,-COR ¹⁵, CO ₂R ¹⁵, OC (O) R ¹³, NR ⁸COR ¹⁵, N (COR ¹⁵) ₂, NR ⁸CONR ¹⁶R ¹⁵, NR ⁸CO ₂R ¹³, NR ¹⁶R ¹⁵, CONR ¹⁶R ¹⁵, aryl, heteroaryl or heterocyclic radical; With

-aryl or heteroaryl.

[27] the preferred compound of the present invention mixture that also comprises such compound and its isomer, steric isomer or steric isomer with and pharmacy acceptable salt or prodrug form, wherein R ^6aAnd R ^7aIdentical and be:

-C ₁-C ₄Alkyl, each C ₁-C ₄Alkyl is optional independently to be selected from following substituting group replacement: C by 1-3 ₁-C ₆Alkyl, C ₃-C ₆Cycloalkyl, halogen, C ₁-C ₄Haloalkyl, cyano group, OR ¹⁵, SH, S (O) _nR ¹³,-COR ¹⁵, CO ₂R ¹⁵, OC (O) R ¹³, NR ⁸COR ¹⁵, N (COR ¹⁵) ₂, NR ⁸CONR ¹⁶R ¹⁵, NR ⁸CO ₂R ¹³, NR ¹⁶R ¹⁵, CONR ¹⁶R ¹⁵, aryl, heteroaryl or heterocyclic radical.

[28] the preferred compound of the present invention mixture that also comprises such compound and its isomer, steric isomer or steric isomer with and pharmacy acceptable salt or prodrug, wherein R ^6aBe selected from:

-H，

R ^7aFor:

[29] the preferred compound of the present invention mixture that also comprises such compound and its isomer, steric isomer or steric isomer with and pharmacy acceptable salt or prodrug form, wherein R ^6aAnd R ^7aOne of be selected from:

-aryl,

-heteroaryl or

[30] the preferred compound of the present invention mixture that also comprises such compound and its isomer, steric isomer or steric isomer with and pharmacy acceptable salt or prodrug form, wherein R ^6aAnd R ^7aIndependent is H or C ₁-C ₁₀Alkyl, each C ₁-C ₁₀Alkyl is optional independently to be selected from following substituting group replacement: C by 1-3 ₁-C ₆Alkyl, C ₃-C ₆Cycloalkyl, halogen, C ₁-C ₄Haloalkyl, cyano group, OR ¹⁵, SH, S (O) _nR ¹³, COR ¹⁵, CO ₂R ¹⁵, OC (O) R ¹³, NR ⁸COR ¹⁵, N (COR ¹⁵) ₂, R ⁸CONR ¹⁶R ¹⁵, NR ⁸CO ₂R ¹³, NR ¹⁶R ¹⁵, CONR ¹⁶R ¹⁵, aryl, heteroaryl or heterocyclic radical.

[31] the preferred compound of the present invention mixture that also comprises such compound and its isomer, steric isomer or steric isomer with and pharmacy acceptable salt or prodrug form, wherein

-Ar is phenyl, pyridyl or 2, the 3-dihydro benzo furyl, and each Ar is optional by 1-4 R ⁴Substituting group replaces;

-R ³Be NR ^6aR ^7aOr OR ⁷And

-R ¹And R ²Independently be selected from H, C ₁-C ₄Alkyl, C ₃-C ₆Cycloalkyl, C ₄-C ₁₀Cycloalkylalkyl.

[32] the preferred compound of the present invention mixture that also comprises such compound and its isomer, steric isomer or steric isomer with and pharmacy acceptable salt or prodrug form, wherein R ^6aIndependently be selected from:

-H，

R ^7aIndependently be selected from:

-H，

-C ₅-C ₁₀Alkyl, C ₃-C ₁₀Alkenyl, C ₃-C ₁₀Alkynyl, has the C of 1-10 halogen atom ₁-C ₁₀Haloalkyl, C ₂-C ₈Alkoxyalkyl, C ₃-C ₆Cycloalkyl, C ₄-C ₁₂Cycloalkylalkyl, C ₅-C ₁₀Cycloalkenyl group or C ₆-C ₁₄Cycloalkenyl alkyl, each is chosen wantonly by 1-3 and independently is selected from following substituting group replacement: C ₁-C ₆Alkyl, C ₃-C ₆Cycloalkyl, halogen, C ₁-C ₄Haloalkyl, cyano group, OR ¹⁵, SH, S (O) _nR ¹³, COR ¹⁵, CO ₂R ¹⁵, OC (O) R ¹⁵, NR ⁸COR ¹⁵, N (COR ¹⁵) ₂, NR ⁸CONR ¹⁶R ¹⁵, NR ⁸CO ₂R ¹³, NR ¹⁶R ¹⁵, CONR ¹⁶R ¹⁵, aryl, heteroaryl or heterocyclic radical;

[33] the preferred compound of the present invention mixture that also comprises such compound and its isomer, steric isomer or steric isomer with and pharmacy acceptable salt or prodrug form, wherein R ^6aAnd R ^7aIdentical and be selected from:

-aryl or heteroaryl.

[34] the preferred compound of the present invention mixture that also comprises such compound and its isomer, steric isomer or steric isomer with and pharmacy acceptable salt or prodrug, wherein R ^6aAnd R ^7aIdentical and be:

-C ₁-C ₄Alkyl, each C ₁-C ₄Alkyl is optional independently to be selected from following substituting group replacement: C by 1-3 ₁-C ₆Alkyl, C ₃-C ₆Cycloalkyl, halogen, C ₁-C ₄Haloalkyl, cyano group, OR ¹⁵, SH, S (O) _nR ¹³, COR ¹⁵, CO ₂R ¹⁵, OC (O) R ¹³, NR ⁸COR ¹⁵, N (COR ¹⁵) ₂, NR ⁸CONR ¹⁶R ¹⁵, NR ⁸CO ₂R ¹³, NR ¹⁶R ¹⁵, CONR ¹⁶R ¹⁵, aryl, heteroaryl or heterocyclic radical.

[35] the preferred compound of the present invention mixture that also comprises such compound and its isomer, steric isomer or steric isomer with and pharmacy acceptable salt or prodrug, wherein R ^6aBe selected from:

-H，

R ^7aFor:

[36] the preferred compound of the present invention mixture that also comprises such compound and its isomer, steric isomer or steric isomer with and pharmacy acceptable salt or prodrug form, wherein R ^6aAnd R ^7aOne of be selected from:

-aryl,

-heteroaryl or

[37] the preferred compound of the present invention mixture that also comprises such compound and its isomer, steric isomer or steric isomer with and pharmacy acceptable salt or prodrug form, wherein R ^6aAnd R ^7aIndependent is H or C ₁-C ₁₀Alkyl, each C ₁-C ₁₀Alkyl is optional independently to be selected from following substituting group replacement: C by 1-3 ₁-C ₆Alkyl, C ₃-C ₆Cycloalkyl, halogen, C ₁-C ₄Haloalkyl, cyano group, OR ¹⁵, SH, S (O) _nR ¹³, COR ¹⁵, CO ₂R ¹⁵, OC (O) R ¹³, NR ⁸COR ¹⁵, N (COR ¹⁵) ₂, R ⁸CONR ¹⁶R ¹⁵, NR ⁸CO ₂R ¹³, NR ¹⁶R ¹⁵, CONR ¹⁶R ¹⁵, aryl, heteroaryl or heterocyclic radical.

[38] the particularly preferred compound of the present invention be formula (50) compound and its isomer, steric isomer or steric isomer mixture with and pharmacy acceptable salt or prodrug form:

Formula (50)

They are selected from: R wherein³For-NHCH (n-Pr)₂，R ^4aFor Cl, R^4bFor H, R^4cFor Cl, R^4dFor H, R^4eFormula (50) compound for H; R wherein³For-N (Et) (n-Bu), R^4aFor Cl, R^4bFor H, R^4cFor Cl, R^4dFor H, R^4eFormula (50) compound for H; R wherein³For-(n-Pr) (CH₂cPr)，R ^4aFor Cl, R^4bFor H, R^4cFor Cl, R^4dFor H, R^4eFormula (50) compound for H; R wherein³For-N (CH₂CH ₂OMe) ₂，R ^4aFor Cl, R^4bFor H, R^4cFor Cl, R^4dFor H, R^4eFormula (50) compound for H; R wherein³For-NNCH (Et) (n-Bu), R^4aFor Cl, R^4bFor H, R^4cFor Cl, R^4dFor H, R^4eFormula (50) compound for H; R wherein³For-NHCH (Et) (CH₂OMe)，R ^4aFor Cl, R^4bFor H, R^4cFor Cl, R^4dFor H, R^4eFormula (50) compound for H; R wherein³For-NHCH (CH₂OMe) ₂，R ^4aFor Cl, R^4bFor H, R^4cFor Cl, R^4dFor H, R^4eFormula (50) compound for H; R wherein³For-N (Et)₂，R ^4aFor Cl, R^4bFor H, R^4cFor Cl, R^4dFor H, R^4eFormula (50) compound for H; R wherein³For-NHCH (CH₂OEt) ₂，R ^4aFor Cl, R^4bFor H, R^4cFor Cl, R^4dFor H, R^4eFormula (50) compound for H; R wherein³For-NHCH (Et)₂，R ^4aFor Cl, R^4bFor H, R^4cFor Cl, R^4dFor H, R^4eFormula (50) compound for H; R wherein³For-N (Me) (Ph), R^4aFor Cl, R^4bFor H, R^4cFor Cl, R^4dFor H, R^4eFormula (50) compound for H; R wherein³For-N (n-Pr)₂，R ^4aFor Cl, R^4bFor H, R^4cFor Cl, R^4dFor H, R^4eFormula (50) compound for H; R wherein³For-NHCH (Et) (n-Pr), R^4aFor Cl, R^4bFor H, R^4cFor Cl, R^4dFor H, R^4eFormula (50) compound for H; R wherein³For-NHCH (CH₂OMe) ₂，R ^4aFor Me, R^4bFor H, R^4cFor Me, R^4dFor H, R^4eFormula (50) compound for Me; R wherein³For-NHCH (CH₂OMe) ₂，R ^4aFor Me, R^4bFor H, R^4cFor Me, R^4dFor H, R^4eFormula (50) compound for H; R wherein³For-N (CH₂CH ₂OMe) ₂，R ^4aFor Me, R^4bFor H, R^4cFor Me, R^4dFor H, R^4eFormula (50) compound for H; R wherein³For-NHCH (Et) (CH₂OMe)，R ^4aFor Me, R^4bFor H, R^4cFor Me, R^4dFor H, R^4eFormula (50) compound for H; R wherein³For-NHCH (Et)₂，R ^4aFor Me, R^4bFor H, R^4cFor Me, R^4dFor H, R^4eFormula (50) compound for H; R wherein³For-OEt, R^4aFor Cl, R^4bFor H, R^4cFor Cl, R^4dFor H, R^4eFormula (50) compound for H; R wherein³For-N (Et)₂，R ^4aFor Me, R^4bFor H, R^4cFor Me, R^4dFor H, R^4eFormula (50) compound for H; R wherein³For-N (CH₂CN) ₂，R ^4aFor Me, R^4bFor H, R^4cFor Me, R^4dFor H, R^4eFormula (50) compound for H; R wherein³For-NHCH (Me) (CH₂OMe)，R ^4aFor Me, R^4bFor H, R^4cFor Me, R^4dFor H, R^4eFormula (50) compound for H; R wherein³For-OCH (Et) (CH₂OMe)，R ^4aFor Me, R^4bFor H, R^4cFor Me, R^4dFor H, R^4eFormula (50) compound for H; R wherein³For-N (n-Pr) (CH₂cPr)，R ^4aFor Me, R^4bFor H, R^4cFor Me, R^4dFor H, R^4eFormula (50) compound for H; R wherein³For-NHCH (Me) (CH₂N(Me) ₂)，R ^4aFor Me, R^4bFor H, R^4cFor Me, R^4dFor H, R^4eFormula (50) compound for H; R wherein³For-N (cPr) (CH₂CH ₂CN)，R ^4aFor Me, R^4bFor H, R^4cFor Me, R^4dFor H, R^4eFormula (50) compound for H; R wherein³For-N (n-Pr) (CH₂CH ₂CN)，R ^4aFor Me, R^4bFor H, R^4cFor Me, R^4dFor H, R^4eFormula (50) compound for H; R wherein³For-N (n-Bu) (CH₂CN)，R ^4aFor Me, R^4bFor H, R^4cFor Me, R^4dFor H, R^4eFormula (50) compound for H; R wherein³For-NHCH (Et) (CH₂OMe)，R ^4aFor Me, R^4bFor H, R^4cFor Me, R^4dFor H, R^4eFormula (50) compound for Me; R wherein³For-NHCH (Et)₂，R ^4aFor Me, R^4bFor H, R^4cFor Me, R^4dFor H, R^4eFormula (50) compound for Me; R wherein³For-N (CH₂CH ₂OMe) ₂，R ^4aFor Me, R^4bFor H, R^4cFor Me, R^4dFor H, R^4eFormula (50) compound for Me; R wherein³For-NHCH (CH₂OMe) ₂，R ^4aFor Br, R^4bFor H, R^4cFor OMe, R^4dFor H, R^4eFormula (50) compound for H; R wherein³For-NHCH (Et) (CH₂OMe)，R ^4aFor Br, R^4bFor H, R^4cFor OMe, R^4dFor H, R^4eFormula (50) compound for H; R wherein³For-N (Et)₂，R ^4aFor Me, R^4bFor H, R^4cFor Me, R^4dFor H, R^4eFormula (50) compound for Me; R wherein³For-NHCH (CH₂OEt) ₂，R ^4aFor Me, R^4bFor H, R^4cFor Me, R^4dFor H, R^4eFormula (50) compound for Me; R wherein³For-NHCH (CH₂CH ₂OMe)(CH ₂OMe) ₂，R ^4aFor Me, R^4bFor H, R^4cFor Me, R^4dFor H, R^4eFormula (50) compound for Me; R wherein³For morpholino, R^4aFor Me, R^4bFor H, R^4cFor Me, R^4dFor H, R^4eFormula (50) compound for H; R wherein³For-N (CH₂CH ₂OMe) ₂，R ^4aFor Br, R^4bFor H, R^4cFor OMe, R^4dFor H, R^4eFormula (50) compound for H; R wherein³For-NHCH (Et)₂，R ^4aFor Br, R^4bFor H, R^4cFor OMe, R^4dFor H, R^4eFormula (50) compound for H; R wherein³For-N (Et)₂，R ^4aFor Br, R^4bFor H, R^4cFor OMe, R^4dFor H, R^4eFormula (50) compound for H; R wherein³For-NH (c-Pr), R^4aFor Me, R^4bFor H, R^4cFor Me, R^4dFor H, R^4eFormula (50) compound for H; R wherein³For-NHCH (CH₂OMe) ₂，R ^4aFor CN, R^4bFor H, R^4cFor OMe, R^4dFor H, R^4eFormula (50) compound for H; R wherein³For-N (c-Pr) (CH₂CH ₂CN)，R ^4aFor Me, R^4bFor H, R^4cFor Me, R^4dFor H, R^4eFormula (50) compound for Me; R wherein³For-NCH (CH₂OMe) ₂，R ^4aFor Me, R^4bFor H, R^4cFor Br, R^4dFor H, R^4eFormula (50) compound for H; R wherein³For-NHCH (CH₂OMe)(CH ₂CH ₂OMe)，R ^4aFor Me, R^4bFor H, R^4cFor Br, R^4dFor H, R^4eFormula (50) compound for H; R wherein³For-NHCH (CH₂OMe) ₂，R ^4aFor Me, R^4bFor H, R^4cFor OMe, R^4dFor Me, R^4eFormula (50) compound for H; R wherein³For-N (CH₂CH ₂OMe) ₂，R ^4aFor Me, R^4bFor H, R^4cFor OMe, R^4dFor Me, R^4eFormula (50) compound for H; R wherein³For-NHCH (Et)₂，R ^4aFor Me, R^4bFor H, R^4cFor OMe, R^4dFor Me, R^4eFormula (50) compound for H; R wherein³For-N (Et)₂，R ^4aFor Me, R^4bFor H, R^4cFor OMe, R^4dFor Me, R^4eFormula (50) compound for H; R wherein³For-NHCH (CH₂OMe) ₂，R ^4aFor Cl, R^4bFor H, R^4cFor Me, R^4dFor H, R^4eFormula (50) compound for H; R wherein³For-NHCH (Et) (CH₂OMe)，R ^4aFor Cl, R^4bFor H, R^4cFor Me, R^4dFor H, R^4eFormula (50) compound for H; R wherein³For-N (CH₂CH ₂OMe) ₂，R ^4aFor Cl, R^4bFor H, R^4cFor Me, R^4dFor H, R^4eFormula (50) compound for H; R wherein³For-NHCH (CH₂OMe)(CH ₂CH ₂OMe)，R ^4aFor Cl, R^4bFor H, R^4cFor Me, R^4dFor H, R^4eFormula (50) compound for H; R wherein³For-N (c-Pr) (CH₂CH ₂CN)，R ^4aFor Me, R^4bFor H, R^4cFor OMe, R^4dFor Me, R^4eFormula (50) compound for H; R wherein³For-N (c-Pr) (CH₂CH ₂CN)，R ^4aFor Cl, R^4bFor H, R^4cFor Cl, R^4dFor H, R^4eFormula (50) compound for H; R wherein³For (S)-NHCH (CH₂OMe)(CH ₂CH ₂OMe)，R ^4aFor Cl, R^4bFor H, R^4cFor Cl, R^4dFor H, R^4eFormula (50) compound for H; R wherein³For-NHCH (CH₂OMe)(CH ₂CH ₂OMe)，R ^4aFor Cl, R^4bFor H, R^4cFor Cl, R^4dFor H, R^4eFormula (50) compound for H; R wherein³For-NHCH (Et)₂，R ^4aFor Me, R^4bFor H, R^4cFor Br, R^4dFor H, R^4eFormula (50) compound for H; R wherein³For-N (CH₂CH ₂OMe) ₂，R ^4aFor Me, R^4bFor H, R^4cFor Br, R^4dFor H, R^4eFormula (50) compound for H; R wherein³For-NH (CH₂OMe)(CH ₂-iPr)，R ^4aFor Me, R^4bFor H, R^4cFor Me, R^4dFor H, R^4eFormula (50) compound for H; R wherein³For-N (CH₂CH ₂OMe) ₂，R ^4aFor Me, R^4bFor H, R^4cFor H, R^4dFor H, R^4eFormula (50) compound for H; R wherein³For-N (CH₂CH ₂OMe) ₂，R ^4aFor Me, R^4bFor H, R^4cFor NMe₂，R ^4dFor H, R^4eFormula (50) compound for H; R wherein³For-NHCH (CH₂OMe)(n-Pr)，R ^4aFor Me, R^4bFor H, R^4cFor Me, R^4dFor H, R^4eFormula (50) compound for H; R wherein³For-NHCH (CH₂OEt)(Et)，R ^4aFor Me, R^4bFor H, R^4cFor Me, R^4dFor H, R^4eFormula (50) compound for H; R wherein³For-NHCH (CH₂OMe)(CH ₂CH ₂OMe)，R ^4aFor Me, R^4bFor H, R^4cFor NMe₂，R ^4dFor H, R^4eFormula (50) compound for H; R wherein³For-N (Et)₂，R ^4aFor Me, R^4bFor H, R^4cFor Cl, R^4dFor H, R^4eFormula (50) compound for H; R wherein³For-NHCH (Et)₂，R ^4aFor Me, R^4bFor H, R^4cFor Cl, R^4dFor H, R^4eFormula (50) compound for H; R wherein³For-N (CH₂CH ₂OMe) ₂，R ^4aFor Me, R^4bFor H, R^4cFor Cl, R^4dFor H, R^4eFormula (50) compound for H; R wherein³For-NHCH (CH₂OMe) ₂，R ^4aFor Me, R^4bFor H, R^4cFor Cl, R^4dFor H, R^4eFormula (50) compound for H; R wherein³For-N (Et)₂，R ^4aFor Me, R^4bFor H, R^4cFor Br, R^4dFor H, R^4eFormula (50) compound for H; R wherein³For-N (Et)₂，R ^4aFor Cl, R^4bFor H, R^4cFor Me, R^4dFor H, R^4eFormula (50) compound for H; R wherein³For-NHCH (Et)₂，R ^4aFor Cl, R^4bFor H, R^4cFor Me, R^4dFor H, R^4eFormula (50) compound for H; R wherein³For-NHCH (Et)₂，R ^4aFor Me, R^4bFor H, R^4cFor NMe₂， R ^4dFor H, R^4eFormula (50) compound for H; R wherein³For (S)-NHCH (CH₂OMe)(CH ₂CH ₂OMe)，R ^4aFor Me, R^4bFor H, R^4cFor Me, R^4dFor H, R^4eFormula (50) compound for H; R wherein³For-NHCH (CH₂OMe)(CH ₂CH ₂OMe)，R ^4aFor Me, R^4bFor H, R^4cFor Me, R^4dFor H, R^4eFormula (50) compound for H; R wherein³For (S)-NHCH (CH₂OMe)(CH ₂CH ₂OMe)，R ^4aFor Me, R^4bFor H, R^4cFor Cl, R^4dFor H, R^4cFormula (50) compound for H; R wherein³For-NHCH (CH₂OMe)(CH ₂CH ₂OMe)，R ^4aFor Me, R^4bFor H, R^4cFor Cl, R^4dFor H, R^4eFormula (50) compound for H; R wherein³For-N (c-Pr) (CH₂CH ₂CN)，R ^4aFor Me, R^4bFor H, R^4cFor Cl, R^4dFor H, R^4eFormula (50) compound for H; R wherein³For-NH (Et) (CH₂CN)，R ^4aFor Me, R^4bFor H, R^4cFor Cl, R^4dFor H, R^4eFormula (50) compound for H; R wherein³For-N (Et)₂，R ^4aFor Me, R^4bFor Me, R^4cFor OMe, R^4dFor H, R^4eFormula (50) compound for H; R wherein³For-N (CH₂CH ₂OMe)(CH ₂CH ₂OH)，R ^4aFor Cl, R^4bFor H, R^4cFor Cl, R^4dFor H, R^4eFormula (50) compound for H; R wherein³For-N (CH₂CH ₂OMe) ₂，R ^4aFor Me, R^4bFor Me, R^4cFor OMe, R^4dFor H, R^4eFormula (50) compound for H; R wherein³For-NHCH (Et)₂，R ^4aFor Me, R^4bFor Me, R^4cFor OMe, R^4dFor H, R^4eFormula (50) compound for H; R wherein³For-N (CH₂c-Pr)(n-Pr)，R ^4aFor Me, R^4bFor H, R^4cFor Cl, R^4dFor H, R^4eFormula (50) compound for H; R wherein³For-N (c-Pr) (CH₂CH ₂CN)，R ^4aFor Me, R^4bFor Me, R^4cFor OMe, R^4dFor H, R^4eFormula (50) compound for H; R wherein³For-NHCH (Et)₂，R ^4aFor Cl, R^4bFor H, R^4cFor OMe, R^4dFor H, R^4eFormula (50) compound for H; R wherein³For-N (Et)₂，R ^4aFor Cl, R^4bFor H, R^4cFor OMe, R^4dFor H, R^4eFormula (50) compound for H; R wherein³For-N (CH₂CH ₂OMe) ₂，R ^4aFor Cl, R^4bFor H, R^4cFor OMe, R^4dFor H, R^4eFormula (50) compound for H; R wherein³For-NHCH (Et) (CH₂OMe)，R ^4aFor Cl, R^4bFor H, R^4cFor OMe, R^4dFor H, R^4eFormula (50) compound for H; R wherein³For-N (Et)₂，R ^4aFor Cl, R^4bFor H, R^4cFor CN, R^4dFor H, R^4eFormula (50) compound for H; R wherein³For-N (c-Pr) (CH₂CH ₂CN)，R ^4aFor Cl, R^4bFor H, R^4cFor OMe, R^4dFor H, R^4eFormula (50) compound for H; R wherein³For-NHCH (CH₂OH) ₂，R ^4aFor Cl, R^4bFor H, R^4cFor Cl, R^4dFor H, R^4eFormula (50) compound for H; R wherein³For-N (CH₂CH ₂OMe) ₂，R ^4aFor Me, R^4bFor H, R^4cFor OMe, R^4dFor H, R^4eFormula (50) compound for H.

[39] more particularly preferred compound is 4-(two-(2-methoxy ethyl) amino)-2,7-dimethyl-8-(2-methyl-4-p-methoxy-phenyl)-[1,5-a]-pyrazolo-1,3, the mixture of 5-triazine and its isomer, steric isomer or steric isomer with and pharmacy acceptable salt or prodrug form.

[40] more particularly preferred compound is 4-(two-(2-methoxy ethyl) amino)-2,7-dimethyl-8-(2,5-dimethyl-4-p-methoxy-phenyl)-[1,5-a]-pyrazolo-1,3, the mixture of 5-triazine and its isomer, steric isomer or steric isomer with and pharmacy acceptable salt or prodrug.

[41] the preferred compound of the present invention be such compound and its isomer, steric isomer or steric isomer mixture with and pharmacy acceptable salt or prodrug form, wherein A is CR.

[42] the preferred compound of the present invention mixture that also comprises all cpds and its isomer, steric isomer or steric isomer with and pharmacy acceptable salt or prodrug form.

[43] the preferred compound of the present invention mixture that also comprises such compound and its isomer, steric isomer or steric isomer with and pharmacy acceptable salt or prodrug form, wherein Ar is phenyl, pyridyl or 2, the 3-dihydro benzo furyl, each Ar is optional by 1-4 R ⁴Substituting group replaces.

[44] the preferred compound of the present invention mixture that also comprises such compound and its isomer, steric isomer or steric isomer with and pharmacy acceptable salt or prodrug form, wherein R ³Be NR ^6aR ^7aOr OR ⁷

[45] the preferred compound of the present invention mixture that also comprises such compound and its isomer, steric isomer or steric isomer with and pharmacy acceptable salt or prodrug form, wherein Ar is phenyl, pyridyl or 2, the 3-dihydro benzo furyl, each Ar is optional by 1-4 R ⁴Substituting group replaces, and R ³Be NR ^6aR ^7aOr OR ⁷

[46] the preferred compound of the present invention mixture that also comprises such compound and its isomer, steric isomer or steric isomer with and pharmacy acceptable salt or prodrug form, wherein Z is CR ²

[47] the preferred compound of the present invention mixture that also comprises such compound and its isomer, steric isomer or steric isomer with and pharmacy acceptable salt or prodrug, wherein Ar is phenyl, pyridyl or 2, the 3-dihydro benzo furyl, each Ar is optional by 1-4 R ⁴Substituting group replaces.

[48] the preferred compound of the present invention mixture that also comprises such compound and its isomer, steric isomer or steric isomer with and pharmacy acceptable salt or prodrug form, wherein R ³Be NR ^6aR ^7aOr OR ⁷

[49] the preferred compound of the present invention mixture that also comprises such compound and its isomer, steric isomer or steric isomer with and pharmacy acceptable salt or prodrug form, wherein Ar is phenyl, pyridyl or 2, the 3-dihydro benzo furyl, each Ar is optional by 1-4 R ⁴Substituting group replaces, and R ³Be NR ^6aR ^7aOr OR ⁷

[50] the preferred compound of the present invention mixture that also comprises such compound and its isomer, steric isomer or steric isomer with and pharmacy acceptable salt or prodrug form, wherein R ^6aAnd R ^7aIndependent is H or C ₁-C ₁₀Alkyl, each C ₁-C ₁₀Alkyl is optional independently to be selected from following substituting group replacement: C by 1-3 ₁-C ₆Alkyl, C ₃-C ₆Cycloalkyl, halogen, C ₁-C ₄Haloalkyl, cyano group, OR ¹⁵, SH, S (O) _nR ¹³, COR ¹⁵, CO ₂R ¹⁵, OC (O) R ¹³, NR ⁸COR ¹⁵, N (COR ¹⁵) ₂, R ⁸CONR ¹⁶R ¹⁵, NR ⁸CO ₂R ¹³, NR ¹⁶R ¹⁵, CONR ¹⁶R ¹⁵, aryl, heteroaryl or heterocyclic radical.

[51] the preferred compound of the present invention mixture that also comprises such compound and its isomer, steric isomer or steric isomer with and pharmacy acceptable salt or prodrug, wherein

-R ³Be NR ^6aR ^7aOr OR ⁷And

[52] the preferred compound of the present invention mixture that also comprises such compound and its isomer, steric isomer or steric isomer with and pharmacy acceptable salt or prodrug form, wherein R ^6aAnd R ^7aIndependent is H or C ₁-C ₁₀Alkyl, each C ₁-C ₁₀Alkyl is optional independently to be selected from following substituting group replacement: C by 1-3 ₁-C ₆Alkyl, C ₃-C ₆Cycloalkyl, halogen, C ₁-C ₄Haloalkyl, cyano group, OR ¹⁵, SH, S (O) _nR ¹³, COR ¹⁵, CO ₂R ¹⁵, OC (O) R ¹³, NR ⁸COR ¹⁵, N (COR ¹⁵) ₂, R ⁸CONR ¹⁶R ¹⁵, NR ⁸CO ₂R ¹³, NR ¹⁶R ¹⁵, CONR ¹⁶R ¹⁵, aryl, heteroaryl or heterocyclic radical.

[53] the particularly preferred compound of the present invention be formula (51) compound and its isomer, steric isomer or steric isomer mixture with and pharmacy acceptable salt or prodrug:

Formula (51)

They are selected from: R wherein³For-NHCH (n-Pr)₂，R ^4aFor Me, R^4bFor H, R^4cFor Me, R^4dFor H, R^4eFormula (51) compound for H; R wherein³For-NHCH (CH₂OMe) ₂，R ^4aFor Me, R^4bFor H, R^4cFor Me, R^4dFor H, R^4eFormula (51) compound for H; R wherein³For-N (CH₂CH ₂OMe) ₂，R ^4aFor Me, R^4bFor H, R^4cFor Me, R^4dFor H, R^4eFormula (51) compound for H; R wherein³For-N (c-Pr) (CH₂CH ₂CN)，R ^4aFor Me, R^4bFor H, R^4cFor Me, R^4dFor H, R^4cFormula (51) compound for H; R wherein³For-N (CH₂CH ₂OMe) ₂，R ^4aFor Cl, R^4bFor H, R^4cFor Me, R^4dFor H, R^4cFormula (51) compound for H; R wherein³For-NHCH (CH₂OMe) ₂，R ^4aFor Cl, R^4bFor H, R^4cFor Me, R^4dFor H, R^4eFormula (51) compound for H; R wherein³For-NHCH (Et)₂，R ^4aFor Cl, R^4bFor H, R^4cFor Me, R^4dFor H, R^4eFormula (51) compound for H; R wherein³For-N (Et)₂，R ^4aFor Me, R^4bFor H, R^4cFor Me, R^4dFor H, R^4eFormula (51) compound for H; R wherein³For-N (n-Pr) (CH₂CH ₂CN)，R ^4aFor Me, R^4bFor H, R^4cFor Me, R^4dFor H, R^4eFormula (51) compound for H; R wherein³For-N (n-Bu) (CH₂CH ₂CN)，R ^4aFor Me, R^4bFor H, R^4cFor Me, R^4dFor H, R^4eFormula (51) compound for H; R wherein³For-NHCH (n-Pr) (CH₂OMe)，R ^4aFor Me, R^4bFor H, R^4cFor Me, R^4dFor H, R^4eFormula (51) compound for H; R wherein³For-NHCH (Et)₂，R ^4aFor Me, R^4bFor H, R^4cFor OMe, R^4dFor H, R^4eFormula (51) compound for H; R wherein³For-NHCH (CH₂OMe) ₂，R ^4aFor Me, R^4bFor H, R^4cFor OMe, R^4dFor H, R^4eFormula (51) compound for H; R wherein³For (S)-NH (CH₂CH ₂OMe)CH ₂OMe，R ^4aFor Me, R^4bFor H, R^4cFor Me, R^4dFor H, R^4eFormula (51) compound for H; R wherein³For-NH (CH₂CH ₂OMe)CH ₂OMe，R ^4aFor Me, R^4bFor H, R^4cFor Me, R^4dFor H, R^4eFormula (51) compound for H; R wherein³For-N (CH₂CH ₂OMe) ₂，R ^4aFor Me, R^4bFor H, R^4cFor Cl, R^4dFor H, R^4eFormula (51) compound for H; R wherein³For-NH (Et), R^4aFor Me, R^4bFor H, R^4cFor Me, R^4dFor H, R^4eFormula (51) compound for H; R wherein³For-NHCH (n-Pr)₂，R ^4aFor Me, R^4bFor H, R^4cFor Cl, R^4dFor H, R^4eFormula (51) compound for H; R wherein³For-NHCH (CH₂OMe) ₂，R ^4aFor Me, R^4bFor H, R^4cFor Cl, R^4dFor H, R^4eFormula (51) compound for H; R wherein³For (S)-NH (CH₂CH ₂OMe)CH ₂OMe，R ^4aFor Me, R^4bFor H, R^4cFor Cl, R^4dFor H, R^4eFormula (51) compound for H; R wherein³For-NH (CH₂CH ₂OMe)CH ₂OMe，R ^4aFor Me, R^4bFor H, R^4cFor Cl, R^4dFor H, R^4eFormula (51) compound for H; R wherein³For-N (n-Pr) (CH₂CH ₂CN)，R ^4aFor Me, R^4bFor H, R^4cFor OMe, R^4dFor H, R^4eFormula (51) compound for H; R wherein³For-N (Et)₂，R ^4aFor Me, R^4bFor H, R^4cFor OMe, R^4dFor H, R^4eFormula (51) compound for H; R wherein³For (S)-NH (CH₂CH ₂OMe)CH ₂OMe，R ^4aFor Cl, R^4bFor H, R^4cFor Me, R^4dFor H, R^4eFormula (51) compound for H; R wherein³For-NH (CH₂CH ₂OMe)CH ₂OMe，R ^4aFor Cl, R^4bFor H, R^4cFor Me, R^4dFor H, R^4eFormula (51) compound for H; R wherein³For-N (Et)₂，R ^4aFor Cl, R^4bFor H, R^4cFor Me, R^4dFor H, R^4eFormula (51) compound for H; R wherein³For-N (c-Pr) (CH₂CH ₂CN)，R ^4aFor Me, R^4bFor H, R^4cFor OMe, R^4dFor H, R^4eFormula (51) compound for H; R wherein³For-N (c-Pr) (CH₂CH ₂CN)，R ^4aFor Cl, R^4bFor H, R^4cFor Me, R^4dFor H, R^4eFormula (51) compound for H; R wherein³For-NHCH (n-Pr) (CH₂OMe)，R ^4aFor Me, R^4bFor H, R^4cFor OMe, R^4dFor H, R^4eFormula (51) compound for H; R wherein³For-NHCH (n-Pr) (CH₂OMe)，R ^4aFor Cl, R^4bFor H, R^4cFor Me, R^4dFor H, R^4eFormula (51) compound for H; R wherein³For-NHCH (Et)₂，R ^4aFor Br, R^4bFor H, R^4cFor OMe, R^4dFor OMe, R^4eFormula (51) compound for H; R wherein³For-NHCH (Et)₂，R ^4aFor Br, R^4bFor H, R^4cFor OMe, R^4dFor H, R^4cFormula (51) compound for H; R wherein³For-N (CH₂CH ₂OMe) ₂，R ^4aFor Br, R^4bFor H, R^4cFor OMe, R^4dFor H, R^4eFormula (51) compound for H; R wherein³For-NHCH (CH₂OMe) ₂，R ^4aFor Br, R^4bFor H, R^4cFor OMe, R^4dFor H, R^4eFormula (51) compound for H; R wherein³For-N (Et)₂，R ^4aFor Me, R^4bFor H, R^4cFor Cl, R^4dFor H, R^4eFormula (51) compound for H; R wherein³For-N (Et)₂，R ^4aFor Cl, R^4bFor H, R^4cFor OMe, R^4dFor OMe, R^4eFormula (51) compound for H; R wherein³For-NHCH (Et)₂，R ^4aFor Cl, R^4bFor H, R^4cFor OMe, R^4dFor OMe, R^4cFormula (51) compound for H; R wherein³For-N (CH₂CH ₂OMe) ₂，R ^4aFor Cl, R^4bFor H, R^4cFor Cl, R^4dFor H, R^4eFormula (51) compound for H; R wherein³For-NHCH (CH₂OMe) ₂，R ^4aFor Cl, R^4bFor H, R^4cFor Cl, R^4dFor H, R^4eFormula (51) compound for H; R wherein³For-N (Pr) (CH₂CH ₂CN)，R ^4aFor Cl, R^4bFor H, R^4cFor Cl, R^4dFor H, R^4eFormula (51) compound for H; R wherein³For-N (Bu) (Et), R^4aFor Cl, R^4bFor H, R^4cFor Cl, R^4dFor H, R^4eFormula (51) compound for H; R wherein³For-NHCH (Et) CH₂OMe，R ^4aFor Cl, R^4bFor H, R^4cFor Cl, R^4dFor H, R^4eFormula (51) compound for H; R wherein³For-NHCH (Et)₂，R ^4aFor Cl, R^4bFor H, R^4cFor Cl, R^4dFor H, R^4eFormula (51) compound for H; R wherein³For-NHCH (Et)₂，R ^4aFor Me, R^4bFor H, R^4cFor Me, R^4dFor H, R^4eFormula (51) compound for H; R wherein³For-NHCH (Et)₂，R ^4aFor Cl, R^4bFor H, R^4cFor Me, R^4dFor H, R^4eFormula (51) compound for H; R wherein³For-NHCH (Et)₂，R ^4aFor Me, R^4bFor H, R^4cFor Cl, R^4dFor H, R^4eFormula (51) compound for H; R wherein³For-NEt₂，R ^4aFor Me, R^4bFor H, R^4cFor OMe, R^4dFor H, R^4eFormula (51) compound for H; R wherein³For-N (Pr) (CH₂CH ₂CN)，R ^4aFor Me, R^4bFor H, R^4cFor OMe, R^4dFor H, R^4eFormula (51) compound for H.

[54] more particularly preferred compound is 7-(3-penta amino)-2, the mixture of 5-dimethyl-3-(2-methyl-4-p-methoxy-phenyl)-[1,5-a]-pyrazolopyrimidine and its isomer, steric isomer or steric isomer with and pharmacy acceptable salt or prodrug form.

[55] more particularly preferred compound is 7-(diethylin)-2, the mixture of 5-dimethyl-3-(2-methyl-4-p-methoxy-phenyl)-[1,5-a] pyrazolopyrimidine and its isomer, steric isomer or steric isomer with and pharmacy acceptable salt or prodrug form.

[56] more particularly preferred compound is 7-(N-(3-cyano group propyl group)-N-third amino)-2,5-dimethyl-3-(2, the 4-3,5-dimethylphenyl)-[1,5-a] mixture of pyrazolopyrimidine and its isomer, steric isomer or steric isomer with and pharmacy acceptable salt or prodrug form.

The present invention also provides the medicinal compositions that contains formula (1) and (2) compound and pharmaceutically acceptable carrier.

Many compounds of the present invention have one or more asymmetric centers or plane.Except that specializing, the present invention includes all chiralitys (enantiomorph and diastereomer) and racemic form.Also can have the multiple geometrical isomer of alkene, the two keys of C=N etc. in the compound, all these type of desmotropes all comprise in the present invention.Can separate described compound with opticity or racemic form.The well known opticity form that how to prepare is for example synthesized by the fractionation of racemic form or by the opticity raw material.Except that specializing specific stereochemistry or isomeric forms, comprise all geometrical isomer forms of all chiralitys (enantiomorph and diastereomer) and racemic form and structure.

Term " alkyl " comprises having specific carbonatoms purpose side chain and straight chained alkyl.Common being abbreviated as of using: Me is methyl, and Et is an ethyl, and Pr is a propyl group, and Bu is a butyl.Prefix " n " expression straight chained alkyl.Prefix " c " representative ring alkyl.Prefix " (S) " expression S enantiomorph, prefix " (R) " expression R enantiomorph." alkenyl " comprises the hydrocarbon chain of straight or branched configuration, can have one or more unsaturated C-Cs, for example vinyl, propenyl etc. at any stable point on this chain." alkynyl " comprises the hydrocarbon chain of straight or branched configuration, can have one or more carbon-to-carbon triple bonds, for example ethynyl, proyl etc. at any stable point on this chain." haloalkyl " is intended to comprise side chain and the straight chained alkyl that has the particular carbon atom number, replaced by one or more halogen atoms; " alkoxyl group " representative is by the alkyl of the particular carbon atom number of oxo bridge connection; " cycloalkyl " be intended to comprise saturated cyclic group, comprises one, two or polycyclic system, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl etc." halo " or " halogen atom " comprises fluorine, chlorine, bromine and iodine.

Replace for the group that the one or more hydrogen on the specified atom are selected from the designated groups in this used term " replacement " meaning, its prerequisite is the common rate that is no more than specified atom, and should replacement produce stable compound.When substituting group is that ketone (promptly=O) time, has two hydrogen to be substituted on described atom so.

As long as the combination results stable compound of substituting group and/or replacement, then this combination is allowed to.The meaning of " stable compound " or " rock steady structure " is separated into the purity of useful degree and makes effective medicine with experience for enough stable from reaction mixture.

Term " suitable amino acid blocking group " refers to the known any group that is used to protect amine or hydroxy-acid group in the organic synthesis field.This type of amine protecting group group comprises that Greene and Wuts are at " Protective Groups in Organic Synthesis " (John Wiley﹠amp; Sons, NewYork (1991)) and those groups described in " The Peptides:Analysis, Syntheis, Biology, Vol.3, Academic Press, New York (1981) ", it is for referencial use to be incorporated herein its disclosed content.Can use any amine protecting group known in the art group.The example of amine protecting group group includes, but is not limited to: 1) for example formyl radical, trifluoroacetyl group, phthaloyl and ptoluene-sulfonyl of acyl group type; 2) for example benzyloxycarbonyl (Cbz) and the benzyloxycarbonyl, 1-(right-xenyl)-1-methyl ethoxy carbonyl and the 9-fluorenyl methoxy carbonyl (Fmoc) that replace of fragrant carbamic acid ester type; 3) for example tert-butoxycarbonyl (Boc), ethoxy carbonyl, di-isopropyl methoxycarbonyl and allyloxy carbonyl of aliphatic carbamate type; 4) for example cyclopentyloxy carbonyl and adamantyl oxygen base carbonyl of cycloalkyl amino manthanoate type; 5) for example trityl and benzyl of alkyl type; 6) trialkyl silane trimethyl silane for example; And 7) contain hydroxyl sulfenyl type for example thiophenyl carbonyl and dithio succinyl.

Term " pharmacy acceptable salt " comprises the acid or the alkali salt of formula (1) and (2) compound.The example of pharmacy acceptable salt includes, but is not limited to the alkaline residue for example mineral acid or the organic acid salt of amine; Acidic residues is the basic metal of carboxylic acid or organic salt etc. for example.

Suitable alkali that can be by making these compound free acids or alkali form and stoichiometric quantity or acid water or in organic solvent or mixture at both the pharmacy acceptable salt of prepared in reaction The compounds of this invention, described solvent generally is preferably non-aqueous media as ether, ethyl acetate, ethanol, Virahol or acetonitrile.Suitable salt is seen Remington ' s PharmaceuticalSciences (17 th ed., Mack Publishing Company, Easton, PA, 1985, the 1418 pages), and it is for referencial use to be incorporated herein its disclosed content.

Think the carrier that " prodrug " links to each other for any covalency, when giving mammalian subject with it, this type of medicine in vivo can release type (I) or (II) active parent drug.Can by the method for routine or in vivo the cracking modification group mode that becomes parent compound modify functional group in the described compound, and the preparation formula (I) and (II) prodrug of compound.Prodrug comprises such compound, and wherein hydroxyl, amine or sulfydryl link to each other with any group that can cracking when giving the mammalian subject medicine forms free hydroxyl, amino or sulfydryl respectively.The example of prodrug includes, but is not limited to formula (I) and (II) acetic ester, manthanoate and the benzoate derivatives etc. of the alkohol and amine functional group of compound.

Term " the treatment significant quantity " compound of the present invention refers to the amount of effective antagonism CRF abnormal level or treatment host affective disorder, anxiety disorder or dysthymia disorders.

Synthetic

According to the method shown in the flow process 1, can prepare segment bounds (1) compound with formula (7) compound intermediate:

Flow process 1

(7)Y＝O (8)

(1) A＝N

In the presence of alkali or alkali-free; exist or do not exist under the inert solvent; between-80 ℃ to 250 ℃ temperature of reaction; handle formula (7) compound (wherein Y is O) with halogenating agent or sulfonyl agent, obtain formula (8) product (wherein X is halogen, alkane sulfonyloxy, aryl-sulfonyl oxygen or haloalkane-sulfonyloxy).Halogenating agent includes, but is not limited to SOCl ₂, POCl ₃, PCl ₃, PCl ₅, POBr ₃, PBr ₃Or PBr ₅Sulfonyl agent includes, but is not limited to alkane sulfonic acid halide or acid anhydrides (for example methylsulfonyl chloride or methylsulfonic acid acid anhydride), aryl sulfonyl halide or acid anhydrides (for example right-tolylsulfonyl oxygen or acid anhydrides) or haloalkyl sulfonic acid halide or acid anhydrides (preferred trifluoromethanesulfanhydride anhydride).Alkali includes, but is not limited to alkalimetal hydride (preferred sodium hydride), alkali metal alcoholate (1-6 carbon atom) (particular methanol sodium or sodium ethylate), alkaline earth metal hydride, basic metal dialkyl group ammonification thing (preferred di-isopropyl lithamide), two (trialkylsilanyl) amides of basic metal (preferred two (TMS) ammonification sodium), trialkylamine (preferred N, N-two-sec.-propyl-N-ethamine or triethylamine) or aromatic amine (preferred pyridine).Inert solvent includes, but is not limited to low alkyl group nitrile (1-6 carbon atom, preferred acetonitrile), dialkyl ether (preferred ether), cyclic ethers (preferred tetrahydrofuran (THF) or 1, the 4-dioxane), N, N-dialkylformamide (preferred dimethyl formamide), N, the haloalkane (preferred methylene dichloride) of N-dialkyl acetamides (preferred N,N-DIMETHYLACETAMIDE), cyclic amide (preferred N-methylpyrrolidin-2-ketone), dialkyl sulphoxide (preferred dimethyl sulfoxide (DMSO)), aromatic hydrocarbon (preferred benzene or toluene) or 1-10 carbon atom and 1-10 halogen atom.Preferable reaction temperature is-20 ℃ to 100 ℃.

In the alkali existence or not,, between-80 ℃ to 250 ℃ temperature of reaction, can make formula (8) compound and formula R in the inert solvent existence or not ³H (R wherein ³Identical with above-mentioned definition, but R ³Be not SH, COR ⁷, CO ₂R ⁷, aryl or heteroaryl) compound reacting generating (1) compound.Alkali can include, but is not limited to alkalimetal hydride (preferred sodium hydride), alkali metal alcoholate (1-6 carbon atom) (particular methanol sodium or sodium ethylate), alkaline earth metal hydride, basic metal dialkyl group ammonification thing (preferred di-isopropyl lithamide), alkaline carbonate, alkali metal hydrocarbonate, two (trialkylsilanyl) amides of basic metal (preferred two (TMS) ammonification sodium), trialkylamine (preferred N, N-two-sec.-propyl-N-ethamine) or aromatic amine (preferred pyridine).Inert solvent includes, but is not limited to alkyl alcohol (1-8 carbon atom, particular methanol or ethanol), low alkyl group nitrile (1-6 carbon atom, preferred acetonitrile), dialkyl ether (preferred ether), cyclic ethers (preferred tetrahydrofuran (THF) or 1, the 4-dioxane), N, N-dialkylformamide (preferred dimethyl formamide), N, N-dialkyl acetamides (preferred N,N-DIMETHYLACETAMIDE), cyclic amide (preferred N-methylpyrrolidin-2-ketone), dialkyl sulphoxide (preferred dimethyl sulfoxide (DMSO)), the haloalkane (preferred methylene dichloride) of aromatic hydrocarbon (preferred benzene or toluene) or 1-10 carbon atom and 1-10 halogen atom.Preferable reaction temperature is 0 ℃ to 140 ℃.

Flow process 2 is described the method that formula (7) midbody compound (wherein Y is S) is converted into segment bounds (1) compound:

Flow process 2

In the alkali existence or not,, between-80 ℃ to 250 ℃ temperature of reaction, can use alkylating agent R in the inert solvent existence or not ¹³X (R wherein ¹³Identical with above-mentioned definition, but R ¹³Be not aryl or heteroaryl) processing formula (7) compound (wherein Y is S).Alkali can include, but is not limited to alkalimetal hydride (preferred sodium hydride), alkali metal alcoholate (1-6 carbon atom) (particular methanol sodium or sodium ethylate), alkaline earth metal hydride, basic metal dialkyl group ammonification thing (preferred di-isopropyl lithamide), alkaline carbonate, alkali metal hydroxide, two (trialkylsilanyl) amides of basic metal (preferred two (TMS) ammonification sodium), trialkylamine (preferred N, N-two-sec.-propyl-N-ethamine or triethylamine) or aromatic amine (preferred pyridine).Inert solvent includes, but is not limited to alkyl alcohol (1-8 carbon atom, particular methanol or ethanol), low alkyl group nitrile (1-6 carbon atom, preferred acetonitrile), dialkyl ether (preferred ether), cyclic ethers (preferred tetrahydrofuran (THF) or 1, the 4-dioxane), N, N-dialkylformamide (preferred dimethyl formamide), N, N-dialkyl acetamides (preferred N,N-DIMETHYLACETAMIDE), cyclic amide (preferred N-methylpyrrolidin-2-ketone), dialkyl sulphoxide (preferred dimethyl sulfoxide (DMSO)), the haloalkane (preferred methylene dichloride) of aromatic hydrocarbon (preferred benzene or toluene) or 1-10 carbon atom and 1-10 halogen atom.Preferable reaction temperature is-80 ℃ to 100 ℃.

Use then that above-mentioned flow process 1 is described to be converted into the same terms and the reagent of formula (1) compound with formula (8) compound, make formula (12) compound (R wherein ³Be SR ¹³Formula (1) compound) with formula R ³The reaction of H compound obtains formula (1) compound.Perhaps, in the presence of inert solvent, between-80 ℃ to 250 ℃ temperature, by with oxidizer treatment with formula (12) compound (R wherein ³Be SR ¹³Formula (1) compound) be oxidized to formula (13) compound (R wherein ³Be S (O) _nR ¹³, n is 1,2 formula (1) compound).Oxygenant comprises (but being not limited to) hydrogen peroxide, alkyl or aryl peracid (preferred acetic hydroperoxide or m-chloro-peroxybenzoic acid), diepoxide for example, oxone or sodium periodate.Inert solvent includes, but is not limited to the haloalkane (preferred methylene dichloride) or their mixture of alkane ketone (3-10 carbon atom, preferred acetone), water, alkyl alcohol (1-6 carbon atom), aromatic hydrocarbon (preferred benzene or toluene) or 1-10 carbon atom and 1-10 halogen atom.Oxygenant and choice of Solvent are well known to those skilled in the art (referring to Uemura, S., Oxidation of Sulfur, Selenium and Tellurium, in Comprehensive Organic Synthesis, Trost, B.M.ed., (Elmsford, NY:Pergamon Press, 1991), 7,762-769).Preferable reaction temperature is-20 ℃ to 100 ℃.Use then shown in the above-mentioned flow process (1) formula (8) compound to be converted into the used the same terms of formula (1) compound, make formula (13) compound (R wherein ³Be S (O) _nR ¹³, n is 1,2 formula (1) compound) and formula R ³The reaction of H compound obtains formula (1) compound.

According to the method shown in the flow process 3, can be by formula (7) compound (wherein Y is NH) preparation formula (1) compound, wherein R ³Can be-NR ⁸COR ⁷,-N (COR ⁷) ₂,-NR ⁸CONR ⁶R ⁷,-NR ⁸CO ₂R ¹³,-NR ⁶R ⁷,-NR ⁸SO ₂R ⁷:

Flow process 3

(7)Y＝NH (1)

A＝N；

R ³＝NR ⁶R ⁷，NR ⁸COR ⁷，

N(COR ⁷) ₂，NR ₈CONR ⁶R ⁷，

NR ₈CO ₂R ₁₃

Being in or be not in alkali exists down; in inert solvent, between-80 ℃ to 250 ℃ temperature of reaction, making Y wherein is formula (7) compound of NH and alkylating agent, sulfonyl agent or acylation reaction or order and their composite reaction; can obtain formula (1) compound, wherein R ³Can be-NR ⁸COR ⁷,-N (COR ⁷) ₂,-NR ⁸CONR ⁶R ⁷,-NR ⁸CO ₂R ¹³,-NR ⁶R ⁷,-NR ⁸SO ₂R ⁷Alkylating agent can include, but is not limited to C ₁-C ₁₀Alkyl-halogenide ,-tosylate ,-methanesulfonates or-triflate; C ₁-C ₁₀Haloalkyl (1-10 halogen atom)-halogenide ,-tosylate ,-methanesulfonates or-triflate; C ₂-C ₈Alkoxyalkyl-halogenide ,-tosylate ,-methanesulfonates or-triflate; C ₃-C ₆Cycloalkyl-halogenide ,-tosylate ,-methanesulfonates or-triflate; C ₄-C ₁₂Cycloalkylalkyl-halogenide ,-tosylate ,-methanesulfonates or-triflate; Aryl (C ₁-C ₄Alkyl)-halogenide ,-tosylate ,-methanesulfonates or-triflate; Heteroaryl (C ₁-C ₄Alkyl)-halogenide ,-tosylate ,-methanesulfonates or-triflate; Or heterocyclic radical (C ₁-C ₄Alkyl)-halogenide ,-tosylate ,-methanesulfonates or-triflate.Acylating agent includes, but is not limited to C ₁-C ₁₀Alkane carboxylic acid halides or acid anhydrides, has the C of 1-10 halogen atom ₁-C ₁₀Halogenated alkane carboxylic acid halides or acid anhydrides, C ₂-C ₈Alkoxyl group alkane carboxylic acid halides or acid anhydrides, C ₃-C ₆Cycloalkyl alkane carboxylic acid halides or acid anhydrides, C ₄-C ₁₂Cycloalkyl alkane carboxylic acid halides or acid anhydrides, fragrant carboxylic acid halides or acid anhydrides, aryl (C ₁-C ₄) alkane carboxylic acid halides or acid anhydrides, assorted fragrant carboxylic acid halides or acid anhydrides, heteroaryl (C ₁-C ₄) alkane carboxylic acid halides or acid anhydrides, heterocycle carboxylic acid halides or acid anhydrides or heterocyclic radical (C ₁-C ₄) alkane carboxylic acid halides or acid anhydrides.Sulfonyl agent includes, but is not limited to C ₁-C ₁₀Heteroaryl-alkylsulfonyl halides or acid anhydrides, has the C of 1-10 halogen atom ₁-C ₁₀Haloalkyl sulfonic acid halide or acid anhydrides, C ₂-C ₈Alkoxyalkyl sulfonic acid halide or acid anhydrides, C ₃-C ₆Naphthene sulfamide halogen or acid anhydrides, C ₄-C ₁₂Cycloalkylalkyl sulfonic acid halide or acid anhydrides, aryl sulfonyl halide or acid anhydrides, aryl (C ₁-C ₄Alkyl)-, heteroaryl sulfonic acid halide or acid anhydrides, heteroaryl (C ₁-C ₄Alkyl) sulfonic acid halide or acid anhydrides, heterocyclic radical sulfonic acid halide or acid anhydrides or heterocyclic radical (C ₁-C ₄Alkyl) sulfonic acid halide or acid anhydrides.Alkali can include, but is not limited to alkalimetal hydride (preferred sodium hydride), alkali metal alcoholate (1-6 carbon atom) (particular methanol sodium or sodium ethylate), alkaline earth metal hydride, basic metal dialkyl group ammonification thing (preferred di-isopropyl lithamide), alkaline carbonate, two (trialkylsilanyl) amides of basic metal (preferred two (TMS) ammonification sodium), trialkylamine (preferred N, N-two-sec.-propyl ethamine) or aromatic amine (preferred pyridine).Inert solvent includes, but is not limited to alkyl alcohol (1-8 carbon atom, particular methanol or ethanol), low alkyl group nitrile (1-6 carbon atom, preferred acetonitrile), dialkyl ether (preferred ether), cyclic ethers (preferred tetrahydrofuran (THF) or 1, the 4-dioxane), N, N-dialkylformamide (preferred dimethyl formamide), N, N-dialkyl acetamides (preferred N,N-DIMETHYLACETAMIDE), cyclic amide (preferred N-methylpyrrolidin-2-ketone), dialkyl sulphoxide (preferred dimethyl sulfoxide (DMSO)) or aromatic hydrocarbon (preferred benzene or toluene).Preferable reaction temperature is 0 ℃ to 100 ℃.

Flow process 4 is described and can be used for preparation formula (7) midbody compound (wherein Y is O, S, and Z is CR ²) method:

Flow process 4

(7)Y＝O，S；Z＝CR ²

In the presence of alkali, in inert solvent, between-78 ℃ to 200 ℃ temperature of reaction, make formula ArCH ₂CN compound and formula R ²COR ^b(R wherein ²Identical with above-mentioned definition, R ^bBeing halogen atom, cyano group, lower alkoxy (1-6 carbon atom) or lower alkane acyloxy (1-6 carbon atom)) compound reaction obtains formula (3) compound.Alkali can include, but is not limited to alkalimetal hydride (preferred sodium hydride), alkali metal alcoholate (1-6 carbon atom) (particular methanol sodium or sodium ethylate), alkaline earth metal hydride, basic metal dialkyl group ammonification thing (preferred di-isopropyl lithamide), alkaline carbonate, alkali metal hydroxide, two (trialkylsilanyl) amides of basic metal (preferred two (TMS) ammonification sodium), trialkylamine (preferred N, N-two-sec.-propyl-N-ethamine) or aromatic amine (preferred pyridine).Inert solvent includes, but is not limited to alkyl alcohol (1-8 carbon atom, particular methanol or ethanol), low alkyl group nitrile (1-6 carbon atom, preferred acetonitrile), water, dialkyl ether (preferred ether), cyclic ethers (preferred tetrahydrofuran (THF) or 1, the 4-dioxane), N, N-dialkylformamide (preferred dimethyl formamide), N, N-dialkyl acetamides (preferred N,N-DIMETHYLACETAMIDE), cyclic amide (preferred N-methylpyrrolidin-2-ketone), dialkyl sulphoxide (preferred dimethyl sulfoxide (DMSO)) or aromatic hydrocarbon (preferred benzene or toluene).Preferable reaction temperature is 0 ℃ to 100 ℃.

In the presence of inert solvent,, in preferred 70 ℃ to the 150 ℃ temperature ranges, handle formula (3) compound production (4) compound with hydrazine-hydrate in 0 ℃ to 200 ℃.Inert solvent includes, but is not limited to water, alkyl alcohol (1-8 carbon atom, particular methanol or ethanol), low alkyl group nitrile (1-6 carbon atom, preferred acetonitrile), cyclic ethers (preferred tetrahydrofuran (THF) or 1, the 4-dioxane), N, N-dialkylformamide (preferred dimethyl formamide), N, N-dialkyl acetamides (preferred N,N-DIMETHYLACETAMIDE), cyclic amide (preferred N-methylpyrrolidin-2-ketone), dialkyl sulphoxide (preferred dimethyl sulfoxide (DMSO)) or aromatic hydrocarbon (preferred benzene or toluene).Be in or be not in acid and exist down, in inert solvent, in 0 ℃ to 200 ℃ temperature range, can make formula (4) compound and formula (5) compound (R wherein ^cBe alkyl (1-6 carbon atom)) reacting generating (6) compound.Acid can include, but is not limited to paraffinic acid (preferred acetate), halogenated-chain acid (2-10 carbon atom, a 1-10 halogen atom, for example trifluoroacetic acid), the aryl sulfonic acid (preferably right-toluenesulphonic acids or Phenylsulfonic acid) of 2-10 carbon atom, alkylsulphonic acid (preferably methylsulfonic acid), hydrochloric acid, sulfuric acid or the phosphoric acid of a 1-10 carbon atom.Can use this type of acid of stoichiometric quantity or catalytic amount.Inert solvent includes, but is not limited to water, alkyl nitrile (1-6 carbon atom, preferred acetonitrile), for example dioxane or tetrahydrofuran (THF) of the alkyl alcohol (preferred alcohol) of the halohydrocarbon of a 1-6 carbon atom and 1-6 halogen atom (preferably methylene dichloride or chloroform), a 1-10 carbon atom, dialkyl ether (4-12 carbon atom, preferably ether or Di Iso Propyl Ether) or cyclic ethers.Preferred temperature range is a room temperature to 100 ℃.

Be in or be not in alkali and exist down, in inert solvent, between-50 ℃ to 200 ℃ temperature of reaction, with Compound C=Y (R ^d) ₂(wherein Y is O or S, R ^dBe halogen atom (preferred chlorine), alkoxyl group (1-4 carbon atom) or alkylthio (1-4 carbon atom)) handle, formula (6) compound can be converted into formula (7) midbody compound.Alkali can include, but is not limited to alkalimetal hydride (preferred sodium hydride), alkali metal alcoholate (1-6 carbon atom) (particular methanol sodium or sodium ethylate), alkaline carbonate, alkali metal hydroxide, trialkylamine (preferred N, N-two-sec.-propyl-N-ethamine or triethylamine) or aromatic amine (preferred pyridine).Inert solvent includes, but is not limited to alkyl alcohol (1-8 carbon atom, particular methanol or ethanol), low alkyl group nitrile (1-6 carbon atom, preferred acetonitrile), cyclic ethers (preferred tetrahydrofuran (THF) or 1, the 4-dioxane), N, N-dialkylformamide (preferred dimethyl formamide), N, N-dialkyl acetamides (preferred N,N-DIMETHYLACETAMIDE), cyclic amide (preferred N-methylpyrrolidin-2-ketone), dialkyl sulphoxide (preferred dimethyl sulfoxide (DMSO)) or aromatic hydrocarbon (preferred benzene or toluene).Preferable reaction temperature is 0 ℃ to 150 ℃.

According to method shown in the flow process 5, can synthesis type (7) midbody compound, wherein Z is N:

Flow process 5

(7)Y＝O，S；Z＝N

Be in or be not in alkali and exist down, in inert solvent, in 0 ℃ to 200 ℃ temperature range, make ArCH ₂CN compound and formula R ^qCH ₂N ₃Compound (R wherein ^qBe the optional phenyl that is replaced by H, alkyl (1-6 carbon atom) or alkoxyl group (1-6 carbon atom)) reacting generating (9) compound.Alkali can include, but is not limited to alkalimetal hydride (preferred sodium hydride), alkali metal alcoholate (1-6 carbon atom) (particular methanol sodium, sodium ethylate or potassium tert.-butoxide), alkaline earth metal hydride, basic metal dialkyl group ammonification thing (preferred di-isopropyl lithamide), alkaline carbonate, alkali metal hydroxide, two (trialkylsilanyl) amides of basic metal (preferred two (TMS) ammonification sodium), trialkylamine (preferred N, N-two-sec.-propyl-N-ethamine or triethylamine) or aromatic amine (preferred pyridine).Inert solvent includes, but is not limited to alkyl alcohol (1-8 carbon atom, particular methanol or ethanol), low alkyl group nitrile (1-6 carbon atom, preferred acetonitrile), dialkyl ether (preferred ether), cyclic ethers (preferred tetrahydrofuran (THF) or 1, the 4-dioxane), N, N-dialkylformamide (preferred dimethyl formamide), N, N-dialkyl acetamides (preferred N,N-DIMETHYLACETAMIDE), cyclic amide (preferred N-methylpyrrolidin-2-ketone), dialkyl sulphoxide (preferred dimethyl sulfoxide (DMSO)) or aromatic hydrocarbon (preferred benzene or toluene).Preferable reaction temperature is a room temperature to 100 ℃.

In inert solvent, between-100 ℃ to 100 ℃ temperature, can handle formula (9) compound with reductive agent and obtain formula (10) product.Reductive agent includes, but is not limited to (a) hydrogen and noble metal catalyst, for example palladium charcoal, PtO ₂, platinum charcoal, rhodium-aluminum oxide or Raney nickel combination, (b) basic metal (preferred sodium) and the combination of liquefied ammonia or (c) ceric ammonium nitrate.Inert solvent includes, but is not limited to alkyl alcohol (1-8 carbon atom, particular methanol or ethanol), low alkyl group nitrile (1-6 carbon atom, preferred acetonitrile), water, dialkyl ether (preferred ether), cyclic ethers (preferred tetrahydrofuran (THF) or 1, the 4-dioxane), N, N-dialkylformamide (preferred dimethyl formamide), N, N-dialkyl acetamides (preferred N,N-DIMETHYLACETAMIDE), cyclic amide (preferred N-methylpyrrolidin-2-ketone), dialkyl sulphoxide (preferred dimethyl sulfoxide (DMSO)) or aromatic hydrocarbon (preferred benzene or toluene).Preferable reaction temperature is-50 ℃ to 60 ℃.Then, use formula (4) compound is converted into formula (7) compound (wherein Z is CR shown in the flow process 4 ²) agents useful for same and reaction conditions, through formula (11) intermediate formula (9) compound is converted into formula (7) compound (wherein Z is N).

Shown in flow process 6, also can be by formula (7) compound (wherein Y is O, S, and Z is identical with above-mentioned definition) preparation formula (1) compound:

Flow process 6

(7)Y＝O，S；Z＝N，CR ² (1)A＝N

In the presence of dewatering agent, in inert solvent, in 0 ℃ to 250 ℃ range of reaction temperature, can make formula (7) compound and formula R ³The reaction of H compound.Dewatering agent includes, but is not limited to P ₂O ₅, molecular sieve or inorganic or organic acid.Acid can include, but is not limited to paraffinic acid (preferred acetate), the aryl sulfonic acid (preferably right-toluenesulphonic acids or Phenylsulfonic acid) of 2-10 carbon atom, alkylsulphonic acid (preferably methylsulfonic acid), hydrochloric acid, sulfuric acid or the phosphoric acid of a 1-10 carbon atom.Inert solvent includes, but is not limited to alkyl alcohol (1-8 carbon atom, particular methanol or ethanol), low alkyl group nitrile (1-6 carbon atom, preferred acetonitrile), dialkyl ether (preferred glyme or diglyme), cyclic ethers (preferred tetrahydrofuran (THF) or 1, the 4-dioxane), N, N-dialkylformamide (preferred dimethyl formamide), N, N-dialkyl acetamides (preferred N,N-DIMETHYLACETAMIDE), cyclic amide (preferred N-methylpyrrolidin-2-ketone), dialkyl sulphoxide (preferred dimethyl sulfoxide (DMSO)), the halohydrocarbon (preferably chloroform) of aromatic hydrocarbon (preferred benzene or toluene) or 1-10 carbon atom and 1-10 halogen atom.Preferred temperature of reaction is a room temperature to 150 ℃.

According to the method shown in the flow process 7, also can prepare segment bounds (1) compound (wherein A is N):

Flow process 7

Be in or be not in acid and exist down, in inert solvent, in 0 ℃ to 250 ℃ range of reaction temperature, can make formula (14) midbody compound (wherein Z is identical with above-mentioned definition) and formula R ³C (OR ^e) ₃(R wherein ^eCan be alkyl (1-6 carbon atom)) the compound reaction.Acid can include, but is not limited to paraffinic acid (preferred acetate), the aryl sulfonic acid (preferably right-toluenesulphonic acids or Phenylsulfonic acid) of 2-10 carbon atom, alkylsulphonic acid (preferably methylsulfonic acid), hydrochloric acid, sulfuric acid or the phosphoric acid of a 1-10 carbon atom.Can use this type of acid of stoichiometric quantity or catalytic amount.Inert solvent includes, but is not limited to low alkyl group nitrile (1-6 carbon atom, preferred acetonitrile), dialkyl ether (preferred ether), cyclic ethers (preferred tetrahydrofuran (THF) or 1, the 4-dioxane), N, N-dialkylformamide (preferred dimethyl formamide), N, the halohydrocarbon (preferably methylene dichloride) of N-dialkyl acetamides (preferred N,N-DIMETHYLACETAMIDE), cyclic amide (preferred N-methylpyrrolidin-2-ketone), dialkyl sulphoxide (preferred dimethyl sulfoxide (DMSO)), aromatic hydrocarbon (preferred benzene or toluene) or 1-10 carbon atom and 1-10 halogen atom.Preferred temperature of reaction is 50 ℃ to 150 ℃.

According to the reaction shown in the flow process 8, also can synthesis type (7) midbody compound:

Flow process 8

Be in or be not in organo-metallic catalyst and exist down, alkali exist or not in the presence of, in inert solvent, in-100 ℃ to 200 ℃ temperature ranges, (wherein Y is OH, SH, NR can to make formula (15) compound ⁶R ⁷Z is identical with above-mentioned definition, and X is Br, Cl, I, O ₃SCF ₃Or B (OR " ") ₂, and R " " be H or alkyl (1-6 carbon atom)) (wherein M is halogen atom, basic metal, ZnCl, ZnBr, ZnI, MgBr, MgCl, MgI, CeCl with formula ArM ₂, CeBr ₂Or copper halide) compound reaction.Those skilled in the art will recognize that reagent A rM can produce on the spot.Organo-metallic catalyst includes, but is not limited to palladium phosphine composition (Pd (PPh for example ₃) ₄), palladium halogenide or alkanoate (PdCl for example ₂(PPh ₃) ₂Or Pd (OAc) ₂) or nickel complex (NiCl for example ₂(PPh ₃) ₂).Alkali can include, but is not limited to alkaline carbonate or trialkylamine (preferred N, N-two-sec.-propyl-N-ethamine or triethylamine).Inert solvent includes, but is not limited to dialkyl ether (preferred ether), cyclic ethers (preferred tetrahydrofuran (THF) or 1, the 4-dioxane), N, N-dialkylformamide (preferred dimethyl formamide), N, N-dialkyl acetamides (preferred N,N-DIMETHYLACETAMIDE), cyclic amide (preferred N-methylpyrrolidin-2-ketone), dialkyl sulphoxide (preferred dimethyl sulfoxide (DMSO)), aromatic hydrocarbon (preferred benzene or toluene) or water.Preferable reaction temperature is-80 ℃ to 100 ℃.The selection of M and X is known (referring to Imamoto, T., Organocerium Reagents in to those skilled in the art Comprehensive Organic Synthesis, Trost, B.M.ed., (Elmsford, NY:Pergamon Press, 1991), 1,231-250; Knochel, P., Organozinc, Organocadmium and Organomercury Reagents in Comprehensive Organic Synthesis, Trost, B.M.ed., (Elmsford, NY:Pergamon Press, 1991), 1,211-230; Knight, D.W., Coupling Reactionsbetween sp ²Carbon Centers, in Comprehensive Organic Synthesis, Trost, B.M.ed., (Elmsford, NY:Pergamon Press, 1991), 3,481-520).According to the method shown in the flow process 9, also can preparation formula (1) compound:

(16)X＝Br，Cl，I， (1)

B(OR″″) ₂，O ₃SCF ₃

Be in or be not in organo-metallic catalyst and exist down, alkali exist or not in the presence of, in inert solvent, in-100 ℃ to 200 ℃ temperature ranges, can make formula (16) compound (wherein A, Z, R ¹And R ³Identical with above-mentioned definition, X is Br, Cl, I, O ₃SCF ₃Or B (OR " ") ₂, and R " " be H or alkyl (1-6 carbon atom)) (wherein M is halogen atom, basic metal, ZnCl, ZnBr, ZnI, MgBr, MgCl, MgI, CeCl with formula ArM ₂, CeBr ₂Or copper halide) compound reaction.Those skilled in the art will recognize that reagent A rM can produce on the spot (sees Comprehensive Organic SynthesisIn above-mentioned reference).Organo-metallic catalyst includes, but is not limited to palladium phosphine composition (Pd (PPh for example ₃) ₄), palladium halogenide or alkanoate (PdCl for example ₂(PPh ₃) ₂Or Pd (OAc) ₂) or nickel complex (NiCl for example ₂(PPh ₃) ₂).Alkali can include, but is not limited to alkaline carbonate or trialkylamine (preferred N, N-two-sec.-propyl-N-ethamine or triethylamine).Inert solvent includes, but is not limited to dialkyl ether (preferred ether), cyclic ethers (preferred tetrahydrofuran (THF) or 1, the 4-dioxane), N, N-dialkylformamide (preferred dimethyl formamide), N, N-dialkyl acetamides (preferred N,N-DIMETHYLACETAMIDE), cyclic amide (preferred N-methylpyrrolidin-2-ketone), dialkyl sulphoxide (preferred dimethyl sulfoxide (DMSO)), aromatic hydrocarbon (preferred benzene or toluene) or water.Preferable reaction temperature is-80 ℃ to 100 ℃.

Shown in flow process 10, can preparation formula (7) midbody compound (wherein Y is O, S, NH, and Z is CR ², R ¹, R ²Identical with Ar with above-mentioned definition):

Flow process 10

(7)Y＝O，S，NH；Z＝CR ²，

Be in or be not in alkali or acid and exist down, in inert solvent, in 0 ℃ to 250 ℃ temperature range, can make formula (3) compound and formula H ₂NNH (C=Y) NH ₂(wherein Y is O, S or NH) compound reacting generating (17) compound.Acid can include, but is not limited to paraffinic acid (preferred acetate), the aryl sulfonic acid (preferably right-toluenesulphonic acids or Phenylsulfonic acid) of 2-10 carbon atom, alkylsulphonic acid (preferably methylsulfonic acid), hydrochloric acid, sulfuric acid or the phosphoric acid of a 1-10 carbon atom.Can use this type of acid of stoichiometric quantity or catalytic amount.Alkali can include, but is not limited to alkalimetal hydride (preferred sodium hydride), alkali metal alcoholate (1-6 carbon atom) (particular methanol sodium or sodium ethylate), alkaline earth metal hydride, basic metal dialkyl group ammonification thing (preferred di-isopropyl lithamide), two (trialkylsilanyl) amides of basic metal (preferred two (TMS) ammonification sodium), trialkylamine (preferred N, N-two-sec.-propyl-N-ethamine or triethylamine) or aromatic amine (preferred pyridine).Inert solvent includes, but is not limited to alkyl alcohol (1-6 carbon atom), low alkyl group nitrile (1-6 carbon atom, preferred acetonitrile), dialkyl ether (preferred ether), cyclic ethers (preferred tetrahydrofuran (THF) or 1, the 4-dioxane), N, N-dialkylformamide (preferred dimethyl formamide), N, the haloalkane (preferred methylene dichloride) of N-dialkyl acetamides (preferred N,N-DIMETHYLACETAMIDE), cyclic amide (preferred N-methylpyrrolidin-2-ketone), dialkyl sulphoxide (preferred dimethyl sulfoxide (DMSO)), aromatic hydrocarbon (preferred benzene or toluene) or 1-10 carbon atom and 1-10 halogen atom.

Preferable reaction temperature is 0 ℃ to 150 ℃.Be in or be not in acid then and exist down, in inert solvent, in 0 ℃ to 250 ℃ range of reaction temperature, can make formula (17) compound and formula R ³C (OR ^e) ₃(R wherein ^eCan be alkyl (1-6 carbon atom)) the compound reaction.Acid can include, but is not limited to paraffinic acid (preferred acetate), the aryl sulfonic acid (preferably right-toluenesulphonic acids or Phenylsulfonic acid) of 2-10 carbon atom, alkylsulphonic acid (preferably methylsulfonic acid), hydrochloric acid, sulfuric acid or the phosphoric acid of a 1-10 carbon atom.Can use this type of acid of stoichiometric quantity or catalytic amount.Inert solvent includes, but is not limited to low alkyl group nitrile (1-6 carbon atom, preferred acetonitrile), dialkyl ether (preferred ether), cyclic ethers (preferred tetrahydrofuran (THF) or 1, the 4-dioxane), N, N-dialkylformamide (preferred dimethyl formamide), N, the halohydrocarbon (preferably methylene dichloride) of N-dialkyl acetamides (preferred N,N-DIMETHYLACETAMIDE), cyclic amide (preferred N-methylpyrrolidin-2-ketone), dialkyl sulphoxide (preferred dimethyl sulfoxide (DMSO)), aromatic hydrocarbon (preferred benzene or toluene) or 1-10 carbon atom and 1-10 halogen atom.Preferred temperature of reaction is 50 ℃ to 150 ℃.

Flow process 11 is depicted as: in inert solvent, and in-80 ℃ to 250 ℃ temperature ranges, can be by handling with class formula (a 1) compound (R wherein with reductive agent ³Be COR ⁷, CO ₂R ⁷, NR ⁸COR ⁷And CONR ⁶R ⁷) be converted into another kind of formula (1) compound (R wherein ³Be CH (OH) R ⁷, CH ₂OH, NR ⁸CH ₂R ⁷And CH ₂NR ⁶R ⁷) method:

Flow process 11

(1)R ³＝COR ⁷，CO ₂R ⁷， (1)R ³＝C(OH)R ⁷，

CONR ⁶R ⁷ CH ₂OH，

CH ₂NR ⁶R ⁷

Reductive agent includes, but is not limited to basic metal or alkaline-earth metal borohydride (preferred lithium borohydride or sodium borohydride), borane, dialkyl group borane (for example two-isopentyl borane), composite alkali aluminum hydride (preferred lithium aluminum hydride), basic metal (tri-alkoxy) alanate or dialkyl aluminum hydride (for example Di-Isobutyl alanate).Inert solvent includes, but is not limited to alkyl alcohol (1-6 carbon atom), dialkyl ether (preferred ether), cyclic ethers (preferred tetrahydrofuran (THF) or 1,4-dioxane), aromatic hydrocarbon (preferred benzene or toluene).Preferable reaction temperature is-80 ℃ to 100 ℃.

In flow process 12, be depicted as in inert solvent, in-80 ℃ to 250 ℃ temperature ranges, by using formula R ⁷The M agent treated can be with class formula (a 1) compound (R wherein ³Be COR ⁷Or CO ₂R ⁷) be converted into another kind of formula (1) compound (R wherein ³Be C (OH) (R ⁷) ₂Method:

Flow process 12

(1)R ³＝COR ⁷，CO ₂R ⁷， (1)R ³＝C(OH)(R ⁷) ₂

M is halogen atom, basic metal, ZnCl, ZnBr, ZnI, MgBr, MgCl, MgI, CeCl ₂, CeBr ₂Or copper halide.Inert solvent includes, but is not limited to dialkyl ether (preferred ether), cyclic ethers (preferred tetrahydrofuran (THF)) or aromatic hydrocarbon (preferred benzene or toluene).Preferable reaction temperature is-80 ℃ to 100 ℃.

As described in flow process 13, can synthesis type (1) compound, wherein R ³For-NR ⁸COR ⁷,-N (COR ⁷) ₂,-NR ⁸CONR ⁶R ⁷,-NR ⁸CO ₂R ¹³,-NR ⁶R ⁷,-NR ⁸SO ₂R ⁷:

Flow process 13

(4)Z＝CR ₂

(10)Z＝N

A＝CR

R ³＝NR ⁶R ⁷，NR ⁸COR ⁷，

N(COR ⁷) ₂，

NR ₈CONR ⁶R ⁷，

NR ₈CO ₂R ₁₃

Be in or be not in alkali and exist down, in inert solvent, in-50 ℃ to 250 ℃ temperature ranges, make formula (18) compound (wherein R and R ¹Identical with above-mentioned definition) and formula (4) or formula (10) compound reacting generating (19) compound.Alkali can include, but is not limited to alkalimetal hydride (preferred sodium hydride), alkali metal alcoholate (1-6 carbon atom) (particular methanol sodium or sodium ethylate), alkaline earth metal hydride, basic metal dialkyl group ammonification thing (preferred di-isopropyl lithamide), alkaline carbonate, two (trialkylsilanyl) amides of basic metal (preferred two (TMS) ammonification sodium), trialkylamine (preferred two-sec.-propyl ethamine) or aromatic amine (preferred pyridine).Inert solvent includes, but is not limited to alkyl alcohol (1-8 carbon atom, particular methanol or ethanol), low alkyl group nitrile (1-6 carbon atom, preferred acetonitrile), dialkyl ether (preferred ether), cyclic ethers (preferred tetrahydrofuran (THF) or 1, the 4-dioxane), N, N-dialkylformamide (preferred dimethyl formamide), N, N-dialkyl acetamides (preferred N,N-DIMETHYLACETAMIDE), cyclic amide (preferred N-methylpyrrolidin-2-ketone), dialkyl sulphoxide (preferred dimethyl sulfoxide (DMSO)) or aromatic hydrocarbon (preferred benzene or toluene).Preferred range of reaction temperature is 0 ℃ to 100 ℃.

Be in or be not in alkali and exist down, in inert solvent, between-80 ℃ to 250 ℃ temperature of reaction, make formula (19) compound and alkylating agent, sulfonyl agent or acylation reaction or in proper order with their composite reaction, can obtain formula (1) compound, wherein R ³Can be-NR ⁸COR ⁷,-N (COR ⁷) ₂,-NR ⁸CONR ⁶R ⁷,-NR ⁸CO ₂R ¹³,-NR ⁶R ⁷,-NR ⁸SO ₂R ⁷Alkylating agent can include, but is not limited to C ₁-C ₁₀Alkyl-halogenide ,-tosylate ,-methanesulfonates or-triflate; C ₁-C ₁₀Haloalkyl (1-10 halogen atom)-halogenide ,-tosylate ,-methanesulfonates or-triflate; C ₂-C ₈Alkoxyalkyl-halogenide ,-tosylate ,-methanesulfonates or-triflate; C ₃-C ₆Cycloalkyl-halogenide ,-tosylate ,-methanesulfonates or-triflate; C ₄-C ₁₂Cycloalkylalkyl-halogenide ,-tosylate ,-methanesulfonates or-triflate; Aryl (C ₁-C ₄Alkyl)-halogenide ,-tosylate ,-methanesulfonates or-triflate; Heteroaryl (C ₁-C ₄Alkyl)-halogenide ,-tosylate ,-methanesulfonates or-triflate; Or heterocyclic radical (C ₁-C ₄Alkyl)-halogenide ,-tosylate ,-methanesulfonates or-triflate.Acylating agent includes, but is not limited to C ₁-C ₁₀Alkane carboxylic acid halides or acid anhydrides, has the C of 1-10 halogen atom ₁-C ₁₀Halogenated alkane carboxylic acid halides or acid anhydrides, C ₂-C ₈Alkoxyl group alkane carboxylic acid halides or acid anhydrides, C ₃-C ₆Cycloalkyl alkane carboxylic acid halides or acid anhydrides, C ₄-C ₁₂Cycloalkyl alkane carboxylic acid halides or acid anhydrides, fragrant carboxylic acid halides or acid anhydrides, aryl (C ₁-C ₄) alkane carboxylic acid halides or acid anhydrides, assorted fragrant carboxylic acid halides or acid anhydrides, heteroaryl (C ₁-C ₄) alkane carboxylic acid halides or acid anhydrides, heterocycle carboxylic acid halides or acid anhydrides or heterocyclic radical (C ₁-C ₄) alkane carboxylic acid halides or acid anhydrides.Sulfonyl agent includes, but is not limited to C ₁-C ₁₀Heteroaryl-alkylsulfonyl halides or acid anhydrides, has the C of 1-10 halogen atom ₁-C ₁₀Haloalkyl sulfonic acid halide or acid anhydrides, C ₂-C ₈Alkoxyalkyl sulfonic acid halide or acid anhydrides, C ₃-C ₆Naphthene sulfamide halogen or acid anhydrides, C ₄-C ₁₂Cycloalkylalkyl sulfonic acid halide or acid anhydrides, aryl sulfonyl halide or acid anhydrides, aryl (C ₁-C ₄Alkyl)-, heteroaryl sulfonic acid halide or acid anhydrides, heteroaryl (C ₁-C ₄Alkyl) sulfonic acid halide or acid anhydrides, heterocyclic radical sulfonic acid halide or acid anhydrides or heterocyclic radical (C ₁-C ₄Alkyl) sulfonic acid halide or acid anhydrides.Alkali can include, but is not limited to alkalimetal hydride (preferred sodium hydride), alkali metal alcoholate (1-6 carbon atom) (particular methanol sodium or sodium ethylate), alkaline earth metal hydride, basic metal dialkyl group ammonification thing (preferred di-isopropyl lithamide), alkaline carbonate, two (trialkylsilanyl) amides of basic metal (preferred two (TMS) ammonification sodium), trialkylamine (preferred two-sec.-propyl ethamine) or aromatic amine (preferred pyridine).Inert solvent includes, but is not limited to alkyl alcohol (1-8 carbon atom, particular methanol or ethanol), low alkyl group nitrile (1-6 carbon atom, preferred acetonitrile), dialkyl ether (preferred ether), cyclic ethers (preferred tetrahydrofuran (THF) or 1, the 4-dioxane), N, N-dialkylformamide (preferred dimethyl formamide), N, N-dialkyl acetamides (preferred N,N-DIMETHYLACETAMIDE), cyclic amide (preferred N-methylpyrrolidin-2-ketone), dialkyl sulphoxide (preferred dimethyl sulfoxide (DMSO)) or aromatic hydrocarbon (preferred benzene or toluene).Preferable reaction temperature is 0 ℃ to 100 ℃.

According to method shown in the flow process 14, can synthesis type (1) compound, wherein A is CR, R is identical with above-mentioned definition:

Flow process 14

Be in or be not in alkali and exist down, in inert solvent, in 0 ℃ to 250 ℃ temperature range, can use formula (20) compound (R wherein ¹And R ³Identical with above-mentioned definition) processing formula (4) or formula (10) compound, obtain formula (1) compound (wherein A is CR, and R is identical with above-mentioned definition).Alkali can include, but is not limited to alkalimetal hydride (preferred sodium hydride), alkali metal alcoholate (1-6 carbon atom) (particular methanol sodium or sodium ethylate), alkaline earth metal hydride, basic metal dialkyl group ammonification thing (preferred di-isopropyl lithamide), alkaline carbonate, two (trialkylsilanyl) amides of basic metal (preferred two (TMS) ammonification sodium), trialkylamine (preferred two-sec.-propyl ethamine) or aromatic amine (preferred pyridine).Inert solvent includes, but is not limited to alkyl alcohol (1-8 carbon atom, particular methanol or ethanol), low alkyl group nitrile (1-6 carbon atom, preferred acetonitrile), dialkyl ether (preferred ether), cyclic ethers (preferred tetrahydrofuran (THF) or 1, the 4-dioxane), N, N-dialkylformamide (preferred dimethyl formamide), N, N-dialkyl acetamides (preferred N,N-DIMETHYLACETAMIDE), cyclic amide (preferred N-methylpyrrolidin-2-ketone), dialkyl sulphoxide (preferred dimethyl sulfoxide (DMSO)) or aromatic hydrocarbon (preferred benzene or toluene).Preferable reaction temperature is 0 ℃ to 100 ℃.Perhaps, can synthesis type (1) compound by intermediate (22) and (23), wherein A is CR, R is identical with above-mentioned definition.

Be in or be not in alkali and exist down, in inert solvent, in 0 ℃ to 250 ℃ temperature range, can use formula (21) compound (R wherein ¹Identical with above-mentioned definition, R ^eBe alkyl (1-6 carbon atom)) processing formula (4) or formula (10) compound, obtain formula (1) compound (wherein A is CR, and R is identical with above-mentioned definition).Alkali can include, but is not limited to alkalimetal hydride (preferred sodium hydride), alkali metal alcoholate (1-6 carbon atom) (particular methanol sodium or sodium ethylate), alkaline earth metal hydride, basic metal dialkyl group ammonification thing (preferred di-isopropyl lithamide), alkaline carbonate, two (trialkylsilanyl) amides of basic metal (preferred two (TMS) ammonification sodium), trialkylamine (preferred two-sec.-propyl ethamine) or aromatic amine (preferred pyridine).Inert solvent includes, but is not limited to alkyl alcohol (1-8 carbon atom, particular methanol or ethanol), low alkyl group nitrile (1-6 carbon atom, preferred acetonitrile), dialkyl ether (preferred ether), cyclic ethers (preferred tetrahydrofuran (THF) or 1, the 4-dioxane), N, N-dialkylformamide (preferred dimethyl formamide), N, N-dialkyl acetamides (preferred N,N-DIMETHYLACETAMIDE), cyclic amide (preferred N-methylpyrrolidin-2-ketone), dialkyl sulphoxide (preferred dimethyl sulfoxide (DMSO)) or aromatic hydrocarbon (preferred benzene or toluene).Preferable reaction temperature is 0 ℃ to 100 ℃.Being in or be not in alkali exists down; being in or be not in inert solvent exists down; in-80 ℃ to 250 ℃ temperature ranges; can handle formula (22) compound with halogenating agent or sulfonyl agent, obtain formula (23) product (wherein X is halogen atom, alkylsulfonyloxy, aryl-sulfonyl oxygen or haloalkyl sulfonyloxy).Halogenating agent includes, but is not limited to SOCl ₂, POCl ₃, PCl ₃, PCl ₅, POBr ₃, PBr ₃Or PBr ₅Sulfonyl agent includes, but is not limited to heteroaryl-alkylsulfonyl halides or acid anhydrides (for example methylsulfonyl chloride or methylsulfonic acid acid anhydride), aryl sulfonyl halide or acid anhydrides (for example p-toluenesulfonyl chloride or acid anhydrides) or haloalkyl sulfonic acid halide or acid anhydrides (preferred trifluoromethanesulfanhydride anhydride).Alkali includes, but is not limited to alkalimetal hydride (preferred sodium hydride), alkali metal alcoholate (1-6 carbon atom) (particular methanol sodium or sodium ethylate), alkaline earth metal hydride, basic metal dialkyl group ammonification thing (preferred di-isopropyl lithamide), two (trialkylsilanyl) amides of basic metal (preferred two (TMS) ammonification sodium), trialkylamine (preferred N, N-two-sec.-propyl-N-ethamine or triethylamine) or aromatic amine (preferred pyridine).Inert solvent includes, but is not limited to low alkyl group nitrile (1-6 carbon atom, preferred acetonitrile), dialkyl ether (preferred ether), cyclic ethers (preferred tetrahydrofuran (THF) or 1, the 4-dioxane), N, N-dialkylformamide (preferred dimethyl formamide), N, the haloalkane (preferred methylene dichloride) of N-dialkyl acetamides (preferred N,N-DIMETHYLACETAMIDE), cyclic amide (preferred N-methylpyrrolidin-2-ketone), dialkyl sulphoxide (preferred dimethyl sulfoxide (DMSO)), aromatic hydrocarbon (preferred benzene or toluene) or 1-10 carbon atom and 1-10 halogen atom.Preferable reaction temperature is-20 ℃ to 100 ℃.

In the alkali existence or not,, between-80 ℃ to 250 ℃ temperature of reaction, can make formula (23) compound and formula R in the inert solvent existence or not ³H (R wherein ³Identical with above-mentioned definition, but R ³Be not SH, COR ⁷, CO ₂R ⁷, aryl or heteroaryl) compound reacting generating (1) compound.Alkali can include, but is not limited to alkalimetal hydride (preferred sodium hydride), alkali metal alcoholate (1-6 carbon atom) (particular methanol sodium or sodium ethylate), alkaline earth metal hydride, basic metal dialkyl group ammonification thing (preferred di-isopropyl lithamide), alkaline carbonate, alkali metal hydrocarbonate, two (trialkylsilanyl) amides of basic metal (preferred two (TMS) ammonification sodium), trialkylamine (preferred N, N-two-sec.-propyl-N-ethamine) or aromatic amine (preferred pyridine).Inert solvent includes, but is not limited to alkyl alcohol (1-8 carbon atom, particular methanol or ethanol), low alkyl group nitrile (1-6 carbon atom, preferred acetonitrile), dialkyl ether (preferred ether), cyclic ethers (preferred tetrahydrofuran (THF) or 1, the 4-dioxane), N, N-dialkylformamide (preferred dimethyl formamide), N, N-dialkyl acetamides (preferred N,N-DIMETHYLACETAMIDE), cyclic amide (preferred N-methylpyrrolidin-2-ketone), dialkyl sulphoxide (preferred dimethyl sulfoxide (DMSO)), the haloalkane (preferred methylene dichloride) of aromatic hydrocarbon (preferred benzene or toluene) or 1-10 carbon atom and 1-10 halogen atom.Preferable reaction temperature is 0 ℃ to 140 ℃.

Use method shown in the flow process 15, also can prepare segment bounds (1) compound:

Flow process 15

(27)Y＝O，S (1)Z＝CR ²

Be in or be not in inert solvent and exist down, can make formula (24) compound (R wherein _cBe low alkyl group, Ar is identical with above-mentioned definition) and hydrazine reaction, formula (25) intermediate (wherein Ar is identical with above-mentioned definition) obtained.Conditional likelihood shown in employed reaction conditions and the flow process 4 by formula (3) compound formula (4) intermediate.Be in or be not in acid and exist down, in inert solvent, can make formula (25) compound (wherein A is N) and formula R ¹C (=NH) OR _e(R wherein ¹Identical with above-mentioned definition, R _eBe low alkyl group) reagent react, then be in or be not in alkali and exist down, in inert solvent, with formula YisC (R _d) ₂(wherein Y is O or S, R ^dBeing halogen atom (preferred chlorine), alkoxyl group (1-4 carbon atom) or alkylthio (1-4 carbon atom)) compound reacts and obtains formula (27) compound (wherein A is N, and Y is O, S).It is identical in the condition of these conversions and the flow process 4 formula (4) compound to be converted into the employed condition of formula (7) compound.

Perhaps, use to flow process 14 is employed formula (21) compound is converted into the similar condition of formula (22) compound, make formula (25) compound (wherein A is CR) and formula R ¹(C=O) CHR (C=Y) OR _c(R wherein ¹Identical with R with above-mentioned definition, R _cBe low alkyl group) the compound reaction, obtain formula (27) compound (wherein A is CR).Be in or be not in alkali and exist down, in inert solvent, can handle formula (27) intermediate (wherein Y is O), then be in or be not in alkali and exist down, in inert solvent, with R with halogenating agent or sulfonyl agent ³H or R ²The H reaction obtains formula (1) compound, and (wherein Z is CR ²).

Those skilled the in art will appreciate that in flow process 15 and can use various halogenating agents, sulfonyl agent, R with the different order of response procedures ³H or R ²The combination of H is to provide formula (I) compound.For example, in some cases, can need to make halogenating agent or the sulfonyl agent reaction and the R of compound and stoichiometric quantity ²H (or R ³H) react, and then react with halogenating agent or sulfonyl agent, and and R ³H (or R ²H) reaction obtains formula (1) compound.These transform, and the reaction conditions use and reagent and flow process 14 are employed to be converted into (23) with formula (22) midbody compound and to be converted into the employed conditional likelihood of (1) (wherein A is CR) again, perhaps with flow process 1 formula (7) midbody compound is converted into (8) and is converted into the employed conditional likelihood of (1) (wherein A is N) again.

Perhaps, can in flow process 15, formula (27) compound (wherein Y is S) be converted into formula (1) compound.In inert solvent, can use compound R ^fX (R wherein ^fBe low alkyl group, X is halogen atom, alkylsulfonyloxy or haloalkyl sulfonyloxy) make formula (27) midbody compound alkylation, (choose wantonly then and use the oxygenant oxidation in inert solvent) then is in or be not in alkali and exists down, in inert solvent with R ³The H reaction obtains formula (1) compound.In employed condition and reagent and the flow process 2 formula (7) midbody compound being converted into (12) (or being converted into 13), to be converted into formula (1) compound more employed similar.

With the other approach shown in the flow process 15, can be by formula (24) compound formula (1) compound.Exist down by being in or be not in acid, in inert solvent, make formula (24) compound warp and formula NH ₂NH (C=NH) NH ₂Compound reaction is then used in the flow process 10 formula (3) compound to be converted into (17) and to be converted into (7) employed condition again, with compound R ¹C (OR _c) ₃(R wherein _cBe low alkyl group, R ¹Identical with above-mentioned definition) reaction, can be translated into formula (27) compound.

According to the method shown in the flow process 16, can prepare segment bounds (2) compound:

Flow process 16

(27b)Y＝O，S (28)Y＝O，S

Be in or be not in alkali and exist down, in inert solvent, can be with various alkylating agent R ¹⁴X (R wherein ¹⁴Identical with above-mentioned definition, X is halogen atom, alkylsulfonyloxy or haloalkyl sulfonyloxy) processing formula (27b) compound, obtain the structure of formula (28).Be in or be not in alkali then and exist down, in inert solvent,, can be translated into formula (2) compound, then be in or be not in alkali and exist down, in inert solvent, with R by handling formula (28) compound (wherein Y is O) with halogenating agent or sulfonyl agent ³The H reaction obtains formula (2) compound.These transform and in employed reaction conditions and the flow process 14 midbody compound (22) are converted into (23) and are converted into the employed conditional likelihood of (1) (wherein A is CR) again, perhaps with in the flow process 1 formula (7) midbody compound is converted into (8) is converted into the employed conditional likelihood of (1) (wherein A is N) again.Perhaps, in inert solvent, can use compound R ^tX (R wherein ^fBe low alkyl group, X is halogen atom, alkylsulfonyloxy or haloalkyl sulfonyloxy) make formula (28) (wherein Y is S) alkylation, (choose wantonly then and use the oxygenant oxidation in inert solvent) then is in or be not in alkali and exists down, in inert solvent with R ³The H reaction obtains formula (1) compound.In employed condition and reagent and the flow process 2 formula (7) midbody compound being converted into (12) (or being converted into 13), to be converted into formula (1) compound more employed similar.

With method shown in the flow process 16, formula (1) compound (wherein Z is COH) can be converted into formula (2) compound.Be in or be not in alkali and exist down, in inert solvent, with various alkylating agent R ¹⁴X (R wherein ¹⁴Identical with above-mentioned definition, X is halogen atom, alkylsulfonyloxy or haloalkyl sulfonyloxy) handle and to obtain structure (2).Those skilled in the art will recognize that (wherein Z is COR to method preparation formula (1) compound that also can use flow process 16 ⁷).

In flow process 16, term " alkali " and " inert solvent " can have following meaning.Alkali can include, but is not limited to alkalimetal hydride (preferred sodium hydride), alkali metal alcoholate (1-6 carbon atom) (particular methanol sodium or sodium ethylate), alkaline earth metal hydride, basic metal dialkyl group ammonification thing (preferred di-isopropyl lithamide), two (trialkylsilanyl) amides of basic metal (preferred two (TMS) ammonification sodium), trialkylamine (preferred N, N-two-sec.-propyl-N-ethamine or triethylamine) or aromatic amine (preferred pyridine).Inert solvent includes, but is not limited to low alkyl group nitrile (1-6 carbon atom, preferred acetonitrile), dialkyl ether (preferred ether), cyclic ethers (preferred tetrahydrofuran (THF) or 1, the 4-dioxane), N, N-dialkylformamide (preferred dimethyl formamide), N, the haloalkane (preferred methylene dichloride) of N-dialkyl acetamides (preferred N,N-DIMETHYLACETAMIDE), cyclic amide (preferred N-methylpyrrolidin-2-ketone), dialkyl sulphoxide (preferred dimethyl sulfoxide (DMSO)), aromatic hydrocarbon (preferred benzene or toluene) or 1-10 carbon atom and 1-10 halogen atom.Preferable reaction temperature is-20 ℃ to 100 ℃.

Embodiment

Analytical data with following general method record following compounds.With IBM-Bruker FT-NMR (300MHz) record proton N MR spectrum; In tritiate chloroform or tritiate dimethyl sulfoxide (DMSO), the ppm (δ) that is offset with mark in tetramethylsilane writes down chemical shift according to following.(NH is used in chemistry-ionization (CI) with Finnegan MAT 8230 spectrographs ₃Do carrier gas, or as following gas chromatography (GC)) or write down mass spectrum (MS) or high resolution mass spectrum (HRMS) with Hewlett Packard 5988A type spectrograph.Fusing point is record on Buchi Model 510 fusing point devices, and does not proofread and correct.Boiling point is not for proofreading and correct.All pH measure and all carry out with test paper in processing.

Reagent is buied by commerce, when needing before use, according to D.Perrin and W.L.F.Armarego at the general method purifying described in the Purification of Laboratory Chemicals (third edition, New York:Pergamon Press, 1988).Chromatography carries out on silica gel, uses the following solvents system.For mixed solvent system, provide the ratio of volume.Except that specializing, all umbers and per-cent are by weight.

Provide the following example to describe the present invention in more detail.These embodiment (having proposed to implement optimal mode of the present invention) are used to illustrate the present invention, and are not used in restriction the present invention.

Embodiment 1

2, the preparation of 7-dimethyl-8-(2, the 4-3,5-dimethylphenyl) [1,5-a]-pyrazolo-[1,3,5]-triazine-4 (3H)-ketone

(formula 7, wherein Y is O, R ₁Be CH ₃, Z is C-CH ₃, Ar is 2, the 4-3,5-dimethylphenyl)

A.1-cyano group-1-(2, the 4-3,5-dimethylphenyl) third-2-ketone

Under room temperature, with the sodium particle (9.8g, 0.43mol) gradation adds to 2, (48g is in ethyl acetate 0.33mol) (150ml) solution for 4-3,5-dimethylphenyl acetonitrile.This reaction mixture is heated to reflux temperature, and stirred 16 hours.The suspension that produces is cooled to room temperature and filtration.With the precipitation of a large amount of ether washing collections, dry air then.Solid is soluble in water, add 1N HCl solution to pH=5-6.(3 * 200ml) extract this mixture, and the organic layer that merges through dried over mgso also filters with ethyl acetate.Vacuum is removed solvent and is obtained white solid (45.7g, 74% productive rate): NMR (CDCl ₃, 300MHz); CI-MS:188 (M+H).

B.5-amino-4-(2, the 4-3,5-dimethylphenyl)-3-methylpyrazole

Under reflux temperature, with 1-cyano group-1-(2, the 4-3,5-dimethylphenyl) third-2-ketone (43.8g, 0.23mol), hydrazine-hydrate (22ml, 0.46mol), glacial acetic acid (45ml, 0.78mol) and the mixture of toluene (500ml) in being furnished with the dean stark trap device, stirred 18 hours.This reaction mixture is cooled to room temperature, and vacuum is removed solvent.Residue is dissolved among the 6N HCl, with ether with the solution extraction that produces three times.Add ammonium hydroxide solution,stronger to pH=11 to water layer.With ethyl acetate will produce not exclusively-solution extraction three times.Through the organic layer of dried over mgso merging, and filter.Vacuum is removed solvent and is obtained the sticking oily matter (34.6g, 75% productive rate) of light brown; NMR (CDCl ₃, 300MHz); 7.10 (s, 1H), 7.05 (d, 2H, J=1), 2.37 (s, 3H), 2.10 (s, 3H); CI-MS:202 (M+H).

C.5-ethanamidine base-4-(2, the 4-3,5-dimethylphenyl)-3-methylpyrazole, acetate

With Ethyl acetamidate hydrochloride (60g, 0.48mol) add to fast salt of wormwood (69.5g, 0.50mol), methylene dichloride (120ml) and water (350ml) is rapidly in the stirred mixture.Separate each layer, with methylene dichloride (2 * 120ml) aqueous layer extracted.Organic layer through dried over mgso merges filters.Removing solvent through simple distillation, is the not purified use of clarifying weak yellow liquid (35.0g) with residue.

With glacial acetic acid (9.7ml, 0.17mol) add to stirring 5-amino-4-(2, the 4-3,5-dimethylphenyl)-3-methylpyrazole (34g, 0.17mol), (22g is 0.25mol) and in acetonitrile (500ml) mixture for ethyl acetamidate.Under room temperature, the reaction mixture that produces was stirred 3 days, then with its vacuum concentration to 1/3rd of about original volume.Filter the suspension that produces, with the solid of a large amount of ether washing collections.Vacuum-drying white solid (31.4g, 61% productive rate); NMR (DMSO-d ₆, 300MHz); 7.00 (s, 1H), 6.90 (dd, 2H, J=7,1), 2.28 (s, 3H), 2.08 (s, 3H), 2.00 (s, 3H), 1.90 (s, 3H), 1.81 (s, 3H); CI-MS:243 (M+H).

D.2,7-dimethyl-8-(2, the 4-3,5-dimethylphenyl) [1,5-a]-pyrazolo-[1,3,5]-triazine-4 (3H)-ketone

Under vigorous stirring, (23g, 1mol) gradation adds in the ethanol (500ml) with the sodium particle.After the reaction of all sodium, add 5-ethanamidine base-4-(2, the 4-3,5-dimethylphenyl)-3-methylpyrazole acetate (31.2g, 0.1mol) and diethyl carbonate (97ml, 0.8mol).The reaction mixture that produces is heated to reflux temperature, stirred 18 hours.With this mixture cool to room temperature, vacuum is removed solvent.Residue is soluble in water, slowly add 1N HCl solution to pH=5-6.With water layer extraction three times, the organic layer that merges through dried over mgso also filters with ethyl acetate.Vacuum is removed solvent and is obtained filbert solid (26g, 98% productive rate); NMR (CDCl ₃, 300MHz); 7.15 (s, 1H), 7.09 (s, 2H), 2.45 (s, 3H), 2.39 (s, 3H), 2.30 (s, 3H); CI-MS:269 (M+H).

Embodiment 2

The preparation of 5-methyl-3-(2,4, the 6-trimethylphenyl) [1,5-a]-[1,2,3]-triazolo-[1,3,5]-triazine-7 (6H)-ketone

(formula 7, wherein Y is O, R ₁Be CH ₃, Z is N, Ar is 2,4, the 6-trimethylphenyl)

A.1-phenyl methyl-4-(2,4, the 6-trimethylphenyl)-5-aminotriazole

Under room temperature, with 2,4,6-trimethyl benzyl cyanogen (1.0g, 6.3mmol), benzyl azide (0.92g, 6.9mmol) and potassium tert.-butoxide (0.78g, tetrahydrofuran (THF) 6.9mmol) (10ml) mixture stirred 2.5 days.The suspension that dilute with water produces is used ethyl acetate extraction three times.Through the organic layer of dried over mgso merging, and filter.Vacuum is removed solvent, obtains brown oil.Grind and filter with ether, obtain yellow solid (1.12g, 61% productive rate); NMR (CDCl ₃, 300MHz); 7.60-7.30 (m, 5H), 7.30-7.20 (m, 2H), 5.50 (s, 2H), 3.18 (br, s, 2H), 2.30 (s, 3H), 2.10 (s, 6H); CI-MS:293 (M+H).

B.4-(2,4, the 6-trimethylphenyl)-5-aminotriazole

Under agitation, (500mg 22mmol) adds to that liquefied ammonia (30ml) and 1-phenyl methyl-4-(2,4, the 6-trimethylphenyl)-(1.1g is in mixture 3.8mmol) for the 5-aminotriazole with sodium.Stirring this reaction mixture to deep green does not take off.Add ammonium chloride solution (ml), stir this mixture simultaneously with being heated to room temperature in 16 hours.With 1M HCl solution-treated residue and filtration.With the ammonium hydroxide solution,stronger water layer (pH=9) that alkalizes, use ethyl acetate extraction then three times.Organic layer through dried over mgso merges filters.Vacuum removes solvent and obtains yellow solid (520mg), proves homogeneous through thin-layer chromatography (ethyl acetate):

NMR(CDCl ₃，300MHz)；6.97(s，2H)，3.68-3.50(br，s，2H)，2.32(s，3H)，2.10(s，6H)；CI-MS：203(M+H)。

C.4-(2,4, the 6-trimethylphenyl)-5-ethanamidine base triazole acetate

Under room temperature, with 4-(2,4, the 6-trimethylphenyl)-5-aminotriazole (400mg, 1.98mmol), ethyl acetamidate (261mg, 3mmol) and glacial acetic acid (0.1ml, mixture in acetonitrile 1.98mmol) (6ml) stirred 4 hours.Filter the suspension that produces, with the solid of a large amount of ether washing collections.Vacuum-drying obtains white solid (490mg, 82% productive rate): NMR (DMSO-d ₆, 300MHz); 7.90-7.70 (br s, 0.5H), 7.50-7.20 (br s, 0.5H), 6.90 (s, 2H), 6.90 (s, 2H), 3.50-3.10 (br, s, 3H), 2.30-2.20 (br s, 3H), 2.05 (d, 1H, J=7), 1.96 (s, 6H), 1.87 (s, 6H); CI-MS:244 (M+H).

D.5-methyl-3-(2,4, the 6-trimethylphenyl) [1,5-a]-[1,2,3]-triazolo-[1,3,5]-triazine-7 (4H)-ketone

In room temperature, stirring down, (368mg 16.2mmol) adds in the ethanol (10ml) with sodium.After the reaction of described sodium, add 4-(2,4, the 6-trimethylphenyl)-5-ethanamidine base triazole acetate (490mg, 1.6mmol) and diethyl carbonate (1.6ml, 13mmol).This reaction mixture was stirred 5 hours down in reflux temperature, be cooled to room temperature then.This reaction mixture of dilute with water adds 1N HCl solution to pH=5-6.With water layer extraction three times, the organic layer through dried over mgso merges filters with ethyl acetate.Vacuum is removed solvent and is obtained yellow residue.Obtain yellow solid (300mg, 69% productive rate) with ether grinding and filtration; NMR (CDCl ₃, 300MHz); 6.98 (s, 2H), 2.55 (s, 3H), 2.35 (s, 3H), 2.10 (s, 6H); CI-MS:270 (M+H).

Embodiment 3

4-(two (carbonyl methoxyl group) methyl)-2, the preparation of 7-dimethyl-8-(2, the 4-3,5-dimethylphenyl) [1,5-a]-pyrazolo-1,3,5-triazines

(formula 1, wherein R ³Be CH (CHCO ₂H ₃) ₂, R ₁Be CH ₃, Z is C-CH ₃, Ar is 2, the 4-3,5-dimethylphenyl)

A.4-chloro-2,7-dimethyl-8-(2,4 dichloro benzene base) [1,5-a]-method for preparation of pyrazolotriazine

Under reflux temperature, with 2,7-dimethyl-8-(2, the 4-3,5-dimethylphenyl) [1,5-a]-(embodiment 1,1.38g for pyrazolo-1,3,5-triazines-4-ketone, 4.5mmol), N, accelerine (1ml, 8mmol) and the mixture of phosphoryl chloride (10ml) stirred 48 hours.Vacuum is removed excessive phosphoryl chloride.Residue is inclined to frozen water, and brief the stirring extracts three times fast with ethyl acetate.Organic layer with the frozen water washing merges also filters with dried over mgso then.Vacuum is removed solvent and is obtained brown oil.Rapid column chromatography (ethyl acetate: hexane=1: 4) obtain a component (R _f=0.5).Vacuum is removed solvent and is obtained yellow oil (1.0g, 68% productive rate); NMR (CDCl ₃, 300MHz); 7.55 (d, 1H, J=1), 7.38 (dd, 1H, J=7,1), 7.30 (d, 1H, J=7), 2.68 (s, 3H), 2.45 (s, 3H); CI-MS:327 (M+H).

B.4-(two (carbonyl methoxyl group) methyl)-2,7-dimethyl-8-(2, the 4-3,5-dimethylphenyl) [1,5-a]-pyrazolo-1,3,5-triazines

With hexane with sodium hydride (2mmol) washed twice is washed hypsokinesis at every turn and is gone out hexane for 60% fluid, 80mg, be dissolved in anhydrous tetrahydro furan (THF, 1ml) in.(0.32g, THF 2mmol) (2ml) solution begin acutely to produce gas this moment to drip diethyl malonate with 5 minutes.Add 4-chloro-2, (0.5g, THF 1.75mmol) (2ml) solution stir this reaction mixture 48 hours down in nitrogen environment 7-dimethyl-8-(2,4 dichloro benzene base) [1,5-a]-method for preparation of pyrazolotriazine then.The suspension that produces is inclined to water, use ethyl acetate extraction three times.With salt solution the organic layer that merges is washed once, through dried over mgso and filtration.Vacuum is removed solvent, obtains brown oil.(ethyl acetate: hexane=1: 9), vacuum obtains faint yellow solid (R after removing solvent through column chromatography _f=0.2,250mg, 35% productive rate); Mp 50-52 ℃; NMR (CDCl ₃, 300MHz): 12.35 (br.s, 1H), 7.15-7.00 (m, 3H), 4.40 (q, 2H, J=7), 4.30 (q, 2H, J=7), 2.4,2.35,2.3,2.2,2.1 (5s, 12H), 1.4 (t, 3H, J=7), 1.35-1.25 (m, 3H); CI-HRMS: calculated value: 411.2032, measured value: 411.2023.

Embodiment 6

4-(1,3-dimethoxy-2-third amino)-2, the preparation of 7-dimethyl-8-(2,4 dichloro benzene base) [1,5-a]-pyrazolo-1,3,5-triazines

(formula 1, wherein R ³Be NHCH (CH ₂OCH ₃) ₂, R ₁Be CH ₃, Z is C-CH ₃, Ar is the 2,4 dichloro benzene base)

Under reflux temperature, with 2,7-dimethyl-8-(2, the 4-3,5-dimethylphenyl) [1,5-a]-(embodiment 1,1.38g for pyrazolo-1,3,5-triazines-4-ketone, 4.5mmol), N, accelerine (1ml, 8mmol) and phosphoryl chloride (10ml) mixture stirred 48 hours.Vacuum is removed excessive phosphoryl chloride.Residue is inclined to frozen water, and brief the stirring extracts three times fast with ethyl acetate.Organic layer with the frozen water washing merges also filters with dried over mgso then.Vacuum is removed solvent and is obtained brown oil.Rapid column chromatography (ethyl acetate: hexane=1: 4) obtain a component (R _f=0.5).Vacuum is removed solvent and is obtained yellow oil (1.0g, 68% productive rate); NMR (CDCl ₃, 300MHz); 7.55 (d, 1H, J=1), 7.38 (dd, 1H, J=7,1), 7.30 (d, 1H, J=7), 2.68 (s, 3H), 2.45 (s, 3H); CI-MS:327 (M+H).

B.4-(1,3-dimethoxy-2-third amino)-2,7-dimethyl-8-(2,4 dichloro benzene base) [1,5-a]-pyrazolo-1,3,5-triazines

Under room temperature, with 4-chloro-2,7-dimethyl-8-(2,4 dichloro benzene base) [1,5-a]-pyrazolo-1,3,5-triazines (part A, 570mg, 1.74mmol), 1,3-dimethoxy propyl group-2-aminopropane (25mg, 2.08mmol) and the mixture of ethanol (10ml) stirred 18 hours.This reaction mixture is inclined to water (25ml), use ethyl acetate extraction three times.The organic layer that merges through dried over mgso also filters.Vacuum is removed solvent.Through column chromatography (methylene dichloride: methyl alcohol=50: 1) obtain a component.Vacuum obtains solid (250mg, 35% productive rate) after removing solvent; Mp 118-120 ℃; NMR (CDCl ₃, 300MHz); 7.50 (s, 1H), 7.28 (dd, 2H, J=8,1), 6.75 (d, 1H, J=8), 4.70-4.58 (m, 1H), 3.70-3.55 (m, 4H), 3.43 (s, 6H), 2.50 (s, 3H), 2.35 (s, 3H); CI-HRMS: calculated value: 409.1072, measured value 409.1085.C ₁₈H ₂₁Cl ₂N ₅O ₂Analytical calculation value: C, 52.69; H, 5.17; N, 17.07, Cl, 17.28; Measured value: C, 52.82; H, 5.06; N, 16.77, Cl, 17.50.

With aforesaid method and the known modification of organic synthesis those skilled in the art, can prepare additional embodiments compound among the 1-4 that tabulates down.

According to embodiment 1,2,3 or 6 described methods, can prepare the described embodiment compound of table 1.Use following abbreviation: Ph to be phenyl, Pr is a propyl group, and Me is a methyl, and Et is an ethyl, and Bu is a butyl, and Ex is embodiment.

Table 1

Ex. Z R3 Ar mp (℃) 6 ^a C-Me NHCH(CH ₂OMe) ₂ 2，4-Cl ₂-Ph 118-120 7 ^b C-Me NHCHPr ₂ 2，4-Cl ₂-Ph 114-116 8 ^c C-Me NEtBu 2，4-Cl ₂-Ph grease 9^d C-Me NPr(CH ₂-c-C ₃H ₅) 2，4-Cl ₂-Ph grease 10^e C-Me N(CH ₂CH ₂OMe) ₂ 2，4-Cl ₂-Ph grease 11^fC-Me NH-3-heptyl 2,4-Cl₂-Ph 90-92 12 ^g C-Me NHCH(E)CH ₂OMe 2，4-Cl ₂-Ph 179-181 13 ^h C-Me NEt ₂ 2，4-Cl ₂-Ph 133-134 14 ⁱ C-Me NHCH(CH ₂OEt) ₂ 2，4-Cl ₂-Ph grease 15^jC-Me NH-3-amyl group 2,4-Cl₂-Ph 139-140 16 ^k C-Me NMePh 2，4-Cl ₂-Ph 60-62 17 ^l C-Me NPr ₂ 2，4-Cl ₂-Ph grease 18^mC-Me NH-3-hexyl 2,4-Cl₂-Ph 130-132 19 C-Me morpholinoes 2,4-Cl₂-Ph 20 C-Me N(CH ₂Ph)CH ₂CH ₂CMe 2，4-Cl ₂-Ph 21 C-Me NHCH(CH ₂Ph)CH ₂OMe 2，4-Cl ₂-Ph 22 C-Me NH-4-THP trtrahydropyranyls 2,4-Cl₂-Ph 23 C-Me NH-cyclopenta 2,4-Cl₂-Ph 24 C-Me 1,2,3,4-tetrahydro isoquinolyl 2,4-Cl₂-Ph 25 C-Me CH ₂-(1,2,3,4-tetrahydro isoquinolyl) 2,4-Cl₂-Ph 26 ⁿ C-Me OEt 2，4-Cl ₂-Ph 141-143 27 C-Me OCH(Et)CH ₂OMe 2，4-Cl ₂-Ph 28 C-Me OCH ₂Ph 2，4-Cl ₂-Ph 29 C-Me O-3-amyl groups 2,4-Cl₂-Ph 30 C-Me SEt 2，4-Cl ₂-Ph 31 C-Me S(O)Et 2，4-Cl ₂-Ph 32 C-Me SO ₂Et 2，4-Cl ₂-Ph 33 C-Me CH(CO ₂Et) ₂ 2，4-Cl ₂-Ph 34 C-Me C(Et)(CO ₂Et) ₂ 2，4-Cl ₂-Ph 35 C-Me CH(Et)CH ₂OH 2，4-Cl ₂-Ph 36 C-Me CH(Et)CH ₂OMe 2，4-Cl ₂-Ph 37 C-Me CONMe ₂ 2，4-Cl ₂-Ph 38 C-Me COCH ₃ 2，4-Cl ₂-Ph 39 C-Me CH(OH)CH ₃ 2，4-Cl ₂-Ph 40 C-Me C (OH) Ph-3-pyridine radicals 2,4-Cl₂-Ph 41 C-Me Ph 2，4-Cl ₂-Ph 42 C-Me 2-CF ₃-Ph 2，4-Cl ₂-Ph 43 C-Me 2-Ph-Ph 2，4-Cl ₂-Ph 44 C-Me 3-amyl groups 2,4-Cl₂-Ph 45 C-Me cyclobutyl 2,4-Cl₂-Ph 46 C-Me 3-pyridine radicals 2,4-Cl₂-Ph 47 C-Me CH(Et)CH ₂CONMe ₂ 2，4-Cl ₂-Ph 48 C-Me CH(Et)CH ₂CH ₂NMe ₂ 2，4-Cl ₂-Ph 49 ^o C-Me NHCH(CH ₂OMe) ₂ 2，4，6-Me ₃-Ph 125-127 50 C-Me NHCHPr ₂ 2，4，6-Me ₃-Ph 51 C-Me NEtBu 2，4，6-Me ₃-Ph 52 C-Me NPr(CH ₂-c-C ₃H ₅) 2，4，6-Me ₃-Ph 53 ^ae C-Me N(CH ₂CH ₂OMe) ₂ 2，4，6-Me ₃-Ph 123-124 54 C-Me NH-3-heptyl 2,4,6-Me₃-Ph 55 ^ac C-Me NHCH(Et)CH ₂OMe 2，4，6-Me ₃-Ph 145-146 56 ^ah C-Me NEt ₂ 2，4，6-Me ₃-Ph 88-90 57 ^ai C-Me NHCH(CH ₂OEt) ₂ 2，4，6-Me ₃-Ph 132-134 58 ^adC-Me NH-3-amyl group 2,4,6-Me₃-Ph 134-135 59 C-Me NMePh 2，4，6-Me ₃-Ph 60 C-Me NPr ₂ 2，4，6-Me ₃-Ph 61 C-Me NH-3-hexyls 2,4,6-Me₃-Ph 62 C-Me morpholinoes 2,4,6-Me₃-Ph 63 C-Me N(CH ₂Ph)CH ₂CH ₂OMe 2，4，6-Me ₃-Ph 64 C-Me NHCH(CH ₂Ph)CH ₂OMe 2，4，6-Me ₃-Ph 65 C-Me NH-4-THP trtrahydropyranyls 2,4,6-Me₃-Ph 66 C-Me NH-cyclopenta 2,4,6-Me₃-Ph 67 C-Me 1,2,3,4-tetrahydro isoquinolyl 2,4,6-Me₃-Ph 68 C-Me CH ₂-(1,2,3,4-tetrahydro isoquinolyl) 2,4,6-Me₃-Ph 69 C-Me OEt 2，4，6-Me ₃-Ph 70 C-Me OCH(Et)CH ₂OMe 2，4，6-Me ₃-Ph 71 C-Me OCH ₂Ph 2，4，6-Me ₃-Ph 72 C-Me O-3-amyl groups 2,4,6-Me₃-Ph 73 C-Me SEt 2，4，6-Me ₃-Ph 74 C-Me S(O)Et 2，4，6-Me ₃-Ph 75 C-Me SO ₂E 2，4，6-Me ₃-Ph 76 C-Me CH(CO ₂Et) ₂ 2，4，6-Me ₃-Ph 77 C-Me C(Et)(CO ₂Et) ₂ 2，4，6-Me ₃-Ph 78 C-Me CH(Et)CH ₂OH 2，4，6-Me ₃-Ph 79 C-Me CH(Et)OH ₂OMe 2，4，6-Me ₃-Ph 80 C-Me CONMe ₂ 2，4，6-Me ₃-Ph 81 C-Me COCH ₃ 2，4，6-Me ₃-Ph 82 C-Me CH(OH)CH ₃ 2，4，6-Me ₃-Ph 83 C-Me C (OH) Ph-3-pyridine radicals 2,4,6-Me₃-Ph 84 C-Me Ph 2，4，6-Me ₃-Ph 85 C-Me 2-CF ₃-Ph 2，4，6-Me ₃-Ph 86 C-Me 2-Ph-Ph 2，4，6-Me ₃-Ph 87 C-Me 3-amyl groups 2,4,6-Me₃-Ph 88 C-Me cyclobutyl 2,4,6-Me₃-Ph 89 C-Me 3-pyridine radicals 2,4,6-Me₃-Ph 90 C-Me CH(Et)CH ₂CONMe ₂ 2，4，6-Me ₃-Ph 91 C-Me CH(Et)CH ₂CH ₂NMe ₂ 2，4，6-Me ₃-Ph 92 ^p C-Me NHCH(CH ₂OMe) ₂ 2，4-Me ₂-Ph 44-45 93 ^q C-Me N(CH ₂CH ₂OMe) ₂ 2，4-Me ₂-Ph grease 94^r C-Me NHCH(Et)CH ₂OMe 2，4-Me ₂-Ph 102-104 95 ^sC-Me NH-3-amyl group 2,4-Me₂-Ph 102-104 96 ^t C-Me NEt ₂ 2，4-Me ₂-Ph grease 97^u C-Me N(CH ₂CN) ₂ 2，4-Me ₂-Ph 148-150 98 ^v C-Me NHCH(Me)CH ₂OMe 2，4-Me ₂-Ph 102-104 99 ^w C-Me OCH(Et)CH ₂OMe 2，4-Me ₂-Ph grease 100^x C-Me NPr-c-C ₃H ₅ 2，4-Me ₂-Ph grease 101^y C-Me NHCH(Me)CH ₂NMe ₂ 2，4-Me ₂-Ph 47-48 102 ^z C-Me N(c-C ₃H ₅)CH ₂CH ₂CN 2，4-Me ₂-Ph 117-118 103 ^aa C-Me N(Pr)CH ₂CH ₂CN 2，4-Me ₂-Ph grease 104^ab C-Me N(Bu)CH ₂CH ₂CN 2，4-Me ₂-Ph grease 105 C-Me NHCHPr₂ 2，4-Me ₂-Ph 106 C-Me NEtBu 2，4-Me ₂-Ph 107 C-Me NPr(CH ₂-c-C ₃H ₅) 2，4-Me ₂-Ph 108 C-Me NH-3-heptyl 2,4-Me₂-Ph 109 C-Me NEt ₂ 2，4-Me ₂-Ph 110 C-Me NHCH(CH ₂OEt) ₂ 2，4-Me ₂-Ph 111 C-Me NH-3-amyl groups 2,4-Me₂-Ph 112 C-Me NMePh 2，4-Me ₂-Ph 113 C-Me NPr ₂ 2，4-Me ₂-Ph 114 C-Me NH-3-hexyls 2,4-Me₂-Ph 115 C-Me morpholinoes 2,4-Me₂-Ph 116 C-Me N(CH ₂Ph)CH ₂CH ₂OMe 2，4-Me ₂-Ph 117 C-Me NHCH(CH ₂Ph)CH ₂OMe 2，4-Me ₂-Ph 118 C-Me NH-4-THP trtrahydropyranyls 2,4-Me₂-Ph 119 C-Me NH-cyclopenta 2,4-Me₂-Ph 120 C-Me 1,2,3,4-tetrahydro isoquinolyl 2,4-Me₂-Ph 121 C-Me CH ₂-(1,2,3,4-tetrahydro isoquinolyl) 2,4-Me₂-Ph 122 C-Me OEt 2，4-Me ₂-Ph 123 C-Me OCH(Et)CH ₂OMe 2，4-Me ₂-Ph 124 C-Me OCH ₂Ph 2，4-Me ₂-Ph 125 C-Me O-3-amyl groups 2,4-Me2-Ph 126 C-Me SEt 2,4-Me₂-Ph 127 C-Me S(O)Et 2，4-Me ₂-Ph 128 C-Me SO ₂Et 2，4-Me ₂-Ph 3 C-Me CH(CO ₂Et) ₂ 2，4-Me ₂-Ph 50-52 129 C-Me C(Et)(CO ₂Et) ₂ 2，4-Me ₂-Ph 130 C-Me CH(Et)CH ₂OH 2，4-Me ₂-Ph 131 C-Me CH(Et)CH ₂OMe 2，4-Me ₂-Ph 132 C-Me CH(Et)CH ₂OEt 2，4-Me ₂-Ph 133 C-Me CONMe ₂ 2，4-Me ₂-Ph 134 C-Me COCH ₃ 2，4-Me ₂-Ph 135 C-Me CH(OH)CH ₃ 2，4-Me ₂-Ph 136 C-Me C (OH) Ph-3-pyridine radicals 2,4-Me₂-Ph 137 C-Me Ph 2，4-Me ₂-Ph 138 C-Me 2-CF ₃-Ph 2，4-Me ₂-Ph 139 C-Me 2-Ph-Ph 2，4-Me ₂-Ph 140 C-Me 3-amyl groups 2,4-Me₂-Ph 141 C-Me cyclobutyl 2,4-Me₂-Ph 142 C-Me 3-pyridine radicals 2,4-Me₂-Ph 143 C-Me CH(Et)CH ₂CONMe ₂ 2，4-Me ₂-Ph 144 C-Me CH(Et)CH ₂CH ₂NMe ₂ 2，4-Me ₂-Ph 145 ^bc C-Me NHCH(CH ₂OMe) ₂ 2-Me-4-MeO-Ph 45-46 146 ^bd C-Me N(CH ₂CH ₂OMe) ₂2-Me-4-MeO-Ph grease 147^be C-Me NHCH(Et)CH ₂OMe 2-Me-4-MeO-Ph 86-88 148 ^bf C-Me N(Pr)CH ₂CH ₂CN 2-Me-4-MeO-Ph grease 149 C-Me OCH (Et) CH₂OMe 2-Me-4-MeO-Ph 150 ^af C-Me NHCH(CH ₂OMe) ₂ 2-Br-4-MeO-Ph 88-90 151 ^al C-Me N(CH ₂CH ₂OMe) ₂2-Br-4-MeO-Ph grease 152^ag C-Me NHCH(Et)CH ₂OMe 2-Br-4-MeO-Ph 95-97 153 C-Me N(Pr)CH ₂CH ₂CN 2-Br-4-MeO-Ph 154 C-Me OCH(Et)CH ₂OMe 2-Br-4-MeO-Ph 155 C-Me NHCH(CH ₂OMe) ₂ 2-Me-4-NMe ₂-Ph 156 C-Me N(CH ₂CH ₂OMe) ₂ 2-Me-4-NMe ₂-Ph grease 157 C-Me NHCH (Et) CH₂OMe 2-Me-4-NMe ₂-Ph 158 C-Me N(Pr)CH ₂CH ₂CN 2-Me-4-NMe ₂-Ph 159 C-Me OCH(Et)CH ₂OMe 2-Me-4-NMe ₂-Ph 160 C-Me NHCH(CH ₂OMe) ₂ 2-Br-4-NMe ₂-Ph 161 C-Me N(CH ₂CH ₂OMe) ₂ 2-Br-4-NMe ₂-Ph 162 C-Me NHCH(Et)CH ₂OMe 2-Br-4-NMe ₂-Ph 163 C-Me N(Pr)CH ₂CH ₂CN 2-Br-4-NMe ₂-Ph 164 C-Me OCH(Et)CH ₂OMe 2-Br-4-NMe ₂-Ph 165 C-Me NHCH(CH ₂OMe) ₂ 2-Br-4-i-Pr-Ph 166 C-Me N(CH ₂CH ₂OMe) ₂ 2-Br-4-i-Pr-Ph 167 C-Me NHCH(Et)CH ₂OMe 2-Br-4-i-Pr-Ph 168 C-Me N(Pr)CH ₂CH ₂CN 2-Br-4-i-Pr-Ph 169 C-Me OCH(Et)CH ₂OMe 2-Br-4-i-Pr-Ph 170 C-Me NHCH(CH ₂OMe) ₂ 2-Br-4-Me-Ph 171 C-Me N(CH ₂CH ₂OMe) ₂ 2-Br-4-Me-Ph 172 C-Me NHCH(Et)CH ₂OMe 2-Br-4-Me-Ph 173 C-Me N(Pr)CH ₂CH ₂CN 2-Br-4-Me-Ph 174 C-Me OCH(Et)CH ₂OMe 2-Br-4-Me-Ph 175 ^ar C-Me NHCH(CH ₂OMe) ₂ 2-Me-4-Br-Ph 108-109 176 C-Me N(CH ₂CH ₂OMe) ₂ 2-Me-4-Br-Ph 177 C-Me NHCH(Et)CH ₂OMe 2-Me-4-Br-Ph 178 C-Me N(Pr)CH ₂CH ₂CN 2-Me-4-Br-Ph 179 C-Me OCH(Et)CH ₂OMe 2-Me-4-Br-Ph 180 C-Me NHCH(CH ₂OMe) ₂ 2-Cl-4，6-Me ₂-Ph 181 C-Me N(CH ₂CH ₂OMe) ₂ 2-Cl-4，6-Me ₂-Ph 182 C-Me NHCH(CH ₂OMe) ₂ 4-Br-2，6-(Me) ₂-Ph 183 C-Me N(CH ₂CH ₂OMe) ₂ 4-Br-2，6-(Me) ₂-Ph 184 C-Me NHCH(CM ₂OMe) ₂ 4-i-Pr-2-SMe-Ph 185 C-Me N(CH ₂CH ₂OMe) ₂ 4-i-Ph-2-SMe-Ph 186 C-Me NHCH(CH ₂OMe) ₂ 2-Br-4-CF ₃-Ph 187 C-Me N(CH ₂CH ₂OMe) ₂ 2-Br-4-CF ₃-Ph 188 C-Me NHCH(CH ₂OMe) ₂ 2-Br-4，6-(MeO) ₂-Ph 189 C-Me N(CH ₂CH ₂OMe) ₂ 2-Br-4，6-(MeO) ₂-Ph 190 C-Me NHCH(CH ₂OMe) ₂ 2-Cl-4，6-(MeO) ₂-Ph 191 C-Me N(CH ₂CH ₂OMe) ₂ 2-Cl-4，6-(MeO) ₂-Ph 192 C-Me NHCH(CH ₂OMe) ₂ 2，6-(Me) ₂-4-SMe-Ph 193 C-Me N(CH ₂CH ₂OMe) ₂ 2，6-(Me) ₂-4-SMe-Ph 194 C-Me NHCH(CH ₂OMe) ₂ 4-(COMe)-2-Br-Ph 195 C-Me N(CH ₂CH ₂OMe) ₂ 4-(COMe)-2-Br-Ph 196 C-Me NHCH(CH ₂OMe) ₂ 2，4，6-Me ₃-pyridin-3-yl 197 C-Me N (CH₂CH ₂OMe) ₂ 2，4，6-Me ₃-pyridin-3-yl 198 C-Me NHCH (CH₂OMe) ₂ 2，4-(Br) ₂-Ph 199 C-Me N(CH ₂CH ₂OMe) ₂ 2，4-(Br) ₂-Ph 200 C-Me NHCH(CH ₂OMe) ₂ 4-i-Pr-2-SMe-Ph 201 C-Me N(CH ₂CH ₂OMe) ₂ 4-i-Pr-2-SMe-Ph 202 C-Me NHCH(CH ₂OMe) ₂ 4-i-Pr-2-SO ₂Me-Ph 203 C-Me N(CH ₂CH ₂OMe) ₂ 4-i-Pr-2-SO ₂Me-Ph 204 C-Me NHCH(CH ₂OMe) ₂ 2，6-(Me) ₂-4-SMe-Ph 205 C-Me N(CH ₂CH ₂OMe) ₂ 2，6-(Me) ₂-4-SMe-Ph 206 C-Me NHCH(CH ₂OMe) ₂ 2，6-(Me) ₂-4-SO ₂Me-Ph 207 C-Me N(CH ₂CH ₂OMe) ₂ 2，6-(Me) ₂-4-SO ₂Me-Ph 208 C-Me NHCH(CH ₂OMe) ₂ 2-I-4-i-Pr-Ph 209 C-Me N(CH ₂CH ₂OMe) ₂ 2-I-4-i-Pr-Ph 210 C-Me NHCH(CH ₂OMe) ₂ 2-Br-4-N(Me) ₂-6-MeO-Ph 211 C-Me N(CH ₂CH ₂OMe) ₂ 2-Br-4-N(Me) ₂-6-MeO-Ph 212 C-Me NHCH(CH ₂OMe) ₂ 2，4-[SMe]2-Ph 213 C-Me N(CH ₂CH ₂OMe) ₂ 2，4-[SMe]2-Ph 214 C-Me NHCH(CH ₂OMe) ₂ 2，4-[SO ₂Me]2-Ph 215 C-Me N(CH ₂CH ₂OMe) ₂ 2，4-[SO ₂Me]2-Ph 216 C-Me NHCH(CH ₂OMe) ₂ 4-i-Pr-2-SMe-Ph 217 C-Me N(CH ₂CH ₂OMe) ₂ 4-i-Pr-2-SMe-Ph 218 C-Me NHCH(CH ₂OMe) ₂ 4-i-Pr-2-SO ₂Me-Ph 219 C-Me N(CH ₂CH ₂OMe) ₂ 4-i-Pr-2-SO ₂Me-Ph 220 C-Me NHCH(CH ₂OMe) ₂ 2-N(Me) ₂-4-Me-Ph 221 C-Me N(CH ₂CH ₂OMe) ₂ 2-N(Me) ₂-4-Me-Ph 222 C-Me NHCH(CH ₂OMe) ₂ 2-MeS-4，6-(Me) ₂-Ph 223 C-Me N(CH ₂CH ₂OMe) ₂ 2-MeS-4，6-(Me) ₂-Ph 224 C-Me NHCH(CH ₂OMe) ₂ 2-(CH ₃CO)-4，6-(Me) ₂-Ph 225 C-Me N(CH ₂CH ₂OMe) ₂ 2-(CH ₃CO)-4，6-(Me) ₂-Ph 226 H NHCH(CH ₂OMe) ₁ 2，4-Me ₂-Ph 227 H NHCH(CH ₂OMe) ₂ 2，4-Me ₂-Ph 228 CF3 N(CH ₂CH ₂OMe) ₂ 2，4-Me ₂-Ph 229 CF3 N(CH ₂CH ₂OMe) ₂ 2，4-Me ₂-Ph 230 N NHCH(CH ₂OMe) ₂ 2，4，6-Me ₃-Ph 231 N NHCHPr ₂ 2，4，6-Me ₃-Ph 232 N NEtBu 2，4，6-Me ₃-Ph 233 N NPr(CH ₂-c-C ₃H ₅)2，4，6-Me ₃-Ph 234 N N(CH ₂CH ₂OMe) ₂ 2，4，6-Me ₃-Ph 235 N NH-3-heptyl 2,4,6-Me₃-Ph 236 N NHCH(Et)CH ₂OMe 2，4，6-Me ₃-Ph 237 N NEt ₂ 2，4，6-Me ₃-Ph 238 N NHCH(CH ₂OEt) ₂ 2，4，6-Me ₃-Ph 239 N NH-3-amyl groups 2,4,6-Me₃-Ph 240 N NMePh 2，4，6-Me ₃-Ph 241 N NPr ₂ 2，4，6-Me ₃-Ph 242 N NH-3-hexyls 2,4,6-Me₃-Ph 243 N morpholinoes 2,4,6-Me₃-Ph 244 N N(CH ₂Ph)CH ₂CH ₂OMe 2，4，6-Me ₃-Ph 245 N NHCH(CH ₂Ph)CH ₂OMe 2，4，6-Me ₃-Ph 246 N NH-4-THP trtrahydropyranyls 2,4,6-Me₃-Ph 247 N NH-cyclopenta 2,4,6-Me₃-Ph 248 N 1,2,3,4-tetrahydro isoquinolyl 2,4,6-Me₃-Ph 249 N CH ₂-(1,2,3,4-tetrahydro isoquinolyl) 2,4,6-Me₃-Ph 250 N OEt 2，4，6-Me ₃-Ph 251 N OCH(Et)CH ₂OMe 2，4，6-Me ₃-Ph 252 N OCH ₂Ph 2，4，6-Me ₃-Ph 253 N O-3-amyl groups 2,4,6-Me₃-Ph 254 N SEt 2，4，6-Me ₃-Ph 255 N S(O)Et 2，4，6-Me ₃-Ph 256 N SO ₂Et 2，4，6-Me ₃-Ph 257 N CH(CO ₂Et) ₂ 2，4，6-Me ₃-Ph 258 N C(Et)(CO ₂Et) ₂ 2，4，6-Me ₃-Ph 259 N CH(Et)CH ₂OH 2，4，6-Me ₃-Ph 260 N CH(E-)CH ₂OMe 2，4，6-Me ₃-Ph 261 N CONMe ₂ 2，4，6-Me ₃-Ph 262 N COCH ₃ 2，4，6-Me ₃-Ph 263 N CH(OH)CH ₃ 2，4，6-Me ₃-Ph 264 N C (OH) Ph-3-pyridine radicals 2,4,6-Me₃-Ph 265 N Ph 2，4，6-Me ₃-Ph 266 N 2-CF ₃-Ph 2，4，6-Me ₃-Ph 267 N 2-Ph-Ph 2，4，6-Me ₃-Ph 268 N 3-amyl groups 2,4,6-Me₃-Ph 269 N cyclobutyl 2,4,6-Me₃-Ph 270 N 3-pyridine radicals 2,4,6-Me₃-Ph 271 N CH(Et)CH ₂CONMe ₂ 2，4，6-Me ₃-Ph 272 N CH(Et)CH ₂CH ₂NMe ₂ 2，4，6-Me ₃-Ph 273 N NHCH(CH ₂OMe) ₂ 2，4-Me ₂-Ph 274 N NHCHPr ₂ 2，4-Me ₂-Ph 275 N NEtBu 2，4-Me ₂-Ph 276 N NPr(CH ₂-c-C ₃H ₅) 2，4-Me ₂-Ph 277 N N(CH ₂CH ₂OMe) ₂ 2，4-Me ₂-Ph 278 N NH-3-heptyl 2,4-Me₂-Ph 279 N NHCH(Et)CH ₂OMe 2，4-Me ₂-Ph 280 N NEt ₂ 2，4-Me ₂-Ph 281 N NHCH(CH ₂OEt) ₂ 2，4-Me ₂-Ph 282 N NH-3-amyl groups 2,4-Me₂-Ph 283 N NMePh 2，4-Me ₂-Ph 284 N NPr ₂ 2，4-Me ₂-Ph 285 N NH-3-hexyls 2,4-Me₂-Ph 286 N morpholinoes 2,4-Me₂-Ph 287 N N(CH ₂Ph)CH ₂CH ₂OMe 2，4-Me ₂-Ph 288 N NHCH(CH ₂Ph)CH ₂OMe 2，4-Me ₂-Ph 289 N NH-4-THP trtrahydropyranyls 2,4-Me₂-Ph 290 N NH-cyclopenta 2,4-Me₂-Ph 291 N 1,2,3,4-tetrahydro isoquinolyl 2,4-Me₂-Ph 292 N CH ₂-(1,2,3,4-tetrahydro isoquinolyl) 2,4-Me₂-Ph 293 N OEt 2，4-Me ₂-Ph 294 N OCH(Et)CH ₂OMe 2，4-Me ₂-Ph 295 N OCH ₂Ph 2，4-Me ₂-Ph 296 N O-3-amyl groups 2,4-Me₂-Ph 297 N SEt 2，4-Me ₂-Ph 298 N S(O)Et 2，4-Me ₂-Ph 299 N SO ₂Et 2，4-Me ₂-Ph 300 N CH(CO ₂Et) ₂ 2，4-Me ₂-Ph 301 N C(Et)(CO ₂Et) ₂ 2，4-Me ₂-Ph 302 N CH(Et)CH ₂OH 2，4-Me ₂-Ph 303 N CH(Et)CH ₂OMe 2，4-Me ₂-Ph 304 N CONMe ₂ 2，4-Me ₂-Ph 305 N COCH ₃ 2，4-Me ₂-Ph 306 N CH(OH)CH ₃ 2，4-Me ₂-Ph 307 N C (OH) Ph-3-pyridine radicals 2,4-Me₂-Ph 308 N Ph 2，4-Me ₂-Ph 309 N 2-CF ₃-Ph 2，4-Me ₂-Ph 310 N 2-Ph-Ph 2，4-Me ₂-Ph 311 N 3-amyl groups 2,4-Me₂-Ph 312 N cyclobutyl 2,4-Me₂-Ph 313 N 3-pyridine radicals 2,4-Me₂-Ph 314 N CH(Et)CH ₂CONMe ₂ 2，4-Me ₂-Ph 315 N CH(Et)CH ₂CH ₂NMe ₂ 2，4-Me ₂-Ph 316 ^an C-Me NEt ₂2-Br-4-MeO-Ph grease 317^amC-Me NH-3-amyl group 2-Br-4-MeO-Ph grease 318^aj C-Me NHCH(CH ₂CH ₂OMe)CH ₂OMe 2，4，6-Me ₃-Ph 101-103 319 ^ao C-Me NH(c-C ₃H ₅) 2，4-Me ₂-Ph grease 320^akC-Me morpholino 2,4,6-Me₃-Ph 139-141 321 ^ap C-Me NHCH(CH ₂OMe) ₂ 2-CN-4-Me-Ph 152-153 322 ^aq C-Me N(c-C ₃H ₅)CH ₂CH ₂CN 2，4，6-Me ₃-Ph 149-151 324 ^as C-Me NHCH(CH ₂CH ₂OMe)CH ₂OMe 2-Me-4-Br-Ph 115-117 325 ^at C-Me NHCH(CH ₂OMe) ₂ 2，5-Me ₂-4-MeO-Ph 55-57 326 ^au C-Me N(CH ₂CH ₂OMe) ₂ 2，5-Me ₂-4-MeO-Ph 72 327 ^avC-Me NH-3-amyl group 2,5-Me₂-4-MeO-Ph 45-47 328 ^aw C-Me NEt ₂ 2，5-Me ₂-4-MeO-Ph grease 329^ax C-Me NHCH(CH ₂OMe) ₂ 2-Cl-4-MePh 80-91 330 ^ay C-Me NCH(Et)CH ₂OMe 2-Cl-4-MePh 77-79 331 ^az C-Me N(CH ₂CH ₂OMe) ₂2-Cl-4-MePh grease 332^ba C-Me (S)-NHCH(CH ₂CH ₂OMe)CH ₂OMe 2-Cl-4-MePh 139-140 333 ^bb C-Me N(c-C ₃H ₅)CH ₂CH ₂CN 2，5-Me ₂-4-MeOPh 120-122 334 ^bg C-Me NEt ₂2-Me-4-MeOPh grease 335^bhC-Me OEt 2-Me-4-MeOPh grease 336^bi C-Me (S)-NHCH(CH ₂CH ₂OMe)CH ₂OMe 2-Me-4-MeOPh grease 337^bj C-Me N(c-C ₃H ₅)CH ₂CH ₂CN 2-Me-4-MeOPh 129 338 ^bk C-Me NHCH(CH ₂CH ₂OEt) ₂The amorphous 339 C-Me N (c-C of 2-Me-4-MeOPh₃H ₅)CH ₂CH ₂CN 2，4-Cl ₂-Ph 109-110 340 C-Me (S)-NHCH(CH ₂CH ₂OMe)CH ₂OMe 2，4-Cl ₂-Ph 93-94 341 C-Me NH-3-amyl group 2-Me-4-BrPh 118-119 342 C-Me N (CH₂CH ₂OMe) ₂2-Me-4-BrPh grease 343 C-Me NHCH (CH₂-iPr)CH ₂OMe 2，4-Me ₂-Ph grease 344 C-Me NHCH (Pr) CH₂OMe 2，4-Me ₂-Ph 94-95 345 C-Me MHCH(Et)CH ₂OEt 2，4-Me ₂-Ph 76-77 346 C-Me NHCH(CH ₂OMe)CH ₂CH ₂OMe 2-Me-4-Me ₂NPh grease 347 C-Me NEt₂2-Me-4-ClPh grease 348 C-Me NH-3-amyl group 2-Me-4-ClPh 122-124 349 C-Me N (CH₂CH ₂OMe) ₂2-Me-4-ClPh grease 350 C-Me NHCH (CH₂OMe) ₂ 2-Me-4-ClPh 122-123 351 C-Me NEt ₂2-Me-4-ClPh grease 352 C-Me NEt₂2-Cl-4-MePh grease 353 C-Me NH-3-amyl group 2-Cl-4-MePh 120-121 354 C-Me NHCH (CH₂OMe) ₂ 2-Cl-4-MeOPh 355 ^bl C-Me N(CH ₂CH ₂OMe) ₂2-Cl-4-MeOPh grease 356^bm C-Me NHCH(Et)CH ₂OMe 2-Cl-4-MeOPh 108-110 357 ^bn C-Me N(c-Pr)CH ₂CH ₂CN 2-Cl-4-MeOPh 127-129 358 ^bo C-Me NEt ₂2-Cl-4-MeOPh grease 359^bpC-Me NH-3-amyl group 2-Cl-4-MeOPh 77-79 360 C-Me NHCH (Et) CH₂CH ₂OMe 2-Cl-4-MeOPh 361 C-Me NHCH(Me)CH ₂CH ₂OMe 2-Cl-4-MeOPh 362 C-Me NHCH(Et)CH ₂CH ₂OMe 2-Br-4-MeOPh 363 C-Me NHCH(Me)CH ₂CH ₂OMe 2-Br-4-MeOPh 364 C-Me MHCH(Et)CH ₂CH ₂OMe 2-Me-4-MeOPh 365 C-Me NHCH(Me)CH ₂CH ₂OMe 2-Me-4-MeOPh 366 C-Me NHCH(CH ₂OMe) ₂ 2-Cl-4，5-(MeO) ₂Ph 367 C-Me N(CH ₂CH ₂OMe) ₂ 2-Cl-4，5-(MeO) ₂Ph 368 C-Me NHCH(Et)CH ₂OMe 2-Cl-4，5-(MeO) ₂Ph 369 C-Me N(c-Pr)CH ₂CH ₂CN 2-Cl-4，5-(MeO) ₂Ph 370 C-Me NEt ₂ 2-Cl-4，5-(MeO) ₂Ph 371 C-Me NH-3-amyl group 2-Cl-4,5-(MeO)₂Ph 372 C-Me NHCH(Et)CH ₂CH ₂OMe 2-Cl-4，5-(MeO) ₂Ph 373 C-Me NHCH(Me)CH ₂CH ₂OMe 2-Cl-4，5-(MeO) ₂Ph 374 ^bq C-Me NHCH(CH ₂OMe) ₂ 2-Br-4，5-(MeO) ₂Ph 137-138 375 C-Me N(CH ₂CH ₂OMe) ₂ 2-Br-4，5-(MeO) ₂Ph 376 ^br C-Me NHCH(Et)CH ₂OMe 2-Br-4，5-(MeO) ₂Ph 147-148 377 C-Me N(c-Pr)CH ₂CH ₂CN 2-Br-4，5-(MeO) ₂Ph 378 ^bs C-Me NEt ₂ 2-Br-4，5-(MeO) ₂Ph 52-58 379 C-Me NH-3-amyl group 2-Br-4,5-(MeO)₂Ph 380 C-Me NHCH(Et)CH ₂CH ₂OMe 2-Br-4，5-(MeO) ₂Ph 381 C-Me NHCH(Me)CH ₂CH ₂OMe 2-Br-4，5-(MeO) ₂Ph 382 C-Me NHCH(CH ₂OMe) ₂ 2-Cl-4，6-(MeO) ₂Ph 383 C-Me N(CH ₂CH ₂OMe) ₂ 2-Cl-4，6-(MeO) ₂Ph 384 C-Me NHCH(Et)CH ₂OMe 2-Cl-4，6-(MeO) ₂Ph 385 C-Me N(c-Pr)CH ₂CH ₂CN 2-Cl-4，6-(MeO) ₂Ph 396 C-Me NEt ₂ 2-Cl-4，6-(MeO) ₂Ph 387 C-Me NH-3-amyl group 2-Cl-4,6-(MeO)₂Ph 388 C-Me NHCH(Et)CH ₂CH ₂OMe 2-Cl-4，6-(MeO) ₂Ph 389 C-Me NHCH(Me)CH ₂CH ₂OMe 2-Cl-4，6-(MeO) ₂Ph 390 C-Me NHCH(CH ₂OMe) ₂ 2-Me-4，6-(MeO) ₂Ph 391 C-Me N(CH ₂CH ₂OMe) ₂ 2-Me-4，6-(MeO) ₂Ph 392 C-Me NHCH(Et)CH ₂OMe 2-Me-4，6-(MeO) ₂Ph 393 C-Me N(c-Pr)CH ₂CH ₂CN 2-Me-4，6-(MeO) ₂Ph 395 C-Me NEt ₂ 2-Me-4，6-(MeO) ₂Ph 396 C-Me NH-3-amyl group 2-Me-4,6-(MeO)₂Ph 397 C-Me NHCH(Et)CH ₂CH ₂OMe 2-Me-4，6-(MeO) ₂Ph 398 C-Me NHCH(Me)CH ₂CH ₂OMe 2-Me-4，6-(MeO) ₂Ph 399 C-Me N(c-Pr)CH ₂CH ₂CN 2-Br-4，6-(MeO) ₂Ph 400 C-Me NEt ₂ 2-Br-4，6-(MeO) ₂Ph 401 C-Me NH-3-amyl group 2-Br-4,6-(MeO)₂Ph 402 C-Me NHCH(Et)CH ₂CH ₂OMe 2-Br-4，6-(MeO) ₂Ph 403 C-Me NHCH(Me)CH ₂CH ₂OMe 2-Br-4，6-(MeO) ₂Ph 404 C-Me NHCH(Et)CH ₂CH ₂OMe 2-Me-4-MeOPh 405 C-Me NHCH(Me)CH ₂CH ₂OMe 2-Me-4-MeOPh 406 C-Me NHCH(CH ₂OMe) ₂ 2-Me0-4-MePh 407 C-Me N(CH ₂CH ₂OMe) ₂ 2-Me0-4-MePh 408 C-Me NHCH(Et)CH ₂OMe 2-Me0-4-MePh 409 C-Me N(c-Pr)CH ₂CH ₂CN 2-Me0-4-MePh 410 C-Me NEt ₂2-Me0-4-MePh 411 C-Me NH-3-amyl group 2-Me0-4-MePh 412 C-Me NHCH (Et) CH₂CH ₂OMe 2-Me0-4-MePh 413 C-Me NHCH(Me)CH ₂CH ₂OMe 2-Me0-4-MePh 414 C-Me NHCH(CH ₂OMe) ₂ 2-Me0-4-MePh 415 C-Me N(CH ₂CH ₂OMe) ₂ 2-Me0-4-MePh 416 C-Me NHCH(Et)CH ₂OMe 2-Me0-4-MePh 417 C-Me N(c-Pr)CH ₂CH ₂CN 2-Me0-4-MePh 418 C-Me NEt ₂2-Me0-4-MePh 419 C-Me NH-3-amyl group 2-Me0-4-MePh 420 C-Me NHCH (Et) CH₂CH ₂OMe 2-Me0-4-MePh 421 C-Me NHCH(Me)CH ₂CH ₂OMe 2-Me0-4-MePh 423 ^bt C-Me NHCH(CH ₂OMe) ₂2-Me0-4-ClPh grease 424 C-Me N (CH₂CH ₂OMe) ₂ 2-Me0-4-ClPh 425 C-Me NHCH(Et)CH ₂OMe 2-Me0-4-ClPh 426 C-Me N(c-Pr)CH ₂CH ₂CN 2-Me0-4-ClPh 427 C-Me NEt ₂2-Me0-4-ClPh 428 C-Me NH-3-amyl group 2-Me0-4-ClPh 429 C-Me NHCH (Et) CH₂CH ₂OMe 2-Me0-4-ClPh 430 C-Me NHCH(Me)CH ₂CH ₂OMe 2-Me0-4-ClPh

Table 1 note 1: a) analytical calculation value: C, 52.69, H, 5.17, N, 17.07, Cl,

17.28; Measured value: C, 52.82, H, 5.06, N, 16.77, Cl,

17.50.b) CI-HRMS: calculated value: 406.1565, measured value: 405.1573 (M+H);

Analytical calculation value: C:59.11; H:6.20; N:17.23; Cl:

17.45; Measured value: C:59.93; H:6.34; N:16.50; Cl:

16.95；

NMR(CDCl ₃，300MHz)：0.95(t，J＝8，4H)，1.30-

1.40(m，4H)，1.50-1.75(m，4H)，2.35(s，3H)，2.48

(s，3H)，4.30-4.45(m，1H)，6.15(d，J＝8，1H)，

7.30 (s, 2H), 7.50 (s, 1H) c) CI-HRMS: calculated value: 392.1409, measured value: 392.1388 (M+H);

NMR(CDCl ₃，300MHz)：1.00(t，J＝8，3H)，1.35(t，

J＝8，3H)，1.41(q，J＝8，2H)，1.65-1.85(m，2H)，

2.30(s，3H)，2.40(s，3H)，3.85-4.20(m，4H)，7.30

(s, 2H), 7.50 (s, 1H) .d) CI-HRMS: calculated value: 404.1409, measured value: 404.1408 (M+H);

NMR(CDCl ₃，300MHz)：0.35-0.45(m，2H)，0.52-0.62

(m，2H)，0.98(t，J＝8，3H)，1.70-1.90(m，2H)，

2.30(s，3H)，2.40(s，3H)，3.85-4.02(m，2H)，

4.02-4.20 (m, 2H), 7.30 (s, 2H), 7.50 (s, 1H) .e) CI-HRMS: calculated value: 424.1307, measured value: 424.1307 (M+H):

NMR(CDCl ₃，300MHz)：2.28(s，3H)，2.40(s，3H)，

3.40(s，6H)，3.75(t，J＝8，4H)，4.20-4.45(m，

4H), 7.30 (s, 2H), 7.50 (s, 1H) .f) CI-HRMS: calculated value: 406.1565, measured value: 406.1578 (M+H);

NMR(CDCl ₃，300MHz)：0.90(t，J＝8，3H)，1.00(t，

J＝8，3H)，1.28-1.45(m，4H)，1.50-1.80(m，4H)，

2.35(s，3H)，2.50(s，3H)，4.20-4.35(m，1H)，

6.10-6.23 (m, 1H), 7.30 (s, 2H), 7.50 (s, 1H) .g) CI-HRMS: calculated value: 394.1201, measured value: 394.1209 (M+H);

NMR(CDCl ₃，300MHz)：1.02(t，J＝8，3H)，1.65-

1.90(m，2H)，2.35(s，3H)，2.48(s，3H)，3.40(s，

3H)，3.50-3.60(m，2H)，4.35-4.45(brs，1H)，6.50-

6.60 (m, 1H), 7.30 (s, 2H), 7.50 (s, 1H) .h) CI-HRMS: calculated value: 364.1096, measured value: 364.1093 (M+H);

Analytical calculation value: C:56.05; H:5.27; N:19.23; Cl:

19.46; Measured value: C:55.96; H:5.24; N:18.93; Cl:

19.25；

NMR(CDCl ₃，300MHz)：1.35(t，J＝8，6H)，2.30(3，

3H)，2.40(s，3H)，3.95-4.15(m，4H)，7.30(s，2H)，

(7.50 d, J=1,1H) .i) CI-HRMS: calculated value: 438.1464, measured value: 438.1454 (M+H);

NMR(CDCl ₃，300MHz)：1.22(t，J＝8，6H)，2.35(s，

3H)，2.47(s，3H)，3.39(q，J＝8，4H)，3.65(dd，J

＝8，1，2H)，3.73(dd，J＝8，1，2H)，4.55-4.65(m，

1H)，6.75(d，J＝8，1H)，7.30(d，J＝1，2H)，7.50

(s, 1H) .j) CI-HRMS: calculated value: 378.1252, measured value: 378.1249 (M+H);

Analytical calculation value: C:57.15; H:5.61; N:18.51; Cl:

1.8.74; Measured value: C:57.56; H:5.65; N:18.35; Cl:

18.45；

NMR(CDCl ₃，300MHz)：1.00(t，J＝8，6H)，1.55-

1.70(m，2H)，1.70-1.85(m，2H)，2.35(s，3H)，2.50

(s，3H)，4.15-4.25(m，1H)，6.18(d，J＝8，1H)，

7.30 (s, 2H), 7.50 (s, 1H) .k) CI-HRMS: calculated value: 398.0939, measured value: 398.0922 (M+H);

Analytical calculation value: C:60.31; H:4.30; N:17.58; Cl:

17.80; Measured value: C:60.29; H:4.59; N:17.09; Cl:

17.57；

NMR(CDCl ₃，300MHz)：2.05(s，3H)，2.50(s，3H)，

3.78(s，3H)，7.20-7.45(m，7H)，7.50(d，J＝1，

1H) .l) CI-HRMS: calculated value: 392.1409, measured value: 392.1391 (M+H);

NMR(CDCl ₃，300MHz)：0.98(t，J＝8，6H)，1.70-

1.85(m，4H)，2.30(s，3H)，2.40(s，3H)，3.80-4.10

(m, 4H), 7.30 (s, 2H), 7.50 (d, J=1,1H) .m) CI-HRMS: calculated value: 392.1409, measured value: 392.1415 (M+H);

Analytical calculation value: C:58.17; H:5.92; N:17.85; Cl:

18.07; Measured value: C:58.41; H:5.85:N:18.10; Cl:

17.75；

NMR(CDCl ₃，300MHz)：0.90-1.05(m，6H)，1.35-1.55

(m，2H)，1.55-1.85(m，4H)，2.35(s，3H)，2.48(s，

3H)，4.20-4.35(m，1H)，6.15(d，J＝8，1H)，7.30

(s, 2H), 7.50 (d, J=1,1H) .n) CI-HRMS: calculated value: 337.0623, measured value: 337.0689 (M+H);

Analytical calculation value: C:53.43; H:4.18; N:16.62; Cl:

21.03, measured value: C:53.56; H:4.33; N:16.56; Cl:

20.75；

NMR(CDCl ₃，300MHz)：1.60(t，J＝8，3H)，2.40(s，

3H)，2.55(s，3H)，4.80(q，J＝8，2H)，7.30(d，J

＝8，1H)，7.35(dd，J＝8，1，1H)，7.55(d，J＝1，

1H) .o) CI-HRMS: calculated value: 383.2321, measured value: 383.2309 (M+H);

NMR(CDCl ₃，300MHz)：2.00(s，6H)，2.20(s，3H)，

2.30(s，3H)，2.45(s，3H)，3.45(s，6H)，3.61(dd，

J＝8，8，2H)，3.70(dd，J＝8，8，2H)，4.60-4.70

(m, 1H), 6.70 (d, J=8,1H), and 6.94 (s, 2H) .p) CI-HRMS: calculated value: 370.2243, measured value: 370.2246 (M+H);

Analytical calculation value: C:65.02; H:7.38; N:18.96;

Measured value: C:65.22; H:7.39; N:18.71;

NMR(CDCl ₃，300MHz)：2.18(s，3H)，2.30(s，3H)，

2.45(s，3H)，3.45(s，6H)，3.60(dd，J＝8，8，

2H)，3.69(dd，J＝8，8，2H)，4.60-4.70(m，1H)，

6.70(d，J＝8，1H)，7.05(d，J＝8，1H)，7.07(d，

J=8,1H), 7.10 (s, 1H) .q) CI-HRMS: calculated value: 384.2400, measured value: 384.2393 (M+H);

NMR(CDCl ₃，300MHz)：2.16(s，3H)，2.25(s，3H)，

2.35(s，3H)，2.39(s，3H)，3.40(s，6H)，3.77(t，

J＝8，4H)，4.20-4.45(m，4H)，7.02(d，J＝8，1H)

7.05 (s, 1H), 7.10 (d, J=7,1H) .r) CI-HRMS: calculated value: 354.2294, measured value: 354.2271 (M+H);

Analytical calculation value: C:67.96; H:7.71; N:19.81;

Measured value: C:67.56; H:7.37; N:19.60;

NMR(CDCl ₃，300MHz)：1.03(t，J＝8，3H)，1.65-

1.88(m，2H)，2.17(s，3H)，2.30(s，3H)，2.35(s，

3H)，2.45(s，3H)，3.40(s，3H)，3.50-3.62(m，2H)，

4.30-4.45(m，1H)，6.51(d，J＝8，1H)，7.04(d，J

=8,1H), 7.10 (d, J=8,1H), and 7.12 (s, 1H) .s) CI-HRMS: calculated value: 338.2345, measured value: 338.2332 (M+H);

Analytical calculation value: C:71.18; H:8.06; N:20.75;

Measured value: C:71.43; H:7.80; N:20.70;

NMR(CDCl ₃，300MHz)：1.00(t，J＝8，6H)，1.55-

1.70(m，2H)，1.70-1.85(m，2H)，2.19(s，3H)，2.30

(s，3H)，2.35(s，3H)，2.46(s，3H)，4.15-4.26(m，

1H)，6.17(d，J＝8，1H)，7.06(d，J＝8，1H)，7.10

(d, J=1,1H), and 7.13 (s, 1H) .t) CI-HRMS: calculated value: 324.2188, measured value: 324.2188 (M+H);

NMR(CDCl ₃，300MHz)：1.25(t，J＝8，6H)，2.16(s，

3H)，2.28(s，3H)，2.35(s，3H)，2.40(s，3H)，

3.95-4.20(m，4H)，7.05(dd，J＝8，1，1H)，7.07

(s, 1H), 7.10 (d, J=1,1H) u) CI-HRMS: calculated value: 346.1780, measured value: 346.1785 (M+H);

Analytical calculation value: C:66.07; H:5.54; N:28.39;

Measured value: C:66.07; H:5.60; N:27.81;

NMR(CDCl ₃，300MHz)：2.15(s，3H)，2.32(s，3H)

2.17(s，3H)，2.52(s，3H)，5.25-5.35(m，4H)，7.08

(s, 2H), 7.15 (s, 1H) .v) CI-HRMS: calculated value: 340.2137, measured value: 340.2137 (M+H);

Analytical calculation value: C:67.23; H:7.42; N:20.63;

Measured value: C:67.11; H:7.39; N:20.26;

NMR(CDCl ₃，300MHz)：1.40(d，J＝8，3H)，2.16(s，

3H)，2.32(s，3H)，2.35(s，3H)，2.47(s，3H)，3.42

(s，3H)，3.50-3.60(m，2H)，4.50-4.15(m，1H)，6.56

(d, J=8,1H), and 7.00-7.15 (m, 3H) .w) CI-HRMS: calculated value: 355.2134, measured value: 355.2134 (M+H);

NMR(CDCl ₃，300MHz)：1.05(t，J＝8，3H)，1.85-

2.00(m，2H)，2.17(s，3H)，2.36(s，6H)，2.50(s，

3H)，3.41(s，3H)，3.45(dd，J＝8，3，1H)，3.82

(dd，J＝8，1，1H)，5.70-5.80(m，1H)，7.00-7.20

(m, 3H) .x) CI-HRMS: calculated value: 364.2501, measured value: 364.2501 (M+H);

NMR(CDCl ₃，300MHz)：0.35-0.43(m，2H)，0.50-0.60

(m，2H)，0.98(t，J＝8，3H)，1.20-1.30(m，1H)，

1.72-1.90(m，2H)，2.18(s，3H)2.28(s，3H)，2.35

(s，3H)，2.40(s，3H)，3.88-4.03(m，2H)，4.03-4.20

(m, 2H), 7.00-7.15 (m, 3H) .y) CI-HRMS: calculated value: 353.2454, measured value: 353.2454 (M+H);

Analytical calculation value: C:68.15; H:8.02; N:23.84;

Measured value: C:67.43; H:7.81; N:23.45;

NMR(CDCl ₃.300MHz)：1.38(d，J＝8，3H)，2.18(s，

3H)，2.30-2.40(m，12H)，2.47 93，3H)，2.60-2.75

(m，2H)，4.30-4.50(m，1H)，6.60-6.70(m，1H)，

(7.00-7.15 m, 3H) .z) CI-HRMS: calculated value: 361.2140, measured value: 361.2128 (M+H);

NMR(CDCl ₃.300MHz)：0.75-0.83(m，2H)，1.00-1.10

(m，2H)，2.17(s，3H)，2.30(s，3H)，2.36(s，3H)，

2.47(s，3H)，2.85(t，J＝8，2H)，3.30-3.40(m，

1H), and 4.40-4.55 (m, 2H), 7.00-7.18 (m, 3H) .aa) CI-HRMS: calculated value: 363.2297, measured value: 363.2311 (M+H);

NMR(CDCl ₃，300MHz)：1.01(t，3H，J＝8)，1.75-1.90

(m，2H)，2.15(s，3H)，2.19(s，3H)，2.35(s，3H)，

2.40(s，3H)，2.40(s，3H)，2.98(t，2H，J＝8)，

3.97-4.15(m，2H)，4.15-4.30(m，2H)，7.03(d，1H，

1H), 7.08 (d, 1H, J=8), and 7.10 (s, 1H) .ab) CI-HRMS: calculated value: 363.2297, measured value: 363.2295 (M+H);

NMR(CDCl ₃，300MHz)：1.01(t，3H，J＝8)，1.35-

1.55(m，2H)，1.75-1.90(m，2H)，2.15(s，3H)，2.30

(s，3H)，2.36(s，3H)，2.46(s，3H)，4.10-4.30(m，

2H)，4.95-5.10(br s，2H)，7.05(d，1H，J＝8)，

7.10 (d, 1H, J=8), and 7.15 (s, 1H) .ac) CI-HRMS: calculated value: 368.2450, measured value: 368.2436;

Analytical calculation value: C, 68.62, H, 7.95, N, 19.06;

Measured value: C, 68.73, H, 7.97, N, 19.09; NMR (CDCl ₃, 300

MHz)：1.05(t，J＝8，3H)，1.70-1.90(m，2H)，2.01

(d，J＝3，6H)，2.20(s，3H)，2.30(s，3H)，2.46，

2.465(s，s，3H)，3.42，3.48(s，s，3H)，3.53-3.63

(m，2H)，4.35-4.45(m，1H)，6.73(d，J＝8，1H)，

6.97 (s, 2H). (ad) CI-HRMS: calculated value: 352.2501, measured value: 352.2500 (M+

H): analytical calculation value: C:71.76; H:8.33; N:19.92,

Measured value: C:71.55; H:8.15; N:19.28;

NMR(CDCl ₃，300MHz)：1.01(t，J＝8，6H)，1.58

-1.70(m，2H)，1.70-1.85(m，2H)，2.02(s，6H)，

2.19(s，3H)，2.4 5(s，3H)，4.12-4.28(m，1H)，6.18

(d, J=8,1H), 6.95 (s, 2H). (ae) CI-HRMS: calculated value: 398.2556, measured value: 398.2551 (M+

H); Analytical calculation value: C:66.47; H:7.86; N:17.62,

Measured value: C:66.74; H:7.79; N:17.70;

NMR(CDCl ₃，300MHz)：2.00(s，6H)，2.12(s，3H)，

2.30(s，3H)，2.37(s，3H)，3.40(s，6H)，3.78(t，

J=8,4H), 4.25-4.40 (m, 4H), 6.93 (s, 2H). (af) CI-HRMS: calculated value: 450.1141, measured value: 450.1133 (M+H);

Analytical calculation value: C:50.67; H:5.37; N:15.55; Br:

17.74; Measured value: C:52.36; H:5.84; N:14.90; Br:

17.44；

NMR(CDCl ₃，300MHz)：2.32(s，3H)，2.57(s，3H)，

3.42(s，6H)，3.60(q，J＝8，2H)，3.69(q，J＝8，

2H)，3.82(s，3H)，4.60-4.70(m，1H)，6.73(d，J＝

8，1H)，6.93(dd，J＝8，1，1H)，7.22(d，J＝8，

1H) .ag) CI-HRMS: calculated value: 434.1192, measured value: 434.1169 (M+H);

Analytical calculation value: C:52.54; H:5.58; N:16.12; Br:

18.40; Measured value: C:52.57; H:5.60; N:15.98; Br:

18.22；

NMR(CDCl ₃，300MHz)：1.00-1.07(m，3H)，1.65-1.85

(m，2H)，2.35(s，3H)，2.46，2.47(s，s，3H)，3.40，

3.45(s，s，3H)，3.83(s，3H)，4.35-4.45(m，1H)，

6.55(d，J＝8，1H)，6.92(dd，J＝8，1，1H)，7.20-

(7.30 m, 2H) .ah) CI-HRMS: calculated value: 337.2266, measured value: 337.2251 (M+H);

Analytical calculation value: C:70.18; H:8.06; N:20.75;

Measured value: C:70.69; H:7.65; N:20.34;

NMR(CDCl ₃，300MHz)：1.35(t，J＝8，6H)，2.01(s，

6H)，2.15(s，3H)，2.30(s，3H)，2.38(s，3H)，4.07

(q, J=8,4H), and 6.93 (s, 2H) .ai) CI-HRMS: calculated value: 412.2713, measured value: 412.2687 (M+H);

Analytical calculation value: C:67.13; H:8.08; N:17.02;

Measured value: C:67.22; H:7.85; N:17.13;

NMR(CDCl ₃，300MHz)：1.24(t，J＝8，6H)，2.00(s，

6H)，2.20(s，3H)，2.30(s，3H)，2.43(s，3H)，3.60

(q，J＝8，4H)，3.66(dd，J＝8，3，2H)，3.75(dd，

J＝8，3，2H)，4.55-4.65(m，1H)，6.75(d，J＝8，

1H), 6.95 (s, 2H) .aj) CI-HRMS: calculated value: 398.2556, measured value: 398.2545 (M+H);

Analytical calculation value: C:66.47; H:7.86; N:17.62;

Measured value: C:66.87; H:7.62; N:17.75;

NMR(CDCl ₃，300MHz)：1.95-2.10(m，8H)，2.20(s，

3H)，2.32(s，3H)，2.44(s，3H)，3.38(s，3H)，3.42

(s，3H)，3.50-3.70(m，4H)，4.58-4.70(m，1H)，6.87

(d, J=8,1H), and 6.95 (s, 2H) .ak) CI-HRMS: calculated value: 338.1981, measured value: 338.1971 (M+H);

Analytical calculation value: C:67.63; H:6.87; N:20.06;

Measured value: C:67.67; H:6.82; N:20.31;

NMR(CDCl ₃，300MHz)：2.15(s，3H)，2.29(s，3H)，

2.35(s，3H)，2.43(s，3H)，3.90(t，J＝8，4H)，

4.35-4.45 (m, 4H), 7.00-7.15 (m, 3H) .al) CI-HRMS: calculated value: 464.1297, measured value: 464.1297 (M+H);

NMR(CDCl ₃，300MHz)：2.28(s，3H)，2.40(s，3H)，

3.40(s，6H)，3.75(t，J＝8，4H)，3.83(s，3H)，

4.20-4.50(m，4H)，6.93(dd，J＝8，1，1H)，7.20

(s, 1H), 7.24 (d, J=1,1H) .am) CI-HRMS: calculated value: 418.1242, measured value: 418.1223 (M+H);

NMR(CDCl ₃，300MHz)：1.00(t，d，J＝8，1，6H)，

1.55-1.75(m，4H)，2.34(s，3H)，2.49(s，3H)，2.84

(s，3H)，4.15-4.27(m，1H)，6.19(d，J＝8，1H)，

6.93 (dd, J=8,1,1H), and 7.21-7.30 (m, 2H) .an) CI-HRMS: calculated value: 404.1086, measured value: 404.1079 (M+H);

NMR(CDCl ₃，300MHz)：1.35(t，J＝8，6H)，2.28(s，

3H)，2.40(s，3H)，3.83(s，3H)，3.90-4.08(m，2H)，

4.08-4.20(m，2H)，6.92(dd，J＝8，1，1H)，7.20-

(7.25 m, 2H) .ao) CI-HRMS: calculated value: 308.1875, measured value: 308.1872 (M+H);

NMR(CDCl ₃，300MHz)：0.75-0.80(m，2H)，0.93-1.00

(m，2H)，2.16(s，3H)，2.28(s，3H)，2.35(s，3H)，

2.53(s，3H)，3.00-3.10(m，1H)，6.50-6.55(m，1H)，

(7.00-7.15 m, 3H) .ap) CI-HRMS: calculated value: 397.1988, measured value: 397.1984 (M+H);

NMR(CDCl ₃，300MHz)：2.43(s，3H)，2.50(s，3H)，

3.43(s，3H)，3.61(dd，J＝8，8，2H)，3.69(dd，J＝

8，8，2H)，3.88(s，3H)，4.58-4.70(m，1H)，6.75

(d，J＝8，1H)，7.20(dd，J＝8，1，1H)，7.25(d，J

=1,1H), 7.40 (s, 1H) .aq) CI-HRMS: calculated value: 375.2297, measured value: 375.2286 (M+H);

Analytical calculation value: C:70.56; H:7.01; N:22.44;

Measured value: C:70.49; H:6.99; N:22.45;

NMR(CDCl ₃，300MHz)：0.79-0.85(m，2H)，1.00-1.05

(m，1H)，2.00(s，6H)，2.19(s，3H)，2.32(s，3H)，

2.44(s，3H)，2.84(t，J＝8，2H)，3.30-3.40(m，

1H), 4.50 (t, J=8,2H), and 6.95 (s, 2H) .ar) CI-HRMS: calculated value: 434.1192, measured value: 434.1189 (M+H);

Analytical calculation value: C:52.54; H:5.58; N:16.12; Br:

18.40; Measured value: C:52.75; H:5.59; N:16.09; Bt:

18.67；

NMR(CDCl ₃，300MHz)：2.19(s，3H)，2.30(s，3H)，

2.47(s，3H)，3.43(s，6H)，3.60(dd，J＝8，8，

2H)，3.70(dd，J＝8，8，2H)，4.58-4.70(m，1H)，

6.71(d，J＝8，1H)，7.08(d，J＝8，1H)，7.37(dd，

J=8,1,1H), and 7.45 (d, J=1,1H) .as) CI-HRMS: calculated value: 448.1348, measured value: 448.1332 (M+H);

Analytical calculation value: C:53.58; H:5.85; N:16.62; Br:

17.82; Measured value: C:53.68; H:5.74; N:15.52; Br:

13.03；

NMR(CDCl ₃，300MHz)：1.95-2.10(m，2H)，2.20(s，

3H)，2.30(s，3H)，2.47(s，3H)，3.28(s，3H)，3.41

(s，3H)，3.50-3.67(m，4H)，4.55-4.70(m，1H)，6.89

(d，J＝8，1H)，7.05(d，J＝8，1H)，7.35(dd，J＝

8,1,1H), 7.47 (d, J=1,1H) .at) CI-HRMS: calculated value: 400.2349, measured value: 400.2348 (M+H);

Analytical calculation value: C:C:63.14; H:7.32; N:17.53;

Measured value: C:63.40; H:7.08; N:17.14;

NMR(CDCl ₃，300MHz)：2.16(s，3H)，2.20(s，3H)，

2.30(s，3H)，2.46(s，3H)，3.42(s，6H)，3.60(q，

J＝8，2H)，3.70(q，J＝8，2H)，3.85(s，3H)，

4.59-4.70(m，1H)，6.70(d，J＝8，1H)，6.76(s，

1H), 6.96 (s, 1H) .au) CI-HRMS: calculated value: 414.2505, measured value: 414.2493 (M+H);

NNR(CDCl ₃，300MHz)：2.15(s，3H)，2.19(s，3H)，

2.25(s，3H)，2.40(s，3H)，3.40(s，6H)，3.76(t，

J＝8，4H)，3.84(s，3H)，4.20-4.45(m，4H)，6.77

(s, 1H), 6.93 (s, 1H) .av) CI-HRMS: calculated value: 368.2450, measured value: 368.2447 (M+H);

NMR(CDCl ₃，300MHz)：1.00(t，J＝8，6H)，1.55-

1.85(m，4H)，2.19(s，3H)，2.20(s，3H)，2.30(s，

3H)，2.47(s，3H)，3.88(s，3H)，4.10-4.30(m，1H)，

6.15 (d, J=8,1H), 6.78 (s, 1H), 6.98 (s, 1H) .aw) CI-HRMS: calculated value: 353.2216, measured value: 353.2197 (M+H);

NMR(CDCl ₃，300MHz)：1.35(t，J＝8，6H)，2.17(s，

3H)，2.19(s，3H)，2.28(s，3H)，2.40(s，3H)，3.85

(s，3H)，3.90-4.20(m，4H)，6.78(s，1H)，6.95(s，

1H) .ax) CI-HRMS: calculated value: 390.1697, measured value: 390.1688 (M+H);

Analytical calculation value: C:58.53; H:6.20; N:17.96; Cl:

9.09; Measured value: C:58.95; H:6.28; N:17.73; Cl:9.15;

NMR(CDCl ₃，300MHz)：2.35(s，3H)，2.37(s，3H)，

2.48(s，3H)，3.42(s，6H)，3.60(dd，J＝8，8，2H)

3.68(dd，J＝8，8，2H)，4.59-4.72(m，1H)，6.72

(d，J＝8，1H)，7.12(d，J＝8，1H)，7.23(d，J＝

8,1H), 7.32 (s, 1H) .ay) CI-HRMS: calculated value: 374.1748, measured value: 374.1735 (M+H);

Analytical calculation value: C:61.04; H:6.47; N:18.73; Cl:

9.48; Measured value: C:61.47; H:6.54; N:18.23; Cl:9.61;

NMR(CDCl ₃，300MHz)：1.01(t，J＝8，3H)，1.62-

1.88(m，4H)，2.35(s，3H)，2.37(s，3H)，2.48(d，

J＝1，3H)，3.40，3.45(s，s，3H)，3.50-3.64(m，

2H)，4.38-4.47(m，1H)，6.53(d，J＝8，1H)，7.12

(d, J=8,1H), 7.07 (d, J=8,1H), and 7.12 (s, 1H) .az) CI-HRMS: calculated value: 404.1853, measured value: 404.1939 (M+H);

NMR(CDCl ₃，300MHz)：2.29(s，3H)，2.38(s，3H)，

2.40(s，3H)，3.40(s，6H)，3.76(t，J＝8，4H)，

4.20-4.45(m，4H)，7.11(d，J＝8，1H)，7.22(d，J

=8,1H), 7.31 (s, 1H) .ba) CI-HRMS: calculated value: 404.1853, measured value: 404.1859 (M+H);

Analytical calculation value: C:59.47; H:6.50; N:17.34; Cl:8.79;

Measured value: C:59.73; H:6.46; N:17.10; Cl:8.73;

NMR(CDCl ₃，300MHz)：1.95-2.08(m，2H)，2.35(s，

3H)，2.38(s，3H)，2.46(s，3H)，3.38(s，3H)，3.41

(s，3H)，3.50-3.65(m，4H)，4.56-4.70(m，1H)，6.85

(d，J＝8，1H)，7.12(d，J＝8，1H)，7.45(d，J＝

8,1H), 7.32 (s, 1H) .bb) CI-HRMS: calculated value: 391.2246, measured value: 391.2258 (M+H);

Analytical calculation value: C:67.67; H:6.71; N:21.52; Measured value: C:

67.93；H：6.70；N：21.48；

NMR(CDCl ₃，300MHz)：0.76-0.84(m，2H)，0.84-0.91

(m，2H)，1.00-1.08(m，2H)，2.15(s，3H)，2.20(s，

3H)，2.29(s，3H)，2.45(s，3H)，2.85(t，J＝8，

2H)，3.28-3.30(m，1H)，3.85(s，3H)，6.78(s，1H)，

(6.95 s, 1H) .bc) CI-HRMS: calculated value: 386.2192, measured value: 386.2181 (M+H);

Analytical calculation value: C:62.32; H:7.06; N:18.17; Measured value: C:

62.48；H：6.83；N：18.15；

NMR(CDCl ₃，300MHz)：7.1(d，1H，J＝8)，6.9(d，

1H，J＝1)，6.8(dd，1H，J＝8，1)，6.7(br.d，1H，

J＝8)，4.7-4.6(m，1H)，3.85(s，3H)，3.70-3.55

(m，4H)，3.45(s，6H)，2.5(s，3H)，2.3(s，3H)，

(2.15 s, 3H) .bd) CI-HRMS: calculated value: 400.2349, measured value: 400.2336 (M+H);

NMR(CDCl ₃，300MHz)：7.1(d，1H，J＝7)，6.85(d，

1H，J＝1)，6.75(dd，1H，J＝7，1)，4.45-4.25

(br.s，4H)，3.75(t，4H，J＝7)，3.4(s，6H)，2.4

(s, 3H), 2.25 (s, 3H), 2.15 (s, 3H) .be) CI-HRMS: calculated value: 370.2243, measured value: 370.2247 (M+H);

Analytical calculation value: C:65.02; H:7.38; N:18.96; Measured value: C:

65.28；H：7.27；N：18.71：

NMR(CDCl ₃，300MHz)：7.1(d，1H，J＝8)，6.85(d，

1H，J＝1)，6.8(dd，1H，J＝8，1)，6.5(br.d，1H，

J＝1)，4.5-4.3(m，1H)，3.85(s，3H)，3.65-3.5(m，

2H)，3.4(s，2H)，2.5(s，3H)，2.3(s，3H)，2.2(s，

3H), and 1.9-1.7 (m, 2H), 1.05 (t, 3H, J=7) .bf) CI-HRMS: calculated value: 379.2246, measured value: 379.2248 (M+H);

NMR(CDCl ₃，300MHz)：7.1(d，1H，J＝8)，6.85(d，

1H，J＝1)，6.8(dd，1H，J＝8，1)，4.3-4.0(m，4H)，

3.85(s，3H)，3.0(t，2H，J＝7)，2.45(s，3H)，2.3

(s，3H)，2.2(s，3H)，1.9-1.8(m，2H)，1.0(t，3H，

J=7) CI-HRMS .bg): calculated value: 340.2137, measured value: 340.2122 (M+H);

NMR(CDCl ₃，300MHz)：7.1(d，1H，J＝8)，6.85(d，

1H，J＝1)，6.75(dd，1H，J＝8，1)，4.2-4.0(br.m，

4H)，3.85(s，3H，2.4(s，3H)，2.3(s，3H)，2.2

(s, 3H), 1.35 (t, 6H, J=7) .bh) CI-HRMS: calculated value: 313.1665, measured value: CI-HRMS 313.6664 (M+H) .bi): calculated value: 400.2349, measured value: 400.2346 (M+H);

NMR(CDCl ₃，300MHz)：7.1(d，1H，J＝7)，6.9-6.75

(m，3H)，4.7-4.55(m，1H)，3.8(s，3H)，3.7-3.5(m，

4H)，3.45(s，3H)，3.35(s，3H)，2.5(s，3H)，2.3

(s, 3H), 2.2 (s, 3H), 2.1-1.95 (m, 2H) .bj) CI-HRMS: calculated value: 377.2090, measured value: 377.2092 (M+H);

Analytical calculation value: C:67.00; H:6.44; N:22.32; Measured value: C:

67.35；H：6.44；N：22.23；

NMR(CDCl ₃，300MHz)：7.1(d，1H，J＝8)，6.9(d，

1H，J＝1)，6.8(dd，1H，J＝8，1)，4.55-4.4(m，

2H)，3.85(s，3H)，3.4-3.3(m，1H)，2.85(t，2H，J

＝7)，2.5(s，3H)，2.3(s，3H)，2.2(s，3H)，1.1-

1.0 (m, 2H), 0.85-0.75 (m, 2H) .bk) CI-HRMS: calculated value: 413.2427, measured value: 413.2416 (M+H);

NMR(CDCl ₃，300Hz)：7.1(d，1H，J＝8)，6.85(d，

1H，J＝1)，6.75(dd，1H，J＝8，1)，4.6(m，1H)，

3.85(s，3H)，3.75-3.6(m，4H)，3.6(q，4H，J＝7)，

2.5(s，3H)，2.3(s，3H)，2.2(s，3H)，1.25(t，6H，

J=7) CI-HRMS .bl): calculated value: 420.1802, measured value: 420.1825 (M+H); Bm) CI-HRMS: calculated value: 390.1697, measured value: 390.1707 (M+H); Bn) CI-HRMS: calculated value: 397.1465, measured value: 397,1462 (M+H); Bo) CI-HRMS: calculated value: 360.1513, measured value: 360.1514 (M+H); Bp) CI-HRMS: calculated value: 374.1748, measured value: 374.1737 (M+H); Bq) CI-HRMS: calculated value: 479.1155, measured value: 479.1154 (M+H); Br) CI-HRMS: calculated value: 463.1219, measured value: 463.1211 (M+H);

Analytical calculation value: C:51.96, H:5.23, N, 15.15, Br:

17.28; Measured value: C:52.29, H:5.62, N:14.79, Br:

17.47bs) CI-HRMS: calculated value: 433.1113, measured value: 433.1114 (M, ⁷⁹Br); Bt) NH ₃-CI MS: calculated value: 406, measured value: 406 (M+H)+; NMR (CDCl ₃, 300MHz): δ 7.28 (d, J=10Hz, 1H), 7.03 (d, J=8Hz, 1H), 6.96 (s, 1H), 6.7 (d, J=9,1H), 4.63 (m, 1H), 3.79 (s, 3H), 3.6 (m, 4H), 3.42 (s, 6H), 2.47 (s, 3H), 2.32 (s, 3H).

Embodiment 431

2,4, the preparation of 7-dimethyl-8-(4-methoxyl group-2-aminomethyl phenyl) [1,5-a]-pyrazolo-1,3,5-triazines

(formula 1, wherein R ³Be CH ₃, R ¹Be CH ₃, Z is C-CH ₃, Ar is 2, the 4-3,5-dimethylphenyl)

(602mg 2mmol) mixes with saturated sodium hydrogen carbonate solution (10ml) with 5-ethanamidine base-4-(4-methoxyl group-2-aminomethyl phenyl)-3-methylpyrazole acetate.With ethyl acetate this water soluble mixt is extracted three times.Organic layer through dried over mgso merges filters and vacuum concentration.Residue is dissolved in the toluene (10ml), in this suspension, add trimethyl orthoacetate (0.36g, 3mmol).Under nitrogen environment, this reaction mixture is heated to reflux temperature, and stirred 16 hours.After being cooled to room temperature, this reaction mixture of vacuum concentration obtains the oily solid.(chloroform: methyl alcohol=9: 1), vacuum obtains yellow sticking oily matter (R after removing solvent to column chromatography _f=0.6,210mg, 37% productive rate): NMR (CDCl ₃, 300MHz), 7.15 (d, 1H, J=8), 6.9 (d, 1H, J=1), 6.85 (dd, 1H, J=8,1), 3.85 (s, 3H), 2.95 (s, 3H), 2.65 (s, 3H), 2.4 (s, 3H), 2.15 (s, 3H); CI-HRMS: calculated value: 283.1559, measured value: 283.1554 (M+H).

Embodiment 432

7-hydroxy-5-methyl base-3-(2-chloro-4-aminomethyl phenyl) pyrazolo [1,5-a] pyrimidine

(formula 1, wherein A is CH, R ¹Be Me, R ³Be OH, Z is C-Me, and Ar is a 2-chloro-4-aminomethyl phenyl)

Under agitation, with 5-amino-4-(2-chloro-4-aminomethyl phenyl)-(1.86g 8.4mmol) is dissolved in the glacial acetic acid (30ml) the 3-methylpyrazole.In the solution that produces, drip then methyl aceto acetate (1.18ml, 9.2mmol).Then this reaction mixture is heated to reflux temperature, stirred 16 hours, be cooled to room temperature.Add ether (100ml), filter and collect the precipitation that produces.Vacuum-drying obtains white solid (1.0g, 42% productive rate): NMR (CDCl ₃, 300MHz), 8.70 (br.s1H), 7.29 (s, 1H), 7.21-7.09 (m, 2H), 5.62 (s, 1H), 2.35 (s, 6H), 2.29 (s, 3H); CI-MS:288 (M+H).

Embodiment 433

7-chloro-5-methyl-3-(2-chloro-4-aminomethyl phenyl) pyrazolo [1,5-a] pyrimidine

(formula 1, wherein A is CH, R ¹Be Me, R ³Be Cl, Z is C-Me, and Ar is a 2-chloro-4-aminomethyl phenyl)

Under reflux temperature, with 7-hydroxy-5-methyl base-3-(2-chloro-4-aminomethyl phenyl) pyrazolo [1,5-a] pyrimidine (1.0g, 3.5mmol), phosphoryl chloride (2.7g, 1.64ml, 17.4mmol), N, N-Diethyl Aniline (0.63g, 0.7ml, 4.2mmol) and toluene (20ml) mixture stirred 3 hours, be cooled to room temperature then.Vacuum is removed volatile matter.Residue is through flash chromatography (ethyl acetate: hexane=1: 2) obtain 7-chloro-5-methyl-3-(2-chloro-4-aminomethyl phenyl) pyrazolo [1,5-a] pyrimidine (900mg, 84% productive rate), be yellow oil: NMR (CDCl ₃, 300MHz): 7.35 (s, 1H), 7.28-7.26 (m, 1H), 71.6 (d, 1H, J=7), 6.80 (s, 1H), 2.55 (s, 3H), 2.45 (s, 3H), 2.40 (s, 3H); CI-MS:306 (M+H).

Embodiment 434

7-(amyl group-3-amino)-5-methyl-3-(2-chloro-4-aminomethyl phenyl) pyrazolo [1,5-a] pyrimidine

(formula 1, wherein A is CH, R ¹Be Me, R ³Be amyl group-3-amino, Z is C-Me, and Ar is a 2-chloro-4-aminomethyl phenyl)

In 150 ℃, (394mg, 6.5mmol) (200mg, (DMSO, 10ml) solution stirring is 2 hours, is cooled to room temperature then for dimethyl sulfoxide (DMSO) 0.65mmol) with 7-chloro-5-methyl-3-(2-chloro-4-aminomethyl phenyl) pyrazolo [1,5-a] pyrimidine with the 3-amylamine.Then this reaction mixture is inclined to water (100ml), and mix.With dichloromethane extraction three times, the organic layer that merges with the salt water washing through dried over mgso, filters and vacuum is removed solvent, obtains yellow solid.Through flash chromatography (ethyl acetate: hexane=1: 4) obtain white solid (140mg, 60% productive rate):

Mp 139-141 ℃; NMR (CDCl ₃, 300Hz): 7.32 (s, 1H), 7.27 (d, 1H, J=8), 7.12 (d, 1H, J=7), 6.02 (d, 1H, J=9), 5.78 (s, 1H), 3.50-3.39 (m, 1H), 2.45 (s, 3H), 2.36 (s, 6H), 1.82-1.60 (m, 4H), 1.01 (t, 6H, J=8); Analytical calculation value C ₂₀H ₂₅ClN ₄: C, 67.31, H, 7.06, N, 15.70, Cl:9.93; Measured value: C, 67.32, H, 6.95, N, 15.50, Cl, 9.93.

According to embodiment 1A, 1B, 432,433,434 described methods, can prepare the compound of the described embodiment of table 2.Commonly used is abbreviated as: Ph is a phenyl, and Pr is a propyl group, and Me is a methyl, and Et is an ethyl, and Bu is a butyl, and Ex is embodiment, and EtOAc is an ethyl acetate.

Table 2 Ex Z R3 Ar Mp (℃)435 ^bC-Me N (CH ₂CH ₂OMe) ₂2,4-Cl ₂-Ph 71-73436 ^cC-Me N (Bu) Et 2,4-Cl ₂-Ph 86-87437 ^dC-Me NHCH (Et) CH ₂OMe 2,4-Cl ₂-Ph 110-111438 ^eC-Me N (Pr) CH ₂CH ₂CN 2,4-Cl ₂-Ph 83-85439 ^fC-Me NH-3-amyl group 2,4-Cl ₂-Ph 175-176440 ^gC-Me NHCH (CH ₂OMe) ₂2,4-Cl ₂-Ph 107441 ^hC-Me NHCH (Et) ₂2,4-Me ₂-Ph oily matter 442 ⁱC-Me NHCH (CH ₂OMe) ₂2,4-Me ₂-Ph 103-105443 ^jC-Me N (CH ₂CH ₂OMe) ₂2,4-Me ₂-Ph 87-89444 ^kC-Me N (c-Pr) CH ₂CH ₂CN 2,4-Me ₂-Ph 133 (dec) 445 ^lC-Me N (CH ₂CH ₂OMe) ₂2-Cl, 4-MePh 77-78446 ^mC-Me NHCH (CH ₂OMe) ₂2-Cl, 4-MePh 131-133447 ⁿC-Me NHCH (Et) ₂2-Cl, 4-MePh 139-141448 ^oC-Me NEt ₂2,4-Me ₂-Ph 92-94449 ^pC-Me N (Pr) CH ₂CH ₂CN 2,4-Me ₂-Ph 143-144450 ^qC-Me N (Bu) CH ₂CH ₂CN 2,4-Me ₂-Ph 115-117451 ^rC-Me NHCH (Et) CH ₂OMe 2,4-Me ₂-Ph oily matter 452 ^sC-Me NHCH (Et) ₂2-Me, 4-MeOPh 104-106453 ^tC-Me NHCH (CH ₂OMe) ₂2-Me, 4-MeOPh 115-116454 ^uC-Me N (CH ₂CH ₂OMe) ₂2-Me, 4-MeOPh oily matter 455 ^vC-Me (S)-NHCH (CH ₂CH ₂OMe)-and 2-Me, 4-MeOPh oily matter

(CH ₂OMe) 456 ^wC-Me (S)-NHCH (CH ₂CH ₂OMe)-2,4-Me ₂-Ph oily matter

(CH ₂OMe) 457 ^xC-Me N (CH ₂CH ₂OMe) ₂2-Me, 4-ClPh oily matter 458 ^yC-Me NHEt 2,4-Me ₂-Ph oily matter 459 ^zC-Me NHCH (Et) ₂2-Me, 4-ClPh 94-96460 ^AaC-Me NHCH (CH ₂OMe) ₂2-Me, 4-ClPh 113-114461 ^AbC-Me N (Ac) Et 2,4-Me ₂-Ph oily matter 462 ^AcC-Me (S)-NHCH (CH ₂CH ₂OMe)-and 2-Me, 4-ClPh oily matter

(CH ₂OMe)463 ^ad C-Me N(Pr)CH ₂CH ₂CN 2-Me，4-MeOPh 118-119464 ^ae C-Me NEt ₂ 2-Me，4-MeOPh 97-99465 ^af C-Me (S)-NHCH(CH ₂CH ₂OMe)- 2-Cl，4-MePh 101-103

(CH ₂OMe) 466 ^ag C-Me NEt ₂ 2-Cl，4-MePh 129-130 467 ^ah C-Me N(c-Pr)CH ₂CH ₂CN 2-Me，4-MeOPh 177-178 468 ^ai C-Me N(c-Pr)CH ₂CH ₂CN 2-Cl，4-MePh 162-163 469 ^aj C-Me NHCH(Et)CH ₂OMe 2-Me, 4-MeOPh grease 470^ak C-Me NHCH(Et)CH ₂OMe 2-Cl，4-MePh 111-113 471 C-Me NHCH(CH ₂OMe) ₂ 2-Cl-4-MeOPh 472 C-Me N(CH ₂CH ₂OMe) ₂ 2-Cl-4-MeOPh 473 C-Me NHCH(Et)CH ₂OMe 2-Cl-4-MeOPh 474 C-Me N(c-Pr)CH ₂CH ₂CN 2-Cl-4-MeOPh 475 C-Me NEt ₂2-Cl-4-MeOPh 476 C-Me NH-3-amyl group 2-Cl-4-MeOPh 477 C-Me NHCH (Et) CH₂CH ₂OMe 2-Cl-4-MeOPh 478 C-Me NHCH(Me)CH ₂CH ₂OMe 2-Cl-4-MeOPh 479 C-Me NHCH(Et)CH ₂CH ₂OMe 2-Er-4-MeOPh 480 C-Me NHCH(Me)CH ₂CH ₂OMe 2-Br-4-MeOPh 481 C-Me NHCH(Et)CH ₂CH ₂OMe 2-Me-4-MeOPh 482 C-Me NHCH(Me)CH ₂CH ₂OMe 2-Me-4-MeOPh 483 C-Me NHCH(CH ₂OMe) ₂ 2-Cl-4，5-(MeO) ₂Ph 484 C-Me N(CH ₂CH ₂OMe) ₂ 2-Cl-4，5-(MeO) ₂Ph 485 C-Me NHCH(Et)CH ₂OMe 2-Cl-4，5-(MeO) ₂Ph 486 C-Me N(c-Pr)CH ₂CH ₂CN 2-Cl-4，5-(MeO) ₂Ph 487 C-Me NEt ₂ 2-Cl-4，5-(MeO) ₂Ph 99-101 488 C-Me NH-3-amyl group 2-Cl-4,5-(MeO)₂Ph 169-170 489 C-Me NHCH(Et)CH ₂CH ₂OMe 2-Cl-4，5-(MeO) ₂Ph 490 C-Me NHCH(Me)CH ₂CH ₂OMe 2-Cl-4，5-(MeO) ₂Ph 491 C-Me NHCH(CH ₂OMe) ₂ 2-Br-4，5-(MeO) ₂Ph 90-93 492 C-Me N(CH ₂CH ₂OMe) ₂ 2-Br-4，5-(MeO) ₂Ph 110 493 C-Me NHCH(Et)CH ₂OMe 2-Br-4，5-(MeO) ₂Ph 494 C-Me N(c-Pr)CH ₂CH ₂CN 2-Br-4，5-(MeO) ₂Ph 495 C-Me NEt ₂ 2-Br-4，5-(MeO) ₂Ph 496 C-Me NH-3-amyl group 2-Br-4,5-(MeO)₂Ph 497 C-Me NHCH(Et)CH ₂CH ₂OMe 2-Br-4，5-(MeO) ₂Ph 498 C-Me NHCH(Me)CH ₂CH ₂OMe 2-Br-4，5-(MeO) ₂Ph 499 C-Me NHCH(CH ₂OMe) ₂ 2-Cl-4，6-(MeO) ₂Ph 500 C-Me N(CH ₂CH ₂OMe) ₂ 2-Cl-4，6-(MeO) ₂Ph 501 C-Me NHCH(Et)CH ₂OMe 2-Cl-4，6-(MeO) ₂Ph 502 C-Me N(c-Pr)CH ₂CH ₂CN 2-Cl-4，6-(MeO) ₂Ph 503 C-Me NEt ₂ 2-Cl-4，6-(MeO) ₂Ph 504 C-Me NH-3-amyl group 2-Cl-4,6-(MeO)₂Ph 505 C-Me NHCH(Et)CH ₂CH ₂OMe 2-Cl-4，6-(MeO) ₂Ph 506 C-Me NHCH(Me)CH ₂CH ₂OMe 2-Cl-4，6-(MeO) ₂Ph 507 C-Me NHCH(CH ₂OMe) ₂ 2-Me-4，6-(MeO) ₂Ph 508 C-Me N(CH ₂CH ₂OMe) ₂ 2-Me-4，6-(MeO) ₂Ph 509 C-Me NHCH(Et)CH ₂OMe 2-Me-4，6-(MeO) ₂Ph 510 C-Me N(c-Pr)CH ₂CH ₂CN 2-Me-4，6-(MeO) ₂Ph 511 C-Me NEt ₂ 2-Me-4，6-(MeO) ₂Ph 512 C-Me NH-3-amyl group 2-Me-4,6-(MeO)₂Ph 513 C-Me NHCH(Et)CH ₂CH ₂OMe 2-Me-4，6-(MeO) ₂Ph 514 C-Me NHCH(Me)CH ₂CH ₂OMe 2-Me-4，6-(MeO) ₂Ph 515 C-Me N(c-Pr)CM ₂CH ₂CN 2-Br-4，6-(MeO) ₂Ph 516 C-Me NEt ₂ 2-Br-4，6-(MeO) ₂Ph 517 C-Me NH-3-amyl group 2-Br-4,6-(MeO)₂Ph 518 C-Me NHCH(Et)CH ₂CH ₂OMe 2-Br-4，6-(MeO) ₂Ph 519 C-Me NHCH(Me)CH ₂CH ₂OMe 2-Br-4，6-(MeO) ₂Ph 520 C-Me NHCH(Et)CH ₂CH ₂OMe 2-Me-4-MeOPh 521 C-Me NHCH(Me)CH ₂CH ₂OMe 2-Me-4-MeOPh 522 C-Me NHCH(CH ₂OMe) ₂ 2-Me0-4-MePh 523 C-Me N(CH ₂CH ₂OMe) ₂ 2-Me0-4-MePh 524 C-Me NHCH(Et)CH ₂OMe 2-Me0-4-MePh 525 C-Me N(c-Pr)CH ₂CH ₂CN 2-Me0-4-MePh 526 C-Me NEt ₂2-Me0-4-MePh 527 C-Me NH-3-amyl group 2-Me0-4-MePh 528 C-Me NHCH (Et) CH₂CH ₂OMe 2-Me0-4-MePh 529 C-Me NHCH(Me)CH ₂CH ₂OMe 2-Me0-4-MePh 530 C-Me NHCH(CH ₂OMe) ₂ 2-Me0-4-MePh 531 C-Me N(CH ₂CH ₂OMe) ₂ 2-Me0-4-MePh 532 C-Me NHCH(Et)CH ₂OMe 2-Me0-4-MePh 533 C-Me N(c-Pr)CH ₂CH ₂CN 2-Me0-4-MePh 534 C-Me NEt ₂2-Me0-4-MePh 535 C-Me NH-3-amyl group 2-Me0-4-MePh 536 C-Me NHCH (Et) CH₂CH ₂OMe 2-Me0-4-MePh 537 C-Me NHCH(Me)CH ₂CH ₂OMe 2-Me0-4-MePh 538 C-Me NHCH(CH ₂OMe) ₂ 2-Me0-4-ClPh 539 C-Me N(CH ₂CH ₂OMe) ₂ 2-Me0-4-ClPh 540 C-Me NHCH(Et)CH ₂OMe 2-Me0-4-ClPh 541 C-Me N(c-Pr)CH ₂CH ₂CN 2-Me0-4-ClPh 542 C-Me NEt ₂2-Me0-4-ClPh 543 C-Me NH-3-amyl group 2-Me0-4-ClPh 544 C-Me NHCH (Et) CH₂CH ₂OMe 2-Me0-4-ClPh 545 C-Me NHCH(Me)CH ₂CH ₂OMe 2-Me0-4-ClPh

Table 2 note b) CI-HRMS: calculated value: 423.1355; Measured value: analytical calculation value: C 423.1337 (M+H) .c), 61.38, H, 6.18, N, 14.32:

Measured value: C, 61.54, H, 6.12, N, 14.37.d) analytical calculation value: C:58.02, H, 5.65, N, 14.24;

Measured value: C, 58.11, H, 5.52, N, 14.26.e) analytical calculation value: C, 59.71, H, 5.26,14.85;

Measured value: C, 59.94, H, 5.09, N, 17.23.f) analytical calculation value: C, 60.48H, 5.89, N, 14.85,

Measured value: C, 60.62, H, 5.88, N, 14.82.h) CI-HRMS: calculated value: 337.2388; Measured value: analytical calculation value: C 337.2392 (M+H) .i), 68.45, H, 7.669, N, 15.21,

Measured value: C, 68.35, H, 7.49 N, 14.91.j) analytical calculation value: C, 69.08, H, 7.915, N, 14.65,

Measured value: C, 68.8 5, H, 7.83, N, 14.54.k) analytical calculation value: C, 73.51, H, 7.01, N, 19.48,

Measured value: C, 71.57, H, 7.15, N, 19.12.l) CI-HRMS: calculated value: 403.1899; Measured value: analytical calculation value: C 403.1901 (M+H) .m), 61.77, H, 6.49, N, 14.41, Cl.

9.13; Measured value: C, 61.90, H, 6.66, N, 13.62, Cl, 9.25.n) analytical calculation value: C, 67.31, H, 7.06, N, 15.70, Cl.

9.93; Measured value: C, 67.32, H, 6.95, N, 15.50, Cl, 9.93.o) analytical calculation value: C, 74.50, H, 8.14, N, 17.38,

Measured value: C, 74.43, H, 7.59, N, 17.16.p) analytical calculation value: C, 73.1O, H, 7.54, N, 19.37,

Measured value: C, 73.18, H, 7.59, N, 18.81.q) analytical calculation value: C, 73.57, H, 7.78, N, 18.65,

Measured value: C, 73.55, H, 7.79, N, 18.64.r) CI-HRMS: calculated value: 353.2333; Measured value: analytical calculation value: C 353.2341 (M+H) .s), 71.56, H, 8.02, N, 15.90,

Measured value: C, 71.45, H, 7.99, N, 15.88.t) analytical calculation value: C, 65.60, H, 7.34, N, 14.57,

Measured value: C, 65.42, H, 7.24, N, 14.37.u) CI-HRMS: calculated value: 399.2398; Measured value: CI-HRMS 399.2396 (M+H) .v): calculated value: 399.2398; Measured value: CI-HRMS 399.2396 (M+H) .w): calculated value: 383.2450; Measured value: CI-HRMS 383.2447 (M+H) .x): calculated value: 403.1887; Measured value: CI-HRMS 403.1901 (M+H) .y): calculated value: 295.1919; Measured value: analytical calculation value: C 295.1923 (M+H) .z), 67.31, H, 7.06, N, 15.70,

Measured value: C, 67.12, H, 6.86, N, 15.53.aa) analytical calculation value: C, 61.77, H, 6.49, N, 14.41, Cl,

9.13; Measured value: C, 62.06, H, 6.37, N, 14.25, Cl, 9.12.ab) CI-HRMS: calculated value: 337.2017; Measured value: CI-HRMS 337.2028 (M+H) .ac): calculated value: 403.1893; Measured value: analytical calculation value: C 403.1901 (M+H) .ad), 70.00, H, 7.22, N, 18.55,

Measured value: C, 7O.05, H, 7.22, N, 18.36.ae) analytical calculation value: C, 70.98, H, 7.74, N, 16.55,

Measured value: C, 71.15, H, 7.46, N, 16.56.ag) analytical calculation value: C, 66.59, H, 6.76, N, 16.34,

Measured value: C, 66.69, H, 6.82, N, 16.20.ah) analytical calculation value: C, 70.38, H, 6.71, N, 18.65,

Measured value: C, 7O.35, H, 6.82, N, 18.83.ai) analytical calculation value: C, 66.39, H, 5.85, N, 18.44, Cl,

9.33；

Measured value: C, 66.29, H, 5.51, N, 18.36, Cl, 9.31.aj) CI-HRMS: calculated value: 369.2278; Measured value: analytical calculation value: C 369.2291 (M+H) .ak), 64.42, H, 6.77, N, 15.02,

Measured value: C, 64.59, H, 6.51, N, 14.81.

According to embodiment 1,2,3 or 6 described methods, can prepare the compound of the described embodiment of table 3.Commonly used is abbreviated as: Ph is a phenyl, and Pr is a propyl group, and Me is a methyl, and Et is an ethyl, and Bu is a butyl, and Ex is embodiment.

Table 3

Ex Z R3 Ar Mp (℃)546 ^aC-Me NHCH (Et) ₂2-Me-4-Me ₂N-Ph 164-166547 ^bC-Me S-NHCH (CH ₂CH ₂OMe) 2,4-Me ₂-Ph oily matter

-CH ₂OMe548 ^cC-Me S-NHCH (CH ₂CH ₂OMe) 2-Me-4-Cl-Ph oily matter

-CH ₂OMe 549 ^d C-Me N(c-Pr)CH ₂CH ₂CN 2-Me-4-Cl-Ph 115-116 550 ^e C-Me NHCH(Et)CH ₂CN 2-Me-4-Cl-Ph 131-132 551 ^f C-Me N(Et) ₂ 2，3-Me ₂-4-OMe-Ph grease 552^g C-Me N(CH ₂CH ₂OMe)CH ₂CH ₂OH 2，4-Cl ₂-Ph grease 553^h C-Me N(CH ₂CH ₂OMe) ₂ 2，3-Me ₂-4-OMe-Ph grease 554ⁱ C-Me NHCH(Et) ₂ 2，3-Me ₂-4-OMePh 123-124 555 ^j C-Me N(CH ₂-c-Pr) Pr 2-Me-4-Cl-Ph grease 556^k C-Me N(c-Pr)CH ₂CH ₂CN 2，3-Me ₂-4-OMePh 158-160 557 C-Me N(c-Pr)Et 2-Cl-4-OMePh 558 C-Me N(c-Pr)Me 2-Cl-4-OMePh 559 C-Me N(c-Pr)Pr 2-Cl-4-OMePh 560 C-Me N(c-Pr)Bu 2-Cl-4-OMePh 561 ^l C-Me N(Et) ₂ 2-Cl-4-CN-Ph 115-117 562 C-Me N(c-Pr) ₂ 2-Cl-4-OMe 127-129 563 ^m C-Me NHCH(CH ₂OH) ₂ 2，4-Cl ₂-Ph 128-129 564 C-Me N(c-Pr)Et 2-Br-4，5-(MeO)2Ph 565 C-Me N(c-Pr)Me 2-Br-4，5-(MeO)2Ph 566 C-Me NH-c-Pr 2-Me-4-MeOPh 126-128 567 C-Me NHCH(Et)CH2OH 2-Me-4-MeOPh 60-62 568 C-Me NMe ₂ 2-Br-4，5-(MeO)2Ph 569 C-Me NHCH(Et) ₂2-Me-4-MeOPh 103-105 570 C-Me N (c-Pr) Et 2-Me-4-MeOPh 173-174 571 C-Me NH-2-amyl groups 2,4-Cl₂-Ph 118-120 572 C-Me NHCH(Et)CH2CN 2，4-Cl ₂-Ph 141-142 573 C-Me NHCH(Pr)CH2OMe 2，4-Cl ₂-Ph 87-88 574 C-Me NHCH(CH2-iPr)CH2OMe 2，4-Cl ₂The amorphous 575 C-Me NH-2-butyl 2 of-Ph, 4-Me₂-Ph grease 576 C-Me NH-2-amyl groups 2,4-Me₂-Ph grease 577 C-Me NH-2-hexyls 2,4-Me₂-Ph grease 578 C-Me NHCH (i-Pr) Me 2,4-Me₂-Ph grease 579 C-Me NHCH (Me) CH2-iPr 2,4-Me₂-Ph grease 580 C-Me NHCH (Me)-c-C6H11 2,4-Me₂-Ph grease 581 C-Me NH-2-(2,3-indanyl) 2,4-Me₂-Ph grease 582 C-Me NH-1-(2,3-indanyl) 2,4-Me₂-Ph grease 583 C-Me NHCH (Me) Ph 2,4-Me₂-Ph grease 584 C-Me NHCH (Me) CH₂-(4-ClPh) 2，4-Me ₂-Ph grease 585 C-Me NHCH (Me) CH₂COCH ₃ 2，4-Me ₂-Ph grease 586 C-Me NHCH (Ph) CH₂Ph 2，4-Me ₂-Ph grease 587 C-Me NHCH (Me) (CH₂)3NEt ₂ 2，4-Me ₂-Ph grease 588 C-Me NH-(2-Ph-c-C₃H ₄) 2，4-Me ₂-Ph grease 589 C-Me NHCH (Et) CH₂CN 2，4-Me ₂-Ph 119-120 590 C-Me NH-3-hexyls 2,4-Me₂-Ph grease 591ⁿ C-Me NEt ₂2-MeO-4-ClPh grease 592^o C-Me NHCH(Et) ₂2-MeO-4-ClPh grease 593^p C-Me NHCH(Et)CH ₂OMe 2-MeO-4-ClPh. grease 594 C-Me NMe₂2-MeO-4-ClPh grease 595^q C-Me NHCH(Et) ₂2-OMe-4-MePh grease 596^r C-Me NEt ₂2-OMe-4-MePh grease 597^s C-c-Pr NHCH(CH ₂OMe) ₂ 2，4-Cl ₂-Ph grease 598 C-Me N (c-Pr) E 2,4-Me₂-Ph 599 C-Me N(c-Pr)E 2，4-Cl ₂-Ph 600 C-Me N(c-Pr)E 2，4，6-Me ₃-Ph 601 C-Me N(c-Pr)Et 2-Me-4-Cl-Ph 602 C-Me N(c-Rr)Et 2-Cl-4-Me-Ph 603 C-Me NHCH(c-Pr) ₂ 2，4-Cl ₂-Ph 604 C-Me NHCH(c-Pr) ₂ 2，4-Me ₂-Ph 605 C-Me NHCH(c-Pr) ₂ 2-Me-4-Cl-Ph 606 C-Me NHCH(c-Pr) ₂ 2-Cl-4-Me-Ph 607 C-Me NHCH(c-Pr) ₂ 2-Me-4-OMe-Ph 608 C-Me NHCH(c-Pr) ₂ 2-Cl-4-OMe-Ph 609 C-Me NHCH(CH ₂OMe) ₂ 2-Cl-5-F-OMePh 610 C-Me NEt ₂ 2-Cl-5-F-OMePh 611 C-Me N(c-Pr)CH ₂CH ₂CN 2-Cl-5-F-OMePh 612 C-Me NHCH(Et) ₂ 2-Cl-5-F-OMePh 613 C-Me N(CH ₂CH ₂OMe) ₂ 2-Cl-5-F-OMePh 614 C-Me NEt ₂ 2，6-Me ₂-pyridin-3-yl 615 C-Me N (c-Pr) CH₂CH ₂CN 2，6-Me ₂-pyridin-3-yl 616 C-Me NHCH (Et)₂ 2，6-Me ₂-pyridin-3-yl 617 C-Me N (CH₂CH ₂OMe) ₂ 2，6-Me ₂-pyridin-3-yl 618 C-OH NHCH (CH₂OMe) ₂ 2，4-Me ₂-Ph 619 C-OH NEt ₂ 2，4-Me ₂-Ph 620 C-OH N(c-Pr)CH ₂CH ₂CN 2，4-Me ₂-Ph 621 C-OH NHCH(Et) ₂ 2，4-Me ₂-Ph 623 C-OH N(CH ₂CH ₂OMe) ₂ 2，4-Me ₂-Ph 624 C-NEt ₂ NHCH(CH ₂OMe) ₂ 2，4-Me ₂-Ph 625 C-NEt ₂ NEt ₂ 2，4-Me ₂-Ph 626 C-NEt ₂ N(c-Pr)CH ₂CH ₂CN 2，4-Me ₂-Ph 627 C-NEt ₂ NHCH(Et) ₂ 2，4-Me ₂-Ph 628 C-NEt ₂ N(CH ₂CH ₂OMe) ₂ 2，4-Me ₂-Ph 629 C-Me NHCH(Et) ₂ 2-Me-4-CN-Ph 630 C-Me N(CH ₂CH ₂OMe) ₂ 2-Me-4-CN-Ph

Table 3 note: a) CI-HRMS: calculated value: 367.2610, measured value: 367.2607 (M+H); B) CI-HRMS: calculated value: 384.2400, measured value: 384.2393 (M-H); C) CI-HRMS: calculated value: 404.1853, measured value: 404.1844 (M+H); D) CI-HRMS: calculated value: 381.1594, measured value: 381.1596 (M+H);

Analytical calculation value: C:63.07, H, 5.57, N, 22.07, Cl,

9.32；

Measured value: C:63.40, H, 5.55, N, 21.96, Cl:9.15e) CI-HRMS: calculated value: 369.1594, measured value: 369.1576 (M+H); F) CI-HRMS: calculated value: 354.2216, measured value: 354.2211 (M+H); G) CI-HRMS: calculated value: 410.1072, measured value: 410.1075 (M+H); H) CI-HRMS: calculated value: 414.2427, measured value: 414.2427 (M+H); I) CI-HRMS: calculated value: 368.2372, measured value: 368.2372 (M+H); J) CI-HRMS: calculated value: 384.1955, measured value: 384.1947 (M+H); K) CI-HRMS: calculated value: 391.2168, measured value: 391.2160 (M+H); L) CI-HRMS: calculated value: 335.1984, measured value: 335.1961 (M+H); M) CI-HRMS: calculated value: 382.0759, measured value: 382.0765 (M+H); N) NH ₃-CI MS: calculated value: 360, measured value: 360 (M+H)+o) NH ₃-CI MS: calculated value: 374, measured value: 374 (M+H)+;

NMR(CDCl ₃，300MHz)：δ7.29(d，J＝8.4Hz，1H)，7.04

(dd，J＝1.8，8Hz，1H)，6.96(d，J＝1.8Hz，1H)，6.15

(d，J＝10，1H)，4.19(m，1H)，3.81(s，3H)，2.47(s，

3H)，2.32(s，3H)，1.65(m，4H)，0.99(t，J＝7.32Hz，

6H) p) NH ₃-CI MS: calculated value: 390, measured value: 390 (M+H)-;

NMR(CDCl ₃，300MHz)：δ7.28(d，J＝8Hz，1H)，7.03

(d，J＝8Hz，1H)，6.96(s，H)，6.52(d，J＝9Hz，1H)，

4.36(m，1H)，3.8(s，3H)，3.55(m，2H)，3.39(s，

3H)，2.47(s，3H)，2.32(s，3H)，1.76(m，2H)，1.01

(t, J=7.32Hz, 3H) .q) CI-HRMS: calculated value: 354.2294, measured value: 354.2279 (M+H)+r) CI-HRMS: calculated value: 340.2137, measured value: 340.2138 (M+H)+s) CI-HRMS: calculated value: 436.1307, measured value: 436.1296 (M+H)+

According to embodiment 1A, 1B, 432,433,434 described methods, can prepare the compound of the described embodiment of table 4.Commonly used is abbreviated as: Ph is a phenyl, and Pr is a propyl group, and Me is a methyl, and Et is an ethyl, and Bu is a butyl, and Ex is embodiment, and EtOAc is an ethyl acetate.

Table 4 Ex Z R3 Ar Mp (℃)631 C-Me NHCH (Et) ₂2-Br-4,5-(MeO) ₂Ph 160-161632 C-Me NHCH (Et) ₂2-Br-4-MeOPh 110-111633 C-Me N (CH ₂CH ₂OMe) ₂2-Br-4-MeOPh 74-76634 C-Me NHCH (CH ₂OMe) ₂2-Br-4-MeOPh 128-130635 C-Me N (Et) ₂2-Me-4-ClPh 113-114636 C-Me N (c-Pr) Et 2,4-Cl ₂Ph637 C-Me N (c-Pr) Et 2,4-Me ₂Ph638 C-Me N (c-Pr) Et 2,4,6-Me ₃Ph639 C-Me N (c-Pr) Et 2-Me-4-MeOPh640 C-Me N (c-Pr) Et 2-Cl-4-MeOPh641 C-Me N (c-Pr) Et 2-Cl-4-MePh642 C-Me N (c-Pr) Et 2-Me-4-ClPh643 C-Me NHCH (c-Pr) ₂2,4-Cl ₂-Ph644 C-Me NHCH (c-Pr) ₂2,4-Me ₂-Ph645 C-Me NHCH (c-Pr) ₂2-Me-4-Cl-Ph646 C-Me NHCH (c-Pr) ₂2-Cl-4-Me-Ph647 C-Me NHCH (c-Pr) ₂2-Me-4-OMe-Ph648 C-Me NHCH (c-Pr) ₂2-Cl-4-OMe-Ph649 C-Me NHCH (CH ₂OMe) ₂2-Cl-5-F-OMePh650 C-Me NEt ₂2-Cl-5-F-OMePh651 C-Me N (c-Pr) CH ₂CH ₂CN 2-Cl-5-F-OMePh652 C-Me NHCH (Et) ₂2-Cl-5-F-OMePh653 C-Me N (CH ₂CH ₂OMe) ₂2-Cl-5-F-OMePh654 C-Me NEt ₂2,6-Me ₂-pyridin-3-yl 655 C-Me N (c-Pr) CH ₂CH ₂CN 2,6-Me ₂-pyridin-3-yl 656 C-Me NHCH (Et) ₂2,6-Me ₂-pyridin-3-yl 657 C-Me N (CH ₂CH ₂OMe) ₂2,6-Me ₂-pyridin-3-yl 658 C-OH NHCH (CH ₂OMe) ₂2,4-Me ₂-Ph659 C-OH NEt ₂2,4-Me ₂-Ph660 C-OH N (c-Pr) CH ₂CH ₂CN 2,4-Me ₂-Ph661 C-OH NHCH (Et) ₂2,4-Me ₂-Ph662 C-OH N (CH ₂CH ₂OMe) ₂2,4-Me ₂-Ph663 C-NEt2 NHCH (CH ₂OMe) ₂2,4-Me ₂-Ph664 C-NEt2 NEt ₂2,4-Me ₂-Ph665 C-NEt2 N (c-Pr) CH ₂CH ₂CN 2,4-Me ₂-Ph666 C-NEt2 NHCH (Et) ₂2,4-Me ₂-Ph667 C-NEt2 N (CH ₂CH ₂OMe) ₂2,4-Me ₂-Ph668 C-Me NHCH (Et) ₂2-Me-4-CN-Ph669 C-Me N (CH ₂CH ₂OMe) ₂2-Me-4-CN-Ph

According to embodiment 1A, 1B, 2,3,6,431,432,433,434 described methods or their appropriate combination, can prepare the compound of table 5 or 6 described embodiment.Commonly used is abbreviated as: Ph is a phenyl, and Pr is a propyl group, and Me is a methyl, and Et is an ethyl, and Bu is a butyl, and Ex is embodiment.

Table 5

Ex R14 R3 Ar 670 Me NHCH(CH ₂OMe) ₂ 2，4-Cl ₂-Ph 671 Me NHCHPr ₂ 2，4-Cl ₂-Ph 672 Me NEtBu 2，4-Cl ₂-Ph 673 Me NPr(CH ₂-c-C ₃H ₅) 2，4-Cl ₂-Ph 674 Me N(CH ₂CH ₂OMe) ₂ 2，4-Cl ₂-Ph 675 Me NH-3-heptyl 2,4-Cl₂-Ph 676 Me NHCH(Et)CH ₂OMe 2，4-Cl ₂-Ph 677 Me NEt ₂ 2，4-Cl ₂-Ph 678 Me NHCH(CH ₂OEt) ₂ 2，4-Cl ₂-Ph 679 Me NH-3-amyl groups 2,4-Cl₂-Ph 680 Me NMePh 2，4-Cl ₂-Ph 681 Me NPr ₂ 2，4-Cl ₂-Ph 682 Me NH-3-hexyls 2,4-Cl₂-Ph 683 Me morpholinoes 2,4-Cl₂-Ph 684 Me N(CH ₂Ph)CH ₂CH ₂OMe 2，4-Cl ₂-Ph 685 Me NHCH(CH ₂Ph)CH ₂OMe 2，4-Cl ₂-Ph 686 Me NH-4-THP trtrahydropyranyls 2,4-Cl₂-Ph 687 Me NH-cyclopenta 2,4-Cl₂-Ph 688 Me OEt 2，4-Cl ₂-Ph 689 Me OCH(Et)CH ₂OMe 2，4-Cl ₂-Ph 690 Me OCH ₂Ph 2，4-Cl ₂-Ph 691 Me O-3-amyl groups 2,4-Cl₂-Ph 692 Me SEt 2，4-Cl ₂-Ph 693 Me S(O)Et 2，4-Cl ₂-Ph 694 Me SO ₂Et 2，4-Cl ₂-Ph 695 Me Ph 2，4-Cl ₂-Ph 696 Me 2-CF ₃-Ph 2，4-Cl ₂-Ph 697 Me 2-Ph-Ph 2，4-Cl ₂-Ph 698 Me 3-amyl groups 2,4-Cl₂-Ph 699 Me cyclobutyl 2,4-Cl₂-Ph 700 Me 3-pyridine radicals 2,4-Cl₂-Ph 701 Me CH(Et)CH ₂CONMe ₂ 2，4-Cl ₂-Ph 702 Me CH(Et)CH ₂CH ₂NMe ₂ 2，4-Cl ₂-Ph 703 Me NHCH(CH ₂OMe) ₂ 2，4，6-Me ₃-Ph 704 Me MHCHPr ₂ 2，4，6-Me ₃-Ph 705 Me NEtBu 2，4，6-Me ₃-Ph 706 Me NPr(CH ₂-c-C ₃H ₅) 2，4，6-Me ₃-Ph 707 Me N(CH ₂CH ₂OMe) ₂ 2，4，6-Me ₃-Ph 708 Me NH-3-heptyl 2,4,6-Me₃-Ph 709 Me NHCH(Et)CH ₂OMe 2，4，6-Me ₃-Ph 710 Me NEt ₂ 2，4，6-Me ₃-Ph 711 Me NHCH(CH ₂OEt) ₂ 2，4，6-Me ₃-Ph 712 Me NH-3-amyl groups 2,4,6-Me₃-Ph 713 Me NMePh 2，4，6-Me ₃-Ph 714 Me NPr ₂ 2，4，6-Me ₃-Ph 715 Me NH-3-hexyls 2,4,6-Me₃-Ph 716 Me morpholinoes 2,4,6-Me₃-Ph 717 Me N(CH ₂Ph)CH ₂CH ₂OMe 2，4，6-Me ₃-Ph 718 Me NHCH(CH ₂Ph)CH ₂OMe 2，4，6-Me ₃-Ph 719 Me NH-4-THP trtrahydropyranyls 2,4,6-Me₃-Ph 720 Me NH-cyclopenta 2,4,6-Me₃-Ph 721 Me OEt 2，4，6-Me ₃-Ph 722 Me OCH(Et)CH ₂OMe 2，4，6-Me ₃-Ph 723 Me OCH ₂Ph 2，4，6-Me ₃-Ph 724 Me O-3-amyl groups 2,4,6-Me₃-Ph 725 Me SEt 2，4，6-Me ₃-Ph 726 Me S(O)Et 2，4，6-Me ₃-Ph 727 Me SO ₂Et 2，4，6-Me ₃-Ph 728 Me CH(CO ₂Et) ₂ 2，4，6-Me ₃-Ph 729 Me C(Et)(CO ₂Et) ₂ 2，4，6-Me ₃-Ph 730 Me CH(Et)CH ₂OH 2，4，6-Me ₃-Ph 731 Me CH(Et)CH ₂OMe 2，4，6-Me ₃-Ph 732 Me CONMe ₂ 2，4，6-Me ₃-Ph 733 Me COCH ₃ 2，4，6-Me ₃-Ph 734 Me CH(OH)CH ₃ 2，4，6-Me ₃-Ph 735 Me C (OH) Ph-3-pyridine radicals 2,4,6-Me₃-Ph 736 Me Ph 2，4，6-Me ₃-Ph 737 Me 2-Ph-Ph 2，4，6-Me ₃-Ph 738 Me 3-amyl groups 2,4,6-Me₃-Ph 739 Me cyclobutyl 2,4,6-Me₃-Ph 740 Me 3-pyridine radicals 2,4,6-Me₃-Ph 741 Me CH(Et)CH ₂CONMe ₂ 2，4，6-Me ₃-Ph 742 Me CH(E-)CH ₂CH ₂NMe ₂ 2，4，6-Me ₃-Ph 743 Me NHCH(CH ₂OMe) ₂ 2，4-Me ₂-Ph 744 Me N(CH ₂CH ₂OMe) ₂ 2，4-Me ₂-Ph 745 Me NHCH(Et)CH ₂OMe 2，4-Me ₂-Ph 746 Me NH-3-amyl groups 2,4-Me₂-Ph 747 Me NEt ₂ 2，4-Me ₂-Ph 748 Me N(CH ₂CN) ₂ 2，4-Me ₂-Ph 749 Me NHCH(Me)CH ₂OMe 2，4-Me ₂-Ph 750 Me OCH(Et)CH ₂OMe 2，4-Me ₂-Ph 751 Me NPr-c-C ₃H ₅ 2，4-Me ₂-Ph 752 Me NHCH(Me)CH ₂NMe ₂ 2，4-Me ₂-Ph 753 Me N(c-C ₃H ₅)CH ₂CH ₂CN 2，4-Me ₂-Ph 754 Me N(Pr)CH ₂CH ₂CN 2，4-Me ₂-Ph 755 Me N(Bu)CH ₂CH ₂CN 2，4-Me ₂-Ph 756 Me NHCHPr ₂ 2，4-Me ₂-Ph 757 Me NEtBu 2，4-Me ₂-Ph 758 Me NPr(CH ₂-c-C ₃H ₅) 2，4-Me ₂-Ph 759 Me NH-3-heptyl 2,4-Me₂-Ph 760 Me NEt ₂ 2，4-Me ₂-Ph 761 Me NHCH(CH ₂OEt) ₂ 2，4-Me ₂-Ph 762 Me NH-3-amyl groups 2,4-Me₂-Ph 763 Me NMePh 2，4-Me ₂-Ph 764 Me NPr ₂ 2，4-Me ₂-Ph 765 Me NH-3-hexyls 2,4-Me₂-Ph 766 Me morpholinoes 2,4-Me₂-Ph 767 Me N(CH ₂Ph)CH ₂CH ₂OMe 2，4-Me ₂-Ph 768 Me NHCH(CH ₂Ph)CH ₂OMe 2，4-Me ₂-Ph 769 Me NH-4-THP trtrahydropyranyls 2,4-Me₂-Ph 770 Me NH-cyclopenta 2,4-Me₂-Ph 771 Me NHCH(CH ₂OMe) ₂ 2-Me-4-MeO-Ph 772 Me N(CH ₂CH ₂OMe) ₂ 2-Me-4-MeO-Ph 773 Me NHCH(Et)CH ₂OMe 2-Me-4-MeO-Ph 774 Me N(Pr)CH ₂CH ₂CN 2-Me-4-MeO-Ph 775 Me OCH(Et)CH ₂OMe 2-Me-4-MeO-Ph 776 Me NHCH(CH ₂OMe) ₂ 2-Br-4-MeO-Ph 777 Me N(CH ₂CH ₂OMe) ₂ 2-Br-4-MeO-Ph 778 Me NHCH(Et)CH ₂OMe 2-Br-4-MeO-Ph 779 Me N(Pr)CH ₂CH ₂CN 2-Br-4-MeO-Ph 780 Me OCH(Et)CH ₂OMe 2-Br-4-MeO-Ph 781 Me NHCH(CH ₂OMe) ₂ 2-Me-4-NMe ₂-Ph 782 Me N(CH ₂CH ₂OMe) ₂ 2-Me-4-NMe ₂-Ph 783 Me NHCH(Et)CH ₂OMe 2-Me-4-NMe ₂-Ph 784 Me N(Pr)CH ₂CH ₂CN 2-Me-4-NMe ₂-Ph 785 Me OCH(Et)CH ₂OMe 2-Me-4-Me ₂-Ph 786 Me NHCH(CH ₂OMe) ₂ 2-Br-4-NMe ₂-Ph 787 Me N(CH ₂CH ₂OMe) ₂ 2-Br-4-NMe ₂-Ph 788 Me NHCH(Et)CH ₂OMe 2-Br-4-NMe ₂-Ph 789 Me N(Pr)CH ₂CH ₂CN 2-Br-4-NMe ₂-Ph 790 Me OCH(Et)CH ₂OMe 2-Br-4-NMe ₂-Ph 791 Me NHCH(CH ₂OMe) ₂ 2-Br-4-i-Pr-Ph 792 Me N(CH ₂CH ₂OMe) ₂ 2-Br-4-i-Pr-Ph 793 Me NHCH(Et)CH ₂OMe 2-Br-4-i-Pr-Ph 794 Me N(Pr)CH ₂CH ₂CN 2-Br-4-i-Pr-Ph 795 Me OCH(Et)CH ₂OMe 2-Br-4-i-Pr-Ph 796 Me NHCH(CH ₂OMe) ₂ 2-Br-4-Me-Ph 797 Me N(CH ₂CH ₂OMe) ₂ 2-Br-4-Me-Ph 798 Me NHCH(Et)CH ₂OMe 2-Br-4-Me-Ph 799 Me N(Pr)CH ₂CH ₂CN 2-Br-4-Me-Ph 800 Me OCH(Et)CH ₂OMe 2-Br-4-Me-Ph 801 Me NHCH(CH ₂OMe) ₂ 2-Me-4-Br-Ph 802 Me N(CH ₂CH ₂OMe) ₂ 2-Me-4-Br-Ph 803 Me NHCH(Et)CH ₂OMe 2-Me-4-Br-Ph 804 Me N(Pr)CH ₂CH ₂CN 2-Me-4-Br-Ph 805 Me OCH(Et)CH ₂OMe 2-Me-4-Br-Ph 806 Me NHCH(CH ₂OMe) ₂ 2-Cl-4，6-Me ₂-Ph 807 Me N(CH ₂CH ₂OMe) ₂ 2-Cl-4，6-Me ₂-Ph 808 Me NHCH(CH ₂OMe) ₂ 4-Br-2，6-(Me) ₂-Ph 809 Me N(CH ₂CH ₂OMe) ₂ 4-Br-2，6-(Me) ₂-Ph 810 Me NHCH(CH ₂OMe) ₂ 4-i-Pr-2-SMe-Ph 811 Me N(CH ₂CH ₂OMe) ₂ 4-i-Pr-2-SMe-Ph 812 Me NHCH(CH ₂OMe) ₂ 2-Br-4-CF ₃-Ph 813 Me N(CH ₂CH ₂OMe) ₂ 2-Br-4-CF ₃-Ph 814 Me NHCH(CH ₂OMe) ₂ 2-Br-4，6-(MeO) ₂-Ph 815 Me N(CH ₂CH ₂OMe) ₂ 2-Br-4，6-(MeO) ₂-Ph 816 Me NHCH(CH ₂OMe) ₂ 2-Cl-4，6-(MeO) ₂-Ph 817 Me N(CH ₂CH ₂OMe) ₂ 2-Cl-4，6-(MeO) ₂-Ph 818 Me NHCH(CH ₂OMe) ₂ 2，6-(Me) ₂-4-SMe-Ph 819 Me N(CH ₂CH ₂OMe) ₂ 2，6-(Me) ₂-4-SMe-Ph 820 Me NHCH(CH ₂OMe) ₂ 4-(COMe)-2-Br-Ph 821 Me N(CH ₂CH ₂OMe) ₂ 4-(COMe)-2-Br-Ph 822 Me NHCH(CH ₂OMe) ₂ 2，4，6-Me ₃-pyridin-3-yl 823 Me N (CH₂CH ₂OMe) ₂ 2，4，6-Me ₃-pyridin-3-yl 824 Me NHCH (CH₂OMe) ₂ 2，4-(Br) ₂-Ph 825 Me N(CH ₂CH ₂OMe) ₂ 2，4-(Br) ₂-Ph 826 Me NHCH(CH ₂OMe) ₂ 4-i-Pr-2-SMe-Ph 827 Me N(CH ₂CH ₂OMe) ₂ 4-i-Pr-2-SMe-Ph 828 Me NHCH(CH ₂OMe) ₂ 4-i-Pr-2-SO ₂Me-Ph 829 Me N(CH ₂CH ₂OMe) ₂ 4-i-Pr-2-SO ₂Me-Ph 830 Me NHCH(CH ₂OMe) ₂ 2，6-(Me) ₂-4-SMe-Ph 831 Me N(CH ₂CH ₂OMe) ₂ 2，6-(Me) ₂-4-SMe-Ph 832 Me NHCH(CH ₂OMe) ₂ 2，6-(Me)2-4-SO ₂Me-Ph 833 Me N(CH ₂CH ₂OMe) ₂ 2，6-(Me)2-4-SO ₂Me-Ph 834 Me NHCH(CH ₂OMe) ₂ 2-I-4-i-Pr-Ph 835 Me N(CH ₂CH ₂OMe) ₂ 2-I-4-i-Pr-Ph 836 Me NHCH(CH ₂OMe) ₂ 2-Br-4-N(Me) ₂-6-MeO-Ph 837 Me N(CH ₂CH ₂OMe) ₂ 2-Br-4-N(Me) ₂-6-MeO-Ph 838 Me NEt ₂2-Br-4-MeO-Ph 839 Me NH-3-amyl group 2-Br-4-MeO-Ph 840 Me NHCH (CH₂OMe) ₂ 2-CN-4-Me-Ph 841 Me N(c-C ₃H ₅)CH ₂CH ₂CN 2，4，6-Me ₃-Ph 842 Me NHCH(CH ₂CH ₂OMe)CH ₂OMe 2-Me-4-Br-Ph 843 Me NHCH(CH ₂OMe) ₂ 2，5-Me ₂-4-MeO-Ph 844 Me N(CH ₂CH ₂OMe) ₂ 2，5-Me ₂-4-MeO-Ph 845 Me NH-3-amyl groups 2,5-Me₂-4-MeO-Ph 846 Me NEt ₂ 2，5-Me ₂-4-MeO-Ph 847 Me NHCH(CH ₂OMe) ₂ 2-Cl-4-MePh 848 Me NCH(Et)CH ₂OMe 2-Cl-4-MePh 849 Me N(CH ₂CH ₂OMe) ₂ 2-Cl-4-MePh 850 Me (S)-NHCH ₄(CH ₂CH ₂OMe)CH ₂OMe 2-Cl-4-MePh 851 Me N(c-C ₃H ₅)CH ₂CH ₂CN 2，5-Me ₂-4-MeOPh 852 Me NEt ₂ 2-Me-4-MeOPh 853 Me OEt 2-Me-4-MeOPh 854 Me (S)-NHCH(CH ₂CH ₂OMe)CH ₂OMe 2-Me-4-MeOPh 855 Me N(c-C ₃H ₅)CH ₂CH ₂CN 2-Me-4-MeOPh 856 Me NHCH(CH ₂CH ₂OEt) ₂ 2-Me-4-MeOPh 857 Me N(c-C ₃H ₅)CH ₂CH ₂CN 2，4-Cl ₂-Ph 858 Me NEt ₂2-Me-4-ClPh 859 Me NH-3-amyl group 2-Me-4-ClPh 860 Me N (CH₂CH ₂OMe) ₂ 2-Me-4-ClPh 861 Me NHCH(CH ₂OMe) ₂ 2-Me-4-ClPh 862 Me NEt ₂ 2-Me-4-ClPh 863 Me NEt ₂2-Cl-4-MePh 864 Me NH-3-amyl group 2-Cl-4-MePh 865 Me NHCH (CH₂OMe) ₂ 2-Cl-4-MeOPh 866 Me N(CH ₂CH ₂OMe) ₂ 2-Cl-4-MeOPh 867 Me NHCH(Et)CH ₂OMe 2-Cl-4-MeOPh 868 Me N(c-Pr)CH ₂CH ₂CN 2-Cl-4-MeOPh 869 Me NEt ₂2-Cl-4-MeOPh 870 Me NH-3-amyl group 2-Cl-4-MeOPh 871 Me NHCH (Et) CH₂CH ₂OMe 2-Cl-4-MeOPh 872 Me NHCH(Me)CH ₂CH ₂OMe 2-Cl-4-MeOPh 873 Me NHCH(Et)CH ₂CH ₂OMe 2-Br-4-MeOPh 874 Me NHCH(Me)CH ₂CH ₂OMe 2-Br-4-MeOPh 875 Me NHCH(Et)CH ₂CH ₂OMe 2-Me-4-MeOPh 876 Me NHCH(Me)CH ₂CH ₂OMe 2-Me-4-MeOPh 877 Me NHCH(CH ₂OMe) ₂ 2-Cl-4，5-(MeO) ₂Ph 878 Me N(CH ₂CH ₂OMe) ₂ 2-Cl-4，5-(MeO) ₂Ph 879 Me NHCH(Et)CH ₂OMe 2-Cl-4，5-(MeO) ₂Ph 880 Me N(c-Pr)CH ₂CH ₂CN 2-Cl-4，5-(MeO) ₂Ph 881 Me NEt ₂ 2-Cl-4，5-(MeO) ₂Ph 882 Me NH-3-amyl group 2-Cl-4,5-(MeO)₂Ph 883 Me NHCH(Et)CH ₂CH ₂OMe 2-Cl-4，5-(MeO) ₂Ph 884 Me NHCH(Me)CH ₂CH ₂OMe 2-Cl-4，5-(MeO) ₂Ph 885 Me NHCH(CH ₂OMe) ₂ 2-Br-4，5-(MeO) ₂Ph 886 Me N(CH ₂CH ₂OMe) ₂ 2-Br-4，5-(MeO) ₂Ph 887 Me NHCH(Et)CH ₂OMe 2-Br-4，5-(MeO) ₂Ph 888 Me N(c-Pr)CH ₂CH ₂CN 2-Br-4，5-(MeO) ₂Ph 889 Me NEt ₂ 2-Br-4，5-(MeO) ₂Ph 890 Me NH-3-amyl group 2-Br-4,5-(MeO)₂Ph 891 Me NHCH(CH ₂OMe) ₂ 2-Cl-4，6-(MeO) ₂Ph 892 Me N(CH ₂CH ₂OMe) ₂ 2-Cl-4，6-(MeO) ₂Ph 893 Me NEt ₂ 2-Cl-4，6-(MeO) ₂Ph 894 Me NH-3-amyl group 2-Cl-4,6-(MeO)₂Ph 895 Me NHCH(CH ₂OMe) ₂ 2-Me-4，6-(MeO) ₂Ph 896 Me N(CH ₂CH ₂OMe) ₂ 2-Me-4，6-(MeO) ₂Ph 897 Me NHCH(Et)CH ₂OMe 2-Me-4，6-(MeO) ₂Ph 898 Me NEt ₂ 2-Me-4，6-(MeO) ₂Ph 899 Me NH-3-amyl group 2-Me-4,6-(MeO)₂Ph 900 Me NHCH(Et)CH ₂CH ₂OMe 2-Me-4-MeOPh 901 Me NHCH(Me)CH ₂CH ₂OMe 2-Me-4-MeOPh 902 Me NHCH(CH ₂OMe) ₂ 2-Me0-4-MePh 903 Me N(CH ₂CH ₂OMe) ₂ 2-Me0-4-MePh 904 Me NHCH(Et)CH ₂OMe 2-Me0-4-MePh 905 Me N(c-Pr)CH ₂CH ₂CN 2-Me0-4-MePh 906 Me NEt ₂2-Me0-4-MePh 907 Me NH-3-amyl group 2-Me0-4-MePh 908 Me NHCH (Et) CH₂CH ₂OMe 2-Me0-4-MePh 909 Me NHCH(Me)CH ₂CH ₂OMe 2-Me0-4-MePh 910 Me NHCH(CH ₂OMe) ₂ 2-Me0-4-MePh 911 Me N(CH ₂CH ₂OMe) ₂ 2-Me0-4-MePh 912 Me NHCH(Et)CH ₂OMe 2-Me0-4-MePh 913 Me N(c-Pr)CH ₂CH ₂CN 2-Me0-4-MePh 914 Me NEt ₂2-Me0-4-MePh 915 Me NH-3-amyl group 2-Me0-4-MePh 916 Me NHCH (CH₂OMe) ₂ 2-Me0-4-ClPh 917 Me N(CH ₂CM ₂OMe) ₂ 2-Me0-4-ClPh 918 Me NHCH(Et)CH ₂OMe 2-Me0-4-ClPh 919 Me NEt ₂2-Me0-4-ClPh 920 Me NH-3-amyl group 2-Me0-4-ClPh

Table 6 Ex R14 R3 Ar 921 Me NHCH(CH ₂OMe) ₂ 2，4-Cl ₂-Ph 922 Me NHCHPr ₂ 2，4-Cl ₂-Ph 923 Me NEtBu 2，4-Cl ₂-Ph 924 Me NPr(CH ₂-c-C ₃H ₅) 2，4-Cl ₂-Ph 925 Me N(CH ₂CH ₂OMe) ₂ 2，4-Cl ₂-Ph 926 Me NH-3-heptyl 2,4-Cl₂-Ph 927 Me NHCH(Et)CH ₂OMe 2，4-Cl ₂-Ph 928 Me NEt ₂ 2，4-Cl ₂-Ph 929 Me NHCH(CH ₂OEt) ₂ 2，4-Cl ₂-Ph 930 Me NH-3-amyl groups 2,4-Cl₂-Ph 931 Me NMePh 2，4-Cl ₂-Ph 932 Me NPr ₂ 2，4-Cl ₂-Ph 933 Me NH-3-hexyls 2,4-Cl₂-Ph 934 Me morpholinoes 2,4-Cl₂-Ph 935 Me N(CH ₂Ph)CH ₂CH ₂OMe 2，4-Cl ₂-Ph 936 Me NHCH(CH ₂Ph)CH ₂OMe 2，4-Cl ₂-Ph 937 Me NH-4-THP trtrahydropyranyls 2,4-Cl₂-Ph 938 Me NH-cyclopenta 2,4-Cl₂-Ph 939 Me OEt 2，4-Cl ₂-Ph 940 Me OCH(Et)CH ₂OMe 2，4-Cl ₂-Ph 941 Me OCH ₂Ph 2，4-Cl ₂-Ph 942 Me O-3-amyl groups 2,4-Cl₂-Ph 943 Me SEt 2，4-Cl ₂-Ph 944 Me S(O)Et 2，4-Cl ₂-Ph 945 Me SO ₂Et 2，4-Cl ₂-Ph 946 Me Ph 2，4-Cl ₂-Ph 947 Me 2-CF ₃-Ph 2，4-Cl ₂-Ph 948 Me 2-Ph-Ph 2，4-Cl ₂-Ph 949 Me 3-pentyl 2，4-Cl ₂-Ph 950 Me cyclobutyl 2,4-Cl₂-Ph 951 Me 3-pyridine radicals 2,4-Cl₂-Ph 952 Me CH(Et)CH ₂CONMe ₂ 2，4-Cl ₂-Ph 953 Me CH(Et)CH ₂CH ₂NMe ₂ 2，4-Cl ₂-Ph 954 Me NHCH(CH ₂OMe) ₂ 2，4，6-Me ₃-Ph 955 Me NHCHPr ₂ 2，4，6-Me ₃-Ph 956 Me NEtBu 2，4，6-Me ₃-Ph 957 Me NPr(CH ₂-c-C ₃H ₅) 2，4，6-Me ₃-Ph 958 Me N(CH ₂CH ₂OMe) ₂ 2，4，6-Me ₃-Ph 959 Me NH-3-heptyl 2,4,6-Me₃-Ph 960 Me NHCH(Et)CH ₂OMe 2，4，6-Me ₃-Ph 961 Me NEt ₂ 2，4，6-Me ₃-Ph 962 Me NHCH(CH ₂OEt) ₂ 2，4，6-Me ₃-Ph 963 Me NH-3-amyl groups 2,4,6-Me₃-Ph 964 Me NMePh 2，4，6-Me ₃-Ph 965 Me NPr ₂ 2，4，6-Me ₃-Ph 966 Me NH-3-hexyls 2,4,6-Me₃-Ph 967 Me morpholinoes 2,4,6-Me₃-Ph 968 Me N(CH ₂Ph)CH ₂CH ₂OMe 2，4，6-Me ₃-Ph 969 Me NHCH(CH ₂Ph)CH ₂OMe 2，4，6-Me ₃-Ph 970 Me NH-4-THP trtrahydropyranyls 2,4,6-Me₃-Ph 971 Me NH-cyclopenta 2,4,6-Me₃-Ph 972 Me OEt 2，4，6-Me ₃-Ph 973 Me OCH(Et)CH ₂OMe 2，4，6-Me ₃-Ph 974 Me OCH ₂Ph 2，4，6-Me ₃-Ph 975 Me O-3-amyl groups 2,4,6-Me₃-Ph 976 Me SEt 2，4，6-Me ₃-Ph 977 Me S(O)Et 2，4，6-Me ₃-Ph 978 Me SO ₂Et 2，4，6-Me ₃-Ph 979 Me CH(CO ₂Et) ₂ 2，4，6-Me ₃-Ph 980 Me C(Et)(CO ₂Et) ₂ 2，4，6-Me ₃-Ph 981 Me CH(Et)CH ₂OH 2，4，6-Me ₃-Ph 982 Me CH(Et)CH ₂OMe 2，4，6-Me ₃-Ph 983 Me CONMe ₂ 2，4，6-Me ₃-Ph 984 Me COCH ₃ 2，4，6-Me ₃-Ph 985 Me CH(OH)CH ₃ 2，4，6-Me ₃-Ph 986 Me C (OH) Ph-3-pyridine radicals 2,4,6-Me₃-Ph 987 Me Ph 2，4，6-Me ₃-Ph 988 Me 2-Ph-Ph 2，4，6-Me ₃-Ph 989 Me 3-amyl groups 2,4,6-Me₃-Ph 990 Me cyclobutyl 2,4,6-Me₃-Ph 991 Me 3-pyridine radicals 2,4,6-Me₃-Ph 992 Me CH(Et)CH ₂CONMe ₂ 2，4，6-Me ₃-Ph 993 Me CH(Et)CH ₂CH ₂NMe ₂ 2，4，6-Me ₃-Ph 994 Me NHCH(CH ₂OMe) ₂ 2，4-Me ₂-Ph 995 Me N(CH ₂CH ₂OMe) ₂ 2，4-Me ₂-Ph 996 Me NHCH(Et)CH ₂OMe 2，4-Me ₂-Ph 997 Me NH-3-amyl groups 2,4-Me₂-Ph 998 Me NEt ₂ 2，4-Me ₂-Ph 999 Me N(CH ₂CN) ₂ 2，4-Me ₂-Ph 1000 Me NHCH(Me)CH ₂OMe 2，4-Me ₂-Ph 1001 Me OCH(Et)CH ₂OMe 2，4-Me ₂-Ph 1002 Me NPr-c-C ₃H ₅ 2，4-Me ₂-Ph 1003 Me NHCH(Me)CH ₂NMe ₂ 2，4-Me ₂-Ph 1004 Me N(c-C ₃H ₅)CH ₂CH ₂CN 2，4-Me ₂-Ph 1005 Me N(Pr)CH ₂CH ₂CN 2，4-Me ₂-Ph 1006 Me N(Bu)CH ₂CH ₂CN 2，4-Me ₂-Ph 1007 Me NHCHPr ₂ 2，4-Me ₂-Ph 1008 Me NEtBu 2，4-Me ₂-Ph 1009 Me NPr(CH ₂-c-C ₃H ₅) 2，4-Me ₂-Ph 1010 Me NH-3-heptyl 2,4-Me₂-Ph 1011 Me NEt ₂ 2，4-Me ₂-Ph 1012 Me NHCH(CH ₂OEt) ₂ 2，4-Me ₂-Ph 1013 Me NH-3-amyl groups 2,4-Me₂-Ph 1014 Me NMePh 2，4-Me ₂-Ph 1015 Me NPr ₂ 2，4-Me ₂-Ph 1016 Me NH-3-hexyl 2，4-Me ₂-Ph 1017 Me morpholino 2，4-Me ₂-Ph 1018 Me N(CH ₂Ph)CH ₂CH ₂OMe 2，4-Me ₂-Ph 1019 Me NHCH(CH ₂Ph)CH ₂OMe 2，4-Me ₂-Ph 1020 Me NH-4-THP trtrahydropyranyls 2,4-Me₂-Ph 1021 Me NH-cyclopenta 2,4-Me₂-Ph 1022 Me NHCH(CH ₂OMe) ₂ 2-Me-4-MeO-Ph 1023 Me N(CH ₂CH ₂OMe) ₂ 2-Me-4-MeO-Ph 1024 Me NHCH(Et)CH ₂OMe 2-Me-4-MeO-Ph 1025 Me N(Pr)CH ₂CH ₂CN 2-Me-4-MeO-Ph 1026 Me OCH(Et)CH ₂OMe 2-Me-4-MeO-Ph 1027 Me NHCH(CH ₂OMe) ₂ 2-Br-4-MeO-Ph 1028 Me N(CH ₂CH ₂OMe) ₂ 2-Br-4-MeO-Ph 1029 Me NHCH(Et)CH ₂OMe 2-Br-4-MeO-Ph 1030 Me N(Pr)CH ₂CH ₂CN 2-Br-4-MeO-Ph 1031 Me OCH(Et)CH ₂OMe 2-Br-4-MeO-Ph 1032 Me NHCH(CH ₂OMe) ₂ 2-Me-4-NMe ₂-Ph 1033 Me N(CH ₂CH ₂OMe) ₂ 2-Me-4-NMe ₂-Ph 1034 Me NHCH(Et)CH ₂OMe 2-Me-4-NMe ₂-Ph 1035 Me N(Pr)CH ₂CH ₂CN 2-Me-4-NMe ₂-Ph 1036 Me OCH(Et)CH ₂OMe 2-Me-4-NMe ₂-Ph 1037 Me NHCH(CH ₂OMe) ₂ 2-Br-4-NMe ₂-Ph 1038 Me N(CH ₂CH ₂OMe) ₂ 2-Br-4-NMe ₂-Ph 1039 Me NHCH(Et)CH ₂OMe 2-Br-4-NMe ₂-Ph 1040 Me N(Pr)CH ₂CH ₂CN 2-Br-4-NMe ₂-Ph 1041 Me OCH(Et)CH ₂OMe 2-Br-4-NMe ₂-Ph 1042 Me NHCH(CH ₂OMe) ₂ 2-Br-4-i-Pr-Ph 1043 Me N(CH ₂CH ₂OMe) ₂ 2-Br-4-i-Pr-Ph 1044 Me NHCH(Et)CH ₂OMe 2-Br-4-i-Pr-Ph 1045 Me N(Pr)CH ₂CH ₂CN 2-Br-4-i-Pr-Ph 1046 Me OCH(Et)CH ₂OMe 2-Br-4-i-Pr-Ph 1047 Me NHCH(CH ₂OMe) ₂ 2-Br-4-Me-Ph 1048 Me N(CH ₂CH ₂OMe) ₂ 2-Br-4-Me-Ph 1049 Me NHCH(Et)CH ₂OMe 2-Br-4-Me-Ph 1050 Me N(Pr)CH ₂CH ₂CN 2-Br-4-Me-Ph 1051 Me OCH(Et)CH ₂OMe 2-Br-4-Me-Ph 1052 Me NHCH(CH ₂OMe) ₂ 2-Me-4-Br-Ph 1053 Me N(CH ₂CH ₂OMe) ₂ 2-Me-4-Br-Ph 1054 Me NHCH(Et)CH ₂OMe 2-Me-4-Br-Ph 1055 Me N(Pr)CH ₂CH ₂CN 2-Me-4-Br-Ph 1056 Me OCH(Et)CH ₂OMe 2-Me-4-Br-Ph 1057 Me NCH(CH ₂OMe) ₂ 2-Cl-4，6-Me ₂-Ph 1058 Me N(CH ₂CH ₂OMe) ₂ 2-Cl-4，6-Me ₂-Ph 1059 Me NHCH(CH ₂OMe) ₂ 4-Br-2，6-(Me) ₂-Ph 1060 Me N(CH ₂CH ₂OMe) ₂ 4-Br-2，6-(Me) ₂-Ph 1061 Me NHCH(CH ₂OMe) ₂ 4-i-Pr-2-SMe-Ph 1062 Me N(CH ₂CH ₂OMe) ₂ 4-i-Pr-2-SMe-Ph 1063 Me NHCH(CH ₂OMe) ₂ 2-Br-4-CF ₃-Ph 1064 Me N(CH ₂CH ₂OMe) ₂ 2-Br-4-CF ₃-Ph 1065 Me NHCH(CH ₂OMe) ₂ 2-Br-4，6-(MeO) ₂-Ph 1066 Me N(CH ₂CH ₂OMe) ₂ 2-Br-4，6-(MeO) ₂-Ph 1067 Me NHCH(CH ₂OMe) ₂ 2-Cl-4，6-(MeO) ₂-Ph 1068 Me N(CH ₂CH ₂OMe) ₂ 2-Cl-4，6-(MeO) ₂-Ph 1069 Me NHCH(CH ₂OMe) ₂ 2，6-(Me) ₂-4-SMe-Ph 1070 Me N(CH ₂CH ₂OMe) ₂ 2，6-(Me) ₂-4-SMe-Ph 1071 Me NHCH(CH ₂OMe) ₂ 4-(COMe)-2-Br-Ph 1072 Me N(CH ₂CH ₂OMe) ₂ 4-(COMe)-2-Br-Ph 1073 Me NHCH(CH ₂OMe) ₂ 2，4，6-Me ₃-pyridin-3-yl 1074 Me N (CH₂CH ₂OMe) ₂ 2，4，6-Me ₃-pyridin-3-yl 1075 Me NHCH (CH₂OMe) ₂ 2，4-(Br) ₂-Ph 1076 Me N(CH ₂CH ₂OMe) ₂ 2，4-(Br) ₂-Ph 1077 Me NHCH(CH ₂OMe) ₂ 4-i-Pr-2-SMe-Ph 1078 Me N(CH ₂CH ₂OMe) ₂ 4-i-Pr-2-SMe-Ph 1079 Me NHCH(CH ₂OMe) ₂ 4-i-Pr-2-SO ₂Me-Ph 1080 Me N(CH ₂CH ₂OMe) ₂ 4-i-Pr-2-SO ₂Me-Ph 1081 Me NHCH(CH ₂OMe) ₂ 2，6-(Me) ₂-4-SMe-Ph 1082 Me N(CH ₂CH ₂OMe) ₂ 2，6-(Me) ₂-4-SMe-Ph 1083 Me NHCH(CH ₂OMe) ₂ 2，6-(Me)2-4-SO ₂Me-Ph 1084 Me N(CH ₂CH ₂OMe) ₂ 2，6-(Me)2-4-SO ₂Me-Ph 1085 Me NHCH(CH ₂OMe) ₂ 2-I-4-i-Pr-Ph 1086 Me N(CH ₂CH ₂OMe) ₂ 2-I-4-i-Pr-Ph 1087 Me NHCH(CH ₂OMe) ₂ 2-Br-4-N(Me) ₂-6-MeO-Ph 1088 Me N(CH ₂CH ₂OMe) ₂ 2-Br-4-N(Me) ₂-6-MeO-Ph 1089 Me NEt ₂2-Br-4-MeO-Ph 1090 Me NH-3-amyl group 2-Br-4-MeO-Ph 1091 Me NHCH (CH₂OMe) ₂ 2-CN-4-Me-Ph 1092 Me N(c-C ₃H ₅)CH ₂CH ₂CN 2，4，6-Me ₃-Ph 1093 Me NHCH(CH ₂CH ₂OMe)CH ₂OMe 2-Me-4-Br-Ph 1094 Me NHCH(CH ₂OMe) ₂ 2，5-Me ₂-4-MeO-Ph 1095 Me N(CH ₂CH ₂OMe) ₂ 2，5-Me ₂-4-MeO-Ph 1096 Me NH-3-amyl groups 2,5-Me₂-4-MeO-Ph 1097 Me NEt ₂ 2，5-Me ₂-4-MeO-Ph 1098 Me NHCH(CH ₂OMe) ₂ 2-Cl-4-MePh 1099 Me NCH(Et)CH ₂OMe 2-Cl-4-MePh 1100 Me N(CH ₂CH ₂OMe) ₂ 2-Cl-4-MePh 1101 Me (S)-NHCH(CH ₂CH ₂OMe)CH ₂OMe 2-Cl-4-MePh 1102 Me N(c-C ₃H ₅)CH ₂CH ₂CN 2，5-Me2-4-MeOPh 1103 Me NEt ₂ 2-Me-4-MeOPh 1104 Me OEt 2-Me-4-MeOPh 1105 Me (S)-NHCH(CH ₂CH ₂OMe)CH ₂OMe 2-Me-4-MeOPh 1106 Me N(c-C ₃H ₅)CH ₂CH ₂CN 2-Me-4-MeOPh 1107 Me NHCH(CH ₂CH ₂OEt) ₂ 2-Me-4-MeOPh 1108 Me N(c-C ₃H ₅)CH ₂CH ₂CN 2，4-Cl ₂-Ph 1109 Me NEt ₂2-Me-4-ClPh 1110 Me NH-3-amyl group 2-Me-4-ClPh 1111 Me N (CH₂CH ₂OMe) ₂ 2-Me-4-ClPh 1112 Me NHCH(CH ₂OMe) ₂ 2-Me-4-ClPh 1113 Me NEt ₂ 2-Me-4-ClPh 1114 Me NEt ₂2-Cl-4-MePh 1115 Me NH-3-amyl group 2-Cl-4-MePh 1116 Me NHCH (CH₂OMe) ₂ 2-Cl-4-MeOPh 1117 Me N(CH ₂CH ₂OMe) ₂ 2-Cl-4-MeOPh 1118 Me NHCH(Et)CH ₂OMe 2-Cl-4-MeOPh 1119 Me N(c-Pr)CH ₂CH ₂CN 2-Cl-4-MeOPh 1120 Me NEt ₂2-Cl-4-MeOPh 1121 Me NH-3-amyl group 2-Cl-4-MeOPh 1123 Me NHCH (Et) CH₂CH ₂OMe 2-Cl-4-MeOPh 1124 Me NHCH(Me)CH ₂CH ₂OMe 2-Cl-4-MeOPh 1125 Me NHCH(Et)CH ₂CH ₂OMe 2-Br-4-MeOPh 1126 Me NHCH(Me)CH ₂CH ₂OMe 2-Br-4-MeOPh 1127 Me NHCH(Et)CH ₂CH ₂OMe 2-Me-4-MeOPh 1128 Me NHCH(Me)CH ₂CH ₂OMe 2-Me-4-MeOPh 1129 Me NHCH(CH ₂OMe) ₂ 2-Cl-4，5-(MeO) ₂Ph 1130 Me N(CH ₂CH ₂OMe) ₂ 2-Cl-4，5-(MeO) ₂Ph 1131 Me NHCH(Et)CH ₂OMe 2-Cl-4，5-(MeO) ₂Ph 1132 Me N(c-Pr)CH ₂CH ₂CN 2-Cl-4，5-(MeO) ₂Ph 1133 Me NEt ₂ 2-Cl-4，5-(MeO) ₂Ph 1134 Me NH-3-amyl group 2-Cl-4,5-(MeO)₂Ph 1135 Me NHCH(Et)CH ₂CH ₂OMe 2-Cl-4，5-(MeO) ₂Ph 1136 Me MHCH(Me)CH ₂CH ₂OMe 2-Cl-4，5-(MeO) ₂Ph 1137 Me NHCH(CH ₂OMe) ₂ 2-Br-4，5-(MeO) ₂Ph 1138 Me N(CH ₂CH ₂OMe) ₂ 2-Br-4，5-(MeO) ₂Ph 1139 Me NHCH(Et)CH ₂OMe 2-Br-4，5-(MeO) ₂Ph 1140 Me N(c-Pr)CH ₂CH ₂CN 2-Br-4，5-(MeO) ₂Ph 1141 Me NEt ₂ 2-Br-4，5-(MeO) ₂Ph 1142 Me NH-3-amyl group 2-Br-4,5-(MeO)₂Ph 1143 Me NHCH(CH ₂OMe) ₂ 2-Cl-4，6-(MeO) ₂Ph 1144 Me N(CH ₂CH ₂OMe) ₂ 2-Cl-4，6-(MeO) ₂Ph 1145 Me NEt ₂ 2-Cl-4，6-(MeO) ₂Ph 1146 Me NH-3-amyl group 2-Cl-4,6-(MeO)₂Ph 1147 Me NHCH(CH ₂OMe) ₂ 2-Me-4，6-(MeO) ₂Ph 1148 Me N(CH ₂CH ₂OMe) ₂ 2-Me-4，6-(MeO) ₂Ph 1149 Me NHCH(Et)CH ₂OMe 2-Me-4，6-(MeO) ₂Ph 1150 Me NEt ₂ 2-Me-4，6-(MeO) ₂Ph 1151 Me NH-3-amyl group 2-Me-4,6-(MeO)₂Ph 1152 Me NHCH(Et)CH ₂CH ₂OMe 2-Me-4-MeOPh 1153 Me NHCH(Me)CH ₂CH ₂OMe 2-Me-4-MeOPh 1154 Me NHCH(CH ₂OMe) ₂ 2-Me0-4-MePh 1155 Me N(CH ₂CH ₂OMe) ₂ 2-Me0-4-MePh 1156 Me NHCH(Et)CH ₂OMe 2-Me0-4-MePh 1157 Me N(c-Pr)CH ₂CH ₂CN 2-Me0-4-MePh 1158 Me NEt ₂2-Me0-4-MePh 1159 Me NH-3-amyl group 2-Me0-4-MePh 1160 Me NHCH (Et) CH₂CH ₂OMe 2-Me0-4-MePh 1161 Me NHCH(Me)CH ₂CH ₂OMe 2-Me0-4-MePh 1162 Me NHCH(CH ₂OMe) ₂ 2-Me0-4-MePh 1163 Me N(CH ₂CH ₂OMe) ₂ 2-Me0-4-MePh 1164 Me NHCH(Et)CH ₂OMe 2-Me0-4-MePh 1165 Me N(c-Pr)CH ₂CH ₂CN 2-Me0-4-MePh 1166 Me NEt ₂2-Me0-4-MePh 1167 Me NH-3-amyl group 2-Me0-4-MePh 1168 Me NHCH (CH₂OMe) ₂ 2-Me0-4-ClPh 1169 Me N(CH ₂CH ₂OMe) ₂ 2-Me0-4-ClPh 1170 Me NHCH(Et)CH ₂OMe 2-Me0-4-ClPh 1171 Me NEt ₂2-Me0-4-ClPh 1172 Me NH-3-amyl group 2-Me0-4-ClPh

Utilizability

Estimating bioactive CRF-R1 receptors bind measures

Classify as down and be used for standard in conjunction with the description of the people CRF-R1 recipient cell membrane sepn of measuring that contains the clone and the description of mensuration itself.

Separate messenger RNA(mRNA) by the people hippocampus.Carry out the reverse transcription of described mRNA with oligomeric (dt) 12-18, by initiator codon to terminator codon increased in the coding region with PCR.With the PCR fragment cloning that produces in the EcoRV site of pGEMV, and reclaim inserting fragment with XhoI+XbaI, and clone thus in the XhoI+XbaI site of carrier pm3ar (the Epstein-Barr virus starting point and the hygromycin selectable marker that contain CMV promotor, SV40 ' t ' montage and early stage poly-a-signal, duplicate).The expression vector that is called phchCRFR that produces dyes at the 293EBNA transit cell, and selects keeping episomal described cell in the presence of 400 μ M Totomycin.Be incorporated under the Totomycin cell of selecting 4 weeks of survival, adapt in suspension growth and be used to produce following in conjunction with the film of measuring.To contain then and have an appointment 1 * 10 ⁸Each equal portions of individual suspension cell are centrifugal, form settling and freezing.

During mensuration, (50mM HEPES damping fluid, pH7.0 contains 10mM MgCl in the ice-cold tissue buffer solution of 10ml with the freezing settling of the above-mentioned 293EBNA cell that contains the transfection of useful hCRFR1 acceptor ₂, 2mM EGTA, 1 μ g/L presses down enzyme peptide, 1 μ g/ml leupeptin and 1 μ g/ml pepstatin) middle homogenize.With homogenize thing centrifugal 12 minutes, with the settling homogenize again in the 10ml tissue buffer solution that produces with 40000xg., after centrifugal 12 minutes settling is used for measuring with protein concentration 360 μ g/ml suspension with 40000xg again.

Carrying out combination on 96 well culture plates measures; Every pore capacities is 300 μ l.Adding 50 μ l in every hole is subjected to reagent thing diluent (the medicine final concentration is 10 ^-10To 10 ^-5M), 100 μ l ¹²⁵I-sheep-CRF ( ¹²⁵I-o-CRF) (final concentration is 150pM) and the above-mentioned cell homogenize of 150 μ l thing.Then culture plate was hatched under room temperature 2 hours, then filter through GF/F filter (soaking with 0.3% polymine in advance) and hatch thing with suitable cell capture instrument.With the filter washed twice, take out independent filter with ice-cold mensuration damping fluid, on gamma counter, they are carried out radioactivity and measure.

By iteration curve fitting procedure LIGAND[P.J.Munson and D.Rodbard, Anal.Biochem.107:220 (1980)] to analyze the various reagent thing diluents that are subjected to right ¹²⁵I-o-CRF combines the curve that suppresses with cytolemma, this curve can provide the K of inhibition _iValue is used to estimate biological activity with this value then.

If the K of compound in CRF suppresses _iValue is lower than about 10000nM, thinks that so this compound is activated.

The inhibition of the adenylate cyclase activity that CRF-stimulates

Can carry out the inhibition of the adenylate cyclase activity of CRF-stimulation and measure according to (Synapse 1:572 (1987)) described methods such as G.Battaglia.In brief, at 37 ℃, contain 100mM Tris-HCl (pH7.4,37 ℃), 10mM MgCl in 200ml ₂, 0.4mMEGTA, 0.1%BSA, 1mM isobutyl methylxanthine (IBMX), 250 units/ml creatine phosphokinase, 5mM phosphocreatine, 100mM guanosine 5 '-triphosphoric acid, 100nMoCRF, (concentration range is 10 to antagonist peptide ^-9To 10 ^-6M) and in the damping fluid of the initial weight in wet base tissue of 0.8mg (about 40-60mg albumen) reacted 10 minutes.By adding 1mMATP/[ ³²P] ATP (about 2-4mCi/ pipe) begins reaction, adds 100ml 50mM Tris-HCl, 45mM ATP and 2% sodium lauryl sulphate termination reaction.Be the rate of recovery of monitoring cAMP, in the every pipe of separate forward, add 1 μ l[ ³H] cAMP (about 40000 dpm).The order with Dowex separate with alumina column [ ³²P] cAMP with [ ³²P] ATP.

Biological activity in the body

All can estimate the activity in vivo of The compounds of this invention with the existing also acceptable bioassay method in any this area.The illustrative example of these tests comprises that startle test, climbing test and chronic administration of the sense of hearing measure.These and other some model that is used to measure The compounds of this invention are seen the Brain Research Reviews (15:71 (1990)) of C.W.Berridge and A.J.Dunn.Can test these compounds with the rodent or the small mammal of any kind.

Compound of the present invention has utilizability when treating the imbalance relevant with the corticotropin releasing factor(CRF) abnormal level in the patient who suffers from dysthymia disorders, affective disorder and/or anxiety disorder.

Can give compound of the present invention, unusual by active substance is contacted treat these with the action site of intravital this material of Mammals.Can use the described compound of the method afford that is used for administration of any routine, perhaps as independent medicine, perhaps in the mode of medicine composition.Can they are individually dosed, but usually with the pharmaceutical carrier administration according to route of administration and standard preparation choice of practice.

The dosage of administration is according to for example kind, the frequency of treatment and the required variations such as effect of the character of the mode of pharmacodynamic profile, the administration of certain drug and approach, patient's age, body weight and healthy state, symptom and severity, treatment simultaneously of purposes and known factor.When being used for the treatment of described disease or disorder, compound of the present invention can be with dosage oral administration every day of 0.002-200mg/kg body weight activeconstituents.Usually with divided dose administration every day of 0.01-10mg/kg 1-4 time, perhaps obtain required pharmacological action effectively with sustained release preparation.

Formulation (composition) per unit that is suitable for administration contains the about 100mg activeconstituents of the 1mg-that has an appointment.In these medicinal compositionss, described activeconstituents generally exists with about 0.5-95% (weight) of composition total weight.

Can be with solid dosage, for example capsule, tablet or powder agent are perhaps with liquid dosage form for example elixir, syrup and/or the described activeconstituents of suspension agent orally give.Also can give compound of the present invention with sterile liquid formulation parenteral.

Can use the gelatine capsule agent that contains activeconstituents and appropriate carriers, described carrier is (but being not limited to) lactose, starch, Magnesium Stearate, stearic acid or derivatived cellulose for example.Similarly thinner can be used to prepare compressed tablets.Tablet and capsule all can be made the slowly-releasing product, so that the continuous release of medicine in for some time to be provided.Compressed tablets can be sugar coating sheet or bag film coated tablet, covering undesirable taste, or is used to protect described activeconstituents not to be subjected to environmental disruption, or makes tablet in the disintegration of gi tract selectivity.

The liquid dosage form of oral administration can contain tinting material or correctives, to increase patient's acceptability.

Generally speaking, water, pharmaceutically acceptable oil, salt solution, dextran (glucose) aqueous solution and relevant sugar soln and polyvalent alcohol are the carriers that is fit to of parenteral solution as propylene glycol or polyoxyethylene glycol.The solution of parenteral admin preferably contains the water-soluble salt of activeconstituents, suitable stablizer and (if desired) buffer substance.Oxidation inhibitor is the stablizer that is fit to as sodium bisulfite, S-WAT or xitix (alone or in combination).Also can use citric acid and its salt and EDTA.In addition, parenteral solution can contain sanitas, for example geramine, methyl p-hydroxybenzoate or propylparaben and chlorobutanol.

" Remington ' s Pharmaceutical Sciences " (A.Osol, canonical reference book of this area) seen and be set forth in to suitable pharmaceutical carrier.

The useful pharmaceutical dosage form of following explanation The compounds of this invention administration: capsule

The Powdered activeconstituents of 100mg, 150mg lactose, 50mg Mierocrystalline cellulose and 6mg Magnesium Stearate are filled in two portions hard gelatin capsule of standard, can prepare many unit capsule.Gelseal

The preparation activeconstituents is at the digestible oil mixture in soya-bean oil, Oleum Gossypii semen or the sweet oil for example, and injects by positive metathetical mode, pumps into and forms the soft gelatin capsule that contains the 100mg activeconstituents in the gelatin.Washing and dry capsule.Tablet

Prepare many tablets with ordinary method, make dose unit contain 100mg activeconstituents, 0.2mg colloid silica, 5mg Magnesium Stearate, 275mg Microcrystalline Cellulose, 11mg starch and 98.8mg lactose.Can carry out suitable dressing to increase palatability or delayed absorption.

Compound of the present invention also can be used as reagent or standard substance in the Biochemical Research of neural function, imbalance and disease.

Although describe and the present invention that demonstrated with the part embodiment preferred, other embodiment is conspicuous to those skilled in the art.Therefore, the invention is not restricted to specific embodiment described and demonstration, but can make amendment or change and do not depart from aim of the present invention it, complete scope of the present invention be described in appending claims.

Claims

1. formula (50) compound and pharmacy acceptable salt thereof:

This compound of formula (50) is selected from: R wherein ³For-N (Et) (n-Bu), R ^4aBe Cl, R ^4bBe H, R ^4cBe Cl, R ^4dBe H, R ^4eFormula (50) compound for H; R wherein ³For-N (n-Pr) (CH ₂CPr), R ^4aBe Cl, R ^4bBe H, R ^4cBe Cl, R ^4dBe H, R ^4eFormula (50) compound for H; R wherein ³For-NHCH (CH ₂OMe) ₂, R ^4aBe Cl, R ^4bBe H, R ^4cBe Cl, R ^4dBe H, R ^4eFormula (50) compound for H; R wherein ³For-N (n-Pr) ₂, R ^4aBe Cl, R ^4bBe H, R ^4cBe Cl, R ^4dBe H, R ^4eFormula (50) compound for H; R wherein ³For-N (Et) ₂, R ^4aBe Br, R ^4bBe H, R ^4cBe OMe, R ^4dBe H, R ^4eFormula (50) compound for H; R wherein ³For-N (CH ₂CH ₂OMe) ₂, R ^4aBe Me, R ^4bBe H, R ^4cBe OMe, R ^4dBe Me, R ^4eFormula (50) compound for H; R wherein ³For-N (Et) ₂, R ^4aBe Me, R ^4bBe H, R ^4cBe OMe, R ^4dBe Me, R ^4eFormula (50) compound for H; R wherein ³For-N (CH ₂CH ₂OMe) ₂, R ^4aBe Me, R ^4bBe H, R ^4cBe Br, R ^4dBe H, R ^4eFormula (50) compound for H; R wherein ³For-N (Et) ₂, R ^4aBe Cl, R ^4bBe H, R ^4cBe OMe, R ^4dBe H, R ^4eFormula (50) compound for H; R wherein ³For-N (CH ₂CH ₂OMe) ₂, R ^4aBe Cl, R ^4bBe H, R ^4cBe OMe, R ^4dBe H, R ^4eFormula (50) compound for H; R wherein ³Be N (CH ₂CH ₂OMe) ₂, R ^4aBe Me, R ^4bBe H, R ^4cBe OMe, R ^4dBe H, R ^4eFormula (50) compound for H.

2. the compound of claim 1 and pharmacy acceptable salt thereof, wherein said compound is selected from:

4-(N-ethyl-N-fourth amino)-2,7-dimethyl-8-(2,4 dichloro benzene base)-[1,5-a]-pyrazoles-1,3,5-triazines;

4-(N-n-propyl-N-(cyclopropyl) methylamino-)-2,7-dimethyl-8-(2,4 dichloro benzene base)-[1,5-a]-pyrazoles-1,3,5-triazines;

4-(1,3-dimethoxy third-2-base is amino)-2,7-dimethyl-8-(2,4 dichloro benzene base)-[1,5-a]-pyrazoles-1,3,5-triazines;

4-dipropyl amino-2,7-dimethyl-8-(2,4 dichloro benzene base)-[1,5-a]-pyrazoles-1,3,5-triazines;

4-diethylin-2,7-dimethyl-8-(2-bromo-4-p-methoxy-phenyl)-[1,5-a]-pyrazoles-1,3,5-triazines;

4-diethylin-2,7-dimethyl-8-(2,5-dimethyl-4-p-methoxy-phenyl)-[1,5-a]-pyrazoles-1,3,5-triazines;

4-(two-(2-methoxy ethyl) amino)-2,7-dimethyl-8-(4-bromo-2-aminomethyl phenyl)-[1,5-a]-pyrazoles-1,3,5-triazines;

4-diethylin-2,7-dimethyl-8-(2-chloro-4-p-methoxy-phenyl)-[1,5-a]-pyrrolo--1,3,5-triazines;

4-(two-(2-methoxy ethyl) amino)-2,7-dimethyl-8-(2-chloro-4-p-methoxy-phenyl)-[1,5-a]-pyrazoles-1,3,5-triazines;

4-(two-(2-methoxy ethyl) amino)-2,7-dimethyl-8-(2-methyl-4-p-methoxy-phenyl)-[1,5-a]-pyrazoles-1,3,5-triazines;

4-(two-(2-methoxy ethyl) amino)-2,7-dimethyl-8-(2,5-dimethyl-4-p-methoxy-phenyl)-[1,5-a]-pyrazoles-1,3,5-triazines.

3. the compound of claim 1 and pharmacy acceptable salt thereof, wherein said compound is a 4-diethylin-2,7-dimethyl-8-(2,5-dimethyl-4-p-methoxy-phenyl)-[1,5-a]-pyrazoles-1,3,5-triazines.

4. the compound of claim 1 and pharmacy acceptable salt thereof, wherein said compound is 4-(N-ethyl-N-fourth amino)-2,7-dimethyl-8-(2,4 dichloro benzene base)-[1,5-a]-pyrazoles-1,3,5-triazines.

5. the compound of claim 1 and pharmacy acceptable salt thereof, wherein said compound is 4-(N-n-propyl-N-(cyclopropyl) methylamino-)-2,7-dimethyl-8-(2,4 dichloro benzene base)-[1,5-a]-pyrazoles-1,3,5-triazines.

6. the compound of claim 1 and pharmacy acceptable salt thereof, wherein said compound is 4-(two-(2-methoxy ethyl) amino)-2,7-dimethyl-8-(2-methyl-4-p-methoxy-phenyl)-[1,5-a]-pyrazoles-1,3,5-triazines.

7. the compound of claim 1 and pharmacy acceptable salt thereof, wherein said compound is 4-(two-(2-methoxy ethyl) amino)-2,7-dimethyl-8-(2,5-dimethyl-4-p-methoxy-phenyl)-[1,5-a]-pyrazolo-1,3,5-triazines.

8. medicinal compositions, said composition contain the compound of the claim 1 of pharmaceutically acceptable carrier and treatment significant quantity.

9. medicinal compositions, said composition contain the compound of the claim 2 of pharmaceutically acceptable carrier and treatment significant quantity.

10. medicinal compositions, said composition contain the compound of the claim 3 of pharmaceutically acceptable carrier and treatment significant quantity.

11. a medicinal compositions, said composition contain the compound of the claim 4 of pharmaceutically acceptable carrier and treatment significant quantity.

12. a medicinal compositions, said composition contain the compound of the claim 5 of pharmaceutically acceptable carrier and treatment significant quantity.

13. a medicinal compositions, said composition contain the compound of the claim 6 of pharmaceutically acceptable carrier and treatment significant quantity.

14. a medicinal compositions, said composition contain the compound of the claim 7 of pharmaceutically acceptable carrier and treatment significant quantity.

15. the purposes of the compound of claim 1 in the medicine of preparation treatment Mammals anxiety disorder or dysthymia disorders.

16. the purposes of the compound of claim 2 in the medicine of preparation treatment Mammals anxiety disorder or dysthymia disorders.

17. the purposes of the compound of claim 3 in the medicine of preparation treatment Mammals anxiety disorder or dysthymia disorders.

18. the purposes of the compound of claim 4 in the medicine of preparation treatment Mammals anxiety disorder or dysthymia disorders.

19. the purposes of the compound of claim 5 in the medicine of preparation treatment Mammals anxiety disorder or dysthymia disorders.

20. the purposes of the compound of claim 6 in the medicine of preparation treatment Mammals anxiety disorder or dysthymia disorders.

21. the purposes of the compound of claim 7 in the medicine of preparation treatment Mammals anxiety disorder or dysthymia disorders.