CN101434604A

CN101434604A - Condensed n-heterocyclic compounds and their use as CRF receptor antagonists

Info

Publication number: CN101434604A
Application number: CNA2008101656972A
Authority: CN
Inventors: 丹尼尔·安德烈奥蒂; 乔瓦尼·伯纳斯科尼; 埃米莉亚诺·卡斯蒂格利奥尼; 斯蒂法尼亚·康蒂尼; 罗马诺·迪法比奥; 伊莱特拉·法佐拉里; 阿尔多·弗里亚尼; 加布里拉·金蒂尔; 马里奥·马蒂奥利; 安娜·明加迪; 法比奥·萨巴蒂尼; 伊维斯·圣丹尼斯
Original assignee: Neurocrine Biosciences Inc; SB Pharmco Puerto Rico Inc
Current assignee: Neurocrine Biosciences Inc; SB Pharmco Puerto Rico Inc
Priority date: 2003-04-09
Filing date: 2004-04-07
Publication date: 2009-05-20
Also published as: ES2348918T3; ZA200507844B

Abstract

The invention relates to condensed N-heterocyclic compounds and their use as CRF receptor antagonists, providing compounds of formula (I) compounds of formula (I) including stereoisomers, prodrugs and pharmaceutically acceptable salts or solvates thereof, method for preparing the same, drug composition and use for the treatment of disease resulting from corticotrophin-releasing factor (CRF). In the formula (I), the mark is defined as in the description.

Description

Condensed N-heterogeneous ring compound and they purposes as the CRF receptor antagonist

The application be that April 7, application number in 2004 are 200480016189.8 the applying date, name is called dividing an application of " condensed N-heterogeneous ring compound and they being as the purposes of CRF receptor antagonist ".

The present invention relates to bicyclic derivatives, their preparation method, the pharmaceutical composition that contains them and their purposes in treatment.

First thyroliberin-releasing hormone (CRF) be from the sheep hypothalamus separate obtain and confirm it be a kind of 41 amino acid whose peptides (Vale etc., " science " (Science), 213:1394-397,1981).Have been found that CRF can cause that internal secretion, nerve and function of immune system produce noticeable change.It is believed that CRF to be thyroliberin (＂ ACTH ＂), beta-endorphin and other POMCs (propiomelanocortin) (＂ POMC ＂) deutero-peptide from prehypophyseal basis discharge and stress-the major physiological conditioning agent that discharges (people such as Vale, " science " (Science), 213:1394-397,1981).

Except stimulating the effect that ATCH and POMC produce, the neurotransmitter of the central nervous system that CRF is seemingly important in the lump comprehensive health to stress comprehensive reaction in play an important role.Directly to brain administration CRF can cause be exposed to stress the animal of environment in viewed identical behavior, physiology and internal secretion react.Therefore, clinical data shows that the CRF receptor antagonist may represent new medicine antidepressant and/or antianxity, can be used for treating the neuropsychiatric disease that demonstrates the CRF supersecretion.

CRF receptor antagonist the earliest be peptide (referring to, Rivier etc. for example, United States Patent (USP) 4,605,642; Rivier etc., " science " (Science), 224:889,1984).Although these peptides have confirmed the pharmacology that the CRF receptor antagonist can weaken CRF and have replied that the CRF peptide receptor antagonists exists the drawbacks common of peptide therapy, comprises deficient in stability and limited Orally active.Reported small molecules CRF receptor antagonist recently.

WO 95/10506 has especially described general formula (A) compound with general CRF antagonistic activity,

Wherein Y can be CR29; V can be nitrogen, and Z can be carbon or nitrogen, and R3 can represent that sulfonamide derivatives and R4 can form 5-person's ring with R29, and be-CH (R28) when R29 be-during CH (R30).

WO95/33750 has also described general formula (B) compound with CRF antagonistic activity,

Wherein A and Y can be nitrogen and carbon, and B can represent sulfonamide derivatives.

Recently, a patent application is open with WO02/08895, and wherein following compounds, CRF antagonist are the purposes of this patent application:

Especially, R ₂And R ₃Can form saturated or unsaturated heterocycle with N, it can be replaced by the 5-6 element heterocycle, and it can be selected from following group by 1-3 and replace :-C1-C6 alkyl, halo C1-C2 alkyl, C1-C6 alkoxyl group, halogen, nitro or cyano group.

Nearest patent application in addition is open with WO 03/008412, and wherein following compounds, CRF antagonist are the purposes of this patent application:

Especially, R ₂And R ₃Can form the 5-14 element heterocycle with N, it can be replaced by the 5-6 element heterocycle, it can be and saturated maybe can contain one to three two key, and it can be by one or more groups such as C3-C7 cycloalkyl, C1-C6 alkyl, C1-C6 alkoxyl group, halo C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo C1-C6 alkoxyl group, hydroxyl, halogen, nitro, cyano group or C (O) NR ₆R ₇Replace.

None discloses the compound that falls in the scope of the invention in the above-mentioned document.

Because the physiology importance of CRF, exploitation have the target that significant CRF receptor-binding activity and bioactive small molecules that can antagonism CRF acceptor remain yearning.These CRF receptor antagonists can be used for the treatment of the illness or the disease of internal secretion, P﹠N, comprise general and disease stress be relevant.

Obtained remarkable progress though regulate CRF, still needed effective small molecules CRF receptor antagonist in this area by administration CRF receptor antagonist.Also need to contain the pharmaceutical composition of described CRF receptor antagonist and use this antagonist for treating for example with the method for illness that stress be relevant.The present invention has satisfied these needs, and has other associated advantages.

Especially, the present invention relates to new compound, it is the antagonist that thyroliberin-releasing hormone (CRF) acceptor is had specificity and validity.

The invention provides general formula (I) compound, comprise its steric isomer, prodrug and pharmacy acceptable salt or solvate

Wherein

Dotted line can be represented two keys;

R is aryl or heteroaryl, and wherein each R group can be selected from following group J by 1-4 and replace: halogen, C1-C6 alkyl, C1-C6 alkoxyl group, halo C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo C1-C6 alkoxyl group ,-C (O) R ₂, nitro, hydroxyl ,-NR ₃R ₄, cyano group or group Z;

R ₁Be hydrogen, C3-C7 cycloalkyl, C1-C6 alkyl, C1-C6 alkoxyl group, C1-C6 alkylthio (thioalkyl), C2-C6 alkenyl, C2-C6 alkynyl, halo C1-C6 alkyl, halo C1-C6 alkoxyl group, halogen, NR ₃R ₄Or cyano group;

R ₂For the C1-C4 alkyl ,-OR ₃Or-NR ₃R ₄

R ₃Be hydrogen or C1-C6 alkyl;

R ₄Be hydrogen or C1-C6 alkyl;

R ₅For C1-C6 alkyl, halo C1-C6 alkyl, C1-C6 alkoxyl group, halo C1-C6 alkoxyl group, C3-C7 cycloalkyl, hydroxyl, halogen, nitro, cyano group ,-NR ₃R ₄-C (O) R ₂

R ₆For C1-C6 alkyl, halo C1-C6 alkyl, C1-C6 alkoxyl group, halo C1-C6 alkoxyl group, C3-C7 cycloalkyl, hydroxyl, halogen, nitro, cyano group ,-NR ₃R ₄-C (O) R ₂

R ₇Be hydrogen, C1-C6 alkyl, halogen or halo C1-C6 alkyl;

R ₈Be hydrogen, C3-C7 cycloalkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, NR ₃R ₄Or cyano group;

R ₉Be hydrogen, C3-C7 cycloalkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, NR ₃R ₄Or cyano group;

R ₁₀Be hydrogen, C3-C7 cycloalkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, NR ₃R ₄Or cyano group;

R ₁₁Be hydrogen, C3-C7 cycloalkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, NR ₃R ₄Or cyano group;

R ₁₂Be R ₃Or-C (O) R ₂

D is CR ₈R ₉Or when linking to each other, be CR with the two keys of G ₈

G is CR ₁₀R ₁₁Or G is CR when linking to each other with the two keys of D ₁₀, or when linking to each other with the two keys of X G is CR when X is carbon ₁₀

X is carbon or nitrogen;

Y be nitrogen or-CR ₇

W is 4-8 person's ring, and it can be saturated 1-3 the two keys that maybe can contain, and

Wherein:

-1 carbon atom is by carbonyl or S (O) _mReplace; With

-1-4 carbon atom can be chosen wantonly by oxygen, nitrogen or NR ₁₂, S (O) _m, carbonyl replaces, and this ring can be further by 1-8 R ₆Group replaces;

Z is the 5-6 element heterocycle, and it can be by 1-8 R ₅Group or phenyl ring replace, and it can be by 1-4 R ₅Group replaces;

M is the integer of 0-2.

The compounds of this invention can be the form of pharmacy acceptable salt and/or form administration that can pharmacy acceptable salt.For the summary of suitable salt referring to people J.Pharm.Sci. such as Berge, 1977,66,1-19.

Typically, if pharmacy acceptable salt is suitable can easily preparing by using required acid or alkali.This salt can be by being precipitated out in the solution, and can collect by filtering, and maybe can reclaim by evaporating solvent.

Form suitable additive salt by the acid that forms non-toxic salt, and the example of this salt is a hydrochloride, hydrobromate, hydriodate, vitriol, hydrosulfate, nitrate, phosphoric acid salt, hydrophosphate, acetate, maleate, malate, fumarate, lactic acid salt, tartrate, Citrate trianion, formate, gluconate, succinate, piruvate, oxalate, oxaloacetate, trifluoroacetate, saccharate, benzoate, mesylate, esilate, benzene sulfonate, tosilate, methylsulfonic acid base (methanesulphonic), ethyl sulfonic acid base (ethanesulphonic), tosic acid base (p-toluenesulphonic) and isethionate.

Pharmaceutically acceptable basic salt comprises ammonium salt, an alkali metal salt such as those sodium salts and sylvite, alkaline earth salt such as those calcium salts and magnesium salts, and with the salt that organic bases forms, comprise primary, the salt of the second month in a season and tertiary amine such as Isopropylamine, diethylamine, thanomin, Trimethylamine 99, dicyclohexylamine and N-methyl D-glucosamine.

The those skilled in the art of organic chemistry filed are to be understood that many organic compound can form complex compound with solvent, wherein they in this solvent, react or they by solvent in the precipitation or crystallization.These complex compounds are called " solvate ".For example, the complex compound with water formation is called " hydrate ".The solvate of The compounds of this invention within the scope of the invention.

In addition, prodrug is also contained in the content of the present invention.Term as used herein " prodrug " refers to this compound and transforms in vivo as by be hydrolyzed to its activity form with medicine effect in blood.Pharmaceutically acceptable prodrug is described in T.Higuchi and V.Stella, Prodrugs as Novel DeliverySystems, Vol.14 of the A.C.S.Symposium Series, Edward B.Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association andPergamon Press, 1987, and in D.Fleisher, S.Ramon and H.Barbra " Improvedoral drug delivery:solubility limitations overcome by the use of prodrugs ", among Advanced Drug Delivery Reviews (1996) 19 (2) 115-130, wherein each is incorporated herein by reference.

After prodrug was delivered medicine to the patient, this prodrug was any carrier with covalent bonding of the compound of releasing structure in its body (I).Prodrug is normally modified by cracking, and perhaps by conventional processing, perhaps mode is in vivo modified its functional group and prepared.Prodrug comprises, for example, compound of the present invention, wherein hydroxyl, amine (amine) or sulfydryl (sulfhydryl) and any group bonding, and after it was delivered medicine to the patient, this group was cleaved, formed hydroxyl, amine or sulfydryl.Therefore, the representative compounds of prodrug includes but is not limited to acetic ester, manthanoate and the benzoate derivatives of hydroxyl, sulfydryl and amine functional group in the compound of structure (I).Further, be that carboxylic acid (COOH) time, can use the form of its ester, for example methyl esters, ethyl ester etc. at it.Ester they self can be activated and/or can be in human body hydrolysis under the condition in vivo.The hydrolyzable ester group is included in those that decompose remaining parent acid or its salt in the human body easily in the suitable pharmaceutically acceptable body.

About steric isomer, the compound of structure (I) can have one or more unsymmetrical carbons, and may exist with racemic modification, racemic mixture and with the form of discrete enantiomer or diastereomer.All these isomeric forms comprise that its mixture all comprises in the present invention.

Wherein The compounds of this invention contains alkenyl (alkenyl) or chain alkenylene (alkenylene) group, also can exist along (E) and anti-(Z) isomeric form.The present invention includes the discrete steric isomer of The compounds of this invention, and if suitable, its discrete tautomeric form, and composition thereof.

The separation of diastereomer or genial trans isomer can be by routine technology for example fractional crystallization, chromatography or the H.P.L.C. of the three-dimensional heterogeneous mixture by this reagent finish, also can by corresponding optically pure intermediate preparation obtain or by as use the H.P.L.C. of suitable chiral support that corresponding racemic compound is split acquisition, or if suitablely carry out fractional crystallization by diastereo-isomerism salt and obtain the reaction formation of the acid of corresponding racemic compound and suitable optically-active or alkali.

In addition, the crystallized form of the compound of some structure (I) can exist by polymorphic form, and it comprises in the present invention.

The term C1-C6 alkyl as the part of group or group as used herein is meant straight chain or the branched-chain alkyl that contains 1-6 carbon atom; This examples of groups comprises methyl, ethyl, propyl group, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, amyl group or hexyl.

Term C3-C7 cycloalkyl refers to the non-fragrant monocyclic hydrocarbon ring of 3-7 carbon atom, for example, and cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or suberyl; And this undersaturated cycloalkyl comprises cyclopentenyl and cyclohexenyl etc.

Term halogen refers to fluorine, chlorine, bromine or iodine atom.

Term halo C1-C6 alkyl or halo C1-C2 alkyl refer to have one or more carbon atoms and wherein at least one hydrogen atom by the displaced alkyl of halogen atom, trifluoromethyl etc. for example.

Term C1-C6 alkylthio can be the alkylthio of straight or branched, for example methylthio group, ethylmercapto group, rosickyite base, iprotiazem base (thioisopropyl), butylthio, secondary butylthio, uncle's butylthio etc.

Term C2-C6 alkenyl is defined as the alkyl that contains one or more pairs of keys and have the straight or branched of 2-6 carbon atom, for example vinyl, 2-propenyl, 3-butenyl, crotyl, pentenyl, 3-pentenyl, 3-methyl-2-butene base or 3-hexenyl etc.

Term C1-C6 alkoxyl group can be the alkoxyl group of straight or branched, for example methoxyl group, oxyethyl group, propoxy-, third-2-oxygen base, butoxy, fourth-2-oxygen base or methyl-prop-2-oxygen base etc.

Term halo C1-C6 alkoxyl group can be by at least by a halogen, the alkoxyl group of C1-C6 as defined above that preferred fluorine replaces, for example OCHF ₂Perhaps OCF ₃

Term C2-C6 alkynyl is defined as the alkyl that contains one or more triple bonds and have the straight or branched of 2-6 carbon atom, comprises ethynyl, proyl, ethyl acetylene base, 1-pentynyl, 3-methyl isophthalic acid-butynyl etc.

Term aryl refers to aromatic carbon ring group, for example phenyl, xenyl or naphthyl.

The term heteroaryl refers to 5-10 person's aromatic heterocycle, and wherein has the heteroatoms that at least one is selected from nitrogen, oxygen and sulphur, and contains at least one carbon atom, comprises monocycle and two member ring systems.

Representative heteroaryl includes, but is not limited to furyl, benzofuryl, thienyl, benzothienyl, pyrryl, indyl, isoindole, azaindolyl, pyridyl, quinolyl, isoquinolyl, oxazolyl, isoxazolyl, benzoxazolyl, pyrazolyl, imidazolyl, benzimidazolyl-, thiazolyl, benzothiazolyl, isothiazolyl, pyridazinyl, pyrimidyl, pyrazinyl, triazinyl, 1,2-phthalazinyl, 2 base, triazolyl, tetrazyl, quinazolyl and benzodioxole base (benzodioxolyl).

Be meant according to above-mentioned definition term 5-6 element heterocycle and contain the heteroatoms that 1-4 is independently selected from nitrogen, oxygen and sulphur, and wherein nitrogen and sulfur heteroatom can be randomly oxidized, and nitrogen heteroatom can be randomly by the quaternary ammonium salinization, saturated, undersaturated or fragrant 5-6 person's monocyclic heterocycles.Heterocycle comprises heteroaryl as defined above.This heterocycle can link to each other by any heteroatoms or carbon atom.Therefore, this term includes, but is not limited to morpholinyl, pyridyl, pyrazinyl, pyrazolyl, thiazolyl, triazolyl, imidazolyl, oxadiazole Ji, oxazolyl, isoxazolyl, pyrrolidone-base (pyrrolidinonyl), pyrrolidyl, piperidyl, glycolylurea base (hydantoinyl), Valerolactim base, Oxyranyle, oxetanyl, tetrahydrofuran base, THP trtrahydropyranyl, tetrahydro pyridyl, tetrahydro-pyrimidine base, tetrahydro-thienyl, tetrahydro thiapyran base etc.

Term W is defined as 4-8 person ring, and it can be saturated 1-3 the two keys that maybe can contain, and wherein:

-1 carbon atom is by carbonyl or S (O) _mReplace; With

It is saturated or unsaturated or fragrant that 4-8 person ring is meant, and 1-4 carbon atom can be by the displaced 4-8 person's monocycle carbocyclic ring of heteroatoms as defined above.This carbocyclic ring can link to each other by any heteroatoms or carbon atom.Therefore, this term includes, but is not limited to: tetramethylene, pentamethylene, hexanaphthene, suberane, cyclooctane, nitrogen heterocyclic propyl group (azirydinyl), azelidinyl, pyrrolidyl, piperidyl, imidazolidyl, morpholinyl, piperazinyl, the glycolylurea base, the Valerolactim base, oxetanyl, tetrahydrofuran base, THP trtrahydropyranyl, tetrahydro pyridyl, tetrahydro-pyrimidine base, tetrahydro-thienyl, tetrahydro thiapyran base, 1, the 3-dihydro-2 H-imidazol-2-one, imidazolidin-2-one, tetrahydropyrimidine-2 (1H)-ketone, 2,5-dihydro-1,2,5-thiadiazoles (thiadiazole) 1-oxide compound, 1,2,5-thiadiazolidine (thiadiazolidine) 1-oxide compound, 2,5-dihydro-1,2,5-thiadiazoles 1, the 1-dioxide, 1,2,6-thiadiazine alkane (thiadiazinane) 1-oxide compound, pyrrolidin-2-one, 2,5-dihydro-1,2,5-thiadiazolidine 1, the 1-dioxide, 1,3-oxazolidine-2-ketone derivatives, isothiazolidine 1, the 1-dioxide, 2 (1H)-pyridones, 3 (2H)-pyridazinones, 2,3-piperazinedione etc.

Representativeness ring in the W definition includes but not limited to down array structure and derivative:

Wherein:

W1 represents 1, the 3-dihydro-2 H-imidazol-2-one derivatives;

W2 represents imidazolidin-2-one derivatives;

W3 represents tetrahydropyrimidine-2 (1H)-ketone derivatives;

W4 represents 2,5-dihydro-1,2,5-thiadiazoles 1-oxide derivative;

W5 represents 1,2,5-thiadiazolidine 1-oxide derivative;

W6 represents 2,5-dihydro-1,2,5-thiadiazoles 1,1-dioxide derivative;

W7 represents 1,2,6-thiadiazine alkane 1-oxide derivative;

W8 represents 1,2,6-thiadiazine alkane 1,1-dioxide derivative;

W9 represents pyrrolidin-2-one derivatives;

W10 represents 2,5-dihydro-1,2,5-thiadiazolidine 1,1-dioxide derivative;

W11 represents 1,3-oxazolidine-2-ketone derivatives;

W12 represents isothiazolidine 1, the 1-dioxide derivative;

W13 represents 2 (1H)-Pyridione derivatives;

W14 represents 3 (2H)-pyridazinones;

W15 represents 2,3-piperazinedione derivative;

And q is the integer of 0-4, and n is the integer of 0-6, and p is the integer of 0-3, and m, R6 and R12 are as defined above.

Formula (II) and (IIa) compound be representative compounds of the present invention.

Especially, they are equivalent to compound (I), and wherein X is that nitrogen or carbon and R, R1, Y, Z, W, D and G have the defined implication in front.Formula (II) compound is a concrete representational compound of the present invention.Particularly preferably be formula (II) compound, wherein W is selected from: W1, W2, W3, W9, W10, W11, W12, W13 and W14.Be preferably formula (II) compound on an equal basis, wherein Z is selected from: pyrimidine, pyridine, thiazole, pyrazoles, triazole and phenyl.Be preferably formula (II) compound on an equal basis, wherein W is selected from: W1, W2, W3, W9, W10, W11, W12, W13 and W14, and wherein Z is selected from: pyrimidine, pyridine, thiazole, pyrazoles, triazole and phenyl.Formula (II) examples for compounds is recorded in experimental section.

Formula (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIl), (IIm), (IIn), (IIo), (IIp) and (IIq) compound be the exemplary compounds of formula (II) compound.

The implication that depends on X and Y, they are equivalent to formula (II) compound, and wherein R, R1, R7, Z, W, D and G have the defined implication in front.Particularly preferably be formula (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIl), (IIm), (IIn), (IIo), (IIp) and (IIq) compound, wherein W is selected from: W1, W2, W3, W9, W10, W11, W12, W13 and W14.Be preferably formula (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIl), (IIm), (IIn), (IIo), (IIp) and (IIq) compound on an equal basis, wherein Z is selected from: pyrimidine, pyridine, thiazole, pyrazoles, triazole and phenyl.Be preferably formula (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIl), (IIm), (IIn), (IIo), (IIp) and (IIq) compound on an equal basis, wherein W is selected from: W1, W2, W3, W9, W10, W11, W12, W13 and W14, and wherein Z is selected from: pyrimidine, pyridine, thiazole, pyrazoles, triazole and phenyl.

Preferred formula (IIr), (IIs) and (IIt) compound, it is equivalent to formula (II) compound, and wherein D and G are-CH ₂

Particularly preferably be formula (IIr), (IIs) and (IIt) compound, wherein W is selected from: W1, W2, W3, W9, W10, W11, W12, W13 and W14.Be preferably formula (IIr) compound on an equal basis, wherein Z is selected from: pyrimidine, pyridine, thiazole, pyrazoles, triazole and phenyl.Be preferably formula (IIr), (IIs) and (IIt) compound on an equal basis, wherein W is selected from: W1, W2, W3, W9, W10, W11, W12, W13 and W14, and wherein Z is selected from: pyrimidine, pyridine, thiazole, pyrazoles, triazole and phenyl.

Especially, formula (III) compound is the representative compounds of formula (II) compound.

They are equivalent to formula (II) compound, and wherein Z is pyrazolyl derivative and R, R ₁, R ₅, Y, W, D, m and G have the defined implication in front, and dotted line can be represented two keys.

Formula (IIIa), (IIIb), (IIIc) and (IIId) compound be the concrete representative compounds of formula (III) compound.

The implication that depends on Y, they are equivalent to formula (III) compound, wherein R, R ₁, R ₅, R ₇, R ₈, R ₉, R ₁₀, R ₁₁, W, D, m and G have the defined implication in front.Particularly preferably be formula (IIIa), (IIIb), (IIIc) and (IIId) compound, wherein W is selected from: W1, W2, W3, W9, W10, W11, W12, W13 and W14, and R, R ₁, R ₅, R ₇, R ₈, R ₉, R ₁₀, R ₁₁, m has the defined implication in front.

Especially, formula (IV) compound is the representative compounds of formula (III) compound.

They are equivalent to formula (III) compound, and wherein W is equivalent to the W2 derivative, and R, R ₁, R ₅, R ₆, R ₇, R ₁₂, m, q, D and G have the defined implication in front, and dotted line can be represented two keys.

Formula (IVa), (IVb) and (IVc) compound be the concrete representational compound of formula (IV) compound.

They are equivalent to formula (IV) compound, wherein R ₇Be hydrogen and R, R ₁, R ₅, R ₆, R ₇, R ₁₂, m, q, D and G have the defined implication in front, and dotted line can be represented two keys.

The formula V compound similarly is the representative compounds of formula (II) compound.

They are equivalent to formula (II) compound, and wherein W is the W2 derivative, and Z, R, R ₁, R ₆, q, Y, W, D and G have the defined implication in front, and dotted line can be represented two keys.

Formula (VI) compound is the concrete representational compound of formula V compound, and wherein Y is-CR ₇, and Z, R, R ₁, R ₆, R ₇, q, Y, W, D and G have the implication of front, and dotted line can be represented two keys.

Formula (VIa), (VIb) and (VIc) compound be the concrete representational compound of formula (VI) compound.

They are equivalent to formula (VI) compound, and wherein R7 is a hydrogen, and R, R ₁, R ₆, R ₈, R ₉, R ₁₀, R ₁₁, R ₁₂, q, D and G have the defined implication in front, and dotted line can be represented two keys.Particularly preferably be formula (VIa), (VIb) and (VIc) compound, wherein Z is selected from: pyrimidine, pyridine, thiazole, pyrazoles, triazole and phenyl, and R, R ₁, R ₆, R ₈, R ₉, R ₁₀, R ₁₁, R ₁₂, q, D and G have the defined implication in front.

Even preferred embodiment of the present invention include but not limited to the compound of formula (I), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIl), (IIm), (IIn), (IIo), (IIp), (IIq), (III), (IIIa), (IIIb), (IIIc), (IIId), (IV), (IVa), (IVb), (IVc), (V), (VI), (VIa), (VIb), (VIc), wherein:

R ₁For C1-C3 alkyl or halo C1-C3 alkyl, be preferably methyl or trifluoromethyl;

R ₇Be hydrogen;

R ₈, (R ₉), R ₁₀(R ₁₁) be hydrogen;

R is selected from following aryl: 2, the 4-dichlorophenyl, 2-chloro-4-aminomethyl phenyl, 2-chloro-4-trifluoromethyl, 2-chloro-4-p-methoxy-phenyl, 2,4, the 5-trimethylphenyl, 2, the 4-3,5-dimethylphenyl, 2-methyl-4-p-methoxy-phenyl, 2-methyl-4-ethoxyl phenenyl, 2-methyl-4-isopropyl phenyl, 2-methyl-4-hydroxy phenyl, 2-methyl-4-chloro-phenyl-, 2-methyl-4-trifluoromethyl, 2, the 4-Dimethoxyphenyl, 2-methoxyl group-4-trifluoromethyl, 2-methoxyl group-4-chloro-phenyl-, 3-methoxyl group-4-chloro-phenyl-, 2,5-dimethoxy-4 '-chloro-phenyl-, 2-methoxyl group-4-isopropyl phenyl, 2-methoxyl group-4-trifluoromethyl, 2-methoxyl group-4-isopropyl phenyl, 2-methoxyl group-4-aminomethyl phenyl, 2-trifluoromethyl-4-chloro-phenyl-, 2,4-pair-trifluoromethyl, 2-trifluoromethyl-4-aminomethyl phenyl, 2-trifluoromethyl-4-p-methoxy-phenyl, 2-difluoromethyl-4-p-methoxy-phenyl, 2-bromo-4-isopropyl phenyl, 2-methyl-4-cyano-phenyl, 2-chloro-4-cyano-phenyl, 2-trifluoromethyl-4-cyano-phenyl, 2-trifluoromethoxy-4-cyano-phenyl, 2-ethyl-4-cyano-phenyl, 2-methyl-4-Trifluoromethoxyphen-l, 4-methyl-6-dimethyl aminopyridine-3-base, 2,6-bi-methoxy-pyridin-3-yl, 2-methyl-6-methoxyl group-pyridin-3-yl, 2-trifluoromethyl-6-methoxyl group-pyridin-3-yl 3-chloro-5-trichloromethyl-pyridine-2-base, 2-methyl-4-(pyrazol-1-yl)-phenyl, 2-methoxyl group-4-(pyrazol-1-yl)-phenyl, 2,4, the 6-trimethoxyphenyl, 2-methyl-4,5-benzodioxole base, 2-methyl-3,4-benzodioxole base.

Preferred compound according to the present invention is:

1-{1-[1-(4-methoxyl group-2-aminomethyl phenyl)-6-methyl-2,3-dihydro-1H-pyrrolo-[2,3-b] pyridin-4-yl]-the 1H-pyrazole-3-yl } imidazolidin-2-one (compound 1-1);

1-{1-[1-(4-methoxyl group-2-aminomethyl phenyl)-6-methyl-2,3-dihydro-1H-pyrrolo-[2,3-b] pyridin-4-yl]-the 1H-pyrazole-3-yl }-3-Methylimidazole alkane-2-ketone (compound 1-2);

1-{1-[1-(2,4 dichloro benzene base)-6-methyl-2,3-dihydro-1H-pyrrolo-[2,3-b] pyridin-4-yl]-the 1H-pyrazole-3-yl } imidazolidin-2-one (compound 1-3);

1-(1-{1-[2, two (trifluoromethyl) phenyl of 4-]-6-methyl-2,3-dihydro-1H-pyrrolo-[2,3-b] pyridin-4-yl }-the 1H-pyrazole-3-yl)-2-imidazolidone (imidazolidinone) (compound 1-4);

1-{1-[1-(4-hydroxy-2-methyl phenyl)-6-methyl-2,3-dihydro-1H-pyrrolo-[2,3-b] pyridin-4-yl]-the 1H-pyrazole-3-yl }-2-imidazolidone (compound 1-5);

1-ethanoyl-3-(1-{6-methyl isophthalic acid-[2-methyl-4-(methoxyl group) phenyl]-2,3-dihydro-1H-pyrrolo-[2,3-b] pyridin-4-yl }-the 1H-pyrazole-3-yl)-2-imidazolidone (compound 1-5);

1-ethanoyl-3-(1-{6-methyl isophthalic acid-[2-methyl-4-(methoxyl group) phenyl]-2,3-dihydro-1H-pyrrolo-[2,3-b] pyridin-4-yl }-the 1H-pyrazole-3-yl)-2-imidazolidone (compound 1-6);

1-(1-{1-[4-(oxyethyl group)-2-aminomethyl phenyl]-6-methyl-2,3-dihydro-1H-pyrrolo-[2,3-b] pyridin-4-yl }-the 1H-pyrazole-3-yl)-2-imidazolidone (compound 1-7);

1-[1-(the 6-methyl isophthalic acid-and 2-methyl-4-[(1-methylethyl) the oxygen base] phenyl }-2,3-dihydro-1H-pyrrolo-[2,3-b] pyridin-4-yl)-the 1H-pyrazole-3-yl]-2-imidazolidone (compound 1-8);

1-[1-(the 6-methyl isophthalic acid-and 2-methyl-4-[(trifluoromethyl) the oxygen base] phenyl }-2,3-dihydro-1H-pyrrolo-[2,3-b] pyridin-4-yl)-the 1H-pyrazole-3-yl]-2-imidazolidone (compound 1-9);

3-methyl-4-{6-methyl-4-[3-(2-oxo-1-imidazolidyl)-1H-pyrazol-1-yl]-2,3-dihydro-1H-pyrrolo-[2,3-b] pyridine-1-yl } benzonitrile (compound 1-10);

1-(1-{6-methyl isophthalic acid-[2-methyl-4-(1H-pyrazol-1-yl) phenyl]-2,3-dihydro-1H-pyrrolo-[2,3-b] pyridin-4-yl }-the 1H-pyrazole-3-yl)-2-imidazolidone (compound 1-11);

4-{6-methyl-4-[3-(2-oxo-1-imidazolidyl)-1H-pyrazol-1-yl]-2,3-dihydro-1H-pyrrolo-[2,3-b] pyridine-1-yl }-3-(trifluoromethyl) benzonitrile (compound 1-12);

1-(1-{1-[2-(difluoromethyl)-4-(methoxyl group) phenyl]-6-methyl-2,3-dihydro-1H-pyrrolo-[2,3-b] pyridin-4-yl }-the 1H-pyrazole-3-yl)-2-imidazolidone (compound 1-13);

4-{6-methyl-4-[3-(2-oxo-1-imidazolidyl)-1H-pyrazol-1-yl]-2,3-dihydro-1H-pyrrolo-[2,3-b] pyridine-1-yl }-the 3-[(trifluoromethyl) the oxygen base] benzonitrile (compound 1-14);

3-ethyl-4-{6-methyl-4-[3-(2-oxo-1-imidazolidyl)-1H-pyrazol-1-yl]-2,3-dihydro-1H-pyrrolo-[2,3-b] pyridine-1-yl } benzonitrile (compound 1-15);

1-(1-{6-methyl isophthalic acid-[2-(methoxyl group)-4-(1H-pyrazol-1-yl) phenyl]-2,3-dihydro-1H-pyrrolo-[2,3-b] pyridin-4-yl }-the 1H-pyrazole-3-yl)-2-imidazolidone (compound 1-16);

1-{1-[6-methyl isophthalic acid-(6-methyl isophthalic acid, 3-benzodioxole-5-yl)-2,3-dihydro-1H-pyrrolo-[2,3-b] pyridin-4-yl]-the 1H-pyrazole-3-yl }-2-imidazolidone (compound 1-17);

1-(1-{6-methyl isophthalic acid-[2,4,6-trimethoxy phenyl]-2,3-dihydro-1H-pyrrolo-[2,3-b] pyridin-4-yl }-the 1H-pyrazole-3-yl)-2-imidazolidone (compound 1-18);

1-{1-[6-methyl isophthalic acid-(6-methyl isophthalic acid, 3-benzodioxole-5-yl)-2,3-dihydro-1H-pyrrolo-[2,3-b] pyridin-4-yl]-the 1H-pyrazole-3-yl }-2-imidazolidone (compound 1-19);

1-(6-{6-methyl isophthalic acid-[2-methyl-4-(methoxyl group) phenyl]-2,3-dihydro-1H-pyrrolo-[2,3-b] pyridin-4-yl }-the 2-pyridyl)-2-imidazolidone (compound 1-20);

1-(4-{6-methyl isophthalic acid-[2-methyl-4-(methoxyl group) phenyl]-2,3-dihydro-1H-pyrrolo-[2,3-b] pyridin-4-yl }-the 2-pyrimidyl)-2-imidazolidone (compound 1-21);

1-(2-{6-methyl isophthalic acid-[2-methyl-4-(methoxyl group) phenyl]-2,3-dihydro-1H-pyrrolo-[2,3-b] pyridin-4-yl }-the 4-pyrimidyl)-2-imidazolidone (compound 1-22);

1-(1-{6-methyl isophthalic acid-[2-methyl-4-(methoxyl group) phenyl]-2,3-dihydro-1H-pyrrolo-[2,3-b] pyridin-4-yl }-the 1H-pyrazole-3-yl)-2-imidazolidone (compound 1-23);

1-(1-{2,6-dimethyl-1-[2-methyl-4-(methoxyl group) phenyl]-2,3-dihydro-1H-pyrrolo-[2,3-b] pyridin-4-yl }-the 1H-pyrazole-3-yl)-2-imidazolidone (compound 1-24);

1-(3-{6-methyl isophthalic acid-[2-methyl-4-(methoxyl group) phenyl]-2,3-dihydro-1H-pyrrolo-[2,3-b] pyridin-4-yl } phenyl)-2-imidazolidone (compound 1-25);

1-(5-methyl isophthalic acid-{ 6-methyl isophthalic acid-[2-methyl-4-(methoxyl group) phenyl]-2,3-dihydro-1H-pyrrolo-[2,3-b] pyridin-4-yl }-1H-pyrazole-3-yl)-2-imidazolidone (compound 1-26);

1-[1-(1-{4-[(difluoromethyl) oxygen base]-the 2-aminomethyl phenyl }-6-methyl-2,3-dihydro-1H-pyrrolo-[2,3-b] pyridin-4-yl)-the 1H-pyrazole-3-yl]-2-imidazolidone (compound 1-27);

1-{1-[1-(4-methoxyl group-2-aminomethyl phenyl)-6-methyl-2,3-dihydro-1H-pyrrolo-[2,3-b] pyridin-4-yl]-the 1H-pyrazole-3-yl } pyrrolidin-2-one (compound 2-1);

1-{1-[1-(4-methoxyl group-2-aminomethyl phenyl)-6-methyl-2,3-dihydro-1H-pyrrolo-[2,3-b] pyridin-4-yl]-the 1H-pyrazole-3-yl } tetrahydropyrimidine-2 (1H)-ketone (compound 3-1);

3-(1-{6-methyl isophthalic acid-[2-methyl-4-(methoxyl group) phenyl]-2,3-dihydro-1H-pyrrolo-[2,3-b] pyridin-4-yl }-the 1H-pyrazole-3-yl)-1,3-oxazolidine-2-ketone (compound 4-1);

5-(1-{6-methyl isophthalic acid-[2-methyl-4-(methoxyl group) phenyl]-2,3-dihydro-1H-pyrrolo-[2,3-b] pyridin-4-yl }-the 1H-pyrazole-3-yl)-1,2,5-thiadiazolidine-2-carboxylate methyl ester 1,1-dioxide) (compound 5-1);

4-[3-(1,1-dioxo (Dioxido)-1,2,5-thiadiazolidine-2-yl)-1H-pyrazol-1-yl]-6-methyl isophthalic acid-[2-methyl-4-(methoxyl group) phenyl]-2,3-dihydro-1H-pyrrolo-[2,3-b] pyridine (compound 5-2).

4-[3-(1,1-dioxo-2-isothiazole alkyl)-1H-pyrazol-1-yl]-6-methyl isophthalic acid-[2-methyl-4-(methoxyl group) phenyl]-2,3-dihydro-1H-pyrrolo-[2,3-b] pyridine (compound 6-1);

The 3-methyl isophthalic acid-(1-{6-methyl isophthalic acid-[2-methyl-4-(methoxyl group) phenyl]-2,3-dihydro-1H-pyrrolo-[2,3-b] pyridin-4-yl }-the 1H-pyrazole-3-yl)-2 (1H)-pyridones (compound 7-1);

2-(1-{6-methyl isophthalic acid-[2-methyl-4-(methoxyl group) phenyl]-2,3-dihydro-1H-pyrrolo-[2,3-b] pyridin-4-yl }-the 1H-pyrazole-3-yl)-3 (2H)-pyridazinones (compound 8-1);

1-(1-{6-methyl isophthalic acid-[2-methyl-4-(methoxyl group) phenyl]-2,3-dihydro-1H-pyrrolo-[2,3-b] pyridin-4-yl }-the 1H-pyrazole-3-yl)-1,3-dihydro-2 H-imidazol-2-one (compound 9-1);

1-(1-{6-methyl isophthalic acid-[2-methyl-4-(methoxyl group) phenyl]-1H-pyrrolo-[2,3-b] pyridin-4-yl }-the 1H-pyrazole-3-yl)-2-imidazolidone (compound 10-1);

1-(6-{6-methyl isophthalic acid-[2-methyl-4-(methoxyl group) phenyl]-2,3-dihydro-1H-pyrrolo-[2,3-b] pyridin-4-yl }-the 3-pyridyl)-2-imidazolidone (compound 11-1);

1-{1-[7-(2,4 dichloro benzene base)-2-methyl-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-yl]-the 1H-pyrazole-3-yl }-2-Pyrrolidone (compound 11-2).

Usually, the compound of structure (I) can prepare according to known organic synthesis technology of persons skilled in the art and described in an embodiment exemplary process.

Formula (I) compound and salt thereof and solvate can prepare by the general method of hereinafter being summarized.In the following description, unless otherwise noted, radicals R, R ₁, R ₂, R ₃, R ₄, R ₅, R ₆, R ₇, R ₈, R ₉, R ₁₀, R ₁₁, R ₁₂, m, n, q, D, G, Z, W, X, Y have the implication of the defined formula in front (I) compound.

Formula (II) compound can be begun by formula (VII) compound, prepares easily according to following scheme 1:

Scheme 1

Wherein

Step a represents by with suitable Z-W derivatives reaction leavings group L being converted into compound (VIII), L is selected from: the reactive residue of halogen or sulfonic acid (for example methylsulfonic acid base (mesylate), toluenesulphonic acids base (tosylate)) is preferably chlorine (chloride);

Step b represents with appropriate reductant (as DIBAl-H) ester group (E) to be reduced to the oh group of compound (IX);

Step c represents to use the P group as to the methoxy-benzyl group, and the NH group that finally is present in the W group is carried out suitable protection;

Steps d represents with suitable oxygenant (crossing iodine alkane (periodinane) as Dess-Martin) oh group to be oxidized to the aldehyde group of compound (XI);

Step e+f is illustrated under the usual conditions, according to the Wittig reaction, carries out acid hydrolysis (step f), the aldehyde group of formation compound (XIII) subsequently by forming enol ether;

Step g represent by with suitable alkali (as LiN (SiMe ₃) ₂) carry out deprotonation, subsequently by the suitable alkylating reagent of addition (as MeI), make the optional alkylation in the α position of aldehyde to form the alkylating aldehyde of compound (XIV), (XV);

Step h represents by Grignard reagent (as MeMgBr) aldehyde group to be converted into compound (XVI) and alcohol groups (XVIII);

Step I represents with suitable oxygenant (crossing iodine alkane as Dess-Martin) oh group to be oxidized to the ketone groups of compound (XVII);

Step j represents oh group is converted into the suitable blocking group of compound (XIX) (as TBS: t-butyldimethylsilyl);

Step k represents to carry out the Buchwald linked reaction with suitable amine RNH2, obtains formula (XX) compound;

Step l represents to carry out deprotection reaction, obtains the oh group of compound (XXI);

Step m represents to carry out intramolecular cyclization after the oh group with compound (XXI) is converted into suitable leavings group (as bromide (bromide), by with CBr4 and PPh3 reaction), obtains the compound (XXII) of cyclisation;

Step n represents that the NH group that will finally be present in the protection in the W group carries out deprotection reaction, obtains final compound (II);

Step o represent when D be CHR8 and G when being CHR10, (as DDQ) carries out oxidation by suitable oxygenant, to form two keys of compound (II).

Formula (VII) compound is compound known or can prepares according to known method in the document.

Perhaps, formula (IIr) compound can be begun by formula (XXIII) compound, wherein R, R ₁, Z and W as defined above, prepare easily according to following scheme 2:

Scheme 2

Wherein:

Step a ' expression is by making compound (XXIII) and butyro-reactive derivative such as the reaction of 4-chlorobutanoylchloride; Form the pyrrolidone group of compound (XXIV) by carry out cyclization under alkaline condition (for example KOtBu) subsequently, it is present in ring B in the final compound (IIr) with formation;

X is worked as in step b ' expression ₁During for oxygen, by making amino crotonate derivative of compound (XXIV) and 3-and POCl ₃Reaction forms amidine; Or X is worked as in expression ₁During for NH, the alkylating that forms by the amidine that makes the reaction of compound (XXIV) and butynoic acid ester derivative;

Step c ' is illustrated under the alkaline condition (for example tBuOK), makes compound (XXV) or (XXVa) carries out cyclic action, obtains the pyridone precursor of the ring A in the final compound (IIr);

Steps d ' expression is by reacting with for example trifluoromethanesulfanhydride anhydride (triflic anhydride), and the reactive derivative that forms the pyridone of compound (XXVI) (is leavings group, Lg) (for example is selected from trifluoromethanesulfonic acid base, halogen and methylsulfonic acid base);

The nucleophilic displacement of the leavings group of step e ' expression compound (XXVII) obtains the compound (XXVIII) of halogenization, the compound of preferred iodinating or bromination;

Step f ' expression is carried out the arylation reaction by linked reaction (for example Buchwald reaction or the Suzuki coupling) step of metal catalytic with suitable-Z-W derivative, obtains final compound (IIr); This-Z-W derivative can be used suitably as defined P radical protection in the scheme 1;

Step g ' (for example acidylate obtains ester group, as carrying out acylation with diethyl carbonate, obtains ethyl ester derivative, E) to represent to make carbon 3 activation by the addition electron-withdrawing group;

When step h ' is oxygen as X1, be equivalent to step b) ';

Step I ' expression metal-halogen exchange reaction (with suitable alkali, as n-BuLi), carry out the metal transfer reaction with suitable metallization reagent (as trialkyl borate or trialkyl stannyl chlorine) subsequently;

Step j ' expression is when Y is N, and the beta-amino ester of formula (XXIVb) and the salt of substituted amidine (example hydrochloric acid salt) (as B amidine hydrochloric acid salt) carry out cyclic action, to form pyrimidine ring A;

Step m ' expression is for example used PO (Hal) by using ₃Halogenating reaction is carried out in processing, and wherein Hal is preferably chlorine oh group is converted into halogen.

Usually, the initial compounds of formula (XXIII) is a compound known, or can prepare according to known method in the document.

The step of scheme 2 is specially suitable for the preparation of general formula (IV), (V), (VI) compound.

General formula (XXIV), (XXIVb), (XXVI), (XXVII), (XXVIII), (XXIX) compound are to be used to prepare the CRF antagonist of the object of the invention or the new intermediate of other CRF antagonist, and these CRF antagonists can use these intermediates to prepare easily.Can use the representational CRF antagonist of above-mentioned intermediate preparation to include but not limited to the patent application of enumerating above-mentioned: those disclosed among WO95/10506, WO 95/33750, WO 02/08895 and the WO 03/008412.Above-mentioned open source literature includes but not limited to patent and patent application, and it is incorporated herein by reference, and resembles every part of indivedual publications and specifically and individually is used as reference in full.

Especially, when Y represented carbon atom, formula (XXVIA) compound was equivalent to formula (XXVI) compound, and it can tautomeric form (XXVIB) exist.

General formula (IIt) compound can prepare with another kind of approach according to the method described in the International Patent Application WO 02/088095, and it is illustrated in the following scheme 3.

Wherein

Step a " represent ester and appropriate reductant (as DIBAl-H) are carried out reduction reaction, obtain compound (XXXI);

Step b " expression is converted into the suitable blocking group of compound (XXXII) (as TBS: t-butyldimethylsilyl) with oh group;

Step c " expression and suitable amine RNH ₂Carry out nucleophilic displacement reaction, obtain the compound of formula (XXXIII);

Steps d " represent to carry out deprotection reaction, obtain the oh group of compound (XXXIV);

Step e " be illustrated in oh group with compound (XXXIV) be converted into suitable leavings group (as the methylsulfonic acid base, by with Et ₃N and CH ₃SO ₂Cl reaction) carries out intramolecular cyclization after, obtain the compound (XXXV) after the cyclisation;

Step f " expression and the linked reaction that suitable Z-W derivative carries out the metal mediation, obtain compound.

Initiator is known in the document, as acid derivative (referring to Snider, Barry B.; Ahn, Yong; Foxman, Bruce M.Synthesis of the tricyclic triamine core of martinelline andmartinellic acid.Tetrahedron Letters (1999), 40(17), 3339-3342).

When formula (I) compound-when the Z-W group was not the known compound of describing in the document, it can be according to preparing with following scheme similar methods.In order to simplify understanding to chemical step, this scheme represents-preparation of the specific derivatives of Z-W group, there is not other as defined above substituting group sometimes.Being used to prepare the validity that contains multi-substituent more or be connected in these methods of the derivative on the different groups can not be restricted.The example of following noodle producing method can find at experimental section.

Be suitable for the synthetic schemes of the derivative of preparation formula (II) compound, wherein Z is equivalent to the pyrazolyl derivative, and W is the W2 derivative, for example 1-(1H-pyrazole-3-yl) imidazolidin-2-one (intermediate 8):

Scheme 4

Wherein

Step a " ' expression 3-amino-pyrazol and chloroethyl isocyanate in DMF in 0 ℃ of reaction;

Step b " ' represent in THF, at room temperature to carry out cyclization with KOt-Bu;

Step c " ' represent by LiOH at MeOH/H ₂Carry out deprotection reaction in 80 ℃ among the O.

Be suitable for the synthetic schemes of the derivative of preparation formula (II) compound, wherein Z is equivalent to the pyrazolyl derivative, and W is the W9 derivative, for example 1-(1H-pyrazole-3-yl) pyrrolidin-2-one (intermediate 10):

Scheme 5

Intermediate 10

Wherein

Step a ^IvExpression 3-amino-pyrazol and 4-chlorobutanoylchloride are at K ₂HPO ₄Under existing and at CH ₂Cl ₂In react;

Step b ^IvExpression is at room temperature carried out cyclization with NaH in DMF;

Step c ^IvExpression is at room temperature carried out deprotection reaction by MeONa/MeOH.

Be suitable for the synthetic schemes of the derivative of preparation formula (II) compound, wherein Z is equivalent to the pyrazolyl derivative and W is the W3 derivative, for example 1-(1H-pyrazole-3-yl) tetrahydropyrimidine-2 (1H)-ketone (intermediate 13)

Scheme 6

Intermediate 13

Wherein

Step a ^vExpression 3-amino-pyrazol and chloropropyl isocyanic ester react in 0 ℃ in DMF;

Step b ^vExpression is carried out cyclization with KOt-Bu under room temperature in THF;

Step c ^vExpression by LiOH at MeOH/H ₂Carry out deprotection reaction in 80 ℃ among the O.

Be suitable for the synthetic schemes of the derivative of preparation formula (II) compound, wherein Z is equivalent to pyridinyl derivatives and W is the W2 derivative, for example protected 1-(6-bromo-2-pyridyl)-2-imidazolidone (intermediate 96).

Scheme 7

Intermediate 96

Wherein

Step a ^ViExpression 1-chloro-2-isocyanide acyl group ethane (isocyanatoethane) carries out condensation with 6-bromo-2-pyridine amine (pyridinamine), obtains urea;

Step b ^ViBe illustrated under the alkaline condition (the THF solution of t-BuOK) and carry out cyclization;

Step c ^ViThe NH group of urea is protected in expression with suitable blocking group (as to the methoxy-benzyl group).

Be suitable for the synthetic schemes of the derivative of preparation formula (II) compound; wherein Z is equivalent to pyrimidinyl derivatives and W is the W2 derivative, for example 1-(2-bromo-4-the pyrimidyl)-2-imidazolidone (intermediate 104) of Bao Hu 1-(4-bromo-2-pyrimidyl)-2-imidazolidone (intermediate 102) and protection.

Scheme 8

Intermediate 102 intermediates 104

Wherein

Step a ^ViiExpression 1-chloro-2-isocyanide acyl group ethane and 4-methoxy-benzyl amine carry out condensation, obtain urea derivatives;

Step b ^ViiBe illustrated under the alkaline condition (the THF solution of t-BuOK) and carry out cyclization;

Step c ^ViiBe illustrated under the alkaline condition (as the DMF solution of NaH), the ring-type urea carries out nucleophilic substitution 2 on the 4-dichloro pyrimidine;

Steps d ^ViiExpression makes cl radical be exchanged for bromine group by reacting with TMSBr (TMS bromine).

The scheme that is used for synthesis type (II) compound, wherein Z is triazolyl or pyrazolyl derivative.Especially, compound (IIr) synthetic, wherein Z is that triazolyl or pyrazolyl derivative and W are the W2 derivative, 1-(1H-1,2,4-triazole-3-yl)-2-imidazolidone substituting group (R ₅=H, X=N) and 1-(5-methyl isophthalic acid H-pyrazole-3-yl)-2-imidazolidone substituting group (R ₅=Me, X=C)

Scheme 9

Wherein

Step a ^ViiiExpression is carried out the arylation reaction by linked reaction (for example Buchwald reaction) step and the 3-amino-heterocycles of metal catalytic;

Step b ^ViiiExpression 1-chloro-2-isocyanide acyl group ethane and amino-heterocycles carry out condensation, obtain urea;

Step c ^ViiiBe illustrated under the alkaline condition (the THF solution of t-BuOK) and carry out cyclization.

Be suitable for the synthetic schemes of the derivative of preparation formula (II) compound, wherein Z is equivalent to phenyl derivatives and W is the W2 derivative, for example 1-phenyl-2-imidazolidone substituting group.

Scheme 10

Wherein

Step a ^IxExpression is as defined step f) in the scheme 2 ' (carrying out the Suzuki coupling) with boric acid (boronic acid) derivative;

Step b ^IxExpression 1-chloro-2-isocyanide acyl group ethane and 6-bromo-2-pyridine amine carry out condensation, obtain urea;

Step c ^IxBe illustrated under the alkaline condition (the THF solution of t-BuOK) and carry out cyclization.

Be suitable for the synthetic schemes of the derivative of preparation formula (II) compound, wherein Z is equivalent to the pyrazolyl derivative and W is W11, W13 or W14 derivative, 3-(1H-pyrazole-3-yl)-1 for example, 3-oxazolidine-2-ketone (intermediate 16), 3-methyl isophthalic acid-(1H-pyrazole-3-yl)-2 (1H)-pyridones (intermediate 26) and 2-(1H-pyrazole-3-yl)-3 (2H)-pyridazinones (intermediate 28).

Scheme 11

Intermediate 16,26 and 28

Wherein

Step a ^xRepresent to carry out the protection of 3-bromine pyrazoles with suitable blocking group (as trityl group);

Step b ^xThe bromo pyrazoles of expression protection is respectively with 1, and 3-oxazolidine-2-ketone, 3-methyl-2 (1H)-pyridone and 3 (2H)-pyridazinone carry out the catalytic linked reaction of copper;

Step c ^xThe expression deprotection reaction obtains required bicyclic derivatives.

Be suitable for the synthetic schemes of the derivative of preparation formula (IIr) compound, wherein Z is equivalent to the pyrazolyl derivative and W is the W10 derivative, 2-(1H-pyrazole-3-yl)-1,2 for example, 5-thiadiazolidine 1,1-dioxide substituting group.

Scheme 12

Wherein

Step a ^XiExpression uses the 2-ethyl bromoacetate to carry out the alkylation of amino group as alkylating reagent;

Step b ^XiExpression uses appropriate reductant (as LiAlH ₄), make ester group be reduced to alcohol;

Step c ^XiExpression uses Burgess ' reagent ((methoxycarbonyl sulfamyl) three second ammonium hydroxide inner salts) to make amino alcohol carry out cyclic action, obtains the cyclic sulfonylurea;

Steps d ^XiExpression uses alkaline condition (as the CH of NaOH ₂Cl ₂/ MeOH mixture) sulfonylurea is carried out deprotection.

Be suitable for the synthetic schemes of the derivative of preparation formula (II) compound, wherein Z is equivalent to the pyrazolyl derivative and W is the W12 derivative, 2-(1H-pyrazole-3-yl) isothiazolidine 1 for example, 1-dioxide substituting group.

Scheme 13

Wherein

Step a ^XiiExpression uses 1,2-oxathiolane (oxathiolane) 2, and the 2-dioxide makes amino group carry out alkylation as alkylating reagent;

Step b ^XiiExpression is by adding POCl ₃The cyclisation step of mediation.

Be suitable for the synthetic schemes of the derivative of preparation formula (IIr) compound, wherein Z is equivalent to the pyrazolyl derivative and W is the W1 derivative, 1-(1H-pyrazole-3-yl)-1 for example, 3-dihydro-2 H-imidazol-2-one substituting group.

Scheme 14

Wherein

Step a ^XiiiExpression uses the chloroformic acid phenylester to carry out the preparation of phenyl carbamate;

Step b ^XiiiExpression adds to the aminoacetaldehyde dimethylacetal on the activatory carbamate groups;

Step c ^XiiiBe illustrated under acid (as the HCl) existence and carry out cyclization, obtain 2H-imidazoles-2-ketone substituting group.

Be present in the R group compound known normally in formula (I) compound.

When this R group was not the compound of having described in the document, it can be according to preparing with following scheme similar methods.In order to simplify the understanding to chemical step, this scheme is represented the preparation of the specific derivatives of R group, does not have other as defined above substituting group J sometimes.The validity that is used to prepare these methods that contain the substituent derivative of more J can not be restricted.

The example of following noodle producing method can find at experimental section.

The synthetic schemes of 2-(difluoromethyl)-4-(methoxyl group) aniline.

Scheme 15

Intermediate 87

Wherein

Step a ^XivExpression acid groups and appropriate reductant are (as cyanuryl chloride/NMM/NaBH ₄) carry out reduction reaction;

Step b ^XivExpression is oxidized to aldehyde with suitable oxygenant (crossing iodine alkane as Dess-Martin) with alcohol;

Step c ^XivSuitable fluorizating agent (as the DAST:(diethylamino) sulfur trifluoride is used in expression) make aldehyde carry out the bifluoride effect;

Steps d ^XivExpression nitryl group and appropriate reductant are (as H ₂, with the palladium catalysis on the gac) and carry out reduction reaction.

The preparation scheme of 2-(methoxyl group)-4-(1H-pyrazol-1-yl) aniline (intermediate 88).

Scheme 16

Intermediate 88

Wherein

Step a ^XvThe catalytic linked reaction of copper between expression 4-bromo-2-(methoxyl group) aniline and the pyrazoles.

Formula (IIn) compound can prepare easily according to following scheme 4, and initiator wherein prepares according to WO 02/088095 A1.

Scheme 17

Wherein

Step a ^XviThe salt of the 'beta '-ketoester of expression (XXIVb) and the amidine of replacement (for example hydrochloride) (as B amidine hydrochloric acid salt) carries out cyclic action;

Step b ^XviExpression is converted into suitable leavings group with the oh group of formula (XXVIb), and this leavings group is selected from: the reactive residue of halogen or sulfonic acid (as methylsulfonic acid base, toluenesulphonic acids base) is preferably chlorine;

Step c ^XviExpression by with suitable-Z-W derivatives reaction, leavings group L is converted into compound (XXVIIIb);

Steps d ^XviBe equivalent to the step o in the aforementioned schemes 1.

Especially, when J be group-OCHF ₂The time, can it be introduced directly in the R group by known method in the document, or final group-OCH ₃In the method for listing in Greene ' the s document of being quoted below can using any carried out deprotection.Then, can use suitable fluoro-alkyl reagent such as CF ₂Br ₂With the oh group alkylation, as illustrational intermediate 125.

Persons skilled in the art are to be understood that in preparation The compounds of this invention or its solvate, may be essential and/or wish to protect one or more sensitive groups in the molecule to prevent bad side reaction.According to appropriate protection group used in the present invention is that persons skilled in the art are known, and can be used in the conventional method.Referring to for example, " Protective groups in organic synthesis " by T.W.Greene and P.G.M.Wuts (John Wiley ﹠amp; Sons 1991) or " Protecting Groups " by P.J.Kocienski (Georg Thieme Verlag 1994).The example of suitable amido protecting group comprises the blocking group (as formyl radical, trifluoroacetyl group, ethanoyl) of acyl group type; aromatic amino ester formate (urethane) type blocking group (as the Cbz of benzyloxycarbonyl (Cbz) and replacement), aliphatic carbamate type blocking group (as 9-fluorenyl methoxy carbonyl (Fmoc), tert-butoxycarbonyl (Boc), isopropoxy carbonyl, cyclohexyloxy carbonyl) and alkyl type blocking group (as benzyl. trityl, chloro trityl).The example of suitable oxygen blocking group can comprise for example alkyl silyl such as TMS or t-butyldimethylsilyl; Alkyl oxide such as THP trtrahydropyranyl or the tertiary butyl; Or ester such as acetic ester.

Pharmacy acceptable salt also can comprise other pharmacy acceptable salt by other salt of formula (I) compound, uses conventional method to prepare.

Can separate formula (I) compound that combines with solvent molecule at an easy rate by with suitable solvent crystallization or evaporation, obtain the corresponding solvent compound.

When needing the given enantiomer of general formula (I) compound, it can be for example obtains by using conventional method that the enantiomeric mixture of corresponding formula (I) compound is split.Therefore, required enantiomer can be obtained by using chirality HPLC method by racemic formula (I) compound.

The present invention also comprises isotope-labeled compound, their compounds below formula I compound reaches are identical, but in fact one or more atom is replaced at the atom with different atomic masses or total mass number that occurring in nature exists with them.Can be incorporated into isotopic example in the The compounds of this invention comprise hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine, iodine and chlorine isotropic substance, as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁷O, ¹⁸O, ³¹P, ³²P, ³⁵S, ¹⁸F, ³⁶Cl, ¹²³I and ¹²⁵I.

Other the isotopic compound of the present invention and the described compound pharmacy acceptable salt that comprise above-mentioned isotropic substance and/or other atom all are included in the scope of the present invention.The isotope-labeled compound of the present invention for example those mix radio isotope as ³H, ¹⁴The compound of C is useful in medicine and/or matrix organization's distribution (substrate tissue distribution) experiment.Preferred especially tritium, promptly ³H and carbon-14, promptly ¹⁴The C isotropic substance is because they are easy to preparation and detect. ¹¹C and ⁸The F isotropic substance is particularly useful in PET (positron emission fault photographic process), and ¹²⁵The I isotropic substance is particularly useful in SPECT (single photon emission computed control tomography method), and all these is used to the brain imaging.In addition, owing to have longer metabolic stability, for example improve the interior transformation period of body or reduce essential dosage, heavier isotropic substance surrogate is as deuterium, promptly ²H can obtain certain treatment advantage, therefore, in some cases can be preferably they.Generally can use the isotope-labeled reagent that obtains easily to replace the compound that nonisotopically labelled reagent prepares isotope-labeled formula I compound of the present invention and back by disclosed method among following diagram and/or the embodiment.

Prove that CRF receptor antagonist of the present invention has activity and it the CRF acceptor site and can be used for treatment by CRF or the receptor-mediated illness of CRF.

Compound can be measured by various test methods as the effectiveness of CRF receptor antagonist.The specificity that appropriate C RF antagonist of the present invention can suppress CRF and its acceptor in conjunction with and the antagonism activity relevant with CRF.The compound of structure (I) can be generally the acceptable test of this purpose by one or more and detect its activity as the CRF antagonist, (" Journal of Neuroscience " be 7:88 (J.Neuroscience) to include, but is not limited to DeSouza etc., 1987) and (" cynapse " be 1:572 (Synapse), 1987) disclosed method such as Battaglia.

Can use similar scintillation proximity assay (SPA) to carry out the test of CRF-receptors bind.Part is connected and is used for expressing on the recombinant chou film of CRF acceptor, and the CFR acceptor is connected again on the SPA pearl that scribbles wheat germ agglutinin.At the particular content of test portion with demonstration test.

With regard to the CRF receptor binding affinity, CRF receptor antagonist of the present invention has the Ki value less than 10 μ m.

Compound of the present invention can be used to treat the central nervous system disease relevant with the CRF acceptor.Especially, it can be used for treatment and prevention is attended by or be not attended by mental illness (psychoticfeatures), catatonia (catatonic features), dysthymia disorders (melancholic features), atypia illness (atypical features) or the illness of showing effect postpartum (postpartum onset) feature comprise bipolarity dysthymia disorders (bipolar depression), unipolar depression (unipolar depression), single or recurrent major depressive episode serious dysthymia disorders such as (major depressive episodes) is used for the treatment of anxiety disorder and panic disorder (panic disorder).Other emotional disorder is included in the serious dysthymia disorders of term, comprises being attended by or not being attended by having of atypical characteristics dysthymic disorder (dysthymic disorder) early stage and that the later stage shows effect, neurotic depression (neurotic depression), spiritual stress disorder after the wound (post traumatic stress disorders), operation back nervous (post operative stress) and social phobia (social phobia), follow early stage or later stage outbreak feature and follow the Alzheimer type dementia of hypothymergasia (depressed mood); Follow hypothymergastic vascular dementia (vasculardementia); By alcohol, amphetamine, Cocaine, halluoinogen, inhalation (inhalants), opioids opioids, phencyclidine, tranquilizer, soporific, anxiolytic and the caused mood disorder of other material (mood disorders); The schizoaffective disorder of depressive type (schizoaffective disorder ofthe depressed type); And hypothymergasia type adjustment disorder (adjustment disorder).Serious dysthymia disorders may be caused that also described disease includes but not limited to myocardial infarction, diabetes, miscarriage (miscarriage) or premature labor (abortion) etc. by general disease.

The compounds of this invention also can be used for treatment or the prevention schizophrenic disturbance comprises paranoid schizophrenia, disorganized schizophrenia (disorganised schizophrenia), catatonic schizophrenia, undifferentiated schizophrenia (undifferentiated schizophrenia), residual schizophrenia (residual schizophrenia).

Compound of the present invention is also as anodyne.Especially, they can be used for treating wound pain such as post-operative pain; Tearing property wound pain (traumatic avulsion pain) is as brachial plexus; Chronic pain for example occurs in the pain of sacroiliitis, rheumatoid arthritis or arthritic psoriasis in the bone; Neuropathic pain such as postherpetic neuralgia, trigeminal neuralgia, segmental or intercostal neuralgia (segmental orintercostal neuralgia), fibromyalgia, cusalgia, peripheral neurophaty, diabetic neuropathy (diabeticneuropathy), the neuropathy that chemotherapy causes, the neuropathy relevant with AIDS, occipital neuralgia (occipitalneuralgia), geniculate neuralgia (geniculate neuralgia), glossopharyngeal neuralgia (glossopharyngealneuralgia), reflex sympathetic dystrophy (reflex sympathetic dystrophy), phantom limb pain (phantom limb pain); Various headaches such as migraine, acute or chronic tension headache, temporomandibular joint pain (temporomandibular pain), maxillary sinus pain (maxillary sinus pain), cluster headache (cluster headache); Toothache; Cancer pain; Come from the pain of internal organ; Gastroenteralgia; Nerve brings out pain (nerve entrapment pain); Motion grieved (sport ' s injury pain); Dysmenorrhoea; Cramp; Meningitis; Arachnoiditis; Musculoskeletal pain; Waist (back of the body) bitterly, as spinal canal stenosis; Uterine prolapse (prolapsed disc); Sciatica; Angor (angina); Ankylosing spondylitis (ankylosing spondyolitis); Gout; Burn (burns); Scar pain (scar pain); Disturb and itch; And thalamic pain such as apoplexy metathalamus pain.

Compound of the present invention also is used to treat appetite and the dysfunction of ingesting, as anorexia, anorexia nervosa and Bulimia nerovsa situation.

Compound of the present invention also is used to treat somnopathy, comprises dysomnia, insomnia, sleep apnea, narcolepsy (narcolepsy) and physiological rhythm disorder (circadian ritmicdisorders).

Compound of the present invention also is used for the treatment of or prevents cognitive disorder.Cognitive disorder comprises dementia, amnesia and other cognitive disorder that does not specify especially.

In addition, compound of the present invention does not also have cognitive and/or letheral healthy man memory and/or cognitive enhancer as those.

Compound of the present invention also is used to treat tolerance and the dependency to many materials.For example, they can be used for the dependent treatment to nicotine, alcohol, caffeine, phencyclidine (the similar compound of phencyclidine); Perhaps be used for the treatment of opiate (opiates) (as hemp, heroine, morphine) or benzodiazepine (benzodiazepines) tolerance and dependence treatment; Also can be used for the addictive disorders treatment of the relevant medicine (as Dextroamphetamine, methyl amphetamine) of cocaine, tranquilizer (sedative ipnotic), amphetamine or amphetamine or its combination.

Also as anti-inflammatory drug, especially, they are used for the treatment of the inflammation of asthma, influenza, chronic bronchitis and rheumatoid arthritis to compound of the present invention; Be used for the treatment of GI inflammatory disease such as Crohn disease, ulcerative colitis, postoperative stomach and intestine block the damage that (POI) (postoperativegastric ileus), inflammatory bowel (IBD) and nonsteroidal anti-inflammatory drug cause; The inflammatory diseases of skin such as bleb and eczema; The inflammatory diseases of bladder such as urocystitis and urge incontinence (urgeincontinence); And the treatment of eye and tooth portion inflammation.

Compound of the present invention also is used for the treatment of allergic disorder, is used for the allergic disorder of skin such as the allergic disorder such as the rhinitis of urticaria and air flue especially.

Compound of the present invention also is used for the treatment of vomiting, i.e. gastric disorder causing nausea, retch and vomiting.Vomiting comprises acute vomiting, tardive vomiting (delayed emesis) and the vomiting (anticipatory emesis) that takes place in advance.Compound of the present invention can be used for treatment by the caused vomiting of any reason.For example, vomiting can be because drug-induced, for example cancer chemotherapeutic medicine, for example alkylating reagent such as endoxan (cyclophosphamide), carmustine (carmustine), lomustine (lomustine) and Chlorambucil (chlorambucil); Cytotoxin microbiotic (cytotoxic antibiotics) is as gengshengmeisu (dactinomycin), Dx (doxorubicin), ametycin (mitomycin-C) and bleomycin (bleomycin); Metabolic antagonist such as cytosine arabinoside (cytarabine), methotrexate and 5 FU 5 fluorouracil; Vinca alkaloids such as Etoposide, vinealeucoblastine(VLB) and vincristine(VCR); And other is such as cis-platinum, Dacarbazine (dacarbazine), methylbenzyl hydrazine (procarbazine) and hydroxyurea (hydroxyurea); And combination; Radiation syndrome; The radiotherapy of radiotherapy such as thoracic cavity or belly is as treatment for cancer; Poison; The toxin of toxin as being caused by metabolism disorder (metabolic disorder) or infection is as the bacterial or viral gastrointestinal tract infection that causes of gastritis; Conceived; Vestibular disorder (vestibular disorder) is as motion sickness (motionsickness), dizzy, dizziness and plum Neil (family name) sick (Meniere ' s disease); Disorders post surgery; Stomach and intestine block; Gastrointestinal peristalsis reduces (reduced gastrointestinal motility); Visceral pain such as myocardial infarction or peritonitis; Migraine; Pressure increases (increased intercranial pressure) between cranium; Pressure reduces (decreased intercranial pressure) (as altitude sickness) between cranium; Opioid analgesics such as morphine; With stomach-esophageal reflux disease (gastro-oesophageal reflux disease), acid maldigestion (acidindigestion), diet overindulgence, hyperchlorhydria, acid stomach (sour stomach), sour regurgitation (waterbrash)/gastric disorder causing nausea, pyrosis (heartburn) are as ictal pyrosis (episodic heartburn), the property sent out pyrosis at night (nocturnal heartburn), and the pyrosis and the dyspeptic treatment of having meal and causing.

Compound of the present invention is used in particular for gastrointestinal illness such as irritable bowel syndrome (IBS); Dermatosis such as psoriasis, itching disease and sunburn; Vasospasm disease such as angor (angina), vascular headache and Reynolds (family name) sick (Reynaud ' s disease); The cerebral vasospasm (cerebral vasospasm following subarachnoidhaemorrhage) of cerebral ischemia (cerebral ischeamia) as causing with subarachnoid hemorrhage; Fibering and collagen diseases (fibrosing and collagen diseases) are as scleroderma and acidophilia fascioliasis (eosinophilic fascioliasis); The disease relevant with immunity system enhancing or inhibition be systemic lupus erythematous and rheumatism such as fibrositis for example; Treatment with cough.

Compound of the present invention is used for the treatment of follows cerebral apoplexy (cerebral stroke), thromboembolism apoplexy (thromboembolic stroke), hemorrhagic stroke (hemorrhagic stroke), cerebral ischemia, cerebral vasospasm (cerebral vasospam), hypoglycemia, hypoxia (hypoxia), anoxia (anoxia), the neurotoxicity damage (neurotoxic injury) of perinatal asphyxia asystole (perinatal asphyxia cardiac arrest).

Therefore, the invention provides and be used for the treatment of, in particular for formula (I) compound or its pharmacy acceptable salt or the solvate of people's medicine.

On the other hand, the invention provides general formula (I) compound or its pharmacy acceptable salt or its solvate purposes in the medicine of the illness that the preparation treatment is mediated by CRF.

The present invention other or others provide and be used for the treatment of Mammals and comprise the people, especially for the method for treatment by the illness of CRF mediation, described method comprises formula (I) compound or its pharmacy acceptable salt or its solvate of effective dosage.

Although be possible, the The compounds of this invention that is used for the treatment of can be with the form administration of raw material chemical substance, but preferably exist, for example when this medicament is mixture with the suitable selected pharmaceutical excipient of the pharmacy practice of considering route of administration and standard, diluent or carrier as the activeconstituents in the pharmaceutical preparation.

On the other hand, the invention provides pharmaceutical composition, it comprises at least a The compounds of this invention or its pharmaceutically acceptable derivates and pharmaceutically acceptable carrier and/or vehicle.This carrier and/or vehicle must be " acceptable ", and be compatible and do not have toxicity for its acceptor with other composition of preparation to a certain extent.

Therefore, the present invention further provides the pharmaceutical preparation that comprises at least a The compounds of this invention or its pharmaceutically acceptable derivates and pharmaceutically acceptable carrier and/or vehicle.This carrier and/or vehicle must be " acceptable ", and be compatible and do not have toxicity for its acceptor with other composition of preparation to a certain extent.

The present invention further provides the method for pharmaceutical compositions, described method comprises with at least a The compounds of this invention or its pharmaceutically acceptable derivates and with pharmaceutically acceptable carrier and/or vehicle and being mixed together.

This pharmaceutical composition can use for the human or animal, is used for people's medicine and veterinary drug, and will typically comprises any or multiple pharmaceutically acceptable thinner, carrier or vehicle.The acceptable carrier or the thinner that are used for the treatment of purposes are that pharmaceutical field is well-known, and are described in for example Remington ' sPharmaceutical Sciences, among the Mack Publishing Co. (A.R.Gennaro edit.1985).The selection of pharmaceutical carrier, vehicle or thinner can consider that the pharmacy practice of route of administration and standard selects.This pharmaceutical composition can comprise conduct-or any suitable binder, lubricant, suspending agent, Drug coating, solubilizing agent except-carrier, vehicle or thinner.

Sanitas, stablizer, dyestuff and or even sweetener can be provided in this pharmaceutical composition.The example of sanitas comprises the ester of Sodium Benzoate, Sorbic Acid and P-hydroxybenzoic acid.Also can use antioxidant and suspending agent.

May there be different compositions/preparation needs according to different delivery systems.Pass through embodiment, pharmaceutical composition of the present invention can be formulated as and use Micropump or pass medicine by mucosal route, for example maybe can take in (ingestible) solution or parenteral admin with gaseous solvents as nasal spray or suction, wherein can be with said composition according to the injectable forms that is used to pass medicine, according to for example intravenously, intramuscular or subcutaneous route preparation.Perhaps, said preparation can be designed to pass medicine by two kinds of approach.

Wherein if said preparation is to carry out mucous membrane by gastrointestinal mucosa to pass medicine, then it should keep stable in by the gi tract transmission course; For example it should resist proteoclastic Decomposition, is stable under acid pH and can resists biliary washing composition effect.

If it is suitable, can be with this pharmaceutical composition by the inhalation administration, with suppository or vaginal suppository form administration, form topical with lotion, solution, emulsion, ointment or dusting, by using the skin patch administration, to contain the tablet form of vehicle such as starch or lactose, or separately with the form of the mixture of capsule or ovule or itself and vehicle, or with the form oral administration of the elixir, solution or the suspension that contain sweetener or tinting material, or they can be through parenteral for example by by intravenously, intramuscular or subcutaneous injection administration.For administered parenterally, said composition can best form with aseptic aqueous solution be used, and can contain other material in this aseptic aqueous solution, for example enough salt or monose so that this solution and blood etc. ooze.For containing agent (buccal) or sublingual administration (sublingual administration), said composition can tablet or the form administration of lozenge, the method preparation that it can be conventional.

For some embodiments, medicament of the present invention also can be united use with cyclodextrin.Known cyclodextrin can form inclusion (inclusion) and non--inclusion complex compound with drug molecule.The formation of drug-cyclodextrin complex compound can change solubleness, dissolution rate, bioavailability and/or the stabilising characteristic of drug molecule.Usually this drug-cyclodextrin complex compound can be used for most of formulations and route of administration.Perhaps for the direct complexing of medicine, this cyclodextrin can be used as supplementary additive, for example as carrier, thinner or solubilizing agent.The most common use α-, β and γ-Huan Hujing, and suitable case description is in WO-A-91/11172, WO-A-94/02518 and WO-A-98/55148.

In a preferred embodiment, medicament of the present invention can be passed medicine through whole body (as per os, contain clothes, hypogloeeis), and more preferably per os is passed medicine.

Therefore, preferably this medicament is to be suitable for the form that per os is passed medicine.

Should be appreciated that not every compound all need be with identical administration.And when comprising more than a kind of activeconstituents as if composition, then those compositions can pass through different administrations.

The compounds of this invention can use known process of lapping such as wet-milling to mill to obtain to be suitable for the particle diameter of tablet formation and other preparation type.The segmentation of The compounds of this invention (nanoparticle) preparation can prepare by methods known in the art, for example referring to international patent application no WO 02/00196 (SmithKline Beecham).

To oral administration, pharmaceutical composition can be with by ordinary method and pharmaceutically acceptable vehicle such as tackiness agent (for example pregelatinized W-Gum, Polyvinylpyrolidone (PVP) or HYDROXY PROPYL METHYLCELLULOSE); Weighting agent (as lactose, Microcrystalline Cellulose or secondary calcium phosphate); Lubricant (as Magnesium Stearate, talcum or tripoli); Disintegrating agent (as yam starch or sodium starch glycolate); Perhaps made tablet or the capsular form of wetting agent (as Sodium Lauryl Sulphate BP/USP).Can use method well known in the art to make tablet.Peroral administration liquid preparation can be the form of solution, syrup or suspension for example, and perhaps the form that they also can the dry labor thing exists, and mixes with water or other suitable carriers before use.These liquid preparations can obtain by ordinary method and pharmaceutically acceptable additive preparation, described additive such as suspending agent (as Sorbitol Powder syrup, derivatived cellulose or hydrogenation edible-fat); Emulsifying agent (as Yelkin TTS or gum arabic); Nonaqueous carrier (as Prunus amygdalus oil, grease (oily esters), ethanol or fractionated vegetable oil (fractionated vegetable oils)); And sanitas (as methyl or propyl group-p-Hydroxybenzoate or Sorbic Acid).Under suitable situation, also can contain buffering salt, sweetener, tinting material and sweeting agent in the preparation.

Peroral administration preparation can be made the release of suitable form with the control active compound.

Can make tablet or prepare for the composition of buccal administration according to ordinary method.

The compounds of this invention can be made the form of administered parenterally by the mode of bolus injection (bolus injection) or continuous infusion.Injection preparation can exist as add sanitas at ampoule or in multi-dose container by unit dosage form.Said composition can be the form of suspension, solution or emulsion in oiliness or aqueous carrier, and may contain preparaton such as suspension agent, stablizer and/or dispersion agent.Perhaps, activeconstituents can be a powdery form, mixes with suitable carrier such as aseptic pyrogen-free water before use.

Compound of the present invention also can be mixed with the topical form of ointment, emulsion, gelifying agent, lotion, vaginal suppository, gaseous solvents or drops (for example eye, ear or nose drops).Ointment and emulsion can add suitable thickening in water-based or oleaginous base and/or jelling agent is made.Ointment to dosing eyes can be to use aseptic composition to make with sterile manner.

Lotion can generally also comprise one or more emulsifying agents, stablizer, dispersion agent, suspending agent, thickening material or tinting material with water-based or oleaginous base preparation.Drops can use or the preparation of non-aqueous matrix, also comprises one or more dispersion agents, stablizer, solubilizing agent or suspending agent.They also can contain sanitas.

Compound of the present invention can also be made the form of rectal compositions, as suppository or enema,retention, for example contains conventional suppository bases such as theobroma oil or other glyceryl ester.

Compound of the present invention also can be made into prolonged action preparation.These prolonged action preparations can be by implanting (implantation) mode (for example subcutaneous or intramuscular) or passing through the muscle injection mode administration.Therefore, compound for example of the present invention can with suitable polymers or hydrophobic material (for example in acceptable oil with the emulsion form) or ion exchange resin, or with the microsolubility derivative for example slightly soluble salt make preparation together.

To intranasal administration, compound of the present invention can be made the solution by the single dose equipment administration of suitable metering, perhaps is mixed with the suitable transfer equipment administration and powdered mixture suitable carrier.

The recommended doses of The compounds of this invention is 1 to about 1000mg/ day.Be to be understood that and come to adjust daily consumption according to patient's age and situation, and accurate dose will finally be abideed by doctor in charge or animal doctor's judgement according to rule.This dosage also should be determined according to route of administration and selected specific compound.Therefore, for the per daily dose of administered parenterally usually 1 to about 100mg, preferred 1 to 80mg every day.To the per daily dose of oral administration usually in 1 to 300mg scope, as 1 to 100mg.

Embodiment

Except as otherwise noted, in intermediate and embodiment:

All temperature are ℃.Infrared spectra is measured on the FT-IR instrument.Compound directly is injected into positive electron spray(ES) (positive electro spray) (ES by the sample that will be dissolved in the acetonitrile ⁺) analyze in the mass spectrum of ionization pattern operation.Proton magnetic resonance (PMR) ( ¹H-NMR) wave spectrum is a record under the 400MHz, and chemical shift is to be that unit and record are used as interior target Me certainly with ppm ₄The downfield of Si (d) displacement, and peak shape is expressed as follows: unimodal (s), wide unimodal (bs), bimodal (d), double doublet (dd), triplet (t), quartet (q) or multiplet (m).Used and comprise the relevant and/or 1H of NOE (nuclear Overhauser effect), the scheme that the long-range scalar of 15N relevant (long range scalar correlations) is measured is to illustrate the structure of the possible regional isomer of The compounds of this invention.Verify the structure (Proposed structures) of suggestion by the spatial neighbor of measuring crucial hydrogen (key hydrogens), therefore use 1D nuclear Ou Wohaosi difference spectrum (Nuclear Overhauser difference spectra) to measure 1H, the 1H-dipole-dipole is relevant.

When NOE measures indeterminate (conclusive), by 1H, 15N-HMBC experiment measuring 1H, the long-range scalar of 15N is relevant.Will be corresponding to the average remote scalar coupling (average long rangescalar coupling) 2 of 6Hz, (1H, delay 15N) is set at optimum to 3J.

Column chromatography is that (Merck AG Darmstaadt carries out on Germany) at silica gel.Use following abbreviation in the literary composition: EtOAc=ethyl acetate, cHex=hexanaphthene, CH ₂Cl ₂=methylene dichloride, Et ₂The O=ether, DMF=N, N '-dimethyl formamide, DIPEA=N, N-diisopropylethylamine, DME=ethylene glycol dimethyl ether, MeOH=methyl alcohol, Et ₃The N=triethylamine, the TFA=trifluoroacetic acid, the THF=tetrahydrofuran (THF), the DIBAl-H=diisobutyl aluminium hydride, the DMAP=dimethyl aminopyridine, LHMDS=hexamethyldisilazane lithium (lithiumhexamethyldisilazane), KOtBu=potassium tert.-butoxide, NMP=M-N-methyl-2-2-pyrrolidone N-, MTBE=methyl-tertbutyl ether, the IPA=Virahol, DAST=(diethylamino) sulfur trifluoride, TMSBr=TMS bromine, DDQ=2,3-two chloro-5,6-dicyano-1,4-benzoquinones, the SCX=strong cation exchanger, Tlc refers to the thin-layer chromatography on silica plate, and the dry solution that refers to through anhydrous sodium sulfate drying, and r.t. (RT) refers to room temperature.

Intermediate 1

1-(4-methoxyl group-2-aminomethyl phenyl) pyrrolidin-2-one

At 0 ℃ at N ₂Down, in the 10L reactor, to Et ₃Drip anhydrous THF (480mL) solution of 4-chlorobutanoylchloride (126mL, 1 equivalent) in anhydrous THF (2.4L) solution of N (156mL, 1 equivalent) and 4-methoxyl group-2-aminotoluene (150g, 1.09 moles).Internal temperature is remained on about 10 ℃, and reaction mixture was stirred 1.5 hours.It is cooled to 0 ℃, and drips KOt-Bu 1M/THF (2.64L, 2.4 equivalents), keep internal temperature＜10 ℃ through time of 1.5 hours.Reaction mixture was stirred 30 minutes under this temperature.Add (20 minutes) water (1.5L) then at leisure, and separate two-phase.Organic layer is handled with dense HCl (250mL) and water (1.26L), and separated two-phase.The water layer that merges is extracted with EtOAc (2.6L), and the organic layer that merges is washed with salt solution (2L).Evaporating solvent, and with resistates by flash chromatography (Biotage 150, EtOAc/cHex 8:2) purifying, obtain filbert solid Title Compound(206g, 92%).

NMR( ¹H，CDCl ₃)：δ 7.05(d，1H)，6.79-6.72(m，2H)，3.75(s，3H)，3.64(t，2H)，2.18(s，6H)。

MS(m/z)：206[MH] ⁺。

Intermediate 2

3-{[1-(4-methoxyl group-2-aminomethyl phenyl) tetramethyleneimine-2-subunit] amino } the but-2-ene acetoacetic ester

At room temperature at N ₂Following, to Intermediate 1(8.3g, 40.49mmol) anhydrous 1 drip POCl in 2-ethylene dichloride (100mL) solution ₃(7.5mL, 2 equivalents) add the amino ethyl crotonate (5.17mL, 1 equivalent) of 3-subsequently.Reaction mixture was heated 3.5 hours in 60 ℃.Then it is cooled to room temperature, and by adding saturated NaHCO carefully ₃It is 7 that the aqueous solution is neutralized to pH.With neutral solution CH ₂Cl ₂(3 x 50mL) extraction.The organic extract that merges is washed with the saturated NaCl aqueous solution, and through anhydrous Na ₂SO ₄Dry.Filter this solid, and evaporating solvent.With this crude product to be used for next step (17.8g) like this.

Perhaps, at room temperature at N ₂Following, to Intermediate 91(3g adds ethyl-2-butyne acid esters (butynoate) (2.23mL, 1.3 equivalents) in anhydrous THF (18mL) solution 14.7mmol).With reaction mixture reflux 14 hours, and be cooled to room temperature then.Reaction mixture is evaporated to dried.The oily matter that this is thick is to be used for next step (5.05g) like this.

MS(m/z)：317[MH] ⁺。

Intermediate 3

1-(4-methoxyl group-2-aminomethyl phenyl)-6-methyl isophthalic acid, 2,3,7-tetrahydrochysene-4H-pyrrolo-[2,3-b] pyridine-4- Ketone

Will Intermediate 2(17.8g, dry DMF 55mmol) (50mL) drips of solution adds in the dry DMF suspension of NaH60%/oil (4.5g, 2 equivalents).Reaction mixture was heated 8 hours in 100 ℃.Add the more NaH60%/oil of volume (2.25g, 1 equivalent), and with reaction mixture reheat 4 hours.It is cooled to room temperature, and is poured into saturated NH carefully ₄In the Cl aqueous solution.With aqueous solution CH ₂Cl ₂(5 x 50mL) extraction, and with the organic extract that merges through anhydrous Na ₂SO ₄Dry.Filter this solid, and evaporating solvent.(Biotage 75, CH by flash chromatography with crude compound ₂Cl ₂The purifying of/MeOH95:5 → 80:20).The acquisition brown oil Title compound(952mg, 9%, two is rapid step by step).

Perhaps, at room temperature at N ₂Following, to Intermediate 2(2.46g adds 1Mt-BuOK/THF (15.6mL, 2 equivalents) in anhydrous THF (10mL) solution 7.77mmol).With the reaction mixture reflux, and stirred 6 hours.Solution is cooled to room temperature, is evaporated to about 10mL, and dilute with MTBE (10mL).With organic layer water (10mL) extraction, remove organic phase simultaneously with water with saturated NH ₄The Cl aqueous solution (10mL) dilution.With waterbearing stratum CH ₂Cl ₂(10mL) extraction.The organic extract that merges is evaporated to dried, and with thus obtained crude product to be used for next step (1.32g) like this.

NMR( ¹H，DMSO-d ₆)：δ 9.8(b，1H)，7.08(d，1H)，6.80(d，1H)，6.75(dd，1H)，5.92(s，1H)，3.72(s，3H)，3.68(t，2H)，2.89(t，2H)，2.12(s，3H)，2.02(s，3H)。

MS(m/z)：271[MH] ⁺。

Intermediate 4

1-(4-methoxyl group-2-aminomethyl phenyl)-6-methyl-2,3-dihydro-1H-pyrrolo-[2,3-b] pyridin-4-yl three The fluorine methanesulfonates

At room temperature at N ₂Following, to Intermediate 3(9.0g, anhydrous CH 33.3mmol) ₂Cl ₂(64mL) add pyridine (5.08mL, 1.8 equivalents) in the solution.Solution is cooled to-20 ℃, and drips trifluoromethanesulfanhydride anhydride (5.9mL, 1.1 equivalents) with time of 50 minutes.This temperature can be above-10 ℃.Reaction mixture is warmed to envrionment temperature, and stirred 30 minutes.Add saturated NaHCO ₃The aqueous solution (31.2mL), and separate two-phase.The further water of organic layer (31.2mL) is washed, and be concentrated into oily matter, it is passed through silicagel pad (12.7g, EtOAc/cHex 1/9).Thus obtained crude product is diluted with MTBE (38.1mL), and wash twice with 10%HCl (63.5mL).With the dense NH of water layer that merges ₄OH (38.1mL) handles, and uses CH ₂Cl ₂(25.4mL) extraction.Further use 10%NaCl (12.7mL) to wash organic layer, and flash to oily matter.This oily matter is dissolved with IPA (38.1mL), and with pure Intermediate 4(0.02g) inoculation (seeded).Suspension was stirred 30 minutes.Add entry (38mL) with 30 minutes times, and mixture was left standstill 1.5 hours.Filter this suspension, filter cake (cake) washed with the 1:1 mixture of IPA/ water (12.7mL), collect and in 40 ℃ under high vacuum in loft drier dry 14 hours.Obtain faint yellow solid Title compound(3.8g, 42%).

NMR( ¹H，DMSO-d ₆)：δ 7.17(d，1H)，6.85(d，1H)，6.77(dd，1H)，6.40(s，1H)，3.89(t，2H)，3.73(s，3H)，3.16(t，2H)，2.17-2.11(2s，6H)

M/S(m/z)：403[MH] ⁺

Intermediate 5

4-iodo-6-methyl isophthalic acid-[2-methyl-4-(methoxyl group) phenyl]-2,3-dihydro-1H-pyrrolo-[2,3-b] pyridine

To Intermediate 4(913mg adds KI (1.13g, 3 equivalents) in anhydrous NMP (7mL) solution 2.27mmol), and in 150 ℃ of stirred reaction mixtures 18 hours.Then it is cooled to room temperature, and in the NaCl aqueous solution of water/saturated, dilutes.With water with EtOAc (3 x 30mL) extraction, and with the organic extract that merges through anhydrous Na ₂SO ₄Dry.Filter this solid, and evaporating solvent.Crude product by flash chromatography (silica gel, cHex/EtOAc 9:1) purifying, is obtained transparent buttery title compound, it is left standstill curing (681mg, 79%).

NMR( ¹H，CDCl ₃)：δ 7.14(d，1H)，6.81-6.74(m，2H)，6.70(s，1H)，3.84(t，2H)，3.81(s，3H)，3.03(t，2H)，2.22(s，6H)。

MS(m/z)：381[MH] ⁺。

Intermediate 6

N-(2-chloroethyl)-3-({ [(2-chloroethyl) amino] carbonyl } amino)-1H-pyrazoles-1-methane amide (carboxamide)

At N ₂Down in 0 ℃, to the 3-amino-pyrazol (500mg adds 3-chloroethyl isocyanate (1.53mL, 3 equivalents) in dry DMF 6mmol) (3mL) solution, and with reaction mixture in stirring at room 2 hours, evaporating solvent subsequently.Crude product by flash chromatography (silica gel, cHex/EtOAc 1:1) purifying, is obtained Title compound(1.593g, 89%).

NMR( ¹H，DMSO)：δ 9.20(s，1H)，8.26(m，1H)，8.10(d，1H)，7.25(bs，1H)，6.37(d，1H)，3.74(m，2H)，3.66(m，2H)，3.58(m，2H)，3.46(m，2H)。

MS(m/z)：296[MH] ⁺。

Intermediate 7

N-(2-chloroethyl)-3-(2-oxo-imidazole alkane-1-yl)-1H-pyrazoles-1-methane amide

At room temperature at N ₂Following, to Intermediate 6(100mg adds KOt-Bu (42mg, 1.1 equivalents) in anhydrous THF (4mL) solution 0.34mmol), and reaction mixture was stirred 2 hours.Add entry (0.5mL) and evaporating solvent.With water layer H ₂O dilutes, and extracts with EtOAc (3 x 20mL).With the organic extract that merges through anhydrous Na ₂SO ₄Dry.Filter this solid, and evaporating solvent.Crude product by flash chromatography (silica gel, EtOAc/cHex 8:2,9:1 then) purifying, is obtained white solid Mark The topic compound(39mg, 44%).

NMR( ¹H，DMSO)：δ 8.18(bt，1H)，8.11(d，1H)，7.14(bs，1H)，6.75(d，1H)，3.89(m，2H)，3.73(m，2H)，3.56(m，2H)，3.40(m，2H)。

MS(m/z)：258[MH] ⁺。

Intermediate 8

1-(1H-pyrazole-3-yl) imidazolidin-2-one

At room temperature at N ₂Following, to Intermediate 7(190mg, MeOH/H 0.74mmol) ₂Add LiOH (177mg, 10 equivalents) in the solution of the 2:1 mixture of O (15mL), and reaction mixture was heated 3 hours in 80 ℃.It is cooled to room temperature, and to be neutralized to pH with 2M HCl be 7.Add silica gel then, and evaporating solvent.The crude product of absorption by flash chromatography (silica gel, EtOAc/MeOH 9:1) purifying, is obtained white solid Title compound(80mg, 71%).

NMR( ¹H，DMSO)：δ 12.10(bs，1H)，7.6(s，1H)，6.7(s，1H)，6.4(s，1H)，3.8(t，2H)，3.4(t，2H)。

MS(m/z)：152[MH] ⁺。

Intermediate 9

4-chloro-N-[1-(4-chlorobutyryl)-1H-pyrazole-3-yl] butyramide

At room temperature at N ₂Down, to 3-amino-pyrazol (300mg, anhydrous CH 3.61mmol) ₂Cl ₂(6mL) add K in the solution ₂HPO ₄(1.26g, 2 equivalents), and with reaction mixture in stirring at room 15 minutes.(406 μ L 3.6mmol), and stir reaction mixture 24 hours to add 4-chloro-butyryl chloride then.Be poured in the water then, and separate two-phase.With the waterbearing stratum with EtOAc (2 x 20mL) extraction, and with the organic extract that merges through anhydrous Na ₂SO ₄Dry.Filter this solid, and evaporating solvent.Crude product by flash chromatography (silica gel, cHex/EtOAc 7:3) purifying, is obtained white solid Title compound(354mg, 34%).

NMR( ¹H，CDCl ₃)：δ 8.09(d，1H)，7.83(bs，1H)，6.98(s，1H)，3.64(m，2H)，3.17(m，1H)，2.57(m，1H)，2.21(m，2H)。

MS(m/z)：292[M] ⁺。

Intermediate 10

1-(1H-pyrazole-3-yl) pyrrolidin-2-one

At room temperature at N ₂In dry DMF (1.5mL) suspension of NaH 80%/oil (31mg, 1.1 equivalents), add down, Intermediate 9(340mg, dry DMF 1.16mmol) (1mL) solution.With reaction mixture in stirring at room 1 hour, subsequently with its carefully water stop.Water is extracted with EtOAc (3 x 20mL), and the organic extract that merges is washed with the saturated NaCl aqueous solution, and through anhydrous Na ₂SO ₄Dry.Filter this solid, and evaporating solvent.At room temperature at N ₂Down, (70mg 0.27mmol) is dissolved among the anhydrous MeOH (3mL), and adding 1M MeONa/MeOH reaches 9 until pH with crude product.Reaction mixture in stirring at room 30 minutes, and is added entry.Water is extracted with EtOAc (3 x 20mL), and the organic extract that merges is washed with the saturated NaCl aqueous solution, and through anhydrous Na ₂SO ₄Dry.Filter this solid, and evaporating solvent.Crude product by flash chromatography (silica gel, cHex/EtOAc 7:3) purifying, is obtained white solid Title compound(35mg, 20%).

NMR( ¹H，CDCl ₃)：δ 7.46(s，1H)，6.55(s，1H)，3.90(t，2H)，2.59(t，2H)，2.18(m，2H)。

MS(m/z)：152[M] ⁺。

Intermediate 11

N-(3-chloropropyl)-3-({ [(3-chloropropyl) amino] carbonyl } amino)-1H-pyrazoles-1-methane amide

At room temperature at N ₂Down, (500mg adds 3-chloropropyl isocyanic ester (1.2mL, 2 equivalents), and will react and stir 24 hours in dry DMF 6mmol) (10mL) solution to the 3-amino-pyrazol.Reaction does not finish, and adds more isocyanic ester (1.2mL, 2 equivalents).With reaction mixture restir 48 hours.Be poured into CH then ₂Cl ₂In/saturated NaCl the aqueous solution, and separate two-phase.With waterbearing stratum CH ₂Cl ₂(2 x 20mL) extraction, and with the organic extract that merges through anhydrous Na ₂SO ₄Dry.Filter this solid, and evaporating solvent.(Biotage 40, and cHex/EtOAc7:3) purifying obtains white solid by flash chromatography with crude product Title compound(620mg, 32%).

NMR( ¹H，DMSO)：δ 9.05(s，1H)，8.25(t，1H)，8.08(d，1H)，7.17(t，1H)，6.30(d，1H)，4.7-4.6(m，4H)，3.37(q，2H)，3.26(q，2H)，2.05-1.87(m，4H)。

MS(m/z)：322[MH] ⁺。

Intermediate 12

N-(3-chloropropyl)-3-(2-oxo tetrahydropyrimidine-1 (2H)-yl)-1H-pyrazoles-1-methane amide

At room temperature at N ₂Following, to Intermediate 11(620mg adds KOt-Bu (237mg, 1.1 equivalents) in anhydrous THF (20mL) solution 1.93mmol).With reaction mixture in stirring at room 2 hours.Add entry and evaporating solvent then.With water with EtOAc (3 x 20mL) extraction, and with the organic extract that merges through anhydrous Na ₂SO ₄Dry.Filter this solid, and evaporating solvent.Crude product is passed through flash chromatography (Flash Master, 10g SiO ₂, cHex/EtOAc 7:3,100%EtOAc then) and purifying, obtain white solid Title compound(200mg, 37%).

NMR( ¹H，DMSO)：δ 8.23(t，1H)，8.06(d，1H)，6.93(bs，1H)，6.82(d，1H)，3.86(t，2H)，3.57(t，2H)，3.34(m，2H)，3.19(m，2H)，1.98(m，2H)，1.91(m，2H)。

MS(m/z)：286[MH] ⁺。

Intermediate 13

1-(1H-pyrazole-3-yl) tetrahydropyrimidine-2 (1H)-ketone

In air-tight bottle, with intermediate 12 (180mg, 0.63mmol) and LiOH (265mg, 10 equivalents) at MeOH/H ₂Solution in the 2:1 mixture (7.5mL) of O carried out microwave radiation (80 ℃) 10 minutes.Then reaction mixture is cooled to room temperature, and solvent evaporation is extremely done.Resistates gone up (EtOAc/MeOH 8:2,100%MeOH then) purifying at SCX post (cartridge), obtain white solid Mark The topic compound(102mg, 98%).

NMR( ¹H，DMSO)：δ 12.13(bs，1H)，7.50(s，1H)，6.60(bs，1H)，6.46(s，1H)，3.73(m，2H)，3.15(m，2H)，1.88(m，2H)。

MS(m/z)：167[MH] ⁺。

Intermediate 14

3-bromo-1-(trityl)-1H-pyrazoles

At room temperature at N ₂Down, to 3-bromo-pyrazoles (2.0g, anhydrous CH 13.6mmol) ₂Cl ₂(40mL) add trityl chloride (4.17g, 1.1 equivalents) and Et in the solution ₃N (2.1mL, 1.1 equivalents).With reaction mixture in stirring at room 4 hours.Be poured into water/CH ₂Cl ₂In.Separate two-phase, and CH is further used in the waterbearing stratum ₂Cl ₂(2 x 30mL) extraction.With the organic extract that merges through anhydrous Na ₂SO ₄Drying is filtered this solid, and evaporating solvent.Resistates is passed through flash chromatography (silica gel, 100%CH ₂Cl ₂) purifying, obtain white solid Title compound(3.39g, 64%).

NMR( ¹H，DMSO-d ₆)：δ 7.34(m，10H)，7.01(m，6H)，6.45(d，1H)。

MS(m/z)：412[M+Na] ⁺。

Intermediate 15

3-[1-(trityl)-1H-pyrazole-3-yl]-1,3-oxazolidine-2-ketone

Will Intermediate 14(389mg, 1mmol), 1,3-oxazolidine-2-ketone (87mg, 1mmol), CuI (20mg, 10mol%), (1R, 2R)-the diamino methylcyclohexane (43mg, 30mol%) and K ₂CO ₃(414mg, anhydrous NMP (2mL) mixture 3mmol) stirred 4 hours in 130 ℃ in air-tight bottle.Be poured among water/EtOAc.Separate two-phase, and EtOAc (2 x 10mL) extraction is further used in the waterbearing stratum.With the organic extract that merges through anhydrous Na ₂SO ₄Drying is filtered this solid, and evaporating solvent.Resistates by flash chromatography (silica gel, EtOAc/cHex 2:8) purifying, is obtained white solid Title chemical combination Thing(210mg, 53%).

NMR( ¹H，CDCl ₃)：δ 7.28(m，9H)，7.21(d，1H)，7.13(m，6H)，6.64(d，1H)，4.40(t，2H)，3.98(t，2H)。

MS(m/z)：418[M+Na] ⁺。

Intermediate 16

3-(1H-pyrazole-3-yl)-1,3-oxazolidine-2-ketone

At N ₂Following, to Intermediate 15(210mg, add in anhydrous MeOH (4mL) solution 0.53mmol) trifluoroacetic acid (0.2mL, 2.66mmol).Reaction mixture was carried out microwave radiation (100 ℃) 15 minutes.Evaporating solvent, and with resistates (100%CH on the SCX post ₂Cl ₂, 0.5M NH then ₃/ MeOH) purifying obtains white solid Title compound(30mg, 37%).

NMR( ¹H，DMSO-d ₆)：δ 7.64(d，1H)，6.40(d，1H)，4.41(t，2H)，3.97(t，2H)。

MS(m/z)：155[MH] ⁺。

Intermediate 17

N-1H-pyrazole-3-yl ethanamide

At 5-10 ℃, to 3-amino-pyrazol (20g, H 0.24mol) ₂Add NaHCO at leisure in O (36mL) solution ₃(9.1g, mol, 3 equivalents), and add Ac then ₂O (6.79ml, 2 equivalents).With reaction mixture refluxed 8 hours.It is cooled to room temperature, and under this temperature, leaves standstill and made its crystallization in 12 hours.Filter this white solid (12.9g), and reduce the mother liquor volume.Obtain second batch white solid (3.4g) after the crystallization.Merge this product of two batches, obtain Title compound(16.3g, 54%).

NMR( ¹H，DMSO-d ₆)：δ 12.22(bs，1H)，10.28(bs，1H)，7.53(bs，1H)，6.43(bs，1H)，1.96(s，1H)。

MS(m/z)：126[MH] ⁺，148[M+Na] ⁺。

Intermediate 18

N-(1-{6-methyl isophthalic acid-[2-methyl-4-(methoxyl group) phenyl]-2,3-dihydro-1H-pyrrolo-[2,3-b] pyridine -4-yl }-the 1H-pyrazole-3-yl) ethanamide

Will Intermediate 5(500mg, 1.32mmol), Intermediate 17(329mg, 2 equivalents), CuI (50mg, 0.2 equivalent), K ₂CO ₃(382mg, 2.1 equivalents), dodecane (60 μ L, 0.2 equivalent) and (+/-)-anti--1, the mixture of the anhydrous NMP (5mL) of 2-diamino-cyclohexane (45 μ L, 0.3 equivalent) in air-tight bottle in 150 ℃ of heating 4 hours.It is cooled to room temperature, and is poured into saturated NH ₄In the Cl aqueous solution.Add EtOAc, and separate two-phase.EtOAc (2 x 10mL) extraction is further used in the waterbearing stratum.With the organic extract that merges through anhydrous Na ₂SO ₄Drying is filtered this solid, and evaporating solvent.With resistates (silica gel, CH on the SCX post ₂Cl ₂, MeOH then, dense then NH ₄The MeOH solution of OH, 25:75) purifying, and then by flash chromatography (cHex/EtOAc 7:3) purifying obtains white solid Titleization Compound(358mg, 72%).

NMR( ¹H，DMSO-d ₆)：δ 10.62(bs，1H)，8.24(d，1H)，7.15(d，1H)，6.84(d，1H)，6.78-6.73(m，3H)，3.83(t，2H)，3.74(s，3H)，3.4(t，2H)，2.16(s，3H)，2.14(s，3H)，2.04(s，3H)。

MS(m/z)：378[MH] ⁺。

Intermediate 19

1-{6-methyl isophthalic acid-[2-methyl-4-(methoxyl group) phenyl]-2,3-dihydro-1H-pyrrolo-[2,3-b] pyridine-4- Base }-1H-pyrazoles-3-amine

At room temperature, to Intermediate 18(358mg 0.95mmol) adds 25% NaOH (2.5mL) in the dispersion liquid in EtOH (7mL), and reaction mixture was carried out microwave radiation (130 ℃) 20 minutes.Evaporation EtOH, and crude product distributed between the EtOAc and the saturated NaCl aqueous solution.Separate two-phase, and EtOAc (2 x 10mL) extraction is further used in the waterbearing stratum.With the organic extract that merges through anhydrous Na ₂SO ₄Drying is filtered this solid, and evaporating solvent, obtains Title compound(282mg, 89%) need not be further purified it and to be used for next step.

NMR( ¹H，DMSO-d ₆)：δ 7.98(d，1H)，7.12(d，1H)，6.83(d，1H)，6.75(dd，1H)，6.67(s，1H)，5.77(d，1H)，5.10(bs，2H)，3.78(t，2H)，3.74(s，3H)，3.35(t，2H)，2.13(s，3H)，2.12(s，3H)。

MS(m/z)：336[MH] ⁺。

Intermediate 20

N-(1-{6-methyl isophthalic acid-[2-methyl-4-(methoxyl group) phenyl]-2,3-dihydro-1H-pyrrolo-[2,3-b] pyridine -4-yl }-the 1H-pyrazole-3-yl) glycine ethyl ester

At room temperature at N ₂Down, (200mg adds NaH 60%/oil (26mg, 1.1 equivalents) in dry DMF 0.6mmol) (5mL) solution to intermediate 19.Reaction mixture in stirring at room 20 minutes, is dripped 2-ethyl bromoacetate (73 μ L, 1.1 equivalents) then, and with reaction mixture in 80 ℃ of heating.Continue to add alkyl bromides (5 x, 36 μ L, 5 x, 0.55 equivalent) in 80 ℃ with 7.2 hours times.Reaction mixture is cooled to room temperature, and is poured into H ₂Among the O.Add EtOAc, and separate two-phase.EtOAc (2 x 10mL) extraction is further used in the waterbearing stratum.With the organic extract that merges through anhydrous Na ₂SO ₄Drying is filtered this solid, and evaporating solvent.Resistates by flash chromatography (silica gel, cHex/EtOAc 7:3) purifying, is obtained yellow oil Title compound(155mg, 62%).

NMR( ¹H，DMSO-d ₆)：δ 8.09(d，1H)，7.13(d，1H)，6.83(d，1H)，6.76(dd，1H)，6.37(s，1H)，6.17(t，1H)，5.86(d，1H)，5.73(s，1H)，4.09(q，2H)，3.89(d，2H)，3.77(t，2H)，3.74(s，3H)，3.36(t，2H)，2.13(bs，6H)，1.17(t，3H)。

MS(m/z)：422[MH] ⁺。

Intermediate 21

2-[(1-{6-methyl isophthalic acid-[2-methyl-4-(methoxyl group) phenyl]-2,3-dihydro-1H-pyrrolo-[2,3-b] pyridine -4-yl }-the 1H-pyrazole-3-yl) amino] ethanol

At N ₂Down, to cold (78 ℃) 1N LiAlH ₄Drip in/THF (0.5mL, the 2.7 equivalents) solution In Mesosome 20(77.5mg, anhydrous THF (5mL) solution 0.184mmol).In-78 ℃ of stirred reaction mixtures 20 minutes.Under this temperature, continue to add 1N LiAlH with 40 minutes time ₄/ THF (3 x, 200 μ L, 3 x, 1.09 equivalents).In this reaction mixture, add entry (42 μ L), 1N NaOH (42 μ L) and water (125 μ L), and form precipitation.Filter this solid, and with EtOAc (2x) and CH ₂Cl ₂(2x) wash.The organic extract that concentrate to merge, and with resistates by flash chromatography (silica gel, cHex/EtOAc 7:3) purifying, obtain yellow solid Title compound(25mg, 36%).

NMR( ¹H，DMSO-d ₆)：δ 8.04(d，1H)，7.13(d，1H)，6.83(d，1H)，6.76(dd，1H)，6.66(s，1H)，5.82(d，1H)，5.58(t，1H)，4.59(t，1H)，3.78(t，2H)，3.74(s，3H)，3.55(q，2H)，3.40(t，2H)，3.20(q，2H)，2.13(bs，6H)。

MS(m/z)：380[MH] ⁺。

Intermediate 22

3-[(1-{6-methyl isophthalic acid-[2-methyl-4-(methoxyl group) phenyl]-2,3-dihydro-1H-pyrrolo-[2,3-b] pyridine -4-yl }-the 1H-pyrazole-3-yl) amino]-the 1-propanesulfonic acid

At room temperature at N ₂Following, to Intermediate 19(25mg adds 1 in n-BuOH 0.0746mmol) (1mL) suspension, 2-oxathiolane (oxathiolane) 2,2-dioxide (30 μ L, 3 equivalents).Reaction mixture is carried out microwave radiation (20+60+60 minute, T=150/180 ℃).Evaporating solvent, and with resistates by flash chromatography (silica gel, 100% EtOAc → 7:3 EtOAc/NH ₃MeOH solution (0.5M)) and SCX post (elutriant: MeOH and NH ₃MeOH solution (0.5M)) purifying, obtain yellow oil Title compound(10mg, 30%).

NMR( ¹H，CDCl ₃)：δ 7.54(bs，1H)，7.05(d，1H)，6.72(m，1H)，6.66(m，1H)，6.48(bs，1H)，5.78(bs，1H)，3.72(m，5H)，3.3(m，4H)，2.97(m，2H)，2.03-2.2(m，8H)。

MS(m/z)：458[MH] ⁺。

Intermediate 23

(1-{6-methyl isophthalic acid-[2-methyl-4-(methoxyl group) phenyl]-2,3-dihydro-1H-pyrrolo-[2,3-b] pyridine-4- Base }-the 1H-pyrazole-3-yl) phenyl carbamate

In 0 ℃ at N ₂Following, to Intermediate 19(391mg, anhydrous CH 1.17mmol) ₂Cl ₂(8mL) add pyridine (103 μ L, 1.1 equivalents) and chloroformic acid phenylester (161 μ L, 1.1 equivalents) in the suspension.With reaction mixture in stirring at room 1 hour.Vacuum evaporating solvent adds the saturated NaCl aqueous solution (50mL) then, and solution is extracted with EtOAc (3 x 15mL).With the organic extract that merges through anhydrous Na ₂SO ₄Drying is filtered this solid, and vacuum evaporating solvent.Thus obtained crude compound by flash chromatography (silica gel, the MeOH solution 0.5M of MeOH-ammoniacal liquor) purifying, is obtained the white solid of 284mg (53%) Title compound

NMR( ¹H，CDCl ₃)：δ 10.8(bs，1H)8.28(d，1H)，7.39(m，2H)，7.18(m，4H)，6.73(dd，1H)，6.64(s，1H)，3.81(t，2H)，3.72(s，3H)，3.32(t，2H)，2.14(s，3H)，2.12(s，3H)。

MS(m/z)：456[MH] ⁺。

Intermediate 24

(1-{6-methyl isophthalic acid-[2-methyl-4-(methoxyl group) phenyl]-2,3-dihydro-1H-pyrrolo-[2,3-b] pyridine-4- Base }-the 1H-pyrazole-3-yl) the carboxylamine phenylester

Will Intermediate 23(284mg, 0.62mmol), pyridine (50 μ L, 1.2 equivalents) and 2, the mixture of two (oxyethyl group) ethamine (108 μ L, 1.2 equivalents) of 2-was in 60 ℃ of heating 3 hours.Add H then ₂O (50mL), and with solution CH ₂Cl ₂(3 x 15mL) extraction.With the organic extract that merges through anhydrous Na ₂SO ₄Drying is filtered this solid, and vacuum evaporating solvent.Thus obtained crude compound by flash chromatography (silica gel, cHex/EtOAc 1:1) purifying, is obtained the title compound of the white solid of 214mg (84%).

NMR( ¹H，CDCl ₃)：δ 9.21(s，1H)，8.24(d，1H)，7.15(d，1H)，6.95(bs，1H)，6.95(d，1H)，6.78(dd，1H)，6.72(s，1H)，6.42(s，1H)，4.5(m，1H)，3.82(t，2H)，3.60(m，1H)，3.48(m，1H)，3.65(s，3H)，3.3(s，6H)，3.23(t，2H)，3.16(s，3H)，2.14(s，3H)。

MS(m/z)：495[MH] ⁺。

Intermediate 25

3-methyl isophthalic acid-[1-(trityl)-1H-pyrazole-3-yl]-2 (1H)-pyridones

Will Intermediate 14(300mg, 0.77mmol), 3-methylpyridone (168mg, 1 equivalent), CuI (146mg, 1 equivalent), K ₂CO ₃(223mg, 2.1 equivalents), N-N '-dimethyl be anti--and anhydrous NMP (4mL) solution of cyclohexane diamine (109mg, 0.5 equivalent) is in 150 ℃ of heating 24 hours.Add saturated NH then ₄The Cl aqueous solution (100mL), and with mixture CH ₂Cl ₂(250mL) extraction.With organic layer through anhydrous Na ₂SO ₄Drying is filtered this solid, and vacuum evaporating solvent.Thus obtained crude compound by flash chromatography (silica gel, cHex/EtOAc 95:5) purifying, is obtained 80mg (25%) white solid Title compound

NMR( ¹H，CDCl ₃)：δ 7.76(d，1H)，7.30(m，11H)，7.15(m，6H)，6.98(d，1H)，6.06(t，1H)，2.15(s，3H)。

MS(m/z)：440[M+Na]。

Intermediate 26

3-methyl isophthalic acid-(1H-pyrazole-3-yl)-2 (1H)-pyridones

At room temperature at N ₂Down, with CF ₃COOH (3mL) joins intermediate 25 (80mg, MeOH/CH 0.19mmol) ₂Cl ₂The solution of 2:1 anhydrous mixture (3mL) in.Solution was heated 18 hours in 80 ℃.Vacuum evaporating solvent.With thus obtained crude compound (1g, prerequisite CH on the SCX post ₂Cl ₂) purifying, obtain 13mg (39%) white solid Title compound

NMR( ¹H，CDCl ₃)：δ 7.61(d，1H)，7.55(s，1H)，7.24(m，1H)，7.1(d，1H)，6.76(d，1H)，6.16(t，1H)，2.15(s，3H)。

MS(m/z)：176[MH] ⁺。

Intermediate 27

2-[1-(trityl)-1H-pyrazole-3-yl]-3 (2H)-pyridazinones

Will Intermediate 14(200mg, 0.52mmol), pyridazinone (50mg, 1 equivalent), CuI (100mg, 1 equivalent), K ₂CO ₃(148mg, 2 equivalents) and N-N '-dimethyl be anti--and anhydrous NMP (4mL) solution of cyclohexane diamine (73mg, 0.5 equivalent) is in 150 ℃ of heating 8 hours.Add saturated NH then ₄The Cl aqueous solution (100mL), and with solution CH ₂Cl ₂(250mL) extraction.With organic layer through anhydrous Na ₂SO ₄Drying is filtered this solid, and vacuum evaporating solvent.Thus obtained crude compound by flash chromatography (silica gel, cHex/EtOAc 1:9) purifying, is obtained Title compoundNmp solution, it need be further purified be used for next step.

MS(m/z)：443[M+K]，427[M+Na]。

Intermediate 28

2-(1H-pyrazole-3-yl)-3 (2H)-pyridazinones

At room temperature at N ₂Down, with above-mentioned acquisition Intermediate 27Solution be dissolved in MeOH/CH ₂Cl ₂2:1 mixture (3mL) in, and add CF ₃COOH (2.5mL).Reaction mixture was heated 4 hours in 80 ℃.Vacuum evaporating solvent.With thus obtained crude compound (1g, prerequisite CH on the SCX post ₂Cl ₂) purifying, obtain the white solid of 20mg (24%, two is rapid step by step) Title compound

NMR( ¹H，CDCl ₃)：δ 7.91(d，1H)，7.59(m，1H)，7.24(m，1H)，7.07(m，1H)，6.76(d，1H)。

MS(m/z)：163[MH] ⁺

Intermediate 29

1-ethanoyl-3-{1-[1-(4-hydroxy-2-methyl phenyl)-6-methyl-2,3-dihydro-1H-pyrrolo-[2,3-b] Pyridin-4-yl]-the 1H-pyrazole-3-yl }-the 2-imidazolidone

At room temperature at N ₂Following, to Embodiment 1-6(80mg, anhydrous CH 0.179mmol) ₂Cl ₂Drip BBr in the solution (1.8mL) ₃1.0M/CH ₂Cl ₂(0.72mL, 5 equivalents).With reaction mixture in stirring at room 90 minutes.Add MeOH (1mL), and evaporating solvent.Resistates is absorbed the saturated NaHCO of EtOAc/ ₃In the aqueous solution, and separate two-phase.With waterbearing stratum CH ₂Cl ₂(2 x 10mL) extraction, and with the organic extract that merges through anhydrous Na ₂SO ₄Dry.Filter this solid, and evaporating solvent.Further (silica gel, 100%EtOAc → 5%MeOH/EtOAc) purifying obtain white solid by flash chromatography with crude compound Title compound(29mg, 37%).

NMR( ¹H，DMSO-d ₆)：δ 9.3(s，1H)，8.40(d，1H)，7.00(d，1H)，6.85(d，1H)，6.75(s，1H)，6.65(d，1H)，6.60(dd，1H)，4.00-3.70(m，6H)，3.40(t，2H)，2.45(s，3H)，2.15(s，3H)，2.05(s，3H)。

MS(m/z)：433[MH] ⁺。

Intermediate 30

1-ethanoyl-3-(1-{1-[4-(oxyethyl group)-2-aminomethyl phenyl]-6-methyl-2,3-dihydro-1H-pyrrolo- [2,3-b] pyridin-4-yl }-the 1H-pyrazole-3-yl)-the 2-imidazolidone

At room temperature at N ₂Following, to Intermediate 29(13.6mg adds NaH 60%/oil (2.5mg, 2 equivalents) in dry DMF 0.0315mmol) (1mL) solution, and with reaction mixture in stirring at room 20 minutes.Add iodoethane (10 μ L, 4 equivalents), and with reaction mixture in stirring at room 1 hour.Be poured in the saturated NaCl aqueous solution of EtOAc/, and separate two-phase.Organic layer is washed with the saturated NaCl aqueous solution (2 x 10mL), and through anhydrous Na ₂SO ₄Dry.Filter this solid, and evaporating solvent.Crude compound is passed through flash chromatography (silica gel, cHex/EtOAc 1:1) purifying.The blended fraction is passed through flash chromatography (silica gel, cHex/EtOAc 7:3) repurity.Obtain the title compound (5mg, 34%) of white solid.

NMR( ¹H，)：δ 7.87(d，1H)，7.13(d，1H)，6.95(d，1H)，6.79(d，1H)，6.74(d，1H)，6.53(s，1H)，4.11-3.97(m，6H)，3.86(t，2H)，3.43(t，2H)，2.58(s，3H)，2.31(s，3H)，2.09(s，3H)，1.39(t，3H)。

MS(m/z)：461[MH] ⁺。

Intermediate 31

1-ethanoyl-3-[1-(the 6-methyl isophthalic acid-and 2-methyl-4-[(1-methylethyl) the oxygen base] phenyl }-2, the 3-dihydro -1H-pyrrolo-[2,3-b] pyridin-4-yl)-the 1H-pyrazole-3-yl]-the 2-imidazolidone

At room temperature at N ₂Following, to Intermediate 29(14mg adds NaH 60%/oil (3mg, 2 equivalents) in dry DMF 0.032mmol) (1mL) solution, and with reaction mixture in stirring at room 20 minutes.Add 2-iodopropane (13 μ L, 4 equivalents), and with reaction mixture in stirring at room 1 hour.Be poured in the saturated NaCl aqueous solution of EtOAc/, and separate two-phase.Organic layer is washed with the saturated NaCl aqueous solution (2 x 10mL), and through anhydrous Na ₂SO ₄Dry.Filter this solid, and evaporating solvent.Crude compound is passed through flash chromatography (silica gel, cHex/EtOAc 2:8) purifying.Obtain transparent buttery Mark The topic compoundWith 1-(1-methylethyl)-3-[1-(6-methyl isophthalic acid-{ 2-methyl-4-[(1-methylethyl) oxygen base] phenyl }-2,3-dihydro-1H-pyrrolo-[2,3-b] pyridin-4-yl)-the 1H-pyrazole-3-yl]-inseparable 2:1 mixture (11mg, 79%) of 2-imidazolidone.

MS(m/z)：475[MH] ⁺。

Intermediate 32

1-(2,4 dichloro benzene base)-2-Pyrrolidone

As Intermediate 1Preparation, replace 4-methoxyl group-2-aminotoluene except using 2,4 dichloro aniline.

NMR( ¹H，CDCl ₃)：δ 7.18-7.35(m，3H)，3.72(t，2H)，2.53(t，2H)，2.22(t，2H)。

MS(m/z)：230[MH] ⁺。

Intermediate 33

1-(2,4 dichloro benzene base)-2-oxo-3-pyrrolidine carboxylic acid ethyl ester

At room temperature at N ₂Following, to Intermediate 32(3.6g, (EtO) 15.65mmol) ₂Drip t-BuOK 1M/THF (47mL, 3 equivalents) in the solution of CO (25.2mL, 13.2 equivalents).The reaction mixture that stirs in 80 ℃ of heating 2 hours, is cooled to room temperature with it then, and is poured on ice.Then mixture is used 6N HCl acidifying, used CH ₂Cl ₂(300mL) extraction is with saturated NaHCO ₃The aqueous solution (100mL), the saturated NaCl aqueous solution (100mL) and water (100mL) are washed.With organic layer through anhydrous Na ₂SO ₄Drying is filtered this solid, and evaporating solvent.Crude product by flash chromatography (silica gel, cHex/EtOAc 6:4) purifying, is obtained yellow oil Title compound(3.2g, 67%).

NMR( ¹H，DMSO-d ₆)：δ 7.61(s，1H)，7.44(m，2H)，4.16(q，2H)，3.80(m，2H)，3.61(t，1H)，2.51(m，2H)，1.24(t，3H)。

MS(m/z)：302[MH] ⁺。

Intermediate 34

1-(2,4 dichloro benzene base)-2-{[3-(oxyethyl group)-1-methyl-3-oxo-1-propylene-1-yl] imido grpup }-3- Pyrrolidine carboxylic acid's ethyl ester

To Intermediate 33Add POCl in the mixture of (0.5g, 1 equivalent) and (2Z)-3-amino-2-butylene acetoacetic ester (0.43g, 2 equivalents) ₃(4mL, 26 equivalents), and the reaction mixture that generates stirred 4 hours in 100 ℃.Then reaction mixture is cooled to room temperature, evaporation is poured on ice, with saturated NaHCO ₃The aqueous solution neutralizes, and extracts with EtOAc (200mL).With organic layer through anhydrous Na ₂SO ₄Drying is filtered this solid, and evaporating solvent.Crude product need be further purified be used for next step.

MS(m/z)：413[M] ⁺。

Intermediate 35

1-(2,4 dichloro benzene base)-6-methyl isophthalic acid, 2,3,7-tetrahydrochysene-4H-pyrrolo-[2,3-b] pyridine-4-ketone

At room temperature at N ₂Down, with thick Intermediate 34Dry DMF (10mL) solution join in dry DMF (10mL) suspension of NaH60%/oil (111mg, 2 equivalents).Reaction mixture was heated 6 hours in 100 ℃.Then mixture is cooled to room temperature, and with saturated NH ₄The Cl aqueous solution is with pH regulator to 5.Then with reaction mixture at the saturated NH of EtOAc/ ₄Distribute between the Cl aqueous solution (200mL/100mL).Separate two-phase, and with organic layer through anhydrous Na ₂SO ₄Drying is filtered this solid, evaporating solvent, and with crude product by flash chromatography (silica gel, cHex/EtOAc 1:1 → EtOAc/MeOH 1:1) purifying, obtain brown oil Title compound(0.038g, 7%, two is rapid step by step).

NMR( ¹H，CDCl ₃)：δ 7.33(m，2H)，7.17(m，1H)，6.00(s，1H)，2.88(t，2H)，2.98(t，2H)，2.22(s，3H)。

MS(m/z)：295[M] ⁺。

Intermediate 36

1-(2,4 dichloro benzene base)-6-methyl-2,3-dihydro-1H-pyrrolo-[2,3-b] pyridin-4-yl fluoroform sulphur Acid esters

As Intermediate 4Preparation.

NMR( ¹H，CDCl ₃)：δ 7.48(s，1H)，7.34(d，1H)，7.26(d，1H)，6.35(s，1H)，4.01(t，2H)，3.25(t，2H)，2.32(s，3H)。

MS(m/z)：427[M] ⁺。

Intermediate 37

1-(2,4 dichloro benzene base)-4-iodo-6-methyl-2,3-dihydro-1H-pyrrolo-[2,3-b] pyridine

As Intermediate 5Preparation.

NMR( ¹H，CDCl ₃)：δ 7.42(m，3H)，6.81(s，1H)，3.96(t，2H)，3.04(t，2H)，2.24(s，3H)。

MS(m/z)：405[M] ⁺。

Intermediate 38

2-chloro-6-methyl-4-[3-(2-oxo-imidazole alkane-1-yl)-1H-pyrazol-1-yl] Nikithan

At room temperature at N ₂Following, to Intermediate 8Add NaH 60%/oil (1.7g, 1 equivalent) in dry DMF (150mL) solution of (9.73g, 1.5 equivalents), and with reaction mixture in stirring at room 20 minutes.Drip 2 then, 4-two chloro-6-methyl-3-pyridine carboxylic acid ethyl ester solution (10g, 42.9mmol), and in 80 ℃ of stirred reaction mixtures 4 hours.Then it is cooled to room temperature, and stops with frozen water.Adding EtOAc makes formation precipitate.Filter and collect white solid, wash with water, and vacuum-drying (5.2g).Filtrate is transferred in the separating funnel, and the waterbearing stratum is extracted with EtOAc (2 x 100mL).The organic layer that merges is washed with the saturated NaCl aqueous solution, through anhydrous Na ₂SO ₄Drying is filtered this solid, and evaporating solvent.Crude product is handled with EtOAc, and it is at room temperature spent the night.Filtering precipitate, vacuum-drying, and mix with preceding a collection of product obtains white solid Title compound(7.2g, 48%).

NMR( ¹H，DMSO-d ₆)：δ 8.53(d，1H)，7.77(s，1H)，7.18(bs，1H)，6.89(d，1H)，4.32(q，2H)，3.75(t，2H)，3.42(t，2H)，3.31(s，3H)，1.26(t，3H)。

MS(m/z)：350[MH] ⁺。

Intermediate 39

1-{1-[2-chloro-3-(hydroxymethyl)-6-methyl-4-pyridyl]-the 1H-pyrazole-3-yl }-the 2-imidazolidone

At 0 ℃ at N ₂Following, to Intermediate 38(7.2g, anhydrous CH 20.6mmol) ₂Cl ₂(120mL) drip DIBA1-H1M/CH in the suspension ₂Cl ₂(41.2mL, 2 equivalents).After adding the solution that generates is warmed to room temperature and stirred 2 hours.Add more that the DIBAl-H of volume finishes (3 x 20.5mL) until reaction,, at room temperature stirred then 1 hour at every turn in 0 ℃ of cooling.Reaction mixture is cooled to 0 ℃ then, stops by adding Rochelle salts solution (50mL) at leisure, and under room temperature, stir and spend the night.With white lattice (lattice) Roschell ' the s salts solution of 4L and the CH of 3L ₂Cl ₂Handle, and at room temperature stirred 20 hours.Separate two-phase, and with waterbearing stratum CH ₂Cl ₂(5 x 500mL) extraction.The organic extract that merges is washed with the saturated NaCl aqueous solution, through anhydrous Na ₂SO ₄Drying is filtered this solid, and evaporating solvent, obtains white solid Title compound(4g, 63%).

NMR( ¹H，DMSO-d ₆)：δ 8.36(d，1H)，7.49(s，1H)，7.12(bs，1H)，6.86(d，1H)，5.47(t，1H)，4.61(d，2H)，3.88(t，2H)，3.44(t，2H)，3.30(s，3H)。

MS(m/z)：308[MH] ⁺。

Intermediate 40

1-{1-[2-chloro-3-(hydroxymethyl)-6-methyl-4-pyridyl]-the 1H-pyrazole-3-yl }-3-{[4-(methoxyl group) Phenyl] methyl }-the 2-imidazolidone

At room temperature at N ₂Following, to Intermediate 39(100mg adds NaH 60%/oil (13mg, 1 equivalent) in dry DMF 0.325mmol) (6.5mL) suspension.At room temperature stirred reaction mixture is until obtaining yellow solution (about 10 minutes).After being cooled to 0 ℃, add 1-(chloromethyl)-4-(methoxyl group) benzene (44 μ L, 1 equivalent), and reaction mixture was stirred 1.5 hours.It is distributed between the saturated NaCl aqueous solution of EtOAc/, separates two-phase, and with organic layer through anhydrous Na ₂SO ₄Dry.Filter this solid, and evaporating solvent.(silica gel, EtOAc/cHex 6:4 → 7:3) purifying obtain white solid by flash chromatography with crude product Title compound(45.5mg, 33%).

NMR( ¹H，CDCl ₃)：δ 7.85(d，1H)，7.20(dd，2H)，7.15(d，1H)，7.10(s，1H)，6.89(dd，2H)，4.85(s，2H)，4.40(s，2H)，3.84(t，2H)，3.80(s，3H)，3.43(t，2H)，2.6(s，3H)。

MS(m/z)：428[MH] ⁺，450[M+23] ⁺。

Intermediate 41

2-chloro-6-methyl-4-[3-(3-{[4-(methoxyl group) phenyl] methyl }-2-oxo-1-imidazolidyl)-the 1H-pyrrole Azoles-1-yl]-the 3-pyridylaldehyde

To Intermediate 40(925mg, CH 2.16mmol) ₂Cl ₂(90mL) add DessMartin with three batches in the solution and cross iodine alkane (1.38g, 1.5 equivalents), and with reaction mixture in stirring at room 2 hours.Add more that the Dess Martin of volume crosses iodine alkane (750mg, 0.2 equivalent), and with reaction mixture restir 30 minutes.Add Na ₂S ₂O ₃The saturated NaHCO of (5 equivalent) ₃The aqueous solution (100mL), and separate two-phase.With waterbearing stratum CH ₂Cl ₂(3 x 50mL) extraction, and with the organic extract that merges through anhydrous Na ₂SO ₄Drying is filtered this solid, and evaporating solvent.(silica gel, EtOAc/cHex6:4 → 7:3) purifying obtain white solid by flash chromatography with crude product Title compound(520mg, 57%).

NMR( ¹H，CDCl ₃)：δ 10.26(s，1H)，7.85(d，1H)，7.23(dd，2H)，7.20(s，1H)，7.13(d，1H)，6.89(dd，2H)，4.41(s，2H)，3.84(t，2H)，3.80(s，3H)，3.39(t，2H)，2.6(s，3H)。

MS(m/z)：426[MH] ⁺。

Intermediate 42

1-(1-{2-chloro-6-methyl-3-[(E)-2-(methoxyl group) vinyl]-the 4-pyridyl }-1H-pyrazoles-3- Base)-and 3-{[4-(methoxyl group) phenyl] methyl }-the 2-imidazolidone

Under 0 ℃ at N ₂N-BuLi 1.6M/ hexane (0.44mL, 3 equivalents) is added drop-wise in THF (5mL) suspension of (methoxymethyl)-triphenyl phosphorus chloride (224mg, 3 equivalents) down.After adding reaction mixture is warmed to room temperature and stirred 20 minutes.Add Intermediate 41(100mg, THF 0.235mmol) (8mL) solution, and at room temperature with reaction mixture restir 1.5 hours.With the mixture water treatment, add EtOAc, and separate two-phase.With organic layer through anhydrous Na ₂SO ₄Drying is filtered this solid, and vacuum evaporating solvent is resistates, with its (100%cHex → cHex/EtOAc 7:3) purifying on the SCX post, obtains anti-: along the white solid of isomer 7:3 mixture Title compound(68mg, 63%).

NMR( ¹H，CDCl ₃)：δ 7.36(d，1H)，7.24(m，3H)，6.99(d，1H)，6.87(d，2H)，6.58(d，2H)，5.59(d，2H)，4.40(s，2H)，3.89(m，2H)，3.78(s，3H)，3.64(s，3H)，3.37(m，2H)，2.50(s，3H)。

MS(m/z)：454[MH] ⁺。

Intermediate 43

2-chloro-6-methyl-4-[3-(3-{[4-(methoxyl group) phenyl] methyl }-2-oxo-1-imidazolidyl)-the 1H-pyrrole Azoles-1-yl]-the 3-pyridyl } acetaldehyde

At room temperature, to Intermediate 42(5.5g adds 6.0MHCl (60mL, 28.4 equivalents) in THF 12.5mmol) (120mL) solution, and reaction mixture was stirred 18 hours.With reaction mixture with saturated NaHCO ₃The aqueous solution stops until reaching neutral pH, and part is removed and desolvated, and crude mixture is distributed between EtOAc/ water.Separate two-phase, and organic layer is washed with the saturated NaCl aqueous solution (2 x 10mL).With it through anhydrous Na ₂SO ₄Drying is filtered this solid, and evaporating solvent.Crude product by flash chromatography (silica gel, cHex/EtOAc 4:6) purifying, is obtained white solid Title compound(4.6g, 86%).

NMR( ¹H，CDCl ₃)：δ 9.73(s，1H)，7.70(d，1H)，7.23(d，2H)，7.06(m，2H)，6.88(d，2H)，4.40(s，2H)，4.01(s，2H)，3.80(s，3H)，3.76(t，2H)，3.37(t，2H)，2.58(s，3H)。

MS(m/z)：440[MH] ⁺。

Intermediate 44

1-{1-[2-chloro-3-(2-hydroxyethyl)-6-methyl-4-pyridyl]-the 1H-pyrazole-3-yl }-3-{[4-(methoxy Base) phenyl] methyl }-the 2-imidazolidone

Under 0 ℃ at N ₂Following, to Intermediate 43(4.4g, the NaBH of adding small portion in anhydrous MeOH (100mL) solution 9.96mmol) ₄(397mg, 1.0 equivalents), and reaction mixture is warmed to room temperature, and stirred 30 minutes.The reaction mixture water is stopped, remove partial solvent, and between EtOAc/ water, distribute.Separate two-phase, and organic layer is washed with the saturated NaCl aqueous solution (2 x 10mL).With it through anhydrous Na ₂SO ₄Drying is filtered this solid, and evaporating solvent.Crude product by flash chromatography (silica gel, cHex/EtOAc 1:1) purifying, is obtained white solid Title compound(4.26g, 96%).

NMR( ¹H，CDCl ₃)：δ 7.65(d，1H)，7.24(d，2H)，7.09(d，1H)，6.97(s，1H)，6.89(d，2H)，4.45(s，2H)，3.96(m，4H)，3.83(s，3H)，3.41(t，2H)，3.14(t，2H)，2.55(s，3H)。

MS(m/z)：442[MH] ⁺。

Intermediate 45

1-{1-[2-chloro-3-(2-{[(1,1-dimethyl ethyl) (dimethyl) silyl] the oxygen base } ethyl)-the 6-methyl -4-pyridyl]-the 1H-pyrazole-3-yl }-3-{[4-(methoxyl group) phenyl] methyl }-the 2-imidazolidone

Under 0 ℃ at N ₂Following, to Intermediate 44(4.26g adds imidazoles (7.19g, 11 equivalents), DMAP (122mg, 0.1 equivalent), TBDMSCl (4.07g, 2.8 equivalents) in dry DMF 7.66mmol) (100mL) solution, and reaction mixture is warmed to room temperature and stirs 1 hour.Then with it at the saturated NH of EtOAc/ ₄Distribute between the Cl aqueous solution.Separate two-phase, and organic layer is washed with the saturated NaCl aqueous solution (2 x 10mL).With it through anhydrous Na ₂SO ₄Drying is filtered this solid, and evaporating solvent.Crude product by flash chromatography (silica gel, cHex/EtOAc 7:3) purifying, is obtained yellow oil Title Compound(4.92g, 92%).

NMR( ¹H，CDCl ₃)：δ 8.05(d，1H)，7.28(d，2H)，7.15(s，1H)，7.05(d，1H)，6.91(d，2H)，4.45(s，2H)，3.96(m，4H)，3.83(s，3H)，3.40(t，2H)，3.14(t，2H)，2.55(s，3H)，0.83(s，9H)，0.00(s，6H)。

MS(m/z)：556[MH] ⁺。

Intermediate 46

1-{1-[3-(2-{[(1,1-dimethyl ethyl) (dimethyl) silyl] the oxygen base } ethyl)-the 6-methyl -2-(2-methyl-4-[(trifluoromethyl) and the oxygen base] phenyl } amino)-the 4-pyridyl]-1H-pyrazoles-3- Base }-3-{[4-(methoxyl group) phenyl] methyl }-the 2-imidazolidone

At room temperature at N ₂Following, to Intermediate 45(500mg adds Pd in anhydrous DME (10mL) solution 0.703mmol) ₂(dba) ₃(82mg, 0.1 equivalent), dicyclohexyl (2 '-methyl-2-xenyl) phosphine (98mg, 0.3 equivalent), K ₃PO ₄(573mg, 3 equivalents) and 2-methyl-4-[(trifluoromethyl) the oxygen base] aniline (258mg, 1.5 equivalents), and stirred reaction mixture, and reflux 3 hours.Then with it at the saturated NH of EtOAc/ ₄Distribute between the Cl aqueous solution.Separate two-phase, and organic layer is washed with the saturated NaCl aqueous solution (2 x 10mL).With it through anhydrous Na ₂SO ₄Drying is filtered this solid, and evaporating solvent.Crude product by flash chromatography (silica gel, cHex/EtOAc 7:3) purifying, is obtained white solid Title chemical combination Thing(555mg, 86%).

NMR( ¹H，CDCl ₃)：δ 7.97(m1H)，7.63(m，2H)，7.44(m，1H)，7.28(d，2H)，7.01(m，2H)，6.91(m，2H)，6.62(s，1H)，4.45(s，2H)，4.18(t，2H)，3.88(t，2H)，3.83(s，3H)，3.41(t，2H)，2.87(t，2H)，2.47(s，3H)，2.31(s，3H)，0.84(s，9H)，0.00(s，6H)。

MS(m/z)：711[MH] ⁺。

Intermediate 47

1-{1-[3-(2-hydroxyethyl)-6-methyl-2-(2-methyl-4-[(trifluoromethyl) and the oxygen base] phenyl } ammonia Base)-the 4-pyridyl]-the 1H-pyrazole-3-yl }-3-{[4-(methoxyl group) phenyl] methyl }-the 2-imidazolidone

At room temperature at N ₂Following, to Intermediate 46(555mg adds Et in anhydrous THF (5mL) solution 0.930mmol) ₃N3HF (637 μ L, 5 equivalents), and with reaction mixture in stirring at room 18 hours.Then it is distributed between EtOAc/ water.Separate two-phase, and organic layer is washed with the saturated NaCl aqueous solution (2 x 10mL).With it through anhydrous Na ₂SO ₄Drying is filtered this solid, and evaporating solvent.Crude product by flash chromatography (silica gel, cHex/EtOAc 1:1) purifying, is obtained white solid Titleization Compound(281mg, 60%).

NMR( ¹H，CDCl ₃)：δ 7.92(d，1H)，7.61(d，1H)，7.35(s，1H)，7.25(d，2H)，7.01(m，2H)，6.89(d，2H)，6.58(s，1H)，4.41(s，2H)，4.14(m，2H)，3.86(t，2H)，3.80(s，3H)，3.38(t，2H)，2.88(t，2H)，2.44(s，3H)，2.28(s，3H)。

MS(m/z)：597[MH] ⁺。

Intermediate 48

1-[1-(the 6-methyl isophthalic acid-and 2-methyl-4-[(trifluoromethyl) the oxygen base] phenyl }-2,3-dihydro-1H-pyrrolo- [2,3-b] pyridin-4-yl)-the 1H-pyrazole-3-yl]-3-{[4-(methoxyl group) phenyl] methyl }-the 2-imidazolidone

At N ₂Following, to Intermediate 47(281mg, CH 0.486mmol) ₂Cl ₂(10mL) add I in the solution ₂(240mg, 2 equivalents), PPh ₃(247mg, 2 equivalents) and Et ₃N (131 μ L, 2 equivalents), and with reaction mixture in stirring at room 2 hours.Evaporating solvent then, and with crude product (100%CH on the SCX post ₂Cl ₂→ 2.0M Et ₃The MeOH solution of N) and through flash chromatography (silica gel, cHex/EtOAc 1:1) purifying, obtain white solid Title compound(168mg, 62%).

NMR( ¹H，CDCl ₃)：δ 7.84(d，1H)，7.29(d，1H)，7.26(d，2H)，7.08(m，3H)，6.89(d，2H)，6.62(s，1H)，4.42(s，2H)，3.91(m，4H)，3.81(s，3H)，3.48(t，2H)，3.40(t，2H)，2.36(s，3H)，2.29(s，3H)。

MS(m/z)：579[MH] ⁺。

Intermediate 49

4-(3-(2-{[(1,1-dimethyl ethyl) (dimethyl) silyl] and the oxygen base } ethyl)-the 6-methyl -4-[3-(3-{[4-(methoxyl group) phenyl] methyl }-2-oxo-1-imidazolidyl)-the 1H-pyrazol-1-yl]-the 2-pyridine Base } amino)-3-methyl benzonitrile

According to Intermediate 46Preparation replaces 2-methyl-4-[(trifluoromethyl except using 4-amino-3-methyl benzonitrile) the oxygen base] aniline.

NMR ( ¹H, CDCl ₃): δ 8.21 (d, 1H), 7.89 (s, 1H), 7.6 (d, 1H), 7.42 (dd, 1H), 7.36 (bs, 1H), 7.23 (d, 2H), 6.99 (d, 1H), 6.87 (d, 2H), 6.71 (s, 1H), 4.41 (s, 2H), 4.19 (m, 2H), 4.04 (wide, 2H), 3.79 (s, 3H), 3.36 (t, 2H), 2.85 (t, 2H), 2.5 (s, 3H), 2.3 (s, 3H), 0.77 (s, 9H) ,-0.08 (s, 6H).

MS(m/z)：652[MH] ⁺。

Intermediate 50

4-(3-(2-hydroxyethyl)-6-methyl-4-[3-(3-{[4-(methoxyl group) phenyl] methyl }-2-oxo-1-miaow Oxazolidinyl)-the 1H-pyrazol-1-yl]-the 2-pyridyl } amino)-3-methyl benzonitrile

According to Intermediate 47Preparation.

NMR( ¹H，CDCl ₃)：δ 8.14(d，1H)，7.92(s，1H)，7.61(d，1H)，7.46(dd，1H)，7.4(bs，1H)，7.23(d，2H)，7.02(d，1H)，6.87(d，2H)，6.69(s，1H)，4.4(s，2H)，4.2(m，2H)，3.84(t，2H)，3.79(s，3H)，3.37(t，2H)，3.15(bs，1H)，2.86(m，2H)，2.48(s，3H)，2.28(s，3H)。

MS(m/z)：538[MH] ⁺。

Intermediate 51

3-methyl-4-{6-methyl-4-[3-(3-{[4-(methoxyl group) phenyl] methyl }-2-oxo-1-imidazolidine Base)-and the 1H-pyrazol-1-yl]-2,3-dihydro-1H-pyrrolo-[2,3-b] pyridine-1-yl } benzonitrile

According to Intermediate 48Preparation.

NMR( ¹H，CDCl ₃)：δ 7.83(d，1H)，7.54(bs，1H)，7.48(dd，1H)，7.35(d，1H)，7.23(d，2H)，7.02(d，1H)，6.87(d，2H)，6.67(s，1H)，4.41(s，2H)，3.94(m，4H)，3.79(s，3H)，3.48(t，2H)，3.38(t，2H)，2.34(s，3H)，2.29(s，3H)。

MS(m/z)：520[MH] ⁺。

Intermediate 52

1-[1-(3-(2-{[(1,1-dimethyl ethyl) (dimethyl) silyl] the oxygen base } ethyl)-the 6-methyl -2-{[2-methyl-4-(1H-pyrazol-1-yl) phenyl] amino }-the 4-pyridyl)-the 1H-pyrazole-3-yl]-3-{[4-(first The oxygen base) phenyl] methyl }-the 2-imidazolidone

According to Intermediate 46Preparation is except using Intermediate 83(2-methyl-4-(1H-pyrazol-1-yl) aniline) replaces 2-methyl-4-[(trifluoromethyl) the oxygen base] aniline.

NMR( ¹H，CDCl ₃)：δ 8.07(d，1H)，7.88(d，1H)，7.70(s，1H)，7.57(m，3H)，7.46(dd，1H)，7.25(d，2H)，7.03(d，1H)，6.91(d，2H)，6.60(s，1H)，6.45(t，1H)，4.44(s，2H)，4.18(t，2H)，3.92(t，2H)，3.88(s，3H)，3.40(s，2H)，2.87(t，2H)，2.46(s，3H)，2.36(s，3)，0.84(s，9H)，0.00(s，6H)。

MS(m/z)：693[MH] ⁺。

Intermediate 53

1-[1-(3-(2-hydroxyethyl)-6-methyl-2-{[2-methyl-4-(1H-pyrazol-1-yl) phenyl] amino }-4- Pyridyl)-the 1H-pyrazole-3-yl]-3-{[4-(methoxyl group) phenyl] methyl }-the 2-imidazolidone

According to Intermediate 47Preparation.

NMR( ¹H，CDCl ₃)：δ 7.94(d，1H)，7.81(d，1H)，7.65(d，1H)，7.57(m，2H)，7.48(d，1H)，7.38(dd，1H)，7.22(d，2H)，6.97(d，1H)，6.86(d，2H)，6.54(s，1H)，6.37(t，1H)，4.38(t，2H)，4.10(m，2H)，3.82(t，2H)，3.78(s，3H)，3.32(t，2H)，2.83(t，2H)，2.40(s，3H)，2.27(s，3H)。

MS(m/z)：579[MH] ⁺。

Intermediate 54

1-(1-{6-methyl isophthalic acid-[2-methyl-4-(1H-pyrazol-1-yl) phenyl]-2,3-dihydro-1H-pyrrolo-[2,3-b] Pyridin-4-yl }-the 1H-pyrazole-3-yl)-3-{[4-(methoxyl group) phenyl] methyl }-the 2-imidazolidone

According to Intermediate 48Preparation.

NMR( ¹H，CDCl ₃)：δ 7.90(d，1H)，7.85(d，1H)，7.71(m，1H)，7.67(m，1H)，7.63(m，1H)，7.36(d，1H)，7.24(d，2H)，7.03(d，1H)，6.90(d，2H)，6.62(s，1H)，6.45(t，1H)，4.43(s，2H)，3.96(m，4H)，3.81(s，3H)，3.49(t，2H)，3.40(t，2H)，2.34(s，3H)，2.29(s，6H)。

MS(m/z)：561[MH] ⁺。

Intermediate 55

4-(3-(2-{[(1,1-dimethyl ethyl) (dimethyl) silyl] and the oxygen base } ethyl)-the 6-methyl -4-[3-(3-{[4-(methoxyl group) phenyl] methyl }-2-oxo-1-imidazolidyl)-the 1H-pyrazol-1-yl]-the 2-pyridine Base } amino)-3-(trifluoromethyl) benzonitrile

According to Intermediate 46Preparation replaces 2-methyl-4-[(trifluoromethyl except using 4-amino-3-(trifluoromethyl) benzonitrile) the oxygen base] aniline.

NMR( ¹H，CDCl ₃)：δ 8.41(d，1H)，8.32(s，1H)，7.92(d，1H)，7.74(m，2H)，7.35(m，3H)，7.12(d，1H)，6.96(d，2H)，4.52(s，2H)，4.18(t，2H)，4.00(m，2H)，3.90(s，3H)，3.48(t，2H)，3.21(t，2H)，2.63(s，3H)，0.91(s，9H)，0.07(s，6H)。

MS(m/z)：706[MH] ⁺。

Intermediate 56

4-(3-(2-hydroxyethyl)-6-methyl-4-[3-(3-{[4-(methoxyl group) phenyl] methyl }-2-oxo-1-miaow Oxazolidinyl)-the 1H-pyrazol-1-yl]-the 2-pyridyl } amino)-3-(trifluoromethyl) benzonitrile

According to Intermediate 47Preparation.

NMR( ¹H，CDCl ₃)：δ 8.28(d，1H)，8.20(s，1H)，7.77(d，1H)，7.61(dd，1H)，7.56(d，1H)，7.16(d，2H)，6.98(d，1H)，6.81(d，2H)，6.72(s，1H)，6.14(t，1H)，4.35(s，2H)，4.06(t，2H)，3.78(t，2H)，3.73(s，3H)，3.32(t，2H)，2.84(t，2H)，2.43(s，3H)。

MS(m/z)：592[MH] ⁺。

Intermediate 57

4-{6-methyl-4-[3-(3-{[4-(methoxyl group) phenyl] methyl }-2-oxo-1-imidazolidyl)-the 1H-pyrazoles -1-yl]-2,3-dihydro-1H-pyrrolo-[2,3-b] pyridine-1-yl }-3-(trifluoromethyl) benzonitrile

According to Intermediate 48Preparation.

NMR( ¹H，CDCl ₃)：δ 8.00(d，1H)，7.85(d，1H)，7.81(dd，1H)，7.68(d，1H)，7.25(d，2H)，7.05(d，1H)，6.89(d，2H)，6.75(s，1H)，4.42(s，2H)，3.93(m，4H)，3.52(t，2H)，3.48(s，3H)，3.40(t，2H)，2.35(s，3H)。

MS(m/z)：574[MH] ⁺。

Intermediate 58

1-{1-[2-{[2-(difluoromethyl)-4-(methoxyl group) phenyl] amino }-3-(2-{[(1,1-dimethyl second Base) (dimethyl) silyl] the oxygen base } ethyl)-6-methyl-4-pyridyl]-the 1H-pyrazole-3-yl }-3-{[4-(first The oxygen base) phenyl] methyl }-the 2-imidazolidone

According to Intermediate 46Preparation is except using Intermediate 87(2-(difluoromethyl)-4-(methoxyl group) aniline) replaces 2-methyl-4-[(trifluoromethyl) the oxygen base] aniline.

NMR( ¹H，CDCl ₃)：δ 7.62(d，1H)，7.56(d，1H)，7.50(s，1H)，7.26(d，2H)，7.13(d，1H)，7.01-6.98(m，2H)，6.87-6.92(m，2H)，6.73(t，1H，J _(H-F)＝56.1Hz)，6.55(s，1H)，4.44(s，2H)，4.11(t，2H)，3.86(t，2H)，3.84(s，3H)，3.82(s，3H)，3.39(t，2H)，2.84(t，2H)，2.35(s，3H)，0.82(s，9H)，0.00(s，6H)。

MS(m/z)：693[MH] ⁺。

Intermediate 59

1-{1-[2-{[2-(difluoromethyl)-4-(methoxyl group) phenyl] amino }-3-(2-hydroxyethyl)-6-methyl-4- Pyridyl]-the 1H-pyrazole-3-yl }-3-{[4-(methoxyl group) phenyl] methyl }-the 2-imidazolidone

According to Intermediate 47Preparation.

NMR( ¹H，DMSO-d ₆)：δ 8.32(bs，1H)，8.02(d，1H)，7.34-7.30(m，1H)，7.21(d，2H)，7.05-7.07(m，2H)，6.9(d，2H)，6.86(t，1H，J _H-F＝54.9Hz)，6.76(d，1H)，6.63(s，1H)，5.29(t，1H)，4.31(s，2H)，3.73-3.84(m，10H)，3.34(t，2H)，2.77(t，2H)，2.19(s，3H)。

MS(m/z)：579[MH] ⁺。

Intermediate 60

1-(1-{1-[2-(difluoromethyl)-4-(methoxyl group) phenyl]-6-methyl-2,3-dihydro-1H-pyrrolo-[2,3-b] Pyridin-4-yl }-the 1H-pyrazole-3-yl)-3-{[4-(methoxyl group) phenyl] methyl }-the 2-imidazolidone

According to Intermediate 48Preparation.

NMR( ¹H，CDCl ₃)：δ 7.84(d，1H)，7.21-7.26(m，4H)，7.02-7.06(m，2H)，6.87-6.89(m，2H)，6.87(t，1H，J _(H-F)＝55.5Hz)，6.64(s，1H)，4.23(s，2H)，3.81-3.97(m，10H)，3.37-3.49(m，4H)，2.32(s，3H)。

MS(m/z)：561[MH] ⁺。

Intermediate 61

4-(3-(2-{[(1,1-dimethyl ethyl) (dimethyl) silyl] and the oxygen base } ethyl)-the 6-methyl -4-[3-(3-{[4-(methoxyl group) phenyl] methyl }-2-oxo-1-imidazolidyl)-the 1H-pyrazol-1-yl]-the 2-pyridine Base } amino)-the 3-[(trifluoromethyl) the oxygen base] benzonitrile

According to Intermediate 46Preparation is except using 4-amino-3-[(trifluoromethyl) the oxygen base] benzonitrile replacement 2-methyl-4-[(trifluoromethyl) the oxygen base] aniline.

MS(m/z)：722[MH] ⁺。

Intermediate 62

4-(3-(2-hydroxyethyl)-6-methyl-4-[3-(3-{[4-(methoxyl group) phenyl] methyl }-2-oxo-1-miaow Oxazolidinyl)-the 1H-pyrazol-1-yl]-the 2-pyridyl } amino)-the 3-[(trifluoromethyl) the oxygen base] benzonitrile

According to Intermediate 47Preparation.

NMR( ¹H，CDCl ₃)：δ 8.84(d，1H)，8.56(d，1H)，7.61(d，1H)，7.5(dd，1H)，7.48(bs，1H)，7.23(d，2H)，7.02(d，1H)，6.87(d，2H)，6.87(d，2H)，6.74(s，1H)，4.4(s，2H)，4.2(m，2H)，3.84(t，2H)，3.79(s，3H)，3.37(t，2H)，3.1(bs，1H)，2.86(m，2H)，2.5(s，3H)。

MS(m/z)：608[MH] ⁺。

Intermediate 63

4-{6-methyl-4-[3-(3-{[4-(methoxyl group) phenyl] methyl }-2-oxo-1-imidazolidyl)-the 1H-pyrazoles -1-yl]-2,3-dihydro-1H-pyrrolo-[2,3-b] pyridine-1-yl }-the 3-[(trifluoromethyl) the oxygen base] benzonitrile

According to Intermediate 48Preparation.

NMR( ¹H，CDCl ₃)：δ 8.05(d，1H)，7.84(m，1H)，7.54(bs，1H)，7.5(m，1H)，7.23(m，1H)，7.03(m，1H)，6.87(d，2H)，6.78(s，1H)，4.41(s，2H)，4.11(m，2H)，3.91(m，2H)，3.79(s，3H)，3.5(t，2H)，3.38(t，2H)，2.41(s，3H)。

MS(m/z)：590[MH] ⁺。

Intermediate 64

4-(3-(2-{[(1,1-dimethyl ethyl) (dimethyl) silyl] and the oxygen base } ethyl)-the 6-methyl -4-[3-(3-{[4-(methoxyl group) phenyl] methyl }-2-oxo-1-imidazolidyl)-the 1H-pyrazol-1-yl]-the 2-pyridine Base } amino)-3-ethyl benzonitrile

According to Intermediate 46Preparation replaces 2-methyl-4-[(trifluoromethyl except using 4-amino-3-ethyl benzonitrile) the oxygen base] aniline.

MS(m/z)：666[MH] ⁺。

Intermediate 65

3-ethyl-4-(3-(2-hydroxyethyl)-6-methyl-4-[3-(3-{[4-(methoxyl group) phenyl] methyl }-2-oxygen Generation-1-imidazolidyl)-the 1H-pyrazol-1-yl]-the 2-pyridyl } amino) benzonitrile

According to Intermediate 47Preparation.

NMR( ¹H，CDCl ₃)：δ 8.11(d，1H)，7.92(s，1H)，7.61(d，1H)，7.43(dd，1H)，7.42(bs，1H)，7.23(d，2H)，7.01(d，1H)，6.87(d，2H)，6.69(s，1H)，4.41(s，2H)，4.19(m，2H)，3.84(t，2H)，3.79(s，3H)，3.37(t，2H)，3.2(bs，1H)，2.86(m，2H)，2.64(m，2H)，2.47(s，3H)，1.27(t，3H)。

MS(m/z)：552[MH] ⁺。

Intermediate 66

3-ethyl-4-{6-methyl-4-[3-(3-{[4-(methoxyl group) phenyl] methyl }-2-oxo-1-imidazolidine Base)-and the 1H-pyrazol-1-yl]-2,3-dihydro-1H-pyrrolo-[2,3-b] pyridine-1-yl } benzonitrile

According to Intermediate 48Preparation.

NMR( ¹H，CDCl ₃)：δ 7.83(d，1H)，7.6(bs，1H)，7.48(dd，1H)，7.35(d，1H)，7.23(d，2H)，7.02(d，1H)，6.87(d，2H)，6.65(s，1H)，4.41(s，2H)，3.92(m，4H)，3.79(s，3H)，3.48(t，2H)，3.38(t，2H)，2.66(q，2H)，2.32(s，3H)，1.22(t，3H)。

MS(m/z)：534[MH] ⁺。

Intermediate 67

1-[1-(3-(2-{[(1,1-dimethyl ethyl) (dimethyl) silyl] the oxygen base } ethyl)-the 6-methyl -2-{[2-(methoxyl group)-4-(1H-pyrazol-1-yl) phenyl] amino }-the 4-pyridyl)-1H-pyrazoles-3- Base]-3-{[4-(methoxyl group) phenyl] methyl }-the 2-imidazolidone

According to Intermediate 46Preparation is except using Intermediate 88(2-(methoxyl group)-4-(1H-pyrazol-1-yl) aniline) replaces 2-methyl-4-[(trifluoromethyl) the oxygen base] aniline.

NMR( ¹H，CDCl ₃)：δ 7.88(d，1H)，7.76(d，1H)，7.65(d，1H)，7.5(bs，1H)，7.35(d，1H)，7.21(m，3H)，7.16(dd，1H)，7.02(d，1H)，6.88(d，2H)，6.69(d，1H)，6.54(s，1H)，6.44(t，1H)，4.41(s，2H)，4.11(t，2H)，3.95(s，3H)，3.86(t，2H)，3.79(s，3H)，3.36(t，2H)，2.85(t，2H)，2.51(s，3H)，0.79(s，9H)，0.07(s，6H)。

MS(m/z)：709[MH] ⁺

Intermediate 68

1-[1-(3-(2-hydroxyethyl)-6-methyl-2-{[2-(methoxyl group)-4-(1H-pyrazol-1-yl) phenyl] ammonia Base }-the 4-pyridyl)-the 1H-pyrazole-3-yl]-3-{[4-(methoxyl group) phenyl] methyl }-the 2-imidazolidone

According to Intermediate 47Preparation.

NMR( ¹H，CDCl ₃)：δ 8.66(m，1H)，7.88(d，1H)，7.69(d，1H)，7.62(d，1H)，7.5(bs，1H)，7.38(d，1H)，7.21(m，3H)，7.16(dd，1H)，7.02(d，1H)，6.88(d，2H)，6.54(s，1H)，6.44(t，1H)，4.41(s，2H)，4.11(t，2H)，3.98(s，3H)，3.9(t，2H)，3.79(s，3H)，3.40(t，2H)，2.9(t，2H)，2.49(s，3H)。

MS(m/z)：595[MH] ⁺。

Intermediate 69

1-(1-{6-methyl isophthalic acid-[2-(methoxyl group)-4-(1H-pyrazol-1-yl) phenyl]-2,3-dihydro-1H-pyrrolo- [2,3-b] pyridin-4-yl }-the 1H-pyrazole-3-yl)-3-{[4-(methoxyl group) phenyl] methyl }-the 2-imidazolidone

According to Intermediate 48Preparation.

NMR( ¹H，CDCl ₃)：δ 7.88(d，1H)，7.83(d，1H)，7.70(d，1H)，7.59(d，1H)，7.42(d，1H)，7.22(m，3H)，7.00(d，1H)，6.88(d，2H)，6.63(s，1H)，6.43(t，1H)，4.41(s，2H)，3.98(m，4H)，3.90(s，3H)，3.78(s，3H)，3.40(m，4H)，2.34(s，3H)。

Intermediate 70

1-(1-{3-(2-{[(1,1-dimethyl ethyl) (dimethyl) silyl] the oxygen base } ethyl)-the 6-methyl -2-[(6-methyl isophthalic acid, 3-benzodioxole-5-yl) amino]-the 4-pyridyl }-1H-pyrazoles-3- Base)-and 3-{[4-(methoxyl group) phenyl] methyl }-the 2-imidazolidone

According to Intermediate 46Preparation is except using Intermediate 89(6-methyl isophthalic acid, 3-benzodioxole-5-amine) replaces 2-methyl-4-[(trifluoromethyl) the oxygen base] aniline.

NMR( ¹H，CDCl ₃)：δ 7.57(d，1H)，7.43(bs，1H)，7.25(bs，1H)，7.21(d，2H)，6.94(d，1H)，6.86(d，2H)，6.64(d，1H)，6.48(bs，1H)，5.88(s，2H)，4.40(s，2H)，4.08(m，2H)，3.83(m，2H)，3.79(s，3H)，3.35(t，2H)，2.78(t，2H)，2.38(bs，3H)，2.16(s，3H)，0.80(s，9H)，-0.04(s，6H)。

MS(m/z)：671[MH] ⁺。

Intermediate 71

1-(1-{3-(2-hydroxyethyl)-6-methyl-2-[(6-methyl isophthalic acid, 3-benzodioxole-5-yl) ammonia Base]-the 4-pyridyl }-the 1H-pyrazole-3-yl)-3-{[4-(methoxyl group) phenyl] methyl }-the 2-imidazolidone

According to Intermediate 47Preparation.

NMR( ¹H，CDCl ₃)：δ 7.59(d，1H)，7.39(bs，1H)，7.24(m，2H)，7.21，6.99(d，1H)，6.87(d，2H)，6.70(bs，1H)，6.65(s，1H)，6.48(s，1H)，5.89(s，2H)，4.40(s，2H)，4.33(t，1H)，4.08(m，2H)，3.85(t，2H)，3.78(s，3H)，3.36(t，2H)，2.85(t，2H)，2.38(s，3H)，2.17(s，3H)。

MS(m/z)：557[MH] ⁺。

Intermediate 72

1-{1-[6-methyl isophthalic acid-(6-methyl isophthalic acid, 3-benzodioxole-5-yl)-2,3-dihydro-1H-pyrroles And [2,3-b] pyridin-4-yl]-the 1H-pyrazole-3-yl }-3-{[4-(methoxyl group) phenyl] methyl }-the 2-imidazolidone

According to Intermediate 48Preparation.

NMR( ¹H，CDCl ₃)：δ 7.81(d，1H)，7.23(m，2H)，6.99(d，1H)，6.87(d，2H)，6.73(d，2H)，6.56(s，1H)，5.90(s，2H)，4.40(s，2H)，3.92(t，2H)，3.78(m，5H)，3.39(m，4H)，2.31(s，3H)，2.15(s，3H)。

MS(m/z)：539[MH] ⁺。

Intermediate 73

1-[1-(3-(2-{[(1,1-dimethyl ethyl) (dimethyl) silyl] the oxygen base } ethyl)-the 6-methyl -2-{[2,4,6-trimethoxy phenyl] amino }-the 4-pyridyl)-the 1H-pyrazole-3-yl]-3-{[4-(methoxyl group) benzene Base] methyl }-the 2-imidazolidone

According to Intermediate 46Preparation, except using 2,4,6-trimethoxy aniline replaces 2-methyl-4-[(trifluoromethyl) the oxygen base] aniline.

MS(m/z)：703[MH] ⁺。

Intermediate 74

1-[1-(3-(2-hydroxyethyl)-6-methyl-2-{[2,4,6-trimethoxy phenyl] amino }-the 4-pyridine Base)-the 1H-pyrazole-3-yl]-3-{[4-(methoxyl group) phenyl] methyl }-the 2-imidazolidone

According to Intermediate 47Preparation.

MS(m/z)：589[MH] ⁺。

Intermediate 75

1-{[4-(methoxyl group) phenyl] methyl }-(1-{6-methyl isophthalic acid-[2,4,6-trimethoxy phenyl]-2,3-two for 3- Hydrogen-1H-pyrrolo-[2,3-b] pyridin-4-yl }-the 1H-pyrazole-3-yl)-the 2-imidazolidone

According to Intermediate 48Preparation.

NMR( ¹H，DMSO-d ₆)：δ 8.84(d，1H)，7.24(bs，2H)，7.01(bs，1H)，6.88-6.83(d-d，2H)，6.54(s，1H)，6.20(d，1H)，6.18(s，1H)，4.44(s，2H)，3.92-3.84(m，2H)，3.81-3.72(m，14H)，3.48-3.36(m，4H)，2.40(bs，3H)。

MS(m/z)：451[MH] ⁺。

Intermediate 76

1-(1-{3-(2-{[(1,1-dimethyl ethyl) (dimethyl) silyl] the oxygen base } ethyl)-the 6-methyl -2-[(4-methyl isophthalic acid, 3-benzodioxole-5-yl) amino]-the 4-pyridyl }-1H-pyrazoles-3- Base)-and 3-{[4-(methoxyl group) phenyl] methyl }-the 2-imidazolidone

According to Intermediate 46Preparation, except using the 4-methyl isophthalic acid, 3-benzodioxole-5-amine (according to preparing described in the United States Patent (USP) 5965595A) replaces 2-methyl-4-[(trifluoromethyl) the oxygen base] aniline.

NMR( ¹H，CDCl ₃)：δ 7.57(d，1H)，7.41(bs，1H)，7.21(m，3H)，7.00(d，1H)，6.95(d，2H)，6.87(d，1H)，6.47(s，1H)，5.92(s，2H)，4.40(s，2H)，4.11(m，2H)，3.83(s，3H)，3.35(t，2H)，2.79(t，2H)，2.33(s，3H)，2.04(s，3H)，0.79(s，9H)，-0.04(s，6H)。

MS(m/z)：671[MH] ⁺。

Intermediate 77

According to Intermediate 47Preparation.

NMR( ¹H，CDCl ₃)：δ 7.59(d，1H)，7.20(m，3H)，7.10(d，1H)，6.99(d，1H)，6.87(d，2H)，6.70(d，1H)，6.47(s，1H)，5.93(s，2H)，4.40(s，2H)，4.08(m，2H)，3.85(t，2H)，3.78(s，3H)，3.36(t，2H)，2.85(t，2H)，2.35(s，3H)，2.09(s，3H)。

MS(m/z)：557[MH] ⁺。

Intermediate 78

According to Intermediate 48Preparation.

NMR( ¹H，CDCl ₃)：δ 7.81(d，1H)，7.23(m，2H)，6.99(d，1H)，6.88(d，2H)，6.72(dd，2H)，6.56(s，1H)，5.95(s，2H)，4.40(s，2H)，3.92(t，2H)，3.81(t，2H)，3.78(s，3H)，3.39(m，4H)，2.31(s，3H)，2.08(s，3H)。

MS(m/z)：539[MH] ⁺

Intermediate 79

1-{1-[2-{[2, two (trifluoromethyl) phenyl of 4-] amino }-3-(2-{[(1,1-dimethyl ethyl) (dimethyl) Silyl] the oxygen base } ethyl)-6-methyl-4-pyridyl]-the 1H-pyrazole-3-yl }-3-{[4-(methoxyl group) phenyl] Methyl }-the 2-imidazolidone

According to Intermediate 46Preparation, except using 2, two (trifluoromethyl) aniline of 4-replace 2-methyl-4-[(trifluoromethyl) the oxygen base] aniline.

NMR( ¹H，CDCl ₃)：δ 8.33(d，1H)，7.99(bs，1H)，7.78(bs，1H)，7.63(m，2H)，7.24(m，2H)，6.99(m，1H)6.85(d，2H)，6.77(bs，1H)，4.40(s，2H)，4.05(m，2H)，3.83(m，2H)，3.78(s，3H)，3.36(t，2H)，2.90(t，2H)，2.49(s，3H)，0.73(s，9H)，-0.11(s，6H)。

MS(m/z)：749[MH] ⁺。

Intermediate 80

1-{1-[2-{[2, two (trifluoromethyl) phenyl of 4-] amino }-3-(2-hydroxyethyl)-6-methyl-4-pyridine Base]-the 1H-pyrazole-3-yl }-3-{[4-(methoxyl group) phenyl] methyl }-the 2-imidazolidone

According to Intermediate 47Preparation.

NMR( ¹H，CDCl ₃)：δ 8.37(d，1H)，7.90(bs，1H)，7.79(bs，1H)，7.67(m，2H)，7.61(d，1H)，7.51(m，1H)7.03(bs，1H)，6.88(d，2H)，6.72(s，1H)，4.40(s，2H)，4.20(t，2H)，4.05(bs，1H)，3.85(t，2H)，3.78(s，3H)，3.37(t，2H)，2.89(t，2H)，2.47(s，3H)。

MS(m/z)：635[MH] ⁺。

Intermediate 81

1-(1-{1-[2, two (trifluoromethyl) phenyl of 4-]-6-methyl-2,3-dihydro-1H-pyrrolo-[2,3-b] pyridine -4-yl }-the 1H-pyrazole-3-yl)-3-{[4-(methoxyl group) phenyl] methyl }-the 2-imidazolidone

According to Intermediate 48Preparation.

NMR( ¹H，CDCl ₃)：δ 7.96(s，1H)，7.84(d，1H)，7.79(bs，1H)，7.58(d，1H)，7.22(d，2H)，7.02(d，1H)，6.88(d，2H)6.70(s，1H)，4.41(s，2H)，3.92(m，4H)，3.79(s，3H)，3.49(t，2H)，3.37(t，2H)，2.31(s，3H)。

MS(m/z)：617[MH] ⁺。

Intermediate 82

1,1-dimethyl ethyl (4-bromo-2-aminomethyl phenyl) carbamate

At room temperature, to 4-bromo-2-aminotoluene (1g, 5.37mmol) 1,4-diox (11mL) and H ₂Add Et in the solution of O (4mL) ₃N (2.7mL, 1.2 equivalents) and BOC ₂O (4.2g, 1.2 equivalents).With reaction mixture in stirring at room 96 hours.Add saturated NH ₄The Cl aqueous solution and EtOAc (20mL), and separate two-phase.EtOAc (2 x 20mL) extraction is further used in the waterbearing stratum.With the organic extract that merges through anhydrous Na ₂SO ₄Drying is filtered this solid, and evaporating solvent.With resistates (CH on the SCX post ₂Cl ₂, MeOH and NH ₃(the MeOH solution of 0.5M)) purifying, obtain white solid Title compound(1.22g, 79%).

NMR( ¹H，DMSO-d ₆)：δ 8.55(s，1H)，7.35(m，1H)，7.28(m，2H)，2.17(s，3H)，1.44(s，9H)。

MS(m/z)：230[MH-tBu] ⁺，186[MH-BOC] ⁺。

Intermediate 83

2-methyl-4-(1H-pyrazol-1-yl) aniline

At N ₂To down, Intermediate 82(200mg, 0.7mmol), 1H-pyrazoles (95mg, 2 equivalents), CuI (133mg, 1 equivalent), K ₂CO ₃(290mg, 2.1 equivalents) and (1R, 2R)-anhydrous NMP (1mL) solution of diamino methylcyclohexane (100mg, 1 equivalent) is in 150 ℃ of heating 6 hours.It is cooled to room temperature, and is poured in the water.Add EtOAc, and separate two-phase.EtOAc (2 x 10mL) extraction is further used in the waterbearing stratum.With the organic extract that merges through anhydrous Na ₂SO ₄Drying is filtered this solid, and evaporating solvent.Resistates by flash chromatography (silica gel, cHex/EtOAc 8:2) purifying, is obtained the title compound (85.6mg, 70%) of white solid.

NMR( ¹H，CDCl ₃)：δ 7.77(dd，1H)，7.66(d，1H)，7.39(d，1H)，7.29(dd，1H)，6.72(d，1H)，6.40(t，1H)，2.85(bs，1H)。

MS(m/z)：174[MH] ⁺。

Intermediate 84

(5-methoxyl group-2-nitro-phenyl)-methyl alcohol

At room temperature at N ₂In anhydrous DME (60mL) suspension of cyanuryl chloride (1.84g, 1 equivalent), add NMM (1.1mL, 1 equivalent) down.Reaction mixture was stirred 2 minutes, and form precipitation.Adding 5-(methoxyl group)-2-nitrobenzoic acid (2.0g, anhydrous DME (20mL) solution 10mmol), and with reaction mixture stirring 4 hours.Filter this suspension, and add NaBH in 0 ℃ ₄Water (30mL) solution of (0.57g, 1.5 equivalents).Reaction mixture was stirred 20 minutes in 0 ℃.Then it is used Et ₂O (10mL) dilution, and by adding saturated NH ₄The Cl acidified aqueous solution is that pH is 5.Separate two-phase, and with waterbearing stratum Et ₂O (2 x 100mL) extraction.With the organic extract that merges with saturated Na ₂CO ₃The aqueous solution is washed, and through anhydrous Na ₂SO ₄Dry.Filter this solid, and solvent evaporation is extremely done.Crude product by flash chromatography (silica gel, cHex/EtOAc 8:2) purifying, is obtained Title compound(958mg, 53%).

NMR( ¹H，CDCl ₃)：δ 8.15(d，1H)，7.19(m，1H)，6.85(dd，1H)，4.95(d，2H)，3.89(s，3H)，2.5(t，1H)。

Intermediate 85

5-(methoxyl group)-2-nitrobenzaldehyde

At room temperature at N ₂Following, to Intermediate 84(1.44g, anhydrous CH 7.9mmol) ₂Cl ₂(40mL) add Dess-Martin in the solution and cross iodine alkane (3.68g, 1.1 equivalents).Reaction mixture was at room temperature stirred 3 hours, add saturated Na then ₂S ₂O ₃The aqueous solution (5mL) and saturated NaHCO ₃The aqueous solution (20mL).Separate two-phase, and the waterbearing stratum is extracted with EtOAc (2 x 100mL).With the organic extract that merges through anhydrous Na ₂SO ₄Drying is filtered this solid, and solvent evaporation is extremely done, and obtains the title compound of 1.45g (100%).

NMR( ¹H，CDCl ₃)：δ 10.47(s，1H)，8.14(d，1H)，7.31(d，1H)，7.13(dd，1H)，3.94(s，3H)。

Intermediate 86

2-(difluoromethyl)-4-(methoxyl group)-1-oil of mirbane

Under-78 ℃ at N ₂Following, to Intermediate 85(250mg, anhydrous CH 1.38mmol) ₂Cl ₂(10mL) slowly add DAST (2 x 0.4mL, 2.2 equivalents) in the solution.Reaction mixture in stirring at room 1.5 hours, is added the saturated NaCl aqueous solution thereafter.Separate two-phase, and the waterbearing stratum is extracted with EtOAc (3 x 20mL).With the organic extract that merges through anhydrous Na ₂SO ₄Drying is filtered this solid, and solvent evaporation is extremely done.Crude product by flash chromatography (silica gel, cHex/EtOAc 8:2) purifying, is obtained yellow oil Title compound(176mg, 63%).

NMR( ¹H，CDCl ₃)：δ 8.21(d，1H)，7.43(t，1H，J _(H-F)＝54.9Hz)，7.33(d，1H)，7.06(dd，1H)，3.95(s，3H)。

Intermediate 87

2-(difluoromethyl)-4-(methoxyl group) aniline

At room temperature at N ₂Following, to Intermediate 86(176mg, add in anhydrous MeOH (8.7mL) solution 0.87mmol) Pd/C10% (88mg, 5%wt).Reaction mixture is placed H ₂Following 5 hours of atmosphere.Leach catalyzer, and the solution evaporation of gained is extremely done.Crude product by flash chromatography (silica gel, cHex/EtOAc 9:1) purifying, is obtained yellow oil Title compound(27mg, 20%).

NMR( ¹H，CDCl ₃)：δ 6.88-6.80(m，2H)，6.7-6.67(m，1H)，6.62(t，1H，J _(H-F)＝55.6Hz)，3.8-3.5(bs，2H)，3.76(s，3H)

MS(m/z)：174[MH] ⁺。

Intermediate 88

2-(methoxyl group)-4-(1H-pyrazol-1-yl) aniline

At room temperature at N ₂Down, (400mg adds pyrazoles (269mg, 2 equivalents), K in anhydrous NMP (4mL) solution 1.979mmol) to 4-bromo-2-(methoxyl group) aniline ₂CO ₃(819mg, 3 equivalents), CuI (377mg, 1 equivalent) and (1R, 2R)-diamino methylcyclohexane (281mg, 1 equivalent).In 150 ℃ of stirred reaction mixtures 3 hours.It is cooled to room temperature, and is poured in the saturated NaCl aqueous solution of EtOAc/.Separate two-phase, and with organic layer with saturated NH ₄The Cl aqueous solution (20mL) and the saturated NaCl aqueous solution (20mL) are washed.With the water layer that merges with EtOAc (20mL) back extraction, and with the organic extract that merges through anhydrous Na ₂SO ₄Dry.Filter this solid, and evaporating solvent.Crude product by flash chromatography (silica gel, cHex/EtOAc 7:3) purifying, is obtained brown oil Title compound(336mg, 90%).

NMR( ¹H，CDCl ₃)：δ 7.78(d，1H)，7.65(d，1H)，7.21(d，1H)，6.97(dd，1H)，6.73(d，1H)，6.40(m，1H)，4.05(bs，2H)，3.87(s，3H)。

MS(m/z)：190[MH] ⁺。

Intermediate 89

The 6-methyl isophthalic acid, 3-benzodioxole-5-amine

With 5-methyl-6-nitro-benzo (1,3) dioxole (50mg, 0.28mmol), Fe (54mg, 3.5 equivalents) and ammonium chloride (51.2mg, 3.5 equivalents) is at MeOH/H ₂Mixture in the 1:1 mixture (2.8mL) of O in 80 ℃ carry out microwave radiation (60W, P=100p.s.i.) four 10 minutes.Brown solution is cooled to room temperature, and adds more Fe (3.5 equivalent) and ammonium chloride (3.5 equivalent).Mixture is carried out microwave radiation (60W, P=100p.s.i.) 10 minutes again in 80 ℃.Leach Fe, and evaporating solvent.With crude product (cHex/EtOAc 9:1) purifying on the SCX post, obtain brown solid Title compound(40mg, 93%).

NMR( ¹H，CDCl ₃)：δ 6.54(s，1H)，6.27(s，1H)，5.80(s，2H)，2.27(bs，2H)，2.07(s，3H)。

MS(m/z)：152[MH] ⁺。

Intermediate 90

4-{[2-methyl-4-(methoxyl group) phenyl] amino } butyronitrile

At N ₂Down, (30g, dry DMF 0.22mol) (90mL) solution is in 100 ℃ of heating with DIPEA (39mL, 1 equivalent) and 4-methoxyl group-2-aminotoluene.Drip 4-bromine butyronitrile (21mL, 1 equivalent).Make internal temperature rise to 110 ℃, and reaction mixture was stirred 2 hours.Cooling mixture is to room temperature, and dilutes with MTBE (240mL).Add entry (270mL), and separate two-phase.The further water of organic layer (150mL) is washed, and be evaporated to 150mL.Add fresh MTBE (150mL), and mixture is evaporated to 150mL once more.Mixture was handled 20 minutes with cHex (540mL), and the suspension that generates was placed room temperature following 1.5 hours.Filter this suspension, and filter cake is washed with mixture M TBE (30mL)/cHex (90mL).Collecting title compound is purple solid (23.8g, 53%).

NMR( ¹H，DMSO-d ₆)：δ 6.65(d，1H)，6.63(dd，1H)，6.47(d，1H)，4.49(bt，1H)，3.64(s，3H)，3.10(q，2H)，2.59(t，2H)，2.09(s，3H)，1.86(m，2H)。

MS(m/z)：205[MH] ⁺。

Intermediate 91

1-[2-methyl-4-(methoxyl group) phenyl]-2-tetramethyleneimine imines (pyrrolidinimine)

At room temperature at N ₂Following, to Intermediate 90(35.0g adds 6N HCl/IPA (51.45mL, 1.5 equivalents) in anhydrous IPA (280mL) suspension 0.173mol).Mixture heating up was refluxed 4 hours, make it be cooled to room temperature, and be evaporated to 140mL.Add entry (350mL), once more with transparent solution evaporation to 140mL, and handle with 10%NaOH (140mL).With mixture CH ₂Cl ₂(350mL) extract, and further use 10%NaCl (140mL) to wash organic layer.Organic layer is evaporated to dried.With this crude product to be used for next step (36.4g, 100%) like this.

NMR( ¹H，DMSO-d ₆)：δ 7.09(d，1H)，6.87(d，1H)，6.80(dd，1H)，5.8-5.4(b，1H)，3.75(s，1H)，3.54(t，2H)，2.51(t，2H)，2.11(s，3H)，2.01(m，2H)。

MS(m/z)：205[MH] ⁺。

Intermediate 92

4-bromo-6-methyl isophthalic acid-[2-methyl-4-(methoxyl group) phenyl]-2,3-dihydro-1H-pyrrolo-[2,3-b] pyridineAt room temperature at N ₂Following, to Intermediate 4(50.0g adds CH in dry DMF 0.15mol) (175mL) solution ₃SO ₃H (58.1mL, 1.2 equivalents) adds NaBr (19.18g, 1.5 equivalents) subsequently, and the mixture that generates was heated 2 hours in 85 ℃.Then it is diluted with MTBE (250mL), and wash with 1N NaOH (250mL).Water is extracted with MTBE (150mL), and the organic extract water (250mL) that merges is washed twice, then through anhydrous Na ₂SO ₄Dry.Filter this solid, and evaporating solvent, former times look solid obtained Title compound(38.g, 76%).

NMR( ¹H，DMSO-d ₆)：δ 7.17(d，1H)，6.87(d，1H)，6.80(dd，1H)，6.56(s，1H)，3.86(t，2H)，3.76(s，3H)，3.06(t，2H)，2.15-2.14(2s，6H)。

MS(m/z)：333/335[MH] ⁺。

Intermediate 93

{ 6-methyl isophthalic acid-[2-methyl-4-(methoxyl group) phenyl]-2,3-dihydro-1H-pyrrolo-[2,3-b] pyridin-4-yl } Boric acid

At-70 ℃ at N ₂Down, to triisopropyl boric acid ester (185 μ L, 3 equivalents) and Intermediate 5Drip n-BuLi (329 μ L, 2 equivalents) in (100mg, 1 equivalent) mixture in the anhydrous 1:4 mixture (0.5mL) of THF/ toluene.Reaction mixture was stirred 2.5 hours in-70 ℃.It is warmed to-20 ℃, and stops with 1M HCl (0.5mL, 2 equivalents).Mixture is warmed to room temperature, and observes the throw out of boric acid.Filter this solid, and use CH ₃CN washes.Obtain white solid Title compound(70mg, 89%).

NMR( ¹H，CDCl ₃)：δ 7.21(d，1H)，6.91(d，1H)，6.84(dd，1H)，6.61(d，1H)，4.02(bt，2H)，3.74(s，3H)，3.29(bt，2H)，2.21(s，3H)，2.15(s，3H)。

MS(m/z)：299[MH] ⁺。

Intermediate 94

N-(6-bromo-2-pyridyl)-N '-(2-chloroethyl) urea

At room temperature at N ₂Down, to 6-bromo-2-pyridine amine (1g adds 1-chloro-2-isocyanide acyl group ethane (1.2mL, 2.5 equivalents) in anhydrous THF (25mL) solution 5.78mmol), and with reaction mixture in stirring at room 18 hours.With crude mixture at CH ₂Cl ₂And distribute between the water.Separate two-phase, and with organic layer through anhydrous Na ₂SO ₄Dry.Filter this solid, and evaporating solvent, obtain Title compound(1.06g, 66%) need not be further purified it and to be used for next step.

NMR( ¹H，DMSO-d ₆)：δ 9.56(bs，1H)，7.75(m，2H)，7.32(t，1H)，7.14(t，1H)，3.65(t，2H)，3.46(m，2H)

Intermediate 95

1-(6-bromo-2-pyridyl)-2-imidazolidone

At 0 ℃ at N ₂Following, to Intermediate 94(1.06g adds t-BuOK (644mg, 1.5 equivalents) in anhydrous THF (25mL) solution 3.82mmol), and reaction mixture is warmed to room temperature, after 1 hour, at room temperature with reaction mixture at CH ₂Cl ₂And distribute between the water.With organic layer through anhydrous Na ₂SO ₄Drying is filtered this solid, and evaporating solvent, obtains Title compound(0.988g, quantitative) need not be further purified it and to be used for next step.

NMR( ¹H，DMSO-d ₆)：δ 8.14(d，1H)，7.61(t，1H)，7.33(bs，1H)，7.19(d，1H)，3.95(t，2H)，3.40(t，2H)。

Intermediate 96

1-(6-bromo-2-pyridyl)-3-{[4-(methoxyl group) phenyl] methyl }-the 2-imidazolidone

At room temperature at N ₂Following, to Intermediate 95(0.5g adds NaH 60%/oil (82mg, 1 equivalent) and to methoxy-benzyl chlorine (280 μ L, 1 equivalent) in dry DMF 2.06mmol) (25mL) solution, and mixture was at room temperature stirred 2 hours.Then with it at CH ₂Cl ₂And distribute between the water.With organic layer through anhydrous Na ₂SO ₄Drying is filtered this solid, and evaporating solvent.The crude product that generates is passed through flash chromatography (silica gel, CH ₂Cl ₂/ MeOH 9:1) purifying obtains Title compound(0.635g, 85%).

NMR( ¹H，CDCl ₃)：δ 8.33(d，1H)，7.71(t，1H)，7.29(d，2H)，7.10(d，1H)，6.85(d，2H)，4.43(s，2H)，4.00(t，2H)，3.83(s，3H)，3.55(t，2H)

Intermediate 97

1-(6-{6-methyl isophthalic acid-[2-methyl-4-(methoxyl group) phenyl]-2,3-dihydro-1H-pyrrolo-[2,3-b] pyridine -4-yl }-the 2-pyridyl)-3-{[4-(methoxyl group) phenyl] methyl }-the 2-imidazolidone

At room temperature at N ₂Following, to Intermediate 93(50mg, 1 equivalent) and Intermediate 96(121mg, 2 equivalents) add 2M Na in the solution of the 1:1 of toluene/EtOH mixture (5mL) ₂CO ₃(168 μ L), Pd (PPh ₃) ₄(19mg, 0.1 equivalent) and four-normal-butyl bromination ammonium (9mg, 0.1 equivalent).Reaction mixture was stirred 2 hours in 90 ℃ in air-tight bottle.It is distributed between EtOAc and water.Separate two-phase, and organic layer is washed with the saturated NaCl aqueous solution.With it through anhydrous Na ₂SO ₄Drying is filtered this solid, and evaporating solvent.Crude product by flash chromatography (silica gel, cHex/EtOAc 8:2) purifying, is obtained white solid Title compound(35mg, 39%).

NMR( ¹H，CDCl ₃)：δ 8.32(d，1H)，7.71(d，1H)，7.30-6.71(m，9H)，4.43(s，2H)，4.09(t，2H)，3.84-3.78(m，8H)，3.43-3.33(m，4H)，2.33(s，3H)，2.24(s，3H)。

MS(m/z)：536[MH] ⁺。

Intermediate 98

N-{[3, two (methoxyl group) phenyl of 4-] methyl }-N '-(2-chloroethyl) urea

At room temperature at N ₂Down, to 3, (2g adds 2-chloroethyl isocyanate (1.02mL, 1 equivalent) to 4-dimethoxy-benzyl amine in anhydrous THF (25mL) solution 12mmol).Adding afterreaction finishes.It is concentrated, and resistates is passed through flash chromatography (silica gel, cHex/EtOAc 1:1 → 7:3 EtOAc/NH ₃(0.5 MeOH solution)) purifying, obtain the title compound (2.9g, 89%) of white solid.

NMR( ¹H，DMSO-d ₆)：δ 6.85(d，1H)，6.82(d，1H)，6.73(dd，1H)，6.41(t，1H)，6.16(t，1H)，4.10(d，2H)，3.70(s，3H)，3.69(s，3H)，3.56(t，2H)，3.31(m，2H)。

MS(m/z)：273[MH] ⁺。

Intermediate 99

1-{[3, two (methoxyl group) phenyl of 4-] methyl }-the 2-imidazolidone

At 0 ℃ at N ₂Following, to Intermediate 98(1g adds t-BuOK (500mg, 1.2 equivalents) in anhydrous THF (30mL) suspension 3.68mmol).Remove ice bath, and with reaction mixture in stirring at room 1 hour.Add saturated NH ₄The Cl aqueous solution, and solvent evaporation is extremely dried.Resistates by flash chromatography (silica gel, 100%EtOAc → EtOAc/MeOH 8:2) purifying, is obtained white solid Titleization Compound(555mg, 64%).

NMR( ¹H，DMSO-d ₆)：δ 6.88(d，1H)，6.79(d，1H)，6.73(dd，1H)，6.33(s，1H)，4.12(s，2H)，3.70(s，6H)，3.16(m，4H)。

MS(m/z)：237[MH] ⁺。

Intermediate 100

1-{[3, two (methoxyl group) phenyl of 4-] methyl }-3-(4-chloro-2-pyrimidyl)-2-imidazolidone

With Intermediate 101

1-{[3, two (methoxyl group) phenyl of 4-] methyl }-3-(2-chloro-4-pyrimidyl)-2-imidazolidone

At room temperature at N ₂Down, to 2,4-dichloro pyrimidine (600mg, 2.54mmol, 1 equivalent) and Middle Body 99(100mg adds NaH 60%/oil (112mg, 1.1 equivalents) in dry DMF 0.42mmol) (27mL) solution.With reaction mixture in stirring at room 1 hour.Add entry and EtOAc, and separate two-phase.EtOAc (3 x 20mL) extraction is further used in the waterbearing stratum.The organic extract that concentrate to merge, and with resistates by flash chromatography (silica gel, cHex/EtOAc 7:3) purifying, obtain white solid Intermediate 100(377mg, 42%).Collect other regional isomer and unreacted Intermediate 99Mixture.The mixture that this is thick is by flash chromatography (silica gel, CH ₂Cl ₂/ NH ₃(0.5 MeOH solution) 95:5) purifying obtains white solid Intermediate 101(193.1mg, 22%).

Intermediate 100

NMR( ¹H，CDCl ₃)：δ 8.36(d，1H)，8.28(d，1H)，6.87(s，1H)，6.86(d，2H)，4.46(s，2H)，4.05(dd，2H)，3.91(s，6H)，3.43(dd，2H)。

MS(m/z)：349[MH] ⁺。

Intermediate 101

NMR( ¹H，DMSO)：δ 8.55(d，1H)，7.19(d，1H)，6.88(d，1H)，6.83(d，1H)，6.78(dd，1H)，4.29(s，2H)，3.88(dd，2H)，3.70(s，3H)，3.69(s，3H)，3.28(dd，2H)。

MS(m/z)：349[MH] ⁺。

Intermediate 102

1-{[3, two (methoxyl group) phenyl of 4-] methyl }-3-(4-bromo-2-pyrimidyl)-2-imidazolidone

At room temperature at N ₂Following, to Intermediate 100(50mg adds TMSBr (38 μ L, 2 equivalents) in propionitrile 0.144mmol) (2mL) suspension.Reaction mixture is carried out microwave radiation (2 x 10 minutes, T=100 ℃).2N NaOH and EtOAc are joined in the reaction mixture, and separate two-phase.EtOAc (3 x 10mL) extraction is further used in the waterbearing stratum, and with the organic extract vacuum concentration that merges.With resistates (100%CH on the SCX post ₂Cl ₂→ NH ₃(0.5 MeOH solution)) purifying, obtain white solid Title compound(43mg, 76%).

NMR( ¹H，CDCl ₃)：δ 8.27(m，2H)，6.81-6.83(m，3H)，4.24(s，2H)，4.01(t，2H)，3.88(s，3H)，3.87(s，3H)，3.40(t，2H)。

MS(m/z)：393[MH] ⁺。

Intermediate 103

1-{[3, two (methoxyl group) phenyl of 4-] methyl }-3-(4-{6-methyl isophthalic acid-[2-methyl-4-(methoxyl group) benzene Base]-2,3-dihydro-1H-pyrrolo-[2,3-b] pyridin-4-yl }-the 2-pyrimidyl)-the 2-imidazolidone

At room temperature at N ₂Following, to Intermediate 102(43mg, 0.112mmol) and Intermediate 93Add Pd (PPh in the solution of the 1:1 mixture (4mL) of the EtOH/ toluene of (50mg, 1.5 equivalents) ₃) ₄(13mg, 0.1 equivalent), tetra-n-butyl ammonium bromide (4mg, 0.1 equivalent) and 2N Na ₂CO ₃(1.6ml, 28.5 equivalents).Reaction mixture was heated 2 hours in 100 ℃.It is cooled to room temperature, and is poured in the water.Add EtOAc, and separate two-phase.EtOAc (2 x 10mL) extraction is further used in the waterbearing stratum.With the organic extract that merges through anhydrous Na ₂SO ₄Drying is filtered this solid, and evaporating solvent.Resistates by flash chromatography (silica gel, cHex/EtOAc 9:1) purifying, is obtained yellow solid Title compound(71mg, quantitative).

NMR( ¹H，CDCl ₃)：δ 8.61(dd，1H)，8.24(dd，1H)，7.18-7.26(m，4H)，6.76-6.85(m，3H)，4.46(s，2H)，4.13(t，2H)，3.80-3.88(m，11H)，3.59(t，2H)，3.44(t，2H)，2.38(s，3H)，2.25(s，3H)。

MS(m/z)：567[MH] ⁺。

Intermediate 104

1-{[3, two (methoxyl group) phenyl of 4-] methyl }-3-(2-bromo-4-pyrimidyl)-2-imidazolidone

At room temperature at N ₂Following, to Intermediate 101(188mg adds TMSBr (143 μ L, 2 equivalents) in propionitrile 0.54mmol) (2mL) suspension.With reaction mixture carry out microwave radiation (10 minutes, P=155W, T=100 ℃, p=60psi).Add 2N NaOH, and with the reaction mixture vacuum concentration.With resistates at MEGA Bond Elut silica column (CH ₂Cl ₂/ MeOH 95:5) goes up purifying, obtain yellow solid Title compound(33mg, 16%).

NMR( ¹H，DMSO-d ₆)：δ 8.44(d，1H)，7.35(d，1H)，6.80-6.90(m，3H)，4.31(s，2H)，3.90(t，2H)，3.73(s，3H)，3.72(s，3H)，3.22-3.34(m，2H)。

MS(m/z)：393[MH] ⁺。

Intermediate 105

1-{[3, two (methoxyl group) phenyl of 4-] methyl }-3-(2-{6-methyl isophthalic acid-[2-methyl-4-(methoxyl group) benzene Base]-2,3-dihydro-1H-pyrrolo-[2,3-b] pyridin-4-yl }-the 4-pyrimidyl)-the 2-imidazolidone

To Intermediate 104(33mg, 0.084mmol) and Intermediate 93(37mg, 1.5 equivalents) add Pd (PPh in the solution of the 1:1 of EtOH/ toluene mixture (3mL) ₃) ₄(10mg, 0.1 equivalent), tetra-n-butyl ammonium bromide (3mg, 0.1 equivalent) and 2N Na ₂CO ₃(1.2mL, 28.5 equivalents).Reaction mixture was heated 2.5 hours in 100 ℃.It is cooled to room temperature, and is poured in the water.Add EtOAc, and separate two-phase.EtOAc (2 x 10mL) extraction is further used in the waterbearing stratum.With the organic extract that merges through anhydrous Na ₂SO ₄Drying is filtered this solid, and evaporating solvent.Resistates is passed through flash chromatography (silica gel, CH ₂Cl ₂/ MeOH 95:5), and at thin slice (Strata) NH ₂(cHex/EtOAc1:0 → cHex/EtOAc 0:1) purifying obtains 13mg's on the silica column of passivation Title compound, it is still by U/I by-product contamination.The mixture that this is thick need not be further purified and be used for next step.

NMR( ¹H，CDCl ₃)：δ 8.73(d，1H)，7.43-7.69(m，4H)，7.17(d，1H)，6.75-6.92(m，2H)，6.70(s，1H)，4.47(s，2H)，4.06-4.15(m，2H)，3.80-3.91(m，8H)，3.80(s，3H)，3.55-3.63(m，2H)，3.40(m，2H)，2.35(s，3H)，2.24(s，3H)。

MS(m/z)：567[MH] ⁺。

Intermediate 106

1-{6-methyl isophthalic acid-[2-methyl-4-(methoxyl group) phenyl]-2,3-dihydro-1H-pyrrolo-[2,3-b] pyridine-4- Base }-1H-1,2,4-triazole-3-amine

At room temperature at N ₂To down, Intermediate 5(50mg, 0.13mmol), 1H-1,2,4-triazole-3-amine (22mg, 2 equivalents), CuI (145mg, 6 equivalents), K ₂CO ₃(37mg, 2.1 equivalents) and 1-2-N, anhydrous NMP (5mL) suspension of N '-dimethyl cyclohexane diamines (106mg, 6 equivalents) carries out microwave radiation (3 x 45 minutes, 150 ℃).Add the saturated NaCl aqueous solution (15mL) then, and with reaction mixture CH ₂Cl ₂(2 x 15mL) extraction.With the organic extract that merges through anhydrous Na ₂SO ₄Drying is filtered this solid, and vacuum evaporating solvent, with thus obtained crude compound (cHex/EtOAc1:1 → EtOAc/MeOH 9:1) purifying on the SCX post, obtains white solid Title compound(20mg, 46%).

NMR( ¹H，CDCl ₃)：δ 8.7(s，1H)，7.2(d，1H)，6.8(d，1H)，6.7(dd，2H)，6.67(s，1H)，5.75(bs，2H)，3.75(t，2H)，3.7(s，3H)，3.4(t，2H)，2.2(s，3H)，2.2(s，3H)。

MS(m/z)：337[MH] ⁺。

Intermediate 107

N-(2-chloroethyl)-N '-(1-{6-methyl isophthalic acid-[2-methyl-4-(methoxyl group) phenyl]-2,3-dihydro-1H-pyrroles And [2,3-b] pyridin-4-yl }-1H-1,2,4-triazole-3-yl) urea

At 0 ℃ at N ₂Following, to Intermediate 106(20mg adds 3-chloroethyl isocyanate (0.5mL, excessive) in dry DMF 0.06mmol) (2mL) solution, and with reaction mixture in stirring at room 6 days.Add H then ₂O (15mL), and with mixture CH ₂Cl ₂(2 x 15mL) extraction.With the organic extract that merges through anhydrous Na ₂SO ₄Drying is filtered this solid, and vacuum evaporating solvent.(cHex/EtOAc 3:7 → 7:3) purifying obtains white solid on MEGA Bond Elut silica column with crude product Title compound(30mg, 100%).

MS(m/z)：442[MH] ⁺。

Intermediate 108

1-{1-[2-chloro-3-(2-hydroxypropyl)-6-methyl-4-pyridyl]-the 1H-pyrazole-3-yl }-3-{[4-(methoxy Base) phenyl] methyl }-the 2-imidazolidone

In 0 ℃ of cooling, to Intermediate 43(160mg, the MeMgBr/Et of adding 3.0M in the clear solution of anhydrous THF (2mL) 0.36mmol) ₂O (0.18mL, 1.5 equivalents).Reaction mixture was stirred 1 hour in 0 ℃, and be warmed to room temperature then at leisure.After 1 hour, this reaction is finished.Add EtOAc and saturated NH ₄The Cl aqueous solution, and separate two-phase.Organic layer is washed with the saturated NaCl aqueous solution, and through anhydrous Na ₂SO ₄Drying is filtered this solid, and evaporating solvent.(silica gel, EtOAc/cHex 1:1 → 6:4) purifying obtain white solid by flash chromatography with crude product Title compound(138mg, 84%).

NMR( ¹H，CDCl ₃)：δ 7.85(bs，1H)，7.65(d，1H)，7.21(d，2H)，7.1(d，1H)，6.88(d，2H)，4.45(q，1H)，4.3(m，1H)，3.9(t，2H)，3.7(s，3H)，3.4(t，2H)，2.95(d，2H)，2.5(s，3H)，1.25(d，3H)。

MS(m/z)：456[MH] ⁺。

Intermediate 109

1-{1-[2-chloro-3-(2-{[(1,1-dimethyl ethyl) (dimethyl) silyl] the oxygen base } propyl group)-the 6-methyl -4-pyridyl]-the 1H-pyrazole-3-yl }-3-{[4-(methoxyl group) phenyl] methyl }-the 2-imidazolidone

At 0 ℃ at N ₂Following, to Intermediate 108(135mg, anhydrous CH 0.3mmol) ₂Cl ₂Add 2 in the clear solution (2mL), 6-lutidine (77 μ L, 2.2 equivalents) and t-butyldimethylsilyl triflate (100 μ L, 1.5 equivalents).With reaction mixture in stirring at room 4 hours.Add saturated NH ₄The Cl aqueous solution separates two-phase, and organic layer is washed with the saturated NaCl aqueous solution, and through anhydrous Na ₂SO ₄Dry.Filter this solid, and evaporating solvent.Crude product by flash chromatography (silica gel, EtOAc/cHex 1:1) purifying, is obtained white solid Title compound(130mg, 76%).

NMR( ¹H，CDCl ₃)：δ 8.35(bs，1H)，7.19(m，3H)，7.00(bs，1H)，6.87(d，2H)，4.40(s，2H)，4.36(m，1H)，3.89(m，2H)，3.79(s，3H)，3.36(t，2H)，2.96(m，2H)，2.50(s，3H)，1.23(d，3H)，0.70(s，9H)，-0.06(s，3H)，-0.33(s，3H)。

MS(m/z)：570[MH] ⁺。

Intermediate 110

1-[1-(3-(2-{[(1,1-dimethyl ethyl) (dimethyl) silyl] the oxygen base } propyl group)-the 6-methyl -2-{[2-methyl-4-(methoxyl group) phenyl] amino }-the 4-pyridyl)-the 1H-pyrazole-3-yl]-3-{[4-(methoxyl group) Phenyl] methyl }-the 2-imidazolidone

At room temperature at N ₂Following, to Intermediate 109(130mg, 0.227mmol), Pd ₂(DBA) ₃(20.8mg, 10%mol), K ₃PO ₄(145mg, 3 equivalents), 2-(dicyclohexyl phosphino-)-2 '-methyl diphenyl (24.8mg, 30%mol) and add anhydrous DME (2mL) in the mixture of 4-methoxyl group-2-aminotoluene (47mg, 1.5 equivalents).Reaction mixture was stirred 3 hours in 90 ℃.Cooling mixture is to room temperature, and adds the more Pd of volume ₂(DBA) ₃(20.8mg, 10%mol) and 2-(dicyclohexyl phosphino-)-2 '-methyl diphenyl (24.8mg, 30%mol).To react on 90 ℃ of reheat 2 hours, and at room temperature place and spend the night.Adding Pd ₂(DBA) ₃(20.8mg, 10%mol) and 2-(dicyclohexyl phosphino-)-2 '-methyl diphenyl (24.8mg, 30%mol) after, with reaction mixture in 90 ℃ of reheat 2 hours.Then it is cooled to room temperature, water and EtOAc handle, and separate two-phase.With organic layer through anhydrous Na ₂SO ₄Drying is filtered this solid, and with the solvent vacuum concentration.(silica gel, cHex/EtOAc 8:2 → 7:3) purifying obtain yellow oil by flash chromatography with crude product Title compound(84mg), it is also polluted by unreacted aniline.This mixture need be further purified be used for next step.

MS(m/z)：671[MH] ⁺。

Intermediate 111

1-[1-(3-(2-hydroxypropyl)-6-methyl-2-{[2-methyl-4-(methoxyl group) phenyl] amino }-the 4-pyridine Base)-the 1H-pyrazole-3-yl]-3-{[4-(methoxyl group) phenyl] methyl }-the 2-imidazolidone

At room temperature at N ₂Down, (80mg adds Et in anhydrous THF (2.5mL) solution 0.12mmol) to intermediate 110 ₃N3HF (156 μ L, 8 equivalents), and with reaction mixture in stirring at room 18 hours.Add EtOAc and water, separate two-phase, and with organic layer through anhydrous Na ₂SO ₄Dry.Filter this solid, and evaporating solvent.Crude product by flash chromatography (silica gel, cHex/EtOAc 1:1) purifying, is obtained faint yellow solid Title compound(23mg, 18%, two is rapid step by step).

( ¹H，CDCl ₃)：δ 7.63(d，1H)，7.57(d，1H)，7.21(d，2H)，7.00(d，1H)，6.87(d，2H)，6.74(s，1H)，6.72(m，2H)，6.44(s，1H)，4.74(m，1H)，4.40(s，2H)，4.35(m，1H)，3.87(m，2H)，3.78(s，3H)，3.77(s，3H)，3.36(t，2H)，2.81(d，1H)，2.78(d，1H)，2.34(s，3H)，2.22(s，3H)，1.33(d，3H)。

MS(m/z)：557[MH] ⁺。

Intermediate 112

1-(1-{2,6-dimethyl-1-[2-methyl-4-(methoxyl group) phenyl]-2,3-dihydro-1H-pyrrolo-[2,3-b] Pyridin-4-yl }-the 1H-pyrazole-3-yl)-3-{[4-(methoxyl group) phenyl] methyl }-the 2-imidazolidone

At room temperature at N ₂Following, to Intermediate 111(23mg, anhydrous CH 0.04mmol) ₂Cl ₂(1mL) add Et in the clear solution ₃N (10 μ L, 2 equivalents), triphenyl phosphine (21.7mg, 2 equivalents) and I ₂(21mg, 2 equivalents), and with reaction mixture in stirring at room 2 hours.Add CH ₂Cl ₂And water, separate two-phase, with organic layer through anhydrous Na ₂SO ₄Drying is filtered this solid, and evaporating solvent.Crude product by flash chromatography (cHex/EtOAc 1:1) purifying, is obtained white solid Title compound(10mg, 46%).

NMR( ¹H，CDCl ₃)：δ 7.80(d，1H)，7.21(d，2H)，7.09(d，1H)，6.99(d，1H)，6.88(d，2H)，6.81(d，1H)，6.76(dd，1H)，6.53(s，1H)，4.41(s，2H)，4.35(m，1H)，3.91(t，2H)，3.79(s，6H)，3.63(dd，1H)，3.42(t，2H)，2.96(dd，1H)，2.28(s，3H)，2.17(s，3H)，1.18(d，3H)。

MS(m/z)：539[MH] ⁺。

Intermediate 113

(4,6-two chloro-2-methyl-5-pyrimidyl) methyl acetate

At 0 ℃ at N ₂Sodium (1.74g, 3 equivalents) is dropped among the anhydrous MeOH (60mL) down.After sodium Metal 99.5 runs out of, add B amidine hydrochloric acid salt (7.06g, 3 equivalents).Stir after 20 minutes, sedimentary NaCl is leached.With 2-ethoxy carbonyl-ethyl succinate (6.04g, anhydrous CH 24.5mmol) ₃OH (20mL) solution joins in free (free) the ethanamidine solution, and mixture was at room temperature stirred 2 days.The vacuum concentration reaction mixture is to dried, and the yellow foam-like material (8.69g) and the POCl that will obtain then ₃(6 equivalent) and CH ₃CN (80mL) mixes, and reflux 18 hours.The solution that generates is cooled to room temperature, and is poured into ice/water and dense NH at leisure ₄Among the OH, the while vigorous stirring.Product is extracted with EtOAc (3 x 50mL).The organic extract that merges is washed with salt, through anhydrous Na ₂SO ₄Drying is filtered and vacuum concentration.Thick oily matter is passed through flash chromatography (silica gel, cHex/EtOAc 8:2) purifying.Obtain yellow solid Title compound(is 98% in rapid step by step two).

NMR( ¹H，CDCl ₃)：δ 5.85(m，1H)，5.15(dq，1H)，5.11(dq，1H)，3.61(dt，2H)，2.67(s，3H)。

MS(m/z)：202[M] ⁺(2Cl)。

Intermediate 114

2-(4,6-two chloro-2-methyl-5-pyrimidyl) ethanol

At-78 ℃ at N ₂Following, to Intermediate 113(4.0g drips DIBAl-H 1M/THF (52.5mL, 3 equivalents) in anhydrous THF (60mL) solution 0.017mol).After adding is finished, reaction mixture was stirred 3 hours in-30 ℃.Add the Rochelle salts solution in 0 ℃ then, and separate two-phase.With the waterbearing stratum with EtOAc (2 x 50mL) extraction, and with the organic extract that merges through anhydrous Na ₂SO ₄Dry.Filter this solid, and evaporating solvent.Obtain transparent buttery Title compound(3.1gr, 89%), and it need be further purified be used for next step.

NMR( ¹H，CDCl ₃)：δ 4.90(t，2H)，3.15(t，2H)，2.64(s，3H)，1.70(bs，1H)。

MS(m/z)：207[MH] ⁺

Intermediate 115

4,6-two chloro-5-(2-{[(1,1-dimethyl ethyl) (dimethyl) silyl] the oxygen base } ethyl)-the 2-methyl Pyrimidine

At 0 ℃ at N ₂Following, to Intermediate 114(3.1g adds imidazoles (17g, 17 equivalents), tert-butyldimethylsilyl chloride (6.35gr, 2.8 equivalents) and DMAP (catalytic amount) in dry DMF 0.015mol) (100mL) solution.This solution was at room temperature stirred 18 hours.Add EtOAc (100mL) and saturated NH ₄The Cl aqueous solution (50mL), and separate two-phase.Organic layer is washed with the saturated NaCl aqueous solution (2 x 100mL), and through anhydrous Na ₂SO ₄Dry.Filter this solid, and evaporating solvent.Crude compound by flash chromatography (silica gel, cHex/EtOAc 9:1) purifying, is obtained transparent buttery Title chemical combination Thing(4.6g, 95%).

NMR( ¹H，CDCl ₃)：δ 3.86(t，2H)，3.12(t，2H)，2.66(s，3H)，0.85(s，9H)，0.01(s，6H)。

MS(m/z)：321[MH] ⁺

Intermediate 116

N-[2, two (trifluoromethyl) phenyl of 4-]-6-chloro-5-(2-{[(1,1-dimethyl ethyl) (dimethyl)-silicomethane Base] the oxygen base } ethyl)-2-methyl-4-PYRIMITHAMINE (pyrimidinamine)

At 0 ℃ at N ₂To 2, add NaH 80%/oil (400mg, 2.2 equivalents) in dry DMF (15mL) solution of 4-pair-trifluoromethyl-aniline (984 μ L, 1 equivalent) down.Reaction mixture was stirred 30 minutes in 0 ℃, and then at room temperature at N ₂Add down, Intermediate 115(2g, dry DMF 6mmol) (15mL) solution.With reaction mixture in stirring at room 30 minutes.Destroy excessive N aH carefully with the saturated NaCl aqueous solution, and reaction mixture is diluted with EtOAc.Separate two-phase, organic layer is washed with the saturated NaCl aqueous solution (2 x 30mL), and through anhydrous Na ₂SO ₄Dry.Filter this solid, and evaporating solvent.With crude compound by flash chromatography (silica gel, the purifying of cHex/EtOAc 95:5 → 90:10).Obtain transparent buttery Title compound(1.84g, 56%).

NMR( ¹H，CDCl ₃)：δ 8.61(d，1H)，8.04(bs，1H)，7.86(s，1H)，7.79(d，1H)，4.95(t，2H)，3.95(t，2H)，2.53(s，3H)，0.73(s，9H)，-0.90(s，6H)。

MS(m/z)：514[MH] ⁺

Intermediate 117

2-(4-{[2, two (trifluoromethyl) phenyl of 4-] amino }-6-chloro-2-methyl-5-pyrimidyl) ethanol

At room temperature at N ₂Following, to Intermediate 116(1.84g adds Et in dry DMF 3.58mmol) (30mL) solution ₃N3HF (2.4mL, 3 equivalents).With reaction mixture in stirring at room 18 hours.Then it is diluted with the cold saturated NaCl aqueous solution (50mL), and extract with EtOAc (3 x 50mL).With the organic extract that merges through anhydrous Na ₂SO ₄Dry.Filter this solid, and evaporating solvent.Obtain transparent buttery Title compound(1.4gr, 98%), and it need be further purified be used for next step.

NMR( ¹H，CDCl ₃)：δ 8.59(bs，1H)，8.22(d，1H)，7.84(s，1H)，7.75(d，1H)，4.06(t，2H)，3.01(t，2H)，2.50(s，3H)

MS(m/z)：400[MH] ⁺

Intermediate 118

7-[2, two (trifluoromethyl) phenyl of 4-]-4-chloro-2-methyl-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine

At 0 ℃ at N ₂Following, to Intermediate 117(514mg, anhydrous CH 1.29mmol) ₂Cl ₂(20mL) add Et in the solution ₃N (712 μ L, 4 equivalents) and methylsulfonyl chloride (197 μ L, 2 equivalents), and with reaction mixture in stirring at room 18 hours.Add entry (20mL) then, and separate two-phase.With waterbearing stratum CH ₂Cl ₂(2 x 20mL) extraction, and with the organic extract that merges through anhydrous Na ₂SO ₄Dry.Filter this solid, and evaporating solvent.Crude product by flash chromatography (silica gel, cHex/EtOAc 8:2) purifying, is obtained white solid Title compound(430mg, 87%).

NMR( ¹H，CDCl ₃)：δ 8.04(s，1H)，7.93(s，1H)，7.53(d，1H)，4.00(t，2H)，3.24(t，2H)，2.42(s，3H)。

MS(m/z)：381[MH] ⁺。

Intermediate 119

2-{4-chloro-6-[(2, the 4-dichlorophenyl) amino]-2-methyl-5-pyrimidyl } ethanol

Will Intermediate 114(1.34g, 6.47mmol) and 2,4 dichloro aniline (1.06g, 1 equivalent) in air-tight bottle in 100 ℃ at N ₂Under heated 18 hours.Add H ₂The 1:1 mixture of O/MeOH, and form white precipitate.With this solid filtering and dry, obtain the title compound (960mg, 44%) of white solid.

MS(m/z)：332[M] ⁺。

Intermediate 120

4-chloro-7-(2,4 dichloro benzene base)-2-methyl-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine

At 0 ℃ at N ₂Following, to Intermediate 119(960mg, anhydrous CH 2.87mmol) ₂Cl ₂(10mL) add Et in the solution ₃N (1.21mL, 3 equivalents) and MsCl (0.5ml, 2.3 equivalents).Reaction mixture was at room temperature kept 4 hours.Add Et then ₃N (0.6mL, 2 equivalents), and with mixture backflow 3 hours.With reaction mixture CH ₂Cl ₂Dilute, and wash with 10%HCl (15mL).Separate this organic phase, and wash with the saturated NaCl aqueous solution.With it through anhydrous Na ₂SO ₄Drying is filtered this solid, and evaporating solvent.Obtain white solid Title compound(900mg, quantitative productive rate), and it need be further purified be used for next step.

NMR( ¹H，CDCl ₃)：δ 7.45(d，1H)，7.3(d，2H)，4.05(t，2H)，3.16(t，2H)，2.45(s，3H)。

MS(m/z)：315[MH] ⁺。

Intermediate 121

3-{6-methyl isophthalic acid-[2-methyl-4-(methoxyl group) phenyl]-2,3-dihydro-1H-pyrrolo-[2,3-b] pyridine-4- Base } aniline

At room temperature at N ₂To down, Intermediate 5(100mg, 0.263mmol), 3-aminophenyl boric acid (61mg, 1.5 equivalents), Pd (PPh ₃) ₄(30mg, 0.1 equivalent), TBAB (8mg, 0.1 equivalent) and 2NNa ₂CO ₃(3.7ml, 28.5 equivalents) suspension in the 1:1 of anhydrous EtOH/ toluene mixture (10mL) was in 100 ℃ of heating 2.5 hours.It is cooled to room temperature, and is poured in the water.Add EtOAc, and separate two-phase.EtOAc (2 x 10mL) extraction is further used in the waterbearing stratum.With the organic extract that merges through anhydrous Na ₂SO ₄Drying is filtered this solid, and evaporating solvent.With resistates (100%CH on the SCX post ₂Cl ₂→ NH ₃(0.5 MeOH solution)) purifying, and on MEGA Bond Elut silica column (CH ₂Cl ₂/ MeOH 95:5) purifying obtains the title compound (91mg, quantitative productive rate) of white solid.

NMR( ¹H，DMSO-d ₆)：δ 7.18(d，1H)，7.09(t，1H)，6.87(d，1H)，6.81(dd，1H)，6.76(d，1H)，6.69(d，2H)，6.61(d，2H)，6.41(s，1H)，5.18(bs，2H)，3.8(m，5H)，3.15(t，2H)，2.2(s，6H)。

MS(m/z)：346[MH] ⁺。

Intermediate 122

N-(2-chloroethyl)-N '-(3-{6-methyl isophthalic acid-[2-methyl-4-(methoxyl group) phenyl]-2,3-dihydro-1H-pyrroles And [2,3-b] pyridin-4-yl } phenyl) urea

At room temperature at N ₂Following, to Intermediate 121(91mg adds 2-chloroethyl isocyanate (51 μ L, 2 equivalents) in anhydrous THF (3mL) solution 0.26mmol).With reaction mixture in stirring at room 2 hours.It is evaporated to dried, and with resistates by flash chromatography (silica gel, cHex/EtOAc7:3 → EtOAc/Et ₃N 1:0.02) purifying obtains white solid Title compound(113.4mg, 97%).

NMR( ¹H，DMSO-d ₆)：δ 8.76(s，1H)，7.69(s，1H)，7.28(m，2H)，7.14(d，1H)，7.05(t，1H)，8.23(d，1H)，6.74(dd，1H)，6.4(m，2H)，3.75(m，5H)，3.6(m，2H)，3.4(m，2H)，3.1(t，2H)，2.15(s，3H)，2.15(s，3H)。

MS(m/z)：451[MH] ⁺。

Intermediate 123

5-methyl isophthalic acid-{ 6-methyl isophthalic acid-[2-methyl-4-(methoxyl group) phenyl]-2,3-dihydro-1H-pyrrolo-[2,3-b] Pyridin-4-yl }-1H-pyrazoles-3-amine

Will Intermediate 5(200mg, 0.52mmol), 5-methyl-3-amino-pyrazol (200mg, 2 equivalents), CuI (285mg, 3 equivalents), K ₂CO ₃Anhydrous NMP (1mL) solution of (150mg, 2.1 equivalents), N-N '-dimethyl trans-ortho-cyclohexanediamine (213mg, 3 equivalents) was in 150 ℃ of heating 36 hours.Add H then ₂O (50mL), and with solution CH ₂Cl ₂(3x25mL) extraction.With organic layer through anhydrous Na 2SO ₄Drying is filtered this solid, and vacuum evaporating solvent.(silica gel, cHex/EtOAc 9:1 → 3:7) purifying obtain white solid by flash chromatography with thus obtained crude compound Title compound(60mg, 33%).

NMR( ¹H，CDCl ₃)：7.15(d，1H)；6.85(d，1H)；6.75(m，1H)；6.45(s，1H)；5.48(s，1H)；4.74(s，2H)；3.71(s，3H)；3.23(t，2H)；3.12(t，2H)；2.20(s，3H)，2.11(s，6H)δ.

MS(m/z)：350[MH] ⁺。

Intermediate 124

N-(2-chloroethyl)-N '-(1-{6-methyl isophthalic acid-[2-methyl-4-(methoxyl group) phenyl]-2,3-dihydro-1H-pyrrole Cough up also [2,3-b] pyridin-4-yl }-1H-1,2,4-triazole-3-yl) urea

At 0 ℃ at N ₂Following, to Intermediate 123(60mg adds 2-chloroethyl isocyanate (0.2mL, excessive) in dry DMF 0.17mmol) (2mL) solution, and with reaction mixture in stirring at room 16 hours.Add H then ₂O (10mL), and with solution CH ₂Cl ₂(2 x 10mL) extraction.With the organic extract that merges through anhydrous Na ₂SO ₄Drying is filtered this solid, and vacuum evaporating solvent.With crude product (CH on the SCX post ₂Cl ₂, 0.05M NH then ₃/ MeOH) purifying obtains white solid Title chemical combination Thing(30mg, 40%).

MS(m/z)：455[MH] ⁺。

Intermediate 125

1-ethanoyl-3-[1-(1-{4-[(difluoromethyl) oxygen base]-the 2-aminomethyl phenyl }-6-methyl-2,3-dihydro-1H- Pyrrolo-[2,3-b] pyridin-4-yl)-the 1H-pyrazole-3-yl]-the 2-imidazolidone

At N ₂Descend at room temperature, to Intermediate 29(2.87g adds NaH 60%/oil (0.240g, 1.2 equivalents) in dry DMF 4.63mmols) (80mL) solution.With reaction mixture in stirring at room 10 minutes, then with the flask Rubber Diaphragm Seal.Add CF ₂Br ₂(2.5mL, 6 equivalents), and with mixture in 60 ℃ the heating 3 hours.Cooling mixture is to room temperature, with saturated NaHCO ₃The aqueous solution stops, and uses CH ₂Cl ₂(1 x 50mL) extraction.Organic layer is washed with the saturated NaCl aqueous solution, and through anhydrous Na ₂SO ₄Dry.Filter this solid, and evaporating solvent.Resistates is passed through flash chromatography (silica gel, 2.5% MeOH/CH ₂Cl ₂) purifying twice, obtain 554mg still by the crude compound of by-product contamination.By segmentation (fraction) lynx chromatography (M+H=483) purifying once more, and the still contaminated fraction (174mg) that will generate is by flash chromatography (silica gel, 2% MeOH/CH with it ₂Cl ₂) purifying once more, obtain white solid Title compound(76mg, 3.4%).

NMR( ¹H，CDCl ₃)：δ 7.93(d，1H)，7.23(dd，1H)，7.1-7.0(m，3H)，6.63(s，1H)，6.54(t，1H)，4.07(m，4H)，4.03(t，2H)，3.53(t，2H)，2.63(s，3H)，2.40(bs，3H)，2.31(s，3H)。

Embodiment 1

Synthesizing of general formula (II) compound,

Wherein

Y is-CR ₇

W is the W2 derivative:

Z be pyrazolyl, phenyl, pyridyl, pyrimidyl, triazolyl (trazolyl), derivative and

M is the integer of 0-2;

Q is the integer of 0-4.

Embodiment 1-1

1-{1-[1-(4-methoxyl group-2-aminomethyl phenyl)-6-methyl-2,3-dihydro-1H-pyrrolo-[2,3-b] pyridine -4-yl]-the 1H-pyrazole-3-yl } imidazolidin-2-one

At room temperature at N ₂Down, will in air-tight bottle Intermediate 5(60mg, 0.158mmol), CuI (6mg, 0.2 equivalent) and K ₂CO ₃(4.5mg, 2.5 equivalents) mix.Add dodecane (14.3 μ L, 0.4 equivalent), anti--cyclohexane diamine (14 μ L, 0.6 equivalent) and Intermediate 8Anhydrous NMP (5mL) solution of (48mg, 2 equivalents), and reaction mixture stirred 3.5 hours in 130 ℃.Then it is cooled to room temperature, and is poured into EtOAc/H ₂Among the O.Separate two-phase, and the waterbearing stratum is extracted with EtOAc (2 x 10mL).With the organic extract that merges through anhydrous Na ₂SO ₄Drying is filtered this solid, and evaporating solvent.Crude product by flash chromatography (EtOAc/cHex 6:4,1:1,3:7 then then), is passed through SCX post (100% MeOH, 2M NH then subsequently ₃/ MeOH) purifying obtains white solid Title chemical combination Thing(34mg, 53%).

Perhaps, at room temperature at N ₂Down, in dry DMF (1.8mL) suspension of CuI (8mg, 0.02 equivalent), add (1R, 2R)-N, N '-dimethyl-1,2-cyclohexane diamine (90mg, 0.3 equivalent), and the blue solution of gained at room temperature stirred 1.5 hours.Add Intermediate 8(0.80g, 2.5 equivalents) and K ₂CO ₃(0.87g, 3.0 equivalents) add subsequently Intermediate 92(0.7g, dry DMF 21mmol) (1.8mL) solution.The mixture that generates was heated 30 hours in 125 ℃.In 60 ℃ of cooling mixtures, and drip water (10mL).Suspension is at room temperature stirred 1 hour, and filter this white precipitate, and wash once with the 1:2 mixture (10mL) of DMF/ water, water (10mL) is washed twice then.With the solid collected in 80 ℃ of dryings 24 hours.Thus obtained thick solid at room temperature is dissolved in CH ₂Cl ₂In 9: 1 mixtures (10mL) of/MeOH.Solution is filtered by carbon liner (carbon pad), and filter cake is washed with identical solvent (10mL).At room temperature drip heptane (20mL), the suspension that generates was left standstill 2 hours, filter, and wash with MeOH.The solid collected in 80 ℃ of dryings 24 hours, is obtained white solid Titleization Compound(410mg, 48%).

Embodiment 1-2

1-{1-[1-(4-methoxyl group-2-aminomethyl phenyl)-6-methyl-2,3-dihydro-1H-pyrrolo-[2,3-b] pyridine -4-yl]-the 1H-pyrazole-3-yl }-3-Methylimidazole alkane-2-ketone

At room temperature at N ₂Following, to Embodiment 1(20mg adds KOt-Bu (5mg, 1 equivalent) in anhydrous THF (1mL) solution 0.05mmol), and reaction mixture was stirred 15 minutes.Add methyl iodide (6 μ L, 2 equivalents) then, and with reaction mixture in stirring at room 3 hours.Be poured into EtOAc/H then ₂Among the O, and separate two-phase.With the waterbearing stratum with EtOAc (2 x 20mL) extraction, and with the organic extract that merges through anhydrous Na ₂SO ₄Dry.Filter this solid, and evaporating solvent.Crude product by flash chromatography (silica gel, cHex/EtOAc 1:1) purifying, is obtained yellow solid Title compound(6mg, 29%).

Embodiment 1-3

1-{1-[1-(2,4 dichloro benzene base)-6-methyl-2,3-dihydro-1H-pyrrolo-[2,3-b] pyridin-4-yl]-1H- Pyrazole-3-yl } imidazolidin-2-one

At room temperature at N ₂Following, to Intermediate 37(25mg 0.062mmol) and in the solution of the anhydrous NMP (2mL) of 1-(1H-pyrazole-3-yl)-2-imidazolidone (18.8mg, 2 equivalents) adds K ₂CO ₃(26mg, 3 equivalents), CuI (1.2mg, 0.1 equivalent) and (1R, 2R)-diamino ethyl hexanaphthene (2.9mg, 0.3 equivalent), and in 100 ℃ of stirred reaction mixtures 1 hour, in 120 ℃ of stirrings 1 hour, in 150 ℃ of stirrings 1 hour, and in 180 ℃ of stirrings 2 hours.Then reaction mixture is cooled to room temperature, between the saturated NaCl aqueous solution (100mL/50mL) of EtOAc/, distributes then.Separate two-phase, and with organic layer through anhydrous Na ₂SO ₄Drying is filtered this solid, evaporating solvent, and with crude product by flash chromatography (silica gel, cHex/EtOAc 2:8) purifying, obtain white solid Title compound(2mg, 7%).

Embodiment 1-4

1-(1-{1-[2, two (trifluoromethyl) phenyl of 4-]-6-methyl-2,3-dihydro-1H-pyrrolo-[2,3-b] pyridine -4-yl }-the 1H-pyrazole-3-yl)-the 2-imidazolidone

At room temperature at N ₂Following, to Intermediate 81(120mg adds phenylmethylether (61 μ L, 3 equivalents) in TFA 0.19mmol) (12mL) solution, and reaction mixture was stirred 2 hours in 80 ℃.This solution of vacuum concentration.With resistates CH ₂Cl ₂Dilution, and with saturated NaHCO ₃The aqueous solution is washed.With organic layer through anhydrous Na ₂SO ₄Drying is filtered this solid, and evaporating solvent.Crude product is passed through flash chromatography (CH ₂Cl ₂→ CH ₂Cl ₂/ MeOH 95:5) purifying obtains white solid Title compound(80mg, 84%).

Embodiment 1-5

1-{1-[1-(4-hydroxy-2-methyl phenyl)-6-methyl-2,3-dihydro-1H-pyrrolo-[2,3-b] pyridine-4- Base]-the 1H-pyrazole-3-yl }-the 2-imidazolidone

At 0 ℃ at N ₂Following, to Embodiment 1(131mg, anhydrous CH 0.324mmol) ₂Cl ₂(6.5mL) add BBr in the solution ₃1M/CH ₂Cl ₂(1.6mL, 5 equivalents), and reaction mixture stirred 3 hours in 0 ℃.Add MeOH (5mL) at leisure, and evaporating solvent.Resistates is absorbed CH ₂Cl ₂In, and with organic layer with saturated NaHCO ₃The aqueous solution (2 x 20mL) is washed, and through anhydrous Na ₂SO ₄Dry.Filter this solid, and evaporating solvent.Crude compound by flash chromatography (silica gel, 100%EtOAc → 5% MeOH/EtOAc) purifying, is obtained yellow solid Title compound(65mg, 51%).

Embodiment 1-6

1-ethanoyl-3-(1-{6-methyl isophthalic acid-[2-methyl-4-(methoxyl group) phenyl]-2,3-dihydro-1H-pyrrolo- [2,3-b] pyridin-4-yl }-the 1H-pyrazole-3-yl)-the 2-imidazolidone

At room temperature at N ₂Following, to Embodiment 1(205mg adds NaH 60%/oil (24mg, 1.2 equivalents) in dry DMF 0.507mmol) (10mL) solution.With reaction mixture in stirring at room 20 minutes.It is cooled to 0 ℃ then, and slowly adds Acetyl Chloride 98Min. (72 μ L, 2 equivalents).Reaction mixture is stirred 15 minutes (formation white precipitate) in 0 ℃, and at room temperature stirred 30 minutes.Be poured into then in the saturated NaCl aqueous solution of EtOAc/, and separate two-phase.Organic layer is washed with the saturated NaCl aqueous solution (2 x 20mL), and with the water CH that merges ₂Cl ₂(2 x 20mL) back extraction.With the organic extract that merges through anhydrous Na ₂SO ₄Drying is filtered this solid, and evaporating solvent.Crude compound is passed through flash chromatography (silica gel, 2.5% MeOH/CH ₂Cl ₂) purifying.Obtain yellow solid Title compound(190mg, 84%).

Embodiment 1-7

1-(1-{1-[4-(oxyethyl group)-2-aminomethyl phenyl]-6-methyl-2,3-dihydro-1H-pyrrolo-[2,3-b] pyridine -4-yl }-the 1H-pyrazole-3-yl)-the 2-imidazolidone

At room temperature at N ₂Following, to Intermediate 30(5mg, MeOH/CH 0.011mmol) ₂Cl ₂Add Cs in the solution of anhydrous 3:1 mixture (1mL) ₂CO ₃(18mg, 5 equivalents), and with reaction mixture in stirring at room 1 hour.Evaporating solvent, and with resistates by flash chromatography (MEGA-Bond Elut, 500mg, cHex/EtOAc 1:1) purifying, obtain white solid Title compound(2.3mg, 50%).

Embodiment 1-8

1-[1-(the 6-methyl isophthalic acid-and 2-methyl-4-[(1-methylethyl) the oxygen base] phenyl }-2,3-dihydro-1H-pyrrolo- [2,3-b] pyridin-4-yl)-the 1H-pyrazole-3-yl]-the 2-imidazolidone

At room temperature at N ₂Following, to Intermediate 31(11mg, MeOH/CH 0.023mmol) ₂Cl ₂Add Cs in the solution of anhydrous 3:1 mixture (1mL) ₂CO ₃(38mg, 5 equivalents), and with reaction mixture in stirring at room 2 hours.Evaporating solvent, and with resistates by flash chromatography (MEGA-BondElut, 1gr, cHex/EtOAc 1:1) purifying, obtain white solid Title compound(2.1mg, 21%).

Embodiment 1-9

1-[1-(the 6-methyl isophthalic acid-and 2-methyl-4-[(trifluoromethyl) the oxygen base] phenyl }-2,3-dihydro-1H-pyrrolo- [2,3-b] pyridin-4-yl)-the 1H-pyrazole-3-yl]-the 2-imidazolidone

At N ₂Following, to Intermediate 48(140mg adds phenylmethylether (263 μ L, 10 equivalents) in TFA 0.242mmol) (3.0mL) solution, and stirred reaction mixture, and in 80 ℃ of heating 2 hours.Then it is cooled to room temperature, the evaporation TFA, and with reaction mixture at CH ₂Cl ₂/ saturated NaHCO ₃Distribute between the aqueous solution.Separate two-phase, and organic layer is washed with the saturated NaCl aqueous solution (2 x 10mL).With it through anhydrous Na ₂SO ₄Drying is filtered this solid, and evaporating solvent.Crude product is passed through flash chromatography (silica gel, CH ₂Cl ₂/ MeOH 95:5) purifying obtains white solid Title compound(110mg, 99%).

Embodiment 1-10

3-methyl-4-{6-methyl-4-[3-(2-oxo-1-imidazolidyl)-1H-pyrazol-1-yl]-2,3-dihydro-1H- Pyrrolo-[2,3-b] pyridine-1-yl } benzonitrile

At room temperature at N ₂Following, to Intermediate 51(120mg adds phenylmethylether (75 μ L, 3 equivalents) in TFA 0.23mmol) (15mL) solution, and reaction mixture was stirred 1.5 hours in 80 ℃.This solution of vacuum concentration.With resistates CH ₂Cl ₂Dilution, and with saturated NaHCO ₃The aqueous solution is washed.With organic layer through anhydrous Na ₂SO ₄Drying is filtered this solid, and evaporating solvent.With crude product (CH on the SCX post ₂Cl ₂→ CH ₂Cl ₂/ MeOH 95:5) purifying obtains white solid Title compound(58mg, 63%).

Embodiment 1-11

1-(1-{6-methyl isophthalic acid-[2-methyl-4-(1H-pyrazol-1-yl) phenyl]-2,3-dihydro-1H-pyrrolo-[2,3-b] Pyridin-4-yl }-the 1H-pyrazole-3-yl)-the 2-imidazolidone

At N ₂Following, to Intermediate 54(95mg adds phenylmethylether (184 μ L, 10 equivalents) in TFA 0.169mmol) (2.0mL) solution, and stirred reaction mixture, and in 80 ℃ of heating 2 hours.Then it is cooled to room temperature, the evaporation TFA, and with reaction mixture at CH ₂Cl ₂/ saturated NaHCO ₃Distribute between the aqueous solution.Separate two-phase, and organic layer is washed with the saturated NaCl aqueous solution (2x10mL).With it through anhydrous Na ₂SO ₄Drying is filtered this solid, and evaporating solvent.Crude product is passed through flash chromatography (silica gel, CH ₂Cl ₂/ MeOH 95:5) purifying obtains white solid Title compound(77mg, 99%).

Embodiment 1-12

4-{6-methyl-4-[3-(2-oxo-1-imidazolidyl)-1H-pyrazol-1-yl]-2,3-dihydro-1H-pyrrolo- [2,3-b] pyridine-1-yl }-3-(trifluoromethyl) benzonitrile

At N ₂Following, to Intermediate 57(70mg adds phenylmethylether (133 μ L, 10 equivalents) in TFA o.122mmol) (2.0mL) solution, and stirred reaction mixture, and in 80 ℃ of heating 2 hours.Then it is cooled to room temperature, evaporation TFA, and with the direct (100%CH on the SCX post of crude product ₂Cl ₂→ CH ₂Cl ₂/ MeOH, and 2.0M Et then ₃N/MeOH) purifying obtains the mark of white solid The topic compound(55mg, 99%).

Embodiment 1-13

1-(1-{1-[2-(difluoromethyl)-4-(methoxyl group) phenyl]-6-methyl-2,3-dihydro-1H-pyrrolo-[2,3-b] Pyridin-4-yl }-the 1H-pyrazole-3-yl)-the 2-imidazolidone

At room temperature at N ₂Following, to Intermediate 60(19.6mg adds phenylmethylether (12 μ L, 0.003 equivalent) in TFA 0.035mmol) (4mL) solution.Reaction mixture was stirred 2 hours.Add saturated NaHCO ₃The aqueous solution is until reaching neutral pH, and mixture is evaporated to dried.With resistates (0.5M NH on the SCX post ₃/ MeOH) purifying obtains the white foam shape Title compound(7.2mg, 47%).

Embodiment 1-14

4-{6-methyl-4-[3-(2-oxo-1-imidazolidyl)-1H-pyrazol-1-yl]-2,3-dihydro-1H-pyrrolo- [2,3-b] pyridine-1-yl }-the 3-[(trifluoromethyl) the oxygen base] benzonitrile

At room temperature at N ₂Following, to Intermediate 63(115mg adds phenylmethylether (61 μ L, 3 equivalents) in TFA 0.19mmol) (12mL) solution, and reaction mixture was stirred 1.5 hours in 80 ℃.This solution of vacuum concentration.With resistates CH ₂Cl ₂Dilution, and with saturated NaHCO ₃The aqueous solution is washed.With organic layer through anhydrous Na ₂SO ₄Drying is filtered this solid, and evaporating solvent.With crude product (CH on the SCX post ₂Cl ₂→ CH ₂Cl ₂/ MeOH 95:5) purifying obtains white solid Title compound(52.9mg, 59%).

Embodiment 1-15

3-ethyl-4-{6-methyl-4-[3-(2-oxo-1-imidazolidyl)-1H-pyrazol-1-yl]-2,3-dihydro-1H- Pyrrolo-[2,3-b] pyridine-1-yl } benzonitrile

At room temperature at N ₂Following, to Intermediate 66(70mg adds phenylmethylether (42 μ L, 3 equivalents) in TFA 0.13mmol) (9mL) solution, and reaction mixture was stirred 1 hour in 80 ℃.This solution of vacuum concentration.With resistates CH ₂Cl ₂Dilution, and with saturated NaHCO ₃The aqueous solution is washed.With organic layer through anhydrous Na ₂SO ₄Drying is filtered this solid, and evaporating solvent.With crude product (100%CH on the SCX post ₂Cl ₂→ CH ₂Cl ₂/ MeOH 95:5) purifying obtains white solid Title compound(29mg, 54%).

Embodiment 1-16

1-(1-{6-methyl isophthalic acid-[2-(methoxyl group)-4-(1H-pyrazol-1-yl) phenyl]-2,3-dihydro-1H-pyrrolo- [2,3-b] pyridin-4-yl }-the 1H-pyrazole-3-yl)-the 2-imidazolidone

At room temperature at N ₂Following, to Intermediate 69(72mg adds phenylmethylether (41 μ L, 3 equivalents) in TFA 0.12mmol) (7.5mL) solution, and reaction mixture was stirred 1.5 hours in 80 ℃.This solution of vacuum concentration.With resistates CH ₂Cl ₂Dilution, and with saturated NaHCO ₃The aqueous solution is washed.With organic layer through anhydrous Na ₂SO ₄Drying is filtered this solid, and evaporating solvent.With crude product (CH on the SCX post ₂Cl ₂/ 0.5M NH3/MeOH 95:5) purifying obtains white solid Title compound(35mg, 64%).

Embodiment 1-17

1-{1-[6-methyl isophthalic acid-(6-methyl isophthalic acid, 3-benzodioxole-5-yl)-2,3-dihydro-1H-pyrroles And [2,3-b] pyridin-4-yl]-the 1H-pyrazole-3-yl }-the 2-imidazolidone

At room temperature at N ₂Following, to Intermediate 72(41mg adds phenylmethylether (25 μ L, 3 equivalents) in TFA 0.076mmol) (4.7mL) solution, and reaction mixture was stirred 1.5 hours in 80 ℃.This solution of vacuum concentration.With resistates CH ₂Cl ₂Dilution, and with saturated NaHCO ₃The aqueous solution is washed.With organic layer through anhydrous Na ₂SO ₄Drying is filtered this solid, and evaporating solvent.With crude product (100%CH on the SCX post ₂Cl ₂→ CH ₂Cl ₂/ MeOH 98:2) purifying obtains white solid Title compound(25mg, 79%).

Embodiment 1-18

1-(1-{6-methyl isophthalic acid-[2,4,6-trimethoxy phenyl]-2,3-dihydro-1H-pyrrolo-[2,3-b] pyridine -4-yl }-the 1H-pyrazole-3-yl)-the 2-imidazolidone

To Intermediate 75(16mg, 0.028mmol) middle TFA (1mL) and the phenylmethylether (10 μ L, 3 equivalents) of adding.With reaction mixture in stirring at room 3 hours, and solvent evaporated under reduced pressure.With thick mixture at CH ₂Cl ₂/ saturated NaHCO ₃Distribute between the aqueous solution.Separate two-phase, and with organic layer through anhydrous Na ₂SO ₄Drying is filtered this solid, and evaporating solvent.Crude product is passed through flash chromatography (silica gel, 100% CH ₂Cl ₂→ CH ₂Cl ₂/ MeOH 97:3) purifying, (100%CH on SCX SPE post subsequently ₂Cl ₂To CH ₂Cl ₂/ MeOH/2M NH ₃MeOH solution 80:19:1) be further purified, obtain white solid Title compound(9.5mg, 71%).

Embodiment 1-19

At room temperature at N ₂Following, to Intermediate 78(20mg adds phenylmethylether (12 μ L, 3 equivalents) in TFA 0.037mmol) (2.3mL) solution, and reaction mixture was stirred 2 hours in 80 ℃.This solution of vacuum concentration.With resistates CH ₂Cl ₂Dilution, and with it with saturated NaHCO ₃The aqueous solution is washed.With organic layer through anhydrous Na ₂SO ₄Drying is filtered this solid, and evaporating solvent.With crude product (CH on the SCX post ₂Cl ₂→ CH ₂Cl ₂/ MeOH 98:2) purifying obtains white solid Title compound(12.4mg, 76%).

Embodiment 1-20

1-(6-{6-methyl isophthalic acid-[2-methyl-4-(methoxyl group) phenyl]-2,3-dihydro-1H-pyrrolo-[2,3-b] pyridine -4-yl }-the 2-pyridyl)-the 2-imidazolidone

At room temperature at N ₂Following, to Intermediate 97Add phenylmethylether (18.3 μ L, 3 equivalents) and a H in TFA (0.75ml) solution of (30mg, 1 equivalent) ₂SO ₄With reaction mixture refluxed 3 hours.It is concentrated, and then at EtOAc and NaHCO ₃Distribute between the saturated solution.Separate two-phase, and organic layer is washed with the saturated NaCl aqueous solution.With it through anhydrous Na ₂SO ₄Drying is filtered this solid, and evaporating solvent.Obtain the compound (22mg, 98%) of white solid.

Embodiment 1-21

1-(4-{6-methyl isophthalic acid-[2-methyl-4-(methoxyl group) phenyl]-2,3-dihydro-1H-pyrrolo-[2,3-b] pyridine -4-yl }-the 2-pyrimidyl)-the 2-imidazolidone

At room temperature at N ₂Following, to Intermediate 103(71mg adds phenylmethylether (50 μ L, 3.7 equivalents) in TFA 0.125mmol) (1mL) solution.With reaction mixture refluxed 3 hours.Analyze the required product that does not detect trace by MS.In this refrigerative reaction mixture, add dense H ₂SO ₄(2).With reaction mixture refluxed 75 minutes, be cooled to room temperature and use solid Na ₂CO ₃Neutralization.Evaporating solvent, and with resistates (CH on MEGA Bond Elut silica column ₂Cl ₂/ Et ₂O/EtOAc 1:1:2 → CH ₂Cl ₂/ MeOH/Et ₃N 1:1:0.02) purifying obtains yellow solid Title compound(24.2mg, 47%).

Embodiment 1-22

1-(2-{6-methyl isophthalic acid-[2-methyl-4-(methoxyl group) phenyl]-2,3-dihydro-1H-pyrrolo-[2,3-b] pyridine -4-yl }-the 4-pyrimidyl)-the 2-imidazolidone

At room temperature at N ₂Following, to Intermediate 105(13mg adds phenylmethylether (10 μ L, 4 equivalents) and dense H in TFA 0.023mmol) (1mL) solution ₂SO ₄(2).With reaction mixture refluxed 2 hours, and use solid NaHCO ₃Neutralization.Reaction mixture is distributed between EtOAc and water.EtOAc (3 x 10mL) extraction is further used in the waterbearing stratum, and with the organic extract vacuum concentration that merges.Resistates is passed through flash chromatography (silica gel, 100% CH ₂Cl ₂→ CH ₂Cl ₂/ MeOH 95:5) (100%CH and on the SCX post ₂Cl ₂→ NH ₃(0.5 MeOH solution)) purifying, obtain white solid Title compound(2.8mg, 10%, 2 step).

Embodiment 1-23

1-(1-{6-methyl isophthalic acid-[2-methyl-4-(methoxyl group) phenyl]-2,3-dihydro-1H-pyrrolo-[2,3-b] pyridine -4-yl }-the 1H-pyrazole-3-yl)-the 2-imidazolidone

At room temperature at N ₂Following, to Intermediate 107(30mg adds KOt-Bu (9mg, 1.2 equivalents) in anhydrous THF (2mL) solution 0.06mmol), and reaction mixture was stirred 1 hour.Add entry (0.5mL), and evaporating solvent.With water layer H ₂The O dilution, and use CH ₂Cl ₂(3 x 20mL) extraction.With the organic extract that merges through anhydrous Na ₂SO ₄Dry.Filter this solid, and evaporating solvent.With crude product (100% EtOAc → EtOAc/MeOH 9:1) purifying on MEGA Bond Elut silica column, obtain white solid Title compound(6mg, 25%).

Embodiment 1-24

1-(1-{2,6-dimethyl-1-[2-methyl-4-(methoxyl group) phenyl]-2,3-dihydro-1H-pyrrolo-[2,3-b] Pyridin-4-yl }-the 1H-pyrazole-3-yl)-the 2-imidazolidone

At room temperature at N ₂Following, to Intermediate 112(10mg adds phenylmethylether (10 μ L, 5 equivalents) in TFA 0.018mmol) (1.1mL) solution, and reaction mixture was stirred 1.5 hours in 80 ℃.Then with solution for vacuum concentration.With resistates CH ₂Cl ₂Dilution is with saturated NaHCO ₃The aqueous solution is washed, and separates two-phase.With organic layer through anhydrous Na ₂SO ₄Drying is filtered this solid, and evaporating solvent.With crude product (100%CH on MEGA Bond Elut silica column ₂Cl ₂→ CH ₂Cl ₂/ MeOH 98:2) purifying obtains the title compound (racemic compound) (6mg, 80%) of white solid.

Embodiment 1-25

1-(3-{6-methyl isophthalic acid-[2-methyl-4-(methoxyl group) phenyl]-2,3-dihydro-1H-pyrrolo-[2,3-b] pyridine -4-yl } phenyl)-the 2-imidazolidone

At room temperature at N ₂Following, to Intermediate 122(60mg adds t-BuOK (18mg, 1.2 equivalents) in anhydrous THF (3mL) suspension 0.13mmol).With reaction mixture in stirring at room 3 hours.Add saturated NH ₄The Cl aqueous solution and EtOAc, and separate two-phase.EtOAc (2 x 10mL) extraction is further used in the waterbearing stratum.With the organic extract that merges through anhydrous Na ₂SO ₄Drying is filtered this solid, and evaporating solvent.(required compound that obtains is still polluted by aliphatic impurities for silica gel, the purifying of cHex/EtOAc 8:2 → 100%EtOAc) by flash chromatography with resistates.This crude product is further passed through preparation property HPLC (post: X Terra MS C 185mm, 30 x 75mm, moving phase: A:H2O+0.1%TFA, B:CH3CN+0.1%TFA, gradient: 10% (B), 1 minute, by 10% (B) to 90% (B), 12 minutes, flow velocity (ml/min): 43, UV wavelength region (nm): 200-400, mass range (amu): 100-900, ionization: ES+) purifying obtains white solid Title compound(31.3mg, 58%).

Embodiment 1-26

1-(5-methyl isophthalic acid-{ 6-methyl isophthalic acid-[2-methyl-4-(methoxyl group) phenyl]-2,3-dihydro-1H-pyrrolo- [2,3-b] pyridin-4-yl }-the 1H-pyrazole-3-yl)-the 2-imidazolidone

At room temperature at N ₂Following, to Intermediate 124(35mg adds t-BuOK (9.8mg, 1.2 equivalents) in anhydrous THF (2mL) solution 0.072mmol), and with reaction mixture in stirring at room 18 hours.Add entry (0.5mL), and evaporating solvent.With water layer H ₂The O dilution, and use CH ₂Cl ₂(3x10mL) extraction.With the organic extract that merges through anhydrous Na ₂SO ₄Dry.Filter this solid, and evaporating solvent.(EtOAc/cHex 2:8 → 3:7) purifying obtains white solid on MEGA Bond Elut silica column with crude product Title compound(12mg, 39%).

Embodiment 1-27

1-[1-(1-{4-[(difluoromethyl) oxygen base]-the 2-aminomethyl phenyl }-6-methyl-2,3-dihydro-1H-pyrrolo- [2,3-b] pyridin-4-yl)-the 1H-pyrazole-3-yl]-the 2-imidazolidone

At room temperature, to Intermediate 125(76mg is 0.156mmol) at MeOH/CH ₂Cl ₂Add Cs in the suspension in the 3:1 mixture (10mL) ₂CO ₃(0.257g, 5 equivalents).Mixture was at room temperature stirred 1 hour.Evaporating solvent, and with resistates by flash chromatography (silica gel, 2% MeOH/CH ₂Cl ₂) purifying, obtain white solid Title compound(45mg, 71%).

All analytical data are listed among the following table 1-1, and wherein:

R ₁For-CH ₃

R ₅Be hydrogen;

R ₆Be hydrogen,

R ₇Be hydrogen;

D is equivalent to-CR ₈R ₉

G is equivalent to-CR ₁₀R ₁₁

R ₈, R ₉, R ₁₀, R ₁₁All be hydrogen, except Embodiment 1-24, R wherein ₁₀Be methyl.

Embodiment 2

Synthesizing of general formula (II) compound

Wherein

Y is-CR ₇

W is the W9 derivative:

Z is the pyrazolyl derivative

M is the integer of 0-2;

N is the integer of 0-6.

Embodiment 2-1

1-{1-[1-(4-methoxyl group-2-aminomethyl phenyl)-6-methyl-2,3-dihydro-1H-pyrrolo-[2,3-b] pyridine -4-yl]-the 1H-pyrazole-3-yl } pyrrolidin-2-one

At room temperature at N ₂Down, in air-tight bottle, will Intermediate 5(50mg, 0.16mmol), CuI (6mg, 0.2 equivalent) and K ₂CO ₃(46mg, 2.1 equivalents) are mixed together.Add dodecane (14.5 μ L, 0.4 equivalent), anti--cyclohexane diamine (11.5 μ L, 0.6 equivalent) and Intermediate 10Anhydrous NMP (1.5mL) solution of (30mg, 1.2 equivalents), and reaction mixture carried out three circulations of microwave radiation (150 ℃) (5 minutes, 10 minutes, 15 minutes).Then it is cooled to room temperature, and is poured into EtOAc/H ₂Among the O.Separate two-phase, and the waterbearing stratum is extracted with EtOAc (2 x 10mL).With the organic extract that merges through anhydrous Na ₂SO ₄Drying is filtered this solid, and evaporating solvent.With crude product at first SCX post (cHex/EtOAc 9:1), second SCX post (CH ₂Cl ₂/ MeOH 9:1), and final (post: X Terra MSC185um, 50 x 4.6mm, moving phase: A:H2O+0.1% TFA. on preparation property HPLC; B:CH3CN+0.1% TFA, gradient: 10% (B) 1 minute, by 10% (B) to 90% (B) 12 minutes, flow velocity: 1ml/ minute, UV wavelength region: 200-400nm, mass range: 150-900amu, ionization: ES+) purifying obtains faint yellow solid Title compound(21mg, 35%).

All analytical data all are listed among the following table 2-1, and wherein:

R ₁For-CH ₃

R ₅Be hydrogen;

R ₆Be hydrogen,

R ₇Be hydrogen;

D is equivalent to-CR ₈R ₉

G is equivalent to-CR ₁₀R ₁₁

R ₈, R ₉, R ₁₀, R ₁₁All be hydrogen.

Compound number	R	Analytical data
Compound number	R	Analytical data	2-1	2-methyl-4-p-methoxy-phenyl	NMR ( ¹H, DMSO): δ 8.35 (d, 1H), 7.20 (d, 1H), 6.95 (d, 1H), 6.85 (d, 1H), 6.75 (m, 2H), 3.90 (m, 4H), 3.70 (s, 3H), 3.45 (t, 2H), 2.50 (m, 2H), 2.15 (s, 3H), 2.10 (m, 2H), 2.10 (s, 3H).MS(m/z)：404[MH] ⁺

Embodiment 3

Synthesizing of general formula (II) compound,

Wherein

Y is-CR ₇

W is the W3 derivative;

Z is the pyrazolyl derivative;

M is the integer of 0-2;

N is the integer of 0-6.

Embodiment 3-1

1-{1-[1-(4-methoxyl group-2-aminomethyl phenyl)-6-methyl-2,3-dihydro-1H-pyrrolo-[2,3-b] pyridine -4-yl]-the 1H-pyrazole-3-yl } tetrahydropyrimidine-2 (1H)-ketone

At room temperature at N ₂Down, in air-tight bottle, will Intermediate 5(15mg, 0.04mmol), CuI (1.5mg, 0.2 equivalent) and K ₂CO ₃(11.6mg, 2.1 equivalents) are mixed together.Add dodecane (2 μ L, 0.2 equivalent), anti--cyclohexane diamine (2 μ L, 0.3 equivalent) and Intermediate 13Anhydrous NMP (2mL) solution of (8mg, 1 equivalent), and reaction mixture stirred 6 hours in 130 ℃.Then it is cooled to room temperature, and is poured into EtOAc/H ₂Among the O.Separate two-phase, and the waterbearing stratum is extracted with EtOAc (2 x 10mL).With the organic extract that merges through anhydrous Na ₂SO ₄Drying is filtered this solid, and evaporating solvent, with crude product (EtOAc/cHex 6:4,100% EtOAc, 5% MeOH/EtOAc then then) purifying on the SCX post, obtains white solid Title compound(5.1mg, 25%).

All analytical data all are listed among the following table 3-1, and wherein:

R ₁For-CH ₃

R ₅Be hydrogen;

R ₆Be hydrogen,

R ₇Be hydrogen;

R ₁₂Be hydrogen;

D is equivalent to-CR ₈R ₉

G is equivalent to-CR ₁₀R ₁₁

R ₈, R ₉, R ₁₀, R ₁₁All be hydrogen.

Compound number	R	Analytical data
Compound number	R	Analytical data	3-1	2-methyl-4-p-methoxy-phenyl	NMR ( ¹H, CDCl ₃): δ 7.80 (d, 1H), 7.2 (d, 1H), 7.0 (d, 1H), 6.80 (d, 1H), 6.75 (dd, 1H), 6.60 (s, 1H), 4.95 (bs, 1H), 4.05 (dd, 2H), 3.90 (t, 2H), 3.80 (s, 3H), 3.45 (t, 2H), 3.40 (bm, 2H), 2.45 (s, 3H), 2.25 (s, 3H), 2.05 (m, 2H).MS(m/z)：419[MH] ⁺

Embodiment 4

Synthesizing of general formula (II) compound,

Wherein

Y is-CR ₇

W is the W11 derivative;

Z is the pyrazolyl derivative

M is the integer of 0-2;

Q is the integer of 0-4.

Embodiment 4-1

3-(1-{6-methyl isophthalic acid-[2-methyl-4-(methoxyl group) phenyl]-2,3-dihydro-1H-pyrrolo-[2,3-b] pyridine -4-yl }-the 1H-pyrazole-3-yl)-1,3-oxazolidine-2-ketone

At N ₂In bottle, add down, Intermediate 5(38mg, 0.1mmol), Intermediate 16(15mg, 0.1mmol), CuI (1.9mg, 0.1 equivalent), (1R, 2R)-diamino methylcyclohexane (4.3mg, 0.3 equivalent), K ₂CO ₃(41mg is 0.3mmol) with anhydrous NMP (1mL).Seal this bottle, and reaction mixture was stirred 4 hours in 130 ℃.Be poured among water/EtOAc.Separate two-phase, and EtOAc (2 x 10mL) extraction is further used in the waterbearing stratum.With the organic extract that merges through anhydrous Na ₂SO ₄Drying is filtered this solid, and evaporating solvent.Resistates by flash chromatography (silica gel, EtOAc/cHex 1:1) purifying, is obtained white solid Title compound(20mg, 49%).

All analytical data all are listed among the following table 4-1, and wherein:

R ₁For-CH ₃

R ₅Be hydrogen;

R ₆Be hydrogen,

R ₇Be hydrogen;

D is equivalent to-CR ₈R ₉

G is equivalent to-CR ₁₀R ₁₁

R ₈, R ₉, R ₁₀, R ₁₁All be hydrogen.

Compound number	R	Analytical data
Compound number	R	Analytical data	4-1	2-methyl-4-p-methoxy-phenyl	NMR ( ¹H, CDCl ₃): δ 7.85 (d, 1H), 7.16 (d, 1H), 6.93 (d, 1H), 6.81 (d, 1H), 6.77 (dd, 1H), 6.55 (s, 1H), 4.54 (t, 2H), 4.2 (t, 2H), 3.87 (t, 2H), 3.8 (s, 3H), 3.44 (t, 2H), 2.32 (s, 3H), 2.24 (s, 3H).MS(m/z)：406[MH] ⁺。

Embodiment 5

Synthesizing of general formula (II) compound,

Wherein

Y is-CR ₇

W is the W10 derivative;

Z is the pyrazolyl derivative;

M is the integer of 0-2;

Q is the integer of 0-4.

Embodiment 5-1

5-(1-{6-methyl isophthalic acid-[2-methyl-4-(methoxyl group) phenyl]-2,3-dihydro-1H-pyrrolo-[2,3-b] pyridine -4-yl }-the 1H-pyrazole-3-yl)-1,2,5-thiadiazolidine-2-carboxylate methyl ester 1,1-dioxide)

At N ₂In bottle, add down, Intermediate 21(20mg, 0.052mmol), (methoxycarbonyl sulfamyl) three second ammonium hydroxide inner salts (40mg, 3.2 equivalents) and anhydrous THF (1mL).With reaction mixture refluxed 1 hour.It is cooled to room temperature, and uses CH ₂Cl ₂Dilution.Add 1N HCl, and separate two-phase.CH is further used in the waterbearing stratum ₂Cl ₂(3 x 10mL) extraction.The organic extract that concentrate to merge, and with resistates by flash chromatography (silica gel, cHex/EtOAc 7:3) purifying, obtain white solid Mark The topic compound(8.2mg, 32%).

Embodiment 5-2

4-[3-(1,1-dioxo-1,2,5-thiadiazolidine-2-yl)-1H-pyrazol-1-yl]-6-methyl isophthalic acid-[2-methyl -4-(methoxyl group) phenyl]-2,3-dihydro-1H-pyrrolo-[2,3-b] pyridine

At room temperature at N ₂Following, to Embodiment 5-1(7.2mg, 0.0144mmol) anhydrous MeOH (1mL) and anhydrous CH ₂Cl ₂Add 25% NaOH (40 μ L) in the solution (2mL).With reaction mixture in stirring at room 30 minutes.Be poured into saturated NaHCO then ₃In the aqueous solution, and add CH ₂Cl ₂Separate two-phase, and CH is further used in the waterbearing stratum ₂Cl ₂(2 x 10mL) extraction.With the organic extract that merges through anhydrous Na ₂SO ₄Drying is filtered this solid, and evaporating solvent, obtains white solid Title chemical combination Thing(6.4mg, quantitative productive rate).

All analytical data all are listed among the following table 5-1, and wherein:

R ₁For-CH ₃

R ₅Be hydrogen;

R ₆Be hydrogen,

R ₇Be hydrogen;

D is equivalent to-CR ₈R ₉

G is equivalent to-CR ₁₀R ₁₁

R ₈, R ₉, R ₁₀, R ₁₁All be hydrogen.

Compound number	R	R ₁₂	Analytical data
Compound number	R	R ₁₂	Analytical data	5-1	2-methyl-4-p-methoxy-phenyl	CO ₂Me	NMR ( ¹H, CDCl ₃): δ 7.88 (d, 1H), 7.17 (d, 1H), 6.82 (d, 1H), 6.77 (dd, 1H), 6.51 (s, 1H), 6.5 (d, 1H), 4.1 (bst, 4H), 3.95 (s, 3H), 3.87 (t, 2H), 3.81 (s, 3H), 3.46 (t, 2H), 2.32 (s, 3H), 2.24 (s, 3H).MS (m/z): 499[MH] ⁺
5-2	2-methyl-4-p-methoxy-phenyl	H	NMR ( ¹H, DMSO-d ₆): δ 8.37 (d, 1H), 7.71 (bs, 1H), 7.15 (d, 1H), 6.84 (d, 1H), 6.76 (dd, 1H), 6.74 (s, 1H), 6.31 (d, 1H), 3.93 (t, 2H), 3.82 (t, 2H), 3.74 (s, 3H), 3.50 (t, 2H), 3.42 (t, 2H), 2.16 (s, 3H), 2.13 (s, 3H).MS(m/z)：441[MH] ⁺	5-1	2-methyl-4-p-methoxy-phenyl	CO ₂Me

Embodiment 6

Synthesizing of general formula (II) compound,

Wherein

Y is-CR ₇

W is the W12 derivative;

Z is the pyrazolyl derivative;

M is the integer of 0-2;

N is the integer of 0-6.

Embodiment 6-1

4-[3-(1,1-dioxo-2-isothiazole alkyl)-1H-pyrazol-1-yl]-6-methyl isophthalic acid-[2-methyl-4-(methoxy Base) phenyl]-2,3-dihydro-1H-pyrrolo-[2,3-b] pyridine

At N ₂To down, Intermediate 22(10mg, 0.022mmol) and POCl ₃(1mL) in bottle, be mixed together.With reaction mixture refluxed 1 hour.Add saturated NaHCO ₃The aqueous solution is until reaching neutral pH, and mixture is distributed between water and EtOAc.Separate two-phase, and EtOAc (3 x 10mL) extraction is further used in the waterbearing stratum.Concentrate the organic extract that merges, and resistates is passed through flash chromatography (silica gel, cHex/EtOAc 1:1 → EtOAc/NH ₃MeOH solution (0.5M) 7:3) purifying, obtain white solid Title compound(4.2mg, 50%).

All analytical data all are listed among the following table 6-1, and wherein:

R ₁For-CH ₃

R ₅Be hydrogen;

R ₆Be hydrogen;

R ₇Be hydrogen;

D is equivalent to-CR ₈R ₉

G is equivalent to-CR ₁₀R ₁₁

R ₈, R ₉, R ₁₀, R ₁₁All be hydrogen.

Compound number	R	Analytical data
Compound number	R	Analytical data	6-1	2-methyl-4-p-methoxy-phenyl	NMR ( ¹H, CDCl ₃): δ 7.84 (d, 1H), 7.16 (d, 1H), 6.82 (d, 1H), 6.77 (dd, 1H), 6.52 (s, 1H), 6.51 (d, 1H), 3.98 (t, 2H), 3.87 (t, 2H), 3.80 (s, 3H), 3.46 (m, 2H), 3.37 (t, 2H), 2.57 (m, 2H), 2.32 (s, 3H), 2.23 (s, 3H).IR(film，cm ^-1)：- MS(m/z)：439[M] ⁺。

Embodiment 7

Synthesizing of general formula (II) compound,

Wherein

Y is-CR ₇

W is the W13 derivative;

Z is the pyrazolyl derivative;

M is the integer of 0-2;

Q is the integer of 0-4.

Embodiment 7-1

3-methyl isophthalic acid-(1-{6-methyl isophthalic acid-[2-methyl-4-(methoxyl group) phenyl]-2,3-dihydro-1H-pyrrolo- [2,3-b] pyridin-4-yl }-the 1H-pyrazole-3-yl)-2 (1H)-pyridones

At room temperature, will Intermediate 5(20mg, 0.05mmol), Intermediate 26(14mg, 2 equivalents), CuI (10mg, 1 equivalent), K ₂CO ₃(15mg, 2.1 equivalents) and N-N '-dimethyl be anti--and anhydrous NMP (1mL) solution of cyclohexane diamine (9mg, 1 equivalent) is in 150 ℃ of heating 18 hours.Add saturated NH then ₄The Cl aqueous solution (10mL), and with solution CH ₂Cl ₂(25mL) extraction.With organic layer through anhydrous Na ₂SO ₄Drying is filtered this solid, and vacuum evaporating solvent.Thus obtained crude compound by flash chromatography (silica gel, cHex/EtOAc 1:9) purifying, is obtained the white solid of 5.5mg (44%) Title Compound

All analytical data all are listed among the following table 7-1, and wherein:

R ₁For-CH ₃

R ₅Be hydrogen;

R ₆Be hydrogen;

R ₇Be hydrogen;

D is equivalent to-CR ₈R ₉

G is equivalent to-CR ₁₀R ₁₁

R ₈, R ₉, R ₁₀, R ₁₁All be hydrogen.

Compound number	R	Analytical data
Compound number	R	Analytical data	7-1	2-methyl-4-p-methoxy-phenyl	NMR ( ¹H, CDCl ₃): δ 8.00 (dd, 1H), 7.9 (d, 1H), 7.3 (m, 2H), 7.25 (d, 1H), 6.8 (m, 2H), 6.7 (s, 1H), 6.2 (t, 1H), 3.9 (t, 2H), 3.4 (t, 2H), 3.7 (s, 3H), 2.4 (s, 3H), 2.3 (s, 3H), 2.25 (s, 3H), MS (m/z): 428[MH] ⁺

Embodiment 8

Synthesizing of general formula (II) compound,

Wherein

Y is-CR ₇

W is the W14 derivative;

Z is the pyrazolyl derivative;

M is the integer of 0-2;

P is the integer of 0-3.

Embodiment 8-1

2-(1-{6-methyl isophthalic acid-[2-methyl-4-(methoxyl group) phenyl]-2,3-dihydro-1H-pyrrolo-[2,3-b] pyridine -4-yl }-the 1H-pyrazole-3-yl)-3 (2H)-pyridazinones

Will Intermediate 5(25mg, 0.06mmol), Intermediate 28(20mg, 2 equivalents), CuI (10mg, 1 equivalent), K ₂CO ₃(15mg, 2.1 equivalents) and N-N '-dimethyl be anti--and anhydrous NMP (1mL) solution of cyclohexane diamine (9mg, 1 equivalent) is in 150 ℃ of heating 3 days.Add saturated NH then ₄The Cl aqueous solution (10mL), and with solution CH ₂Cl ₂(25ml) extraction.With organic layer through anhydrous Na ₂SO ₄Drying is filtered this solid, and vacuum evaporating solvent.Thus obtained crude compound by flash chromatography (silica gel, cHex/EtOAc 1:9) purifying, is obtained the white solid of 6mg (24%) Title compound

All analytical data all are listed among the following table 8-1, and wherein:

R ₁For-CH ₃

R ₅Be hydrogen;

R ₆Be hydrogen;

R ₇Be hydrogen;

D is equivalent to-CR ₈R ₉

G is equivalent to-CR ₁₀R ₁₁

R ₈, R ₉, R ₁₀, R ₁₁All be hydrogen.

Compound number	R	Analytical data
Compound number	R	Analytical data	8-1	2-methyl-4-p-methoxy-phenyl	NMR ( ¹H, CDCl ₃): δ 7.96 (dd-d, 2H), 7.27 (dd, 1H), 7.16 (d, 1H), 6.98 (d, 1H), 6.82 (d, 1H), 6.77 (dd, 1H), 6.64 (s, 1H), 3.88 (t, 2H), 3.8 (s, 3H), 3.46 (t, 2H), 2.33 (s, 3H), 2.23 (s, 3H).MS(m/z)：415[MH] ⁺。

Embodiment 9

Synthesizing of general formula (II) compound,

Wherein

Y is-CR ₇

W is the W1 derivative;

Z is the pyrazolyl derivative;

M is the integer of 0-2.

Embodiment 9-1

1-(1-{6-methyl isophthalic acid-[2-methyl-4-(methoxyl group) phenyl]-2,3-dihydro-1H-pyrrolo-[2,3-b] pyridine -4-yl }-the 1H-pyrazole-3-yl)-1, the 3-dihydro-2 H-imidazol-2-one

To Intermediate 24(50mg, anhydrous CH 0.1mmol) ₂Cl ₂(2mL) add HCl6N (200 μ L) in the solution.With reaction mixture in stirring at room 45 minutes.Then it is used 1M NaHCO ₃(1mL) neutralization, and vacuum evaporating solvent.Thus obtained crude compound by flash chromatography (silica gel, cHex/EtOAc 1:1) purifying, is obtained the white solid of 18mg (45%) Title compound

All analytical data all are listed among the following table 9-1, and wherein:

R ₁For-CH ₃

R ₅Be hydrogen;

R ₆Be hydrogen,

R ₇Be hydrogen;

R ₁₂Be hydrogen;

D is equivalent to-CR ₈R ₉

G is equivalent to-CR ₁₀R ₁₁

R ₈, R ₉, R ₁₀, R ₁₁All be hydrogen.

Compound number	R	Analytical data
Compound number	R	Analytical data	9-1	2-methyl-4-p-methoxy-phenyl	NMR ( ¹H, CDCl ₃): δ 7.85 (d, 1H), 7.79 (bs, 1H), 7.12 (d, 1H), 7.03 (d, 1H), 6.96 (m, 1H), 6.76 (d, 1H), 6.72 (dd, 1H), 6.52 (s, 1H), 6.33 (m, 1H), 3.82 (t, 2H), 3.74 (s, 3H), 3.41 (t, 2H), 3.27 (s, 3H), 2.18 (s, 3H).MS(m/z)：403[MH] ⁺。

Embodiment 10

Synthesizing of general formula (II) compound,

Wherein

Y is-CR ₇

W is the W2 derivative;

Z is the pyrazolyl derivative;

M is the integer of 0-2;

Q is the integer of 0-4.

Embodiment 10-1

1-(1-{6-methyl isophthalic acid-[2-methyl-4-(methoxyl group) phenyl]-1H-pyrrolo-[2,3-b] pyridine-4- Base }-the 1H-pyrazole-3-yl)-the 2-imidazolidone

At room temperature at N ₂Following, to Embodiment 1(90mg, anhydrous CH 0.223mmol) ₂Cl ₂(6mL) add DDQ (56mg, 5 equivalents) in the solution.With reaction mixture in stirring at room 24 hours.Vacuum evaporating solvent.Thus obtained crude compound by flash chromatography (silica gel, cHex/EtOAc 1:1) purifying, is obtained the white solid of 14.8mg, it further by Mass Direct Autoprep (Fraction Lynks) purifying, is obtained white solid Title compound(9mg, 10%).

All analytical data all are listed among the following table 10-1, and wherein:

R ₁For-CH ₃

R ₅Be hydrogen;

R ₆Be hydrogen;

R ₇Be hydrogen;

R ₁₂Be hydrogen;

D is equivalent to-CR ₈

G is equivalent to-CR ₁₀

D is that two keys link to each other with G;

R ₈, R ₁₀All be hydrogen.

Compound number	R	Analytical data
Compound number	R	Analytical data	10-1	2-methyl-4-p-methoxy-phenyl	NMR ( ¹H, CDCl ₃): 8.57 (d, 1H), 7.42 (d, 1H), 7.37 (s, 1H), 7.21 (d, 1H), 7.18 (d, 1H), 7.09 (bs, 1H), 6.97 (d, 1H), 6.89 (dd, 1H), 4.00 (m, 2H), 3.81 (s, 3H), 3.48 (m, 2H), 2.46 (s, 3H), 1.95 (s, 3H) δ. MS (m/z): 403[MH] ⁺

Embodiment 11

Synthesizing of general formula (II) compound,

Wherein

Y is a nitrogen;

W is W2 derivative, for example 11-1;

Be W11 derivative, for example 11-2;

Z is the pyrazolyl derivative;

M is the integer of 0-2;

Q is the integer of 0-4.

Embodiment 11-1

1-(1-{7-[2, two (trifluoromethyl) phenyl of 4-]-2-methyl-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine -4-yl }-the 1H-pyrazole-3-yl)-the 2-imidazolidone

At room temperature at N ₂Following, to Intermediate 8Add NaH 60%/oil (2mg, 2 equivalents) in dry DMF (3.5mL) solution of (7mg, 2 equivalents).With reaction mixture in stirring at room 20 minutes.Will Middle Body 118(8mg, dry DMF 0.021mmol) (3mL) solution joins in the reaction mixture, and it was heated 5 hours in 80 ℃.Add entry and EtOAc, and separate two-phase.EtOAc (2 x 10mL) extraction is further used in the waterbearing stratum.With the organic extract that merges through anhydrous Na ₂SO ₄Drying is filtered this solid, and evaporating solvent.With resistates (100% cHex → 100% EtOAc) purifying on MEGA Bond Elut silica column, obtain white solid Title compound(1.2mg, 12%).

Embodiment 11-2

1-{1-[7-(2,4 dichloro benzene base)-2-methyl-6,7-dihydro-5H-pyrrolo-[2,3-d] pyrimidine-4-yl]-1H- Pyrazole-3-yl }-2-Pyrrolidone

At room temperature at N ₂In dry DMF (1mL) suspension of NaH 60%/oil (5mg, 3.0 equivalents), add down, Intermediate 10(30mg, 3 equivalents).Reaction mixture was stirred 30 minutes in 80 ℃.Add then Intermediate 120(20mg, 0.064mmol), and with reaction mixture in 100 ℃ the heating 5 hours.Then it is cooled to room temperature, is poured among the EtOAc, (3 x 10mL) washes with the saturated NaCl aqueous solution, and through anhydrous Na ₂SO ₄Dry.Filter this solid, and evaporating solvent.Crude product by flash chromatography (silica gel, cHex/EtOAc 7:3) purifying, is obtained white solid Title compound(10mg, 35%).

All analytical data all are listed among the following table 11-1, and wherein:

R ₁For-CH ₃

R ₅Be hydrogen;

R ₆Be hydrogen,

R ₁₂Be hydrogen;

D is equivalent to-CR ₈R ₉

G is equivalent to-CR ₁₀R ₁₁

R ₈, R ₉, R ₁₀, R ₁₁All be hydrogen.

Embodiment 12

CRF is in conjunction with activity

Substitute by compound ¹²⁵I-oCRF and ¹²⁵I-rope watt peptide (sauvagine) is respectively in conjunction with the ability of CRF1 and CRF2 SPA, and external test CRF binding affinity, described CRF1 and CRF2 SPA come the recombinant human CRF acceptor of expressing in comfortable Chinese hamster ovary (CHO) cytolemma.For the preparation of film, Chinese hamster ovary celI is collected SPA damping fluid (HEPES/KOH 50mM, EDTA 2mM, MgCl the 50mL centrifuge tube from (confluent) T shape flask that merges ₂10mM, pH 7.4) in, with the Polytron homogenizing and centrifugal (4 ℃, 50 ' 000g, 5 minutes: the Beckman whizzer that has the JA20 rotor).As mentioned above, with flaky precipitate (pellet) suspension once more, homogenizing and centrifugal.

In the 1 μ l diluted chemical compound liquid (100% DMSO solution) of every hole, add 100 μ l reagent mixtures, in Optiplate, carry out the SPA experiment.By mix SPA damping fluid, WGA SPA pearl (2.5mg/mL), BSA (1mg/mL) and film (for CRF1 and CRF2, be respectively 50 and 5ug protein/mL) and the 50pM radioligand prepare test mixture.

With plate incubated at room temperature spend the night (〉 18 hours), and with having WGA-SPA ¹²⁵The Packard Topcount reading of data of I counting procedure.

Embodiment 13

The CRF function test

Be used for measuring the characteristic that its function test that suppresses to render a service is measured The compounds of this invention.With CRF stimulating human CRF-CHO cell, and assess the receptor activation effect by the accumulation of measuring cAMP.

To be suspended in once more in the substratum that does not have G418 by the Chinese hamster ovary celI that obtains in the T-shape flask that merges, and be distributed in the 96-orifice plate 25 ' 000c/ hole, 100 μ l/ holes, overnight incubation.After the cultivation, substratum is descended warm 100 μ L cAMP IBMX damping fluids (5mM KCl, 5mMNaHCO with 37 ℃ ₃, 154mM NaCl, 5mM HEPES, 2.3mM CaCl ₂, 1mM MgCl ₂, 1g/L glucose is regulated pH to 7.4 by adding 1mg/mL BSA and 1mM IBMX) and the l μ L antagonist diluent replacement in pure DMSO.At 37 ℃, there be not CO ₂The plate incubator in cultivate 10 minutes again after, add the agonist diluent of l μ L in pure DMSO.As mentioned above, plate was cultivated 10 minutes, and used the content (cellularcontent) of Amersham RPA538 kit measurement cAMP cell then.

All open source literatures that drawn in this specification sheets include but not limited to that patent and patent application are incorporated herein by reference, and resemble each independent publication and are used as reference particularly and individually in full.

Be appreciated that all combinations that the present invention includes concrete and preferred kind mentioned above.

Comprise that the application of specification sheets and claims can be used as the basis for priority of any subsequent application.The claim of described subsequent application can relate to arbitrary feature or the combination of features of describing among the present invention.They can be product, composition, method or purposes claim, and can comprise following claim (only be as an example, and be not limited only to this).

Claims

1. the compound of formula (IV) comprises its steric isomer, prodrug and pharmacy acceptable salt or solvate,

Wherein

Dotted line can be represented two keys;

R is aryl or heteroaryl, and each R group can be selected from following group J by 1-4 and replace: halogen, C1-C6 alkyl, C1-C6 alkoxyl group, halo C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo C1-C6 alkoxyl group ,-C (O) R ₂, nitro, hydroxyl ,-NR ₃R ₄, cyano group and group Z;

R ₁Be hydrogen, C3-C7 cycloalkyl, C1-C6 alkyl, C1-C6 alkoxyl group, C1-C6 alkylthio, C2-C6 alkenyl, C2-C6 alkynyl, halo C1-C6 alkyl, halo C1-C6 alkoxyl group, halogen, NR ₃R ₄Or cyano group;

R ₂For the C1-C4 alkyl ,-OR ₃Or-NR ₃R ₄

R ₃Be hydrogen or C1-C6 alkyl;

R ₄Be hydrogen or C1-C6 alkyl;

R ₅For C1-C6 alkyl, halo C1-C6 alkyl, C1-C6 alkoxyl group, halo C1-C6 alkoxyl group, C3-C7 cycloalkyl, hydroxyl, halogen, nitro, cyano group ,-NR ₃R ₄Or-C (O) R ₂

R ₆For C1-C6 alkyl, halo C1-C6 alkyl, C1-C6 alkoxyl group, halo C1-C6 alkoxyl group, C3-C7 cycloalkyl, hydroxyl, halogen, nitro, cyano group ,-NR ₃R ₄Or-C (O) R ₂

R ₇Be hydrogen, C1-C6 alkyl, halogen or halo C1-C6 alkyl;

R ₁₂Be R ₃Or-C (O) R ₂

D is CR ₈R ₉Or D is CR when linking to each other with the two keys of G ₈

G is CR ₁₀R ₁₁Or G is CR when linking to each other with the two keys of D ₁₀

Z is a 5-6 unit heterocycle, and it can be replaced by phenyl ring;

M is the integer of 0-2; With

Q is the integer of 0-4.

2. according to the formula (IVa) of claim 1, (IVb) or (IVc) compound, comprise its steric isomer, prodrug and pharmacy acceptable salt or solvate,

Wherein R, R ₁, R ₅, R ₆, R ₈, R ₉, R ₁₀, R ₁₁, R ₁₂, m, q, D and G have the definition in the claim 1, and dotted line can be represented two keys.

3. the compound of formula (IVa) comprises its steric isomer, prodrug and pharmacy acceptable salt or solvate

Wherein

Dotted line can be represented two keys;

R ₁Be hydrogen or C1-C6 alkyl;

R ₂Be the C1-C4 alkyl;

R ₃Be hydrogen or C1-C6 alkyl;

R ₄Be hydrogen or C1-C6 alkyl;

R ₈Be hydrogen;

R ₉Be hydrogen;

R ₁₀Be hydrogen;

R ₁₁Be hydrogen;

R ₁₂Be R ₃

D is CR ₈R ₉

G is CR ₁₀R ₁₁

Z is a 5-6 unit heterocycle, and it can be replaced by phenyl ring;

M is 0; With

Q is 0.

4. according to formula (IVa) compound of claim 3, comprise its steric isomer, prodrug and pharmacy acceptable salt or solvate, wherein:

R ₁Be the C1-C3 alkyl;

R is selected from following aryl: 2, the 4-dichlorophenyl, 2-chloro-4-aminomethyl phenyl, 2-chloro-4-trifluoromethyl, 2-chloro-4-p-methoxy-phenyl, 2,4, the 5-trimethylphenyl, 2, the 4-3,5-dimethylphenyl, 2-methyl-4-p-methoxy-phenyl, 2-methyl-4-ethoxyl phenenyl, 2-methyl-4-isopropyl phenyl, 2-methyl-4-hydroxy phenyl, 2-methyl-4-chloro-phenyl-, 2-methyl-4-trifluoromethyl, 2, the 4-Dimethoxyphenyl, 2-methoxyl group-4-trifluoromethyl, 2-methoxyl group-4-chloro-phenyl-, 3-methoxyl group-4-chloro-phenyl-, 2,5-dimethoxy-4 '-chloro-phenyl-, 2-methoxyl group-4-isopropyl phenyl, 2-methoxyl group-4-trifluoromethyl, 2-methoxyl group-4-isopropyl phenyl, 2-methoxyl group-4-aminomethyl phenyl, 2-trifluoromethyl-4-chloro-phenyl-, 2, the 4-bis trifluoromethyl phenyl, 2-trifluoromethyl-4-aminomethyl phenyl, 2-trifluoromethyl-4-p-methoxy-phenyl, 2-difluoromethyl-4-p-methoxy-phenyl, 2-bromo-4-isopropyl phenyl, 2-methyl-4-cyano-phenyl, 2-chloro-4-cyano-phenyl, 2-trifluoromethyl-4-cyano-phenyl, 2-trifluoromethoxy-4-cyano-phenyl, 2-ethyl-4-cyano-phenyl, 2-methyl-4-Trifluoromethoxyphen-l, 4-methyl-6-dimethyl aminopyridine-3-base, 2,6-bi-methoxy-pyridin-3-yl, 2-methyl-6-methoxyl group-pyridin-3-yl, 2-trifluoromethyl-6-methoxyl group-pyridin-3-yl, 3-chloro-5-trichloromethyl-pyridine-2-base, 2-methyl-4-(pyrazol-1-yl)-phenyl, 2-methoxyl group-4-(pyrazol-1-yl)-phenyl, 2,4, the 6-trimethoxyphenyl, 2-methyl-4,5-benzodioxole base, 2-methyl-3,4-benzodioxole base.

5. according to formula (IVa) compound of claim 3 or 4, comprise its steric isomer, prodrug and pharmacy acceptable salt or solvate, described compound is selected from:

1-(1-{1-[2, two (trifluoromethyl) phenyl of 4-]-6-methyl-2,3-dihydro-1H-pyrrolo-[2,3-b] pyridin-4-yl }-the 1H-pyrazole-3-yl)-2-imidazolidone (compound 1-4);

And pharmacy acceptable salt or solvate.

(6.1-{1-[1-4-methoxyl group-2-aminomethyl phenyl)-6-methyl-2,3-dihydro-1H-pyrrolo-[2,3-b] pyridin-4-yl]-the 1H-pyrazole-3-yl } imidazolidin-2-one (compound 1-1) or its pharmacy acceptable salt or solvate.

7. the formula V compound comprises its steric isomer, prodrug and pharmacy acceptable salt or solvate,

Wherein

Z is a 5-6 unit heterocycle, and it can be by 1-8 R ₅Group replaces, or Z is phenyl ring, and it can be by 1-4 R ₅Group replaces; With

Y be nitrogen or-CR ₇With

R, R ₁, R ₅, R ₆, R ₁₂, q, D and G have defined implication in the claim 1, and dotted line can be represented two keys.

8. according to formula (VI) compound of claim 7, comprise its steric isomer, prodrug and pharmacy acceptable salt or solvate,

Wherein Z, R, R ₁, R ₆, R ₇, q, Y, D and G have defined implication in the claim 7, and dotted line can be represented two keys.

9. formula according to Claim 8 (VIa), (VIb) or (VIc) compound comprise its steric isomer, prodrug and pharmacy acceptable salt or solvate,

Wherein Z, R, R ₁, R ₆, R ₈, R ₉, R ₁₀, R ₁₁, R ₁₂, q, D and G have defined implication in the claim 7, and dotted line can be represented two keys.

10. according to the formula (VIa) of claim 9, (VIb) or (VIc) compound, comprise its steric isomer, prodrug and pharmacy acceptable salt or solvate, wherein Z is selected from: pyrimidine, pyridine, thiazole, pyrazoles, triazole and phenyl, and R, R ₁, R ₆, R ₈, R ₉, R ₁₀, R ₁₁, R ₁₂, q, D and G have defined implication in the claim 7.

11. according to claim 1,2 and 7-10 in each formula (IV), (IVa), (IVb), (IVc), (V), (VI), (VIa), (VIb) or (VIc) compound, comprise its steric isomer, prodrug and pharmacy acceptable salt or solvate, wherein:

R ₁Be C1-C3 alkyl or halo C1-C3 alkyl, preferable methyl or trifluoromethyl;

R ₇Be hydrogen;

R ₈, (R ₉), R ₁₀, (R ₁₁) be hydrogen;

R is selected from following aryl: 2, the 4-dichlorophenyl, 2-chloro-4-aminomethyl phenyl, 2-chloro-4-trifluoromethyl, 2-chloro-4-p-methoxy-phenyl, 2,4, the 5-trimethylphenyl, 2, the 4-3,5-dimethylphenyl, 2-methyl-4-p-methoxy-phenyl, 2-methyl-4-ethoxyl phenenyl, 2-methyl-4-isopropyl phenyl, 2-methyl-4-hydroxy phenyl, 2-methyl-4-chloro-phenyl-, 2-methyl-4-trifluoromethyl, 2, the 4-Dimethoxyphenyl, 2-methoxyl group-4-trifluoromethyl, 2-methoxyl group-4-chloro-phenyl-, 3-methoxyl group-4-chloro-phenyl-, 2,5-dimethoxy-4 '-chloro-phenyl-, 2-methoxyl group-4-isopropyl phenyl, 2-methoxyl group-4-trifluoromethyl, 2-methoxyl group-4-isopropyl phenyl, 2-methoxyl group-4-aminomethyl phenyl, 2-trifluoromethyl-4-chloro-phenyl-, 2,4-pair-trifluoromethyl, 2-trifluoromethyl-4-aminomethyl phenyl, 2-trifluoromethyl-4-p-methoxy-phenyl, 2-difluoromethyl-4-p-methoxy-phenyl, 2-bromo-4-isopropyl phenyl, 2-methyl-4-cyano-phenyl, 2-chloro-4-cyano-phenyl, 2-trifluoromethyl-4-cyano-phenyl, 2-trifluoromethoxy-4-cyano-phenyl, 2-ethyl-4-cyano-phenyl, 2-methyl-4-Trifluoromethoxyphen-l, 4-methyl-6-dimethyl aminopyridine-3-base, 2,6-bi-methoxy-pyridin-3-yl, 2-methyl-6-methoxyl group-pyridin-3-yl, 2-trifluoromethyl-6-methoxyl group-pyridin-3-yl, 3-chloro-5-trichloromethyl-pyridine-2-base, 2-methyl-4-(pyrazol-1-yl)-phenyl, 2-methoxyl group-4-(pyrazol-1-yl)-phenyl, 2,4, the 6-trimethoxyphenyl, 2-methyl-4,5-benzodioxole base, 2-methyl-3,4-benzodioxole base.

12. according to claim 1,2 and 7-10 in each formula (IV), (IVa), (IVb), (IVc), (V), (VI), (VIa), (VIb) or compound (VIc), comprise its steric isomer, prodrug and pharmacy acceptable salt or solvate, described compound is selected from:

1-{1-[1-(4-methoxyl group-2-aminomethyl phenyl)-6-methyl-2,3-dihydro-1H-pyrrolo-[2,3b] pyridin-4-yl]-the 1H-pyrazole-3-yl }-3-Methylimidazole alkane-2-ketone (compound 1-2);

1-(6-{6-methyl isophthalic acid-[2-methyl-4-(methoxyl group) phenyl]-2,3-dihydro-1H-pyrrolo-[2,3-b] pyridin-4-yl }-the 3-pyridyl)-2-imidazolidone (compound 11-1).

13. one kind begins to prepare the method for formula V compound by formula (VII) compound, described method comprises the following step in the scheme 1:

Wherein

Step a represents that L is selected from: the reactive residue of halogen or sulfonic acid (for example methylsulfonic acid base, toluenesulphonic acids base) is preferably chlorine by with suitable Z-W derivatives reaction leavings group L being converted into compound (VIII);

Steps d represents with suitable oxygenant (crossing iodine alkane as Dess-Martin) oh group to be oxidized to the aldehyde group of compound (XI);

Step g representative by with suitable alkali (as LiN (SiMe ₃) ₂) carry out deprotonation, subsequently by the suitable alkylating reagent of addition (as MeI), make the optional alkylation in the α position of aldehyde to form the alkylating aldehyde of compound (XIV), (XV);

Step h representative is converted into compound (XVI) and alcohol groups (XVIII) by Grignard reagent (as MeMgBr) with aldehyde group;

The step I representative is oxidized to oh group with suitable oxygenant (crossing iodine alkane as Dess-Martin) ketone groups of compound (XVII);

Step j representative is converted into the suitable blocking group of compound (XIX) (as TBS: t-butyldimethylsilyl) with oh group;

Step k representative and suitable amine RNH ₂Carry out the Buchwald linked reaction, obtain formula (XX) compound;

Deprotection reaction is carried out in step l representative, obtains the oh group of compound (XXI);

Step m representative with the oh group of compound (XXI) be converted into suitable leavings group (as bromide, by with CBr ₄And PPh ₃Reaction) carries out intramolecular cyclization after, obtain the compound (XXII) of cyclisation;

The NH group that step n representative will finally be present in the protection in the W group carries out deprotection reaction, obtains final compound (V);

It is CHR that D is worked as in step o representative ₈And G is CHR ₁₀The time, (as DDQ) carries out oxidation by suitable oxygenant, to form two keys of compound (V).

Wherein the W in the above-claimed cpd is expressed as

And each variable R, R ₁, Z, Y, R ₆, R ₁₂, D, G and q as defined in claim 7.

14. a method for preparing the compound of claim 1, it is corresponding to formula (IIr) compound in the following scheme 2, wherein:

R is 4-methoxyl group-2-methyl-phenyl;

R ₁Be methyl;

X ₁Be oxygen;

Y is CH-;

Lg be the trifluoromethanesulfonic acid base and

Z-W is:

From formula (XXIII) compound, comprise the step in the scheme 2,

Scheme 2

Wherein:

Steps d ' expression by with for example trifluoromethanesulfonic acid anhydride reactant, the reactive derivative that forms the pyridone of compound (XXVI) (is leavings group, Lg) (for example is selected from trifluoromethanesulfonic acid base, halogen and methylsulfonic acid base);

Step e ' represents the nucleophilic displacement of the leavings group of compound (XXVII), obtains the compound (XXVIII) of halogenization;

When step h ' is oxygen as X1, be equivalent to step b) ';

Step m ' expression is for example used PO (Hal) by using ₃Halogenating reaction is carried out in processing, and oh group is converted into halogen.

(15.1-4-methoxyl group-2-aminomethyl phenyl) pyrrolidin-2-one (intermediate 1).

(16.3-{[1-4-methoxyl group-2-aminomethyl phenyl) tetramethyleneimine-2-subunit] amino } but-2-ene acetoacetic ester (intermediate 2).

(17.1-4-methoxyl group-2-aminomethyl phenyl)-6-methyl isophthalic acid, 2,3,7-tetrahydrochysene-4H-pyrrolo-[2,3-b] pyridine-4-ketone (intermediate 3).

(18.1-4-methoxyl group-2-aminomethyl phenyl)-6-methyl-2,3-dihydro-1H-pyrrolo-[2,3-b] pyridin-4-yl triflate (intermediate 4).

19.4-iodo-6-methyl isophthalic acid-[2-methyl-4-(methoxyl group) phenyl]-2,3-dihydro-1H-pyrrolo-[2,3-b] pyridine (intermediate 5).

20.1-[2-methyl-4-(methoxyl group) phenyl]-2-tetramethyleneimine imines (intermediate 91).

21.4-{[2-methyl-4-(methoxyl group) phenyl] amino } butyronitrile (intermediate 90).

(22.N-2-chloroethyl)-3-({ [(2-chloroethyl) amino] carbonyl } amino)-1H-pyrazoles-1-methane amide (intermediate 6).

(23.N-2-chloroethyl)-3-(2-oxo-imidazolidine-1-yl)-1H-pyrazoles-1-methane amide (intermediate 7).

(24.1-1H-pyrazole-3-yl) imidazolidin-2-one (intermediate 8).

25. be used for the treatment of by the purposes in the medicine of the illness of CRF (thyroliberin-releasing hormone) mediation in preparation according to each compound among the claim 1-12.

26. be used for the treatment of purposes in the medicine of dysthymia disorders and anxiety disorder in preparation according to the compound of claim 25.

27. be used for the treatment of purposes in the medicine of IBS (irritable bowel syndrome) and IBD (inflammatory bowel) in preparation according to the compound of claim 25.

28. pharmaceutical composition, it comprises according to each compound and one or more physiologically acceptable carrier or vehicle among the claim 1-12.