CN105712992A

CN105712992A - Compound serving as cMet inhibitor and preparation method and application of compound

Info

Publication number: CN105712992A
Application number: CN201610056902.6A
Authority: CN
Inventors: 田红旗; 黄功超; 程瑛
Original assignee: KECHOW PHARMA Inc
Current assignee: KECHOW PHARMA Inc
Priority date: 2012-09-29
Filing date: 2013-09-23
Publication date: 2016-06-29
Anticipated expiration: 2033-09-23
Also published as: CN103613591B; CN103613591A; CN105712992B

Abstract

The invention relates to a substitute 1H-pyrrole and [2,3-b] pyridine and substitute 1H-pyrrole and [3,4-b] pyridine compound serving as cMet inhibitor and a preparation method and application of the compound, a compound as shown in formula (I) and medically-acceptable salt, prodrug and solvate of the compound and a preparation method of the compound, wherein X<1>, X<2>, X<3>, X<4>, W, R<2> and R1<a-e> are as defined in the specification. The invention further discloses a preparation method of the compound as shown in formula (I) and a medicine composition containing the compound.

Description

Compound as cMet inhibitor and its production and use

The present patent application is Application No. 201310441805.5, filing date on 09 23rd, 2013, invention entitled " as cMet Compound of inhibitor and its production and use " divisional application.

Technical field

The present invention relates to receptor tyrosine kinase (especially receptor tyrosine kinase cMet) inhibitor, more specifically, relate to conduct The amino heteroaromatic compound of receptor tyrosine kinase (especially receptor tyrosine kinase cMet) inhibitor and pharmaceutically acceptable Salt, prodrug, solvate and comprise the pharmaceutical composition of these materials.

Background technology

World Health Organization's investigation report shows, whole world cancer condition is day by day serious, and the number of 20 years from now on new patients is by by current Annual 10000000 increase to 15,000,000, and because of cancer, the number of death also will be increased to 10,000,000 by annual 6,000,000.Its Central Plains Diagnosis is that the canceration hepatocyte Yu intrahepatic biliary epithelium cell occurs, and is one of modal malignant tumor of the mankind；Pulmonary carcinoma is normal The malignant tumor seen, comes from bronchiolar epithelium at different levels, is divided into cell lung cancer and nonsmall-cell lung cancer；Along with growth in the living standard, drink The change of food structure, the sickness rate of colon cancer is in ascendant trend year by year.

At present oneself antitumor drug of listing is more, such as alkylating agent medicine, antimetabolite, antitumor antibiotics, immunomodulator etc., But big drug is relatively big due to toxicity, and patient does not tolerates.Along with the Study on Molecular Mechanism that tumor occurs development is more and more clearer, Molecular targeted therapy Several Kinds of Malignancy is of great interest and pays much attention to.Molecular targeted agents selectivity is high, wide spectrum is effective, Its safety is better than cytotoxic chemotherapy agents, is the new direction of current therapeutic field of tumor development.

Hepatocyte growth factor (HGF) is a kind of polypeptide growth factor, have promotion include hepatocyte, epithelial cell, endotheliocyte, The growths of polytype cell such as hematopoietic cell, migration and morphogenetic effect.It also participates in the propagation of various kinds of cell, migration, right The Invasion and Metastasis of all kinds of tumors has important inducing action.HGF is induced after being combined by receptor cMet special on its target cell CMet receptor tyrosine phosphorylation on after birth, plays the biological effect of HGF, in tumor by signal transduction pathway in various kinds of cell The generation of cell, migrate and transfer process played an important role.

CMet was identified in 1991, was the albumen of proto-oncogene cMet coding, was the class cross-film with autonomous phosphorylation activity Receptor, has tyrosine kinase activity, relevant to multiple oncoprotein and regulation albumen, participates in cellular informatics conduction, cytoskeleton The regulation and control reset are it is considered to be penetrating property grows, tumor is formed and the key regulators of metabolic processes.In kinds cancer oneself CMet gene amplification detected, change, suddenly change and via autocrine or the protein overexpression of cMet of paracrine mechanism or activation. Such as, in Human Gastric carcinoma organizes, oneself finds that cMet is overexpressed and expands；At human glioblastoma and pulmonary carcinoma, first shape In adenocarcinoma and breast carcinoma, it has been found that cMet activates because of the HGF level increased and the conduction of autocrine signal.In Human Lung Cancer tissue, Have been found that the conduction of cMet signal is raised because of drug resistance mechanism.Although the most common, oneself be reported in sporadic with heritability papillary renal carcinoma, Head and neck squamous cell carcinoma and gastric cancer and the Activating mutations of cMet in pulmonary carcinoma.Additionally, the expression increased is to send out in many human tumors Existing modal cMet changes and (includes but not limited to renal carcinoma, ovarian cancer, hepatocarcinoma, nonsmall-cell lung cancer, osteocarcinoma, colon cancer The dirty cancer of hepatic metastasis, oral squamous cell carcinoma, esophageal carcinoma, gastric cancer, film and carcinoma of prostate) relevant with prognosis incessantly.Therefore, suppression The activity of cMet may to the generation of tumor cell, attack and shift and play important intervention effect.Grinding or own entrance clinical research CMet inhibitor have PF-02341066, SGX523 and PHA665752 etc..

Due to cMet pivotal role in cancer and other diseases, the suppression of cMet is the discovery that particularly attractive for new therapy Target.

Summary of the invention

One aspect of the present invention provides the compound of formula (I), and pharmaceutically acceptable salt, prodrug and solvate,

Wherein

X¹、X²、X³、X⁴It is each independently selected from N, NH, C, CH or CH₂；

W is selected from C3-C10 cycloalkyl, C (C1-C10 alkyl)₂, carbonyl ,-C (O) NH-,-S (O)_m-；

R1^a, R1^b, R1^c, R1^dAnd R1^eIt is each independently selected from hydrogen, halogen ,-CN, C1-10 alkyl ,-CF₃、-OCF₃、-OCHF₂、 -OC0-10 alkyl ,-S (O) mC0-10 alkyl ,-SO₂N (C0-10 alkyl) (C0-10 alkyl) ,-N (C0-10 alkyl) (C0-10 alkyl), -N (C0-10 alkyl) C (=O) (C0-10 alkyl) ,-N (C0-10 alkyl) C (=O) O (C0-10 alkyl) ,-N (C0-10 alkane Base) C (=O) N (C0-10 alkyl) ,-C (=O) C0-10 alkyl ,-C (=O) OC0-10 alkyl ,-C (=O) N (C0-10 alkyl) ,-O be miscellaneous Cycloalkyl ,-N (C0-10 alkyl) Heterocyclylalkyl ,-N (C0-10 alkyl) heterocyclic aromatic base, Heterocyclylalkyl, heterocyclic aromatic base ,-S heterocycle Aromatic radical or-O heterocyclic aromatic base, wherein Heterocyclylalkyl arbitrarily can be replaced by one or more following groups: oxygen, C1-10 alkyl, C (=O) OC0-10 alkyl, C (=O) N (C0-10 alkyl) (C0-10 alkyl) ,-SO₂N (C0-10 alkyl) (C0-10 alkyl) or SO2C1-10 alkyl, wherein said moieties arbitrarily can be replaced by one or more following groups: hydroxyl ,-OC1-10 alkyl, -N (C0-10 alkyl) (C0-10 alkyl) ,-C (=O) N (C0-10 alkyl) (C0-10 alkyl), C (=O) OC0-10 alkyl, C (=O) C0-10 Alkyl, Heterocyclylalkyl or heterocyclic aromatic base；

R²Selected from hydrogen, halogen, cyano group ,-CF₃, nitro, C1-C10 alkyl, C2-C10 thiazolinyl, C2-C10 alkynyl, C3-C10 Cycloalkyl C0-C10 alkyl, ternary are to ten yuan of Heterocyclylalkyl C0-C10 alkyl, aromatic radical C0-C10 alkyl, aromatic radical C1-C10 Cycloalkyl, aromatic radical ternary to ten yuan Heterocyclylalkyl, heterocyclic aromatic base, heterocyclic aromatic base C1-C10 alkyl, heterocyclic aromatic base ternary To ten-ring alkyl, wherein arbitrarily group all can be replaced by one or more G1 groups independently of one another；

Or R²It is selected from

R³Selected from hydrogen, C1-C10 alkyl, C2-C10 alkyl-OR⁴, C2-C10 alkyl-NR⁴R⁵, C2-C10 alkyl-S (O)_mR⁴、 C3-C10 cycloalkyl C0-C10 alkyl, C3-C10 cyclenes alkyl C1-C10 alkyl, Heterocyclylalkyl C0-C10 alkyl, aromatic radical C0-C10 Alkyl, heterocyclic aromatic base C0-C10 alkyl, C1-C10 alkyl C3-C10 cycloalkyl, C3-C10 cycloalkyl C3-C10 cycloalkyl, C3-C10 cyclenes alkyl C3-C10 cycloalkyl, Heterocyclylalkyl C3-C10 cycloalkyl, aromatic radical C3-C10 cycloalkyl, heteroaromatic Base C3-C10 cycloalkyl, C1-C10 Alkyl cycloheteroalkyl, C3-C10 cycloalkylcycloheteroalkyl, C3-C10 cyclenes Alkyl cycloheteroalkyl, Heterocyclylalkyl Heterocyclylalkyl, aromatic radical Heterocyclylalkyl, heterocyclic aromatic base Heterocyclylalkyl ,-C (O) R^a、R⁴O-C0-C10 alkyl C (O)-, R⁴R⁵N-C0-C10 alkyl C (O)-, R⁴S(O)_mC0-C10 alkyl C (O)-,-CO₂R⁴、-C(O)NR⁴R⁵、-S(O)_mR⁴、-SO₂NR⁴R⁵ Or-C (S) OR⁴, wherein arbitrarily group all can be replaced by one or more G2 groups independently of one another；

G1 and G2 is each independently selected from hydrogen, halogen, cyano group ,-CF₃、-OCF₃, nitro, oxo, R⁶, C1-C10 alkyl, C2-C10 Thiazolinyl, C2-C10 alkynyl, C3-C10 cycloalkyl C0-10 alkyl, Heterocyclylalkyl C0-10 alkyl, aromatic radical C0-C10 alkyl, heterocycle Aromatic radical C0-C10 alkyl ,-OR⁶、-S(O)_mR⁶、-NR⁶R⁷、-SO₂NR⁶R⁷、-C(O)R^b、-C(O)NR⁶R⁷、-C(O)-C(O)NR⁶R⁷、 -C(O)OR⁶、-C(O)-C(O)OR⁶、-OC(O)R^b、-NR⁶C(O)R^b、-NR⁶SO₂R⁷、-(CR⁸R⁹)_nC(O)R^b、 -(CR⁸R⁹)_nC(O)OR⁶、-(CR⁸R⁹)_nC(O)NR⁶R⁷、-(CR⁸R⁹)_nS(O)₂NR⁶R⁷、-(CR⁸R⁹)_nNR⁶R⁷、-(CR⁸R⁹)_nOR⁶、 -(CR⁸R⁹)_nS(O)_mR⁶、-NR¹⁰C(O)NR⁶R⁷、-NR¹⁰S(O)₂NR⁶R⁷Or-NR¹⁰S(O)NR⁶R⁷, wherein arbitrarily group is the most permissible Replaced by PG independently of one another；

PG be selected from, but not limited to, hydrogen, trityl, benzyl, to methoxy-benzyl, p-toluenesulfonyl, formoxyl, trifluoroacetyl Base, benzyloxycarbonyl group and tertbutyloxycarbonyl；

Need explanation for avoidance of doubt, include multiring structure (containing bridged ring and volution) when G1 is cyclic substituents；

R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R^a, R^bIt is each independently selected from hydrogen, C1-C10 alkyl or C3-C10 cycloalkyl, Wherein arbitrarily group all can be independently of one another by halogen ,-OCF₃Or-OC0-3 alkyl, aromatic radical C0-10 alkyl, heterocyclic aromatic base C0-10 alkyl, C3-10 cycloalkyl C0-C10 alkyl, Heterocyclylalkyl C0-10 alkyl, aromatic radical C3-10 cycloalkyl, heteroaromatic Base ternary is to ten yuan of Heterocyclylalkyls, Heterocyclylalkyl C3-10 cycloalkyl, C3-10 cycloalkyl C3-10 cycloalkyl, C1-10 alkyl-heterocycle Alkyl, Heterocyclylalkyl-Heterocyclylalkyl, aromatic radical-Heterocyclylalkyl or heterocyclic aromatic base-Heterocyclylalkyl replace；

-NR⁴R⁵With-NR⁶R⁷It is independent linear structure, or R⁴And R⁵, R⁶And R⁷The nitrogen all can being connected with them respectively is former Son forms saturated or unsaturated heterocycle together, and heterocycle described herein can arbitrarily comprise one or more selected from O, N or S (O)_mMiscellaneous Atom；

-CR⁸R⁹For independent linear structure, R⁸And R⁹Saturated or unsaturated ring is formed with them together with the carbon atom can being connected, this Ring described in place can arbitrarily comprise one or more selected from O, N or S (O)_mHetero atom；

M is selected from 0-2；

N is selected from 0-7；

Wherein said alkyl, thiazolinyl, alkynyl and cycloalkyl moiety all can be independently of one another by one or more optional selected from following group Replace: hydroxyl, oxygen, halogen, cyano group, nitro, trifluoromethyl, azido, amino, carboxyl, sulfydryl；

Saturated or unsaturated alkyl, such as C1-C10 alkyl, alkane diyl or thiazolinyl, including with heteroatomic combination, such as alkoxyl, Can be all straight chain or with side chain respectively.

Another aspect of the present invention provides the preparation method of formula (I) compound, including:

(A) when W be-S (O)-time, be raw material successively experience sulfide oxidation with the compound of formula (I-2) and be prepared by deprotection base two-step reaction:

(B) when W is selected from C3-C6 cycloalkyl or C (C1-C3 alkyl)₂Time, directly slough protection group PG by the compound of formula (I-2) With PG ' preparation:

Wherein

X²Selected from N or CH；

G1 is selected from N azetidinyl, pyrrolidinyl, piperidines, piperazine, morpholine, homopiperazine, and wherein arbitrarily group all can be respective Independently by PG ' replacement；

G3 is selected from N azetidinyl, pyrrolidinyl, piperidines, piperazine, morpholine, homopiperazine；

PG and PG ' be each independently selected from but be not limited to trityl, benzyl, to methoxy-benzyl, p-toluenesulfonyl, formoxyl, Trifluoroacetyl group, benzyloxycarbonyl group and tertbutyloxycarbonyl；

And, the compound of formula (I), and pharmaceutically acceptable salt, prodrug and solvate,

Wherein

R1^a, R1^b, R1^c, R1^dAnd R1^eIt is each independently selected from hydrogen, halogen ,-CN, C1-C10 alkyl ,-CF₃、-OCF₃、 -OCHF₂,-OC0-10 alkyl ,-S (O) mC0-10 alkyl ,-SO₂N (C0-10 alkyl) (C0-10 alkyl) ,-N (C0-10 alkyl) (C0-10 Alkyl) ,-N (C0-10 alkyl) C (=O) (C0-10 alkyl) ,-N (C0-10 alkyl) C (=O) O (C0-10 alkyl) ,-N (C0-C10 alkane Base) C (=O) N (C0-C10 alkyl) ,-C (=O) C0-C10 alkyl ,-C (=O) OC0-C10 alkyl ,-C (=O) N (C0-10 alkyl) ,-O Heterocyclylalkyl ,-N (C0-10 alkyl) Heterocyclylalkyl ,-N (C0-10 alkyl) heterocyclic aromatic base, Heterocyclylalkyl, heterocyclic aromatic base ,-S are miscellaneous Polycyclic aromatic group or-O heterocyclic aromatic base, wherein Heterocyclylalkyl arbitrarily can be replaced by one or more following groups: oxygen, C1-10 alkyl, C (=O) OC0-10 alkyl, C (=O) N (C0-10 alkyl) (C0-10 alkyl) ,-SO₂N (C0-10 alkyl) (C0-10 alkyl) or SO₂C1-10 alkyl, wherein said moieties arbitrarily can be replaced by one or more following groups: hydroxyl ,-OC1-10 alkyl, -N (C0-10 alkyl) (C0-10 alkyl) ,-C (=O) N (C0-10 alkyl) (C0-10 alkyl), C (=O) OC0-10 alkyl, C (=O) C0-10 Alkyl, Heterocyclylalkyl or heterocyclic aromatic base；

Or R²It is selected from

M is selected from 0-2；

N is selected from 0-7；

And, formula (I) compound, and pharmaceutically acceptable salt, prodrug and solvate, wherein X⁴Represent N；

And, formula (I) compound, and pharmaceutically acceptable salt, prodrug and solvate, wherein X⁴Represent CH；

And, formula (I) compound, and pharmaceutically acceptable salt, prodrug and solvate, wherein X¹Selected from CH or CH₂；

And, formula (I) compound, and pharmaceutically acceptable salt, prodrug and solvate, wherein X¹Selected from N or NH；

And, formula (I) compound, and pharmaceutically acceptable salt, prodrug and solvate, wherein X¹Represent N；

And, formula (I) compound, and pharmaceutically acceptable salt, prodrug and solvate, wherein

X¹Represent NH；

X²Selected from N or CH；

X³Represent C；

R²It is selected from

G2 is selected from hydrogen, halogen, cyano group ,-CF₃、-OCF₃, nitro, oxo, R⁶, C1-C10 alkyl, C2-C10 thiazolinyl, C2-C10 Alkynyl, C3-C10 cycloalkyl C0-10 alkyl, Heterocyclylalkyl C0-10 alkyl, aromatic radical C0-C10 alkyl, heterocyclic aromatic base C0-C10 Alkyl ,-OR⁶、-S(O)_mR⁶、-NR⁶R⁷、-SO₂NR⁶R⁷、-C(O)R^b、-C(O)NR⁶R⁷、-C(O)-C(O)NR⁶R⁷、-C(O)OR⁶、 -C(O)-C(O)OR⁶、-OC(O)R^b、-NR⁶C(O)R^b、-NR⁶SO₂R⁷、-(CR⁸R⁹)_nC(O)R^b、-(CR⁸R⁹)_nC(O)OR⁶、 -(CR⁸R⁹)_nC(O)NR⁶R⁷、-(CR⁸R⁹)_nS(O)₂NR⁶R⁷、-(CR⁸R⁹)_nNR⁶R⁷、-(CR⁸R⁹)_nOR⁶、-(CR⁸R⁹)_nS(O)_mR⁶、 -NR¹⁰C(O)NR⁶R⁷、-NR¹⁰S(O)₂NR⁶R⁷Or-NR¹⁰S(O)NR⁶R⁷, wherein arbitrarily group all can be taken by PG independently of one another Generation；

M is selected from 0-2；

N is selected from 0-7；

And, formula (I) compound, and pharmaceutically acceptable salt, prodrug and solvate.Wherein

R²It is selected from

M is selected from 0-2；

N is selected from 0-7；

And, formula (I) compound, and pharmaceutically acceptable salt, prodrug and solvate.Wherein,

R²During 5-membered aromatic heterocycle substituted for G1, formula (I) has a structure that

Y¹And Y³It is each independently selected from N or C, but Y¹And Y³It is not simultaneously selected from N；

Y², Y⁴And Y⁵It is each independently selected from N or CH；

G1 is selected from hydrogen, halogen, cyano group ,-CF₃、-OCF₃, nitro, oxo, R⁶, C1-C10 alkyl, C2-C10 thiazolinyl, C2-C10 Alkynyl, C3-C10 cycloalkyl C0-10 alkyl, Heterocyclylalkyl C0-10 alkyl, aromatic radical C0-C10 alkyl, heterocyclic aromatic base C0-C10 Alkyl ,-OR⁶、-S(O)_mR⁶、-NR⁶R⁷、-SO₂NR⁶R⁷、-C(O)R^b、-C(O)NR⁶R⁷、-C(O)-C(O)NR⁶R⁷、-C(O)OR⁶、 -C(O)-C(O)OR⁶、-OC(O)R^b、-NR⁶C(O)R^b、-NR⁶SO₂R⁷、-(CR⁸R⁹)_nC(O)R^b、-(CR⁸R⁹)_nC(O)OR⁶、 -(CR⁸R⁹)_nC(O)NR⁶R⁷、-(CR⁸R⁹)_nS(O)₂NR⁶R⁷、-(CR⁸R⁹)_nNR⁶R⁷、-(CR⁸R⁹)_nOR⁶、-(CR⁸R⁹)_nS(O)_mR⁶、 -NR¹⁰C(O)NR⁶R⁷、-NR¹⁰S(O)₂NR⁶R⁷Or-NR¹⁰S(O)NR⁶R⁷, wherein arbitrarily group all can be taken by PG independently of one another Generation；

M is selected from 0-2；

N is selected from 0-7；

And, formula (I) compound, and pharmaceutically acceptable salt, prodrug and solvate.Wherein, R1^cAnd R1^dAll represent H.

In the synthetic route of following claims, as non-specifically indicates:

W is selected from C3-C10 cycloalkyl, C (C1-C10 alkyl)₂、-S(O)_m-；

R1^aAnd R1^eIt is each independently selected from chlorine and bromine；

R1^bSelected from fluorine and-CF₃；

PG be selected from, but not limited to, hydrogen, trityl, benzyl, to methoxy-benzyl, p-toluenesulfonyl, formoxyl, trifluoroacetyl Base, benzyloxycarbonyl group and tertbutyloxycarbonyl.

M is selected from 0-2.

And, the preparation method of formula (I) compound, including:

(A) when W be-S (O)-time, be raw material successively experience sulfide oxidation with the compound of formula (I-1) and be prepared by deprotection base:

Wherein

X²Selected from N or CH；

G1 is selected from N azetidinyl, pyrrolidinyl, piperidines, piperazine, morpholine, homopiperazine, and wherein arbitrarily group all can be respective Replaced by PG independently；

(B) when W is selected from C3-C10 cycloalkyl or C (C1-C10 alkyl)₂Time, directly slough protection group PG by the compound of formula (I-1) With PG ' preparation:

And, in the presence of coupling reagent, there is Suzuki in the preparation method of formula (I-1) compound, i.e. compound (I-2) and (I-3) Coupling reaction:

W is selected from C3-C6 cycloalkyl, C (C1-C3 alkyl)₂、-S-；

And, the preparation method of formula (I-2) compound, including:

(A) X is worked as²Selected from N or CH, W be S time prepared by following steps:

(B) X is worked as²For N, W selected from C3-C10 cycloalkyl or C (C1-C10 alkyl)₂, with the compound of formula (I-6) be raw material pass through with Prepared by lower step:

And, the preparation method of formula (I-4) compound, including:

(A) when X2 is CH, the compound of formula (I-4) is prepared by the following method:

(B) when X2 is N, the compound of formula (I-4) is prepared by the following method:

And, the preparation method of formula (I-5) compound:

And, the preparation method of formula (I-6) compound, including:

(A) when W is C3-C10 cycloalkyl, formula (I-6) compound is prepared with dihalo hydrocarbon reaction by intermediate (I-7):

Wherein

X is selected from bromine, iodine；

R is selected from-(CH2) p-, and wherein p is selected from 2-9；

(B) when W is C (C1-C10 alkyl) 2, formula (I-6) compound is prepared by the monohaloalkyl hydrocarbon reaction of (I-7) with two equivalents:

Wherein

X is selected from bromine, iodine；

R is selected from C1-C10 alkyl.

And, intermediate formula (I-7) is prepared according to following steps:

Another aspect of the invention provides a kind of pharmaceutical composition, and this pharmaceutical composition comprises according to the embodiment above and change side Any one compound in case and one or more pharmaceutically acceptable excipient.

Accompanying drawing explanation

Fig. 1 is the test compound suppression ratio to gastric carcinoma cells MKN45

Detailed description of the invention

Without it is further noted that use following term to define the most in full: term " prodrug " refers to can be converted in vivo accordingly Any derivant of active pharmaceutical compounds.In one embodiment, when the compound of the present invention contains and sends out base, its prodrug can To be itself and the enzyme that suitably acid is formed, described acid includes such as lactic acid, twists and sow acid, ascorbic acid etc..Term is " pharmaceutically acceptable Salt " except as otherwise noted, the salt including the acidic-group that may be present in the compounds of this invention (such as, but not limited to, clock salt, is received Salt, money salt, calcium salt etc.) or the salt of basic group (such as, but not limited to, sulfate, hydrochlorate, phosphate, nitrate, carbonic acid Salt etc.).Term " solvate " refers in the solution, and solute molecule or ion are by Coulomb force, Van der Waals for, charge transfer The compound molecule compound that the solvent molecule that between power, hydrogen bond equimolecular, gravitational attraction is adjacent is formed.In one embodiment, solvent is water, I.e. the compounds of this invention forms hydrate.

In some embodiments of the present invention, it is provided that the compound of formula (I), and pharmaceutically acceptable salt, prodrug and solvate.

Wherein

X1, X2, X3, X4 are each independently selected from N, NH, C, CH or CH2；

W is selected from C3-C10 cycloalkyl, C (C1-C10 alkyl) 2, carbonyl ,-C (O) NH-,-S (O) m-；

R1a, R1b, R1c, R1d and R1e be each independently selected from hydrogen, halogen ,-CN, C1-10 alkyl ,-CF3 ,-OCF3, -OCHF2 ,-OC0-10 alkyl ,-S (O) mC0-10 alkyl ,-SO2N (C0-10 alkyl) (C0-10 alkyl) ,-N (C0-10 alkyl) (C0-10 alkyl) ,-N (C0-10 alkyl) C (=O) (C0-10 alkyl) ,-N (C0-10 alkyl) C (=O) O (C0-10 alkyl) ,-N (C0-10 Alkyl) C (=O) N (C0-10 alkyl) ,-C (=O) C0-10 alkyl ,-C (=O) OC0-10 alkyl ,-C (=O) N (C0-10 alkyl) ,-O Heterocyclylalkyl ,-N (C0-10 alkyl) Heterocyclylalkyl ,-N (C0-10 alkyl) heterocyclic aromatic base, Heterocyclylalkyl, heterocyclic aromatic base ,-S are miscellaneous Polycyclic aromatic group or-O heterocyclic aromatic base, wherein Heterocyclylalkyl arbitrarily can be replaced by one or more following groups: oxygen, C1-10 alkyl, C (=O) OC0-10 alkyl, C (=O) N (C0-10 alkyl) (C0-10 alkyl) ,-SO2N (C0-10 alkyl) (C0-10 alkyl) or SO2C1-10 alkyl, wherein said moieties arbitrarily can be replaced by one or more following groups: hydroxyl ,-OC1-10 alkyl, -N (C0-10 alkyl) (C0-10 alkyl) ,-C (=O) N (C0-10 alkyl) (C0-10 alkyl), C (=O) OC0-10 alkyl, C (=O) C0-10 Alkyl, Heterocyclylalkyl or heterocyclic aromatic base；

R2 is selected from hydrogen, halogen, cyano group ,-CF3, nitro, C1-C10 alkyl, C2-C10 thiazolinyl, C2-C10 alkynyl, C3-C10 Cycloalkyl C0-C10 alkyl, ternary are to ten yuan of Heterocyclylalkyl C0-C10 alkyl, aromatic radical C0-C10 alkyl, aromatic radical C1-C10 Cycloalkyl, aromatic radical ternary to ten yuan Heterocyclylalkyl, heterocyclic aromatic base, heterocyclic aromatic base C1-C10 alkyl, heterocyclic aromatic base ternary To ten-ring alkyl, wherein arbitrarily group all can be replaced by one or more G1 groups independently of one another；

Or R2 is selected from

R3 selected from hydrogen, C1-C10 alkyl, C2-C10 alkyl-OR4, C2-C10 alkyl-NR4R5, C2-C10 alkyl-S (O) mR4, C3-C10 cycloalkyl C0-C10 alkyl, C3-C10 cyclenes alkyl C1-C10 alkyl, Heterocyclylalkyl C0-C10 alkyl, aromatic radical C0-C10 Alkyl, heterocyclic aromatic base C0-C10 alkyl, C1-C10 alkyl C3-C10 cycloalkyl, C3-C10 cycloalkyl C3-C10 cycloalkyl, C3-C10 cyclenes alkyl C3-C10 cycloalkyl, Heterocyclylalkyl C3-C10 cycloalkyl, aromatic radical C3-C10 cycloalkyl, heteroaromatic Base C3-C10 cycloalkyl, C1-C10 Alkyl cycloheteroalkyl, C3-C10 cycloalkylcycloheteroalkyl, C3-C10 cyclenes Alkyl cycloheteroalkyl, Heterocyclylalkyl Heterocyclylalkyl, aromatic radical Heterocyclylalkyl, heterocyclic aromatic base Heterocyclylalkyl ,-C (O) Ra, R4O-C0-C10 alkyl C (O)-, R4R5N-C0-C10 alkyl C (O)-, R4S (O) mC0-C10 alkyl C (O)-,-CO2R4 ,-C (O) NR4R5 ,-S (O) mR4, -SO2NR4R5 or-C (S) OR4, wherein arbitrarily group all can be replaced by one or more G2 groups independently of one another；

G1 and G2 be each independently selected from hydrogen, halogen, cyano group ,-CF3 ,-OCF3, nitro, oxo, R6, C1-C10 alkyl, C2-C10 thiazolinyl, C2-C10 alkynyl, C3-C10 cycloalkyl C0-10 alkyl, Heterocyclylalkyl C0-10 alkyl, aromatic radical C0-C10 Alkyl, heterocyclic aromatic base C0-C10 alkyl ,-OR6 ,-S (O) mR6 ,-NR6R7 ,-SO2NR6R7 ,-C (O) Rb ,-C (O) NR6R7, -C(O)-C(O)NR6R7、-C(O)OR6、-C(O)-C(O)OR6、-OC(O)Rb、-NR6C(O)Rb、-NR6SO2R7、 -(CR8R9)nC(O)Rb、-(CR8R9)nC(O)OR6、-(CR8R9)nC(O)NR6R7、-(CR8R9)nS(O)2NR6R7、 -(CR8R9)nNR6R7、-(CR8R9)nOR6、-(CR8R9)nS(O)mR6、-NR10C(O)NR6R7、-NR10S(O)2NR6R7 Or-NR10S (O) NR6R7, wherein arbitrarily group all can be replaced by PG independently of one another；

R4, R5, R6, R7, R8, R9, R10, Ra, Rb are each independently selected from hydrogen, C1-C10 alkyl or C3-C10 cycloalkanes Base, wherein arbitrarily group all can be independently of one another by halogen ,-OCF3 or-OC0-3 alkyl, aromatic radical C0-10 alkyl, heteroaromatic Base C0-10 alkyl, C3-10 cycloalkyl C0-C10 alkyl, Heterocyclylalkyl C0-10 alkyl, aromatic radical C3-10 cycloalkyl, heterocycle Aromatic radical ternary to ten yuan of Heterocyclylalkyls, Heterocyclylalkyl C3-10 cycloalkyl, C3-10 cycloalkyl C3-10 cycloalkyl, C1-10 alkyl- Heterocyclylalkyl, Heterocyclylalkyl-Heterocyclylalkyl, aromatic radical-Heterocyclylalkyl or heterocyclic aromatic base-Heterocyclylalkyl replace；

-NR4R5 and-NR6R7 be independent linear structure, or R4 and R5, R6 and R7 all can be connected with them respectively Nitrogen-atoms forms saturated or unsaturated heterocycle together, and heterocycle described herein can arbitrarily comprise one or more selected from O, N or S (O) m Hetero atom；

-CR8R9 is independent linear structure, forms saturated or unsaturated ring with them together with the carbon atom that R8 and R9 can be connected, Ring described herein can arbitrarily comprise one or more hetero atom selected from O, N or S (O) m；

M is selected from 0-2；

N is selected from 0-7；

Above-mentioned general formula compound (I) and following preferred formula (I) compound are preferably as follows substituent group or group:

X1 preferably is selected from NH or CH.

X1 is more preferably NH.

X2 preferably is selected from N or CH.

X3 preferably is selected from N or C.

X3 is more preferably C.

X4 preferably is selected from N or CH.

X4 is more preferably N.

R1a and R1e preferably is selected from halogen ,-CF3 ,-OCHF2, nitro, azido, hydroxyl independently of one another.

R1a and R1e is the most more preferably from halogen ,-CF3 ,-OCHF2, nitro.

R1a and R1e is independently of one another particularly preferably from halogen.

R1a and R1e is especially preferably chlorine, bromine independently of one another.

R1b preferably is selected from hydrogen, halogen ,-CF3 ,-OCHF2, C1-C10 alkoxyl.

R1b is more selected from hydrogen, halogen ,-CF3.

R1b is particularly preferably from halogen ,-CF3.

R1b is especially preferably fluorine ,-CF3.

R1c and R1d preferably is selected from hydrogen, halogen ,-CF3 ,-OCHF2, C1-C10 alkoxyl independently of one another.

R1c and R1d is the most more preferably from hydrogen, halogen ,-CF3 ,-OCHF2.

R1c and R1d is preferably hydrogen independently of one another.

W is selected from C3-C10 cycloalkyl, C (C1-C10 alkyl) 2, carbonyl ,-C (O) NH-,-S (O) m-, and wherein m is selected from 0-2.

W is more preferably from C3-C6 cycloalkyl, and C (C1-C5 alkyl) 2 ,-S (O) m-, wherein m preferably is selected from 0-2.

W is the most certainly-C (CH3) 2-,-S (O) m-, wherein m preferably is selected from 0-2.

R²It is preferably

R²It is more preferably

R²Particularly preferably

Y1 and Y3 preferably is selected from N or C independently of one another, but preferably is selected from N when Y1 with Y3 is different.

Y2, Y4 and Y5 preferably are selected from N or CH independently of one another.

Y1 is more preferably C, Y3 and is more preferably N.

Y4 is more preferably N, Y2 and Y5 and is more preferably CH.

G1 preferably is selected from C4-C6 Heterocyclylalkyl.

G1 is more preferably from N azetidine, pyrrolidine, piperidines, piperazine, morpholine, homopiperazine.

G1 is particularly preferably 4-piperidines.

Each group in above-mentioned logical formula (I) compound and preferred formula (I) compound can combination with one another, i.e. include in described logical formula (I) compound Not preferred, and the combination between the different other substituent group of priority and group.Any of the above compound mode is not only suitable for end product, And therefore it is also applied for precursor and intermediate.

Present invention preferably comprises formula (I) compound of above-mentioned preferred substituents and group and combinations thereof.

History of the present invention preferably comprises formula (I) compound of above-mentioned history preferred substituents and group and combinations thereof.

Formula (I) compound comprising above-mentioned particularly preferred substituent group and group and combinations thereof specifically preferred according to the invention.

The present invention particularly preferably comprises formula (I) compound of above-mentioned particularly preferred substituent group and group and combinations thereof.

Except as otherwise noted, optionally substituted group can be monosubstituted or polysubstituted, wherein in the case of polysubstituted, and substituent group Can be identical or different.

Synthesis

Suitable solvent conventional in organic reaction all can use in each step reaction of present invention below preparation method, such as, but not limited to Hydrocarbon (such as pentane, hexane, heptane, hexamethylene, the oil of water, buffer solution, aliphatic and hydrocarbon aromatic, optional or halogenation Ether, gasoline, volatile oil, benzene,toluene,xylene, dichloromethane, dichloroethanes, chloroform, carbon tetrachloride, chlorobenzene and adjacent dichloro Benzene), aliphatic and aromatic, optional alcohols (such as methanol, ethanol, propanol, isopropanol, the tert-butyl alcohol, ethylene glycol etc.), alcohol (such as ethanol and butyl oxide, glycol dimethyl ether and diethylene glycol dimethyl ether, oxolane and dioxanes etc.), ester (such as methyl acetate or Ethyl acetate etc.), nitrile (such as acetonitrile or propionitrile etc.), ketone (such as acetone, butanone etc.), amide (such as dimethylformamide, dimethyl Acetamide and N-Methyl pyrrolidone etc.) and dimethyl sulfoxide, tetramethylene sulfone and HMPA and N, N-dimethyl Trimethylene urea (DMPU) etc..

Synthetic route (one)

Formula (I) compound in claim 7, when W is S (O), is synthesized by following route:

Reaction 1:

Formula (I) compound can in the presence of acidic materials, in conventional suitable solvent or solvent-free under the conditions of, make formula (I-1-1) Intermediate is sloughed protection group PG and PG ' and is prepared.

Described acidic materials are the acid compound being usually used in this purpose, such as, but not limited to trifluoracetic acid, hydrochloric acid, hydrobromic acid, three Fluorine methanesulfonic acid etc..

Conventional suitable solvent as defined above, preferably dichloromethane, 1,2-dichloroethanes, chloroform.

Reaction 2:

The intermediate of formula (I-1-1) in conventional suitable solvent, can make the compound quilt of formula (I-1) by the presence of oxidant Aoxidize and prepare.

Described oxidant is the oxidant being usually used in this purpose, such as, but not limited to metachloroperbenzoic acid (mCPBA), the tertiary fourth of peroxide Alcohol (tBuOOH), ozone, hydrogen peroxide, magnesium monoperoxyphthalate, oxaziridine.

Reaction 3:

The compound of formula (I-1) can be in the presence of Pd catalyst and alkali, in conventional suitable solvent, make formula (I-2) compound and The compound of formula (I-3) occurs Suzuki coupling to prepare.

Described Pd catalyst is the Pd catalyst being usually used in this contents, such as, but not limited to Pd (Ph3P) 4, PdCl2 (dppf), Pd(OAc)2。

Described alkali is the alkali being usually used in this purpose, such as, but not limited to sodium carbonate (Na2CO3), potassium carbonate (K2CO3), cesium carbonate (Cs2CO3), diisopropyl ethyl amine (DIPEA).

Conventional suitable solvent as defined above, preferably dichloromethane, acetonitrile, DMF, dioxane and four Hydrogen furan.

Reaction 4:

The compound of formula (I-2) can be in the presence of CuI and alkali, in conventional suitable solvent, makes intermediate and the formula (I-5) of formula (I-4-1) Compound generation coupling prepare.

Conventional suitable solvent as defined above, preferably ethylene glycol, isopropanol.

Reaction 5:

The intermediate of formula (I-4-1) can in the presence of base, and in conventional suitable solvent, the compound making formula (I-4) is anti-with PG ' X Answer and prepare.

Described PG ' X is the compound being usually used in this purpose, such as, but not limited to paratoluensulfonyl chloride, benzyl chlorine, fert-butyidimethylsilyl Chlorosilane.

Described alkali is the alkali being usually used in this purpose, such as, but not limited to sodium carbonate (Na2CO3), potassium carbonate (K2CO3), cesium carbonate (Cs2CO3)。

Conventional suitable solvent as defined above, preferably DMF (DMF), acetonitrile.

Reaction 6:

(A) when X2 is CH, the compound of formula (I-4) is reacted in conventional conjunction with NIS by 5-bromo-1H-pyrrolo-[2,3-b] pyridine Prepared by suitable solvent:

Conventional suitable solvent as defined above, preferably acetone, butanone, DMF (DMF).

(B) X is worked as²During for N, the compound of formula (I-4) passes through 5-bromo-1H-pyrazolo [3,4-b] pyridine with iodine in the presence of base, Prepared by conventional suitable solvent:

Described alkali is the alkali being usually used in this purpose, such as, but not limited to potassium hydroxide, sodium hydroxide.

Conventional suitable solvent as defined above, preferably DMF (DMF), dimethyl sulfoxide, acetonitrile.

Reaction 7:

The compound of formula (I-5) can by 1,2,4-trisubstituted benzenes in the presence of a base, with elemental sulfur in conventional suitable solvent Reaction preparation.

Described alkali is the alkali being usually used in this purpose, such as, but not limited to n-BuLi, N, N-lithium diisopropylamine, hexamethyl two silicon Base Lithamide..

Conventional suitable solvent as defined above, preferably oxolane.

Synthetic route (two)

When formula (I) compound in claim 7, when W is selected from C3-C6 cycloalkyl, C (C1-C3 alkyl)₂Time, by following Route synthesizes:

As shown above, in the route by formula (I-2) preparation of compounds of formula (I) compound, when W is selected from C3-C6 cycloalkyl and C (C1-C3 Alkyl)₂Time when being S (O) with W route essentially identical, difference is that being not related to sulfur in synthetic route (two) is oxidized to sulfoxide, accordingly Eliminate above-mentioned reaction 2.

Reaction 1:

The compound of formula (I-2) can in the presence of base, and in conventional suitable solvent, the intermediate making formula (I-6-1) is anti-with PG ' X Answer and prepare.

Described alkali is the alkali being usually used in this purpose, such as, but not limited to sodium carbonate (Na₂CO₃), potassium carbonate (K₂CO₃), cesium carbonate (Cs₂CO₃), sodium hydride (NaH).

Conventional suitable solvent as defined above, preferably DMF (DMF), acetonitrile, oxolane.

Reaction 2:

The intermediate of formula (I-6-1) can be prepared with anhydrous hydrazine cyclization in conventional suitable solvent by the intermediate of formula (I-6-2).

Conventional suitable solvent as defined above, preferably absolute methanol, dehydrated alcohol, anhydrous propanol, anhydrous isopropyl alcohol.

Reaction 3:

The intermediate of formula (I-6-2) can be by the presence of a strong base, in conventional suitable solvent, make the intermediate of formula (I-6-3) with Prepared by the reaction of 2-fluoro-5-bromopyridine.

Described highly basic is the highly basic being usually used in this purpose, such as, but not limited to n-BuLi, N, N-lithium diisopropylamine, hexamethyl Two silica-based Lithamide .s.

Conventional suitable solvent as defined above, preferably oxolane.

Reaction 4:

The intermediate of formula (I-6-3) in conventional suitable solvent, can make intermediate and the knot of formula (I-6-4) by the presence of coupling agent Structure formula is prepared by the azanol reaction of MeONHMe.

Described coupling agent is the coupling agent being usually used in this purpose, such as, but not limited to I-hydroxybenzotriazole (HOBt), 1-ethyl-3-(3- Dimethylamino-propyl) carbodiimide hydrochloride (EDCI), 2-(7-azo BTA)-N, N, N', N'-tetramethylurea hexafluorophosphoric acid ester (HATU), O-BTA-N, N, N', N'-tetramethylurea Tetrafluoroboric acid (TBTU) etc..

Conventional suitable solvent as defined above, preferably dichloromethane, 1,2-dichloroethanes, DMF.

Reaction 5:

The intermediate of formula (I-6-4) can in the presence of acids or bases, in conventional suitable solvent, makes the compound of formula (I-6) hydrolyze Reaction preparation.

Described acid is the acid being usually used in this purpose, such as, but not limited to concentrated sulphuric acid, concentrated hydrochloric acid, trifluoromethanesulfonic acid.

Described alkali is the alkali being usually used in this purpose, such as, but not limited to sodium hydroxide, potassium hydroxide.

Conventional suitable solvent as defined above, preferably water and ethylene glycol mixture.

Reaction 6:

(A) when W is C3-C6 cycloalkyl, the compound of formula (1-6) can pass through the compound of formula (I-7) in the presence of a base, conventional Suitable solvent in prepare with dihalo hydrocarbon reaction:

Described alkali is the alkali being usually used in this purpose, such as, but not limited to sodium hydride, potassium carbonate, n-BuLi.

Conventional suitable solvent as defined above, preferably DMF, oxolane.

(B) it is C (C1-C3 alkyl) as W₂Time, formula (I-6) compound can pass through the compound of formula (I-7) in the presence of a base, conventional Suitable solvent in prepare with the monohaloalkyl hydrocarbon reaction of two equivalents:

Conventional suitable solvent as defined above, preferably DMF, oxolane.

Reaction 7:

The compound of formula (I-7) can pass through the intermediate of formula (I-7-1) and be dehydrated in conventional suitable solvent and prepare.

It is usually used in the reagent of this reaction such as, but not limited to thionyl chloride, phosphorus oxychloride, oxalyl chloride, Cyanuric Chloride.

Conventional suitable solvent as defined above, preferably toluene.

Reaction 8:

The intermediate of formula (I-7-1) can pass through the ammonolysis reaction of the intermediate of formula (I-7-2), in conventional suitable solvent or condition of no solvent Lower preparation.

Belonging to ammonolysis reagent be the ammonolysis reagent being usually used in this purpose, such as, but not limited to ammonia, ammonia, ammonia oxolane molten Liquid.

Conventional suitable solvent as defined above, preferably dichloromethane, oxolane.

Reaction 9:

The intermediate of formula (I-7-2) can pass through the intermediate of formula (I-7-3) in the presence of suitable agent, prepares in conventional suitable solvent.

Described reagent is the reagent being usually used in this purpose, such as, but not limited to thionyl chloride, oxalyl chloride, phosphorus oxychloride.

Conventional suitable solvent as defined above, preferably dichloromethane.

Reaction 10:

The intermediate of formula (I-7-3) can pass through the intermediate of formula (I-7-4) in the presence of oxidant, oxidation system in conventional suitable solvent Standby.

Described oxidant is the oxidant being usually used in this purpose, such as, but not limited to 2,2,6,6-tetramethyl piperidine oxides/sodium hypochlorite/ Sodium chlorite, periodic acid/pyridinium chloro-chromate.

Conventional suitable solvent as defined above, preferably acetonitrile, water, phosphate buffer solution.

Reaction 11:

The intermediate of formula (I-7-4) can be by 1,2,4-trisubstituted benzenes in the presence of highly basic, in conventional suitable solvent, with oxirane Reaction preparation.

Conventional suitable solvent as defined above, preferably oxolane.

Synthetic example

Embodiment 1:3-[(2,6-bis-chloro-3-fluorophenyl) sulfinyl]-5-(1-(piperidin-4-yl)-1H-(pyrazoles-4-base)-1H-pyrroles [2,3-b] pyridine

The synthesis of the bromo-3-of step 1:5-iodo-1H-pyrrolo-[2,3-b] pyridine

Bromo-for 5-1H-pyrrolo-[2,3-b] pyridine (2.0g, 10.2mmol) is added in 20mL acetone, is stirred to dissolve, is subsequently adding N-N-iodosuccinimide (2.7g, 12.0mmol), stirring reaction 1h under room temperature.After reaction terminates, remove solvent, acetic acid second under reduced pressure Ester (20mL) dissolves, the most successively with saturated sodium thiosulfate solution (2 × 30mL) and saturated aqueous common salt (2 × 30mL) washing, organic It is dried with anhydrous sodium sulfate, concentrates, obtain off-white color solid (2.9g, 88.0%).1H NMR(400MHz,CDCl3)δ9.27(s, 1H), 8.37 (d, J=2.0Hz, 1H), 7.93 (d, J=1.6Hz, 1H), 7.45 (d, J=2.5Hz, 1H).

The synthesis of the iodo-1-of the bromo-3-of step 2:5-(4-methoxy-benzyl)-1H-pyrrolo-[2,3-b] pyridine

Bromo-for 5-3-iodo-1H-pyrrolo-[2,3-b] pyridine (2.9g, 9.0mmol) is added in 20mL DMF, is stirred to dissolve, then Add potassium carbonate (3.7g, 26.8mmol) and 4-methoxy-benzyl chlorine (1.7g, 10.8mmol), stirring reaction 4h under room temperature.Reaction terminates After, reactant liquor add water (50mL) then with ethyl acetate (3 × 20mL) extract, merge organic facies, with saturated aqueous common salt (2 × 50mL) Washing, organic facies anhydrous sodium sulfate is dried, concentrate, column chromatography purification (petroleum ether: ethyl acetate=10:1) i.e. obtain white solid (3.6g, 90.3%).1H NMR (400MHz, CDCl3) δ 8.39 (d, J=2.1Hz, 1H), 7.87 (d, J=2.1Hz, 1H), 7.27 (s, 1H), 7.21 (d, J=8.6Hz, 2H), 6.88 (t, J=5.8Hz, 2H), 5.39 (s, 2H), 3.81 (s, 3H).

The synthesis of the bromo-3-of step 3:5-(2,6-bis-chloro-3-fluorophenyl sulfur)-1-(4-methoxy-benzyl)-1H-pyrrolo-[2,3-b] pyridine

The iodo-1-of the bromo-3-of 5-(4-methoxy-benzyl)-1H-pyrrolo-[2,3-b] pyridine (3.6g, 8.1mmol) adds in 50mL isopropanol, so Rear addition 2,6-bis-chloro-3-fluoro thiophenol (1.9g, 9.7mmol), potassium carbonate (2.2g, 16.2mmol), Hydro-Giene (Water Science). (1.5g, 8.1mmol), Ethylene glycol (1.0g, 16.2mmol), the lower 100 DEG C of stirring reaction 5h of nitrogen protection.After reaction terminates, filter, ethyl acetate (50mL) Washing filtering residue, filtrate is washed with ammonia (2 × 50mL) and saturated aqueous common salt (2 × 50mL) successively, and organic facies anhydrous sodium sulfate is dried, Concentrating, column chromatography purification (petroleum ether: ethyl acetate=10:1) i.e. obtains white solid (2.5g, 70.0%).1H-NMR(400MHz, CDCl3) 1H NMR (400MHz, CDCl3) δ 8.37 (d, J=2.0Hz, 1H), 8.21 (d, J=2.1Hz, 1H), 7.58 (s, 1H), 7.35(m,1H),7.19(m,2H),7.06(m,1H),6.87(m,2H),5.38(s,2H),3.81(s,3H).

Step 4:5-((N-t-butoxycarbonyl-piperidin-4-base)-1H-pyrazoles-4-base)-3-(2,6-bis-chloro-3-fluorophenyl sulfur)-1-(4-methoxybenzyl Base) synthesis of-1H-pyrrolo-[2,3-b] pyridine

Bromo-for 5-3-(2,6-bis-chloro-3-fluorophenyl sulfur)-1-(4-methoxy-benzyl)-1H-pyrrolo-[2,3-b] pyridine (2.5g, 4.9mmol) is dissolved in In dioxane/water (20mL, 4:1), add 1-(1-t-butoxycarbonylpiperidin-4-base) pyrazoles-4-boric acid pinacol ester (2.6g, 6.8mmol), Then tetra-triphenylphosphine palladium (170mg, 0.15mmol), cesium carbonate (4.8g, 14.7mmol), 80 DEG C of stirring reactions are added under nitrogen protection Overnight.After reaction terminates, reactant liquor dilute, ethyl acetate (3 × 20mL) extracts, and merges organic facies, then uses saturated common salt Water (2 × 30mL) washs, and anhydrous sodium sulfate is dried, and concentrates, column chromatography purification (petroleum ether: ethyl acetate=10:1), obtains off-white color Solid (1.4g, 41.7%).1H NMR (400MHz, CDCl3) δ 8.45 (d, J=2.1Hz, 1H), 8.12 (m, 1H), 7.74 (s, 1H), 7.67(s,1H),7.52(s,1H),7.36(m,1H),7.21(m,2H),7.07(m,1H),6.88(m,2H),5.38(s,2H),4.33(m, 3H),3.81(s,3H),2.89(m,2H),2.15(m,2H),1.95(m,2H),1.51(s,9H).

The synthesis of step 5:3-(2,6-bis-chloro-3-fluorophenyl sulfur)-5-(1-(piperidin-4-yl)-1H-pyrazoles-4-base)-1H-pyrrolo-[2,3-b] pyridine

By 5-((N-t-butoxycarbonyl-piperidin-4-base)-1H-pyrazoles-4-base)-3-(2,6-bis-chloro-3-fluorophenyl sulfur)-1-(4-methoxybenzyl Base)-1H-pyrrolo-[2,3-b] pyridine (1.4g, 2.1mmol) is dissolved in dichloromethane (10mL), then drips trifluoroacetic acid (5mL) and dense Sulphuric acid (1mL), stirring reaction 2h under room temperature.After reaction terminates, reaction system ammonia is neutralized to meta-alkalescence, dichloromethane (2 × 20mL) Extraction, the most successively with saturated sodium bicarbonate solution (2 × 30mL) and saturated aqueous common salt (2 × 30mL) washing, organic facies anhydrous slufuric acid Sodium is dried, and concentrates, obtains Light brown solid (761.5mg, 78.4%).1H NMR(400MHz,CDCl3)δ9.21(s,1H),8.43 (m,1H),8.15(m,1H),7.78(s,1H),7.68(s,1H),7.55(s,1H),7.37(m,1H),7.09(m,1H),4.50(m,1H), 3.73(m,2H),3.22(m,2H),2.49(m,4H).

The conjunction of step 6:3-(2,6-bis-chloro-3-fluorophenyl sulfoxide group)-5-(1-(piperidin-4-yl)-1H-pyrazoles-4-base)-1H-pyrrolo-[2,3-b] pyridine Become

By 3-(2,6-bis-chloro-3-fluorophenyl sulfur)-5-(1-(piperidin-4-yl)-1H-pyrazoles-4-base)-1H-pyrrolo-[2,3-b] pyridine (761.5mg, 1.6mmol) it is dissolved in dichloromethane (20mL), ice bath borehole cooling, is subsequently adding metachloroperbenzoic acid (334.0mg, 1.8mmol), Stirring reaction 2h.After reaction terminates, reactant liquor adds saturated sodium bicarbonate solution cancellation, and dichloromethane (2 × 10mL) extracts, and then depends on Secondary saturated sodium bicarbonate solution (2 × 10mL) and saturated aqueous common salt (2 × 10mL) washing, organic facies anhydrous sodium sulfate is dried, and concentrates, Column chromatography purification (dichloromethane: methanol=10:1), obtains off-white color solid (608.0mg, 77.2%).1H NMR(400MHz,CDCl3) δ9.30(s,1H),8.46(m,1H),8.20(m,1H),7.85(s,1H),7.70(s,1H),7.57(s,1H),7.45(m,1H),7.14 (m,1H),4.52(m,1H),3.75(m,2H),3.24(m,2H),2.50(m,4H).

The conjunction of embodiment 2:3-(2,6-bis-chloro-3-fluorophenyl sulfoxide group)-5-(1-(piperidin-4-yl)-1H-pyrazoles-4-base)-1H-pyrazolo [3,4-b] pyridine Become

The synthesis of the bromo-3-of step 1:5-iodo-1H-pyrazolo [3,4-b] pyridine

Bromo-for 5-1H-pyrazolo [3,4-b] pyridine (2.0g, 10.1mmol) being added in 20mL DMF, stirring makes molten Solve, be subsequently adding hydroxide flake potassium (1.2g, 21.4mmol), under room temperature stirring reaction 10 minutes, be subsequently adding solid iodine (2.8g, 11.1 Mmol), stirring reaction 4 lab scales under room temperature, then add water (30mL) dilution, and ethyl acetate (3 × 20mL) extracts, the most successively with full Washing with hypo solution (2 × 30mL) and saturated aqueous common salt (2 × 30mL), organic facies anhydrous sodium sulfate is dried, and concentrates.So After solid added dioxane (30mL) dissolve, add potassium hydroxide (1.2g, 21.4mmol), stirring reaction 10 minutes under room temperature, then Add solid iodine (2.8g, 11.1mmol), under room temperature stirring reaction overnight, reaction end add water (30mL) dilution, ethyl acetate (3 × 20 ML) extraction, the most successively by saturated sodium thiosulfate solution (2 × 30mL) and saturated aqueous common salt (2 × 30mL) washing, organic facies nothing Aqueous sodium persulfate is dried, and concentrates and i.e. obtains Light brown solid (2.8g, 85.6%).1H NMR(400MHz,DMSO-d6)δ14.30(s,1H), 8.65 (d, J=2.0Hz, 1H), 8.21 (d, J=2.0Hz, 1H).

The synthesis of the iodo-1-of the bromo-3-of step 2:5-(4-methoxy-benzyl)-1H-pyrazolo [3,4-b] pyridine

Bromo-for 5-3-iodo-1H-pyrazolo [3,4-b] pyridine (2.8g, 8.6mmol) is added in 20mL DMF, is stirred to dissolve, then Add potassium carbonate (3.6g, 26.0mmol) and 4-methoxy-benzyl chlorine (1.7g, 10.9mmol), stirring reaction 4h under room temperature.Reaction terminates After, reactant liquor add water (50mL) then with ethyl acetate (3 × 20mL) extract, merge organic facies, with saturated aqueous common salt (2 × 50mL) Washing, organic facies anhydrous sodium sulfate is dried, concentrate, column chromatography purification (petroleum ether: ethyl acetate=10:1) i.e. obtain white solid (3.6g, 90.3%).1H NMR (400MHz, CDCl3) δ 8.60 (d, J=2.0Hz, 1H), 7.94 (d, J=2.4Hz, 1H), 7.35 (d, J= 25.2Hz, 2H), 6.84 (d, J=5.8Hz, 2H), 5.63 (s, 2H), 3.79 (s, 3H).

The synthesis of the bromo-3-of step 3:5-(2,6-bis-chloro-3-fluorophenyl sulfur)-1-(4-methoxy-benzyl)-1H-pyrazolo [3,4-b] pyridine

The iodo-1-of the bromo-3-of 5-(4-methoxy-benzyl)-1H-pyrazolo [3,4-b] pyridine (3.6g, 8.1mmol) adds in 50mL isopropanol, so Rear addition 2,6-bis-chloro-3-fluoro thiophenol (1.9g, 9.7mmol), potassium carbonate (2.2g, 16.2mmol), Hydro-Giene (Water Science). (1.5g, 8.1mmol), Ethylene glycol (1.0g, 16.2mmol), the lower 100 DEG C of stirring reaction 5h of nitrogen protection.After reaction terminates, filter, ethyl acetate (50mL) Washing filtering residue, filtrate is washed with ammonia (2 × 50mL) and saturated aqueous common salt (2 × 50mL) successively, and organic facies anhydrous sodium sulfate is dried, Concentrating, column chromatography purification (petroleum ether: ethyl acetate=10:1) i.e. obtains white solid (2.5g, 70.0%).1H-NMR(400MHz, CDCl3) δ 8.54 (d, J=2.0Hz, 1H), 7.94 (d, J=2.1Hz, 1H), 7.40 (m, 1H), 7.28 (m, 2H), 7.16 (m, 1H), 6.81(m,2H),5.60(s,2H),3.78(s,3H).

Step 4:5-((N-t-butoxycarbonyl-piperidin-4-base)-1H-pyrazoles-4-base)-3-(2,6-bis-chloro-3-fluorophenyl sulfur)-1-(4-methoxybenzyl Base) synthesis of-1H-pyrazolo [3,4-b] pyridine

Bromo-for 5-3-(2,6-bis-chloro-3-fluorophenyl sulfur)-1-(4-methoxy-benzyl)-1H-pyrazolo [3,4-b] pyridine (2.5g, 4.9mmol) is dissolved in In glycol dimethyl ether/water (20mL, 4:1), and addition 1-(1-t-butoxycarbonylpiperidin-4-base) pyrazoles-4-boric acid pinacol ester (2.6g, 6.8 Mmol), then add tetra-triphenylphosphine palladium (170mg, 0.15mmol) under nitrogen protection, cesium carbonate (4.8g, 14.7mmol), 80 DEG C Stirring reaction is overnight.After reaction terminates, reactant liquor dilute, ethyl acetate (3 × 20mL) extracts, and merges organic facies, then uses Saturated aqueous common salt (2 × 30mL) washs, and anhydrous sodium sulfate is dried, and concentrates, column chromatography purification (petroleum ether: ethyl acetate=10:1), i.e. Obtain off-white color solid (1.6g, 47.8%).1H NMR(400MHz,CDCl3)δ8.67(m,1H),7.84(m,1H),7.74(s,1H), 7.66(s,1H),7.39(s,1H),7.31(m,2H),7.15(m,1H),6.82(m,2H),5.63(s,2H),4.33(m,3H),3.78(s, 3H),2.94(m,2H),2.18(m,2H),2.01(m,2H),1.51(s,9H).

The synthesis of step 5:3-(2,6-bis-chloro-3-fluorophenyl sulfur)-5-(1-(piperidin-4-yl)-1H-pyrazoles-4-base)-1H-pyrazolo [3,4-b] pyridine

By the tert-butyl group-4-(4-(3-(2,6-bis-chloro-3-fluorophenyl sulfur)-1-(4-methoxy-benzyl)-1H-pyrazolo [3,4-b] pyridine-5-base)-1H-pyrrole Azoles-1-base) piperidines-1-carboxylic acid (1.6g, 2.3mmol) is dissolved in dichloromethane (20mL), then drips trifluoroacetic acid (5mL) and concentrated sulphuric acid (1mL), stirring reaction 2h under room temperature.After reaction terminates, reaction system ammonia is neutralized to meta-alkalescence, dichloromethane (2 × 20mL) Extraction, the most successively with saturated sodium bicarbonate solution (2 × 30mL) and saturated aqueous common salt (2 × 30mL) washing, organic facies anhydrous slufuric acid Sodium is dried, and concentrates, obtains off-white color solid (870.5mg, 80.3%).1H NMR(400MHz,CDCl3)δ8.85(s,1H),8.20 (s,1H),8.01(s,1H),7.77(s,1H),7.44(m,1H),7.18(m,1H),4.40(m,1H),3.38(m,2H),2.89(m,2H), 2.26(m,4H).

The conjunction of step 6:3-(2,6-bis-chloro-3-fluorophenyl sulfoxide group)-5-(1-(piperidin-4-yl)-1H-pyrazoles-4-base)-1H-pyrazolo [3,4-b] pyridine Become

By 3-(2,6-bis-chloro-3-fluorophenyl sulfur)-5-(1-(piperidin-4-yl)-1H-pyrazoles-4-base)-1H-pyrazolo [3,4-b] pyridine (870.5mg, 1.9mmol) it is dissolved in dichloromethane (20mL), ice bath borehole cooling, is subsequently adding metachloroperbenzoic acid (380mg, 2.2mmol), Stirring reaction 2h.After reaction terminates, reactant liquor adds saturated sodium bicarbonate solution cancellation, and dichloromethane (2 × 20mL) extracts, and then depends on Secondary saturated sodium bicarbonate solution (2 × 30mL) and saturated aqueous common salt (2 × 30mL) washing, organic facies anhydrous sodium sulfate is dried, and concentrates, Column chromatography purification (dichloromethane: methanol=10:1), obtains off-white color solid (703.8mg, 78.2%).1H NMR(400MHz,CDCl3) δ8.92(s,1H),8.18(s,1H),8.10(s,1H),7.82(s,1H),7.46(m,1H),7.20(m,1H),4.41(m,1H),3.37 (m,2H),2.90(m,2H),2.25(m,4H).

Embodiment 3:3-(1-(2,6-bis-chloro-3-fluorophenyl) cyclopropyl)-5-(1-(piperidin-4-yl)-1H-pyrazoles-4-base)-1H-pyrazolo [3,4-b] pyridine Synthesis

The synthesis of the fluoro-phenethanol of the chloro-3-of step 1:2,6-bis-

2,4-Dichlorofluorobenzene (165.0g, 1000.0mmol) is added in 500mL anhydrous tetrahydro furan, is then cooled to-78 DEG C, drip Add n-BuLi (42.0mL, 2.5M, 1050.0mmol), at-78 DEG C stirring reaction 1 hour, be subsequently adding oxirane (44.0g, 1000.0mmol), it is stirred for reacting 2 hours at-78 DEG C.After reaction terminates, use saturated ammonium chloride solution cancellation, ethyl acetate (3 × 200 ML) extraction, organic phase washed with water (2 × 100mL) and saturated aqueous common salt (2 × 100mL) washing, anhydrous sodium sulfate is dried, and concentrates i.e. Obtain colourless liquid (156.7g, 75.0%).1H NMR(400MHz,CDCl3)δ7.25(m,1H),7.03(m,1H),3.89(m,2H), 3.29(m,2H).

The synthesis of the fluoro-phenylacetic acid of the chloro-3-of step 2:2,6-bis-

By 2, the fluoro-phenethanol of the chloro-3-of 6-bis-(156.7g, 750.0mmol) adds in 500mL (pH 6.5) phosphate buffer, then adds Enter TEMPO oxidant (129.0g, 825.0mmol), lower alternate dropwise addition sodium chlorite and liquor natrii hypochloritis are stirred at room temperature.At 40 DEG C Stirring reaction 3 hours.After reaction terminates, reactant liquor dilute hydrochloric acid regulates pH to 2-3, and ethyl acetate (3 × 200mL) extracts, organic Washing with water (2 × 100mL) and saturated aqueous common salt (2 × 100mL) the most successively mutually, anhydrous sodium sulfate is dried, concentrate i.e. obtain white solid (150.5g, 90.0%).1H NMR(400MHz,CDCl3)δ7.35(m,1H),7.12(m,1H),4.10(s,2H).

The synthesis of the fluoro-phenyl acetamide of the chloro-3-of step 3:2,6-bis-

By 2, the fluoro-phenylacetic acid of the chloro-3-of 6-bis-(150.5g, 674.9mmol) adds in 100mL thionyl chloride, 85 DEG C of return stirring reactions 1 Hour, then removing thionyl chloride under reduced pressure, residue dichloromethane dissolves, and drops at 0 DEG C in the ammonia (300mL) of cooling, Stirring reaction 3h.Reaction terminate after, reactant liquor with dichloromethane (3 × 200mL) extract, organic phase washed with water (2 × 100mL) and satisfy Washing with saline solution (2 × 100mL), anhydrous sodium sulfate is dried, and concentrates and i.e. obtains white solid (142.3g, 95.0%).1H NMR(400 MHz,CDCl3)δ7.35(m,1H),7.12(m,1H),4.10(s,2H).

The synthesis of the fluoro-benzene acetonitrile of the chloro-3-of step 4:2,6-bis-

By 2, the fluoro-phenyl acetamide of the chloro-3-of 6-bis-(142.3g, 641.0mmol) is dissolved in pyridine (1000mL), drips thionyl chloride under ice bath (mL), then stirring reaction 2 hours under ice bath, after reaction terminates, reactant liquor adds cancellation in frozen water, petroleum ether extraction (3 × 200 ML) extraction, merges organic facies, the most successively with copper/saturated copper sulphate (2 × 100mL) and saturated aqueous common salt (2 × 100mL) washing, anhydrous Sodium sulfate is dried, and concentrates, obtains off-white color solid (85.9g, 65.7%).1H NMR(400MHz,CDCl3)δ7.39(m,1H), 7.19(m,1H),4.04(s,2H).

The synthesis of step 5:1-(2,6-bis-chloro-3-fluoro-phenyl) cyclopropylniitrile

By 2, the fluoro-benzene acetonitrile of the chloro-3-of 6-bis-(85.9g, 421.1mmol) is dissolved in DMF (500mL), and ice bath borehole cooling is subsequently adding NaH (42.1g, content 60%, 1052.7mmol), under room temperature stirring reaction 1h after, add glycol dibromide (95.0g, 505.3 Mmol), stirring reaction 3h under room temperature, after reaction terminates, reactant liquor saturated ammonium chloride cancellation, ethyl acetate (2 × 200mL) extracts, Merging organic facies, the most successively with water (2 × 100mL) and saturated aqueous common salt (2 × 100mL) washing, organic facies anhydrous sodium sulfate is dried, Concentrate, column chromatography purification (petroleum ether: ethyl acetate=50:1), obtain off-white color solid (83.1g, 85.8%).1H NMR(400MHz, CDCl3)δ7.36(m,1H),7.17(m,1H),1.98(m,2H),1.50(m,2H).

The synthesis of step 6:1-(2,6-bis-chloro-3-fluoro-phenyl) ring propyl formamide

1-(2,6-bis-chloro-3-fluoro-phenyl) cyclopropylniitrile (83.1g, 361.1mmol) is dissolved in ethanol (100mL), adds the hydrogen-oxygen of 40% Changing sodium water solution (400mL), stirred at reflux reacts 10 hours.After reaction terminates, reactant liquor is cooled to room temperature, dilute, analysis Going out a large amount of solid, filter, filter cake is washed with water to neutrality, is dried, obtains off-white color solid (85.5g, 95.4%).1H NMR(400 MHz,DMSO-d6)δ7.50(m,1H),7.41(m,1H),6.98(s,1H),6.67(s,1H),1.65(m,2H),1.08(m,2H).

The synthesis of step 7:1-(2,6-bis-chloro-3-fluoro-phenyl) cyclopropanecarboxylic acid

1-(2,6-bis-chloro-3-fluoro-phenyl) ring propyl formamide (85.5g, 344.6mmol) is dissolved in acetic acid (200mL), adds concentrated sulphuric acid (50mL) with sodium nitrite (2.4g, 34.5mmol) aqueous solution (20mL), stirred at reflux reacts 20 hours.After reaction terminates, reaction Liquid is cooled to room temperature, dilute, separates out a large amount of solid, filters, and filter cake is washed with water to neutrality, is dried, obtains off-white color solid (73.3g, 85.4%).1H NMR(400MHz,DMSO-d6)δ12.6(s,1H),7.51(m,1H),7.42(m,1H),1.75(m, 2H),1.29(m,2H).

The synthesis of step 8:N-methyl-N-methoxy-1-(2,6-bis-chloro-3-fluoro-phenyl) ring propyl formamide

1-(2,6-bis-chloro-3-fluoro-phenyl) cyclopropanecarboxylic acid (73.3g, 294.4mmol) is dissolved in thionyl chloride (100mL), stirs under backflow Mix reaction 1 hour, remove the thionyl chloride of excess, residue dchloromethane under reduced pressure, drop to N-methyl-N-methoxy amine In the cold dichloromethane solution (500mL) of hydrochlorate (34.4g.353.3mmol) and triethylamine (153mL, 1060mmol), under room temperature Stirring reaction 3 hours.After reaction terminates, reactant liquor is successively by water (2 × 200) and saturated aqueous common salt (2 × 200) washing, organic facies nothing Aqueous sodium persulfate is dried, and concentrates, column chromatography purification (petroleum ether: ethyl acetate=20:1), obtains colourless oil liquid (69.5g, 80.8%). 1H NMR(400MHz,CDCl3)7.29(m,1H),7.04(m,1H),3.13(s,3H),3.00(s,3H),1.98(m,2H),1.28 (m,2H).

Step 9:(5-bromo-2-fluorine pyridin-3-yl) synthesis of (1-(2,6-bis-chloro-3-fluoro-phenyl) cyclopropyl) ketone

Add to LDA (56.8mL, 1M, 56.8mmol), in anhydrous tetrahydro furan (200mL), be cooled to-78 DEG C, then drip 5- The fluoro-pyridine of bromo-2-(10.0g, 56.8mmol), maintains-78 DEG C of stirring reactions 2 hours, then dropping N-methyl-N-methoxy-1-(2,6- Two chloro-3-fluoro-phenyls) oxolane (100mL) solution of ring propyl formamide (18.2g, 62.5mmol), drip complete again-78 DEG C of stirrings React 2 hours.After reaction terminates, reactant liquor is cooled to room temperature, adds saturated ammonium chloride cancellation, and ethyl acetate (2 × 100mL) extracts, Merging organic facies, the most successively with water (2 × 100mL) and saturated aqueous common salt (2 × 100mL) washing, organic facies anhydrous sodium sulfate is dried, Concentrate, column chromatography purification (petroleum ether: ethyl acetate=50:1), obtain off-white color solid (10.6g, 45.8%).1H NMR(400MHz, CDCl3)δ8.60(m,1H),8.12(m,1H),7.41(m,1H),7.16(m,1H),1.95(m,2H),1.30(m,2H).

The synthesis of the bromo-3-of step 10:5-(1-(2,6-bis-chloro-3-fluorophenyl) cyclopropyl)-1H-pyrazolo [3,4-b] pyridine

(5-bromo-2-fluorine pyridin-3-yl) (1-(2,6-bis-chloro-3-fluoro-phenyl) cyclopropyl) ketone (10.6g, 26.0mmol) is dissolved in ethanol (100 ML) in, adding hydrazine hydrate (10mL), stirred at reflux reacts 10 hours.After reaction terminates, remove ethanol under reduced pressure, dilute, Separating out a large amount of solid, filter, filter cake washes with water, is dried, column chromatography purification (petroleum ether: ethyl acetate=10:1), obtains class white Color solid (5.8g, 55.3%).1H-NMR(400MHz,CDCl3)δ14.28(s,1H),8.36(m,1H),8.22(m,1H),7.33(m, 1H),7.12(m,1H),2.03(m,2H),1.34(m,2H).

The synthesis of the bromo-3-of step 11:5-(1-(2,6-bis-chloro-3-fluorophenyl) cyclopropyl)-1-(4-methoxy-benzyl)-1H-pyrazolo [3,4-b] pyridine

Bromo-for 5-3-(1-(2,6-bis-chloro-3-fluorophenyl) cyclopropyl)-1H-pyrazolo [3,4-b] pyridine (5.8g, 14.5mmol) is dissolved in DMF (50 ML) in, adding potassium carbonate (6.0g, 43.5mmol) and to methoxy-benzyl chlorine (2.5g, 16.0mmol), under room temperature, stirring reaction 5 is little Time.After reaction terminates, reactant liquor dilute, ethyl acetate (2 × 50mL) extracts, and merges organic facies, the most successively with water (2 × 50mL) Washing with saturated aqueous common salt (2 × 50mL), organic facies anhydrous sodium sulfate is dried, and concentrates, column chromatography purification (petroleum ether: ethyl acetate =20:1), obtain off-white color solid (6.9g, 90.8%).1H NMR(400MHz,CDCl3)δ8.40(m,1H),8.21(m,1H), 7.41(m,1H),7.26(m,2H),7.16(m,1H),6.97(m,2H),5.38(s,2H),3.81(s,3H),1.98(m,2H),1.29(m, 2H).

Step 12:5-((N-t-butoxycarbonyl-piperidin-4-base)-1H-pyrazoles-4-base)-3-(1-(2,6-bis-chloro-3-fluorophenyl) cyclopropyl)-1-(4-methoxy Base benzyl) synthesis of-1H-pyrazolo [3,4-b] pyridine

By bromo-for 5-3-(1-(2,6-bis-chloro-3-fluorophenyl) cyclopropyl)-1-(4-methoxy-benzyl)-1H-pyrazolo [3,4-b] pyridine (6.9g, 13.2 Mmol) it is dissolved in dioxane/water (100mL, 4:1), adds 1-(1-t-butoxycarbonylpiperidin-4-base) pyrazoles-4-boric acid pinacol ester (7.5 G, 19.8mmol), then add tetra-triphenylphosphine palladium (462mg, 0.4mmol) under nitrogen protection, cesium carbonate (12.9g, 39.6mmol), 80 DEG C of stirring reactions are overnight.After reaction terminates, reactant liquor dilute, ethyl acetate (3 × 50mL) extracts, and merges organic facies, so Washing with saturated aqueous common salt (2 × 50mL) afterwards, anhydrous sodium sulfate is dried, and concentrates, column chromatography purification (petroleum ether: ethyl acetate=5:1), Obtain faint yellow jelly (3.3g, 35.7%).1H NMR(400MHz,CDCl3)δ8.67(m,1H),7.85(m,1H),7.76(s, 1H),7.63(s,1H),7.39(m,1H),7.31(m,2H),7.15(m,1H),6.82(m,2H),5.63(s,2H),4.33(m,3H), 3.78(s,3H),2.94(m,2H),2.18(m,2H),2.00(m,2H),1.95(m,2H),1.50(s,9H),1.31(m,2H).

Step 13:3-(1-(2,6-bis-chloro-3-fluorophenyl) cyclopropyl)-5-(1-(piperidin-4-yl)-1H-pyrazoles-4-base)-1H-pyrazolo [3,4-b] pyridine Synthesis

By 5-((N-t-butoxycarbonyl-piperidin-4-base)-1H-pyrazoles-4-base)-3-(1-(2,6-bis-chloro-3-fluorophenyl) cyclopropyl)-1-(4-methoxyl group Benzyl)-1H-pyrazolo [3,4-b] pyridine (3.3g, 4.8mmol) is dissolved in dichloromethane (20mL), then drips trifluoroacetic acid (5mL) With concentrated sulphuric acid (2mL), stirring reaction 2h under room temperature.After reaction terminates, reaction system ammonia is neutralized to meta-alkalescence, dichloromethane (2 × 20 ML) extraction, the most successively with saturated sodium bicarbonate solution (2 × 30mL) and saturated aqueous common salt (2 × 30mL) washing, organic facies is with anhydrous Sodium sulfate is dried, and concentrates, column chromatography purification (dichloromethane: methanol=10:1), obtains off-white color solid (1.3g, 57.5%).1H NMR (400MHz,CDCl3)δ14.30(s,1H),8.87(m,1H),8.22(m,1H),8.02(s,1H),7.75(s,1H),7.39(m,1H), 7.15(m,1H),4.40(m,1H),3.38(m,2H),2.89(m,2H),2.26(m,4H),1.98(m,2H),1.35(m,2H).

Active testing part:

The active testing experimental procedure of gastric carcinoma cells MKN45:

1. bed board.Being digested by the cell Digestive system being in exponential phase, fresh culture terminates, and counts cell, with new Cell concentration is adjusted to 2*105/ml by fresh culture medium, and every hole adds 200 μ L, if zeroing hole (only adding culture medium) 3, other limits Edge is filled with aseptic PBS.

2. cultivate.Hatch in 5%CO2 at 37 DEG C 48 hours, allow cell be paved with at the bottom of hole about 60%.

3. it is administered.If zeroing hole, matched group, experimental group.Each dosage sets 3 multiple holes.Medicine DMSO is dissolved, is made into 10mmol/L mother solution, then be diluted with DMSO, make 1mmol/L, 100 μm ol/L, 10 μm ol/L, 1mol/L, 0.1mol/L solution, during administration, takes above-mentioned strength solution 1 μ L culture medium and is diluted to 1mL, i.e. administration concentration be 10 μm ol/L, (matched group adds 1 μ L DMSO and uses for 1 μm ol/L, 100nmol/L, 10nmol/L, 1nmol/L, 0.1nmol/L, 0nmol/L Culture medium is diluted to 1ml).During administration, liquid in original hole is exhausted, add the fresh culture containing variable concentrations medicine, every hole 200μl.Every day is administered, continuous three days.

● zeroing hole, only add culture medium；

● matched group, containing the solvent with experimental group same volume, dilute with complete medium.Every hole 200 μ l；

● experimental group, the medicine culture medium dissolved is diluted to 0.1,1,10,100,1000,10000nM concentration, often Hole 200 μ l.

4. at 37 DEG C, in 5%CO2, hatch 72h.

5.MTT terminates.After 72h, every hole adds 20 μ L MTT solution (5mg/ml), continues to cultivate 4h.

6. terminate cultivating, the careful culture fluid exhausted in hole.

7. every hole adds 150 μ l dimethyl sulfoxide (DMSO), and low speed concussion 10min, after thing to be crystallized fully dissolves, at enzyme mark Instrument, surveys its light absorption value at 490nm wavelength.

Shown according to the form below 2, the compounds of this invention is numbered.All the IC50 value of compound 1-4 is both less than 1000nM.

Test compound according to the form below 1 is numbered, and acquired results is as shown in table 1 below.

Compound tested by table 1.

The test compound suppression ratio active testing to gastric carcinoma cells MKN45, acquired results is as shown in Fig. 1 of adnexa.

Claims

1. the compound of formula (I), and pharmaceutically acceptable salt, prodrug and solvate,

Wherein

R1^a, R1^b, R1^c, R1^dAnd R1^eIt is each independently selected from hydrogen, halogen ,-CN, C1-C10 alkyl ,-CF₃、-OCF₃、 -OCHF₂,-OC0-10 alkyl ,-S (O)_mC0-10 alkyl ,-SO₂N (C0-10 alkyl) (C0-10 alkyl) ,-N (C0-10 alkyl) (C0-10 Alkyl) ,-N (C0-10 alkyl) C (=O) (C0-10 alkyl) ,-N (C0-10 alkyl) C (=O) O (C0-10 alkyl) ,-N (C0-C10 alkane Base) C (=O) N (C0-C10 alkyl) ,-C (=O) C0-C10 alkyl ,-C (=O) OC0-C10 alkyl ,-C (=O) N (C0-10 alkyl) ,-O Heterocyclylalkyl ,-N (C0-10 alkyl) Heterocyclylalkyl ,-N (C0-10 alkyl) heterocyclic aromatic base, Heterocyclylalkyl, heterocyclic aromatic base ,-S are miscellaneous Polycyclic aromatic group or-O heterocyclic aromatic base, wherein Heterocyclylalkyl arbitrarily can be replaced by one or more following groups: oxygen, C1-10 alkyl, C (=O) OC0-10 alkyl, C (=O) N (C0-10 alkyl) (C0-10 alkyl) ,-SO₂N (C0-10 alkyl) (C0-10 alkyl) or SO₂C1-10 alkyl, wherein said moieties arbitrarily can be replaced by one or more following groups: hydroxyl ,-OC1-10 alkyl, -N (C0-10 alkyl) (C0-10 alkyl) ,-C (=O) N (C0-10 alkyl) (C0-10 alkyl), C (=O) OC0-10 alkyl, C (=O) C0-10 Alkyl, Heterocyclylalkyl or heterocyclic aromatic base；

Or R²It is selected from

M is selected from 0-2；

N is selected from 0-7；

2. formula (I) compound of claim 1, and pharmaceutically acceptable salt, prodrug and solvate, wherein X⁴Represent N； Or X⁴Represent CH.

3. formula (I) compound of claim 2, and pharmaceutically acceptable salt, prodrug and solvate, wherein X¹Selected from CH Or CH₂；Or X¹Selected from N or NH or X¹Represent N.

4. formula (I) compound of claim 3, and pharmaceutically acceptable salt, prodrug and solvate, wherein

X¹Represent NH；

X²Selected from N or CH；

X³Represent C.

5. formula (I) compound of claim 4, and pharmaceutically acceptable salt, prodrug and solvate, wherein

R²It is selected from

M is selected from 0-2；

N is selected from 0-7；

6. formula (I) compound of claim 5, and pharmaceutically acceptable salt, prodrug and solvate, wherein

R²It is selected from

M is selected from 0-2；

N is selected from 0-7；

7. formula (I) compound of claim 6, and pharmaceutically acceptable salt, prodrug and solvate, wherein,

Y², Y⁴And Y⁵It is each independently selected from N or CH；

M is selected from 0-2；

N is selected from 0-7；

8. formula (I) compound of claim 7, and pharmaceutically acceptable salt, prodrug and solvate, wherein, R1^cAnd R1^d All represent H；

In the synthetic route of following claims, as non-specifically indicates:

W is selected from C3-C10 cycloalkyl, C (C1-C10 alkyl)₂、-S(O)_m-；

R1^aAnd R1^eIt is each independently selected from chlorine and bromine；

R1^bSelected from fluorine and-CF₃；

M is selected from 0-2.

9. the preparation method of the formula in claim 8 (I) compound, including:

Wherein

X²Selected from N or CH；

10. the preparation method of formula (I-1) compound of claim 9, i.e. compound (I-2) and (I-3) are in the presence of coupling reagent Generation Suzuki coupling reaction:

W is selected from C3-C6 cycloalkyl, C (C1-C3 alkyl)₂、-S-；

G1 is selected from N azetidinyl, pyrrolidinyl, piperidines, piperazine, morpholine, homopiperazine, and wherein arbitrarily group all can be respective Replaced by PG independently.

The preparation method of formula (I-2) compound of 11. claim 10, including:

The preparation method of formula (I-4) compound in 12. claim 11, including:

(A) X is worked as²During for CH, the compound of formula (I-4) is prepared by the following method:

(B) X is worked as²During for N, the compound of formula (I-4) is prepared by the following method:

Or the preparation method of formula (I-5) compound:

Or the preparation method of formula (I-6) compound:

Wherein

X is selected from bromine, iodine；

R is selected from-(CH₂)_p-, wherein p is selected from 2-9；

(B) it is C (C1-C10 alkyl) as W₂Time, formula (I-6) compound prepared by the monohaloalkyl hydrocarbon reaction of (I-7) with two equivalents:

Wherein

X is selected from bromine, iodine；

R is selected from C1-C10 alkyl.

Intermediate formula (I-7) in 13. claim 12 is prepared according to following steps: