CN104987324B - Pyrimidine derivatives as ALK inhibitor - Google Patents
Pyrimidine derivatives as ALK inhibitor Download PDFInfo
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- CN104987324B CN104987324B CN201510304880.6A CN201510304880A CN104987324B CN 104987324 B CN104987324 B CN 104987324B CN 201510304880 A CN201510304880 A CN 201510304880A CN 104987324 B CN104987324 B CN 104987324B
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- 0 C*(C)N1CCOCCC1 Chemical compound C*(C)N1CCOCCC1 0.000 description 18
- YYBXNWIRMJXEQJ-UHFFFAOYSA-N C(CNCC1)C1N1CCOCC1 Chemical compound C(CNCC1)C1N1CCOCC1 YYBXNWIRMJXEQJ-UHFFFAOYSA-N 0.000 description 1
- ALLYMTUZTABTPC-UHFFFAOYSA-N CC(C)S(c([s]cc1)c1Nc1cc(Nc(cc2)ccc2NC(CN(CC2)CCC2N(C)C)=O)ncc1Cl)(=O)=O Chemical compound CC(C)S(c([s]cc1)c1Nc1cc(Nc(cc2)ccc2NC(CN(CC2)CCC2N(C)C)=O)ncc1Cl)(=O)=O ALLYMTUZTABTPC-UHFFFAOYSA-N 0.000 description 1
- XSCXQYCCQCKQEJ-UHFFFAOYSA-N CC(C)S(c1c(C)cccc1)(=O)=O Chemical compound CC(C)S(c1c(C)cccc1)(=O)=O XSCXQYCCQCKQEJ-UHFFFAOYSA-N 0.000 description 1
- WGCYRFWNGRMRJA-UHFFFAOYSA-N CCN1CCNCC1 Chemical compound CCN1CCNCC1 WGCYRFWNGRMRJA-UHFFFAOYSA-N 0.000 description 1
- AIRVCSGEUIGZQP-UHFFFAOYSA-N CN(CCCN1)CC1=O Chemical compound CN(CCCN1)CC1=O AIRVCSGEUIGZQP-UHFFFAOYSA-N 0.000 description 1
- TYMLOMAKGOJONV-UHFFFAOYSA-N Nc(cc1)ccc1[N+]([O-])=O Chemical compound Nc(cc1)ccc1[N+]([O-])=O TYMLOMAKGOJONV-UHFFFAOYSA-N 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/48—Two nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
Abstract
The present invention provides the pyrimidine derivatives as ALK inhibitor.The compound is officinal salt, hydrate, solvate, metabolite or the prodrug of compound shown in compound shown in Formulas I or Formulas I, wherein, R1、R2、R3And R4It is defined as in the description.ALK inhibitor is can act as using the compound and pharmaceutical composition, is used to prepare into the antineoplaston medicine for suppressing anaplastic lymphoma kinase.
Description
Technical field
The invention belongs to pharmaceutical technology field, is related to compounds, prepares the method and pharmaceutical composition of the compound
And purposes, specifically, the present invention relates to the novel poyrimidine derivatives as ALK inhibitor, and it is prepared by these compounds
The purposes in medicine for treating and preventing cancer.
Background technology
Non-small cell lung cancer (Non-small-cell carcinoma, NSCLC) is synonymous with " non-small cell carcinoma ".It is non-small thin
Born of the same parents' type lung cancer, including squamous carcinoma, gland cancer, large cell carcinoma, its growth of cancer cells divides slower, diffusion transfer phase compared with small cell carcinoma
To later.Non-small cell lung cancer accounts for the 80-85% of lung cancer sum.Data show that lung cancer morbidity rate in China's increases every year at present
26.9%, between 2000 to 2005, number of the infected estimation 120,000 people of increase of lung cancer in China.Wherein, male lung cancer patient
260,000 people from 2000 increase to 330,000 people of 2005, and same period female lung cancer patient increases to 170,000 people from 120,000 people.This
Outside, lung cancer also becomes " first of many cancers " in the more areas in the whole nation.Beijing's lung cancer morbidity rate increased by 56% from 2001 to 2010.
During the decade, 1/5th it is patients with lung cancer in Beijing new cancer patient；Zhejiang Province in 2011 of Zhejiang Prov. Tumor Hospital's issue
In " cancer spectrum ", lung cancer is still the cancer to rank the first；Compared with before 30 years, lung cancer morbidity rate increases 7 times for In Guangzhou Area.
As molecular medicine progress and targeted drug continue to bring out, the treatment of advanced NSCLC has enter into individuation and controls
The epoch for the treatment of.The individuation targeted therapy of clinical practice at present is mainly for EGFR saltant types and ALK (Anaplastic
Lymphoma kinase, anaplastic lymphoma kinase) fusion type lung cancer, both genetic mutation type lung cancer are respectively provided with bright
True molecular target, target spot detection technique and the targeted drug of listing, clinical efficacy are improved significantly.ALK makes a variation in lung cancer
Predominantly ALK gene occurs to reset and other Gene Fusions.It is reported that the gene unconventionality on ALK gene site has with kinds cancer
Close.Since echinoderm micro-pipe related protein sample 4 (EML4)-ALK fusions caused by chromosomal rearrangement are in non-small cell lung cancer
(NSCLC) had been reported in patient population.
Although having been studied largely has protein kinase the compound of inhibitory activity, and some protein kinases press down
Preparation such as gram azoles has listed the treatment for NSCLC for Buddhist nun, but can produce drug resistance, the defects of presence to a certain degree.
Treat effective patient such as gram azoles for Buddhist nun usually will occur drug resistance after 6 months to 1 year in medication.Moreover, two grams of azoles replace Buddhist nun
The most common adverse reaction that clinical research observation arrives is vision disorder, nausea, diarrhea, vomiting, oedema and constipation, adverse reaction
Incidence >=25%.Thus, the new A LK inhibitor medicaments for developing safer, efficient treating cancer have huge society
It can be worth and economic benefit, and the research hotspot of major medicine enterprise at present.
Therefore, current ALK inhibitor still has much room for improvement.
The content of the invention
It is contemplated that one of above-mentioned technical problem is solved at least to a certain extent or provides at a kind of useful business
Industry selects.For this reason, an object of the present invention is to provide a kind of compound for the medicine that can be used in preparing treating cancer.
According to an aspect of the present invention, the present invention proposes a kind of compound.According to an embodiment of the invention, describedization
Compound is officinal salt, hydrate, solvate, metabolite or the prodrug of compound shown in compound shown in Formulas I or Formulas I,
Wherein,
R1For hydrogen, halogen, C1-6Alkyl or C1-6Alkoxy；
R2For 5-6 members cycloalkyl, 5-6 circle heterocycles base, 5-6 members aryl or 5-6 unit's heteroaryls, implement according to the present invention
Example, the 5-6 members cycloalkyl, 5-6 circle heterocycles base, 5-6 members aryl and 5-6 unit's heteroaryls are selected by one or more independently of one another
From halogen, hydroxyl, cyano group, nitro, C1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl group, C3-8Cycloalkyl, 3-8 circle heterocycles base, C5-10
Aryl, 5-10 unit's heteroaryls, C1-6Alkoxy, C3-8Cycloalkyloxy ,-S (O) pR5、-C(O)R5、-C(O)OR5、-NR6R7Or-C (O)
NR7Substituent substitution, wherein, R5、R6、R7It is each independently hydrogen or Cl-4Alkyl, p 0,1 or 2；
R3For selected from the piperazinyl optionally substituted the, piperidyl optionally substituted, the morpholinyl optionally substituted, optional thio
Morpholinyl or the amino optionally substituted；
R4For selected from hydrogen, halogen, C1-6Alkyl or C1-6Alkoxy.
According to an embodiment of the invention, R2For selected from one of following：
According to an embodiment of the invention, R3For selected from one of following：
It will be understood by those skilled in the art that according to convention used in the art, in the structural formula of the application,For describing chemical bond, the point that the chemical bond is part or substituent is connected with nuclear structure or skeleton structure.Separately
Outside, in the structural formula of the application,For describe the substituting group position on phenyl ring in structural formula with substituent
Adjacent two position of key is learned, i.e., the position of the annulus mark in the chemical formula
Thus, throughout this manual, those skilled in the art can be to R described in compound shown in Formulas I1~R7Base
Group and its substituent and p make choice, with provide compound shown in Formulas I described in the embodiment of the present invention, stablizing or
Its officinal salt, hydrate, solvate, metabolite or prodrug.
According to an embodiment of the invention, compound shown in Formulas I of the present invention can be selected from following at least one：
Used term in the present invention, " officinal salt " are anti-for compound shown in general formula I and inorganic acid or organic acid
The conventional nontoxic salts that should be formed.For example, the conventional nontoxic salts can pass through compound shown in general formula I and inorganic acid or organic
Acid reaction is made.Wherein, inorganic acid can be hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, amidosulfonic acid and phosphoric acid etc., and organic acid can be with
Be include citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, benzene sulfonic acid, p-methyl benzenesulfonic acid, methanesulfonic acid, naphthalene sulfonic acids, ethyl sulfonic acid,
Naphthalenedisulfonic acid, maleic acid, malic acid, malonic acid, fumaric acid, butanedioic acid, propionic acid, oxalic acid, trifluoroacetic acid, stearic acid, flutter acid, hydroxyl
Base maleic acid, phenylacetic acid, benzoic acid, salicylic acid, glutamic acid, ascorbic acid, para-anilinesulfonic acid, Aspirin and
Isethionic acid etc..Or " officinal salt " of compound shown in general formula I can also be by making compound shown in Formulas I and third in advance
Acid, oxalic acid, malonic acid, butanedioic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, aspartic acid or paddy ammonia
Acid forms sodium salt, sylvite, calcium salt, aluminium salt or the ammonium salt formed again with inorganic base after ester.Or compound shown in general formula I with it is organic
Methylamine salt, ethylamine salt or the ethanolamine salt that alkali is formed.Or compound shown in general formula I is formed with lysine, arginine, ornithine
After ester again with hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid formed corresponding inorganic acid salt or with formic acid, acetic acid, hardship
The corresponding acylate that sour, methanesulfonic acid and ethyl sulfonic acid are formed.
Used term in the present invention, " prodrug " represent once to give the compound to subject, the chemical combination
Thing just carries out chemical conversion by metabolic process or chemical process, thus obtain compound shown in Formulas I and/or its salt and/or
Solvate.It is in this hair that can convert in vivo with any compound for providing bioactive substance (i.e. compound shown in Formulas I)
Prodrug in bright scope and spirit.For example, the compound containing carboxyl can hydrolyzable ester on physiology, it passes through in body
Interior hydrolysis serves as prodrug in itself to obtain compound shown in Formulas I.The prodrug is preferably administered orally, this is because hydrolysis is being permitted
Mainly occur in the case of more under the influence of digestive ferment.When ester itself is active or hydrolysis occurs in blood, can be used
Parenteral administration.
It should also be understood that the hydrate of compound shown in formula I, solvate (such as methylate, ethanol
Compound, DMSO compounds) it is also within the scope of the invention.The method of solvation is well known in the art.
According to the second aspect of the invention, the present invention proposes a kind of intermediate, according to a particular embodiment of the invention, institute
Intermediate is stated with the compound shown in formula 5, compound shown in the formula 5 is to prepare the intermediate of compound shown in formula I,
Using compound shown in formula 5, available for compound shown in manufacturing cost invention Formulas I.
Wherein, R1For hydrogen, halogen, C1-6Alkyl or C1-6Alkoxy；
R2For 5-6 members cycloalkyl, 5-6 circle heterocycles base, 5-6 members aryl or 5-6 unit's heteroaryls, optionally, the 5-6 members
Cycloalkyl, 5-6 circle heterocycles base, 5-6 members aryl and 5-6 unit's heteroaryls independently of one another by one or more selected from halogen, hydroxyl,
Cyano group, nitro, C1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl group, C3-8Cycloalkyl, 3-8 circle heterocycles base, C5-10Aryl, 5-10 members are miscellaneous
Aryl, C1-6Alkoxy, C3-8Cycloalkyloxy ,-S (O) pR5、-C(O)R5、-C(O)OR5、-NR6R7Or-C (O) NR7Substituent take
Generation, wherein, R5、R6、R7It is each independently hydrogen or Cl-4Alkyl, p 0,1 or 2；
R4For selected from hydrogen, halogen, C1-6Alkyl or C1-6Alkoxy；
Preferably, R2For selected from one of following：
According to the third aspect of the invention we, the present invention proposes a kind of intermediate, according to a particular embodiment of the invention, institute
Intermediate is stated with the compound shown in formula 6, compound shown in the formula 6 is to prepare the intermediate of compound shown in formula I,
Using compound shown in formula 6, available for compound shown in manufacturing cost invention Formulas I.
Wherein, R1For hydrogen, halogen, C1-6Alkyl or C1-6Alkoxy；
R2For 5-6 members cycloalkyl, 5-6 circle heterocycles base, 5-6 members aryl or 5-6 unit's heteroaryls, optionally, the 5-6 members
Cycloalkyl, 5-6 circle heterocycles base, 5-6 members aryl and 5-6 unit's heteroaryls independently of one another by one or more selected from halogen, hydroxyl,
Cyano group, nitro, C1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl group, C3-8Cycloalkyl, 3-8 circle heterocycles base, C5-10Aryl, 5-10 members are miscellaneous
Aryl, C1-6Alkoxy, C3-8Cycloalkyloxy ,-S (O) pR5、-C(O)R5、-C(O)OR5、-NR6R7Or-C (O) NR7Substituent take
Generation, wherein, R5、R6、R7It is each independently hydrogen or Cl-4Alkyl, p 0,1 or 2；
R4For selected from hydrogen, halogen, C1-6Alkyl or C1-6Alkoxy；
Preferably, R2For selected from one of following：
According to the fourth aspect of the invention, the present invention proposes a kind of intermediate, according to a particular embodiment of the invention, institute
Intermediate is stated with the compound shown in formula 8, compound shown in the formula 8 is to prepare the intermediate of compound shown in formula I,
Using compound shown in formula 8, available for compound shown in manufacturing cost invention Formulas I.
Wherein, R1For hydrogen, halogen, C1-6Alkyl or C1-6Alkoxy；
R2For 5-6 members cycloalkyl, 5-6 circle heterocycles base, 5-6 members aryl or 5-6 unit's heteroaryls, optionally, the 5-6 members
Cycloalkyl, 5-6 circle heterocycles base, 5-6 members aryl and 5-6 unit's heteroaryls independently of one another by one or more selected from halogen, hydroxyl,
Cyano group, nitro, C1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl group, C3-8Cycloalkyl, 3-8 circle heterocycles base, C5-10Aryl, 5-10 members are miscellaneous
Aryl, C1-6Alkoxy, C3-8Cycloalkyloxy ,-S (O) pR5、-C(O)R5、-C(O)OR5、-NR6R7Or-C (O) NR7Substituent take
Generation, wherein, R5、R6、R7It is each independently hydrogen or Cl-4Alkyl, p 0,1 or 2；
R4For selected from hydrogen, halogen, C1-6Alkyl or C1-6Alkoxy；
Preferably, R2For selected from one of following：
According to a particular embodiment of the invention, wherein, the compound shown in compound, formula 6 shown in formula 5, shown in formula 8
R in compound1、R2And R4Defined in previously mentioned.
According to the fifth aspect of the invention, the method that the present invention proposes compound shown in a kind of formula Ι.According to this hair
Bright embodiment, the method for compound includes shown in formula Ι：
(1) compound shown in the formula 1 is made to be contacted with compound shown in formula 2, to obtain compound shown in formula 3；
(2) compound shown in the formula 3 is made to be contacted with compound shown in formula 4, to obtain compound shown in formula 5；
(3) make compound shown in the formula 5 that hydrogenation reaction occur, to obtain compound shown in formula 6；
(4) compound shown in the formula 6 is made to be contacted with compound shown in formula 7, to obtain compound shown in formula 8；
And
(5) compound shown in the formula 8 is made to be contacted with compound shown in formula 9, to obtain compound shown in Formulas I,
According to an embodiment of the invention, in the compound of compound shown in above-mentioned formula 1-9 and Formulas I, R1For hydrogen, halogen,
C1-6Alkyl or C1-6Alkoxy；R2For 5-6 members cycloalkyl, 5-6 circle heterocycles base, 5-6 members aryl or 5-6 unit's heteroaryls, according to
The present invention specific example, state 5-6 members cycloalkyl, 5-6 circle heterocycles base, 5-6 members aryl and 5-6 unit's heteroaryls independently of one another by
One or more is selected from halogen, hydroxyl, cyano group, nitro, C1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl group, C3-8Cycloalkyl, 3-8 members
Heterocyclic radical, C5-10Aryl, 5-10 unit's heteroaryls, C1-6Alkoxy, C3-8Cycloalkyloxy ,-S (O) pR5、-C(O)R5、-C(O)OR5、-
NR6R7Or-C (O) NR7Substituent substitution, wherein, R5、R6、R7It is each independently hydrogen or Cl-4Alkyl, p 0,1 or 2；R3
For selected from the piperazinyl optionally substituted, the piperidyl optionally substituted, the morpholinyl optionally substituted, optional thio-morpholinyl or
The amino optionally substituted；R4For selected from hydrogen, halogen, C1-6Alkyl or C1-6Alkoxy.
According to a particular embodiment of the invention, R2Can be preferably one of following：
According to a particular embodiment of the invention, R3Can be preferably one of following：
Inventor has found, using the above embodiment of the present invention method can fast and effeciently compound shown in formula I,
And short, environmental-friendly, target product the yield of synthetic route and purity are higher, raw material is easy to get, operates and post-processes simple, suitable
Industrialized production.In one embodiment of the invention, the synthetic route of compound shown in Formulas I is：
Below to the conventional method of compound is described shown in used formula I in an embodiment of the present invention：
Step (1)：The preparation of compound (intermediate) shown in formula 3
According to a particular embodiment of the invention, in step (1), in the first organic solvent, there are during NaH, institute is made
Compound shown in formula 1 is stated to contact with compound shown in the formula 2.Specific example according to the present invention, the first organic solvent can be with
For at least one in 1-methyl-2-pyrrolidinone, DMF, dimethyl sulfoxide (DMSO), dimethylacetylamide, DMAC N,N' dimethyl acetamide
Kind.It is preferred that DMF.It is possible thereby to provide good reaction environment for compound shown in compound shown in formula 1 and formula 2, and then improve
The yield of compound shown in formula 3.
Specific example according to the present invention, in step (1), at 0 degree Celsius, makes compound and institute shown in the formula 1
State the contact of compound shown in formula 2.By selecting suitable reaction temperature, compound shown in formula 3 can be further improved
Yield.Another specific example according to the present invention, in step (1), compound shown in formula 1 is rubbed with compound shown in formula 2
Your ratio can be (25-30)：(15-30).According to a preferred embodiment of the invention, compound shown in formula 1 and compound shown in formula 2
Molar ratio can be (27-28)：(20-26).And then while compound yield shown in formula 3 can be improved, save raw material into
This.
A specific embodiment according to the present invention, the preparation of compound (intermediate) shown in formula 3 specifically can be under
Row step carries out：Compound shown in formula 2 is dissolved in DMF, NaH is added portionwise at 0 DEG C, rear reaction solution is added and continues at 0 DEG C
Lower stirring half an hour, then 2,5,6- trichloropyrimidines (compound shown in formula 1) are instilled into reaction solution at 0 DEG C, will after being added dropwise
Mixture is warmed to room temperature down naturally to be stirred overnight.Frozen water is added dropwise after completion of the reaction to be quenched, and is extracted with ethyl acetate, merges organic
Phase, it is dry after saturated common salt washing three times, it is concentrated under reduced pressure, gained crude product obtains product through column chromatography, is compound shown in formula 3.
Step (2)：The preparation of compound (intermediate) shown in formula 5
According to a particular embodiment of the invention, in step (2), compound shown in the formula 3 and chemical combination shown in the formula 4
Thing is contacted in n-butanol, contains p-methyl benzenesulfonic acid in the n-butanol.
According to a particular embodiment of the invention, in step (2), at 80 degrees Celsius, make compound shown in the formula 3 with
When the contact of compound shown in the formula 46 is small, it is possible thereby to while improving reaction efficiency, the two is set fully to react, and then finally
The yield of compound shown in raising formula 5.According to a particular embodiment of the invention, in step (2), compound shown in the formula 3,
Molar ratio shown in the formula 4 between compound and p-methyl benzenesulfonic acid is (4-6)：(5-7)：(5-7).It is specific according to the present invention
Embodiment, is preferably (5-6)：(5.5-6.5)：(5.5-6.5).And then while compound yield shown in formula 5 can be improved, section
Save cost of material.
A specific embodiment according to the present invention, the preparation of compound (intermediate) shown in formula 5 specifically can be under
Row step carries out：Compound shown in formula 3 is dissolved in n-butanol, adds compound and p-methyl benzenesulfonic acid shown in formula 4 thereto, will
Mixture is at a temperature of 80 DEG C, when stirring reaction 6 is small.TLC is detected after completion of the reaction, and decompression boils off solvent, by residual solids thing
It is scattered in ethyl acetate, according to this with saturated sodium bicarbonate aqueous solution, water and saturated common salt water washing, is done with anhydrous sodium sulfate
Dry, be concentrated under reduced pressure to obtain crude product, and product is obtained through column chromatography for separation, is compound shown in formula 5.
Step (3)：The preparation of compound (intermediate) shown in formula 6
According to a particular embodiment of the invention, in step (3), the hydrogenation reaction be using palladium/carbon as catalyst,
Carried out in hydrogen atmosphere.According to a particular embodiment of the invention, containing 5% palladium in the palladium/charcoal, it is possible thereby to effectively
The reaction potential energy of the two is reduced, improves the reaction efficiency of the two.According to a particular embodiment of the invention, the hydrogen atmosphere
1 standard atmospheric pressure.It is possible thereby to further improve hydrogenation reaction efficiency, and then improve compound yield shown in formula 6.According to this
The specific embodiment of invention, in step (3), compound shown in the formula 5 and the proportioning of palladium/carbon are (0.5-1mmol)：(35-
55mg), it is preferably (0.7-0.9mmol)：(40-50mg), it is possible thereby to while improving compound yield shown in formula 6, is saved
Cost of material.
A specific embodiment according to the present invention, the preparation of compound (intermediate) shown in formula 6 specifically can be under
Row step carries out：Compound shown in formula 5 is placed in hydrogenation bottle, addition methanol, by palladium/charcoal (Pd contents 5%) after nitrogen displacement
It is added in bottle, after being replaced with hydrogen balloon, reaction is stirred under the conditions of hydrogen (1atm), TLC monitorings after completion of the reaction will reaction
Liquid filters, and filtrate decompression concentration is dry up to product, is compound shown in formula 6.
Step (4)：The preparation of compound (intermediate) shown in formula 8
According to a particular embodiment of the invention, in step (4), compound shown in formula 6 is carried out with compound shown in formula 7
Contact, to obtain compound shown in formula 8, carries out through the following steps：
(4-1), which is provided, contains the first dichloromethane solution of compound and triethylamine shown in the formula 6, and containing described
Second dichloromethane solution of compound described in formula 7；
(4-2) mixes the first dichloromethane solution with second dichloromethane solution.
Compound shown in formula 8 can be effectively prepared using above-mentioned preparation method, while can be carried to greatest extent
The yield of compound shown in high formula 8.
According to a particular embodiment of the invention, it is combined by second dichloromethane solution being added drop-wise to described first
Carried out in dichloromethane solution, and then the reaction effect of compound shown in compound shown in formula 6 and formula 7 can be further improved
Rate.According to a particular embodiment of the invention, in step (4), the dropwise addition carries out under ice-water bath cooling condition, described
When time of contact is 2-5 small, it is possible thereby to effectively improve the reaction efficiency of the two, the yield of compound shown in formula 8 is improved.According to
The specific embodiment of the present invention, in step (4), the molar ratio of compound and compound shown in the formula 7 is shown in the formula 6
(0.5-1)：(1-2), is preferably (0.7-0.75)：(1-1.2).It is possible thereby to while improving compound yield shown in formula 8, section
Save cost of material.
A specific embodiment according to the present invention, the preparation of compound (intermediate) shown in formula 8 specifically can be under
Row step carries out：Compound shown in formula 6 is dissolved in dichloromethane, triethylamine is added into solution, is stirred, ice-water bath cooling bar
Under part, the dichloromethane solution of compound shown in formula 7 is added dropwise.By reaction mixture be stirred at room temperature 2 it is small when, use unsaturated carbonate
Sodium water solution is quenched, and dichloromethane extraction, merges organic phase, washed through saturated common salt, and anhydrous magnesium sulfate drying, is filtered, decompression
The crude product that organic solvent obtains compound shown in formula 8 is boiled off, gained crude product is directly used in the next step without purifying.
Step (5)：The preparation of compound shown in Formulas I
According to a particular embodiment of the invention, in step (5), compound shown in the formula 8 and compound shown in formula 9 are made
Contacted, to obtain compound shown in Formulas I, carried out through the following steps：
Offer contains compound, the acetonitrile solution of triethylamine shown in the formula 8,
Compound shown in the formula 9 is added into the acetonitrile solution, to make compound shown in the formula 8 and the institute of formula 9
Show that compound is contacted.Compound shown in Formulas I can effectively be prepared from there through using the above method.
According to a particular embodiment of the invention, in step (5), the contact is that progress 3-5 is small under heated reflux condition
When.It is possible thereby to so that the two is fully reacted, and then improve the yield of compound shown in Formulas I.
According to a particular embodiment of the invention, in step (5), compound shown in the formula 8 and chemical combination shown in the formula 9
The molar ratio of thing is (0.5-1.5)：(1.5-2.5), is preferably (0.8-1.2)：(1.8-2.2).It is specific real according to the present invention
Example is applied, in step (5), compound shown in the formula 8 and the molar ratio of triethylamine are (0.1-0.5)：(0.5-1.5)：, preferably
For (0.2-0.25)：(1-1.1).It is possible thereby to while improving compound yield shown in Formulas I, cost of material is saved.
According to a particular embodiment of the invention, the preparation of compound shown in Formulas I, can specifically carry out according to the following steps：
The crude product of compound shown in formula 8 is dissolved in acetonitrile, and sequentially adds triethylamine thereto, the lower institute of dropwise addition formula 9 is stirred at room temperature
To show compound, be heated to reflux, reaction is finished, and decompression boils off solvent, and residue diluted with water, dichloromethane extraction, merges organic phase,
Washed through saturated common salt, anhydrous magnesium sulfate drying, filtering, decompression boils off the crude product that organic solvent obtains compound shown in Formulas I, passes through
Column chromatography for separation obtains the product of compound shown in Formulas I.
According to the sixth aspect of the invention, the present invention proposes a kind of pharmaceutical composition.Specific implementation according to the present invention
Example, the pharmaceutical composition contain foregoing compound.Specific example according to the present invention, pharmaceutical composition further include
Pharmaceutically acceptable carrier, excipient, diluent, assistant agent, medium or its combination.
According to a particular embodiment of the invention, pharmaceutical composition in tablet, capsule, injection, powder-injection, pulvis, syrup,
Solution shape, suspension or aerosol.It is possible thereby to significantly improve the applicability of the pharmaceutical composition.And the above-mentioned implementation of the present invention
The pharmaceutical composition of example can reside in the carrier or dilution of suitable solid or liquid to be used to inject or drip with suitable
In the disinfector of note.
The various formulations of the pharmaceutical composition of the present invention can be prepared according to the customary preparation methods of pharmaceutical field.The present invention's
Compound and pharmaceutical composition can to mammal Clinical practice, including humans and animals, can by mouth, nose, skin, lung or
The approach administration of intestines and stomach etc..No matter use which kind of instructions of taking, personal optimal dose should according to specific therapeutic scheme and
It is fixed.It is since low dose under normal conditions, gradual incremental dose is until find most suitable dosage.Most preferably administration way
Footpath is oral.
According to the seventh aspect of the invention, the present invention proposes foregoing compound, prepared by foregoing method
The purposes of obtained compound or foregoing pharmaceutical composition in medicine preparation.
According to a particular embodiment of the invention, the medicine is used at least one following：As kinase inhibitor, suppress
ALK kinase activity, treatment or pre- anti-cancer and the propagation for suppressing cancer cell.Specific example according to the present invention, the present invention are right
The compound in vitro ALK kinase inhibiting activities determination experiment the results show that compound shown in Formulas I of the present invention is respectively provided with
Good ALK kinase inhibiting activities, compound of the present invention can be used as ALK inhibitor, be used to prepare into denaturation leaching between suppression
The antineoplaston medicine of bar knurl kinases.
Therefore, medicine of the present invention can be effectively as ALK inhibitor, for treating one or more kinds of and ALK
The related tumor disease of activity, the tumor disease include but not limited to lung cancer.It is of the present invention as the phonetic of ALK inhibitor
Piperidine derivatives (compound shown in Formulas I), it has good clinical practice and medical usage as ALK inhibitor.
The additional aspect and advantage of the present invention will be set forth in part in the description, and will partly become from the following description
Obtain substantially, or recognized by the practice of the present invention.
Embodiment
The embodiment of the present invention is described below in detail.The embodiments described below is exemplary, and is only used for explaining this hair
It is bright, and be not considered as limiting the invention.Particular technique or condition are not specified in embodiment, according to text in the art
Offer described technology or condition or carried out according to product description.
In the specific embodiment being described below, compound structure is by nuclear magnetic resonance (NMR) or/and LC-MS
Chromatography (LC-MS) determines.Wherein, NMR displacements (δ) are provided with the unit of hundred a ten thousandths (ppm), and the measure of NMR is to use
Bruker AVANCE-400 nuclear magnetic resonance spectrometers, measure solvent are deuterated dimethyl sulfoxide (DMSO-d6), deuterochloroform (CDCl3), it is deuterated
Methanol (CD3OD), is inside designated as tetramethylsilane (TMS)；The measure Agilent of LC-MS chromatography LC-MS
1200Infinity Series mass spectrographs.The measure of HPLC uses Agilent 1200DAD high pressure liquid chromatographs (Sunfire
150 × 4.6mm of C18 chromatographic columns)
The monitoring of reaction process in example below uses thin-layered chromatography (TLC), solvent used in reaction
System has：Dichloromethane and methanol system, n-hexane/petroleum ether and ethyl acetate system, the volume ratio of solvent is according to compound
Polarity it is different and be adjusted.Tlc silica gel plate uses Yantai Huanghai Sea HSGF254 or Qingdao GF254 silica gel plates, thin layer
The specification that the silica gel plate that chromatography (TLC) uses uses is 0.15mm~0.2mm, and thin-layer chromatography isolates and purifies the rule of product use
Lattice are 0.4mm~0.5mm.Column chromatography is carrier generally using 200~300 mesh silica gel of Yantai Huanghai Sea silica gel.
The system of eluant, eluent and the solvent of thin-layered chromatography for the column chromatography that purifying compound uses in example below
System includes：A：Dichloromethane and methanol system, B：N-hexane/petroleum ether and ethyl acetate system, the volume ratio of solvent according to
The polarity of compound is different and is adjusted, and can also add the alkalescence such as a small amount of triethylamine and acetic acid or acid reagent is adjusted
Section.
Starting material used in example below can be used or synthesized according to methods known in the art, or can
Purchase is scientific and technological from ABCR GmbH＆Co.KG, Acros Organics, Aldrich Chemical Company, splendid remote chemistry
(Accela ChemBio Inc), up to companies such as auspicious chemicals.
The embodiment provides compound or pharmaceutically acceptable salt thereof shown in Formulas I, hydrate, solvate, metabolin
Or prodrug, compound or pharmaceutically acceptable salt thereof shown in formula Ι, hydrate, method and intermediate, the medicine of solvate or prodrug
The purposes of the compound and pharmaceutical composition of composition and the present invention in medicine preparation.
Embodiment 1：Compound (intermediate) shown in formula 2-1
By compound (15g, 106.31mmol) shown in formula a, potassium carbonate (29.38g, 212.61mmol) is placed in 500mL circles
In the bottle of bottom, 150 milliliters of DMF are added, add isopropyl mercaptan (compound shown in formula b) (8.5g, 111.62mmol) under agitation, will
Mixture is heated with stirring to 80 DEG C, when reaction 5 is small, and decompression after completion of the reaction boils off reaction dissolvent, and gained crude product is through washing, acetic acid
Ethyl ester extracts, and is concentrated after dry, compound shown in formula c (must measure 19.5g, yield 95%) is obtained through column chromatography.
By compound (19.5g, 98.86mmol) shown in formula c and metachloroperbenzoic acid (mCPBA, compound shown in formula d)
(60.2g, 348.84mmol) is placed in 1000mL round-bottomed bottles, adds 500 milliliters of dichloromethane, mixture is stirred at room temperature
Overnight, it is quenched with saturated sodium sulfite aqueous solution, dichloromethane extraction, through unsaturated carbonate potassium solution, saturated common salt washing, does
It is dry, it is spin-dried for, then compound shown in formula e (20.4g, yield 90% must be measured) is obtained through column chromatography.
Compound (20.4g, 88.98mmol) shown in formula e is placed in 500mL hydrogenation bottles, adds 250 ml methanols, nitrogen
1000mg palladiums charcoal (Pd contents 5%) is added in bottle after gas displacement, after being replaced with hydrogen balloon, is stirred under the conditions of hydrogen (1atm)
Mix overnight, monitor after completion of the reaction by reacting liquid filtering, filtrate decompression be spin-dried for up to compound shown in formula 2-1 (15.95g must be measured,
Yield 90%)
Embodiment 2：Compound (intermediate) shown in formula 2-2
By compound (14.2g, 0.1mol) shown in formula f, potassium carbonate (27.6g, 0.2mol) is placed in 500mL round-bottomed bottles,
150 milliliters of DMF are added, isopropyl mercaptan (compound shown in formula b) (8.0g, 0.105mol) is added under agitation, mixture is stirred
Mix and be heated to 75 DEG C, when reaction 6 is small, decompression after completion of the reaction boils off reaction dissolvent, and gained crude product is through washing, ethyl acetate extraction
Take, concentrated after dry, compound shown in formula g (17.9g, yield 92.5% must be measured) is obtained through column chromatography.
By compound (19.8g, 0.1mol) shown in formula g and metachloroperbenzoic acid (mCPBA, compound shown in formula d)
(60.9g, 0.35mol) is placed in 1000mL round-bottomed bottles, adds 500 milliliters of dichloromethane, mixture was stirred at room temperature
At night, be quenched with saturated sodium bisulfite solution, dichloromethane extraction, through unsaturated carbonate potassium solution, saturated common salt washing, dry, rotation
It is dry, then obtain compound shown in formula h (21.1g, yield 92% must be measured) through column chromatography.
Compound (23.0g, 0.1mol) shown in formula h is placed in 500mL hydrogenation bottles, adds 250 ml methanols, nitrogen is put
1000mg palladiums charcoal (Pd contents 5%) is added in bottle after changing, it is stirred under the conditions of hydrogen (1atm) after being replaced with hydrogen balloon
At night, monitor after completion of the reaction by reacting liquid filtering, and filtrate decompression is spin-dried for that (18.6g, yield must be measured up to compound shown in formula 2-2
93.5%)
Embodiment 3：Compound (intermediate) shown in formula 2-2
By compound (15.9g, 0.1mmol) shown in formula j, potassium carbonate (27.6g, 0.2mmol) is placed in 500mL round-bottomed bottles
In, 150 milliliters of DMF are added, isopropyl mercaptan (compound shown in formula b) (8.0g, 0.105mol) are added under agitation, by mixture
80 DEG C, when reaction 5 is small are heated with stirring to, decompression after completion of the reaction boils off reaction dissolvent, and gained crude product is through washing, ethyl acetate extraction
Take, concentrated after dry, compound shown in formula g (18.1g, yield 93% must be measured) is obtained through column chromatography.
By compound (19.8g, 0.1mol) shown in formula g and metachloroperbenzoic acid (mCPBA, compound shown in formula d)
(48.7g, 0.28mol) is placed in 1000mL round-bottomed bottles, adds 500 milliliters of dichloromethane, mixture was stirred at room temperature
At night, be quenched with saturated sodium bisulfite solution, dichloromethane extraction, through unsaturated carbonate potassium solution, saturated common salt washing, dry, rotation
It is dry, then obtain compound shown in formula h (21.5g, yield 93.5% must be measured) through column chromatography.
Compound (23.0g, 0.1mol) shown in formula h is placed in 500mL hydrogenation bottles, adds 250 ml methanols, nitrogen is put
1000mg palladiums charcoal (Pd contents 5%) is added in bottle after changing, after being replaced with hydrogen balloon, is stirred under the conditions of hydrogen (1.5atm)
Overnight, monitor after completion of the reaction by reacting liquid filtering, filtrate decompression is spin-dried for (to measure 18.4g up to compound shown in formula 2-2, producing
Rate 92%)
Embodiment 4：Compound (intermediate) shown in formula 2-3
By compound (16.4g, 0.1mol) shown in formula k, potassium carbonate (27.6g, 0.2mol) is placed in 500mL round-bottomed bottles,
150 milliliters of DMF are added, isopropyl mercaptan (compound shown in formula b) (8.0g, 0.105mol) is added under agitation, mixture is stirred
Mix and be heated to 75 DEG C, when reaction 6 is small, decompression after completion of the reaction boils off reaction dissolvent, and gained crude product is through washing, ethyl acetate extraction
Take, concentrated after dry, compound shown in formula m (18.3g, yield 92% must be measured) is obtained through column chromatography.
By compound (20.3g, 0.1mol) shown in formula m and metachloroperbenzoic acid (mCPBA, compound shown in formula d)
(60.9g, 0.35mol) is placed in 1000mL round-bottomed bottles, adds 500 milliliters of dichloromethane, mixture was stirred at room temperature
At night, be quenched with saturated sodium bisulfite solution, dichloromethane extraction, through unsaturated carbonate potassium solution, saturated common salt washing, dry, rotation
It is dry, then obtain compound shown in formula n (21.7g, yield 92.5% must be measured) through column chromatography.
Compound (23.5g, 0.1mol) shown in formula n is placed in 500mL hydrogenation bottles, adds 250 ml methanols, nitrogen is put
1000mg palladiums charcoal (Pd contents 5%) is added in bottle after changing, it is stirred under the conditions of hydrogen (1atm) after being replaced with hydrogen balloon
At night, monitor after completion of the reaction by reacting liquid filtering, and filtrate decompression is spin-dried for that (18.9g, yield must be measured up to compound shown in formula 2-3
92%)
Embodiment 5：Compound shown in formula 6-1
Compound (5g, 25.09mmol) shown in formula 2-1 is dissolved in DMF (100mL), NaH is slowly added at 0 DEG C
(1.1g, 27.6mmol), adds rear reaction solution and continues to stir half an hour at 0 DEG C, then by 2,5,6- trichloropyrimidines (shown in formula 1
Compound) (5.06g, 27.6mmol) instill reaction solution at 0 DEG C, and after being added dropwise, mixture is warmed to room temperature down naturally and is stirred
Mix overnight.300mL frozen water is added after completion of the reaction to be quenched, and (200mL × 3) are extracted with ethyl acetate, and merges organic phase, through full
It is dry after salt washing three times, it is concentrated under reduced pressure, gained crude product obtains compound shown in formula 3-1 through column chromatography and (must measure 2.26g, produce
Rate 26%).
Compound (2g, 5.77mmol) shown in formula 3-1 is dissolved in 60mL n-butanols, adds 3- nitroanilines thereto
(compound shown in formula 4-1) (798mg, 5.77mmol) and p-methyl benzenesulfonic acid (993mg, 5.77mmol), by mixture at 80 DEG C
At a temperature of, when stirring reaction 6 is small.TLC is detected after completion of the reaction, and decompression boils off solvent, and residual solids thing is scattered in 200mL second
In acetoacetic ester, successively with saturated sodium bicarbonate aqueous solution, water and saturated common salt water washing, dried with anhydrous sodium sulfate, decompression is dense
Contract to obtain crude product, and compound shown in formula 5-1 (must measure 1.24g, yield 48%) is obtained through column chromatography for separation.
Compound (400mg, 0.893mmol) shown in formula 5-1 is placed in 100mL hydrogenation bottles, adds 50 ml methanols, nitrogen
40mg palladiums charcoal (Pd contents 5%) is added in bottle after gas displacement, after being replaced with hydrogen balloon, is stirred under the conditions of hydrogen (1atm)
Overnight, after completion of the reaction by reacting liquid filtering, filtrate decompression concentration is dry (must to measure up to compound shown in formula 6-1 for TLC monitorings
316mg, yield 85%).
Embodiment 6：Compound shown in formula 6-2
Compound (2g, 5.77mmol) shown in formula 3-1 is dissolved in 60mL isopropanols, adds formula 4-2 shownization thereto
Compound (798mg, 5.77mmol) and p-methyl benzenesulfonic acid (993mg, 5.77mmol), by mixture at a temperature of 70 DEG C, stirring is anti-
Answer 6 it is small when.TLC is detected after completion of the reaction, and decompression boils off solvent, residual solids thing is scattered in 200mL ethyl acetate, successively
With saturated sodium bicarbonate aqueous solution, water and saturated common salt water washing, are dried with anhydrous sodium sulfate, and be concentrated under reduced pressure to obtain crude product, warp
Column chromatography for separation obtains compound shown in formula 5-2 (must measure 0.84g, yield 32.5%).
Compound (400mg, 0.893mmol) shown in formula 5-2 is placed in 100mL hydrogenation bottles, adds 50 ml methanols, nitrogen
40mg palladiums charcoal (Pd contents 5%) is added in bottle after gas displacement, after being replaced with hydrogen balloon, is stirred under the conditions of hydrogen (1atm)
Overnight, after completion of the reaction by reacting liquid filtering, filtrate decompression concentration is dry (must to measure up to compound shown in formula 6-2 for TLC monitorings
279mg, yield 75%).
Embodiment 7：Compound shown in formula 6-3
Compound (2g, 5.77mmol) shown in formula 3-1 is dissolved in 60mL n-butanols, adds formula 4-3 shownization thereto
Compound (1019mg, 6.06mmol) and p-methyl benzenesulfonic acid (1043mg, 6.06mmol), by mixture at a temperature of 80 DEG C, stirring
React 6 it is small when.TLC is detected after completion of the reaction, and decompression boils off solvent, and residual solids thing is scattered in 200mL ethyl acetate, according to
It is secondary to use saturated sodium bicarbonate aqueous solution, water and saturated common salt water washing, dried with anhydrous sodium sulfate, be concentrated under reduced pressure to obtain crude product,
Compound shown in formula 5-3 (1544mg, yield 56% must be measured) is obtained through column chromatography for separation.
Compound (427mg, 0.893mmol) shown in formula 5-3 is placed in 100mL hydrogenation bottles, adds 50 ml methanols, nitrogen
50mg palladiums charcoal (Pd contents 5%) is added in bottle after gas displacement, after being replaced with hydrogen balloon, is stirred under the conditions of hydrogen (1atm)
Overnight, after completion of the reaction by reacting liquid filtering, filtrate decompression concentration is dry (must to measure up to compound shown in formula 6-3 for TLC monitorings
376mg, yield 80%).
Embodiment 8：Compound shown in formula 6-4
The synthetic method of embodiment 8 is with reference to embodiment 7.
LCMS:431(M+H+).
Embodiment 9：Compound shown in formula 6-5
The synthetic method of embodiment 9 is with reference to embodiment 7.
LCMS:451(M+H+).
Embodiment 10：Compound shown in formula 6-6
The synthetic method of embodiment 10 is with reference to embodiment 5.
LCMS:418(M+H+).
Embodiment 11：Compound shown in formula 6-7
The synthetic method of embodiment 11 is with reference to embodiment 6.
LCMS:418(M+H+).
Embodiment 12：Compound shown in formula 6-8
In embodiment 12, the synthetic method of compound shown in formula 2-2 is with reference to embodiment 5.
Compound (2.0g, 5.77mmol) shown in formula 3-2 is dissolved in 60mL n-butanols, is added thereto shown in formula 4-3
Compound (1019mg, 6.06mmol) and p-methyl benzenesulfonic acid (1043mg, 6.06mmol), by mixture at a temperature of 80 DEG C, are stirred
Mix reaction 6 it is small when.TLC is detected after completion of the reaction, and decompression boils off solvent, and residual solids thing is scattered in 200mL ethyl acetate,
Saturated sodium bicarbonate aqueous solution, water and saturated common salt water washing are used successively, is dried with anhydrous sodium sulfate, are concentrated under reduced pressure slightly to produce
Product, compound shown in formula 5-8 (must measure 1.71g, yield 62%) is obtained through column chromatography for separation.
Compound (428mg, 0.893mmol) shown in formula 5-8 is placed in 100mL hydrogenation bottles, adds 50 ml methanols, nitrogen
50mg palladiums charcoal (Pd contents 5%) is added in bottle after gas displacement, after being replaced with hydrogen balloon, is stirred under the conditions of hydrogen (1.0atm)
Mix overnight, after completion of the reaction by reacting liquid filtering, filtrate decompression concentration is dry (must to measure up to compound shown in formula 6-8 for TLC monitorings
348mg, yield 74%).LCMS:418(M+H+).
Embodiment 13：Compound shown in formula 6-9
The synthetic method of embodiment 13 is with reference to embodiment 7.
LCMS:432(M+H+).
Embodiment 14：Compound shown in formula 6-10
The synthetic method of embodiment 14 is with reference to embodiment 7.
LCMS:452(M+H+).
Embodiment 15：Compound shown in formula 6-11
Compound (4.1g, 20mmol) shown in formula 2-3 is dissolved in DMF (100mL), NaH is slowly added at 0 DEG C
(1.1g, 27.6mmol), adds rear reaction solution and continues to stir half an hour at 0 DEG C, then by compound shown in formula 1 (5.06g,
Reaction solution 27.6mmol) is instilled at 0 DEG C, after being added dropwise, mixture is warmed to room temperature down naturally and is stirred overnight.Reaction finishes
300mL water quenchings are added afterwards to go out, and (200mL × 3) are extracted with ethyl acetate, and merge organic phase, after saturated common salt washing three times,
It is dry, it is concentrated under reduced pressure, gained crude product obtains compound shown in formula 3-3 (must measure 3.52g, yield 50%) through column chromatography.
Compound (2.03g, 5.77mmol) shown in formula 3-3 is dissolved in 60mL n-butanols, is added thereto shown in formula 4-1
Compound (798mg, 5.77mmol) and p-methyl benzenesulfonic acid (993mg, 5.77mmol), by mixture at a temperature of 70 DEG C, stirring
React 6 it is small when.TLC is detected after completion of the reaction, and decompression boils off solvent, and residual solids thing is scattered in 200mL ethyl acetate, according to
This uses saturated sodium bicarbonate aqueous solution, water and saturated common salt water washing, is dried with anhydrous sodium sulfate, and be concentrated under reduced pressure to obtain crude product,
Compound shown in formula 5-11 (2.1g, yield 80% must be measured) is obtained through column chromatography for separation.
Compound (363mg, 0.8mmol) shown in formula 5-11 is placed in 100mL hydrogenation bottles, adds 50 ml methanols, nitrogen
40mg palladiums charcoal (Pd contents 5%) is added in bottle after gas displacement, after being replaced with hydrogen balloon, is stirred under the conditions of hydrogen (1atm)
Overnight, monitoring is after completion of the reaction by reacting liquid filtering, filtrate decompression concentration it is dry up to compound shown in formula 6-11 (254mg must be measured,
Yield 75%).LCMS:423(M+H+).
Embodiment 16：Compound shown in formula 6-12
Compound (2.03g, 5.77mmol) shown in formula 3-3 is dissolved in 60mL isopropanols, is added thereto shown in formula 4-2
Compound (798mg, 5.77mmol) and p-methyl benzenesulfonic acid (993mg, 5.77mmol), by mixture at a temperature of 70 DEG C, stirring
React 6 it is small when.TLC is detected after completion of the reaction, and decompression boils off solvent, and residual solids thing is scattered in 200mL ethyl acetate, according to
This uses saturated sodium bicarbonate aqueous solution, water and saturated common salt water washing, is dried with anhydrous sodium sulfate, and be concentrated under reduced pressure to obtain crude product,
Compound shown in formula 5-12 (1.89g, yield 72% must be measured) is obtained through column chromatography for separation.
Compound (363mg, 0.8mmol) shown in formula 5-12 is placed in 100mL hydrogenation bottles, adds 50 ml methanols, nitrogen
40mg palladiums charcoal (Pd contents 5%) is added in bottle after gas displacement, after being replaced with hydrogen balloon, is stirred under the conditions of hydrogen (1atm)
Overnight, monitoring is after completion of the reaction by reacting liquid filtering, filtrate decompression concentration it is dry up to compound shown in formula 6-12 (278mg must be measured,
Yield 82%).LCMS:423(M+H+).
Embodiment 17：Compound shown in formula 6-13
The synthetic method of embodiment 17 is with reference to embodiment 7.
LCMS:453(M+H+).
Embodiment 18：Compound shown in formula 6-14
The synthetic method of embodiment 18 is with reference to embodiment 7.
LCMS:437(M+H+).
Embodiment 19：Compound shown in formula 6-15
The synthetic method of embodiment 19 is with reference to embodiment 7.
LCMS:457(M+H+).
Embodiment 20：Compound shown in formula 8-1
Compound (300mg, 0.717mmol) shown in formula 6-1 is dissolved in dry dichloromethane (15mL), into solution
Triethylamine (289.67mg, 399uL, 2.868mmol) is added, is stirred, under ice-water bath cooling condition, 2- chloracetyl chloride (formulas are added dropwise
Compound shown in 7-1) (85.1mg, 0.753mmol) dichloromethane (2mL) solution.Reaction mixture is stirred at room temperature 2
Hour, it is quenched with saturated aqueous sodium carbonate, dichloromethane extraction (20mL × 3), merges organic phase, is washed through saturated common salt,
Anhydrous magnesium sulfate is dried, and filtering, decompression boils off the crude product 350mg that organic solvent obtains compound shown in formula 8-a, gained crude product
Without purifying, the next step can be directly used for.
21~embodiment of embodiment 43：Formula 8-2~compound shown in formula 8-24
Formula 8-2~structural formula of compound shown in formula 8-24 see the table below, the synthesis side of formula 8-2~compound shown in formula 8-24
Method, with reference to embodiment 20.
Embodiment 44：Compound shown in formula I-11
Compound (100mg, 0.202mmol) shown in formula 8-1 is dissolved in dry acetonitrile (3mL), and thereto successively
Add triethylamine (102mg, 1.01mmol), be stirred at room temperature it is lower dropwise addition dicarbapentaborane piperazine (compound shown in formula 9-1) (40mg,
0.404mmol), be heated to reflux 5 it is small when, decompression boils off solvent, residue diluted with water, and dichloromethane extraction (20mL × 3), is closed
And organic phase, washed through saturated common salt, anhydrous magnesium sulfate drying, filtering, decompression boils off organic solvent and obtains crude product, through column chromatography
Separate to obtain compound shown in Formulas I -11 (68.8mg, yield 61% must be measured).
1H NMR(400MHz,cd3Od) δ 8.67 (d, J=8.3Hz, 1H), 8.16 (s, 1H), 7.91-7.85 (m, 2H),
7.67-7.59 (m, 1H), 7.35-7.27 (m, 2H), 7.22 (dd, J=5.0,1.6Hz, 2H), 3.41-3.34 (m, 2H), 3.27
(d, J=5.1Hz, 4H), 3.20 (q, J=7.3Hz, 1H), 2.86-2.75 (m, 2H), 1.28 (d, 6H) .LCMS:T=
0.716min,558(M+H+).
Embodiment 45：Compound shown in formula I-33
Compound (100mg, 0.200mmol) shown in formula 8-11 is dissolved in dry acetonitrile (3mL), and thereto successively
Triethylamine (102mg, 1.01mmol) is added, compound (19.2mg, 0.22mmol) shown in lower dropwise addition formula 9-2 is stirred at room temperature, adds
When heat reflux 4.5 is small, decompression boils off solvent, and residue diluted with water, dichloromethane extraction (20mL × 3), merges organic phase, warp
Saturated common salt is washed, anhydrous magnesium sulfate drying, filtering, and decompression boils off organic solvent and obtains crude product, through column chromatography for separation obtain Formulas I-
Compound shown in 33 (must measure 75mg, yield 68%).
1H NMR(400MHz,cd3Od) δ 8.41 (d, J=5.5Hz, 1H), 8.15 (s, 1H), 7.91 (s, 1H), 7.87 (d,
J=5.5Hz, 1H), 7.33-7.22 (m, 3H), 3.81-3.68 (m, 4H), 3.37 (dd, J=16.2,9.4Hz, 1H), 3.19
(s, 2H), 2.67-2.54 (m, 4H), 1.33 (d, J=6.8Hz, 6H) .LCMS:T=0.667min, 551.2 (M+H+).
Embodiment 46：Compound shown in formula I-93
Compound (105mg, 0.20mmol) shown in formula 8-5 is dissolved in dry acetonitrile (5mL), and is added successively thereto
Enter triethylamine (102mg, 1.01mmol), compound (29mg, 0.40mmol) shown in lower dropwise addition formula 9-3 is stirred at room temperature, heats back
Flow 4 it is small when, decompression boils off solvent, residue diluted with water, and dichloromethane extraction (20mL × 3), merges organic phase, eaten through saturation
Salt is washed, anhydrous magnesium sulfate drying, filtering, and decompression boils off organic solvent and obtains crude product, obtained through column chromatography for separation shown in Formulas I -93
Compound (must measure 60.5mg, yield 44%).
Embodiment 47：Compound shown in formula I-3
Compound (100mg, 0.202mmol) shown in formula 8-4 is dissolved in dry acetonitrile (4mL), and thereto successively
Triethylamine (102mg, 1.01mmol) is added, compound (25mg, 0.404mmol) shown in lower dropwise addition formula 9-4 is stirred at room temperature, is heated
Flow back 4 it is small when, decompression boils off solvent, residue diluted with water, and dichloromethane extraction (20mL × 3), merges organic phase, through saturation
Salt is washed, anhydrous magnesium sulfate drying, filtering, and decompression boils off organic solvent and obtains crude product, obtained through column chromatography for separation shown in Formulas I -3
Compound (must measure 78.8mg, yield 75%).1H NMR(400MHz,cd3Od) δ 9.32 (d, J=8.6Hz, 1H), 8.35 (dd, J
=4.4,1.4Hz, 1H), 8.18 (s, 1H), 7.54 (dd, J=8.7,4.4Hz, 1H), 7.32-7.19 (m, 4H), 3.85 (m,
1H), 3.80-3.66 (m, 2H), 3.44 (s, 2H), 2.88-2.74 (m, 2H), 1.31 (d, J=5.6Hz, 6H)
LCMS:T=0.654min, 520.2 (M+H+).
Embodiment 48：Compound shown in formula I-100
Compound (105mg, 0.2mmol) shown in formula 8-10 is dissolved in acetonitrile (3mL), and sequentially adds three second thereto
Amine (102mg, 1.01mmol), is stirred at room temperature compound (40mg, 0.404mmol) shown in lower dropwise addition formula 9-1, it is small to be heated to reflux 3
When, decompression boils off solvent, and residue diluted with water, dichloromethane extraction (20mL × 3), merges organic phase, through saturated salt solution
Wash, anhydrous magnesium sulfate drying, filtering, decompression boils off organic solvent and obtains crude product, and chemical combination shown in Formulas I -100 is obtained through column chromatography for separation
Thing (must measure 84.8mg, yield 72%).
Embodiment 49：Compound shown in formula I-24
Compound (105mg, 0.2mmol) shown in formula 8-10 is dissolved in acetonitrile (3mL), and sequentially adds three second thereto
Amine (102mg, 1.01mmol), is stirred at room temperature compound (51mg, 0.4mmol) shown in lower dropwise addition formula 9-5, it is small to be heated to reflux 4.5
When, decompression boils off solvent, and residue diluted with water, dichloromethane extraction (20mL × 3), merges organic phase, through saturated salt solution
Wash, anhydrous magnesium sulfate drying, filtering, decompression boils off organic solvent and obtains crude product, and chemical combination shown in Formulas I -156 is obtained through column chromatography for separation
Thing (must measure 74mg, yield 60%).
1H NMR(400MHz,cd3Od) δ 9.10 (d, J=8.4Hz, 1H), 8.36 (d, J=3.3Hz, 1H), 8.14 (s,
1H), 7.76 (d, J=8.6Hz, 1H), 7.58 (dd, J=8.7,4.3Hz, 1H), 7.45 (d, J=2.0Hz, 1H), 7.09 (dd,
J=8.6,2.1Hz, 1H), 3.90-3.78 (m, 4H), 3.24 (d, J=7.4Hz, 2H), 3.13 (d, J=11.9Hz, 2H),
2.87 (s, 6H), 2.36 (t, J=11.3Hz, 2H), 2.08 (d, J=11.4Hz, 2H), 1.91 (dd, J=12.0,3.5Hz,
2H), 1.30 (d, J=6.9Hz, 6H) .LCMS:T=0.611min, 617.3 (M+H+).
Embodiment 50：Compound shown in formula I-17
Compound (100mg, 0.202mmol) shown in formula 8-1 is dissolved in acetonitrile (3mL), and sequentially adds three thereto
Ethamine (102mg, 1.01mmol), is stirred at room temperature compound (12.5mg, 0.202mmol) shown in lower dropwise addition formula 9-4, is heated to reflux
3 it is small when, decompression boils off solvent, residue diluted with water, and dichloromethane extraction (20mL × 3), merges organic phase, through saturated common salt
Washing, anhydrous magnesium sulfate drying, filtering, decompression boil off organic solvent and obtain crude product, and -17 shownization of Formulas I is obtained through column chromatography for separation
Compound (must measure 57.7mg, yield 55%).Data：1H NMR(400MHz,cd3Od) δ 8.66 (d, J=8.4Hz, 1H), 8.15
(s, 1H), 7.94-7.83 (m, 2H), 7.68-7.56 (m, 1H), 7.29 (dt, J=8.0,6.4Hz, 2H), 7.24-7.17 (m,
2H), 3.70-3.61 (m, 2H), 3.39 (s, 2H), 3.35-3.31 (m, 1H), 2.80-2.70 (m, 2H), 1.26 (d, J=
6.8Hz,6H).LCMS:T=0.694min, 519.2 (M+H+)
Embodiment 51：Compound shown in formula I-25
Compound (105mg, 0.2mmol) shown in formula 8-10 is dissolved in acetonitrile (3mL), and sequentially adds three second thereto
Amine (102mg, 1.01mmol), is stirred at room temperature compound (20mg, 0.201mmol) shown in lower dropwise addition formula 9-6, it is small to be heated to reflux 5
When, decompression boils off solvent, and residue diluted with water, dichloromethane extraction (20mL × 3), merges organic phase, through saturated salt solution
Wash, anhydrous magnesium sulfate drying, filtering, decompression boils off organic solvent and obtains crude product, and chemical combination shown in Formulas I -25 is obtained through column chromatography for separation
Thing (must measure 68.3mg, yield 64%).
1H NMR(400MHz,cd3Od) δ 9.09 (d, J=8.5Hz, 1H), 8.35 (dd, J=4.4,1.3Hz, 1H), 8.14
(s, 1H), 7.73 (d, J=8.6Hz, 1H), 7.57 (dd, J=8.7,4.4Hz, 1H), 7.45 (d, J=2.2Hz, 1H), 7.08
(dd, J=8.6,2.2Hz, 1H), 3.89-3.77 (m, 4H), 3.21 (s, 2H), 2.42 (s, 6H), 1.30 (d, J=6.9Hz,
6H).LCMS:T=0.641min, 534.2 (M+H+).
Embodiment 52：Compound shown in formula I-34
Compound (100mg, 0.200mmol) shown in formula 8-11 is dissolved in acetonitrile (3mL), and sequentially adds three thereto
Ethamine (102mg, 1.01mmol), is stirred at room temperature compound (21mg, 0.21mmol) shown in lower dropwise addition formula 9-7, it is small to be heated to reflux 5
When, decompression boils off solvent, and residue diluted with water, dichloromethane extraction (20mL × 3), merges organic phase, through saturated salt solution
Wash, anhydrous magnesium sulfate drying, filtering, decompression boils off organic solvent and obtains crude product, and chemical combination shown in Formulas I -34 is obtained through column chromatography for separation
Thing (must measure 88mg, yield 78%).1H NMR(400MHz,cd3Od) δ 8.42 (d, J=5.4Hz, 1H), 8.16 (s, 1H), 7.94
(s, 1H), 7.88 (d, J=5.5Hz, 1H), 7.27 (q, J=3.7Hz, 3H), 3.37 (dd, J=17.1,10.3Hz, 1H),
3.24 (s, 2H), 2.82 (b, 8H), 2.56 (s, 3H), 1.34 (dd, J=11.1,6.8Hz, 6H) .LCMS:T=0.683min,
564.2(M+H+).
Embodiment 53：Compound shown in formula I-48
Compound (102mg, 0.200mmol) shown in formula 8-19 is dissolved in acetonitrile (3mL), and sequentially adds three thereto
Ethamine (102mg, 1.01mmol), is stirred at room temperature compound (18.1mg, 0.21mmol) shown in lower dropwise addition formula 9-8, is heated to reflux 3
Hour, decompression boils off solvent, and residue diluted with water, dichloromethane extraction (20mL × 3), merges organic phase, through saturated common salt
Washing, anhydrous magnesium sulfate drying, filtering, decompression boil off organic solvent and obtain crude product, and -48 shownization of Formulas I is obtained through column chromatography for separation
Compound (must measure 87.2mg, yield 78%).
1H NMR(400MHz,cd3Od) δ 8.64 (s, 1H), 8.53 (d, J=4.0Hz, 1H), 8.23 (s, 1H), 7.74 (d,
J=2.0Hz, 1H), 7.48 (dd, J=8.3,1.9Hz, 2H), 7.34 (d, J=8.4Hz, 1H), 4.15 (d, J=9.1Hz,
2H), 3.96 (dt, J=13.7,6.9Hz, 1H), 3.73-3.48 (m, 8H), 2.23 (s, 3H), 1.29 (d, J=6.9Hz, 6H)
LCMS:T=0.661min, 559.3 (M+H+)
Embodiment 54：Compound shown in formula I-48
Compound (99mg, 0.200mmol) shown in formula 8-9 is dissolved in acetonitrile (3mL), and sequentially adds three second thereto
Amine (102mg, 1.01mmol), is stirred at room temperature compound (341mg, 0.200mmol) shown in lower dropwise addition formula 9-8, it is small to be heated to reflux 4
When, decompression boils off solvent, and residue diluted with water, dichloromethane extraction (20mL × 3), merges organic phase, through saturated salt solution
Wash, anhydrous magnesium sulfate drying, filtering, decompression boils off organic solvent and obtains crude product, and chemical combination shown in Formulas I -50 is obtained through column chromatography for separation
Thing (must measure 100.6mg, yield 80%).
1H NMR(400MHz,cd3Od) δ 9.29 (d, J=8.5Hz, 1H), 8.36 (dd, J=4.4,1.4Hz, 1H), 8.16
(s, 1H), 7.62 (dd, J=8.7,4.4Hz, 1H), 7.51 (s, 4H), 3.84 (dt, J=13.7,6.9Hz, 1H), 3.78-
3.64 (m, 4H), 3.17 (s, 2H), 3.04 (d, J=11.8Hz, 2H), 2.70-2.56 (m, 4H), 2.33-2.18 (m, 3H),
1.95 (d, J=12.7Hz, 2H), 1.66 (td, J=12.0,3.6Hz, 2H), 1.30 (t, J=9.2Hz, 6H) .LCMS:T=
0.639min,629.3(M+H+)
Embodiment 55：Compound shown in formula I-36
Compound (105mg, 0.20mmol) shown in formula 8-5 is dissolved in acetonitrile (4mL), and sequentially adds three second thereto
Amine (102mg, 1.01mmol), is stirred at room temperature compound (12.5mg, 0.202mmol) shown in lower dropwise addition formula 9-4, is heated to reflux 5
Hour, decompression boils off solvent, and residue diluted with water, dichloromethane extraction (20mL × 3), merges organic phase, through saturated common salt
Washing, anhydrous magnesium sulfate drying, filtering, decompression boil off organic solvent and obtain crude product, and -36 shownization of Formulas I is obtained through column chromatography for separation
Compound (must measure 76mg, yield 69%).
Embodiment 56：Compound shown in formula I-42
Compound (100mg, 0.20mmol) shown in formula 8-14 is dissolved in acetonitrile (4mL), and sequentially adds three thereto
Ethamine (102mg, 1.01mmol), is stirred at room temperature compound (15mg, 0.205mmol) shown in lower dropwise addition formula 9-11, is heated to reflux
4.5 it is small when, decompression boils off solvent, residue diluted with water, and dichloromethane extraction (20mL × 3), merges organic phase, eaten through saturation
Salt is washed, anhydrous magnesium sulfate drying, filtering, and decompression boils off organic solvent and obtains crude product, obtained through column chromatography for separation shown in Formulas I -42
Compound (must measure 82.7mg, yield 77%).
Embodiment 57：Compound shown in formula I-96
Compound (103mg, 0.20mmol) shown in formula 8-22 is dissolved in acetonitrile (4mL), and sequentially adds three thereto
Ethamine (102mg, 1.01mmol), is stirred at room temperature compound (12.4mg, 0.21mmol) shown in lower dropwise addition formula 9-12, is heated to reflux
3 it is small when, decompression boils off solvent, residue diluted with water, and dichloromethane extraction (20mL × 3), merges organic phase, through saturated common salt
Washing, anhydrous magnesium sulfate drying, filtering, decompression boil off organic solvent and obtain crude product, and -96 shownization of Formulas I is obtained through column chromatography for separation
Compound (must measure 85mg, yield 79%).
Embodiment 58：Compound shown in formula I-111
Compound (106mg, 0.20mmol) shown in formula 8-24 is dissolved in acetonitrile (4mL), and sequentially adds three thereto
Ethamine (102mg, 1.01mmol), is stirred at room temperature compound (15.4mg, 0.21mmol) shown in lower dropwise addition formula 9-12, is heated to reflux
5 it is small when, decompression boils off solvent, residue diluted with water, and dichloromethane extraction (20mL × 3), merges organic phase, through saturated common salt
Washing, anhydrous magnesium sulfate drying, filtering, decompression boil off organic solvent and obtain crude product, and -111 shownization of Formulas I is obtained through column chromatography for separation
Compound (must measure 93mg, yield 82%).
Embodiment 59：
The synthesis preparation method of compound described in embodiment 59 is with reference to embodiment 49.
1H NMR(400MHz,cd3Od) δ 9.29 (d, J=8.5Hz, 1H), 8.36 (dd, J=4.4,1.4Hz, 1H), 8.16
(s, 1H), 7.61 (dd, J=8.7,4.4Hz, 1H), 7.50 (s, 4H), 3.80-3.87 (m, 1H), 3.15 (s, 2H), 3.02
(d, J=11.8Hz, 2H), 2.31 (s, 6H), 2.28-2.15 (m, 3H), 1.90 (d, J=12.4Hz, 2H), 1.72-1.56 (m,
2H), 1.31 (d, J=6.9Hz, 6H) .LCMS:T=0.646min, 587.3 (M+H+).
Embodiment 60：
The synthesis preparation method of compound described in embodiment 60 is with reference to embodiment 44.
1H NMR(400MHz,cd3Od) δ 9.30 (d, J=8.6Hz, 1H), 8.38 (d, J=4.1Hz, 1H), 8.18 (s,
1H), 7.63 (dd, J=8.6,4.3Hz, 1H), 7.51 (s, 3H), 4.10 (dd, J=14.4,7.3Hz, 1H), 3.82-3.86
(m,1H),3.42-3.40(m,2H),3.32-3.29(m,2H),2.83-2.86(m,2H),1.02–0.66(m,6H).LCMS:t
=0.679min, 559.2 (M+H+).
Embodiment 61：
The synthesis preparation method of compound described in embodiment 61 is with reference to embodiment 49.
1H NMR(400MHz,cd3Od) δ 9.33 (d, J=8.6Hz, 1H), 8.35 (dd, J=4.4,1.4Hz, 1H), 8.19
(s, 1H), 7.90 (s, 1H), 7.54 (dd, J=8.7,4.4Hz, 1H), 7.33-7.21 (m, 3H), 3.84-3.81 (m, 1H),
3.12 (s, 2H), 2.97 (d, J=11.8Hz, 2H), 2.30 (s, 6H), 2.26-2.11 (m, 3H), 1.94-1.81 (m, 2H),
1.62-1.33 (m, 2H), 1.32 (d, J=6.9Hz, 6H) .LCMS:T=0.658min, 587.3 (M+H+).
Embodiment 62：
The synthesis preparation method of compound described in embodiment 62 is with reference to embodiment 44.
1H NMR(400MHz,cd3Od) δ 9.29 (d, J=8.4Hz, 1H), 8.37 (dd, J=4.4,1.3Hz, 1H), 8.17
(s, 1H), 7.62 (dd, J=8.7,4.4Hz, 1H), 7.57-7.44 (m, 3H), 3.81-3.88 (m, 1H), 3.74-3.63 (m,
2H), 3.44-3.37 (m, 3H), 2.82-2.79 (m, 2H), 1.32 (d, J=6.9Hz, 6H)
LCMS:T=0.696min, 559.2 (M+H+).
Embodiment 63：
The synthesis preparation method of compound described in embodiment 63 is with reference to embodiment 47.
1H NMR(400MHz,cd3Od) δ 9.29 (d, J=8.4Hz, 1H), 8.37 (dd, J=4.4,1.3Hz, 1H), 8.17
(s, 1H), 7.94 (s, 1H), 7.54 (dd, J=8.7,4.4Hz, 1H), 7.26-7.23 (m, 3H), 3.87-3.80 (m, 1H),
3.67-3.64 (m, 2H), 3.43 (s, 2H), 2.79-2.76 (m, 2H), 1.32 (d, J=6.9Hz, 6H)
LCMS:T=0.673min, 520.2 (M+H+).
Embodiment 64：
The synthesis preparation method of compound described in embodiment 64 is with reference to embodiment 51.
1H NMR(400MHz,cd3Od) δ 9.29 (d, J=8.7Hz, 1H), 8.37 (dd, J=4.4,1.4Hz, 1H), 8.17
(s,1H),7.64-7.61(m,1H),7.53-7.48(m,4H),3.87-3.80(m,1H),3.14(s,2H),2.38(s,6H),
1.30 (d, J=6.9Hz, 6H)
LCMS:T=0.670min, 504.2 (M+H+).
Embodiment 65：
The synthesis preparation method of compound described in embodiment 65 is with reference to embodiment 51.
1H NMR(400MHz,cd3Od) δ 9.33 (d, J=8.7Hz, 1H), 8.36 (dd, J=4.4,1.4Hz, 1H), 8.19
(s, 1H), 7.90 (s, 1H), 7.55 (dd, J=8.7,4.4Hz, 1H), 7.32-7.20 (m, 3H), 3.87-3.80 (m, 1H),
3.11 (s, 2H), 2.35 (s, 6H), 1.32 (d, J=6.9Hz, 6H) .LCMS:T=0.689min, 504.1 (M+H+).
Embodiment 66：
The synthesis preparation method of compound described in embodiment 66 is with reference to embodiment 44.
1H NMR(400MHz,CD3OD) δ 8.62 (d, J=8.0Hz, 1H), 8.14 (s, 1H), 7.94 (d, J=7.6Hz,
1H), 7.89 (dd, J=8.0,1.6Hz, 1H), 7.74-7.67 (m, 1H), 7.50 (dt, J=6.7,5.9Hz, 4H), 7.34
(dd, J=11.2,4.1Hz, 1H), 4.49-4.44 (m, 1H), 3.88-3.80 (m, 1H), 3.44-3.37 (m, 2H), 2.88-
2.79 (m, 2H), 1.24 (d, J=6.7Hz, 6H)
LCMS:T=0.695min, 557 (M), 580.3 (M+Na+).
Embodiment 67：
The synthesis preparation method of compound described in embodiment 67 is with reference to embodiment 56.
LCMS:561.2(M+H+).
Embodiment 68：
The synthesis preparation method of compound described in embodiment 68 is with reference to embodiment 51.
1H NMR (400MHz, CD3OD) δ 8.62 (d, J=8.4Hz, 1H), 8.13 (s, 1H), 7.88 (dd, J=8.0,
1.6Hz, 1H), 7.74-7.65 (m, 1H), 7.55-7.43 (m, 4H), 7.37-7.27 (m, 1H), 3.33 (d, J=5.7Hz,
1H),3.15(s,2H),2.39(s,6H),1.28–1.21(m,6H).
LCMS:T=0.685min, 503.2 (M+H+).
Embodiment 69：
The synthesis preparation method of compound described in embodiment 69 is with reference to embodiment 49.
1H NMR (400MHz, CD3OD) δ 8.62 (d, J=8.3Hz, 1H), 8.13 (s, 1H), 7.88 (dd, J=8.0,
1.5Hz, 1H), 7.75-7.65 (m, 1H), 7.56-7.43 (m, 4H), 7.32 (dd, J=11.2,4.1Hz, 1H), 3.33 (m,
1H), 3.15 (s, 2H), 3.03 (d, J=11.9Hz, 2H), 2.37 (s, 6H), 2.27-2.22 (m, 2H), 1.94-1.91 (m,
2H),1.68-1.65(m,2H),1.25(d,6H).
LCMS:T=0.654min, 586.3 (M+H+).
Embodiment 70：
The synthesis preparation method of compound described in embodiment 70 is with reference to embodiment 49.
1H NMR(400MHz,cd3Od) δ 8.69 (d, J=8.3Hz, 1H), 8.15 (s, 1H), 7.90-7.83 (m, 2H),
7.67-7.58 (m, 1H), 7.31 (ddd, J=12.1,5.7,1.6Hz, 2H), 7.25-7.14 (m, 2H), 3.38-3.31 (m,
1H), 3.13 (s, 2H), 3.00 (d, J=11.9Hz, 2H), 2.50-2.31 (m, 7H), 2.23 (dd, J=12.0,10.2Hz,
2H), 1.91 (d, J=13.0Hz, 2H), 1.65 (td, J=12.2,3.7Hz, 2H), 1.26 (d, 6H)
LCMS:T=0.673min, 586.3 (M+H+).
Embodiment 71：
The synthesis preparation method of compound described in embodiment 71 is with reference to embodiment 47.
1H NMR(400MHz,cd3Od) δ 8.63 (d, J=8.5Hz, 1H), 8.14 (s, 1H), 7.89 (dd, J=8.0,
1.4Hz, 1H), 7.74-7.65 (m, 1H), 7.50 (q, J=9.1Hz, 4H), 7.32 (t, J=7.2Hz, 1H), 3.77 (dd, J=
17.8,12.7Hz,2H),3.69(s,2H),3.37–3.32(m,1H),3.03–2.90(m,2H),1.95(s,3H),1.25(d,
6H).
LCMS:T=0.673min, 519.2 (M+H+)
Embodiment 72：
The synthesis preparation method of compound described in embodiment 72 is with reference to embodiment 53.
1H NMR(400MHz,cd3Od) δ 8.24-8.19 (m, 2H), 7.98 (d, J=7.2Hz, 1H), 7.74 (b, 1H),
7.67-7.49 (m, 3H), 7.34 (d, J=8.6Hz, 2H), 4.26 (s, 2H), 3.92-3.46 (m, 8H), 3.42-3.34 (m,
1H), 1.23 (d, J=6.8Hz, 6H)
LCMS:T=0.675min, 544.3 (M+H+)
Embodiment 73：
The synthesis preparation method of compound described in embodiment 73 is with reference to embodiment 53.
1H NMR(400MHz,cd3Od) δ 8.69 (b, 1H), 8.58 (d, J=4.1Hz, 1H), 8.25 (s, 1H), 7.73-
7.53 (m, 3H), 7.35 (d, J=8.5Hz, 2H), 4.31 (s, 2H), 3.99-3.92 (m, 1H), 3.85-3.57 (m, 8H),
1.27 (d, J=6.8Hz, 6H)
LCMS:T=0.665min, 545.3 (M+H+)
Embodiment 74：
The synthesis preparation method of compound described in embodiment 74 is with reference to embodiment 53.
1H NMR(400MHz,cd3Od) δ 8.68 (b, 1H), 8.60 (dd, J=4.5,1.2Hz, 1H), 8.28 (s, 1H),
7.82 (t, J=1.9Hz, 1H), 7.61 (dd, J=8.3,4.4Hz, 1H), 7.47-7.31 (m, 2H), 7.15 (d, J=8.5Hz,
1H), 4.27 (s, 2H), 3.97 (dt, J=13.7,6.8Hz, 1H), 3.65 (dd, J=24.0,19.1Hz, 8H), 1.27 (t, J
=14.4Hz, 6H)
LCMS:T=0.680min, 545.3 (M+H+)
Embodiment 75：
The synthesis preparation method of compound described in embodiment 75 is with reference to embodiment 45.
1H NMR(400MHz,cd3Od) δ 9.29 (d, J=8.5Hz, 1H), 8.36 (dd, J=4.3,1.2Hz, 1H), 8.16
(s, 1H), 7.61 (dt, J=8.6,4.2Hz, 1H), 7.51 (s, 4H), 3.86-3.84 (m, 1H), 3.76 (dd, J=10.4,
5.8Hz, 4H), 3.17 (s, 2H), 2.62-2.60 (m, 4H), 1.31 (d, J=6.9Hz, 6H)
LCMS:T=0.679min, 546.2 (M+H+)
Embodiment 76：
The synthesis preparation method of compound described in embodiment 76 is with reference to embodiment 45.
1H NMR(400MHz,cd3Od) δ 9.34 (d, J=8.6Hz, 1H), 8.36 (dd, J=4.4,1.3Hz, 1H), 8.19
(s, 1H), 7.92 (s, 1H), 7.55 (dd, J=8.7,4.4Hz, 1H), 7.37-7.20 (m, 3H), 3.86-2.83 (m, 1H),
3.75-3.70 (m, 4H), 3.15 (s, 2H), 2.62-2.52 (m, 4H), 1.32 (d, J=6.9Hz, 6H)
LCMS:T=0.698min, 546.2 (M+H+)
Embodiment 77：
The synthesis preparation method of compound described in embodiment 77 is with reference to embodiment 45.
1H NMR(400MHz,cd3Od) δ 8.62 (d, J=8.2Hz, 1H), 8.13 (s, 1H), 7.88 (d, J=7.9Hz,
1H), 7.70 (t, J=7.9Hz, 1H), 7.50 (q, J=8.9Hz, 4H), 7.32 (t, J=7.6Hz, 1H), 3.82-3.68 (m,
4H), 3.32-3.30 (m, 1H), 3.17 (s, 2H), 2.62-2.60 (m, 4H), 1.24 (d, J=6.8Hz, 6H)
LCMS:T=0.698min, 545.2 (M+H+).
Embodiment 78：
The synthesis preparation method of compound described in embodiment 78 is with reference to embodiment 53.
1H NMR(400MHz,cd3Od) δ 8.72 (s, 1H), 8.59 (dd, J=4.4,1.1Hz, 1H), 8.23 (s, 1H),
7.68 (s, 1H), 7.57 (s, 1H), 7.35 (d, J=8.6Hz, 1H), 7.18 (s, 1H), 4.23 (s, 2H), 3.98 (dt, J=
13.6,6.8Hz, 1H), 3.78-3.49 (m, 8H), 1.29 (d, J=6.9Hz, 6H)
LCMS:T=0.636min, 575.2 (M+H+).
Embodiment 79：
The synthesis preparation method of compound described in embodiment 79 is with reference to embodiment 45.
1H NMR(400MHz,cd3Od) δ 9.07 (d, J=8.6Hz, 1H), 8.39 (dd, J=4.4,1.3Hz, 1H), 8.17
(s, 1H), 7.74 (d, J=8.6Hz, 1H), 7.58 (dd, J=8.7,4.4Hz, 1H), 7.45 (d, J=2.2Hz, 1H), 7.09
(dd, J=8.6,2.3Hz, 1H), 4.17 (s, 2H), 3.99 (s, 4H), 3.91-3.79 (m, 4H), 3.47 (s, 4H), 1.30 (d,
J=6.9Hz, 6H)
LCMS:T=0.646min, 576.2 (M+H+).
Embodiment 80：
The synthesis preparation method of compound described in embodiment 80 is with reference to embodiment 52.
1H NMR(400MHz,cd3Od) δ 9.33 (d, J=8.5Hz, 1H), 8.35 (dd, J=4.4,1.3Hz, 1H), 8.19
(s, 1H), 7.90 (s, 1H), 7.54 (dd, J=8.7,4.4Hz, 1H), 7.27 (ddd, J=10.4,6.1,1.6Hz, 3H),
3.89-3.82 (m, 1H), 3.18 (s, 2H), 2.62 (b, 8H), 2.34 (s, 3H), 1.31 (d, J=6.5Hz, 6H)
LCMS:T=0.632min, 559.2 (M+H+).
Embodiment 81：
The synthesis preparation method of compound described in embodiment 81 is with reference to embodiment 52.
1H NMR(400MHz,cd3Od) δ 9.29 (d, J=8.4Hz, 1H), 8.36 (d, J=4.3Hz, 1H), 8.16 (d, J
=1.0Hz, 1H), 7.61 (dd, J=8.7,4.3Hz, 1H), 7.50 (s, 4H), 3.87-3.80 (m, 1H), 3.21 (s, 2H),
2.69 (b, 8H), 2.40 (s, 3H), 1.31 (d, J=6.9Hz, 6H) .LCMS:T=0.638min, 559.2 (M+H+).
Embodiment 82：
The synthesis preparation method of compound described in embodiment 82 is with reference to embodiment 52.
1H NMR(400MHz,cd3Od) δ 9.11 (d, J=8.4Hz, 1H), 8.36 (dd, J=4.4,1.3Hz, 1H), 8.15
(s, 1H), 7.75 (d, J=8.6Hz, 1H), 7.58 (dd, J=8.7,4.4Hz, 1H), 7.44 (d, J=2.2Hz, 1H), 7.08
(dd, J=8.6,2.2Hz, 1H), 3.90-3.78 (m, 4H), 3.27 (s, 2H), 2.84 (b, 8H), 2.56 (s, 3H), 1.30 (d,
J=6.9Hz, 6H) .LCMS:T=0.650min, 589.3 (M+H+).
Embodiment 83：
The synthesis preparation method of compound described in embodiment 83 is with reference to embodiment 51.
1H NMR(400MHz,cd3Od) δ 8.41 (d, J=5.5Hz, 1H), 8.15 (s, 1H), 7.91 (s, 1H), 7.88 (d,
J=5.5Hz, 1H), 7.34-7.21 (m, 3H), 3.42-3.34 (m, 1H), 3.17 (s, 2H), 2.38 (d, J=7.7Hz, 6H),
1.33 (d, J=6.8Hz, 6H) .LCMS:T=0.673min, 509.1 (M+H+).
Embodiment 84：
The synthesis preparation method of compound described in embodiment 84 is with reference to embodiment 49.
1H NMR(400MHz,cd3Od) δ 8.41 (d, J=5.5Hz, 1H), 8.15 (s, 1H), 7.95 (s, 1H), 7.87 (d,
J=5.5Hz, 1H), 7.27 (td, J=5.5,2.6Hz, 3H), 3.38 (dd, J=13.6,6.8Hz, 1H), 3.21 (s, 2H),
3.17-3.00 (m, 3H), 2.82 (s, 6H), 2.31 (dd, J=11.9,10.3Hz, 2H), 2.03 (d, J=11.7Hz, 2H),
1.90-1.73 (m, 2H), 1.33 (d, J=6.8Hz, 6H) .LCMS:T=0.612min, 592.3 (M+H+).
Embodiment 85：
The synthesis preparation method of compound described in embodiment 85 is with reference to embodiment 53.
1H NMR(400MHz,cd3Od) δ 8.25 (s, 1H), 8.02 (b, 1H), 7.94 (d, J=5.4Hz, 1H), 7.86 (s,
1H), 7.54 (d, J=8.3Hz, 1H), 7.45 (t, J=8.1Hz, 1H), 7.25 (d, J=7.9Hz, 1H), 4.19 (d, J=
5.5Hz, 2H), 3.59 (dd, J=14.0,7.0Hz, 8H), 3.45 (dt, J=13.6,6.8Hz, 2H), 1.32 (d, J=
6.8Hz,6H).
LCMS:T=0.685min, 549.1 (M+H+)
Embodiment 86：
The synthesis preparation method of compound described in embodiment 86 is with reference to embodiment 49.
1H NMR(400MHz,cd3Od) δ 9.02 (d, J=8.7Hz, 1H), 8.27 (d, J=3.4Hz, 1H), 8.13 (s,
1H), 7.71 (d, J=2.0Hz, 1H), 7.44 (dd, J=8.2,2.0Hz, 1H), 7.34-7.22 (m, 2H), 3.85 (dt, J=
13.7,6.8Hz, 1H), 3.18 (d, J=8.2Hz, 2H), 3.05-2.96 (m, 2H), 2.82 (s, 6H), 2.34-2.15 (m,
5H), 2.00 (d, J=11.4Hz, 2H), 1.77 (dt, J=12.1,8.5Hz, 2H), 1.29 (t, J=6.3Hz, 6H)
LCMS:T=0.647min, 601.3 (M+H+)
Embodiment 87：
The synthesis preparation method of compound described in embodiment 87 is with reference to embodiment 45.
1H NMR(400MHz,cd3Od) δ 9.01 (d, J=8.8Hz, 1H), 8.28-8.23 (m, 1H), 8.12 (s, 1H),
7.71 (d, J=2.2Hz, 1H), 7.40 (dt, J=7.3,3.7Hz, 1H), 7.30 (dd, J=8.8,4.3Hz, 1H), 7.24 (d,
J=8.3Hz, 1H), 3.82 (dt, J=13.7,6.9Hz, 1H), 3.74-3.65 (m, 4H), 3.14 (s, 2H), 2.56-2.54
(m, 4H), 2.21 (s, 3H), 1.29 (d, J=6.9Hz, 6H)
LCMS:T=0.681min, 560.2 (M+H+)
Embodiment 88：
The synthesis preparation method of compound described in embodiment 88 is with reference to embodiment 52.
1H NMR(400MHz,cd3Od) δ 9.01 (d, J=8.7Hz, 1H), 8.27 (dd, J=4.3,1.1Hz, 1H), 8.12
(s, 1H), 7.72 (d, J=2.1Hz, 1H), 7.41 (dd, J=8.2,2.2Hz, 1H), 7.33-7.22 (m, 2H), 3.84 (dt, J
=13.7,6.9Hz, 1H), 3.22 (d, J=7.3Hz, 2H), 2.99 (s, 4H), 2.71 (s, 4H), 2.64 (s, 3H), 2.21 (s,
3H), 1.30 (d, J=6.9Hz, 6H)
LCMS:T=0.676min, 573.3 (M+H+)
Embodiment 89：
The synthesis preparation method of compound described in embodiment 89 is with reference to embodiment 52.
LCMS:598.6(M+H+).
Embodiment 90：
The synthesis preparation method of compound described in embodiment 90 is with reference to embodiment 54.
1H NMR(400MHz,cd3Od) δ 9.33 (d, J=8.2Hz, 1H), 8.35 (dd, J=4.4,1.3Hz, 1H), 8.19
(s, 1H), 7.90 (s, 1H), 7.53 (dd, J=8.7,4.4Hz, 1H), 7.34-7.18 (m, 3H), 3.85 (dt, J=13.7,
6.8Hz, 1H), 3.77-3.64 (m, 4H), 3.14 (s, 2H), 2.98 (d, J=11.5Hz, 2H), 2.61 (d, J=4.3Hz,
4H), 2.23 (t, J=11.2Hz, 3H), 1.92 (d, J=12.6Hz, 2H), 1.63-1.52 (m, 2H), 1.30 (d, J=
6.9Hz,6H).
LCMS:T=0.646min, 629.3 (M+H+)
Embodiment 91
The synthesis preparation method of compound described in embodiment 91 is with reference to embodiment 52.
LCMS:572.3(M+H+).
Embodiment 92
The synthesis preparation method of compound described in embodiment 92 is with reference to embodiment 52.
LCMS:592.5(M+H+).
Embodiment 93
The synthesis preparation method of compound described in embodiment 93 is with reference to embodiment 45.
LCMS:559.1(M+H+).
Embodiment 94
The synthesis preparation method of compound described in embodiment 94 is with reference to embodiment 45.
LCMS:579.5(M+H+).
Embodiment 95
The synthesis preparation method of compound described in embodiment 95 is with reference to embodiment 53.
LCMS:558(M+H+).
Embodiment 96
The synthesis preparation method of compound described in embodiment 96 is with reference to embodiment 53.LCMS:577(M+H+)
Embodiment 97
The synthesis preparation method of compound described in embodiment 97 is with reference to embodiment 51.
LCMS:517.1(M+H+).
Embodiment 98
The synthesis preparation method of compound described in embodiment 98 is with reference to embodiment 49.
LCMS:600.2(M+H+).
Embodiment 99
The synthesis preparation method of compound described in embodiment 99 is with reference to embodiment 49.
LCMS:620.1(M+H+).
Embodiment 100
The synthesis preparation method of compound described in embodiment 100 is with reference to embodiment 51.
LCMS:509.1(M+H+).
Embodiment 101
The synthesis preparation method of compound described in embodiment 101 is with reference to embodiment 46.
LCMS:531.1(M+H+).
Embodiment 102
The synthesis preparation method of compound described in embodiment 102 is with reference to embodiment 44.
LCMS:588.1(M+H+).
Embodiment 103
The synthesis preparation method of compound described in embodiment 103 is with reference to embodiment 47.
LCMS:549.1(M+H+).
Embodiment 104
The synthesis preparation method of compound described in embodiment 104 is with reference to embodiment 49.
LCMS:616.2(M+H+).
Embodiment 105
The synthesis preparation method of compound described in embodiment 105 is with reference to embodiment 44.
LCMS:610.1(M+H+).
Embodiment 106
The synthesis preparation method of compound described in embodiment 106 is with reference to embodiment 49.
LCMS:586.2(M+H+).
Embodiment 107
The synthesis preparation method of compound described in embodiment 107 is with reference to embodiment 50.
LCMS:555.1(M+H+)
Embodiment 108
The synthesis preparation method of compound described in embodiment 108 is with reference to embodiment 49.
LCMS:622.2(M+H+)
Embodiment 109
The synthesis preparation method of compound described in embodiment 109 is with reference to embodiment 58.
LCMS:530.2(M+H+).
Embodiment 110
The synthesis preparation method of compound described in embodiment 110 is with reference to embodiment 52.
LCMS:593.5(M+H+)
Embodiment 111
The synthesis preparation method of compound described in embodiment 111 is with reference to embodiment 45.
LCMS:580.5(M+H+)
Embodiment 112
The synthesis preparation method of compound described in embodiment 112 is with reference to embodiment 53.
LCMS:578(M+H+)
Embodiment 113
The synthesis preparation method of compound described in embodiment 113 is with reference to embodiment 51.
LCMS:518.1(M+H+)
Embodiment 114
The synthesis preparation method of compound described in embodiment 114 is with reference to embodiment 51.
LCMS:538.5(M+H+)
Embodiment 115
The synthesis preparation method of compound described in embodiment 115 is with reference to embodiment 49.
LCMS:621.6(M+H+)
Embodiment 116
The synthesis preparation method of compound described in embodiment 116 is with reference to embodiment 51.
LCMS:539.1(M+H+)
Embodiment 117
The synthesis preparation method of compound described in embodiment 117 is with reference to embodiment 50.
LCMS:550.1(M+H+)
Embodiment 118
The synthesis preparation method of compound described in embodiment 118 is with reference to embodiment 58.
LCMS:544.2(M+H+).
Embodiment 119
The synthesis preparation method of compound described in embodiment 119 is with reference to embodiment 46.
LCMS:562.1(M+H+)
Embodiment 120
The synthesis preparation method of compound described in embodiment 120 is with reference to embodiment 52.
LCMS:578.2(M+H+).
Embodiment 121
The synthesis preparation method of compound described in embodiment 121 is with reference to embodiment 45.
LCMS:585.5(M+H+).
Embodiment 122
The synthesis preparation method of compound described in embodiment 122 is with reference to embodiment 45.
LCMS:565.1(M+H+)
Embodiment 123
The synthesis preparation method of compound described in embodiment 123 is with reference to embodiment 53.
LCMS:583(M+H+)
Embodiment 124
The synthesis preparation method of compound described in embodiment 124 is with reference to embodiment 53.
LCMS:563(M+H+)
Embodiment 125
The synthesis preparation method of compound described in embodiment 125 is with reference to embodiment 51.
LCMS:543.5(M+H+)
Embodiment 126
The synthesis preparation method of compound described in embodiment 126 is with reference to embodiment 51.
LCMS:523.1(M+H+)
Embodiment 127
The synthesis preparation method of compound described in embodiment 127 is with reference to embodiment 49.
LCMS:626.6(M+H+)
Embodiment 128
The synthesis preparation method of compound described in embodiment 128 is with reference to embodiment 49.
LCMS:606.2(M+H+)
Embodiment 129
The synthesis preparation method of compound described in embodiment 129 is with reference to embodiment 44.
LCMS:564.1(M+H+)
Embodiment 130
The synthesis preparation method of compound described in embodiment 130 is with reference to embodiment 46.
LCMS:567.1(M+H+)
Embodiment 131
The synthesis preparation method of compound described in embodiment 131 is with reference to embodiment 47.
LCMS:525.1(M+H+).
Embodiment 132
The synthesis preparation method of compound described in embodiment 132 is with reference to embodiment 47.
LCMS:525.1(M+H+).
Embodiment 133
The synthesis preparation method of compound described in embodiment 133 is with reference to embodiment 49.
LCMS:592.2(M+H+).
Embodiment 134
The synthesis preparation method of compound described in embodiment 134 is with reference to embodiment 57.
LCMS:516.2(M+H+).
Embodiment 135
The synthesis preparation method of compound described in embodiment 135 is with reference to embodiment 57.
LCMS:516.2(M+H+).
Embodiment 136
The synthesis preparation method of compound described in embodiment 136 is with reference to embodiment 57.
LCMS:531.2(M+H+).
Embodiment 137
The synthesis preparation method of compound described in embodiment 137 is with reference to embodiment 57.
LCMS:531.2(M+H+).
Embodiment 138：The measure of ALK kinase inhibiting activities
The compound of the present invention is measured in vitro to the inhibitory activity of ALK kinases, the inhibitory activity using following methods
Represented using this index of IC50, the concentration of the compound during activity inhibited 50% of IC50, that is, ALK kinases.
Write a Chinese character in simplified form and define
Mg milligrams
ML milliliters
μ g micrograms
μ l microlitre
MM mMs
EDTA Ethylenediamine tetra-acetic acid
DMSO dimethyl sulfoxides
SD standard deviations
SOP S.O.P.s
Experiment material：
ALK(Carna,Cat.No 08-105,Lot.No.08CBS-0112)
ALK L1196M(Carna,Cat.No 08-529,Lot.No.11CBS-1134)
Peptide FAM-P22(GL Biochem,Cat.No.112393,Lot.No.P080401-XY112393)
ATP(Sigma,Cat.No.A7699-1G,CAS No.987-65-5)
DMSO(Sigma,Cat.No.D2650,Lot.No.474382)
EDTA(Sigma,Cat.No.E5134,CAS No.60-00-4)
96 orifice plates (Corning, Cat.No.3365, Lot.No.22008026)
384 orifice plates (Corning, Cat.No.3573, Lot.No.12608008)
Staurosporine(Sigma,Cat.No.S4400-1MG,Lot.No.046K4080)
Experimental method：
1. prepare 1 times of kinase buffer liquid and terminate liquid
1) 1 times of kinase buffer liquid
50mM HEPES,pH 7.5
0.0015%Brij-35
10mM MgCl2
2mM DTT
2) terminate liquid
100mM HEPES,pH 7.5
0.015%Brij-35
0.2%Coating Reagent#3
50mM EDTA
2. compound is prepared
1) by the 100%DMSO solution of 50 times of final required highest inhibition concentrations of diluted chemical compound.Shift 100 μ L this
Chemical compound diluted liquid is in 96 orifice plates.For example, being 1 μM if necessary to highest inhibitor concentration, 50 μM are just prepared in this step
DMSO solution.
2) compound is pressed into 3 times of serial dilutions into 10 concentration.
3) the empty 96 identical orifice plates controlled without compound and controlled without enzyme of addition 100 μ l 100%DMSO to 2
In.Mark source plate.
4) preparation of intermediate plate
10 μ L compounds are shifted from source plate and are used as intermediate plate into a 96 new orifice plates.
90 μ L1 times kinase buffer liquids are added into the hole of each intermediate plate.
Mixed compound is into intermediate plate and vibrates 10 minutes.
3. prepare breadboard
Transferase 45 μ l are used as repetition into 384 orifice plates in each hole from 96 hole intermediate plates.For example, the A1 in 96 orifice plates
The A1 and A2 being transferred in 384 orifice plates.A2 in 96 orifice plates is transferred to the A3 and A4 of 384 orifice plates.
4. kinase reaction
1) 2.5 times of enzyme solutions are prepared
Kinases is added into 1 times of kinase buffer liquid, forms 2.5 times of enzyme solutions.
2) 2.5 times of substrate solution is prepared
The polypeptide of FAM marks and ATP are added into 1 times of kinase buffer liquid, form 2.5 times of substrate solutions.
3) 10% DMSO solution of the breadboard containing 5 μ l compounds.
4) .5 times of enzyme solutions of transferase 12 are to breadboard.
5) it is incubated 10 minutes at room temperature
6) .5 times of peptide solution of transferase 12 is to breadboard.
7) reaction and stopping of kinases
It is incubated 20 minutes at 28 DEG C.Add 25 μ l stop solutions and terminate reaction.
5.Caliper reads data
The upper reading and converting rate data of Caliper.
6. curve matching
1) conversion data is replicated from Caliper.
2) conversion into inhibiting rate data.Wherein max refers to the conversion ratio of DMSO controls, and min refers to no enzyme activity
The conversion ratio of control.
Percent inhibition=(max-conversion)/(max-min) * 100.
3) MS Excel are imported data to and carry out curve plan using XLFit excel add-in version 4.3.1
Close.
The formula used is:
Y=Bottom+ (Top-Bottom)/(1+10^ ((LogIC50-X) * HillSlope)) following table shows the present invention
Compound shown in Formulas I -1~Formulas I -159 activity in ALK kinase inhibitions measure in vitro.The results show that formula of the present invention
Compound shown in I is respectively provided with good ALK kinase inhibiting activities, and compound of the present invention can be used as ALK inhibitor, for controlling
One or more kinds of tumor diseases related with ALK activity are treated, is used to prepare into and suppresses the anti-swollen of anaplastic lymphoma kinase
Knurl medicine.
| Compound number | IC50(nM) |
| I-1 | <100 |
| I-2 | <100 |
| I-3 | <100 |
| I-4 | <100 |
| I-5 | <100 |
| I-6 | <100 |
| I-7 | <100 |
| I-8 | <100 |
| I-10 | <10 |
| I-11 | <10 |
| I-12 | <10 |
| I-14 | <10 |
| I-15 | <10 |
| I-16 | <10 |
| I-17 | <10 |
| I-18 | <10 |
| I-19 | <100 |
| I-20 | <100 |
| I-21 | <100 |
| I-22 | 124 |
| I-23 | <10 |
| I-24 | <100 |
| I-25 | <100 |
| I-26 | <10 |
| I-27 | <100 |
| I-28 | <100 |
| I-29 | <100 |
| I-30 | <10 |
| I-31 | <10 |
| I-32 | <10 |
| I-33 | <10 |
| I-34 | <10 |
| I-35 | <10 |
| I-36 | <10 |
| I-42 | <100 |
| I-45 | <100 |
| I-46 | <100 |
| I-47 | <100 |
| I-48 | <100 |
| I-49 | <100 |
| I-50 | <100 |
| I-52 | <100 |
| I-53 | <100 |
| I-54 | <100 |
| I-55 | <10 |
| I-56 | <10 |
| I-57 | <10 |
| I-58 | <10 |
| I-59 | <100 |
| I-60 | <100 |
| I-61 | 138 |
| I-62 | <100 |
| I-63 | <100 |
| I-64 | <10 |
| I-65 | 124 |
| I-66 | <100 |
| I-67 | <100 |
| I-68 | <100 |
| I-69 | <100 |
| I-70 | <100 |
| I-71 | <100 |
| I-72 | <100 |
| I-73 | <100 |
| I-74 | <10 |
| I-75 | <10 |
| I-76 | <100 |
| I-77 | <10 |
| I-80 | <10 |
| I-81 | 100 |
| I-82 | <10 |
| I-83 | <10 |
| I-84 | <100 |
| I-86 | <100 |
| I-87 | <100 |
| I-90 | <100 |
| I-91 | <100 |
| I-93 | <100 |
| I-96 | <100 |
| I-97 | <100 |
| I-98 | <10 |
| I-99 | <10 |
| I-100 | <100 |
| I-107 | <100 |
| I-109 | <100 |
| I-110 | <100 |
| I-111 | <100 |
| I-113 | <100 |
| I-114 | <100 |
| I-115 | <100 |
| I-116 | <100 |
| I-119 | <100 |
| I-121 | <100 |
| I-122 | <100 |
| I-123 | <100 |
| I-129 | <100 |
| I-132 | <100 |
| I-144 | <100 |
| I-157 | <100 |
| I-158 | <100 |
| I-159 | <10 |
Embodiment 139：Tablet for oral administration, prescription see the table below
| Component | Bulk pharmaceutical chemicals (gram) |
| Active ingredient | 10 |
| Guar gum | 15 |
| Microcrystalline cellulose | 150 |
| Sodium carboxymethyl starch | 25 |
| Magnesium stearate | 2 |
| It is prepared into | 1000 |
Active ingredient in upper table is crossed into 100 mesh sieves, then with crossing guar gum, sodium carboxymethyl starch, the crystallite fibre of 100 mesh sieves
Dimension element, magnesium stearate are uniformly mixed, then are formed as tablet with suitable tablet press machine, are prepared into 1000 altogether, the activity of every into
It is 10mg to divide (compound of the invention).
In the description of this specification, reference term " one embodiment ", " some embodiments ", " example ", " specifically show
The description of example " or " some examples " etc. means to combine the embodiment or example particular features, structures, materials, or characteristics described
It is contained at least one embodiment of the present invention or example.In the present specification, schematic expression of the above terms differs
Surely identical embodiment or example are referred to.Moreover, particular features, structures, materials, or characteristics described can be any
Combined in an appropriate manner in one or more embodiments or example.
Although the embodiment of the present invention has been shown and described above, it is to be understood that above-described embodiment is example
Property, it is impossible to limitation of the present invention is interpreted as, those of ordinary skill in the art are not departing from the principle of the present invention and objective
In the case of above-described embodiment can be changed within the scope of the invention, change, replace and modification.
Claims (6)
1. a kind of compound, it is the officinal salt of compound shown in compound shown in Formulas I or Formulas I,
Wherein,
R1For hydrogen, halogen, C1-6Alkyl or C1-6Alkoxy；
R4For hydrogen, halogen, C1-6Alkyl or C1-6Alkoxy,
Wherein, R2To be one of following：
R3To be one of following：
2. a kind of method of compound shown in formula Ι, it is characterised in that including：
(1) compound is contacted with compound shown in formula 2 shown in formula 1, to obtain compound shown in formula 3；
(2) compound shown in the formula 3 is made to be contacted with compound shown in formula 4, to obtain compound shown in formula 5；
(3) make compound shown in the formula 5 that hydrogenation reaction occur, to obtain compound shown in formula 6；
(4) compound shown in the formula 6 is made to be contacted with compound shown in formula 7, to obtain compound shown in formula 8；And
(5) compound shown in the formula 8 is made to be contacted with compound shown in formula 9, to obtain compound shown in Formulas I,
Wherein,
R1For hydrogen, halogen, C1-6Alkyl or C1-6Alkoxy；
R4For hydrogen, halogen, C1-6Alkyl or C1-6Alkoxy,
R2To be one of following：
R3To be one of following：
3. according to the method described in claim 2, it is characterized in that,
In step (1), in the first organic solvent, there are during NaH, make shown in compound shown in the formula 1 and the formula 2
Compound contacts at a temperature of 0 degree Celsius, and first organic solvent is selected from 1-methyl-2-pyrrolidinone, N, N- dimethyl methyls
At least one of acid amides, dimethyl sulfoxide (DMSO), n,N-dimethylacetamide,
In step (2), in n-butanol, there are p-methyl benzenesulfonic acid under the conditions of, make compound shown in the formula 3 and the formula 4
Shown compound contact,
In step (4), compound shown in the formula 6 is set to be contacted with compound shown in formula 7, to obtain 8 shownization of formula
Compound, carries out through the following steps：
(4-1), which is provided, contains the first dichloromethane solution of compound and triethylamine shown in the formula 6, and contains the formula 7
Second dichloromethane solution of the compound；
(4-2) mixes first dichloromethane solution with second dichloromethane solution, described to be combined by institute
State the second dichloromethane solution and be added drop-wise to what is carried out in first dichloromethane solution, the dropwise addition is to cool down bar in ice-water bath
Carried out under part, when the time of contact is 2-5 small,
In step (5), compound shown in the formula 8 is set to be contacted with compound shown in formula 9, to obtain change shown in Formulas I
Compound, carries out through the following steps：
Offer contains compound, the acetonitrile solution of triethylamine shown in the formula 8,
Compound shown in the formula 9 is added into the acetonitrile solution, to make compound shown in the formula 8 and the institute of formula 9
Show that compound is contacted, when the contact is that progress 3-5 is small under heated reflux condition.
4. according to the method described in claim 3, it is characterized in that, in step (1), first organic solvent is N, N- bis-
Methylformamide.
5. according to the method described in claim 3, it is characterized in that, in step (2), at 80 degrees Celsius, make the institute of formula 3
Show that compound is contacted with compound shown in the formula 4.
6. according to the method described in claim 2, it is characterized in that, in step (3), the hydrogenation reaction is to use palladium/carbon
As catalyst, carried out in hydrogen atmosphere.
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| CN201510304880.6A CN104987324B (en) | 2015-06-04 | 2015-06-04 | Pyrimidine derivatives as ALK inhibitor |
| PCT/CN2015/081487 WO2016192132A1 (en) | 2015-06-04 | 2015-06-15 | Pyrimidine derivative serving as alk inhibitor |
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| GB201514021D0 (en) | 2015-08-07 | 2015-09-23 | Arner Elias Set Jeno | Novel Pyridines and their use in the treatment of cancer |
| CN106699743B (en) * | 2015-11-05 | 2020-06-12 | 湖北生物医药产业技术研究院有限公司 | Pyrimidine derivative and application thereof |
| CN107586278B (en) * | 2016-07-08 | 2020-01-10 | 中国科学院上海药物研究所 | 2, 4-diamino pyrimidine compound, preparation method, pharmaceutical composition and application thereof |
| CN110382464A (en) | 2017-02-07 | 2019-10-25 | 欧比力克治疗公司 | The pyridine and its purposes in cancer treatment that alkylsulfonyl replaces |
| CN110382465A (en) | 2017-02-07 | 2019-10-25 | 欧比力克治疗公司 | Sulfinyl pyridine and its purposes in cancer treatment |
| AU2018218519B2 (en) | 2017-02-07 | 2021-08-05 | Oblique Therapeutics Ab | Heteroarylsulfonyl-substituted pyridines and their use in the treatment of cancer |
| US11168069B2 (en) | 2017-02-07 | 2021-11-09 | Oblique Therapeutics Ab | Heterocyclylsulfonyl-substituted pyridines and their use in the treatment of cancer |
| CN107235931B (en) * | 2017-07-11 | 2019-09-24 | 大连医科大学 | New pyrimidine anti-tumor compounds and preparation method thereof and purposes |
| CN109422733A (en) * | 2017-09-03 | 2019-03-05 | 上海美志医药科技有限公司 | One kind inhibits and the compound for the tyrosine protein kinase ALK that degrades |
| CN108047204A (en) * | 2018-01-08 | 2018-05-18 | 沈阳药科大学 | 2,4- diarylamino pyrimidine derivatives and its preparation method and application |
| CN110294750A (en) * | 2018-03-21 | 2019-10-01 | 密执安州立大学董事会 | 5,6- dihydro -11H- indoles as ALK inhibitor simultaneously [2,3-B] quinoline -11- ketone compound |
| WO2021003417A1 (en) | 2019-07-03 | 2021-01-07 | Sumitomo Dainippon Pharma Oncology, Inc. | Tyrosine kinase non-receptor 1 (tnk1) inhibitors and uses thereof |
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| US8367689B2 (en) * | 2009-05-06 | 2013-02-05 | Portola Pharmaceuticals, Inc. | Inhibitors of JAK |
| US20130137709A1 (en) * | 2010-05-05 | 2013-05-30 | Nathanael S. Gray | Compounds that modulate EGFR activity and methods for treating or preventing conditions therewith |
| EP2686323A1 (en) * | 2011-03-16 | 2014-01-22 | Cephalon, Inc. | Macrocyclic compounds as alk, fak and jak2 inhibitors |
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