CN104987324A - Pyrimidine derivative used as anaplastic lymphoma kinase (ALK) inhibitor - Google Patents
Pyrimidine derivative used as anaplastic lymphoma kinase (ALK) inhibitor Download PDFInfo
- Publication number
- CN104987324A CN104987324A CN201510304880.6A CN201510304880A CN104987324A CN 104987324 A CN104987324 A CN 104987324A CN 201510304880 A CN201510304880 A CN 201510304880A CN 104987324 A CN104987324 A CN 104987324A
- Authority
- CN
- China
- Prior art keywords
- formula
- compound
- unit
- compound shown
- alkyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 0 *c1ccc*(*)c1I#C Chemical compound *c1ccc*(*)c1I#C 0.000 description 12
- YYBXNWIRMJXEQJ-UHFFFAOYSA-N C(CNCC1)C1N1CCOCC1 Chemical compound C(CNCC1)C1N1CCOCC1 YYBXNWIRMJXEQJ-UHFFFAOYSA-N 0.000 description 1
- OYPCMNHIJFIKGL-UHFFFAOYSA-N CC(C)S(C(N=CCC1)=C1Nc(nc(Nc(cc(cc1)NC(CN2CCNCC2)=O)c1Cl)nc1)c1Cl)(=O)=O Chemical compound CC(C)S(C(N=CCC1)=C1Nc(nc(Nc(cc(cc1)NC(CN2CCNCC2)=O)c1Cl)nc1)c1Cl)(=O)=O OYPCMNHIJFIKGL-UHFFFAOYSA-N 0.000 description 1
- CBAGHOTVMCYWMC-UHFFFAOYSA-N CC(C)S(C1N=CC=CC1Nc(nc(Nc1cccc(NC(CNCCO)=O)c1)nc1)c1Cl)(=O)=O Chemical compound CC(C)S(C1N=CC=CC1Nc(nc(Nc1cccc(NC(CNCCO)=O)c1)nc1)c1Cl)(=O)=O CBAGHOTVMCYWMC-UHFFFAOYSA-N 0.000 description 1
- HYBSUODTVCKGOM-XQNSMLJCSA-N CC(C)S(c([s]cc1)c1NC(C)/C(/Cl)=C\N=C(/N)\Nc(cc1)ccc1NC(CN(CC1)CCC1N(C)C)=O)(=O)=O Chemical compound CC(C)S(c([s]cc1)c1NC(C)/C(/Cl)=C\N=C(/N)\Nc(cc1)ccc1NC(CN(CC1)CCC1N(C)C)=O)(=O)=O HYBSUODTVCKGOM-XQNSMLJCSA-N 0.000 description 1
- JQJSHKYQUXKUDC-UHFFFAOYSA-N CC(C)S(c1ccccc1Nc(nc(Nc(c(OC)c1)ccc1NC(CN(CCN)CC=O)=O)nc1)c1Cl)(=O)=O Chemical compound CC(C)S(c1ccccc1Nc(nc(Nc(c(OC)c1)ccc1NC(CN(CCN)CC=O)=O)nc1)c1Cl)(=O)=O JQJSHKYQUXKUDC-UHFFFAOYSA-N 0.000 description 1
- ONUCCCHQLMIEHM-UHFFFAOYSA-N CC(C)S(c1ccccc1Nc(nc(Nc(cc1)ccc1NC(CN(CC1)CCC1N(C)C)=O)nc1)c1Cl)(=O)=O Chemical compound CC(C)S(c1ccccc1Nc(nc(Nc(cc1)ccc1NC(CN(CC1)CCC1N(C)C)=O)nc1)c1Cl)(=O)=O ONUCCCHQLMIEHM-UHFFFAOYSA-N 0.000 description 1
- QERRTOYCKHBUTP-UHFFFAOYSA-N CC(C)S(c1ccccc1Nc(nc(Nc1cccc(N)c1)nc1)c1Cl)(=O)=O Chemical compound CC(C)S(c1ccccc1Nc(nc(Nc1cccc(N)c1)nc1)c1Cl)(=O)=O QERRTOYCKHBUTP-UHFFFAOYSA-N 0.000 description 1
- KXDJHQMSFPWPDI-UHFFFAOYSA-N CC(C)S(c1ccccc1Nc(nc(Nc1cccc(NC(CCl)=O)c1)nc1)c1Cl)(=O)=O Chemical compound CC(C)S(c1ccccc1Nc(nc(Nc1cccc(NC(CCl)=O)c1)nc1)c1Cl)(=O)=O KXDJHQMSFPWPDI-UHFFFAOYSA-N 0.000 description 1
- ARKDKEOEHQTMBM-UHFFFAOYSA-N CC(C)S(c1ncccc1Nc(nc(Nc(cc(cc1)NC(CN2CCOCC2)=O)c1Cl)nc1)c1Cl)(=O)=O Chemical compound CC(C)S(c1ncccc1Nc(nc(Nc(cc(cc1)NC(CN2CCOCC2)=O)c1Cl)nc1)c1Cl)(=O)=O ARKDKEOEHQTMBM-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
-
- 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
-
- 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
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a pyrimidine derivative used as an ALK inhibitor. The pyrimidine derivative is a compound as shown in a formula I which is described in the specification or a pharmaceutical salt, hydrate, solvate, metabolite or prodrug thereof. R1, R2, R3 and R4 in the formula are as defined in the specification. The compound and a pharmaceutical composition thereof can be used as the ALK inhibitor and for preparation of an antineoplastic therapeutic capable of inhibiting ALK.
Description
Technical field
The invention belongs to medical art, relate to compounds, prepare the method for this compound and pharmaceutical composition and purposes, concrete, the present invention relates to the novel poyrimidine derivatives as ALK inhibitor, and the purposes of these compounds in the medicine for the preparation for the treatment of and preventing cancer.
Background technology
Nonsmall-cell lung cancer (Non-small-cell carcinoma, NSCLC) and " non-small cell carcinoma " synonym.Non-small cell type lung cancer, comprises squama cancer, gland cancer, large cell carcinoma, and the division of its growth of cancer cells is comparatively slow compared with small cell carcinoma, and diffusion transfer is relatively late.Nonsmall-cell lung cancer accounts for the 80-85% of lung cancer sum.Data presentation, current China lung cancer morbidity rate increases by 26.9% every year, and between 2000 to 2005, the number of the infected of lung cancer in China estimates increase by 120,000 people.Wherein, male lung cancer patient is increased to 330,000 people of 2005 from 260,000 people of 2000, and the same period, female lung cancer patient was increased to 170,000 people from 120,000 people.In addition, lung cancer also becomes " first of many cancers " in many areas, the whole nation.Beijing's lung cancer morbidity rate increases by 56% from calendar year 2001 to 2010 year.During the decade, 1/5th be patients with lung cancer in Beijing new cancer patient; In the Zhejiang Province in 2011 " cancer spectrum " that Zhejiang Prov. Tumor Hospital issues, lung cancer is still the cancer ranked the first; In Guangzhou Area is compared with before 30 years, and lung cancer morbidity rate increases 7 times.
Along with molecular medicine progress and the continuing to bring out of targeted drug, the treatment of advanced NSCLC has entered into the epoch of individualized treatment.The individuation targeted therapy of current clinical application is mainly for EGFR saltant type and ALK (Anaplastic lymphoma kinase, Nucleophosmin-anaplastic lymphoma kinase) fusion gene type lung cancer, these two kinds of genovariation type lung cancer all have the targeted drug of clear and definite molecular target, target spot detection technique and listing, and clinical efficacy is improved significantly.In lung cancer, ALK variation is mainly ALK gene generation rearrangement and other gene fusion.It is reported that the gene unconventionality on ALK gene site is relevant with kinds cancer.Echinoderms microtubule related protein sample 4 (the EML4)-ALK fusion caused due to chromosome rearrangement has been reported in nonsmall-cell lung cancer (NSCLC) patient group.
Although people have studied a large amount of compounds protein kinase being had to inhibit activities, and some kinases inhibitors have gone on the market for the treatment of NSCLC as gram azoles for Buddhist nun etc., can produce resistance, there is defect to a certain degree.Treat effective patient as gram azoles for Buddhist nun and usually resistance will occur in medication after 6 months to 1 year.And, two grams of azoles for Buddhist nun's clinical research observation to modal untoward reaction be visual disorder, feel sick, diarrhoea, vomiting, oedema and constipation, adverse reaction rate >=25%.Thus, the new A LK inhibitor medicaments developing safer, efficient Therapeutic cancer has huge social value and economic benefit, is also the study hotspot of current each large medicine enterprise.
Therefore, current ALK inhibitor still haves much room for improvement.
Summary of the invention
The present invention one of is intended to solve the problems of the technologies described above at least to a certain extent or at least provides a kind of useful business to select.For this reason, one object of the present invention is to propose a kind of compound that can be used in preparing the medicine of Therapeutic cancer.
According to an aspect of the present invention, the present invention proposes a kind of compound.According to embodiments of the invention, the pharmacologically acceptable salt that described compound is compound shown in compound shown in formula I or formula I, hydrate, solvate, meta-bolites or prodrug,
Wherein,
R
1for hydrogen, halogen, C
1-6alkyl or C
1-6alkoxyl group;
R
2for 5-6 unit cycloalkyl, 5-6 unit heterocyclic radical, 5-6 unit's aryl or 5-6 unit heteroaryl, according to embodiments of the invention, described 5-6 unit cycloalkyl, 5-6 unit heterocyclic radical, 5-6 unit's aryl and 5-6 unit heteroaryl are selected from halogen, hydroxyl, cyano group, nitro, C by one or more independently of one another
1-8alkyl, C
2-8alkenyl, C
2-8alkynyl group, C
3-8cycloalkyl, 3-8 unit heterocyclic radical, C
5-10aryl, 5-10 unit heteroaryl, C
1- 6alkoxyl group, C
3-8cycloalkyloxy ,-S (O) pR
5,-C (O) R
5,-C (O) OR
5,-NR
6r
7or-C (O) NR
7substituting group replace, wherein, R
5, R
6, R
7be hydrogen or C independently of one another
l-4alkyl, p is 0,1 or 2;
R
3for being selected from the optional piperazinyl, optional piperidyl, optional morpholinyl, optional thio-morpholinyl or the optional amino replaced replaced replaced that replace;
R
4for being selected from hydrogen, halogen, C
1-6alkyl or C
1-6alkoxyl group.
According to embodiments of the invention, R
2one of following for being selected from:
According to embodiments of the invention, R
3one of following for being selected from:
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, described chemical bond is the point that part or substituting group are connected with core texture or skeleton structure.In addition, in the structural formula of the application,
for the substituting group position described on phenyl ring be in structural formula with two adjacent positions of substituting group chemical bond, the position of the annulus mark namely in this chemical formula
Thus, this specification sheets in the whole text in, those skilled in the art can to R described in compound shown in formula I
1~ R
7group and substituting group and p select, to provide compound or pharmaceutically acceptable salt thereof, hydrate, solvate, meta-bolites or prodrug shown in described in embodiments of the invention, stable formula I.
According to embodiments of the invention, compound shown in formula I of the present invention can for being selected from following at least one:
Term used in the present invention, the non-toxic salt of the routine that " pharmacologically acceptable salt " is formed for compound shown in general formula I and mineral acid or organic acid reaction.Such as, the non-toxic salt of described routine obtains by compound shown in general formula I and mineral acid or organic acid reaction.Wherein, mineral acid can be hydrochloric acid, Hydrogen bromide, sulfuric acid, nitric acid, amidosulfonic acid and phosphoric acid etc., and organic acid can for comprising citric acid, tartrate, lactic acid, pyruvic acid, acetic acid, Phenylsulfonic acid, tosic acid, methylsulfonic acid, naphthene sulfonic acid, ethyl sulfonic acid, naphthalene disulfonic acid, toxilic acid, oxysuccinic acid, propanedioic acid, fumaric acid, succsinic acid, propionic acid, oxalic acid, trifluoroacetic acid, stearic acid, flutterring acid, hydroxymaleic acid, toluylic acid, phenylformic acid, Whitfield's ointment, L-glutamic acid, xitix, para-anilinesulfonic acid, Aspirin and isethionic acid etc.Or sodium salt, sylvite, calcium salt, aluminium salt or ammonium salt that " pharmacologically acceptable salt " of compound shown in general formula I is formed with mineral alkali after also can passing through to make compound shown in formula I and propionic acid, oxalic acid, propanedioic acid, succsinic acid, fumaric acid, toxilic acid, lactic acid, oxysuccinic acid, tartrate, citric acid, aspartic acid or L-glutamic acid form ester in advance again.Or methylamine salt, ethylamine salt or ethanolamine salt that compound shown in general formula I and organic bases are formed.Or compound shown in general formula I and Methionin, arginine, ornithine form the corresponding inorganic acid salt formed with hydrochloric acid, Hydrogen bromide, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid again after ester or the corresponding organic acid salt formed with formic acid, acetic acid, picric acid, methylsulfonic acid and ethyl sulfonic acid.
Term used in the present invention, " prodrug " represents once give experimenter by described compound, and described compound just carries out chemical conversion by metabolic process or chemical process, thus obtains compound shown in formula I and/or its salt and/or solvate.Any compound that can transform to provide biologically active substance (i.e. compound shown in formula I) is in vivo the prodrug in the scope and spirit of the present invention.Such as, the compound containing carboxyl can hydrolyzable ester on physiology, and it is by being hydrolyzed obtain compound shown in formula I itself and serve as prodrug in vivo.The administration of described prodrug preferred oral, occurs under the impact of digestive ferment this is because hydrolysis is main in many cases.When ester itself has activity or hydrolysis occurs in blood, administered parenterally can be used.
Should also be understood that the hydrate of compound shown in formula I, solvate (such as methylate, ethylate, DMSO compound) also within the scope of the invention.The method of solvation is well known in the art.
According to a second aspect of the invention, the present invention proposes a kind of intermediate, according to a particular embodiment of the invention, described intermediate has the compound shown in formula 5, shown in this formula 5, compound is the intermediate preparing compound shown in formula I, utilize compound shown in formula 5, can be used for being prepared into compound shown in formula I.
Wherein, R
1for hydrogen, halogen, C
1-6alkyl or C
1-6alkoxyl group;
R
2for 5-6 unit cycloalkyl, 5-6 unit heterocyclic radical, 5-6 unit's aryl or 5-6 unit heteroaryl, optionally, described 5-6 unit cycloalkyl, 5-6 unit heterocyclic radical, 5-6 unit's aryl and 5-6 unit heteroaryl are selected from halogen, hydroxyl, cyano group, nitro, C by one or more independently of one another
1-8alkyl, C
2-8alkenyl, C
2-8alkynyl group, C
3-8cycloalkyl, 3-8 unit heterocyclic radical, C
5-10aryl, 5-10 unit heteroaryl, C
1-6alkoxyl group, C
3-8cycloalkyloxy ,-S (O) pR
5,-C (O) R
5,-C (O) OR
5,-NR
6r
7or-C (O) NR
7substituting group replace, wherein, R
5, R
6, R
7be hydrogen or C independently of one another
l-4alkyl, p is 0,1 or 2;
R
4for being selected from hydrogen, halogen, C
1-6alkyl or C
1-6alkoxyl group;
Preferably, R
2one of following for being selected from:
According to a third aspect of the invention we, the present invention proposes a kind of intermediate, according to a particular embodiment of the invention, described intermediate has the compound shown in formula 6, shown in this formula 6, compound is the intermediate preparing compound shown in formula I, utilize compound shown in formula 6, can be used for being prepared into compound shown in formula I.
Wherein, R
1for hydrogen, halogen, C
1-6alkyl or C
1-6alkoxyl group;
R
2for 5-6 unit cycloalkyl, 5-6 unit heterocyclic radical, 5-6 unit's aryl or 5-6 unit heteroaryl, optionally, described 5-6 unit cycloalkyl, 5-6 unit heterocyclic radical, 5-6 unit's aryl and 5-6 unit heteroaryl are selected from halogen, hydroxyl, cyano group, nitro, C by one or more independently of one another
1-8alkyl, C
2-8alkenyl, C
2-8alkynyl group, C
3-8cycloalkyl, 3-8 unit heterocyclic radical, C
5-10aryl, 5-10 unit heteroaryl, C
1-6alkoxyl group, C
3-8cycloalkyloxy ,-S (O) pR
5,-C (O) R
5,-C (O) OR
5,-NR
6r
7or-C (O) NR
7substituting group replace, wherein, R
5, R
6, R
7be hydrogen or C independently of one another
l-4alkyl, p is 0,1 or 2;
R
4for being selected from hydrogen, halogen, C
1-6alkyl or C
1-6alkoxyl group;
Preferably, R
2one of following for being selected from:
According to a forth aspect of the invention, the present invention proposes a kind of intermediate, according to a particular embodiment of the invention, described intermediate has the compound shown in formula 8, shown in this formula 8, compound is the intermediate preparing compound shown in formula I, utilize compound shown in formula 8, can be used for being prepared into compound shown in formula I.
Wherein, R
1for hydrogen, halogen, C
1-6alkyl or C
1-6alkoxyl group;
R
2for 5-6 unit cycloalkyl, 5-6 unit heterocyclic radical, 5-6 unit's aryl or 5-6 unit heteroaryl, optionally, described 5-6 unit cycloalkyl, 5-6 unit heterocyclic radical, 5-6 unit's aryl and 5-6 unit heteroaryl are selected from halogen, hydroxyl, cyano group, nitro, C by one or more independently of one another
1-8alkyl, C
2-8alkenyl, C
2-8alkynyl group, C
3-8cycloalkyl, 3-8 unit heterocyclic radical, C
5-10aryl, 5-10 unit heteroaryl, C
1-6alkoxyl group, C
3-8cycloalkyloxy ,-S (O) pR
5,-C (O) R
5,-C (O) OR
5,-NR
6r
7or-C (O) NR
7substituting group replace, wherein, R
5, R
6, R
7be hydrogen or C independently of one another
l-4alkyl, p is 0,1 or 2;
R
4for being selected from hydrogen, halogen, C
1-6alkyl or C
1-6alkoxyl group;
Preferably, R
2one of following for being selected from:
According to a particular embodiment of the invention, wherein, the R in the compound shown in formula 5, the compound shown in formula 6, the compound shown in formula 8
1, R
2, and R
4for what define in description above.
According to a fifth aspect of the invention, the present invention proposes the method for compound shown in a kind of preparation formula Ι.According to embodiments of the invention, the method for compound shown in preparation formula Ι comprises:
(1) compound shown in compound with formula 2 shown in described formula 1 is made to contact, to obtain compound shown in formula 3;
(2) compound shown in compound with formula 4 shown in described formula 3 is made to contact, to obtain compound shown in formula 5;
(3) compound generation hydrogenation reaction shown in described formula 5 is made, to obtain compound shown in formula 6;
(4) compound shown in compound with formula 7 shown in described formula 6 is made to contact, to obtain compound shown in formula 8; And
(5) compound shown in compound with formula 9 shown in described formula 8 is made to contact, to obtain compound shown in formula I,
According to embodiments of the invention, in the compound of compound shown in above-mentioned formula 1-9 and formula I, R
1for hydrogen, halogen, C
1-6alkyl or C
1-6alkoxyl group; R
2for 5-6 unit cycloalkyl, 5-6 unit heterocyclic radical, 5-6 unit's aryl or 5-6 unit heteroaryl, according to concrete example of the present invention, state 5-6 unit cycloalkyl, 5-6 unit heterocyclic radical, 5-6 unit's aryl and 5-6 unit heteroaryl and be selected from halogen, hydroxyl, cyano group, nitro, C by one or more independently of one another
1-8alkyl, C
2-8alkenyl, C
2-8alkynyl group, C
3-8cycloalkyl, 3-8 unit heterocyclic radical, C
5-10aryl, 5-10 unit heteroaryl, C
1-6alkoxyl group, C
3-8cycloalkyloxy ,-S (O) pR
5,-C (O) R
5,-C (O) OR
5,-NR
6r
7or-C (O) NR
7substituting group replace, wherein, R
5, R
6, R
7be hydrogen or C independently of one another
l-4alkyl, p is 0,1 or 2; R
3for being selected from the optional piperazinyl, optional piperidyl, optional morpholinyl, optional thio-morpholinyl or the optional amino replaced replaced replaced that replace; R
4for being selected from hydrogen, halogen, C
1-6alkyl or C
1-6alkoxyl group.
According to a particular embodiment of the invention, R
2can be preferably one of following:
According to a particular embodiment of the invention, R
3can be preferably one of following:
Contriver finds, utilize the method for the above embodiment of the present invention can fast and effeciently compound shown in preparation formula I, and synthetic route is short, the yield of environmental friendliness, target product and purity higher, raw material is easy to get, operate and aftertreatment is simple, be applicable to suitability for industrialized production.In one embodiment of the invention, the synthetic route of compound shown in formula I is:
Below the general method of compound shown in preparation formula I adopted in an embodiment of the present invention is described:
Step (1): the preparation of compound shown in formula 3 (intermediate)
According to a particular embodiment of the invention, in step (1), in the first organic solvent, when there is NaH, compound shown in compound with described formula 2 shown in described formula 1 is contacted.According to concrete example of the present invention, the first organic solvent can for being selected from least one in N-Methyl pyrrolidone, DMF, dimethyl sulfoxide (DMSO), N,N-DIMETHYLACETAMIDE, N,N-dimethylacetamide.Preferred DMF.Good reaction environment can be provided for compound shown in compound and formula 2 shown in formula 1 thus, and then improve the yield of compound shown in formula 3.
According to concrete example of the present invention, in step (1), 0 degree Celsius time, compound shown in compound with described formula 2 shown in described formula 1 is contacted.By selecting the temperature of reaction be suitable for, the yield of compound shown in preparation formula 3 can be improved further.According to another concrete example of the present invention, in step (1), the mol ratio of compound shown in compound and formula 2 shown in formula 1 can be (25-30): (15-30).According to a preferred embodiment of the invention, the mol ratio of compound shown in compound and formula 2 shown in formula 1 can be (27-28): (20-26).And then while compound productive rate shown in formula 3 can be improved, conservation cost.
According to a specific embodiment of the present invention, the preparation of compound shown in formula 3 (intermediate), specifically can carry out according to the following step: compound shown in formula 2 is dissolved in DMF, at 0 DEG C, add NaH in batches, add rear reaction solution and continue to stir half an hour at 0 DEG C, then by 2,5,6-trichloropyrimidine (shown in formula 1 compound) instills reaction solution at 0 DEG C, after dropwising, mixture is risen to room temperature for overnight naturally.Drip frozen water cancellation after completion of the reaction, and be extracted with ethyl acetate, merge organic phase, after saturated common salt washes three times, dry, concentrating under reduced pressure, gained crude product obtains product through column chromatography, is compound shown in formula 3.
Step (2): the preparation of compound shown in formula 5 (intermediate)
According to a particular embodiment of the invention, in step (2), shown in described formula 3, shown in compound with described formula 4, compound contacts in propyl carbinol, containing tosic acid in described propyl carbinol.
According to a particular embodiment of the invention, in step (2), 80 degrees Celsius time, compound shown in compound with described formula 4 shown in described formula 3 is made to contact 6 hours, while can reaction efficiency being improved thus, make the two fully reaction, and then the productive rate of compound shown in final raising formula 5.According to a particular embodiment of the invention, in step (2), the mol ratio shown in described formula 3 shown in compound, described formula 4 between compound and tosic acid is (4-6): (5-7): (5-7).According to a particular embodiment of the invention, (5-6) is preferably: (5.5-6.5): (5.5-6.5).And then while compound productive rate shown in formula 5 can be improved, conservation cost.
According to a specific embodiment of the present invention, the preparation of compound shown in formula 5 (intermediate), specifically can carry out according to the following step: compound shown in formula 3 is dissolved in propyl carbinol, add compound and tosic acid shown in formula 4 wherein, by mixture at 80 DEG C of temperature, stirring reaction 6 hours.After TLC detection reaction, pressure reducing and steaming solvent, is scattered in ethyl acetate by residual solids thing, use saturated sodium bicarbonate aqueous solution according to this, water and saturated common salt water washing, with anhydrous sodium sulfate drying, concentrating under reduced pressure obtains thick product, obtains product through column chromatography for separation, is compound shown in formula 5.
Step (3): the preparation of compound shown in formula 6 (intermediate)
According to a particular embodiment of the invention, in step (3), described hydrogenation reaction adopts palladium/carbon as catalyzer, carries out in hydrogen atmosphere.According to a particular embodiment of the invention, containing the palladium of 5% in described palladium/charcoal, the reaction potential energy of the two can effectively be reduced thus, the reaction efficiency of both raisings.According to a particular embodiment of the invention, described hydrogen atmosphere 1 standard atmospheric pressure being.Hydrogenation reaction efficiency can be improved further thus, and then improve compound productive rate shown in formula 6.According to a particular embodiment of the invention, in step (3), shown in described formula 5, the proportioning of compound and palladium/carbon is (0.5-1mmol): (35-55mg), be preferably (0.7-0.9mmol): (40-50mg), while compound productive rate shown in formula 6 can being improved thus, conservation cost.
According to a specific embodiment of the present invention, the preparation of compound shown in formula 6 (intermediate), specifically can carry out according to the following step: compound shown in formula 5 is placed in hydrogenation bottle, add methyl alcohol, after nitrogen replacement, palladium/charcoal (Pd content 5%) is joined in bottle, after hydrogen balloon displacement, stirring reaction under hydrogen (1atm) condition, TLC monitoring is after completion of the reaction by reacting liquid filtering, and filtrate reduced in volume is done and obtained product, is compound shown in formula 6.
Step (4): the preparation of compound shown in formula 8 (intermediate)
According to a particular embodiment of the invention, in step (4), compound shown in compound with formula 7 shown in formula 6 is contacted, to obtain compound shown in formula 8, carries out through the following steps:
(4-1) the first dichloromethane solution containing compound shown in described formula 6 and triethylamine is provided, and the second dichloromethane solution containing compound described in described formula 7;
(4-2) the first dichloromethane solution is mixed with described second dichloromethane solution.
Adopt above-mentioned preparation method can effectively prepare compound shown in formula 8, the productive rate of compound shown in formula 8 can be improved simultaneously to greatest extent.
According to a particular embodiment of the invention, mixing is undertaken by being added drop-wise in described first dichloromethane solution by described second dichloromethane solution, and then can improve the reaction efficiency of compound shown in compound and formula 7 shown in formula 6 further.According to a particular embodiment of the invention, in step (4), described dropping is carried out under ice-water bath cooling conditions, and described duration of contact is 2-5 hour, effectively can improve the reaction efficiency of the two thus, improves the productive rate of compound shown in formula 8.According to a particular embodiment of the invention, in step (4), shown in described formula 6, shown in compound and described formula 7, the mol ratio of compound is (0.5-1): (1-2), is preferably (0.7-0.75): (1-1.2).While compound productive rate shown in formula 8 can being improved thus, conservation cost.
According to a specific embodiment of the present invention, the preparation of compound shown in formula 8 (intermediate), specifically can carry out according to the following step: compound shown in formula 6 is dissolved in methylene dichloride, triethylamine is added in solution, stir, under ice-water bath cooling conditions, drip the dichloromethane solution of compound shown in formula 7.Reaction mixture is at room temperature stirred 2 hours, use saturated aqueous sodium carbonate cancellation, dichloromethane extraction, merge organic phase, through saturated common salt washing, anhydrous magnesium sulfate drying, filter, pressure reducing and steaming organic solvent obtains the thick product of compound shown in formula 8, and the thick product of gained, without the need to purifying, is directly used in the next step.
Step (5): the preparation of compound shown in formula I
According to a particular embodiment of the invention, in step (5), compound shown in compound with formula 9 shown in described formula 8 is contacted, to obtain compound shown in formula I, carries out through the following steps:
Acetonitrile solution containing compound shown in described formula 8, triethylamine is provided,
Compound shown in described formula 9 is added, to make compound shown in compound with formula 9 shown in described formula 8 contact in described acetonitrile solution.Thus by adopting aforesaid method can effectively prepare compound shown in formula I.
According to a particular embodiment of the invention, in step (5), described contact carries out 3-5 hour under heated reflux condition.The two can be made thus fully to be reacted, and then improve the productive rate of compound shown in formula I.
According to a particular embodiment of the invention, in step (5), shown in described formula 8, shown in compound and described formula 9, the mol ratio of compound is (0.5-1.5): (1.5-2.5), is preferably (0.8-1.2): (1.8-2.2).According to a particular embodiment of the invention, in step (5), shown in described formula 8, the mol ratio of compound and triethylamine is (0.1-0.5): (0.5-1.5):, be preferably (0.2-0.25): (1-1.1).While the productive rate of compound shown in formula I can be improved thus, conservation cost.
According to a particular embodiment of the invention, the preparation of compound shown in formula I, specifically can carry out according to the following step: the thick product of compound shown in formula 8 is dissolved in acetonitrile, and add triethylamine successively wherein, compound shown in formula 9 is dripped under stirring at room temperature, reflux, reaction is finished, pressure reducing and steaming solvent, residue diluted with water, dichloromethane extraction, merges organic phase, washes through saturated common salt, anhydrous magnesium sulfate drying, filter, pressure reducing and steaming organic solvent obtains the thick product of compound shown in formula I, obtains the product of compound shown in formula I through column chromatography for separation.
According to a sixth aspect of the invention, the present invention proposes a kind of pharmaceutical composition.According to a particular embodiment of the invention, this pharmaceutical composition contains foregoing compound.According to concrete example of the present invention, pharmaceutical composition comprises pharmaceutically acceptable carrier, vehicle, thinner, assistant agent, vehicle or its combination further.
According to a particular embodiment of the invention, pharmaceutical composition is tablet, capsule, injection, powder injection, pulvis, syrup, solution shape, suspension or aerosol.The suitability of this pharmaceutical composition can be significantly improved thus.And the pharmaceutical composition of the above embodiment of the present invention may reside in in the carrier of suitable solid or liquid or diluent and the suitable disinfector for injecting or instil.
The various formulations of pharmaceutical composition of the present invention can be prepared according to the customary preparation methods of pharmaceutical field.Compound of the present invention and pharmaceutical composition to Mammals Clinical practice, can comprise humans and animals, can pass through the administration of mouth, nose, skin, lung or gi tract etc.No matter adopt which kind of instructions of taking, the optimal dose of individual should be determined according to concrete treatment plan.Increase dosage until find optimal dosage gradually under normal circumstances from low dose.Most preferred route of administration is oral.
According to a seventh aspect of the invention, the present invention proposes foregoing compound, compound that foregoing method prepares or foregoing pharmaceutical composition preparing the purposes in medicine.
According to a particular embodiment of the invention, described medicine be used for following one of at least: as kinase inhibitor, suppress the propagation of ALK kinase activity, treatment or preventing cancer and anticancer.According to concrete example of the present invention, the present invention is to the ALK kinase inhibiting activity determination experiment result display in vitro of described compound, compound shown in formula I of the present invention all has good ALK kinase inhibiting activity, compound of the present invention can be used as ALK inhibitor, for the preparation of the antineoplaston medicine becoming to suppress Nucleophosmin-anaplastic lymphoma kinase.
Therefore, medicine of the present invention can effectively as ALK inhibitor, and be used for the treatment of one or more relevant tumor diseases active in ALK, described tumor disease includes but not limited to lung cancer.Pyrimidine derivatives as ALK inhibitor of the present invention (shown in formula I compound), it has good clinical application and medicinal use as ALK inhibitor.
Additional aspect of the present invention and advantage will part provide in the following description, and part will become obvious from the following description, or be recognized by practice of the present invention.
Embodiment
Embodiments of the invention are described below in detail.Embodiment described below is exemplary, only for explaining the present invention, and can not be interpreted as limitation of the present invention.Unreceipted concrete technology or condition in embodiment, according to the technology described by the document in this area or condition or carry out according to product description.
In specific embodiment described below, compound structure is or/and LC-MS chromatogram (LC-MS) is determined by nucleus magnetic resonance (NMR).Wherein, NMR displacement (δ) provides with the unit of 1,000,000/(ppm), and the mensuration of NMR is that measuring solvent is deuterated dimethyl sulfoxide (DMSO-d with Bruker AVANCE-400 nuclear magnetic resonance spectrometer
6), deuterochloroform (CDCl
3), deuterated methanol (CD3OD), is inside designated as tetramethylsilane (TMS); The mensuration Agilent 1200Infinity Series mass spectrograph of LC-MS chromatogram LC-MS.The mensuration of HPLC uses Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18 150 × 4.6mm chromatographic column)
The monitoring of the reaction process below in embodiment adopts tlc (TLC), the system of reacting the developping agent used has: methylene dichloride and methanol system, normal hexane/sherwood oil and ethyl acetate system, the volume ratio of solvent regulates according to the polarity difference of compound.Tlc silica gel plate uses Yantai Huanghai Sea HSGF254 or Qingdao GF254 silica-gel plate, and the specification that the silica-gel plate that tlc (TLC) uses adopts is 0.15mm ~ 0.2mm, and the specification that thin-layer chromatography separation and purification product adopts is 0.4mm ~ 0.5mm.Column chromatography generally uses Yantai Huanghai Sea silica gel 200 ~ 300 order silica gel to be carrier.
The system of eluent of column chromatography that in embodiment, purifying compounds adopts below and the developping agent system of tlc comprise: A: methylene dichloride and methanol system, B: normal hexane/sherwood oil and ethyl acetate system, the volume ratio of solvent is different and regulate according to the polarity of compound, also can add the alkalescence such as a small amount of triethylamine and acetic acid or acid reagent regulates.
The starting raw material used in embodiment below can adopt or synthesize according to methods known in the art, maybe can buy from ABCRGmbH & Co.KG, Acros Organics, Aldrich Chemical Company, splendid far away chemistry science and technology (Accela ChemBio Inc), reach the companies such as auspicious chemical.
The embodiment provides compound or pharmaceutically acceptable salt thereof shown in formula I, hydrate, solvate, metabolite or prodrug, the method for compound or pharmaceutically acceptable salt thereof shown in preparation formula Ι, hydrate, solvate or prodrug and intermediate, pharmaceutical composition and compound of the present invention and pharmaceutical composition are preparing the purposes in medicine.
Embodiment 1: compound shown in preparation formula 2-1 (intermediate)
By (the 15g of compound shown in formula a, 106.31mmol), salt of wormwood (29.38g, 212.61mmol) be placed in 500mL round-bottomed bottle, add 150 milliliters of DMF, under agitation add isopropyl mercaptan (shown in formula b compound) (8.5g, 111.62mmol), mixture is heated with stirring to 80 DEG C, reacts 5 hours, pressure reducing and steaming reaction solvent after completion of the reaction, gained crude product is through washing, and extraction into ethyl acetate, concentrates after dry, compound shown in formula c (19.5g must be measured, productive rate 95%) is obtained through column chromatography.
By (the 19.5g of compound shown in formula c, 98.86mmol) with metachloroperbenzoic acid (mCPBA, compound shown in formula d) (60.2g, 348.84mmol) be placed in 1000mL round-bottomed bottle, add 500 milliliters of methylene dichloride, mixture is at room temperature stirred and spends the night, with the cancellation of the saturated sodium sulfite aqueous solution, dichloromethane extraction, through unsaturated carbonate potassium solution, saturated common salt is washed, dry, be spin-dried for, then obtain compound shown in formula e (must 20.4g be measured, productive rate 90%) through column chromatography.
By (the 20.4g of compound shown in formula e, 88.98mmol) be placed in 500mL hydrogenation bottle, add 250 ml methanol, after nitrogen replacement, 1000mg palladium charcoal (Pd content 5%) is joined in bottle, after hydrogen balloon displacement, stir and spend the night under hydrogen (1atm) condition, monitoring is after completion of the reaction by reacting liquid filtering, filtrate decompression is spin-dried for and obtains compound shown in formula 2-1 (must measure 15.95g, productive rate 90%).
Embodiment 2: compound shown in preparation formula 2-2 (intermediate)
By (the 14.2g of compound shown in formula f, 0.1mol), salt of wormwood (27.6g, 0.2mol) be placed in 500mL round-bottomed bottle, add 150 milliliters of DMF, under agitation add isopropyl mercaptan (shown in formula b compound) (8.0g, 0.105mol), mixture is heated with stirring to 75 DEG C, reacts 6 hours, pressure reducing and steaming reaction solvent after completion of the reaction, gained crude product is through washing, and extraction into ethyl acetate, concentrates after dry, compound shown in formula g (17.9g must be measured, productive rate 92.5%) is obtained through column chromatography.
By (the 19.8g of compound shown in formula g, 0.1mol) with metachloroperbenzoic acid (mCPBA, compound shown in formula d) (60.9g, 0.35mol) be placed in 1000mL round-bottomed bottle, add 500 milliliters of methylene dichloride, mixture is at room temperature stirred and spends the night, use saturated sodium bisulfite solution cancellation, dichloromethane extraction, through unsaturated carbonate potassium solution, saturated common salt is washed, dry, be spin-dried for, then obtain compound shown in formula h (must 21.1g be measured, productive rate 92%) through column chromatography.
By (the 23.0g of compound shown in formula h, 0.1mol) be placed in 500mL hydrogenation bottle, add 250 ml methanol, after nitrogen replacement, 1000mg palladium charcoal (Pd content 5%) is joined in bottle, after hydrogen balloon displacement, stir and spend the night under hydrogen (1atm) condition, monitoring is after completion of the reaction by reacting liquid filtering, filtrate decompression is spin-dried for and obtains compound shown in formula 2-2 (must measure 18.6g, productive rate 93.5%).
Embodiment 3: compound shown in preparation formula 2-2 (intermediate)
By (the 15.9g of compound shown in formula j, 0.1mmol), salt of wormwood (27.6g, 0.2mmol) be placed in 500mL round-bottomed bottle, add 150 milliliters of DMF, under agitation add isopropyl mercaptan (shown in formula b compound) (8.0g, 0.105mol), mixture is heated with stirring to 80 DEG C, reacts 5 hours, pressure reducing and steaming reaction solvent after completion of the reaction, gained crude product is through washing, and extraction into ethyl acetate, concentrates after dry, compound shown in formula g (18.1g must be measured, productive rate 93%) is obtained through column chromatography.
By (the 19.8g of compound shown in formula g, 0.1mol) with metachloroperbenzoic acid (mCPBA, compound shown in formula d) (48.7g, 0.28mol) be placed in 1000mL round-bottomed bottle, add 500 milliliters of methylene dichloride, mixture is at room temperature stirred and spends the night, use saturated sodium bisulfite solution cancellation, dichloromethane extraction, through unsaturated carbonate potassium solution, saturated common salt is washed, dry, be spin-dried for, then obtain compound shown in formula h (must 21.5g be measured, productive rate 93.5%) through column chromatography.
By (the 23.0g of compound shown in formula h, 0.1mol) be placed in 500mL hydrogenation bottle, add 250 ml methanol, after nitrogen replacement, 1000mg palladium charcoal (Pd content 5%) is joined in bottle, after hydrogen balloon displacement, stir and spend the night under hydrogen (1.5atm) condition, monitoring is after completion of the reaction by reacting liquid filtering, filtrate decompression is spin-dried for and obtains compound shown in formula 2-2 (must measure 18.4g, productive rate 92%).
Embodiment 4: compound shown in preparation formula 2-3 (intermediate)
By (the 16.4g of compound shown in formula k, 0.1mol), salt of wormwood (27.6g, 0.2mol) be placed in 500mL round-bottomed bottle, add 150 milliliters of DMF, under agitation add isopropyl mercaptan (shown in formula b compound) (8.0g, 0.105mol), mixture is heated with stirring to 75 DEG C, reacts 6 hours, pressure reducing and steaming reaction solvent after completion of the reaction, gained crude product is through washing, and extraction into ethyl acetate, concentrates after dry, compound shown in formula m (18.3g must be measured, productive rate 92%) is obtained through column chromatography.
By (the 20.3g of compound shown in formula m, 0.1mol) with metachloroperbenzoic acid (mCPBA, compound shown in formula d) (60.9g, 0.35mol) be placed in 1000mL round-bottomed bottle, add 500 milliliters of methylene dichloride, mixture is at room temperature stirred and spends the night, use saturated sodium bisulfite solution cancellation, dichloromethane extraction, through unsaturated carbonate potassium solution, saturated common salt is washed, dry, be spin-dried for, then obtain compound shown in formula n (must 21.7g be measured, productive rate 92.5%) through column chromatography.
By (the 23.5g of compound shown in formula n, 0.1mol) be placed in 500mL hydrogenation bottle, add 250 ml methanol, after nitrogen replacement, 1000mg palladium charcoal (Pd content 5%) is joined in bottle, after hydrogen balloon displacement, stir and spend the night under hydrogen (1atm) condition, monitoring is after completion of the reaction by reacting liquid filtering, filtrate decompression is spin-dried for and obtains compound shown in formula 2-3 (must measure 18.9g, productive rate 92%).
Embodiment 5: compound shown in preparation formula 6-1
By (the 5g of compound shown in formula 2-1,25.09mmol) be dissolved in DMF (100mL), at 0 DEG C, slowly add NaH (1.1g, 27.6mmol), add rear reaction solution and continue to stir half an hour at 0 DEG C, again by 2,5,6-trichloropyrimidine (shown in formula 1 compound) (5.06g, 27.6mmol) instills reaction solution at 0 DEG C, after dropwising, mixture is risen to room temperature for overnight naturally.Add the cancellation of 300mL frozen water after completion of the reaction, and be extracted with ethyl acetate (200mL × 3), merge organic phase, after saturated common salt washes three times, dry, concentrating under reduced pressure, gained crude product obtains compound shown in formula 3-1 (must measure 2.26g, productive rate 26%) through column chromatography.
By (the 2g of compound shown in formula 3-1,5.77mmol) be dissolved in 60mL propyl carbinol, add 3-N-methyl-p-nitroaniline (shown in formula 4-1 compound) (798mg wherein, 5.77mmol) with tosic acid (993mg, 5.77mmol), by mixture at 80 DEG C of temperature, stirring reaction 6 hours.After TLC detection reaction, pressure reducing and steaming solvent, residual solids thing is scattered in 200mL ethyl acetate, use saturated sodium bicarbonate aqueous solution successively, water and saturated common salt water washing, with anhydrous sodium sulfate drying, concentrating under reduced pressure obtains thick product, compound shown in formula 5-1 (1.24g must be measured, productive rate 48%) is obtained through column chromatography for separation.
By (the 400mg of compound shown in formula 5-1,0.893mmol) be placed in 100mL hydrogenation bottle, add 50 ml methanol, after nitrogen replacement, 40mg palladium charcoal (Pd content 5%) is joined in bottle, after hydrogen balloon displacement, stir and spend the night under hydrogen (1atm) condition, TLC monitoring is after completion of the reaction by reacting liquid filtering, compound shown in formula 6-1 (must measure 316mg, productive rate 85%) is done and obtained to filtrate reduced in volume.
Embodiment 6: compound shown in preparation formula 6-2
By (the 2g of compound shown in formula 3-1,5.77mmol) be dissolved in 60mL Virahol, add (the 798mg of compound shown in formula 4-2 wherein, 5.77mmol) with tosic acid (993mg, 5.77mmol), by mixture at 70 DEG C of temperature, stirring reaction 6 hours.After TLC detection reaction, pressure reducing and steaming solvent, residual solids thing is scattered in 200mL ethyl acetate, use saturated sodium bicarbonate aqueous solution successively, water and saturated common salt water washing, with anhydrous sodium sulfate drying, concentrating under reduced pressure obtains thick product, compound shown in formula 5-2 (0.84g must be measured, productive rate 32.5%) is obtained through column chromatography for separation.
By (the 400mg of compound shown in formula 5-2,0.893mmol) be placed in 100mL hydrogenation bottle, add 50 ml methanol, after nitrogen replacement, 40mg palladium charcoal (Pd content 5%) is joined in bottle, after hydrogen balloon displacement, stir and spend the night under hydrogen (1atm) condition, TLC monitoring is after completion of the reaction by reacting liquid filtering, compound shown in formula 6-2 (must measure 279mg, productive rate 75%) is done and obtained to filtrate reduced in volume.
Embodiment 7: compound shown in preparation formula 6-3
By (the 2g of compound shown in formula 3-1,5.77mmol) be dissolved in 60mL propyl carbinol, add (the 1019mg of compound shown in formula 4-3 wherein, 6.06mmol) with tosic acid (1043mg, 6.06mmol), by mixture at 80 DEG C of temperature, stirring reaction 6 hours.After TLC detection reaction, pressure reducing and steaming solvent, residual solids thing is scattered in 200mL ethyl acetate, use saturated sodium bicarbonate aqueous solution successively, water and saturated common salt water washing, with anhydrous sodium sulfate drying, concentrating under reduced pressure obtains thick product, compound shown in formula 5-3 (1544mg must be measured, productive rate 56%) is obtained through column chromatography for separation.
By (the 427mg of compound shown in formula 5-3,0.893mmol) be placed in 100mL hydrogenation bottle, add 50 ml methanol, after nitrogen replacement, 50mg palladium charcoal (Pd content 5%) is joined in bottle, after hydrogen balloon displacement, stir and spend the night under hydrogen (1atm) condition, TLC monitoring is after completion of the reaction by reacting liquid filtering, compound shown in formula 6-3 (must measure 376mg, productive rate 80%) is done and obtained to filtrate reduced in volume.
Embodiment 8: compound shown in preparation formula 6-4
The synthetic method of embodiment 8 is with reference to embodiment 7.
LCMS:431(M+H
+).
Embodiment 9: compound shown in preparation formula 6-5
The synthetic method of embodiment 9 is with reference to embodiment 7.
LCMS:451(M+H
+).
Embodiment 10: compound shown in preparation formula 6-6
The synthetic method of embodiment 10 is with reference to embodiment 5.
LCMS:418(M+H
+).
Embodiment 11: compound shown in preparation formula 6-7
The synthetic method of embodiment 11 is with reference to embodiment 6.
LCMS:418(M+H
+).
Embodiment 12: compound shown in preparation formula 6-8
In embodiment 12, the synthetic method of compound shown in formula 2-2 is with reference to embodiment 5.
By (the 2.0g of compound shown in formula 3-2,5.77mmol) be dissolved in 60mL propyl carbinol, add (the 1019mg of compound shown in formula 4-3 wherein, 6.06mmol) with tosic acid (1043mg, 6.06mmol), by mixture at 80 DEG C of temperature, stirring reaction 6 hours.After TLC detection reaction, pressure reducing and steaming solvent, residual solids thing is scattered in 200mL ethyl acetate, use saturated sodium bicarbonate aqueous solution successively, water and saturated common salt water washing, with anhydrous sodium sulfate drying, concentrating under reduced pressure obtains thick product, compound shown in formula 5-8 (1.71g must be measured, productive rate 62%) is obtained through column chromatography for separation.
By (the 428mg of compound shown in formula 5-8,0.893mmol) be placed in 100mL hydrogenation bottle, add 50 ml methanol, after nitrogen replacement, 50mg palladium charcoal (Pd content 5%) is joined in bottle, after hydrogen balloon displacement, stir and spend the night under hydrogen (1.0atm) condition, TLC monitoring is after completion of the reaction by reacting liquid filtering, compound shown in formula 6-8 (must measure 348mg, productive rate 74%) is done and obtained to filtrate reduced in volume.LCMS:418(M+H
+).
Embodiment 13: compound shown in preparation formula 6-9
The synthetic method of embodiment 13 is with reference to embodiment 7.
LCMS:432(M+H
+).
Embodiment 14: compound shown in preparation formula 6-10
The synthetic method of embodiment 14 is with reference to embodiment 7.
LCMS:452(M+H
+).
Embodiment 15: compound shown in preparation formula 6-11
By (the 4.1g of compound shown in formula 2-3,20mmol) be dissolved in DMF (100mL), NaH (1.1g is slowly added at 0 DEG C, 27.6mmol), add rear reaction solution to continue to stir half an hour at 0 DEG C, then compound (5.06g, 27.6mmol) shown in formula 1 is instilled reaction solution at 0 DEG C, after dropwising, mixture is risen to room temperature for overnight naturally.Add 300mL shrend after completion of the reaction to go out, and be extracted with ethyl acetate (200mL × 3), merge organic phase, after saturated common salt washes three times, dry, concentrating under reduced pressure, gained crude product obtains compound shown in formula 3-3 (must measure 3.52g, productive rate 50%) through column chromatography.
By (the 2.03g of compound shown in formula 3-3,5.77mmol) be dissolved in 60mL propyl carbinol, add (the 798mg of compound shown in formula 4-1 wherein, 5.77mmol) with tosic acid (993mg, 5.77mmol), by mixture at 70 DEG C of temperature, stirring reaction 6 hours.After TLC detection reaction, pressure reducing and steaming solvent, residual solids thing is scattered in 200mL ethyl acetate, use saturated sodium bicarbonate aqueous solution according to this, water and saturated common salt water washing, with anhydrous sodium sulfate drying, concentrating under reduced pressure obtains thick product, compound shown in formula 5-11 (2.1g must be measured, productive rate 80%) is obtained through column chromatography for separation.
By (the 363mg of compound shown in formula 5-11,0.8mmol) be placed in 100mL hydrogenation bottle, add 50 ml methanol, after nitrogen replacement, 40mg palladium charcoal (Pd content 5%) is joined in bottle, after hydrogen balloon displacement, stir and spend the night under hydrogen (1atm) condition, monitoring is after completion of the reaction by reacting liquid filtering, compound shown in formula 6-11 (must measure 254mg, productive rate 75%) is done and obtained to filtrate reduced in volume.LCMS:423(M+H
+).
Embodiment 16: compound shown in preparation formula 6-12
By (the 2.03g of compound shown in formula 3-3,5.77mmol) be dissolved in 60mL Virahol, add (the 798mg of compound shown in formula 4-2 wherein, 5.77mmol) with tosic acid (993mg, 5.77mmol), by mixture at 70 DEG C of temperature, stirring reaction 6 hours.After TLC detection reaction, pressure reducing and steaming solvent, residual solids thing is scattered in 200mL ethyl acetate, use saturated sodium bicarbonate aqueous solution according to this, water and saturated common salt water washing, with anhydrous sodium sulfate drying, concentrating under reduced pressure obtains thick product, compound shown in formula 5-12 (1.89g must be measured, productive rate 72%) is obtained through column chromatography for separation.
By (the 363mg of compound shown in formula 5-12,0.8mmol) be placed in 100mL hydrogenation bottle, add 50 ml methanol, after nitrogen replacement, 40mg palladium charcoal (Pd content 5%) is joined in bottle, after hydrogen balloon displacement, stir and spend the night under hydrogen (1atm) condition, monitoring is after completion of the reaction by reacting liquid filtering, compound shown in formula 6-12 (must measure 278mg, productive rate 82%) is done and obtained to filtrate reduced in volume.LCMS:423(M+H
+).
Embodiment 17: compound shown in preparation formula 6-13
The synthetic method of embodiment 17 is with reference to embodiment 7.
LCMS:453(M+H
+).
Embodiment 18: compound shown in preparation formula 6-14
The synthetic method of embodiment 18 is with reference to embodiment 7.
LCMS:437(M+H
+).
Embodiment 19: compound shown in preparation formula 6-15
The synthetic method of embodiment 19 is with reference to embodiment 7.
LCMS:457(M+H
+).
Embodiment 20: compound shown in preparation formula 8-1
By (the 300mg of compound shown in formula 6-1,0.717mmol) be dissolved in dry methylene dichloride (15mL), triethylamine (289.67mg is added in solution, 399uL, 2.868mmol), stir, under ice-water bath cooling conditions, drip methylene dichloride (2mL) solution of 2-chloroacetyl chloride (shown in formula 7-1 compound) (85.1mg, 0.753mmol).Reaction mixture is at room temperature stirred 2 hours, use saturated aqueous sodium carbonate cancellation, dichloromethane extraction (20mL × 3), merge organic phase, through saturated common salt washing, anhydrous magnesium sulfate drying, filter, pressure reducing and steaming organic solvent obtains the thick product 350mg of compound shown in formula 8-a, and the thick product of gained, without the need to purifying, can be directly used in the next step.
Compound shown in embodiment 21 ~ embodiment 43: preparation formula 8-2 ~ formula 8-24
Shown in formula 8-2 ~ formula 8-24, the structural formula of compound sees the following form, and the synthetic method of compound shown in formula 8-2 ~ formula 8-24, all with reference to embodiment 20.
Embodiment 44: compound shown in preparation formula I-11
By (the 100mg of compound shown in formula 8-1, 0.202mmol) be dissolved in dry acetonitrile (3mL), and add triethylamine (102mg successively wherein, 1.01mmol), dicarbapentaborane piperazine (shown in formula 9-1 compound) (40mg is dripped under stirring at room temperature, 0.404mmol), reflux 5 hours, pressure reducing and steaming solvent, residue diluted with water, dichloromethane extraction (20mL × 3), merge organic phase, wash through saturated common salt, anhydrous magnesium sulfate drying, filter, pressure reducing and steaming organic solvent obtains thick product, obtain compound shown in formula I-11 through column chromatography for separation and (must 68.8mg be measured, productive rate 61%).
1H NMR(400MHz,cd
3od)δ8.67(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 preparation formula I-33
By (the 100mg of compound shown in formula 8-11, 0.200mmol) be dissolved in dry acetonitrile (3mL), and add triethylamine (102mg successively wherein, 1.01mmol), (the 19.2mg of compound shown in formula 9-2 is dripped under stirring at room temperature, 0.22mmol), reflux 4.5 hours, pressure reducing and steaming solvent, residue diluted with water, dichloromethane extraction (20mL × 3), merge organic phase, wash through saturated common salt, anhydrous magnesium sulfate drying, filter, pressure reducing and steaming organic solvent obtains thick product, obtain compound shown in formula I-33 through column chromatography for separation and (must 75mg be measured, productive rate 68%).
1H NMR(400MHz,cd
3od)δ8.41(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 preparation formula I-93
By (the 105mg of compound shown in formula 8-5, 0.20mmol) be dissolved in dry acetonitrile (5mL), and add triethylamine (102mg successively wherein, 1.01mmol), (the 29mg of compound shown in formula 9-3 is dripped under stirring at room temperature, 0.40mmol), reflux 4 hours, pressure reducing and steaming solvent, residue diluted with water, dichloromethane extraction (20mL × 3), merge organic phase, wash through saturated common salt, anhydrous magnesium sulfate drying, filter, pressure reducing and steaming organic solvent obtains thick product, obtain compound shown in formula I-93 through column chromatography for separation and (must 60.5mg be measured, productive rate 44%).
Embodiment 47: compound shown in preparation formula I-3
By (the 100mg of compound shown in formula 8-4, 0.202mmol) be dissolved in dry acetonitrile (4mL), and add triethylamine (102mg successively wherein, 1.01mmol), (the 25mg of compound shown in formula 9-4 is dripped under stirring at room temperature, 0.404mmol), reflux 4 hours, pressure reducing and steaming solvent, residue diluted with water, dichloromethane extraction (20mL × 3), merge organic phase, wash through saturated common salt, anhydrous magnesium sulfate drying, filter, pressure reducing and steaming organic solvent obtains thick product, obtain compound shown in formula I-3 through column chromatography for separation and (must 78.8mg be measured, productive rate 75%).
1H NMR(400MHz,cd
3od)δ9.32(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 preparation formula I-100
By (the 105mg of compound shown in formula 8-10, 0.2mmol) be dissolved in acetonitrile (3mL), and add triethylamine (102mg successively wherein, 1.01mmol), (the 40mg of compound shown in formula 9-1 is dripped under stirring at room temperature, 0.404mmol), reflux 3 hours, pressure reducing and steaming solvent, residue diluted with water, dichloromethane extraction (20mL × 3), merge organic phase, wash through saturated common salt, anhydrous magnesium sulfate drying, filter, pressure reducing and steaming organic solvent obtains thick product, obtain compound shown in formula I-100 through column chromatography for separation and (must 84.8mg be measured, productive rate 72%).
Embodiment 49: compound shown in preparation formula I-24
By (the 105mg of compound shown in formula 8-10, 0.2mmol) be dissolved in acetonitrile (3mL), and add triethylamine (102mg successively wherein, 1.01mmol), (the 51mg of compound shown in formula 9-5 is dripped under stirring at room temperature, 0.4mmol), reflux 4.5 hours, pressure reducing and steaming solvent, residue diluted with water, dichloromethane extraction (20mL × 3), merge organic phase, wash through saturated common salt, anhydrous magnesium sulfate drying, filter, pressure reducing and steaming organic solvent obtains thick product, obtain compound shown in formula I-156 through column chromatography for separation and (must 74mg be measured, productive rate 60%).
1H NMR(400MHz,cd
3od)δ9.10(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 preparation formula I-17
By (the 100mg of compound shown in formula 8-1, 0.202mmol) be dissolved in acetonitrile (3mL), and add triethylamine (102mg successively wherein, 1.01mmol), (the 12.5mg of compound shown in formula 9-4 is dripped under stirring at room temperature, 0.202mmol), reflux 3 hours, pressure reducing and steaming solvent, residue diluted with water, dichloromethane extraction (20mL × 3), merge organic phase, wash through saturated common salt, anhydrous magnesium sulfate drying, filter, pressure reducing and steaming organic solvent obtains thick product, obtain compound shown in formula I-17 through column chromatography for separation and (must 57.7mg be measured, productive rate 55%).Data:
1h NMR (400MHz, cd
3od) 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 preparation formula I-25
By (the 105mg of compound shown in formula 8-10, 0.2mmol) be dissolved in acetonitrile (3mL), and add triethylamine (102mg successively wherein, 1.01mmol), (the 20mg of compound shown in formula 9-6 is dripped under stirring at room temperature, 0.201mmol), reflux 5 hours, pressure reducing and steaming solvent, residue diluted with water, dichloromethane extraction (20mL × 3), merge organic phase, wash through saturated common salt, anhydrous magnesium sulfate drying, filter, pressure reducing and steaming organic solvent obtains thick product, obtain compound shown in formula I-25 through column chromatography for separation and (must 68.3mg be measured, productive rate 64%).
1H NMR(400MHz,cd
3od)δ9.09(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 preparation formula I-34
By (the 100mg of compound shown in formula 8-11, 0.200mmol) be dissolved in acetonitrile (3mL), and add triethylamine (102mg successively wherein, 1.01mmol), (the 21mg of compound shown in formula 9-7 is dripped under stirring at room temperature, 0.21mmol), reflux 5 hours, pressure reducing and steaming solvent, residue diluted with water, dichloromethane extraction (20mL × 3), merge organic phase, wash through saturated common salt, anhydrous magnesium sulfate drying, filter, pressure reducing and steaming organic solvent obtains thick product, obtain compound shown in formula I-34 through column chromatography for separation and (must 88mg be measured, productive rate 78%).
1H NMR(400MHz,cd
3od)δ8.42(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 preparation formula I-48
By (the 102mg of compound shown in formula 8-19, 0.200mmol) be dissolved in acetonitrile (3mL), and add triethylamine (102mg successively wherein, 1.01mmol), (the 18.1mg of compound shown in formula 9-8 is dripped under stirring at room temperature, 0.21mmol), reflux 3 hours, pressure reducing and steaming solvent, residue diluted with water, dichloromethane extraction (20mL × 3), merge organic phase, wash through saturated common salt, anhydrous magnesium sulfate drying, filter, pressure reducing and steaming organic solvent obtains thick product, obtain compound shown in formula I-48 through column chromatography for separation and (must 87.2mg be measured, productive rate 78%).
1H NMR(400MHz,cd
3od)δ8.64(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 preparation formula I-48
By (the 99mg of compound shown in formula 8-9, 0.200mmol) be dissolved in acetonitrile (3mL), and add triethylamine (102mg successively wherein, 1.01mmol), (the 341mg of compound shown in formula 9-8 is dripped under stirring at room temperature, 0.200mmol), reflux 4 hours, pressure reducing and steaming solvent, residue diluted with water, dichloromethane extraction (20mL × 3), merge organic phase, wash through saturated common salt, anhydrous magnesium sulfate drying, filter, pressure reducing and steaming organic solvent obtains thick product, obtain compound shown in formula I-50 through column chromatography for separation and (must 100.6mg be measured, productive rate 80%).
1H NMR(400MHz,cd
3od)δ9.29(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 preparation formula I-36
By (the 105mg of compound shown in formula 8-5, 0.20mmol) be dissolved in acetonitrile (4mL), and add triethylamine (102mg successively wherein, 1.01mmol), (the 12.5mg of compound shown in formula 9-4 is dripped under stirring at room temperature, 0.202mmol), reflux 5 hours, pressure reducing and steaming solvent, residue diluted with water, dichloromethane extraction (20mL × 3), merge organic phase, wash through saturated common salt, anhydrous magnesium sulfate drying, filter, pressure reducing and steaming organic solvent obtains thick product, obtain compound shown in formula I-36 through column chromatography for separation and (must 76mg be measured, productive rate 69%).
Embodiment 56: compound shown in preparation formula I-42
By (the 100mg of compound shown in formula 8-14, 0.20mmol) be dissolved in acetonitrile (4mL), and add triethylamine (102mg successively wherein, 1.01mmol), (the 15mg of compound shown in formula 9-11 is dripped under stirring at room temperature, 0.205mmol), reflux 4.5 hours, pressure reducing and steaming solvent, residue diluted with water, dichloromethane extraction (20mL × 3), merge organic phase, wash through saturated common salt, anhydrous magnesium sulfate drying, filter, pressure reducing and steaming organic solvent obtains thick product, obtain compound shown in formula I-42 through column chromatography for separation and (must 82.7mg be measured, productive rate 77%).
Embodiment 57: compound shown in preparation formula I-96
By (the 103mg of compound shown in formula 8-22, 0.20mmol) be dissolved in acetonitrile (4mL), and add triethylamine (102mg successively wherein, 1.01mmol), (the 12.4mg of compound shown in formula 9-12 is dripped under stirring at room temperature, 0.21mmol), reflux 3 hours, pressure reducing and steaming solvent, residue diluted with water, dichloromethane extraction (20mL × 3), merge organic phase, wash through saturated common salt, anhydrous magnesium sulfate drying, filter, pressure reducing and steaming organic solvent obtains thick product, obtain compound shown in formula I-96 through column chromatography for separation and (must 85mg be measured, productive rate 79%).
Embodiment 58: compound shown in preparation formula I-111
By (the 106mg of compound shown in formula 8-24, 0.20mmol) be dissolved in acetonitrile (4mL), and add triethylamine (102mg successively wherein, 1.01mmol), (the 15.4mg of compound shown in formula 9-12 is dripped under stirring at room temperature, 0.21mmol), reflux 5 hours, pressure reducing and steaming solvent, residue diluted with water, dichloromethane extraction (20mL × 3), merge organic phase, wash through saturated common salt, anhydrous magnesium sulfate drying, filter, pressure reducing and steaming organic solvent obtains thick product, obtain compound shown in formula I-111 through column chromatography for separation and (must 93mg be measured, productive rate 82%).
Embodiment 59:
The synthesis preparation method of compound described in embodiment 59 is with reference to embodiment 49.
1H NMR(400MHz,cd
3od)δ9.29(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,cd
3od)δ9.30(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,cd
3od)δ9.33(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,cd
3od)δ9.29(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,cd
3od)δ9.29(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,cd
3od)δ9.29(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,cd
3od)δ9.33(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,CD
3OD)δ8.62(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)δ8.62(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)δ8.62(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,cd
3od)δ8.69(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,cd
3od)δ8.63(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,cd
3od)δ8.24-8.19(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,cd
3od)δ8.69(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,cd
3od)δ8.68(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,cd
3od)δ9.29(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,cd
3od)δ9.34(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,cd
3od)δ8.62(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,cd
3od)δ8.72(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,cd
3od)δ9.07(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,cd
3od)δ9.33(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,cd
3od)δ9.29(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,cd
3od)δ9.11(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,cd
3od)δ8.41(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,cd
3od)δ8.41(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,cd
3od)δ8.25(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,cd
3od)δ9.02(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,cd
3od)δ9.01(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,cd
3od)δ9.01(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,cd
3od)δ9.33(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
+).
The mensuration of embodiment 138:ALK kinase inhibiting activity
Adopt following methods to measure compound of the present invention in vitro to the kinase whose inhibit activities of ALK, this inhibit activities adopts IC50 this index to represent, the concentration of compound during the kinase whose activity inhibited 50% of IC50 and ALK.
Write a Chinese character in simplified form and define
Mg milligram
ML milliliter
μ g microgram
μ l microlitre
MM mmole
EDTA
ethylenediamine tetraacetic acid (EDTA)
DMSO methyl-sulphoxide
SD standard deviation
SOP Standard operation procedure SOP
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 technique:
1. prepare kinase buffer liquid and the stop buffer of 1 times
1) 1 times of kinase buffer liquid
50mM HEPES,pH 7.5
0.0015％Brij-35
10mM MgCl
2
2mM DTT
2) stop buffer
100mM HEPES,pH 7.5
0.015％Brij-35
0.2％Coating Reagent#3
50mM EDTA
2. compound preparation
1) by the 100%DMSO solution of final for diluted chemical compound 50 times the highest required inhibition concentration.Shift this diluted chemical compound liquid of 100 μ L in 96 orifice plates.Such as, if need the highest inhibitor concentration to be 1 μM, just prepare the DMSO solution of 50 μMs in this step.
2) compound is become 10 concentration by 3 times of serial dilutions.
3) adding 100 μ l 100%DMSO empty does not have compound to control with in the 96 identical orifice plates controlled without enzyme to 2.Mark source plate.
4) preparation of intermediate plate
Shift from source plate in 10 μ L compounds to new 96 orifice plates as intermediate plate.
Add 90 μ L1 times kinase buffer liquid in the hole of each intermediate plate.
To vibrate 10 minutes in mixing cpd to intermediate plate.
3. prepare test board
From 96 hole intermediate plates, in each hole, in transferase 45 μ l to 384 orifice plates, conduct repeats.Such as, the A1 in 96 orifice plates transfers to A1 and A2 in 384 orifice plates.A2 in 96 orifice plates transfers to A3 and A4 of 384 orifice plates.
4. kinase reaction
1) 2.5 times of enzyme solution are prepared
Kinases is added 1 times of kinase buffer liquid, form 2.5 times of enzyme solution.
2) substrate solution of 2.5 times is prepared
The polypeptide mark FAM and ATP add 1 times of kinase buffer liquid, form 2.5 times of substrate solutions.
3) test board has contained the DMSO solution of 10% of 5 μ l compounds.
4) transferase 12 .5 times of enzyme solution is to test board.
5) incubated at room temperature 10 minutes
6) transferase 12 .5 times of peptide solution is to test board.
7) kinase whose reaction and stopping
20 minutes are hatched at 28 DEG C.Add 25 μ l stop solution termination reactions.
5.Caliper reading of data
Caliper upper reading and converting rate data.
6. fitting of a curve
1) conversion data is copied from Caliper.
2) conversion is become inhibiting rate data.Wherein max refers to that the transformation efficiency that DMSO contrasts, min refer to the transformation efficiency without enzyme contrast alive.
Percent inhibition＝(max-conversion)/(max-min)*100.
3) XLFit excel add-in version 4.3.1 is used to carry out curve fitting data importing MS Excel.
The formula used is:
Y=Bottom+ (Top-Bottom)/(1+10^ ((LogIC50-X) * HillSlope)) following table show the compound shown in formula I-1 ~ formula I-159 in vitro ALK kinase inhibition measure in activity.Result shows, compound shown in formula I of the present invention all has good ALK kinase inhibiting activity, compound of the present invention can be used as ALK inhibitor, be used for the treatment of one or more relevant tumor diseases active in ALK, for the preparation of the antineoplaston medicine becoming to suppress Nucleophosmin-anaplastic lymphoma kinase.
| 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: for the tablet of oral administration, prescription sees the following form
| Composition | Bulk drug (gram) |
| Activeconstituents | 10 |
| Guar gum | 15 |
| Microcrystalline Cellulose | 150 |
| Sodium starch glycolate | 25 |
| Magnesium Stearate | 2 |
| Be prepared into | 1000 |
Activeconstituents in upper table is crossed 100 mesh sieves, again with cross the guar gum of 100 mesh sieves, sodium starch glycolate, Microcrystalline Cellulose, Magnesium Stearate mix, tablet is formed as again with suitable tabletting machine, be prepared into 1000 altogether, the activeconstituents (compound of the present invention) of every sheet is 10mg.
In the description of this specification sheets, specific features, structure, material or feature that the description of reference term " embodiment ", " some embodiments ", " example ", " concrete example " or " some examples " etc. means to describe in conjunction with this embodiment or example are contained at least one embodiment of the present invention or example.In this manual, identical embodiment or example are not necessarily referred to the schematic representation of above-mentioned term.And the specific features of description, structure, material or feature can combine in an appropriate manner in any one or more embodiment or example.
Although illustrate and describe embodiments of the invention above, be understandable that, above-described embodiment is exemplary, can not be interpreted as limitation of the present invention, those of ordinary skill in the art can change above-described embodiment within the scope of the invention when not departing from principle of the present invention and aim, revising, replacing and modification.
Claims (14)
1. a compound, its pharmacologically acceptable salt for compound shown in compound shown in formula I or formula I, hydrate, solvate, meta-bolites or prodrug,
Wherein,
R
1for hydrogen, halogen, C
1-6alkyl or C
1-6alkoxyl group;
R
2for 5-6 unit cycloalkyl, 5-6 unit heterocyclic radical, 5-6 unit's aryl or 5-6 unit heteroaryl, optionally, described 5-6 unit cycloalkyl, 5-6 unit heterocyclic radical, 5-6 unit's aryl and 5-6 unit heteroaryl are selected from halogen, hydroxyl, cyano group, nitro, C by one or more independently of one another
1-8alkyl, C
2-8alkenyl, C
2-8alkynyl group, C
3-8cycloalkyl, 3-8 unit heterocyclic radical, C
5-10aryl, 5-10 unit heteroaryl, C
1-6alkoxyl group, C
3-8cycloalkyloxy ,-S (O) pR
5,-C (O) R
5,-C (O) OR
5,-NR
6r
7or-C (O) NR
7substituting group replace, wherein, R
5, R
6, R
7be hydrogen or C independently of one another
l-4alkyl, p is 0,1 or 2;
R
3for the piperazinyl optionally replaced, optional piperidyl, optional morpholinyl, optional thio-morpholinyl or the optional amino replaced replaced replaced;
R
4for hydrogen, halogen, C
1-6alkyl or C
1-6alkoxyl group.
2. compound according to claim 1, is characterized in that,
R
2for one of following:
Optionally, R
3for one of following:
3. a method for compound shown in preparation formula Ι, is characterized in that, comprising:
(1) compound shown in compound with formula 2 shown in formula 1 is made to contact, to obtain compound shown in formula 3;
(2) compound shown in compound with formula 4 shown in described formula 3 is made to contact, to obtain compound shown in formula 5;
(3) compound generation hydrogenation reaction shown in described formula 5 is made, to obtain compound shown in formula 6;
(4) compound shown in compound with formula 7 shown in described formula 6 is made to contact, to obtain compound shown in formula 8; And
(5) compound shown in compound with formula 9 shown in described formula 8 is made to contact, to obtain compound shown in formula I,
Wherein,
R
1for hydrogen, halogen, C
1-6alkyl or C
1-6alkoxyl group;
R
2for 5-6 unit cycloalkyl, 5-6 unit heterocyclic radical, 5-6 unit's aryl or 5-6 unit heteroaryl, optionally, described 5-6 unit cycloalkyl, 5-6 unit heterocyclic radical, 5-6 unit's aryl and 5-6 unit heteroaryl are selected from halogen, hydroxyl, cyano group, nitro, C by one or more independently of one another
1-8alkyl, C
2-8alkenyl, C
2-8alkynyl group, C
3-8cycloalkyl, 3-8 unit heterocyclic radical, C
5-10aryl, 5-10 unit heteroaryl, C
1-6alkoxyl group, C
3-8cycloalkyloxy ,-S (O) pR
5,-C (O) R
5,-C (O) OR
5,-NR
6r
7or-C (O) NR
7substituting group replace, wherein, R
5, R
6, R
7be hydrogen or C independently of one another
l-4alkyl, p is 0,1 or 2;
R
3for the piperazinyl optionally replaced, optional piperidyl, optional morpholinyl, optional thio-morpholinyl or the optional amino replaced replaced replaced;
R
4for hydrogen, halogen, C
1-6alkyl or C
1-6alkoxyl group.
4. method according to claim 3, is characterized in that, R
2for one of following:
Optionally, R
3for one of following:
5. method according to claim 3, is characterized in that, in step (1), in the first organic solvent, when there is NaH, compound shown in compound with described formula 2 shown in described formula 1 is contacted,
Optionally, described first organic solvent is be selected from least one in N-Methyl pyrrolidone, DMF, dimethyl sulfoxide (DMSO), N,N-DIMETHYLACETAMIDE, N,N-dimethylacetamide, preferred DMF,
Optionally, in step (1), 0 degree Celsius time, compound shown in compound with described formula 2 shown in described formula 1 is contacted.
6. method according to claim 3, is characterized in that, in step (2), in propyl carbinol, there is tosic acid condition under, compound shown in compound with described formula 4 shown in described formula 3 is contacted,
Optionally, in step (2), 80 degrees Celsius time, compound shown in compound with described formula 4 shown in described formula 3 is contacted.
7. method according to claim 3, is characterized in that, in step (3), described hydrogenation reaction adopts palladium/carbon as catalyzer, carries out in hydrogen atmosphere.
8. method according to claim 3, is characterized in that, in step (4), compound shown in compound with formula 7 shown in described formula 6 is contacted, to obtain compound shown in formula 8, carries out through the following steps:
(4-1) the first dichloromethane solution containing compound shown in described formula 6 and triethylamine is provided, and the second dichloromethane solution containing compound described in described formula 7;
(4-2) described first dichloromethane solution is mixed with described second dichloromethane solution,
Optionally, described mixing is undertaken by being added drop-wise in described first dichloromethane solution by described second dichloromethane solution,
Optionally, in step (4), described dropping is carried out under ice-water bath cooling conditions,
Optionally, in step (4), described duration of contact is 2-5 hour.
9. method according to claim 3, is characterized in that, in step (5), compound shown in compound with formula 9 shown in described formula 8 is contacted, to obtain compound shown in formula I, carries out through the following steps:
There is provided containing compound, triethylamine acetonitrile solution shown in described formula 8,
Compound shown in described formula 9 is added in described acetonitrile solution, to make compound shown in compound with described formula 9 shown in described formula 8 contact,
Optionally, in step (5), described contact carries out 3-5 hour under heated reflux condition.
10. an intermediate, described intermediate is the compound shown in formula 5,
Wherein, R
1for hydrogen, halogen, C
1-6alkyl or C
1-6alkoxyl group;
R
2for 5-6 unit cycloalkyl, 5-6 unit heterocyclic radical, 5-6 unit's aryl or 5-6 unit heteroaryl, optionally, described 5-6 unit cycloalkyl, 5-6 unit heterocyclic radical, 5-6 unit's aryl and 5-6 unit heteroaryl are selected from halogen, hydroxyl, cyano group, nitro, C by one or more independently of one another
1-8alkyl, C
2-8alkenyl, C
2-8alkynyl group, C
3-8cycloalkyl, 3-8 unit heterocyclic radical, C
5-10aryl, 5-10 unit heteroaryl, C
1-6alkoxyl group, C
3-8cycloalkyloxy ,-S (O) pR
5,-C (O) R
5,-C (O) OR
5,-NR
6r
7or-C (O) NR
7substituting group replace, wherein, R
5, R
6, R
7be hydrogen or C independently of one another
l-4alkyl, p is 0,1 or 2;
R
4for hydrogen, halogen, C
1-6alkyl or C
1-6alkoxyl group.
11. 1 kinds of intermediates, described intermediate is the compound shown in formula 6,
Wherein, R
1for hydrogen, halogen, C
1-6alkyl or C
1-6alkoxyl group;
R
2for 5-6 unit cycloalkyl, 5-6 unit heterocyclic radical, 5-6 unit's aryl or 5-6 unit heteroaryl, optionally, described 5-6 unit cycloalkyl, 5-6 unit heterocyclic radical, 5-6 unit's aryl and 5-6 unit heteroaryl are selected from halogen, hydroxyl, cyano group, nitro, C by one or more independently of one another
1-8alkyl, C
2-8alkenyl, C
2-8alkynyl group, C
3-8cycloalkyl, 3-8 unit heterocyclic radical, C
5-10aryl, 5-10 unit heteroaryl, C
1-6alkoxyl group, C
3-8cycloalkyloxy ,-S (O) pR
5,-C (O) R
5,-C (O) OR
5,-NR
6r
7or-C (O) NR
7substituting group replace, wherein, R
5, R
6, R
7be hydrogen or C independently of one another
l-4alkyl, p is 0,1 or 2;
R
4for hydrogen, halogen, C
1-6alkyl or C
1-6alkoxyl group.
12. 1 kinds of intermediates, described intermediate is the compound shown in formula 8,
Wherein, R
1for hydrogen, halogen, C
1-6alkyl or C
1-6alkoxyl group;
R
2for 5-6 unit cycloalkyl, 5-6 unit heterocyclic radical, 5-6 unit's aryl or 5-6 unit heteroaryl, optionally, described 5-6 unit cycloalkyl, 5-6 unit heterocyclic radical, 5-6 unit's aryl and 5-6 unit heteroaryl are selected from halogen, hydroxyl, cyano group, nitro, C by one or more independently of one another
1-8alkyl, C
2-8alkenyl, C
2-8alkynyl group, C
3-8cycloalkyl, 3-8 unit heterocyclic radical, C
5-10aryl, 5-10 unit heteroaryl, C
1-6alkoxyl group, C
3-8cycloalkyloxy ,-S (O) pR
5,-C (O) R
5,-C (O) OR
5,-NR
6r
7or-C (O) NR
7substituting group replace, wherein, R
5, R
6, R
7be hydrogen or C independently of one another
l-4alkyl, p is 0,1 or 2;
R
4for being selected from hydrogen, halogen, C
1-6alkyl or C
1-6alkoxyl group.
13. intermediates according to any one of claim 10-12, is characterized in that, R
2for one of following:
Compound described in 14. claims 1 or 2 is preparing the purposes in medicine, and described medicine is for suppressing Nucleophosmin-anaplastic lymphoma kinase.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| 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 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510304880.6A CN104987324B (en) | 2015-06-04 | 2015-06-04 | Pyrimidine derivatives as ALK inhibitor |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN104987324A true CN104987324A (en) | 2015-10-21 |
| CN104987324B CN104987324B (en) | 2018-05-04 |
Family
ID=54299244
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510304880.6A Active CN104987324B (en) | 2015-06-04 | 2015-06-04 | Pyrimidine derivatives as ALK inhibitor |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN104987324B (en) |
| WO (1) | WO2016192132A1 (en) |
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106699743A (en) * | 2015-11-05 | 2017-05-24 | 湖北生物医药产业技术研究院有限公司 | Pyrimidine derivative and application thereof |
| CN107235931A (en) * | 2017-07-11 | 2017-10-10 | 大连医科大学 | New pyrimidine anti-tumor compounds and preparation method thereof and purposes |
| CN107586278A (en) * | 2016-07-08 | 2018-01-16 | 中国科学院上海药物研究所 | 2,4 2 amine pyrimidine compounds, its preparation method, pharmaceutical composition and the purposes of a kind of fragment containing phenol |
| 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 |
| WO2018146472A1 (en) | 2017-02-07 | 2018-08-16 | Oblique Therapeutics Ab | Hydrocarbylsulfonyl-substituted pyridines and their use in the treatment of cancer |
| 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 |
| US10899710B2 (en) | 2015-08-07 | 2021-01-26 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Pyridines and their use in the treatment of cancer |
| US11028067B2 (en) | 2017-02-07 | 2021-06-08 | 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 |
| US11208384B2 (en) | 2017-02-07 | 2021-12-28 | Oblique Therapeutics Ab | Sulfinylpyridines and their use in the treatment of cancer |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| WO2021003417A1 (en) | 2019-07-03 | 2021-01-07 | Sumitomo Dainippon Pharma Oncology, Inc. | Tyrosine kinase non-receptor 1 (tnk1) inhibitors and uses thereof |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20090306067A1 (en) * | 2006-04-10 | 2009-12-10 | Harald Engelhardt | 2, 4-diaminopyrimidide derivates and their use for the treatment of cancer |
| US20110005947A1 (en) * | 2009-05-06 | 2011-01-13 | Portola Pharmaceuticals, Inc. | Inhibitors of jak |
| WO2013169401A1 (en) * | 2012-05-05 | 2013-11-14 | Ariad Pharmaceuticals, Inc. | Compounds for inhibiting cell proliferation in egfr-driven cancers |
| CN104230954A (en) * | 2013-06-08 | 2014-12-24 | 中国科学院上海药物研究所 | 2,4-diaminopyrimidine compounds and medical applications thereof |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20130137709A1 (en) * | 2010-05-05 | 2013-05-30 | Nathanael S. Gray | Compounds that modulate EGFR activity and methods for treating or preventing conditions therewith |
| WO2012125603A1 (en) * | 2011-03-16 | 2012-09-20 | Cephalon, Inc. | Macrocyclic compounds as alk, fak and jak2 inhibitors |
| CN105085483B (en) * | 2015-06-04 | 2019-01-01 | 湖北生物医药产业技术研究院有限公司 | Kinase inhibitor and its application |
-
2015
- 2015-06-04 CN CN201510304880.6A patent/CN104987324B/en active Active
- 2015-06-15 WO PCT/CN2015/081487 patent/WO2016192132A1/en active Application Filing
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20090306067A1 (en) * | 2006-04-10 | 2009-12-10 | Harald Engelhardt | 2, 4-diaminopyrimidide derivates and their use for the treatment of cancer |
| US20110005947A1 (en) * | 2009-05-06 | 2011-01-13 | Portola Pharmaceuticals, Inc. | Inhibitors of jak |
| WO2013169401A1 (en) * | 2012-05-05 | 2013-11-14 | Ariad Pharmaceuticals, Inc. | Compounds for inhibiting cell proliferation in egfr-driven cancers |
| CN104230954A (en) * | 2013-06-08 | 2014-12-24 | 中国科学院上海药物研究所 | 2,4-diaminopyrimidine compounds and medical applications thereof |
Non-Patent Citations (1)
| Title |
|---|
| SONG, ZILAN等: ""Discovery of Novel,4-Diarylaminopyrimidine Analogues(DAAPalogues) Showing Potent Inhibitory Activities against Both Wild-type and Mutant ALK Kinases"", 《JOURNAL OF MEDICINAL CHEMISTRY》 * |
Cited By (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10899710B2 (en) | 2015-08-07 | 2021-01-26 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Pyridines and their use in the treatment of cancer |
| US10695347B2 (en) | 2015-11-05 | 2020-06-30 | Hubei Bio-Pharmaceutical Industrial Technological Institute, Inc. | Pyrimidine derivative and use thereof |
| CN106699743A (en) * | 2015-11-05 | 2017-05-24 | 湖北生物医药产业技术研究院有限公司 | Pyrimidine derivative and application thereof |
| 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 |
| CN107586278A (en) * | 2016-07-08 | 2018-01-16 | 中国科学院上海药物研究所 | 2,4 2 amine pyrimidine compounds, its preparation method, pharmaceutical composition and the purposes of a kind of fragment containing phenol |
| 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 |
| WO2018146472A1 (en) | 2017-02-07 | 2018-08-16 | Oblique Therapeutics Ab | Hydrocarbylsulfonyl-substituted pyridines and their use in the treatment of cancer |
| US11208384B2 (en) | 2017-02-07 | 2021-12-28 | Oblique Therapeutics Ab | Sulfinylpyridines 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 |
| US11028067B2 (en) | 2017-02-07 | 2021-06-08 | Oblique Therapeutics Ab | Heteroarylsulfonyl-substituted pyridines and their use in the treatment of cancer |
| US11161815B2 (en) | 2017-02-07 | 2021-11-02 | Oblique Therapeutics Ab | Hydrocarbylsulfonyl-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 |
| CN107235931A (en) * | 2017-07-11 | 2017-10-10 | 大连医科大学 | New pyrimidine anti-tumor compounds and preparation method thereof and purposes |
| 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 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN104987324B (en) | 2018-05-04 |
| WO2016192132A1 (en) | 2016-12-08 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN104987324A (en) | Pyrimidine derivative used as anaplastic lymphoma kinase (ALK) inhibitor | |
| CN101902911B (en) | Heteroaryl compound and its purposes | |
| CN101883764B (en) | Pyrazole derivatives and use thereof as inhibitors of cyclin dependent kinases | |
| KR20210018204A (en) | Heterocyclic compounds as immunomodulators | |
| AU2012228090B2 (en) | Pyrrolopyridineamino derivatives as Mps1 inhibitors | |
| CN104788427B (en) | 3 (2 pyrimdinyl-amino) phenylacryloyl amine compounds and its application | |
| KR20210018282A (en) | Tetrahydro-imidazo[4,5-c]pyridine derivatives as PD-L1 immunomodulators | |
| KR102455519B1 (en) | SUBSTITUTED 4,5,6,7-TETRAHYDRO-PYRAZOLO[1,5-a]PYRAZINE DERIVATIVES AND 5,6,7,8-TETRAHYDRO-4H-PYRAZOLO[1,5-a][1,4]DIAZEPINE DERIVATIVES AS ROS1 INHIBITORS | |
| CN105051043B (en) | Novel heterocyclic derivatives as modulators of kinase activity | |
| TWI736578B (en) | Certain protein kinase inhibitors | |
| WO2017198149A1 (en) | Fgfr4 inhibitor, preparation method therefor, and applications thereof | |
| CN102209714A (en) | Triazine, pyrimidine and pyridine analogs and their use as therapeutic agents and diagnostic probes | |
| TW200946531A (en) | HSP90 inhibitors | |
| JP2018532759A (en) | Pyrimidine derivatives and uses thereof | |
| CN105308038A (en) | Enhancer of zeste homolog 2 inhibitors | |
| US11174245B2 (en) | Benzimidazole compounds and derivatives as EGFR inhibitors | |
| CN105085483A (en) | Kinase inhibitor and application thereof | |
| WO2016173557A1 (en) | Compound having kinase inhibition activity, and preparation method and uses | |
| JP2021517555A (en) | Phenyl-2-hydroxy-acetylamino-2-methyl-phenyl compound | |
| CN105712998B (en) | Azaindole derivatives, preparation method and medical application thereof | |
| CN107848986A (en) | Pyridazinone compound, its preparation method, pharmaceutical composition and purposes | |
| WO2022135432A1 (en) | Macrocyclic heterocyclic compounds as egfr inhibitors, and use thereof | |
| CN105732615A (en) | CDK kinase inhibitor | |
| CN111171049A (en) | Tyrosine kinase inhibitors and uses thereof | |
| WO2019120194A1 (en) | Substituted pyrazolo[1,5-a]pyrimidine compound and pharmaceutical composition and use thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |