CN110343090A

CN110343090A - Quinazoline derivant salt form crystal form and preparation method and application

Info

Publication number: CN110343090A
Application number: CN201810423951.8A
Authority: CN
Inventors: 钟卫; 张金强
Original assignee: Shanghai Bio Pharmaceutical Co Ltd
Current assignee: Shanghai Bio Pharmaceutical Co Ltd
Priority date: 2018-04-08
Filing date: 2018-05-04
Publication date: 2019-10-18
Anticipated expiration: 2038-05-04
Also published as: CN110343090B

Abstract

The invention discloses a kind of quinazoline derivant salt form crystal form and preparation method and application；The specially hydrochloride Form A, B, C, D of quinazoline derivant shown in formula (I), F, H, I, sulfate crystal form A, maleate crystal form A, succinate crystal form A, adipate crystal form A, glycollate crystal form A, malate crystal form A, fumarate crystal form A, benzene sulfonate crystal form A, B, C, benzoate crystal form A, hippurate crystal form A and Crystal form of oxalate A.Salt form crystal form provided by the invention is with good stability, can be in treatment brain transplantation of non small cell Lung transfer, meninx transfer is applied in the drug of primary brain cancer or glioma etc., and there is preferable bioavilability, be of great significance to the curative effect for further studying such solid drugs.

Description

Quinazoline derivant salt form crystal form and preparation method and application

Technical field

The present invention relates to a kind of quinazoline derivant salt form and its crystal forms；More particularly to (R) -6- [(fluoro- 1- first of 3,3- bis- Phenylpiperidines -4- base) oxygroup]-nitrogen-(3- acetenyl -2- fluorophenyl) -7- methoxyquinazoline hydrochloride -4- amine (I) hydrochloride Form A, B, C, D, F, H, I, sulfate crystal form A, maleate crystal form A, succinate crystal form A, adipate crystal form A, glycollate are brilliant Type A, malate crystal form A, fumarate crystal form A, benzene sulfonate crystal form A, B, C, benzoate crystal form A, hippurate crystal form A And Crystal form of oxalate A and its preparation method and application.

Background technique

Biological signal conduction refers to stimulation or signal is inhibited to be sent into the cell, is transmitted by a series of signal, makes cell Interior generation biological response.Many researchs have been carried out in many signal transduction paths and its biological respinse.In signal transduction pathway It is cancer the reason of leading to many diseases, including diversified forms, dysbolism, inflammatory disease that the different defects of middle appearance, which have found, Disease, blood vessel and neuronal disease.These defects often occur to be inserted into gene level, such as DNA, missing or transposition, one Cell is proliferated uncontrollably in a little cancers.

Signal transduction is often mediated by the certain albumen for being referred to as kinases.Kinases is commonly divided into protein kinase and lipid Kinases and certain kinases for showing dual specificity.Protein kinase be catalyzed other protein phosphorylation enzyme and/or from Body phosphorylation, and can be classified based on them to the effect of substrate, such as: tyrosine kinase refers to major phosphate junket ammonia Sour residue (for example, Kit, EGFR, HER2, VEGFR, PDGFR, SRC and ABL etc.), serine/threonine kinase refers to major phosphate Change serine and/or threonine residues (for example, mTORC1, mTORC2, ATM, ATR, Akt etc.) and dual-specificity kinase phosphoric acid Change the tyrosine of substrate, serine and/or threonine residues.

EGF-R ELISA (EGFR) belongs to the transmembrane protein tyrosine kinases of ErbB receptor family, including epidermis life Growth factor receptor body EGFR/ERBB1, HER2/ERBB2/NEU, HER3/ERBB3 and HER4/ERBB4.With epidermal growth factor (EGF) ligand binding, the EGFR receptor of induction and another EGFR receptor or another family member, for example, HER2/ERBB2/ NEU, HER3/ERBB3 or HER4/ERBB4 form homopolymer or heterodimer, lead to the activation of EGFR tyrosine kinase activity. The EGFR of activation then its substrate of phosphorylation, so as to cause multiple downstream passages in the cell, including Pl3K-AKT-mTOR Approach (activation for participating in cell survival) and RAS-RAF-MEK-ERK approach (being related to cell Proliferation).ErbB receptor signal transduction And its participation in tumour, see, e.g., Chong et al.Nature Med.2013；19(11):1389-1400)；N Engl J Med.(2008)Vol.358,1160-74and Biochemical and Biophysical Research Communications(2004)Vol.319,1-11。

Glioma is the most common primary intracranial tumour, accounts for the 40-50% of intracranial tumour.Patients with gliomas is about 60% has the relevant EGFR mutation of tumour.Wherein about 70% mutation is that exon 2-7 lacks EGFRV3 (EGFRVIII).It is this prominent Become the kinase activity for increasing EGFR, downstream is caused to promote the overactivity of survival signaling pathway.EGFRV3 (EGFRVIII) is The missing gene of the exon 2-7 of epidermal growth factor EGFR and prevent mutant receptor from any of ligand binding. EGFRV3 is mutated in the cancer of the brain, glioma, bladder cancer, breast cancer, colorectal cancer, cancer of the esophagus, Head and neck squamous cell carcinoma, lung cancer, Lung squamous cancer, oophoroma, prostate cancer are expressed in brain stem tumor etc..Referring to Terrance G.Johns etc., FEBS Journal 280(2013)5350–5370。

The derepression of ErbB family signal transduction promotes proliferation, invades, transfer, angiogenesis and tumor cell survival, And in many human cancers, including lung, head and neck and breast are described, therefore ErbB family represents anticancer drug hair The small-molecule drug of the logical targets of exhibition, targeting EGFR or ErbB2, including Gefitinib (Iressa Iressa^TM), Tarceva (Erlotinib^TM), Afatinib, Tai Ruisha and Lapatinib (TYKERB^TM, TYVERB^TM) non-small cell lung cancer clinically It gets the Green Light, being specifically used for EGFR mutation is exons 19 (Exon 19del) missing or exon 2 1L858R (Exon 21L858R) it is mutated.Because EGFRVIII be the missing gene of EGFR exon 2-7 and prevent mutant receptor from it is any known Ligand binding, with exons 19 (Exon 19del) missing or exon 2 1L858R (Exon21L858R) mutation completely not Together, existing EGFR inhibitor can not effectively inhibit EGFRVIII, be far below outside to EGFR to the bioactivity of EGFRVIII Aobvious 19 (Exon 19del) of son missing or exon 2 1L858R (Exon 21L858R) mutation, activity usually reduce by 10 times, even 100 times or more, see, e.g., Paul S.Mischel et al, Molecular Cell, 60,307-318,2015.Meanwhile Because of the presence of blood-brain barrier (BBB), these drugs of existing approved more can not reach effective quantity in encephalic.For brain colloid Tumor, radiotherapy and surgical operation are aided with the main means that chemotherapeutics (for amine is not frustrated) is still treatment, but therapeutic effect is limited, Overall survival about 10 months.

Therefore, there is the high bioactivity of EGFRVIII mutation to have simultaneously across blood-brain barrier barrier for treating for research and development Or the glioma that prevention is mediated for EGFR is particularly useful.

It is well known that the crystal form of the different crystal forms of same drug, salt form and salt, stability, solubility and biological utilisation Degree etc. may have notable difference, to influence the curative effect of drug.Therefore, research and development are more advantageous to drug processing and drug The new salt form of quinazoline derivant used in composition and the novel crystal forms of salt mention for the curative effect and safety research of solid drugs Be for more qualitative, quantitative information it is highly useful, be of great significance.

Summary of the invention

Problem to be solved by this invention is can not effectively to inhibit EGFR Activating mutations for existing EGFR inhibitor EGFRVIII and effective the problem of reaching effective blood drug concentration across blood-brain barrier to encephalic and quinazoline of the present invention spread out Biology (R) -6- [(the fluoro- 1- methyl piperidine -4- base of 3,3- bis-) oxygroup]-nitrogen-(3- acetenyl -2- fluorophenyl) -7- methoxyl group quinoline The property of the free alkali of oxazoline -4- amine (I) is unfavorable for the problem used in drug processing and pharmaceutical composition, provides one kind more Be conducive to quinazoline derivant salt form crystal form and preparation method and application used in drug processing and pharmaceutical composition, be solid The curative effect and safety research of drug provide more qualitative, quantitative information.

Quinazoline derivant provided by the invention has the bioactivity for EGFRVIII Activating mutations, effectively passes through blood Brain barrier.Shown in the quinazoline derivant such as formula (I):

The purpose of the present invention is achieved through the following technical solutions:

A technical solution of the present invention is to provide a kind of chiral novel quinazoline derivant (I) for being R.

Preferably, chiral purity ee > 90%, it is highly preferred that chiral purity ee > 97%.

A technical solution of the present invention is to provide a kind of chiral novel quinazoline derivant (I) tool for being R There is the bioactivity of EGFRVIII Activating mutations.

A technical solution of the present invention is to provide a kind of chiral novel quinazoline derivant (I) tool for being R Have the bioactivity of EGFRVIII Activating mutations, at the same have height pass through blood-brain barrier ability.

The present invention also provides a kind of synthetic methods for preparing quinazoline derivant of the present invention (I).

A technical solution of the present invention is to provide the hydrochloride Form A, XRPD of a kind of quinazoline derivant Map is in 2 θ

Principal character peak: 6.5,13.1,9.4

Secondary feature peak: 7.3,18.2,20.0

Characteristic peak again: 27.5,26.6,21.6

Place has diffraction maximum, wherein the error range of 2 θ values is ± 0.2.

Preferably, the XRPD map of the hydrochloride Form A of quinazoline derivant (I) provided by the invention is in 2 θ=6.48, 7.31,9.36,10.26,13.12,14.37,14.98,16.06,16.88,17.48,18.25,20.01,20.83,21.55, 22.21,23.35,25.47,26.60,27.46,28.29,29.98,34.07,34.89,36.25,36.47,36.87,37.54 Place has derivative peak, and the error range of above-mentioned 2 θ value is ± 0.2.

Another technical solution of the present invention is to provide the hydrochloride Form B, XRPD of a kind of quinazoline derivant Map is in 2 θ

Principal character peak: 6.5,17.7,19.8

Secondary feature peak: 7.3,8.2,10.5,13.2

Preferably, the XRPD map of the hydrochloride Form B of quinazoline derivant (I) provided by the invention is in 2 θ=4.32, 5.98,6.54,7.28,8.17,10.52,13.20,15.99,17.74,18.48,19.32,19.84,22.56,23.88, There is derivative peak, the error model of above-mentioned 2 θ value at 24.36,24.87,30.47,32.92,33.55,34.60,38.06,38.34 Enclose is ± 0.2.

Another technical solution of the present invention is to provide the hydrochloride Form C, XRPD of a kind of quinazoline derivant Map is in 2 θ

Principal character peak: 7.2,17.6,22.0

Secondary feature peak: 14.0,13.6,12.8

Characteristic peak again: 24.6,26.2,27.3

Preferably, the XRPD map of the hydrochloride Form C of quinazoline derivant (I) provided by the invention is in 2 θ=5.66, 7.16,8.32,8.86,9.52,10.98,11.63,12.80,13.57,13.96,14.81,15.14,15.49,16.55, 16.86,17.61,22.04,22.93,24.55,26.19,27.30,28.49,34.12,34.76,35.65,36.68, There is derivative peak, the error range of above-mentioned 2 θ value is ± 0.2 at 37.31,37.80,38.20,38.53.

Another technical solution of the present invention is to provide the hydrochloride Form D, XRPD of a kind of quinazoline derivant Map is in 2 θ

Principal character peak: 13.4,7.1,25.4

Secondary feature peak: 6.7,18.0,19.8

Characteristic peak again: 17.2,27.3,24.7

Preferably, the XRPD map of the hydrochloride Form D of quinazoline derivant (I) provided by the invention is in 2 θ=3.43, 6.72,7.12,8.47,9.32,12.25,13.44,14.07,15.69,16.87,17.22,17.97,19.77,20.73, 22.25,22.82,23.64,24.77,25.40,27.28,28.13,29.69,31.01,33.48,34.87,35.42,38.08 Place has derivative peak, and the error range of above-mentioned 2 θ value is ± 0.2.

Another technical solution of the present invention is to provide the hydrochloride Form F, XRPD of a kind of quinazoline derivant Map is in 2 θ

Principal character peak: 6.8,20.5,13.6

Secondary feature peak: 14.8,14.3,17.9,11.9

Preferably, the XRPD map of the hydrochloride Form F of quinazoline derivant (I) provided by the invention is in 2 θ=4.91, 5.67,6.51,6.77,7.44,8.58,9.20,9.73,10.40,10.85,11.86,13.58,14.30,14.78,15.57, Have at 15.85,16.15,16.41,16.97,17.89,18.96,19.76,20.45,20.79,21.57,22.21,24.17 Derivative peak, the error range of above-mentioned 2 θ value are ± 0.2.

Another technical solution of the present invention is to provide the hydrochloride Form H, XRPD of a kind of quinazoline derivant Map is in 2 θ

Principal character peak: 7.3,18.0,14.1

Secondary feature peak: 6.4,13.2,15.8

Characteristic peak again: 16.8,14.5,20.3

Preferably, the XRPD map of the hydrochloride Form H of quinazoline derivant (I) provided by the invention is in 2 θ=5.83, 6.43,7.26,8.10,10.24,11.93,13.22,14.11,14.45,14.88,15.78,16.80,17.95,18.96, There is derivative peak at 20.25,21.07,21.65,24.16,24.53,25.67,26.37,27.03,27.61, above-mentioned 2 θ value Error range is ± 0.2.

Another technical solution of the present invention is to provide the hydrochloride Form I, XRPD of a kind of quinazoline derivant Map is in 2 θ

Principal character peak: 18.6,7.4,6.9

Secondary feature peak: 13.2,25.1,12.3

Characteristic peak again: 14.7,28.1,14.2

Preferably, the XRPD map of the hydrochloride Form I of quinazoline derivant (I) provided by the invention is in 2 θ=6.88, 7.42,8.20,12.31,13.20,13.88,14.23,14.66,15.69,17.48,17.90,18.64,19.23,20.24, 20.92,21.94,22.88,23.42,23.88,25.12,25.40,25.85,26.64,28.07,28.92,31.19,33.10 Place has derivative peak, and the error range of above-mentioned 2 θ value is ± 0.2.

Another technical solution of the present invention is to provide a kind of fumarate crystal form A of quinazoline derivant, XRPD map is in 2 θ

Principal character peak: 6.5,17.8,9.4

Secondary feature peak: 13.4,7.5,19.7

Characteristic peak again: 14.6,18.5

Preferably, the XRPD map of the fumarate crystal form A of quinazoline derivant (I) provided by the invention 2 θ= 6.51,6.74,7.47,9.37,10.82,13.43,13.97,14.61,17.78,18.51,18.80,19.69,20.90, 21.36,21.68,22.63,23.76,24.39,27.09,28.73,29.69,30.52,31.07,35.14,36.12,38.33 Place has derivative peak, and the error range of above-mentioned 2 θ value is ± 0.2.

Another technical solution of the present invention is to provide a kind of succinate crystal form A of quinazoline derivant, XRPD map is in 2 θ

Principal character peak: 6.6,17.8,7.5

Secondary feature peak: 9.4,20.3,18.5

Characteristic peak again: 21.0,14.5,19.5

Preferably, the XRPD map of the succinate crystal form A of quinazoline derivant (I) provided by the invention 2 θ= 3.92,4.40,6.56,6.74,7.50,9.42,11.92,12.68,13.53,14.50,14.84,15.22,15.68, 16.25,17.82,18.55,19.48,20.34,20.99,22.08,22.59,24.14,24.52,24.92,28.07, There is derivative peak, the error range of above-mentioned 2 θ value is ± 0.2 at 30.92,36.11.

Another technical solution of the present invention is to provide a kind of maleate crystal form A of quinazoline derivant, XRPD map is in 2 θ

Principal character peak: 6.3,18.8,16.7

Secondary feature peak: 25.2,21.2

Preferably, the XRPD map of the maleate crystal form A of quinazoline derivant provided by the invention is in 2 θ=6.25, 8.44,8.68,9.42,10.41,14.42,14.88,16.65,17.93,18.78,20.58,21.17,22.63,25.16, There is derivative peak at 31.15,32.40,33.66,34.34,34.52,35.82,36.06,36.35,36.91, above-mentioned 2 θ value Error range is ± 0.2.

Another technical solution of the present invention is to provide a kind of glycollate crystal form A of quinazoline derivant, XRPD map is in 2 θ

Principal character peak: 6.6,7.4,17.9

Secondary feature peak: 13.3

Preferably, the XRPD map of the glycollate crystal form A of quinazoline derivant provided by the invention is in 2 θ=4.53, 5.89,6.59,7.35,10.02,12.54,13.26,15.94,17.93,18.67,19.36,19.84,21.06,24.99, There is derivative peak, the error range of above-mentioned 2 θ value is ± 0.2 at 31.13,33.48,34.79,35.56,36.17.

Another technical solution of the present invention is to provide sulfate the crystal form A, XRPD of a kind of quinazoline derivant Map is in 2 θ

Principal character peak: 7.3,18.2,15.0

Preferably, the XRPD map of the sulfuric acid crystal form A of quinazoline derivant (I) provided by the invention is in 2 θ=7.27, 8.41,11.88,14.96,18.23,19.68,20.64,24.83,25.82,27.10,28.16,29.79,30.71,32.35, There is derivative peak, the error range of above-mentioned 2 θ value is ± 0.2 at 34.12,35.56,37.56,38.37.

Another technical solution of the present invention is to provide a kind of oxalate crystal form A of quinazoline derivant, XRPD map is in 2 θ

Principal character peak: 6.9,15.1,13.7

Secondary feature peak: 15.4,9.6,19.0

Characteristic peak again: 20.6,27.3,23.4

Preferably, the XRPD map of the oxalate crystal form A of quinazoline derivant (I) provided by the invention 2 θ= 5.43,6.88,7.38,9.56,13.68,15.10,15.43,16.32,16.88,17.68,18.60,19.02,20.58, 21.62,22.33,22.70,23.35,25.68,27.29,27.88,28.53,29.37,31.35,34.89,37.11, There is derivative peak, the error range of above-mentioned 2 θ value is ± 0.2 at 37.78,38.17,38.36,39.65.

Another technical solution of the present invention is to provide a kind of malate crystal form A of quinazoline derivant, XRPD map is in 2 θ

Principal character peak: 6.5,18.8,19.9

Secondary feature peak: 7.5,8.4,9.2

The XRPD map of the malate crystal form A of quinazoline derivant (I) provided by the invention is in 2 θ=5.43, and 6.53, 7.49,8.35,9.17,12.10,13.16,16.17,18.77,19.85,20.79,23.14,23.94,26.66,28.25, There is derivative peak, the error model of above-mentioned 2 θ value at 29.32,30.38,33.24,33.69,34.80,35.97,36.87,37.88 Enclose is ± 0.2.

Another technical solution of the present invention is to provide a kind of benzene sulfonate crystal form A of quinazoline derivant, XRPD map is in 2 θ

Principal character peak: 6.6,14.0,15.3

Secondary feature peak: 7.1,5.5,19.7

Characteristic peak again: 17.8,16.9,21.0

The XRPD map of the benzene sulfonate crystal form A of quinazoline derivant provided by the invention is in 2 θ=5.48, and 6.56, 7.08,7.65,8.14,8.48,9.71,10.55,11.14,11.77,13.32,13.95,15.32,16.46,16.89, 17.82,19.15,19.70,20.43,21.02,21.98,22.68,23.23,25.26,26.07,26.59,28.63, Have at 29.09,30.45,31.12,32.09,32.55,33.66,35.76,37.86,38.67,39.11 and derives peak, above-mentioned 2 The error range of θ value is ± 0.2.

Another technical solution of the present invention is to provide a kind of benzene sulfonate crystal form B of quinazoline derivant, XRPD map is in 2 θ

Principal character peak: 8.5,14.5,23.4

Secondary feature peak: 18.3,19.7

The XRPD map of the benzene sulfonate crystal form B of quinazoline derivant provided by the invention is in 2 θ=5.50, and 6.32, 7.28,8.50,9.74,10.79,11.55,13.22,14.49,15.53,16.26,16.97,18.29,19.71,21.36, There is derivative peak, the error range of above-mentioned 2 θ value is ± 0.2 at 22.21,23.44,24.19,25.34,25.87,27.16.

Another technical solution of the present invention is to provide a kind of benzene sulfonate crystal form C of quinazoline derivant, XRPD map is in 2 θ

Principal character peak: 14.0,14.7,7.7

Secondary feature peak: 8.3,21.2,19.4,

Characteristic peak again: 27.5,24.7

Preferably, the XRPD map of the benzene sulfonate crystal form C of quinazoline derivant (I) provided by the invention 2 θ= 4.24,7.07,7.68,8.31,9.92,12.55,14.03,14.74,18.72,19.40,20.36,21.19,24.08, 24.73,26.14,27.49,28.28,31.68,33.90,34.82,35.06,35.78,36.54,37.57,37.89, There is derivative peak, the error range of above-mentioned 2 θ value is ± 0.2 at 38.36,39.0.

Another technical solution of the present invention is to provide a kind of benzoate crystal form A of quinazoline derivant, XRPD map is in 2 θ

Principal character peak: 7.3,6.3,16.8

Secondary feature peak: 13.5,18.7,27.0

The XRPD map of the benzoate crystal form A of quinazoline derivant (I) provided by the invention is in 2 θ=4.45, and 6.31, 6.65,7.33,7.69,8.01,11.85,13.53,16.02,16.77,18.75,19.95,21.06,21.76,22.56, 23.41,26.94,27.44,27.61,27.98,28.55,29.05,31.92,32.29,32.93,33.72,34.61, There is derivative peak, the error range of above-mentioned 2 θ value is ± 0.2 at 35.35,35.95,37.08,38.13,39.62.

Another technical solution of the present invention is to provide a kind of hippurate crystal form A of quinazoline derivant, XRPD map is in 2 θ

Principal character peak: 5.6,6.9,20.0

Secondary feature peak: 16.0,7.7,13.7

Characteristic peak again: 24.3,26.4

Preferably, the XRPD map of the hippurate crystal form A of quinazoline derivant (I) provided by the invention 2 θ= 4.35,5.59,6.85,7.74,9.17,9.95,13.74,14.73,15.96,16.44,18.10,18.63,19.96, 21.38,24.25,25.37,25.72,26.39,27.23,28.56,30.25,30.82,33.31,34.58,35.29, There is derivative peak, the error range of above-mentioned 2 θ value is ± 0.2 at 36.39,37.24,37.9.

Another technical solution of the present invention is to provide the Crystal form of oxalate A, XRPD of a kind of quinazoline derivant Map is in 2 θ

Principal character peak: 6.4,9.1,17.5

Secondary feature peak: 12.9,14.5,26.4

Characteristic peak again: 19.4,18.3,15.9

Preferably, the XRPD map of the Crystal form of oxalate A of quinazoline derivant (I) provided by the invention is in 2 θ=4.11, 6.44,7.15,8.75,9.06,9.88,11.26,11.58,12.92,14.52,15.87,17.47,18.29,19.43, 20.14,20.49,23.70,24.34,26.36,26.92,29.75,31.72,32.67,32.99,34.21,34.52, There is derivative peak, the error range of above-mentioned 2 θ value is ± 0.2 at 34.86,36.36,36.91,37.91,39.03.

Preferably, there is the hydrochloride Form A of quinazoline derivant of the present invention XRPD substantially as shown in Fig. 1 to scheme Spectrum.

Preferably, there is the hydrochloride Form B of quinazoline derivant of the present invention XRPD substantially as shown in Fig. 2 to scheme Spectrum.

Preferably, the hydrochloride Form C of quinazoline derivant of the present invention has XRPD substantially as shown in Fig. 10 Map.

Preferably, the hydrochloride Form D of quinazoline derivant of the present invention has XRPD substantially as shown in Fig. 11 Map.

Preferably, the hydrochloride Form F of quinazoline derivant of the present invention schemes with substantially as of fig. 9 shown XRPD Spectrum.

Preferably, there is the hydrochloride Form H of quinazoline derivant of the present invention XRPD substantially as shown in Fig. 3 to scheme Spectrum.

Preferably, there is the hydrochloride Form I of quinazoline derivant of the present invention XRPD substantially as shown in Fig. 4 to scheme Spectrum.

Preferably, the fumarate crystal form A of quinazoline derivant of the present invention has XRPD substantially as shown in Fig. 5 Map.

Preferably, the succinate crystal form A of quinazoline derivant of the present invention has XRPD substantially as shown in Fig. 6 Map.

Preferably, the maleate crystal form A of quinazoline derivant of the present invention has XRPD substantially as shown in Fig. 7 Map.

Preferably, the glycollate crystal form A of quinazoline derivant of the present invention has XRPD substantially as shown in Fig. 8 Map.

Preferably, the sulfate crystal form A of quinazoline derivant of the present invention has XRPD substantially as shown in Fig. 12 Map.

Preferably, the oxalate crystal form A of quinazoline derivant of the present invention has substantially as shown in Fig. 13 XRPD map.

Preferably, the malate crystal form A of quinazoline derivant of the present invention has substantially as shown in Fig. 14 XRPD map.

Preferably, the benzene sulfonate crystal form A of quinazoline derivant of the present invention has substantially as shown in Fig. 15 XRPD map.

Preferably, the benzene sulfonate crystal form B of quinazoline derivant of the present invention has substantially as shown in Fig. 16 XRPD map.

Preferably, the benzene sulfonate crystal form C of quinazoline derivant of the present invention has substantially as shown in Fig. 17 XRPD map.

Preferably, the benzoate crystal form A of quinazoline derivant of the present invention has substantially as shown in Fig. 18 XRPD map.

Preferably, the hippurate crystal form A of quinazoline derivant of the present invention has substantially as shown in Fig. 19 XRPD map.

Preferably, the Crystal form of oxalate I of quinazoline derivant of the present invention has XRPD substantially as shown in Fig. 20 Map.

The present invention also provides the method for hydrochloride Form A for preparing quinazoline derivant of the present invention (I) a kind of, packets It includes following steps: quinazoline derivant sample shown in formula (I) is added in organic solvent and 0.8~1.2 equivalent of hydrochloric acid and is taken the photograph in 22-28 Lower layer's solid, which is centrifugated out, after stirring under family name's degree obtains crystal form A；Wherein, quinoline azoles shown in formula (I) is added in every milliliter of organic solvent 10~200 milligrams of quinoline derivant.

The present invention also provides the method for hydrochloride Form B for preparing quinazoline derivant of the present invention (I) a kind of, packets It includes following steps: quinazoline derivant shown in formula (I) is added in organic solvent, and 0.8~1.2 equivalent is added to the suspension Hydrochloric acid stirs under 22-28 degrees Celsius, is centrifugated out the wet sample solid of lower layer and obtains crystal form B；Wherein, every milliliter of organic solvent adds Enter shown in formula (I) 10~200 milligrams of quinazoline derivant.

The present invention also provides the method for hydrochloride Form C for preparing quinazoline derivant of the present invention (I) a kind of, packets It includes following steps: organic solvent is added in quinazoline derivant sample shown in formula (I) and 2~2.5 equivalent of hydrochloric acid is added in 22-28 The wet sample solid of lower layer, which is centrifugated out, after stirring under degree Celsius obtains dihydrochloride crystal form C；Wherein, it is added in every milliliter of organic solvent 10~200 milligrams of quinazoline derivant shown in formula (I).

The present invention also provides the method for hydrochloride Form D for preparing quinazoline derivant of the present invention (I) a kind of, packets It includes following steps: being cooled to 22-28 degrees Celsius after hydrochloride Form C sample is heated to high temperature, obtain dihydrochloride crystal form D.

The present invention also provides the method for hydrochloride Form F for preparing quinazoline derivant of the present invention (I) a kind of, packets It includes following steps: alcohols and based organic solvent will be added in quinazoline derivant hydrochloride Form B shown in formula (I), in 22-28 Degree Celsius lower gas-liquid diffusion, until there is solid that crystal form F is precipitated to obtain；Wherein, hydrochloric acid shown in formula (I) is added in every milliliter of organic solvent 10~200 milligrams of salt crystal form B.

The present invention also provides the method for hydrochloride Form H for preparing quinazoline derivant of the present invention (I) a kind of, packets It includes following steps: organic solvent being added in hydrochloride Form B, (open quick) volatilizees under 22-28 degrees Celsius after filtering Crystal form H；Wherein, hydrochloride Form B 10~200 milligram are added shown in formula (I) in every milliliter of organic solvent.

The present invention also provides the method for hydrochloride Form I for preparing quinazoline derivant of the present invention (I) a kind of, packets It includes following steps: being cooled to 22-28 degrees Celsius after heating hydrochloride Form H sample to high temperature.

The present invention also provides the method for fumarate crystal form A for preparing quinazoline derivant of the present invention (I) a kind of, The following steps are included: after organic solvent is added in the quinazoline derivant shown in formula (I) and 0.4-0.6 equivalent fumaric acid, in 22-28 It is stirred under degree Celsius, solid is collected by centrifugation；Wherein, in every milliliter of organic solvent be added formula (I) shown in quinazoline derivant 10~ 200 milligrams.

The present invention also provides the method for succinate crystal form A for preparing quinazoline derivant of the present invention (I) a kind of, The following steps are included: after organic solvent is added in the quinazoline derivant shown in formula (I) and 0.8-1.2 equivalent succinic acid, in 22-28 It is stirred under degree Celsius, solid is collected by centrifugation and obtains the crystal form；Wherein, quinazoline shown in formula (I) is added in every milliliter of organic solvent 10~200 milligrams of derivative.

The present invention also provides the method for maleate crystal form A for preparing quinazoline derivant of the present invention (I) a kind of, The following steps are included: being stirred under 22-28 degrees Celsius after organic solvent is added in the quinazoline derivant shown in formula (I) and maleic acid It mixes, solid is collected by centrifugation and obtains the crystal form；Wherein, in every milliliter of organic solvent be added formula (I) shown in quinazoline derivant 10~ 200 milligrams.

The present invention also provides the method for glycollate crystal form A for preparing quinazoline derivant of the present invention (I) a kind of, The following steps are included: after organic solvent is added in the quinazoline derivant shown in formula (I) and 0.8-1.2 eq. ethanol acid, in room temperature Lower stirring, is collected by centrifugation solid.

The present invention also provides the method for sulfate crystal form A for preparing quinazoline derivant of the present invention (I) a kind of, packets It includes following steps: organic solvent is added in quinazoline derivant sample shown in formula (I) and 0.8-1.2 equiv. sulfuric acid aqueous solution exists It is stirred under 22-28 degrees Celsius, solid is collected by centrifugation and obtains the crystal form；Wherein, quinoline shown in formula (I) is added in every milliliter of organic solvent 10~200 milligrams of oxazoline derivative.

The present invention also provides the method for oxalate crystal form A for preparing quinazoline derivant of the present invention (I) a kind of, The following steps are included: organic solvent and 0.8-1.2 equivalent ethanedioic acid is added in 22- in quinazoline derivant sample shown in formula (I) It is stirred under 28 degrees Celsius, solid is collected by centrifugation and obtains the crystal form；Wherein, quinoline azoles shown in formula (I) is added in every milliliter of organic solvent 10~200 milligrams of quinoline derivant.

The present invention also provides the method for malate crystal form A for preparing quinazoline derivant of the present invention (I) a kind of, The following steps are included: organic solvent and 0.8-1.2 equivalent malic acid is added in 22- in quinazoline derivant sample shown in formula (I) It is stirred under 28 degrees Celsius, solid is collected by centrifugation and obtains the crystal form；Wherein, quinoline azoles shown in formula (I) is added in every milliliter of organic solvent 10~200 milligrams of quinoline derivant.

The present invention also provides the method for benzene sulfonate crystal form A for preparing quinazoline derivant of the present invention (I) a kind of, The following steps are included: organic solvent and 0.8-1.2 equivalent benzene sulfonic acid is added in 22- in quinazoline derivant sample shown in formula (I) It is stirred under 28 degrees Celsius, solid is collected by centrifugation and obtains the crystal form；Wherein, quinoline azoles shown in formula (I) is added in every milliliter of organic solvent 10~200 milligrams of quinoline derivant.

The present invention also provides the method for benzene sulfonate crystal form B for preparing quinazoline derivant of the present invention (I) a kind of, The following steps are included: organic solvent and 0.8-1.2 equivalent benzene sulfonic acid is added in 22- in quinazoline derivant sample shown in formula (I) It is stirred under 28 degrees Celsius, solid is collected by centrifugation and obtains the crystal form；Wherein, quinoline azoles shown in formula (I) is added in every milliliter of organic solvent 10~200 milligrams of quinoline derivant.

The present invention also provides the method for benzene sulfonate crystal form C for preparing quinazoline derivant of the present invention (I) a kind of, The following steps are included: organic solvent and 0.8-1.2 equivalent benzene sulfonic acid is added in 22- in quinazoline derivant sample shown in formula (I) It is stirred under 28 degrees Celsius, solid is collected by centrifugation and obtains the crystal form；Wherein, quinoline azoles shown in formula (I) is added in every milliliter of organic solvent 10~200 milligrams of quinoline derivant.

The present invention also provides the method for benzoate crystal form A for preparing quinazoline derivant of the present invention (I) a kind of, The following steps are included: organic solvent and 0.8-1.2 equivalent benzoic acid is added in 22- in quinazoline derivant sample shown in formula (I) It is stirred under 28 degrees Celsius, solid is collected by centrifugation and obtains the crystal form；Wherein, quinoline azoles shown in formula (I) is added in every milliliter of organic solvent 10~200 milligrams of quinoline derivant.

The present invention also provides the method for hippurate crystal form A for preparing quinazoline derivant of the present invention (I) a kind of, The following steps are included: organic solvent and 0.8-1.2 equivalent hippuric acid is added in 22- in quinazoline derivant sample shown in formula (I) It is stirred under 28 degrees Celsius, solid is collected by centrifugation and obtains the crystal form；Wherein, quinoline azoles shown in formula (I) is added in every milliliter of organic solvent 10~200 milligrams of quinoline derivant.

The present invention also provides the method for Crystal form of oxalate A for preparing quinazoline derivant of the present invention (I) a kind of, packets It includes following steps: organic solvent and 0.8-1.2 equivalent oxalic acid is added in quinazoline derivant sample shown in formula (I) and is taken the photograph in 22-28 It is stirred under family name's degree, solid is collected by centrifugation and obtains the crystal form；Wherein, quinazoline shown in formula (I) is added in every milliliter of organic solvent to spread out 10~200 milligrams of biology.

In the above-mentioned methods, it is preferred that the organic solvent is alcohols, ethers, esters, fat hydrocarbon, arene have One or more of solvent.

It is furthermore preferred that the alcohol organic solvent is methanol, in ethyl alcohol, isopropanol, normal propyl alcohol, isobutanol, n-butanol It is one or more of.

It is furthermore preferred that the ether organic solvent is ether, isopropyl ether or methyl tertiary butyl ether(MTBE).

It is furthermore preferred that the based organic solvent is ethyl acetate, butyl acetate or isopropyl acetate.

It is furthermore preferred that the organic solvent of ketone is acetone, butanone or 4-methyl-2 pentanone.

It is furthermore preferred that the fat hydrocarbon organic solvent is normal heptane or acetonitrile.

It is furthermore preferred that the arene organic solvent is toluene.

It is further preferred that the preparation method of the hydrochloride Form A of the quinazoline derivant (I), preferably organic molten Agent is methanol.

The preparation method of the hydrochloride Form B of the quinazoline derivant (I), preferably organic solvent are acetonitrile, acetic acid Ethyl ester or tetrahydrofuran/water (15-20/1, v/v).

The preparation method of the hydrochloride Form C of the quinazoline derivant (I), preferably organic solvent are acetone.

The preparation method of the hydrochloride Form D of the quinazoline derivant (I), preferably the temperature range 120- of high temperature 160 degrees Celsius.

The preparation method of the hydrochloride Form F of the quinazoline derivant (I), preferably alcohols are methanol, and esters are second Isopropyl propionate.More preferable methanol, ethyl acetate weight ratio be 1:1.

Preferably organic solvent is ethyl alcohol in the preparation method of the hydrochloride Form H of the quinazoline derivant (I).

The preparation method of the hydrochloride Form I of the quinazoline derivant (I), preferably high-temperature temperature are taken the photograph for 120-130 Family name's degree.

The preparation method of the fumarate crystal form A of the quinazoline derivant (I), preferably organic solvent are methanol, third Ketone, ethyl acetate or volume ratio are tetrahydrofuran/water mixed liquid of 15-20:1.

The preparation method of the succinate crystal form A of the quinazoline derivant (I), preferably organic solvent are methanol or third Ketone.

The preparation method of the maleate crystal form A of the quinazoline derivant (I), preferably organic solvent are acetone.

The preparation method of the glycollate crystal form A of the quinazoline derivant (I), preferably organic solvent are methanol, second Nitrile or ethyl acetate.

The preparation method of the sulfate crystal form A of the quinazoline derivant (I), preferably organic solvent be methanol, acetonitrile, Acetone, ethyl acetate or volume ratio are tetrahydrofuran/water mixed liquid of 15-20:1.

The preparation method of the oxalate crystal form A of the quinazoline derivant (I), preferably organic solvent are methanol or second Acetoacetic ester.

The preparation method of the malate crystal form A of the quinazoline derivant (I), preferably organic solvent are methanol, second Tetrahydrofuran/water mixed liquid that acetoacetic ester or volume ratio are 15-20:1.

The preparation method of the benzene sulfonate crystal form A of the quinazoline derivant (I), preferably organic solvent are methanol.

The preparation method of the benzene sulfonate crystal form B of the quinazoline derivant (I), preferably organic solvent are acetonitrile.

The preparation method of the benzene sulfonate crystal form C of the quinazoline derivant (I), preferably organic solvent are tetrahydrofuran With the mixed solvent (volume ratio 15-20:1, more preferably 19:1) of water.

The preparation method of the benzoate crystal form A of the quinazoline derivant (I), preferably organic solvent are methanol, second Nitrile, acetone or volume ratio are tetrahydrofuran/water mixed liquid of 15-20:1.

The preparation method of the hippurate crystal form A of the quinazoline derivant (I), preferably organic solvent are methanol.

The preparation method of the Crystal form of oxalate A of the quinazoline derivant (I), preferably organic solvent are methanol.

The present invention also provides a kind of pharmaceutical composition, the composition includes quinazoline derivant shown in formula (I) Hydrochloride Form A, B, C, D, F, H, I, sulfate crystal form A, maleate crystal form A, succinate crystal form A, adipate crystal form A, glycollate crystal form A, malate crystal form A, fumarate crystal form A, benzene sulfonate crystal form A, B, C, benzoate crystal form A, Hippurate crystal form A and Crystal form of oxalate A or their combination and pharmaceutically acceptable auxiliary material or complementary ingredient.

Preferably, the auxiliary material or auxiliary sexual element include carrier, excipient, diluent, medium, adjuvant.

The present invention also provides the hydrochloride Form A, B, C, D, F, H, I of quinazoline derivant shown in a kind of formula (I), sulphur Hydrochlorate crystal form A, maleate crystal form A, succinate crystal form A, adipate crystal form A, glycollate crystal form A, malate are brilliant Type A, fumarate crystal form A, benzene sulfonate crystal form A, B, C, benzoate crystal form A, hippurate crystal form A and Crystal form of oxalate A Or above-mentioned pharmaceutical composition treats or prevents the drug by EGF-R ELISA EGFR protein mediated disease in preparation In purposes.

Preferably, the drug is that treatment or prevention are protein mediated by EGF-R ELISA EGFR, and are The drug of disease caused by EGFRVIII Activating mutations.

The drug be treat or prevent it is protein mediated by EGF-R ELISA EGFR, and be EGFR Del19 and/ Or the drug of disease caused by EGFR L858R Activating mutations.

It is furthermore preferred that the drug is that preparation treats or prevents brain transplantation of non small cell Lung transfer, meninx transfer, incidence squama The drug of shape cell cancer, squamous cell carcinoma, brain stem tumor, primary brain cancer or glioma.

Those of ordinary skill in the art can according to its knowledge and experience, dosage and method to agents useful for same of the present invention into Row adjustment, including raw material or solvent usage are proportionally zoomed in or out, the scheme of these adjustment is also contained in side of the invention In method.

Compared with prior art, the invention has the following beneficial effects:

1) quinazoline derivant (I) and its pharmaceutical salts that novel chirality of the invention is R have having beyond expection Across the ability of blood-brain barrier, and can be as the medicinal property of kinases inhibitor, in particular for passing through epidermal growth factor The medical conditions that certain activated mutated forms of sub- receptor mediate are (for example, the missing activation of epidermal growth receptor EGFR exon 2-7 Mutant), for example, the glioma with EGFRVIII mutation, and can be used to treat or prevent abnormal protein kinase activity Relevant disorder, such as cancer, cancer brain metastes, the transfer of cancer meninx and nerve center disease etc..

2) quinazoline derivant of the invention (I) and its pharmaceutical salts have low discharge rate, are not P- glycoprotein outlet enzyme bottoms Object or breast carcinoma resistance outlet zymolyte can reduce the drug resistance generated by outlet enzyme.

3) quinazoline derivant of the invention and its pharmaceutical salts have good pharmacokinetics and high bioactivity, can drop The tablet of low patient takes in burden, improves the tablet intake compliance of patient.

4) the hydrochloride Form A, B, C, D, F, H, I of quinazoline derivant of the present invention (I) provided by the invention, sulfate are brilliant Type A, maleate crystal form A, succinate crystal form A, adipate crystal form A, glycollate crystal form A, malate crystal form A are rich Horse hydrochlorate crystal form A, benzene sulfonate crystal form A, B, C, benzoate crystal form A, hippurate crystal form A and Crystal form of oxalate A have good Good stability and water solubility is conducive to process in drug and use in pharmaceutical composition, can treat prominent by EGFR activation Become the cancer that (for example, EGFRVIII, EGFR del19 or EGFR L858R) is mediated, for example, brain transplantation of non small cell Lung shifts, The application of meninx transfer, head and neck squamous cell carcinoma, squamous cell carcinoma, brain stem tumor, primary brain cancer or glioma etc., and And there is preferable bioavilability, while providing the qualitative, quantitative information of efficacy and saferry, it is such solid to further studying The curative effect of body drug has great importance.

Detailed description of the invention

Upon reading the detailed description of non-limiting embodiments with reference to the following drawings, other feature of the invention, Objects and advantages will become more apparent upon:

Fig. 1 is the XRPD map of the hydrochloride Form A of quinazoline derivant of the invention；

Fig. 2 is the XRPD map of the hydrochloride Form B of quinazoline derivant of the invention；

Fig. 3 is the XRPD map of the hydrochloride Form H of quinazoline derivant of the invention；

Fig. 4 is the XRPD map of the hydrochloride Form I of quinazoline derivant of the invention；

Fig. 5 is the XRPD map of the fumarate crystal form A of quinazoline derivant of the invention；

Fig. 6 is the XRPD map of the succinate crystal form A of quinazoline derivant of the invention；

Fig. 7 is the XRPD map of the maleate crystal form A of quinazoline derivant of the invention；

Fig. 8 is the XRPD map of the glycollate crystal form A of quinazoline derivant of the invention；

Fig. 9 is the XRPD map of the hydrochloride Form F of quinazoline derivant of the invention；

Figure 10 is the XRPD map of the hydrochloride Form C of quinazoline derivant of the invention；

Figure 11 is the XRPD map of the hydrochloride Form D of quinazoline derivant of the invention；

Figure 12 is the XRPD map of the sulfate crystal form A of quinazoline derivant of the invention；

Figure 13 is the XRPD map of the oxalate crystal form A of quinazoline derivant of the invention；

Figure 14 is the XRPD map of the malate crystal form A of quinazoline derivant of the invention；

Figure 15 is the XRPD map of the benzene sulfonate crystal form A of quinazoline derivant of the invention；

Figure 16 is the XRPD map of the benzene sulfonate crystal form B of quinazoline derivant of the invention；

Figure 17 is the XRPD map of the benzene sulfonate crystal form C of quinazoline derivant of the invention；

Figure 18 is the XRPD map of the benzoate crystal form A of quinazoline derivant of the invention；

Figure 19 is the XRPD map of the hippurate crystal form A of quinazoline derivant of the invention；

Figure 20 is the XRPD map of the Crystal form of oxalate A of quinazoline derivant of the invention；

Figure 21 is the inhibition schematic diagram of quinazoline derivant of the invention to EGFRVIII phosphorylation；

Figure 22 is that quinazoline derivant of the invention is illustrated in the drug efficacy study of humanization glioma mouse subcutaneous model Figure；

Figure 23 is TGA the and DSC map of quinazoline derivant fumarate of the invention；Wherein, a is TGA map, without bright Aobvious weightlessness；B is DSC map, and crystal form is stable during heating, and crystal form does not change, and fusing point is 240 degrees Celsius；

Figure 24 is the inhibiting mechanism schematic diagram of quinazoline derivant and EGFR of the invention.

Specific embodiment

Term of the present invention is explained as follows:

Term " improvement " and " treatment " may be used interchangeably, and indicate to reduce, weaken, inhibit, reduce, prevent or stablize disease The generation or progress (for example, disease described herein or disorder) of disease, refer to a kind of method for obtain include it is beneficial or It is desired as a result, but being not limited to treatment benefit and/or preventative benefit.

" disease " refer to damage or interfere cell, organ or tissue normal function any illness or disorder.

" marker " refers to any change relevant to disease or disorder.For example, expression water relevant to disease or disorder Flat or activity has any albumen or multicore acid anhydride acid of change.

Herein, " comprising ", " containing " and " having " and similar terms have the meaning that them are assigned in Patent Law； "consisting essentially of ..." or " consisting essentially of " equally assign their meaning with Patent Law, and the term is open Formula, allow the presence of the object other than cited object, as long as the basis for the object that is cited or new feature not because cited object with The presence of outer object and change, but do not include the embodiment of the prior art.

As used herein term " antagonist " and " inhibitor " are used interchangeably, they refer to compound or reagent tool There are the ability for the biological function for inhibiting targeting proteins or polypeptide, such as activity or expression by inhibiting protein or polypeptide. Although some antagonists and specific target protein or polypeptide effect (for example, in conjunction with EGFR) herein, compound by with others Other members of the signal transduction path of targeting protein or polypeptide interact and inhibit the bioactivity of target protein or polypeptide Also clearly include in this definition, also include inhibiting and developing, growth, or the tumour of diffusion, or shown in autoimmune disease Those of undesirable immune response correlation bioactivity.

As used herein term " anticancer agent ", " antitumor agent " or " chemotherapeutics " refers to be had in neoplastic conditions treatment Any reagent.A kind of anticancer agent includes chemotherapeutics." chemotherapy " refer to one or more chemotherapeutics and/or other reagents with By various methods, including it is intravenous, it takes orally, it is subcutaneously, intramuscular, in peritonaeum, in bladder, percutaneously, cheek, or the form sucked is to cancer Disease patient application.

As used herein term " cell Proliferation ", which refers to, to be increased by cell number as fissional result The phenomenon that, also include and the consistent cell growth (for example, size increase) changed by the cellular morphology of proliferation signal.

As used herein term " co-administration ", refers to and two or more drugs is used alone in the same time, Be included in the same time using all existing composition of two or more reagents, be also included within the different time be administered alone or Apply two or more drugs and/or its metabolin.

As used herein term " effective quantity " or " effective therapeutic dose " refer to compound as described herein or medicine group The amount for closing object is to sufficiently achieve expected application, includes, but are not limited to treat disease.In some embodiments, the amount is Detect effective for killing or inhibiting growth of cancer cells or diffusion；The size or quantity of tumour；Or the seriousness water of cancer It is flat, stage and progress.Effective therapeutic dose can change according to scheduled application, such as external or internal, the situation of disease And severity, subject age, weight or administration mode etc..The term is also applied for dosage for inducing target cell, for example, Reduce a specific response of cell migration.Specific dosage will depend on, for example, choosing in specific compound, subject The risk of species and their age/existing health status or health status, administration route, the severity of disease, with it His medicament combination medicine-feeding, administration time, tissue and drug delivery device for being applied to it etc..

As used herein term " therapeutic effect ", including treatment benefit and/or prevention benefit.Preventive effect includes prolonging Late or eliminate the appearance of disease or illness, delay or the paresthesia epilepsy for eliminating disease or illness, slow down, stop or reverse disease or The progress of illness or their any combination.

As used herein term " signal transduction " be during this period, stimulation or inhibit signal be sent into the cell with Cause the process responded into the cell, " regulator " of signal transduction pathway refers to that compound adjusts one or more cell proteins Activity pass through signal specific transduction pathway." regulator " can increase (agonist) or inhibit (antagonist) signal transduction molecule Activity.

As used herein term " selective depression " reduces echo signal conduction with referring to the compound property of can choose Active ability is compared for signal activity of missing the target, and direct interaction or Indirect Interaction etc. are passed through.For example, a chemical combination The activity of the EGFR of object selective depression mutation is to be directed at least about 2 times of the activity of Wild type EGFR, about 3 times, about 5 times, and about 10 Times, about 20 times, about 50 times, about 100 times or more.

As used herein term " radiotherapy " refers to that subject is exposed to radiation transmitter, such as, but not limited to, Alpha particle emits radioactive nucleus element (for example, actinium and thorium radioactive nucleus element), low linear energy transfer (LET) radiation transmitter (that is, beta emitter), converted electronic emission device (for example, strontium -89 and samarium 153-EDTMP) or high-energy radiation, include, but are not limited to X-ray, gamma-rays and neutron.

Term " subject " as used herein includes, but are not limited to the mankind (that is, any age group, for example, a size The sex (for example, baby, children, teenager) of section subject or Adult human subjects are (for example, Young adult, the middle year's harvest People or advanced adult)) and/or other primates (for example, machin, rhesus macaque)；Mammal, including the related food in one's mouth of business Newborn animal, such as ox, sheep, goat, pig, horse, cat and/or dog；And/or birds, including the relevant birds of business, such as chicken, goose, Quail, duck and/or turkey.

Term " internal " as used herein refers to the intracorporal activity of body occurred in subject.It is also included within and nibbles in vivo The event occurred in tooth class animal, such as rat, mouse, cavy and analog.

Term " external " as used herein refers to the event that the place other than body occurs at one.For example, external Testing inspection includes any detection for occurring to carry out except body.External test includes the cell based on alive or dead cell Measurement, is also included within without cell-less measurement method used in complete cell.

As used herein term " compound ", is also intended to the salt, prodrug and prodrug of the general formula compound including this paper Salt.The term further includes any one of aforementioned any solvate, hydrate and polymorph.This hair described in this application In bright some aspects, the specific of " prodrug ", " prodrug salt ", " solvate ", " hydrate " or " polymorph " is quoted not Should be interpreted using term " compound " without quote these other forms other aspects of the present invention in, it is intended that Exclude these forms.

The salt of the compound of the present invention is in the sour basic group with compound, such as is formed between amido functional group.According to Another preferred embodiment, the compound are pharmaceutically acceptable acid-addition salts.

The salt of the compound of the present invention such as is formed in the acidic-group of alkali and compound between carboxyl functional group.According to Another preferred embodiment, the compound are pharmaceutically acceptable base addition salts.

As used herein and unless otherwise specified, term " prodrug " refers to the derivative of compound, can be in biology It hydrolyzed under condition (in vitro or in vivo), aoxidize or otherwise react to provide the compound of the present invention.Prodrug can be only Become active after such reaction under biological condition, or can be active under its unreacted form.Of the invention The example of prodrug includes, but are not limited to the analog or derivative of the compound of any one general formula disclosed herein, also includes The hydrolyzable part of biology, such as amide and ester analogs.

Prodrug salt is the basic group of acid with prodrug, such as the acidic-group of amido functional group or alkali and prodrug, such as carboxylic The compound formed between base functional group.In one embodiment, prodrug salt is pharmaceutically acceptable salt.

Particularly preferred prodrug and prodrug salt are when such compound is for increasing change of the invention when mammal or people It closes the bioavilability (for example, by making the compound of oral administration be easier to be absorbed) of object or promotes relative to parent species Compound is delivered to those of biological compartment (for example, brain or central nervous system).Preferred prodrug includes that will wherein increase water Dissolubility increases derivative of the group addition for passing through the active transport of goldbeater's skin on general formula structure as described herein.Referring to example Such as, Design of Prodrugs, edited by H.Bundgaard, (Elsevier, 1985) and Methods in Enzymology,Vol.42,p.309-396,edited by K.Widder,et al.(Academic Press,1985)；A Textbook of Drug Design and Development,edited by Krogsgaard-Larsen and H.Bundgaard, Chapter 5 " Design and Application of Prodrugs ", by H.Bundgaard p.113-191(1991)；H.Bundgaard,Advanced Drug Delivery Reviews,8,1-38(1992)； H.Bundgaard,et al.,Journal of Pharmaceutical Sciences,77,285(1988)；and N.Kakeya, et al., Chem Pharm Bull, 32,692 (1984) are described.

Term " pharmaceutically acceptable " as used herein refers within the scope of reasonable medicine, is suitable for and people and other The tissue of mammal contacts without excessive toxicity, irritates, allergic reaction etc., and has the group of reasonable interests/Hazard ratio Point." pharmaceutically acceptable salt " refers to any avirulent salt, after being applied to receptor, can directly or indirectly provide this The compound of invention or the prodrug of compound.

The acid for being commonly used to form pharmaceutically acceptable salt includes inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, hydroiodic acid And phosphoric acid and organic acid, such as trifluoroacetic acid, citric acid, maleic acid, oxalic acid, picric acid, acetic acid, adipic acid, alginic acid, day Aspartic acid, sulfuric acid, boric acid, butyric acid, valeric acid, camphoric acid, thiocyanic acid camphorsulfonic acid, didextrose acid, dodecyl sulphate, new penta Acid, formic acid, enanthic acid, fumaric acid, hydroiodic acid, benzoic acid, 2- hydroxy-ethanesulfonic acid, fumaric acid, stearic acid lactobionic acid, propionic acid laurel Acid, oleic acid nitric acid niacin, lactic acid cinnamic acid, succinic acid, mandelic acid, malic acid, tartaric acid, two tartaric acid, lactic acid, pyruvic acid, Pectic acid, methanesulfonic acid flutter acid, benzene sulfonic acid, persulfuric acid, palmitinic acid, malonic acid phosphoglycerol, 2- naphthalene sulfonic acids, p-methyl benzenesulfonic acid, water Poplar acid, ascorbic acid, 3- phenylpropionic acid, gluconic acid, glucuronic acid, phosphoric acid, glutamic acid, ethanesulfonic acid, to bromo-benzene sulfonic acid and Carbonic acid and relevant inorganic and organic acid.The alkali for being commonly used to form pharmaceutically acceptable salt includes alkali metal, alkaline earth gold Belong to, ammonium salt, N⁺(C1-4 alkyl)₄Salt and relevant inorganic and organic base.Representative alkali and alkaline earth metal ions such as sodium, The salt that lithium, potassium, calcium, magnesium, iron, copper, manganese, zinc, aluminium etc. and organic base are formed, including, for example, primary, secondary and tertiary aminess replace amine, Including naturally occurring substitution amine, cyclammonium, deacidite and analog, such as isopropylamine, trimethylamine, diethylamine, three Ethamine, tripropyl amine (TPA) and ethanol amine.In some embodiments, pharmaceutically acceptable base addition salts can be from ammonium, potassium, sodium, calcium It is selected with magnesium salts.See, e.g. Berge et al.J.Pharmaceutical Sciences (1977) 66:1-19.

As used herein term " hydrate " refers to including stoichiometry or non-stoichiometric passes through non-covalent bond The compound for the water that intermolecular force combines.As used herein term " solvate " refers to including stoichiometry or non- The compound for the solvent of stoichiometry combined by active force between Non-covalent molecular, the solvent such as water, methylene chloride, 2- Propyl alcohol, acetone, methanol, ethyl alcohol or the like.Pharmaceutically acceptable solvate and hydrate are compounds, for example, can be with Including 1 to about 100 or 1 to about 10 or 1 to about 4, about 3 or about 2, solvent or hydrone.It should be understood that as used herein Term " compound " include the compound and compound solvate, hydrate and their mixture.

As used herein term " polymorph " refers to compound or the solid crystallization way of its compound.Mutually assimilate The different polymorphs for closing object can show different physics, chemistry and/or spectral property.Different physical properties include, but It is not limited to stability (for example, to heat, light or moisture), density, hygroscopicity, soluble, compressibility and rate of dissolution.

Term " isomers " as used herein is the different compounds with identical molecular formula." stereoisomer " is only In the different isomers of the space arrangement mode of atom." isomers " word includes any and all several as used herein What isomers and stereoisomer.For example, " isomers " includes the cis and trans isomer of geometry double bond, also referred to as E- and Z- Isomers；R- and S- enantiomer；Diastereomer, (D) isomers and (L) isomers, racemic mixture and they its Its mixture, it is disclosed herein.

Be designated as around carbon-to-carbon substituent group double bond in " Z " or " E " configuration, wherein term " Z " and " E " according to IUPAC Standard uses.Unless otherwise specified, structure delineation double bond both included " E " and " Z " isomers.

Interchangeable substituent group around carbon-to-carbon double bond can be referred to as " cis- " or " trans- ", take wherein " cis- " refers to For Dai Ji in the same side of double bond, " trans- " represents substituent group in the two sides of double bond.The arrangement of surrounding's carbocyclic ring of substituent group can also be with It is designated as " cis- " or " trans- "." cis- " the same side substituent group indicated in plane of a loop of term, " trans- " the expression ring of term The two sides substituent group of plane.Wherein the mixture of compound of the substituent group in the identical and opposite side of the plane of two rings indicates For " cis/trans ".

It is each other the stereoisomer of non-superimposable mirror image that term " enantiomer " as used herein, which is a pair of,.A pair with The mixture of the enantiomer of any ratio is referred to alternatively as " racemic " mixture.Term " (±) " is used in appropriate specified racemic Mixture." diastereo-isomerism " refers to at least two asymmetric atoms, but its stereoisomer is mutual mirror image Picture.Absolute stereochemistry is specified according to Cahn-lngold-Prelog R-S system.When compound is enantiomer, in each chiral carbon Spatial chemistry can be by being appointed as R or S.The compound of fractionation, absolute configuration are unknown, it is possible to specify (+) or (-), this depends on them in the direction (dextrorotation or left-handed) of the wavelength Plane of rotation polarised light of sodium D-line.

Refer to the compound in compound or (S)-that each asymmetric atom is (R)-, pharmaceutical composition for absolute stereo Object and method include all these possible isomers, including racemic mixture, optical voidness form and intermediate mixture.Light It learns active (R)-and (S)-Chiral Synthesis also can be used or prepared by chiral reagent, or torn open using routine techniques Point.

The composition of term " enantiomeric excess " or " % enantiomeric excess " is usable as follows as used herein Formula calculate.In example shown in below, composition contains a kind of 90% enantiomer, for example, S enantiomer, and Containing 10% another enantiomer, for example, R enantiomer.

Ee value=(90-10)/100=80%.

Therefore, the composition for being 10% containing a kind of 90% enantiomer and another enantiomer is said to be with enantiomer mistake Amount 80%.Some compositions as described herein contain at least about 50% enantiomeric excess, about 75%, about 90%, about 95%, or About the 99% of S enantiomer.In other words, the composition includes the S enantiomer of enantiomeric excess in R enantiomer.In other implementations In scheme, some compositions as described herein contain at least about 50% enantiomeric excess, about 75%, about 90%, about 95%, or About the 99% of R enantiomer.In other words, the composition includes the R enantiomer of enantiomeric excess in S enantiomer.For example, one different Structure body/enantiomter can be in some embodiments, it is possible to provide the ee value of corresponding enantiomter, and can also be by Referred to as " optically enriched ", " enantiomer enrichment ", " enantiomer-pure " and " non-raceme ", as interchangeably used herein.These Term refers to that the weight percent of one of enantiomer is control of the composition than the racemic composition in a kind of enantiomer The amount of mixture is bigger (for example, the weight ratio for being greater than 1:1).For example, the enantiomer of S enantiomer is enriched with the S enantiomer of (weight) Relative to R enantiomer, the method for such as by weight at least about 75% compound with greater than about 50%, also as at least About 80% (weight).In some embodiments, enrichment is greater than by weight about 80%, provides " substantially enantiomer enrichment ", the preparation of " substantially enantiomer-pure " or " substantially non-racemic ", this refers to that the enantiomer of its weight is right relative to other The composition that one of isomers has at least 85%, such as by weight at least about 90% preparation are reflected, and further, such as By weight at least about 95%.In certain embodiments, compound provided herein can be by a kind of mapping of at least weight About the 90% of isomers.In other embodiments, the compound can by least about 95%, about 98% or weight one About the 99% of kind enantiomter.In some embodiments, the compound is (S)-and (R)-racemic mixture.At it In his embodiment, there is provided herein a kind of methods, and wherein the single compound (S)-of mixture is mainly existing compound Mixture or (R)-mixture of compound for being primarily present.For example, (S)-enantiomer that the compound mixture has Excessive greater than about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5%, or more.In other embodiments, the mixture of compound has (S)-enantiomeric excess be greater than about 55% to about 99.5%, greater than about 60% to about 99.5%, greater than about 65% to about 99.5%, greater than about 70% to about 99.5%, greater than about 75% to about 99.5%, greater than about 80% to about 99.5%, greater than about 85% to about 99.5%, greater than about 90% to about 99.5%, greater than about 95% to about 99.5%, greater than about 96% to about 99.5%, greater than about 97% to about 99.5%, greater than about 98% to greater than about 99.5%, greater than about 99% to about 99.5%, or It is higher.In other embodiments, compound mixture (R)-enantiomeric purity has greater than about 55%, about 60%, about 65%, About 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5% or more.In some other embodiment, there is the mixture of compound (R)-enantiomeric excess to be greater than about 55% To about 99.5%, greater than about 60% to about 99.5%, greater than about 65% to about 99.5%, greater than about 70% to about 99.5%, greatly In about 75% to about 99.5%, greater than about 80% to about 99.5%, greater than about 85% to about 99.5%, greater than about 90% To about 99.5%, it is greater than 95% to about 99.5%, greater than about 96% to about 99.5%, greater than about 97% to about 99.5%, is greater than About 98% to greater than about 99.5%, greater than about 99% to about 99.5% or more.

In other embodiments, which includes, in addition to their stereochemical orientation, i.e., (S)-or (R)-identical chemical entities.For example, if disclosing in compound here has-CH (R)-unit, and R is not hydrogen, that - CH (R)-is the orientation in the identical chemical entities of each of (S)-or (R)-spatial chemistry.In some embodiments, exist (S)-isomers in the mixture of identical chemical entities is present in (S)-enantiomeric excess and is greater than about 55% to about 99.5%, greater than about 60% to about 99.5%, greater than about 65% to about 99.5%, greater than about 70% to about 99.5%, greater than about 75% to about 99.5%, greater than about 80% to about 99.5%, greater than about 85% to about 99.5%, greater than about 90% to about 99.5%, greater than about 95% to about 99.5%, greater than about 96% to about 99.5%, greater than about 97% to about 99.5%, greater than about 98% to greater than about 99.5%, greater than about 99% to about 99.5% or more.

In another embodiment, (R)-isomers is in the mixture of identical chemical entities (in addition to its spatial chemistry takes To) relative to (S)-isomers, it is about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5% or higher.In some embodiments, (R)- In mixture (in addition to its stereochemical orientation) isomers of identical chemical entities, it is present in (R)-enantiomeric excess and is greater than about 55% to about 99.5%, greater than about 60% to about 99.5%, it is greater than 65% to about 99.5%, greater than about 70% to about 99.5%, greater than about 75% to about 99.5%, greater than about 80% to about 99.5%, greater than about 85% to about 99.5%, greater than about 90% to about 99.5%, greater than about 95% to about 99.5%, greater than about 96% to about 99.5%, greater than about 97% to about 99.5%, greater than about 98% to greater than about 99.5%, greater than about 99% to about 99.5%, or more.

Enantiomter can pass through any method of known those skilled in the art, including chirality from racemic mixture High performance liquid chromatography (HPLC), the formation and crystallization of chiral salt or asymmetric synthesis are separated.See, e.g., Enantiomers,Racemates and Resolutions(Jacques,Ed.,Wiley lnterscience,New York,1981)；Wilen et al.,Tetrahedron 33:2725(1977)；Stereochemistry of Carbon Compounds(E.L.Eliel,Ed.,McGraw-Hill,NY,1962)；and Tables of Resolving Agents And Optical Resolutions p.268 (E.L.EIM, Et al., Univ.of Notre Dame Press, Notre Dame,Ind.1972).

Optical isomer can also be obtained with optically active acid or alkali according to a conventional method by resolving racemic mixtures, example Such as, by forming diastereomeric salt.The example of suitable acid includes, but are not limited to tartaric acid, diacetyl, dibenzoyl, Ditoluoyltartaric and camphorsulfonic acid.Diastereomer crystallization then obtains from the mixture of optically active alkali of these salt different The separation of structure body.Another method passes through the optically pure acid or optically pure isocyanic acid of disclosed compound and activated form Ester reaction is related to the synthesis of covalent diastereo-isomerism molecule.Synthesizing enantiomter can steam by conventional method such as chromatography It evaporates, crystallizes or distil, then hydrolyze to provide enantiomer enriched compound and be separated.Optically active compound can also pass through It is obtained using activated feedstock.In some embodiments, these isomers can be with free acid, free alkali, the shape of ester or salt Formula.

In certain embodiments, pharmaceutically acceptable form is a tautomer.Terms used herein " interconversion Isomers " is a type of isomers comprising two or more compounds mutually converted are from hydrogen atom and covalently The migration of at least one form of key and change gained (for example, singly-bound is to double bond, three keys to singly-bound, or vice versa)." interconversion Isomery " includes proton or proton transfer tautomerism, is considered the subset of Acid-Base chemistry." proton transfer tautomerism " or " proton translocation tautomerism " is related to the proton transfer changed with bond order.The definite ratio of tautomer depend on it is several because Element, including temperature, solvent and pH value.Wherein, tautomerism is possible (for example, in the solution), the chemistry of tautomer Balance is i.e. reachable.Tautomerization (that is, providing the reaction of tautomer pair) can be by sour or base catalysis or no external The effect or presence of agent can occur.Such as tautomerization includes, but are not limited to ketone to enol；Amide is to acid imide；Interior acyl Amine is to lactim；Enamine is to imines；With a form of enamine to different enamines.Ketone to enol tautomeric specific reality Example is pentane -2,4- diketone and the amyl- 3- alkene -2- keto tautomer of 4- hydroxyl.Tautomeric another example is that phenol and ketone are mutual Make a variation structure.Phenol and the tautomeric specific example of ketone are pyridine 4- phenol and pyridine -4 (1H) -one tautomer.

Unless otherwise indicated, also mean that structure as described herein includes compound, only in one or more isotope enrichments The presence of atom.For example, compound has this structure for replacing a hydrogen by deuterium or tritium, or in the range of replacement the displosure What carbon 13 or carbon 14 were enriched with.

The disclosure also includes those " derivatives of isotope labelling ", is those identical compounds enumerated herein Pharmaceutically acceptable form, the difference is that one or more atoms are had originals different from what is be generally found in nature The atom of protonatomic mass or mass number is replaced.The example for the isotope that can be incorporated into disclosed compound includes hydrogen, carbon, nitrogen, The isotope of oxygen, phosphorus, fluorine and chlorine, such as²H,³H,¹³C,¹⁴C,¹⁵N,¹⁸O,¹⁷O,¹⁸F, and³⁶Cl.Certain isotope labellings it is disclosed Compound is (for example, those are indicated³H and¹⁴C measurement compound and/or substrate tissue distribution) be can be used for.Tritium is (i.e.³) and carbon H 14 (i.e.¹⁴C) isotope can be readily made and detect.In addition, with heavier isotope such as deuterium (that is,²H or D) replace can provide The certain treatment advantages (for example, increasing half-life period in vivo or reduced dose requirements) generated by larger metabolic stability. The disclosed compound of isotope labelling can usually pass through the examination to a kind of isotope-labeled reagent substitution isotope labelling It is prepared by agent.In some embodiments, it provided herein is can also contain one or more non-natural atom isotope groups At this compound.All isotopic variations of compound as disclosed are used herein, regardless of whether being radioactivity, all In range disclosed herein.In some embodiments, radiolabeled compound can be used for studying metabolism and Compound Tissue distribution is to change metabolic pathway or rate or other biological functions.

Term " CDCl₃" refer to deuterated chloroform.

Term " DMSO-d6 " refers to deuterated dimethyl sulfoxide

Term " LC-MS:(ESI) " refer to electrospray ionisation liquid chromatography mass

Albumen " change " is defined as used herein, the term, changes relative to normal physiological condition.Show The change of example property includes mutation, missing and other protein fusions, overexpression or low expression.

The compound of the present invention:

On the one hand, the present invention provides the compound of formula (I):

Or its salt；Or the salt of its prodrug or its prodrug；Or its hydrate, solvate or polymorph.

The synthesis of the chiral novel quinazoline quinoline derivant (I) for being R of the present invention can be easily by commonly synthesizing chemistry Technical staff realizes.For example, correlation technique disclosed herein and intermediate.Each patent being mentioned above, patent Shen Please and publication be integrally incorporated herein by reference regardless of it can be obtained in traditional magazine or only by internet.

The other modes for synthesizing compound described herein (I) can easily be changed from references cited herein It is dynamic.The version of these programs and its optimization are in the limit of power of those of ordinary skill.

The present invention also provides compositions comprising a effective amount of compound as described herein, or if applicable, the chemical combination Pharmaceutically acceptable salt, solvate, hydrate, polymorph or the prodrug of object；And acceptable carrier.Preferably, originally The composition of invention prepares (" pharmaceutical composition ") for pharmaceutical usage, wherein the carrier is pharmaceutically acceptable carrier.It examines Consider compatible with preparation other compositions, and in the case where pharmaceutically acceptable carrier, the carrier must be " acceptable ", do not damage its recipient under the amount being typically used in drug.

" pharmaceutically acceptable carrier " or " pharmaceutically acceptable excipient " includes any and all solvents, and dispersion is situated between Matter, coating, antibacterial agent and antifungal agent, wait and blend absorption delaying agent and the like.Pharmaceutically acceptable carrier or figuration Agent does not destroy the pharmacological activity of disclosed compound, is nontoxic when being applied with the dosage for being enough the therapeutic dose of the compound delivered 's.It is well known in the art for pharmaceutically active substances using such medium and reagent.Unless any conventional media Or reagent is incompatible with active constituent, it is expected in the use of therapeutic combination as disclosed herein.It is pharmaceutically acceptable Carrier example and excipient include but is not limited to: sugar, for example, lactose, sucrose and glucose；Starch, for example, potato is formed sediment Powder and cornstarch；Cellulose and its derivates, such as sodium carboxymethylcellulose, cellulose acetate and ethyl cellulose；Gelatin； Tragacanth gum powder；Talcum；Malt；Cocoa butter and suppository wax；Oil, for example, peanut oil, safflower oil, cottonseed oil, olive oil, sesame Oil, corn oil and soybean oil；Glycol, such as polyethylene glycol and propylene glycol；Ester, for example, ethyl oleate and ethyl laurate；Fine jade Rouge；Buffer, for example, magnesium hydroxide and aluminium hydroxide；Alginic acid；Ringer's solution；Isotonic saline solution；Ethyl alcohol；Phosphate buffer； The lubricant of non-toxic compatible, for example, NaLS and magnesium stearate；Colorant；Coating agent；Releasing agent；Sweetener, seasoning Agent and aromatic；Antioxidant；Preservative；Ion exchange；Aluminium oxide；Lecithin；Aluminum stearate；Self-emulsifying drug delivery systems (SEDDS) such as TPGS 1000；For the surfactant of pharmaceutical dosage form, for example, Tweens or its Its similar polymeric delivery matrices；Haemocyanin, for example, human serum albumins；Glycine；Sorbic acid；Potassium sorbate；It is full With the partial glyceride mixture of vegetable fatty acid；Water, salt or electrolyte, for example, protamine sulfate, potassium hydrogen phosphate, phosphoric acid hydrogen Disodium, sodium chloride and zinc salt；Colloidal silicon dioxide；Magnesium trisilicate；Polyvinylpyrrolidone；Substance based on cellulose；Poly- third Olefin(e) acid ester；Wax；With polyethylene-polyoxypropylene-block polymer.Cyclodextrin, for example, alpha, beta and gamma- cyclodextrin, Or the derivative of chemical modification, for example, hydroxyalkylcyclodextrins, including 2- and 3- hydroxy propyl cyclodextrin or other for improving The derivative of the solubilising of the delivering of compound as described herein.

Pharmaceutical composition of the invention can be in solid or liquid form for being administered, comprising: oral administration, for example, It gavages agent (aqueous or non-aqueous solution or suspension), tablet (for example, those are directed to oral cavity, sublingual and systemic Absorption), firmly Or soft capsule, pill, syrup, powder, granule, paste are applied to tongue, intraduodenal route；Parenteral administration, including vein Interior, intra-arterial is subcutaneously, intramuscular, and intraocularly, lung is intravascular, in peritonaeum or is infused, for example, sterile solution or suspension, or continue Delivery formulations；Local use, such as emulsifiable paste, ointment, gelling agent, aqueous or oily solution or suspension, or it is suitable for skin The control-released plaster of skin is spraying；In intravaginal or rectum, such as vaginal suppository, emulsifiable paste, bracket or foam；Sublingual administration； It is locally transmitted by conduit or bracket；Intrathecal or nose is used by being blown into use (such as attritive powder) or pass through sucking (such as attritive powder or Liquid Aerosol).

Suitable aqueous and non-aqueous carrier example includes water in pharmaceutical composition, ethyl alcohol, polyalcohol (such as glycerol, Propylene glycol, polyethylene glycol, etc.) and its suitable mixture, the organic ester of vegetable oil, such as olive oil and injectable, such as oil Acetoacetic ester.By using coating material, for example, lecithin, by the dispersion of the granular size needed for maintaining, and by using Surfactant keeps mobility appropriate.These compositions can also contain adjuvant, such as preservative, wetting agent, and emulsifier divides Powder, lubricant and/or antioxidant.The effect of the pre- preventing microorganism of compound as described herein can be by the inclusion of different Antibacterial agent and antifungal agent ensure, for example, p-hydroxybenzoate, methaform, phenol sorbic acid and analog.It can also be with Being includes isotonic agent, such as sugar, in the composition of sodium chloride etc..In addition, absorb can be by the inclusion of for the extension of injectable drug form Delayed absorber, such as aluminum monostearate and gelatin.

The method for preparing these preparations or composition include compound as described herein and/or with chemotherapy carrier and appoint The step of association of one or more auxiliary elements of choosing.In general, preparation be by equably with chemical combination disclosed herein Object and liquid-carrier or subdivided solids carrier or both closely combine, then if it is necessary, making product shaping.Preparation is in this way Pharmaceutical composition be well known in the art.See, e.g., Anderson, Philip O.；Knoben,James E.； Troutman,William G,eds.,Handbook of Clinical Drug Data,Tenth Edition,McGraw- Hill,2002；Pratt and Taylor,eds.,Principles of Drug Action,Third Edition, Churchill Livingston,New York,1990；Katzung,ed.,Basic and Clinical Pharmacology,Ninth Edition,McGraw Hill,2003；Goodman and Gilman,eds.,The Pharmacological Basis of Therapeutics,Tenth Edition,McGraw Hill,2001；The g's of Rem N's Pharmaceutical Sciences, 20th Edition, Lippincott Williams&Wilkins., 2000； Martindale,TheExtra Pharmacopoeia,Thirty-Second Edition(ThePharmaceutical Press,London,1999)；These bibliography are integrally incorporated herein by reference.Unless any conventional excipients are situated between Matter is incompatible with compound provided herein, such as passes through any other component phase interaction with pharmaceutically acceptable composition With generating any undesirable biological effect or with harmful effect, the use of excipient be also covered by the scope of the present disclosure it It is interior.

In some embodiments, the concentration that pharmaceutical composition provides compound disclosed in one or more can be small In about 100%, about 90%, about 80%, about 70%, about 60%, about 50%, about 40%, about 30%, about 20%, about 19%, about 18%, about 17%, about 16%, about 15%, about 14%, about 13%, about 12%, about 11%, about 10%, about 9%, about 8%, about 7%, about 6%, about 5%, about 4%, about 3%, about 2%, about 1%, about 0.5%, about 0.4%, about 0.3%, about 0.2%, about 0.1%, about 0.09%, about 0.08%, about 0.07%, about 0.06%, about 0.05%, about 0.04%, about 0.03%, about 0.02%, about 0.01%, about 0.009%, about 0.008%, about 0.007%, about 0.006%, about 0.005%, about 0.004%, About 0.003%, about 0.002%, about 0.001%, about 0.0009%, about 0.0008%, about 0.0007%, about 0.0006%, about 0.0005%, about 0.0004%0.0003%0.0002% or about 0.0001% weight/weight ratio, weight/volume or body Product/volume ratio.

In some embodiments, the concentration of one or more compounds as disclosed herein can be greater than about 90% with On, about 80%, about 70%, about 60%, about 50%, about 40%, about 30%, about 20%, about 19.75%, about 19.50%, about 19.25% about 19%, about 18.75%, about 18.50%, about 18.25%, about 18%, about 17.75%, about 17.50%, about 17.25%, about 17%, about 16.75%, about 16.50%, about 16.25%, about 16%, about 15.75%, about 15.50%, about 15.25%, about 15%, about 14.75%, about 14.50%, about 14.25%, about 14%, about 13.75%, about 13.50%, about 13.25%, about 13%, about 12.75%, about 12.50%, about 12.25%, about 12%, about 11.75%, about 11.50%, about 11.25%, about 11%, about 10.75%, about 10.50%, about 10.25%, about 10%, about 9.75%, about 9.50%, about 9.25%, about 9%, about 8.75%, about 8.50%, about 8.25%, about 8%, about 7.75%, about 7.50%, about 7.25%, about 7%, about 6.75%, about 6.50%, about 6.25%, about 6%, about 5.75%, about 5.50%, about 5.25%, about 5%, about 4.75%, about 4.50%, about 4.25%, about 4%, about 3.75%, about 3.50%, about 3.25%, about 3%, about 2.75%, about 2.50%, about 2.25%, about 2%, about 1.75%, about 1.50%, about 1.25%, about 1%, about 0.5%, about 0.4%, about 0.3%, about 0.2%, about 0.1%, about 0.09%, about 0.08%, about 0.07%, about 0.06%, about 0.05%, about 0.04%, About 0.03%, about 0.02%, about 0.01%, about 0.009%, about 0.008%, about 0.007%, about 0.006%, about 0.005%, About 0.004%, about 0.003%, about 0.002%, about 0.001%, about 0.0009%, about 0.0008%, about 0.0007%, about 0.0006%, about 0.0005%, about 0.0004%, about 0.0003%, about 0.0002%, or about 0.0001% weight/weight ratio, Weight/volume or volume/volume ratio.In some embodiments, the concentration of one or more compounds disclosed herein, Can range from about 0.0001% to about 50%, about 0.001% to about 40%, about 0.01% to about 30%, about 0.02% to About 29%, about 0.03% to about 28%, about 0.04% to about 27%, about 0.05% to about 26%, about 0.06% to about 25%, about 0.07% to about 24%, about 0.08% to about 23%, about 0.09% to about 22%, about 0.1% to about 21%, about 0.2% to about 20%, about 0.3% to about 19%, about 0.4% to about 18%, about 0.5% to about 17%, about 0.6% to about 16%, about 0.7% To about 15%, about 0.8% to about 14%, about 0.9% to about 12%, about 1% to about 10% weight/weight ratio, weight/volume Or volume/volume ratio.In some embodiments, the concentration of one or more compounds can be in range as disclosed herein From about 0.001% to about 10%, about 0.01% to about 5%, about 0.02% to about 4.5%, about 0.03% to about 4%, about 0.04% to about 3.5%, about 0.05% to about 3%, about 0.06% to about 2.5%, about 0.07% to about 2%, about 0.08% to About 1.5%, about 0.09% to about 1%, about 0.1% to about 0.9% weight/weight ratio, weight/volume or volume/volume ratio.

In some embodiments, the amount of one or more compounds as disclosed herein, which can be, is equal to or less than About 10g, about 9.5 grams, about 9.0 grams, about 8.5 grams, about 8.0 grams, about 7.5 grams, about 7.0 grams, about 6.5 grams, about 6.0 grams, about 5.5 Gram, 5.0 grams, about 4.5 grams, about 4.0 grams, 3.5 grams, about 3.0 grams, about 2.5 grams, about 2.0 grams, about 1.5 grams, about 1.0 grams, about 0.95 Gram, about 0.9 gram, about 0.85 gram, about 0.8 gram, about 0.75 gram, about 0.7 gram, about 0.65 gram, about 0.6 gram, about 0.55 gram, about 0.5g, about 0.45 gram, about 0.4 gram, about 0.35 gram, about 0.3 gram, about 0.25 gram, about 0.2 gram, about 0.15 gram, about 0.1 gram, about 0.09 gram, about 0.08 gram, about 0.07 gram, about 0.06 gram, about 0.05g, about 0.04 gram, about 0.03 gram, about 0.02 gram, about 0.01 Gram, 0.009 gram, about 0.008 gram, about 0.007 gram, about 0.006 gram, about 0.005 gram, about 0.004 gram, about 0.003 gram, about 0.002g, about 0.001 gram, about 0.0009 gram, 0.0008g, about 0.0007 gram, about 0.0006 gram, about 0.0005 gram, about 0.0004 gram, 0.0003 gram, 0.0002 gram, or about 0.0001 gram.In some embodiments, disclosed herein a kind of or more The amount of kind compound can be more than about 0.0001 gram, about 0.0002 gram, 0.0003 gram, about 0.0004 gram, about 0.0005g, about 0.0006 gram, about 0.0007 gram, about 0.0008g, about 0.0009 gram, about 0.001 gram, 0.0015 gram, about 0.002 gram, 0.0025 Gram, about 0.003 gram, about 0.0035 gram.About 0.004 gram, about 0.0045 gram, about 0.005 gram, about 0.0055 gram, about 0.006 gram, About 0.0065 gram, about 0.007 gram, about 0.0075 gram, about 0.008 gram, about 0.0085 gram, 0.009g, about 0.0095 gram, about 0.01 Gram, about 0.015 gram, about 0.02 gram, about 0.025 gram, about 0.03 gram, about 0.035 gram, about 0.04 gram, about 0.045 gram, about 0.05 Gram, about 0.055 gram, about 0.06 gram, about 0.065 gram, about 0.07 gram, about 0.075 gram, about 0.08 gram, about 0.085 gram, about 0.09 Gram, about 0.095 gram, about 0.1g, about 0.15 gram, about 0.2 gram, about 0.25 gram, about 0.3 gram, about 0.35 gram, about 0.4 gram, about 0.45 Gram, about 0.5g, about 0.55 gram, about 0.6 gram, about 0.6 gram, about 0.7 gram, about 0.75 gram, about 0.8 gram, about 0.85 gram, about 0.9 gram, About 0.95 gram, about 1 gram, about 1.5 grams, about 2 grams, about 2.5, about 3 grams, about 3.5, about 4 grams, about 4.5 grams, about 5 grams, about 5.5 grams, about 6 grams, about 6.5 grams, about 7 grams, about 7.5 grams, about 8 grams, about 8.5 grams, about 9 grams, about 9.5 grams, or about 10g.

In some embodiments, the range of the amount of one or more compounds disclosed herein can be at about 0.0001 gram To about 10 grams, about 0.0005 gram to about 9 grams, about 0.001 gram to about 0.5 gram, about 0.001 gram to about 2 grams, about 0.001 gram to about 8 Gram, about 0.005 gram to about 2 grams, about 0.005 gram to about 7 grams, about 0.01 gram to about 6 grams, about 0.05 gram to about 5 grams, about 0.1 gram To about 4 grams, about 0.5 gram to about 4 grams, or about 1 gram to about 3 grams.

In certain preferred aspects, containing compound as disclosed herein be administered orally, and suitable for take orally to The pharmaceutical composition of the drug excipient of medicine.In some embodiments, provided herein is the pharmaceutical compositions of oral administration: (1) Optional a effective amount of disclosed compound；(2) a effective amount of one or more second reagents；(3) it is suitable for oral administration One or more pharmaceutical excipients.In some embodiments, pharmaceutical composition further includes: (4) a effective amount of third examination Agent.

In some embodiments, pharmaceutical composition can be suitable for oral composition of liquid medicine.Suitable for oral The pharmaceutical composition of administration can be used as discrete dosage form, such as the glue of the predetermined amounts of active ingredients each containing powder or particle Capsule, cachet or tablet or liquid, solution aerosol spray or suspension are in aqueous or non-aqueous liquid, and oil is in water Lotion or water liquid emulsion in the oil.Such dosage form can be prepared by any method of pharmacy, but all methods include By the way that active constituent and liquid-carrier, liposome or finely divided solid carrier or both progress equably and are closely associated Come the step of preparing composition.Under normal circumstances, pharmaceutical composition be by by active constituent equably and closely with liquid Body carrier or solid carrier fine crushing or both mixing, if it is necessary, product is made to be configured to required form.For example, tablet can Be will choose any one kind of them or Multiple components compacting or molding.Tabletting can be by by free-flowing form such as powder or particle Active constituent, optionally with excipient, such as, but not limited to, adhesive, lubricant, inert diluent and/or surfactant Or dispersant, it is suppressed in suitable machine.Molded tablet can by suitable machine by inert liquid diluent The mixture of the powder compound of wetting moulds to prepare.Tablet is optionally uncoated, is coated or indentation, and can be formulated To provide the slow or controlled release of wherein active constituent, so that the continuous action of longer term is provided, the delay that can be used Material, such as glycerin monostearate or bi-tristearin.Formulations for oral use can also be hard gelatin capsule, Wherein active constituent can be mixed with inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft bright Glue capsule, wherein active constituent can be with water or oil medium, for example, peanut oil, atoleine or olive oil mixing.

Active component can closely be combined with pharmaceutical carrier by conventional medicine hybrid technology.The carrier can be adopted Diversified forms are taken, this depends on the form that required preparation is administered.When preparing pharmaceutical composition for peroral dosage form, Ren Hechang Drug media is used as carrier, for example, water, glycol, oil, ethyl alcohol, flavoring agent, preservative, colorant and liquid oral Preparation (for example, suspension, solution and elixir) or aerosol or carrier, for example, starch, sugar, microcrystalline cellulose, diluent, Granulating agent, lubricant, adhesive and disintegrating agent can use in the case where oral solid formulation, not make in some embodiments Use lactose.In some embodiments, compound can be with lactose, sucrose, starch powder, the cellulose esters of alkanoic acid, fiber Plain Arrcostab, talcum, stearic acid, magnesium stearate, magnesia, calcium phosphate, sodium phosphate, calcium sulfate, sodium sulphate, gelatin are Arabic Glue, mosanom, polyvinylpyrrolidone and/or polyvinyl alcohol are used for further preparation.For example, the system of solid orally ingestible Standby, suitable carrier further includes powder, capsule and tablet.In some embodiments, tablet can be by standard aqueous or non- Aqueous technology is coated.

Suitable for the coating of pharmaceutical composition and dosage form, include, but are not limited to cornstarch, potato starch or other Starch, gelatin, natural glue and paragutta such as Arabic gum, mosanom, alginic acid, other alginates, powdered Huang alpine yarrow Glue, guar gum, cellulose and its derivates are (for example, ethyl cellulose, cellulose acetate, calcium carboxymethylcellulose, carboxymethyl are fine Tie up plain sodium), polyvinylpyrrolidone, methylcellulose, pregelatinized starch, hydroxypropyl methyl cellulose, microcrystalline cellulose, and Their mixture.

Include, but are not limited to slide there is disclosed herein the example for the suitable filler in pharmaceutical composition and dosage form Stone, calcium carbonate (for example, particle or powder), microcrystalline cellulose, cellulose powder, dextrates, kaolin, mannitol, Silicic acid, sorbierite, starch, pregelatinized starch and their mixture.

Disintegrating agent can be collapsed with providing when being exposed to water environment in pharmaceutical composition using as provided herein The tablet of solution.Too many disintegrating agent can cause tablet to be disintegrated in bottle.It may be not enough to be disintegrated generation very little, and therefore can be with Change the rate of release and degree of the active constituent of dosage form.Therefore, disintegrating agent should sufficient amount, it is neither very little also not many and have Change the release of active constituent harmfully.The amount of disintegrating agent depends on formula and administration mode, and can be and be easy to by this field In those of ordinary skill realize.The disintegrating agent of about 0.5 to about 15 weight %, or the disintegrating agent of about 1 to about 5 weight %, can be with It is used in pharmaceutical composition.It can be used to form the disintegrating agent of pharmaceutical composition and dosage form, including but not limited to, agar, seaweed Acid, calcium carbonate, microcrystalline cellulose, cross-linked carboxymethyl sodium, Crospovidone, polacrilin potassium, primojel, potato or wood Sweet potato starch, other starch, pre- gelatine starch, clay, other phycocolloid, other celluloses, or mixtures thereof natural gum.

Lubricant can be used for being formed pharmaceutical composition and dosage form, include, but are not limited to calcium stearate, magnesium stearate, Mineral oil, light mineral oil, glycerol, sorbierite, mannitol, polyethylene glycol, other glycol, stearic acid, NaLS are sliding Stone, hydrogenated vegetable oil (for example, peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil and soybean oil) are stearic Sour zinc, ethyl oleate, ethyl laurate, agar or their mixture.Lubricant further includes that, for example, silica gel, solidified gas is molten Or mixtures thereof glue,.Lubricant is optionally added with the amount of the pharmaceutical composition less than about 1 weight %.

When aqueous suspension and/or elixir are for when being administered orally, active constituent can with various sweeteners or flavoring agent, Colorant or dyestuff, and for example, emulsifier and/or suspending agent, diluent are combined together, for example, water, ethyl alcohol, propylene glycol are sweet Oil and their various combinations.

The surfactant that can be used for being formed pharmaceutical composition and dosage form includes, but are not limited to hydrophilic surfactant Agent, lipophilic surfactant and their mixture.Suitable hydrophilic surfactant usually can have at least about 10 HLB value, and suitable lipophilic surfactant can generally have the HLB value less than about 10.It is relatively close for what is characterized Aqueous and hydrophobic empirical parameter is hydrophilic lipophilic balance HLB (" HLB " value).The surfactant of lower HLB value is More lipophilic is hydrophobic, and has biggish solubility in the oil, and having compared with the activating agent of high hlb is more hydrophilic property, and And there is bigger solubility in aqueous solution.Hydrophilic surfactant active, which is generally considered to be, is greater than about 10 with HLB value Those compounds, however, anion, cation or zwitterionic compound, HLB scale are usually not applicable.Similarly, lipophilicity (that is, hydrophobicity) surfactant is to be equal to or less than about 10 with HLB value.However, the HLB value of surfactant is only one As for industry, the rough guide of drug and cosmetic emulsions.

Hydrophilic surfactant active can be ion or non-ionic.Suitable ionic surface active agent includes, but unlimited In alkylammonium salt；Fusidic Acid salt；The derivative of fatty acid of amino acid, oligopeptides and polypeptide；Amino acid, oligopeptides and polypeptide it is sweet The derivative of grease；Lecithin and hydrolecithin；Lysolecithin and hydrogenated lyso lecithin；Phosphatide and its derivative；It is molten Blood phospholipid and its derivative；Carnitine fatty acid ester salt；Alkyl sulfate；Fatty acid salt；Docusate sodium；Acyl-lactate；It is mono- and The tartrate of the list of diacetylation and two glyceride；Succinylation list and two glyceride；The citric acid of mono-and diglycerides Ester；With their mixture.Ionic surfactant includes, but are not limited to for example, lecithin, lysolecithin, phosphatide, Lysophosphatide and its derivative；Carnitine fatty acid ester salt；Alkyl sulfate；Fatty acid salt；Docusate sodium；Acyl-lactate；It is mono- With the diacetylation tartrate of mono-and diglycerides；Succinylation list and two glyceride；The lemon of mono-and diglycerides Acid esters；With their mixture.Hydrophilic nonionic surfactant includes, but are not limited to alkyl glycosides；Alkyl maltose；Alkane Base thio glycoside；Lauroyl LABRAFIL M 1944CS；Polyoxyalkylene alkyl, for example, polyethylene glycol alkyl ether；Polyoxyalkylene alkane Base phenol, for example, polyalkylene glycol alkyl phenol；Polyoxyalkylene alkylphenol aliphatic ester, for example, polyethylene glycol fatty acid monoesters and poly- Glycol fatty acid diester；Polyethylene glycol glycerol aliphatic ester；Polyglyceryl fatty acid ester；Polyoxyalkylene sorbitan polyol fatty acid Ester, for example, polyethylene glycol sorbitan fatty acid ester；With glyceride, vegetable oil, hydrogenated vegetable oil, in fatty acid and sterol The hydrophily transesterification product of at least one polyalcohol；Polyoxyethylene sterol, derivative, and the like；It is polyoxyethylated Vitamin and its derivative；Polyox-yethylene-polyoxypropylene block copolymer；With their mixture；Polyethylene glycol anhydrosorbitol The hydrophily transesterification product of the polyalcohol of alcohol fatty acid ester and at least one triglycerides, vegetable oil and hydrogenated vegetable oil.It should Polyalcohol can be glycerol, ethylene glycol, polyethylene glycol, sorbierite, propylene glycol, pentaerythrite or carbohydrate.Other hydrophilies it is non-from Sub- surfactant includes, but are not limited to PEG-10 laurate, PEG-12 laurate, PEG-20 laurate, PEG-32 Laurate, PEG-32 dilaurate, PEG-12 oleate, PEG-15 oleate.PEG-20 oleate, bis- oleic acid of PEG-20 Ester, PEG-32 oleate, PEG-200 oleate, PEG-400 oleate, PEG-15 stearate, PEG-32 distearate, PEG-40 stearate, PEG-100 stearate, PEG-20 dilaurate, PEG-25 glycerol trioleate, bis- oil of PEG-32 Acid esters, PEG-20 glyceryl laurate, PEG-30 glyceryl laurate, PEG-20glyce kowtow my stearate, PEG-20 Olein, PEG-30 olein, PEG-30glyce kowtow my laurate, PEG-40 glyceryl laurate, PEG- 40 palm-kernel oils, PEG-50 rilanit special, PEG-40 castor oil, Cremophor ELP, PEG-60 castor oil, PEG-40 hydrogenation Castor oil, PEG-60 rilanit special, PEG-60 corn oil, the PEG-6 last of the ten Heavenly stems/glycerol caprylate, PEG-8 decylate/cap are kowtowed late sweet Grease, polyglyce kowtow 1-10 laurate, PEG-30 cholesterol, PEG-25 phytosterol, PEG-30 sojasterol, PEG- 20 trioleates, PEG-40 Oleate, PEG-80 sorbitan laurate, polysorbate 20, poly- sorb Alcohol ester 80, POE-9 lauryl ether, POE-23 laurel ether, POE-10 oleyl ether, POE-20 oleyl ether, POE-20 stearyl ether, PEG-100 tocopherol succinate, PEG-24 cholesterol, Tween 40, Tween 60, sucrose monostearate, sucrose Dan Yue Cinnamic acid ester, sucrose palmitic acid ester, PEG 10-100 nonylphenol series, PEG 15-100 octyl phenol series and poloxamer.It closes Suitable lipophilic surfactants include, but are not limited to for example, fatty alcohol；Fatty acid glyceride；Acetylated glycerol fatty acid esters； Lower alcohol fatty acid esters；Methyl glycol fatty acid ester；Sorbitan fatty acid ester；Polyethylene glycol fatty acid esters of sorbitan；Gu Pure and mild steroid derivatives；Polyoxyethylated sterol and sterol derivative；Polyethylene glycol alkyl ether；Sugar ester；Sugar ether；Single and two glycerol The lactic acid derivative of ester.

Pharmaceutical composition may include solubilizer to ensure good solubilising and/or the dissolution of compound, and reduce chemical combination to the greatest extent The precipitating of object.This can be for non-oral use, for example, the pharmaceutical composition of the pharmaceutical composition for injection is especially heavy It wants.Solubilizer can also be added, to increase hydrophilic medicament and/or other components, such as the solubility of surfactant, or maintenance Pharmaceutical composition as stable or uniform solution or dispersion.The example of suitable solubilizer includes, but are not limited to example Such as, pure and mild polyalcohol, for example, ethyl alcohol, isopropanol, butanol, benzylalcohol, ethylene glycol, propylene glycol, butanediol and its isomers, glycerol, Pentaerythrite, sorbierite, mannitol, Isosorbide dimethyl ether, polyethylene glycol, polypropylene glycol, polyvinyl alcohol and other fibers Plain derivative, cyclodextrin and cyclodextrine derivatives；The ether of polyethylene glycol has molecular weight about 200 to about 6000, such as tetrahydro chaff Alcohol PEG ether (Tetrahydrofurfuryl polyethylene glycol ether) or methoxyl group PEG；Amide and other nitrogenous compounds, such as 2-Pyrrolidone, 2- Piperidones, epsilon-caprolactams, N- alkyl pyrrolidone, N- hydroxyalkylpyrrolidone, N- Alkylpiperidine, N- alkyl caprolactam, Dimethyl acetamide and polyvinylpyrrolidone；Ester, for example, ethyl propionate, tributyl citrate, acetyl triethyl citrate, Acetyl tributyl citrate, triethyl citrate, ethyl oleate, ethyl caprilate, ethyl butyrate, glycerol triacetate, the third two Alcohol monoacetate, propylene-glycol diacetate, the isomers of 6-caprolactone and they, delta- valerolactone and its isomers, in fourth Ester and its isomers；With other known solubilizer, such as dimethyl acetamide, Isosorbide dimethyl ether, N-Methyl pyrrolidone, Diethylene glycol monoethyl ether and water.Also the mixture of solubilizer can be used.

The amount of given solubilizer can be limited in a biological acceptable amount, can pass through those skilled in the art It is readily determined.Solubilizer can be about 10%, about 25%, about 50%, about 100% weight ratio, or at most by weight About 200%, based on the total weight of drug and other auxiliary materials.If necessary, a small amount of solubilizer can also be used, for example, about 5%, 2%, 1% or even less.Typically, solubilizer can reside in about 1% to about 100%, and typically about 5% to about 25% (weight).

The pharmaceutical composition can also include one or more pharmaceutically acceptable additives and excipient.In this way Additive and excipient includes, but are not limited to for example, antitack agent, anti-foaming agent, buffer, polymer, antioxidant is prevented Rotten agent, chelating agent, flavoring agent, colorant, essential oil, fragrance, opacifier, suspending agent, adhesive, filler, plasticizer, lubrication Agent and their mixture.Preservative may include, but be not limited to, for example, antioxidant, chelating agent, antimicrobial anti-corrosion Agent, antifungal preservative, alcohol preservative, acidic preservative and other preservatives.Antioxidant includes, but are not limited to α-fertility Phenol, ascorbic acid, butylated hydroxyanisol, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, gallate third Ester, sodium ascorbate, sodium hydrogensulfite and sodium sulfite.Chelating agent includes, but are not limited to for example, ethylenediamine tetra-acetic acid (EDTA), citric acid monohydrate closes object, disodium ethylene diamine tetraacetate, dipotassium edetate, edetic acid(EDTA), fumaric acid, apple Acid, phosphoric acid, edetate sodium, tartaric acid and citric acid triethylenediamine tetrem.Anti-microbial preservative includes, but are not limited to example Such as, benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimonium bromide, cetylpyridinium chloride, dichloroxylenol, first Phenol, ethyl alcohol, glycerol, Hexetidine, imidazolidine urea, phenol, phenoxetol, benzyl carbinol, phenylmercuric nitrate and propylene glycol.It is anti-true Microbial inoculum includes, but are not limited to for example, butyl p-hydroxybenzoate, methyl p-hydroxybenzoate, ethyl-para-hydroxybenzoate are right Nipasol, benzoic acid, hydroxybenzoic acid, Potassium Benzoate, potassium sorbate, sodium benzoate, sodium propionate and sorbic acid.It is anti- Rotten agent includes, but are not limited to for example, ethyl alcohol, polyethylene glycol, phenol, phenolic compounds, bis-phenol, methaform, hydroxybenzoate, And benzyl carbinol.Acidic preservative includes, but are not limited to for example, vitamin A, vitamin C, vitamin E, beta carotene, lemon Acid, acetic acid, dehydroactic acid, ascorbic acid, sorbic acid and phytic acid.Other preservatives include, but are not limited to for example, tocopherol vinegar Acid esters, cetrimonium bromide, butylated hydroxyanisol (BHA), butylated hydroxytoluene (BHT), ethylenediamine, NaLS (SLS), sodium laureth sulfate (SLES), hydrogen sulfate sodium salt, sodium pyrosulfite, potassium sulfite, potassium metabisulfite, para hydroxybenzene Methyl formate.In certain embodiments, preservative can be a kind of antioxidant.In other embodiments, preservative can To be chelating agent.In some embodiments, it provided herein is the pharmaceutical compositions contained for parenteral: (1) one The effective quantity of a disclosed compound；A effective amount of one or more second reagents in optional (2)；(3) it is suitable for parenteral to apply One or more drug excipients and (4) a effective amount of third reagent.

Wherein pharmaceutical composition can include aqueous by way of drug administration by injection or oily suspensions or emulsion, sesame oil, Corn oil, cotton seed oil or peanut oil and elixir, mannitol, dextrose or aseptic aqueous solution and similar drug carry Body.Physiological saline aqueous solution is also commonly used for injecting.Ethyl alcohol, glycerol, propylene glycol, liquid macrogol, benzylalcohol, wait (and its close They suitable mixture), cyclodextrine derivatives, sodium chloride, bassora gum, buffer and vegetable oil can also use.It is appropriate Mobility can be by using coating, for example, lecithin, or keeps institute by using surfactant in the case of a dispersion The granular size needed is kept.The prevention of microbial action can be by various antibacterial agents and antifungal agent, for example, para hydroxybenzene first Esters of gallic acid, methaform, phenol, sorbic acid acid, thimerosal etc..Pharmaceutical composition can also be injected by suitable carrier, including Salt water, glucose or water, or with cyclodextrin, cosolvent (for example, propylene glycol) or Micellar Solubilization (for example, Tween80).

Aseptic injectable solution can pass through the conjunction of the desired amount of compounds as disclosed herein and various above-mentioned other ingredients It is prepared by suitable solvent, filtration sterilization.In general, dispersion is situated between by being incorporated into the active constituent of various sterilizings containing basic dispersion It the sterile carrier of matter and prepares from other components appropriate those of listed above.Sterile note is being prepared with aseptic powdery Penetrate liquid, certain methods of preparation are that active constituent and any other above-mentioned sterile is generated with vacuum drying and Freeze Drying Technique The ingredient of filtering.Sterile injectable preparation can also pass through the suspension in the nontoxic acceptable diluent of parenteral or solvent Liquid, for example, prepared by solution or aseptic injectable solution in 1,3-BDO.In the acceptable carrier and solvent that can be used Include, but are not limited to for example, water, Ringer's solution and isotonic sodium chlorrde solution.In addition, sterile, fixed oil is typically used as Solvent or suspension media include, but are not limited to list or two glyceride for example, synthesizing.In addition, fatty acid, for example, oleic acid It can be used in the preparation of injection using.Injectable formulation can keep filter filtering before use by, for example, bacterium, Or the bactericidal agent that can be dissolved or dispersed in the incorporation aseptic solid composite of sterile water or other sterile injectable mediums is added It sterilizes.Injectable composition can be in the compound disclosed herein of about 0.1 to about 5% weight ratio.

In some embodiments, it provided herein is containing as disclosed herein, contain one kind suitable for local administration Or the compound or pharmaceutical composition of (for example, percutaneous) of a variety of drug excipients.In some embodiments, provided herein It is the composition containing drug for local administration: (1) effective quantity of a disclosed compound；Optional (2) effective quantity One or more second reagents；(3) it is suitable for the one or more drug excipients and (4) a effective amount of third of local administration Medicament.

Pharmaceutical composition provided herein can be configured to be suitable for the solid of local or local application, semisolid or liquid Form, such as gelling agent, water soluble gel, liniment, creme, lotion, suspension, foaming agent, pulvis, paste preparation agent are soft Paste, solution is oily, paste, suppository, spray, emulsion, saline solution, the solution based on dimethyl sulfoxide (DMSO).One As in the case of, the carrier with higher density is capable of providing with being exposed to the region of active constituent for a long time.On the contrary, pharmaceutical solutions The more direct contact in the selected region of the active constituent can be provided.For example, ointment formulation can have paraffin or water mixed Dissolubility.Alternatively, active constituent can be configured to emulsifiable paste together with the emulsifiable paste matrix of oil in water.The water phase of emulsifiable paste matrix can Polyalcohol including for example, at least about 30% weight ratio, for example, propylene glycol, butane -1,3- glycol, mannitol, sorbierite are sweet Oil, the mixture of polyethylene glycol and they.The pharmaceutical composition also may include suitable solid or gel phase carriers or tax Shape agent, they can increase infiltration, or the stratum corneum penetration barrier for assisting delivering compound to pass through skin.Such carrier and tax The example of shape agent includes, but are not limited to for example, wetting agent (for example, urea), glycol (for example, propylene glycol), alcohol is (for example, second Alcohol), fatty acid (for example, oleic acid), surfactant (for example, isopropyl myristate and fine gold sodium kowtow my sodium sulphate), pyrrolidines Ketone, glyceryl monolaurate, sulfoxide, terpene (for example, menthol), amine, amide, alkane, alkanol, water, calcium carbonate, calcium phosphate, respectively Kind sugar, starch, cellulose derivative, the polymer of gelatin and such as polyethylene glycol.

Another exemplary formulation used in the disclosed methods uses percutaneous dosing (" patch ").Such transdermal patch Agent can be used for continuously or discontinuously providing the pharmaceutical composition of control amount.If activating agent by skin absorb, activating agent by Control and predetermined amount of flow can be administered to subject.In the case where microcapsules, encapsulation agent is also used as film.For transdermal patch Use be as known in the art.See, e.g., U.S. Patent number 5,023,252,4992445 and 5,001,139.

Pharmaceutical composition of the invention can be applied with the suppository form of rectally.These compositions can be by incite somebody to action this The compound of invention mixes to prepare with suitable nonirritant excipient, and the excipient is solid but in rectum at room temperature At a temperature of be liquid, to will melt in the rectum and release active component.This material includes, but are not limited to for example, poly- Ethylene glycol, beeswax and cocoa butter.

Pharmaceutical composition of the invention can be administered by nasal aerosol or inhalant.According to known to field of pharmaceutical preparations Technology prepare this composition, and the solution of salt water can be prepared as, and can be used benzyl alcohol or other be suitble to Preservative, improve the sorbefacient of bioavilability, other known solubilizer of fluorocarbons and this field or dispersion Agent.

Particularly advantageous derivative and prodrug is that change of the invention is improved when this compound is administered to mammal It closes those of bioavilability of object (for example, by allowing the compound being administered orally more easily to be absorbed), or relative to Parent species can enhance delivering those of of the compound to maternal biological chamber (for example, brain or central nervous system).Preferably Prodrug includes wherein enhancing group that is water-soluble or wearing goldbeater's skin active transport to be affixed to spreading out on general formula structure as described herein Biology.See, e.g., Alexander et al., Journal of Medicinal Chemistry l988,31,318- 322；Bundgaard et al., Design of Prodrugs, Elsevier:Amsterdam, 1985,1-92； Bundgaard et al.,Journal of Medicinal Chemistry l987,30,451-454；Bundgaard et Al., Textbook of Drug Design and Development, Harwood Academic Publ.: Switzerland,1991,113-191；Digenis et al.Handbook of Experimental Pharmacology, 1975,28,86-112。

Subject agent application can be it is local, to be applied in target site.Various technologies can be used in target Provider's composition at position, such as inject, use conduit, gel, bracket, trocar, propellant, sustained drug release polymerization The equipment that object or other offers are used for internal path.

According to another embodiment, the present invention provides a kind of implantable medical supply, and it includes have change of the invention Object or the composition including the compound of the present invention are closed, so that the compound has therapeutic activity.

According to another embodiment, the present invention provides a kind of method of drug release device that injection is implantable, including The step of drug release device and the compound of the present invention or composition are contacted.Implantable drug release device packet It includes, but is not limited to, biodegradable polymer capsule or pill are nondegradable, diffusible polymer capsule and Ke Sheng The polymer flake of object degradation.

In another embodiment, composition of the invention further includes second therapeutic agent.Second therapeutic agent includes any Compound or therapeutic agent, when being administered alone or being administered together with any general formula compound herein, oneself knows have or prove for they Favorable property.It can include other kinase inhibitors with the drug that these compounds usefully combine, and/or be used for treatment or more The disease of discussion and other chemotherapeutants of disorder.Such reagent is described in detail in this field.Preferably, it second controls Treating agent is the reagent that can be used for the treatment or prevention of disease or illness selected from cancer.

In another embodiment, the present invention provides the only of the compound of the present invention and second therapeutic agent associated each other Vertical dosage form.Term " associating each other " as used herein refers to that the separate dosage forms are packaged together or with other side Formula is connected to each other, thus the separate dosage forms it is expected sold or be administered together (be less than within 24 hours each other, continuously or Simultaneously).

In pharmaceutical composition of the invention, the compound of the present invention exists with effective quantity.Term as used herein " has Effect amount " refers to that the amount reduces enough or improve the severity of disorder to be treated when with the application of suitable dosage regimen, continues Time or development prevent the progress of disorder to be treated, cause the recession of disorder to be treated, or enhancing or another treatment of improvement The prevention or therapeutic effect of method.

Dosage is described in Freireich et al., (1966) Cancer Chemother Rep 50:219 to dynamic The correlation of object and people (according to every square metre of body surface area of milligram).Body surface area can be big according to the height and weight of patient Ground is caused to determine.See, e.g., Scientific Tables, Geigy Pharmaceuticals, Ardley, N.Y., 1970, 537.The effective quantity of the compound of the present invention can be from about 0.001-lmg/kg to about 500mg/kg, and about 0.01mg/kg is to about 50mg/kg, about 0.lmg/kg are to about 2.5mg/kg.Effective dosage can also change, as understood by those skilled in the art, Depending on the disease treated, the severity of disease, administration route, the age of patient, gender and general health, excipient The judgement of usage, a possibility that (such as using other reagents) being used in conjunction with other treatment method and treating physician.

For the pharmaceutical composition including second therapeutic agent, the effective quantity of second therapeutic agent is in the list that the reagent is used only Between about 20% to the 100% of the dosage usually utilized in therapeutic scheme.Preferably, effective quantity is in normal single therapeutic dose Between about 70% and 100%.Normal single therapeutic dose of these second therapeutic agents is well known in the art.See, e.g., Wells et al., Pharmacotherapy Handbook, Appleton and Lange, Stamford, Conn. (2000)；PDR Pharmacopoeia, Tarascon Pocket Pharmacopoeia 2000, Tarascon Publishing, Loma Linda, Calif. (2000), these bibliography are integrally incorporated herein by reference.

It is synergistically acted on it is expected that the certain second therapeutic agents being mentioned herein will have with the compound of the present invention.When this happens, It will allow for the effective dose of second therapeutic agent and/or the compound of the present invention less than dosage needed for single treatment.This has The advantages of be: make the toxic side effect of second therapeutic agent or the compound of the present invention minimize, improve effect, improve administration or use Convenience, and/or reduce the overall cost of compound preparations or preparation.

Treatment method is as follows:

According to another embodiment, disease or disorder or its symptom (example are suffered from or are susceptible to the present invention provides treatment Such as, those of be described herein) subject method, including to the subject with a effective amount of the compound of the present invention or group Close the step of object is administered.These diseases are it is known in the art that also disclosed herein.

Treatment method is related to by the treatment of the protein kinase such as EGFR disorder mediated.

On the other hand, the present invention provides the method that disease is treated in subject, including to subject's application comprising appointing The composition of the compound of what this paper general formula.

In some embodiments, disease is kinase mediated by EGFR.

In another embodiment, disease is cancer or hyperplasia.

In another embodiment, the inhibitor as the activated mutant body lacked for EGFR exon 2-7, formula (I) Compound and pharmaceutically acceptable salt, it is expected to be the activity by EGFRVIII mutant individually or part mediate, example If the treatment of Cancerous disease or medical conditions is useful.This cancer types that the compound of formula (I) may be used to treat or medicine Acceptable salt on, including but not limited to, oophoroma, cervix cancer, colorectal cancer, breast cancer, cancer of pancreas, neuroglia Tumor, glioblastoma, melanoma, prostate cancer, leukaemia, lymthoma, non-Hodgkin lymphoma, gastric cancer, lung cancer, liver cancer, Osteocarcinoma, gastrointestinal stromal tumor (GIST), thyroid cancer, cholangiocarcinoma, carcinoma of endometrium, kidney, primary cutaneous type are anxious Property myelomatosis (AML), Huppert's disease, melanoma, celiothelioma, the cancer of the brain, film gland cancer, cutaneum carcinoma or incidence squamous Cell cancer.

In another embodiment, activated mutant is lacked as EGFR Exon 21L858R mutant and Exon19 The inhibitor of body, the compound and pharmaceutically acceptable salt of formula (I), it is expected to be by EGFR mutant activity individually or Part mediate, such as the treatment of Cancerous disease or medical conditions is useful.This may use the compound of formula (I) to treat Cancer types or pharmaceutically acceptable salt, including but not limited to, oophoroma, cervix cancer, colorectal cancer, breast cancer, pancreas Gland cancer, glioma, glioblastoma, melanoma, prostate cancer, leukaemia, lymthoma, non-Hodgkin lymphoma, stomach Cancer, lung cancer, liver cancer, osteocarcinoma, gastrointestinal stromal tumor (GIST), thyroid cancer, cholangiocarcinoma, carcinoma of endometrium, kidney, denaturation are big Cell lymphoma, acute myelogenous leukemia (AML), Huppert's disease, melanoma, celiothelioma, the cancer of the brain, film gland cancer, skin Cancer or head and neck squamous cell carcinoma.

In another embodiment, disease is glioma.

In another embodiment, disease is the non-small cell lung cancer (NSCLC) shifted with brain.

In another embodiment, disease is nerve center disease.

In one embodiment, method of the invention is for treating the subject for suffering from or being susceptible to disease or symptom. These diseases, disorder or its symptom include, for example, by those of protein kinase (for example, EGFR protein kinase) regulation.Disease or Disease symptoms can be, for example, cancer or hyperplasia or disorder.The disease or disease symptoms can be oophoroma, uterus Neck cancer, colorectal cancer, breast cancer, cancer of pancreas, glioma, glioblastoma, melanoma, prostate cancer, leukaemia, Lymthoma, non-Hodgkin lymphoma, gastric cancer, lung cancer, liver cancer, osteocarcinoma, gastrointestinal stromal tumor (GIST), thyroid cancer, cholangiocarcinoma, Carcinoma of endometrium, kidney, primary cutaneous type, acute myelogenous leukemia (AML), Huppert's disease, melanoma, Celiothelioma, the cancer of the brain, film gland cancer, cutaneum carcinoma or head and neck squamous cell carcinoma.The method described herein is reflected including wherein subject Those of the treatment that Wei do not need to illustrate subject.Identifying subject needs this treatment can be in subject or care specialists Judgement within, and can be subjective (for example, opinion) or objectively (for example, can measure by test or diagnostic method ).

In another embodiment, this paper compound (and combinations thereof) can be used to treat with disease or disorder And oneself through with other therapeutic agents (for example, anticancer agent, neurological disease agent, mental disease agent, cardiovascular disease act on Agent, anti-fat or diabetes agent) treat and formed the subject of resistance.On the one hand, methods herein includes wherein to controlling The subject for treating resistant (or be accredited as oneself and formed the resistance treated for Buddhist nun, Tarceva non-for lattice) is administered with this Those of literary general formula compound (or combinations thereof object) method.In other aspects, therefore subject has response to the treatment, thus phase For with before the treatment of this paper general formula compound, disorder is adjusted or improves.

In another embodiment, the present invention provides the protein kinase in adjusting cell (for example, protease propylhomoserin swashs Enzyme, kinases exemplified here) active method, including the compound of cell and one or more any this paper general formulas is carried out Contact.

Anti-cancer therapies described above can use the compound of the present invention as monotherapy or and the compound of the present invention Routine operation or radiotherapy or chemotherapy or immunotherapy are applied together.Such chemotherapy can be common with the compound of the present invention, together When, it is sequential or apply respectively, and can include but is not limited to following classification antitumor agent it is one or more: for example, anti- Proliferation/antineoplastic, alkylating agent (such as cis-platinum, oxaliplatin, carboplatin, cyclophosphamide, mustargen, melphalan, benzenebutanoic acid nitrogen Mustard, busulfan, Temozolomide and nitroso ureas), antimetabolite (such as gemcitabine and anti-folic acid as 5 FU 5 fluorouracil and Tegafur, Raltitrexed, methotrexate (MTX), cytarabine and hydroxycarbamide)；Antitumor antibiotics (such as anthracene nucleus medicament such as Ah mould Element, bleomycin, adriamycin, daunorubicin, Epi-ADM, idarubicin, mitomycin C, dactinomycin D and mithramycin)； Antimitotic agent (such as vinca alkaloids such as vincristine, vincaleukoblastinum, eldisine and vinorelbine and taxanes Close object such as taxol and taxotere and polokinase inhibitor)；With topoisomerase enzyme inhibitor (such as epipodophyllotoxin class according to Support pool glycosides and Teniposide, amsacrine, Hycamtin and camptothecine)；Cytostatic agent such as antiestrogenic (effect) medicine (example Such as tamoxifen, fulvestrant, Toremifene, Raloxifene, Droloxifene and idoxifene), antiandrogen (effect) medicine (example Such as, Bicalutamide, Flutamide, acetic acid Nilutamide and acetic acid cyclopropyl), lhrh antagonist or LHRH agonist (such as Ge Sherui Woods, Leuprorelin and Buserelin, progestational hormone (such as megestrol acetate, aromatase inhibitor (such as such as Anastrozole, come Bent azoles, Vorozole and Exemestane) and 5 alpha-reductases such as Finasteride inhibitor；Anti-invasion agent is (for example, c-Src kinases man Group inhibitor, such as saracatinib；Dasatinib and posupini and posupini and metal protease inhibitors such as Ma Masi He, the inhibitor or antibody heparanase of urokinase plasminogen activator function of receptors.The inhibitor of growth factor function: example If such inhibitor includes growth factor antibodies and the growth factor receptor antibody (such as antibody trastuzumab [He Sai of anti-erbB 2 Spit of fland^TM], anti-egfr antibodies Victibix, anti-ErbB antibody cetuximab (Erbitux, C225) and by Stem et Any growth disclosed in al.Critical reviews in oncology/haematology, 2005, Vol.54, l1-29 The antibody of the factor or growth factor receptors.Such inhibitor further includes tyrosine kinase inhibitor, such as epidermal growth factor Family's group inhibitor (such as EGFR family tyrosine kinase inhibitors such as Gefitinib, Tarceva, Kai Meina and tower gires, erbB2 Tyrosine kinase inhibitor, such as Lapatinib, linatinib)；The inhibitor of hepatocyte growth factor family；Insulin is raw The inhibitor of long factor family；The inhibitor of platelet-derived growth factor family, such as Imatinib and/or nilotinib； (such as RAS/RAF signal inhibitor such as farnesyl transferase inhibitor, such as rope are drawn the inhibitor of serine/threonine kinase Non- Buddhist nun, tipifamib and lonafamib, by MEK and/or AKT kinases cell signal inhibitor, c-kit inhibitor, abl melts Kinase inhibitor is closed, PI3 kinase inhibitor, PLT3 kinase inhibitor, CSF-1R kinase inhibitor, (Insulin-Like is raw for IGF receptor The long factor) kinase inhibitor；Aurora kinase inhibitors and cell cycle protein dependent kinase inhibitor such as CDK2 and/or CDK4 Inhibitor；Anti-angiogenic agent, such as the influence of those inhibition vascular endothelial growth factor, such as anti-vascular endothelial cell growth Factor antibody bevacizumab (Avastin^TM) and such as vegf receptor tyrosine kinase inhibitor such as Vande Thani, vatalanib, Sutent, Axitinib, pazopanib and Si Dinibu pass through the compounds of other mechanism works (such as tricarboxylic amino quinoline Quinoline, the depressant of functions and angiogenic inhibitor of integin αV 3)；Antisense (nucleic acid) therapy gene therapy, such as on those The target that face is listed, such as ISIS 2503, antisense (nucleic acid) therapy of anti-ras gene；Gene therapy method, including for example replace Aberrant gene such as abnormal p53 or abnormal BRCA1 or BRCA2 (for example, olaparib, Niraparib, Rucaparib, Talazoparib), the method for GDEPT (gene-directed enzyme prodrug therapy) is for example using cytosine deaminase, thymidine kinase or thin The enzyme of bacterium nitroreductase and those to improve patient tolerance's chemotherapy or radiotherapy such as multidrug resistance gene therapy immunotherapy method, Immunogenicity including for example increasing the tumour cell of patient, such as with cell factor such as interleukin-22, IL-4 or granulocyte- Macrophage stimulation factor transfection immunogenicity, the method to reduce T cell anergy, using transfection immunocyte such as The method of the Dendritic Cells of cytokine transfection, the method for the tumor cell line of cytokine transfection are anti-using antiidiotype The method of body, to reduce the function of immunosuppressant cell, such as regulatory T cells, marrow source inhibits cell or IDO, TDO, and makes With by coming from tumor associated antigen such as NY-ES0-1, the cancer epidemic disease of the derivative protein or peptide of MAGE-3, WTI or HER2/neu Seedling.Or any other reagent of basic medicament or adjuvant application is typically used as in modality of cancer treatment (for example, antemetic, anti- Anaemia agent etc.).

Terms used herein " co-administration " refer to second therapeutic agent can together with the compound of the present invention, as The part of single formulation (e.g., including the present composition of the compound of the present invention and second therapeutic agent as described above) or It is applied as independent, multiple dose form.Alternatively, before the compound of the present invention application or successively or its it Afterwards, other reagent can be applied.In such combination therapy, the compound of the present invention and second therapeutic agent pass through routine side Method is applied.Administration of the composition of the invention including the compound of the present invention and second therapeutic agent to subject, however not excluded that Same therapeutic agent, the other times of any other second therapeutic agent or any compound of the invention over the course for the treatment of are to described The separate administrable of subject.Wherein continuous or isolated application, or delay are applied the second component and should not be lost from using group The advantages of effect caused by closing.

The effective quantity of second therapeutic agent is well known to those skilled in the art, see, e.g., Wells et al., Pharmacotherapy Handbook,Appleton and Lange,Stamford,Conn.(2000)；PDR Pharmacopoeia,Tarascon Pocket Pharmacopoeia 2000,Tarascon Publishing,Loma In Linda, Calif. (2000) and other medical text books.However, determining the best available amount range of the second therapeutic agent Within the ability of those skilled in the art.

In an embodiment of the invention, when second therapeutic agent is administered to subject, the compound of the present invention Effective quantity be lower than when not applying second therapeutic agent its effective quantity.In another embodiment, second therapeutic agent is effective Amount is lower than its effective quantity when not applying the compound of the present invention.In this way, any reagent to high dose is relevant undesirable Side effect can be minimized.For those skilled in the art, potential advantage will be apparent (including, but are not limited to For example, improving dosage regimen and/or reducing drug cost).

In yet another aspect, the present invention provide the compound of any general formula herein individually or with it is described herein a kind of or A variety of second therapeutic agents application in manufacture drug together, as single composition or as independent dosage form, the drug For treating or preventing disease enumerated herein, disorder or symptom in subject.Another aspect of the present invention is that use is led to herein The compound of formula treats or prevents disease described herein, disorder or symptom in subject.

In other respects, methods herein includes further comprising monitoring subject to those of reaction of therapeutic administratp side Method.Such monitoring may include subject's tissue of the marker or indicant as therapeutic scheme, body fluid, cerebrospinal fluid, sample This, cell, protein, chemical marker, the periodic sampling of inhereditary material etc..In other methods, pass through the related mark of assessment To the adaptability of such treatment, subject, which is screened or is accredited as in advance, needs such treatment for will object or indicant.

In one embodiment, the present invention provides a kind of method for monitoring therapeutic advance.The method includes measurements to suffer from Have or is susceptible in the subject of disorder described herein or its symptom diagnosis marker (marker) (for example, by the change of this paper Close any target described herein or cell type that object is adjusted) or diagnostic measurement value (for example, screening, measurement) horizontal step Suddenly, wherein the subject oneself applied and be enough to treat the compound of this paper of therapeutic dose of the disease or its symptom.? The marker measured in the method it is horizontal can with the marker in the normal control of health or in other afflicted patients oneself Know that level compares, to establish the disease condition of subject.In a preferred embodiment, be later than measurement first level when Between marker in point measurement subject it is second horizontal, and compare two levels to monitor the process of disease or the function of therapy Effect.In some preferred embodiments, the marker levels before treating in subject are starting treatment according to the present invention It is preceding measured；The preceding level of the treatment of this marker can start the marker levels in rear subject with treatment and be compared, To determine the effect for the treatment of.

Marker or marker active horizontal measured at least one in certain method implementations, in subject It is secondary.Marker levels and the marker levels for example obtained previously or then from same patient, another patient or normal subjects Another measured value be compared, can be used for determining whether therapy according to the present invention has desired effect, and thus Allow optionally to adjust dosage level.It is known or described herein any suitable that the measurement of marker levels can use this field The sampling of conjunction/expression measuring method carries out.Preferably, tissue or fluid sample are taken out from subject first.Suitable sample Example include blood, urine, cerebrospinal fluid, tissue, mouth or cheek cell and the hair sample containing root.Other suitable samples Product are that those skilled in the art is known.Protein level in sample, ctDNA, cfDNA and/or mRNA level in-site are (for example, mark Will object is horizontal) measurement can use the known any suitable technology in this field, including but not limited to, enzyme immunoassay (EIA), ELISA, radioactive label determination techniques, trace/chemiluminescence method, real-time PCR, electrochemical signals etc. carry out.

The present invention also provides a kind of reagents for treating including disease those of described herein, disorder or its symptom Box.These kits include: 1) include this paper any general formula compound or its salt；Or the salt of its prodrug or prodrug；Or its The pharmaceutical composition of hydrate, solvate or polymorph, wherein described pharmaceutical composition is in container；And it 2) describes The specification of the method including disease described herein, disorder or its symptom is treated using described pharmaceutical composition.The appearance Device can be any container that can accommodate described pharmaceutical composition or other sealings or sealable equipment.Example includes bottle Son, separated or multicell reservoir bottle, wherein each subregion or compartment include the single dose of the composition；The foil packet of separation Dress, wherein each subregion includes the composition of single dose；Or distributor, distribute the composition of single dose.It is described Container can be this field known any conventional shape or form, be made of pharmaceutically acceptable material, for example, paper or Cardboard case, glass or plastic bottle or tank, resealable sack (for example, to accommodate " the recharging object " of tablet for putting Set in different vessels) or blister package with single dosage for being squeezed out from the package according to treatment schedule.It uses Container can depend on related definite dosage form, for example, conventional cardboard case will generally be not used in receiving liquid suspension.It can It is capable, more than one container can be used together in individual packaging by the single formulation marketization.For example, tablet can hold It is contained in bottle, bottle is then contained in box.Preferably, container is blister package.

Kit can also comprise the information and/or specification of doctor, pharmacists or subject.These memory aids Including the number being printed upon on each compartment containing medicament or subregion, the side that should be taken in specified tablet or capsule The number of days of case is consistent, or the number of days weekly being printed upon on each compartment or subregion, or the card comprising same type information.

It is of the present invention with EGFRV3 Activating mutations use on the way, quinazoline derivant (I) of the present invention Enantiomeric purity has greater than about 55% to about 99.5%, greater than about 60% to about 99.5%, greater than about 65% to about 99.5%, Greater than about 70% to about 99.5%, greater than about 75% to about 99.5%, greater than about 80% to about 99.5%, greater than about 85% to about 99.5%, greater than about 90% to about 99.5%, greater than about 95% to about 99.5%, greater than about 96% to about 99.5%, greater than about 97% to about 99.5%, greater than about 98% to greater than about 99.5%, greater than about 99% to about 99.5%, or higher.

Known scheme in this field can be used in the compound described herein, including, for example, that described herein A bit, their bioactivity is evaluated.Certain compounds of this paper demonstrate unexpected excellent attribute (for example, metabolism Stability, highly selective, low discharge rate, high permeability, non-P glycoprotein outlet substrate etc.) so that they become potential treatment agent Excellent candidate.

All references cited herein, either with electronics, printing, computer-readable preservation medium or its His form, is all clearly incorporated herein entirety for reference, includes, but are not limited to abstract, article, periodical, publication, religion section Book, paper, technical data sheet, internet site, database, patent, patent application and patent publications.

The following describes the present invention in detail with reference to examples.Following embodiment will be helpful to those skilled in the art The present invention is further understood, but the invention is not limited in any way.It should be pointed out that those skilled in the art For, without departing from the inventive concept of the premise, it can also make certain adjustments and improvements.These belong to guarantor of the invention Protect range.

The preparation of 1. quinazoline derivant of embodiment (I)

The 1.1 intermediate 5- bromo- 5- of fluoro- 4- methoxyl group -2- nitrobenzonitrile A6 and 1- fluoro- 4- (deuterated methoxyl group) -2- nitro The synthesis of benzene C1

Synthetic route is as follows:

Step 1: in the methylene chloride (10 milliliters) of A1 (2.0 grams, 10.5mmol) and triethylamine (1.3 grams, 12.6mmol) Ethyl chloroformate (1.4 grams, 12.6mmol) solution in methylene chloride (3 milliliters) is added dropwise for 0 DEG C in solution.Reaction is mixed Object stirs 1 hour under 0 degree Celsius, and reaches room temperature.Then reaction mixture is washed twice with water.By organic layer sulphur Sour magnesium is dry and is evaporated in vacuo, and obtains the product A2 (2.7 grams, yield 100%) for colorless oil.

Step 2: hair is added dropwise for 10 degrees Celsius in the solution of the concentrated sulfuric acid (4.6mL) to A2 (2.7 grams, 10.3mmol) Cigarette nitric acid (0.73 milliliter, 15.5mmol).After 1 hour, reaction mixture is poured into ice/water, and is extracted with ethyl acetate two It is secondary.By combined organic layer water, sodium bicarbonate and salt water washing are dried over sodium sulfate and are evaporated in vacuo, obtain residue, will Its with silicagel column (n-hexane/ethyl acetate=20/1) purify, obtain for yellow oil product A3 (3.0 grams, yield 94.6%).

Step 3: A3 (3.0 grams, 9.8mmol) be added in the solution in methanol (17 milliliters) sodium bicarbonate (1.6 grams, 19.6mmol).Reaction mixture is stirred at 60 c 3 hours.Methanol evaporates under vacuum.Water (15 milliliters) is added to In residue, water layer is acidified to pH=5 by the way that the solution of 5 moles of hydrogen chloride is added.Water layer is extracted with ethyl acetate twice.Merge Organic layer it is dry with magnesium sulfate, and be evaporated in vacuo, obtain the product A4 (2.3 grams, yield 100%) for yellow solid.

Step 4: carbon is added in the nitrogen of A4 (2.31 grams, 9.8mmol), nitrogen-dimethylformamide (18.5 milliliters) solution Sour potassium (2.7 grams, 19.6mmol) and methyl iodide (1.22 milliliters, 19.6mmol).Reaction mixture is stirred 3 at 60 c Hour.Gained mixture is separated between water and ethyl acetate.Organic layer is dried over sodium sulfate and is evaporated in vacuo, obtain for The product A5 (2.35 grams, yield 97%) of yellow solid.

Step 5: in the nitrogen of A5 (5.17 grams, 20.7mmol) and the mixture of zinc cyanide (1.46 grams, 12.4mmol), nitrogen- It is stirred in dimethyl acetamide (104 milliliters) solution, and with after nitrogen discharge air, palladium catalyst, Pd is added₂(dba)₃(1.90 Gram, 2.07mmol) and ligand, 2- dicyclohexylphosphino -2'- (nitrogen, nitrogen-dimethylamine)-biphenyl (815 milligrams, 2.07mmol), and The reaction mixture is stirred 5 hours at 110 degrees Celsius.It is then cooled to room temperature, is diluted in ethyl acetate, silicon is passed through Diatomaceous earth filtering.Organics washed with brine is dried over sodium sulfate, be concentrated in a vacuum and by silicagel column (ethyl acetate/just oneself Alkane: 1:50 to 1:10) purifying obtains as product as light yellow solid A6 (3.47 grams, yield 85.7%).¹HNMR:(400MHz, DMSO-d6) δ ppm:8.28 (d, J=10.7Hz, 1H), 8.13 (d, J=7.5Hz, 1H), 4.08 (s, 1H) .LC-MS:(ESI) M/z=197 (M+H)⁺。

1.2 intermediate tert-butyl 3,3-, the bis- fluoro- 1- methyl piperazine of fluoro- 4- hydroxy piperidine -1- t-butyl formate B8 and 3,3- bis- The synthesis of pyridine -4- alcohol C2

Synthetic route is as follows:

Step 1: B1 (81.7 is added in methanol (300 milliliters) solution to benzotriazole (47 grams, 394.5mmol) Gram, 394.5mmol) and 37% formaldehyde (37.9 milliliters, 512.9mmol), obtained mixture be stirred at room temperature 16 hours. Mixture is removed under vacuum, residue is poured into water (500 milliliters), is extracted with ethyl acetate (500 milliliters × 3), is passed through Sodium sulphate is dried, filtered and concentrated, and is obtained as yellow oil product B2 (132 grams, yield 98.8%).

Step 2: at room temperature, to what is be added in the tetrahydrofuran of zinc powder (56 grams, 862mmol) (500 milliliters) solution Trimethyl silicane chlorine (49 grams, 452mmol).Then difluoro bromine second is added dropwise in the stirring of gained suspension at room temperature after 15 minutes Acetoacetic ester (96 grams, 474mmol), stirs the mixture for 15 minutes.Then B2 (146 grams, 431mmol) are added at room temperature in tetrahydro Solution in furans (500 milliliters), and be stirred overnight.The mixture pours into the saturated aqueous solution of sodium bicarbonate (2.5 liters), uses second (500 milliliters) of acetoacetic ester extractions, are filtered with diatomite, are separated, and organic phase is dried over sodium sulfate, filters and be concentrated, obtain remnants It is used silica gel column purification (ethyl acetate/n-hexane=1/50 to 1/20), obtains the product B3 (90 for yellow oil by object Gram, yield 60.8%).

Step 3: it is taken the photograph into tetrahydrofuran (500 milliliters) solution of diisopropylamine (63.0 grams, 629mmol) subzero 70 N-BuLi (2.5M hexane, 231.5 milliliters, 576mmol) solution is added dropwise in family name's degree, and it is Celsius that gained mixture is warming up to subzero 10 Degree reaction 30 minutes.Then system is cooled to the tetrahydro furan that B3 (90 grams, 262mmol) are added dropwise after subzero 70 degrees Celsius It mutters solution (500 liters).Stirring 30 minutes, and be gradually heated to room temperature and be stirred for 1 hour.Mixture is poured into saturated ammonium chloride It in aqueous solution (500 milliliters), is extracted with ethyl acetate (500 liters × 3), organic phase is dried over sodium sulfate, filters and be concentrated, obtain For yellow oil product B4 (90.7 grams).Crude product is directly used in next step without further purification.

Step 4: (90 grams, 302mmol) addition 6 mole hydrochlorides (900 milliliters) aqueous solutions of B4 heat the mixture to back Stream 3 hours.After being cooled to room temperature, mixture is poured slowly into 8 molar sodium hydroxides (1 liter), (1 liter) three is extracted with ethyl acetate Secondary, organic phase is concentrated into 4-5 liter, is added n-hexane (600 milliliters), stirs the mixture for 1 hour and filter, and obtains as white admittedly Body product B5 (34 grams, two step yields 46.5%).

Step 5: boron hydrogen is added portionwise at 0-5 degrees Celsius into methanol (730 milliliters) solution of B5 (34 grams, 139mmol) Change sodium (7.9 grams, 209mmol).Sodium bicarbonate aqueous solution (0.1 is added after mixture is stirred for 15 minutes under 0-5 degrees Celsius Mole, 54 milliliters), and stir the mixture for 5 minutes, mixture is dry with sodium sulphate, concentration, and pass through silica gel column purification (ethyl acetate/n-hexane=1/20 to 1/10) obtains colorless oil as product B6 (30 grams, yield 97.1%).

Step 6: catalyst palladium dydroxide/activity is added into ethyl alcohol (600 milliliters) solution of B6 (30 grams, 134mmol) Charcoal (10%, 3.0 grams) stirs mixture 4 hours under hydrogen balloon.It filters the mixture and is concentrated, obtain as white solid Product B7 (15.8 grams, yield 85.8%).1HNMR:(400MHz, DMSO-d6) δ ppm:5.43 (d, J=5.1Hz, 1H), 3.71 (m,1H,),2.98(m,1H),2.84–2.57(m,2H),2.23(s,1H),1.85–1.64(m,1H),1.60–1.34(m, 1H).LC-MS:(ESI) m/z=138.0 (M+H)⁺

Step 7: at room temperature, until 88% formic acid solution (941 milligrams, 18.0mmol) of B7 (500 milligrams, 3.6mmol) Middle additionFormaldehyde (584 milligrams, 7.2mmol) solution.Solution is stirred 30 minutes under 78 degrees Celsius.The mixing Object with sodium hydrate aqueous solution wash adjust pH toMixture (30 milliliters × 3) are extracted with ethyl acetate.By organic phase It is dried and concentrated, is obtained as white solid product B8 (340 milligrams, yield 62.5%) with sodium sulphate.¹H NMR(400MHz, DMSO-d6) δ 5.48 (d, J=5.4Hz, 1H), 3.79-3.48 (m, 1H), 2.74 (dd, J=22.1,12.2Hz, 1H), 2.46- 2.34(m,1H),2.20(s,4H),1.90–1.69(m,1H),1.69–1.47(m,1H).LC-MS:(ESI) m/z=152 [M+ H]⁺。

1.3 intermediates (Z)-nitrogen '-{ 2- cyano -4- [(the fluoro- 1- methyl piperidine -4- base of 3,3- bis-) oxygroup] -5- methoxyl group Phenyl }-nitrogen, the synthesis of -2 methylrnethwirnidamide A9 of nitrogen

Synthetic route is as follows:

Step 1: to the nitrogen of sodium hydride (4.85 grams, 102mmol), 50 in nitrogen-dimethyl acetamide (10 milliliters) solution The nitrogen of A6 (10 grams, 51mmol) and B8 (7.71 grams, 51mmol), nitrogen-dimethyl acetamide (30 are added dropwise under degree Celsius nitrogen protection Milliliter) solution.It is stirred 1 hour under 0 degree Celsius.The saturated solution of ammonium chloride is poured the mixture into, and is extracted with ethyl acetate. Organic phase is washed with brine, is dried over sodium sulfate, be concentrated in a vacuum and passes through silica gel column purification (ethyl acetate/n-hexane =1:3 to 1:1) obtains as yellow solid product A7 (12 grams, yield 71%).¹HNMR:(400MHz,CDCl₃-d6)δppm: 7.85 (s, 1H), 7.39 (s, 1H), 4.56 (td, J=9.7,4.9Hz, 1H), 4.06 (s, 3H), 2.96-2.86 (m, 1H), 2.79 (dd, J=19.9,12.3Hz, 1H), 2.57 (dd, J=29.0,23.4Hz, 2H), 2.43 (s, 3H), 2.18 (dd, J= 8.1,3.9Hz, 2H) .LC-MS:(ESI) m/z=328 (M+H)⁺

Step 2: in acetic acid (250 milliliters) solution of A7 (5 grams, 15.28mmol) be added zinc powder (9.93 grams, In 152.8mmol).Mixture stirs 0.5 hour at 30-40 degrees Celsius.Reaction solution pours into ethyl acetate (200mL) and water It is to 7. separation organic phases and dry with sodium sulphate that sodium bicarbonate adjusting pH value is added in (400mL).It is dense to filter the mixture vacuum Contracting filtrate obtains being directly used in for yellow oil product A8 (4.4 grams, yield 88.0%) in next step.LC-MS:(ESI)m/z =298 (M+H)⁺

Step 3: A8 (4.4 grams, 14.8mmol) and nitrogen, nitrogen-dimethylformamide dimethyl acetal (8.8 grams, 74mmol) Toluene (50 milliliters) solution in mixture 100 degrees Celsius under nitrogen protection stir 20 hours.It is concentrated in vacuo the mixing Object obtains residue, it is used silica gel column purification (methylene chloride/methanol=100:1), is obtained as yellow oil product A9 (3.4 grams, 63%).¹HNMR:(400MHz,DMSO)δppm:7.58(s,1H),7.17(s,1H),6.47(s,1H),4.20 (tt, J=10.1,5.1Hz, 1H), 3.88 (s, 3H), 3.08 (s, 6H), 2.90 (ddd, J=18.4,11.8,4.4Hz, 1H), 2.69 (dt, J=30.2,9.6Hz, 2H), 2.46 (dd, J=15.2,8.9Hz, 1H), 2.39 (s, 3H), 2.08 (s, 2H) .LC- MS:(ESI) m/z=353 (M+H)⁺。

The synthesis of 1.4 quinazoline derivants (I)

Synthetic route is as follows:

Step 1: A9 (3.4 grams, 9.65mmol) and the fluoro- 3- of 2- ((trimethyl silicane methyl) acetenyl) aniline (4 grams, 19.3mmol) in the mixture of acetic acid (90 milliliters), 80 degrees Celsius stirred under nitrogen atmosphere 16 hours.After cooling, carbonic acid is used Hydrogen sodium saturated solution is handled to pH=8, and is extracted with dichloromethane.Organic phase sodium sulphate is dry and vacuum concentration obtains remnants Object, by its use silica gel column purification (methylene chloride/methanol=100:1), obtain for white solid product A10 (2.4 grams, yield 48%).LC-MS:(ESI) m/z=515 (M+H)⁺

Step 2: TBAF (1M tetrahydro furan is added in the solution of tetrahydrofuran (10 milliliters) in A10 (1 gram, 1.94mmol) It mutters solution, 1.94 milliliters, 1.94mmol), it is stirred at room temperature 0.5 hour.It is used silica gel column purification (dichloro by vacuum concentration Methane/methanol=200:1 to 100:1) obtains as yellow solid product A11 (800 milligrams, yield 93%).¹HNMR: (400MHz,CDCl₃- d6) δ ppm:8.74 (s, 1H), 8.63 (td, J=8.0,1.7Hz, 1H), 7.42 (s, 1H), 7.35 (d, J =8.5Hz, 2H), 7.28-7.18 (m, 2H), 4.50 (dd, J=9.5,4.9Hz, 1H), 4.05 (s, 3H), 3.38 (s, 1H), 3.07–2.91(m,1H),2.88–2.69(m,2H),2.56(s,1H),2.45(s,3H),2.30–2.13(m,2H)。LC-MS: (ESI) m/z=443 (M+H)⁺

Step 3: racemic mixture A11 (1.03 grams) makes through efficient liquid phase chiral separation column OJ-H (4.6*100*5um) With methanol (0.2% methanol ammonia) cross column obtain enantiomer-pure (R)/(-) free alkali cpd (I) (480 milligrams, ee% > 99%, LC-MS:(ESI) m/z=443 (M+H)⁺)。

The above method is hydrate, has hygroscopicity, crystal form conversion occurs in heating process.Due to moisture absorption and thermally labile It is difficult to that solid pharmaceutical preparation is made under drug processing conditions.Therefore, it is necessary to further prepare with superior physicochemical properties The preferred salt form of quinazoline derivant and the crystal form of salt advantageous can use in drug processing and pharmaceutical composition.

The preparation of the hydrochloride Form A of 2. quinazoline derivant of the present invention (I) of embodiment

Quinazoline derivant shown in about 20 milligrams of formula (I) is weighed (that is, (R) -6- [(3,3- bis- fluoro- 1- methyl piperidine -4- Base) oxygroup]-nitrogen-(3- acetenyl -2- fluorophenyl) -7- methoxyquinazoline hydrochloride -4- amine (I)) sample in 1.5 milliliters of bottles, adds Enter 0.6 ml methanol and 46 microlitres of hydrochloric acid (1mol/L), be stirred at room temperature about two days later, it is solid to be centrifugated out the wet sample of lower layer Body.It is detected through XRPD, which is hydrochloride Form A.

The preparation of the hydrochloride Form B of 3. quinazoline derivant of the present invention (I) of embodiment

Quinazoline derivant sample shown in about 160 milligrams of formula (I) is weighed, 5 milliliters of tetrahydrofuran/water (19/1, v/ are added V), 0.37 milliliter of hydrochloric acid (1mol/L) and into the suspension is added, is stirred at room temperature about two days, is centrifugated out lower layer Wet sample solid.It is detected through XRPD, which is hydrochloride Form B.

The preparation of the hydrochloride Form H of 4. quinazoline derivant of the present invention (I) of embodiment

In 3 milliliters of bottles 2 milliliters of ethyl alcohol are added, in room temperature after filtering in the hydrochloride Form B sample for weighing about 10 milligrams Lower open mouth quickly volatilizees.It is detected through XRPD, obtained solid is hydrochloride Form H.

The preparation of the hydrochloride Form I of 5. quinazoline derivant of the present invention (I) of embodiment

The hydrochloride Form H sample for weighing about 10 milligrams, is cooled to room after being heated to 125 DEG C using DSC Q2000 Temperature obtains hydrochloride Form I.

The preparation of the fumarate crystal form A of 6. quinazoline derivant of the present invention (I) of embodiment

Quinazoline derivant shown in about 160 milligrams of formulas (I) and 45 milligrams of fumaric acid samples are weighed in 20 milliliters of vials, After 5 ml methanols are added, it is stirred at room temperature about two days, solid is collected by centrifugation.It is detected through XRPD, which is that fumarate is brilliant Type A.

The preparation of the succinate crystal form A of 7. quinazoline derivant of the present invention (I) of embodiment

Quinazoline derivant shown in about 160 milligrams of formulas (I) and 43 milligrams of succinic acid samples are weighed in 20 milliliters of vials, After 5 milliliters of acetone are added, it is stirred at room temperature about two days, solid is collected by centrifugation.It is detected through XRPD, which is that succinate is brilliant Type A.

The preparation of the maleate crystal form A of 8. quinazoline derivant of the present invention (I) of embodiment

Quinazoline derivant shown in about 10 milligrams of formulas (I) and 2.6 milligrams of maleic acid samples are weighed in 1.5 milliliters of vials In, 0.3 milliliter of acetone is added, is stirred at room temperature about two days, solid is collected by centrifugation.It is detected through XRPD, which is maleic acid Salt crystal form A.

The preparation of the glycollate crystal form A of 9. quinazoline derivant of the present invention (I) of embodiment

Quinazoline derivant shown in about 150 milligrams of formulas (I) and 27 milligrams of glycolic samples are weighed in 1.5 milliliters of vials In, 5 milliliters of ethyl acetate are added, is stirred at room temperature about two days, solid is collected by centrifugation.It is detected through XRPD, which is ethyl alcohol Hydrochlorate crystal form A.

The preparation of the hydrochloride Form F of 10. quinazoline derivant of the present invention (I) of embodiment

The hydrochloride sample for weighing about 5 milligrams is added 0.1 ml methanol and makes it dissolve in 3 milliliters of vials.By institute It obtains clear solution to be placed in 20 milliliters of vials for filling 5 milliliters of isopropyl acetates, gas-liquid is spread at room temperature, until there is solid It is precipitated.It is detected through XRPD, obtained solid is hydrochloride Form F.

The preparation of the hydrochloride Form C of 11. quinazoline derivant of the present invention (I) of embodiment

Quinazoline derivant sample shown in about 10 milligrams of formula (I) is weighed, is added 0.3 milliliter of acetonitrile, and to the suspension The middle hydrochloric acid (1mol/L) for being added 46 microlitres, is stirred at room temperature and is about centrifugated out the wet sample solid of lower layer two days later.Through XRPD Detection, is accredited as dihydrochloride crystal form C.

The preparation of the hydrochloride Form D of 12. quinazoline derivant of the present invention (I) of embodiment

The hydrochloride Form C sample for weighing about 2 milligrams, is cooled to room after being heated to 140 degree using DSC Q2000 Temperature obtains dihydrochloride crystal form D.

The preparation of the sulfate crystal form A of 13. quinazoline derivant of the present invention (I) of embodiment

Quinazoline derivant sample shown in about 10 milligrams of formulas (I) is weighed in 1.5 milliliters of vials, 0.3 milliliter of first is added Alcohol and 23 microlitres of aqueous sulfuric acids (1mol/L), are stirred at room temperature about two days, solid are collected by centrifugation.It is detected through XRPD, this is solid Body is sulfate crystal form A.

The preparation of the oxalate crystal form A of 14. quinazoline derivant of the present invention (I) of embodiment

Quinazoline derivant shown in about 10 milligrams of formulas (I) and 3.7 milligrams of adipic acid samples are weighed in 1.5 milliliters of vials In, 0.3 ml methanol is added, is stirred at room temperature about two days, solid is collected by centrifugation.It is detected through XRPD, which is adipic acid Salt crystal form A (the complete adipic acid containing a small amount of unreacted, characteristic peak are as follows: 21.6,25.7).

The preparation of the malate crystal form A of 15. quinazoline derivant of the present invention (I) of embodiment

Quinazoline derivant shown in about 10 milligrams of formulas (I) and 2.9 milligrams of malic acid samples are weighed in 1.5 milliliters of vials In, after 0.3 ml methanol is added, it is stirred at room temperature about two days, solid is collected by centrifugation.It is detected through XRPD, which is apple Hydrochlorate crystal form A.

The preparation of the benzene sulfonate crystal form A of 16. quinazoline derivant of the present invention (I) of embodiment

Quinazoline derivant shown in about 10 milligrams of formulas (I) and 3.7 milligrams of benzene sulfonic acid samples are weighed in 1.5 milliliters of vials In, 0.3 ml methanol is added, is stirred at room temperature about two days, solid is collected by centrifugation.It is detected through XRPD, which is benzene sulfonic acid Salt crystal form A.

The preparation of the benzene sulfonate crystal form B of 17. quinazoline derivant of the present invention (I) of embodiment

Quinazoline derivant shown in about 10 milligrams of formulas (I) and 3.5 milligrams of benzene sulfonic acid samples are weighed in 1.5 milliliters of vials In, 0.3 milliliter of acetonitrile is added, is stirred at room temperature about two days, solid is collected by centrifugation.It is detected through XRPD, which is benzene sulfonic acid Salt crystal form B.

The preparation of the benzene sulfonate crystal form C of 18. quinazoline derivant of the present invention (I) of embodiment

Quinazoline derivant shown in about 10 milligrams of formulas (I) and 3.9 milligrams of benzene sulfonic acid samples are weighed in 1.5 milliliters of vials In, the mixed solvent (19:1, v/v) of 0.3 milliliter of tetrahydrofuran and water is added, is stirred at room temperature about two days, is collected by centrifugation solid Body.It is detected through XRPD, which is benzene sulfonate crystal form C.

The preparation of the benzoate crystal form A of 19. quinazoline derivant of the present invention (I) of embodiment

Quinazoline derivant shown in about 10 milligrams of formulas (I) and 3.0 milligrams of benzoic acid samples are weighed in 1.5 milliliters of vials In, after 0.3 ml methanol is added, it is stirred at room temperature about two days, solid is collected by centrifugation.It is detected through XRPD, which is benzene first Hydrochlorate crystal form A.

The preparation of the hippurate crystal form A of 20. quinazoline derivant of the present invention (I) of embodiment

Quinazoline derivant shown in about 10 milligrams of formulas (I) and 4.2 milligrams of hippuric acid samples are weighed in 1.5 milliliters of vials In, after 0.3 ml methanol is added, it is stirred at room temperature about two days, solid is collected by centrifugation.It is detected through XRPD, which is horse urine Hydrochlorate crystal form A.

The preparation of the Crystal form of oxalate A of 21. quinazoline derivant of the present invention (I) of embodiment

Quinazoline derivant shown in about 10 milligrams of formulas (I) and 2.0 milligrams of oxalic acid samples are weighed in 1.5 milliliters of vials, After 0.3 ml methanol is added, it is stirred at room temperature about two days, solid is collected by centrifugation.It is detected through XRPD, which is that oxalates is brilliant Type A.

Embodiment 22. characterizes the crystal form of the salt of quinazoline derivant of the invention (I) by XRPD figure

XRPD device information is as follows:

XRPD map acquires on the X-ray powder diffraction analyzer of Bruker, and XRPD parameter is as shown in table 1.

1 XRPD test parameter of table

According to hydrochloride Form A, XRPD (the X-ray powder of the quinazoline derivant (I) of the present embodiment the method preparation Last diffraction) map is as shown in Fig. 1, embodiments such as the following table 2:

Table 2

According to hydrochloride Form B, the XRPD (x-ray powder of the quinazoline derivant (I) of embodiment the method preparation Diffraction) map is as shown in Fig. 2, embodiments such as the following table 3:

Table 3

According to hydrochloride Form H, the XRPD (x-ray powder of the quinazoline derivant (I) of embodiment the method preparation Diffraction) map is as shown in Fig. 3, embodiments such as the following table 4:

Table 4

According to hydrochloride Form I, the XRPD (x-ray powder of the quinazoline derivant (I) of embodiment the method preparation Diffraction) map is as shown in Fig. 4, embodiments such as the following table 5:

Table 5

According to fumarate crystal form A, XRPD (the X-ray powder of the quinazoline derivant (I) of embodiment the method preparation Last diffraction) map is as shown in Fig. 5, embodiments such as the following table 6:

Table 6

According to succinate crystal form A, XRPD (the X-ray powder of the quinazoline derivant (I) of embodiment the method preparation Last diffraction) map is as shown in Fig. 6, embodiments such as the following table 7:

Table 7

According to maleate crystal form A, XRPD (the X-ray powder of the quinazoline derivant (I) of embodiment the method preparation Last diffraction) map is as shown in Fig. 7, embodiments such as the following table 8:

Table 8

According to glycollate crystal form A, XRPD (the X-ray powder of the quinazoline derivant (I) of embodiment the method preparation Last diffraction) map is as shown in Fig. 8, embodiments such as the following table 9:

Table 9

According to hydrochloride Form F, the XRPD (x-ray powder of the quinazoline derivant (I) of embodiment the method preparation Diffraction) map is as shown in Fig. 9, embodiments such as the following table 10:

Table 10

According to hydrochloride Form C, the XRPD (x-ray powder of the quinazoline derivant (I) of embodiment the method preparation Diffraction) map is as shown in Fig. 10, embodiments such as the following table 11:

Table 11

According to hydrochloride Form D, the XRPD (x-ray powder of the quinazoline derivant (I) of embodiment the method preparation Diffraction) map is as shown in Fig. 11, embodiments such as the following table 12:

Table 12

According to sulfate crystal form A, the XRPD (x-ray powder of the quinazoline derivant (I) of embodiment the method preparation Diffraction) map is as shown in Fig. 12, embodiments such as the following table 13:

Table 13

According to oxalate crystal form A, XRPD (the X-ray powder of the quinazoline derivant (I) of embodiment the method preparation Last diffraction) map is as shown in Fig. 13, embodiments such as the following table 14:

Table 14

According to malate crystal form A, XRPD (the X-ray powder of the quinazoline derivant (I) of embodiment the method preparation Last diffraction) map is as shown in Fig. 14, embodiments such as the following table 15:

Table 15

According to benzene sulfonate crystal form A, XRPD (the X-ray powder of the quinazoline derivant (I) of embodiment the method preparation Last diffraction) map is as shown in Fig. 15, embodiments such as the following table 16:

Table 16

According to benzene sulfonate crystal form B, XRPD (the X-ray powder of the quinazoline derivant (I) of embodiment the method preparation Last diffraction) map is as shown in Fig. 16, embodiments such as the following table 17:

Table 17

According to benzene sulfonate crystal form C, XRPD (the X-ray powder of the quinazoline derivant (I) of embodiment the method preparation Last diffraction) map is as shown in Fig. 17, embodiments such as the following table 18:

Table 18

According to benzoate crystal form A, XRPD (the X-ray powder of the quinazoline derivant (I) of embodiment the method preparation Last diffraction) map is as shown in Fig. 18, embodiments such as the following table 19:

Table 19

According to hippurate crystal form A, XRPD (the X-ray powder of the quinazoline derivant (I) of embodiment the method preparation Last diffraction) map is as shown in Fig. 19, embodiments such as the following table 20:

Table 20

According to Crystal form of oxalate A, the XRPD (x-ray powder of the quinazoline derivant (I) of embodiment the method preparation Diffraction) map is as shown in Fig. 20, embodiments such as the following table 21:

Table 21

D is the interplanar distance of two neighboring crystal face in crystal lattices, by angstrom as unit of, I% is intensity.

As shown in Figure 1, the XRPD map of the hydrochloride Form A of quinazoline derivant (I) provided by the invention 2 θ= 6.48,7.31,9.36,10.26,13.12,14.37,14.98,16.06,16.88,17.48,18.25,20.01,20.83, 21.55,22.21,23.35,25.47,26.60,27.46,28.29,29.98,34.07,34.89,36.25,36.47, There is derivative peak, the error range of above-mentioned 2 θ value is ± 0.2 at 36.87,37.54.

As shown in Figure 2, the XRPD map of the hydrochloride Form B of quinazoline derivant (I) provided by the invention 2 θ= 4.32,5.98,6.54,7.28,8.17,10.52,13.20,15.99,17.74,18.48,19.32,19.84,22.56, There is derivative peak at 23.88,24.36,24.87,30.47,32.92,33.55,34.60,38.06,38.34, above-mentioned 2 θ value Error range is ± 0.2.

From the figure 3, it may be seen that the XRPD map of the hydrochloride Form H of quinazoline derivant (I) provided by the invention 2 θ= 5.83,6.43,7.26,8.10,10.24,11.93,13.22,14.11,14.45,14.88,15.78,16.80,17.95, Have at 18.96,20.25,21.07,21.65,24.16,24.53,25.67,26.37,27.03,27.61 and derives peak, above-mentioned 2 The error range of θ value is ± 0.2.

As shown in Figure 4, the XRPD map of the hydrochloride Form I of quinazoline derivant (I) provided by the invention 2 θ= 6.88,7.42,8.20,12.31,13.20,13.88,14.23,14.66,15.69,17.48,17.90,18.64,19.23, 20.24,20.92,21.94,22.88,23.42,23.88,25.12,25.40,25.85,26.64,28.07,28.92, There is derivative peak, the error range of above-mentioned 2 θ value is ± 0.2 at 31.19,33.10.

As shown in Figure 5, the XRPD map of the fumarate crystal form A of quinazoline derivant (I) provided by the invention 2 θ= 6.51,6.74,7.47,9.37,10.82,13.43,13.97,14.61,17.78,18.51,18.80,19.69,20.90, 21.36,21.68,22.63,23.76,24.39,27.09,28.73,29.69,30.52,31.07,35.14,36.12,38.33 Place has derivative peak, and the error range of above-mentioned 2 θ value is ± 0.2.

It will be appreciated from fig. 6 that the XRPD map of the succinate crystal form A of quinazoline derivant (I) provided by the invention 2 θ= 3.92,4.40,6.56,6.74,7.50,9.42,11.92,12.68,13.53,14.50,14.84,15.22,15.68, 16.25,17.82,18.55,19.48,20.34,20.99,22.08,22.59,24.14,24.52,24.92,28.07, There is derivative peak, the error range of above-mentioned 2 θ value is ± 0.2 at 30.92,36.11.

As shown in Figure 7, the XRPD map of the maleate crystal form A of quinazoline derivant provided by the invention 2 θ= 6.25,8.44,8.68,9.42,10.41,14.42,14.88,16.65,17.93,18.78,20.58,21.17,22.63, Have at 25.16,31.15,32.40,33.66,34.34,34.52,35.82,36.06,36.35,36.91 and derives peak, above-mentioned 2 The error range of θ value is ± 0.2.

As shown in Figure 8, the XRPD map of the glycollate crystal form A of quinazoline derivant provided by the invention 2 θ= 4.53,5.89,6.59,7.35,10.02,12.54,13.26,15.94,17.93,18.67,19.36,19.84,21.06, There is derivative peak, the error range of above-mentioned 2 θ value is ± 0.2 at 24.99,31.13,33.48,34.79,35.56,36.17.

As shown in Figure 9, the XRPD map of the hydrochloride Form F of quinazoline derivant (I) provided by the invention 2 θ= 4.91,5.67,6.51,6.77,7.44,8.58,9.20,9.73,10.40,10.85,11.86,13.58,14.30,14.78, 15.57,15.85,16.15,16.41,16.97,17.89,18.96,19.76,20.45,20.79,21.57,22.21,24.17 Place has derivative peak, and the error range of above-mentioned 2 θ value is ± 0.2.

As shown in Figure 10, the XRPD map of the hydrochloride Form C of quinazoline derivant (I) provided by the invention 2 θ= 5.66,7.16,8.32,8.86,9.52,10.98,11.63,12.80,13.57,13.96,14.81,15.14,15.49, 16.55,16.86,17.61,22.04,22.93,24.55,26.19,27.30,28.49,34.12,34.76,35.65, There is derivative peak, the error range of above-mentioned 2 θ value is ± 0.2 at 36.68,37.31,37.80,38.20,38.53.

As shown in Figure 11, the XRPD map of the hydrochloride Form D of quinazoline derivant (I) provided by the invention 2 θ= 3.43,6.72,7.12,8.47,9.32,12.25,13.44,14.07,15.69,16.87,17.22,17.97,19.77, 20.73,22.25,22.82,23.64,24.77,25.40,27.28,28.13,29.69,31.01,33.48,34.87, There is derivative peak, the error range of above-mentioned 2 θ value is ± 0.2 at 35.42,38.08.

As shown in Figure 12, the XRPD map of the sulfuric acid crystal form A of quinazoline derivant (I) provided by the invention 2 θ= 7.27,8.41,11.88,14.96,18.23,19.68,20.64,24.83,25.82,27.10,28.16,29.79,30.71, There is derivative peak, the error range of above-mentioned 2 θ value is ± 0.2 at 32.35,34.12,35.56,37.56,38.37.

As shown in Figure 13, the XRPD map of the oxalate crystal form A of quinazoline derivant (I) provided by the invention 2 θ= 5.43,6.88,7.38,9.56,13.68,15.10,15.43,16.32,16.88,17.68,18.60,19.02,20.58, 21.62,22.33,22.70,23.35,25.68,27.29,27.88,28.53,29.37,31.35,34.89,37.11, There is derivative peak, the error range of above-mentioned 2 θ value is ± 0.2 at 37.78,38.17,38.36,39.65.

As shown in Figure 14, the XRPD map of the malate crystal form A of quinazoline derivant (I) provided by the invention 2 θ= 5.43,6.53,7.49,8.35,9.17,12.10,13.16,16.17,18.77,19.85,20.79,23.14,23.94, Have at 26.66,28.25,29.32,30.38,33.24,33.69,34.80,35.97,36.87,37.88 and derives peak, above-mentioned 2 The error range of θ value is ± 0.2.

As shown in Figure 15, the XRPD map of the benzene sulfonate crystal form A of quinazoline derivant provided by the invention 2 θ= 5.48,6.56,7.08,7.65,8.14,8.48,9.71,10.55,11.14,11.77,13.32,13.95,15.32,16.46, 16.89,17.82,19.15,19.70,20.43,21.02,21.98,22.68,23.23,25.26,26.07,26.59, Have at 28.63,29.09,30.45,31.12,32.09,32.55,33.66,35.76,37.86,38.67,39.11 and derives Peak, the error range of above-mentioned 2 θ value are ± 0.2.

As shown in Figure 16, the XRPD map of the benzene sulfonate crystal form B of quinazoline derivant provided by the invention 2 θ= 5.50,6.32,7.28,8.50,9.74,10.79,11.55,13.22,14.49,15.53,16.26,16.97,18.29, There is derivative peak, the error model of above-mentioned 2 θ value at 19.71,21.36,22.21,23.44,24.19,25.34,25.87,27.16 Enclose is ± 0.2.

As shown in Figure 17, the XRPD map of the benzene sulfonate crystal form C of quinazoline derivant (I) provided by the invention 2 θ= 4.24,7.07,7.68,8.31,9.92,12.55,14.03,14.74,18.72,19.40,20.36,21.19,24.08, 24.73,26.14,27.49,28.28,31.68,33.90,34.82,35.06,35.78,36.54,37.57,37.89, There is derivative peak, the error range of above-mentioned 2 θ value is ± 0.2 at 38.36,39.0.

As shown in Figure 18, the XRPD map of the benzoate crystal form A of quinazoline derivant (I) provided by the invention 2 θ= 4.45,6.31,6.65,7.33,7.69,8.01,11.85,13.53,16.02,16.77,18.75,19.95,21.06, 21.76,22.56,23.41,26.94,27.44,27.61,27.98,28.55,29.05,31.92,32.29,32.93, There is derivative peak at 33.72,34.61,35.35,35.95,37.08,38.13,39.62, the error range of above-mentioned 2 θ value is ± 0.2。

It appears from figure 19 that the XRPD map of the hippurate crystal form A of quinazoline derivant (I) provided by the invention 2 θ= 4.35,5.59,6.85,7.74,9.17,9.95,13.74,14.73,15.96,16.44,18.10,18.63,19.96, 21.38,24.25,25.37,25.72,26.39,27.23,28.56,30.25,30.82,33.31,34.58,35.29, There is derivative peak, the error range of above-mentioned 2 θ value is ± 0.2 at 36.39,37.24,37.9.

As shown in Figure 20, the XRPD map of the Crystal form of oxalate A of quinazoline derivant (I) provided by the invention 2 θ= 4.11,6.44,7.15,8.75,9.06,9.88,11.26,11.58,12.92,14.52,15.87,17.47,18.29, 19.43,20.14,20.49,23.70,24.34,26.36,26.92,29.75,31.72,32.67,32.99,34.21, There is derivative peak, the error range of above-mentioned 2 θ value is ± 0.2 at 34.52,34.86,36.36,36.91,37.91,39.03.

After tested, the error range of 2 θ values be also possible to ± 0.2. it will be understood by those skilled in the art that these diffraction maximums not Represent the hydrochloride Form A, B, C, D, F, H, I of quinazoline derivant (I), sulfate crystal form A, maleate crystal form A, succinic acid Salt crystal form A, adipate crystal form A, glycollate crystal form A, malate crystal form A, fumarate crystal form A, benzene sulfonate crystal form A, B, C, the detailed situation of diffraction maximum shown by benzoate crystal form A, hippurate crystal form A and Crystal form of oxalate A.X-ray powder 2 θ values of last diffraction pattern are slight change can to occur with changing between the variation and batch in machine and sample preparation, institute The value of reference is not intended as absolute value.It will also be appreciated that the absolute intensity at peak may also become with orientation effect, therefore, this Intensity shown in inventing is exemplary, and is not used to absolutely relatively.

The bioactivity of 23. quinazoline derivant of embodiment (I)

Tumour cell and glioma with EGFR Activating mutations (exons 19 lack Exon 19Del) albumen it is thin Born of the same parents' viability examination uses CellTiter-Glo (CTG) assay；For about 5000 cell kinds in 96 orifice plates of each blank, 16 is small Diluted compound in proportion is added in Shi Hou, after drug adds 72 hours, at equilibrium at room temperature 30 minutes.It is added in every hole 100 microlitres of CellTiter-Glo reagents are mixed with inducing cell lysis for orbital shaker 2 minutes.The plate is incubated at room temperature 10 points Clock is with stabilized illumination signal.In TECAN Infinite M1000Pro instrument record luminous signal.

Inhibition (the IC of table 22. non-small cell lung cancer PC-9 tumour cell and glioma growth of tumour cell_5oUnit be nM)

As shown in Table 22, the quinazoline derivant (I) of the present invention for being configured as R is prominent with unexpected EGFRVIII The activity of change is higher than enantiomter activity > 100 times.With the bioactivity similar with EGFR Del19 Activating mutations.

As shown in figure 21, in protein immunoblot (western blot) experiment, the phosphorylation of EGFRV3 is spread out by quinazoline Biological (I) inhibits, and display quinazoline derivant (I) has good bioactivity, and special is situated between for EGFRV3 phosphorylation The cancer led.

24. quinazoline derivant of embodiment (I) passes through blood-brain barrier rate

To determine whether quinazoline derivant (I) can pass through blood-brain barrier (BBB), rat is carried out with test compound Administration.After 4 hours are administered, rat is killed, collects blood and brain tissue, analysis test compound concentration.Brain infiltration is defined as The ratio between the concentration in compound concentration and blood plasma in brain tissue.Across the free concentration of drug that blood-brain barrier rate is in brain tissue With the ratio between the free concentration of drug in blood plasma.P- glycoprotein is blood-brain barrier efflux protein, and cranium will be discharged outside P- glycoprotein substrate It is interior.Breast drug-resistance protein is blood-brain barrier efflux protein, and encephalic will be discharged outside breast drug-resistance protein.

23. quinazoline derivant of table (I) passes through blood-brain barrier ability

Pass through blood-brain barrier rate detection in, compound free concentration of the compound of the present invention (I) in brain tissue with The ratio between free concentration in blood plasma is higher than 50%, and not P- glycoprotein substrate or breast drug-resistance protein outlet substrate, energy Across blood-brain barrier, therefore they are with the potentiality of effective blood drug concentration are reached in encephalic, for treating glioma or treatment With pre- anti-cancer brain metastes, meninx transfer, the cancer of the brain and other central nervous diseases, and reduce occur outside cranium it is dose-limiting The risk of toxicity.

25. quinazoline derivant of embodiment (I) is to the brain tumor being mutated with EGFRV3 in mouse subcutaneous patient's Primary Tumor The drug effect of the tumour transplatation animal model of tissue

Patient's Primary Tumor tissue (brain tumor) is planted subcutaneous into mouse, is started medication, is controlled after long to about 150 cubic millimeters of tumour It treats three weeks.

The brain tumor being mutated with EGFRV3 mouse subcutaneous patient's Primary Tumor tissue tumour transplatation animal model medicine In effect experiment, first group is control group, is free of any drug.The single medicine of second group of quinazoline derivant (I), 3 mgs/kg, mouth Clothes, twice a day, third group quinazoline derivant (I) list medicine, take orally by 10 mgs/kg, twice a day, the 4th group of quinazoline Derivative (I) list medicine, takes orally, twice a day by 20 mgs/kg.As shown in figure 22, medication group (second, three, four groups) comparison the One group (control group) shows the good inhibition increased to tumour, and the drug effect with statistical significance is shown in animal model Dose dependent drug effect, the 4th group of cause tumour reduce, and show good drug effect.And the drug effect difference with statistical significance.It is swollen The mutation of the RNA sequencing display EGFRV3 of tumor, display quinazoline derivant (I) have the good biological for EGFRV3 mutation living Property and drug effect.

The equilbrium solubility of 26. quinazoline derivant of embodiment (I) and its salt crystal form in water

Experimental method: weighing the solid sample (free alkali and each salt form and crystal form) of about 10mg, 1.5mL water is added, in room Temperature balance takes out the turbid solution of 0.3mL respectively after 24 hours, be centrifugated lower layer's solid and supernatant liquor.Supernatant liquor passes through After 0.45 μm of (PTFE) filter filtering, the concentration of free alkali is tested respectively.

Table 23

As shown in Table 23, each salt form crystal form of quinazoline derivant (I) of the present invention is molten with good balance in water Xie Du, it is preferable that the hydrochloride Form A, B, H, I and fumarate crystal form A of quinazoline derivant (I) of the present invention are in water Equilbrium solubility > 500ug/mL.This absorption of drugs is highly beneficial.

27. stability experiment of embodiment

The salt form of one week physical and chemical stability quinazoline derivant (I) of the present invention and crystal form in 25 DEG C/60%RH and One week physicochemical properties is stored under 40 DEG C/75%RH to stablize.TGA map shows each in embodiment 2-21 during heating Crystal form has no significant change, and particularly, DSC map shows that fumarate crystal form A shows good stability.As shown in figure 23, Fumarate crystal form A is during heating without obvious weightlessness, and fusing point is at about 240 degrees Celsius.Such property is to be conducive to prepare It is processed into tablet.

28. quinazoline derivant of the present invention (I) of embodiment has good bioavilability

In pharmacokinetics in rats research, one group rat (three) are injected intravenously 1-2 mgs/kg, second group of rat (three) 2-40 mgs/kg oral, and it is of the present invention that 7 time points (0.25,0.5,1,2,4,8,16 small time point) take blood to survey Concentration of the quinazoline derivant (I) in blood calculates peak area and half-life period.The calculation of bioavilability are as follows: (drug port Take peak area/oral dose)/(medical intravenous injects peak area/intravenous injection dosage) x100%.Quinazoline of the present invention spreads out Each salt form and crystal form of biological (I) have good bioavilability, are all larger than > 35%.

Preferably: hydrochloride Form B, H, I (bioavilability > 60%) and fumarate crystal form A (bioavilability 80%)；

More preferably: fumarate crystal form A (bioavilability 80%, 7.4 hours half-life period).

The mechanism of action of 29. quinazoline derivant of the present invention (I) of embodiment

In the experiment that quinazoline derivant of the present invention (I) inhibits the mechanism of action of EGFR, from 0.4nM equal proportion (2 EGFR enzyme is added in the solution of PolyE4Y1 to 0.0125nM and 384 orifice plates of 0 concentration in diluted 6 concentration again), hatches 15 points Clock is added from the ATP of diluted 7 concentration of 600uM equal proportion (2 times) reaction after sixty minutes, and ADP-Glo reagent and detection is added 40 minutes survey RLU signals of reagent.As shown in figure 24, quinazoline derivant (I) of the present invention shows unexpected non- ATP Competition mechanism.The benefit of this mechanism of action is it will be apparent that having at quinazoline derivant of the present invention (I) There is this mechanism of action to show high activity and highly selective, there is the characteristics of Small side effects, overriding resistance.

In conclusion state quinazoline derivant (I) of the present invention has chiral 6 substitution (3, the 3- bis- fluoro- 1- for being R Methyl piperidine -4- base) oxygroup, there can be high activity simultaneously, highly selective, the blood-brain barrier of height passes through rate, non-outlet substrate, Inhibition activity with non ATP competition mechanism, while there is significant drug effect to non-small cell lung cancer and glioma, height Bioavailability.It is emphasized that quinazoline derivant (I) of the present invention can have simultaneously to non-with unexpected Small Cell Lung Cancer (is mediated, special EGFR Del19 and/or EGFR L858R Activating mutations by certain EGFR activated form It is those of caused) and brain colloid (mediated by certain EGFR activated form, caused by special EGFRVIII Activating mutations Those of) high bioactivity, the selectivity of height, the blood-brain barrier of height passes through the non ATP competitive inhibitor of rate.Especially , the Noncompetition inhibition characteristic bring high activity and high selection of the chiral quinazoline derivant (I) for being R of the present invention Property, can particularly have the activity of height to glioma.

The hydrochloride Form A, B, C, D, F, H, I of quinazoline derivant of the present invention, sulfate crystal form A, maleate crystal form A, succinate crystal form A, adipate crystal form A, glycollate crystal form A, malate crystal form A, fumarate crystal form A, benzene sulphur Hydrochlorate crystal form A, B, C, the solubility of benzoate crystal form A, hippurate crystal form A and Crystal form of oxalate A in water are all larger than formula (I) quinazoline derivant shown in has better solubility, transformation of crystal does not occur in heating process, has good stabilization Property.

The hydrochloride Form A, B, C, D, F, H, I of quinazoline derivant of the present invention, sulfate crystal form A, maleate are brilliant Type A, succinate crystal form A, adipate crystal form A, glycollate crystal form A, malate crystal form A, fumarate crystal form A, benzene Sulfonate crystal form A, B, C, benzoate crystal form A, hippurate crystal form A and Crystal form of oxalate A have unexpected superior Physicochemical properties use conducive in drug processing and pharmaceutical composition.It can be applied to treatment brain transplantation of non small cell Lung transfer, The drug of meninx transfer, head and neck squamous cell carcinoma, squamous cell carcinoma, brain stem tumor, primary brain cancer or glioma etc., together When the qualitative, quantitative information of curative effect and safety is provided, there is weight to the curative effect and safety for further studying such solid drugs The meaning wanted.

Specific embodiments of the present invention are described above.It is to be appreciated that the invention is not limited to above-mentioned Particular implementation, those skilled in the art can make various deformations or amendments within the scope of the claims, this not shadow Ring substantive content of the invention.

Claims

1. the crystal form of the hydrochloride of quinazoline derivant shown in formula (I), wherein the crystal form is crystal form A, crystal form B, crystal form C, crystalline substance Type D, crystal form F, crystal form H or crystal form I；

Wherein, the XRPD map of the crystal form A is at following 2 θ with principal character peak: 6.5,13.1,9.4；At following 2 θ With secondary feature peak: 7.3,18.2,20.0；With characteristic peak again at following 2 θ: 27.5,26.6,21.6；

The XRPD map of the crystal form B is at following 2 θ with principal character peak: 6.5,17.7,19.8；Have at following 2 θ Secondary feature peak: 7.3,8.2,10.5,13.2；

The XRPD map of the crystal form C is at following 2 θ with principal character peak: 7.2,17.6,22.0

Secondary feature peak: 14.0,13.6,12.8

Characteristic peak again: 24.6,26.2,27.3

The XRPD map of the crystal form D is at following 2 θ with principal character peak: 13.4,7.1,25.4；Have at following 2 θ Secondary feature peak: 6.7,18.0,19.8；With characteristic peak again at following 2 θ: 17.2,27.3,24.7；

The XRPD map of the crystal form F is at following 2 θ with principal character peak: 6.8,20.5,13.6；Have at following 2 θ Secondary feature peak: 14.8,14.3,17.9,11.9；

The XRPD map of the crystal form H is at following 2 θ with principal character peak: 7.3,18.0,14.1；Have at following 2 θ Secondary feature peak: 6.4,13.2,15.8；With characteristic peak again at following 2 θ: 16.8,14.5,20.3；

The XRPD map of the crystal form I is at following 2 θ with principal character peak: 18.6,7.4,6.9；Have at following 2 θ secondary Want characteristic peak: 13.2,25.1,12.3；With characteristic peak again at following 2 θ: 14.7,28.1,14.2；

Wherein the error range of 2 θ values is ± 0.2.

2. crystal form as described in claim 1, which is characterized in that the crystal form A has substantially with XRPD map shown in FIG. 1；

The crystal form B has substantially with XRPD map shown in Fig. 2；

The crystal form C has substantially with XRPD map shown in Fig. 10；

The crystal form D has substantially with XRPD map shown in Figure 11；

The crystal form F has substantially with XRPD map shown in Fig. 9；

The crystal form H has substantially with XRPD map shown in Fig. 3；

The crystal form I has substantially with XRPD map shown in Fig. 4.

3. the preparation method of crystal form as claimed in claim 1 or 2, which is characterized in that

The preparation method of the crystal form A includes the following steps: for organic solvent and 0.8~1.2 equivalent of hydrochloric acid to be added shown in formula (I) Quinazoline derivant stirs under 22-28 degrees Celsius, is centrifugated out lower layer's solid and obtains crystal form A；Wherein, every milliliter it is organic molten Quinazoline derivant 10~200 milligram are added shown in formula (I) in agent；The organic solvent is methanol；

The preparation method of the crystal form B includes the following steps: for quinazoline derivant shown in formula (I) to be added in organic solvent, and 0.8~1.2 equivalent hydrochloric acid is added to the suspension to stir under 22-28 degrees Celsius, is centrifugated out the wet sample solid of lower layer and obtains Crystal form B；Wherein, quinazoline derivant 10~200 milligram are added shown in formula (I) in every milliliter of organic solvent；The organic solvent Tetrahydrofuran/the aqueous solution for being 15-20:1 for acetonitrile, ethyl acetate or volume ratio.

The preparation method of the crystal form C includes the following steps: that organic solvent for quinazoline derivant shown in formula (I) is added and is added 2~2.5 equivalent of hydrochloric acid stirs under 22-28 degrees Celsius, is centrifugated out the wet sample solid of lower layer and obtains dihydrochloride crystal form C；Wherein, Every milliliter of organic solvent is added shown in formula (I) 10~200 milligrams of quinazoline derivant；The organic solvent is acetone；

The preparation method of the crystal form D includes the following steps: to add quinazoline derivant hydrochloride Form C sample shown in formula (I) Heat obtains dihydrochloride crystal form D to being cooled to 22-28 degrees Celsius after 120~160 degrees Celsius；

The preparation method of the crystal form F includes the following steps: the quinazoline derivant hydrochloride Form B shown in formula (I) alcohol is added Class organic solvent and based organic solvent, in 22-28 degrees Celsius of lower gas-liquid diffusion, until there is solid that crystal form F is precipitated to obtain；Wherein, Hydrochloride Form B 10~200 milligram are added shown in formula (I) in every milliliter of organic solvent；The alcohol organic solvent is first Alcohol, the based organic solvent are isopropyl acetate；

The preparation method of the crystal form H includes the following steps: to be added in the quinazoline derivant hydrochloride Form B shown in formula (I) Organic solvent, volatilize to obtain crystal form H after filtering under 22-28 degrees Celsius；Wherein, it is added shown in formula (I) in every milliliter of organic solvent 10~200 milligrams of hydrochloride Form B；The organic solvent is ethyl alcohol；

The preparation method of the crystal form I includes the following steps: to heat quinazoline derivant hydrochloride Form H sample shown in formula (I) 22-28 degrees Celsius is cooled to after to 120~130 degrees Celsius.

4. the crystal form of the fumarate of quinazoline derivant shown in formula (I), wherein the crystal form is crystal form A；

The XRPD map of the crystal form A is at following 2 θ with principal character peak: 6.5,17.8,9.4；Have at following 2 θ secondary Want characteristic peak: 13.4,7.5,19.7；With characteristic peak again at following 2 θ: 14.6,18.5；The wherein error range of 2 θ values It is ± 0.2.

5. crystal form as claimed in claim 4, which is characterized in that the crystal form A has substantially with XRPD map shown in fig. 5.

6. a kind of preparation method of crystal form as described in claim 4 or 5, which is characterized in that the described method includes: at formula (I) It after organic solvent is added in shown quinazoline derivant and 0.4-0.6 equivalent fumaric acid, is stirred under 22-28 degrees Celsius, centrifugation is received Collection solid obtains the crystal form；Wherein, quinazoline derivant 10~200 milligram are added shown in formula (I) in every milliliter of organic solvent.

7. the crystal form of the succinate of quinazoline derivant shown in formula (I), wherein the crystal form is crystal form A；

The XRPD map of the crystal form A is at following 2 θ with principal character peak: 6.6,17.8,7.5；Have at following 2 θ secondary Want characteristic peak: 9.4,20.3,18.5；With characteristic peak again at following 2 θ: 21.0,14.5,19.5；The wherein error of 2 θ values Range is ± 0.2.

8. crystal form as claimed in claim 7, which is characterized in that the crystal form A has substantially with XRPD map shown in fig. 6.

9. a kind of preparation method of crystal form as claimed in claim 7 or 8, which is characterized in that the described method includes: at formula (I) It after organic solvent is added in shown quinazoline derivant and 0.8-1.2 equivalent succinic acid, is stirred under 22-28 degrees Celsius, centrifugation is received Collection solid obtains the crystal form；Wherein, quinazoline derivant 10~200 milligram are added shown in formula (I) in every milliliter of organic solvent.

10. the crystal form of the maleate of quinazoline derivant shown in formula (I), wherein the crystal form is crystal form A；

The XRPD map of the crystal form A is at following 2 θ with principal character peak: 6.3,18.8,16.7；Have at following 2 θ Secondary feature peak: 25.2,21.2；Wherein the error range of 2 θ values is ± 0.2.

11. crystal form as claimed in claim 10, which is characterized in that the crystal form A has to scheme with XRPD shown in Fig. 7 substantially Spectrum.

12. a kind of preparation method of crystal form as described in claim 10 or 11, which is characterized in that the described method includes: in formula (I) it after organic solvent is added in quinazoline derivant shown in and 0.8-1.2 equivalent maleic acid, stirs, is centrifuged under 22-28 degrees Celsius It collects solid and obtains the crystal form；Wherein, quinazoline derivant 10~200 milligram are added shown in formula (I) in every milliliter of organic solvent.

13. the crystal form of the glycollate of quinazoline derivant shown in formula (I), wherein the crystal form is crystal form A；

The XRPD map of the crystal form A is at following 2 θ with principal character peak: 6.6,7.4,17.9；Have at following 2 θ secondary Want characteristic peak: 13.3；Wherein the error range of 2 θ values is ± 0.2.

14. crystal form as claimed in claim 13, which is characterized in that the crystal form A has to scheme with XRPD shown in Fig. 8 substantially Spectrum.

15. a kind of preparation method of crystal form according to claim 13 or 14, which is characterized in that the described method includes: in formula (I) it after organic solvent is added in quinazoline derivant shown in and 0.8-1.2 eq. ethanol acid, stirs, is centrifuged under 22-28 degrees Celsius It collects solid and obtains the crystal form；Wherein, quinazoline derivant 10~200 milligram are added shown in formula (I) in every milliliter of organic solvent.

16. the crystal form of the sulfate of quinazoline derivant shown in formula (I), wherein the crystal form is crystal form A；

The XRPD map of the crystal form A is at following 2 θ with principal character peak: 7.3,18.2,15.0；The wherein error of 2 θ values Range is ± 0.2.

17. crystal form as claimed in claim 16, which is characterized in that the crystal form A has to scheme with XRPD shown in Figure 12 substantially Spectrum.

18. a kind of preparation method of the crystal form as described in claim 16 or 17, which is characterized in that the described method includes: by formula (I) organic solvent is added in quinazoline derivant sample shown in and 0.8-1.2 equiv. sulfuric acid aqueous solution stirs under 22-28 degrees Celsius It mixes, solid is collected by centrifugation and obtains the crystal form；Wherein, in every milliliter of organic solvent be added formula (I) shown in quinazoline derivant 10~ 200 milligrams.

19. the crystal form of the oxalate of quinazoline derivant shown in formula (I), wherein the crystal form is crystal form A；

The XRPD map of the crystal form A is at following 2 θ with principal character peak: 6.9,15.1,13.7；Have at following 2 θ Secondary feature peak: 15.4,9.6,19.0；With characteristic peak again at following 2 θ: 20.6,27.3,23.4；The wherein mistake of 2 θ values Poor range is ± 0.2.

20. crystal form as claimed in claim 19, which is characterized in that the crystal form A has to scheme with XRPD shown in Figure 13 substantially Spectrum.

21. a kind of preparation method of the crystal form as described in claim 19 or 20, which is characterized in that the described method includes: by formula (I) organic solvent is added in quinazoline derivant sample shown in and 0.8-1.2 equivalent ethanedioic acid stirs under 22-28 degrees Celsius, from The heart collects solid and obtains the crystal form；Wherein, the milli of quinazoline derivant 10~200 shown in formula (I) is added in every milliliter of organic solvent Gram.

22. the crystal form of the malate of quinazoline derivant shown in formula (I), wherein the crystal form is crystal form A；

The XRPD map of the crystal form A is at following 2 θ with principal character peak: 6.5,18.8,19.9；Have at following 2 θ Secondary feature peak: 7.5,8.4,9.2；Wherein the error range of 2 θ values is ± 0.2.

23. crystal form as claimed in claim 22, which is characterized in that the crystal form A has to scheme with XRPD shown in Figure 14 substantially Spectrum.

24. a kind of preparation method of the crystal form as described in claim 22 or 23, which is characterized in that the described method includes: by formula (I) organic solvent is added in quinazoline derivant sample shown in and 0.8-1.2 equivalent malic acid stirs under 22-28 degrees Celsius, from The heart collects solid and obtains the crystal form；Wherein, the milli of quinazoline derivant 10~200 shown in formula (I) is added in every milliliter of organic solvent Gram.

25. the crystal form of the benzene sulfonate of quinazoline derivant shown in formula (I), wherein the crystal form is crystal form A, crystal form B or crystal form C；

Wherein, the XRPD map of the crystal form A is at following 2 θ with principal character peak: 6.6,14.0,15.3；At following 2 θ With secondary feature peak: 7.1,5.5,19.7；With characteristic peak again at following 2 θ: 17.8,16.9,21.0；

The XRPD map of the crystal form B is at following 2 θ with principal character peak: 8.5,14.5,23.4；Have at following 2 θ Secondary feature peak: 18.3,19.7；

The XRPD map of the crystal form C is at following 2 θ with principal character peak: 14.0,14.7,7.7；Have at following 2 θ Secondary feature peak: 8.3,21.2,19.4；With characteristic peak again at following 2 θ: 27.5,24.7；

Wherein the error range of 2 θ values is ± 0.2.

26. crystal form as claimed in claim 25, which is characterized in that the crystal form A has to scheme with XRPD shown in figure 15 substantially Spectrum；

The crystal form B has substantially with XRPD map shown in Figure 16；

The crystal form C has substantially with XRPD map shown in Figure 17.

27. a kind of preparation method of the crystal form as described in claim 25 or 26, which is characterized in that the preparation side of the crystal form A Method includes: that the addition organic solvent of quinazoline derivant sample shown in formula (I) and 0.8-1.2 equivalent benzene sulfonic acid is Celsius in 22-28 The lower stirring of degree, is collected by centrifugation solid and obtains the crystal form A；Wherein, quinazoline derivative shown in formula (I) is added in every milliliter of organic solvent 10~200 milligrams of object；The organic solvent is methanol；

The preparation method of the crystal form B includes: that organic solvent and 0.8-1.2 is added in quinazoline derivant sample shown in formula (I) Equivalent benzene sulfonic acid stirs under 22-28 degrees Celsius, and solid is collected by centrifugation and obtains the crystal form B；Wherein, add in every milliliter of organic solvent Enter shown in formula (I) 10~200 milligrams of quinazoline derivant；The organic solvent is acetonitrile；

The preparation method of the crystal form C includes: that organic solvent and 0.8-1.2 is added in quinazoline derivant sample shown in formula (I) Equivalent benzene sulfonic acid stirs under 22-28 degrees Celsius, and solid is collected by centrifugation and obtains the crystal form C；Wherein, add in every milliliter of organic solvent Enter shown in formula (I) 10~200 milligrams of quinazoline derivant；The organic solvent be volume ratio be 15-20:1de tetrahydrofuran and The mixed solvent of water.

28. the crystal form of the benzoate of quinazoline derivant shown in formula (I), wherein the crystal form is crystal form A；

The XRPD map of the crystal form A is at following 2 θ with principal character peak: 7.3,6.3,16.8；Have at following 2 θ secondary Want characteristic peak: 13.5,18.7,27.0；Wherein the error range of 2 θ values is ± 0.2.

29. crystal form as claimed in claim 28, which is characterized in that the crystal form A has to scheme with XRPD shown in Figure 18 substantially Spectrum.

30. a kind of preparation method of the crystal form as described in claim 28 or 29, which is characterized in that the described method includes: by formula (I) organic solvent is added in quinazoline derivant sample shown in and 0.8-1.2 equivalent benzoic acid stirs under 22-28 degrees Celsius, from The heart collects solid and obtains the crystal form；Wherein, the milli of quinazoline derivant 10~200 shown in formula (I) is added in every milliliter of organic solvent Gram.

31. the crystal form of the hippurate of quinazoline derivant shown in formula (I), wherein the crystal form is crystal form A；

The XRPD map of the crystal form A is at following 2 θ with principal character peak: 5.6,6.9,20.0；Have at following 2 θ secondary Want characteristic peak: 16.0,7.7,13.7；With characteristic peak again at following 2 θ: 24.3,26.4；The wherein error range of 2 θ values It is ± 0.2.

32. crystal form as claimed in claim 31, which is characterized in that the crystal form A has to scheme with XRPD shown in Figure 19 substantially Spectrum.

33. a kind of preparation method of the crystal form as described in claim 31 or 32, which is characterized in that the described method includes: by formula (I) organic solvent is added in quinazoline derivant sample shown in and 0.8-1.2 equivalent hippuric acid stirs under 22-28 degrees Celsius, from The heart collects solid and obtains the crystal form；Wherein, the milli of quinazoline derivant 10~200 shown in formula (I) is added in every milliliter of organic solvent Gram.

34. the crystal form of the oxalates of quinazoline derivant shown in formula (I), wherein the crystal form is crystal form A；

The XRPD map of the crystal form A is at following 2 θ with principal character peak: 6.4,9.1,17.5；Have at following 2 θ secondary Want characteristic peak: 12.9,14.5,26.4；With characteristic peak again at following 2 θ: 19.4,18.3,15.9；The wherein mistake of 2 θ values Poor range is ± 0.2.

35. crystal form as claimed in claim 34, which is characterized in that the crystal form A has to scheme with XRPD shown in Figure 20 substantially Spectrum.

36. a kind of preparation method of the crystal form as described in claim 34 or 35, which is characterized in that the described method includes: by formula (I) organic solvent is added in quinazoline derivant sample shown in and 0.8-1.2 equivalent oxalic acid stirs under 22-28 degrees Celsius, is centrifuged It collects solid and obtains the crystal form；Wherein, quinazoline derivant 10~200 milligram are added shown in formula (I) in every milliliter of organic solvent.

37. a kind of pharmaceutical composition, which is characterized in that the composition include as claim 1,4,7,10,13,16,19, 22, crystal form or their combination described in any one of 25,28,31,34 and pharmaceutically acceptable auxiliary material or it is complementary at Point.

38. a kind of crystal form or right as described in any one of claim 1,4,7,10,13,16,19,22,25,28,31,34 It is required that pharmaceutical composition described in 37 is treated or prevented in preparation by EGF-R ELISA EGFR protein mediated disease Purposes in drug.

39. purposes as claimed in claim 38, which is characterized in that the drug is to treat or prevent by epidermal growth factor receptor Body EGFR is protein mediated, and is the drug of disease caused by EGFRVIII Activating mutations.

40. purposes as claimed in claim 38, which is characterized in that the drug is to treat or prevent by epidermal growth factor receptor Body EGFR is protein mediated, and is the drug of disease caused by EGFR Del19 and/or EGFR L858R Activating mutations.

41. the purposes as described in claim 38,39 or 40, which is characterized in that the drug is to treat or prevent non-small cell Brain metastasis, meninx transfer, head and neck squamous cell carcinoma, squamous cell carcinoma, brain stem tumor, primary brain cancer or glioma Drug.