WO2019196619A1 - 喹唑啉衍生物盐型晶型及制备方法和应用 - Google Patents

喹唑啉衍生物盐型晶型及制备方法和应用 Download PDF

Info

Publication number
WO2019196619A1
WO2019196619A1 PCT/CN2019/079043 CN2019079043W WO2019196619A1 WO 2019196619 A1 WO2019196619 A1 WO 2019196619A1 CN 2019079043 W CN2019079043 W CN 2019079043W WO 2019196619 A1 WO2019196619 A1 WO 2019196619A1
Authority
WO
WIPO (PCT)
Prior art keywords
quinazoline derivative
formula
crystal form
organic solvent
xrpd pattern
Prior art date
Application number
PCT/CN2019/079043
Other languages
English (en)
French (fr)
Inventor
钟卫
张金强
Original Assignee
威尚（上海）生物医药有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from CN201810423951.8A external-priority patent/CN110343090B/zh
Application filed by 威尚（上海）生物医药有限公司 filed Critical 威尚（上海）生物医药有限公司
Priority to US17/625,315 priority Critical patent/US20240025874A1/en
Publication of WO2019196619A1 publication Critical patent/WO2019196619A1/zh

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/94—Nitrogen atoms

Definitions

  • the present invention relates to a quinazoline derivative salt type and a crystal form thereof; in particular, (R)-6-[(3,3-difluoro-1-methylpiperidin-4-yl)oxy]-nitrogen -(3-ethynyl-2-fluorophenyl)-7-methoxyquinazolin-4-amine (I) hydrochloride salt form A, B, C, D, F, H, I, sulfuric acid Salt crystal form A, maleate salt form A, succinate crystal form A, adipate form A, glycolate form A, malate form A, fumarate form A, Benzene sulfonate crystal form A, B, C, benzoate crystal form A, hippurate crystal form A and oxalate crystal form A and preparation method and application thereof.
  • Biosignaling refers to the transmission of a stimulus or inhibition signal into a cell, which is transmitted through a series of signals to cause a biological response within the cell.
  • Many studies have been conducted on many signaling pathways and their biological responses. Different defects that have emerged in signaling pathways have been found to be responsible for many diseases, including various forms of cancer, metabolic disorders, inflammatory diseases, vascular and neuronal diseases. These defects often occur at the genetic level, such as DNA insertions, deletions or translocations, which allow cells to proliferate uncontrolled in some cancers.
  • kinases are generally classified into protein kinases and lipid kinases, and certain kinases that exhibit dual specificity. Protein kinases are enzymes and/or autophosphorylation that catalyze the phosphorylation of other proteins and can be classified based on their effect on substrates, for example, tyrosine kinases refer to major phosphorylated tyrosine residues (eg, Kit, EGFR, HER2, VEGFR, PDGFR, SRC and ABL, etc.), serine/threonine kinases refer to predominantly phosphorylated serine and/or threonine residues (eg, mTORC1, mTORC2, ATM, ATR, Akt, etc.), and Specific kinases phosphorylate the tyrosine, serine and/or threonine residues of the substrate.
  • tyrosine kinases refer to major phosphorylated tyrosine residues (eg, Kit, EGFR,
  • the epidermal growth factor receptor belongs to the transmembrane protein tyrosine kinase of the ErbB receptor family, including the epidermal growth factor receptors EGFR/ERBB1, HER2/ERBB2/NEU, HER3/ERBB3, and HER4/ERBB4.
  • the induced EGFR receptor forms a homopolymer with another EGFR receptor or another family member, eg, HER2/ERBB2/NEU, HER3/ERBB3, or HER4/ERBB4 or Heterodimers, which result in the activation of EGFR tyrosine kinase activity.
  • Activated EGFR then phosphorylates its substrate, resulting in multiple downstream pathways within the cell, including the Pl3K-AKT-mTOR pathway (involved in the activation of cell survival), and the RAS-RAF-MEK-ERK pathway (involving cell proliferation) ).
  • ErbB receptor signaling and its involvement in tumors see, for example, 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.
  • Gliomas are the most common primary brain tumors, accounting for 40-50% of brain tumors. About 60% of patients with glioma have tumor-associated EGFR mutations. About 70% of the mutations are exon 2-7 deletions of EGFRV3 (EGFRVIII). This mutation increases the kinase activity of EGFR, leading to excessive activation of the downstream pro-survival signaling pathway. EGFRV3 (EGFRVIII) is a deletion gene for exon 2-7 of epidermal growth factor EGFR and prevents the mutant receptor from binding to any known ligand.
  • EGFRV3 mutations are expressed in brain cancer, glioma, bladder cancer, breast cancer, colorectal cancer, esophageal cancer, head and neck squamous cell carcinoma, lung cancer, lung squamous cell carcinoma, ovarian cancer, prostate cancer, brainstem tumor, and the like. See, Terrance G. Johns et al, FEBS Journal 280 (2013) 5350-5370.
  • ErbB family signaling promotes proliferation, invasion, metastasis, angiogenesis and tumor cell survival, and has been described in many human cancers, including the lungs, head and neck, and breast, so the ErbB family represents the development of anticancer drugs.
  • a small molecule drug targeting EGFR or ErbB2 including gefitinib (Iressa Iressa (TM)), erlotinib (Tarceva (TM)), a method erlotinib, lapatinib, and Theresa (TYKERB TM, TYVERB TM) has been approved in clinical non-small cell lung cancer, particularly for EGFR mutations in exon 19 (exon 19 del) deletion or exon 21 L858R (exon 21 L858R) mutation.
  • EGFRVIII is a deletion gene of EGFR exon 2-7 and the mutant receptor cannot bind to any known ligand, with exon 19 (Exon 19 del) deletion or exon 21 L858R (Exon 21 L858R)
  • the mutations are completely different.
  • the existing EGFR inhibitors are not effective in inhibiting EGFRVIII.
  • the biological activity against EGFRVIII is much lower than that of EGFR exon 19 (Exon 19 del) deletion or exon 21 L858R (Exon 21 L858R) mutation. Activity is often reduced by a factor of 10 or even more than 100, see, for example, Paul S. Mischel et al, Molecular Cell, 60, 307-318, 2015.
  • BBB blood-brain barrier
  • the problem to be solved by the present invention is to solve the problem that the existing EGFR inhibitor cannot effectively inhibit the EGFR activating mutant EGFRVIII and effectively cross the blood-brain barrier to reach an effective blood concentration in the brain, and the quinazoline derivative (R) of the present invention.
  • the nature of the free base of phenyl-4-amine (I) is detrimental to the problems of use in pharmaceutical processing and pharmaceutical compositions, providing a quinazoline derivative salt-type crystal that is more advantageous for use in pharmaceutical processing and pharmaceutical compositions.
  • Type and preparation methods and applications provide more qualitative and quantitative information for the efficacy and safety of solid drugs.
  • the quinazoline derivatives provided by the present invention have biological activity against EGFRVIII activating mutations and effectively cross the blood brain barrier.
  • the quinazoline derivative is as shown in formula (I):
  • One technical solution adopted by the present invention is to provide a novel quinazoline derivative (I) having a chiral R.
  • the chiral purity ee > 90%, more preferably, the chiral purity ee > 97%.
  • One technical solution adopted by the present invention is to provide a novel quinazoline derivative (I) having a chiral R having a biological activity of an EGFRVIII activating mutation.
  • One technical solution adopted by the present invention is to provide a novel quinazoline derivative (I) having a chiral R having a biological activity of an EGFRVIII activating mutation while having a high ability to cross the blood-brain barrier.
  • the present invention also provides a synthetic method for producing the quinazoline derivative (I) of the present invention.
  • One technical solution adopted by the present invention is to provide a hydrochloride crystal form A of a quinazoline derivative, the XRPD pattern of which is 2 ⁇
  • Another technical solution adopted by the present invention is to provide a hydrochloride salt form B of a quinazoline derivative, the XRPD pattern of which is 2 ⁇
  • Another technical solution adopted by the present invention is to provide a hydrochloride salt form C of a quinazoline derivative, the XRPD pattern of which is 2 ⁇
  • Another technical solution adopted by the present invention is to provide a hydrochloride salt form D of a quinazoline derivative, the XRPD pattern of which is in 2?
  • Another technical solution adopted by the present invention is to provide a hydrochloride salt form F of a quinazoline derivative, the XRPD pattern of which is 2 ⁇
  • Another technical solution adopted by the present invention is to provide a hydrochloride salt form H of a quinazoline derivative, the XRPD pattern of which is 2 ⁇
  • Another technical solution adopted by the present invention is to provide a hydrochloride salt form I of a quinazoline derivative, the XRPD pattern of which is 2 ⁇
  • Another technical solution adopted by the present invention is to provide a fumarate crystal form A of a quinazoline derivative, the XRPD pattern of which is 2 ⁇
  • Another technical solution adopted by the present invention is to provide a succinate crystal form A of a quinazoline derivative, the XRPD pattern of which is 2 ⁇
  • Another technical solution adopted by the present invention is to provide a maleate salt crystal form A of a quinazoline derivative, the XRPD pattern of which is 2 ⁇
  • Another technical solution adopted by the present invention is to provide a glycolate form A of a quinazoline derivative, the XRPD pattern of which is 2 ⁇
  • Another technical solution adopted by the present invention is to provide a sulfate crystal form A of a quinazoline derivative, the XRPD pattern of which is 2 ⁇
  • Another technical solution adopted by the present invention is to provide an oxalate salt form A of a quinazoline derivative, the XRPD pattern of which is in 2 ⁇
  • Another technical solution adopted by the present invention is to provide a malate crystal form A of a quinazoline derivative, the XRPD pattern of which is 2 ⁇
  • Another technical solution adopted by the present invention is to provide a benzene sulfonate salt form A of a quinazoline derivative, the XRPD pattern of which is 2 ⁇
  • the error range of the above 2 ⁇ value is ⁇ 0.2.
  • Another technical solution adopted by the present invention is to provide a benzene sulfonate salt form B of a quinazoline derivative, the XRPD pattern of which is 2 ⁇
  • Another technical solution adopted by the present invention is to provide a benzene sulfonate salt form C of a quinazoline derivative, the XRPD pattern of which is 2 ⁇
  • Another technical solution adopted by the present invention is to provide a benzoate crystal form A of a quinazoline derivative, the XRPD pattern of which is 2 ⁇
  • Another technical solution adopted by the present invention is to provide a quinazoline derivative of the hippurate crystal form A, the XRPD pattern of which is in 2 ⁇
  • Another technical solution adopted by the present invention is to provide an oxalate crystal form A of a quinazoline derivative, the XRPD pattern of which is 2 ⁇
  • the hydrochloride salt form A of the quinazoline derivative of the present invention has an XRPD pattern substantially as shown in Figure 1.
  • the hydrochloride salt form B of the quinazoline derivative of the present invention has an XRPD pattern substantially as shown in Figure 2.
  • the hydrochloride salt form C of the quinazoline derivative of the present invention has an XRPD pattern substantially as shown in FIG.
  • the hydrochloride salt form D of the quinazoline derivative of the present invention has an XRPD pattern substantially as shown in FIG.
  • the hydrochloride salt Form F of the quinazoline derivative of the present invention has an XRPD pattern substantially as shown in Figure 9.
  • the hydrochloride salt form H of the quinazoline derivative of the present invention has an XRPD pattern substantially as shown in Figure 3.
  • the hydrochloride salt form I of the quinazoline derivative of the present invention has an XRPD pattern substantially as shown in Figure 4.
  • the fumarate crystal form A of the quinazoline derivative of the present invention has an XRPD pattern substantially as shown in FIG.
  • the succinate crystal form A of the quinazoline derivative of the present invention has an XRPD pattern substantially as shown in Figure 6.
  • the maleate salt form A of the quinazoline derivative of the present invention has an XRPD pattern substantially as shown in FIG.
  • the glycolate Form A of the quinazoline derivative of the present invention has an XRPD pattern substantially as shown in Figure 8.
  • the sulfate form A of the quinazoline derivative of the present invention has an XRPD pattern substantially as shown in FIG.
  • the oxalate salt form A of the quinazoline derivative of the present invention has an XRPD pattern substantially as shown in FIG.
  • the malate salt form A of the quinazoline derivative of the present invention has an XRPD pattern substantially as shown in FIG.
  • the benzenesulfonate crystal form A of the quinazoline derivative of the present invention has an XRPD pattern substantially as shown in FIG.
  • the benzenesulfonate salt form B of the quinazoline derivative of the present invention has an XRPD pattern substantially as shown in FIG.
  • the benzenesulfonate salt form C of the quinazoline derivative of the present invention has an XRPD pattern substantially as shown in FIG.
  • the benzoate crystal form A of the quinazoline derivative of the present invention has an XRPD pattern substantially as shown in FIG.
  • the horse urate crystal form A of the quinazoline derivative of the present invention has an XRPD pattern substantially as shown in FIG.
  • the oxalate crystal form I of the quinazoline derivative of the present invention has an XRPD pattern substantially as shown in FIG.
  • the present invention also provides a method for preparing the hydrochloride salt form A of the quinazoline derivative (I) of the present invention, comprising the steps of: adding 0.8 to 1.2 equivalents of an organic solvent and hydrochloric acid to the formula (I).
  • the quinazoline derivative sample was stirred at 22-28 degrees Celsius, and the lower layer solid was centrifuged to obtain Form A; wherein 10 to 200 mg of the quinazoline derivative represented by the formula (I) was added per ml of the organic solvent.
  • the present invention also provides a process for preparing the hydrochloride salt form B of the quinazoline derivative (I) of the present invention, comprising the steps of: adding a quinazoline derivative represented by the formula (I) to an organic solvent; And adding 0.8-1.2 equivalent hydrochloric acid to the suspension, stirring at 22-28 degrees Celsius, and separating the lower wet sample solid to obtain the crystal form B; wherein, the quinazoline derivative represented by the formula (I) is added per ml of the organic solvent. 10 to 200 mg.
  • the present invention also provides a process for preparing the hydrochloride salt form C of the quinazoline derivative (I) of the present invention, comprising the steps of: adding a sample of the quinazoline derivative represented by the formula (I) to an organic solvent. And adding 2 to 2.5 equivalents of hydrochloric acid, stirring at 22-28 degrees Celsius, and then centrifuging the lower layer of the wet sample solid to obtain the dihydrochloride salt form C; wherein, the quinazoline derivative represented by the formula (I) is added per ml of the organic solvent. 10 to 200 mg.
  • the present invention also provides a method for preparing the hydrochloride salt form D of the quinazoline derivative (I) of the present invention, comprising the steps of: heating a sample of the hydrochloride salt form C to a high temperature and then cooling to 22- At 28 degrees Celsius, the dihydrochloride salt form D is obtained.
  • the present invention also provides a process for preparing the hydrochloride salt form F of the quinazoline derivative (I) of the present invention, comprising the steps of: quinazoline derivative hydrochloride represented by the formula (I) Form B is added to an organic solvent of an alcohol and an ester, and is gas-liquid dispersed at 22-28 degrees Celsius until a solid precipitates to form Form F; wherein the hydrochloride form of the formula (I) is added per ml of the organic solvent. B 10 ⁇ 200 mg.
  • the present invention also provides a method for preparing the hydrochloride salt form H of the quinazoline derivative (I) of the present invention, comprising the steps of: adding an organic solvent to the hydrochloride salt form B, and filtering at 22
  • the crystal form H is volatilized at -28 degrees Celsius (fast opening); wherein 10 to 200 mg of the hydrochloride salt form B of the formula (I) is added per ml of the organic solvent.
  • the present invention also provides a method for preparing the hydrochloride salt form I of the quinazoline derivative (I) of the present invention, comprising the steps of: heating the hydrochloride salt form H sample to a high temperature and then cooling to 22-28 Celsius.
  • the present invention also provides a process for preparing the fumarate salt form A of the quinazoline derivative (I) of the present invention, comprising the steps of: a quinazoline derivative represented by the formula (I) and 0.4- After 0.6 equivalent of fumaric acid is added to the organic solvent, the mixture is stirred at 22 to 28 ° C, and the solid is collected by centrifugation; wherein 10 to 200 mg of the quinazoline derivative represented by the formula (I) is added per ml of the organic solvent.
  • the present invention also provides a process for preparing the succinate crystal form A of the quinazoline derivative (I) of the present invention, comprising the steps of: a quinazoline derivative represented by the formula (I) and 0.8-1.2 After the equivalent succinic acid is added to the organic solvent, the mixture is stirred at 22 to 28 ° C, and the solid is collected by centrifugation to obtain the crystal form; wherein 10 to 200 mg of the quinazoline derivative represented by the formula (I) is added per ml of the organic solvent.
  • the present invention also provides a process for preparing the maleate salt form A of the quinazoline derivative (I) of the present invention, comprising the steps of: a quinazoline derivative represented by the formula (I) and a Malay After the acid is added to the organic solvent, the mixture is stirred at 22 to 28 ° C, and the solid is collected by centrifugation to obtain the crystal form; wherein 10 to 200 mg of the quinazoline derivative represented by the formula (I) is added per ml of the organic solvent.
  • the present invention also provides a process for preparing the glycolate form A of the quinazoline derivative (I) of the present invention, comprising the steps of: a quinazoline derivative represented by the formula (I) and 0.8-1.2 After adding the equivalent of glycolic acid to the organic solvent, the mixture was stirred at room temperature, and the solid was collected by centrifugation.
  • the present invention also provides a method for preparing the sulfate crystal form A of the quinazoline derivative (I) of the present invention, comprising the steps of: adding a sample of the quinazoline derivative represented by the formula (I) to an organic solvent and The 0.8-1.2 equivalent aqueous sulfuric acid solution is stirred at 22-28 degrees Celsius, and the solid is collected by centrifugation to obtain the crystalline form; wherein, in an organic solvent, 10 to 200 mg of the quinazoline derivative represented by the formula (I) is added per ml.
  • the present invention also provides a method for preparing the oxalate salt form A of the quinazoline derivative (I) of the present invention, comprising the steps of: adding a sample of the quinazoline derivative represented by the formula (I) to an organic compound The solvent and 0.8-1.2 equivalents of oxalic acid are stirred at 22-28 degrees Celsius, and the solid is collected by centrifugation to obtain the crystal form; wherein 10 to 200 mg of the quinazoline derivative represented by the formula (I) is added per ml of the organic solvent.
  • the present invention also provides a method for preparing the malate salt form A of the quinazoline derivative (I) of the present invention, comprising the steps of: adding a sample of the quinazoline derivative represented by the formula (I) to an organic solvent; The crystal form is obtained by stirring with 0.8-1.2 equivalents of malic acid at 22-28 degrees Celsius, and collecting the solid by centrifugation; wherein 10 to 200 mg of the quinazoline derivative represented by the formula (I) is added per ml of the organic solvent.
  • the present invention also provides a process for preparing the benzenesulfonate salt form A of the quinazoline derivative (I) of the present invention, comprising the steps of: adding a sample of the quinazoline derivative represented by the formula (I) to an organic The solvent and 0.8-1.2 equivalents of benzenesulfonic acid are stirred at 22-28 degrees Celsius, and the solid is collected by centrifugation to obtain the crystalline form; wherein 10 to 200 mg of the quinazoline derivative represented by the formula (I) is added per ml of the organic solvent.
  • the present invention also provides a process for preparing the benzenesulfonate salt form B of the quinazoline derivative (I) of the present invention, comprising the steps of: adding a sample of the quinazoline derivative represented by the formula (I) to an organic The solvent and 0.8-1.2 equivalents of benzenesulfonic acid are stirred at 22-28 degrees Celsius, and the solid is collected by centrifugation to obtain the crystalline form; wherein 10 to 200 mg of the quinazoline derivative represented by the formula (I) is added per ml of the organic solvent.
  • the present invention also provides a process for preparing the benzenesulfonate salt form C of the quinazoline derivative (I) of the present invention, comprising the steps of: adding a sample of the quinazoline derivative represented by the formula (I) to an organic The solvent and 0.8-1.2 equivalents of benzenesulfonic acid are stirred at 22-28 degrees Celsius, and the solid is collected by centrifugation to obtain the crystalline form; wherein 10 to 200 mg of the quinazoline derivative represented by the formula (I) is added per ml of the organic solvent.
  • the present invention also provides a method for preparing the benzoate crystal form A of the quinazoline derivative (I) of the present invention, comprising the steps of: adding a sample of the quinazoline derivative represented by the formula (I) to an organic compound The solvent and 0.8-1.2 equivalents of benzoic acid are stirred at 22-28 degrees Celsius, and the solid is collected by centrifugation to obtain the crystalline form; wherein 10 to 200 mg of the quinazoline derivative represented by the formula (I) is added per ml of the organic solvent.
  • the present invention also provides a method for preparing a horse urate crystal form A of the quinazoline derivative (I) of the present invention, comprising the steps of: adding a sample of the quinazoline derivative represented by the formula (I) to an organic compound The solvent and 0.8-1.2 equivalents of hippuric acid are stirred at 22-28 degrees Celsius, and the solid is collected by centrifugation to obtain the crystalline form; wherein 10 to 200 mg of the quinazoline derivative represented by the formula (I) is added per ml of the organic solvent.
  • the present invention also provides a process for preparing the oxalate salt form A of the quinazoline derivative (I) of the present invention, comprising the steps of: adding a sample of the quinazoline derivative represented by the formula (I) to an organic solvent; The crystal form is obtained by stirring with 0.8-1.2 equivalents of oxalic acid at 22-28 degrees Celsius, and collecting the solid by centrifugation; wherein 10 to 200 mg of the quinazoline derivative represented by the formula (I) is added per ml of the organic solvent.
  • the organic solvent is one or more selected from the group consisting of alcohols, ethers, esters, aliphatic hydrocarbons, and aromatic hydrocarbon organic solvents.
  • the alcohol organic solvent is one or more of methanol, ethanol, isopropanol, n-propanol, isobutanol, and n-butanol.
  • the ether organic solvent is diethyl ether, diisopropyl ether or methyl tert-butyl ether.
  • the ester organic solvent is ethyl acetate, butyl acetate or isopropyl acetate.
  • the ketone organic solvent is acetone, methyl ethyl ketone or 4-methyl-2-pentanone.
  • the aliphatic hydrocarbon organic solvent is n-heptane or acetonitrile.
  • the aromatic hydrocarbon organic solvent is toluene.
  • the method for producing the hydrochloride salt form A of the quinazoline derivative (I) is preferably methanol.
  • the method for preparing the hydrochloride salt form D of the quinazoline derivative (I) preferably has a high temperature range of from 120 to 160 °C.
  • the method for producing the hydrochloride salt form F of the quinazoline derivative (I) is preferably methanol and the ester is isopropyl acetate. More preferably, the weight ratio of methanol to ethyl acetate is 1:1.
  • the organic solvent is ethanol.
  • the method for producing the hydrochloride salt form I of the quinazoline derivative (I) preferably has a high temperature of 120 to 130 ° C.
  • the method for producing the fumarate crystal form A of the quinazoline derivative (I) is preferably a mixture of methanol, acetone, ethyl acetate or tetrahydrofuran/water in a volume ratio of 15 to 20:1.
  • the method for producing the sulfate crystal form A of the quinazoline derivative (I) is preferably a mixture of methanol, acetonitrile, acetone, ethyl acetate or tetrahydrofuran/water in a volume ratio of 15 to 20:1.
  • the method for producing the malate salt form A of the quinazoline derivative (I) is preferably a mixture of methanol, ethyl acetate or tetrahydrofuran/water in a volume ratio of 15 to 20:1.
  • the organic solvent is a mixed solvent of tetrahydrofuran and water (volume ratio of 15-20:1, more preferably 19:1) .
  • the method for producing the benzoate crystal form A of the quinazoline derivative (I) is preferably a mixture of methanol, acetonitrile, acetone or tetrahydrofuran/water in a volume ratio of 15 to 20:1.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the hydrochloride salt form A, B, C, D, F, H, I, sulfate of the quinazoline derivative represented by the formula (I).
  • Form A maleate salt form A, succinate crystal form A, adipate form A, glycolate form A, malate form A, fumarate form A, benzene
  • the adjuvant or auxiliary ingredient comprises a carrier, an excipient, a diluent, a vehicle, and an adjuvant.
  • the present invention also provides a hydrochloride salt crystal form A, B, C, D, F, H, I, sulfate crystal form A, maleate crystal form of the quinazoline derivative represented by the formula (I).
  • Form A succinate crystal form A, adipate crystal form A, glycolate form A, malate form A, fumarate form A, besylate form A, B, C, benzoate crystal form A, hippurate crystal form A and oxalate crystal form A or a pharmaceutical composition as described above in the preparation of a medicament for treating or preventing a disease mediated by the epidermal growth factor receptor EGFR protein the use of.
  • the medicament is a medicament for treating or preventing a disease caused by an epidermal growth factor receptor EGFR protein and which is caused by an EGFRVIII activating mutation.
  • the medicament is a medicament for treating or preventing a disease caused by an epidermal growth factor receptor EGFR protein and which is caused by an EGFR Del19 and/or EGFR L858R activating mutation.
  • the medicament is for preparing or preventing non-small cell lung cancer brain metastasis, meningeal metastasis, head and neck squamous cell carcinoma, squamous cell carcinoma, brain stem tumor, primary brain cancer or glioma. drug.
  • the present invention has the following beneficial effects:
  • novel chiral R-quinazoline derivative (I) of the present invention and its pharmaceutically acceptable salt have an unexpected ability to cross the blood-brain barrier and serve as a protein kinase inhibitor, especially Is directed to a medical condition mediated by certain activating mutant forms of the epidermal growth factor receptor (eg, epidermal growth receptor EGFR exon 2-7 deletion activating mutant), eg, a glioma having an EGFRVIII mutation, It can also be used to treat or prevent disorders associated with abnormal protein kinase activity, such as cancer, cancer brain metastasis, cancer meningeal metastasis, and neurological diseases.
  • epidermal growth factor receptor eg, epidermal growth receptor EGFR exon 2-7 deletion activating mutant
  • a glioma having an EGFRVIII mutation eg, a glioma having an EGFRVIII mutation
  • the quinazoline derivative (I) of the present invention and its pharmaceutically acceptable salt have a low efflux rate, are not a P-glycoprotein efflux enzyme substrate, or a breast cancer resistant efflux enzyme substrate, which can reduce the efflux enzyme The resulting resistance.
  • the quinazoline derivative of the present invention and the pharmaceutically acceptable salt thereof have good pharmacokinetics and high biological activity, can reduce the burden of the patient's tablet intake, and improve the patient's tablet intake compliance.
  • hydrochloride salt crystal form A, B, C, D, F, H, I, sulfate crystal form A, maleate salt crystal form A of the quinazoline derivative (I) of the present invention provided by the present invention Succinate crystal form A, adipate crystal form A, glycolate crystal form A, malate form A, fumarate form A, besylate form A, B, C, benzene Formate Form A, Hippurate Form A and Oxalate Form A have good stability and water solubility, are useful in pharmaceutical processing and pharmaceutical compositions, and can be used to treat mutations activated by EGFR (eg , EGFRVIII, EGFR del19 or EGFR L858R) mediated cancer, for example, non-small cell lung cancer brain metastasis, meningeal metastasis, head and neck squamous cell carcinoma, squamous cell carcinoma, brainstem tumor, primary brain cancer or The application of glioma, etc., and its good bioavail
  • Figure 1 is an XRPD pattern of the hydrochloride salt form A of the quinazoline derivative of the present invention
  • Figure 2 is an XRPD pattern of the hydrochloride salt form B of the quinazoline derivative of the present invention
  • Figure 3 is an XRPD pattern of the hydrochloride salt form H of the quinazoline derivative of the present invention
  • Figure 4 is an XRPD pattern of the hydrochloride salt form I of the quinazoline derivative of the present invention
  • Figure 5 is an XRPD pattern of the fumarate crystal form A of the quinazoline derivative of the present invention.
  • Figure 6 is an XRPD pattern of the succinate crystal form A of the quinazoline derivative of the present invention.
  • Figure 7 is an XRPD pattern of the maleate salt crystal form A of the quinazoline derivative of the present invention.
  • Figure 8 is an XRPD pattern of the glycolate form A of the quinazoline derivative of the present invention.
  • Figure 9 is an XRPD pattern of the hydrochloride salt form F of the quinazoline derivative of the present invention.
  • Figure 10 is an XRPD pattern of the hydrochloride salt form C of the quinazoline derivative of the present invention.
  • Figure 11 is an XRPD pattern of the hydrochloride salt form D of the quinazoline derivative of the present invention.
  • Figure 12 is an XRPD pattern of the sulfate crystal form A of the quinazoline derivative of the present invention.
  • Figure 13 is an XRPD pattern of the oxalate salt form A of the quinazoline derivative of the present invention.
  • Figure 14 is an XRPD pattern of the malate salt form A of the quinazoline derivative of the present invention.
  • Figure 15 is an XRPD pattern of the benzenesulfonate salt form A of the quinazoline derivative of the present invention.
  • Figure 16 is an XRPD pattern of the benzenesulfonate salt form B of the quinazoline derivative of the present invention.
  • Figure 17 is an XRPD pattern of the benzenesulfonate salt form C of the quinazoline derivative of the present invention.
  • Figure 18 is an XRPD pattern of the benzoate crystal form A of the quinazoline derivative of the present invention.
  • Figure 19 is an XRPD pattern of the horse urate crystal form A of the quinazoline derivative of the present invention.
  • Figure 20 is an XRPD pattern of the oxalate salt form A of the quinazoline derivative of the present invention.
  • Figure 21 is a schematic diagram showing the inhibition of EGFRVIII phosphorylation by a quinazoline derivative of the present invention.
  • Figure 22 is a schematic diagram showing the pharmacodynamics of a quinazoline derivative of the present invention in a subcutaneous model of a humanized glioma mouse;
  • Figure 23 is a TGA and DSC pattern of the quinazoline derivative fumarate of the present invention. wherein a is a TGA pattern and no significant weight loss; b is a DSC pattern, the crystal form is stable during heating, and the crystal form is not transformed. , melting point is 240 degrees Celsius;
  • Figure 24 is a schematic view showing the inhibition mechanism of the quinazoline derivative of the present invention and EGFR.
  • proving and “treating” are used interchangeably and are meant to mean reducing, attenuating, inhibiting, reducing, preventing or stabilizing the onset or progression of a disease (eg, a disease or disorder described herein), which refers to a method. Included includes beneficial or desired results, but is not limited to therapeutic benefits and/or prophylactic benefits.
  • Disease refers to any condition or disorder that damages or interferes with the normal function of a cell, organ or tissue.
  • Marker means any change associated with a disease or disorder. For example, any protein or polynuclear anhydride that has altered expression levels or activity associated with a disease or disorder.
  • antagonists as used herein are used interchangeably and mean that the compound or agent has the ability to inhibit the biological function of the targeting protein or polypeptide, for example by inhibiting the activity or expression of the protein or polypeptide.
  • the antagonists herein interact with a particular target protein or polypeptide (eg, binding to EGFR)
  • the compound inhibits the biological activity of the target protein or polypeptide by interacting with other members of the signaling pathway that target the protein or polypeptide.
  • tumors that are associated with development, growth, or spread, or those that are associated with an undesired immune response exhibited by autoimmune diseases.
  • anticancer agent refers to any agent useful in the treatment of a tumor condition.
  • One class of anticancer agents includes chemotherapeutic agents.
  • “Chemotherapy” means that one or more chemotherapeutic agents and/or other agents are administered by various methods including intravenous, oral, subcutaneous, intramuscular, intraperitoneal, intravesical, transdermal, buccal, or inhalation. Apply to cancer patients.
  • cell proliferation refers to a phenomenon in which the number of cells is increased as a result of cell division, and also includes cell growth (e.g., size increase) that is altered by the cell morphology consistent with the proliferation signal.
  • co-administered refers to the use of two or more drugs alone at the same time, as well as compositions in which two or more agents are present at the same time, also at different times. Two or more drugs and/or their metabolites are administered alone or administered.
  • an effective amount or “effective therapeutic amount” as used herein means that the amount of a compound or pharmaceutical composition described herein is sufficient to achieve the intended use, including, but not limited to, treating a disease. In some embodiments, the amount is detectable effective to kill or inhibit cancer cell growth or spread; the size or number of tumors; or the severity level, stage and progression of cancer.
  • the effective therapeutic amount can vary depending on the intended application, such as in vitro or in vivo, the condition and severity of the disease, the subject's age, weight, or mode of administration. The term also applies to a specific response that a dose will induce a target cell, for example, to reduce cell migration.
  • the particular dosage will depend, for example, on the particular compound selected, the subject species and their age/risk of the current state of health or health, the route of administration, the severity of the disease, and in combination with other agents, The time of administration, the tissue to which it is administered, and the drug delivery device and the like.
  • therapeutic effect includes therapeutic benefits and/or prophylactic benefits.
  • Prophylactic effects include delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of the disease or condition, slowing, halting or reversing the progression of the disease or condition, or any combination thereof.
  • signalling is the process during which a stimulation or inhibition signal is delivered to a cell to elicit an intracellular response
  • a modulator of a signal transduction pathway refers to a compound that modulates one or more The activity of cellular proteins is through specific signal transduction pathways.
  • a “modulator” can increase the activity of an (agonist) or inhibitory (antagonist) signaling molecule.
  • selective inhibition refers to the ability of a compound to selectively reduce a target signaling activity as compared to off-target signal activity, by direct or indirect interactions, and the like.
  • a compound selectively inhibits the activity of a mutated EGFR that is at least about 2-fold, about 3-fold, about 5-fold, about 10-fold, about 20-fold, about 50-fold, about 100-fold or more active against wild-type EGFR. .
  • radiation therapy refers to a subject being exposed to a radiation emitter, such as, but not limited to, alpha-particle emitting radioactive nuclear elements (eg, neon and neon radioactive nuclear elements), low linear energy transfer ( LET) radiation emitters (ie, beta emitters), converted electron emitters (eg, ⁇ -89 and ⁇ 153-EDTMP), or high energy radiation, including, but not limited to, X-rays, gamma rays, and neutrons.
  • a radiation emitter such as, but not limited to, alpha-particle emitting radioactive nuclear elements (eg, neon and neon radioactive nuclear elements), low linear energy transfer ( LET) radiation emitters (ie, beta emitters), converted electron emitters (eg, ⁇ -89 and ⁇ 153-EDTMP), or high energy radiation, including, but not limited to, X-rays, gamma rays, and neutrons.
  • a radiation emitter such as, but not limited to, alpha-particle emitting radioactive nuclear elements
  • subject includes, but is not limited to, humans (ie, any age group, eg, a male or female (eg, infant, child, adolescent) or adult subject of a pediatric subject ( For example, young adults, middle-aged adults or senior adults) and/or other primates (eg, cynomolgus monkeys, rhesus monkeys); mammals, including commercial-related mammals, such as cattle, sheep, goats, pigs , horses, cats and/or dogs; and/or birds, including commercial-related birds such as chickens, geese, quails, ducks, and/or turkeys.
  • humans ie, any age group, eg, a male or female (eg, infant, child, adolescent) or adult subject of a pediatric subject ( For example, young adults, middle-aged adults or senior adults) and/or other primates (eg, cynomolgus monkeys, rhesus monkeys); mammals, including commercial-related mammals, such as
  • in vivo refers to an activity that occurs within the body of a subject. Events occurring in rodents, such as rats, mice, guinea pigs, and the like, are also included in the body.
  • in vitro refers to an event that occurs outside of the body.
  • in vitro test detection includes any test that occurs outside of the body.
  • in vitro assays include cell assays based on live or dead cells, as well as cell-free assays used in cells where intact cells are not present.
  • compound as used herein is also meant to include the salts, prodrugs and prodrug salts of the compounds of the formula herein.
  • the term also includes any solvate, hydrate, and polymorph of any of the foregoing.
  • specific references to "prodrugs”, “prodrug salts”, “solvates”, “hydrates” or “polymorphs” should not be construed In other aspects of the invention in which the term “compound” is used without reference to these other forms, it is intended to exclude such forms.
  • Salts of the compounds of the invention are formed between an acid and a basic group of the compound, such as an amino functional group.
  • the compound is a pharmaceutically acceptable acid addition salt.
  • Salts of the compounds of the invention are formed between a base and an acidic group of the compound, such as a carboxyl function.
  • the compound is a pharmaceutically acceptable base addition salt.
  • prodrug refers to a derivative of a compound that can be hydrolyzed, oxidized, or otherwise reacted under biological conditions (in vitro or in vivo) to provide a compound of the invention. Prodrugs may become active only after such reactions under biological conditions, or may be active in their unreacted form. Examples of prodrugs of the invention include, but are not limited to, analogs or derivatives of compounds of any of the formulae disclosed herein, as well as biohydrolyzable moieties such as amides and ester analogs.
  • Prodrug salts are basic groups of acids and prodrugs, such as amino functional groups, or compounds formed between the base and an acidic group of a prodrug, such as a carboxyl functional group.
  • the prodrug salt is a pharmaceutically acceptable salt.
  • prodrug and prodrug salts are those which increase the bioavailability of the compounds of the invention when such compounds are used in mammals or humans (e.g., by making the orally administered compound more readily absorbed) or relative to the parent species Those that promote delivery of the compound to a biological chamber (eg, the brain or central nervous system).
  • Preferred prodrugs include those in which a group that increases water solubility or increases active transport through the intestinal membrane is added to the general structure described herein. See, for example, Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al.
  • pharmaceutically acceptable means that it is suitable for contact with tissues of humans and other mammals without undue toxicity, irritation, allergic reactions, etc., and has reasonable benefits/risks within a reasonable medical range. Specific components. "Pharmaceutically acceptable salt” refers to any non-toxic salt which, upon administration to a recipient, is capable of providing a prodrug of a compound or compound of the invention, either directly or indirectly.
  • the acids commonly used to form pharmaceutically acceptable salts include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, hydroiodic acid and phosphoric acid, and organic acids such as trifluoroacetic acid, citric acid, maleic acid, oxalic acid, picric acid.
  • acetic acid, adipic acid alginic acid, aspartic acid, sulfuric acid, boric acid, butyric acid, valeric acid, camphoric acid, camphorsulfonic acid thiocyanate, digluconic acid, dodecyl sulfate, pivalic acid,
  • Bases commonly used to form pharmaceutically acceptable salts include the alkali metal, alkaline earth metal, ammonium salt, N + (C 1-4 alkyl) 4 salt, and related inorganic and organic bases.
  • Representative alkali and alkaline earth metals such as sodium, lithium, potassium, calcium, magnesium, iron, copper, manganese, zinc, aluminum, etc., and salts formed from organic bases, including, for example, primary, secondary and tertiary amines, substituted amines These include naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine.
  • the pharmaceutically acceptable base addition salt can be selected from the group consisting of ammonium, potassium, sodium, calcium, and magnesium salts. See, for example, Berge et al. J. Pharmaceutical Sciences (1977) 66: 1-19.
  • hydrate refers to a compound comprising a stoichiometric or non-stoichiometric amount of water bound by intermolecular forces of non-covalent bonds.
  • solvate refers to a compound comprising a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces, such as water, dichloromethane, 2-propanol, Acetone, methanol, ethanol or the like.
  • the pharmaceutically acceptable solvates and hydrates are complexes, for example, may comprise from 1 to about 100, or from 1 to about 10, or from 1 to about 4, from about 3 or about 2, solvent or water molecules. It will be understood that the term “compound” as used herein includes solvates, hydrates, and mixtures thereof of the compounds and compounds.
  • polymorph refers to a solid crystalline form of a compound or complex thereof. Different polymorphs of the same compound may exhibit different physical, chemical and/or spectral properties. Different physical properties include, but are not limited to, stability (eg, for heat, light, or moisture), density, hygroscopicity, solubility, compressibility, and dissolution rate.
  • Stepoisomers are isomers that differ only in the manner in which the atoms are spatially aligned.
  • the term “isomer” as used herein includes any and all geometric isomers and stereoisomers.
  • “isomer” includes both cis and trans isomers of geometric double bonds, also known as E- and Z-isomers; R- and S-enantiomers; diastereomers, (D) Isomers and (L) isomers, racemic mixtures thereof, and other mixtures thereof are disclosed herein.
  • Substitutable substituents surrounding a carbon-carbon double bond may be referred to as “cis” or “trans”, wherein “cis” refers to the substituent on the same side of the double bond and “trans” represents the substituent in the double Both sides of the key.
  • the arrangement of the surrounding carbocyclic rings of the substituents can also be designated as “cis” or “trans”.
  • cis denotes the substituent on the same side of the plane of the ring
  • trans denotes the substituent on both sides of the plane of the ring.
  • a mixture of compounds in which the substituents are on the same and opposite sides of the plane of the two rings is indicated as "cis/reverse".
  • enantiomer as used herein is a pair of stereoisomers that are non-superimposable mirror images of each other.
  • a mixture of a pair of enantiomers in any ratio may be referred to as a "racemic” mixture.
  • ( ⁇ ) is used to designate a racemic mixture as appropriate.
  • Diastereomeric refers to a mirror image having at least two asymmetric atoms, but whose stereoisomers are not each other.
  • Absolute stereochemistry is specified according to the Cahn-lngold-Prelog R-S system. When the compound is an enantiomer, the stereochemistry at each chiral carbon can be specified as R or S.
  • the absolute configuration is unknown, and (+) or (-) can be specified depending on the direction in which they rotate the plane-polarized light at the wavelength of the sodium D line (right-handed or left-handed).
  • a compound or (S)- compound in each asymmetric atom the pharmaceutical composition and method include all such possible isomers, including racemic mixtures, optically pure forms And a mixture of intermediates.
  • Optically active (R)- and (S)- can also be prepared using chiral synthetic methods or chiral reagents, or resolved using conventional techniques.
  • composition of the term "enantiomeric excess” or "% enantiomeric excess” as used herein can be calculated using the formula shown below.
  • the composition contains 90% of one enantiomer, for example, the S enantiomer, and contains 10% of the other enantiomer, for example, the R enantiomer.
  • compositions containing 90% of one enantiomer and 10% of the other enantiomer is said to have an enantiomeric excess of 80%.
  • Some of the compositions described herein contain at least about 50% enantiomeric excess, about 75%, about 90%, about 95%, or about 99% of the S enantiomer.
  • the composition comprises an enantiomeric excess of the S enantiomer in the R enantiomer.
  • some of the compositions described herein contain at least about 50% enantiomeric excess, about 75%, about 90%, about 95%, or about 99% of the R enantiomer.
  • the composition comprises an enantiomeric excess of the R enantiomer in the S enantiomer.
  • one isomer/enantiomer may, in some embodiments, provide the ee value of the corresponding enantiomer and may also be referred to as "optical enrichment", “enantiomeric enrichment” “Enantiomerically pure” and “non-racemic” are used interchangeably herein. These terms mean that the weight percent of one of the enantiomers is greater than the amount of the control mixture of the racemic composition in one enantiomer (eg, a weight ratio greater than 1:1).
  • the enantiomerically enriched (by weight) S enantiomer of the S enantiomer relative to the R enantiomer is also At least about 80% by weight.
  • the enrichment is greater than about 80% by weight, providing a "substantially enantiomerically enriched", “substantially enantiomerically pure” or “substantially non-racemic" preparation, which By reference is made to a composition having at least 85% by weight of one enantiomer relative to one of the other enantiomers, such as at least about 90% by weight of the formulation, and further, for example, at least about 95% by weight.
  • the compounds provided herein can be from about 90% of at least one enantiomer by weight. In other embodiments, the compound can be from about 99%, about 98%, or about 99% by weight of one enantiomer. In some embodiments, the compound is a (S)- and (R)-racemic mixture. In other embodiments, provided herein is a process wherein a single compound (S) of the mixture - primarily a mixture of compounds present or (R) - is a mixture of primarily present compounds.
  • the compound mixture has a (S)-enantiomeric excess of 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.
  • the mixture of compounds has an (S)-enantiomeric excess of 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%.
  • the (R)-enantiomer purity of the compound mixture 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.
  • the mixture of compounds has a (R)-enantiomeric excess of 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%.
  • a (R)-enantiomeric excess of 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 greater than about 90% to about 99.5%, greater than 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 greater.
  • the mixture of compounds comprises, in addition to their stereochemical orientation, ie (S)- or (R)-the same chemical entity.
  • stereochemical orientation ie (S)- or (R)-the same chemical entity.
  • a compound has a -CH(R)- unit disclosed herein, and R is not hydrogen, then -CH(R)- is the same chemical entity in each of the (S)- or (R)-stereochemistry orientation.
  • the (S)-isomer in a mixture of the same chemical entities is present in a (S)-enantiomeric excess of from 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.
  • the (R)-isomer is in a mixture of the same chemical entity (except for its stereochemical orientation) relative to the (S)-isomer, at 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.
  • the enantiomers can be separated from the racemic mixture by any of the methods known to those skilled in the art, including chiral high performance liquid chromatography (HPLC), formation and crystallization of chiral salts, or not. See, for example, Enantiomers, Racemates and Resolutions (Jacques, Ed., Wiley lnterscience, New York, 1981); Wilen et al., Tetrahedron 33: 2725 (1977); Stereochemistry of Carbon Compounds (ELEliel, Ed., McGraw- Hill, NY, 1962); and Tables of Resolving Agents and Optical Resolutions p. 268 (ELEIM, Et al., Univ. of Notre Dame Press, Notre Dame, Ind. 1972).
  • HPLC high performance liquid chromatography
  • Optical isomers can also be obtained by resolution of the racemic mixture with an optically active acid or base in a conventional manner, for example, by formation of diastereomeric salts.
  • suitable acids include, but are not limited to, tartaric acid, diacetyl, dibenzoyl, xylyl tartaric acid, and camphorsulfonic acid.
  • the reaction of a disclosed compound with an optically pure acid or optically pure isocyanate in an activated form involves the synthesis of a covalent diastereomeric molecule.
  • the synthetic enantiomers can be separated by conventional methods such as chromatography, distillation, crystallization or sublimation followed by hydrolysis to provide enantiomerically enriched compounds.
  • Optically active compounds can also be obtained by using active starting materials. In some embodiments, these isomers may be in the form of the free acid, free base, ester or salt.
  • the pharmaceutically acceptable form is a tautomer.
  • tautomer as used herein is a type of isomer comprising two or more interconverted compounds derived from the migration and alteration of at least one form of a hydrogen atom and a covalent bond (eg, , single button to double button, triple button to single button, or vice versa).
  • Tautomeric includes proton or proton transfer tautomerism, which is considered a subset of acid-base chemistry.
  • Proton transfer tautomerism or “proton transfer tautomerism” refers to proton transfer accompanied by bond level changes. The exact ratio of tautomers depends on several factors including temperature, solvent and pH.
  • Tautomization i.e., providing a reaction of a tautomeric pair
  • Tautomerization can be catalyzed by an acid or base, or can be effected without the action or presence of an external agent.
  • tautomerization includes, but is not limited to, ketone to enol; amide to imide; lactam to lactam; enamine to imine; and one form of enamine to different enamine.
  • Specific examples of ketone to enol tautomerization are pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers.
  • Another example of tautomerization is phenol and ketone tautomerization.
  • Specific examples of tautomerization of phenols and ketones are pyridine 4-phenol and pyridine-4(1H)-one tautomers.
  • the structures described herein include compounds that exist only in one or more isotopically enriched atoms.
  • the compound has the present structure in which one hydrogen is replaced by ruthenium or osmium, or carbon 13 or carbon 14 enriched within the scope of this disclosure.
  • the disclosure also includes those "isotopically labeled derivatives" which are pharmaceutically acceptable forms of the compounds recited herein, except that one or more atoms are of a different atomic mass than are normally found in nature. Or the mass of the atom is replaced.
  • isotopes which may be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O , 18 F, and 36 Cl.
  • Certain isotopically-labeled disclosed compounds eg, those labeled with 3 H and 14 C) can be used to determine compound and/or substrate tissue distribution.
  • Isotopically labeled disclosed compounds can generally be prepared by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
  • an isotopically labeled reagent for a non-isotopically labeled reagent.
  • provided herein are compounds that may also contain one or more non-natural atomic isotopes. All isotopic variations of the disclosed compounds, as used herein, whether radioactive or not, are within the scope of the disclosure herein.
  • radiolabeled compounds can be used to study metabolism and compound tissue distribution to alter metabolic pathways, or rates or other biological functions.
  • DMSO-d6 refers to deuterated dimethyl sulfoxide
  • LC-MS: (ESI) refers to electrospray ionization liquid chromatography mass spectrometry
  • alteration is defined as a change from a normal physiological state. Exemplary changes include mutations, deletions, fusions with other proteins, overexpression or underexpression.
  • the invention provides a compound of formula (I):
  • compositions comprising an effective amount of a compound described herein, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph or prodrug of the compound, if applicable; a.
  • the compositions of the invention are formulated for pharmaceutical use ("pharmaceutical compositions"), wherein the carrier is a pharmaceutically acceptable carrier.
  • the carrier In view of being compatible with the other ingredients of the formulation, and in the case of a pharmaceutically acceptable carrier, the carrier must be "acceptable" and does not impair its recipient in the amounts typically employed in the pharmaceutical.
  • “Pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like.
  • a pharmaceutically acceptable carrier or excipient does not destroy the pharmacological activity of the disclosed compounds, and is non-toxic when administered in a therapeutic amount sufficient to deliver the compound.
  • the use of such media and agents for pharmaceutically active substances is well known in the art. Unless any conventional media or agent is incompatible with the active ingredient, its use in a therapeutic composition as disclosed herein is contemplated.
  • Examples and excipients of pharmaceutically acceptable carriers include, but are not limited to, sugars, for example, lactose, sucrose, and glucose; starches, for example, potato starch and corn starch; cellulose and its derivatives, such as carboxymethyl cellulose.
  • Cyclodextrins for example, alpha, beta and gamma-cyclodextrin, or chemically modified derivatives, for example, hydroxyalkyl cyclodextrins, including 2- and 3-hydroxypropyl cyclodextrin or others for enhancing the text A solubilized derivative of the delivery of the compound.
  • compositions of the present invention may be administered in solid or liquid form, including: oral administration, for example, a douche (aqueous or non-aqueous solution or suspension), tablets (for example, those for the oral cavity) , sublingual and systemic absorption), hard or soft capsules, pills, syrup, powder, granules, paste applied to the tongue, intraduodenal route; parenteral administration, including intravenous, intraarterial, subcutaneous, intramuscular , intraocular, pulmonary, intravascular, intraperitoneal or infusion, for example, sterile solutions or suspensions, or sustained release formulations; topical use, for example as a cream, ointment, gel, aqueous or oily solution or suspension, Or a controlled release patch or spray suitable for the skin; intravaginal or rectal, for example as a vaginal suppository, cream, stent or foam; sublingual; local delivery through a catheter or stent; intrathecal, or nasal, by blowing It is used (for example as
  • aqueous and nonaqueous vehicles in the pharmaceutical compositions include water, ethanol, polyol (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils such as olive oil, and Injection of organic esters such as ethyl oleate.
  • a coating material for example, lecithin
  • surfactants for example, surfactants, surfactants, surfactants.
  • These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, dispersing agents, lubricants, and/or antioxidants.
  • the compounds described herein prevent the action of microorganisms by ensuring the inclusion of different antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol sorbic acid and the like. It may also be in a composition comprising an isotonic agent, such as sugar, sodium chloride, and the like.
  • prolonged absorption of the injectable pharmaceutical form may be by the inclusion of a delay absorbent such as aluminum monostearate and gelatin.
  • compositions or compositions include the steps of the compounds described herein and/or associated with a chemotherapeutic carrier and, optionally, one or more accessory ingredients.
  • the formulation is formed by uniformly and in combination with a liquid carrier, or a finely divided solid carrier, or both, and then, if necessary, shaping the product.
  • a liquid carrier or a finely divided solid carrier, or both.
  • the preparation of such pharmaceutical compositions is well known in the art.
  • the pharmaceutical composition provides one or more of the disclosed compounds at a concentration of less than 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% by weight/weight ratio, weight/volume ratio, or volume/volume ratio.
  • the concentration of one or more compounds as disclosed herein can be greater than about 90%, 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.
  • the concentration of one or more compounds disclosed herein can range from about 0.0001% to about 50%, from about 0.001% to about 40%, from about 0.01% to about 30%, from about 0.02% to About 29%, from about 0.03% to about 28%, from about 0.04% to about 27%, from about 0.05% to about 26%, from about 0.06% to about 25%, from about 0.07% to about 24%, from about 0.08% to about 23% %, from about 0.09% to about 22%, from about 0.1% to about 21%, from about 0.2% to about 20%, from about 0.3% to about 19%, from about 0.4% to about 18%, from about 0.5% to about 17%, From about 0.6% to about 16%, from about 0.7% to about 15%, from about 0.8% to about 14%, from about 0.9% to about 12%, from about 1% to about 10% by weight, by weight/volume ratio or volume /Volume ratio.
  • the concentration of one or more compounds as disclosed herein can range from about 0.001% to about 10%, from about 0.01% to about 5%, from about 0.02% to about 4.5%, to about 0.03%. Up to about 4%, from about 0.04% to about 3.5%, from about 0.05% to about 3%, from about 0.06% to about 2.5%, from about 0.07% to about 2%, from about 0.08% to about 1.5%, from about 0.09% to about 1%, from about 0.1% to about 0.9% by weight/weight ratio, weight/volume ratio or volume/volume ratio.
  • the amount of one or more compounds as disclosed herein can be equal to or less than about 10 g, 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 grams, 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.
  • Grams about 0.9 grams, about 0.85 grams, about 0.8 grams, about 0.75 grams, about 0.7 grams, about 0.65 grams, about 0.6 grams, about 0.55 grams, about 0.5 grams, about 0.45 grams, about 0.4 grams, about 0.35 grams, About 0.3 grams, about 0.25 grams, about 0.2 grams, about 0.15 grams, about 0.1 grams, about 0.09 grams, about 0.08 grams, about 0.07 grams, about 0.06 grams, about 0.05 grams, about 0.04 grams, about 0.03 grams, about 0.02.
  • Grams about 0.01 gram, 0.009 grams, about 0.008 grams, about 0.007 grams, about 0.006 grams, about 0.005 grams, about 0.004 grams, about 0.003 grams, about 0.002 grams, about 0.001 grams, about 0.0009 grams, 0.0008 grams, about 0.0007.
  • the amount of one or more compounds disclosed herein can exceed about 0.0001 grams, about 0.0002 grams, 0.0003 grams, about 0.0004 grams, about 0.0005 grams, about 0.0006 grams, about 0.0007 grams, about 0.0008 grams.
  • the amount of one or more compounds disclosed herein can range from about 0.0001 grams to about 10 grams, from about 0.0005 grams to about 9 grams, from about 0.001 grams to about 0.5 grams, from about 0.001 grams to About 2 grams, from about 0.001 grams to about 8 grams, from about 0.005 grams to about 2 grams, from about 0.005 grams to about 7 grams, from about 0.01 grams to about 6 grams, from about 0.05 grams to about 5 grams, from about 0.1 grams to about 4 grams. Grams, from about 0.5 grams to about 4 grams, or from about 1 gram to about 3 grams.
  • a pharmaceutical composition comprising a compound as disclosed herein for oral administration, and a pharmaceutical excipient suitable for oral administration.
  • pharmaceutical compositions for oral administration (1) an optional effective amount of the disclosed compound; (2) an effective amount of one or more second agents; and (3) One or more pharmaceutically acceptable excipients for oral administration.
  • the pharmaceutical composition further comprises: (4) an effective amount of a third agent.
  • the pharmaceutical composition can be a liquid pharmaceutical composition suitable for oral administration.
  • Pharmaceutical compositions adapted for oral administration can be presented as discrete dosage forms, such as capsules, cachets, or tablets, or liquid, solution aerosol sprays or suspensions, each containing a predetermined amount of active ingredient in powder or granules.
  • Such dosage forms can be prepared by any of the methods of pharmacy, but all methods include the steps of preparing the compositions by the association of the active ingredient with liquid carriers, liposomes or finely divided solid carriers, or both.
  • the pharmaceutical compositions are formed by intimately and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers, or both, if necessary, in a desired form.
  • the tablet can be compressed or molded with optional one or more ingredients.
  • the tableting may be by the active ingredient in a free-flowing form such as a powder or granule, optionally with excipients such as, but not limited to, binders, lubricants, inert diluents and/or surfactants or dispersing agents Mix and press in a suitable machine.
  • Molded tablets may be made by molding a mixture of the powdered compound moistened with an inert liquid diluent in a suitable machine.
  • the tablets may optionally be uncoated, coated or scored and may be formulated to provide a slow or controlled release of the active ingredient therein to provide a sustained action over a longer period of time, such as a time delay material that may be used, for example Glyceryl monostearate or glyceryl distearate.
  • the preparation for oral use may also be a hard gelatin capsule, wherein the active ingredient may be mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as a soft gelatin capsule, wherein the active ingredient may be combined with a water or oil medium. For example, peanut oil, liquid paraffin or olive oil is mixed.
  • the active ingredient can be intimately combined with a pharmaceutically acceptable carrier by conventional pharmaceutical mixing techniques.
  • the carrier may take a wide variety of forms depending on the form of administration of the desired formulation.
  • any of the usual pharmaceutical media can be used as a carrier, for example, water, glycols, oils, ethanol, flavoring agents, preservatives, coloring agents, and oral liquid preparations (for example, suspension).
  • Liquid, solution, and elixirs) or aerosols, or carriers, for example, starch, sugar, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrants may be in oral solid preparations
  • lactose is not used in some embodiments.
  • the compound can be combined with lactose, sucrose, starch powder, cellulose ester of alkanoic acid, cellulose alkyl ester, talc, stearic acid, magnesium stearate, magnesium oxide, calcium phosphate, sodium phosphate, Calcium sulphate, sodium sulphate, gelatin, gum arabic, sodium alginate, polyvinylpyrrolidone and/or polyvinyl alcohol are used in further formulations.
  • suitable carriers also include powders, capsules and tablets.
  • the tablets can be coated by standard aqueous or non-aqueous techniques.
  • Suitable for coatings of pharmaceutical compositions and dosage forms including, but not limited to, corn starch, potato starch, or other starches, gelatin, natural binders and synthetic gums such as acacia, sodium alginate, alginic acid, other alginic acids Salt, powdered tragacanth, guar gum, cellulose and its derivatives (eg, ethyl cellulose, cellulose acetate, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose), polyvinylpyrrolidone, A Cellulose, pregelatinized starch, hydroxypropyl methylcellulose, microcrystalline cellulose, and mixtures thereof.
  • natural binders and synthetic gums such as acacia, sodium alginate, alginic acid, other alginic acids Salt, powdered tragacanth, guar gum, cellulose and its derivatives (eg, ethyl cellulose, cellulose acetate, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose), polyvinyl
  • suitable fillers for use in pharmaceutical compositions and dosage forms are disclosed herein including, but not limited to, talc, calcium carbonate (eg, granules or powders), microcrystalline cellulose, powdered cellulose, glucose binder, kaolin , mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and mixtures thereof.
  • talc calcium carbonate (eg, granules or powders)
  • microcrystalline cellulose powdered cellulose
  • glucose binder e.g, kaolin , mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and mixtures thereof.
  • Disintegrants can be used in pharmaceutical compositions as provided herein to provide tablets that disintegrate upon exposure to an aqueous environment. Too much disintegrant can cause the tablet to disintegrate in the bottle. Too little may not be sufficient for disintegration to occur, and thus the rate and extent of release of the active ingredient of the dosage form may be altered. Therefore, the disintegrant should be in a sufficient amount to change the release of the active ingredient either too little or too much.
  • the amount of disintegrant depends on the formulation and mode of administration, and can be readily accomplished by one of ordinary skill in the art. From about 0.5 to about 15% by weight of the disintegrant, or from about 1 to about 5% by weight of the disintegrant, can be used in the pharmaceutical composition.
  • Disintegrants which can be used to form pharmaceutical compositions and dosage forms, including, but not limited to, agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, potassium blakelin, starch hydroxy Sodium acetate, potato or tapioca starch, other starches, pregelatinized starch, clay, other algin, other cellulose, gum or mixtures thereof.
  • Lubricants can be used to form pharmaceutical compositions and dosage forms including, but not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, Other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oils (eg, peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil and soybean oil), zinc stearate, ethyl oleate , ethyl laurate, agar or a mixture thereof.
  • Lubricants also include, for example, silica gel, coagulated aerosols, or mixtures thereof.
  • the lubricant can optionally be added in an amount of less than about 1% by weight of the pharmaceutical composition.
  • the active ingredient may be combined with various sweetening or flavoring agents, colorants or dyes, and, for example, emulsifiers and/or suspending agents, diluents.
  • various sweetening or flavoring agents for example, water, ethanol, propylene glycol, glycerin, and various combinations thereof.
  • Surfactants that can be used to form pharmaceutical compositions and dosage forms include, but are not limited to, hydrophilic surfactants, lipophilic surfactants, and mixtures thereof. Suitable hydrophilic surfactants can generally have an HLB value of at least about 10, while suitable lipophilic surfactants can generally have an HLB value of less than about 10.
  • the empirical parameter used to characterize the relative hydrophilicity and hydrophobicity is the hydrophilic-lipophilic balance value HLB ("HLB" value).
  • HLB hydrophilic-lipophilic balance value
  • Surfactants with lower HLB values are more lipophilic or hydrophobic and have greater solubility in oil, while active agents with higher HLB values are more hydrophilic and have greater in aqueous solutions. Solubility.
  • Hydrophilic surfactants are generally considered to be those having an HLB value greater than about 10, however, anionic, cationic or zwitterionic compounds, the HLB scale is generally not applicable.
  • a lipophilic (i.e., hydrophobic) surfactant has an HLB value of equal to or less than about 10.
  • the HLB value of surfactants is only a rough guide for general use in industrial, pharmaceutical and cosmetic emulsions.
  • Hydrophilic surfactants can be ionic or nonionic. Suitable ionic surfactants include, but are not limited to, alkylammonium salts; fusidate; fatty acid derivatives of amino acids, oligopeptides and polypeptides; derivatives of glycerides of amino acids, oligopeptides and polypeptides; lecithin and Hydrogenated lecithin; lysolecithin and hydrogenated lysolecithin; phospholipids and derivatives thereof; lysophospholipids and derivatives thereof; carnitine fatty acid ester salts; alkyl sulfates; fatty acid salts; sodium docusate; Salt; tartaric acid esters of mono- and diacetylated mono- and diglycerides; succinylated mono- and diglycerides; citrate esters of mono- and di-glycerides; and mixtures thereof.
  • Ionic surfactants include, but are not limited to, for example, lecithin, lysolecithin, phospholipids, lysophospholipids and derivatives thereof; carnitine fatty acid ester salts; alkyl sulfates; fatty acid salts; sodium docusate; Acyl lactate; diacetylated tartrate of mono- and mono- and di-glycerides; succinylated mono- and diglycerides; citrate esters of mono- and di-glycerides; and mixtures thereof.
  • Hydrophilic nonionic surfactants include, but are not limited to, alkyl glycosides; alkyl maltose; alkyl thioglycosides; lauroyl polyethylene glycol glycerides; polyoxyalkylene alkyl ethers, for example, polyethylene glycol alkanes Polyether olefin phenol, for example, polyethylene glycol alkyl phenol; polyoxyalkylene alkyl phenol fatty acid ester, for example, polyethylene glycol fatty acid monoester and polyethylene glycol fatty acid diester; Glycol glycerol fatty acid ester; polyglycerol fatty acid ester; polyoxyalkylene sorbitan fatty acid ester, for example, polyethylene glycol sorbitol fatty acid ester; and glyceride, vegetable oil, hydrogenated vegetable oil, fatty acid and sterol a hydrophilic transesterification product of at least one polyol; polyoxyethylene sterol, derivatives thereof, and
  • the polyol may be glycerin, ethylene glycol, polyethylene glycol, sorbitol, propylene glycol, pentaerythritol or sugars.
  • Other hydrophilic nonionic surfactants include, 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.
  • Suitable lipophilic surfactants include, but are not limited to, for example, fatty alcohols; glycerol fatty acid esters; acetylated glycerol fatty acid esters; lower alcohol fatty acid esters; propylene glycol fatty acid esters; sorbitol fatty acid esters; Glycol sorbitan fatty acid esters; sterols and sterol derivatives; polyoxyethylated sterols and sterol derivatives; polyethylene glycol alkyl ethers; sugar esters; sugar ethers; lactic acid derivatives of mono- and diglycerides.
  • the pharmaceutical composition may include a solubilizing agent to ensure good solubilization and/or dissolution of the compound and to minimize precipitation of the compound.
  • This may be a pharmaceutical composition for non-oral use, for example, a pharmaceutical composition for injection, which is especially important.
  • Solubilizers may also be added to increase the solubility of the hydrophilic drug and/or other components, such as surfactants, or to maintain a pharmaceutical composition as a stable or uniform solution or dispersion.
  • solubilizing agents include, but are not limited to, for example, alcohols and polyols, for example, ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butylene glycol and isomers thereof, glycerin, pentaerythritol , sorbitol, mannitol, dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinyl alcohol, and other cellulose derivatives, cyclodextrin and cyclodextrin derivatives; ethers of polyethylene glycol , having a molecular weight of from about 200 to about 6000, such as tetrahydrofurfuryl PEG ether (tetrahydrofuran polyglycol ether) or methoxy PEG; amide and other nitrogen-containing compounds, such as 2-pyrrolidone, 2-piperidone, ⁇ -caprolactam , N-alkylpyrrol
  • the amount of a given solubilizer can be limited to a biologically acceptable amount, which can be readily determined by one skilled in the art.
  • the solubilizer can be at a weight ratio of about 10%, about 25%, about 50%, about 100%, or up to about 200% by weight, based on the total weight of the drug, and other excipients. Small amounts of solubilizing agents can also be used if desired, for example about 5%, 2%, 1% or even less. Typically, the solubilizer may be present from about 1% to about 100%, typically from about 5% to about 25% by weight.
  • the pharmaceutical compositions may also include one or more pharmaceutically acceptable additives and excipients.
  • additives and excipients include, but are not limited to, for example, anti-adherents, anti-foaming agents, buffers, polymers, antioxidants, preservatives, chelating agents, flavoring agents, colorants, essential oils, fragrances, shading Agents, suspending agents, binders, fillers, plasticizers, lubricants, and mixtures thereof.
  • Preservatives can include, but are not limited to, for example, antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, alcohol preservatives, acidic preservatives, and other preservatives.
  • Antioxidants include, but are not limited to, alpha-tocopherol, ascorbic acid, butylated hydroxyanisole, butylhydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sub Sodium hydrogen sulfate, and sodium sulfite.
  • Chelating agents include, but are not limited to, for example, ethylenediaminetetraacetic acid (EDTA), citric acid monohydrate, disodium edetate, dipotassium edetate, edetic acid, fumaric acid , malic acid, phosphoric acid, sodium edetate, tartaric acid, and triethylenediamine tetraethyl citrate.
  • EDTA ethylenediaminetetraacetic acid
  • citric acid monohydrate disodium edetate
  • dipotassium edetate dipotassium edetate
  • edetic acid fumaric acid
  • malic acid malic acid
  • phosphoric acid sodium edetate
  • tartaric acid tartaric acid
  • triethylenediamine tetraethyl citrate triethylenediamine tetraethyl citrate
  • Antimicrobial preservatives include, but are not limited to, for example, benzalkonium chloride, benzethonium chloride, benzyl alcohol, bromide, cetrimonium bromide, cetylpyridinium chloride, chloroxylenol, cresol, Ethanol, glycerol, heptetidine, imidazolidine, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, and propylene glycol.
  • Antifungal agents including, but not limited to, for example, butyl paraben, methyl paraben, ethyl p-hydroxybenzoate, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate , potassium sorbate, sodium benzoate, sodium propionate and sorbic acid.
  • Preservatives include, but are not limited to, for example, ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and phenylethyl alcohol.
  • Acidic preservatives include, but are not limited to, for example, vitamin A, vitamin C, vitamin E, beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid.
  • preservatives include, but are not limited to, for example, tocopheryl acetate, cetrimonium bromide, butylated hydroxyanisole (BHA), butylhydroxytoluene (BHT), ethylenediamine, sodium lauryl sulfate (SLS) ), sodium lauryl ether sulfate (SLES), sodium hydrogen sulfate, sodium metabisulfite, potassium sulfite, potassium pyrosulfite, methyl p-hydroxybenzoate.
  • the preservative can be an antioxidant.
  • the preservative can be a chelating agent.
  • compositions for parenteral administration (1) an effective amount of a disclosed compound; optionally (2) an effective amount of one or more second An agent; (3) one or more pharmaceutical excipients suitable for parenteral administration and (4) an effective amount of a third agent.
  • the pharmaceutical composition can be administered by injection, including an aqueous or oily suspension, or an emulsion, sesame oil, corn oil, cottonseed oil, or peanut oil, and an elixir, mannitol, dextrose, or a sterile aqueous solution, and A similar drug carrier.
  • Aqueous saline solution is also commonly used for injection.
  • Ethanol, glycerin, propylene glycol, liquid polyethylene glycol, benzyl alcohol, and the like (and suitable mixtures thereof), cyclodextrin derivatives, sodium chloride, tragacanth, buffers, and vegetable oils may also be employed.
  • Proper fluidity can be maintained by the use of a coating, for example lecithin, or by the use of a surfactant to maintain the desired particle size in the case of dispersions.
  • a coating for example lecithin
  • a surfactant to maintain the desired particle size in the case of dispersions.
  • Prevention of the action of microorganisms can be carried out by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.
  • the pharmaceutical compositions may also be injected by a suitable carrier, including saline, dextrose or water, or by cyclodextrin, co-solvent (e.g., propylene glycol) or micelle solubilization (e.g., Tween 80).
  • Sterile injectable solutions can be prepared by filtration and sterilizing the required amount of the compound disclosed herein with a suitable solvent of the various other ingredients described above.
  • dispersions are prepared by incorporating the various ⁇ Desc/Clms Page number>> ⁇ / RTI> ⁇ RTIgt; ⁇ / RTI> ⁇ RTIgt; ⁇ / RTI> ⁇ RTIgt; ⁇ / RTI> ⁇ RTIgt; ⁇ / RTI> ⁇ RTIgt; ⁇ / RTI> ⁇ RTIgt;
  • the compositions are prepared by vacuum drying and freeze drying techniques to produce the active ingredient and any additional sterile filtered ingredients described above.
  • the sterile injectable preparation may also be prepared in a dispersion or a solution in a non-toxic parenterally acceptable diluent or solvent, for example, 1,3-butanediol or a sterile injectable solution.
  • a non-toxic parenterally acceptable diluent or solvent for example, 1,3-butanediol or a sterile injectable solution.
  • acceptable vehicles and solvents that may be employed are, but are not limited to, for example, water, Ringer's solution, and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspension medium including, but not limited to, for example, synthetic mono or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • the injectable preparation may be sterilized prior to use by, for example, bacterial retention filter filtration, or by addition of a sterilizing agent incorporating the sterile solid composition which can be dissolved or dispersed in sterile water or other sterile injectable medium.
  • the injectable compositions can be from about 0.1 to about 5% by weight of the compounds disclosed herein.
  • provided herein are compounds (eg, transdermal) containing a compound or pharmaceutical composition comprising one or more pharmaceutical excipients suitable for topical administration as disclosed herein.
  • pharmaceutical-containing compositions for topical administration (1) an effective amount of a disclosed compound; optionally (2) an effective amount of one or more second agents (3) one or more pharmaceutical excipients suitable for topical administration and (4) an effective amount of a third agent.
  • compositions provided herein may be formulated in solid, semi-solid or liquid form suitable for local or topical application, such as gels, water-soluble gels, elixirs, creams, lotions, suspensions, foams. , powders, ointments, ointments, solutions, oils, pastes, suppositories, sprays, emulsions, saline solutions, dimethyl sulfoxide (DMSO) based solutions.
  • a carrier having a higher density can provide a region with long-term exposure to the active ingredient.
  • a solution formulation can provide a more direct contact of the selected region of the active ingredient.
  • the ointment formulation can be paraffin or water miscible.
  • the active ingredient can be formulated into a cream with the cream base of the oil in water.
  • the aqueous phase of the cream base can include, for example, at least about 30% by weight of a polyol, for example, propylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerin, polyethylene glycol, and mixtures thereof.
  • the pharmaceutical compositions may also contain suitable solid or gel phase carriers or excipients which may increase penetration or assist in the delivery of the compound through the stratum corneum barrier of the skin.
  • Such carriers and excipients include, but are not limited to, for example, wetting agents (eg, urea), glycols (eg, propylene glycol), alcohols (eg, ethanol), fatty acids (eg, oleic acid), surfaces Active agents (for example, isopropyl myristate and sodium citrate), pyrrolidone, glycerol monolaurate, sulfoxide, hydrazine (eg, menthol), amines, amides, alkanes, alkanols, water, Calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin and polymers such as polyethylene glycol.
  • wetting agents eg, urea
  • glycols eg, propylene glycol
  • alcohols eg, ethanol
  • fatty acids eg, oleic acid
  • surfaces Active agents for example, isopropyl myristate and sodium citrate
  • pyrrolidone
  • transdermal administration Such transdermal patches can be used to provide a controlled amount of the pharmaceutical composition continuously or discontinuously. If the active agent is absorbed through the skin, a controlled and predetermined flow rate of the active agent can be administered to the subject. In the case of microcapsules, an encapsulant can also be used as the film.
  • transdermal patches is well known in the art. See, for example, U.S. Patent Nos. 5,023,252, 4,992,445 and 5,001,139.
  • compositions of the present invention can be administered in the form of a suppository for rectal administration.
  • These compositions can be prepared by admixing a compound of the invention with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature so as to be melted in the rectum and released Active ingredient.
  • suitable non-irritating excipient include, but are not limited to, for example, polyethylene glycol, beeswax, and cocoa butter.
  • compositions of the present invention can be administered by nasal aerosol or inhalation.
  • Such compositions are prepared according to techniques known in the art of pharmaceutical formulation, and may be prepared as solutions of saline, and may employ benzyl alcohol or other suitable preservatives to enhance the bioavailability of absorption enhancers, fluorocarbons, And other solubilizing or dispersing agents known in the art.
  • Particularly advantageous derivatives and prodrugs are those which increase the bioavailability of the compounds of the invention when such compounds are administered to a mammal (e.g., by allowing the compound to be administered orally to be more readily absorbed), or relative to Maternal species can enhance the delivery of compounds to maternal biological chambers (eg, the brain or central nervous system).
  • Preferred prodrugs include those in which a group which enhances water solubility or active transport through the intestinal membrane is attached to the general structure described herein.
  • the application of the subject therapeutic agent can be topical for administration at the target site.
  • Various techniques can be used to provide a subject composition at the target site, such as injection, use of a catheter, gel, stent, trocar, propellant, drug sustained release polymer, or other device that provides for internal access.
  • the invention provides an implantable medical device comprising a compound of the invention or a composition comprising a compound of the invention such that the compound is therapeutically active.
  • the invention provides a method of injecting an implantable drug release device comprising the step of contacting the drug release device with a compound or composition of the invention.
  • Implantable drug delivery devices include, but are not limited to, biodegradable polymer capsules or pills, non-degradable, diffusible polymer capsules, and biodegradable polymer sheets.
  • compositions of the present invention further comprise a second therapeutic agent.
  • the second therapeutic agent includes any compound or therapeutic agent which is known to have or prove advantageous properties when administered alone or with any of the compounds of the formula herein.
  • Drugs that may be usefully combined with these compounds include other kinase inhibitors, and/or other chemotherapeutic agents useful in the treatment of the diseases and disorders discussed above. Such agents are described in detail in the art.
  • the second therapeutic agent is an agent useful for the treatment or prevention of a disease or condition selected from cancer.
  • the invention provides separate dosage forms of a compound of the invention and a second therapeutic agent associated with each other.
  • association with each other means that the separate dosage forms are packaged together or otherwise linked to one another such that the separate dosage forms are intended to be sold or administered together (less than 24 hours each other) Internally, continuously or simultaneously).
  • the compounds of the invention are present in an effective amount.
  • effective amount means that when administered in a suitable dosage regimen, the amount is sufficient to reduce or improve the severity, duration or development of the disorder to be treated, preventing the progression of the disorder to be treated, causing The resolution of the disorder of treatment, or enhance or improve the preventive or therapeutic effect of another therapy.
  • An effective amount of a compound of the invention may range from about 0.001 to 1 mg/kg to about 500 mg/kg, from about 0.01 mg/kg to about 50 mg/kg, from about 0.1 mg/kg to about 2.5 mg/kg.
  • Effective dosages can also vary, as will be appreciated by those skilled in the art, depending on the disease being treated, the severity of the disease, the route of administration, the age, sex and general health of the patient, the excipient usage, and other treatments.
  • the method is used together (eg using other reagents) and the judgment of the treating physician.
  • the effective amount of the second therapeutic agent is between about 20% and 100% of the dosage typically utilized in a single treatment regimen using only the agent.
  • the effective amount is between about 70% and 100% of the normal single therapeutic dose.
  • Normal single therapeutic doses of these second therapeutic agents are well known in the art. See, for example, Wells et al., Pharmacotherapy Handbook, Appleton and Lange, Stamford, Conn. (2000); PDR Pharmacopoeia, Tarascon Pocket Pharmacopoeia 2000, Tarascon Publishing, Loma Linda, Calif. (2000), all of which are collectively This document is incorporated by reference.
  • certain second therapeutic agents mentioned herein will act synergistically with the compounds of the invention. When it occurs, it will allow the second therapeutic agent and/or the effective amount of the compound of the invention to be less than the dose required in a single treatment. This has the advantage of minimizing toxic side effects of the second therapeutic agent or compound of the invention, improving efficacy, improving ease of administration or use, and/or reducing the overall cost of the compound preparation or formulation.
  • the treatment is as follows:
  • the invention provides a method of treating a subject having or susceptible to a disease or disorder, or a symptom thereof (eg, those described herein), comprising administering to the subject an effective amount of the subject The step of administering the compound or composition of the invention.
  • diseases are well known in the art and are also disclosed herein.
  • Therapeutic methods involve the treatment of disorders mediated by protein kinases such as EGFR.
  • the invention provides a method of treating a disease in a subject comprising administering to the subject a composition comprising any compound of the formula.
  • the disease is mediated by EGFR kinase.
  • the disease is cancer or a proliferative disease.
  • the compound of formula (I), and a pharmaceutically acceptable salt are inhibitors of activation mutants against EGFR exon 2-7 deletion, which are expected to be exemplified by the activity of the EGFR VIII mutant
  • the treatment of a partially mediated, for example cancer or medical condition is useful.
  • This may be a type of cancer treated with a compound of formula (I), or a pharmaceutically acceptable salt including, but not limited to, ovarian cancer, cervical cancer, colorectal cancer, breast cancer, pancreatic cancer, glioma, glue Hepatoblastoma, melanoma, prostate cancer, leukemia, lymphoma, non-Hodgkin's lymphoma, gastric cancer, lung cancer, liver cancer, bone cancer, gastrointestinal stromal tumor (GIST), thyroid cancer, cholangiocarcinoma, uterus Endometrial cancer, renal cancer, anaplastic large cell lymphoma, acute myeloid leukemia (AML), multiple myeloma, melanoma, mesothelioma, brain cancer, membrane adenocarcinoma, skin cancer or head and neck squamous Cellular cancer.
  • ovarian cancer cervical cancer, colorectal cancer, breast cancer, pancreatic cancer, glioma, glue Hepatoblasto
  • the compound of formula (I), and a pharmaceutically acceptable salt are inhibitors of EGFR Exon 21 L858R mutant and Exon19 deletion activating mutant, which are expected to be exemplified by the activity of the EGFR mutant
  • the treatment of a partially mediated, for example cancer or medical condition is useful.
  • This may be a type of cancer treated with a compound of formula (I), or a pharmaceutically acceptable salt including, but not limited to, ovarian cancer, cervical cancer, colorectal cancer, breast cancer, pancreatic cancer, glioma, glue Hepatoblastoma, melanoma, prostate cancer, leukemia, lymphoma, non-Hodgkin's lymphoma, gastric cancer, lung cancer, liver cancer, bone cancer, gastrointestinal stromal tumor (GIST), thyroid cancer, cholangiocarcinoma, uterus Endometrial cancer, renal cancer, anaplastic large cell lymphoma, acute myeloid leukemia (AML), multiple myeloma, melanoma, mesothelioma, brain cancer, membrane adenocarcinoma, skin cancer or head and neck squamous Cellular cancer.
  • ovarian cancer cervical cancer, colorectal cancer, breast cancer, pancreatic cancer, glioma, glue Hepatoblasto
  • the disease is a glioma.
  • the disease is non-small cell lung cancer (NSCLC) with brain metastasis.
  • NSCLC non-small cell lung cancer
  • the disease is a neurological disease.
  • the methods of the invention are used to treat a subject having or susceptible to a disease or condition.
  • diseases, disorders or symptoms thereof include, for example, those regulated by protein kinases (e.g., EGFR protein kinases).
  • the disease or condition of the disease can be, for example, a cancer or a proliferative disease or disorder.
  • the disease or disease symptoms may be ovarian cancer, cervical cancer, colorectal cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, melanoma, prostate cancer, leukemia, lymphoma, non-ho Qijin lymphoma, gastric cancer, lung cancer, liver cancer, bone cancer, gastrointestinal stromal tumor (GIST), thyroid cancer, cholangiocarcinoma, endometrial cancer, renal cancer, anaplastic large cell lymphoma, acute myeloid leukemia ( AML), multiple myeloma, melanoma, mesothelioma, brain cancer, membrane adenocarcinoma, skin cancer or head and neck squamous cell carcinoma.
  • GIST gastrointestinal stromal tumor
  • the methods depicted herein include those subjects in which the subject is identified as requiring specific treatment. Identifying a subject in need of such treatment can be within the judgment of the subject or healthcare professional and can be subjective (eg, opinion) or objective (eg, measurable by a test or diagnostic method).
  • the compounds (and compositions thereof) can be used to treat a disease or disorder and have been treated with other therapeutic agents (eg, anticancer agents, neurological agents, psychotic agents, hearts)
  • a vascular disease agent, an anti-obesity or a diabetic agent treats and forms a resistant subject.
  • the methods herein comprise a subject having a resistance to treatment (or identified as having developed resistance to gefitinib, erlotinib treatment) administered with a compound of the formula (or Those methods of the composition).
  • the subject is therefore responsive to the treatment such that the disorder is modulated or ameliorated prior to treatment with a compound of the formula.
  • the invention provides a method of modulating the activity of a protein kinase (eg, a protease kinase, a kinase exemplified herein) in a cell, comprising: reacting the cell with one or more compounds of any of the formulae contact.
  • a protein kinase eg, a protease kinase, a kinase exemplified herein
  • anti-cancer treatments described above may be administered as a monotherapy with a compound of the invention or with conventional surgery or radiation or chemotherapy or immunotherapy with a compound of the invention.
  • Such chemotherapy may be co-administered with the compounds of the invention, simultaneously, sequentially or separately, and may include, but is not limited to, one or more of the following classes of anti-tumor agents: for example, anti-proliferative/anti-tumor agents, alkylation Agents (eg cisplatin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulfan, temozolomide and nitrosourea), antimetabolites (eg gemcitabine and Antifolates such as 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytarabine, and hydroxyurea; antitumor antibiotics (eg anthracyclines such as doxorubic
  • luciferase inhibitors of growth factor function include growth factor antibodies and growth factor receptor antibodies (e.g., anti-erbB2 antibody trastuzumab [Herceptin (TM)], anti-EGFR antibody panitumumab, Anti-ErbB antibody cetuximab (Erbitux, C225) and by Stem et al. Critical reviews in oncology/haematology, 2005, Vol. 54, l1-29 Any of the growth factor or growth factor receptor antibodies.
  • growth factor antibodies and growth factor receptor antibodies e.g., anti-erbB2 antibody trastuzumab [Herceptin (TM)], anti-EGFR antibody panitumumab, Anti-ErbB antibody cetuximab (Erbitux, C225) and by Stem et al. Critical reviews in oncology/haematology, 2005, Vol. 54, l1-29 Any of the growth factor or growth factor receptor antibodies.
  • Such inhibitors also include tyrosine kinase inhibitors, such as epidermal growth factor family inhibitors (eg, EGFR family tyrosine inhibitors such as gefitinib, erlotidine) Niem, Kemena and Tagres, tyrosine kinase inhibitors of erbB2, such as lapatinib, natenatib); inhibitors of the hepatocyte growth factor family; inhibitors of the insulin growth factor family; platelets Inhibitors of the derived growth factor family, such as imatinib and/or nilotinib; inhibitors of serine/threonine kinases (eg RAS/RAF signaling inhibitors such as farnesyltransferase inhibitors, eg Lafini, tipifamib and lonafamib, via MEK and/or AKT kinase cell signaling inhibitor, c-kit inhibitor, abl fusion kinase inhibitor, PI3 kinase inhibitor,
  • antisense (nucleic acid) therapy gene therapy For example, those listed above, such as ISIS 2503, antisense (nucleic acid) therapy against ras gene; gene therapy methods including, for example, replacement of abnormal genes such as abnormal p53 or abnormal BRCA1 or BRCA2 (eg, olapa , Niraparib, Rucaparib, Talazoparib), GDEPT (gene-directed enzyme prodrug therapy) methods such as cytosine deaminase, thymidine kinase or bacterial nitroreductase enzymes and those to improve patient tolerance to chemotherapy or radiotherapy Drug resistance gene therapy immunotherapy methods, including, for example, increasing the immunogenicity of a patient's tumor cells, such as immunogenicity transf
  • co-administered refers to a second therapeutic agent that can be combined with a compound of the invention as a single dosage form (eg, a composition of the invention comprising a compound of the invention and a second therapeutic agent as described above). Partially or as a separate, multiple dose form. Alternatively, additional agents can be administered prior to, or successively with, or after administration of the compounds of the invention. In such combination therapy, the compound of the invention and the second therapeutic agent are administered by conventional methods. Administration of a composition of the invention comprising a compound of the invention and a second therapeutic agent to a subject does not exclude other time courses of the same therapeutic agent, any other second therapeutic agent or any of the compounds of the invention during the course of treatment The subject is administered separately. The continuous or separate application, or delayed administration of the second component, should not lose the advantage of the effect produced by the use of the combination.
  • an effective amount of a second therapeutic agent is well known to those skilled in the art, see, for example, Wells et al., Pharmacotherapy Handbook, Appleton and Lange, Stamford, Conn. (2000); PDR Pharmacopoeia, Tarascon Pocket Pharmacopoeia 2000, Tarascon Publishing, Loma Linda, Calif. (2000) and other medical textbooks. However, determining the optimal effective amount of the second therapeutic agent is within the abilities of those skilled in the art.
  • the effective amount of the compound of the invention when the second therapeutic agent is administered to the subject, is less than its effective amount when the second therapeutic agent is not administered. In another embodiment, the effective amount of the second therapeutic agent is less than its effective amount when the compound of the invention is not administered. In this way, undesirable side effects associated with any of the high doses of the agent can be minimized. Potential advantages will be apparent to those skilled in the art (including, but not limited to, for example, improving dosage regimens and/or reducing drug costs).
  • the present invention provides the use of a compound of any of the formulae herein, alone or in combination with one or more second therapeutic agents described herein, in the manufacture of a medicament, as a single composition or as a separate dosage form,
  • the medicament is for the treatment or prevention of a disease, disorder or symptom listed herein in a subject.
  • Another aspect of the invention is the use of a compound of the formula herein to treat or prevent a disease, disorder or condition described herein in a subject.
  • the methods herein include those methods that further include monitoring the subject's response to therapeutic administration. Such monitoring may include periodic sampling of subject tissue, body fluids, cerebrospinal fluid, samples, cells, proteins, chemical markers, genetic material, etc., as markers or indicators of treatment regimens. In other methods, the subject is pre-screened or identified as requiring such treatment by assessing the suitability of the relevant marker or indicator for such treatment.
  • the invention provides a method of monitoring the progress of treatment.
  • the methods comprise determining a diagnostic marker (marker) in a subject having or susceptible to a disorder or a symptom thereof described herein (eg, any target or cell type as described herein modulated by a compound herein) or diagnostic
  • the step of measuring the level of a value eg, screening, assay
  • the level of marker determined in the method can be compared to a known level of marker in a healthy normal control or other diseased patient to establish a subject's disease condition.
  • the second level of the marker in the subject is measured at a time point later than the first level of measurement and the two levels are compared to monitor the progression of the disease or the efficacy of the therapy.
  • the pre-treatment marker level in the subject is determined prior to initiation of treatment in accordance with the present invention; the pre-treatment level of such marker can be a marker in the subject after the start of treatment Levels are compared to determine the efficacy of the treatment.
  • the level of marker or marker activity in the subject is determined at least once.
  • the marker level is compared to another measure of, for example, a marker level obtained earlier or subsequently from the same patient, another patient or a normal subject, and can be used to determine if the therapy according to the invention has the desired effect, and thereby Allow dose levels to be adjusted as appropriate.
  • Determination of the level of the marker can be performed using any suitable sampling/expression assay method known in the art or described herein.
  • the tissue or liquid sample is first removed from the subject. Examples of suitable samples include blood, urine, cerebrospinal fluid, tissue, oral or buccal cells, and hair samples containing roots. Other suitable samples are known to those skilled in the art.
  • Determination of protein levels, ctDNA, cfDNA and/or mRNA levels (eg, marker levels) in a sample can utilize any suitable technique known in the art including, but not limited to, enzyme immunoassays, ELISA, radiolabel assay techniques, Imprinting/chemiluminescence methods, real-time PCR, electrochemical signals, and the like.
  • kits for treating a disease, disorder or symptom thereof including those described herein.
  • kits include: 1) a pharmaceutical composition comprising a compound of any of the formulae herein or a salt thereof; or a prodrug thereof, or a salt of a prodrug; or a hydrate, solvate or polymorph thereof,
  • the pharmaceutical composition is in a container; and 2) instructions for using the pharmaceutical composition to treat a method comprising a disease, disorder, or symptom thereof described herein.
  • the container may be any container or other sealed or sealable device capable of holding the pharmaceutical composition.
  • Examples include bottles, separate or multi-chambered reservoir bottles, wherein each compartment or compartment comprises a single dose of the composition; a separate foil package, wherein each partition comprises a single dose of the composition; or dispense A single dose of the composition is dispensed.
  • the container may be of any conventional shape or form known in the art, made of a pharmaceutically acceptable material, such as a paper or cardboard box, a glass or plastic bottle or can, a resealable bag (eg, to accommodate A "refill" of the tablet is used to place into a different container, or a single dose of blister pack is used to extrude from the package according to the treatment schedule.
  • the container employed may depend on the exact dosage form involved, for example, conventional cardboard boxes will generally not be used to hold a liquid suspension. It is feasible that more than one container can be used together in a single package to market a single dosage form.
  • the tablet can be contained in a bottle which is then contained within the box.
  • the container is a blister pack.
  • the kit may additionally include information and/or instructions for the physician, pharmacist, or subject.
  • These memory aids include numbers printed on each compartment or section containing the medicament, which corresponds to the number of days that the specified tablet or capsule should be ingested, or printed on each compartment or partition. The number of days in the week, or a card containing the same type of information.
  • the quinazoline derivative (I) of the present invention has an enantiomeric purity of from 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.
  • the compounds depicted herein can be evaluated for their biological activity using protocols known in the art, including, for example, those depicted herein.
  • Certain compounds herein demonstrate surprisingly superior properties (eg, metabolic stability, high selectivity, low efflux, high permeability, non-P-glycoprotein efflux substrates, etc.), making them excellent potential therapeutic agents Candidate.
  • the synthetic route is as follows:
  • Step 1 A solution of A1 (2.0 g, 10.5 mmol) and triethylamine (1.3 g, 12.6 mmol) in dichloromethane (10 mL) A solution of ester (1.4 g, 12.6 mmol). The reaction mixture was stirred at 0 ° C for 1 hour and allowed to reach room temperature. The reaction mixture was then washed twice with water. The organic layer was dried with EtOAc EtOAc EtOAc EtOAcjjjjjjjjj
  • Step 2 To a solution of A2 (2.7 g, 10.3 mmol) in concentrated sulphuric acid (4.6 mL), EtOAc (0.73 mL, 15.5 mmol). After 1 hour, the reaction mixture was poured into ice/water and extracted twice with ethyl acetate. The combined organic layers were washed with w ⁇ Product A3 (3.0 g, yield 94.6%).
  • Step 3 A3 (3.0 g, 9.8 mmol) EtOAc m.
  • the reaction mixture was stirred at 60 ° C for 3 hours.
  • the methanol was evaporated under vacuum.
  • the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were dried with EtOAc EtOAc m.
  • Step 4 To a solution of EtOAc (2. The reaction mixture was stirred at 60 ° C for 3 hours. The resulting mixture was separated between water and ethyl acetate. The organic layer was dried with EtOAc (EtOAc m.
  • Step 5 Stir a mixture of A5 (5.17 g, 20.7 mmol) and zinc cyanide (1.46 g, 12.4 mmol) in nitrogen, nitrogen-dimethylacetamide (104 ml), and then purge the air with nitrogen, then add Palladium catalyst, Pd 2 (dba) 3 (1.90 g, 2.07 mmol), and ligand, 2-dicyclohexylphosphino-2'-(nitrogen, nitrogen-dimethylamine)-biphenyl (815 mg, 2.07 mmol) The reaction mixture was stirred at 110 ° C for 5 hours. It was then cooled to room temperature, diluted to ethyl acetate and filtered through Celite.
  • the synthetic route is as follows:
  • Step 1 To a solution of benzotriazole (47 g, 394.5 mmol) in MeOH (300 mL), EtOAc (EtOAc, EtOAc (EtOAc) Stir at room temperature for 16 hours. The mixture was removed under EtOAc (EtOAc) (EtOAc m. , yield 98.8%).
  • Step 3 To a solution of diisopropylamine (63.0 g, 629 mmol) in tetrahydrofuran (500 ml), a solution of n-butyllithium (2.5 M hexane, 231.5 ml, 576 mmol) was added dropwise at minus 70 ° C, and the mixture was warmed to below zero. Reaction at 10 degrees Celsius for 30 minutes. The system was then cooled to a solution of B3 (90 g, 262 mmol) in tetrahydrofuran (500 L). Stir for 30 minutes and gradually warm to room temperature and stir for an additional hour. The mixture was poured into aq. EtOAc (EtOAc) (EtOAc) The crude material was used in the next step without purification.
  • EtOAc EtOAc
  • Step 4 B4 (90 g, 302 mmol) was added to aq. After cooling to room temperature, the mixture was slowly poured into 8 mol of sodium hydroxide (1 L), extracted with ethyl acetate (1 L) three times, the organic phase was concentrated to 4-5 liters, and n-hexane (600 ml) was added to the mixture. It was stirred for 1 hour and filtered to give a white solid product B5 (34 g, 46.5%).
  • Step 7 Add to B7 (500 mg, 3.6 mmol) in 88% formic acid (941 mg, 18.0 mmol) at room temperature A solution of formaldehyde (584 mg, 7.2 mmol). The solution was stirred at 78 ° C for 30 minutes. The mixture is washed with aqueous sodium hydroxide to adjust the pH to The mixture was extracted with ethyl acetate (30 ml ⁇ 3). The organic phase was dried with EtOAc (EtOAc m.
  • the synthetic route is as follows:
  • Step 1 A6 (10 g, 51 mmol) and B8 (7.71 g, 51 mmol) were added dropwise to a solution of sodium hydride (4.85 g, 102 mmol) in nitrogen and nitrogen-dimethylacetamide (10 ml) under nitrogen at 50 °C. A solution of nitrogen, nitrogen-dimethylacetamide (30 ml). Stir at 0 ° C for 1 hour. The mixture was poured into a saturated solution of ammonium chloride and extracted with ethyl acetate. The organic phase was washed with EtOAc (EtOAcq. 71%).
  • Step 3 A mixture of A8 (4.4 g, 14.8 mmol) and a solution of nitrogen, nitrogen-dimethylformamide dimethyl acetal (8.8 g, 74 mmol) in toluene (50 ml) was stirred at 100 ° C under nitrogen. 20 hours.
  • the synthetic route is as follows:
  • the above method is a hydrate, has hygroscopicity, and undergoes crystal transformation during heating. It is difficult to make a solid preparation under drug processing conditions due to moisture absorption and heat instability. Therefore, there is a need to further prepare a preferred salt form of a quinazoline derivative having a superior physicochemical property and a crystal form of a salt, which can be advantageously used in pharmaceutical processing and pharmaceutical compositions.
  • hydrochloride salt Form H sample was weighed and heated to 125 ° C using DSC Q2000 and then cooled to room temperature to give the hydrochloride salt form I.
  • Example 22 Characterization of the crystalline form of the salt of the quinazoline derivative (I) of the present invention by XRPD pattern
  • the XRPD instrument information is as follows:
  • the XRPD pattern was acquired on a Bruker X-ray powder diffraction analyzer and the XRPD parameters are shown in Table 1.
  • the hydrochloride crystal form A of the quinazoline derivative (I) prepared according to the method of the present embodiment has an XRPD (X-ray powder diffraction) pattern as shown in Fig. 1, and is specifically characterized as shown in Table 2 below:
  • the hydrochloride salt form B of the quinazoline derivative (I) prepared according to the method described in the examples has an XRPD (X-ray powder diffraction) pattern as shown in Fig. 2, and is specifically characterized as shown in Table 3 below:
  • the hydrochloride salt form H of the quinazoline derivative (I) prepared according to the method described in the examples has an XRPD (X-ray powder diffraction) pattern as shown in Fig. 3, and is specifically characterized as shown in Table 4 below:
  • the hydrochloride salt form I of the quinazoline derivative (I) prepared according to the method described in the examples has an XRPD (X-ray powder diffraction) pattern as shown in Fig. 4, and is specifically characterized as shown in Table 5 below:
  • the fumarate crystal form A of the quinazoline derivative (I) prepared according to the method described in the examples has an XRPD (X-ray powder diffraction) pattern as shown in Fig. 5, and is specifically characterized as follows in Table 6:
  • the succinate crystal form A of the quinazoline derivative (I) prepared according to the method described in the examples has an XRPD (X-ray powder diffraction) pattern as shown in Fig. 6, and is specifically characterized as shown in Table 7 below:
  • the maleate salt form A of the quinazoline derivative (I) prepared according to the method described in the examples has an XRPD (X-ray powder diffraction) pattern as shown in Fig. 7, and is specifically characterized as shown in Table 8 below:
  • the glycolate crystal form A of the quinazoline derivative (I) prepared according to the method described in the examples has an XRPD (X-ray powder diffraction) pattern as shown in Fig. 8, and is specifically characterized as shown in Table 9 below:
  • hydrochloride salt form F of the quinazoline derivative (I) prepared according to the method described in the examples, and its XRPD (X-ray powder diffraction) pattern is shown in Fig. 9, and is specifically characterized as shown in Table 10 below:
  • the hydrochloride salt form C of the quinazoline derivative (I) prepared according to the method described in the examples has an XRPD (X-ray powder diffraction) pattern as shown in Fig. 10, and is specifically characterized as shown in Table 11 below:
  • hydrochloride salt form D of the quinazoline derivative (I) prepared according to the method described in the examples, and its XRPD (X-ray powder diffraction) pattern is shown in Fig. 11, and is specifically characterized as shown in Table 12 below:
  • the sulfate crystal form A of the quinazoline derivative (I) prepared according to the method described in the examples has an XRPD (X-ray powder diffraction) pattern as shown in Fig. 12, and is specifically characterized as shown in Table 13 below:
  • the oxalate salt form A of the quinazoline derivative (I) prepared according to the method described in the examples has an XRPD (X-ray powder diffraction) pattern as shown in Fig. 13, and is specifically characterized as shown in Table 14 below:
  • the malate salt form A of the quinazoline derivative (I) prepared according to the method described in the examples has an XRPD (X-ray powder diffraction) pattern as shown in Fig. 14, and is specifically characterized as shown in Table 15 below:
  • the benzenesulfonate crystal form A of the quinazoline derivative (I) prepared according to the method described in the examples has an XRPD (X-ray powder diffraction) pattern as shown in Fig. 15, and is specifically characterized as shown in Table 16:
  • the benzenesulfonate salt form B of the quinazoline derivative (I) prepared according to the method described in the examples has an XRPD (X-ray powder diffraction) pattern as shown in Fig. 16, and is specifically characterized as shown in Table 17 below:
  • the benzenesulfonate salt form C of the quinazoline derivative (I) prepared according to the method described in the examples has an XRPD (X-ray powder diffraction) pattern as shown in Fig. 17, and is specifically characterized as shown in Table 18 below:
  • the benzoate crystal form A of the quinazoline derivative (I) prepared according to the method described in the examples has an XRPD (X-ray powder diffraction) pattern as shown in Fig. 18, and is specifically characterized as shown in Table 19 below:
  • the horse urate crystal form A of the quinazoline derivative (I) prepared according to the method described in the examples has an XRPD (X-ray powder diffraction) pattern as shown in Fig. 19, and is specifically characterized as shown in Table 20 below:
  • the oxalate crystal form A of the quinazoline derivative (I) prepared according to the method described in the examples has an XRPD (X-ray powder diffraction) pattern as shown in Fig. 20, and is specifically characterized as follows in Table 21:
  • d is the interplanar spacing of two adjacent crystal faces in the crystal lattice, in units of angstroms, and I% is the intensity.
  • the 2 ⁇ value has an error range of ⁇ 0.2.
  • the error range is ⁇ 0.2.
  • the error range of the 2 ⁇ value may also be tested to be ⁇ 0.2. It will be understood by those skilled in the art that these diffraction peaks do not represent the hydrochloride crystal forms A, B, C, D, F of the quinazoline derivative (I), H, I, sulfate crystal form A, maleate salt form A, succinate crystal form A, adipate crystal form A, glycolate form A, malate form A, fumaric acid Detailed description of the diffraction peaks of salt crystal form A, benzsulfonate crystal form A, B, C, benzoate crystal form A, hippurate crystal form A and oxalate form A.
  • the 2 ⁇ values of the X-ray powder diffraction pattern can vary slightly with changes in the machine and sample preparation and variations between batches, and the values quoted are not considered absolute values. It should also be understood that the absolute intensity of the peaks may also vary with orientation effects, and thus the strengths shown herein are exemplary and are not intended for absolute comparison.
  • Cell viability assays of tumor cells and gliomas with EGFR activating mutations (exon 19 deletion of Exon 19 Del) protein were performed using CellTiter-Glo (CTG) assay; approximately 5000 cells were seeded in each blank 96-well plate After 16 hours, the diluted compound was added and after 72 hours of drug addition, it was equilibrated at room temperature for 30 minutes. 100 microliters of CellTiter-Glo reagent was added to each well and mixed by orbital shaker for 2 minutes to induce cell lysis. The plate was incubated for 10 minutes at room temperature to stabilize the luminescent signal. The illuminating signal was recorded on a TECAN Infinite M1000 Pro instrument.
  • the quinazoline derivative (I) of the present invention having the configuration of R has an unexpected activity of EGFRVIII mutation and is more than 100-fold more potent than the enantiomer. It has a similar biological activity as the EGFR Del19 activating mutation.
  • the test compound was administered to the rats. After 4 hours of administration, the rats were sacrificed, blood and brain tissues were collected, and the concentration of the test compound was analyzed. Brain penetration is defined as the ratio of the concentration of a compound in brain tissue to the concentration in plasma. Crossing the blood-brain barrier rate is the ratio of the free concentration of drug in the brain tissue to the free concentration of drug in the plasma.
  • P-glycoprotein is a blood-brain barrier efflux protein that excretes the P-glycoprotein substrate out of the brain.
  • the breast cancer resistance protein is the blood-brain barrier efflux protein, which discharges the breast cancer resistance protein out of the skull.
  • the ratio of the compound free concentration of the compound (I) in the brain tissue to the free concentration in plasma is higher than 50%, and is not a P-glycoprotein substrate or a breast cancer resistant Drug protein efflux substrates that cross the blood-brain barrier, so they have the potential to achieve effective blood levels in the brain for the treatment of glioma or for the treatment and prevention of cancer brain metastases, meningeal metastases, brain cancer and others.
  • Example 25 Quinazoline Derivative (I) for Brain Tumors with EGFRV3 Mutation in Primary Tumor Tissue of Subcutaneous Patient in Mice The efficacy of animal models of tumor transplantation
  • the patient's primary tumor tissue (brain tumor) was implanted subcutaneously in the mouse, and the tumor began to be administered after the tumor grew to about 150 cubic millimeters for three weeks.
  • the first group was a control group and did not contain any drug.
  • the second group of quinazoline derivatives (I) single agent 3 mg / kg, orally, twice a day
  • the third group of quinazoline derivatives (I) single agent 10 mg / kg, oral, two a day
  • the fourth group of quinazoline derivatives (I) single agent 20 mg / kg, orally, twice a day.
  • the drug group (second, third, and fourth groups) showed a good inhibition of tumor growth compared with the first group (control group), with statistically significant pharmacological effects, showing dose dependence in animal models.
  • RNA sequencing of the tumor revealed a mutation in EGFRV3, indicating that the quinazoline derivative (I) has good biological activity and efficacy against the EGFRV3 mutation.
  • the salt form of each of the quinazoline derivatives (I) of the present invention has a good equilibrium solubility in water, and preferably, the hydrochloride crystal of the quinazoline derivative (I) of the present invention
  • the equilibrium solubility of Form A, B, H, I and fumarate Form A in water is > 500 ug/mL. This is very beneficial for the absorption of the drug.
  • the salt form and crystal form of the physicochemically stable quinazoline derivative (I) of the present invention are stable in physical and chemical properties for one week at 25 ° C / 60% RH and 40 ° C / 75% RH.
  • the TGA pattern during heating showed no significant change in each of the crystal forms in Examples 2-21.
  • the DSC pattern showed that the fumarate crystal form A showed good stability.
  • the fumarate crystal form A showed no significant weight loss during heating and had a melting point of about 240 degrees Celsius. Such properties are advantageous for the preparation of processed tablets.
  • Example 28 The quinazoline derivative (I) of the present invention has good bioavailability
  • hydrochloride salt form B, H, I bioavailability > 60%
  • fumarate crystal form A bioavailability 80%
  • fumarate crystal form A bioavailability 80%, half life 7.4 hours.
  • the quinazoline derivative (I) of the present invention inhibits the mechanism of action of EGFR
  • EGFR enzyme is added from a concentration of 0.4 nM (2-fold) diluted 6 concentrations to 0.0125 nM and 0 concentration of 384-well plates.
  • the solution of PolyE4Y1 was incubated for 15 minutes.
  • the RLU signal was measured for 40 minutes by adding ADP-Glo reagent and detection reagent.
  • the quinazoline derivative (I) of the present invention exhibits an unexpected mechanism of non-ATP competition. The advantage of this mechanism of action is obvious.
  • the quinazoline derivative (I) of the present invention exhibits high activity and high selectivity, has small side effects, and is resistant to drug resistance.
  • the quinazoline derivative (I) of the present invention has a 6-substituted (3,3-difluoro-1-methylpiperidin-4-yl)oxy group which is a chiral R. At the same time, it has high activity, high selectivity, high blood-brain barrier permeation rate, non-external substrate, non-ATP competitive mechanism, and significant drug efficacy for non-small cell lung cancer and glioma. High bioavailability. It is emphasized that the quinazoline derivative (I) of the present invention has unexpected susceptibility to non-small cell lung cancer (mediated by an EGFR-activated form, particularly EGFR Del19 and/or EGFR L858R).
  • the non-competitive inhibitory properties of the quinazoline derivative (I) of the R of the present invention are highly active and highly selective, and are particularly active against gliomas.
  • the hydrochloride salt of the quinazoline derivative of the present invention has crystal forms A, B, C, D, F, H, I, sulfate crystal form A, maleate crystal form A, succinate crystal form A, Acid crystal form A, glycolate crystal form A, malate salt form A, fumarate crystal form A, besylate form A, B, C, benzoate crystal form A, equine
  • the salt form A and the oxalate crystal form A have higher solubility in water than the quinazoline derivative represented by formula (I), have better solubility, have no crystal form conversion during heating, and have good stability. .
  • the hydrochloride salt form of the quinazoline derivative of the present invention is A, B, C, D, F, H, I, sulfate crystal form A, maleate salt form A, succinate crystal form A, Diacid salt crystal form A, glycolate crystal form A, malate salt crystal form A, fumarate crystal form A, besylate salt form A, B, C, benzoate crystal form A, horse Urinate Form A and Oxalate Form A have unexpectedly superior physicochemical properties that facilitate use in pharmaceutical processing and pharmaceutical compositions.

Abstract

本发明公开了一种喹唑啉衍生物盐型晶型及制备方法和应用；具体为式(I)所示的喹唑啉衍生物的盐酸盐晶型A,B,C,D,F,H,I,硫酸盐晶型A,马来酸盐晶型A,琥珀酸盐晶型A,己二酸盐晶型A,乙醇酸盐晶型A,苹果酸盐晶型A,富马酸盐晶型A,苯磺酸盐晶型A,B,C,苯甲酸盐晶型A,马尿酸盐晶型A及草酸盐晶型A。本发明提供的盐型晶型具有良好的稳定性，可以在治疗非小细胞肺癌脑转移，脑膜转移，原发性脑癌或脑胶质瘤等的药物中应用，并且具有较好的生物利用度，对进一步研究此类固体药物的疗效具有重要意义。

Description

喹唑啉衍生物盐型晶型及制备方法和应用 技术领域
本发明涉及一种喹唑啉衍生物盐型及其晶型；具体涉及(R)-6-[(3,3-二氟-1-甲基哌啶-4-基)氧基]-氮-(3-乙炔基-2-氟苯基)-7-甲氧基喹唑啉-4-胺(I)的盐酸盐晶型A,B,C,D,F,H,I,硫酸盐晶型A,马来酸盐晶型A,琥珀酸盐晶型A,己二酸盐晶型A,乙醇酸盐晶型A,苹果酸盐晶型A,富马酸盐晶型A,苯磺酸盐晶型A,B,C,苯甲酸盐晶型A,马尿酸盐晶型A及草酸盐晶型A及其制备方法和应用。
背景技术
生物信号传导是指刺激或抑制信号发送到细胞内，通过一系列信号传输，使细胞内发生生物响应。许多信号传导途径及其生物反应已经进行了许多研究。在信号传导通路中出现的不同缺陷已发现是导致许多疾病的原因，包括多种形式的癌症，代谢障碍，炎性疾病，血管和神经元疾病。这些缺陷往往会发生在基因水平，例如DNA***，缺失或易位，在一些癌症中使细胞不受控制地增殖。
信号传导经常由被称为激酶的某些蛋白所介导。激酶通常可分为蛋白激酶和脂质激酶，和某些表现出双重特异性的激酶。蛋白激酶是催化其他蛋白质的磷酸化的酶和/或自身磷酸化，并且可以基于它们对底物的作用进行分类，例如：酪氨酸激酶指主要磷酸化酪氨酸残基(例如，Kit，EGFR,HER2，VEGFR,PDGFR，SRC和ABL等)，丝氨酸/苏氨酸激酶指主要磷酸化丝氨酸和/或苏氨酸残基(例如，mTORC1，mTORC2，ATM，ATR，Akt等)，和双特异性激酶磷酸化底物的酪氨酸，丝氨酸和/或苏氨酸残基。
表皮生长因子受体(EGFR)属于ErbB受体家族的跨膜蛋白酪氨酸激酶，包括表皮生长因子受体EGFR/ERBB1，HER2/ERBB2/NEU，HER3/ERBB3，和HER4/ERBB4。在与表皮生长因子(EGF)配体结合，诱导的EGFR受体与另一个EGFR受体或另一家族成员，例如，HER2/ERBB2/NEU，HER3/ERBB3，或HER4/ERBB4形成均聚物或异二聚体，导致EGFR酪氨酸激 酶活性的激活。激活的EGFR然后磷酸化其底物，从而导致在细胞内的多个的下游通路，包括Pl3K-AKT-mTOR途径(参与细胞存活的活化)，和RAS-RAF-MEK-ERK途径(涉及细胞增殖)。ErbB受体信号传导及其在肿瘤的参与，参见，例如，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。
脑胶质瘤是最常见的原发性颅脑肿瘤，占颅脑肿瘤的40-50％。脑胶质瘤患者约60％有肿瘤相关的EGFR突变。其中约70％突变是外显子2-7缺失EGFRV3(EGFRVIII)。这种突变增加EGFR的激酶活性，导致下游促存活信号传导途径的过度活化。EGFRV3(EGFRVIII)是表皮生长因子EGFR的外显子2-7的缺失基因并使突变体受体不能与任何已知的配体结合。EGFRV3突变在脑癌，脑胶质瘤，膀胱癌，乳腺癌，结直肠癌，食道癌，头颈鳞状细胞癌，肺癌，肺鳞癌，卵巢癌，***癌，脑干肿瘤等中表达。参见，Terrance G.Johns等，FEBS Journal 280(2013)5350–5370。
ErbB家族信号传导的解除抑制促进增殖，侵袭，转移，血管发生和肿瘤细胞存活，并已在许多人类癌症，包括肺，头和颈及***进行了描述，因此ErbB家族代表了抗癌药物发展的合理靶标，靶向EGFR或ErbB2的小分子药物，包括吉非替尼(Iressa易瑞沙 TM)，厄洛替尼(特罗凯 TM)，阿法替尼，泰瑞莎和拉帕替尼(TYKERB TM，TYVERB TM)已在非小细胞肺癌的临床上获得批准，特别的用于EGFR突变是外显子19(Exon 19 del)缺失或外显子21 L858R(Exon 21 L858R)突变。因EGFRVIII是EGFR外显子2-7的缺失基因并使突变体受体不能与任何已知的配体结合，与外显子19(Exon 19 del)缺失或外显子21 L858R(Exon 21 L858R)突变完全不同，现有的EGFR抑制剂对EGFRVIII无法有效抑制，对EGFRVIII的生物活性远低于对EGFR外显子19(Exon 19 del)缺失或外显子21 L858R(Exon 21 L858R)突变，活性常常降低10倍，甚至100倍以上，参见，例如，Paul S.Mischel et al,Molecular Cell，60,307–318，2015。同时，因血脑屏障(BBB)的存在，现有已批准的这些药物更加无法在颅内达到有效量。对于脑胶质瘤，放射治疗和外科手术辅以化疗药物(替莫挫胺)仍是治疗的主要手段，但治疗效果有限，总生存期约10个月。
因此，研发具有EGFRVIII突变的高生物活性同时具有穿过血脑屏障屏障用于治疗或预防用于EGFR所介导的脑胶质瘤特别有用。
众所周知，同一药物的不同晶型，盐型及盐的晶型，其稳定性，溶解度及生物利用度等 方面可能会存在明显差异，从而影响药物的疗效。因此，研发更有利于药物加工和药物组合物中使用的喹唑啉衍生物的新盐型及盐的新晶型，为固体药物的疗效及安全性研究提供更多的定性定量信息是非常有用的，具有重要意义。
发明内容
本发明所要解决的问题是针对现有EGFR抑制剂无法有效抑制EGFR活化突变EGFRVIII和有效穿过血脑屏障至颅内达到有效血药浓度的问题，以及本发明所述喹唑啉衍生物(R)-6-[(3,3-二氟-1-甲基哌啶-4-基)氧基]-氮-(3-乙炔基-2-氟苯基)-7-甲氧基喹唑啉-4-胺(I)的游离碱的性质不利于在药物加工和药物组合物中使用的问题，提供一种更有利于药物加工和药物组合物中使用的喹唑啉衍生物盐型晶型及制备方法和应用，为固体药物的疗效及安全性研究提供更多的定性定量信息。
本发明提供的喹唑啉衍生物具有针对EGFRVIII活化突变的生物活性，有效穿过血脑屏障。所述喹唑啉衍生物如式(I)所示：
Figure PCTCN2019079043-appb-000001
本发明的目的是通过以下技术方案来实现的：
本发明所采用的一个技术方案是提供一种手性为R的新型的喹唑啉衍生物(I)。
优选地，手性纯度ee>90％,更优选地，手性纯度ee>97％。
本发明所采用的一个技术方案是提供一种手性为R的新型的喹唑啉衍生物(I)具有EGFRVIII活化突变的生物活性。
本发明所采用的一个技术方案是提供一种手性为R的新型的喹唑啉衍生物(I)具有EGFRVIII活化突变的生物活性，同时具有高度的穿过血脑屏障能力。
本发明还提供了一种制备本发明所述喹唑啉衍生物(I)的合成方法。
本发明所采用的一个技术方案是提供一种喹唑啉衍生物的盐酸盐晶型A，其XRPD图谱在2θ
主要特征峰：6.5，13.1，9.4
次要特征峰：7.3，18.2，20.0
再次特征峰：27.5，26.6，21.6
处具有衍射峰，其中2θ值的误差范围为±0.2。
优选的，本发明提供的喹唑啉衍生物(I)的盐酸盐晶型A的XRPD图谱在2θ＝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处具有衍生峰，上述2θ值的误差范围为±0.2。
本发明所采用的另一技术方案是提供一种喹唑啉衍生物的盐酸盐晶型B，其XRPD图谱在2θ
主要特征峰：6.5，17.7，19.8
次要特征峰：7.3，8.2，10.5，13.2
处具有衍射峰，其中2θ值的误差范围为±0.2。
优选的，本发明提供的喹唑啉衍生物(I)的盐酸盐晶型B的XRPD图谱在2θ＝4.32，5.98，6.54，7.28，8.17，10.52，13.20，15.99，17.74，18.48，19.32，19.84，22.56，23.88，24.36，24.87，30.47，32.92，33.55，34.60，38.06，38.34处具有衍生峰，上述2θ值的误差范围为±0.2。
本发明所采用的另一技术方案是提供一种喹唑啉衍生物的盐酸盐晶型C，其XRPD图谱在2θ
主要特征峰：7.2，17.6，22.0
次要特征峰：14.0，13.6，12.8
再次特征峰：24.6，26.2，27.3
处具有衍射峰，其中2θ值的误差范围为±0.2。
优选的，本发明提供的喹唑啉衍生物(I)的盐酸盐晶型C的XRPD图谱在2θ＝5.66，7.16，8.32，8.86，9.52，10.98，11.63，12.80，13.57，13.96，14.81，15.14，15.49，16.55，16.86，17.61，22.04，22.93，24.55，26.19，27.30，28.49，34.12，34.76，35.65，36.68，37.31，37.80，38.20，38.53处具有衍生峰，上述2θ值的误差范围为±0.2。
本发明所采用的另一技术方案是提供一种喹唑啉衍生物的盐酸盐晶型D，其XRPD图谱在 2θ
主要特征峰：13.4，7.1，25.4
次要特征峰：6.7，18.0，19.8
再次特征峰：17.2，27.3，24.7
处具有衍射峰，其中2θ值的误差范围为±0.2。
优选的，本发明提供的喹唑啉衍生物(I)的盐酸盐晶型D的XRPD图谱在2θ＝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处具有衍生峰，上述2θ值的误差范围为±0.2。
本发明所采用的另一技术方案是提供一种喹唑啉衍生物的盐酸盐晶型F，其XRPD图谱在2θ
主要特征峰：6.8，20.5，13.6
次要特征峰：14.8，14.3，17.9，11.9
处具有衍射峰，其中2θ值的误差范围为±0.2。
优选的，本发明提供的喹唑啉衍生物(I)的盐酸盐晶型F的XRPD图谱在2θ＝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处具有衍生峰，上述2θ值的误差范围为±0.2。
本发明所采用的另一技术方案是提供一种喹唑啉衍生物的盐酸盐晶型H，其XRPD图谱在2θ
主要特征峰：7.3，18.0，14.1
次要特征峰：6.4，13.2，15.8
再次特征峰：16.8，14.5，20.3
处具有衍射峰，其中2θ值的误差范围为±0.2。
优选的，本发明提供的喹唑啉衍生物(I)的盐酸盐晶型H的XRPD图谱在2θ＝5.83，6.43，7.26，8.10，10.24，11.93，13.22，14.11，14.45，14.88，15.78，16.80，17.95，18.96，20.25，21.07，21.65，24.16，24.53，25.67，26.37，27.03，27.61处具有衍生峰，上述2θ值的误差范围为±0.2。
本发明所采用的另一技术方案是提供一种喹唑啉衍生物的盐酸盐晶型I，其XRPD图谱在2θ
主要特征峰：18.6，7.4，6.9
次要特征峰：13.2，25.1，12.3
再次特征峰：14.7，28.1，14.2
处具有衍射峰，其中2θ值的误差范围为±0.2。
优选的，本发明提供的喹唑啉衍生物(I)的盐酸盐晶型I的XRPD图谱在2θ＝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处具有衍生峰，上述2θ值的误差范围为±0.2。
本发明所采用的另一技术方案是提供一种喹唑啉衍生物的富马酸盐晶型A，其XRPD图谱在2θ
主要特征峰：6.5，17.8，9.4
次要特征峰：13.4，7.5，19.7
再次特征峰：14.6，18.5
处具有衍射峰，其中2θ值的误差范围为±0.2。
优选的，本发明提供的喹唑啉衍生物(I)的富马酸盐晶型A的XRPD图谱在2θ＝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处具有衍生峰，上述2θ值的误差范围为±0.2。
本发明所采用的另一技术方案是提供一种喹唑啉衍生物的琥珀酸盐晶型A，其XRPD图谱在2θ
主要特征峰：6.6，17.8，7.5
次要特征峰：9.4，20.3，18.5
再次特征峰：21.0，14.5，19.5
处具有衍射峰，其中2θ值的误差范围为±0.2。
优选的，本发明提供的喹唑啉衍生物(I)的琥珀酸盐晶型A的XRPD图谱在2θ＝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， 17.82，18.55，19.48，20.34，20.99，22.08，22.59，24.14，24.52，24.92，28.07，30.92，36.11处具有衍生峰，上述2θ值的误差范围为±0.2。
本发明所采用的另一技术方案是提供一种喹唑啉衍生物的马来酸盐晶型A，其XRPD图谱在2θ
主要特征峰：6.3，18.8，16.7
次要特征峰：25.2，21.2
处具有衍射峰，其中2θ值的误差范围为±0.2。
优选的，本发明提供的喹唑啉衍生物的马来酸盐晶型A的XRPD图谱在2θ＝6.25，8.44，8.68，9.42，10.41，14.42，14.88，16.65，17.93，18.78，20.58，21.17，22.63，25.16，31.15，32.40，33.66，34.34，34.52，35.82，36.06，36.35，36.91处具有衍生峰，上述2θ值的误差范围为±0.2。
本发明所采用的另一技术方案是提供一种喹唑啉衍生物的乙醇酸盐晶型A，其XRPD图谱在2θ
主要特征峰：6.6，7.4，17.9
次要特征峰：13.3
处具有衍射峰，其中2θ值的误差范围为±0.2。
优选的，本发明提供的喹唑啉衍生物的乙醇酸盐晶型A的XRPD图谱在2θ＝4.53，5.89，6.59，7.35，10.02，12.54，13.26，15.94，17.93，18.67，19.36，19.84，21.06，24.99，31.13，33.48，34.79，35.56，36.17处具有衍生峰，上述2θ值的误差范围为±0.2。
本发明所采用的另一技术方案是提供一种喹唑啉衍生物的硫酸盐晶型A，其XRPD图谱在2θ
主要特征峰：7.3，18.2，15.0
处具有衍射峰，其中2θ值的误差范围为±0.2。
优选的，本发明提供的喹唑啉衍生物(I)的硫酸晶型A的XRPD图谱在2θ＝7.27，8.41，11.88，14.96，18.23，19.68，20.64，24.83，25.82，27.10，28.16，29.79，30.71，32.35，34.12，35.56，37.56，38.37处具有衍生峰，上述2θ值的误差范围为±0.2。
本发明所采用的另一技术方案是提供一种喹唑啉衍生物的乙二酸盐晶型A，其XRPD图谱在2θ
主要特征峰：6.9，15.1，13.7
次要特征峰：15.4，9.6，19.0
再次特征峰：20.6，27.3，23.4
处具有衍射峰，其中2θ值的误差范围为±0.2。
优选的，本发明提供的喹唑啉衍生物(I)的乙二酸盐晶型A的XRPD图谱在2θ＝5.43，6.88，7.38，9.56，13.68，15.10，15.43，16.32，16.88，17.68，18.60，19.02，20.58，21.62，22.33，22.70，23.35，25.68，27.29，27.88，28.53，29.37，31.35，34.89，37.11，37.78，38.17，38.36，39.65处具有衍生峰，上述2θ值的误差范围为±0.2。
本发明所采用的另一技术方案是提供一种喹唑啉衍生物的苹果酸盐晶型A，其XRPD图谱在2θ
主要特征峰：6.5，18.8，19.9
次要特征峰：7.5，8.4，9.2
处具有衍射峰，其中2θ值的误差范围为±0.2。
本发明提供的喹唑啉衍生物(I)的苹果酸盐晶型A的XRPD图谱在2θ＝5.43，6.53，7.49，8.35，9.17，12.10，13.16，16.17，18.77，19.85，20.79，23.14，23.94，26.66，28.25，29.32，30.38，33.24，33.69，34.80，35.97，36.87，37.88处具有衍生峰，上述2θ值的误差范围为±0.2。
本发明所采用的另一技术方案是提供一种喹唑啉衍生物的苯磺酸盐晶型A，其XRPD图谱在2θ
主要特征峰：6.6，14.0，15.3
次要特征峰：7.1，5.5，19.7
再次特征峰：17.8，16.9，21.0
处具有衍射峰，其中2θ值的误差范围为±0.2。
本发明提供的喹唑啉衍生物的苯磺酸盐晶型A的XRPD图谱在2θ＝5.48，6.56，7.08，7.65，8.14，8.48，9.71，10.55，11.14，11.77，13.32，13.95，15.32，16.46，16.89，17.82，19.15，19.70，20.43，21.02，21.98，22.68，23.23，25.26，26.07，26.59，28.63，29.09，30.45，31.12，32.09，32.55，33.66，35.76，37.86，38.67，39.11处具有衍生峰，上述2θ值的误差范围为±0.2。
本发明所采用的另一技术方案是提供一种喹唑啉衍生物的苯磺酸盐晶型B，其XRPD图谱在2θ
主要特征峰：8.5，14.5，23.4
次要特征峰：18.3，19.7
处具有衍射峰，其中2θ值的误差范围为±0.2。
本发明提供的喹唑啉衍生物的苯磺酸盐晶型B的XRPD图谱在2θ＝5.50，6.32，7.28，8.50，9.74，10.79，11.55，13.22，14.49，15.53，16.26，16.97，18.29，19.71，21.36，22.21，23.44，24.19，25.34，25.87，27.16处具有衍生峰，上述2θ值的误差范围为±0.2。
本发明所采用的另一技术方案是提供一种喹唑啉衍生物的苯磺酸盐晶型C，其XRPD图谱在2θ
主要特征峰：14.0，14.7，7.7
次要特征峰：8.3，21.2，19.4，
再次特征峰：27.5，24.7
处具有衍射峰，其中2θ值的误差范围为±0.2。
优选的，本发明提供的喹唑啉衍生物(I)的苯磺酸盐晶型C的XRPD图谱在2θ＝4.24，7.07，7.68，8.31，9.92，12.55，14.03，14.74，18.72，19.40，20.36，21.19，24.08，24.73，26.14，27.49，28.28，31.68，33.90，34.82，35.06，35.78，36.54，37.57，37.89，38.36，39.0处具有衍生峰，上述2θ值的误差范围为±0.2。
本发明所采用的另一技术方案是提供一种喹唑啉衍生物的苯甲酸盐晶型A，其XRPD图谱在2θ
主要特征峰：7.3，6.3，16.8
次要特征峰：13.5，18.7，27.0
处具有衍射峰，其中2θ值的误差范围为±0.2。
本发明提供的喹唑啉衍生物(I)的苯甲酸盐晶型A的XRPD图谱在2θ＝4.45，6.31，6.65，7.33，7.69，8.01，11.85，13.53，16.02，16.77，18.75，19.95，21.06，21.76，22.56，23.41，26.94，27.44，27.61，27.98，28.55，29.05，31.92，32.29，32.93，33.72，34.61，35.35，35.95，37.08，38.13，39.62处具有衍生峰，上述2θ值的误差范围为±0.2。
本发明所采用的另一技术方案是提供一种喹唑啉衍生物的马尿酸盐晶型A，其XRPD图谱 在2θ
主要特征峰：5.6，6.9，20.0
次要特征峰：16.0，7.7，13.7
再次特征峰：24.3，26.4
处具有衍射峰，其中2θ值的误差范围为±0.2。
优选的，本发明提供的喹唑啉衍生物(I)的马尿酸盐晶型A的XRPD图谱在2θ＝4.35，5.59，6.85，7.74，9.17，9.95，13.74，14.73，15.96，16.44，18.10，18.63，19.96，21.38，24.25，25.37，25.72，26.39，27.23，28.56，30.25，30.82，33.31，34.58，35.29，36.39，37.24，37.9处具有衍生峰，上述2θ值的误差范围为±0.2。
本发明所采用的另一技术方案是提供一种喹唑啉衍生物的草酸盐晶型A，其XRPD图谱在2θ
主要特征峰：6.4，9.1，17.5
次要特征峰：12.9，14.5，26.4
再次特征峰：19.4，18.3，15.9
处具有衍射峰，其中2θ值的误差范围为±0.2。
优选的，本发明提供的喹唑啉衍生物(I)的草酸盐晶型A的XRPD图谱在2θ＝4.11，6.44，7.15，8.75，9.06，9.88，11.26，11.58，12.92，14.52，15.87，17.47，18.29，19.43，20.14，20.49，23.70，24.34，26.36，26.92，29.75，31.72，32.67，32.99，34.21，34.52，34.86，36.36，36.91，37.91，39.03处具有衍生峰，上述2θ值的误差范围为±0.2。
优选的，本发明所述喹唑啉衍生物的盐酸盐晶型A具有基本如附图1所示的XRPD图谱。
优选的，本发明所述喹唑啉衍生物的盐酸盐晶型B具有基本如附图2所示的XRPD图谱。
优选的，本发明所述喹唑啉衍生物的盐酸盐晶型C具有基本如附图10所示的XRPD图谱。
优选的，本发明所述喹唑啉衍生物的盐酸盐晶型D具有基本如附图11所示的XRPD图谱。
优选的，本发明所述喹唑啉衍生物的盐酸盐晶型F具有基本如附图9所示的XRPD图谱。
优选的，本发明所述喹唑啉衍生物的盐酸盐晶型H具有基本如附图3所示的XRPD图谱。
优选的，本发明所述喹唑啉衍生物的盐酸盐晶型I具有基本如附图4所示的XRPD图谱。
优选的，本发明所述喹唑啉衍生物的富马酸盐晶型A具有基本如附图5所示的XRPD图谱。
优选的，本发明所述喹唑啉衍生物的琥珀酸盐晶型A具有基本如附图6所示的XRPD图谱。
优选的，本发明所述喹唑啉衍生物的马来酸盐晶型A具有基本如附图7所示的XRPD图谱。
优选的，本发明所述喹唑啉衍生物的乙醇酸盐晶型A具有基本如附图8所示的XRPD图谱。
优选的，本发明所述喹唑啉衍生物的硫酸盐晶型A具有基本如附图12所示的XRPD图谱。
优选的，本发明所述喹唑啉衍生物的乙二酸盐晶型A具有基本如附图13所示的XRPD图谱。
优选的，本发明所述喹唑啉衍生物的苹果酸盐晶型A具有基本如附图14所示的XRPD图谱。
优选的，本发明所述喹唑啉衍生物的苯磺酸盐晶型A具有基本如附图15所示的XRPD图谱。
优选的，本发明所述喹唑啉衍生物的苯磺酸盐晶型B具有基本如附图16所示的XRPD图谱。
优选的，本发明所述喹唑啉衍生物的苯磺酸盐晶型C具有基本如附图17所示的XRPD图谱。
优选的，本发明所述喹唑啉衍生物的苯甲酸盐晶型A具有基本如附图18所示的XRPD图谱。
优选的，本发明所述喹唑啉衍生物的马尿酸盐晶型A具有基本如附图19所示的XRPD图谱。
优选的，本发明所述喹唑啉衍生物的草酸盐晶型I具有基本如附图20所示的XRPD图谱。
本发明还提供了一种制备本发明所述喹唑啉衍生物(I)的盐酸盐晶型A的方法，包括以下步骤：将有机溶剂和盐酸0.8～1.2当量加入式(I)所示喹唑啉衍生物样品在22-28摄氏度下搅拌后离心分离出下层固体得到晶型A；其中，每毫升有机溶剂加入式(I)所示喹唑啉衍生物10～200毫克。
本发明还提供了一种制备本发明所述喹唑啉衍生物(I)的盐酸盐晶型B的方法，包括以下步骤：将式(I)所示喹唑啉衍生物加入有机溶剂中，并向该悬浮液加入0.8～1.2当量盐酸 在22-28摄氏度下搅拌，离心分离出下层湿样固体得到晶型B；其中，每毫升有机溶剂加入式(I)所示喹唑啉衍生物10～200毫克。
本发明还提供了一种制备本发明所述喹唑啉衍生物(I)的盐酸盐晶型C的方法，包括以下步骤：将式(I)所示喹唑啉衍生物样品加入有机溶剂并加入盐酸2～2.5当量在22-28摄氏度下搅拌后离心分离出下层湿样固体得二盐酸盐晶型C；其中，每毫升有机溶剂中加入式(I)所示喹唑啉衍生物10～200毫克。
本发明还提供了一种制备本发明所述喹唑啉衍生物(I)的盐酸盐晶型D的方法，包括以下步骤：将盐酸盐晶型C样品加热至高温后冷却至22-28摄氏度，得到二盐酸盐晶型D。
本发明还提供了一种制备本发明所述喹唑啉衍生物(I)的盐酸盐晶型F的方法，包括以下步骤：将将式(I)所示喹唑啉衍生物盐酸盐晶型B加入醇类和酯类有机溶剂，于22-28摄氏度下气液扩散，直至有固体析出得晶型F；其中，每毫升有机溶剂中加入式(I)所示盐酸盐晶型B 10～200毫克。
本发明还提供了一种制备本发明所述喹唑啉衍生物(I)的盐酸盐晶型H的方法，包括以下步骤：在盐酸盐晶型B中加入有机溶剂，过滤后于22-28摄氏度下(敞口快速)挥发得晶型H；其中，每毫升有机溶剂中加入式(I)所示盐酸盐晶型B 10～200毫克。
本发明还提供了一种制备本发明所述喹唑啉衍生物(I)的盐酸盐晶型I的方法，包括以下步骤：加热盐酸盐晶型H样品至高温后降温至22-28摄氏度。
本发明还提供了一种制备本发明所述喹唑啉衍生物(I)的富马酸盐晶型A的方法，包括以下步骤：在式(I)所示喹唑啉衍生物和0.4-0.6当量富马酸加入有机溶剂后，在22-28摄氏度下搅拌，离心收集固体；其中，每毫升有机溶剂中加入式(I)所示喹唑啉衍生物10～200毫克。
本发明还提供了一种制备本发明所述喹唑啉衍生物(I)的琥珀酸盐晶型A的方法，包括以下步骤：在式(I)所示喹唑啉衍生物和0.8-1.2当量琥珀酸加入有机溶剂后，在22-28摄氏度下搅拌，离心收集固体得所述晶型；其中，每毫升有机溶剂中加入式(I)所示喹唑啉衍生物10～200毫克。
本发明还提供了一种制备本发明所述喹唑啉衍生物(I)的马来酸盐晶型A的方法，包括以下步骤：在式(I)所示喹唑啉衍生物和马来酸加入有机溶剂后，在22-28摄氏度下搅拌，离 心收集固体得所述晶型；其中，每毫升有机溶剂中加入式(I)所示喹唑啉衍生物10～200毫克。
本发明还提供了一种制备本发明所述喹唑啉衍生物(I)的乙醇酸盐晶型A的方法，包括以下步骤：在式(I)所示喹唑啉衍生物和0.8-1.2当量乙醇酸加入有机溶剂后，在室温下搅拌，离心收集固体。
本发明还提供了一种制备本发明所述喹唑啉衍生物(I)的硫酸盐晶型A的方法，包括以下步骤：将式(I)所示喹唑啉衍生物样品加入有机溶剂和0.8-1.2当量硫酸水溶液在22-28摄氏度下搅拌，离心收集固体得所述晶型；其中，每毫升有机溶剂中加入式(I)所示喹唑啉衍生物10～200毫克。
本发明还提供了一种制备本发明所述喹唑啉衍生物(I)的乙二酸盐晶型A的方法，包括以下步骤：将式(I)所示喹唑啉衍生物样品加入有机溶剂和0.8-1.2当量乙二酸在22-28摄氏度下搅拌，离心收集固体得所述晶型；其中，每毫升有机溶剂中加入式(I)所示喹唑啉衍生物10～200毫克。
本发明还提供了一种制备本发明所述喹唑啉衍生物(I)的苹果酸盐晶型A的方法，包括以下步骤：将式(I)所示喹唑啉衍生物样品加入有机溶剂和0.8-1.2当量苹果酸在22-28摄氏度下搅拌，离心收集固体得所述晶型；其中，每毫升有机溶剂中加入式(I)所示喹唑啉衍生物10～200毫克。
本发明还提供了一种制备本发明所述喹唑啉衍生物(I)的苯磺酸盐晶型A的方法，包括以下步骤：将式(I)所示喹唑啉衍生物样品加入有机溶剂和0.8-1.2当量苯磺酸在22-28摄氏度下搅拌，离心收集固体得所述晶型；其中，每毫升有机溶剂中加入式(I)所示喹唑啉衍生物10～200毫克。
本发明还提供了一种制备本发明所述喹唑啉衍生物(I)的苯磺酸盐晶型B的方法，包括以下步骤：将式(I)所示喹唑啉衍生物样品加入有机溶剂和0.8-1.2当量苯磺酸在22-28摄氏度下搅拌，离心收集固体得所述晶型；其中，每毫升有机溶剂中加入式(I)所示喹唑啉衍生物10～200毫克。
本发明还提供了一种制备本发明所述喹唑啉衍生物(I)的苯磺酸盐晶型C的方法，包括以下步骤：将式(I)所示喹唑啉衍生物样品加入有机溶剂和0.8-1.2当量苯磺酸在22-28摄氏度 下搅拌，离心收集固体得所述晶型；其中，每毫升有机溶剂中加入式(I)所示喹唑啉衍生物10～200毫克。
本发明还提供了一种制备本发明所述喹唑啉衍生物(I)的苯甲酸盐晶型A的方法，包括以下步骤：将式(I)所示喹唑啉衍生物样品加入有机溶剂和0.8-1.2当量苯甲酸在22-28摄氏度下搅拌，离心收集固体得所述晶型；其中，每毫升有机溶剂中加入式(I)所示喹唑啉衍生物10～200毫克。
本发明还提供了一种制备本发明所述喹唑啉衍生物(I)的马尿酸盐晶型A的方法，包括以下步骤：将式(I)所示喹唑啉衍生物样品加入有机溶剂和0.8-1.2当量马尿酸在22-28摄氏度下搅拌，离心收集固体得所述晶型；其中，每毫升有机溶剂中加入式(I)所示喹唑啉衍生物10～200毫克。
本发明还提供了一种制备本发明所述喹唑啉衍生物(I)的草酸盐晶型A的方法，包括以下步骤：将式(I)所示喹唑啉衍生物样品加入有机溶剂和0.8-1.2当量草酸在22-28摄氏度下搅拌，离心收集固体得所述晶型；其中，每毫升有机溶剂中加入式(I)所示喹唑啉衍生物10～200毫克。
在上述方法中，优选的，所述有机溶剂为醇类、醚类、酯类、脂肪烃类、芳香烃类有机溶剂中的一种或几种。
更优选的，所述醇类有机溶剂为甲醇、乙醇、异丙醇、正丙醇、异丁醇、正丁醇中的一种或几种。
更优选的，所述醚类有机溶剂为***、异丙醚或甲基叔丁基醚。
更优选的，所述酯类有机溶剂为乙酸乙酯、乙酸丁酯或乙酸异丙酯。
更优选的，所述酮类有机溶剂为丙酮、丁酮或4-甲基-2-戊酮。
更优选的，所述脂肪烃类有机溶剂为正庚烷或乙腈。
更优选的，所述芳香烃类有机溶剂为甲苯。
进一步优选的，所述喹唑啉衍生物(I)的盐酸盐晶型A的制备方法，优选地有机溶剂为甲醇。
所述喹唑啉衍生物(I)的盐酸盐晶型B的制备方法，优选地有机溶剂为乙腈、乙酸乙酯或四氢呋喃/水(15-20/1,v/v)。
所述喹唑啉衍生物(I)的盐酸盐晶型C的制备方法，优选地有机溶剂为丙酮。
所述喹唑啉衍生物(I)的盐酸盐晶型D的制备方法，优选地高温的温度范围120-160摄氏度。
所述喹唑啉衍生物(I)的盐酸盐晶型F的制备方法，优选地醇类为甲醇，酯类为乙酸异丙酯。更优选甲醇、乙酸乙酯的重量比为1:1。
所述喹唑啉衍生物(I)的盐酸盐晶型H的的制备方法中优选地有机溶剂为乙醇。
所述喹唑啉衍生物(I)的盐酸盐晶型I的制备方法，优选地高温温度为120-130摄氏度。
所述喹唑啉衍生物(I)的富马酸盐晶型A的制备方法，优选地有机溶剂为甲醇、丙酮、乙酸乙酯或体积比为15-20：1的四氢呋喃/水混合液。
所述喹唑啉衍生物(I)的琥珀酸盐晶型A的制备方法，优选地有机溶剂为甲醇或丙酮。
所述喹唑啉衍生物(I)的马来酸盐晶型A的制备方法，优选地有机溶剂为丙酮。
所述喹唑啉衍生物(I)的乙醇酸盐晶型A的制备方法，优选地有机溶剂为甲醇、乙腈或乙酸乙酯。
所述喹唑啉衍生物(I)的硫酸盐晶型A的制备方法，优选地有机溶剂为甲醇、乙腈、丙酮、乙酸乙酯或体积比为15-20：1的四氢呋喃/水混合液。
所述喹唑啉衍生物(I)的乙二酸盐晶型A的制备方法，优选地有机溶剂为甲醇或乙酸乙酯。
所述喹唑啉衍生物(I)的苹果酸盐晶型A的制备方法，优选地有机溶剂为甲醇、乙酸乙酯或体积比为15-20：1的四氢呋喃/水混合液。
所述喹唑啉衍生物(I)的苯磺酸盐晶型A的制备方法，优选地有机溶剂为甲醇。
所述喹唑啉衍生物(I)的苯磺酸盐晶型B的制备方法，优选地有机溶剂为乙腈。
所述喹唑啉衍生物(I)的苯磺酸盐晶型C的制备方法，优选地有机溶剂为四氢呋喃和水的混合溶剂(体积比为15-20：1，更优选为19:1)。
所述喹唑啉衍生物(I)的苯甲酸盐晶型A的制备方法，优选地有机溶剂为甲醇、乙腈、丙酮或体积比为15-20：1的四氢呋喃/水混合液。
所述喹唑啉衍生物(I)的马尿酸盐晶型A的制备方法，优选地有机溶剂为甲醇。
所述喹唑啉衍生物(I)的草酸盐晶型A的制备方法，优选地有机溶剂为甲醇。
本发明还提供了一种药物组合物，所述组合物包括式(I)所示的喹唑啉衍生物的盐酸盐晶型A,B,C,D,F,H,I,硫酸盐晶型A,马来酸盐晶型A,琥珀酸盐晶型A,己二酸盐晶型A,乙醇 酸盐晶型A,苹果酸盐晶型A,富马酸盐晶型A,苯磺酸盐晶型A,B,C,苯甲酸盐晶型A,马尿酸盐晶型A及草酸盐晶型A或它们的组合，以及药学上可接受的辅料或辅助性成分。
优选的，所述辅料或辅助性成份包括载体、赋形剂、稀释剂、媒介物、辅剂。
本发明还提供了一种式(I)所示的喹唑啉衍生物的盐酸盐晶型A,B,C,D,F,H,I,硫酸盐晶型A,马来酸盐晶型A,琥珀酸盐晶型A,己二酸盐晶型A,乙醇酸盐晶型A,苹果酸盐晶型A,富马酸盐晶型A,苯磺酸盐晶型A,B,C,苯甲酸盐晶型A,马尿酸盐晶型A及草酸盐晶型A或上述的药物组合物在制备治疗或预防由表皮生长因子受体EGFR蛋白介导的疾病的药物中的用途。
优选的，所述药物为治疗或预防由表皮生长因子受体EGFR蛋白介导，且是EGFRVIII活化突变所导致的疾病的药物。
所述药物为治疗或预防由表皮生长因子受体EGFR蛋白介导，且是EGFR Del19和/或EGFR L858R活化突变所导致的的疾病的药物。
更优选的，所述药物为制备治疗或预防非小细胞肺癌脑转移，脑膜转移，头颈部鳞状细胞癌，鳞状细胞癌，脑干肿瘤，原发性脑癌或脑胶质瘤的药物。
本领域普通技术人员可以根据其知识和经验，对本发明所用试剂的用量和方法进行调整，包括按照比例放大或缩小原料或溶剂用量，这些调整的方案也包含在本发明的方法中。
与现有技术相比，本发明具有如下有益效果：
1)本发明的新型的手性为R的喹唑啉衍生物(I)及其药学盐具有预料之外的具有穿过血脑屏障的能力，并能作为蛋白激酶抑制剂的药物特性，尤其是针对通过表皮生长因子受体的某些活化突变形式介导的医疗状况(例如，表皮生长受体EGFR外显子2-7缺失活化突变体)，例如，具有EGFRVIII突变的脑胶质瘤，并且可用于治疗或预防异常蛋白激酶活性相关的紊乱，例如癌症、癌症脑转移，癌症脑膜转移和神经中枢疾病等。
2)本发明的喹唑啉衍生物(I)及其药学盐具有低流出率，不是P-糖蛋白外排酶底物，或乳腺癌耐药外排酶底物，可降低因外排酶产生的耐药。
3)本发明的喹唑啉衍生物及其药学盐具有良好的药代动力学和高生物活性，可降低病人的药片摄入负担，提高病人的药片摄入依从性。
4)本发明提供的本发明喹唑啉衍生物(I)的盐酸盐晶型A,B,C,D,F,H,I,硫酸盐晶型A,马来酸盐晶型A,琥珀酸盐晶型A,己二酸盐晶型A,乙醇酸盐晶型A,苹果酸盐晶型A,富马酸盐晶型A,苯磺酸盐晶型A,B,C,苯甲酸盐晶型A,马尿酸盐晶型A及草酸盐晶型A具有良好的 稳定性和水溶解度，有利于在药物加工和药物组合物中使用，可以治疗由EGFR活化突变(例如，EGFRVIII，EGFR del19或EGFR L858R)所介导的癌症,例如，非小细胞肺癌脑转移，脑膜转移，头颈部鳞状细胞癌，鳞状细胞癌，脑干肿瘤，原发性脑癌或脑胶质瘤等的应用，并且具有较好的生物利用度，同时提供疗效和安全性的定性定量信息，对进一步研究此类固体药物的疗效具有重要的意义。
附图说明
通过阅读参照以下附图对非限制性实施例所作的详细描述，本发明的其它特征、目的和优点将会变得更明显：
图1为本发明的喹唑啉衍生物的盐酸盐晶型A的XRPD图谱；
图2为本发明的喹唑啉衍生物的盐酸盐晶型B的XRPD图谱；
图3为本发明的喹唑啉衍生物的盐酸盐晶型H的XRPD图谱；
图4为本发明的喹唑啉衍生物的盐酸盐晶型I的XRPD图谱；
图5为本发明的喹唑啉衍生物的富马酸盐晶型A的XRPD图谱；
图6为本发明的喹唑啉衍生物的琥珀酸盐晶型A的XRPD图谱；
图7为本发明的喹唑啉衍生物的马来酸盐晶型A的XRPD图谱；
图8为本发明的喹唑啉衍生物的乙醇酸盐晶型A的XRPD图谱；
图9为本发明的喹唑啉衍生物的盐酸盐晶型F的XRPD图谱；
图10为本发明的喹唑啉衍生物的盐酸盐晶型C的XRPD图谱；
图11为本发明的喹唑啉衍生物的盐酸盐晶型D的XRPD图谱；
图12为本发明的喹唑啉衍生物的硫酸盐晶型A的XRPD图谱；
图13为本发明的喹唑啉衍生物的乙二酸盐晶型A的XRPD图谱；
图14为本发明的喹唑啉衍生物的苹果酸盐晶型A的XRPD图谱；
图15为本发明的喹唑啉衍生物的苯磺酸盐晶型A的XRPD图谱；
图16为本发明的喹唑啉衍生物的苯磺酸盐晶型B的XRPD图谱；
图17为本发明的喹唑啉衍生物的苯磺酸盐晶型C的XRPD图谱；
图18为本发明的喹唑啉衍生物的苯甲酸盐晶型A的XRPD图谱；
图19为本发明的喹唑啉衍生物的马尿酸盐晶型A的XRPD图谱；
图20为本发明的喹唑啉衍生物的草酸盐晶型A的XRPD图谱；
图21为本发明的喹唑啉衍生物对EGFRVIII磷酸化的抑制示意图；
图22为本发明的喹唑啉衍生物在人源化脑胶质瘤小鼠皮下模型的药效研究示意图；
图23为本发明的喹唑啉衍生物富马酸盐的TGA和DSC图谱；其中，a为TGA图谱，无明显失重；b为DSC图谱，晶型在加热过程中稳定，晶型未发生转变，熔点为240摄氏度；
图24为本发明的喹唑啉衍生物与EGFR的抑制机理示意图。
具体实施方式
本发明涉及的术语解释如下：
术语“改善”和“治疗”可以互换使用，均表示减少、减弱、抑制、减小、阻止或稳定疾病的发生或进展(例如，本文所描述的疾病或紊乱)，是指一种方法用于获得包括有益的或期望的结果，但不限于治疗益处和/或预防性益处。
“疾病”是指损害或干扰细胞、器官或组织的正常功能的任何病症或紊乱。
“标志物”是指与疾病或紊乱相关的任何改变。例如，与疾病或紊乱相关的表达水平或活性有改变的任何蛋白或多核酐酸。
在本文中，“包括”、“含有”和“具有”和类似术语具有专利法中所赋予它们的含义；“基本上由…组成”或“基本上包括”同样具有专利法所赋予它们的含义，并且该术语是开放式的，允许所引用物以外的对象的存在，只要被引用物的基础或新的特征不因所引用物以外的对象的存在而改变，但不包括现有技术的实施方式。
如本文所使用的术语“拮抗剂”和“抑制剂”可互换使用，它们是指化合物或试剂具有抑制靶向蛋白或多肽的生物学功能的能力，例如通过抑制蛋白质或多肽的活性或表达。虽然本文一些拮抗剂与具体的靶蛋白或多肽作用(例如，结合EGFR)，化合物通过与其他的靶向蛋白质或多肽的信号传导途径的其它成员相互作用而抑制靶蛋白或多肽的生物活性也明确包括该定义内，也包括抑制与发育，生长，或扩散的肿瘤，或在自身免疫疾病表现出的不希望的免疫应答相关的那些生物活性。
如本文所使用的术语“抗癌剂”，“抗肿瘤剂”或“化疗剂”是指在肿瘤病症治疗中有用的任何试剂。一类抗癌剂包括化疗剂。“化疗”是指一种或多种化疗药物和/或其它试剂以通过各种方法，包括静脉内，口服，皮下，肌内，腹膜内，膀胱内，经皮，颊，或吸入的形式给癌症患者施用。
如本文所使用的术语“细胞增殖”是指由细胞数目作为细胞***的结果发生增加的现象，也包括与增殖信号一致的由该细胞形态改变的细胞生长(例如，尺寸增加)。
如本文所使用的术语“共同施用”，是指在同一时间单独使用两种或多种药物，也包括在在同一时间使用两种或多种试剂都存在的组合物，也包括在不同的时间单独给药或施用两种或多种药物和/或其代谢物。
如本文所使用的术语“有效量”或“有效治疗量”是指本文所述的化合物或药物组合物的量是足以达到预期的应用，包括，但不限于治疗疾病。在一些实施方案中，所述量是检测到的有效用于杀伤或抑制癌细胞生长或扩散；肿瘤的大小或数量；或癌症的严重性水平，阶段和进展。有效治疗量可以根据预定应用发生变化，例如体外或者体内，疾病的状况和严重程度，受试者年龄，重量，或给药方式等。该术语也适用于剂量将诱导靶细胞，例如，减少细胞迁移的一个特定的响应。具体剂量将取决于，例如，特定的化合物中选取，受试者物种和他们的年龄/现有的健康状况或健康状况的风险，给药途径，疾病的严重程度，与其他药剂组合给药，给药时间，给其施用的组织，和给药装置等。
如本文所使用的术语“治疗效果”，包括治疗益处和/或预防益处。预防效果包括延迟或消除疾病或病症的出现，延迟或消除疾病或病症的症状发作，减缓，停止或逆转疾病或病症，或它们的任意组合的进展。
如本文所使用的术语“信号传导”是在此期间，刺激或抑制信号被发送到细胞内以引发细胞内响应的过程，信号转导途径的“调节剂”是指化合物调节一种或多种细胞蛋白质的活性通过特定信号转导途径。“调节剂”可以增加(激动剂)或抑制(拮抗剂)信号传导分子的活性。
如本文所使用的术语“选择性抑制”是指化合物可以选择性地降低目标信号传导活性的能力相比对于脱靶信号活性，通过直接相互作用或间接相互作用等。例如，一个化合物选择性抑制突变的EGFR的活性是针对野生型EGFR的活性至少约2倍，约3倍，约5倍，约10倍，约20倍，约50倍，约100倍或更多。
如本文所使用的术语“放射治疗”是指受试者暴露于辐射发射器，例如,但不限于，α-粒子发射放射性核元素(例如，锕和钍放射性核元素)，低线性能量转移(LET)辐射发射器(即，β发射体)，转换电子发射器(例如，锶-89和钐153-EDTMP)，或高能辐射，包括，但不限于X射线，γ射线和中子。
如本文使用的术语“受试者”包括，但不限于，人类(即，任何年龄组，例如，一个儿科受试者的男性或女性(例如，婴儿，儿童，青少年)或成人受试者(例如，年轻成年，中年成人或高级成人))和/或其它灵长类动物(例如，食蟹猴，恒河猴)；哺乳动物，包括商业相关哺乳动物，例如牛，绵羊，山羊，猪，马，猫和/或狗；和/或鸟类，包括商业相关的鸟类，如鸡，鹅，鹌鹑，鸭，和/或火鸡。
如本文使用的术语“体内”是指发生在受试者的身体内的活动。在体内也包括在啮齿类动物中发生的事件，例如大鼠，小鼠，豚鼠，和类似物。
如本文使用的术语“体外”是指在一个发生在身体以外的地方的事件。例如，体外试验检测包括发生在身体之外进行的任何检测。体外测定包括基于活的或死的细胞的细胞测定，也包括在其中没有完整的细胞中使用的无细胞测定方法。
如本文所使用的术语“化合物”，也意在包括本文的通式化合物的盐、前药和前药盐。该术语还包括前述任一项的任意溶剂合物、水合物和多晶型物。在本申请中描述的本发明的某些方面中，对“前药”、“前药盐”、“溶剂合物”、“水合物”或“多晶型物”的具体引用不应该被解释为在使用术语“化合物”而没有引用这些其他形式的本发明的其他方面中，意在排除这些形式。
本发明的化合物的盐在酸与化合物的碱性基团，例如氨基官能团之间形成。根据另一个优选的实施方式，该化合物是药学可接受的酸加成盐。
本发明的化合物的盐在碱与化合物的酸性基团，例如羧基官能团之间形成。根据另一个优选的实施方式，该化合物是药学可接受的碱加成盐。
如本文中使用且除非另外指明，术语“前药”是指化合物的衍生物，其可以在生物学条件(体外或体内)下水解、氧化或以其他方式反应以提供本发明的化合物。前药可以仅在生物学条件下的此类反应后变得有活性，或可以在其未反应形式下具有活性。本发明的前药的实例包括，但不限于，本文公开的任意一个通式的化合物的类似物或衍生物，也包括生物可水解的部分，例如酰胺和酯类似物。
前药盐是酸与前药的碱性基团，例如氨基官能团，或碱与前药的酸性基团，例如羧基官能团之间形成的化合物。在一个实施方式中，前药盐是药学可接受的盐。
特别优选的前药和前药盐是当此类化合物用于哺乳动物或人时增加本发明的化合物的生物利用度(例如，通过使口服给药的化合物更容易被吸收)或相对于母体物种促进化合物 递送至生物腔室(例如，脑或中枢神经***)的那些。优选的前药包括其中将增加水溶性或增加通过肠膜的主动转运的基团添加在本文所述的通式结构上的衍生物。参见，例如，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)所述。
如本文使用的术语“药学可接受的”是指在合理的医学范围内，适用于与人和其他哺乳动物的组织接触而没有过度毒性、剌激、过敏反应等，并且有合理的利益/风险比的组分。“药学可接受的盐”是指任何无毒性的盐，其在施用于受者后，能够直接或间接地提供本发明的化合物或化合物的前药。
通常用来形成药学可接受的盐的酸包括无机酸，例如盐酸，氢溴酸，硫酸、氢碘酸和磷酸，以及有机酸，例如三氟乙酸，柠檬酸，马来酸，草酸，苦味酸，乙酸，己二酸，藻酸，天冬氨酸，硫酸，硼酸，丁酸，戊酸，樟脑酸，硫氰酸樟脑磺酸，二葡糖酸，十二烷基硫酸，新戊酸，甲酸，庚酸，富马酸，氢碘酸，苯甲酸，2-羟基-乙磺酸，富马酸，硬脂酸乳糖酸，丙酸月桂酸，油酸硝酸烟酸，乳酸肉桂酸，琥珀酸，扁桃酸，苹果酸，酒石酸，二酒石酸，乳酸，丙酮酸，果胶酸，甲磺酸，扑酸，苯磺酸，过硫酸，棕榈酸，丙二酸甘油磷酸，2-萘磺酸，对甲苯磺酸、水杨酸、抗坏血酸、3-苯基丙酸，葡萄糖酸、葡萄糖醛酸，磷酸、谷氨酸、乙磺酸、对溴苯磺酸和碳酸，以及相关的无机和有机酸。通常用来形成药学可接受的盐的碱包括碱金属，碱土金属，铵盐，N +(C1-4烷基) 4盐，以及相关的无机和有机碱。代表性的碱金属和碱土金属例如钠，锂，钾，钙，镁，铁，铜，锰，锌，铝等，以及有机碱形成的盐，包括，例如，伯，仲和叔胺，取代胺，包括天然存在的取代胺，环胺，碱性离子交换树脂，和类似物，如异丙胺，三甲胺，二乙胺，三乙胺，三丙胺和乙醇胺。在一些实施方案中，药学上可接受的碱加成盐可以从铵，钾，钠，钙和镁盐来选择。参见，例如Berge et al.J.Pharmaceutical Sciences(1977)66:1-19。
如本文所使用的术语“水合物”是指包括化学计量或非化学计量的通过非共价键分子间 作用力结合的水的化合物。如本文所使用的术语“溶剂合物”是指包括化学计量或非化学计量的通过非共价分子间作用力结合的溶剂的化合物，所述溶剂例如水，二氯甲烷，2-丙醇，丙酮，甲醇，乙醇或类似物。药学上可接受的溶剂合物和水合物是复合物，例如，可以包括1至约100，或1至约10，或1至约4，约3或约2，溶剂或水分子。应该理解的是，如本文所用的术语“化合物”包括所述化合物和化合物的溶剂合物，水合物，以及它们的混合物。
如本文所使用的术语“多晶型物”是指化合物或其复合物的固体结晶形式。相同化合物的不同多晶型物可以显示不同的物理、化学和/或光谱性质。不同的物理性质包括，但不限于稳定性(例如，对热，光或水分)，密度，吸湿性，可溶性，可压缩性和溶解速率。
如本文使用的术语“异构体”是具有相同分子式的不同化合物。“立体异构体”是仅在原子的空间排列方式不同的异构体。如本文中所使用的“异构体”一词包括任何和所有几何异构体和立体异构体。例如，“异构体”包括几何双键的顺式和反式异构体，也称作E-和Z-异构体；R-和S-对映体；非对映体，(D)异构体和(L)异构体，其外消旋混合物，以及它们的其它混合物，在本文中公开。
围绕碳-碳取代基双键被指定为在“Z”或“E”构型，其中术语“Z”和“E”的按照IUPAC标准使用。除非另外指明，结构描绘双键既包括“E”和“Z”异构体。
围绕碳-碳双键的可替换的取代基可以被称为“顺式”或“反式”，其中“顺式”指取代基在双键的同一侧，“反式”代表取代基在双键的两侧。取代基的周围碳环的排列也可以被指定为“顺式”或“反式”。术语“顺式”表示在环平面的相同侧取代基，术语“反式”表示环平面的两侧取代基。其中取代基在两个环的平面的相同和相反侧上的化合物的混合物表示为“顺/反”。
如本文使用的术语“对映体”是一对彼此为不可重叠的镜像的立体异构体。一对以任何比例的对映体的混合物可被称为“外消旋”混合物。术语“(±)”用于在适当指定外消旋混合物。“非对映异构”指具有至少两个不对称原子，但其立体异构体是不是彼此的镜像图像。绝对立体化学根据Cahn-lngold-Prelog R-S***指定。当化合物是对映体，在各手性碳的立体化学可以通过指定为R或S。拆分的化合物，其绝对构型是未知的，可以指定(+)或(-)，这取决于它们在钠D线的波长旋转平面偏振光的方向(右旋或左旋)。
在绝对立体而言指在每个不对称原子为(R)-的化合物或(S)-的化合物，药物组合物 和方法包括所有这些可能的异构体，包括外消旋混合物，光学纯形式和中间体混合物。光学活性(R)-和(S)-也可以使用手性合成方法或手性试剂进行制备，或者使用常规技术拆分。
如本文使用的术语“对映体过量”或“％对映体过量”的组合物的可使用如下所示的公式来计算。在下面所示的例子中，组合物含有90％的一种对映体，例如，S对映体，并且含有10％另一对映体，例如，R对映体。
ee值＝(90-10)/100＝80％。
因此，含有90％的一种对映体和另一对映体为10％的组合物被说成具有对映体过量80％。本文所述的一些组合物含有至少约50％的对映体过量，约75％，约90％，约95％，或S对映体的约99％。换言之，该组合物包含对映体过量的S对映体在R对映体内。在其他实施方案中，本文所述的一些组合物含有至少约50％的对映体过量，约75％，约90％，约95％，或R对映体的约99％。换言之，该组合物包含对映体过量的R对映体在S对映体内。例如，一个异构体/对映异构体可以，在一些实施方案中，可提供相应对映异构体的ee值，并且也可以被称为“光学富集”，“对映体富集”，“对映体纯”和“非消旋体“，作为本文中可互换使用。这些术语是指其中一种对映体的重量百分比是组合物比一种对映体中的外消旋组合物的控制混合物的量更大(例如，大于1：1的重量比)。例如，S对映体的对映体富集(重量)的S对映体的相对于R对映体，如按重量计至少约75％的具有大于约50％的该化合物的方法，还如至少约80％(重量)。在一些实施方案中，富集大于按重量计约80％，提供了“基本上对映体富集的”，“基本上对映体纯”或“基本上非外消旋”的制备，这是指其重量的对映体相对于其他对映异构体之一具有至少85％的组合物，如按重量计至少约90％的制剂，并且进一步，例如在按重量计至少约95％。在某些实施方案中，本文提供的化合物可以由至少重量的一种对映异构体的约90％。在其他实施方案中，所述化合物可以由至少约95％，约98％，或重量的一种对映异构体的约99％。在一些实施方案中，所述化合物是(S)-和(R)-外消旋混合物。在其他实施方案中，本文提供了一种方法，其中混合物的单个化合物(S)-主要是存在的化合物的混合物或(R)-是主要存在的化合物的混合物。例如，该化合物混合物具有的(S)-对映体过量的大于约55％，约60％，约65％，约70％，约75％，约80％，约85％，约90％，约95％，约96％，约97％，约98％，约99％，约99.5％，或更多。在其他实施方案中，化合物的混合物具有的(S)-对映体过量大于约55％至约99.5％，大于约60％至约99.5％，大于约65％至约99.5％，大于约70％至 约99.5％，大于约75％至约99.5％，大于约80％至约99.5％，大于约85％至约99.5％，大于约90％至约99.5％，大于约95％至约99.5％，大于约96％至约99.5％，大于约97％至约99.5％，大于约98％至大于约99.5％，大于约99％至约99.5％，或更高。在其他实施方案中，化合物混合物(R)-对映体纯度具有大于约55％，约60％，约65％，约70％，约75％，约80％，约85％，约90％，约95％，约96％，约97％，约98％，约99％，约99.5％或更多。在其它一些实施方案中，化合物的混合物具有(R)-对映体过量大于约55％至约99.5％，大于约60％至约99.5％，大于约65％至约99.5％，大于约70％至约99.5％，大于约75％至约99.5％，大于约80％至约99.5％，大于约85％至约99.5％，大于约大于约90％至约99.5％，大于95％至约99.5％，大于约96％至约99.5％，大于约97％至约99.5％，大于约98％至大于约99.5％，大于约99％至约99.5％或更多。
在其他实施方案中，该化合物混合物包含，除了他们的立体化学取向，即(S)-或(R)-相同的化学实体。例如，如果化合物中公开这里有一个-CH(R)-单元，并且R不是氢，那么-CH(R)-是在(S)-或(R)-立体化学的每个相同的化学实体的取向。在一些实施方案中，在相同的化学实体的混合物中的(S)-异构体存在于一个(S)-对映体过量高于约55％至约99.5％，大于约60％至约99.5％，大于约65％至约99.5％，大于约70％至约99.5％，大于约75％至约99.5％，大于约80％至约99.5％，大于约85％至约99.5％，大于约90％至约99.5％，大于约95％至约99.5％，大于约96％至约99.5％，大于约97％至约99.5％，大于约98％至大于约99.5％，大于约99％至约99.5％或更多。
在另一实施方案中，(R)-异构体在相同的化学实体的混合物(除了其立体化学取向)相对于(S)-异构体，是在约55％，约60％，约65％，约70％，约75％，约80％，约85％，约90％，约95％，约96％，约97％，约98％，约99％，约99.5％或更高。在一些实施方案中，(R)-在相同的化学实体的混合物(除了其立体化学取向)异构体，存在于(R)-对映体过量大于约55％至约99.5％，大于约大于约60％至约99.5％，大于65％至约99.5％，大于约70％至约99.5％，大于约75％至约99.5％，大于约80％至约99.5％，大于约85％至约99.5％，大于约90％至约99.5％，大于约95％至约99.5％，大于约96％至约99.5％，大于约97％至约99.5％，大于约98％至大于约99.5％，大于约99％至约99.5％，或更多。
对映异构体可从外消旋混合物通过已知的本领域技术人员的任何方法，包括手性高效液 相色谱(HPLC)，手性盐的形成和结晶，或不对成合成进行分离。参见，例如，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).
光学异构体还可以通过拆分外消旋混合物按常规方法与光学活性酸或碱获得，例如，通过形成非对映异构盐。合适的酸的实例包括，但不限于，酒石酸，二乙酰基，二苯甲酰，二甲苯酰酒石酸和樟脑磺酸。非对映体结晶接着从这些盐的光学活性的碱的混合物得到异构体的分离。另一种方法，通过公开的化合物与活化形式的光学纯的酸或光学纯的异氰酸酯反应涉及共价非对映异构分子的合成。合成对映异构体可以通过常规方法如色谱法，蒸馏，结晶或升华，然后水解以提供对映体富集化合物进行分离。光学活性化合物也可以通过使用活性原料来获得。在一些实施方案中，这些异构体可以以游离酸，游离碱，酯或盐的形式。
在某些实施方案中，药学上可接受的形式是一个互变异构体。本文所用术语“互变异构体”是一种类型的异构体，其包括两个或更多个相互转换的化合物来自氢原子和共价键的至少一种形式的迁移和改变所得(例如，单键至双键，三键至单键，或反之亦然)。“互变异构”包括质子或质子迁移互变异构，其被认为酸-碱化学的子集。“质子迁移互变异构”或“质子转移互变异构”涉及伴有键级变化的质子迁移。互变异构体的确切比例取决于若干因素，包括温度，溶剂和pH值。其中，互变异构是可能的(例如，在溶液中)，互变异构体的化学平衡即可到达。互变异构化(即，提供互变异构体对的反应)可由酸或碱催化的，或没有外部剂的作用或存在可以发生。例如互变异构化包括，但不限于酮至烯醇；酰胺至酰亚胺；内酰胺至内酰亚胺；烯胺至亚胺；和一种形式的烯胺至不同的烯胺。酮至烯醇互变异构的具体实例是戊烷-2,4-二酮和4-羟基戊-3-烯-2-酮互变异构体。互变异构的另一例子是酚和酮互变异构。酚和酮互变异构的具体实例是吡啶4-酚和吡啶-4(1H)-酮互变异构体。
除非另有说明，也意指本文所述的结构包括化合物，仅在一个或多个同位素富集原子的存在。例如，化合物具有由氘或氚更换一个氢的本结构，或者更换此公开的范围内的碳13或碳14富集的。
本公开也包括那些“同位素标记的衍生物”,其是那些相同本文中列举的化合物的药学 上可接受的形式，不同之处在于一个或多个原子被具有与自然界中通常发现的不同原子质量或质量数的原子所代替。可掺入到所公开化合物中的同位素的实例包括氢，碳，氮，氧，磷，氟和氯的同位素，如 2H， 3H， 13C， 14C， 15N， 18O， 17O， 18F，和 36Cl。某些同位素标记的公开的化合物(例如，那些标有 3H和 14C)是可以用于测定化合物和/或底物组织分布。氚(即 3H)和碳14(即 14C)同位素可易于制备和检测。此外，用较重的同位素例如氘(即， 2H或D)取代可提供由较大代谢稳定性产生的某些治疗优点(例如，增加在体内的半衰期或降低的剂量要求)。同位素标记的公开的化合物通常可通过对一种非同位素标记的试剂取代同位素标记的试剂来制备。在一些实施方案中，本文提供的是也可含有一个或多个非天然的原子同位素组成这种化合物。如所公开的化合物的所有同位素变体本文所用，无论是否是放射性与否，都在本文披露的范围内。在一些实施方案中，放射性标记的化合物可用于研究新陈代谢以及化合物组织分布以改变代谢路径，或速率或其他的生物学功能。
术语“CDCl 3”是指氘代氯仿。
术语“DMSO-d6”是指氘代二甲基亚砜
术语“LC-MS:(ESI)”是指电喷雾电离液相色谱质谱
如本文中所使用的术语蛋白“改变”被定义为，相对于正常生理状态发生变化。示例性的改变包括突变、缺失、与其他蛋白融合、过表达或低表达。
本发明的化合物：
一方面，本发明提供式(I)的化合物：
Figure PCTCN2019079043-appb-000002
或其盐；或其前药或其前药的盐；或其水合物、溶剂合物或多晶型物。
本发明所述手性为R的新型喹唑啉衍生物(I)的合成可以容易地由普通合成化学技术人员来实现。例如，本文中公开的相关方法和中间体。本文提及的每一篇专利、专利申请和出版物,不管其在传统的杂志中或仅可通过互联网获得，均整体地引入本文以供参考。
合成本文所述化合物(I)的其他方式可以容易地从本文引用的参考文献进行改动。这些 程序的变化形式和其优化在普通技术人员的能力范围内。
本发明还提供组合物，其包括有效量的本文所述的化合物，或如果适用，所述化合物的药学可接受的盐、溶剂合物、水合物、多晶型物或前药；以及可接受的载体。优选地，本发明的组合物为药用用途而配制(“药物组合物”)，其中所述载体是药学可接受的载体。考虑到与制剂其他成分相容，并且在药学可接受的载体的情况下，所述载体必须是“可接受的”，在典型用于药物中的量下不损害其接受者。
“药学上可接受的载体”或“药学上可接受的赋形剂”包括任何和所有溶剂，分散介质，包衣，抗菌剂和抗真菌剂，等渗和吸收延迟剂以及类似物。药学上可接受的载体或赋形剂不破坏所公开的化合物的药理活性，当以足以递送的化合物的治疗量的剂量施用是无毒的。用于药学活性物质使用此类介质和试剂在本领域中是众所周知的。除非任何常规介质或试剂与活性成分不相容，如本文所公开其在治疗组合物的使用是预期的。药学上可接受的载体的实例和赋形剂包括但不限于：糖，例如，乳糖，蔗糖和葡萄糖；淀粉，例如，马铃薯淀粉和玉米淀粉；纤维素及其衍生物，例如羧甲基纤维素钠，醋酸纤维素和乙基纤维素；明胶；黄蓍胶粉末；滑石；麦芽；可可脂和栓剂蜡；油,例如，花生油，红花油，棉籽油，橄榄油,芝麻油，玉米油和大豆油；二醇，例如聚乙二醇和丙二醇；酯，例如，油酸乙酯和月桂酸乙酯；琼脂；缓冲剂，例如，氢氧化镁和氢氧化铝；藻酸；林格氏溶液；等渗盐水；乙醇；磷酸盐缓冲液；无毒相容的润滑剂，例如，月桂基硫酸钠和硬脂酸镁；着色剂；涂层剂；释放剂；甜味剂，调味剂和芳香剂；抗氧化剂；防腐剂；离子交换；氧化铝；卵磷脂；硬脂酸铝；自乳化药物递送***(SEDDS)如维生素E聚乙二醇1000琥珀酸酯；用于药物剂型的表面活性剂，例如Tweens或其它类似的聚合物递送基质的；血清蛋白，例如，人血清白蛋白；甘氨酸；山梨酸；山梨酸钾；饱和植物脂肪酸的偏甘油酯混合物；水，盐或电解质，例如，硫酸鱼精蛋白，磷酸氢钾，磷酸氢二钠，氯化钠和锌盐；胶体二氧化硅；三硅酸镁；聚乙烯吡咯烷酮；基于纤维素的物质；聚丙烯酸酯；蜡；和聚乙烯-聚氧丙烯-嵌段聚合物。环糊精，例如，alpha，beta和gamma-环糊精，或化学修饰的衍生物，例如，羟基烷基环糊精，包括2-和3-羟基丙基环糊精或其他用于提高本文所述的化合物的递送的增溶的衍生物。
本发明的药物组合物可以是以固体或液体形式用于给药，包括：口服给药，例如，灌服剂(含水的或非水的溶液或悬浮液)，片剂(例如，那些针对口腔，舌下和全身吸收)，硬或软胶囊，丸剂，糖浆，粉末，颗粒，糊剂施用于舌，十二指肠内途径；肠胃外给药，包括 静脉内，动脉内，皮下，肌内，眼内，肺，血管内，腹膜内或输液，例如，无菌溶液或悬浮液，或持续释放制剂；局部使用，例如作为乳膏，软膏，凝胶剂，水性或油性溶液或悬浮液，或适用于皮肤的控释贴剂或喷雾；***内或直肠内，例如作为***栓剂，乳膏，支架或泡沫；舌下含服；通过导管或支架本地传送；鞘内，或鼻，通过吹入使用(例如作为微细粉末)或通过吸入使用(例如作为微细粉末或液体气雾剂)。
在药物组合物中合适的水性和非水性载体的实例包括水，乙醇，多元醇(如甘油，丙二醇，聚乙二醇，等等)，及其合适的混合物，植物油，如橄榄油，和可注射的有机酯，如油酸乙酯。通过使用包衣材料，例如，卵磷脂，通过维持所需的颗粒大小的分散体，和通过使用表面活性剂保持适当的流动性。这些组合物还可以含有佐剂，如防腐剂，润湿剂，乳化剂，分散剂，润滑剂，和/或抗氧化剂。本文所述的化合物预防微生物的作用可以通过包含不同的抗菌剂和抗真菌剂来确保，例如，对羟基苯甲酸酯，氯丁醇，苯酚山梨酸和类似物。它也可以是包括等渗剂，如糖，氯化钠等的组合物中。此外，可注射药物形式的延长吸收可通过包含延迟吸收剂，例如单硬脂酸铝和明胶。
制备这些制剂或组合物的方法包括本文所述的化合物和/或与化学治疗载体和任选的一种或多种辅助成分的关联的步骤。一般而言，制剂是通过均匀地和在此公开的化合物与液体载体，或细碎固体载体或两者紧密地结合，然后如有必要，使产品成形。制备这样的药物组合物在本领域是公知的。参见，例如，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；Rem的g的n's Pharmaceutical Sciences,20th Edition，Lippincott Williams&Wilkins.,2000；Martindale,The Extra Pharmacopoeia,Thirty-Second Edition(The Pharmaceutical Press,London,1999)；这些参考文献均整体地引入本文以供参考。除非任何常规赋形剂介质与本文提供的化合物不相容，例如通过与药学上可接受的组合物的任何其他组分相互作用产生任何不希望的生物学效应或以有害的作用，赋形剂的使用也涵盖在本公开的范围之内。
在一些实施方案中，药物组合物提供一个或多个所公开的化合物的浓度可以是小于约100％，约90％，约80％，约70％，约60％，约50％，约40％，约30％，约20％，约19％，约18％，约为17％，约16％，约15％，约14％，约13％，约12％，约11％，约10％，约9％，约8％，约7％，约6％，约5％，约4％，约3％，约2％，约1％，约0.5％，约0.4％，约0.3％，约0.2％，约0.1％，约0.09％，约0.08％，约0.07％，约0.06％，约0.05％，约0.04％，约0.03％，约0.02％，约0.01％，约0.009％，约0.008％，约0.007％，约0.006％，约0.005％，约0.004％，约0.003％，约0.002％，约0.001％，约0.0009％，约0.0008％，约0.0007％，约0.0006％，约0.0005％，约0.0004％0.0003％0.0002％或约0.0001％重量/重量比，重量/体积比，或体积/体积比。
在一些实施方案中，一种或多种如本文所公开的化合物的浓度可大于约90％以上，约80％，约70％，约60％，约50％，约40％，约30％，约20％，约19.75％，约19.50％，约19.25％约19％，约18.75％，约18.50％，约18.25％，约18％，约17.75％，约17.50％，约17.25％，约17％，约16.75％，约16.50％，约16.25％，约16％，约15.75％，约15.50％，约15.25％，约15％，约14.75％，约14.50％，约14.25％，约14％，约13.75％，约13.50％，约13.25％，约13％，约12.75％，约12.50％，约12.25％，约12％，约11.75％，约11.50％，约11.25％，约11％，约10.75％，约10.50％，约10.25％，约10％，约9.75％，约9.50％，约9.25％，约9％，约8.75％，约8.50％，约8.25％，约8％，约7.75％，约7.50％，约7.25％，约7％，约6.75％，约6.50％，约6.25％，约6％，约5.75％，约5.50％，约5.25％，约5％，约4.75％，约4.50％，约4.25％，约4％，约3.75％，约3.50％，约3.25％，约3％，约2.75％，约2.50％，约2.25％，约2％，约1.75％，约1.50％，约1.25％，约1％，约0.5％，约0.4％，约0.3％，约0.2％，约0.1％，约0.09％，约0.08％，约0.07％，约0.06％，约0.05％，约0.04％，约0.03％，约0.02％，约0.01％，约0.009％，约0.008％，约0.007％，约0.006％，约0.005％，约0.004％，约0.003％，约0.002％，约0.001％，约0.0009％，约0.0008％，约0.0007％，约0.0006％，约0.0005％，约0.0004％，约0.0003％，约0.0002％，或约0.0001％重量/重量比，重量/体积比，或体积/体积比。在一些实施方案中，本文所公开一种或多种化合物的浓度，可以在范围从约0.0001％至约50％，约0.001％至约40％，约0.01％至约30％，约0.02％至约29％，约0.03％至约28％，约 0.04％至约27％，约0.05％至约26％，约0.06％至约25％，约0.07％至约24％，约0.08％至约23％，约0.09％至约22％，约0.1％至约21％，约0.2％至约20％，约0.3％至约19％，约0.4％至约18％，约0.5％至约17％，约0.6％至约16％，约0.7％至约15％，约0.8％至约14％，约0.9％至约12％，约1％至约10％重量/重量比，重量/体积比或体积/体积比。在一些实施方案中，如本文所公开的一种或多种化合物的浓度可以在范围从约0.001％至约10％，约0.01％至约5％，约0.02％至约4.5％，约0.03％至约4％，约0.04％至约3.5％，约0.05％至约3％，约0.06％至约2.5％，约0.07％至约2％，约0.08％至约1.5％，约0.09％至约1％，约0.1％至约0.9％重量/重量比，重量/体积比或体积/体积比。
在一些实施方案中，如本文中所公开的一种或多种化合物的量可以是等于或小于约10g，约9.5克，约9.0克，约8.5克，约8.0克，约7.5克，约7.0克，约6.5克，约6.0克，约5.5克，5.0克，约4.5克，约4.0克，3.5克，约3.0克，约2.5克，约2.0克，约1.5克，约1.0克，约0.95克，约0.9克，约0.85克，约0.8克，约0.75克，约0.7克，约0.65克，约0.6克，约0.55克，约0.5g，约0.45克，约0.4克，约0.35克，约0.3克，约0.25克，约0.2克，约0.15克，约0.1克，约0.09克，约0.08克，约0.07克，约0.06克，约0.05g，约0.04克，约0.03克，约0.02克，约0.01克，0.009克，约0.008克，约0.007克，大约0.006克，约0.005克，约0.004克，约0.003克，约0.002g，约0.001克，约0.0009克，0.0008g，约0.0007克，约0.0006克，大约0.0005克，约0.0004克，0.0003克，0.0002克，或约0.0001克。在一些实施方案中，本文所公开的一种或多种化合物的量可超过约0.0001克，约0.0002克，0.0003克，约0.0004克，约0.0005g，约0.0006克，约0.0007克，约0.0008g，约0.0009克，约0.001克，0.0015克，约0.002克，0.0025克，约0.003克，约0.0035克。约0.004克，约0.0045克，约0.005克，约0.0055克，约0.006克，约0.0065克，约0.007克，约0.0075克，约0.008克，约0.0085克，0.009g，约0.0095克，约0.01克，约0.015克，约0.02克，约0.025克，约0.03克，约0.035克，约0.04克，约0.045克，约0.05克，约0.055克，约0.06克，约0.065克，约0.07克，约0.075克，约0.08克，约0.085克，约0.09克，约0.095克，约0.1g，约0.15克，约0.2克，约0.25克，约0.3克，约0.35克，约0.4克，约0.45克，约0.5g，约0.55克，约0.6克，约0.6克，约0.7克，约0.75克，约0.8克，约0.85克，约0.9克，约0.95克，约1克，约1.5克，约2克，约2.5，约3克，约3.5，约 4克，约4.5克，约5克，约5.5克，约6克，约6.5克，约7克，约7.5克，约8克，约8.5克，约9克，约9.5克，或约10g。
在一些实施方案中，本文所公开的一种或多种化合物的量的范围可在约0.0001克至约10克，约0.0005克至约9克，约0.001克至约0.5克，约0.001克至约2克，约0.001克至约8克，约0.005克至约2克，约0.005克至约7克，约0.01克至约6克，约0.05克至约5克，约0.1克至约4克，约0.5克至约4克，或约1克至约3克。
在某些优选的实施方案中，含有如本文所公开的化合物口服给药，和适于口服给药的药物赋形剂的药物组合物。在一些实施方案中，本文提供口服给药的药物组合物：(1)任选的有效量的公开的化合物；(2)有效量的一种或多种第二试剂；和(3)适于口服给药的一种或多种药用赋形剂。在一些实施方案中，药物组合物进一步包含：(4)有效量的第三试剂。
在一些实施方案中，药物组合物可以是适合于口服的液体药物组合物。适于口服给药的药物组合物可以作为离散的剂型，例如每个含有粉末或颗粒的预定量活性成分的胶囊，扁囊剂，或片剂，或液体，溶液气溶胶喷雾剂或悬浮液在水性或非水性液体中，油在水中的乳液或水在油中液体乳剂。这样的剂型可通过任何药学方法制备，但是所有的方法包括通过将活性成分与液体载体、脂质体或细分散的固体载体或两者进行均匀地和紧密地缔合来制备组合物的步骤。在一般情况下，药物组合物是通过将活性成分均匀地和紧密地与液体载体或细碎的固体载体或两者混合，如有必要，使产物成形为所需的形式。例如，片剂可以是将任选一种或多种成分压制或模制。压片可以是通过将自由流动形式如粉末或颗粒的活性成分，任选地与赋形剂，例如，但不限于，粘合剂，润滑剂，惰性稀释剂和/或表面活性剂或分散剂混合，在合适的机器中压制。模制片剂可通过在合适的机器中将惰性液体稀释剂润湿的粉状化合物的混合物模制来制备。片剂可任选地未包衣，被包衣或刻痕，并可被配制以提供其中活性成分的缓慢或受控释放，从而提供较长时期的持续作用，可以使用的延时材料，例如单硬脂酸甘油酯或双硬脂酸甘油酯。用于口服使用的制剂还可以为硬明胶胶囊，其中活性成分可以与惰性固体稀释剂混合，例如，碳酸钙，磷酸钙或高岭土，或者作为软明胶胶囊，其中活性成分可以与水或油介质，例如，花生油，液体石蜡或橄榄油混合。
活性组分可以与药用载体通过常规药物混合技术来紧密相结合。所述载体可以采取多种形式，这取决于所需的制剂给药的形式。在制备药物组合物用于口服剂型时，任何常用的药物介质都可用作载体，例如，水，二醇，油，乙醇，调味剂，防腐剂，着色剂，和口服液体 制剂(例如，悬浮液，溶液，和酏剂)或气雾剂，或载体，例如，淀粉，糖，微晶纤维素，稀释剂，成粒剂，润滑剂，粘合剂，和崩解剂可在口服固体制剂的情况下使用，在一些实施例里不使用乳糖。在一些实施方案中，化合物可以与乳糖，蔗糖，淀粉粉末，链烷酸的纤维素酯，纤维素烷基酯，滑石，硬脂酸，硬脂酸镁，氧化镁，磷酸钙，磷酸钠，硫酸钙，硫酸钠，明胶，***胶，藻酸钠，聚乙烯吡咯烷酮和/或聚乙烯醇用于进一步的制剂。例如，固体口服制剂的制备，合适的载体还包括粉末，胶囊和片剂。在一些实施方案中，片剂可以通过标准水性或非水性技术进行包衣。
适用于药物组合物和剂型的包衣，包括，但不限于，玉米淀粉，马铃薯淀粉，或其它淀粉，明胶，天然粘合剂和合成树胶如***胶，藻酸钠，海藻酸，其它藻酸盐，粉末状黄蓍胶，瓜尔胶，纤维素及其衍生物(例如，乙基纤维素，醋酸纤维素，羧甲基纤维素钙，羧甲基纤维素钠)，聚乙烯吡咯烷酮，甲基纤维素，预胶化淀粉，羟丙基甲基纤维素，微晶纤维素，以及它们的混合物。
本文中公开了用于在药物组合物和剂型的合适的填料的实例包括，但不限于，滑石，碳酸钙(例如，颗粒或粉末)，微晶纤维素，粉末纤维素，葡萄糖结合剂，高岭土，甘露醇，硅酸，山梨醇，淀粉，预胶化淀粉，以及它们的混合物。
崩解剂可以在药物组合物中使用如本文所提供，以提供在暴露于水环境时发生崩解的片剂。太多的崩解剂可以导致片剂在瓶中崩解。太少可能不足以崩解发生，并因此可以改变剂型的活性成分的释放速率和程度。因此，崩解剂应该足够量，既不太少也不太多而有害地改变活性成分的释放。崩解剂的量取决于配方和给药方式，并且可以是易于由本领域中的普通技术人员实现。约0.5至约15重量％的崩解剂，或约1至约5重量％的崩解剂，可以在药物组合物中使用。可用于形成药物组合物和剂型的崩解剂，包括但不限于，琼脂，海藻酸，碳酸钙，微晶纤维素，交联羧甲基钠，交聚维酮，波拉克林钾，淀粉羟乙酸钠，马铃薯或木薯淀粉，其它淀粉，预明胶淀粉，粘土，其它藻胶，其它纤维素，树胶或其混合物。
润滑剂可以用于形成药物组合物和剂型的，包括，但不限于，硬脂酸钙，硬脂酸镁，矿物油，轻质矿物油，甘油，山梨醇，甘露醇，聚乙二醇，其它二醇，硬脂酸，月桂基硫酸钠，滑石，氢化植物油(例如，花生油，棉籽油，葵花籽油，芝麻油，橄榄油，玉米油和大豆油)，硬脂酸锌，油酸乙酯，月桂酸乙酯，琼脂或它们的混合物。润滑剂还包括，例如，硅胶，凝固气溶胶，或其混合物。润滑剂可任选地以小于约1重量％的药物组合物的量加入。
当水性悬浮液和/或酏剂用于口服给药时，活性成分可以与各种甜味剂或调味剂，着色剂或染料，和例如，乳化剂和/或悬浮剂，稀释剂结合在一起，例如，水，乙醇，丙二醇，甘油和它们的各种组合。
可以用于形成药物组合物和剂型的表面活性剂包括，但不限于亲水性表面活性剂，亲脂性表面活性剂，以及它们的混合物。合适的亲水表面活性剂通常可以具有至少约10的HLB值，而合适的亲脂性表面活性剂可以一般具有小于约10的HLB值。用来表征的相对亲水性和疏水性的经验参数是亲水亲油平衡值HLB(“HLB”值)。较低的HLB值的表面活性剂是更亲脂或疏水的，且在油中有较大的溶解度，而具有较高HLB值的活性剂是更亲水性的，并且在水溶液中具有更大的溶解度。亲水性表面活性剂一般被认为是具有HLB值大于约10的那些化合物，然而，阴离子，阳离子或两性离子化合物，HLB尺度通常不适用。类似地，亲脂性(即，疏水性)表面活性剂是具有HLB值等于或小于约10。然而，表面活性剂的HLB值仅仅是一般用于工业，药物和化妆品乳剂的粗略指导。
亲水性表面活性剂可以是离子或非离子的。合适的离子表面活性剂包括，但不限于，烷基铵盐；夫西地酸盐；氨基酸，寡肽和多肽的脂肪酸衍生物；氨基酸，寡肽和多肽的甘油酯的衍生物；卵磷脂和氢化卵磷脂；溶血卵磷脂和氢化溶血卵磷脂；磷脂及其衍生物；溶血磷脂及其衍生物；肉碱脂肪酸酯盐；烷基硫酸盐；脂肪酸盐；多库酯钠；酰基乳酸盐；单-和二乙酰化的单和二甘油酯的酒石酸酯；琥珀酰化单和二甘油酯；单-和二-甘油酯的柠檬酸酯；和它们的混合物。离子型表面活性剂包括，但不限于，例如，卵磷脂，溶血卵磷脂，磷脂，溶血磷脂及其衍生物；肉碱脂肪酸酯盐；烷基硫酸盐；脂肪酸盐；多库酯钠；酰基乳酸盐；单-和单-和二-甘油酯的二乙酰化酒石酸酯；琥珀酰化单和二甘油酯；单-和二-甘油酯的柠檬酸酯；和它们的混合物。亲水非离子表面活性剂包括，但不限于，烷基糖苷；烷基麦芽糖；烷基硫代糖苷；月桂酰聚乙二醇甘油酯；聚氧化烯烷基醚，例如，聚乙二醇烷基醚；聚氧化烯烷基酚，例如，聚乙二醇烷基酚；聚氧化烯烷基苯酚脂肪酸酯，例如，聚乙二醇脂肪酸单酯和聚乙二醇脂肪酸二酯；聚乙二醇甘油脂肪酸酯；聚甘油脂肪酸酯；聚氧化烯脱水山梨醇脂肪酸酯，例如，聚乙二醇山梨糖醇脂肪酸酯；与甘油酯，植物油，氢化植物油，脂肪酸和甾醇中的至少一种多元醇的亲水性酯交换产物；聚氧乙烯甾醇，其衍生物，及其类似物；聚氧乙烯化维生素及其衍生物；聚氧乙烯-聚氧丙烯嵌段共聚物；和它们的混合物；聚乙二醇脱水山梨醇脂肪酸酯和至少一个甘油三酯，植物油和氢化植物油的多元醇的亲水性酯交换产物。该多元醇可 以是甘油，乙二醇，聚乙二醇，山梨醇，丙二醇，季戊四醇或糖类。其它亲水性非离子表面活性剂包括，但不限于，PEG-10月桂酸酯，PEG-12月桂酸酯，PEG-20月桂酸酯，PEG-32月桂酸酯，PEG-32二月桂酸酯，PEG-12油酸酯，PEG-15油酸酯。PEG-20油酸酯，PEG-20二油酸酯，PEG-32油酸酯，PEG-200油酸酯，PEG-400油酸酯，PEG-15硬脂酸酯，PEG-32二硬脂酸酯，PEG-40硬脂酸酯，PEG-100硬脂酸酯，PEG-20二月桂酸酯，PEG-25甘油三油酸酯，PEG-32二油酸酯，PEG-20甘油基月桂酸酯，PEG-30甘油基月桂酸酯，PEG-20glyce叩我硬脂酸酯，PEG-20油酸甘油酯，PEG-30油酸甘油酯，PEG-30glyce叩我月桂酸酯，PEG-40甘油基月桂酸酯，PEG-40棕榈仁油，PEG-50氢化蓖麻油，PEG-40蓖麻油，PEG-35蓖麻油，PEG-60蓖麻油，PEG-40氢化蓖麻油，PEG-60氢化蓖麻油，PEG-60玉米油，PEG-6癸/辛酸甘油酯，PEG-8癸酸酯/帽叩晚甘油酯，polyglyce叩1-10月桂酸酯，PEG-30胆固醇，PEG-25植物固醇，PEG-30大豆甾醇，PEG-20三油酸酯，PEG-40山梨糖醇油酸酯，PEG-80脱水山梨醇月桂酸酯，聚山梨酸酯20，聚山梨醇酯80，POE-9十二烷基醚，POE-23月桂醚，POE-10油基醚，POE-20油基醚，POE-20硬脂醚，PEG-100生育酚琥珀酸酯，PEG-24胆固醇，Tween 40，Tween 60，蔗糖单硬脂酸酯，蔗糖单月桂酸酯，蔗糖单棕榈酸酯，PEG 10-100壬基酚系列，PEG 15-100辛基酚系列和泊洛沙姆。合适的亲脂表面活性剂包括，但不限于，例如，脂肪醇；甘油脂肪酸酯；乙酰化甘油脂肪酸酯；低级醇脂肪酸酯；丙二醇脂肪酸酯；山梨糖醇脂肪酸酯；聚乙二醇脱水山梨醇脂肪酸酯；固醇和固醇衍生物；聚氧乙烯化甾醇和甾醇衍生物；聚乙二醇烷基醚；糖酯；糖醚；单和二甘油酯的乳酸衍生物。
药物组合物可包括增溶剂以确保化合物的良好增溶和/或溶解，并尽量减少化合物的沉淀。这可以是用于非口服使用，例如，用于注射的药物组合物的药物组合物尤其重要。增溶剂也可以加入，以增加亲水性药物和/或其它组分，如表面活性剂的溶解度，或维持的药物组合物作为稳定或均一的溶液或分散体。合适的增溶剂的实例包括，但不限于，例如，醇和多元醇，例如，乙醇，异丙醇，丁醇，苄醇，乙二醇，丙二醇，丁二醇及其异构体，甘油，季戊四醇，山梨醇，甘露糖醇，二甲基异山梨醇，聚乙二醇，聚丙二醇，聚乙烯醇，和其它纤维素衍生物，环糊精和环糊精衍生物；聚乙二醇的醚，具有分子量约200至约6000，例如四氢糠醇PEG醚(四氢呋喃聚乙二醇醚)或甲氧基PEG；酰胺和其它含氮化合物，例如2-吡咯烷酮，2-哌啶酮，ε-己内酰胺，N-烷基吡咯烷酮，N-羟烷基吡咯烷酮，N-烷基哌啶，N-烷基己内酰胺，二甲基乙酰胺和聚乙烯吡咯烷酮；酯，例如，丙酸乙酯，柠檬酸三丁酯，乙 酰柠檬酸三乙酯，柠檬酸乙酰基三丁酯，柠檬酸三乙酯，油酸乙酯，辛酸乙酯，丁酸乙酯，甘油三乙酸酯，丙二醇单乙酸酯，丙二醇二乙酸酯，ε-己内酯和它们的异构体，delta-戊内酯及其异构体，丁内酯及其异构体；和已知的其他增溶剂，如二甲基乙酰胺，二甲基异山梨醇，N-甲基吡咯烷酮，二乙二醇单***和水。也可以使用增溶剂的混合物。
给定的增溶剂的量可以被限制在一个生物可接受量，其可以通过本领域技术人员容易地确定。增溶剂可以是在约10％，约25％，约50％，约100％的重量比，或至多按重量计约200％，基于药物的总重量，以及其他辅料。如果需要的话，少量增溶剂也可使用，例如约5％，2％，1％或甚至更少。典型地，增溶剂可以存在于约1％至约100％，通常为约5％至约25％(重量)。
所述的药物组合物还可以包括一种或多种药学上可接受的添加剂和赋形剂。这样的添加剂和赋形剂包括，但不限于，例如，防粘剂，抗发泡剂，缓冲剂，聚合物，抗氧化剂，防腐剂，螯合剂，调味剂，着色剂，精油，香料，遮光剂，悬浮剂，粘合剂，填充剂，增塑剂，润滑剂，以及它们的混合物。防腐剂可包括，但不限于，例如，抗氧化剂，螯合剂，抗微生物防腐剂，抗真菌防腐剂，醇防腐剂，酸性防腐剂和其它防腐剂。抗氧化剂包括，但不限于，α-生育酚，抗坏血酸，丁基化羟基苯甲醚，丁基羟基甲苯，单硫代甘油，焦亚硫酸钾，丙酸，棓酸丙酯，抗坏血酸钠，亚硫酸氢钠，和亚硫酸钠。螯合剂包括，但不限于，例如，乙二胺四乙酸(EDTA)，柠檬酸一水合物，乙二胺四乙酸二钠，二钾乙二胺四乙酸盐，依地酸，富马酸，苹果酸，磷酸，依地酸钠，酒石酸，和柠檬酸三乙二胺四乙。抗微生物防腐剂包括，但不限于，例如，苯扎氯铵，苄索氯铵，苯甲醇，溴硝丙二醇，西曲溴铵，氯化十六烷基吡啶，氯二甲酚，甲酚，乙醇，甘油，海克替啶，咪唑烷脲，苯酚，苯氧基乙醇，苯乙醇，硝酸苯汞，和丙二醇。抗真菌剂，包括，但不限于，例如，对羟基苯甲酸丁酯，对羟基苯甲酸甲酯，对羟基苯甲酸乙酯，对羟基苯甲酸丙酯，苯甲酸，羟基苯甲酸，苯甲酸钾，山梨酸钾，苯甲酸钠，丙酸钠和山梨酸。防腐剂包括，但不限于，例如，乙醇，聚乙二醇，苯酚，酚化合物，双酚，氯丁醇，羟基苯甲酸酯，和苯乙醇。酸性防腐剂包括，但不限于，例如，维生素A，维生素C，维生素E，β-胡萝卜素，柠檬酸，乙酸，脱氢乙酸，抗坏血酸，山梨酸和植酸。其它防腐剂包括，但不限于，例如，生育酚醋酸酯，西曲溴铵，丁基化羟基苯甲醚(BHA)，丁基羟基甲苯(BHT)，乙二胺，月桂基硫酸钠(SLS)，月桂基醚硫酸钠(SLES)，硫酸氢钠盐，焦亚硫酸钠，亚硫酸钾，焦亚硫酸钾，对羟基苯甲酸甲酯。在某些 实施方案中，防腐剂可以是一种抗氧化剂。在其他实施方案中，防腐剂可以是螯合剂。在一些实施方案中，本文提供的是用于胃肠外给药含有的药物组合物：(1)一个公开的化合物的有效量；任选的(2)有效量的一种或多种第二试剂；(3)适合于肠胃外施用的一种或多种药物赋形剂和(4)有效量的第三试剂。
其中药物组合物可以通过注射给药的形式包括水性或油性悬浮液，或乳剂，麻油，玉米油，棉子油，或花生油，以及酏剂，甘露醇，右旋糖，或无菌水溶液，以及类似的药物载体。生理盐水水溶液也通常用于注射。乙醇，甘油，丙二醇，液体聚乙二醇，苄醇，等(及其合适的它们的混合物)，环糊精衍生物，氯化钠，黄蓍胶，缓冲剂，和植物油也可以采用。适当的流动性可以通过使用包衣，例如，卵磷脂，或在分散体的情况下通过使用表面活性剂保持所需的颗粒大小来保持。微生物作用的预防可通过各种抗菌剂和抗真菌剂，例如，对羟基苯甲酸酯类，氯丁醇，苯酚，山梨酸酸，硫柳汞等。药物组合物还可通过合适的载体来注射，包括盐水，葡萄糖或水，或用环糊精，共溶剂(例如，丙二醇)或胶束增溶(例如，Tween80)。
无菌注射溶液可以通过所需量的本文所公开的化合物与各种上述其它成分的合适溶剂，过滤灭菌来制备。通常，分散体通过将各种灭菌的活性成分掺入到含有基础分散介质的无菌载体和来自上文列举的那些适当的其它组分来制备。在用无菌粉末来制备无菌注射液，制备的某些方法是用真空干燥和冷冻干燥技术产生活性成分和任何另外的上述无菌过滤的成分。无菌可注射制剂还可以通过在无毒的肠胃外可接受的稀释剂或溶剂的悬浮液，例如，1,3-丁二醇中的溶液或无菌注射溶液来制备。在可以使用的可接受的载体和溶剂包括，但不限于，例如，水，林格氏溶液和等渗氯化钠溶液。此外，无菌，不挥发性油通常用作溶剂或悬浮介质，包括，但不限于，例如，合成的单或二甘油酯。此外，脂肪酸，例如，油酸也可用于注射剂的制备中使用。可注射制剂在使用前可以通过，例如，细菌保持过滤器过滤，或加入可以溶解或分散在无菌水或其它无菌可注射介质的掺入无菌固体组合物的灭菌剂进行灭菌。注射组合物可以在约0.1至约5％重量比的本文公开的化合物。
在一些实施方案中，本文提供的是含有如本文所公开，适于局部给药的含有一种或多种药物赋形剂的(例如，经皮)的化合物或药物组合物。在一些实施方案中，本文提供的是用于局部给药的含有药物的组合物：(1)一个公开的化合物的有效量；任选的(2)有效量的一种或多种第二试剂；(3)适合于局部给药的一种或多种药物赋形剂和(4)有效量的第三 药剂。
本文提供的药物组合物可以配制成适合于本地或局部施用的固体，半固体或液体形式，例如凝胶剂，水溶性凝胶剂，搽剂，霜剂，洗剂，混悬剂，泡沫剂，粉剂，膏剂制剂剂，软膏剂，溶液，油，糊剂，栓剂，喷雾剂，乳剂，盐水溶液，二甲基亚砜(DMSO)为基础的溶液。在一般情况下，具有较高密度的载体能够提供具有长期暴露于活性成分的区域。相反，溶液制剂可以提供所述活性成分所选择的区域的更直接的接触。例如，软膏制剂可以有石蜡或水混溶性。可替代地，活性成分可以与油在水中的乳膏基质一起配制成乳膏。乳膏基质的水相可包括例如至少约30％重量比的多元醇，例如，丙二醇，丁烷-1,3-二醇，甘露醇，山梨醇，甘油，聚乙二醇和它们的混合物。所述的药物组合物还可包含合适的固体或凝胶相载体或赋形剂，它们可以增加渗透，或协助递送化合物穿过皮肤的角质层渗透屏障。这样的载体和赋形剂的实例包括，但不限于，例如，润湿剂(例如，尿素)，二醇(例如，丙二醇)，醇(例如，乙醇)，脂肪酸(例如，油酸)，表面活性剂(例如，肉豆蔻酸异丙酯和鎏钠叩我硫酸钠)，吡咯烷酮，甘油单月桂酸酯，亚砜，萜(例如，薄荷醇)，胺，酰胺，烷烃，烷醇，水，碳酸钙，磷酸钙，各种糖，淀粉，纤维素衍生物，明胶和诸如聚乙二醇的聚合物。
在公开的方法中使用的另一种示例性制剂使用经皮给药(“贴剂”)。这样的透皮贴剂可用于连续或不连续提供控制量的药物组合物。如果活性剂通过皮肤吸收，活性剂的受控和预定流量可以施用给受试者。在微胶囊的情况下，包封剂也可以用作膜。对于透皮贴剂的使用是本领域中公知的。参见，例如，美国专利号5,023,252，4992445和5,001，139。
本发明的药物组合物可以直肠给药的栓剂形式来施用。这些组合物可以通过将本发明的化合物与适合的无刺激性赋形剂混合来制备，所述赋形剂在室温下是固体但在直肠温度下是液体，从而将在直肠中融化而释放出活性组分。这种材料包括，但不限于，例如，聚乙二醇，蜂蜡和可可脂。
本发明的药物组合物可以通过鼻气雾剂或吸入剂来给药。根据药物制剂领域已知的技术来制备这种组合物，并且可以将其制备为盐水的溶液，并可使用苯甲醇或其他适合的防腐剂，提高生物利用度的吸收促进剂，氟碳化合物，和本领域己知的其他增溶剂或分散剂。
特别有利的衍生物和前药是，当将这种化合物施用给哺乳动物时提高本发明的化合物的生物利用度的那些(例如，通过容许口服施用的化合物更容易地被吸收)，或相对于母体物种能增强化合物向母体生物腔室(例如，脑或中枢神经***)的递送的那些。优选的前药包 括其中增强水溶性或穿肠膜主动转运的基团被附加到本文所述的通式结构上的衍生物。参见，例如，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。
主体治疗剂的应用可以是局部的，以在目标部位施用。各种技术可以用于在目标部位处提供主体组合物，例如注射，使用导管，凝胶，支架，套针，抛射剂，药物持续释放聚合物或其他提供用于内部通路的设备。
根据另一个实施方式，本发明提供一种可植入的医学设备，其包含有本发明的化合物或包括本发明的化合物的组合物，使得所述化合物是有治疗活性的。
根据另一个实施方式，本发明提供一种注入可植入的药物释放装置的方法，包括将所述药物释放装置与本发明的化合物或组合物接触的步骤。可植入的药物释放装置包括，但不限于，可生物降解的聚合物胶囊或丸剂，不可降解的，可扩散的聚合物胶囊和可生物降解的聚合物薄片。
在另一个实施方式中，本发明的组合物还包括第二治疗剂。第二治疗剂包括任何化合物或治疗剂，它们当单独给药或与本文任何通式化合物一起给药时己知具有或证明有有利性质。可以与这些化合物有用地组合的药物包括其他激酶抑制剂，和/或用于治疗以上讨论的疾病和紊乱的其他化学治疗剂。这样的试剂是本领域中详细描述的。优选地，第二治疗剂是可用于选自癌症的疾病或病症的治疗或预防的试剂。
在另一个实施方式中，本发明提供彼此缔合的本发明的化合物与第二治疗剂的独立剂型。如本文使用的术语“彼此缔合的”是指，所述独立剂型被包装在一起或以另外的方式彼此连接，从而所述独立剂型预期被一同销售或给药(相互间少于24小时之内，连续地或同时地)。
在本发明的药物组合物中，本发明的化合物以有效量存在。如本文使用的术语“有效量”是指当以合适的给药方案施用时，该量足够降低或改善要治疗的紊乱的严重度，持续时间或发展，防止要治疗的紊乱的进展，引起要治疗的紊乱的消退，或增强或改善另一种疗法的预防或治疗效果。
在Freireich et al.，(1966)Cancer Chemother Rep 50:219中描述了剂量对动物和人的相互关系(根据毫克每平方米体表面积)。体表面积可以根据患者的身高和体重大致地确定。参见，例如，Scientific Tables,Geigy Pharmaceuticals，Ardley,N.Y.,1970,537。本发明的化合物的有效量可以从约0.001-lmg/kg到约500mg/kg,约0.01mg/kg到约50mg/kg，约0.lmg/kg到约2.5mg/kg。有效的剂量也可以变化，如本领域技术人员所了解的，取决于所治疗的疾病，疾病的严重度，给药途径，患者的年龄，性别和一般健康状况，赋形剂用法，与其他治疗方法共同使用的可能性(例如使用其他试剂)、以及治疗医师的判断。
对于包括第二治疗剂的药物组合物，第二治疗剂的有效量为在仅使用该试剂的单治疗方案中通常利用的剂量的约20％到100％之间。优选地，有效量在正常的单治疗剂量的约70％和100％之间。这些第二治疗剂的正常单治疗剂量是本领域公知的。参见，例如，Wells et al.，Pharmacotherapy Handbook，Appleton and Lange,Stamford,Conn.(2000)；PDR Pharmacopoeia,Tarascon Pocket Pharmacopoeia 2000，Tarascon Publishing,Loma Linda,Calif.(2000)，这些参考文献均整体地引入本文以供参考。
预期本文提到的某些第二治疗剂将与本发明的化合物有协同地作用。当发生时，它将容许第二治疗剂和/或本发明的化合物的有效剂量少于单治疗中所需的剂量。这具有的优点是：使第二治疗剂或本发明的化合物的毒副作用最小化,改善功效,改善给药或使用的方便性,和/或降低化合物制品或制剂的总体花费。
治疗方法如下：
根据另一个实施方式，本发明提供了治疗患有或易患有疾病或紊乱或其症状(例如，本文描述的那些)的受试者的方法，包括对所述受试者以有效量的本发明的化合物或组合物进行给药的步骤。这些疾病是本领域公知的，也在本文中公开。
治疗方法涉及由蛋白激酶例如EGFR介导的紊乱的治疗。
在另一方面，本发明提供在受试者中治疗疾病的方法，包括向受试者施用包含任何本文通式的化合物的组合物。
在某些实施方式中，疾病由EGFR激酶介导。
在另一实施方式中，疾病是癌症或增殖疾病。
在另一实施方式中，作为针对EGFR外显子2-7缺失的激活突变体的抑制剂，式(I)的化合物，和药学上可接受的盐，预计是在由EGFRVIII突变体的活性单独或部分介导的，例 如癌症疾病或医学病症的治疗是有用的。这可能使用式(I)的化合物治疗的癌症类型，或药学上可接受的盐，包括但不限于，卵巢癌，子***，结肠直肠癌，乳腺癌，胰腺癌，神经胶质瘤，胶质母细胞瘤，黑素瘤，***癌，白血病，淋巴瘤，非霍奇金淋巴瘤，胃癌，肺癌，肝癌，骨癌，胃肠道间质瘤(GIST)，甲状腺癌，胆管癌，子宫内膜癌，肾癌，间变性大细胞淋巴瘤，急性骨髓性白血病(AML)，多发性骨髓瘤，黑素瘤，间皮瘤，脑癌，膜腺癌，皮肤癌或头颈部鳞状细胞癌。
在另一实施方式中，作为针对EGFR Exon 21 L858R突变体和Exon19缺失激活突变体的抑制剂，式(I)的化合物，和药学上可接受的盐，预计是在由EGFR突变体的活性单独或部分介导的，例如癌症疾病或医学病症的治疗是有用的。这可能使用式(I)的化合物治疗的癌症类型，或药学上可接受的盐，包括但不限于，卵巢癌，子***，结肠直肠癌，乳腺癌，胰腺癌，神经胶质瘤，胶质母细胞瘤，黑素瘤，***癌，白血病，淋巴瘤，非霍奇金淋巴瘤，胃癌，肺癌，肝癌，骨癌，胃肠道间质瘤(GIST)，甲状腺癌，胆管癌，子宫内膜癌，肾癌，间变性大细胞淋巴瘤，急性骨髓性白血病(AML)，多发性骨髓瘤，黑素瘤，间皮瘤，脑癌，膜腺癌，皮肤癌或头颈部鳞状细胞癌。
在另一实施方式中，疾病是脑胶质瘤。
在另一实施方式中，疾病是伴有脑部转移的非小细胞肺癌(NSCLC)。
在另一个实施方式中，疾病是神经中枢疾病。
在一个实施方式中，本发明的方法用于治疗患有或易患有疾病或症状的受试者。这些疾病，紊乱或其症状包括，例如，由蛋白激酶(例如，EGFR蛋白激酶)调控的那些。疾病或疾病症状可以是，例如，癌症或增殖疾病或紊乱。所述疾病或疾病症状可以是卵巢癌，子***，结肠直肠癌，乳腺癌，胰腺癌，神经胶质瘤，胶质母细胞瘤，黑素瘤，***癌，白血病，淋巴瘤，非霍奇金淋巴瘤，胃癌，肺癌，肝癌，骨癌，胃肠道间质瘤(GIST)，甲状腺癌，胆管癌，子宫内膜癌，肾癌，间变性大细胞淋巴瘤，急性骨髓性白血病(AML)，多发性骨髓瘤，黑素瘤，间皮瘤，脑癌，膜腺癌，皮肤癌或头颈部鳞状细胞癌。本文描绘的方法包括其中受试者被鉴别为需要具体说明的治疗的那些受试者。鉴别受试者需要此治疗可以在受试者或医护专家的判断之内，并且可以是主观的(例如，意见)或客观的(例如，通过测试或诊断方法可测量的)。
在另一个实施方式中，本文的化合物(及其组合物)可以用来治疗患有疾病或紊乱且己 经用其他治疗剂(例如，抗癌剂、神经疾病作用剂、精神疾病作用剂、心血管疾病作用剂、抗肥胖或糖尿病作用剂)治疗并形成抗性的受试者。一方面，本文的方法包括其中对治疗有抗性(或被鉴定为己经形成对于格非替尼，厄洛替尼治疗的抗性)的受试者被施用以本文通式化合物(或其组合物)的那些方法。在其它方面，受试者因此对该治疗有响应，从而相对于用本文通式化合物治疗之前，紊乱被调控或改善。
在另一个实施方式中，本发明提供调节细胞中的蛋白激酶(例如，蛋白酶氨酸激酶、本文所列举激酶)的活性的方法，包括将细胞与一种或多种任何本文通式的化合物进行接触。
上文所述的抗癌症治疗可用本发明的化合物作为单一疗法或与本发明的化合物一起施用常规手术或放疗或化疗或免疫疗法。这样的化疗可以与本发明的化合物共同，同时，序贯或分别施用，并且可以包括但不限于以下类别的抗肿瘤剂的一种或多种：例如，抗增殖/抗肿瘤药，烷基化剂(例如顺铂，奥沙利铂，卡铂，环磷酰胺，氮芥，美法仑，苯丁酸氮芥，白消安，替莫唑胺和亚硝基脲)，抗代谢药物(例如吉西他滨和抗叶酸如像5-氟尿嘧啶和替加氟，雷替曲塞，甲氨蝶呤，阿糖胞苷，和羟基脲)；抗肿瘤抗生素(例如蒽环类药物如阿霉素，博莱霉素，阿霉素，柔红霉素，表阿霉素，伊达比星，丝裂霉素C，更生霉素和光辉霉素)；抗有丝***剂(例如长春花生物碱如长春新碱，长春碱，长春地辛和长春瑞滨和紫杉烷类化合物如紫杉酚和泰索帝和polokinase抑制剂)；和拓扑异构酶抑制剂(例如表鬼臼毒素类依托泊苷和替尼泊苷，安吖啶，托泊替康和喜树碱)；细胞生长抑制剂如抗***(作用)药(例如他莫昔芬，氟维司群，托瑞米芬，雷洛昔芬，屈洛昔芬和碘昔芬)，抗雄激素(作用)药(例如，比卡鲁胺，氟他胺，醋酸尼鲁米特和醋酸环丙)，LHRH拮抗剂或LHRH激动剂(例如戈舍瑞林，亮丙瑞林和布舍瑞林，孕激素(例如醋酸甲地孕酮，芳香酶抑制剂(例如如阿那曲唑，来曲唑，伏氯唑，和依西美坦)和5α还原酶如非那雄胺的抑制剂；抗侵袭剂(例如，c-Src激酶家族抑制剂，如塞卡替尼；达沙替尼和波舒替尼和波舒替尼，和金属蛋白酶抑制剂如马马司他，尿激酶纤溶酶原激活剂受体功能的抑制剂或抗体类肝素酶。生长因子功能的抑制剂：例如此类抑制剂包括生长因子抗体和生长因子受体抗体(例如抗erbB2的抗体曲妥单抗[赫赛汀 TM]，抗EGFR抗体帕尼单抗，抗的ErbB抗体西妥昔单抗(爱必妥，C225)和由Stem et al.Critical reviews in oncology/haematology,2005,Vol.54,l1-29所公开的任何生长因子或生长因子受体的抗体。这样的抑制剂还包括酪氨酸激酶抑制剂，例如表皮生长因子家族抑制剂(例如EGFR家族酪氨酸抑制剂如吉非替尼，厄洛替尼， 凯美纳和塔格瑞斯，erbB2的酪氨酸激酶抑制剂，例如拉帕替尼，来那替尼)；肝细胞生长因子家族的抑制剂；胰岛素生长因子家族的抑制剂；血小板衍生的生长因子家族的抑制剂，如伊马替尼和/或尼洛替尼；丝氨酸/苏氨酸激酶的抑制剂(例如RAS/RAF信号抑制剂如法尼基转移酶抑制剂，例如索拉非尼,tipifamib和lonafamib，通过MEK和/或AKT激酶细胞信号抑制剂，c-kit抑制剂，abl融合激酶抑制剂，PI3激酶抑制剂，PLT3激酶抑制剂，CSF-1R激酶抑制剂，IGF受体(***)激酶抑制剂；极光激酶抑制剂和细胞周期蛋白依赖性激酶抑制剂如CDK2和/或CDK4抑制剂；抗血管生成剂，例如那些抑制血管内皮生长因子的影响，例如抗血管内皮细胞生长因子抗体贝伐单抗(阿瓦斯丁 TM)和例如VEGF受体酪氨酸激酶抑制剂如凡德他尼，伐他拉尼，舒尼替尼，阿西替尼，帕唑帕尼和西地尼布，通过其他机制工作的化合物(例如三羧氨基喹啉，整合素αV3的功能抑制剂和血管增生抑制剂)；反义(核酸)疗法基因治疗法，例如那些上面列出的靶标，如ISIS 2503，抗ras基因的反义(核酸)疗法；基因治疗方法，包括例如替换异常基因如异常的p53或异常的BRCA1或BRCA2(例如，奥拉帕尼,Niraparib,Rucaparib,Talazoparib)，GDEPT(基因导向酶前药疗法)的方法例如使用胞嘧啶脱氨酶，胸苷激酶或细菌硝基还原酶的酶和那些以提高患者耐受化疗或放疗如多药耐药基因疗法免疫治疗方法，包括例如增加患者的肿瘤细胞的免疫原性，例如用细胞因子如白介素2，白介素4或粒细胞-巨噬细胞刺激因子转染的免疫原性，以降低T细胞无反应性的方法，采用转染的免疫细胞如细胞因子转染的树突状细胞的方法，细胞因子转染的肿瘤细胞系的方法，采用抗独特型抗体的方法，以减少免疫抑制细胞的功能，例如调节性T细胞，髓源抑制细胞或IDO,TDO，和使用由来自肿瘤相关抗原如NY-ES0-1，MAGE-3，WTI或HER2/neu的衍生的蛋白质或肽的癌症疫苗。或在癌症治疗方案中一般用作基础药剂或佐剂施用的任何其他试剂(例如，止吐剂、抗贫血剂等等)。
本文使用的术语“共同施用的”是指第二治疗剂可以与本发明的化合物一起，作为单一剂型(例如，包括本发明的化合物和如上所述的第二治疗剂的本发明组合物)的部分或作为独立的、多剂量形式来施用。或者，在本发明的化合物施用之前、或接续地、或在其之后，可以施用另外的试剂。在这样的联合治疗中，本发明的化合物和第二治疗剂通过常规方法来施用。包括本发明的化合物和第二治疗剂的本发明的组合物向受试者的给药，不排除同一治疗剂、任何其他第二治疗剂或本发明的任何化合物在治疗过程中的其他时间向所述受试者的独立给药。其中连续的或分离的施用，或延迟施用第二组分不应该失去从使用组合所产生的 效果的优点。
第二治疗剂的有效量是本领域技术人员公知的，参见，例如，Wells et al.，Pharmacotherapy Handbook,Appleton and Lange,Stamford,Conn.(2000)；PDR Pharmacopoeia,Tarascon Pocket Pharmacopoeia 2000,Tarascon Publishing,Loma Linda,Calif.(2000)和其他医学教科书中。然而，确定所述第二治疗剂的最佳有效量范围在本领域技术人员的能力之内。
在本发明的一个实施方式中，当第二治疗剂被施用给受试者时，本发明的化合物的有效量低于不施用第二治疗剂时它的有效量。在另一个实施方式中，第二治疗剂的有效量低于不施用本发明的化合物时它的有效量。这样，与高剂量的任一试剂相关的不希望的副作用可以被最小化。对于本领域技术人员，潜在的优点将是显而易见的(包括，但不限于，例如，改善给药方案和/或降低药物成本)。
在又一个方面，本发明提供本文任何通式的化合物单独地或与本文描述的一种或多种第二治疗剂一起在制造药物中的应用，作为单一组合物或作为独立的剂型，所述药物用于治疗或预防受试者中本文列举的疾病，紊乱或症状。本发明的另一个方面是用本文通式的化合物治疗或预防受试者中本文描述的疾病，紊乱或症状。
在其他方面，本文的方法包括进一步包括监测受试者对治疗给药的反应的那些方法。这样的监测可以包括作为治疗方案的标志物或指示物的受试者组织，体液，脑脊液，样本，细胞，蛋白质，化学标志物，遗传物质等等的定期采样。在其他方法中，通过评估相关标志物或指示物对这样的治疗的适应性，受试者被预先筛选或鉴定为需要这样的治疗。
在一个实施方式中，本发明提供一种监测治疗进展的方法。所述方法包括测定患有或易患有本文描述的紊乱或其症状的受试者中诊断标志物(标志物)(例如，由本文的化合物调节的本文描绘的任何靶标或细胞类型)或诊断测量值(例如，筛选、测定)的水平的步骤，其中所述受试者己经施用了足以治疗所述疾病或其症状的治疗量的本文的化合物。在所述方法中测定的标志物的水平可以与健康的正常对照中或其他患病患者中的标志物己知水平相比较，以确立受试者的疾病状况。在优选的实施方式中，在晚于测定第一水平的时间点测量受试者中的标志物的第二水平，并且比较两个水平来监测疾病的进程或疗法的功效。在某些优选的实施方式中，受试者中治疗前的标志物水平在开始根据本发明的治疗之前被测定；这种标志物的治疗前水平可以与治疗开始后受试者中的标志物水平进行比较，来确定治疗的效力。
在某些方法实施方式中，受试者中的标志物或标志物活性的水平被测定至少一次。标志物水平与例如从同一患者、另一患者或正常受试者早先或随后获得的标志物水平的另一个测量值进行比较，可用于确定根据本发明的疗法是否具有期望的效果，并且由此允许视情况调整剂量水平。标志物水平的测定可以利用本领域己知的或本文描述的任何适合的采样/表达测定方法来进行。优选地，首先从受试者取出组织或液体样品。适合的样品的实例包括血液、尿、脑脊液，组织、口或颊细胞、以及含有根部的毛发样品。其他适合的样品是本领域的技术人员己知的。样品中蛋白质水平，ctDNA,cfDNA和/或mRNA水平(例如，标志物水平)的测定可以利用本领域己知的任何适合的技术，包括但不限于，酶免疫测定、ELISA、放射性标记测定技术、印迹/化学发光方法、实时PCR,电化学信号等等来进行。
本发明还提供一种用于治疗包括本文所描述的那些的疾病、紊乱或其症状的试剂盒。这些试剂盒包括：1)包括本文的任何通式的化合物或其盐；或其前药、或前药的盐；或其水合物、溶剂合物或多晶型物的药物组合物，其中所述药物组合物处于容器中；以及2)描述利用所述药物组合物来治疗包括本文描述的疾病、紊乱或其症状的方法的说明书。所述容器可以是能够容纳所述药物组合物的任何容器或其他密封的或可密封的设备。实例包括瓶子，分开的或多室的储器瓶，其中每个分区或隔室包括所述组合物的单剂量；分隔的箔包装，其中每个分区包括单剂量的所述组合物；或分配器，其分配单剂量的所述组合物。所述容器可以是本领域己知的任何常规的形状或形式，其由药学可接受的材料制成，例如纸或纸板盒、玻璃或塑料瓶或罐、可重新密封的袋子(例如，以容纳片剂的“重新装填物”用于放置到不同容器中)、或具有单个剂量的泡罩包装用于根据治疗时间表从包装中挤出。采用的容器可以取决于所涉及的确切剂型，例如，常规的纸板盒一般将不用于容纳液体悬浮液。可行的是，可以在单个包装中一起使用超过一个容器来将单一剂型市场化。例如，片剂可以容纳在瓶子中，瓶子接着容纳在盒子内。优选地，容器是泡罩包装。
试剂盒可以另外包括医师、药剂师或受试者的信息和/或说明书。这些记忆辅助物包括打印在含有药剂的每个隔室或分区上的数字，其与所指定的片剂或胶囊应当摄入的方案的天数相符，或打印在每个隔室或分区上的每周的天数，或包含相同类型信息的卡片。
在本发明所述在具有EGFRV3活化突变的用途中，本发明所述喹唑啉衍生物(I)的对映体纯度具有大于约55％至约99.5％，大于约60％至约99.5％，大于约65％至约99.5％，大于约70％至约99.5％，大于约75％至约99.5％，大于约80％至约99.5％，大于约85％至约 99.5％，大于约90％至约99.5％，大于约95％至约99.5％，大于约96％至约99.5％，大于约97％至约99.5％，大于约98％至大于约99.5％，大于约99％至约99.5％，或更高。
本文描绘的化合物可以使用本领域中己知的方案，包括，例如，本文中描绘的那些，来评价它们的生物活性。本文的某些化合物证明了出人意料的优异的属性(例如，代谢稳定性，高选择性，低流出率，高渗透率，非P糖蛋白外排底物等)，使得它们成为潜在治疗剂的优异候选物。
本文引用的所有参考文献，无论是以电子的，打印的，计算机可读的保存介质或其他形式，都明确地整体引入本文以供参考，包括，但不限于，摘要、文章、期刊、出版物、教科书、论文、技术数据表、互联网网站、数据库、专利、专利申请以及专利出版物。
下面结合实施例对本发明进行详细说明。以下实施例将有助于本领域的技术人员进一步理解本发明，但不以任何形式限制本发明。应当指出的是，对本领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干调整和改进。这些都属于本发明的保护范围。
实施例1.喹唑啉衍生物(I)的制备
1.1中间体5-氟-4-甲氧基-2-硝基苄腈A6和1-溴-5-氟-4-(氘代甲氧基)-2-硝基苯C1的合成
合成路线如下：
Figure PCTCN2019079043-appb-000003
步骤一：在A1(2.0克，10.5mmol)和三乙胺(1.3克，12.6mmol)的二氯甲烷(10毫升)溶液中0℃逐滴加入在二氯甲烷(3毫升)的氯甲酸乙酯(1.4克，12.6mmol)溶液。将反应混合物在0摄氏度下搅拌1小时，并使其达到室温。反应混合物然后用水洗涤两次。将有机层用硫酸镁干燥并真空蒸发，得到为无色油状物的产物A2(2.7克，产率100％)。
步骤二:向A2(2.7克，10.3mmol)在浓硫酸(4.6mL)的溶液中10摄氏度逐滴加入发烟硝酸(0.73毫升，15.5mmol)。1小时后，将反应混合物倒入冰/水中，并用乙酸乙酯萃取两次。将合并的有机层用水，碳酸氢钠和盐水洗涤，经硫酸钠干燥并真空蒸发，得到残余物，将其用硅胶柱(正己烷/乙酸乙酯＝20/1)纯化，得到为黄色油状物产物A3(3.0克，产 率94.6％)。
步骤三:A3(3.0克，9.8mmol)在甲醇(17毫升)中的溶液中加入碳酸氢钠(1.6克，19.6mmol)。将反应混合物在60摄氏度下搅拌3小时。甲醇在真空下蒸发。水(15毫升)加入到残余物中，水层通过加入5摩尔氯化氢的溶液酸化至pH＝5。用乙酸乙酯萃取水层两次。合并的有机层用硫酸镁干燥，并真空蒸发，得到为黄色固体的产物A4(2.3克，产率100％)。
步骤四:在A4(2.31克，9.8mmol)的氮,氮-二甲基甲酰胺(18.5毫升)溶液中加入碳酸钾(2.7克，19.6mmol)和甲基碘(1.22毫升，19.6mmol)。将反应混合物在60摄氏度下搅拌3小时。将所得混合物在水和乙酸乙酯之间分离。将有机层经硫酸钠干燥并真空蒸发，得到为黄色固体的产物A5(2.35克，产率97％)。
步骤五:在A5(5.17克，20.7mmol)和氰化锌(1.46克，12.4mmol)的混合物的氮,氮-二甲基乙酰胺(104毫升)溶液中搅拌，并用氮气排出空气后，加入钯催化剂，Pd 2(dba) 3(1.90克,2.07mmol)，和配体，2-二环己膦基-2'-(氮,氮-二甲胺)-联苯(815毫克，2.07mmol)，并将该反应混合物在110摄氏度搅拌5小时。然后将其冷却至室温，稀释至乙酸乙酯中，通过硅藻土过滤。有机液用盐水洗涤，经硫酸钠干燥，在真空中浓缩并通过硅胶柱(乙酸乙酯/正己烷：1:50至1：10)纯化，得到为浅黄色固体产物A6(3.47克，产率85.7％)。 1HNMR:(400MHz,DMSO-d6)δppm: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中间体叔丁基3,3-二氟-4-羟基哌啶-1-甲酸叔丁酯B8和3,3-二氟-1-甲基哌啶-4-醇C2的合成
合成路线如下：
Figure PCTCN2019079043-appb-000004
步骤一：到苯并三氮唑(47克，394.5mmol)在甲醇(300毫升)溶液中加入B1(81.7 克，394.5mmol)和37％甲醛(37.9毫升，512.9mmol)，所得到的混合物在室温下搅拌16小时。在真空下除去混合物，将残余物倾入到水(500毫升)中，用乙酸乙酯萃取(500毫升×3)，经硫酸钠干燥，过滤并浓缩，得到为黄色油状物产品B2(132克，产率98.8％)。
步骤二：在室温下,向在锌粉(56克，862mmol)的四氢呋喃(500毫升)溶液中加入的三甲基硅氯(49克，452mmol)。将所得悬浮液搅拌在室温下15分钟后然后逐滴加入二氟溴乙酸乙酯(96克，474mmol)，将混合物搅拌15分钟。然后室温下加入B2(146克，431mmol)在四氢呋喃(500毫升)中的溶液，并搅拌过夜。该混合物倒入碳酸氢钠(2.5升)的饱和水溶液，用乙酸乙酯(500毫升)萃取，用硅藻土过滤，分离，有机相经硫酸钠干燥，过滤并浓缩，得到残余物，将其用硅胶柱纯化(乙酸乙酯/正己烷＝1/50至1/20)，得到为黄色油状物的产物B3(90克，产率60.8％)。
步骤三：向二异丙胺(63.0克，629mmol)的四氢呋喃(500毫升)溶液中在零下70摄氏度滴加正丁基锂(2.5M己烷，231.5毫升，576mmol)溶液，将所得混合物升温至零下10摄氏度反应30分钟。然后将体系冷却至在零下70摄氏度后逐滴加入B3(90克，262mmol)的四氢呋喃溶液(500升)。搅拌30分钟，并逐渐升温至室温并再搅拌1小时。将混合物倾入饱和氯化铵水溶液(500毫升)中，用乙酸乙酯(500升×3)萃取，有机相经硫酸钠干燥，过滤并浓缩，得到为黄色油状物产品B4(90.7克)。粗品不经纯化直接用于下一步骤中。
步骤四：B4(90克，302mmol)加入6摩尔盐酸(900毫升)水溶液，将混合物加热至回流3小时。冷却至室温后，将混合物缓慢倒入8摩尔氢氧化钠(1升)，用乙酸乙酯萃取(1升)三次，有机相浓缩至4-5升，加入正己烷(600毫升)，将混合物搅拌1小时并过滤，得到为白色固体产物B5(34克，两步产率46.5％)。
步骤五：到B5(34克，139mmol)的甲醇(730毫升)溶液中在0-5摄氏度分批加入硼氢化钠(7.9克，209mmol)。将混合物在0-5摄氏度下再搅拌15分钟后加入碳酸氢钠水溶液(0.1摩尔，54毫升)，并将混合物搅拌5分钟，将混合物用硫酸钠干燥，浓缩，并通过硅胶柱纯化(乙酸乙酯/正己烷＝1/20至1/10)，得到无色油状产物B6(30克，产率97.1％)。
步骤六：到B6(30克，134mmol)的乙醇(600毫升)溶液中加入催化剂氢氧化钯/活性炭(10％，3.0克)，将混合物在氢气球下搅拌4小时。过滤该混合物并浓缩，得到为白色固体产物B7(15.8克，产率85.8％)。1HNMR:(400MHz,DMSO-d6)δppm: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) +
步骤七：在室温下,至B7(500毫克，3.6mmol)的88％甲酸溶液(941毫克，18.0mmol)中加入
Figure PCTCN2019079043-appb-000005
的甲醛(584毫克，7.2mmol)溶液。将溶液在78摄氏度下搅拌30分钟。该混合物用氢氧化钠水溶液洗涤调节pH至
Figure PCTCN2019079043-appb-000006
用乙酸乙酯萃取混合物(30毫升×3)。将有机相用硫酸钠干燥并浓缩，得到为白色固体产物B8(340毫克，产率62.5％)。 1H NMR(400MHz,DMSO-d6)δ5.48(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中间体(Z)-氮’-{2-氰基-4-[(3,3-二氟-1-甲基哌啶-4-基)氧基]-5-甲氧基苯基}-氮，氮-2甲基甲脒A9的合成
合成路线如下：
Figure PCTCN2019079043-appb-000007
步骤一：向氢化钠(4.85克，102mmol)的氮,氮-二甲基乙酰胺(10毫升)溶液中在50摄氏度氮气保护下滴加A6(10克，51mmol)和B8(7.71克，51mmol)的氮,氮-二甲基乙酰胺(30毫升)溶液。在0摄氏度下搅拌1小时。将混合物倒入氯化铵的饱和溶液，并用乙酸乙酯萃取。将有机相用盐水洗涤，经硫酸钠干燥，在真空中浓缩并通过硅胶柱纯化(乙酸乙酯/正己烷＝1:3至1：1)，得到为黄色固体产物A7(12克，产率71％)。 1HNMR:(400MHz,CDCl 3-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) +
步骤二：在A7(5克，15.28mmol)的醋酸(250毫升)溶液中加入锌粉(9.93克，152.8mmol)中。混合物在30-40摄氏度搅拌0.5小时。反应液倒入乙酸乙酯(200mL)和水(400mL)中加入碳酸氢钠调节pH值至7.分离有机相并用硫酸钠干燥。过滤该混合物真空浓缩 滤液，得到为黄色油状物产物A8(4.4克，产率88.0％)直接用于下一步。LC-MS:(ESI)m/z＝298(M+H) +
步骤三：A8(4.4克，14.8mmol)和氮,氮-二甲基甲酰胺二甲基缩醛(8.8克，74mmol)的甲苯(50毫升)溶液中的混合物在100摄氏度在氮气保护下搅拌20小时。真空浓缩该混合物，得到残余物，将其用硅胶柱纯化(二氯甲烷/甲醇＝100:1)，得到为黄色油状物产物A9(3.4克，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) +。
1.4喹唑啉衍生物(I)的合成
合成路线如下：
Figure PCTCN2019079043-appb-000008
步骤一：A9(3.4克，9.65mmol)和2-氟-3-((三甲基硅甲烷基)乙炔基)苯胺(4克，19.3mmol)在醋酸(90毫升)的混合物，在80摄氏度氮气保护下搅拌16小时。冷却后，用碳酸氢钠饱和溶液处理至pH＝8，并用二氯甲烷萃取。有机相用硫酸钠干燥并真空浓缩得到残余物，将其用硅胶柱纯化(二氯甲烷/甲醇＝100：1)，得到为白色固体产物A10(2.4克，产率48％)。LC-MS:(ESI)m/z＝515(M+H) +
步骤二：在A10(1克，1.94mmol)在四氢呋喃(10毫升)的溶液中加入TBAF(1M四氢呋喃溶液，1.94毫升，1.94mmol)，在室温下搅拌0.5小时。真空浓缩，将其用硅胶柱纯化(二氯甲烷/甲醇＝200：1至100：1)，得到为黄色固体产物A11(800毫克，产率93％)。 1HNMR:(400MHz,CDCl 3-d6)δppm: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) +
步骤三：外消旋混合物A11(1.03克)经高效液相手性分离柱OJ-H(4.6*100*5um)使用甲醇(0.2％甲醇氨)过柱得对映体纯(R)/(-)的自由碱化合物(I)(480毫克，ee％>99％,LC-MS:(ESI)m/z＝443(M+H) +)。
上述方法为水合物，具有吸湿性，加热过程中出现晶型转换。由于吸湿且热不稳定难以在药物加工条件下制成固体制剂。因此，需要进一步制备具有优越的物理化学性质的喹唑啉衍生物的优选盐型及盐的晶型，其可有利的在药物加工和药物组合物中使用。
实施例2.本发明喹唑啉衍生物(I)的盐酸盐晶型A的制备
称取约20毫克的式(I)所示喹唑啉衍生物(即，(R)-6-[(3,3-二氟-1-甲基哌啶-4-基)氧基]-氮-(3-乙炔基-2-氟苯基)-7-甲氧基喹唑啉-4-胺(I))样品于1.5毫升小瓶中，加入0.6毫升甲醇和46微升盐酸(1mol/L)，在室温下搅拌约两天后，离心分离出下层湿样固体。经XRPD检测，该固体为盐酸盐晶型A。
实施例3.本发明喹唑啉衍生物(I)的盐酸盐晶型B的制备
称取约160毫克的式(I)所示喹唑啉衍生物样品，加入5毫升四氢呋喃/水(19/1,v/v)，并向该悬浮液中加入0.37毫升的盐酸(1mol/L)，在室温下搅拌约两天，离心分离出下层湿样固体。经XRPD检测，该固体为盐酸盐晶型B。
实施例4.本发明喹唑啉衍生物(I)的盐酸盐晶型H的制备
称取约10毫克的盐酸盐晶型B样品于3毫升小瓶中，加入2毫升乙醇，过滤后于室温下敞口快速挥发。经XRPD检测，所得固体为盐酸盐晶型H。
实施例5.本发明喹唑啉衍生物(I)的盐酸盐晶型I的制备
称取约10毫克的盐酸盐晶型H样品，采用DSC Q2000将其加热至125℃后降温至室温，得到盐酸盐晶型I。
实施例6.本发明喹唑啉衍生物(I)的富马酸盐晶型A的制备
称取约160毫克式(I)所示喹唑啉衍生物及45毫克富马酸样品于20毫升玻璃瓶中，加入5毫升甲醇后，在室温下搅拌约两天，离心收集固体。经XRPD检测，该固体为富马酸盐晶型A。
实施例7.本发明喹唑啉衍生物(I)的琥珀酸盐晶型A的制备
称取约160毫克式(I)所示喹唑啉衍生物及43毫克琥珀酸样品于20毫升玻璃瓶中，加入5毫升丙酮后，在室温下搅拌约两天，离心收集固体。经XRPD检测，该固体为琥珀酸盐晶型A。
实施例8.本发明喹唑啉衍生物(I)的马来酸盐晶型A的制备
称取约10毫克式(I)所示喹唑啉衍生物及2.6毫克马来酸样品于1.5毫升玻璃瓶中，加入0.3毫升丙酮，在室温下搅拌约两天，离心收集固体。经XRPD检测，该固体为马来酸盐晶型A。
实施例9.本发明喹唑啉衍生物(I)的乙醇酸盐晶型A的制备
称取约150毫克式(I)所示喹唑啉衍生物及27毫克乙醇酸样品于1.5毫升玻璃瓶中，加入5毫升乙酸乙酯，在室温下搅拌约两天，离心收集固体。经XRPD检测，该固体为乙醇酸盐晶型A。
实施例10.本发明喹唑啉衍生物(I)的盐酸盐晶型F的制备
称取约5毫克的盐酸盐样品于3毫升玻璃小瓶中，加入0.1毫升甲醇使其溶解。将所得澄清溶液置于盛有5毫升乙酸异丙酯的20毫升玻璃瓶中，于室温下气液扩散，直至有固体析出。经XRPD检测，所得固体为盐酸盐晶型F。
实施例11.本发明喹唑啉衍生物(I)的盐酸盐晶型C的制备
称取约10毫克的式(I)所示喹唑啉衍生物样品，加入0.3毫升乙腈，并向该悬浮液中加入46微升的盐酸(1mol/L)，在室温下搅拌约两天后离心分离出下层湿样固体。经XRPD检测，鉴定为二盐酸盐晶型C。
实施例12.本发明喹唑啉衍生物(I)的盐酸盐晶型D的制备
称取约2毫克的盐酸盐晶型C样品，采用DSC Q2000将其加热至140度后冷却至室温，得到二盐酸盐晶型D。
实施例13.本发明喹唑啉衍生物(I)的硫酸盐晶型A的制备
称取约10毫克式(I)所示喹唑啉衍生物样品于1.5毫升玻璃瓶中，加入0.3毫升甲醇及23微升硫酸水溶液(1mol/L)，在室温下搅拌约两天，离心收集固体。经XRPD检测，该固体为硫酸盐晶型A。
实施例14.本发明喹唑啉衍生物(I)的乙二酸盐晶型A的制备
称取约10毫克式(I)所示喹唑啉衍生物及3.7毫克己二酸样品于1.5毫升玻璃瓶中，加入0.3毫升甲醇，在室温下搅拌约两天，离心收集固体。经XRPD检测，该固体为己二酸盐晶型A(含少量未反应完全的己二酸，特征峰为：21.6，25.7)。
实施例15.本发明喹唑啉衍生物(I)的苹果酸盐晶型A的制备
称取约10毫克式(I)所示喹唑啉衍生物及2.9毫克苹果酸样品于1.5毫升玻璃瓶中，加入0.3毫升甲醇后，在室温下搅拌约两天，离心收集固体。经XRPD检测，该固体为苹果酸盐晶型A。
实施例16.本发明喹唑啉衍生物(I)的苯磺酸盐晶型A的制备
称取约10毫克式(I)所示喹唑啉衍生物及3.7毫克苯磺酸样品于1.5毫升玻璃瓶中，加入0.3毫升甲醇，在室温下搅拌约两天，离心收集固体。经XRPD检测，该固体为苯磺酸盐晶型A。
实施例17.本发明喹唑啉衍生物(I)的苯磺酸盐晶型B的制备
称取约10毫克式(I)所示喹唑啉衍生物及3.5毫克苯磺酸样品于1.5毫升玻璃瓶中，加入0.3毫升乙腈，在室温下搅拌约两天，离心收集固体。经XRPD检测，该固体为苯磺酸盐晶型B。
实施例18.本发明喹唑啉衍生物(I)的苯磺酸盐晶型C的制备
称取约10毫克式(I)所示喹唑啉衍生物及3.9毫克苯磺酸样品于1.5毫升玻璃瓶中，加入0.3毫升四氢呋喃和水的混合溶剂(19:1,v/v)，在室温下搅拌约两天，离心收集固体。经XRPD检测，该固体为苯磺酸盐晶型C。
实施例19.本发明喹唑啉衍生物(I)的苯甲酸盐晶型A的制备
称取约10毫克式(I)所示喹唑啉衍生物及3.0毫克苯甲酸样品于1.5毫升玻璃瓶中，加入0.3毫升甲醇后，在室温下搅拌约两天，离心收集固体。经XRPD检测，该固体为苯甲酸盐晶型A。
实施例20.本发明喹唑啉衍生物(I)的马尿酸盐晶型A的制备
称取约10毫克式(I)所示喹唑啉衍生物及4.2毫克马尿酸样品于1.5毫升玻璃瓶中，加入0.3毫升甲醇后，在室温下搅拌约两天，离心收集固体。经XRPD检测，该固体为马尿酸盐晶型A。
实施例21.本发明喹唑啉衍生物(I)的草酸盐晶型A的制备
称取约10毫克式(I)所示喹唑啉衍生物及2.0毫克草酸样品于1.5毫升玻璃瓶中，加入0.3毫升甲醇后，在室温下搅拌约两天，离心收集固体。经XRPD检测，该固体为草酸盐晶型A。
实施例22.通过XRPD图来表征本发明的喹唑啉衍生物(I)的盐的晶型
XRPD仪器信息如下：
XRPD图谱在Bruker的X射线粉末衍射分析仪上采集，XRPD参数如表1所示。
表1 XRPD测试参数
Figure PCTCN2019079043-appb-000009
根据本实施例所述方法制备的喹唑啉衍生物(I)的盐酸盐晶型A，其XRPD(X射线粉末衍射)图谱如附图1所示，具体表征如下表2：
表2
Figure PCTCN2019079043-appb-000010
Figure PCTCN2019079043-appb-000011
根据实施例所述方法制备的喹唑啉衍生物(I)的盐酸盐晶型B，其XRPD(X射线粉末衍射)图谱如附图2所示，具体表征如下表3：
表3
Figure PCTCN2019079043-appb-000012
根据实施例所述方法制备的喹唑啉衍生物(I)的盐酸盐晶型H，其XRPD(X射线粉末衍射)图谱如附图3所示，具体表征如下表4：
表4
Figure PCTCN2019079043-appb-000013
Figure PCTCN2019079043-appb-000014
根据实施例所述方法制备的喹唑啉衍生物(I)的盐酸盐晶型I，其XRPD(X射线粉末衍射)图谱如附图4所示，具体表征如下表5：
表5
Figure PCTCN2019079043-appb-000015
Figure PCTCN2019079043-appb-000016
根据实施例所述方法制备的喹唑啉衍生物(I)的富马酸盐晶型A，其XRPD(X射线粉末衍射)图谱如附图5所示，具体表征如下表6：
表6
Figure PCTCN2019079043-appb-000017
Figure PCTCN2019079043-appb-000018
根据实施例所述方法制备的喹唑啉衍生物(I)的琥珀酸盐晶型A，其XRPD(X射线粉末衍射)图谱如附图6所示，具体表征如下表7：
表7
Figure PCTCN2019079043-appb-000019
Figure PCTCN2019079043-appb-000020
根据实施例所述方法制备的喹唑啉衍生物(I)的马来酸盐晶型A，其XRPD(X射线粉末衍射)图谱如附图7所示，具体表征如下表8：
表8
Figure PCTCN2019079043-appb-000021
Figure PCTCN2019079043-appb-000022
根据实施例所述方法制备的喹唑啉衍生物(I)的乙醇酸盐晶型A，其XRPD(X射线粉末衍射)图谱如附图8所示，具体表征如下表9：
表9
Figure PCTCN2019079043-appb-000023
Figure PCTCN2019079043-appb-000024
根据实施例所述方法制备的喹唑啉衍生物(I)的盐酸盐晶型F，其XRPD(X射线粉末衍射)图谱如附图9所示，具体表征如下表10：
表10
Figure PCTCN2019079043-appb-000025
Figure PCTCN2019079043-appb-000026
根据实施例所述方法制备的喹唑啉衍生物(I)的盐酸盐晶型C，其XRPD(X射线粉末衍射)图谱如附图10所示，具体表征如下表11：
表11
Figure PCTCN2019079043-appb-000027
Figure PCTCN2019079043-appb-000028
根据实施例所述方法制备的喹唑啉衍生物(I)的盐酸盐晶型D，其XRPD(X射线粉末衍射)图谱如附图11所示，具体表征如下表12：
表12
Figure PCTCN2019079043-appb-000029
Figure PCTCN2019079043-appb-000030
根据实施例所述方法制备的喹唑啉衍生物(I)的硫酸盐晶型A，其XRPD(X射线粉末衍射)图谱如附图12所示，具体表征如下表13：
表13
Figure PCTCN2019079043-appb-000031
Figure PCTCN2019079043-appb-000032
根据实施例所述方法制备的喹唑啉衍生物(I)的乙二酸盐晶型A，其XRPD(X射线粉末衍射)图谱如附图13所示，具体表征如下表14：
表14
Figure PCTCN2019079043-appb-000033
Figure PCTCN2019079043-appb-000034
根据实施例所述方法制备的喹唑啉衍生物(I)的苹果酸盐晶型A，其XRPD(X射线粉末衍射)图谱如附图14所示，具体表征如下表15：
表15
Figure PCTCN2019079043-appb-000035
Figure PCTCN2019079043-appb-000036
根据实施例所述方法制备的喹唑啉衍生物(I)的苯磺酸盐晶型A，其XRPD(X射线粉末衍射)图谱如附图15所示，具体表征如下表16：
表16
Figure PCTCN2019079043-appb-000037
Figure PCTCN2019079043-appb-000038
根据实施例所述方法制备的喹唑啉衍生物(I)的苯磺酸盐晶型B，其XRPD(X射线粉末衍射)图谱如附图16所示，具体表征如下表17：
表17
Figure PCTCN2019079043-appb-000039
根据实施例所述方法制备的喹唑啉衍生物(I)的苯磺酸盐晶型C，其XRPD(X射线粉末衍射)图谱如附图17所示，具体表征如下表18：
表18
Figure PCTCN2019079043-appb-000040
Figure PCTCN2019079043-appb-000041
根据实施例所述方法制备的喹唑啉衍生物(I)的苯甲酸盐晶型A，其XRPD(X射线粉末衍射)图谱如附图18所示，具体表征如下表19：
表19
Figure PCTCN2019079043-appb-000042
Figure PCTCN2019079043-appb-000043
根据实施例所述方法制备的喹唑啉衍生物(I)的马尿酸盐晶型A，其XRPD(X射线粉末衍射)图谱如附图19所示，具体表征如下表20：
表20
Figure PCTCN2019079043-appb-000044
Figure PCTCN2019079043-appb-000045
根据实施例所述方法制备的喹唑啉衍生物(I)的草酸盐晶型A，其XRPD(X射线粉末衍射)图谱如附图20所示，具体表征如下表21：
表21
Figure PCTCN2019079043-appb-000046
Figure PCTCN2019079043-appb-000047
d是晶体晶格中相邻两个晶面的面间距，以埃为单位，I％是强度。
由图1可知，本发明提供的喹唑啉衍生物(I)的盐酸盐晶型A的XRPD图谱在2θ＝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处具有衍生峰，上述2θ值的误差范围为±0.2。
由图2可知，本发明提供的喹唑啉衍生物(I)的盐酸盐晶型B的XRPD图谱在2θ＝4.32，5.98，6.54，7.28，8.17，10.52，13.20，15.99，17.74，18.48，19.32，19.84，22.56，23.88，24.36，24.87，30.47，32.92，33.55，34.60，38.06，38.34处具有衍生峰，上述2θ值的误差范围为±0.2。
由图3可知，本发明提供的喹唑啉衍生物(I)的盐酸盐晶型H的XRPD图谱在2θ＝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， 20.25，21.07，21.65，24.16，24.53，25.67，26.37，27.03，27.61处具有衍生峰，上述2θ值的误差范围为±0.2。
由图4可知，本发明提供的喹唑啉衍生物(I)的盐酸盐晶型I的XRPD图谱在2θ＝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处具有衍生峰，上述2θ值的误差范围为±0.2。
由图5可知，本发明提供的喹唑啉衍生物(I)的富马酸盐晶型A的XRPD图谱在2θ＝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处具有衍生峰，上述2θ值的误差范围为±0.2。
由图6可知，本发明提供的喹唑啉衍生物(I)的琥珀酸盐晶型A的XRPD图谱在2θ＝3.92，4.40，6.56，6.74，7.50，9.42，11.92，12.68，13.53，14.50，14.84，15.22，15.68，16.25，17.82，18.55，19.48，20.34，20.99，22.08，22.59，24.14，24.52，24.92，28.07，30.92，36.11处具有衍生峰，上述2θ值的误差范围为±0.2。
由图7可知，本发明提供的喹唑啉衍生物的马来酸盐晶型A的XRPD图谱在2θ＝6.25，8.44，8.68，9.42，10.41，14.42，14.88，16.65，17.93，18.78，20.58，21.17，22.63，25.16，31.15，32.40，33.66，34.34，34.52，35.82，36.06，36.35，36.91处具有衍生峰，上述2θ值的误差范围为±0.2。
由图8可知，本发明提供的喹唑啉衍生物的乙醇酸盐晶型A的XRPD图谱在2θ＝4.53，5.89，6.59，7.35，10.02，12.54，13.26，15.94，17.93，18.67，19.36，19.84，21.06，24.99，31.13，33.48，34.79，35.56，36.17处具有衍生峰，上述2θ值的误差范围为±0.2。
由图9可知，本发明提供的喹唑啉衍生物(I)的盐酸盐晶型F的XRPD图谱在2θ＝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处具有衍生峰，上述2θ值的误差范围为±0.2。
由图10可知，本发明提供的喹唑啉衍生物(I)的盐酸盐晶型C的XRPD图谱在2θ＝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， 16.86，17.61，22.04，22.93，24.55，26.19，27.30，28.49，34.12，34.76，35.65，36.68，37.31，37.80，38.20，38.53处具有衍生峰，上述2θ值的误差范围为±0.2。
由图11可知，本发明提供的喹唑啉衍生物(I)的盐酸盐晶型D的XRPD图谱在2θ＝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处具有衍生峰，上述2θ值的误差范围为±0.2。
由图12可知，本发明提供的喹唑啉衍生物(I)的硫酸晶型A的XRPD图谱在2θ＝7.27，8.41，11.88，14.96，18.23，19.68，20.64，24.83，25.82，27.10，28.16，29.79，30.71，32.35，34.12，35.56，37.56，38.37处具有衍生峰，上述2θ值的误差范围为±0.2。
由图13可知，本发明提供的喹唑啉衍生物(I)的乙二酸盐晶型A的XRPD图谱在2θ＝5.43，6.88，7.38，9.56，13.68，15.10，15.43，16.32，16.88，17.68，18.60，19.02，20.58，21.62，22.33，22.70，23.35，25.68，27.29，27.88，28.53，29.37，31.35，34.89，37.11，37.78，38.17，38.36，39.65处具有衍生峰，上述2θ值的误差范围为±0.2。
由图14可知，本发明提供的喹唑啉衍生物(I)的苹果酸盐晶型A的XRPD图谱在2θ＝5.43，6.53，7.49，8.35，9.17，12.10，13.16，16.17，18.77，19.85，20.79，23.14，23.94，26.66，28.25，29.32，30.38，33.24，33.69，34.80，35.97，36.87，37.88处具有衍生峰，上述2θ值的误差范围为±0.2。
由图15可知，本发明提供的喹唑啉衍生物的苯磺酸盐晶型A的XRPD图谱在2θ＝5.48，6.56，7.08，7.65，8.14，8.48，9.71，10.55，11.14，11.77，13.32，13.95，15.32，16.46，16.89，17.82，19.15，19.70，20.43，21.02，21.98，22.68，23.23，25.26，26.07，26.59，28.63，29.09，30.45，31.12，32.09，32.55，33.66，35.76，37.86，38.67，39.11处具有衍生峰，上述2θ值的误差范围为±0.2。
由图16可知，本发明提供的喹唑啉衍生物的苯磺酸盐晶型B的XRPD图谱在2θ＝5.50，6.32，7.28，8.50，9.74，10.79，11.55，13.22，14.49，15.53，16.26，16.97，18.29，19.71，21.36，22.21，23.44，24.19，25.34，25.87，27.16处具有衍生峰，上述2θ值的误差范围为±0.2。
由图17可知，本发明提供的喹唑啉衍生物(I)的苯磺酸盐晶型C的XRPD图谱在2θ＝4.24，7.07，7.68，8.31，9.92，12.55，14.03，14.74，18.72，19.40，20.36，21.19， 24.08，24.73，26.14，27.49，28.28，31.68，33.90，34.82，35.06，35.78，36.54，37.57，37.89，38.36，39.0处具有衍生峰，上述2θ值的误差范围为±0.2。
由图18可知，本发明提供的喹唑啉衍生物(I)的苯甲酸盐晶型A的XRPD图谱在2θ＝4.45，6.31，6.65，7.33，7.69，8.01，11.85，13.53，16.02，16.77，18.75，19.95，21.06，21.76，22.56，23.41，26.94，27.44，27.61，27.98，28.55，29.05，31.92，32.29，32.93，33.72，34.61，35.35，35.95，37.08，38.13，39.62处具有衍生峰，上述2θ值的误差范围为±0.2。
由图19可知，本发明提供的喹唑啉衍生物(I)的马尿酸盐晶型A的XRPD图谱在2θ＝4.35，5.59，6.85，7.74，9.17，9.95，13.74，14.73，15.96，16.44，18.10，18.63，19.96，21.38，24.25，25.37，25.72，26.39，27.23，28.56，30.25，30.82，33.31，34.58，35.29，36.39，37.24，37.9处具有衍生峰，上述2θ值的误差范围为±0.2。
由图20可知，本发明提供的喹唑啉衍生物(I)的草酸盐晶型A的XRPD图谱在2θ＝4.11，6.44，7.15，8.75，9.06，9.88，11.26，11.58，12.92，14.52，15.87，17.47，18.29，19.43，20.14，20.49，23.70，24.34，26.36，26.92，29.75，31.72，32.67，32.99，34.21，34.52，34.86，36.36，36.91，37.91，39.03处具有衍生峰，上述2θ值的误差范围为±0.2。
经测试，2θ值的误差范围也可以是±0.2.本领域技术人员应理解，这些衍射峰不代表喹唑啉衍生物(I)的盐酸盐晶型A,B,C,D,F,H,I,硫酸盐晶型A,马来酸盐晶型A,琥珀酸盐晶型A,己二酸盐晶型A,乙醇酸盐晶型A,苹果酸盐晶型A,富马酸盐晶型A,苯磺酸盐晶型A,B,C,苯甲酸盐晶型A,马尿酸盐晶型A及草酸盐晶型A所显示衍射峰的详尽情况。X-射线粉末衍射图的2θ值是可以随着机器以及样品制备中的变化和批次间变化而发生轻微变化，所引用的值不视为绝对值。还应理解的是，峰的绝对强度也可能随着取向效应而变，因此，本发明所示强度是示例性的，并不用于绝对比较。
实施例23.喹唑啉衍生物(I)的生物活性
具有EGFR活化突变(外显子19缺失Exon 19 Del)蛋白的肿瘤细胞和脑胶质瘤的细胞活力检测使用CellTiter-Glo(CTG)assay；约5000个细胞种在每个空白的96孔板中，16小时后，加入按比例稀释的化合物，在药物添加72小时后，在室温平衡30分钟。在每孔中加入100微升CellTiter-Glo试剂，轨道摇床2分钟混匀以诱导细胞裂解。该板在室温下孵育10分钟以稳定发光信号。在TECAN Infinite M1000 Pro仪器记录发光信号。
表22.非小细胞肺癌PC-9肿瘤细胞和脑胶质瘤肿瘤细胞生长的抑制(IC 5o的单位是nM)
Figure PCTCN2019079043-appb-000048
由表22可知，本发明所述构型为R的喹唑啉衍生物(I)具有意想不到的EGFRVIII突变的活性，比对映异构体活性高>100倍。具有与EGFR Del19活化突变类似的生物活性。
如图21所示，蛋白免疫印迹(western blot)实验中，EGFRV3的磷酸化被喹唑啉衍生物(I)抑制，显示喹唑啉衍生物(I)具有良好的生物活性，特异的针对EGFRV3磷酸化所介导的癌症。
实施例24.喹唑啉衍生物(I)的穿过血脑屏障率
为确定喹唑啉衍生物(I)是否能够穿过血脑屏障(BBB)，用测试化合物对大鼠进行给药。在给药4个小时后，杀大鼠，收集血和脑组织，分析测试化合物浓度。脑渗透被定义为脑组织中的化合物浓度与血浆中的浓度之比。穿过血脑屏障率为脑组织中的药物自由浓度与血浆中的药物自由浓度之比。P-糖蛋白是血脑屏障外排蛋白，将P-糖蛋白底物外排出颅内。乳腺癌耐药蛋白是血脑屏障外排蛋白，将乳腺癌耐药蛋白外排出颅内。
表23.喹唑啉衍生物(I)的穿过血脑屏障能力
  喹唑啉衍生物(I)
穿过血脑屏障率 >50％
P-糖蛋白外排底物 不是
乳腺癌耐药蛋白外排底物 不是
在穿过血脑屏障率检测中，本发明的化合物(I)在脑组织中的化合物自由浓度与血浆中的自由浓度之比高于50％，并且不是P-糖蛋白底物或乳腺癌耐药蛋白外排底物，能穿过血脑屏障，因此它们具有在颅内达到有效血药浓度的潜力，用于治疗脑胶质瘤或治疗和预防癌症脑转移，脑膜转移，脑癌和其他中枢神经疾病，并且减少在颅外出现剂量限制性毒性的风险。
实施例25.喹唑啉衍生物(I)对具有EGFRV3突变的脑瘤在小鼠皮下患者原代肿瘤组织的 肿瘤移植动物模型的药效
患者原代肿瘤组织(脑瘤)种入小鼠皮下，肿瘤长至约150立方毫米后开始用药，治疗三周。
在具有EGFRV3突变的脑瘤在小鼠皮下患者原代肿瘤组织的肿瘤移植动物模型药效实验中，第一组为对照组，不含任何药物。第二组喹唑啉衍生物(I)单药，3毫克/公斤，口服，一日两次，第三组喹唑啉衍生物(I)单药，10毫克/公斤，口服，一日两次，第四组喹唑啉衍生物(I)单药，20毫克/公斤，口服，一日两次。如图22所示，用药组(第二，三，四组)对比第一组(对照组)均显示对肿瘤增长的良好抑制，具有统计学意义的药效，在动物模型中显示剂量依赖性药效，第四组致肿瘤减小，显示良好的药效。并具有统计学意义的药效差异。肿瘤的RNA测序显示EGFRV3的突变，显示喹唑啉衍生物(I)具有针对EGFRV3突变的良好生物活性和药效。
实施例26.喹唑啉衍生物(I)及其盐晶型在水中的平衡溶解度
实验方法：称取约10mg的固体样品(游离碱及各盐型和晶型)，加入1.5mL水，在室温平衡24小时后分别取出0.3mL的浑浊溶液，离心分离下层固体和上层清液。上层清液通过0.45μm(PTFE)滤头过滤后，分别测试游离碱的浓度。
表23
Figure PCTCN2019079043-appb-000049
Figure PCTCN2019079043-appb-000050
由表23可知，本发明所述喹唑啉衍生物(I)各盐型晶型具有在水中良好的平衡溶解度，优选地，本发明所述喹唑啉衍生物(I)的盐酸盐晶型A,B,H,I和富马酸盐晶型A在水中的平衡溶解度>500ug/mL。这对药物的吸收非常有利。
实施例27.稳定性实验
本发明所述一周理化稳定性喹唑啉衍生物(I)的盐型和晶型在在25℃/60％RH和40℃/75％RH下存放一周物理化学性质稳定。在加热过程中TGA图谱显示实施例2-21中的各晶型均无明显变化，特别的，DSC图谱显示富马酸盐晶型A显示良好的稳定性。如图23所示，富马酸盐晶型A在加热过程中无明显失重，熔点在约240摄氏度。这样的性质是有利于制备加工成药片。
实施例28.本发明所述喹唑啉衍生物(I)具有良好的生物利用度
在大鼠药代动力学研究中，一组大鼠(三只)静脉注射1-2毫克/公斤，第二组大鼠(三只)口服2-40毫克/公斤，7个时间点(0.25，0.5，1，2，4，8，16小时点)取血测本发明所述喹唑啉衍生物(I)在血中的浓度，计算峰面积及半衰期。生物利用度的计算方式为：(药物口服峰面积/口服剂量)/(药物静脉注射峰面积/静脉注射剂量)x100％。本发明所述喹唑啉衍生物(I)的各盐型和晶型具有良好的生物利用度，均大于>35％。
优选地：盐酸盐晶型B,H，I(生物利用度>60％)和富马酸盐晶型A(生物利用度80％)；
更优选地：富马酸盐晶型A(生物利用度80％，半衰期7.4小时)。
实施例29.本发明所述喹唑啉衍生物(I)的作用机制
在本发明所述喹唑啉衍生物(I)抑制EGFR的作用机制的实验中，从0.4nM等比例(2倍)稀释的6个浓度至0.0125nM和0浓度的384孔板加入EGFR酶在PolyE4Y1的溶液，孵化15分钟加入从600uM等比例(2倍)稀释的7个浓度的ATP反应60分钟后，加入ADP-Glo试剂和检测试剂四十分钟测RLU信号。如图24所示，本发明所述喹唑啉衍生物(I)显示出意想不到的非ATP竞争作用机制。这种作用机制的好处是显而易见的，在本发明所述喹唑啉衍生物(I)具有此作用机制显示出高活性和高选择性，具有副作用小，抗耐药的特点。
综上所述，本发明所述的述喹唑啉衍生物(I)具有手性为R的6取代(3,3-二氟-1-甲基哌啶-4-基)氧基，能同时具有高活性，高选择性，高度的血脑屏障穿过率，非外排底物，具有非ATP竞争机制的抑制性质，同时对非小细胞肺癌和脑胶质瘤具有显著的药效，高度的生物利用率。需要强调的是，本发明所述喹唑啉衍生物(I)具有意想不到的能同时具有对非小细胞肺癌(由某种EGFR活化形式所介导的，特别的EGFR Del19和/或EGFR L858R活化突变所导致的那些)和脑胶质(由某种EGFR活化形式所介导的，特别的EGFRVIII活化突变所导致的那些)的高生物活性，高度的选择性，高度的血脑屏障穿过率的非ATP竞争性抑制剂。特别的，本发明所述手性为R的喹唑啉衍生物(I)的非竞争性抑制特性带来的高活性和高选择性，特别的能对脑胶质瘤具有高度的活性。
本发明喹唑啉衍生物的盐酸盐晶型A,B,C,D,F,H,I,硫酸盐晶型A,马来酸盐晶型A,琥珀酸盐晶型A,己二酸盐晶型A,乙醇酸盐晶型A,苹果酸盐晶型A,富马酸盐晶型A,苯磺酸盐晶型A,B,C,苯甲酸盐晶型A,马尿酸盐晶型A及草酸盐晶型A在水中的溶解度均大于式(I)所示喹唑啉衍生物，具有更好的溶解度，加热过程中未发生晶型转化，具有良好的稳定性。
本发明喹唑啉衍生物的的盐酸盐晶型A,B,C,D,F,H,I,硫酸盐晶型A,马来酸盐晶型A,琥珀酸盐晶型A,己二酸盐晶型A,乙醇酸盐晶型A,苹果酸盐晶型A,富马酸盐晶型A,苯磺酸盐晶型A,B,C,苯甲酸盐晶型A,马尿酸盐晶型A及草酸盐晶型A具有意想不到的优越的物理化学性质，利于在药物加工和药物组合物中使用。可应用于治疗非小细胞肺癌脑转移，脑膜转移，头颈部鳞状细胞癌，鳞状细胞癌，脑干肿瘤，原发性脑癌或脑胶质瘤等的药物，同时提供疗效及安全性的定性定量信息，对进一步研究此类固体药物的疗效及安全性具有重要的意义。
以上对本发明的具体实施例进行了描述。需要理解的是，本发明并不局限于上述特定实施方式，本领域技术人员可以在权利要求的范围内做出各种变形或修改，这并不影响本发明的实质内容。

Claims (41)

  1. 式(I)所示喹唑啉衍生物的盐酸盐的晶型，其中所述晶型为晶型A、晶型B、晶型C、晶型D、晶型F、晶型H或晶型I；
    Figure PCTCN2019079043-appb-100001
    其中，所述晶型A的XRPD图谱在下列2θ处具有主要特征峰：6.5，13.1，9.4；在下列2θ处具有次要特征峰：7.3，18.2，20.0；在下列2θ处具有再次特征峰：27.5，26.6，21.6；
    所述晶型B的XRPD图谱在下列2θ处具有主要特征峰：6.5，17.7，19.8；在下列2θ处具有次要特征峰：7.3，8.2，10.5，13.2；
    所述晶型C的XRPD图谱在下列2θ处具有主要特征峰：7.2，17.6，22.0
    次要特征峰：14.0，13.6，12.8
    再次特征峰：24.6，26.2，27.3
    所述晶型D的XRPD图谱在下列2θ处具有主要特征峰：13.4，7.1，25.4；在下列2θ处具有次要特征峰：6.7，18.0，19.8；在下列2θ处具有再次特征峰：17.2，27.3，24.7；
    所述晶型F的XRPD图谱在下列2θ处具有主要特征峰：6.8，20.5，13.6；在下列2θ处具有次要特征峰：14.8，14.3，17.9，11.9；
    所述晶型H的XRPD图谱在下列2θ处具有主要特征峰：7.3，18.0，14.1；在下列2θ处具有次要特征峰：6.4，13.2，15.8；在下列2θ处具有再次特征峰：16.8，14.5，20.3；
    所述晶型I的XRPD图谱在下列2θ处具有主要特征峰：18.6，7.4，6.9；在下列2θ处具有次要特征峰：13.2，25.1，12.3；在下列2θ处具有再次特征峰：14.7，28.1，14.2；
    其中2θ值的误差范围为±0.2。
  2. 如权利要求1所述的晶型，其特征在于，所述晶型A具有基本同图1所示的XRPD图谱；
    所述晶型B具有基本同图2所示的XRPD图谱；
    所述晶型C具有基本同图10所示的XRPD图谱；
    所述晶型D具有基本同图11所示的XRPD图谱；
    所述晶型F具有基本同图9所示的XRPD图谱；
    所述晶型H具有基本同图3所示的XRPD图谱；
    所述晶型I具有基本同图4所示的XRPD图谱。
  3. 如权利要求1或2所述的晶型的制备方法，其特征在于，
    所述晶型A的制备方法包括如下步骤：将有机溶剂和盐酸0.8～1.2当量加入式(I)所示喹唑啉衍生物在22-28摄氏度下搅拌，离心分离出下层固体得到晶型A；其中，每毫升有机溶剂中加入式(I)所示喹唑啉衍生物10～200毫克；所述有机溶剂为甲醇；
    所述晶型B的制备方法包括如下步骤：将式(I)所示喹唑啉衍生物加入有机溶剂中，并向该悬浮液加入0.8～1.2当量盐酸在22-28摄氏度下搅拌，离心分离出下层湿样固体得到晶型B；其中，每毫升有机溶剂中加入式(I)所示喹唑啉衍生物10～200毫克；所述有机溶剂为乙腈、乙酸乙酯或体积比为15-20:1的四氢呋喃/水溶液。
    所述晶型C的制备方法包括如下步骤：将式(I)所示喹唑啉衍生物加入有机溶剂并加入盐酸2～2.5当量在22-28摄氏度下搅拌，离心分离出下层湿样固体得二盐酸盐晶型C；其中，每毫升有机溶剂加入式(I)所示喹唑啉衍生物10～200毫克；所述有机溶剂为丙酮；
    所述晶型D的制备方法包括如下步骤：将式(I)所示喹唑啉衍生物盐酸盐晶型C样品加热至120～160摄氏度后冷却至22-28摄氏度，得到二盐酸盐晶型D；
    所述晶型F的制备方法包括如下步骤：将式(I)所示喹唑啉衍生物盐酸盐晶型B加入醇类有机溶剂和酯类有机溶剂，于22-28摄氏度下气液扩散，直至有固体析出得晶型F；其中，每毫升有机溶剂中加入式(I)所示盐酸盐晶型B 10～200毫克；所述醇类有机溶剂为为甲醇，所述酯类有机溶剂为乙酸异丙酯；
    所述晶型H的制备方法包括如下步骤：在式(I)所示喹唑啉衍生物盐酸盐晶型B中加入有机溶剂，过滤后于22-28摄氏度下挥发得晶型H；其中，每毫升有机溶剂中加入式(I)所示盐酸盐晶型B 10～200毫克；所述有机溶剂为乙醇；
    所述晶型I的制备方法包括如下步骤：加热式(I)所示喹唑啉衍生物盐酸盐晶型H样品至120～130摄氏度后降温至22-28摄氏度。
  4. 式(I)所示喹唑啉衍生物的富马酸盐的晶型，其中所述晶型为晶型A；
    Figure PCTCN2019079043-appb-100002
    所述晶型A的XRPD图谱在下列2θ处具有主要特征峰：6.5，17.8，9.4；在下列2θ处具有次要特征峰：13.4，7.5，19.7；在下列2θ处具有再次特征峰：14.6，18.5；其中2θ值的误差范围为±0.2。
  5. 如权利要求4所述的晶型，其特征在于，所述晶型A具有基本同图5所示的XRPD图谱。
  6. 一种如权利要求4或5所述的晶型的制备方法，其特征在于，所述方法包括：在式(I)所示喹唑啉衍生物和0.4-0.6当量富马酸加入有机溶剂后，在22-28摄氏度下搅拌，离心收集固体得所述晶型；其中，每毫升有机溶剂中加入式(I)所示喹唑啉衍生物10～200毫克。
  7. 式(I)所示喹唑啉衍生物的琥珀酸盐的晶型，其中所述晶型为晶型A；
    Figure PCTCN2019079043-appb-100003
    所述晶型A的XRPD图谱在下列2θ处具有主要特征峰：6.6，17.8，7.5；在下列2θ处具有次要特征峰：9.4，20.3，18.5；在下列2θ处具有再次特征峰：21.0，14.5，19.5；其中2θ值的误差范围为±0.2。
  8. 如权利要求7所述的晶型，其特征在于，所述晶型A具有基本同图6所示的XRPD图谱。
  9. 一种如权利要求7或8所述的晶型的制备方法，其特征在于，所述方法包括：在式(I)所示喹唑啉衍生物和0.8-1.2当量琥珀酸加入有机溶剂后，在22-28摄氏度下搅拌，离心收集 固体得所述晶型；其中，每毫升有机溶剂中加入式(I)所示喹唑啉衍生物10～200毫克。
  10. 式(I)所示喹唑啉衍生物的马来酸盐的晶型，其中所述晶型为晶型A；
    Figure PCTCN2019079043-appb-100004
    所述晶型A的XRPD图谱在下列2θ处具有主要特征峰：6.3，18.8，16.7；在下列2θ处具有次要特征峰：25.2，21.2；其中2θ值的误差范围为±0.2。
  11. 如权利要求10所述的晶型，其特征在于，所述晶型A具有基本同图7所示的XRPD图谱。
  12. 一种如权利要求10或11所述的晶型的制备方法，其特征在于，所述方法包括：在式(I)所示喹唑啉衍生物和0.8-1.2当量马来酸加入有机溶剂后，在22-28摄氏度下搅拌，离心收集固体得所述晶型；其中，每毫升有机溶剂中加入式(I)所示喹唑啉衍生物10～200毫克。
  13. 式(I)所示喹唑啉衍生物的乙醇酸盐的晶型，其中所述晶型为晶型A；
    Figure PCTCN2019079043-appb-100005
    所述晶型A的XRPD图谱在下列2θ处具有主要特征峰：6.6，7.4，17.9；在下列2θ处具有次要特征峰：13.3；其中2θ值的误差范围为±0.2。
  14. 如权利要求13所述的晶型，其特征在于，所述晶型A具有基本同图8所示的XRPD图谱。
  15. 一种如权利要求13或14所述的晶型的制备方法，其特征在于，所述方法包括：在式(I)所示喹唑啉衍生物和0.8-1.2当量乙醇酸加入有机溶剂后，在22-28摄氏度下搅拌，离心收集固体得所述晶型；其中，每毫升有机溶剂中加入式(I)所示喹唑啉衍生物10～200毫克。
  16. 式(I)所示喹唑啉衍生物的硫酸盐的晶型，其中所述晶型为晶型A；
    Figure PCTCN2019079043-appb-100006
    所述晶型A的XRPD图谱在下列2θ处具有主要特征峰：7.3，18.2，15.0；其中2θ值的误差范围为±0.2。
  17. 如权利要求16所述的晶型，其特征在于，所述晶型A具有基本同图12所示的XRPD图谱。
  18. 一种如权利要求16或17所述的晶型的制备方法，其特征在于，所述方法包括：将式(I)所示喹唑啉衍生物样品加入有机溶剂和0.8-1.2当量硫酸水溶液在22-28摄氏度下搅拌，离心收集固体得所述晶型；其中，每毫升有机溶剂中加入式(I)所示喹唑啉衍生物10～200毫克。
  19. 式(I)所示喹唑啉衍生物的乙二酸盐的晶型，其中所述晶型为晶型A；
    Figure PCTCN2019079043-appb-100007
    所述晶型A的XRPD图谱在下列2θ处具有主要特征峰：6.9，15.1，13.7；在下列2θ处具有次要特征峰：15.4，9.6，19.0；在下列2θ处具有再次特征峰：20.6，27.3，23.4；其中2θ值的误差范围为±0.2。
  20. 如权利要求19所述的晶型，其特征在于，所述晶型A具有基本同图13所示的XRPD图谱。
  21. 一种如权利要求19或20所述的晶型的制备方法，其特征在于，所述方法包括：将式(I)所示喹唑啉衍生物样品加入有机溶剂和0.8-1.2当量乙二酸在22-28摄氏度下搅拌，离心 收集固体得所述晶型；其中，每毫升有机溶剂中加入式(I)所示喹唑啉衍生物10～200毫克。
  22. 式(I)所示喹唑啉衍生物的苹果酸盐的晶型，其中所述晶型为晶型A；
    Figure PCTCN2019079043-appb-100008
    所述晶型A的XRPD图谱在下列2θ处具有主要特征峰：6.5，18.8，19.9；在下列2θ处具有次要特征峰：7.5，8.4，9.2；其中2θ值的误差范围为±0.2。
  23. 如权利要求22所述的晶型，其特征在于，所述晶型A具有基本同图14所示的XRPD图谱。
  24. 一种如权利要求22或23所述的晶型的制备方法，其特征在于，所述方法包括：将式(I)所示喹唑啉衍生物样品加入有机溶剂和0.8-1.2当量苹果酸在22-28摄氏度下搅拌，离心收集固体得所述晶型；其中，每毫升有机溶剂中加入式(I)所示喹唑啉衍生物10～200毫克。
  25. 式(I)所示喹唑啉衍生物的苯磺酸盐的晶型，其中所述晶型为晶型A、晶型B或晶型C；
    Figure PCTCN2019079043-appb-100009
    其中，所述晶型A的XRPD图谱在下列2θ处具有主要特征峰：6.6，14.0，15.3；在下列2θ处具有次要特征峰：7.1，5.5，19.7；在下列2θ处具有再次特征峰：17.8，16.9，21.0；
    所述晶型B的XRPD图谱在下列2θ处具有主要特征峰：8.5，14.5，23.4；在下列2θ处具有次要特征峰：18.3，19.7；
    所述晶型C的XRPD图谱在下列2θ处具有主要特征峰：14.0，14.7，7.7；在下列2θ处具有次要特征峰：8.3，21.2，19.4；在下列2θ处具有再次特征峰：27.5，24.7；
    其中2θ值的误差范围为±0.2。
  26. 如权利要求25所述的晶型，其特征在于，所述晶型A具有基本同图15所示的XRPD图谱；
    所述晶型B具有基本同图16所示的XRPD图谱；
    所述晶型C具有基本同图17所示的XRPD图谱。
  27. 一种如权利要求25或26所述的晶型的制备方法，其特征在于，所述晶型A的制备方法包括：将式(I)所示喹唑啉衍生物样品加入有机溶剂和0.8-1.2当量苯磺酸在22-28摄氏度下搅拌，离心收集固体得所述晶型A；其中，每毫升有机溶剂中加入式(I)所示喹唑啉衍生物10～200毫克；所述有机溶剂为甲醇；
    所述晶型B的制备方法包括：将式(I)所示喹唑啉衍生物样品加入有机溶剂和0.8-1.2当量苯磺酸在22-28摄氏度下搅拌，离心收集固体得所述晶型B；其中，每毫升有机溶剂中加入式(I)所示喹唑啉衍生物10～200毫克；所述有机溶剂为乙腈；
    所述晶型C的制备方法包括：将式(I)所示喹唑啉衍生物样品加入有机溶剂和0.8-1.2当量苯磺酸在22-28摄氏度下搅拌，离心收集固体得所述晶型C；其中，每毫升有机溶剂中加入式(I)所示喹唑啉衍生物10～200毫克；所述有机溶剂为体积比为15-20:1de四氢呋喃和水的混合溶剂。
  28. 式(I)所示喹唑啉衍生物的苯甲酸盐的晶型，其中所述晶型为晶型A；
    Figure PCTCN2019079043-appb-100010
    所述晶型A的XRPD图谱在下列2θ处具有主要特征峰：7.3，6.3，16.8；在下列2θ处具有次要特征峰：13.5，18.7，27.0；其中2θ值的误差范围为±0.2。
  29. 如权利要求28所述的晶型，其特征在于，所述晶型A具有基本同图18所示的XRPD图谱。
  30. 一种如权利要求28或29所述的晶型的制备方法，其特征在于，所述方法包括：将 式(I)所示喹唑啉衍生物样品加入有机溶剂和0.8-1.2当量苯甲酸在22-28摄氏度下搅拌，离心收集固体得所述晶型；其中，每毫升有机溶剂中加入式(I)所示喹唑啉衍生物10～200毫克。
  31. 式(I)所示喹唑啉衍生物的马尿酸盐的晶型，其中所述晶型为晶型A；
    Figure PCTCN2019079043-appb-100011
    所述晶型A的XRPD图谱在下列2θ处具有主要特征峰：5.6，6.9，20.0；在下列2θ处具有次要特征峰：16.0，7.7，13.7；在下列2θ处具有再次特征峰：24.3，26.4；其中2θ值的误差范围为±0.2。
  32. 如权利要求31所述的晶型，其特征在于，所述晶型A具有基本同图19所示的XRPD图谱。
  33. 一种如权利要求31或32所述的晶型的制备方法，其特征在于，所述方法包括：将式(I)所示喹唑啉衍生物样品加入有机溶剂和0.8-1.2当量马尿酸在22-28摄氏度下搅拌，离心收集固体得所述晶型；其中，每毫升有机溶剂中加入式(I)所示喹唑啉衍生物10～200毫克。
  34. 式(I)所示喹唑啉衍生物的草酸盐的晶型，其中所述晶型为晶型A；
    Figure PCTCN2019079043-appb-100012
    所述晶型A的XRPD图谱在下列2θ处具有主要特征峰：6.4，9.1，17.5；在下列2θ处具有次要特征峰：12.9，14.5，26.4；在下列2θ处具有再次特征峰：19.4，18.3，15.9；其中2θ值的误差范围为±0.2。
  35. 如权利要求34所述的晶型，其特征在于，所述晶型A具有基本同图20所示的XRPD图谱。
  36. 一种如权利要求34或35所述的晶型的制备方法，其特征在于，所述方法包括：将式(I)所示喹唑啉衍生物样品加入有机溶剂和0.8-1.2当量草酸在22-28摄氏度下搅拌，离心收集固体得所述晶型；其中，每毫升有机溶剂中加入式(I)所示喹唑啉衍生物10～200毫克。
  37. 一种药物组合物，其特征在于，所述组合物包括如权利要求1、4、7、10、13、16、19、22、25、28、31、34中任一项所述的晶型或它们的组合，以及药学上可接受的辅料或辅助性成分。
  38. 一种如权利要求1、4、7、10、13、16、19、22、25、28、31、34中任一项所述的晶型或权利要求37所述的药物组合物在制备治疗或预防由表皮生长因子受体EGFR蛋白介导的疾病的药物中的用途。
  39. 如权利要求38所述的用途，其特征在于，所述药物为治疗或预防由表皮生长因子受体EGFR蛋白介导，且是EGFRVIII活化突变所导致的疾病的药物。
  40. 如权利要求38所述的用途，其特征在于，所述药物为治疗或预防由表皮生长因子受体EGFR蛋白介导，且是EGFR Del19和/或EGFR L858R活化突变所导致的的疾病的药物。
  41. 如权利要求38、39或40所述的用途，其特征在于，所述药物为治疗或预防非小细胞肺癌脑转移、脑膜转移、头颈部鳞状细胞癌、鳞状细胞癌、脑干肿瘤、原发性脑癌或脑胶质瘤的药物。
PCT/CN2019/079043 2018-04-08 2019-03-21 喹唑啉衍生物盐型晶型及制备方法和应用 WO2019196619A1 (zh)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US17/625,315 US20240025874A1 (en) 2018-04-08 2019-03-21 Quinazoline Derivative Salt Crystal Form, Preparation Method and Application

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CN201810309035.1 2018-04-08
CN201810309035 2018-04-08
CN201810423951.8 2018-05-04
CN201810423951.8A CN110343090B (zh) 2018-04-08 2018-05-04 喹唑啉衍生物盐型晶型及制备方法和应用

Publications (1)

Publication Number Publication Date
WO2019196619A1 true WO2019196619A1 (zh) 2019-10-17

Family

ID=68163909

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2019/079043 WO2019196619A1 (zh) 2018-04-08 2019-03-21 喹唑啉衍生物盐型晶型及制备方法和应用

Country Status (2)

Country Link
US (1) US20240025874A1 (zh)
WO (1) WO2019196619A1 (zh)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115260153A (zh) * 2022-07-21 2022-11-01 威尚（上海）生物医药有限公司 一种6取代手性纯二氟哌啶喹唑啉衍生物及其制备方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101128456A (zh) * 2005-02-26 2008-02-20 阿斯利康(瑞典)有限公司 作为酪氨酸激酶抑制剂的喹唑啉衍生物
CN102088979A (zh) * 2008-05-13 2011-06-08 阿斯利康(瑞典)有限公司 4-(3-氯-2-氟苯胺基)-7-甲氧基-6-{[1-(n-甲基氨基甲酰基甲基)哌啶-4-基]氧基}喹唑啉的富马酸盐
WO2015154725A1 (zh) * 2014-04-11 2015-10-15 四川海思科制药有限公司 喹唑啉衍生物及其制备方法和在医药上的应用
CN105859641A (zh) * 2015-05-05 2016-08-17 杭州华东医药集团新药研究院有限公司 喹唑啉巴豆基化合物二马来酸盐的晶体及其制备方法和用途

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101128456A (zh) * 2005-02-26 2008-02-20 阿斯利康(瑞典)有限公司 作为酪氨酸激酶抑制剂的喹唑啉衍生物
CN102088979A (zh) * 2008-05-13 2011-06-08 阿斯利康(瑞典)有限公司 4-(3-氯-2-氟苯胺基)-7-甲氧基-6-{[1-(n-甲基氨基甲酰基甲基)哌啶-4-基]氧基}喹唑啉的富马酸盐
WO2015154725A1 (zh) * 2014-04-11 2015-10-15 四川海思科制药有限公司 喹唑啉衍生物及其制备方法和在医药上的应用
CN105859641A (zh) * 2015-05-05 2016-08-17 杭州华东医药集团新药研究院有限公司 喹唑啉巴豆基化合物二马来酸盐的晶体及其制备方法和用途

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115260153A (zh) * 2022-07-21 2022-11-01 威尚（上海）生物医药有限公司 一种6取代手性纯二氟哌啶喹唑啉衍生物及其制备方法
CN115260153B (zh) * 2022-07-21 2023-10-27 威尚（上海）生物医药有限公司 一种6取代手性纯二氟哌啶喹唑啉衍生物及其制备方法

Also Published As

Publication number Publication date
US20240025874A1 (en) 2024-01-25

Similar Documents

Publication Publication Date Title
CN110343090B (zh) 喹唑啉衍生物盐型晶型及制备方法和应用
WO2018086446A1 (zh) 具有穿过血脑屏障能力的取代的喹唑啉化合物
JP2022106967A (ja) 癌の治療のためのｅｒｂｂチロシンキナーゼ阻害剤としてのベンゾイミダゾール誘導体
EP2952510B1 (en) Substituted 2-aminopyridine protein kinase inhibitor
TW200946531A (en) HSP90 inhibitors
EA018964B1 (ru) СОЕДИНЕНИЯ ПИРИДО[2,3-d]ПИРИМИДИН-7-ОНА В КАЧЕСТВЕ ИНГИБИТОРОВ PI3K-АЛЬФА ДЛЯ ЛЕЧЕНИЯ РАКА
WO2019154091A1 (zh) 取代的二氨基嘧啶化合物
WO2021043208A1 (en) 3, 5-disubstituted pyrazole compounds as kinase inhibitors and uses thereof
CN110357858B (zh) 具有穿过血脑屏障能力的5取代二氟哌啶化合物
CN110903283B (zh) 一种取代的喹唑啉类化合物、包含该化合物的药物组合物和该化合物的用途
WO2022089398A1 (zh) 一种高活性的hpk1激酶抑制剂
WO2019196619A1 (zh) 喹唑啉衍生物盐型晶型及制备方法和应用
WO2019196622A1 (zh) 具有穿过血脑屏障能力的5取代二氟哌啶化合物
US20220143001A1 (en) Novel pan-raf kinase inhibitor and use thereof
EP2170891B1 (en) Pyrazolopyrimidinone kinase inhibitor
AU2020468487B2 (en) Substituted 1-(3,3-difluoropiperidin-4-yl)-imidazo(4,5-c) quinolin-2-one compounds with blood-brain barrier penetrable capability
WO2022218296A1 (en) Substituted fused bicyclic compounds as parp inhibitors and the use thereof
WO2017092523A1 (zh) 一种稠合嘧啶化合物及包含该化合物的组合物及其用途
JP2019518032A (ja) Ｐｉ３ｋ ｂｅｔａ阻害薬としての二環式ピリジン、ピラジンおよびピリミジン誘導体
WO2023200427A1 (en) Substituted 1-(3,3-difluoropiperidin-4-yl)-imidazo[4,5-c] quinolin-2-one derivative crystal form, salt crystal form, preparation method and application
WO2020043078A1 (zh) 新型氮杂三环类化合物的盐型、晶型及其用途
WO2021004482A1 (zh) 取代的吡唑并喹唑啉酮化合物及其应用
CN116670134A (zh) 取代的咪唑并[1,5-b]哒嗪化合物作为激酶抑制剂及其应用
WO2014154026A1 (zh) PI3K和/或mTOR抑制剂的前药

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 19785921

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 19785921

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 17625315

Country of ref document: US