WO2018108084A1 - 一类含有三环杂芳基的化合物 - Google Patents

一类含有三环杂芳基的化合物 Download PDF

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WO2018108084A1
WO2018108084A1 PCT/CN2017/115756 CN2017115756W WO2018108084A1 WO 2018108084 A1 WO2018108084 A1 WO 2018108084A1 CN 2017115756 W CN2017115756 W CN 2017115756W WO 2018108084 A1 WO2018108084 A1 WO 2018108084A1
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compound
group
formula
mmol
alkyl
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PCT/CN2017/115756
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English (en)
French (fr)
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张汉承
刘世峰
叶向阳
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杭州英创医药科技有限公司
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Priority to US16/468,810 priority Critical patent/US10730887B2/en
Priority to CN201780027692.0A priority patent/CN109153687B/zh
Priority to EP17879976.3A priority patent/EP3553064B1/en
Priority to CN202110921965.4A priority patent/CN113603707B/zh
Priority to JP2019552329A priority patent/JP6854496B2/ja
Publication of WO2018108084A1 publication Critical patent/WO2018108084A1/zh
Priority to US16/937,119 priority patent/US10968234B2/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • 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
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to the field of medicinal chemistry; in particular, the present invention relates to a novel class of derivatives containing a tricyclic heteroaryl group, a method for its synthesis and its use as a one or more protein kinase inhibitors in the preparation of a medicament for the treatment of tumors, Non-alcoholic steatohepatitis (NASH), idiopathic pulmonary fibrosis (IPF) and other related diseases.
  • NASH Non-alcoholic steatohepatitis
  • IPF idiopathic pulmonary fibrosis
  • Cancer also known as malignant tumor, is one of the highest morbidity and mortality in the world. It is characterized by abnormal cell proliferation and metastasis, which spread and metastasize in a short time or relatively short time after onset.
  • Traditional treatment options include resection (if resection conditions are met), radiation therapy, and chemotherapy.
  • the targeted therapy developed in recent years has the advantages of reducing toxicity, negative effects on patients, and improving survival rate.
  • the use of targeted drugs will produce resistance for a period of time, and then the growth of cancer cells will be extremely rapid.
  • Common cancers are: blood cancer, lung cancer, liver cancer, bladder cancer, rectal cancer, stomach cancer, and so on.
  • Idiopathic pulmonary fibrosis is a chronic, progressive, fibrotic interstitial lung disease that is confined to the lungs and occurs in the middle-aged and elderly population. Its lung histology and/or High-resolution chest CT (HRCT) is characterized by common interstitial pneumonia (UIP), and the cause is unclear. As a chronic interstitial lung disease, IPF onset is concealed, the condition is gradually worsened, and it can also be manifested as acute exacerbation. The average survival after IPF diagnosis is only 2.8 years, and the mortality rate is higher than most tumors. IPF is called a "tumor-like disease.”
  • Nonalcoholic fatty liver disease refers to the clinical pathological syndrome characterized by excessive deposition of intrahepatic fat due to alcohol and other well-defined liver-damaging factors, and is closely related to insulin resistance and genetic susceptibility. Metabolic stress liver damage. With the global trend of obesity and its related metabolic syndrome, nonalcoholic fatty liver disease has become an important cause of chronic liver disease in developed countries such as Europe and the United States and in rich areas of China. The prevalence of NAFLD in ordinary adults is 10% to 30%. Among them, 10% to 20% are NASH, and the latter has a cirrhosis rate of 25% within 10 years.
  • Non-alcoholic fatty liver disease can directly lead to decompensated cirrhosis, hepatocellular carcinoma and transplanted liver recurrence, and can also affect the progression of other chronic liver diseases, and participate in the onset of type 2 diabetes and atherosclerosis. Metabolic syndrome-related malignancies, atherosclerotic cardiovascular and cerebrovascular diseases, and cirrhosis are important factors influencing the quality of life and life expectancy of patients with nonalcoholic fatty liver disease. To this end, nonalcoholic fatty liver disease is a new challenge in the field of contemporary medicine, and the risk of non-alcoholic fatty liver disease to human health will continue to increase in the near future.
  • protein kinases are a class of biologically active organisms that catalyze the transfer of the gamma phosphate of ATP to the residues of many important proteins, phosphorylate them, and thus transmit signals, thereby participating in a series of Cell activity is closely related to cell growth, differentiation and proliferation.
  • the development of selective protein kinase inhibitors to block or regulate diseases that are abnormal due to these signaling pathways has been recognized as an effective research strategy for anticancer drug development. Validated in clinical trials and multiple protein kinase inhibitors were approved for marketing.
  • the epidermal growth factor receptor tyrosine kinase is a transmembrane glycoprotein composed of 1186 amino acids and encoding a molecular weight of 170-kDa. EGFR can mediate multiple signaling pathways and transmit extracellular signals to the intracellular cells, which play an important regulatory role in the proliferation, differentiation and apoptosis of normal and tumor cells (Cell, 2000, 100, 113-127). EGFR is a constitutive expression component of many normal epithelial tissues (such as skin and hair follicles), and in most solid tumors, EGFR is overexpressed or highly expressed. For example, in lung cancer, the expression rate of EGFR is reached.
  • EGFR targeted drugs such as gefitinib Erlotinib Waiting for first-line drugs has proven to be very effective in the treatment of lung cancer.
  • the use of these drugs will lead to acquired resistance within 6-12 months.
  • the resistance of approximately 50% of cases is related to a mutation in one amino acid residue in the EGFR kinase domain (mutation of the 790 threonine residue to methionine, T790M) (The New England Journal of Medicine, 2005, 352, 786) -792).
  • the T790M mutation results in steric hindrance when the inhibitor binds to EGFR or increases the affinity of EGFR to ATP, making the anticancer effect of such reversible binding competitive inhibitors greatly diminished.
  • the emergence of drug resistance not only reduces the patient's sensitivity to drugs, but also greatly reduces the quality of life of cancer patients. Therefore, studies targeting other targets including inhibitors of other protein kinases are even more important.
  • the spleen tyrosine kinase (SYK) gene was first cloned from pig spleen cDNA in 1991 and encodes a non-receptor protein tyrosine kinase.
  • the human SYK gene is located in the q22 region of chromosome 9, and the SYK protein contains 635 amino acids. It plays an important role in autoimmune diseases and hematological malignancies. For example, SYK gene can inhibit the proliferation of malignant tumor cells such as breast cancer, melanoma and liver cancer. Transfer.
  • SYK inhibitors have been used in clinical phase II/III trials of rheumatoid arthritis, chronic lymphocytic leukemia, and the like. Recent studies have shown that the use of SYK inhibitors or interference with the expression of the SYK gene can effectively slow the progression of liver fibrosis/hardening and has a good therapeutic effect (see CN 105664178A).
  • FAK Focal Adhesion Kinase
  • AXL is an important tyrosine receptor kinase, the English name is AXL receptor tyrosine kinase. AXL is also called UFO/ARK/Tyro, and its ligand is vitamin K-dependent growth promoting factor GAS6.
  • the first discovery of AXL was as a transforming gene for chronic myeloid leukemia (CML). AXL is overexpressed in metastatic colon cancer, thyroid cancer, breast cancer, prostate cancer, and melanoma. Inhibition of AXL activity can inhibit tumor growth, spread and metastasis.
  • FLT-3 (Fms-related tyrosine kinase 3) belongs to a family member of the type III receptor tyrosine kinase and is a signaling molecule. FLT-3 is expressed in various tissues such as liver, spleen, lymph, brain, placenta and gonads, and is also expressed in normal bone marrow cells and lymphoid cell precursors, and is expressed in many hematopoietic malignancies. Its signal transduction pathway is associated with many tumor conduction pathways. Therefore, FLT-3 has become an ideal anti-tumor drug target.
  • CDKs Cyclin-dependent kinases
  • the tumor suppressor protein Rb phosphorylates to release its transcription factor E2F, which binds tightly in an unphosphorylated state. E2F activation further promotes cell cycle through the restriction point (R point) and progresses from G1 phase to S phase. , entered the cycle of cell proliferation. Therefore, inhibition of CDK4/6 prevents the formation of the Cyclin D-CDK4/6 complex, which can block the progression of the cell cycle from the G1 phase to the S phase, thereby achieving the purpose of inhibiting tumor proliferation.
  • Janus kinase is a cytoplasmic tyrosine kinase that transduces cytokine signaling from membrane receptors to STAT transcription factors. Scientific research has shown that inhibition of JAK can be a promising target for anticancer drugs.
  • M is a group represented by the following formula (II):
  • connection site representing the U in formula (II) and formula (I);
  • A is selected from aryl or heteroaryl
  • B is an aryl group, a heteroaryl group, a C 3-8 cycloalkyl group, a 3- to 12-membered heterocyclic group, NR a R b , OR b , SR b , or SO 2 R b , wherein the aryl group a heteroaryl group, a cycloalkyl group, a heterocyclic group may be independently substituted with one or more R c ;
  • U is NR d , O or S
  • X is hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, 3- to 10-membered heterocyclic ring Base, OR e , SR e , NR e R e , CN, C(O)R e , C(O)OR e , C(O)NR e R e , OC(O)R e , NR e C(O ) R e , or S(O) 2 R e ;
  • J and G are each independently NR f , O, S, S(O), S(O) 2 or CR g R g ;
  • R 1 and R 2 are each independently selected from the group consisting of hydrogen, halogen, C 1-4 alkyl, C 3-6 cycloalkyl, 3- to 8-membered heterocyclic, or C(O)NR e R And wherein the alkyl group, cycloalkyl group, heterocyclic group may be optionally substituted by one or more R c ;
  • n 0, 1, 2, or 3;
  • R a is hydrogen, C 1-4 alkyl, C 3-6 cycloalkyl, or 3- to 12-membered heterocyclic group; wherein the alkyl group, cycloalkyl group, heterocyclic group herein may be optionally Independently substituted by one or more halogens, OR e , CN, SO 2 NR e R e , as long as the chemical structure formed is stable and meaningful;
  • R b is aryl, heteroaryl, C 1-4 alkyl, C 3-8 cycloalkyl, 3- to 12-membered heterocyclic, C(O)R e , or C(O)NR e R And wherein the aryl, heteroaryl, alkyl, cycloalkyl, heterocyclyl can be optionally substituted by one or more R c ;
  • Each R c is independently halogen, C 1-4 alkyl, C 3-8 cycloalkyl, 3- to 8-membered heterocyclic, C(O)NR e R e , NR e C(O)R e , OR e , CN, or SO 2 NR e R e ;
  • R d is hydrogen or C 1-4 alkyl
  • Each R e is independently selected from the group consisting of hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3 a to a 8-membered heterocyclic group, an aryl group, or a heteroaryl group; or two R e together with a nitrogen atom to which they are bonded form a 3- to 8-membered heterocyclic group, the heterocyclic group having 1 or 2 a N atom and 0 or 1 hetero atom selected from O, S;
  • R f is hydrogen, C 1-8 alkyl, C 1-8 haloalkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3- to 12-membered heterocyclic group , aryl, heteroaryl, C(O)R e , C(O)OR e , C(O)NR e R e , S(O) 2 R e , or S(O) 2 NR h R h ;
  • Each R h is independently hydrogen or C 1-4 alkyl; or two R h together with the nitrogen atom to which they are attached form a 3- to-membered cyclic structure
  • each of the above alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, cyclic, aryl and heteroaryl groups is optionally and independently independently selected from 1 to 3 each independently selected from the group consisting of Substituent substituents of the group: halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3- to 12-membered Heterocyclyl, aryl, heteroaryl, CN, NO 2 , OR e , SR e , NR e R e , C(O)R e , C(O)OR e , C(O)NR e R e , NR e C(O)R e , or S(O) 2 R e , provided that the chemical structure formed is stable and meaningful;
  • the above aryl group is an aromatic group having 6 to 12 carbon atoms;
  • the heteroaryl group is a 5- to 15-membered heteroaromatic group; and the cyclic structure is saturated or unsaturated, containing a hetero atom. Or a cyclic group containing no heteroatoms;
  • A is not selected from the group of the following group:
  • the M is a group represented by the following formula (IIa):
  • X, R 3 , G, and n are as defined above.
  • the M is selected from the group consisting of formula (IIb), formula (IIc), or formula (IId):
  • R f is as defined above.
  • a in formula (I) is independently selected from the group consisting of:
  • U is NR d .
  • B in the formula (I) is selected from the group consisting of -NH-aryl, -NH-C 3-8 cycloalkyl, -NH-(3- to 12-membered heterocyclic), a heteroaryl group, a C 3-8 cycloalkyl group, a 3- to 12-membered heterocyclic group, wherein any of the above-mentioned aryl, heteroaryl, cycloalkyl, heterocyclic groups (alone or in combination with other groups)
  • the base time can be independently substituted by one or more R c .
  • B in formula (I) is selected from the group consisting of:
  • R 1 , R 2 , A, U, M, and B are the corresponding groups corresponding to the compounds of the specific formula (I) prepared in the examples, respectively.
  • formula (I) is:
  • X is H
  • G is NR f or O; wherein R f is as defined above;
  • R 1 is selected from hydrogen, halogen, or C 1-4 alkyl, wherein the alkyl group may be optionally substituted with one or more halogens;
  • n 0, 1, or 2.
  • formula (I) is:
  • X is H
  • G is NR f or O; wherein R f is as defined above;
  • R 1 is selected from hydrogen, halogen, or C 1-4 alkyl
  • n 0, 1, or 2.
  • formula (I) is:
  • X is H
  • G is NR f or O; wherein R f is as defined in the first aspect of the invention.
  • R 1 is selected from the group consisting of hydrogen, halogen, or CONH 2 ;
  • n 0, 1, or 2.
  • formula (I) is:
  • X is H
  • G is NR f or O; wherein R f is as defined above;
  • R 1 is selected from hydrogen or C 1-4 alkyl;
  • R 2 is CONH 2 ;
  • n 0, 1, or 2.
  • formula (I) is:
  • X is H
  • G is NR f or O; wherein R f is as defined above;
  • R 1 is selected from hydrogen, halogen, or C 1-4 alkyl, wherein the alkyl group may be optionally substituted with one or more halogens;
  • n 0, 1, or 2.
  • the compound is selected from one of the group consisting of:
  • a compound according to the first aspect of the invention or an optical isomer thereof, a pharmaceutically acceptable salt, a prodrug, a deuterated derivative, a hydrate, a solvate Use for:
  • the protein kinase is selected from the group consisting of: EGFR, CDK, SYK, JAK, Flt-3, Axl, FAK, or a combination thereof.
  • a compound according to the first aspect of the invention or an optical isomer thereof, a pharmaceutically acceptable salt, a prodrug, a deuterated derivative, a hydrate, a solvate Its use as an EGFR inhibitor or for the treatment of diseases associated with high expression of EGFR.
  • a compound according to the first aspect of the invention or an optical isomer thereof, a pharmaceutically acceptable salt, a prodrug, a deuterated derivative, a hydrate, a solvate
  • a pharmaceutically acceptable salt for the treatment of diseases associated with high CDK expression.
  • a compound according to the first aspect of the invention or an optical isomer thereof, a pharmaceutically acceptable salt, a prodrug, a deuterated derivative, a hydrate, a solvate Its use as a SYK and JAK inhibitor, or for the treatment of diseases associated with high expression of SYK and JAK.
  • a compound according to the first aspect of the invention or an optical isomer thereof, a pharmaceutically acceptable salt, a prodrug, a deuterated derivative, a hydrate, a solvate Its use as a Flt-3 and Axl inhibitor, or for the treatment of diseases associated with high expression of Flt-3 and Axl.
  • a compound according to the first aspect of the invention or an optical isomer thereof, a pharmaceutically acceptable salt, a prodrug, a deuterated derivative, a hydrate, a solvate
  • a pharmaceutically acceptable salt for the treatment of diseases associated with high expression of FAK.
  • a pharmaceutical composition comprising: (i) an effective amount of a compound of formula I according to the first aspect of the invention, or an optical isomer thereof, pharmaceutically Acceptable salts, prodrugs, deuterated derivatives, hydrates, solvates; and (ii) pharmaceutically acceptable carriers.
  • a ninth aspect of the invention provides a method of inhibiting protein kinase activity, the method comprising the steps of: administering to a subject, an inhibitory effective amount of a compound of formula I according to the first aspect of the invention, or optical isomerism thereof Or a pharmaceutically acceptable salt, a prodrug, a deuterated derivative, a hydrate, a solvate, or an inhibitory effective amount of a pharmaceutical composition according to the eighth aspect of the invention;
  • the protein kinase is selected from the group consisting of EGFR, FAK, SYK, FLT-3, Axl, CDK, JAK, or a combination thereof.
  • the compound of formula Ia is prepared by the following method:
  • the present inventors have unexpectedly discovered a novel class of protein kinase inhibitors containing tricyclic aryl compounds, as well as their preparation methods and applications.
  • the protein kinase inhibitor can inhibit various protein kinases including EGFR, FAK, SYK, FLT-3, Axl, CDK, JAK and the like.
  • the compounds of the invention may be applied to the treatment of various diseases associated with the activity of said kinases. Based on the above findings, the inventors completed the present invention.
  • each chiral carbon atom may optionally be in the R configuration or the S configuration, or a mixture of the R configuration and the S configuration.
  • alkyl refers to a straight (ie, unbranched) or branched saturated hydrocarbon group containing only carbon atoms, or a combination of straight and branched chains. .
  • the alkyl group has a carbon number limitation (e.g., C 1-10 ) it means that the alkyl group has 1 to 10 carbon atoms.
  • C 1-8 alkyl refers to an alkyl group containing from 1 to 8 carbon atoms, including methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, or Similar group.
  • alkenyl when used alone or as part of another substituent, refers to a straight or branched, carbon chain group having at least one carbon-carbon double bond. Alkenyl groups can be substituted or unsubstituted. When the alkenyl group has a carbon number limitation (e.g., C 2-8 ), it means that the alkenyl group has 2 to 8 carbon atoms. For example, C 2-8 alkenyl refers to an alkenyl group having 2-8 carbon atoms, including ethenyl, propenyl, 1,2-butenyl, 2,3-butenyl, butadienyl, or the like. group.
  • C 2-8 alkenyl refers to an alkenyl group having 2-8 carbon atoms, including ethenyl, propenyl, 1,2-butenyl, 2,3-butenyl, butadienyl, or the like. group.
  • alkynyl when used alone or as part of another substituent, refers to an aliphatic hydrocarbon group having at least one carbon-carbon triple bond.
  • the alkynyl group can be straight or branched, or a combination thereof.
  • the alkynyl group has a carbon number limitation (e.g., C 2-8 alkynyl group), it means that the alkynyl group has 2 to 8 carbon atoms.
  • C 2-8 alkynyl refers to a straight or branched alkynyl group having 2-8 carbon atoms, including ethynyl, propynyl, isopropynyl, butynyl, isobutynyl, A sec-butynyl group, a tert-butynyl group, or the like.
  • cycloalkyl refers to a unit ring having a saturated or partially saturated ring, a bicyclic or polycyclic (fused ring, bridged or spiro) ring system. .
  • a certain cycloalkyl group has a carbon number limitation (e.g., C 3-10 )
  • C 3-8 cycloalkyl refers to a saturated or partially saturated monocyclic or bicyclic alkyl group having from 3 to 8 carbon atoms, including cyclopropyl, cyclobutyl, cyclopentane.
  • Spirocycloalkyl refers to a bicyclic or polycyclic group that shares a carbon atom (called a spiro atom) between the monocyclic rings. These may contain one or more double bonds, but none of the rings have fully conjugated ⁇ electrons. system.
  • Fused cycloalkyl means an all-carbon bicyclic or polycyclic group in which each ring of the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or more Key, but none of the rings have a fully conjugated ⁇ -electron system.
  • “Bridge cycloalkyl” refers to an all-carbon polycyclic group in which two rings share two carbon atoms that are not directly bonded, which may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system .
  • the atoms contained in the cycloalkyl group are all carbon atoms.
  • Aryl means an all-carbon monocyclic or fused polycyclic (ie, a ring that shares a pair of adjacent carbon atoms) groups having a conjugated ⁇ -electron system, such as phenyl and naphthyl.
  • the aryl ring may be fused to other cyclic groups (including saturated and unsaturated rings), but may not contain heteroatoms such as nitrogen, oxygen, or sulfur, while the point of attachment to the parent must be in a conjugated pi-electron system.
  • the aryl group can be substituted or unsubstituted. The following are some examples of aryl groups, and the present invention is not limited to the aryl groups described below.
  • Heteroaryl refers to a heteroaromatic group containing one to more heteroatoms.
  • the heteroatoms referred to herein include oxygen, sulfur, and nitrogen.
  • the heteroaryl ring may be fused to an aryl, heterocyclic or cycloalkyl ring wherein the ring to which the parent structure is attached is a heteroaryl ring.
  • the heteroaryl group can be optionally substituted or unsubstituted.
  • the following are some examples of heteroaryl groups, and the present invention is not limited to the following heteroaryl groups. Among them, the last three heteroaryl groups are tricyclic heteroaryl groups, which are the focus of the present invention.
  • Heterocyclyl means a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent wherein one or more of the ring atoms are selected from nitrogen, oxygen or sulfur and the remaining ring atoms are carbon.
  • monocyclic heterocyclic groups include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl.
  • Polycyclic heterocyclic group refers to a heterocyclic group including a spiro ring, a fused ring, and a bridged ring.
  • Spirocyclic heterocyclyl refers to a polycyclic heterocyclic group in which each ring of the system shares an atom (referred to as a spiro atom) with other rings in the system, wherein one or more of the ring atoms is selected from the group consisting of nitrogen and oxygen. Or sulfur, the remaining ring atoms are carbon.
  • “Fused ring heterocyclyl” refers to a polycyclic heterocyclic group in which each ring of the system shares an adjacent pair of atoms with other rings in the system, and one or more rings may contain one or more double bonds, but none One ring has a fully conjugated pi-electron system, and wherein one or more ring atoms are selected from nitrogen, oxygen or sulfur, and the remaining ring atoms are carbon.
  • “Bridged heterocyclyl” refers to a polycyclic heterocyclic group in which any two rings share two atoms which are not directly bonded, these may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system And wherein one or more of the ring atoms are selected from nitrogen, oxygen or sulfur, and the remaining ring atoms are carbon. If a heterocyclic group has both a saturated ring and an aromatic ring (for example, the saturated ring and the aromatic ring are fused together), the point attached to the parent must be on the saturated ring. Note: When the point attached to the parent is on the aromatic ring, it is called a heteroaryl group and is not called a heterocyclic group. Some examples of the heterocyclic group are as follows, and the present invention is not limited to the following heterocyclic group.
  • halogen when used alone or as part of another substituent, refers to F, Cl, Br, and I.
  • substituted when with or without “optionally” means that one or more hydrogen atoms on a particular group are replaced by a particular substituent.
  • Particular substituents are the substituents described above in the corresponding paragraphs, or the substituents which appear in the examples.
  • an optionally substituted group may have a substituent selected from a particular group at any substitutable position of the group, and the substituents may be the same or different at each position.
  • a cyclic substituent, such as a heterocyclic group may be attached to another ring, such as a cycloalkyl group, to form a spirobicyclic ring system, i.e., the two rings have a common carbon atom.
  • substituents contemplated by the present invention are those that are stable or chemically achievable.
  • the substituents are, for example but not limited to, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3- to 12-membered heterocyclic , aryl, heteroaryl, halogen, hydroxy, carboxy (-COOH), C 1-8 aldehyde, C 2-10 acyl, C 2-10 ester, amino.
  • a pharmaceutically acceptable salt of a compound of the invention refers to a salt that is suitable for contact with the tissue of a subject (eg, a human) without causing unpleasant side effects.
  • a pharmaceutically acceptable salt of a compound of the invention includes a salt (eg, a potassium salt, a sodium salt, a magnesium salt, a calcium salt) of a compound of the invention having an acidic group or is basic A salt of a compound of the invention (e.g., a sulfate, a hydrochloride, a phosphate, a nitrate, a carbonate).
  • the present invention provides a compound of the formula (I) or formula (II), or a deuterated derivative thereof, a salt thereof, an isomer (enantiomer or diastereomer, if present In the case of a hydrate, a pharmaceutically acceptable carrier or excipient for inhibiting the use of a protein kinase.
  • the protein kinases referred to herein include EGFR, CDK, SYK, JAK, Flt-3, Axl, and FAK, but are not limited to the above several kinases.
  • the compounds of the invention may be used as one or more kinase inhibitors, for example, in some embodiments, certain classes of compounds of the invention may be used as EGFR kinase inhibitors; in some embodiments, certain classes of compounds of the invention may be used As a CDK kinase inhibitor; in some embodiments, certain compounds of the invention may be used as SYK kinase inhibitors; in some embodiments, certain classes of compounds of the invention may be used as FAK kinase inhibitors; in some embodiments Certain compounds of the invention are useful as dual inhibitors of SYK kinase and JAK kinase; in other embodiments, certain classes of compounds of the invention are useful as dual inhibitors of Flt-3 kinase and Axl kinase.
  • the expression or activity of various protein kinases mentioned above is significantly increased. These levels of overexpression and/or abnormal protein kinase activity are directly linked to the development of tumors.
  • the compounds of the invention are single and/or dual inhibitors of these protein kinases. Diseases are prevented, alleviated or cured by modulating these protein kinase activities.
  • the diseases include allergic asthma, myelofibrosis, rheumatoid arthritis, B-cell lymphoma, monocytic leukemia, splenomegaly, eosinophilic syndrome, primary thrombocytopenia, systemic Giant cell disease, liver cancer, rectal cancer, bladder cancer, throat cancer, non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, breast cancer, prostate cancer, glioma, ovarian cancer, head and neck Squamous cell carcinoma, cervical cancer, esophageal cancer, kidney cancer, pancreatic cancer, colon cancer, skin cancer, lymphoma, gastric cancer, multiple myeloma and solid tumors, and the like.
  • dual protein kinase inhibitors interfere with two different kinases at the same time, and the anti-tumor effects produced are often superimposed, thus having the potential to treat various cancers more effectively.
  • the compounds of the invention may be combined with biological agents such as PD-1 inhibitors with As a combination drug for the treatment of various cancers and related diseases.
  • the carriers are formulated together and the resulting compositions are administered to mammals, such as men, women and animals, for the treatment of conditions, conditions and diseases.
  • the composition may be: a tablet, a pill, a suspension, a solution, an emulsion, a capsule, an aerosol, a sterile injectable solution. Sterile powder, etc.
  • pharmaceutically acceptable excipients include microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, calcium hydrogen phosphate, mannitol, hydroxypropyl-beta-cyclodextrin, beta-cyclodextrin. (increased), glycine, disintegrants (such as starch, croscarmellose sodium, complex silicates and high molecular weight polyethylene glycols), granulating binders (such as polyvinylpyrrolidone, sucrose, gelatin and Acacia gum) and lubricants (such as magnesium stearate, glycerin and talc).
  • disintegrants such as starch, croscarmellose sodium, complex silicates and high molecular weight polyethylene glycols
  • granulating binders such as polyvinylpyrrolidone, sucrose, gelatin and Acacia gum
  • lubricants such as magnesium stearate, glycerin and talc
  • the pharmaceutical composition is a dosage form suitable for oral administration, including but not limited to tablets, solutions, suspensions, capsules, granules, powders.
  • the amount of the compound or pharmaceutical composition of the invention administered to a patient is not fixed and is usually administered in a pharmaceutically effective amount.
  • the amount of the compound actually administered can be determined by the physician based on the actual conditions, including the condition being treated, the route of administration selected, the actual compound administered, the individual condition of the patient, and the like.
  • the dosage of the compound of the invention depends on the particular use of the treatment, the mode of administration, the condition of the patient, and the judgment of the physician.
  • the proportion or concentration of a compound of the invention in a pharmaceutical composition depends on a variety of factors including dosage, physicochemical properties, route of administration, and the like.
  • the compounds of formula I of the present invention can be prepared by the following methods:
  • each group is as described above.
  • the reagents and conditions for each step may be selected from those conventional in the art for carrying out such preparation methods. After the structure of the compound of the present invention is disclosed, the above selection may be carried out by those skilled in the art based on the knowledge in the art.
  • the compound of the formula I of the present invention can be obtained by the following method, however, the conditions of the method, such as the reactant, the solvent, the base, the amount of the compound used, the reaction temperature, the time required for the reaction, and the like are not limited to the following. explanation of. this invention
  • the compounds may also be conveniently prepared by combining various synthetic methods described in the specification or known in the art, and such combinations are readily made by those skilled in the art to which the present invention pertains.
  • each reaction is usually carried out in an inert solvent at a reaction temperature of usually -20 to 150 ° C (preferably 0 to 120 ° C).
  • the reaction time in each step is usually from 0.5 to 48 h, preferably from 2 to 12 h.
  • Scheme 1 describes the general synthetic method for compounds 1-A7 and 1-A8:
  • the compound of the present invention has excellent inhibitory activity against a series of protein kinases, the compound of the present invention and various crystal forms thereof, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and compounds containing the present invention are
  • the pharmaceutical composition of the main active ingredient can be used to treat, prevent, and alleviate diseases associated with EGFR, FAK, SYK, FLT-3, Axl, CDK, JAK activity or expression levels.
  • compositions of the present invention comprise a safe or effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.
  • safe and effective amount it is meant that the amount of the compound is sufficient to significantly improve the condition without causing serious side effects.
  • the pharmaceutical compositions contain from 1 to 2000 mg of the compound of the invention per agent, more preferably from 5 to 200 mg of the compound of the invention per agent.
  • the "one dose” is a capsule or tablet.
  • “Pharmaceutically acceptable carrier” means: one or more compatible solid or liquid fillers or gel materials which are suitable for human use and which must be of sufficient purity and of sufficiently low toxicity. By “compatibility” it is meant herein that the components of the composition are capable of intermixing with the compounds of the invention and with each other without significantly reducing the potency of the compound.
  • pharmaceutically acceptable carriers are cellulose and its derivatives (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid).
  • magnesium stearate magnesium stearate
  • calcium sulfate vegetable oil (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyol (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifier (such as Tween ), a wetting agent (such as sodium lauryl sulfate), a coloring agent, a flavoring agent, a stabilizer, an antioxidant, a preservative, a pyrogen-free water, and the like.
  • vegetable oil such as soybean oil, sesame oil, peanut oil, olive oil, etc.
  • polyol such as propylene glycol, glycerin, mannitol, sorbitol, etc.
  • emulsifier such as Tween
  • a wetting agent such as sodium lauryl sulfate
  • a coloring agent such as a flavoring agent, a stabilizer, an antioxidant, a preservative
  • the mode of administration of the compound or pharmaceutical composition of the present invention is not particularly limited, and representative modes of administration include, but are not limited to, oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration. .
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or mixed with: (a) a filler or compatibilizer, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) humectants, For example, glycerin; (d) a disintegrant such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) a slow solvent such as paraffin; (f) Absorbing accelerators, for example, quaternary amine compounds; (g) wetting agents, such as cetyl alcohol and
  • Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other materials known in the art. They may contain opacifying agents and the release of the active compound or compound in such compositions may be released in a portion of the digestive tract in a delayed manner. Examples of embedding components that can be employed are polymeric and waxy materials. If necessary, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs.
  • the liquid dosage form may contain inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or a mixture of these substances.
  • inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethyl
  • compositions may contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and perfumes.
  • the suspension may contain suspending agents, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these and the like.
  • suspending agents for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these and the like.
  • compositions for parenteral injection may comprise a physiologically acceptable sterile aqueous or nonaqueous solution, dispersion, suspension or emulsion, and a sterile powder for reconstitution into a sterile injectable solution or dispersion.
  • Suitable aqueous and nonaqueous vehicles, diluents, solvents or vehicles include water, ethanol, polyols, and suitable mixtures thereof.
  • Dosage forms for the compounds of the invention for topical administration include ointments, powders, patches, propellants and inhalants.
  • the active ingredient is admixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or, if necessary, propellants.
  • the compounds of the invention may be administered alone or in combination with other pharmaceutically acceptable compounds.
  • a safe and effective amount of a compound of the invention is administered to a mammal (e.g., a human) in need of treatment wherein the dosage is a pharmaceutically effective effective dosage, for a 60 kg body weight
  • the dose to be administered is usually from 1 to 2000 mg, preferably from 5 to 500 mg.
  • specific doses should also consider factors such as the route of administration, the health of the patient, etc., which are within the skill of the skilled physician.
  • the inhibitor can be at a very low concentration
  • the activity of the above protein kinase is inhibited.
  • a pharmaceutical composition for treating diseases associated with protein kinase activity such as EGFR, FAK, SYK, FLT-3, Axl, CDK, JAK, etc. is provided.
  • the compound A1Sd (1.2 g, 5.1 mmol) was dissolved in 20 ml of methanol, 37% aqueous formaldehyde (6 ml) was added, and 2 drops of acetic acid were added thereto, and stirred at room temperature for 30 minutes, then sodium cyanoborohydride (0.8 g) was added. , 12.7 mmol), stirred at room temperature for 3 hours, and the reaction was completed by TLC. The reaction mixture was concentrated to dryness crystals crystals crystals crystals crystals crystals crystals MS m/z 250.2 [M + H] + .
  • an intermediate A1Rf was obtained by using A1Rb (100% ee) as a raw material.
  • Compound Aa1a (80 mg, 0.23 mmol) and A1Rf (51 mg, 0.23 mmol) were dissolved in 1.5 ml of 1,4-dioxane, and 100 ml of trifluoroacetic acid was added dropwise.
  • the reaction mixture was heated to 60 ° C for 6 hours, and after completion of the reaction, sodium hydrogencarbonate was added to adjust the pH to 8-9.
  • the compound A2Sa (150 mg, 0.54 mmol) was dissolved in 3 ml of methanol at room temperature, and 15 mg of palladium carbon catalyst was added thereto, and hydrogenation was carried out at room temperature under normal pressure for 1 hour, and the reaction was monitored by TLC.
  • the reaction mixture was filtered through EtOAc (EtOAc)EtOAc.
  • the compound A2Rb was prepared by the method described in Example 4 using A1Rd as a starting material.
  • Compound A1a 40 mg, 0.11 mmol
  • compound A2Rb 30 mg, 0.12 mmol
  • 100 mg of trifluoroacetic acid was added.
  • the reaction mixture was reacted at 60 ° C for 6 hours.
  • sodium hydrogencarbonate was added to adjust the pH to 8-9, and dichloromethane was added for 3 times.
  • the organic phase was combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product.
  • reaction solution was cooled to room temperature, then poured into a saturated aqueous solution of sodium bicarbonate, and extracted with ethyl acetate (3 ml) (3 ml), and the organic layer was washed with brine (10 ml), then anhydrous sodium sulfate The mixture was dried, filtered, and evaporated tolulululululululululululululululululululululu MS m/z 612.2 (M+H) + .
  • the compound A3Rb was prepared by the method described in Example 6 using A1Rc as a starting material.
  • Compound A3Rb (45 mg, 0.074 mmol) was dissolved in isopropyl alcohol (3 ml), and then HCl (1% isopropyl alcohol solution, 986 mg, 0.296 mmol) was added dropwise.
  • the reaction solution was heated to 70 ° C and stirred for 16 hours. After the reaction was completed by LCMS, the reaction mixture was evaporated to dryness, and then evaporated to ethyl ether to give a yellow solid A3R hydrochloride (33.20 mg, yield 74%).
  • reaction mixture was cooled to room temperature, then poured into saturated sodium carbonate solution (10 ml) and extracted three times with ethyl acetate (15 ml x 3) The organic layer was combined and washed with saturated brine (15 ml), dried over anhydrous sodium sulfate, and filtered, and the filtrate was concentrated under reduced pressure.
  • the compound A6Ra (30 mg, 0.11 mmol) was placed in a 50 ml single-necked flask, dissolved in methanol (3 ml), and then Pd/C (10%, 10 mg) was added thereto, and the bottle was replaced with hydrogen. The air was stirred at room temperature for 1 hour under a hydrogen atmosphere. TLC monitoring showed the reaction was completed, the reaction mixture was filtered, and then the filtrate was evaporated to give a brown solid compound A6Rb (25 mg, yield 94%).
  • the reaction mixture was poured, and the mixture was poured into water and extracted three times with ethyl acetate (15 ml x 3), and the organic layer was combined and washed with brine (15 ml) Then, it is dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure.
  • A8Ra (>99% ee) was used as a raw material to prepare an intermediate A8Rd.
  • the reaction mixture was cooled to room temperature, then poured into a saturated aqueous solution of sodium hydrogen carbonate (10 ml), EtOAc (3 mL) The residue was dried over anhydrous sodium sulfate (MgSO4) 99% ee).
  • the compound A9Sf (26 mg, 0.099 mmol) was placed in a 25 ml single-necked flask, dissolved in methanol (3 ml), then Pd/C (10%, 5 mg) was added thereto, and the bottle was replaced with hydrogen. The air was stirred at room temperature for 40 minutes under a hydrogen atmosphere. The TLC monitoring showed the reaction was completed, the reaction mixture was filtered, and then the filtrate was evaporated to dryness to give a white solid compound A9Sg (23 mg, yield 99%).
  • the intermediate A8Rg was obtained by using A9Ra (>99% ee) as a raw material.
  • the compound A9Rg (8 mg, 0.034 mmol) and the compound A1a (12 mg, 0.035 mmol) were dissolved in dry isopropyl alcohol (1 ml), and trifluoroacetic acid (4 mg, 0.035 mmol) was added.
  • the system was heated to 40 ° C and the reaction was stirred for 16 hours.
  • the reaction mixture was cooled to room temperature, then poured into a saturated aqueous solution of sodium hydrogen carbonate (10 ml), EtOAc (3 mL) The residue was dried over anhydrous sodium sulfate (MgSO4).
  • Compound C3R was prepared by the preparation of the compound A2Rb and C1Rd according to the compound C1R.
  • the compound C4R was obtained by the preparation of the compound B2Rb and C1Rd according to the compound C1R.
  • the compound C11R is synthesized from the compound C8R and methylsulfonyl chloride according to the preparation method of the compound C9R.
  • LCMS
  • the compound C12R is synthesized from the compound C8R and 2-propylsulfonyl chloride according to the preparation method of the compound C9R.
  • 1 H NMR 500MHz, MeOD
  • ⁇ 8.39 s, 1H
  • 7.64 s, 1H
  • the compound C13R is synthesized from the compound C8R and tetrahydropyran-4-sulfonyl chloride according to the preparation method of the compound C9R.
  • the compound C17h (8 mg, 0.029 mmol) was dissolved in dilute hydrochloric acid (6 N, 0.5 ml), and the air in the flask was replaced with argon gas, and the reaction was heated to 85 ° C under an argon atmosphere for 2 hours.
  • the reaction mixture was neutralized with a sodium hydroxide solution to pH 8 and extracted with EtOAc EtOAc (EtOAc)EtOAc. Rate 74%).
  • the intermediate E1b is the racemate of the intermediates A8Rd and A8Sd. It can be prepared according to the synthesis method of A8Rd and A8Sd.
  • Compound C19R is prepared by reacting compound C8R with acryloyl chloride in dichloromethane and triethylamine.
  • Compound C20Ra is prepared by reacting compound A1Rd acryloyl chloride in dichloromethane and triethylamine.
  • the compound C20Rb is obtained by reducing the compound C20Ra by iron powder and ammonium chloride (refer to the synthesis of the compound C17Rd).
  • the compound C20R is obtained by reacting the compound C20Rb with the compound C1Rd (according to the synthesis method of A8Rd and A8Sd).
  • EGFR and EGFR (T790M/L858R) protein kinase activities were determined using the Caliper mobility shift assay.
  • the compound was dissolved in DMSO and diluted with kinase buffer (EGFR (T790M/L858R): 50 mM HEPES, pH 7.5, 0.0015% Brij-35, 10 mM MgCl 2 , 2 mM DTT; EGFR: pH 7.5 50 mM HEPES, 0.0015% Brij -35, 10 mM MgCl 2 , 10 mM MnCl 2 , 2 mM DTT), 5 ul of a 5-fold final concentration of the compound (10% DMSO) was added to a 384-well plate.
  • kinase buffer kinase buffer
  • Compound EGFR EGFR (T790M/L858R) A1 ⁇ 100 ⁇ 10 A1S ⁇ 100 ⁇ 1 A1R ⁇ 100 ⁇ 1 A2S ⁇ 100 ⁇ 10 A2R ⁇ 100 ⁇ 10 A3S ⁇ 1 A3R ⁇ 50 ⁇ 1 A4R ⁇ 100 ⁇ 10 A5R ⁇ 100 ⁇ 1 A6R ⁇ 100 ⁇ 10 A7R ⁇ 500 ⁇ 50 A8S ⁇ 100 ⁇ 10 A8R ⁇ 100 ⁇ 10 A9S ⁇ 100 ⁇ 10 A9R ⁇ 100 ⁇ 10 ⁇ 10
  • CDK2/CycA2 CDK4/CycD3 and CDK6/cycD3 protein kinase activities were determined using the Caliper mobility shift assay.
  • the compound was dissolved in DMSO and diluted with kinase buffer (CDK2/CycA2 and CDK6/cycD3 with 50 mM HEPES (pH 7.5), 10 mM MgCl 2 , 0.0015% Brij-35, and 2 mM dithiothreitol; CDK4/CycD3 with 20 mM HEPES (pH 7.
  • FLT3 protein kinase activity was measured using the Caliper mobility shift assay.
  • the compound was dissolved in DMSO and diluted with a kinase buffer (50 mM HEPES, pH 7.5, 0.0015% Brij-35, 2 mM DTT), and 5 ul of a 5-fold final concentration of the compound (10% DMSO) was added to a 384-well plate. After adding 10 ⁇ l of a 2.5-fold FLT3 enzyme solution, incubation was carried out for 10 minutes at room temperature, and then 10 ⁇ L of a 2.5-fold substrate (FAM-labeled polypeptide and ATP) solution was added.
  • a kinase buffer 50 mM HEPES, pH 7.5, 0.0015% Brij-35, 2 mM DTT
  • Axl protein kinase activity was determined using the Caliper mobility shift assay.
  • the compound was dissolved in DMSO and diluted with kinase buffer (50 mM HEPES, pH 7.5, 0.0015% Brij-35, 2 mM DTT), and 5 ⁇ L of a 5-fold final concentration of the compound (10% DMSO) was added to a 384-well plate. After adding 10 ⁇ l of a 2.5-fold Axl enzyme solution, incubate for 10 minutes at room temperature, and then add 10 ⁇ L of a 2.5-fold substrate (FAM-labeled polypeptide and ATP) solution.
  • FAM-labeled polypeptide and ATP 2.5-fold substrate
  • FAK protein kinase activity was determined by Latha screen analysis.
  • the compound was dissolved in DMSO and diluted with kinase buffer (25 mM HEPES, pH 7.5, 0.01 mM Triton, 10 mM MgCl 2 , 0.5 mM EGTA, 0.01% BRIJ-35, 2 mM DTT), and 2.5 ⁇ L of 4 was added to the 384-well plate. The final concentration of the compound (4% DMSO) was doubled. After adding 5 ⁇ L of 2 ⁇ FAK enzyme solution, incubate for 10 minutes at room temperature, and then add 2.5 ⁇ L of 4 times substrate (Fluorescein-polyGT and ATP) solution.
  • kinase buffer 25 mM HEPES, pH 7.5, 0.01 mM Triton, 10 mM MgCl 2 , 0.5 mM EGTA, 0.01% BRIJ-35, 2 mM DTT
  • SYK protein kinase activity was determined using the Caliper mobility shift assay.
  • the compound was dissolved in DMSO and diluted with kinase buffer (20 mM HEPES, 0.01% Triton X-100, 5 mM MgCl 2 , 1 mM MnCl 2 , 2 mM DTT), and 5 ⁇ L of a 5-fold final concentration of the compound was added to the 384-well plate ( 10% DMSO). After adding 10 ⁇ L of a 2.5-fold enzyme (with SYK) solution, it was incubated at room temperature for 10 minutes, and then 10 ⁇ L of a 2.5-fold substrate (Peptide FAM-P22 and ATP) solution was added.
  • kinase buffer 20 mM HEPES, 0.01% Triton X-100, 5 mM MgCl 2 , 1 mM MnCl 2 , 2 mM DTT
  • the buffer is configured of the following components: 50 mM HEPES, pH 7.5,0.00015% Brij-35.
  • Compounds were placed in a concentration gradient in 100% DMSO and diluted to 10% DMSO with buffer and added to 384 well plates. For example, when the initial concentration of the compound is 250 nM, it is made into 12.5 ⁇ M with 100% DMSO, and diluted by 5 or 6 concentrations, and then diluted 10-fold with buffer to prepare an intermediate dilution of the compound containing 10% DMSO, and transfer 5 ⁇ L. Go to the 384-well plate.
  • the Jak1 and Jak2 enzymes were diluted to the optimal concentration with the following buffer: 50 mM HEPES, pH 7.5, 0.00015% Brij-35, 2 mM DTT. Transfer 10 ⁇ L to a 384-well plate and incubate with the compound for 10-15 minutes. Substrate was diluted to an optimum concentration following buffers: 50mM HEPES, pH 7.5,0.00015% Brij -35,10 mM MgCl 2, ATP at Km. The reaction was initiated by adding 10 ⁇ L to a 384-well plate and reacted at 28 ° C for 1 hour. The conversion rate was then read using a Caliper Reader and the inhibition rate was calculated.
  • mice 12 ICR male mice, weighing 22-26 g, were used after 2 days of feeding in the laboratory of the experimental animal center. They were fasted 12 hours before the administration and 4 hours after the administration, and were free to drink during the test. Mice were randomly divided into four groups of 3 animals each. After intragastric administration, blood samples were taken at two different time points in each group.
  • Solvent 0.5% Methycellulose (aqueous solution containing 0.4% Tween 80).
  • Formulation of the intragastric administration solution The compound is accurately weighed, added to the solvent, and ultrasonically dissolved at room temperature for 5 minutes to completely dissolve the drug, and formulated into a drug solution of 0.33 mg/ml.
  • Drug sample A representative compound of the structure represented by the patent formula (I) of the present invention generally adopts a plurality of samples having similar structures (molecular weight difference of more than 2 units), accurately weighed, and administered together (cassette PK). This allows multiple compounds to be screened simultaneously and their oral absorption rates compared. Single drug administration was also used to study the pharmacokinetics of drug samples in mice.
  • Blood was taken from the eyelids at 0.25, 0.5, 1, 2, 4, 8, 12, and 24 hours after intragastric administration. In the heparin-treated tube, the supernatant was centrifuged for LC-MS/MS analysis. .

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Abstract

提供了一类含有三环杂芳基化合物。具体地，提供了如下式（I）所示结构的化合物（各基团定义如说明书中所述）、含有式（I）化合物的药物组合物及所述化合物，以及这些化合物的同位素衍生物，手性异构体，变构体，不同的盐，前药，制剂等等。其能够有效抑制蛋白激酶（例如EGFR，FAK，SYK，FLT-3，Axl，CDK，JAK等），从而起到治疗各种肿瘤，非酒精性肝病（NASH），肺纤微化（IPF）等相关多种疾病的作用。

Description

一类含有三环杂芳基的化合物 技术领域
本发明涉及药物化学领域；具体地说，本发明涉及一类新型含有三环杂芳基的衍生物，其合成方法及其作为一种或多种蛋白激酶抑制剂在制备药物用于治疗肿瘤，非酒精性脂肪性肝炎(NASH)，特发性肺纤维化(IPF)等相关多种疾病中的应用。
背景技术
癌症亦称恶性肿瘤，是世界上发病率最高和死亡率最高的一种疾病之一，其特点是以细胞异常增殖及转移，在发病后短时间内或相对短时间内扩散，转移。传统的治疗方案包括切除(如果符合切除条件)，放疗，化疗。近年来发展起来的靶向治疗法，有降低毒性和对病人的负作用，及提高生存率等优点。但在使用靶向药物一段时间内又会产生抗药性，之后癌细胞的生长扩散就会异常迅猛。常见的癌症有：血癌，肺癌，肝癌，膀胱癌，直肠癌，胃癌，等等。
特发性肺纤维化(idiopathic pulmonary fibrosis,或IPF)是一种慢性、进行性、纤维化性间质性肺疾病，病变局限在肺脏，好发于中老年人群，其肺组织学和/或胸部高分辨率CT(HRCT)特征性表现为普通型间质性肺炎(UIP)，病因不清。作为一种慢性间质性肺病，IPF起病隐匿、病情逐渐加重，也可表现为急性加重。IPF诊断后的平均生存期仅2.8年，死亡率高于大多数肿瘤，IPF被称为一种“类肿瘤疾病”。
非酒精性脂肪性肝病(NASH)是指除外酒精和其他明确的损肝因素所致的肝细胞内脂肪过度沉积为主要特征的临床病理综合征，与胰岛素抵抗和遗传易感性密切相关的获得性代谢应激性肝损伤。随着肥胖及其相关代谢综合征全球化的流行趋势，非酒精性脂肪性肝病现已成为欧美等发达国家和我国富裕地区慢性肝病的重要病因，普通成人NAFLD患病率10％～30％，其中10％～20％为NASH，后者10年内肝硬化发生率高达25％。非酒精性脂肪性肝病除可直接导致失代偿期肝硬化、肝细胞癌和移植肝复发外，还可影响其他慢性肝病的进展，并参与2型糖尿病和动脉粥样硬化的发病。代谢综合征相关恶性肿瘤、动脉硬化性心脑血管疾病以及肝硬化为影响非酒精性脂肪性肝病患者生活质量和预期寿命的重要因素。为此，非酒精性脂肪性肝病是当代医学领域的新挑战，近期内非酒精性脂肪性肝病对人类健康的危害仍将不断增加。
随着肿瘤分子生物学研究的深入，人们对肿瘤发生、发展的分子机制，以及不同的致病靶点的认识日益加深。在诸多涉及诱发癌症的信息传导和通路中，蛋白激酶是一类生物活性体，催化ATP的γ磷酸基转移到许多重要蛋白质的残基上，使之磷酸化，从而传递信号，从而参与一系列细胞活动，与细胞生长、分化、增殖密切相关。发展选择性的蛋白激酶抑制剂来阻断或者调控由于这些信号通路异常产生的疾病已经被视为抗肿瘤药物开发的一个有效的研究策略。在临床试验中得到验证，并有多个蛋白激酶抑制剂被批准上市。
表皮生长因子受体酪氨酸激酶(epidermal growth factor receptor tyrosine kinase,EGFR)是由1186个氨基酸组成，编码分子量为170-kDa的一种跨膜糖蛋白。EGFR能够介导多条信号传导通路，将胞外信号传递到胞内，对正常细胞和肿瘤细胞的增殖、分化和凋亡 均发挥重要的调节作用(Cell,2000,100,113-127)。EGFR是许多正常上皮组织(如皮肤和毛囊)的组成性表达成分，而在大部分实体瘤中，EGFR存在过表达或者高表达。例如，在肺癌中，EGFR的表达率达到
Figure PCTCN2017115756-appb-000001
因此选择性地抑制EGFR，干扰其介导的信号转导途径，可以达到治疗肺癌的目的，为靶向治疗肺癌开辟了一条可行之路。临床治疗上，结合传统的放疗、化疗，以EGFR靶向药物如吉非替尼
Figure PCTCN2017115756-appb-000002
厄洛替尼
Figure PCTCN2017115756-appb-000003
等进行一线药物在肺癌治疗中被证明是非常有效的。但是，使用这类药物会在6-12月内出现获得性耐药。其中大约50％病例的耐药性与EGFR激酶结构域中一个氨基酸残基的突变(790位苏氨酸残基突变为甲硫氨酸，T790M)有关(The New England Journal of Medicine,2005,352,786-792)。T790M突变导致抑制剂与EGFR结合时产生空间位阻或者增加EGFR与ATP的亲和力，使得这类可逆性结合的竞争性抑制剂的抗癌效果大大减弱。耐药性的产生不但降低了病人对药物的敏感性，也大大降低了肿瘤患者的生存质量。因此针对其它靶点包括其它蛋白激酶的抑制剂的研究显得更加重要。
脾酪氨酸激酶(spleen tyrosine kinase,SYK)基因是1991年首次从猪脾cDNA克隆出来，编码一种非受体型蛋白酪氨酸激酶。人类SYK基因定位于9号染色体q22区，SYK蛋白含635个氨基酸，在自身免疫性疾病和血液恶性肿瘤中作用重要，如SYK基因可抑制乳腺癌、黑色素瘤和肝癌等恶性肿瘤细胞的增殖与迀移。目前，SYK抑制剂已用于类风湿性关节炎、慢性淋巴细胞白血病等的临床II/III期实验。最近研究表明，使用SYK抑制剂或者干扰SYK基因的表达，可以有效地减缓肝纤维化/硬化的进程，具有很好地治疗作用(参见CN 105664178A)。
局部粘着斑激酶(Focal Adhesion Kinase,FAK)是一种非受体型酪氨酸蛋白激酶，1992年被鉴定为是一种与癌基因v-src相关的高度磷酸化蛋白，位于正常细胞的富含整合素黏着斑区域。FAK是细胞内重要的骨架蛋白和多种信号通路的关键分子，对细胞存活、增殖迁移和侵袭都有重要作用。多项科学研究表明FAK抑制剂可能成为有效的抗肿瘤药物。近年来的科学研究还表明，FAK抑制剂也可能有效的治疗肺纤维化。
AXL是一个重要的酪氨酸受体激酶,英文全称为AXL receptor tyrosine kinase。AXL也叫UFO/ARK/Tyro，其配体是维生素K依赖性的生长促进因子GAS6。AXL的首次发现是作为慢性髓细胞性白血病(CML)的转化基因。AXL在转移性结肠癌、甲状腺癌、乳腺癌、前列腺癌和黑色素瘤中过度表达。抑制AXL的活性可起到抑制肿瘤生长、扩散和转移的目的。
FLT-3(Fms-related tyrosine kinase 3)属于III型受体酪氨酸激酶的家族成员，是一种信号分子。FLT-3在肝脏、脾脏、淋巴、脑、胎盘和生殖腺等各种组织中均有表达，同时在正常的骨髓细胞和淋巴系细胞前体中也有表达，在许多造血系统恶性病中都有表达，其信号传导途径与众多肿瘤传导途径有关联，因此，FLT-3成为一个理想抗肿瘤的药物作用靶点。
细胞周期的调控主要受一系列丝氨酸/苏氨酸激酶的影响，这类丝氨酸/苏氨酸激酶又被称作细胞周期蛋白依赖性激酶(Cyclin-dependent kinase，CDK)，它们通过与其相对应的调节亚基周期素(cydins)相结合，推动细胞周期的进行、遗传信息的转录和细胞的正常分裂增殖。CDK4/6是细胞周期的关键调节因子，能够触发细胞周期从生长期(Gl期)向DNA复制期(SI期)转变。在细胞增殖过程中，细胞周期素D(Cyclin D)与CDK4/6形成 的复合物能够磷酸化视网膜母细胞瘤蛋白(Rb)。肿瘤抑制蛋白Rb—旦发生磷酸化，可释放其在未被磷酸化的状态下紧密结合的转录因子E2F，E2F激活进一步转录推动细胞周期通过限制点(R点)并从Gl期进展到S期，进入了细胞增殖的周期。因此，抑制CDK4/6使之无法形成Cyclin D-CDK4/6复合物，就能够阻滞细胞周期自Gl期向S期的进程，从而达到抑制肿瘤增殖的目的。
Janus激酶(Janus kinase，JAK)是转导细胞因子信号从膜受体到STAT转录因子的细胞质酪氨酸激酶。科学研究表明，抑制JAK可以成为有前途的抗癌药的靶点。
综上所述，开发新型的蛋白激酶抑制剂具有重要的意义。
发明内容
本发明的目的是提供一类新型的蛋白激酶抑制剂。
本发明的第一方面，提供了一种如下式(I)所示结构的化合物：
Figure PCTCN2017115756-appb-000004
其中，所述的M为下式(II)所示的基团：
Figure PCTCN2017115756-appb-000005
式(I)和式(II)中：
Figure PCTCN2017115756-appb-000006
表示式(II)与式(I)中的U的连接位点；
“*”表示手性中心；
A选自芳基或杂芳基；
B为芳基、杂芳基、C3-8环烷基、3-至12-元杂环基、NRaRb、ORb、SRb、或SO2Rb，其中所述的芳基、杂芳基、环烷基、杂环基可以独立地被一个或多个Rc取代；
U为NRd、O或S；
X为氢、卤素、C1-4烷基、C1-4卤代烷基、C3-6环烷基、C2-4烯基、C2-4炔基、3-至10-元杂环基、ORe、SRe、NReRe、CN、C(O)Re、C(O)ORe，C(O)NReRe、OC(O)Re、NReC(O)Re、或S(O)2Re；
J和G各自独立地为NRf、O、S、S(O)、S(O)2或CRgRg；
R1和R2各自独立地选自下组：氢、卤素、C1-4烷基、C3-6环烷基、3-至8-元杂环基、或C(O)NReRe；其中，所述的烷基、环烷基、杂环基可以任选地被一个或多个Rc取代；
各个R3各自独立为氢、或C1-4烷基；当两个R3同时连接到同一个碳原子上时，这两个R3与其相连的碳原子可以任选共同形成羰基(C＝O)；
n为0、1、2、或3；
Ra为氢、C1-4烷基、C3-6环烷基、或3-至12-元杂环基；其中，所述这里的烷基、环烷基、杂环基可以任选独立地被一个或多个卤素、ORe、CN、SO2NReRe取代，只要所形成的化学结构式是稳定的和有意义的；
Rb为芳基、杂芳基、C1-4烷基、C3-8环烷基、3-至12-元杂环基、C(O)Re、或C(O)NReRe；其中，所述的芳基、杂芳基、烷基、环烷基、杂环基可以任选地被一个或多个Rc取代；
各个Rc各自独立为卤素、C1-4烷基、C3-8环烷基、3-至8-元杂环基、C(O)NReRe、NReC(O)Re、ORe、CN、或SO2NReRe；
Rd为氢或C1-4烷基；
各个Re各自独立地选自下组：氢、C1-4烷基、C1-4卤代烷基、C2-4烯基、C2-4炔基、C3-8环烷基、3-至8-元杂环基、芳基、或杂芳基；或者两个Re与和它们连接的氮原子一起形成3-至8-元杂环基，此杂环基含有1或2个N原子以及0或1个选自O、S的杂原子；
Rf为氢、C1-8烷基、C1-8卤代烷基、C2-8烯基、C2-8炔基、C3-8环烷基、3-至12-元杂环基、芳基、杂芳基、C(O)Re、C(O)ORe、C(O)NReRe、S(O)2Re、或S(O)2NRhRh；
各个Rg各自独立地选自下组：氢、卤素、或C1-4烷基；或两个Rg与其相连的碳原子共同形成羰基(C＝O)；或两个Rg与其连接的同一个碳原子一起形成3-至8-元环状结构，此环状结构任选地含有0、1或2个选自N、O、S的杂原子；
各个Rh各自独立为氢、或C1-4烷基；或两个Rh与其连接的氮原子一起形成3-至-元环状结构
其中，各个上述的烷基、烯基、炔基、环烷基、杂环基、环状结构、芳基和杂芳基任选地且各自独立地被1-3个各自独立地选自下组的取代基取代：卤素、C1-4烷基、C1-4卤代烷基、C2-4烯基、C2-4炔基、C3-8环烷基、3-至12-元杂环基、芳基、杂芳基、CN、NO2、ORe、SRe、NReRe、C(O)Re、C(O)ORe、C(O)NReRe、NReC(O)Re、或S(O)2Re，前提条件是所形成的化学结构是稳定的和有意义的；
除非特别说明，上述的芳基为含有6-12个碳原子的芳香基团；杂芳基为5-至15-元杂芳香基团；环状结构为饱和的或不饱和的、含杂原子或不含杂原子的环状基团；
附加条件为，A不选自下组的基团：
Figure PCTCN2017115756-appb-000007
其中，“**”表示与U连接；“***”表示与B连接；
且所述的式(I)化合物不为
Figure PCTCN2017115756-appb-000008
在另一优选例中，所述的M为下式(IIa)所示的基团：
Figure PCTCN2017115756-appb-000009
其中X、R3、G、和n的定义如上文中所述。
在另一优选例中，所述的M选自式(IIb)、式(IIc)、或式(IId)所示的基团：
Figure PCTCN2017115756-appb-000010
其中Rf的定义如上文中所述。
在另一优选例中，式(I)中A分别独立地选自如下基团：
Figure PCTCN2017115756-appb-000011
其中，“**”表示与U连接；“***”表示与B连接；
U为NRd。
在另一优选例中，式(I)中B选自下组：-NH-芳基、-NH-C3-8环烷基、-NH-(3-至12-元杂环基)、杂芳基、C3-8环烷基、3-至12-元杂环基，其中上述的任意芳基、杂芳基、环烷基、杂环基(单独或与其他基团共同组成取代基时)可以独立地被一个或多个Rc取代。
在另一优选例中，式(I)中B选自下组：
Figure PCTCN2017115756-appb-000012
在另一优选例中，R1、R2、A、U、M、B分别为实施例中所制备的各具体式(I)化合物所对应的相应基团。
在另一优选例中，式(I)为：
Figure PCTCN2017115756-appb-000013
X为H；
G为NRf或O；其中Rf的定义如上文中所述；
R1选自氢、卤素、或C1-4烷基，其中，所述的烷基可以任选地被一个或多个卤素取代；
各个R3各自独立为氢、或两个R3相连在同一个碳原子共同形成羰基(C＝O)；
n为0、1、或2。
在另一优选例中，式(I)为：
Figure PCTCN2017115756-appb-000014
X为H；
G为NRf或O；其中Rf的定义如上所述；
R1选自氢、卤素、或C1-4烷基；
各个R3各自独立为氢、或两个R3相连在同一个碳原子共同形成羰基(C＝O)；
n为0、1、或2。
在另一优选例中，式(I)为：
Figure PCTCN2017115756-appb-000015
X为H；
G为NRf或O；其中Rf的定义如本发明第一方面中所述；
R1选自氢、卤素、或CONH2；
各个R3各自独立为氢、或两个R3相连在同一个碳原子共同形成羰基(C＝O)；
n为0、1、或2。
在另一优选例中，式(I)为：
Figure PCTCN2017115756-appb-000016
X为H；
G为NRf或O；其中Rf的定义同上；
R1选自氢、或C1-4烷基；R2为CONH2；
各个R3各自独立为氢、或两个R3相连在同一个碳原子共同形成羰基(C＝O)；
n为0、1、或2。
在另一优选例中，式(I)为：
Figure PCTCN2017115756-appb-000017
X为H；
G为NRf或O；其中Rf的定义同上；
R1选自氢、卤素、或C1-4烷基，其中，所述的烷基可以任选地被一个或多个卤素取代；
各个R3各自独立为氢、或两个R3相连在同一个碳原子共同形成羰基(C＝O)；
n为0、1、或2。
在另一优选例中，所述的化合物选自下组之一：
Figure PCTCN2017115756-appb-000018
Figure PCTCN2017115756-appb-000019
Figure PCTCN2017115756-appb-000020
Figure PCTCN2017115756-appb-000021
Figure PCTCN2017115756-appb-000022
本发明的第二方面，提供了一种如本发明第一方面所述的化合物，或其光学异构体，药学上可接受的盐，前药，氘代衍生物，水合物，溶剂合物的用途，用于：
(a)制备治疗与蛋白激酶活性或表达量相关的疾病的药物；
(b)制备蛋白激酶靶向抑制剂；和/或
(c)体外非治疗性地抑制蛋白激酶的活性；
其中，所述的蛋白激酶选自下组但不限制于：EGFR、CDK、SYK、JAK、Flt-3、Axl、FAK，或其组合。
本发明的第三方面，提供了一种如本发明第一方面所述的化合物，或其光学异构体，药学上可接受的盐，前药，氘代衍生物，水合物，溶剂合物的用途，作为EGFR抑制剂，或用于治疗与EGFR高表达相关的疾病。
本发明的第四方面，提供了一种如本发明第一方面所述的化合物，或其光学异构体，药学上可接受的盐，前药，氘代衍生物，水合物，溶剂合物的用途，作为CDK抑制剂，或用于治疗与CDK高表达相关的疾病。
本发明的第五方面，提供了一种如本发明第一方面所述的化合物，或其光学异构体，药学上可接受的盐，前药，氘代衍生物，水合物，溶剂合物的用途，作为SYK和JAK抑制剂，或用于治疗与SYK和JAK高表达相关的疾病。
本发明的第六方面，提供了一种如本发明第一方面所述的化合物，或其光学异构体，药学上可接受的盐，前药，氘代衍生物，水合物，溶剂合物的用途，作为Flt-3和Axl抑制剂，或用于治疗与Flt-3和Axl高表达相关的疾病。
本发明的第七方面，提供了一种如本发明第一方面所述的化合物，或其光学异构体，药学上可接受的盐，前药，氘代衍生物，水合物，溶剂合物的用途，作为FAK抑制剂，或用于治疗与FAK高表达相关的疾病。
本发明的第八方面，提供了一种药物组合物，所述的药物组合物包括：(i)有效量的如本发明第一方面所述的式I化合物，或其光学异构体，药学上可接受的盐，前药，氘代衍生物，水合物，溶剂合物；和(ii)药学上可接受的载体。
本发明的第九方面，提供了一种抑制蛋白激酶活性的方法，所述方法包括步骤：对抑制对象施用抑制有效量的如本发明第一方面所述的式I化合物，或其光学异构体，药学上可接受的盐，前药，氘代衍生物，水合物，溶剂合物，或对抑制对象施用抑制有效量的如本发明第八方面所述的药物组合物；其中，所述的蛋白激酶选自下组：EGFR、FAK、SYK、FLT-3、Axl、CDK、JAK，或其组合。
本发明的第十方面，提供了一种如本发明第一方面所述化合物的制备方法，该方法包括步骤：
Figure PCTCN2017115756-appb-000023
在惰性溶剂中，用Ia化合物与Ib反应，得到式I化合物；
优选地所述的式Ia化合物是通过以下方法制备的：
Figure PCTCN2017115756-appb-000024
(i)在碱性条件下，式(Va)化合物与式(Vb)化合物反应，得到式(Vc-1)和(Vc-2)化合物；
任选的(ii)在酸性条件下，分别用式(Vc-1)和(Vc-2)化合物反应，从而脱去保护基；
(iii)用脱去保护基的式(Vc-1)和(Vc-2)化合物分别反应，分别得到式(Vd-1)和(Vd-2)化合物；
和任选的(iv)分别对式(Vd-1)和(Vd-2)化合物进行还原，分别得到式(V-1)和(V-2)化合物。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
具体实施方式
本发明人经过长期而深入的研究，意外地发现了一类结构新颖的含有三环芳基化合物的蛋白激酶抑制剂，以及它们的制备方法和应用。所述的蛋白激酶抑制剂可以抑制包括有EGFR、FAK、SYK、FLT-3、Axl、CDK、JAK等在内的多种蛋白激酶。本发明化合物可以应用于与所述激酶的活性相关的各种疾病的治疗。基于上述发现，发明人完成了本发明。
术语
除特别说明之处，本文中提到的“或”具有与“和/或”相同的意义(指“或”以及“和”)。
除特别说明之处，本发明的所有化合物之中，各手性碳原子(手性中心)可以任选地为R构型或S构型，或R构型和S构型的混合物。
如本文所用，在单独或作为其他取代基一部分时，术语“烷基”指只含碳原子的直链(即， 无支链)或支链饱和烃基，或直链和支链组合的基团。当烷基前具有碳原子数限定(如C1-10)时，指所述的烷基含有1-10个碳原子。例如，C1-8烷基指含有1-8个碳原子的烷基，包括甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、或类似基团。
如本文所用，在单独或作为其他取代基一部分时，术语“烯基”是指直链或支链，具有至少一个碳-碳双键的碳链基团。烯基可以是取代的或未取代的。当烯基前具有碳原子数限定(如C2-8)时，指所述的烯基含有2-8个碳原子。例如，C2-8烯基指含有2-8个碳原子烯基，包括乙烯基、丙烯基、1,2-丁烯基、2,3-丁烯基、丁二烯基、或类似基团。
如本文所用，在单独或作为其他取代基一部分时，术语“炔基”是指具有至少一个碳-碳三键的脂肪族碳氢基团。所述的炔基可以是直链或支链的，或其组合。当炔基前具有碳原子数限定(如C2-8炔基)时，指所述的炔基含有2-8个碳原子。例如，术语“C2-8炔基”指具有2-8个碳原子的直链或支链炔基，包括乙炔基、丙炔基、异丙炔基、丁炔基、异丁炔基、仲丁炔基、叔丁炔基、或类似基团。
如本文所用，在单独或作为其他取代基一部分时，术语“环烷基”指具有饱和的或部分饱和的单元环，二环或多环(稠环、桥环或螺环)环系基团。当某个环烷基前具有碳原子数限定(如C3-10)时，指所述的环烷基含有3-10个碳原子。在一些优选实施例中，术语“C3-8环烷基”指具有3-8个碳原子的饱和或部分饱和的单环或二环烷基，包括环丙基、环丁基、环戊基、环庚基、或类似基团。“螺环烷基”指单环之间共用一个碳原子(称螺原子)的二环或多环基团，这些可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。“稠环烷基”指系统中的每个环与体系中的其他环共享毗邻的一对碳原子的全碳二环或多环基团，其中一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。“桥环烷基”指任意两个环共用两个不直接连接的碳原子的全碳多环基团，这些可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。所述环烷基所含原子全部为碳原子。如下是环烷基的一些例子，本发明并不仅局限下述的环烷基。
Figure PCTCN2017115756-appb-000025
除非有相反陈述，否则下列用在说明书和权利要求书中的术语具有下述含义。“芳基”指具有共轭的π电子体系的全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团，例如苯基和萘基。所述芳基环可以稠合于其它环状基团(包括饱和和不饱和环)，但不能含有杂原子如氮，氧，或硫，同时连接母体的点必须在具有共轭的π电子体系的环上的碳原子上。芳基可以是取代的或未取代的。如下是芳基的一些例子，本发明并不仅局限下述的芳基。
Figure PCTCN2017115756-appb-000026
“杂芳基”指包含一个到多个杂原子的杂芳族基团。这里所指的杂原子包括氧、硫和氮。例如呋喃基、噻吩基、吡啶基、吡唑基、吡咯基、N-烷基吡咯基、嘧啶基、吡嗪基、咪唑基、四唑基等。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环。杂芳基可以是任选取代的或未取代的。如下是杂芳基的一些例子，本发明并不仅局限下述的杂芳基。其中，最后三个杂芳基是三环杂芳基，是本发明的重点。
Figure PCTCN2017115756-appb-000027
“杂环基”指饱和或部分不饱和单环或多环环状烃取代基，其中一个或多个环原子选自氮、氧或硫，其余环原子为碳。单环杂环基的非限制性实施例包含吡咯烷基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基。多环杂环基指包括螺环、稠环和桥环的杂环基。“螺环杂环基”指系统中的每个环与体系中的其他环之间共用一个原子(称螺原子)的多环杂环基团，其中一个或多个环原子选自氮、氧或硫，其余环原子为碳。“稠环杂环基”指系统中的每个环与体系中的其他环共享毗邻的一对原子的多环杂环基团，一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统，而且其中一个或多个环原子选自氮、氧或硫，其余环原子为碳。“桥环杂环基”指任意两个环共用两个不直接连接的原子的多环杂环基团，这些可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统，而且其中一个或多个环原子选自氮、氧或硫，其余环原子为碳。如果杂环基里同时有饱和环和芳环存在(比如说饱和环和芳环稠合在一起)，连接到母体的点一定是在饱和的环上。注：当连接到母体的点在芳环上时，称为杂芳基，不称为杂环基。如下是杂环基的一些例子，本发明并不仅局限下述的杂环基。
Figure PCTCN2017115756-appb-000028
如本文所用，在单独或作为其他取代基一部分时，术语“卤素”指F、Cl、Br和I。
如本文所用，术语“取代”(在有或无“任意地”修饰时)指特定的基团上的一个或多个氢原子被特定的取代基所取代。特定的取代基为在前文中相应描述的取代基，或各实施例中所出现的取代基。除非特别说明，某个任意取代的基团可以在该基团的任何可取代的位点上具有一个选自特定组的取代基，所述的取代基在各个位置上可以是相同或不同的。环状取代基，例如杂环基，可以与另一个环相连，例如环烷基，从而形成螺二环系，即两个环具有一个共用碳原子。本领域技术人员应理解，本发明所预期的取代基的组合是那些稳定的或化学上可实现的组合。所述取代基例如(但并不限于)：C1-8烷基、C2-8烯基、C2-8炔基、C3-8环烷基、3-至12-元杂环基，芳基、杂芳基、卤素、羟基、羧基(-COOH)、C1-8醛基、C2-10酰基、C2-10酯基、氨基。
为了方便以及符合常规理解，术语“任意取代”或“任选取代”只适用于能够被取代基所取代的位点，而不包括那些化学上不能实现的取代。
如本文所用，除非特别说明，术语“药学上可接受的盐”指适合与对象(例如，人)的组织接触，而不会产生不适度的副作用的盐。在一些实施例中，本发明的某一化合物的药学上可接受的盐包括具有酸性基团的本发明的化合物的盐(例如，钾盐，钠盐，镁盐，钙盐)或具有碱性基团的本发明的化合物的盐(例如，硫酸盐，盐酸盐，磷酸盐，硝酸盐，碳酸盐)。
用途：
本发明提供了一类式(I)或式(II)的化合物，或它们的氘代衍生物、它们的盐、异构体(对映异构体或非对映异构体，如果存在的情况下)、水合物、可药用载体或赋形剂用于抑制蛋白激酶的用途。这里所指的蛋白激酶包括EGFR、CDK、SYK、JAK、Flt-3、Axl和FAK在内，但并不仅限于以上几种激酶。
本发明化合物可用作一种或多种激酶抑制剂，例如一些实施例中，本发明中的某类化合物可用作EGFR激酶抑制剂；一些实施例中，本发明中的某类化合物可用作CDK激酶抑制剂；一些实施例中，本发明中的某类化合物可用作SYK激酶抑制剂；一些实施例中，本发明中的某类化合物可用作FAK激酶抑制剂；一些实施例中，本发明中的某类化合物可用作SYK激酶和JAK激酶的双重抑制剂；另一些实施例中，本发明中的某类化合物可用作Flt-3激酶和Axl激酶的双重抑制剂。
在癌症病人体内，上述所提到的各种蛋白激酶的表达或活性都明显增高。这些过度表达和/或异常的蛋白激酶活性水平与肿瘤的发生发展直接关联。本发明化合物是这些蛋白激酶的单一和/或双重抑制剂。通过调节这些蛋白激酶活性得到预防、缓解或治愈疾病。 所指疾病包括过敏性哮喘、骨髓纤维化、类风湿性关节炎、B细胞淋巴瘤、单核细胞白血病、脾大性红细胞增多、嗜酸性白细胞增多综合征、原发性血小板减少症、系统性巨细胞疾病、肝癌、直肠癌、膀胱癌、咽喉癌、非小细胞肺癌、小细胞肺癌、肺腺癌、肺鳞癌、乳腺癌、前列腺癌、神经胶质细胞瘤、卵巢癌、头颈部鳞癌、宫颈癌、食管癌、肾癌、胰腺癌、结肠癌、皮肤癌、淋巴瘤、胃癌、多发性骨髓癌和实体瘤等等。
从某种角度上说，双重蛋白激酶抑制剂同时干扰两种不同的激酶，所产生的抗肿瘤效果往往具有叠加性，因此具有更有效治疗各种癌症的潜力。
本发明化合物可与生物制剂如PD-1抑制剂
Figure PCTCN2017115756-appb-000029
和
Figure PCTCN2017115756-appb-000030
作为组合药物治疗各种癌症及相关疾病。
可将本发明化合物及其氘代衍生物，以及药学上可接受的盐或其异构体(如果存在的情况下)或其水合物和/或组合物与药学上可接受的赋形剂或载体配制在一起，得到的组合物可在体内给予哺乳动物，例如男人、妇女和动物，用于治疗病症、症状和疾病。组合物可以是：片剂、丸剂、混悬剂、溶液剂、乳剂、胶囊、气雾剂、无菌注射液。无菌粉末等。一些实施例中，药学上可接受的赋形剂包括微晶纤维素、乳糖、柠檬酸钠、碳酸钙、磷酸氢钙、甘露醇、羟丙基-β-环糊精、β-环糊精(增加)、甘氨酸、崩解剂(如淀粉、交联羧甲基纤维素钠、复合硅酸盐和高分子聚乙二醇)，造粒粘合剂(如聚乙烯吡咯烷酮、蔗糖、明胶和阿拉伯胶)和润滑剂(如硬脂酸镁、甘油和滑石粉)。在优选的实施方式中，所述药物组合物是适于口服的剂型，包括但不限于片剂、溶液剂、混悬液、胶囊剂、颗粒剂、粉剂。向患者施用本发明化合物或药物组合物的量不固定，通常按药用有效量给药。同时，实际给予的化合物的量可由医师根据实际情况决定，包括治疗的病症、选择的给药途径、给予的实际化合物、患者的个体情况等。本发明化合物的剂量取决于治疗的具体用途、给药方式、患者状态、医师判断。本发明化合物在药物组合物中的比例或浓度取决于多种因素，包括剂量、理化性质、给药途径等。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。
化合物的通用合成方法
本发明的式I化合物可以通过以下方法制备得到：
Figure PCTCN2017115756-appb-000031
在惰性溶剂中，用(Ia)化合物与(Ib)反应，得到(I)化合物；
上述各式中，各基团的定义如上文中所述。各步骤的试剂和条件可以选用本领域进行该类制备方法常规的试剂或条件，在本发明的化合物结构公开后，上述选择可以由本领域技术人员根据本领域知识进行。
更具体地，本发明通式I所示化合物可通过如下的方法制得，然而该方法的条件，例如反应物、溶剂、碱、所用化合物的量、反应温度、反应所需时间等不限于下面的解释。本发明 化合物还可以任选将在本说明书中描述的或本领域已知的各种合成方法组合起来而方便的制得，这样的组合可由本发明所属领域的技术人员容易地进行。
在本发明的制备方法中，各反应通常在惰性溶剂中，反应温度通常为-20～150℃(优选0～120℃)下进行。各步反应时间通常为0.5～48h，较佳地为2～12h。
反应式1描述了化合物1-A7和1-A8的通用合成方法：
反应式1:
Figure PCTCN2017115756-appb-000032
反应式2描述了化合物2-B4和2-B5的通用合成方法：
反应式2:
Figure PCTCN2017115756-appb-000033
反应式3描述了化合物3-C8的通用合成方法：
反应式3:
Figure PCTCN2017115756-appb-000034
反应式4描述了化合物4-D2的通用合成方法：
反应式4:
Figure PCTCN2017115756-appb-000035
反应式5描述了化合物5-E2的通用合成方法：
反应式5:
Figure PCTCN2017115756-appb-000036
反应式6描述了化合物6-F4的通用合成方法：
反应式6:
Figure PCTCN2017115756-appb-000037
反应式7描述了化合物7-G3的通用合成方法：
反应式7:
Figure PCTCN2017115756-appb-000038
反应式8描述了化合物8-H3的通用合成方法：
反应式8:
Figure PCTCN2017115756-appb-000039
反应式9描述了化合物9-I2的通用合成方法：
反应式9:
Figure PCTCN2017115756-appb-000040
反应式10描述了化合物10-J2的通用合成方法：
反应式10:
Figure PCTCN2017115756-appb-000041
药物组合物和施用方法
由于本发明化合物具有优异的对一系列蛋白激酶的抑制活性，因此本发明化合物及其各种晶型，药学上可接受的无机或有机盐，水合物或溶剂合物，以及含有本发明化合物为主要活性成分的药物组合物可用于治疗、预防以及缓解与EGFR、FAK、SYK、FLT-3、Axl、CDK、JAK活性或表达量相关的疾病。
本发明的药物组合物包含安全有效量范围内的本发明化合物或其药理上可接受的盐及药理上可以接受的赋形剂或载体。其中“安全有效量”指的是：化合物的量足以明显改善病情，而不至于产生严重的副作用。通常，药物组合物含有1-2000mg本发明化合物/剂，更佳地，含有5-200mg本发明化合物/剂。较佳地，所述的“一剂”为一个胶囊或药片。
“药学上可以接受的载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能 和本发明的化合物以及它们之间相互掺和，而不明显降低化合物的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如吐温
Figure PCTCN2017115756-appb-000042
)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
本发明化合物或药物组合物的施用方式没有特别限制，代表性的施用方式包括(但并不限于)：口服、瘤内、直肠、肠胃外(静脉内、肌肉内或皮下)、和局部给药。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，活性化合物与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例知，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性化合物外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂，或必要时可能需要的推进剂一起混合。
本发明化合物可以单独给药，或者与其他药学上可接受的化合物联合给药。
使用药物组合物时，是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人)，其中施用时剂量为药学上认为的有效给药剂量，对于60kg体重的人而言，日给药剂量通常为1～2000mg，优选5～500mg。当然，具体剂量还应考虑给药途径、病人健康状况等因素，这些都是熟练医师技能范围之内的。
本发明的主要优点包括：
1.提供了一种如式I所示的化合物。
2.提供了一种结构新颖的EGFR、FAK、SYK、FLT-3、Axl、CDK、JAK等蛋白激酶的活性抑制剂，及其制备和应用，所述的抑制剂在极低浓度下即可抑制上述蛋白激酶的活性。
3.提供了一类治疗与EGFR、FAK、SYK、FLT-3、Axl、CDK、JAK等蛋白激酶活性相关疾病的药物组合物。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。
实施例1化合物A1的制备
Figure PCTCN2017115756-appb-000043
化合物A1a(34.2毫克,0.10毫摩尔)和A1b(21.9毫克，0.10毫摩尔)溶于2毫升1,4-二氧六环中，再滴加入100毫克的三氟乙酸。反应混合物加热至60℃反应6小时，LC-MS监测反应。反应完成后冷却到室温，减压浓缩得到残留物，用制备高压液相纯化得到黄色固体化合物A1(5.4毫克，收率10％)。1H NMR(400MHz,CD3OD)δ8.21(s,1H),7.83-7.60(m,2H),7.33(dd,J＝8.4Hz,8.0Hz,1H),7.20(d,J＝7.6Hz,1H),7.00-6.89(m,2H),6.70-6.55(brs,1H),6.47-6.30(m,2H),5.77(d,J＝9.6Hz,2.4Hz,1H),4.15(dd,J＝10.4Hz,2.4Hz,1H),3.94-3.84(m,1H),3.71-3.60(m,1H),3.05-2.90(m,2H),2.87-2.80(m,1H),.2.70-2.58(m,1H),2.33(s,3H),2.29-2.20(m,1H),1.83(t,J＝10.8Hz,1H)；MS m/z526.2[M+H]+.
实施例2化合物A1S的制备
Figure PCTCN2017115756-appb-000044
在30毫升DMSO中室温搅拌下依次加入化合物A1Sa(3.0克,18.8毫摩尔)，化合物A1Sb(3.0克,13.8毫摩尔，100％ee)和氢氧化钾(2.4克,42.8毫摩尔)。反应混合物加热至30℃搅拌3小时，再升温到60℃搅拌5小时。反应完成后将体系冷却到室温，加入300毫升水，有固体析出，室温搅拌过夜。过滤，收集滤饼，将所得固体加入到5:1石油醚:乙酸乙酯的25毫升混合溶剂中，室温搅拌半小时，过滤，得到黄色固体化合物A1Sc(3.0克，收率64％)。MS 336.2[M+H]+。
将化合物A1Sc(2.0克,6.0毫摩尔)溶于20毫升二氯甲烷中，在室温搅拌下加入5毫升三氟乙酸。室温搅拌1小时后，TLC监测反应完成。反应液减压浓缩除去三氟乙酸，再将残留物溶于30毫升二氯甲烷中，用1M碳酸钠水溶液调PH到9～10，分液。水层用二氯甲烷萃取两次，合并有机相，用饱和食盐水(30毫升)洗一次。有机相用无水硫酸钠干燥后过滤，滤液减压浓缩得到黄色固体A1Sd(1.2克，收率86％)。MS m/z 236.1[M+H]+.
将化合物A1Sd(1.2克,5.1毫摩尔)溶于20毫升甲醇中，加入37％甲醛水溶液(6毫升)，再加入2滴醋酸，室温下搅拌30分钟后，加入氰基硼氢化钠(0.8克,12.7毫摩尔)，室温下搅拌3小时，TLC监测反应完成。反应液减压浓缩得到粗产物，粗品过硅胶柱纯化(DCM:MeOH＝60:1)得黄色固体A1Se(1.0克,收率79％)。MS m/z 250.2[M+H]+。
在3毫升甲醇中室温下加入化合物A1Se(145毫克,0.58毫摩尔)和15毫克钯碳催化剂，该反应混合物在室温常压下加氢反应1小时，TLC监测反应完成。反应混合物经过硅藻土过滤，滤液经减压浓缩得到棕色固体化合物A1Sf(100毫克，收率79％)，产品直接用于下一步。MS m/z 220.2[M+H]+。
化合物A1a(100毫克,0.29毫摩尔)和A1Sf(64毫克，0.29毫摩尔)溶于1.5毫升1,4-二氧六环中，再滴加入100毫升的三氟乙酸。反应混合物加热至60℃反应6小时，反应完成后加入碳酸氢钠调pH到8-9。加入二氯甲烷分3次萃取(10毫升x3)，合并有机相并用无水硫酸钠干燥，过滤，滤液减压浓缩得到残留物，先用硅胶制备层析薄板纯化，然后用制备高压液相纯化得到白色固体化合物A1S(29.3毫克，100％ee)。1H NMR(CD3OD,400Hz):δ8.21(s,1H),7.74(br,1H),7.65(br,1H),7.33(dd,J＝8.0Hz,8.00Hz,1H),7.21-7.19(m,1H),6.97-6.94(m,2H),6.62(br,1H),6.47-6.33(m,2H),5.77(dd,J＝9.6Hz,2.4Hz,1H),4.15(dd,J＝10.8Hz,2.0Hz,1H),3.88(t,J＝9.6Hz,1H),3.66(d,J＝11.6 Hz,1H),3.05-2.96(m,2H),2.86(d,J＝10.8Hz,1H),2.66(td,J＝12.0Hz,2.4Hz,1H),2.37(s,3H),2.28(td,J＝12.0Hz,3.2Hz,1H),1.88(t,J＝10.8Hz,1H)；MS m/z 526.2[M+H]+.
实施例3化合物A1R的制备
Figure PCTCN2017115756-appb-000045
参照实施例4中中间体A1Sf的制备方法，用A1Rb(100％ee)做原料制备得到中间体A1Rf。化合物Aa1a(80毫克,0.23毫摩尔)和A1Rf(51毫克，0.23毫摩尔)溶于1.5毫升1,4-二氧六环中，再滴加入100毫升的三氟乙酸。反应混合物加热至60℃反应6小时，反应完成后加入碳酸氢钠调pH到8-9。加入二氯甲烷分3次萃取(10毫升x3)，合并有机相并用无水硫酸钠干燥，过滤，滤液减压浓缩得到残留物，先用硅胶制备层析薄板纯化，然后用制备高压液相纯化得到白色固体化合物A1R(12.5毫克，99.9％ee)。1H NMR(CD3OD,400Hz):δ8.21(s,1H),7.74(br,1H),7.64(br,1H),7.33(t,J＝8.0Hz,1H),7.21-7.19(m,1H),6.96-6.94(m,2H),6.62(br,1H),6.47-6.33(m,2H),5.77(dd,J＝9.6Hz,2.4Hz,1H),4.15(dd,J＝10.4Hz,2.4Hz,1H),3.88(t,J＝9.6Hz,1H),3.65(d,J＝12.4Hz,1H),3.00-2.94(m,2H),2.84(d,J＝10.8Hz,1H),2.65(td,J＝12.0Hz,2.4Hz,1H),2.34(s,3H),2.25(td,J＝11.6Hz,3.2Hz,1H),1.84(t,J＝10.8Hz,1H)；MS m/z 526.2[M+H]+.
实施例4化合物A2S的制备
Figure PCTCN2017115756-appb-000046
化合物A1Sd(180毫克,0.77毫摩尔)在室温下溶于4毫升二氯甲烷中，加入DIPEA(200毫克,1.54毫摩尔)，再滴加乙酰氯(90毫克,1.16毫摩尔)。室温搅拌一小时，TLC监控反应完全。反应液用二氯甲烷(50毫升)稀释。有机相用饱和食盐水(10毫升x2)洗涤，无水硫酸钠干燥，过滤，滤液经减压浓缩得黄色固体化合物A2Sa(150毫克)。
化合物A2Sa(150毫克,0.54毫摩尔)室温下溶于3毫升甲醇中，加入15毫克钯碳催化剂，在室温常压下加氢反应1小时，TLC监测反应完成。反应混合物经过硅藻土过滤，滤液经减压旋转蒸发得到类白色固体化合物A2Sb(100毫克)。
将化合物A1a(40毫克,0.11毫摩尔)和化合物A2Sb(30毫克，0.12毫摩尔)溶解在1毫升二氧六环中，再滴加100毫克三氟乙酸。反应混合物在在60℃反应6小时。反应完成后加入碳酸氢钠调PH到8-9，加入二氯甲烷分3次萃取(10毫升x3)，合并有机相并用无水硫酸钠干燥，过滤，滤液减压浓缩得到粗产物，粗产物经硅胶柱分离纯化(1:1石油醚:乙酸乙酯)得到白色固体化合物A2S(22毫克，收率34％)。1H NMR(CDCl3,400MHz):δ8.29(s,1H),7.32(t,J＝8.0Hz,2H),7.26-7.03(m,3H),7.00-6.89(m,1H),6.86(brs,1H),6.75-6.65(m,1H),6.46(d,J＝16.8Hz,1H),6.31-6.20(m,1H),5.79(d,J＝10.4Hz,1H),4.72-4.59(m,1H),4.30-4.20(m,1H),4.10-3.83(m,1.5H),3.78-3.63(m,1.5H),3.43-3.35(m,0.5H),3.14-2.58(m,3H),2.45-2.36(m,0.5H),2.20-2.10(m,3H)；MS m/z 554.2(M+H)+.
实施例5化合物A2R的制备
Figure PCTCN2017115756-appb-000047
采用实施例4描述的方法，以A1Rd作为原料制备得到化合物A2Rb。将化合物A1a(40毫克,0.11毫摩尔)和化合物A2Rb(30毫克，0.12毫摩尔)溶解在1毫升二氧六环中，再滴100毫克三氟乙酸。反应混合物在在60℃反应6小时。反应完成后加入碳酸氢钠调PH到8-9，加入二氯甲烷分3次萃取，合并有机相并用无水硫酸钠干燥，过滤，滤液减压浓缩得到粗产物，粗产物经硅胶柱分离纯化(1:1石油醚：乙酸乙酯)得到白色固体化合物A2R(22毫克，收率34％)。1H NMR(CDCl3,400Hz):δ8.29(s,1H),7.32(t,J＝8.0Hz,2H),7.26-7.03(m,3H),7.00-6.89(m,1H),6.86(brs,1H),6.75-6.65(m,1H),6.46(d,J＝16.8Hz,1H),6.31-6.20(m,1H),5.79(d,J＝10.4Hz,1H),4.72-4.59(m,1H), 4.30-4.20(m,1H),4.10-3.83(m,1.5H),3.78-3.63(m,1.5H),3.43-3.35(m,0.5H),3.14-2.58(m,3H),2.45-2.36(m,0.5H),2.20-2.10(m,3H)；MS m/z 554.2(M+H)+.
实施例6化合物A3S的制备
Figure PCTCN2017115756-appb-000048
将化合物A1Sc(300毫克，0.896毫摩尔)置于50毫升的单口烧瓶中，用甲醇(10毫升)将其溶解，然后向其中加入Pd/C(10％，50毫克)，用氢气置换瓶中的空气，该反应体系在氢气氛围下常温搅拌1小时。TLC监测显示反应完毕，将反应液过滤，然后将滤液减压浓缩得到棕色固体化合A3Sa(280毫克，收率99％)。MS m/z 306.2(M+H)+.
将化合物A1a(120毫克，0.351毫摩尔)和A3Sa(107毫克，0.351毫摩尔)溶于异丙醇中(3毫升)中，然后滴加三氟乙酸(40毫克，0.351毫摩尔)。该反应溶液在40℃搅拌反应16小时。将反应液冷却至室温，然后倒入饱和碳酸氢钠溶液中，用乙酸乙酯萃取三遍(10毫升x3)，将有机层合并用饱和食盐水洗涤(10毫升))，然后无水硫酸钠干燥，过滤，滤液减压浓缩后得到的残留物通过层析薄板分离(二氯甲烷/甲醇＝30/1)得到淡黄色固体化合物A3Sb(180毫克，收率84％)。MS m/z 612.2(M+H)+.
将化合物A3Sb(5毫克，0.008毫摩尔)溶于异丙醇(1毫升)，然后向其中滴加HCl(1％的异丙醇溶液，109毫克，0.033毫摩尔)。该反应溶液加热至70℃搅拌反应16小时。LCMS监测反应完毕，将该反应溶液直接旋干，然后无水乙醚打浆得到黄色固体A3S盐酸盐(4毫克，收率80％)。1H NMR(DMSO-d6,400MHz)δ10.30(s,1H),9.74-9.58(br,1H),9.25-9.10(m,2H),9.10-8.78(br,1H),8.34(s,1H),7.85-7.60(m,2H),7.32(dd,J＝8.4Hz,8.0Hz,1H),7.22-6.80(m,3H),6.77-6.49(m,1H),6.48(dd,J＝17.2Hz,10.0Hz,1H),6.25(dd,J＝17.2Hz,2.0Hz,1H),5.75(dd,J＝10.4Hz,2.0Hz,1H),4.25-4.18(m,1H),3.98-3.70(m,4H),3.42-3.20(m,3H),3.10-2.97(m,1H),2.85-2.63(m,2H)；MS m/z 512.3[M+H]+.
实施例7化合物A3R的制备
Figure PCTCN2017115756-appb-000049
采用实施例6描述的方法，以A1Rc作为原料制备得到化合物A3Rb。将化合物A3Rb(45毫克，0.074毫摩尔)溶于异丙醇(3毫升)，然后向其中滴加HCl(1％的异丙醇溶液，986毫克，0.296毫摩尔)。该反应溶液加热至70℃搅拌反应16小时。LCMS监测反应完毕，将该反应溶液直接旋干，然后无水乙醚打浆得到黄色固体A3R盐酸盐(33.20毫克，收率74％)。1H NMR(DMSO-d6,400MHz)δ10.37(s,1H),9.93-9.70(br,1H),9.40-9.20(m,2H),9.20-8.97(br,1H),8.36(s,1H),7.83-7.60(m,2H),7.32(dd,J＝8.0Hz,8.0Hz,1H),7.22-6.80(m,3H),6.73-6.44(m,2H),6.25(dd,J＝17.2Hz,2.0Hz,1H),5.75(dd,J＝10.4Hz,2.0Hz,1H),4.25-4.18(m,1H),4.10-3.80(m,4H),3.42-3.22(m,3H),3.10-2.94(m,1H),2.90-2.63(m,2H)；MS m/z 512.3[M+H]+.
实施例8化合物A4R的制备
Figure PCTCN2017115756-appb-000050
将化合物A1Rd三氟乙酸盐(500毫克，1.43毫摩尔)和DIPEA(554毫克,4.29毫摩尔)加入二氯甲烷(20毫升)中，然后在室温条件下缓慢加入三氟乙酸酐(601毫克,2.86毫摩尔)，该反应混合物在室温下搅拌反应2小时。LCMS检测反应完成后，将该反应混合物倒入水(50毫升)中，用二氯甲烷(20毫升x4)萃取后，合并有机相用饱和食盐水 (10毫升x2)洗涤，无水硫酸钠干燥、过滤，滤液减压浓缩后残留物通过制备薄板层析(石油醚/乙酸乙酯＝2/1)分离纯化得到黄色固体化合物A4Ra(320毫克，收率68％)。1HNMR(CDCl3,400MHz)δ7.86-7.80(m,1H),7.70(d,J＝2.4Hz,1H),6.82and 6.78(twod,J＝9.2Hz,8.8Hz,1H),4.71-4.65and 4.60-4.55(twom,1H),4.39-4.33(m,1H),4.19-3.90(m,3H),3.52-3.36(m,2H),3.19-3.00(m,2H),2；MS m/z 332.2[M+H]+.
将化合物A4Ra(200毫克，0.60毫摩尔)溶于甲醇(6毫升)中，然后将Pd/C(10％,100毫克)小心加入反应体系中，再用氢气置换三次，该反应混合物在常温条件下搅拌反应2小时。LCMS检测反应完成后，用硅藻土过滤，再用无水甲醇洗滤饼三次，合并有机相减压浓缩后得到棕色固体化合物A4Rb(170毫克，收率93％)。MS m/z 302.3[M+H]+.
将化合物A4Rb(17毫克，0.06毫摩尔)和化合物A1a(21毫克，0.06毫摩尔)溶于干燥的异丙醇(2毫升)中，然后加入三氟乙酸(10毫克，0.09毫摩尔)。反应混合物加热至40℃并搅拌反应16小时。将反应液冷却至室温，然后倒入饱和碳酸氢钠溶液中，用乙酸乙酯萃取三遍(10毫升x3)，将有机层合并用饱和食盐水洗涤(10毫升))，然后无水硫酸钠干燥，过滤，滤液减压浓缩后得到的残留物通过薄层析板分离(二氯甲烷/甲醇＝35/1)得到淡黄色固体化合物A4R(15毫克，收率44％)。1H NMR(DMSO-d6,400MHz)δ10.15(s,1H),9.58-9.37(br,1H),8.78-8.61(br,1H),8.31(s,1H),7.74(s,1H),7.64-7.56(m,1H),7.32(dd,J＝8.4Hz,8.0Hz,1H),7.20-7.10(m,1H),7.07-7.01(m,1H),7.00-6.83(m,1H),6.66-6.45(m,1H),6.44-6.38(m,1H),6.28-6.20(m,1H),5.79-5.68(m,1H),4.39-4.24(m,2H),3.96-3.72(m,3H),3.50-3.40(m,0.5H),3.19-2.95(m,2H),2.79-2.71(m,0.5H),2.67-2.53(m,1H)；MS m/z 608.1(M+H)+.
实施例9化合物A5R的制备
Figure PCTCN2017115756-appb-000051
将化合物A1Rd三氟乙酸盐(590毫克，1.69毫摩尔)和乙醛(1.30克，29.45毫摩尔)溶于甲醇(30毫升)中，在搅拌的状态下，分批次加入氰基硼氢化钠(678毫克，10.79毫摩尔)，将温度控制在10℃以下。该反应体系在室温下搅拌反应1小时，TLC监测显示反应完毕，然后在室温下减压除去溶剂。将所得残留物分散到饱和碳酸钠溶液中，用乙酸乙酯萃取三遍 (25毫升x3)，将有机层合并用饱和食盐水洗涤，然后用无水硫酸钠干燥，过滤，滤液减压浓缩后得到的粗品通过硅胶柱分离(二氯甲烷/甲醇＝50/1混合溶剂淋洗)得到黄色固体化合物A5Ra(430毫克，收率97％)。1H NMR(CDCl3,400MHz)δ7.80(dd,J＝9.2Hz,2.8Hz,1H),7.65(d,J＝2.8Hz,1H),6.74(d,J＝9.2Hz,1H),4.26(dd,J＝10.8Hz,2.8Hz,1H),4.00(dd,J＝10.8Hz,8.4Hz,1H),3.80-3.74(m,1H),3.43-3.36(m,1H),3.08-2.90(m,3H),2.50-2.46(m,2H),2.21-2.14(m,1H),1.81(dd,J＝7.6Hz,7.2Hz,1H),1.13(t,J＝7.2Hz,3H)；MS m/z 264.2[M+H]+.
将化合物A5Ra(408毫克，1.55毫摩尔)置于50毫升的单口烧瓶中，用甲醇(3毫升)将其溶解，然后向其中加入Pd/C(10％，40毫克)，用氢气置换瓶中的空气，该反应体系在氢气氛围下常温搅拌1小时。TLC监测显示反应完毕，将反应液过滤，然后将滤液减压浓缩得到棕色固体化合物A5Rb(361毫克，收率99％)，化合物无需进一步纯化直接用于下一步反应。
将化合物A5Rb(361毫克，1.55毫摩尔)和化合物A1a(583毫克，1.70毫摩尔)溶于干燥的异丙醇(8毫升)中，加入三氟乙酸(194毫克，1.70毫摩尔)，该反应体系加热至40℃搅拌16小时。反应混合物冷却至室温，然后将其倒入饱和碳酸氢钠溶液中(10毫升)，用乙酸乙酯萃取三遍(20毫升x3)，合并的有机层用饱和食盐水洗涤(20毫升)，然后无水硫酸钠干燥，过滤，减压浓缩后得到的残留物通过硅胶柱分离(二氯甲烷/甲醇＝50/1)得到淡黄色固体化合物A5R(416毫克，收率50％)。1H NMR(DMSO-d6,400MHz)δ10.17(s,1H),9.49-9.39(br,1H),8.80-8.60(br,1H),8.30(s,1H),7.70(s,1H),7.65-7.57(m,1H),7.32(dd,J＝8.0Hz,8.0Hz,1H),7.18-7.08(m,1H),7.04(dd,J＝8.8Hz,2.0Hz,1H),6.89-6.79(br,1H),6.53-6.38(m,2H),6.25(dd,J＝16.8Hz,1.6Hz,1H),5.75(dd,J＝10.0Hz,1.6Hz,1H),4.19-4.11(m,1H),3.85-3.75(m,1H),3.60-3.50(m,1H),2.96-2.80(m,3H),2.50-2.43(m,1H),2.41-2.29(m,2H),2.09-1.99(m,1H),1.62(dd,J＝10.8Hz,10.8Hz,1H),1.02(t,J＝7.2Hz,3H)；MS m/z 540.2(M+H)+.
实施例10化合物A6R的制备
Figure PCTCN2017115756-appb-000052
将化合物A1Rd三氟乙酸盐(150毫克，0.43毫摩尔)和1-乙氧基-1-三甲硅氧基环丙烷(234毫克，1.34毫摩尔)溶于甲醇(6毫升)中，在搅拌的状态下，加入氰基硼氢化钠(84毫 克，1.34毫摩尔)。该反应体系加热至65℃搅拌16小时，TLC监测显示反应完毕，待反应体系冷却至室温，然后将其倒入饱和碳酸钠溶液中(10毫升)，用乙酸乙酯萃取三遍(15毫升x3)，将有机层合并用饱和食盐水洗涤(15毫升)，然后无水硫酸钠干燥，过滤，滤液减压浓缩后得到的粗品通过硅胶柱分离(二氯甲烷/甲醇＝60/1混合溶剂淋洗)得到黄色固体化合物A6Ra(95毫克，收率80％)。1H NMR(CDCl3,400MHz)δ7.79(dd,J＝9.2Hz,2.4Hz,1H),7.65(d,J＝2.8Hz,1H),6.73(d,J＝9.2Hz,1H),4.26(dd,J＝10.8Hz,3.2Hz,1H),3.99(dd,J＝10.8Hz,8.4Hz,1H),3.79-3.71(m,1H),3.34-3.27(m,1H),3.15-3.08(m,1H),3.04-2.88(m,2H),2.47-2.41(m,1H),2.09(dd,J＝10.4Hz,10.0Hz,1H),1.71-1.65(m,1H),0.55-0.42(m,4H)；MS m/z 276.2[M+H]+.
将化合物A6Ra(30毫克，0.11毫摩尔)置于50毫升的单口烧瓶中，用甲醇(3毫升)将其溶解，然后向其中加入Pd/C(10％，10毫克)，用氢气置换瓶中的空气，该反应体系在氢气氛围下常温搅拌1小时。TLC监测显示反应完毕，将反应液过滤，然后将滤液旋干得到棕色固体化合物A6Rb(25毫克，收率94％)，化合物无需进一步纯化直接用于下一步反应。
将化合物A6Rb(25毫克，0.10毫摩尔)和化合物A1a(29毫克，0.08毫摩尔)溶于干燥的异丙醇(2毫升)中，加入三氟乙酸(11毫克，0.10毫摩尔)。反应混合物加热至40℃并搅拌16小时。TLC监测显示反应完毕，待反应体系冷却至室温，然后将其倒入饱和碳酸钠溶液中(10毫升)，用乙酸乙酯萃取三遍(10毫升x3)，将有机层合并用饱和食盐水洗涤(10毫升)，然后无水硫酸钠干燥，过滤，滤液减压浓缩后得到的残留物通过薄板层析(二氯甲烷/甲醇＝20/1)分离得到黄色固体化合物A6R(30毫克，收率64％)。1H NMR(DMSO-d6,400MHz)δ10.16(s,1H),9.50-9.35(br,1H),8.78-8.60(m,1H),8.30(s,1H),7.69(s,1H),7.65-7.57(m,1H),7.31(dd,J＝8.0Hz,8.0Hz,1H),7.18-7.08(m,1H),7.03(dd,J＝8.8Hz,2.4Hz,1H),6.94-6.78(m,1H),6.60-6.38(m,2H),6.24(dd,J＝16.8Hz,2.0Hz,1H),5.75(dd,J＝10.4Hz,2.0Hz,1H),4.20-4.12(m,1H),3.84-3.77(m,1H),3.59-3.51(m,1H),3.00-2.74(m,3H),2.51-2.32(m,2H),1.94(dd,J＝10.4Hz,10.4Hz,1H),1.67-1.61(m,1H),0.47-0.30(m,4H)；MS m/z 552.3[M+H]+.
实施例11化合物A7R的制备
Figure PCTCN2017115756-appb-000053
将化合物A1Rd(430毫克，1.83毫摩尔)和N,N-二异丙基乙胺(706毫克，5.46毫摩尔)溶于干燥的四氢呋喃(8毫升)中，在搅拌的状态下加入2,2,2-三氟乙基三氟甲烷磺酸酯(551毫克，2.37毫摩尔)。该反应体系加热至60℃搅拌16小时，TLC监测显示反应完毕，将反应体系倒入水中，用乙酸乙酯萃取三遍(15毫升x3)，将有机层合并用饱和食盐水洗涤(15毫升)，然后用无水硫酸钠干燥，过滤，滤液减压浓缩后得到的粗品通过硅胶柱分离(石油醚/乙酸乙酯＝3/1混合溶剂淋洗)得到黄色固体化合物A7Ra(550毫克，收率：95％)。1H NMR(CDCl3,400MHz)δ7.80(dd,J＝9.2Hz,2.8Hz,1H),7.66(d,J＝2.8Hz,1H),6.75(d,J＝9.2Hz,1H),4.25(dd,J＝10.8Hz,2.8Hz,1H),3.99(dd,J＝11.2Hz,8.4Hz,1H),3.81-3.75(m,1H),3.48-3.41(m,1H),3.10-2.95(m,5H),2.70-2.63(m,1H),2.31(dd,J＝10.8Hz,10.8Hz,1H)；MS m/z 318.2[M+H]+.
将化合物A7Ra(300毫克，0.95毫摩尔)置于50毫升的单口烧瓶中，用甲醇(15毫升)将其溶解，然后向其中加入Pd/C(10％，50毫克)，用氢气置换瓶中的空气，该反应体系在氢气氛围下常温搅拌1小时。TLC监测显示反应完毕，将反应液过滤，然后将滤液减压浓缩得到棕色固体化合物A7Rb(250毫克，收率92％)。
将化合物A7Rb(250毫克，0.87毫摩尔)和化合物A1a(327毫克，0.95毫摩尔)溶于干燥的异丙醇(7毫升)中，加入三氟乙酸(198毫克，1.74毫摩尔)，反应混合物加热至40℃搅拌反应16小时。TLC监测显示反应完毕，待反应体系冷却至室温，然后将其倒入饱和碳酸钠溶液中(10毫升)，用乙酸乙酯萃取三遍(10毫升x3)，将有机层合并用饱和食盐水洗涤(10毫升)，然后无水硫酸钠干燥，过滤，滤液减压浓缩后得到的残留物通过硅胶柱层析(二氯甲烷/甲醇＝60/1)分离得到淡黄色固体化合物A7R(300毫克，收率58％)。1H NMR(DMSO-d6,400MHz,)δ10.17(s,1H),9.58-9.46(br,1H),8.79-8.60(,1H),8.30(s,1H),7.73(s,1H),7.66-7.56(m,1H),7.32(dd,J＝8.0Hz,8.0Hz,1H),7.21-7.07(m,1H),7.04-7.00(m,1H),6.93-6.77(m,1H),6.60-6.38(m,2H),6.29-6.20(m,1H),5.75(dd,J＝10.0Hz,1.6Hz,1H),4.19-4.10(m,1H),3.85-3.73(m,1H),3.64-3.51(m,1H),3.32-3.18(m,2H),3.03-2.84(m,3H),2.60-2.50(m,2H),2.14(dd,J＝11.2Hz,11.2Hz,1H)；MS m/z 594.2[M+H]+.
实施例12化合物A8S的制备
Figure PCTCN2017115756-appb-000054
将(3R)-3-(羟甲基)吗啉-4-羧酸叔丁酯(2.0克，9.21毫摩尔)溶于干燥的1,4-二氧六环(10毫升)中，在搅拌的状态下，加入氯化氢的1,4-二氧六环溶液(4M，5毫升)。该反应体系在室温下搅拌反应3小时，然后在35℃下减压除去溶剂，加入三氯甲烷超声，然后浓缩得到白色固体化合物粗品A8Sb，直接用于下一步反应。将得到的A8Sb粗品和化合物A1Sa(1.5g,9.43毫摩尔)溶于DMSO(6毫升)中，然后加入KOH粉末(2.1g,37.49毫摩尔)。先将混合物在室温下搅拌3小时，再加热到60℃反应16小时。反应液冷却至室温,然后将其倒入水中，用乙酸乙酯萃取三遍(15毫升x3)，将有机层合并用饱和食盐水洗涤(15毫升)，然后无水硫酸钠干燥，过滤浓缩后得到的粗品，硅胶柱分离(石油醚/乙酸乙酯＝1/1)得到黄色固体化合物A8Sc(400毫克，两步收率18％)。
将化合物A8Sc(140毫克，0.59毫摩尔)置于50毫升的单口烧瓶中，加入甲醇(5毫升)将其溶解，然后向其中加入Pd/C(10％，20毫克)，用氢气置换瓶中的空气，该反应体系在氢气氛围下常温搅拌1小时。TLC监测显示反应完毕，将反应液过滤，然后将滤液旋干得到棕色固体化合物A8Sd(110毫克，收率90％)。MS m/z 207.2[M+H]+.
将化合物A1a(25毫克，0.073毫摩尔)和A8Sd(15毫克，0.073毫摩尔)溶于异丙醇中(2毫升)中，然后滴加三氟乙酸(8毫克，0.073毫摩尔)。该反应混合物在40℃搅拌16小时。反应混合物冷却至室温，然后将其倒入饱和碳酸氢钠溶液中(10毫升)，用乙酸乙酯萃取三遍(10毫升x3)，合并的有机层用饱和食盐水洗涤(10毫升)，然后无水硫酸钠干燥，过滤，减压浓缩后得到的残留物通过制备层析薄板(二氯甲烷/甲醇＝25/1)分离得到类白色固体化合物A8S(7.64毫克，收率20％，99％ee)。1H NMR(DMSO-d6,400MHz)δ10.17(s,1H),9.55-9.35(br,1H),8.78-8.60(br,1H),8.31(s,1H),7.70(s,1H),7.64-7.56(m,1H),7.31(dd,J＝8.4Hz,8.0Hz,1H),7.20-7.07(m,1H),7.04(dd,J＝8.8Hz,2.0Hz,1H),6.93-6.79(br,1H),6.58-6.38(m,2H),6.24(dd,J＝16.8Hz,2.0Hz,1H),5.75(dd,J＝10.0Hz,2.0Hz,1H),4.17-4.07(m,1H),3.96-3.90(m,1H),3.85-3.71(m,2H),3.61-3.52(m,1H),3.49-3.40(m,1H),3.13(dd,J＝10.8Hz,10.4Hz,1H),2.99-2.87(m,1H),2.60-2.50(m,1H)；MS m/z 513.2(M+H)+.
实施例13化合物A8R的制备
Figure PCTCN2017115756-appb-000055
参照实施例12中中间体A8Sd的制备方法，用A8Ra(>99％ee)做原料制备得到中间体A8Rd。将化合物A1a(45毫克，0.131毫摩尔)和A8Rd(30毫克，0.146毫摩尔)溶于异丙醇中(2毫升)中，然后滴加三氟乙酸(17毫克，0.146毫摩尔)，反应混合物在40℃搅拌16小时。反应混合物冷却至室温，然后将其倒入饱和碳酸氢钠溶液中(10毫升)，用乙酸乙酯萃取三遍(10毫升x3)，合并的有机层用饱和食盐水洗涤(10毫升)，然后无水硫酸钠干燥，过滤，减压浓缩后得到的残留物通过制备博层层析(二氯甲烷/甲醇＝25/1)分离纯化得到灰色固体化合物A8R(19.4毫克，收率29％，>99％ee)。1H NMR(DMSO-d6,400MHz)δ10.16(s,1H),9.55-9.33(br,1H),8.78-8.60(br,1H),8.31(s,1H),7.70(s,1H),7.64-7.56(m,1H),7.31(dd,J＝8.4Hz,8.0Hz,1H),7.21-7.08(m,1H),7.04(dd,J＝8.8Hz,2.0Hz,1H),6.94-6.80(br,1H),6.58-6.38(m,2H),6.24(dd,J＝16.8Hz,2.0Hz,1H),5.75(dd,J＝10.0Hz,2.0Hz,1H),4.17-4.07(m,1H),3.96-3.90(m,1H),3.85-3.71(m,2H),3.61-3.52(m,1H),3.50-3.40(m,1H),3.13(dd,J＝10.8Hz,10.8Hz,1H),2.99-2.88(m,1H),2.60-2.50(m,1H)；MS m/z 513.2(M+H)+.
实施例14化合物A9S的制备
Figure PCTCN2017115756-appb-000056
将化合物A9Sa(1.3克，5.67毫摩尔)和肌氨酸乙酯盐酸盐(1.7克，11.07毫摩尔)溶于干燥的甲醇(15毫升)中，混合物在室温下搅拌2小时，向体系中加入乙酸(664毫克，11.06毫摩尔)，然后将反应体系置于冰浴中，分批加入氰基硼氢化钠(692毫克，11.01毫摩尔)，保持温度低于5℃，加完后，反应体系在室温搅拌3小时。将反应液倒入饱和碳酸氢钠溶液中(10毫升)，乙酸乙酯萃取三遍(15毫升x3)，将有机层合并用饱和食盐水洗涤(15毫升)，然后无水硫酸钠干燥，过滤浓缩后得到的粗品，硅胶柱分离纯化(石油醚/乙酸乙酯＝4/1)得到无色油状化合物A9Sb(800毫克，收率43％)。MS m/z 331.2[M+H]+.
将化合物A9Sb(800毫克,2.42毫摩尔)溶于甲醇(8毫升)中，然后加入0.8毫升的6N盐酸溶液，反应体系加热至75℃搅拌16h。反应冷却至室温后,将其倒入碳酸氢钠溶液中(10毫升)，用乙酸乙酯萃取两遍(10毫升x2)。水层减压浓缩，所得固体分散于二氯甲烷/甲醇/氨水(100/10/1)中,过滤,将滤液旋干得到黄色固体化合物A9Sc(320毫克，收率92％)。1H NMR(CDCl3,400MHz)δ6.79(s,1H),3.74-3.66(m,2H),3.63-3.55(m,1H),3.14(d,J＝16.4Hz,1H),3.03(d,J＝16.8Hz,1H),2.72(dd,J＝12.0Hz,4.4Hz,1H),2.58(dd,J＝12.0Hz,5.2Hz,1H),2.34(s,3H)；MS m/z 145.1[M+H]+.
将化合物A9Sc(100毫克，0.69毫摩尔),化合物A9Sd(174毫克，1.11毫摩尔)和三苯基 膦(365毫克，1.39毫摩尔)溶于干燥的二氯甲烷(4毫升)中，在室温下向反应体系其中加入偶氮二甲酸二异丙酯(283毫克，1.40毫摩尔)，然后将该反应体系室温搅拌16h。减压浓缩得到粗品，粗品经制备层析薄板(乙酸乙酯)纯化得到黄色固体化合物A9Se(85毫克，产率43％)。1H NMR(CDCl3,400MHz)δ7.96-7.83(m,2H),7.23(dd,J＝9.2Hz,0.8Hz,1H),6.32(s,1H),4.25-4.16(m,1H),4.14(dd,J＝8.8Hz,8.0Hz,1H),4.01-3.92(m,1H),3.20(d,J＝16.4Hz,1H),3.05(d,J＝16.8Hz,1H),2.77(dd,J＝15.8Hz,3.6Hz,1H),2.58(dd,J＝16.4Hz,5.2Hz,1H),2.37(s,3H).
将化合物A9Se(50毫克，0.177毫摩尔)悬浮于干燥的DMF(3毫升)中，加入碳酸铯(115毫克，0.353毫摩尔),混合物加热至45℃搅拌反应3小时。反应液冷却至室温，将反应液倒入冰水中，用乙酸乙酯萃取三遍(10毫升x3)，将有机层合并用饱和食盐水洗涤，然后无水硫酸钠干燥，过滤浓缩后得到的粗品，制备层析薄板分离纯化(二氯甲烷/甲醇＝60/1)得到黄色固体化合物A9Sf(28毫克，收率60％)。1H NMR(CDCl3,400MHz)δ8.45(d,J＝9.2Hz,1H),7.82-7.76(m,2H),4.40(dd,J＝10.4Hz,2.4Hz,1H),4.11(dd,J＝10.4Hz,10.4Hz,1H),4.04-3.96(m,1H),3.52(dd,J＝16.8Hz,2.0Hz,1H),3.13-3.02(m,2H),2.40-2.36(m,4H)；MS m/z264.2[M+H]+.
将化合物A9Sf(26毫克，0.099毫摩尔)置于25毫升的单口烧瓶中，用甲醇(3毫升)将其溶解，然后向其中加入Pd/C(10％，5毫克)，用氢气置换瓶中的空气，该反应体系在氢气氛围下常温搅拌40分钟。TLC监测显示反应完毕，将反应液过滤，然后将滤液旋干得到灰色固体化合物A9Sg(23毫克，收率99％)。1H NMR(CDCl3,400MHz)δ8.00(d,J＝8.4Hz,1H),6.27(dd,J＝8.8Hz,2.4Hz,1H),6.20(d,J＝2.8Hz,1H),4.25(dd,J＝10.4Hz,2.4Hz,1H),4.03(dd,J＝10.4Hz,10.0Hz,1H),4.00-3.90(m,1H),3.80-3.45(brs,2H),3.44(dd,J＝16.4Hz,2.0Hz,1H),3.04-2.95(m,2H),2.36-2.27(m,4H).
将化合物A9Sg(8毫克，0.034毫摩尔)和化合物A1a(12毫克，0.035毫摩尔)溶于干燥的异丙醇(1毫升)中，加入三氟乙酸(4毫克，0.035毫摩尔)，该反应混合物加热至40℃搅拌反应16小时。反应混合物冷却至室温，然后将其倒入饱和碳酸氢钠溶液中(10毫升)，用乙酸乙酯萃取三遍(10毫升x3)，合并的有机层用饱和食盐水洗涤(10毫升)，然后无水硫酸钠干燥，过滤，减压浓缩后得到的残留物通过制备层析薄板(二氯甲烷/甲醇＝25/1)分离纯化得到淡黄色色固体化合物A9S(5毫克，收率27％)。1H NMR(DMSO-d6,400MHz)δ10.14(s,1H),9.70-9.57(br,1H),8.77(brs,1H),8.36(s,1H),7.90-7.80(m,1H),7.76(s,1H),7.57(d,J＝8.0Hz,1H),7.32(dd,J＝8.4Hz,8.0Hz,1H),7.24-7.10(m,2H),7.04(d,J＝8.8Hz,1H),6.43(dd,J＝16.8Hz,10Hz,1H),6.24(dd,J＝17.2Hz,2.0Hz,1H),5.74(dd,J＝10.0Hz,2.0Hz,1H),4.33-4.26(m,1H),3.92-3.75(m,2H),3.31-3.25(m,1H),3.00-2.85(m,2H),2.35-2.25(m,1H),2.20(s,3H)；MS m/z 540.2(M+H)+.
实施例15化合物A9R的制备
Figure PCTCN2017115756-appb-000057
参照实施例14中中间体A9Sg的制备方法，用A9Ra(>99％ee)做原料制备得到中间体A8Rg。将化合物A9Rg(8毫克，0.034毫摩尔)和化合物A1a(12毫克，0.035毫摩尔)溶于干燥的异丙醇(1毫升)中，加入三氟乙酸(4毫克，0.035毫摩尔)，该反应体系加热至40℃搅拌反应16小时。反应混合物冷却至室温，然后将其倒入饱和碳酸氢钠溶液中(10毫升)，用乙酸乙酯萃取三遍(10毫升x3)，合并的有机层用饱和食盐水洗涤(10毫升)，然后无水硫酸钠干燥，过滤，减压浓缩后得到的残留物通过制备层析薄板(二氯甲烷/甲醇＝25/1)分离纯化得到淡黄色色固体化合物A9R(5毫克，收率27％)。1H NMR(DMSO-d6,400MHz)δ10.14(s,1H),9.70-9.56(br,1H),8.76(brs,1H),8.36(s,1H),7.90-7.80(m,1H),7.75(s,1H),7.57(d,J＝7.2Hz,1H),7.32(dd,J＝8.0Hz,8.0Hz,1H),7.23-7.10(m,2H),7.04(d,J＝8.8Hz,1H),6.43(dd,J＝17.2Hz,10Hz,1H),6.24(dd,J＝17.2Hz,2.0Hz,1H),5.74(dd,J＝10.0Hz,2.0Hz,1H),4.33-4.26(m,1H),3.92-3.75(m,2H),3.31-3.25(m,1H),3.00-2.85(m,2H),2.35-2.25(m,1H),2.24(s,3H)；MS m/z 540.2(M+H)+.
实施例16化合物B1S的制备
Figure PCTCN2017115756-appb-000058
将化合物A1Sf(66毫克，0.301毫摩尔)，B1Sa(80毫克，0.248毫摩尔)，Pd(OAc)2(20毫克)，BINAP(20毫克)和碳酸铯(294毫克，0.903毫摩尔)加入1,4-二氧六环(3毫升)中，置换氮气后将该反应混合物在封管中加热到120℃搅拌反应2小时。LCMS检测反应完成后，将反应液过滤、滤液浓缩后的残留物通过硅胶柱层析(二氯甲烷/甲醇＝30/1～25/1混合溶液淋洗)分离纯化得到黄色固体化合物B1S(32毫克，收率25％，>99％ee)。1H NMR(CD3OD,400MHz)δ8.39-8.36(m,2H),7.78(dd,J＝12.0Hz,0.8Hz,1H),7.35(d,J＝2.4Hz,1H),7.07(dd,J＝8.8Hz,2.8Hz,1H),6.83(d,J＝9.2Hz,1H),4.94-4.89(m,1H),4.24(dd,J＝10.4Hz,2.8Hz,1H),3.99(dd,J＝10.8Hz,9.2Hz,1H),3.77-3.72(m,1H),3.13-3.07(m,1H),3.00(d,J＝11.2Hz,1H),2.93-2.87(m,1H),2.78-2.70(m,1H),2.69(s,3H),2.38(s,3H),2.37-2.27(m,1H),1.91(dd,J＝11.2Hz,10.8 Hz,1H),1.72(d,J＝6.8Hz,6H)；MS m/z 506.3[M+H]+.
实施例17化合物B1R的制备
Figure PCTCN2017115756-appb-000059
将化合物A1Rf(50毫克，0.228毫摩尔)，B1S(73毫克，0.228毫摩尔)，Pd(OAc)2(20毫克)，BINAP(20毫克)和碳酸铯(223毫克，0.684毫摩尔)加入1,4-二氧六环(3毫升)中，置换氮气后将该反应混合物在封管中加热到120℃搅拌反应2小时。LCMS检测反应完成后，将反应液过滤、滤液浓缩后的残留物通过硅胶柱层析(二氯甲烷/甲醇＝30/1～25/1混合溶液淋洗)分离纯化得到黄色固体化合物B1R(45毫克，收率39％，>99％ee)。1H NMR(CD3OD,400MHz)δ8.39-8.36(m,2H),7.78(d,J＝12.0Hz,1H),7.35(d,J＝2.8Hz,1H),7.07(dd,J＝8.8Hz,2.8Hz,1H),6.84(d,J＝8.8Hz,1H),4.91-4.85(m,1H),4.25(dd,J＝10.4Hz,2.4Hz,1H),3.99(dd,J＝10.4Hz,8.8Hz,1H),3.79-3.73(m,1H),3.15-3.07(m,1H),3.06-2.99(m,1H),2.95-2.89(m,1H),2.79-2.69(m,1H),2.68(s,3H),2.40(s,3H),2.39-2.30(m,1H),1.94(dd,J＝11.2Hz,10.8Hz,1H),1.72(d,J＝7.2Hz,6H)；MS m/z 506.3[M+H]+.
实施例18化合物B2R的制备
Figure PCTCN2017115756-appb-000060
将化合物A1Rd(600毫克，2.55毫摩尔)和四氢吡喃酮(511毫克，5.10毫摩尔)溶于甲醇(25毫升)中，在搅拌的状态下，加入乙酸(153毫克，2.55毫摩尔),然后分批次加入氰基硼氢化钠(481毫克，7.65毫摩尔)，将温度控制在10℃以下。该反应体系在室温下搅拌过夜，TLC监测显示反应完毕，然后在室温下减压除去溶剂。将所得残留物分散到饱和碳酸钠溶液中，用乙酸乙酯萃取三遍(20毫升x3)，将有机层合并用饱和食盐水洗涤(20毫升)，然后用无水硫酸钠干燥，过滤，滤液浓缩后得到的残留物通过硅胶柱分离(二氯甲烷/甲醇＝30/1混合溶剂淋洗)得到黄色固体化合物B2Ra(800毫克，收率98％)。MS m/z 320.2[M+H]+.
将化合物B2Ra(200毫克，0.63毫摩尔)置于50毫升的单口烧瓶中，用甲醇(5毫升)将其溶解，然后向其中加入Pd/C(10％，30毫克)，用氢气置换瓶中的空气，该反应 体系在氢气氛围下常温搅拌一小时。TLC监测显示反应完毕，将反应液过滤，然后将滤液减压浓缩得到残留物通过硅胶柱分离(二氯甲烷/甲醇＝30/1混合溶剂淋洗)得到棕色固体化合物B2Rb(80毫克，收率44％)。MS m/z 290.2[M+H]+.
分别将化合物B2Rb(30毫克,0.10毫摩尔),B1Sa(50毫克,0.16毫摩尔),Pd(OAc)2(2.3毫克,0.01毫摩尔),BINAP(12.5毫克,0.02毫摩尔),Cs2CO3(65毫克,0.20毫摩尔)以及1,4-二氧六环(2.0毫升)加入到反应试管中，置换氮气后将该反应混合物在封管中加热到120℃搅拌反应2小时。冷却至室温，将反应液倒入水中,乙酸乙酯进行萃取(5毫升x3),合并有机相用饱和食盐水洗,无水硫酸镁进行干燥,过滤,滤液浓缩后的残留物通过硅胶柱层析(二氯甲烷/甲醇＝15:1)分离纯化得到粗产品，进一步通过制备HPLC纯化得到黄色固体化合物B2R(22毫克,收率37％)。1H NMR(DMSO-d6,400MHz)δ9.48(s,1H),8.58(d,J＝3.6Hz,1H),8.22(s,1H),7.64(d,J＝12.4Hz,1H),7.30(d,J＝2.4Hz,1H),7.13(dd,J＝8.8Hz,2.0Hz,1H),6.79(d,J＝8.8Hz,1H),4.87-4.78(m,1H),4.26-4.20(m,1H),3.94-3.86(m,3H),3.68(d,J＝11.6Hz,1H),3.34-3.24(m,2H),3.03-2.87(m,3H),2.64(s,3H),2.52-2.37(m,2H),2.35-2.25(m,1H),1.88(dd,J＝10.8Hz,10.0Hz,1H),1.78-1.68(m,2H),1.62(d,J＝6.8Hz,6H),1.47-1.35(m,2H)；MS m/z 576.3(M+H)+.
实施例19化合物B3R的制备
Figure PCTCN2017115756-appb-000061
将化合物A1Rd(970毫克，4.12毫摩尔)和N-甲基-4-哌啶酮(933毫克，8.24毫摩尔)溶于甲醇(35毫升)中，在搅拌的状态下，加入乙酸(247毫克，4.12毫摩尔),然后分批次加入氰基硼氢化钠(776毫克，12.35毫摩尔)，将温度控制在10℃以下。该反应体系在室温下搅拌16小时，TLC监测显示反应完毕，然后在室温下减压除去溶剂。将所得残留物分散到饱和碳酸钠溶液中，用乙酸乙酯萃取三遍(25毫升x3)，将有机层合并用饱和食盐水洗涤(20毫升)，然后用无水硫酸钠干燥，过滤，滤液减压浓缩后得到的残留物通过硅胶柱分离(二氯甲烷/甲醇＝20/1混合溶剂淋洗)得到黄色固体化合物B3Ra(860毫克，收率63％)。MS m/z 333.2[M+H]+.
将化合物B3Ra(373毫克，1.12毫摩尔)置于50毫升的单口烧瓶中，用甲醇(7毫升)将其溶解，然后向其中加入Pd/C(10％，40毫克)，用氢气置换瓶中的空气，该反应体系在氢气氛围下常温搅拌2小时。TLC监测显示反应完毕，将反应液过滤，然后将滤液减压浓缩得到粗品通过硅胶柱分离(二氯甲烷/甲醇/氨水＝10/1/0.25混合溶剂淋洗)得 到棕色固体化合物B3Rb(150毫克，收率44％)。MS m/z 303.3[M+H]+.
分别将化合物B3Rb(30毫克,0.099毫摩尔),B1Sa(48毫克,0.15毫摩尔),Pd(OAc)2(2.3毫克,0.01毫摩尔),BINAP(12.5毫克,0.02毫摩尔),Cs2CO3(65毫克,0.20毫摩尔)以及1,4-二氧六环(2.0毫升)加入到反应试管中,置换氮气后将该反应混合物在封管中加热到120℃搅拌反应2小时。冷却至室温，将反应液倒入水中,乙酸乙酯进行萃取(5毫升x3),合并有机相用饱和食盐水洗,无水硫酸镁进行干燥,过滤,滤液浓缩后的残留物通过硅胶柱层析(CH2Cl2/MeOH/NH4OH＝10:1:0.05)分离纯化得到粗产品，进一步通过制备HPLC纯化得到黄色固体化合物B3R(12毫克,收率21％)。1H NMR(DMSO-d6,400MHz)δ9.46(s,1H),8.57(d,J＝4.0Hz,1H),8.21(s,1H),7.64(d,J＝12.4Hz,1H),7.30(d,J＝2.0Hz,1H),7.13(dd,J＝8.4Hz,2.4Hz,1H),6.78(d,J＝8.8Hz,1H),4.87-4.78(m,1H),4.25-4.19(m,1H),3.89(dd,J＝9.6Hz,9.6Hz,1H),3.66(d,J＝11.6Hz,1H),3.01-2.85(m,4H),2.85-2.74(m,2H),2.64(s,3H),2.35-2.25(m,1H),2.16(s,3H),1.93-1.78(m,4H),1.77-1.68(m,2H),1.62(d,J＝6.8Hz,6H),1.48-1.35(m,2H)；MS m/z 589.4(M+H)+.
实施例20化合物C1R的制备
Figure PCTCN2017115756-appb-000062
将化合物A1Rc(200毫克,0.60毫摩尔)溶于二氯甲烷(10毫升),向反应体系中加入三氟醋酸(1.5毫升)并室温搅拌2小时。在40℃下减压浓缩除去三氟醋酸,将所得残余物溶于二氯甲烷(10毫升)，并向其中加入乙基磺酰氯(116毫克,0.90毫摩尔)和三乙胺(121毫克,1.20毫摩尔)，在室温下搅拌16小时。反应混合物水洗(10毫升x2)后,有机相经无水硫酸镁干燥,过滤,滤液减压浓缩后得到残留,通过正相硅胶柱层析纯化(二氯甲烷/乙酸乙酯＝1:1)得到黄色固体C1Ra(150毫克,收率77％)。MS m/z 328.0[M+H]+.
将化合物C1Ra(150毫克,0.46毫摩尔)溶于甲醇(10毫升)中,随后加入Pd/C(10％，25毫克)。该反应混合物室温下搅拌2小时。过滤,收集滤液,并用二氯甲烷/甲醇(10:1)冲洗滤渣至产品被完全洗脱,合并滤液,滤液减压浓缩后得到灰色固体化合物C1Rb(100毫克,收率73％)。1H NMR(DMSO-d6,400MHz)δ6.61(d,J＝8.4Hz,1H),6.09(dd,J＝8.4Hz,2.0Hz,1H),6.03(d,J＝2.4Hz,1H),4.56(brs,2H),4.22(dd,J＝10.4Hz,2.4Hz,1H),3.82(dd,J＝10.4Hz,9.2Hz,1H),3.70(d,J＝12.4Hz,1H),3.59(dd, J＝10.0H,10Hz,2H),3.10(q,J＝7.2Hz,2H),3.01-2.95(m,1H),2.91-2.82(m,1H),2.70-2.55(m,2H),1.22(t,J＝7.2Hz,3H)；MS m/z 298.0[M+H]+.
将化合物C1Rc(120毫克,0.54毫摩尔)溶于二氯甲烷(10毫升)中,缓慢加入间氯过氧苯甲酸(186毫克,1.08毫摩尔)，反应混合物在室温下搅拌16小时。将反应混合物减压浓缩后得到的残留物,通过正相硅胶柱层析纯化(CH2Cl2/MeOH＝30:1)分离得到无色固体化合物C1Rd(70毫克,收率54％)。MS m/z 241.0[M+H]+.
将化合物C1Rd(70毫克,0.29毫摩尔)和C1Rb(70毫克,0.20毫摩尔)溶于NMP(2毫升)中,随后加入TsOH-H2O(57毫克,0.30毫摩尔)，反应混合物在100℃下搅拌反应16小时。反应混合物冷却至室温后,将反应体系加入到水(4毫升)中,用二氯甲烷萃取(5毫升x3),合并有机相用饱和食盐水洗涤(5毫升),无水硫酸镁干燥,过滤，滤液浓缩后得到的残留物通过层析薄板(CH2Cl2/MeOH＝15:1)分离得到粗品化合物,然后用乙腈打浆，过滤干燥得到灰色固体化合物C1R(30毫克,收率32％)。1H NMR(DMSO-d6,400MHz)δ9.34(brs,1H),9.10(s,1H),8.48(s,1H),7.90-7.60(br,1H),7.60(s,1H),7.29(d,J＝8.8Hz,1H),7.20-6.98(brs,1H),6.84(d,J＝8.8Hz,1H),4.30(dd,J＝10.4Hz,2.4Hz,1H),3.93-3.82(m,2H),3.70-3.60(m,2H),3.11(q,J＝7.2Hz,2H),3.07-2.96(m,2H),2.75-2.65(m,1H),2.70-2.54(m,2H),1.22(t,J＝7.2Hz,3H),0.89-0.80(m,2H),0.57-0.50(m,2H)；MS m/z 474.2[M+H]+.
实施例21化合物C2R的制备
Figure PCTCN2017115756-appb-000063
化合物C2R是用中间体B3Rb和C1Rd根据化合物C1R的制备方法制得的。1H NMR(500MHz,CD3OD)δ8.35(s,1H),7.57(s,1H),7.06(dd,J＝8.7,2.2Hz,1H),6.77(d,J＝8.9Hz,1H),4.57(s,1H),4.20(dd,J＝10.5,2.5Hz,1H),4.01-3.86(m,1H),3.71(d,J＝11.7Hz,1H),3.10-2.59(m,7H),2.43(m,1H),2.35(s,3H),2.20(t,J＝12.0Hz,2H),2.03-1.92(m,3H),1.65-1.60(m,2H),0.89-0.87(m,2H),0.57-0.55(m,2H)。LCMS m/z479.2[M+H]+。
实施例22化合物C3R的制备
Figure PCTCN2017115756-appb-000064
化合物C3R是用中间体A2Rb和C1Rd根据化合物C1R的制备方法制得的。1H NMR(500MHz,CDCl3)δ8.78(s,1H),8.20(s,1H),7.57(s,1H),7.22(s,1H),7.05(t,J＝9.3Hz,1H),6.74(dd,J＝15.5,8.9Hz,1H),5.59(s,2H),4.65(dd,J＝52.1,12.8Hz,1H),4.35– 3.95(m,2H),3.72(d,J＝10.2Hz,1H),3.49(s,1H),3.03–2.45(m,5H),2.15(d,J＝4.7Hz,3H),0.91–0.88(m,2H),0.63(t,J＝7.7Hz,2H)。
实施例23化合物C4R的制备
Figure PCTCN2017115756-appb-000065
化合物C4R是用中间体B2Rb和C1Rd根据化合物C1R的制备方法制得的。1H NMR(500MHz,CDCl3)δ8.78(s,1H),8.20(s,1H),7.48(d,J＝42.2Hz,2H),7.05(d,J＝8.0Hz,1H),6.72(d,J＝8.9Hz,1H),5.65(s,2H),4.18(dd,J＝10.4,2.5Hz,1H),4.05-3.99(m,3H),3.65(d,J＝11.4Hz,1H),3.39(t,J＝11.2Hz,2H),3.11-2.76(m,5H),2.48-2.43(m,2H),2.01(t,J＝10.6Hz,1H),1.78(d,J＝12.3Hz,2H),1.60(dd,J＝8.3,3.7Hz,2H),0.88(t,J＝13.9Hz,2H),0.64-0.61(m,2H)。LCMS m/z 466.3[M+H]+。
实施例24化合物C5R的制备
Figure PCTCN2017115756-appb-000066
化合物C5R是用中间体A1Rf和C1Rd根据化合物C1R的制备方法制得的。1H NMR(500MHz,CDCl3)δ8.77(s,1H),8.18(s,1H),7.54(s,1H),7.34(d,J＝4.6Hz,1H),7.05(d,J＝7.0Hz,1H),6.72(d,J＝8.8Hz,1H),5.51(s,2H),4.17(dd,J＝10.5,2.6Hz,1H),4.02-3.98(m,1H),3.63(d,J＝11.5Hz,1H),3.49(s,1H),3.23-3.11(m,1H),3.02-2.78(m,4H),2.35(s,3H),2.28-2.23(m,1H),0.88(dd,J＝13.7,6.8Hz,2H),0.64-0.61(m,2H)。LCMS m/z 396.2[M+H]+。
实施例25化合物C6R的制备
Figure PCTCN2017115756-appb-000067
化合物C6R是用中间体A4Rb和C1Rd根据化合物C1R的制备方法制得的。1H NMR(500MHz,CDCl3)δ8.80(s,1H),8.19(s,1H),7.63(s,1H),7.23(s,1H),7.04(d,J＝4.1Hz,1H),6.74(dd,J＝15.9,8.8Hz,1H),5.49(s,2H),4.56(dd,J＝59.4,12.8Hz,1H),4.29-4.25(m,1H),4.07-4.03(m,1H),3.80-3.77(m,1H),3.49-2.85(m,4H),2.38-2.35(m,1H),2.03(dd,J＝13.4,5.8Hz,1H),0.83-0.81(m,2H),0.63(m,2H)。LCMS m/z 478.3[M+H]+。
实施例26和27化合物C7R和C8R的制备
Figure PCTCN2017115756-appb-000068
将化合物C1Rd(278毫克，1.15毫摩尔)和A3Ra(530毫克，1.73毫摩尔)溶于N-甲基-2-吡咯烷酮(5毫升)中，随后加入TsOH-H2O(556毫克，2.92毫摩尔)。反应体系在100℃下搅拌过夜。冷却至室温后，反应液直接通过硅胶柱层析(先用石油醚/乙酸乙酯＝1/1后用二氯甲烷/甲醇＝10/1混合溶剂)，得到黄色固体C8R(100毫克，收率23％)，以及约200毫克的粗品C7R(纯度约50％)。化合物C8R:1H NMR(500MHz,MeOD)δ8.36(s,1H),7.58(s,1H),7.06(d,J＝8.6Hz,1H),6.79(d,J＝8.9Hz,1H),4.18(dd,J＝10.6,2.5Hz,1H),3.95-3.91(m,1H),3.68(d,J＝11.8Hz,1H),3.10(d,J＝12.5Hz,1H),2.99–2.84(m,4H),2.63–2.58(m,1H),2.48–2.43(m,1H),0.91–0.88(m,2H),0.58–0.55(m,2H)。LCMS m/z 382.4[M+H]+。
Figure PCTCN2017115756-appb-000069
将化合物C8R(20毫克,0.05毫摩尔)溶于二氯甲烷(2毫升)中，加入二碳酸二叔丁酯(23毫克,0.1毫摩尔)，最后滴加三乙胺(16毫克,0.16毫摩尔)，室温下搅拌30分钟。加入5毫升二氯甲烷，然后用饱和氯化钠洗涤反应液，将有机相用硫酸钠干燥，过滤，浓缩，通过硅胶柱层析(0-80％，乙酸乙酯:石油醚)，得到黄色固体化合物C7R(11.5毫克,收率45％)。1H NMR(500MHz,CD3OD)δ8.36(s,1H),7.60(s,1H),7.08(dd,J＝8.8,2.3Hz,1H),6.82(d,J＝8.9Hz,1H),4.25(dd,J＝10.7,2.7Hz,1H),4.13(d,J＝12.9Hz,1H),4.03(d,J＝11.9Hz,1H),3.94–3.98(m,1H),3.75(d,J＝12.0Hz,1H),3.04–2.93(m,2H),2.88–2.85(m,1H),2.65–2.56(m 2H),1.48(s,9H),0.91–0.88(m,2H),0.59–0.55(m,2H)。LCMS m/z 482.4[M+H]+。
实施例28化合物C9R的制备
Figure PCTCN2017115756-appb-000070
将化合物C8R(30毫克,0.075毫摩尔)溶于二氯甲烷(2毫升)中，加入苯磺酰氯(26毫克,0.15毫摩尔)，最后滴加三乙胺(24毫克,0.24毫摩尔)，室温下搅拌10分钟。加入二氯甲烷(5毫升)，然后用饱和氯化钠洗涤反应液，将有机相用硫酸钠干燥，过滤，浓缩，通过硅胶柱层析(0-100％，乙酸乙酯:石油醚)，得到黄色固体化合物C9R(17毫克,收率41％)。1H NMR(500MHz,CD3OD)δ8.35(s,1H),7.82–7.80(m,2H),7.70–7.68(m,1H), 7.64–7.61(m,2H),7.58(s,1H),7.05(d,J＝8.6Hz,1H),6.77(d,J＝8.7Hz,1H),4.24(dd,J＝10.7,2.6Hz,1H),3.90–3.86(m,1H),3.84–3.80(m,2H),3.77–3.74(m,1H),3.13(s,1H),2.86–2.82(m,1H),2.78–2.73(m,1H),2.50–2.45(m,1H),2.12(t,J＝10.9Hz,1H),0.91–0.86(m,3H),0.57–0.54(m,2H)。LCMS m/z 522.3[M+H]+。
实施例29化合物C10R的制备
Figure PCTCN2017115756-appb-000071
化合物C10R是由化合物C8R和环丙基磺酰氯根据化合物C9R的制备方法合成得到的。1H NMR(500MHz,CD3OD)δ8.36(s,1H),7.63(s,1H),7.10(d,J＝8.2Hz,1H),6.84(d,J＝8.8Hz,1H),4.27(dd,J＝10.7,2.5Hz,1H),4.00(dd,J＝10.6,8.5Hz,1H),3.88(d,J＝12.3Hz,1H),3.78(d,J＝10.9Hz,1H),3.71(d,J＝11.3Hz,1H),3.14–3.09(m,2H),2.89–2.85(m,1H),2.76(t,J＝11.1Hz,2H),2.52–2.49(m,1H),1.10–1.01(m,4H),0.92–0.88(m,2H),0.59–0.56(m,2H)。LCMS m/z 486.3[M+H]+。
实施例30化合物C11R的制备
Figure PCTCN2017115756-appb-000072
化合物C11R是由化合物C8R和甲基磺酰氯根据化合物C9R的制备方法合成得到的。1H NMR(500MHz,DMSO-d6)δ9.81(s,1H),9.48(s,1H),8.44(s,1H),7.96(s,1H),7.46–7.37(m,2H),7.21(s,1H),6.92–6.90(m,1H),4.34(d,J＝9.8Hz,1H),3.94–3.90(m,2H),3.60(d,J＝10.4Hz,2H),3.12–3.08(m,1H),2.93(s,3H),2.85(s,1H),2.71–2.67(m,1H),2.59–2.55(m,1H),2.33–2.32(m,1H),0.86(d,J＝6.0Hz,2H),0.61–0.57(m,2H)。LCMS m/z 460.2[M+H]+。
实施例31化合物C12R的制备
Figure PCTCN2017115756-appb-000073
化合物C12R是由化合物C8R和2-丙基磺酰氯根据化合物C9R的制备方法合成得到的。1H NMR(500MHz,MeOD)δ8.39(s,1H),7.64(s,1H),7.12(d,J＝8.8Hz,1H),6.86(d,J＝9.0Hz,1H),4.28(d,J＝11.0Hz,1H),4.01–3.98(m,1H),3.86(d,J＝11.1Hz,1H), 3.77(d,J＝11.9Hz,1H),3.70–3.66(m,1H),3.22–3.17(m,1H),3.11–3.07(m,1H),2.91–2.81(m,2H),2.75–2.71(m,1H),1.36(d,J＝6.79Hz,6H),0.92(d,J＝6.3Hz,2H),0.61–0.58(m,2H)。LCMS m/z 488.28[M+H]+。
实施例32化合物C13R的制备
Figure PCTCN2017115756-appb-000074
化合物C13R是由化合物C8R和四氢吡喃-4-磺酰氯根据化合物C9R的制备方法合成得到的。1H NMR(500MHz,CDCl3)δ8.80(s,1H),8.20(s,1H),7.60(s,1H),7.23(s,1H),7.05(d,J＝10.0Hz,1H),6.73(dd,J＝8.9Hz,3.2Hz,1H),5.50(s,2H),4.22(d,J＝10.8Hz,1H),4.09(d,J＝11.5Hz,2H),4.01-3.98(m,1H),3.85(d,J＝12.1Hz,1H),3.74(d,J＝10.3Hz,2H),3.37(t,J＝11.9Hz,2H),3.22-3.17(m,3H),2.88-2.85(m,2H),1.99-1.86(m,5H),0.90(d,J＝5.3Hz,2H),0.65-0.60(m,2H)。LCMS m/z 530.24[M+H]+。
实施例33化合物C14R的制备
Figure PCTCN2017115756-appb-000075
将化合物C8R(5毫克,0.013毫摩尔)溶于二氯甲烷(1毫升)中，加入二甲氨基磺酰氯(2.5毫克,0.013毫摩尔)，最后滴加三乙胺(4.0毫克,0.039毫摩尔)，在80℃下搅拌3个小时。加入二氯甲烷(5毫升)，然后用饱和氯化钠洗涤反应液，将有机相用Na2SO4干燥，过滤，浓缩，通过硅胶柱层析((0-10％，甲醇:二氯甲烷)，得到黄色固体化合物C14R(2.0毫克,收率31％)。1H NMR(500MHz,CDCl3)δ8.78(s,1H),8.20(s,1H),7.57(s,1H),7.14(s,1H),7.06–7.04(m,1H),6.74–6.73(m,1H),5.52(s,2H),4.23–4.20(m,1H),4.03–3.99(m,1H),3.75–3.70(m,2H),3.61–3.58(m,1H),3.21–3.17(m,1H),3.12–3.06(m,1H),2.90–2.80(m,7H),2.74–2.69(m,1H),0.90–0.88(m,2H),0.65–0.62(m,2H)。LCMS m/z 489.24[M+H]+。
实施例34化合物C15R的制备
Figure PCTCN2017115756-appb-000076
将化合物C8R(5毫克,0.013毫摩尔)溶于二氯甲烷(1毫升)中，加入2-氯乙烷磺酰氯(2.6毫克,0.13毫摩尔)，最后滴加三乙胺(4.0毫克,0.039毫摩尔)，在80℃下搅拌3个小时。加入饱和氯化铵溶液，二氯甲烷(5毫升)，饱和氯化钠洗反应液，将有机相用硫酸钠干燥，过滤，浓缩，通过硅胶柱层析((0-10％，甲醇:二氯甲烷)，得到黄色固体化合物C15R(0.41毫克,收率7％)。LCMS m/z 472.19[M+H]+。
实施例35化合物C16R的制备
Figure PCTCN2017115756-appb-000077
将化合物C8R(5毫克,0.013毫摩尔)溶于二氧六环(1毫升)中，加入磺酰胺(3毫克,0.026毫摩尔)，最后滴加三乙胺(4毫克,0.039毫摩尔)，100℃下反应5小时，TLC检测C8R反应完全。加入饱和氯化铵溶液，乙酸乙酯萃取，饱和氯化钠洗反应液，将有机相用硫酸钠干燥，过滤，浓缩，通过制备薄板层析(0-10％，甲醇-二氯甲烷)，得到淡黄色固体化合物C16R(1.47毫克,收率25％)。1H NMR(500MHz,CD3OD)δ8.36(s,1H),7.61(s,1H),7.09(d,J＝8.9Hz,1H),6.84(d,J＝8.9Hz,1H),4.27(dd,J＝10.7,2.6Hz,1H),4.00(dd,J＝10.7,8.5Hz,1H),3.87(d,J＝11.5Hz,1H),3.69–3.55(m,3H),3.18–3.11(m,2H),2.89–2.82(m,2H),2.78(dd,J＝12.9,10.3Hz,1H),2.48(t,J＝11.0Hz,1H),2.03(s,1H),0.89(dd,J＝6.2,3.4Hz,5H),0.59–0.54(m,2H)。LCMS m/z 461.26[M+H]+。
实施例36化合物C17的制备
Figure PCTCN2017115756-appb-000078
将化合物C17a(1.1克，3.43毫摩尔)，对氟硝基苯C17b(1.4克，9.93毫摩尔)和N,N-二异丙基乙胺(2.6克，20.16毫摩尔)溶于干燥的N-甲基吡咯烷酮(9毫升)中，混合物在微波照射下加热至160℃反应5小时(共总8批次1.1g C17a规模的反应)，反应体系冷却至室温。 将反应液倒入冰水中，用乙酸乙酯萃取三遍，将有机层合并用饱和食盐水洗涤，然后无水硫酸钠干燥，浓缩后得到的粗品通过硅胶柱分离(石油醚/乙酸乙酯＝6/1混合溶剂淋洗)得到黄色固体化合物C17c(1.8克，收率18％)。1H NMR(400MHz,CDCl3)δ8.12(d,J＝6.5Hz,2H),7.33(m,5H),6.84(d,J＝6.3Hz,2H),4.47(s,1H),3.65–3.57(m,2H),3.54(s,3H),3.48(m,1H),3.21(td,J＝12.3,3.7Hz,1H),3.08(dd,J＝15.5,9.3Hz,1H),2.97(d,J＝11.3Hz,1H),2.85(d,J＝11.8Hz,1H),2.48(dd,J＝15.6,3.7Hz,1H),2.33(dd,J＝11.7,2.6Hz,1H),2.26(td,J＝11.6,3.6Hz,1H)。LCMS m/z 370.2[M+H]+。
将化合物C17c(1.8克，4.87毫摩尔)，氯化铵(1.1克，20.56毫摩尔)和铁粉(1.1克，19.70毫摩尔)，溶于乙醇/水(50毫升/10毫升)中，反应体系加热至70℃搅拌反应3小时。反应液冷却至室温,过滤，滤液减压浓缩，将所得粗品通过硅胶柱分离(二氯甲烷/甲醇＝20/1混合溶剂淋洗)得到黄色固体化合物C17d(1.6克，收率97％)。1H NMR(400MHz,)δ7.32(m,7.9Hz,5H),6.80(d,J＝8.6Hz,2H),6.64(d,J＝8.8Hz,2H),4.02(d,J＝9.7Hz,1H),3.59(d,J＝13.8Hz,2H),3.49(s,3H),3.49(s,2H),3.04(d,J＝12.5Hz,2H),2.83(d,J＝23.6Hz,2H),2.68(d,J＝8.8Hz,1H),2.52(d,J＝10.0Hz,1H),2.34(m,2H)。LCMS m/z 340.2[M+H]+。
将化合物C17d(1.6克，4.71毫摩尔)和三乙胺(1.4克，13.86毫摩尔)溶于干燥的二氯甲烷(25毫升)中，在室温下向反应体系其中加入醋酸酐(964毫克，9.44毫摩尔)，然后将该反应体系室温搅拌反应3小时。将反应液倒入冰水中，用乙酸乙酯萃取三遍，将有机层合并用饱和食盐水洗涤，然后无水硫酸钠干燥，浓缩后得到的粗品通过硅胶柱分离(二氯甲烷/甲醇＝50/1混合溶剂淋洗)得到黄色固体化合物C17e(1.7克，收率95％)。1H NMR(400MHz,CDCl3)δ7.39–7.28(m,7H),7.03(s,1H),6.86(d,J＝8.9Hz,2H),4.23(d,J＝7.5Hz,1H),3.59(d,J＝13.2Hz,1H),3.51(s,3H),3.47(m,3H),3.24(d,J＝11.8Hz,1H),3.02(ddd,J＝25.4,13.4,9.1Hz,2H),2.89(d,J＝11.2Hz,1H),2.79(d,J＝11.4Hz,1H),2.47–2.24(m,3H),2.12(s,3H)。LCMS m/z 382.2[M+H]+。
将化合物C17e(1.7克，4.46毫摩尔)溶于甲醇/水(25毫升/5毫升)中，加入氢氧化锂一水化合物(750毫克，17.86毫摩尔),混合物加热至35℃搅拌过夜。将反应液浓缩除去甲醇，加入水(20毫升)，用乙酸乙酯萃取一次，水层用稀盐酸中和至pH为6，水层直接浓缩干，将所得混合物分散于二氯甲烷/甲醇(10/1)中，搅拌，过滤，固体用二氯甲烷/甲醇(10/1)洗涤数次，合并滤液，浓缩后得到的粗品通过硅胶柱分离(二氯甲烷/甲醇＝10/1混合溶剂淋洗)得到灰色固体化合物C17f(1.6克，收率98％)。LCMS m/z 368.2[M+H]+。
将化合物C17f(1.6克，4.35毫摩尔)和10毫升多聚磷酸置于50毫升的单口烧瓶中，混合物加热至100℃搅拌反应7小时，反应体系冷却至室温，倒入至冰水中，用氢 氧化钠溶液中和至pH为8，将所得混合物浓缩干，然后分散于二氯甲烷/甲醇(10/1)中，搅拌，过滤，固体用二氯甲烷/甲醇(10/1)洗涤数次，合并滤液，浓缩后得到的粗品通过硅胶柱分离(二氯甲烷/甲醇＝20/1混合溶剂淋洗)得到灰色固体化合物C17g(890毫克，收率58％)。LCMS m/z 350.2[M+H]+。
将化合物C17g(640毫克，1.83毫摩尔)和甲醛水溶液(37％，3.0克，37.0毫摩尔)置于250毫升的单口烧瓶中，用甲醇(100毫升)将其溶解，然后向其中加入Pd/C(10％，100毫克)，用氢气置换瓶中的空气，该反应体系在氢气氛围下常温搅拌过夜。TLC监测显示部分原料剩余，将反应液过滤，然后将滤液旋干得到的粗品通过硅胶柱分离(二氯甲烷/甲醇＝50/1～25/1混合溶剂淋洗)得到黄色固体化合物C17h(160毫克，收率32％)。LCMS m/z 274.2[M+H]+。
将化合物C17h(8毫克，0.029毫摩尔)溶于的稀盐酸(6N，0.5毫升)中，用氩气置换瓶中的空气，该反应体系在氩气氛围下加热至85℃搅拌反应2小时。反应液用氢氧化钠溶液中和至pH为8，用乙酸乙酯萃取三遍，将有机层合并用饱和食盐水洗涤，然后无水硫酸钠干燥，浓缩得到黄色固体化合物C17i(3毫克，收率74％)。NMR(400MHz,DMSO-d6)δ7.00(d,J＝2.2Hz,1H),6.84(t,J＝6.7Hz,2H),4.76(s,2H),3.70(d,J＝11.5Hz,1H),3.21–3.01(m,1H),2.85(dd,J＝27.1,11.4Hz,2H),2.63–2.53(m,2H),2.43(d,J＝8.6Hz,2H),2.19(s,3H),1.91(m,1H)。LCMS m/z 232.2[M+H]+。
化合物C17是用中间体C17i和C1Rd根据化合物C1R的制备方法制得的。1H NMR(500MHz,CD3OD)δ8.87(s,1H),8.48(s,1H),8.28(s,1H),8.16(s,1H),7.27(d,J＝9.3Hz,2H),6.91(d,J＝9.3Hz,1H),5.85(s,1H),3.77(d,J＝11.5Hz,1H),3.45(t,J＝8.0Hz,1H),2.98-2.88(m,4H),2.58(d,J＝8.5Hz,2H),2.36(s,3H),2.33-2.31(m,1H),2.10(t,J＝10.8Hz,1H),0.92(d,J＝5.5Hz,2H),0.64(d,J＝1.7Hz,2H)。LCMS m/z 408.4[M+H]+。
实施例37化合物C18R的制备
Figure PCTCN2017115756-appb-000079
中间体E1b是中间体A8Rd和A8Sd的消旋体。它可根据A8Rd和A8Sd的合成方法制备得到。
化合物C18R是用中间体E1b和C1Rd根据化合物C1R的制备方法制得的。1H NMR(500MHz,CD3OD)δ8.78(s,1H),8.20(s,1H),7.54(s,1H),7.24(s,1H),7.05(dd,J＝8.6,2.1Hz,1H),6.69(d,J＝8.8Hz,1H),5.60(s,2H),4.14(dd,J＝10.6,2.6Hz,1H),4.04(dd, J＝11.4,3.3Hz,1H),3.97(dd,J＝10.4,9.2Hz,1H),3.86(dd,J＝10.9,2.9Hz,1H),3.77-3.73(m,1H),3.47(d,J＝11.3Hz,1H),3.29(t,J＝10.7Hz,1H),3.21-3.16(m,1H),2.90-2.90(m,2H),0.92-0.89(m,2H),0.64-0.62(m,2H)。LCMS m/z 383.3[M+H]+。
实施例38化合物C19R的制备
Figure PCTCN2017115756-appb-000080
化合物C19R是由化合物C8R和丙烯酰氯在二氯甲烷和三乙胺里反应制备得到的。1H NMR(500MHz,CDOD3)δ8.50(s,1H),6.96-6.93(m,1H),6.87-6.81(m,1H),6.74(dd,J＝8.7Hz,2.4Hz,1H),6.68-6.60(m,2H),6.37(dd,J＝16.8Hz,1.8Hz,1H),6.28(dd,J＝16.8Hz,1.8Hz,1H),5.80(dd,J＝10.6Hz,1.8Hz,1H),5.73(dd,J＝10.6Hz,1.8Hz,1H),4.60-4.58(m,1H),4.33(dd,J＝10.8Hz,2.6Hz,1H),4.03-4.00(m,1H),3.94-3.87(m,2H),3.16-3.10(m,1H),3.05-2.98(m,1H),2.82-2.63(m,3H),0.77-0.73(m,2H),0.53-0.50(m,2H)。LCMS m/z 490.28[M+H]+。
实施例39化合物C20R的制备
Figure PCTCN2017115756-appb-000081
化合物C20Ra是由化合物A1Rd丙烯酰氯在二氯甲烷和三乙胺里反应制备得到的。化合物C20Rb是由化合物C20Ra经铁粉和氯化铵还原得到的(参照化合物C17Rd的合成)。化合物C20R是由化合物C20Rb和化合物C1Rd反应得到的(根据A8Rd和A8Sd的合成方法)。1H NMR(500MHz,CDCl3)δ8.82(s,1H),8.24(s,1H),7.57(s,1H),7.34(s,1H),7.05(s,1H),6.73(s,1H),6.62-6.57(m,1H),6.33(d,J＝16.8Hz,1H),5.75(dd,J＝10.5Hz,1.5Hz,1H),5.64(s,2H),4.73-4.63(m,1H),4.26-4.23(m,1H),4.02(dd,J＝10.5Hz,8.9Hz,1H),3.72(d,J＝11.8Hz,1H),3.42-3.38(m,1H),3.07-2.96(m,2H),2.90-2.86(m,1H),2.74-2.69(m,1H),2.58-2.53(m,1H),0.90-0.88(m,2H),0.63-0.61(m,2H)。LCMS m/z 436.24[M+H]+。
实施例40化合物D1S的制备
Figure PCTCN2017115756-appb-000082
将化合物D1Sa(100毫克，0.455毫摩尔)，A1Sf(109毫克，0.499毫摩尔)和N,N-二甲基乙基胺(117毫克，0.909毫摩尔)溶于1,4-二氧六环(3毫升)中，该反应液在封管中加热到130℃搅拌反应16小时。LCMS检测反应完成后，将反应混合物减压浓缩，残留物通过硅胶柱(二氯甲烷/甲醇＝30/1)分离纯化得到淡黄色固体化合物D1Sb(160毫克，收率88％)。1HNMR(DMSO-d6,400MHz)δ10.93(s,1H),8.21(s,1H),7.98(s,1H),7.14(d,J＝2.0Hz,1H),6.93-6.82(m,2H),4.23(dd,J＝10.8Hz,2.8Hz,1H),3.90(dd,J＝10.4Hz,9.2Hz,1H),3.66(d,J＝11.6Hz,1H),3.05-2.95(m,1H),2.89-2.74(m,4H),2.65-2.55(m,1H),2.22(s,3H),2.13-2.03(m,1H),1.68(dd,J＝10.8Hz,10.8Hz,1H),1.24(t,J＝7.4Hz,3H)。MS m/z 403.2[M+H]+,405.2[M+H]+。
将化合物D1Sb(200毫克，0.498毫摩尔)和D1Sc(251毫克，2.488毫摩尔)溶于N-甲基吡咯烷酮(5毫升)中。该反应液在微波照射的条件下加热至180℃搅拌反应1小时。LCMS检测反应完成后，将该反应液倒入乙酸乙酯(10毫升)中，再用饱和食盐水(10毫升x2)洗涤，合并有机相无水硫酸钠干燥、过滤，浓缩后的残留物通过硅胶柱(二氯甲烷/甲醇＝30/1)分离纯化得到黄色固体化合物D1S(113毫克，收率49％，>99％ee)。1H NMR(DMSO-d6,400MHz)δ10.91(s,1H),7.51(s,1H),7.35(d,J＝2.0Hz,1H),7.21(s,1H),6.85-6.75(m,3H),4.22(dd,J＝10.4Hz,2.4Hz,1H),4.14-4.00(m,1H),3.97-3.85(m,3H),3.64(d,J＝11.6Hz,1H),3.43(dd,J＝12.0Hz,12.0Hz,2H),3.01-2.93(m,1H),2.89-2.75(m,2H),2.61-2.51(m,3H),2.22(s,3H),2.14-2.04(m,1H),1.90-1.82(m,2H),1.72-1.53(m,3H),1.18(t,J＝7.2Hz,3H)。MS m/z 468.4[M+H]+。
实施例41化合物D1R制备
Figure PCTCN2017115756-appb-000083
将化合物D1Ra(100毫克，0.455毫摩尔)，A1Rf(109毫克，0.499毫摩尔)和N,N-二甲基乙基胺(117毫克，0.909毫摩尔)溶于1,4-二氧六环(3毫升)中，该反应液在封管中加热到130℃搅拌反应16小时。LCMS检测反应完成后，将反应混合物减压浓缩，残留物通过硅胶柱(二氯甲烷/甲醇＝30/1)分离纯化得到淡黄色固体化合物D1Rb(150毫克，收率82％)。1HNMR(DMSO-d6,400MHz)δ10.93(s,1H),8.21(s,1H),7.98(s,1H),7.14(d,J＝2.0Hz,1H),6.93-6.82(m,2H),4.23(dd,J＝10.8Hz,2.8Hz,1H),3.90(dd,J＝10.4Hz,9.2Hz,1H),3.66(d,J＝11.2Hz,1H),3.05-2.95(m,1H),2.89-2.74(m,4H),2.65-2.55(m,1H),2.22(s,3H),2.13-2.03 (m,1H),1.68(dd,J＝10.4Hz,10.0Hz,1H),1.24(t,J＝7.4Hz,3H)。MS m/z 403.2[M+H]+,405.2[M+H]+.
将化合物D1Rb(200毫克，0.498毫摩尔)和(251毫克，2.488毫摩尔)溶于N-甲基吡咯烷酮(5毫升)中。该反应液在微波照射的条件下加热至180℃搅拌反应1小时。LCMS检测反应完成后，将该反应液倒入乙酸乙酯(10毫升)中，再用饱和食盐水(10毫升x2)洗涤，乙酸乙酯层用无水硫酸钠干燥、过滤，浓缩后的粗品通过硅胶柱(二氯甲烷/甲醇＝30/1的混合溶剂淋洗)进行分离纯化，得到的化合物H1-7R为黄色固体(123毫克，收率：53％)。
将化合物D1Rb(200毫克，0.498毫摩尔)和D1Rc(251毫克，2.488毫摩尔)溶于N-甲基吡咯烷酮(5毫升)中。该反应液在微波照射的条件下加热至180℃搅拌反应1小时。LCMS检测反应完成后，将该反应液倒入乙酸乙酯(10毫升)中，再用饱和食盐水(10毫升x2)洗涤，合并有机相无水硫酸钠干燥、过滤，浓缩后的残留物通过硅胶柱(二氯甲烷/甲醇＝30/1)分离纯化得到黄色固体化合物D1R(123毫克，收率53％，>99％ee)。1H NMR(DMSO-d6,400MHz)δ10.91(s,1H),7.51(s,1H),7.35(d,J＝1.6Hz,1H),7.21(s,1H),6.85-6.75(m,3H),4.22(dd,J＝10.4Hz,2.4Hz,1H),4.14-4.00(m,1H),3.97-3.85(m,3H),3.64(d,J＝11.6Hz,1H),3.43(dd,J＝12.4Hz,11.6Hz,2H),3.01-2.93(m,1H),2.88-2.75(m,2H),2.61-2.51(m,3H),2.22(s,3H),2.14-2.04(m,1H),1.90-1.82(m,2H),1.72-1.53(m,3H),1.18(t,J＝7.2Hz,3H)。MS m/z 468.4[M+H]+。
实施例42化合物D2S的制备
Figure PCTCN2017115756-appb-000084
将化合物D1Sa(25毫克，0.114毫摩尔)，A8Sd(26毫克，0.126毫摩尔)和N,N-二甲基乙基胺(29毫克，0.228毫摩尔)溶于1,4-二氧六环(2毫升)中，该反应液在封管中加热到130℃搅拌反应16小时。LCMS检测反应完成后，将反应混合物减压浓缩，残留物通过硅胶柱(二氯甲烷/甲醇＝50/1)分离纯化得到淡黄色固体化合物D2Sb(43毫克，收率97％)。MS m/z390.2[M+H]+,392.2[M+H]+.
将化合物D2Sb(43毫克，0.111毫摩尔)和D1Sc(56毫克，0.553毫摩尔)溶于N-甲基吡咯烷酮(1毫升)中。该反应液在微波照射的条件下加热至180℃搅拌反应1小时。LCMS检测反应完成后，将该反应液倒入乙酸乙酯(5毫升)中，再用饱和食盐水(2毫升x2)洗涤，合并有机相用无水硫酸钠干燥、过滤，浓缩后的残留物通过硅胶柱(二氯甲烷/甲醇＝50/1)分离纯化得到黄色固体化合物D2S(22毫克，收率44％)。1H NMR(DMSO-d6,400MHz)δ10.91(s,1H),7.50(s,1H),7.36(d,J＝2.4Hz,1H),7.20(s,1H),6.85-6.75(m,3H),4.21(dd,J＝10.8Hz,2.8Hz,1H),4.12-4.01(m,1H),3.97-3.80(m,5H),3.64-3.52(m,2H),3.48-3.37(m,2H),3.16(dd,J＝10.8Hz,10.8Hz,1H),3.07-2.97(m,1H),2.70-2.53(m,3H),1.92-1.85(m,2H),1.69-1.55(m, 2H),1.18(t,J＝7.2Hz,3H)。MS m/z 455.2[M+H]+。
实施例43化合物D2R制备
Figure PCTCN2017115756-appb-000085
将化合物D1Sa(26毫克，0.119毫摩尔)，A8Rd(27毫克，0.131毫摩尔)和N,N-二甲基乙基胺(31毫克，0.237毫摩尔)溶于1,4-二氧六环(2毫升)中，该反应液在封管中加热到130℃搅拌反应16小时。LCMS检测反应完成后，将反应混合物减压浓缩，残留物通过硅胶柱(二氯甲烷/甲醇＝50/1)分离纯化得到淡黄色固体化合物D2Rb(44毫克，收率96％)。MS m/z 390.2[M+H]+,392.2[M+H]+.
将化合物D2Rb(44毫克，0.113毫摩尔)和D1Sc(57毫克，0.566毫摩尔)溶于N-甲基吡咯烷酮(1毫升)中。该反应液在微波照射的条件下加热至180℃搅拌反应1小时。LCMS检测反应完成后，将该反应液倒入乙酸乙酯(5毫升)中，再用饱和食盐水(2毫升x2)洗涤，合并有机相用无水硫酸钠干燥、过滤，浓缩后的残留物通过制备层析薄板(二氯甲烷/甲醇＝50/1)分离纯化得到黄色固体化合物D2R(20毫克，收率39％)。1H NMR(DMSO-d6,400MHz)δ10.91(s,1H),7.50(s,1H),7.36(d,J＝2.4Hz,1H),7.20(s,1H),6.85-6.75(m,3H),4.21(dd,J＝10.8Hz,2.8Hz,1H),4.13-4.01(m,1H),3.97-3.82(m,5H),3.64-3.52(m,2H),3.47-3.38(m,2H),3.16(dd,J＝10.8Hz,10.8Hz,1H),3.07-2.97(m,1H),2.70-2.53(m,3H),1.92-1.85(m,2H),1.69-1.55(m,2H),1.18(t,J＝7.2Hz,3H)。MS m/z 455.2[M+H]+。
实施例44化合物D3R的制备
Figure PCTCN2017115756-appb-000086
将化合物D1Sa(23毫克，0.105毫摩尔)，A7Rb(30毫克，0.104毫摩尔)和N,N-二甲基乙基胺(40毫克，0.310毫摩尔)溶于1,4-二氧六环(2毫升)中，该反应液在封管中加热到130℃搅拌反应16小时。LCMS检测反应完成后，将反应混合物减压浓缩，残留物通过硅胶柱(二氯甲烷/甲醇＝100/1)分离纯化得到淡黄色固体化合物D3Rb(47毫克，收率95％)。MS m/z471.2[M+H]+,473.2[M+H]+.
将化合物D3Rb(47毫克，0.100毫摩尔)和D1Sc(60毫克，0.593毫摩尔)溶于N-甲基吡咯烷酮(1毫升)中。该反应液在微波照射的条件下加热至180℃搅拌反应1小时。LCMS检测反应完成后，将该反应液倒入乙酸乙酯(5毫升)中，再用饱和食盐水(3毫升x2)洗涤，合并有机相用无水硫酸钠干燥、过滤，浓缩后的残留物通过制备层析薄板(二氯甲烷/甲醇＝40/1) 分离纯化得到黄色固体化合物D3R(25毫克，收率47％)。1H NMR(DMSO-d6,400MHz)δ10.90(s,1H),7.50(d,s,1H),7.34(d,J＝2.0Hz,1H),7.20(s,1H),6.85-6.75(m,3H),4.24(dd,J＝10.8Hz,2.8Hz,1H),4.15-4.01(m,1H),3.96-3.85(m,3H),3.71-3.65(m,1H),3.48-3.39(m,2H),3.33-3.20(m,2H),3.04-2.90(m,3H),2.62-2.51(m,4H),2.18(dd,J＝11.2Hz,10.4Hz,1H),1.93-1.82(m,2H),1.67-1.56(m,2H),1.18(t,J＝7.2Hz,3H)。MS m/z 536.2[M+H]+。
实施例45化合物D4R的制备
Figure PCTCN2017115756-appb-000087
将化合物D1Sa(26毫克，0.118毫摩尔)，A6Rb(29毫克，0.118毫摩尔）和N,N-二甲基乙基胺(46毫克，0.357毫摩尔)溶于1,4-二氧六环(2毫升)中，该反应液在封管中加热到130℃搅拌反应16小时。LCMS检测反应完成后，将反应混合物减压浓缩，残留物通过硅胶柱(二氯甲烷/甲醇＝100/1)分离纯化得到淡黄色固体化合物D4Rb(47毫克，收率92％)。MS m/z 429.2[M+H]+,430.2[M+H]+.
将化合物D4Rb(47毫克，0.110毫摩尔)和D1Sc(67毫克，0.662毫摩尔)溶于N-甲基吡咯烷酮(1毫升)中。该反应液在微波照射的条件下加热至180℃搅拌反应1小时。LCMS检测反应完成后，将该反应液倒入乙酸乙酯(5毫升)中，再用饱和食盐水(3毫升x2)洗涤，合并有机相用无水硫酸钠干燥、过滤，浓缩后的残留物通过制备层析薄板(二氯甲烷/甲醇＝35/1)分离纯化得到黄色固体化合物D4R(25毫克，收率46％)。1H NMR(DMSO-d6,400MHz)δ10.89(s,1H),7.50(s,1H),7.34(d,J＝2.0Hz,1H),7.19(s,1H),6.85-6.75(m,3H),4.24(dd,J＝10.8Hz,2.8Hz,1H),4.13-4.00(m,1H),3.96-3.87(m,3H),3.70-3.63(m,1H),3.47-3.38(m,2H),3.04-2.83(m,3H),2.56(q,J＝7.6Hz,2H),2.45-2.32(m,1H),1.98(dd,J＝10.8Hz,10.8Hz,1H),1.92-1.82(m,2H),1.70-1.55(m,3H),1.18(t,J＝7.6Hz,3H),0.89-0.81(m,1H),0.48-0.40(m,2H),0.38-0.31(m,2H)。MS m/z 494.2[M+H]+。
实施例46化合物D5S制备
Figure PCTCN2017115756-appb-000088
将化合物D1Sa(27毫克，0.123毫摩尔)，A9Sg(29毫克，0.124毫摩尔)和N,N-二甲基乙基胺(48毫克，0.372毫摩尔)溶于1,4-二氧六环(1毫升)中，该反应液在封管中加热到150℃搅拌反应16小时。LCMS检测反应完成后，将反应混合物减压浓缩，残留物通过制备层析薄板(二氯甲烷/甲醇＝25/1)分离纯化得到淡黄色固体化合物D5Sb(9毫克，收率18％)。MS  m/z 417.2[M+H]+,419.2[M+H]+。
将化合物D5Sb(7毫克，0.017毫摩尔)和D1Sc(10毫克，0.099毫摩尔)溶于异丙醇(0.5毫升)中,加入三氟乙酸(3毫克，0.026毫摩尔)。该反应液在封管中加热到100℃搅拌反应16小时。反应液冷却至室温，然后将其倒入饱和碳酸氢钠溶液中(5毫升)，用乙酸乙酯萃取三遍(5毫升x3)，将有机层合并用饱和食盐水洗涤(5毫升)，然后无水硫酸钠干燥，过滤，滤液浓缩后得到的残留物通过制备层析薄板分离(二氯甲烷/甲醇＝20/1)得到黄色固体化合物D5S(4毫克，收率49％)。1H NMR(DMSO-d6,400MHz)δ11.20(s,1H),8.08(d,J＝8.8Hz,1H),7.64(d,J＝2.8Hz,1H),7.57(s,1H),7.30(s,1H),6.91(d,J＝7.2Hz,1H),7.57(dd,J＝9.2Hz,J＝2.4Hz,1H),4.42-4.36(m,1H),4.14-4.05(m,1H),4.02-3.88(m,4H),3.48-3.38(m,2H),3.05-2.85(m,3H),2.59(q,J＝7.2Hz,2H),2.35-2.30(m,1H),2.25(s,3H),1.93-1.85(m,2H),1.70-1.59(m,2H),1.19(t,J＝7.2Hz,3H)。MS m/z 482.2[M+H]+。
实施例47化合物D6R的制备
Figure PCTCN2017115756-appb-000089
将化合物D1Sa(30毫克，0.137毫摩尔)，B3Rb(41毫克，0.137毫摩尔)和N,N-二甲基乙基胺(35毫克，0.274毫摩尔)溶于1,4-二氧六环(2毫升)中，该反应液在封管中加热到130℃搅拌反应16小时。LCMS检测反应完成后，将反应混合物减压浓缩，残留物通过制备层析薄板(二氯甲烷/甲醇＝15/1)分离纯化得到淡黄色固体化合物D6Rb(30毫克，收率：45％)。MS m/z 486.2[M+H]+,488.2[M+H]+。
将化合物D6Rb(30毫克，0.062毫摩尔)和D1Sc(31毫克，0.309毫摩尔)加入至N-甲基吡咯烷酮(1毫升)中。该反应液在微波照射的条件下加热至180℃搅拌反应1小时。LCMS检测反应完成后，将该反应液倒入乙酸乙酯(5毫升)中，再用饱和食盐水(3毫升x2)洗涤，合并有机相用无水硫酸钠干燥、过滤，浓缩后的残留物通过制备层析薄板(二氯甲烷/甲醇＝5/1)分离纯化,柱层析分离的产物再经二氯甲烷和石油醚打浆处理得到黄色固体化合物D6R(3毫克，收率9％)。1H NMR(DMSO-d6,400MHz)δ10.88(s,1H),7.50(s,1H),7.33(d,J＝2.0Hz,1H),7.18(s,1H),6.83-6.74(m,3H),4.27-4.20(m,1H),4.13-4.00(m,1H),3.95-3.85(m,3H),3.66(d,J＝11.2Hz,1H),3.48-3.38(m,2H),3.01-2.75(m,6H),2.56(q,J＝7.2Hz,2H),2.37-2.24(m,2H),2.24-2.09(m,3H),1.92-1.80(m,5H),1.80-1.70(m,2H),1.67-1.55(m,2H),1.50-1.36(m,2H),1.18(t,J＝7.2Hz,3H)。MS m/z 551.3[M+H]+。
实施例48化合物D7R的制备
Figure PCTCN2017115756-appb-000090
将化合物D1Sa(46毫克,0.21毫摩尔)，B2Rb(40毫克,0.14毫摩尔)和N,N-二甲基乙基 胺(36毫克，0.28毫摩尔)溶于1,4-二氧六环(2毫升)中，该反应液在封管中加热到130℃搅拌反应16小时。LCMS检测反应完成后，将反应混合物减压浓缩，将反应液倒入水中,过滤,滤饼用二氯甲烷冲洗后得到黄色固体D7Rb(36毫克,收率55％)。MS m/z 473.2[M+H]+,475.2[M+H]+。
将化合物D7Rb(35毫克,0.074毫摩尔)和D1Sc(37毫克,0.37毫摩尔)溶于N-甲基吡咯烷酮(1毫升)中。该反应液在微波照射的条件下加热至180℃搅拌反应1小时。将反应液倒入水中,加入二氯甲烷进行萃取(5毫升x3),合并有机相用饱和食盐水洗涤,无水硫酸镁干燥,过滤,滤液在35℃下减压浓缩后,通过正相硅胶柱层析纯化(CH2Cl2/MeOH＝30:1)得到固体粗产物，进一步通过制备HPLC纯化得到黄色固体化合物D7R(14毫克,收率35％)。1H NMR(DMSO-d6,400MHz)δ10.89(s,1H),7.50(s,1H),7.34(d,J＝2.0Hz,1H),7.21(s,1H),6.85-6.75(m,3H),4.24(dd,J＝10.4Hz,2.0Hz,1H),4.13-4.01(m,1H),3.97-3.85(m,5H),3.67(d,J＝11.2Hz,1H),3.53-3.36(m,3H),3.35-3.23(m,2H),3.03-2.87(m,3H),2.56(q,J＝7.2Hz,2H),2.47-2.37(m,1H),2.35-2.25(m,1H),1.93-1.83(m,3H),1.76-1.55(m,4H),1.48-1.32(m,2H),1.18(t,J＝7.2Hz,3H)。MS m/z 538.4[M+H]+。
实施例49化合物E1制备
Figure PCTCN2017115756-appb-000091
将化合物E1a(50毫克，0.152毫摩尔)，E1b(34毫克，0.167毫摩尔)和浓盐酸(0.1毫升)依次加入至正丁醇(2毫升)中，该反应混合物在封管中搅拌加热至110℃反应16小时。LCMS检测反应完成后，将该反应混合物用饱和碳酸氢钠溶液调至pH＝7，然后用乙酸乙酯(5毫升x2)萃取，合并有机相用饱和食盐水(5毫升)洗涤，无水硫酸钠干燥、过滤，滤液减压浓缩后的残留物通过制备层析薄板(石油醚/乙酸乙酯＝1/1)分离纯化得到灰色固体化合物E1(37毫克，收率49％)。1H NMR(DMSO-d6,400MHz)δ10.16(s,1H),8.98(s,1H),8.71-8.64(m,1H),8.23(s,1H),7.70(d,J＝8.0Hz,1H),7.56(d,J＝8.4Hz,1H),7.49(dd,J＝7.6Hz,7.2Hz,1H),7.13-7.05(m,2H),6.93(dd,J＝8.8Hz,2.0Hz,1H),6.76(d,J＝8.8Hz,1H),6.67(s,1H),4.19(dd,J＝10.4Hz,2.0Hz,1H),3.94(dd,J＝11.6Hz,2.8Hz,1H),3.88-3.80(m,2H),3.62-3.50(m,2H),3.16(dd,J＝10.8Hz,10.4Hz,1H),3.04-2.98(m,1H),2.76(d,J＝4.0Hz,3H),2.64-2.55(m,1H)。MS m/z 500.2[M+H]+。
实施例50化合物E1S的制备
Figure PCTCN2017115756-appb-000092
将化合物E1a(55毫克，0.167毫摩尔)，A1Sf(37毫克，0.167毫摩尔)和浓盐酸(0.1毫升)依次加入至正丁醇(2毫升)中。该反应混合物在封管中搅拌加热至110℃反应16小时。LCMS检测反应完成后，将该反应混合物用饱和碳酸氢钠溶液调至pH＝7，然后用乙酸乙酯(5毫升x2)萃取，合并有机相用饱和食盐水(5毫升)洗涤，无水硫酸钠干燥、过滤，滤液减压浓缩后的残留物通过制备层析薄板(二氯甲烷/甲醇＝15/1)分离纯化得到灰色固体化合物E1S(16毫克，收率19％)。1H NMR(CD3OD,400MHz)δ8.12(s,1H),7.62(dd,J＝8.0Hz,1.2Hz,1H),7.52(d,J＝6.8Hz,1H),7.48-7.43(m,1H),7.13-7.08(m,1H),6.83-6.78(m,3H),6.57(s,1H),4.23(dd,J＝10.8Hz,2.8Hz,1H),3.95(dd,J＝10.4Hz,8.8Hz,1H),3.72(d,J＝12.4Hz,1H),3.10-3.02(m,1H),2.98(d,J＝11.6Hz,1H),2.90-2.84(m,4H),2.76-2.65(m,1H),2.36(s,3H),2.32-2.23(m,1H),1.88(dd,J＝11.2Hz,10.8Hz,1H)。MS m/z 513.2[M+H]+。
实施例51化合物E1R的制备
Figure PCTCN2017115756-appb-000093
将化合物E1a(50毫克，0.152毫摩尔)，A1Rf(33毫克，0.152毫摩尔)和浓盐酸(0.1毫升)依次加入至正丁醇(2毫升)中。该反应混合物在封管中搅拌加热至110℃反应16小时。LCMS检测反应完成后，将该反应混合物用饱和碳酸氢钠溶液调至pH＝7，然后用乙酸乙酯(5毫升x2)萃取，合并有机相用饱和食盐水(5毫升)洗涤,无水硫酸钠干燥、过滤，滤液减压浓缩后的残留物通过制备层析薄板(二氯甲烷/甲醇＝15/1)分离纯化得到浅黄色固体E1R(30毫克，收率39％)。1H NMR(CD3OD,400MHz)δ8.11(s,1H),7.61(dd,J＝7.6Hz,1.2Hz,1H),7.50(d,J＝7.6Hz,1H),7.48-7.42(m,1H),7.12-7.07(m,1H),6.82-6.78(m,3H),6.56(s,1H),4.21(dd,J＝10.4Hz,2.4Hz,1H),3.94(dd,J＝10.4Hz,8.8Hz,1H),3.71(d,J＝12.0Hz,1H),3.09-3.02(m,1H),2.96(d,J＝11.6Hz,1H),2.90-2.84(m,4H),2.74-2.65(m,1H),2.34(s,3H),2.32-2.23(m,1H),1.86(dd,J＝11.2Hz,10.8Hz,1H)。MS m/z 513.2[M+H]+。
实施例52化合物E2R制备
Figure PCTCN2017115756-appb-000094
将化合物E1a(30毫克,0.091毫摩尔)，B3Rb(41毫克,0.14毫摩尔)和浓盐酸(0.1毫升)依次加入至正丁醇(1.5毫升)中。该反应混合物在封管中搅拌加热至160℃反应8小时。LCMS检测反应完成后，将该反应混合物用饱和碳酸氢钠溶液调至pH＝7，然后用二氯甲烷萃取(5毫升x3)，合并有机相用饱和食盐水(5毫升)洗涤，无水硫酸钠干燥、过滤，滤液减压浓缩后的残留物通过制备层析薄板(二氯甲烷/甲醇＝5/1)分离纯化得到浅黄色固体E2R(4.0毫克，收率7％)。1H NMR(DMSO-d6,400MHz)δ10.16(s,1H),8.96(s,1H),8.72-8.65(br,1H),8.22(s,1H),7.70(d,J＝8.0Hz,1H),7.60-7.44(m,2H),7.10(dd,J＝7.6Hz,7.2Hz,1H),7.03(s,1H),6.90(d,J＝7.6Hz,1H),6.75(d,J＝8.8Hz,1H),6.66(s,1H),4.21(d,J＝10.0Hz,1H),3.87(dd,J＝9.6Hz,1H),3.64(d,J＝11.2Hz,1H),3.01-2.70(m,9H),2.35-2.22(m,1H),2.21-2.09(m,4H),1.92-1.80(m,3H),1.77-1.68(m,2H),1.50-1.35(m,2H)。MS m/z 596.3[M+H]+。
实施例53化合物E3R的制备
Figure PCTCN2017115756-appb-000095
将化合物E1a(30毫克,0.10毫摩尔)，B2Rb(50毫克,0.16毫摩尔)和浓盐酸(0.1毫升)依次加入至正丁醇(2.0毫升)中。该反应混合物在封管中搅拌加热至150℃反应6小时。LCMS检测反应完成后，将该反应混合物用饱和碳酸氢钠溶液调至pH＝7，然后用二氯甲烷萃取(5毫升x3)，合并有机相用饱和食盐水(5毫升)洗涤，无水硫酸钠干燥、过滤，滤液减压浓缩后的残留物通过制备层析薄板(二氯甲烷/甲醇＝10/1)分离纯化得到淡黄色固体E3R(10毫克,收率19％)。1H NMR(DMSO-d6,400MHz)δ10.20-10.13(br,1H),9.00-8.90(br,1H),8.71-8.62(br,1H),8.23(d,J＝8.4Hz,1H),7.74-7.67(m,1H),7.60-7.42(m,2H),7.14-6.99(m,2H),6.95-6.87(m,1H),6.76(dd,J＝8.8Hz,8.8Hz,1H),6.67(d,J＝8.4Hz,1H),4.27-4.18(m,1H),3.95-3.82(m,3H),3.70-3.60(m,1H),3.28-3.22(m,2H),3.03-2.85(m,4H),2.81-2.72(m,3H),2.48-2.23(m,2H),1.91-1.81(m,1H),1.78-1.68(m,2H),1.50-1.35(m,2H)。MS m/z 583.3[M+H]+。
实施例54蛋白激酶活性抑制的测定
EGFR和EGFR(T790M/L858R)激酶活性抑制实验
采用Caliper迁移率变动检测技术(Caliper mobility shift assay)测定EGFR和EGFR(T790M/L858R)蛋白激酶活性。将化合物用DMSO溶解后用激酶缓冲液稀释(EGFR(T790M/L858R)：pH7.5的50mM HEPES，0.0015％Brij-35,10mM MgCl2，2mM DTT；EGFR:pH7.5 50mM HEPES,0.0015％Brij-35,10mM MgCl2,10mM MnCl2,2mM DTT)，在384孔板中加入5ul的5倍反应终浓度的化合物(10％DMSO)。加入10μL的2.5倍酶(分别用EGFR和EGFR(T790M/L858R))溶液后在室温下孵育10分钟，再加入10μL的2.5倍底物(Peptide FAM-P22和ATP)溶液。28℃下孵育60分钟后加25μL终止液(pH7.5的100mM HEPES,0.015％Brij-35，0.2％Coating Reagent#3，50mM EDTA)终止反应。Caliper EZ Reader II(Caliper Life Sciences)上读取转化率数据。把转化率转化成抑制率数据(％抑制率＝(max-转化率)/(max-min)*100)。其中max是指DMSO对照的转化率，min是指无酶活对照的转化率。以化合物浓度和抑制率为横纵坐标，绘制曲线，使用XLFit excel add-in version4.3.1软件拟合曲线并计算IC50。部分代表性化合物的活性如表1所示。
表1 EGFR和EGFR(T790M/L858R)激酶活性抑制(IC50，nM)
化合物 EGFR EGFR(T790M/L858R)
A1 <100 <10
A1S <100 <1
A1R <100 <1
A2S <100 <10
A2R <100 <10
A3S   <1
A3R <50 <1
A4R <100 <10
A5R <100 <1
A6R <100 <10
A7R <500 <50
A8S <100 <10
A8R <100 <10
A9S <100 <10
A9R <100 <10
CDK2、CDK4和CDK6激酶活性抑制实验
采用Caliper迁移率变动检测技术(Caliper mobility shift assay)测定CDK2/CycA2,CDK4/CycD3和CDK6/cycD3蛋白激酶活性。将化合物用DMSO溶解后用激酶缓冲液稀释(CDK2/CycA2and CDK6/cycD3用50mM HEPES(pH7.5),10mM MgCl2,0.0015％Brij-35,and 2mM dithiothreitol；CDK4/CycD3用20mM HEPES(pH7.5),10mM MgCl2,0.01％Triton X-100,and 2mM dithiothreitol)，在384孔板中加入5μl的5倍反应终浓度的化合物(10％DMSO)。加入10μl的2.5倍Axl酶溶液后在室温下孵育10分钟，再加入10μL的2.5倍底物溶液(相应酶和底物浓度CDK2/CycA2 12nM,ATP Km 39μM；CDK4/CycD3 10nM,ATP Km 221μM；CDK6/cycD3 15nM,ATP Km 800μM)。28℃下各自孵育(60分钟CDK2,180分钟CDK4,60分钟CDK6)后加25μl终止液(100mM HEPES(pH7.5),0.015％Brij-35，0.2％Coating Reagent#3，50mM EDTA)终止反应。Caliper EZ Reader II(Caliper Life Sciences)上读取转化率数据。把转化率转化成抑制率数据(％抑制率＝(max-转化率)/(max-min)*100)。其中max是指DMSO对照的转化率，min 是指无酶活对照的转化率。以化合物浓度和抑制率为横纵坐标，绘制曲线，使用XLFit excel add-in version4.3.1软件拟合曲线并计算IC50。部分代表性化合物的活性如表2所
示。
表2 CDK2、CDK4和CDK6激酶活性抑制(IC50，nM)
化合物 CDK2 CDK4 CDK6
B1S <10 <10 <50
B1R <10 <10 <50
B2R <10 <10 <50
B3R <10 <10 <10
FLT3激酶活性抑制实验
采用Caliper迁移率变动检测技术(Caliper mobility shift assay)测定FLT3蛋白激酶活性。将化合物用DMSO溶解后用激酶缓冲(pH 7.5的50mM HEPES,0.0015％Brij-35，2mM DTT)稀释，在384孔板中加入5ul的5倍反应终浓度的化合物(10％DMSO)。加入10μl的2.5倍FLT3酶溶液后在室温下孵育10分钟，再加入10μL的2.5倍底物(将FAM标记的多肽和ATP)溶液。28℃下孵育60分钟后加25μl终止液(pH 7.5的100mM HEPES,0.015％Brij-35，0.2％Coating Reagent#3，50mM EDTA)终止反应。Caliper EZ Reader II(Caliper Life Sciences)上读取转化率数据。把转化率转化成抑制率数据(％抑制率＝(max-转化率)/(max-min)*100)。其中max是指DMSO对照的转化率，min是指无酶活对照的转化率。以化合物浓度和抑制率为横纵坐标，绘制曲线，使用XLFit excel add-in version4.3.1软件拟合曲线并计算IC50。部分代表性化合物的活性如表3所示。
Axl激酶活性抑制实验
采用Caliper迁移率变动检测技术(Caliper mobility shift assay)测定Axl蛋白激酶活性。将化合物用DMSO溶解后用激酶缓冲液(pH 7.5的50mM HEPES,0.0015％Brij-35，2mM DTT)稀释，在384孔板中加入5μL的5倍反应终浓度的化合物(10％DMSO)。加入10μl的2.5倍Axl酶溶液后在室温下孵育10分钟，再加入10μL的2.5倍底物(将FAM标记的多肽和ATP)溶液。28℃下孵育60分钟后加25μL终止液(pH 7.5的100mM HEPES,0.015％Brij-35，0.2％Coating Reagent#3，50mM EDTA)终止反应。Caliper EZ Reader II(Caliper Life Sciences)上读取转化率数据。把转化率转化成抑制率数据(％抑制率＝(max-转化率)/(max-min)*100)。其中max是指DMSO对照的转化率，min是指无酶活对照的转化率。以化合物浓度和抑制率为横纵坐标，绘制曲线，使用XLFit excel add-in version4.3.1软件拟合曲线并计算IC50。部分代表性化合物的活性如表3所示。
表3 FLT3和AXL激酶活性抑制(IC50，nM)
化合物 FLT3 AXL
D1S <1 <10
D1R <1 <10
D2S <10  
D2R <10  
D3R <10  
D4R <1  
D5S <10  
D6R <1 <10
FAK激酶活性抑制实验
采用Latha screen分析测定FAK蛋白激酶活性。将化合物用DMSO溶解后用激酶缓冲液(25mM HEPES，pH 7.5,0.01mM Triton,10mM MgCl2,0.5mM EGTA,0.01％BRIJ-35,2mM DTT)稀释，在384孔板中加入2.5μL的4倍反应终浓度的化合物(4％DMSO)。加入5μL的2倍FAK酶溶液后在室温下孵育10分钟，再加入2.5μL的4倍底物(Fluorescein-polyGT和ATP)溶液。25℃下孵育30分钟后加10μL检测溶液(识别磷酸化位点的抗体2nM和EDTA 10mM)溶液终止反应。从Envision上读取在340nm处激发，520nm.处发射的数据，从Envision程序上复制发光读数的数据，将发光读数的值通过公式转换为抑制百分率。把转化率转化成抑制率数据(％抑制率＝(max-转化率)/(max-min)*100)。“min”为不加酶进行反应的对照样荧光读数；“max”为加入DMSO作为对照的样品荧光读数。以化合物浓度和抑制率为横纵坐标，绘制曲线，使用XLFit excel add-in version4.3.1软件拟合曲线并计算IC50。部分代表性化合物的活性如表4所示。
表4 FAK激酶活性抑制(IC50，nM)
化合物 FAK
E1 <1
E1S <1
E1R <1
Syk激酶活性抑制实验
采用Caliper迁移率变动检测技术(Caliper mobility shift assay)测定SYK蛋白激酶活性。将化合物用DMSO溶解后用激酶缓冲液(20mM HEPES,0.01％Triton X-100，5mM MgCl2，1mM MnCl2，2mM DTT)稀释，在384孔板中加入5μL的5倍反应终浓度的化合物(10％DMSO)。加入10μL的2.5倍酶(用SYK)溶液后在室温下孵育10分钟，再加入10μL的2.5倍底物(Peptide FAM-P22和ATP)溶液。28℃下孵育30分钟，后加25μL终止液(pH 7.5的100mM HEPES,0.015％Brij-35，0.2％Coating Reagent#3，50mM EDTA)终止反应。Caliper EZ Reader II(Caliper Life Sciences)上读取转化率数据。把转化率转化成抑制率数据(％抑制率＝(max-转化率)/(max-min)*100)。其中max是指DMSO对照的转化率，min是指无酶活对照的转化率。以化合物浓度和抑制率为横纵坐标，绘制曲线，使用XLFit excel add-in version4.3.1软件拟合曲线并计算IC50。部分代表性化合物的活性如表5所示。
表5 Syk激酶活性抑制(IC50，nM)
化合物 Syk
C1R <10
C2R <50
C3R <50
C4R <50
C5R <50
C6R <50
C7R <50
C8R <50
C9R <10
C10R <10
C11R <10
C12R <10
C13R <10
C14R <10
C15R <50
C16R <50
C17R <50
C18R <50
Jak1和Jak2激酶活性抑制实验
激酶JAk1和Jak2酶活抑制IC50评价实验：缓冲液是由如下成分配置的：50 mM HEPES,pH 7.5，0.00015％Brij-35。将化合物在100％DMSO中配置成浓度梯度，并用缓冲液稀释成10％DMSO,加入384孔板。例如化合物起始浓度为250 nM，则用100％DMSO配制成12.5μM，并梯度稀释5或6个浓度，再用缓冲液稀释10倍，配成含10％DMSO的化合物中间稀释体，转移5μL到384孔板。Jak1和Jak2酶用以下缓冲液稀释成最佳浓度：50mM HEPES,pH 7.5，0.00015％Brij-35，2 mM DTT。转移10μL到384孔板中，与化合物孵育10-15分钟。底物用以下缓冲液稀释成最佳浓度：50mM HEPES,pH 7.5，0.00015％Brij-35，10 mM MgCl2，Km下的三磷酸腺苷。加入10μL到384孔板起始反应，并于28℃反应1小时。然后用Caliper Reader读取转化率，计算抑制率。公式如下：Percent inhibition＝(max-conversion)/(max-min)*100。其中max是指DMSO对照的转化率，min是指无酶活对照的转化率。用XLFit excel add-in version 5.4.0.8拟合IC50值。拟合公式:Y＝Bottom+(Top-Bottom)/(1+(IC50/X)^HillSlope)。
表6 Jak1和Jak2激酶活性抑制(IC50，nM)
化合物 Jak1 Jak2
C1R <100 <10
C2R <500 <20
C3R <100 <10
C4R <500 <20
C5R <100 <10
C6R <500 <50
C7R   <50
C8R   <10
C9R   <50
C10R   <10
C11R   <10
C12R   <10
C13R   <10
C14R   <10
C15R   <50
C16R   <50
C17   <50
C18R   <50
实施例55小鼠体内的药物动力学研究
仪器：AB Sciex生产的API4000+液质联用仪，所有的测定数据由Analyst 1.6.3软 件采集并处理，用Microsoft Excel计算和处理数据。用DAS 3.2.8软件，采用统计矩法进行药代动学参数计算。主要包括动力学参数Tmax、T1/2、Cmax、AUC(0-t)等。色谱柱：ACQUITY UPLC BEH C18(2.1mm×50mm，1.7μm)；柱温40℃；流动相A为水(0.1％甲酸+5mM乙酸铵)，流动相B为乙腈(0.1％乙酸)，流速为0.30毫升/分钟，采用等度洗脱90％的B维持1.5分钟。进样量：5μL。
动物：ICR雄性小鼠12只，体重范围22-26g，购入后在实验动物中心实验室饲养2天后使用，给药前12小时及给药后4小时内禁食，试验期间自由饮水。小鼠被随机分成四组，每组3只，灌胃后，每组分别在两个不同时间点取血样。
溶媒：0.5％Methycellulose(含0.4％Tween80的水溶液)。灌胃给药溶液的配制：精密称量化合物，加入溶媒中，常温下超声5分钟使药品完全溶解，配制成0.33毫克/毫升的药液。
药物样品：本发明专利式(I)所示结构的代表性化合物，一般采取多个结构类似的样品(分子量相差在2个单位以上)，准确称量，一起给药(cassette PK)。这样可以同时筛选多个化合物，比较它们的口服吸收率。也采用单一给药来研究药物样品在小鼠体内的药物动力学。
灌胃给药后分别于0.25、0.5、1、2、4、8、12和24小时眼眶取血，于肝素钠处理的试管中，离心后取上清液血浆用于LC-MS/MS分析。
准确称量化合物配制成不同的浓度，在质谱上进行定量分析，从而建立起标准曲线，然后测试上述血浆里化合物的浓度，得出不同时间点的化合物浓度。所有的测定数据由相关的软件采集并处理，采用统计矩法进行药代动学参数计算(主要包括动力学参数Tmax、T1/2、Cmax、AUC(0-t)等)。
采用上述方法，本发明专利式(I)所示结构的代表性化合物具有良好的口服吸收，如化合物C10R和B2R的口服吸收结果如下表所示：
Figure PCTCN2017115756-appb-000096
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (20)

  1. 一种如下式(I)所示结构的化合物，或其光学异构体，药学上可接受的盐，前药，氘代衍生物，水合物，溶剂合物：
    Figure PCTCN2017115756-appb-100001
    其中，所述的M为下式(II)所示的基团：
    Figure PCTCN2017115756-appb-100002
    式(I)和式(II)中：
    Figure PCTCN2017115756-appb-100003
    表示式(II)与式(I)中的U的连接位点；
    “*”表示手性中心；
    A选自芳基或杂芳基；
    B为芳基、杂芳基、C3-8环烷基、3-至12-元杂环基、NRaRb、ORb、SRb、或SO2Rb，其中所述的芳基、杂芳基、环烷基、杂环基可以独立地被一个或多个Rc取代；
    U为NRd、O或S；
    X为氢、卤素、C1-4烷基、C1-4卤代烷基、C3-6环烷基、C2-4烯基、C2-4炔基、3-至10-元杂环基、ORe、SRe、NReRe、CN、C(O)Re、C(O)ORe，C(O)NReRe、OC(O)Re、NReC(O)Re、或S(O)2Re；
    J和G各自独立地为NRf、O、S、S(O)、S(O)2或CRgRg；
    R1和R2各自独立地选自下组：氢、卤素、C1-4烷基、C3-6环烷基、3-至8-元杂环基、或C(O)NReRe；其中，所述的烷基、环烷基、杂环基可以任选地被一个或多个Rc取代；
    各个R3各自独立为氢、或C1-4烷基；当两个R3同时连接到同一个碳原子上时，这两个R3与其相连的碳原子可以任选共同形成羰基(C＝O)；
    n为0、1、2、或3；
    Ra为氢、C1-4烷基、C3-6环烷基、或3-至12-元杂环基；其中，所述这里的烷基、环烷基、杂环基可以任选独立地被一个或多个卤素、ORe、CN、SO2NReRe取代，只要所形成的化学结构式是稳定的和有意义的；
    Rb为芳基、杂芳基、C1-4烷基、C3-8环烷基、3-至12-元杂环基、C(O)Re、或C(O)NReRe；其中，所述的芳基、杂芳基、烷基、环烷基、杂环基可以任选地被一个或多个Rc取代；
    各个Rc各自独立为卤素、C1-4烷基、C3-8环烷基、3-至8-元杂环基、C(O)NReRe、NReC(O)Re、ORe、CN、或SO2NReRe；
    Rd为氢或C1-4烷基；
    各个Re各自独立地选自下组：氢、C1-4烷基、C1-4卤代烷基、C2-4烯基、C2-4炔基、C3-8环烷基、3-至8-元杂环基、芳基、或杂芳基；或者两个Re与和它们连接的氮原子一起形成3-至8-元杂环基，此杂环基含有1或2个N原子以及0或1个选自O、S的杂原子；
    Rf为氢、C1-8烷基、C1-8卤代烷基、C2-8烯基、C2-8炔基、C3-8环烷基、3-至12-元杂环基、芳基、杂芳基、C(O)Re、C(O)ORe、C(O)NReRe、S(O)2Re、或S(O)2NRhRh；
    各个Rg各自独立地选自下组：氢、卤素、或C1-4烷基；或两个Rg与其相连的碳原子共同形成羰基(C＝O)；或两个Rg与其连接的同一个碳原子一起形成3-至8-元环状结构，此环状结构任选地含有0、1或2个选自N、O、S的杂原子；
    各个Rh各自独立为氢、或C1-4烷基；或两个Rh与其连接的氮原子一起形成3-至-元环状结构
    其中，各个上述的烷基、烯基、炔基、环烷基、杂环基、环状结构、芳基和杂芳基任选地且各自独立地被1-3个各自独立地选自下组的取代基取代：卤素、C1-4烷基、C1-4卤代烷基、C2-4烯基、C2-4炔基、C3-8环烷基、3-至12-元杂环基、芳基、杂芳基、CN、NO2、ORe、SRe、NReRe、C(O)Re、C(O)ORe、C(O)NReRe、NReC(O)Re、或S(O)2Re，前提条件是所形成的化学结构是稳定的和有意义的；
    除非特别说明，上述的芳基为含有6-12个碳原子的芳香基团；杂芳基为5-至15-元杂芳香基团；环状结构为饱和的或不饱和的、含杂原子或不含杂原子的环状基团；
    附加条件为，A不选自下组的基团：
    Figure PCTCN2017115756-appb-100004
    其中，“**”表示与U连接；“***”表示与B连接；
    且所述的式(I)化合物不为
    Figure PCTCN2017115756-appb-100005
  2. 如权利要求1所述的化合物，或其光学异构体，药学上可接受的盐，前药，氘代衍生物，水合物，溶剂合物，其特征在于，所述的M为下式(IIa)所示的基团：
    Figure PCTCN2017115756-appb-100006
    其中X、R3、G、和n的定义如权利要求1中所述。
  3. 如权利要求1-2任一所述的化合物，或其光学异构体，药学上可接受的盐，前药，氘代衍生物，水合物，溶剂合物，其特征在于，所述的M选自式(IIb)、式(IIc)、或式(IId)所示的基团：
    Figure PCTCN2017115756-appb-100007
    其中Rf的定义如权利要求1中所述。
  4. 如权利要求1-3任一所述的化合物，或其光学异构体，药学上可接受的盐，前药，氘代衍生物，水合物，溶剂合物，其特征在于，式(I)中A分别独立地选自如下基团：
    Figure PCTCN2017115756-appb-100008
    其中，“**”表示与U连接；“***”表示与B连接；
    U为NRd。
  5. 如权利要求1-3任一所述的化合物，或其光学异构体，药学上可接受的盐，前药，氘代衍生物，水合物，溶剂合物，其特征在于，式(I)中B选自下组：
    Figure PCTCN2017115756-appb-100009
  6. 如权利要求1所述的化合物，或其光学异构体，药学上可接受的盐，前药，氘代衍生物，水合物，溶剂合物，其特征在于，式(I)为：
    Figure PCTCN2017115756-appb-100010
    X为H；
    G为NRf或O；其中Rf的定义如权利要求1中所述；
    R1选自氢、卤素、或C1-4烷基，其中，所述的烷基可以任选地被一个或多个卤素取代；
    各个R3各自独立为氢、或两个R3相连在同一个碳原子共同形成羰基(C＝O)；
    n为0、1、或2。
  7. 如权利要求1所述的化合物，或其光学异构体，药学上可接受的盐，前药，氘代衍生物，水合物，溶剂合物，式(I)为：
    Figure PCTCN2017115756-appb-100011
    X为H；
    G为NRf或O；其中Rf的定义如权利要求1中所述；
    R1选自氢、卤素、或C1-4烷基；
    各个R3各自独立为氢、或两个R3相连在同一个碳原子共同形成羰基(C＝O)；
    n为0、1、或2。
  8. 如权利要求1所述的化合物，或其光学异构体，药学上可接受的盐，前药，氘代衍生物，水合物，溶剂合物，式(I)为：
    Figure PCTCN2017115756-appb-100012
    X为H；
    G为NRf或O；其中Rf的定义如权利要求1中所述；
    R1选自氢、卤素、或CONH2；
    各个R3各自独立为氢、或两个R3相连在同一个碳原子共同形成羰基(C＝O)；
    n为0、1、或2。
  9. 如权利要求1所述的化合物，或其光学异构体，药学上可接受的盐，前药，氘代衍生物，水合物，溶剂合物，式(I)为：
    Figure PCTCN2017115756-appb-100013
    X为H；
    G为NRf或O；其中Rf的定义如权利要求1中所述；
    R1选自氢、或C1-4烷基；R2为CONH2；
    各个R3各自独立为氢、或两个R3相连在同一个碳原子共同形成羰基(C＝O)；
    n为0、1、或2。
  10. 如权利要求1所述的化合物，或其光学异构体，药学上可接受的盐，前药，氘代衍生物，水合物，溶剂合物，式(I)为：
    Figure PCTCN2017115756-appb-100014
    X为H；
    G为NRf或O；其中Rf的定义如权利要求1中所述；
    R1选自氢、卤素、或C1-4烷基，其中，所述的烷基可以任选地被一个或多个卤素取代；
    各个R3各自独立为氢、或两个R3相连在同一个碳原子共同形成羰基(C＝O)；
    n为0、1、或2。
  11. 如权利要求1所述的化合物，或其光学异构体，药学上可接受的盐，前药，氘代衍生物，水合物，溶剂合物，选自下组之一：
    Figure PCTCN2017115756-appb-100015
    Figure PCTCN2017115756-appb-100016
    Figure PCTCN2017115756-appb-100017
    Figure PCTCN2017115756-appb-100018
    Figure PCTCN2017115756-appb-100019
    Figure PCTCN2017115756-appb-100020
  12. 如权利要求1所述的式(I)化合物，或其光学异构体，药学上可接受的盐，前药，氘代衍生物，水合物，溶剂合物的用途，其特征在于，用于：
    (a)制备治疗与蛋白激酶活性或表达量相关的疾病的药物；
    (b)制备蛋白激酶靶向抑制剂；和/或
    (c)体外非治疗性地抑制蛋白激酶的活性；
    其中，所述的蛋白激酶选自下组但不限制于：EGFR、CDK、SYK、JAK、Flt-3、Axl、FAK，或其组合。
  13. 如权利要求6所述的化合物，或其光学异构体，药学上可接受的盐，前药，氘代衍生物，水合物，溶剂合物的用途，其特征在于，可作为EGFR抑制剂，或用于治疗与EGFR高表达相关的疾病。
  14. 如权利要求7所述的化合物，或其光学异构体，药学上可接受的盐，前药，氘代衍生物，水合物，溶剂合物的用途，其特征在于，可作为CDK抑制剂，或用于治疗与CDK高表达相关的疾病。
  15. 如权利要求8所述的化合物，或其光学异构体，药学上可接受的盐，前药，氘代衍生物，水合物，溶剂合物的用途，其特征在于，可作为SYK和JAK抑制剂，或用于治疗与SYK 和JAK高表达相关的疾病。
  16. 如权利要求9所述的化合物，或其光学异构体，药学上可接受的盐，前药，氘代衍生物，水合物，溶剂合物的用途，其特征在于，可作为Flt-3和Axl抑制剂，或用于治疗与Flt-3和Axl高表达相关的疾病。
  17. 如权利要求10所述的化合物，或其光学异构体，药学上可接受的盐，前药，氘代衍生物，水合物，溶剂合物的用途，其特征在于，可作为FAK抑制剂，或用于治疗与FAK高表达相关的疾病。
  18. 一种药物组合物，其特征在于，所述的药物组合物包括：(i)有效量的如权利要求1所述的式I化合物，或其光学异构体，药学上可接受的盐，前药，氘代衍生物，水合物，溶剂合物；和(ii)药学上可接受的载体。
  19. 一种抑制蛋白激酶活性的方法，其特征在于，包括步骤：对抑制对象施用抑制有效量的如权利要求1所述的式I化合物，或其光学异构体，药学上可接受的盐，前药，氘代衍生物，水合物，溶剂合物，或对抑制对象施用抑制有效量的如权利要求18所述的药物组合物；其中，所述的蛋白激酶选自下组：EGFR、FAK、SYK、FLT-3、Axl、CDK、JAK，或其组合。
  20. 一种如权利要求1所述化合物的制备方法，该方法包括步骤：
    Figure PCTCN2017115756-appb-100021
    在惰性溶剂中，用Ia化合物与Ib反应，得到式I化合物；
    优选地所述的式Ia化合物是通过以下方法制备的：
    Figure PCTCN2017115756-appb-100022
    (i)在碱性条件下，式(Va)化合物与式(Vb)化合物反应，得到式(Vc-1)和(Vc-2)化合物；
    任选的(ii)在酸性条件下，分别用式(Vc-1)和(Vc-2)化合物反应，从而脱去保护基；
    (iii)用脱去保护基的式(Vc-1)和(Vc-2)化合物分别反应，分别得到式(Vd-1)和(Vd-2)化合物；
    和任选的(iv)分别对式(Vd-1)和(Vd-2)化合物进行还原，分别得到式(V-1)和(V-2)化合物。
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