WO2018161871A1 - 作为p53-MDM2抑制剂的咪唑并吡咯酮化合物 - Google Patents

作为p53-MDM2抑制剂的咪唑并吡咯酮化合物 Download PDF

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Publication number
WO2018161871A1
WO2018161871A1 PCT/CN2018/078010 CN2018078010W WO2018161871A1 WO 2018161871 A1 WO2018161871 A1 WO 2018161871A1 CN 2018078010 W CN2018078010 W CN 2018078010W WO 2018161871 A1 WO2018161871 A1 WO 2018161871A1
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compound
group
mmol
mixture
pharmaceutically acceptable
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PCT/CN2018/078010
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English (en)
French (fr)
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陈新海
颜小兵
梁娜
胡国平
黎健
陈曙辉
董加强
王铁林
Original Assignee
罗欣生物科技（上海）有限公司
山东罗欣药业集团股份有限公司
南京明德新药研发股份有限公司
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Priority to CN201880016257.2A priority Critical patent/CN110418790B/zh
Publication of WO2018161871A1 publication Critical patent/WO2018161871A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • 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
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to a novel compound as a p53-MDM2 inhibitor, and specifically discloses a compound of the formula (II) and a pharmaceutically acceptable salt thereof.
  • the present invention also relates to the use of a compound as a p53-MDM2 inhibitor or a pharmaceutical composition thereof for the preparation of a medicament for treating cancer, bacterial infection, viral infection.
  • P53 is a tumor suppressor and transcription factor that responds to cellular stress by activating the transcription of many genes involved in cell cycle arrest, apoptosis, senescence, and DNA repair. Unlike p53 activation, which is caused by uncommon causes of normal cells, tumor cells are under constant cellular stress from various lesions including hypoxia and proapoptotic oncogene activation. Thus, there is a strong selectivity advantage for inactivation of the p53 pathway in tumors, and it has been proposed that elimination of p53 function may be a prerequisite for tumor survival. To support this view, three investigative research groups have used mouse models to demonstrate that the lack of p53 function is an ongoing requirement for established tumor maintenance. When the investigator resumed p53 function in p53-inactivated tumors, the tumor resolved.
  • MDM2 is a cancer protein that inhibits p53 function and is activated by gene amplification at a rate of up to 10% reported. MDM2 is in turn inhibited by another tumor suppressor, p14ARF. Changes downstream of p53 are thought to be responsible for at least partially inactivating the p53 pathway in p53 WT tumors (p53 wild type). To support this concept, some p53 WT tumors appear to show reduced apoptotic function, but their ability to undergo cell cycle arrest remains intact.
  • MDM2 inhibits p53 activity through three mechanisms: 1) as an E3 ubiquitin ligase to promote p53 degradation; 2) binding to the p53 transcriptional activation domain and blocking the p53 transcriptional activation domain; and 3) exporting p53 from the nucleus to the cytoplasm . All three mechanisms will block by counteracting the MDM2-p53 interaction.
  • this therapeutic strategy can be applied to p53 WT tumors, and studies using small molecule MDM2 inhibitors have shown that tumor growth is promisingly reduced in vitro and in vivo. Further, in patients with p53-inactivated tumors, stabilization of wild-type p53 in normal tissues caused by MDM2 inhibition may allow selective protection of normal tissues from mitotic toxicants.
  • MDM2 means human MDM2 protein
  • p53 means human p53 protein. It should be noted that human MDM2 may also be referred to as HDM2 or hMDM2.
  • NVP-HDM201 Data from the reported NVP-HDM201 molecule showed better activity in vitro, but the PK properties needed further improvement.
  • the drug is less stable in mouse liver microsomes, has a short half-life in mice, and has low drug plasma exposure.
  • the present invention modifies a part of NVP-HDM201 which is easily metabolized based on the drug molecule, and designs a novel class of compounds having higher plasma exposure of mice and oral bioavailability of mice.
  • the present invention provides a compound of the formula (II) or a pharmaceutically acceptable salt thereof,
  • Ring A is selected from the group consisting of phenyl and 5- to 6-membered heteroaryl
  • Ring B is selected from the group consisting of phenyl and 5- to 7-membered heterocyclic groups
  • R 1 is selected from the group consisting of 1, 2 or 3 R substituted: 5-membered heteroaryl, phenyl or 6- to 10-membered heterocyclic;
  • R 2 is selected from phenyl or 5- to 6-membered heteroaryl optionally substituted by 1, 2 or 3 R;
  • R 3 , R 4 , R 5 and R 7 are each independently selected from H, halogen, OH, CN, NH 2 , NO 2 , or independently selected from, optionally substituted by 1, 2 or 3 R: C a 1-3 alkyl group, a C 1-3 heteroalkyl group, a C 3-6 cycloalkyl group; and R 3 , R 4 , R 5 and R 7 are each independently located on Ring A or Ring B;
  • R 6 is selected from H or is selected from C 1 1-3 alkyl, C 1-6 alkenyl and C 1-3 heteroalkyl optionally substituted by 1, 2 or 3 R;
  • R is selected from halogen, OH, CN, NH 2 or selected from the group consisting of 1, 2 or 3 R's substituted: C 1-3 alkyl, C 3-5 cycloalkyl and C 1-3 heteroalkane base;
  • R' is selected from the group consisting of: F, Cl, Br, I, OH, CN, NH 2 , CH 3 , CH 3 CH 2 , CF 3 , CHF 2 , CH 2 F, CH 3 O;
  • hetero of the 5- to 6-membered heteroaryl group, the 5- to 7-membered heterocyclic group, the 5-membered heteroaryl group, the 6- to 10-membered heterocyclic group, and the C 1-3 heteroalkyl group means a hetero atom or a hetero atom group.
  • the number of heteroatoms or heteroatoms is independently selected from 1, 2 or 3.
  • the above R is selected from the group consisting of: F, Cl, Br, I, OH, CN, NH 2 , CH 3 , CH 3 CH 2 , CF 3 , CHF 2 , CH 2 F, CH 3 O, Cyclopropyl.
  • ring A is selected from the group consisting of phenyl, pyrrolyl, pyridyl.
  • the structural unit From:
  • the above ring B is selected from the group consisting of: 1,3-dioxocyclopentyl, 1,3-dioxocyclopentenyl, phenyl, isoxazolyl, oxazolyl, pyrimidine-4 (1H)-keto, imidazolyl, pyrazinyl, pyrrolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-tri Azyl, 4H-1,2,4-triazolyl, 3,4-dihydropyridine-2(1H)-one, pyrazolyl, oxazol-2(3H)-keto, pyrimidinyl, 4 ,5-dihydro-1H-azepine-2(3H)-keto, pyridyl, 1H-pyrrole-2(3H)-one, pyrrolidin-2-one, 1,3-oxazine
  • the structural unit From:
  • the structural unit From:
  • R 1 above is selected from the group consisting of 1, 2 or 3 R substituted: thiazolyl, phenyl, indolyl, oxazolyl, isoxazolyl, [1, 2, 4] Triazolo[4,3-a]pyridyl, 2-pyridinone, imidazo(1,2-a)pyridyl, benzo[d][1,3]dioxole Alkenyl, 2,3-benzodihydro[b][1,4]dioxanyl, benzo[d]oxazole-2(3H)-one.
  • R 1 is selected from the group consisting of: 1, 2 or 3, R:
  • R 1 is selected from the group consisting of
  • R 2 above is selected from the group consisting of 1, 2 or 3 R substituted: thienyl, thiazolyl, phenyl.
  • R 2 is selected from the group consisting of: 1, 2 or 3, R:
  • R 2 is selected from the group consisting of
  • R 3 , R 4 , R 5 and R 7 are each independently selected from H, F, Cl, Br, I, OH, CN, NH 2 , NO 2 , or independently selected Substituted by 1, 2 or 3 R: C 1-3 alkyl, C 1-3 alkoxy, cyclopropyl, cyclobutyl.
  • R 3 , R 4 , R 5 and R 7 are each independently selected from H, F, Cl, Br, I, OH, CN, NH 2 , NO 2 , or independently selected Substituted by 1, 2 or 3 R: CH 3 , Cyclopropyl.
  • R 3 , R 4 , R 5 and R 7 are each independently selected from the group consisting of: H, F, Cl, Br, I, OH, CN, NH 2 , NO 2 , CH 3 , CF 3 , CHF 2 , CH 2 F, CHF 2 O, CH 2 FO, Cyclopropyl.
  • the structural unit From:
  • the structural unit From:
  • R 6 is selected from the group consisting of: H, CH 3 , Or CH 2 OH.
  • the above R is selected from the group consisting of: F, Cl, Br, I, OH, CN, NH 2 , CH 3 , CH 3 CH 2 , CF 3 , CHF 2 , CH 2 F, CH 3 O, Cyclopropyl, other variables are as defined above.
  • Ring A is selected from the group consisting of phenyl, pyrrolyl, pyridyl, and other variables are as defined above.
  • the above ring B is selected from the group consisting of: 1,3-dioxocyclopentyl, 1,3-dioxocyclopentenyl, phenyl, isoxazolyl, oxazolyl, pyrimidine-4 (1H)-keto, imidazolyl, pyrazinyl, pyrrolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-tri Azyl, 4H-1,2,4-triazolyl, 3,4-dihydropyridine-2(1H)-one, pyrazolyl, oxazol-2(3H)-keto, pyrimidinyl, 4 ,5-dihydro-1H-azepine-2(3H)-keto, pyridyl, 1H-pyrrole-2(3H)-one, pyrrolidin-2-one, 1,3-oxazine
  • R 1 above is selected from the group consisting of 1, 2 or 3 R substituted: thiazolyl, phenyl, indolyl, oxazolyl, isoxazolyl, [1, 2, 4] Triazolo[4,3-a]pyridyl, 2-pyridinone, imidazo(1,2-a)pyridyl, benzo[d][1,3]dioxole Alkenyl, 2,3-benzodihydro[b][1,4]dioxanyl, benzo[d]oxazole-2(3H)-one, other variables are as defined above.
  • R 1 is selected from the group consisting of: 1, 2 or 3, R: Other variables are as defined above.
  • R 1 is selected from the group consisting of Other variables are as defined above.
  • R 2 above is selected from the group consisting of: 1, 2 or 3 R substituted: thienyl, thiazolyl, phenyl, and other variables are as defined above.
  • R 2 is selected from the group consisting of: 1, 2 or 3, R: Other variables are as defined above.
  • R 2 is selected from the group consisting of Other variables are as defined above.
  • R 3 , R 4 , R 5 and R 7 are each independently selected from H, F, Cl, Br, I, OH, CN, NH 2 , NO 2 , or independently selected Substituted by 1, 2 or 3 R: C 1-3 alkyl, C 1-3 alkoxy, cyclopropyl, cyclobutyl, and other variables are as defined above.
  • R 3 , R 4 , R 5 and R 7 are each independently selected from H, F, Cl, Br, I, OH, CN, NH 2 , NO 2 , or independently selected Substituted by 1, 2 or 3 R: CH 3 , Cyclopropyl, other variables are as defined above.
  • R 3 , R 4 , R 5 and R 7 are each independently selected from the group consisting of: H, F, Cl, Br, I, OH, CN, NH 2 , NO 2 , CH 3 , CF 3 , CHF 2 , CH 2 F, CHF 2 O, CH 2 FO, Cyclopropyl, other variables are as defined above.
  • R 6 is selected from the group consisting of: H, CH 3 , Or CH 2 OH.
  • the above compound is selected from the group consisting of
  • R 3 , R 4 , R 5 , R 6 , R 7 and R are as defined above.
  • the present invention also provides a compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:
  • the above compound is selected from the group consisting of
  • the present invention provides a compound of the formula (I) or a pharmaceutically acceptable salt thereof
  • Ring A is selected from the group consisting of: phenyl, 5- to 6-membered heteroaryl;
  • Ring B is selected from the group consisting of: phenyl, 5- to 7-membered heterocyclic group;
  • R 1 is selected from the group consisting of 1, 2 or 3 R substituted: 5-membered heteroaryl, benzene, 6- to 9-membered heterocyclic;
  • R 2 is selected from benzene or a 5- to 6-membered heteroaryl optionally substituted by 1, 2 or 3 R;
  • R 3 , R 4 , R 5 are each independently selected from H, halogen, OH, CN, or independently selected from, optionally substituted by 1, 2 or 3 R: C 1-3 alkyl or C 1- 3 heteroalkyl;
  • R 6 is selected from the group consisting of: H or C 1-3 alkyl
  • R is selected from halogen, OH, CN, NH 2 or from a group optionally substituted by 1, 2 or 3 R': C 1-3 alkyl, C 3-5 cycloalkyl or C 1-3 heteroalkane base;
  • R' is selected from the group consisting of: F, Cl, Br, I, OH, CN, NH 2 , CH 3 , CH 3 CH 2 , CF 3 , CHF 2 , CH 2 F, CH 3 O;
  • the number of heteroatoms or heteroatoms is independently selected from 1, 2 or 3.
  • the above R is selected from the group consisting of: F, Cl, Br, I, OH, CN, NH 2 , CH 3 , CH 3 CH 2 , CF 3 , CHF 2 , CH 2 F, CH 3 O, Cyclopropyl.
  • ring A is selected from the group consisting of phenyl, pyrrolyl, pyridyl.
  • the structural unit From:
  • the above ring B is selected from the group consisting of: 1,3-dioxocyclopentyl, 1,3-dioxocyclopentenyl, phenyl, isoxazolyl, pyrimidine-4(1H)- Keto group, imidazolyl, pyrazinyl, pyrrolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl, 4H -1,2,4-triazolyl, 3,4-dihydropyridine-2(1H)-one, pyrazolyl, oxazol-2(3H)-one, pyrimidinyl, 4,5-di Hydrogen-1H-azepine-2(3H)-keto.
  • the structural unit From:
  • the structural unit From:
  • R 1 above is selected from the group consisting of 1, 2 or 3 R substituted: thiazolyl, phenyl, indolyl, oxazolyl, isoxazolyl, [1, 2, 4 Triazolo[4,3-a]pyridyl, 2-pyridinone, imidazo(1,2-a)pyridyl.
  • R 1 is selected from the group consisting of: 1, 2 or 3, R:
  • R 1 is selected from the group consisting of
  • R 2 above is selected from the group consisting of 1, 2 or 3 R substituted: thienyl, thiazolyl, phenyl.
  • R 2 is selected from the group consisting of: 1, 2 or 3, R:
  • R 2 is selected from the group consisting of
  • R 3 , R 4 , R 5 are each independently selected from H, F, Cl, Br, I, OH, CN, or are independently selected from, optionally, 1, 2 or 3, respectively.
  • R C 1-3 alkyl, C 1-3 alkoxy.
  • R 3 , R 4 , R 5 are each independently selected from H, F, Cl, Br, I, OH, CN, or are independently selected from, optionally, 1, 2 or 3, respectively.
  • R 3 , R 4 , and R 5 are each independently selected from the group consisting of H, F, Cl, Br, I, OH, CN, CH 3 ,
  • the structural unit From:
  • the structural unit From:
  • R 6 is selected from H or
  • the compound, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:
  • R 3 , R 4 , R 6 and R are as defined above.
  • the present invention also provides a compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:
  • the compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of the above-mentioned compound or a pharmaceutically acceptable salt thereof as an active ingredient and a pharmaceutically acceptable carrier.
  • the present invention also provides the use of the above compound or a pharmaceutically acceptable salt thereof for the preparation of a medicament for treating cancer, bacterial infection, viral infection.
  • the present invention also provides the use of the above pharmaceutical composition for the preparation of a medicament for treating cancer, bacterial infection, viral infection.
  • Ring A is selected from the group consisting of phenyl, pyrrolyl, pyridyl, and other variables are as defined above.
  • the above ring B is selected from the group consisting of: 1,3-dioxocyclopentyl, 1,3-dioxocyclopentenyl, phenyl, isoxazolyl, pyrimidine-4(1H)- Keto group, imidazolyl, pyrazinyl, pyrrolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl, 4H -1,2,4-triazolyl, 3,4-dihydropyridine-2(1H)-one, pyrazolyl, oxazol-2(3H)-one, pyrimidinyl, 4,5-di Hydrogen-1H-azepine-2(3H)-keto, other variables are as defined above.
  • the structural unit From:
  • R 1 above is selected from the group consisting of 1, 2 or 3 R substituted: thiazolyl, phenyl, indolyl, oxazolyl, isoxazolyl, [1, 2, 4 Triazolo[4,3-a]pyridyl, 2-pyridinone, imidazo(1,2-a)pyridinyl, other variables are as defined above.
  • R 1 is selected from the group consisting of: 1, 2 or 3, R: Other variables are as defined above.
  • R 1 is selected from the group consisting of Other variables are as defined above.
  • R 2 above is selected from the group consisting of: 1, 2 or 3 R substituted: thienyl, thiazolyl, phenyl, and other variables are as defined above.
  • R 2 is selected from the group consisting of: 1, 2 or 3, R: Other variables are as defined above.
  • R 2 is selected from the group consisting of Other variables are as defined above.
  • R 3 , R 4 , R 5 are each independently selected from H, F, Cl, Br, I, OH, CN, or are independently selected from, optionally, 1, 2 or 3, respectively.
  • R is a substituted: C 1-3 alkyl, C 1-3 alkoxy, the other variables are as defined above.
  • R 3 , R 4 , R 5 are each independently selected from H, F, Cl, Br, I, OH, CN, or are independently selected from, optionally, 1, 2 or 3, respectively.
  • R: CH 3 Other variables are as defined above.
  • R 3 , R 4 , and R 5 are each independently selected from the group consisting of H, F, Cl, Br, I, OH, CN, CH 3 , Other variables are as defined above.
  • R 6 is selected from H or Other variables are as defined above.
  • the present invention relates to a compound capable of inhibiting the interaction between p53 and MDM2 and capable of activating a p53 downstream effector gene.
  • the compounds of the invention will be useful in the treatment of cancer, bacterial infections, viral infections, ulcers and inflammation.
  • the compounds of the invention are useful in the treatment of solid tumors such as breast tumors, colon tumors, pulmonary tumors, esophageal tumors, and prostate tumors, as well as liquid tumors such as lymphomas and leukemias.
  • the drug molecule having the structure of imidazopyrrolidone according to the present invention is distinctly different from the p53-MDM2 inhibitor reported in earlier patents, which is capable of inhibiting the interaction between p53 and MDM2 while activating the p53 downstream effector group.
  • the drug molecule having an imidazopyrrolidone structure exhibits good activity in binding to the MDM2 protein target and inhibiting the growth of SJSA-1 tumor cells in an in vitro experiment. Furthermore, in vivo experiments in mice, the drug molecule exhibited more excellent PK properties than the reference molecule.
  • the drug molecule having the structure of imidazopyrrolidone according to the present invention will be useful for the treatment of solid tumors such as breast tumors, colon tumors, lung tumors, esophageal tumors and prostate tumors, and liquid tumors such as lymphoma and leukemia. Cancer, bacterial infections, viral infections, ulcers and inflammation.
  • pharmaceutically acceptable salt refers to a salt of a compound of the invention prepared from a compound having a particular substituent found in the present invention and a relatively non-toxic acid or base.
  • a base addition salt can be obtained by contacting a neutral amount of such a compound with a sufficient amount of a base in a neat solution or a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonia or magnesium salts or similar salts.
  • an acid addition salt can be obtained by contacting a neutral form of such a compound with a sufficient amount of an acid in a neat solution or a suitable inert solvent.
  • pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, hydrogencarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and an organic acid salt, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Similar acids such as fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and me
  • the salt is contacted with a base or acid in a conventional manner, and the parent compound is separated, thereby regenerating the neutral form of the compound.
  • the parent form of the compound differs from the form of its various salts by certain physical properties, such as differences in solubility in polar solvents.
  • a "pharmaceutically acceptable salt” is a derivative of a compound of the invention wherein the parent compound is modified by salt formation with an acid or with a base.
  • pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of bases such as amines, alkali metal or organic salts of acid groups such as carboxylic acids, and the like.
  • Pharmaceutically acceptable salts include the conventional non-toxic salts or quaternary ammonium salts of the parent compound, for example salts formed from non-toxic inorganic or organic acids.
  • non-toxic salts include, but are not limited to, those derived from inorganic acids and organic acids selected from the group consisting of 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, Benzenesulfonic acid, benzoic acid, hydrogencarbonate, carbonic acid, citric acid, edetic acid, ethane disulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptose, gluconic acid, glutamic acid, glycolic acid, Hydrobromic acid, hydrochloric acid, hydroiodide, hydroxyl, hydroxynaphthalene, isethionethane, lactic acid, lactose, dodecylsulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, nitric acid, oxalic acid, Pamoic acid, pantothenic acid, phenylacetic acid, phen
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing an acid group or a base by conventional chemical methods.
  • such salts are prepared by reacting these compounds in water or an organic solvent or a mixture of the two via a free acid or base form with a stoichiometric amount of a suitable base or acid.
  • a nonaqueous medium such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile is preferred.
  • the compounds provided herein also exist in the form of prodrugs.
  • Prodrugs of the compounds described herein are readily chemically altered under physiological conditions to convert to the compounds of the invention.
  • prodrugs can be converted to the compounds of the invention by chemical or biochemical methods in an in vivo setting.
  • Certain compounds of the invention may exist in unsolvated or solvated forms, including hydrated forms.
  • the solvated forms are equivalent to the unsolvated forms and are included within the scope of the invention.
  • Certain compounds of the invention may have asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers and individual isomers are included within the scope of the invention.
  • wedge-shaped dashed keys Represents the absolute configuration of a stereocenter, using wavy lines Indicates a wedge solid key Or wedge-shaped dotted key Straight solid key And straight dashed keys Indicates the relative configuration of the stereocenter.
  • the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, they include the E and Z geometric isomers unless otherwise specified. Likewise, all tautomeric forms are included within the scope of the invention.
  • the compounds of the invention may exist in specific geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including the cis and trans isomers, the (-)- and (+)-p-enantiomers, the (R)- and (S)-enantiomers, and the diastereomeric a conformation, a (D)-isomer, a (L)-isomer, and a racemic mixture thereof, and other mixtures, such as enantiomerically or diastereomeric enriched mixtures, all of which belong to It is within the scope of the invention.
  • Additional asymmetric carbon atoms may be present in the substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the invention.
  • optically active (R)- and (S)-isomers as well as the D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If an enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary wherein the resulting mixture of diastereomers is separated and the auxiliary group cleaved to provide pure The desired enantiomer.
  • a diastereomeric salt is formed with a suitable optically active acid or base, followed by conventional methods well known in the art.
  • the diastereomers are resolved and the pure enantiomer is recovered.
  • the separation of enantiomers and diastereomers is generally accomplished by the use of chromatography using a chiral stationary phase, optionally in combination with chemical derivatization (eg, formation of an amino group from an amine). Formate).
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up the compound.
  • radiolabeled compounds can be used, such as tritium (3 H), iodine -125 (125 I) or C-14 (14 C). Alterations of all isotopic compositions of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.
  • pharmaceutically acceptable carrier refers to any formulation or carrier medium that is capable of delivering an effective amount of an active substance of the present invention, does not interfere with the biological activity of the active substance, and has no toxic side effects to the host or patient, including water, oil, Vegetables and minerals, cream bases, lotion bases, ointment bases, etc. These bases include suspending agents, tackifiers, transdermal enhancers and the like. Their formulations are well known to those skilled in the cosmetic or topical pharmaceutical arts. For additional information on the vector, reference is made to Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), the disclosure of which is incorporated herein by reference.
  • excipient generally refers to the carrier, diluent and/or vehicle required to formulate an effective pharmaceutical composition.
  • an "effective amount” or “therapeutically effective amount” with respect to a pharmaceutical or pharmacologically active agent refers to a sufficient amount of a drug or agent that is non-toxic but that achieves the desired effect.
  • an "effective amount” of an active substance in a composition refers to the amount required to achieve the desired effect when used in combination with another active substance in the composition. The determination of the effective amount will vary from person to person, depending on the age and general condition of the recipient, and also on the particular active substance, and a suitable effective amount in a case can be determined by one skilled in the art based on routine experimentation.
  • active ingredient refers to a chemical entity that is effective in treating a target disorder, disease or condition.
  • substituted means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, and may include variants of heavy hydrogen and hydrogen, as long as the valence of the particular atom is normal and the substituted compound is stable. of.
  • Ketone substitution does not occur on the aryl group.
  • optionally substituted means that it may or may not be substituted, and unless otherwise specified, the kind and number of substituents may be arbitrary on the basis of chemically achievable.
  • any variable eg, R
  • its definition in each case is independent.
  • the group may optionally be substituted with at most two R, and each case has an independent option.
  • combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
  • linking group When the number of one linking group is 0, such as -(CRR) 0 -, it indicates that the linking group is a single bond.
  • one of the variables When one of the variables is selected from a single bond, it means that the two groups to which it is attached are directly linked. For example, when L represents a single bond in A-L-Z, the structure is actually A-Z.
  • a substituent When a substituent is vacant, it means that the substituent is absent. For example, when X is vacant in AX, the structure is actually A.
  • the substituent can be attached to more than one atom on a ring, the substituent can be bonded to any atom on the ring, for example, a structural unit. It is indicated that the substituent R can be substituted at any position on the cyclohexyl group or cyclohexadiene.
  • substituents When the listed substituents are not indicated by which atom is attached to the substituted group, such a substituent may be bonded through any atom thereof, for example, a pyridyl group as a substituent may be passed through any one of the pyridine rings. A carbon atom is attached to the substituted group.
  • the medium linking group L is -MW-, and at this time, -MW- can be connected in the same direction as the reading order from left to right to form ring A and ring B. It is also possible to connect the ring A and the ring B in a direction opposite to the reading order from left to right. Combinations of the linking groups, substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
  • hetero denotes a hetero atom or a hetero atomic group (ie, a radical containing a hetero atom), including atoms other than carbon (C) and hydrogen (H), and radicals containing such heteroatoms, including, for example, oxygen (O).
  • ring means substituted or unsubstituted cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aryl or heteroaryl. So-called rings include single rings, interlocking rings, spiral rings, parallel rings or bridge rings. The number of atoms on the ring is usually defined as the number of elements of the ring. For example, "5 to 7-membered ring” means 5 to 7 atoms arranged in a circle. Unless otherwise specified, the ring optionally contains from 1 to 3 heteroatoms.
  • 5- to 7-membered ring includes, for example, phenyl, pyridine, and piperidinyl; on the other hand, the term “5- to 7-membered heterocycloalkyl ring” includes pyridyl and piperidinyl, but does not include phenyl.
  • ring also includes ring systems containing at least one ring, each of which "ring” independently conforms to the above definition.
  • heterocycle or “heterocyclyl” means a stable monocyclic, bicyclic or tricyclic ring containing a hetero atom or a heteroatom group which may be saturated, partially unsaturated or unsaturated ( Aromatic) which comprise a carbon atom and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S, wherein any of the above heterocycles may be fused to a phenyl ring to form a bicyclic ring.
  • the nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O)p, p is 1 or 2).
  • the nitrogen atom can be substituted or unsubstituted (i.e., N or NR, wherein R is H or other substituents as already defined herein).
  • the heterocyclic ring can be attached to the side groups of any hetero atom or carbon atom to form a stable structure. If the resulting compound is stable, the heterocycles described herein can undergo substitutions at the carbon or nitrogen sites.
  • the nitrogen atom in the heterocycle is optionally quaternized.
  • a preferred embodiment is that when the total number of S and O atoms in the heterocycle exceeds 1, these heteroatoms are not adjacent to each other. Another preferred embodiment is that the total number of S and O atoms in the heterocycle does not exceed one.
  • aromatic heterocyclic group or "heteroaryl” as used herein means a stable 5, 6, or 7 membered monocyclic or bicyclic or aromatic ring of a 7, 8, 9 or 10 membered bicyclic heterocyclic group, It contains carbon atoms and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S.
  • the nitrogen atom can be substituted or unsubstituted (i.e., N or NR, wherein R is H or other substituents as already defined herein).
  • the nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O)p, p is 1 or 2).
  • bridged rings are also included in the definition of heterocycles.
  • a bridged ring is formed when one or more atoms (ie, C, O, N, or S) join two non-adjacent carbon or nitrogen atoms.
  • Preferred bridged rings include, but are not limited to, one carbon atom, two carbon atoms, one nitrogen atom, two nitrogen atoms, and one carbon-nitrogen group. It is worth noting that a bridge always converts a single ring into a three ring. In the bridged ring, a substituent on the ring can also be present on the bridge.
  • heterocyclic compounds include, but are not limited to, acridinyl, octanoyl, benzimidazolyl, benzofuranyl, benzofuranylfuranyl, benzindenylphenyl, benzoxazolyl, benzimidin Oxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, oxazolyl, 4aH-carbazolyl, Porphyrin, chroman, chromene, porphyrin-decahydroquinolinyl, 2H, 6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b] Tetrahydrofuranyl, furyl, furfuryl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-carbazolyl, nonenyl,
  • hydrocarbyl or its subordinate concept (such as alkyl, alkenyl, alkynyl, aryl, etc.), by itself or as part of another substituent, is meant to be straight-chain, branched or cyclic.
  • the hydrocarbon atom group or a combination thereof may be fully saturated (such as an alkyl group), a unit or a polyunsaturated (such as an alkenyl group, an alkynyl group, an aryl group), may be monosubstituted or polysubstituted, and may be monovalent (such as Methyl), divalent (such as methylene) or polyvalent (such as methine), may include divalent or polyvalent radicals with a specified number of carbon atoms (eg, C 1 -C 12 represents 1 to 12 carbons) , C 1-12 is selected from C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 and C 12 ; C 3-12 is selected from C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 and C 12 .).
  • C 1-12 is selected from C 1
  • Hydrocarbyl includes, but is not limited to, aliphatic hydrocarbyl groups including chain and cyclic, including but not limited to alkyl, alkenyl, alkynyl groups including, but not limited to, 6-12 members.
  • An aromatic hydrocarbon group such as benzene, naphthalene or the like.
  • hydrocarbyl means a straight or branched chain radical or a combination thereof, which may be fully saturated, unitary or polyunsaturated, and may include divalent and multivalent radicals.
  • saturated hydrocarbon radicals include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, isobutyl, cyclohexyl, (cyclohexyl).
  • a homolog or isomer of a methyl group, a cyclopropylmethyl group, and an atomic group such as n-pentyl, n-hexyl, n-heptyl, n-octyl.
  • the unsaturated hydrocarbon group has one or more double or triple bonds, and examples thereof include, but are not limited to, a vinyl group, a 2-propenyl group, a butenyl group, a crotyl group, a 2-isopentenyl group, and a 2-(butadienyl group). , 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and higher homologs and isomers body.
  • heterohydrocarbyl or its subordinate concept (such as heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, etc.), by itself or in combination with another term, means a stable straight chain, branched chain. Or a cyclic hydrocarbon radical or a combination thereof having a number of carbon atoms and at least one heteroatom.
  • heteroalkyl by itself or in conjunction with another term refers to a stable straight chain, branched hydrocarbon radical or combination thereof, having a number of carbon atoms and at least one heteroatom.
  • the heteroatoms are selected from the group consisting of B, O, N, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen heteroatoms are optionally quaternized.
  • the hetero atom or heteroatom group may be located at any internal position of the heterohydrocarbyl group, including where the hydrocarbyl group is attached to the rest of the molecule, but the terms "alkoxy”, “alkylamino” and “alkylthio” (or thioalkoxy). By customary expression, those alkyl groups which are attached to the remainder of the molecule through an oxygen atom, an amino group or a sulfur atom, respectively.
  • Up to two heteroatoms may be consecutive, for example, -CH 2 -NH-OCH 3.
  • cycloalkyl refers to any heterocyclic alkynyl group, etc., by itself or in combination with other terms, denotes a cyclized “hydrocarbyl group” or “heterohydrocarbyl group”, respectively.
  • a hetero atom may occupy a position at which the hetero ring is attached to the rest of the molecule.
  • cycloalkyl groups include, but are not limited to, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like.
  • heterocyclic groups include 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothiophen-2-yl, tetrahydrothiophen-3-yl, 1-piperazinyl and 2-piperazinyl.
  • alkyl is used to denote a straight or branched saturated hydrocarbon group, which may be monosubstituted (eg, -CH 2 F) or polysubstituted (eg, -CF 3 ), and may be monovalent (eg, Methyl), divalent (such as methylene) or polyvalent (such as methine).
  • alkyl group include methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, s-butyl). , t-butyl), pentyl (eg, n-pentyl, isopentyl, neopentyl) and the like.
  • alkenyl refers to an alkyl group having one or more carbon-carbon double bonds at any position of the chain, which may be mono- or poly-substituted, and may be monovalent, divalent or multivalent.
  • alkenyl group include a vinyl group, a propenyl group, a butenyl group, a pentenyl group, a hexenyl group, a butadienyl group, a pentadienyl group, a hexadienyl group and the like.
  • alkynyl refers to an alkyl group having one or more carbon-carbon triple bonds at any position of the chain, which may be mono- or poly-substituted, and may be monovalent, divalent or multivalent.
  • alkynyl groups include ethynyl, propynyl, butynyl, pentynyl and the like.
  • a cycloalkyl group includes any stable cyclic or polycyclic hydrocarbon group, any carbon atom which is saturated, may be monosubstituted or polysubstituted, and may be monovalent, divalent or multivalent.
  • Examples of such cycloalkyl groups include, but are not limited to, cyclopropyl, norbornyl, [2.2.2]bicyclooctane, [4.4.0]bicyclononane, and the like.
  • a cycloalkenyl group includes any stable cyclic or polycyclic hydrocarbon group which contains one or more unsaturated carbon-carbon double bonds at any position of the ring, and may be monosubstituted or polysubstituted, It can be one price, two price or multiple price.
  • Examples of such cycloalkenyl groups include, but are not limited to, cyclopentenyl, cyclohexenyl, and the like.
  • a cycloalkynyl group includes any stable cyclic or polycyclic hydrocarbon group which contains one or more carbon-carbon triple bonds at any position of the ring, which may be monosubstituted or polysubstituted, and may be one Price, price or price.
  • halo or “halogen”, by itself or as part of another substituent, denotes a fluorine, chlorine, bromine or iodine atom.
  • haloalkyl is intended to include both monohaloalkyl and polyhaloalkyl.
  • halo(C 1 -C 4 )alkyl is intended to include, but is not limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like. Wait.
  • examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl.
  • alkoxy represents attached through an oxygen bridge
  • C 1-6 alkoxy groups include C 1, C 2, C 3 , C 4, C 5 , and C 6 alkoxy groups.
  • alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy and S- Pentyloxy.
  • aryl denotes a polyunsaturated, aromatic hydrocarbon substituent which may be monosubstituted or polysubstituted, which may be monovalent, divalent or polyvalent, which may be monocyclic or polycyclic ( For example, 1 to 3 rings; at least one of which is aromatic), they are fused together or covalently linked.
  • heteroaryl refers to an aryl (or ring) containing one to four heteroatoms. In an illustrative example, the heteroatoms are selected from the group consisting of B, N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized.
  • a heteroaryl group can be attached to the remainder of the molecule through a heteroatom.
  • aryl or heteroaryl groups include phenyl, naphthyl, biphenyl, pyrrolyl, pyrazolyl, imidazolyl, pyrazinyl, oxazolyl, phenyl-oxazolyl, isomerism Azyl, thiazolyl, furyl, thienyl, pyridyl, pyrimidinyl, benzothiazolyl, indolyl, benzimidazolyl, indolyl, isoquinolyl, quinoxalinyl, quinolinyl, 1 -naphthyl, 2-naphthyl, 4-biphenylyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl
  • aryl groups when used in conjunction with other terms (e.g., aryloxy, arylthio, aralkyl), include aryl and heteroaryl rings as defined above.
  • aralkyl is intended to include those radicals to which an aryl group is attached to an alkyl group (eg, benzyl, phenethyl, pyridylmethyl, and the like), including wherein the carbon atom (eg, methylene) has been, for example, oxygen.
  • alkyl groups substituted by an atom such as phenoxymethyl, 2-pyridyloxymethyl 3-(1-naphthyloxy)propyl and the like.
  • leaving group refers to a functional group or atom which may be substituted by another functional group or atom by a substitution reaction (for example, an affinity substitution reaction).
  • substituent groups include triflate; chlorine, bromine, iodine; sulfonate groups such as mesylate, tosylate, p-bromobenzenesulfonate, p-toluenesulfonic acid Esters and the like; acyloxy groups such as acetoxy, trifluoroacetoxy and the like.
  • protecting group includes, but is not limited to, "amino protecting group", “hydroxy protecting group” or “thiol protecting group”.
  • amino protecting group refers to a protecting group suitable for preventing side reactions at the amino nitrogen position.
  • Representative amino protecting groups include, but are not limited to, formyl; acyl, such as alkanoyl (e.g., acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl, e.g., tert-butoxycarbonyl (Boc) Arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl (Tr), 1, 1-di -(4'-methoxyphenyl)methyl; silyl groups such as trimethylsilyl (TMS) and tert-
  • hydroxy protecting group refers to a protecting group suitable for use in preventing hydroxy side reactions.
  • Representative hydroxy protecting groups include, but are not limited to, alkyl groups such as methyl, ethyl and t-butyl groups; acyl groups such as alkanoyl groups (e.g., acetyl); arylmethyl groups such as benzyl (Bn), Oxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyl Dimethylsilyl (TBS) and the like.
  • alkyl groups such as methyl, ethyl and t-butyl groups
  • acyl groups such as alkanoyl groups (e.g., acetyl)
  • arylmethyl groups such as benzyl (Bn), Oxybenzyl (PMB), 9-fluoreny
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments set forth below, combinations thereof with other chemical synthetic methods, and those well known to those skilled in the art. Equivalent alternatives, preferred embodiments include, but are not limited to, embodiments of the invention.
  • the solvent used in the present invention is commercially available.
  • the present invention employs the following abbreviations: aq for water; HATU for O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate ; EDC stands for N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride; m-CPBA stands for 3-chloroperoxybenzoic acid; eq stands for equivalent; mol stands for mole; Representative millimoles; kg for kilograms; g for grams; mg for milligrams; mL for milliliters; mm for millimeters; ⁇ m for micrometers; CDI for carbonyldiimidazole; DCM for methylene chloride; DCE for 1,2-dichloroethane AlCl 3 stands for aluminum trichloride; MeI stands for methyl io
  • Step A To a solution of compound 1-1 (2.00 kg, 17.68 mol, 1.94 L, 1.00 eq) in EtOH (25.00 L) was added 1,1-dimethoxy-N,N-dimethyl-methylamine ( 2.74 kg, 22.98 mol, 3.04 L, 1.30 eq). The mixture was stirred at 25 ° C for 16 hours. The mixture was concentrated and the residue was purifiedjjjjjjj
  • Step B Compound 1-a (25.00 g, 148.64 mmol, 1.00 eq) and 2-propylamine (26.36 g, 445.92 mmol, 38.20 mL, 3.00 eq) were added to the vial. The mixture was stirred at 75 ° C for 13 hours. After cooling, the mixture was concentrated in vacuo and EtOAcqqqqqq
  • Step D LDA (2M, 11.49 mL, 1.50 eq) was added dropwise to a solution of compound 1-c (4.00 g, 15.32 mmol, 1.00 eq) in dry THF (70.00 mL). After stirring at -78 ° C for 2 hours, a solution of 4-chlorobenzaldehyde (2.80 g, 19.92 mmol, 1.30 eq) in THF (7.00 mL) was slowly added to the mixture and stirring was continued at -70 ° C for 0.5 hour. The temperature was then slowly raised to -20 ° C over 0.5 hours.
  • Step G To a solution of compound 1-f (1.30g, 2.53mmol, 1.00eq) and DIEA (980.23mg, 7.58mmol, 1.32mL, 3.00eq) in DMF (35.00mL) was added HATU (1.15g, 3.03) Mmmol, 1.20 eq). The mixture was warmed to 60 ° C and stirred for 15 hours. The mixture was concentrated under reduced pressure to dryness crystals crystals crystals The organic phase was washed with brine (30 mL) The residue was taken up in EtOAc (15 mL).
  • Step H (30.00mL) was added MeI acetone solution of compound 1-2 (3.00g, 21.72mmol, 1.00eq) of (6.17g, 43.44mmol, 2.71mL, 2.00eq ) and K 2 CO 3 (9.01g, 65.16 mmol, 3.00 eq). The mixture was stirred at 25 ° C for 24 hours. The reaction solution was filtered and the filtrate was concentrated in vacuo to yield compound 1-h.
  • Step I To a solution of compound 1-h (500.00 mg, 3.29 mmol, 1.00 eq. The reaction solution was stirred at 25 ° C for 12 hours. The mixture was quenched with saturated Na 2 S 2 O 3 solution (20mL), and extracted with EtOAc (20mL ⁇ 2). The organic layers were combined and washed with brine (20mL) was washed, dried over anhydrous Na 2 SO 4, filtered and concentrated in vacuo to give compound 1-i.
  • Step J Compound 1-i (690.00 mg, 2.99 mmol, 1.00 eq), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl) under N2. -1,3,1,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (1.14 g, 4.49 mmol, 1.50 eq), Pd (dppf) Cl 2 (109.39 mg, 149.50 ⁇ mol, 0.05 eq) and KOAc (586.88 mg, 5.98 mmol, 2.00 eq) were added to dioxane (10.00 mL). The mixture was heated to 80 ° C under N 2 and stirred for 12 hours. After cooling, the solution was filtered and concentrated to give crystals crystall
  • Step K Under the protection of nitrogen, compound 1-g (80.00 mg, 161.23 ⁇ mol, 1.00 eq), compound 1-j (89.68 mg, 322.46 ⁇ mol, 2.00 eq) and Na 2 CO 3 (51.27 mg, 483.69) were dissolved. Pd(PPh 3 ) 4 (18.63 mg, 16.12 ⁇ mol, 0.10 eq) was added to a mixture of dimol, 3.00 eq. of dioxane (3.00 mL) / water (1.00 mL). The mixture was heated to 100 ° C and stirred for 2 hours. The mixture was cooled with EtOAc EtOAc (EtOAc)EtOAc. The combined organics were washed with brine (30 mL) The residue was purified by preparative EtOAc (EtOAc:EtOAc)
  • Step A To a solution of compound 2 (70.00 mg, 131.48 ⁇ mol, 1.00 eq) and 2-iodopropane (44.70 mg, 262.96 ⁇ mol, 26.29 ⁇ L, 85.67 mg, 262.96 mgol, 2.00 eq) in DMF (2.00 mL) 2 CO 3 (85.67 mg, 262.96 ⁇ mol, 2.00 eq). The mixture was stirred at 75 ° C for 3 hours under a nitrogen atmosphere. After cooling the mixture was concentrated in EtOAc EtOAc m.
  • Step A Compound 4 was prepared according to Step 3 of Example 3, wherein 2-iodopropane was increased from 2 eq to 3 eq.
  • Step A To a solution of compound 5-1 (10.00 g, 61.29 mmol, 1.00 eq) in DMF (100.00 ⁇ RTIgt; After the addition was completed, the mixture was stirred for 1 hour, and a saturated aqueous ammonium chloride solution (300 mL) was added to the reaction mixture, and the mixture was filtered to give Compound 5-a.
  • Step D Compound 5-c (480.54 mg, 1.52 mmol, 1.50 eq), Compound 1- g (500.00 mg, 1.01 mmol, 1.00 eq), XPHOS-PD-G2 (145.57 mg, 202.00 ⁇ mol) , 0.20 eq) and K 3 PO 4 (643.18 mg, 3.03 mmol, 3.00 eq) were added to a mixture of dioxane (5 mL) and water (1.5 mL). The mixture was warmed to 80 ° C and stirred for 2 hours. After cooling, the mixture was concentrated to give a crude material.
  • Step A a mixed solution of AcOH (29.94 g, 498.71 mmol, 28.51 mL, 56.93 eq) and water (30.00 mL) dissolved in compound 6-1 (2.64 g, 8.76 mmol, 1.00 eq) at 0-5 °.
  • Step A To a solution of compound 7-1 (15.00 g, 97.31 mmol, 1.00 eq.) in EtOAc (15 ⁇ RTIgt; ⁇ /RTI> ⁇ RTIgt; The mixture was stirred at 0 °C 2 h, saturated aqueous Na 2 SO 3 (150 mL) was added to the solution, the mixture was filtered to give compound 7-a.
  • Step B Compound 7-a (12.00 g, 51.50 mmol, 1.00 eq), methyl hydrazine (22.43 g, 154.50 mmol, 3.00 eq) and K 2 CO 3 (21.35 g, 154.50 mmol, 3.00). Eq) was added to DMSO (120.00 mL). The mixture was warmed to 60 ° C and stirred for 85 hours. After cooling, water (500 mL) was added to the solution, the mixture was filtered and the cake was collected to give compound 7-b.
  • Step D Compound 7-c (477.29 mg, 1.66 mmol, 1.64 eq), Compound 1- g (502.24 mg, 1.01 mmol, 1.00 eq), K 3 PO 4 (644.58 mg, 3.04 mmol, 3.00 eq) and XPHOS-PD-G2 (131.29 mg, 182.20 ⁇ mol, 0.18 eq) were added to dioxane (7.00 mL) and water (2.00 mL). The mixture was warmed to 80 ° C and stirred for 2 hours. After cooling, the mixture was concentrated to give a crude material.
  • Step A Concentrated hydrochloric acid (10.82 g, 108.31 mmol) was added to a mixed solution of compound 8-1 (10.90 g, 60.17 mmol, 1.00 eq) in ethanol (200.00 mL), water (100.00 mL) and acetic acid (200.00 mL). , 10.61 mL, 1.80 eq) and iron powder (20.16 g, 361.02 mmol, 6.00 eq). The mixture was stirred at 60 ° C for 2 hours, and after cooling, a saturated aqueous solution of Na 2 CO 3 (60 mL) was slowly added to the reaction mixture to adjust pH to about 7. Further DCM (100 mL) was added to the mixture, the mixture was filtered and the filtrate was separated. The organic layer was dried over anhydrous Na 2 SO 4, filtered, and concentrated to give compound 8-a.
  • Step B To a solution of compound 8-a (8.90 g, 58.88 mmol, 1.00 eq. The mixture was stirred at 20 ° C for 1 hour. The mixture was filtered and the cake was dried in vacuo to give compound 8-b.
  • Step D Compound 8-c (2.40 g, 10.04 mmol, 1.00 eq), bis-pinacol borate (3.82 g, 15.06 mmol, 1.50 eq), KOAc (1.97 g, 20.08 mmol) , 2.00 eq) and Pd(dppf)Cl 2 (367.28 mg, 0.05 eq) were added to a solution of dioxane (30.00 mL). The mixture was warmed to 100 ° C and stirred for 17 hours. After cooling, the mixture was filtered and concentrated to give a residue. The residue was purified by preparative HPLC (neutral conditions) to afford compound 8-d.
  • Step E Compound 8-d (30.00 mg, 147.07 ⁇ mol, 1.50 eq), Compound 1-g (48.65 mg, 98.05 ⁇ mol, 1.00 eq), K 3 PO 4 (124.87 mg, 588.28 ⁇ mol, 6.00 eq) and Pd(dppf)Cl 2 (35.87 mg, 49.02 ⁇ mol, 0.50 eq) were added to a mixture of dioxane (2.00 mL) and water (200.00 ⁇ L). The mixture was then warmed to 80 ° C and stirred for 2 hours. The reaction mixture was cooled and concentrated, then purified, mjjjjj
  • Step A According to the sequence of Steps C and D of Example 6, wherein 5-bromo-6-methoxy-2-methyl-benzotriazole was replaced by 5-bromo-6-methoxy-1-methyl Base-benzotriazole, product by preparative HPLC (column: C18 150mm*25mm*10um; mobile phase: [water r (0.225%FA)-ACN]; B%: 30%-60%, 11min) and SFC (Column: AD (250 mm * 30 mm, 10 um); mobile phase: [0.1% ammonia, ethanol]; [0.1% ammonia, ethanol]%: 45% - 45%) purified to give compound 9-I (retention time 3.464 min) ) and 9-II (retention time 3.746min).
  • Step A To a solution of compound 10-1 (10.00 g, 59.82 mmol, 1.00 eq) in DMF (100.00 ⁇ RTIgt; The mixture was stirred at 20 ° C for 6 hours, a saturated aqueous solution of ammonium chloride (10 mL) was added to the solution, and the mixture was filtered to give compound 10-a.
  • Step C Add methyl iodide to a solution of compound 10-b (4.00 g, 15.68 mmol, 1.00 eq) and NaH (627.28 mg, 15.68 mmol, 60% purity, 1.00 eq) in DMF (40.00 mL). (6.50 g, 45.79 mmol, 2.85 mL, 2.92 eq). The mixture was stirred at 25 ° C for 1 hour. The mixture was poured into saturated aqueous NaHCO 3 (300 mL), and the mixture was filtered to give compound 10-c.
  • Step D Compound 10-c (400.00 mg, 1.49 mmol, 1.00 eq.), carbaryl bis-borate (1.14 g, 4.47 mmol, 3.00 eq), Pd(dppf)Cl 2 108.77 mg, 148.65 ⁇ mol, 0.10 eq) and KOAc (437.65 mg, 4.46 mmol, 3.00 eq) were added to dioxane (5.00 mL). The mixture was then warmed to 95 ° C and stirred for 12 hours. After cooling, the mixture was filtered and concentrated, and the residue was purifiedjjjjjjjj
  • Step E Compound 10-d (22.94 mg, 72.56 ⁇ mol, 1.80 eq), 2-bromo-5-(5-chloro-1-methyl-2-oxo-3-pyridyl) under nitrogen.
  • 4-(4-Chlorophenyl)-3-isopropyl-4H-pyrrolo[3,4-d]imidazol-6-one (20.00 mg, 40.31 ⁇ mol, 1.00 eq)
  • K 3 PO 4 25.67 Mg, 120.93 ⁇ mol, 3.00 eq
  • XPHOS-PD-G2 14.52 mg, 20.16 ⁇ mol, 0.50 eq
  • Step A Acetic anhydride (8.29 g, 81.20 mmol, 7.61 mL, 1.00 eq) was added in one portion to a solution of compound 11-1 (10.00 g, 81.20 mmol, 1.00 eq) in acetic acid (50.00 mL). After the mixture was stirred at 25 ° C for 1 hour, the mixture was poured into water (200 mL) and stirred for 5 minutes. The aqueous phase was extracted with ethyl acetate (20 mL*4). The combined organic phases are washed with saturated sodium bicarbonate solution, brine (100 mL), then dried over anhydrous Na 2 SO 4. Filtration and concentration in vacuo gave compound 11-a.
  • Step B Nitric acid (11.80 g, 121.68 mmol, 8.43 mL, 1.50 eq) was added dropwise to compound 11-a (13.40 g, 81.12 mmol, 1.00 eq) in dichloromethane (150.00 mL) at 0 °C. In solution. After the addition was completed, the mixture was stirred at 0 ° C for 3 hours. A saturated aqueous solution of sodium hydrogencarbonate (350 mL) was added to the mixture. The mixture was extracted with DCM (100mL), the combined organic phases were dried over anhydrous Na 2 SO 4. Filtration and concentration in vacuo gave compound 11-b.
  • Step C Compound 11-b (15.75 g, 74.93 mmol, 1.00 eq) was taken in EtOAc (4M, 250.00 ⁇ RTIgt; The reaction mixture was warmed to 60 ° C and stirred for 4 hours. The mixture was cooled to 25 <0>C and aqueous was extracted with ethyl acetate (200 mL). The combined organic phases were washed with brine (200mL), dried over anhydrous Na 2 SO 4. Filtration and concentration in vacuo gave compound 11-c.
  • Step D at 25 °C, to a solution of Compound 11-c (12.12g, 72.08mmol, 1.00eq), iron powder (40.26g, 720.80mmol, 10.00eq) and NH 4 Cl (38.55g, 720.80mmol, 25.20
  • Formic acid 146.40 g, 3.18 mol, 120.00 mL, 44.13 eq
  • the mixture was heated to 80 ° C and stirred for 3 hours.
  • the mixture was cooled to 25 ° C, filtered and concentrated in vacuo.
  • Step F To a mixture of NaH (1.32 g, 33.03 mmol, 60% purity, 3.00 eq) in DMF (25.00 mL) was added to compound 11-e (2.50 g, 11.01 mmol, 1.00eq). The mixture was stirred at 25 ° C for 30 minutes, and iodomethane (3.13 g, 22.02 mmol, 1.37 mL, 2.00 eq) was added to the mixture and stirred for 16 hr. The residue was poured into water (200 mL) and stirred for 20 min. The aqueous phase was extracted with ethyl acetate (200 mL). The combined organic phases were washed with brine (200mL) washed, dried over anhydrous Na 2 SO 4, filtered and concentrated in vacuo. The residue was purified by column chromatography (EtOAc /EtOAcEtOAc
  • Step H Compound 1-g (500.00 mg, 1.01 mmol, 1.00 eq), Compound 11- g (566.94 mg, 1.52 mmol, 1.50 eq), K 3 PO 4 (428.79 mg, 2.02 mmol, 2.00 eq) and sPHOS-PD-G2 (82.93 mg, 202.00, 0.20 eq) were added to a mixed solvent of dioxane (8.00 mL) and water (1.60 mL), and the mixture was warmed to 90 ° C and stirred for 12 hours. The mixture was cooled to 20 ° C and concentrated under reduced pressure at 50 ° C. The residue was poured into water (20 mL) and stirred for 5 min.
  • Step A Compound 12 was prepared according to the procedure of Example 6 Steps C and D, in which compound compound 6-b was replaced by compound 6-d.
  • Step A To a solution of compound 13-1 (5.00 g, 25.38 mmol, 1.00 eq) in THF (50.00 ⁇ RTIgt; ⁇ /RTI> ⁇ RTIgt; ⁇ /RTI> ⁇ RTIgt; ⁇ /RTI> ⁇ RTIgt; ⁇ /RTI> ⁇ RTIgt; ⁇ /RTI> ⁇ RTIgt; ⁇ /RTI> ⁇ RTIgt; The mixture was stirred at 25 ° C for 2 hours. The reaction mixture was filtered, and the cake was collected to give compound 13-a.
  • Step C To a solution of compound 13-b (300.00 mg, 1.30 mmol, 1.00 eq) in DMF (6.00 mL), NaH (104.00 mg, 2.60 mmol, 60% purity, 2.00 eq) Methyl iodide (3.16 g, 22.26 mmol, 1.39 mL, 17.13 eq), and the mixture was warmed to 25 ° C and stirred for 2 hours. The mixture was diluted with 30 mL of water, the suspension was filtered, and the filter cake was collected and dried to give compound 13-c.
  • Step F Compound 1-g (50.00 mg, 100.77 ⁇ mol, 1.00 eq) and compound 13-e (40.00 mg, 127.02 ⁇ mol, 1.26 eq) of dioxane (1.50 mL) and water (400.00). To the mixed solution was added K 3 PO 4 (42.78 mg, 201.54 ⁇ mol, 2.00 eq) and Sphos G2-Pd (14.52 mg, 20.15 ⁇ mol, 0.20 eq). The mixture was warmed to 85 ° C and stirred for 2 hours.
  • Step C Compound was added to the DMF 14-b (2.80g, 11.47mmol , 1.00eq) of (30.00 mL) solution of MeI (4.07g, 28.68mmol, 1.79mL, 2.50eq) and K 2 CO 3 (4.76g, 34.41 mmol, 3.00 eq). After the mixture was stirred at 25 ° C for 12 hours, water (150 mL) was added to the solution, and the mixture was filtered to give Compound 14-c.
  • Step D According to the procedure of Steps E and F of Example 13, wherein compound 13-d was replaced with compound 14-c, after which crude was obtained, and then passed through preparative HPLC (column: Daiso 150 mm * 25 mm 5 ⁇ m; mobile phase: [water] (0.225% FA)-ACN]; ACN%: 35%-60%) and SFC (column: AD (250 mm*30 mm, 10 ⁇ m); mobile phase: [0.1% ammonia, methanol]; [0.1% ammonia, methanol] %: 55%-55%) purification gave compound 14-I (retention time 1.739 min) and 14-II (retention time 3.195 min).
  • Step A Compound 15 was prepared according to the sequence of Steps E and F of Example 13 in which 13-d was replaced with 5-bromo-6-methoxy-1-methyl-benzimidazole.
  • PE: EA 3:1 to 1:1
  • Step C Compound 16-b (8.86 g, 21.01 mmol, 1.00 eq) and LiOH (2.01 g, 84.04 mmol, 4.00 eq) were dissolved in a mixture of solvent tetrahydrofuran (40.00 mL), ethanol (30.00 mL) and water (30.00 mL) )in. The reaction solution was stirred at 25 ° C for 12 hours. The mixture was concentrated under reduced pressure to remove EtOH and THF and then extracted with EA (EtOAc). The aqueous phase was adjusted to pH 3 with hydrochloric acid (3 mol/L), and the solid was collected by filtration and dried under reduced pressure to give compound 16-c.
  • Step D Compound 16-c (6.43 g, 15.52 mmol, 1.00 eq), HATU (8.85 g, 23.28 mmol, 1.50 eq) and DIPEA (4.01 g, 31.04 mmol, 5.42 mL, 2.00 eq) was dissolved in DMF (60.00) In mL), the reaction solution was stirred at 60 ° C for 12 hours. To the reaction mixture was added water (200 mL), with EA (80mL) and extracted three times, the combined organic phases were washed twice with water (50mL), brine (50mL), washed once, dried over anhydrous Na 2 SO 4, filtered, and concentrated under reduced pressure to give Compound 16-d.
  • Step E Compound 16-d (1.00 g, 2.82 mmol, 1.00 eq), Compound 11-c (994.16 mg, 4.23 mmol, 1.50 eq), sPHOS-PD-G2 (443.73 mg, 564.00 ⁇ mol). 0.20 eq) and K 3 PO 4 (1.20 g, 5.64 mmol, 2.00 eq) were added to a mixed solution of dioxane (20.00 mL) and water (10.00 mL). The mixture was stirred at 80 ° C for 12 hours. After cooling the mixture was quenched with water (20 mL). The mixture was extracted with EA (20mL), the combined organic layers (20mL) and washed with brine, dried over anhydrous Na 2 SO 4. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (EA) to afford compound 16-e.
  • EA preparative TLC
  • Step F Compound 16-e (100.00 mg, 215.08 ⁇ mol, 1.00 eq), 8-bromo-6-chloro-imidazo[1,2-a]pyridine (59.74 mg, 258.10 ⁇ mol, 1.20). Eq), Pd 2 (dba) 3 (9.85 mg, 10.75 ⁇ mol, 0.05 eq), Xantphos (9.96 mg, 17.21 ⁇ mol, 0.08 eq) and Cs 2 CO 3 (105.12 mg, 322.62 ⁇ mol, 1.50 eq) were added to the dioxane. (3.00 mL). The mixture was warmed to 90 ° C and stirred for 12 hours. The mixture was quenched with water (5 mL)EtOAc. The combined organic layers were washed with (5mL) with brine, dried over anhydrous Na 2 SO 4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (EA) to afford compound 16.
  • EA preparative TLC
  • Step B at 0 °C, a solution of compound 17-a (2.50g, 6.13mmol, 1.00eq) in methylene chloride (60.00mL) was added SOCl 2 (4.38g, 36.78mmol, 2.67mL , 6.00eq). After the addition was completed, the reaction solution was heated to 30 ° C and stirred for 1.5 hours. The reaction mixture was concentrated to give the compound 17-b.
  • Step C To a solution of compound 17-b (2.50 g, 5.87 mmol, 1.00 eq) in acetonitrile (25.00 mL), DIEA (3.03 g, 23.48 mmol, 4.10 mL, 4.00 eq) and 3-amino-5-chloro- 1-Methyl-pyridin-2-one (930.34 mg, 5.87 mmol, 1.00 eq).
  • the reaction solution was heated to 80 ° C and stirred for 30 hours. After the reaction mixture was cooled, the reaction mixture was diluted with 1M EtOAc (30 mL). The combined organic phase was washed with 1mol / L dilute hydrochloric acid (30mL), brine (30mL) was washed, dried over anhydrous Na 2 SO 4, filtered, to give Compound 17-c concentrated under reduced pressure.
  • Step D To a mixed solution of the compound 17-c (2.60 g, 4.74 mmol, 1.00 eq) of tetrahydrofuran (25.00 mL) and methanol (25.00 mL) was added NaOH (2M, 23.70 mL, 10.00 eq). Stir at ° C for 2 hours. The reaction mixture was adjusted to a pH of about 4 with 1M diluted hydrochloric acid (47 mL), then concentrated and then diluted with water (30mL). Was treated with DCM (50mL) and extracted twice, the combined organic phases were dried over anhydrous Na 2 SO 4, filtered, concentrated under reduced pressure to give the crude product. The crude product was triturated with EA (10 mL) to afford compound 17-d.
  • Step F under N 2, the compound 14-d (544.66mg, 1.78mmol, 1.50eq), compound 17-e (600.00mg, 1.19mmol, 1.00eq), sPHOS-PD-G2 (85.75mg, 119.00 ⁇ mol, 0.10 eq) and K 3 PO 4 (757.80 mg, 3.57 mmol, 3.00 eq) were added to a mixed solution of water (1.3 mL) and dioxane (5.0 mL). The mixture was heated to 80 ° C and stirred for 1 hour. After the mixture was cooled, EA (3 mL) and water (3 mL) were added.
  • Step A under N 2, the compound 17-e (500.00mg, 995.60 ⁇ mol, 1.00eq), compound 7-c (430.32mg, 1.49mmol, 1.50eq), K 3 PO 4 (422.67mg, 1.99mmol , 2.00 eq) and sPHOS-PD-G2 (81.74 mg, 199.12 ⁇ mol, 0.20 eq) were added to a mixed solution of dioxane (10.0 mL) and water (2.0 mL). The mixture was heated to 80 ° C and stirred for 12 hours. The mixture was cooled to room temperature and concentrated under reduced pressure at 50 °C.
  • Step A NaH (1.63 g, 40.76 mmol, 60% purity, 2.00 eq) was added to a solution of compound 20-1 (3.00 g, 20.38 mmol, 1.00 eq) in DMF (30.00 mL). After the mixture was stirred at 25 ° C for 30 minutes, MeI (5.79 g, 40.76 mmol, 2.54 mL, 2.00 eq). The resulting mixture was stirred at 25 ° C for an additional 1 hour. The solution was quenched with saturated aqueous NH 4 Cl (50mL), and extracted with EtOAc (50mLx2). The organic layers were combined, washed with brine (30mLx2), dried over anhydrous Na 2 SO 4, filtered and concentrated in vacuo to give compound 20-a, was used directly in the next step.
  • MeI 5.79 g, 40.76 mmol, 2.54 mL, 2.00 eq
  • Step B solution of methanol to the compound 20-a (2.30g, 14.27mmol, 1.00eq) of (40.00 mL) was added NaBH 3 CN (3.59g, 57.08mmol, 4.00eq) and formic acid (4.11g, 85.62 M, 6.00 eq). The mixture was stirred at 25 ° C for 1 hour. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (25 mL*2). The organic layers were combined, washed with brine (20 mL), dried over anhydrous Na 2 SO 4, filtered and concentrated in vacuo to give the crude product. The crude product was purified by column chromatography (EtOAc /EtOAcEtOAc
  • Step F Dioxane (15.0 mL) and water dissolved in compound 1-g (700.00 mg, 1.41 mmol, 1.00 eq) and compound 20-e (907.16 mg, 2.78 mmol, 1.97 eq. (4 mL) was added K 3 PO 4 (598.93 mg, 2.82 mmol, 2.00 eq) and XPHOS-PD-G2 (203.33 mg, 282.00 ⁇ mol, 0.20 eq). The mixture was warmed to 80 ° C and stirred for 12 hours.
  • Step A room temperature, (50.00mL) was added hydroxylamine hydrochloride in ethanol to compound 21-1 (5.00g, 28.38mmol, 1.00eq) of (3.94g, 56.76mmol, 2.00eq) and K 2 CO 3 ( 7.84 g, 56.76 mmol, 2.00 eq). The mixture was warmed to 60 ° C and stirred for 12 hours. After cooling, water (20 mL) was added to the solution and extracted with EA (20 mL ⁇ 2). The organic layers were combined, dried over anhydrous Na 2 SO 4, filtered, and concentrated to give compound 21-a.
  • Step B A mixture of PPA (1.00 mL) and Compound 21-a (2.00 g, 10.46 mmol, 1.00 eq) was warmed to 70 ° C under stirring for 12 hours. After the mixture was cooled, aqueous NaOH (3M, 5 mL) was added. Water (10 mL) was added and the solution was extracted with EA (20 mL*2). The organic layers were combined, dried over anhydrous Na 2 SO 4, filtered, and concentrated to give compound 21-b.
  • Step C To a solution of compound 21-b (EtOAc: EtOAc, EtOAc. The mixture was stirred at 20 ° C for 1 hour. Water (20 mL) was added to the solution and the solution was extracted with EA (20 mL ⁇ 2). The organic layers were combined, dried over anhydrous Na 2 SO 4, filtered, and concentrated to give Compound 21-c.
  • Step D To a solution of Compound 21-c (1.00g, 3.70mmol, 1.00eq) in DMF (10.00mL) was added K 2 CO 3 (1.53g, g , 11.10mmol, 3.00eq). After the mixture was stirred at 20 ° C for 40 hours, water (50 mL) was added to the solution. The mixture was extracted by EA (20mL * 2), the organic layers were combined, dried over anhydrous Na 2 SO 4, filtered, and concentrated to give Compound 21-d.
  • Step F Compound 21-e (1.00 g, 3.03 mmol, 1.50 eq.), Compound 1- g (1.00 g, 2.02 mmol, 1.00 eq), K 3 PO 4 (1.29 g, 6.06 mmol, 3.00 eq), XPHOS-PD-G2 (232.90 mg, 323.20 ⁇ mol, 0.16 equivalent) was added to a mixed solution of dioxane (12.0 mL) and water (4 mL). The mixture was then warmed to 80 ° C and stirred for 2 hours. After cooling, the mixture was filtered and concentrated.
  • Step A Mix of compound 16-d (500 mg, 1.41 mmol, 1 eq) and compound 7-c (600 mg, 2.08 mmol, 1.48 eq) of dioxane (9 mL) and water (3 mL).
  • Step B Compound 22-a (150 mg, 344.11 umol, 1 eq) and 5-iodo-1,3-benzodioxole (135.00 mg, 544.32 umol, 1.58 eq) of dioxane at room temperature under nitrogen. (8 mL) was added Cs 2 CO 3 (225.00mg, 690.57 ⁇ mol , 2.01eq) respectively, CuI (660.00mg, 3.47mmol, 10.07eq ) and DMEDA (160mg, 1.82mmol, 195.36uL, 5.27eq), the reaction system The nitrogen gas was replaced 3 times and the temperature was raised to 75 ° C and stirred for 10 hours.
  • Step B at 25 °C, (10mL) was added LiOH.H of compound 23-a (1.6g, 2.99mmol, 1eq) in tetrahydrofuran 2 O (627.69mg, 14.96mmol, 5eq ) in ethanol (10mL) and A solution of water (5 mL) was stirred for 12 hours. The reaction mixture was concentrated, and the residue was evaporated, mjjjjjjjjjj
  • Step D Compound 23-c (500 mg, 1.02 mmol, 1 eq) and compound 7-c (383.21 mg, 1.33 mmol, 1.3 eq) of dioxane (10 mL) and water (5 mL) K 3 PO 4 (434.29 mg, 2.05 mmol, 2 eq) and Pd(dppf)Cl 2 (74.85 mg, 102.30 umol, 0.1 eq) were respectively added to the solution, and the reaction system was replaced with nitrogen three times and heated to 90 ° C for 2 hours. The reaction mixture was cooled and filtered with EtOAc EtOAc (EtOAc)EtOAc.
  • EtOAc EtOAc
  • Step B Pd/C (100 mg, 60% purity) was added to a solution of compound 24-a (1 g, 5.55 mmol, 1 eq) in ethanol (5 mL) and methanol (15 mL). The mixture was stirred 3 times at 25 ° C under a hydrogen (15 psi) atmosphere for 2 hours. The reaction solution was concentrated by filtration to give Compound 24-b.
  • Step C Compound 23-1 was replaced with compound 24-b according to the procedure of Steps A, B, C and D of Example 23.
  • Purification of compound 24-I retention time: 2.058 min
  • compound 24-II retention time: 2.398 min
  • Step A To a solution of compound 22-a (25 mg, 57.35 umol, 1 eq) and compound 25-1 (25 mg, 123.81 umol, 2.16 eq) in tetrahydrofuran (4 mL) 60.56 umol, 1.06 eq), 4A molecular sieve (20 mg) and triethylamine (15 mg, 148.24 umol, 20.63 uL, 2.58 eq). The reaction system was replaced with oxygen three times and warmed to 50 ° C and stirred under an oxygen atmosphere for 12 hours. After the reaction system was cooled, it was filtered and concentrated. The residue was purified by preparative HPLC (column: C 18 150*25*10 ⁇ m; mobile phase: [water (0.225%FA)-ACN]; ACN%: 48%-78%) to afford compound 25.
  • Step A To a solution of compound 26-1 (1 g, 3.99 mmol, 1 eq) in dimethyl sulfoxide (10.00 mL) was added potassium carbonate (1.66 g, 11.98 mmol, 3 eq) and aq. g, 21.44 mmol, 2.82 mL, 5.37 eq). The mixture was warmed to 80 ° C and stirred for 12 hours. After cooling, the reaction liquid was added to water (50 mL), filtered, and the filter cake was washed with water to give compound 26-a.
  • PE: EA 3:1
  • Step C Following the procedure of Steps A and B of Example 22, wherein compound 22-b was replaced with 6-methoxy-1-methyl-5-(4,4,5,5-tetramethyl-1, 3,2-Biaborone-2-yl)carbazole.
  • Step A Compound 27-a was prepared according to the procedure of Example 17 Steps C, D, and E, in which 3-amino-5-chloro-1-methyl-pyridin-2-one was replaced with piperamine.
  • Step B Compound 27-a (0.4 g, 832.01 umol, 1 eq), Compound 7-c (359.62 mg, 1.25 mmol, 1.5 eq), K 3 PO 4 (529.83 mg, 2.50 mmol, 3 eq. And Pd(dppf)Cl 2 .CH 2 Cl 2 (54.36 mg, 66.56 umol, 0.08 eq) were added to dioxane (5 mL) and water (2 mL), respectively. The temperature of the reaction solution was then raised to 80 ° C and stirred for 12 hours.
  • Step B To a mixed solution of the compound 28-a (14 g, 34.42 mmol, 1 eq) of tetrahydrofuran (100.00 mL), ethanol (100.00 mL) and water (150 mL) was added LiOH.H 2 O (2.89 g, 68.84 mmol, 2 eq), and the reaction mixture was stirred at 25 ° C for 12 hours. The reaction solution was adjusted to a pH of about 6 with 1M diluted hydrochloric acid, and concentrated to give a solid.
  • Step C To a solution of compound 28-b (12 g, 31.69 mmol, 1 eq) in DMF (40.00 ⁇ RTIgt; ⁇ /RTI> ⁇ RTIgt; ⁇ /RTI> ⁇ RTIgt; ⁇ /RTI> ⁇ RTIgt; ⁇ /RTI> ⁇ RTIgt; ⁇ /RTI> ⁇ RTIgt; 2 eq), the reaction solution was heated to 60 ° C and stirred for 12 hours. The reaction solution was cooled to room temperature and poured into water (500 mL) to precipitate a solid, which was filtered to afford compound 28-c.
  • Step D Compound 28-c (500 mg, 1.29 mmol, 1 eq) and compound 26-b (447.39 mg, 1.55 mmol, 1.2 eq) of dioxane (10mL) and water (2mL) Pd(dppf)Cl 2 .CH 2 Cl 2 (105.30 mg, 128.95 umol, 0.1 eq) and K 3 PO 4 (821.12 mg, 3.87 mmol, 3 eq) were added to the mixed solution, and the reaction system was replaced with nitrogen three times and heated. Stir at 90 ° C for 12 hours. After the reaction system was cooled, it was filtered, and the filtrate was diluted with water (30 mL) and EA (30mL*2). The organic layers were combined, washed with a solution of NaCl (10mL * 2), dried over anhydrous Na 2 SO 4, filtered and concentrated. The residue was purified by column chromatography (EtOAc:EtOAc:EtOAc
  • Step E Compound 28-d (300 mg, 677.32 umol, 1 eq) and 3,4-(Methylenedioxy)phenylboronic acid (337.18 mg, 2.03 mmol, 3 eq), mp.
  • dichloromethane 5 mL
  • copper acetate 135.33 mg, 745.05 umol, 1.1 eq
  • pyridine 160.73 mg, 2.03 mmol, 164.01 uL, 3 eq
  • triethylamine 137.08 mg, 1.35 mmol, 188.55 uL, 2 eq And 4A molecular sieve (400 mg)
  • the reaction system was stirred at 30 ° C for 12 hours in an oxygen atmosphere.
  • Step A To a solution of compound 27 (0.8 g, 1.44 mmol, 1 eq) and bromomethyl methyl ether (1.80 g, 14.39 mmol, 1.18 mL, 10 eq) in acetonitrile (8 mL) 21.58 mmol, 15 eq), and the reaction mixture was stirred at 20 ° C for 2 hours. Water (10 mL) and ethyl acetate (10 mL x 2) were added to the mixture.
  • Step A To a solution of compound 7-b (1 g, 4.15 mmol, 1 eq) in acetic acid (25 mL), EtOAc (2 ⁇ Stir at 25 ° C for 1 hour. The reaction solution was added to 150 mL of water and stirred for 10 minutes, filtered, and the filter cake was collected to give Compound 30-a.
  • Step C To a solution of compound 30-b (1.1 g, 4.30 mmol, 1 eq) in aqueous hydrogen chloride (4M, 20 mL) Cuprous (850.44 mg, 8.59 mmol, 2 eq), stirred at 0 °C for 2 h. The reaction mixture was quenched by the addition of 20 mL of water. EtOAc (30 mL*3).
  • Step D To a solution of compound 30-c (700 mg, 2.54 mmol, 1 eq) in dioxane (10 mL), EtOAc (EtOAc, EtOAc, EtOAc) Cl 2 (185.89 mg, 254.06 ⁇ mol, 0.1 eq) and pinacol bis-borate (774.17 mg, 3.05 mmol, 1.2 eq).
  • EtOAc EtOAc
  • EtOAc EtOAc
  • EtOAc EtOAc Cl 2
  • Step E Compound 30-d (642.35 mg, 1.99 mmol, 4 eq) and compound 17-e (250 mg, 0.5 mmol, 1 eq) of dioxane (4 mL) and water (1 mL) K 3 PO 4 (317 mg, 1.49 mmol, 3 eq) and Pd(dppf)Cl 2 were added to the mixture, and the reaction system was replaced with nitrogen three times, and then the mixture was heated to 100 ° C and stirred under nitrogen for 2 hours. After the reaction mixture was cooled to room temperature, the mixture was filtered.
  • Step A To a solution of compound 31-1 (5 g, 29.73 mmol, 1 eq) in acetic acid (50 mL) was added EtOAc (EtOAc, EtOAc. 12 hours. The reaction solution was poured into water (200 mL), filtered, and then filtered to afford compound 31-a.
  • Step B To a solution of compound 31-a (4 g, 16.19 mmol, 1 eq) in DMSO (40 mL), EtOAc (EtOAc, EtOAc (EtOAc) 48.57 mmol, 3 eq), the reaction system was heated to 90 ° C and stirred for 12 hours. The reaction solution was cooled to room temperature and poured into water (200 mL), filtered, and the filter cake was collected, and the filter cake was purified by column chromatography to give compound 31-b.
  • Step D Compound 31-c (902.53 mg, 2.99 mmol, 6 eq) and compound 24-e (250 mg, 194.80 ⁇ mol, 1 eq) of dioxane (10 mL) and water (3 mL) at 25 ° C under nitrogen atmosphere.
  • K 3 PO 4 (317 mg, 1.49 mmol, 3 eq) and Pd(dppf)Cl 2 (36.42 mg, 49.87 mmol, 0.1 eq) were added to the mixed solution, and the reaction system was replaced with nitrogen three times, and the temperature was raised to 100 ° C and nitrogen. Stir for 2 hours under the atmosphere.
  • Step B Lithium tetrahydrogenate (431.85 mg, 11.38 mmol, 2.00 eq) was added dropwise to a solution of compound 32-a (1.4 g, 5.69 mmol, 1.00 eq) in THF (10 mL). A solution of tetrahydrofuran (10 mL) was added and the mixture was warmed to 0 ° C and stirred for 1 hour, then warmed to 15 ° C and stirred for 12 hours. The reaction mixture was quenched with EtOAc EtOAc EtOAc (EtOAc) Concentration by pressure gave compound 32-b.
  • EtOAc EtOAc
  • Step C To a solution of compound 32-b (1.42 g, 5.51 mmol, 1.00 eq) in THF (40 mL), bis(trichloromethyl) carbonate (1.63 g, 5.51 mmol, 1.00 eq), the reaction system was stirred at 0 ° C for 2 hours under a nitrogen atmosphere. The reaction mixture was poured into water (50 mL), EtOAc (EtOAc) (EtOAc (EtOAc) The filtrate was concentrated by pressure to give a residue.
  • EtOAc EtOAc
  • EtOAc EtOAc
  • Step F Compound 31-c was replaced with compound 32-e according to step D of Example 31.
  • Step C To a solution of compound 33-b (2 g, 8.88 mmol, 1 eq) in AcOH (15 mL) was added iron powder (1.98 g, 35.52 mmol, 4 eq) at 25 ° C, and the reaction system was warmed to 100 ° C and stirred 1 hour. The reaction mixture was cooled to EtOAc EtOAc EtOAc (EtOAc)EtOAc. Dry over anhydrous Na 2 SO 4 , filtered, and then filtered.
  • EtOAc EtOAc EtOAc
  • Step E To a solution of compound 33-d (500 mg, 2.07 mmol, 1 eq) in toluene (3 mL), a solution of NaH (91 mg, 2.28 mmol, 60% purity, 1.1 eq) in toluene (9 mL). In the solution, the reaction system was heated to 100 ° C and stirred for 1 hour. Dimethyl sulfate (200 mg, 1.59 mmol, 150.38 uL, 0.77 eq) was added to the reaction mixture, and the mixture was stirred at 100 ° C for 2 hr.
  • Step G Compound 32-e was replaced with compound 33-f according to step F of Example 32.
  • Step A A solution of LDA (2.0 M, 19.51 mL, 2 eq) in tetrahydrofuran (10 mL) was added dropwise to a solution of compound 34-1 (4 g, 19.51 mmol, 1 eq) in THF (10 mL). Stir for 1 hour. Then, DMF (2.14 g, 29.26 mmol, 2.25 mL, 1.5 eq) was added dropwise at -78 ° C and stirred for 1 hour.
  • Step B To a solution of compound 34-a (4.2 g, 9.01 mmol, 1 eq) in DME (20 mL), MeOH (1.77 g, 21.19 mmol, 2.35 eq) 3.2 g, 23.15 mmol, 2.57 eq), the reaction was stirred for 12 hours. After the reaction mixture was concentrated under reduced pressure, hydrazine hydrate (30mL) and N,N-dimethylacetamide (30mL) were added, and the reaction mixture was stirred at 150 ° C for 2 hours.
  • Step D To a solution of compound 34-c (590 mg, 2.45 mmol, 1 eq) in 1,4-dioxane (35 mL) was added bis-pinacol borate at 25 ° C under nitrogen atmosphere ( 1.24g, 4.89mmol, 2eq), KOAc (720.54mg, 7.34mmol, 3eq) and Pd(dppf)Cl 2 (358.14mg, 489.46umol, 0.2eq), the reaction system was replaced with nitrogen three times and heated to 100 ° C The mixture was stirred for 12 hours under a nitrogen atmosphere.
  • Step E Compound 32-e was replaced with compound 34-d according to step F of Example 32.
  • the residue obtained by work-up was purified by HPLC (column: Boston Green ODS 150mm*25mm*10um; mobile phase: [water (0.225%FA)-ACN]; ACN%: 35%-65%).
  • Separation and SFC (column: AD (250mm*30mm, 10um); mobile phase: [0.1% ammonia, methanol]; [0.1% ammonia, methanol]%: 40%-40%) Resolution separation to give compound 34-I (retention time: 2.790min)
  • Compound 34-II (retention time: 3.676 min).
  • Step A A 25 °C, a solution of compound 35-1 (0.6g, 2.30mmol, 1eq) in hydrochloric acid (12 mL) was added SnCl 2 .2H 2 O (5.19g, 22.98mmol, 10eq), the reaction system at 25 Stir at ° C for 0.5 hours.
  • Compound 35-a was concentrated.
  • Step D Compound 32-e was replaced with compound 35-c according to step F of Example 32.
  • the residue obtained by work-up was purified by HPLC (column: Boston Green ODS 150mm*25mm*5um; mobile phase: [water (0.225%FA)-ACN]; ACN%: 18%-48%) and SFC (column: AD (250mm*30mm, 10um); mobile phase: [0.1% ammonia, methanol]; [0.1% ammonia, methanol]%: 45%-45%), which was purified by resolution to give compound 35-I (retention time: 1.814 min) and Compound 35-II (retention time: 2.749 min).
  • PE: EA 1:1
  • Step C Compound 32-e was replaced with compound 36-b according to step F of Example 32.
  • PE: EA 2:1
  • Step C Compound 32-e was replaced with compound 37-b according to step F of Example 32.
  • Step A Compound 14-d was replaced with compound 32-e according to step F of Example 17.
  • the residue obtained by post-treatment was purified by preparative HPLC (column: Phenomenex Synergi C18 150mm*30mm*4um; mobile phase: [water (0.225%FA)-ACN]; ACN%: 40%-70%) Separation and purification and SFC (column) :AD(250mm*30mm, 10um); mobile phase: [0.1% ammonia, ethanol]; [0.1% ammonia, ethanol]%: 50%-50%) Resolution separation to give compound 38-I (retention time: 1.342min) And compound 38-II (retention time: 2.923 min).
  • Step A Compound 14-d was replaced with compound 33-f according to step F of Example 17.
  • Step A Compound 17 was added to a mixed solution of compound 34-d (320 mg, 1.11 mmol, 1.5 eq) in 1,4-dioxane (30 mL) and water (3 mL) at 25 ° C under nitrogen atmosphere.
  • - e (371.82 mg, 740.36 umol, 1 eq)
  • K 3 PO 4 (314.31 mg, 1.48 mmol, 2 eq)
  • Pd (dppf) Cl 2 108.34 mg, 148.07 umol, 0.2 eq.
  • the reaction system was purged with nitrogen three times and heated to 100 ° C and stirred under a nitrogen atmosphere for 2 hours.
  • Step A To a solution of compound 7-1 (1 g, 4.29 mmol, 1 eq) in DMF (16 mL), EtOAc (EtOAc, EtOAc, EtOAc 4 eq), the reaction system was warmed to 60 ° C and stirred for 12 hours. The reaction mixture was quenched with water (50 mL), EtOAc (EtOAc (EtOAc) Things. The residue was purified by column chromatography to give Compound 41-a.
  • Step C Following Compound 40 Step A, Compound 34-d was replaced with Compound 41-b.
  • Step A To a solution of compound 7-c (1 g, 3.47 mmol, 1 eq) in EtOAc (15 mL) Washed, EtOAc (20mL * 2) The reaction solution was extracted with saturated aqueous NH 4 Cl (20 mL), the organic phases were combined, saturated brine (20mL * 2) washed, dried over anhydrous Na 2 SO 4, filtered, and the filtrate concentrated in vacuo to give The residue. The residue was purified by column chromatography (EtOAc / EtOAc:EtOAc:
  • Step B Compound 34-d was replaced with compound 42-a according to step 40 of Example 40.
  • Step A Concentrated nitric acid (345.71 mg, 3.29 mmol, 246.93 uL, 2 eq) was added to a solution of compound 7-b (400 mg, 1.65 mmol, 1 eq) in acetic acid (2 mL). The reaction was stirred at 0 °C 1 hour, the reaction was poured into EtOAc (15mL), the organic phase was washed with saturated sodium bicarbonate solution (10mL * 2) was washed with saturated brine (10mL * 2), dried over anhydrous Na 2 SO 4 Dry, filter, and concentrate the filtrate in vacuo to give compound 43-a.
  • Step B Compound 43-a (400 mg, 1.40 mmol, 1 eq), pinacol bis-borate (532.58 mg, 2.10 mmol, 1.5 eq), KOAc (411.67 mg, 4.19) at 25 ° C under nitrogen.
  • Methyl, 3 eq) and Pd(dppf)Cl 2 (102.31 mg, 139.82 umol, 0.1 eq) were added to a solution of dioxane (8.00 mL), and the reaction was warmed to 90 ° C for 12 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure.
  • Step C Compound 34-d was replaced with compound 43-b according to step 40 of Example 40.
  • Step D at 25 °C, Compound 43-c (180mg, 286.40umol, 1eq), iron powder (47.98mg, 859.21umol, 3eq) and NH 4 Cl (45.96mg, 859.21umol, 30.04uL, 3eq) was added A mixed solution of EtOH (2 mL) and H 2 O (0.5 mL) was then warmed to 80 ° C and stirred for 6 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated in vacuo. The residue was poured into water (10mL) in dichloromethane 10mL * 2).
  • PE: EA 3:1
  • Step C Compound 17 was added to a mixed solution of compound 44-b (300 mg, 992.80 umol, 1.5 eq) in 1,4-dioxane (10 mL) and water (2 mL) at 25 ° C under nitrogen atmosphere.
  • -e (332.40 mg, 661.87 umol, 1 eq)
  • sPHOS-PD-G 95.39 mg, 132.37 umol, 0.2 eq
  • K 3 PO 4 280.98 mg, 1.32 mmol, 2 eq
  • Step A Concentrated nitric acid (4.43 g, 42.17 mmol, 3.16 mL, 1.3 eq) was added dropwise to a solution of compound 7-1 (5 g, 32.44 mmol, 1 eq) in concentrated sulfuric acid (50 mL) at -15 ° C. Stir at -15 ° C for 2 hours. The reaction droplets were added to water (200 mL), filtered, and filtered to afford compound 45-a.
  • Step B To a solution of compound 45-a (5.5 g, 27.62 mmol, 1 eq) in dimethyl sulfoxide (50 mL) was added hydrazine hydrate (4.88 g, 82.86 mmol, 4.74 mL, 3 eq) and carbonic acid at 25 ° C Potassium (7.63 g, 55.24 mmol, 2 eq), and the mixture was warmed to 80 ° C and stirred for 2 hours. The reaction droplets were added to water (200 mL), filtered, and filtered to afford compound 45-b.
  • Step D at 25 °C, EtOH solution of compound 45-c (1.68g, 6.11mmol, 1eq) in (20mL) and H 2 O (2mL) were added to a solution of iron powder (1.70g, 30.53mmol, 5eq), and Ammonium chloride (1.63 g, 30.53 mmol, 1.07 mL, 5 eq) was stirred and stirred at 80 ° C for 2 hours. The reaction solution was concentrated under reduced pressure to give Compound 45-d.
  • Step F Compound 34-d was replaced with compound 45-e according to step 40 of Example 40.
  • Purification and resolution gave compound 45-I (retention time: 1.764 min) and compound 45-II (retention time: 2.277 min).
  • Step B To a solution of compound 46-a (850 mg, 2.06 mmol, 1 eq) in water (0.5 mL) and DMF (5 mL) Sodium chloroacetate (1.57 g, 10.29 mmol, 5 eq) was added, and the reaction system was replaced with nitrogen three times and warmed to 110 ° C and stirred for 12 hours under nitrogen atmosphere.
  • Step C To a solution of compound 46-b (241 mg, 869.83 umol, 1 eq) in 1,4-dioxane (20 mL) at 25 ° C under a nitrogen atmosphere, respectively, bis-pinacol borate (265.06) Mg, 1.04 mmol, 1.2 eq), KOAc (170.73 mg, 1.74 mmol, 2 eq), and Pd(dppf)Cl 2 (63.65 mg, 86.98 umol, 0.1 eq), the reaction system was replaced with nitrogen three times and heated to 90 ° C The mixture was stirred for 12 hours under a nitrogen atmosphere. After the reaction mixture was cooled to room temperature, it was filtered, and then filtered, and then filtered and evaporated. The residue was purified by HPLC (column: Boston Green ODS 150mm*30mm*4um; mobile phase: [water (0.225%FA)-ACN]; B%: 50%-80%, 10.5 min) to afford compound 46-c.
  • Step D Following the procedure of Example 40 Step A, Compound 34-d was replaced with Compound 46-c.
  • Purification and SFC column chromatography (column: AD (250 mm*30 mm, 10 um); mobile phase: [0.1% ammonia, methanol]; [0.1% ammonia, methanol]%: 50%-50%)
  • Resolution of compound 46-I retention time: 2.306 min
  • compound 46-II retention time: 2.942 min
  • Step A Compound 47-1 (3.8 g, 13.24 mmol, 1 eq), iron powder (7.39 g, 132.35 mmol, 10 eq) and ammonium chloride (7.08 g, 132.35 mmol, 4.63 mL, 10 eq) at 15 °C
  • Formic acid 97% was added to a solution of isopropyl alcohol (80 mL), and the mixture was warmed to 70 ° C and stirred for 2 hours.
  • reaction solution was cooled to room temperature, and the reaction mixture was slowly added to an aqueous solution of potassium hydroxide (150 mL) and filtered, and the filtrate was extracted with ethyl acetate (200 mL*2), and the organic phase was combined and washed with saturated brine (100 mL*2) The organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to give compound 47-a.
  • potassium hydroxide 150 mL
  • ethyl acetate 200 mL*2
  • saturated brine 100 mL*2
  • Step B Compound 47-a (0.5 g, 1.87 mmol, 1 eq), bis-pinacol borate (950.64 mg, 3.74 mmol, 2 eq), potassium acetate (25 cc) was added to a three-necked flask at 25 ° C under nitrogen. 551.11 mg, 5.62 mmol, 3 eq), palladium acetate (84.05 mg, 374.36 umol, 0.2 eq) and ligand PCy3 (209.96 mg, 748.72 umol, 242.73 uL, 0.4 eq), followed by the addition of dioxane solution (8 mL). The reaction system was heated to 80 ° C and stirred for 12 hours.
  • reaction liquid was cooled to room temperature and filtered, and the filtrate was concentrated under reduced pressure to give residue.
  • residue was purified by HPLC (column: Phenomenex Synergi C18 150mm*30mm*4um; mobile phase: [water (0.225%FA)-ACN]; ACN%: 0% - 30%, 10.5 min) to give compound 47-b.
  • Step C Compound 34-d was replaced with compound 47-b according to step 40 of Example 40.
  • Step A Compound 34-d was replaced with compound 11-g according to step 40 of Example 40.
  • Step A A solution of the compound 18 in tetrahydrofuran (2 mL) was added dropwise to KHMDS (1M, 488.44 uL, 2 eq), and the mixture was warmed to 0 ° C for 30 minutes. The reaction solution was cooled to -78 ° C, MeI (103.99 mg, 732.66 umol, 45.61 uL, 3 eq) was added dropwise and stirred for 30 minutes. The reaction system was heated to 20 ° C and stirred for 1 hour.
  • Step C The compound 3-amino-5-chloro-1-methyl-pyridin-2-one was replaced with the compound 51-b according to the procedure of Steps C and D of Example 16. Post-treatment gave compound 51-c.
  • Step D Mix of compound 51-c (500 mg, 1.04 mmol, 1 eq) and 26-b (390 mg, 1.35 mmol, 1.3 eq) of dioxane (20 mL) and water (5 mL) at 25 ° C under nitrogen atmosphere Potassium phosphate (440 mg, 2.07 mmol, 2 eq) and Pd(dppf)Cl 2 (76 mg, 103.9 mmol, 0.1 eq) were added to the solution, and the mixture was warmed to 100 ° C and stirred under nitrogen for 12 hr. The reaction solution was cooled to room temperature, filtered, and the filtered cake was washed with EA (15 mL).
  • Step A A 0 °C, a solution of compound 52-1 (7.5g, 47.44mmol, 1eq) in DMF (40mL) was added K 2 CO 3 (13.11g, 94.88mmol , 2eq) and CH 3 I (13.02g , 91.73 mmol, 5.71 mL, 1.93 eq), the reaction system was warmed to 30 ° C and stirred for 12 hours. The reaction system was poured into water (200 mL), and ethyl acetate (100 mL*2) was evaporated.
  • Step C The compound 3-amino-5-chloro-1-methyl-pyridin-2-one was replaced with the compound 52-b according to the procedure of Steps C and D of Example 16. Work-up gives compound 52-c.
  • Step D Following the procedure of Example 51, compound 51-d was replaced with compound 52-c.
  • the residue obtained by work-up was separated and purified by preparative HPLC (column: Boston Green ODS 150mm*25mm*10um; mobile phase: [water (0.225%FA)-ACN]; ACN%: 42%-62%).
  • Step A NaH (313.15 mg, 7.83 mmol, 60% purity, 2 eq) was added to a solution of compound 53-1 (1 g, 3.91 mmol, 1 eq) in tetrahydrofuran (10 mL).
  • the reaction system was stirred for 11.5 hours.
  • the mixture was poured into (100 mL) water, (80mL * 3) extracted with EtOAc, washed, dried combined organic phases with saturated brine (100mL) Na 2 SO 4, filtered, and the filtrate was concentrated under reduced pressure to give a residue.
  • Step B Compound 28-c (1.5 g, 4.16 mmol, 1 eq) and compound 5-c (1.44 g, 4.99 mmol, 1.2 eq) of dioxane (20 mL) and water K 3 PO 4 (1.32 g, 6.24 mmol, 1.5 eq) and Pd(dppf)Cl 2 (243.46 mg, 332.73 umol, 0.08 eq) were added to the mixture of 6 mL), and the reaction system was heated to 80 ° C under nitrogen atmosphere. Stir for 24 hours.
  • Step C Compound 53-b (0.2 g, 407.30 umol, 1 eq), compound 53-a (188.52 mg, 488.76 umol, 1.2 eq), Xantphos (23.57 mg, 40.73 umol, 0.1) at 25 ° C under nitrogen. Eq), Cs 2 CO 3 (199.06 mg, 610.95 umol, 1.5 eq) and Pd 2 (dba) 3 (29.84 mg, 32.58 umol, 0.08 eq) dissolved in dioxane (2 mL), the reaction was warmed to 80 ° C Stir under a nitrogen atmosphere for 12 hours.
  • Step D To a solution of compound 53-c (0.07 g, 100.04 umol, 1 eq) in DCM (1 mL) was added TFA (22.81 mg, 200.08 umol, 14.81 uL, 2 eq) at 20 ° C. Stir for 24 hours. The reaction solution was concentrated under reduced pressure to give a residue.
  • Step B Compound 53-a was replaced with compound 54-a according to step C from Example 53.
  • the post-treated residue was purified by preparative HPLC (column: Phenomenex Synergi C18 150mm*25*10um; mobile phase: [water (0.225%FA)-ACN]; ACN%: 30%-60%) Separation and purification and SFC (column) : OD (250 mm * 30 mm, 10 um); mobile phase: [0.1% ammonia, methanol]; [0.1% ammonia, methanol]%: 35% - 35%) Compound 54 was isolated.
  • Step B Compound 53-a was replaced with compound 55-a according to step C of Example 53.
  • Step A A mixture of 6-methoxy-3-nitro-pyridin-2-amine (5.00 g, 29.56 mmol, 1.00 equiv) and NBS (5.52 g, 31.04 mmol, 1.05 eq.) in DMF (100.00 mL) Stir at 25 ° C for 12 hours. The mixture was quenched with water (500 mL) and a solid precipitate was collected by filtration to give 5-bromo-6-methoxy-3-nitro-pyridin-2-amine.
  • Step B 5-Bromo-6-methoxy-3-nitro-pyridin-2-amine (3.80 g, 15.32 mmol, 1.00 eq.) and NaH (919.24 mg, 22.98 mmol, 60% purity, 1.50 eq.)
  • a solution of DMF (30.00 mL) was stirred at 25 ° C for 0.5 h.
  • MeI (2.28 g, 16.09 mmol, 1.00 mL, 1.05 equivalent) was then added to the mixture.
  • the mixture was stirred at 25 °C for 0.5 h and the mixture was quenched with water (500 mL).
  • the solid precipitate was collected by filtration to give 5-bromo-6-methoxy-N-methyl-3-nitro-pyridin-2-amine.
  • Step C 5-Bromo-6-methoxy-N-methyl-3-nitro-pyridin-2-amine (1.00 g, 3.82 mmol, 1.00 eq.) and iron powder (2.13 g, 38.20 mmol, 10.00)
  • a mixture of HCOOH (10.00 mL) and i-PrOH (10.00 mL) was stirred at 80 ° C for 12 hours.
  • the mixture was filtered and the filtrate was adjusted to pH 8 with aqueous NaOH.
  • the mixture was extracted with EA (5 mL EtOAc) and brine.
  • the organic layer was concentrated under reduced pressure to give 5-methoxy-3-methyl-imidazo[4,5-b]pyridine.
  • Step E 6-Bromo-5-methoxy-3-methyl-imidazo[4,5-b]pyridine (400.00 mg, 1.65 mmol, 1.00 eq.), Pd (dppf) Cl 2 (120.73 mg, 165.00 ⁇ mol, 0.10 equivalent), KOAc (323.86 mg, 3.30 mmol, 2.00 eq.) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3, 2-Dioxaborolan-2-yl)-1,3,2-dioxaborolane (628.50 mg, 2.47 mmol, 1.50 equiv) in dioxane (10.00 mL) The mixture was replaced with nitrogen three times, and the mixture was stirred at 80 ° C for 12 hours.
  • Step F 2-Bromo-5-(5-chloro-1-methyl-2-oxo-3-pyridyl)-4-(4-chlorophenyl)-3-isopropyl-4H-pyrrole And [3,4-d]imidazole (10.00 mg, 20.15 umol, 1.00 equivalent), (5-methoxy-3-methyl-imidazo[4,5-b]pyridin-6-yl)boronic acid (4.59 Mg, 22.16 umol, 1.10 equivalents of a mixture of dioxane (300.00 ⁇ L) and water (100.00 ⁇ L) were added with S-Phos (413.61 ⁇ g, 1.01 ⁇ mol, 0.05 eq.) and K 3 PO 4 (6.42 mg, 30.22 ⁇ mol).
  • Step A Compound 57-1 (50 mg, 157 ⁇ mol, 1.50 eq), Compound 1-g (51.00 mg, 105 ⁇ mol, 1.00 eq), XPOS-PD-G2 (42 mg, 54 ⁇ mol, 0.50 eq), K 3 PO 4 (68.45 mg, 322 ⁇ mol, 3.00 eq) was added to a mixed solvent of dioxane (1 mL) and water (300.00 ⁇ L). The resulting mixture was then heated to 80 ° C and stirred for 2 hours. After cooling, the mixture was filtered and concentrated.
  • Step A To a solution of compound 35-b (40.00 mg, 84.39 umol, 1.05 eq.) and 1-g (40.00 mg, 80.61 umol, 1.00 eq.) of dioxane (1.50 mL) and H 2 O (400.00 uL) 3 PO 4 (34.22 mg, 161.22 umol, 2.00 eq.) and XPHOS-PD-G2 (11.62 mg, 16.12 umol, 0.20 eq.), and the reaction was stirred at 80 ° C for 3.5 hours under nitrogen atmosphere. The reaction solution was concentrated under reduced pressure to give a residue.
  • Step A A 0 °C, 2-amino-phenol (10.00g, 91.63mmol, 1.00 eq) in chloroform (100.00) was added TEBACl (8.51g, 45.82mmol, 7.95mL, 0.50 eq), NaHCO 3 ( 30.79 g, 366.52 mmol, 14.25 mL, 4.00 eq.) and 2-chloroacetyl chloride (15.52 g, 137.45 mmol, 10.93 mL, 1.50 eq.). The reaction mixture was then heated at 60 ° C for 60 hours. The reaction mixture was diluted with water (100 mL) then EtOAc.
  • Step B To a solution of tetrahydro-1,4-benzoxazin-3-one (5.00 g, 33.52 mmol, 1.00 eq.) in TFA (200.00 mL), EtOAc (17.30 g, 40.22 mmol, 1.20 eq. It was then heated at 80 ° C for 0.5 hours. The reaction mixture was poured into ice water (600 mL). The aqueous layer was extracted with EA (200 mL ⁇ 2). The combined organic layers were dried over anhydrous Na 2 SO 4, filtered, and concentrated to give a residue. The residue was purified by EtOAcqqq elut elut elut elut elut elut elut elut
  • Step D To a solution of 6-methoxy-4-methyl-1,4-benzoxazin-3-one (900.00 mg, 4.66 mmol, 1.00 equiv) in DCM (10.00 mL) (1.49 g, 1.00 equivalent), then stirred at 10 ° C for 12 hours. The reaction mixture was diluted with water (30 mL) and thenEtOAc. The combined organic layers were dried over anhydrous Na 2 SO 4, filtered, and concentrated to obtain a residue. The residue was purified by silica gel chromatography (EtOAc/EtOAc/EtOAc)
  • Step E a mixture of 7-bromo-6-methoxy-4-methyl-1,4-benzoxazin-3-one (150.00 mg, 551.29 umol, 1.00 eq.) in dioxane (5.00 mL) Add 4,4,5,5(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxa Boron heterocycle (209.99 mg, 826.94 ⁇ mol, 1.50 equiv), KOAc (115.99 mg, 1.65 mmol, 3.00 equiv) and Pd (dppf) Cl 2 (40.34 mg, 55.13 umol, 0.10 eq.), then replaced with nitrogen 3 Times.
  • Step F To 2-bromo-5-(5-chloro-1-methyl-2-oxo-3-pyridyl)-4-(4-chlorophenyl)-3-isopropyl-4H-pyrrole And [3,4-d] (80.00 mg, 161.23 umol, 1.00 equivalent) of dioxane (3.00 mL) and water (1.00 mL) were added 6-methoxy-4-methyl-7-(4) ,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,4-benzoxazin-3-one (102.92 mg, 322.46 ⁇ mol, 2.00 Equivalent), K 3 PO 4 (136.90 mg, 644.93 ⁇ mol, 4.00 equivalents) and [2-(2)-dioxaborolan-2-yl)-1,4-benzoxazine-3- Keto-aminophenyl)phenyl]-chloro-palladium; dicyclohexyl-[2-(2,6-
  • Step A To 1-bromo-2,4-difluoro-5-nitro-benzene (500.00 mg, 2.10 mmol, 1.00 eq.) and K 2 CO 3 (290.37 mg, 2.10 mmol, 1.00 eq. A mixture of propan-2-amine (124.19 mg, 2.10 mmol, 179.99 uL, 1.00 eq.) in THF (4.00 mL) was added. The mixture was then stirred at 0 ° C for 10 minutes and warmed to 15 ° C for 12 hours. The reaction mixture was filtered and the filtrate was concentrated to give 4-bromo-5-fluoro-N-isopropyl-2-nitro-phenylamine.
  • Step B An aqueous solution of KOH (1M, 25.00 mL, 12.32 eq.) was added dropwise to stirred 4-bromo-5-fluoro-N-isopropyl-2-nitro-phenylamine (563.00 mg, 2.03 mmol, 1.00 eq. In a solution of MeOH (5.00 mL) and THF (5.00 mL) until a yellow precipitate appeared. The mixture was stirred at 15 ° C for a further 30 minutes. The mixture was filtered to give a yellow solid. The residue was purified by silica gel chromatography eluting elut elut elut elut elut elut elut -aniline.
  • Step D Dissolving 4-bromo-N-isopropyl-5-methoxy-benzene-1,2-diamine (0.344 g, 663.73 umol, 1.00 eq.) in diethoxymethoxyethane ( 2.50 mL). TsOH.H 2 O (12.63 mg, 66.37 umol, 0.10 eq.) was added to the mixture and stirred at 15 ° C for 30 min. The mixture was concentrated under reduced pressure at 50 °C. The residue was purified by silica gel chromatography (EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc .
  • Step E 5-Bromo-1-isopropyl-6-methoxy-benzimidazole (0.213 g, 648.96 umol, 1.00 eq.), 4,4,5,5-tetramethyl-2-(4) ,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborane (329.59 mg, 1.30 mmol, 2.00 equivalents) ), KOAc (191.07 mg, 1.95 mmol, 3.00 equivalents), tricyclohexylphosphane (145.59 mg, 519.17 umol, 167.35 uL, 0.8 eq.) and Pd(OAc) 2 (58.28 mg, 259.59 umol, 0.4 eq.) The methane (5 mL) mixture was replaced with nitrogen and then heated to 90 ° C for 12 hours.
  • Step F 2-Bromo-5-(5-chloro-1-methyl-2-oxo-3-pyridyl)-4-(4-chlorophenyl)-3-isopropyl-4H-pyrrole And [3,4-d]imidazole-6-(40 mg, 80.62 umol, 1 equivalent), 1-isopropyl-6-methoxy-5-(4,4,5,5-tetramethyl-1 , 3,2-dioxaborolan-2-yl)benzimidazole (93.26 mg, 120.92 umol, 1.5 eq.), SPhos (33.09 mg, 80.62 umol, 1 eq.) and K 3 PO 4 (17.11 mg) 80.62 umol, 1 eq.) The nitrogen solution was replaced with a mixed solution of dioxane (2 mL) and H 2 O (0.4 mL), then heated to 100 ° C and stirred for 12 hours.
  • Step A In the same manner as in the preparation of Example 72, isopropylamine was replaced with ethylamine only in the step A of Example 61.
  • Step A 2-Bromo-5-(5-chloro-1-methyl-2-oxo-3-pyridyl)-4-(5-chloro-2-thienyl)-3-isopropyl-4H -pyrrolo[3,4-d]imidazol-6-one (0.4 g, 796.48 umol, 1 equivalent), 6-methoxy-1-methyl-5-(4,4,5,5-tetramethyl -1,3,2-dioxaborolan-2-yl)benzotriazole (454.52 mg, 1.19 mmol, 1.5 eq), [2-(2-aminophenyl)phenyl]-chloro -Palladium; Dicyclohexyl-[2-(2,6-dimethoxyphenyl)phenyl]phosphane (114.79 mg, 159.30 umol, 0.2 eq) and K 3 PO 4 (338.14 mg, 1.59 mmol, 2 Equivalent) Displacement of nitrogen in a mixture of di
  • Step A To 2-bromo-5-(5-chloro-1-methyl-2-oxo-3-pyridyl)-4-(5-chloro-2-thienyl)-3-isopropyl- Add 6-methoxy-1- to 4H-pyrrolo[3,2-4-d]imidazol-6-one (420 mg, 836.30 umol, 1 eq.) in dioxane (8 mL) and water (4 mL) Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[3,4-b]pyridine (460 mg , 1.10 mmol, 1.31 eq.), K 3 PO 4 (355.04 mg, 1.67 mmol, 2 eq.) and S-phos (120.53 mg, 167.26 ⁇ mol, 0.2 eq.).
  • Step A 4-Bromo-1,3-benzodioxole (150 mg, 746.20 umol, 1 eq.), triisopropyl borate (168.41 mg, 895.45 umol, 205.88) at -78 °C uL, 1.2 equivalents of THF (5 mL) was added dropwise n-BuLi (2.5 M, 447.72 uL, 1.5 eq.) and stirred for 3 hours. Then, the temperature was raised to 0 ° C, and the solution was acidified to pH 2 with 2M hydrochloric acid, and then neutralized to pH 7 with 2M aqueous NaOH. The reaction mixture was extracted with EA (10 mL ⁇ 2). The combined organic layer was dried over anhydrous Na 2 SO 4, filtered, and concentrated to give the crude product between 1,3-dioxol-4-yl boronic acid (crude product was used directly in the next step).
  • Step B To 2-bromo-5-(5-chloro-1-methyl-2-oxo-3-pyridyl)-4-(5-chloro-2-thienyl)-3-isopropyl- 4H-pyrrolo[3,2-4-d]imidazol-6-one (50 mg, 99.56 umol, 5.18 uL, 1 eq.) was added Pd in a mixed solution of dioxane (3 mL) and water (0.6 mL).
  • Step A 2-Bromo-5-(5-chloro-1-methyl-2-oxo-3-pyridyl)-4-(4-chlorophenyl)-3-isopropyl-4H-pyrrole And [3,4-d]imidazole (270 mg, 544.15 umol, 1 equivalent), 1-cyclopropyl-6-methoxy-5-(4,4,5,5-tetramethyl-1,3, 2-Dioxaborolan-2-yl)benzimidazole (205.16 mg, 652.98 ⁇ mol, 1.2 eq.), S-phos (78.43 mg, 108.83 umol, 0.2 eq.), K 3 PO 4 (231.01 mg) , 1.09mmol, 2 eq.) in dioxane (7 mL) and H 2 O mixture (1.4 mL of) is replaced with nitrogen three times, then the mixture was stirred under a nitrogen atmosphere at 80 °C 12 hours.
  • Step A The synthesis procedure is shown in Example 43-c.
  • the crude product was purified by column chromatography (EtOAc/EtOAc/EtOAc)
  • Step A To 2-bromo-5-[chloro-(4-chlorophenyl)methyl]-1-isopropyl-imidazole-4-carboxylic acid ethyl ester (1.04 g, 2.48 mmol, 1 eq.) and 3- To a solution of methoxyaniline (304.86 mg, 2.48 mmol, 277.14 uL, 1 eq.) in EtOAc (10 mL) EtOAc (EtOAc) After the mixture was stirred at 85 ° C for 12 hours, the mixture was concentrated in vacuo.
  • Step C 2-Bromo-5-[(4-chlorophenyl)-(3-methoxyanilino)methyl]-1-isopropyl-imidazole-4-carboxylic acid (0.65 g, 1.36 mmol
  • DIEA 350.94 mg, 2.72 mmol, 472.96 uL, 2 eq.
  • the mixture was replaced 3 times with nitrogen, and then the mixture was stirred at 60 ° C for 12 hours.
  • Step D To 2-bromo-4-(4-chlorophenyl)-3-isopropyl-5-(3-methoxyphenyl)-4H-pyrrolo[3,4-d]imidazole-6 - 6-methoxy-1-methyl-5-(4,4,5,5-tetramethyl) was added to a solution of ketone (300 mg, 651.11 umol, 1 eq.) in dioxane (10 mL) and water (4 mL) Base-1,3,2-dioxaborolan-2-yl)carbazole (244 mg, 846.78umol, 1.30 equivalents), K 3 PO 4 (277 mg, 1.30 mmol, 2 equivalents) and Pd (dppf) ) Cl 2 (60 mg, 82.00 umol, 0.126 equivalents).
  • Step A Steps A to D were prepared as in Example 69, and only in the step 69 of Example 69, 3-methoxyaniline was replaced with 3,4-dimethoxyaniline.
  • Step C To a solution of 2,6-dichloro-N-methoxy-N-methylnicotinamide (2.5 g, 10.84 mmol, 1 eq.) in THF (30 mL) , 4.70 mL, 1.3 eq.), then stirred for 12 hours. The reaction solution was poured into aqueous NH 4 Cl (100 mL) and then extracted with EA (80mL ⁇ 2). The combined organic layers were dried over anhydrous Na 2 SO 4, filtered, and concentrated to give the compound 1- (2-chloro-6-methoxy-3-pyridyl) ethanone.
  • Step D To a solution of 1-(2-chloro-6-methoxy-3-pyridinyl)ethanone (1.3 g, 7.00 mmol, 1 eq.) in EtOH (10 mL) MeOH (25.89 g, 168.59 Methyl, 29.59 mL, 24.07 equivalents, then heated at 90 °C for 12 hours. Concentration gave the residue. The residue was diluted with water (20 mL) then EtOAc (EtOAc) The combined organic layers were dried over anhydrous Na 2 SO 4, filtered, and concentrated to give compound 6-methoxy-1,3-dimethyl - pyrazolo [3,4-b] pyridine.
  • Step E Add NBS (2.21) to a solution of 6-methoxy-1,3-dimethyl-pyrazolo[3,4-b]pyridine (1.1 g, 6.21 mmol, 1 eq.) in MeCN (10 mL). g, 12.42 mmol, 2 eq.), then stirred at 20 ° C for 1 hour. It was diluted with a saturated aqueous solution of Na 2 SO 3 (40 mL) and then extracted with EA (40mL ⁇ 2).
  • Step F To 5-bromo-6-methoxy-1,3-dimethyl-pyrazolo[3,4-b]pyridine (1.5 g, 5.86 mmol, 1 eq.) of dioxane (30 mL) 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 1,3,2-dioxaborolane (2.97 g, 11.71 mmol, 2 equivalents), AcOK (1.72 g, 17.57 mmol, 3 eq.), Pd (dppf) Cl 2 (428.57 mg, 585.71 ⁇ mol, 0.1 equivalent), nitrogen was substituted 3 times, and then heated and stirred at 100 ° C for 12 hours.
  • Step G To 2-bromo-5-(5-chloro-1-methyl-2-oxo-3-pyridyl)-4-(5-chloro-2-thienyl)-3-isopropyl- 4H-Pyrolo[3,2-d]pyrimidin-4-yl]imidazol-6-one (500 mg, 995.60 umol, 1 eq.) was added to a mixture of dioxane (10 mL) and water (2 mL).
  • Step A To a solution of 5-bromo-6-methoxy-1-methyl-pyrazolo[3,4-b]pyridine (1.5 g, 6.20 mmol, 1 eq.) in MeCN (2 mL) 910.18 mg, 6.82 mmol, 1.1 eq.), AcOH (372.11 mg, 6.20 mmol, 354.39 uL, 1 eq.), then was replaced with nitrogen three times and then heated at 80 ° C for 2 hours.
  • Step B To 5-bromo-3-chloro-6-methoxy-1-methyl-pyrazolo[3,4-b]pyridine (1.6 g, 5.79 mmol, 1 eq.) of dioxane (30 mL) Add 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) to the solution -1,3,2-dioxaborolane (2.20 g, 8.68 mmol, 1.5 eq.), AcOK (1.70 g, 17.36 mmol, 3 eq.) and Pd(dppf)Cl 2 (423.39 mg, 578.63 ⁇ mol , 0.1 equivalent), then replaced with nitrogen three times, and then stirred at 100 ° C for 1 hour with heating. The reaction mixture was filtered through EtOAc (EtOAc m. 2-Dihydro-dioxaborolan-2-yl)pyrazolo[3,4-b]pyridine (cru
  • Step C To 2-bromo-5-(5-chloro-1-methyl-2-oxo-3-pyridyl)-4-(5-chloro-2-thienyl)-3-isopropyl- Add 4-chloro-6-methoxy to a mixture of 4H-pyrrolo[3,4-d]imidazol-6-one (500 mg, 995.60 umol, 1 eq.) in dioxane (10 mL) and water (2 mL) 1-methyl-5-(1H-1,2,4-triazolo[1,2-a]pyridin-4-yl]imidazol-6-one (1.61 g, 4.98 mmol, 5 eq) , K 3 PO 4 (634.01 mg, 2.99 mmol, 3 eq) and Pd (dppf) Cl 2 (72.85mg , 99.56umol, 0.1 eq) was purged with nitrogen three times, then heated and stirred for 1 hour at 100 °C.
  • the MDM2/p53 protein protein binding assay is detected by the TR-FRET method.
  • the specific steps were as follows: 3.46 times dilution of the test compound was performed with an Echo pipette (Labcyte), and each compound was diluted 11 concentrations and transferred to 250 nL to 384-well plates, respectively, with two duplicate wells per compound concentration. Wells with positive compounds (100% inhibition) were set as positive controls, and wells with only DMSO were used as negative controls.
  • the GST-MDM2 protein (R&D-E3-202-050) was diluted to 0.625 nM with buffer (125 mM NaCl, 1 mM DTT, 0.01% Gelatin (animal gelatin), 0.1% Pluronic f-127 (polyether), 1 PBS). Add 20 ⁇ L to the 384-well plate. After centrifugation, shake the 384-well plate in a 23 ° C incubator for 20 min.
  • the His-p53 protein (R&D-SP-450-020) was diluted to 12.5 nM with buffer and 20 ⁇ L was added to a 384-well plate. After centrifugation, the 384-well plate was incubated in a 23 ° C incubator for 60 min.
  • the Eu2+anti-GST antibody (Cisbio-61GSTKLB) and the XL665anti-His antibody (Cisbio-61HISXLB) were diluted with a buffer, and the resulting mixture was diluted to contain 0.3 nM of Eu2+anti-GST antibody and 9 nM of XL665 anti-His antibody.
  • the 50 values are shown in Table 1 below.
  • the SJSA-1 cell proliferation assay was detected by propidium iodide staining. Propidium iodide can not pass through the cell membrane of living cells, but can pass through the cell membrane of apoptotic cells, thereby staining the cells.
  • the specific steps are as follows: Separate the SJSA-1 cells in the logarithmic growth phase in the cell culture flask (from the cell bank of the PharmaTech) and count. SJSA-1 cells were diluted to 1 X 105 cells per ml with RPMI 1640 cell culture medium supplemented with 10% FBS, 1% double antibody and 1% L-glutamine.
  • cell lysate 150 mM NaCl, 2 mM Tris pH 7.5, 1 mM EDTA, 1 mM EGTA, 1% Triton X-100, ddH 2 O
  • cell lysate 150 mM NaCl, 2 mM Tris pH 7.5, 1 mM EDTA, 1 mM EGTA, 1% Triton X-100, ddH 2 O
  • inhibition rate (adding compound hole signal - negative control Signal) / (positive control signal - negative control signal) * 100%.
  • the compounds of the present invention show good activity in binding to MDM2 protein targets and inhibiting the growth of SJSA-1 tumor cells.
  • mice Female Balb/c mice were used as test animals, and the tail vein injection and oral cassette dosing were simultaneously applied to the positive reference compound NVP-HDM201 by LC/MS/MS method.
  • NVP-HDM201 and the inventive compounds 17-II and 18-II were formulated into a clear solution of 0.2 mg/mL in 5% DMSO / 40% PEG 400/55% water for intravenous injection and oral administration.
  • mice Six female Balb/c mice were administered intravenously at a dose of 0.5 mg/kg after one night of fasting, and the other three were administered orally at a dose of 2 mg/kg.
  • Blood samples were taken before administration and 0.08, 0.25, 0.5, 1, 2, 4, 8, and 24 hours after administration, placed in heparinized anticoagulation tubes, centrifuged at 7000 rpm (5204 g), and centrifuged at 4 ° C to separate plasma. Store at 80 ° C. Eat 4 hours after administration.
  • the content of the test compound in the plasma of the mouse after administration of iv and oral administration was determined by LC/MS/MS. Plasma samples were pre-treated with precipitated proteins for analysis.
  • the compounds of the present invention 17-II and 18-II have higher plasma exposure, higher oral bioavailability, and superior pharmacokinetics when administered orally at a dose of 2 mg/kg in mice. Nature of study.

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Abstract

一类具有咪唑并吡咯酮结构的p53-MDM2抑制剂的化合物，具体公开了式(II)所示化合物及其药学上可接受的盐。

Description

作为p53-MDM2抑制剂的咪唑并吡咯酮化合物
相关申请的交叉引用
本申请主张2017年3月6日提交的中国专利申请CN201710128142.X的优先权，其内容在此并入本申请。
技术领域
本发明涉及新的作为p53-MDM2抑制剂的的化合物，具体公开了式(II)所示化合物及其药学上可接受的盐。本发明还涉及作为p53-MDM2抑制剂的化合物或其药物组合物在制备治疗癌症、细菌感染、病毒感染的药物中的用途。
背景技术
p53是通过激活细胞周期停滞、凋亡、衰老和DNA修复中所涉及的许多基因的转录而响应于细胞应激的肿瘤抑制剂和转录因子。与p53激活是由不常见原因引起的正常细胞不同，肿瘤细胞处于来自包括缺氧和促凋亡癌基因激活在内的各种损害的恒定细胞应激下。因而，对肿瘤中p53途径的灭活具有强的选择性优势，并且已提出消除p53功能可能是肿瘤存活的前提。为了支持这一观点，三个调查研究组已经使用小鼠模型证明p53功能的缺少是已建立肿瘤的维持的持续要求。当调查研究人员恢复p53灭活的肿瘤的p53功能时，该肿瘤消退。
在50％的实体瘤和10％的液体瘤中，p53通过突变和/或缺失来进行灭活。在癌症中，p53途径的其他主要成员也发生遗传或表观遗传改变。MDM2是一种癌蛋白质，它抑制p53功能并且它以报道高达10％的发生率被基因扩增激活。MDM2继而被另一种肿瘤抑制剂p14ARF抑制。p53下游的改变被认为可能负责至少部分地灭活p53 WT肿瘤(p53野生型)中的p53途径。为了支持这一概念，一些p53 WT肿瘤似乎显示出降低的凋亡功能，但它们经受细胞周期停滞的能力仍然是完整的。一种癌症治疗策略涉及使用结合MDM2并抵消它与p53的相互作用的小分子。MDM2通过三种机制抑制p53活性：1)用作E3泛素连接酶以促进p53降解；2)结合至p53转录激活结构域并阻断p53转录激活结构域；以及3)从细胞核向细胞质输出p53。这三种机制都将通过抵消MDM2-p53相互作用来进行阻断。特别地，这种治疗策略可以应用于p53 WT肿瘤，并且利用小分子MDM2抑制剂进行的研究已经显示出肿瘤生长在体外和体内有希望地减小。进一步地，在患有p53-灭活的肿瘤的患者中，由MDM2抑制引起的正常组织中野生型p53的稳定化可能允许选择性地保护正常组织免受有丝分裂毒物的损害。
如本文所使用的，MDM2意指人MDM2蛋白，并且p53意指人p53蛋白。应注意，人MDM2也可以称为HDM2或hMDM2。
基于发展小分子抑制剂抑制p53和MDM2之间的相互作用来治疗肿瘤等疾病的研究已进行了多年，目前尚无该靶点药物上市，但已有多个分子进入不同的临床阶段。诺华公司开发的小分子p53-MDM2抑制剂NVP-HDM201目前已进入临床II期，用于治疗脂肪肉瘤，其在专利WO2013111105中公开，结构如下：
Figure PCTCN2018078010-appb-000001
已报道的NVP-HDM201分子的数据显示其体外活性较好，但PK性质有待进一步的改善。特别是药物在小鼠肝微粒体中稳定性较差，在小鼠中的半衰期短，药物血浆暴露量低。本发明在该药物分子基础上修饰了NVP-HDM201部分易代谢的位点，设计得到了一类新型的具有更高的小鼠血浆暴露量和小鼠口服生物利用度的化合物。
发明内容
本发明提供式(II)所示化合物或其药学上可接受的盐，
Figure PCTCN2018078010-appb-000002
其中，
环A选自苯基和5～6元杂芳基；
环B选自苯基和5～7元杂环基；
R 1选自任选被1、2或3个R取代的：5元杂芳基、苯基或6～10元杂环基；
R 2选自任选被1、2或3个R取代的：苯基或5～6元杂芳基；
R 3、R 4、R 5和R 7分别独立地选自H、卤素、OH、CN、NH 2、NO 2，或者分别独立地选自任选被1、2或3个R取代的：C 1-3烷基、C 1-3杂烷基、C 3-6环烷基；且R 3、R 4、R 5和R 7分别独立地位于环A或环B上；
R 6选自H，或者选自任选被1、2或3个R取代的：C 1-3烷基、C 1-6烯基和C 1-3杂烷基；
R选自卤素、OH、CN、NH 2，或者选自任选被1、2或3个R’取代的：C 1-3烷基、C 3-5环烷基和C 1-3杂烷基；
R’选自：F、Cl、Br、I、OH、CN、NH 2、CH 3、CH 3CH 2、CF 3、CHF 2、CH 2F、CH 3O；
所述5～6元杂芳基、5～7元杂环基、5元杂芳基、6～10元杂环基、C 1-3杂烷基之“杂”表示杂原子或杂原子团，分别独立地选自N、-NH-、-N(R)-、-O-、-S-、＝O、＝S和-C(＝O)-；
以上任何一种情况下，杂原子或杂原子团的数目分别独立地选自1、2或3。
在本发明的一些方案中，上述R选自：F、Cl、Br、I、OH、CN、NH 2、CH 3、CH 3CH 2、CF 3、CHF 2、CH 2F、CH 3O、环丙基。
在本发明的一些方案中，上述环A选自：苯基、吡咯基、吡啶基。
在本发明的一些方案中，上述结构单元
Figure PCTCN2018078010-appb-000003
选自：
Figure PCTCN2018078010-appb-000004
Figure PCTCN2018078010-appb-000005
在本发明的一些方案中，上述环B选自：1,3-二氧环戊基、1,3-二氧环戊烯基、苯基、异恶唑基、恶唑基、嘧啶-4(1H)-酮基、咪唑基、吡嗪基、吡咯基、1H-1,2,3-三唑基、2H-1,2,3-三唑基、1H-1,2,4-三唑基、4H-1,2,4-三唑基、3,4-二氢吡啶-2(1H)-酮基、吡唑基、恶唑-2(3H)-酮基、嘧啶基、4,5-二氢-1H-氮杂卓-2(3H)-酮基、吡啶基、1H-吡咯-2(3H)-酮基、吡咯烷-2-酮基、1,3-恶嗪-2-酮基、3,6-二氢-2H-1,3-嗪-2-酮基。
在本发明的一些方案中，上述结构单元
Figure PCTCN2018078010-appb-000006
选自：
Figure PCTCN2018078010-appb-000008
在本发明的一些方案中，上述结构单元
Figure PCTCN2018078010-appb-000009
选自：
Figure PCTCN2018078010-appb-000010
Figure PCTCN2018078010-appb-000011
在本发明的一些方案中，上述R 1选自任选被1、2或3个R取代的：噻唑基、苯基、吲哚基、吲唑基、异吲唑基、[1,2,4]三氮唑并[4,3-a]吡啶基、2-吡啶酮基、咪唑并(1,2-a)吡啶基、苯并[d][1,3]间二氧杂环戊烯基、2,3-苯并二氢[b][1,4]二氧六环基、苯并[d]恶唑-2(3H)-酮基。
在本发明的一些方案中，上述R 1选自任选被1、2或3个R取代的：
Figure PCTCN2018078010-appb-000012
Figure PCTCN2018078010-appb-000013
在本发明的一些方案中，上述R 1选自：
Figure PCTCN2018078010-appb-000014
Figure PCTCN2018078010-appb-000015
在本发明的一些方案中，上述R 2选自任选被1、2或3个R取代的：噻吩基、噻唑基、苯基。
在本发明的一些方案中，上述R 2选自任选被1、2或3个R取代的：
Figure PCTCN2018078010-appb-000016
在本发明的一些方案中，上述R 2选自：
Figure PCTCN2018078010-appb-000017
Figure PCTCN2018078010-appb-000018
在本发明的一些方案中，上述R 3、R 4、R 5和R 7分别独立地选自H、F、Cl、Br、I、OH、CN、NH 2、NO 2，或者分别独立地选自任选被1、2或3个R取代的：C 1-3烷基、C 1-3烷氧基、环丙基、环丁基。
在本发明的一些方案中，上述R 3、R 4、R 5和R 7分别独立地选自H、F、Cl、Br、I、OH、CN、NH 2、NO 2，或者分别独立地选自任选被1、2或3个R取代的：CH 3、
Figure PCTCN2018078010-appb-000019
环丙基。
在本发明的一些方案中，上述R 3、R 4、R 5和R 7分别独立地选自：H、F、Cl、Br、I、OH、CN、NH 2、NO 2、CH 3、CF 3、CHF 2、CH 2F、CHF 2O、CH 2FO、
Figure PCTCN2018078010-appb-000020
环丙基。
在本发明的一些方案中，上述结构单元
Figure PCTCN2018078010-appb-000021
选自：
Figure PCTCN2018078010-appb-000022
Figure PCTCN2018078010-appb-000023
在本发明的一些方案中，上述结构单元
Figure PCTCN2018078010-appb-000024
选自：
Figure PCTCN2018078010-appb-000025
Figure PCTCN2018078010-appb-000026
Figure PCTCN2018078010-appb-000027
在本发明的一些方案中，上述R 6选自：H、CH 3、
Figure PCTCN2018078010-appb-000028
或CH 2OH。
在本发明的一些方案中，上述R选自：F、Cl、Br、I、OH、CN、NH 2、CH 3、CH 3CH 2、CF 3、CHF 2、CH 2F、CH 3O、环丙基，其他变量如上述所定义。
在本发明的一些方案中，上述环A选自：苯基、吡咯基、吡啶基，其他变量如上述所定义。
在本发明的一些方案中，上述结构单元
Figure PCTCN2018078010-appb-000029
选自：
Figure PCTCN2018078010-appb-000030
Figure PCTCN2018078010-appb-000031
其他变量如上述所定义。
在本发明的一些方案中，上述环B选自：1,3-二氧环戊基、1,3-二氧环戊烯基、苯基、异恶唑基、恶唑基、嘧啶-4(1H)-酮基、咪唑基、吡嗪基、吡咯基、1H-1,2,3-三唑基、2H-1,2,3-三唑基、1H-1,2,4-三唑基、4H-1,2,4-三唑基、3,4-二氢吡啶-2(1H)-酮基、吡唑基、恶唑-2(3H)-酮基、嘧啶基、4,5-二氢-1H-氮杂卓-2(3H)-酮基、吡啶基、1H-吡咯-2(3H)-酮基、吡咯烷-2-酮基、1,3-恶嗪-2-酮基、3,6-二氢-2H-1,3-嗪-2-酮基，其他变量如上述所定义。
在本发明的一些方案中，上述结构单元
Figure PCTCN2018078010-appb-000032
选自：
Figure PCTCN2018078010-appb-000033
Figure PCTCN2018078010-appb-000034
Figure PCTCN2018078010-appb-000035
其他变量如上述所定义。
在本发明的一些方案中，上述结构单元
Figure PCTCN2018078010-appb-000036
选自：
Figure PCTCN2018078010-appb-000037
Figure PCTCN2018078010-appb-000038
Figure PCTCN2018078010-appb-000039
其他变量如上述所定义。
在本发明的一些方案中，上述R 1选自任选被1、2或3个R取代的：噻唑基、苯基、吲哚基、吲唑基、异吲唑基、[1,2,4]三氮唑并[4,3-a]吡啶基、2-吡啶酮基、咪唑并(1,2-a)吡啶基、苯并[d][1,3]间二氧杂环戊烯基、2,3-苯并二氢[b][1,4]二氧六环基、苯并[d]恶唑-2(3H)-酮基，其他变量如上述所定义。
在本发明的一些方案中，上述R 1选自任选被1、2或3个R取代的：
Figure PCTCN2018078010-appb-000040
Figure PCTCN2018078010-appb-000041
其他变量如上述所定义。
在本发明的一些方案中，上述R 1选自：
Figure PCTCN2018078010-appb-000042
Figure PCTCN2018078010-appb-000043
Figure PCTCN2018078010-appb-000044
其他变量如上述所定义。
在本发明的一些方案中，上述R 2选自任选被1、2或3个R取代的：噻吩基、噻唑基、苯基，其他变量如上述所定义。
在本发明的一些方案中，上述R 2选自任选被1、2或3个R取代的：
Figure PCTCN2018078010-appb-000045
其他变量如上述所定义。
在本发明的一些方案中，上述R 2选自：
Figure PCTCN2018078010-appb-000046
Figure PCTCN2018078010-appb-000047
其他变量如上述所定义。
在本发明的一些方案中，上述R 3、R 4、R 5和R 7分别独立地选自H、F、Cl、Br、I、OH、CN、NH 2、NO 2，或者分别独立地选自任选被1、2或3个R取代的：C 1-3烷基、C 1-3烷氧基、环丙基、环丁基，其他变量如上述所定义。
在本发明的一些方案中，上述R 3、R 4、R 5和R 7分别独立地选自H、F、Cl、Br、I、OH、CN、NH 2、NO 2，或者分别独立地选自任选被1、2或3个R取代的：CH 3、
Figure PCTCN2018078010-appb-000048
环丙基，其他变量如上述所定义。
在本发明的一些方案中，上述R 3、R 4、R 5和R 7分别独立地选自：H、F、Cl、Br、I、OH、CN、NH 2、NO 2、CH 3、CF 3、CHF 2、CH 2F、CHF 2O、CH 2FO、
Figure PCTCN2018078010-appb-000049
环丙基，其他变量如上述所定义。
在本发明的一些方案中，上述结构单元
Figure PCTCN2018078010-appb-000050
选自：
Figure PCTCN2018078010-appb-000051
Figure PCTCN2018078010-appb-000052
Figure PCTCN2018078010-appb-000053
Figure PCTCN2018078010-appb-000054
其他变量如上述所定义。
在本发明的一些方案中，上述结构单元
Figure PCTCN2018078010-appb-000055
选自：
Figure PCTCN2018078010-appb-000056
Figure PCTCN2018078010-appb-000057
Figure PCTCN2018078010-appb-000058
Figure PCTCN2018078010-appb-000059
其他变量如上述所定义。
在本发明的一些方案中，上述R 6选自：H、CH 3、
Figure PCTCN2018078010-appb-000060
或CH 2OH。
在本发明的一些方案中，上述化合物选自：
Figure PCTCN2018078010-appb-000061
Figure PCTCN2018078010-appb-000062
其中，R 3、R 4、R 5、R 6、R 7和R如上述所定义。
本发明还提供化合物或其药学上可接受的盐，其中，化合物选自：
Figure PCTCN2018078010-appb-000063
Figure PCTCN2018078010-appb-000064
Figure PCTCN2018078010-appb-000065
Figure PCTCN2018078010-appb-000066
Figure PCTCN2018078010-appb-000067
在本发明的一些方案中，上述化合物选自
Figure PCTCN2018078010-appb-000068
Figure PCTCN2018078010-appb-000069
Figure PCTCN2018078010-appb-000070
Figure PCTCN2018078010-appb-000071
Figure PCTCN2018078010-appb-000072
Figure PCTCN2018078010-appb-000073
本发明提供了式(I)所示化合物或其药学上可接受的盐
Figure PCTCN2018078010-appb-000074
其中，
环A选自：苯基、5～6元杂芳基；
环B选自：苯基、5～7元杂环基；
R 1选自任选被1、2或3个R取代的：5元杂芳基、苯、6～9元杂环基；
R 2选自任选被1、2或3个R取代的：苯或5～6元杂芳基；
R 3、R 4、R 5分别独立地选自H、卤素、OH、CN，或者分别独立地选自任选被1、2或3个R取代的：C 1-3烷基或C 1-3杂烷基；
R 6选自：H或C 1-3烷基；
R选自卤素、OH、CN、NH 2，或选自任选被1、2或3个R’取代的：C 1-3烷基、C 3-5环烷基或C 1-3杂烷基；
R’选自：F、Cl、Br、I、OH、CN、NH 2、CH 3、CH 3CH 2、CF 3、CHF 2、CH 2F、CH 3O；
所述5～6元杂芳基、5～7元杂环基、5元杂芳基、6～9元杂环基、C 1-3杂烷基之“杂”，分别独立地选自：N、-NH-、-N(R)-、-O-、-S-、＝O、＝S、-C(＝O)-；
以上任何一种情况下，杂原子或杂原子团的数目分别独立地选自1、2或3。
在本发明的一些方案中，上述R选自：F、Cl、Br、I、OH、CN、NH 2、CH 3、CH 3CH 2、CF 3、CHF 2、CH 2F、CH 3O、环丙基。
在本发明的一些方案中，上述环A选自：苯基、吡咯基、吡啶基。
在本发明的一些方案中，上述结构单元
Figure PCTCN2018078010-appb-000075
选自：
Figure PCTCN2018078010-appb-000076
Figure PCTCN2018078010-appb-000077
在本发明的一些方案中，上述环B选自：1,3-二氧环戊基、1,3-二氧环戊烯基、苯基、异恶唑基、嘧啶-4(1H)-酮基、咪唑基、吡嗪基、吡咯基、1H-1,2,3-三唑基、2H-1,2,3-三唑基、1H-1,2,4-三唑基、4H-1,2,4-三唑基、3,4-二氢吡啶-2(1H)-酮基、吡唑基、恶唑-2(3H)-酮基、嘧啶基、4,5-二氢-1H-氮杂卓-2(3H)-酮基。
在本发明的一些方案中，上述结构单元
Figure PCTCN2018078010-appb-000078
选自：
Figure PCTCN2018078010-appb-000079
Figure PCTCN2018078010-appb-000080
在本发明的一些方案中，上述结构单元
Figure PCTCN2018078010-appb-000081
选自：
Figure PCTCN2018078010-appb-000082
Figure PCTCN2018078010-appb-000083
在本发明的一些方案中，上述R 1选自任选被1、2或3个R取代的：噻唑基、苯、吲哚基、吲唑基、异吲唑基、[1,2,4]三氮唑并[4,3-a]吡啶基、2-吡啶酮基、咪唑并(1,2-a)吡啶基。
在本发明的一些方案中，上述R 1选自任选被1、2或3个R取代的：
Figure PCTCN2018078010-appb-000084
Figure PCTCN2018078010-appb-000085
在本发明的一些方案中，上述R 1选自：
Figure PCTCN2018078010-appb-000086
Figure PCTCN2018078010-appb-000087
在本发明的一些方案中，上述R 2选自任选被1、2或3个R取代的：噻吩基、噻唑基、苯基。
在本发明的一些方案中，上述R 2选自任选被1、2或3个R取代的：
Figure PCTCN2018078010-appb-000088
在本发明的一些方案中，上述R 2选自：
Figure PCTCN2018078010-appb-000089
Figure PCTCN2018078010-appb-000090
在本发明的一些方案中，上述R 3、R 4、R 5分别独立地选自H、F、Cl、Br、I、OH、CN，或者分别独立地选自任选被1、2或3个R取代的：C 1-3烷基、C 1-3烷氧基。
在本发明的一些方案中，上述R 3、R 4、R 5分别独立地选自H、F、Cl、Br、I、OH、CN，或者分别独立地选自任选被1、2或3个R取代的：CH 3、
Figure PCTCN2018078010-appb-000091
在本发明的一些方案中，上述R 3、R 4、R 5分别独立地选自H、F、Cl、Br、I、OH、CN、CH 3、
Figure PCTCN2018078010-appb-000092
Figure PCTCN2018078010-appb-000093
在本发明的一些方案中，上述结构单元
Figure PCTCN2018078010-appb-000094
选自：
Figure PCTCN2018078010-appb-000095
Figure PCTCN2018078010-appb-000096
在本发明的一些方案中，上述结构单元
Figure PCTCN2018078010-appb-000097
选自：
Figure PCTCN2018078010-appb-000098
Figure PCTCN2018078010-appb-000099
Figure PCTCN2018078010-appb-000100
在本发明的一些方案中，上述R 6选自H或
Figure PCTCN2018078010-appb-000101
在本发明的一些方案中，上述化合物或其药学上可接受的盐，其中，化合物选自：
Figure PCTCN2018078010-appb-000102
Figure PCTCN2018078010-appb-000103
其中，R 3、R 4、R 6、R如上述所定义。
本发明还提供了化合物或其药学上可接受的盐，其中，化合物选自：
Figure PCTCN2018078010-appb-000104
Figure PCTCN2018078010-appb-000105
Figure PCTCN2018078010-appb-000106
在本发明的一些方案中，上述化合物或其药学上可接受的盐，其中，化合物选自
Figure PCTCN2018078010-appb-000107
Figure PCTCN2018078010-appb-000108
Figure PCTCN2018078010-appb-000109
本发明还提供一种药物组合物，包括治疗有效量的上述的化合物或其药学上可接受的盐作为活性成分以及药学上可接受的载体。
本发明还提供上述的化合物或其药学上可接受的盐在制备治疗癌症、细菌感染、病毒感染的药物上的应用。
本发明还提供上述的药物组合物在制备治疗癌症、细菌感染、病毒感染的药物上的应用。
在本发明的一些方案中，上述环A选自：苯基、吡咯基、吡啶基，其他变量如上述所定义。
在本发明的一些方案中，上述结构单元
Figure PCTCN2018078010-appb-000110
选自：
Figure PCTCN2018078010-appb-000111
Figure PCTCN2018078010-appb-000112
其他变量如上述所定义。
在本发明的一些方案中，上述环B选自：1,3-二氧环戊基、1,3-二氧环戊烯基、苯基、异恶唑基、嘧啶-4(1H)-酮基、咪唑基、吡嗪基、吡咯基、1H-1,2,3-三唑基、2H-1,2,3-三唑基、1H-1,2,4-三唑基、4H-1,2,4-三唑基、3,4-二氢吡啶-2(1H)-酮基、吡唑基、恶唑-2(3H)-酮基、嘧啶基、4,5-二氢-1H-氮杂卓-2(3H)-酮基，其他变量如上述所定义。
在本发明的一些方案中，上述结构单元
Figure PCTCN2018078010-appb-000113
选自：
Figure PCTCN2018078010-appb-000114
Figure PCTCN2018078010-appb-000115
其他变量如上述所定义。
在本发明的一些方案中，上述结构单元
Figure PCTCN2018078010-appb-000116
选自：
Figure PCTCN2018078010-appb-000117
Figure PCTCN2018078010-appb-000118
Figure PCTCN2018078010-appb-000119
其他变量如上述所定义。
在本发明的一些方案中，上述R 1选自任选被1、2或3个R取代的：噻唑基、苯、吲哚基、吲唑基、异吲唑基、[1,2,4]三氮唑并[4,3-a]吡啶基、2-吡啶酮基、咪唑并(1,2-a)吡啶基，其他变量如上述所定 义。
在本发明的一些方案中，上述R 1选自任选被1、2或3个R取代的：
Figure PCTCN2018078010-appb-000120
Figure PCTCN2018078010-appb-000121
其他变量如上述所定义。
在本发明的一些方案中，上述R 1选自：
Figure PCTCN2018078010-appb-000122
Figure PCTCN2018078010-appb-000123
其他变量如上述所定义。
在本发明的一些方案中，上述R 2选自任选被1、2或3个R取代的：噻吩基、噻唑基、苯基，其他变量如上述所定义。
在本发明的一些方案中，上述R 2选自任选被1、2或3个R取代的：
Figure PCTCN2018078010-appb-000124
其他变量如上述所定义。
在本发明的一些方案中，上述R 2选自：
Figure PCTCN2018078010-appb-000125
Figure PCTCN2018078010-appb-000126
其他变量如上述所定义。
在本发明的一些方案中，上述R 3、R 4、R 5分别独立地选自H、F、Cl、Br、I、OH、CN，或者分别独立地选自任选被1、2或3个R取代的：C 1-3烷基、C 1-3烷氧基，其他变量如上述所定义。
在本发明的一些方案中，上述R 3、R 4、R 5分别独立地选自H、F、Cl、Br、I、OH、CN，或者分别独立地选自任选被1、2或3个R取代的：CH 3、
Figure PCTCN2018078010-appb-000127
其他变量如上述所定义。
在本发明的一些方案中，上述R 3、R 4、R 5分别独立地选自H、F、Cl、Br、I、OH、CN、CH 3、
Figure PCTCN2018078010-appb-000128
Figure PCTCN2018078010-appb-000129
其他变量如上述所定义。
在本发明的一些方案中，上述结构单元
Figure PCTCN2018078010-appb-000130
选自：
Figure PCTCN2018078010-appb-000131
Figure PCTCN2018078010-appb-000132
Figure PCTCN2018078010-appb-000133
其他变量如上述所定义。
在本发明的一些方案中，上述结构单元
Figure PCTCN2018078010-appb-000134
选自：
Figure PCTCN2018078010-appb-000135
Figure PCTCN2018078010-appb-000136
Figure PCTCN2018078010-appb-000137
Figure PCTCN2018078010-appb-000138
其他变量如上述所定义。
在本发明的一些方案中，上述R 6选自H或
Figure PCTCN2018078010-appb-000139
其他变量如上述所定义。
本发明还有一些方案是由上述各变量任意组合而来。
本发明涉及能够抑制p53和MDM2之间的相互作用并且能够激活p53下游效应基因的化合物。因此，本发明化合物将可用于治疗癌症、细菌感染、病毒感染、溃疡和炎症。特别地，本发明化合物可用于治疗诸如乳腺肿瘤、结肠肿瘤、肺肿、食管肿瘤和前列腺肿瘤等实体瘤以及诸如淋巴瘤和白血病的液体瘤。
技术效果
本发明涉及的具有咪唑并吡咯酮结构的药物分子明显有别于较早专利报道的p53-MDM2抑制剂，该药物分子能够抑制p53和MDM2之间的相互作用同时激活p53下游效应基团。在体外实验中具有咪唑并吡咯酮结构的药物分子与MDM2蛋白靶点的结合和抑制SJSA-1肿瘤细胞生长方面表现出良好的活性。此外，在小鼠的体内实验中，该药物分子相较于参比分子表现出更加优异的PK性质。基于此，我们预测本发明涉及的具有咪唑并吡咯酮结构的药物分子将可用于治疗诸如乳腺肿瘤、结肠肿瘤、肺肿、食管肿瘤和前列腺肿瘤等实体瘤以及诸如淋巴瘤和白血病的液体瘤等癌症、细菌感染、病毒感染、溃疡和炎症。
定义和说明
除非另有说明，本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。这里所采用的术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。
术语“药学上可接受的盐”是指本发明化合物的盐，由本发明发现的具有特定取代基的化合物与相对无毒的酸或碱制备。当本发明的化合物中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物的中性形式接触的方式获得碱加成盐。药学上可接受的碱加成盐包括钠、钾、钙、铵、有机氨或镁盐或类似的盐。当本发明的化合物中含有相对碱性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与这类化合物的中性形式接触的方式获得酸加成盐。 药学上可接受的酸加成盐的实例包括无机酸盐，所述无机酸包括例如盐酸、氢溴酸、硝酸、碳酸，碳酸氢根，磷酸、磷酸一氢根、磷酸二氢根、硫酸、硫酸氢根、氢碘酸、亚磷酸等；以及有机酸盐，所述有机酸包括如乙酸、丙酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸和甲磺酸等类似的酸；还包括氨基酸(如精氨酸等)的盐，以及如葡糖醛酸等有机酸的盐(参见Berge et al.,"Pharmaceutical Salts",Journal of Pharmaceutical Science 66:1-19(1977))。本发明的某些特定的化合物含有碱性和酸性的官能团，从而可以被转换成任一碱或酸加成盐。
优选地，以常规方式使盐与碱或酸接触，再分离母体化合物，由此再生化合物的中性形式。化合物的母体形式与其各种盐的形式的不同之处在于某些物理性质，例如在极性溶剂中的溶解度不同。
本文所用的“药学上可接受的盐”属于本发明化合物的衍生物，其中，通过与酸成盐或与碱成盐的方式修饰所述母体化合物。药学上可接受的盐的实例包括但不限于：碱基比如胺的无机酸或有机酸盐、酸根比如羧酸的碱金属或有机盐等等。药学上可接受的盐包括常规的无毒性的盐或母体化合物的季铵盐，例如无毒的无机酸或有机酸所形成的盐。常规的无毒性的盐包括但不限于那些衍生自无机酸和有机酸的盐，所述的无机酸或有机酸选自2-乙酰氧基苯甲酸、2-羟基乙磺酸、乙酸、抗坏血酸、苯磺酸、苯甲酸、碳酸氢根、碳酸、柠檬酸、依地酸、乙烷二磺酸、乙烷磺酸、富马酸、葡庚糖、葡糖酸、谷氨酸、乙醇酸、氢溴酸、盐酸、氢碘酸盐、羟基、羟萘、羟乙磺酸、乳酸、乳糖、十二烷基磺酸、马来酸、苹果酸、扁桃酸、甲烷磺酸、硝酸、草酸、双羟萘酸、泛酸、苯乙酸、磷酸、多聚半乳糖醛、丙酸、水杨酸、硬脂酸、亚乙酸、琥珀酸、氨基磺酸、对氨基苯磺酸、硫酸、单宁、酒石酸和对甲苯磺酸。
本发明的药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下，这样的盐的制备方法是：在水或有机溶剂或两者的混合物中，经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。一般地，优选醚、乙酸乙酯、乙醇、异丙醇或乙腈等非水介质。
除了盐的形式，本发明所提供的化合物还存在前药形式。本文所描述的化合物的前药容易地在生理条件下发生化学变化从而转化成本发明的化合物。此外，前体药物可以在体内环境中通过化学或生化方法被转换到本发明的化合物。
本发明的某些化合物可以以非溶剂化形式或者溶剂化形式存在，包括水合物形式。一般而言，溶剂化形式与非溶剂化的形式相当，都包含在本发明的范围之内。
本发明的某些化合物可以具有不对称碳原子(光学中心)或双键。外消旋体、非对映异构体、几何异构体和单个的异构体都包括在本发明的范围之内。
除非另有说明，用楔形实线键
Figure PCTCN2018078010-appb-000140
和楔形虚线键
Figure PCTCN2018078010-appb-000141
表示一个立体中心的绝对构型，用波浪线
Figure PCTCN2018078010-appb-000142
表示楔形实线键
Figure PCTCN2018078010-appb-000143
或楔形虚线键
Figure PCTCN2018078010-appb-000144
用直形实线键
Figure PCTCN2018078010-appb-000145
和直形虚线键
Figure PCTCN2018078010-appb-000146
表示立体中心的相对构型。当本文所述化合物含有烯属双键或其它几何不对称中心，除非另有规定，它们包括E、Z几何异构体。同样地，所有的互变异构形式均包括在本发明的范围之内。
本发明的化合物可以存在特定的几何或立体异构体形式。本发明设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本发 明的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本发明的范围之内。
可以通过的手性合成或手性试剂或者其他常规技术制备光学活性的(R)-和(S)-异构体以及D和L异构体。如果想得到本发明某化合物的一种对映体，可以通过不对称合成或者具有手性助剂的衍生作用来制备，其中将所得非对映体混合物分离，并且辅助基团裂开以提供纯的所需对映异构体。或者，当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时，与适当的光学活性的酸或碱形成非对映异构体的盐，然后通过本领域所公知的常规方法进行非对映异构体拆分，然后回收得到纯的对映体。此外，对映异构体和非对映异构体的分离通常是通过使用色谱法完成的，所述色谱法采用手性固定相，并任选地与化学衍生法相结合(例如由胺生成氨基甲酸盐)。
本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氚( 3H)，碘-125( 125I)或C-14( 14C)。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包括在本发明的范围之内。
术语“药学上可接受的载体”是指能够递送本发明有效量活性物质、不干扰活性物质的生物活性并且对宿主或者患者无毒副作用的任何制剂或载体介质代表性的载体包括水、油、蔬菜和矿物质、膏基、洗剂基质、软膏基质等。这些基质包括悬浮剂、增粘剂、透皮促进剂等。它们的制剂为化妆品领域或局部药物领域的技术人员所周知。关于载体的其他信息，可以参考Remington:The Science and Practice of Pharmacy,21st Ed.,Lippincott,Williams & Wilkins(2005)，该文献的内容通过引用的方式并入本文。
术语“赋形剂”通常是指配制有效的药物组合物所需要载体、稀释剂和/或介质。
针对药物或药理学活性剂而言，术语“有效量”或“治疗有效量”是指无毒的但能达到预期效果的药物或药剂的足够用量。对于本发明中的口服剂型，组合物中一种活性物质的“有效量”是指与该组合物中另一种活性物质联用时为了达到预期效果所需要的用量。有效量的确定因人而异，取决于受体的年龄和一般情况，也取决于具体的活性物质，个案中合适的有效量可以由本领域技术人员根据常规试验确定。
术语“活性成分”、“治疗剂”，“活性物质”或“活性剂”是指一种化学实体，它可以有效地治疗目标紊乱、疾病或病症。
“任选”或“任选地”指的是随后描述的事件或状况可能但不是必需出现的，并且该描述包括其中所述事件或状况发生的情况以及所述事件或状况不发生的情况。
术语“被取代的”是指特定原子上的任意一个或多个氢原子被取代基取代，可以包括重氢和氢的变体，只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为酮基(即＝O)时，意味着两个氢原子被取代。酮取代不会发生在芳香基上。术语“任选被取代的”是指可以被取代，也可以不被取代，除非另有规定，取代基的种类和数目在化学上可以实现的基础上可以是任意的。
当任何变量(例如R)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。因此，例如，如果一个基团被0-2个R所取代，则所述基团可以任选地至多被两个R所取代，并且每种情况下的R都有独立的选项。此外，取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
当一个连接基团的数量为0时，比如-(CRR) 0-，表示该连接基团为单键。
当其中一个变量选自单键时，表示其连接的两个基团直接相连，比如A-L-Z中L代表单键时表示该结构实际上是A-Z。
当一个取代基为空缺时，表示该取代基是不存在的，比如A-X中X为空缺时表示该结构实际上是A。当一个取代基可以连接到一个环上的一个以上原子时，这种取代基可以与这个环上的任意原子相键合，例如，结构单元
Figure PCTCN2018078010-appb-000147
表示取代基R可在环己基或者环己二烯上的任意一个位置发生取代。当所列举的取代基中没有指明其通过哪一个原子连接到被取代的基团上时，这种取代基可以通过其任何原子相键合，例如，吡啶基作为取代基可以通过吡啶环上任意一个碳原子连接到被取代的基团上。当所列举的连接基团没有指明其连接方向，其连接方向是任意的，例如，
Figure PCTCN2018078010-appb-000148
中连接基团L为-M-W-，此时-M-W-既可以按与从左往右的读取顺序相同的方向连接环A和环B构成
Figure PCTCN2018078010-appb-000149
也可以按照与从左往右的读取顺序相反的方向连接环A和环B构成
Figure PCTCN2018078010-appb-000150
所述连接基团、取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
除非另有规定，术语“杂”表示杂原子或杂原子团(即含有杂原子的原子团)，包括碳(C)和氢(H)以外的原子以及含有这些杂原子的原子团，例如包括氧(O)、氮(N)、硫(S)、硅(Si)、锗(Ge)、铝(Al)、硼(B)、-O-、-S-、＝O、＝S、-C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)、-S(＝O) 2-，以及任选被取代的-C(＝O)N(H)-、-N(H)-、-C(＝NH)-、-S(＝O) 2N(H)-或-S(＝O)N(H)-。
除非另有规定，“环”表示被取代或未被取代的环烷基、杂环烷基、环烯基、杂环烯基、环炔基、杂环炔基、芳基或杂芳基。所谓的环包括单环、联环、螺环、并环或桥环。环上原子的数目通常被定义为环的元数，例如，“5～7元环”是指环绕排列5～7个原子。除非另有规定，该环任选地包含1～3个杂原子。因此，“5～7元环”包括例如苯基、吡啶和哌啶基；另一方面，术语“5～7元杂环烷基环”包括吡啶基和哌啶基，但不包括苯基。术语“环”还包括含有至少一个环的环系，其中的每一个“环”均独立地符合上述定义。
除非另有规定，术语“杂环”或“杂环基”意指稳定的含杂原子或杂原子团的单环、双环或三环，它们可以是饱和的、部分不饱和的或不饱和的(芳族的)，它们包含碳原子和1、2、3或4个独立地选自N、O和S的环杂原子，其中上述任意杂环可以稠合到一个苯环上形成双环。氮和硫杂原子可任选被氧化(即NO和S(O)p，p是1或2)。氮原子可以是被取代的或未取代的(即N或NR，其中R是H或本文已经定义过的其他取代基)。该杂环可以附着到任何杂原子或碳原子的侧基上从而形成稳定的结构。如果产生的化合物是稳定的，本文所述的杂环可以发生碳位或氮位上的取代。杂环中的氮原子任选地被季铵化。一个优选方案是，当杂环中S及O原子的总数超过1时，这些杂原子彼此不相邻。另一个优选方案是，杂环中S及O原子的总数不超过1。如本文所用，术语“芳族杂环基团”或“杂芳基”意指稳定 的5、6、7元单环或双环或7、8、9或10元双环杂环基的芳香环，它包含碳原子和1、2、3或4个独立地选自N、O和S的环杂原子。氮原子可以是被取代的或未取代的(即N或NR，其中R是H或本文已经定义过的其他取代基)。氮和硫杂原子可任选被氧化(即NO和S(O)p，p是1或2)。值得注意的是，芳香杂环上S和O原子的总数不超过1。桥环也包含在杂环的定义中。当一个或多个原子(即C、O、N或S)连接两个不相邻的碳原子或氮原子时形成桥环。优选的桥环包括但不限于：一个碳原子、两个碳原子、一个氮原子、两个氮原子和一个碳-氮基。值得注意的是，一个桥总是将单环转换成三环。桥环中，环上的取代基也可以出现在桥上。
杂环化合物的实例包括但不限于：吖啶基、吖辛因基、苯并咪唑基、苯并呋喃基、苯并巯基呋喃基、苯并巯基苯基、苯并恶唑基、苯并恶唑啉基、苯并噻唑基、苯并三唑基、苯并四唑基、苯并异恶唑基、苯并异噻唑基、苯并咪唑啉基、咔唑基、4aH-咔唑基、咔啉基、苯并二氢吡喃基、色烯、噌啉基十氢喹啉基、2H,6H-1,5,2-二噻嗪基、二氢呋喃并[2,3-b]四氢呋喃基、呋喃基、呋咱基、咪唑烷基、咪唑啉基、咪唑基、1H-吲唑基、吲哚烯基、二氢吲哚基、中氮茚基、吲哚基、3H-吲哚基、异苯并呋喃基、异吲哚基、异二氢吲哚基、异喹啉基、异噻唑基、异恶唑基、亚甲二氧基苯基、吗啉基、萘啶基，八氢异喹啉基、恶二唑基、1,2,3-恶二唑基、1,2,4-恶二唑基、1,2,5-恶二唑基、1,3,4-恶二唑基、恶唑烷基、恶唑基、羟吲哚基、嘧啶基、菲啶基、菲咯啉基、吩嗪、吩噻嗪、苯并黄嘌呤基、酚恶嗪基、酞嗪基、哌嗪基、哌啶基、哌啶酮基、4-哌啶酮基、胡椒基、蝶啶基、嘌呤基、吡喃基、吡嗪基、吡唑烷基、吡唑啉基、吡唑基、哒嗪基、吡啶并恶唑、吡啶并咪唑、吡啶并噻唑、吡啶基、吡咯烷基、吡咯啉基、2H-吡咯基、吡咯基、喹唑啉基、喹啉基、4H-喹嗪基、喹喔啉基、奎宁环基、四氢呋喃基、四氢异喹啉基、四氢喹啉基、四唑基，6H-1,2,5-噻二嗪基、1,2,3-噻二唑基、1,2,4-噻二唑基、1,2,5-噻二唑基、1,3,4-噻二唑基、噻蒽基、噻唑基、异噻唑基噻吩基、噻吩并恶唑基、噻吩并噻唑基、噻吩并咪唑基、噻吩基、三嗪基、1H-1,2,3-三唑基、2H-1,2,3-三唑基、1H-1,2,4-三唑基、4H-1,2,4-三唑基和呫吨基。还包括稠环和螺环化合物。
除非另有规定，术语“烃基”或者其下位概念(比如烷基、烯基、炔基、芳基等等)本身或者作为另一取代基的一部分表示直链的、支链的或环状的烃原子团或其组合，可以是完全饱和的(如烷基)、单元或多元不饱和的(如烯基、炔基、芳基)，可以是单取代或多取代的，可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)，可以包括二价或多价原子团，具有指定数量的碳原子(如C 1-C 12表示1至12个碳，C 1-12选自C 1、C 2、C 3、C 4、C 5、C 6、C 7、C 8、C 9、C 10、C 11和C 12；C 3-12选自C 3、C 4、C 5、C 6、C 7、C 8、C 9、C 10、C 11和C 12。)。“烃基”包括但不限于脂肪烃基和芳香烃基，所述脂肪烃基包括链状和环状，具体包括但不限于烷基、烯基、炔基，所述芳香烃基包括但不限于6-12元的芳香烃基，例如苯、萘等。在一些实施例中，术语“烃基”表示直链的或支链的原子团或它们的组合，可以是完全饱和的、单元或多元不饱和的，可以包括二价和多价原子团。饱和烃原子团的实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、仲丁基、异丁基、环己基、(环己基)甲基、环丙基甲基，以及正戊基、正己基、正庚基、正辛基等原子团的同系物或异构体。不饱和烃基具有一个或多个双键或三键，其实例包括但不限于乙烯基、2-丙烯基、丁烯基、巴豆基、2-异戊烯基、2-(丁二烯基)、2，4-戊二烯基、3-(1，4-戊二烯基)、乙炔基、1-和3-丙炔基，3-丁炔基，以及更高级的同系物和异构 体。
除非另有规定，术语“杂烃基”或者其下位概念(比如杂烷基、杂烯基、杂炔基、杂芳基等等)本身或者与另一术语联合表示稳定的直链的、支链的或环状的烃原子团或其组合，有一定数目的碳原子和至少一个杂原子组成。在一些实施例中，术语“杂烷基”本身或者与另一术语联合表示稳定的直链的、支链的烃原子团或其组合物，有一定数目的碳原子和至少一个杂原子组成。在一个典型实施例中，杂原子选自B、O、N和S，其中氮和硫原子任选地被氧化，氮杂原子任选地被季铵化。杂原子或杂原子团可以位于杂烃基的任何内部位置，包括该烃基附着于分子其余部分的位置，但术语“烷氧基”、“烷氨基”和“烷硫基”(或硫代烷氧基)属于惯用表达，是指分别通过一个氧原子、氨基或硫原子连接到分子的其余部分的那些烷基基团。实例包括但不限于-CH 2-CH 2-O-CH 3、-CH 2-CH 2-NH-CH 3、-CH 2-CH 2-N(CH 3)-CH 3、-CH 2-S-CH 2-CH 3、-CH 2-CH 2、-S(O)-CH 3、-CH 2-CH 2-S(O) 2-CH 3、-CH＝CH-O-CH 3、-CH 2-CH＝N-OCH 3和–CH＝CH-N(CH 3)-CH 3。至多两个杂原子可以是连续的，例如-CH 2-NH-OCH 3。
除非另有规定，术语“环烃基”、“杂环烃基”或者其下位概念(比如芳基、杂芳基、环烷基、杂环烷基、环烯基、杂环烯基、环炔基、杂环炔基等等)本身或与其他术语联合分别表示环化的“烃基”、“杂烃基”。此外，就杂烃基或杂环烃基(比如杂烷基、杂环烷基)而言，杂原子可以占据该杂环附着于分子其余部分的位置。环烃基的实例包括但不限于环戊基、环己基、1-环己烯基、3-环己烯基、环庚基等。杂环基的非限制性实例包括1-(1,2,5,6-四氢吡啶基)、1-哌啶基、2-哌啶基，3-哌啶基、4-吗啉基、3-吗啉基、四氢呋喃-2-基、四氢呋喃吲哚-3-基、四氢噻吩-2-基、四氢噻吩-3-基，1-哌嗪基和2-哌嗪基。
除非另有规定，术语“烷基”用于表示直链或支链的饱和烃基,可以是单取代(如-CH 2F)或多取代的(如-CF 3)，可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。烷基的例子包括甲基(Me)，乙基(Et)，丙基(如，n-丙基和异丙基)，丁基(如，n-丁基，异丁基，s-丁基，t-丁基)，戊基(如，n-戊基，异戊基，新戊基)等。
除非另有规定，“烯基”指在链的任何位点上具有一个或多个碳碳双键的烷基,可以是单取代或多取代的，可以是一价、二价或者多价。烯基的例子包括乙烯基，丙烯基，丁烯基，戊烯基，己烯基，丁间二烯基，戊间二烯基，己间二烯基等。
除非另有规定，“炔基”指在链的任何位点上具有一个或多个碳碳三键的烷基，可以是单取代或多取代的，可以是一价、二价或者多价。炔基的例子包括乙炔基，丙炔基，丁炔基，戊炔基等。
除非另有规定，环烷基包括任何稳定的环状或多环烃基，任何碳原子都是饱和的，可以是单取代或多取代的，可以是一价、二价或者多价。这些环烷基的实例包括，但不限于，环丙基、降冰片烷基、[2.2.2]二环辛烷、[4.4.0]二环癸烷等。
除非另有规定，环烯基包括任何稳定的环状或多环烃基，该烃基在环的任何位点含有一个或多个不饱和的碳-碳双键，可以是单取代或多取代的，可以是一价、二价或者多价。这些环烯基的实例包括，但不限于，环戊烯基、环己烯基等。
除非另有规定，环炔基包括任何稳定的环状或多环烃基，该烃基在环的任何位点含有一个或多个碳-碳三键，可以是单取代或多取代的，可以是一价、二价或者多价。
除非另有规定，术语“卤代素”或“卤素”本身或作为另一取代基的一部分表示氟、氯、溴或碘原子。 此外，术语“卤代烷基”意在包括单卤代烷基和多卤代烷基。例如，术语“卤代(C 1-C 4)烷基”意在包括但不仅限于三氟甲基、2，2，2-三氟乙基、4-氯丁基和3-溴丙基等等。除非另有规定，卤代烷基的实例包括但不仅限于：三氟甲基、三氯甲基、五氟乙基，和五氯乙基。
“烷氧基”代表通过氧桥连接的具有特定数目碳原子的上述烷基，除非另有规定，C 1-6烷氧基包括C 1、C 2、C 3、C 4、C 5和C 6的烷氧基。烷氧基的例子包括但不限于：甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、叔丁氧基、正戊氧基和S-戊氧基。
除非另有规定，术语“芳基”表示多不饱和的芳族烃取代基，可以是单取代或多取代的，可以是一价、二价或者多价，它可以是单环或多环(比如1至3个环；其中至少一个环是芳族的)，它们稠合在一起或共价连接。术语“杂芳基”是指含有一至四个杂原子的芳基(或环)。在一个示范性实例中，杂原子选自B、N、O和S，其中氮和硫原子任选地被氧化，氮原子任选地被季铵化。杂芳基可通过杂原子连接到分子的其余部分。芳基或杂芳基的非限制性实施例包括苯基、萘基、联苯基、吡咯基、吡唑基、咪唑基、吡嗪基、恶唑基、苯基-恶唑基、异恶唑基、噻唑基、呋喃基、噻吩基、吡啶基、嘧啶基、苯并噻唑基、嘌呤基、苯并咪唑基、吲哚基、异喹啉基、喹喔啉基、喹啉基、1-萘基、2-萘基、4-联苯基、1-吡咯基、2-吡咯基、3-吡咯基、3-吡唑基、2-咪唑基、4-咪唑基、吡嗪基、2-恶唑基、4-恶唑基、2-苯基-4-恶唑基、5-恶唑基、3-异恶唑基、4-异恶唑基、5-异恶唑基、2-噻唑基、4-噻唑基、5-噻唑基、2-呋喃基、3-呋喃基、2-噻吩基、3-噻吩基、2-吡啶基、3-吡啶基、4-吡啶基、2-嘧啶基、4-嘧啶基、5-苯并噻唑基、嘌呤基、2-苯并咪唑基、5-吲哚基、1-异喹啉基、5-异喹啉基、2-喹喔啉基、5-喹喔啉基、3-喹啉基和6-喹啉基。上述任意一个芳基和杂芳基环系的取代基选自下文所述的可接受的取代基。
除非另有规定，芳基在与其他术语联合使用时(例如芳氧基、芳硫基、芳烷基)包括如上定义的芳基和杂芳基环。因此，术语“芳烷基”意在包括芳基附着于烷基的那些原子团(例如苄基、苯乙基、吡啶基甲基等)，包括其中碳原子(如亚甲基)已经被例如氧原子代替的那些烷基，例如苯氧基甲基、2-吡啶氧甲基3-(1-萘氧基)丙基等。
术语“离去基团”是指可以被另一种官能团或原子通过取代反应(例如亲和取代反应)所取代的官能团或原子。例如，代表性的离去基团包括三氟甲磺酸酯；氯、溴、碘；磺酸酯基，如甲磺酸酯、甲苯磺酸酯、对溴苯磺酸酯、对甲苯磺酸酯等；酰氧基，如乙酰氧基、三氟乙酰氧基等等。
术语“保护基”包括但不限于“氨基保护基”、“羟基保护基”或“巯基保护基”。术语“氨基保护基”是指适合用于阻止氨基氮位上副反应的保护基团。代表性的氨基保护基包括但不限于：甲酰基；酰基，例如链烷酰基(如乙酰基、三氯乙酰基或三氟乙酰基)；烷氧基羰基，如叔丁氧基羰基(Boc)；芳基甲氧羰基，如苄氧羰基(Cbz)和9-芴甲氧羰基(Fmoc)；芳基甲基，如苄基(Bn)、三苯甲基(Tr)、1,1-二-(4'-甲氧基苯基)甲基；甲硅烷基，如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。术语“羟基保护基”是指适合用于阻止羟基副反应的保护基。代表性羟基保护基包括但不限于：烷基，如甲基、乙基和叔丁基；酰基，例如链烷酰基(如乙酰基)；芳基甲基，如苄基(Bn)，对甲氧基苄基(PMB)、9-芴基甲基(Fm)和二苯基甲基(二苯甲基，DPM)；甲硅烷基，如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。
本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实 施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。
本发明所使用的溶剂可经市售获得。本发明采用下述缩略词：aq代表水；HATU代表O-(7-氮杂苯并三唑-1-基)-N，N，N'，N'-四甲基脲六氟磷酸盐；EDC代表N-(3-二甲基氨基丙基)-N'-乙基碳二亚胺盐酸盐；m-CPBA代表3-氯过氧苯甲酸；eq代表当量；mol代表摩尔；mmol代表毫摩尔；kg代表千克；g代表克；mg代表毫克；mL代表毫升；mm代表毫米；μm代表微米；CDI代表羰基二咪唑；DCM代表二氯甲烷；DCE代表1,2-二氯乙烷；AlCl 3代表三氯化铝；MeI代表碘甲烷；NH 4Cl代表氯化铵；MnO 2代表二氧化锰；NaCl代表氯化钠；Na 2SO 4代表硫酸钠；LiOH代表氢氧化锂；NaOH代表氢氧化钠；t-BuOK代表叔丁醇钾；K 3PO 4代表磷酸钾；CuI代表碘化亚铜；Cs 2CO 3代表碳酸锶；Na 2CO 3代表碳酸钠；NaHCO 3代表碳酸氢钠；Na 2S 2O 3代表硫代硫酸钠；K 2CO 3代表碳酸钾；KOAc代表醋酸钾；NaH代表钠氢；DIEA代表N,N-二异丙基乙胺；TEA或Et 3N代表三乙胺；PtO 2代表二氧化铂；DMEDA代表N,N’-二甲基乙二胺；NBS代表N-溴代丁二酰亚胺；THF代表四氢呋喃；PE代表石油醚；DIAD代表偶氮二羧酸二异丙酯；DMF代表N，N-二甲基甲酰胺；DMSO代表二甲亚砜；EtOAc或EA代表乙酸乙酯；EtOH代表乙醇；MeOH代表甲醇；IPA代表异丙醇；MTBE代表甲基叔丁基醚；FA代表甲酸；CAN代表乙腈；CBz代表苄氧羰基，是一种胺保护基团；BOC代表叔丁氧羰基是一种胺保护基团；HOAc代表乙酸；NaCNBH 3代表氰基硼氢化钠；DMAP代表4-二甲氨基吡啶；r.t.代表室温；O/N代表过夜；Boc 2O代表二-叔丁基二碳酸酯；TFA代表三氟乙酸；DIPEA代表二异丙基乙基胺；SOCl 2代表氯化亚砜；CS 2代表二硫化碳；TsOH代表对甲苯磺酸；NCS代表1-氯吡咯烷-2,5-二酮；LDA代表二异丙基胺基锂；tBuXPhos Pd G3代表甲烷磺酸(2-二叔丁基膦基-2',4',6'-三异丙基-1,1'-联苯基)(2'-氨基-1,1'-联苯-2-基)钯(II)；Pd 2(dba) 3代表三(二亚苄基丙酮)二钯；Xantphos代表4,5-双二苯基膦-9,9-二甲基氧杂蒽；Pd(dppf)Cl 2CH 2Cl 2代表[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物；；Pd(PPh 3) 4代表四三苯基膦钯；XPHOS-PD-G2代表氯(2-二环己基膦基-2',4',6'-三异丙基-1,1'-联苯基)[2-(2'-氨基-1,1'-联苯)]钯(II)；sPHOS-PD-G2代表氯(2-二环己基膦基-2',6'-二甲氧基-1,1'-联苯基)(2'-氨基-1,1'-联苯-2-基)钯(II)；TLC代表薄层色谱分析；HPLC代表高效液相色谱分析；SFC表示超临界流体色谱分离。
化合物经手工或者
Figure PCTCN2018078010-appb-000151
软件命名，市售化合物采用供应商目录名称。
具体实施方式
下面通过实施例对本发明进行详细描述，但并不意味着对本发明任何不利限制。本文已经详细地描述了本发明，其中也公开了其具体实施例方式，对本领域的技术人员而言，在不脱离本发明精神和范围的情况下针对本发明具体实施方式进行各种变化和改进将是显而易见的。
实施例1
Figure PCTCN2018078010-appb-000152
步骤A：向化合物1-1(2.00kg，17.68mol，1.94L，1.00eq)的EtOH(25.00L)溶液中加入1,1-二甲氧基-N,N-二甲基-甲胺(2.74kg，22.98mol，3.04L，1.30eq)。将混合物在25℃下搅拌16小时。将混 合物浓缩，残余物通过柱层析(PE:EtOAc＝1:0-2.5:1)纯化得到化合物1-a。
步骤B：在西林瓶中加入化合物1-a(25.00g，148.64mmol，1.00eq)和2-丙胺(26.36g，445.92mmol，38.20mL，3.00eq)。将混合物在75℃下搅拌13小时。冷却后将混合物真空浓缩，残余物通过柱层析(EtOAc:PE＝2:1洗脱)纯化得到化合物1-b。
步骤C：在25℃下，向化合物1-b(53.00g，290.86mmol，1.00eq)的THF(700.00mL)溶液中缓慢加入NBS(67.30g，378.12mmol，1.30eq)。加完后将混合物搅拌16小时。混合物用饱和NaHCO 3水溶液(120mL)洗涤，EtOAc(100mL×2)萃取，有机相合并后用无水Na 2SO 4干燥，过滤并真空浓缩。粗产品通过柱层析(EtOAc/PE＝1:20～1:6)纯化得到化合物1-c。
步骤D：在-78℃和氮气保护下，向化合物1-c(4.00g，15.32mmol，1.00eq)的无水THF(70.00mL)溶液中逐滴加入LDA(2M，11.49mL，1.50eq)，-78℃下搅拌2小时，然后将溶有4-氯苯甲醛(2.80g，19.92mmol，1.30eq)的THF(7.00mL)溶液缓慢加入混合物中并在-70℃下继续搅拌0.5小时，然后经0.5小时缓慢升温至-20℃。将混合物在-20℃用10％NH 4Cl水溶液(75mL)淬灭，然后用EtOAc(60mL×3)萃取，合并的有机相用盐水(100mL)洗涤并真空浓缩。残余物通过柱层析(EtOAc/PE＝1:10)纯化得到化合物1-d。
步骤E：在5℃下，将甲基磺酰酐(2.08g，11.95mmol，1.20eq)加入到化合物1-d(4.00g，9.96mmol，1.00eq)和TEA(2.52g，24.90mmol，3.45mL，2.50eq)的DCM(50.00mL)溶液中。混合物在5℃下搅拌1小时，然后向混合物中加入3-氨基-5-氯-1-甲基-吡啶-2-酮(1.90g，11.95mmol，1.20eq)。加完后缓慢升温至25℃并继续搅拌12小时。混合物倒入水(50mL)中，用DCM(50mL×3)萃取。合并的有机相用食盐水洗涤并浓缩。残余物通过柱层析(PE:EA＝10:1)纯化得到化合物1-e。
步骤F：室温下将NaOH(885.20mg，22.13mmol，5.00eq)加入到化合物1-e(2.40g，4.43mmol，1.00eq)的MeOH(30.00mL)/THF(30.00mL)/H 2O(20.00mL)混合溶液中，然后将混合物搅拌1.5小时。混合物真空浓缩以除去MeOH和THF，然后加水(35mL)稀释。水溶液用2M稀盐酸调节至pH＝3，用DCM(50mL×3)萃取。合并的有机相用盐水(60mL)洗涤，减压浓缩得到化合物1-f。
步骤G：向溶有化合物1-f(1.30g，2.53mmol，1.00eq)和DIEA(980.23mg，7.58mmol，1.32mL，3.00eq)的DMF(35.00mL)溶液中加入HATU(1.15g，3.03mmol，1.20eq)。混合物升温至60℃下并搅拌15小时。混合物减压浓缩除去大部分DMF，剩余物加入水(30mL)并用EtOAc(35mL×3)萃取。有机相用盐水(30mL)洗涤并真空浓缩。将残余物加入EtOAc(15mL)中打浆得到化合物1-g。
步骤H：向化合物1-2(3.00g，21.72mmol，1.00eq)的丙酮(30.00mL)溶液中加入MeI(6.17g，43.44mmol，2.71mL，2.00eq)和K 2CO 3(9.01g，65.16mmol，3.00eq)。将混合物在25℃下搅拌24小时。反应液过滤并将滤液真空浓缩，得到化合物1-h。
步骤I：向化合物1-h(500.00mg，3.29mmol，1.00eq)的乙腈(5.00mL)溶液中加入NBS(702.67mg，3.95mmol，1.20eq)。将反应液在25℃下搅拌12小时。混合物用饱和Na 2S 2O 3水溶液(20mL)淬灭，用EtOAc(20mL×2)萃取。合并有机层并用盐水(20mL)洗涤，无水Na 2SO 4干燥，过滤并真空浓缩得到化合物1-i。
步骤J：在氮气保护下，将化合物1-i(690.00mg，2.99mmol，1.00eq)，4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3，1,2-二氧杂环戊硼烷-2-基)-1,3,2-二氧杂硼杂环戊烷(1.14g，4.49mmol，1.50eq)，Pd(dppf)Cl 2(109.39mg，149.50μmol，0.05eq)和KOAc(586.88mg，5.98mmol，2.00eq)加入二恶烷(10.00mL)溶液中。混合物在N 2下加热至80℃并搅拌12小时。冷却后将溶液过滤并浓缩，得到的残余物通过硅胶色谱(石油醚/乙酸乙酯＝50/1,5/1)纯化得到化合物1-j。
步骤K：在氮气保护下，在溶有化合物1-g(80.00mg，161.23μmol，1.00eq)，化合物1-j(89.68mg，322.46μmol，2.00eq)和Na 2CO 3(51.27mg，483.69μmol，3.00eq)的二恶烷(3.00mL)/水(1.00mL)混合物中加入Pd(PPh 3) 4(18.63mg，16.12μmol，0.10eq)。将混合物升温至100℃下搅拌2小时。混合物冷却后真空浓缩，加入水(20mL)，用EtOAc(20mL×3)萃取。合并的有机相用盐水(30mL)洗涤，然后真空浓缩。通过制备型TLC(DCM:EtOAc＝1:1)纯化残余物得到化合物1。
1: 1H NMR(400MHz,DMSO-d 6)δ:7.91(d,J＝2.8Hz,1H),7.49(d,J＝3.2Hz,1H),7.42(d,J＝8.4Hz,2H),7.31(d,J＝8.0Hz,2H),6.95(s,2H),6.69(s,1H),6.07(s,2H),4.08-4.01(m,1H),3.71(s,3H),3.44(s,3H),1.32(d,J＝6.4Hz,3H),0.48(d,J＝5.2Hz,3H).MS(ESI)m/z:567.1(M+H) +.
实施例2
Figure PCTCN2018078010-appb-000153
步骤A：在氮气保护下，向加有化合物1-g(500.00mg，1.01mmol，1.00eq)，(1-叔丁氧基羰基吲哚-2-基)硼酸(316.43mg，1.21mmol，1.20eq)和K 2CO 3(418.78mg，3.03mmol，3.00eq)的二恶烷(10.00mL)和水(3.00mL)的混合溶液中加入Pd(PPh 3) 4(116.71mg，101.00μmol，0.10eq)。将混合物升温至100℃下搅拌16小时。冷却后，通过硅藻土过滤混合物。滤液加入水(40mL)，用EtOAc(50mL)萃取。合并的有机相用盐水(50mL)洗涤，减压浓缩。残余物通过柱层析(EtOAc/PE＝2:1)纯化和制备级HPLC(碱性)纯化得到化合物2。
2: 1H NMR(400MHz,DMSO-d 6)δ:11.86(s,1H),7.93(d,J＝2.8Hz,1H),7.61(d,J＝8.0Hz,1H),7.52(d,J＝2.8Hz,1H),7.47-7.43(m,3H),7.42(d,J＝4.0Hz,2H),7.31(t,J＝2.8Hz,1H),7.05(t,J＝2.8Hz,1H),6.86(s,1H),6.81(s,1H),5.01-4.94(m,1H),3.45(s,3H),1.47(d,J＝6.8Hz,3H),0.80(d,J＝6.4Hz,3H).MS(ESI)m/z:532.1(M+H) +.
实施例3
Figure PCTCN2018078010-appb-000154
步骤A：向化合物2(70.00mg，131.48μmol，1.00eq)和2-碘丙烷(44.70mg，262.96μmol，26.29μL，85.67mg，262.96mgol，2.00eq)的DMF(2.00mL)溶液中加入Cs 2CO 3(85.67mg,262.96μmol,2.00eq)。在氮气氛下，将混合物在75℃下搅拌3小时。冷却后将混合物真空浓缩，用DCM(15mL)/水(15mL)萃取。有机相用盐水(20mL)洗涤并真空浓缩。通过制备型TLC板(EtOAc:PE＝3:1)纯化残余物得到粗产物。粗产品继续通过反相快速柱(FA，0.1％水溶液/乙腈)纯化，得到化合物3。
3: 1H NMR(400MHz,DMSO-d 6)δ:7.93(d,J＝2.8Hz,1H),7.72(d,J＝6.8Hz,1H),7.64(d,J＝6.8Hz,1H),7.54(d,J＝2.8Hz,1H),7.44(d,J＝8.4Hz,2H),7.35(d,J＝8.0Hz,2H),7.24(t,J＝2.8Hz,1H),7.10(t,J＝2.8Hz,1H),6.78(d,J＝7.2Hz,1H),4.70-4.62(m,1H),4.39-4.32(m,2H),3.45(s,3H),1.52-1.49(m,5H),1.40-1.36(m,4H),0.59(d,J＝6.8Hz,3H).MS(ESI)m/z:574.2(M+H) +.
实施例4
Figure PCTCN2018078010-appb-000155
步骤A：根据实施例3步骤A，其中将2-碘丙烷由2eq增加到3eq，制备得到化合物4。
4: 1H NMR(400MHz,DMSO-d 6)δ:7.93(d,J＝2.4Hz,1H),7.80(d,J＝7.6Hz,1H),7.67(d,J＝8.4Hz,1H),7.57(s,1H),7.45-7.39(m,4H),7.21(t,J＝2.8Hz,1H),7.08(t,J＝2.8Hz,1H),6.78(s,1H),4.21-4.17(m,1H),4.11(d,J＝5.2Hz,1H),3.45(s,3H),1.53(d,J＝6.8Hz,3H),1.52-1.24(m,12H),0.47(d,J＝6.4Hz,3H).MS(ESI)m/z:616.2(M+H) +.
实施例5
Figure PCTCN2018078010-appb-000156
步骤A：在0℃下，向化合物5-1(10.00g，61.29mmol，1.00eq)的DMF(100.00mL)溶液中加入NBS(10.91g，61.29mmol，1.00eq)。加完后将混合物在搅拌1小时，将饱和氯化铵水溶液(300mL)加入到反应液中，混合物过滤得到化合物5-a。
步骤B：在氮气保护下，将化合物5-a(5.00g，20.66mmol，1.00eq)，MeI(8.80g，61.98mmol，3.86mL，3.00eq)和K 2CO 3(8.56g，61.98mmol，3.00eq)加入DMF(50.00mL)中。混合物在20℃下搅拌5小时。将水(200mL)加入到该溶液中，再加入EA(150mL)分液。有机相浓缩后得到的残余物通过柱层析(石油醚：乙酸乙酯＝20:1至5:1)纯化得到化合物5-b。
步骤C：在氮气保护下，将化合物5-b(1.00g，3.70mmol，1.00eq)，双联频哪醇硼酸酯(1.41g，5.55mmol，1.50eq)，KOAc(1.09g，11.11mmol，3.00eq)和Pd(dppf)Cl 2(270.88mg，370.21μmol，0.10eq)加入二恶烷(20.00mL)溶液中。然后将混合物在100℃下搅拌3小时。冷却后将混合物过滤并浓缩，得到残余物。残余物通过柱层析(石油醚/乙酸乙酯＝20:1至5:1)纯化得到化合物5-c。
步骤D：在氮气保护下，将化合物5-c(480.54mg,1.52mmol,1.50eq)，化合物1-g(500.00mg,1.01mmol,1.00eq)，XPHOS-PD-G2(145.57mg,202.00μmol,0.20eq)和K 3PO 4(643.18mg,3.03mmol,3.00eq) 加入二恶烷(5mL)和水(1.5mL)的混合液中。将混合物升温至80℃下搅拌2小时。冷却后将混合物浓缩，得到粗品。粗品通过制备型TLC(PE:EA＝0:1)和SFC[柱：AD(250mm*30mm,10um)；流动相:[0.1％氨水，异丙醇]；[0.1氨水，异丙醇]％:40％-40％]纯化得到化合物5-I(保留时间1.667min)和5-II(保留时间2.387min)。
5-I： 1H NMR(400MHz,METHANOL-d4)δppm:7.75(d,J＝2.8Hz,1H),7.56(d,J＝2.8Hz,1H),7.41(d,J＝8.7Hz,2H),7.35-7.26(m,3H),6.87(s,1H),6.75(s,1H),4.24(q,J＝6.8Hz,1H),3.89(s,3H),3.58(s,3H),3.45(s,3H),2.97-2.88(m,2H),2.73-2.63(m,2H),1.45(br d,J＝6.7Hz,3H),0.67(br s,3H).MS(ESI)m/z:606.2(M+H) +.
5-II： 1H NMR(400MHz,METHANOL-d4)δppm:7.75(d,J＝2.8Hz,1H),7.56(d,J＝2.8Hz,1H),7.41(d,J＝8.7Hz,2H),7.35-7.26(m,3H),6.87(s,1H),6.75(s,1H),4.24(quin,J＝6.8Hz,1H),3.89(s,3H),3.58(s,3H),3.45(s,3H),2.97-2.88(m,2H),2.73-2.63(m,2H),1.45(br d,J＝6.7Hz,3H),0.67(br s,3H).MS(ESI)m/z:606.2(M+H) +.
实施例6
Figure PCTCN2018078010-appb-000157
步骤A：在0-5℃下，向溶有化合物6-1(2.64g，8.76mmol，1.00eq)的AcOH(29.94g，498.71mmol，28.51mL，56.93eq)和水(30.00mL)混合溶液中滴加亚硝酸钠(906.35mg，13.14mmol，713.66mo，1.50eq)的50.00mL水溶液。加完后，将混合物升温至25℃并搅拌3小时。向混合物中加入Na 2CO 3溶液调节至pH＝8-9。用乙酸乙酯(200mL)萃取水相，合并的有机相用盐水(100mL)洗涤，无水Na 2SO 4干燥，过滤并真空浓缩得到化合物6-a。
步骤B：在25℃下，将加有NaH(1.04g，26.04mmol，60％纯度，3.00eq)的DMF(30.00mL)混合物中加入化合物6-a(2.20g，8.68mmol，1.00eq)。混合物在25℃下搅拌30分钟。在25℃下，向混合物中加入MeI(2.46g，17.36mmol，1.08mL，2.00eq)，并搅拌4小时。将残余物倒入水(100mL)中并搅拌10分钟，水相用乙酸乙酯(100mL用乙)萃取。合并的有机相用盐水(100mL)洗涤，无水Na 2SO 4 干燥，过滤并真空浓缩。残余物通过柱层析(石油醚/乙酸乙酯＝10/1,3/1)纯化，得到化合物6-b、6-c、6-d。
步骤C：在氮气保护下，将化合物6-b(150.00mg，619.66μmol，1.00eq)，频哪醇双联硼酸酯(236.03mg，929.49μmol，1.50eq)，KOAc(182.44mg，1.86mmol，3.00eq)和Pd(dppf)Cl 2.CH 2Cl 2(101.21mg,123.93μmol，0.20eq)加入二恶烷(5.00mL)溶液中。混合物加热至80℃下搅拌16小时。将混合物冷却至25℃，并在50℃下减压浓缩。残余物通过柱层析(石油醚/乙酸乙酯＝20/1～8/1)纯化得到化合物6-e。
步骤D：在氮气保护下，将化合物1-g(100.00mg，201.54μmol，1.00eq)，化合物6-e(90.11mg，302.31μmol，K 3PO 4(85.56mg,403.08μmol,2.00eq)和SPhos(16.55mg,40.31μmol,0.20eq)加入到二恶烷(2.00mL)和水(400.00mL)的混合溶液中。然后将混合物加热至80℃下搅拌12小时。将混合物冷却至25℃，并在50℃下减压浓缩。残余物通过制备型TLC(石油醚：乙酸乙酯＝0:1)纯化得到化合物6。
6: 1H NMR(400MHz,METHANOL-d4)δppm:8.00(s,1H),7.73(d,J＝2.8Hz,1H),7.55(d,J＝2.8Hz,1H),7.42-7.27(m,5H),6.77(s,1H),4.49(s,3H),4.22-4.11(m,1H),3.90(br s,3H),3.56(s,3H),1.56-1.32(m,3H),0.78-0.47(m,3H).MS(ESI)m/z:578.2(M+H) +.
实施例7
Figure PCTCN2018078010-appb-000158
步骤A：在0℃下，向化合物7-1(15.00g，97.31mmol，1.00eq)的AcOH(150.00mL)溶液中加入液溴(12.44g，77.85mmol，4.01mL，0.80eq)。将混合物在0℃下搅拌2小时，将饱和Na 2SO 3水溶液(150mL)加入到溶液中，将混合物过滤得到化合物7-a。
步骤B：在氮气保护下，将化合物7-a(12.00g，51.50mmol，1.00eq)，甲基肼(22.43g，154.50mmol，3.00eq)和K 2CO 3(21.35g，154.50mmol，3.00eq)加入DMSO(120.00mL)中。将混合物升温至60℃下搅拌85小时。冷却后将水(500mL)加入到溶液中，将混合物过滤并收集滤饼，得到化合物7-b。
步骤C：在氮气保护下，将化合物13-b(1.00g，4.15mmol，1.00eq)，双联频哪醇硼酸酯(1.58g，6.23mmol，1.50eq)，KOAc(1.22g，12.45mmol，3.00eq)和Pd(dppf)Cl 2(607.03mg，830.00μmol，0.20eq)加入二恶烷(10.00mL)中。然后将混合物升温至100℃下搅拌2小时。冷却后将混合物过滤并减压浓缩。残余物通过柱层析(石油醚/乙酸乙酯＝20:1至6:1)纯化得到化合物7-c。
步骤D：在氮气保护下，将化合物7-c(477.29mg,1.66mmol,1.64eq)，化合物1-g(502.24mg,1.01mmol,1.00eq)，K 3PO 4(644.58mg,3.04mmol,3.00eq)和XPHOS-PD-G2(131.29mg,182.20μmol,0.18eq)加入二恶烷(7.00mL)和水(2.00mL)中。将混合物升温至80℃下搅拌2小时。冷却后将混合物浓缩，得到粗品。粗品通过制备型TLC(PE:EA＝0:1)和SFC(柱:AD(250mm*30mm,10um)；流动相:[0.1％氨水，异丙醇]；[0.1％氨水，异丙醇]％:40％-40％)纯化得到化合物7-I(保留时间1.400min)和7-II(保留时间2.130min)。
7-I： 1H NMR(400MHz,METHANOL-d 4)δppm:8.03(s,1H),7.85(s,1H),7.75(d,J＝2.8Hz,1H),7.56(d,J＝2.8Hz,1H),7.45-7.39(m,2H),7.36-7.30(m,2H),7.20(s,1H),6.77(s,1H),4.27-4.16(m,1H),4.10(s,3H),3.95(br s,3H),3.58(s,3H),1.55-1.36(m,3H),0.58(br s,3H).MS(ESI)m/z:577.2(M+H) +.
7-II： 1HNMR(400MHz,METHANOL-d 4)δ＝8.03(s,1H),7.85(s,1H),7.75(d,J＝2.8Hz,1H),7.56(d,J＝2.8Hz,1H),7.45-7.39(m,2H),7.36-7.30(m,2H),7.20(s,1H),6.77(s,1H),4.27-4.16(m,1H),4.10(s,3H),3.95(br s,3H),3.58(s,3H),1.55-1.36(m,3H),0.58(br s,3H).MS(ESI)m/z:577.2(M+H) +.
实施例8
Figure PCTCN2018078010-appb-000159
步骤A：向溶有化合物8-1(10.90g，60.17mmol，1.00eq)的乙醇(200.00mL)、水(100.00mL)和乙酸(200.00mL)混合溶液中加入浓盐酸(10.82g，108.31mmol，10.61mL，1.80eq)和铁粉(20.16g，361.02mmol，6.00eq)。将混合物在60℃下搅拌2小时，冷却后将饱和Na 2CO 3水溶液(60mL)缓慢加入到反应液中，使pH调节至约7。再向混合液中加入DCM(100mL)，过滤混合物并分离滤液。有机层用无水Na 2SO 4干燥，过滤并浓缩，得到化合物8-a。
步骤B：向化合物8-a(8.90g，58.88mmol，1.00eq)的DCM(90.00mL)溶液中加入NBS(10.48g，58.88mmol，1.00eq)。将混合物在20℃下搅拌1小时。混合物过滤，滤饼真空干燥，得到化合物8-b。
步骤C：在氮气保护下，将化合物8-b(5.00g，21.73mmol，1.00eq)，甲脒乙酸盐(3.39g，32.60mmol，1.50eq)加入乙醇(50.00mL)溶液中。然后将混合物升温至60℃搅拌15小时。冷却后向溶液中加入NaHCO 3(10％，30mL)水溶液将溶液pH调节至约7。再向混合液中加入EA(30mL*2)以萃取混合物。合并有机层并用无水Na 2SO 4干燥，过滤并浓缩，得到残余物。残余物通过柱层析法(石油醚/乙酸乙酯＝10:1至5:1)纯化得到化合物8-c。
步骤D：在氮气保护下，将化合物8-c(2.40g，10.04mmol，1.00eq)，双联频哪醇硼酸酯(3.82g，15.06mmol，1.50eq)，KOAc(1.97g，20.08mmol，2.00eq)和Pd(dppf)Cl 2(367.28mg，0.05eq)加入二恶烷(30.00mL)溶液中。将混合物升温至100℃下搅拌17小时。冷却后将混合物过滤并浓缩，得到残余物。残余物通过制备型HPLC(中性条件)纯化得到化合物8-d。
步骤E：在氮气保护下，将化合物8-d(30.00mg，147.07μmol，1.50eq)，化合物1-g(48.65mg，98.05μmol，1.00eq)，K 3PO 4(124.87mg,588.28μmol,6.00eq)和Pd(dppf)Cl 2(35.87mg，49.02μmol，0.50eq)加入二恶烷(2.00mL)和水(200.00μL)的混合物中。然后将混合物升温至80℃下搅拌2小时。反应液冷却后浓缩，通过制备型TLC(DCM:MeOH＝10:1)纯化得到化合物8。
8: 1HNMR(400MHz,METHANOL-d 4)δ＝9.49(s,1H),9.25(s,1H),8.32(s,1H),7.77(d,J＝2.8Hz,1H),7.63-7.55(m,2H),7.47-7.41(m,2H),7.38-7.30(m,2H),6.80(s,1H),4.27-4.16(m,1H),4.08(s,3H),3.59(s,3H),1.54-1.41(m,3H),0.68(br s,3H).MS(ESI)m/z:575.1(M+H) +.
实施例9
Figure PCTCN2018078010-appb-000160
步骤A：根据实施例6步骤C和D的顺序，其中将5-溴-6-甲氧基-2-甲基-苯并三唑替换为5-溴-6-甲氧基-1-甲基-苯并三唑，产物经制备型HPLC(柱:C18 150mm*25mm*10um；流动相:[水r(0.225％FA)-ACN]；B％:30％-60％,11min)和SFC(柱:AD(250mm*30mm,10um)；流动相:[0.1％氨水，乙醇]；[0.1％氨水，乙醇]％:45％-45％)纯化，得到化合物9-I(保留时间3.464min)和9-II(保留时间3.746min)。
9-I： 1H NMR(400MHz,DMSO-d 6)δ＝8.11(s,1H),7.93(d,J＝2.7Hz,1H),7.56-7.49(m,2H),7.43(d,J＝8.4Hz,2H),7.34(br d,J＝8.1Hz,2H),6.73(s,1H),4.31(s,3H),3.99(td,J＝6.7,13.3Hz,1H),3.90(br s,3H),3.45(s,3H),1.41-1.26(m,3H),0.45(br s,3H).MS(ESI)m/z:578.1(M+H) +.
9-II： 1H NMR(400MHz,DMSO-d 6)δ＝8.10(s,1H),7.93(br d,J＝2.2Hz,1H),7.55-7.49(m,2H),7.43(br d,J＝8.2Hz,2H),7.33(br d,J＝7.7Hz,2H),6.72(s,1H),4.30(s,3H),4.04-3.94(m,1H),3.89(br s,3H),3.45-3.44(m,1H),3.45(br s,2H),1.33(br s,3H),0.44(br s,3H).MS(ESI)m/z:578.1(M+H) +.
实施例10
Figure PCTCN2018078010-appb-000161
步骤A：向溶有化合物10-1(10.00g，59.82mmol，1.00eq)的DMF(100.00mL)溶液中加入NBS(11.71g，65.80mmol，1.10eq)。将混合物在20℃下搅拌6小时，饱和氯化铵水溶液(10mL)加入到该溶液中，将混合物过滤得到化合物10-a。
步骤B：在氮气保护下，将化合物10-a(9.60g，39.01mmol，1.00eq)，甲脒乙酸盐(4.87g，46.81mmol，1.20eq)加入乙醇(60.00mL)溶液中。然后将混合物升温至70℃下搅拌12小时，冷却后减压除去溶剂，残余物通过柱层析法(石油醚/乙酸乙酯＝20:1至8:1)纯化得到化合物10-b。
步骤C：室温下，向溶有化合物10-b(4.00g，15.68mmol，1.00eq)和NaH(627.28mg，15.68mmol，60％纯度，1.00eq)的DMF(40.00mL)溶液中加入碘甲烷(6.50g，45.79mmol，2.85mL，2.92eq)。将 混合物在25℃下搅拌1小时。混合物倒入饱和NaHCO 3水溶液(300mL)中，混合物过滤，得到化合物10-c。
步骤D：在氮气保护下，将化合物10-c(400.00mg，1.49mmol，1.00eq)，频哪醇双联硼酸酯(1.14g，4.47mmol，3.00eq)，Pd(dppf)Cl 2(108.77mg，148.65μmol，0.10eq)和KOAc(437.65mg，4.46mmol，3.00eq)加入二恶烷(5.00mL)溶液中。然后将混合物升温至95℃下搅拌12小时。冷却后将混合物过滤并浓缩，残余物通过柱层析(石油醚/乙酸乙酯＝1:1至0:1)纯化得到化合物10-d。
步骤E：在氮气保护下，将化合物10-d(22.94mg，72.56μmol，1.80eq)，2-溴-5-(5-氯-1-甲基-2-氧代-3-吡啶基)-4-(4-氯苯基)-3-异丙基-4H-吡咯并[3,4-d]咪唑-6-酮(20.00mg，40.31μmol，1.00eq)，K 3PO 4(25.67mg，120.93μmol，3.00eq)和XPHOS-PD-G2(14.52mg，20.16μmol，0.50eq)加入二恶烷(500.00μL)和水(150.00μL)的混合溶剂中。然后将混合物升温至80℃搅拌1小时。冷却后将混合物过滤并浓缩，得到残余物。残余物通过制备型TLC(PE:EA＝0:1)纯化得到化合物10。
10: 1HNMR(400MHz,METHANOL-d4)δ＝8.39(s,1H),8.32(s,1H),7.75(d,J＝2.8Hz,1H),7.57(d,J＝2.6Hz,1H),7.46-7.39(m,2H),7.37-7.30(m,3H),6.78(s,1H),4.20(td,J＝6.8,13.6Hz,1H),4.00(s,3H),3.62(s,3H),3.58(s,3H),1.46(br d,J＝6.5Hz,3H),0.67(br s,3H).MS(ESI)m/z:605.1(M+H) +.
实施例11
Figure PCTCN2018078010-appb-000162
步骤A：在25℃下，向化合物11-1(10.00g，81.20mmol，1.00eq)的乙酸(50.00mL)溶液中一次性加入乙酸酐(8.29g，81.20mmol，7.61mL，1.00eq)。混合物在25℃下搅拌1小时后，将混合物倒入水(200mL)中搅拌5分钟分液。水相用乙酸乙酯(20mL*4)萃取。合并的有机相依次用饱和碳酸氢钠 溶液、盐水(100mL)洗涤，再用无水Na 2SO 4干燥。过滤并真空浓缩得到化合物11-a。
步骤B：在0℃下，将硝酸(11.80g，121.68mmol，8.43mL，1.50eq)逐滴滴加到化合物11-a(13.40g，81.12mmol，1.00eq)的二氯甲烷(150.00mL)溶液中。加完后混合物在0℃下搅拌3小时。向反应混合物中加入饱和碳酸氢钠水溶液(350mL)。将混合物用DCM(100mL)萃取，将合并的有机相用无水Na 2SO 4干燥。过滤并真空浓缩得到化合物11-b。
步骤C：将化合物11-b(15.75g，74.93mmol，1.00eq)中加入NaOH水溶液(4M，250.00mL，13.35eq)中。将反应混合物升温至60℃下搅拌4小时。将混合物冷却至25℃，并用乙酸乙酯(200mL)萃取水相。将合并的有机相用盐水(200mL)洗涤，用无水Na 2SO 4干燥。过滤并真空浓缩得到化合物11-c。
步骤D：在25℃下，向溶有化合物11-c(12.12g，72.08mmol，1.00eq)，铁粉(40.26g，720.80mmol，10.00eq)和NH 4Cl(38.55g，720.80mmol，25.20mL，10.00eq)的异丙醇(120.00mL)的混合溶液中一次性加入甲酸(146.40g，3.18mol，120.00mL，44.13eq)。将混合物加热至80℃并搅拌3小时。将混合物冷却至25℃，过滤，真空浓缩。将残余物倒入水(400mL)中，搅拌10分钟。然后将水溶液用NaOH固体调节至pH＝9。将溶液用DCM(200mL*9)萃取，合并的有机相用无水Na 2SO 4干燥。过滤并真空浓缩得到化合物11-d。
步骤E：在25℃下，向化合物11-d(10.39g，70.13mmol，1.00eq)的AcOH(150.00mL)溶液中滴加液溴(16.81g，105.19mmol，5.42mL，1.50eq)。将混合物在25℃下搅拌16小时。将混合物在55℃下减压浓缩，残余物倒入水(200mL)中。将水相用固体Na 2CO 3调节至pH＝9，水相用乙酸乙酯(100mL酸乙)萃取。合并的有机相用盐水(100mL)洗涤，无水Na 2SO 4干燥，过滤并真空浓缩。残余物通过柱层析(石油醚/乙酸乙酯＝10/1～0/1)纯化得到化合物11-e。
步骤F：在氮气保护下，在25℃下向溶有NaH(1.32g，33.03mmol，60％纯度，3.00eq)的DMF(25.00mL)混合物中加入化合物11-e(2.50g，11.01mmol，1.00eq)。混合物在25℃下搅拌混合物30分钟，向混合物中加入碘甲烷(3.13g，22.02mmol，1.37mL，2.00eq)并搅拌16小时。将残余物倒入水(200mL)中并搅拌20分钟。水相用乙酸乙酯(200mL)萃取。合并的有机相用盐水(200mL)洗涤，无水Na 2SO 4干燥，过滤并真空浓缩。残留物通过柱层析(石油醚/乙酸乙酯＝10/1,0/1)纯化得到化合物11-f。
步骤G：在氮气保护下，将化合物11-f(500.00mg，2.07mmol，1.00eq)，频哪醇双联硼酸酯(1.05g，4.14mmol，2.00eq)，KOAc(609.45mg，6.21mmol，3.00eq)，三环己基膦(232.20mg，828.00μmol，0.40eq)和Pd(OAc) 2(92.95mg，414.00μmol，0.20eq)加入二恶烷(10.00mL)溶液中，然后在加热至90℃下搅拌18小时。将混合物冷却至20℃，在50℃下减压浓缩。残余物通过柱层析(石油:乙酸乙酯＝10:1～乙酸乙酯:甲醇＝3:1)纯化得到化合物11-g。
步骤H：在氮气保护下，将化合物1-g(500.00mg,1.01mmol,1.00eq)，化合物11-g(566.94mg,1.52mmol,1.50eq)，K 3PO 4(428.79mg,2.02mmol,2.00eq)和sPHOS-PD-G2(82.93mg,202.00,0.20eq)加入二恶烷(8.00mL)和水(1.60mL)的混合溶剂中，混合物升温至90℃下搅拌12小时。将混合物冷却至20℃，在50℃下减压浓缩。将残余物倾入水(20mL)中并搅拌5分钟。水相用EA(10mL)萃取三次。合并的有机相用食盐水(10mL)洗涤两次，无水Na 2SO 4干燥。过滤并浓缩后的残余物用制备型 HPLC(柱：Boston pH-lex 150mm*25mm*10um；流动相：[水(0.225％FA)-ACN]；ACN％:15％-45％)纯化，并进一步通过SFC(柱：AD(250mm*30mm，10μm)；流动相：[0.1％氨水，甲醇]；[0.1％氨水，甲醇]％:45％-45％)纯化得到化合物11-I(保留时间3.199min)和化合物11-II(保留时间3.666min)。
11-I： 1H NMR(400MHz,DMSO-d6)δ＝8.16(s,1H),7.92(d,J＝2.8Hz,1H),7.63(s,1H),7.51(d,J＝2.9Hz,1H),7.43(d,J＝8.7Hz,2H),7.37-7.27(m,3H),6.72(s,1H),4.01(td,J＝6.5,13.3Hz,1H),3.91-3.79(m,6H),3.45(s,3H),1.33(br s,3H),0.73-0.27(m,3H).MS(ESI)m/z:577.1(M+H) +.
11-II： 1H NMR(400MHz,DMSO-d6)δ＝8.16(s,1H),7.92(d,J＝2.8Hz,1H),7.63(s,1H),7.51(d,J＝2.8Hz,1H),7.43(d,J＝8.5Hz,2H),7.37-7.28(m,3H),6.72(s,1H),4.08-3.95(m,1H),3.93-3.78(m,6H),3.45(s,3H),1.33(br s,3H),0.44(br s,3H).MS(ESI)m/z:577.1(M+H) +.
实施例12
Figure PCTCN2018078010-appb-000163
步骤A：根据实施例6步骤C和D的顺序，其中将化合物化合物6-b替换为化合物6-d，制备得到化合物12。
12: 1H NMR(400MHz,METHANOL-d 4)δ＝7.96(s,1H),7.74(d,J＝2.8Hz,1H),7.62-7.53(m,2H),7.44-7.27(m,4H),6.78(s,1H),4.35(s,3H),4.23-4.12(m,1H),4.02-3.86(m,3H),3.60-3.53(m,3H),1.57-1.32(m,3H),0.83-0.44(m,3H).MS(ESI)m/z:578.1(M+H) +.
实施例13
Figure PCTCN2018078010-appb-000164
Figure PCTCN2018078010-appb-000165
步骤A：在氮气保护下，向化合物13-1(5.00g，25.38mmol，1.00eq)的四氢呋喃(50.00mL)溶液中加入m-CPBA(9.02g，44.42mmol，85％纯度，1.75eq)。将混合物在25℃下搅拌2小时。反应混合物过滤，收集滤饼得到化合物13-a。
步骤B：向化合物13-a(4.00g，18.57mmol，1.00eq)的四氢呋喃(80.00mL)溶液中加入双(三甲基甲硅烷)胺(3.30g，20.43mmol，4.28mL，1.10eq)。将混合物冷却至5℃，逐滴滴加氯甲酸甲酯(7.50g，79.37mmol，6.15mL，4.27eq)。加完后将混合物在5℃下搅拌3小时。将混合物倒入水(50mL)中，用EA(80mL)萃取产物。将合并的有机相用无水Na 2SO 4干燥，过滤并浓缩，得到粗产物。粗产品通过柱层析法(PE:EA＝1:0～5:1)纯化得到化合物13-b。
步骤C：在0℃下，向化合物13-b(300.00mg，1.30mmol，1.00eq)的DMF(6.00mL)溶液中加入NaH(104.00mg，2.60mmol，60％纯度，2.00eq)，然后加入碘甲烷(3.16g，22.26mmol，1.39mL，17.13eq)，将混合物升温至25℃搅拌2小时。将混合物用30mL水稀释，过滤悬浮液，收集滤饼并干燥得到化合物13-c。
步骤D：在0℃下，将金属钠(216.60mg，9.42mmol，7.22mL，11.11eq)加入到甲醇(5.00mL)中，将悬浮液在0℃下搅拌直至钠消失，然后加入化合物13-c(210.00mg，847.70μmol，1.00eq)。将所得混合物在微波115℃下搅拌1小时。冷却后将混合物用水(15mL)稀释并用2M稀盐酸中和至pH＝7。然后用EA(30mL*7)萃取溶液，将合并的有机相用无水Na 2SO 4干燥，过滤并浓缩。残余物通过制备型TLC(PE:EA＝8:1)纯化得到化合物13-d。
步骤E：在氮气保护下，向化合物13-d(130.00mg，531.15mg向体，1.00eq)，频哪醇双联硼酸酯(269.76mg，1.06mmol，2.00eq)的二恶烷(4.00mL)溶液中加入KOAc(156.38 1.59mmol，3.00eq) 和Pd(dppf)Cl 2.CH 2Cl 2(86.75mg，106.23μmol，0.20eq)。将混合物升温至80℃下搅拌12小时。冷却后将混合物过滤，浓缩滤液。残余物通过制备型TLC(PE:EA＝5:1)纯化得到化合物13-e。
步骤F：在氮气保护下，向化合物1-g(50.00mg,100.77μmol,1.00eq)和化合物13-e(40.00mg,127.02μmol,1.26eq)的二恶烷(1.50mL)和水(400.00μL)混合溶液中加入K 3PO 4(42.78mg,201.54μmol,2.00eq)和Sphos G2-Pd(14.52mg,20.15μmol,0.20eq)。将混合物升温至85℃下搅拌2小时。冷却后将混合物浓缩，残余物通过制备型TLC(PE:EA＝0:1)纯化得到粗产物。然后将粗产物通过制备型HPLC(柱：C18 150mm*25mm*10μm；条件：水(0.1％TFA)-ACN；ACN％:50％-80％)和SFC(柱:AD(250mm*30mm,10μm)；流动相:[0.1％氨水，异丙醇]；[0.1％氨水，异丙醇]％:40％-40％)纯化，得到化合物13-I(保留时间3.605min)和13-II(保留时间4.281min)。
13-I： 1H NMR(400MHz,DMSO-d 6):δ＝8.04(s,1H),7.93(d,J＝2.6Hz,1H),7.51(d,J＝2.6Hz,1H),7.44(d,J＝8.4Hz,2H),7.38(d,J＝3.4Hz,1H),7.34(br d,J＝8.2Hz,2H),6.73(s,1H),6.47(d,J＝3.4Hz,1H),4.07(td,J＝6.7,13.3Hz,1H),3.94(s,3H),3.81(s,3H),3.45(s,3H),1.34(br d,J＝6.8Hz,3H),0.50(br s,3H).MS(ESI)m/z:577.1(M+H) +.
13-II: 1H NMR(400MHz,METHANOL-d 4):δ＝8.00(s,1H),7.76(d,J＝2.8Hz,1H),7.58(d,J＝2.9Hz,1H),7.44-7.40(m,2H),7.33(br d,J＝8.3Hz,2H),7.24(d,J＝3.5Hz,1H),6.77(s,1H),6.50(d,J＝3.5Hz,1H),4.23(quin,J＝6.7Hz,1H),4.02(s,3H),3.87(s,3H),3.58(s,3H),1.46(br d,J＝6.8Hz,3H),0.66(br d,J＝6.4Hz,3H).MS(ESI)m/z:577.1(M+H) +.
实施例14
Figure PCTCN2018078010-appb-000166
步骤A：向化合物14-1(3.00g，21.56mmol，1.00eq)的四氢呋喃(60.00mL)溶液中加入CDI(3.85g，23.72mmol，1.10eq)。将混合物升温至80℃下搅拌2小时。冷却后减压除去溶剂，残余物加入EA(50mL)和H 2O(30mL)分液。用稀盐酸(1M，40mL x 2)洗涤有机相。合并有机层用无水Na 2SO 4干燥，过滤并浓缩，得到化合物14-a。
步骤B：向化合物14-a(1.90g，11.50mmol，1.00eq)的DMF(20.00mL)溶液中加入NBS(2.05g，11.50mmol，1.00eq)。将混合物在25℃下搅拌1小时后，将水(100mL)加入到该溶液中，将混合物过滤得到化合物14-b。
步骤C：向化合物14-b(2.80g，11.47mmol，1.00eq)的DMF(30.00mL)溶液中加入MeI(4.07g，28.68mmol，1.79mL，2.50eq)和K 2CO 3(4.76g，34.41mmol，3.00eq)。将混合物在25℃下搅拌12小时后，将水(150mL)加入到该溶液中，将混合物过滤得到化合物14-c。
步骤D：根据实施例13步骤E和F的顺序，其中将化合物13-d替换为化合物14-c，得到粗品后，继续通过制备型HPLC(柱:Daiso 150mm*25mm 5μm；流动相:[水(0.225％FA)-ACN]；ACN％:35％-60％)和SFC(柱:AD(250mm*30mm,10μm)；流动相:[0.1％氨水，甲醇]；[0.1％氨水，甲醇]％:55％-55％)纯化得到化合物14-I(保留时间1.739min)和14-II(保留时间3.195min)。
14-I： 1HNMR(400MHz,METHANOL-d 4)δ＝7.76(d,J＝2.8Hz,1H),7.56(d,J＝2.8Hz,1H),7.44-7.39(m,2H),7.37-7.27(m,3H),7.11-7.08(m,1H),6.76(s,1H),4.21(br t,J＝7.2Hz,1H),3.90(s,3H),3.62-3.53(m,3H),3.49(s,3H),1.55-1.35(m,3H),0.65(br s,3H).MS(ESI)m/z:594.1(M+H) +.
14-II： 1HNMR(400MHz,METHANOL-d 4)δ＝7.76(d,J＝2.8Hz,1H),7.56(d,J＝2.8Hz,1H),7.44-7.39(m,2H),7.37-7.27(m,3H),7.11-7.08(m,1H),6.76(s,1H),4.21(br t,J＝7.2Hz,1H),3.90(s,3H),3.62-3.53(m,3H),3.49(s,3H),1.55-1.35(m,3H),0.65(br s,3H).MS(ESI)m/z:594.1(M+H) +.
实施例15
Figure PCTCN2018078010-appb-000167
步骤A：根据实施例13步骤E和F的顺序，其中将13-d替换为5-溴-6-甲氧基-1-甲基-苯并咪唑，制备得到化合物15。
15: 1H NMR(400MHz,METHANOL-d 4)δ＝8.21-8.11(m,1H),7.75-7.65(m,2H),7.58-7.54(m,1H),7.44-7.27(m,5H),6.76(d,J＝2.6Hz,1H),4.19(dd,J＝6.4,13.4Hz,1H),3.96-3.83(m,6H),3.56(s,3H),1.53-1.32(m,3H),0.80-0.46(m,3H).MS(ESI)m/z:577.1(M+H) +.
实施例16
Figure PCTCN2018078010-appb-000168
步骤A：在0℃氮气保护下，向化合物1-d(28.00g,69.71mmol,1.00eq)的二氯甲烷(300mL)溶液中加入SOCl 2(49.76g,418.26mmol,30.34mL,6.00eq)。将混合物升温至25℃，并在25℃下搅拌2小时。将反应混合物用水(500mL)淬灭。将混合物用EA(300mL)萃取三次。将合并的有机层用盐水(400mL)洗涤。用无水Na 2SO 4干燥，过滤并在减压下浓缩滤液。残余物通过硅胶色谱纯化(PE:EA＝8:1～3:1)得到化合物16-a。
步骤B：将化合物16-a(9.00g,21.42mmol,1.00eq)和氨水(12.85g,128.31mmol,661.14μL,5.99eq)溶在二氧六环(30.00mL)中，将反应液在100℃下密封搅拌4小时。冷却后向反应液中加水(60mL)，用EA(40mL)萃取三次。将合并的有机相用盐水(40mL)洗涤，无水Na 2SO 4干燥，过滤，减压浓缩得到粗品。粗品通过柱层析纯化(PE:EA＝3:1～1:1)得到化合物16-b。
步骤C：将化合物16-b(8.86g,21.01mmol,1.00eq)和LiOH(2.01g,84.04mmol,4.00eq)溶在混合溶剂四氢呋喃(40.00mL)、乙醇(30.00mL)和水(30.00mL)中。将反应液在25℃下搅拌12小时。先将混合物减压浓缩除去EtOH和THF，然后用EA(80mL)萃取。水相用盐酸(3mol/L)调节pH至3，过滤收集固体并减压干燥得到化合物16-c。
步骤D：将化合物16-c(6.43g,15.52mmol,1.00eq)，HATU(8.85g,23.28mmol,1.50eq)和DIPEA(4.01g,31.04mmol,5.42mL,2.00eq)溶在DMF(60.00mL)中，将反应液在60℃下搅拌12小时。向反应液中加水(200mL)，用EA(80mL)萃取三次，合并的有机相用水(50mL)洗涤两次，盐水(50mL)洗涤一次，无水Na 2SO 4干燥，过滤，减压浓缩得到化合物16-d。
步骤E：在氮气保护下，将化合物16-d(1.00g，2.82mmol，1.00eq)，化合物11-c(994.16mg，4.23mmol，1.50eq)，sPHOS-PD-G2(443.73mg，564.00μmol，0.20eq)和K 3PO 4(1.20g，5.64mmol，2.00eq)加入二恶烷(20.00mL)和水(10.00mL)混合溶液中。将混合物在80℃下搅拌12小时。冷却后将混合物用水(20mL)淬灭。混合物用EA(20mL)萃取，将合并的有机层用盐水(20mL)洗涤，无水Na 2SO 4干燥。将混合物过滤，在减压下浓缩滤液。残余物通过制备型TLC(EA)纯化得到化合物16-e。
步骤F：在氮气保护下，将化合物16-e(100.00mg，215.08μmol，1.00eq)，8-溴-6-氯-咪唑并[1,2-a]吡啶(59.74mg，258.10μmol，1.20eq)，Pd 2(dba) 3(9.85mg，10.75μmol，0.05eq)，Xantphos(9.96mg，17.21μmol，0.08eq)和Cs 2CO 3(105.12mg，322.62μmol，1.50eq)加入二恶烷(3.00mL)中。将混合物升温至90℃下搅拌12小时。将混合物用水(5mL)淬灭，混合物用EtOAc(3mL*3)萃取。将合并的有机层用盐水(5mL)洗涤，用无水Na 2SO 4干燥，过滤，在减压下浓缩滤液。残余物通过制备型TLC(EA)纯化得到化合物16。
16： 1H NMR(400MHz,DMSO-d 6):δ8.68(s,1H),7.95(s,1H),7.72(s,1H),7.43-7.26(m,7H),6.83(s,1H),4.15-4.10(m,1H),2.87-2.84(m,2H),2.60-2.56(m,2H),1.42-1.40(m,3H),0.50-0.48(m,3H).MS(ESI)m/z:615.2(M+H) +.
实施例17
Figure PCTCN2018078010-appb-000169
Figure PCTCN2018078010-appb-000170
步骤A：在-70℃下，向化合物1-c(1.50g,5.74mmol,1.00eq)的四氢呋喃(10.00mL)溶液中逐滴加入LDA(2M,4.31mL)，加完后在-70℃下继续搅拌1.5小时。在-70℃下继续向反应液中逐滴加入5-氯噻吩-2-甲醛(1.10g,7.47mmol,1.30eq)的四氢呋喃(3.00mL)溶液，加完后搅拌30分钟。反应混合物用10％的NH 4Cl水溶液(15mL)淬灭，然后用水(30mL)稀释，用EA(30mL)萃取两次。合并的有机层用无水Na 2SO 4干燥，过滤并浓缩，得到粗产物。将粗产物通过硅胶色谱柱(PE:EA＝5:1)纯化，得到化合物17-a。
步骤B：在0℃下，向化合物17-a(2.50g,6.13mmol,1.00eq)的二氯甲烷(60.00mL)溶液中加入SOCl 2(4.38g,36.78mmol,2.67mL,6.00eq)。加完后反应液升温至30℃并搅拌1.5小时。将反应混合物浓缩得到化合物17-b。
步骤C：向化合物17-b(2.50g,5.87mmol,1.00eq)的乙腈(25.00mL)溶液中加入DIEA(3.03g,23.48mmol,4.10mL,4.00eq)和3-氨基-5-氯-1-甲基-吡啶-2-酮(930.34mg,5.87mmol,1.00eq)。反应液升温至80℃搅拌30小时。反应液冷却后用1M稀盐酸(30mL)稀释反应混合物后，用EA(30mL)萃取三次。将合并的有机相用1mol/L稀盐酸(30mL)，食盐水(30mL)洗涤，无水Na 2SO 4干燥，过滤，减压浓缩得到化合物17-c。
步骤D：向化合物17-c(2.60g,4.74mmol,1.00eq)的四氢呋喃(25.00mL)和甲醇(25.00mL)混合溶液中加入NaOH(2M,23.70mL,10.00eq)，将反应液在30℃下搅拌2小时。用1M稀盐酸(47mL)将反应混合物调节至pH为4左右，然后浓缩，再用水(30mL)稀释。溶液用DCM(50mL)萃取两次，将合并的有机相用无水Na 2SO 4干燥，过滤，减压浓缩得到粗品。将粗产物用EA(10mL)打浆过滤得到化合物17-d。
步骤E：向化合物17-d(1.70g,2.65mmol,1.00eq)的DMF(40.00mL)溶液中加入HATU(1.51g,3.97mmol,1.50eq)和DIEA(1.03g,7.94mmol,1.39mL,3.00eq)。反应液升温至80℃加热30小时。将反应混合物用H 2O(200mL)稀释，用EA(100mL)萃取两次，将合并的有机相用水(100mL)，盐水(100mL)洗涤，无水Na 2SO 4干燥，过滤，减压浓缩，通过柱层析(EA)纯化得到化合物17-e。
步骤F：在N 2保护下，将化合物14-d(544.66mg,1.78mmol,1.50eq)，化合物17-e(600.00mg,1.19mmol,1.00eq)，sPHOS-PD-G2(85.75mg,119.00μmol,0.10eq)和K 3PO 4(757.80mg,3.57mmol,3.00eq)加入水(1.3mL)和二恶烷(5.0mL)的混合溶液中。混合物升温至80℃下搅拌1小时。混合液冷却后加入EA(3mL)和水(3mL)分液。有机相浓缩后的残余物通过制备型HPLC和SFC(柱：AD(250mm*30mm,10μm)；流动相:[0.1％氨水，异丙醇]；[0.1％氨水，异丙醇]％:50％-50％)分离纯化得到化合物17-I(保留时间1.682min)和17-II(保留时间2.528min)。
17-I： 1H NMR(400MHz,METHANOL-d 4)δ＝7.82(d,J＝2.8Hz,1H),7.60(d,J＝2.6Hz,1H),7.37(s,1H),7.15-7.09(m,2H),7.07(s,1H),6.89(d,J＝3.8Hz,1H),4.28(td,J＝6.8,13.6Hz,1H),3.92(s,3H),3.69-3.56(m,3H),3.49(s,3H),1.49(br s,3H),0.92(br s,3H).MS(ESI)m/z:600.1(M+H) +.
17-II： 1HNMR(400MHz,METHANOL-d 4)δ＝7.82(d,J＝2.8Hz,1H),7.60(d,J＝2.6Hz,1H),7.37(s,1H),7.15-7.09(m,2H),7.07(s,1H),6.89(d,J＝3.8Hz,1H),4.28(td,J＝6.8,13.6Hz,1H),3.92(s,3H),3.69-3.56(m,3H),3.49(s,3H),1.49(br s,3H),0.92(br s,3H).MS(ESI)m/z:600.1(M+H) +.
实施例18
Figure PCTCN2018078010-appb-000171
步骤A：在N 2保护下，将化合物17-e(500.00mg,995.60μmol,1.00eq)，化合物7-c(430.32mg,1.49mmol,1.50eq)，K 3PO 4(422.67mg,1.99mmol,2.00eq)和sPHOS-PD-G2(81.74mg,199.12μmol,0.20eq)加入到二恶烷(10.0mL)和水(2.0mL)的混合溶液中。将混合物加热至80℃下搅拌12小时。将混合物冷却室温后在50℃下减压浓缩。残留物通过制备型HPLC(柱：Phenomenex Synergi Max-RP250mm*50mm,10μm；流动相：[水(0.225％FA)-ACN]；ACN％:35％-60％)和SFC(柱:AD(250mm*30mm,10μm)；流动相:[0.1％氨水，乙醇]；[0.1％氨水，乙醇]％:40％-40％)纯化得到化合物18I(保留时间3.004min)和18-II(保留时间3.979min)。
18-I： 1H NMR(400MHz,DMSO-d6)δ＝8.08-7.96(m,2H),7.82(s,1H),7.54(br d,J＝2.6Hz,1H),7.32(s,1H),7.20(br d,J＝3.3Hz,1H),7.02(s,2H),4.06(s,4H),3.89(br s,3H),3.52-3.47(m,3H),1.40(br d,J＝6.7Hz,3H),0.71(br s,3H).MS(ESI)m/z:583.1(M+H) +.
18-II： 1H NMR(400MHz,DMSO-d6)δ＝8.06-7.99(m,2H),7.82(s,1H),7.54(d,J＝2.8Hz,1H),7.32(s,1H),7.20(d,J＝3.7Hz,1H),7.05-6.98(m,2H),4.06(s,4H),3.89(s,3H),3.50(s,3H),1.43-1.29(m,3H),0.71(br s,3H).MS(ESI)m/z:583.1(M+H) +.
实施例19
Figure PCTCN2018078010-appb-000172
步骤A：在氮气保护下，将化合物5-c(47.37mg，149.34μmol，1.50eq)，化合物17-e(50.00mg，99.56μmol，1.00eq)，K 3PO 4(63.40mg，298.68μmol，3.00eq)和sPHOS-PD-G2(35.87mg，49.78μmol，0.50eq)加入水(300.00μL)和二恶烷(1.00mL)的混合溶液中。将混合物升温至80℃下搅拌1小时。冷却后将混合物过滤，减压除去溶剂，得到残余物。残余物通过制备型TLC(EA:MeOH＝15:1)纯化得到19：
19: 1HNMR(400MHz,METHANOL-d 4):δ＝7.82(d,J＝2.6Hz,1H),7.60(d,J＝2.6Hz,1H),7.30(s,1H),7.13-7.09(m,1H),7.07(s,1H),6.91-6.87(m,2H),4.31(quin,J＝6.8Hz,1H),3.91(s,3H),3.62(s,3H),3.46(s,3H),2.97-2.90(m,2H),2.72-2.64(m,2H),1.49(br d,J＝6.3Hz,3H),1.01-0.86(m,3H).MS(ESI)m/z:612.1(M+H) +.
实施例20
Figure PCTCN2018078010-appb-000173
Figure PCTCN2018078010-appb-000174
步骤A：室温下，向溶有化合物20-1(3.00g，20.38mmol，1.00eq)的DMF(30.00mL)溶液中加入NaH(1.63g，40.76mmol，60％纯度，2.00eq)。将混合物在25℃下搅拌30分钟后加入MeI(5.79g，40.76mmol，2.54mL，2.00eq)。所得混合物在25℃下继续搅拌1小时。将溶液用饱和NH 4Cl水溶液(50mL)淬灭，用EtOAc(50mLx2)萃取。将有机层合并，用盐水(30mLx2)洗涤，无水Na 2SO 4干燥，过滤并真空浓缩，得到化合物20-a，直接用于下一步。
步骤B：室温下，向化合物20-a(2.30g，14.27mmol，1.00eq)的甲醇(40.00mL)溶液中加入NaBH 3CN(3.59g，57.08mmol，4.00eq)和甲酸(4.11g，85.62mmol，6.00eq)。将混合物在25℃下搅拌1小时。向反应液中加入水(20mL)，用二氯甲烷(25mL*2)萃取分液。将有机层合并，用盐水(20mL)洗涤，无水Na 2SO 4干燥，过滤并真空浓缩，得到粗品。粗品通过柱层析纯化(石油醚/乙酸乙酯＝25/1,5/1)，得到化合物20-b。
步骤C：在0℃下，向化合物20-b(1.10g，6.74mmol，1.00eq)的二氯甲烷(60.00mL)溶液中加入吡啶溴鎓盐(2.16g，6.74mmol，1.00eq)。将混合物在0℃下搅拌0.5小时。混合物用30mL水稀释，然后将所得溶液用DCM(40mL)萃取。将合并的有机物用盐水(30mL)洗涤，无水Na 2SO 4干燥，过滤并浓缩。粗品通过柱层析(PE:EA＝1:0～15:1)纯化得到化合物20-c。
步骤D：在15℃下，向化合物20-c(1.00g，3.67mmol，1.00eq)的二氯甲烷(20.00mL)溶液中加入MnO 2(4.79g，55.05mmol，15.00eq)。然后将混合物在15℃下搅拌12小时。混合物通过硅藻土垫过滤，将滤液浓缩。残余物通过柱层析(PE:EA＝1:0～20:1)纯化，得到化合物20-d。
步骤E：在氮气保护下，向化合物20-d(100.00mg，405.25μmol，1.00eq)的二恶烷(2.50mL)溶液中加入频哪醇双联硼酸酯(154.36mg，607.88μmol，1.50eq)，Pd(dppf)Cl 2.CH 2Cl 2(66.19mg，81.05μmol，0.20eq)和KOAc(119.31mg，1.22mmol，3.00eq)。将混合物升温至80℃下搅拌12小时。冷却后将混 合物过滤，滤液浓缩。残余物通过制备型TLC(PE:EA＝6:1)纯化得到化合物20-e。
步骤F：在氮气保护下，向溶有化合物1-g(700.00mg,1.41mmol,1.00eq)和化合物20-e(907.16mg,2.78mmol,1.97eq)的二恶烷(15.0mL)和水(4mL)混合溶液中加入K 3PO 4(598.93mg,2.82mmol,2.00eq)和XPHOS-PD-G2(203.33mg,282.00μmol,0.20eq)。将混合物升温至80℃下搅拌12小时。冷却后将混合物浓缩，残余物通过制备型HPLC(柱:Luna C18 150mm*25mm,5μm；流动相:[水(0.225％FA)-ACN]；ACN％:47％-77％)和SFC(柱:AD(250mm*30mm,10μm)；流动相:[0.1％氨水，异丙醇]；[0.1％氨水，异丙醇]％:40％-40％)纯化得到化合物20-I(保留时间3.727min)和20-II(保留时间4.155min)。
20-I： 1H NMR(400MHz,DMSO-d 6):δ＝7.92(d,J＝2.8Hz,1H),7.55(s,1H),7.51(d,J＝2.9Hz,1H),7.43(d,J＝8.5Hz,2H),7.33(br d,J＝7.9Hz,2H),7.28(d,J＝3.0Hz,1H),7.16(s,1H),6.72(s,1H),6.42(d,J＝3.1Hz,1H),4.09-4.00(m,1H),3.81(s,6H),3.45(s,3H),1.34(br s,3H),0.41(br s,3H).MS(ESI)m/z:576.2(M+H) +.
20-II： 1H NMR(400MHz,DMSO-d 6):δ＝7.93(d,J＝2.8Hz,1H),7.55(s,1H),7.51(d,J＝2.8Hz,1H),7.43(d,J＝8.5Hz,2H),7.33(br d,J＝8.0Hz,2H),7.29(d,J＝3.1Hz,1H),7.16(s,1H),6.72(s,1H),6.42(d,J＝3.0Hz,1H),4.10-3.99(m,1H),3.82(s,6H),3.45(s,3H),1.45-1.27(m,3H),0.42(br s,3H).MS(ESI)m/z:576.2(M+H) +.
实施例21
Figure PCTCN2018078010-appb-000175
Figure PCTCN2018078010-appb-000176
步骤A：室温下，向化合物21-1(5.00g，28.38mmol，1.00eq)的乙醇(50.00mL)溶液中加入羟胺盐酸盐(3.94g，56.76mmol，2.00eq)和K 2CO 3(7.84g，56.76mmol，2.00eq)。将混合物升温至60℃下搅拌12小时。冷却后将水(20mL)加入溶液中，并用EA(20mLx2)萃取。合并有机层，用无水Na 2SO 4干燥，过滤并浓缩，得到化合物21-a。
步骤B：在氮气保护下，将PPA(1.00mL)和化合物21-a(2.00g，10.46mmol，1.00eq)的混合物升温至70℃下搅拌12小时。混合物冷却后加入NaOH水溶液(3M，5mL)。继续加入水(10mL)，用EA(20mL*2)萃取溶液。合并有机层，用无水Na 2SO 4干燥，过滤并浓缩，得到化合物21-b。
步骤C：室温下，向化合物21-b(800.00mg，4.18mmol，1.00eq)的DMF(10.00mL)溶液中加入NBS(744.57mg，4.18mmol，1.00eq)。将混合物在20℃下搅拌1小时。将水(20mL)加入到溶液中，溶液通过EA(20mLx2)萃取。合并有机层，用无水Na 2SO 4干燥，过滤并浓缩，得到化合物21-c。
步骤D：室温下，向化合物21-c(1.00g，3.70mmol，1.00eq)的DMF(10.00mL)溶液中加入K 2CO 3(1.53g，g，11.10mmol，3.00eq)。将混合物在20℃下搅拌40小时后，将水(50mL)加入到溶液中。混合物通过EA(20mL*2)萃取，合并有机层，用无水Na 2SO 4干燥，过滤并浓缩得到化合物21-d。
步骤E：在氮气保护下，将化合物21-d(250.00mg，879.82μmol，1.00eq)，频哪醇双联硼酸酯(335.13mg，1.32mmol，1.50eq)，KOAc(259.04mg，2.64mmol，3.00eq)和Pd(dppf)Cl 2(128.75mg，175.96μmol，0.20eq)加入二恶烷(5.00mL)中，然后将混合物升温至80℃下搅拌3小时。冷却后将混合物过滤并浓缩，残余物通过制备型TLC(PE:EA＝5:1)纯化得到化合物21-e。
步骤F：在氮气保护下，将化合物21-e(1.00g,3.03mmol,1.50当量)，化合物1-g(1.00g,2.02mmol,1.00eq)，K 3PO 4(1.29g,6.06mmol,3.00eq)，XPHOS-PD-G2(232.90mg,323.20μmol,0.16当量)加入二恶烷(12.0mL)和水(4mL)的混合溶液中。然后将混合物升温至80℃下搅拌2小时。冷却后将混合物过滤并浓缩。残余物通过制备型TLC(EA:MeOH＝10:1)和SFC(柱:AD(250mm*30mm,10μm)；流动相:[0.1％氨水，异丙醇]；[0.1％氨水，异丙醇]％:40％-40％)纯化得到化合物21-I(保留时间0.971min)和21-II(保留时间1.783min)。
21-I： 1HNMR(400MHz,METHANOL-d4)δ＝7.76-7.72(m,1H),7.55(d,J＝2.7Hz,1H),7.44-7.37(m,2H),7.35-7.26(m,3H),7.11(s,1H),6.74(s,1H),4.23(td,J＝6.8,13.6Hz,1H),3.86(s,3H),3.56(s,3H),3.41(s,3H),2.73(t,J＝7.0Hz,2H),2.39-2.29(m,2H),2.26-2.11(m,2H),1.44(br d,J＝6.4Hz,3H),0.65(br s,3H).MS(ESI)m/z:620.2(M+H) +.
21-II: 1HNMR(400MHz,METHANOL-d 4)δ＝7.76-7.72(m,1H),7.55(d,J＝2.7Hz,1H),7.44-7.37(m,2H),7.35-7.26(m,3H),7.11(s,1H),6.74(s,1H),4.23(td,J＝6.8,13.6Hz,1H),3.86(s,3H),3.56(s,3H),3.41(s,3H),2.73(t,J＝7.0Hz,2H),2.39-2.29(m,2H),2.26-2.11(m,2H),1.44(br d,J＝6.4Hz,3H),0.65(br s,3H).MS(ESI)m/z:620.2(M+H) +.
实施例22
Figure PCTCN2018078010-appb-000177
步骤A：室温、氮气保护下，向化合物16-d(500mg,1.41mmol,1eq)和化合物7-c(600mg,2.08mmol,1.48eq)的二恶烷(9mL)和水(3mL)的混合溶液中分别加入K 3PO 4(449mg,2.12mmol,1.5eq)和Pd(dppf)Cl 2.CH 2Cl 2(116mg,142.05umol,1.01e-1eq)，反应体系置换氮气3次并升温至85℃搅拌12小时，待反应体系冷却后过滤并浓缩。残余物经柱分离(PE:EA＝1:0-1:1,DCM:EA＝0:1-4:1)纯化分离得到化 合物22-a。
步骤B：室温、氮气保护下，向化合物22-a(150mg,344.11umol,1eq)和5-碘-1,3-苯并二恶茂(135.00mg,544.32umol,1.58eq)的二恶烷(8mL)溶液中分别加入Cs 2CO 3(225.00mg,690.57μmol,2.01eq)，CuI(660.00mg,3.47mmol,10.07eq)和DMEDA(160mg,1.82mmol,195.36uL,5.27eq)，反应体系置换氮气3次并升温至75℃搅拌10小时。待反应体系冷却后过滤并浓缩。残余物经制备型TLC(EA:MeOH＝10:1)和SFC(柱:AD(250mm*50mm,10μm)；流动相:[0.1％氨水，甲醇]；[0.1％氨水，甲醇]％:45％-45％)纯化分离得到化合物22-I(保留时间3.288min)和化合物22-II(保留时间3.567min)。
22-I: 1H NMR(400MHz,DMSO-d 6):δ＝8.01(s,1H),7.78(s,1H),7.43-7.38(m,4H),7.30(s,1H),7.13(d,J＝2.0Hz,1H),6.93(dd,J＝2.1,8.3Hz,1H),6.83(d,J＝8.3Hz,1H),6.60(s,1H),5.99(d,J＝0.6Hz,1H),5.96(s,1H),4.06(s,3H),4.00(td,J＝6.8,13.6Hz,1H),3.86(s,3H),1.38(dd,J＝6.1,14.1Hz,3H),0.39(s,3H).MS(ESI)m/z:556.2(M+H) +.
22-II: 1H NMR(400MHz,DMSO-d 6):δ＝8.01(s,1H),7.78(s,1H),7.42-7.38(m,4H),7.30(s,1H),7.12(d,J＝2.0Hz,1H),6.92(dd,J＝2.0,8.4Hz,1H),6.82(d,J＝8.4Hz,1H),6.60(s,1H),5.99(s,1H),5.96(s,1H),4.05(s,3H),4.03-3.94(m,1H),3.86(s,3H),1.38(s,3H),0.36(s,3H).MS(ESI)m/z:556.2(M+H) +.
实施例23
Figure PCTCN2018078010-appb-000178
步骤A：室温下，向化合物23-1(1.05g,6.99mmol,1eq)和化合物16-a(2.94g,6.99mmol,1eq)的乙腈(5mL)溶液中加入DIPEA(1.81g,13.99mmol,2.44mL,2eq)，反应体系升温至70℃搅拌12小 时。待反应体系冷却后将水(15mL)加入反应液中，EA(10mL x 3)萃取。合并有机层，无水Na 2SO 4干燥，过滤并浓缩得到粗产物。粗产物经硅胶色谱柱(PE:EA＝2:1-3:1)纯化分离得到化合物23-a。
步骤B：在25℃下，向化合物23-a(1.6g,2.99mmol,1eq)的四氢呋喃(10mL)溶液中加入LiOH.H 2O(627.69mg,14.96mmol,5eq)的乙醇(10mL)和水(5mL)溶液，搅拌12小时。反应液浓缩，残余物溶于1M盐酸(20mL)溶液，搅拌片刻有固体析出，过滤，滤饼用甲苯(10mL)溶解，减压浓缩得到化合物23-b。
步骤C：室温下，向化合物23-b(1.6g,3.13mmol,1eq)的DMF(20mL)溶液中分别加入HATU(1.78g,4.69mmol,1.5eq)和DIEA(807.93mg,6.25mmol,1.09mL,2eq)，反应体系升温至60℃搅拌12小时。待反应体系冷却后加入水(100mL)，搅拌片刻有固体析出，过滤，滤饼用水(10mL)洗涤后干燥得到化合物23-c。
步骤D：室温、氮气保护条件下，向化合物23-c(500mg,1.02mmol,1eq)和化合物7-c(383.21mg,1.33mmol,1.3eq)的二恶烷(10mL)和水(5mL)溶液中分别加入K 3PO 4(434.29mg,2.05mmol,2eq)和Pd(dppf)Cl 2(74.85mg,102.30umol,0.1eq)，反应体系用氮气置换三次并升温至90℃搅拌2小时。待反应液冷却，用硅藻土过滤，滤液用EA(20mL x 2)萃取，合并有机相，饱和食盐水(10mL x 2)萃取，无水硫酸钠干燥，过滤并减压浓缩得到粗品。粗产物经硅胶色谱柱(PE:EA＝1:1-1:2-0:1)和SFC(柱:AD(250mm*30mm,10um)；流动相:[0.1％氨水，乙醇]；[0.1％氨水，乙醇]％:50％-50％)纯化分离得到化合物23-I(保留时间3.572min)和化合物23-II(保留时间4.175min)。
23-I: 1H NMR(400MHz,DMSO-d 6)δ＝8.01(s,1H),7.78(s,1H),7.46-7.32(m,5H),7.29(s,1H),7.06(d,J＝2.4Hz,1H),6.96(dd,J＝2.4,8.7Hz,1H),6.75(d,J＝8.8Hz,1H),6.60(s,1H),4.19(s,3H),4.05(s,3H),4.02-3.97(m,1H),3.86(s,3H),1.42-1.32(m,3H),0.39(s,3H).MS(ESI)m/z:570.2(M+H) +.
23-II:1H NMR(400MHz,DMSO-d 6)δ＝8.01(s,1H),7.78(s,1H),7.62-7.32(m,5H),7.29(s,1H),7.06(d,J＝2.1Hz,1H),6.96(dd,J＝2.1,8.7Hz,1H),6.75(d,J＝8.7Hz,1H),6.60(s,1H),4.19(s,3H),4.05(s,3H),4.02-3.97(m,1H),3.86(s,3H),1.42-1.27(m,3H),0.39(s,3H).MS(ESI)m/z:570.2(M+H) +.
实施例24
Figure PCTCN2018078010-appb-000179
Figure PCTCN2018078010-appb-000180
步骤A：0℃、氮气保护下，向化合物24-1(2g,12.98mmol,1eq)的四氢呋喃(10mL)溶液中缓慢加入CDI(2.52g,15.57mmol,1.2eq)的四氢呋喃(10mL)溶液，反应体系升温至25℃搅拌12小时。反应液浓缩，残余物用20mL水稀释后经1M盐酸水溶液调节pH至4时有沉淀析出，过滤，收集滤饼并干燥得到化合物24-a。
步骤B：室温、氮气保护下，向化合物24-a(1g,5.55mmol,1eq)的乙醇(5mL)和甲醇(15mL)溶液中加入Pd/C(100mg,60％纯度)，反应体系置换氢气3次于25℃、氢气(15psi)氛搅拌2小时。反应液过滤浓缩得到化合物24-b。
步骤C：根据实施例23步骤A、B、C和D的顺序，将化合物23-1替换为化合物24-b。残余物通过制备型TLC(PE:EA＝0:1)和SFC(柱:OD(250mm*30mm,10um)；流动相:[0.1％氨水,甲醇]；[0.1％氨水,甲醇]％:45％-45％)纯化分离得到化合物24-I(保留时间：2.058min)和化合物24-II(保留时间：2.398min)。
24-I: 1H NMR(400MHz,DMSO-d 6):δ＝8.02(s,1H),7.79(s,1H),7.51(d,J＝1.6Hz,1H),7.40(s,4H),7.33-7.23(m,2H),7.00(d,J＝8.3Hz,1H),6.69(s,1H),4.06(s,3H),4.03-3.95(m,1H),3.87(s,3H),1.49-1.29(m,3H),0.39(s,3H).MS(ESI)m/z:569.2(M+H) +.
24-II: 1H NMR(400MHz,DMSO-d 6):δ＝8.08(s,1H),7.85(s,1H),7.57(s,1H),7.46(s,4H),7.38-7.29(m,2H),7.05(d,J＝8.4Hz,1H),6.75(s,1H),4.12(s,3H),4.09-4.02(m,1H),3.93(s,3H),1.46-1.41(m,3H),0.43(s,3H).MS(ESI)m/z:569.2(M+H) +.
实施例25
Figure PCTCN2018078010-appb-000181
Figure PCTCN2018078010-appb-000182
步骤A：室温、氮气保护下，向化合物22-a(25mg,57.35umol,1eq)和化合物25-1(25mg,123.81umol,2.16eq)的四氢呋喃(4mL)溶液中分别加入醋酸铜(11mg,60.56umol,1.06eq)、4A分子筛(20mg)和三乙胺(15mg,148.24umol,20.63uL,2.58eq)，反应体系置换氧气3次并升温至50℃于氧气氛下搅拌12小时。待反应体系冷却后过滤并浓缩。残余物经制备型HPLC(柱:C18 150*25*10μm；流动相:[水(0.225％FA)-ACN]；ACN％:48％-78％)纯化分离得到化合物25。
25: 1H NMR(400MHz,DMSO-d 6):δ＝8.02(s,1H),7.80(s,1H),7.69(s,1H),7.43(s,4H),7.35(s,2H),7.31(s,1H),6.74(s,1H),4.06(s,3H),4.03–4.00(m,1H),3.87(s,3H),1.39(s,3H),0.39(s,3H).MS(ESI)m/z:592.2(M+H) +.
实施例26
Figure PCTCN2018078010-appb-000183
步骤A:室温下，向化合物26-1(1g,3.99mmol,1eq)的二甲亚砜(10.00mL)溶液中分别加入碳酸钾(1.66g,11.98mmol,3eq)和甲基肼水溶液(2.47g,21.44mmol,2.82mL,5.37eq)。将混合物升温至80℃搅拌12小时。冷却后将反应液滴加入水(50mL)中，过滤，滤饼用水洗得到化合物26-a。
步骤B:在氮气保护下，向溶有化合物26-a(380mg,1.57mmol,1eq)的二氧六环(5mL)溶液中加 入频哪醇双联硼酸酯(518.21mg,2.04mmol,1.3eq)，醋酸钾(462.17mg,4.71mmol,3eq)和Pd(dppf)Cl 2(114.86mg,156.98umol,0.1eq)，混合物升温至80℃搅拌12小时。冷却后将混合物过滤并浓缩。残余物通过柱层析(PE:EA＝3:1)纯化，得到化合物26-b。
步骤C:根据实施例22步骤A和B的顺序，其中将化合物22-b替换为6-甲氧基-1-甲基-5-(4,4,5,5-四甲基-1,3,2-二硼氧-2-基)吲唑。残余物通过柱层析(PE:EA＝0:1)纯化和SFC(柱:AD(250mm*30mm,10μm)；流动相:[0.1％氨水，异丙醇]；[0.1％氨水，异丙醇]％:50％-50％)纯化得到化合物26-I(保留时间：0.916min)和化合物26-II(保留时间：1.447min)。
26-I: 1H NMR(400MHz,DMSO-d 6)δ＝8.29(s,1H),8.08(s,1H),7.43-7.39(m,4H),7.12(d,J＝1.6Hz,1H),6.93-6.91(m,1H),6.91-6.81(m,1H),6.61(s,1H),5.95(s,2H),4.12(dt,J＝13.40,6.54Hz,1H),4.02(s,3H),3.98(s,3H),1.37(d,J＝6.8Hz,3H),0.47(s,3H).MS(ESI)m/z:557.2(M+H) +.
26-II: 1H NMR(400MHz,DMSO-d 6)δ＝8.29(s,1H),8.08(s,1H),7.43-7.39(m,4H),7.12(d,J＝1.6Hz,1H),6.93-6.91(m,1H),6.91-6.81(m,1H),6.61(s,1H),5.95(s,2H),4.12(dt,J＝13.40,6.54Hz,1H),4.01(s,3H),3.98(s,3H),1.37(d,J＝6.8Hz,3H),0.47(s,3H).MS(ESI)m/z:557.2(M+H) +.
实施例27
Figure PCTCN2018078010-appb-000184
步骤A:根据实施例17步骤C、D和E的顺序，其中将3-氨基-5-氯-1-甲基-吡啶-2-酮替换为胡椒胺，制备得到化合物27-a。
步骤B:在氮气保护下，将化合物27-a(0.4g,832.01umol,1eq)，化合物7-c(359.62mg,1.25mmol,1.5eq)，K 3PO 4(529.83mg,2.50mmol,3eq)和Pd(dppf)Cl 2.CH 2Cl 2(54.36mg,66.56umol,0.08eq)分别加入到二恶烷(5mL)和水(2mL)。然后将反应液温度升至80℃，搅拌12小时。反应液冷却至室温，用水(15mL)淬灭，EA(10mL x 3)萃取，合并有机层，饱和食盐水(15mL)洗涤，无水Na 2SO 4干燥，过滤并浓缩。残留物通过柱层析(石油醚/乙酸乙酯＝1:1)纯化后，经SFC(柱:OD(250mm*30mm,10μm)；流动相:[0.1％氨水,甲醇]；[0.1％氨水,甲醇]％:45％-45％)纯化得到化合物27-I(保留时间3.305min)和27-II(保留时间3.642min)。
27-I: 1H NMR(400MHz,CDCl 3):δ＝7.88(s,1H),7.76(s,1H),6.85-6.84(m,2H),6.72-6.64(m,4H),5.99(s,1H),5.87(s,2H),4.15-4.11(m,1H),4.01(s,3H),3.82(s,3H),1.37-1.34(m,3H),0.77-0.72(m,3H).MS(ESI) m/z:562.1(M+H) +.
27-II: 1H NMR(400MHz,CDCl 3):δ＝7.97(s,1H),7.85(s,1H),6.93-6.81(m,1H),6.76-6.73(m,3H),6.08(s,1H),5.87(s,2H),4.23-4.22(m,1H),4.09(s,3H),3.91(s,3H),1.48-1.45(m,3H),0.88-0.84(m,3H).MS(ESI)m/z:562.1(M+H) +.
实施例28
Figure PCTCN2018078010-appb-000185
步骤A：室温下，向化合物17-b(17g,39.89mmol,1eq)的二恶烷(200.00mL)溶液中滴加氨水(23.97g,239.35mmol,26.34mL,6eq)，将反应液于25℃下搅拌12小时。反应液通过EtOAc(150mL x 3)萃取，饱和食盐水洗，无水Na 2SO 4干燥，过滤并浓缩。残余物经柱层析(PE:EA＝5:1～3:1)纯化分离得到化合物28-a。
步骤B：室温下，向化合物28-a(14g,34.42mmol,1eq)的四氢呋喃(100.00mL)、乙醇(100.00mL)和水(150mL)的混合溶液中加入LiOH.H 2O(2.89g,68.84mmol,2eq)，反应液于25℃搅拌12小时。反应液经1M稀盐酸调节pH为6左右，减压浓缩有固体析出，过滤得到化合物28-b。
步骤C：室温下，向化合物28-b(12g,31.69mmol,1eq)的DMF(40.00mL)溶液中加入HATU(18.07g,47.53mmol,1.5eq)和DIPEA(8.19g,63.38mmol,11.04mL,2eq)，反应液升温至60℃搅拌12小时。待反应液冷却至室温倒入水(500mL)中有固体析出，过滤得到化合物28-c。
步骤D：室温、氮气保护下，向化合物28-c(500mg,1.29mmol,1eq)和化合物26-b(447.39mg,1.55mmol,1.2eq)的二氧六环(10mL)和水(2mL)的混合溶液中分别加入Pd(dppf)Cl 2.CH 2Cl 2(105.30mg,128.95umol,0.1eq)和K 3PO 4(821.12mg,3.87mmol,3eq)，反应体系置换氮气3次并升温至90℃搅拌 12小时。待反应体系冷却后过滤，滤液用水(30mL)稀释，EA(30mL*2)萃取。合并有机层，NaCl(10mL*2)溶液洗涤，无水Na 2SO 4干燥，过滤并浓缩。残余物经柱层析(PE:EtOAc＝0:1,EA/MeOH＝20:1)纯化得到化合物28-d。
步骤E：室温、氧气(15psi)保护下，向化合物28-d(300mg,677.32umol,1eq)和3,4-(亚甲基二氧基)苯硼酸(337.18mg,2.03mmol,3eq)的二氯甲烷(5mL)溶液中加入醋酸铜(135.33mg,745.05umol,1.1eq)、吡啶(160.73mg,2.03mmol,164.01uL,3eq)、三乙胺(137.08mg,1.35mmol,188.55uL,2eq)和4A分子筛(400mg)，反应体系在氧气氛、30℃搅拌12小时。将混合物用硅藻土过滤，滤液用水(20mL)稀释，二氯甲烷(20mL*2)萃取。合并有机层，NaCl(10mL*2)溶液洗涤，无水Na 2SO 4干燥，过滤并缩。残余物通过柱层析(PE:EtOAc＝0:1)及SFC(柱:OD(250mm*30mm,10μm)；流动相:[中性-MeOH]；MeOH％:55％-55％)纯化得到化合物28-I(保留时间：3.516min)和化合物28-II(保留时间：4.087min)。
28-I: 1H NMR(400MHz,DMSO-d 6)δ＝8.41(s,1H),8.31(s,1H),7.32(s,1H),7.13(s,1H),6.98-6.95(m,3H),6.90-6.87(m,1H),6.01(s,2H),4.14-4.08(m,1H),4.02(s,3H),3.99(s,3H),1.42(d,J＝5.6Hz,3H),0.74(s,3H).MS(ESI)m/z:563.1(M+H) +.
28-II: 1H NMR(400MHz,DMSO-d 6)δ＝8.32(s,1H),8.10(s,1H),7.30(s,1H),7.14(s,1H),7.13(s,2H),6.98-6.88(m,2H),6.01(s,2H),4.14-4.08(m,1H),4.02(s,3H),3.99(s,3H),1.42(d,J＝5.6Hz,3H),0.74(s,3H).MS(ESI)m/z:563.1(M+H) +.
实施例29
Figure PCTCN2018078010-appb-000186
步骤A：室温下，向化合物27(0.8g,1.44mmol,1eq)和溴甲基甲基醚(1.80g,14.39mmol,1.18mL,10eq)的乙腈(8mL)溶液中加入碳酸钾(2.98g,21.58mmol,15eq)，反应液在20℃搅拌2小时。向反应液中加入水(10mL)，乙酸乙酯(10mL x 2)萃取。合并有机相，饱和食盐水洗涤(10mL x 2)，无水硫酸钠干燥，过滤浓缩。残余物经制备板和SFC(柱:AD(250mm*50mm,10μm)；流动相:[中性-MeOH]；MeOH％:50％-50％)纯化分离得到化合物29-I(保留时间：2.562min)和化合物29-II(保留时间：3.204min)。
29-I: 1HNMR(400MHz,METHANOL-d 4)δ＝8.03(s,1H),7.88(s,1H),7.45(d,J＝8.5Hz,2H),7.30-7.13(m,3H),6.78-6.72(m,1H),6.44(s,1H),6.36(d,J＝7.7Hz,1H),5.98(s,2H),4.63-4.61(m,1H),4.69-4.61 (m,2H),4.10(s,3H),3.94(s,3H),1.28-1.15(m,3H),0.98-0.78(m,3H).MS(ESI)m/z:586.2(M+H) +.
29-II: 1HNMR(400MHz,METHANOL-d 4)δ＝7.91(s,1H),7.80-7.68(m,1H),7.32(d,J＝8.5Hz,2H),7.19-7.00(m,3H),6.62(d,J＝8.3Hz,1H),6.31(s,1H),6.23(d,J＝7.3Hz,1H),5.85(s,2H),4.59-4.48(m,1H),4.28-4.09(m,2H),3.98(s,3H),3.82(s,3H),1.16-0.97(m,3H),0.89-0.59(m,3H).MS(ESI)m/z:586.2(M+H) +.
实施例30
Figure PCTCN2018078010-appb-000187
步骤A：0℃条件下，向化合物7-b(1g,4.15mmol,1eq)的乙酸酐(25mL)溶液中逐滴滴加硝酸(2.26g,23.31mmol,1.61mL,5.62eq)，升温至25℃并搅拌1小时。将反应液加入到150mL水中搅拌10分钟，过滤，收集滤饼得到化合物30-a。
步骤B：25℃，向化合物30-a(1.4g,4.89mmol,1eq)的乙醇(10mL)和水(2mL)溶液中加入氯化铵(1.31g,24.47mmol,855.46μL,5eq)和铁粉(1.37g,24.47mmol,5eq)，升温至90℃并搅拌2小时。反应液过滤，滤液减压浓缩后加入水(20mL),DCM(10mL*2)萃取，收集有机相，无水硫酸钠干燥，过滤并加压浓缩得到化合物30-b。
步骤C：0℃条件下，向化合物30-b(1.1g,4.30mmol,1eq)的氯化氢水溶液(4M,20mL)中分别加入亚硝酸钠水溶液(385.25mg,5.58mmol,1.3eq)和氯化亚铜(850.44mg,8.59mmol,2eq),0℃搅拌2小时。向反应液中加入20mL水淬灭反应，EA(30mL*3)萃取，收集有机相，饱和食盐水(20mL*2)洗，无水硫酸钠干燥，过滤减压浓缩得到化合物30-c。
步骤D：25℃,氮气氛条件下，向化合物30-c(700mg,2.54mmol,1eq)的二恶烷(10mL)溶液中分别加入KOAc(498.67mg,5.08mmol,2eq)、Pd(dppf)Cl 2(185.89mg,254.06μmol,0.1eq)和频哪醇双联硼酸酯(774.17mg,3.05mmol,1.2eq)，反应体系转换氮气3次升温至100℃于氮气氛下搅拌0.5小时。待反应液冷却至室温，过滤，滤液经减压蒸馏浓缩后经柱层析(PE:EA＝10:1)纯化得到化合物30-d。
步骤E：25℃,氮气氛条件下，向化合物30-d(642.35mg,1.99mmol,4eq)和化合物17-e(250mg,0.5mmol,1eq)的二恶烷(4mL)和水(1mL)的混合液中加入K 3PO 4(317mg,1.49mmol,3eq)和Pd(dppf)Cl 2,反应体系置换氮气3次后升温至100℃于氮气氛下搅拌2小时。待反应液冷却至室温后过滤，滤液经EA(10mL*2)萃取，无水硫酸钠干燥，过滤减压浓缩得到残余物。残余物经柱层析(PE:EA＝10:1)分离后再经HPLC(柱：C18 150*30mm*4um；流动相:[水(0.225％FA)-ACN]；acn％:48％-78％,10min)和SFC(柱:AS(250mm*30mm,10um)；流动相:[中性-乙醇]；乙醇％:35％-35％)纯化分离后得到化合物30-I(保留时间：0.78min)和化合物30-II(保留时间：1.26min)。
30-I: 1H NMR(400MHz,DMSO-d 6)δ＝8.01(d,J＝2.81Hz,1H),7.74(s,1H),7.54(d,J＝2.81Hz,1H),7.39(s,1H),7.20(d,J＝3.79Hz,1H),6.97-7.05(m,2H),4.00-4.12(m,4H),3.90(s,3H),3.49(s,3H),1.39(br s,3H),0.52-0.93(m,3H).MS(ESI)m/z:617.1(M+H) +.
30-II:1H NMR(400MHz,DMSO-d 6)δ＝8.01(d,J＝2.69Hz,1H),7.74(s,1H),7.54(d,J＝2.69Hz,1H),7.39(s,1H),7.20(d,J＝3.67Hz,1H),6.96-7.06(m,2H),3.98-4.15(m,4H),3.90(s,3H),3.49(s,3H),1.38(br s,3H),0.55-0.86(m,3H).MS(ESI)m/z:617.1(M+H) +.
实施例31
Figure PCTCN2018078010-appb-000188
步骤A：10℃条件下，向化合物31-1(5g,29.73mmol,1eq)的乙酸酐(50mL)溶液中加入液溴(5.23g,32.71mmol,1.1eq)，反应体系在该温度下搅拌12小时。将反应液倒入水(200mL)中，过滤，收集滤饼得到化合物31-a。
步骤B：25℃条件下，向化合物31-a(4g,16.19mmol,1eq)的DMSO(40mL)溶液中分别加入 甲基肼(12.59g,109.31mmol,6.75eq)和碳酸钾(6.71g,48.57mmol,3eq)，反应体系升温至90℃搅拌12小时。待反应液冷却至室温倒入水中(200mL)，过滤，收集滤饼，滤饼经柱层析分离纯化得到化合物31-b。
步骤C：25℃、氮气氛条件下，向化合物31-b(2g,7.84mmol,1eq)的二恶烷(20mL)溶液中分别加入频哪醇双联硼酸酯(2.99g,11.76mmol,1.5eq)、KOAc(2.31g,23.52mmol,3eq)和Pd(dppf)Cl 2(573.64mg,783.97μmol,0.1eq)，反应体系置换氮气3次，升温至100℃于氮气氛中搅拌2小时。待反应液冷却至室温后过滤，收集滤液，滤液经减压浓缩获得残余物，残余物经柱层析(PE:EA＝5:1)分离纯化得到化合物31-c。
步骤D：25℃、氮气氛条件下，向化合物31-c(902.53mg,2.99mmol,6eq)和化合物24-e(250mg,194.80μmol,1eq)的二恶烷(10mL)和水(3mL)的混合溶液中分别加入K 3PO 4(317mg,1.49mmol,3eq)和Pd(dppf)Cl 2(36.42mg,49.87mmol,0.1eq)，反应体系置换氮气3次，升温至100℃并于氮气氛下搅拌2小时。待反应液冷却至室温后过滤，滤液经EA(20mL*2)萃取，收集有机相，饱和食盐水(10mL*2)洗,无水硫酸钠干燥，过滤浓缩得到残余物。残余物经柱层析(PE:EA＝0:1-EA:MeOH＝10:1)分离后再经HPLC(柱:Phenomenex Synergi C18 150mm*30mm*4μm；流动相:[水(0.225％FA)-ACN]；ACN％:45％-75％)、HPLC(柱:Luna C18 150mm*25mm 5μm；流动相:[水(0.225％FA)-ACN]；ACN％:44％-64％)和SFC(柱:AD(250mm*30mm,10μm)；流动相:[中性-乙醇]；乙醇％:40乙醇(中性)％-40乙醇(中性)％)分离纯化后得到化合物31-I(保留时间：1.79min)和化合物31-II(保留时间：2.06min)。
31-I: 1H NMR(400MHz,DMSO-d 6)δ＝8.01(d,J＝2.81Hz,1H),7.79(s,1H),7.53(d,J＝2.69Hz,1H),7.13-7.28(m,2H),6.93-7.06(m,2H),4.03-4.16(m,1H),3.97(s,3H),3.80-3.91(m,3H),3.49(s,3H),2.44(s,3H),1.19-1.57(m,3H),0.67(s,3H).MS(ESI)m/z:597.1(M+H) +.
31-II: 1H NMR(400MHz,DMSO-d 6)δ＝8.00(s,1H),7.79(s,1H),7.53(s,1H),7.12-7.28(m,2H),7.01(s,2H),4.04-4.19(m,1H),3.97(s,3H),3.87(s,3H),3.49(s,3H),2.44(s,3H),1.40(s,3H),0.68(s,3H).MS(ESI)m/z:597.1(M+H) +.
实施例32
Figure PCTCN2018078010-appb-000189
步骤A:在0℃下，向化合物32-1(1g,5.98mmol,1.00eq)的DMF(30mL)溶液中加入NBS(1.17g,6.58mmol,1.10eq)，反应体系升温至15℃并搅拌1小时。反应液冷却到0℃，用饱和亚硫酸钠溶液(50mL)淬灭，盐酸调节pH到3。将其倒入到水(50mL)中，用乙酸乙酯(50mL*4)萃取，合并有机相，饱和食盐水(50mL*4)洗，无水Na 2SO 4干燥，过滤，滤液经减压浓缩得到化合物32-a。
步骤B:在-78℃、氮气氛下，向化合物32-a(1.4g,5.69mmol,1.00eq)的四氢呋喃溶液(10mL)中滴加四氢铝锂(431.85mg,11.38mmol,2.00eq)的四氢呋喃(10mL)溶液，反应体系升温至0℃搅拌1小时，随后升温至15℃搅拌12小时。反应液用饱和的氯化铵溶液(20mL)淬灭，乙酸乙酯萃取(30mL*3)，合并有机相，饱和食盐水(30mL*2)洗涤，无水硫酸钠干燥，过滤，滤液经减压浓缩得到化合物32-b。
步骤C:0℃、氮气保护下，向化合物32-b(1.42g,5.51mmol,1.00eq)的四氢呋喃(40mL)溶液中滴加双(三氯甲基)碳酸酯(1.63g,5.51mmol,1.00eq)，反应体系在0℃、氮气氛下搅拌2小时。将反应液倒入水(50mL)中，碳酸钾调节至pH＝9，乙酸乙酯萃取(50mL*3)，合并有机相并用饱和食盐水(50mL*2)洗涤,无水硫酸钠干燥，过滤，滤液经加压浓缩得到残余物，残余物经石油醚(50mL)打浆得到化合物32-c。
步骤D:在15℃条件下，向化合物32-c(500mg,1.94mmol,1.00eq)和Cs 2CO 3(1.26g,3.87mmol,2eq)的DMF(15mL)溶液中加入MeI(825.00mg,5.81mmol,361.84uL,3.00eq)，反应体系于15℃搅拌1小时。反应液倒入水(20mL)中，乙酸乙酯(20mL*3)萃取，合并有机相并用饱和食盐水(20mL*2)洗涤，无水硫酸钠干燥，过滤，滤液经减压浓缩得到残余物，残余物经柱层析(PE:EA＝1:0-3:2)纯化分离得到化合物32-d。
步骤E:在25℃、氮气保护条件下，向化合物32-d(0.307g,1.13mmol,1.00eq)的二氧六环溶液(4mL)中分别加入双联频哪醇硼酸酯(573.03mg,2.26mmol,2.00eq)、醋酸钾(221.46mg,2.26mmol,2.00eq)和Pd(dppf)Cl 2.CH 2Cl 2(184.28mg,225.66umol,0.20eq)。反应体系升温至90℃于氮气氛搅拌12小时。待反应液冷却至室温过滤，滤液经减压浓缩得到残余物。残余物经柱层析(PE:EA＝20:1-0/1)纯化分离得到化合物32-e。
步骤F:根据实施例31步骤D，将化合物31-c替换为化合物32-e。后处理得到的残余物经柱层析(PE:EA＝10:1-0:1)纯化分离、制备型HPLC(柱:Luna C18 150mm*25mm 5um；流动相:[水(0.225％FA)-ACN]；ACN％:45％-75％)纯化和SFC(柱:OJ(250mm*30mm,10um)；流动相:[0.1％氨水，甲醇]；0.1％氨水，甲醇]％:40％-40％)拆分分离得到化合物32-I(保留时间：3.298min)和化合物32-II(保留时间：3.291min)。
32-I: 1H NMR(400MHz,DMSO-d 6)δ＝7.93(d,J＝2.6Hz,1H),7.51(d,J＝2.6Hz,1H),7.42(d,J＝8.5Hz,2H),7.37-7.27(m,3H),6.88-6.66(m,2H),5.23(s,2H),4.04(td,J＝7.0,13.6Hz,1H),3.86(s,3H),3.44(s,3H),3.36(s,3H),1.33(d,J＝6.7Hz,3H),0.47(s,3H).MS(ESI)m/z:608.1(M+H) +.
32-II: 1H NMR(400MHz,DMSO-d 6)δ＝7.93(d,J＝2.6Hz,1H),7.51(d,J＝2.8Hz,1H),7.42(d,J＝8.5Hz,2H),7.35-7.28(m,3H),6.83(s,1H),6.71(s,1H),5.23(s,2H),4.04(td,J＝7.2,14.1Hz,1H),3.85(s,3H),3.44(s,3H),3.36(s,3H),1.33(d,J＝6.8Hz,3H),0.48(s,3H).MS(ESI)m/z:608.1(M+H) +.
实施例33
Figure PCTCN2018078010-appb-000190
步骤A：在25℃条件下，向丙二酸二甲酯(20.14g,152.47mmol,17.52mL,2.2eq)的DMF(150mL))溶液中加入t-BuOK(17.11g,152.47mmol,2.2eq)和化合物33-1(13g,69.30mmol,1eq)，加完后将反应体系升温至100℃搅拌24小时。待反应体系冷却至室温用水溶液(100mL)淬灭反应，EtOAc(150mL*2)萃取，合并有机相，饱和食盐水(50mL)洗，无水Na 2SO 4干燥，过滤，滤液经减压浓缩得到残余物。残余物通过柱层析(乙酸乙酯/石油醚＝0:1～1:10)分离纯化得到化合物33-a。
步骤B：在25℃条件下，向化合物33-a(13.5g,43.28mmol,1eq)的DMSO(100mL)溶液中加入氯化锂(5.50g,129.84mmol,2.66mL,3eq)，加完后将反应体系升温至100℃搅拌12小时。待反应液冷却至室温用水溶液(150mL)淬灭反应，EtOAc(150mL*2)萃取，有机相合并后用水(50mL*2)洗，饱和食盐水(30mL)洗涤，无水Na 2SO 4干燥，过滤，滤液经减压浓缩得到残余物。残余物通过柱层析(乙酸乙酯/石油醚＝0:1～1:10)分离纯化得到化合物33-b。
步骤C：在25℃条件下，向化合物33-b(2g,8.88mmol,1eq)的AcOH(15mL)溶液中加入铁粉(1.98g,35.52mmol,4eq)，反应体系升温至100℃搅拌1小时。待反应液冷却至室温用EtOAc(20mL)稀释，过滤，收集滤液并减压浓缩，残余物溶于EtOAc(30mL)后用1N HCl溶液(10mL*2)洗，饱和食盐水(10mL)洗，无水Na 2SO 4干燥，过滤，滤液经减压浓缩得到化合物33-c。
步骤D：在0℃条件下，向化合物33-c(1.3g,7.97mmol,1eq)的DMF(15mL)溶液中加入NBS(1.49g,8.37mmol,1.05eq)，加完后将混合物于0℃搅拌1小时。反应液用水(30mL)稀释，EtOAc(30mL*2)萃取，有机相合并后用饱和食盐水(15mL)洗涤，无水Na 2SO 4干燥，过滤，滤液经真空浓缩得到残余物。残余物经柱层析(乙酸乙酯/石油醚＝0:1～1:1)分离纯化得到化合物33-d。
步骤E：在25℃、氮气保护下，将NaH(91mg,2.28mmol,60％纯度,1.1eq)的甲苯(9mL)溶液加入到化合物33-d(500mg,2.07mmol,1eq)的甲苯(3mL)溶液中，反应体系升温至100℃搅拌1小时。将硫酸二甲酯(200mg,1.59mmol,150.38uL,0.77eq)加入到反应液，反应液于100℃继续搅拌2小时。待反应液冷却至室温后用水(10mL)稀释反应，EtOAc(15mL*2)萃取，有机相合并后用饱和食 盐水(150mL)洗涤，无水Na 2SO 4干燥，过滤，滤液经减压浓缩得到残余物。残余物经柱层析(乙酸乙酯/石油醚＝0:1～1:3)分离纯化得到化合物33-e。
步骤F：在25℃、氮气保护下，将化合物33-e(310mg,1.21mmol,1eq)，频哪醇硼酸酯(550mg,2.17mmol,1.79eq)，KOAc(356mg,3.63mmol,3eq)和Pd(dppf)Cl 2.CH 2Cl 2(198mg,242.46umol,0.2eq)加入到二恶烷(10mL)溶液中，反应体系升温至100℃搅拌12小时。待反应体系冷却至室温后过滤，滤液经减压浓缩得到残余物。残余物经柱层析(乙酸乙酯/石油醚＝0:1～1:5)分离纯化得到化合物33-f。
步骤G：根据实施例32步骤F，将化合物32-e替换为化合物33-f。后处理得到的残余物经柱层析(乙酸乙酯/甲醇＝20:1)分离纯化及制备SFC(柱:OJ(250mm*30mm,10um)；流动相:[0.1％氨水，甲醇]；[0.1％氨水，甲醇]％:25％-25％)拆分分离得到化合物33-I(保留时间:2.148min)和化合物33-II(保留时间:2.374min)。
33-I: 1H NMR(400MHz,DMSO-d 6):δ＝7.92(d,J＝2.8Hz,1H),7.50(d,J＝2.9Hz,1H),7.42(d,J＝8.5Hz,2H),7.31(d,J＝8.0Hz,2H),7.24(s,1H),6.88(s,1H),6.70(s,1H),4.05(td,J＝6.7,13.5Hz,1H),3.83(s,3H),3.53(s,2H),3.44(s,3H),3.19(s,3H),1.33(d,J＝4.5Hz,3H),0.46(s,3H).MS(ESI)m/z:592.1(M+H) +.
33-II: 1H NMR(400MHz,DMSO-d 6):δ＝7.92(d,J＝2.9Hz,1H),7.50(d,J＝2.9Hz,1H),7.42(d,J＝8.7Hz,2H),7.31(d,J＝7.8Hz,2H),7.24(s,1H),6.88(s,1H),6.70(s,1H),4.05(td,J＝6.8,13.6Hz,1H),3.83(s,3H),3.53(s,2H),3.44(s,3H),3.19(s,3H),1.33(d,J＝5.6Hz,3H),0.47(s,3H).MS(ESI)m/z:592.1(M+H) +.
实施例34
Figure PCTCN2018078010-appb-000191
步骤A：在-78℃、氮气氛下，向化合物34-1(4g,19.51mmol,1eq)的四氢呋喃(10mL)溶液中滴加LDA(2.0M,19.51mL,2eq)的四氢呋喃(10mL)溶液，加毕搅拌1小时。然后在-78℃下滴加DMF(2.14g,29.26mmol,2.25mL,1.5eq)后搅拌1小时。向反应液中加入饱和NH 4Cl水溶液(400mL)淬灭反应，EA(100mL*2)萃取，饱和食盐水(100mL*2)洗，无水硫酸钠干燥，过滤，滤液经减压浓缩得 到化合物34-a。
步骤B：在30℃下，向化合物34-a(4.2g,9.01mmol,1eq)的DME(20mL)溶液中分别加入甲氧胺盐酸呀(1.77g,21.19mmol,2.35eq)和碳酸钾(3.2g,23.15mmol,2.57eq)，反应体系搅拌12小时。反应液经减压浓缩后加入水合肼(30mL)和N,N-二甲基乙酰胺(30mL)，反应体系升温150℃搅拌2小时。待反应液冷却至室温，EA(50mL*2)萃取，饱和食盐水(50mL*2)洗，无水硫酸钠干燥，过滤，滤液经减压浓缩得到残余物，残余物经柱层析(PE:EA＝20:1至10:1)纯化分离得到化合物34-b。
步骤C：在0℃下，向化合物34-b(1.4g,6.17mmol,1eq)的四氢呋喃(30mL)溶液中加分批加入NaH(739.90mg,18.50mmol,60％纯度,3eq)，反应液在0℃下搅拌0.5小时后加入碘甲烷(3.78g,26.63mmol,1.66mL,4.32eq)，反应体系升温至25℃搅拌2小时。向反应液中加入无水乙醇(15mL)淬灭反应，EA(30mL*2)萃取，饱和食盐水(30mL*2)洗，无水硫酸钠干燥，过滤，滤液经减压浓缩得到残余物，残余物经柱层析(PE:EA＝20:1至5:1)纯化分离得到化合物34-c。
步骤D：在25℃、氮气氛条件下，向化合物34-c(590mg,2.45mmol,1eq)的1,4-二氧六环(35mL)溶液中分别加入双联频哪醇硼酸酯(1.24g,4.89mmol,2eq)、KOAc(720.54mg,7.34mmol,3eq)和Pd(dppf)Cl 2(358.14mg,489.46umol,0.2eq)，反应体系用氮气置换3次并升温至100℃于氮气氛搅拌12小时。待反应液冷却至室温后过滤，向滤液中加入水(40mL)，EA(30mL*2)萃取，饱和食盐水(30mL*2)洗，无水硫酸钠干燥，过滤，滤液经减压浓缩得到残余物，残余物经柱层析(PE:EA＝20:1至5:1)纯化分离得到化合物34-d。
步骤E：根据实施例32步骤F，将化合物32-e替换为化合物34-d。后处理得到的残余物经HPLC(柱:Boston Green ODS 150mm*25mm*10um；流动相:[水(0.225％FA)-ACN]；ACN％:35％-65％)纯化分离和SFC(柱:AD(250mm*30mm,10um)；流动相:[0.1％氨水，甲醇]；[0.1％氨水，甲醇]％:40％-40％)拆分分离得到化合物34-I(保留时间：2.790min)化合物34-II(保留时间:3.676min)。
34-I: 1H NMR(400MHz,DMSO-d 6)δ＝8.46(s,1H),7.93(d,J＝2.9Hz,1H),7.51(d,J＝2.8Hz,1H),7.44(d,J＝8.7Hz,2H),7.37-7.31(m,4H),6.73(s,1H),4.17(s,3H),4.10(d,J＝6.4Hz,1H),4.07(s,3H),3.46(s,3H),1.34(d,J＝6.4Hz,3H),0.48(s,3H).MS(ESI)m/z:577.1(M+H) +.
34-II:1H NMR(400MHz,DMSO-d6)δ＝8.46(s,1H),7.93(d,J＝2.8Hz,1H),7.51(d,J＝2.9Hz,1H),7.44(d,J＝8.7Hz,2H),7.38-7.31(m,4H),6.73(s,1H),4.17(s,3H),4.10(d,J＝6.8Hz,1H),4.07(s,3H),3.45(s,3H),1.34(d,J＝5.5Hz,3H),0.48(s,3H).MS(ESI)m/z:577.1(M+H) +.
实施例35
Figure PCTCN2018078010-appb-000192
Figure PCTCN2018078010-appb-000193
步骤A：在25℃下，向化合物35-1(0.6g,2.30mmol,1eq)的盐酸(12mL)溶液中加入SnCl 2.2H 2O(5.19g,22.98mmol,10eq)，反应体系在25℃下搅拌0.5小时。反应液经NaOH(1M)溶液调节至pH＝9-10，EA(50mL*3)萃取，收集有机相，饱和食盐水(50mL*2)洗，无水硫酸钠干燥，过滤，滤液经减压浓缩化合物35-a。
步骤B：在0℃下，向化合物35-a(0.5g,2.16mmol,1eq)的原乙酸三乙酯(2.35g,14.49mmol,2.66mL,6.70eq)溶液中加入对甲苯磺酸(27.33mg,143.68mmol,0.066eq)，反应体系搅拌5分钟。反应液经减压浓缩后加入水(10mL)，EA(20mL*2)萃取，饱和食盐水(20mL*2)洗，无水硫酸钠干燥，过滤，滤液经减压浓缩得到残余物，残余物经柱层析(PE:EA＝3:1至0:1)纯化分离得到化合物35-b。
步骤C：在25℃、氮气氛条件下，向化合物35-b(190mg,744.77umol,1eq)的1,4-二氧六环(40mL)溶液中分别加入双联频哪醇硼酸酯(378.25mg,1.49mmol,2eq)，KOAc(219.28mg,2.23mmol,3eq)，三环己基膦(83.54mg,297.91umol,96.58uL,0.4eq)和Pd(OAc) 2(33.44mg,148.95umol,0.2eq)，反应体系用氮气置换3次并升温至100℃于氮气氛搅拌3小时。待反应液冷却至室温后过滤，EA(50mL*2)萃取，饱和食盐水(50mL*2)洗，无水硫酸钠干燥，过滤，滤液经减压浓缩得到残余物，残余物经柱层析(PE:EA＝3:1至0:1)纯化分离得到化合物35-c。
步骤D：根据实施例32步骤F，将化合物32-e替换为化合物35-c。后处理得到的残余物经HPLC(柱:Boston Green ODS 150mm*25mm*5um；流动相:[水(0.225％FA)-ACN]；ACN％:18％-48％)纯化和SFC(柱:AD(250mm*30mm,10um)；流动相:[0.1％氨水，甲醇]；[0.1％氨水，甲醇]％:45％-45％)拆分纯化得到化合物35-I(保留时间：1.814min)和化合物35-II(保留时间:2.749min)。
35-I: 1H NMR(400MHz,DMSO-d 6)δ＝7.92(s,1H),7.50(d,J＝3.4Hz,2H),7.43(d,J＝8.2Hz,2H),7.33(d,J＝7.8Hz,2H),7.27(s,1H),6.72(s,1H),4.00(d,J＝6.2Hz,1H),3.83(s,3H),3.76(s,3H),3.45(s,3H),2.54-2.53(m,3H),1.33(s,3H),0.42(s,3H).MS(ESI)m/z:591.2(M+H) +.
35-II: 1H NMR(400MHz,DMSO-d 6)δ＝7.92(d,J＝2.8Hz,1H),7.51(d,J＝2.8Hz,1H),7.49(s,1H),7.43(d,J＝8.7Hz,2H),7.33(d,J＝8.1Hz,2H),7.27(s,1H),6.72(s,1H),4.06-3.97(m,1H),3.83(s,3H),3.76(s,3H),3.45(s,3H),2.53(s,3H),1.34(d,J＝13.0Hz,3H),0.41(s,3H).MS(ESI)m/z:591.2(M+H) +.
实施例36
Figure PCTCN2018078010-appb-000194
步骤A：0℃，向NaH(70.00mg,1.75mmol,60％纯度,4.24eq)的DMF(3mL)溶液中加入化合物36-1(100mg,413.11umol,1eq)的DMF(3mL)溶液，然后向混合液中加CH 3I(264mg,1.86mmol,115.79uL,4.5eq)。反应体系升温至20℃搅拌1小时。向混合液中加入5mL水，EtOAc(10mL*2)萃取,合并有机相，水洗(8mL*2),饱和食盐水(10mL)洗,Na 2SO 4干燥,过滤，滤液经减压浓缩得到残余物。残余物经柱层析(SiO 2,PE:EA＝1:0-3:1)分离纯化得到化合物36-a。
步骤B：在25℃、氮气保护条件下，向溶有化合物36-a(100mg,351.93umol,1eq)的二恶烷(5mL)溶液中分别加入双联频哪醇硼酸酯(180mg,708.84umol,2.01eq)、KOAc(108mg,1.10mmol,3.13eq)和Pd(dppf)Cl 2.CH 2Cl 2(60mg,73.47umol,0.2eq)，反应体系升温至100-110℃于氮气氛搅拌24小时。待反应液冷却至室温过滤，滤液经减压浓缩得到残余物。残余物经柱层析(PE:EA＝1:1)分离纯化得到化合物36-b。
步骤C：根据实施例32步骤F，将化合物32-e替换为化合物36-b。后处理得到残余物经柱层析(EA:MeOH＝1:0-20:1)分离纯化、HPLC(柱:Phenomenex Synergi C18 150mm*30mm*4um；流动相:[水(0.225％FA)-ACN]；ACN％:40％-70％)分离纯化和SFC(柱:AD(250mm*30mm,10um)；流动相:[0.1％氨水，异丙醇]；[0.1％氨水，异丙醇]％:35％-35％)拆分分离纯化得到化合物36-I(保留时间：0.710min)和化合物36-II(保留时间：1.108min)。
36-I: 1H NMR(400MHz,DMSO-d 6):δ＝7.92(d,J＝2.8Hz,1H),7.51(d,J＝2.8Hz,1H),7.43(d,J＝8.5Hz,2H),7.38(s,1H),7.31(d,J＝8.0Hz,2H),6.91(s,1H),6.72(s,1H),4.07(td,J＝6.8,13.6Hz,1H),3.85(s,3H),3.45(s,3H),3.22(s,3H),1.34(s,J＝6.1Hz,3H),1.27(d,J＝7.9Hz,6H),0.48(s,3H).MS(ESI)m/z:620.2(M+H) +.
36-II: 1H NMR(400MHz,DMSO-d 6):δ＝7.92(d,J＝2.8Hz,1H),7.51(d,J＝2.9Hz,1H),7.43(d,J＝8.7Hz,2H),7.38(s,1H),7.31(br d,J＝8.2Hz,2H),6.91(s,1H),6.72(s,1H),4.12-4.01(m,1H),3.84(s,3H),3.45 (s,3H),3.22(s,3H),1.34(s,J＝6.0Hz,3H),1.27(d,J＝7.8Hz,6H),0.48(s,3H).MS(ESI)m/z:620.2(M+H) +.
实施例37
Figure PCTCN2018078010-appb-000195
步骤A：在0℃下，向化合物37-1(340mg,1.50mmol,1eq)的四氢呋喃(6mL)溶液中加分批加入NaH(179.67mg,4.49mmol,60％纯度,3eq)后搅拌0.5小时，然后加入MeI(0.72g,5.07mmol,315.79uL,3.39eq)，反应体系升温至25℃并搅拌2小时。向反应液中加入无水乙醇(10mL)淬灭反应，EA(15mL*2)萃取，收集有机相，饱和食盐水(15mL*2)洗，无水硫酸钠干燥，过滤，滤液经减压浓缩得到残余物。残余物经柱层析(PE:EA＝20:1至5:1)纯化分离得到化合物37-a。
步骤B：在25℃、氮气氛条件下，向化合物37-a(220.00mg,912.54umol,1eq)的1,4-二氧六环(20mL)溶液中分别加入双联频哪醇硼酸酯(463.46mg,1.83mmol,2eq)，Pd(dppf)Cl 2(133.54mg,182.51umol,0.2eq)和KOAc(268.67mg,2.74mmol,3eq)。反应体系用氮气置换3次并升温至100℃于氮气氛搅拌12小时。待反应液冷却至室温后过滤，滤液经减压浓缩得到残余物。残余物经柱层析(PE:EA＝2:1)纯化分离得到化合物37-b。
步骤C：根据实施例32步骤F，将化合物32-e替换为化合物37-b。处理后的残余物经柱层析(EA:MeOH＝50:1)纯化分离和SFC(柱:AD(250mm*30mm,10um)；流动相:[0.1％氨水，乙醇]；[0.1％氨水，乙醇]％:35％-35％)纯化拆分得到化合物37-I(保留时间：2.046min)和化合物37-II(保留时间:2.230min)。
37-I: 1H NMR(400MHz,DMSO-d 6)δ＝8.83(s,1H),7.92(d,J＝2.7Hz,1H),7.51(d,J＝2.7Hz,1H),7.43(d,J＝8.6Hz,2H),7.37-7.28(m,3H),7.15(d,J＝8.8Hz,1H),6.72(s,1H),4.19(s,3H),4.17-4.11(m,1H),4.08(s,3H),3.67-3.57(m,3H),1.34(d,J＝6.4Hz,3H),0.48(s,3H).MS(ESI)m/z:577.1(M+H) +.
37-II: 1H NMR(400MHz,DMSO-d6)δ＝8.83(s,1H),7.92(d,J＝2.8Hz,1H),7.51(d,J＝2.8Hz,1H),7.43(d,J＝8.6Hz,2H),7.35-7.29(m,3H),7.15(d,J＝8.7Hz,1H),6.72(s,1H),4.19(s,3H),4.15-4.11(m,1H),4.08 (s,3H),3.57-3.54(m,3H),1.34(d,J＝6.6Hz,3H),0.48(s,3H).MS(ESI)m/z:577.1(M+H) +.
实施例38
Figure PCTCN2018078010-appb-000196
步骤A：根据实施例17步骤F，将化合物14-d替换为化合物32-e。后处理得到残余物通过制备型HPLC(柱:Phenomenex Synergi C18 150mm*30mm*4um；流动相:[水(0.225％FA)-ACN]；ACN％:40％-70％)分离纯化和SFC(柱:AD(250mm*30mm,10um)；流动相:[0.1％氨水，乙醇]；[0.1％氨水，乙醇]％:50％-50％)拆分分离得到化合物38-I(保留时间：1.342min)和化合物38-II(保留时间：2.923min)。
38-I: 1HNMR(400MHz,DMSO-d 6)δ＝8.00(d,J＝2.8Hz,1H),7.52(d,J＝2.8Hz,1H),7.35(s,1H),7.19(d,J＝3.9Hz,1H),7.04-6.96(m,2H),6.84(s,1H),5.23(s,2H),4.11(td,J＝6.7,13.4Hz,1H),3.87(s,3H),3.48(s,3H),3.37(s,3H),1.38(d,J＝6.4Hz,3H),0.75(d,J＝5.7Hz,3H).MS(ESI)m/z:614.1(M+H) +.
38-II: 1H NMR(400MHz,DMSO-d 6)δ＝8.00(d,J＝2.8Hz,1H),7.52(d,J＝2.8Hz,1H),7.35(s,1H),7.19(d,J＝3.8Hz,1H),7.04-6.96(m,2H),6.84(s,1H),5.23(s,2H),4.11(td,J＝6.7,13.5Hz,1H),3.87(s,3H),3.48(s,3H),3.37(s,3H),1.38(d,J＝6.5Hz,3H),0.75(d,J＝5.5Hz,3H).MS(ESI)m/z:614.1(M+H) +.
实施例39
Figure PCTCN2018078010-appb-000197
步骤A：根据实施例17步骤F，将化合物14-d替换为化合物33-f。后处理得到的残余物依次用柱 层析(EA:MeOH＝10:1)分离纯化、制备型HPLC(柱:Phenomenex Synergi C18 150mm*30mm*4um；流动相:[水(0.225％FA)-ACN]；ACN％:35％-65％)分离纯化和SFC(柱:AD(250mm*50mm,10um)；流动相:[中性-甲醇]；甲醇％:40％-40％)拆分分离得到化合物39-I(0.937min)和化合物39-II(保留时间：1.609min)。
39-I： 1H NMR(400MHz,METHANOL-d 4):δ＝7.70(d,J＝2.8Hz,1H),7.48(d,J＝2.7Hz,1H),7.20(s,1H),6.99(d,J＝3.8Hz,1H),6.94(s,1H),6.79-6.74(m,2H),4.18(td,J＝6.7,13.5Hz,1H),3.81(s,3H),3.50(s,3H),3.19(s,3H),1.44-1.33(d,3H),0.79(d,J＝7.0Hz,3H).MS(ESI)m/z:598.1(M+H) +.
39-II： 1H NMR(400MHz,METHANOL-d 4):δ＝7.70(d,J＝2.8Hz,1H),7.48(d,J＝2.7Hz,1H),7.20(s,1H),6.99(d,J＝3.8Hz,1H),6.94(s,1H),6.79-6.73(m,2H),4.24-4.13(m,1H),3.81(s,3H),3.50(s,3H),3.19(s,3H),1.43-1.31(d,3H),0.80(d,3H).MS(ESI)m/z:598.1(M+H) +.
实施例40
Figure PCTCN2018078010-appb-000198
步骤A：在25℃,氮气氛下，向化合物34-d(320mg,1.11mmol,1.5eq)的1,4-二氧六环(30mL)和水(3mL)的混合溶液中分别加入化合物17-e(371.82mg,740.36umol,1eq)、K 3PO 4(314.31mg,1.48mmol,2eq)和Pd(dppf)Cl 2(108.34mg,148.07umol,0.2eq)。反应体系置换氮气3次并升温至100℃于氮气氛搅拌2小时。待反应液冷却室温后过滤，滤液经减压浓缩得到残余物。后处理得到的残余物经HPLC(柱:Boston Green ODS 150mm*25mm*10um；流动相:[水(0.225％FA)-ACN]；ACN％:42％-62％)纯化分离和SFC(柱:AD(250mm*50mm,10um)；流动相:[0.1％氨水，甲醇]；[0.1％氨水，甲醇]％:50％-50％)拆分分离得到化合物40-I(保留时间：1.925min)和化合物40-II(保留时间:2.244min)。
40-I: 1H NMR(400MHz,DMSO-d 6)δ＝8.47(s,1H),8.01(d,J＝2.8Hz,1H),7.54(d,J＝2.8Hz,1H),7.36(s,2H),7.20(d,J＝3.8Hz,1H),7.02(d,J＝3.8Hz,2H),4.19(s,3H),4.16-4.08(m,1H),4.07(s,3H),3.50(s,3H),1.39(d,J＝4.6Hz,3H),0.75(s,3H).MS(ESI)m/z:583.2(M+H) +.
40-II: 1H NMR(400MHz,DMSO-d 6)δ＝8.47(s,1H),8.01(d,J＝2.7Hz,1H),7.54(d,J＝2.8Hz,1H),7.36(s,2H),7.20(d,J＝3.8Hz,1H),7.04-6.99(m,2H),4.19(s,3H),4.17-4.08(m,1H),4.07(s,3H),3.50(s,3H),1.56-1.31(m,3H),0.75(s,3H).MS(ESI)m/z:583.2(M+H) +.
实施例41
Figure PCTCN2018078010-appb-000199
步骤A：20℃条件下，向化合物7-1(1g,4.29mmol,1eq)的DMF(16mL)溶液中分别加入碳酸钾(1.78g,12.87mmol,3eq)和水合肼(1.01g,17.16mmol,4eq)，反应体系升温至60℃并搅拌12小时。向反应液中加入水(50mL)淬灭反应，EA(50mL*2)萃取，收集有机相，饱和食盐水(100mL*2)洗，无水硫酸钠干燥，过滤，滤液经减压浓缩得到残余物。残余物经柱层析分离纯化得到化合物41-a。
步骤B：25℃、氮气氛下，向化合物41-a(500mg,2.2mmol,1eq)和频哪醇联硼酸酯(1.12g,4.4mmol,2eq)的二恶烷(25mL)溶液中分别加入醋酸钾(432.2mg,4.4mmol,2eq)和Pd(dppf)Cl 2.CH 2Cl 2(359.6mg,0.44mmol,0.2eq)，反应体系升温至80℃于氮气氛下搅拌12小时，待反应液冷却至室温，过滤，滤液减压浓缩得到残余物。残余物经柱层析(PE:EA＝3:1-1:1)分离纯化得到化合物41-b。
步骤C：根据实施例40步骤A，将化合物34-d替换为化合物41-b。经过后处理残余物经过柱层析(EA:MeOH＝20:1-10:1)纯化和SFC(柱:AD(250mm*50mm,10um)；流动相:[0.1％氨水乙醇]；[0.1％氨水乙醇]％:50％-50％)拆分纯化得到化合物41-I(保留时间：3.101min)和化合物41-II(保留时间：3.797min)。
41-I: 1H NMR(400MHz,DMSO-d 6)δ＝13.08(s,1H),8.03(s,1H),7.99(d,J＝2.76Hz,1H),7.81(s,1H),7.51(d,J＝2.76Hz,1H),7.18(d,J＝3.51Hz,1H),7.09(s,1H),6.99(d,J＝3.64Hz,2H),4.14-3.98(m,1H),3.89-3.77(m,3H),3.47(s,3H),1.45-1.30(m,3H),0.67(s,3H).MS(ESI)m/z:569.1(M+H) +.
41-II: 1H NMR(400MHz,DMSO-d 6)δ＝13.08(s,1H),8.03(s,1H),7.99(d,J＝2.76Hz,1H),7.81(s,1H),7.51(d,J＝2.89Hz,1H),7.18(d,J＝3.76Hz,1H),7.09(s,1H),6.99(d,J＝3.64Hz,2H),4.12-4.00(m,1H),3.83(s,3H),3.47(s,3H),1.44-1.30(m,3H),0.67(s,3H).MS(ESI)m/z:569.1(M+H) +.
实施例42
Figure PCTCN2018078010-appb-000200
Figure PCTCN2018078010-appb-000201
步骤A：在25℃下，向化合物7-c(1g,3.47mmol,1eq)的乙腈(15mL)溶液中加入Select F试剂(1.48g,4.16mmol,1.2eq)，反应体系搅拌4小时。反应液经饱和NH 4Cl水溶液(20mL)洗涤，EtOAc(20mL*2)萃取，有机相合并，饱和食盐水(20mL*2)洗，无水Na 2SO 4干燥，过滤，滤液经真空浓缩得到残余物。残余物经柱层析(EtOAc/PE＝1:3～1:1)分离纯化得到化合物42-a。
步骤B：根据实施例40步骤A，将化合物34-d替换为化合物42-a。后处理得到的残余物通过柱层析(DCM:MeOH＝20:1)分离纯化和SFC(柱:AD(250mm*50mm,10um)；流动相:[0.1％氨水，甲醇]；[0.1％氨水，甲醇]％:60％-60％)拆分分离得到化合物42-I(保留时间0.571min)和化合物42-II(保留时间1.621min)。
42-I： 1H NMR(400MHz,DMSO-d 6)δppm 0.76(d,J＝4.89Hz,3H)1.37(d,J＝6.24Hz,3H)3.83(s,3H)4.13(s,1H)4.19(s,3H)6.91-7.09(m,2H)7.18(d,J＝2.93Hz,1H)7.53(s,1H)7.73(s,1H)7.98(s,1H)8.15(s,1H).MS(ESI)m/z:601.1(M+H) +.
42-II: 1H NMR(400MHz,DMSO-d 6)δppm 0.76(d,J＝6.11Hz,3H)1.37(d,J＝6.48Hz,3H)3.47-3.52(m,3H)3.83(s,3H)4.10-4.17(m,1H)4.19(s,3H)7.01(d,J＝3.79Hz,1H)7.04(s,1H)7.19(d,J＝3.79Hz,1H)7.54(d,J＝2.81Hz,1H)7.74(s,1H)8.00(d,J＝2.69Hz,1H)8.15(d,J＝2.20Hz,1H).MS(ESI)m/z:601.1(M+H) +.
实施例43
Figure PCTCN2018078010-appb-000202
步骤A：在0℃下，向化合物7-b(400mg,1.65mmol,1eq)的乙酸酐(2mL)溶液中加入浓硝酸(345.71mg,3.29mmol,246.93uL,2eq)。反应体系于0℃搅拌1小时，将反应液倒入EtOAc(15mL)中，有机相用饱和碳酸氢钠溶液(10mL*2)洗涤，饱和食盐水(10mL*2)洗，无水Na 2SO 4干燥，过滤，滤液经真空浓缩得到化合物43-a。
步骤B：在25℃、氮气保护下，将化合物43-a(400mg,1.40mmol,1eq)、频哪醇双联硼酸酯(532.58mg,2.10mmol,1.5eq)、KOAc(411.67mg,4.19mmol,3eq)和Pd(dppf)Cl 2(102.31mg,139.82umol,0.1eq)加入二恶烷(8.00mL)溶液中，反应体系升温至90℃下搅拌12小时。待反应液冷却至室温减压浓缩。将残余物倒入水(20mL)中，乙酸乙酯(20mL*2)萃取，合并的有机相，饱和食盐水(20mL*2)洗，无水Na 2SO 4干燥，过滤,滤液经真空浓缩得到。残余物通过柱层析(石油醚:乙酸乙酯＝0:1)分离纯化得到化合物43-b。
步骤C：根据实施例40步骤a，将化合物34-d替换为化合物43-b。后处理得到残余物通过柱层析(EtOAc:MeOH＝20:1)分离纯化后得到化合物43-c。
步骤D：在25℃下，将化合物43-c(180mg,286.40umol,1eq)、铁粉(47.98mg,859.21umol,3eq)和NH 4Cl(45.96mg,859.21umol,30.04uL,3eq)加入EtOH(2mL)和H 2O(0.5mL)的混合溶液，反应液升温至80℃并搅拌6小时。待反应液冷却至室温，过滤，滤液经真空浓缩得到残余物。将残余物倒入水(10mL)中，二氯甲烷10mL*2)萃取，合并有机相，饱和食盐水(10mL*2)洗，无水Na 2SO 4干燥,过滤，滤液经真空浓缩得到残余物。残余物用制备型HPLC(柱:Boston Green ODS 150*30 5u；流动相:[水(0.225％FA)-ACN]；ACN％:40％-67％)分离纯化和SFC(柱:AD(250mm*30mm,10um)；流动相:[0.1％氨水，乙醇]；[0.1％氨水，乙醇]％:50％-50％)拆分分离得到化合物43-I(保留时间3.441min)和化合物43-II(保留时间4.283min)。
43-I： 1HNMR(400MHz,CHLOROFORM-d)δppm 0.46-1.01(m,3H)1.38(s,3H)3.45-3.51(m,3H)3.74(s,3H)3.84(s,3H)4.01-4.16(m,1H)5.49(s,2H)6.92-7.04(m,3H)7.19(d,J＝3.76Hz,1H)7.53(d,J＝2.76Hz,1H)7.75(s,1H)7.93-8.06(m,1H).MS(ESI)m/z:598.1(M+H) +.
43-II: 1HNMR(400MHz,CHLOROFORM-d)δppm 0.53-0.91(m,3H)1.26-1.49(m,3H)3.49(s,3H)3.74(s,3H)3.99-4.17(m,1H)5.49(s,2H)6.93-7.07(m,3H)7.19(br d,J＝3.51Hz,1H)7.53(d,J＝2.76Hz,1H)7.76(s,1H)8.00(d,J＝2.76Hz,1H).MS(ESI)m/z:598.1(M+H) +.
实施例44
Figure PCTCN2018078010-appb-000203
Figure PCTCN2018078010-appb-000204
步骤A：在0℃下，向化合物41-a(1.4g,6.17mmol,1eq)的四氢呋喃(3mL)溶液中加NaH(616.52mg,15.41mmol,60％纯度,2.5eq)，反应液搅拌0.5小时。向反应液中加入碘乙烷(1.92g,12.33mmol,986.31uL,2eq)，在30℃下搅拌2小时。反应液经减压浓缩得到残余物。残余物通过柱层析(PE:EA＝5:1)纯化分离得到化合物44-a。
步骤B：在25℃下，向化合物44-a(600mg,2.35mmol,1eq)的1,4-二氧六环(20mL)溶液中分别加入双联频哪醇硼酸酯(1.19g,4.70mmol,2eq)，KOAc(692.47mg,7.06mmol,3eq)，和Pd(dppf)Cl 2(344.18mg,470.38umol,0.2eq)，反应体系用氮气置换三次并升温至100℃于氮气氛搅拌3小时。反应液冷却至室温后，过滤，滤液经减压浓缩得到残余物。残余物经柱层析(PE:EA＝3:1)纯化分离得到化合物44-b。
步骤C：在25℃、氮气氛下，向化合物44-b(300mg,992.80umol,1.5eq)的1,4-二氧六环(10mL)和水(2mL)的混合溶液中分别加入化合物17-e(332.40mg,661.87umol,1eq)、sPHOS-PD-G(95.39mg,132.37umol,0.2eq)和K 3PO 4(280.98mg,1.32mmol,2eq)，反应体系置换氮气三次并升温至80℃于氮气氛搅拌3小时。反应液冷却至室温后过滤，滤液经减压浓缩得到残余物。残余物经柱层析(PE:EA＝0:1)分离和SFC(柱:AD(250mm*30mm,10um)；流动相:[0.1％氨水，甲醇]；[0.1％氨水，甲醇]％:40％-40％)纯化拆分得到化合物44-I(保留时间：2.617min)和化合物44-II(保留时间:3.409min)。
44-I： 1H NMR(400MHz,DMSO-d 6)δ＝8.03(s,1H),8.00(d,J＝2.89Hz,1H),7.82(s,1H),7.53(d,J＝2.89Hz,1H),7.34(s,1H),7.20(d,J＝3.51Hz,1H),7.01(d,J＝3.39Hz,2H),4.46(q,J＝6.99Hz,2H),4.11-4.03(m,1H),3.88(s,3H),3.49(s,3H),1.46-1.30(m,6H),0.70(s,3H).MS(ESI)m/z:597.1(M+H) +.
44-II: 1H NMR(400MHz,DMSO-d 6)δ＝8.04(s,1H),8.01(d,J＝2.8Hz,1H),7.82(s,1H),7.54(d,J＝2.8Hz,1H),7.34(s,1H),7.20(d,J＝3.8Hz,1H),7.05-6.99(m,2H),4.46(q,J＝7.2Hz,2H),4.09(td,J＝6.3,13.1Hz,1H),3.89(s,3H),3.50(s,3H),1.52-1.38(m,6H),0.90-0.77(m,3H).MS(ESI)m/z:597.1(M+H) +.
实施例45
Figure PCTCN2018078010-appb-000205
Figure PCTCN2018078010-appb-000206
步骤A：在-15℃下，向化合物7-1(5g,32.44mmol,1eq)的浓硫酸(50mL)溶液中滴加浓硝酸(4.43g,42.17mmol,3.16mL,1.3eq)，反应液在-15℃下搅拌2小时。反应液滴加至水中(200mL)，过滤，收集滤饼得到化合物45-a。
步骤B：在25℃下，向化合物45-a(5.5g,27.62mmol,1eq)的二甲亚砜(50mL)溶液中分别加入水合肼(4.88g,82.86mmol,4.74mL,3eq)和碳酸钾(7.63g,55.24mmol,2eq)，反应液升温至80℃搅拌2小时。反应液滴加至水中(200mL)，过滤，收集滤饼得到化合物45-b。
步骤C：在25℃下，向化合物45-b(3g,15.53mmol,1eq)和2-碘-1,1,1-三氟乙烷的DMF(30mL)溶液中加入碳酸钾(6.44g,46.59mmol,3eq)，反应体系升温至80℃下搅拌12小时。反应液经减压浓缩得到残余物。残余物经柱层析(PE:EA＝5:1)纯化分离得到化合物45-c。
步骤D：在25℃下，向化合物45-c(1.68g,6.11mmol,1eq)的EtOH(20mL)和H 2O(2mL)溶液中分别加入铁粉(1.70g,30.53mmol,5eq)和氯化铵(1.63g,30.53mmol,1.07mL,5eq)，反应体系升温至80℃下搅拌2小时。反应液经减压浓缩得到化合物45-d。
步骤E：在0℃下，向化合物45-d(600mg,2.45mmol,1eq)的MeOH(5mL)溶液中分别滴加盐酸溶液(3M,2.45mL,3eq)和亚硝酸钠(202.60mg,2.94mmol,1.20eq)的水(1.5mL)溶液，反应体系搅拌1小时。随后将频哪醇双联硼酸酯(1.86g,7.34mmol,3eq)的甲醇(5mL)溶液加入并升温至25℃下搅拌12小时。反应液经减压浓缩得到残余物，残余物经柱层析(PE:EA＝5:1)纯化分离得到化合物45-e。
步骤F：根据实施例40步骤A，将化合物34-d替换为化合物45-e。后处理得到的残余物经柱层析(PE:EA＝1:2)纯化分离和SFC(柱:AD(250mm*30mm,10um)；流动相:[0.1％氨水，甲醇]；[0.1％氨水，甲醇]％:45％-45％)纯化拆分得到化合物45-I(保留时间：1.764min)和化合物45-II(保留时间:2.277min)。
45-I: 1H NMR(400MHz,DMSO-d 6)δ＝8.20(s,1H),8.00(d,J＝2.6Hz,1H),7.89(s,1H),7.56(s,1H),7.54(d,J＝2.7Hz,1H),7.20(br d,J＝3.3Hz,1H),7.04-7.00(m,2H),5.47(q,J＝9.0Hz,2H),4.14-4.03(m,1H),3.88(s,3H),3.50(s,3H),1.39(br s,3H),0.73(br s,3H).MS(ESI)m/z:651.1(M+H) +.
45-II: 1H NMR(400MHz,DMSO-d 6)δ＝8.19(s,1H),8.01(d,J＝2.8Hz,1H),7.89(s,1H),7.57(s,1H),7.54(d,J＝2.8Hz,1H),7.20(d,J＝3.7Hz,1H),7.03-7.01(m,2H),5.47(q,J＝9.2Hz,2H),4.12-4.05(m,1H),3.88(s,3H),3.50(s,3H),1.49-1.34(m,3H),0.73(br s,3H).MS(ESI)m/z:651.1(M+H) +.
实施例46
Figure PCTCN2018078010-appb-000207
步骤A：在0℃下，向化合物7-b(500mg,2.07mmol,1eq)的二氯甲烷(5mL)溶液中滴加三溴化硼(1.56g,6.22mmol,599.51uL,3eq)，反应体系置换氮气三次于氮气氛搅拌0.5小时后升温至25℃搅拌16小时。25℃下，向反应液中加入甲醇(20mL)搅拌15分钟淬灭反应，反应液经减压浓缩得到残余物。残余物经柱层析(PE:EA＝10:1；PE:MeOH＝50:1)纯化分离得到化合物46-a。
步骤B：在25℃下，向化合物46-a(850mg,2.06mmol,1eq)的水(0.5mL)和DMF(5mL)溶液中分别加入碳酸钾(1.42g,10.29mmol,5eq)和二氟氯乙酸钠(1.57g,10.29mmol,5eq)，反应体系置换氮气3次并升温至110℃于氮气氛搅拌12小时。反应冷却至25℃后加入至水(20mL)中搅拌5分钟，EA(20mL*4)萃取，收集有机相，饱和食盐水(20mL*4)洗，无水硫酸钠干燥，过滤，滤液经减压浓缩得到残余物，残余物经柱层析(PE:EA＝10:1)纯化分离得到化合物46-b。
步骤C：在25℃、氮气氛下，向化合物46-b(241mg,869.83umol,1eq)的1,4-二氧六环(20mL)溶液中分别加入双联频哪醇硼酸酯(265.06mg,1.04mmol,1.2eq)，KOAc(170.73mg,1.74mmol,2eq)，和Pd(dppf)Cl 2(63.65mg,86.98umol,0.1eq)，反应体系置换氮气3次并升温至90℃于氮气氛搅拌12小时。待反应液冷却至室温后过滤，EA(20mL)冲洗滤饼，滤液经减压浓缩得到残余物。残余物经HPLC(柱:Boston Green ODS 150mm*30mm*4um；流动相:[水(0.225％FA)-ACN]；B％:50％-80％,10.5min)纯化分离得到化合物46-c。
步骤D：根据实施例40步骤A，将化合物34-d替换为化合物46-c。后处理得到残余物经柱层析(PE:EA＝2:1)分离纯化、制备型HPLC(柱:Boston Green ODS 150mm*30mm*4um；流动相:[水(0.225％FA)-ACN]；ACN％:55％-85％)纯化和SFC(柱:AD(250mm*30mm,10um)；流动相:[0.1％氨水，甲醇]；[0.1％氨水，甲醇]％:50％-50％)拆分分离得到化合物46-I(保留时间：2.306min)和化合物46-II(保留时间:2.942min)。
46-I: 1H NMR(400MHz,DMSO-d 6)δ＝8.17(s,1H),8.04(s,1H),7.99(d,J＝2.8Hz,1H),7.65(s,1H),7.57-7.49(m,1H),7.33(s,1H),7.23-7.12(m,1H),7.05(s,1H),7.00(d,J＝3.8Hz,1H),4.17-4.08(m,4H),3.49(s,3H),1.39-1.33(m,3H),0.78(d,J＝5.4Hz,3H).MS(ESI)m/z:619.1(M+H) +.
46-II: 1H NMR(400MHz,DMSO-d6)δ＝8.18(s,1H),8.04(s,1H),8.00(d,J＝2.8Hz,1H),7.66(s,1H),7.56-7.51(m,1H),7.56-7.51(m,1H),7.34(s,1H),7.20-7.14(m,1H),7.06(s,1H),7.01(d,J＝3.8Hz,1H),4.19-4.07(m,5H),3.50(s,3H),1.43-1.33(m,3H),0.78(d,J＝5.6Hz,3H).MS(ESI)m/z:619.1(M+H) +.
实施例47
Figure PCTCN2018078010-appb-000208
步骤A：在15℃下，向化合物47-1(3.8g,13.24mmol,1eq)、铁粉(7.39g,132.35mmol,10eq)和氯化铵(7.08g,132.35mmol,4.63mL,10eq)的异丙醇(80mL)溶液中加入甲酸(97.60g,2.12mol,80mL,160.22eq)，反应体系升温至70℃搅拌2小时。待反应液冷却至室温，将反应液缓慢加入到氢氧化钾的水溶液(150mL)中并过滤，滤液用乙酸乙酯萃取(200mL*2)，合并有机相，饱和食盐水(100mL*2)洗，无水硫酸钠干燥，过滤，滤液经减压浓缩滤液得到化合物47-a。
步骤B：在25℃、氮气保护下，向三口瓶中加入化合物47-a(0.5g,1.87mmol,1eq)、双频哪醇硼酸酯(950.64mg,3.74mmol,2eq)、醋酸钾(551.11mg,5.62mmol,3eq)、醋酸钯(84.05mg,374.36umol,0.2eq)和配体PCy3(209.96mg,748.72umol,242.73uL,0.4eq)，随后加入二氧六环溶液(8mL)，反应体系升温至80℃搅拌12小时。待反应液冷却至室温过滤，滤液经减压浓缩滤液得到残余物。残余物经HPLC(柱：Phenomenex Synergi C18 150mm*30mm*4um；流动相:[水(0.225％FA)-ACN]；ACN％:0％- 30％,10.5min)纯化得到化合物47-b。
步骤C：根据实施例40步骤A，将化合物34-d替换为化合物47-b。后处理得到的残余物分别通过柱层析(EA:MeOH＝7：1)纯化分离、HPLC(柱：Phenomenex Synergi C18 150mm*30mm*4um；流动相:[水(0.225％FA)-ACN]；ACN％:35％-59％,10.5min)分离纯化和SFC(柱:OJ(250mm*30mm,10um)；流动相:[0.1％氨水，甲醇]；[0.1％氨水，甲醇]％:50％-50％)拆分分离得到化合物47-I(保留时间：1.228min)和化合物47-II(保留时间：2.372min)。
47-I: 1H NMR(400MHz,METHANOL-d 4)δ＝8.20(s,1H),7.81(d,J＝2.64Hz,1H),7.73(s,1H),7.60(d,J＝2.64Hz,1H),7.36(s,1H),7.10(d,J＝3.76Hz,1H),7.07(s,1H),6.87(d,J＝3.76Hz,1H),4.24(d,J＝7.78Hz,1H),3.95(s,3H),3.60-3.51(m,2H),1.67-1.36(m,3H),1.24(d,J＝6.90Hz,2H),1.13(s,2H),0.97-0.68(m,3H).MS(ESI)m/z:609.1(M+H) +.
47-II: 1H NMR(400MHz,METHANOL-d 4)δ＝8.21(s,1H),7.80(d,J＝2.76Hz,1H),7.72(s,1H),7.60(d,J＝2.51Hz,1H),7.36(s,1H),7.10(d,J＝3.76Hz,1H),7.06(s,1H),6.87(d,J＝3.89Hz,1H),4.24(br s,1H),3.94(s,3H),3.66-3.48(m,4H),1.48(dd,J＝9.54,7.03Hz,3H),1.24(d,J＝6.65Hz,2H),1.12(s,2H),1.01–0.75(m,3H).MS(ESI)m/z:609.1(M+H) +.
实施例48
Figure PCTCN2018078010-appb-000209
步骤A：根据实施例40步骤A，将化合物34-d替换为化合物11-g。后处理得到的残余物通过柱层析(PE:EA＝10:1-EA:MeOH＝5:1)HPLC(柱:Phenomenex Synergi C18 150mm*25mm*10um；流动相:[水(0.225％FA)-ACN]；ACN％:21％-51％)分离纯化和SFC(柱:AS(250mm*30mm,10um)；流动相:[0.1％氨水，甲醇]；[0.1％氨水，甲醇]％:30％-30％)拆分分离得到化合物48-I(保留时间：2.147min)和化合物48-II(保留时间:2.396min)。
48-I: 1H NMR(400MHz,DMSO-d 6)δ＝8.17(s,1H),7.99(d,J＝2.8Hz,1H),7.65(s,1H),7.53(d,J＝2.8Hz,1H),7.34(s,1H),7.19(d,J＝3.6Hz,1H),7.01(d,J＝2.3Hz,2H),4.16-4.02(m,1H),3.90-3.81(m,6H),3.49(s,3H),1.38(s,3H),0.90-0.52(m,3H).MS(ESI)m/z:583.1(M+H) +.
48-II: 1H NMR(400MHz,DMSO-d 6)δ＝8.18(s,1H),8.00(d,J＝2.6Hz,1H),7.66(s,1H),7.54(d,J＝2.8Hz,1H),7.35(s,1H),7.19(d,J＝3.8Hz,1H),7.01(d,J＝2.3Hz,2H),4.16-4.00(m,1H),3.92-3.79(m,6H),3.49(s,3H),1.39(d,J＝6.8Hz,3H),0.71(s,3H).MS(ESI)m/z:583.1(M+H) +.
实施例49
Figure PCTCN2018078010-appb-000210
步骤A：-70℃、氮气氛下，向化合物18(140mg,0.24mmol,1eq)的四氢呋喃溶液(2mL)中逐滴加入KHMDS(1M,1.20mL,5eq)溶液，滴加完毕反应体系于-70℃、氮气氛下搅拌30分钟。随后向反应液中滴加溴甲基甲基醚(89.95mg,0.72mmol,3eq)，滴加完毕，反应体系于-70℃、氮气氛下搅拌30分钟。反应体系升温至20℃搅拌12小时。向反应体系中加入氯化铵水溶液(10mL)淬灭反应，EA(10mL*3)萃取，收集有机相，饱和食盐水(10mL*2)洗，无水硫酸钠干燥，过滤，减压浓缩得到残余物。残余物经柱层析分离(EA:MeOH＝10:1)、HPLC(柱：Phenomenex Synergi C18 150mm*30mm*4um；流动相:[水(0.225％FA)-ACN]；ACN％:40％-70％,10.5min)纯化以及SFC(柱:OD(250mm*30mm,10um)；流动相:[0.1％氨水，甲醇]；[0.1％氨水，甲醇]％:30％-30％)拆分得到化合物49-I(保留时间：2.826min)和化合物49-II(保留时间：3.014min)。
49-I: 1H NMR(400MHz,DMSO-d 6)δ＝8.09(d,J＝2.8Hz,1H),8.03(s,1H),7.83(s,1H),7.29(s,1H),7.05(d,J＝3.7Hz,1H),6.95(s,1H),6.82(s,1H),4.36(s,1H),4.17-4.02(m,5H),3.86(s,3H),3.43(s,2H),3.33-3.32(m,3H),1.23(s,1H),1.16-1.07(m,3H),1.02-0.92(m,3H).MS(ESI)m/z:627.1(M+H) +.
49-II: 1H NMR(400MHz,DMSO-d 6)δ＝8.09(d,J＝2.8Hz,1H),8.03(s,1H),7.83(s,1H),7.29(s,1H),7.05(d,J＝3.8Hz,1H),6.95(s,1H),6.81(s,1H),4.29(s,1H),4.18-4.01(m,5H),3.86(s,3H),3.43(s,3H),3.32(s,3H),1.15-0.92(m,6H).MS(ESI)m/z:627.1(M+H) +.
实施例50
Figure PCTCN2018078010-appb-000211
Figure PCTCN2018078010-appb-000212
步骤A：在-78℃、氮气保护条件下，向KHMDS(1M,488.44uL,2eq)中逐滴加入化合物18的四氢呋喃(2mL)溶液，反应体系升温至0℃下搅拌30分钟。反应液冷却至-78℃，滴加MeI(103.99mg,732.66umol,45.61uL,3eq)并搅拌30分钟。反应体系升温至20℃搅拌1小时。向反应液中加入NH 4Cl水溶液(10mL)，乙酸乙酯(20mL*4)萃取，合并有机相，饱和食盐水(20mL*2)洗涤,Na 2SO 4干燥,过滤，滤液经减压浓缩得到残余物。残余物经HPLC(柱:Phenomenex Synergi C18 150mm*30mm*4um；流动相:[水(0.225％FA)-ACN]；ACN％:38％-68％,10.5min)分离纯化和SFC(柱:OD(250mm*30mm,10um)；流动相:[0.1％氨水，乙醇]；[0.1％氨水，乙醇]％:40％-40％)拆分分离得到化合物50-I(保留时间：2.787min)和化合物50-II(保留时间：3.038min)。
50-I： 1H NMR(400MHz,METHANOL-d 4)δ＝8.01(s,1H),7.93(d,J＝2.8Hz,1H),7.86(s,1H),7.18(s,1H),7.14-7.03(m,1H),6.95(d,J＝3.9Hz,1H),6.86-6.70(m,1H),4.38-4.20(m,1H),4.08(s,3H),3.93(s,3H),3.58(s,3H),2.12-1.97(m,3H),1.40-1.26(m,3H),1.17(m,3H).MS(ESI)m/z:597.1(M+H) +.
50-II: 1H NMR(400MHz,METHANOL-d 4)δ＝8.02(s,1H),7.94(d,J＝2.6Hz,1H),7.86(s,1H),7.19(s,1H),7.14-7.03(m,1H),6.96(d,J＝3.8Hz,1H),6.87-6.68(m,1H),4.28(td,J＝6.8,13.7Hz,1H),4.08(s,3H),3.93(s,3H),3.58(s,3H),2.06(s,3H),1.37-1.27(m,3H),1.23-1.14(m,3H).MS(ESI)m/z:597.1(M+H) +.
实施例51
Figure PCTCN2018078010-appb-000213
Figure PCTCN2018078010-appb-000214
步骤A：20℃条件下，向化合物51-1(10g,64.88mmol,1eq)的DMF(150mL)溶液中分别加入碳酸钾(27g,195.36mmol,3.01eq)和碘甲烷(18.24g,128.51mmol,8mL,1.98eq)，反应体系搅拌12小时。反应液过滤，滤液减压浓缩后溶于二氯甲烷(200mL)，过滤，滤液经减压浓缩得到化合物51-a。
步骤B：25℃条件下，向化合物51-a(4g,23.79mmol,1eq)的乙醇(80mL)和水(8mL)的混合溶液中分别加入铁粉(13.28g,237.88mmol,10eq)和氯化铵(7.63g,142.73mmol,6eq)，反应体系升温至100℃搅拌12小时。待反应体系冷却至室温后过滤，滤饼经EA(40mL)洗，收集滤液，饱和食盐水洗(20mL*2)，无水硫酸钠干燥，过滤，滤液经减压浓缩得到残余物。残余物经柱层析(PE:EA＝1:0-0:1)分离纯化得到化合物51-b。
步骤C：根据实施例16步骤C、D的顺序，将化合物3-氨基-5-氯-1-甲基-吡啶-2-酮替换为化合物51-b。后处理的得到化合物51-c。
步骤D：25℃、氮气氛下，向化合物51-c(500mg,1.04mmol,1eq)和26-b(390mg,1.35mmol,1.3eq)的二恶烷(20mL)和水(5mL)的混合溶液中分别加入磷酸钾(440mg,2.07mmol,2eq)和Pd(dppf)Cl 2(76mg,103.9mmol,0.1eq)，反应体系升温至100℃于氮气氛下搅拌12小时。待反应液冷却至室温，过滤，滤饼经EA(15mL)洗，收集滤液减压浓缩得到残余物。残余物经经柱层析(PE:EA＝1:0-0:1)分析纯化、HPLC(柱:Luna C18 150mm*25mm 5um；流动相:[水(0.225％FA)-ACN]；ACN％:45％-65％)分离及SFC(柱:DAICEL CHIRALPAK AD(250mm*30mm,10um)；流动相:[0.1％氨水，乙醇]；[0.1％氨水，乙醇]％:50％-50％)分离纯化得到化合物51-I(保留时间：0.543min)和化合物51-II(保留时间：1.499min)。
51-I: 1H NMR(400MHz,DMSO-d 6)δ＝8.34(s,1H),8.10(s,1H),7.52(s,1H),7.31(d,J＝2.0Hz,1H),7.20(d,J＝3.7Hz,1H),7.00(s,2H),4.13(td,J＝6.7,13.4Hz,1H),4.02(d,J＝6.7Hz,6H),3.47(s,3H),2.02(s,3H),1.39(d,J＝6.2Hz,3H),0.77(d,J＝4.3Hz,3H).MS(ESI)m/z:564.2(M+H) +.
51-II: 1H NMR(400MHz,DMSO-d 6)δ＝8.34(s,1H),8.10(s,1H),7.52(s,1H),7.31(s,1H),7.20(d,J＝2.7Hz,1H),7.00(s,2H),4.17-4.09(m,1H),4.02(d,J＝6.2Hz,6H),3.47(s,3H),2.02(s,3H),1.39(d,J＝5.0Hz,3H),0.77(s,3H).MS(ESI)m/z:564.2(M+H) +.
实施例52
Figure PCTCN2018078010-appb-000215
步骤A：在0℃下，向化合物52-1(7.5g,47.44mmol,1eq)的DMF(40mL)溶液中加K 2CO 3(13.11g,94.88mmol,2eq)和CH 3I(13.02g,91.73mmol,5.71mL,1.93eq)，反应体系升温至30℃搅拌12小时。将反应体系加入到水中(200mL)，乙酸乙酯(100mL*2)萃取，饱和食盐水(100mL*2)洗次，无水硫酸钠干燥，过滤，滤液经减压浓缩得到化合物52-a。
步骤B：在25℃下，向化合物52-a(6g,34.86mmol,1eq)的乙醇(100mL)和水(10mL)溶液中分别加入还原铁粉(5.84g,104.58mmol,3eq)和NH 4Cl(5.59g,104.58mmol,3.66mL,3eq)，反应体系升温至80℃搅拌2小时。待反应液冷却至室温后，乙酸乙酯(30mL进行稀释，过滤，滤液经减压浓缩得到残余物。残余物通过柱层析(PE:EA＝5:1至1:1)纯化分离得到化合物52-b。
步骤C：根据实施例16步骤C和D的顺序，将化合物3-氨基-5-氯-1-甲基-吡啶-2-酮替换为化合物52-b。后处理得到化合物52-c。
步骤D：根据实施例51步骤，将化合物51-d替换为化合物52-c。后处理得到的残余物通过制备型HPLC(柱:Boston Green ODS 150mm*25mm*10um；流动相:[水(0.225％FA)-ACN]；ACN％:42％-62％)分离纯化和SFC(柱:AD(250mm*30mm,10um)；流动相:[0.1％氨水，甲醇]；[0.1％氨水，甲醇]％:30％-30％)拆分分离得到化合物52-I(保留时间：2.630min)和化合物52-II(保留时间:2.842min)。
52-I: 1H NMR(400MHz,DMSO-d 6)δ＝8.34(s,1H),8.10(s,1H),8.01-7.94(m,1H),7.65(dd,J＝3.3,8.4Hz,1H),7.20(d,J＝3.9Hz,1H),7.09(s,1H),7.02(d,J＝3.8Hz,1H),4.21-4.09(m,1H),4.03(s,3H),4.01(s,3H),3.49(s,3H),1.39(d,J＝6.5Hz,3H),0.78(d,J＝5.9Hz,3H).MS(ESI)m/z:568.1(M+H) +.
52-II: 1H NMR(400MHz,DMSO-d 6)δ＝8.34(s,1H),8.10(s,1H),7.97(dd,J＝3.5,4.3Hz,1H),7.65(dd, J＝3.3,8.4Hz,1H),7.20(d,J＝3.9Hz,1H),7.08(s,1H),7.02(d,J＝3.8Hz,1H),4.20-4.10(m,1H),4.03(s,3H),4.01(s,3H),3.49(s,3H),1.39(d,J＝6.7Hz,3H),0.78(d,J＝5.9Hz,3H).MS(ESI)m/z:568.1(M+H) +.
实施例53
Figure PCTCN2018078010-appb-000216
步骤A：20℃条件下，向化合物53-1(1g,3.91mmol,1eq)的四氢呋喃(10mL)溶液中加入NaH(313.15mg,7.83mmol,60％纯度,2eq)，反应体系搅拌0.5小时后加入SEM-Cl(979.02mg,5.87mmol,1.04mL,1.5eq)的四氢呋喃(10mL)溶液。反应体系搅拌11.5小时。混合液倒入(100mL)水中，EtOAc(80mL*3)萃取，合并有机相，饱和食盐水(100mL)洗涤，Na 2SO 4干燥，过滤，滤液经减压浓缩得到残余物。残余物经柱层析(PE/EA＝3:1)分离纯化得到53-a。
步骤B：在80℃、氮气保护下，向化合物28-c(1.5g,4.16mmol,1eq)和化合物5-c(1.44g,4.99mmol,1.2eq)的二恶烷(20mL)和水(6mL)的混合液中分别加入K 3PO 4(1.32g,6.24mmol,1.5eq)和Pd(dppf)Cl 2(243.46mg,332.73umol,0.08eq)，反应体系升温至80℃于氮气氛下搅拌24小时。待反应体系冷却至室温，将混合液倒入150m水，EtOAc(100mL*3)萃取，合并有机相，饱和食盐100mL洗涤,Na 2SO 4干燥，过滤，滤液经减压浓缩得到残余物。残余物经柱层析(EA)纯化分离得到化合物53-b。
步骤C：在25℃、氮气保护下,将化合物53-b(0.2g,407.30umol,1eq)、化合物53-a(188.52mg,488.76 umol,1.2eq)、Xantphos(23.57mg,40.73umol,0.1eq)、Cs 2CO 3(199.06mg,610.95umol,1.5eq)和Pd 2(dba) 3(29.84mg,32.58umol,0.08eq)溶于二恶烷(2mL)溶液，反应体系升温至80℃于氮气氛下搅拌12小时。待反应液冷却至室温加入5mL水，EtOAc(5mL*3)萃取，合并有机相，饱和食盐水(3mL)洗涤,Na 2SO 4干燥，过滤滤液经减压浓缩得到残余物。残余物经柱层析(EA)纯化分离得到化合物53-c。
步骤D：在20℃条件下，向化合物53-c(0.07g,100.04umol,1eq)的DCM(1mL)溶液中加入TFA(22.81mg,200.08umol,14.81uL,2eq)，反应体系在20℃搅拌24小时。反应液经减压浓缩得到残余物。残余物经制备型HPLC(柱:Phenomenex Synergi C18 150mm*30mm*4um；流动相:[水(0.225％FA)-ACN]；ACN％:30％-60％)分离纯化和SFC(柱:AD(250mm*50mm,10um)；流动相:[0.1％氨水，异丙醇]；[0.1％氨水，异丙醇]％:60％-60％)拆分分离得到化合物53-I(保留时间：2.423min)和化合物53-II(保留时间：2.497min)。
53-I: 1H NMR 400MHz,CDCl 3):δ＝7.97(s,1H),7.85(s,1H),7.80(s,1H),7.33(s,1H),7.17(s,1H),7.02(s,1H),6.81(s,1H),7.76(s,1H),6.75(s,1H),4.22-4.18(m,1H),4.10(s,3H),3.91(s,3H),0.90-0.82(m,6H).MS(ESI)m/z:569.1(M+H) +.
53-II: 1H NMR(400MHz,CDCl 3):δ＝7.97(s,1H),7.85(s,1H),7.80(s,1H),7.33(s,1H),7.17(s,1H),7.02(s,1H),6.81(s,1H),7.76(s,1H),6.75(s,1H),4.22-4.18(m,1H),4.10(s,3H),3.91(s,3H),0.90-0.82(m,6H).MS(ESI)m/z:569.1(M+H) +.
实施例54
Figure PCTCN2018078010-appb-000217
步骤A：20℃条件下，向溶有化合物54-1(1g,3.91mmol,1eq)的DMF(10mL)溶液中加入K 2CO 3(1.08g,7.81mmol,2.00eq)和2-溴乙醇(740.00mg,5.92mmol,420.45uL,1.51eq)，反应体系于25℃搅拌12小时。向反应液中加入水(50mL)，EtOAc(50mL*2)萃取，合并有机相，饱和食盐水(20mL*2)洗涤,Na 2SO 4干燥,过滤，滤液经减压浓缩得到残余物。残余物通过柱层析(SiO 2,PE:EA＝1:0-5:1-1:1)分离纯化得到化合物54-a。
步骤B:根据实施例53步骤C，将化合物53-a替换为化合物54-a。后处理的残余物采用制备型 HPLC(柱:Phenomenex Synergi C18 150mm*25*10um；流动相:[水(0.225％FA)-ACN]；ACN％:30％-60％)分离纯化和SFC(柱:OD(250mm*30mm,10um)；流动相:[0.1％氨水，甲醇]；[0.1％氨水，甲醇]％:35％-35％)分离得到化合物54。
54: 1H NMR(400MHz,DMSO-d 6):δ＝8.03(s,1H),7.89-7.82(m,2H),7.55(d,J＝2.7Hz,1H),7.38(s,1H),7.33(s,1H),7.25(s,1H),7.18(d,J＝3.7Hz,1H),7.12(s,1H),7.07(s,1H),7.01(d,J＝3.8Hz,1H),4.10(br s,1H),4.06(s,3H),4.02(s,2H),3.89(s,3H),3.64(s,2H),1.38(s,3H),0.92-0.59(m,3H).MS(ESI)m/z:613.1(M+H) +.
实施例55
Figure PCTCN2018078010-appb-000218
步骤A：在0C、氮气保护下，向溶有化合物54-1(200mg,782.96umol,1eq)的DMF(5mL)溶液中加入NaH(50mg,1.25mmol,60％纯度,1.60eq)和2-溴乙基甲基醚(164mg,1.18mmol,110.81uL,1.51eq)，反应体系升温至20℃搅拌12小时。向混合液中加入5mL水，EtOAc(8mL*2)萃取，有机相合并，饱和食盐水(5mL*2)洗涤,Na 2SO 4干燥,过滤，滤液减压浓缩得到残余物。残余物采用柱层析(SiO 2,PE:EA＝1:0-10:1)分离纯化得到化合物55-a。
步骤B：根据实施例53步骤C，将化合物53-a替换为化合物55-a。后处理得到的残余物采用柱层析(EA:MeOH＝20:1)分离纯化、制备型HPLC(柱:Gemini 150*25 5u；流动相:[水(0.04％NH 3H 2O)-ACN]；ACN％:45％-72％)纯化得到化合物55。
55: 1H NMR(400MHz,CHLOROFORM-d,):δ＝7.96(d,J＝0.6Hz,1H),7.83(s,1H),7.71(d,J＝2.6Hz,1H),7.34(s,1H),7.30(d,J＝2.8Hz,1H),6.94(d,J＝3.8Hz,1H),6.79(s,1H),6.73(d,J＝3.8Hz,1H),4.23-4.14(m,2H),4.08(s,3H),4.07-4.02(m,1H),3.90(s,3H),3.65(t,J＝4.9Hz,2H),3.33(s,3H),1.42(s,3H),0.92-0.85(m,3H).MS(ESI)m/z:627.1(M+H) +.
实施例56
Figure PCTCN2018078010-appb-000219
步骤A：将6-甲氧基-3-硝基-吡啶-2-胺(5.00g，29.56mmol，1.00当量)和NBS(5.52g，31.04mmol，1.05当量)的DMF(100.00mL)混合物在25℃下搅拌12小时。用水(500mL)淬灭混合物，固体沉淀通过过滤收集，得到5-溴-6-甲氧基-3-硝基-吡啶-2-胺。
步骤B：5-溴-6-甲氧基-3-硝基-吡啶-2-胺(3.80g，15.32mmol，1.00当量)和NaH(919.24mg，22.98mmol，60％纯度，1.50当量))的DMF(30.00mL)溶液在25℃下搅拌0.5小时。然后将MeI(2.28g，16.09mmol，1.00mL，1.05当量)加入到混合物中。混合物在25℃下继续搅拌0.5小时，用水(500mL)淬灭混合物。固体沉淀通过过滤收集，得到5-溴-6-甲氧基-N-甲基-3-硝基-吡啶-2-胺。
步骤C：将5-溴-6-甲氧基-N-甲基-3-硝基-吡啶-2-胺(1.00g，3.82mmol，1.00当量)和铁粉(2.13g，38.20mmol，10.00当量)的HCOOH(10.00mL)和i-PrOH(10.00mL)混合物在80℃下搅拌12小时。过滤混合物，滤液用NaOH水溶液调节pH到8。用EA(5mL X 3)萃取混合物，用盐水(15mL)洗涤合并的有机层。有机层减压浓缩后得到5-甲氧基-3-甲基-咪唑并[4,5-b]吡啶。
步骤D：将5-甲氧基-3-甲基-咪唑并[4,5-b]吡啶(900.00mg，5.52mmol，1.00当量)和NBS(1.03g，5.80mmol，1.05当量)的DMF(5.00mL)混合物在25℃下搅拌12小时。用水(25mL)淬灭混合物，固体沉淀通过过滤收集。通过硅胶色谱法(PE/EA＝3:1～1:1)纯化粗品，得到6-溴-5-甲氧基-3-甲基-咪唑并[4,5-b]吡啶。
步骤E：将6-溴-5-甲氧基-3-甲基-咪唑并[4,5-b]吡啶(400.00mg，1.65mmol，1.00当量)，Pd(dppf)Cl 2(120.73mg，165.00μmol，0.10当量)，KOAc(323.86mg，3.30mmol，2.00当量)和4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1,3,2-二氧杂硼杂环戊烷(628.50mg，2.47mmol，1.50 当量)的二恶烷(10.00mL)溶液用氮气置换3次，将混合物在80℃搅拌12小时。将混合物用饱和NH 4Cl水溶液(30mL)淬灭，用EA(20mL x3)萃取混合物。将合并的有机层用盐水(10mL)洗涤，用无水Na 2SO 4干燥。过滤，减压浓缩滤液，残余物通过制备型HPLC纯化(柱：Phenomenex Synergi C18 150*25*10um；流动相：[水(0.225％FA)-ACN]；ACN％：0％-10％)，得到(5-甲氧基-3-甲基-咪唑并[4,5-b]吡啶-6-基)硼酸。
步骤F：将2-溴-5-(5-氯-1-甲基-2-氧代-3-吡啶基)-4-(4-氯苯基)-3-异丙基-4H-吡咯并[3,4-d]咪唑(10.00mg，20.15umol，1.00当量)，(5-甲氧基-3-甲基-咪唑并[4,5-b]吡啶-6-基)硼酸(4.59mg，22.16umol，1.10当量)的二氧六环(300.00μL)和水(100.00μL)混合物中加入S-Phos(413.61μg，1.01μmol，0.05当量)和K 3PO 4(6.42mg，30.22μmol，1.50当量)，氮气置换3次。在氮气保护下，将混合物在85℃下搅拌12h。过滤混合物，滤液用水(1mL)淬灭。用EA(1mL×2)萃取混合物。将合并的有机层用盐水洗涤，经无水Na 2SO 4干燥，过滤，减压浓缩滤液。残余物用TLC制备板(EA)纯化，得到化合物56。
56: 1H NMR(400MHz,DMSO-d 6):δ＝8.39-8.22(m,1H),8.14(s,1H),7.75(d,J＝2.6Hz,1H),7.57(d,J＝2.8Hz,1H),7.45-7.39(m,2H),7.35-7.28(m,2H),6.78(s,1H),4.21(td,J＝6.8,13.6Hz,1H),4.06(s,3H),3.96-3.91(m,4H),3.58(s,3H),1.51-1.43(m,3H),1.38-1.29(m,7H),0.68(br d,J＝4.0Hz,3H).MS(ESI)m/z:578.2(M+H) +.
实施例57
Figure PCTCN2018078010-appb-000220
步骤A：在氮气保护下，将化合物57-1(50mg，157μmol，1.50eq)，化合物1-g(51.00mg，105μmol，1.00eq)，XPHOS-PD-G2(42mg，54μmol，0.50eq)，和K 3PO 4(68.45mg，322μmol，3.00eq)加入二恶烷(1mL)和水(300.00μL)的混合溶剂中。然后将所得混合物升温至80℃下搅拌2小时。冷却后将混合物过滤并浓缩，残余物经柱层析(PE:EA＝0:1～EA:MeOH＝10:1)分离后得到化合物57。
57: 1H NMR(400MHz,DMSO-d 6)δ＝8.09(s,1H),7.75(d,J＝2.8Hz,1H),7.56(d,J＝2.8Hz,1H),7.41(d,J＝8.7Hz,2H),7.35-7.26(m,3H),4.24(q,J＝6.8Hz,1H),3.89(s,3H),3.58(s,3H),3.45(s,3H),2.97-2.88(m,2H),2.73-2.63(m,2H),1.45(br d,J＝6.7Hz,3H),0.67(br s,3H).MS(ESI)m/z:607.2(M+H) +.
实施例58
Figure PCTCN2018078010-appb-000221
步骤A：向化合物35-b(40.00mg,84.39umol,1.05当量)和1-g(40.00mg,80.61umol,1.00当量)的dioxane(1.50mL)和H 2O(400.00uL)溶液中加入K 3PO 4(34.22mg,161.22umol,2.00当量)和XPHOS-PD-G2(11.62mg,16.12umol,0.20当量)，反应体系在氮气保护下在80℃搅拌3.5小时。反应液经减压浓缩得到残余物。残余物经TLC制备板(EA)分离纯化和SFC(柱:AD(250mm*30mm,10um)；流动相:[0.1％NH 3H 2O IPA]；[0.1％NH 3H 2O IPA]％:45％-45％)拆分分离得到化合物58-I(保留时间：1.573min)和化合物58-II(保留时间：2.34min)。
58-I: 1H NMR 400MHz,DMSO-d 6):δ＝8.32(s,1H),8.09(s,1H),7.93(br s,1H),7.52(br s,1H),7.43(br d,J＝7.9Hz,2H),7.34(br d,J＝6.7Hz,2H),6.73(s,1H),4.07-3.93(m,7H),3.44(br s,3H),1.33(br d,J＝4.8Hz,3H),0.49(br s,3H).MS(ESI)m/z:578.2(M+H) +.
58-II: 1H NMR(400MHz,DMSO-d 6):δ＝8.32(s,1H),8.09(s,1H),7.93(d,J＝2.8Hz,1H),7.52(d,J＝2.8Hz,1H),7.43(d,J＝8.7Hz,2H),7.34(br d,J＝8.0Hz,2H),6.73(s,1H),4.10-4.04(m,1H),4.02(s,3H),3.99(s,3H),3.44(s,3H),1.33(br d,J＝6.5Hz,3H),0.49(br s,3H).MS(ESI)m/z:578.2(M+H) +.
实施例59
Figure PCTCN2018078010-appb-000222
Figure PCTCN2018078010-appb-000223
步骤A：在0℃下，向2-氨基苯酚(10.00g，91.63mmol，1.00当量)的氯仿(100.00mL)溶液中加入TEBACl(8.51g，45.82mmol，7.95mL，0.50当量)，NaHCO 3(30.79g，366.52mmol，14.25mL，4.00当量)和2-氯乙酰氯(15.52克，137.45毫摩尔，10.93毫升，1.50当量)。然后将反应混合物在60℃下加热60小时。将反应混合物用水(100mL)稀释，然后用DCM(100mL×2)萃取。将合并的有机层经无水Na 2SO 4干燥，过滤，然后浓缩获得粗产物。粗产物通过DCM/PE＝2/1(100mL)重结晶，得到化合物4H-1,4-苯并恶嗪-3-酮。
步骤B：向四氢-1,4-苯并恶嗪-3-酮(5.00g，33.52mmol，1.00当量)的TFA(200.00mL)溶液中加入PIFA(17.30g，40.22mmol，1.20当量)，然后在80℃下加热0.5小时。将反应混合物倒入冰水(600mL)中，然后过滤得到有机相。水层用EA(200mL×2)萃取。合并的有机层经无水Na 2SO 4干燥，过滤，然后浓缩得到残余物。通过硅胶色谱法(DCM/MeOH＝20/1)纯化残余物，得到化合物6-羟基-4H-1,4-苯并恶嗪-3-酮(粗品直接用于下一步)。
步骤C：向6-羟基-4H-1,4-苯并恶嗪-3-酮(1.00克，6.06毫摩尔，1.00当量)的DMF(10.00毫升)溶液中加入t-BuOK(2.04克，18.18毫摩尔，3.00当量)和MeI(3.75g，26.42mmol，1.64mL，4.36当量)，然后在10℃搅拌1小时。将反应混合物倒入水(50mL)中，然后用EA(30mL×2)萃取。有机层用无水Na 2SO 4干燥，过滤，然后浓缩得到粗产物。通过硅胶色谱法(DCM/MeOH＝20/1)纯化粗产物，获化合物6-甲氧基-4-甲基-1,4-苯并恶嗪-3-酮。
步骤D：向6-甲氧基-4-甲基-1,4-苯并恶嗪-3-酮(900.00mg，4.66mmol，1.00当量)的DCM(10.00mL)溶液中加入吡啶溴鎓盐(1.49g，1.00当量)，然后在10℃搅拌12小时。反应混合物用水(30mL)稀释，然后用DCM(30mL×2)萃取。合并的有机层经无水Na 2SO 4干燥，过滤并浓缩获得残余物。通过硅胶色谱法(PE/EA＝2/1)纯化残余物，获得化合物7-溴-6-甲氧基-4-甲基-1,4-苯并恶嗪-3-酮。
步骤E：向7-溴-6-甲氧基-4-甲基-1,4-苯并恶嗪-3-酮(150.00mg，551.29umol，1.00当量)的二恶烷(5.00mL)混合物中加入4,4,5,5(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1,3,2-二氧杂硼杂环戊烷(209.99mg，826.94μmol，1.50当量)，KOAc(115.99mg，1.65mmol，3.00当量)和Pd(dppf)Cl 2(40.34mg，55.13umol，0.10当量)，然后用氮气置换3次。将混合物在80℃下加热12小时，过滤反应混合物，浓缩得到粗产物。通过制备型TLC(PE/EA＝2/1)纯化粗产物以获得化合物6-甲氧基-4-甲基-7-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1,4-苯并恶嗪-3-酮(粗品直接用于下一步)。
步骤F：向2-溴-5-(5-氯-1-甲基-2-氧代-3-吡啶基)-4-(4-氯苯基)-3-异丙基-4H-吡咯并[3,4-d](80.00mg，161.23umol，1.00当量)的二恶烷(3.00mL)和水(1.00mL)溶液中加入6-甲氧基-4-甲基-7-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1,4-苯并恶嗪-3-酮(102.92mg，322.46μmol，2.00当量)，K 3PO 4(136.90mg，644.93μmol，4.00当量)和[2-(2)-二氧杂硼杂环戊烷-2-基)-1,4-苯并恶嗪-3-酮-氨基苯基)苯基]-氯-钯；二环己基-[2-(2,6-二甲氧基苯基)苯基]磷烷(11.62mg，16.12umol，0.10当量)，氮气置换3次，然后在80℃加热12小时。将反应混合物过滤，用水(15mL)稀释，然后用EA(15mL×2)萃取。将合并的有机层用无水Na 2SO 4干燥，过滤，然后浓缩以获得粗产物。通过制备型TLC(PE/EA＝10/1)将粗产物纯化两次，得到化合物59。
59: 1H NMR(400MHz,CDCl 3):δ＝7.92(d,J＝2.5Hz,1H),7.50(d,J＝2.4Hz,1H),7.42(br d,J＝8.3Hz,2H),7.32(br d,J＝7.8Hz,2H),7.06(s,1H),6.91(s,1H),6.70(s,1H),4.66(s,2H),4.11-3.99(m,1H),3.81(s,3H),3.44(s,3H),1.34(br d,J＝6.5Hz,3H),0.49(br d,J＝5.8Hz,3H).MS(ESI)m/z:608.2(M+H) +.
实施例60
Figure PCTCN2018078010-appb-000224
步骤A：在氮气保护下，将化合物60-1(200mg，700μmol，1.50eq)，化合物1-g(227mg，467μmol，1.00eq)，XPHOS-PD-G2(187.74mg，241.38μmol，0.50eq)，和K 3PO 4(306mg，1439μmol，3.00eq)加入二恶烷(5mL)和水(1.5mL)的混合溶剂中。然后将所得混合物升温至80℃下搅拌2小时。冷却后将混合物过滤并浓缩，残余物经柱层析(PE:EA＝0:1～EA:MeOH＝10:1)分离后得到化合物60。
60: 1H NMR(400MHz,DMSO-d 6)δ＝8.81(d,J＝4.4Hz,1H),8.42(s,1H),8.16(s,1H),7.76(d,J＝2.8Hz,1H),7.60(m,3H),7.45(m,2H),7.40(m,2H),6.80(s,1H),4.24(q,J＝6.8Hz,1H),4.01(s,3H),3.58(s,3H),1.47(brs,3H),0.66(br s,3H).MS(ESI)m/z:574.2(M+H) +.
实施例61
Figure PCTCN2018078010-appb-000225
步骤A：向1-溴-2,4-二氟-5-硝基-苯(500.00mg，2.10mmol，1.00当量)和K 2CO 3(290.37mg，2.10mmol，1.00当量)的THF(6.00mL)混合物中加入丙-2-胺(124.19mg，2.10mmol，179.99uL，1.00当量)的THF(4.00mL)溶液。然后将该混合物在0℃下搅拌10分钟并升温至15℃搅拌12小时。将反应混合物过滤并将滤液浓缩，得到4-溴-5-氟-N-异丙基-2-硝基-苯胺。
步骤B：将KOH(1M，25.00mL，12.32当量)水溶液滴加到搅拌着的4-溴-5-氟-N-异丙基-2-硝基-苯胺(563.00mg，2.03mmol，1.00当量)的MeOH(5.00mL)和THF(5.00mL)溶液中，直至出现黄色沉淀。混合物在15℃下继续搅拌30分钟。过滤混合物，得到黄色固体。通过硅胶色谱(100-200目硅胶，石油醚/乙酸乙酯＝100/1～50/1)纯化残余物，得到4-溴-N-异丙基-5-甲氧基-2-硝基-苯胺。
步骤C：在15℃下，向4-溴-N-异丙基-5-甲氧基-2-硝基-苯胺(200.00mg，691.73umol，1.00当量)的盐酸(8.00mL)溶液中加入SnCl 2.2H 2O(3.12g，13.83毫摩尔，1.15毫升，20.00当量)。将反应混合物在15℃搅拌30分钟。在0℃下，通过KOH(1M)水溶液将混合物调节至pH＝9-10。将水相用乙酸乙酯(15mL×3)萃取。合并的有机相用盐水(15mL×2)洗涤，用无水Na 2SO 4干燥，过滤并真空浓缩，得到黄色油状的4-溴-N-异丙基-5-甲氧基-苯-1,2-二胺(粗品直接用于下一步)。
步骤D：将4-溴-N-异丙基-5-甲氧基-苯-1,2-二胺(0.344g，663.73umol，1.00当量)溶于二乙氧基甲氧基乙烷(2.50mL)中。向混合物中加入TsOH.H 2O(12.63mg，66.37umol，0.10当量)并在15℃搅拌30分钟。将该混合物在50℃减压浓缩。通过硅胶色谱法(100-200目硅胶，石油醚/乙酸乙酯＝10/1～0/1)纯化残余物，得到5-溴-1-异丙基-6-甲氧基-苯并咪唑。
步骤E：将5-溴-1-异丙基-6-甲氧基-苯并咪唑(0.213g，648.96umol，1.00当量)，4,4,5,5-四甲基- 2-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1,3,2-二氧杂硼烷(329.59mg，1.30mmol，2.00当量)，KOAc(191.07mg，1.95mmol，3.00当量)，三环己基磷烷(145.59mg，519.17umol，167.35uL，0.8当量)和Pd(OAc) 2(58.28mg，259.59umol，0.4当量)的二恶烷(5mL)混合物置换氮气，然后加热至90℃搅拌12小时。将该混合物冷却至15℃并在50℃减压浓缩。通过硅胶色谱(100-200目硅胶，石油醚/乙酸乙酯＝10/1,0/1)纯化残余物，得到1-异丙基-6-甲氧基-5-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯并咪唑。
步骤F：将2-溴-5-(5-氯-1-甲基-2-氧代-3-吡啶基)-4-(4-氯苯基)-3-异丙基-4H-吡咯并[3,4-d]咪唑-6-(40mg，80.62umol，1当量)，1-异丙基-6-甲氧基-5-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯并咪唑(93.26mg，120.92umol,1.5当量)，SPhos(33.09mg,80.62umol,1当量)和K 3PO 4(17.11mg,80.62umol,1当量)在dioxane(2mL)和H 2O(0.4mL)的混合溶液置换氮气，然后加热至100℃，搅拌12小时。将该混合物冷却至15℃并在50℃减压浓缩，残余物通过TLC制备板(EA)和制备型HPLC(柱：Phenomenex Synergi C18 150mm*30mm*4um；流动相：[水(0.225％FA)-ACN]；ACN％28％-58％)纯化，得到化合物61。
61: 1H NMR(400MHz,DMSO-d 6):δ＝8.34(s,1H),7.92(d,J＝2.8Hz,1H),7.63(s,1H),7.51(d,J＝2.8Hz,1H),7.46-7.39(m,2H),7.38-7.30(m,3H),6.72(s,1H),4.91-4.73(m,1H),4.02(br d,J＝6.4Hz,1H),3.89-3.79(m,3H),3.45(s,3H),1.56(br d,J＝6.5Hz,6H),1.34(br s,3H),0.44(br s,3H).MS(ESI)m/z:605.2(M+H) +.
实施例62
Figure PCTCN2018078010-appb-000226
步骤A：与实施例72制备方法相同，仅在实施例61步骤A中将异丙胺替换为乙胺。粗品通过柱 层析(PE:EA＝1:0～0:1)制备板(EA)和制备型HPLC(柱：Phenomenex Synergi C18 150mm*25mm*10um；流动相:[水(0.225％FA)-ACN]；ACN％:36％-47％)纯化，得到化合物62。
62: 1H NMR(400MHz,DMSO-d 6):δ＝8.25(s,1H),7.93(d,J＝2.7Hz,1H),7.64(s,1H),7.51(d,J＝2.7Hz,1H),7.44(d,J＝8.6Hz,2H),7.39-7.31(m,3H),6.73(s,1H),4.32(q,J＝7.2Hz,2H),4.04(td,J＝6.5,13.2Hz,1H),3.85(br s,3H),3.46(s,3H),1.45(t,J＝7.2Hz,3H),1.38-1.28(m,3H),0.44(br s,3H).MS(ESI)m/z:591.2(M+H) +.
实施例63
Figure PCTCN2018078010-appb-000227
步骤A：2-溴-5-(5-氯-1-甲基-2-氧代-3-吡啶基)-4-(5-氯-2-噻吩基)-3-异丙基-4H-吡咯并[3,4-d]咪唑-6-酮(0.4g，796.48umol，1当量)，6-甲氧基-1-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯并三唑(454.52mg，1.19mmol，1.5eq)，[2-(2-氨基苯基)苯基]-氯-钯；二环己基-[2-(2,6-二甲氧基苯基)苯基]磷烷(114.79mg，159.30umol，0.2eq)和K 3PO 4(338.14mg，1.59mmol，2当量)在二恶烷(8mL)和H 2O(1.6mL)中的混合物置换氮气，然后在氮气保护下加热至80℃并搅拌12小时。将该混合物冷却至15℃并通过硅藻土垫过滤，滤饼用EA(10mL)洗涤。将合并的滤液在45℃减压浓缩。残余物经柱层析(PE:EA＝10:1～5:1)和制备型HPLC(柱：Phenomenex Synergi C18 150mm*30mm*4um；流动相:[水(0.225％FA)-ACN]；ACN％:35％-65％)分离纯化，再经SFC(柱:AD(250mm*30mm,10um)；流动相:[0.1％NH 3H 2O MeOH]；[0.1％NH 3H 2O MeOH]％:40％-40％)拆分后得到化合物63-I(保留时间：2.923min)和化合物63-II(保留时间：3.518min)。
63-I: 1H NMR(400MHz,DMSO-d 6)δ＝8.14(s,1H),8.01(d,J＝2.8Hz,1H),7.54(s,2H),7.20(d,J＝3.8Hz,1H),7.08-6.96(m,2H),4.32(s,3H),4.16-4.00(m,1H),3.92(s,3H),3.50(s,3H),1.40(br d,J＝6.8Hz,3H),0.75(br s,3H).MS(ESI)m/z:584.1(M+H) +.
63-II: 1H NMR(400MHz,DMSO-d 6)δ＝8.14(s,1H),8.00(d,J＝2.6Hz,1H),7.54(s,2H),7.20(d,J＝3.6Hz,1H),7.05-6.99(m,2H),4.32(s,3H),4.06(td,J＝6.7,13.3Hz,1H),3.92(s,3H),3.50(s,3H),1.40(br d,J＝6.8Hz,3H),0.90-0.63(m,3H).MS(ESI)m/z:584.1(M+H) +.
实施例64
Figure PCTCN2018078010-appb-000228
步骤A：向2-溴-5-(5-氯-1-甲基-2-氧代-3-吡啶基)-4-(5-氯-2-噻吩基)-3-异丙基-4H-吡咯并[3,2-4-d]咪唑-6-酮(420mg，836.30umol，1当量)的二恶烷(8mL)和水(4mL)溶液中加入6-甲氧基-1-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)吡唑并[3,4-b]吡啶(460毫克，1.10毫摩尔，1.31当量)，K 3PO 4(355.04毫克，1.67毫摩尔，2当量)和S-phos(120.53mg，167.26μmol，0.2当量)。然后将混合物用氮气置换三次并在氮气气氛下在80℃下搅拌12小时。将反应混合物冷却至15℃并过滤。然后浓缩滤液。残余物经柱层析(PE:EA＝1:3～0:1)和制备型HPLC(柱：Phenomenex Synergi C18150mm*30mm*4um；流动相:[水(0.225％FA)-ACN]；ACN％:40％-70％)分离纯化，再经SFC(柱:AD(250mm*30mm,10um)；流动相:[0.1％NH 3H 2O IPA]；[0.1％NH 3H 2O IPA]％:60IPA(NH 4OH)％-60IPA(NH 4OH)％)拆分后得到化合物64-I(保留时间：0.767min)和化合物64-II(保留时间：1.433min)。
64-I: 1H NMR(400MHz,DMSO-d 6)δ＝8.35(s,1H),8.10(s,1H),8.01(d,J＝2.9Hz,1H),7.54(d,J＝2.8Hz,1H),7.21(d,J＝3.9Hz,1H),7.05-7.00(m,2H),4.14(td,J＝6.6,13.5Hz,1H),4.03(s,3H),4.01(s,3H),3.50(s,3H),1.43-1.36(m,3H),0.77(br d,J＝5.3Hz,3H).MS(ESI)m/z:584.1(M+H) +.
64-II: 1H NMR(400MHz,DMSO-d 6)δ＝8.35(s,1H),8.10(s,1H),8.01(d,J＝2.8Hz,1H),7.54(d,J＝2.6Hz,1H),7.21(d,J＝3.8Hz,1H),7.05-7.00(m,2H),4.14(td,J＝6.7,13.5Hz,1H),4.03(s,3H),4.01(s,3H),3.50(s,3H),1.43-1.35(m,3H),0.77(br d,J＝5.0Hz,3H).MS(ESI)m/z:584.1(M+H) +.
实施例65
Figure PCTCN2018078010-appb-000229
Figure PCTCN2018078010-appb-000230
步骤A：在-78℃下，向4-溴-1,3-苯并间二氧杂环戊烯(150mg，746.20umol，1当量)，硼酸三异丙酯(168.41mg，895.45umol，205.88uL，1.2当量)的THF(5mL)溶液中加入逐滴滴加n-BuLi(2.5M，447.72uL，1.5当量)，搅拌3小时。然后升温至0℃，用2M盐酸将溶液酸化至pH为2，然后用2M NaOH水溶液中和至pH为7。反应混合物用EA(10mL×2)萃取。合并的有机层用无水Na 2SO 4干燥，过滤，然后浓缩得到粗产物1,3-苯并间二氧杂环戊烯-4-基硼酸(粗品直接用于下一步)。
步骤B:向2-溴-5-(5-氯-1-甲基-2-氧代-3-吡啶基)-4-(5-氯-2-噻吩基)-3-异丙基-4H-吡咯并[3,2-4-d]咪唑-6-酮(50mg,99.56umol,5.18uL,1当量)在二恶烷(3mL)和水(0.6mL)的混合溶液中加入Pd(dppf)Cl 2(7.28mg，9.96umol，0.1当量)，K 3PO 4(63.40mg，298.68umol，3当量)和1,3-苯并间二氧杂环戊烯-4-基硼酸(33.04mg，199.12umol，2当量)，然后脱气3次，然后在80℃下加热1.5小时。过滤反应混合物，然后浓缩，得到粗产物。粗产物通过硅胶色谱法(PE/EA＝0/1)纯化,得到化合物65。65: 1H NMR(400MHz,DMSO-d 6):δ＝8.00(d,J＝2.9Hz,1H),7.54(d,J＝2.8Hz,1H),7.19(d,J＝3.8Hz,1H),7.11(dd,J＝2.5,6.5Hz,1H),7.06-6.96(m,4H),6.10(d,J＝5.9Hz,2H),4.40(q,J＝6.8Hz,1H),3.48(s,3H),1.40(d,J＝6.8Hz,3H),0.84(d,J＝6.7Hz,3H).MS(ESI)m/z:543.1(M+H) +.
实施例66
Figure PCTCN2018078010-appb-000231
步骤A：将2-溴-5-(5-氯-1-甲基-2-氧代-3-吡啶基)-4-(4-氯苯基)-3-异丙基-4H-吡咯并[3,4-d]咪唑(270mg，544.15umol，1当量)，1-环丙基-6-甲氧基-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯并咪唑(205.16mg，652.98μmol，1.2当量)，S-phos(78.43mg，108.83umol，0.2当量)，K 3PO 4(231.01mg，1.09mmol，2当量)在二恶烷(7mL)和H 2O(1.4mL)中的混合物置换氮气3次，然后在氮气气氛下 将混合物在80℃搅拌12小时。将混合物真空浓缩得到粗产物。残余物经柱层析(EA:MeOH＝7:1)和制备型HPLC(柱：Phenomenex Synergi C18 150mm×30mm×4um；流动相：[水(0.225％FA)-ACN]；ACN％：32％-62％)分离纯化，再经SFC(柱:AD(250mm×30mm，10um)；流动相：[0.1％NH 3H 2O EtOH]；[0.1％NH 3H 2O EtOH]％：50％-50％)拆分后得到化合物66-I(保留时间：1.52min)和化合物66-II(保留时间：2.228min)。
66-I: 1H NMR(400MHz,DMSO-d 6)δ＝8.20(s,1H),7.92(d,J＝2.76Hz,1H),7.64(s,1H),7.50(d,J＝2.76Hz,1H),7.43(d,J＝8.53Hz,2H),7.33(br d,J＝8.16Hz,2H),7.27(s,1H),6.72(s,1H),4.01(br d,J＝7.65Hz,1H),3.86(br s,3H),3.52(br d,J＝3.39Hz,1H),3.44(s,3H),1.40-1.26(m,3H),1.15-1.05(m,4H),0.43(br s,3H).MS(ESI)m/z:603.2(M+H) +.
66-II: 1H NMR(400MHz,DMSO-d 6)δ＝8.20(s,1H),7.93(d,J＝2.76Hz,1H),7.65(s,1H),7.51(d,J＝2.76Hz,1H),7.43(d,J＝8.53Hz,2H),7.34(br d,J＝8.03Hz,2H),7.28(s,1H),6.72(s,1H),4.11-3.96(m,1H),3.87(br s,3H),3.59-3.50(m,1H),3.45(s,3H),3.31(br s,3H),1.42-1.26(m,3H),1.18-1.05(m,4H),0.43(br s,3H).MS(ESI)m/z:603.2(M+H) +.
实施例67
Figure PCTCN2018078010-appb-000232
步骤A:合成过程见实施例43-c。粗品经柱层析((PE/EA＝0/1和DCM/MeOH＝10/1))纯化后得到化合物67。
67: 1H NMR(400MHz,DMSO-d 6):δ＝8.16(s,1H),8.01(d,J＝2.8Hz,1H),7.63(s,1H),7.54(d,J＝2.8Hz,1H),7.21(d,J＝3.7Hz,1H),7.07-6.99(m,2H),4.24(s,3H),4.08(td,J＝6.5,13.3Hz,1H),3.95(s,3H),3.49(s,3H),1.51-1.28(m,3H),0.89-0.53(m,3H).MS(ESI)m/z:628.1(M+H) +.
实施例68
Figure PCTCN2018078010-appb-000233
步骤A：在-70℃氮气保护下，向实施例化合物18(200mg，329.06umol，1当量)的THF(3mL)溶液中加入逐滴加入KHMDS(1M，987.17uL，3eq)，历时5分钟滴加完。混合物在-70℃下搅拌30分钟。然后在-70℃下向混合物中加入3-溴丙-1-烯(398.08mg，3.29mmol，10当量)并搅拌30分钟。将混合物升温至20℃并搅拌2小时。反应混合物用饱和氯化铵水溶液(10mL)淬灭。将水相用乙酸乙酯(10mL×3)萃取。合并的有机相用盐水(10mL×2)洗涤，无水Na 2SO 4干燥过滤并真空浓缩。粗品通过硅胶色谱法(EA：MeOH＝1/0～30/1)和制备型HPLC(柱：Phenomenex Synergi C18150mm×30mm×4um；流动相：[水(0.225％FA)-ACN]；ACN％：40％-70％)纯化，得到化合物68。
68: 1H NMR(400MHz,DMSO-d 6)δ＝8.08(d,J＝2.8Hz,1H),8.02(s,1H),7.82(br s,1H),7.28(s,1H),7.24-7.01(m,2H),6.75(br s,1H),5.93-5.74(m,1H),5.21(br s,1H),5.10(br s,1H),4.20-4.01(m,4H),3.83(br s,3H),3.42(br s,4H),3.25-3.15(m,1H),1.22-0.77(m,6H).MS(ESI)m/z:623.1(M+H) +.
实施例69
Figure PCTCN2018078010-appb-000234
Figure PCTCN2018078010-appb-000235
步骤A：向2-溴-5-[氯-(4-氯苯基)甲基]-1-异丙基-咪唑-4-甲酸乙酯(1.04g，2.48mmol，1当量)和3-甲氧基苯胺(304.86mg，2.48mmol,277.14uL,1当量)的MeCN(10mL)溶液中加入DIEA(1.04g，8.04mmol，1.4mL，3.25当量)。将该混合物在85℃下搅拌12小时后将混合物真空浓缩。残余物通过柱色谱(PE:EA＝1:0～1:1)过柱纯化，得到(2-溴-5-[(4-氯苯基)-(3-甲氧基苯胺基)甲基]咪唑-4-羧酸乙酯。
步骤B：向2-溴-5-[(4-氯苯基)-(3-甲氧基苯胺基)甲基]-1-异丙基-咪唑-4-甲酸乙酯(1.12g，2.21mmol，1当量)的THF(10mL)溶液中加入溶有LiOH.H 2O(463.67mg，11.05mmol，5当量)的EtOH(8mL)和H 2O(5mL)混合溶液。将该混合物在25℃下搅拌12小时，反应液在真空中浓缩。残余物用1M稀盐酸调节至pH＝5，搅拌并过滤，滤饼溶于甲苯(8mL)并真空浓缩，得到所需产物为2-溴-5-[(4-氯苯基)-(3-甲氧基苯胺基)甲基]-1-异丙基-咪唑-4-羧酸。
步骤C：将2-溴-5-[(4-氯苯基)-(3-甲氧基苯胺基)甲基]-1-异丙基-咪唑-4-羧酸(0.65g，1.36mmol，1当量)，HATU(774.33mg，2.0当量，1.5当量)的DMF(10mL)溶液中加入DIEA(350.94mg，2.72mmol，472.96uL，2当量)。混合物用氮气置换3次，然后将混合物在60℃下搅拌12小时。将反应混合物冷却至25℃并用水(80mL)淬灭，然后过滤混合物，滤饼用水(10mL)洗涤并真空干燥，得到2-溴-4-(4-氯苯基)-3-异丙基-5-(3-甲氧基苯基)-4H-吡咯并[3,4-d]咪唑-6-酮。
步骤D:向2-溴-4-(4-氯苯基)-3-异丙基-5-(3-甲氧基苯基)-4H-吡咯并[3,4-d]咪唑-6-酮(300mg，651.11umol，1当量)的二恶烷(10mL)和水(4mL)溶液中加入6-甲氧基-1-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)吲唑(244mg，846.78umol，1.30当量)，K 3PO 4(277mg，1.30mmol，2当量)和Pd(dppf)Cl 2(60mg，82.00umol，0.126当量)。然后将混合物用氮气置换并在氮气气氛下于100℃搅拌12小时。将反应混合物冷却至25℃并通过硅藻土垫过滤，然后浓缩滤液。残余物经柱层析(PE:EA＝1:0～0：1)和制备型HPLC(柱：Phenomenex Synergi C18 150mm*25mm*10um；流动相:[水(0.225％FA)-ACN]；ACN％:40％-70％)分离纯化，再经SFC(柱:AD(250mm*30mm,10um)；流动相:[0.1％NH 3H 2O EtOH]；[0.1％NH 3H 2O EtOH]％:45％-45％)拆分后得到化合物69-I(保留时间：2.082min)和化合物69-II(保留 时间：2.282min)。
69-I: 1H NMR(400MHz,DMSO-d 6)δ＝8.02(s,1H),7.79(s,1H),7.42(s,4H),7.30(s,1H),7.18(d,J＝2.9Hz,3H),6.74(s,1H),6.66-6.61(m,1H),4.06(s,3H),4.03-3.96(m,1H),3.87(br s,3H),3.73(s,3H),1.49-1.31(m,3H),0.40(br s,3H).MS(ESI)m/z:542.2(M+H) +.
69-II: 1H NMR(400MHz,DMSO-d 6)δ＝8.02(s,1H),7.79(s,1H),7.42(s,4H),7.30(s,1H),7.23-7.14(m,3H),6.74(s,1H),6.64(br dd,J＝2.8,6.2Hz,1H),4.06(s,3H),4.03-3.96(m,1H),3.87(br s,3H),3.73(s,3H),1.40(br d,J＝6.7Hz,3H),0.40(br s,3H).MS(ESI)m/z:542.2(M+H) +.
实施例70
Figure PCTCN2018078010-appb-000236
步骤A：同实施例69制备步骤A至步骤D，仅在实施例69步骤A中将3-甲氧基苯胺替换为3,4-二甲氧基苯胺。在步骤D中粗品通过柱层析(PE:EA＝1:0～0:1)和制备型HPLC(柱：Phenomenex Synergi C18 150mm*25mm*10um；流动相:[水(0.225％FA)-ACN]；ACN％:40％-70％)纯化，再经SFC(柱:OD(250mm*30mm,10um)；流动相:[0.1％NH 3H 2O MeOH]；[0.1％NH 3H 2O MeOH]％:40％-40％.)拆分后得到化合物70-I(保留时间：3.270min)和化合物70-II(保留时间：3.579min)。
70-I: 1H NMR(400MHz,DMSO-d 6)δ＝8.02(s,1H),7.79(s,1H),7.40(br s,4H),7.30(s,1H),7.14(d,J＝1.6Hz,1H),6.99(dd,J＝2.0,8.7Hz,1H),6.84(d,J＝8.8Hz,1H),6.66(s,1H),4.08-3.96(m,4H),3.87(br s,3H),3.71(d,J＝15.9Hz,6H),1.45-1.29(m,3H),0.39(br s,3H).MS(ESI)m/z:572.2(M+H) +.
70-II: 1H NMR(400MHz,DMSO-d 6)δ＝8.02(s,1H),7.79(s,1H),7.44-7.38(m,4H),7.30(s,1H),7.14(d,J＝2.1Hz,1H),6.99(dd,J＝2.3,8.6Hz,1H),6.84(d,J＝8.8Hz,1H),6.66(s,1H),4.08-3.98(m,4H),3.87(br s,3H),3.71(d,J＝15.9Hz,6H),1.44-1.33(m,3H),0.39(br s,3H).MS(ESI)m/z:572.2(M+H) +.
实施例71
Figure PCTCN2018078010-appb-000237
步骤A：向2,6-二氯吡啶-3-羧酸(10g，78.13mmol，1.5当量)的DMF(120毫升)中加入DIEA(20.19克，156.25毫摩尔，27.22毫升，3当量)，HATU(29.71克，52.2毫摩尔，1当量)和N-甲氧基甲胺盐酸盐(5.33g，54.69mmol，1.05当量)，然后在20℃下搅拌12小时。将混合物倒入水(500mL)中，然后用EA萃取，用水(300ml×2)洗涤合并的有机层。有机相用无水Na 2SO 4干燥，过滤，然后浓缩得到粗产物。粗产物通过硅胶色谱法(PE:EA＝10:1)纯化，得到2,6-二氯-N-甲氧基-N-甲基-吡啶-3-甲酰胺。
步骤B：向2,6-二氯-N-甲氧基-N-甲基-吡啶-3-甲酰胺(6g，25.52mmol，1当量)的MeOH(60mL)溶液中加入甲醇钠(2.07g，38.29mmol，1.5当量)，然后在80℃下搅拌12小时。将混合物用水(30mL)稀释，然后用EA(30mL×2)萃取。将合并的有机层经无水Na 2SO 4干燥，过滤浓缩。粗品通过硅胶色谱法(PE:EA＝5:1)纯化，得到化合物2,6-二氯-N-甲氧基-N-甲基烟酰胺。
步骤C：在20℃下，向2,6-二氯-N-甲氧基-N-甲基烟酰胺(2.5g，10.84mmol，1当量)的THF(30mL)溶液中加入MeMgBr(3.0M，4.70mL，1.3当量)，然后搅拌12小时。将反应液倒入NH 4Cl水溶液(100mL)中，然后用EA(80mL×2)萃取。将合并的有机层经无水Na 2SO 4干燥，过滤，然后浓缩，得到化合物1-(2-氯-6-甲氧基-3-吡啶基)乙酮。
步骤D：向1-(2-氯-6-甲氧基-3-吡啶基)乙酮(1.3g，7.00mmol，1当量)的EtOH(10mL)溶液中加入甲基肼(25.89g，168.59mmol，29.59mL，24.07当量)，然后在90℃下加热12小时。浓缩得到残余物。用水(20mL)稀释残余物，然后用EA(20mL×2)萃取。将合并的有机层经无水Na 2SO 4干燥，过滤，然后浓缩，得到化合物6-甲氧基-1,3-二甲基-吡唑并[3,4-b]吡啶。
步骤E：向6-甲氧基-1,3-二甲基-吡唑并[3,4-b]吡啶(1.1g，6.21mmol，1当量)的MeCN(10mL) 溶液中加入NBS(2.21g，12.42mmol，2当量)，然后在20℃下搅拌1小时。用饱和Na 2SO 3水溶液(40mL)稀释，然后用EA(40mL×2)萃取。合并的有机层用水(40mL×3)洗涤，然后用无水Na 2SO 4干燥，过滤并浓缩，得到化合物5-溴-6-甲氧基-1,3-二甲基-吡唑并[3,4-b]吡啶。
步骤F：向5-溴-6-甲氧基-1,3-二甲基-吡唑并[3,4-b]吡啶(1.5g，5.86mmol，1当量)的二恶烷(30mL)溶液中加入4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1,3,2-二氧杂硼杂环戊烷(2.97g，11.71mmol，2当量)，AcOK(1.72g，17.57mmol，3当量)，Pd(dppf)Cl 2(428.57mg，585.71μmol，0.1当量)，氮气置换3次，然后在100℃下加热搅拌12小时。混合物用水(50mL)稀释，用EA(50mL×2)萃取。将合并的有机层用无水Na 2SO 4干燥，过滤并浓缩。粗产物通过硅胶色谱法(PE:EA＝20:1)纯化,得到化合物6-甲氧基-1,3-二甲基-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)吡唑并[3,4-b]吡啶(粗品直接用于下一步)。
步骤G:向2-溴-5-(5-氯-1-甲基-2-氧代-3-吡啶基)-4-(5-氯-2-噻吩基)-3-异丙基-4H-吡咯并[3,2-d]嘧啶-4-基]咪唑-6-酮(500mg，995.60umol，1当量)在二恶烷(10mL)和水(2mL)的混合液中加入6-甲氧基-1,3-二甲基-5--(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)吡唑并[3,4-b]吡啶(905.48毫克，2.99毫摩尔，3当量)，K 3PO 4(633.99毫克，2.99毫摩尔，3当量)，Pd(dppf)Cl 2(72.85mg，99.56umol，0.1当量)，用氮气置换3次，然后在氮气保护下在100℃加热1小时。将混合物通过硅藻土过滤并将滤液用水稀释(20mL)，然后用EA(20mL×2)萃取。将合并的有机层用无水Na 2SO 4干燥，过滤，然后浓缩，得到粗产物。粗产物通过硅胶色谱(EA:MeOH＝10:1～5:1)和制备型HPLC(柱：DAICEL CHIRALPAK AD(250mm*30mm,10um)；流动相:[0.1％NH 3H 2O EtOH]；[0.1％NH 3H 2O EtOH]％:40％-40％)纯化,得到化合物71
71: 1H NMR(400MHz,DMSO-d 6):δ＝8.34(s,1H),8.00(d,J＝2.76Hz,1H),7.53(d,J＝2.89Hz,1H),7.20(d,J＝3.89Hz,1H),6.98-7.05(m,2H),4.14(dt,J＝13.55,6.78Hz,1H),3.99(s,3H),3.93(s,3H),3.49(s,3H),2.46(s,3H),1.39(br d,J＝6.27Hz,3H),0.76(br s,3H).MS(ESI)m/z:598.1(M+H) +.
实施例72
Figure PCTCN2018078010-appb-000238
Figure PCTCN2018078010-appb-000239
步骤A：向5-溴-6-甲氧基-1-甲基-吡唑并[3,4-b]吡啶(1.5g，6.20mmol，1当量)的MeCN(2mL)溶液中加入NCS(910.18mg，6.82mmol，1.1当量)，AcOH(372.11mg，6.20mmol，354.39uL，1当量)，然后用氮气置换3次，然后在80℃加热2小时。将反应液倒入饱和Na 2SO 3水溶液(60mL)中，然后过滤得到5-溴-3-氯-6-甲氧基-1-甲基-吡唑并[3,4-b]吡啶(粗品直接用于下一步)。
步骤B：向5-溴-3-氯-6-甲氧基-1-甲基-吡唑并[3,4-b]吡啶(1.6g，5.79mmol，1当量)的二恶烷(30mL)溶液中加入4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1,3,2-二氧杂硼杂环戊烷(2.20g，8.68mmol，1.5当量)，AcOK(1.70g，17.36mmol，3当量)和Pd(dppf)Cl 2(423.39mg，578.63μmol，0.1当量)，然后用氮气置换3次，然后在100℃下加热搅拌1小时。反应混合物通过硅藻土过滤，然后减压浓缩滤液，得到粗品3-氯-6-甲氧基-1-甲基-5-(4,4,5,5-四甲基-1,3,2-二氢--二氧杂硼杂环戊烷-2-基)吡唑并[3,4-b]吡啶(粗品直接用于下一步)。
步骤C:向2-溴-5-(5-氯-1-甲基-2-氧代-3-吡啶基)-4-(5-氯-2-噻吩基)-3-异丙基-4H-吡咯并[3,4-d]咪唑-6-酮(500mg,995.60umol,1当量)的二恶烷(10mL)and水(2mL)混合液中加入3-氯-6-甲氧基-1-甲基-5-(1H-1,2,4-三唑并[1,2-a]吡啶-4-基]咪唑-6-酮((1.61克，4.98毫摩尔，5当量)，K 3PO 4(634.01毫克，2.99毫摩尔，3当量)和Pd(dppf)Cl 2(72.85mg，99.56umol，0.1当量)，用氮气置换3次，然后在100℃加热搅拌1小时。将反应混合物通过硅藻土过滤，然后用水(30mL)稀释并用EA(30mL×2)萃取。将合并的有机层用30mL水(30mL×2)洗涤，无水Na 2SO 4干燥，过滤并减压浓缩，得到粗品。粗品通过硅胶色谱法(DCM/MeOH＝10/1)将残余物纯化至获得所需的原油产品。然后通过制备型TLC(EA/MeOH＝20/1)纯化，得到粗产物。残余物经柱层析(DCM:MeOH＝10:1)和制备型HPLC(柱：Phenomenex Synergi C18 150mm*25mm*10um；流动相:[水(0.225％FA)-ACN]；ACN％:55％-85％)分离纯化，再经SFC(柱:DAICEL CHIRALPAK AD(250mm*30mm,10um)；流动相:[0.1％NH 3H 2O IPA]；[0.1％NH 3H 2O IPA]％:45％-45％)拆分后得到化合物72-I(保留时间：0.789min)和化合物72-II(保留时间：1.457min)。
72-I: 1H NMR(400MHz,DMSO-d 6)δ＝8.33(s,1H),8.01(br s,1H),7.54(d,J＝2.32Hz,1H),7.20(br d,J＝3.42Hz,1H),7.02(s,2H),4.08-4.21(m,1H),4.01(br d,J＝9.17Hz,7H),3.49(s,3H),1.39(br d,J＝5.87Hz,3H),0.77(br s,3H).MS(ESI)m/z:618.1(M+H) +.
72-II: 1H NMR(400MHz,DMSO-d 6)δ＝8.33(s,1H),8.01(d,J＝2.69Hz,1H),7.54(d,J＝2.69Hz,1H),7.20(d,J＝3.79Hz,1H),6.94-7.09(m,2H),4.14(dt,J＝13.42,6.56Hz,1H),3.95-4.03(m,1H),3.49(s,3H),1.30-1.44(m,3H),0.77(br d,J＝5.50Hz,3H).MS(ESI)m/z:618.1(M+H) +.
效果实施例1：化合物酶水平活性测
本发明中应用MDM2/p53蛋白蛋白结合实验采用TR-FRET方法检测。具体步骤如下：用Echo移液器(Labcyte)对受试化合物进行3.162倍梯度稀释，每个化合物稀释11个浓度并分别转移250nL到384孔板中，每个化合物浓度设两复孔。设置加阳性化合物(100％抑制)的孔作为阳性对照，只加DMSO的孔作为阴性对照。用缓冲液(125mM NaCl，1mM DTT，0.01％Gelatin(动物明胶)，0.1％Pluronic f-127(聚醚)，1 PBS)将GST-MDM2蛋白(R&D-E3-202-050)稀释至0.625nM并加20μL到384孔板中。离心，震荡后将384孔板放入23℃温箱中孵育20min。用缓冲液将His-p53蛋白(R&D-SP-450-020)稀释至12.5nM并加20μL到384孔板中。离心，震荡后将384孔板放入23℃温箱中孵育60min。用缓冲液稀释Eu2+anti-GST抗体(Cisbio-61GSTKLB)和XL665anti-His抗体(Cisbio-61HISXLB)，稀释得到的混合物中包含0.3nM的Eu2+anti-GST抗体和9nM的XL665anti-His抗体。加10μL两种抗体的混合物到384孔板中。离心，震荡后将384孔板放入23℃温箱中孵育20h。在Envision多功能酶标仪(PerkinElmer)上读数(激发光340nm，发射光665nm、615nm)。Ratio＝Signal665nm/Signal615nm X 10000，用Ratio值计算得到抑制率，公式如下：抑制率＝(加化合物孔Ratio-阴性对照Ratio)/(阳性对照Ratio-阴性对照Ratio)*100％，各化合物的IC 50值示于下表1中。
效果实施例2：化合物细胞水平活性测定
SJSA-1细胞增殖实验采用碘化丙啶染色检测。碘化丙啶无法通过活细胞的细胞膜，却可以透过凋亡细胞的细胞膜，从而对细胞进行染色。具体步骤如下：分离细胞培养瓶中处于对数生长期的SJSA-1细胞(来自药明康德生物部细胞库)，计数。用添加了10％FBS、1％双抗和1％L-谷氨酰胺的RPMI1640细胞培养基将SJSA-1细胞稀释到1X105个细胞每毫升。向384孔板的最外围一圈孔中加入100μL PBS，向第二列孔中加入25μL RPMI1640细胞培养基作为阳性对照，向其它孔中加入25μL细胞悬液(2500个细胞每孔)。室温静置20min后，将细胞板放入细胞培养箱中过夜培养。第二天用Echo移液器(Labcyte)对受试化合物进行3.162倍梯度稀释，每个化合物稀释10个浓度并分别转移300nL到化合物板中，每个化合物浓度设两复孔。第24列不加化合物作为阴性对照。向化合物板除最外围一圈孔的所有孔中加30μL RPMI1640细胞培养基，离心，震荡。然后从化合物板中转移25μL化合物到细胞板中。将细胞板放入细胞培养箱中培养。72h后，向细胞板除最外围一圈孔的所有孔中加10μL 15uM YO-PRO-1(Invitrogen-Y3603)染料。离心，室温避光震荡20min后在Envision多功能酶标仪(PerkinElmer)上读数(激发光485nm，发射光535nm)。再向细胞板除最外围一圈孔的所有孔中加20μL细胞裂解液(150mM NaCl，2mM Tris pH 7.5，1mM EDTA，1mM EGTA，1％Triton X-100，ddH 2O)。离心，室温避光震荡20min后在Envision多功能酶标仪上读数。
用第二次读数得到的信号值减去第一次读数的信号值得到活细胞的信号值，按以下列公式计算药物对肿瘤细胞生长的抑制率：抑制率＝(加化合物孔信号-阴性对照信号)/(阳性对照信号-阴性对照信号)*100％。各化合物对SJSA-1细胞的抗增殖活性(IC50值)示于下表1中：
表1 本发明化合物体外筛选试验结果
化合物 靶点结合能力MDM2IC50(nM) 骨肉瘤细胞SJSA-1Cell IC50(nM)
1 1.54 -
3 2.51 -
4 3.92 -
5-II 0.18 77.6
6 1.06 -
7-II 0.18 105.9
8 1.63 -
9-II 0.38 52.8
10 1.26 -
11-I 0.4 33
12 0.91 -
13-II 0.55 -
14-I 0.37 106.8
15 5.4 -
16 0.3 167.1
17-II 0.71 105.2
18-II 0.29 69.2
19 0.29 73.5
20-II 0.31 -
21-II 0.86 113.6
22-I 0.1 73.3
23-I 0.76 -
24-I 1.24 -
25 0.53 -
26-I 0.17 -
27-I 0.13 -
28-I 0.27 -
29-II 0.16 53.8
30-II 0.26 96.0
31-II 0.15 26.9
32-II 0.18 23.6
33-II 0.17 15.3
34-II 0.19 68.8
35-II 0.21 33.3
36-II 0.10 -
37-II 0.32 -
38-II 0.16 15.9
39-II 0.11 82.4
40-II 0.19 69.3
41-II 0.15 102.6
42-II 0.24 -
43-II 0.07 68.1
44-II 0.24 198
45-II 0.75 -
46-II 0.16 126.5
47-II 0.29 104.3
48-II 0.20 21.0
49-II 0.13 65.8
50-II 0.17 155.1
51-II 0.78 -
52-II 0.91 -
53-II 0.04 69.3
54 0.21 136.8
55 0.22 -
56 3.81 -
57 0.64 -
58-II 0.19 -
59 1.04 -
60 0.48 -
61 0.82
62 0.41 160.5
63-II 0.21 35.9
64-II 0.14 158.8
65 4.77 -
66-II 0.19 50
67 0.44 -
68 0.51 -
69-I 0.44 -
70-I 0.35 103.8
71 0.57 -
72-I 0.18 -
结论：本发明化合物在与MDM2蛋白靶点的结合和抑制SJSA-1肿瘤细胞生长方面表现出良好的活性。
效果实施例3：药代动力学研究
1.摘要
以雌性Balb/c小鼠为受试动物，应用LC/MS/MS法测定了小鼠尾部静脉注射和口服盒式给药法(cassette dosing)同时给予阳性参照化合物NVP-HDM201、实施例17-II和18-II后不同时刻血浆中的药物浓度。研究本发明的化合物在小鼠体内的药代动力学行为，评价其药代动力学特征。
2.试验方案
2.1实验药品：NVP-HDM201，实施例17-II和18-II化合物。
2.2试验动物
健康幼年雌性Balb/c小鼠20-30g，总共6只。
2.3药物配制
称取适量样品，将NVP-HDM201和本发明化合物17-II和18-II配制成0.2mg/mL in 5％DMSO/40％PEG400/55％水的澄清溶液用于静脉注射和口服组。
2.4给药
雌性Balb/c小鼠6只，禁食一夜后3只尾端静脉注射给药，剂量为0.5mg/kg；另外3只口服给药，剂量为2mg/kg。
3.操作
于给药前及给药后0.08、0.25、0.5、1、2、4、8、24小时采血，置于肝素化抗凝试管中，7000rpm(5204g)、4℃下离心，分离血浆，于-80℃保存。给药后4小时进食。
用LC/MS/MS法测定iv和口服给药给药后小鼠血浆中的待测化合物含量。血浆样品经沉淀蛋白预 处理后进行分析。
4.药代动力学参数结果
表2
Figure PCTCN2018078010-appb-000240
5.结论
与NVP-HDM201比较，在小鼠口服给药剂量为2mg/kg水平时，本发明化合物17-II和18-II血浆暴露量更大，口服生物利用度更高，具有更优的药代动力学性质。

Claims (25)

  1. 式(II)所示化合物或其药学上可接受的盐，
    Figure PCTCN2018078010-appb-100001
    其中，
    环A选自苯基和5～6元杂芳基；
    环B选自苯基和5～7元杂环基；
    R 1选自任选被1、2或3个R取代的：5元杂芳基、苯基或6～10元杂环基；
    R 2选自任选被1、2或3个R取代的：苯基或5～6元杂芳基；
    R 3、R 4、R 5和R 7分别独立地选自H、卤素、OH、CN、NH 2、NO 2，或者分别独立地选自任选被1、2或3个R取代的：C 1-3烷基、C 1-3杂烷基、C 3-6环烷基；且R 3、R 4、R 5和R 7分别独立地位于环A或环B上；
    R 6选自H，或者选自任选被1、2或3个R取代的：C 1-3烷基、C 1-6烯基和C 1-3杂烷基；
    R选自卤素、OH、CN、NH 2，或者选自任选被1、2或3个R’取代的：C 1-3烷基、C 3-5环烷基和C 1-3杂烷基；
    R’选自：F、Cl、Br、I、OH、CN、NH 2、CH 3、CH 3CH 2、CF 3、CHF 2、CH 2F、CH 3O；
    所述5～6元杂芳基、5～7元杂环基、5元杂芳基、6～10元杂环基、C 1-3杂烷基之“杂”表示杂原子或杂原子团，分别独立地选自N、-NH-、-N(R)-、-O-、-S-、＝O、＝S和-C(＝O)-；
    以上任何一种情况下，杂原子或杂原子团的数目分别独立地选自1、2或3。
  2. 根据权利要求1所述的化合物或其药学上可接受的盐，其中，R选自：F、Cl、Br、I、OH、CN、NH 2、CH 3、CH 3CH 2、CF 3、CHF 2、CH 2F、CH 3O、环丙基。
  3. 根据权利要求1或2所述的化合物或其药学上可接受的盐，其中，环A选自：苯基、吡咯基、吡啶基。
  4. 根据权利要求3所述的化合物或其药学上可接受的盐，其中，结构单元
    Figure PCTCN2018078010-appb-100002
    选自：
    Figure PCTCN2018078010-appb-100003
  5. 根据权利要求1或2所述的化合物或其药学上可接受的盐，其中，环B选自：1,3-二氧环戊基、1,3-二氧环戊烯基、苯基、异恶唑基、恶唑基、嘧啶-4(1H)-酮基、咪唑基、吡嗪基、吡咯基、1H-1,2,3-三唑基、 2H-1,2,3-三唑基、1H-1,2,4-三唑基、4H-1,2,4-三唑基、3,4-二氢吡啶-2(1H)-酮基、吡唑基、恶唑-2(3H)-酮基、嘧啶基、4,5-二氢-1H-氮杂卓-2(3H)-酮基、吡啶基、1H-吡咯-2(3H)-酮基、吡咯烷-2-酮基、1,3-恶嗪-2-酮基、3,6-二氢-2H-1,3-嗪-2-酮基。
  6. 根据权利要求5所述的化合物或其药学上可接受的盐，其中，结构单元
    Figure PCTCN2018078010-appb-100004
    选自：
    Figure PCTCN2018078010-appb-100005
  7. 根据权利要求4或6所述的化合物或其药学上可接受的盐，其中，结构单元
    Figure PCTCN2018078010-appb-100006
    选自：
    Figure PCTCN2018078010-appb-100007
    Figure PCTCN2018078010-appb-100008
  8. 根据权利要求1或2所述的化合物或其药学上可接受的盐，其中，R 1选自任选被1、2或3个R取代的：噻唑基、苯基、吲哚基、吲唑基、异吲唑基、[1,2,4]三氮唑并[4,3-a]吡啶基、2-吡啶酮基、咪唑并(1,2-a)吡啶基、苯并[d][1,3]间二氧杂环戊烯基、2,3-苯并二氢[b][1,4]二氧六环基、苯并[d]恶唑-2(3H)-酮基。
  9. 根据权利要求8所述的化合物或其药学上可接受的盐，其中，R 1选自任选被1、2或3个R取代的：
    Figure PCTCN2018078010-appb-100009
  10. 根据权利要求9所述的化合物或其药学上可接受的盐，其中，R 1选自：
    Figure PCTCN2018078010-appb-100010
    Figure PCTCN2018078010-appb-100011
  11. 根据权利要求1或2所述的化合物或其药学上可接受的盐，其中，R 2选自任选被1、2或3个R取代的：噻吩基、噻唑基、苯基。
  12. 根据权利要求11所述的化合物或其药学上可接受的盐，其中，R 2选自任选被1、2或3个R取代的：
    Figure PCTCN2018078010-appb-100012
  13. 根据权利要求12所述的化合物或其药学上可接受的盐，其中，R 2选自：
    Figure PCTCN2018078010-appb-100013
    Figure PCTCN2018078010-appb-100014
  14. 根据权利要求1或2所述的化合物或其药学上可接受的盐，其中，R 3、R 4、R 5和R 7分别独立地选自H、F、Cl、Br、I、OH、CN、NH 2、NO 2，或者分别独立地选自任选被1、2或3个R取代的：C 1-3烷基、C 1-3烷氧基、环丙基、环丁基。
  15. 根据权利要求14所述的化合物或其药学上可接受的盐，其中，R 3、R 4、R 5和R 7分别独立地选自H、F、Cl、Br、I、OH、CN、NH 2、NO 2，或者分别独立地选自任选被1、2或3个R取代的：CH 3、
    Figure PCTCN2018078010-appb-100015
    Figure PCTCN2018078010-appb-100016
    环丙基。
  16. 根据权利要求15所述的化合物或其药学上可接受的盐，其中，R 3、R 4、R 5和R 7分别独立地选自：H、F、Cl、Br、I、OH、CN、NH 2、NO 2、CH 3、CF 3、CHF 2、CH 2F、CHF 2O、CH 2FO、
    Figure PCTCN2018078010-appb-100017
    Figure PCTCN2018078010-appb-100018
    环丙基。
  17. 根据权利要求7所述的化合物或其药学上可接受的盐，其中，结构单元
    Figure PCTCN2018078010-appb-100019
    选自：
    Figure PCTCN2018078010-appb-100020
    Figure PCTCN2018078010-appb-100021
  18. 根据权利要求16或17所述的化合物或其药学上可接受的盐，其中，结构单元
    Figure PCTCN2018078010-appb-100022
    选自：
    Figure PCTCN2018078010-appb-100023
    Figure PCTCN2018078010-appb-100024
    Figure PCTCN2018078010-appb-100025
  19. 根据权利要求1或2所述的化合物或其药学上可接受的盐，其中，R 6选自：H、CH 3、
    Figure PCTCN2018078010-appb-100026
    Figure PCTCN2018078010-appb-100027
    或CH 2OH。
  20. 根据权利要求1～19任意一项所述化合物或其药学上可接受的盐，其中，化合物选自：
    Figure PCTCN2018078010-appb-100028
    Figure PCTCN2018078010-appb-100029
    Figure PCTCN2018078010-appb-100030
    其中，R 3、R 4、R 5、R 6、R 7、R如权利要求1～19所定义。
  21. 化合物或其药学上可接受的盐，其中，化合物选自：
    Figure PCTCN2018078010-appb-100031
    Figure PCTCN2018078010-appb-100032
    Figure PCTCN2018078010-appb-100033
    Figure PCTCN2018078010-appb-100034
  22. 根据权利要求21所述的化合物或其药学上可接受的盐，其中，化合物选自
    Figure PCTCN2018078010-appb-100035
    Figure PCTCN2018078010-appb-100036
    Figure PCTCN2018078010-appb-100037
    Figure PCTCN2018078010-appb-100038
    Figure PCTCN2018078010-appb-100039
    Figure PCTCN2018078010-appb-100040
    Figure PCTCN2018078010-appb-100041
  23. 一种药物组合物，包括治疗有效量的根据权利要求1～22任意一项所述的化合物或其药学上可接受的盐作为活性成分以及药学上可接受的载体。
  24. 根据权利要求1～22任意一项所述的化合物或其药学上可接受的盐在制备治疗癌症、细菌感染、病毒感染的药物上的应用。
  25. 根据权利要求23所述的药物组合物在制备治疗癌症、细菌感染、病毒感染的药物上的应用。
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