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WO2018161871A1 - Composé imidazopyridine utilisé en tant qu'inhibiteur de p53-mdm2 - Google Patents

Composé imidazopyridine utilisé en tant qu'inhibiteur de p53-mdm2 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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Prior art keywords
compound
group
mmol
mixture
pharmaceutically acceptable
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PCT/CN2018/078010
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English (en)
Chinese (zh)
Inventor
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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Application filed by 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 filed Critical 罗欣生物科技（上海）有限公司
Priority to CN201880016257.2A priority Critical patent/CN110418790B/zh
Publication of WO2018161871A1 publication Critical patent/WO2018161871A1/fr

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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

L'invention concerne un composé inhibiteur de p53-MDM2 ayant la structure d'une imidazopyridine, et en particulier un composé tel que représenté par la formule (II) et un sel pharmaceutiquement acceptable de celui-ci.
PCT/CN2018/078010 2017-03-06 2018-03-05 Composé imidazopyridine utilisé en tant qu'inhibiteur de p53-mdm2 WO2018161871A1 (fr)

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EP3766883A4 (fr) * 2018-03-12 2021-03-24 Luoxin Pharmaceutical (Shanghai) Co., Ltd. Composé imidaxopyrolone et son application
CN114746413A (zh) * 2019-11-29 2022-07-12 南京明德新药研发有限公司 二氮杂吲哚类衍生物及其作为Chk1抑制剂的应用

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CN104203952A (zh) * 2012-01-26 2014-12-10 诺华股份有限公司 咪唑并吡咯烷酮化合物
CN105209467A (zh) * 2013-05-27 2015-12-30 诺华股份有限公司 咪唑并吡咯烷酮衍生物及其在治疗疾病中的用途
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EP3766883A4 (fr) * 2018-03-12 2021-03-24 Luoxin Pharmaceutical (Shanghai) Co., Ltd. Composé imidaxopyrolone et son application
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WO2021047466A1 (fr) * 2019-09-12 2021-03-18 罗欣药业(上海)有限公司 Forme cristalline d'un inhibiteur de p53-mdm2 et son procédé de préparation
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CN114746413A (zh) * 2019-11-29 2022-07-12 南京明德新药研发有限公司 二氮杂吲哚类衍生物及其作为Chk1抑制剂的应用
CN114746413B (zh) * 2019-11-29 2024-02-23 南京明德新药研发有限公司 二氮杂吲哚类衍生物及其作为Chk1抑制剂的应用

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