WO2019134661A1 - Isoindolinone and derivative thereof as csf-1r inhibitor - Google Patents

Isoindolinone and derivative thereof as csf-1r inhibitor Download PDF

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Publication number
WO2019134661A1
WO2019134661A1 PCT/CN2019/070227 CN2019070227W WO2019134661A1 WO 2019134661 A1 WO2019134661 A1 WO 2019134661A1 CN 2019070227 W CN2019070227 W CN 2019070227W WO 2019134661 A1 WO2019134661 A1 WO 2019134661A1
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compound
synthesis
mmol
group
μmol
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PCT/CN2019/070227
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French (fr)
Chinese (zh)
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钱文远
杨纯道
徐光海
李婕
黎健
陈曙辉
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南京明德新药研发股份有限公司
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Publication of WO2019134661A1 publication Critical patent/WO2019134661A1/en

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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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/4035—Isoindoles, e.g. phthalimide
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/46—Iso-indoles; Hydrogenated iso-indoles with an oxygen atom in position 1
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • 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
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings

Definitions

  • the present invention relates to a class of isoindolinone derivatives and their use in the preparation of a medicament for the treatment of a disease associated with a novel colony stimulating factor 1 receptor (CSF-1R) inhibitor. Specifically, it relates to a compound of the formula (I), and a pharmaceutically acceptable salt thereof or a stereoisomer thereof.
  • CSF-1R colony stimulating factor 1 receptor
  • Colony stimulating factor 1 (CSF-1, also known as macrophage colony stimulating factor, M-CSF) is an important growth factor that controls bone marrow progenitor cells, monocytes, macrophages, and giants. The growth of osteoclasts and dendritic cells differentiated by phagocytes must be combined with its unique cell surface receptor CSF-1R to exert its biological effects.
  • CSF-1R is encoded by the proto-oncogene c-FMS, also known as c-FMS, a receptor tyrosine kinase that binds CSF-1 and CSF-1R in the extracellular domain and induces dimerization of CSF-1R. Furthermore, the CSF-1R kinase domain is autophosphorylated in the cell.
  • CSF-1R acts as a docking site for several cytoplasmic signaling molecules, which ultimately triggers a series of signal cascades. For example, phosphorylation of the 697th tyrosine residue of CSF-1R activates the MAPK signaling pathway, and phosphorylation of its 721th tyrosine residue initiates the PI3K and PLC ⁇ signaling pathways.
  • CSF-1 tumor-associated macrophage
  • TAM tumor-associated macrophage
  • CSF-1 can also be secreted by cells. Their addition promotes the formation of complex micro-environment of tumors. This micro-environment can help tumor cells to develop immune tolerance to autoimmune functions, thereby promoting the proliferation, invasion and metastasis of tumor cells in vivo. .
  • CSF-1R By inhibiting CSF-1R, it may be beneficial to treat diseases caused by osteoclasts, dendritic cells, and macrophage lesions, such as autoimmune/infectious diseases, cancer, and bone-related diseases.
  • CSF-1R inhibitors can be used in a variety of ways in the field of disease treatment. It can be used alone or in combination with a variety of anti-cancer therapies, such as anti-angiogenesis, adoptive transfer of T cells, Radiotherapy, chemotherapy, and immunological checkpoint therapy. Many of the drugs on the market have inhibitory activities against CSF-1R, such as imatinib, dasatinib and sunitinib, but selective CSF-1R inhibitors are not yet marketed.
  • PLX-3397 a dual inhibitor of CSF-1R and c-Kit, is currently in clinical phase III for the treatment of multiple cancers such as giant cell tumor of the tendon sheath (TGCT).
  • Array's ARRY-382 and Novartis' BLZ-945 are more selective CSF-1R inhibitors and are currently in clinical phase II.
  • Patent No. WO2016179412 discloses a reference 1, mainly related to the targets c-kit, c-fms and Flt3, for the treatment of giant cell tumor of tendon sheath;
  • Patent No. US2005026976 discloses a reference 2, the main target is KDR, for treating tumors cancer.
  • the present invention provides a compound of the formula (I): and a pharmaceutically acceptable salt thereof or a stereoisomer thereof:
  • T is selected from N or CH;
  • R 1 is selected from H, F, Cl, Br, I, OH or CN, or is selected from the group consisting of 1, 2 or 3 R substituted: C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkenyl, C 1-6 alkynyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl-O- or 3- to 7-membered heterocycloalkyl-O-;
  • R 2 is independently selected from H, F, Cl, Br, I, OH, NH 2 or CN, respectively, or independently selected from C 1-3 alkyl optionally substituted by 1, 2 or 3 R;
  • R 3 is independently selected from H, F, Cl, Br, I, OH, NH 2 or CN, respectively, or independently selected from C 1 1-6 alkyl optionally substituted by 1, 2 or 3 R, C 1-6 heteroalkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl-O-, 3-7 -membered heterocycloalkyl-O- or 3-7-membered heterocycloalkyl-C 1 -3 alkyl-;
  • Ring A is selected from C 4-8 cycloalkyl, phenyl or 5- to 10-membered heteroaryl;
  • n 0, 1 or 2;
  • n 1, 2 or 3;
  • R is independently selected from H, F, Cl, Br, I, OH, NH 2 or CN, or from a group optionally substituted by 1, 2 or 3 R': C 1-6 alkyl or C 1- 6 heteroalkyl;
  • R' is independently selected from the group consisting of F, Cl, Br, I, OH, NH 2 , CN or -CH 3 ;
  • the hetero atom or hetero atom in the C 1-6 heteroalkyl group, the 5-10 membered heteroaryl group, the 3 to 7 membered heterocycloalkyl group is independently selected from N, —O—, —S—, —NH. -;
  • the number of the above heteroatoms or heteroatoms is independently selected from 1, 2, 3 or 4.
  • the above R is selected from the group consisting of H, F, Cl, Br, I, OH, NH 2 , CN, or selected from: C 1-3 alkane optionally substituted by 1, 2 or 3 R'
  • the group, C 1-3 alkoxy group and C 1-3 alkylamino group, other variables are as defined in the present invention.
  • said R is selected from the group consisting of H, F, Cl, Br, I, OH, NH 2 , CN, or selected from: -CH 3 , optionally substituted by 1, 2 or 3 R', CH 2 CH 3 , Other variables are as defined by the present invention.
  • the above R is selected from the group consisting of: H, F, Cl, Br, I, OH, NH 2 , CN, -CH 3 , -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CH 3 , Other variables are as defined by the present invention.
  • R 1 is selected from the group consisting of H, F, Cl, Br, I, OH, CN, or selected from the group consisting of 1, 2 or 3 R: C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkynyl, cyclopropane, cyclopropyl-O-, oxetanyl-O-, other variables are as defined in the present invention.
  • said R 1 is selected from the group consisting of H, F, Cl, Br, I, OH, CN, or selected from the group consisting of: 1, 2 or 3 R: -CH 3 , -CH 2 CH 3 , -CH 2 CH 3 CH 3 , Other variables are as defined by the present invention.
  • R 1 is selected from the group consisting of H, F, Cl, Br, I, OH, CN, -CH 3 , -CH 2 CH 3 , -CH 2 CH 3 CH 3 , Other variables are as defined by the present invention.
  • R 2 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, or independently selected from, optionally substituted by 1, 2 or 3 R. :-CH 3 or -CH 2 CH 3 , other variables are as defined in the present invention.
  • R 2 is selected from the group consisting of H, F, Cl, Br, I, OH, NH 2 , CN, -CH 3 , respectively, and other variables are as defined herein.
  • said R 3 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, or independently selected from, optionally substituted by 1, 2 or 3 R :C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, cyclopropyl, cyclobutane, cyclopentyl, acetonyl, tetrahydrofuranyl, tetrahydropyranyl , piperazinyl, piperidinyl, morpholinyl, -CH 2 -piperazinyl, -CH 2 -piperidinyl, -O-cyclopropane, -O-cyclobutane, -O-tetrahydrofuranyl, -O-tetrahydropyranyl, imidazol-2-one, oxazolidin-2-one or pyrrolidin-2-one, other variables are as defined herein.
  • said R 3 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, or independently selected from, optionally substituted by 1, 2 or 3 R :-CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -C(CH 3 ) 3 , -OCH 3 , -OCH 2 CH 3 , -NH(CH 3 ), -N(CH 3 ) 2 , Other variables are as defined by the present invention.
  • the above R 3 are independently selected from the group consisting of H, F, Cl, Br, I, OH, NH 2 , CN, CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , -C(CH 3 ) 3 , -OCH 3 , -OCH 2 CH 3 , -NH(CH 3 ), -N(CH 3 ) 2 ,
  • Other variables are as defined by the present invention.
  • the above ring A is selected from the group consisting of phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiazolyl, oxazolyl, pyrazolyl, benzo[b]thiophene, 2,3 -dihydro-[1,4]dioxan[2,3-b]pyridine, benzo[d]thiazolyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, others Variables are as defined by the present invention.
  • the structural unit Selected from Other variables are as defined by the present invention.
  • the structural unit Selected from Other variables are as defined by the present invention.
  • the structural unit Selected from Other variables are as defined by the present invention.
  • the structural unit Selected from Other variables are as defined by the present invention.
  • the structural unit Selected from Other variables are as defined by the present invention.
  • the present invention provides a compound represented by the formula (I), and a pharmaceutically acceptable salt thereof or a stereoisomer thereof
  • T is selected from N or CH;
  • R 1 is selected from H, F, Cl, Br, I, OH, NH 2 , CN, or selected from C 1 1-6 alkyl, C 1-6 alkoxy optionally substituted by 1, 2 or 3 R a group, a C 1-6 alkenyl group, a C 1-6 alkynyl group, a C 3-7 cycloalkyl group, a C 3-7 cycloalkyl-O-, a 3 to 7 membered heterocycloalkyl-O-;
  • R 2 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, or independently selected from: C 1-3 alkyl optionally substituted by 1, 2 or 3 R;
  • R 3 is each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, or independently selected from C 1 1-6 alkyl optionally substituted by 1, 2 or 3 R, C 1-6 heteroalkyl, C 3-7 cycloalkyl, 3-7 -membered heterocycloalkyl-C 1-3 alkyl-;
  • Ring A is selected from: C 5-8 cycloalkyl, phenyl or 5- to 6-membered heteroaryl;
  • n is selected from: 0, 1 or 2;
  • n is selected from: 1, 2 or 3;
  • R is selected from the group consisting of: H, F, Cl, Br, I, OH, NH 2 , CN, or selected from the group consisting of 1, 2 or 3 R's substituted: C 1-6 alkyl, C 1-6 hetero alkyl;
  • R' is selected from the group consisting of: F, Cl, Br, I, OH, NH 2 , CN, Me;
  • hetero of the C 1-6 heteroalkyl, 5-6 membered heteroaryl, 3 to 7 membered heterocycloalkyl is selected from the group consisting of N, -O-, -S-, -NH-;
  • the number of the above heteroatoms or heteroatoms is independently selected from 1, 2, 3 or 4.
  • the above R is selected from the group consisting of H, F, Cl, Br, I, OH, NH 2 , CN, or selected from: C 1-3 alkane optionally substituted by 1, 2 or 3 R'
  • the group, C 1-3 alkoxy group and C 1-3 alkylamino group, other variables are as defined in the present invention.
  • R is selected from the group consisting of H, F, Cl, Br, I, OH, NH 2 , CN, or selected from the group consisting of 1, 2 or 3 R' substitutions: Me, Et, Other variables are as defined by the present invention.
  • the above R is selected from the group consisting of: H, F, Cl, Br, I, OH, NH 2 , CN, Me, CH 2 F, CHF 2 , CF 3 , Et, Other variables are as defined by the present invention.
  • R 1 is selected from the group consisting of H, F, Cl, Br, I, OH, CN, or selected from: C 1-3 alkyl optionally substituted by 1, 2 or 3 R', C 1-3 alkoxy, C 1-3 alkynyl, cyclopropane, cyclopropyl-O-, oxetanyl-O-, other variables are as defined in the present invention.
  • R 1 is selected from the group consisting of H, F, Cl, Br, I, OH, CN, or selected from the group consisting of 1, 2 or 3 R' substitutions: Me, Et, Pr, Other variables are as defined by the present invention.
  • R 1 is selected from the group consisting of H, F, Cl, Br, I, OH, CN, Me, Et, Pr, Other variables are as defined by the present invention.
  • R 2 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, or independently selected from, optionally substituted by 1, 2 or 3 R. : Me, Et, other variables as defined by the present invention.
  • R 2 is selected from the group consisting of H, F, Cl, Br, I, OH, NH 2 , CN, Me, respectively, and other variables are as defined herein.
  • said R 3 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, or independently selected from, optionally substituted by 1, 2 or 3 R : C 1-3 alkyl, C 1-3 heteroalkyl, cyclopentyl, piperazinyl-CH 2 -, piperidinyl-CH 2 -, other variables are as defined in the invention.
  • said R 3 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, or independently selected from, optionally substituted by 1, 2 or 3 R :Me, Other variables are as defined by the present invention.
  • R 3 are independently selected from the group consisting of H, F, Cl, Br, I, OH, NH 2 , CN, Me, Other variables are as defined by the present invention.
  • the above ring A is selected from the group consisting of phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiazolyl, oxazolyl, cyclopentyl, cyclohexyl, cyclooctyl, and other variables such as The invention is defined.
  • the structural unit Selected from Other variables are as defined by the present invention.
  • the structural unit Selected from Other variables are as defined by the present invention.
  • the structural unit Selected from Other variables are as defined by the present invention.
  • the structural unit Selected from Other variables are as defined by the present invention.
  • the structural unit Selected from Other variables are as defined by the present invention.
  • the structural unit Selected from Other variables are as defined by the present invention.
  • f is selected from: 1, 2, 3 or 4;
  • l selected from: 0 or 1;
  • n, m, T, R 1 to R 3 are as defined in the present invention.
  • the above compound, an isomer thereof or a pharmaceutically acceptable salt thereof is
  • f is selected from: 1, 2, 3 or 4;
  • l selected from: 0 or 1;
  • R 1 to R 3 are as defined in the present invention.
  • the present invention also provides the following compound, an isomer thereof or a pharmaceutically acceptable salt thereof, which 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 compound or a pharmaceutically acceptable salt thereof as an active ingredient together with a pharmaceutically acceptable carrier.
  • the present invention also provides the use of the above compound, an isomer thereof or a pharmaceutically acceptable salt thereof or the above composition for the preparation of a medicament for treating a novel colony stimulating factor-1 receptor inhibitor.
  • the above-described drug associated with the novel colony stimulating factor-1 receptor inhibitor is a drug for treating tumor and autoimmune diseases.
  • 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 amine 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 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.
  • 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.
  • enantiomer or “optical isomer” refer to stereoisomers that are mirror images of one another.
  • cis-trans isomer or “geometric isomer” is caused by the inability to freely rotate a single bond due to a double bond or a ring-forming carbon atom.
  • diastereomer refers to a stereoisomer in which the molecule has two or more chiral centers and the molecules are in a non-mirrored relationship.
  • wedge-shaped dashed keys Represents the absolute configuration of a solid center with straight solid keys
  • straight dashed keys Indicates the relative configuration of the stereocenter, using wavy lines Indicates a wedge solid key Or wedge-shaped dotted key Or with wavy lines Represents a straight solid key And straight dashed keys
  • tautomer or “tautomeric form” mean that the different functional isomers are in dynamic equilibrium at room temperature and can be rapidly converted into each other. If tautomers are possible (as in solution), the chemical equilibrium of the tautomers can be achieved.
  • proton tautomers also known as prototropic tautomers
  • prototropic tautomers include interconversions by proton transfer, such as keto-enol isomerization and imine-enes. Amine isomerization.
  • the valence tautomer includes the mutual transformation of some of the bonding electrons.
  • keto-enol tautomerization is the interconversion between two tautomers of pentane-2,4-dione and 4-hydroxypent-3-en-2-one.
  • the terms "enriched in one isomer”, “isomer enriched”, “enriched in one enantiomer” or “enantiomeric enriched” refer to one of the isomers or pairs
  • the content of the oligo is less than 100%, and the content of the isomer or enantiomer is 60% or more, or 70% or more, or 80% or more, or 90% or more, or 95% or more, or 96% or more, or 97% or more, 98% or more, 99% or more, 99.5% or more, 99.6% or more, 99.7% or more, 99.8% or more, or greater than or equal to 99.9%.
  • the term “isomer excess” or “enantiomeric excess” refers to the difference between the two isomers or the relative percentages of the two enantiomers. For example, if one of the isomers or enantiomers is present in an amount of 90% and the other isomer or enantiomer is present in an amount of 10%, the isomer or enantiomeric excess (ee value) is 80%. .
  • 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).
  • hydrogen can be replaced by heavy hydrogen to form a deuterated drug.
  • the bond composed of barium and carbon is stronger than the bond composed of common hydrogen and carbon.
  • deuterated drugs have reduced side effects and increased drug stability. Enhance the efficacy and prolong the biological half-life of the drug. Alterations of all isotopic compositions of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.
  • 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.
  • Oxygen substitution does not occur on the aromatic 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 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.
  • cycloalkenylalkyl or “cycloalkenylalkyl” refers to a cycloalkenyl substituted alkyl.
  • cycloalkynyl or “cycloalkynylalkyl” refers to a cycloalkynyl substituted alkyl.
  • 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, equivalent; CDI stands for Carbonyldiimidazole; DCM stands for dichloromethane; PE stands for petroleum ether; DIAD stands for diisopropyl azodicarboxylate; DMF stands for N,N-dimethylformamide; DMSO stands for dimethyl sulfoxide; EtOAc stands for acetic acid Esters; EtOH for ethanol; MeOH for methanol; CBz for benzyl
  • the compounds of the present invention have significant CSF-1R kinase inhibition with a significant increase in permeability and metabolic stability.
  • Compound 2-B was prepared in the same manner as Compound II-B in Intermediate II except that the corresponding material was used.
  • N-Bromosuccinimide 800.73 mg, 4.50 mmol, 1.10 eq was added to a solution of 3-A (500.00 mg, 4.09 mmol) in acetonitrile (10.00 mL), and stirred at 25 ° C for 2 hours. Filtration gave a solid which gave compound 5-B without purification.
  • N-bromosuccinimide (106.07 mg, 595.99 ⁇ mol) was added to a solution of 6-E (170.00 mg, 95.99 ⁇ mol) in acetonitrile (10.00 mL), and stirred under an atmosphere of 25 ° C for 0.5 hour. Concentration gave the crude product which was purified by preparative EtOAc (EtOAc:EtOAc
  • Compound 8-B was prepared in the same manner as in the compound 5-C of Example 5 except that the corresponding material was used.
  • Aqueous ammonia (3.64 g, 103.85 mmol, 4.00 mL) was added to a solution of Compound 11-B (170.00 mg, 521.54 ⁇ mol) in acetonitrile (2.00 mL) at 20 ° C. After the addition, the reaction mixture was stirred at 25 °C for 2 hours. The reaction solution was concentrated under reduced pressure to give Compound 11-C.
  • Compound 21-G was prepared in the same manner as in the preparation of Compound I in Intermediate I, except that the corresponding materials were used.
  • Compound 22-B was prepared in the same manner as in the preparation of compound 21-B in Example 21 except that the corresponding materials were used.
  • 24-F (120.00 mg, 268.26 ⁇ mol) was dissolved in dioxane (10 mL) and water (1 mL), and Compound II-B (92.86 mg, 268.26 ⁇ mol), 2-dicyclohexylphosphonium-2 was added thereto.
  • ',4',6'-triisopropylbiphenyl 51.15 mg, 107.30 ⁇ mol
  • potassium phosphate 17.3 mg, 804.78 ⁇ mol
  • Compound 25-C was prepared in the same manner as in the preparation of compound 9-A in Example 9 except that the corresponding materials were used.
  • Compound 25 was prepared in the same manner as in the preparation of compound 9 in Example 9 except that the corresponding materials were used.
  • Compound 26-A was prepared in the same manner as in the preparation of compound 22-B in Example 22 except that the corresponding material was used.
  • Acetone dipalladium (74.61 mg, 81.48 ⁇ mol), and the mixture was stirred at 90 ° C for 12 hours under nitrogen atmosphere, and then water (10 mL) was added and extracted with dichloromethane (40 mL), and brine (10 mL) The organic layer was dried over sodium sulfate, filtered and evaporated to dryness.
  • 28-E (130 mg, 230.29 ⁇ mol) was dissolved in dichloromethane (8 mL), trifluoroacetic acid (770.00 mg, 6.75 mmol) was added thereto, and the reaction was stirred at 24 ° C for 30 minutes, then saturated carbonate was added to the mixture.
  • the sodium hydrogen hydride solution was adjusted to pH 8 and then diluted with water (20 mL), dichloromethane (50 mL), and brine (50 mL).
  • the petroleum ether/ethyl acetate 6/1) (6 mL) was washed and worked up to afford 28.
  • Compound 31-E was prepared in the same manner as in the preparation of compound 9-A in Example 9 except that the corresponding material was used.
  • Compound 31 was prepared in the same manner as in the preparation of compound 9 in Example 9 except that the corresponding materials were used.
  • Compound 33 was prepared in the same manner as in the preparation of compound 9 in Example 9 except that the corresponding material was used.
  • Compound 34-A was prepared in the same manner as in the preparation of compound 32-A in Example 32 except that the corresponding material was used.
  • Compound 34 was prepared in the same manner as in the preparation of compound 32 in Example 32 except that the corresponding material was used.
  • Compound 35-A was prepared in the same manner as in the preparation of compound 32-A in Example 32 except that the corresponding material was used.
  • Compound 35 was prepared in the same manner as in the preparation of compound 32 in Example 32 except that the corresponding material was used.
  • Compound 36-B was prepared in the same manner as in the preparation of compound 5-C in Example 5 except that the corresponding material was used.
  • Compound 36-C was prepared in the same manner as in the preparation of compound 9-A in Example 9 except that the corresponding material was used.
  • Compound 36 was prepared in the same manner as in the preparation of compound 9 in Example 9 except that the corresponding materials were used.
  • Compound 42 was prepared in the same manner as in the preparation of compound 9 in Example 9 except that the corresponding materials were used.
  • Compound 44-A was prepared in the same manner as in the preparation of compound 32-A in Example 32 except that the corresponding material was used.
  • Compound 44 was prepared in the same manner as in the preparation of compound 32 in Example 32 except that the corresponding material was used.
  • Compound 45-B was prepared in the same manner as in the preparation of compound 32-A in Example 32 except that the corresponding material was used.
  • Compound 45 was prepared in the same manner as in the preparation of compound 32 in Example 32 except that the corresponding material was used.
  • Compound 47-A was prepared in the same manner as in the preparation of compound 32-A in Example 32 except that the corresponding material was used.
  • Compound 47 was prepared in the same manner as in the preparation of compound 32 in Example 32 except that the corresponding material was used.
  • Compound 48-B was prepared in the same manner as in the preparation of compound 32-A in Example 32 except that the corresponding material was used.
  • Compound 48 was prepared in the same manner as in the preparation of compound 32 in Example 32 except that the corresponding material was used.
  • 2,5-Dibromopyridine 500 mg, 2.11 mmol was dissolved in toluene (10 mL), n-butyllithium (162.24 mg, 2.53 mmol, 2.5 M) was added dropwise at -70 ° C, and the reaction was at -70 ° C. After stirring for 1 hour, a solution of 49-A (167.31 mg, 2.32 mmol) dissolved in toluene (1 mL) was added dropwise.
  • Compound 49-C was prepared in the same manner as in the preparation of compound 32-A in Example 32 except that the corresponding material was used.
  • Compound 49 was prepared in the same manner as in the preparation of compound 32 in Example 32 except that the corresponding material was used.
  • Compound 50-D was prepared in the same manner as in the preparation of compound 9-A in Example 9 except that the corresponding material was used.
  • Compound 50 was prepared in the same manner as Compound 9 in Example 9, except that the corresponding materials were used.
  • Compound 51-E was prepared in the same manner as in the preparation of compound 9-A in Example 9 except that the corresponding material was used.
  • Compound 51 was prepared in the same manner as in the preparation of compound 9 in Example 9 except that the corresponding materials were used.
  • Compound 52-B was prepared in the same manner as in the preparation of compound 5C in Example 5 except that the corresponding material was used.
  • Compound 52-C was prepared in the same manner as in the preparation of compound 9-A in Example 9 except that the corresponding material was used.
  • Compound 52 was prepared in the same manner as in the preparation of compound 9 in Example 9 except that the corresponding material was used.
  • Compound 53-C was prepared in the same manner as in the preparation of compound 9-A in Example 9 except that the corresponding material was used.
  • Compound 53 was prepared in the same manner as in the preparation of compound 9 in Example 9 except that the corresponding material was used.
  • Compound 54-D was prepared in the same manner as in the preparation of compound 9-A in Example 9 except that the corresponding material was used.
  • Compound 54 was prepared in the same manner as in the preparation of compound 9 in Example 9 except that the corresponding material was used.
  • Compound 56-C was prepared in the same manner as in the preparation of compound 32-A in Example 32 except that the corresponding material was used.
  • Compound 56-D was prepared in the same manner as in the preparation of compound 9-A in Example 9 except that the corresponding material was used.
  • Compound 56 was prepared in the same manner as in the preparation of compound 9 in Example 9 except that the corresponding materials were used.
  • Step 1 Synthesis of Compound 57-B

Abstract

The present invention relates to a type of isoindolinone derivatives and use thereof in the preparation of a medicament for treating diseases associated with a novel colony stimulating factor 1 receptor (CSF-1R) inhibitor. In particular, the present invention relates to a compound of formula (I) and a pharmaceutically acceptable salt thereof or a stereoisomer thereof.

Description

异吲哚啉酮及其衍生物作为CSF-1R抑制剂Isoindolinone and its derivatives as CSF-1R inhibitors
相关申请的引用Reference to related application
本申请主张如下优先权：This application claims the following priority:
CN201810005701.2，申请日2018-01-03；CN201810005701.2, application date 2018-01-03;
CN201810097248.2，申请日2018-01-31。CN201810097248.2, application date 2018-01-31.
技术领域Technical field
本发明涉及一类异吲哚啉酮衍生物，及其在制备治疗与新型集落刺激因子-1受体(colony stimulating factor 1 receptor，CSF-1R)抑制剂相关疾病的药物中的应用。具体涉及式(Ⅰ)所示化合物及其药学上可接受的盐或其立体异构体。The present invention relates to a class of isoindolinone derivatives and their use in the preparation of a medicament for the treatment of a disease associated with a novel colony stimulating factor 1 receptor (CSF-1R) inhibitor. Specifically, it relates to a compound of the formula (I), and a pharmaceutically acceptable salt thereof or a stereoisomer thereof.
背景技术Background technique
集落刺激因子1(colony stimulating factor 1，CSF-1，又称为macrophage colony stimulating factor，M-CSF)是一种重要的生长因子，控制骨髓祖代细胞、单核细胞、巨噬细胞、以及巨噬细胞分化出的破骨细胞和树突细胞等的生长，它必须与它唯一的细胞表面受体CSF-1R相结合，才能发挥出它的生物学效应。CSF-1R由原癌基因c-FMS编码，因此也称为c-FMS，是一种受体酪氨酸激酶，CSF-1和CSF-1R的在细胞外域结合，诱导CSF-1R的二聚，进一步导致细胞内的CSF-1R激酶区自身磷酸化，一旦发生磷酸化，CSF-1R就充当了几种细胞质信号分子的docking位点，最终引发一系列信号级联反应。例如，CSF-1R的第697位酪氨酸残基的磷酸化作用可以激活MAPK信号通路，而它的第721位酪氨酸残基的磷酸化作用则可以启动PI3K和PLCγ信号通路等。Colony stimulating factor 1 (CSF-1, also known as macrophage colony stimulating factor, M-CSF) is an important growth factor that controls bone marrow progenitor cells, monocytes, macrophages, and giants. The growth of osteoclasts and dendritic cells differentiated by phagocytes must be combined with its unique cell surface receptor CSF-1R to exert its biological effects. CSF-1R is encoded by the proto-oncogene c-FMS, also known as c-FMS, a receptor tyrosine kinase that binds CSF-1 and CSF-1R in the extracellular domain and induces dimerization of CSF-1R. Furthermore, the CSF-1R kinase domain is autophosphorylated in the cell. Once phosphorylation occurs, CSF-1R acts as a docking site for several cytoplasmic signaling molecules, which ultimately triggers a series of signal cascades. For example, phosphorylation of the 697th tyrosine residue of CSF-1R activates the MAPK signaling pathway, and phosphorylation of its 721th tyrosine residue initiates the PI3K and PLCγ signaling pathways.
很多肿瘤细胞在生长过程中能分泌像CSF-1这样的生长因子，而后者又可以招募巨噬细胞(肿瘤相关巨噬细胞，tumor-associated macrophage，TAM)进入到肿瘤区域，巨噬细胞和肿瘤细胞一样也能分泌CSF-1，它们的加入促进了肿瘤复杂微环境的形成，这种微环境可以帮助肿瘤细胞对自身免疫功能产生免疫耐受，进而促进肿瘤细胞在体内的增殖、侵袭和转移。通过对CSF-1R的抑制，可能有益于治疗一些破骨细胞、树突细胞和巨噬细胞病变造成的疾病，例如自身免疫/感染类疾病、癌症以及骨相关疾病等。Many tumor cells secrete growth factors like CSF-1 during growth, which in turn recruit macrophages (tumor-associated macrophage, TAM) into tumor areas, macrophages and tumors. CSF-1 can also be secreted by cells. Their addition promotes the formation of complex micro-environment of tumors. This micro-environment can help tumor cells to develop immune tolerance to autoimmune functions, thereby promoting the proliferation, invasion and metastasis of tumor cells in vivo. . By inhibiting CSF-1R, it may be beneficial to treat diseases caused by osteoclasts, dendritic cells, and macrophage lesions, such as autoimmune/infectious diseases, cancer, and bone-related diseases.
近年来的研究表明，CSF-1R的抑制剂可以通过多种途径应用于疾病治疗领域，它既可以单独使用，也可以和多种抗癌疗法联用，如抗血管生成、T细胞过继转移、放疗、化疗以及免疫检查点疗法等。很多已上市的药物具有CSF-1R的抑制活性，如伊马替尼、达沙替尼和舒尼替尼等，但选择性的CSF-1R抑制剂还没有上市的药物。由Plexxikon公司研发、第一三共收购的Pexidartinib(PLX-3397)是CSF-1R和c-Kit的双抑制剂，目前处于临床三期，用于治疗腱鞘巨细胞瘤(TGCT)等多种癌症，Array公司的ARRY-382和诺华的BLZ-945是选择性更好的CSF-1R抑制剂，目前均处于临床二期。Recent studies have shown that CSF-1R inhibitors can be used in a variety of ways in the field of disease treatment. It can be used alone or in combination with a variety of anti-cancer therapies, such as anti-angiogenesis, adoptive transfer of T cells, Radiotherapy, chemotherapy, and immunological checkpoint therapy. Many of the drugs on the market have inhibitory activities against CSF-1R, such as imatinib, dasatinib and sunitinib, but selective CSF-1R inhibitors are not yet marketed. Developed by Plexxikon, Pexidartinib (PLX-3397), a dual inhibitor of CSF-1R and c-Kit, is currently in clinical phase III for the treatment of multiple cancers such as giant cell tumor of the tendon sheath (TGCT). Array's ARRY-382 and Novartis' BLZ-945 are more selective CSF-1R inhibitors and are currently in clinical phase II.
专利号WO2016179412公开了对照品1，主要涉及靶点c-kit、c-fms和Flt3,用于治疗腱鞘巨细胞瘤； 专利号US2005026976公开了对照品2，主要靶点为KDR,用于***癌。Patent No. WO2016179412 discloses a reference 1, mainly related to the targets c-kit, c-fms and Flt3, for the treatment of giant cell tumor of tendon sheath; Patent No. US2005026976 discloses a reference 2, the main target is KDR, for treating tumors cancer.
Figure PCTCN2019070227-appb-000001
Figure PCTCN2019070227-appb-000001
发明内容Summary of the invention
本发明提供了式(I)所示的化合物及其药学上可接受的盐或其立体异构体：The present invention provides a compound of the formula (I): and a pharmaceutically acceptable salt thereof or a stereoisomer thereof:
Figure PCTCN2019070227-appb-000002
Figure PCTCN2019070227-appb-000002
其中，among them,
T选自N或CH；T is selected from N or CH;
R 1选自H、F、Cl、Br、I、OH或CN，或选自任选被1、2或3个R取代的：C 1-6烷基、C 1-6烷氧基、C 1-6烯基、C 1-6炔基、C 3-7环烷基、C 3-7环烷基-O-或3～7元杂环烷基-O-； R 1 is selected from H, F, Cl, Br, I, OH or CN, or is selected from the group consisting of 1, 2 or 3 R substituted: C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkenyl, C 1-6 alkynyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl-O- or 3- to 7-membered heterocycloalkyl-O-;
R 2分别独立地选自H、F、Cl、Br、I、OH、NH 2或CN，或分别独立地选自任选被1、2或3个R取代的C 1-3烷基； R 2 is independently selected from H, F, Cl, Br, I, OH, NH 2 or CN, respectively, or independently selected from C 1-3 alkyl optionally substituted by 1, 2 or 3 R;
R 3分别独立地选自H、F、Cl、Br、I、OH、NH 2或CN，或分别独立地选自任选被1、2或3个R取代的：C 1-6烷基、C 1-6杂烷基、C 3-7环烷基、C 3-7环烷基-O-、3～7元杂环烷基-O-或3～7元杂环烷基-C 1-3烷基-； R 3 is independently selected from H, F, Cl, Br, I, OH, NH 2 or CN, respectively, or independently selected from C 1 1-6 alkyl optionally substituted by 1, 2 or 3 R, C 1-6 heteroalkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl-O-, 3-7 -membered heterocycloalkyl-O- or 3-7-membered heterocycloalkyl-C 1 -3 alkyl-;
L选自-NH-、-NHCHR-、-O-、-O-CH 2-或-NHC(＝O)-； L is selected from -NH-, -NHCHR-, -O-, -O-CH 2 - or -NHC(=O)-;
环A选自C 4-8环烷基、苯基或5～10元杂芳基； Ring A is selected from C 4-8 cycloalkyl, phenyl or 5- to 10-membered heteroaryl;
n是0、1或2；n is 0, 1 or 2;
m是1、2或3；m is 1, 2 or 3;
R分别独立地选自H、F、Cl、Br、I、OH、NH 2或CN，或选自任选被1、2或3个R’取代的：C 1-6烷基或C 1-6杂烷基； R is independently selected from H, F, Cl, Br, I, OH, NH 2 or CN, or from a group optionally substituted by 1, 2 or 3 R': C 1-6 alkyl or C 1- 6 heteroalkyl;
R’分别独立地选自F、Cl、Br、I、OH、NH 2、CN或-CH 3； R' is independently selected from the group consisting of F, Cl, Br, I, OH, NH 2 , CN or -CH 3 ;
所述C 1-6杂烷基、5-10元杂芳基、3～7元杂环烷基中的杂原子或杂原子团分别独立地选自N、-O-、-S-、-NH-； The hetero atom or hetero atom in the C 1-6 heteroalkyl group, the 5-10 membered heteroaryl group, the 3 to 7 membered heterocycloalkyl group is independently selected from N, —O—, —S—, —NH. -;
上述杂原子或杂原子团的数目分别独立地选自1、2、3或4。The number of the above heteroatoms or heteroatoms is independently selected from 1, 2, 3 or 4.
本发明的一些方案中，上述R选自H、F、Cl、Br、I、OH、NH 2、CN，或选自任选被1、2或3个R’取代的：C 1-3烷基、C 1-3烷氧基和C 1-3烷氨基，其他变量如本发明所定义。 In some embodiments of the invention, the above R is selected from the group consisting of H, F, Cl, Br, I, OH, NH 2 , CN, or selected from: C 1-3 alkane optionally substituted by 1, 2 or 3 R' The group, C 1-3 alkoxy group and C 1-3 alkylamino group, other variables are as defined in the present invention.
本发明的一些方案中，上述R选自H、F、Cl、Br、I、OH、NH 2、CN，或选自任选被1、2或3个R’取代的：-CH 3、-CH 2CH 3、
Figure PCTCN2019070227-appb-000003
其他变量如本发明所定义。 In some embodiments of the invention, said R is selected from the group consisting of H, F, Cl, Br, I, OH, NH 2 , CN, or selected from: -CH 3 , optionally substituted by 1, 2 or 3 R', CH 2 CH 3 ,
Figure PCTCN2019070227-appb-000003
Other variables are as defined by the present invention.
本发明的一些方案中，上述R选自：H、F、Cl、Br、I、OH、NH 2、CN、-CH 3、-CH 2F、-CHF 2、-CF 3、-CH 2CH 3、
Figure PCTCN2019070227-appb-000004
其他变量如本发明所定义。 In some embodiments of the invention, the above R is selected from the group consisting of: H, F, Cl, Br, I, OH, NH 2 , CN, -CH 3 , -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CH 3 ,
Figure PCTCN2019070227-appb-000004
Other variables are as defined by the present invention.
本发明的一些方案中，上述R 1选自H、F、Cl、Br、I、OH、CN，或选自任选被1、2或3个R取代的：C 1-3烷基、C 1-3烷氧基、C 1-3炔基、环丙烷基、环丙烷基-O-、氧杂环丁烷基-O-，其他变量如本发明所定义。 In some embodiments of the invention, the above R 1 is selected from the group consisting of H, F, Cl, Br, I, OH, CN, or selected from the group consisting of 1, 2 or 3 R: C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkynyl, cyclopropane, cyclopropyl-O-, oxetanyl-O-, other variables are as defined in the present invention.
本发明的一些方案中，上述R 1选自H、F、Cl、Br、I、OH、CN，或选自任选被1、2或3个R取代的：-CH 3、-CH 2CH 3、-CH 2CH 3CH 3、
Figure PCTCN2019070227-appb-000005
其他变量如本发明所定义。 In some embodiments of the invention, said R 1 is selected from the group consisting of H, F, Cl, Br, I, OH, CN, or selected from the group consisting of: 1, 2 or 3 R: -CH 3 , -CH 2 CH 3 , -CH 2 CH 3 CH 3 ,
Figure PCTCN2019070227-appb-000005
Other variables are as defined by the present invention.
本发明的一些方案中，上述R 1选自H、F、Cl、Br、I、OH、CN、-CH 3、-CH 2CH 3、-CH 2CH 3CH 3、
Figure PCTCN2019070227-appb-000006
Figure PCTCN2019070227-appb-000007
Figure PCTCN2019070227-appb-000008
其他变量如本发明所定义。 In some embodiments of the invention, the above R 1 is selected from the group consisting of H, F, Cl, Br, I, OH, CN, -CH 3 , -CH 2 CH 3 , -CH 2 CH 3 CH 3 ,
Figure PCTCN2019070227-appb-000006
Figure PCTCN2019070227-appb-000007
Figure PCTCN2019070227-appb-000008
Other variables are as defined by the present invention.
本发明的一些方案中，上述R 2分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN，或分别独立地选自任选被1、2或3个R取代的：-CH 3或-CH 2CH 3，其他变量如本发明所定义。 In some embodiments of the invention, the above R 2 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, or independently selected from, optionally substituted by 1, 2 or 3 R. :-CH 3 or -CH 2 CH 3 , other variables are as defined in the present invention.
本发明的一些方案中，上述R 2选自：分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN、-CH 3，其他变量如本发明所定义。 In some aspects of the invention, the above R 2 is selected from the group consisting of H, F, Cl, Br, I, OH, NH 2 , CN, -CH 3 , respectively, and other variables are as defined herein.
本发明的一些方案中，上述R 3分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN，或分别独立地选自任选被1、2或3个R取代的：C 1-4烷基、C 1-4烷氧基、C 1-4烷氨基、环丙烷基、环丁环基、环戊烷基、噁丁环基、四氢呋喃基、四氢吡喃基、哌嗪基、哌啶基、吗啉基、-CH 2-哌嗪基、-CH 2-哌啶基、-O-环丙烷基、-O-环丁烷基、-O-四氢呋喃基、-O-四氢吡喃基、咪唑烷-2-酮基、恶唑烷-2-酮或吡咯烷-2-酮基，其他变量如本发明所定义。 In some embodiments of the invention, said R 3 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, or independently selected from, optionally substituted by 1, 2 or 3 R :C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, cyclopropyl, cyclobutane, cyclopentyl, acetonyl, tetrahydrofuranyl, tetrahydropyranyl , piperazinyl, piperidinyl, morpholinyl, -CH 2 -piperazinyl, -CH 2 -piperidinyl, -O-cyclopropane, -O-cyclobutane, -O-tetrahydrofuranyl, -O-tetrahydropyranyl, imidazol-2-one, oxazolidin-2-one or pyrrolidin-2-one, other variables are as defined herein.
本发明的一些方案中，上述R 3分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN，或分别独立地选自任选被1、2或3个R取代的：-CH 3、-CH 2CH 3、-CH 2CH 2CH 3、-CH(CH 3) 2、-C(CH 3) 3、-OCH 3、-OCH 2CH 3、 -NH(CH 3)、-N(CH 3) 2、
Figure PCTCN2019070227-appb-000009
Figure PCTCN2019070227-appb-000010
其他变量如本发明所定义。 In some embodiments of the invention, said R 3 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, or independently selected from, optionally substituted by 1, 2 or 3 R :-CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -C(CH 3 ) 3 , -OCH 3 , -OCH 2 CH 3 , -NH(CH 3 ), -N(CH 3 ) 2 ,
Figure PCTCN2019070227-appb-000009
Figure PCTCN2019070227-appb-000010
Other variables are as defined by the present invention.
本发明的一些方案中，上述R 3分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN、CH 3、-CH 2CH 3、-CH 2CH 2CH 3、-CH(CH 3) 2、-C(CH 3) 3、-OCH 3、-OCH 2CH 3、-NH(CH 3)、-N(CH 3) 2、
Figure PCTCN2019070227-appb-000011
Figure PCTCN2019070227-appb-000012
Figure PCTCN2019070227-appb-000013
其他变量如本发明所定义。 In some embodiments of the invention, the above R 3 are independently selected from the group consisting of H, F, Cl, Br, I, OH, NH 2 , CN, CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , -C(CH 3 ) 3 , -OCH 3 , -OCH 2 CH 3 , -NH(CH 3 ), -N(CH 3 ) 2 ,
Figure PCTCN2019070227-appb-000011
Figure PCTCN2019070227-appb-000012
Figure PCTCN2019070227-appb-000013
Other variables are as defined by the present invention.
本发明的一些方案中，上述L选自-NH-、-NHCH 2-、-NHCH(CH 3)-、、-O-、-O-CH 2-、-NHC(＝O)-，其他变量如本发明所定义。 In some embodiments of the invention, the above L is selected from the group consisting of -NH-, -NHCH 2 -, -NHCH(CH 3 )-, -O-, -O-CH 2 -, -NHC(=O)-, other variables As defined by the present invention.
本发明的一些方案中，上述环A选自苯基、吡啶基、嘧啶基、吡嗪基、哒嗪基、噻唑基、恶唑基、吡唑基、苯并[b]噻吩、2,3-二氢-[1,4]二氧杂环己二烯并[2,3-b]吡啶、苯并[d]噻唑基、环丁基、环戊基、环己基、环辛基，其他变量如本发明所定义。In some embodiments of the invention, the above ring A is selected from the group consisting of phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiazolyl, oxazolyl, pyrazolyl, benzo[b]thiophene, 2,3 -dihydro-[1,4]dioxan[2,3-b]pyridine, benzo[d]thiazolyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, others Variables are as defined by the present invention.
本发明的一些方案中，上述结构单元
Figure PCTCN2019070227-appb-000014
选自
Figure PCTCN2019070227-appb-000015
Figure PCTCN2019070227-appb-000016
其他变量如本发明所定义。 In some aspects of the invention, the structural unit
Figure PCTCN2019070227-appb-000014
Selected from
Figure PCTCN2019070227-appb-000015
Figure PCTCN2019070227-appb-000016
Other variables are as defined by the present invention.
本发明的一些方案中，上述结构单元
Figure PCTCN2019070227-appb-000017
选自
Figure PCTCN2019070227-appb-000018
Figure PCTCN2019070227-appb-000019
其他变量如本发明所定义。 In some aspects of the invention, the structural unit
Figure PCTCN2019070227-appb-000017
Selected from
Figure PCTCN2019070227-appb-000018
Figure PCTCN2019070227-appb-000019
Other variables are as defined by the present invention.
本发明的一些方案中，上述结构单元
Figure PCTCN2019070227-appb-000020
选自 In some aspects of the invention, the structural unit
Figure PCTCN2019070227-appb-000020
Selected from
Figure PCTCN2019070227-appb-000021
Figure PCTCN2019070227-appb-000021
Figure PCTCN2019070227-appb-000022
Figure PCTCN2019070227-appb-000022
，其他变量如本发明所定义。Other variables are as defined by the present invention.
本发明的一些方案中，上述结构单元
Figure PCTCN2019070227-appb-000023
选自
Figure PCTCN2019070227-appb-000024
Figure PCTCN2019070227-appb-000025
其他变量如本发明所定义。 In some aspects of the invention, the structural unit
Figure PCTCN2019070227-appb-000023
Selected from
Figure PCTCN2019070227-appb-000024
Figure PCTCN2019070227-appb-000025
Other variables are as defined by the present invention.
本发明的一些方案中，上述结构单元
Figure PCTCN2019070227-appb-000026
选自
Figure PCTCN2019070227-appb-000027
Figure PCTCN2019070227-appb-000028
Figure PCTCN2019070227-appb-000029
其他变量如本发明所定义。 In some aspects of the invention, the structural unit
Figure PCTCN2019070227-appb-000026
Selected from
Figure PCTCN2019070227-appb-000027
Figure PCTCN2019070227-appb-000028
Figure PCTCN2019070227-appb-000029
Other variables are as defined by the present invention.
本发明的一些方案中，上述结构单元
Figure PCTCN2019070227-appb-000030
选自
Figure PCTCN2019070227-appb-000031
Figure PCTCN2019070227-appb-000032
其他变量如本发明所定义。 In some aspects of the invention, the structural unit
Figure PCTCN2019070227-appb-000030
Selected from
Figure PCTCN2019070227-appb-000031
Figure PCTCN2019070227-appb-000032
Other variables are as defined by the present invention.
本发明提供了式(I)所示的化合物及其药学上可接受的盐或其立体异构体The present invention provides a compound represented by the formula (I), and a pharmaceutically acceptable salt thereof or a stereoisomer thereof
Figure PCTCN2019070227-appb-000033
Figure PCTCN2019070227-appb-000033
其中，among them,
T选自N或CH；T is selected from N or CH;
R 1选自H、F、Cl、Br、I、OH、NH 2、CN，或选自任选被1、2或3个R取代的：C 1-6烷基、C 1-6烷氧基、C 1-6烯基、C 1-6炔基、C 3-7环烷基、C 3-7环烷基-O-、3～7元杂环烷基-O-； R 1 is selected from H, F, Cl, Br, I, OH, NH 2 , CN, or selected from C 1 1-6 alkyl, C 1-6 alkoxy optionally substituted by 1, 2 or 3 R a group, a C 1-6 alkenyl group, a C 1-6 alkynyl group, a C 3-7 cycloalkyl group, a C 3-7 cycloalkyl-O-, a 3 to 7 membered heterocycloalkyl-O-;
R 2分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN，或分别独立地选自任选被1、2或3个R取代的：C 1-3烷基； R 2 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, or independently selected from: C 1-3 alkyl optionally substituted by 1, 2 or 3 R;
R 3分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN，或分别独立地选自任选被1、2或3个R取代的：C 1-6烷基、C 1-6杂烷基、C 3-7环烷基、3～7元杂环烷基-C 1-3烷基-； R 3 is each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, or independently selected from C 1 1-6 alkyl optionally substituted by 1, 2 or 3 R, C 1-6 heteroalkyl, C 3-7 cycloalkyl, 3-7 -membered heterocycloalkyl-C 1-3 alkyl-;
L选自：-NH-、-NHCHR-、-NHC(＝O)-；L is selected from the group consisting of: -NH-, -NHCHR-, -NHC(=O)-;
环A选自：C 5-8环烷基、苯基或5～6元杂芳基； Ring A is selected from: C 5-8 cycloalkyl, phenyl or 5- to 6-membered heteroaryl;
n选自：0、1或2；n is selected from: 0, 1 or 2;
m选自：1，2或3；m is selected from: 1, 2 or 3;
R选自：H、F、Cl、Br、I、OH、NH 2、CN，或选自任选被1、2或3个R’取代的：C 1-6烷基、C 1-6杂烷基； R is selected from the group consisting of: H, F, Cl, Br, I, OH, NH 2 , CN, or selected from the group consisting of 1, 2 or 3 R's substituted: C 1-6 alkyl, C 1-6 hetero alkyl;
R’选自：F、Cl、Br、I、OH、NH 2、CN、Me； R' is selected from the group consisting of: F, Cl, Br, I, OH, NH 2 , CN, Me;
所述C 1-6杂烷基、5-6元杂芳基、3～7元杂环烷基之“杂”选自N、-O-、-S-、-NH-； The "hetero" of the C 1-6 heteroalkyl, 5-6 membered heteroaryl, 3 to 7 membered heterocycloalkyl is selected from the group consisting of N, -O-, -S-, -NH-;
上述杂原子或杂原子团的数目分别独立地选自1、2、3或4。The number of the above heteroatoms or heteroatoms is independently selected from 1, 2, 3 or 4.
本发明的一些方案中，上述R选自H、F、Cl、Br、I、OH、NH 2、CN，或选自任选被1、2或3个R’取代的：C 1-3烷基、C 1-3烷氧基和C 1-3烷氨基，其他变量如本发明所定义。 In some embodiments of the invention, the above R is selected from the group consisting of H, F, Cl, Br, I, OH, NH 2 , CN, or selected from: C 1-3 alkane optionally substituted by 1, 2 or 3 R' The group, C 1-3 alkoxy group and C 1-3 alkylamino group, other variables are as defined in the present invention.
本发明的一些方案中，上述R选自H、F、Cl、Br、I、OH、NH 2、CN，或选自任选被1、2或3个R’取代的：Me、Et、
Figure PCTCN2019070227-appb-000034
其他变量如本发明所定义。 In some embodiments of the invention, the above R is selected from the group consisting of H, F, Cl, Br, I, OH, NH 2 , CN, or selected from the group consisting of 1, 2 or 3 R' substitutions: Me, Et,
Figure PCTCN2019070227-appb-000034
Other variables are as defined by the present invention.
本发明的一些方案中，上述R选自：H、F、Cl、Br、I、OH、NH 2、CN、Me、CH 2F、CHF 2、CF 3、Et、
Figure PCTCN2019070227-appb-000035
其他变量如本发明所定义。 In some aspects of the invention, the above R is selected from the group consisting of: H, F, Cl, Br, I, OH, NH 2 , CN, Me, CH 2 F, CHF 2 , CF 3 , Et,
Figure PCTCN2019070227-appb-000035
Other variables are as defined by the present invention.
本发明的一些方案中，上述R 1选自H、F、Cl、Br、I、OH、CN，或选自任选被1、2或3个R’取代的：C 1-3烷基、C 1-3烷氧基、C 1-3炔基、环丙烷基、环丙烷基-O-、氧杂环丁烷基-O-，其他变量如本发明所定义。 In some embodiments of the invention, the above R 1 is selected from the group consisting of H, F, Cl, Br, I, OH, CN, or selected from: C 1-3 alkyl optionally substituted by 1, 2 or 3 R', C 1-3 alkoxy, C 1-3 alkynyl, cyclopropane, cyclopropyl-O-, oxetanyl-O-, other variables are as defined in the present invention.
本发明的一些方案中，上述R 1选自H、F、Cl、Br、I、OH、CN，或选自任选被1、2或3个R’取代的：Me、Et、Pr、
Figure PCTCN2019070227-appb-000036
其他变量如本发明所定义。 In some embodiments of the invention, the above R 1 is selected from the group consisting of H, F, Cl, Br, I, OH, CN, or selected from the group consisting of 1, 2 or 3 R' substitutions: Me, Et, Pr,
Figure PCTCN2019070227-appb-000036
Other variables are as defined by the present invention.
本发明的一些方案中，上述R 1选自H、F、Cl、Br、I、OH、CN、Me、Et、Pr、
Figure PCTCN2019070227-appb-000038
其他变量如本发明所定义。 In some aspects of the invention, the above R 1 is selected from the group consisting of H, F, Cl, Br, I, OH, CN, Me, Et, Pr,
Figure PCTCN2019070227-appb-000038
Other variables are as defined by the present invention.
本发明的一些方案中，上述R 2分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN，或分别独立地选自任选被1、2或3个R取代的：Me、Et，其他变量如本发明所定义。 In some embodiments of the invention, the above R 2 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, or independently selected from, optionally substituted by 1, 2 or 3 R. : Me, Et, other variables as defined by the present invention.
本发明的一些方案中，上述R 2选自：分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN、Me，其他变量如本发明所定义。 In some aspects of the invention, R 2 is selected from the group consisting of H, F, Cl, Br, I, OH, NH 2 , CN, Me, respectively, and other variables are as defined herein.
本发明的一些方案中，上述R 3分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN，或分别独立地选自任选被1、2或3个R取代的：C 1-3烷基、C 1-3杂烷基、环戊烷基、哌嗪基-CH 2-、哌啶基-CH 2-，其他变量如本发明所定义。 In some embodiments of the invention, said R 3 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, or independently selected from, optionally substituted by 1, 2 or 3 R : C 1-3 alkyl, C 1-3 heteroalkyl, cyclopentyl, piperazinyl-CH 2 -, piperidinyl-CH 2 -, other variables are as defined in the invention.
本发明的一些方案中，上述R 3分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN，或分别独立地选自任选被1、2或3个R取代的：Me、
Figure PCTCN2019070227-appb-000039
其他变量如本发明所定义。 In some embodiments of the invention, said R 3 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, or independently selected from, optionally substituted by 1, 2 or 3 R :Me,
Figure PCTCN2019070227-appb-000039
Other variables are as defined by the present invention.
本发明的一些方案中，上述R 3分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN、Me、
Figure PCTCN2019070227-appb-000040
Figure PCTCN2019070227-appb-000041
其他变量如本发明所定义。 In some aspects of the invention, the above R 3 are independently selected from the group consisting of H, F, Cl, Br, I, OH, NH 2 , CN, Me,
Figure PCTCN2019070227-appb-000040
Figure PCTCN2019070227-appb-000041
Other variables are as defined by the present invention.
本发明的一些方案中，上述L选自-NH-、-NHCH 2-、-NHCH(CH 3)-、-NHC(＝O)-，其他变量如本发明所定义。 Some aspects of the present invention, the above-mentioned L is selected from -NH -, - NHCH 2 -, - NHCH (CH 3) -, - NHC (= O) -, the other variables are as defined in the present invention.
本发明的一些方案中，上述环A选自苯基、吡啶基、嘧啶基、吡嗪基、哒嗪基、噻唑基、恶唑基、环戊基、环己基、环辛基，其他变量如本发明所定义。In some embodiments of the invention, the above ring A is selected from the group consisting of phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiazolyl, oxazolyl, cyclopentyl, cyclohexyl, cyclooctyl, and other variables such as The invention is defined.
本发明的一些方案中，上述结构单元
Figure PCTCN2019070227-appb-000042
选自
Figure PCTCN2019070227-appb-000043
Figure PCTCN2019070227-appb-000044
其他变量如本发明所定义。 In some aspects of the invention, the structural unit
Figure PCTCN2019070227-appb-000042
Selected from
Figure PCTCN2019070227-appb-000043
Figure PCTCN2019070227-appb-000044
Other variables are as defined by the present invention.
本发明的一些方案中，上述结构单元
Figure PCTCN2019070227-appb-000045
选自
Figure PCTCN2019070227-appb-000046
Figure PCTCN2019070227-appb-000047
其他变量如本发明所定义。 In some aspects of the invention, the structural unit
Figure PCTCN2019070227-appb-000045
Selected from
Figure PCTCN2019070227-appb-000046
Figure PCTCN2019070227-appb-000047
Other variables are as defined by the present invention.
本发明的一些方案中，上述结构单元
Figure PCTCN2019070227-appb-000048
选自
Figure PCTCN2019070227-appb-000049
Figure PCTCN2019070227-appb-000050
Figure PCTCN2019070227-appb-000051
Figure PCTCN2019070227-appb-000052
其他变量如本发明所定义。 In some aspects of the invention, the structural unit
Figure PCTCN2019070227-appb-000048
Selected from
Figure PCTCN2019070227-appb-000049
Figure PCTCN2019070227-appb-000050
Figure PCTCN2019070227-appb-000051
Figure PCTCN2019070227-appb-000052
Other variables are as defined by the present invention.
本发明的一些方案中，上述结构单元
Figure PCTCN2019070227-appb-000053
选自
Figure PCTCN2019070227-appb-000054
其他变量如本发明所定义。 In some aspects of the invention, the structural unit
Figure PCTCN2019070227-appb-000053
Selected from
Figure PCTCN2019070227-appb-000054
Other variables are as defined by the present invention.
本发明的一些方案中，上述结构单元
Figure PCTCN2019070227-appb-000055
选自
Figure PCTCN2019070227-appb-000056
Figure PCTCN2019070227-appb-000057
Figure PCTCN2019070227-appb-000058
其他变量如本发明所定义。 In some aspects of the invention, the structural unit
Figure PCTCN2019070227-appb-000055
Selected from
Figure PCTCN2019070227-appb-000056
Figure PCTCN2019070227-appb-000057
Figure PCTCN2019070227-appb-000058
Other variables are as defined by the present invention.
本发明的一些方案中，上述结构单元
Figure PCTCN2019070227-appb-000059
选自
Figure PCTCN2019070227-appb-000060
Figure PCTCN2019070227-appb-000061
其他变量如本发明所定义。 In some aspects of the invention, the structural unit
Figure PCTCN2019070227-appb-000059
Selected from
Figure PCTCN2019070227-appb-000060
Figure PCTCN2019070227-appb-000061
Other variables are as defined by the present invention.
本发明还有一些方案由上述变量任意组合而来。Still other aspects of the invention are arbitrarily combined by the above variables.
本发明的一些方案中，上述化合物、其异构体或其药学上可接受的盐，其选自In some embodiments of the invention, the above compound, an isomer thereof, or a pharmaceutically acceptable salt thereof, selected from the group consisting of
Figure PCTCN2019070227-appb-000062
Figure PCTCN2019070227-appb-000062
Figure PCTCN2019070227-appb-000063
Figure PCTCN2019070227-appb-000063
其中，among them,
f选自：1、2、3或4；f is selected from: 1, 2, 3 or 4;
l选自：0或1；l selected from: 0 or 1;
n、m、T、R 1～R 3如本发明所定义。 n, m, T, R 1 to R 3 are as defined in the present invention.
本发明的一些方案中，上述化合物、其异构体或其药学上可接受的盐是In some embodiments of the invention, the above compound, an isomer thereof or a pharmaceutically acceptable salt thereof is
Figure PCTCN2019070227-appb-000064
Figure PCTCN2019070227-appb-000064
Figure PCTCN2019070227-appb-000065
Figure PCTCN2019070227-appb-000065
其中，among them,
f选自：1、2、3或4；f is selected from: 1, 2, 3 or 4;
l选自：0或1；l selected from: 0 or 1;
T、R 1～R 3如本发明所定义。 T, R 1 to R 3 are as defined in the present invention.
本发明还提供了下列化合物、其异构体或其药学上可接受的盐，其选自The present invention also provides the following compound, an isomer thereof or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of
Figure PCTCN2019070227-appb-000066
Figure PCTCN2019070227-appb-000066
Figure PCTCN2019070227-appb-000067
Figure PCTCN2019070227-appb-000067
Figure PCTCN2019070227-appb-000068
Figure PCTCN2019070227-appb-000068
Figure PCTCN2019070227-appb-000069
Figure PCTCN2019070227-appb-000069
Figure PCTCN2019070227-appb-000070
Figure PCTCN2019070227-appb-000070
Figure PCTCN2019070227-appb-000071
Figure PCTCN2019070227-appb-000071
本发明的一些方案中，上述化合物、其异构体或其药学上可接受的盐，其选自In some embodiments of the invention, the above compound, an isomer thereof, or a pharmaceutically acceptable salt thereof, selected from the group consisting of
Figure PCTCN2019070227-appb-000072
Figure PCTCN2019070227-appb-000072
本发明还提供了一种药物组合物，包括治疗有效量的上述的化合物或其药学上可接受的盐作为活性成分以及药学上可接受的载体。The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of the above compound or a pharmaceutically acceptable salt thereof as an active ingredient together with a pharmaceutically acceptable carrier.
本发明还提供了上述的化合物、其异构体或其药学上可接受的盐或者上述组合物在制备治疗与新型集落刺激因子-1受体抑制剂相关药物上的应用。The present invention also provides the use of the above compound, an isomer thereof or a pharmaceutically acceptable salt thereof or the above composition for the preparation of a medicament for treating a novel colony stimulating factor-1 receptor inhibitor.
本发明的一些方案中，上述与新型集落刺激因子-1受体抑制剂相关药物是用于***和自身免疫类疾病的药物。In some aspects of the invention, the above-described drug associated with the novel colony stimulating factor-1 receptor inhibitor is a drug for treating tumor and autoimmune diseases.
定义和说明Definition and description
除非另有说明，本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。这里所采用的术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。Unless otherwise stated, the following terms and phrases as used herein are intended to have the following meanings. A particular term or phrase should not be considered undefined or unclear without a particular definition, but should be understood in the ordinary sense. When a trade name appears in this document, it is intended to refer to its corresponding commodity or its active ingredient. The term "pharmaceutically acceptable" as used herein is intended to mean that those compounds, materials, compositions and/or dosage forms are within the scope of sound medical judgment and are suitable for use in contact with human and animal tissues. Without excessive toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.
术语“药学上可接受的盐”是指本发明化合物的盐，由本发明发现的具有特定取代基的化合物与相对无 毒的酸或碱制备。当本发明的化合物中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物的中性形式接触的方式获得碱加成盐。药学上可接受的碱加成盐包括钠、钾、钙、铵、有机胺或镁盐或类似的盐。当本发明的化合物中含有相对碱性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与这类化合物的中性形式接触的方式获得酸加成盐。药学上可接受的酸加成盐的实例包括无机酸盐，所述无机酸包括例如盐酸、氢溴酸、硝酸、碳酸，碳酸氢根，磷酸、磷酸一氢根、磷酸二氢根、硫酸、硫酸氢根、氢碘酸、亚磷酸等；以及有机酸盐，所述有机酸包括如乙酸、丙酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸和甲磺酸等类似的酸；还包括氨基酸(如精氨酸等)的盐，以及如葡糖醛酸等有机酸的盐。本发明的某些特定的化合物含有碱性和酸性的官能团，从而可以被转换成任一碱或酸加成盐。The term "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. When a relatively acidic functional group is contained in the compound of the present invention, 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 amine or magnesium salts or similar salts. When a relatively basic functional group is contained in the compound of the present invention, 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. Examples of 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 methanesulfonic acid; and salts of amino acids (such as arginine, etc.) And salts of organic acids such as glucuronic acid. Certain specific compounds of the invention contain both basic and acidic functional groups which can be converted to any base or acid addition salt.
本发明的药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下，这样的盐的制备方法是：在水或有机溶剂或两者的混合物中，经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。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. In general, 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.
本发明的化合物可以存在特定的几何或立体异构体形式。本发明设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本发明的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本发明的范围之内。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.
除非另有说明，术语“对映异构体”或者“旋光异构体”是指互为镜像关系的立体异构体。Unless otherwise indicated, the terms "enantiomer" or "optical isomer" refer to stereoisomers that are mirror images of one another.
除非另有说明，术语“顺反异构体”或者“几何异构体”系由因双键或者成环碳原子单键不能自由旋转而引起。Unless otherwise indicated, the term "cis-trans isomer" or "geometric isomer" is caused by the inability to freely rotate a single bond due to a double bond or a ring-forming carbon atom.
除非另有说明，术语“非对映异构体”是指分子具有两个或多个手性中心，并且分子间为非镜像的关系的立体异构体。Unless otherwise indicated, the term "diastereomer" refers to a stereoisomer in which the molecule has two or more chiral centers and the molecules are in a non-mirrored relationship.
除非另有说明，“(D)”或者“(+)”表示右旋，“(L)”或者“(-)”表示左旋，“(DL)”或者“(±)”表示外消旋。Unless otherwise indicated, "(D)" or "(+)" means dextrorotatory, "(L)" or "(-)" means left-handed, "(DL)" or "(±)" means racemic.
除非另有说明，用楔形实线键
Figure PCTCN2019070227-appb-000073
和楔形虚线键
Figure PCTCN2019070227-appb-000074
表示一个立体中心的绝对构型，用直形实线键
Figure PCTCN2019070227-appb-000075
和直形虚线键
Figure PCTCN2019070227-appb-000076
表示立体中心的相对构型，用波浪线
Figure PCTCN2019070227-appb-000077
表示楔形实线键
Figure PCTCN2019070227-appb-000078
或楔形虚线键
Figure PCTCN2019070227-appb-000079
或用波浪线
Figure PCTCN2019070227-appb-000080
表示直形实线键
Figure PCTCN2019070227-appb-000081
和直形虚线键
Figure PCTCN2019070227-appb-000082
Wedge solid key unless otherwise stated
Figure PCTCN2019070227-appb-000073
And wedge-shaped dashed keys
Figure PCTCN2019070227-appb-000074
Represents the absolute configuration of a solid center with straight solid keys
Figure PCTCN2019070227-appb-000075
And straight dashed keys
Figure PCTCN2019070227-appb-000076
Indicates the relative configuration of the stereocenter, using wavy lines
Figure PCTCN2019070227-appb-000077
Indicates a wedge solid key
Figure PCTCN2019070227-appb-000078
Or wedge-shaped dotted key
Figure PCTCN2019070227-appb-000079
Or with wavy lines
Figure PCTCN2019070227-appb-000080
Represents a straight solid key
Figure PCTCN2019070227-appb-000081
And straight dashed keys
Figure PCTCN2019070227-appb-000082
本发明的化合物可以存在特定的。除非另有说明，术语“互变异构体”或“互变异构体形式”是指在室温下，不同官能团异构体处于动态平衡，并能很快的相互转化。若互变异构体是可能的(如在溶液中)，则可以达到互变异构体的化学平衡。例如，质子互变异构体(proton tautomer)(也称质子转移互变异构体 (prototropic tautomer))包括通过质子迁移来进行的互相转化，如酮-烯醇异构化和亚胺-烯胺异构化。价键异构体(valence tautomer)包括一些成键电子的重组来进行的相互转化。其中酮-烯醇互变异构化的具体实例是戊烷-2,4-二酮与4-羟基戊-3-烯-2-酮两个互变异构体之间的互变。The compounds of the invention may be present in particular. Unless otherwise indicated, the terms "tautomer" or "tautomeric form" mean that the different functional isomers are in dynamic equilibrium at room temperature and can be rapidly converted into each other. If tautomers are possible (as in solution), the chemical equilibrium of the tautomers can be achieved. For example, proton tautomers (also known as prototropic tautomers) include interconversions by proton transfer, such as keto-enol isomerization and imine-enes. Amine isomerization. The valence tautomer includes the mutual transformation of some of the bonding electrons. A specific example of keto-enol tautomerization is the interconversion between two tautomers of pentane-2,4-dione and 4-hydroxypent-3-en-2-one.
除非另有说明，术语“富含一种异构体”、“异构体富集”、“富含一种对映体”或者“对映体富集”指其中一种异构体或对映体的含量小于100％，并且，该异构体或对映体的含量大于等于60％，或者大于等于70％，或者大于等于80％，或者大于等于90％，或者大于等于95％，或者大于等于96％，或者大于等于97％，或者大于等于98％，或者大于等于99％，或者大于等于99.5％，或者大于等于99.6％，或者大于等于99.7％，或者大于等于99.8％，或者大于等于99.9％。Unless otherwise indicated, the terms "enriched in one isomer", "isomer enriched", "enriched in one enantiomer" or "enantiomeric enriched" refer to one of the isomers or pairs The content of the oligo is less than 100%, and the content of the isomer or enantiomer is 60% or more, or 70% or more, or 80% or more, or 90% or more, or 95% or more, or 96% or more, or 97% or more, 98% or more, 99% or more, 99.5% or more, 99.6% or more, 99.7% or more, 99.8% or more, or greater than or equal to 99.9%.
除非另有说明，术语“异构体过量”或“对映体过量”指两种异构体或两种对映体相对百分数之间的差值。例如，其中一种异构体或对映体的含量为90％，另一种异构体或对映体的含量为10％，则异构体或对映体过量(ee值)为80％。Unless otherwise indicated, the term "isomer excess" or "enantiomeric excess" refers to the difference between the two isomers or the relative percentages of the two enantiomers. For example, if one of the isomers or enantiomers is present in an amount of 90% and the other isomer or enantiomer is present in an amount of 10%, the isomer or enantiomeric excess (ee value) is 80%. .
可以通过的手性合成或手性试剂或者其他常规技术制备光学活性的(R)-和(S)-异构体以及D和L异构体。如果想得到本发明某化合物的一种对映体，可以通过不对称合成或者具有手性助剂的衍生作用来制备，其中将所得非对映体混合物分离，并且辅助基团裂开以提供纯的所需对映异构体。或者，当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时，与适当的光学活性的酸或碱形成非对映异构体的盐，然后通过本领域所公知的常规方法进行非对映异构体拆分，然后回收得到纯的对映体。此外，对映异构体和非对映异构体的分离通常是通过使用色谱法完成的，所述色谱法采用手性固定相，并任选地与化学衍生法相结合(例如由胺生成氨基甲酸盐)。本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氚( 3H)，碘-125( 125I)或C-14( 14C)。又例如，可用重氢取代氢形成氘代药物，氘与碳构成的键比普通氢与碳构成的键更坚固，相比于未氘化药物，氘代药物有降低毒副作用、增加药物稳定性、增强疗效、延长药物生物半衰期等优势。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包括在本发明的范围之内。 The 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. Alternatively, when a molecule contains a basic functional group (e.g., an amino group) or an acidic functional group (e.g., a carboxyl group), 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. Furthermore, 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. For example, radiolabeled compounds can be used, such as tritium (3 H), iodine -125 (125 I) or C-14 (14 C). For another example, hydrogen can be replaced by heavy hydrogen to form a deuterated drug. The bond composed of barium and carbon is stronger than the bond composed of common hydrogen and carbon. Compared with undeuterated drugs, deuterated drugs have reduced side effects and increased drug stability. Enhance the efficacy and prolong the biological half-life of the drug. Alterations of all isotopic compositions of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.
“任选”或“任选地”指的是随后描述的事件或状况可能但不是必需出现的，并且该描述包括其中所述事件或状况发生的情况以及所述事件或状况不发生的情况。"Optional" or "optionally" means that the subsequently described event or condition may, but is not necessarily, to occur, and that the description includes instances in which the event or condition occurs and instances in which the event or condition does not occur.
术语“被取代的”是指特定原子上的任意一个或多个氢原子被取代基取代，可以包括重氢和氢的变体，只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为氧(即＝O)时，意味着两个氢原子被取代。氧取代不会发生在芳香基上。术语“任选被取代的”是指可以被取代，也可以不被取代，除非另有规定，取代基的种类和数目在化学上可以实现的基础上可以是任意的。The term "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. When the substituent is oxygen (ie, =0), it means that two hydrogen atoms are substituted. Oxygen substitution does not occur on the aromatic group. The term "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.
当任何变量(例如R)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。因此，例如，如果一个基团被0-2个R所取代，则所述基团可以任选地至多被两个R所取代，并且每种情况下的R都有独立的选项。此外，取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物 的情况下才是被允许的。When any variable (eg, R) occurs more than once in the composition or structure of a compound, its definition in each case is independent. Thus, for example, if a group is substituted with 0-2 R, the group may optionally be substituted with at most two R, and each case has an independent option. Furthermore, combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
当一个连接基团的数量为0时，比如-(CRR) 0-，表示该连接基团为单键。 When the number of one linking group is 0, such as -(CRR) 0 -, it indicates that the linking group is a single bond.
当其中一个变量选自单键时，表示其连接的两个基团直接相连，比如A-L-Z中L代表单键时表示该结构实际上是A-Z。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.
当一个取代基为空缺时，表示该取代基是不存在的，比如A-X中X为空缺时表示该结构实际上是A。当一个取代基可以连接到一个环上的一个以上原子时，这种取代基可以与这个环上的任意原子相键合，例如，结构单元
Figure PCTCN2019070227-appb-000083
表示取代基R可在环己基或者环己二烯上的任意一个位置发生取代。当所列举的取代基中没有指明其通过哪一个原子连接到被取代的基团上时，这种取代基可以通过其任何原子相键合，例如，吡啶基作为取代基可以通过吡啶环上任意一个碳原子连接到被取代的基团上。当所列举的连接基团没有指明其连接方向，其连接方向是任意的，例如，
Figure PCTCN2019070227-appb-000084
中连接基团L为-M-W-，此时-M-W-既可以按与从左往右的读取顺序相同的方向连接环A和环B构成
Figure PCTCN2019070227-appb-000085
也可以按照与从左往右的读取顺序相反的方向连接环A和环B构成
Figure PCTCN2019070227-appb-000086
所述连接基团、取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。 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. When a 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.
Figure PCTCN2019070227-appb-000083
It is indicated that the substituent R can be substituted at any position on the cyclohexyl group or cyclohexadiene. 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. When the listed linking group does not indicate its direction of attachment, its connection direction is arbitrary, for example,
Figure PCTCN2019070227-appb-000084
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.
Figure PCTCN2019070227-appb-000085
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.
Figure PCTCN2019070227-appb-000086
Combinations of the linking groups, substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
除非另有规定，术语“杂”表示杂原子或杂原子团(即含有杂原子的原子团)，包括碳(C)和氢(H)以外的原子以及含有这些杂原子的原子团，例如包括氧(O)、氮(N)、硫(S)、硅(Si)、锗(Ge)、铝(Al)、硼(B)、-O-、-S-、＝O、＝S、-C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)、-S(＝O) 2-，以及任选被取代的-C(＝O)N(H)-、-N(H)-、-C(＝NH)-、-S(＝O) 2N(H)-或-S(＝O)N(H)-。 Unless otherwise specified, the term "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). ), nitrogen (N), sulfur (S), silicon (Si), germanium (Ge), aluminum (Al), boron (B), -O-, -S-, =O, =S, -C (= O) O-, -C(=O)-, -C(=S)-, -S(=O), -S(=O) 2 -, and optionally substituted -C(=O)N (H)-, -N(H)-, -C(=NH)-, -S(=O) 2 N(H)- or -S(=O)N(H)-.
除非另有规定，“环”表示被取代或未被取代的环烷基、杂环烷基、环烯基、杂环烯基、环炔基、杂环炔基、芳基或杂芳基。所谓的环包括单环、联环、螺环、并环或桥环。环上原子的数目通常被定义为环的元数，例如，“5～7元环”是指环绕排列5～7个原子。除非另有规定，该环任选地包含1～3个杂原子。因此，“5～7元环”包括例如苯基、吡啶和哌啶基；另一方面，术语“5～7元杂环烷基环”包括吡啶基和哌啶基，但不包括苯基。术语“环”还包括含有至少一个环的环系，其中的每一个“环”均独立地符合上述定义。Unless otherwise specified, "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. Thus, "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. The term "ring" also includes ring systems containing at least one ring, each of which "ring" independently conforms to the above definition.
除非另有规定，术语“杂环”或“杂环基”意指稳定的含杂原子或杂原子团的单环、双环或三环，它们可以是饱和的、部分不饱和的或不饱和的(芳族的)，它们包含碳原子和1、2、3或4个独立地选自N、O和S的环杂原子，其中上述任意杂环可以稠合到一个苯环上形成双环。氮和硫杂原子可任选被氧化(即NO和S(O)p，p是1或2)。氮原子可以是被取代的或未取代的(即N或NR，其中R是H或本文已经定义 过的其他取代基)。该杂环可以附着到任何杂原子或碳原子的侧基上从而形成稳定的结构。如果产生的化合物是稳定的，本文所述的杂环可以发生碳位或氮位上的取代。杂环中的氮原子任选地被季铵化。一个优选方案是，当杂环中S及O原子的总数超过1时，这些杂原子彼此不相邻。另一个优选方案是，杂环中S及O原子的总数不超过1。如本文所用，术语“芳族杂环基团”或“杂芳基”意指稳定的5、6、7元单环或双环或7、8、9或10元双环杂环基的芳香环，它包含碳原子和1、2、3或4个独立地选自N、O和S的环杂原子。氮原子可以是被取代的或未取代的(即N或NR，其中R是H或本文已经定义过的其他取代基)。氮和硫杂原子可任选被氧化(即NO和S(O)p，p是1或2)。值得注意的是，芳香杂环上S和O原子的总数不超过1。桥环也包含在杂环的定义中。当一个或多个原子(即C、O、N或S)连接两个不相邻的碳原子或氮原子时形成桥环。优选的桥环包括但不限于：一个碳原子、两个碳原子、一个氮原子、两个氮原子和一个碳-氮基。值得注意的是，一个桥总是将单环转换成三环。桥环中，环上的取代基也可以出现在桥上。Unless otherwise specified, the term "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 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. The term "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). It is worth noting that the total number of S and O atoms on the aromatic heterocycle does not exceed one. 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.
杂环化合物的实例包括但不限于：吖啶基、吖辛因基、苯并咪唑基、苯并呋喃基、苯并巯基呋喃基、苯并巯基苯基、苯并恶唑基、苯并恶唑啉基、苯并噻唑基、苯并***基、苯并四唑基、苯并异恶唑基、苯并异噻唑基、苯并咪唑啉基、咔唑基、4aH-咔唑基、咔啉基、苯并二氢吡喃基、色烯、噌啉基十氢喹啉基、2H,6H-1,5,2-二噻嗪基、二氢呋喃并[2,3-b]四氢呋喃基、呋喃基、呋咱基、咪唑烷基、咪唑啉基、咪唑基、1H-吲唑基、吲哚烯基、二氢吲哚基、中氮茚基、吲哚基、3H-吲哚基、异苯并呋喃基、异吲哚基、异二氢吲哚基、异喹啉基、异噻唑基、异恶唑基、亚甲二氧基苯基、吗啉基、萘啶基，八氢异喹啉基、恶二唑基、1,2,3-恶二唑基、1,2,4-恶二唑基、1,2,5-恶二唑基、1,3,4-恶二唑基、恶唑烷基、恶唑基、羟吲哚基、嘧啶基、菲啶基、菲咯啉基、吩嗪、吩噻嗪、苯并黄嘌呤基、酚恶嗪基、酞嗪基、哌嗪基、哌啶基、哌啶酮基、4-哌啶酮基、胡椒基、蝶啶基、嘌呤基、吡喃基、吡嗪基、吡唑烷基、吡唑啉基、吡唑基、哒嗪基、吡啶并恶唑、吡啶并咪唑、吡啶并噻唑、吡啶基、吡咯烷基、吡咯啉基、2H-吡咯基、吡咯基、喹唑啉基、喹啉基、4H-喹嗪基、喹喔啉基、奎宁环基、四氢呋喃基、四氢异喹啉基、四氢喹啉基、四唑基，6H-1,2,5-噻二嗪基、1,2,3-噻二唑基、1,2,4-噻二唑基、1,2,5-噻二唑基、1,3,4-噻二唑基、噻蒽基、噻唑基、异噻唑基噻吩基、噻吩并恶唑基、噻吩并噻唑基、噻吩并咪唑基、噻吩基、三嗪基、1H-1,2,3-***基、2H-1,2,3-***基、1H-1,2,4-***基、4H-1,2,4-***基和呫吨基。还包括稠环和螺环化合物。Examples of 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, indanyl, mesoindolyl, fluorenyl, 3H-indole Mercapto, isobenzofuranyl, isodecyl, isoindoline, isoquinolyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl , octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3, 4-oxadiazolyl, oxazolidinyl, oxazolyl, hydroxymethyl, pyrimidinyl, phenanthryl, phenanthroline, phenazine, phenothiazine , benzoxanthyl, phenoloxazinyl, pyridazinyl, piperazinyl, piperidinyl, piperidinone, 4-piperidinone, piperonyl, pteridinyl, fluorenyl, pyranyl, Pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridylthiazole, pyridyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl , pyrrolyl, quinazolinyl, quinolyl, 4H-quinazinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolyl, tetrazolyl, 6H -1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4 -thiadiazolyl, thiazolidine, thiazolyl, isothiazolylthiophenyl, thienooxazolyl, thienothiazolyl, thienoimidazolyl, thienyl, triazinyl, 1H-1, 2,3- Triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl, 4H-1,2,4-triazolyl and xanthene. Also included are fused ring and spiro compounds.
除非另有规定，术语“烃基”或者其下位概念(比如烷基、烯基、炔基、芳基等等)本身或者作为另一取代基的一部分表示直链的、支链的或环状的烃原子团或其组合，可以是完全饱和的(如烷基)、单元或多元不饱和的(如烯基、炔基、芳基)，可以是单取代或多取代的，可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)，可以包括二价或多价原子团，具有指定数量的碳原子(如C 1-C 12表示1至12个碳，C 1-12选自C 1、C 2、C 3、C 4、C 5、C 6、C 7、C 8、C 9、C 10、C 11和C 12；C 3-12选自C 3、C 4、C 5、C 6、C 7、C 8、C 9、C 10、C 11和C 12。)。“烃基”包括但不限于脂肪烃基和芳香烃基，所述脂肪烃基包括链状和环状，具体 包括但不限于烷基、烯基、炔基，所述芳香烃基包括但不限于6-12元的芳香烃基，例如苯、萘等。在一些实施例中，术语“烃基”表示直链的或支链的原子团或它们的组合，可以是完全饱和的、单元或多元不饱和的，可以包括二价和多价原子团。饱和烃原子团的实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、仲丁基、异丁基、环己基、(环己基)甲基、环丙基甲基，以及正戊基、正己基、正庚基、正辛基等原子团的同系物或异构体。不饱和烃基具有一个或多个双键或三键，其实例包括但不限于乙烯基、2-丙烯基、丁烯基、巴豆基、2-异戊烯基、2-(丁二烯基)、2，4-戊二烯基、3-(1，4-戊二烯基)、乙炔基、1-和3-丙炔基，3-丁炔基，以及更高级的同系物和异构体。 Unless otherwise specified, the term "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 .). "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. In some embodiments, the term "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. Examples of 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.
除非另有规定，术语“杂烃基”或者其下位概念(比如杂烷基、杂烯基、杂炔基、杂芳基等等)本身或者与另一术语联合表示稳定的直链的、支链的或环状的烃原子团或其组合，有一定数目的碳原子和至少一个杂原子组成。在一些实施例中，术语“杂烷基”本身或者与另一术语联合表示稳定的直链的、支链的烃原子团或其组合物，有一定数目的碳原子和至少一个杂原子组成。在一个典型实施例中，杂原子选自B、O、N和S，其中氮和硫原子任选地被氧化，氮杂原子任选地被季铵化。杂原子或杂原子团可以位于杂烃基的任何内部位置，包括该烃基附着于分子其余部分的位置，但术语“烷氧基”、“烷氨基”和“烷硫基”(或硫代烷氧基)属于惯用表达，是指分别通过一个氧原子、氨基或硫原子连接到分子的其余部分的那些烷基基团。实例包括但不限于-CH 2-CH 2-O-CH 3、-CH 2-CH 2-NH-CH 3、-CH 2-CH 2-N(CH 3)-CH 3、-CH 2-S-CH 2-CH 3、-CH 2-CH 2、-S(O)-CH 3、-CH 2-CH 2-S(O) 2-CH 3、-CH＝CH-O-CH 3、-CH 2-CH＝N-OCH 3和–CH＝CH-N(CH 3)-CH 3。至多两个杂原子可以是连续的，例如-CH 2-NH-OCH 3。 Unless otherwise specified, the term "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. In some embodiments, the term "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. In a typical embodiment, 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. Examples include, but are not limited to, -CH 2 -CH 2 -O-CH 3 , -CH 2 -CH 2 -NH-CH 3 , -CH 2 -CH 2 -N(CH 3 )-CH 3 , -CH 2 -S -CH 2 -CH 3 , -CH 2 -CH 2 , -S(O)-CH 3 , -CH 2 -CH 2 -S(O) 2 -CH 3 , -CH=CH-O-CH 3 ,- CH 2 -CH=N-OCH 3 and -CH=CH-N(CH 3 )-CH 3 . Up to two heteroatoms may be consecutive, for example, -CH 2 -NH-OCH 3.
除非另有规定，术语“环烃基”、“杂环烃基”或者其下位概念(比如芳基、杂芳基、环烷基、杂环烷基、环烯基、杂环烯基、环炔基、杂环炔基等等)本身或与其他术语联合分别表示环化的“烃基”、“杂烃基”。此外，就杂烃基或杂环烃基(比如杂烷基、杂环烷基)而言，杂原子可以占据该杂环附着于分子其余部分的位置。环烃基的实例包括但不限于环戊基、环己基、1-环己烯基、3-环己烯基、环庚基等。杂环基的非限制性实例包括1-(1,2,5,6-四氢吡啶基)、1-哌啶基、2-哌啶基，3-哌啶基、4-吗啉基、3-吗啉基、四氢呋喃-2-基、四氢呋喃吲哚-3-基、四氢噻吩-2-基、四氢噻吩-3-基，1-哌嗪基和2-哌嗪基。Unless otherwise specified, the term "cycloalkyl", "heterocycloalkyl" or its subordinate concept (such as aryl, heteroaryl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl) A heterocyclic alkynyl group, etc., by itself or in combination with other terms, denotes a cyclized "hydrocarbyl group" or "heterohydrocarbyl group", respectively. Further, in the case of a heterohydrocarbyl group or a heterocycloalkyl group (such as a heteroalkyl group or a heterocycloalkyl group), a hetero atom may occupy a position at which the hetero ring is attached to the rest of the molecule. Examples of cycloalkyl groups include, but are not limited to, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Non-limiting examples of 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.
除非另有规定，术语“烷基”用于表示直链或支链的饱和烃基,可以是单取代(如-CH 2F)或多取代的(如-CF 3)，可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。烷基的例子包括甲基(Me)，乙基(Et)，丙基(如，n-丙基和异丙基)，丁基(如，n-丁基，异丁基，s-丁基，t-丁基)，戊基(如，n-戊基，异戊基，新戊基)等。 Unless otherwise specified, the term "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). Examples of the 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.
除非另有规定，“烯基”指在链的任何位点上具有一个或多个碳碳双键的烷基,可以是单取代或多取代的，可以是一价、二价或者多价。烯基的例子包括乙烯基，丙烯基，丁烯基，戊烯基，己烯基，丁间二烯基，戊间二烯基，己间二烯基等。Unless otherwise specified, "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. Examples of the 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.
除非另有规定，“炔基”指在链的任何位点上具有一个或多个碳碳三键的烷基，可以是单取代或多取代 的，可以是一价、二价或者多价。炔基的例子包括乙炔基，丙炔基，丁炔基，戊炔基等。Unless otherwise specified, "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. Examples of alkynyl groups include ethynyl, propynyl, butynyl, pentynyl and the like.
除非另有规定，环烷基包括任何稳定的环状或多环烃基，任何碳原子都是饱和的，可以是单取代或多取代的，可以是一价、二价或者多价。这些环烷基的实例包括，但不限于，环丙基、降冰片烷基、[2.2.2]二环辛烷、[4.4.0]二环癸烷等。Unless otherwise specified, 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.
除非另有规定，环烯基包括任何稳定的环状或多环烃基，该烃基在环的任何位点含有一个或多个不饱和的碳-碳双键，可以是单取代或多取代的，可以是一价、二价或者多价。这些环烯基的实例包括，但不限于，环戊烯基、环己烯基等。Unless otherwise specified, 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.
除非另有规定，环炔基包括任何稳定的环状或多环烃基，该烃基在环的任何位点含有一个或多个碳-碳三键，可以是单取代或多取代的，可以是一价、二价或者多价。Unless otherwise specified, 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.
除非另有规定，“环烯烷基”或“环烯基烷基”指环烯基取代的烷基。Unless otherwise specified, "cycloalkenylalkyl" or "cycloalkenylalkyl" refers to a cycloalkenyl substituted alkyl.
除非另有规定，“环炔烷基”或“环炔基烷基”指环炔基取代的烷基。Unless otherwise specified, "cycloalkynyl" or "cycloalkynylalkyl" refers to a cycloalkynyl substituted alkyl.
除非另有规定，术语“卤代素”或“卤素”本身或作为另一取代基的一部分表示氟、氯、溴或碘原子。此外，术语“卤代烷基”意在包括单卤代烷基和多卤代烷基。例如，术语“卤代(C 1-C 4)烷基”意在包括但不仅限于三氟甲基、2，2，2-三氟乙基、4-氯丁基和3-溴丙基等等。除非另有规定，卤代烷基的实例包括但不仅限于：三氟甲基、三氯甲基、五氟乙基，和五氯乙基。 Unless otherwise specified, the term "halo" or "halogen", by itself or as part of another substituent, denotes a fluorine, chlorine, bromine or iodine atom. Further, the term "haloalkyl" is intended to include both monohaloalkyl and polyhaloalkyl. For example, the term "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. Unless otherwise specified, examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl.
“烷氧基”代表通过氧桥连接的具有特定数目碳原子的上述烷基，除非另有规定，C 1-6烷氧基包括C 1、C 2、C 3、C 4、C 5和C 6的烷氧基。烷氧基的例子包括但不限于：甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、叔丁氧基、正戊氧基和S-戊氧基。 The above-described alkyl groups having the specified number of carbon atoms, "alkoxy" represents attached through an oxygen bridge, unless otherwise specified, C 1-6 alkoxy groups include C 1, C 2, C 3 , C 4, C 5 , and C 6 alkoxy groups. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy and S- Pentyloxy.
除非另有规定，术语“芳基”表示多不饱和的芳族烃取代基，可以是单取代或多取代的，可以是一价、二价或者多价，它可以是单环或多环(比如1至3个环；其中至少一个环是芳族的)，它们稠合在一起或共价连接。术语“杂芳基”是指含有一至四个杂原子的芳基(或环)。在一个示范性实例中，杂原子选自B、N、O和S，其中氮和硫原子任选地被氧化，氮原子任选地被季铵化。杂芳基可通过杂原子连接到分子的其余部分。芳基或杂芳基的非限制性实施例包括苯基、萘基、联苯基、吡咯基、吡唑基、咪唑基、吡嗪基、恶唑基、苯基-恶唑基、异恶唑基、噻唑基、呋喃基、噻吩基、吡啶基、嘧啶基、苯并噻唑基、嘌呤基、苯并咪唑基、吲哚基、异喹啉基、喹喔啉基、喹啉基、1-萘基、2-萘基、4-联苯基、1-吡咯基、2-吡咯基、3-吡咯基、3-吡唑基、2-咪唑基、4-咪唑基、吡嗪基、2-恶唑基、4-恶唑基、2-苯基-4-恶唑基、5-恶唑基、3-异恶唑基、4-异恶唑基、5-异恶唑基、2-噻唑基、4-噻唑基、5-噻唑基、2-呋喃基、3-呋喃基、2-噻吩基、3-噻吩基、2-吡啶基、3-吡啶基、4-吡啶基、2-嘧啶基、4-嘧啶基、5-苯并噻唑基、嘌呤基、2-苯并咪唑基、5-吲哚基、1-异喹啉基、5-异喹啉基、2-喹喔啉基、5-喹喔啉基、3-喹啉基和6-喹啉基。上述任意一个芳基和杂芳基环系的取代基选自下文所述的可接受的取代基。Unless otherwise specified, the term "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. The term "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. Non-limiting examples of 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, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-benzothiazolyl, fluorenyl, 2-benzimidazolyl, 5-indenyl, 1-isoquinolinyl, 5-isoquinolinyl, 2-quina Porphyrin, 5-quinoxalinyl, 3-quinolyl and 6-quinolinyl. The substituents of any of the above aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below.
除非另有规定，芳基在与其他术语联合使用时(例如芳氧基、芳硫基、芳烷基)包括如上定义的芳基 和杂芳基环。因此，术语“芳烷基”意在包括芳基附着于烷基的那些原子团(例如苄基、苯乙基、吡啶基甲基等)，包括其中碳原子(如亚甲基)已经被例如氧原子代替的那些烷基，例如苯氧基甲基、2-吡啶氧甲基3-(1-萘氧基)丙基等。Unless otherwise specified, aryl groups, when used in conjunction with other terms (e.g., aryloxy, arylthio, aralkyl), include aryl and heteroaryl rings as defined above. Thus, the term "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. Those alkyl groups substituted by an atom, such as phenoxymethyl, 2-pyridyloxymethyl 3-(1-naphthyloxy)propyl and the like.
术语“离去基团”是指可以被另一种官能团或原子通过取代反应(例如亲和取代反应)所取代的官能团或原子。例如，代表性的离去基团包括三氟甲磺酸酯；氯、溴、碘；磺酸酯基，如甲磺酸酯、甲苯磺酸酯、对溴苯磺酸酯、对甲苯磺酸酯等；酰氧基，如乙酰氧基、三氟乙酰氧基等等。The term "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). For example, representative leaving 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.
术语“保护基”包括但不限于“氨基保护基”、“羟基保护基”或“巯基保护基”。术语“氨基保护基”是指适合用于阻止氨基氮位上副反应的保护基团。代表性的氨基保护基包括但不限于：甲酰基；酰基，例如链烷酰基(如乙酰基、三氯乙酰基或三氟乙酰基)；烷氧基羰基，如叔丁氧基羰基(Boc)；芳基甲氧羰基，如苄氧羰基(Cbz)和9-芴甲氧羰基(Fmoc)；芳基甲基，如苄基(Bn)、三苯甲基(Tr)、1,1-二-(4'-甲氧基苯基)甲基；甲硅烷基，如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。术语“羟基保护基”是指适合用于阻止羟基副反应的保护基。代表性羟基保护基包括但不限于：烷基，如甲基、乙基和叔丁基；酰基，例如链烷酰基(如乙酰基)；芳基甲基，如苄基(Bn)，对甲氧基苄基(PMB)、9-芴基甲基(Fm)和二苯基甲基(二苯甲基，DPM)；甲硅烷基，如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。The term "protecting group" includes, but is not limited to, "amino protecting group", "hydroxy protecting group" or "thiol protecting group". The term "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-butyldimethylsilyl (TBS) and the like. The term "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.
本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。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.
本发明所使用的溶剂可经市售获得。本发明采用下述缩略词：aq代表水；HATU代表O-(7-氮杂苯并***-1-基)-N，N，N'，N'-四甲基脲六氟磷酸盐；EDC代表N-(3-二甲基氨基丙基)-N'-乙基碳二亚胺盐酸盐；m-CPBA代表3-氯过氧苯甲酸；eq代表当量、等量；CDI代表羰基二咪唑；DCM代表二氯甲烷；PE代表石油醚；DIAD代表偶氮二羧酸二异丙酯；DMF代表N，N-二甲基甲酰胺；DMSO代表二甲亚砜；EtOAc代表乙酸乙酯；EtOH代表乙醇；MeOH代表甲醇；CBz代表苄氧羰基，是一种胺保护基团；BOC代表叔丁氧羰基是一种胺保护基团；HOAc代表乙酸；NaCNBH 3代表氰基硼氢化钠；r.t.代表室温；O/N代表过夜；THF代表四氢呋喃；Boc 2O代表二-叔丁基二碳酸酯；TFA代表三氟乙酸；DIPEA代表二异丙基乙基胺；SOCl 2代表氯化亚砜；CS 2代表二硫化碳；TsOH代表对甲苯磺酸；NFSI代表N-氟-N-(苯磺酰基)苯磺酰胺；NCS代表1-氯吡咯烷-2,5-二酮；n-Bu 4NF代表氟化四丁基铵；iPrOH代表2-丙醇；mp代表熔点；LDA代表二异丙基胺基锂；EDCI代表1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐；NBS代表N-溴代琥珀酰亚胺；Pd2(dba)3代表三(二亚苄基丙酮)二钯；AIBN代表偶氮二异丁腈；Pd(dppf)Cl2代表1,1'-双二苯基膦二茂铁二氯化钯；XPhos代表2-二环己基磷-2',4',6'-三异丙基联苯；DIBAL-H代表二异丁基氢化铝；NaBH3CN代表氰基硼氢化钠；EGTA代表乙二醇双(2-氨基乙基醚)四乙酸。 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, equivalent; CDI stands for Carbonyldiimidazole; DCM stands for dichloromethane; PE stands for petroleum ether; DIAD stands for diisopropyl azodicarboxylate; DMF stands for N,N-dimethylformamide; DMSO stands for dimethyl sulfoxide; EtOAc stands for acetic acid Esters; EtOH for ethanol; MeOH for methanol; CBz for benzyloxycarbonyl, an amine protecting group; BOC for t-butoxycarbonyl is an amine protecting group; HOAc for acetic acid; NaCNBH 3 for sodium cyanoborohydride ; rt stands for room temperature; O/N stands for overnight; THF stands for tetrahydrofuran; Boc 2 O stands for di-tert-butyl dicarbonate; TFA stands for trifluoroacetic acid; DIPEA stands for diisopropylethylamine; SOCl 2 stands for chloride Sulfone; CS 2 represents carbon disulfide; TsOH represents p-toluenesulfonic acid; NFSI stands for N-fluoro-N-(phenylsulfonyl)benzenesulfonamide; NCS stands for 1-chloropyrrolidine-2,5-dione; n-Bu 4 NF stands for fluorine Tetrabutylammonium; iPrOH stands for 2-propanol; mp stands for melting point; LDA stands for diisopropylamino lithium; EDCI stands for 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride Salt; NBS stands for N-bromosuccinimide; Pd2(dba)3 stands for tris(dibenzylideneacetone)dipalladium; AIBN stands for azobisisobutyronitrile; Pd(dppf)Cl2 stands for 1,1'- Bis-diphenylphosphinoferrocene palladium dichloride; XPhos stands for 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl; DIBAL-H stands for diisobutylaluminum hydride; NaBH3CN Represents sodium cyanoborohydride; EGTA stands for ethylene glycol bis(2-aminoethyl ether) tetraacetic acid.
化合物经手工或者
Figure PCTCN2019070227-appb-000087
软件命名，市售化合物采用供应商目录名称。 Compound by hand or
Figure PCTCN2019070227-appb-000087
Software naming, commercially available compounds using the supplier catalog name.
本发明化合物具有显著的CSF-1R激酶抑制作用，其渗透性和代谢稳定性有显著提升。The compounds of the present invention have significant CSF-1R kinase inhibition with a significant increase in permeability and metabolic stability.
具体实施方式Detailed ways
下面通过实施例对本发明进行详细描述，但并不意味着对本发明任何不利限制。本文已经详细地描述了本发明，其中也公开了其具体实施例方式，对本领域的技术人员而言，在不脱离本发明精神和范围的情况下针对本发明具体实施方式进行各种变化和改进将是显而易见的。The invention is described in detail below by the examples, but is not intended to limit the invention. The present invention has been described in detail herein, the embodiments of the present invention are disclosed herein, and various modifications and changes may be made to the embodiments of the present invention without departing from the spirit and scope of the invention. It will be obvious.
中间体IIntermediate I
Figure PCTCN2019070227-appb-000088
Figure PCTCN2019070227-appb-000088
合成路线：synthetic route:
Figure PCTCN2019070227-appb-000089
Figure PCTCN2019070227-appb-000089
步骤1：化合物I-B的合成Step 1: Synthesis of Compound I-B
将化合物I-A(8g,52.58mmol)，碘甲烷(22.39g,157.74mmol,9.82mL)和碳酸钾(25.43g,184.03mmol)溶解在N,N-二甲基甲酰胺(20.00mL)中，反应液在60℃下搅拌12小时。减压除去溶剂得到粗品。粗品使用过柱机(石油醚/乙酸乙酯＝10/1)纯化得到无色液体化合物I-B。Compound IA (8 g, 52.58 mmol), iodomethane (22.39 g, 157.74 mmol, 9.82 mL) and potassium carbonate (25.43 g, 184.03 mmol) were dissolved in N,N-dimethylformamide (20.00 mL). The solution was stirred at 60 ° C for 12 hours. The solvent was removed under reduced pressure to give a crude material. The crude product was purified using a column chromatography ( petroleum ether / ethyl acetate = 10/1) to afford the colourless liquid compound I-B.
步骤2：化合物I-C的合成Step 2: Synthesis of Compound I-C
在0℃下向溶有化合物I-B(8g,44.40mmol)的二氯甲烷(200.00mL)溶液中滴加用二氯甲烷(200.00mL)稀释的液溴(7.80g,48.83mmol,2.52mL)，反应液在0℃下搅拌0.5小时。加水(20mL)稀释，用二氯甲烷(40mL)萃取，有机相用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，滤去干燥剂后，减压除去溶剂得到产品物I-C。To a solution of compound IB (8 g, 44.40 mmol) in dichloromethane (200.00 mL), EtOAc (EtOAc) The reaction solution was stirred at 0 ° C for 0.5 hour. The mixture was diluted with EtOAc (EtOAc) (EtOAc)
1H NMR(400MHz,CDCl 3)δppm 7.53(d,J＝8.78Hz,1H)6.68(d,J＝9.03Hz,1H)3.94(s,3H)3.82(s,3H)2.33(s,3H) 1 H NMR (400MHz, CDCl 3 ) δppm 7.53 (d, J = 8.78Hz, 1H) 6.68 (d, J = 9.03Hz, 1H) 3.94 (s, 3H) 3.82 (s, 3H) 2.33 (s, 3H)
步骤3：化合物I-D的合成Step 3: Synthesis of Compound I-D
将化合物I-C(8.2g,31.65mmol)，NBS(6.48g,36.40mmol)和AIBN(1.04g,6.33mmol)溶解在四氯化碳 (150.00mL)中，反应液在80℃下搅拌12小时。减压除去溶剂得到粗品。粗品使用过柱机(石油醚/乙酸乙酯＝20/1～10/1)纯化得到化合物I-D。Compound I-C (8.2 g, 31.65 mmol), NBS (6.48 g, 36.40 mmol) and AIBN (1.04 g, 6.33 mmol) were dissolved in carbon tetrachloride (150.00 mL), and the reaction mixture was stirred at 80 ° C for 12 hours. The solvent was removed under reduced pressure to give a crude material. The crude product was purified using a column chromatography ( petroleum ether / ethyl acetate = 20/1 to 10/1) to afford compound I-D.
步骤4：化合物I-E的合成Step 4: Synthesis of Compound I-E
将化合物I-D(8.3g,24.56mmol)溶解在氨水(6.88g,49.11mmol,7.57mL,25％纯度)和乙腈(150.00mL)中，反应液在25℃下搅拌30分钟。将反应液浓缩后过滤，滤饼用乙腈(25mL)和水(25mL)的混合溶液洗涤得到I-E。Compound I-D (8.3 g, 24.56 mmol) was dissolved in aqueous ammonia (6.88 g, 49.11 mmol, 7.57 mL, 25% purity) and acetonitrile (150.00 mL), and the mixture was stirred at 25 ° C for 30 min. The reaction solution was concentrated and filtered, and the filtered cake was washed with a mixture of acetonitrile (25mL) and water (25mL) to afford I-E.
MS m/z:241.8[M+H] + MS m/z: 241.8 [M+H] +
步骤5：化合物I-F的合成Step 5: Synthesis of Compound I-F
将化合物I-E(5g,20.66mmol)，二甲基氨基吡啶(2.78g,22.72mmol)和Boc 2O(6.76g,30.98mmol,7.12mL)溶解在二甲基亚砜(100mL)中，反应液在50℃下搅拌2小时。加水(300mL)稀释，用乙酸乙酯(300mL)萃取，有机相用饱和食盐水(100mL)洗涤，无水硫酸钠干燥，滤去干燥剂后，减压除去溶剂得到粗品。粗品使用过柱机(石油醚/四氢呋喃＝2/1)纯化得到化合物I-F。 Compound IE (5 g, 20.66 mmol), dimethylaminopyridine (2.78 g, 22.72 mmol) and Boc 2 O (6.76 g, 30.98 mmol, 7.12 mL) were dissolved in dimethyl sulfoxide (100 mL). Stir at 50 ° C for 2 hours. It was diluted with water (300 mL), and extracted with ethyl acetate (300 mL). The crude product was purified using a column chromatography (petroleum ether / tetrahydrofuran = 2 / 1) to afford compound IF.
MS m/z:386.8[M+H] + MS m/z: 386.8 [M+H] +
步骤6：中间体I的合成Step 6: Synthesis of Intermediate I
将化合物I-F(4g,11.69mmol)，双联频哪醇硼酸酯(4.45g,17.53mmol)，醋酸钾(2.87g,29.22mmol)和Pd(dppf)Cl 2.CH 2Cl 2(954.62mg,1.17mmol)溶解在1,4-二氧六环(100mL)中，反应液在90℃氮气保护下搅拌12小时。将反应液浓缩得到粗品，粗品使用过柱机(石油醚/四氢呋喃＝2/1)纯化得到中间体I。 Compound IF (4 g, 11.69 mmol), bis-pinacol borate (4.45 g, 17.53 mmol), potassium acetate (2.87 g, 29.22 mmol) and Pd(dppf)Cl 2 .CH 2 Cl 2 (954.62 mg , 1.17 mmol) was dissolved in 1,4-dioxane (100 mL), and the reaction mixture was stirred at 90 ° C under nitrogen for 12 hours. The reaction mixture was concentrated to give a crude material.
MS m/z:390.1[M+H] + MS m/z: 390.1 [M+H] +
中间体IIIntermediate II
Figure PCTCN2019070227-appb-000090
Figure PCTCN2019070227-appb-000090
合成路线：synthetic route:
Figure PCTCN2019070227-appb-000091
Figure PCTCN2019070227-appb-000091
步骤1：化合物II-B的合成Step 1: Synthesis of Compound II-B
将化合物II-A(3.00g,16.04mmol)和2-三氟甲基吡啶-5-甲醛(2.60g,14.85mmol)溶于乙腈(92.00mL)中，将三氟乙酸(6.91mg,60.60mmol)，三乙基硅烷(6.75g,58.07mmol)加入到反应体系，然后在93℃搅拌4小时后，减压浓缩得到粗品，将粗品倒入碳酸钾的水溶液中，用乙酸乙酯(30mL×3)萃取，合并有机相，无水 硫酸钠干燥。滤去干燥剂后，减压除去溶剂得到粗品。经柱层析(石油醚/乙酸乙酯＝8/1～2/1)纯化得II-B。Compound II-A (3.00 g, 16.04 mmol) and 2-trifluoromethylpyridine-5-carbaldehyde (2.60 g, 14.85 mmol) were dissolved in acetonitrile (92.00 mL), trifluoroacetic acid (6.91 mg, 60.60 mmol Triethylsilane (6.75 g, 58.07 mmol) was added to the reaction system, and the mixture was stirred at 93 ° C for 4 hours, then concentrated under reduced pressure to give a crude material. 3) Extraction, combining the organic phases, and drying over anhydrous sodium sulfate. After filtering off the desiccant, the solvent was removed under reduced pressure to give a crude material. Purification by column chromatography (petroleum ether/ethyl acetate = 8/1 to 2/1) afforded II-B.
MS m/z:346.1[M+H] + MS m/z: 346.1 [M+H] +
步骤2：化合物II的合成Step 2: Synthesis of Compound II
在氮气氛围下，将化合物II-B(300.00mg,866.68μmol)，乙酸钾(170.11mg,1.73mmol)，联硼酸频那醇酯(330.13mg,1.30mmol)和Pd(dppf)Cl2(31.71mg,43.33μmol)加入到1,4-二氧六环(5.00mL)溶液中，在90℃的氮气氛围下搅拌14小时后，加水(4mL)稀释，用乙酸乙酯(15mL×3)萃取，合并有机相，用饱和食盐水(20mL)洗涤，无水硫酸钠干燥。滤去干燥剂后，减压除去溶剂得到粗品。经制备TLC(石油醚/乙酸乙酯＝3/1)纯化得II。Compound II-B (300.00 mg, 866.68 μmol), potassium acetate (170.11 mg, 1.73 mmol), boranoic acid pinacol ester (330.13 mg, 1.30 mmol) and Pd(dppf)Cl2 (31.71 mg) under a nitrogen atmosphere. , 43.33 μmol) was added to a solution of 1,4-dioxane (5.00 mL), and stirred under a nitrogen atmosphere at 90 ° C for 14 hours, then diluted with water (4 mL) and extracted with ethyl acetate (15 mL×3). The combined organic layers were washed with brine (20 mL) After filtering off the desiccant, the solvent was removed under reduced pressure to give a crude material. Purified by preparative TLC (petroleum ether / ethyl acetate = 3 / 1).
MS m/z:394.1[M+H] + MS m/z: 394.1 [M+H] +
中间体ⅢIntermediate III
Figure PCTCN2019070227-appb-000092
Figure PCTCN2019070227-appb-000092
合成路线：synthetic route:
Figure PCTCN2019070227-appb-000093
Figure PCTCN2019070227-appb-000093
步骤1：中间体Ⅲ的合成Step 1: Synthesis of Intermediate III
将I(1g,2.57mmol)溶于二氧六环(20mL)，水(2mL)中，向其中加入5-溴-4-甲基吡啶-2-胺(480.51mg,2.57mmol)，2-二环己基磷-2’,4’,6’-三异丙基联苯(244.94mg,513.81μmol)，磷酸钾(1.64g,7.71mmol)，反应体系用氮气置换3次后加入三(二亚苄基丙酮)二钯(235.25mg,256.90μmol)。在氮气保护、100℃下搅拌12小时后，反应液减压除去溶剂，残留物经层析柱分离(石油醚/四氢呋喃＝3/1-2/3)得到中间体Ⅲ。I (1 g, 2.57 mmol) was dissolved in dioxane (20 mL), water (2 mL), and 5-bromo-4-methylpyridin-2-amine (480.51 mg, 2.57 mmol), 2- Dicyclohexylphos-2',4',6'-triisopropylbiphenyl (244.94 mg, 513.81 μmol), potassium phosphate (1.64 g, 7.71 mmol), the reaction system was replaced with nitrogen three times and then added three (two) Benzylideneacetone) dipalladium (235.25 mg, 256.90 μmol). After stirring under nitrogen for 10 hours at 100 ° C, the solvent was removed under reduced pressure and the residue was purified by chromatography ( petroleum ether / THF / / / / / / / / / / / /
MS m/z:370.1[M+H] + MS m/z: 370.1 [M+H] +
实施例1：化合物1Example 1: Compound 1
Figure PCTCN2019070227-appb-000094
Figure PCTCN2019070227-appb-000094
合成路线：synthetic route:
Figure PCTCN2019070227-appb-000095
Figure PCTCN2019070227-appb-000095
步骤1：化合物1-B的合成Step 1: Synthesis of Compound 1-B
在氮气氛围下，将化合物1-A(100.00mg,0.47mmol)，乙酸钾(69.43mg,0.71mmol)，联硼酸频那醇酯(131.74mg,0.52mmol)和Pd(dppf)Cl 2(17.25mg,0.024mmol)加入到1,4-二氧六环(4.00mL)溶液中，在80℃的氮气氛围下搅拌15小时后，加水(3mL)稀释，用乙酸乙酯(10mL×3)萃取，合并有机相，用饱和食盐水(10mL)洗涤，无水硫酸钠干燥。滤去干燥剂后，减压除去溶剂得到粗品1-B。粗品可以直接用于下一步反应。 Compound 1-A (100.00 mg, 0.47 mmol), potassium acetate (69.43 mg, 0.71 mmol), boranoic acid pinacol ester (131.74 mg, 0.52 mmol) and Pd(dppf)Cl 2 (17.25). The solution was added to a solution of 1,4-dioxane (4.00 mL), and stirred under a nitrogen atmosphere at 80 ° C for 15 hours, then diluted with water (3 mL) and extracted with ethyl acetate (10 mL×3) The organic phase was combined, washed with brine (10 mL) After filtering off the desiccant, the solvent was removed under reduced pressure to give crude 1-B. The crude product can be used directly in the next reaction.
MS m/z:260.0[M+H] + MS m/z: 260.0 [M+H] +
1H NMR(400MHz,CHLOROFORM-d)δppm 7.98(ddd,J＝15.06,7.53,1.00Hz,1H)7.42-7.54(m,1H)7.49(t,J＝7.40Hz,1H)4.61(s,2H)1.35(s,12H) 1 H NMR (ddd, J = 15.06,7.53,1.00Hz, 1H) (400MHz, CHLOROFORM-d) δppm 7.98 7.42-7.54 (m, 1H) 7.49 (t, J = 7.40Hz, 1H) 4.61 (s, 2H ) 1.35 (s, 12H)
步骤2：化合物1的合成Step 2: Synthesis of Compound 1
在氮气氛围下，将化合物II-B(29.39mg,84.91μmol)，1-B(20.00mg,77.19μmol)，碳酸钠(16.36mg,154.38μmol)和Pd(dppf)Cl 2(5.65mg,7.72μmol)加入到1,4-二氧六环(1.00mL)和水(0.10mL)溶液中，在90℃的氮气氛围下搅拌6小时后，加水(3mL)稀释，用乙酸乙酯(10mL×3)萃取，合并有机相，用饱和食盐水(10mL)洗涤，无水硫酸钠干燥。滤去干燥剂后，减压除去溶剂得到粗品，粗品经制备HPLC(中性,乙腈和水)分离得到化合物1。 Compound II-B (29.39 mg, 84.91 μmol), 1-B (20.00 mg, 77.19 μmol), sodium carbonate (16.36 mg, 154.38 μmol) and Pd(dppf)Cl 2 (5.65 mg, 7.72) under a nitrogen atmosphere. Μmol) was added to a solution of 1,4-dioxane (1.00 mL) and water (0.10 mL), and stirred under a nitrogen atmosphere at 90 ° C for 6 hours, then diluted with water (3 mL), with ethyl acetate (10 mL × 3) The organic phase was combined, washed with brine (10 mL) and dried over anhydrous sodium sulfate. After filtering off the desiccant, the solvent was removed under reduced pressure to give a crude material.
MS m/z:399.0[M+H] + MS m/z: 399.0 [M+H] +
1H NMR(400MHz,CDCl 3)δppm 9.46(br s,1H)8.78(s,1H)8.06(br d,J＝7.53Hz,1H)7.98(d,J＝7.53Hz,1H)7.71-7.80(m,2H)7.61(t,J＝7.53Hz,1H)7.36(d,J＝7.28Hz,1H)6.64(s,1H)6.42(br s,1H)4.73(br s,2H)4.20(br s,2H)2.18(s,3H) 1 H NMR (400 MHz, CDCl 3 ) δ ppm 9.46 (br s, 1H) 8.78 (s, 1H) 8.06 (brd, J = 7.53 Hz, 1H) 7.98 (d, J = 7.53 Hz, 1H) 7.71 - 7.80 ( m, 2H) 7.61 (t, J = 7.53 Hz, 1H) 7.36 (d, J = 7.28 Hz, 1H) 6.64 (s, 1H) 6.42 (br s, 1H) 4.73 (br s, 2H) 4.20 (br s , 2H) 2.18 (s, 3H)
实施例2：化合物2Example 2: Compound 2
Figure PCTCN2019070227-appb-000096
Figure PCTCN2019070227-appb-000096
合成路线：synthetic route:
Figure PCTCN2019070227-appb-000097
Figure PCTCN2019070227-appb-000097
步骤1：化合物2-B的合成Step 1: Synthesis of Compound 2-B
除了使用相应的原料外，以中间体II中的化合物II-B相同的方法制备化合物2-B。Compound 2-B was prepared in the same manner as Compound II-B in Intermediate II except that the corresponding material was used.
MS m/z:331.8[M+H] + MS m/z: 331.8 [M+H] +
1H NMR(400MHz,CD 3OD)δppm 8.73(d,J＝1.00Hz,1H)8.01-8.08(m,2H)7.73-7.84(m,2H)6.79(d,J＝9.03Hz,1H)4.71(s,2H) 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.73 (d, J = 1.00 Hz, 1H) 8.01-8.08 (m, 2H) 7.73-7.84 (m, 2H) 6.79 (d, J = 9.03 Hz, 1H) 4.71 (s, 2H)
步骤2：化合物2-C的合成Step 2: Synthesis of Compound 2-C
在氮气氛围下，将化合物2-B(300.00mg,903.29μmol)，乙酸钾(177.30mg,1.81mmol)，联硼酸频那醇酯(344.07mg,1.35mmol)和Pd(dppf)Cl 2(33.05mg,45.16μmol)加入到1,4-二氧六环(5.00mL)溶液中，在90℃的氮气氛围下搅拌14小时后，加水(4mL)稀释，用乙酸乙酯(15mL×3)萃取，合并有机相，用饱和食盐水(20mL)洗涤，无水硫酸钠干燥。滤去干燥剂后，减压除去溶剂得到粗品。经制备TLC(石油醚/乙酸乙酯＝3/1)纯化得2-C。 Compound 2-B (300.00 mg, 903.29 μmol), potassium acetate (177.30 mg, 1.81 mmol), boranoic acid pinacol ester (344.07 mg, 1.35 mmol) and Pd(dppf)Cl 2 (33.05) under a nitrogen atmosphere Mg, 45.16 μmol) was added to a solution of 1,4-dioxane (5.00 mL), and stirred under a nitrogen atmosphere at 90 ° C for 14 hours, then diluted with water (4 mL) and extracted with ethyl acetate (15 mL×3) The combined organic layers were washed with brine brine (20 mL) After filtering off the desiccant, the solvent was removed under reduced pressure to give a crude material. Purification by preparative TLC (petroleum ether / ethyl acetate = 3 / 1) gave 2-C.
MS m/z:380.0[M+H] + MS m/z: 380.0 [M+H] +
步骤3：化合物2的合成Step 3: Synthesis of Compound 2
在氮气氛围下，将化合物2-C(28.61mg,75.46μmol)，4-溴异吲哚啉-1-酮(20.00mg,94.32μmol)，碳酸钠(19.99mg,188.64μmol)和Pd(dppf)Cl 2(3.45mg,4.72μmol)加入到1,4-二氧六环(2.00mL)和水(0.20mL)溶液中，在100℃的氮气氛围下搅拌6小时后，加水(3mL)稀释，用乙酸乙酯(10mL×3)萃取，合并有机相，用饱和食盐水(20mL)洗涤，无水硫酸钠干燥。滤去干燥剂后，减压除去溶剂得到粗品，粗品经制备HPLC(中性,乙腈和水)分离得到化合物2。 Compound 2-C (28.61 mg, 75.46 μmol), 4-bromoisoindolin-1-one (20.00 mg, 94.32 μmol), sodium carbonate (19.99 mg, 188.64 μmol) and Pd (dppf) under a nitrogen atmosphere Cl 2 (3.45 mg, 4.72 μmol) was added to a solution of 1,4-dioxane (2.00 mL) and water (0.20 mL), and stirred for 6 hours under nitrogen atmosphere at 100 ° C, then diluted with water (3 mL) The extract was extracted with ethyl acetate (10 mL × 3). After filtering off the desiccant, the solvent was removed under reduced pressure to give a crude material.
MS m/z:385.0[M+H] + MS m/z: 385.0 [M+H] +
1H NMR(400MHz,DMSO-d 6)δppm 8.77(br s,1H)8.65(br s,1H)8.23(br s,1H)8.02(br d,J＝7.53Hz,1H)7.88(br d,J＝7.78Hz,1H)7.73(br d,J＝7.78Hz,1H)7.46-7.67(m,4H)6.69(br d,J＝8.28Hz,1H)4.67(br d,J＝4.02Hz,2H)4.50(br s,2H) 1 H NMR (400MHz, DMSO- d 6) δppm 8.77 (br s, 1H) 8.65 (br s, 1H) 8.23 (br s, 1H) 8.02 (br d, J = 7.53Hz, 1H) 7.88 (br d, J=7.78 Hz, 1H) 7.73 (br d, J=7.78 Hz, 1H) 7.46-7.67 (m, 4H) 6.69 (br d, J=8.28 Hz, 1H) 4.67 (br d, J=4.02 Hz, 2H ) 4.50 (br s, 2H)
实施例3：化合物3Example 3: Compound 3
Figure PCTCN2019070227-appb-000098
Figure PCTCN2019070227-appb-000098
合成路线：synthetic route:
Figure PCTCN2019070227-appb-000099
Figure PCTCN2019070227-appb-000099
步骤1：化合物3-B的合成Step 1: Synthesis of Compound 3-B
20℃下向化合物3-A(2.00g,10.20mmol)的N’N-二甲基-甲酰胺(10mL)溶液中加入[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(833.14mg,1.02mmol)，三乙胺(4.13g,40.81mmol,5.66mL)，甲醇(326.87mg,10.20mmol,5.00mL)，一氧化碳(50psi)氛围下，80℃搅拌12小时，然后45℃减压浓缩，向浓缩物加入水(20mL)，然后用乙酸乙酯(20mL×2)萃取，合并有机相，用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，滤液浓缩得到粗品3-B，粗品可以直接用于下一步反应。To a solution of compound 3-A (2.00 g, 10.20 mmol) in N'N-dimethyl-carboxamide (10 mL), [1,1'-bis(diphenylphosphino)ferrocene] Palladium chloride methylene chloride complex (833.14 mg, 1.02 mmol), triethylamine (4.13 g, 40.81 mmol, 5.66 mL), methanol (326.87 mg, 10.20 mmol, 5.00 mL), under a carbon monoxide (50 psi) atmosphere. After stirring at 80 ° C for 12 hours, and then concentrated under reduced pressure at 45 ° C, water (20 mL) was added to the concentrate, then extracted with ethyl acetate (20 mL × 2), and the organic phase was combined and washed with saturated brine (20 mL) The sodium is dried, filtered, and the filtrate is concentrated to give crude 3-B.
步骤2：化合物3-C的合成Step 2: Synthesis of Compound 3-C
20℃氮气氛围下向化合物3-B(700.00mg,4.00mmol)的甲醇(15.00mL)，氨水(1.50mL)溶液中加入雷尼-镍(1.50g,17.51mmol)。加完后反应液在氢气氛围(50psi)60℃下搅拌12小时。反应液冷却至室温过滤，滤液减压浓缩得到粗品3-C，粗品可以直接用于下一步反应。To a solution of compound 3-B (700.00 mg, 4.00 mmol) in methanol (15.00 mL), EtOAc (1. After the addition, the reaction solution was stirred under a hydrogen atmosphere (50 psi) at 60 ° C for 12 hours. The reaction solution was cooled to room temperature and filtered, and the filtrate was evaporated.
1H NMR(400MHz,DMSO-d)δppm 8.42(s,1H)7.53(d,1H)7.35(s,1H)7.26(d,1H)4.30(s.,2H)2.39(s.,3H) 1 H NMR (400 MHz, DMSO-d) δ ppm 8.42 (s, 1H) 7.53 (d, 1H) 7.35 (s, 1H) 7.26 (d, 1H) 4.30 (s., 2H) 2.39 (s., 3H)
步骤3：化合物3-D的合成Step 3: Synthesis of Compound 3-D
0℃下向化合物3-C(400.00mg,2.72mmol)的二氯甲烷(10.00mL)溶液中加入溴-丁二酰亚胺(484.12mg,2.72mmol)，加完后反应液在0℃，氮气氛围下搅拌2小时。反应液用饱和碳酸氢钠(20mL)溶液萃灭，搅拌2分钟后用二氯甲烷(20mL×2)萃取，合并有机相，用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，过滤，滤液浓缩得到粗品，粗品经层析硅胶柱(石油醚/乙酸乙酯＝2:1～1:2)分离得到化合物3-D。To a solution of compound 3-C (400.00 mg, 2.72 mmol) in dichloromethane (10.00 mL), bromo-succinimide (484.12 mg, 2.72 mmol) was added at 0 ° C. Stir for 2 hours under a nitrogen atmosphere. The reaction mixture was extracted with EtOAc EtOAc (EtOAc m. The filtrate was concentrated to give a crude material. EtOAc m.
1H NMR(400MHz,DMSO-d)δppm 8.45(s,1H)7.55(d,1H)7.37(s,1H)7.28(d,1H)4.32(s,2H)2.41(s.,3H) 1 H NMR (400 MHz, DMSO-d) δ ppm 8.45 (s, 1H) 7.55 (d, 1H) 7.37 (s, 1H) 7.28 (d, 1H) 4.32 (s, 2H) 2.41 (s., 3H)
步骤4：化合物3的合成Step 4: Synthesis of Compound 3
在氮气氛围下，将化合物II(95.66mg,243.29μmol)，3-D(55.00mg,243.29μmol)，磷酸钾(103.29mg,486.58μmol)，XPhos(17.40mg,36.49μmol)和Pd 2(dba) 3(11.14mg,12.16μmol)加入到1,4-二氧六环(1.50mL)和水(0.15mL)溶液中，在110℃的氮气氛围下搅拌14小时后，加水(5mL)稀释，用乙酸乙酯(10mL×3)萃取，合并有机相，用饱和食盐水(10mL)洗涤，无水硫酸钠干燥。滤去干燥剂后，减压除去溶剂得到粗品，粗品经制备HPLC(中性，乙腈和水)分离得到化合物3。 Compound II (95.66 mg, 243.29 μmol), 3-D (55.00 mg, 243.29 μmol), potassium phosphate (103.29 mg, 486.58 μmol), XPhos (17.40 mg, 36.49 μmol) and Pd 2 (dba) under a nitrogen atmosphere 3 (11.14 mg, 12.16 μmol) was added to a solution of 1,4-dioxane (1.50 mL) and water (0.15 mL), and stirred under a nitrogen atmosphere at 110 ° C for 14 hours, then diluted with water (5 mL). The organic layer was combined with EtOAc (EtOAc) (EtOAc) After filtering off the desiccant, the solvent was removed under reduced pressure to give a crude material.
MS m/z:413.0[M+H] + MS m/z: 413.0 [M+H] +
1H NMR(400MHz,MeOD-d 4)δppm 8.82(s,1H)8.14(br d,J＝8.78Hz,1H)7.90(d,J＝8.53Hz,1H)7.72(s,1H)7.61(s,1H)7.56-7.59(m,1H)7.08-7.12(m,1H)4.82(br s,2H)4.52(s,2H)2.26(s,3H)2.13(s,3H) 1 H NMR (400 MHz, MeOD-d 4 ) δ ppm 8.82 (s, 1H) 8.14 (brd, J = 8.78 Hz, 1H) 7.90 (d, J = 8.53 Hz, 1H) 7.72 (s, 1H) 7.61 (s ,1H)7.56-7.59(m,1H)7.08-7.12(m,1H)4.82(br s,2H)4.52(s,2H)2.26(s,3H)2.13(s,3H)
实施例5：化合物5Example 5: Compound 5
Figure PCTCN2019070227-appb-000100
Figure PCTCN2019070227-appb-000100
合成路线：synthetic route:
Figure PCTCN2019070227-appb-000101
Figure PCTCN2019070227-appb-000101
步骤1：化合物5-B的合成Step 1: Synthesis of Compound 5-B
将N-溴代丁二酰亚胺(800.73mg,4.50mmol,1.10eq)加入到3-A(500.00mg,4.09mmol)的乙腈(10.00mL)溶液中，在25℃下搅拌2小时后，过滤得到一个固体，无需纯化直接得到化合物5-B。N-Bromosuccinimide (800.73 mg, 4.50 mmol, 1.10 eq) was added to a solution of 3-A (500.00 mg, 4.09 mmol) in acetonitrile (10.00 mL), and stirred at 25 ° C for 2 hours. Filtration gave a solid which gave compound 5-B without purification.
MS m/z:201.0[M+H] + MS m/z: 201.0 [M+H] +
1H NMR(400MHz,CDCl 3)δppm 6.48-6.09(m,1H)4.74-4.13(m,2H)2.57-2.49(m,3H)2.28(s,3H) 1 H NMR (400 MHz, CDCl 3 ) δ ppm 6.48-6.09 (m, 1H) 4.74 - 4.13 (m, 2H) 2.57-2.49 (m, 3H) 2.28 (s, 3H)
步骤2：化合物5-C的合成Step 2: Synthesis of Compound 5-C
将化合物5-B(480.00mg,2.39mmol)，2-三氟甲基吡啶-5-甲醛(418.51mg,2.39mmol)，三氟醋酸(2.73g,23.90mmol)和三乙基硅烷(2.78g,23.90mmol)加入到乙腈(5.00mL)溶液中，在90℃的氮气氛围下搅拌4小时后， 浓缩，加入氢氧化钠(20mL,10％)，并加水(50mL)稀释，用乙酸乙酯(50mL×2)萃取，合并有机相，用饱和食盐水(50mL)洗涤，无水硫酸钠干燥。滤去干燥剂后，减压除去溶剂得到粗品。粗品用柱分离(石油醚/乙酸乙酯＝10/1)纯化得到化合物5-C。Compound 5-B (480.00 mg, 2.39 mmol), 2-trifluoromethylpyridine-5-carbaldehyde (418.51 mg, 2.39 mmol), trifluoroacetic acid (2.73 g, 23.90 mmol) and triethylsilane (2.78 g) , 23.90 mmol), added to a solution of acetonitrile (5.00 mL), and stirred for 4 hr under nitrogen atmosphere at 90 ° C, then concentrated, then added sodium hydroxide (20 mL, 10%) and diluted with water (50 mL) (50 mL × 2), the organic phase was combined, washed with brine (50 mL) After filtering off the desiccant, the solvent was removed under reduced pressure to give a crude material. The crude product was purified by column chromatography ( petroleum ether / ethyl acetate = 10/1) to afford compound 5-C.
MS m/z:360.0[M+H] + MS m/z: 360.0 [M+H] +
步骤3：化合物5的合成Step 3: Synthesis of Compound 5
将化合物5-C(150.00mg,431-A16.47μmol)，1-B(161.87mg,624.71μmol)，三(二亚苄基丙酮)二钯(76.27mg,83.29μmol)，2-二环己基磷-2,4,6-三异丙基联苯(79.42mg,166.59μmol)和磷酸钾(265.21mg,1.25mmol)加入到二氧六环(5.00mL)和水(500uL)溶液中，在用氮气进行除气和净化3次,混合体系在90℃的氮气氛围下搅拌14小时后，过滤并浓缩得到粗品。粗品经制备HPLC(中性,乙腈和水)分离得到化合物5。Compound 5-C (150.00 mg, 431-A 16.47 μmol), 1-B (161.87 mg, 624.71 μmol), tris(dibenzylideneacetone)dipalladium (76.27 mg, 83.29 μmol), 2-dicyclohexyl Phosphorus-2,4,6-triisopropylbiphenyl (79.42 mg, 166.59 μmol) and potassium phosphate (265.21 mg, 1.25 mmol) were added to a solution of dioxane (5.00 mL) and water (500 uL). The mixture was degassed and purified three times with nitrogen, and the mixture was stirred under a nitrogen atmosphere at 90 ° C for 14 hours, filtered and concentrated to give a crude material. The crude product was isolated by preparative HPLC (neutral, acetonitrile and water) to afford compound 5.
MS m/z:413.0[M+H] + MS m/z: 413.0 [M+H] +
1H NMR(400MHz,CD 3OD)δppm 8.74(s,1H)8.05(d,J＝7.5Hz,1H)7.80(dd,J＝7.8,12.5Hz,2H)7.69-7.55(m,1H)7.38(d,J＝7.5Hz,1H)6.36(s,1H)4.69(s,2H)4.15-4.01(m,2H)3.31(s,3H)2.00(s,3H) 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.74 (s, 1H) 8.05 (d, J = 7.5 Hz, 1H) 7.80 (dd, J = 7.8, 12.5 Hz, 2H) 7.69-7.55 (m, 1H) 7.38 (d, J = 7.5 Hz, 1H) 6.36 (s, 1H) 4.69 (s, 2H) 4.15 - 4.01 (m, 2H) 3.31 (s, 3H) 2.00 (s, 3H)
实施例6：化合物6Example 6: Compound 6
Figure PCTCN2019070227-appb-000102
Figure PCTCN2019070227-appb-000102
合成路线：synthetic route:
Figure PCTCN2019070227-appb-000103
Figure PCTCN2019070227-appb-000103
步骤1：化合物6-B的合成Step 1: Synthesis of Compound 6-B
化合物6-A(450.00mg,2.61mmol)溶于硫酸(5.00mL)溶液中，在75℃的下搅拌2小时后，加入氢氧化钠(50mL,10％)淬灭反应，并加水(50mL)稀释，用乙酸乙酯(50mL×3)萃取，合并有机相，用饱和食盐水(50mL)洗涤，无水硫酸钠干燥。滤去干燥剂后，减压浓缩得到化合物6-B。Compound 6-A (450.00 mg, 2.61 mmol) was dissolved in sulfuric acid (5.00 mL) and stirred at 75 ° C for 2 hrs, then EtOAc (50 mL, 10%). The mixture was diluted with EtOAc (EtOAc m. After filtering off the desiccant, it was concentrated under reduced pressure to give Compound 6-B.
MS m/z:191.0[M+H] + MS m/z: 191.0 [M+H] +
步骤2：化合物6-D的合成Step 2: Synthesis of Compound 6-D
将化合物6-B(340.00mg,1.79mmol)，6-C(339.80mg,1.79mmol)，三(二亚苄基丙酮)二钯(327.52mg,357.67μmol)，4,5-双二苯基膦-9,9-二甲基氧杂基氧杂蒽杂蒽(413.91mg,715.34μmol)和碳酸铯(1.75g,5.37mmol)加入到二氧六环(5.00mL)溶液中，在100℃的氮气氛围下搅拌2.5小时后。浓缩得到粗品。粗品用柱分离(石油醚/乙酸乙酯＝8/1)纯化得到化合物6-D。Compound 6-B (340.00 mg, 1.79 mmol), 6-C (339.80 mg, 1.79 mmol), tris(dibenzylideneacetone) dipalladium (327.52 mg, 357.67 μmol), 4,5-bisdiphenyl Phosphine-9,9-dimethyloxaheteroxanthene (413.91 mg, 715.34 μmol) and cesium carbonate (1.75 g, 5.37 mmol) were added to a solution of dioxane (5.00 mL) at 100 ° C After stirring for 2.5 hours under a nitrogen atmosphere. Concentrate to give a crude product. The crude product was purified by column chromatography ( petroleum ether / ethyl acetate = 8 / 1) to afford compound 6-D.
MS m/z:300.0[M+H] + MS m/z: 300.0 [M+H] +
步骤3：化合物6-E的合成Step 3: Synthesis of Compound 6-E
将硼烷四氢呋喃(1M,6.68mL,5.00eq)加入到化合物6-D(400.00mg,1.34mmol)的甲苯(5.00mL)溶液中，然后在90℃搅拌0.5小时后，加入甲醇(5mL)淬灭反应，并加盐酸(1N，10mL)稀释，加氢氧化钠(40mL,10％)调节至pH＝10，用乙酸乙酯(50mL×2)萃取，合并有机相，用饱和食盐水(50mL)洗涤，无水硫酸钠干燥。滤去干燥剂后，减压除去溶剂得到粗品，粗品用柱分离(石油醚/乙酸乙酯＝1/1)纯化得到化合物6-E。Borane tetrahydrofuran (1 M, 6.68 mL, 5.00 eq) was added to a solution of compound 6-D (400.00 mg, 1.34 mmol) in toluene (5.00 mL), and then stirred at 90 ° C for 0.5 hr, then added with methanol (5 mL) The reaction was quenched and diluted with EtOAc (EtOAc (EtOAc) (EtOAc) (EtOAc) Washed and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the solvent was evaporated under reduced pressure to afford crude crystals.
MS m/z:285.9[M+H] + MS m/z: 285.9 [M+H] +
步骤4：化合物6-F的合成Step 4: Synthesis of Compound 6-F
将N-溴代丁二酰亚胺(106.07mg,595.99μmol)加入6-E(170.00mg,95.99μmol)的乙腈(10.00mL)溶液中，在25℃的氧气氛围下搅拌0.5小时。浓缩得到粗品，粗品经制备TLC分离(石油醚/乙酸乙酯＝1/1)纯化得到化合物6-F。N-bromosuccinimide (106.07 mg, 595.99 μmol) was added to a solution of 6-E (170.00 mg, 95.99 μmol) in acetonitrile (10.00 mL), and stirred under an atmosphere of 25 ° C for 0.5 hour. Concentration gave the crude product which was purified by preparative EtOAc (EtOAc:EtOAc
MS m/z:363.9[M+H] + MS m/z: 363.9 [M+H] +
步骤5：化合物6的合成Step 5: Synthesis of Compound 6
将化合物6-F(70.00mg,192.23μmol)，1-B(74.71mg,288.35μmol)，三(二亚苄基丙酮)二钯(35.21mg,38.45μmol)，2-二环己基磷-2,4,6-三异丙基联苯(36.66mg,76.89μmol)和磷酸钾(122.42mg,576.70μmol)加入到二氧六环(4.00mL)和水(400μL)溶液中，在用氮气进行除气和净化3次，混合体系在100℃的氮气氛围下搅拌14小时。过滤并浓缩得到粗品，粗品经制备HPLC(中性,乙腈和水)分离得到化合物6。Compound 6-F (70.00 mg, 192.23 μmol), 1-B (74.71 mg, 288.35 μmol), tris(dibenzylideneacetone)dipalladium (35.21 mg, 38.45 μmol), 2-dicyclohexylphosphon-2 4,6-triisopropylbiphenyl (36.66 mg, 76.89 μmol) and potassium phosphate (122.42 mg, 576.70 μmol) were added to a solution of dioxane (4.00 mL) and water (400 μL) under nitrogen. The mixture was degassed and purified three times, and the mixed system was stirred under a nitrogen atmosphere at 100 ° C for 14 hours. Filtration and concentration gave a crude material which was purified by preparative HPLC (neut.
MS m/z:417.0[M+H] + MS m/z: 417.0 [M+H] +
1H NMR(400MHz,CD 3OD)δppm 8.74(s,1H)8.06(br d,J＝7.3Hz,1H)7.82(t,J＝8.9Hz,2H)7.61(t,J＝7.7Hz,1H)7.48(d,J＝7.5Hz,1H)6.45(s,1H)4.68(s,2H)4.40-3.88(m,2H)3.31(s,3H) 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.74 (s, 1H) 8.06 (brd, J = 7.3 Hz, 1H) 7.82 (t, J = 8.9 Hz, 2H) 7.61 (t, J = 7.7 Hz, 1H) ) 7.48 (d, J = 7.5 Hz, 1H) 6.45 (s, 1H) 4.68 (s, 2H) 4.40 - 3.88 (m, 2H) 3.31 (s, 3H)
实施例7：化合物7Example 7: Compound 7
Figure PCTCN2019070227-appb-000104
Figure PCTCN2019070227-appb-000104
合成路线：synthetic route:
Figure PCTCN2019070227-appb-000105
Figure PCTCN2019070227-appb-000105
步骤1：化合物7-C的合成Step 1: Synthesis of Compound 7-C
将化合物7-A(320.44mg,1.71mmol)，2-三氟甲基吡啶-5-甲醛(300.00mg,1.71mmol)，三氟醋酸(1.95g,17.13mmol)和三乙基硅烷(1.99g,17.13mmol)加入到乙腈(5.00mL)溶液中，在90℃的氮气氛围下搅拌14小时后，浓缩得到粗品，加入氢氧化钠(30mL,0.5N)，用乙酸乙酯(50mL×2)萃取，合并有机相，用饱和食盐水(50mL)洗涤，无水硫酸钠干燥。滤去干燥剂后，减压除去溶剂得到粗品。粗品用柱分离(石油醚/乙酸乙酯＝5：1)纯化得到化合物7-C。Compound 7-A (320.44 mg, 1.71 mmol), 2-trifluoromethylpyridine-5-carbaldehyde (300.00 mg, 1.71 mmol), trifluoroacetic acid (1.95 g, 17.13 mmol) and triethylsilane (1.99 g) , 17.13 mmol) was added to a solution of acetonitrile (5.00 mL), and stirred under a nitrogen atmosphere at 90 ° C for 14 hours, then concentrated to give a crude product, sodium hydroxide (30mL, 0.5N), ethyl acetate (50mL × 2) The organic layer was combined, washed with brine (50 mL) After filtering off the desiccant, the solvent was removed under reduced pressure to give a crude material. The crude product was purified by column chromatography ( petroleum ether / ethyl acetate = 5:1) to afford compound 7-C.
MS m/z:345.9[M+H] + MS m/z: 345.9 [M+H] +
步骤2：化合物7的合成Step 2: Synthesis of Compound 7
将化合物7-C(70.00mg,202.22μmol)，1-B(78.60mg,303.33μmol,)，三(二亚苄基丙酮)二钯(37.04mg,40.44μmol)，2-二环己基磷-2,4,6-三异丙基联苯(38.56mg,80.89μmol)和磷酸钾(128.78mg,606.66μmol)加入到二氧六环(5.00mL)和水(500uL)溶液中，在用氮气进行除气和净化3次,混合体系在90℃的氮气氛围下搅拌14小时后，过滤并浓缩得到粗品，粗品经制备HPLC分离得到化合物7。Compound 7-C (70.00 mg, 202.22 μmol), 1-B (78.60 mg, 303.33 μmol,), tris(dibenzylideneacetone)dipalladium (37.04 mg, 40.44 μmol), 2-dicyclohexylphosphine- 2,4,6-Triisopropylbiphenyl (38.56 mg, 80.89 μmol) and potassium phosphate (128.78 mg, 606.66 μmol) were added to a solution of dioxane (5.00 mL) and water (500 uL) with nitrogen. After degassing and purifying three times, the mixed system was stirred under a nitrogen atmosphere at 90 ° C for 14 hours, filtered and concentrated to give a crude product which was obtained by preparative HPLC.
MS m/z:399.0[M+H] + MS m/z: 399.0 [M+H] +
1H NMR(400MHz,MeOD-d 4)δppm 8.72(s,1H)8.08-7.96(m,2H)7.81-7.72(m,2H)7.63-7.49(m,3H)4.83(s,3H)4.55(s,2H)2.46-2.11(m,3H) 1 H NMR (400 MHz, MeOD-d 4 ) δ ppm 8.72 (s, 1H) 8.08-7.96 (m, 2H) 7.81-7.72 (m, 2H) 7.63-7.49 (m, 3H) 4.83 (s, 3H) 4.55 ( s, 2H) 2.46-2.11 (m, 3H)
实施例8：化合物8Example 8: Compound 8
Figure PCTCN2019070227-appb-000106
Figure PCTCN2019070227-appb-000106
合成路线：synthetic route:
Figure PCTCN2019070227-appb-000107
Figure PCTCN2019070227-appb-000107
步骤1：化合物8-B的合成Step 1: Synthesis of Compound 8-B
除了使用相应的原料外，以实施例5中的化合物5-C相同的方法制备化合物8-B。Compound 8-B was prepared in the same manner as in the compound 5-C of Example 5 except that the corresponding material was used.
MS m/z:345.9[M+H] + MS m/z: 345.9 [M+H] +
步骤2：化合物5的合成Step 2: Synthesis of Compound 5
将化合物8-B(100.00mg,288.89μmol)，1-B(112.28mg,433.34μmol)，三(二亚苄基丙酮)二钯(52.91mg,57.78μmol)，2-二环己基磷-2,4,6-三异丙基联苯(55.09mg,115.56μmol)和磷酸钾(183.97mg,866.67μmol)加入到二氧六环(8.00mL)和水(800uL)溶液中，在用氮气进行除气和净化3次，混合体系在85℃的氮气氛围下搅拌14小时后，过滤并浓缩得到粗品，粗品经制备HPLC(中性,乙腈和水)分离得到化合物8。Compound 8-B (100.00 mg, 288.89 μmol), 1-B (112.28 mg, 433.34 μmol), tris(dibenzylideneacetone)dipalladium (52.91 mg, 57.78 μmol), 2-dicyclohexylphosphon-2 4,6-triisopropylbiphenyl (55.09 mg, 115.56 μmol) and potassium phosphate (183.97 mg, 866.67 μmol) were added to a solution of dioxane (8.00 mL) and water (800 uL) under nitrogen. After degassing and purifying 3 times, the mixed system was stirred under a nitrogen atmosphere at 85 ° C for 14 hours, filtered and concentrated to give a crude product which was purified by preparative HPLC (neutral, acetonitrile and water).
MS m/z:399.0[M+H] + MS m/z: 399.0 [M+H] +
1H NMR(400MHz,CD 3OD)δppm 8.74(s,1H)8.06(d,J＝8.0Hz,1H)7.78(d,J＝7.5Hz,2H)7.57(t,J＝7.5Hz,1H)7.45(d,J＝7.5Hz,1H)7.31(d,J＝8.5Hz,1H)6.46(d,J＝8.3Hz,1H)4.71(s,2H)4.22(s,2H)2.16(s,3H) 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.74 (s, 1H) 8.06 (d, J = 8.0 Hz, 1H) 7.78 (d, J = 7.5 Hz, 2H) 7.57 (t, J = 7.5 Hz, 1H) 7.45 (d, J = 7.5 Hz, 1H) 7.31 (d, J = 8.5 Hz, 1H) 6.46 (d, J = 8.3 Hz, 1H) 4.71 (s, 2H) 4.22 (s, 2H) 2.16 (s, 3H) )
实施例9：化合物9Example 9: Compound 9
Figure PCTCN2019070227-appb-000108
Figure PCTCN2019070227-appb-000108
合成路线：synthetic route:
Figure PCTCN2019070227-appb-000109
Figure PCTCN2019070227-appb-000109
步骤1：化合物9-A的合成Step 1: Synthesis of Compound 9-A
将化合物I(5g,12.85mmol)溶于二氧六环(100mL)和水(10mL)中，向其中加入化合物II-B(4.45g,12.85mmol)，2-二环己基磷-2’,4’,6’-三异丙基联苯(1.22g,2.57mmol)，磷酸钾(8.18g,38.54mmol)，反应用氮气置换3次后，向其中加入三(二亚苄基丙酮)二钯(1.18g,1.28mmol)，反应在氮气保护下90℃下搅拌12小时后，向其中加入水(200mL)，用乙酸乙酯(500mL)萃取，饱和食盐水(100mL)洗涤，硫酸钠干燥，过滤干燥剂，减压浓缩得到粗品，粗品用(石油醚/四氢呋喃＝1/1)纯化得到化合物9-A。Compound I (5 g, 12.85 mmol) was dissolved in dioxane (100 mL) and water (10 mL), and compound II-B (4.45 g, 12.85 mmol), 2-dicyclohexylphosphon-2', 4',6'-triisopropylbiphenyl (1.22 g, 2.57 mmol), potassium phosphate (8.18 g, 38.54 mmol), after the reaction was replaced with nitrogen for 3 times, tris(dibenzylideneacetone) was added thereto. Palladium (1.18 g, 1.28 mmol), and the mixture was stirred at 90 ° C for 12 hours under nitrogen atmosphere, water (200 mL) was added, and ethyl acetate (500 mL) was evaporated. The desiccant was filtered, and concentrated under reduced pressure to give a crude material.
MS m/z:529.1[M+H] + MS m/z: 529.1 [M+H] +
1H NMR(400MHz,CDCl 3)δppm 8.78(s,1H)7.94(br d,J＝8.03Hz,1H)7.88(s,1H)7.70(s,1H)7.36(d,J＝8.53Hz,1H)6.98(d,J＝8.53Hz,1H)6.37(s,1H)4.62-4.81(m,2H)4.43(s,2H)4.02(s,3H)2.03(s,3H)1.58(s,9H) 1 H NMR (400 MHz, CDCl 3 ) δ ppm 8.78 (s, 1H) 7.94 (brd, J = 8.03 Hz, 1H) 7.88 (s, 1H) 7.70 (s, 1H) 7.36 (d, J = 8.53 Hz, 1H 6.98(d, J=8.53Hz, 1H) 6.37(s,1H)4.62-4.81(m,2H)4.43(s,2H)4.02(s,3H)2.03(s,3H)1.58(s,9H)
步骤2：化合物9的合成Step 2: Synthesis of Compound 9
将化合物9-A(5.4g,10.22mmol)溶于二氯甲烷(60mL)中，向其中加入三氟乙酸(15.40g,135.06mmol)，反应在16℃下搅拌2小时后，向其中加入饱和碳酸氢钠溶液调节pH至8后，用二氯甲烷(400mL)萃取，饱和食盐水(100mL)洗涤，硫酸钠干燥，过滤干燥剂，减压浓缩得到粗品，粗品用石油醚：乙酸乙酯＝5:1(60mL)洗涤得到化合物9。Compound 9-A (5.4 g, 10.22 mmol) was dissolved in dichloromethane (60 mL), trifluoroacetic acid (15.40 g, 135.06 mmol) was added thereto, and the mixture was stirred at 16 ° C for 2 hours, and then saturated. The sodium hydrogencarbonate solution was adjusted to pH 8 and then extracted with dichloromethane (400 mL). EtOAc (EtOAc) Washing at 5:1 (60 mL) gave Compound 9.
MS m/z:429.0[M+H] + MS m/z: 429.0 [M+H] +
1H NMR(400MHz,METHANOL-d 4)δppm 8.62-8.88(m,1H)8.04(br d,J＝7.03Hz,1H)7.72-7.88(m,2H)7.38(d,J＝8.53Hz,1H)7.12(d,J＝8.53Hz,1H)6.60(s,1H)4.71(s,2H)4.15(s,2H)3.97(s,3H)2.06(s,3H) 1 H NMR (400 MHz, METHANOL-d 4 ) δ ppm 8.62-8.88 (m, 1H) 8.04 (brd, J = 7.03 Hz, 1H) 7.72-7.88 (m, 2H) 7.38 (d, J = 8.53 Hz, 1H) 7.12 (d, J = 8.53 Hz, 1H) 6.60 (s, 1H) 4.71 (s, 2H) 4.15 (s, 2H) 3.97 (s, 3H) 2.06 (s, 3H)
实施例11：化合物11Example 11: Compound 11
Figure PCTCN2019070227-appb-000110
Figure PCTCN2019070227-appb-000110
合成路线：synthetic route:
Figure PCTCN2019070227-appb-000111
Figure PCTCN2019070227-appb-000111
步骤1：化合物11-B的合成Step 1: Synthesis of Compound 11-B
20度下向化合物11-A(150.00mg,607.14μmol)的四氯化碳(5mL)溶液中加入溴-丁二酰亚胺(118.86mg,667.85μmol)，过氧化苯甲酰(14.71mg,60.71μmol)，然后反应液在75度搅拌12小时。反应液冷却至室温然后在45度下减压浓缩，浓缩物用乙酸乙酯(40mL)溶解，然后用饱和碳酸氢钠溶液(20mL)洗涤，饱和食 盐水(30mL)洗涤,无水硫酸钠干燥，过滤，滤液浓缩得到粗品，粗品经制备硅胶板(石油醚/乙酸乙酯＝6:1)分离得到化合物11-B。To a solution of compound 11-A (150.00 mg, 607.14 μmol) in carbon tetrachloride (5 mL) was added bromo-succinimide (118.86 mg, 667.85 μmol), benzoyl peroxide (14.71 mg, 60.71 μmol), and then the reaction solution was stirred at 75 °C for 12 hours. The reaction mixture was cooled to room temperature and then evaporated to dryness. EtOAc (EtOAc) Filtration and concentration of the filtrate gave a crude material.
1H NMR(400MHz,DMSO-d)δppm 7.99(q,1H)7.73(q,1H)5.00(br s,2H)3.90(br s,3H) 1 H NMR (400 MHz, DMSO-d) δ ppm 7.99 (q, 1H) 7.73 (q, 1H) 5.00 (br s, 2H) 3.90 (br s, 3H)
步骤2：化合物11-C的合成Step 2: Synthesis of Compound 11-C
20度下向化合物11-B(170.00mg,521.54μmol)的乙腈(2.00mL)溶液中加入氨水(3.64g,103.85mmol,4.00mL)，加完后反应液在25度下搅拌2小时。反应液减压浓缩得到化合物11-C。Aqueous ammonia (3.64 g, 103.85 mmol, 4.00 mL) was added to a solution of Compound 11-B (170.00 mg, 521.54 μmol) in acetonitrile (2.00 mL) at 20 ° C. After the addition, the reaction mixture was stirred at 25 °C for 2 hours. The reaction solution was concentrated under reduced pressure to give Compound 11-C.
1H NMR(400MHz,DMSO-d)δppm 9.04(s,1H)7.90(q,1H)7.59(q,1H)4.36(s.,2H) 1 H NMR (400MHz, DMSO- d) δppm 9.04 (s, 1H) 7.90 (q, 1H) 7.59 (q, 1H) 4.36 (s., 2H)
步骤3：化合物11的合成Step 3: Synthesis of Compound 11
20度下向化合物II(100.00mg,254.32μmol)的1,4-二氧六环(5.00mL溶液中加入11-C(64.35mg,279.75μmol)，Pd 2(dba) 3(232.89mg,254.32μmol)，XPhos(121.24mg,254.32μmol)，磷酸钾(53.98mg,254.32μmol,1.00eq)，水(500.00uL)，加完后溶液在100度氮气氛围下搅拌12小时。反应液冷却后在45度下减压浓缩得到浓缩物，然后向浓缩物中加入水(20mL)稀释，然后用乙酸乙酯(20mL×2)萃取，合并有机相，用盐水(20mL×2)洗涤，无水硫酸钠干燥，过滤，滤液浓缩得到粗品，粗品经制备HPLC(碱性)分离得到化合物11。 To a solution of compound II (100.00 mg, 254.32 μmol) in 1,4-dioxane (20 mL), add 11-C (64.35 mg, 279.75 μmol), Pd 2 (dba) 3 (232.89 mg, 254.32). Molmol), XPhos (121.24mg, 254.32μmol), potassium phosphate (53.98mg, 254.32μmol, 1.00eq), water (500.00uL), after the addition, the solution is stirred under a nitrogen atmosphere of 100 ° for 12 hours. Concentration under reduced pressure at 45 ° to give a concentrate, which was then diluted with water (20 mL), and then extracted with ethyl acetate (20 mL×2). The organic phase was combined and washed with brine (20 mL×2) The sodium was dried, filtered, and the filtrate was concentrated to give a crude material.
MS m/z:417.0[M+H] + MS m/z: 417.0 [M+H] +
1H NMR(400MHz,DMSO-d)δppm 8.75(d,1H)8.02(d,1H)7.87(t,2H)7.33-7.44(m,3H)6.54(s,1H)4.65(d,2H)4.16(s,2H)2.03(s,3H) 1 H NMR (400MHz, DMSO- d) δppm 8.75 (d, 1H) 8.02 (d, 1H) 7.87 (t, 2H) 7.33-7.44 (m, 3H) 6.54 (s, 1H) 4.65 (d, 2H) 4.16 (s, 2H) 2.03 (s, 3H)
实施例13：化合物13Example 13: Compound 13
Figure PCTCN2019070227-appb-000112
Figure PCTCN2019070227-appb-000112
合成路线：synthetic route:
Figure PCTCN2019070227-appb-000113
Figure PCTCN2019070227-appb-000113
步骤1：化合物13-B的合成Step 1: Synthesis of Compound 13-B
在0℃下向溶有化合物13-A(430.00mg,2.90mmol)的乙腈(10.00mL)溶液中加入NBS(309.69mg,1.74mmol)，反应液在0℃下搅拌0.5小时。加水(20mL)稀释，用乙酸乙酯(40mL)萃取，有机相用饱和食盐水(20mL)洗涤，无水硫酸钠干燥。滤去干燥剂后，减压除去溶剂得到粗品。粗品用过柱机(石油醚/四氢呋喃＝2/1)纯化得到化合物13-B。NBS (309.69 mg, 1.74 mmol) was added to a solution of Compound 13-A (430.00 mg, 2.90 mmol) in acetonitrile (10.00 mL), and the mixture was stirred at 0 ° C for 0.5 hour. It was diluted with water (20 mL), EtOAc (EtOAc) After filtering off the desiccant, the solvent was removed under reduced pressure to give a crude material. The crude product was purified by column chromatography (petroleum ether / tetrahydrofuran = 2 / 1) to afford compound 13-B.
MS m/z:226.9[M+H] + MS m/z: 226.9 [M+H] +
步骤2：化合物13-C的合成Step 2: Synthesis of Compound 13-C
在0℃下向溶有化合物13-B(430.00mg,2.90mmol)和盐酸(6M,440.41μL)的N,N-二甲基甲酰胺(10.00mL)和水(4.00mL)的混合溶液中滴加亚硝酸钠(72.93mg,1.06mmol)的水(0.5mL)溶液。反应液在0℃下搅拌0.5小时。向反应液滴加碘化钾(731.08mg,4.40mmol)的水溶液中，反应液在0℃下搅拌0.5小时。加水(20mL)稀释，用乙酸乙酯(40mL)萃取，有机相用饱和食盐水(20mL)洗涤，无水硫酸钠干燥。滤去干燥剂后，减压除去溶剂得到粗品。粗品用过柱机(石油醚/四氢呋喃＝2/1)纯化得到化合物13-C。To a mixed solution of compound 13-B (430.00 mg, 2.90 mmol) and hydrochloric acid (6M, 440.41 μL) in N,N-dimethylformamide (10.00 mL) and water (4.00 mL) at 0 °C A solution of sodium nitrite (72.93 mg, 1.06 mmol) in water (0.5 mL) was added dropwise. The reaction solution was stirred at 0 ° C for 0.5 hour. An aqueous solution of potassium iodide (731.08 mg, 4.40 mmol) was added to the reaction liquid, and the reaction solution was stirred at 0 ° C for 0.5 hour. It was diluted with water (20 mL), EtOAc (EtOAc) After filtering off the desiccant, the solvent was removed under reduced pressure to give a crude material. The crude product was purified by column chromatography (petroleum ether / tetrahydrofuran = 2 / 1) to afford compound 13-C.
MS m/z:337.7[M+H] + MS m/z: 337.7 [M+H] +
步骤3：化合物13的合成Step 3: Synthesis of Compound 13
化合物13-C(80.00mg,236.73μmol)，化合物II(186.17mg,473.46μmol)，磷酸钾(150.75mg,710.19μmol)和XPhos(22.57mg,47.35μmol)溶于1,4-二氧六环(5.00mL)和水(500.00μL)中，在氮气保护下加入Pd 2(dba) 3(21.68mg,23.67μmol)。反应液在65℃下搅拌4个小时。将反应液浓缩，制备分离(中性，乙腈和水)得到化合物13。 Compound 13-C (80.00 mg, 236.73 μmol), Compound II (186.17 mg, 473.46 μmol), potassium phosphate (150.75 mg, 710.19 μmol) and XPhos (22.57 mg, 47.35 μmol) were dissolved in 1,4-dioxane. Pd 2 (dba) 3 (21.68 mg, 23.67 μmol) was added under a nitrogen atmosphere in (5.00 mL) and water (500.00 μL). The reaction solution was stirred at 65 ° C for 4 hours. The reaction solution was concentrated to give a separation (neutral, acetonitrile and water) to afford compound 13.
MS m/z:476.8[M+H] + MS m/z: 476.8 [M+H] +
1H NMR(400MHz,CD 3OD)δppm 8.72(s,1H)8.04(br d,J＝8.28Hz,1H)7.76-7.82(m,2H)7.71(d,J＝8.03Hz,1H)7.31(d,J＝8.03Hz,1H)6.59(s,1H)4.71(s,2H)4.18(s,2H)2.06(s,3H) 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.72 (s, 1H) 8.04 (brd, J = 8.28 Hz, 1H) 7.76-7.82 (m, 2H) 7.71 (d, J = 8.03 Hz, 1H) 7.31 ( d, J = 8.03 Hz, 1H) 6.59 (s, 1H) 4.71 (s, 2H) 4.18 (s, 2H) 2.06 (s, 3H)
实施例16：化合物16Example 16: Compound 16
Figure PCTCN2019070227-appb-000114
Figure PCTCN2019070227-appb-000114
合成路线：synthetic route:
Figure PCTCN2019070227-appb-000115
Figure PCTCN2019070227-appb-000115
步骤1：化合物16-A的合成Step 1: Synthesis of Compound 16-A
将化合物13-B(1.50g,6.61mmol)，甲基硼酸(791.35mg,13.22mmol)，三(二亚苄基丙酮)二钯(605.29mg,661.00μmol)，2-二环己基磷-2,4,6-三异丙基联苯(630.22mg,1.32mmol)和磷酸钾(4.21g,19.83mmol)加入到二氧六环(10.00mL)和水(1.00mL)溶液中，在用氮气进行除气和净化3次,混合体系在90℃的氮气氛围下搅拌14小时后。浓缩，盐酸(2N，50mL)加入到反应体系中，用乙酸乙酯(50mL×2)萃取，水相加入氢氧化钠(10％，100mL)调节pH＝11，用乙酸乙酯(50mL×2)萃取，用饱和食盐水(50mL)洗涤，无水硫酸钠干燥。减压浓缩得到粗品，无需纯化得到化合物16-A。Compound 13-B (1.50 g, 6.61 mmol), methylboronic acid (791.35 mg, 13.22 mmol), tris(dibenzylideneacetone) dipalladium (605.29 mg, 661.00 μmol), 2-dicyclohexylphosphon-2 4,6-triisopropylbiphenyl (630.22 mg, 1.32 mmol) and potassium phosphate (4.21 g, 19.83 mmol) were added to a solution of dioxane (10.00 mL) and water (1.00 mL) with nitrogen Degassing and purification were carried out 3 times, and the mixed system was stirred under a nitrogen atmosphere at 90 ° C for 14 hours. Concentrated, hydrochloric acid (2N, 50 mL) was added to the reaction system, extracted with ethyl acetate (50 mL×2), and the aqueous phase was adjusted to pH=11 with sodium hydroxide (10%, 100 mL), with ethyl acetate (50 mL×2) The extract was washed with brine (50 mL) and dried over anhydrous sodium sulfate. Concentration under reduced pressure gave a crude material which was obtained without purification.
MS m/z:162.9[M+H] + MS m/z: 162.9 [M+H] +
步骤2：化合物16-B的合成Step 2: Synthesis of Compound 16-B
将亚硝酸钠(382.88mg,5.55mmol)溶于水(1mL)中滴加到0℃的16-A(300.00mg,1.85mmol)的二甲基甲酰胺(4mL)和盐酸(1mL)溶液中，反应体系在此温度下搅拌0.5小时，碘化钾(3.07g,18.50mmol)加入反应体系，并在20℃下搅拌1.0小时。氢氧化钠(10％，50mL)加入到反应体系中，用乙酸乙酯(50mL×2)萃取，合并有机相并用饱和食盐水(50mL)洗涤，无水硫酸钠干燥。减压浓缩得到粗品，粗品经制备TLC(石油醚/乙酸乙酯，1/1)分离得到化合物16-B。Sodium nitrite (382.88 mg, 5.55 mmol) was dissolved in water (1 mL) and added dropwise to a solution of 16-A (300.00 mg, 1.85 mmol) of dimethylformamide (4 mL) and hydrochloric acid (1 mL) The reaction system was stirred at this temperature for 0.5 hour, potassium iodide (3.07 g, 18.50 mmol) was added to the reaction system, and stirred at 20 ° C for 1.0 hour. Sodium hydroxide (10%, 50 mL) was added to the reaction mixture, and ethyl acetate (50 mL × 2) was evaporated. Concentration under reduced pressure gave the crude material.
MS m/z:273.9[M+H] + MS m/z: 273.9 [M+H] +
步骤3：化合物16的合成Step 3: Synthesis of Compound 16
将化合物16-B(60.00mg,219.72μmol)，化合物II(86.40mg,219.72μmol)，三(二亚苄基丙酮)二钯(40.24mg,43.94μmol)，2-二环己基磷-2,4,6-三异丙基联苯(41.90mg,87.89μmol)和磷酸钾(139.92mg,659.16μmol)加入到二氧六环(10.00mL)和水(1.00mL)溶液中，在用氮气进行除气和净化3次，混合体系在70℃的氮气氛围下搅拌14小时后，过滤并浓缩得到粗品，粗品经制备HPLC(中性，乙腈和水)分离得到化合物16。Compound 16-B (60.00 mg, 219.72 μmol), Compound II (86.40 mg, 219.72 μmol), tris(dibenzylideneacetone)dipalladium (40.24 mg, 43.94 μmol), 2-dicyclohexylphosphorane-2, 4,6-Triisopropylbiphenyl (41.90 mg, 87.89 μmol) and potassium phosphate (139.92 mg, 659.16 μmol) were added to a solution of dioxane (10.00 mL) and water (1.00 mL) under nitrogen. After degassing and purifying 3 times, the mixed system was stirred under a nitrogen atmosphere at 70 ° C for 14 hours, filtered and concentrated to give a crude material which was purified by preparative HPLC ( neutral, acetonitrile and water).
MS m/z:413.0[M+H] + MS m/z: 413.0 [M+H] +
1H NMR(400MHz,CD 3OD)δppm 8.71(s,1H)8.02(d,J＝8.0Hz,1H)7.81-7.71(m,2H)7.36-7.20(m,2H)6.56(s,1H)4.69(s,2H)4.13(s,2H)2.70(s,3H)2.02-2.02(m,1H)2.03(s,3H) 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.71 (s, 1H) 8.02 (d, J = 8.0 Hz, 1H) 7.81-7.71 (m, 2H) 7.36-7.20 (m, 2H) 6.56 (s, 1H) 4.69(s,2H)4.13(s,2H)2.70(s,3H)2.02-2.02(m,1H)2.03(s,3H)
实施例17：化合物17Example 17: Compound 17
Figure PCTCN2019070227-appb-000116
Figure PCTCN2019070227-appb-000116
合成路线：synthetic route:
Figure PCTCN2019070227-appb-000117
Figure PCTCN2019070227-appb-000117
步骤1：化合物17-A的合成Step 1: Synthesis of Compound 17-A
将化合物13-B(800.00mg,3.52mmo)，环丙基氟硼酸钾(782.07mg,5.28mmol)，三(二亚苄基丙酮)二钯(322.64mg,352.33μmol)，2-二环己基磷-2,4,6-三异丙基联苯(335.93mg,704.66μmol)和磷酸钾(2.24g,10.57mmol)加入到二氧六环(10.00mL)和水(1.00mL)溶液中，在用氮气进行除气和净化3次,混合体系在80℃的氮气氛围下搅拌14小时后。浓缩，盐酸(2N，50mL)加入到反应体系中，用乙酸乙酯(50mL×2)萃取，水相加入氢氧化钠(10％，100mL)调节pH＝11,用乙酸乙酯(50mL×2)萃取，用饱和食盐水(50mL)洗涤，无水硫酸钠干燥。减压浓缩得到粗品，无需纯化得到化合物17-A。Compound 13-B (800.00 mg, 3.52 mmol), potassium cyclopropyl fluoroborate (782.07 mg, 5.28 mmol), tris(dibenzylideneacetone) dipalladium (322.64 mg, 352.33 μmol), 2-dicyclohexyl Phosphorus-2,4,6-triisopropylbiphenyl (335.93 mg, 704.66 μmol) and potassium phosphate (2.24 g, 10.57 mmol) were added to a solution of dioxane (10.00 mL) and water (1.00 mL). After degassing and purifying three times with nitrogen, the mixed system was stirred under a nitrogen atmosphere at 80 ° C for 14 hours. Concentrated, hydrochloric acid (2N, 50 mL) was added to the reaction system, extracted with ethyl acetate (50 mL×2), and the aqueous phase was adjusted to pH=11 with sodium hydroxide (10%, 100 mL), with ethyl acetate (50 mL×2) The extract was washed with brine (50 mL) and dried over anhydrous sodium sulfate. Concentration under reduced pressure gave a crude material which was obtained without purification.
MS m/z:189.0[M+H] + MS m/z: 189.0 [M+H] +
步骤2：化合物17-B的合成Step 2: Synthesis of Compound 17-B
将亚硝酸钠(109.97mg,1.59mmol)溶于水(1mL)中滴加到0℃下的化合物17-A(100.00mg,1.85mmol)的二甲基甲酰胺(4mL)和盐酸(1mL)溶液中，反应体系在此温度下搅拌0.5小时，碘化钾(881.90mg,5.31mmol)加入反应体系，并在20℃下搅拌1.0小时。氢氧化钠(10％，50mL)加入到反应体系中，用乙酸乙酯(50mL×2)萃取，用饱和食盐水(50mL)洗涤，无水硫酸钠干燥。减压浓缩得到粗品，粗品经制备TLC(石油醚/乙酸乙酯，1/1)分离得到化合物17-B。Sodium nitrite (109.97 mg, 1.59 mmol) was dissolved in water (1 mL) and EtOAc (1 mL) (1 mL) In the solution, the reaction system was stirred at this temperature for 0.5 hour, potassium iodide (881.90 mg, 5.31 mmol) was added to the reaction system, and stirred at 20 ° C for 1.0 hour. Sodium hydroxide (10%, 50 mL) was added to the reaction mixture. EtOAc (EtOAc m. Concentration under reduced pressure gave the crude material. EtOAc m.
MS m/z:299.9[M+H] + MS m/z: 299.9 [M+H] +
步骤3：化合物17的合成Step 3: Synthesis of Compound 17
将化合物17-B(50.00mg,167.16umo)，化合物II(65.73mg,167.16μmol)，三(二亚苄基丙酮)二钯(30.61mg,33.43μmol)，2-二环己基磷-2,4,6-三异丙基联苯(31.88mg,66.87μmol)和磷酸钾(106.45mg,501.49μmol)加入到二氧六环(10.00mL)和水(1.00mL)溶液中，在用氮气进行除气和净化3次,混合体系在70℃的氮气氛围下搅拌4小时后，过滤并浓缩得到粗品，粗品经制备HPLC(中性，乙腈和水)分离得到化合物17。Compound 17-B (50.00 mg, 167.16 umo), compound II (65.73 mg, 167.16 μmol), tris(dibenzylideneacetone)dipalladium (30.61 mg, 33.43 μmol), 2-dicyclohexylphosphorane-2, 4,6-Triisopropylbiphenyl (31.88 mg, 66.87 μmol) and potassium phosphate (106.45 mg, 501.49 μmol) were added to a solution of dioxane (10.00 mL) and water (1.00 mL) under nitrogen. After degassing and purifying 3 times, the mixed system was stirred under a nitrogen atmosphere at 70 ° C for 4 hours, filtered and concentrated to give a crude product which was obtained by preparative HPLC (neutral, acetonitrile and water).
MS m/z:439.0[M+H] + MS m/z: 439.0 [M+H] +
1H NMR(400MHz,CD 3OD)δppm 8.71(s,1H)8.02(d,J＝7.5Hz,1H)7.83-7.69(m,2H)7.26(d,J＝7.8Hz,1H)6.94(d,J＝8.0Hz,1H)6.56(s,1H)4.60(br s,2H)4.17-4.08(m,3H)2.02(d,J＝3.5Hz,3H)1.24(t,J＝7.2Hz,2H)1.16-1.04(m,2H) 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.71 (s, 1H) 8.02 (d, J = 7.5 Hz, 1H) 7.83 - 7.69 (m, 2H) 7.26 (d, J = 7.8 Hz, 1H) 6.94 (d) , J=8.0Hz, 1H) 6.56(s,1H)4.60(br s,2H)4.17-4.08(m,3H)2.02(d,J=3.5Hz,3H)1.24(t,J=7.2Hz,2H )1.16-1.04(m,2H)
实施例18：化合物18Example 18: Compound 18
Figure PCTCN2019070227-appb-000118
Figure PCTCN2019070227-appb-000118
合成路线：synthetic route:
Figure PCTCN2019070227-appb-000119
Figure PCTCN2019070227-appb-000119
步骤1：化合物18-B的合成Step 1: Synthesis of Compound 18-B
将化合物18-A(500mg,2.41mmol)溶于N-甲基吡咯烷酮(10mL)中，向其中分别加入环庚胺(272mg,2.41mmol)，三乙胺(731.6mg,7.23mmol)，在110℃中搅拌3小时后，加入水(10mL)稀释，用乙酸乙酯(40mL)萃取，用饱和食盐水(5mL)洗涤，无水硫酸钠干燥，过滤干燥剂后，减压旋蒸出去溶剂得到粗品，粗品用柱层析(石油醚/乙酸乙酯＝10:1)纯化得到化合物18-B。Compound 18-A (500 mg, 2.41 mmol) was dissolved in N-methylpyrrolidone (10 mL), and then cycloheptylamine (272 mg, 2.41 mmol), triethylamine (731.6 mg, 7.23 mmol), After stirring for 3 hours at ° C, it was diluted with water (10 mL), EtOAc (EtOAc)EtOAc. The crude product was purified by column chromatography ( petroleum ether / ethyl acetate = 10:1) to afford compound 18-B.
MS m/z:283.9[M+H] + MS m/z: 283.9 [M+H] +
1H NMR(400MHz,CHLOROFORM-d)δppm 8.05-8.18(m,1H)4.94(br d,J＝7.03Hz,1H)3.90(dt,J＝8.34,4.24Hz,1H)2.34(s,3H)1.88-1.96(m,2H)1.52-1.61(m,4H)1.39-1.50(m,6H) 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.05-8.18 (m, 1H) 4.94 (brd, J = 7.03 Hz, 1H) 3.90 (dt, J = 8.34, 4.24 Hz, 1H) 2.34 (s, 3H) 1.88-1.96 (m, 2H) 1.52-1.61 (m, 4H) 1.39-1.50 (m, 6H)
步骤2：化合物18的合成Step 2: Synthesis of Compound 18
将化合物1-B溶于二氧六环(10mL)和H2O(1mL)中，向其中分别加入18-B(224.08mg,1.1mmol)，2-二环己基磷-2’,4’,6’-三异丙基联苯(67.01mg,140,75μmol)，磷酸钾(224.08mg,1.06mmol)，反应用氮气置换3次后，向其中加入三(二亚苄基丙酮)二钯(64.44mg,70.38μmol)，反应在氮气保护下90℃下搅拌2小时后，将反应液减压旋蒸得到粗品，粗品用制备HPLC分离得到化合物18。Compound 1-B was dissolved in dioxane (10 mL) and H.sub.2O (1 mL), and 18-B (224.08 mg, 1.1 mmol), 2-dicyclohexylphosphorin-2', 4', '-Triisopropylbiphenyl (67.01 mg, 140, 75 μmol), potassium phosphate (224.08 mg, 1.06 mmol), after the reaction was replaced with nitrogen for 3 times, tris(dibenzylideneacetone)dipalladium (64.44) was added thereto. After the reaction was stirred at 90 ° C for 2 hours under a nitrogen atmosphere, the reaction mixture was evaporated under reduced pressure to give a crude material.
MS m/z:337.1[M+H] + MS m/z: 337.1 [M+H] +
1H NMR(400MHz,METHANOL-d 4)δppm 7.85(dd,J＝7.53,1.00Hz,1H)7.58-7.71(m,1H)7.48-7.56(m, 1H)4.32(s,2H)4.06(br d,J＝4.02Hz,1H)2.20(s,3H)1.99-2.09(m,2H)1.54-1.78(m,10H) 1 H NMR (400 MHz, METHANOL-d 4 ) δ ppm 7.85 (dd, J = 7.53, 1.00 Hz, 1H) 7.58-7.71 (m, 1H) 7.48-7.56 (m, 1H) 4.32 (s, 2H) 4.06 (br d, J = 4.02 Hz, 1H) 2.20 (s, 3H) 1.99-2.09 (m, 2H) 1.54-1.78 (m, 10H)
实施例19：化合物19Example 19: Compound 19
Figure PCTCN2019070227-appb-000120
Figure PCTCN2019070227-appb-000120
合成路线：synthetic route:
Figure PCTCN2019070227-appb-000121
Figure PCTCN2019070227-appb-000121
合成路线：synthetic route:
步骤1：化合物19-B的合成Step 1: Synthesis of Compound 19-B
将19-A(20mg,96.87μmol)与环庚胺(267mg,2.36mol)混合，在160℃，氮气保护下，密闭封管反应6小时后，向其中加入水(3mL)，用乙酸乙酯(15mL)萃取，饱和食盐水(3mL)洗涤，硫酸钠干燥，过滤后减压旋蒸得到粗品，粗品用制备TLC(石油醚:乙酸乙酯＝10:1)纯化得到透明油状化合物19-B。19-A (20 mg, 96.87 μmol) was mixed with cycloheptylamine (267 mg, 2.36 mol), and sealed at 600 ° C under nitrogen for 6 hours, then water (3 mL) was added thereto, and ethyl acetate was added. (15 mL), EtOAc (3 mL), EtOAc (EtOAc) (HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH .
MS m/z:282.9[M+H] + MS m/z: 282.9 [M+H] +
步骤2：化合物19的合成Step 2: Synthesis of Compound 19
将化合物19-B溶于二氧六环(10mL)和H 2O(1mL)中，向其中分别加入1-B(10.06mg,38.84μmol)，2-二环己基磷-2’,4’,6’-三异丙基联苯(7.41mg,15.54μmol)，磷酸钾(24.73mg,116.52μmol)，反应用氮气置换3次后，向其中加入三(二亚苄基丙酮)二钯(7.11mg,7.77μmol)，反应在氮气保护下90℃下搅拌2小时后，将反应液减压旋蒸得到粗品，粗品用制备HPLC分离后，加入饱和碳酸氢钠溶液调节pH至9后，用乙酸乙酯(20mL)萃取，饱和食盐水(5mL)洗涤，硫酸钠干燥，过滤旋蒸得到化合物19。 Compound 19-B was dissolved in dioxane (10 mL) and H 2 O (1 mL), and 1-B (10.06 mg, 38.84 μmol), 2-dicyclohexylphosphon-2', 4', respectively, were added thereto. , 6'-triisopropylbiphenyl (7.41 mg, 15.54 μmol), potassium phosphate (24.73 mg, 116.52 μmol), and after the reaction was replaced with nitrogen for 3 times, tris(dibenzylideneacetone)dipalladium was added thereto. 7.11mg, 7.77μmol), the reaction was stirred under nitrogen for 2 hours at 90 ° C, the reaction solution was evaporated under reduced pressure to give a crude product. The crude product was separated by preparative HPLC and then adjusted to pH 9 with saturated sodium hydrogen carbonate solution. Ethyl acetate (20 mL) was extracted, washed with brine (5 mL)
MS m/z:336.1[M+H] + MS m/z: 336.1 [M+H] +
1H NMR(400MHz,METHANOL-d 4)δppm 7.68-7.74(m,1H)7.63(s,1H)7.49(t,J＝7.53Hz,1H)7.36(dd,J＝7.53,1.00Hz,1H)6.34-6.43(m,1H)4.11-4.22(m,2H)3.68-3.83(m,1H)1.94(s,3H)1.44-1.65(m,12H) 1 H NMR (400 MHz, METHANOL-d 4 ) δ ppm 7.68-7.74 (m, 1H) 7.63 (s, 1H) 7.49 (t, J = 7.53 Hz, 1H) 7.36 (dd, J = 7.53, 1.00 Hz, 1H) 6.34-6.43(m,1H)4.11-4.22(m,2H)3.68-3.83(m,1H)1.94(s,3H)1.44-1.65(m,12H)
实施例20：化合物20Example 20: Compound 20
Figure PCTCN2019070227-appb-000122
Figure PCTCN2019070227-appb-000122
合成路线synthetic route
Figure PCTCN2019070227-appb-000123
Figure PCTCN2019070227-appb-000123
步骤1：化合物20的合成Step 1: Synthesis of Compound 20
将13(50.00mg,104.76μmol)溶于N,N-二甲基甲酰胺(2mL)，向其中加入20-A(34.83mg,419.04μmol)，碘化亚铜(2.00mg,10.48μmol)，向反应中吹入氮气后加入双三苯基膦二氯化钯(7.35mg,10.48μmol)，反应在氮气保护下100℃微波反应3小时后，所得混合物用制备HPLC分离得到粗品并用制备TLC(二氯甲烷:甲醇＝10:1)纯化得到化合物20。13 (50.00 mg, 104.76 μmol) was dissolved in N,N-dimethylformamide (2 mL), and 20-A (34.83 mg, 419.04 μmol), cuprous iodide (2.00 mg, 10.48 μmol) was added thereto. After nitrogen gas was blown into the reaction, bistriphenylphosphine palladium dichloride (7.35 mg, 10.48 μmol) was added, and the reaction was subjected to microwave reaction at 100 ° C for 3 hours under a nitrogen atmosphere, and the resulting mixture was separated by preparative HPLC to give a crude product. Methylene chloride:methanol = 10:1) was purified to give compound 20.
MS m/z:480.0[M+H] + MS m/z: 480.0 [M+H] +
1H NMR(400MHz,CHLOROFORM-d)δppm 8.57-8.75(m,1H)7.77-7.89(m,2H)7.60(d,J＝8.03Hz,1H)7.51(d,J＝7.53Hz,1H)7.25(d,J＝7.53Hz,1H)6.27-6.37(m,2H)4.97(s,1H)4.65(d,J＝6.02Hz,2H)4.11(s,2H)3.76(s,2H)2.64(s,6H)1.97(s,3H) 1 H NMR (400MHz, CHLOROFORM- d) δppm 8.57-8.75 (m, 1H) 7.77-7.89 (m, 2H) 7.60 (d, J = 8.03Hz, 1H) 7.51 (d, J = 7.53Hz, 1H) 7.25 (d, J = 7.53 Hz, 1H) 6.27-6.37 (m, 2H) 4.97 (s, 1H) 4.65 (d, J = 6.02 Hz, 2H) 4.11 (s, 2H) 3.76 (s, 2H) 2.64 (s , 6H) 1.97 (s, 3H)
实施例21：化合物21Example 21: Compound 21
Figure PCTCN2019070227-appb-000124
Figure PCTCN2019070227-appb-000124
合成路线：synthetic route:
Figure PCTCN2019070227-appb-000125
Figure PCTCN2019070227-appb-000125
步骤1：化合物21-B的合成Step 1: Synthesis of Compound 21-B
将化合物21-A(500.00mg,3.01mmol)，碳酸钾(1.04g,7.52mmol)和碘乙烷(469.28mg,3.01mmol)溶解在N,N-二甲基甲酰胺(10.00mL)中，反应液在40℃下搅拌12小时。加水(20mL)稀释，用乙酸乙酯(40mL)萃取，有机相用饱和食盐水(20mL)洗涤，无水硫酸钠干燥。滤去干燥剂后，减压除去溶剂得到化合物21-B。Compound 21-A (500.00 mg, 3.01 mmol), potassium carbonate (1.04 g, 7.52 mmol) and ethyl iodide (469.28 mg, 3.01 mmol) were dissolved in N,N-dimethylformamide (10.00 mL). The reaction solution was stirred at 40 ° C for 12 hours. It was diluted with water (20 mL), EtOAc (EtOAc) After filtering off the desiccant, the solvent was removed under reduced pressure to give Compound 21-B.
1H NMR(400MHz,CDCl 3)δppm 7.21(t,J＝8.03Hz,1H)6.77(dd,J＝15.94,7.91Hz,2H)4.05(q,J＝7.03Hz,2H)3.89-3.94(s,3H)2.26-2.32(s,3H)1.37(t,J＝7.03Hz,3H) 1 H NMR (400 MHz, CDCl 3 ) δ ppm 7.21 (t, J = 8.03 Hz, 1H) 6.77 (dd, J = 15.94, 7.91 Hz, 2H) 4.05 (q, J = 7.03 Hz, 2H) 3.89-3.94 (s , 3H) 2.26-2.32 (s, 3H) 1.37 (t, J = 7.03 Hz, 3H)
步骤2：化合物21-C的合成Step 2: Synthesis of Compound 21-C
除了使用相应的原料外，以中间体I中的制备化合物I-C相同的方法制备化合物21-C。Compound 21-C was prepared in the same manner as in the preparation of compound I-C in Intermediate I, except that the corresponding materials were used.
1H NMR(400MHz,CDCl 3)δppm 7.48(d,J＝8.78Hz,1H)6.65(d,J＝9.03Hz,1H)4.03(q,J＝7.03Hz,2H)3.92(s,3H)2.32(s,3H)1.37(t,J＝7.03Hz,3H) 1 H NMR (400MHz, CDCl 3 ) δppm 7.48 (d, J = 8.78Hz, 1H) 6.65 (d, J = 9.03Hz, 1H) 4.03 (q, J = 7.03Hz, 2H) 3.92 (s, 3H) 2.32 (s, 3H) 1.37 (t, J = 7.03 Hz, 3H)
步骤3：化合物21-D的合成Step 3: Synthesis of Compound 21-D
将化合物21-C(500.00mg,1.83mmol)，NBS(358.41mg,2.01mmol)和过氧化苯甲酰(110.82mg,457.50μmol)溶解在四氯化碳(10.00mL)中，反应液在80℃下搅拌12小时。减压除去溶剂得到粗品。粗品使用过柱机(石油醚/乙酸乙酯＝3/1)纯化得到化合物21-D。Compound 21-C (500.00 mg, 1.83 mmol), NBS (358.41 mg, 2.01 mmol) and benzoyl peroxide (110.82 mg, 457.50 μmol) were dissolved in carbon tetrachloride (10.00 mL). Stir at °C for 12 hours. The solvent was removed under reduced pressure to give a crude material. The crude product was purified using a column chromatography ( petroleum ether / ethyl acetate = 3/1) to afford compound 21-D.
步骤4：化合物21-E的合成Step 4: Synthesis of Compound 21-E
除了使用相应的原料外，以中间体I中的制备化合物I-E相同的方法制备化合物21-E。Compound 21-E was prepared in the same manner as in the preparation of compound I-E in Intermediate I, except that the corresponding materials were used.
1H NMR(400MHz,CD3OD)δppm 7.63(d,J＝8.78Hz,1H)6.99(d,J＝8.78Hz,1H)4.27(s,2H)4.19(q,J＝7.03Hz,2H)1.45(t,J＝7.03Hz,3H) 1 H NMR (400MHz, CD3OD) δppm 7.63 (d, J = 8.78Hz, 1H) 6.99 (d, J = 8.78Hz, 1H) 4.27 (s, 2H) 4.19 (q, J = 7.03Hz, 2H) 1.45 ( t, J=7.03Hz, 3H)
步骤5：化合物21-F的合成Step 5: Synthesis of Compound 21-F
除了使用相应的原料外，以中间体I中的制备化合物I-F相同的方法制备化合物21-F。Compound 21-F was prepared in the same manner as in the preparation of compound I-F in Intermediate I, except that the corresponding materials were used.
MS m/z:356.1[M+H] + MS m/z: 356.1 [M+H] +
步骤6：化合物21-G的合成Step 6: Synthesis of Compound 21-G
除了使用相应的原料外，以中间体I中的制备化合物I相同的方法制备化合物21-G。Compound 21-G was prepared in the same manner as in the preparation of Compound I in Intermediate I, except that the corresponding materials were used.
MS m/z:404.2[M+H] + MS m/z: 404.2 [M+H] +
步骤7：化合物21-H的合成Step 7: Synthesis of Compound 21-H
将化合物II-B(171.67mg,495.93μmol)，21-G(200.00mg,495.93μmol)，磷酸钾(315.81mg,1.49mmol)和XPhos(47.28mg,99.19μmol)溶解在水(500.00μL)和1,4-二氧六环(5.00mL)中，在氮气保护下加入Pd 2(dba) 3(45.41mg,49.59μmol)，反应液在90℃搅拌2.5小时。加水(20mL)稀释，用乙酸乙酯(40mL)萃取，有机相用饱和食盐水(20mL)洗涤，无水硫酸钠干燥。滤去干燥剂后，减压除去溶剂得到粗品。通过制备TLC纯化(石油醚/四氢呋喃＝1/1)得到化合物21-H。 Compound II-B (171.67 mg, 495.93 μmol), 21-G (200.00 mg, 495.93 μmol), potassium phosphate (315.81 mg, 1.49 mmol) and XPhos (47.28 mg, 99.19 μmol) were dissolved in water (500.00 μL) and To 1,4-dioxane (5.00 mL), Pd 2 (dba) 3 (45.41 mg, 49.59 μmol) was added under a nitrogen atmosphere, and the reaction mixture was stirred at 90 ° C for 2.5 hours. It was diluted with water (20 mL), EtOAc (EtOAc) After filtering off the desiccant, the solvent was removed under reduced pressure to give a crude material. Purification by preparative TLC (petroleum ether / tetrahydrofuran = 1 / 1) gave compound 21-H.
MS m/z:543.1[M+H] + MS m/z: 543.1 [M+H] +
步骤8：化合物21的合成Step 8: Synthesis of Compound 21
将化合物21-H(70.00mg,129.02μmol)溶解在三氟乙酸(1.00mL)和二氯甲烷(5.00mL)中，并在20℃搅拌0.5小时。将反应液浓缩，用饱和的碳酸氢钠调节pH＝7～8，用乙酸乙酯(20mL)萃取，有机相用饱和食盐水(20mL)洗涤，无水硫酸钠干燥。滤去干燥剂后，减压除去溶剂得到化合物21。Compound 21-H (70.00 mg, 129.02 μmol) was dissolved in trifluoroacetic acid (1.00 mL) and dichloromethane (5.00 mL) and stirred at 20 ° C for 0.5 hr. The reaction mixture was concentrated, EtOAc (EtOAc m. After filtering off the desiccant, the solvent was removed under reduced pressure to give Compound 21.
MS m/z:443.0[M+H] + MS m/z: 443.0 [M+H] +
1H NMR(400MHz,CD 3OD)δppm 8.70(s,1H)8.02(br d,J＝8.03Hz,1H)7.72-7.80(m,2H)7.33(d,J＝8.28Hz,1H)7.08(d,J＝8.53Hz,1H)6.56(s,1H)4.68(s,2H)4.24(q,J＝7.03Hz,2H)4.11(s,2H)2.03(s,3H)1.48(t,J＝7.03Hz,3H) 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.70 (s, 1H) 8.02 (brd, J = 8.03 Hz, 1H) 7.72 - 7.80 (m, 2H) 7.33 (d, J = 8.28 Hz, 1H) 7.08 ( d, J = 8.53 Hz, 1H) 6.56 (s, 1H) 4.68 (s, 2H) 4.24 (q, J = 7.03 Hz, 2H) 4.11 (s, 2H) 2.03 (s, 3H) 1.48 (t, J = 7.03Hz, 3H)
实施例22：化合物22Example 22: Compound 22
Figure PCTCN2019070227-appb-000126
Figure PCTCN2019070227-appb-000126
合成路线：synthetic route:
Figure PCTCN2019070227-appb-000127
Figure PCTCN2019070227-appb-000127
步骤1：化合物22-A的合成Step 1: Synthesis of Compound 22-A
除了使用相应的原料外，以中间体I中的制备化合物I-C相同的方法制备化合物22-A。Compound 22-A was prepared in the same manner as in the preparation of compound I-C in Intermediate I, except that the corresponding materials were used.
1H NMR(400MHz,CDCl 3)δppm 10.75(s,1H)7.49(d,J＝8.78Hz,1H)6.67(d,J＝8.78Hz,1H)3.87-3.92(m,3H)2.55(s,3H) 1 H NMR (400 MHz, CDCl 3 ) δ ppm 10.75 (s, 1H) 7.49 (d, J = 8.78 Hz, 1H) 6.67 (d, J = 8.78 Hz, 1H) 3.87-3.92 (m, 3H) 2.55 (s, 3H)
步骤2：化合物22-B的合成Step 2: Synthesis of Compound 22-B
除了使用相应的原料外，以实施例21中的制备化合物21-B相同的方法制备化合物22-B。Compound 22-B was prepared in the same manner as in the preparation of compound 21-B in Example 21 except that the corresponding materials were used.
步骤3：化合物22-C的合成Step 3: Synthesis of Compound 22-C
除了使用相应的原料外，以中间体I中的制备化合物I-D相同的方法制备化合物22-C。Compound 22-C was prepared in the same manner as in the preparation of compound I-D in Intermediate I, except that the corresponding materials were used.
步骤4：化合物22-D的合成Step 4: Synthesis of Compound 22-D
除了使用相应的原料外，以中间体I中的制备化合物I-E相同的方法制备化合物22-D。Compound 22-D was prepared in the same manner as in the preparation of compound I-E in Intermediate I, except that the corresponding materials were used.
MS m/z:285.8[M+H] + MS m/z: 285.8 [M+H] +
步骤5：化合物22的合成Step 5: Synthesis of Compound 22
将化合物22-D(50.00mg,175.99μmol)，II(103.80mg,263.99μmol)，磷酸钾(112.07mg,527.96μmol)和XPhos(16.78mg,35.20μmol)溶解在水(500.00μL)和1,4-二氧六环(5.00mL)中，在氮气保护下加入Pd 2(dba) 3(16.12mg,17.60μmol)，反应液在110℃微波反应10分钟。加水(20mL)稀释，用乙酸乙酯(40mL)萃取，有机相用饱和食盐水(20mL)洗涤，无水硫酸钠干燥。滤去干燥剂后，减压除去溶剂得到粗品。通过中性制备HPLC(乙腈和水)纯化得到化合物22。 Compound 22-D (50.00 mg, 175.99 μmol), II (103.80 mg, 263.99 μmol), potassium phosphate (112.07 mg, 527.96 μmol) and XPhos (16.78 mg, 35.20 μmol) were dissolved in water (500.00 μL) and 1, To 4-dioxane (5.00 mL), Pd 2 (dba) 3 (16.12 mg, 17.60 μmol) was added under a nitrogen atmosphere, and the reaction solution was subjected to microwave reaction at 110 ° C for 10 minutes. It was diluted with water (20 mL), EtOAc (EtOAc) After filtering off the desiccant, the solvent was removed under reduced pressure to give a crude material. Purification by neutral preparative HPLC (acetonitrile and water) gave compound 22.
MS m/z:470.1[M+H] + MS m/z: 470.1 [M+H] +
1H NMR(400MHz,CD3OD)δppm 8.72(s,1H)8.04(br d,J＝8.03Hz,1H)7.71-7.85(m,2H)7.34(br d,J＝8.28Hz,1H)6.71(br d,J＝8.28Hz,1H)6.58(s,1H)5.41-5.50(m,1H)5.07(br t,J＝6.53Hz,4H)4.70(s,2H)4.16(s,2H)2.05(s,3H) 1 H NMR (400 MHz, CD3 OD) δ ppm 8.72 (s, 1H) 8.04 (brd, J = 8.03 Hz, 1H) 7.71 - 7.85 (m, 2H) 7.34 (brd, J = 8.28 Hz, 1H) 6.71 (br d, J = 8.28 Hz, 1H) 6.58 (s, 1H) 5.41-5.50 (m, 1H) 5.07 (br t, J = 6.53 Hz, 4H) 4.70 (s, 2H) 4.16 (s, 2H) 2.05 (s , 3H)
实施例23：化合物23Example 23: Compound 23
Figure PCTCN2019070227-appb-000128
Figure PCTCN2019070227-appb-000128
合成路线：synthetic route:
Figure PCTCN2019070227-appb-000129
Figure PCTCN2019070227-appb-000129
步骤1：化合物23-A的合成Step 1: Synthesis of Compound 23-A
将2-溴乙基甲醚(293.27mg,2.11mmol)溶于N,N-二甲基甲酰胺(15mL)中，向其中加入21-A(350.00mg,2.11mmol)和碳酸钾(874.87mg,6.33mmol)，反应在50℃下搅拌2小时后，在60℃下搅拌1小时，向其中加入水(30mL)，用乙酸乙酯(50mL)萃取，饱和食盐水(10mL)洗涤，硫酸钠干燥，过滤干燥剂，减压浓缩得到粗品，粗品用柱层析(石油醚/乙酸乙酯＝20/1)纯化得到化合物23-A。2-Bromoethyl methyl ether (293.27 mg, 2.11 mmol) was dissolved in N,N-dimethylformamide (15 mL), and 21-A (350.00 mg, 2.11 mmol) and potassium carbonate (874.87 mg) were added thereto. After the reaction was stirred at 50 ° C for 2 hours, the mixture was stirred at 60 ° C for 1 hour, water (30 mL) was added thereto, and extracted with ethyl acetate (50 mL), brine (10 mL) Drying, filtration of the drying agent, EtOAc (EtOAc:EtOAc)
1H NMR(400MHz,CHLOROFORM-d)δppm 7.15(t,J＝8.03Hz,1H)6.72(dd,J＝14.56,8.03Hz,2H)4.03-4.11(m,2H)3.83(s,3H)3.60-3.69(m,2H)3.36(s,3H)2.22(s,3H) 1 H NMR (400MHz, CHLOROFORM- d) δppm 7.15 (t, J = 8.03Hz, 1H) 6.72 (dd, J = 14.56,8.03Hz, 2H) 4.03-4.11 (m, 2H) 3.83 (s, 3H) 3.60 -3.69(m,2H)3.36(s,3H)2.22(s,3H)
步骤2：化合物23-B的合成Step 2: Synthesis of Compound 23-B
将23-A(863.00mg,3.85mmol)溶于二氯甲烷(15mL)中，在0℃下，向其中加入液溴(738.32mg,4.62mmol)，反应在0℃下搅拌1.5小时后，向其中加入水(10mL)，用二氯甲烷(40mL)萃取，饱和的硫代硫酸钠(10mL)洗涤，饱和食盐水(10mL)洗涤，硫酸钠干燥，过滤干燥剂，减压旋蒸得到粗品，粗品用柱层析(石油醚/乙酸乙酯＝2/1)纯化得到黄色液体化合物23-B。23-A (863.00 mg, 3.85 mmol) was dissolved in dichloromethane (15 mL), and liquid bromine (738.32 mg, 4.62 mmol) was added thereto at 0 ° C, and the reaction was stirred at 0 ° C for 1.5 hours. Water (10 mL) was added, and the mixture was washed with methylene chloride (40 mL), EtOAc (EtOAc) The crude product was purified by column chromatography (EtOAc /EtOAc)
1H NMR(400MHz,CDCl 3)δppm 7.34-7.61(m,1H)6.62(d,J＝8.53Hz,1H)4.02-4.06(m,2H)3.83(s,3H)3.61-3.66(m,2H)3.34(s,3H)2.24(s,3H) 1 H NMR (400 MHz, CDCl 3 ) δ ppm 7.34 - 7.61 (m, 1H) 6.62 (d, J = 8.53 Hz, 1H) 4.02-4.06 (m, 2H) 3.83 (s, 3H) 3.61-3.66 (m, 2H) ) 3.34(s,3H)2.24(s,3H)
步骤3：化合物23-C的合成Step 3: Synthesis of Compound 23-C
将23-B溶于四氯化碳(10mL)中，向其中加入N-溴代琥珀酰亚胺(683.44mg,3.84mmol)，过氧化苯甲酰 (77.51mg,320.00μmol)，反应在80℃下搅拌12小时后，将反应液减压旋蒸得到粗品，粗品用柱层析(石油醚/乙酸乙酯＝3/1)纯化得到化合物23-C并回收原料。23-B was dissolved in carbon tetrachloride (10 mL), and N-bromosuccinimide (683.44 mg, 3.84 mmol), benzoyl peroxide (77.51 mg, 320.00 μmol) was added thereto, and the reaction was carried out at 80. After stirring at ° C for 12 hours, the reaction mixture was evaporated to dryness crystals crystals crystals
1H NMR(400MHz,CDCl 3)δppm 7.48(d,J＝8.53Hz,1H)6.76(d,J＝9.03Hz,1H)4.51(s,2H)4.06(t,J＝4.77Hz,2H)3.88(s,3H)3.60-3.66(m,2H)3.34(s,3H) 1 H NMR (400 MHz, CDCl 3 ) δ ppm 7.48 (d, J = 8.53 Hz, 1H) 6.76 (d, J = 9.03 Hz, 1H) 4.51 (s, 2H) 4.06 (t, J = 4.77 Hz, 2H) 3.88 (s, 3H) 3.60-3.66 (m, 2H) 3.34 (s, 3H)
步骤4：化合物23-D的合成Step 4: Synthesis of Compound 23-D
将23-C(135.00mg,353.37μmol)溶于乙腈(10mL)中，向其中加入氨水(910.00mg,25.96mmol)，反应在20℃下搅拌1.5小时后，将其减压旋蒸干得到粗品化合物23-D(130.00mg)直接用于下一步反应。23-C (135.00 mg, 353.37 μmol) was dissolved in acetonitrile (10 mL), and aqueous ammonia (910.00 mg, 25.96 mmol) was added thereto, and the mixture was stirred at 20 ° C for 1.5 hours, and then evaporated to dryness under reduced pressure. Compound 23-D (130.00 mg) was used directly in the next step.
MS m/z:285.7[M+H] + MS m/z: 285.7 [M+H] +
步骤5：化合物23-E的合成Step 5: Synthesis of Compound 23-E
将23-D(200.00mg,699.01μmol)溶于四氢呋喃(10mL)，向其中加入Boc酸酐(305.12mg,1.40mmol)，4-二甲氨基吡啶(128.10mg,1.05mmol)，三乙胺(212.20mg,2.10mmol)，反应在80℃下搅拌2小时后，将反应液减压旋蒸得到粗品，粗品用柱层析(石油醚/四氢呋喃＝1/1)纯化得到粗品23-E直接投入到下一步反应。23-D (200.00 mg, 699.01 μmol) was dissolved in tetrahydrofuran (10 mL), and Boc anhydride (305.12 mg, 1.40 mmol), 4-dimethylaminopyridine (128.10 mg, 1.05 mmol), triethylamine (212.20) was added thereto. After the reaction was stirred at 80 ° C for 2 hours, the reaction mixture was evaporated to dryness crystalsjjjjjjjjjjjjjjjjjjjjjjjjjjjj The next step is to react.
步骤6：化合物23-F的合成Step 6: Synthesis of Compound 23-F
将23-E(115.00mg,297.74μmol)溶于二氧六环(10mL)中，向其中加入双联频哪醇硼酸酯(113.41mg,446.61μmol)和醋酸钾(87.66mg,893.22μmol)，反应用氮气置换3次后，加入[1,1’-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(24.31mg,29.77μmol)后，反应在90℃下搅拌12小时后，向反应液中加入水(10mL)，用乙酸乙酯(40mL)萃取，饱和食盐水(5mL)洗涤，硫酸钠干燥，过滤干燥剂并减压旋蒸得到粗品，粗品用柱层析(石油醚/四氢呋喃＝1/1)纯化得到粗品化合物23-F并直接投入下一步反应。23-E (115.00 mg, 297.74 μmol) was dissolved in dioxane (10 mL), and bispinacol borate (113.41 mg, 446.61 μmol) and potassium acetate (87.66 mg, 893.22 μmol) were added thereto. After the reaction was replaced with nitrogen for 3 times, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (24.31 mg, 29.77 μmol) was added, and the reaction was carried out at 90 ° C. After stirring for 12 hours, water (10 mL) was added to the mixture, and the mixture was evaporated. Column chromatography (petroleum ether / tetrahydrofuran = 1 / 1) was purified to give the crude compound 23-F and was taken directly to the next reaction.
步骤7：化合物23-G的合成Step 7: Synthesis of Compound 23-G
将23-F(80.00mg,184.63μmol)和II-B(63.9mg,184.63μmol)溶于二氧六环(10mL)和水(1mL)中，向其中加入2-二环己基磷-2’,4’,6’-三异丙基联苯(35.21mg,73.85μmol)，磷酸钾(117.57mg,553.89μmol)，反应用氮气置换3次后，向其中加入三(二亚苄基丙酮)二钯(33.81mg,36.93μmol)，反应在氮气保护下90℃下搅拌12小时后，向其中加入水(10mL)，用二氯甲烷(40mL)萃取，饱和食盐水(5mL)洗涤，硫酸钠干燥，过滤干燥剂，减压旋蒸得到粗品，粗品用制备TLC(石油醚/四氢呋喃＝1/1)纯化得到23-G。23-F (80.00 mg, 184.63 μmol) and II-B (63.9 mg, 184.63 μmol) were dissolved in dioxane (10 mL) and water (1 mL), and 2-dicyclohexylphosphorane-2' was added thereto. 4',6'-triisopropylbiphenyl (35.21 mg, 73.85 μmol), potassium phosphate (117.57 mg, 553.89 μmol), after the reaction was replaced with nitrogen for 3 times, tris(dibenzylideneacetone) was added thereto. Di-palladium (33.81 mg, 36.93 μmol), the reaction was stirred at 90 ° C for 12 hours under a nitrogen atmosphere, then water (10 mL) was added and extracted with dichloromethane (40 mL), brine (5 mL) Drying, filtration of the desiccant, EtOAc (EtOAc) m.
MS m/z:573.2[M+H] + MS m/z: 573.2 [M+H] +
步骤8：化合物23的合成Step 8: Synthesis of Compound 23
将23-G(19.00mg,33.18μmol)溶于二氯甲烷(2.5mL)中，向其中加入三氟乙酸(770.00mg,6.75mmol)，反应在16℃下搅拌40分钟后，将反应液减压旋蒸得到粗品，粗品用制备HPLC(中性,乙腈和水)分离得到化合物12。23-G (19.00 mg, 33.18 μmol) was dissolved in dichloromethane (2.5 mL), trifluoroacetic acid (770.00 mg, 6.75 mmol) was added thereto, and the reaction was stirred at 16 ° C for 40 minutes, then the reaction solution was reduced. The crude product was obtained by trituration. The crude material was purified using preparative HPLC (neut, acetonitrile and water).
MS m/z:473.0[M+H] + MS m/z: 473.0 [M+H] +
1H NMR(400MHz,CD 3OD)δppm 8.64-8.78(m,1H)8.04(d,J＝7.03Hz,1H)7.71-7.85(m,2H)7.36(d, J＝8.53Hz,1H)7.14(d,J＝8.53Hz,1H)6.58(s,1H)4.66-4.77(m,2H)4.28-4.38(m,2H)4.14(s,2H)3.84-3.91(m,2H)3.48(s,3H)2.05(s,3H) 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.64-8.78 (m, 1H) 8.04 (d, J = 7.03 Hz, 1H) 7.71-7.85 (m, 2H) 7.36 (d, J = 8.53 Hz, 1H) 7.14 (d, J = 8.53 Hz, 1H) 6.58 (s, 1H) 4.66 - 4.77 (m, 2H) 4.28 - 4.38 (m, 2H) 4.14 (s, 2H) 3.84 - 3.91 (m, 2H) 3.48 (s, 3H)2.05(s,3H)
实施例24：化合物24Example 24: Compound 24
Figure PCTCN2019070227-appb-000130
Figure PCTCN2019070227-appb-000130
合成路线：synthetic route:
Figure PCTCN2019070227-appb-000131
Figure PCTCN2019070227-appb-000131
步骤1：化合物24-A的合成Step 1: Synthesis of Compound 24-A
将21-A(20.00mg,130.70μmol)溶于N,N-二甲基甲酰胺(6mL)中，向其中加入2-溴丙基甲醚(21.72mg，130.70μmol)，碳酸钾(54.19mg,392.10μmol)，反应在氮气保护下，50℃搅拌2小时后，向其中加入水(20mL)，用乙酸乙酯(30mL)萃取，饱和食盐水(5mL)洗涤，硫酸钠干燥，过滤干燥剂，减压旋蒸得到粗品为化合物24-A。21-A (20.00 mg, 130.70 μmol) was dissolved in N,N-dimethylformamide (6 mL), and 2-bromopropyl methyl ether (21.72 mg, 130.70 μmol), potassium carbonate (54.19 mg) was added thereto. , 392.10 μmol), the reaction was stirred under nitrogen for 2 hours at 50 ° C, then water (20 mL) was added, extracted with ethyl acetate (30 mL), washed with brine (5 mL), dried over sodium sulfate The crude product was obtained by rotary distillation under reduced pressure to give Compound 24-A.
1H NMR(400MHz,CDCl 3)δppm 7.14(t,J＝8.03Hz,1H)6.66-6.74(m,2H)4.00(t,J＝6.27Hz,2H)3.83(s,3H)3.44(t,J＝6.27Hz,2H)3.27(s,3H)2.21(s,3H)1.94(quin,J＝6.15Hz,2H) 1 H NMR (400 MHz, CDCl 3 ) δ ppm 7.14 (t,J=8.03 Hz, 1H) 6.66-6.74 (m, 2H) 4.00 (t, J = 6.27 Hz, 2H) 3.83 (s, 3H) 3.44 (t, J = 6.27 Hz, 2H) 3.27 (s, 3H) 2.21 (s, 3H) 1.94 (quin, J = 6.15 Hz, 2H)
步骤2：化合物24-B的合成Step 2: Synthesis of Compound 24-B
将24-A(1.19g,4.99mmol)溶于二氯甲烷(15mL)中，在0℃下搅拌10分钟后，滴加液溴(957.73mg,5.99mmol)，反应保持在0℃下搅拌120分钟后，向其中加入水(20mL)，用二氯甲烷(40mL)萃取，饱和的硫代硫酸钠溶液(10mL)洗涤，饱和食盐水(10mL)洗涤，硫酸钠干燥，过滤干燥剂后减压浓缩得到粗品，粗品经柱层析(石油醚/乙酸乙酯＝2/1)纯化得到24-B。24-A (1.19 g, 4.99 mmol) was dissolved in dichloromethane (15 mL). After stirring at 0 ° C for 10 min, liquid bromine (957.73 mg, 5.99 mmol) was added dropwise and the reaction was kept at 0 ° C. After a few minutes, water (20 mL) was added, and the mixture was evaporated with methylene chloride (40 mL), washed with saturated sodium thiosulfate (10 mL), washed with brine (10 mL), dried over sodium sulfate Concentration gave a crude product which was purified by column chromatography (EtOAc /EtOAc
1H NMR(400MHz,CDCl 3)δppm 7.41(d,J＝9.03Hz,1H)6.60(d,J＝9.03Hz,1H)3.98(t,J＝6.27Hz,2H)3.84(s,3H)3.43(t,J＝6.02Hz,2H)3.26(s,3H)2.24(s,3H)1.93(quin,J＝6.15Hz,2H) 1 H NMR (400MHz, CDCl 3 ) δppm 7.41 (d, J = 9.03Hz, 1H) 6.60 (d, J = 9.03Hz, 1H) 3.98 (t, J = 6.27Hz, 2H) 3.84 (s, 3H) 3.43 (t, J = 6.02 Hz, 2H) 3.26 (s, 3H) 2.24 (s, 3H) 1.93 (quin, J = 6.15 Hz, 2H)
步骤3：化合物24-C的合成Step 3: Synthesis of Compound 24-C
将24-B(1.10g,3.47mmol)溶于四氯化碳(10mL)中，向其中加入N-溴代琥珀酰亚胺(741.11mg,4.16mmol)，过氧化苯甲酰(84.05mg,347.00μmol)，反应在80℃下搅拌12小时后，将反应混合液减压浓缩得到粗品，粗品经柱层析(石油醚/乙酸乙酯＝3/1)纯化得到粗品化合物24-C。24-B (1.10 g, 3.47 mmol) was dissolved in carbon tetrachloride (10 mL), and N-bromosuccinimide (741.11 mg, 4.16 mmol), benzoyl peroxide (84.05 mg, 347.00 μmol), the reaction was stirred at 80 ° C for 12 hr.
MS m/z:473.0[M+H] + MS m/z: 473.0 [M+H] +
1H NMR(400MHz,CDCl 3)δppm 7.52-7.59(m,1H)6.77-6.84(m,1H)4.58(s,2H)4.07(t,J＝6.02Hz,2H)3.96(s,3H)3.50(t,J＝6.02Hz,2H)3.34(s,3H)2.01(quin,J＝6.15Hz,2H) 1 H NMR (400MHz, CDCl 3 ) δppm 7.52-7.59 (m, 1H) 6.77-6.84 (m, 1H) 4.58 (s, 2H) 4.07 (t, J = 6.02Hz, 2H) 3.96 (s, 3H) 3.50 (t, J = 6.02 Hz, 2H) 3.34 (s, 3H) 2.01 (quin, J = 6.15 Hz, 2H)
步骤4：化合物24-D的合成Step 4: Synthesis of Compound 24-D
将24-C(118.00mg,297.93μmol)溶于乙腈(10mL)中，向其中加入氨水(910.00mg,25.96mmol)，反应在20℃下搅拌12小时后，将反应混合液减压浓缩得到粗品，粗品用(石油醚/乙酸乙酯/乙腈＝10/1/1)洗涤得到24-D。24-C (118.00 mg, 297.93 μmol) was dissolved in acetonitrile (10 mL), aqueous ammonia (910.00 mg, 25.96 mmol) was added thereto, and the mixture was stirred at 20 ° C for 12 hr. The crude product was washed with (petroleum ether / ethyl acetate / acetonitrile = 10/1 / 1) to afford 24-D.
1H NMR(400MHz CD 3OD)δppm 7.64-7.76(m,1H)7.04(d,J＝9.03Hz,1H)4.30(s,2H)4.22(t,J＝6.53Hz,2H)3.63(t,J＝6.27Hz,2H)3.36(s,3H)2.12(quin,J＝6.27Hz,2H) 1 H NMR (400 MHz CD 3 OD) δ ppm 7.64-7.76 (m, 1H) 7.04 (d, J = 9.03 Hz, 1H) 4.30 (s, 2H) 4.22 (t, J = 6.53 Hz, 2H) 3.63 (t, J=6.27Hz, 2H)3.36(s,3H)2.12 (quin, J=6.27Hz, 2H)
步骤5：化合物24-E的合成Step 5: Synthesis of Compound 24-E
将24-D溶于四氢呋喃(10mL)中，向其中加入(Boc) 2O(261.77mg,1.20mmol)，4-二甲氨基吡啶(73.26mg,599.70μmol)，三乙胺(182.05mg,1.80mmol)，反应在80℃下搅拌2小时后，向混合液中加入水(10mL)，用乙酸乙酯(50mL)萃取，饱和食盐水(10mL)洗涤，硫酸钠干燥，过滤干燥剂，减压浓缩得到粗品，粗品经柱层析(石油醚/四氢呋喃＝1/1)纯化得到粗品24-E。 24-D was dissolved in tetrahydrofuran (10 mL), and (Boc) 2 O (261.77 mg, 1.20 mmol), 4-dimethylaminopyridine (73.26 mg, 599.70 μmol), triethylamine (182.05 mg, 1.80) was added thereto. After the reaction was stirred at 80 ° C for 2 hours, water (10 mL) was added toEtOAc. Concentration gave the crude product which was purified eluted elut elut elut
步骤6：化合物24-F的合成Step 6: Synthesis of Compound 24-F
将24-E(170.00mg,424.72μmol)溶于二氧六环(12mL)中，向其中加入双联频哪醇硼酸酯(161.78mg,637.08μmol)和醋酸钾(125.05mg,1.27mmol)，反应用氮气置换3次后，加入[1,1’-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(34.68mg,42.47μmol)后，反应在氮气保护下90℃搅拌12小时后，向反应液中加入水(10mL)，用乙酸乙酯(40mL)萃取，饱和食盐水(10mL)洗涤，硫酸钠干燥，过滤干燥剂并减压浓缩得到粗品，粗品经柱层析(石油醚/四氢呋喃＝1/1)纯化得到粗品化合物24-F并直接投入下一步反应。24-E (170.00 mg, 424.72 μmol) was dissolved in dioxane (12 mL), and bis-pinacol borate (161.78 mg, 637.08 μmol) and potassium acetate (125.05 mg, 1.27 mmol) were added thereto. After the reaction was replaced with nitrogen for 3 times, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (34.68 mg, 42.47 μmol) was added, and the reaction was protected with nitrogen. After stirring at 90 ° C for 12 hours, water (10 mL) was added, and the mixture was evaporated, evaporated, evaporated. Purification by column chromatography (petroleum ether / tetrahydrofuran = 1 / 1) afforded crude compound 24-F and was taken directly to the next reaction.
步骤7：化合物24-G的合成Step 7: Synthesis of Compound 24-G
将24-F(120.00mg,268.26μmol)溶于二氧六环(10mL)和水(1mL)中，向其中加入化合物II-B(92.86mg,268.26μmol)，2-二环己基磷-2’,4’,6’-三异丙基联苯(51.15mg,107.30μmol)，磷酸钾(170.83mg,804.78μmol)，反应用氮气置换3次后，向其中加入三(二亚苄基丙酮)二钯(49.13mg,53.65μmol)，反应在氮气保护下90℃下搅拌12小时后，向其中加入水(10mL)，用二氯甲烷(40mL)萃取，饱和食盐水(10mL)洗涤，硫酸钠干 燥，过滤干燥剂，减压浓缩得到粗品，粗品用制备TLC(石油醚/四氢呋喃＝1/1)纯化得到24-G。24-F (120.00 mg, 268.26 μmol) was dissolved in dioxane (10 mL) and water (1 mL), and Compound II-B (92.86 mg, 268.26 μmol), 2-dicyclohexylphosphonium-2 was added thereto. ',4',6'-triisopropylbiphenyl (51.15 mg, 107.30 μmol), potassium phosphate (170.83 mg, 804.78 μmol), after the reaction was replaced with nitrogen for 3 times, tris(dibenzylideneacetone) was added thereto. Dipalladium (49.13 mg, 53.65 μmol), the reaction was stirred under nitrogen for 12 hours at 90 ° C, then water (10 mL) was added thereto, extracted with dichloromethane (40 mL), and brine (10 mL) The mixture was dried with sodium EtOAc (EtOAc m.)
MS m/z:587.2[M+H] + MS m/z: 587.2 [M+H] +
步骤8：化合物24的合成Step 8: Synthesis of Compound 24
将24-G(16.00mg,27.28μmol)溶于二氯甲烷(3mL)中，向其中加入三氟乙酸(924.00mg,8.10mmol)，反应在20℃下搅拌40分钟后，将反应液减压浓缩得到粗品，粗品用制备HPLC(中性,乙腈和水)分离得到化合物24。24-G (16.00 mg, 27.28 μmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (924.00 mg, 8.10 mmol) was added thereto, and the reaction was stirred at 20 ° C for 40 minutes, and then the reaction solution was evaporated. Concentration gave the crude product which was isolated using preparative HPLC (neut, EtOAc and water).
MS m/z:487.0[M+H] + MS m/z: 487.0 [M+H] +
1H NMR(400MHz,CD 3OD)δppm 8.59-8.78(m,1H)8.04(br d,J＝8.03Hz,1H)7.67-7.89(m,2H)7.36(d,J＝8.53Hz,1H)7.11(d,J＝8.53Hz,1H)6.58(s,1H)4.70(s,2H)4.26(t,J＝6.27Hz,2H)4.10-4.17(m,2H)3.66(t,J＝6.02Hz,2H)3.37(s,3H)2.15(quin,J＝6.27Hz,2H)2.06(s,3H) 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.59-8.78 (m, 1H) 8.04 (brd, J = 8.03 Hz, 1H) 7.67-7.89 (m, 2H) 7.36 (d, J = 8.53 Hz, 1H) 7.11 (d, J = 8.53 Hz, 1H) 6.58 (s, 1H) 4.70 (s, 2H) 4.26 (t, J = 6.27 Hz, 2H) 4.10 - 4.17 (m, 2H) 3.66 (t, J = 6.02 Hz) , 2H) 3.37 (s, 3H) 2.15 (quin, J = 6.27 Hz, 2H) 2.06 (s, 3H)
实施例25：化合物25Example 25: Compound 25
Figure PCTCN2019070227-appb-000132
Figure PCTCN2019070227-appb-000132
合成路线：synthetic route:
Figure PCTCN2019070227-appb-000133
Figure PCTCN2019070227-appb-000133
步骤1：化合物25-B的合成Step 1: Synthesis of Compound 25-B
将化合物25-A(200.00mg,1.06mmol)，2-三氟甲基吡啶-5-甲醛(186.26mg,1.06mmol)，三乙基硅(371.05mg,3.19mmol)，三氟乙酸(363.84mg,3.19mmol)溶解在乙腈(50.00mL)中，反应液在80℃搅拌12小时。将反应液浓缩，粗品经柱层析纯化(石油醚/四氢呋喃＝3/1)得到25-B。Compound 25-A (200.00 mg, 1.06 mmol), 2-trifluoromethylpyridine-5-carbaldehyde (186.26 mg, 1.06 mmol), triethylsilane (371.05 mg, 3.19 mmol), trifluoroacetic acid (363.84 mg) , 3.19 mmol) was dissolved in acetonitrile (50.00 mL), and the reaction mixture was stirred at 80 ° C for 12 hours. The reaction solution was concentrated, and the crude material was purified (jjjjjjjjj
MS m/z:346.8[M+H] + MS m/z: 346.8 [M+H] +
步骤2：化合物25-C的合成Step 2: Synthesis of Compound 25-C
除了使用相应的原料外，以实施例9中的制备化合物9-A相同的方法制备化合物25-C。Compound 25-C was prepared in the same manner as in the preparation of compound 9-A in Example 9 except that the corresponding materials were used.
MS m/z:530.3[M+H] + MS m/z: 530.3 [M+H] +
步骤3：化合物25的合成Step 3: Synthesis of Compound 25
除了使用相应的原料外，以实施例9中的制备化合物9相同的方法制备化合物25。Compound 25 was prepared in the same manner as in the preparation of compound 9 in Example 9 except that the corresponding materials were used.
1H NMR(400MHz,CD 3OD)δppm 8.75(s,1H)8.04-8.13(m,2H)7.80(d,J＝8.03Hz,1H)7.42(d,J＝8.28Hz,1H)7.14(d,J＝8.53Hz,1H)4.76(s,2H)4.64(br s,1H)4.19(s,2H)3.98(s,3H)2.19(s,3H) 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.75 (s, 1H) 8.04 - 8.13 (m, 2H) 7.80 (d, J = 8.03 Hz, 1H) 7.42 (d, J = 8.28 Hz, 1H) 7.14 (d) , J=8.53Hz, 1H) 4.76(s,2H)4.64(br s,1H)4.19(s,2H)3.98(s,3H)2.19(s,3H)
实施例26：化合物26Example 26: Compound 26
Figure PCTCN2019070227-appb-000134
Figure PCTCN2019070227-appb-000134
合成路线：synthetic route:
Figure PCTCN2019070227-appb-000135
Figure PCTCN2019070227-appb-000135
步骤1：化合物26-A的合成Step 1: Synthesis of Compound 26-A
除了使用相应的原料外，以实施例22中的制备化合物22-B相同的方法制备化合物26-A。Compound 26-A was prepared in the same manner as in the preparation of compound 22-B in Example 22 except that the corresponding material was used.
步骤2：化合物26-B的合成Step 2: Synthesis of Compound 26-B
将化合物26-A(20.00mg,66.85μmol)溶于四氯化碳(10mL)中，向其中加入偶氮二异丁腈(3.29mg,20.06μmol)，N-溴代琥珀酰亚胺(14.28mg,80.22μmol)，反应在氮气保护下，80℃搅拌12小时后，将混合液减压浓缩得到粗品，粗品用制备TLC(石油醚/乙酸乙酯＝10/1)纯化得到粗品26-B直接用于下步反应。Compound 26-A (20.00 mg, 66.85 μmol) was dissolved in carbon tetrachloride (10 mL), and azobisisobutyronitrile (3.29 mg, 20.06 μmol), N-bromosuccinimide (14.28) was added thereto. The mixture was stirred under a nitrogen atmosphere for 12 hours at 80 ° C. The mixture was concentrated under reduced pressure to give crude crystals crystals. Used directly in the next step of the reaction.
1H NMR(400MHz,CDCl 3)δppm 7.37-7.53(m,1H)6.56(d,J＝9.03Hz,1H)4.52-4.60(m,1H)4.50(s,2H)3.90(s,3H)2.27-2.41(m,2H)2.01-2.16(m,2H)1.72-1.85(m,1H)1.54-1.68(m,1H) 1 H NMR (400MHz, CDCl 3 ) δppm 7.37-7.53 (m, 1H) 6.56 (d, J = 9.03Hz, 1H) 4.52-4.60 (m, 1H) 4.50 (s, 2H) 3.90 (s, 3H) 2.27 -2.41(m,2H)2.01-2.16(m,2H)1.72-1.85(m,1H)1.54-1.68(m,1H)
步骤3：化合物26-C的合成Step 3: Synthesis of Compound 26-C
将化合物26-B(280.00mg,740.62μmol)溶于乙腈(10mL)中，向其中加入氨水(910.00mg,25.97μmol)，反应在20℃下搅拌2小时后，将混合液减压浓缩得到粗品26-C直接用于下步反应。The compound 26-B (280.00 mg, 740.62 μmol) was dissolved in acetonitrile (10 mL), and aqueous ammonia (910.00 mg, 25.97 μmol) was added thereto, and the mixture was stirred at 20 ° C for 2 hours, and then the mixture was concentrated under reduced pressure to give crude. 26-C is used directly in the next step.
MS m/z:281.8[M+H] + MS m/z: 281.8 [M+H] +
步骤4：化合物26-D的合成Step 4: Synthesis of Compound 26-D
将化合物26-C(278.00mg,985.36μmol)溶于四氢呋喃(10mL)中，向其中加入(Boc) 2O(430.11mg,1.97mmol)，4-二甲氨基吡啶(120.38mg,985.36μmol)，三乙胺(299.13mg,2.96mmol)，反应在80℃下搅拌3小时后，将反应液减压浓缩得到粗品，粗品经柱层析(石油醚/四氢呋喃＝3/1)纯化得到化合物26-D。 Compound 26-C (278.00 mg, 985.36 μmol) was dissolved in tetrahydrofuran (10 mL), and (Boc) 2 O (430.11 mg, 1.97 mmol), 4-dimethylaminopyridine (120.38 mg, 985.36 μmol), Triethylamine (299.13 mg, 2.96 mmol), the reaction was stirred at 80 ° C for 3 hr. D.
步骤5：化合物26-E的合成Step 5: Synthesis of Compound 26-E
将化合物26-D(180.00mg,470.90μmol)溶于二氧六环(10mL)中，向其中加入双联频哪醇硼酸酯(179.37mg,706.35μmol)和醋酸钾(138.64mg,1.41mmol)，反应用氮气置换3次后，加入[1,1’-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(38.46mg,47.09μmol)后，反应在氮气保护下90℃搅拌12小时后，将混合物用制备级HPLC(中性,乙腈和水)纯化得到粗品化合物26-E并直接投入下一步反应。Compound 26-D (180.00 mg, 470.90 μmol) was dissolved in dioxane (10 mL), and thereto was added bispinacol borate (179.37 mg, 706.35 μmol) and potassium acetate (138.64 mg, 1.41 mmol). After the reaction was replaced with nitrogen for 3 times, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (38.46 mg, 47.09 μmol) was added, and the reaction was carried out under nitrogen. After stirring at 90 ° C for 12 hours under protection, the mixture was purified by preparative HPLC (neut., EtOAc and water) to afford crude compound 26-E and directly.
步骤6：化合物26-F的合成Step 6: Synthesis of Compound 26-F
将化合物26-E(30.00mg,121.45μmol)溶于二氧六环(10mL)，水(0.1mL)中，向其中加入化合物II-B(42.03mg,121.43μmol)，2-二环己基磷-2’,4’,6’-三异丙基联苯(23.16mg,48.57μmol)，磷酸钾(77.33mg,364.29μmol)，反应用氮气置换3次后，向其中加入三(二亚苄基丙酮)二钯(22.24mg,24.29μmol)，反应在氮气保护下90℃下搅拌12小时后，向其中加入水(20mL)，用二氯甲烷(30mL)萃取，饱和食盐水(5mL)洗涤，硫酸钠干燥，过滤干燥剂，减压浓缩得到粗品，粗品经柱层析(石油醚/四氢呋喃＝1/1)纯化得到化合物26-F。Compound 26-E (30.00 mg, 121.45 μmol) was dissolved in dioxane (10 mL), water (0.1 mL), and Compound II-B (42.03 mg, 121.43 μmol), 2-dicyclohexylphosphonate was added thereto. -2',4',6'-triisopropylbiphenyl (23.16 mg, 48.57 μmol), potassium phosphate (77.33 mg, 364.29 μmol), after the reaction was replaced with nitrogen for 3 times, tris(benzylidene) was added thereto. Acetone) dipalladium (22.24 mg, 24.29 μmol), the reaction was stirred at 90 ° C for 12 hours under a nitrogen atmosphere, then water (20 mL) was added and extracted with dichloromethane (30 mL) and brine (5 mL) The organic layer was dried over sodium sulfate, filtered and evaporated to dryness.
MS m/z:569.1[M+H] + MS m/z: 569.1 [M+H] +
步骤7：化合物26的合成Step 7: Synthesis of Compound 26
将26-F(13.00mg,22.86μmol)溶于二氯甲烷(3mL中，向其中加入三氟乙酸(770.00mg,6.75mmol)，反应在20℃下搅拌40分钟后，将反应液减压浓缩得到粗品，粗品用制备HPLC(中性,乙腈和水)分离得到化合物26。26-F (13.00 mg, 22.86 μmol) was dissolved in dichloromethane (3 mL, trifluoroacetic acid (770.00 mg, 6.75 mmol) was added thereto, and the reaction was stirred at 20 ° C for 40 minutes, and then the reaction mixture was concentrated under reduced pressure. The crude product was obtained, which was purified using preparative HPLC (neut, acetonitrile and water).
MS m/z:468.9[M+H] + MS m/z: 468.9 [M+H] +
1H NMR(400MHz,CD 3OD)δppm 8.72(s,1H)8.04(br d,J＝8.53Hz,1H)7.69-7.87(m,2H)7.32(d,J＝8.53Hz,1H)6.95(d,J＝8.53Hz,1H)6.58(s,1H)4.70(s,2H)4.52-4.60(m,1H)4.13(s,2H)2.48-2.62(m,2H)2.26-2.42(m,2H)2.05(s,3H)1.85-1.98(m,1H)1.71-1.85(m,1H) 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.72 (s, 1H) 8.04 (brd, J = 8.53 Hz, 1H) 7.69-7.87 (m, 2H) 7.32 (d, J = 8.53 Hz, 1H) 6.95 ( d, J=8.53 Hz, 1H) 6.58 (s, 1H) 4.70 (s, 2H) 4.52-4.60 (m, 1H) 4.13 (s, 2H) 2.48-2.62 (m, 2H) 2.26-2.42 (m, 2H) ) 2.05(s,3H)1.85-1.98(m,1H)1.71-1.85(m,1H)
实施例27：化合物27Example 27: Compound 27
Figure PCTCN2019070227-appb-000136
Figure PCTCN2019070227-appb-000136
合成路线：synthetic route:
Figure PCTCN2019070227-appb-000137
Figure PCTCN2019070227-appb-000137
步骤1：化合物27-A的合成Step 1: Synthesis of Compound 27-A
将化合物21-A(500.00mg,3.01mmol)溶于N,N-二甲基甲酰胺(10mL)中，向其加入碘代异丙烷(511.49mg,3.01mmol)，碳酸钾(1.25g,9.03mmol)，反应在50℃下搅拌3小时后，向其中加入水(20mL)，用乙酸乙酯(50mL)萃取，饱和食盐水(10mL)洗涤，硫酸钠干燥，过滤干燥剂，减压浓缩得到粗品，粗品化合物27-A直接用于下一步反应。Compound 21-A (500.00 mg, 3.01 mmol) was dissolved in N,N-dimethylformamide (10 mL), and iodoisopropane (511.49 mg, 3.01 mmol), potassium carbonate (1.25 g, 9.03) After the reaction was stirred at 50 ° C for 3 hours, water (20 mL) was evaporated, evaporated, evaporated. The crude product, crude compound 27-A, was used directly in the next step.
步骤2：化合物27-B的合成Step 2: Synthesis of Compound 27-B
将化合物27-A(706.00mg,3.39mmol)溶于二氯甲烷(10mL)中，在0℃下搅拌10分钟后，在0℃下滴加溶于二氯甲烷(2mL)的液溴(650.11mg,4.07mmol)，反应在0℃下搅拌1小时后，向其中加入水(10mL)，用DCM(40mL)萃取，硫代硫酸钠溶液(10mL)干燥，饱和食盐水(10mL)洗涤，硫酸钠干燥，过滤干燥剂，减压浓缩得到化合物27-B。Compound 27-A (706.00 mg, 3.39 mmol) was dissolved in dichloromethane (10 mL) and stirred at 0 ° C for 10 min, then EtOAc (2. After the reaction was stirred at 0 ° C for 1 hour, water (10 mL) was added thereto, and extracted with DCM (40 mL), dried over sodium thiosulfate (10 mL), and brine (10 mL) The sodium was dried, and the desiccant was filtered, and concentrated under reduced pressure to give Compound 27-B.
1H NMR(400MHz,CDCl 3)δppm 7.37(s,1H)6.59(d,J＝9.03Hz,1H)4.41(m,1H)3.82(s,3H)2.22(s,3H)1.22(d,J＝6.02Hz,6H) 1 H NMR (400 MHz, CDCl 3 ) δ ppm 7.37 (s, 1H) 6.59 (d, J = 9.03 Hz, 1H) 4.41 (m, 1H) 3.82 (s, 3H) 2.22 (s, 3H) 1.22 (d, J =6.02Hz, 6H)
步骤3：化合物27-C的合成Step 3: Synthesis of Compound 27-C
将化合物27-B(814.00mg,2.83mmol)溶于四氯化碳(10mL)中，向其中加入过氧化苯甲酰(205.65mg,849.00μmol)，N-溴代琥珀酰亚胺(604.42mg,3.40mmol)，反应在氮气保护下，80℃搅拌12小时后，将反应液减 压浓缩得到粗品，粗品经柱层析(石油醚/乙酸乙酯＝10/1)纯化得到粗品化合物27-C直接用于下一步反应。 1H NMR(400MHz,CDCl 3)δppm 7.46(d,J＝8.53Hz,1H)6.72(d,J＝9.03Hz,1H)4.49(s,2H)4.39-4.46(m,1H)3.88(s,3H)1.25(s,3H)1.23(s,3H) Compound 27-B (814.00 mg, 2.83 mmol) was dissolved in carbon tetrachloride (10 mL), and benzoyl peroxide (205.65 mg, 849.00 μmol), N-bromosuccinimide (604.42 mg) was added thereto. , 3.40 mmol), the reaction was stirred under a nitrogen atmosphere, and the mixture was stirred at 80 ° C for 12 hr. C is used directly for the next reaction. 1 H NMR (400 MHz, CDCl 3 ) δ ppm 7.46 (d, J = 8.53 Hz, 1H) 6.72 (d, J = 9.03 Hz, 1H) 4.49 (s, 2H) 4.39 - 4.46 (m, 1H) 3.88 (s, 3H) 1.25 (s, 3H) 1.23 (s, 3H)
步骤4：化合物27-D的合成Step 4: Synthesis of Compound 27-D
将化合物27-C(274.00mg,748.53μmol)溶于乙腈(10mL)中，向其中加入氨水(910.00mg,25.96mmol)，反应在20℃下搅拌12小时后，将反应液减压浓缩得到粗品化合物27-D直接用于下一步反应。The compound 27-C (274.00 mg, 748.53 μmol) was dissolved in acetonitrile (10 mL), and aqueous ammonia (910.00 mg, 25.96 mmol) was added thereto, and the mixture was stirred at 20 ° C for 12 hours, and then the reaction mixture was concentrated under reduced pressure to give crude. Compound 27-D was used directly in the next reaction.
MS m/z:269.8[M+H] + MS m/z: 269.8 [M+H] +
步骤5：化合物27-E的合成Step 5: Synthesis of Compound 27-E
将化合物27-D(650.00mg,2.41mmol)溶于四氢呋喃(10mL)中，向其中加入Boc 2O(1.05g,4.82mmol)，4-二甲氨基吡啶(294.41mg,2.41mmol)，三乙胺(731.60mg,7.23mmol)，反应在80℃下搅拌3小时后，将反应液减压浓缩得到粗品，粗品经柱层析(石油醚/四氢呋喃＝3/1)纯化得到化合物27-E。 Compound 27-D (650.00 mg, 2.41 mmol) was dissolved in tetrahydrofuran (10 mL), to which was added Boc 2 O (1.05 g, 4.82 mmol), 4-dimethylaminopyridine (294.41 mg, 2.41 mmol), triethyl The amine (731.60 mg, 7.23 mmol) was stirred at 80 ° C for 3 hr.
MS m/z:369.8[M+H] + MS m/z: 369.8 [M+H] +
步骤6：化合物27-F的合成Step 6: Synthesis of Compound 27-F
将化合物27-E(284.00mg,767.07μmol)溶于二氧六环(10mL)中，向其中加入双联频哪醇硼酸酯(292.18mg,1.15mmol)和醋酸钾(225.84mg,2.30mmol)，反应用氮气置换3次后，加入[1,1’-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(62.64mg,76.71μmol)后，反应在氮气保护下90℃搅拌12小时后，向混合液中加入水(20mL)，用乙酸乙酯(50mL)萃取，饱和食盐水(10mL)洗涤，硫酸钠干燥，过滤干燥剂，减压浓缩得到粗品，粗品经柱层析(石油醚/四氢呋喃＝3/1)纯化得到化合物27-F。Compound 27-E (284.00 mg, 767.07 μmol) was dissolved in dioxane (10 mL), and bis-pinacol borate (292.18 mg, 1.15 mmol) and potassium acetate (225.84 mg, 2.30 mmol) were added thereto. After the reaction was replaced with nitrogen for 3 times, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (62.64 mg, 76.71 μmol) was added, and the reaction was carried out under nitrogen. After the mixture was stirred at 90 ° C for 12 hours, water (20 mL) was evaporated, evaporated, evaporated, evaporated The crude product was purified by column chromatography ( petroleum ether / THF / 3 / 1) to afford compound 27-F.
步骤7：化合物27-G的合成Step 7: Synthesis of Compound 27-G
将化合物27-F(170.00mg,407.38μmol)溶于二氧六环(10mL)，水(1mL)中，向其中加入化合物II-B(141.01mg,407.38μmol)，2-二环己基磷-2’,4’,6’-三异丙基联苯(77.68mg,162.95μmol)，磷酸钾(259.41mg,1.22mmol)，反应用氮气置换3次后，向其中加入三(二亚苄基丙酮)二钯(74.61mg,81.48μmol)，反应在氮气保护下90℃下搅拌12小时后，向其中加入水(10mL)，用二氯甲烷(40mL)萃取，饱和食盐水(10mL)洗涤，硫酸钠干燥，过滤干燥剂，减压浓缩得到粗品，粗品经柱层析(石油醚/四氢呋喃＝1/1)纯化得到化合物27-G。Compound 27-F (170.00 mg, 407.38 μmol) was dissolved in dioxane (10 mL), water (1 mL), and Compound II-B (141.01 mg, 407.38 μmol), 2-dicyclohexylphosphine- 2',4',6'-triisopropylbiphenyl (77.68 mg, 162.95 μmol), potassium phosphate (259.41 mg, 1.22 mmol), after the reaction was replaced with nitrogen for 3 times, tris(dibenzylidene) was added thereto. Acetone) dipalladium (74.61 mg, 81.48 μmol), and the mixture was stirred at 90 ° C for 12 hours under nitrogen atmosphere, and then water (10 mL) was added and extracted with dichloromethane (40 mL), and brine (10 mL) The organic layer was dried over sodium sulfate, filtered and evaporated to dryness.
MS m/z:557.1[M+H] + MS m/z: 557.1 [M+H] +
步骤8：化合物27的合成Step 8: Synthesis of Compound 27
将化合物27-G(70.00mg,125.77μmol)溶于二氯甲烷(3mL)中，向其中加入三氟乙酸(770.00mg,6.75mmol)，反应在20℃下搅拌40分钟后，将反应也减压浓缩得到粗品，粗品用制备HPLC(中性,乙腈和水)分离得到化合物27。Compound 27-G (70.00 mg, 125.77 μmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (770.00 mg, 6.75 mmol) was added thereto, and the reaction was stirred at 20 ° C for 40 minutes, and the reaction was also reduced. Concentration by pressure gave the crude product which was purified using preparative HPLC (neut.
MS m/z:457.0[M+H] + MS m/z: 457.0 [M+H] +
1H NMR(400MHz,CD 3OD)δppm 8.50-8.82(m,1H)7.96-8.12(m,1H)7.76(s,2H)7.25-7.42(m,1H)7.12(s,1H)6.58(s,1H)4.79-4.84(m,1H)4.70(s,2H)4.13(s,2H)2.06(s,3H)1.43(d,J＝6.02Hz,6H) 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.50-8.82 (m, 1H) 7.96-8.12 (m, 1H) 7.76 (s, 2H) 7.25-7.42 (m, 1H) 7.12 (s, 1H) 6.58 (s ,1H)4.79-4.84(m,1H)4.70(s,2H)4.13(s,2H)2.06(s,3H)1.43(d,J=6.02Hz,6H)
实施例28：化合物28Example 28: Compound 28
Figure PCTCN2019070227-appb-000138
Figure PCTCN2019070227-appb-000138
合成路线：synthetic route:
Figure PCTCN2019070227-appb-000139
Figure PCTCN2019070227-appb-000139
步骤1：化合物28-A的合成Step 1: Synthesis of Compound 28-A
将化合物22-A(100mg,408.05μmol)溶于乙腈3mL中，在0℃下向其中滴加溶于水(3mL)的氢氧化钾(457.87mg,8.16mmol)后，将反应温度降至-70℃，在氮气保护下再加入溴氟甲基磷酸二乙酯(217.90mg,816.09μmol)，将反应温度升温至0℃，并在0℃下搅拌40分钟后，在0℃下向混合液中滴加10％的盐酸溶液调节pH至3，用乙酸乙酯(30mL)萃取，饱和食盐水(20mL)洗涤，硫酸钠干燥，过滤干燥剂，减压浓缩得到粗品，粗品用柱层析(石油醚/乙酸乙酯＝9/1)纯化得到化合物28-A。Compound 22-A (100 mg, 408.05 μmol) was dissolved in 3 mL of acetonitrile, and after dropwise addition of potassium hydroxide (457.87 mg, 8.16 mmol) dissolved in water (3 mL) at 0 ° C, the reaction temperature was lowered to - Further, at 25 ° C, diethyl bromofluoromethyl phosphate (217.90 mg, 816.09 μmol) was added under nitrogen, the reaction temperature was raised to 0 ° C, and stirred at 0 ° C for 40 minutes, then at 0 ° C to the mixture. A 10% hydrochloric acid solution was added dropwise to adjust the pH to 3, which was extracted with ethyl acetate (30 mL), brine (20 mL) Purification of petroleum ether / ethyl acetate = 9 / 1) gave compound 28-A.
1H NMR(400MHz,CDCl 3)δppm 7.51(d,J＝9.03Hz,1H)6.87(d,J＝8.53Hz,1H)6.14-6.59(m,1H)3.86(s,3H)2.30(s,3H) 1 H NMR (400 MHz, CDCl 3 ) δ ppm 7.51 (d, J = 9.03 Hz, 1H) 6.87 (d, J = 8.53 Hz, 1H) 6.14 - 6.59 (m, 1H) 3.86 (s, 3H) 2.30 (s, 3H)
步骤2：化合物28-B的合成Step 2: Synthesis of Compound 28-B
将化合物28-A(793mg,2.69mmol)溶于四氯化碳(10mL)中，向其中分别加入N-溴代琥珀酰亚胺(540.67mg,3.04mmol)，偶氮二异丁腈(136.05mg,828.52μmol)，反应体系用氮气置换3次后，80℃下搅拌12小时后，将反应混合物过滤，滤液减压浓缩得到粗品，粗品经柱层析(石油醚/乙酸乙酯＝9/1)纯化得到化合物28-B。Compound 28-A (793 mg, 2.69 mmol) was dissolved in carbon tetrachloride (10 mL), and N-bromosuccinimide (540.67 mg, 3.04 mmol), azobisisobutyronitrile (136.05) was separately added thereto. After the reaction system was replaced with nitrogen for 3 times, and the mixture was stirred at 80 ° C for 12 hours, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give crude crystals. 1) Purification afforded compound 28-B.
1H NMR(400MHz,CDCl 3)δppm 7.50-7.69(m,1H)7.02(d,J＝8.78Hz,1H)6.15-6.64(m,1H)4.58(s,2H)3.92(s,3H) 1 H NMR (400 MHz, CDCl 3 ) δ ppm 7.50-7.69 (m, 1H) 7.02 (d, J = 8.78 Hz, 1H) 6.15-6.64 (m, 1H) 4.58 (s, 2H) 3.92 (s, 3H)
步骤3：化合物28-C的合成Step 3: Synthesis of Compound 28-C
将28-B(700mg,1.87mmol)溶于乙腈(10mL)中，向其中缓慢滴加氨水(32.50g,259.63mmol)，反应在25℃下搅拌12小时后，将反应混合物减压浓缩得到干燥粗品28-C并直接用于下步实验。28-B (700 mg, 1.87 mmol) was dissolved in acetonitrile (10 mL), and aqueous ammonia (32.50 g, 259.63 mmol) was slowly added dropwise thereto, and the reaction was stirred at 25 ° C for 12 hours, and then the reaction mixture was concentrated under reduced pressure to dry. Crude 28-C was used directly in the next experiment.
MS m/z:277.8[M+H] + MS m/z: 277.8 [M+H] +
步骤4：化合物28-D的合成Step 4: Synthesis of Compound 28-D
将28-C(900mg,3.24mmol)溶于四氢呋喃(20mL)，二甲基亚砜(2mL)中，向其中加入Boc 2O(1.77g,8.09mmol)，4-二甲氨基吡啶(395.44mg,3.24mmol)，三乙胺(982.60mg,9.71mmol)，反应在65℃下搅拌2小时后，向反应液中加入水(100mL)，用乙酸乙酯(100mL)萃取，用水(50mL)洗涤2次，用饱和食盐水(50mL)洗涤，硫酸钠干燥，减压浓缩得到粗品，粗品经柱层析(石油醚/四氢呋喃＝3/1)纯化得到28-D。 28-C (900 mg, 3.24 mmol) was dissolved in tetrahydrofuran (20 mL), dimethyl sulfoxide (2 mL), and Boc 2 O (1.77 g, 8.09 mmol), 4-dimethylaminopyridine (395.44 mg) was added thereto. , 3.24 mmol), triethylamine (982.60 mg, 9.71 mmol). After stirring at 65 ° C for 2 hr, water (100 mL) was evaporated. After 2 times, it was washed with brine (50 mL), dried over sodium sulfate.
MS m/z:377.8[M+H] + MS m/z: 377.8 [M+H] +
步骤5：化合物28-E的合成Step 5: Synthesis of Compound 28-E
将28-D(400mg,1.06mmol)溶于二氧六环(6mL)，水(0.6mL)，向其中加入II(540.69mg，1.38mmol)，2-二环己基磷-2’,4’,6’-三异丙基联苯(100.85mg,211.55μmol)，磷酸钾(673.58mg,3.17mmol)，反应充入氮气后加入三(二亚苄基丙酮)二钯(96.86mg，105.77μmol)，反应在氮气保护下115℃下微波搅拌15分钟后，向混合物中加入水(10mL)，用乙酸乙酯(100mL)萃取，饱和食盐水(5mL)洗涤，硫酸钠干燥，过滤干燥剂，减压浓缩得到粗品，粗品经柱层析(石油醚/四氢呋喃＝4/1-1/1)纯化得到28-E。28-D (400 mg, 1.06 mmol) was dissolved in dioxane (6 mL), water (0.6 mL), and II (540.69 mg, 1.38 mmol), 2-dicyclohexylphosphon-2', 4' was added thereto. , 6'-triisopropylbiphenyl (100.85mg, 211.55μmol), potassium phosphate (673.58mg, 3.17mmol), the reaction was filled with nitrogen and then added tris(dibenzylideneacetone)dipalladium (96.86mg, 105.77μmol) After the mixture was stirred under a nitrogen atmosphere for 15 minutes at 115 ° C, water (10 mL) was added to the mixture, which was extracted with ethyl acetate (100 mL), brine (5 mL) Concentration under reduced pressure gave a crude material.
MS m/z:565.1[M+H] + MS m/z: 565.1 [M+H] +
步骤6：化合物28的合成Step 6: Synthesis of Compound 28
将28-E(130mg,230.29μmol)溶于二氯甲烷(8mL)中，向其中加入三氟乙酸(770.00mg,6.75mmol)，反应在24℃下搅拌30分钟后，向混合物中加入饱和碳酸氢钠溶液调节pH至8后，用水(20mL)稀释，二氯甲烷(50mL)萃取，饱和食盐水(50mL)洗涤，硫酸钠干燥，过滤干燥剂，减压浓缩得到粗品，粗品用混合溶剂(石油醚/乙酸乙酯＝6/1)(6mL)洗涤，后处理得到28。28-E (130 mg, 230.29 μmol) was dissolved in dichloromethane (8 mL), trifluoroacetic acid (770.00 mg, 6.75 mmol) was added thereto, and the reaction was stirred at 24 ° C for 30 minutes, then saturated carbonate was added to the mixture. The sodium hydrogen hydride solution was adjusted to pH 8 and then diluted with water (20 mL), dichloromethane (50 mL), and brine (50 mL). The petroleum ether/ethyl acetate = 6/1) (6 mL) was washed and worked up to afford 28.
MS m/z:465.1[M+H] + MS m/z: 465.1 [M+H] +
1H NMR(400MHz,CD3OD)δppm 8.59-8.85(m,1H)8.04(d,J＝6.52Hz,1H)7.79(t,J＝4.02Hz,2H)7.46(d,J＝8.28Hz,1H)6.55-7.35(m,3H)4.71(s,2H)4.13-4.27(m,2H)2.05(s,3H) 1 H NMR (400MHz, CD3OD) δppm 8.59-8.85 (m, 1H) 8.04 (d, J = 6.52Hz, 1H) 7.79 (t, J = 4.02Hz, 2H) 7.46 (d, J = 8.28Hz, 1H) 6.55-7.35(m,3H)4.71(s,2H)4.13-4.27(m,2H)2.05(s,3H)
实施例29：化合物29Example 29: Compound 29
Figure PCTCN2019070227-appb-000140
Figure PCTCN2019070227-appb-000140
合成路线：synthetic route:
Figure PCTCN2019070227-appb-000141
Figure PCTCN2019070227-appb-000141
步骤1：化合物29-B的合成Step 1: Synthesis of Compound 29-B
将化合物13(70.00mg,146.66μmol)溶于N,N-二甲基甲酰胺(3mL)中，向其中加入N,N-二甲基炔丙胺(60.96mg,733.30μmol)，碘化亚铜(2.79mg,14.67μmol)，三乙胺(44.52mg,439.98μmol)，向其中充入氮气后，加入二氯双(三苯基膦)钯(10.29mg,14.67μmol)，反应在氮气保护下，100℃微波搅拌3小时后，混合物用制备HPLC分离得到粗品29-B。Compound 13 (70.00 mg, 146.66 μmol) was dissolved in N,N-dimethylformamide (3 mL), and N,N-dimethylpropargylamine (60.96 mg, 733.30 μmol), cuprous iodide was added thereto. (2.79 mg, 14.67 μmol), triethylamine (44.52 mg, 439.98 μmol), after charging nitrogen gas thereto, dichlorobis(triphenylphosphine)palladium (10.29 mg, 14.67 μmol) was added, and the reaction was under nitrogen atmosphere. After stirring at 100 ° C for 3 hours, the mixture was separated by preparative HPLC to give crude material 29-B.
MS m/z:480.0[M+H] + MS m/z: 480.0 [M+H] +
步骤2：化合物29的合成Step 2: Synthesis of Compound 29
将29-B(11.00mg,22.94μmol)溶于甲醇(3mL)中，向其中加入钯碳(10mg,10％)，反应用H 2置换3次后，在氢气球下，20℃下搅拌12小时后，将反应混合物用硅藻土过滤，滤液减压浓缩得到粗品，粗品用制备HPLC(中性，乙腈和水)分离得到化合物29。 29-B (11.00 mg, 22.94 μmol) was dissolved in methanol (3 mL), palladium carbon (10 mg, 10%) was added thereto, and the reaction was replaced with H 2 for 3 times, and then stirred under a hydrogen balloon at 20 ° C. After </RTI></RTI></RTI><RTIID=0.0></RTI>
MS m/z:484.1[M+H] + MS m/z: 484.1 [M+H] +
1H NMR(400MHz,METHANOL-d 4)δppm 8.61-8.99(m,1H)8.08-8.24(m,1H)7.83-7.94(m,2H)7.49(s,2H)7.16(s,1H)4.85(br s,2H)4.28(s,2H)3.26(br t,J＝7.53Hz,4H)2.95(s,6H)2.21-2.25(m,3H)2.15(br d,J＝8.03Hz,2H) 1 H NMR (400 MHz, METHANOL-d 4 ) δ ppm 8.61-8.99 (m, 1H) 8.08-8.24 (m, 1H) 7.83-7.94 (m, 2H) 7.49 (s, 2H) 7.16 (s, 1H) 4.85 ( Br s,2H)4.28(s,2H)3.26(br t,J=7.53Hz,4H)2.95(s,6H)2.21-2.25(m,3H)2.15(br d,J=8.03Hz,2H)
实施例30：化合物30Example 30: Compound 30
Figure PCTCN2019070227-appb-000142
Figure PCTCN2019070227-appb-000142
合成路线：synthetic route:
Figure PCTCN2019070227-appb-000143
Figure PCTCN2019070227-appb-000143
步骤1：化合物30-D的合成Step 1: Synthesis of Compound 30-D
将19-B(300mg,1.06mmol)溶于二氧六环(20mL)，水(2mL)中，向其中加入I(412.33mg,1.06mmol)，2-二环己基磷-2’,4’,6’-三异丙基联苯(201.99mg,423.72μmol)，磷酸钾(674.56mg,3.18mmol)，反应用氮气置换3次后加入三(二亚苄基丙酮)二钯(194.00mg，211.86μmol)，反应在氮气保护下，90℃搅拌12小时后，向其中加入水(20mL)，用乙酸乙酯(50mL)萃取，饱和食盐水(10mL)洗涤，硫酸钠干燥，过滤干燥剂，减压浓缩得到粗品，粗品经柱层析(二氯甲烷：四氢呋喃＝3:1)纯化得到30-D。19-B (300 mg, 1.06 mmol) was dissolved in dioxane (20 mL), water (2 mL), and I(412.33 mg, 1.06 mmol), 2-dicyclohexylphosphon-2', 4' , 6'-triisopropylbiphenyl (201.99 mg, 423.72 μmol), potassium phosphate (674.56 mg, 3.18 mmol), the reaction was replaced with nitrogen three times, then tris(dibenzylideneacetone)dipalladium (194.00 mg, 211.86 μmol), the reaction was stirred under a nitrogen atmosphere, and the mixture was stirred at 90 ° C for 12 hours, then water (20 mL) was added thereto, and the mixture was extracted with ethyl acetate (50 mL), brine (10 mL) Concentration under reduced pressure gave a crude material.
MS m/z:466.2[M+H] + MS m/z: 466.2 [M+H] +
步骤2：化合物30的合成Step 2: Synthesis of Compound 30
将30-D(290mg,622.87μmol)溶于二氯甲烷(6mL)中，向其中加入三氟乙酸(1.54g,13.51mmol)，反应在20℃下搅拌30分钟后，将反应液减压浓缩得到粗品，粗品用制备HPLC(中性，乙腈和水)分离得到化合物30。30-D (290 mg, 622.87 μmol) was dissolved in dichloromethane (6 mL), trifluoroacetic acid (1.54 g, 13.51 mmol) was added thereto, and the mixture was stirred at 20 ° C for 30 min. The crude product was obtained, which was purified using preparative HPLC (neut.
MS m/z:366.2[M+H] + MS m/z: 366.2 [M+H] +
1H NMR(400MHz,METHANOL-d 4)δppm 7.60-7.79(m,1H)7.38(d,J＝8.03Hz,1H)7.13(s,1H)6.45(s,1H)4.16(s,2H)3.98(s,3H)3.86(br d,J＝4.02Hz,1H)1.96-2.12(m,4H)1.50-1.79(m,8H) 1 H NMR (400 MHz, METHANOL-d 4 ) δ ppm 7.60-7.79 (m, 1H) 7.38 (d, J = 8.03 Hz, 1H) 7.13 (s, 1H) 6.45 (s, 1H) 4.16 (s, 2H) 3.98 (s,3H)3.86(br d,J=4.02Hz,1H)1.96-2.12(m,4H)1.50-1.79(m,8H)
实施例31：化合物31Example 31: Compound 31
Figure PCTCN2019070227-appb-000144
Figure PCTCN2019070227-appb-000144
合成路线：synthetic route:
Figure PCTCN2019070227-appb-000145
Figure PCTCN2019070227-appb-000145
步骤1：化合物31-C的合成Step 1: Synthesis of Compound 31-C
除了使用相应的原料外，以实施例5中的制备化合物5-C相同的方法制备化合物31-C。Compound 31-C was prepared in the same manner as in the preparation of compound 5-C in Example 5 except that the corresponding materials were used.
MS m/z:304.8[M+H] + MS m/z: 304.8 [M+H] +
步骤2：化合物31-E的合成Step 2: Synthesis of Compound 31-E
除了使用相应的原料外，以实施例9中的制备化合物9-A相同的方法制备化合物31-E。Compound 31-E was prepared in the same manner as in the preparation of compound 9-A in Example 9 except that the corresponding material was used.
MS m/z:488.1[M+H] + MS m/z: 488.1 [M+H] +
步骤3：化合物31的合成Step 3: Synthesis of Compound 31
除了使用相应的原料外，以实施例9中的制备化合物9相同的方法制备化合物31。Compound 31 was prepared in the same manner as in the preparation of compound 9 in Example 9 except that the corresponding materials were used.
MS m/z:388.0[M+H] + MS m/z: 388.0 [M+H] +
1H NMR(400MHz,CHLOROFORM-d)δppm 7.79(s,1H)7.14-7.26(m,1H)6.89(d,J＝8.28Hz,1H)6.59(br s,1H)6.10-6.11(m,1H)6.24(s,1H)4.32(br d,J＝7.78Hz,1H)4.06(s,2H)3.95(s,3H)2.08(br d,J＝9.54Hz,4H)1.96(s,3H)1.76-1.94(m,2H)1.50-1.58(m,2H) 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.79 (s, 1H) 7.14-7.26 (m, 1H) 6.89 (d, J = 8.28 Hz, 1H) 6.59 (br s, 1H) 6.10-6.11 (m, 1H) 6.24(s,1H)4.32(br d,J=7.78Hz,1H)4.06(s,2H)3.95(s,3H)2.08(br d,J=9.54Hz,4H)1.96(s,3H)1.76 -1.94(m,2H)1.50-1.58(m,2H)
实施例32：化合物32Example 32: Compound 32
Figure PCTCN2019070227-appb-000146
Figure PCTCN2019070227-appb-000146
合成路线：synthetic route:
Figure PCTCN2019070227-appb-000147
Figure PCTCN2019070227-appb-000147
步骤1：化合物32-A的合成Step 1: Synthesis of Compound 32-A
将中间体Ⅲ(77mg,208.44μmol)溶于二氧六环(10mL)中，向其中加入5-溴-2-甲氧基吡啶(47.03mg,250.13μmol)，4,5-双二苯基膦-9,9-二甲基氧杂蒽(48.24mg,83.38μmol)，碳酸铯(203.74mg,625.32μmol)，反应用氮气置换3次后加入醋酸钯(9.36mg,41.69μmol)，在氮气保护、90℃下搅拌12小时后，将反应液过滤，向其中加入水(30mL)，用乙酸乙酯(100mL)萃取，饱和食盐水(10mL)洗涤，硫酸钠干燥，过滤干燥剂，减压浓缩得到粗品，粗品经柱层析(二氯甲烷/四氢呋喃＝3/1)纯化得到粗品32-A。Intermediate III (77 mg, 208.44 μmol) was dissolved in dioxane (10 mL), and 5-bromo-2-methoxypyridine (47.03 mg, 250.13 μmol), 4,5-bisdiphenyl was added thereto. Phosphine-9,9-dimethyloxaxan (48.24 mg, 83.38 μmol), cesium carbonate (203.74 mg, 625.32 μmol), the reaction was replaced with nitrogen three times, then palladium acetate (9.36 mg, 41.69 μmol) was added in nitrogen. After the mixture was stirred at 90 ° C for 12 hours, the reaction mixture was filtered, EtOAcjjjjjjjjjjjjjjjjj Concentration gave the crude product which was purified eluting elut elut elut elut
MS m/z:477.1[M+H] + MS m/z: 477.1 [M+H] +
步骤2：化合物32的合成Step 2: Synthesis of Compound 32
将32-A(43mg,90.24μmol)溶于二氯甲烷(6mL)中，向其中加入三氟乙酸(1.54g,13.51mmol)，反应在20℃下搅拌30分钟后，将反应液减压浓缩得到粗品，粗品用制备HPLC分离得到化合物32。32-A (43 mg, 90.24 μmol) was dissolved in dichloromethane (6 mL), trifluoroacetic acid (1.54 g, 13.51 mmol) was added thereto, and the reaction was stirred at 20 ° C for 30 minutes, then the reaction mixture was concentrated under reduced pressure. The crude product was obtained, and the crude material was purified by preparative HPLC.
MS m/z:377.1[M+H] + MS m/z: 377.1 [M+H] +
1H NMR(400MHz,CDCl 3)δppm 8.18-8.29(m,1H)7.96(s,1H)7.71(dd,J＝8.53,2.51Hz,1H)7.34(d,J＝8.53Hz,1H)7.00(d,J＝8.53Hz,1H)6.82(d,J＝8.53Hz,1H)6.57(s,1H)6.30-6.44(m,2H)4.16(s,2H)4.04(s,3H)3.98(s,3H)2.03-2.09(m,3H) 1 H NMR (400 MHz, CDCl 3 ) δ ppm 8.18-8.29 (m, 1H) 7.96 (s, 1H) 7.71 (dd, J = 8.53, 2.51 Hz, 1H) 7.34 (d, J = 8.53 Hz, 1H) 7.00 ( d, J = 8.53 Hz, 1H) 6.82 (d, J = 8.53 Hz, 1H) 6.57 (s, 1H) 6.30 - 6.44 (m, 2H) 4.16 (s, 2H) 4.04 (s, 3H) 3.98 (s, 3H) 2.03-2.09 (m, 3H)
实施例33：化合物33Example 33: Compound 33
Figure PCTCN2019070227-appb-000148
Figure PCTCN2019070227-appb-000148
合成路线：synthetic route:
Figure PCTCN2019070227-appb-000149
Figure PCTCN2019070227-appb-000149
步骤1：化合物33-C的合成Step 1: Synthesis of Compound 33-C
将化合物Ⅲ(0.1g,270.70μmol)，33-B(38.49mg,270.70μmol)，HATU(154.39mg,406.05μmol)溶解在THF(10mL)中，随后加入三乙胺(68.48mg,676.75μmol)。反应液在60℃搅拌12小时。加水(20mL)稀释，用乙酸乙酯(40mL)萃取，有机相用饱和食盐水(20mL)洗涤，无水硫酸钠干燥。滤去干燥剂后，减压除去溶剂得到粗品。通过制备TLC纯化(PE:THF＝2:1)得到化合物33-C。Compound III (0.1 g, 270.70 μmol), 33-B (38.49 mg, 270.70 μmol), HATU (154.39 mg, 406.05 μmol) was dissolved in THF (10 mL), followed by triethylamine (68.48 mg, 676.75 μmol) . The reaction solution was stirred at 60 ° C for 12 hours. It was diluted with water (20 mL), EtOAc (EtOAc) After filtering off the desiccant, the solvent was removed under reduced pressure to give a crude material. Purification by preparative TLC (PE: THF = 2:1) gave compound 33-C.
MS m/z:494.2[M+H] + MS m/z: 494.2 [M+H] +
步骤2：化合物33的合成Step 2: Synthesis of Compound 33
除了使用相应的原料外，以实施例9中的制备化合物9相同的方法制备化合物33。Compound 33 was prepared in the same manner as in the preparation of compound 9 in Example 9 except that the corresponding material was used.
MS m/z:394.1[M+H] + MS m/z: 394.1 [M+H] +
1H NMR(400MHz,CHLOROFORM-d)δppm 8.22(s,1H)8.04(s,1H)7.92(s,1H)7.32(d,J＝8.28Hz,1H)7.00(d,J＝8.28Hz,1H)6.61(s,1H)4.11(s,2H)4.04(s,3H)2.42-2.52(m,1H)2.16(s,3H)1.97-2.08(m,2H)1.73-1.89(m,4H)1.47-1.60(m,4H) 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.22 (s, 1H) 8.04 (s, 1H) 7.92 (s, 1H) 7.32 (d, J = 8.28 Hz, 1H) 7.00 (d, J = 8.28 Hz, 1H) 6.61(s,1H)4.11(s,2H)4.04(s,3H)2.42-2.52(m,1H)2.16(s,3H)1.97-2.08(m,2H)1.73-1.89(m,4H)1.47 -1.60(m,4H)
实施例34：化合物34Example 34: Compound 34
Figure PCTCN2019070227-appb-000150
Figure PCTCN2019070227-appb-000150
合成路线：synthetic route:
Figure PCTCN2019070227-appb-000151
Figure PCTCN2019070227-appb-000151
步骤1：化合物34-A的合成Step 1: Synthesis of Compound 34-A
除了使用相应的原料外，以实施例32中的制备化合物32-A相同的方法制备化合物34-A。Compound 34-A was prepared in the same manner as in the preparation of compound 32-A in Example 32 except that the corresponding material was used.
MS m/z:464.1[M+H] + MS m/z: 464.1 [M+H] +
步骤2：化合物34的合成Step 2: Synthesis of Compound 34
除了使用相应的原料外，以实施例32中的制备化合物32相同的方法制备化合物34。Compound 34 was prepared in the same manner as in the preparation of compound 32 in Example 32 except that the corresponding material was used.
MS m/z:364.0[M+H] + MS m/z: 364.0 [M+H] +
1H NMR(400MHz,DMSO-d 6)δppm 8.62-8.70(m,1H)8.23(s,1H)8.11-8.20(m,1H)7.94(s,1H)7.35(d,J＝8.28Hz,1H)7.19(ddd,J＝11.67,8.16,1.25Hz,1H)7.05-7.14(m,2H)6.89-7.00(m,2H)4.05(s,2H)3.86(s,3H)2.02(s,3H) 1 H NMR (400MHz, DMSO- d 6) δppm 8.62-8.70 (m, 1H) 8.23 (s, 1H) 8.11-8.20 (m, 1H) 7.94 (s, 1H) 7.35 (d, J = 8.28Hz, 1H 7.19 (ddd, J=11.67, 8.16, 1.25 Hz, 1H) 7.05-7.14 (m, 2H) 6.89-7.00 (m, 2H) 4.05 (s, 2H) 3.86 (s, 3H) 2.02 (s, 3H)
实施例35：化合物35Example 35: Compound 35
Figure PCTCN2019070227-appb-000152
Figure PCTCN2019070227-appb-000152
合成路线：synthetic route:
Figure PCTCN2019070227-appb-000153
Figure PCTCN2019070227-appb-000153
步骤1：化合物35-A的合成Step 1: Synthesis of Compound 35-A
除了使用相应的原料外，以实施例32中的制备化合物32-A相同的方法制备化合物35-A。Compound 35-A was prepared in the same manner as in the preparation of compound 32-A in Example 32 except that the corresponding material was used.
MS m/z:461.2[M+H] + MS m/z: 461.2 [M+H] +
步骤2：化合物35的合成Step 2: Synthesis of Compound 35
除了使用相应的原料外，以实施例32中的制备化合物32相同的方法制备化合物35。Compound 35 was prepared in the same manner as in the preparation of compound 32 in Example 32 except that the corresponding material was used.
MS m/z:361.0[M+H] + MS m/z: 361.0 [M+H] +
1H NMR(400MHz,CD 3OD)δppm 8.49-8.75(m,1H)8.05(dd,J＝8.28,2.76Hz,1H)7.93(s,1H)7.39(d,J＝8.53Hz,1H)7.19(d,J＝8.53Hz,1H)7.10(d,J＝8.53Hz,1H)6.76(s,1H)4.17(s,2H)3.99(s,3H)2.49(s,3H)2.10(s,3H) 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.49-8.75 (m, 1H) 8.05 (dd, J = 8.28, 2.76 Hz, 1H) 7.93 (s, 1H) 7.39 (d, J = 8.53 Hz, 1H) 7.19 (d, J = 8.53 Hz, 1H) 7.10 (d, J = 8.53 Hz, 1H) 6.76 (s, 1H) 4.17 (s, 2H) 3.99 (s, 3H) 2.49 (s, 3H) 2.10 (s, 3H) )
实施例36：化合物36Example 36: Compound 36
Figure PCTCN2019070227-appb-000154
Figure PCTCN2019070227-appb-000154
合成路线：synthetic route:
Figure PCTCN2019070227-appb-000155
Figure PCTCN2019070227-appb-000155
步骤1：化合物36-B的合成Step 1: Synthesis of Compound 36-B
除了使用相应的原料外，以实施例5中的制备化合物5-C相同的方法制备化合物36-B。Compound 36-B was prepared in the same manner as in the preparation of compound 5-C in Example 5 except that the corresponding material was used.
MS m/z:347.0[M+H] + MS m/z: 347.0 [M+H] +
步骤2：化合物36-C的合成Step 2: Synthesis of Compound 36-C
除了使用相应的原料外，以实施例9中的制备化合物9-A相同的方法制备化合物36-C。Compound 36-C was prepared in the same manner as in the preparation of compound 9-A in Example 9 except that the corresponding material was used.
MS m/z:530.1[M+H] + MS m/z: 530.1 [M+H] +
步骤3：化合物36的合成Step 3: Synthesis of Compound 36
除了使用相应的原料外，以实施例9中的制备化合物9相同的方法制备化合物36。Compound 36 was prepared in the same manner as in the preparation of compound 9 in Example 9 except that the corresponding materials were used.
MS m/z:430.1[M+H] + MS m/z: 430.1 [M+H] +
1H NMR(400MHz,CDCl 3)δppm 8.96(s,2H)7.88(s,1H)7.31(d,J＝8.28Hz,1H)6.99(d,J＝8.53Hz,1H)6.36-6.44(m,2H)5.20(br s,1H)4.76(d,J＝5.77Hz,2H)4.14(s,2H)4.04(s,3H)2.05(s,3H) 1 H NMR (400MHz, CDCl 3 ) δppm 8.96 (s, 2H) 7.88 (s, 1H) 7.31 (d, J = 8.28Hz, 1H) 6.99 (d, J = 8.53Hz, 1H) 6.36-6.44 (m, 2H) 5.20 (br s, 1H) 4.76 (d, J = 5.77 Hz, 2H) 4.14 (s, 2H) 4.04 (s, 3H) 2.05 (s, 3H)
实施例37：化合物37Example 37: Compound 37
Figure PCTCN2019070227-appb-000156
Figure PCTCN2019070227-appb-000156
合成路线：synthetic route:
Figure PCTCN2019070227-appb-000157
Figure PCTCN2019070227-appb-000157
步骤1：化合物37-B的合成Step 1: Synthesis of Compound 37-B
将(1R,2R)-2-氨基环己醇(798.02mg,5.26mmol)溶于N-甲基吡咯烷酮(1mL)中，向其中加入37-A(200mg,1.05mmol)，N,N-二异丙基乙胺(2.23g,17.22mmol)，反应在氮气保护148℃下，密闭小管搅拌4小时后，将反应液减压浓缩得到粗品，粗品经柱层析(二氯甲烷:甲醇＝20:1)纯化得到37-B。(1R,2R)-2-Aminocyclohexanol (798.02 mg, 5.26 mmol) was dissolved in N-methylpyrrolidone (1 mL), and 37-A (200 mg, 1.05 mmol), N, N- Isopropylethylamine (2.23 g, 17.22 mmol), the reaction was stirred at 148 ° C under nitrogen atmosphere, and the mixture was stirred for 4 hr. The reaction mixture was concentrated under reduced pressure to give crude crystals. :1) Purification affords 37-B.
MS m/z:284.8[M+H] + MS m/z: 284.8 [M+H] +
步骤2：化合物37-C的合成Step 2: Synthesis of Compound 37-C
将37-B(110mg,385.72μmol)溶于二氧六环(10mL)和水(1mL)中，向其中加入I(150.14mg,385.72μmol)，2-二环己基磷-2’,4’,6’-三异丙基联苯(150.14mg,385.72μmol)，磷酸钾(245.63mg,1.16mmol)，反应用氮气置换3次后加入三(二亚苄基丙酮)二钯(35.32mg,38.57μmol)，反应在氮气保护下，90℃搅拌12小时后，向其中加入水(30mL)，用乙酸乙酯(100mL)萃取，饱和食盐水(30mL)洗涤，硫酸钠干燥，过滤干燥剂，减压浓缩得到粗品，粗品经柱层析(二氯甲烷：四氢呋喃＝1:1)纯化得到物37-C。37-B (110 mg, 385.72 μmol) was dissolved in dioxane (10 mL) and water (1 mL), and I(150.14 mg, 385.72 μmol), 2-dicyclohexylphosphorin-2', 4' was added thereto. , 6'-triisopropylbiphenyl (150.14 mg, 385.72 μmol), potassium phosphate (245.63 mg, 1.16 mmol), the reaction was replaced with nitrogen three times, then tris(dibenzylideneacetone)dipalladium (35.32 mg, 38.57 μmol), the reaction was stirred under nitrogen for 12 hours at 90 ° C, then water (30 mL) was added, ethyl acetate (100 mL) was extracted, washed with brine (30 mL) Concentration under reduced pressure gave a crude material.
MS m/z:468.1[M+H] + MS m/z: 468.1 [M+H] +
步骤3：化合物37的合成Step 3: Synthesis of Compound 37
将37-C(110mg,235.27μmol)溶于二氯甲烷(6mL)，向其中加入三氟乙酸(770.00mg,6.75mmol)，反应在20℃下搅拌30分钟后，将反应液减压浓缩得到粗品，粗品用制备HPLC(中性，乙腈，水)分离得到化合物37。37-C (110 mg, 235.27 μmol) was dissolved in dichloromethane (6 mL), trifluoroacetic acid (770.00 mg, 6.75 mmol) was added thereto, and the mixture was stirred at 20 ° C for 30 min. The crude product was isolated using preparative HPLC (neut. EtOAc, water).
MS m/z:368.1[M+H] + MS m/z: 368.1 [M+H] +
1H NMR(400MHz,DMSO-d 6)δppm 8.13-8.35(m,1H)7.75(s,1H)7.30(d,J＝8.28Hz,1H)7.05(d,J＝8.53Hz,1H)6.44(s,1H)6.28(d,J＝7.03Hz,1H)4.86(br s,1H)4.04(s,2H)3.87(s,3H)3.44-3.64(m,1H)1.85-2.03(m,5H)1.58-1.67(m,2H)1.24(br s,2H)1.17-1.37(m,1H) 1 H NMR (400MHz, DMSO- d 6) δppm 8.13-8.35 (m, 1H) 7.75 (s, 1H) 7.30 (d, J = 8.28Hz, 1H) 7.05 (d, J = 8.53Hz, 1H) 6.44 ( s,1H)6.28(d,J=7.03Hz,1H)4.86(br s,1H)4.04(s,2H)3.87(s,3H)3.44-3.64(m,1H)1.85-2.03(m,5H) 1.58-1.67(m,2H)1.24(br s,2H)1.17-1.37(m,1H)
实施例38：化合物38Example 38: Compound 38
Figure PCTCN2019070227-appb-000158
Figure PCTCN2019070227-appb-000158
合成路线：synthetic route:
Figure PCTCN2019070227-appb-000159
Figure PCTCN2019070227-appb-000159
步骤1：化合物38-B的合成Step 1: Synthesis of Compound 38-B
将37-A(300mg,1.58mmol)与环己胺(3.47g,34.95mmol)混合后，在氮气保护148℃下，密闭小管搅拌4小时后，向反应液中加入水(10mL)，用乙酸乙酯(50mL)萃取，饱和食盐水(10mL)洗涤，硫酸钠干燥，过滤干燥剂，减压浓缩得到粗品，粗品经柱层析(石油醚：乙酸乙酯＝6:1)纯化得到38-B。After mixing 37-A (300 mg, 1.58 mmol) and cyclohexylamine (3.47 g, 34.95 mmol), the sealed tube was stirred at 148 ° C for 4 hours under nitrogen atmosphere, and then water (10 mL) was added to the reaction mixture with acetic acid. Ethyl acetate (50 mL) was evaporated. EtOAc (EtOAc m. B.
MS m/z:268.9[M+H] + MS m/z: 268.9 [M+H] +
1H NMR(400MHz,CHLOROFORM-d)δppm 8.08(s,1H)6.27(s,1H)4.28-4.53(m,1H)3.39-3.60(m,1H)2.29(s,3H)1.99-2.08(m,2H)1.77(dt,J＝13.43,3.83Hz,2H)1.35-1.48(m,2H)1.14-1.31(m,4H) 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.08 (s, 1H) 6.27 (s, 1H) 4.28 - 4.53 (m, 1H) 3.39 - 3.60 (m, 1H) 2.29 (s, 3H) 1.99 - 2.08 (m , 2H) 1.77 (dt, J = 13.43, 3.83 Hz, 2H) 1.35-1.48 (m, 2H) 1.14-1.31 (m, 4H)
步骤2：化合物38-C的合成Step 2: Synthesis of Compound 38-C
将38-B(100mg,371.50μmol)溶于二氧六环(10mL)和水(1mL)中，向其中加入I(144.61mg,371.50μmol)，2-二环己基磷-2’,4’,6’-三异丙基联苯(35.42mg,74.30μmol)，磷酸钾(236.57mg,1.11mmol)，反应用氮气置换3次后加入三(二亚苄基丙酮)二钯(34.02mg,37.15μmol)，反应在氮气保护下，90℃搅拌12小时后，向其中加入水(20mL)，用乙酸乙酯(100mL)萃取，饱和食盐水(10mL)洗涤，硫酸钠干燥，过滤干燥剂，减压浓缩得到粗品，粗品经柱层析(二氯甲烷：四氢呋喃＝3:1)纯化得到物38-C。38-B (100 mg, 371.50 μmol) was dissolved in dioxane (10 mL) and water (1 mL), and I(144.61 mg, 371.50 μmol), 2-dicyclohexylphosphorin-2', 4' was added thereto. , 6'-triisopropylbiphenyl (35.42 mg, 74.30 μmol), potassium phosphate (236.57 mg, 1.11 mmol), the reaction was replaced with nitrogen three times, then tris(dibenzylideneacetone)dipalladium (34.02 mg, 37.15 μmol), the reaction was stirred under nitrogen for 12 hours at 90 ° C, then water (20 mL) was added, ethyl acetate (100 mL) was extracted, washed with brine (10 mL) Concentration under reduced pressure gave a crude material.
MS m/z:452.2[M+H] + MS m/z: 452.2 [M+H] +
步骤3：化合物38的合成Step 3: Synthesis of Compound 38
将38-C(150mg,332.18μmol)溶于二氯甲烷(6mL)中，向其中加入三氟乙酸(770.00mg,6.75mmol)，反应在15℃下搅拌30分钟后，将反应液减压浓缩得到粗品，粗品用制备HPLC(中性，乙腈，水)分离得到化合物38。The residue was dissolved in dichloromethane (6 mL). The crude product was obtained.
MS m/z:352.2[M+H] + MS m/z: 352.2 [M+H] +
1H NMR(400MHz,METHANOL-d 4)δppm 7.54-7.93(m,1H)7.38(d,J＝8.53Hz,1H)7.12(d,J＝8.28Hz,1H)6.47(s,1H)4.16(s,2H)3.98(s,3H)3.58-3.73(m,1H)2.03(s,5H)1.75-1.86(m,2H)1.63-1.74(m,1H)1.39-1.53(m,2H)1.20-1.36(m,3H) 1 H NMR (400 MHz, METHANOL-d 4 ) δ ppm 7.54-7.93 (m, 1H) 7.38 (d, J = 8.53 Hz, 1H) 7.12 (d, J = 8.28 Hz, 1H) 6.47 (s, 1H) 4.16 ( s,2H)3.98(s,3H)3.58-3.73(m,1H)2.03(s,5H)1.75-1.86(m,2H)1.63-1.74(m,1H)1.39-1.53(m,2H)1.20- 1.36 (m, 3H)
实施例39：化合物39Example 39: Compound 39
Figure PCTCN2019070227-appb-000160
Figure PCTCN2019070227-appb-000160
合成路线：synthetic route:
Figure PCTCN2019070227-appb-000161
Figure PCTCN2019070227-appb-000161
步骤1：化合物39-B的合成Step 1: Synthesis of Compound 39-B
将化合物37-A(200mg,1.05mmol)溶于2-甲基吡咯烷酮(1mL)中，向其中加入1-(2-噻唑基)乙胺(404.80mg,3.16mmol)，N,N-二异丙基乙胺(74.20mg,574.11μmol)，在氮气保护155℃下，密闭小管搅拌5小时后，向反应液中加入水(10mL)，用乙酸乙酯(100mL)萃取，饱和食盐水(10mL)洗涤，硫酸钠干燥，过滤干燥剂，减压浓缩得到粗品，粗品经柱层析(石油醚/乙酸乙酯＝2/1)纯化得到化合物39-B。Compound 37-A (200 mg, 1.05 mmol) was dissolved in 2-methylpyrrolidone (1 mL), and 1-(2-thiazolyl)ethylamine (404.80 mg, 3.16 mmol), N,N-di Propylethylamine (74.20 mg, 574.11 μmol), and the mixture was stirred at 155 ° C for 5 hours under nitrogen atmosphere. Water (10 mL) was added to the reaction mixture and extracted with ethyl acetate (100 mL). The mixture was washed with MgSO4, EtOAc (EtOAc m.
MS m/z:297.8[M+H] + MS m/z: 297.8 [M+H] +
步骤2：化合物39-C的合成Step 2: Synthesis of Compound 39-C
将化合物39-B(91mg,305.16μmol)溶于二氧六环(10mL)和水(1mL)中，向其中加入化合物I(118.78mg,305.16μmol)，2-二环己基磷-2’,4’,6’-三异丙基联苯(29.10mg,61.03μmol)，磷酸钾(194.33mg,915.49μmol)，反应用氮气置换3次后加入三(二亚苄基丙酮)二钯(27.94mg,30.52μmol)，反应在氮气保护下，90℃搅拌12小时后，向其中加入水(20mL)，用乙酸乙酯(50mL)萃取，饱和食盐水(10mL)洗涤，硫酸钠干燥，过滤干燥剂，减压浓缩得到粗品，粗品经柱层析(二氯甲烷/四氢呋喃＝3/1)纯化得到棕色油状物39-C。Compound 39-B (91 mg, 305.16 μmol) was dissolved in dioxane (10 mL) and water (1 mL), and Compound I (118.78 mg, 305.16 μmol), 2-dicyclohexylphosphon-2', 4',6'-triisopropylbiphenyl (29.10 mg, 61.03 μmol), potassium phosphate (194.33 mg, 915.49 μmol), the reaction was replaced with nitrogen three times and then tris(dibenzylideneacetone)dipalladium (27.94) was added. After the reaction was carried out under a nitrogen atmosphere for 12 hours at 90 ° C, water (20 mL) was added, and the mixture was extracted with ethyl acetate (50 mL), brine (10 mL) The residue was purified by EtOAcqqqqqqqqq
MS m/z:481.1[M+H] + MS m/z: 481.1 [M+H] +
步骤3：化合物39的合成Step 3: Synthesis of Compound 39
将化合物39-C(45mg,93.64μmol)溶于二氯甲烷(6mL)中，向其中加入三氟乙酸(770.00mg,6.75mmol)，反应在15℃下搅拌30分钟后，将反应液减压浓缩得到粗品，粗品用制备HPLC(中性,乙腈和水)分离得到化合物39。Compound 39-C (45 mg, 93.64 μmol) was dissolved in dichloromethane (6 mL), trifluoroacetic acid (770.00 mg, 6.75 mmol) was added thereto, and the reaction was stirred at 15 ° C for 30 minutes, and then the reaction solution was evaporated. Concentration gave the crude material which was purified using EtOAc EtOAc EtOAc
MS m/z:381.0[M+H] + MS m/z: 381.0 [M+H] +
1H NMR(400MHz,CD 3OD)δppm 7.71-7.87(m,2H)7.33-7.52(m,2H)7.11(d,J＝8.53Hz,1H)6.59(br s,1H)5.41(br d,J＝6.02Hz,1H)4.14(s,2H)3.97(s,3H)2.05(s,3H)1.68(br d,J＝6.53Hz,3H) 1 H NMR (400 MHz, CD 3 OD) δ ppm 7.71-7.87 (m, 2H) 7.33-7.52 (m, 2H) 7.11 (d, J = 8.53 Hz, 1H) 6.59 (br s, 1H) 5.41 (brd, J=6.02 Hz, 1H) 4.14 (s, 2H) 3.97 (s, 3H) 2.05 (s, 3H) 1.68 (br d, J = 6.53 Hz, 3H)
实施例41：化合物41Example 41: Compound 41
Figure PCTCN2019070227-appb-000162
Figure PCTCN2019070227-appb-000162
合成路线：synthetic route:
Figure PCTCN2019070227-appb-000163
Figure PCTCN2019070227-appb-000163
步骤1：化合物41-B的合成Step 1: Synthesis of Compound 41-B
将化合物41-A(300mg,1.94mmol)溶于乙腈(30mL)中，向其中加入5-溴-4-甲基-2-氨基吡啶(362.96mg,1.94mmol)，三氟乙酸(663.81mg,5.82mmol)，三乙基硅烷(676.93mg,5.82mmol)，反应在氮气保护下，80℃下搅拌12小时后，向反应液中加入水(50mL)，用乙酸乙酯(200mL)萃取，饱和食盐水(30mL)洗涤，硫酸钠干燥，过滤干燥剂，减压浓缩得到粗品，粗品经柱层析(石油醚/乙酸乙酯＝1/1)纯化得到化合物41-B。Compound 41-A (300 mg, 1.94 mmol) was dissolved in acetonitrile (30 mL), and 5-bromo-4-methyl-2-aminopyridine (362.96 mg, 1.94 mmol), trifluoroacetic acid (663.81 mg, 5.82 mmol), triethylsilane (676.93 mg, 5.82 mmol), the reaction was stirred under nitrogen for 12 hours at 80 ° C, then water (50 mL) was added to the reaction mixture, and extracted with ethyl acetate (200 mL) The organic layer was washed with brine (30 mL).
MS m/z:324.8[M+H] + MS m/z: 324.8 [M+H] +
步骤2：化合物41-C的合成Step 2: Synthesis of Compound 41-C
将化合物41-B(50mg,153.55μmol)溶于乙腈(10mL)中，向其中加入N-甲基哌嗪(30.76mg,307.10μmol)，碳酸钾(63.66mg,460.64μmol)，碘化钾(25.49mg,153.55μmol)，反应在氮气保护下，75℃下搅拌12小时后，向反应液中加入水(20mL)，用乙酸乙酯(30mL)萃取，饱和食盐水(20mL)洗涤，硫酸钠干燥，过滤干燥剂，减压浓缩得到粗品，粗品经柱层析(二氯甲烷/甲醇＝10/1)纯化得到化合物41-C。Compound 41-B (50 mg, 153.55 μmol) was dissolved in acetonitrile (10 mL), and N-methylpiperazine (30.76 mg, 307.10 μmol), potassium carbonate (63.66 mg, 460.64 μmol), potassium iodide (25.49 mg) was added thereto. , 153.55 μmol), the reaction was stirred under a nitrogen atmosphere, and the mixture was stirred at 75 ° C for 12 hr, then water (20 mL) The desiccant was filtered and concentrated under reduced pressure to give crude crystals.
MS m/z:389.0[M+H] + MS m/z: 389.0 [M+H] +
1H NMR(400MHz,CDCl 3)δppm 8.01(s,1H)7.21(s,4H)6.21(s,1H)4.81(br t,J＝5.27Hz,1H)4.37(d,J＝6.02Hz,2H)3.44(s,2H)2.31-2.64(m,8H)2.28(s,3H)2.18(s,3H) 1 H NMR (400 MHz, CDCl 3 ) δ ppm 8.01 (s, 1H) 7.21 (s, 4H) 6.21 (s, 1H) 4.81 (brt, J = 5.27 Hz, 1H) 4.37 (d, J = 6.02 Hz, 2H ) 3.44(s,2H)2.31-2.64(m,8H)2.28(s,3H)2.18(s,3H)
步骤3：化合物41-D的合成Step 3: Synthesis of Compound 41-D
将化合物I(100mg,256.90μmol)溶于二氧六环(10mL)和水(1mL)中，向其中加入41-C(100.02mg,256.90μmol)，2-二环己基磷-2’,4’,6’-三异丙基联苯(24.49mg,51.38μmol)，磷酸钾(163.60mg,770.71μmol)，反应用氮气置换3次后加入三(二亚苄基丙酮)二钯(23.53mg,25.69μmol)，反应在氮气保护下，90℃搅拌12小时后，向其中加入水(50mL)，用乙酸乙酯(200mL)萃取，饱和食盐水(30mL)洗涤，硫酸钠干燥，过滤干燥剂，减压浓缩得到粗品，粗品经柱层析(二氯甲烷/甲醇＝10/1)纯化得到化合物41-D。Compound I (100 mg, 256.90 μmol) was dissolved in dioxane (10 mL) and water (1 mL), and 41-C (100.02 mg, 256.90 μmol), 2-dicyclohexylphosphon-2',4 was added thereto. ',6'-triisopropylbiphenyl (24.49 mg, 51.38 μmol), potassium phosphate (163.60 mg, 770.71 μmol), the reaction was replaced with nitrogen three times and then added tris(dibenzylideneacetone)dipalladium (23.53 mg). , 25.69 μmol), the reaction was stirred under nitrogen for 12 hours at 90 ° C, then water (50 mL) was added, extracted with ethyl acetate (200 mL), washed with brine (30 mL) Concentration under reduced pressure afforded crude material.
MS m/z:572.3[M+H] + MS m/z: 572.3 [M+H] +
步骤4：化合物41的合成Step 4: Synthesis of Compound 41
将化合物41-D(100mg,174.91μmol)溶于二氯甲烷(6mL)中，向其中加入三氟乙酸(770.00mg,6.75mmol)，反应在16℃下搅拌30分钟后，将反应液减压浓缩得到粗品，粗品用制备HPLC(中性,乙腈和水)分离得到化合物41。The compound 41-D (100 mg, 174.91 μmol) was dissolved in dichloromethane (6 mL), trifluoroacetic acid (770.00 mg, 6.75 mmol) was added thereto, and the reaction was stirred at 16 ° C for 30 minutes, and then the reaction solution was decompressed. Concentration gave the crude product which was purified using EtOAc (EtOAc: EtOAc
MS m/z:472.1[M+H] + MS m/z: 472.1 [M+H] +
1H NMR(400MHz,DMSO-d 6)δppm 8.20(s,1H)7.78(s,1H)7.27-7.33(m,3H)7.19-7.26(m,2H)6.99-7.08(m,2H)6.45(s,1H)4.48(s,2H)4.03(s,2H)3.86(s,3H)3.41(s,2H)2.33(br s,8H)2.14(s,3H)1.95(s,3H) 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 8.20 (s, 1H) 7.78 (s, 1H) 7.27-7.33 (m, 3H) 7.19-7.26 (m, 2H) 6.99-7.08 (m, 2H) 6.45 ( s,1H)4.48(s,2H)4.03(s,2H)3.86(s,3H)3.41(s,2H)2.33(br s,8H)2.14(s,3H)1.95(s,3H)
实施例42：化合物42Example 42: Compound 42
Figure PCTCN2019070227-appb-000164
Figure PCTCN2019070227-appb-000164
合成路线：synthetic route:
Figure PCTCN2019070227-appb-000165
Figure PCTCN2019070227-appb-000165
步骤1：化合物42-A的合成Step 1: Synthesis of Compound 42-A
将5-溴-4-甲基-2-氨基吡啶(772.17mg,4.13mmol)溶于N-甲基吡咯烷酮(10mL)中，向其中加入对氟苯腈(500mg,4.13mmol)，碳酸钾(1.71g,12.39mmol)，反应在60℃下搅拌6小时后，加入碳酸铯(4.04g,12.39mmol)，反应在120℃下搅拌12小时后，向其中加入水(300mL)，用乙酸乙酯(300mL)萃取，饱和食盐水(100mL)洗涤，硫酸钠干燥，过滤干燥剂，减压浓缩得到粗品，粗品经柱层析(乙酸乙酯/石油＝3/1)纯化得到42-A。5-Bromo-4-methyl-2-aminopyridine (772.17 mg, 4.13 mmol) was dissolved in N-methylpyrrolidone (10 mL), and p-fluorobenzonitrile (500 mg, 4.13 mmol). After the reaction was stirred at 60 ° C for 6 hours, cesium carbonate (4.04 g, 12.39 mmol) was added, and the mixture was stirred at 120 ° C for 12 hours, then water (300 mL) was added to ethyl acetate. (300 mL), extracted with EtOAc (EtOAc) (EtOAc)EtOAc.
MS m/z:287.9[M+H] + MS m/z: 287.9 [M+H] +
1H NMR(400MHz,CDCl 3)δppm 8.27-8.34(m,1H)7.58-7.62(m,2H)7.51-7.56(m,2H)6.79(s,1H)6.70(br s,1H)2.39(s,3H) 1 H NMR (400 MHz, CDCl 3 ) δ ppm 8.27-8.34 (m, 1H) 7.58-7.62 (m, 2H) 7.51-7.56 (m, 2H) 6.79 (s, 1H) 6.70 (br s, 1H) 2.39 (s , 3H)
步骤2：化合物42-B的合成Step 2: Synthesis of Compound 42-B
将化合物42-A(234mg,812.10μmol)溶于甲苯(20mL)中，氮气保护下，在-70℃下搅拌20分钟后，在-70℃向其中滴加DIBAL(1M,2.44mL)，反应在-70℃下，氮气保护搅拌120分钟后，向其中加入水(50mL)，将混合物过滤后，滤液用乙酸乙酯(150mL)萃取，饱和食盐水(30mL)洗涤，硫酸钠干燥，过滤干燥剂，减压浓缩得到粗品，粗品经柱层析(石油醚/乙酸乙酯＝3/1)纯化得到42-B。Compound 42-A (234 mg, 812.10 μmol) was dissolved in toluene (20 mL), and the mixture was stirred at -70 ° C for 20 minutes under nitrogen atmosphere, and DIBAL (1M, 2.44 mL) was added dropwise at -70 ° C. After stirring under nitrogen for a period of 120 minutes at -70 ° C, water (50 mL) was added and the mixture was filtered and filtered, ethyl acetate (150 mL). The residue was concentrated under reduced pressure to give crude crystals.
MS m/z:290.8[M+H] + MS m/z: 290.8 [M+H] +
步骤3：化合物42-C的合成Step 3: Synthesis of Compound 42-C
在0℃下，将42-B(132mg,453.39μmol)溶于二氯甲烷(10mL)中，向其中加入N-甲基哌嗪(90.82mg,906.77μmol)，乙酸(525.00mg,8.74mmol)，反应在16℃下搅拌2小时后，0℃加入三乙酰基硼氢化钠(480.46mg,2.27mmol)，反应在16℃下搅拌12小时后，向反应液中加入饱和碳酸氢钠溶液调节pH至8，用二氯甲烷(100mL)萃取，饱和食盐水(30mL)洗涤，硫酸钠干燥，过滤干燥剂，减压浓缩得到粗品，粗品经柱层析(二氯甲烷/甲醇＝10/1)纯化得到42-C。42-B (132 mg, 453.39 μmol) was dissolved in dichloromethane (10 mL), and N-methylpiperazine (90.82 mg, 906.77 μmol), acetic acid (525.00 mg, 8.74 mmol) was added thereto at 0 °C. After the reaction was stirred at 16 ° C for 2 hours, sodium triacetoxyborohydride (480.46 mg, 2.27 mmol) was added at 0 ° C. After the reaction was stirred at 16 ° C for 12 hours, a saturated sodium hydrogencarbonate solution was added to the reaction mixture to adjust the pH. The mixture was extracted with EtOAc (EtOAc/EtOAc (EtOAc)EtOAc. Purification afforded 42-C.
MS m/z:374.9[M+H] + MS m/z: 374.9 [M+H] +
步骤4：化合物42-D的合成Step 4: Synthesis of Compound 42-D
将42-C(62mg,165.20μmol)溶于二氧六环(10mL)和水(1mL)中，向其中加入中间体I(64.30mg,165.20μmol)，2-二环己基磷-2’,4’,6’-三异丙基联苯(15.75mg,33.04μmol)，磷酸钾(105.20mg,495.60μmol)，反应用氮气置换3次后加入三(二亚苄基丙酮)二钯(15.13mg,16.52μmol)，反应在氮气保护下，90℃搅拌12小时后，向其中加入水(30mL)，用乙酸乙酯(200mL)萃取，饱和食盐水(50mL)洗涤，硫酸钠干燥，过滤干燥剂，减压浓缩得到粗品，粗品经柱层析(二氯甲烷/甲醇＝10/1)纯化得到棕色油状物42-D。42-C (62 mg, 165.20 μmol) was dissolved in dioxane (10 mL) and water (1 mL), and Intermediate I (64.30 mg, 165.20 μmol), 2-dicyclohexylphosphon-2', 4',6'-triisopropylbiphenyl (15.75 mg, 33.04 μmol), potassium phosphate (105.20 mg, 495.60 μmol), the reaction was replaced with nitrogen three times and then tris(dibenzylideneacetone)dipalladium (15.13) was added. After the reaction was carried out under a nitrogen atmosphere for 12 hours at 90 ° C, water (30 mL) was added thereto, and extracted with ethyl acetate (200 mL), brine (50 mL) The residue was purified by EtOAc EtOAcqHHHHHH
MS m/z:558.4[M+H] + MS m/z: 558.4 [M+H] +
步骤5：化合物42的合成Step 5: Synthesis of Compound 42
除了使用相应的原料外，以实施例9中的制备化合物9相同的方法制备化合物42。Compound 42 was prepared in the same manner as in the preparation of compound 9 in Example 9 except that the corresponding materials were used.
MS m/z:458.1[M+H] + MS m/z: 458.1 [M+H] +
1H NMR(400MHz,CD 3OD)δppm 7.87-8.14(m,1H)7.51(d,J＝8.53Hz,2H)7.43(d,J＝8.53Hz,1H)7.27(d,J＝8.53Hz,2H)7.15(d,J＝8.53Hz,1H)6.81(s,1H)4.19(s,2H)3.99(s,3H)3.52(s,2H)2.54(br s,7H)2.31(s,3H)2.10(s,3H) 1 H NMR (400 MHz, CD 3 OD) δ ppm 7.87-8.14 (m, 1H) 7.51 (d, J = 8.53 Hz, 2H) 7.43 (d, J = 8.53 Hz, 1H) 7.27 (d, J = 8.53 Hz, 2H)7.15(d,J=8.53Hz,1H)6.81(s,1H)4.19(s,2H)3.99(s,3H)3.52(s,2H)2.54(br s,7H)2.31(s,3H) 2.10(s,3H)
实施例43：化合物43Example 43: Compound 43
Figure PCTCN2019070227-appb-000166
Figure PCTCN2019070227-appb-000166
合成路线：synthetic route:
Figure PCTCN2019070227-appb-000167
Figure PCTCN2019070227-appb-000167
步骤1：化合物43-B的合成Step 1: Synthesis of Compound 43-B
在0℃下，将4-甲酰基苯甲酸(300mg,2.00mmol)溶于二氯甲烷(7mL)中，向其中滴加溶于二氯甲烷(1mL)的二氯亚砜(4.92g,41.35mmol)，反应在40℃下，氮气保护搅拌3小时后，将反应液减压浓缩得到粗品43-B。4-formylbenzoic acid (300 mg, 2.00 mmol) was dissolved in dichloromethane (7 mL), and dichloromethane (1. (mmol), the reaction was stirred at 40 ° C for 3 hours under nitrogen. The reaction mixture was concentrated under reduced pressure to afford crude product 43-B.
MS m/z:164.8[M+H] + MS m/z: 164.8 [M+H] +
步骤2：化合物43-C的合成Step 2: Synthesis of Compound 43-C
将2-氨基-4-甲基-5-溴吡啶(206.37mg,1.10mmol)溶于二氯甲烷(9mL)中，向其中加入三乙胺(363.50mg,3.59mmol)，并滴加43-B(279mg,1.66mmol)，反应氮气保护下，在22℃下搅拌20小时后，向其中加入冰水(20mL)，用二氯甲烷(50mL)萃取，饱和食盐水(20mL)洗涤，硫酸钠干燥，过滤干燥剂，减压浓缩得到粗品，粗品经柱层析(石油醚：乙酸乙酯＝3:1)纯化得到粗品43-C。2-Amino-4-methyl-5-bromopyridine (206.37 mg, 1.10 mmol) was dissolved in dichloromethane (9 mL), triethylamine (363.50 mg, 3.59 mmol) was added thereto, and 43- B (279 mg, 1.66 mmol), and the mixture was stirred under a nitrogen atmosphere, and the mixture was stirred at 22 ° C for 20 hours, then ice water (20 mL) was added thereto, and extracted with dichloromethane (50 mL). Drying, filtration of the dried material, EtOAc (EtOAc:EtOAc)
MS m/z:318.8[M+H] + MS m/z: 318.8 [M+H] +
1H NMR(400MHz,CHLOROFORM-d)δppm 10.05(s,1H)8.40-8.58(m,1H)8.25(br s,1H)7.91-8.06(m,4H)2.40(s,3H) 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 10.05 (s, 1H) 8.40-8.58 (m, 1H) 8.25 (br s, 1H) 7.91-8.06 (m, 4H) 2.40 (s, 3H)
步骤3：化合物43-D的合成Step 3: Synthesis of Compound 43-D
将43-C(21mg,65.80μmol)溶于二氯甲烷(6mL)中，在0℃下向其中加入N-甲基哌嗪(19.77mg,197.40μmol)，醋酸(52.50mg,874.24μmol)，反应在16℃下搅拌1小时后，将温度降至0℃,向其中加入三乙酰基硼氢化钠(69.73mg,329.00μmol)，反应在16℃下搅拌12小时后，向其中加入饱和碳酸氢钠溶液调节pH至8，用二氯甲烷(40mL)萃取，饱和食盐水(10mL)洗涤，硫酸钠干燥，过滤干燥剂，减压浓缩得到粗品，粗品经柱层 析(二氯甲烷：甲醇＝10:1)纯化得到43-D。43-C (21 mg, 65.80 μmol) was dissolved in dichloromethane (6 mL), and N-methylpiperazine (19.77 mg, 197.40 μmol), acetic acid (52.50 mg, 874.24 μmol) was added thereto at 0 °C. After the reaction was stirred at 16 ° C for 1 hour, the temperature was lowered to 0 ° C, sodium triacetoxyborohydride (69.73 mg, 329.00 μmol) was added thereto, and the reaction was stirred at 16 ° C for 12 hours, and then saturated hydrogen carbonate was added thereto. The sodium solution was adjusted to pH 8 and extracted with dichloromethane (40 mL). EtOAc (EtOAc)EtOAc. 10:1) Purification affords 43-D.
MS m/z:403.0[M+H] + MS m/z: 403.0 [M+H] +
1H NMR(400MHz,CHLOROFORM-d)δppm 8.38-8.54(m,1H)8.27(d,J＝12.05Hz,2H)7.79(d,J＝8.03Hz,2H)7.40(d,J＝8.53Hz,2H)3.53(s,2H)2.35-2.61(m,11H)2.32(s,3H) 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.38-8.54 (m, 1H) 8.27 (d, J = 12.05 Hz, 2H) 7.79 (d, J = 8.03 Hz, 2H) 7.40 (d, J = 8.53 Hz, 2H)3.53(s,2H)2.35-2.61(m,11H)2.32(s,3H)
步骤4：化合物43-F的合成Step 4: Synthesis of Compound 43-F
将43-D(20mg,49.59μmol)溶于二氧六环(8mL)和水(0.8mL)中，向其中加入I(19.30mg,49.59μmol)，2-二环己基磷-2’,4’,6’-三异丙基联苯(9.46mg,19.84μmol)，磷酸钾(31.58mg,148.77μmol)，反应用氮气置换3次后加入三(二亚苄基丙酮)二钯(9.08mg,9.92μmol)，反应在氮气保护下，90℃搅拌12小时后，向其中加入水(10mL)，用乙酸乙酯(50mL)萃取，饱和食盐水(10mL)洗涤，硫酸钠干燥，过滤干燥剂，减压浓缩得到粗品，粗品经柱层析(二氯甲烷：甲醇＝10:1)纯化得到棕色油状物43-F。43-D (20 mg, 49.59 μmol) was dissolved in dioxane (8 mL) and water (0.8 mL), and I(19.30 mg, 49.59 μmol), 2-dicyclohexylphosphon-2',4 was added thereto. ',6'-triisopropylbiphenyl (9.46 mg, 19.84 μmol), potassium phosphate (31.58 mg, 148.77 μmol), the reaction was replaced with nitrogen three times, and then tris(dibenzylideneacetone)dipalladium (9.08 mg) was added. , 9.92 μmol), the reaction was stirred under nitrogen for 12 hours at 90 ° C, then water (10 mL) was added, extracted with ethyl acetate (50 mL), brine (10 mL) Concentration under reduced pressure afforded crude crystals.
MS m/z:586.3[M+H] + MS m/z: 586.3 [M+H] +
步骤5：化合物43的合成Step 5: Synthesis of Compound 43
将43-F(18mg,30.73μmol)溶于二氯甲烷(6mL)中，向其中加入三氟乙酸(770.00mg,6.75mmol)，反应在16℃下搅拌30分钟后，将反应液减压浓缩得到粗品，粗品用制备HPLC分离得到化合物43。43-F (18 mg, 30.73 μmol) was dissolved in dichloromethane (6 mL), trifluoroacetic acid (770.00 mg, 6.75 mmol) was added thereto, and the reaction was stirred at 16 ° C for 30 min. The crude product was obtained, and the crude material was purified by preparative HPLC.
MS m/z:486.2[M+H] + MS m/z: 486.2 [M+H] +
1H NMR(400MHz,METHANOL-d 4)δppm 8.15-8.31(m,2H)7.99(d,J＝8.03Hz,2H)7.44-7.58(m,3H)7.19(d,J＝8.53Hz,1H)4.19(s,2H)4.00(s,3H)3.65(s,2H)2.27-2.78(m,11H)2.25(s,3H) 1 H NMR (400 MHz, METHANOL-d 4 ) δ ppm 8.15-8.31 (m, 2H) 7.79 (d, J = 8.03 Hz, 2H) 7.44 - 7.58 (m, 3H) 7.19 (d, J = 8.53 Hz, 1H) 4.19(s,2H)4.00(s,3H)3.65(s,2H)2.27-2.78(m,11H)2.25(s,3H)
实施例44：化合物44Example 44: Compound 44
Figure PCTCN2019070227-appb-000168
Figure PCTCN2019070227-appb-000168
合成路线：synthetic route:
Figure PCTCN2019070227-appb-000169
Figure PCTCN2019070227-appb-000169
步骤1：化合物44-A的合成Step 1: Synthesis of Compound 44-A
除了使用相应的原料外，以实施例32中的制备化合物32-A相同的方法制备化合物44-A。Compound 44-A was prepared in the same manner as in the preparation of compound 32-A in Example 32 except that the corresponding material was used.
MS m/z:515.2[M+H] + MS m/z: 515.2 [M+H] +
步骤2：化合物44的合成Step 2: Synthesis of Compound 44
除了使用相应的原料外，以实施例32中的制备化合物32相同的方法制备化合物44。Compound 44 was prepared in the same manner as in the preparation of compound 32 in Example 32 except that the corresponding material was used.
MS m/z:415.0[M+H] + MS m/z: 415.0 [M+H] +
1H NMR(400MHz,CD 3OD)δppm 8.84-8.99(m,1H)8.55(dd,J＝8.53,2.26Hz,1H)8.08(s,1H)7.65-7.74(m,1H)7.44(d,J＝8.28Hz,1H)7.16(d,J＝8.53Hz,1H)6.89(s,1H)4.19(s,2H)3.99(s,3H)2.15(s,3H) 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.84-8.99 (m, 1H) 8.55 (dd, J = 8.53, 2.26 Hz, 1H) 8.08 (s, 1H) 7.65 - 7.74 (m, 1H) 7.44 (d, J = 8.28 Hz, 1H) 7.16 (d, J = 8.53 Hz, 1H) 6.89 (s, 1H) 4.19 (s, 2H) 3.99 (s, 3H) 2.15 (s, 3H)
实施例45：化合物45Example 45: Compound 45
Figure PCTCN2019070227-appb-000170
Figure PCTCN2019070227-appb-000170
合成路线：synthetic route:
Figure PCTCN2019070227-appb-000171
Figure PCTCN2019070227-appb-000171
步骤1：化合物45-B的合成Step 1: Synthesis of Compound 45-B
除了使用相应的原料外，以实施例32中的制备化合物32-A相同的方法制备化合物45-B。Compound 45-B was prepared in the same manner as in the preparation of compound 32-A in Example 32 except that the corresponding material was used.
MS m/z:539.1[M+H] + MS m/z: 539.1 [M+H] +
步骤2：化合物45的合成Step 2: Synthesis of Compound 45
除了使用相应的原料外，以实施例32中的制备化合物32相同的方法制备化合物45。Compound 45 was prepared in the same manner as in the preparation of compound 32 in Example 32 except that the corresponding material was used.
MS m/z:439.1[M+H] + MS m/z: 439.1 [M+H] +
1H NMR(400MHz,CDCl 3)δppm 7.91(br s,1H)7.32-7.41(m,4H)7.30(br d,J＝8.28Hz,1H)6.95(br d,J＝8.53Hz,1H)6.79(br s,1H)4.11(s,2H)3.97(d,J＝3.01Hz,3H)2.84(br s,3H)2.43(br s,2H)2.03(s,3H)1.87-1.98(m,3H) 1 H NMR (400 MHz, CDCl 3 ) δ ppm 7.91 (br s, 1H) 7.32-7.41 (m, 4H) 7.30 (brd, J = 8.28 Hz, 1H) 6.95 (br d, J = 8.53 Hz, 1H) 6.79 (br s,1H)4.11(s,2H)3.97(d,J=3.01Hz,3H)2.84(br s,3H)2.43(br s,2H)2.03(s,3H)1.87-1.98(m,3H )
实施例46：化合物46Example 46: Compound 46
Figure PCTCN2019070227-appb-000172
Figure PCTCN2019070227-appb-000172
合成路线：synthetic route:
Figure PCTCN2019070227-appb-000173
Figure PCTCN2019070227-appb-000173
步骤1：化合物46-A的合成Step 1: Synthesis of Compound 46-A
将N-甲基哌嗪(709.87mg,7.09mmol)溶于N,N-二甲基甲酰胺(10mL)中，向其中加入碳酸钾(979.49mg,7.09mmol)，反应在30℃下搅拌1h后，加入对氟硝基苯(500mg,3.54mmol)，反应体系用氮气置换3次后，在90℃下搅拌12h。向混合物中加入水(50mL)，用乙酸乙酯(100mL)萃取，萃取液用饱和食盐水(50mL)洗涤，硫酸钠干燥，过滤干燥剂，减压浓缩得到粗品，粗品经柱层析(洗脱剂：二氯甲烷/甲醇＝20/1)纯化得到46-A。N-methylpiperazine (709.87 mg, 7.09 mmol) was dissolved in N,N-dimethylformamide (10 mL), and potassium carbonate (979.49 mg, 7.09 mmol) was added thereto, and the reaction was stirred at 30 ° C for 1 h. Thereafter, p-fluoronitrobenzene (500 mg, 3.54 mmol) was added, and the reaction system was replaced with nitrogen three times, and then stirred at 90 ° C for 12 hours. Water (50 mL) was added to the mixture, and the mixture was evaporated, evaporated, evaporated. Deprotection: dichloromethane / methanol = 20/1) was purified to give 46-A.
MS m/z:222.0[M+H] + MS m/z: 222.0 [M+H] +
1H NMR(400MHz,CHLOROFORM-d)δppm 8.05(d,J＝9.54Hz,2H)6.75(d,J＝9.54Hz,2H)3.19-3.56(m,4H)2.42-2.61(m,4H)2.23-2.34(m,3H) 1 H NMR (400MHz, CHLOROFORM- d) δppm 8.05 (d, J = 9.54Hz, 2H) 6.75 (d, J = 9.54Hz, 2H) 3.19-3.56 (m, 4H) 2.42-2.61 (m, 4H) 2.23 -2.34(m,3H)
步骤2：化合物46-B的合成Step 2: Synthesis of Compound 46-B
将Pd/C(100mg,10％)加入到甲醇(30mL)中，向其中加入46-A(400mg,1.81mmol)，反应用氢气置换3次后，在氢气(15Psi)气氛下，加热到27℃搅拌12h。将混合液用硅藻土过滤，滤液减压浓缩得到粗品46-B，该粗品直接用于下一步反应。Pd/C (100 mg, 10%) was added to methanol (30 mL), 46-A (400 mg, 1.81 mmol) was added thereto, and the reaction was replaced with hydrogen three times, and then heated to 27 under a hydrogen (15 Psi) atmosphere. Stir at °C for 12 h. The mixture was filtered through celite, and the filtrate was evaporated.
MS m/z:192.0[M+H] + MS m/z: 192.0 [M+H] +
步骤3：化合物46-C的合成Step 3: Synthesis of Compound 46-C
将46-B(200mg,1.05mmol)溶于二氧六环中，向其中加入2,5-二溴-4-甲基吡啶(262.37mg,1.05mmol)，Xantphos(121.00mg,209.13μmol)，碳酸铯(1.02g,3.14mmol)。反应体系用氮气置换3次后加入醋酸钯(23.48mg,104.56μmol)，在氮气保护下，加热到90℃搅拌12h。向其中加入水(50mL)，用乙酸乙酯(100mL)萃取，萃取液用饱和食盐水(50mL)洗涤，硫酸钠干燥，过滤。滤液经减压浓缩得到粗品，粗品经柱层析(洗脱剂：二氯甲烷/甲醇＝10/1)纯化得到46-C。46-B (200 mg, 1.05 mmol) was dissolved in dioxane, and 2,5-dibromo-4-methylpyridine (262.37 mg, 1.05 mmol), Xantphos (121.00 mg, 209. Barium carbonate (1.02 g, 3.14 mmol). After the reaction system was replaced with nitrogen three times, palladium acetate (23.48 mg, 104.56 μmol) was added, and the mixture was heated to 90 ° C for 12 hours under nitrogen atmosphere. Water (50 mL) was added thereto, and ethyl acetate (100 mL) was evaporated. The filtrate was concentrated under reduced pressure to give a crude material.
MS m/z:361.0[M+H] + MS m/z: 361.0 [M+H] +
步骤4：化合物46-D的合成Step 4: Synthesis of Compound 46-D
将46-C(220mg,608.95μmol)溶于二氧六环(10mL)和水(1mL)中，向其中加入中间体I(237.03mg,608.95μmol)，Xphos(58.06mg,121.79μmol)，磷酸钾(387.78mg,1.83mmol)，反应体系用氮气置换3次后加入Pd 2(dba) 3(55.76mg,60.89μmol)，在氮气保护下，90℃搅拌12h后，反应液用硅藻土过滤，向滤液中加入水(50mL)，用乙酸乙酯(100mL)萃取，饱和食盐水(50mL)洗涤，硫酸钠干燥，过滤干燥剂，减压浓缩得到粗品，粗品经柱层析(洗脱剂：二氯甲烷/甲醇＝10/1)纯化得到46-D。 46-C (220 mg, 608.95 μmol) was dissolved in dioxane (10 mL) and water (1 mL), and Intermediate I (237.03 mg, 608.95 μmol), Xphos (58.06 mg, 121.79 μmol), phosphoric acid was added thereto. Potassium (387.78 mg, 1.83 mmol), the reaction system was replaced with nitrogen for 3 times, then Pd 2 (dba) 3 (55.76 mg, 60.89 μmol) was added. After stirring at 90 ° C for 12 h under nitrogen atmosphere, the reaction mixture was filtered through Celite. Water (50 mL) was added to the filtrate, and ethyl acetate (100 mL) was evaporated. : dichloromethane/methanol = 10/1) was purified to give 46-D.
MS m/z:544.3[M+H] + MS m/z: 544.3 [M+H] +
步骤5：化合物46的合成Step 5: Synthesis of Compound 46
将46-D(250mg,459.86μmol)溶于二氯甲烷(10mL)中，向其中加入三氟乙酸(1.54g,13.51mmol)，反应在28℃下搅拌30min后，将反应液减压浓缩得到粗品，粗品用制备HPLC(中性，乙腈，水)分离得到46。46-D (250 mg, 459.86 μmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (1.54 g, 13.51 mmol) was added thereto, and the reaction was stirred at 28 ° C for 30 min. The crude product was isolated using preparative HPLC (neut. EtOAc, EtOAc).
MS m/z:444.3[M+H] + MS m/z: 444.3 [M+H] +
1H NMR(400MHz,METHANOL-d 4)δppm 7.80-7.86(m,1H)7.40(d,J＝8.28Hz,1H)7.36(d,J＝9.03Hz,2H)7.12(d,J＝8.28Hz,1H)7.00(d,J＝9.03Hz,2H)6.70(s,1H)4.18(s,2H)3.98(s,3H)3.13-3.23(m,4H)2.62-2.70(m,4H)2.37(s,3H)2.07(s,3H) 1 H NMR (400 MHz, METHANOL-d 4 ) δ ppm 7.80-7.86 (m, 1H) 7.40 (d, J = 8.28 Hz, 1H) 7.36 (d, J = 9.03 Hz, 2H) 7.12 (d, J = 8.28 Hz) , 1H) 7.00 (d, J = 9.03 Hz, 2H) 6.70 (s, 1H) 4.18 (s, 2H) 3.98 (s, 3H) 3.13 - 3.23 (m, 4H) 2.62 - 2.70 (m, 4H) 2.37 ( s,3H)2.07(s,3H)
实施例47：化合物47Example 47: Compound 47
Figure PCTCN2019070227-appb-000174
Figure PCTCN2019070227-appb-000174
合成路线：synthetic route:
Figure PCTCN2019070227-appb-000175
Figure PCTCN2019070227-appb-000175
步骤1：化合物47-A的合成Step 1: Synthesis of Compound 47-A
除了使用相应的原料外，以实施例32中的制备化合物32-A相同的方法制备化合物47-A。Compound 47-A was prepared in the same manner as in the preparation of compound 32-A in Example 32 except that the corresponding material was used.
MS m/z:475.2[M+H] + MS m/z: 475.2 [M+H] +
步骤2：化合物47的合成Step 2: Synthesis of Compound 47
除了使用相应的原料外，以实施例32中的制备化合物32相同的方法制备化合物47。Compound 47 was prepared in the same manner as in the preparation of compound 32 in Example 32 except that the corresponding material was used.
MS m/z:375.2[M+H] + MS m/z: 375.2 [M+H] +
1H NMR(400MHz,CD3OD)δppm 8.68(d,J＝2.51Hz,1H)8.11(dd,J＝8.53,2.51Hz,1H)7.96(s,1H)7.43(d,J＝8.53Hz,1H)7.24(d,J＝8.53Hz,1H)7.15(d,J＝8.28Hz,1H)6.79(s,1H)4.19(s,2H)3.99(s,3H)2.77(q,J＝7.70Hz,2H)2.12(s,3H)1.29(t,J＝7.65Hz,3H) 1 H NMR (400MHz, CD3OD) δppm 8.68 (d, J = 2.51Hz, 1H) 8.11 (dd, J = 8.53,2.51Hz, 1H) 7.96 (s, 1H) 7.43 (d, J = 8.53Hz, 1H) 7.24 (d, J = 8.53 Hz, 1H) 7.15 (d, J = 8.28 Hz, 1H) 6.79 (s, 1H) 4.19 (s, 2H) 3.99 (s, 3H) 2.77 (q, J = 7.70 Hz, 2H) ) 2.12 (s, 3H) 1.29 (t, J = 7.65 Hz, 3H)
实施例48：化合物48Example 48: Compound 48
Figure PCTCN2019070227-appb-000176
Figure PCTCN2019070227-appb-000176
合成路线：synthetic route:
Figure PCTCN2019070227-appb-000177
Figure PCTCN2019070227-appb-000177
步骤1：化合物48-B的合成Step 1: Synthesis of Compound 48-B
除了使用相应的原料外，以实施例32中的制备化合物32-A相同的方法制备化合物48-B。Compound 48-B was prepared in the same manner as in the preparation of compound 32-A in Example 32 except that the corresponding material was used.
MS m/z:487.2[M+H] + MS m/z: 487.2 [M+H] +
步骤2：化合物48的合成Step 2: Synthesis of Compound 48
除了使用相应的原料外，以实施例32中的制备化合物32相同的方法制备化合物48。Compound 48 was prepared in the same manner as in the preparation of compound 32 in Example 32 except that the corresponding material was used.
MS m/z:387.2[M+H] + MS m/z: 387.2 [M+H] +
1H NMR(400MHz,CD 3OD)δppm 8.49-8.61(m,1H)8.00(dd,J＝8.53,2.51Hz,1H)7.92(s,1H)7.40(d,J＝8.53Hz,1H)7.11(d,J＝8.53Hz,2H)6.76(s,1H)4.18(s,2H)3.99(s,3H)2.02-2.12(m,4H)0.96-1.04(m,2H)0.85-0.93(m,2H) 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.49-8.61 (m, 1H) 8.00 (dd, J = 8.53, 2.51 Hz, 1H) 7.92 (s, 1H) 7.40 (d, J = 8.53 Hz, 1H) 7.11 (d, J = 8.53 Hz, 2H) 6.76 (s, 1H) 4.18 (s, 2H) 3.99 (s, 3H) 2.02 - 2.12 (m, 4H) 0.96-1.04 (m, 2H) 0.85 - 0.93 (m, 2H)
实施例49：化合物49Example 49: Compound 49
Figure PCTCN2019070227-appb-000178
Figure PCTCN2019070227-appb-000178
合成路线：synthetic route:
Figure PCTCN2019070227-appb-000179
Figure PCTCN2019070227-appb-000179
步骤1：化合物49-B的合成Step 1: Synthesis of Compound 49-B
将2,5-二溴吡啶(500mg,2.11mmol)溶于甲苯(10mL)中，在-70℃下将正丁基锂(162.24mg,2.53mmol,2.5M)滴入，反应在-70℃下搅拌1h后，向其中滴入溶于甲苯(1mL)的49-A(167.31mg,2.32mmol)溶液。反应在-70℃下搅拌30min后，向混合液中滴加饱和氯化铵溶液(10mL)，用乙酸乙酯(50mL)萃取，饱和食盐水(10mL)洗涤，硫酸钠干燥，过滤干燥剂，减压浓缩得到粗品，粗品经柱层析(洗脱剂：石油醚/乙酸乙酯＝3/1)纯化得到49-B。2,5-Dibromopyridine (500 mg, 2.11 mmol) was dissolved in toluene (10 mL), n-butyllithium (162.24 mg, 2.53 mmol, 2.5 M) was added dropwise at -70 ° C, and the reaction was at -70 ° C. After stirring for 1 hour, a solution of 49-A (167.31 mg, 2.32 mmol) dissolved in toluene (1 mL) was added dropwise. After the reaction was stirred at -70 ° C for 30 min, a saturated aqueous solution of ammonium chloride (10 mL) was added dropwise, ethyl acetate (50 mL), and brine (10 mL) Concentration under reduced pressure gave a crude material.
MS m/z:229.8[M+H] + MS m/z: 229.8 [M+H] +
1H NMR(400MHz,CDCl 3)δppm 8.52(d,J＝2.01Hz,1H)7.93(dd,J＝8.28,2.26Hz,1H)7.82(d,J＝8.53Hz,1H)5.48(br s,1H)5.01(d,J＝7.03Hz,2H)4.64(d,J＝7.53Hz,2H) 1 H NMR (400MHz, CDCl 3 ) δppm 8.52 (d, J = 2.01Hz, 1H) 7.93 (dd, J = 8.28,2.26Hz, 1H) 7.82 (d, J = 8.53Hz, 1H) 5.48 (br s, 1H) 5.01 (d, J = 7.03 Hz, 2H) 4.64 (d, J = 7.53 Hz, 2H)
步骤2：化合物49-C的合成Step 2: Synthesis of Compound 49-C
除了使用相应的原料外，以实施例32中的制备化合物32-A相同的方法制备化合物49-C。Compound 49-C was prepared in the same manner as in the preparation of compound 32-A in Example 32 except that the corresponding material was used.
MS m/z:519.1[M+H] + MS m/z: 519.1 [M+H] +
步骤3：化合物49的合成Step 3: Synthesis of Compound 49
除了使用相应的原料外，以实施例32中的制备化合物32相同的方法制备化合物49。Compound 49 was prepared in the same manner as in the preparation of compound 32 in Example 32 except that the corresponding material was used.
MS m/z:419.1[M+H] + MS m/z: 419.1 [M+H] +
1H NMR(400MHz,CD 3OD)δppm 8.85-8.94(m,1H)8.28(dd,J＝8.66,2.63Hz,1H)8.00(s,1H)7.67(d,J＝8.78Hz,1H)7.44(d,J＝8.28Hz,1H)7.16(d,J＝8.53Hz,1H)6.84(s,1H)5.04(d,J＝6.53Hz,2H)4.86(d,J＝6.53Hz,2H)4.20(s,2H)3.99(s,3H)2.14(s,3H) 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.85-8.94 (m, 1H) 8.28 (dd, J = 8.66, 2.63 Hz, 1H) 8.00 (s, 1H) 7.67 (d, J = 8.78 Hz, 1H) 7.44 (d, J = 8.28 Hz, 1H) 7.16 (d, J = 8.53 Hz, 1H) 6.84 (s, 1H) 5.04 (d, J = 6.53 Hz, 2H) 4.86 (d, J = 6.53 Hz, 2H) 4.20 (s, 2H) 3.99 (s, 3H) 2.14 (s, 3H)
实施例50：化合物50Example 50: Compound 50
Figure PCTCN2019070227-appb-000180
Figure PCTCN2019070227-appb-000180
合成路线：synthetic route:
Figure PCTCN2019070227-appb-000181
Figure PCTCN2019070227-appb-000181
步骤1：化合物50-B的合成Step 1: Synthesis of Compound 50-B
将化合物50-A(300mg,2.02mmol)溶于乙腈(20mL)中，向其中加入化合物II-A(378.72mg,2.02mmol)，三氟乙酸(2.31g,20.25mmol)，三乙基硅烷(2.35g,20.25mmol)，反应在氮气保护下，80℃下搅拌12h后，向反应液中加入饱和碳酸氢钠溶液调节pH至8，用乙酸乙酯(100mL)萃取，饱和食盐水洗涤，硫酸钠干燥，过滤干燥剂，减压浓缩得到粗品，粗品经柱层析(洗脱剂：石油醚/四氢呋喃＝2/1)纯化后得到化合物50-B。Compound 50-A (300 mg, 2.02 mmol) was dissolved in acetonitrile (20 mL), to which compound II-A (378.72 mg, 2.02 mmol), trifluoroacetic acid (2.31 g, 20.25 mmol), triethyl silane ( 2.35g, 20.25mmol), the reaction was stirred under nitrogen for 12h at 80 ° C, then added saturated sodium bicarbonate solution to adjust the pH to 8, extracted with ethyl acetate (100mL), washed with saturated brine, sulfuric acid The mixture was dried over sodium sulfate, filtered and evaporated to dryness crystals.
MS m/z:319.0[M+H] + MS m/z: 319.0 [M+H] +
1H NMR(400MHz,CDCl 3)δppm 8.03(s,1H)7.85(d,J＝8.53Hz,2H)7.35(d,J＝8.03Hz,2H)7.19(s,1H) 6.20(s,1H)4.49(d,J＝6.02Hz,2H)2.52(s,3H)2.18(s,3H) 1 H NMR (400 MHz, CDCl 3 ) δ ppm 8.03 (s, 1H) 7.85 (d, J = 8.53 Hz, 2H) 7.35 (d, J = 8.03 Hz, 2H) 7.19 (s, 1H) 6.20 (s, 1H) 4.49 (d, J = 6.02 Hz, 2H) 2.52 (s, 3H) 2.18 (s, 3H)
步骤2：化合物50-C的合成Step 2: Synthesis of Compound 50-C
将化合物50-B(200mg,626.57μmol)溶于四氢呋喃(15mL)中，反应体系用氮气置换3次后，在氮气保护，0℃下向其中滴加甲基溴化镁(3M,1.67mL)。反应在氮气保护，25℃下搅拌2h后，降温到0℃，向其中滴加饱和氯化铵溶液(3mL)，用乙酸乙酯(50mL)萃取3次，合并的萃取液用饱和食盐水(10mL)洗涤，硫酸钠干燥，过滤干燥剂，减压浓缩得到粗品，粗品经柱层析(洗脱剂：石油醚/四氢呋喃＝1/1)纯化得到化合物50-C。Compound 50-B (200 mg, 626.57 μmol) was dissolved in tetrahydrofuran (15 mL). After the reaction was replaced with nitrogen three times, methyl magnesium bromide (3M, 1.67 mL) was added dropwise at 0 ° C under nitrogen. . The reaction was stirred under nitrogen for 2 h at 25 ° C, then cooled to 0 ° C, then saturated aqueous ammonium chloride solution (3 mL) was added dropwise, and extracted three times with ethyl acetate (50 mL). The mixture was washed with EtOAc (3 mL).
MS m/z:334.9[M+H] + MS m/z: 334.9 [M+H] +
步骤3：化合物50-D的合成Step 3: Synthesis of Compound 50-D
除了使用相应的原料外，以实施例9中的制备化合物9-A相同的方法制备化合物50-D。Compound 50-D was prepared in the same manner as in the preparation of compound 9-A in Example 9 except that the corresponding material was used.
MS m/z:518.3[M+H] + MS m/z: 518.3 [M+H] +
步骤4：化合物50的合成Step 4: Synthesis of Compound 50
除了使用相应的原料外，以实施例9中的化合物9相同的方法制备化合物50。Compound 50 was prepared in the same manner as Compound 9 in Example 9, except that the corresponding materials were used.
MS m/z:418.0[M+H] + MS m/z: 418.0 [M+H] +
1H NMR(400MHz,CD 3OD)δppm 7.74(s,1H)7.47(d,J＝8.28Hz,2H)7.39(d,J＝8.53Hz,1H)7.35(d,J＝8.28Hz,2H)7.12(d,J＝8.28Hz,1H)6.52(s,1H)4.51(s,2H)4.16(s,2H)3.98(s,3H)2.03(s,3H)1.54(s,6H) 1 H NMR (400 MHz, CD 3 OD) δ ppm 7.74 (s, 1H) 7.47 (d, J = 8.28 Hz, 2H) 7.39 (d, J = 8.53 Hz, 1H) 7.35 (d, J = 8.28 Hz, 2H) 7.12 (d, J = 8.28 Hz, 1H) 6.52 (s, 1H) 4.51 (s, 2H) 4.16 (s, 2H) 3.98 (s, 3H) 2.03 (s, 3H) 1.54 (s, 6H)
实施例51：化合物51Example 51: Compound 51
Figure PCTCN2019070227-appb-000182
Figure PCTCN2019070227-appb-000182
合成路线：synthetic route:
Figure PCTCN2019070227-appb-000183
Figure PCTCN2019070227-appb-000183
步骤1：化合物51-B的合成Step 1: Synthesis of Compound 51-B
将化合物51-A(200mg,892.47μmol)溶于二氧六环(10mL)和水(1mL)中，向其中加入乙烯基三氟硼酸钾(179.32mg,1.34mmol)，碳酸钾(370.03mg,2.68mmol)，反应体系用氮气置换3次后，加入Pd(dppf)Cl 2-DCM(72.88mg,89.25μmol)。反应在氮气保护90℃下搅拌2h后，将反应液用硅藻土过滤，向其中加入水(50mL)，用乙酸乙酯(100mL)萃取，饱和食盐水(50mL)洗涤，硫酸钠干燥，过滤干燥剂，减压浓缩得到粗品，粗品经柱层析(洗脱剂：石油醚/乙酸乙酯＝6/1)纯化得到化合物51-B。 Compound 51-A (200 mg, 892.47 μmol) was dissolved in dioxane (10 mL) and water (1 mL), and potassium trifluoroborate (179.32 mg, 1.34 mmol), potassium carbonate (370.03 mg, 2.68 mmol), after the reaction system was replaced with nitrogen three times, Pd(dppf)Cl 2 -DCM (72.88 mg, 89.25 μmol) was added. After the reaction was stirred at 90 ° C for 2 h under nitrogen, EtOAc (EtOAc)EtOAc. The desiccant was concentrated under reduced pressure to give a crude material.
MS m/z:173.1[M+H] + MS m/z: 173.1 [M+H] +
步骤2：化合物51-C的合成Step 2: Synthesis of Compound 51-C
将化合物51-B(200mg,1.17mmol)溶于四氢呋喃(10mL)和水(10mL)中，向其中加入高碘酸钠(499.63mg,2.34mmol)，四氧化锇(1.19g,116.80μmol)，反应在28℃下搅拌12h后，向反应液中加入水(30mL)，用乙酸乙酯(100mL)萃取，无水硫酸钠干燥，过滤干燥剂，减压浓缩得到粗品，粗品用制备TLC(展开剂：PE/EA＝5/1)纯化得到化合物51-C。Compound 51-B (200 mg, 1.17 mmol) was dissolved in tetrahydrofuran (10 mL) and water (10 mL), and sodium iodate (499.63 mg, 2.34 mmol), osmium tetroxide (1.19 g, 116.80 μmol), After the reaction was stirred at 28 ° C for 12 h, water (30 mL) was evaporated, evaporated, evaporated. The compound: PE/EA = 5/1) was purified to give the compound 51-C.
1H NMR(400MHz,CDCl 3)δppm 9.92-10.14(m,1H)7.92(d,J＝8.03Hz,1H)7.66(d,J＝8.53Hz,2H)1.76(s,6H) 1 H NMR (400MHz, CDCl 3 ) δppm 9.92-10.14 (m, 1H) 7.92 (d, J = 8.03Hz, 1H) 7.66 (d, J = 8.53Hz, 2H) 1.76 (s, 6H)
步骤3：化合物51-D的合成Step 3: Synthesis of Compound 51-D
将化合物51-C(210mg,1.21mmol)溶于乙腈(20mL)中，向其中加入化合物II-A(226.76mg,1.21mmol)，三氟乙酸(3.85g,33.77mmol)，三乙基硅氢(3.64g,31.30mmol)，反应在氮气保护，80℃下搅拌12h后，将反应液减压浓缩，用饱和碳酸氢钠溶液调节pH至8，用乙酸乙酯(100mL)萃取，饱和食盐水(50mL)洗涤，硫酸钠干燥，过滤干燥剂，减压浓缩得到粗品，粗品经柱层析(洗脱剂：石油醚/乙酸乙酯＝3/1)纯化得到化合物51-D。Compound 51-C (210 mg, 1.21 mmol) was dissolved in acetonitrile (20 mL). Compound II-A (226.76 mg, 1.21 mmol), trifluoroacetic acid (3.85 g, 33.77 mmol), triethylsilylhydrogen (3.64g, 31.30mmol), the reaction was stirred under nitrogen, and then stirred at 80 ° C for 12h, then the reaction mixture was concentrated under reduced pressure. The mixture was adjusted to pH 8 with saturated sodium hydrogen carbonate solution and extracted with ethyl acetate (100 mL) (50 mL) was washed with EtOAc EtOAc (EtOAc m.
MS m/z:344.1[M+H] + MS m/z: 344.1 [M+H] +
步骤4：化合物51-E的合成Step 4: Synthesis of Compound 51-E
除了使用相应的原料外，以实施例9中的制备化合物9-A相同的方法制备化合物51-E。Compound 51-E was prepared in the same manner as in the preparation of compound 9-A in Example 9 except that the corresponding material was used.
MS m/z:527.2[M+H] + MS m/z: 527.2 [M+H] +
步骤5：化合物51的合成Step 5: Synthesis of Compound 51
除了使用相应的原料外，以实施例9中的制备化合物9相同的方法制备化合物51。Compound 51 was prepared in the same manner as in the preparation of compound 9 in Example 9 except that the corresponding materials were used.
MS m/z:427.2[M+H] + MS m/z: 427.2 [M+H] +
1H NMR(400MHz,CD 3OD)δppm 7.75(s,1H)7.48-7.53(m,2H)7.42-7.47(m,2H)7.39(d,J＝8.53Hz,1H)7.12(d,J＝8.03Hz,1H)6.53(s,1H)4.56(s,2H)4.16(s,2H)3.98(s,3H)2.04(s,3H)1.73(s,6H) 1 H NMR (400 MHz, CD 3 OD) δ ppm 7.75 (s, 1H) 7.48-7.53 (m, 2H) 7.42-7.47 (m, 2H) 7.39 (d, J = 8.53 Hz, 1H) 7.12 (d, J = 8.03Hz,1H)6.53(s,1H)4.56(s,2H)4.16(s,2H)3.98(s,3H)2.04(s,3H)1.73(s,6H)
实施例52：化合物52Example 52: Compound 52
Figure PCTCN2019070227-appb-000184
Figure PCTCN2019070227-appb-000184
合成路线：synthetic route:
Figure PCTCN2019070227-appb-000185
Figure PCTCN2019070227-appb-000185
步骤1：化合物52-B的合成Step 1: Synthesis of Compound 52-B
除了使用相应的原料外，以实施例5中的制备化合物5C相同的方法制备化合物52-B。Compound 52-B was prepared in the same manner as in the preparation of compound 5C in Example 5 except that the corresponding material was used.
MS m/z:336.0[M+H] + MS m/z: 336.0 [M+H] +
步骤2：化合物52-C的合成Step 2: Synthesis of Compound 52-C
除了使用相应的原料外，以实施例9中的制备化合物9-A相同的方法制备化合物52-C。Compound 52-C was prepared in the same manner as in the preparation of compound 9-A in Example 9 except that the corresponding material was used.
MS m/z:519.1[M+H] + MS m/z: 519.1 [M+H] +
步骤3：化合物52的合成Step 3: Synthesis of Compound 52
除了使用相应的原料外，以实施例9中的制备化合物9相同的方法制备化合物52。Compound 52 was prepared in the same manner as in the preparation of compound 9 in Example 9 except that the corresponding material was used.
MS m/z:419.2[M+H] + MS m/z: 419.2 [M+H] +
1H NMR(400MHz,CD 3OD)δppm 8.51(d,J＝1.51Hz,1H)7.83(dd,J＝8.03,2.01Hz,1H)7.76(s,1H)7.67(d,J＝8.53Hz,1H)7.38(d,J＝8.53Hz,1H)7.12(d,J＝8.53Hz,1H)6.55(s,1H)4.59(s,2H)4.15(s,2H)3.90-4.02(m,3H)1.95-2.15(m,3H)1.49-1.65(m,6H) 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.51 (d, J = 1.51 Hz, 1H) 7.83 (dd, J = 8.03, 2.01 Hz, 1H) 7.76 (s, 1H) 7.67 (d, J = 8.53 Hz, 1H) 7.38 (d, J = 8.53 Hz, 1H) 7.12 (d, J = 8.53 Hz, 1H) 6.55 (s, 1H) 4.59 (s, 2H) 4.15 (s, 2H) 3.90-4.02 (m, 3H) 1.95-2.15(m,3H)1.49-1.65(m,6H)
实施例53：化合物53Example 53: Compound 53
Figure PCTCN2019070227-appb-000186
Figure PCTCN2019070227-appb-000186
合成路线：synthetic route:
Figure PCTCN2019070227-appb-000187
Figure PCTCN2019070227-appb-000187
步骤1：化合物53-B的合成Step 1: Synthesis of Compound 53-B
将37-A(100mg,526.28μmol)溶于N,N-二甲基甲酰胺(10mL)中，向其中加入53-A(65.85mg,526.28μmol)，碳酸钾(218.21mkg,1.58mmol)，反应用氮气置换3次后，在氮气保护，130℃下搅拌12h后，向反应液中加入水(50mL)，用乙酸乙酯(100mL)萃取，水(20mL)洗涤，饱和食盐水(50mL)洗涤，硫酸钠干燥，过滤干燥剂，减压浓缩得到粗品，粗品经柱层析(洗脱剂：石油醚/乙酸乙酯＝6/1)纯化得到53-B。37-A (100 mg, 526.28 μmol) was dissolved in N,N-dimethylformamide (10 mL), and 53-A (65.85 mg, 526.28 μmol), potassium carbonate (218.21 mkg, 1.58 mmol), After the reaction was replaced with nitrogen for 3 times, the mixture was stirred under a nitrogen atmosphere and stirred at 130 ° C for 12 h, then water (50 mL) was added to the reaction mixture, which was extracted with ethyl acetate (100 mL), water (20 mL), and brine (50 mL) The organic layer was dried (MgSO4).
MS m/z:294.9[M+H] + MS m/z: 294.9 [M+H] +
1H NMR(400MHz,CHLOROFORM-d)δppm 8.16(s,1H)8.01(d,J＝3.01Hz,1H)7.39(dd,J＝8.78,2.76Hz,1H)6.83(s,1H)6.78(d,J＝9.03Hz,1H)3.94(s,3H)2.40(s,3H)1.56(d,J＝2.51Hz,3H) 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.16 (s, 1H) 8.01 (d, J = 3.01 Hz, 1H) 7.39 (dd, J = 8.78, 2.76 Hz, 1H) 6.83 (s, 1H) 6.78 (d) , J=9.03Hz, 1H)3.94(s,3H)2.40(s,3H)1.56(d,J=2.51Hz,3H)
步骤2：化合物53-C的合成Step 2: Synthesis of Compound 53-C
除了使用相应的原料外，以实施例9中的制备化合物9-A相同的方法制备化合物53-C。Compound 53-C was prepared in the same manner as in the preparation of compound 9-A in Example 9 except that the corresponding material was used.
MS m/z:478.2[M+H] + MS m/z: 478.2 [M+H] +
步骤3：化合物53的合成Step 3: Synthesis of Compound 53
除了使用相应的原料外，以实施例9中的制备化合物9相同的方法制备化合物53。Compound 53 was prepared in the same manner as in the preparation of compound 9 in Example 9 except that the corresponding material was used.
MS m/z:378.1[M+H] + MS m/z: 378.1 [M+H] +
1H NMR(400MHz,DMSO-d 6)δppm 8.26(s,1H)8.06(d,J＝2.51Hz,1H)7.96(s,1H)7.62(dd,J＝9.03,3.01Hz,1H)7.39(d,J＝8.03Hz,1H)7.04-7.16(m,2H)6.90(d,J＝8.53Hz,1H)4.04(s,2H)3.89(s,3H)3.87(s, 3H)2.14(s,3H) 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 8.26 (s, 1H) 8.06 (d, J = 2.51 Hz, 1H) 7.96 (s, 1H) 7.62 (dd, J = 9.03, 3.01 Hz, 1H) 7.39 ( d, J = 8.03 Hz, 1H) 7.04-7.16 (m, 2H) 6.90 (d, J = 8.53 Hz, 1H) 4.04 (s, 2H) 3.89 (s, 3H) 3.87 (s, 3H) 2.14 (s, 3H)
实施例54：化合物54Example 54: Compound 54
Figure PCTCN2019070227-appb-000188
Figure PCTCN2019070227-appb-000188
合成路线：synthetic route:
Figure PCTCN2019070227-appb-000189
Figure PCTCN2019070227-appb-000189
步骤1：化合物54-B的合成Step 1: Synthesis of Compound 54-B
将54-A(225.2mg,2.56mmol)溶于N,N-二甲基甲酰胺(20mL)中，向其中加入碳酸铯(1.67g,5.11mmol)，2-氟-5-溴吡啶(300mg,1.70mmol)，反应用氮气置换3次后，在氮气保护，130℃下搅拌12h后，向反应液中加入水(30mL)，用二氯甲烷(50mL)萃取，饱和食盐水(30mL)洗涤，硫酸钠干燥，过滤干燥剂，减压浓缩得到粗品，粗品经柱层析(洗脱剂：石油醚/乙酸乙酯＝8/1)纯化得到54-B。54-A (225.2 mg, 2.56 mmol) was dissolved in N,N-dimethylformamide (20 mL), and cesium carbonate (1.67 g, 5.11 mmol), 2-fluoro-5-bromopyridine (300 mg) was added thereto. After the reaction was replaced with nitrogen for 3 times, the mixture was stirred under nitrogen for 12 h at 130 ° C, then water (30 mL) was added to the reaction mixture, and the mixture was washed with dichloromethane (50 mL) and brine (30 mL) The organic layer was dried over sodium sulfate, filtered and evaporated to dryness.
MS m/z:243.9[M+H] + MS m/z: 243.9 [M+H] +
1H NMR(400MHz,CDCl 3)δppm 8.05-8.27(m,1H)7.53-7.71(m,1H)6.55-6.74(m,1H)5.38-5.58(m,1H)3.93-4.04(m,2H)3.83-3.93(m,2H)2.18-2.32(m,1H)2.05-2.15(m,1H) 1 H NMR (400 MHz, CDCl 3 ) δ ppm 8.05-8.27 (m, 1H) 7.53-7.71 (m, 1H) 6.55-6.74 (m, 1H) 5.38-5.58 (m, 1H) 3.93-4.04 (m, 2H) 3.83-3.93(m,2H)2.18-2.32(m,1H)2.05-2.15(m,1H)
步骤2：化合物54-C的合成Step 2: Synthesis of Compound 54-C
将54-B(369mg,1.51mmol)溶于二氧六环(20mL)中，向其中加入Ⅱ-A(282.76mg,1.51mmol)，4,5-双二苯基膦-9,9-二甲基氧杂蒽(174.95mg,302.35umol),碳酸铯(1.48g,4.54mmol),反应用N 2置换3次后加入醋酸钯(33.94mg,151.18umol),反应在N 2保护下，90℃搅拌12h后，向其中加入水(50mL)，用乙酸乙酯(100mL)萃取，饱和食盐水(50mL)洗涤，硫酸钠干燥，过滤干燥剂，减压旋蒸得到粗品，粗品经柱层析(洗脱剂，石油醚/乙 酸乙酯＝1/1)纯化后得到54-C。 54-B (369 mg, 1.51 mmol) was dissolved in dioxane (20 mL), and II-A (282.76 mg, 1.51 mmol), 4,5-bisdiphenylphosphine-9,9-di Methyl xanthene (174.95 mg, 302.35 umol), cesium carbonate (1.48 g, 4.54 mmol), the reaction was replaced with N 2 for 3 times, then palladium acetate (33.94 mg, 151.18 umol) was added, the reaction was under N 2 protection, 90 After stirring at °C for 12 h, water (50 mL) was evaporated, evaporated, evaporated, evaporated. (eluent, petroleum ether / ethyl acetate = 1 / 1) was purified to give 54-C.
MS m/z:350.0[M+H] + MS m/z: 350.0 [M+H] +
步骤3：化合物54-D的合成Step 3: Synthesis of Compound 54-D
除了使用相应的原料外，以实施例9中的制备化合物9-A相同的方法制备化合物54-D。Compound 54-D was prepared in the same manner as in the preparation of compound 9-A in Example 9 except that the corresponding material was used.
MS m/z:533.2[M+H] + MS m/z: 533.2 [M+H] +
步骤4：化合物54的合成Step 4: Synthesis of Compound 54
除了使用相应的原料外，以实施例9中的制备化合物9相同的方法制备化合物54。Compound 54 was prepared in the same manner as in the preparation of compound 9 in Example 9 except that the corresponding material was used.
MS m/z:433.2[M+H] + MS m/z: 433.2 [M+H] +
1H NMR(400MHz,CD 3OD)δppm 8.27-8.36(m,1H)7.90(dd,J＝8.78,2.76Hz,1H)7.86(s,1H)7.43(d,J＝8.28Hz,1H)7.15(d,J＝8.53Hz,1H)6.83(d,J＝9.03Hz,1H)6.79(s,1H)5.34-5.62(m,1H)4.19(s,2H)3.98-4.07(m,5H)3.87-3.94(m,2H)2.24-2.37(m,1H)2.10-2.19(m,4H) 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.27-8.36 (m, 1H) 7.90 (dd, J = 8.78, 2.76 Hz, 1H) 7.86 (s, 1H) 7.43 (d, J = 8.28 Hz, 1H) 7.15 (d, J = 8.53 Hz, 1H) 6.83 (d, J = 9.03 Hz, 1H) 6.79 (s, 1H) 5.34 - 5.62 (m, 1H) 4.19 (s, 2H) 3.98 - 4.07 (m, 5H) 3.87 -3.94(m,2H)2.24-2.37(m,1H)2.10-2.19(m,4H)
实施例55：化合物55Example 55: Compound 55
Figure PCTCN2019070227-appb-000190
Figure PCTCN2019070227-appb-000190
合成路线：synthetic route:
Figure PCTCN2019070227-appb-000191
Figure PCTCN2019070227-appb-000191
步骤1：化合物55-B的合成Step 1: Synthesis of Compound 55-B
将NaH(33.90mg,847.58μmol,60％purity)加入四氢呋喃(5mL)中，在0℃下加入环丙醇(24.61mg,423.79μmol)，反应在25℃下搅拌30min后，降温到0℃并加入55-A(50mg,282.53μmol)，反应在25℃下搅拌1.5h后，再 在0℃下，向其中滴加饱和氯化铵溶液(5mL)淬灭反应，用乙酸乙酯(30mL)萃取，食盐水(20mL)洗涤，硫酸钠干燥，过滤干燥剂，减压浓缩得到粗品，粗品用制备TLC(展开剂：石油醚/乙酸乙酯＝10/1)纯化得到55-B。To a tetrahydrofuran (5 mL), NaH (33. After adding 55-A (50 mg, 282.53 μmol), the reaction was stirred at 25 ° C for 1.5 h, and then a saturated ammonium chloride solution (5 mL) was added dropwise at 0 ° C to quench the reaction with ethyl acetate (30 mL) The extract was washed with brine (20 mL), dried over sodium sulfate.
MS m/z:214.5[M+H] + MS m/z: 214.5 [M+H] +
1H NMR(400MHz,CDCl 3)δppm 8.27(s,1H)8.03(s,1H)4.25(tt,J＝6.05,3.11Hz,1H)0.78-0.91(m,4H) 1 H NMR (400 MHz, CDCl 3 ) δ ppm 8.27 (s, 1H) 8.03 (s, 1H) 4.25 (tt, J = 6.05, 3.11 Hz, 1H) 0.78-0.91 (m, 4H)
步骤2：化合物55-C的合成Step 2: Synthesis of Compound 55-C
将55-B(50mg,232.51umol)溶于二氧六环(10mL)中，向其中加入2-氨基-4-甲基-5-溴吡啶(39.14mg,209.26umol),4,5-双二苯基膦-9,9-二甲基氧杂蒽(53.81mg,93.00umol),碳酸铯(227.27mg,697.52umol),反应用N2置换3次后加入醋酸钯(10.44mg,46.50umol),反应在N2保护下，90℃搅拌12h后，将反应液用硅藻土过滤后，向滤液中加入水(50mL)，用乙酸乙酯(80mL)萃取，饱和食盐水(50mL)洗涤，硫酸钠干燥，过滤干燥剂，减压浓缩得到粗品，粗品用制备TLC(展开剂，石油醚:乙酸乙酯＝3:1)纯化后得到化合物55-C。55-B (50 mg, 232.51 umol) was dissolved in dioxane (10 mL), and 2-amino-4-methyl-5-bromopyridine (39.14 mg, 209.26 umol), 4,5-bis Diphenylphosphine-9,9-dimethyloxaxime (53.81 mg, 93.00 umol), cesium carbonate (227.27 mg, 697.52 umol), the reaction was replaced with N2 three times and then palladium acetate (10.44 mg, 46.50 umol) was added. The reaction was stirred under N2 and stirred at 90 ° C for 12h. After the mixture was filtered over Celite, water (50 mL) was added to the filtrate, and the mixture was extracted with ethyl acetate (80 mL) The sodium was dried, and the residue was evaporated to dryness crystals crystals crystals
MS m/z:320.7[M+H] + MS m/z: 320.7 [M+H] +
1H NMR(400MHz,CDCl 3)δppm 8.55(d,J＝1.25Hz,1H)8.19(s,1H)7.85(d,J＝1.51Hz,1H)7.15(s,1H)4.05-4.16(m,1H)2.30(s,3H)0.70-0.78(m,4H) 1 H NMR (400 MHz, CDCl 3 ) δ ppm 8.55 (d, J = 1.25 Hz, 1H) 8.19 (s, 1H) 7.85 (d, J = 1.51 Hz, 1H) 7.15 (s, 1H) 4.05 - 4.16 (m, 1H) 2.30 (s, 3H) 0.70-0.78 (m, 4H)
步骤3：化合物55-D的合成Step 3: Synthesis of Compound 55-D
将55-C(100mg,465.01umol)溶于二氧六环(10mL)，水(1mL)中，向其中加入I(186.64mg,479.49umol),2-二环己基磷-2’,4’,6’-三异丙基联苯(41.56mg,87.18umol)，磷酸钾(277.58mg,1.31mmol),反应用N2置换3次后加入三(二亚苄基丙酮)二钯(39.92mg,43.59umol)，反应在N 2保护下，90℃搅拌3h后，向反应液中加入水(50mL),用乙酸乙酯(100mL)萃取，饱和食盐水(50mL)洗涤，硫酸钠干燥，过滤干燥剂，减压浓缩得到粗品，粗品经柱层析(洗脱剂，石油醚：四氢呋喃＝1:1)纯化得到化合物55-D。 55-C (100 mg, 465.01 umol) was dissolved in dioxane (10 mL), water (1 mL), and I (186.64 mg, 479.49 umol), 2-dicyclohexylphosphon-2', 4' , 6'-triisopropylbiphenyl (41.56 mg, 87.18 umol), potassium phosphate (277.58 mg, 1.31 mmol), the reaction was replaced with N2 three times, then tris(dibenzylideneacetone)dipalladium (39.92 mg, 43.59 umol), the reaction was stirred under N 2 and then stirred at 90 ° C for 3h, then water (50 mL) was added to the mixture, which was extracted with ethyl acetate (100 mL), washed with brine (50 mL) The mixture was concentrated under reduced pressure to give crude crystals.
MS m/z:504.2[M+H] + MS m/z: 504.2 [M+H] +
步骤4：化合物55的合成Step 4: Synthesis of Compound 55
将55-D(160mg,317.74umol)溶于二氯甲烷(10mL)中，向其中加入三氟乙酸(770.00mg,6.75mmol),反应在20℃下搅拌15min后,向反应液中加入饱和碳酸氢钠溶液调节pH至8，用二氯甲烷(50mL)萃取，饱和食盐水(50mL)洗涤，硫酸钠干燥，过滤干燥剂，减压浓缩得到粗品，粗品用(石油醚：乙酸乙酯＝2:1)(3mL)洗涤，过滤固体，减压抽干，得到化合物55。55-D (160 mg, 317.74 umol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (770.00 mg, 6.75 mmol) was added thereto, and the reaction was stirred at 20 ° C for 15 min, then saturated carbonic acid was added to the reaction mixture. The sodium hydrogen hydride solution was adjusted to pH 8 and extracted with dichloromethane (50 mL). EtOAc (EtOAc)EtOAc :1) (3 mL) was washed, and the solid was filtered and evaporated to dryness to give Compound 55.
MS m/z:404.0[M+H] + MS m/z: 404.0 [M+H] +
1H NMR(400MHz,DMSO-d 6)δppm 9.66-9.83(m,1H)8.87(s,1H)8.25(s,1H)8.05(br s,2H)7.39(d,J＝8.53Hz,1H)7.33(s,1H)7.10(br d,J＝8.28Hz,1H)4.18(br d,J＝3.01Hz,1H)4.07(s,2H)3.89(s,3H)2.07(s,3H)0.79(br d,J＝5.77Hz,2H)0.71(br s,2H) 1 H NMR (400MHz, DMSO- d 6) δppm 9.66-9.83 (m, 1H) 8.87 (s, 1H) 8.25 (s, 1H) 8.05 (br s, 2H) 7.39 (d, J = 8.53Hz, 1H) 7.33(s,1H)7.10(br d,J=8.28Hz,1H)4.18(br d,J=3.01Hz,1H)4.07(s,2H)3.89(s,3H)2.07(s,3H)0.79( Br d, J=5.77Hz, 2H) 0.71(br s, 2H)
实施例56：化合物56Example 56: Compound 56
Figure PCTCN2019070227-appb-000192
Figure PCTCN2019070227-appb-000192
合成路线：synthetic route:
Figure PCTCN2019070227-appb-000193
Figure PCTCN2019070227-appb-000193
步骤1：化合物56-B的合成Step 1: Synthesis of Compound 56-B
在氮气保护下，向四氢呋喃(6mL)中加入NaH(67.80mg,1.70mmol,60％purity)，0℃下加入环丙醇(49.23mg,847.58μmol)，反应在25℃下搅拌30min后，降温到0℃加入56-A(100mg,565.05μmol)。反应在25℃下搅拌1.5h后，再在0℃下，向其中滴加饱和氯化铵溶液(5mL)，用乙酸乙酯(50mL)萃取，食盐水(50mL)洗涤，硫酸钠干燥，过滤干燥剂，减压浓缩得到粗品，粗品用制备TLC(展开剂：石油醚/乙酸乙酯＝10/1)纯化得到56-B。Under a nitrogen atmosphere, NaH (67.80 mg, 1.70 mmol, 60% purity) was added to tetrahydrofuran (6 mL), cyclopropanol (49.23 mg, 847.58 μmol) was added at 0 ° C, and the reaction was stirred at 25 ° C for 30 min, then cooled. 56-A (100 mg, 565.05 μmol) was added at 0 °C. After the reaction was stirred at 25 ° C for 1.5 h, a saturated aqueous solution of ammonium chloride (5 mL) was added dropwise at 0 ° C, and ethyl acetate (50 mL) was evaporated. The desiccant was concentrated under reduced pressure to give a crude material. m. m.
1H NMR(400MHz,CDCl 3)δppm 8.49(s,2H)4.05-4.44(m,1H)0.63-0.95(m,4H) 1 H NMR (400 MHz, CDCl 3 ) δ ppm 8.49 (s, 2H) 4.05 - 4.44 (m, 1H) 0.63-0.95 (m, 4H)
步骤2：化合物56-C的合成Step 2: Synthesis of Compound 56-C
除了使用相应的原料外，以实施例32中的制备化合物32-A相同的方法制备化合物56-C。Compound 56-C was prepared in the same manner as in the preparation of compound 32-A in Example 32 except that the corresponding material was used.
MS m/z:320.7[M+H] + MS m/z: 320.7 [M+H] +
1H NMR(400MHz,CDCl 3)δppm 8.59(s,2H)8.48(d,J＝4.52Hz,1H)8.13(s,1H)6.47(s,1H)4.25(ddt,J＝9.35,6.21,3.01,3.01Hz,1H)2.25(s,3H)0.75-0.79(m,4H) 1 H NMR (400 MHz, CDCl 3 ) δ ppm 8.59 (s, 2H) 8.48 (d, J = 4.52 Hz, 1H) 8.13 (s, 1H) 6.47 (s, 1H) 4.25 (ddt, J = 9.35, 6.21, 3.01 , 3.01 Hz, 1H) 2.25 (s, 3H) 0.75-0.79 (m, 4H)
步骤3：化合物56-D的合成Step 3: Synthesis of Compound 56-D
除了使用相应的原料外，以实施例9中的制备化合物9-A相同的方法制备化合物56-D。Compound 56-D was prepared in the same manner as in the preparation of compound 9-A in Example 9 except that the corresponding material was used.
MS m/z:504.0[M+H] + MS m/z: 504.0 [M+H] +
步骤4：化合物56的合成Step 4: Synthesis of Compound 56
除了使用相应的原料外，以实施例9中的制备化合物9相同的方法制备化合物56。Compound 56 was prepared in the same manner as in the preparation of compound 9 in Example 9 except that the corresponding materials were used.
MS m/z:404.1[M+H] + MS m/z: 404.1 [M+H] +
1H NMR(400MHz,DMSO-d 6)δppm 9.16(s,1H)8.90(s,2H)8.25(s,1H)7.97(s,1H)7.37(d,J＝8.03Hz,1H)7.09(d,J＝8.53Hz,1H)6.75(s,1H)4.20-4.31(m,1H)4.00-4.14(m,2H)3.89(s,3H)2.06(s,3H)0.73-0.78(m,2H)0.68-0.73(m,2H) 1 H NMR (400MHz, DMSO- d 6) δppm 9.16 (s, 1H) 8.90 (s, 2H) 8.25 (s, 1H) 7.97 (s, 1H) 7.37 (d, J = 8.03Hz, 1H) 7.09 (d , J=8.53Hz,1H)6.75(s,1H)4.20-4.31(m,1H)4.00-4.14(m,2H)3.89(s,3H)2.06(s,3H)0.73-0.78(m,2H) 0.68-0.73 (m, 2H)
实施例57：化合物57Example 57: Compound 57
Figure PCTCN2019070227-appb-000194
Figure PCTCN2019070227-appb-000194
合成路线：synthetic route:
Figure PCTCN2019070227-appb-000195
Figure PCTCN2019070227-appb-000195
步骤1：化合物57-B的合成Step 1: Synthesis of Compound 57-B
将57-A(500mg,2.60mmol)溶于N,N-二甲基甲酰胺(20mL)中，向其中加入2-溴乙醇(488.18mg,3.91mmol)，碳酸铯(2.55g,7.81mmol)，碘化钾(216.16mg,1.30mmol)，反应在氮气保护，125℃下搅拌12h后，向其中加入水(50mL)，用乙酸乙酯(100mL)萃取，水(30mL)洗涤，饱和食盐水(30mL)洗涤，硫酸钠干燥，过滤干燥剂，减压浓缩得到粗品，粗品经柱层析(石油醚/乙酸乙酯＝2/1)纯化得到57-B。57-A (500 mg, 2.60 mmol) was dissolved in N,N-dimethylformamide (20 mL), and 2-bromoethanol (488.18 mg, 3.91 mmol), cesium carbonate (2.55 g, 7.81 mmol) Potassium iodide (216.16 mg, 1.30 mmol), the reaction was stirred under nitrogen, and stirred at 125 ° C for 12 h, then water (50 mL) was added, ethyl acetate (100 mL) was taken, and water (30 mL) was washed and brine (30 mL) The organic layer was dried (MgSO4), filtered, evaporated
步骤2：化合物57-C的合成Step 2: Synthesis of Compound 57-C
除了使用相应的原料外，以实施例32中的制备化合物32-A相同的方法制备化合物57-C。Compound 57-C was prepared in the same manner as in the preparation of compound 32-A in Example 32 except that the corresponding material was used.
MS m/z:505.1[M+H] + MS m/z: 505.1 [M+H] +
步骤3：化合物57的合成Step 3: Synthesis of Compound 57
除了使用相应的原料外，以实施例32中的制备化合物32相同的方法制备化合物57。Compound 57 was prepared in the same manner as in the preparation of compound 32 in Example 32 except that the corresponding material was used.
MS m/z:405.0[M+H] + MS m/z: 405.0 [M+H] +
1H NMR(400MHz,DMSO-d 6)δppm 9.01(s,1H)8.22(s,1H)7.95(s,1H)7.92(d,J＝2.26Hz,1H)7.83(d,J＝2.26Hz,1H)7.35(d,J＝8.28Hz,1H)7.08(d,J＝8.28Hz,1H)6.70(s,1H)4.33(br d,J＝4.02Hz,2H)4.23(br d,J＝2.26Hz,2H)4.06(s,2H)3.88(s,3H)2.03(s,3H) 1 H NMR (400MHz, DMSO- d 6) δppm 9.01 (s, 1H) 8.22 (s, 1H) 7.95 (s, 1H) 7.92 (d, J = 2.26Hz, 1H) 7.83 (d, J = 2.26Hz, 1H) 7.35 (d, J = 8.28 Hz, 1H) 7.08 (d, J = 8.28 Hz, 1H) 6.70 (s, 1H) 4.33 (br d, J = 4.02 Hz, 2H) 4.23 (br d, J = 2.26) Hz, 2H) 4.06 (s, 2H) 3.88 (s, 3H) 2.03 (s, 3H)
实施例58：化合物58Example 58: Compound 58
Figure PCTCN2019070227-appb-000196
Figure PCTCN2019070227-appb-000196
合成路线：synthetic route:
Figure PCTCN2019070227-appb-000197
Figure PCTCN2019070227-appb-000197
步骤1：化合物58-A的合成Step 1: Synthesis of Compound 58-A
除了使用相应的原料外，以实施例32中的制备化合物32-A相同的方法制备化合物58-A。Compound 58-A was prepared in the same manner as in the preparation of compound 32-A in Example 32 except that the corresponding material was used.
MS m/z:281.1[M+H] + MS m/z: 281.1 [M+H] +
步骤2：化合物58-B的合成Step 2: Synthesis of Compound 58-B
除了使用相应的原料外，以实施例9中的制备化合物9-A相同的方法制备化合物58-B。Compound 58-B was prepared in the same manner as in the preparation of compound 9-A in Example 9 except that the corresponding material was used.
MS m/z:464.4[M+H] + MS m/z: 464.4 [M+H] +
步骤3：化合物58的合成Step 3: Synthesis of Compound 58
除了使用相应的原料外，以实施例9中的制备化合物9相同的方法制备化合物58。Compound 58 was prepared in the same manner as in the preparation of compound 9 in Example 9 except that the corresponding material was used.
MS m/z:364.2[M+H] + MS m/z: 364.2 [M+H] +
1H NMR(400MHz,DMSO-d 6)δppm 9.06(s,1H),8.24(s,1H),7.96(s,1H),7.71(dd,J＝5.0,9.0Hz,2H),7.37 (d,J＝8.0Hz,1H),7.12-7.08(m,3H),6.73(s,1H),4.07(s,2H),3.88(s,3H),2.04(s,3H) 1 H NMR (400MHz, DMSO- d 6) δppm 9.06 (s, 1H), 8.24 (s, 1H), 7.96 (s, 1H), 7.71 (dd, J = 5.0,9.0Hz, 2H), 7.37 (d , J=8.0Hz, 1H), 7.12-7.08 (m, 3H), 6.73 (s, 1H), 4.07 (s, 2H), 3.88 (s, 3H), 2.04 (s, 3H)
实施例59：化合物59Example 59: Compound 59
Figure PCTCN2019070227-appb-000198
Figure PCTCN2019070227-appb-000198
合成路线synthetic route
Figure PCTCN2019070227-appb-000199
Figure PCTCN2019070227-appb-000199
步骤1：化合物58-A的合成Step 1: Synthesis of Compound 58-A
除了使用相应的原料外，以实施例32中的制备化合物32-A相同的方法制备化合物58-A。Compound 58-A was prepared in the same manner as in the preparation of compound 32-A in Example 32 except that the corresponding material was used.
MS m/z:516.1[M+H] + MS m/z: 516.1 [M+H] +
步骤2：化合物58的合成Step 2: Synthesis of Compound 58
除了使用相应的原料外，以实施例32中的制备化合物32相同的方法制备化合物58。Compound 58 was prepared in the same manner as in the preparation of compound 32 in Example 32 except that the corresponding material was used.
MS m/z:416[M+H] + MS m/z: 416 [M+H] +
1H NMR(400MHz,DMSO-d 6)δppm 10.01(s,1H),9.36(s,2H),8.26(s,1H),8.14(s,1H),7.40(d,J＝8.0Hz,1H),7.11(d,J＝8.0Hz,1H),6.93(s,1H),4.08(s,2H),3.89(s,3H),2.11(s,3H) 1 H NMR (400MHz, DMSO- d 6) δppm 10.01 (s, 1H), 9.36 (s, 2H), 8.26 (s, 1H), 8.14 (s, 1H), 7.40 (d, J = 8.0Hz, 1H ), 7.11 (d, J = 8.0 Hz, 1H), 6.93 (s, 1H), 4.08 (s, 2H), 3.89 (s, 3H), 2.11 (s, 3H)
实施例60：化合物60Example 60: Compound 60
Figure PCTCN2019070227-appb-000200
Figure PCTCN2019070227-appb-000200
合成路线:synthetic route:
Figure PCTCN2019070227-appb-000201
Figure PCTCN2019070227-appb-000201
步骤1：化合物60-A的合成Step 1: Synthesis of Compound 60-A
除了使用相应的原料外，以实施例32中的制备化合物32-A相同的方法制备化合物60-A。Compound 60-A was prepared in the same manner as in the preparation of compound 32-A in Example 32 except that the corresponding material was used.
MS m/z:472.2[M+H] + MS m/z: 472.2 [M+H] +
步骤2：化合物60的合成Step 2: Synthesis of Compound 60
除了使用相应的原料外，以实施例32中的制备化合物32相同的方法制备化合物60。Compound 60 was prepared in the same manner as in the preparation of compound 32 in Example 32 except that the corresponding material was used.
MS m/z:372.0[M+H] + MS m/z: 372.0 [M+H] +
1H NMR(400MHz,CD 3OD)δppm 8.76(d,J＝2.0Hz,1H),8.44-8.42(m,1H),7.97(s,1H),7.61(d,J＝9.0Hz,1H),7.31(d,J＝8.0Hz,1H),7.02(d,J＝8.0Hz,1H),6.78(s,1H),4.08(s,2H),3.90(s,3H),2.05(s,3H) 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.76 (d, J = 2.0 Hz, 1H), 8.44 - 8.42 (m, 1H), 7.97 (s, 1H), 7.61 (d, J = 9.0 Hz, 1H) , 7.31 (d, J = 8.0 Hz, 1H), 7.02 (d, J = 8.0 Hz, 1H), 6.78 (s, 1H), 4.08 (s, 2H), 3.90 (s, 3H), 2.05 (s, 3H)
实施例61：化合物61Example 61: Compound 61
Figure PCTCN2019070227-appb-000202
Figure PCTCN2019070227-appb-000202
合成路线:synthetic route:
Figure PCTCN2019070227-appb-000203
Figure PCTCN2019070227-appb-000203
步骤1：化合物61-B的合成Step 1: Synthesis of Compound 61-B
除了使用相应的原料外，以实施例32中的制备化合物32-A相同的方法制备化合物61-B。Compound 61-B was prepared in the same manner as in the preparation of compound 32-A in Example 32 except that the corresponding material was used.
MS m/z:511.3[M+H] + MS m/z: 511.3 [M+H] +
步骤2：化合物61的合成Step 2: Synthesis of Compound 61
除了使用相应的原料外，以实施例32中的制备化合物32相同的方法制备化合物61。Compound 61 was prepared in the same manner as in the preparation of compound 32 in Example 32 except that the corresponding material was used.
MS m/z:411.0[M+H] + MS m/z: 411.0 [M+H] +
1H NMR(400MHz,CD 3OD)δppm 7.98-7.82(m,1H),7.60-7.54(m,2H),7.45-7.38(m,1H),7.28(d,J＝8.8Hz,2H),7.14(s,1H),6.80(s,1H),4.19(s,2H),3.99(s,3H),2.11(s,3H),1.71-1.65(m,2H),1.47-1.41(m,2H) 1 H NMR (400 MHz, CD 3 OD) δ ppm 7.98-7.82 (m, 1H), 7.60-7.54 (m, 2H), 7.45-7.38 (m, 1H), 7.28 (d, J = 8.8 Hz, 2H), 7.14(s,1H), 6.80(s,1H), 4.19(s,2H),3.99(s,3H),2.11(s,3H),1.71-1.65(m,2H),1.47-1.41(m, 2H)
实施例62：化合物62Example 62: Compound 62
Figure PCTCN2019070227-appb-000204
Figure PCTCN2019070227-appb-000204
合成路线:synthetic route:
Figure PCTCN2019070227-appb-000205
Figure PCTCN2019070227-appb-000205
步骤1：化合物62-B的合成Step 1: Synthesis of Compound 62-B
除了使用相应的原料外，以实施例32中的制备化合物32-A相同的方法制备化合物62-B。Compound 62-B was prepared in the same manner as in the preparation of compound 32-A in Example 32 except that the corresponding material was used.
MS m/z:307.8[M+H] + MS m/z: 307.8 [M+H] +
步骤2：化合物62-C的合成Step 2: Synthesis of Compound 62-C
除了使用相应的原料外，以实施例9中的制备化合物9-A相同的方法制备化合物62-C。Compound 62-C was prepared in the same manner as in the preparation of compound 9-A in Example 9 except that the corresponding material was used.
MS m/z:491.2[M+H] + MS m/z: 491.2 [M+H] +
步骤3：化合物62的合成Step 3: Synthesis of Compound 62
除了使用相应的原料外，以实施例9中的制备化合物9相同的方法制备化合物62。Compound 62 was prepared in the same manner as in the preparation of compound 9 in Example 9 except that the corresponding materials were used.
MS m/z:391.0[M+H] + MS m/z: 391.0 [M+H] +
1H NMR(400MHz,CD 3OD)δppm 8.31-8.27(m,1H),7.94-7.86(m,2H),7.45-7.39(m,1H),7.17-7.12(m,1H),6.83-6.76(m,1H),6.72-6.68(m,1H),4.35-4.24(m,2H),4.22-4.15(m,2H),3.99(s,3H),2.10(s,3H),1.40(t,J＝7.0Hz,3H) 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.31-8.27 (m, 1H), 7.94-7.86 (m, 2H), 7.45-7.39 (m, 1H), 7.17-7.12 (m, 1H), 6.83-6.76 (m, 1H), 6.72-6.68 (m, 1H), 4.35-4.24 (m, 2H), 4.22-4.15 (m, 2H), 3.99 (s, 3H), 2.10 (s, 3H), 1.40 (t , J=7.0Hz, 3H)
实施例63：化合物63Example 63: Compound 63
Figure PCTCN2019070227-appb-000206
Figure PCTCN2019070227-appb-000206
合成路线:synthetic route:
Figure PCTCN2019070227-appb-000207
Figure PCTCN2019070227-appb-000207
步骤1：化合物63-A的合成Step 1: Synthesis of Compound 63-A
除了使用相应的原料外，以实施例32中的制备化合物32-A相同的方法制备化合物63-A。Compound 63-A was prepared in the same manner as in the preparation of compound 32-A in Example 32 except that the corresponding material was used.
MS m/z:290.9[M+H] + MS m/z: 290.9 [M+H] +
步骤2：化合物63-B的合成Step 2: Synthesis of Compound 63-B
除了使用相应的原料外，以实施例9中的制备化合物9-A相同的方法制备化合物63-B。Compound 63-B was prepared in the same manner as in the preparation of compound 9-A in Example 9 except that the corresponding materials were used.
MS m/z:476.2[M+H] + MS m/z: 476.2 [M+H] +
步骤3：化合物63的合成Step 3: Synthesis of Compound 63
除了使用相应的原料外，以实施例9中的制备化合物9相同的方法制备化合物63。Compound 63 was prepared in the same manner as in the preparation of compound 9 in Example 9 except that the corresponding materials were used.
MS m/z:376.0[M+H] + MS m/z: 376.0 [M+H] +
1H NMR(400MHz,DMSO-d 6)δppm 8.79(s,1H),8.23(s,1H),7.92(s,1H),7.55(d,J＝9.0Hz,2H),7.35(d,J＝8.4 Hz,1H),7.08(d,J＝8.4Hz,1H),6.91-6.84(m,2H),6.70-6.66(m,1H),4.09-4.04(m,2H),3.88(s,3H),3.72(s,3H),2.02(s,3H) 1 H NMR (400MHz, DMSO- d 6) δppm 8.79 (s, 1H), 8.23 (s, 1H), 7.92 (s, 1H), 7.55 (d, J = 9.0Hz, 2H), 7.35 (d, J = 8.4 Hz, 1H), 7.08 (d, J = 8.4 Hz, 1H), 6.91-6.84 (m, 2H), 6.70-6.66 (m, 1H), 4.09-4.04 (m, 2H), 3.88 (s, 3H), 3.72 (s, 3H), 2.02 (s, 3H)
实施例64：化合物64Example 64: Compound 64
Figure PCTCN2019070227-appb-000208
Figure PCTCN2019070227-appb-000208
合成路线:synthetic route:
Figure PCTCN2019070227-appb-000209
Figure PCTCN2019070227-appb-000209
步骤1：化合物64-B的合成Step 1: Synthesis of Compound 64-B
除了使用相应的原料外，以实施例32中的制备化合物32-A相同的方法制备化合物64-B。Compound 64-B was prepared in the same manner as in the preparation of compound 32-A in Example 32 except that the corresponding material was used.
MS m/z:505.2[M+H] + MS m/z: 505.2 [M+H] +
步骤2：化合物64的合成Step 2: Synthesis of Compound 64
除了使用相应的原料外，以实施例32中的制备化合物32相同的方法制备化合物64。Compound 64 was prepared in the same manner as in the preparation of compound 32 in Example 32 except that the corresponding material was used.
MS m/z:405.0[M+H] + MS m/z: 405.0 [M+H] +
1H NMR(400MHz,CD 3OD)δppm 8.72(d,J＝2.0Hz,1H),8.17-8.15(m,1H),7.97(s,1H),7.61(d,J＝9.0Hz,1H),7.44(d,J＝8.0Hz,1H),7.16(d,J＝8.0Hz,1H),6.81(s,1H),4.20(s,2H),3.99(s,3H),2.12(s,3H),1.57(s,6H) 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.72 (d, J = 2.0 Hz, 1H), 8.17-8.15 (m, 1H), 7.97 (s, 1H), 7.61 (d, J = 9.0 Hz, 1H) , 7.44 (d, J = 8.0 Hz, 1H), 7.16 (d, J = 8.0 Hz, 1H), 6.81 (s, 1H), 4.20 (s, 2H), 3.99 (s, 3H), 2.12 (s, 3H), 1.57 (s, 6H)
实施例65：化合物65Example 65: Compound 65
Figure PCTCN2019070227-appb-000210
Figure PCTCN2019070227-appb-000210
合成路线:synthetic route:
Figure PCTCN2019070227-appb-000211
Figure PCTCN2019070227-appb-000211
步骤1：化合物65-B的合成Step 1: Synthesis of Compound 65-B
除了使用相应的原料外，以实施例32中的制备化合物32-A相同的方法制备化合物65-B。Compound 65-B was prepared in the same manner as in the preparation of compound 32-A in Example 32 except that the corresponding material was used.
MS m/z:327.9[M+H] + MS m/z: 327.9 [M+H] +
步骤2：化合物65-C的合成Step 2: Synthesis of Compound 65-C
除了使用相应的原料外，以实施例9中的制备化合物9-A相同的方法制备化合物65-C。Compound 65-C was prepared in the same manner as in the preparation of compound 9-A in Example 9 except that the corresponding material was used.
MS m/z:513.2[M+H] + MS m/z: 513.2 [M+H] +
步骤3：化合物65的合成Step 3: Synthesis of Compound 65
除了使用相应的原料外，以实施例9中的制备化合物9相同的方法制备化合物65。Compound 65 was prepared in the same manner as in the preparation of compound 9 in Example 9 except that the corresponding materials were used.
MS m/z:412.9[M+H] + MS m/z: 412.9 [M+H] +
1H NMR(400MHz,CD 3OD)δppm 8.44(d,J＝2.0Hz,1H),8.17(dd,J＝3.0,9.0Hz,1H),7.93(s,1H),7.44-7.38(m,2H),7.13(d,J＝8.0Hz,1H),6.94(d,J＝9.0Hz,1H),6.76(s,1H),4.18(s,2H),3.99(s,3H),2.11(s,3H) 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.44 (d, J = 2.0 Hz, 1H), 8.17 (dd, J = 3.0, 9.0 Hz, 1H), 7.93 (s, 1H), 7.44 - 7.38 (m, 2H), 7.13 (d, J = 8.0 Hz, 1H), 6.94 (d, J = 9.0 Hz, 1H), 6.76 (s, 1H), 4.18 (s, 2H), 3.99 (s, 3H), 2.11 ( s, 3H)
实施例66：化合物66Example 66: Compound 66
Figure PCTCN2019070227-appb-000212
Figure PCTCN2019070227-appb-000212
合成路线:synthetic route:
Figure PCTCN2019070227-appb-000213
Figure PCTCN2019070227-appb-000213
步骤1：化合物66-A的合成Step 1: Synthesis of Compound 66-A
将化合物2-醛基-5-溴吡啶(0.2g,1.08mmol)，二甲胺(3M,3.58mL)溶于二氯乙烷(10mL)，加入醋酸(322.85mg,5.38mmol,307.48μL)在30-35℃搅拌0.5小时，降温至-10-0℃，向反应体系中加入醋酸硼氢化钠(683.66mg,3.23mmol,3eq)，反应液在30-35℃搅拌2小时。反应液减压除去溶剂，残留物经层析柱分离(石油醚/四氢呋喃＝10/1-1/1)得到66-A。The compound 2-aldehyde-5-bromopyridine (0.2 g, 1.08 mmol), dimethylamine (3M, 3.58 mL) was dissolved in dichloroethane (10 mL), and acetic acid (322.85 mg, 5.38 mmol, 307.48 μL) was added. After stirring at 30-35 ° C for 0.5 hour, the temperature was lowered to -10 ° C, and sodium borohydride (683.66 mg, 3.23 mmol, 3 eq) was added to the reaction mixture, and the reaction mixture was stirred at 30-35 ° C for 2 hours. The reaction solution was evaporated under reduced pressure and the residue was purified crystalljjjjjjjj
MS m/z:214.8[M+H] + MS m/z: 214.8 [M+H] +
步骤2：化合物66-B的合成Step 2: Synthesis of Compound 66-B
除了使用相应的原料外，以实施例32中的制备化合物32-A相同的方法制备化合物66-B。Compound 66-B was prepared in the same manner as in the preparation of compound 32-A in Example 32 except that the corresponding material was used.
MS m/z:320.9[M+H] + MS m/z: 320.9 [M+H] +
步骤3：化合物66-C的合成Step 3: Synthesis of Compound 66-C
除了使用相应的原料外，以实施例9中的制备化合物9-A相同的方法制备化合物66-C。Compound 66-C was prepared in the same manner as in the preparation of compound 9-A in Example 9 except that the corresponding materials were used.
MS m/z:504.3[M+H] + MS m/z: 504.3 [M+H] +
步骤4：化合物66的合成Step 4: Synthesis of Compound 66
除了使用相应的原料外，以实施例9中的制备化合物9相同的方法制备化合物66。Compound 66 was prepared in the same manner as in the preparation of compound 9 in Example 9 except that the corresponding material was used.
MS m/z:404.0[M+H] + MS m/z: 404.0 [M+H] +
1H NMR(400MHz,CD 3OD)δppm 8.78(br s,1H),8.24(dd,J＝2.4,8.4Hz,1H),8.00(s,1H),7.47-7.36(m,2H),7.15(d,J＝9.0Hz,1H),6.82(s,1H),4.19(s,2H),3.99(s,3H),3.58(s,2H),2.31(s,6H),2.13(s,3H) 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.78 (br s, 1H), 8.24 (dd, J = 2.4, 8.4 Hz, 1H), 8.00 (s, 1H), 7.47-7.36 (m, 2H), 7.15 (d, J = 9.0 Hz, 1H), 6.82 (s, 1H), 4.19 (s, 2H), 3.99 (s, 3H), 3.58 (s, 2H), 2.31 (s, 6H), 2.13 (s, 3H)
实施例67：化合物67Example 67: Compound 67
Figure PCTCN2019070227-appb-000214
Figure PCTCN2019070227-appb-000214
合成路线:synthetic route:
Figure PCTCN2019070227-appb-000215
Figure PCTCN2019070227-appb-000215
步骤1：化合物67-A的合成Step 1: Synthesis of Compound 67-A
除了使用相应的原料外，以实施例32中的制备化合物32-A相同的方法制备化合物67-A。Compound 67-A was prepared in the same manner as in the preparation of compound 32-A in Example 32 except that the corresponding material was used.
MS m/z:298.8[M+H] + MS m/z: 298.8 [M+H] +
步骤2：化合物67-B的合成Step 2: Synthesis of Compound 67-B
除了使用相应的原料外，以实施例9中的制备化合物9-A相同的方法制备化合物67-B。Compound 67-B was prepared in the same manner as in the preparation of compound 9-A in Example 9 except that the corresponding material was used.
MS m/z:482.1[M+H] + MS m/z: 482.1 [M+H] +
步骤3：化合物67的合成Step 3: Synthesis of Compound 67
除了使用相应的原料外，以实施例9中的制备化合物9相同的方法制备化合物67。Compound 67 was prepared in the same manner as in the preparation of compound 9 in Example 9 except that the corresponding material was used.
MS m/z:382.0[M+H] + MS m/z: 382.0 [M+H] +
1H NMR(400MHz,DMSO-d 6)δppm 9.30(s,1H),8.25(s,1H),8.09-8.00(m,2H),7.40-7.28(m,3H),7.09(d,J＝8.0Hz,1H),6.76(s,1H),4.07(s,2H),3.89(s,3H),2.06(s,3H) 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 9.30 (s, 1H), 8.25 (s, 1H), 8.09-8.00 (m, 2H), 7.40-7.28 (m, 3H), 7.09 (d, J = 8.0 Hz, 1H), 6.76 (s, 1H), 4.07 (s, 2H), 3.89 (s, 3H), 2.06 (s, 3H)
实施例68：化合物68Example 68: Compound 68
Figure PCTCN2019070227-appb-000216
Figure PCTCN2019070227-appb-000216
合成路线:synthetic route:
Figure PCTCN2019070227-appb-000217
Figure PCTCN2019070227-appb-000217
步骤1：化合物68-A的合成Step 1: Synthesis of Compound 68-A
将化合物2-甲氧基乙醇(86.48mg,1.14mmol,89.61μL)溶于N,N-二甲基甲酰胺(10mL)，在-10-0℃加入钠氢(136.36mg,3.41mmol,60％纯度)，在-10-0℃加入2-氟-5-溴吡啶(0.2g,1.14mmol,116.96μL)，反应体系在60℃搅拌2小时。把反应液缓慢加入水中(10mL)，用乙酸乙酯60mL(20mL*3)萃取，合并的萃取液用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤除去干燥剂后，减压除去溶剂，所得残留物经柱层析分离得到68-A。The compound 2-methoxyethanol (86.48 mg, 1.14 mmol, 89.61 μL) was dissolved in N,N-dimethylformamide (10 mL), and sodium hydrogen (136.36 mg, 3.41 mmol, 60) was added at -10-0 °C. % purity), 2-fluoro-5-bromopyridine (0.2 g, 1.14 mmol, 116.96 μL) was added at -10 ° C, and the reaction was stirred at 60 ° C for 2 hours. The reaction solution was slowly added to water (10 mL), and extracted with ethyl acetate (60 mL) (20 mL*3), and the combined extracts were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate The solvent was obtained and the residue obtained was purified by column chromatography to afford 68-A.
MS m/z:231.9[M+H] + MS m/z: 231.9 [M+H] +
步骤2：化合物68-B的合成Step 2: Synthesis of Compound 68-B
除了使用相应的原料外，以实施例32中的制备化合物32-A相同的方法制备化合物68-B。Compound 68-B was prepared in the same manner as in the preparation of compound 32-A in Example 32 except that the corresponding material was used.
MS m/z:338.0[M+H] + MS m/z: 338.0 [M+H] +
步骤3：化合物68-C的合成Step 3: Synthesis of Compound 68-C
除了使用相应的原料外，以实施例9中的制备化合物9-A相同的方法制备化合物68-C。Compound 68-C was prepared in the same manner as in the preparation of compound 9-A in Example 9 except that the corresponding materials were used.
MS m/z:521.2[M+H] + MS m/z: 521.2 [M+H] +
步骤4：化合物68的合成Step 4: Synthesis of Compound 68
除了使用相应的原料外，以实施例9中的制备化合物9相同的方法制备化合物68。Compound 68 was prepared in the same manner as in the preparation of compound 9 in Example 9 except that the corresponding material was used.
MS m/z:421.0[M+H] + MS m/z: 421.0 [M+H] +
1H NMR(400MHz,CD 3OD)δppm 8.29(d,J＝2.0Hz,1H),7.94-7.84(m,2H),7.41(d,J＝8.0Hz,1H),7.12(d,J＝8.0Hz,1H),6.82(d,J＝9.0Hz,1H),6.70(s,1H),4.43-4.37(m,2H),4.18(s,2H),3.99(s,3H),3.80-3.74(m,2H),3.44(s,3H),2.09(s,3H) 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.29 (d, J = 2.0 Hz, 1H), 7.94 - 7.84 (m, 2H), 7.41 (d, J = 8.0 Hz, 1H), 7.12 (d, J = 8.0 Hz, 1H), 6.82 (d, J = 9.0 Hz, 1H), 6.70 (s, 1H), 4.43-4.37 (m, 2H), 4.18 (s, 2H), 3.99 (s, 3H), 3.80- 3.74 (m, 2H), 3.44 (s, 3H), 2.09 (s, 3H)
实施例69：化合物69Example 69: Compound 69
Figure PCTCN2019070227-appb-000218
Figure PCTCN2019070227-appb-000218
合成路线:synthetic route:
Figure PCTCN2019070227-appb-000219
Figure PCTCN2019070227-appb-000219
步骤1：化合物69-B的合成Step 1: Synthesis of Compound 69-B
将化合物69-A(0.5g,5.15mmol)，II-A(1.29g,5.15mmol)用异丙醇(30mL)混合均匀，加入一水合对甲苯磺酸(2.66g,15.45mmol)，反应液在130-150℃回流搅拌111小时。减压除去溶剂，所得残留物经柱层析纯化得到69-B。Compound 69-A (0.5 g, 5.15 mmol), II-A (1.29 g, 5.15 mmol) was uniformly mixed with isopropyl alcohol (30 mL), and p-toluenesulfonic acid monohydrate (2.66 g, 15.45 mmol) was added. Stir at 111-150 ° C for 111 hours under reflux. The solvent was removed under reduced pressure and the residue was purified mjjjjjj
MS m/z:268.8[M+H] + MS m/z: 268.8 [M+H] +
步骤2：化合物69-C的合成Step 2: Synthesis of Compound 69-C
除了使用相应的原料外，以实施例9中的制备化合物9-A相同的方法制备化合物69-C。Compound 69-C was prepared in the same manner as in the preparation of compound 9-A in Example 9 except that the corresponding materials were used.
MS m/z:450.2[M+H] + MS m/z: 450.2 [M+H] +
步骤3：化合物69的合成Step 3: Synthesis of Compound 69
除了使用相应的原料外，以实施例9中的制备化合物9相同的方法制备化合物69。Compound 69 was prepared in the same manner as in the preparation of compound 9 in Example 9 except that the corresponding materials were used.
MS m/z:350.0[M+H] + MS m/z: 350.0 [M+H] +
1H NMR(400MHz,METHANOL-d 4)δppm 7.86(s,2H),7.49(s,1H),7.39(d,J＝8.4Hz,1H),7.12(d,J＝8.0Hz,1H),6.62(s,1H),4.17(s,2H),3.98(s,3H),3.89(s,3H),2.09-2.05(m,3H) 1 H NMR (400 MHz, METHANOL-d 4 ) δ ppm 7.86 (s, 2H), 7.49 (s, 1H), 7.39 (d, J = 8.4 Hz, 1H), 7.12 (d, J = 8.0 Hz, 1H), 6.62(s,1H), 4.17(s,2H), 3.98(s,3H),3.89(s,3H),2.09-2.05(m,3H)
实施例70：化合物70Example 70: Compound 70
Figure PCTCN2019070227-appb-000220
Figure PCTCN2019070227-appb-000220
合成路线:synthetic route:
Figure PCTCN2019070227-appb-000221
Figure PCTCN2019070227-appb-000221
步骤1：化合物70-A的合成Step 1: Synthesis of Compound 70-A
除了使用相应的原料外，以实施例32中的制备化合物32-A相同的方法制备化合物70-A。Compound 70-A was prepared in the same manner as in the preparation of compound 32-A in Example 32 except that the corresponding material was used.
MS m/z:320.8[M+H] + MS m/z: 320.8 [M+H] +
步骤2：化合物70-B的合成Step 2: Synthesis of Compound 70-B
除了使用相应的原料外，以实施例9中的制备化合物9-A相同的方法制备化合物70-B。Compound 70-B was prepared in the same manner as in the preparation of compound 9-A in Example 9 except that the corresponding materials were used.
MS m/z:504.2[M+H] + MS m/z: 504.2 [M+H] +
步骤3：化合物70-C的合成Step 3: Synthesis of Compound 70-C
除了使用相应的原料外，以实施例9中的制备化合物9相同的方法制备化合物70-C。Compound 70-C was prepared in the same manner as in the preparation of compound 9 in Example 9 except that the corresponding material was used.
MS m/z:404.1[M+H] + MS m/z: 404.1 [M+H] +
步骤4：化合物70的合成Step 4: Synthesis of Compound 70
将化合物70-C(0.05g,123.94μmol)用四氢呋喃(5mL)混合均匀，在-10-0℃加入硼氢化锂(0.05g,2.30mmol)，反应液在-10-65℃搅拌43小时。将反应液倒入水(10mL)中，用乙酸乙酯30mL(10mL*3)萃取，分离乙酸乙酯层，用饱和食盐水(20mL)洗涤，用无水硫酸钠干燥。过滤除去干燥剂后，减压除去溶剂，经HPLC(中性)分离得到70。Compound 70-C (0.05 g, 123.94 μmol) was uniformly mixed with tetrahydrofuran (5 mL), and lithium borohydride (0.05 g, 2.30 mmol) was added at -10 ° C, and the reaction mixture was stirred at -10-65 ° C for 43 hours. The reaction solution was poured into water (10 mL), EtOAc (EtOAc) After removing the desiccant by filtration, the solvent was removed under reduced pressure and the residue was purified by HPLC (neut).
MS m/z:376.0[M+H] + MS m/z: 376.0 [M+H] +
1H NMR(400MHz,CD 3OD)δppm 8.09(s,1H),7.50(d,J＝8.0Hz,2H),7.45(d,J＝8.0Hz,1H),7.35(d,J＝9.0Hz,2H),7.17(d,J＝9.0Hz,1H),6.92(s,1H),4.67(s,2H),4.20(s,2H),3.99(s,3H),2.08(s,3H) 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.09 (s, 1H), 7.50 (d, J = 8.0 Hz, 2H), 7.45 (d, J = 8.0 Hz, 1H), 7.35 (d, J = 9.0 Hz) , 2H), 7.17 (d, J = 9.0 Hz, 1H), 6.92 (s, 1H), 4.67 (s, 2H), 4.20 (s, 2H), 3.99 (s, 3H), 2.08 (s, 3H)
实施例71：化合物71Example 71: Compound 71
Figure PCTCN2019070227-appb-000222
Figure PCTCN2019070227-appb-000222
合成路线：synthetic route:
Figure PCTCN2019070227-appb-000223
Figure PCTCN2019070227-appb-000223
步骤1：化合物71-A的合成Step 1: Synthesis of Compound 71-A
将2-氟-5-溴吡啶(460mg,2.61mmol,269.01μL)和环丙醇(227.71mg,3.92mmol)，溶于1-甲基-2-吡诺烷酮(1mL)中，在冰浴下缓慢滴加叔丁醇钾的四氢呋喃溶液(1M,3.92mL)，然后将混合物在28℃下搅拌4小时。用乙酸乙酯和石油醚(20mL,v/v＝1/1)萃取，用水(30mL×1)洗涤，再用饱和食盐水(30mL)洗涤，无水硫酸钠干燥。滤去干燥剂后，减压除去溶剂得到粗品。粗品经柱层析(洗脱剂：石油醚/乙酸乙酯＝1/0～40/1)纯 化得到71-A。2-Fluoro-5-bromopyridine (460 mg, 2.61 mmol, 269.01 μL) and cyclopropanol (227.71 mg, 3.92 mmol) in 1-methyl-2-pyranidone (1 mL) in ice A solution of potassium tert-butoxide in tetrahydrofuran (1 M, 3.92 mL) was slowly added dropwise, and the mixture was stirred at 28 ° C for 4 hr. It was extracted with ethyl acetate and petroleum ether (20 mL, v/v = 1/1), washed with water (30 mL, 1), and washed with brine (30 mL). After filtering off the desiccant, the solvent was removed under reduced pressure to give a crude material. The crude product was purified by column chromatography (eluent: petroleum ether/ethyl acetate = 1/0 to 40/1) to afford 71-A.
MS m/z:213.9[M+H] + MS m/z: 213.9 [M+H] +
1H NMR(400MHz,DMSO-d 6)δppm 8.31(d,J＝2.51Hz,1H)7.92(dd,J＝8.78,2.51Hz,1H)6.87(d,J＝8.78Hz,1H)4.16(tt,J＝6.21,3.07Hz,1H)0.73-0.79(m,2H)0.64-0.69(m,2H) 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 8.31 (d, J = 2.51 Hz, 1H) 7.92 (dd, J = 8.78, 2.51 Hz, 1H) 6.87 (d, J = 8.78 Hz, 1H) 4.16 (tt , J=6.21, 3.07Hz, 1H) 0.73-0.79(m, 2H)0.64-0.69(m, 2H)
步骤2：化合物71-B的合成Step 2: Synthesis of Compound 71-B
除了使用相应的原料外，以实施例32中的制备化合物32-A相同的方法制备化合物71-B。Compound 71-B was prepared in the same manner as in the preparation of compound 32-A in Example 32 except that the corresponding material was used.
MS m/z:319.8[M+H] + MS m/z: 319.8 [M+H] +
步骤3：化合物71-C的合成Step 3: Synthesis of Compound 71-C
除了使用相应的原料外，以实施例9中的制备化合物9-A相同的方法制备化合物71-C。Compound 71-C was prepared in the same manner as in the preparation of compound 9-A in Example 9 except that the corresponding materials were used.
MS m/z:503.2[M+H] + MS m/z: 503.2 [M+H] +
步骤4：化合物71的合成Step 4: Synthesis of Compound 71
除了使用相应的原料外，以实施例9中的制备化合物9相同的方法制备化合物71。Compound 71 was prepared in the same manner as in the preparation of compound 9 in Example 9 except that the corresponding material was used.
MS m/z:403.0[M+H] + MS m/z: 403.0 [M+H] +
1H NMR(400MHz,DMSO-d 6)δppm 8.97(s,1H)8.41(d,J＝2.51Hz,1H)8.23(s,1H)8.05(dd,J＝8.78,2.76Hz,1H)7.93(s,1H)7.36(d,J＝8.53Hz,1H)7.08(d,J＝8.53Hz,1H)6.82(d,J＝9.03Hz,1H)6.70(s,1H)4.09-4.17(m,1H)4.04-4.07(m,1H)3.87(s,3H)2.03(s,3H)0.74(q,J＝6.19Hz,2H)0.60-0.68(m,2H) 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 8.97 (s, 1H) 8.41 (d, J = 2.51 Hz, 1H) 8.23 (s, 1H) 8.05 (dd, J = 8.78, 2.76 Hz, 1H) 7.93 ( s,1H)7.36(d,J=8.53Hz,1H)7.08(d,J=8.53Hz,1H)6.82(d,J=9.03Hz,1H)6.70(s,1H)4.09-4.17(m,1H ) 4.04-4.07(m,1H)3.87(s,3H)2.03(s,3H)0.74(q,J=6.19Hz,2H)0.60-0.68(m,2H)
实施例72：化合物72Example 72: Compound 72
Figure PCTCN2019070227-appb-000224
Figure PCTCN2019070227-appb-000224
合成路线：synthetic route:
Figure PCTCN2019070227-appb-000225
Figure PCTCN2019070227-appb-000225
步骤1：化合物72-B的合成Step 1: Synthesis of Compound 72-B
将化合物2,5-二溴-4甲基吡啶(200mg,797.07μmol)，27-A(71mg,435.31μmol)，碳酸铯(389.55mg,1.20mmol)，Xantphos(46.12mg,79.71μmol)，Pd 2(dba) 3(36.49mg,39.85μmol)溶于无水1,4-二氧六环(3ml)中，在氮气保护、90℃下搅拌15小时。将反应液用硅藻土过滤，然后将滤液减压浓缩得到粗品。粗品用制备TLC(展开剂：石油醚/乙酸乙酯＝6/1)纯化得到72-B。 Compound 2,5-dibromo-4-methylpyridine (200 mg, 797.07 μmol), 27-A (71 mg, 435.31 μmol), cesium carbonate (389.55 mg, 1.20 mmol), Xantphos (46.12 mg, 79.71 μmol), Pd 2 (dba) 3 (36.49 mg, 39.85 μmol) was dissolved in anhydrous 1,4-dioxane (3 ml), and stirred under nitrogen for 15 hours at 90 °C. The reaction solution was filtered through Celite, and then filtered and evaporated. The crude product was purified by preparative TLC (developing solvent: petroleum ether / ethyl acetate = 6/1) to afford 72-B.
MS m/z:334.9[M+H] + MS m/z: 334.9 [M+H] +
步骤2：化合物72-C的合成Step 2: Synthesis of Compound 72-C
除了使用相应的原料外，以实施例9中的制备化合物9-A相同的方法制备化合物72-C。Compound 72-C was prepared in the same manner as in the preparation of compound 9-A in Example 9 except that the corresponding material was used.
MS m/z:516.1[M+H] + MS m/z: 516.1 [M+H] +
步骤3：化合物72的合成Step 3: Synthesis of Compound 72
除了使用相应的原料外，以实施例9中的制备化合物9相同的方法制备化合物72。Compound 72 was prepared in the same manner as in the preparation of compound 9 in Example 9 except that the corresponding materials were used.
MS m/z:416.0[M+H] + MS m/z: 416.0 [M+H] +
1H NMR(400MHz,DMSO-d 6)δppm 10.69(s,1H)9.09(s,1H)8.73(s,1H)8.26(s,1H)8.19(s,1H)7.78(s,1H)7.42(d,J＝8.53Hz,1H)7.12(d,J＝8.53Hz,1H)4.08(s,2H)3.89(s,3H)2.13(s,3H) 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 10.69 (s, 1H) 9.09 (s, 1H) 8.73 (s, 1H) 8.26 (s, 1H) 8.19 (s, 1H) 7.78 (s, 1H) 7.42 ( d, J = 8.53 Hz, 1H) 7.12 (d, J = 8.53 Hz, 1H) 4.08 (s, 2H) 3.89 (s, 3H) 2.13 (s, 3H)
实施例73：化合物73Example 73: Compound 73
Figure PCTCN2019070227-appb-000226
Figure PCTCN2019070227-appb-000226
合成路线：synthetic route:
Figure PCTCN2019070227-appb-000227
Figure PCTCN2019070227-appb-000227
步骤1：化合物73-B的合成Step 1: Synthesis of Compound 73-B
将化合物73-A(200mg,1.02mmol)，化合物1,2-二溴乙烷(381.38mg,2.03mmol)，和四丁基溴铵(327.22mg,1.02mmol)溶于乙腈(5mL)中，再向反应体系中加入5ml的氢氧化钠水溶液(50％)，在28℃下搅拌1.5小时。向反应液中加入20ml水，用20ml乙酸乙酯萃取，再用15ml饱和食盐水洗涤，无水硫酸钠干燥。滤去干燥剂后，减压除去溶剂得到粗品。粗品经柱层析法(洗脱剂：石油醚/乙酸乙酯＝4/1)纯化，得到73-B。Compound 73-A (200 mg, 1.02 mmol), compound 1,2-dibromoethane (381.38 mg, 2.03 mmol), and tetrabutyl ammonium bromide (327.22 mg, 1.02 mmol) were dissolved in acetonitrile (5 mL). Further, 5 ml of an aqueous sodium hydroxide solution (50%) was added to the reaction system, and the mixture was stirred at 28 ° C for 1.5 hours. 20 ml of water was added to the reaction mixture, and the mixture was extracted with 20 ml of ethyl acetate. After filtering off the desiccant, the solvent was removed under reduced pressure to give a crude material. The crude product was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 4/1) to afford 73-B.
MS m/z:222.7[M+H] + MS m/z: 222.7 [M+H] +
步骤2：化合物73-C的合成Step 2: Synthesis of Compound 73-C
除了使用相应的原料外，以实施例32中的制备化合物32-A相同的方法制备化合物73-C。Compound 73-C was prepared in the same manner as in the preparation of compound 32-A in Example 32 except that the corresponding material was used.
MS m/z:328.9[M+H] + MS m/z: 328.9 [M+H] +
步骤3：化合物73-D的合成Step 3: Synthesis of Compound 73-D
除了使用相应的原料外，以实施例9中的制备化合物9-A相同的方法制备化合物73-D。Compound 73-D was prepared in the same manner as in the preparation of compound 9-A in Example 9 except that the corresponding material was used.
MS m/z:512.1[M+H] + MS m/z: 512.1 [M+H] +
步骤4：化合物73的合成Step 4: Synthesis of Compound 73
除了使用相应的原料外，以实施例9中的制备化合物9相同的方法制备化合物73。Compound 73 was prepared in the same manner as in the preparation of compound 9 in Example 9 except that the corresponding material was used.
MS m/z:412.0[M+H] + MS m/z: 412.0 [M+H] +
1H NMR(400MHz,DMSO-d 6)δppm 9.34(s,1H)8.74(d,J＝2.51Hz,1H)8.21-8.27(m,2H)7.99(s,1H) 1 H NMR (400MHz, DMSO- d 6) δppm 9.34 (s, 1H) 8.74 (d, J = 2.51Hz, 1H) 8.21-8.27 (m, 2H) 7.99 (s, 1H)
7.43(d,J＝8.53Hz,1H)7.36(d,J＝8.03Hz,1H)7.08(d,J＝8.53Hz,1H)6.78(s,1H)4.05(s,2H)3.87(s,3H)2.03-2.08(m,3H)1.68-1.74(m,2H)1.57-1.62(m,2H)7.43 (d, J = 8.53 Hz, 1H) 7.36 (d, J = 8.03 Hz, 1H) 7.08 (d, J = 8.53 Hz, 1H) 6.78 (s, 1H) 4.05 (s, 2H) 3.87 (s, 3H) ) 2.03-2.08(m,3H)1.68-1.74(m,2H)1.57-1.62(m,2H)
实施例74：化合物74Example 74: Compound 74
Figure PCTCN2019070227-appb-000228
Figure PCTCN2019070227-appb-000228
合成路线：synthetic route:
Figure PCTCN2019070227-appb-000229
Figure PCTCN2019070227-appb-000229
步骤1：化合物74-A的合成Step 1: Synthesis of Compound 74-A
将化合物2-氟-5-溴吡啶(1g,5.68mmol,584.80uL)，***啉(1.49g,17.05mmol,1.50mL)，碳酸钾(2.36g,17.05mmol)溶于二甲基甲酰胺(20ml)中，在氮气保护，120℃下搅拌12小时。向反应液中加入50ml水，用50ml乙酸乙酯萃取，再用40ml饱和食盐水洗涤，无水硫酸钠干燥。滤去干燥剂后，减压除去溶剂得到粗品。粗品经柱层析(洗脱剂：石油醚/乙酸乙酯＝10/1)纯化得到74-A。The compound 2-fluoro-5-bromopyridine (1 g, 5.68 mmol, 584.80 uL), morpholine (1.49 g, 17.05 mmol, 1.50 mL), potassium carbonate (2.36 g, 17.05 mmol) was dissolved in dimethylformamide ( In 20 ml), it was stirred under nitrogen for 12 hours at 120 °C. 50 ml of water was added to the reaction mixture, and the mixture was extracted with 50 ml of ethyl acetate. After filtering off the desiccant, the solvent was removed under reduced pressure to give a crude material. The crude product was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 10/1) to afford 74-A.
MS m/z:242.9[M+H] + MS m/z: 242.9 [M+H] +
步骤2：化合物74-B的合成Step 2: Synthesis of Compound 74-B
除了使用相应的原料外，以实施例32中的制备化合物32-A相同的方法制备化合物74-B。Compound 74-B was prepared in the same manner as in the preparation of compound 32-A in Example 32 except that the corresponding material was used.
MS m/z:348.9[M+H] + MS m/z: 348.9 [M+H] +
步骤3：化合物74-C的合成Step 3: Synthesis of Compound 74-C
除了使用相应的原料外，以实施例9中的制备化合物9-A相同的方法制备化合物74-C。Compound 74-C was prepared in the same manner as in the preparation of compound 9-A in Example 9 except that the corresponding materials were used.
MS m/z:532.2[M+H] + MS m/z: 532.2 [M+H] +
步骤4：化合物74的合成Step 4: Synthesis of Compound 74
除了使用相应的原料外，以实施例9中的制备化合物9相同的方法制备化合物74。Compound 74 was prepared in the same manner as in the preparation of compound 9 in Example 9 except that the corresponding material was used.
MS m/z:432.2[M+H] + MS m/z: 432.2 [M+H] +
1H NMR(400MHz,CD 3OD)δppm 8.29(d,J＝2.51Hz,1H)7.80-7.84(m,2H)7.40(d,J＝8.53Hz,1H)7.12(d,J＝8.28Hz,1H)6.92(s,1H)6.85(d,J＝9.03Hz,1H)6.66(s,1H)4.16(s,2H)3.97(s,3H)3.80-3.83(m,4 H)3.38-3.44(m,4H)2.07(s,3H) 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.29 (d, J = 2.51 Hz, 1H) 7.80-7.84 (m, 2H) 7.40 (d, J = 8.53 Hz, 1H) 7.12 (d, J = 8.28 Hz, 1H) 6.92 (s, 1H) 6.85 (d, J = 9.03 Hz, 1H) 6.66 (s, 1H) 4.16 (s, 2H) 3.97 (s, 3H) 3.80-3.83 (m, 4 H) 3.38-3.44 ( m, 4H) 2.07 (s, 3H)
实施例75：化合物75Example 75: Compound 75
Figure PCTCN2019070227-appb-000230
Figure PCTCN2019070227-appb-000230
合成路线：synthetic route:
Figure PCTCN2019070227-appb-000231
Figure PCTCN2019070227-appb-000231
步骤1：化合物75-A的合成Step 1: Synthesis of Compound 75-A
除了使用相应的原料外，以实施例32中的制备化合物32-A相同的方法制备化合物75-A。Compound 75-A was prepared in the same manner as in the preparation of compound 32-A in Example 32 except that the corresponding material was used.
MS m/z:281.9[M+H] + MS m/z: 281.9 [M+H] +
步骤2：化合物75-B的合成Step 2: Synthesis of Compound 75-B
将化合物75-A(100mg,354.47μmol)溶于甲胺的乙醇溶液(2M,2mL)中，在26℃下搅拌16小时，然后在130℃下封管反应15小时。减压除去溶剂得到粗品，粗品经柱层析(洗脱剂：石油醚/乙酸乙酯＝3/1～1/1)得到75-B。Compound 75-A (100 mg, 354.47 μmol) was dissolved in a solution of methylamine in ethanol (2M, 2 mL), stirred at 26 ° C for 16 hours, and then the reaction was sealed at 130 ° C for 15 hours. The solvent was removed under reduced pressure to give a crude material. m.j.
MS m/z:292.9[M+H] + MS m/z: 292.9 [M+H] +
1H NMR(400MHz,DMSO-d 6)δppm 8.56(s,1H)8.06-8.07(m,1H)8.05-8.07(m,1H)7.54(dd,J＝8.78,2.76Hz,1H)6.59(s,1H)6.43(d,J＝9.03Hz,1H)6.17-6.22(m,1H)2.74(d,J＝5.02Hz,3H)2.22(s,3H) 1 H NMR (400MHz, DMSO- d 6) δppm 8.56 (s, 1H) 8.06-8.07 (m, 1H) 8.05-8.07 (m, 1H) 7.54 (dd, J = 8.78,2.76Hz, 1H) 6.59 (s , 1H) 6.43 (d, J = 9.03 Hz, 1H) 6.17 - 6.22 (m, 1H) 2.74 (d, J = 5.02 Hz, 3H) 2.22 (s, 3H)
步骤3：化合物75-C的合成Step 3: Synthesis of Compound 75-C
除了使用相应的原料外，以实施例9中的制备化合物9-A相同的方法制备化合物75-C。Compound 75-C was prepared in the same manner as in the preparation of compound 9-A in Example 9 except that the corresponding materials were used.
MS m/z:476.2[M+H] + MS m/z: 476.2 [M+H] +
步骤4：化合物75的合成Step 4: Synthesis of Compound 75
除了使用相应的原料外，以实施例9中的制备化合物9相同的方法制备化合物75。Compound 75 was prepared in the same manner as in the preparation of compound 9 in Example 9 except that the corresponding material was used.
MS m/z:376.2[M+H] + MS m/z: 376.2 [M+H] +
1H NMR(400MHz,DMSO-d 6)δppm 8.49(s,1H)8.23(s,1H)8.13(d,J＝2.01Hz,1H)7.85(s,1H)7.63(dd,J＝8.78,2.76Hz,1H)7.34(d,J＝8.03Hz,1H)7.07(d,J＝8.53Hz,1H)6.56(s,1H)6.44(d,J＝9.03Hz,1H)6.17(q,J＝4.68Hz,1H)4.06(s,2H)3.88(s,3H)2.75(d,J＝5.02Hz,3H)2.00(s,3H) 1 H NMR (400MHz, DMSO- d 6) δppm 8.49 (s, 1H) 8.23 (s, 1H) 8.13 (d, J = 2.01Hz, 1H) 7.85 (s, 1H) 7.63 (dd, J = 8.78,2.76 Hz,1H)7.34(d,J=8.03Hz,1H)7.07(d,J=8.53Hz,1H)6.56(s,1H)6.44(d,J=9.03Hz,1H)6.17(q,J=4.68 Hz, 1H) 4.06 (s, 2H) 3.88 (s, 3H) 2.75 (d, J = 5.02 Hz, 3H) 2.00 (s, 3H)
实施例76：化合物76Example 76: Compound 76
Figure PCTCN2019070227-appb-000232
Figure PCTCN2019070227-appb-000232
合成路线：synthetic route:
Figure PCTCN2019070227-appb-000233
Figure PCTCN2019070227-appb-000233
步骤1：化合物76-A的合成Step 1: Synthesis of Compound 76-A
将化合物75-A(100mg,354.47μmol)溶于二甲胺的水溶液中(10ml，33％)，在130℃下封管搅拌12小时。加入5ml的水，过滤抽干得到粗品。粗品经3ml的水洗涤，过滤抽干得到76-A。Compound 75-A (100 mg, 354.47 μmol) was dissolved in dimethylamine aqueous solution (10 ml, 33%), and the mixture was stirred at 130 ° C for 12 hours. 5 ml of water was added and filtered to obtain a crude product. The crude product was washed with 3 ml of water and filtered to dryness to afford 76-A.
MS m/z:306.9[M+H] + MS m/z: 306.9 [M+H] +
步骤2：化合物76-B的合成Step 2: Synthesis of Compound 76-B
除了使用相应的原料外，以实施例9中的制备化合物9-A相同的方法制备化合物76-B。Compound 76-B was prepared in the same manner as in the preparation of compound 9-A in Example 9 except that the corresponding material was used.
MS m/z:490.3[M+H] + MS m/z: 490.3 [M+H] +
步骤3：化合物76的合成Step 3: Synthesis of Compound 76
除了使用相应的原料外，以实施例9中的制备化合物9相同的方法制备化合物76。Compound 76 was prepared in the same manner as in the preparation of compound 9 in Example 9 except that the corresponding material was used.
MS m/z:390.1[M+H] + MS m/z: 390.1 [M+H] +
1H NMR(400MHz,DMSO-d 6)δppm 8.65(br s,1H)8.29(br s,1H)8.24(s,1H)7.88(s,1H)7.79(dd,J＝9.03, 2.76Hz,1H)7.35(d,J＝8.53Hz,1H)7.08(d,J＝8.53Hz,1H)6.67(br d,J＝8.53Hz,1H)6.61(s,1H)4.06(s,2H)3.88(s,3H)2.99(s,6H)2.01(s,3H) 1 H NMR (400MHz, DMSO- d 6) δppm 8.65 (br s, 1H) 8.29 (br s, 1H) 8.24 (s, 1H) 7.88 (s, 1H) 7.79 (dd, J = 9.03, 2.76Hz, 1H 7.35 (d, J = 8.53 Hz, 1H) 7.08 (d, J = 8.53 Hz, 1H) 6.67 (br d, J = 8.53 Hz, 1H) 6.61 (s, 1H) 4.06 (s, 2H) 3.88 (s) , 3H) 2.99 (s, 6H) 2.01 (s, 3H)
实施例77：化合物77Example 77: Compound 77
Figure PCTCN2019070227-appb-000234
Figure PCTCN2019070227-appb-000234
合成路线：synthetic route:
Figure PCTCN2019070227-appb-000235
Figure PCTCN2019070227-appb-000235
步骤1：化合物77-A的合成Step 1: Synthesis of Compound 77-A
除了使用相应的原料外，以实施例9中的制备化合物9-A相同的方法制备化合物77-A。Compound 77-A was prepared in the same manner as in the preparation of compound 9-A in Example 9 except that the corresponding material was used.
MS m/z:465.2[M+H] + MS m/z: 465.2 [M+H] +
步骤2：化合物77的合成Step 2: Synthesis of Compound 77
除了使用相应的原料外，以实施例9中的制备化合物9相同的方法制备化合物77。Compound 77 was prepared in the same manner as in the preparation of compound 9 in Example 9 except that the corresponding material was used.
MS m/z:365.1[M+H] + MS m/z: 365.1 [M+H] +
1HNMR(400MHz,CD 3OD)δppm 8.38(s,1H),8.17-8.10(m,1H),7.88(s,1H),7.45(d,J＝8.5Hz,1H),7.16(d,J＝8.3Hz,2H),7.00(s,1H),4.19(s,2H),3.97(s,3H),2.19(s,3H) 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.38 (s, 1H), 8.17-8.10 (m, 1H), 7.88 (s, 1H), 7.45 (d, J = 8.5 Hz, 1H), 7.16 (d, J) =8.3 Hz, 2H), 7.00 (s, 1H), 4.19 (s, 2H), 3.97 (s, 3H), 2.19 (s, 3H)
实施例78：化合物78Example 78: Compound 78
Figure PCTCN2019070227-appb-000236
Figure PCTCN2019070227-appb-000236
合成路线：synthetic route:
Figure PCTCN2019070227-appb-000237
Figure PCTCN2019070227-appb-000237
步骤1：化合物78-B的合成Step 1: Synthesis of Compound 78-B
将对溴苯酚(3g,17.34mmol)，环丙基溴(3g,24.80mmol,1.99mL)和碳酸铯(11.30g,34.68mmol)溶解在DMF(50mL)中，反应液在130℃搅拌12小时。冷却后将反应液倒入50mL乙酸乙酯和20mL水的混合溶液中，分出乙酸乙酯层，用饱和食盐水(20mL)洗涤一次，无水硫酸钠干燥，过滤，浓缩。将所得到的粗品经硅胶柱纯化(洗脱剂：PE/EA＝10/1～5/1)，得到78-B。The p-bromophenol (3 g, 17.34 mmol), cyclopropyl bromide (3 g, 24.80 mmol, 1.99 mL) and cesium carbonate (11.30 g, 34.68 mmol) were dissolved in DMF (50 mL), and the mixture was stirred at 130 ° C for 12 hours. . After cooling, the reaction mixture was poured into a mixture of 50 mL of ethyl acetate and 20 mL of water, and the mixture was evaporated. The obtained crude product was purified through a silica gel column (eluent: PE/EA = 10/1 to 5/1) to afford 78-B.
1H NMR(400MHz,CD 3OD)δppm 7.40(d,J＝8.78Hz,2H)6.99(d,J＝8.78Hz,2H)3.72-3.82(m,1H)0.77-0.84(m,2H)0.66-0.72(m,2H) 1 H NMR (400 MHz, CD 3 OD) δ ppm 7.40 (d, J = 8.78 Hz, 2H) 6.99 (d, J = 8.78 Hz, 2H) 3.72-3.82 (m, 1H) 0.77-0.84 (m, 2H) 0.66 -0.72 (m, 2H)
步骤2：化合物78-C的合成Step 2: Synthesis of Compound 78-C
除了使用相应的原料外，以实施例32中的制备化合物32-A相同的方法制备化合物78-C。Compound 78-C was prepared in the same manner as in the preparation of compound 32-A in Example 32 except that the corresponding material was used.
MS m/z:318.9[M+H] + MS m/z: 318.9 [M+H] +
步骤3：化合物78-D的合成Step 3: Synthesis of Compound 78-D
除了使用相应的原料外，以实施例9中的制备化合物9-A相同的方法制备化合物78-D。Compound 78-D was prepared in the same manner as in the preparation of compound 9-A in Example 9 except that the corresponding materials were used.
MS m/z:502.2[M+H] + MS m/z: 502.2 [M+H] +
步骤4：化合物78的合成Step 4: Synthesis of Compound 78
除了使用相应的原料外，以实施例9中的制备化合物9相同的方法制备化合物78。Compound 78 was prepared in the same manner as in the preparation of compound 9 in Example 9 except that the corresponding material was used.
MS m/z:402.0[M+H] + MS m/z: 402.0 [M+H] +
1HNMR(400MHz,CD 3OD)δppm 7.81(s,1H),7.40(d,J＝8.3Hz,1H),7.35(d,J＝9.0Hz,2H),7.12(d,J＝8.5Hz,1H),7.02(d,J＝9.0Hz,2H),6.68(s,1H),4.17(s,2H),3.97(s,3H),3.77(m,J＝2.9,6.0Hz,1H),2.05(s,3H),0.81-0.63(m,4H) 1 H NMR (400 MHz, CD 3 OD) δ ppm 7.81 (s, 1H), 7.40 (d, J = 8.3 Hz, 1H), 7.35 (d, J = 9.0 Hz, 2H), 7.12 (d, J = 8.5 Hz, 1H), 7.02 (d, J = 9.0 Hz, 2H), 6.68 (s, 1H), 4.17 (s, 2H), 3.97 (s, 3H), 3.77 (m, J = 2.9, 6.0 Hz, 1H), 2.05(s,3H), 0.81-0.63 (m, 4H)
实施例79：化合物79Example 79: Compound 79
Figure PCTCN2019070227-appb-000238
Figure PCTCN2019070227-appb-000238
合成路线：synthetic route:
Figure PCTCN2019070227-appb-000239
Figure PCTCN2019070227-appb-000239
步骤1：化合物79-B的合成Step 1: Synthesis of Compound 79-B
将NaH(2.73g,68.19mmol)加入三口烧瓶中，加入THF(50mL)，在0℃下滴加溶于THF(5mL)的79-A(1.00g,11.36mmol)，继续搅拌0.5小时，加入2-氟-5-溴吡啶(2g,11.36mmol)，氮气保护，并升温至30℃反应1小时。降温到0℃，加入氯化铵溶液至无气泡冒出。粗品用H 2O(300mL)洗涤，用乙酸乙酯(300mL)萃取，饱和食盐水(90mL)洗涤，Na 2SO 4干燥，过滤干燥剂，减压浓缩，浓缩物经柱层析(洗脱剂：石油醚/乙酸乙酯＝20/1～5/1)纯化，得到79-B。 NaH (2.73 g, 68.19 mmol) was added to a three-necked flask, THF (50 mL) was added, and 79-A (1.00 g, 11.36 mmol) dissolved in THF (5 mL) was added dropwise at 0 ° C, and stirring was continued for 0.5 hour. 2-Fluoro-5-bromopyridine (2 g, 11.36 mmol) was protected with nitrogen and warmed to 30 ° C for 1 hour. The temperature was lowered to 0 ° C, and an ammonium chloride solution was added until no bubbles appeared. The crude product was washed, extracted with H 2 O (300mL) with ethyl acetate (300 mL), dried with saturated brine (90mL) Na 2 SO 4, the drying agent filtered, and concentrated under reduced pressure, concentrate was purified by column chromatography (eluting Purification: petroleum ether / ethyl acetate = 20/1 ~ 5 / 1) was purified to give 79-B.
MS m/z:244.9[M+H] +。 MS m/z: 244.9 [M+H] + .
1H NMR(400MHz,CDCl 3)δppm 8.17(d,J＝2.3Hz,1H),7.65(dd,J＝2.8,8.8Hz,1H),6.66(d,J＝8.8Hz,1H),5.51(m,J＝2.0,4.4,6.4Hz,1H),4.05-3.95(m,2H),3.95-3.86(m,2H),2.31-2.07(m,2H) 1 H NMR (400 MHz, CDCl 3 ) δ ppm 8.17 (d, J = 2.3 Hz, 1H), 7.65 (dd, J = 2.8, 8.8 Hz, 1H), 6.66 (d, J = 8.8 Hz, 1H), 5.51 ( m, J = 2.0, 4.4, 6.4 Hz, 1H), 4.05-3.95 (m, 2H), 3.95-3.86 (m, 2H), 2.31-2.07 (m, 2H)
步骤2：化合物79-C的合成Step 2: Synthesis of Compound 79-C
除了使用相应的原料外，以实施例32中的制备化合物32-A相同的方法制备化合物79-C。Compound 79-C was prepared in the same manner as in the preparation of compound 32-A in Example 32 except that the corresponding material was used.
MS m/z:533.1[M+H] + MS m/z: 533.1 [M+H] +
步骤3：化合物79的合成Step 3: Synthesis of Compound 79
除了使用相应的原料外，以实施例32中的制备化合物32相同的方法制备化合物79。Compound 79 was prepared in the same manner as in the preparation of compound 32 in Example 32 except that the corresponding material was used.
MS m/z:433.0[M+H] + MS m/z: 433.0 [M+H] +
1H NMR(400MHz,CD 3OD)δppm 8.29(d,J＝2.8Hz,1H),7.90(dd,J＝2.9,8.9Hz,1H),7.85(s,1H),7.39(d,J＝8.5Hz,1H),7.12(d,J＝8.3Hz,1H),6.77(d,J＝8.8Hz,1H),6.69(s,1H),5.50-5.43(m,1H),4.16(s,2H),4.03-3.94(m,5H),3.92-3.85(m,2H),2.32-2.21(m,1H),2.17-2.09(m,1H),2.07(s,3H) 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.29 (d, J = 2.8 Hz, 1H), 7.90 (dd, J = 2.9, 8.9 Hz, 1H), 7.85 (s, 1H), 7.39 (d, J = 8.5 Hz, 1H), 7.12 (d, J = 8.3 Hz, 1H), 6.77 (d, J = 8.8 Hz, 1H), 6.69 (s, 1H), 5.50 - 5.43 (m, 1H), 4.16 (s, 2H), 4.03-3.94 (m, 5H), 3.92-3.85 (m, 2H), 2.32-2.21 (m, 1H), 2.17-2.09 (m, 1H), 2.07 (s, 3H)
实施例80：化合物80Example 80: Compound 80
Figure PCTCN2019070227-appb-000240
Figure PCTCN2019070227-appb-000240
合成路线：synthetic route:
Figure PCTCN2019070227-appb-000241
Figure PCTCN2019070227-appb-000241
步骤1：化合物80-B的合成Step 1: Synthesis of Compound 80-B
将80-A(200mg,1.15mmol)溶于氢氟酸吡啶溶液(5mL)，在0℃下缓慢加入亚硝酸钠(79.31mg,1.15mmol)，继续搅拌1.5小时，反应液用饱和碳酸氢钠溶液调至pH＝8，用水(300mL)洗涤，乙酸乙酯(150mL)萃取，分液，有机相用饱和食盐水(50mL)洗涤，无水Na 2SO 4干燥，减压浓缩。浓缩物经柱层析(洗脱剂：PE/EA＝10/1～8/1)纯化，得到80-B。 80-A (200 mg, 1.15 mmol) was dissolved in a solution of pyridine hydrofluoric acid (5 mL), sodium nitrite (79.31 mg, 1.15 mmol) was slowly added at 0 ° C, stirring was continued for 1.5 hours, and the reaction solution was saturated sodium bicarbonate. solution was adjusted to pH = 8, washed with water (300 mL) and washed with ethyl acetate (150 mL) was extracted, separated, the organic phase was washed with saturated brine (50mL) was washed, dried over anhydrous Na 2 SO 4, and concentrated under reduced pressure. The concentrate was purified by column chromatography (eluent: PE/EA = 10/1 to 8/1) to afford 80-B.
MS m/z:176.8[M+H] + MS m/z: 176.8 [M+H] +
1HNMR(400MHz,CHLOROFORM-d)δppm 7.77(dd,J＝6.5,9.0Hz,1H),7.14(dd,J＝2.0,9.0Hz,1H) 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.77 (dd, J = 6.5, 9.0 Hz, 1H), 7.14 (dd, J = 2.0, 9.0 Hz, 1H)
步骤2：化合物80-C的合成Step 2: Synthesis of Compound 80-C
将NaH(113.00mg,2.83mmol)加入三口烧瓶中，加入THF(5mL)，在0℃下滴加溶于THF(1mL)的环丙醇(24.61mg,423.79μmol)，继续搅拌0.5小时，加入80-B(50mg,245.80μmol)，氮气保护，升温至30℃反应1小时，降温至0℃并加入氯化铵溶液至无气泡冒出，粗品用H 2O(150mL)洗涤，用EA(50mL)萃取，饱和 食盐水(50mL)洗涤，无水Na 2SO 4干燥，过滤，减压浓缩。浓缩物经柱层析(洗脱剂：PE/EA＝20/1～5/1)纯化，减压浓缩得到80-C。 NaH (113.00 mg, 2.83 mmol) was added to a three-necked flask, THF (5 mL) was added, and cyclopropanol (24.61 mg, 423.79 μmol) dissolved in THF (1 mL) was added dropwise at 0 ° C, and stirring was continued for 0.5 hour. 80-B (50 mg, 245.80 μmol), nitrogen-protected, warmed to 30 ° C for 1 hour, cooled to 0 ° C and added ammonium chloride solution until no bubbles emerged, the crude product was washed with H 2 O (150 mL), using EA ( 50 mL) extracted with saturated brine (50mL) was washed, dried over anhydrous Na 2 SO 4, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (eluent: EtOAc/EtOAc = EtOAc:
MS m/z:216.8[M+H] + MS m/z: 216.8 [M+H] +
1H NMR(400MHz,CHLOROFORM-d)δppm 7.49(d,J＝9.0Hz,1H),6.83(d,J＝9.0Hz,1H),4.47(tt,J＝3.0,6.2Hz,1H),0.92-0.85(m,2H),0.85-0.78(m,2H) 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.49 (d, J = 9.0 Hz, 1H), 6.83 (d, J = 9.0 Hz, 1H), 4.47 (tt, J = 3.0, 6.2 Hz, 1H), 0.92 -0.85 (m, 2H), 0.85-0.78 (m, 2H)
步骤3：化合物80-D的合成Step 3: Synthesis of Compound 80-D
除了使用相应的原料外，以实施例32中的制备化合物32-A相同的方法制备化合物80-D。Compound 80-D was prepared in the same manner as in the preparation of compound 32-A in Example 32 except that the corresponding material was used.
MS m/z:504.2[M+H] + MS m/z: 504.2 [M+H] +
步骤4：化合物80的合成Step 4: Synthesis of Compound 80
除了使用相应的原料外，以实施例32中的制备化合物32相同的方法制备化合物80。Compound 80 was prepared in the same manner as in the preparation of compound 32 in Example 32 except that the corresponding material was used.
MS m/z:404.0[M+H] + MS m/z: 404.0 [M+H] +
1H NMR(400MHz,DMSO-d6)δppm 9.87(s,1H),8.23(s,1H),8.02(s,1H),7.92(d,J＝9.5Hz,1H),7.73(s,1H),7.37(d,J＝8.5Hz,1H),7.14(d,J＝9.5Hz,1H),7.07(d,J＝8.5Hz,1H),4.30(m,J＝3.0,6.2Hz,1H),4.04(s,2H),3.86(s,3H),2.08(s,3H),0.80-0.74(m,2H),0.69(m,2H) 1 H NMR (400MHz, DMSO- d6) δppm 9.87 (s, 1H), 8.23 (s, 1H), 8.02 (s, 1H), 7.92 (d, J = 9.5Hz, 1H), 7.73 (s, 1H) , 7.37 (d, J = 8.5 Hz, 1H), 7.14 (d, J = 9.5 Hz, 1H), 7.07 (d, J = 8.5 Hz, 1H), 4.30 (m, J = 3.0, 6.2 Hz, 1H) , 4.04 (s, 2H), 3.86 (s, 3H), 2.08 (s, 3H), 0.80-0.74 (m, 2H), 0.69 (m, 2H)
实施例81：化合物81Example 81: Compound 81
Figure PCTCN2019070227-appb-000242
Figure PCTCN2019070227-appb-000242
合成路线：synthetic route:
Figure PCTCN2019070227-appb-000243
Figure PCTCN2019070227-appb-000243
步骤1：化合物81-A的合成Step 1: Synthesis of Compound 81-A
除了使用相应的原料外，以实施例32中的制备化合物32-A相同的方法制备化合物81-A。Compound 81-A was prepared in the same manner as in the preparation of compound 32-A in Example 32 except that the corresponding material was used.
MS m/z:471.2[M+H] + MS m/z: 471.2 [M+H] +
步骤2：化合物81的合成Step 2: Synthesis of Compound 81
除了使用相应的原料外，以实施例32中的制备化合物32相同的方法制备化合物81。Compound 81 was prepared in the same manner as in the preparation of compound 32 in Example 32 except that the corresponding material was used.
MS m/z:371.0[M+H] + MS m/z: 371.0 [M+H] +
1H NMR(400MHz,CD 3OD)δppm 8.03(s,1H),7.83(d,J＝8.8Hz,2H),7.58(d,J＝8.8Hz,2H),7.43(d,J＝8.3Hz,1H),7.15(d,J＝8.5Hz,1H),6.86(s,1H),4.18(s,2H),3.98(s,3H),2.13(s,3H) 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.03 (s, 1H), 7.83 (d, J = 8.8 Hz, 2H), 7.58 (d, J = 8.8 Hz, 2H), 7.43 (d, J = 8.3 Hz) , 1H), 7.15 (d, J = 8.5 Hz, 1H), 6.86 (s, 1H), 4.18 (s, 2H), 3.98 (s, 3H), 2.13 (s, 3H)
实施例82：化合物82Example 82: Compound 82
Figure PCTCN2019070227-appb-000244
Figure PCTCN2019070227-appb-000244
合成路线：synthetic route:
Figure PCTCN2019070227-appb-000245
Figure PCTCN2019070227-appb-000245
步骤1：化合物82-B的合成Step 1: Synthesis of Compound 82-B
将化合物82-A(0.3g,1.33mmol)，乙烯基三氟硼酸钾(267.80mg,2.00mmol)，碳酸钾(460.51mg,3.33mmol)加入1,4-二氧六环(10mL)和水(1mL)中，在氮气保护下加入Pd(dppf)Cl 2·DCM(54.42mg,66.64μmol)，反应在100℃下搅拌4小时。冷却后将反应液过滤，滤液浓缩，粗品经层析柱(石油醚/乙酸乙酯＝4/1～2/1)纯化得到化合物82-B。 Compound 82-A (0.3 g, 1.33 mmol), potassium vinyl trifluoroborate (267.80 mg, 2.00 mmol), potassium carbonate (460.51 mg, 3.33 mmol) was added to 1,4-dioxane (10 mL) and water (1 mL) Pd(dppf)Cl 2 ·DCM (54.42 mg, 66.64 μmol) was added under a nitrogen atmosphere, and the reaction was stirred at 100 ° C for 4 hours. After cooling, the reaction solution was filtered, and the filtrate was concentrated, and the crude material was purified by chromatography ( petroleum ether/ethyl acetate = 4/1 to 2/1) to afford compound 82-B.
MS m/z:172.1[M+H] + MS m/z: 172.1 [M+H] +
步骤2：化合物82-C的合成Step 2: Synthesis of Compound 82-C
将化合物82-B(0.17g,987.08μmol)溶解在四氢呋喃(10mL)和水(5mL)中，加入四氧化锇(2.45g,481.85μmol)和高碘酸钠(422.25mg,1.97mmol)，反应液在25℃搅拌12小时。将反应液加到50mL的乙酸乙酯和20mL的水中，分离乙酸乙酯层，用饱和食盐水(20mL)洗涤一次，用无水硫酸钠干燥，过滤，浓缩。将所得到的粗品经硅胶柱纯化(洗脱剂：石油醚/乙酸乙酯＝3/1～1/1)得到化合物82-C。Compound 82-B (0.17 g, 987.08 μmol) was dissolved in tetrahydrofuran (10 mL) and water (5 mL), and osmium tetroxide (2.45 g, 481.85 μmol) and sodium periodate (422.25 mg, 1.97 mmol) were reacted. The solution was stirred at 25 ° C for 12 hours. The reaction solution was poured into 50 mL of ethyl acetate and 20 mL of EtOAc. The obtained crude product was purified through silica gel column (eluent: petroleum ether/ethyl acetate = 3/1 to 1/1) to afford compound 82-C.
步骤3：化合物82-D的合成Step 3: Synthesis of Compound 82-D
将化合物82-C(0.13g,746.27μmol)，II-A(139.58mg,746.27μmol)，三氟乙酸(1.91g,16.72mmol)和三乙基硅氢(1.80g,15.51mmol)溶解在MeCN(20mL)中，反应液在80℃搅拌2小时后，向反应液中加入NaHCO 3调至碱性，用H 2O(150mL)洗涤，EA(100mL)萃取，饱和食盐水(50mL)洗涤，Na 2SO 4干燥，过滤干燥剂，减压浓缩。浓缩物经柱层析(洗脱剂：石油醚/乙酸乙酯＝20/1～2/1)纯化得到化合物82-D。 Compound 82-C (0.13 g, 746.27 μmol), II-A (139.58 mg, 746.27 μmol), trifluoroacetic acid (1.91 g, 16.72 mmol) and triethylsilylhydrogen (1.80 g, 15.51 mmol) were dissolved in MeCN (20 mL), the reaction mixture was stirred at 80 ° C for 2 hours, then NaHCO 3 was added to the reaction mixture to make basic, washed with H 2 O (150 mL), EA (100 mL), and brine (50 mL) The Na 2 SO 4 was dried, filtered and dried and evaporated. The concentrate was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 20/1 to 2/1) to afford compound 82-D.
MS m/z:344.1[M+H] +。 MS m/z: 344.1 [M+H] + .
步骤4：化合物82-E的合成Step 4: Synthesis of Compound 82-E
除了使用相应的原料外，以实施例9中的制备化合物9-A相同的方法制备化合物82-E。Compound 82-E was prepared in the same manner as in the preparation of compound 9-A in Example 9 except that the corresponding material was used.
MS m/z:527.2[M+H] + MS m/z: 527.2 [M+H] +
步骤5：化合物82的合成Step 5: Synthesis of Compound 82
除了使用相应的原料外，以实施例9中的制备化合物9相同的方法制备化合物82。Compound 82 was prepared in the same manner as in the preparation of compound 9 in Example 9 except that the corresponding materials were used.
MS m/z:427.0[M+H] + MS m/z: 427.0 [M+H] +
1H NMR(400MHz,CD 3OD)δppm 7.75(s,1H)7.48-7.53(m,2H)7.42-7.47(m,2H)7.39(d,J＝8.53Hz,1H)7.12(d,J＝8.03Hz,1H)6.53(s,1H)4.56(s,2H)4.16(s,2H)3.98(s,3H)2.04(s,3H)1.73(s,6H) 1 H NMR (400 MHz, CD 3 OD) δ ppm 7.75 (s, 1H) 7.48-7.53 (m, 2H) 7.42-7.47 (m, 2H) 7.39 (d, J = 8.53 Hz, 1H) 7.12 (d, J = 8.03Hz,1H)6.53(s,1H)4.56(s,2H)4.16(s,2H)3.98(s,3H)2.04(s,3H)1.73(s,6H)
实施例83：化合物83Example 83: Compound 83
Figure PCTCN2019070227-appb-000246
Figure PCTCN2019070227-appb-000246
合成路线：synthetic route:
Figure PCTCN2019070227-appb-000247
Figure PCTCN2019070227-appb-000247
步骤1：化合物83-B的合成Step 1: Synthesis of Compound 83-B
除了使用相应的原料外，以实施例82中的制备化合物82-B相同的方法制备化合物83-B。Compound 83-B was prepared in the same manner as in the preparation of compound 82-B in Example 82 except that the corresponding material was used.
1H NMR(400MHz,CHLOROFORM-d)δ7.84(s,1H),7.68-7.77(q,2H),6.74(dd,J＝11.04,17.57Hz,1H),5.94(d,J＝17.57Hz,1H),5.55(d,J＝11.04Hz,1H) 1 H NMR (J = 11.04,17.57Hz dd ,, 1H) (400MHz, CHLOROFORM-d) δ7.84 (s, 1H), 7.68-7.77 (q, 2H), 6.74, 5.94 (d, J = 17.57Hz , 1H), 5.55 (d, J = 11.04 Hz, 1H)
步骤2：化合物83-C的合成Step 2: Synthesis of Compound 83-C
除了使用相应的原料外，以实施例82中的制备化合物82-C相同的方法制备化合物83-C。Compound 83-C was prepared in the same manner as in the preparation of compound 82-C in Example 82, except using the corresponding material.
1H NMR(400MHz,CHLOROFORM-d)δ10.13(s,1H),8.36(s,1H),8.24(d,J＝8.28Hz,1H),8.03(d,J＝8.28Hz,1H) 1 H NMR (400MHz, CHLOROFORM- d) δ10.13 (s, 1H), 8.36 (s, 1H), 8.24 (d, J = 8.28Hz, 1H), 8.03 (d, J = 8.28Hz, 1H)
步骤3：化合物83-D的合成Step 3: Synthesis of Compound 83-D
除了使用相应的原料外，以实施例82中的制备化合物82-D相同的方法制备化合物83-D。Compound 83-D was prepared in the same manner as in the preparation of compound 82-D in Example 82 except that the corresponding material was used.
MS m/z:369.9[M+H] + MS m/z: 369.9 [M+H] +
步骤4：化合物83-E的合成Step 4: Synthesis of Compound 83-E
除了使用相应的原料外，以实施例9中的制备化合物9-A相同的方法制备化合物83-E。Compound 83-E was prepared in the same manner as in the preparation of compound 9-A in Example 9 except that the corresponding materials were used.
MS m/z:553.1[M+H] +。 MS m/z: 553.1 [M + H] + .
步骤5：化合物83的合成Step 5: Synthesis of Compound 83
除了使用相应的原料外，以实施例9中的制备化合物9相同的方法制备化合物83。Compound 83 was prepared in the same manner as in the preparation of compound 9 in Example 9 except that the corresponding materials were used.
MS m/z:452.9[M+H] + MS m/z: 452.9 [M+H] +
1H NMR(400MHz,CD 3OD)δppm 7.95(s,1H),7.83-7.88(d,2H),7.73(s,1H),7.36(d,J＝8.28Hz,1H),7.10(d,J＝8.53Hz,1H),6.56(s,1H),4.67(s,2H),4.13(s,2H),3.95(s,3H),2.04(s,3H) 1 H NMR (400 MHz, CD 3 OD) δ ppm 7.95 (s, 1H), 7.83-7.88 (d, 2H), 7.73 (s, 1H), 7.36 (d, J = 8.28 Hz, 1H), 7.10 (d, J=8.53 Hz, 1H), 6.56 (s, 1H), 4.67 (s, 2H), 4.13 (s, 2H), 3.95 (s, 3H), 2.04 (s, 3H)
实施例84：化合物84Example 84: Compound 84
Figure PCTCN2019070227-appb-000248
Figure PCTCN2019070227-appb-000248
合成路线：synthetic route:
Figure PCTCN2019070227-appb-000249
Figure PCTCN2019070227-appb-000249
步骤1：化合物84-B的合成Step 1: Synthesis of Compound 84-B
在0℃下向含有化合物2-氨基-5-溴吡啶(1g,5.78mmol)的THF(10mL)溶液中滴加2-氯乙基异氰酸酯(731.91mg,6.94mmol)，反应液在20℃搅拌12小时。将反应液过滤得到84-B。2-Chloroethyl isocyanate (731.91 mg, 6.94 mmol) was added dropwise to a solution of the compound 2-amino-5-bromopyridine (1 g, 5.78 mmol) in THF (10 mL). 12 hours. The reaction solution was filtered to give 84-B.
MS m/z:279.8[M+H] + MS m/z: 279.8 [M+H] +
步骤2：化合物84-C的合成Step 2: Synthesis of Compound 84-C
将化合物84-B(1.2g,4.31mmol)溶解在DMF(20mL)中，在0℃下加入NaH(430.79mg,10.77mmol)，反应液在60℃搅拌2.5小时。将反应液加到50mL的乙酸乙酯和20mL的水中，分离乙酸乙酯层，用饱和食盐水(20mL)洗涤一次，用无水硫酸钠干燥，过滤，浓缩。得到84-C。Compound 84-B (1.2 g, 4.31 mmol) was dissolved in DMF (20 mL), NaH (430.79 mg, 10.77 mmol). The reaction solution was poured into 50 mL of ethyl acetate and 20 mL of EtOAc. Get 84-C.
MS m/z:241.9[M+H] + MS m/z: 241.9 [M+H] +
步骤3：化合物84-D的合成Step 3: Synthesis of Compound 84-D
将84-C(0.2g,826.20μmol)溶于DMSO(10mL)中，逐滴加入Et 3N(250.81mg,2.48mmol,344.99uL)， DMAP(100.94mg,826.20μmol)和Boc酸酐(450.79mg,2.07mmol)，25℃下搅拌1小时，再升温至48℃搅拌12小时。反应液用水(200mL)洗涤，乙酸乙酯(150mL)萃取，分液，有机相用饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤干燥剂，减压浓缩。浓缩物经柱层析(洗脱剂：PE/EA＝20/1～5/1)纯化得到84-D。 The 84-C (0.2g, 826.20μmol) was dissolved in DMSO (10mL) dropwise addition of Et 3 N (250.81mg, 2.48mmol, 344.99uL), DMAP (100.94mg, 826.20μmol) and Boc anhydride (450.79mg , 2.07 mmol), stirred at 25 ° C for 1 hour, and then warmed to 48 ° C and stirred for 12 hours. The reaction mixture was washed with EtOAc EtOAc. The concentrate was purified by column chromatography (eluent: PE/EA = 20/1 to 5/1) to afford 84-D.
MS m/z:341.9[M+H] + MS m/z: 341.9 [M+H] +
1H NMR(400MHz,CDCl 3)δppm 8.36(d,J＝2.0Hz,1H),8.27(d,J＝9.0Hz,1H),7.77(dd,J＝2.5,9.0Hz,1H),4.05-4.00(m,2H),3.93-3.87(m,2H),1.58(s,9H) 1 H NMR (400 MHz, CDCl 3 ) δ ppm 8.36 (d, J = 2.0 Hz, 1H), 8.27 (d, J = 9.0 Hz, 1H), 7.77 (dd, J = 2.5, 9.0 Hz, 1H), 4.05- 4.00 (m, 2H), 3.93-3.87 (m, 2H), 1.58 (s, 9H)
步骤4：化合物84-E的合成Step 4: Synthesis of Compound 84-E
除了使用相应的原料外，以实施例32中的制备化合物32-A相同的方法制备化合物84-E。Compound 84-E was prepared in the same manner as in the preparation of compound 32-A in Example 32 except that the corresponding material was used.
MS m/z:631.3[M+H] + MS m/z: 631.3 [M+H] +
步骤5：化合物84的合成Step 5: Synthesis of Compound 84
除了使用相应的原料外，以实施例32中的制备化合物32相同的方法制备化合物84。Compound 84 was prepared in the same manner as in the preparation of compound 32 in Example 32 except that the corresponding material was used.
MS m/z:431.1[M+H] + MS m/z: 431.1 [M+H] +
1H NMR(400MHz,DMSO-d 6)δppm 9.01(s,1H),8.58(d,J＝2.3Hz,1H),8.24(s,1H),8.08-8.04(m,1H),8.02-7.97(m,1H),7.94(s,1H),7.36(d,J＝8.5Hz,1H),7.08(d,J＝8.8Hz,1H),7.04(s,1H),6.71(s,1H),4.06(s,2H),3.97(t,J＝8.0Hz,2H),3.87(s,3H),3.40(m,J＝7.8Hz,2H),2.03(s,3H) 1 H NMR (400MHz, DMSO- d 6) δppm 9.01 (s, 1H), 8.58 (d, J = 2.3Hz, 1H), 8.24 (s, 1H), 8.08-8.04 (m, 1H), 8.02-7.97 (m, 1H), 7.94 (s, 1H), 7.36 (d, J = 8.5 Hz, 1H), 7.08 (d, J = 8.8 Hz, 1H), 7.04 (s, 1H), 6.71 (s, 1H) , 4.06 (s, 2H), 3.97 (t, J = 8.0 Hz, 2H), 3.87 (s, 3H), 3.40 (m, J = 7.8 Hz, 2H), 2.03 (s, 3H)
实施例85：化合物85Example 85: Compound 85
Figure PCTCN2019070227-appb-000250
Figure PCTCN2019070227-appb-000250
合成路线：synthetic route:
Figure PCTCN2019070227-appb-000251
Figure PCTCN2019070227-appb-000251
步骤1：化合物85-B的合成Step 1: Synthesis of Compound 85-B
将化合物2,5-二溴吡啶(0.2g,844.27μmol)，85-A(73.52mg,844.27μmol)，碳酸铯(825.24mg,2.53mmol)加到1,4-二氧六环(10mL)中，氮气保护下加入Xantphos(97.70mg,168.85μmol)和醋酸钯(18.95mg,84.43μmol)，反应液在100℃，氮气保护下搅拌1.5小时。冷却后用水(200mL)洗涤，乙酸乙酯(100mL)萃取，分液，有机相用饱和食盐水(50mL)洗涤，用无水硫酸钠干燥，过滤干燥剂，减压浓缩。浓缩物经柱层析(洗脱剂：PE/EA＝10/1～3/1)纯化，减压浓缩得到85-B。The compound 2,5-dibromopyridine (0.2 g, 844.27 μmol), 85-A (73.52 mg, 844.27 μmol), cesium carbonate (825.24 mg, 2.53 mmol) was added to 1,4-dioxane (10 mL) Xantphos (97.70 mg, 168.85 μmol) and palladium acetate (18.95 mg, 84.43 μmol) were added under a nitrogen atmosphere, and the reaction solution was stirred at 100 ° C for 1.5 hours under nitrogen atmosphere. After cooling, the mixture was washed with EtOAc EtOAc. The concentrate was purified by column chromatography (eluent: EtOAc/EtOAc/EtOAc/EtOAc)
MS m/z:242.8[M+H] + MS m/z: 242.8 [M+H] +
步骤2：化合物85-C的合成Step 2: Synthesis of Compound 85-C
除了使用相应的原料外，以实施例32中的制备化合物32-A相同的方法制备化合物85-C。Compound 85-C was prepared in the same manner as in the preparation of compound 32-A in Example 32 except that the corresponding material was used.
MS m/z:532.1[M+H] + MS m/z: 532.1 [M+H] +
步骤3：化合物85的合成Step 3: Synthesis of Compound 85
除了使用相应的原料外，以实施例32中的制备化合物32相同的方法制备化合物85。Compound 85 was prepared in the same manner as in the preparation of compound 32 in Example 32 except that the corresponding material was used.
MS m/z:432.0[M+H] + MS m/z: 432.0 [M+H] +
1H NMR(400MHz,DMSO-d 6)δppm 9.19(s,1H),8.68(d,J＝2.5Hz,1H),8.24(s,1H),8.16(dd,J＝2.8,9.0Hz,1H),8.00-7.94(t,2H),7.36(d,J＝8.3Hz,1H),7.08(d,J＝8.3Hz,1H),6.75(s,1H),4.48-4.40(t,2H),4.19-4.10(t,2H),4.06(s,2H),3.88(s,3H),2.04(s,3H) 1 H NMR (400MHz, DMSO- d 6) δppm 9.19 (s, 1H), 8.68 (d, J = 2.5Hz, 1H), 8.24 (s, 1H), 8.16 (dd, J = 2.8,9.0Hz, 1H ), 8.00-7.94(t, 2H), 7.36 (d, J = 8.3 Hz, 1H), 7.08 (d, J = 8.3 Hz, 1H), 6.75 (s, 1H), 4.48-4.40 (t, 2H) , 4.19-4.10(t, 2H), 4.06(s, 2H), 3.88(s, 3H), 2.04(s, 3H)
实施例86：化合物86Example 86: Compound 86
Figure PCTCN2019070227-appb-000252
Figure PCTCN2019070227-appb-000252
合成路线：synthetic route:
Figure PCTCN2019070227-appb-000253
Figure PCTCN2019070227-appb-000253
步骤1：化合物86-B的合成Step 1: Synthesis of Compound 86-B
除了使用相应的原料外，以实施例32中的制备化合物32A相同的方法制备化合物86-B。Compound 86-B was prepared in the same manner as in the preparation of compound 32A in Example 32 except that the corresponding material was used.
MS m/z:462.2[M+H] + MS m/z: 462.2 [M+H] +
步骤2：化合物86的合成Step 2: Synthesis of Compound 86
除了使用相应的原料外，以实施例32中的制备化合物32相同的方法制备化合物86。Compound 86 was prepared in the same manner as in the preparation of compound 32 in Example 32 except that the corresponding material was used.
MS m/z:362.0[M+H] + MS m/z: 362.0 [M+H] +
1H NMR(400MHz,CDCl 3)δppm 8.90(s,2H)8.04(s,1H)7.35(d,J＝8.28Hz,1H)7.02(d,J＝8.04Hz,1H)6.70(s,1H)6.32(s,1H)5.99(br s,1H)5.34-5.38(m,1H)4.16(s,2H)4.05(s,3H)2.74(s,3H)2.12(s,3H) 1 H NMR (400MHz, CDCl 3 ) δppm 8.90 (s, 2H) 8.04 (s, 1H) 7.35 (d, J = 8.28Hz, 1H) 7.02 (d, J = 8.04Hz, 1H) 6.70 (s, 1H) 6.32(s,1H)5.99(br s,1H)5.34-5.38(m,1H)4.16(s,2H)4.05(s,3H)2.74(s,3H)2.12(s,3H)
实施例87：化合物87Example 87: Compound 87
Figure PCTCN2019070227-appb-000254
Figure PCTCN2019070227-appb-000254
合成路线：synthetic route:
Figure PCTCN2019070227-appb-000255
Figure PCTCN2019070227-appb-000255
步骤1：化合物87-B的合成Step 1: Synthesis of Compound 87-B
除了使用相应的原料外，以实施例32中的制备化合物32-A相同的方法制备化合物87-B。Compound 87-B was prepared in the same manner as in the preparation of compound 32-A in Example 32 except that the corresponding material was used.
MS m/z:478.2[M+H] + MS m/z: 478.2 [M+H] +
步骤2：化合物87的合成Step 2: Synthesis of Compound 87
除了使用相应的原料外，以实施例32中的制备化合物32相同的方法制备化合物87。Compound 87 was prepared in the same manner as in the preparation of compound 32 in Example 32 except that the corresponding material was used.
MS m/z:378.0[M+H] + MS m/z: 378.0 [M+H] +
1H NMR(400MHz,CDCl 3)δppm 8.69(br s,1H)8.05(br s,1H)7.97(br s,1H)7.36(d,J＝8.28Hz,1H)7.19(br s,1H)7.10(br s,1H)7.02(br d,J＝8.28Hz,1H)6.25(br s,1H)4.16(s,2H)4.05(s,3H)3.98(s,3H)2.14(s,3H) 1 H NMR (400 MHz, CDCl 3 ) δ ppm 8.69 (br s, 1H) 8.05 (br s, 1H) 7.97 (br s, 1H) 7.36 (d, J = 8.28 Hz, 1H) 7.19 (br s, 1H) 7.10 (br s,1H)7.02(br d,J=8.28Hz,1H)6.25(br s,1H)4.16(s,2H)4.05(s,3H)3.98(s,3H)2.14(s,3H)
实施例88：化合物88Example 88: Compound 88
Figure PCTCN2019070227-appb-000256
Figure PCTCN2019070227-appb-000256
合成路线：synthetic route:
Figure PCTCN2019070227-appb-000257
Figure PCTCN2019070227-appb-000257
步骤1：化合物88-B的合成Step 1: Synthesis of Compound 88-B
将化合物2-氟-5-溴-4甲基吡啶(0.30g,1.58mmol)，88-A(338.19mg,3.16mmol)和二异丙基乙胺(816.22mg,6.32mmol)加入到甲基吡咯烷酮(2.00mL)中，在148℃下搅拌4小时，冷却后，加水(20mL)稀释，用乙酸乙酯(20mL×3)萃取，合并有机相，用饱和食盐水(60mL)洗涤，无水硫酸钠干燥。滤去干燥剂后，减压除去溶剂得到粗品。粗品用制备TLC(流动相：石油醚/乙酸乙酯＝1/1)纯化得到88-B。Add compound 2-fluoro-5-bromo-4-methylpyridine (0.30 g, 1.58 mmol), 88-A (338.19 mg, 3.16 mmol) and diisopropylethylamine (816.22 mg, 6.32 mmol) to methyl The pyrrolidone (2.00 mL) was stirred at 148 ° C for 4 hours. After cooling, it was diluted with water (20 mL) and extracted with ethyl acetate (20 mL×3). The organic phase was combined and washed with saturated brine (60 mL) Dry over sodium sulfate. After filtering off the desiccant, the solvent was removed under reduced pressure to give a crude material. The crude product was purified by preparative TLC (mobile phase: petroleum ether / ethyl acetate = 1 / 1) to afford 88-B.
MS m/z:276.9[M+H] + MS m/z: 276.9 [M+H] +
步骤2：化合物88-C的合成Step 2: Synthesis of Compound 88-C
除了使用相应的原料外，以实施例9中的制备化合物9-A相同的方法制备化合物88-C。Compound 88-C was prepared in the same manner as in the preparation of compound 9-A in Example 9 except that the corresponding materials were used.
MS m/z:460.1[M+H] + MS m/z: 460.1 [M+H] +
步骤3：化合物88的合成Step 3: Synthesis of Compound 88
除了使用相应的原料外，以实施例9中的制备化合物9相同的方法制备化合物88。Compound 88 was prepared in the same manner as in the preparation of compound 9 in Example 9 except that the corresponding material was used.
MS m/z:360.1[M+H] + MS m/z: 360.1 [M+H] +
1H NMR(400MHz,CHLOROFORM-d)δppm 7.89(s,1H)7.32-7.34(m,1H)7.32(d,J＝8.28Hz,1H)7.00(d,J＝8.28Hz,1H)6.48(br s,1H)6.33(s,1H)5.19-5.47(m,1H)4.14(s,3H)4.04(s,3H)3.03-3.22(m,2H)2.42-2.66(m,2H) 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.89 (s, 1H) 7.32-7.34 (m, 1H) 7.32 (d, J = 8.28 Hz, 1H) 7.00 (d, J = 8.28 Hz, 1H) 6.48 (br) s,1H)6.33(s,1H)5.19-5.47(m,1H)4.14(s,3H)4.04(s,3H)3.03-3.22(m,2H)2.42-2.66(m,2H)
实施例89：化合物89Example 89: Compound 89
Figure PCTCN2019070227-appb-000258
Figure PCTCN2019070227-appb-000258
合成路线：synthetic route:
Figure PCTCN2019070227-appb-000259
Figure PCTCN2019070227-appb-000259
步骤1：化合物89-B的合成Step 1: Synthesis of Compound 89-B
除了使用相应的原料外，以实施例5中的制备化合物5-C相同的方法制备化合物89-B。Compound 89-B was prepared in the same manner as in the preparation of compound 5-C in Example 5 except that the corresponding materials were used.
MS m/z:291.9[M+H] + MS m/z: 291.9 [M+H] +
步骤2：化合物89-C的合成Step 2: Synthesis of Compound 89-C
除了使用相应的原料外，以实施例9中的制备化合物9-A相同的方法制备化合物89-C。Compound 89-C was prepared in the same manner as in the preparation of compound 9-A in Example 9 except that the corresponding materials were used.
MS m/z:475.3[M+H] + MS m/z: 475.3 [M+H] +
步骤3：化合物89的合成Step 3: Synthesis of Compound 89
除了使用相应的原料外，以实施例9中的制备化合物9相同的方法制备化合物89。Compound 89 was prepared in the same manner as in the preparation of compound 9 in Example 9 except that the corresponding materials were used.
MS m/z:375.1[M+H] + MS m/z: 375.1 [M+H] +
1H NMR(400MHz,CDCl 3)δppm 8.55(s,1H)7.91(s,1H)7.64(br d,J＝8.28Hz,1H)7.32(d,J＝8.28Hz,1H)7.17(d,J＝7.53Hz,1H)6.99(d,J＝8.28Hz,1H)6.35(s,1H)6.01(s,1H)4.91(br s,1H)4.56(s,2H)4.15(s,2H)4.04(s,3H)2.58(s,3H)2.04(s,3H) 1 H NMR (400 MHz, CDCl 3 ) δ ppm 8.55 (s, 1H) 7.91 (s, 1H) 7.64 (brd, J = 8.28 Hz, 1H) 7.32 (d, J = 8.28 Hz, 1H) 7.17 (d, J =7.53Hz,1H)6.99(d,J=8.28Hz,1H)6.35(s,1H)6.01(s,1H)4.91(br s,1H)4.56(s,2H)4.15(s,2H)4.04( s,3H)2.58(s,3H)2.04(s,3H)
实施例90：化合物90Example 90: Compound 90
Figure PCTCN2019070227-appb-000260
Figure PCTCN2019070227-appb-000260
合成路线：synthetic route:
Figure PCTCN2019070227-appb-000261
Figure PCTCN2019070227-appb-000261
步骤1：化合物90-B的合成Step 1: Synthesis of Compound 90-B
除了使用相应的原料外，以实施例32中的制备化合物32-A相同的方法制备化合物90-B。Compound 90-B was prepared in the same manner as in the preparation of compound 32-A in Example 32 except that the corresponding material was used.
MS m/z:502.2[M+H] + MS m/z: 502.2 [M+H] +
步骤2：化合物90的合成Step 2: Synthesis of Compound 90
除了使用相应的原料外，以实施例32中的制备化合物32相同的方法制备化合物90。Compound 90 was prepared in the same manner as in the preparation of compound 32 in Example 32 except that the corresponding material was used.
MS m/z:402.1[M+H] + MS m/z: 402.1 [M+H] +
1H NMR(400MHz,METHANOL-d 4)δppm 8.13(d,J＝2.01Hz,1H)7.92(br s,1H)7.82(d,J＝8.78Hz,1H)7.56(d,J＝5.52Hz,1H)7.40-7.46(m,2H)7.31(d,J＝5.52Hz,1H)7.15(d,J＝8.28Hz,1H)6.83(s,1H)4.21(s,2H)3.99(s,3H)2.11(s,3H) 1 H NMR (400 MHz, METHANOL-d 4 ) δ ppm 8.13 (d, J = 2.01 Hz, 1H) 7.92 (br s, 1H) 7.82 (d, J = 8.78 Hz, 1H) 7.56 (d, J = 5.52 Hz, 1H) 7.40-7.46 (m, 2H) 7.31 (d, J = 5.52 Hz, 1H) 7.15 (d, J = 8.28 Hz, 1H) 6.83 (s, 1H) 4.21 (s, 2H) 3.99 (s, 3H) 2.11(s,3H)
实施例91：化合物91Example 91: Compound 91
Figure PCTCN2019070227-appb-000262
Figure PCTCN2019070227-appb-000262
合成路线：synthetic route:
Figure PCTCN2019070227-appb-000263
Figure PCTCN2019070227-appb-000263
步骤1：化合物91-B的合成Step 1: Synthesis of Compound 91-B
将化合物91-A(0.3g,1.69mmol)溶解在DMF(10mL)中，在0℃下加入NaH(169.37mg,4.23mmol)，反应液在0℃下搅拌30分钟。反应液升温到60℃，加入化合物5-溴-2-氟-4-甲基吡啶(354.01mg,1.86mmol)，继续在60℃搅拌12小时。冷却后，将反应液加到50mL的乙酸乙酯和20mL的水中，分离乙酸乙酯层，用饱和食盐水(20mL)洗涤一次，用无水硫酸钠干燥，过滤，浓缩。将所得到的粗品用硅胶柱(洗脱剂：PE/EA＝3/1～1/1)纯化，得到91-B。Compound 91-A (0.3 g, 1.69 mmol) was dissolved in DMF (10 mL). NaH. The reaction solution was warmed to 60 ° C, and the compound 5-bromo-2-fluoro-4-methylpyridine (354.01 mg, 1.86 mmol) was added, and stirring was continued at 60 ° C for 12 hours. After cooling, the reaction mixture was poured into EtOAc EtOAc EtOAc. The obtained crude product was purified through a silica gel column (eluent: PE/EA = 3/1 to 1/1) to afford 91-B.
MS m/z:346.8[M+H] + MS m/z: 346.8 [M+H] +
步骤2：化合物91-C的合成Step 2: Synthesis of Compound 91-C
除了使用相应的原料外，以实施例9中的制备化合物9-A相同的方法制备化合物91-C。Compound 91-C was prepared in the same manner as in the preparation of compound 9-A in Example 9 except that the corresponding material was used.
MS m/z:530.1[M+H] + MS m/z: 530.1 [M+H] +
步骤3：化合物91的合成Step 3: Synthesis of Compound 91
除了使用相应的原料外，以实施例9中的制备化合物9相同的方法制备化合物91。Compound 91 was prepared in the same manner as in the preparation of compound 9 in Example 9 except that the corresponding material was used.
MS m/z:430.2[M+H] + MS m/z: 430.2 [M+H] +
1H NMR(400MHz,METHANOL-d 4)δppm 8.84(s,1H)8.16(br d,J＝8.04Hz,1H)7.97(s,1H)7.85(d,J＝8.04Hz,1H)7.42(d,J＝8.28Hz,1H)7.15(d,J＝8.28Hz,1H)6.92(s,1H)5.57(s,2H)4.14(s,2H)3.99(s,3H)2.15(s,3H) 1 H NMR (400 MHz, METHANOL-d 4 ) δ ppm 8.84 (s, 1H) 8.16 (br d, J = 8.04 Hz, 1H) 7.97 (s, 1H) 7.85 (d, J = 8.04 Hz, 1H) 7.42 (d , J = 8.28 Hz, 1H) 7.15 (d, J = 8.28 Hz, 1H) 6.92 (s, 1H) 5.57 (s, 2H) 4.14 (s, 2H) 3.99 (s, 3H) 2.15 (s, 3H)
实施例92：化合物92Example 92: Compound 92
合成路线：synthetic route:
Figure PCTCN2019070227-appb-000265
Figure PCTCN2019070227-appb-000265
步骤1：化合物92-A的合成Step 1: Synthesis of Compound 92-A
向含有化合物2-氨基-5-溴吡啶(1g,5.78mmol)和碳酸钾(3.20g,23.12mmol)的乙腈(15mL)溶液中滴加4-溴丁酰氯(1.39g,7.51mmol)，反应液在25℃搅拌12小时。将反应液加到50mL的乙酸乙酯和20mL的水中，分离乙酸乙酯层，用饱和食盐水(20mL)洗涤一次，用无水硫酸钠干燥，过滤，浓缩。将所得到的粗品用硅胶柱(洗脱剂PE/THF＝3/1～1/1)纯化，得到92-A。4-Bromobutyryl chloride (1.39 g, 7.51 mmol) was added dropwise to a solution of the compound 2-amino-5-bromopyridine (1 g, 5.78 mmol) and potassium carbonate (3.20 g, 23.12 mmol) in acetonitrile (15 mL). The solution was stirred at 25 ° C for 12 hours. The reaction solution was poured into 50 mL of ethyl acetate and 20 mL of EtOAc. The obtained crude product was purified through a silica gel column (eluent PE/THF = 3/1 to 1/1) to afford 92-A.
MS m/z:240.9[M+H] + MS m/z: 240.9 [M+H] +
步骤2：化合物92-B的合成Step 2: Synthesis of Compound 92-B
除了使用相应的原料外，以实施例32中的制备化合物32-A相同的方法制备化合物92-B。Compound 92-B was prepared in the same manner as in the preparation of compound 32-A in Example 32 except that the corresponding material was used.
MS m/z:349.1[M+H] + MS m/z: 349.1 [M+H] +
步骤3：化合物92-C的合成Step 3: Synthesis of Compound 92-C
除了使用相应的原料外，以实施例9中的制备化合物9-A相同的方法制备化合物92-C。Compound 92-C was prepared in the same manner as in the preparation of compound 9-A in Example 9 except that the corresponding material was used.
MS m/z:530.1[M+H] + MS m/z: 530.1 [M+H] +
步骤4：化合物92的合成Step 4: Synthesis of Compound 92
除了使用相应的原料外，以实施例9中的制备化合物9相同的方法制备化合物92。Compound 92 was prepared in the same manner as in the preparation of compound 9 in Example 9 except that the corresponding materials were used.
MS m/z:430.3[M+H] + MS m/z: 430.3 [M+H] +
1H NMR(400MHz,CDCl 3)δppm 8.41(br d,J＝14.05Hz,1H)8.17-8.25(m,1H)7.82-7.93(m,2H)7.23- 7.27(m,1H)6.89-6.98(m,1H)6.66(br d,J＝15.31Hz,1H)4.38-4.37(m,1H)4.07(br dd,J＝14.68,7.91Hz,4H)3.92-3.97(m,3H)3.30(br d,J＝12.55Hz,3H)2.56-2.67(m,2H)2.06-2.16(m,2H)1.98-2.04(m,3H) 1 H NMR (400 MHz, CDCl 3 ) δ ppm 8.41 (br d, J = 14.05 Hz, 1H) 8.17 - 8.25 (m, 1H) 7.82 - 7.93 (m, 2H) 7.23 - 7.27 (m, 1H) 6.89-6.98 ( m,1H)6.66(br d,J=15.31Hz,1H)4.38-4.37(m,1H)4.07(br dd,J=14.68,7.91Hz,4H)3.92-3.97(m,3H)3.30(br d , J=12.55Hz, 3H)2.56-2.67(m,2H)2.06-2.16(m,2H)1.98-2.04(m,3H)
实施例93：化合物93Example 93: Compound 93
Figure PCTCN2019070227-appb-000266
Figure PCTCN2019070227-appb-000266
合成路线：synthetic route:
Figure PCTCN2019070227-appb-000267
Figure PCTCN2019070227-appb-000267
步骤1：化合物93-A的合成Step 1: Synthesis of Compound 93-A
将71-A(178mg,831.55μmol)溶于二氧六环(10mL)和水(1mL)中，向其中加入乙烯基三氟硼酸钾(167.08mg,1.25mmol)和碳酸钾(344.77mg,2.49mmol)。反应用氮气置换3次后加入[1,1’-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(67.91mg,83.15μmol)，反应在氮气保护下90℃搅拌12h后，将反应液用硅藻土过滤，向其中加入水(50mL)，用乙酸乙酯(50mL)萃取，饱和食盐水(50mL)洗涤，硫酸钠干燥，过滤干燥剂，减压浓缩得到粗品，粗品经柱层析(洗脱剂：石油醚/乙酸乙酯＝20/1)纯化，得到化合物93-A。71-A (178 mg, 831.55 μmol) was dissolved in dioxane (10 mL) and water (1 mL), and potassium trifluoroborate (167.08 mg, 1.25 mmol) and potassium carbonate (344.77 mg, 2.49) were added thereto. Mm). After the reaction was replaced with nitrogen for 3 times, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (67.91 mg, 83.15 μmol) was added, and the reaction was carried out under nitrogen atmosphere at 90 ° C. After stirring for 12 hours, the reaction mixture was filtered over EtOAc EtOAc (EtOAc m. The crude product was purified by column chromatography eluting elut elut elut elut
MS m/z:162.0[M+H] + MS m/z: 162.0 [M+H] +
1H NMR(400MHz,CDCl 3)δppm 8.21(d,J＝2.26Hz,1H)7.71(dd,J＝8.66,2.38Hz,1H)6.76(d,J＝8.78Hz,1H)6.66(dd,J＝17.69,10.92Hz,1H)5.67(d,J＝17.57Hz,1H)5.24(d,J＝11.04Hz,1H)4.14-4.31(m,1H)0.73-0.88(m,4H) 1 H NMR (400 MHz, CDCl 3 ) δ ppm 8.21 (d, J = 2.26 Hz, 1H) 7.71 (dd, J = 8.66, 2.38 Hz, 1H) 6.76 (d, J = 8.78 Hz, 1H) 6.66 (dd, J =17.69, 10.92 Hz, 1H) 5.67 (d, J = 17.57 Hz, 1H) 5.24 (d, J = 11.04 Hz, 1H) 4.14 - 4.31 (m, 1H) 0.73-0.88 (m, 4H)
步骤2：化合物93-B的合成Step 2: Synthesis of Compound 93-B
将93-A(200mg,1.17mmol)溶于四氢呋喃(5mL)和水(5mL)中，向其中加入四氧化锇(630.84mg,62.03μmol)和高碘酸钠(291.91mg,1.36mmol)。反应在20℃下搅拌12h后，向反应液中加入水(50mL)，用乙酸乙酯(50mL)萃取，饱和食盐水(50mL)洗涤，硫酸钠干燥，过滤干燥剂，减压浓缩得到粗品，粗品经柱层析(洗脱剂：石油醚/乙酸乙酯＝5/1)纯化，得到化合物93-B。93-A (200 mg, 1.17 mmol) was dissolved in tetrahydrofuran (5 mL) and water (5 mL), and osmium oxide (630.84 mg, 62.03 μmol) and sodium periodate (291.91 mg, 1.36 mmol) were added thereto. After the reaction was stirred at 20 ° C for 12 h, water (50 mL) was evaporated, evaporated, evaporated, evaporated. The crude product was purified by column chromatography (EtOAc:EtOAc:EtOAc
MS m/z:163.8[M+H] + MS m/z: 163.8 [M+H] +
步骤3：化合物93-C的合成Step 3: Synthesis of Compound 93-C
除了使用相应的原料外，以实施例5中的化合物5-C相同的方法制备化合物93-C。Compound 93-C was prepared in the same manner as Compound 5-C of Example 5 except that the corresponding material was used.
MS m/z:333.9[M+H] + MS m/z: 333.9 [M+H] +
1H NMR(400MHz,CDCl 3)δppm 8.19(d,J＝2.26Hz,1H)8.11(s,1H)7.59(dd,J＝8.53,2.51Hz,1H)6.75(d,J＝8.53Hz,1H)6.29(s,1H)4.68(br s,1H)4.42(d,J＝5.77Hz,2H)4.11-4.23(m,1H)2.27(s,3H)0.73-0.82(m,4H) 1 H NMR (400MHz, CDCl 3 ) δppm 8.19 (d, J = 2.26Hz, 1H) 8.11 (s, 1H) 7.59 (dd, J = 8.53,2.51Hz, 1H) 6.75 (d, J = 8.53Hz, 1H 6.29(s,1H)4.68(br s,1H)4.42(d,J=5.77Hz,2H)4.11-4.23(m,1H)2.27(s,3H)0.73-0.82(m,4H)
步骤4：化合物93-D的合成Step 4: Synthesis of Compound 93-D
除了使用相应的原料外，以实施例9中的化合物9-A相同的方法制备化合物93-D。Compound 93-D was prepared in the same manner as Compound 9-A in Example 9 except that the corresponding material was used.
MS m/z:517.2[M+H] + MS m/z: 517.2 [M+H] +
步骤5：化合物93的合成Step 5: Synthesis of Compound 93
除了使用相应的原料外，以实施例9中的化合物9相同的方法制备化合物93。Compound 93 was prepared in the same manner as Compound 9 in Example 9 except that the corresponding material was used.
MS m/z:417.1[M+H] + MS m/z: 417.1 [M+H] +
1H NMR(400MHz,DMSO-d6)δppm 8.03-8.30(m,2H)7.80(s,1H)7.70(dd,J＝8.41,2.38Hz,1H)7.31(d,J＝8.28Hz,1H)7.00-7.10(m,2H)6.82(d,J＝8.53Hz,1H)6.45(s,1H)4.43(d,J＝5.52Hz,2H)4.17(tt,J＝6.21,3.20Hz,1H)4.03(s,2H)3.86(s,3H)1.95(s,3H)0.69-0.79(m,2H)0.57-0.67(m,2H) 1 H NMR (400MHz, DMSO- d6) δppm 8.03-8.30 (m, 2H) 7.80 (s, 1H) 7.70 (dd, J = 8.41,2.38Hz, 1H) 7.31 (d, J = 8.28Hz, 1H) 7.00 -7.10(m,2H)6.82(d,J=8.53Hz,1H)6.45(s,1H)4.43(d,J=5.52Hz,2H)4.17(tt,J=6.21,3.20Hz,1H)4.03( s,2H)3.86(s,3H)1.95(s,3H)0.69-0.79(m,2H)0.57-0.67(m,2H)
实施例94：化合物94Example 94: Compound 94
Figure PCTCN2019070227-appb-000268
Figure PCTCN2019070227-appb-000268
合成路线：synthetic route:
Figure PCTCN2019070227-appb-000269
Figure PCTCN2019070227-appb-000269
步骤1：化合物94-B的合成Step 1: Synthesis of Compound 94-B
除了使用相应的原料外，以实施例32中的化合物32-A相同的方法制备化合物94-B。Compound 94-B was prepared in the same manner as Compound 32-A in Example 32 except that the corresponding material was used.
MS m/z:503.1[M+H] + MS m/z: 503.1 [M+H] +
步骤2：化合物94的合成Step 2: Synthesis of Compound 94
除了使用相应的原料外，以实施例32中的化合物32相同的方法制备化合物94。Compound 94 was prepared in the same manner as Compound 32 in Example 32 except that the corresponding material was used.
MS m/z:402.9[M+H] + MS m/z: 402.9 [M+H] +
1H NMR(400MHz,METHANOL-d4)δppm 9.05(s,1H),8.65(d,J＝2.0Hz,1H),8.04-7.92(m,2H),7.56(dd,J＝2.4,8.8Hz,1H),7.45(d,J＝8.4Hz,1H),7.16(d,J＝8.4Hz,1H),6.86(s,1H),4.21(s,2H),3.99(s,3H),2.13(s,3H) 1 H NMR (400MHz, METHANOL- d4) δppm 9.05 (s, 1H), 8.65 (d, J = 2.0Hz, 1H), 8.04-7.92 (m, 2H), 7.56 (dd, J = 2.4,8.8Hz, 1H), 7.45 (d, J = 8.4 Hz, 1H), 7.16 (d, J = 8.4 Hz, 1H), 6.86 (s, 1H), 4.21 (s, 2H), 3.99 (s, 3H), 2.13 ( s, 3H)
实施例95：化合物95Example 95: Compound 95
Figure PCTCN2019070227-appb-000270
Figure PCTCN2019070227-appb-000270
合成路线：synthetic route:
Figure PCTCN2019070227-appb-000271
Figure PCTCN2019070227-appb-000271
步骤1：化合物95-A的合成Step 1: Synthesis of Compound 95-A
在0℃下，向异丙醇(341.48mg,5.68mmol)的四氢呋喃(20mL)溶液中加入钠氢(340.90mg,8.52mmol,60％purity)，并搅拌20分钟，再加入化合物2-氟-5溴吡啶(1g,5.68mmol)，并搅拌10分钟。将反应液升温至60℃，搅拌48小时。向反应液加入水(10mL)，用乙酸乙酯(10mL*3)萃取，合并的乙酸乙酯层用饱和食盐水(20mL)洗涤，用无水硫酸钠干燥。过滤除去干燥剂后，减压除去溶剂。所得残留物经过柱机分离(展开剂：乙酸乙酯/石油醚＝0～10％)，得到化合物95-A。Add sodium hydrogen (340.90 mg, 8.52 mmol, 60% purity) to a solution of isopropanol (341.48 mg, 5.68 mmol) in tetrahydrofuran (20 mL) at 0 ° C, and stir for 20 min. 5 Bromopyridine (1 g, 5.68 mmol) and stirred for 10 minutes. The reaction solution was warmed to 60 ° C and stirred for 48 hours. Water (10 mL) was added to the mixture, and the mixture was evaporated. After removing the desiccant by filtration, the solvent was removed under reduced pressure. The residue obtained was separated by a column apparatus (developing solvent: ethyl acetate / petroleum ether = 0 to 10%) to afford compound 95-A.
MS m/z:215.9[M+H] + MS m/z: 215.9 [M+H] +
1H NMR(400MHz,CDCl 3)δppm 8.10(d,J＝2.8Hz,1H),7.54(dd,J＝2.0,3.2Hz,1H),6.52(d,J＝9.2Hz,1H),5.22-5.10(m,1H),1.26(d,J＝6.0Hz,6H) 1 H NMR (400 MHz, CDCl 3 ) δ ppm 8.10 (d, J = 2.8 Hz, 1H), 7.54 (dd, J = 2.0, 3.2 Hz, 1H), 6.52 (d, J = 9.2 Hz, 1H), 5.22 5.10(m,1H), 1.26 (d, J=6.0Hz, 6H)
步骤2：化合物95-B的合成Step 2: Synthesis of Compound 95-B
除了使用相应的原料外，以实施例32中的化合物32-A相同的方法制备化合物95-B。Compound 95-B was prepared in the same manner as Compound 32-A in Example 32 except that the corresponding material was used.
MS m/z:321.9[M+H]+MS m/z: 321.9 [M+H]+
步骤3：化合物95-C的合成Step 3: Synthesis of Compound 95-C
除了使用相应的原料外，以实施例9中的化合物9-A相同的方法制备化合物95-C。Compound 95-C was prepared in the same manner as in the compound 9-A of Example 9 except that the corresponding material was used.
MS m/z:505.2[M+H] + MS m/z: 505.2 [M+H] +
步骤4：化合物95的合成Step 4: Synthesis of Compound 95
除了使用相应的原料外，以实施例9中的化合物9相同的方法制备化合物95。Compound 95 was prepared in the same manner as Compound 9 in Example 9 except that the corresponding material was used.
MS m/z:405.0[M+H] + MS m/z: 405.0 [M+H] +
1H NMR(400MHz,DMSO-d 6)δppm 8.91(s,1H),8.38(d,J＝2.4Hz,1H),8.24(s,1H),8.00(dd,J＝2.8,3.2Hz,1H),7.93(s,1H),7.36(d,J＝8.4Hz,1H),7.08(d,J＝8.4Hz,1H),6.75-6.66(m,2H),5.19-5.13(m,1H),4.06(s,2H),3.88(s,3H),2.03(s,3H),1.28(d,J＝6.0Hz,6H) 1 H NMR (400MHz, DMSO- d 6) δppm 8.91 (s, 1H), 8.38 (d, J = 2.4Hz, 1H), 8.24 (s, 1H), 8.00 (dd, J = 2.8,3.2Hz, 1H ), 7.93 (s, 1H), 7.36 (d, J = 8.4 Hz, 1H), 7.08 (d, J = 8.4 Hz, 1H), 6.75-6.66 (m, 2H), 5.19-5.13 (m, 1H) , 4.06 (s, 2H), 3.88 (s, 3H), 2.03 (s, 3H), 1.28 (d, J = 6.0 Hz, 6H)
实施例96：化合物96Example 96: Compound 96
Figure PCTCN2019070227-appb-000272
Figure PCTCN2019070227-appb-000272
合成路线：synthetic route:
Figure PCTCN2019070227-appb-000273
Figure PCTCN2019070227-appb-000273
步骤1：化合物96-A的合成Step 1: Synthesis of Compound 96-A
将2,5-二溴吡啶(15g,63.32mmol)溶于甲苯(200mL)和水(20mL)中，向其中加入环丙基硼酸(16.32g,189.96mmol)和K 3PO 4(40.32g,189.96mmol)，反应体系用氮气置换3次后，再向其中加入三环己基膦(3.55g,12.66 mmol)，醋酸钯(1.42g,6.33mmol)。反应在氮气保护、100℃下搅拌4小时后，向反应液中加入水(400mL)，用乙酸乙酯(300mL)萃取，再用水(400mL)洗涤两次，饱和食盐水(250mL)洗涤一次，无水硫酸钠干燥，过滤干燥剂，减压浓缩得到浓缩物，经柱层析(洗脱剂：石油醚/乙酸乙酯＝100/1-8/1)纯化，得到化合物96-A。 2,5-Dibromopyridine (15 g, 63.32 mmol) was dissolved in toluene (200 mL) and water (20 mL), and cyclopropylboronic acid (16.32 g, 189.96 mmol) and K 3 PO 4 (40.32 g, 189.96 mmol), after the reaction system was replaced with nitrogen three times, tricyclohexylphosphine (3.55 g, 12.66 mmol) and palladium acetate (1.42 g, 6.33 mmol) were added thereto. After the reaction was stirred under nitrogen for 4 hours at 100 ° C, water (400 mL) was added to the reaction mixture, which was extracted with ethyl acetate (300 mL), and then washed twice with water (400 mL), and brine (250 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, evaporated, evaporated, evaporated.
MS m/z:197.8[M+H] + MS m/z: 197.8 [M+H] +
步骤2：化合物96-B的合成Step 2: Synthesis of Compound 96-B
除了使用相应的原料外，以实施例32中的化合物32-A相同的方法制备化合物96-B。Compound 96-B was prepared in the same manner as Compound 32-A in Example 32 except that the corresponding material was used.
MS m/z:303.9[M+H] + MS m/z: 303.9 [M+H] +
1H NMR(400MHz,CDCl 3)δppm 8.25(s,1H),8.10(d,J＝2.0Hz,1H),7.50(s,1H),7.35-7.28(m,2H),7.15(s,1H),2.38(s,3H),1.91-1.81(m,1H),1.00-0.92(m,2H),0.70-0.62(m,2H) 1 H NMR (400 MHz, CDCl 3 ) δ ppm 8.25 (s, 1H), 8.10 (d, J = 2.0 Hz, 1H), 7.50 (s, 1H), 7.35-7.28 (m, 2H), 7.15 (s, 1H) ), 2.38 (s, 3H), 1.91-1.81 (m, 1H), 1.00-0.92 (m, 2H), 0.70-0.62 (m, 2H)
步骤3：化合物96-C的合成Step 3: Synthesis of Compound 96-C
除了使用相应的原料外，以实施例9中的化合物9-A相同的方法制备化合物96-C。Compound 96-C was prepared in the same manner as Compound 9-A in Example 9 except that the corresponding material was used.
MS m/z:487.2[M+H] + MS m/z: 487.2 [M+H] +
步骤4：化合物96的合成Step 4: Synthesis of Compound 96
除了使用相应的原料外，以实施例9中的化合物9相同的方法制备化合物96。Compound 96 was prepared in the same manner as Compound 9 in Example 9 except that the corresponding material was used.
MS m/z:387.1[M+H] + MS m/z: 387.1 [M+H] +
1H NMR(400MHz,DMSO-d6)δppm 8.23(s,1H),8.08(d,J＝2.3Hz,1H),8.03(s,1H),7.62(br d,J＝8.6Hz,1H),7.54(s,1H),7.38(d,J＝8.4Hz,2H),7.09(d,J＝8.5Hz,1H),4.06(s,2H),3.87(s,3H),2.08(s,3H),1.94-1.84(m,1H),0.99-0.87(m,2H),0.72-0.60(m,2H) 1 H NMR (400MHz, DMSO- d6) δppm 8.23 (s, 1H), 8.08 (d, J = 2.3Hz, 1H), 8.03 (s, 1H), 7.62 (br d, J = 8.6Hz, 1H), 7.54 (s, 1H), 7.38 (d, J = 8.4 Hz, 2H), 7.09 (d, J = 8.5 Hz, 1H), 4.06 (s, 2H), 3.87 (s, 3H), 2.08 (s, 3H) ), 1.94-1.84 (m, 1H), 0.99-0.87 (m, 2H), 0.72-0.60 (m, 2H)
实施例97：化合物97Example 97: Compound 97
Figure PCTCN2019070227-appb-000274
Figure PCTCN2019070227-appb-000274
合成路线：synthetic route:
Figure PCTCN2019070227-appb-000275
Figure PCTCN2019070227-appb-000275
步骤1：化合物97-A的合成Step 1: Synthesis of Compound 97-A
将5-溴-2-氯嘧啶(1g,5.17mmol)溶于甲苯(30mL)和水(6mL)中，向其中加入环丙基硼酸(53.89mg,6.20mmol)，三环己基膦(289.96mg,1.03mmol)和磷酸钾(3.29g,15.51mmol)，反应体系用氮气置换3次后，加入醋酸钯(116.07mg,516.99μmol)。在氮气保护、100℃下搅拌12h后，将反应液用硅藻土过滤，将滤液减压旋蒸，向粗品中加入水(100mL)，用乙酸乙酯(100mL)萃取，萃取液用饱和食盐水(100mL)洗涤，硫酸钠干燥，过滤干燥剂，减压浓缩得到粗品，经柱层析(洗脱剂：石油醚/乙酸乙酯＝10/1)纯化，得到化合物97-A。5-Bromo-2-chloropyrimidine (1 g, 5.17 mmol) was dissolved in toluene (30 mL) and water (6 mL), and cyclopropylboronic acid (53.89 mg, 6.20 mmol), tricyclohexylphosphine (289.96 mg) was added thereto. , 1.03 mmol) and potassium phosphate (3.29 g, 15.51 mmol). After the reaction system was replaced with nitrogen three times, palladium acetate (116.07 mg, 516.99 μmol) was added. After stirring under nitrogen for 10 h at 100 ° C, the reaction mixture was filtered over EtOAc EtOAc (EtOAc)EtOAc. The organic layer was washed with water (100 mL).
MS m/z:154.8[M+H] + MS m/z: 154.8 [M+H] +
步骤2：化合物97-B的合成Step 2: Synthesis of Compound 97-B
除了使用相应的原料外，以实施例32中的化合物32-A相同的方法制备化合物97-B。Compound 97-B was prepared in the same manner as Compound 32-A in Example 32 except that the corresponding material was used.
MS m/z:488.1[M+H] + MS m/z: 488.1 [M+H] +
步骤3：化合物97的合成Step 3: Synthesis of Compound 97
除了使用相应的原料外，以实施例32中的化合物32相同的方法制备化合物97。Compound 97 was prepared in the same manner as Compound 32 in Example 32 except that the corresponding material was used.
MS m/z:388.0[M+H] + MS m/z: 388.0 [M+H] +
1H NMR(400MHz,CD 3OD)δppm 8.59(s,2H)8.24(d,J＝1.51Hz,1H)7.56(d,J＝8.53Hz,1H)7.46(s,1H)7.23(d,J＝8.53Hz,1H)4.26(s,2H)4.01(s,3H)2.36(s,3H)1.96-2.11(m,1H)1.10-1.19(m,2H)0.78-0.94(m,2H) 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.59 (s, 2H) 8.24 (d, J = 1.51 Hz, 1H) 7.56 (d, J = 8.53 Hz, 1H) 7.46 (s, 1H) 7.23 (d, J =8.53Hz,1H)4.26(s,2H)4.01(s,3H)2.36(s,3H)1.96-2.11(m,1H)1.10-1.19(m,2H)0.78-0.94(m,2H)
实施例98：化合物98Example 98: Compound 98
Figure PCTCN2019070227-appb-000276
Figure PCTCN2019070227-appb-000276
合成路线：synthetic route:
Figure PCTCN2019070227-appb-000277
Figure PCTCN2019070227-appb-000277
步骤1：化合物98-B的合成Step 1: Synthesis of Compound 98-B
将49-B(400mg,1.74mmol)溶于二氯甲烷(20mL)中，在氮气保护、-70℃下向其中缓慢滴加DAST(336.31mg,2.09mmol)。反应在此条件下搅拌2h后，升温至0℃，向其中缓慢逐滴加入饱和碳酸氢铵溶液(10mL)，加入水(50mL)稀释，用乙酸乙酯(100mL)萃取，萃取液用饱和食盐水(50mL)洗涤，硫酸钠干燥，过滤干燥剂，减压浓缩得到粗品，粗品经柱层析(洗脱剂：石油醚/乙酸乙酯＝20/1～6/1)纯化，得到化合物98-B。49-B (400 mg, 1.74 mmol) was dissolved in dichloromethane (20 mL), and DAST (336.31 mg, 2.09 mmol) was slowly added dropwise thereto at -70 °C under nitrogen atmosphere. After the reaction was stirred for 2 hours, the mixture was heated to 0 ° C, and then a saturated aqueous solution of sodium hydrogencarbonate (10 mL) was slowly added dropwise, diluted with water (50 mL), and extracted with ethyl acetate (100 mL). The organic layer was washed with water (50 mL) -B.
MS m/z:231.8[M+H] + MS m/z: 231.8 [M+H] +
1H NMR(400MHz,CDCl 3)δppm 8.61-8.82(m,1H)7.81(dd,J＝8.28,2.26Hz,1H)7.26-7.44(m,1H)5.03-5.08(m,1H)4.96-5.02(m,2H)4.88-4.95(m,1H) 1 H NMR (400MHz, CDCl 3 ) δppm 8.61-8.82 (m, 1H) 7.81 (dd, J = 8.28,2.26Hz, 1H) 7.26-7.44 (m, 1H) 5.03-5.08 (m, 1H) 4.96-5.02 (m, 2H) 4.88-4.95 (m, 1H)
步骤2：化合物98-C的合成Step 2: Synthesis of Compound 98-C
除了使用相应的原料外，以实施例32中的化合物32A相同的方法制备化合物98-C。Compound 98-C was prepared in the same manner as Compound 32A in Example 32 except that the corresponding material was used.
MS m/z:521.1[M+H] + MS m/z: 521.1 [M+H] +
步骤3：化合物98的合成Step 3: Synthesis of Compound 98
除了使用相应的原料外，以实施例32中的化合物32相同的方法制备化合物98。Compound 98 was prepared in the same manner as Compound 32 in Example 32 except that the corresponding material was used.
MS m/z:421.0[M+H] + MS m/z: 421.0 [M+H] +
1H NMR(400MHz,CD 3OD)δppm 9.16-8.92(m,1H)8.42-8.15(m,1H)8.10-7.88(m,2H)7.53(d,J＝8.28 Hz,1H)7.31(s,1H)7.21(d,J＝8.53Hz,1H)5.24-5.01(m,2H)4.37-4.23(m,3H)4.05-4.17(m,1H)4.00(s,3H)2.29(s,3H) 1 H NMR (400 MHz, CD 3 OD) δ ppm 9.16-8.92 (m, 1H) 8.42 - 8.15 (m, 1H) 8.10-7.88 (m, 2H) 7.53 (d, J = 8.28 Hz, 1H) 7.31 (s, 1H)7.21(d,J=8.53Hz,1H)5.24-5.01(m,2H)4.37-4.23(m,3H)4.05-4.17(m,1H)4.00(s,3H)2.29(s,3H)
实施例99：化合物99Example 99: Compound 99
Figure PCTCN2019070227-appb-000278
Figure PCTCN2019070227-appb-000278
合成路线：synthetic route:
Figure PCTCN2019070227-appb-000279
Figure PCTCN2019070227-appb-000279
步骤1：化合物99-A的合成Step 1: Synthesis of Compound 99-A
除了使用相应的原料外，以实施例32中的化合物32-A相同的方法制备化合物99-A。Compound 99-A was prepared in the same manner as Compound 32-A in Example 32 except that the corresponding material was used.
MS m/z:488.2[M+H] + MS m/z: 488.2 [M+H] +
步骤2：化合物99的合成Step 2: Synthesis of Compound 99
除了使用相应的原料外，以实施例32中的化合物32相同的方法制备化合物99。Compound 99 was prepared in the same manner as Compound 32 in Example 32 except that the corresponding material was used.
MS m/z:388.0[M+H] + MS m/z: 388.0 [M+H] +
1HNMR(400MHz,CD 3OD)δppm 9.15(s,2H),8.04-7.92(m,1H),7.50(d,J＝8.3Hz,1H),7.26-7.18(m,2H),4.24(s,2H),4.00(s,3H),2.44-2.36(m,1H),2.29-2.25(m,3H),1.39-1.31(m,4H) 1 H NMR (400 MHz, CD 3 OD) δ ppm 9.15 (s, 2H), 8.04-7.92 (m, 1H), 7.50 (d, J = 8.3 Hz, 1H), 7.26-7.18 (m, 2H), 4.24 (s) , 2H), 4.00 (s, 3H), 2.44 - 2.36 (m, 1H), 2.29-2.25 (m, 3H), 1.39-1.31 (m, 4H)
实施例100：化合物100Example 100: Compound 100
Figure PCTCN2019070227-appb-000280
Figure PCTCN2019070227-appb-000280
合成路线：synthetic route:
Figure PCTCN2019070227-appb-000281
Figure PCTCN2019070227-appb-000281
步骤1：化合物100-A的合成Step 1: Synthesis of Compound 100-A
将2-溴-5-羟基吡啶(2g,11.49mmol)溶于N,N-二甲基甲酰胺(50mL)中，向其中加入环丙基溴(4.17g,34.48mmol)，碳酸铯(11.24g,34.48mmol)和碘化钾(1.91g,11.49mmol)，在氮气保护、140℃下搅拌20h后，向反应液中加入水(500mL)，用乙酸乙酯(500mL)萃取，萃取液用水(200mL)、饱和食盐水(200mL)洗涤，硫酸钠干燥，过滤干燥剂，减压浓缩得到粗品，粗品经柱层析(洗脱剂：石油醚/乙酸乙酯＝10/1)纯化，得到化合物100-A。2-Bromo-5-hydroxypyridine (2 g, 11.49 mmol) was dissolved in N,N-dimethylformamide (50 mL), and cyclopropyl bromide (4.17 g, 34.48 mmol), cesium carbonate (11.24) was added thereto. g, 34.48 mmol) and potassium iodide (1.91 g, 11.49 mmol). After stirring under a nitrogen atmosphere and stirring at 140 ° C for 20 h, water (500 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (500 mL). The residue was washed with saturated brine (200 mL) -A.
MS m/z:213.8[M+H] + MS m/z: 213.8 [M+H] +
步骤2：化合物100-B的合成Step 2: Synthesis of Compound 100-B
除了使用相应的原料外，以实施例32中的化合物32-A相同的方法制备化合物100-B。Compound 100-B was prepared in the same manner as Compound 32-A in Example 32 except that the corresponding material was used.
MS m/z:319.9[M+H] + MS m/z: 319.9 [M+H] +
1H NMR(400MHz,CDCl 3)δppm 8.23(s,1H)8.10(d,J＝2.76Hz,1H)7.38-7.44(m,2H)7.31-7.37(m,1H)7.10-7.21(m,1H)3.72-3.80(m,1H)2.37(s,3H)0.79(d,J＝4.52Hz,4H) 1 H NMR (400 MHz, CDCl 3 ) δ ppm 8.23 (s, 1H) 8.10 (d, J = 2.76 Hz, 1H) 7.38-7.44 (m, 2H) 7.31-7.37 (m, 1H) 7.10-7.21 (m, 1H) ) 3.72-3.80 (m, 1H) 2.37 (s, 3H) 0.79 (d, J = 4.52 Hz, 4H)
步骤3：化合物100-C的合成Step 3: Synthesis of Compound 100-C
除了使用相应的原料外，以实施例9中的化合物9-A相同的方法制备化合物100-C。Compound 100-C was prepared in the same manner as in the compound 9-A of Example 9 except that the corresponding materials were used.
MS m/z:503.1[M+H] + MS m/z: 503.1 [M+H] +
步骤4：化合物100的合成Step 4: Synthesis of Compound 100
除了使用相应的原料外，以实施例9中的化合物9相同的方法制备化合物100。Compound 100 was prepared in the same manner as Compound 9 in Example 9, except that the corresponding materials were used.
MS m/z:403.1[M+H] + MS m/z: 403.1 [M+H] +
1H NMR(400MHz,CD 3OD)δppm 8.27(d,J＝2.76Hz,1H)8.14(s,1H)7.79(dd,J＝9.04,3.01Hz,1H)7.54(d,J＝8.52Hz,1H)7.13-7.31(m,3H)4.25(s,2H)4.01(s,3H)3.96(tt,J＝6.04,3.14Hz,1H)2.32(s,3H)0.85-0.96(m,2H)0.74-0.84(m,2H) 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.27 (d, J = 2.76 Hz, 1H) 8.14 (s, 1H) 7.79 (dd, J = 9.04, 3.01 Hz, 1H) 7.54 (d, J = 8.52 Hz, 1H)7.13-7.31(m,3H)4.25(s,2H)4.01(s,3H)3.96(tt,J=6.04,3.14Hz,1H)2.32(s,3H)0.85-0.96(m,2H)0.74 -0.84(m,2H)
实施例101：化合物101Example 101: Compound 101
Figure PCTCN2019070227-appb-000282
Figure PCTCN2019070227-appb-000282
合成路线：synthetic route:
Figure PCTCN2019070227-appb-000283
Figure PCTCN2019070227-appb-000283
步骤1：化合物101-A的合成Step 1: Synthesis of Compound 101-A
将环丙基硼酸(1g,11.64mmol)溶于水(5mL)和甲苯(50mL)中，向其中分别加入3,6-二溴哒嗪(3.32g,13.97mmol)和碳酸铯(11.38g,34.93mmol)，反应体系用氮气置换3次后，加入Pd(dppf)Cl 2·DCM(950.72mg,1.16mmol)，在氮气保护、120℃下搅拌3小时后，冷却。反应液稀释后用乙酸乙酯(50mL)萃取，萃取液经饱和食盐水(50mL)洗涤，无水硫酸钠干燥后，浓缩得到粗品，经过层析柱(SiO2,石油醚/乙酸乙酯＝1/1)分离纯化，得到化合物101-A。 Cyclopropylboronic acid (1 g, 11.64 mmol) was dissolved in water (5 mL) and toluene (50 mL), and then, 3,6-dibromopyridazine (3.32 g, 13.97 mmol) and cesium carbonate (11. After the reaction system was replaced with nitrogen three times, Pd(dppf)Cl 2 ·DCM (950.72 mg, 1.16 mmol) was added, and the mixture was stirred under nitrogen atmosphere at 120 ° C for 3 hours, and then cooled. The reaction mixture was diluted and extracted with ethyl acetate (50 mL). EtOAc (EtOAc)EtOAc. /1) Separation and purification gave Compound 101-A.
MS m/z:198.8[M+H] + MS m/z: 198.8 [M+H] +
1H NMR(400MHz,CDCl 3)δppm 7.47(d,J＝8.8Hz,1H),7.10(d,J＝8.8Hz,1H),2.11(tt,J＝5.2,8.0Hz,1H),1.21-1.13(m,4H) 1 H NMR (400 MHz, CDCl 3 ) δ ppm 7.47 (d, J = 8.8 Hz, 1H), 7.10 (d, J = 8.8 Hz, 1H), 2.11 (tt, J = 5.2, 8.0 Hz, 1H), 1.21. 1.13(m,4H)
步骤2：化合物101-B的合成Step 2: Synthesis of Compound 101-B
除了使用相应的原料外，以实施例32中的化合物32-A相同的方法制备化合物101-B。Compound 101-B was prepared in the same manner as Compound 32-A in Example 32 except that the corresponding material was used.
MS m/z:304.8[M+H] + MS m/z: 304.8 [M+H] +
步骤3：化合物101-C的合成Step 3: Synthesis of Compound 101-C
除了使用相应的原料外，以实施例9中的化合物9-A相同的方法制备化合物101-C。Compound 101-C was prepared in the same manner as in the compound 9-A of Example 9 except for using the corresponding materials.
MS m/z:488.2[M+H] + MS m/z: 488.2 [M+H] +
步骤4：化合物101的合成Step 4: Synthesis of Compound 101
将化合物101-C(90mg,184.60μmol)溶于盐酸/乙酸乙酯(10mL)中，并在10℃下搅拌0.5小时后，减压除去溶剂，得到化合物101。The compound 101-C (90 mg, 184.60 μmol) was dissolved in hydrochloric acid / ethyl acetate (10 mL) and stirred at 10 ° C for 0.5 hr.
MS m/z:388.1[M+H] + MS m/z: 388.1 [M+H] +
1H NMR(400MHz,CD 3OD)δppm 8.34(s,1H),7.93(d,J＝9.5Hz,1H),7.80(br d,J＝9.3Hz,1H),7.50(d,J＝8.5Hz,1H),7.36(s,1H),7.20(d,J＝8.3Hz,1H),4.21(s,2H),3.99(s,3H),2.43-2.22(m,4H),1.34-1.25(m,2H),1.23-1.13(m,2H) 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.34 (s, 1H), 7.93 (d, J = 9.5 Hz, 1H), 7.80 (brd, J = 9.3 Hz, 1H), 7.50 (d, J = 8.5 Hz, 1H), 7.36 (s, 1H), 7.20 (d, J = 8.3 Hz, 1H), 4.21 (s, 2H), 3.99 (s, 3H), 2.43-2.22 (m, 4H), 1.34-1.25 (m, 2H), 1.23-1.13 (m, 2H)
实施例102：化合物102Example 102: Compound 102
Figure PCTCN2019070227-appb-000284
Figure PCTCN2019070227-appb-000284
合成路线：synthetic route:
Figure PCTCN2019070227-appb-000285
Figure PCTCN2019070227-appb-000285
步骤1：化合物102-A的合成Step 1: Synthesis of Compound 102-A
将化合物2,5-二氯吡嗪(2g,8.41mmol)、环丙基硼酸(866.63mg,10.09mmol)、碳酸铯(8.22g,25.22mmol)溶于无水甲苯(90mL)和水(9mL)中，用氮气置换三次，再加入Pd(dppf)Cl 2(615.19mg,840.76μmol)，反应在氮气保护、100℃下搅拌4小时。向反应液中加入水(50mL)，用乙酸乙酯(40mL)萃取，饱和食盐水(40mL)洗涤，经无水硫酸钠干燥后过滤，将滤液减压浓缩得到粗品。粗品经柱层析(洗脱剂：PE/EA＝60/1)纯化，得到化合物102-A。 The compound 2,5-dichloropyrazine (2 g, 8.41 mmol), cyclopropylboronic acid (866.63 mg, 10.09 mmol), cesium carbonate (8.22 g, 25.22 mmol) was dissolved in anhydrous toluene (90 mL) and water (9 mL) Among them, three times with nitrogen, and then Pd(dppf)Cl 2 (615.19 mg, 840.76 μmol) was added, and the reaction was stirred under nitrogen atmosphere at 100 ° C for 4 hours. Water (50 mL) was added to the mixture, and the mixture was evaporated. The crude product was purified by column chromatography (eluent: EtOAc/EtOAc) to afford Compound 102-A.
MS m/z:198.8[M+H] + MS m/z: 198.8 [M+H] +
步骤2：化合物102-B的合成Step 2: Synthesis of Compound 102-B
除了使用相应的原料外，以实施例32中的化合物32-A相同的方法制备化合物102-B。Compound 102-B was prepared in the same manner as Compound 32-A in Example 32 except that the corresponding material was used.
MS m/z:304.9[M+H] + MS m/z: 304.9 [M+H] +
步骤3：化合物102-C的合成Step 3: Synthesis of Compound 102-C
除了使用相应的原料外，以实施例9中的化合物9-A相同的方法制备化合物102-C。Compound 102-C was prepared in the same manner as Compound 9-A in Example 9 except that the corresponding material was used.
MS m/z:488.2[M+H] + MS m/z: 488.2 [M+H] +
步骤4：化合物102的合成Step 4: Synthesis of Compound 102
除了使用相应的原料外，以实施例9中的化合物9相同的方法制备化合物102。Compound 102 was prepared in the same manner as Compound 9 in Example 9 except that the corresponding material was used.
MS m/z:388.0[M+H] + MS m/z: 388.0 [M+H] +
1H NMR(400MHz,DMSO-d 6)δppm 12.31(br s,1H),8.65(s,1H),8.39(s,1H),8.35(s,1H),8.20(s,1H),7.56(s,1H),7.49(d,J＝8.5Hz,1H),7.16(d,J＝8.5Hz,1H),4.10(s,2H),3.91(s,3H),2.24(s,3H),1.24(br s,1H),1.07-1.00(m,2H),0.96-0.89(m,2H) 1 H NMR (400MHz, DMSO- d 6) δppm 12.31 (br s, 1H), 8.65 (s, 1H), 8.39 (s, 1H), 8.35 (s, 1H), 8.20 (s, 1H), 7.56 ( s, 1H), 7.49 (d, J = 8.5 Hz, 1H), 7.16 (d, J = 8.5 Hz, 1H), 4.10 (s, 2H), 3.91 (s, 3H), 2.24 (s, 3H), 1.24(br s,1H),1.07-1.00(m,2H),0.96-0.89(m,2H)
实施例103：化合物103Example 103: Compound 103
Figure PCTCN2019070227-appb-000286
Figure PCTCN2019070227-appb-000286
合成路线：synthetic route:
Figure PCTCN2019070227-appb-000287
Figure PCTCN2019070227-appb-000287
步骤1：化合物103-A的合成Step 1: Synthesis of Compound 103-A
在-10℃下，将60％钠氢(113.01mg,2.83mmol)溶于THF(20mL)中，向其中加入化合物环丙醇(246.13mg,4.24mmol)，搅拌0.5小时后再加入2-溴-5-氟嘧啶(500mg,2.83mmol)，体系继续在此条件下搅拌1.5小时。反应液用饱和氯化铵溶液(100mL)中淬灭，再用乙酸乙酯(30mL×3)萃取，合并的萃取液用饱和食盐水(50mL)洗涤，无水硫酸钠干燥后过滤，浓缩得粗品。粗品经层析柱(洗脱剂：石油醚/四氢呋喃＝1/0～3/1)分离纯化，得到化合物103-A。60% sodium hydrogen (113.01 mg, 2.83 mmol) was dissolved in THF (20 mL) at -10 ° C, and the compound cyclopropanol (246.13 mg, 4.24 mmol) was added thereto, and stirred for 0.5 hour, then 2-bromo was added. -5-fluoropyrimidine (500 mg, 2.83 mmol), the system was further stirred under this condition for 1.5 hours. The reaction mixture was quenched with EtOAc EtOAc (EtOAc (EtOAc) Crude. The crude product was separated and purified by chromatography (eluent: petroleum ether / tetrahydrofuran = 1/0 to 3/1) to afford compound 103-A.
MS m/z:214.8[M+H] + MS m/z: 214.8 [M+H] +
步骤2：化合物103-B的合成Step 2: Synthesis of Compound 103-B
除了使用相应的原料外，以实施例32中的化合物32-A相同的方法制备化合物103-B。Compound 103-B was prepared in the same manner as Compound 32-A in Example 32 except that the corresponding material was used.
MS m/z:320.9[M+H] + MS m/z: 320.9 [M+H] +
步骤3：化合物103-C的合成Step 3: Synthesis of Compound 103-C
除了使用相应的原料外，以实施例9中的化合物9-A相同的方法制备化合物103-C。Compound 103-C was prepared in the same manner as Compound 9-A in Example 9 except that the corresponding material was used.
MS m/z:504.1[M+H] + MS m/z: 504.1 [M+H] +
步骤4：化合物103的合成Step 4: Synthesis of Compound 103
将化合物103-C(40mg,79.44μmol)溶于盐酸/乙酸乙酯(10mL)中，在18℃下搅拌0.5小时后，浓缩除去溶剂，得到粗产品。粗品经过制备HPLC(中性，乙腈，水)分离纯化，得到化合物103。The compound 103-C (40 mg, 79.44 μmol) was dissolved in hydrochloric acid / ethyl acetate (10 mL), and stirred at 18 ° C for 0.5 hr. The crude product was isolated and purified by preparative HPLC (neut., acetonitrile, water) to afford compound 103.
MS m/z:404.1[M+H] + MS m/z: 404.1 [M+H] +
1H NMR(400MHz,CD 3OD)δppm 8.62(s,2H),8.15(s,1H),7.54(d,J＝8.4Hz,1H),7.42(s,1H),7.22(d,J＝8.5Hz,1H),4.24(s,2H),4.08-4.03(m,1H),4.00(s,3H),3.49-3.05(m,1H),2.34(s,3H),0.94-0.88(m,2H),0.86-0.79(m,2H) 1 H NMR (400MHz, CD 3 OD) δppm 8.62 (s, 2H), 8.15 (s, 1H), 7.54 (d, J = 8.4Hz, 1H), 7.42 (s, 1H), 7.22 (d, J = 8.5 Hz, 1H), 4.24 (s, 2H), 4.08-4.03 (m, 1H), 4.00 (s, 3H), 3.49-3.05 (m, 1H), 2.34 (s, 3H), 0.94-0.88 (m) , 2H), 0.86-0.79 (m, 2H)
实验例1：本发明化合物的体外体外酶学抑制活性Experimental Example 1: In vitro and in vitro enzymatic inhibitory activity of the compound of the present invention
供实验用的本发明化合物均为自制，其结构式见各化合物的制备实施例，实验测试在美国Reaction Biology Corporation进行，实验结果由该公司提供。The compounds of the present invention for experimental use were all self-made, and the structural formulas thereof are shown in the preparation examples of the respective compounds. The experimental tests were carried out in Reaction Biology Corporation, USA, and the experimental results were provided by the company.
实验试剂：Experimental reagents:
基本反应缓冲液：20mM羟乙基哌嗪乙硫磺酸(pH 7.5)，10mM氯化镁，1mM EGTA，0.02％Brij35，0.02mg/ml牛血清蛋白，0.1mM Na 3VO 4，2mMDTT，1％DMSO Basic reaction buffer: 20 mM hydroxyethylpiperazine ethanesulfuric acid (pH 7.5), 10 mM magnesium chloride, 1 mM EGTA, 0.02% Brij35, 0.02 mg/ml bovine serum albumin, 0.1 mM Na 3 VO 4 , 2 mM DTT, 1% DMSO
必要的辅助因子单独加到CSF-1R激酶反应中。The necessary cofactors are added separately to the CSF-1R kinase reaction.
酶:CSF-1R浓度为2.5nMEnzyme: CSF-1R concentration is 2.5nM
化合物的处理：Compound treatment:
待测化合物用100％DMSO配成特定浓度的溶液，连续稀释用DMSO通过智能移液助手Integra Viaflo Assist进行。The test compound was formulated into a specific concentration of solution with 100% DMSO, and serial dilutions were performed with DMSO via the intelligent pipetting assistant Integra Viaflo Assist.
实验过程：experiment procedure:
1.制备新鲜的基质配置反应缓冲液；1. Preparation of a fresh matrix configuration reaction buffer;
2.把所有必须的辅助因子加到上述反应缓冲液中；2. Add all necessary cofactors to the above reaction buffer;
3.把激酶加入基质溶液中并轻轻摇匀；3. Add the kinase to the matrix solution and shake gently;
4.利用声学技术(Echo550；纳升范围)将化合物的DMSO溶液加入激酶反应混合物中，室温下孵化20分钟；4. Acquire a DMSO solution of the compound into the kinase reaction mixture using an acoustic technique (Echo 550; nanoliter range) and incubate for 20 minutes at room temperature;
5.向反应混合物中加入 33P-ATP(比活度，10μCi/μl)激发反应； 5. Add 33 P-ATP (specific activity, 10 μCi/μl) to the reaction mixture to stimulate the reaction;
6.在室温下孵化2小时；6. Incubate for 2 hours at room temperature;
7.通过filter-binding方法检测激酶活性；7. Detection of kinase activity by a filter-binding method;
8.激酶活性为试验样本中剩下的激酶与溶媒(DMSO)组相比，IC 50的数值和曲线通过使用Prism(GraphPad软件)获得。测定结果如表1. Group compared to the test sample 8. kinase activity remaining kinases vehicle (DMSO), IC 50 values and the curve is obtained by using the Prism (GraphPad Software). The measurement results are shown in Table 1.
表1：本发明化合物体外酶学活性测定结果(IC 50) Table 1: Results of in vitro enzymatic activity determination of compounds of the invention (IC 50 )
Figure PCTCN2019070227-appb-000288
Figure PCTCN2019070227-appb-000288
Figure PCTCN2019070227-appb-000289
Figure PCTCN2019070227-appb-000289
实验结论：本发明化合物对CSF-1R激酶具有显著的抑制作用。Experimental results: The compounds of the present invention have a significant inhibitory effect on CSF-1R kinase.
实验例2 细胞色素酶抑制研究(CYP inhibition)Experimental Example 2 Cytochrome Inhibition Study (CYP inhibition)
实验目的：Purpose:
采用CYP同工酶的混合探针底物来评价供试品对人肝微粒体细胞色素P450同工酶(CYP1A2、CYP2C9、CYP2C19、CYP2D6和CYP3A4)的抑制性。The inhibitory substrate of the CYP isoenzyme was used to evaluate the inhibitory effect of the test sample on human liver microsomal cytochrome P450 isoenzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4).
实验方法：experimental method:
供试品将用DMSO配制成10mM的储存液。在反应板的无抑制剂对照(NIC)、供试品样品孔中加入178μL人肝微粒体与底物混合物溶液，置于冰上。从稀释板中分别取2μL空白溶剂、供试品工作溶液加入到反应板中(终浓度为0.05-50μM)。反应板在37±0.2℃水浴锅中预热10分钟。用液体处理工作站取20μL辅助因子溶液加入到反应板中，启动反应。The test article will be formulated into a 10 mM stock solution in DMSO. 178 μL of human liver microsomes and substrate mixture solution was added to the reaction-free control-free control (NIC) and test sample wells, and placed on ice. 2 μL of blank solvent was taken from the dilution plate, and the test solution was added to the reaction plate (final concentration was 0.05-50 μM). The reaction plate was preheated in a 37 ± 0.2 ° C water bath for 10 minutes. A 20 μL cofactor solution was added to the reaction plate using a liquid handling station to initiate the reaction.
10分钟后加入400μL终止液到反应板终止反应，并将反应板置于冰上5分钟。摇板10分钟使溶液均匀，4000转/分钟离心20分钟，然后取出上清液并按适当的比例加入超纯水。采液相色谱串联质谱法(LC/MS/MS)检测底物和产物的峰面积。样品在检测前保存在2-8℃环境下。After 10 minutes, 400 μL of the stop solution was added to the reaction plate to terminate the reaction, and the reaction plate was placed on ice for 5 minutes. The plate was shaken for 10 minutes to homogenize the solution, centrifuged at 4000 rpm for 20 minutes, then the supernatant was removed and ultrapure water was added in an appropriate ratio. The peak areas of the substrate and product were determined by liquid chromatography tandem mass spectrometry (LC/MS/MS). Samples were stored at 2-8 °C prior to testing.
采用液相色谱-串联质谱(LC-MS/MS)方法进行测定探针底物生成的代谢产物与内标峰面积的比值。分析物和内标的保留时间、色谱图采集和色谱图的积分采用软件Analyst(AB Sciex,Framingham,Massachusetts, USA)进行处理。The ratio of the metabolites produced by the probe substrate to the internal standard peak area was determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The retention time of the analyte and internal standard, chromatogram acquisition and chromatogram integration were processed using the software Analyst (AB Sciex, Framingham, Massachusetts, USA).
数据处理：data processing:
使用SigmaPlot(V.11)对供试品平均百分比活性对浓度作非线性回归分析。通过三参数或四参数反曲对数方程来计算IC 50值。当在供试品最高浓度(50μM)作用下CYP百分比活性大于50％时，IC 50值被标记为“>50μM”。 Non-linear regression analysis was performed on the average percent activity versus concentration of the test article using SigmaPlot (V.11). The IC 50 value is calculated by a three-parameter or four-parameter recursive logarithmic equation. When the CYP percentage activity was greater than 50% under the highest concentration of the test article (50 μM), the IC 50 value was marked as ">50 μM".
三参数反曲对数方程：Three-parameter recursive logarithmic equation:
Figure PCTCN2019070227-appb-000290
Figure PCTCN2019070227-appb-000290
四参数反曲对数方程：Four-parameter recursive logarithmic equation:
Figure PCTCN2019070227-appb-000291
Figure PCTCN2019070227-appb-000291
max:最大酶活性。Max: maximum enzyme activity.
min:最小酶活性。Min: minimum enzyme activity.
x:供试品或阳性对照抑制剂的浓度。x: concentration of the test article or positive control inhibitor.
y:对应浓度下的酶活性，hillslope:斜率。y: enzyme activity at the corresponding concentration, hillslope: slope.
IC 50:半抑制浓度。 IC 50 : half inhibitory concentration.
当最小酶活性在±10％内时使用四参数反曲对数方程，否则使用三参数方程。A four-parameter recursive logarithmic equation is used when the minimum enzyme activity is within ±10%, otherwise a three-parameter equation is used.
表2：本发明化合物细胞色素酶抑制测定结果(IC 50,μM) Table 2: Results of cytochrome inhibition assay of the compounds of the invention (IC 50 , μM)
测试化合物Test compound CYP1A2CYP1A2 CYP 2C9CYP 2C9 CYP2C19CYP2C19 CYP 2D6CYP 2D6 CYP 3A4CYP 3A4
对照品1Reference 1 24.024.0 3.813.81 8.328.32 8.778.77 >35.6>35.6
化合物44Compound 44 >50>50 20.320.3 40.140.1 44.944.9 >50>50
化合物55Compound 55 >50>50 27.127.1 >50>50 >50>50 >50>50
结论：本发明化合物对五个CYP同工酶抑制程度均弱于对照品1。Conclusion: The compounds of the present invention inhibited the five CYP isozymes to a lesser extent than the control 1 .
实验例3：动力学溶解度的测定Experimental Example 3: Determination of kinetic solubility
1.pH＝7.4缓冲液的配置：1. pH=7.4 buffer configuration:
将0.39g NaH 2PO 4·2H 2O和1.4025g Na 2HPO 4用约240mL水溶解在烧瓶中，混合液用10M NaOH调节pH＝7.4，转入250mL容积烧瓶，装满水至水平。 0.39 g of NaH 2 PO 4 ·2H 2 O and 1.4025 g of Na 2 HPO 4 were dissolved in a flask with about 240 mL of water, and the mixture was adjusted to pH = 7.4 with 10 M NaOH, transferred to a 250 mL volumetric flask, and filled with water to a level.
2.标准溶液制备2. Standard solution preparation
a.将50％的ACN与50％的缓冲液混合，得到稀释液。a. Mix 50% ACN with 50% buffer to obtain a dilution.
b.将10mM(10μL/化合物)原液与稀释液(490μL/化合物)混合,得到200μM的紫外标准溶液。b. Mix 10 mM (10 μL/compound) stock solution with diluent (490 μL/compound) to obtain a 200 μM UV standard solution.
c.将200μM紫外标准溶液用稀释液稀释10倍和200倍，得到20μM和1μM的紫外标准溶液，用1、20和200μM的紫外标准溶液作为标准样品进行动力学溶解度试验。c. The 200 μM ultraviolet standard solution was diluted 10-fold and 200-fold with a dilution solution to obtain an ultraviolet standard solution of 20 μM and 1 μM, and a kinetic solubility test was performed using 1, 20 and 200 μM of the ultraviolet standard solution as a standard sample.
3.测试方法3. Test method
a.将试验化合物溶于DMSO，制成10mM的原液。将盐酸胺碘酮、卡马西平和氯霉素作为溶解度测定的对照样品，至少需要200μL的原液。a. The test compound was dissolved in DMSO to make a 10 mM stock solution. Amidoxime hydrochloride, carbamazepine, and chloramphenicol were used as control samples for solubility determination, and at least 200 μL of stock solution was required.
b.将试验化合物和对照(10mM的DMSO，10μL/孔)加入到放置在96孔板含pH＝7.4缓冲液(490μL/孔)中。试验化合物和DMSO的最终浓度分别为200μM和2％。理论最大浓度为200μM。在摇床上以500rpm的速度在室温下摇动溶解度溶液24小时。b. Test compound and control (10 mM DMSO, 10 μL/well) were added to a 96-well plate containing pH=7.4 buffer (490 μL/well). The final concentrations of the test compound and DMSO were 200 μM and 2%, respectively. The theoretical maximum concentration is 200 μM. The solution was shaken at 500 rpm on a shaker at room temperature for 24 hours.
c.将200μL的溶解度溶液分别转移到一个新的多屏滤板(聚碳酸酯膜)中，用密理博(Millipore)真空集流管过滤，收集滤液作为测试样品。c. Transfer 200 μL of the solubility solution to a new multi-screen filter plate (polycarbonate membrane), filter with a Millipore vacuum manifold, and collect the filtrate as a test sample.
d.采用高效液相色谱-紫外光谱法测定滤液的试验配合物浓度。d. Determination of the concentration of the test complex of the filtrate by high performance liquid chromatography-ultraviolet spectroscopy.
表3table 3
化合物Compound 溶解度(μM)pH 7.4Solubility (μM) pH 7.4
对照品1Reference 1 <1<1
化合物32Compound 32 159.3159.3
化合物44Compound 44 5.05.0
化合物48Compound 48 1.431.43
化合物55Compound 55 3.293.29
化合物63Compound 63 1.851.85
化合物71Compound 71 4.484.48
结论：表3中所示，与对照品1相比，本发明化合物在缓冲溶液中表现出优异的溶解度(在pH＝7.4)。Conclusion: As shown in Table 3, the compound of the present invention exhibited excellent solubility (at pH = 7.4) in a buffer solution as compared with Control 1.
实验例4 渗透性研究(MDR1-MDCK,Caco2)Experimental Example 4 Permeability Study (MDR1-MDCK, Caco2)
实验目的：Purpose:
采用Caco-2单层细胞模型测定本发明化合物的双向渗透性。The bidirectional permeability of the compounds of the invention was determined using a Caco-2 monolayer cell model.
实验方法：experimental method:
Caco-2细胞(药明康德，HTB-37)接种于Transwell-96孔板里，接种密度为1×10 5细胞/cm 2。细胞置于二氧化碳培养箱中培养28天后用于转运实验，期间每隔四到五天更换一次培养基。 Caco-2 cells (Pharmaceutical, HTB-37) were seeded in Transwell-96 well plates at a seeding density of 1 x 10 5 cells/cm 2 . The cells were cultured for 28 days in a carbon dioxide incubator for transport experiments, during which the medium was changed every four to five days.
缓冲液为10mM HEPES(Hank’s平衡盐溶液)的Hank’s平衡盐缓冲液(pH 7.40±0.05)。将本发明化合物用缓冲液稀释到2μM。去除培养板中培养基，用已预热的转运缓冲液将细胞润洗两遍。将给药液和缓冲液分别加入到对应的细胞板孔位(每个顶端和基底端孔分别加样75和250μL,n＝2)，开始启动双向转运实验。加样后，将细胞板置于37±1℃，5％CO 2及饱和湿度条件下孵育120分钟。 The buffer was Hank's Balanced Salt Buffer (pH 7.40 ± 0.05) of 10 mM HEPES (Hank's Balanced Salt Solution). The compound of the invention was diluted to 2 μM with buffer. The medium in the plates was removed and the cells were rinsed twice with pre-warmed transport buffer. The dosing solution and the buffer were separately added to the corresponding cell plate wells (75 and 250 μL, n=2, respectively for each of the apical and basal end wells), and a bidirectional transport experiment was initiated. After loading, the cell plates were incubated for 120 minutes at 37 ± 1 ° C, 5% CO 2 and saturated humidity.
起始给药液即为T0样品，加样后，取其与转运缓冲液和终止液(含250ng/mL甲苯磺丁脲(tolbutamide)的乙腈溶液)按一定比例混合。孵育120分钟后，从给药端和接收端收集最终样品，同样与转运缓冲液和终止液按一定比例混合。The initial dosing solution is the T0 sample, and after the addition, it is mixed with the transport buffer and the stop solution (250 ng/mL tolbutamide in acetonitrile solution) in a certain ratio. After 120 minutes of incubation, the final sample was collected from the drug delivery end and the receiving end, and was also mixed with the transfer buffer and stop solution in a certain ratio.
所有的样品漩涡震荡后，于4000rpm，20℃离心20分钟，取上清用超纯水1:1(v:v)稀释后储存于2-8℃，采用液相色谱串联质谱(LC/MS/MS)进行分析测试。After vortexing, all samples were centrifuged at 4000 rpm for 20 minutes at 20 ° C. The supernatant was diluted with 1:1 (v:v) ultrapure water and stored at 2-8 ° C by liquid chromatography tandem mass spectrometry (LC/MS). /MS) Perform analytical testing.
采用荧光黄外排实验(the Lucifer Yellow Rejection Assay)来测试Caco-2细胞层的完整性。每块细胞板随机选取6个细胞孔，顶端加入75μL 100μM荧光黄，基底端加入250μL转运缓冲液。孵育120分钟后，从顶端取20μL样品与60μL转运缓冲液混合，从基底端取80μL样品。采用M2e读板仪在425/528nm(激发/发射)波谱处检测样品中荧光黄的相对荧光强度(the relative fluorescence unit,RFU)。The Lucifer Yellow Rejection Assay was used to test the integrity of the Caco-2 cell layer. Six cell wells were randomly selected from each cell plate, 75 μL of 100 μM fluorescent yellow was added to the top, and 250 μL of transport buffer was added to the basal end. After 120 minutes of incubation, 20 μL of the sample was mixed with 60 μL of the transport buffer from the apex and 80 μL of the sample was taken from the basal end. The relative fluorescence unit (RFU) of the fluorescent yellow in the sample was detected at a 425/528 nm (excitation/emission) spectrum using an M2e plate reader.
数据处理：data processing:
采用如下公式计算表观渗透系数(P app,cm/s)，外排率(effulx ratio，ER)，溶液回收率(％)(％Solution Recovery)。 The apparent permeability coefficient (P app , cm/s), efflux ratio (ER), and solution recovery rate (%) (% Solution Recovery) were calculated using the following formula.
Figure PCTCN2019070227-appb-000292
Figure PCTCN2019070227-appb-000292
Figure PCTCN2019070227-appb-000293
Figure PCTCN2019070227-appb-000293
Figure PCTCN2019070227-appb-000294
Figure PCTCN2019070227-appb-000294
V R是接收端溶液的体积(A面为0.075mL，B面为0.25mL)；Area是细胞单层的相对表面积(0.0804cm 2)；Time是孵育时间(7200s)；C 0是给药端供试品的峰面积比值；V D是给药端的体积(A面为0.075mL，B面为0.25mL)；C D和C R分别为给药端和接收端供试品的峰面积比值。 V R is the volume of the solution at the receiving end (0.075 mL on the A side and 0.25 mL on the B side); Area is the relative surface area of the cell monolayer (0.0804 cm 2 ); Time is the incubation time (7200 s); C 0 is the dosing end The peak area ratio of the test sample; V D is the volume of the drug delivery end (0.075 mL on the A side and 0.25 mL on the B side); C D and C R are the peak area ratios of the test sample at the drug delivery end and the receiving end, respectively.
荧光黄透过到基底端的百分率用以下公式计算：The percentage of fluorescing yellow that passes through the base end is calculated using the following formula:
Figure PCTCN2019070227-appb-000295
Figure PCTCN2019070227-appb-000295
RFU Apical和RFU Basolateral分别是荧光黄在顶端和基底端的相对荧光强度。V Apical与V Basolateral分别是顶端和基底端的上样体积(分别为0.075mL和0.25mL)。结果见表4。 RFU Apical and RFU Basolateral are the relative fluorescence intensities of the fluorescent yellow at the apical and basal ends, respectively. V Apical and V Basolateral were the loading volumes of the apical and basal ends, respectively ( 0.075 mL and 0.25 mL, respectively). The results are shown in Table 4.
表4渗透性的比较Table 4 Comparison of permeability
Figure PCTCN2019070227-appb-000296
Figure PCTCN2019070227-appb-000296
结论：本发明化合物的渗透性要优于对照品1。Conclusion: The permeability of the compound of the present invention is superior to that of the control 1 .
实验例5 微粒体稳定性研究(Microsome stability)Experimental Example 5 Microsome stability study (Microsome stability)
实验目的：Purpose:
是评定本发明化合物在CD-1小鼠、SD大鼠、比格犬、食蟹猴和人肝微粒体中的一相代谢稳定性。One-phase metabolic stability of the compounds of the invention in CD-1 mice, SD rats, beagle dogs, cynomolgus monkeys and human liver microsomes was assessed.
实验方法：experimental method:
分别在反应板和NCF60板上添加10μL供试品工作液和80μL微粒体工作液(0.625mg/mL肝微粒体蛋白)，在Blank60板中只添加微粒体工作液，然后将上述孵育板放置于37℃水浴锅中预孵育大约10分钟。预孵育结束后，除NCF60板和T0板外，每个样品孔内添加10μL还原型辅酶Ⅱ(NADPH)再生体系工作液以启动反应，在NCF60板上每孔添加10μL磷酸钾盐缓冲液。供试品或对照品的反应终浓度为1μM，肝微粒体的浓度为0.5mg/mL。Add 10 μL of test solution and 80 μL of microsome working solution (0.625 mg/mL liver microsomal protein) to the reaction plate and NCF60 plate, add only microsome working solution to the Blank60 plate, and then place the above incubation plate on the plate. Pre-incubate for approximately 10 minutes in a 37 ° C water bath. After the pre-incubation, in addition to the NCF60 plate and the T0 plate, 10 μL of the reduced coenzyme II (NADPH) regeneration system working solution was added to each sample well to initiate the reaction, and 10 μL of potassium phosphate buffer solution was added to each well of the NCF 60 plate. The final concentration of the test or control was 1 μM, and the concentration of liver microsomes was 0.5 mg/mL.
孵育适当时间后，分别在每个样品孔中加入300μL终止液(含200ng/mL甲苯磺丁脲的乙腈溶液)以终止反应。T0板样品先加入终止液后再添加NADPH再生体系工作液。After the appropriate time of incubation, 300 μL of stop solution (acetic acid solution containing 200 ng/mL tolbutamide) was added to each sample well to terminate the reaction. The T0 plate sample was first added with a stop solution and then the NADPH regeneration system working solution was added.
所有样品板摇匀并在4000转离心20分钟，然后每孔取100μL上清液稀释到300μL纯水中用于LC-MS/MS分析。All sample plates were shaken and centrifuged at 4000 rpm for 20 minutes, and then 100 μL of supernatant per well was diluted to 300 μL of pure water for LC-MS/MS analysis.
数据处理：data processing:
通过下面公式中样品与内标峰面积的比值转化成剩余百分比求得供试品和对照品的体外消除速率常数ke：The in vitro elimination rate constant ke of the test sample and the control substance is obtained by converting the ratio of the sample to the internal standard peak area in the following formula to obtain the remaining percentage:
Figure PCTCN2019070227-appb-000297
Figure PCTCN2019070227-appb-000297
CL int(mic)＝0.693/半衰期/mg微粒体蛋白每mL(孵育时微粒体浓度) CL int(mic) =0.693/half-life/mg microsomal protein per mL (microsomal concentration at incubation)
CL int(liver)＝CL int(mic)×mg微粒体蛋白/g肝重×肝重体重比 CL int(liver) =CL int(mic) ×mg microsomal protein / g liver weight × liver weight to body weight ratio
mg微粒体蛋白/g肝重：动物和人物种中数值均为45Mg microsomal protein / g liver weight: both in animal and human species are 45
肝重体重比：小鼠、大鼠、犬、猴及人中参数分别为88、40、32、30和20g/kgLiver weight to body weight ratio: parameters for mice, rats, dogs, monkeys, and humans are 88, 40, 32, 30, and 20 g/kg, respectively.
表5 微粒体稳定性研究Table 5 Microsomal stability study
Figure PCTCN2019070227-appb-000298
Figure PCTCN2019070227-appb-000298
结论：本发明化合物在CD-1小鼠、SD大鼠、比格犬、食蟹猴和人肝微粒体中的一相代谢稳定性要好于对照品。Conclusion: The phase stability of the compounds of the present invention in CD-1 mice, SD rats, beagle dogs, cynomolgus monkeys and human liver microsomes is better than that of the control.
实验例6 小鼠、大鼠药代动力学研究(PK)Experimental Example 6 Pharmacokinetic Study of Mouse and Rat (PK)
实验目的：Purpose:
本实验旨在研究供试品静脉注射和口服给药后在雄性C57BL/6J小鼠和SD大鼠血浆中的药代动力学情况。The aim of this study was to investigate the pharmacokinetics of the test samples in the plasma of male C57BL/6J mice and SD rats after intravenous and oral administration.
实验方法：experimental method:
将动物随机分为两组，每组3只雄性。将化合物配制为指定制剂，静脉注射制剂为澄清溶液，口服制剂可以为澄清或者均一混悬液。Animals were randomly divided into two groups of 3 males each. The compound is formulated as a defined formulation, the intravenous formulation is a clear solution, and the oral formulation can be a clear or uniform suspension.
动物在给药后5、15、30分钟、1、2、4、6、8小时从颈静脉穿刺或者隐静脉采集全血样品。将全血样品加入含有抗凝剂的离心管中，4℃，3000g离心15min，取上清血浆于干冰上快速冷冻，然后保存在-70±10℃冰箱中直到进行LC-MS/MS分析。Animals were harvested from the jugular vein or saphenous vein at 5, 15, 30, 1, 2, 4, 6, and 8 hours after dosing. The whole blood sample was added to a centrifuge tube containing an anticoagulant, centrifuged at 3000 g for 15 min at 4 ° C, and the supernatant plasma was quickly frozen on dry ice and then stored in a -70 ± 10 ° C refrigerator until LC-MS/MS analysis.
数据处理：data processing:
使用WinNonlin TM Version 6.3.0(Pharsight,Mountain View,CA)药动学软件，以非房室模型对化合物的血浆药物浓度数据进行处理。达峰浓度(C max)和达峰时间(T max)以及可定量末时间，从血药浓度-时间图中直接获得。 Using WinNonlin TM Version 6.3.0 (Pharsight, Mountain View, CA) pharmacokinetics software to process the non-compartmental model plasma drug concentration data of the compound. Peak concentration ( Cmax ) and peak time ( Tmax ) and quantifiable end time were obtained directly from the plasma concentration-time plot.
使用对数线性梯形法计算下列药代动力学参数：血浆清除率(CL)，分布容积(Vd)，消除相半衰期(T 1/2)，0点到末端时间点药物在体内的平均滞留时间(MRT 0-last)，0点到无限时间药物在体内的平均滞留时间(MRT 0-inf)，0点到末端时间点时间-血浆浓度曲线下面积(AUC 0-last)，0点到无限时间-血浆浓度曲线下面积(AUC 0-inf)和生物利用度(F)，IV(注射)，PO(口服)。 The following pharmacokinetic parameters were calculated using a log-linear trapezoidal method: plasma clearance (CL), volume of distribution (Vd), elimination phase half-life (T 1/2 ), mean residence time of drug in vivo from 0 to the end of time (MRT 0-last ), mean time to stay in the body from 0 o'clock to infinity (MRT 0-inf ), time from 0 o'clock to end time - area under the plasma concentration curve (AUC 0-last ), 0 to infinity Time-area under plasma concentration curve (AUC 0-inf ) and bioavailability (F), IV (injection), PO (oral).
实验结果：Experimental results:
表6 PK的研究对比Table 6 Comparison of PK studies
Figure PCTCN2019070227-appb-000299
Figure PCTCN2019070227-appb-000299
结论：本发明化合物可以显著提高大鼠药代动力学的药物暴露量浓度和生物利用度。Conclusion: The compounds of the present invention can significantly increase the drug exposure concentration and bioavailability of rat pharmacokinetics.
实验例7：化合物在3LL细胞皮下移植肿瘤C57/BL6小鼠模型的研究Experimental Example 7: Study of subcutaneous transplantation of tumor C57/BL6 mouse model in 3LL cells
实验目的：Purpose:
评价受试药化合物在小鼠肺癌3LL细胞皮下移植肿瘤模型上的体内药效。The in vivo efficacy of the test compound on the subcutaneously transplanted tumor model of mouse lung cancer 3LL cells was evaluated.
本次实验目的是考察化合物实施例55在3LL细胞皮下移植肿瘤C57/BL6小鼠模型的治疗效果，从而为之后的临床研究提供临床前药效学相关信息。The purpose of this experiment was to examine the therapeutic effect of Compound Example 55 on a subcutaneously transplanted tumor C57/BL6 mouse model in 3LL cells, thereby providing preclinical pharmacodynamics information for subsequent clinical studies.
实验设计：experimental design:
细胞培养：小鼠肺癌3LL细胞(JCRB-1348)，体外单层培养，培养条件为RPMI1640培养基中加10％胎牛血清，100U/mL青霉素和100μg/mL链霉素，37℃，5％CO 2培养。一周两次用胰酶-乙二胺四乙酸进行常规消化处理传代。当细胞饱和度为80％-90％时，收取细胞，计数，接种。 Cell culture: mouse lung cancer 3LL cells (JCRB-1348), in vitro monolayer culture, culture conditions of RPMI1640 medium plus 10% fetal bovine serum, 100 U / mL penicillin and 100 μg / mL streptomycin, 37 ° C, 5% CO 2 culture. Passage was routinely digested with trypsin-ethylenediaminetetraacetic acid twice a week. When the cell saturation is 80%-90%, the cells are collected, counted, and inoculated.
■动物：C57/BL6小鼠，雌性，6-8周龄，体重18-22克。■ Animals: C57/BL6 mice, female, 6-8 weeks old, weighing 18-22 grams.
■肿瘤接种：将0.1mL(2x 10 6个)3LL细胞皮下接种于每只C57/BL6小鼠的右后肢，肿瘤平均体积达到约30-50mm 3时开始分组给药。实验分组和给药方案见下表。 Tumor inoculation: 0.1 mL (2 x 10 6 ) of 3LL cells were subcutaneously inoculated into the right hind limb of each C57/BL6 mouse, and group administration was started when the average tumor volume reached about 30-50 mm 3 . The experimental grouping and dosing schedule are shown in the table below.
■动物实验分组和给药方案：■ Animal experiment grouping and dosing schedule:
Figure PCTCN2019070227-appb-000300
Figure PCTCN2019070227-appb-000300
Figure PCTCN2019070227-appb-000301
Figure PCTCN2019070227-appb-000301
注：Note:
1.N:每组小鼠数目1.N: number of mice per group
2.给药容积：根据小鼠体重10μl/g。如果体重下降超过15％，给药方案应做出相应调整。2. Dosing volume: 10 μl/g based on the body weight of the mice. If the weight loss exceeds 15%, the dosage regimen should be adjusted accordingly.
3.PO:口服，IP:腹腔注射3.PO: Oral, IP: intraperitoneal injection
4.PD-L1:厂家BioXcell(批号：665717o1B)4.PD-L1: Manufacturer BioXcell (batch number: 665717o1B)
■动物饲养：动物到达后在实验环境饲养3－7天后方能开始实验。动物在SPF级动物房以IVC(独立送风***)笼具饲养(每笼4只)。所有笼具、垫料及饮水在使用前均需灭菌。所有实验人员在动物房操作时应穿着防护服和乳胶手套。每笼动物信息卡应注明笼内动物数目，性别，品系，接收日期，给药方案，实验编号，组别以及实验开始日期。笼具、饲料及饮水每周更换两次。饲养环境及光照情况如下：■ Animal feeding: After the animals arrive, they can be started in the experimental environment for 3-7 days. Animals were housed in an IVC (independent air supply system) cage at the SPF level animal house (4 per cage). All cages, litter and drinking water must be sterilized before use. All laboratory personnel should wear protective clothing and latex gloves when operating in the animal room. The animal information card for each cage should indicate the number of animals in the cage, gender, strain, date of receipt, dosing schedule, experiment number, group, and start date of the experiment. Cage, feed and drinking water are changed twice a week. The feeding environment and lighting conditions are as follows:
√温度：20～26℃√ Temperature: 20～26°C
√湿度：40～70％√ Humidity: 40 to 70%
√光照周期：12小时光照，12小时无光照√Lighting cycle: 12 hours of light, 12 hours of no light
■饲料成分：饲料符合实验动物食物鉴定标准。污染物最高含量在可控范围内并由生产厂家负责例检。饮水采用高压灭菌的饮用水。■Feed ingredients: The feed meets the animal food identification criteria. The maximum content of pollutants is within the controllable range and is inspected by the manufacturer. Drinking water is autoclaved drinking water.
■动物分组：给药前称重动物，测量瘤体积。根据瘤体积随机分组(随机区组设计)。■ Animal grouping: Animals were weighed prior to dosing and tumor volume was measured. Randomly grouped according to tumor volume (random block design).
■观察：本实验方案的拟定及任何修改将在苏州药明康德实验动物伦理委员会(IACUC)进行评估核准后方可实行。实验动物的使用及福利将遵照国际实验动物评估和认可委员会(AAALAC)的规则执行。每天监测动物的健康状况及死亡情况，例行检查包括观察肿瘤生长和药物治疗对动物日常行为表现的影响如行为活动，摄食摄水量，体重变化(每周测量三次体重)，外观体征或其它不正常情况。基于各组动物数量记录组内动物死亡数和副作用。■ Observation: The preparation and any modification of this experimental protocol will be carried out after the evaluation and approval of the Suzhou WuXi PharmaTech Animal Ethics Committee (IACUC). The use and welfare of laboratory animals will be performed in accordance with the rules of the International Laboratory Animal Evaluation and Accreditation Council (AAALAC). Animals were monitored daily for health and mortality. Routine examinations included observations of tumor growth and drug treatment effects on daily behavior of animals such as behavioral activities, food intake, body weight changes (three weights per week), signs of appearance or other normal situation. The number of animal deaths and side effects in the group were recorded based on the number of animals in each group.
■实验指标：实验指标是考察肿瘤生长是否被抑制、延缓或治愈。每周三次用游标卡尺测量肿瘤直径。肿瘤体积的计算公式为：V＝0.5a×b 2，a和b分别表示肿瘤的长径和短径。 ■Experimental indicators: The experimental indicators are to investigate whether tumor growth is inhibited, delayed or cured. Tumor diameters were measured with vernier calipers three times a week. The calculation formula of tumor volume is: V = 0.5a × b 2 , and a and b represent the long diameter and short diameter of the tumor, respectively.
化合物的抑瘤疗效用TGI(％)或相对肿瘤增殖率T/C(％)评价。TGI(％)，反映肿瘤生长抑制率。TGI(％)的计算：TGI(％)＝[(1-(某处理组给药结束时平均瘤体积－该处理组开始给药时平均瘤体积)/(溶剂对照组治疗结束时平均瘤体积－溶剂对照组开始治疗时平均瘤体积)]×100％。The antitumor effect of the compound was evaluated by TGI (%) or relative tumor growth rate T/C (%). TGI (%), reflecting the tumor growth inhibition rate. Calculation of TGI (%): TGI (%) = [(1 - mean tumor volume at the end of administration of a treatment group - mean tumor volume at the start of administration of the treatment group) / (mean tumor volume at the end of treatment of the solvent control group) - The average tumor volume at the start of treatment in the solvent control group)] x 100%.
相对肿瘤增殖率T/C(％)：计算公式如下：T/C％＝T RTV/C RTV×100％(T RTV：治疗组平均RTV；C RTV：阴性对照组平均RTV)。根据肿瘤测量的结果计算出相对肿瘤体积(relative tumor volume，RTV)，计算公式为RTV＝V t/V 0，其中V 0是分组给药时(即d0)测量所得肿瘤体积，V t为某一次测量时的肿瘤体积，T RTV与C RTV取同一天数据。 Relative tumor proliferation rate T/C (%): The formula is as follows: T/C% = T RTV / C RTV × 100% (T RTV : treatment group mean RTV; C RTV : negative control group mean RTV). Calculate the relative tumor volume (RTV) according to the results of tumor measurement, and calculate the formula as RTV=V t /V 0 , where V 0 is the tumor volume measured at the time of group administration (ie, d0), and V t is a certain Tumor volume at one measurement, T RTV and C RTV took the same day data.
实验终止：若动物健康状况持续恶化，或瘤体积超过3,000mm 3，或有严重疾病，或疼痛，须处以安乐死。有以下情况者，通知兽医并处以安乐死： End of experiment: If the animal's health continues to deteriorate, or the tumor volume exceeds 3,000 mm 3 , or there is a serious illness, or pain, it must be euthanized. The veterinarian is informed and euthanized if:
√明显消瘦，体重降低大于20％；√ obviously lost weight, weight loss is greater than 20%;
√不能自由取食和饮水；√ not free to eat and drink;
√动物出现以下临床表现且持续恶化：√ animals have the following clinical manifestations and continue to deteriorate:
o立毛o
o弓背o bow back
o耳、鼻、眼或足色发白o whitish in the ear, nose, eyes or feet
o呼吸仓促o breathing rush
o抽搐o convulsions
o连续腹泻o continuous diarrhea
o脱水o dehydration
o行动迟缓o Slow action
o发声o vocalization
■数据分析：T检验用于两组间比较。三组或多组间比较用one-way ANOVA。如果F值有显著性差异，应在ANOVA分析之后再进行多重比较。用SPSS 17.0进行所有数据分析。p<0.05认为有显著性差异。■ Data analysis: The T test was used to compare between the two groups. One-way ANOVA was used for comparison between three or more groups. If there is a significant difference in F values, multiple comparisons should be made after ANOVA analysis. All data analysis was performed with SPSS 17.0. A significant difference was considered at p < 0.05.
实验结果：Experimental results:
表7 3LL细胞皮下移植肿瘤C57/BL6小鼠模型的研究Table 7 Study of C57/BL6 mouse model of subcutaneous transplantation of 3LL cells
Figure PCTCN2019070227-appb-000302
Figure PCTCN2019070227-appb-000302
Figure PCTCN2019070227-appb-000303
Figure PCTCN2019070227-appb-000303
结论：实验结果表明在同等剂量下，本发明化合物对肿瘤的抑瘤效用优于对照品化合物，即使剂量减半的情况下，本发明化合物对肿瘤的抑瘤效用也优于对照品化合物。Conclusion: The experimental results show that the compound of the present invention has better antitumor effect on tumors than the reference compound at the same dose, and even if the dose is halved, the antitumor effect of the compound of the present invention on tumor is superior to that of the reference compound.

Claims (27)

  1. 式(Ⅰ)所示化合物、其异构体或其药学上可接受的盐，a compound of the formula (I), an isomer thereof or a pharmaceutically acceptable salt thereof,
    Figure PCTCN2019070227-appb-100001
    Figure PCTCN2019070227-appb-100001
    其中，among them,
    T选自N或CH；T is selected from N or CH;
    R 1选自H、F、Cl、Br、I、OH或CN，或选自任选被1、2或3个R取代的：C 1-6烷基、C 1-6烷氧基、C 1-6烯基、C 1-6炔基、C 3-7环烷基、C 3-7环烷基-O-或3～7元杂环烷基-O-； R 1 is selected from H, F, Cl, Br, I, OH or CN, or is selected from the group consisting of 1, 2 or 3 R substituted: C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkenyl, C 1-6 alkynyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl-O- or 3- to 7-membered heterocycloalkyl-O-;
    R 2分别独立地选自H、F、Cl、Br、I、OH、NH 2或CN，或分别独立地选自任选被1、2或3个R取代的C 1-3烷基； R 2 is independently selected from H, F, Cl, Br, I, OH, NH 2 or CN, respectively, or independently selected from C 1-3 alkyl optionally substituted by 1, 2 or 3 R;
    R 3分别独立地选自H、F、Cl、Br、I、OH、NH 2或CN，或分别独立地选自任选被1、2或3个R取代的：C 1-6烷基、C 1-6杂烷基、C 3-7环烷基、C 3-7环烷基-O-、3～7元杂环烷基-O-或3～7元杂环烷基-C 1-3烷基-； R 3 is independently selected from H, F, Cl, Br, I, OH, NH 2 or CN, respectively, or independently selected from C 1 1-6 alkyl optionally substituted by 1, 2 or 3 R, C 1-6 heteroalkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl-O-, 3-7 -membered heterocycloalkyl-O- or 3-7-membered heterocycloalkyl-C 1 -3 alkyl-;
    L选自-NH-、-NHCHR-、-O-、-O-CH 2-或-NHC(＝O)-； L is selected from -NH-, -NHCHR-, -O-, -O-CH 2 - or -NHC(=O)-;
    环A选自C 4-8环烷基、苯基或5～10元杂芳基； Ring A is selected from C 4-8 cycloalkyl, phenyl or 5- to 10-membered heteroaryl;
    n是0、1或2；n is 0, 1 or 2;
    m是1、2或3；m is 1, 2 or 3;
    R分别独立地选自H、F、Cl、Br、I、OH、NH 2或CN，或选自任选被1、2或3个R’取代的：C 1-6烷基或C 1-6杂烷基； R is independently selected from H, F, Cl, Br, I, OH, NH 2 or CN, or from a group optionally substituted by 1, 2 or 3 R': C 1-6 alkyl or C 1- 6 heteroalkyl;
    R’分别独立地选自F、Cl、Br、I、OH、NH 2、CN或-CH 3； R' is independently selected from the group consisting of F, Cl, Br, I, OH, NH 2 , CN or -CH 3 ;
    所述C 1-6杂烷基、5-10元杂芳基、3～7元杂环烷基中的杂原子或杂原子团分别独立地选自N、-O-、-S-、-NH-； The hetero atom or hetero atom in the C 1-6 heteroalkyl group, the 5-10 membered heteroaryl group, the 3 to 7 membered heterocycloalkyl group is independently selected from N, —O—, —S—, —NH. -;
    上述杂原子或杂原子团的数目分别独立地选自1、2、3或4。The number of the above heteroatoms or heteroatoms is independently selected from 1, 2, 3 or 4.
  2. 根据权利要求1所述化合物、其异构体或其药学上可接受的盐，其中，R分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN，或选自任选被1、2或3个R’取代的：C 1-3烷基、C 1-3烷氧基或C 1-3烷氨基。 The compound according to claim 1, an isomer thereof or a pharmaceutically acceptable salt thereof, wherein R is each independently selected from the group consisting of H, F, Cl, Br, I, OH, NH 2 , CN, or selected from any Substituted by 1, 2 or 3 R': C 1-3 alkyl, C 1-3 alkoxy or C 1-3 alkylamino.
  3. 根据权利要求2所述化合物、其异构体或其药学上可接受的盐，其中，R分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN，或选自任选被1、2或3个R’取代的：-CH 3、-CH 2CH 3、
    Figure PCTCN2019070227-appb-100002
    The compound according to claim 2, an isomer thereof or a pharmaceutically acceptable salt thereof, wherein R is each independently selected from the group consisting of H, F, Cl, Br, I, OH, NH 2 , CN, or selected from any Substituted by 1, 2 or 3 R's: -CH 3 , -CH 2 CH 3 ,
    Figure PCTCN2019070227-appb-100002
  4. 根据权利要求3所述化合物、其异构体或其药学上可接受的盐，其中，R分别独立地选自H、F、Cl、Br、 I、OH、NH 2、CN、-CH 3、-CH 2F、-CHF 2、-CF 3、-CH 2CH 3、
    Figure PCTCN2019070227-appb-100003
    The compound according to claim 3, an isomer thereof or a pharmaceutically acceptable salt thereof, wherein R is independently selected from the group consisting of H, F, Cl, Br, I, OH, NH 2 , CN, -CH 3 , -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CH 3 ,
    Figure PCTCN2019070227-appb-100003
  5. 根据权利要求1～4任意一项所述化合物、其异构体或其药学上可接受的盐，其中，R 1选自H、F、Cl、Br、I、-OH、-CN，或选自任选被1、2或3个R取代的：C 1-3烷基、C 1-3烷氧基、C 1-3炔基、环丙烷基、环丙烷基-O-或氧杂环丁烷基-O-。 The compound according to any one of claims 1 to 4, an isomer thereof or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group consisting of H, F, Cl, Br, I, -OH, -CN, or Substituted by 1, 2 or 3 R: C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkynyl, cyclopropane, cyclopropyl-O- or oxocycle Butanyl-O-.
  6. 根据权利要求5所述化合物、其异构体或其药学上可接受的盐，其中，R 1选自H、F、Cl、Br、I、OH、CN，或选自任选被1、2或3个R取代的：-CH 3、-CH 2CH 3、-CH 2CH 3CH 3、
    Figure PCTCN2019070227-appb-100004
    Figure PCTCN2019070227-appb-100005
    The compound according to claim 5, an isomer thereof or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group consisting of H, F, Cl, Br, I, OH, CN, or selected from the group consisting of 1, 2 Or 3 R substituted: -CH 3 , -CH 2 CH 3 , -CH 2 CH 3 CH 3 ,
    Figure PCTCN2019070227-appb-100004
    Figure PCTCN2019070227-appb-100005
  7. 根据权利要求6所述化合物、其异构体或其药学上可接受的盐，其中，R 1选自H、F、Cl、Br、I、OH、CN、-CH 3、-CH 2CH 3、-CH 2CH 3CH 3、
    Figure PCTCN2019070227-appb-100006
    Figure PCTCN2019070227-appb-100007
    The compound according to claim 6, an isomer thereof or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group consisting of H, F, Cl, Br, I, OH, CN, -CH 3 , -CH 2 CH 3 , -CH 2 CH 3 CH 3 ,
    Figure PCTCN2019070227-appb-100006
    Figure PCTCN2019070227-appb-100007
  8. 根据权利要求1～4任意一项所述化合物、其异构体或其药学上可接受的盐，其中，R 2分别独立地选自H、F、Cl、Br、I、OH、NH 2或CN，或分别独立地选自任选被1、2或3个R取代的：-CH 3或-CH 2CH 3。 The compound according to any one of claims 1 to 4, an isomer thereof or a pharmaceutically acceptable salt thereof, wherein R 2 is independently selected from H, F, Cl, Br, I, OH, NH 2 or CN, or independently selected from: -CH 3 or -CH 2 CH 3 optionally substituted by 1, 2 or 3 R.
  9. 根据权利要求8所述化合物、其异构体或其药学上可接受的盐，其中，R 2分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN或-CH 3。 The compound according to claim 8, an isomer thereof or a pharmaceutically acceptable salt thereof, wherein R 2 is independently selected from the group consisting of H, F, Cl, Br, I, OH, NH 2 , CN or -CH 3 .
  10. 根据权利要求1～4任意一项所述化合物、其异构体或其药学上可接受的盐，其中，R 3分别独立地选自H、F、Cl、Br、I、OH、NH 2或CN，或分别独立地选自任选被1、2或3个R取代的：C 1-4烷基、C 1-4烷氧基、C 1-4烷氨基、环丙烷基、环丁环基、环戊烷基、噁丁环基、四氢呋喃基、四氢吡喃基、哌嗪基、哌啶基、吗啉基、-CH 2-哌嗪基、-CH 2-哌啶基、-O-环丙烷基、-O-环丁烷基、-O-四氢呋喃基、-O-四氢吡喃基、咪唑烷-2-酮基、恶唑烷-2-酮基或吡咯烷-2-酮基。 The compound according to any one of claims 1 to 4, an isomer thereof or a pharmaceutically acceptable salt thereof, wherein R 3 is independently selected from H, F, Cl, Br, I, OH, NH 2 or CN, or independently selected from, optionally substituted by 1, 2 or 3 R: C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, cyclopropane, cyclobutane , cyclopentyl, acetonyl, tetrahydrofuranyl, tetrahydropyranyl, piperazinyl, piperidinyl, morpholinyl, -CH 2 -piperazinyl, -CH 2 -piperidinyl, - O-cyclopropane, -O-cyclobutane, -O-tetrahydrofuranyl, -O-tetrahydropyranyl, imidazolidin-2-one, oxazolidin-2-one or pyrrolidine-2 - Keto group.
  11. 根据权利要求10所述化合物、其异构体或其药学上可接受的盐，其中，R 3分别独立地选自H、F、Cl、Br、I、OH、NH 2或CN，或分别独立地选自任选被1、2或3个R取代的：-CH 3、-CH 2CH 3、-CH 2CH 2CH 3、-CH(CH 3) 2、-C(CH 3) 3、-OCH 3、-OCH 2CH 3、-NH(CH 3)、-N(CH 3) 2、
    Figure PCTCN2019070227-appb-100008
    Figure PCTCN2019070227-appb-100009
    The compound according to claim 10, an isomer thereof or a pharmaceutically acceptable salt thereof, wherein R 3 is each independently selected from H, F, Cl, Br, I, OH, NH 2 or CN, or independently Described from -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -C(CH 3 ) 3 , optionally substituted by 1, 2 or 3 R -OCH 3 , -OCH 2 CH 3 , -NH(CH 3 ), -N(CH 3 ) 2 ,
    Figure PCTCN2019070227-appb-100008
    Figure PCTCN2019070227-appb-100009
  12. 根据权利要求11所述化合物、其异构体或其药学上可接受的盐，其中，R 3分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN、-CH 3、-CH 2CH 3、-CH 2CH 2CH 3、-CH(CH 3) 2、-C(CH 3) 3、-OCH 3、-OCH 2CH 3、-NH(CH 3)、 -N(CH 3) 2、
    Figure PCTCN2019070227-appb-100010
    Figure PCTCN2019070227-appb-100011
    The compound according to claim 11, an isomer thereof or a pharmaceutically acceptable salt thereof, wherein R 3 is independently selected from the group consisting of H, F, Cl, Br, I, OH, NH 2 , CN, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -C(CH 3 ) 3 , -OCH 3 , -OCH 2 CH 3 , -NH(CH 3 ), -N (CH 3 ) 2 ,
    Figure PCTCN2019070227-appb-100010
    Figure PCTCN2019070227-appb-100011
  13. 根据权利要求1～4任意一项所述化合物、其异构体或其药学上可接受的盐，其中，L选自-NH-、-NHCH 2-、-NHCH(CH 3)-、-O-、-O-CH 2-或-NHC(＝O)-。 The compound according to any one of claims 1 to 4, an isomer thereof or a pharmaceutically acceptable salt thereof, wherein L is selected from the group consisting of -NH-, -NHCH 2 -, -NHCH(CH 3 )-, -O -, -O-CH 2 - or -NHC(=O)-.
  14. 根据权利要求1～4任意一项所述化合物、其异构体或其药学上可接受的盐，其中，环A选自苯基、吡啶基、嘧啶基、吡嗪基、哒嗪基、噻唑基、恶唑基、吡唑基、苯并[b]噻吩基、2,3-二氢-[1,4]二氧杂环己二烯并[2,3-b]吡啶基、苯并[d]噻唑基、环丁基、环戊基、环己基或环辛基。The compound according to any one of claims 1 to 4, an isomer thereof or a pharmaceutically acceptable salt thereof, wherein ring A is selected from the group consisting of phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiazole , oxazolyl, pyrazolyl, benzo[b]thienyl, 2,3-dihydro-[1,4]dioxan[2,3-b]pyridinyl, benzo [d]thiazolyl, cyclobutyl, cyclopentyl, cyclohexyl or cyclooctyl.
  15. 根据权利要求14所述化合物、其异构体或其药学上可接受的盐，其中，结构单元
    Figure PCTCN2019070227-appb-100012
    选自
    Figure PCTCN2019070227-appb-100013
    The compound according to claim 14, an isomer thereof or a pharmaceutically acceptable salt thereof, wherein the structural unit
    Figure PCTCN2019070227-appb-100012
    Selected from
    Figure PCTCN2019070227-appb-100013
  16. 根据权利要求1或15所述化合物、其异构体或其药学上可接受的盐，其中，结构单元
    Figure PCTCN2019070227-appb-100014
    选自
    Figure PCTCN2019070227-appb-100015
    The compound according to claim 1 or 15, an isomer thereof or a pharmaceutically acceptable salt thereof, wherein the structural unit
    Figure PCTCN2019070227-appb-100014
    Selected from
    Figure PCTCN2019070227-appb-100015
    Figure PCTCN2019070227-appb-100016
    Figure PCTCN2019070227-appb-100016
  17. 根据权利要求1所述化合物、其异构体或其药学上可接受的盐，其中，结构单元
    Figure PCTCN2019070227-appb-100017
    选自     The compound according to claim 1, an isomer thereof or a pharmaceutically acceptable salt thereof, wherein the structural unit
    Figure PCTCN2019070227-appb-100017
    Selected from
    Figure PCTCN2019070227-appb-100018
    Figure PCTCN2019070227-appb-100018
    Figure PCTCN2019070227-appb-100019
    Figure PCTCN2019070227-appb-100019
  18. 根据权利要1～4任意一项所述化合物、其异构体或其药学上可接受的盐，其中，结构单元
    Figure PCTCN2019070227-appb-100020
    选自
    Figure PCTCN2019070227-appb-100021
    The compound according to any one of claims 1 to 4, an isomer thereof, or a pharmaceutically acceptable salt thereof, wherein the structural unit
    Figure PCTCN2019070227-appb-100020
    Selected from
    Figure PCTCN2019070227-appb-100021
  19. 根据权利要1或7所述化合物、其异构体或其药学上可接受的盐，其中，结构单元
    Figure PCTCN2019070227-appb-100022
    选自
    Figure PCTCN2019070227-appb-100023
    The compound according to claim 1 or 7, an isomer thereof or a pharmaceutically acceptable salt thereof, wherein the structural unit
    Figure PCTCN2019070227-appb-100022
    Selected from
    Figure PCTCN2019070227-appb-100023
  20. 根据权利要1或9所述化合物、其异构体或其药学上可接受的盐，其中，结构单元
    Figure PCTCN2019070227-appb-100024
    选自
    Figure PCTCN2019070227-appb-100025
    The compound according to claim 1 or 9, an isomer thereof or a pharmaceutically acceptable salt thereof, wherein the structural unit
    Figure PCTCN2019070227-appb-100024
    Selected from
    Figure PCTCN2019070227-appb-100025
  21. 根据权利要求1～12任意一项所述化合物、其异构体或其药学上可接受的盐，其选自The compound according to any one of claims 1 to 12, an isomer thereof or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of
    Figure PCTCN2019070227-appb-100026
    Figure PCTCN2019070227-appb-100026
    Figure PCTCN2019070227-appb-100027
    Figure PCTCN2019070227-appb-100027
    其中，among them,
    f选自：1、2、3或4；f is selected from: 1, 2, 3 or 4;
    l选自：0或1；l selected from: 0 or 1;
    n、m、T、R 1～R 3如权利要求1～12所定义。 n, m, T, R 1 to R 3 are as defined in claims 1 to 12.
  22. 根据权利要求21所述化合物、其异构体或其药学上可接受的盐是The compound according to claim 21, an isomer thereof or a pharmaceutically acceptable salt thereof
    Figure PCTCN2019070227-appb-100028
    Figure PCTCN2019070227-appb-100028
    Figure PCTCN2019070227-appb-100029
    Figure PCTCN2019070227-appb-100029
    其中，among them,
    f选自：1、2、3或4；f is selected from: 1, 2, 3 or 4;
    l选自：0或1；l selected from: 0 or 1;
    T、R 1～R 3如权利要求1～12所定义。 T, R 1 to R 3 are as defined in claims 1 to 12.
  23. 下式所示化合物、其异构体或其药学上可接受的盐，其选自a compound represented by the formula: an isomer thereof, or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of
    Figure PCTCN2019070227-appb-100030
    Figure PCTCN2019070227-appb-100030
    Figure PCTCN2019070227-appb-100031
    Figure PCTCN2019070227-appb-100031
    Figure PCTCN2019070227-appb-100032
    Figure PCTCN2019070227-appb-100032
    Figure PCTCN2019070227-appb-100033
    Figure PCTCN2019070227-appb-100033
    Figure PCTCN2019070227-appb-100034
    Figure PCTCN2019070227-appb-100034
    Figure PCTCN2019070227-appb-100035
    Figure PCTCN2019070227-appb-100035
  24. 根据权利要求23所述化合物，其选自A compound according to claim 23 selected from the group consisting of
    Figure PCTCN2019070227-appb-100036
    Figure PCTCN2019070227-appb-100036
  25. 一种药物组合物，包括治疗有效量的根据权利要求1～24任意一项所述的化合物或其药学上可接受的盐作为活性成分以及药学上可接受的载体。A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, as an active ingredient, and a pharmaceutically acceptable carrier.
  26. 根据权利要求1～24任意一项所述的化合物或其药学上可接受的盐或者权利要求25的组合物在制备治疗与新型集落刺激因子-1受体抑制剂相关药物上的应用。The use of a compound according to any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, or a composition according to claim 25, for the manufacture of a medicament for the treatment of a novel colony stimulating factor-1 receptor inhibitor.
  27. 根据权利要求26所述的应用，其特征在于，所述与新型集落刺激因子-1受体抑制剂相关药物是用于治 疗肿瘤和自身免疫类疾病的药物。The use according to claim 26, wherein the drug associated with the novel colony stimulating factor-1 receptor inhibitor is a drug for treating a tumor and an autoimmune disease.
PCT/CN2019/070227 2018-01-03 2019-01-03 Isoindolinone and derivative thereof as csf-1r inhibitor WO2019134661A1 (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3738961A4 (en) * 2018-01-03 2021-06-30 Medshine Discovery Inc. Heterocyclic compound as csf-1r inhibitor and use thereof
WO2023125896A1 (en) * 2021-12-31 2023-07-06 海思科医药集团股份有限公司 Glp-1 agonist intermediate, preparation method therefor, and use thereof in medicine

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7129260B2 (en) * 2003-06-02 2006-10-31 Abbott Laboratories Isoindolinone kinase inhibitors
WO2013052394A1 (en) * 2011-10-05 2013-04-11 Merck Sharp & Dohme Corp. 2-pyridyl carboxamide-containing spleen tyrosine kinase (syk) inhibitors
CN104583199A (en) * 2012-06-26 2015-04-29 色品疗法有限公司 2-aminopyrazine derivatives as CSF-1R kinase inhibitors
CN105712974A (en) * 2010-04-23 2016-06-29 赛特凯恩蒂克公司 Certain Amino-Pyridazines, Compositions Thereof, And Methods Of Their Use

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7129260B2 (en) * 2003-06-02 2006-10-31 Abbott Laboratories Isoindolinone kinase inhibitors
CN105712974A (en) * 2010-04-23 2016-06-29 赛特凯恩蒂克公司 Certain Amino-Pyridazines, Compositions Thereof, And Methods Of Their Use
WO2013052394A1 (en) * 2011-10-05 2013-04-11 Merck Sharp & Dohme Corp. 2-pyridyl carboxamide-containing spleen tyrosine kinase (syk) inhibitors
CN104583199A (en) * 2012-06-26 2015-04-29 色品疗法有限公司 2-aminopyrazine derivatives as CSF-1R kinase inhibitors

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3738961A4 (en) * 2018-01-03 2021-06-30 Medshine Discovery Inc. Heterocyclic compound as csf-1r inhibitor and use thereof
US11384065B2 (en) 2018-01-03 2022-07-12 Medshine Discovery Inc. Heterocyclic compound as CSF-1R inhibitor and use thereof
WO2023125896A1 (en) * 2021-12-31 2023-07-06 海思科医药集团股份有限公司 Glp-1 agonist intermediate, preparation method therefor, and use thereof in medicine

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