WO2021129827A1 - Benzo fused ring-based compound - Google Patents

Benzo fused ring-based compound Download PDF

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Publication number
WO2021129827A1
WO2021129827A1 PCT/CN2020/139562 CN2020139562W WO2021129827A1 WO 2021129827 A1 WO2021129827 A1 WO 2021129827A1 CN 2020139562 W CN2020139562 W CN 2020139562W WO 2021129827 A1 WO2021129827 A1 WO 2021129827A1
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compound
added
ethyl acetate
alkyl
group
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PCT/CN2020/139562
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French (fr)
Chinese (zh)
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李鹏
杨亚讯
张建臣
贺海鹰
刘金鑫
胡国平
黎健
陈曙辉
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南京明德新药研发有限公司
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Priority to CN202080089752.3A priority Critical patent/CN114846001B/en
Publication of WO2021129827A1 publication Critical patent/WO2021129827A1/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
    • A61K31/66—Phosphorus compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/38—Nitrogen atoms
    • C07D277/44—Acylated amino or imino radicals
    • C07D277/46—Acylated amino or imino radicals by carboxylic acids, or sulfur or nitrogen analogues thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
    • C07F9/6571—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms

Definitions

  • the present invention relates to a class of benzo-fused ring compounds. Specifically, it relates to the compound represented by formula (IV), its isomers and pharmaceutically acceptable salts thereof.
  • Thyroid hormone is produced by the thyroid gland and is secreted into the circulatory system (hypothalamus/pituitary/thyroid system) in two different forms: 3,5,3',5'-tetraiodo-L-thyroid Protoine (T4) and 3,5,3'-Triiodo-L-thyronine (T3).
  • T4 is the main form secreted by the thyroid
  • T3 is the more active form of physiological increase.
  • T4 is converted into T3 by tissue-specific deiodinase, which is present in all tissues, but mainly in liver and kidney.
  • TRs thyroid receptors
  • TRs are encoded by different genes ⁇ and ⁇ located on human chromosomes 17 and 3 respectively. Different protein subtypes are produced by selective splicing of primary transcripts. Each gene produces two subtypes, namely TR ⁇ 1 and TR ⁇ 2. , TR ⁇ 1, TR ⁇ 2.
  • TR ⁇ 1 and TR ⁇ 2 are differentially expressed by promoters, and these two subtypes differ only at the amino terminus.
  • TR ⁇ 1 and TR ⁇ 2 come from the differential splicing of the precursor mRNA, and there are differences mainly in the carboxyl terminal. Among them, TR ⁇ 1, TR ⁇ 1 and TR ⁇ 2 can be combined with thyroid hormones. It has been shown that thyroid hormone receptor subtypes can differ in their contribution to specific physiological responses.
  • TR ⁇ 1 plays an important role in the regulation of thyroid stimulating hormone nuclear regulation of thyroid hormone in the liver; TR ⁇ 2 plays a major role in regulating thyroid stimulating hormone.
  • Thyroid hormone has the effect of lowering serum low-density lipoprotein (LDL). Hyperthyroidism is associated with low total serum cholesterol, which is due to thyroid hormones increasing liver LDL receptor expression and stimulating the metabolism of cholesterol to bile acids. Thyroid hormones can also reduce the risk of atherosclerosis and other cardiovascular diseases. Thyroid hormones have beneficial effects on obese patients by increasing metabolic rate, oxygen consumption and heat release, thereby reducing body weight and improving obesity-related comorbidities.
  • LDL serum low-density lipoprotein
  • thyroid analogs that maintain the beneficial effects of thyroid hormone will open up new ways to treat diseases: metabolic diseases such as obesity, hyperlipidemia, hypercholesterolemia, diabetes and others Diseases such as steatosis and non-alcoholic steatohepatitis (NASH), atherosclerosis and other related diseases and diseases.
  • metabolic diseases such as obesity, hyperlipidemia, hypercholesterolemia, diabetes and others
  • Diseases such as steatosis and non-alcoholic steatohepatitis (NASH), atherosclerosis and other related diseases and diseases.
  • NASH non-alcoholic steatohepatitis
  • the present invention provides a compound represented by formula (IV), an isomer thereof or a pharmaceutically acceptable salt thereof, which is selected from:
  • R 1 is selected from H, halogen, OH, NHR a , C 1-3 alkyl and C 1-3 alkoxy.
  • the C 1-3 alkyl and C 1-3 alkoxy are optionally selected by 1, 2 Or 3 halogen substitutions;
  • R 2 is selected from H, halogen, OH, NHR a , C 1-3 alkyl, C 1-3 alkoxy and C 3-6 cycloalkyl, the C 1-3 alkyl, C 1-3 alkane
  • the oxy group and the C 3-6 cycloalkyl group are optionally substituted with 1, 2 or 3 halogens;
  • R 3 , R 4 and R 5 are each independently selected from H, halogen, OH, NHR a , C 1-3 alkyl, C 1-3 alkoxy, C 3-6 cycloalkyl and 4-6 membered hetero Cycloalkyl, the C 1-3 alkyl, C 1-3 alkoxy, C 3-6 cycloalkyl and 4-6 membered heterocycloalkyl are optionally substituted with 1, 2 or 3 R;
  • Each R is independently selected from halogen or C 1-3 alkyl
  • L 1 is selected from -(CR b R c ) m -, -NH(CR b R c ) m -, -O(CR b R c ) m -, C 3-6 cycloalkyl and 3-6 membered heterocyclic ring alkyl;
  • E 1 and E 2 are independently selected from -(CR b R c ) n -, NR a and O;
  • R a is selected from H, C 1-3 alkyl, -COCH 3 and -SO 2 R';
  • R b and R c are independently selected from H, C 1 ⁇ 3 alkyl group and a C 1-3 alkoxy group, a C 1-3 alkyl group and a C 1-3 alkoxy group optionally substituted with 1, 2 or 3 halogen substitutions; alternatively, R 1 and R b or R c and the carbon atoms connected together form a cyclopropyl group;
  • R b and R c and the carbon atoms connected together form a cyclopropyl group
  • R' is selected from a C 1-3 alkyl group, and the C 1-3 alkyl group is optionally substituted with 1, 2 or 3 halogens;
  • n is each independently selected from 0, 1 and 2;
  • n is selected from 1 and 2;
  • X is selected from -PO(OH) 2 , -P(O)[-OC(R d ) 2 OC(O)R e ] 2 , -P(O)[-OC(R d ) 2 OC(O)OR e ] 2 , -P(O)[-N(H)C(R d ) 2 C(O)OR e ][-OR e ], -P(O)[-N(H)C(R d ) 2 C(O)OR e ] 2 and
  • V is selected from a C 6-10 aryl group and a 5-10 membered heteroaryl group, the C 6-10 aryl group and a 5-10 membered heteroaryl group are optionally substituted by 1, 2 or 3 halogens;
  • Each R d and R e is independently selected from H;
  • Each R e is independently selected from a C 1-4 alkyl group and a C 6-10 aryl group, the C 1-4 alkyl group and C 6-10 aryl group are optionally substituted with 1, 2 or 3 halogens;
  • hetero includes 1, 2 or 3 heteroatoms or heteroatom groups independently selected from -O-, -NH-, -S- and N.
  • the above-mentioned R 1 is selected from H, F, OH, NH 2 , C 1-3 alkyl and C 1-3 alkoxy, the C 1-3 alkyl and C 1-3 alkane
  • the oxy group is optionally substituted with 1, 2 or 3 halogens, and other variables are as defined in the present invention.
  • R 1 is selected from H, F, OH, NH 2 and CH 3 , and other variables are as defined in the present invention.
  • R 2 is selected from H, F, Cl, Br, NH 2 , C 1-3 alkyl and cyclopropyl, and the C 1-3 alkyl is optionally selected by 1, 2 or 3 Replace with F, and other variables are as defined in the present invention.
  • R 2 is selected from Cl, Br, CH 3 , CF 3 and cyclopropyl, and other variables are as defined in the present invention.
  • each R above is independently selected from F and CH 3 , and other variables are as defined in the present invention.
  • R 3 , R 4 and R 5 are each independently selected from H, halogen, OH, NH 2 , C 1-3 alkyl, C 3-6 cycloalkyl and 4-6 membered hetero Cycloalkyl, the C 1-3 alkyl, C 3-6 cycloalkyl and 4-6 membered heterocycloalkyl are optionally substituted with 1, 2 or 3 R, and other variables are as defined in the present invention.
  • R 3 , R 4 and R 5 are each independently selected from H, F, Cl, OH, CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , Other variables are as defined in the present invention.
  • the aforementioned L 1 is selected from -(CH 2 ) m -, -NH(CH 2 ) m -and -O(CH 2 ) m -, and other variables are as defined in the present invention.
  • the aforementioned L 1 is selected from -CH 2 -, -(CH 2 ) 2 -, -NHCH 2 -and -OCH 2 -, and other variables are as defined in the present invention.
  • the above-mentioned V is selected from a phenyl group, and the phenyl group is optionally substituted with 1, 2 or 3 halogens, and other variables are as defined in the present invention.
  • R e is selected from -CH 3, -CH 2 CH 3, -CH (CH 3) 2, -C (CH 3) 3 , and phenyl, the other variables are as defined in the present invention.
  • the above-mentioned X is selected from -PO(OH) 2 , -P(O)[-OCH 2 OC(O)-tert-butyl] 2 , -P(O)[-OCH 2 OC(O )O-isopropyl] 2 , -P(O)[-N(H)CH(CH 3 )C(O)OCH 2 CH 3 ] 2 , -P(O)[-N(H)C(CH 3 ) 2 C(O)OCH 2 CH 3 ] 2 ⁇
  • Other variables are as defined in the present invention.
  • the above-mentioned X is selected from -PO(OH) 2 ,
  • Other variables are as defined in the present invention.
  • the present invention provides a compound represented by formula (I), an isomer thereof or a pharmaceutically acceptable salt thereof, which is selected from:
  • R 1 is selected from H, halogen, OH, NHR a , C 1-3 alkyl and C 1-3 alkoxy.
  • the C 1-3 alkyl and C 1-3 alkoxy are optionally selected by 1, 2 Or 3 halogen substitutions;
  • R 2 is selected from H, halogen, OH, NHR a , C 1-3 alkyl and C 1-3 alkoxy.
  • the C 1-3 alkyl and C 1-3 alkoxy are optionally selected by 1, 2 Or 3 halogen substitutions;
  • R 3, R 4 and R 5 are each independently selected from H, halo, OH, NHR a, C 1-3 alkyl group and a C 1-3 alkoxy group, a C 1-3 alkyl and C 1- 3 Alkoxy is optionally substituted with 1, 2 or 3 halogens;
  • L 1 is selected from -(CR b R c ) m -, -NH(R b R c ) m -, -O(R b R c ) m -, C 3-6 cycloalkyl and 3-6 membered heterocyclic ring alkyl;
  • E 1 and E 2 are each independently selected from -CR b R c -, NR a and O;
  • R a is selected from H, C 1-3 alkyl, -COCH 3 and -SO 2 R;
  • R b and R c each independently selected from H, C 1 ⁇ 3 alkyl group and a C 1-3 alkoxy group, a C 1-3 alkyl group and a C 1-3 alkoxy group optionally substituted with 1, 2 or 3 halogen substitutions;
  • R is selected from a C 1-3 alkyl group, and the C 1-3 alkyl group is optionally substituted with 1, 2 or 3 halogens;
  • n 0, 1 and 2;
  • X is selected from -PO(OH) 2 , -P(O)[-OC(R d ) 2 OC(O)R e ] 2 , -P(O)[-OC(R d ) 2 OC(O)OR e ] 2 , -P(O)[-N(H)C(R d ) 2 C(O)OR e ] 2 and
  • V is selected from a C 6-10 aryl group and a 5-10 membered heteroaryl group, the C 6-10 aryl group and a 5-10 membered heteroaryl group are optionally substituted by 1, 2 or 3 halogens;
  • Each R d and R e is independently selected from H;
  • Each R e is independently selected from a C 1-4 alkyl group and a C 6-10 aryl group, the C 1-4 alkyl group and C 6-10 aryl group are optionally substituted with 1, 2 or 3 halogens;
  • hetero includes 1, 2 or 3 heteroatoms independently selected from O, S and N.
  • the above-mentioned R 1 is selected from H, F, OH, NH 2 , C 1-3 alkyl and C 1-3 alkoxy, the C 1-3 alkyl and C 1-3 alkane
  • the oxy group is optionally substituted with 1, 2 or 3 halogens, and other variables are as defined in the present invention.
  • R 1 is selected from H, F, OH, NH 2 and CH 3 , and other variables are as defined in the present invention.
  • the above-mentioned R 2 is selected from H, halogen and C 1-3 alkyl, and the C 1-3 alkyl is optionally substituted by 1, 2 or 3 halogens, and other variables are as defined in the present invention. definition.
  • R 2 is selected from H, F, Cl, Br and C 1-3 alkyl groups, and other variables are as defined in the present invention.
  • R 3 , R 4 and R 5 are each independently selected from H, halogen, OH and C 1-3 alkyl, and the C 1-3 alkyl is optionally selected by 1, 2 or 3 One halogen is substituted, and other variables are as defined in the present invention.
  • R 3 , R 4 and R 5 are each independently selected from H, F, Cl, OH, CH 3 , CH 2 CH 3 and CH(CH 3 ) 2 , and other variables are as defined in the present invention definition.
  • the aforementioned L 1 is selected from -(CH 2 ) m -, -NH(CH 2 ) m -and -O(CH 2 ) m -, and other variables are as defined in the present invention.
  • the aforementioned L 1 is selected from -CH 2 -, -(CH 2 ) 2 -, -NHCH 2 -and -OCH 2 -, and other variables are as defined in the present invention.
  • E 1 and E 2 are each independently selected from -CH 2 -, NH and O, and other variables are as defined in the present invention.
  • E 1 and E 2 are each independently selected from -CH 2 -, and other variables are as defined in the present invention.
  • the above-mentioned X is selected from -PO(OH) 2 , -P(O)[-OCH 2 OC(O)-tert-butyl] 2 , -P(O)[-OCH 2 OC(O )O-isopropyl] 2 , -P(O)[-N(H)CH(CH 3 )C(O)OCH 2 CH 3 ] 2 , -P(O)[-N(H)C(CH 3 ) 2 C(O)OCH 2 CH 3 ] 2 and Other variables are as defined in the present invention.
  • the above-mentioned X is selected from -PO(OH) 2 and Other variables are as defined in the present invention.
  • the present invention provides a compound represented by the following formula, an isomer thereof or a pharmaceutically acceptable salt thereof, which is selected from:
  • R 1 is selected from H, halogen, OH, NHR a , C 1-3 alkyl and C 1-3 alkoxy.
  • the C 1-3 alkyl and C 1-3 alkoxy are optionally selected by 1, 2 Or 3 halogen substitutions;
  • R 2 is selected from H, halogen, OH, NHR a , C 1-3 alkyl and C 1-3 alkoxy.
  • the C 1-3 alkyl and C 1-3 alkoxy are optionally selected by 1, 2 Or 3 halogen substitutions;
  • R 3, R 4 and R 5 are each independently selected from H, halo, OH, NHR a, C 1-3 alkyl group and a C 1-3 alkoxy group, a C 1-3 alkyl and C 1- 3 Alkoxy is optionally substituted with 1, 2 or 3 halogens;
  • L 1 is selected from -(CR b R c ) m -, -NH(R b R c ) m -, -O(R b R c ) m -, C 3-6 cycloalkyl and 3-6 membered heterocyclic ring alkyl;
  • E 1 and E 2 are each independently selected from -(CR b R c ) n -, NR a and O;
  • R a is selected from H, C 1-3 alkyl, -COCH 3 and -SO 2 R;
  • R b and R c each independently selected from H, C 1 ⁇ 3 alkyl group and a C 1-3 alkoxy group, a C 1-3 alkyl group and a C 1-3 alkoxy group optionally substituted with 1, 2 or 3 halogen substitutions;
  • R is selected from a C 1-3 alkyl group, and the C 1-3 alkyl group is optionally substituted with 1, 2 or 3 halogens;
  • n 0, 1 and 2;
  • n is selected from 1 and 2;
  • X is selected from -PO(OH) 2 , -P(O)[-OC(R d ) 2 OC(O)R e ] 2 , -P(O)[-OC(R d ) 2 OC(O)OR e ] 2 , -P(O)[- N(H)C(R d ) 2 C(O)OR e ] 2 and
  • V is selected from a C 6-10 aryl group and a 5-10 membered heteroaryl group, the C 6-10 aryl group and a 5-10 membered heteroaryl group are optionally substituted by 1, 2 or 3 halogens;
  • Each R d and R e is independently selected from H;
  • Each R e is independently selected from a C 1-4 alkyl group and a C 6-10 aryl group, the C 1-4 alkyl group and C 6-10 aryl group are optionally substituted with 1, 2 or 3 halogens;
  • hetero includes 1, 2 or 3 heteroatoms independently selected from O, S and N.
  • the above-mentioned R 1 is selected from H, F, OH, NH 2 , C 1-3 alkyl and C 1-3 alkoxy, the C 1-3 alkyl and C 1-3 alkane
  • the oxy group is optionally substituted with 1, 2 or 3 halogens, and other variables are as defined in the present invention.
  • R 1 is selected from H, F, OH, NH 2 and CH 3 , and other variables are as defined in the present invention.
  • the above-mentioned R 2 is selected from H, halogen and C 1-3 alkyl, and the C 1-3 alkyl is optionally substituted by 1, 2 or 3 halogens, and other variables are as defined in the present invention. definition.
  • R 2 is selected from H, F, Cl, Br and C 1-3 alkyl groups, and other variables are as defined in the present invention.
  • R 2 is selected from methyl, and other variables are as defined in the present invention.
  • R 3 , R 4 and R 5 are each independently selected from H, halogen, OH and C 1-3 alkyl, and the C 1-3 alkyl is optionally selected by 1, 2 or 3 One halogen is substituted, and other variables are as defined in the present invention.
  • R 3 , R 4 and R 5 are each independently selected from H, F, Cl, OH, CH 3 , CH 2 CH 3 and CH(CH 3 ) 2 , and other variables are as defined in the present invention definition.
  • the aforementioned L 1 is selected from -(CH 2 ) m -, -NH(CH 2 ) m -and -O(CH 2 ) m -, and other variables are as defined in the present invention.
  • the aforementioned L 1 is selected from -CH 2 -, -(CH 2 ) 2 -, -NHCH 2 -and -OCH 2 -, and other variables are as defined in the present invention.
  • E 1 and E 2 are each independently selected from -CH 2 -, -CH 2 CH 2 -, NH and O, and other variables are as defined in the present invention.
  • E 1 and E 2 are each independently selected from -CH 2 -and -CH 2 CH 2 -, and other variables are as defined in the present invention.
  • the above-mentioned X is selected from -PO(OH) 2 , -P(O)[-OCH 2 OC(O)-tert-butyl] 2 , -P(O)[-OCH 2 OC(O )O-isopropyl] 2 , -P(O)[-N(H)CH(CH 3 )C(O)OCH 2 CH 3 ] 2 , -P(O)[-N(H)C(CH 3 ) 2 C(O)OCH 2 CH 3 ] 2 and Other variables are as defined in the present invention.
  • the above-mentioned X is selected from -PO(OH) 2 and Other variables are as defined in the present invention.
  • the present invention provides a compound represented by formula (IV), an isomer thereof or a pharmaceutically acceptable salt thereof, which is selected from:
  • R 1 is selected from H, halogen, OH, NHR a , C 1-3 alkyl and C 1-3 alkoxy.
  • the C 1-3 alkyl and C 1-3 alkoxy are optionally selected by 1, 2 Or 3 halogen substitutions;
  • R 2 is selected from H, halogen, OH, NHR a , C 1-3 alkyl and C 1-3 alkoxy.
  • the C 1-3 alkyl and C 1-3 alkoxy are optionally selected by 1, 2 Or 3 halogen substitutions;
  • R 3 , R 4 and R 5 are each independently selected from H, halogen, OH, NHR a , C 1-3 alkyl, C 1-3 alkoxy and C 3-6 cycloalkyl, the C 1- 3 alkyl, C 1-3 alkoxy and C 3-6 cycloalkyl are optionally substituted with 1, 2 or 3 halogens;
  • L 1 is selected from -(CR b R c ) m -, -NH(CR b R c ) m -, -O(CR b R c ) m -, C 3-6 cycloalkyl and 3-6 membered heterocyclic ring alkyl;
  • E 1 and E 2 are each independently selected from -(CR b R c ) n -, NR a and O;
  • R a is selected from H, C 1-3 alkyl, -COCH 3 and -SO 2 R;
  • R b and R c each independently selected from H, C 1 ⁇ 3 alkyl group and a C 1-3 alkoxy group, a C 1-3 alkyl group and a C 1-3 alkoxy group optionally substituted with 1, 2 or 3 halogen substitutions;
  • R is selected from a C 1-3 alkyl group, and the C 1-3 alkyl group is optionally substituted with 1, 2 or 3 halogens;
  • n is each independently selected from 0, 1 and 2;
  • n is selected from 1 and 2;
  • X is selected from -PO(OH) 2 , -P(O)[-OC(R d ) 2 OC(O)R e ] 2 , -P(O)[-OC(R d ) 2 OC(O)OR e ] 2 , -P(O)[-N(H)C(R d ) 2 C(O)OR e ] 2 and
  • V is selected from a C 6-10 aryl group and a 5-10 membered heteroaryl group, the C 6-10 aryl group and a 5-10 membered heteroaryl group are optionally substituted by 1, 2 or 3 halogens;
  • Each R d and R e is independently selected from H;
  • Each R e is independently selected from a C 1-4 alkyl group and a C 6-10 aryl group, the C 1-4 alkyl group and C 6-10 aryl group are optionally substituted with 1, 2 or 3 halogens;
  • hetero includes 1, 2 or 3 heteroatoms independently selected from O, S and N.
  • the above-mentioned R 1 is selected from H, F, OH, NH 2 , C 1-3 alkyl and C 1-3 alkoxy, the C 1-3 alkyl and C 1-3 alkane
  • the oxy group is optionally substituted with 1, 2 or 3 halogens, and other variables are as defined in the present invention.
  • R 1 is selected from H, F, OH, NH 2 and CH 3 , and other variables are as defined in the present invention.
  • the above-mentioned R 2 is selected from H, halogen and C 1-3 alkyl, and the C 1-3 alkyl is optionally substituted by 1, 2 or 3 halogens, and other variables are as defined in the present invention. definition.
  • the above-mentioned R 2 is selected from H, F, Cl, Br, and C 1-3 alkyl groups, the C 1-3 alkyl groups are optionally substituted by 1, 2 or 3 F, and other variables such as Defined by the present invention.
  • R 2 is selected from Cl, Br, CH 3 and CF 3 , and other variables are as defined in the present invention.
  • R 3 , R 4 and R 5 are each independently selected from H, halogen, OH, NH 2 , C 1-3 alkyl and C 3-6 cycloalkyl, and the C 1-
  • the 3 alkyl group and C 3-6 cycloalkyl group are optionally substituted with 1, 2 or 3 halogens, and other variables are as defined in the present invention.
  • R 3 , R 4 and R 5 are each independently selected from H, F, Cl, OH, CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , Other variables are as defined in the present invention.
  • the aforementioned L 1 is selected from -(CH 2 ) m -, -NH(CH 2 ) m -and -O(CH 2 ) m -, and other variables are as defined in the present invention.
  • the aforementioned L 1 is selected from -CH 2 -, -(CH 2 ) 2 -, -NHCH 2 -and -OCH 2 -, and other variables are as defined in the present invention.
  • E 1 and E 2 are each independently selected from -CH 2 -, -CH 2 CH 2 -, NH and O, and other variables are as defined in the present invention.
  • E 1 and E 2 are each independently selected from -CH 2 -and -CH 2 CH 2 -, and other variables are as defined in the present invention.
  • the above-mentioned X is selected from -PO(OH) 2 , -P(O)[-OCH 2 OC(O)-tert-butyl] 2 , -P(O)[-OCH 2 OC(O )O-isopropyl] 2 , -P(O)[-N(H)CH(CH 3 )C(O)OCH 2 CH 3 ] 2 , -P(O)[-N(H)C(CH 3 ) 2 C(O)OCH 2 CH 3 ] 2 and Other variables are as defined in the present invention.
  • the above-mentioned X is selected from -PO(OH) 2 and Other variables are as defined in the present invention.
  • the present invention provides a compound represented by formula (IV), an isomer thereof or a pharmaceutically acceptable salt thereof, which is selected from:
  • R 1 is selected from H, halogen, OH, NHR a , C 1-3 alkyl and C 1-3 alkoxy.
  • the C 1-3 alkyl and C 1-3 alkoxy are optionally selected by 1, 2 Or 3 halogen substitutions;
  • R 2 is selected from H, halogen, OH, NHR a , C 1-3 alkyl and C 1-3 alkoxy.
  • the C 1-3 alkyl and C 1-3 alkoxy are optionally selected by 1, 2 Or 3 halogen substitutions;
  • R 3 , R 4 and R 5 are each independently selected from H, halogen, OH, NHR a , C 1-3 alkyl, C 1-3 alkoxy and C 3-6 cycloalkyl, the C 1- 3 alkyl groups, C 1-3 alkoxy groups and C 3-6 cycloalkyl groups are optionally substituted with 1, 2 or 3 halogens or C 1-3 alkyl groups;
  • L 1 is selected from -(CR b R c ) m -, -NH(CR b R c ) m -, -O(CR b R c ) m -, C 3-6 cycloalkyl and 3-6 membered heterocyclic ring alkyl;
  • E 1 and E 2 are each independently selected from -(CR b R c ) n -, NR a and O;
  • R a is selected from H, C 1-3 alkyl, -COCH 3 and -SO 2 R;
  • R b and R c each independently selected from H, C 1 ⁇ 3 alkyl group and a C 1-3 alkoxy group, a C 1-3 alkyl group and a C 1-3 alkoxy group optionally substituted with 1, 2 or 3 halogen substitutions;
  • R is selected from a C 1-3 alkyl group, and the C 1-3 alkyl group is optionally substituted with 1, 2 or 3 halogens;
  • n is each independently selected from 0, 1 and 2;
  • n is selected from 1 and 2;
  • X is selected from -PO(OH) 2 , -P(O)[-OC(R d ) 2 OC(O)R e ] 2 , -P(O)[-OC(R d ) 2 OC(O)OR e ] 2 , -P(O)[-N(H)C(R d ) 2 C(O)OR e ] 2 and
  • V is selected from a C 6-10 aryl group and a 5-10 membered heteroaryl group, the C 6-10 aryl group and a 5-10 membered heteroaryl group are optionally substituted by 1, 2 or 3 halogens;
  • Each R d and R e is independently selected from H;
  • Each R e is independently selected from a C 1-4 alkyl group and a C 6-10 aryl group, the C 1-4 alkyl group and C 6-10 aryl group are optionally substituted with 1, 2 or 3 halogens;
  • hetero includes 1, 2 or 3 heteroatoms independently selected from O, S and N.
  • the above-mentioned R 1 is selected from H, F, OH, NH 2 , C 1-3 alkyl and C 1-3 alkoxy, the C 1-3 alkyl and C 1-3 alkane
  • the oxy group is optionally substituted with 1, 2 or 3 halogens, and other variables are as defined in the present invention.
  • R 1 is selected from H, F, OH, NH 2 and CH 3 , and other variables are as defined in the present invention.
  • R 2 is selected from H, halogen and C 1-3 alkyl, and the C 1-3 alkyl is optionally substituted by 1, 2 or 3 halogens, and other variables are as defined in the present invention .
  • the above-mentioned R 2 is selected from H, F, Cl, Br, and C 1-3 alkyl groups, the C 1-3 alkyl groups are optionally substituted by 1, 2 or 3 F, and other variables such as Defined by the present invention.
  • R 2 is selected from Cl, Br, CH 3 and CF 3 , and other variables are as defined in the present invention.
  • R 3 , R 4 and R 5 are each independently selected from H, halogen, OH, NH 2 , C 1-3 alkyl and C 3-6 cycloalkyl, and the C 1-
  • the 3 alkyl group and C 3-6 cycloalkyl group are optionally substituted with 1, 2 or 3 F or methyl groups, and other variables are as defined in the present invention.
  • R 3 , R 4 and R 5 are each independently selected from H, F, Cl, OH, CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , Other variables are as defined in the present invention.
  • the aforementioned L 1 is selected from -(CH 2 ) m -, -NH(CH 2 ) m -and -O(CH 2 ) m -, and other variables are as defined in the present invention.
  • the aforementioned L 1 is selected from -CH 2 -, -(CH 2 ) 2 -, -NHCH 2 -and -OCH 2 -, and other variables are as defined in the present invention.
  • E 1 and E 2 are each independently selected from -CH 2 -, -CH 2 CH 2 -, NH and O, and other variables are as defined in the present invention.
  • E 1 and E 2 are each independently selected from -CH 2 -and -CH 2 CH 2 -, and other variables are as defined in the present invention.
  • the above-mentioned X is selected from -PO(OH) 2 , -P(O)[-OCH 2 OC(O)-tert-butyl] 2 , -P(O)[-OCH 2 OC(O )O-isopropyl] 2 , -P(O)[-N(H)CH(CH 3 )C(O)OCH 2 CH 3 ] 2 , -P(O)[-N(H)C(CH 3 ) 2 C(O)OCH 2 CH 3 ] 2 ⁇
  • Other variables are as defined in the present invention.
  • the above-mentioned X is selected from -PO(OH) 2 ,
  • Other variables are as defined in the present invention.
  • the present invention provides a compound represented by the following formula, an isomer thereof or a pharmaceutically acceptable salt thereof, which is selected from:
  • R 1 is selected from H, halogen, OH, NHR a , C 1-3 alkyl and C 1-3 alkoxy.
  • the C 1-3 alkyl and C 1-3 alkoxy are optionally selected by 1, 2 Or 3 halogen substitutions;
  • R 2 is selected from H, halogen, OH, NHR a , C 1-3 alkyl, C 1-3 alkoxy and C 3-6 cycloalkyl, the C 1-3 alkyl, C 1-3 alkane
  • the oxy group and the C 3-6 cycloalkyl group are optionally substituted with 1, 2 or 3 halogens;
  • R 3 , R 4 and R 5 are each independently selected from H, halogen, OH, NHR a , C 1-3 alkyl, C 1-3 alkoxy and C 3-6 cycloalkyl, the C 1- 3 alkyl, C 1-3 alkoxy and C 3-6 cycloalkyl are optionally substituted with 1, 2 or 3 R;
  • Each R is independently selected from halogen or C 1-3 alkyl
  • L 1 is selected from -(CR b R c ) m -, -NH(CR b R c ) m -, -O(CR b R c ) m -, C 3-6 cycloalkyl and 3-6 membered heterocyclic ring alkyl;
  • E 1 and E 2 are each independently selected from -(CR b R c ) n -, NR a and O;
  • R a is selected from H, C 1-3 alkyl, -COCH 3 and -SO 2 R;
  • R b and R c each independently selected from H, C 1 ⁇ 3 alkyl group and a C 1-3 alkoxy group, a C 1-3 alkyl group and a C 1-3 alkoxy group optionally substituted with 1, 2 or 3 halogen substitutions; alternatively, R 1 and R b or R c and the carbon atoms connected together form a cyclopropyl group;
  • R is selected from a C 1-3 alkyl group, and the C 1-3 alkyl group is optionally substituted with 1, 2 or 3 halogens;
  • n is each independently selected from 0, 1 and 2;
  • n is selected from 1 and 2;
  • X is selected from -PO(OH) 2 , -P(O)[-OC(R d ) 2 OC(O)R e ] 2 , -P(O)[-OC(R d ) 2 OC(O)OR e ] 2 , -P(O)[-N(H)C(R d ) 2 C(O)OR e ][-OR e ], -P(O)[-N(H)C(R d ) 2 C(O)OR e ] 2 and
  • V is selected from a C 6-10 aryl group and a 5-10 membered heteroaryl group, the C 6-10 aryl group and a 5-10 membered heteroaryl group are optionally substituted by 1, 2 or 3 halogens;
  • Each R d and R e is independently selected from H;
  • Each R e is independently selected from a C 1-4 alkyl group and a C 6-10 aryl group, the C 1-4 alkyl group and C 6-10 aryl group are optionally substituted with 1, 2 or 3 halogens;
  • hetero includes 1, 2 or 3 heteroatoms or heteroatom groups independently selected from -O-, -NH-, -S- and N.
  • the above-mentioned R 1 is selected from H, F, OH, NH 2 , C 1-3 alkyl and C 1-3 alkoxy, the C 1-3 alkyl and C 1-3 alkane
  • the oxy group is optionally substituted with 1, 2 or 3 halogens, and other variables are as defined in the present invention.
  • R 1 is selected from H, F, OH, NH 2 and CH 3 , and other variables are as defined in the present invention.
  • the above-mentioned R 2 is selected from H, halogen, C 1-3 alkyl and cyclopropyl, and the C 1-3 alkyl and cyclopropyl are optionally substituted by 1, 2 or 3 halogens.
  • Other variables are as defined in the present invention.
  • R 2 is selected from H, F, Cl, Br, C 1-3 alkyl and cyclopropyl, and the C 1-3 alkyl is optionally substituted by 1, 2 or 3 F ,
  • Other variables are as defined in the present invention.
  • R 2 is selected from Cl, Br, CH 3 , CF 3 and cyclopropyl, and other variables are as defined in the present invention.
  • R 3 , R 4 and R 5 are each independently selected from H, halogen, OH, NH 2 , C 1-3 alkyl and C 3-6 cycloalkyl, and the C 1-
  • the 3 alkyl group and C 3-6 cycloalkyl group are optionally substituted with 1, 2 or 3 F or methyl groups, and other variables are as defined in the present invention.
  • R 3 , R 4 and R 5 are each independently selected from H, F, Cl, OH, CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , Other variables are as defined in the present invention.
  • the aforementioned L 1 is selected from -(CH 2 ) m -, -NH(CH 2 ) m -and -O(CH 2 ) m -, and other variables are as defined in the present invention.
  • the aforementioned L 1 is selected from -CH 2 -, -(CH 2 ) 2 -, -NHCH 2 -and -OCH 2 -, and other variables are as defined in the present invention.
  • E 1 and E 2 are each independently selected from -CH 2 -, -CH 2 CH 2 -, NH and O, and other variables are as defined in the present invention.
  • E 1 and E 2 are each independently selected from -CH 2 -, -CH 2 CH 2 -and O, and other variables are as defined in the present invention.
  • the above-mentioned X is selected from -PO(OH) 2 , -P(O)[-OCH 2 OC(O)-tert-butyl] 2 , -P(O)[-OCH 2 OC(O )O-isopropyl] 2 , -P(O)[-N(H)CH(CH 3 )C(O)OCH 2 CH 3 ] 2 , -P(O)[-N(H)C(CH 3 ) 2 C(O)OCH 2 CH 3 ] 2 ⁇
  • Other variables are as defined in the present invention.
  • the above-mentioned X is selected from -PO(OH) 2 ,
  • Other variables are as defined in the present invention.
  • the present invention provides a compound represented by formula (IV), an isomer thereof or a pharmaceutically acceptable salt thereof, which is selected from:
  • R 1 is selected from H, halogen, OH, NHR a , C 1-3 alkyl and C 1-3 alkoxy.
  • the C 1-3 alkyl and C 1-3 alkoxy are optionally selected by 1, 2 Or 3 halogen substitutions;
  • R 2 is selected from H, halogen, OH, NHR a , C 1-3 alkyl, C 1-3 alkoxy and C 3-6 cycloalkyl, the C 1-3 alkyl, C 1-3 alkane
  • the oxy group and the C 3-6 cycloalkyl group are optionally substituted with 1, 2 or 3 halogens;
  • R 3 , R 4 and R 5 are each independently selected from H, halogen, OH, NHR a , C 1-3 alkyl, C 1-3 alkoxy and C 3-6 cycloalkyl, the C 1- 3 alkyl, C 1-3 alkoxy and C 3-6 cycloalkyl are optionally substituted with 1, 2 or 3 R;
  • Each R is independently selected from halogen or C 1-3 alkyl
  • L 1 is selected from -(CR b R c ) m -, -NH(CR b R c ) m -, -O(CR b R c ) m -, C 3-6 cycloalkyl and 3-6 membered heterocyclic ring alkyl;
  • E 1 and E 2 are independently selected from -(CR b R c ) n -, NR a and O;
  • R a is selected from H, C 1-3 alkyl, -COCH 3 and -SO 2 R';
  • R b and R c are independently selected from H, C 1 ⁇ 3 alkyl group and a C 1-3 alkoxy group, a C 1-3 alkyl group and a C 1-3 alkoxy group optionally substituted with 1, 2 or 3 halogen substitutions;
  • R 1 forms a cyclopropyl group with R b or R c and the carbon atoms connected together;
  • R b and R c and the carbon atoms connected together form a cyclopropyl group
  • R' is selected from a C 1-3 alkyl group, and the C 1-3 alkyl group is optionally substituted with 1, 2 or 3 halogens;
  • n is each independently selected from 0, 1 and 2;
  • n is selected from 1 and 2;
  • X is selected from -PO(OH) 2 , -P(O)[-OC(R d ) 2 OC(O)R e ] 2 , -P(O)[-OC(R d ) 2 OC(O)OR e ] 2 , -P(O)[-N(H)C(R d ) 2 C(O)OR e ][-OR e ], -P(O)[-N(H)C(R d ) 2 C(O)OR e ] 2 and
  • V is selected from a C 6-10 aryl group and a 5-10 membered heteroaryl group, the C 6-10 aryl group and a 5-10 membered heteroaryl group are optionally substituted by 1, 2 or 3 halogens;
  • Each R d and R e is independently selected from H;
  • Each R e is independently selected from a C 1-4 alkyl group and a C 6-10 aryl group, the C 1-4 alkyl group and C 6-10 aryl group are optionally substituted with 1, 2 or 3 halogens;
  • hetero includes 1, 2 or 3 heteroatoms or heteroatom groups independently selected from -O-, -NH-, -S- and N.
  • the above-mentioned R 1 is selected from H, F, OH, NH 2 , C 1-3 alkyl and C 1-3 alkoxy, the C 1-3 alkyl and C 1-3 alkane
  • the oxy group is optionally substituted with 1, 2 or 3 halogens, and other variables are as defined in the present invention.
  • R 1 is selected from H, F, OH, NH 2 and CH 3 , and other variables are as defined in the present invention.
  • R 2 is selected from H, F, Cl, Br, NH 2 , C 1-3 alkyl and cyclopropyl, and the C 1-3 alkyl is optionally selected by 1, 2 or 3 Replace with F, and other variables are as defined in the present invention.
  • R 2 is selected from Cl, Br, CH 3 , CF 3 and cyclopropyl, and other variables are as defined in the present invention.
  • each R above is independently selected from F and CH 3 , and other variables are as defined in the present invention.
  • R 3 , R 4 and R 5 are each independently selected from H, halogen, OH, NH 2 , C 1-3 alkyl and C 3-6 cycloalkyl, and the C 1-
  • the 3 alkyl group and C 3-6 cycloalkyl group are optionally substituted with 1, 2 or 3 R, and other variables are as defined in the present invention.
  • R 3 , R 4 and R 5 are each independently selected from H, F, Cl, OH, CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , Other variables are as defined in the present invention.
  • the aforementioned L 1 is selected from -(CH 2 ) m -, -NH(CH 2 ) m -and -O(CH 2 ) m -, and other variables are as defined in the present invention.
  • the aforementioned L 1 is selected from -CH 2 -, -(CH 2 ) 2 -, -NHCH 2 -and -OCH 2 -, and other variables are as defined in the present invention.
  • the above-mentioned V is selected from a phenyl group, and the phenyl group is optionally substituted with 1, 2 or 3 halogens, and other variables are as defined in the present invention.
  • R e is selected from -CH 3, -CH 2 CH 3, -CH (CH 3) 2, -C (CH 3) 3 , and phenyl, the other variables are as defined in the present invention.
  • the above-mentioned X is selected from -PO(OH) 2 , -P(O)[-OCH 2 OC(O)-tert-butyl] 2 , -P(O)[-OCH 2 OC(O )O-isopropyl] 2 , -P(O)[-N(H)CH(CH 3 )C(O)OCH 2 CH 3 ] 2 , -P(O)[-N(H)C(CH 3 ) 2 C(O)OCH 2 CH 3 ] 2 ⁇
  • Other variables are as defined in the present invention.
  • the above-mentioned X is selected from -PO(OH) 2 ,
  • Other variables are as defined in the present invention.
  • the above-mentioned compound, its isomer or pharmaceutically acceptable salt thereof is selected from
  • R 1 , R 2 , R 3 , R 4 , R 5 and L 1 are as defined in the present invention.
  • the present invention also provides the following compounds, isomers thereof, or pharmaceutically acceptable salts thereof:
  • the present invention also provides the above-mentioned compound, its isomer or pharmaceutically acceptable salt thereof, which is selected from
  • the present invention also provides the application of the above-mentioned compound, its isomer or pharmaceutically acceptable salt in the preparation of a medicine for the treatment of diseases related to THR- ⁇ agonists.
  • the above-mentioned THR- ⁇ agonist-related drugs are drugs for non-alcoholic steatohepatitis (NASH).
  • NASH non-alcoholic steatohepatitis
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms that are within the scope of reliable 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.
  • pharmaceutically acceptable salt refers to a salt of the compound of the present invention, which is prepared from a compound with specific substituents discovered in the present invention and a relatively non-toxic acid or base.
  • a base addition salt can be obtained by contacting the compound with a sufficient amount of base in a pure solution or a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salt or similar salts.
  • the acid addition salt can be obtained by contacting the compound with a sufficient amount of acid in a pure 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, hydrogen carbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts, the organic acid includes, for example, 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; also include salts of amino acids (such as arginine, etc.) , And salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain basic and
  • the pharmaceutically acceptable salt of the present invention can be synthesized from the parent compound containing acid or base by conventional chemical methods. In general, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of appropriate base or acid in water or organic solvent or a mixture of both.
  • C 1-3 alkyl is used to indicate a linear or branched saturated hydrocarbon group composed of 1 to 3 carbon atoms.
  • the C 1-3 alkyl group includes C 1-2 and C 2-3 alkyl groups, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or multivalent (such as methine) .
  • Examples of C 1-3 alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.
  • C 1-3 alkoxy refers to those alkyl groups containing 1 to 3 carbon atoms that are attached to the rest of the molecule through an oxygen atom.
  • the C 1-3 alkoxy group includes C 1-2 , C 2-3 , C 3 and C 2 alkoxy groups and the like.
  • Examples of C 1-3 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.
  • C 3-6 cycloalkyl means a saturated cyclic hydrocarbon group composed of 3 to 6 carbon atoms, which is a monocyclic and bicyclic ring system, and the C 3-6 cycloalkyl includes C 3-5 , C 4-5 and C 5-6 cycloalkyl, etc.; it can be monovalent, divalent or multivalent.
  • Examples of C 3-6 cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
  • 3-6 membered heterocycloalkyl by itself or in combination with other terms means a saturated cyclic group consisting of 3 to 6 ring atoms, with 1, 2, 3 or 4 ring atoms.
  • heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein nitrogen atoms are optionally quaternized, and nitrogen and sulfur heteroatoms can be optionally oxidized (ie, NO and S(O) p , p Is 1 or 2). It includes monocyclic and bicyclic ring systems, where the bicyclic ring system includes spiro, fused, and bridged rings.
  • a heteroatom may occupy the connection position of the heterocycloalkyl group with the rest of the molecule.
  • the 3-6 membered heterocycloalkyl group includes 4-6 membered, 5-6 membered, 4-membered, 5-membered and 6-membered heterocycloalkyl group.
  • Examples of 3-6 membered heterocycloalkyl include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl ( Including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2- Piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), Dioxanyl, dithiazinyl, isoxazolidinyl, isothiazolid
  • 4-6 membered heterocycloalkyl by itself or in combination with other terms means a saturated cyclic group consisting of 4 to 6 ring atoms, with 1, 2, 3 or 4 ring atoms.
  • heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein nitrogen atoms are optionally quaternized, and nitrogen and sulfur heteroatoms can be optionally oxidized (ie, NO and S(O) p , p Is 1 or 2). It includes monocyclic and bicyclic ring systems, where the bicyclic ring system includes spiro, fused, and bridged rings.
  • a heteroatom may occupy the connection position of the heterocycloalkyl group with the rest of the molecule.
  • the 4-6 membered heterocycloalkyl group includes 5-6 membered, 4-membered, 5-membered and 6-membered heterocycloalkyl groups.
  • 4-6 membered heterocycloalkyl examples include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl ( Including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2- Piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), Dioxanyl, dithiazinyl, isoxazolidinyl, isothiazolidin
  • C 6-10 aromatic ring and “C 6-10 aryl” in the present invention can be used interchangeably, and the term “C 6-10 aromatic ring” or “C 6-10 aryl” means A cyclic hydrocarbon group with a conjugated ⁇ -electron system composed of 6 to 10 carbon atoms, which can be a monocyclic, fused bicyclic or fused tricyclic system, in which each ring is aromatic. It may be monovalent, divalent or multivalent, and C 6-10 aryl groups include C 6-9 , C 9 , C 10 and C 6 aryl groups and the like. Examples of C 6-10 aryl groups include, but are not limited to, phenyl, naphthyl (including 1-naphthyl, 2-naphthyl, etc.).
  • 5-10 membered heteroaryl ring and “5-10 membered heteroaryl group” can be used interchangeably in the present invention.
  • the term “5-10 membered heteroaryl group” means a ring consisting of 5 to 10 A cyclic group composed of atoms with a conjugated ⁇ -electron system, wherein 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, and the rest are carbon atoms. It can be a monocyclic, fused bicyclic or fused tricyclic system, where each ring is aromatic.
  • the nitrogen and sulfur heteroatoms may optionally be oxidized (ie NO and S(O) p , p is 1 or 2).
  • the 5-10 membered heteroaryl group can be attached to the rest of the molecule through a heteroatom or a carbon atom.
  • the 5-10 membered heteroaryl groups include 5-8 membered, 5-7 membered, 5-6 membered, 5 membered and 6 membered heteroaryl groups and the like.
  • Examples of the 5-10 membered heteroaryl include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrrolyl, etc.) Azolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5- Oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl and 4H-1, 2,4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl and 5-isoxazolyl, etc.), thiazolyl (including 2-thi
  • halogen or halogen by itself or as part of another substituent represents a fluorine, chlorine, bromine or iodine atom.
  • the compounds of the present invention may exist in specific geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers Isomers, (D)-isomers, (L)-isomers, and their racemic mixtures and other mixtures, such as enantiomers or diastereomer-enriched mixtures, all of these mixtures belong to this Within the scope of the invention.
  • Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All these isomers and their mixtures are included in the scope of the present invention.
  • enantiomer or “optical isomer” refers to stereoisomers that are mirror images of each other.
  • cis-trans isomer or “geometric isomer” is caused by the inability to rotate freely because of double bonds or single bonds of ring-forming carbon atoms.
  • diastereomer refers to a stereoisomer in which the molecule has two or more chiral centers and the relationship between the molecules is non-mirror-image relationship.
  • wedge-shaped solid line keys And wedge-shaped dashed key Represents the absolute configuration of a three-dimensional center, with a straight solid line key And straight dashed key Indicates the relative configuration of the three-dimensional center, using wavy lines Represents a wedge-shaped solid line key Or wedge-shaped dashed key Or use wavy lines Represents a straight solid line key Or straight dashed key
  • the terms “enriched in one isomer”, “enriched in isomers”, “enriched in one enantiomer” or “enriched in enantiomers” refer to one of the isomers or pairs of
  • the content of the enantiomer is less than 100%, and the content of the isomer or enantiomer is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or 96% or greater, or 97% or greater, or 98% or greater, or 99% or greater, or 99.5% or greater, or 99.6% or greater, or 99.7% or greater, or 99.8% or greater, or greater than or equal 99.9%.
  • the term “isomer excess” or “enantiomeric excess” refers to the difference between the relative percentages of two isomers or two enantiomers. For example, if the content of one isomer or enantiomer is 90%, and the content of the other isomer or enantiomer is 10%, the isomer or enantiomeric excess (ee value) is 80% .
  • optically active (R)- and (S)-isomers and D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If you want to obtain an enantiomer of a compound of the present invention, it can be prepared by asymmetric synthesis or derivatization with chiral auxiliary agents, in which the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide pure The desired enantiomer.
  • the molecule when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), it forms a diastereomeric salt with a suitable optically active acid or base, and then passes through a conventional method known in the art The diastereoisomers are resolved, and then the pure enantiomers are recovered.
  • the separation of enantiomers and diastereomers is usually accomplished through the use of chromatography, which uses a chiral stationary phase and is optionally combined with chemical derivatization (for example, the formation of amino groups from amines). Formate).
  • the carbon atom with "*" in the structure is a chiral carbon atom and exists in the form of (R) or (S) single enantiomer or enriched in one enantiomer.
  • the compound of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms constituting the compound.
  • compounds can be labeled with radioisotopes, such as tritium ( 3 H), iodine-125 ( 125 I), or C-14 ( 14 C).
  • deuterium can be substituted for hydrogen to form deuterated drugs.
  • the bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon.
  • deuterated drugs can reduce toxic side effects and increase drug stability. , Enhance the efficacy, extend the biological half-life of drugs and other advantages. All changes in the isotopic composition of the compounds of the present invention, whether radioactive or not, are included in the scope of the present invention.
  • substituted means that any one or more hydrogen atoms on a specific atom are replaced by substituents, and may include deuterium and hydrogen variants, as long as the valence of the specific atom is normal and the substituted compound is stable of.
  • oxygen it means that two hydrogen atoms are replaced. Oxygen substitution does not occur on aromatic groups.
  • optionally substituted means that it can be substituted or unsubstituted. Unless otherwise specified, the type and number of substituents can be arbitrary on the basis that they can be chemically realized.
  • any variable such as R
  • its definition in each case is independent.
  • the group can optionally be substituted with up to two Rs, and R has independent options in each case.
  • combinations of substituents and/or variants thereof are only permitted if such combinations result in stable compounds.
  • linking group When the number of a linking group is 0, such as -(CRR) 0 -, it means that the linking group is a single bond.
  • the substituent can be bonded to any atom on the ring, for example, a structural unit It means that the substituent R can be substituted at any position on the cyclohexyl or cyclohexadiene.
  • substituents do not indicate which atom is connected to the substituted group, such substituents can be bonded via any atom.
  • a pyridyl group can pass through any one of the pyridine ring as a substituent. The carbon atom is attached to the substituted group.
  • the middle linking group L is -MW-, at this time -MW- can be formed by connecting ring A and ring B in the same direction as the reading order from left to right It can also be formed by connecting ring A and ring B in the opposite direction to the reading order from left to right
  • Combinations of the linking groups, substituents, and/or variants thereof are only permitted if such combinations result in stable compounds.
  • any one or more sites of the group can be connected to other groups through chemical bonds.
  • the connection method of the chemical bond is not positioned, and there is a H atom at the connectable site, when the chemical bond is connected, the number of H atoms at the site will correspondingly decrease with the number of chemical bonds connected to become the corresponding valence number ⁇ The group.
  • the chemical bond between the site and other groups can be a straight solid bond Straight dashed key Or wavy line Said.
  • the straight solid bond in OCH 3 means that it is connected to other groups through the oxygen atom in the group;
  • the straight dashed bond in indicates that the two ends of the nitrogen atom in the group are connected to other groups;
  • the wavy line in indicates that the phenyl group is connected to other groups through the 1 and 2 carbon atoms;
  • the number of atoms in a ring is generally defined as the number of ring members.
  • “5-7 membered ring” refers to a “ring” in which 5-7 atoms are arranged around.
  • 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 (such as acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl, such as tert-butoxycarbonyl (Boc) ; Arylmethyloxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethyloxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl (Tr), 1,1-di -(4'-Methoxyphenyl)methyl; silyl groups, such as trimethylsilyl (TMS) and tert-butyldi
  • hydroxy protecting group refers to a protecting group suitable for preventing side reactions of the hydroxyl group.
  • Representative hydroxy protecting groups include but are not limited to: alkyl groups, such as methyl, ethyl, and tert-butyl; acyl groups, such as alkanoyl groups (such as acetyl); arylmethyl groups, such as benzyl (Bn), p-methyl Oxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyl Dimethylsilyl (TBS) and so on.
  • alkyl groups such as methyl, ethyl, and tert-butyl
  • acyl groups such as alkanoyl groups (such as acetyl)
  • arylmethyl groups such as benzyl (Bn), p-methyl Oxybenzyl (P
  • 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 listed below, the embodiments formed by combining them with other chemical synthesis methods, and those well known to those skilled in the art Equivalent alternatives, preferred implementations include but are not limited to the embodiments of the present invention.
  • the structure of the compound of the present invention can be confirmed by conventional methods well known to those skilled in the art. If the present invention relates to the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the field.
  • SXRD single crystal X-ray diffraction
  • the cultured single crystal is collected with the Bruker D8 venture diffractometer to collect the diffraction intensity data
  • the light source is CuK ⁇ radiation
  • the scanning method After scanning and collecting relevant data, the direct method (Shelxs97) is further used to analyze the crystal structure to confirm the absolute configuration.
  • the solvent used in the present invention is commercially available.
  • aq stands for water
  • HATU O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethylurea hexafluorophosphonium salt
  • eq stands for equivalent and equivalent
  • ACN stands for acetonitrile
  • DCM stands for dichloromethane
  • PE stands for petroleum ether
  • DMSO stands for dimethyl sulfoxide
  • EtOAc stands for ethyl acetate
  • EtOH stands for ethanol
  • MeOH stands for methanol
  • Cbz stands for benzyloxycarbonyl, yes An amine protecting group
  • Boc represents tert-butoxycarbonyl is an amine protecting group
  • MOM represents methoxymethyl
  • DEA diethylamine
  • rt represents room temperature
  • O/N represents overnight
  • THF represents tetrahydrofuran
  • Boc 2 O stands for di-tert-butyl dicarbonate
  • TFA trifluoroace
  • the compound of the present invention has strong agonistic activity on thyroid receptor ⁇ .
  • the compound of the present invention has good bioavailability, high exposure in the liver, low exposure in plasma and heart, and good liver targeting.
  • the non-alcoholic fatty liver disease activity score improved significantly.
  • Figure 1 is an ellipsoid diagram of the molecular structure of compound 6 acetonate.
  • Fig. 2 is a unit cell packing diagram of compound 6 acetonate along the b-axis.
  • Figure 3 is the absolute configuration diagram of the compound of compound 6 acetonate.
  • Figures 4a and 4b are schematic diagrams of liver weight changes and liver-to-body ratios of NASH model mice induced by HFD-CCl 4 administration of compound 6 (Note: The NASH group is used as a control, and the data are displayed as mean ⁇ standard deviation. * indicates statistics Differences in science, ***p ⁇ 0.001, **p ⁇ 0.01, *p ⁇ 0.05).
  • FIGS 5a and 5b are schematic diagrams of liver histopathological analysis of NASH model mice induced by HFD-CCl 4 given compound 6 (Note: The NASH group is used as a control, and the data are shown as mean ⁇ standard deviation. * indicates statistical difference, ***p ⁇ 0.001, **p ⁇ 0.01, *p ⁇ 0.05.
  • Figures 6a and 6b are schematic diagrams of liver weight changes and liver-to-body ratios in NASH model mice induced by HFD-CCl 4 administration of compound 6 and compound 36.
  • Figures 7a and 7b are schematic diagrams of liver tissue pathological analysis of NASH model mice induced by HFD-CCl 4 administered with compound 6 and compound 36.
  • Dissolve compound 1-13 (0.08g, 184.98 ⁇ mol) in dichloromethane (5mL), reduce to 0°C, add trimethyl silicon bromide (283.18mg, 1.85mmol), gradually increase the temperature to 20°C and stir for 16 hours .
  • the reaction was concentrated under reduced pressure, ethyl acetate (30 mL) was added, washed with half-saturated sodium chloride solution (20 mL), ethyl acetate was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • Step 1 Synthesis of compounds 2-1 and 2-2
  • the reaction solution was concentrated under reduced pressure, ethyl acetate (50 mL) was added, and half-saturated sodium chloride solution (30 mL) was added to wash. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • the crude product was prepared by prep-HPLC (column type: Phenomenex luna C18 250mm*50mm*10 ⁇ m; mobile phase: [H 2 O(0.05% HCl)-ACN]; B(ACN)%: 20%-60%, 10min) Compound 3.
  • the crystal of compound 6 was obtained by culturing for 5 days under the condition of acetone using solvent volatilization method at room temperature.
  • the number of asymmetric units in the unit cell Z 2.
  • the Bruker D8 Venture Photon II diffractometer was used to collect the diffraction intensity data, the light source was CuK ⁇ radiation, and the scanning method: Scanning, the total number of diffraction points collected is 16,909, the number of independent diffraction points is 5938, and the number of observable points (I/sigma ⁇ 2) is 3601.
  • the direct method (Shelxs97) was used to analyze the crystal structure, and all 40 non-hydrogen atom positions were obtained.
  • the least square method was used to modify the structural parameters and distinguish the atom types.
  • the geometric calculation method and the difference Fourier method were used to obtain all the hydrogen atom positions.
  • R 1 0.0585
  • S 1.035.
  • the final stoichiometric formula is C 29 H 32 ClO 5 P ⁇ C 3 H 6 O, the calculated molecular weight is 585.04, and the calculated crystal density is 1.224 g/cm 3 .
  • the three-dimensional structure ellipsoid diagram of the compound 6 acetone compound, the unit cell packing diagram along the b-axis direction and the absolute configuration diagram of the compound are shown in Figures 1, 2 and 3.
  • the crystal structure data and parameters of compound 6 acetonate are shown in Tables 1, 2, 3, 4 and 5.
  • Table 1 Crystal structure refinement information table
  • reaction solution was filtered with celite, the filtrate was diluted with ethyl acetate (100mL), water (100mL) was added, the organic phase was washed with saturated brine (100mL ⁇ 2), the organic phase was dried over anhydrous sodium sulfate, filtered, and reduced pressure Concentrate to obtain crude product.
  • Trifluoroacetic acid (518.38 mg, 4.55 mmol, 336.61 ⁇ L) was added to the dichloromethane (2 mL) of compound 9-4 (0.85 g, 1.52 mmol) at 0°C, and the reaction was carried out at 20°C for 2 hours.
  • the reaction solution was poured into saturated sodium bicarbonate solution, dichloromethane (50mL) was added, the aqueous phase was extracted with dichloromethane (50mL ⁇ 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the compound 9-5.
  • Tetrabutylammonium fluoride solution (1M, 1.77 mL) was added to compound 9-5 (0.8 g, 1.47 mmol) in tetrahydrofuran (2 mL), and reacted at 20° C. for 1 hour.
  • the reaction solution was concentrated under reduced pressure to obtain a crude product.
  • Trimethylbromosilane (1.34 g, 8.73 mmol, 1.13 mL) was added to the dichloromethane (10 mL) of compound 9-9 (0.39 g, 873.43 ⁇ mol) at 0°C, and reacted at 20°C for 12 hours.
  • the reaction solution was concentrated under reduced pressure to obtain a crude product. Separated by pre-HPLC (column type: Phenomenex luna C18 250*50mm*10 ⁇ m; mobile phase: water (0.04%HCl)-ACN; gradient: B(ACN)%: 30%-60%, 10min).
  • Compound 9 was obtained.
  • Trimethylsilyl bromide (135.21 mg, 883.18 ⁇ mol, 114.58 ⁇ L) was added to compound 9-10 (40 mg, 88.32 ⁇ mol) in dichloromethane (2 mL) at 0°C, and reacted at 20°C for 12 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. Separated by pre-HPLC (column type: Welch Xtimate C18 150*25mm*5 ⁇ m; mobile phase: water (0.04%HCl)-ACN; gradient: B(ACN)%: 40%-65%, 8min) to obtain compound 10 .
  • n-butyllithium (2.5M, 1.14mL) was added to compound 1-8 (868.75mg, 2.85mmol) in tetrahydrofuran (10mL), and compound 11-1 (0.65g, 2.19mmol) was added after 1 hour. ), after reacting for 1 hour, react at 20°C for 2 hours.
  • the reaction solution was poured into saturated ammonium chloride solution, ethyl acetate (100mL) was added for separation, the aqueous phase was extracted with ethyl acetate (100mL ⁇ 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure Get crude product.
  • Trimethylsilyl bromide (135.21 mg, 883.18 ⁇ mol) was added to the dichloromethane (2 mL) of compound 11-7 (40 mg, 88.32 ⁇ mol) at 0°C, and reacted at 20°C for 12 hours.
  • the reaction solution was concentrated under reduced pressure to obtain a crude product. Separated by prep-HPLC (column type: Welch Xtimate C18 150*25mm*5 ⁇ m; mobile phase: water (0.04% HCl)-acetonitrile; gradient: B(ACN)%: 40%-65%, 8min).
  • Compound 11 was obtained.
  • Trimethylsilyl bromide (135.21 mg, 883.18 ⁇ mol) was added to the dichloromethane (2 mL) of compound 11-8 (40 mg, 88.32 ⁇ mol) at 0°C, and reacted at 20°C for 12 hours.
  • the reaction solution was concentrated under reduced pressure to obtain a crude product. Separate by prep-HPLC (column type: Welch Xtimate C18 150*25mm*5 ⁇ m; mobile phase: water (0.04%HCl)-acetonitrile; gradient: B(ACN)%: 40%-65%, 8min) to obtain compound 12 .
  • Step 6 Split to get 17-7 and 17-8
  • n-butyllithium (2.5M, 16.55mL) was added to compound 19-1 (10g, 37.60mmol) in tetrahydrofuran (100mL), and N,N-dimethylformamide (3.30 g, 45.12mmol, 3.47mL), react for 1 hour.
  • a hydrobromic acid aqueous solution (16.46 g, 97.67 mmol, 11.05 mL, 48%) was added to a reaction flask containing compound 19-5 (1.7 g, 4.58 mmol, 65%), and the reaction was carried out at 130°C for 2 hours.
  • Ethyl acetate (50 mL) was added for liquid separation, the aqueous phase was extracted with ethyl acetate (50 mL ⁇ 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product.
  • it was purified by beating petroleum ether: ethyl acetate at room temperature (10:1, 5 mL), and filtered to obtain compound 19-6.
  • reaction solution was poured into saturated ammonium chloride solution, ethyl acetate (50mL) was added for separation, the aqueous phase was extracted with ethyl acetate (50mL ⁇ 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure
  • Tetrabutylammonium fluoride (1M, 1.43 mL) was added to compound 19-11 (0.7 g, 1.19 mmol) in tetrahydrofuran (20 mL), and reacted at 20°C for 2 hours.
  • Water (20mL) was added to the reaction solution for quenching, ethyl acetate (50mL) was added for separation, the aqueous phase was extracted with ethyl acetate (50mL ⁇ 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure Get crude product. It was separated by silica gel column chromatography (petroleum ether/ethyl acetate 3:1) to obtain compound 19-12.
  • Trimethylsilyl bromide (61.56 mg, 402.12 ⁇ mol, 52.17 ⁇ L) was added to compound 19-15 (20 mg, 40.21 ⁇ mol) in dichloromethane (2 mL) at 0°C, and reacted at 20°C for 12 hours.
  • the reaction solution was concentrated under reduced pressure to obtain a crude product. Separated by pre-HPLC (column type: Phenomenex luna C18 80*40mm*3 ⁇ m; mobile phase: water (0.04% HCl)-acetonitrile; gradient: B (acetonitrile)%: 35%-55%, 7min).
  • Compound 19 was obtained.
  • Trimethylsilyl bromide (61.56 mg, 402.12 ⁇ mol, 52.17 ⁇ L) was added to compound 19-16 (20 mg, 40.21 ⁇ mol) in dichloromethane (2 mL) at 0°C, and reacted at 20°C for 12 hours.
  • the reaction solution was concentrated under reduced pressure to obtain a crude product. Separated by pre-HPLC (column type: Phenomenex luna C18 80*40mm*3 ⁇ m; mobile phase: water (0.04% HCl)-acetonitrile; gradient: B (acetonitrile)%: 38%-56%, 7min).
  • Compound 20 was obtained.
  • the compound 21-9 (0.7g, 1.57mmol) was resolved by SFC.
  • SFC column type: DAICEL CHIRALPAK AD (250mm*50mm*10 ⁇ m); mobile phase: [Neu-IPA]: 40%-40%, 8min) resolution.
  • Compounds 21-10 and 21-11 were obtained.
  • ABPR 1800psi.
  • Compound 23-1 (5g, 24.49mmol) was added to pyridine (50mL), malonic acid (3.82g, 36.74mmol, 3.82mL) and piperidine (417.09mg, 4.90mmol, 483.75 ⁇ L) were added and stirred at 90°C Reaction for 16 hours. After the reaction, 4M hydrochloric acid was added to the reaction solution to adjust the pH to about 4, ethyl acetate was added about 50mL, and the layers were separated.
  • Step 6 Split to get 25-7 and 25-8
  • This step is 25-6 resolution, chiral separation: Column type: DAICEL CHIRALPAK AD (250mm*30mm*10 ⁇ m); mobile phase: [0.1%NH 3 .H 2 O-IPA]; IPA%: 40%-40 %, 8min to get 25-7 and 25-8.
  • Analysis method Column type: DAICEL CHIRALPAK AD, 50 ⁇ 4.6mm, ID, 3 ⁇ m.
  • Gradient Phase B increased from 5% to 50% in 1.2 minutes, maintained for 1 minute, and decreased to 5% in 0.8 minutes, flow rate: 3.4 mL/min. Column temperature: 35°C. Column pressure: 1800psi. Retention time of compound 25-7: 1.232 min. Compound 25-8 retention time: 1.350min.
  • the crude product was obtained by prep-HPLC (column type: Xtimate C18 100*30mm*3 ⁇ m; mobile Phase: [H 2 O(0.2% FA)-ACN]; B(ACN)%: 23%-53%, 9 min) to obtain compound 25 by purification.
  • the crude product was purified by machine, purification method: column type: Phenomenex Gemini-NX 150*30mm*5 ⁇ m; mobile phase: [water (0.04%HCl)-ACN]; ACN%: 30%-60%, 8min. Compound 27 was obtained.
  • the crude product was purified by machine, purification method: column type: Phenomenex Gemini-NX 150*30mm*5 ⁇ m; mobile phase: [water (0.04%HCl)-ACN]; ACN%: 30%-60%, 8min. Compound 28 was obtained.
  • Compound 29-6 was separated by chiral column type: DAICEL CHIRALPAK AD (250mm*30mm, 10 ⁇ m); mobile phase: [0.1%NH 3 H 2 O IPA]: 35%-35%, 8min resolution to obtain compound 29-7 and 30-7.
  • Analysis method Column type: Chiralpak AD-3, 50 ⁇ 4.6mm, ID, 3 ⁇ m.
  • Triphenylphosphine (58.65g, 223.60mmol) and potassium iodide (17.68g, 106.48mmol) were added to acetonitrile (300mL), heated to 70°C, compound 31-2 (31g, 106.48mmol) was added, and stirred for 30 minutes.
  • a solution of methyl fluorosulfonyl difluoroacetate (40.91 g, 212.96 mmol) in acetonitrile (30 mL) was added, and the reaction was stirred at 70° C. for 3 hours.
  • the reaction solution was concentrated under reduced pressure, ethyl acetate (200 mL) was added, and saturated sodium chloride solution (100 mL) was added to wash.
  • Trimethylsulfoxide iodide (16.92g, 76.89mmol) was added to dimethylsulfoxide (50mL), potassium tert-butoxide (1M, 67.66mL) was added, heated to 50°C and stirred for 1 hour, then the compound was added 31-3 (10g, 30.76mmol) in dimethyl sulfoxide (10mL) solution, the reaction was stirred at 50°C for 16 hours.
  • the reaction solution was added with ethyl acetate (300 mL), washed with saturated sodium chloride solution (100 mL ⁇ 4), the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • prep-HPLC column type: Waters Xbridge BEH C18 100*30mm*10 ⁇ m; mobile phase: [H 2 O (10mM NH 4 HCO 3 )-acetonitrile]; acetonitrile%: 40%-70%, 6min) to obtain compound 36 And crude compound 37.
  • the crude compound 36 was purified by prep-HPLC (column type: Waters Xbridge BEH C18 100*30mm*10 ⁇ m; mobile phase: [water(10mM NH 4 HCO 3 )-acetonitrile]; acetonitrile%: 40%-70%, 6min).
  • Compound 36 The configuration of the phosphorus atom position of compound 36 was confirmed by NOE.
  • the raw material 40-8 (0.7g, 1.57mmol) was resolved by SFC. It was resolved by SFC (column type: DAICEL CHIRALPAK AD (250mm*50mm, 10 ⁇ m); mobile phase: [0.1% NH 3 H 2 O/IPA]: 20%-20%, 4.5min). Compound 40-9 was obtained. Analysis method: Column type: Chiralpak AD-3, 50 ⁇ 4.6mm, ID, 3 ⁇ m. Mobile phase: A: CO 2 B: IPA (0.05% IPAm, v/v. Gradient: Phase B rose from 5% to 50% in 1 minute, maintained for 1 minute, and decreased to 5% in 0.8 minutes. Flow rate: 3.4mL /min. Column temperature: 35° C. ABPR: 1800 psi. Compound 40-9 retention time: 1.011 min.
  • reaction solution was concentrated under reduced pressure, diluted with ethyl acetate (100 mL), washed with 10% citric acid aqueous solution (100 mL ⁇ 2), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product is directly put into the next step without purification. Compound 41-2 was obtained.

Abstract

Disclosed are a compound as shown in formula (IV), an isomer thereof and a pharmaceutically acceptable salt thereof. The compound can be used for preparing medicaments in the treatment of diseases related to a THR-β agonist.

Description

苯并稠环类化合物Benzo fused ring compounds
本申请主张如下优先权This application claims the following priority
CN201911379378.6，申请日：2019-12-27；CN201911379378.6, application date: 2019-12-27;
CN202010070530.9，申请日：2020-01-21；CN202010070530.9, application date: 2020-01-21;
CN202010152655.6，申请日：2020-03-06；CN202010152655.6, application date: 2020-03-06;
CN202010198251.0，申请日：2020-03-19；CN202010198251.0, application date: 2020-03-19;
CN202010302096.2，申请日：2020-04-16；CN202010302096.2, application date: 2020-04-16;
CN202010565413.X，申请日：2020-06-19；CN202010565413.X, application date: 2020-06-19;
CN202010581064.0，申请日：2020-06-23；CN202010581064.0, application date: 2020-06-23;
CN202010681790.X，申请日：2020-07-15；CN202010681790.X, application date: 2020-07-15;
CN202011054149.X，申请日：2020-09-29；CN202011054149.X, application date: 2020-09-29;
CN202011146814.8，申请日：2020-10-23；CN202011146814.8, application date: 2020-10-23;
CN202011326523.7，申请日：2020-11-23。CN202011326523.7, application date: 2020-11-23.
技术领域Technical field
本发明涉及一类苯并稠环化合物。具体涉及了式(IV)所示化合物、其异构体及其药学上可接受的盐。The present invention relates to a class of benzo-fused ring compounds. Specifically, it relates to the compound represented by formula (IV), its isomers and pharmaceutically acceptable salts thereof.
背景技术Background technique
甲状腺激素(Thyroid hormone,TH)有甲状腺产生并且以下面的两种不同形式分泌到循环系统(下丘脑/垂体/甲状腺系统)中：3,5,3’,5’-四碘-L-甲状腺原氨酸(T4)和3,5,3’–三碘-L-甲状腺原氨酸(T3)。尽管T4是由甲状腺分泌的主要形式，但是T3是生理升更活跃的形式。T4通过组织特异性脱碘酶被转化成T3，组织特异性脱碘酶存在于所有组织中，但是主要在肝和肾中。Thyroid hormone (TH) is produced by the thyroid gland and is secreted into the circulatory system (hypothalamus/pituitary/thyroid system) in two different forms: 3,5,3',5'-tetraiodo-L-thyroid Protoine (T4) and 3,5,3'-Triiodo-L-thyronine (T3). Although T4 is the main form secreted by the thyroid, T3 is the more active form of physiological increase. T4 is converted into T3 by tissue-specific deiodinase, which is present in all tissues, but mainly in liver and kidney.
甲状腺激素的生理活性由甲状腺受体(TRs)介导。TRs分别位于人类染色体17和3上的不同基因α和β编码而来，通过对初级转录物进行选择性剪切后产生不同的蛋白亚型，每个基因产生两个亚型，即TRα1，TRα2，TRβ1，TRβ2。TRβ1和TRβ2由启动子差异表达得到，这两个亚型仅在氨基末端存在差异。TRα1和TRα2由前体mRNA的差异剪接而来，主要在羧基末端存在差异。其中，TRα1，TRβ1和TRβ2可结合甲状腺激素。已经显示，甲状腺激素受体亚型在特殊生理响应的贡献方面可以不同。TRβ1在肝中在调节促甲状腺激素核调节甲状腺激素的作用中起着重要作用；TRβ2在调节甲状腺刺激激素方面起着主要作用。The physiological activity of thyroid hormones is mediated by thyroid receptors (TRs). TRs are encoded by different genes α and β located on human chromosomes 17 and 3 respectively. Different protein subtypes are produced by selective splicing of primary transcripts. Each gene produces two subtypes, namely TRα1 and TRα2. , TRβ1, TRβ2. TRβ1 and TRβ2 are differentially expressed by promoters, and these two subtypes differ only at the amino terminus. TRα1 and TRα2 come from the differential splicing of the precursor mRNA, and there are differences mainly in the carboxyl terminal. Among them, TRα1, TRβ1 and TRβ2 can be combined with thyroid hormones. It has been shown that thyroid hormone receptor subtypes can differ in their contribution to specific physiological responses. TRβ1 plays an important role in the regulation of thyroid stimulating hormone nuclear regulation of thyroid hormone in the liver; TRβ2 plays a major role in regulating thyroid stimulating hormone.
甲状腺激素具有降低血清低密度脂蛋白(LDL)作用。甲状腺机能亢进与低的总血清胆固醇有关，这归因于甲状腺激素增加肝LDL受体表达并且刺激胆固醇向胆汁酸的代谢。甲状腺激素还可以降低动脉粥样硬化症和其它心血管疾病危险。甲状腺激素通过增加代谢率，氧消耗和放热，从而降低体重， 改善与肥胖有关的共发病而对肥胖患者具有有益效果。同时避免甲状腺机能亢进和甲状腺功能减退的不良效果，保持甲状腺激素的有益效果的甲状腺类似物将打开治疗一下疾病的新途径：代谢疾病如肥胖，高脂血症，高胆固醇血症，糖尿病和其它病症如脂肪变性和非酒精性脂肪肝炎(NASH)，动脉粥样硬化等相关病症和疾病。Thyroid hormone has the effect of lowering serum low-density lipoprotein (LDL). Hyperthyroidism is associated with low total serum cholesterol, which is due to thyroid hormones increasing liver LDL receptor expression and stimulating the metabolism of cholesterol to bile acids. Thyroid hormones can also reduce the risk of atherosclerosis and other cardiovascular diseases. Thyroid hormones have beneficial effects on obese patients by increasing metabolic rate, oxygen consumption and heat release, thereby reducing body weight and improving obesity-related comorbidities. At the same time to avoid the adverse effects of hyperthyroidism and hypothyroidism, thyroid analogs that maintain the beneficial effects of thyroid hormone will open up new ways to treat diseases: metabolic diseases such as obesity, hyperlipidemia, hypercholesterolemia, diabetes and others Diseases such as steatosis and non-alcoholic steatohepatitis (NASH), atherosclerosis and other related diseases and diseases.
发明内容Summary of the invention
本发明提供了式(IV)所示化合物、其异构体或其药学上可接受的盐，其选自：The present invention provides a compound represented by formula (IV), an isomer thereof or a pharmaceutically acceptable salt thereof, which is selected from:
Figure PCTCN2020139562-appb-000001
Figure PCTCN2020139562-appb-000001
其中，among them,
R 1选自H、卤素、OH、NHR a、C 1-3烷基和C 1-3烷氧基，所述C 1-3烷基和C 1-3烷氧基任选被1、2或3个卤素取代； R 1 is selected from H, halogen, OH, NHR a , C 1-3 alkyl and C 1-3 alkoxy. The C 1-3 alkyl and C 1-3 alkoxy are optionally selected by 1, 2 Or 3 halogen substitutions;
R 2选自H、卤素、OH、NHR a、C 1-3烷基、C 1-3烷氧基和C 3-6环烷基，所述C 1-3烷基、C 1-3烷氧基和C 3-6环烷基任选被1、2或3个卤素取代； R 2 is selected from H, halogen, OH, NHR a , C 1-3 alkyl, C 1-3 alkoxy and C 3-6 cycloalkyl, the C 1-3 alkyl, C 1-3 alkane The oxy group and the C 3-6 cycloalkyl group are optionally substituted with 1, 2 or 3 halogens;
R 3、R 4和R 5各自独立地选自H、卤素、OH、NHR a、C 1-3烷基、C 1-3烷氧基、C 3-6环烷基和4-6元杂环烷基，所述C 1-3烷基、C 1-3烷氧基、C 3-6环烷基和4-6元杂环烷基任选被1、2或3个R取代； R 3 , R 4 and R 5 are each independently selected from H, halogen, OH, NHR a , C 1-3 alkyl, C 1-3 alkoxy, C 3-6 cycloalkyl and 4-6 membered hetero Cycloalkyl, the C 1-3 alkyl, C 1-3 alkoxy, C 3-6 cycloalkyl and 4-6 membered heterocycloalkyl are optionally substituted with 1, 2 or 3 R;
各R分别独立地选自卤素或C 1-3烷基； Each R is independently selected from halogen or C 1-3 alkyl;
L 1选自-(CR bR c) m-、-NH(CR bR c) m-、-O(CR bR c) m-、C 3-6环烷基和3-6元杂环烷基； L 1 is selected from -(CR b R c ) m -, -NH(CR b R c ) m -, -O(CR b R c ) m -, C 3-6 cycloalkyl and 3-6 membered heterocyclic ring alkyl;
E 1和E 2分别独立地选自-(CR bR c) n-、NR a和O； E 1 and E 2 are independently selected from -(CR b R c ) n -, NR a and O;
R a选自H、C 1-3烷基、-COCH 3和-SO 2R’； R a is selected from H, C 1-3 alkyl, -COCH 3 and -SO 2 R';
R b和R c分别独立地选自H、C 1～3烷基和C 1-3烷氧基，所述C 1-3烷基和C 1-3烷氧基任选被1、2或3个卤素取代；或者，R 1与R b或R c及共同相连的碳原子成环丙基； R b and R c are independently selected from H, C 1 ~ 3 alkyl group and a C 1-3 alkoxy group, a C 1-3 alkyl group and a C 1-3 alkoxy group optionally substituted with 1, 2 or 3 halogen substitutions; alternatively, R 1 and R b or R c and the carbon atoms connected together form a cyclopropyl group;
或者，R b与R c及共同相连的碳原子成环丙基； Alternatively, R b and R c and the carbon atoms connected together form a cyclopropyl group;
R’选自C 1～3烷基，所述C 1～3烷基任选被1、2或3个卤素取代； R'is selected from a C 1-3 alkyl group, and the C 1-3 alkyl group is optionally substituted with 1, 2 or 3 halogens;
m各自独立地选自0、1和2；m is each independently selected from 0, 1 and 2;
n选自1和2；n is selected from 1 and 2;
X选自-PO(OH) 2、-P(O)[-OC(R d) 2OC(O)R e] 2、-P(O)[-OC(R d) 2OC(O)OR e] 2、-P(O)[-N(H)C(R d) 2C(O)OR e][-OR e]、-P(O)[-N(H)C(R d) 2C(O)OR e] 2和
Figure PCTCN2020139562-appb-000002
X is selected from -PO(OH) 2 , -P(O)[-OC(R d ) 2 OC(O)R e ] 2 , -P(O)[-OC(R d ) 2 OC(O)OR e ] 2 , -P(O)[-N(H)C(R d ) 2 C(O)OR e ][-OR e ], -P(O)[-N(H)C(R d ) 2 C(O)OR e ] 2 and
Figure PCTCN2020139562-appb-000002
V选自C 6-10芳基和5～10元杂芳基，所述C 6-10芳基和5～10元杂芳基任选被1、2或3个卤素取代； V is selected from a C 6-10 aryl group and a 5-10 membered heteroaryl group, the C 6-10 aryl group and a 5-10 membered heteroaryl group are optionally substituted by 1, 2 or 3 halogens;
各R d独立地选自R e和H； Each R d and R e is independently selected from H;
各R e独立地选自C 1-4烷基和C 6-10芳基，所述C 1-4烷基和C 6-10芳基任选被1、2或3个卤素取代； Each R e is independently selected from a C 1-4 alkyl group and a C 6-10 aryl group, the C 1-4 alkyl group and C 6-10 aryl group are optionally substituted with 1, 2 or 3 halogens;
所述“杂”包含1、2或3个独立地选自-O-、-NH-、-S-和N的杂原子或杂原子团。The "hetero" includes 1, 2 or 3 heteroatoms or heteroatom groups independently selected from -O-, -NH-, -S- and N.
本发明的一些方案中，上述R 1选自H、F、OH、NH 2、C 1-3烷基和C 1-3烷氧基，所述C 1-3烷基和C 1-3烷氧基任选被1、2或3个卤素取代，其它变量如本发明所定义。 In some embodiments of the present invention, the above-mentioned R 1 is selected from H, F, OH, NH 2 , C 1-3 alkyl and C 1-3 alkoxy, the C 1-3 alkyl and C 1-3 alkane The oxy group is optionally substituted with 1, 2 or 3 halogens, and 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、OH、NH 2和CH 3，其它变量如本发明所定义。 In some aspects of the present invention, the above-mentioned R 1 is selected from H, F, OH, NH 2 and CH 3 , and other variables are as defined in the present invention.
本发明的一些方案中，上述R 2选自H、F、Cl、Br、NH 2、C 1～3烷基和环丙基，所述C 1～3烷基任选被1、2或3个F取代，其它变量如本发明所定义。 In some embodiments of the present invention, the above-mentioned R 2 is selected from H, F, Cl, Br, NH 2 , C 1-3 alkyl and cyclopropyl, and the C 1-3 alkyl is optionally selected by 1, 2 or 3 Replace with F, and other variables are as defined in the present invention.
本发明的一些方案中，上述R 2选自Cl、Br、CH 3、CF 3和环丙基，其它变量如本发明所定义。 In some aspects of the present invention, the above-mentioned R 2 is selected from Cl, Br, CH 3 , CF 3 and cyclopropyl, and other variables are as defined in the present invention.
本发明的一些方案中，上述各R分别独立地选自F和CH 3，其它变量如本发明所定义。 In some aspects of the present invention, each R above is independently selected from F and CH 3 , and other variables are as defined in the present invention.
本发明的一些方案中，上述R 3、R 4和R 5各自独立地选自H、卤素、OH、NH 2、C 1-3烷基、C 3-6环烷基和4-6元杂环烷基，所述C 1-3烷基、C 3-6环烷基和4-6元杂环烷基任选被1、2或3个R取代，其它变量如本发明所定义。 In some embodiments of the present invention, the above-mentioned R 3 , R 4 and R 5 are each independently selected from H, halogen, OH, NH 2 , C 1-3 alkyl, C 3-6 cycloalkyl and 4-6 membered hetero Cycloalkyl, the C 1-3 alkyl, C 3-6 cycloalkyl and 4-6 membered heterocycloalkyl are optionally substituted with 1, 2 or 3 R, and other variables are as defined in the present invention.
本发明的一些方案中，上述R 3、R 4和R 5各自独立地选自H、F、Cl、OH、CH 3、CH 2CH 3、CH(CH 3) 2、
Figure PCTCN2020139562-appb-000003
其它变量如本发明所定义。 In some aspects of the present invention, the above-mentioned R 3 , R 4 and R 5 are each independently selected from H, F, Cl, OH, CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 ,
Figure PCTCN2020139562-appb-000003
Other variables are as defined in the present invention.
本发明的一些方案中，上述L 1选自-(CH 2) m-、-NH(CH 2) m-和-O(CH 2) m-，其它变量如本发明所定义。 In some aspects of the present invention, the aforementioned L 1 is selected from -(CH 2 ) m -, -NH(CH 2 ) m -and -O(CH 2 ) m -, and other variables are as defined in the present invention.
本发明的一些方案中，上述L 1选自-CH 2-、-(CH 2) 2-、-NHCH 2-和-OCH 2-，其它变量如本发明所定义。 In some aspects of the present invention, the aforementioned L 1 is selected from -CH 2 -, -(CH 2 ) 2 -, -NHCH 2 -and -OCH 2 -, and other variables are as defined in the present invention.
本发明的一些方案中，上述结构单元
Figure PCTCN2020139562-appb-000004
选自
Figure PCTCN2020139562-appb-000005
Figure PCTCN2020139562-appb-000006
其它变量如本发明所定义。 In some aspects of the present invention, the above-mentioned structural unit
Figure PCTCN2020139562-appb-000004
Selected from
Figure PCTCN2020139562-appb-000005
Figure PCTCN2020139562-appb-000006
Other variables are as defined in the present invention.
本发明的一些方案中，上述结构单元
Figure PCTCN2020139562-appb-000007
选自
Figure PCTCN2020139562-appb-000008
Figure PCTCN2020139562-appb-000009
其它变量如本发明所定义。 In some aspects of the present invention, the above-mentioned structural unit
Figure PCTCN2020139562-appb-000007
Selected from
Figure PCTCN2020139562-appb-000008
Figure PCTCN2020139562-appb-000009
Other variables are as defined in the present invention.
本发明的一些方案中，上述V选自苯基，所述苯基任选被1、2或3个卤素取代，其它变量如本发明所定义。In some embodiments of the present invention, the above-mentioned V is selected from a phenyl group, and the phenyl group is optionally substituted with 1, 2 or 3 halogens, and other variables are as defined in the present invention.
本发明的一些方案中，上述V选自
Figure PCTCN2020139562-appb-000010
其它变量如本发明所定义。 In some aspects of the present invention, the above-mentioned V is selected from
Figure PCTCN2020139562-appb-000010
Other variables are as defined in the present invention.
本发明的一些方案中，上述R e选自-CH 3、-CH 2CH 3、-CH(CH 3) 2、-C(CH 3) 3和苯基，其它变量如本发明所定义。 Some aspects of the present invention, the above-mentioned R e is selected from -CH 3, -CH 2 CH 3, -CH (CH 3) 2, -C (CH 3) 3 , and phenyl, the other variables are as defined in the present invention.
本发明的一些方案中，上述X选自-PO(OH) 2、-P(O)[-OCH 2OC(O)-叔丁基] 2、-P(O)[-OCH 2OC(O)O-异丙基] 2、-P(O)[-N(H)CH(CH 3)C(O)OCH 2CH 3] 2、-P(O)[-N(H)C(CH 3) 2C(O)OCH 2CH 3] 2、
Figure PCTCN2020139562-appb-000011
Figure PCTCN2020139562-appb-000012
其它变量如本发明所定义。 In some aspects of the present invention, the above-mentioned X is selected from -PO(OH) 2 , -P(O)[-OCH 2 OC(O)-tert-butyl] 2 , -P(O)[-OCH 2 OC(O )O-isopropyl] 2 , -P(O)[-N(H)CH(CH 3 )C(O)OCH 2 CH 3 ] 2 , -P(O)[-N(H)C(CH 3 ) 2 C(O)OCH 2 CH 3 ] 2 、
Figure PCTCN2020139562-appb-000011
Figure PCTCN2020139562-appb-000012
Other variables are as defined in the present invention.
本发明的一些方案中，上述X选自-PO(OH) 2、
Figure PCTCN2020139562-appb-000013
Figure PCTCN2020139562-appb-000014
其它变量如本发明所定义。 In some aspects of the present invention, the above-mentioned X is selected from -PO(OH) 2 ,
Figure PCTCN2020139562-appb-000013
Figure PCTCN2020139562-appb-000014
Other variables are as defined in the present invention.
本发明提供了式(I)所示化合物、其异构体或其药学上可接受的盐，其选自：The present invention provides a compound represented by formula (I), an isomer thereof or a pharmaceutically acceptable salt thereof, which is selected from:
Figure PCTCN2020139562-appb-000015
Figure PCTCN2020139562-appb-000015
其中，among them,
R 1选自H、卤素、OH、NHR a、C 1-3烷基和C 1-3烷氧基，所述C 1-3烷基和C 1-3烷氧基任选被1、2或3个卤素取代； R 1 is selected from H, halogen, OH, NHR a , C 1-3 alkyl and C 1-3 alkoxy. The C 1-3 alkyl and C 1-3 alkoxy are optionally selected by 1, 2 Or 3 halogen substitutions;
R 2选自H、卤素、OH、NHR a、C 1-3烷基和C 1-3烷氧基，所述C 1-3烷基和C 1-3烷氧基任选被1、2或3个卤素取代； R 2 is selected from H, halogen, OH, NHR a , C 1-3 alkyl and C 1-3 alkoxy. The C 1-3 alkyl and C 1-3 alkoxy are optionally selected by 1, 2 Or 3 halogen substitutions;
R 3、R 4和R 5各自独立地选自H、卤素、OH、NHR a、C 1-3烷基和C 1-3烷氧基，所述C 1-3烷基和C 1- 3烷氧基任选被1、2或3个卤素取代； R 3, R 4 and R 5 are each independently selected from H, halo, OH, NHR a, C 1-3 alkyl group and a C 1-3 alkoxy group, a C 1-3 alkyl and C 1- 3 Alkoxy is optionally substituted with 1, 2 or 3 halogens;
L 1选自-(CR bR c) m-、-NH(R bR c) m-、-O(R bR c) m-、C 3-6环烷基和3-6元杂环烷基； L 1 is selected from -(CR b R c ) m -, -NH(R b R c ) m -, -O(R b R c ) m -, C 3-6 cycloalkyl and 3-6 membered heterocyclic ring alkyl;
E 1和E 2各自独立地选自-CR bR c-、NR a和O； E 1 and E 2 are each independently selected from -CR b R c -, NR a and O;
R a选自H、C 1-3烷基、-COCH 3和-SO 2R； R a is selected from H, C 1-3 alkyl, -COCH 3 and -SO 2 R;
R b和R c各自独立地选自H、C 1～3烷基和C 1-3烷氧基，所述C 1-3烷基和C 1-3烷氧基任选被1、2或3个卤素取代； R b and R c each independently selected from H, C 1 ~ 3 alkyl group and a C 1-3 alkoxy group, a C 1-3 alkyl group and a C 1-3 alkoxy group optionally substituted with 1, 2 or 3 halogen substitutions;
R选自C 1～3烷基，所述C 1～3烷基任选被1、2或3个卤素取代； R is selected from a C 1-3 alkyl group, and the C 1-3 alkyl group is optionally substituted with 1, 2 or 3 halogens;
m选自0、1和2；m is selected from 0, 1 and 2;
X选自-PO(OH) 2、-P(O)[-OC(R d) 2OC(O)R e] 2、-P(O)[-OC(R d) 2OC(O)OR e] 2、-P(O)[-N(H)C(R d) 2C(O)OR e] 2和
Figure PCTCN2020139562-appb-000016
X is selected from -PO(OH) 2 , -P(O)[-OC(R d ) 2 OC(O)R e ] 2 , -P(O)[-OC(R d ) 2 OC(O)OR e ] 2 , -P(O)[-N(H)C(R d ) 2 C(O)OR e ] 2 and
Figure PCTCN2020139562-appb-000016
V选自C 6-10芳基和5～10元杂芳基，所述C 6-10芳基和5～10元杂芳基任选被1、2或3个卤素取代； V is selected from a C 6-10 aryl group and a 5-10 membered heteroaryl group, the C 6-10 aryl group and a 5-10 membered heteroaryl group are optionally substituted by 1, 2 or 3 halogens;
各R d独立地选自R e和H； Each R d and R e is independently selected from H;
各R e独立地选自C 1-4烷基和C 6-10芳基，所述C 1-4烷基和C 6-10芳基任选被1、2或3个卤素取代； Each R e is independently selected from a C 1-4 alkyl group and a C 6-10 aryl group, the C 1-4 alkyl group and C 6-10 aryl group are optionally substituted with 1, 2 or 3 halogens;
所述“杂”包含1、2或3个独立选自O、S和N的杂原子。The "hetero" includes 1, 2 or 3 heteroatoms independently selected from O, S and N.
本发明的一些方案中，上述R 1选自H、F、OH、NH 2、C 1-3烷基和C 1-3烷氧基，所述C 1-3烷基和C 1-3烷氧基任选被1、2或3个卤素取代，其它变量如本发明所定义。 In some embodiments of the present invention, the above-mentioned R 1 is selected from H, F, OH, NH 2 , C 1-3 alkyl and C 1-3 alkoxy, the C 1-3 alkyl and C 1-3 alkane The oxy group is optionally substituted with 1, 2 or 3 halogens, and 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、OH、NH 2和CH 3，其它变量如本发明所定义。 In some aspects of the present invention, the above-mentioned R 1 is selected from H, F, OH, NH 2 and CH 3 , and other variables are as defined in the present invention.
本发明的一些方案中，上述化R 2选自H、卤素和C 1～3烷基，所述C 1～3烷基任选被1、2或3个卤素取代，其它变量如本发明所定义。 In some embodiments of the present invention, the above-mentioned R 2 is selected from H, halogen and C 1-3 alkyl, and the C 1-3 alkyl is optionally substituted by 1, 2 or 3 halogens, and other variables are as defined in the present invention. definition.
本发明的一些方案中，上述R 2选自H、F、Cl、Br和C 1～3烷基，其它变量如本发明所定义。 In some embodiments of the present invention, the above-mentioned R 2 is selected from H, F, Cl, Br and C 1-3 alkyl groups, and other variables are as defined in the present invention.
本发明的一些方案中，上述R 3、R 4和R 5各自独立地选自H、卤素、OH和C 1-3烷基，所述C 1-3烷基任选被1、2或3个卤素取代，其它变量如本发明所定义。 In some embodiments of the present invention, the above-mentioned R 3 , R 4 and R 5 are each independently selected from H, halogen, OH and C 1-3 alkyl, and the C 1-3 alkyl is optionally selected by 1, 2 or 3 One halogen is substituted, and other variables are as defined in the present invention.
本发明的一些方案中，上述R 3、R 4和R 5各自独立地选自H、F、Cl、OH、CH 3、CH 2CH 3和CH(CH 3) 2，其它变量如本发明所定义。 In some aspects of the present invention, the above-mentioned R 3 , R 4 and R 5 are each independently selected from H, F, Cl, OH, CH 3 , CH 2 CH 3 and CH(CH 3 ) 2 , and other variables are as defined in the present invention definition.
本发明的一些方案中，上述L 1选自-(CH 2) m-、-NH(CH 2) m-和-O(CH 2) m-，其它变量如本发明所定义。 In some aspects of the present invention, the aforementioned L 1 is selected from -(CH 2 ) m -, -NH(CH 2 ) m -and -O(CH 2 ) m -, and other variables are as defined in the present invention.
本发明的一些方案中，上述L 1选自-CH 2-、-(CH 2) 2-、-NHCH 2-和-OCH 2-，其它变量如本发明所定义。 In some aspects of the present invention, the aforementioned L 1 is selected from -CH 2 -, -(CH 2 ) 2 -, -NHCH 2 -and -OCH 2 -, and other variables are as defined in the present invention.
本发明的一些方案中，上述E 1和E 2各自独立地选自-CH 2-、NH和O，其它变量如本发明所定义。 In some aspects of the present invention, the above-mentioned E 1 and E 2 are each independently selected from -CH 2 -, NH and O, and other variables are as defined in the present invention.
本发明的一些方案中，上述E 1和E 2各自独立地选自-CH 2-，其它变量如本发明所定义。 In some aspects of the present invention, the above E 1 and E 2 are each independently selected from -CH 2 -, and other variables are as defined in the present invention.
本发明的一些方案中，上述X选自-PO(OH) 2、-P(O)[-OCH 2OC(O)-叔丁基] 2、-P(O)[-OCH 2OC(O)O-异丙基] 2、-P(O)[-N(H)CH(CH 3)C(O)OCH 2CH 3] 2、-P(O)[-N(H)C(CH 3) 2C(O)OCH 2CH 3] 2和
Figure PCTCN2020139562-appb-000017
其它变量如本发明所定义。 In some aspects of the present invention, the above-mentioned X is selected from -PO(OH) 2 , -P(O)[-OCH 2 OC(O)-tert-butyl] 2 , -P(O)[-OCH 2 OC(O )O-isopropyl] 2 , -P(O)[-N(H)CH(CH 3 )C(O)OCH 2 CH 3 ] 2 , -P(O)[-N(H)C(CH 3 ) 2 C(O)OCH 2 CH 3 ] 2 and
Figure PCTCN2020139562-appb-000017
Other variables are as defined in the present invention.
本发明的一些方案中，上述X选自-PO(OH) 2和
Figure PCTCN2020139562-appb-000018
其它变量如本发明所定义。 In some aspects of the present invention, the above-mentioned X is selected from -PO(OH) 2 and
Figure PCTCN2020139562-appb-000018
Other variables are as defined in the present invention.
本发明提供了下式所示化合物、其异构体或其药学上可接受的盐，其选自：The present invention provides a compound represented by the following formula, an isomer thereof or a pharmaceutically acceptable salt thereof, which is selected from:
Figure PCTCN2020139562-appb-000019
Figure PCTCN2020139562-appb-000019
其中，among them,
R 1选自H、卤素、OH、NHR a、C 1-3烷基和C 1-3烷氧基，所述C 1-3烷基和C 1-3烷氧基任选被1、2或3个卤素取代； R 1 is selected from H, halogen, OH, NHR a , C 1-3 alkyl and C 1-3 alkoxy. The C 1-3 alkyl and C 1-3 alkoxy are optionally selected by 1, 2 Or 3 halogen substitutions;
R 2选自H、卤素、OH、NHR a、C 1-3烷基和C 1-3烷氧基，所述C 1-3烷基和C 1-3烷氧基任选被1、2或3个卤素取代； R 2 is selected from H, halogen, OH, NHR a , C 1-3 alkyl and C 1-3 alkoxy. The C 1-3 alkyl and C 1-3 alkoxy are optionally selected by 1, 2 Or 3 halogen substitutions;
R 3、R 4和R 5各自独立地选自H、卤素、OH、NHR a、C 1-3烷基和C 1-3烷氧基，所述C 1-3烷基和C 1- 3烷氧基任选被1、2或3个卤素取代； R 3, R 4 and R 5 are each independently selected from H, halo, OH, NHR a, C 1-3 alkyl group and a C 1-3 alkoxy group, a C 1-3 alkyl and C 1- 3 Alkoxy is optionally substituted with 1, 2 or 3 halogens;
L 1选自-(CR bR c) m-、-NH(R bR c) m-、-O(R bR c) m-、C 3-6环烷基和3-6元杂环烷基； L 1 is selected from -(CR b R c ) m -, -NH(R b R c ) m -, -O(R b R c ) m -, C 3-6 cycloalkyl and 3-6 membered heterocyclic ring alkyl;
E 1和E 2各自独立地选自-(CR bR c) n-、NR a和O； E 1 and E 2 are each independently selected from -(CR b R c ) n -, NR a and O;
R a选自H、C 1-3烷基、-COCH 3和-SO 2R； R a is selected from H, C 1-3 alkyl, -COCH 3 and -SO 2 R;
R b和R c各自独立地选自H、C 1～3烷基和C 1-3烷氧基，所述C 1-3烷基和C 1-3烷氧基任选被1、2或3个卤素取代； R b and R c each independently selected from H, C 1 ~ 3 alkyl group and a C 1-3 alkoxy group, a C 1-3 alkyl group and a C 1-3 alkoxy group optionally substituted with 1, 2 or 3 halogen substitutions;
R选自C 1～3烷基，所述C 1～3烷基任选被1、2或3个卤素取代； R is selected from a C 1-3 alkyl group, and the C 1-3 alkyl group is optionally substituted with 1, 2 or 3 halogens;
m选自0、1和2；m is selected from 0, 1 and 2;
n选自1和2；n is selected from 1 and 2;
X选自-PO(OH) 2、-P(O)[-OC(R d) 2OC(O)R e] 2、-P(O)[-OC(R d) 2OC(O)OR e] 2、-P(O)[- N(H)C(R d) 2C(O)OR e] 2和
Figure PCTCN2020139562-appb-000020
X is selected from -PO(OH) 2 , -P(O)[-OC(R d ) 2 OC(O)R e ] 2 , -P(O)[-OC(R d ) 2 OC(O)OR e ] 2 , -P(O)[- N(H)C(R d ) 2 C(O)OR e ] 2 and
Figure PCTCN2020139562-appb-000020
V选自C 6-10芳基和5～10元杂芳基，所述C 6-10芳基和5～10元杂芳基任选被1、2或3个卤素取代； V is selected from a C 6-10 aryl group and a 5-10 membered heteroaryl group, the C 6-10 aryl group and a 5-10 membered heteroaryl group are optionally substituted by 1, 2 or 3 halogens;
各R d独立地选自R e和H； Each R d and R e is independently selected from H;
各R e独立地选自C 1-4烷基和C 6-10芳基，所述C 1-4烷基和C 6-10芳基任选被1、2或3个卤素取代； Each R e is independently selected from a C 1-4 alkyl group and a C 6-10 aryl group, the C 1-4 alkyl group and C 6-10 aryl group are optionally substituted with 1, 2 or 3 halogens;
所述“杂”包含1、2或3个独立选自O、S和N的杂原子。The "hetero" includes 1, 2 or 3 heteroatoms independently selected from O, S and N.
本发明的一些方案中，上述R 1选自H、F、OH、NH 2、C 1-3烷基和C 1-3烷氧基，所述C 1-3烷基和C 1-3烷氧基任选被1、2或3个卤素取代，其它变量如本发明所定义。 In some embodiments of the present invention, the above-mentioned R 1 is selected from H, F, OH, NH 2 , C 1-3 alkyl and C 1-3 alkoxy, the C 1-3 alkyl and C 1-3 alkane The oxy group is optionally substituted with 1, 2 or 3 halogens, and 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、OH、NH 2和CH 3，其它变量如本发明所定义。 In some aspects of the present invention, the above-mentioned R 1 is selected from H, F, OH, NH 2 and CH 3 , and other variables are as defined in the present invention.
本发明的一些方案中，上述化R 2选自H、卤素和C 1～3烷基，所述C 1～3烷基任选被1、2或3个卤素取代，其它变量如本发明所定义。 In some embodiments of the present invention, the above-mentioned R 2 is selected from H, halogen and C 1-3 alkyl, and the C 1-3 alkyl is optionally substituted by 1, 2 or 3 halogens, and other variables are as defined in the present invention. definition.
本发明的一些方案中，上述R 2选自H、F、Cl、Br和C 1～3烷基，其它变量如本发明所定义。 In some embodiments of the present invention, the above-mentioned R 2 is selected from H, F, Cl, Br and C 1-3 alkyl groups, and other variables are as defined in the present invention.
本发明的一些方案中，上述R 2选自甲基，其它变量如本发明所定义。 In some aspects of the present invention, the above-mentioned R 2 is selected from methyl, and other variables are as defined in the present invention.
本发明的一些方案中，上述R 3、R 4和R 5各自独立地选自H、卤素、OH和C 1-3烷基，所述C 1-3烷基任选被1、2或3个卤素取代，其它变量如本发明所定义。 In some embodiments of the present invention, the above-mentioned R 3 , R 4 and R 5 are each independently selected from H, halogen, OH and C 1-3 alkyl, and the C 1-3 alkyl is optionally selected by 1, 2 or 3 One halogen is substituted, and other variables are as defined in the present invention.
本发明的一些方案中，上述R 3、R 4和R 5各自独立地选自H、F、Cl、OH、CH 3、CH 2CH 3和CH(CH 3) 2，其它变量如本发明所定义。 In some aspects of the present invention, the above-mentioned R 3 , R 4 and R 5 are each independently selected from H, F, Cl, OH, CH 3 , CH 2 CH 3 and CH(CH 3 ) 2 , and other variables are as defined in the present invention definition.
本发明的一些方案中，上述L 1选自-(CH 2) m-、-NH(CH 2) m-和-O(CH 2) m-，其它变量如本发明所定义。 In some aspects of the present invention, the aforementioned L 1 is selected from -(CH 2 ) m -, -NH(CH 2 ) m -and -O(CH 2 ) m -, and other variables are as defined in the present invention.
本发明的一些方案中，上述L 1选自-CH 2-、-(CH 2) 2-、-NHCH 2-和-OCH 2-，其它变量如本发明所定义。 In some aspects of the present invention, the aforementioned L 1 is selected from -CH 2 -, -(CH 2 ) 2 -, -NHCH 2 -and -OCH 2 -, and other variables are as defined in the present invention.
本发明的一些方案中，上述E 1和E 2各自独立地选自-CH 2-、-CH 2CH 2-、NH和O，其它变量如本发明所定义。 In some aspects of the present invention, the above-mentioned E 1 and E 2 are each independently selected from -CH 2 -, -CH 2 CH 2 -, NH and O, and other variables are as defined in the present invention.
本发明的一些方案中，上述E 1和E 2各自独立地选自-CH 2-和-CH 2CH 2-，其它变量如本发明所定义。 In some aspects of the present invention, the above-mentioned E 1 and E 2 are each independently selected from -CH 2 -and -CH 2 CH 2 -, and other variables are as defined in the present invention.
本发明的一些方案中，上述X选自-PO(OH) 2、-P(O)[-OCH 2OC(O)-叔丁基] 2、-P(O)[-OCH 2OC(O)O-异丙基] 2、-P(O)[-N(H)CH(CH 3)C(O)OCH 2CH 3] 2、-P(O)[-N(H)C(CH 3) 2C(O)OCH 2CH 3] 2和
Figure PCTCN2020139562-appb-000021
其它变量如本发明所定义。 In some aspects of the present invention, the above-mentioned X is selected from -PO(OH) 2 , -P(O)[-OCH 2 OC(O)-tert-butyl] 2 , -P(O)[-OCH 2 OC(O )O-isopropyl] 2 , -P(O)[-N(H)CH(CH 3 )C(O)OCH 2 CH 3 ] 2 , -P(O)[-N(H)C(CH 3 ) 2 C(O)OCH 2 CH 3 ] 2 and
Figure PCTCN2020139562-appb-000021
Other variables are as defined in the present invention.
本发明的一些方案中，上述X选自-PO(OH) 2和
Figure PCTCN2020139562-appb-000022
其它变量如本发明所定义。 In some aspects of the present invention, the above-mentioned X is selected from -PO(OH) 2 and
Figure PCTCN2020139562-appb-000022
Other variables are as defined in the present invention.
本发明提供了式(IV)所示化合物、其异构体或其药学上可接受的盐，其选自：The present invention provides a compound represented by formula (IV), an isomer thereof or a pharmaceutically acceptable salt thereof, which is selected from:
Figure PCTCN2020139562-appb-000023
Figure PCTCN2020139562-appb-000023
其中，among them,
R 1选自H、卤素、OH、NHR a、C 1-3烷基和C 1-3烷氧基，所述C 1-3烷基和C 1-3烷氧基任选被1、2或3个卤素取代； R 1 is selected from H, halogen, OH, NHR a , C 1-3 alkyl and C 1-3 alkoxy. The C 1-3 alkyl and C 1-3 alkoxy are optionally selected by 1, 2 Or 3 halogen substitutions;
R 2选自H、卤素、OH、NHR a、C 1-3烷基和C 1-3烷氧基，所述C 1-3烷基和C 1-3烷氧基任选被1、2或3个卤素取代； R 2 is selected from H, halogen, OH, NHR a , C 1-3 alkyl and C 1-3 alkoxy. The C 1-3 alkyl and C 1-3 alkoxy are optionally selected by 1, 2 Or 3 halogen substitutions;
R 3、R 4和R 5各自独立地选自H、卤素、OH、NHR a、C 1-3烷基、C 1-3烷氧基和C 3-6环烷基，所述C 1-3烷基、C 1-3烷氧基和C 3-6环烷基任选被1、2或3个卤素取代； R 3 , R 4 and R 5 are each independently selected from H, halogen, OH, NHR a , C 1-3 alkyl, C 1-3 alkoxy and C 3-6 cycloalkyl, the C 1- 3 alkyl, C 1-3 alkoxy and C 3-6 cycloalkyl are optionally substituted with 1, 2 or 3 halogens;
L 1选自-(CR bR c) m-、-NH(CR bR c) m-、-O(CR bR c) m-、C 3-6环烷基和3-6元杂环烷基； L 1 is selected from -(CR b R c ) m -, -NH(CR b R c ) m -, -O(CR b R c ) m -, C 3-6 cycloalkyl and 3-6 membered heterocyclic ring alkyl;
E 1和E 2各自独立地选自-(CR bR c) n-、NR a和O； E 1 and E 2 are each independently selected from -(CR b R c ) n -, NR a and O;
R a选自H、C 1-3烷基、-COCH 3和-SO 2R； R a is selected from H, C 1-3 alkyl, -COCH 3 and -SO 2 R;
R b和R c各自独立地选自H、C 1～3烷基和C 1-3烷氧基，所述C 1-3烷基和C 1-3烷氧基任选被1、2或3个卤素取代； R b and R c each independently selected from H, C 1 ~ 3 alkyl group and a C 1-3 alkoxy group, a C 1-3 alkyl group and a C 1-3 alkoxy group optionally substituted with 1, 2 or 3 halogen substitutions;
R选自C 1～3烷基，所述C 1～3烷基任选被1、2或3个卤素取代； R is selected from a C 1-3 alkyl group, and the C 1-3 alkyl group is optionally substituted with 1, 2 or 3 halogens;
m各自独立地选自0、1和2；m is each independently selected from 0, 1 and 2;
n选自1和2；n is selected from 1 and 2;
X选自-PO(OH) 2、-P(O)[-OC(R d) 2OC(O)R e] 2、-P(O)[-OC(R d) 2OC(O)OR e] 2、-P(O)[-N(H)C(R d) 2C(O)OR e] 2和
Figure PCTCN2020139562-appb-000024
X is selected from -PO(OH) 2 , -P(O)[-OC(R d ) 2 OC(O)R e ] 2 , -P(O)[-OC(R d ) 2 OC(O)OR e ] 2 , -P(O)[-N(H)C(R d ) 2 C(O)OR e ] 2 and
Figure PCTCN2020139562-appb-000024
V选自C 6-10芳基和5～10元杂芳基，所述C 6-10芳基和5～10元杂芳基任选被1、2或3个卤素取代； V is selected from a C 6-10 aryl group and a 5-10 membered heteroaryl group, the C 6-10 aryl group and a 5-10 membered heteroaryl group are optionally substituted by 1, 2 or 3 halogens;
各R d独立地选自R e和H； Each R d and R e is independently selected from H;
各R e独立地选自C 1-4烷基和C 6-10芳基，所述C 1-4烷基和C 6-10芳基任选被1、2或3个卤素取代； Each R e is independently selected from a C 1-4 alkyl group and a C 6-10 aryl group, the C 1-4 alkyl group and C 6-10 aryl group are optionally substituted with 1, 2 or 3 halogens;
所述“杂”包含1、2或3个独立选自O、S和N的杂原子。The "hetero" includes 1, 2 or 3 heteroatoms independently selected from O, S and N.
本发明的一些方案中，上述R 1选自H、F、OH、NH 2、C 1-3烷基和C 1-3烷氧基，所述C 1-3烷基和C 1-3烷氧基任选被1、2或3个卤素取代，其它变量如本发明所定义。 In some embodiments of the present invention, the above-mentioned R 1 is selected from H, F, OH, NH 2 , C 1-3 alkyl and C 1-3 alkoxy, the C 1-3 alkyl and C 1-3 alkane The oxy group is optionally substituted with 1, 2 or 3 halogens, and 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、OH、NH 2和CH 3，其它变量如本发明所定义。 In some aspects of the present invention, the above-mentioned R 1 is selected from H, F, OH, NH 2 and CH 3 , and other variables are as defined in the present invention.
本发明的一些方案中，上述化R 2选自H、卤素和C 1～3烷基，所述C 1～3烷基任选被1、2或3个卤素取代，其它变量如本发明所定义。 In some embodiments of the present invention, the above-mentioned R 2 is selected from H, halogen and C 1-3 alkyl, and the C 1-3 alkyl is optionally substituted by 1, 2 or 3 halogens, and other variables are as defined in the present invention. definition.
本发明的一些方案中，上述R 2选自H、F、Cl、Br和C 1～3烷基，所述C 1～3烷基任选被1、2或3个F取代，其它变量如本发明所定义。 In some embodiments of the present invention, the above-mentioned R 2 is selected from H, F, Cl, Br, and C 1-3 alkyl groups, the C 1-3 alkyl groups are optionally substituted by 1, 2 or 3 F, and other variables such as Defined by the present invention.
本发明的一些方案中，上述R 2选自Cl、Br、CH 3和CF 3，其它变量如本发明所定义。 In some aspects of the present invention, the above-mentioned R 2 is selected from Cl, Br, CH 3 and CF 3 , and other variables are as defined in the present invention.
本发明的一些方案中，上述R 3、R 4和R 5各自独立地选自H、卤素、OH、NH 2、C 1-3烷基和C 3-6环烷基，所述C 1-3烷基和C 3-6环烷基任选被1、2或3个卤素取代，其它变量如本发明所定义。 In some embodiments of the present invention, the above-mentioned R 3 , R 4 and R 5 are each independently selected from H, halogen, OH, NH 2 , C 1-3 alkyl and C 3-6 cycloalkyl, and the C 1- The 3 alkyl group and C 3-6 cycloalkyl group are optionally substituted with 1, 2 or 3 halogens, and other variables are as defined in the present invention.
本发明的一些方案中，上述R 3、R 4和R 5各自独立地选自H、F、Cl、OH、CH 3、CH 2CH 3、CH(CH 3) 2、
Figure PCTCN2020139562-appb-000025
其它变量如本发明所定义。 In some aspects of the present invention, the above-mentioned R 3 , R 4 and R 5 are each independently selected from H, F, Cl, OH, CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 ,
Figure PCTCN2020139562-appb-000025
Other variables are as defined in the present invention.
本发明的一些方案中，上述L 1选自-(CH 2) m-、-NH(CH 2) m-和-O(CH 2) m-，其它变量如本发明所定义。 In some aspects of the present invention, the aforementioned L 1 is selected from -(CH 2 ) m -, -NH(CH 2 ) m -and -O(CH 2 ) m -, and other variables are as defined in the present invention.
本发明的一些方案中，上述L 1选自-CH 2-、-(CH 2) 2-、-NHCH 2-和-OCH 2-，其它变量如本发明所定义。 In some aspects of the present invention, the aforementioned L 1 is selected from -CH 2 -, -(CH 2 ) 2 -, -NHCH 2 -and -OCH 2 -, and other variables are as defined in the present invention.
本发明的一些方案中，上述E 1和E 2各自独立地选自-CH 2-、-CH 2CH 2-、NH和O，其它变量如本发明所定义。 In some aspects of the present invention, the above-mentioned E 1 and E 2 are each independently selected from -CH 2 -, -CH 2 CH 2 -, NH and O, and other variables are as defined in the present invention.
本发明的一些方案中，上述E 1和E 2各自独立地选自-CH 2-和-CH 2CH 2-，其它变量如本发明所定义。 In some aspects of the present invention, the above-mentioned E 1 and E 2 are each independently selected from -CH 2 -and -CH 2 CH 2 -, and other variables are as defined in the present invention.
本发明的一些方案中，上述X选自-PO(OH) 2、-P(O)[-OCH 2OC(O)-叔丁基] 2、-P(O)[-OCH 2OC(O)O-异丙基] 2、-P(O)[-N(H)CH(CH 3)C(O)OCH 2CH 3] 2、-P(O)[-N(H)C(CH 3) 2C(O)OCH 2CH 3] 2和
Figure PCTCN2020139562-appb-000026
其它变量如本发明所定义。 In some aspects of the present invention, the above-mentioned X is selected from -PO(OH) 2 , -P(O)[-OCH 2 OC(O)-tert-butyl] 2 , -P(O)[-OCH 2 OC(O )O-isopropyl] 2 , -P(O)[-N(H)CH(CH 3 )C(O)OCH 2 CH 3 ] 2 , -P(O)[-N(H)C(CH 3 ) 2 C(O)OCH 2 CH 3 ] 2 and
Figure PCTCN2020139562-appb-000026
Other variables are as defined in the present invention.
本发明的一些方案中，上述X选自-PO(OH) 2和
Figure PCTCN2020139562-appb-000027
其它变量如本发明所定义。 In some aspects of the present invention, the above-mentioned X is selected from -PO(OH) 2 and
Figure PCTCN2020139562-appb-000027
Other variables are as defined in the present invention.
本发明提供了式(IV)所示化合物、其异构体或其药学上可接受的盐，其选自：The present invention provides a compound represented by formula (IV), an isomer thereof or a pharmaceutically acceptable salt thereof, which is selected from:
Figure PCTCN2020139562-appb-000028
Figure PCTCN2020139562-appb-000028
其中，among them,
R 1选自H、卤素、OH、NHR a、C 1-3烷基和C 1-3烷氧基，所述C 1-3烷基和C 1-3烷氧基任选被1、2或3个卤素取代； R 1 is selected from H, halogen, OH, NHR a , C 1-3 alkyl and C 1-3 alkoxy. The C 1-3 alkyl and C 1-3 alkoxy are optionally selected by 1, 2 Or 3 halogen substitutions;
R 2选自H、卤素、OH、NHR a、C 1-3烷基和C 1-3烷氧基，所述C 1-3烷基和C 1-3烷氧基任选被1、2或3个卤素取代； R 2 is selected from H, halogen, OH, NHR a , C 1-3 alkyl and C 1-3 alkoxy. The C 1-3 alkyl and C 1-3 alkoxy are optionally selected by 1, 2 Or 3 halogen substitutions;
R 3、R 4和R 5各自独立地选自H、卤素、OH、NHR a、C 1-3烷基、C 1-3烷氧基和C 3-6环烷基，所述C 1-3烷基、C 1-3烷氧基和C 3-6环烷基任选被1、2或3个卤素或C 1-3烷基取代； R 3 , R 4 and R 5 are each independently selected from H, halogen, OH, NHR a , C 1-3 alkyl, C 1-3 alkoxy and C 3-6 cycloalkyl, the C 1- 3 alkyl groups, C 1-3 alkoxy groups and C 3-6 cycloalkyl groups are optionally substituted with 1, 2 or 3 halogens or C 1-3 alkyl groups;
L 1选自-(CR bR c) m-、-NH(CR bR c) m-、-O(CR bR c) m-、C 3-6环烷基和3-6元杂环烷基； L 1 is selected from -(CR b R c ) m -, -NH(CR b R c ) m -, -O(CR b R c ) m -, C 3-6 cycloalkyl and 3-6 membered heterocyclic ring alkyl;
E 1和E 2各自独立地选自-(CR bR c) n-、NR a和O； E 1 and E 2 are each independently selected from -(CR b R c ) n -, NR a and O;
R a选自H、C 1-3烷基、-COCH 3和-SO 2R； R a is selected from H, C 1-3 alkyl, -COCH 3 and -SO 2 R;
R b和R c各自独立地选自H、C 1～3烷基和C 1-3烷氧基，所述C 1-3烷基和C 1-3烷氧基任选被1、2或3个卤素取代； R b and R c each independently selected from H, C 1 ~ 3 alkyl group and a C 1-3 alkoxy group, a C 1-3 alkyl group and a C 1-3 alkoxy group optionally substituted with 1, 2 or 3 halogen substitutions;
R选自C 1～3烷基，所述C 1～3烷基任选被1、2或3个卤素取代； R is selected from a C 1-3 alkyl group, and the C 1-3 alkyl group is optionally substituted with 1, 2 or 3 halogens;
m各自独立地选自0、1和2；m is each independently selected from 0, 1 and 2;
n选自1和2；n is selected from 1 and 2;
X选自-PO(OH) 2、-P(O)[-OC(R d) 2OC(O)R e] 2、-P(O)[-OC(R d) 2OC(O)OR e] 2、-P(O)[-N(H)C(R d) 2C(O)OR e] 2和
Figure PCTCN2020139562-appb-000029
X is selected from -PO(OH) 2 , -P(O)[-OC(R d ) 2 OC(O)R e ] 2 , -P(O)[-OC(R d ) 2 OC(O)OR e ] 2 , -P(O)[-N(H)C(R d ) 2 C(O)OR e ] 2 and
Figure PCTCN2020139562-appb-000029
V选自C 6-10芳基和5～10元杂芳基，所述C 6-10芳基和5～10元杂芳基任选被1、2或3个卤素取代； V is selected from a C 6-10 aryl group and a 5-10 membered heteroaryl group, the C 6-10 aryl group and a 5-10 membered heteroaryl group are optionally substituted by 1, 2 or 3 halogens;
各R d独立地选自R e和H； Each R d and R e is independently selected from H;
各R e独立地选自C 1-4烷基和C 6-10芳基，所述C 1-4烷基和C 6-10芳基任选被1、2或3个卤素取代； Each R e is independently selected from a C 1-4 alkyl group and a C 6-10 aryl group, the C 1-4 alkyl group and C 6-10 aryl group are optionally substituted with 1, 2 or 3 halogens;
所述“杂”包含1、2或3个独立选自O、S和N的杂原子。The "hetero" includes 1, 2 or 3 heteroatoms independently selected from O, S and N.
本发明的一些方案中，上述R 1选自H、F、OH、NH 2、C 1-3烷基和C 1-3烷氧基，所述C 1-3烷基和C 1-3烷氧基任选被1、2或3个卤素取代，其它变量如本发明所定义。 In some embodiments of the present invention, the above-mentioned R 1 is selected from H, F, OH, NH 2 , C 1-3 alkyl and C 1-3 alkoxy, the C 1-3 alkyl and C 1-3 alkane The oxy group is optionally substituted with 1, 2 or 3 halogens, and 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、OH、NH 2和CH 3，其它变量如本发明所定义。 In some aspects of the present invention, the above-mentioned R 1 is selected from H, F, OH, NH 2 and CH 3 , and other variables are as defined in the present invention.
本发明的一些方案中，上述R 2选自H、卤素和C 1～3烷基，所述C 1～3烷基任选被1、2或3个卤素 取代，其它变量如本发明所定义。 In some embodiments of the present invention, the above-mentioned R 2 is selected from H, halogen and C 1-3 alkyl, and the C 1-3 alkyl is optionally substituted by 1, 2 or 3 halogens, and other variables are as defined in the present invention .
本发明的一些方案中，上述R 2选自H、F、Cl、Br和C 1～3烷基，所述C 1～3烷基任选被1、2或3个F取代，其它变量如本发明所定义。 In some embodiments of the present invention, the above-mentioned R 2 is selected from H, F, Cl, Br, and C 1-3 alkyl groups, the C 1-3 alkyl groups are optionally substituted by 1, 2 or 3 F, and other variables such as Defined by the present invention.
本发明的一些方案中，上述R 2选自Cl、Br、CH 3和CF 3，其它变量如本发明所定义。 In some aspects of the present invention, the above-mentioned R 2 is selected from Cl, Br, CH 3 and CF 3 , and other variables are as defined in the present invention.
本发明的一些方案中，上述R 3、R 4和R 5各自独立地选自H、卤素、OH、NH 2、C 1-3烷基和C 3-6环烷基，所述C 1-3烷基和C 3-6环烷基任选被1、2或3个F或甲基取代，其它变量如本发明所定义。 In some embodiments of the present invention, the above-mentioned R 3 , R 4 and R 5 are each independently selected from H, halogen, OH, NH 2 , C 1-3 alkyl and C 3-6 cycloalkyl, and the C 1- The 3 alkyl group and C 3-6 cycloalkyl group are optionally substituted with 1, 2 or 3 F or methyl groups, and other variables are as defined in the present invention.
本发明的一些方案中，上述R 3、R 4和R 5各自独立地选自H、F、Cl、OH、CH 3、CH 2CH 3、CH(CH 3) 2、
Figure PCTCN2020139562-appb-000030
其它变量如本发明所定义。 In some aspects of the present invention, the above-mentioned R 3 , R 4 and R 5 are each independently selected from H, F, Cl, OH, CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 ,
Figure PCTCN2020139562-appb-000030
Other variables are as defined in the present invention.
本发明的一些方案中，上述L 1选自-(CH 2) m-、-NH(CH 2) m-和-O(CH 2) m-，其它变量如本发明所定义。 In some aspects of the present invention, the aforementioned L 1 is selected from -(CH 2 ) m -, -NH(CH 2 ) m -and -O(CH 2 ) m -, and other variables are as defined in the present invention.
本发明的一些方案中，上述L 1选自-CH 2-、-(CH 2) 2-、-NHCH 2-和-OCH 2-，其它变量如本发明所定义。 In some aspects of the present invention, the aforementioned L 1 is selected from -CH 2 -, -(CH 2 ) 2 -, -NHCH 2 -and -OCH 2 -, and other variables are as defined in the present invention.
本发明的一些方案中，上述E 1和E 2各自独立地选自-CH 2-、-CH 2CH 2-、NH和O，其它变量如本发明所定义。 In some aspects of the present invention, the above-mentioned E 1 and E 2 are each independently selected from -CH 2 -, -CH 2 CH 2 -, NH and O, and other variables are as defined in the present invention.
本发明的一些方案中，上述E 1和E 2各自独立地选自-CH 2-和-CH 2CH 2-，其它变量如本发明所定义。 In some aspects of the present invention, the above-mentioned E 1 and E 2 are each independently selected from -CH 2 -and -CH 2 CH 2 -, and other variables are as defined in the present invention.
本发明的一些方案中，上述X选自-PO(OH) 2、-P(O)[-OCH 2OC(O)-叔丁基] 2、-P(O)[-OCH 2OC(O)O-异丙基] 2、-P(O)[-N(H)CH(CH 3)C(O)OCH 2CH 3] 2、-P(O)[-N(H)C(CH 3) 2C(O)OCH 2CH 3] 2、
Figure PCTCN2020139562-appb-000031
Figure PCTCN2020139562-appb-000032
其它变量如本发明所定义。 In some aspects of the present invention, the above-mentioned X is selected from -PO(OH) 2 , -P(O)[-OCH 2 OC(O)-tert-butyl] 2 , -P(O)[-OCH 2 OC(O )O-isopropyl] 2 , -P(O)[-N(H)CH(CH 3 )C(O)OCH 2 CH 3 ] 2 , -P(O)[-N(H)C(CH 3 ) 2 C(O)OCH 2 CH 3 ] 2 、
Figure PCTCN2020139562-appb-000031
Figure PCTCN2020139562-appb-000032
Other variables are as defined in the present invention.
本发明的一些方案中，上述X选自-PO(OH) 2、
Figure PCTCN2020139562-appb-000033
Figure PCTCN2020139562-appb-000034
其它变量如本发明所定义。 In some aspects of the present invention, the above-mentioned X is selected from -PO(OH) 2 ,
Figure PCTCN2020139562-appb-000033
Figure PCTCN2020139562-appb-000034
Other variables are as defined in the present invention.
本发明提供了下式所示化合物、其异构体或其药学上可接受的盐，其选自：The present invention provides a compound represented by the following formula, an isomer thereof or a pharmaceutically acceptable salt thereof, which is selected from:
Figure PCTCN2020139562-appb-000035
Figure PCTCN2020139562-appb-000035
其中，among them,
R 1选自H、卤素、OH、NHR a、C 1-3烷基和C 1-3烷氧基，所述C 1-3烷基和C 1-3烷氧基任选被1、2或3个卤素取代； R 1 is selected from H, halogen, OH, NHR a , C 1-3 alkyl and C 1-3 alkoxy. The C 1-3 alkyl and C 1-3 alkoxy are optionally selected by 1, 2 Or 3 halogen substitutions;
R 2选自H、卤素、OH、NHR a、C 1-3烷基、C 1-3烷氧基和C 3-6环烷基，所述C 1-3烷基、C 1-3烷氧基和C 3-6环烷基任选被1、2或3个卤素取代； R 2 is selected from H, halogen, OH, NHR a , C 1-3 alkyl, C 1-3 alkoxy and C 3-6 cycloalkyl, the C 1-3 alkyl, C 1-3 alkane The oxy group and the C 3-6 cycloalkyl group are optionally substituted with 1, 2 or 3 halogens;
R 3、R 4和R 5各自独立地选自H、卤素、OH、NHR a、C 1-3烷基、C 1-3烷氧基和C 3-6环烷基，所述C 1-3烷基、C 1-3烷氧基和C 3-6环烷基任选被1、2或3个R取代； R 3 , R 4 and R 5 are each independently selected from H, halogen, OH, NHR a , C 1-3 alkyl, C 1-3 alkoxy and C 3-6 cycloalkyl, the C 1- 3 alkyl, C 1-3 alkoxy and C 3-6 cycloalkyl are optionally substituted with 1, 2 or 3 R;
各R分别独立地选自卤素或C 1-3烷基； Each R is independently selected from halogen or C 1-3 alkyl;
L 1选自-(CR bR c) m-、-NH(CR bR c) m-、-O(CR bR c) m-、C 3-6环烷基和3-6元杂环烷基； L 1 is selected from -(CR b R c ) m -, -NH(CR b R c ) m -, -O(CR b R c ) m -, C 3-6 cycloalkyl and 3-6 membered heterocyclic ring alkyl;
E 1和E 2各自独立地选自-(CR bR c) n-、NR a和O； E 1 and E 2 are each independently selected from -(CR b R c ) n -, NR a and O;
R a选自H、C 1-3烷基、-COCH 3和-SO 2R； R a is selected from H, C 1-3 alkyl, -COCH 3 and -SO 2 R;
R b和R c各自独立地选自H、C 1～3烷基和C 1-3烷氧基，所述C 1-3烷基和C 1-3烷氧基任选被1、2或3个卤素取代；或者，R 1与R b或R c及共同相连的碳原子成环丙基； R b and R c each independently selected from H, C 1 ~ 3 alkyl group and a C 1-3 alkoxy group, a C 1-3 alkyl group and a C 1-3 alkoxy group optionally substituted with 1, 2 or 3 halogen substitutions; alternatively, R 1 and R b or R c and the carbon atoms connected together form a cyclopropyl group;
R选自C 1～3烷基，所述C 1～3烷基任选被1、2或3个卤素取代； R is selected from a C 1-3 alkyl group, and the C 1-3 alkyl group is optionally substituted with 1, 2 or 3 halogens;
m各自独立地选自0、1和2；m is each independently selected from 0, 1 and 2;
n选自1和2；n is selected from 1 and 2;
X选自-PO(OH) 2、-P(O)[-OC(R d) 2OC(O)R e] 2、-P(O)[-OC(R d) 2OC(O)OR e] 2、-P(O)[-N(H)C(R d) 2C(O)OR e][-OR e]、-P(O)[-N(H)C(R d) 2C(O)OR e] 2和
Figure PCTCN2020139562-appb-000036
X is selected from -PO(OH) 2 , -P(O)[-OC(R d ) 2 OC(O)R e ] 2 , -P(O)[-OC(R d ) 2 OC(O)OR e ] 2 , -P(O)[-N(H)C(R d ) 2 C(O)OR e ][-OR e ], -P(O)[-N(H)C(R d ) 2 C(O)OR e ] 2 and
Figure PCTCN2020139562-appb-000036
V选自C 6-10芳基和5～10元杂芳基，所述C 6-10芳基和5～10元杂芳基任选被1、2或3个卤素取代； V is selected from a C 6-10 aryl group and a 5-10 membered heteroaryl group, the C 6-10 aryl group and a 5-10 membered heteroaryl group are optionally substituted by 1, 2 or 3 halogens;
各R d独立地选自R e和H； Each R d and R e is independently selected from H;
各R e独立地选自C 1-4烷基和C 6-10芳基，所述C 1-4烷基和C 6-10芳基任选被1、2或3个卤素取代； Each R e is independently selected from a C 1-4 alkyl group and a C 6-10 aryl group, the C 1-4 alkyl group and C 6-10 aryl group are optionally substituted with 1, 2 or 3 halogens;
所述“杂”包含1、2或3个独立地选自-O-、-NH-、-S-和N的杂原子或杂原子团。The "hetero" includes 1, 2 or 3 heteroatoms or heteroatom groups independently selected from -O-, -NH-, -S- and N.
本发明的一些方案中，上述R 1选自H、F、OH、NH 2、C 1-3烷基和C 1-3烷氧基，所述C 1-3烷基和C 1-3烷氧基任选被1、2或3个卤素取代，其它变量如本发明所定义。 In some embodiments of the present invention, the above-mentioned R 1 is selected from H, F, OH, NH 2 , C 1-3 alkyl and C 1-3 alkoxy, the C 1-3 alkyl and C 1-3 alkane The oxy group is optionally substituted with 1, 2 or 3 halogens, and 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、OH、NH 2和CH 3，其它变量如本发明所定义。 In some aspects of the present invention, the above-mentioned R 1 is selected from H, F, OH, NH 2 and CH 3 , and other variables are as defined in the present invention.
本发明的一些方案中，上述R 2选自H、卤素、C 1～3烷基和环丙基，所述C 1～3烷基和环丙基任选被1、2或3个卤素取代，其它变量如本发明所定义。 In some embodiments of the present invention, the above-mentioned R 2 is selected from H, halogen, C 1-3 alkyl and cyclopropyl, and the C 1-3 alkyl and cyclopropyl are optionally substituted by 1, 2 or 3 halogens. , Other variables are as defined in the present invention.
本发明的一些方案中，上述R 2选自H、F、Cl、Br、C 1～3烷基和环丙基，所述C 1～3烷基任选被1、2或3个F取代，其它变量如本发明所定义。 In some embodiments of the present invention, the above-mentioned R 2 is selected from H, F, Cl, Br, C 1-3 alkyl and cyclopropyl, and the C 1-3 alkyl is optionally substituted by 1, 2 or 3 F , Other variables are as defined in the present invention.
本发明的一些方案中，上述R 2选自Cl、Br、CH 3、CF 3和环丙基，其它变量如本发明所定义。 In some aspects of the present invention, the above-mentioned R 2 is selected from Cl, Br, CH 3 , CF 3 and cyclopropyl, and other variables are as defined in the present invention.
本发明的一些方案中，上述R 3、R 4和R 5各自独立地选自H、卤素、OH、NH 2、C 1-3烷基和C 3-6环烷基，所述C 1-3烷基和C 3-6环烷基任选被1、2或3个F或甲基取代，其它变量如本发明所定义。 In some embodiments of the present invention, the above-mentioned R 3 , R 4 and R 5 are each independently selected from H, halogen, OH, NH 2 , C 1-3 alkyl and C 3-6 cycloalkyl, and the C 1- The 3 alkyl group and C 3-6 cycloalkyl group are optionally substituted with 1, 2 or 3 F or methyl groups, and other variables are as defined in the present invention.
本发明的一些方案中，上述R 3、R 4和R 5各自独立地选自H、F、Cl、OH、CH 3、CH 2CH 3、CH(CH 3) 2、
Figure PCTCN2020139562-appb-000037
其它变量如本发明所定义。 In some aspects of the present invention, the above-mentioned R 3 , R 4 and R 5 are each independently selected from H, F, Cl, OH, CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 ,
Figure PCTCN2020139562-appb-000037
Other variables are as defined in the present invention.
本发明的一些方案中，上述L 1选自-(CH 2) m-、-NH(CH 2) m-和-O(CH 2) m-，其它变量如本发明所定义。 In some aspects of the present invention, the aforementioned L 1 is selected from -(CH 2 ) m -, -NH(CH 2 ) m -and -O(CH 2 ) m -, and other variables are as defined in the present invention.
本发明的一些方案中，上述L 1选自-CH 2-、-(CH 2) 2-、-NHCH 2-和-OCH 2-，其它变量如本发明所定义。 In some aspects of the present invention, the aforementioned L 1 is selected from -CH 2 -, -(CH 2 ) 2 -, -NHCH 2 -and -OCH 2 -, and other variables are as defined in the present invention.
本发明的一些方案中，上述E 1和E 2各自独立地选自-CH 2-、-CH 2CH 2-、NH和O，其它变量如本发明所定义。 In some aspects of the present invention, the above-mentioned E 1 and E 2 are each independently selected from -CH 2 -, -CH 2 CH 2 -, NH and O, and other variables are as defined in the present invention.
本发明的一些方案中，上述E 1和E 2各自独立地选自-CH 2-、-CH 2CH 2-和O，其它变量如本发明所定义。 In some aspects of the present invention, the above E 1 and E 2 are each independently selected from -CH 2 -, -CH 2 CH 2 -and O, and other variables are as defined in the present invention.
本发明的一些方案中，上述X选自-PO(OH) 2、-P(O)[-OCH 2OC(O)-叔丁基] 2、-P(O)[-OCH 2OC(O)O-异丙基] 2、-P(O)[-N(H)CH(CH 3)C(O)OCH 2CH 3] 2、-P(O)[-N(H)C(CH 3) 2C(O)OCH 2CH 3] 2、
Figure PCTCN2020139562-appb-000038
Figure PCTCN2020139562-appb-000039
其它变量如本发明所定义。 In some aspects of the present invention, the above-mentioned X is selected from -PO(OH) 2 , -P(O)[-OCH 2 OC(O)-tert-butyl] 2 , -P(O)[-OCH 2 OC(O )O-isopropyl] 2 , -P(O)[-N(H)CH(CH 3 )C(O)OCH 2 CH 3 ] 2 , -P(O)[-N(H)C(CH 3 ) 2 C(O)OCH 2 CH 3 ] 2 、
Figure PCTCN2020139562-appb-000038
Figure PCTCN2020139562-appb-000039
Other variables are as defined in the present invention.
本发明的一些方案中，上述X选自-PO(OH) 2、
Figure PCTCN2020139562-appb-000040
Figure PCTCN2020139562-appb-000041
其它变量如本发明所定义。 In some aspects of the present invention, the above-mentioned X is selected from -PO(OH) 2 ,
Figure PCTCN2020139562-appb-000040
Figure PCTCN2020139562-appb-000041
Other variables are as defined in the present invention.
本发明提供了式(IV)所示化合物、其异构体或其药学上可接受的盐，其选自：The present invention provides a compound represented by formula (IV), an isomer thereof or a pharmaceutically acceptable salt thereof, which is selected from:
Figure PCTCN2020139562-appb-000042
Figure PCTCN2020139562-appb-000042
其中，among them,
R 1选自H、卤素、OH、NHR a、C 1-3烷基和C 1-3烷氧基，所述C 1-3烷基和C 1-3烷氧基任选被1、2或3个卤素取代； R 1 is selected from H, halogen, OH, NHR a , C 1-3 alkyl and C 1-3 alkoxy. The C 1-3 alkyl and C 1-3 alkoxy are optionally selected by 1, 2 Or 3 halogen substitutions;
R 2选自H、卤素、OH、NHR a、C 1-3烷基、C 1-3烷氧基和C 3-6环烷基，所述C 1-3烷基、C 1-3烷氧基和C 3-6环烷基任选被1、2或3个卤素取代； R 2 is selected from H, halogen, OH, NHR a , C 1-3 alkyl, C 1-3 alkoxy and C 3-6 cycloalkyl, the C 1-3 alkyl, C 1-3 alkane The oxy group and the C 3-6 cycloalkyl group are optionally substituted with 1, 2 or 3 halogens;
R 3、R 4和R 5各自独立地选自H、卤素、OH、NHR a、C 1-3烷基、C 1-3烷氧基和C 3-6环烷基，所述C 1-3烷基、C 1-3烷氧基和C 3-6环烷基任选被1、2或3个R取代； R 3 , R 4 and R 5 are each independently selected from H, halogen, OH, NHR a , C 1-3 alkyl, C 1-3 alkoxy and C 3-6 cycloalkyl, the C 1- 3 alkyl, C 1-3 alkoxy and C 3-6 cycloalkyl are optionally substituted with 1, 2 or 3 R;
各R分别独立地选自卤素或C 1-3烷基； Each R is independently selected from halogen or C 1-3 alkyl;
L 1选自-(CR bR c) m-、-NH(CR bR c) m-、-O(CR bR c) m-、C 3-6环烷基和3-6元杂环烷基； L 1 is selected from -(CR b R c ) m -, -NH(CR b R c ) m -, -O(CR b R c ) m -, C 3-6 cycloalkyl and 3-6 membered heterocyclic ring alkyl;
E 1和E 2分别独立地选自-(CR bR c) n-、NR a和O； E 1 and E 2 are independently selected from -(CR b R c ) n -, NR a and O;
R a选自H、C 1-3烷基、-COCH 3和-SO 2R’； R a is selected from H, C 1-3 alkyl, -COCH 3 and -SO 2 R';
R b和R c分别独立地选自H、C 1～3烷基和C 1-3烷氧基，所述C 1-3烷基和C 1-3烷氧基任选被1、2或3个卤素取代； R b and R c are independently selected from H, C 1 ~ 3 alkyl group and a C 1-3 alkoxy group, a C 1-3 alkyl group and a C 1-3 alkoxy group optionally substituted with 1, 2 or 3 halogen substitutions;
或者，R 1与R b或R c及共同相连的碳原子成环丙基； Alternatively, R 1 forms a cyclopropyl group with R b or R c and the carbon atoms connected together;
或者，R b与R c及共同相连的碳原子成环丙基； Alternatively, R b and R c and the carbon atoms connected together form a cyclopropyl group;
R’选自C 1～3烷基，所述C 1～3烷基任选被1、2或3个卤素取代； R'is selected from a C 1-3 alkyl group, and the C 1-3 alkyl group is optionally substituted with 1, 2 or 3 halogens;
m各自独立地选自0、1和2；m is each independently selected from 0, 1 and 2;
n选自1和2；n is selected from 1 and 2;
X选自-PO(OH) 2、-P(O)[-OC(R d) 2OC(O)R e] 2、-P(O)[-OC(R d) 2OC(O)OR e] 2、-P(O)[-N(H)C(R d) 2C(O)OR e][-OR e]、-P(O)[-N(H)C(R d) 2C(O)OR e] 2和
Figure PCTCN2020139562-appb-000043
X is selected from -PO(OH) 2 , -P(O)[-OC(R d ) 2 OC(O)R e ] 2 , -P(O)[-OC(R d ) 2 OC(O)OR e ] 2 , -P(O)[-N(H)C(R d ) 2 C(O)OR e ][-OR e ], -P(O)[-N(H)C(R d ) 2 C(O)OR e ] 2 and
Figure PCTCN2020139562-appb-000043
V选自C 6-10芳基和5～10元杂芳基，所述C 6-10芳基和5～10元杂芳基任选被1、2或3个卤素取代； V is selected from a C 6-10 aryl group and a 5-10 membered heteroaryl group, the C 6-10 aryl group and a 5-10 membered heteroaryl group are optionally substituted by 1, 2 or 3 halogens;
各R d独立地选自R e和H； Each R d and R e is independently selected from H;
各R e独立地选自C 1-4烷基和C 6-10芳基，所述C 1-4烷基和C 6-10芳基任选被1、2或3个卤素取代； Each R e is independently selected from a C 1-4 alkyl group and a C 6-10 aryl group, the C 1-4 alkyl group and C 6-10 aryl group are optionally substituted with 1, 2 or 3 halogens;
所述“杂”包含1、2或3个独立地选自-O-、-NH-、-S-和N的杂原子或杂原子团。The "hetero" includes 1, 2 or 3 heteroatoms or heteroatom groups independently selected from -O-, -NH-, -S- and N.
本发明的一些方案中，上述R 1选自H、F、OH、NH 2、C 1-3烷基和C 1-3烷氧基，所述C 1-3烷基和C 1-3烷氧基任选被1、2或3个卤素取代，其它变量如本发明所定义。 In some embodiments of the present invention, the above-mentioned R 1 is selected from H, F, OH, NH 2 , C 1-3 alkyl and C 1-3 alkoxy, the C 1-3 alkyl and C 1-3 alkane The oxy group is optionally substituted with 1, 2 or 3 halogens, and 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、OH、NH 2和CH 3，其它变量如本发明所定义。 In some aspects of the present invention, the above-mentioned R 1 is selected from H, F, OH, NH 2 and CH 3 , and other variables are as defined in the present invention.
本发明的一些方案中，上述R 2选自H、F、Cl、Br、NH 2、C 1～3烷基和环丙基，所述C 1～3烷基任选被1、2或3个F取代，其它变量如本发明所定义。 In some embodiments of the present invention, the above-mentioned R 2 is selected from H, F, Cl, Br, NH 2 , C 1-3 alkyl and cyclopropyl, and the C 1-3 alkyl is optionally selected by 1, 2 or 3 Replace with F, and other variables are as defined in the present invention.
本发明的一些方案中，上述R 2选自Cl、Br、CH 3、CF 3和环丙基，其它变量如本发明所定义。 In some aspects of the present invention, the above-mentioned R 2 is selected from Cl, Br, CH 3 , CF 3 and cyclopropyl, and other variables are as defined in the present invention.
本发明的一些方案中，上述各R分别独立地选自F和CH 3，其它变量如本发明所定义。 In some aspects of the present invention, each R above is independently selected from F and CH 3 , and other variables are as defined in the present invention.
本发明的一些方案中，上述R 3、R 4和R 5各自独立地选自H、卤素、OH、NH 2、C 1-3烷基和C 3-6环烷基，所述C 1-3烷基和C 3-6环烷基任选被1、2或3个R取代，其它变量如本发明所定义。 In some embodiments of the present invention, the above-mentioned R 3 , R 4 and R 5 are each independently selected from H, halogen, OH, NH 2 , C 1-3 alkyl and C 3-6 cycloalkyl, and the C 1- The 3 alkyl group and C 3-6 cycloalkyl group are optionally substituted with 1, 2 or 3 R, and other variables are as defined in the present invention.
本发明的一些方案中，上述R 3、R 4和R 5各自独立地选自H、F、Cl、OH、CH 3、CH 2CH 3、CH(CH 3) 2、
Figure PCTCN2020139562-appb-000044
其它变量如本发明所定义。 In some aspects of the present invention, the above-mentioned R 3 , R 4 and R 5 are each independently selected from H, F, Cl, OH, CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 ,
Figure PCTCN2020139562-appb-000044
Other variables are as defined in the present invention.
本发明的一些方案中，上述L 1选自-(CH 2) m-、-NH(CH 2) m-和-O(CH 2) m-，其它变量如本发明所定义。 In some aspects of the present invention, the aforementioned L 1 is selected from -(CH 2 ) m -, -NH(CH 2 ) m -and -O(CH 2 ) m -, and other variables are as defined in the present invention.
本发明的一些方案中，上述L 1选自-CH 2-、-(CH 2) 2-、-NHCH 2-和-OCH 2-，其它变量如本发明所定义。 In some aspects of the present invention, the aforementioned L 1 is selected from -CH 2 -, -(CH 2 ) 2 -, -NHCH 2 -and -OCH 2 -, and other variables are as defined in the present invention.
本发明的一些方案中，上述结构单元
Figure PCTCN2020139562-appb-000045
选自
Figure PCTCN2020139562-appb-000046
Figure PCTCN2020139562-appb-000047
其它变量如本发明所定义。 In some aspects of the present invention, the above-mentioned structural unit
Figure PCTCN2020139562-appb-000045
Selected from
Figure PCTCN2020139562-appb-000046
Figure PCTCN2020139562-appb-000047
Other variables are as defined in the present invention.
本发明的一些方案中，上述结构单元
Figure PCTCN2020139562-appb-000048
选自
Figure PCTCN2020139562-appb-000049
Figure PCTCN2020139562-appb-000050
其它变量如本发明所定义。 In some aspects of the present invention, the above-mentioned structural unit
Figure PCTCN2020139562-appb-000048
Selected from
Figure PCTCN2020139562-appb-000049
Figure PCTCN2020139562-appb-000050
Other variables are as defined in the present invention.
本发明的一些方案中，上述V选自苯基，所述苯基任选被1、2或3个卤素取代，其它变量如本发明所定义。In some embodiments of the present invention, the above-mentioned V is selected from a phenyl group, and the phenyl group is optionally substituted with 1, 2 or 3 halogens, and other variables are as defined in the present invention.
本发明的一些方案中，上述V选自
Figure PCTCN2020139562-appb-000051
其它变量如本发明所定义。 In some aspects of the present invention, the above-mentioned V is selected from
Figure PCTCN2020139562-appb-000051
Other variables are as defined in the present invention.
本发明的一些方案中，上述R e选自-CH 3、-CH 2CH 3、-CH(CH 3) 2、-C(CH 3) 3和苯基，其它变量如本发明所定义。 Some aspects of the present invention, the above-mentioned R e is selected from -CH 3, -CH 2 CH 3, -CH (CH 3) 2, -C (CH 3) 3 , and phenyl, the other variables are as defined in the present invention.
本发明的一些方案中，上述X选自-PO(OH) 2、-P(O)[-OCH 2OC(O)-叔丁基] 2、-P(O)[-OCH 2OC(O)O-异丙基] 2、-P(O)[-N(H)CH(CH 3)C(O)OCH 2CH 3] 2、-P(O)[-N(H)C(CH 3) 2C(O)OCH 2CH 3] 2、
Figure PCTCN2020139562-appb-000052
Figure PCTCN2020139562-appb-000053
其它变量如本发明所定义。 In some aspects of the present invention, the above-mentioned X is selected from -PO(OH) 2 , -P(O)[-OCH 2 OC(O)-tert-butyl] 2 , -P(O)[-OCH 2 OC(O )O-isopropyl] 2 , -P(O)[-N(H)CH(CH 3 )C(O)OCH 2 CH 3 ] 2 , -P(O)[-N(H)C(CH 3 ) 2 C(O)OCH 2 CH 3 ] 2 、
Figure PCTCN2020139562-appb-000052
Figure PCTCN2020139562-appb-000053
Other variables are as defined in the present invention.
本发明的一些方案中，上述X选自-PO(OH) 2、
Figure PCTCN2020139562-appb-000054
Figure PCTCN2020139562-appb-000055
其它变量如本发明所定义。 In some aspects of the present invention, the above-mentioned X is selected from -PO(OH) 2 ,
Figure PCTCN2020139562-appb-000054
Figure PCTCN2020139562-appb-000055
Other variables 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，其选自In some aspects of the present invention, the above-mentioned compound, its isomer or pharmaceutically acceptable salt thereof is selected from
Figure PCTCN2020139562-appb-000056
Figure PCTCN2020139562-appb-000056
Figure PCTCN2020139562-appb-000057
Figure PCTCN2020139562-appb-000057
其中，among them,
R 1、R 2、R 3、R 4、R 5和L 1如本发明所定义。 R 1 , R 2 , R 3 , R 4 , R 5 and L 1 are as defined in the present invention.
本发明还有一些方案是由上述各变量任意组合而来。There are also some schemes of the present invention that come from any combination of the above-mentioned variables.
本发明还提供下述化合物、其异构体或其药学上可接受的盐：The present invention also provides the following compounds, isomers thereof, or pharmaceutically acceptable salts thereof:
Figure PCTCN2020139562-appb-000058
Figure PCTCN2020139562-appb-000058
Figure PCTCN2020139562-appb-000059
Figure PCTCN2020139562-appb-000059
Figure PCTCN2020139562-appb-000060
Figure PCTCN2020139562-appb-000060
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，其选自The present invention also provides the above-mentioned compound, its isomer or pharmaceutically acceptable salt thereof, which is selected from
Figure PCTCN2020139562-appb-000061
Figure PCTCN2020139562-appb-000061
Figure PCTCN2020139562-appb-000062
Figure PCTCN2020139562-appb-000062
Figure PCTCN2020139562-appb-000063
Figure PCTCN2020139562-appb-000063
Figure PCTCN2020139562-appb-000064
Figure PCTCN2020139562-appb-000064
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在制备治疗THR-β激动剂相关疾病的药物上的应用。The present invention also provides the application of the above-mentioned compound, its isomer or pharmaceutically acceptable salt in the preparation of a medicine for the treatment of diseases related to THR-β agonists.
在本发明的一些方案中，上述THR-β激动剂相关药物是用于非酒精性脂肪性肝炎(NASH)的药物。In some aspects of the present invention, the above-mentioned THR-β agonist-related drugs are drugs for non-alcoholic steatohepatitis (NASH).
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。Unless otherwise stated, the following terms and phrases used herein are intended to have the following meanings. A specific term or phrase should not be considered uncertain or unclear without a special definition, but should be understood in its ordinary meaning. When a trade name appears in this article, it is meant to refer to its corresponding commodity or its active ingredient.
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。The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and/or dosage forms that are within the scope of reliable 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 the compound of the present invention, which is prepared from a compound with specific substituents discovered in the present invention and a relatively non-toxic acid or base. When the compound of the present invention contains a relatively acidic functional group, a base addition salt can be obtained by contacting the compound with a sufficient amount of base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salt or similar salts. When the compound of the present invention contains a relatively basic functional group, the acid addition salt can be obtained by contacting the compound with a sufficient amount of acid in a pure 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, hydrogen carbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts, the organic acid includes, for example, 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; also include salts of amino acids (such as arginine, etc.) , And salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain basic and acidic functional groups, which can be converted into 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 salt of the present invention can be synthesized from the parent compound containing acid or base by conventional chemical methods. In general, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of appropriate base or acid in water or organic solvent or a mixture of both.
除非另有规定，术语“C 1-3烷基”用于表示直链或支链的由1至3个碳原子组成的饱和碳氢基团。所述C 1-3烷基包括C 1-2和C 2-3烷基等；其可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。C 1-3烷基的实例包括但不限于甲基(Me)、乙基(Et)、丙基(包括n-丙基和异丙基)等。 Unless otherwise specified, the term "C 1-3 alkyl" is used to indicate a linear or branched saturated hydrocarbon group composed of 1 to 3 carbon atoms. The C 1-3 alkyl group includes C 1-2 and C 2-3 alkyl groups, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or multivalent (such as methine) . Examples of C 1-3 alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.
除非另有规定，术语“C 1-3烷氧基”表示通过一个氧原子连接到分子的其余部分的那些包含1至3个碳原子的烷基基团。所述C 1-3烷氧基包括C 1-2、C 2-3、C 3和C 2烷氧基等。C 1-3烷氧基的实例包括但不限于甲氧基、乙氧基、丙氧基(包括正丙氧基和异丙氧基)等。 Unless otherwise specified, the term "C 1-3 alkoxy" refers to those alkyl groups containing 1 to 3 carbon atoms that are attached to the rest of the molecule through an oxygen atom. The C 1-3 alkoxy group includes C 1-2 , C 2-3 , C 3 and C 2 alkoxy groups and the like. Examples of C 1-3 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.
除非另有规定，“C 3-6环烷基”表示由3至6个碳原子组成的饱和环状碳氢基团，其为单环和双环体系，所述C 3-6环烷基包括C 3-5、C 4-5和C 5-6环烷基等；其可以是一价、二价或者多价。C 3-6环烷基的实例包括，但不限于，环丙基、环丁基、环戊基、环己基等。 Unless otherwise specified, "C 3-6 cycloalkyl" means a saturated cyclic hydrocarbon group composed of 3 to 6 carbon atoms, which is a monocyclic and bicyclic ring system, and the C 3-6 cycloalkyl includes C 3-5 , C 4-5 and C 5-6 cycloalkyl, etc.; it can be monovalent, divalent or multivalent. Examples of C 3-6 cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
除非另有规定，术语“3-6元杂环烷基”本身或者与其他术语联合分别表示由3至6个环原子组成的饱和环状基团，其1、2、3或4个环原子为独立选自O、S和N的杂原子，其余为碳原子，其中氮原子任选地被季铵化，氮和硫杂原子可任选被氧化(即NO和S(O) p，p是1或2)。其包括单环和双环体系，其中双环体系包括螺环、并环和桥环。此外，就该“3-6元杂环烷基”而言，杂原子可以占据杂环烷基与分子其余部分的连接位置。所述3-6元杂环烷基包括4-6元、5-6元、4元、5元和6元杂环烷基等。3-6元杂环烷基的实例包括但不限于氮杂环丁基、氧杂环丁基、硫杂环丁基、吡咯烷基、吡唑烷基、咪唑烷基、四氢噻吩基(包括四氢噻吩-2-基和四氢噻吩-3-基等)、四氢呋喃基(包括四氢呋喃-2-基等)、四氢吡喃基、哌啶基(包括1-哌啶基、2-哌啶基和3-哌啶基等)、哌嗪基(包括1-哌嗪基和2-哌嗪基等)、吗啉基(包括3-吗啉基和4-吗啉基等)、二噁烷基、二噻烷基、异噁唑烷基、异噻唑烷基、1,2-噁嗪基、1,2-噻嗪基、六氢哒嗪基、高哌嗪基或高哌啶基等。 Unless otherwise specified, the term "3-6 membered heterocycloalkyl" by itself or in combination with other terms means a saturated cyclic group consisting of 3 to 6 ring atoms, with 1, 2, 3 or 4 ring atoms. Are heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein nitrogen atoms are optionally quaternized, and nitrogen and sulfur heteroatoms can be optionally oxidized (ie, NO and S(O) p , p Is 1 or 2). It includes monocyclic and bicyclic ring systems, where the bicyclic ring system includes spiro, fused, and bridged rings. In addition, for the "3-6 membered heterocycloalkyl group", a heteroatom may occupy the connection position of the heterocycloalkyl group with the rest of the molecule. The 3-6 membered heterocycloalkyl group includes 4-6 membered, 5-6 membered, 4-membered, 5-membered and 6-membered heterocycloalkyl group. Examples of 3-6 membered heterocycloalkyl include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl ( Including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2- Piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), Dioxanyl, dithiazinyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl, homopiperazinyl, or homopiperazinyl Pyridyl and so on.
除非另有规定，术语“4-6元杂环烷基”本身或者与其他术语联合分别表示由4至6个环原子组成 的饱和环状基团，其1、2、3或4个环原子为独立选自O、S和N的杂原子，其余为碳原子，其中氮原子任选地被季铵化，氮和硫杂原子可任选被氧化(即NO和S(O) p，p是1或2)。其包括单环和双环体系，其中双环体系包括螺环、并环和桥环。此外，就该“4-6元杂环烷基”而言，杂原子可以占据杂环烷基与分子其余部分的连接位置。所述4-6元杂环烷基包括5-6元、4元、5元和6元杂环烷基等。4-6元杂环烷基的实例包括但不限于氮杂环丁基、氧杂环丁基、硫杂环丁基、吡咯烷基、吡唑烷基、咪唑烷基、四氢噻吩基(包括四氢噻吩-2-基和四氢噻吩-3-基等)、四氢呋喃基(包括四氢呋喃-2-基等)、四氢吡喃基、哌啶基(包括1-哌啶基、2-哌啶基和3-哌啶基等)、哌嗪基(包括1-哌嗪基和2-哌嗪基等)、吗啉基(包括3-吗啉基和4-吗啉基等)、二噁烷基、二噻烷基、异噁唑烷基、异噻唑烷基、1,2-噁嗪基、1,2-噻嗪基、六氢哒嗪基、高哌嗪基或高哌啶基等。 Unless otherwise specified, the term "4-6 membered heterocycloalkyl" by itself or in combination with other terms means a saturated cyclic group consisting of 4 to 6 ring atoms, with 1, 2, 3 or 4 ring atoms. Are heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein nitrogen atoms are optionally quaternized, and nitrogen and sulfur heteroatoms can be optionally oxidized (ie, NO and S(O) p , p Is 1 or 2). It includes monocyclic and bicyclic ring systems, where the bicyclic ring system includes spiro, fused, and bridged rings. In addition, with regard to the "4-6 membered heterocycloalkyl group", a heteroatom may occupy the connection position of the heterocycloalkyl group with the rest of the molecule. The 4-6 membered heterocycloalkyl group includes 5-6 membered, 4-membered, 5-membered and 6-membered heterocycloalkyl groups. Examples of 4-6 membered heterocycloalkyl include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl ( Including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2- Piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), Dioxanyl, dithiazinyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl, homopiperazinyl, or homopiperazinyl Pyridyl and so on.
除非另有规定，本发明术语“C 6-10芳环”和“C 6-10芳基”可以互换使用，术语“C 6-10芳环”或“C 6-10芳基”表示由6至10个碳原子组成的具有共轭π电子体系的环状碳氢基团，它可以是单环、稠合双环或稠合三环体系，其中各个环均为芳香性的。其可以是一价、二价或者多价，C 6-10芳基包括C 6-9、C 9、C 10和C 6芳基等。C 6-10芳基的实例包括但不限于苯基、萘基(包括1-萘基和2-萘基等)。 Unless otherwise specified, the terms "C 6-10 aromatic ring" and "C 6-10 aryl" in the present invention can be used interchangeably, and the term "C 6-10 aromatic ring" or "C 6-10 aryl" means A cyclic hydrocarbon group with a conjugated π-electron system composed of 6 to 10 carbon atoms, which can be a monocyclic, fused bicyclic or fused tricyclic system, in which each ring is aromatic. It may be monovalent, divalent or multivalent, and C 6-10 aryl groups include C 6-9 , C 9 , C 10 and C 6 aryl groups and the like. Examples of C 6-10 aryl groups include, but are not limited to, phenyl, naphthyl (including 1-naphthyl, 2-naphthyl, etc.).
除非另有规定，本发明术语“5-10元杂芳环”和“5-10元杂芳基”可以互换使用，术语“5-10元杂芳基”是表示由5至10个环原子组成的具有共轭π电子体系的环状基团，其1、2、3或4个环原子为独立选自O、S和N的杂原子，其余为碳原子。其可以是单环、稠合双环或稠合三环体系，其中各个环均为芳香性的。其中氮原子任选地被季铵化，氮和硫杂原子可任选被氧化(即NO和S(O) p，p是1或2)。5-10元杂芳基可通过杂原子或碳原子连接到分子的其余部分。所述5-10元杂芳基包括5-8元、5-7元、5-6元、5元和6元杂芳基等。所述5-10元杂芳基的实例包括但不限于吡咯基(包括N-吡咯基、2-吡咯基和3-吡咯基等)、吡唑基(包括2-吡唑基和3-吡唑基等)、咪唑基(包括N-咪唑基、2-咪唑基、4-咪唑基和5-咪唑基等)、噁唑基(包括2-噁唑基、4-噁唑基和5-噁唑基等)、三唑基(1H-1,2,3-三唑基、2H-1,2,3-三唑基、1H-1,2,4-三唑基和4H-1,2,4-三唑基等)、四唑基、异噁唑基(3-异噁唑基、4-异噁唑基和5-异噁唑基等)、噻唑基(包括2-噻唑基、4-噻唑基和5-噻唑基等)、呋喃基(包括2-呋喃基和3-呋喃基等)、噻吩基(包括2-噻吩基和3-噻吩基等)、吡啶基(包括2-吡啶基、3-吡啶基和4-吡啶基等)、吡嗪基、嘧啶基(包括2-嘧啶基和4-嘧啶基等)、苯并噻唑基(包括5-苯并噻唑基等)、嘌呤基、苯并咪唑基(包括2-苯并咪唑基等)、苯并噁唑基、吲哚基(包括5-吲哚基等)、异喹啉基(包括1-异喹啉基和5-异喹啉基等)、喹喔啉基(包括2-喹喔啉基和5-喹喔啉基等)或喹啉基(包括3-喹啉基和6-喹啉基等)。 Unless otherwise specified, the terms "5-10 membered heteroaryl ring" and "5-10 membered heteroaryl group" can be used interchangeably in the present invention. The term "5-10 membered heteroaryl group" means a ring consisting of 5 to 10 A cyclic group composed of atoms with a conjugated π-electron system, wherein 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, and the rest are carbon atoms. It can be a monocyclic, fused bicyclic or fused tricyclic system, where each ring is aromatic. Where the nitrogen atom is optionally quaternized, the nitrogen and sulfur heteroatoms may optionally be oxidized (ie NO and S(O) p , p is 1 or 2). The 5-10 membered heteroaryl group can be attached to the rest of the molecule through a heteroatom or a carbon atom. The 5-10 membered heteroaryl groups include 5-8 membered, 5-7 membered, 5-6 membered, 5 membered and 6 membered heteroaryl groups and the like. Examples of the 5-10 membered heteroaryl include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrrolyl, etc.) Azolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5- Oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl and 4H-1, 2,4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl and 5-isoxazolyl, etc.), thiazolyl (including 2-thiazolyl, etc.) , 4-thiazolyl and 5-thiazolyl, etc.), furyl (including 2-furyl and 3-furyl, etc.), thienyl (including 2-thienyl and 3-thienyl, etc.), pyridyl (including 2 -Pyridyl, 3-pyridyl and 4-pyridyl, etc.), pyrazinyl, pyrimidinyl (including 2-pyrimidinyl and 4-pyrimidinyl, etc.), benzothiazolyl (including 5-benzothiazolyl, etc.) , Purinyl, benzimidazolyl (including 2-benzimidazolyl, etc.), benzoxazolyl, indolyl (including 5-indolyl, etc.), isoquinolinyl (including 1-isoquinolinyl) And 5-isoquinolinyl, etc.), quinoxalinyl (including 2-quinoxalinyl and 5-quinoxalinyl, etc.) or quinolinyl (including 3-quinolinyl and 6-quinolinyl, etc.) .
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。Unless otherwise specified, the term "halogen" or "halogen" by itself or as part of another substituent represents a fluorine, chlorine, bromine or iodine atom.
除非另有说明，术语“异构体”意在包括几何异构体、顺反异构体、立体异构体、对映异构体、旋光异构体、非对映异构体和互变异构体。Unless otherwise specified, the term "isomer" is intended to include geometric isomers, cis-trans isomers, stereoisomers, enantiomers, optical isomers, diastereomers, and tautomers. isomer.
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 present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers Isomers, (D)-isomers, (L)-isomers, and their racemic mixtures and other mixtures, such as enantiomers or diastereomer-enriched mixtures, all of these mixtures belong to this Within the scope of the invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All these isomers and their mixtures are included in the scope of the present 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 specified, the term "enantiomer" or "optical isomer" refers to stereoisomers that are mirror images of each other.
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 specified, the term "cis-trans isomer" or "geometric isomer" is caused by the inability to rotate freely because of double bonds or single bonds of ring-forming carbon atoms.
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 specified, the term "diastereomer" refers to a stereoisomer in which the molecule has two or more chiral centers and the relationship between the molecules is non-mirror-image relationship.
除非另有说明，“(+)”表示右旋，“(-)”表示左旋，“(±)”表示外消旋。Unless otherwise specified, "(+)" means right-handed, "(-)" means left-handed, and "(±)" means racemic.
除非另有说明，用楔形实线键
Figure PCTCN2020139562-appb-000065
和楔形虚线键
Figure PCTCN2020139562-appb-000066
表示一个立体中心的绝对构型，用直形实线键
Figure PCTCN2020139562-appb-000067
和直形虚线键
Figure PCTCN2020139562-appb-000068
表示立体中心的相对构型，用波浪线
Figure PCTCN2020139562-appb-000069
表示楔形实线键
Figure PCTCN2020139562-appb-000070
或楔形虚线键
Figure PCTCN2020139562-appb-000071
或用波浪线
Figure PCTCN2020139562-appb-000072
表示直形实线键
Figure PCTCN2020139562-appb-000073
或直形虚线键
Figure PCTCN2020139562-appb-000074
Unless otherwise specified, use wedge-shaped solid line keys
Figure PCTCN2020139562-appb-000065
And wedge-shaped dashed key
Figure PCTCN2020139562-appb-000066
Represents the absolute configuration of a three-dimensional center, with a straight solid line key
Figure PCTCN2020139562-appb-000067
And straight dashed key
Figure PCTCN2020139562-appb-000068
Indicates the relative configuration of the three-dimensional center, using wavy lines
Figure PCTCN2020139562-appb-000069
Represents a wedge-shaped solid line key
Figure PCTCN2020139562-appb-000070
Or wedge-shaped dashed key
Figure PCTCN2020139562-appb-000071
Or use wavy lines
Figure PCTCN2020139562-appb-000072
Represents a straight solid line key
Figure PCTCN2020139562-appb-000073
Or straight dashed key
Figure PCTCN2020139562-appb-000074
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 specified, the terms "enriched in one isomer", "enriched in isomers", "enriched in one enantiomer" or "enriched in enantiomers" refer to one of the isomers or pairs of The content of the enantiomer is less than 100%, and the content of the isomer or enantiomer is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or 96% or greater, or 97% or greater, or 98% or greater, or 99% or greater, or 99.5% or greater, or 99.6% or greater, or 99.7% or greater, or 99.8% or greater, or greater than or equal 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 stated, the term "isomer excess" or "enantiomeric excess" refers to the difference between the relative percentages of two isomers or two enantiomers. For example, if the content of one isomer or enantiomer is 90%, and the content of the other isomer or enantiomer is 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)。The optically active (R)- and (S)-isomers and D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If you want to obtain an enantiomer of a compound of the present invention, it can be prepared by asymmetric synthesis or derivatization with chiral auxiliary agents, in which the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide pure The desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), it forms a diastereomeric salt with a suitable optically active acid or base, and then passes through a conventional method known in the art The diastereoisomers are resolved, and then the pure enantiomers are recovered. In addition, the separation of enantiomers and diastereomers is usually accomplished through the use of chromatography, which uses a chiral stationary phase and is optionally combined with chemical derivatization (for example, the formation of amino groups from amines). Formate).
除非另有说明，结构中带“*”碳原子为手性碳原子，以(R)或(S)单一对映体形式或富含一种对映体形式存在。Unless otherwise specified, the carbon atom with "*" in the structure is a chiral carbon atom and exists in the form of (R) or (S) single enantiomer or enriched in one enantiomer.
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 compound of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms constituting the compound. For example, compounds can be labeled with radioisotopes, such as tritium ( 3 H), iodine-125 ( 125 I), or C-14 ( 14 C). For another example, deuterium can be substituted for hydrogen to form deuterated drugs. The bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon. Compared with undeuterated drugs, deuterated drugs can reduce toxic side effects and increase drug stability. , Enhance the efficacy, extend the biological half-life of drugs and other advantages. All changes in the isotopic composition of the compounds of the present invention, whether radioactive or not, are included in the scope of the present invention.
术语“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。The term "optional" or "optionally" refers to the event or condition described later that may but not necessarily occur, and the description includes the situation in which the event or condition occurs and the situation 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 specific atom are replaced by substituents, and may include deuterium and hydrogen variants, as long as the valence of the specific atom is normal and the substituted compound is stable of. When the substituent is oxygen (ie =O), it means that two hydrogen atoms are replaced. Oxygen substitution does not occur on aromatic groups. The term "optionally substituted" means that it can be substituted or unsubstituted. Unless otherwise specified, the type and number of substituents can be arbitrary on the basis that they can be chemically realized.
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 (such as 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 Rs, the group can optionally be substituted with up to two Rs, and R has independent options in each case. In addition, combinations of substituents and/or variants thereof are only permitted 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 a linking group is 0, such as -(CRR) 0 -, it means that the linking group is a single bond.
当一个取代基数量为0时，表示该取代基是不存在的，比如-A-(R) 0表示该结构实际上是-A。 When the number of a substituent is 0, it means that the substituent is absent. For example, -A-(R) 0 means that the structure is actually -A.
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。When a substituent is vacant, it means that the substituent is absent. For example, when X in A-X is vacant, it means that the structure is actually A.
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 connected groups are directly connected. For example, when L in A-L-Z represents a single bond, it means that the structure is actually A-Z.
当一个取代基的键可以交叉连接到一个环上的两个以上原子时，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 PCTCN2020139562-appb-000075
表示其取代基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。 When the bond of a substituent can be cross-connected to two or more atoms on a ring, the substituent can be bonded to any atom on the ring, for example, a structural unit
Figure PCTCN2020139562-appb-000075
It means that the substituent R can be substituted at any position on the cyclohexyl or cyclohexadiene. When the listed substituents do not indicate which atom is connected to the substituted group, such substituents can be bonded via any atom. For example, a pyridyl group can pass through any one of the pyridine ring as a substituent. The carbon atom is attached to the substituted group.
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 PCTCN2020139562-appb-000076
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 PCTCN2020139562-appb-000077
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 PCTCN2020139562-appb-000078
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 the listed linking group does not indicate its linking direction, its linking direction is arbitrary, for example,
Figure PCTCN2020139562-appb-000076
The middle linking group L is -MW-, at this time -MW- can be formed by connecting ring A and ring B in the same direction as the reading order from left to right
Figure PCTCN2020139562-appb-000077
It can also be formed by connecting ring A and ring B in the opposite direction to the reading order from left to right
Figure PCTCN2020139562-appb-000078
Combinations of the linking groups, substituents, and/or variants thereof are only permitted if such combinations result in stable compounds.
除非另有规定，当某一基团具有一个或多个可连接位点时，该基团的任意一个或多个位点可以通过化学键与其他基团相连。当该化学键的连接方式是不定位的，且可连接位点存在H原子时，则连接化学键时，该位点的H原子的个数会随所连接化学键的个数而对应减少变成相应价数的基团。所述位点与其他基团连接的化学键可以用直形实线键
Figure PCTCN2020139562-appb-000079
直形虚线键
Figure PCTCN2020139562-appb-000080
或波浪线
Figure PCTCN2020139562-appb-000081
表示。例如- OCH 3中的直形实线键表示通过该基团中的氧原子与其他基团相连；
Figure PCTCN2020139562-appb-000082
中的直形虚线键表示通过该基团中的氮原子的两端与其他基团相连；
Figure PCTCN2020139562-appb-000083
中的波浪线表示通过该苯基基团中的1和2位碳原子与其他基团相连；
Figure PCTCN2020139562-appb-000084
表示该哌啶基上的任意可连接位点可以通过1个化学键与其他基团相连，至少包括
Figure PCTCN2020139562-appb-000085
这4种连接方式，即使-N-上画出了H原子，但是
Figure PCTCN2020139562-appb-000086
仍包括
Figure PCTCN2020139562-appb-000087
这种连接方式的基团，只是在连接1个化学键时，该位点的的H会对应减少1个变成相应的一价哌啶基。 Unless otherwise specified, when a group has one or more connectable sites, any one or more sites of the group can be connected to other groups through chemical bonds. When the connection method of the chemical bond is not positioned, and there is a H atom at the connectable site, when the chemical bond is connected, the number of H atoms at the site will correspondingly decrease with the number of chemical bonds connected to become the corresponding valence number的组。 The group. The chemical bond between the site and other groups can be a straight solid bond
Figure PCTCN2020139562-appb-000079
Straight dashed key
Figure PCTCN2020139562-appb-000080
Or wavy line
Figure PCTCN2020139562-appb-000081
Said. For example- the straight solid bond in OCH 3 means that it is connected to other groups through the oxygen atom in the group;
Figure PCTCN2020139562-appb-000082
The straight dashed bond in indicates that the two ends of the nitrogen atom in the group are connected to other groups;
Figure PCTCN2020139562-appb-000083
The wavy line in indicates that the phenyl group is connected to other groups through the 1 and 2 carbon atoms;
Figure PCTCN2020139562-appb-000084
Indicates that any linkable site on the piperidinyl group can be connected to other groups through a chemical bond, including at least
Figure PCTCN2020139562-appb-000085
These four connection methods, even though the H atom is drawn on -N-, but
Figure PCTCN2020139562-appb-000086
Still include
Figure PCTCN2020139562-appb-000087
The group in this connection mode, only when one chemical bond is connected, the H at this position will decrease by one and become the corresponding monovalent piperidinyl group.
除非另有规定，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个原子的“环”。Unless otherwise specified, the number of atoms in a ring is generally defined as the number of ring members. For example, "5-7 membered ring" refers to a "ring" in which 5-7 atoms are arranged around.
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 (such as acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl, such as tert-butoxycarbonyl (Boc) ; Arylmethyloxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethyloxycarbonyl (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 so on. The term "hydroxy protecting group" refers to a protecting group suitable for preventing side reactions of the hydroxyl group. Representative hydroxy protecting groups include but are not limited to: alkyl groups, such as methyl, ethyl, and tert-butyl; acyl groups, such as alkanoyl groups (such as acetyl); arylmethyl groups, such as benzyl (Bn), p-methyl Oxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyl Dimethylsilyl (TBS) and so on.
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 listed below, the embodiments formed by combining them with other chemical synthesis methods, and those well known to those skilled in the art Equivalent alternatives, preferred implementations include but are not limited to the embodiments of the present invention.
本发明的化合物可以通过本领域技术人员所熟知的常规方法来确认结构，如果本发明涉及化合物的绝对构型，则该绝对构型可以通过本领域常规技术手段予以确证。例如单晶X射线衍射法(SXRD)，把培养出的单晶用Bruker D8 venture衍射仪收集衍射强度数据，光源为CuKα辐射，扫描方式：
Figure PCTCN2020139562-appb-000088
扫描，收集相关数据后，进一步采用直接法(Shelxs97)解析晶体结构，便可以确证绝对构型。 The structure of the compound of the present invention can be confirmed by conventional methods well known to those skilled in the art. If the present invention relates to the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the field. For example, single crystal X-ray diffraction (SXRD), the cultured single crystal is collected with the Bruker D8 venture diffractometer to collect the diffraction intensity data, the light source is CuKα radiation, and the scanning method:
Figure PCTCN2020139562-appb-000088
After scanning and collecting relevant data, the direct method (Shelxs97) is further used to analyze the crystal structure to confirm the absolute configuration.
本发明所使用的溶剂可经市售获得。The solvent used in the present invention is commercially available.
本发明采用下述缩略词：aq代表水；HATU代表O-(7-氮杂苯并三氮唑-1-基)-N,N,N,N-四甲基脲六氟膦盐；eq代表当量、等量；ACN代表乙腈；DCM代表二氯甲烷；PE代表石油醚；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；MOM代表甲氧甲基；DEA代表二乙胺；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；iPrOH或IPA代表异丙醇；TBS代表叔丁基二甲基硅；Bn代表苄基；Et代表乙基；mp代表熔点；Prep-HPLC代表制备高效液相色谱；TLC代表薄层层析色谱；℃代表摄氏度。 The present invention uses the following abbreviations: aq stands for water; HATU stands for O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethylurea hexafluorophosphonium salt; eq stands for equivalent and equivalent; ACN stands for acetonitrile; DCM stands for dichloromethane; PE stands for petroleum ether; DMSO stands for dimethyl sulfoxide; EtOAc stands for ethyl acetate; EtOH stands for ethanol; MeOH stands for methanol; Cbz stands for benzyloxycarbonyl, yes An amine protecting group; Boc represents tert-butoxycarbonyl is an amine protecting group; MOM represents methoxymethyl; DEA represents diethylamine; rt represents room temperature; O/N represents overnight; THF represents tetrahydrofuran; Boc 2 O stands for di-tert-butyl dicarbonate; TFA stands for trifluoroacetic acid; DIPEA stands for diisopropylethylamine; iPrOH or IPA stands for isopropanol; TBS stands for tert-butyl dimethyl silicon; Bn stands for benzyl; Et Stands for ethyl; mp stands for melting point; Prep-HPLC stands for preparative high performance liquid chromatography; TLC stands for thin layer chromatography; °C stands for Celsius.
化合物依据本领域常规命名原则或者使用
Figure PCTCN2020139562-appb-000089
软件命名，市售化合物采用供应商目录名称。 Compounds are based on conventional naming principles in the field or use
Figure PCTCN2020139562-appb-000089
The software is named, and the commercially available compounds use the supplier catalog name.
技术效果Technical effect
本发明化合物对甲状腺受体β有较强的激动活性。本发明化合物生物利用度较好，在肝脏中的暴露量较高，血浆、心脏中暴露量较低，对于肝脏的靶向性较好。对于DIO+CCl 4模型小鼠的非酒精性脂肪肝病活动性评分改善明显。 The compound of the present invention has strong agonistic activity on thyroid receptor β. The compound of the present invention has good bioavailability, high exposure in the liver, low exposure in plasma and heart, and good liver targeting. For DIO+CCl 4 model mice, the non-alcoholic fatty liver disease activity score improved significantly.
附图说明Description of the drawings
图1为化合物6丙酮合物的分子立体结构椭球图。Figure 1 is an ellipsoid diagram of the molecular structure of compound 6 acetonate.
图2为化合物6丙酮合物的沿b轴方向的晶胞堆积图。Fig. 2 is a unit cell packing diagram of compound 6 acetonate along the b-axis.
图3为化合物6丙酮合物的化合物的绝对构型图。Figure 3 is the absolute configuration diagram of the compound of compound 6 acetonate.
图4a和4b为给予化合物6的HFD-CCl 4诱导的NASH模型小鼠的肝重变化和肝体比示意图(注：以NASH组作为对照，数据以平均值±标准差展示。*号表示统计学差异，***p＜0.001,**p＜0.01,*p＜0.05)。 Figures 4a and 4b are schematic diagrams of liver weight changes and liver-to-body ratios of NASH model mice induced by HFD-CCl 4 administration of compound 6 (Note: The NASH group is used as a control, and the data are displayed as mean ± standard deviation. * indicates statistics Differences in science, ***p<0.001, **p<0.01, *p<0.05).
图5a和5b为给予化合物6的HFD-CCl 4诱导的NASH模型小鼠的肝脏组织病理分析示意图(注：以NASH组作为对照，数据以平均值±标准差展示。*号表示统计学差异，***p＜0.001,**p＜0.01,*p＜0.05。 Figures 5a and 5b are schematic diagrams of liver histopathological analysis of NASH model mice induced by HFD-CCl 4 given compound 6 (Note: The NASH group is used as a control, and the data are shown as mean ± standard deviation. * indicates statistical difference, ***p<0.001, **p<0.01, *p<0.05.
图6a和6b为给予化合物6和化合物36的HFD-CCl 4诱导的NASH模型小鼠的肝重变化和肝体比示意图。 Figures 6a and 6b are schematic diagrams of liver weight changes and liver-to-body ratios in NASH model mice induced by HFD-CCl 4 administration of compound 6 and compound 36.
图7a和7b为给予化合物6和化合物36的HFD-CCl 4诱导的NASH模型小鼠的肝脏组织病理分析示意图。 Figures 7a and 7b are schematic diagrams of liver tissue pathological analysis of NASH model mice induced by HFD-CCl 4 administered with compound 6 and compound 36.
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 present invention will be described in detail through the following examples, but it is not meant to impose any disadvantageous restriction on the present invention. The present invention has been described in detail herein, and its specific embodiments are also disclosed. For those skilled in the art, various changes and improvements can be made to the specific embodiments of the present invention without departing from the spirit and scope of the present invention. Will be obvious.
实施例1Example 1
Figure PCTCN2020139562-appb-000090
Figure PCTCN2020139562-appb-000090
合成路线：synthetic route:
Figure PCTCN2020139562-appb-000091
Figure PCTCN2020139562-appb-000091
步骤1：化合物1-2的合成Step 1: Synthesis of compound 1-2
将化合物1-1(0.2g,1.3mmol)，丙二酸(0.21g,2mmol)加入至吡啶(2mL)，加入哌啶(0.018g,0.3mmol,0.02mL)，升温至120℃搅拌1.5小时。TLC显示原料消失，存在产物生成。降至24℃，加2mL水稀释，小心用12N HCl调pH小于3，有沉淀析出。过滤，取滤渣，未经纯化。得到化合物1-2。Add compound 1-1 (0.2g, 1.3mmol), malonic acid (0.21g, 2mmol) to pyridine (2mL), add piperidine (0.018g, 0.3mmol, 0.02mL), heat to 120°C and stir for 1.5 hours . TLC showed that the starting material disappeared and the product was formed. Reduce to 24°C, dilute with 2mL of water, carefully adjust the pH to less than 3 with 12N HCl, and precipitate. Filter and take the filter residue without purification. Compound 1-2 is obtained.
1H NMR(400MHz,CDCl 3)δ＝2.29(s,3H),3.77(s,3H),6.52(d,J＝16.18Hz,1H),6.82(s,1H),7.07(d,J＝8.59Hz,2H),7.51(d,J＝15.85Hz,1H)。 1 H NMR (400MHz, CDCl 3 )δ = 2.29 (s, 3H), 3.77 (s, 3H), 6.52 (d, J = 16.18 Hz, 1H), 6.82 (s, 1H), 7.07 (d, J = 8.59Hz, 2H), 7.51(d, J=15.85Hz, 1H).
步骤2：化合物1-3的合成Step 2: Synthesis of compound 1-3
将化合物1-2(6.06g,32mmol)，加入至四氢呋喃(120mL)，加入5％钯碳(0.6g)，24℃搅拌18小时。TLC显示原料消失，存在产物生成。硅藻土过滤，减压浓缩。粗品经硅胶柱层析纯化(石油醚:乙 酸乙酯＝5:1-2:1)，得到化合物1-3。Compound 1-2 (6.06 g, 32 mmol) was added to tetrahydrofuran (120 mL), 5% palladium on carbon (0.6 g) was added, and the mixture was stirred at 24° C. for 18 hours. TLC showed that the starting material disappeared and the product was formed. Filter through celite and concentrate under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1-2:1) to obtain compound 1-3.
1H NMR(400MHz,CDCl 3)δ＝2.24(s,3H),2.50(m,2H),2.74(t,J＝7.70Hz,2H),3.71(s,3H),6.55-6.63(m,3H)。 1 H NMR (400MHz, CDCl 3 ) δ = 2.24 (s, 3H), 2.50 (m, 2H), 2.74 (t, J = 7.70 Hz, 2H), 3.71 (s, 3H), 6.55-6.63 (m, 3H).
步骤3：化合物1-4的合成Step 3: Synthesis of compound 1-4
将化合物1-3(0.24g,1.2mmol)加入至多聚磷酸(3g)，升温至80℃搅拌1小时。TLC显示原料消失，存在产物生成。降至24℃，加30mL冰水稀释，乙酸乙酯(10mL×3)萃取，饱和碳酸氢钠水(10mL×2)洗，饱和食盐水(10mL)洗。无水硫酸钠干燥，减压浓缩。硅胶柱层析纯化(石油醚:乙酸乙酯＝2:1)，得到化合物1-4。Compound 1-3 (0.24g, 1.2mmol) was added to polyphosphoric acid (3g), and the temperature was raised to 80°C and stirred for 1 hour. TLC showed that the starting material disappeared and the product was formed. Reduce to 24°C, dilute with 30 mL ice water, extract with ethyl acetate (10 mL×3), wash with saturated sodium bicarbonate water (10 mL×2), and wash with saturated brine (10 mL). Dry over anhydrous sodium sulfate and concentrate under reduced pressure. Purification by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1) to obtain compound 1-4.
1H NMR(400MHz,CDCl 3)δ＝2.49-2.51(m,3H),2.54-2.57(m,2H),2.97-3.03(m,2H)3.83,(s,3H),6.72(d,J＝0.55Hz,1H),6.90(s,1H)。 1 H NMR (400MHz, CDCl 3 ) δ = 2.49-2.51 (m, 3H), 2.54-2.57 (m, 2H), 2.97-3.03 (m, 2H) 3.83, (s, 3H), 6.72 (d, J = 0.55 Hz, 1H), 6.90 (s, 1H).
步骤4：化合物1-5的合成Step 4: Synthesis of compound 1-5
将化合物1-4(2.4g,13.6mmol)，加入至三溴化硼的二氯甲烷溶液(1M,20mL)。降温至0℃搅拌0.5小时，升温至40℃反应18小时，TLC显示原料消失，存在产物生成。减压浓缩，硅胶柱层析纯化(二氯甲烷/甲醇＝50:1)得到化合物1-5。Compound 1-4 (2.4 g, 13.6 mmol) was added to a dichloromethane solution of boron tribromide (1M, 20 mL). The temperature was lowered to 0°C and stirred for 0.5 hour, and the temperature was raised to 40°C for 18 hours. TLC showed that the raw material disappeared and the product was formed. Concentrate under reduced pressure, and purify by silica gel column chromatography (dichloromethane/methanol=50:1) to obtain compound 1-5.
1H NMR(400MHz,CDCl 3)δ＝2.45(s,3H),2.51-2.54(m,2H),2.91-2.96(m,2H),6.54(s,1H),6.67(d,J＝1.28Hz,1H),10.34(s,1H)。 1 H NMR (400MHz, CDCl 3 ) δ = 2.45 (s, 3H), 2.51-2.54 (m, 2H), 2.91-2.96 (m, 2H), 6.54 (s, 1H), 6.67 (d, J = 1.28 Hz, 1H), 10.34 (s, 1H).
步骤5：化合物BB-1的合成Step 5: Synthesis of compound BB-1
将化合物1-5(0.14g,0.86mmol)，加入至二氯甲烷(3mL)，加入N,N-二甲基-4吡啶(0.2g,1.5mmol)，叔丁基二甲基氯化硅(0.2g,1.3mmol)。20℃搅拌24小时。TLC显示原料消失，存在产物生成。加10mL饱和氯化铵水稀释，二氯甲烷(3×10mL)萃取，饱和食盐水(10mL)洗。无水硫酸钠干燥，减压浓缩。硅胶柱层析(石油醚/乙酸乙酯＝1:0-30:1)，得到化合物BB-1。Compound 1-5 (0.14g, 0.86mmol) was added to dichloromethane (3mL), N,N-dimethyl-4pyridine (0.2g, 1.5mmol) was added, tert-butyldimethyl silicon chloride (0.2g, 1.3mmol). Stir at 20°C for 24 hours. TLC showed that the starting material disappeared and the product was formed. Dilute with 10 mL saturated ammonium chloride water, extract with dichloromethane (3×10 mL), and wash with saturated brine (10 mL). Dry over anhydrous sodium sulfate and concentrate under reduced pressure. Silica gel column chromatography (petroleum ether/ethyl acetate=1:0-30:1) to obtain compound BB-1.
1H NMR(400MHz,CDCl 3)δ＝0.23(s,6H),0.96(s,9H),2.46-2.49(m,3H),2.53-2.58(m,2H),2.93-3.00(m,2H),6.60-6.64(m,1H),6.75-6.82(m,1H)。 1 H NMR (400MHz, CDCl 3 )δ = 0.23 (s, 6H), 0.96 (s, 9H), 2.46-2.49 (m, 3H), 2.53-2.58 (m, 2H), 2.93-3.00 (m, 2H) ), 6.60-6.64 (m, 1H), 6.75-6.82 (m, 1H).
步骤6：化合物1-7的合成Step 6: Synthesis of compounds 1-7
将化合物1-6(5g,36.71mmol)加入至乙腈(50mL)，降至0℃，分批次缓慢加入N-溴代丁二酰亚胺(6.86g,38.55mmol)，控制温度在0-5℃，完毕后升温至20℃继续搅拌3小时反应液减压浓缩。加入乙酸乙酯(50mL)，半饱和氯化钠溶液(30mL×3)洗，有机相经无水硫酸钠干燥后，过滤，减压浓缩。得到化合物1-7。经H-NMR鉴定。Compound 1-6 (5g, 36.71mmol) was added to acetonitrile (50mL), reduced to 0°C, N-bromosuccinimide (6.86g, 38.55mmol) was slowly added in batches, and the temperature was controlled at 0- At 5°C, after completion, the temperature was raised to 20°C and stirring was continued for 3 hours. Ethyl acetate (50 mL) was added, washed with half-saturated sodium chloride solution (30 mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Compound 1-7 is obtained. It was identified by H-NMR.
1H NMR(400MHz,CDCl 3)δ＝7.29(d,J＝2.4Hz,1H),7.19-7.13(m,1H),6.67-6.61(m,1H),3.24-3.12(m,1H),1.27-1.22(m,6H)。 1 H NMR (400MHz, CDCl 3 )δ = 7.29 (d, J = 2.4 Hz, 1H), 7.19-7.13 (m, 1H), 6.67-6.61 (m, 1H), 3.24-3.12 (m, 1H), 1.27-1.22 (m, 6H).
步骤7：化合物1-8的合成Step 7: Synthesis of compounds 1-8
化合物1-7(2g,9.30mmol)加入至乙腈(20mL)，加入碳酸铯(4.54g,13.95mmol)，溴化苄(1.91g,11.16mmol)，升温至70℃继续搅拌5小时。TLC(石油醚:乙酸乙酯＝10:1)显示原料消失，存在新点生成。反应液减压浓缩。加入乙酸乙酯(50mL)，半饱和氯化钠溶液(30mL)洗，有机相经无水硫酸钠干 燥后，过滤，减压浓缩。粗品经硅胶柱层析纯化(石油醚:乙酸乙酯＝10:1)，得到化合物1-8。经H-NMR鉴定。Compound 1-7 (2 g, 9.30 mmol) was added to acetonitrile (20 mL), cesium carbonate (4.54 g, 13.95 mmol), benzyl bromide (1.91 g, 11.16 mmol) were added, and the temperature was raised to 70° C. and stirring was continued for 5 hours. TLC (petroleum ether: ethyl acetate = 10:1) showed that the raw materials disappeared and new spots were formed. The reaction solution was concentrated under reduced pressure. Add ethyl acetate (50 mL), wash with half-saturated sodium chloride solution (30 mL), dry the organic phase over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain compound 1-8. It was identified by H-NMR.
1H NMR(400MHz,CDCl 3)δ＝7.46-7.34(m,5H),7.34-7.32(m,1H),7.26-7.22(m,1H),6.78(d,J＝8.6Hz,1H),5.09-5.04(m,2H),3.45-3.30(m,1H),1.26-1.19(m,6H)。 1 H NMR(400MHz, CDCl 3 )δ=7.46-7.34(m,5H), 7.34-7.32(m,1H), 7.26-7.22(m,1H), 6.78(d,J=8.6Hz,1H), 5.09-5.04 (m, 2H), 3.45-3.30 (m, 1H), 1.26-1.19 (m, 6H).
步骤8：化合物1-9的合成Step 8: Synthesis of compounds 1-9
将化合物1-8(500.00mg,1.64mmol)溶解于四氢呋喃(10mL)中，降温至-78℃，滴加正丁基锂(2.5M,982.93μL)，反应在-78℃搅拌0.5小时，滴加原料BB-1(452.88mg,1.64mmol)的四氢呋喃(5mL)溶液，缓慢升温至20℃搅拌0.5小时。反应液加入至乙酸乙酯(30mL)和饱和氯化铵溶液(10mL)。有机相经无水硫酸钠干燥后，过滤，减压浓缩。粗品经硅胶柱层析纯化(石油醚:乙酸乙酯＝5:1)，得到化合物1-9。Compound 1-8 (500.00mg, 1.64mmol) was dissolved in tetrahydrofuran (10mL), the temperature was reduced to -78°C, n-butyllithium (2.5M, 982.93μL) was added dropwise, and the reaction was stirred at -78°C for 0.5 hours. Add raw material BB-1 (452.88mg, 1.64mmol) in tetrahydrofuran (5mL) solution, slowly raise the temperature to 20°C and stir for 0.5 hour. The reaction solution was added to ethyl acetate (30 mL) and saturated ammonium chloride solution (10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain compound 1-9.
1H NMR(400MHz,CDCl 3)δ＝7.51-7.39(m,4H),7.38-7.30(m,1H),7.25-7.23(m,1H),7.16-7.11(m,1H),6.94-6.91(m,1H),6.89-6.86(m,1H),6.55-6.51(m,1H),6.24-6.19(m,1H),5.16-5.05(m,2H),3.51-3.41(m,1H),3.40-3.35(m,2H),2.01-1.96(m,2H),1.58-1.50(m,3H),1.28-1.23(m,6H),1.04-0.97(m,9H),0.22(s,6H)。 1 H NMR (400MHz, CDCl 3 ) δ = 7.51-7.39 (m, 4H), 7.38-7.30 (m, 1H), 7.25-7.23 (m, 1H), 7.16-7.11 (m, 1H), 6.94-6.91 (m,1H),6.89-6.86(m,1H),6.55-6.51(m,1H),6.24-6.19(m,1H),5.16-5.05(m,2H),3.51-3.41(m,1H) , 3.40-3.35(m,2H),2.01-1.96(m,2H),1.58-1.50(m,3H),1.28-1.23(m,6H),1.04-0.97(m,9H),0.22(s, 6H).
步骤9：化合物1-10的合成Step 9: Synthesis of compound 1-10
将化合物1-9(0.16g,318.24μmol)溶解于二氯甲烷(2mL)中，滴加三氟乙酸(54.43mg,477.37μmol)，三乙基硅氢(111.02mg,954.73μmol)，20℃搅拌1小时。反应液减压浓缩。得到化合物1-10，直接进行下一步反应。Compound 1-9 (0.16g, 318.24μmol) was dissolved in dichloromethane (2mL), and trifluoroacetic acid (54.43mg, 477.37μmol) and triethylsilylhydrogen (111.02mg, 954.73μmol) were added dropwise at 20°C Stir for 1 hour. The reaction solution was concentrated under reduced pressure. Compound 1-10 is obtained, and the next step reaction is directly carried out.
步骤10：化合物1-11的合成Step 10: Synthesis of compound 1-11
将化合物1-10(0.4g,821.76μmol)溶解于甲醇(8mL)和四氢呋喃(8mL)中，加入氟化铵(304.36mg,8.22mmol)，升至50℃搅拌3小时。TLC(石油醚:乙酸乙酯＝3:1)显示原料消失，存在新点生成。反应减压浓缩，加入乙酸乙酯(50mL)，半饱和氯化钠溶液洗(30mL)洗，乙酸乙酯经无水硫酸钠干燥后，过滤，减压浓缩。粗品经硅胶柱层析纯化(石油醚:乙酸乙酯＝3:1)，得到化合物1-11，经LCMS鉴定。Compound 1-10 (0.4 g, 821.76 μmol) was dissolved in methanol (8 mL) and tetrahydrofuran (8 mL), ammonium fluoride (304.36 mg, 8.22 mmol) was added, and the temperature was raised to 50° C. and stirred for 3 hours. TLC (petroleum ether: ethyl acetate = 3:1) showed that the raw materials disappeared and new spots were formed. The reaction was concentrated under reduced pressure, ethyl acetate (50 mL) was added, washed with half-saturated sodium chloride solution (30 mL), ethyl acetate was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain compound 1-11, which was identified by LCMS.
[M+1] +＝373.3 [M+1] + = 373.3
步骤11：化合物1-12的合成Step 11: Synthesis of compound 1-12
将化合物1-11(0.3g,805.37μmol)溶解于二甲基甲酰胺(2mL)中，加入碳酸铯(393.61mg,1.21mmol)，0℃，滴加三氟甲磺酸甲基二乙基磷脂(265.94mg,885.91μmol)，逐渐升温至20℃搅拌16小时。反应液加入乙酸乙酯(50mL)，半饱和氯化钠溶液洗(30mL×4)洗，乙酸乙酯经无水硫酸钠干燥后，过滤，减压浓缩。粗品经硅胶柱层析纯化(石油醚:乙酸乙酯＝1:3)，得到化合物1-12。Compound 1-11 (0.3g, 805.37μmol) was dissolved in dimethylformamide (2mL), cesium carbonate (393.61mg, 1.21mmol) was added, 0°C, methyldiethyl trifluoromethanesulfonate was added dropwise Phospholipids (265.94mg, 885.91μmol) were gradually heated to 20°C and stirred for 16 hours. The reaction solution was added with ethyl acetate (50 mL), washed with half-saturated sodium chloride solution (30 mL×4), and the ethyl acetate was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:3) to obtain compound 1-12.
1H NMR(400MHz,CDCl 3)δ＝7.47-7.30(m,5H),6.96(d,J＝2.0Hz,1H),6.79-6.73(m,2H),6.72-6.68(m,1H),6.61-6.57(m,1H),5.05-5.00(m,2H),4.28-4.24(m,4H),3.42-3.31(m,1H),3.09-2.99(m,1H),2.97-2.89(m,3H),2.87-2.78(m,1H),2.63-2.51(m,1H),2.06-1.96(m,1H),1.95-1.90(m,3H),1.39(t,J＝7.2Hz,6H),1.22-1.16(m,6H)。 1 H NMR (400MHz, CDCl 3 ) δ = 7.47-7.30 (m, 5H), 6.96 (d, J = 2.0 Hz, 1H), 6.79-6.73 (m, 2H), 6.72-6.68 (m, 1H), 6.61-6.57 (m, 1H), 5.05-5.00 (m, 2H), 4.28-4.24 (m, 4H), 3.42-3.31 (m, 1H), 3.09-2.99 (m, 1H), 2.97-2.89 (m ,3H), 2.87-2.78(m,1H),2.63-2.51(m,1H),2.06-1.96(m,1H),1.95-1.90(m,3H),1.39(t,J=7.2Hz,6H ), 1.22-1.16 (m, 6H).
步骤12：1-13的合成Step 12: Synthesis of 1-13
将化合物1-12(0.1g,191.35μmol)溶解于甲醇(3mL)中，加入钯碳(0.1g,191.35μmol,钯含量5％)，氢气置换三次，20℃，15psi搅拌1小时。反应过滤除去钯碳，滤液减压浓缩。得到化合物1-13，直接进行下一步反应。[M+1] +＝433.2 Compound 1-12 (0.1g, 191.35μmol) was dissolved in methanol (3mL), palladium on carbon (0.1g, 191.35μmol, palladium content 5%) was added, replaced with hydrogen three times, and stirred at 20°C, 15psi for 1 hour. The reaction was filtered to remove palladium on carbon, and the filtrate was concentrated under reduced pressure. Compound 1-13 is obtained, and the next step reaction is directly carried out. [M+1] + = 433.2
步骤13：化合物1的合成Step 13: Synthesis of compound 1
将化合物1-13(0.08g,184.98μmol)溶解于二氯甲烷(5mL)中，降至0℃，加入三甲基溴化硅(283.18mg,1.85mmol)，逐渐升温至20℃搅拌16小时。反应减压浓缩，加入乙酸乙酯(30mL)，半饱和氯化钠溶液洗(20mL)洗，乙酸乙酯经无水硫酸钠干燥后，过滤，减压浓缩。粗品经prep-HPLC(柱型:Phenomenex luna C18 80mm*40mm*3μm；流动相:[H 2O(0.04％HCl)-乙腈]；B(ACN)％(乙腈):32％-52％,7min)纯化。得到化合物1。 Dissolve compound 1-13 (0.08g, 184.98μmol) in dichloromethane (5mL), reduce to 0℃, add trimethyl silicon bromide (283.18mg, 1.85mmol), gradually increase the temperature to 20℃ and stir for 16 hours . The reaction was concentrated under reduced pressure, ethyl acetate (30 mL) was added, washed with half-saturated sodium chloride solution (20 mL), ethyl acetate was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was subjected to prep-HPLC (column type: Phenomenex luna C18 80mm*40mm*3μm; mobile phase: [H 2 O (0.04% HCl)-acetonitrile]; B (ACN)% (acetonitrile): 32%-52%, 7min )purification. Compound 1 was obtained.
[M-1] +＝375.2 [M-1] + = 375.2
1H NMR(400MHz,CD 3OD)δ＝6.82-6.80(m,1H),6.78-6.76(m,1H),6.62-6.56(m,3H),4.24(dd,J＝3.8,8.6Hz,1H),4.19(d,J＝10.4Hz,2H),3.26-3.15(m,1H),3.00(td,J＝8.1,16.0Hz,1H),2.80(ddd,J＝4.3,8.8,15.9Hz,1H),2.52(qd,J＝8.5,12.6Hz,1H),1.97-1.91(m,1H),1.89(s,3H),1.18-1.09(m,6H)。 1 H NMR (400MHz, CD 3 OD) δ = 6.82-6.80 (m, 1H), 6.78-6.76 (m, 1H), 6.62-6.56 (m, 3H), 4.24 (dd, J = 3.8, 8.6 Hz, 1H), 4.19 (d, J = 10.4 Hz, 2H), 3.26-3.15 (m, 1H), 3.00 (td, J = 8.1, 16.0 Hz, 1H), 2.80 (ddd, J = 4.3, 8.8, 15.9 Hz , 1H), 2.52 (qd, J=8.5, 12.6 Hz, 1H), 1.97-1.91 (m, 1H), 1.89 (s, 3H), 1.18-1.09 (m, 6H).
实施例2、3、4、5、6和7Examples 2, 3, 4, 5, 6, and 7
Figure PCTCN2020139562-appb-000092
Figure PCTCN2020139562-appb-000092
合成路线：synthetic route:
Figure PCTCN2020139562-appb-000093
Figure PCTCN2020139562-appb-000093
化合物2、3、4、5、7的绝对构型由化合物6的构型确定后推测而来。The absolute configurations of compounds 2, 3, 4, 5, and 7 were inferred from the configuration of compound 6.
步骤1：化合物2-1和2-2的合成Step 1: Synthesis of compounds 2-1 and 2-2
将化合物1-13(500mg,1.16mmol)进行SFC分离。经SFC(柱型:DAICEL CHIRALPAK AD(250mm*30mm,10μm)；流动相:[Neu-EtOH]:33％-33％,6min)分离得到化合物2-1和2-2。分析方法:仪器:Thar analytical SFC,柱型:Chiralpak AD-3，50mm*4.6mm*3μm,流动相:A:CO 2，B：EtOH(0.05％IPAm),梯度:B:A＝5％～50％，4min,流速:4.0mL/min,柱温:35℃,波长:220nm,柱压:100bar。化合物2-1保留时间：1.26min。化合物2-2保留时间：1.42min。 Compound 1-13 (500 mg, 1.16 mmol) was subjected to SFC separation. SFC (column type: DAICEL CHIRALPAK AD (250mm*30mm, 10μm); mobile phase: [Neu-EtOH]: 33%-33%, 6min) to obtain compounds 2-1 and 2-2. Analysis method: instrument: Thar analytical SFC, column type: Chiralpak AD-3, 50mm*4.6mm*3μm, mobile phase: A: CO 2 , B: EtOH (0.05% IPAm), gradient: B: A = 5%～ 50%, 4min, flow rate: 4.0mL/min, column temperature: 35°C, wavelength: 220nm, column pressure: 100bar. Compound 2-1 retention time: 1.26min. Compound 2-2 retention time: 1.42min.
步骤2：化合物2的合成Step 2: Synthesis of compound 2
将化合物2-1(212mg,490.19μmol)溶解于二氯甲烷(5mL)中，降至0℃，加入三甲基溴化硅(750.43mg,4.90mmol)，逐渐升温至30℃搅拌5小时。反应减压浓缩，加入乙酸乙酯(30mL)，半饱和氯化钠溶液(20mL)洗，有机相经无水硫酸钠干燥后，过滤，减压浓缩。粗品经prep-HPLC(柱型：Phenomenex luna C18 250mm*50mm*10μm；流动相：[H 2O(0.05％HCl)-ACN]；B(ACN)％:30％-60％,10min)纯化。得到化合物2。 Compound 2-1 (212 mg, 490.19 μmol) was dissolved in dichloromethane (5 mL), reduced to 0° C., trimethyl silicon bromide (750.43 mg, 4.90 mmol) was added, and the temperature was gradually raised to 30° C. and the mixture was stirred for 5 hours. The reaction was concentrated under reduced pressure, ethyl acetate (30 mL) was added, and half-saturated sodium chloride solution (20 mL) was added to wash. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by prep-HPLC (column type: Phenomenex luna C18 250mm*50mm*10μm; mobile phase: [H 2 O (0.05% HCl)-ACN]; B (ACN)%: 30%-60%, 10 min). Compound 2 is obtained.
[M+1] +＝377.1 [M+1] + = 377.1
1H NMR(400MHz,CD 3OD)δ＝6.83-6.75(m,2H),6.63-6.53(m,3H),4.24(dd,J＝3.7,8.6Hz,1H),4.19(d,J＝10.5Hz,2H),3.21(td,J＝7.0,13.7Hz,1H),3.05-2.95(m,1H),2.86-2.75(m,1H),2.53(qd,J＝8.6,12.7Hz,1H),1.97-1.91(m,1H),1.90(s,3H),1.13(t,J＝7.2Hz,6H)。 1 H NMR(400MHz,CD 3 OD)δ=6.83-6.75(m,2H),6.63-6.53(m,3H), 4.24(dd,J=3.7,8.6Hz,1H), 4.19(d,J= 10.5Hz,2H),3.21(td,J=7.0,13.7Hz,1H),3.05-2.95(m,1H),2.86-2.75(m,1H),2.53(qd,J=8.6,12.7Hz,1H ), 1.97-1.91 (m, 1H), 1.90 (s, 3H), 1.13 (t, J=7.2 Hz, 6H).
步骤3：化合物4，化合物5的合成Step 3: Synthesis of compound 4 and compound 5
将化合物2(65.9mg,175.09μmol)溶解于二甲基甲酰胺(5mL)中，加入化合物BB-2(65.36mg,350.18mmol)，二环己基亚胺(108.38mg,525.26μmol),吡啶(332.39mg,4.20mmol)逐渐升温至70℃搅 拌16小时。过滤，收集滤液，加入乙酸乙酯(100mL)和水(100mL)，分液,收集有机相，用饱和食盐水(100mL×3)洗涤,有机相通过无水硫酸钠干燥，过滤，滤液减压浓缩，得粗品。粗品经prep-HPLC(柱型:Waters Xbridge Prep OBD C18 150mm*40mm*10μm；流动相:[H 2O(10mM NH 4HCO 3)-ACN]；B(ACN)％:45％-65％,8min)纯化。得到化合物4，化合物5。分析方法：柱型：X-bridge Shield RP18 2.1mm*50mm*5μm，流动相：A：10mmol/L NH 4HCO 3，B：乙腈，梯度：10-80％B(3.00min)，80％B保持0.9min,然后80-10％B(0.03min),最后10％B保持0.57min(流速：0.01-3.91min:0.8mL/min；3.92-4.50min:1.2mL/min)，监测方法：二极管矩阵检测器(diode array:DAD)。化合物4保留时间：3.116min，化合物5保留时间：3.165min。化合物4和5磷酸位置的构型通过NOE来确认。 Compound 2 (65.9mg, 175.09μmol) was dissolved in dimethylformamide (5mL), compound BB-2 (65.36mg, 350.18mmol), dicyclohexylimine (108.38mg, 525.26μmol), pyridine ( 332.39mg, 4.20mmol) was gradually heated to 70°C and stirred for 16 hours. Filter, collect the filtrate, add ethyl acetate (100mL) and water (100mL), separate the layers, collect the organic phase, wash with saturated brine (100mL×3), dry the organic phase over anhydrous sodium sulfate, filter, and depressurize the filtrate Concentrate to get crude product. The crude product was subjected to prep-HPLC (column type: Waters Xbridge Prep OBD C18 150mm*40mm*10μm; mobile phase: [H 2 O(10mM NH 4 HCO 3 )-ACN]; B(ACN)%: 45%-65%, 8min) Purification. Compound 4 and Compound 5 are obtained. Analysis method: Column type: X-bridge Shield RP18 2.1mm*50mm*5μm, mobile phase: A: 10mmol/L NH 4 HCO 3 , B: acetonitrile, gradient: 10-80% B (3.00 min), 80% B Hold for 0.9 min, then 80-10% B (0.03 min), and finally 10% B for 0.57 min (flow rate: 0.01-3.91 min: 0.8 mL/min; 3.92-4.50 min: 1.2 mL/min), monitoring method: diode Matrix detector (diode array: DAD). Compound 4 retention time: 3.116 min, Compound 5 retention time: 3.165 min. The configuration of the phosphate positions of compounds 4 and 5 was confirmed by NOE.
化合物4：[M+1] +＝527.3； 1H NMR(400MHz,CDCl 3)δ＝7.43(s,1H),7.35-7.28(m,2H),7.27-7.23(m,1H),6.93(s,1H),6.75(s,1H),6.66-6.55(m,3H),5.64(br d,J＝11.3Hz,1H),5.67-5.60(m,1H),4.75-4.65(m,1H),4.51(dddd,J＝2.3,4.8,11.2,16.4Hz,1H),4.44(d,J＝9.7Hz,2H),4.29(dd,J＝3.9,8.8Hz,1H),3.24-3.12(m,1H),3.09-2.97(m,1H),2.90-2.77(m,1H),2.64-2.42(m,2H),2.01(tdd,J＝4.1,8.4,12.7Hz,1H),1.93(s,3H),1.22(dd,J＝4.8,6.8Hz,6H)。 Compound 4: [M+1] + = 527.3; 1 H NMR (400MHz, CDCl 3 ) δ = 7.43 (s, 1H), 7.35-7.28 (m, 2H), 7.27-7.23 (m, 1H), 6.93 ( s,1H),6.75(s,1H),6.66-6.55(m,3H),5.64(br d,J=11.3Hz,1H),5.67-5.60(m,1H),4.75-4.65(m,1H) ), 4.51 (dddd, J = 2.3, 4.8, 11.2, 16.4 Hz, 1H), 4.44 (d, J = 9.7 Hz, 2H), 4.29 (dd, J = 3.9, 8.8 Hz, 1H), 3.24-3.12 ( m,1H),3.09-2.97(m,1H),2.90-2.77(m,1H),2.64-2.42(m,2H),2.01(tdd,J=4.1,8.4,12.7Hz,1H),1.93( s, 3H), 1.22 (dd, J=4.8, 6.8 Hz, 6H).
化合物5：[M+1] +＝527.3； 1H NMR(400MHz,CDCl 3)δ＝7.42(s,1H),7.36-7.28(m,3H),6.93(s,1H),6.75(s,1H),6.64-6.56(m,3H),5.90(br d,J＝11.0Hz,1H),4.98(br t,J＝11.7Hz,1H),4.63-4.52(m,3H),4.30(dd,J＝4.0,8.6Hz,1H),3.17(td,J＝6.9,13.8Hz,1H),3.11-2.98(m,1H),2.89-2.80(m,1H),2.64-2.52(m,1H),2.50-2.38(m,1H),2.18-2.10(m,1H),2.02(tdd,J＝4.4,8.4,12.6Hz,1H),1.95(s,3H),1.23(dd,J＝5.5,6.7Hz,6H)。 Compound 5: [M+1] + = 527.3; 1 H NMR (400MHz, CDCl 3 ) δ = 7.42 (s, 1H), 7.36-7.28 (m, 3H), 6.93 (s, 1H), 6.75 (s, 1H),6.64-6.56(m,3H),5.90(br d,J=11.0Hz,1H), 4.98(br t,J=11.7Hz,1H),4.63-4.52(m,3H), 4.30(dd ,J=4.0,8.6Hz,1H),3.17(td,J=6.9,13.8Hz,1H),3.11-2.98(m,1H),2.89-2.80(m,1H),2.64-2.52(m,1H ), 2.50-2.38(m,1H), 2.18-2.10(m,1H), 2.02(tdd,J=4.4,8.4,12.6Hz,1H),1.95(s,3H),1.23(dd,J=5.5 ,6.7Hz,6H).
步骤4：化合物3的合成Step 4: Synthesis of compound 3
将原料2-2(0.27g,624.29μmol)溶解于二氯甲烷(5mL)中，降至0℃，加入三甲基溴化硅(955.75mg,6.24mmol)，反应升至20℃继续搅拌8小时。反应液减压浓缩，加入乙酸乙酯(50mL)，半饱和氯化钠溶液(30mL)洗，有机层经无水硫酸钠干燥后，过滤，减压浓缩。粗品经prep-HPLC(柱型:Phenomenex luna C18 250mm*50mm*10μm；流动相:[H 2O(0.05％HCl)-ACN]；B(ACN)％:20％-60％,10min)制备得化合物3。 Dissolve raw material 2-2 (0.27g, 624.29μmol) in dichloromethane (5mL), reduce to 0℃, add trimethyl silicon bromide (955.75mg, 6.24mmol), increase the reaction to 20℃ and continue stirring 8 hour. The reaction solution was concentrated under reduced pressure, ethyl acetate (50 mL) was added, and half-saturated sodium chloride solution (30 mL) was added to wash. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was prepared by prep-HPLC (column type: Phenomenex luna C18 250mm*50mm*10μm; mobile phase: [H 2 O(0.05% HCl)-ACN]; B(ACN)%: 20%-60%, 10min) Compound 3.
1H NMR(400MHz,CD 3OD)δ＝6.81(d,J＝1.6Hz,1H),6.79-6.76(m,1H),6.63-6.55(m,3H),4.27-4.22(m,1H),4.19(d,J＝10.4Hz,2H),3.25-3.16(m,1H),3.05-2.93(m,1H),2.86-2.75(m,1H),2.58-2.46(m,1H),1.97-1.91(m,1H),1.90-1.88(m,3H),1.13(t,J＝7.4Hz,6H)。 1 H NMR (400MHz, CD 3 OD) δ = 6.81 (d, J = 1.6 Hz, 1H), 6.79-6.76 (m, 1H), 6.63-6.55 (m, 3H), 4.27-4.22 (m, 1H) ,4.19(d,J=10.4Hz,2H),3.25-3.16(m,1H),3.05-2.93(m,1H),2.86-2.75(m,1H),2.58-2.46(m,1H),1.97 -1.91 (m, 1H), 1.90-1.88 (m, 3H), 1.13 (t, J=7.4 Hz, 6H).
步骤5：化合物6，化合物7的合成Step 5: Synthesis of compound 6, compound 7
将化合物3(60mg,159.41μmol)溶解于二甲基甲酰胺(2.5mL)和吡啶(0.25mL)中，加入二环己基碳二亚胺(98.67mg,478.24μmol)，化合物BB-2(29.75mg,159.41μmol)，反应升至70℃继续搅拌16小时。反应液中加入乙酸乙酯(50mL)，半饱和氯化钠溶液(30mL)洗，有机层经无水硫酸钠干燥后，过滤，减压浓缩。粗品经prep-HPLC分离(柱型:Waters Xbridge Prep OBD C18 150mm*40mm*10μm；流动相:[H 2O(10mM NH 4HCO 3)-ACN]；B(ACN)％:25％-55％,8min)得到化合物6和化合物7的粗品。再经SFC方法分离(柱型:DAICEL CHIRALPAK AS(250mm*30mm*10μm)；流动相:[中性-甲醇]:33％- 33％,min)，得到化合物6和化合物7。分析方法：柱型:Chiralpak AS-3,50mm*4.6mm*3μm,流动相:A:CO 2，B:甲醇(0.05％DEA),梯度:B相1.2分钟内从5％升至50％，维持1分钟，0.8分钟内降至5％,流速:3.4mL/min,柱温:35℃,ABPR:1500psi。化合物6保留时间：1.450min，化合物7保留时间：1.311min。化合物6和7磷酸位置的构型通过NOE来确认。 Compound 3 (60mg, 159.41μmol) was dissolved in dimethylformamide (2.5mL) and pyridine (0.25mL), and dicyclohexylcarbodiimide (98.67mg, 478.24μmol) was added, compound BB-2 (29.75) mg, 159.41μmol), the reaction was raised to 70°C and stirring was continued for 16 hours. Ethyl acetate (50 mL) was added to the reaction solution, washed with half-saturated sodium chloride solution (30 mL), the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by prep-HPLC (column type: Waters Xbridge Prep OBD C18 150mm*40mm*10μm; mobile phase: [H 2 O(10mM NH 4 HCO 3 )-ACN]; B(ACN)%: 25%-55% , 8min) to obtain the crude products of compound 6 and compound 7. After separation by SFC method (column type: DAICEL CHIRALPAK AS (250mm*30mm*10μm); mobile phase: [neutral-methanol]: 33%-33%, min), compound 6 and compound 7 are obtained. Analysis method: Column type: Chiralpak AS-3, 50mm*4.6mm*3μm, mobile phase: A: CO 2 , B: methanol (0.05% DEA), gradient: Phase B rises from 5% to 50% in 1.2 minutes, Maintained for 1 minute, decreased to 5% within 0.8 minutes, flow rate: 3.4 mL/min, column temperature: 35°C, ABPR: 1500 psi. Compound 6 retention time: 1.450 min, compound 7 retention time: 1.311 min. The configuration of the phosphate positions of compounds 6 and 7 was confirmed by NOE.
化合物6：Compound 6:
1H NMR(400MHz,CDCl 3)δ＝7.43(s,1H),7.35-7.28(m,2H),7.26-7.22(m,1H),6.93(s,1H),6.76-6.73(m,1H),6.62(s,2H),6.60-6.57(m,1H),5.68-5.60(m,1H),4.75-4.64(m,2H),4.58-4.39(m,3H),4.29(br dd,J＝3.6,8.5Hz,1H),3.24-3.13(m,1H),3.04(td,J＝8.1,16.1Hz,1H),2.90-2.77(m,1H),2.65-2.40(m,2H),2.20-2.08(m,1H),2.01(ddd,J＝4.1,8.3,12.5Hz,1H),1.96-1.89(m,3H),1.22(t,J＝6.4Hz,6H)。 1 H NMR(400MHz,CDCl 3 )δ=7.43(s,1H),7.35-7.28(m,2H),7.26-7.22(m,1H),6.93(s,1H),6.76-6.73(m,1H) ), 6.62 (s, 2H), 6.60-6.57 (m, 1H), 5.68-5.60 (m, 1H), 4.75-4.64 (m, 2H), 4.58-4.39 (m, 3H), 4.29 (br dd, J=3.6,8.5Hz,1H),3.24-3.13(m,1H),3.04(td,J=8.1,16.1Hz,1H),2.90-2.77(m,1H),2.65-2.40(m,2H) , 2.20-2.08 (m, 1H), 2.01 (ddd, J = 4.1, 8.3, 12.5 Hz, 1H), 1.96-1.89 (m, 3H), 1.22 (t, J = 6.4 Hz, 6H).
化合物7：Compound 7:
1H NMR(400MHz,CDCl 3)δ＝7.42(s,1H),7.37-7.29(m,3H),6.93(s,1H),6.77-6.74(m,1H),6.63-6.60(m,2H),6.60-6.57(m,1H),5.93-5.86(m,1H),5.02-4.94(m,1H),4.70-4.66(m,1H),4.63-4.52(m,3H),4.33-4.26(m,1H),3.24-3.12(m,1H),3.09-3.00(m,1H),2.91-2.81(m,1H),2.64-2.53(m,1H),2.50-2.37(m,1H),2.18-2.10(m,1H),2.07-1.97(m,1H),1.97-1.92(m,3H),1.22(dd,J＝4.8,6.8Hz,6H)。 1 H NMR (400MHz, CDCl 3 ) δ = 7.42 (s, 1H), 7.37-7.29 (m, 3H), 6.93 (s, 1H), 6.77-6.74 (m, 1H), 6.63-6.60 (m, 2H) ), 6.60-6.57(m,1H),5.93-5.86(m,1H),5.02-4.94(m,1H),4.70-4.66(m,1H),4.63-4.52(m,3H),4.33-4.26 (m,1H),3.24-3.12(m,1H),3.09-3.00(m,1H),2.91-2.81(m,1H),2.64-2.53(m,1H),2.50-2.37(m,1H) , 2.18-2.10 (m, 1H), 2.07-1.97 (m, 1H), 1.97-1.92 (m, 3H), 1.22 (dd, J=4.8, 6.8 Hz, 6H).
化合物6的单晶X射线衍射检测分析Single crystal X-ray diffraction analysis of compound 6
化合物6的晶体在丙酮条件下，使用溶剂挥发法，室温经过5天培养获得，衍射用晶体尺寸为0.08×0.12×0.20mm，晶体属于单斜晶系，空间群为P2 1，晶胞参数：a＝11.8483(3)，b＝9.3533(3)，c＝
Figure PCTCN2020139562-appb-000094
α＝γ＝90°，β＝109.013(2)°，晶胞体积
Figure PCTCN2020139562-appb-000095
晶胞内不对称单位数Z＝2。 The crystal of compound 6 was obtained by culturing for 5 days under the condition of acetone using solvent volatilization method at room temperature. The crystal size for diffraction is 0.08×0.12×0.20mm, the crystal belongs to the monoclinic crystal system, the space group is P2 1 , and the unit cell parameters: a=11.8483(3), b=9.3533(3), c=
Figure PCTCN2020139562-appb-000094
α=γ=90°, β=109.013(2)°, unit cell volume
Figure PCTCN2020139562-appb-000095
The number of asymmetric units in the unit cell Z=2.
用Bruker D8 Venture Photon II衍射仪收集衍射强度数据，光源为CuK α辐射，扫描方式：
Figure PCTCN2020139562-appb-000096
扫描，收集总衍射点数为16909个，独立衍射点数为5938个，可观察点数(I/sigma≥2)为3601个。 The Bruker D8 Venture Photon II diffractometer was used to collect the diffraction intensity data, the light source was CuK α radiation, and the scanning method:
Figure PCTCN2020139562-appb-000096
Scanning, the total number of diffraction points collected is 16,909, the number of independent diffraction points is 5938, and the number of observable points (I/sigma≥2) is 3601.
采用直接法(Shelxs97)解析晶体结构，获得全部40个非氢原子位置，使用最小二乘法修正结构参数和判别原子种类，使用几何计算法和差值Fourier法获得全部氢原子位置，精修后R 1＝0.0585，wR 2＝0.1812(w＝1/σ|F| 2)，S＝1.035。最终确定化学计量式为C 29H 32ClO 5P·C 3H 6O，计算分子量为585.04，计算晶体密度为1.224g/cm 3。 The direct method (Shelxs97) was used to analyze the crystal structure, and all 40 non-hydrogen atom positions were obtained. The least square method was used to modify the structural parameters and distinguish the atom types. The geometric calculation method and the difference Fourier method were used to obtain all the hydrogen atom positions. After finishing R 1 = 0.0585, wR 2 = 0.1812 (w = 1/σ|F| 2 ), S = 1.035. The final stoichiometric formula is C 29 H 32 ClO 5 P·C 3 H 6 O, the calculated molecular weight is 585.04, and the calculated crystal density is 1.224 g/cm 3 .
单晶结果表明：晶态下分子排列属第一类空间群，化合物应具有旋光活性，Flack系数0.047(15)，可确定晶体中化合物的绝对构型。晶态下分子间存在氢键联系，分子间以氢键和范德华力维系其在空间的稳定排列。The single crystal results show that the molecular arrangement in the crystalline state belongs to the first space group, the compound should have optical activity, and the Flack coefficient is 0.047 (15), which can determine the absolute configuration of the compound in the crystal. In the crystalline state, there are hydrogen bonds between molecules, and hydrogen bonds and van der Waals forces maintain their stable arrangement in space.
化合物6丙酮合物的立体结构椭球图、沿b轴方向的晶胞堆积图以及化合物的绝对构型图见附图1、2和3。化合物6丙酮合物晶体结构数据和参数见表1、2、3、4和5。The three-dimensional structure ellipsoid diagram of the compound 6 acetone compound, the unit cell packing diagram along the b-axis direction and the absolute configuration diagram of the compound are shown in Figures 1, 2 and 3. The crystal structure data and parameters of compound 6 acetonate are shown in Tables 1, 2, 3, 4 and 5.
表1：晶体结构精修信息表Table 1: Crystal structure refinement information table
Figure PCTCN2020139562-appb-000097
Figure PCTCN2020139562-appb-000097
Figure PCTCN2020139562-appb-000098
Figure PCTCN2020139562-appb-000098
表2：晶体的原子坐标(×10 4)和等价各向同性移位参数
Figure PCTCN2020139562-appb-000099
Table 2: Atomic coordinates (×10 4 ) and equivalent isotropic shift parameters of the crystal
Figure PCTCN2020139562-appb-000099
Figure PCTCN2020139562-appb-000100
Figure PCTCN2020139562-appb-000100
Figure PCTCN2020139562-appb-000101
Figure PCTCN2020139562-appb-000101
Figure PCTCN2020139562-appb-000102
Figure PCTCN2020139562-appb-000102
表3：成键原子的键长
Figure PCTCN2020139562-appb-000103
和键角(°) Table 3: Bond lengths of bonding atoms
Figure PCTCN2020139562-appb-000103
And bond angle (°)
Figure PCTCN2020139562-appb-000104
Figure PCTCN2020139562-appb-000104
Figure PCTCN2020139562-appb-000105
Figure PCTCN2020139562-appb-000105
Figure PCTCN2020139562-appb-000106
Figure PCTCN2020139562-appb-000106
Figure PCTCN2020139562-appb-000107
Figure PCTCN2020139562-appb-000107
表4：原子间扭角值(°)Table 4: Torsion angle between atoms (°)
Figure PCTCN2020139562-appb-000108
Figure PCTCN2020139562-appb-000108
Figure PCTCN2020139562-appb-000109
Figure PCTCN2020139562-appb-000109
Figure PCTCN2020139562-appb-000110
Figure PCTCN2020139562-appb-000110
表5：氢键列表Table 5: List of hydrogen bonds
Figure PCTCN2020139562-appb-000111
Figure PCTCN2020139562-appb-000111
用于生成等效原子的对称变换:#1x,y,z+1Symmetric transformation used to generate equivalent atoms: #1x,y,z+1
实施例8Example 8
Figure PCTCN2020139562-appb-000112
Figure PCTCN2020139562-appb-000112
合成路线：synthetic route:
Figure PCTCN2020139562-appb-000113
Figure PCTCN2020139562-appb-000113
步骤1：化合物8-2的合成Step 1: Synthesis of compound 8-2
将化合物8-1(3.00g,11.58mmol)溶解于四氢呋喃(50mL)中，降温至-78℃，滴加正丁基锂溶液(2.5M,6.95mL)，反应在-78℃搅拌30分钟，滴加化合物BB-1(3.20g,11.58mmol)的四氢呋喃(20mL)溶液，缓慢升温至20℃搅拌16小时。反应液中加入饱和氯化铵溶液(50mL)，乙酸乙酯(200mL)萃取。有机相经无水硫酸钠干燥后，过滤，减压浓缩。粗品经硅胶柱层析纯化(石油醚:乙酸乙酯＝5:1)，得到化合物8-2。Compound 8-1 (3.00g, 11.58mmol) was dissolved in tetrahydrofuran (50mL), cooled to -78°C, n-butyllithium solution (2.5M, 6.95mL) was added dropwise, and the reaction was stirred at -78°C for 30 minutes. A tetrahydrofuran (20 mL) solution of compound BB-1 (3.20 g, 11.58 mmol) was added dropwise, and the temperature was slowly raised to 20° C. and the mixture was stirred for 16 hours. Saturated ammonium chloride solution (50 mL) was added to the reaction solution and extracted with ethyl acetate (200 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain compound 8-2.
[M-17] +＝439.3 [M-17] + = 439.3
步骤2：化合物8-3的合成Step 2: Synthesis of compound 8-3
将化合物8-2(1g,2.19mmol)加入至二氯甲烷(20mL)，加入三乙基硅氢(763.85mg,6.57mmol)，降至0℃，滴加三氟乙酸(299.60mg,2.63mmol)，反应逐渐升温至20℃搅拌16小时。反应液加入二氯甲烷(50mL)，半饱和碳酸氢钠溶液(30mL)洗，有机相经无水硫酸钠干燥后，过滤，减压浓缩。粗品经硅胶柱层析纯化(石油醚:乙酸乙酯＝5:1)，得到化合物8-3。Compound 8-2 (1g, 2.19mmol) was added to dichloromethane (20mL), triethylsilylhydrogen (763.85mg, 6.57mmol) was added, the temperature was reduced to 0°C, and trifluoroacetic acid (299.60mg, 2.63mmol) was added dropwise ), the reaction was gradually heated to 20°C and stirred for 16 hours. The reaction solution was added with dichloromethane (50 mL), washed with half-saturated sodium bicarbonate solution (30 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain compound 8-3.
1H NMR(400MHz,CDCl 3)δ＝6.91-6.87(m,2H),6.74-6.69(m,1H),6.64-6.60(m,1H),6.48-6.45(m,1H),5.18-5.14(m,2H),4.30-4.25(m,1H),3.49(s,3H),3.35-3.24(m,1H),3.03-2.93(m,1H),2.83-2.74(m,1H),2.61-2.50(m,1H),2.02-1.94(m,1H),1.91-1.87(m,3H),1.19-1.15(m,6H),1.00(s,9H),0.24-0.19(m,6H)。 1 H NMR (400MHz, CDCl 3 ) δ=6.91-6.87 (m, 2H), 6.74-6.69 (m, 1H), 6.64-6.60 (m, 1H), 6.48-6.45 (m, 1H), 5.18-5.14 (m,2H),4.30-4.25(m,1H),3.49(s,3H),3.35-3.24(m,1H),3.03-2.93(m,1H),2.83-2.74(m,1H),2.61 -2.50(m,1H),2.02-1.94(m,1H),1.91-1.87(m,3H),1.19-1.15(m,6H),1.00(s,9H),0.24-0.19(m,6H) .
步骤3：化合物8-4的合成Step 3: Synthesis of compound 8-4
将化合物8-3(1.26g,2.86mmol)加入至甲醇(30mL)和四氢呋喃(30mL)，加入氟化铵(1.06g,28.59mmol)，反应在20℃搅拌16小时。反应液减压浓缩。粗品经硅胶柱层析纯化(石油醚:乙酸乙酯＝5:1)，得到化合物8-4。Compound 8-3 (1.26 g, 2.86 mmol) was added to methanol (30 mL) and tetrahydrofuran (30 mL), ammonium fluoride (1.06 g, 28.59 mmol) was added, and the reaction was stirred at 20°C for 16 hours. The reaction solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain compound 8-4.
1H NMR(400MHz,CDCl 3)δ＝6.93(d,J＝2.1Hz,1H),6.92-6.89(m,1H),6.74-6.70(m,1H),6.63-6.60(m,1H),6.47-6.44(m,1H),5.17(s,2H),4.55-4.51(m,1H),4.31-4.24(m,1H),3.51-3.47(m,3H),3.35-3.25(m,1H),3.06-2.94(m,1H),2.86-2.75(m,1H),2.64-2.49(m,1H),2.04-1.95(m,1H),1.93-1.89(m,3H),1.21- 1.16(m,6H)。 1 H NMR (400MHz, CDCl 3 ) δ = 6.93 (d, J = 2.1 Hz, 1H), 6.92-6.89 (m, 1H), 6.74-6.70 (m, 1H), 6.63-6.60 (m, 1H), 6.47-6.44(m,1H),5.17(s,2H),4.55-4.51(m,1H),4.31-4.24(m,1H),3.51-3.47(m,3H),3.35-3.25(m,1H) ),3.06-2.94(m,1H),2.86-2.75(m,1H),2.64-2.49(m,1H),2.04-1.95(m,1H),1.93-1.89(m,3H),1.21- 1.16 (m,6H).
步骤4：化合物8-5的合成Step 4: Synthesis of compound 8-5
将化合物8-4(1.05g,3.22mmol)加入至二氯甲烷(20mL)和N,N-二甲基吡啶(1.57g,12.87mmol)中，降温至0℃，加入三氟甲磺酸酐(1.36g,4.82mmol)，反应逐渐升至20℃搅拌2小时。反应液减压浓缩。粗品经硅胶柱层析纯化(石油醚:乙酸乙酯＝5:1)，得到化合物8-5。Compound 8-4 (1.05g, 3.22mmol) was added to dichloromethane (20mL) and N,N-lutidine (1.57g, 12.87mmol), the temperature was reduced to 0°C, and trifluoromethanesulfonic anhydride ( 1.36g, 4.82mmol), the reaction was gradually raised to 20°C and stirred for 2 hours. The reaction solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain compound 8-5.
1H NMR(400MHz,CDCl 3)δ＝7.05-7.02(m,1H),6.93(d,J＝8.3Hz,1H),6.90(d,J＝2.2Hz,1H),6.88-6.83(m,1H),6.70-6.64(m,1H),5.20-5.14(m,2H),4.36-4.30(m,1H),3.48(d,J＝2.6Hz,3H),3.35-3.25(m,1H),3.14-3.04(m,1H),2.95-2.85(m,1H),2.69-2.55(m,1H),2.11-2.06(m,1H),1.99-1.96(m,3H),1.18(t,J＝6.8Hz,6H)。 1 H NMR(400MHz, CDCl 3 )δ=7.05-7.02(m,1H), 6.93(d,J=8.3Hz,1H), 6.90(d,J=2.2Hz,1H), 6.88-6.83(m, 1H), 6.70-6.64(m,1H), 5.20-5.14(m,2H), 4.36-4.30(m,1H), 3.48(d,J=2.6Hz,3H), 3.35-3.25(m,1H) ,3.14-3.04(m,1H),2.95-2.85(m,1H),2.69-2.55(m,1H),2.11-2.06(m,1H),1.99-1.96(m,3H),1.18(t, J=6.8Hz, 6H).
步骤5：化合物8-6的合成Step 5: Synthesis of compound 8-6
将化合物8-5(0.1g,218.11μmol)加入至二甲基甲酰胺(2mL)中，加入三乙胺(55.18mg,545.27μmol)，双三苯基膦二氯化钯(15.31mg,21.81μmol)，乙烯基磷酸二乙酯(39.38mg,239.92μmol)，氮气置换三次，反应在80℃，封管搅拌16小时。反应液中加入乙酸乙酯(50mL)，半饱和氯化钠溶液洗(30mL×4)洗，有机相经无水硫酸钠干燥后，过滤，减压浓缩。粗品根据TLC(石油醚:乙酸乙酯＝0:1，Rf＝0.55)，经硅胶柱层析纯化(石油醚:乙酸乙酯＝5:1至石油醚:乙酸乙酯＝1:1)，得到化合物8-6。Compound 8-5 (0.1g, 218.11μmol) was added to dimethylformamide (2mL), triethylamine (55.18mg, 545.27μmol), bistriphenylphosphine palladium dichloride (15.31mg, 21.81 μmol), vinyl diethyl phosphate (39.38 mg, 239.92 μmol), replaced with nitrogen three times, the reaction was carried out at 80°C, and the tube was sealed and stirred for 16 hours. Ethyl acetate (50 mL) was added to the reaction solution, washed with half-saturated sodium chloride solution (30 mL×4), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1 to petroleum ether: ethyl acetate = 1:1) according to TLC (petroleum ether: ethyl acetate = 0:1, Rf = 0.55), Compound 8-6 is obtained.
1H NMR(400MHz,CDCl 3)δ＝7.31-7.28(m,1H),7.12-7.08(m,1H),6.93(d,J＝2.1Hz,1H),6.91(d,J＝8.3Hz,1H),6.71-6.66(m,1H),6.37-6.31(m,1H),6.20-6.17(m,1H),5.20-5.13(m,2H),4.34(dd,J＝3.8,8.7Hz,1H),4.20-4.13(m,4H),3.50-3.48(m,3H),3.35-3.22(m,1H),3.07(td,J＝8.2,16.1Hz,1H),2.94-2.81(m,1H),2.63-2.51(m,1H),2.10-1.99(m,1H),1.98-1.94(m,3H),1.39-1.36(m,6H),1.22-1.14(m,6H)。 1 H NMR(400MHz, CDCl 3 )δ=7.31-7.28(m,1H), 7.12-7.08(m,1H), 6.93(d,J=2.1Hz,1H), 6.91(d,J=8.3Hz, 1H), 6.71-6.66(m,1H), 6.37-6.31(m,1H), 6.20-6.17(m,1H), 5.20-5.13(m,2H), 4.34(dd,J=3.8,8.7Hz, 1H), 4.20-4.13(m,4H),3.50-3.48(m,3H),3.35-3.22(m,1H),3.07(td,J=8.2,16.1Hz,1H),2.94-2.81(m, 1H), 2.63-2.51 (m, 1H), 2.10-1.99 (m, 1H), 1.98-1.94 (m, 3H), 1.39-1.36 (m, 6H), 1.22-1.14 (m, 6H).
步骤6：化合物8-7的合成Step 6: Synthesis of compound 8-7
将化合物8-6(0.11g,232.78μmol)加入至甲醇(3mL)中，加入钯碳(0.1g,21.16μmol,钯含量5％)，氢气置换三次，反应在20℃，15psi搅拌16小时。反应液过滤，滤液减压浓缩得到化合物8-7。Compound 8-6 (0.11 g, 232.78 μmol) was added to methanol (3 mL), palladium on carbon (0.1 g, 21.16 μmol, palladium content 5%) was added, and hydrogen was replaced three times. The reaction was stirred at 20° C. and 15 psi for 16 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain compound 8-7.
1H NMR(400MHz,CDCl 3)δ＝6.99-6.97(m,1H),6.96-6.93(m,1H),6.91-6.87(m,1H),6.79(s,1H),6.71-6.66(m,1H),5.18-5.13(m,2H),4.10-4.04(m,4H),3.50-3.46(m,3H),3.35-3.24(m,1H),3.09-2.97(m,1H),2.96-2.83(m,4H),2.61-2.49(m,1H),2.07-1.96(m,3H),1.95-1.90(m,3H),1.37-1.34(m,6H),1.22-1.18(m,6H)。 1 H NMR (400MHz, CDCl 3 ) δ = 6.99-6.97 (m, 1H), 6.96-6.93 (m, 1H), 6.91-6.87 (m, 1H), 6.79 (s, 1H), 6.71-6.66 (m , 1H), 5.18-5.13 (m, 2H), 4.10-4.04 (m, 4H), 3.50-3.46 (m, 3H), 3.35-3.24 (m, 1H), 3.09-2.97 (m, 1H), 2.96 -2.83(m,4H),2.61-2.49(m,1H),2.07-1.96(m,3H),1.95-1.90(m,3H),1.37-1.34(m,6H),1.22-1.18(m, 6H).
步骤7：化合物8的合成Step 7: Synthesis of compound 8
将化合物8-7(0.09g,189.65μmol)加入至二氯甲烷(6mL)中，降至0℃，加入三甲基溴硅烷(290.33mg,1.90mmol)，反应逐渐升至20℃搅拌5小时。反应液中加入二氯甲烷(50mL)，水(30mL×2)洗，有机相经无水硫酸钠干燥后，过滤，滤液减压浓缩。粗品经prep-HPLC(柱型:Welch Xtimate C18 150mm*25mm*5μm；流动相:[水(0.04％HCl)-乙腈]；乙腈％:30％-60％,8min)纯化。得到化合物8。Compound 8-7 (0.09g, 189.65μmol) was added to dichloromethane (6mL), reduced to 0°C, trimethylbromosilane (290.33mg, 1.90mmol) was added, and the reaction was gradually raised to 20°C and stirred for 5 hours . Dichloromethane (50 mL) was added to the reaction solution, washed with water (30 mL×2), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by prep-HPLC (column type: Welch Xtimate C18 150mm*25mm*5μm; mobile phase: [water (0.04% HCl)-acetonitrile]; acetonitrile%: 30%-60%, 8min). Compound 8 was obtained.
1H NMR(400MHz,CD 3OD)δ＝7.00-6.95(m,1H),6.84-6.80(m,1H),6.80-6.78(m,1H),6.61-6.58(m,1H),6.58-6.54(m,1H),4.31-4.22(m,1H),3.25-3.16(m,1H),3.05-2.95(m,1H),2.90-2.74(m,3H),2.58-2.43(m,1H),2.03-1.91(m,3H),1.90(s,3H),1.13(t,J＝7.4Hz,6H)。 1 H NMR (400MHz, CD 3 OD) δ = 7.00-6.95 (m, 1H), 6.84-6.80 (m, 1H), 6.80-6.78 (m, 1H), 6.61-6.58 (m, 1H), 6.58- 6.54(m,1H),4.31-4.22(m,1H),3.25-3.16(m,1H),3.05-2.95(m,1H),2.90-2.74(m,3H),2.58-2.43(m,1H) ), 2.03-1.91 (m, 3H), 1.90 (s, 3H), 1.13 (t, J=7.4 Hz, 6H).
实施例9、10Examples 9, 10
Figure PCTCN2020139562-appb-000114
Figure PCTCN2020139562-appb-000114
合成路线：synthetic route:
Figure PCTCN2020139562-appb-000115
Figure PCTCN2020139562-appb-000115
步骤1：化合物9-2的合成Step 1: Synthesis of compound 9-2
在0℃向化合物9-1(3g,11.80mmol)的四氢呋喃(50mL)溶液中加入乙烯基溴化镁(1M,11.80mL)，于20℃反应12小时。将反应液倒入饱和氯化铵溶液中，用乙酸乙酯萃取(50mL×3)，合并有机相，无水硫酸钠干燥，过滤，减压浓缩得到粗品。粗品用硅胶柱层析法分离(石油醚：乙酸乙酯＝10：1)，得到化合物9-2。To a solution of compound 9-1 (3 g, 11.80 mmol) in tetrahydrofuran (50 mL) at 0°C was added vinylmagnesium bromide (1M, 11.80 mL), and reacted at 20°C for 12 hours. The reaction solution was poured into saturated ammonium chloride solution, extracted with ethyl acetate (50 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was separated by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain compound 9-2.
1H NMR(400MHz,DMSO-d 6)δ＝7.37-7.46(m,4H),7.28-7.35(m,1H),7.17(d,J＝1.96Hz,1H),7.07(dd,J＝8.44,1.96Hz,1H),6.97(d,J＝8.31Hz,1H),5.93(ddd,J＝17.06,10.33,5.75Hz,1H),5.32(d,J＝4.52Hz,1H),5.21(dt,J＝17.12,1.71Hz,1H),5.10(s,2H),4.94-5.04(m,2H),3.25-3.31(m,1H),1.17(d,J＝6.72Hz,6H). 1 H NMR(400MHz,DMSO-d 6 )δ=7.37-7.46(m,4H), 7.28-7.35(m,1H), 7.17(d,J=1.96Hz,1H), 7.07(dd,J=8.44 ,1.96Hz,1H),6.97(d,J＝8.31Hz,1H),5.93(ddd,J＝17.06,10.33,5.75Hz,1H),5.32(d,J＝4.52Hz,1H),5.21(dt ,J=17.12,1.71Hz,1H),5.10(s,2H),4.94-5.04(m,2H),3.25-3.31(m,1H),1.17(d,J=6.72Hz,6H).
步骤2：化合物9-3的合成Step 2: Synthesis of compound 9-3
向化合物9-11(2.19g,6.37mmol)的N,N-二甲基甲酰胺溶液(15mL)中加入双乙腈氯化钯(137.81mg,531.21μmol)，三(邻甲基苯基)膦(161.68mg,531.21μmol)，N,N-二环己基甲胺(1.56g,7.97mmol,1.69mL)， 化合物9-2(1.5g,5.31mmol)，在90℃反应12小时。将反应液用硅藻土过滤，滤液加入乙酸乙酯(100mL)稀释，加入水(100mL)，有机相用饱和食盐水洗(100mL×2)，有机相用无水硫酸钠干燥，过滤，减压浓缩得到粗品。粗品用硅胶柱层析法分离(石油醚：乙酸乙酯＝20：1)，得到化合物9-3。MS m/z:545[M+1] +。 To the N,N-dimethylformamide solution (15mL) of compound 9-11 (2.19g, 6.37mmol) was added bisacetonitrile palladium chloride (137.81mg, 531.21μmol), tris(o-methylphenyl)phosphine (161.68 mg, 531.21 μmol), N,N-dicyclohexylmethylamine (1.56 g, 7.97 mmol, 1.69 mL), compound 9-2 (1.5 g, 5.31 mmol), reacted at 90°C for 12 hours. The reaction solution was filtered with celite, the filtrate was diluted with ethyl acetate (100mL), water (100mL) was added, the organic phase was washed with saturated brine (100mL×2), the organic phase was dried over anhydrous sodium sulfate, filtered, and reduced pressure Concentrate to obtain crude product. The crude product was separated by silica gel column chromatography (petroleum ether: ethyl acetate = 20:1) to obtain compound 9-3. MS m/z: 545[M+1] + .
步骤3：化合物9-4的合成Step 3: Synthesis of compound 9-4
在-78℃，向化合物9-3(0.8g,1.47mmol)的四氢呋喃(10mL)中加入甲基锂(1.6M,1.10mL)，自然恢复至20℃反应2小时。将反应液倒入饱和氯化铵溶液中，加入乙酸乙酯(50mL)，水相用乙酸乙酯萃取(50mL×3)，合并有机相，无水硫酸钠干燥，过滤，减压浓缩得到粗品。粗品用硅胶柱层析法分离(石油醚：乙酸乙酯＝20：1)，得到化合物9-4。At -78°C, methyl lithium (1.6M, 1.10 mL) was added to the tetrahydrofuran (10 mL) of compound 9-3 (0.8 g, 1.47 mmol), and the mixture was naturally returned to 20°C and reacted for 2 hours. The reaction solution was poured into saturated ammonium chloride solution, ethyl acetate (50mL) was added, the aqueous phase was extracted with ethyl acetate (50mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product . The crude product was separated by silica gel column chromatography (petroleum ether: ethyl acetate = 20:1) to obtain compound 9-4.
1H NMR(400MHz,CDCl 3)δ＝7.46-7.52(m,2H),7.40-7.45(m,2H),7.32-7.38(m,2H),7.27(d,J＝2.4Hz,1H),7.25(d,J＝2.4Hz,1H),6.92(d,J＝8.5Hz,1H),6.53(d,J＝8.4Hz,2H),6.48(s,1H),5.11(s,2H),3.46(spt,J＝6.9Hz,1H),2.46-2.56(m,1H),2.35-2.45(m,1H),2.26(s,3H),2.08-2.16(m,2H),1.61(s,3H),1.27-1.30(m,6H),1.20-1.27(m,3H),1.09-1.13(m,18H).MS m/z:543[M-17] +。 1 H NMR(400MHz, CDCl 3 )δ=7.46-7.52(m,2H), 7.40-7.45(m,2H), 7.32-7.38(m,2H), 7.27(d,J=2.4Hz,1H), 7.25(d,J=2.4Hz,1H), 6.92(d,J=8.5Hz,1H), 6.53(d,J=8.4Hz,2H), 6.48(s,1H), 5.11(s,2H), 3.46(spt,J=6.9Hz,1H),2.46-2.56(m,1H),2.35-2.45(m,1H),2.26(s,3H),2.08-2.16(m,2H),1.61(s, 3H), 1.27-1.30 (m, 6H), 1.20-1.27 (m, 3H), 1.09-1.13 (m, 18H). MS m/z: 543[M-17] + .
步骤4：化合物9-5的合成Step 4: Synthesis of compound 9-5
在0℃向化合物9-4(0.85g,1.52mmol)的二氯甲烷(2mL)中加入三氟乙酸(518.38mg,4.55mmol,336.61μL)，在20℃反应2小时。将反应液倒入饱和碳酸氢钠溶液中，加入二氯甲烷(50mL)，水相用二氯甲烷萃取(50mL×3)，合并有机相，无水硫酸钠干燥，过滤，减压浓缩得到化合物9-5。Trifluoroacetic acid (518.38 mg, 4.55 mmol, 336.61 μL) was added to the dichloromethane (2 mL) of compound 9-4 (0.85 g, 1.52 mmol) at 0°C, and the reaction was carried out at 20°C for 2 hours. The reaction solution was poured into saturated sodium bicarbonate solution, dichloromethane (50mL) was added, the aqueous phase was extracted with dichloromethane (50mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the compound 9-5.
步骤5：化合物9-6的合成Step 5: Synthesis of compound 9-6
向化合物9-5(0.8g,1.47mmol)的四氢呋喃(2mL)中加入四丁基氟化铵溶液(1M,1.77mL)，在20℃反应1小时。将反应液减压浓缩得到粗品。粗品用硅胶柱层析法分离(石油醚：乙酸乙酯＝5:1)，得到化合物9-6。Tetrabutylammonium fluoride solution (1M, 1.77 mL) was added to compound 9-5 (0.8 g, 1.47 mmol) in tetrahydrofuran (2 mL), and reacted at 20° C. for 1 hour. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was separated by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain compound 9-6.
1H NMR(400MHz,CDCl 3)δ＝7.44-7.49(m,2H),7.40(t,J＝7.4Hz,2H),7.30-7.37(m,1H),7.09(d,J＝2.4Hz,1H),6.98(dd,J＝8.4,2.4Hz,1H),6.82(d,J＝8.4Hz,1H),6.60(d,J＝1.8Hz,1H),6.42(d,J＝1.5Hz,1H),5.07(s,2H),3.39(spt,J＝6.9Hz,1H),2.80-2.96(m,2H),2.22-2.34(m,1H),2.11-2.20(m,1H),1.78(s,3H),1.65(s,3H),1.19ppm(t,J＝6.8Hz,6H). 1 H NMR(400MHz, CDCl 3 )δ=7.44-7.49(m,2H), 7.40(t,J=7.4Hz,2H), 7.30-7.37(m,1H), 7.09(d,J=2.4Hz, 1H), 6.98 (dd, J = 8.4, 2.4 Hz, 1H), 6.82 (d, J = 8.4 Hz, 1H), 6.60 (d, J = 1.8 Hz, 1H), 6.42 (d, J = 1.5 Hz, 1H),5.07(s,2H),3.39(spt,J=6.9Hz,1H),2.80-2.96(m,2H),2.22-2.34(m,1H),2.11-2.20(m,1H),1.78 (s,3H),1.65(s,3H),1.19ppm(t,J=6.8Hz,6H).
步骤6：化合物9-7的合成Step 6: Synthesis of compound 9-7
在0℃向化合物9-6(0.5g,1.29mmol)的N,N-二甲基甲酰胺(5mL)中加入碳酸铯(505.77mg,1.55mmol)，对甲苯磺酰氧甲基膦酸二乙酯(970.80mg,3.23mmol)，在20℃反应12小时。向反应液中倒入饱和食盐水，用乙酸乙酯萃取(30mL×3)，合并有机相，用饱和食盐水洗(100mL×3)，有机相用无水硫酸钠干燥，过滤，减压浓缩得到粗品。粗品用硅胶柱层析法分离(石油醚：乙酸乙酯＝2:1)，得到化合物9-7。To the N,N-dimethylformamide (5mL) of compound 9-6 (0.5g, 1.29mmol) at 0°C was added cesium carbonate (505.77mg, 1.55mmol), p-toluenesulfonyloxymethylphosphonic acid two Ethyl ester (970.80 mg, 3.23 mmol), react at 20°C for 12 hours. Pour saturated brine into the reaction solution, extract with ethyl acetate (30 mL×3), combine the organic phases, wash with saturated brine (100 mL×3), dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain Crude. The crude product was separated by silica gel column chromatography (petroleum ether: ethyl acetate=2:1) to obtain compound 9-7.
1H NMR(400MHz,CDCl 3)δ＝7.43-7.49(m,2H),7.36-7.42(m,2H),7.30-7.36(m,1H),7.07(d,J＝2.4Hz,1H),6.95(dd,J＝8.4,2.4Hz,1H),6.81(d,J＝8.4Hz,1H),6.72(d,J＝2.0Hz,1H),6.55(d,J＝2.0Hz,1H),5.06(s,2H),4.19-4.31(m,6H),3.37(spt,J＝6.9Hz,1H),2.79-2.99(m,2H),2.22-2.33(m,1H),2.11-2.21(m,1H),1.78(s,3H),1.64(s,3H),1.38(t,J＝7.0Hz,6H),1.18ppm(t,J＝7.1Hz,6H).MS m/z:537[M+1] +。 1 H NMR(400MHz, CDCl 3 )δ=7.43-7.49(m,2H), 7.36-7.42(m,2H), 7.30-7.36(m,1H), 7.07(d,J=2.4Hz,1H), 6.95(dd,J=8.4,2.4Hz,1H), 6.81(d,J=8.4Hz,1H), 6.72(d,J=2.0Hz,1H), 6.55(d,J=2.0Hz,1H), 5.06(s,2H),4.19-4.31(m,6H), 3.37(spt,J=6.9Hz,1H), 2.79-2.99(m,2H),2.22-2.33(m,1H),2.11-2.21( m,1H),1.78(s,3H),1.64(s,3H),1.38(t,J=7.0Hz,6H),1.18ppm(t,J=7.1Hz,6H).MS m/z:537 [M+1] + .
步骤7：9-8的合成Step 7: Synthesis of 9-8
向化合物9-7(0.35g,652.21μmol)的甲醇(5mL)中加入钯/碳(0.1g,钯含量5％)，在氢气环境(15psi)下，于20℃反应2小时。将反应液用硅藻土过滤，滤液经减压浓缩得到粗品。粗品用硅胶柱层析法分离(石油醚：乙酸乙酯＝1:1)，得到化合物9-8。Palladium/carbon (0.1 g, palladium content 5%) was added to compound 9-7 (0.35 g, 652.21 μmol) in methanol (5 mL), and reacted at 20° C. for 2 hours under a hydrogen atmosphere (15 psi). The reaction solution was filtered with Celite, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated by silica gel column chromatography (petroleum ether: ethyl acetate=1:1) to obtain compound 9-8.
1H NMR(400MHz,DMSO-d 6)δ＝9.02(s,1H),6.88(d,J＝2.0Hz,1H),6.71-6.80(m,2H),6.62-6.68(m,1H),6.56(s,1H),4.35(d,J＝9.7Hz,2H),4.06-4.17(m,4H),3.05-3.20(m,1H),2.71-2.94(m,2H),2.03-2.20(m,2H),1.69(s,3H),1.52(s,3H),1.25(t,J＝7.1Hz,6H),1.07ppm(t,J＝6.6Hz,6H). 1 H NMR(400MHz,DMSO-d 6 )δ=9.02(s,1H), 6.88(d,J=2.0Hz,1H), 6.71-6.80(m,2H), 6.62-6.68(m,1H), 6.56(s,1H), 4.35(d,J=9.7Hz,2H),4.06-4.17(m,4H),3.05-3.20(m,1H),2.71-2.94(m,2H),2.03-2.20( m,2H),1.69(s,3H),1.52(s,3H),1.25(t,J=7.1Hz,6H),1.07ppm(t,J=6.6Hz,6H).
步骤8：化合物9-9和9-10的合成Step 8: Synthesis of compounds 9-9 and 9-10
将化合物9-8(1g,2.24mmol)进行SFC分离。经SFC(柱型:DAICEL CHIRALPAK AD(250mm*30mm,10μm)；流动相：[0.1％NH 3H 2O IPA]:35％-35％,7min)分离得到化合物9-9和9-10。分析方法：仪器：Thar analytical SFC,柱型:Chiralpak AD-3，50mm*4.6mm*3μm,流动相：A:CO 2，B：IPA(0.05％DEA),梯度:B:A＝5％～50％，3min,流速:3.4mL/min,柱温:35℃,波长:220nm,柱压:1800psi。化合物9-9保留时间：1.136min。化合物9-10保留时间：1.211min。 Compound 9-8 (1 g, 2.24 mmol) was subjected to SFC separation. SFC (column type: DAICEL CHIRALPAK AD (250mm*30mm, 10μm); mobile phase: [0.1% NH 3 H 2 O IPA]: 35%-35%, 7min) to obtain compounds 9-9 and 9-10. Analysis method: instrument: Thar analytical SFC, column type: Chiralpak AD-3, 50mm*4.6mm*3μm, mobile phase: A: CO 2 , B: IPA (0.05% DEA), gradient: B:A=5%～ 50%, 3min, flow rate: 3.4mL/min, column temperature: 35°C, wavelength: 220nm, column pressure: 1800psi. Compound 9-9 retention time: 1.136min. Compound 9-10 retention time: 1.211min.
步骤9：化合物9的合成Step 9: Synthesis of compound 9
在0℃向化合物9-9(0.39g,873.43μmol)的二氯甲烷(10mL)中加入三甲基溴硅烷(1.34g,8.73mmol,1.13mL)，于20℃反应12小时。将反应液减压浓缩得到粗品。用pre-HPLC(柱型:Phenomenex luna C18 250*50mm*10μm；流动相:水(0.04％HCl)-ACN；梯度：B(ACN)％:30％-60％,10min)分离。得到化合物9。Trimethylbromosilane (1.34 g, 8.73 mmol, 1.13 mL) was added to the dichloromethane (10 mL) of compound 9-9 (0.39 g, 873.43 μmol) at 0°C, and reacted at 20°C for 12 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. Separated by pre-HPLC (column type: Phenomenex luna C18 250*50mm*10μm; mobile phase: water (0.04%HCl)-ACN; gradient: B(ACN)%: 30%-60%, 10min). Compound 9 was obtained.
1H NMR(400MHz,CD 3OD)δ＝6.94(d,J＝2.3Hz,1H),6.81(dd,J＝8.3,2.4Hz,1H),6.74(d,J＝1.8Hz,1H),6.63(d,J＝8.3Hz,1H),6.56(d,J＝1.8Hz,1H),4.18(d,J＝10.4Hz,2H),3.15-3.27(m,1H),2.79-2.95(m,2H),2.06-2.27(m,2H),1.76(s,3H),1.59(s,3H),1.11ppm(t,J＝6.9Hz,6H). 1 H NMR (400MHz, CD 3 OD) δ = 6.94 (d, J = 2.3 Hz, 1H), 6.81 (dd, J = 8.3, 2.4 Hz, 1H), 6.74 (d, J = 1.8 Hz, 1H), 6.63 (d, J = 8.3 Hz, 1H), 6.56 (d, J = 1.8 Hz, 1H), 4.18 (d, J = 10.4 Hz, 2H), 3.15-3.27 (m, 1H), 2.79-2.95 (m ,2H),2.06-2.27(m,2H),1.76(s,3H),1.59(s,3H), 1.11ppm(t,J=6.9Hz,6H).
步骤10：化合物10的合成Step 10: Synthesis of compound 10
在0℃向化合物9-10(40mg,88.32μmol)的二氯甲烷(2mL)中加入三甲基溴硅烷(135.21mg,883.18μmol,114.58μL)，在20℃反应12小时。将反应液减压浓缩得到粗品。用pre-HPLC(柱型：Welch Xtimate C18 150*25mm*5μm；流动相:水(0.04％HCl)-ACN；梯度:B(ACN)％:40％-65％,8min)分离，得到化合物10。Trimethylsilyl bromide (135.21 mg, 883.18 μmol, 114.58 μL) was added to compound 9-10 (40 mg, 88.32 μmol) in dichloromethane (2 mL) at 0°C, and reacted at 20°C for 12 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. Separated by pre-HPLC (column type: Welch Xtimate C18 150*25mm*5μm; mobile phase: water (0.04%HCl)-ACN; gradient: B(ACN)%: 40%-65%, 8min) to obtain compound 10 .
1H NMR(400MHz,CD 3OD)δ＝6.88-6.94(m,1H),6.81(dd,J＝8.8,2.1Hz,2H),6.52-6.61(m,2H),4.34(dd,J＝8.7,2.8Hz,1H),4.21(d,J＝10.4Hz,2H),3.14-3.25(m,1H),2.99-3.12(m,1H),2.87(ddd,J＝16.1,8.9,2.9Hz,1H),2.54(dq,J＝12.6,9.0Hz,1H),1.91-2.02(m,1H),1.13(t,J＝6.8Hz,6H). 1 H NMR (400MHz, CD 3 OD) δ = 6.88-6.94 (m, 1H), 6.81 (dd, J = 8.8, 2.1 Hz, 2H), 6.52-6.61 (m, 2H), 4.34 (dd, J = 8.7,2.8Hz,1H),4.21(d,J=10.4Hz,2H),3.14-3.25(m,1H),2.99-3.12(m,1H),2.87(ddd,J=16.1,8.9,2.9Hz ,1H),2.54(dq,J=12.6,9.0Hz,1H),1.91-2.02(m,1H),1.13(t,J=6.8Hz,6H).
实施例11、12Examples 11, 12
Figure PCTCN2020139562-appb-000116
Figure PCTCN2020139562-appb-000116
合成路线：synthetic route:
Figure PCTCN2020139562-appb-000117
Figure PCTCN2020139562-appb-000117
步骤1：11-2的合成Step 1: Synthesis of 11-2
在-78℃，向化合物1-8(868.75mg,2.85mmol)的四氢呋喃(10mL)中加入正丁基锂(2.5M,1.14mL)，1小时后加入化合物11-1(0.65g,2.19mmol)，反应1小时后，在20℃反应2小时。将反应液倒入饱和氯化铵溶液中，加入乙酸乙酯(100mL)分液，水相用乙酸乙酯萃取(100mL×3)，合并有机相，无水硫酸钠干燥，过滤，减压浓缩得到粗品。粗品用硅胶柱层析法分离(石油醚/乙酸乙酯＝20:1)，得到化合物11-2。MS m/z:505[M-17] +。 At -78°C, n-butyllithium (2.5M, 1.14mL) was added to compound 1-8 (868.75mg, 2.85mmol) in tetrahydrofuran (10mL), and compound 11-1 (0.65g, 2.19mmol) was added after 1 hour. ), after reacting for 1 hour, react at 20°C for 2 hours. The reaction solution was poured into saturated ammonium chloride solution, ethyl acetate (100mL) was added for separation, the aqueous phase was extracted with ethyl acetate (100mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure Get crude product. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate=20:1) to obtain compound 11-2. MS m/z: 505[M-17] + .
步骤2：11-3的合成Step 2: Synthesis of 11-3
在0℃向化合物11-2(0.7g,1.34mmol)的二氯甲烷(20mL)中加入三乙基硅氢(466.74mg,4.01mmol,641.13μL)，三氟乙酸(228.83mg,2.01mmol,148.59μL,1.5eq)，在20℃反应2小时。将反应液倒入饱和碳酸氢钠溶液中，加入二氯甲烷(50mL)，水相用二氯甲烷萃取(50mL×3)，合并有机相，无水硫酸钠干燥，过滤，减压浓缩得到粗品。粗品用硅胶柱层析法分离(石油醚/乙酸乙酯＝50:1)，得到化合物11-3。To compound 11-2 (0.7g, 1.34mmol) in dichloromethane (20mL) was added triethylsilylhydrogen (466.74mg, 4.01mmol, 641.13μL), trifluoroacetic acid (228.83mg, 2.01mmol, 148.59μL, 1.5eq), react at 20°C for 2 hours. The reaction solution was poured into saturated sodium bicarbonate solution, dichloromethane (50mL) was added, the aqueous phase was extracted with dichloromethane (50mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product . The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate=50:1) to obtain compound 11-3.
步骤3：11-4的合成Step 3: Synthesis of 11-4
向化合物11-3(0.56g,1.10mmol)的四氢呋喃(10mL)中加入四丁基氟化铵的四氢呋喃溶液(1M,1.32mL)，在20℃反应1小时。将反应液减压浓缩得到粗品。用硅胶柱层析法分离(石油醚/乙酸乙酯＝5:1)，得到化合物11-4。To compound 11-3 (0.56 g, 1.10 mmol) in tetrahydrofuran (10 mL) was added a tetrabutylammonium fluoride solution (1M, 1.32 mL) in tetrahydrofuran, and reacted at 20° C. for 1 hour. The reaction solution was concentrated under reduced pressure to obtain a crude product. It was separated by silica gel column chromatography (petroleum ether/ethyl acetate=5:1) to obtain compound 11-4.
1H NMR(DMSO-d 6,400MHz)δ＝9.68(s,1H),7.42-7.47(m,2H),7.37-7.42(m,2H),7.29-7.35(m,1H),6.93(d,J＝2.1Hz,1H),6.88(d,J＝8.5Hz,1H),6.64-6.71(m,2H),6.58(d,J＝1.8Hz,1H),5.04(s,2H),4.31(dd,J＝8.6,2.6Hz,1H),3.23(spt,J＝6.9Hz,1H),2.91-3.03(m,1H),2.74-2.87(m,1H),1.81-1.94(m,1H),1.22-1.39(m,1H),1.12ppm(dd,J＝6.7,5.5Hz,6H). 1 H NMR(DMSO-d 6 ,400MHz)δ=9.68(s,1H),7.42-7.47(m,2H),7.37-7.42(m,2H),7.29-7.35(m,1H),6.93(d ,J=2.1Hz,1H),6.88(d,J=8.5Hz,1H),6.64-6.71(m,2H),6.58(d,J=1.8Hz,1H),5.04(s,2H),4.31 (dd,J=8.6,2.6Hz,1H),3.23(spt,J=6.9Hz,1H),2.91-3.03(m,1H),2.74-2.87(m,1H),1.81-1.94(m,1H) ), 1.22-1.39 (m, 1H), 1.12 ppm (dd, J = 6.7, 5.5 Hz, 6H).
步骤4：11-5的合成Step 4: Synthesis of 11-5
向化合物11-4(0.45g,1.15mmol)的N,N-二甲基甲酰胺(5mL)中加入碳酸铯(559.73mg,1.72mmol)，对甲苯磺酰氧甲基膦酸二乙酯(442.97mg,1.37mmol)，在50℃反应3小时。将反应液倒入饱和氯化钠溶液中，加入乙酸乙酯(50mL)，水相用乙酸乙酯萃取(50mL×3)，合并有机相，无水硫酸钠干燥、过滤、减压浓缩得到粗品。粗品用硅胶柱层析法分离(石油醚/乙酸乙酯＝1:1)，得到化合物11-5。To compound 11-4 (0.45g, 1.15mmol) in N,N-dimethylformamide (5mL) was added cesium carbonate (559.73mg, 1.72mmol), diethyl p-toluenesulfonyloxymethylphosphonate ( 442.97mg, 1.37mmol), reacted at 50°C for 3 hours. The reaction solution was poured into saturated sodium chloride solution, ethyl acetate (50mL) was added, the aqueous phase was extracted with ethyl acetate (50mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product . The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate=1:1) to obtain compound 11-5.
1H NMR(CDCl 3,400MHz)δ＝7.42-7.47(m,2H),7.39(t,J＝7.5Hz,2H),7.29-7.35(m,1H),6.99(d,J＝2.0Hz,1H),6.83(s,1H),6.78(d,J＝8.6Hz,2H),6.68-6.73(m,1H),5.04(s,2H),4.43(dd,J＝8.7,2.9Hz,1H),4.21-4.31(m,6H),3.31-3.42(m,1H),3.10(dt,J＝16.5,8.4Hz,1H),2.88(ddd,J＝16.2,8.8,3.1Hz,1H),2.59(dq,J＝12.8,8.9Hz,1H),2.06(s,1H),1.39(t,J＝7.0Hz,6H),1.21(dd,J＝6.8,5.1Hz,6H). 1 H NMR(CDCl 3 , 400MHz)δ=7.42-7.47(m,2H), 7.39(t,J=7.5Hz,2H), 7.29-7.35(m,1H), 6.99(d,J=2.0Hz, 1H), 6.83 (s, 1H), 6.78 (d, J = 8.6Hz, 2H), 6.68-6.73 (m, 1H), 5.04 (s, 2H), 4.43 (dd, J = 8.7, 2.9Hz, 1H) ), 4.21-4.31 (m, 6H), 3.31-3.42 (m, 1H), 3.10 (dt, J = 16.5, 8.4 Hz, 1H), 2.88 (ddd, J = 16.2, 8.8, 3.1 Hz, 1H), 2.59 (dq, J = 12.8, 8.9 Hz, 1H), 2.06 (s, 1H), 1.39 (t, J = 7.0 Hz, 6H), 1.21 (dd, J = 6.8, 5.1 Hz, 6H).
步骤5：11-6的合成Step 5: Synthesis of 11-6
向化合物11-5(0.22g,405.13μmol)的乙醇(10mL)中加入二氧化铂(110.00mg,484.42μmol)，在氢气环境下(15psi)，于20℃反应12小时。将反应液用硅藻土过滤，滤液减压浓缩得到粗品。粗品用硅胶柱层析法分离(石油醚/乙酸乙酯＝1:1)，得到化合物11-6。Platinum dioxide (110.00 mg, 484.42 μmol) was added to compound 11-5 (0.22 g, 405.13 μmol) in ethanol (10 mL), and reacted at 20° C. for 12 hours under hydrogen atmosphere (15 psi). The reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate=1:1) to obtain compound 11-6.
步骤6：11-7和11-8的合成Step 6: Synthesis of 11-7 and 11-8
将化合物11-6(0.13g,0.29mmol)进行SFC分离。经SFC(柱型:DAICEL CHIRALPAK AD(250mm*30mm,10μm)；流动相:[0.1％NH 3H 2O IPA]:40％-40％,8min)分离得到化合物11-7和11-8。分析方法:仪器:Thar analytical SFC,柱型:Chiralpak AD-3，50mm*4.6mm*3μm,流动相:A:CO 2，B：IPA(0.05％DEA),梯度:B:A＝5％～50％，3min,流速:3.4mL/min,柱温:35℃,波长:220nm,柱压:1800psi。化合物11-7保留时间：1.171min。化合物11-8保留时间：1.306min。 Compound 11-6 (0.13 g, 0.29 mmol) was subjected to SFC separation. After SFC (column type: DAICEL CHIRALPAK AD (250mm*30mm, 10μm); mobile phase: [0.1% NH 3 H 2 O IPA]: 40%-40%, 8 min), compounds 11-7 and 11-8 were separated. Analysis method: instrument: Thar analytical SFC, column type: Chiralpak AD-3, 50mm*4.6mm*3μm, mobile phase: A: CO 2 , B: IPA (0.05% DEA), gradient: B: A = 5%～ 50%, 3min, flow rate: 3.4mL/min, column temperature: 35°C, wavelength: 220nm, column pressure: 1800psi. Compound 11-7 retention time: 1.171 min. Compound 11-8 retention time: 1.306min.
步骤7：化合物11的合成Step 7: Synthesis of compound 11
在0℃向化合物11-7(40mg,88.32μmol)的二氯甲烷(2mL)中加入三甲基溴硅烷(135.21mg,883.18μmol)，在20℃反应12小时。将反应液减压浓缩得到粗品。用prep-HPLC(柱型:Welch Xtimate C18 150*25mm*5μm；流动相:水(0.04％HCl)-乙腈；梯度:B(ACN)％:40％-65％,8min)分离。得到化合物11。Trimethylsilyl bromide (135.21 mg, 883.18 μmol) was added to the dichloromethane (2 mL) of compound 11-7 (40 mg, 88.32 μmol) at 0°C, and reacted at 20°C for 12 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. Separated by prep-HPLC (column type: Welch Xtimate C18 150*25mm*5μm; mobile phase: water (0.04% HCl)-acetonitrile; gradient: B(ACN)%: 40%-65%, 8min). Compound 11 was obtained.
1H NMR(CD 3OD,400MHz)δ＝6.88-6.94(m,1H),6.81(dd,J＝8.8,2.1Hz,2H),6.52-6.61(m,2H),4.34(dd,J＝8.7,2.8Hz,1H),4.21(d,J＝10.4Hz,2H),3.14-3.25(m,1H),2.99-3.12(m,1H),2.87(ddd,J＝16.1,8.9,2.9Hz,1H),2.54(dq,J＝12.6,9.0Hz,1H),1.91-2.02(m,1H),1.13ppm(t,J＝6.8Hz,6H). 1 H NMR (CD 3 OD, 400MHz) δ = 6.88-6.94 (m, 1H), 6.81 (dd, J = 8.8, 2.1 Hz, 2H), 6.52-6.61 (m, 2H), 4.34 (dd, J = 8.7,2.8Hz,1H),4.21(d,J=10.4Hz,2H),3.14-3.25(m,1H),2.99-3.12(m,1H),2.87(ddd,J=16.1,8.9,2.9Hz ,1H),2.54(dq,J=12.6,9.0Hz,1H),1.91-2.02(m,1H),1.13ppm(t,J=6.8Hz,6H).
步骤8：化合物12的合成Step 8: Synthesis of compound 12
在0℃向化合物11-8(40mg,88.32μmol)的二氯甲烷(2mL)中加入三甲基溴硅烷(135.21mg,883.18μmol)，在20℃反应12小时。将反应液减压浓缩得到粗品。用prep-HPLC(柱型:Welch Xtimate C18 150*25mm*5μm；流动相:水(0.04％HCl)-乙腈；梯度:B(ACN)％:40％-65％,8min)分离，得到化合物12。Trimethylsilyl bromide (135.21 mg, 883.18 μmol) was added to the dichloromethane (2 mL) of compound 11-8 (40 mg, 88.32 μmol) at 0°C, and reacted at 20°C for 12 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. Separate by prep-HPLC (column type: Welch Xtimate C18 150*25mm*5μm; mobile phase: water (0.04%HCl)-acetonitrile; gradient: B(ACN)%: 40%-65%, 8min) to obtain compound 12 .
1H NMR(CD 3OD,400MHz)δ＝6.92(s,1H),6.82(dd,J＝9.0,1.9Hz,2H),6.53-6.61(m,2H),4.35(dd,J＝8.7,2.8Hz,1H),4.22(d,J＝10.4Hz,2H),3.15-3.27(m,1H),3.00-3.12(m,1H),2.83-2.94(m,1H),2.55(dq,J＝12.7,9.0Hz,1H),1.91-2.05(m,1H),1.14ppm(t,J＝6.8Hz,6H) 1 H NMR (CD 3 OD, 400MHz) δ = 6.92 (s, 1H), 6.82 (dd, J = 9.0, 1.9 Hz, 2H), 6.53-6.61 (m, 2H), 4.35 (dd, J = 8.7, 2.8Hz,1H),4.22(d,J=10.4Hz,2H),3.15-3.27(m,1H),3.00-3.12(m,1H),2.83-2.94(m,1H),2.55(dq,J =12.7,9.0Hz,1H),1.91-2.05(m,1H),1.14ppm(t,J=6.8Hz,6H)
实施例13,14Examples 13, 14
Figure PCTCN2020139562-appb-000118
Figure PCTCN2020139562-appb-000118
合成路线：synthetic route:
Figure PCTCN2020139562-appb-000119
Figure PCTCN2020139562-appb-000119
步骤1：化合物13-2的合成Step 1: Synthesis of compound 13-2
将化合物13-1(13g,64.66mmol)溶解于四氢呋喃(130mL)中，降至-78℃，加入正丁基锂(2.5M,28.45mL)，-78℃搅拌1小时，滴加二甲基甲酰胺(6.14g,84.05mmol)，反应在-78℃搅拌1小时。反应液加入至氯化铵溶液(150mL)和乙酸乙酯(150mL)混合液，有机相经无水硫酸钠干燥后，过滤，减压浓缩。得到化合物13-2。Dissolve compound 13-1 (13g, 64.66mmol) in tetrahydrofuran (130mL), reduce to -78°C, add n-butyllithium (2.5M, 28.45mL), stir at -78°C for 1 hour, add dropwise dimethyl Formamide (6.14g, 84.05mmol), the reaction was stirred at -78°C for 1 hour. The reaction solution was added to the mixed solution of ammonium chloride solution (150 mL) and ethyl acetate (150 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Compound 13-2 was obtained.
1H NMR(400MHz,CDCl 3)δ＝9.97-9.90(m,1H),7.29(s,1H),7.21(s,1H),7.02-6.98(m,1H),3.89-3.82(m,3H),2.45-2.39(m,3H)。 1 H NMR (400MHz, CDCl 3 ) δ = 9.97-9.90 (m, 1H), 7.29 (s, 1H), 7.21 (s, 1H), 7.02-6.98 (m, 1H), 3.89-3.82 (m, 3H) ), 2.45-2.39 (m, 3H).
步骤2：化合物13-3的合成Step 2: Synthesis of compound 13-3
将化合物13-2(9.5g,63.26mmol)，2-羧乙基三苯基溴化磷(26.27g,63.26mmol)加入至二氯甲烷(100mL)中，降至0℃，加入叔丁醇钾(1M,145.50mL)，反应逐渐升温至20℃搅拌16小时。反应液减压浓缩，加 入乙酸乙酯(200mL)和水(200mL)，有机相经饱和碳酸钠溶液洗(50mL×2)，合并水相，乙酸乙酯(100mL)萃取，有机相丢弃，水相中加入乙酸乙酯(200mL)，搅拌，加入12M盐酸调节pH至5左右，有机相经无水硫酸钠干燥后，过滤，减压浓缩。粗品经硅胶柱层析纯化(二氯甲烷：乙醇＝10:1)，得到化合物13-3。Add compound 13-2 (9.5g, 63.26mmol), 2-carboxyethyltriphenylphosphonium bromide (26.27g, 63.26mmol) to dichloromethane (100mL), reduce to 0°C, add tert-butanol Potassium (1M, 145.50 mL), the reaction was gradually heated to 20°C and stirred for 16 hours. The reaction solution was concentrated under reduced pressure, ethyl acetate (200mL) and water (200mL) were added, the organic phase was washed with saturated sodium carbonate solution (50mL×2), the aqueous phases were combined, extracted with ethyl acetate (100mL), and the organic phase was discarded. Ethyl acetate (200 mL) was added to the phase, stirred, 12M hydrochloric acid was added to adjust the pH to about 5. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:ethanol=10:1) to obtain compound 13-3.
1H NMR(400MHz,CDCl 3)δ＝11.61-10.76(m,1H),6.83-6.79(m,1H),6.75-6.71(m,1H),6.63(s,1H),6.50-6.42(m,1H),6.32-6.23(m,1H),3.82-3.80(m,3H),3.33-3.27(m,2H),2.34-2.30(m,3H)。 1 H NMR (400MHz, CDCl 3 ) δ = 11.61-10.76 (m, 1H), 6.83-6.79 (m, 1H), 6.75-6.71 (m, 1H), 6.63 (s, 1H), 6.50-6.42 (m , 1H), 6.32-6.23 (m, 1H), 3.82-3.80 (m, 3H), 3.33-3.27 (m, 2H), 2.34-2.30 (m, 3H).
步骤3：化合物13-4的合成Step 3: Synthesis of compound 13-4
将化合物13-3(9g,43.64mmol)加入至甲醇(100mL)中，加入钯碳(3g,钯含量5％)，氢气置换三次，反应在20℃，15psi搅拌16小时。反应液过滤，滤液减压浓缩。得到化合物13-4。Compound 13-3 (9 g, 43.64 mmol) was added to methanol (100 mL), palladium carbon (3 g, palladium content 5%) was added, and hydrogen was replaced three times. The reaction was stirred at 20° C. and 15 psi for 16 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. Compound 13-4 was obtained.
1H NMR(400MHz,CD 3OD)δ＝6.59(s,1H),6.57-6.52(m,2H),3.77-3.73(m,3H),2.61-2.53(m,2H),2.32-2.23(m,5H),1.94-1.82(m,2H)。 1 H NMR (400MHz, CD 3 OD) δ = 6.59 (s, 1H), 6.57-6.52 (m, 2H), 3.77-3.73 (m, 3H), 2.61-2.53 (m, 2H), 2.32-2.23 ( m, 5H), 1.94-1.82 (m, 2H).
步骤4：化合物13-5的合成Step 4: Synthesis of compound 13-5
将化合物13-4(5.2g,24.97mmol)加入至1,2-二氯乙烷(100mL)中，降至0℃，滴加三氟乙酸酐(6.29g,29.96mmol)，反应逐渐升至20℃搅拌16小时。反应液中加入饱和碳酸氢钠溶液(100mL)和二氯甲烷(100mL)混合液，有机相经无水硫酸钠干燥后，过滤，减压浓缩。粗品经硅胶柱层析纯化(石油醚:乙酸乙酯＝5:1)，得到化合物13-5。Compound 13-4 (5.2g, 24.97mmol) was added to 1,2-dichloroethane (100mL), reduced to 0°C, trifluoroacetic anhydride (6.29g, 29.96mmol) was added dropwise, and the reaction gradually increased to Stir at 20°C for 16 hours. A mixture of saturated sodium bicarbonate solution (100 mL) and dichloromethane (100 mL) was added to the reaction solution, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain compound 13-5.
1H NMR(400MHz,CDCl 3)δ＝6.61(s,1H),6.60-6.58(m,1H),3.87-3.80(m,3H),2.96-2.88(m,2H),2.66-2.63(m,3H),2.63-2.58(m,2H),2.10-2.01(m,2H)。 1 H NMR (400MHz, CDCl 3 ) δ = 6.61 (s, 1H), 6.60-6.58 (m, 1H), 3.87-3.80 (m, 3H), 2.96-2.88 (m, 2H), 2.66-2.63 (m , 3H), 2.63-2.58 (m, 2H), 2.10-2.01 (m, 2H).
步骤5：化合物13-6的合成Step 5: Synthesis of compound 13-6
将化合物13-5(4.50g,23.65mmol)加入至二氯甲烷(50mL)中，降至-78℃，滴加三溴化硼(11.85g,47.31mmol,4.56mL)，反应逐渐升至20℃搅拌16小时。反应液加入至水(50mL)和二氯甲烷(50mL)混合液，有机相经无水硫酸钠干燥后，过滤，减压浓缩。粗品经硅胶柱层析纯化(石油醚:乙酸乙酯＝5:1)，得到化合物13-6。Compound 13-5 (4.50g, 23.65mmol) was added to dichloromethane (50mL), reduced to -78°C, boron tribromide (11.85g, 47.31mmol, 4.56mL) was added dropwise, and the reaction gradually increased to 20 Stir at °C for 16 hours. The reaction solution was added to a mixture of water (50 mL) and dichloromethane (50 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain compound 13-6.
1H NMR(400MHz,CDCl 3)δ＝6.58(s,2H),5.92-5.87(m,1H),2.90(t,J＝6.1Hz,2H),2.67-2.58(m,5H),2.09-2.00(m,2H)。 1 H NMR (400MHz, CDCl 3 ) δ = 6.58 (s, 2H), 5.92-5.87 (m, 1H), 2.90 (t, J = 6.1 Hz, 2H), 2.67-2.58 (m, 5H), 2.09- 2.00 (m, 2H).
步骤6：化合物13-7的合成Step 6: Synthesis of compound 13-7
将化合物13-6(3.6g,20.43mmol)加入至四氢呋喃(70mL)中，加入咪唑(2.78g,40.86mmol)，降温至0℃，加入叔丁基二甲基氯硅烷(4.00g,26.56mmol)，反应逐渐升至20℃搅拌16小时。反应液中加入半饱和氯化钠溶液(100mL)和乙酸乙酯(100mL)混合液，分液，有机层经无水硫酸钠干燥后，过滤，减压浓缩。粗品经硅胶柱层析纯化(石油醚:乙酸乙酯＝5:1)，得到化合物13-7。Compound 13-6 (3.6g, 20.43mmol) was added to tetrahydrofuran (70mL), imidazole (2.78g, 40.86mmol) was added, the temperature was reduced to 0°C, tert-butyldimethylchlorosilane (4.00g, 26.56mmol) was added ), the reaction was gradually raised to 20°C and stirred for 16 hours. A mixed solution of half-saturated sodium chloride solution (100 mL) and ethyl acetate (100 mL) was added to the reaction solution for liquid separation. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain compound 13-7.
1H NMR(400MHz,CDCl 3)δ＝6.54(d,J＝1.8Hz,2H),2.89(t,J＝6.1Hz,2H),2.63-2.55(m,5H),2.10-1.97(m,2H),1.01-0.98(m,9H),0.26-0.21(m,6H)。 1 H NMR (400MHz, CDCl 3 ) δ = 6.54 (d, J = 1.8 Hz, 2H), 2.89 (t, J = 6.1 Hz, 2H), 2.63-2.55 (m, 5H), 2.10-1.97 (m, 2H), 1.01-0.98 (m, 9H), 0.26-0.21 (m, 6H).
步骤7：化合物13-8的合成Step 7: Synthesis of compound 13-8
将化合物1-8(4.98g,12.40mmol)加入至四氢呋喃(30mL)中，降至-78℃，滴加正丁基锂(2.5M,4.55mL)，继续反应0.5小时，缓慢滴加化合物13-7(3g,10.33mmol)的四氢呋喃(10mL)溶液，反应逐渐升至20℃搅 拌2小时。反应液加入至氯化铵溶液(50mL)和乙酸乙酯(50mL)混合液，有机相经无水硫酸钠干燥后，过滤，减压浓缩。粗品经硅胶柱层析纯化(石油醚:乙酸乙酯＝5:1)，得到化合物13-8。Compound 1-8 (4.98g, 12.40mmol) was added to tetrahydrofuran (30mL), down to -78°C, n-butyllithium (2.5M, 4.55mL) was added dropwise, the reaction was continued for 0.5 hours, and compound 13 was slowly added dropwise -7 (3g, 10.33mmol) in tetrahydrofuran (10mL), the reaction was gradually raised to 20°C and stirred for 2 hours. The reaction solution was added to the mixed solution of ammonium chloride solution (50 mL) and ethyl acetate (50 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain compound 13-8.
1H NMR(400MHz,CDCl 3)δ＝7.40-7.30(m,5H),7.08-7.07(m,1H),7.05-7.01(m,1H),6.88-6.85(m,1H),6.60-6.58(m,1H),6.47-6.45(m,1H),6.10-6.06(m,1H),5.10(s,2H),3.41-3.34(m,1H),2.90-2.86(m,1H),2.66(br d,J＝7.6Hz,1H),2.62-2.57(m,4H),2.24-2.20(m,2H),2.15-2.07(m,2H),1.23-1.19(m,6H),1.00(s,9H),0.24(s,6H)。 1 H NMR (400MHz, CDCl 3 ) δ = 7.40-7.30 (m, 5H), 7.08-7.07 (m, 1H), 7.05-7.01 (m, 1H), 6.88-6.85 (m, 1H), 6.60-6.58 (m,1H),6.47-6.45(m,1H),6.10-6.06(m,1H),5.10(s,2H),3.41-3.34(m,1H),2.90-2.86(m,1H),2.66 (br d,J=7.6Hz,1H),2.62-2.57(m,4H),2.24-2.20(m,2H),2.15-2.07(m,2H),1.23-1.19(m,6H),1.00( s, 9H), 0.24 (s, 6H).
步骤8：化合物13-9的合成Step 8: Synthesis of compound 13-9
将化合物13-8(4.8g,9.29mmol)加入至二氯甲烷(100mL)中，降至0℃，滴加三乙基硅氢(3.24g,27.86mmol)，三氟乙酸(1.59g,13.93mmol)，反应逐渐升至20℃搅拌16小时。反应液中加入饱和碳酸氢钠溶液(10mL)和二氯甲烷(50mL)，有机相经无水硫酸钠干燥后，过滤，减压浓缩。粗品经硅胶柱层析纯化(石油醚:乙酸乙酯＝5:1)，得到化合物13-9。Compound 13-8 (4.8g, 9.29mmol) was added to dichloromethane (100mL), reduced to 0°C, triethylsilylhydrogen (3.24g, 27.86mmol), trifluoroacetic acid (1.59g, 13.93) were added dropwise mmol), the reaction was gradually raised to 20°C and stirred for 16 hours. Saturated sodium bicarbonate solution (10 mL) and dichloromethane (50 mL) were added to the reaction solution, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain compound 13-9.
1H NMR(400MHz,CDCl 3)δ＝7.47-7.29(m,5H),6.91-6.88(m,1H),6.74(d,J＝8.2Hz,1H),6.63-6.59(m,1H),6.53-6.50(m,1H),6.49(d,J＝2.0Hz,1H),5.04-4.99(m,2H),4.14-4.08(m,1H),3.39-3.29(m,1H),2.82-2.75(m,2H),2.10-2.00(m,1H),1.97-1.90(m,1H),1.59(br d,J＝6.2Hz,1H),1.24-1.11(m,6H),1.00(s,9H),0.26-0.19(m,6H)。 1 H NMR (400MHz, CDCl 3 ) δ = 7.47-7.29 (m, 5H), 6.91-6.88 (m, 1H), 6.74 (d, J = 8.2 Hz, 1H), 6.63-6.59 (m, 1H), 6.53-6.50(m,1H),6.49(d,J=2.0Hz,1H),5.04-4.99(m,2H),4.14-4.08(m,1H),3.39-3.29(m,1H),2.82- 2.75(m,2H),2.10-2.00(m,1H),1.97-1.90(m,1H),1.59(br d,J=6.2Hz,1H),1.24-1.11(m,6H),1.00(s , 9H), 0.26-0.19 (m, 6H).
步骤9：化合物13-10的合成Step 9: Synthesis of compound 13-10
将化合物13-9(3.35g,6.69mmol)加入至甲醇(30mL)中和四氢呋喃(30mL)，加入氟化铵(2.48g,66.89mmol)，反应逐渐升至20℃搅拌16小时。反应液减压浓缩，加入乙酸乙酯(50mL)，半饱和氯化钠溶液(30mL)洗，有机相经无水硫酸钠干燥后，过滤，减压浓缩。粗品经硅胶柱层析纯化(石油醚:乙酸乙酯＝3:1)，得到化合物13-10。Compound 13-9 (3.35 g, 6.69 mmol) was added to methanol (30 mL) to neutralize tetrahydrofuran (30 mL), ammonium fluoride (2.48 g, 66.89 mmol) was added, and the reaction was gradually raised to 20° C. and stirred for 16 hours. The reaction solution was concentrated under reduced pressure, ethyl acetate (50 mL) was added, and half-saturated sodium chloride solution (30 mL) was added to wash, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain compound 13-10.
1H NMR(400MHz,CDCl 3)δ＝7.46-7.30(m,5H),6.94(d,J＝2.2Hz,1H),6.74(d,J＝8.4Hz,1H),6.59(dd,J＝2.3,8.3Hz,1H),6.52(d,J＝2.3Hz,1H),6.50-6.47(m,1H),5.02(s,2H),4.48(s,1H),4.11(br t,J＝3.8Hz,1H),3.42-3.30(m,1H),2.85-2.73(m,2H),2.05-1.91(m,2H),1.90(s,3H),1.68-1.58(m,2H),1.23-1.15(m,6H)。 1 H NMR(400MHz, CDCl 3 )δ=7.46-7.30(m,5H), 6.94(d,J=2.2Hz,1H), 6.74(d,J=8.4Hz,1H), 6.59(dd,J= 2.3, 8.3 Hz, 1H), 6.52 (d, J = 2.3 Hz, 1H), 6.50-6.47 (m, 1H), 5.02 (s, 2H), 4.48 (s, 1H), 4.11 (br t, J = 3.8Hz, 1H), 3.42-3.30 (m, 1H), 2.85-2.73 (m, 2H), 2.05-1.91 (m, 2H), 1.90 (s, 3H), 1.68-1.58 (m, 2H), 1.23 -1.15 (m, 6H).
步骤10：化合物13-11的合成Step 10: Synthesis of compound 13-11
将化合物13-10(1.8g,4.66mmol)加入至二甲基甲酰胺(18mL)中，加入对甲苯磺酰氧甲基膦酸二乙酯(1.43g,4.42mmol)，碳酸铯(2.28g,6.99mmol)，反应逐渐升至50℃搅拌16小时。反应液中加入乙酸乙酯(100mL)，半饱和氯化钠溶液(50mL×4)洗，有机相经无水硫酸钠干燥后，过滤，减压浓缩。粗品经硅胶柱层析纯化(石油醚:乙酸乙酯＝1:1至1:2)，得到化合物13-11。Compound 13-10 (1.8g, 4.66mmol) was added to dimethylformamide (18mL), diethyl p-toluenesulfonyloxymethylphosphonate (1.43g, 4.42mmol), cesium carbonate (2.28g) , 6.99mmol), the reaction was gradually raised to 50°C and stirred for 16 hours. Ethyl acetate (100 mL) was added to the reaction solution, washed with half-saturated sodium chloride solution (50 mL×4), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate=1:1 to 1:2) to obtain compound 13-11.
1H NMR(400MHz,CDCl 3)δ＝7.46-7.29(m,5H),6.95-6.91(m,1H),6.75-6.71(m,1H),6.63-6.60(m,2H),6.56(dd,J＝2.2,8.3Hz,1H),5.04-5.00(m,2H),4.31-4.21(m,6H),4.12-4.10(m,1H),3.41-3.31(m,1H),2.86-2.78(m,2H),2.05-1.94(m,2H),1.94-1.90(m,3H),1.68-1.59(m,2H),1.58(s,1H),1.39(t,J＝7.0Hz,6H),1.19(dd,J＝6.9,10.1Hz,6H)。 1 H NMR(400MHz, CDCl 3 )δ=7.46-7.29(m,5H), 6.95-6.91(m,1H), 6.75-6.71(m,1H), 6.63-6.60(m,2H), 6.56(dd ,J=2.2,8.3Hz,1H),5.04-5.00(m,2H),4.31-4.21(m,6H),4.12-4.10(m,1H),3.41-3.31(m,1H),2.86-2.78 (m,2H),2.05-1.94(m,2H),1.94-1.90(m,3H),1.68-1.59(m,2H),1.58(s,1H),1.39(t,J=7.0Hz,6H ), 1.19 (dd, J=6.9, 10.1 Hz, 6H).
步骤11：化合物13-12的合成Step 11: Synthesis of compound 13-12
将化合物13-11(2g,3.73mmol)加入至甲醇(10mL)中，加入钯碳(0.3g,钯含量5％)，氢气置换三次， 反应在20℃，15psi，搅拌16小时。反应液过滤，减压浓缩。得到化合物13-12。Compound 13-11 (2 g, 3.73 mmol) was added to methanol (10 mL), palladium carbon (0.3 g, palladium content 5%) was added, and hydrogen was replaced three times. The reaction was carried out at 20° C., 15 psi, and stirred for 16 hours. The reaction solution was filtered and concentrated under reduced pressure. Compound 13-12 was obtained.
1H NMR(400MHz,CDCl 3)δ＝6.87(d,J＝2.0Hz,1H),6.61(s,2H),6.59(d,J＝8.2Hz,1H),6.48(dd,J＝2.1,8.2Hz,1H),4.84-4.80(m,1H),4.30-4.21(m,6H),4.09(dd,J＝2.3,5.1Hz,1H),3.21-3.11(m,1H),2.84-2.76(m,2H),2.07-1.93(m,2H),1.92-1.89(m,3H),1.65-1.59(m,2H),1.38(t,J＝7.0Hz,6H),1.21(dd,J＝6.9,10.4Hz,6H)。 1 H NMR (400MHz, CDCl 3 )δ = 6.87 (d, J = 2.0 Hz, 1H), 6.61 (s, 2H), 6.59 (d, J = 8.2 Hz, 1H), 6.48 (dd, J = 2.1, 8.2Hz,1H),4.84-4.80(m,1H),4.30-4.21(m,6H),4.09(dd,J=2.3,5.1Hz,1H),3.21-3.11(m,1H),2.84-2.76 (m,2H),2.07-1.93(m,2H),1.92-1.89(m,3H),1.65-1.59(m,2H),1.38(t,J=7.0Hz,6H),1.21(dd,J =6.9, 10.4 Hz, 6H).
步骤12：化合物13-13和化合物13-14的合成Step 12: Synthesis of compound 13-13 and compound 13-14
将化合物13-12(1.30g,2.91mmol)进行SFC分离。经SFC分离纯化(柱型:DAICEL CHIRALPAK AD(250mm*30mm,10μm)；流动相:[0.1％NH 3H 2O-IPA]:42％-42％,min)，得到化合物13-13，13-14。分析方法：柱型:Chiralpak AD-3,50×4.6mm,I.D,3μm。流动相:A:CO 2B:IPA(0.05％DEA)。梯度:B相1.2分钟内从5％升至50％，维持1分钟，0.8分钟内降至5％,流速:3.4mL/min。柱温.:35℃。CABPR:1800psi。得到化合物13-13和化合物13-14。化合物13-13保留时间：1.163min，化合物13-14保留时间：1.300min。 Compound 13-12 (1.30 g, 2.91 mmol) was subjected to SFC separation. After SFC separation and purification (column type: DAICEL CHIRALPAK AD (250mm*30mm, 10μm); mobile phase: [0.1% NH 3 H 2 O-IPA]: 42%-42%, min), compounds 13-13, 13 -14. Analysis method: Column type: Chiralpak AD-3, 50×4.6mm, ID, 3μm. Mobile phase: A: CO 2 B: IPA (0.05% DEA). Gradient: Phase B increased from 5% to 50% in 1.2 minutes, maintained for 1 minute, and decreased to 5% in 0.8 minutes, flow rate: 3.4 mL/min. Column temperature.: 35℃. CABPR: 1800psi. Compound 13-13 and compound 13-14 are obtained. Compound 13-13 retention time: 1.163 min, compound 13-14 retention time: 1.300 min.
步骤13：化合物13的合成Step 13: Synthesis of compound 13
将化合物13-13(0.07g,156.77μmol)溶解于二氯甲烷(2mL)中，加入三甲基溴硅烷(240.00mg,1.57mmol)，反应在20℃搅拌16小时。反应液减压浓缩，加入乙酸乙酯(30mL)，水(10mL×2)洗，有机相经无水硫酸钠干燥后，过滤，减压浓缩。经prep-HPLC纯化(柱型:Welch Xtimate C18 150*25mm*5μm；流动相:[水(0.04％HCl)-ACN]；B(ACN)％:30％-60％,8min)，得到化合物13。Compound 13-13 (0.07 g, 156.77 μmol) was dissolved in dichloromethane (2 mL), trimethylsilyl bromide (240.00 mg, 1.57 mmol) was added, and the reaction was stirred at 20° C. for 16 hours. The reaction solution was concentrated under reduced pressure, ethyl acetate (30 mL) was added, washed with water (10 mL×2), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purified by prep-HPLC (column type: Welch Xtimate C18 150*25mm*5μm; mobile phase: [water (0.04%HCl)-ACN]; B(ACN)%: 30%-60%, 8min) to obtain compound 13 .
1H NMR(400MHz,CD 3OD)δ＝6.78-6.72(m,1H),6.67-6.60(m,2H),6.60-6.53(m,1H),6.50-6.43(m,1H),4.18(br d,J＝10.3Hz,2H),4.10-4.04(m,1H),3.25-3.13(m,1H),2.89-2.72(m,2H),2.06-1.90(m,2H),1.89(s,3H),1.69-1.51(m,2H),1.16-1.04(m,6H)。 1 H NMR (400MHz, CD 3 OD) δ = 6.78-6.72 (m, 1H), 6.67-6.60 (m, 2H), 6.60-6.53 (m, 1H), 6.50-6.43 (m, 1H), 4.18 ( br d, J = 10.3Hz, 2H), 4.10-4.04 (m, 1H), 3.25-3.13 (m, 1H), 2.89-2.72 (m, 2H), 2.06-1.90 (m, 2H), 1.89 (s , 3H), 1.69-1.51 (m, 2H), 1.16-1.04 (m, 6H).
步骤14：化合物14的合成Step 14: Synthesis of compound 14
将化合物13-14(70.00mg,156.77μmol)溶解于二氯甲烷(2mL)中，加入三甲基溴硅烷(240.00mg,1.57mmol)，反应在20℃搅拌16小时。反应液减压浓缩，加入乙酸乙酯(30mL)，水(10mL×2)洗，有机相经无水硫酸钠干燥后，过滤，减压浓缩。经prep-HPLC纯化(柱型:Welch Xtimate C18 150*25mm*5μm；流动相:[水(0.04％HCl)-ACN]；B(ACN)％:30％-60％,8min)，得到化合物14。Compound 13-14 (70.00 mg, 156.77 μmol) was dissolved in dichloromethane (2 mL), trimethylbromosilane (240.00 mg, 1.57 mmol) was added, and the reaction was stirred at 20° C. for 16 hours. The reaction solution was concentrated under reduced pressure, ethyl acetate (30 mL) was added, washed with water (10 mL×2), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purified by prep-HPLC (column type: Welch Xtimate C18 150*25mm*5μm; mobile phase: [water (0.04%HCl)-ACN]; B(ACN)%: 30%-60%, 8min) to obtain compound 14 .
1H NMR(400MHz,CD 3OD)δ＝6.79-6.73(m,1H),6.69-6.61(m,2H),6.59-6.54(m,1H),6.51-6.44(m,1H),4.26-4.14(m,2H),4.12-4.04(m,1H),3.24-3.13(m,1H),2.89-2.72(m,2H),2.03-1.82(m,5H),1.70-1.53(m,2H),1.19-1.03(m,6H)。 1 H NMR (400MHz, CD 3 OD) δ = 6.79-6.73 (m, 1H), 6.69-6.61 (m, 2H), 6.59-6.54 (m, 1H), 6.51-6.44 (m, 1H), 4.26- 4.14(m,2H),4.12-4.04(m,1H),3.24-3.13(m,1H),2.89-2.72(m,2H),2.03-1.82(m,5H),1.70-1.53(m,2H) ), 1.19-1.03 (m, 6H).
实施例15,16Examples 15, 16
Figure PCTCN2020139562-appb-000120
Figure PCTCN2020139562-appb-000120
合成路线：synthetic route:
Figure PCTCN2020139562-appb-000121
Figure PCTCN2020139562-appb-000121
步骤1：化合物15-2的合成Step 1: Synthesis of compound 15-2
将化合物15-1(3.00g,11.58mmol)溶解于四氢呋喃(50mL)中，降温至-78℃，滴加正丁基锂(2.5M,6.95mL)，反应在-78℃搅拌30分钟，滴加化合物BB-1(3.20g,11.58mmol)的四氢呋喃(20mL)溶液，缓慢升温至20℃搅拌16小时。反应液中加入饱和氯化铵溶液(50mL)，乙酸乙酯(200mL)萃取。有机相经无水硫酸钠干燥后，过滤，减压浓缩。粗品经硅胶柱层析纯化(石油醚:乙酸乙酯＝5:1)，得到化合物15-2。[M-17] +＝439.3 Compound 15-1 (3.00g, 11.58mmol) was dissolved in tetrahydrofuran (50mL), the temperature was lowered to -78°C, n-butyllithium (2.5M, 6.95mL) was added dropwise, and the reaction was stirred at -78°C for 30 minutes. A solution of compound BB-1 (3.20 g, 11.58 mmol) in tetrahydrofuran (20 mL) was added, and the temperature was slowly raised to 20° C. and stirred for 16 hours. Saturated ammonium chloride solution (50 mL) was added to the reaction solution and extracted with ethyl acetate (200 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain compound 15-2. [M-17] + = 439.3
步骤2：化合物15-3的合成Step 2: Synthesis of compound 15-3
将化合物15-2(1g,2.19mmol)加入至二氯甲烷(20mL)，加入三乙基硅氢(763.85mg,6.57mmol)，降至0℃，滴加TFA(299.60mg,2.63mmol)，反应逐渐升温至20℃搅拌16小时。加入二氯甲烷(50mL)，半饱和碳酸氢钠溶液(30mL)洗，有机相经无水硫酸钠干燥后，过滤，减压浓缩。粗品经硅胶柱层析纯化(石油醚:乙酸乙酯＝5:1)，得到化合物15-3。Compound 15-2 (1g, 2.19mmol) was added to dichloromethane (20mL), triethylsilylhydrogen (763.85mg, 6.57mmol) was added, the temperature was reduced to 0°C, TFA (299.60mg, 2.63mmol) was added dropwise, The reaction was gradually heated to 20°C and stirred for 16 hours. Add dichloromethane (50 mL), wash with half-saturated sodium bicarbonate solution (30 mL), dry the organic phase over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain compound 15-3.
1H NMR(400MHz,CDCl 3)δ＝6.91-6.87(m,2H),6.74-6.69(m,1H),6.64-6.60(m,1H),6.48-6.45(m,1H),5.18-5.14(m,2H),4.30-4.25(m,1H),3.49(s,3H),3.35-3.24(m,1H),3.03-2.93(m,1H),2.83-2.74(m,1H),2.61-2.50(m,1H),2.02-1.94(m,1H),1.91-1.87(m,3H),1.19-1.15(m,6H),1.00(s,9H),0.24-0.19(m,6H)。 1 H NMR (400MHz, CDCl 3 ) δ=6.91-6.87 (m, 2H), 6.74-6.69 (m, 1H), 6.64-6.60 (m, 1H), 6.48-6.45 (m, 1H), 5.18-5.14 (m,2H),4.30-4.25(m,1H),3.49(s,3H),3.35-3.24(m,1H),3.03-2.93(m,1H),2.83-2.74(m,1H),2.61 -2.50(m,1H),2.02-1.94(m,1H),1.91-1.87(m,3H),1.19-1.15(m,6H),1.00(s,9H),0.24-0.19(m,6H) .
步骤3：化合物15-4的合成Step 3: Synthesis of compound 15-4
将化合物15-3(1.26g,2.86mmol)加入至甲醇(30mL)和四氢呋喃(30mL)中，加入氟化铵(1.06g,28.59mmol)，反应在20℃搅拌16小时。反应液减压浓缩。粗品经硅胶柱层析纯化(石油醚:乙酸乙酯＝5:1)，得到化合物15-4。Compound 15-3 (1.26 g, 2.86 mmol) was added to methanol (30 mL) and tetrahydrofuran (30 mL), ammonium fluoride (1.06 g, 28.59 mmol) was added, and the reaction was stirred at 20°C for 16 hours. The reaction solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain compound 15-4.
1H NMR(400MHz,CDCl 3)δ＝6.93(d,J＝2.1Hz,1H),6.92-6.89(m,1H),6.74-6.70(m,1H),6.63-6.60(m,1H),6.47-6.44(m,1H),5.17(s,2H),4.55-4.51(m,1H),4.31-4.24(m,1H),3.51-3.47(m,3H),3.35-3.25(m,1H),3.06-2.94(m,1H),2.86-2.75(m,1H),2.64-2.49(m,1H),2.04-1.95(m,1H),1.93-1.89(m,3H),1.21-1.16(m,6H)。 1 H NMR (400MHz, CDCl 3 ) δ = 6.93 (d, J = 2.1 Hz, 1H), 6.92-6.89 (m, 1H), 6.74-6.70 (m, 1H), 6.63-6.60 (m, 1H), 6.47-6.44(m,1H),5.17(s,2H),4.55-4.51(m,1H),4.31-4.24(m,1H),3.51-3.47(m,3H),3.35-3.25(m,1H) ),3.06-2.94(m,1H),2.86-2.75(m,1H),2.64-2.49(m,1H),2.04-1.95(m,1H),1.93-1.89(m,3H),1.21-1.16 (m,6H).
步骤4：化合物15-5的合成Step 4: Synthesis of compound 15-5
将化合物15-4(1.05g,3.22mmol,1eq)加入至二氯甲烷(20mL)和4-二甲氨基吡啶(1.57g,12.87mmol)，降至0℃，加入三氟甲磺酸酐(1.36g,4.82mmol)，反应逐渐升至20℃搅拌2小时。反应液减压浓缩。粗品经硅胶柱层析纯化(石油醚:乙酸乙酯＝5:1)，得到化合物15-5。Compound 15-4 (1.05g, 3.22mmol, 1eq) was added to dichloromethane (20mL) and 4-dimethylaminopyridine (1.57g, 12.87mmol), reduced to 0°C, added trifluoromethanesulfonic anhydride (1.36 g, 4.82mmol), the reaction was gradually raised to 20°C and stirred for 2 hours. The reaction solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain compound 15-5.
1H NMR(400MHz,CDCl 3)δ＝7.05-7.02(m,1H),6.93(d,J＝8.3Hz,1H),6.90(d,J＝2.2Hz,1H),6.88-6.83(m,1H),6.70-6.64(m,1H),5.20-5.14(m,2H),4.36-4.30(m,1H),3.48(d,J＝2.6Hz,3H),3.35-3.25(m,1H),3.14-3.04(m,1H),2.95-2.85(m,1H),2.69-2.55(m,1H),2.11-2.06(m,1H),1.99-1.96(m,3H),1.18(t,J＝6.8Hz,6H)。 1 H NMR(400MHz, CDCl 3 )δ=7.05-7.02(m,1H), 6.93(d,J=8.3Hz,1H), 6.90(d,J=2.2Hz,1H), 6.88-6.83(m, 1H), 6.70-6.64(m,1H), 5.20-5.14(m,2H), 4.36-4.30(m,1H), 3.48(d,J=2.6Hz,3H), 3.35-3.25(m,1H) ,3.14-3.04(m,1H),2.95-2.85(m,1H),2.69-2.55(m,1H),2.11-2.06(m,1H),1.99-1.96(m,3H),1.18(t, J=6.8Hz, 6H).
步骤5：化合物15-6的合成Step 5: Synthesis of compound 15-6
将化合物15-5(0.4g,872.43μmol,1eq)加入至二甲基甲酰胺(5mL)中，加入三乙胺(176.56mg,1.74mmol)，1,3-双(二苯基膦)丙烷(35.98mg,87.24μmol)，甲醇(559.05mg,17.45mmol)，醋酸钯(19.59mg)，一氧化碳(9.78μL)置换三次，反应在70℃，50psi搅拌16小时。反应液中加入乙酸乙酯(50mL)，半饱和氯化钠溶液(30mL×4)洗，有机相经无水硫酸钠干燥后，过滤，滤液减压浓缩。粗品经硅胶柱层析纯化(石油醚:乙酸乙酯＝5:1)，得到化合物15-6。Compound 15-5 (0.4g, 872.43μmol, 1eq) was added to dimethylformamide (5mL), triethylamine (176.56mg, 1.74mmol), 1,3-bis(diphenylphosphine)propane were added (35.98mg, 87.24μmol), methanol (559.05mg, 17.45mmol), palladium acetate (19.59mg), carbon monoxide (9.78μL) were replaced three times, and the reaction was stirred at 70°C and 50psi for 16 hours. Ethyl acetate (50 mL) was added to the reaction solution, washed with half-saturated sodium chloride solution (30 mL×4), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain compound 15-6.
1H NMR(400MHz,CDCl 3)δ＝7.81(s,1H),7.70-7.61(m,1H),6.94-6.89(m,2H),6.73-6.66(m,1H),5.19-5.12(m,2H),4.37(dd,J＝3.8,8.8Hz,1H),3.92(s,3H),3.49(s,3H),3.34-3.23(m,1H),3.17-3.04(m,1H),2.96-2.85(m,1H),2.66-2.53(m,1H),2.10-2.02(m,1H),2.02-1.98(m,3H),1.17(t,J＝7.1Hz,6H)。 1 H NMR (400MHz, CDCl 3 ) δ = 7.81 (s, 1H), 7.70-7.61 (m, 1H), 6.94-6.89 (m, 2H), 6.73-6.66 (m, 1H), 5.19-5.12 (m ,2H), 4.37(dd,J=3.8,8.8Hz,1H),3.92(s,3H),3.49(s,3H),3.34-3.23(m,1H),3.17-3.04(m,1H), 2.96-2.85 (m, 1H), 2.66-2.53 (m, 1H), 2.10-2.02 (m, 1H), 2.02-1.98 (m, 3H), 1.17 (t, J=7.1 Hz, 6H).
步骤6：化合物15-7的合成Step 6: Synthesis of compound 15-7
将化合物15-6(0.26g,705.63μmol)加入至甲醇(10mL)中，加入对甲苯磺酸(364.53mg,2.12mmol)，反应在20℃搅拌16小时。反应液中加入3当量碳酸氢钠，乙酸乙酯(50mL)，水(50mL)洗，有机相经无水硫酸钠干燥后，过滤，滤液减压浓缩。得到化合物15-7。[M+1] +＝325.1 Compound 15-6 (0.26 g, 705.63 μmol) was added to methanol (10 mL), p-toluenesulfonic acid (364.53 mg, 2.12 mmol) was added, and the reaction was stirred at 20°C for 16 hours. Add 3 equivalents of sodium bicarbonate, ethyl acetate (50 mL), and water (50 mL) to the reaction solution. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Compound 15-7 was obtained. [M+1] + ＝325.1
步骤7：化合物15-8的合成Step 7: Synthesis of compound 15-8
将化合物15-7(0.22g,678.15μmol)加入至乙腈(5mL)中，加入碳酸铯(441.91mg,1.36mmol)，溴化苄(173.98mg,1.02mmol)，反应在20℃搅拌16小时。反应液减压浓缩。粗品经硅胶柱层析纯化(石油醚:乙酸乙酯＝5:1)，得到化合物15-8。[M+1] +＝415.3 Compound 15-7 (0.22 g, 678.15 μmol) was added to acetonitrile (5 mL), cesium carbonate (441.91 mg, 1.36 mmol) and benzyl bromide (173.98 mg, 1.02 mmol) were added, and the reaction was stirred at 20°C for 16 hours. The reaction solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain compound 15-8. [M+1] + = 415.3
步骤8：化合物15-9的合成Step 8: Synthesis of compound 15-9
将化合物15-8(0.25g,603.09μmol)加入至四氢呋喃(5mL)中，降至0℃，加入四氢铝锂(45.77mg,1.21 mmol)，反应逐渐升至20℃搅拌2小时。反应液中加入饱和氯化铵溶液(20mL)，乙酸乙酯(30mL)萃取，有机相经无水硫酸钠干燥后，过滤，滤液减压浓缩。得到化合物15-9。[M-17] +＝369.4 Compound 15-8 (0.25 g, 603.09 μmol) was added to tetrahydrofuran (5 mL), reduced to 0° C., lithium aluminum tetrahydrogen (45.77 mg, 1.21 mmol) was added, and the reaction was gradually raised to 20° C. and stirred for 2 hours. Saturated ammonium chloride solution (20 mL) was added to the reaction solution, extracted with ethyl acetate (30 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Compound 15-9 was obtained. [M-17] + ＝369.4
步骤9：化合物15-10的合成Step 9: Synthesis of compound 15-10
将化合物15-9(180mg,465.69μmol)加入至二氯甲烷(5mL)中，降至0℃，加入三苯基膦(183.22mg,698.53μmol)，四溴化碳(231.65mg,698.53μmol)，反应逐渐升至20℃搅拌2小时。反应液减压浓缩。粗品经硅胶柱层析纯化(石油醚:乙酸乙酯＝5:1)，得到化合物15-10。Compound 15-9 (180mg, 465.69μmol) was added to dichloromethane (5mL), reduced to 0°C, triphenylphosphine (183.22mg, 698.53μmol), carbon tetrabromide (231.65mg, 698.53μmol) The reaction was gradually raised to 20°C and stirred for 2 hours. The reaction solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain compound 15-10.
1H NMR(400MHz,CDCl 3)δ＝7.47-7.30(m,5H),7.18(s,1H),7.02-6.96(m,2H),6.80-6.75(m,1H),6.72-6.66(m,1H),5.04(s,2H),4.52(s,2H),4.33(dd,J＝4.0,8.6Hz,1H),3.42-3.31(m,1H),3.11-3.00(m,1H),2.92-2.82(m,1H),2.64-2.52(m,1H),2.08-1.99(m,1H),1.98-1.93(m,3H),1.21(dd,J＝5.3,6.9Hz,6H)。 1 H NMR (400MHz, CDCl 3 ) δ = 7.47-7.30 (m, 5H), 7.18 (s, 1H), 7.02-6.96 (m, 2H), 6.80-6.75 (m, 1H), 6.72-6.66 (m ,1H),5.04(s,2H),4.52(s,2H),4.33(dd,J=4.0,8.6Hz,1H),3.42-3.31(m,1H),3.11-3.00(m,1H), 2.92-2.82 (m, 1H), 2.64-2.52 (m, 1H), 2.08-1.99 (m, 1H), 1.98-1.93 (m, 3H), 1.21 (dd, J=5.3, 6.9 Hz, 6H).
步骤10：化合物15-11的合成Step 10: Synthesis of compound 15-11
将亚磷酸二乙酯(110.62mg,801.03μmol)，碳酸铯(260.99mg,801.03μmol)，四丁基碘化铵(147.94mg,400.51μmol)加入至二甲基甲酰胺(4mL)中，20℃搅拌1小时，加入化合物15-10(0.18g,400.51μmol)，反应在20℃搅拌16小时。加入乙酸乙酯(50mL)，半饱和氯化钠溶液(30mL×4)洗，有机相经无水硫酸钠干燥后，过滤，减压浓缩。经硅胶柱层析纯化(纯石油醚至石油醚:乙酸乙酯＝1:1)，得到化合物15-11。Diethyl phosphite (110.62mg, 801.03μmol), cesium carbonate (260.99mg, 801.03μmol), tetrabutylammonium iodide (147.94mg, 400.51μmol) were added to dimethylformamide (4mL), 20 After stirring for 1 hour at °C, compound 15-10 (0.18 g, 400.51 μmol) was added, and the reaction was stirred at 20 °C for 16 hours. Ethyl acetate (50 mL) was added, washed with half-saturated sodium chloride solution (30 mL×4), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purified by silica gel column chromatography (pure petroleum ether to petroleum ether: ethyl acetate = 1:1) to obtain compound 15-11.
1H NMR(400MHz,CDCl 3)δ＝7.46-7.30(m,5H),7.11-7.05(m,1H),6.94(d,J＝2.2Hz,1H),6.89(s,1H),6.79-6.75(m,1H),6.73-6.69(m,1H),5.06-5.00(m,2H),4.35-4.29(m,1H),4.10-3.96(m,4H),3.41-3.30(m,1H),3.17-3.10(m,2H),3.09-2.99(m,1H),2.90-2.79(m,1H),2.61-2.49(m,1H),2.05-1.96(m,1H),1.95-1.91(m,3H),1.30-1.23(m,6H),1.20-1.14(m,6H)。 1 H NMR(400MHz, CDCl 3 )δ=7.46-7.30(m,5H), 7.11-7.05(m,1H), 6.94(d,J=2.2Hz,1H), 6.89(s,1H), 6.79- 6.75(m,1H),6.73-6.69(m,1H),5.06-5.00(m,2H),4.35-4.29(m,1H),4.10-3.96(m,4H),3.41-3.30(m,1H) ), 3.17-3.10 (m, 2H), 3.09-2.99 (m, 1H), 2.90-2.79 (m, 1H), 2.61-2.49 (m, 1H), 2.05-1.96 (m, 1H), 1.95-1.91 (m,3H),1.30-1.23(m,6H),1.20-1.14(m,6H).
步骤11：化合物15-12的合成Step 11: Synthesis of compound 15-12
将化合物15-11(200mg,394.78μmol)加入至甲醇(10mL)中，加入钯碳(0.2g,5％钯含量)，氢气置换三次，反应在50℃，50psi搅拌16小时。过滤，滤液减压浓缩。得到化合物15-12。[M+1] +＝417.3 Compound 15-11 (200 mg, 394.78 μmol) was added to methanol (10 mL), palladium carbon (0.2 g, 5% palladium content) was added, and hydrogen was replaced three times. The reaction was stirred at 50° C. and 50 psi for 16 hours. After filtration, the filtrate was concentrated under reduced pressure. Compound 15-12 was obtained. [M+1] + = 417.3
步骤12：化合物15-13的合成Step 12: Synthesis of compound 15-13
将化合物15-12(0.19g,456.19μmol)用SFC拆分。经SFC(柱型:DAICEL CHIRALPAK AD(250mm*30mm,10μm)；流动相:[0.1％NH 3H 2O IPA]:35％-35％,6min)拆分。得到化合物15-13，15-14。分析方法：柱型:Chiralpak AD-3,50×4.6mm,I.D.,3μm。流动相:A:CO 2，B:IPA(0.05％DEA)。梯度:B相1.2分钟内从5％升至50％，维持1分钟，0.8分钟内降至5％,流速:3.4mL/min。柱温:35℃。ABPR:1800psi。化合物15-13保留时间：1.142min。化合物15-14保留时间：1.211min。 Compound 15-12 (0.19g, 456.19μmol) was resolved by SFC. SFC (column type: DAICEL CHIRALPAK AD (250mm*30mm, 10μm); mobile phase: [0.1% NH 3 H 2 O IPA]: 35%-35%, 6min) resolution. Compounds 15-13 and 15-14 were obtained. Analysis method: Column type: Chiralpak AD-3, 50×4.6mm, ID, 3μm. Mobile phase: A: CO 2 , B: IPA (0.05% DEA). Gradient: Phase B increased from 5% to 50% in 1.2 minutes, maintained for 1 minute, and decreased to 5% in 0.8 minutes, flow rate: 3.4 mL/min. Column temperature: 35°C. ABPR: 1800psi. Retention time of compound 15-13: 1.142 min. Retention time of compound 15-14: 1.211 min.
步骤13：化合物15的合成Step 13: Synthesis of compound 15
将化合物15-13(60.00mg,144.06μmol)溶解于二氯甲烷(3mL)中，加入三甲基溴硅烷(220.55mg,1.44mmol)，反应在20℃继续搅拌16小时。反应液减压浓缩，加入乙酸乙酯(20mL)，水(10mL×2)洗，分液，有机相经无水硫酸钠干燥后，过滤，减压浓缩。经prep-HPLC(柱型:Welch Xtimate C18 150*25mm*5μm；流动相:[水(0.04％HCl)-ACN]；B(ACN)％:40％-65％,8min)纯化。得到化合物15。Compound 15-13 (60.00 mg, 144.06 μmol) was dissolved in dichloromethane (3 mL), trimethylsilyl bromide (220.55 mg, 1.44 mmol) was added, and the reaction was stirred at 20° C. for 16 hours. The reaction solution was concentrated under reduced pressure, ethyl acetate (20 mL) was added, washed with water (10 mL×2), and separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purified by prep-HPLC (column type: Welch Xtimate C18 150*25mm*5μm; mobile phase: [water (0.04%HCl)-ACN]; B(ACN)%: 40%-65%, 8min). Compound 15 was obtained.
1H NMR(400MHz,CD 3OD)δ＝7.07(s,1H),6.88(s,1H),6.86(d,J＝1.8Hz,1H),6.60-6.54(m,2H),4.30-4.24(m,1H),3.21(td,J＝7.0,13.8Hz,1H),3.12-3.03(m,2H),3.03-2.93(m,1H),2.87-2.74(m,1H),2.57- 2.44(m,1H),1.98-1.91(m,1H),1.90(s,3H),1.14(t,J＝7.0Hz,6H)。 1 H NMR (400MHz, CD 3 OD) δ = 7.07 (s, 1H), 6.88 (s, 1H), 6.86 (d, J = 1.8 Hz, 1H), 6.60-6.54 (m, 2H), 4.30-4.24 (m, 1H), 3.21 (td, J = 7.0, 13.8 Hz, 1H), 3.12-3.03 (m, 2H), 3.03-2.93 (m, 1H), 2.87-2.74 (m, 1H), 2.57- 2.44 (m, 1H), 1.98-1.91 (m, 1H), 1.90 (s, 3H), 1.14 (t, J=7.0 Hz, 6H).
步骤14：化合物16的合成Step 14: Synthesis of compound 16
将化合物15-14(60.00mg,144.06μmol)溶解于二氯甲烷(3mL)中，加入三甲基溴硅烷(220.55mg,1.44mmol)，反应在20℃继续搅拌16小时。反应液减压浓缩，加入乙酸乙酯(20mL)，水(10mL×2)洗，分液，有机相经无水硫酸钠干燥后，过滤，减压浓缩。经prep-HPLC(柱型:Welch Xtimate C18 150*25mm*5μm；流动相:[水(0.04％HCl)-ACN]；B(ACN)％:40％-65％,8min)，得到化合物16。Compound 15-14 (60.00 mg, 144.06 μmol) was dissolved in dichloromethane (3 mL), trimethylbromosilane (220.55 mg, 1.44 mmol) was added, and the reaction was stirred at 20° C. for 16 hours. The reaction solution was concentrated under reduced pressure, ethyl acetate (20 mL) was added, washed with water (10 mL×2), and separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. After prep-HPLC (column type: Welch Xtimate C18 150*25mm*5μm; mobile phase: [water (0.04%HCl)-ACN]; B(ACN)%: 40%-65%, 8min), compound 16 was obtained.
1H NMR(400MHz,CD 3OD)δ＝7.07(s,1H),6.90-6.87(m,1H),6.87-6.84(m,1H),6.60-6.53(m,2H),4.30-4.23(m,1H),3.21(td,J＝6.9,13.8Hz,1H),3.12-3.04(m,2H),3.03-2.96(m,1H),2.87-2.77(m,1H),2.57-2.44(m,1H),1.98-1.92(m,1H),1.90(s,3H),1.14(t,J＝7.0Hz,6H)。 1 H NMR (400MHz, CD 3 OD) δ = 7.07 (s, 1H), 6.90-6.87 (m, 1H), 6.87-6.84 (m, 1H), 6.60-6.53 (m, 2H), 4.30-4.23 ( m,1H),3.21(td,J=6.9,13.8Hz,1H),3.12-3.04(m,2H),3.03-2.96(m,1H),2.87-2.77(m,1H),2.57-2.44( m, 1H), 1.98-1.92 (m, 1H), 1.90 (s, 3H), 1.14 (t, J=7.0 Hz, 6H).
实施例17、18Examples 17, 18
Figure PCTCN2020139562-appb-000122
Figure PCTCN2020139562-appb-000122
合成路线：synthetic route:
Figure PCTCN2020139562-appb-000123
Figure PCTCN2020139562-appb-000123
步骤1：17-2的合成Step 1: Synthesis of 17-2
向干燥洁净的三口瓶加17-1(2g,6.19mmol)和四氢呋喃(60mL)，开启搅拌，控制温度-70℃，缓慢滴加正丁基锂(2.5M,2.97mL)，反应30min，控制温度-70℃，加入BB-1(1.71g,6.19mmol)，继续反应2小时，在氮气保护下，缓慢滴加饱和氯化铵溶液(100mL)，随后加入乙酸乙酯(100mL)萃取，分得有机相，无水硫酸钠干燥，旋干得到化合物17-2。[M-17] +＝503.4 Add 17-1 (2g, 6.19mmol) and tetrahydrofuran (60mL) to a dry and clean three-necked flask, turn on the stirring, control the temperature to -70℃, slowly add n-butyllithium (2.5M, 2.97mL) dropwise, react for 30min, control The temperature was -70℃, BB-1 (1.71g, 6.19mmol) was added, and the reaction was continued for 2 hours. Under the protection of nitrogen, saturated ammonium chloride solution (100mL) was slowly added dropwise, followed by ethyl acetate (100mL) for extraction. The organic phase is obtained, dried with anhydrous sodium sulfate, and spin-dried to obtain compound 17-2. [M-17] + ＝503.4
步骤2：17-3的合成Step 2: Synthesis of 17-3
向拇指瓶加入17-2(3.6g,3.46mmol)和二氯甲烷(35mL)，开启搅拌，加入乙酸乙酯(591.18mg,5.18mmol)，随后加入三乙基硅氢(1.21g,10.37mmol,1.66mL)，在20℃反应2小时。向反应体系，加入饱和碳酸钠溶液(80mL)搅拌10min，随后加入(40mL)萃取分得有机相，无水硫酸钠干燥，旋干得到化合物17-3。Add 17-2 (3.6g, 3.46mmol) and dichloromethane (35mL) to the thumb bottle, turn on the stirring, add ethyl acetate (591.18mg, 5.18mmol), and then add triethylsilylhydrogen (1.21g, 10.37mmol) ,1.66mL), react at 20°C for 2 hours. To the reaction system, saturated sodium carbonate solution (80 mL) was added and stirred for 10 min, and then (40 mL) was added to extract and separate the organic phase, which was dried with anhydrous sodium sulfate and spin-dried to obtain compound 17-3.
1H NMR(400MHz,CDCl 3)δ＝7.44(dd,J＝1.1,3.7Hz,5H),7.23-7.19(m,2H),6.50-6.47(m,2H),5.03(s,2H),4.57(dd,J＝3.5,8.8Hz,1H),3.42-3.31(m,2H),3.03-2.95(m,1H),2.88-2.80(m,1H),2.01-1.97(m,1H),1.91(s,3H),1.24(s,6H),1.22(s,6H),1.01(s,9H)。 1 H NMR (400MHz, CDCl 3 )δ = 7.44 (dd, J = 1.1, 3.7 Hz, 5H), 7.23-7.19 (m, 2H), 6.50-6.47 (m, 2H), 5.03 (s, 2H), 4.57(dd,J=3.5,8.8Hz,1H),3.42-3.31(m,2H),3.03-2.95(m,1H),2.88-2.80(m,1H),2.01-1.97(m,1H), 1.91 (s, 3H), 1.24 (s, 6H), 1.22 (s, 6H), 1.01 (s, 9H).
步骤3：17-4的合成Step 3: Synthesis of 17-4
向干燥洁净的拇指瓶加入17-3(1.6g,3.17mmol)，随后加入甲醇(16mL)和四氢呋喃(16mL)，开启搅拌，加入氟化铵(1.17g,31.70mmol)，在50℃温度反应2小时；旋干得到粗品；经硅胶柱层析(石油醚:乙酸乙酯＝10:1～3:1)纯化得到化合物17-4。Add 17-3 (1.6g, 3.17mmol) to a dry and clean thumb bottle, then add methanol (16mL) and tetrahydrofuran (16mL), turn on the stirring, add ammonium fluoride (1.17g, 31.70mmol), and react at 50℃ 2 hours; Rotate to dry to obtain the crude product; Purify by silica gel column chromatography (petroleum ether: ethyl acetate=10:1～3:1) to obtain compound 17-4.
1H NMR(400MHz,CDCl 3)δ＝7.46-7.42(m,5H),7.22-7.14(m,2H),6.66-6.63(m,2H),5.07(s,2H),5.04(s,1H),4.56(dd,J＝3.9,8.8Hz,1H),3.41-3.19(m,2H),3.04-2.95(m,1H),2.90-2.79(m,1H),2.66-2.54(m,1H),1.24(s,3H),1.22(s,3H)。 1 H NMR(400MHz,CDCl 3 )δ=7.46-7.42(m,5H),7.22-7.14(m,2H),6.66-6.63(m,2H),5.07(s,2H),5.04(s,1H) ),4.56(dd,J=3.9,8.8Hz,1H),3.41-3.19(m,2H),3.04-2.95(m,1H),2.90-2.79(m,1H),2.66-2.54(m,1H) ), 1.24(s, 3H), 1.22(s, 3H).
步骤4：17-5的合成Step 4: Synthesis of 17-5
向拇指瓶加入17-4(1.2g,3.07mmol)和N,N-二甲基甲酰胺(7mL)，开启搅拌，加入碳酸铯(2.00g,6.15mmol)，随后加入对甲苯磺酰氧甲基膦酸二乙酯(891.43mg,2.77mmol,713.15μL)，控制温度50℃，反应3小时；向反应体系加入乙酸乙酯(50mL)，随后依次用水(50mL)和饱和食盐水(50mL)萃取，分得有机相，用无水硫酸钠干燥，旋干得到目标粗品；经硅胶柱层析(石油醚:乙酸乙酯＝10:1-3:1)纯化得到化合物17-5。Add 17-4 (1.2g, 3.07mmol) and N,N-dimethylformamide (7mL) to the thumb bottle, turn on the stirring, add cesium carbonate (2.00g, 6.15mmol), and then add p-toluenesulfonyloxymethane Diethyl phosphonate (891.43mg, 2.77mmol, 713.15μL), control the temperature at 50℃, react for 3 hours; add ethyl acetate (50mL) to the reaction system, followed by water (50mL) and saturated brine (50mL) After extraction, the organic phase was separated, dried with anhydrous sodium sulfate, and spin-dried to obtain the target crude product; purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1-3:1) to obtain compound 17-5.
[M+1] +:541.3 [M+1] + :541.3
步骤5：化合物17-6的合成Step 5: Synthesis of compound 17-6
向拇指瓶加入化合物17-5(1g,1.85mmol)和乙酸乙酯(28mL)，开启搅拌，随后加入钯碳(1.3g,1.85mmol,5％)，在氢气球15psi氛围下，20℃温度，反应1小时；反应体系通过2g硅藻土的五孔漏斗过滤，并用乙酸乙酯(25mL×2)冲洗两次，滤液旋干得到粗品，经硅胶柱层析(石油醚:乙酸乙酯＝10:1～1:1)纯化得到化合物17-6。Add compound 17-5 (1g, 1.85mmol) and ethyl acetate (28mL) to the thumb bottle, turn on the stirring, then add palladium on carbon (1.3g, 1.85mmol, 5%), under a hydrogen balloon 15psi atmosphere, 20℃ temperature , React for 1 hour; the reaction system was filtered through a five-hole funnel of 2g diatomaceous earth, and washed twice with ethyl acetate (25mL×2), the filtrate was spin-dried to obtain the crude product, which was subjected to silica gel column chromatography (petroleum ether: ethyl acetate = 10:1～1:1) Purify to obtain compound 17-6.
1H NMR(400MHz,CDCl 3)δ＝6.74(s,1H),6.62-6.56(m,2H),6.47(d,J＝8.8Hz,1H),4.52(dd,J＝4.0,8.8Hz,1H),4.33-4.24(m,6H),3.16-2.95(m,2H),2.88-2.78(m,1H),2.54(qd,J＝8.5,12.8Hz,1H),2.00(tdd,J＝4.3,8.4,12.7Hz,1H),1.91(s,3H),1.39(t,J＝7.1Hz,6H),1.07(dd,J＝6.9,10.4Hz,6H)。 1 H NMR (400MHz, CDCl 3 ) δ = 6.74 (s, 1H), 6.62-6.56 (m, 2H), 6.47 (d, J = 8.8 Hz, 1H), 4.52 (dd, J = 4.0, 8.8 Hz, 1H),4.33-4.24(m,6H),3.16-2.95(m,2H),2.88-2.78(m,1H),2.54(qd,J=8.5,12.8Hz,1H),2.00(tdd,J= 4.3, 8.4, 12.7 Hz, 1H), 1.91 (s, 3H), 1.39 (t, J = 7.1 Hz, 6H), 1.07 (dd, J = 6.9, 10.4 Hz, 6H).
F NMR(400MHz,CDCl 3)δppm-121.571。 F NMR (400MHz, CDCl 3 ) δ ppm-121.571.
步骤6：拆分得到17-7和17-8Step 6: Split to get 17-7 and 17-8
此步骤用于中间体17-6拆分，经手性分离：柱型:DAICEL CHIRALPAK AD(250mm*30mm,10μm)；流动相:[0.1％NH 3.H 2O IPA]；B(ACN)％:20％-20％,min，拆分得到化合物17-7，17-8。分析方法：柱型:Chiralpak AD-3,50×4.6mm,I.D.,3μm。流动相:A:CO 2B:IPA(0.05％DEA)。梯度:B相1.2分钟内从5％升至50％，维持1分钟，0.8分钟内降至5％，流速:3.4mL/min。柱温:35℃。ABPR:1800psi。化合物17-7保留时间： 1.046min。化合物17-7保留时间：1.115min。 This step is used for the resolution of intermediate 17-6 and chiral separation: Column type: DAICEL CHIRALPAK AD (250mm*30mm, 10μm); mobile phase: [0.1%NH 3 .H 2 O IPA]; B(ACN)% : 20%-20%, min. Resolve to obtain compounds 17-7 and 17-8. Analysis method: Column type: Chiralpak AD-3, 50×4.6mm, ID, 3μm. Mobile phase: A: CO 2 B: IPA (0.05% DEA). Gradient: Phase B increased from 5% to 50% in 1.2 minutes, maintained for 1 minute, and decreased to 5% in 0.8 minutes, flow rate: 3.4 mL/min. Column temperature: 35°C. ABPR: 1800psi. Compound 17-7 retention time: 1.046min. Compound 17-7 retention time: 1.115min.
步骤7：17的合成Step 7: Synthesis of 17
向拇指瓶加入17-7(215.00mg,477.27μmol)和二氯甲烷(4mL)，开启搅拌；降温至0℃，加入三甲基溴硅烷(730.65mg,4.77mmol,619.20μL)，缓慢升温至20℃，反应16小时；反应体系旋干得到目标粗品；经prep-HPLC(柱型:Phenomenex Luna C18 100*30mm*5μm；流动相:[水(0.04％HCl)-ACN]；B(ACN)％:30％-65％,10min)纯化得到化合物17。Add 17-7 (215.00mg, 477.27μmol) and dichloromethane (4mL) to the thumb bottle, turn on the stirring; reduce the temperature to 0℃, add trimethylsilyl bromide (730.65mg, 4.77mmol, 619.20μL), and slowly raise the temperature to React at 20°C for 16 hours; the reaction system is spin-dried to obtain the target crude product; prep-HPLC (column type: Phenomenex Luna C18 100*30mm*5μm; mobile phase: [水(0.04%HCl)-ACN]; B(ACN) %: 30%-65%, 10min) to obtain compound 17.
1H NMR(400MHz,DMSO)δ＝9.54(s,1H),6.77(s,1H),6.60(s,1H),6.52(d,J＝11.9Hz,1H),6.44(d,J＝9.2Hz,1H),4.42(br dd,J＝4.1,8.5Hz,1H),4.04(br d,J＝10.2Hz,2H),3.10-2.89(m,4H),2.83-2.74(m,1H),1.84(s,3H),0.97(dd,J＝7.1,8.8Hz,6H)。 1 H NMR (400MHz, DMSO) δ = 9.54 (s, 1H), 6.77 (s, 1H), 6.60 (s, 1H), 6.52 (d, J = 11.9 Hz, 1H), 6.44 (d, J = 9.2 Hz, 1H), 4.42 (br dd, J = 4.1, 8.5 Hz, 1H), 4.04 (br d, J = 10.2 Hz, 2H), 3.10-2.89 (m, 4H), 2.83-2.74 (m, 1H) , 1.84 (s, 3H), 0.97 (dd, J=7.1, 8.8 Hz, 6H).
F NMR(400MHz,DMSO)δppm-121.434。F NMR (400MHz, DMSO) δppm-121.434.
31P NMR(400MHz,DMSO)δppm 14.922。 31 P NMR (400MHz, DMSO) δ ppm 14.922.
步骤8：化合物18的合成Step 8: Synthesis of compound 18
向拇指瓶加入17-8(200.00mg,443.97μmol)和二氯甲烷(4mL)，开启搅拌，降温至0℃，加入三甲基溴硅烷(679.68mg,4.44mmol,576.00μL)，缓慢升温至20℃，反应16小时，反应体系旋干得到粗品；经prep-HPLC(柱型:Phenomenex Luna C18 100*30mm*5μm；流动相:[水(0.04％HCl)-ACN]；B(ACN)％:30％-65％,10min)纯化得到化合物18。Add 17-8 (200.00mg, 443.97μmol) and dichloromethane (4mL) to the thumb bottle, turn on the stirring, reduce the temperature to 0℃, add trimethylsilyl bromide (679.68mg, 4.44mmol, 576.00μL), and slowly raise the temperature to React at 20°C for 16 hours, and the reaction system is spin-dried to obtain the crude product; prep-HPLC (column type: Phenomenex Luna C18 100*30mm*5μm; mobile phase: [水(0.04%HCl)-ACN]; B(ACN)% : 30%-65%, 10min) to obtain compound 18.
1H NMR(400MHz,DMSO-d 6)δ＝9.54(br s,1H),6.77(s,1H),6.60(s,1H),6.53(d,J＝11.9Hz,1H),6.44(d,J＝9.0Hz,1H),4.42(br dd,J＝4.1,8.5Hz,1H),4.04(d,J＝10.3Hz,2H),3.10-2.71(m,5H),1.84(s,3H),0.97(dd,J＝7.0,9.0Hz,6H)。 1 H NMR (400MHz, DMSO-d 6 ) δ = 9.54 (br s, 1H), 6.77 (s, 1H), 6.60 (s, 1H), 6.53 (d, J = 11.9 Hz, 1H), 6.44 (d ,J=9.0Hz,1H),4.42(br dd,J=4.1,8.5Hz,1H),4.04(d,J=10.3Hz,2H),3.10-2.71(m,5H),1.84(s,3H) ), 0.97 (dd, J=7.0, 9.0 Hz, 6H).
实施例19、20Examples 19, 20
Figure PCTCN2020139562-appb-000124
Figure PCTCN2020139562-appb-000124
合成路线：synthetic route:
Figure PCTCN2020139562-appb-000125
Figure PCTCN2020139562-appb-000125
步骤1：19-2的合成Step 1: Synthesis of 19-2
在-78℃，向化合物19-1(10g,37.60mmol)的四氢呋喃(100mL)中加入正丁基锂(2.5M,16.55mL)，0.5小时后加入N,N-二甲基甲酰胺(3.30g,45.12mmol,3.47mL)，反应1小时。将反应液倒入饱和氯化铵溶液中，加入乙酸乙酯(50mL)分液，水相用乙酸乙酯萃取(50mL×3)，合并有机相，无水硫酸钠干燥，过滤，减压浓缩得到粗品。用硅胶柱层析法分离(石油醚/乙酸乙酯＝20:1)得到化合物19-2。At -78°C, n-butyllithium (2.5M, 16.55mL) was added to compound 19-1 (10g, 37.60mmol) in tetrahydrofuran (100mL), and N,N-dimethylformamide (3.30 g, 45.12mmol, 3.47mL), react for 1 hour. The reaction solution was poured into saturated ammonium chloride solution, ethyl acetate (50mL) was added for separation, the aqueous phase was extracted with ethyl acetate (50mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure Get crude product. It was separated by silica gel column chromatography (petroleum ether/ethyl acetate=20:1) to obtain compound 19-2.
1H NMR(400MHz,CDCl 3)δ＝9.91(s,1H),7.59(t,J＝1.5Hz,1H),7.33(q,J＝2.1Hz,2H),3.87ppm(s,3H). 1 H NMR (400MHz, CDCl 3 ) δ = 9.91 (s, 1H), 7.59 (t, J = 1.5 Hz, 1H), 7.33 (q, J = 2.1 Hz, 2H), 3.87 ppm (s, 3H).
步骤2：19-3的合成Step 2: Synthesis of 19-3
向化合物19-2(11.2g,52.08mmol)的吡啶(120mL)中加入丙二酸(8.13g,78.12mmol,8.13mL)，哌啶(886.96mg,10.42mmol,1.03mL)，在120℃反应1.5小时。加80mL水稀释，小心用12N HCl调pH小于3，有沉淀析出，过滤，收集滤饼。粗品未经进一步纯化，得到化合物19-3。Add malonic acid (8.13g, 78.12mmol, 8.13mL) and piperidine (886.96mg, 10.42mmol, 1.03mL) to the pyridine (120mL) of compound 19-2 (11.2g, 52.08mmol), and react at 120°C 1.5 hours. Dilute with 80 mL of water, carefully adjust the pH to less than 3 with 12N HCl, and precipitate precipitation, filter, and collect the filter cake. The crude product was not further purified to obtain compound 19-3.
1H NMR(400MHz,DMSO-d 6)δ＝7.48-7.54(m,2H),7.27-7.30(m,1H),7.18(t,J＝2.0Hz,1H),6.63(d,J＝16.0Hz,1H),3.80ppm(s,3H). 1 H NMR(400MHz,DMSO-d 6 )δ=7.48-7.54(m,2H), 7.27-7.30(m,1H), 7.18(t,J=2.0Hz,1H), 6.63(d,J=16.0 Hz, 1H), 3.80ppm (s, 3H).
步骤3：19-4的合成Step 3: Synthesis of 19-4
向化合物19-3(11.2g,43.57mmol)的乙醇(10mL)中加入二氧化铂(2.28g,10.02mmol),在氢气环境下，20℃，15psi,反应2小时。将反应液用硅藻土过滤，滤液减压浓缩得到粗品。粗品未经纯化，得到化合物19-4。Platinum dioxide (2.28 g, 10.02 mmol) was added to compound 19-3 (11.2 g, 43.57 mmol) in ethanol (10 mL), and reacted for 2 hours at 20° C., 15 psi under a hydrogen environment. The reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was not purified to obtain compound 19-4.
步骤4：19-5的合成Step 4: Synthesis of 19-5
向装有化合物19-4(11g,25.47mmol,60％)的反应瓶中加入多聚磷酸(120mL)，在95℃反应12小时。将反应液缓缓倒入冰水中稀释，析出黄色固体过滤，收集滤饼。粗品未经进一步纯化，得到化合物19-5。Polyphosphoric acid (120 mL) was added to the reaction flask containing compound 19-4 (11 g, 25.47 mmol, 60%), and reacted at 95° C. for 12 hours. The reaction solution was slowly poured into ice water for dilution, a yellow solid was precipitated out, filtered, and the filter cake was collected. The crude product was not further purified to obtain compound 19-5.
1H NMR(400MHz,CDCl 3)δ＝7.08(d,J＝2.1Hz,1H),6.83-6.90(d,1H),3.88(s,3H),2.98-3.09(m,2H),2.68-2.77ppm(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ = 7.08 (d, J = 2.1 Hz, 1H), 6.83-6.90 (d, 1H), 3.88 (s, 3H), 2.98-3.09 (m, 2H), 2.68- 2.77ppm(m,2H).
步骤5：19-6的合成Step 5: Synthesis of 19-6
向装有化合物19-5(1.7g,4.58mmol,65％)的反应瓶中加入氢溴酸水溶液(16.46g,97.67mmol,11.05mL,48％)，在130℃反应2小时。加入乙酸乙酯(50mL)分液，水相用乙酸乙酯萃取(50mL×3)，合并有机相，无水硫酸钠干燥，过滤，减压浓缩得到粗品。室温，经石油醚:乙酸乙酯室温打浆纯化(10:1，5mL)，过滤得到化合物19-6。A hydrobromic acid aqueous solution (16.46 g, 97.67 mmol, 11.05 mL, 48%) was added to a reaction flask containing compound 19-5 (1.7 g, 4.58 mmol, 65%), and the reaction was carried out at 130°C for 2 hours. Ethyl acetate (50 mL) was added for liquid separation, the aqueous phase was extracted with ethyl acetate (50 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. At room temperature, it was purified by beating petroleum ether: ethyl acetate at room temperature (10:1, 5 mL), and filtered to obtain compound 19-6.
1H NMR(400MHz,DMSO-d 6)δ＝10.85(br s,1H),6.96(d,J＝1.9Hz,1H),6.87(s,1H),2.90-2.99(m,2H),2.54-2.63ppm(m,2H). 1 H NMR (400MHz, DMSO-d 6 ) δ = 10.85 (br s, 1H), 6.96 (d, J = 1.9 Hz, 1H), 6.87 (s, 1H), 2.90-2.99 (m, 2H), 2.54 -2.63ppm(m,2H).
步骤6：19-7的合成Step 6: Synthesis of 19-7
向化合物19-6(1.2g,5.29mmol)的二氯甲烷(20mL)中加入4-二甲氨基吡啶(1.16g,9.51mmol)，三异丙基氯硅烷(917.07mg,4.76mmol,1.02mL)，在20℃反应2小时。将反应液倒入饱和氯化钠溶液中，加入二氯甲烷(50mL)分液，水相用二氯甲烷萃取(50mL×3)，合并有机相，无水硫酸钠干燥，过滤，减压浓缩得到粗品。用硅胶柱层析法纯化(石油醚/乙酸乙酯＝50:1)，得到化合物19-7。To compound 19-6 (1.2g, 5.29mmol) in dichloromethane (20mL) was added 4-dimethylaminopyridine (1.16g, 9.51mmol), triisopropylchlorosilane (917.07mg, 4.76mmol, 1.02mL) ), react at 20°C for 2 hours. The reaction solution was poured into saturated sodium chloride solution, dichloromethane (50mL) was added for separation, the aqueous phase was extracted with dichloromethane (50mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure Get crude product. Purified by silica gel column chromatography (petroleum ether/ethyl acetate=50:1) to obtain compound 19-7.
步骤7：19-8的合成Step 7: Synthesis of 19-8
向化合物19-17(1.93g,6.46mmol)的四氢呋喃(20mL)溶液中加入正丁基锂(2.5M,2.41mL)，在-78℃反应0.5小时后，加入化合物19-7(1.65g,4.30mmol)，自然恢复至20℃反应2小时。将反应液倒入饱和氯化铵溶液中，加入乙酸乙酯(50mL)分液，水相用乙酸乙酯萃取(50mL×3)，合并有机相，无水硫酸钠干燥，过滤，减压浓缩得到粗品，用硅胶柱层析法分离(石油醚/乙酸乙酯＝20:1)，得到化合物19-8。To a solution of compound 19-17 (1.93g, 6.46mmol) in tetrahydrofuran (20mL) was added n-butyllithium (2.5M, 2.41mL), reacted at -78°C for 0.5 hours, compound 19-7 (1.65g, 4.30mmol), naturally return to 20°C and react for 2 hours. The reaction solution was poured into saturated ammonium chloride solution, ethyl acetate (50mL) was added for separation, the aqueous phase was extracted with ethyl acetate (50mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure The crude product was obtained, which was separated by silica gel column chromatography (petroleum ether/ethyl acetate=20:1) to obtain compound 19-8.
步骤8：19-9的合成Step 8: Synthesis of 19-9
在0℃，向化合物19-8(1.9g,1.57mmol,50％)的二氯甲烷(10mL)中加入三乙基硅氢(548.94mg,4.72mmol,754.04μL,)，三氟乙酸(269.14mg,2.36mmol,174.76μL)，在20℃反应2小时。将反应液倒入饱和碳酸氢钠溶液中，加入二氯甲烷(50mL)分液，水相用二氯甲烷萃取(50mL×3)，合并有机相，无水硫酸钠干燥，过滤，减压浓缩得到粗品。用硅胶柱层析法分离(石油醚/乙酸乙酯＝20:1)得到化合物19-9。At 0°C, to compound 19-8 (1.9g, 1.57mmol, 50%) in dichloromethane (10mL) was added triethylsilylhydrogen (548.94mg, 4.72mmol, 754.04μL,), trifluoroacetic acid (269.14) mg, 2.36 mmol, 174.76 μL), react at 20°C for 2 hours. The reaction solution was poured into saturated sodium bicarbonate solution, dichloromethane (50mL) was added for separation, the aqueous phase was extracted with dichloromethane (50mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure Get crude product. It was separated by silica gel column chromatography (petroleum ether/ethyl acetate=20:1) to obtain compound 19-9.
步骤9：19-10的合成Step 9: Synthesis of 19-10
在0℃，向化合物19-9(0.7g,1.35mmol)的二氯甲烷(2mL)中加入三乙基硅氢(469.96mg,4.04mmol,645.54μL)，三氟乙酸(230.42mg,2.02mmol,149.63μL)，在20℃反应2小时。将反应液减压浓缩得到粗品，用硅胶柱层析法分离(石油醚/乙酸乙酯＝50:1)得到化合物19-10。At 0°C, to compound 19-9 (0.7g, 1.35mmol) in dichloromethane (2mL) was added triethylsilylhydrogen (469.96mg, 4.04mmol, 645.54μL), trifluoroacetic acid (230.42mg, 2.02mmol) , 149.63μL) and react at 20°C for 2 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was separated by silica gel column chromatography (petroleum ether/ethyl acetate=50:1) to obtain compound 19-10.
1H NMR(400MHz,CDCl 3)δ＝6.83-6.95(m,2H),6.77(s,1H),6.55-6.70(m,2H),4.52(s,1H),4.30-4.40(m,1H),2.99-3.22(m,2H),2.86(ddd,J＝16.0,8.9,2.5Hz,1H),2.58(dq,J＝12.6,9.1Hz,1H),1.98-2.05(m,1H),1.26-1.30(m,3H),1.20(dd,J＝6.8,5.2Hz,6H),1.12ppm(d,J＝7.3Hz,18H). 1 H NMR (400MHz, CDCl 3 )δ = 6.83-6.95 (m, 2H), 6.77 (s, 1H), 6.55-6.70 (m, 2H), 4.52 (s, 1H), 4.30-4.40 (m, 1H) ), 2.99-3.22 (m, 2H), 2.86 (ddd, J = 16.0, 8.9, 2.5 Hz, 1H), 2.58 (dq, J = 12.6, 9.1 Hz, 1H), 1.98-2.05 (m, 1H), 1.26-1.30(m,3H), 1.20(dd,J=6.8,5.2Hz,6H), 1.12ppm(d,J=7.3Hz,18H).
步骤10：19-11的合成Step 10: Synthesis of 19-11
向化合物19-10(0.7g,1.39mmol)的二氯甲烷(10mL)中加入吡啶对甲苯磺酸盐(34.93mg,139.00μmol)，2,3-二氢吡喃(140.31mg,1.67mmol,152.51μL)，在20℃反应12小时。将反应液减压浓缩得到粗品。用硅胶柱层析法分离(石油醚/乙酸乙酯＝50:1)得到化合物19-11。To compound 19-10 (0.7g, 1.39mmol) in dichloromethane (10mL) was added pyridine p-toluenesulfonate (34.93mg, 139.00μmol), 2,3-dihydropyran (140.31mg, 1.67mmol, 152.51μL), react at 20°C for 12 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. It was separated by silica gel column chromatography (petroleum ether/ethyl acetate=50:1) to obtain compound 19-11.
1H NMR(400MHz,CDCl 3)δ＝6.97(dd,J＝8.3,6.8Hz,1H),6.82-6.92(m,2H),6.64-6.78(m,2H),5.38(t,J＝3.0Hz,1H),4.36(br d,J＝7.5Hz,1H),3.86-3.99(m,1H),3.61(br d,J＝11.4Hz,1H),3.22-3.35(m,1H),3.00-3.15(m,1H),2.80-2.91(m,1H),2.57(dq,J＝12.6,9.1Hz,1H),1.96-2.06(m,2H),1.86(dt,J＝7.4,3.6Hz,2H),1.58-1.77(m,3H),1.25-1.30(m,3H),1.14-1.21(m,6H),1.12ppm(d,J＝7.2Hz,18H). 1 H NMR (400MHz, CDCl 3 ) δ = 6.97 (dd, J = 8.3, 6.8 Hz, 1H), 6.82-6.92 (m, 2H), 6.64-6.78 (m, 2H), 5.38 (t, J = 3.0 Hz, 1H), 4.36 (br d, J = 7.5 Hz, 1H), 3.86-3.99 (m, 1H), 3.61 (br d, J = 11.4 Hz, 1H), 3.22-3.35 (m, 1H), 3.00 -3.15(m,1H),2.80-2.91(m,1H), 2.57(dq,J=12.6,9.1Hz,1H),1.96-2.06(m,2H),1.86(dt,J=7.4,3.6Hz ,2H), 1.58-1.77(m,3H), 1.25-1.30(m,3H), 1.14-1.21(m,6H), 1.12ppm(d,J=7.2Hz,18H).
步骤11：19-12的合成Step 11: Synthesis of 19-12
向化合物19-11(0.7g,1.19mmol)的四氢呋喃(20mL)中加入四丁基氟化铵(1M,1.43mL)，在20℃反应2小时。向反应液中加入水(20mL)淬灭，加入乙酸乙酯(50mL)分液，水相用乙酸乙酯萃取(50mL×3)，合并有机相，无水硫酸钠干燥，过滤，减压浓缩得到粗品。用硅胶柱层析法分离(石油醚/乙酸乙酯＝3:1)，得到化合物19-12。Tetrabutylammonium fluoride (1M, 1.43 mL) was added to compound 19-11 (0.7 g, 1.19 mmol) in tetrahydrofuran (20 mL), and reacted at 20°C for 2 hours. Water (20mL) was added to the reaction solution for quenching, ethyl acetate (50mL) was added for separation, the aqueous phase was extracted with ethyl acetate (50mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure Get crude product. It was separated by silica gel column chromatography (petroleum ether/ethyl acetate=3:1) to obtain compound 19-12.
1H NMR(400MHz,CDCl 3)δ＝6.87-7.01(m,2H),6.84(d,J＝2.1Hz,1H),6.63-6.75(m,2H),5.38(t,J＝3.1Hz,1H),4.35(br d,J＝6.9Hz,1H),3.86-3.97(m,1H),3.56-3.66(m,1H),3.23-3.35(m,1H),3.01-3.16(m,1H),2.80-2.92(m,1H),2.46-2.65(m,2H),1.95-2.03(m,1H),1.86(dt,J＝7.4,3.7Hz,2H),1.56-1.76(m,3H),1.18-1.24ppm(m,6H). 1 H NMR (400MHz, CDCl 3 ) δ = 6.87-7.01 (m, 2H), 6.84 (d, J = 2.1Hz, 1H), 6.63 6.75 (m, 2H), 5.38 (t, J = 3.1Hz, 1H), 4.35 (br d, J = 6.9Hz, 1H), 3.86-3.97 (m, 1H), 3.56-3.66 (m, 1H), 3.23-3.35 (m, 1H), 3.01-3.16 (m, 1H) ), 2.80-2.92(m,1H),2.46-2.65(m,2H),1.95-2.03(m,1H),1.86(dt,J=7.4,3.7Hz,2H),1.56-1.76(m,3H ), 1.18-1.24ppm (m, 6H).
步骤12：19-13的合成Step 12: Synthesis of 19-13
向化合物19-12(0.4g,927.30μmol)的N,N-二甲基甲酰胺(2mL)中加入碳酸铯(453.20mg,1.39mmol)，对甲苯磺酰氧甲基膦酸二乙酯(298.88mg,927.30μmol,239.10μL)，在50℃反应3小时。将反应液倒入饱和氯化钠溶液中，加入50mL乙酸乙酯分液，水相用乙酸乙酯萃取(50mL×3)，合并有机相，无水硫酸钠干燥，过滤，减压浓缩得到粗品。用硅胶柱层析法分离(石油醚/乙酸乙酯＝1:1)，得到化合物19-13。To compound 19-12 (0.4g, 927.30μmol) of N,N-dimethylformamide (2mL) was added cesium carbonate (453.20mg, 1.39mmol), diethyl p-toluenesulfonyloxymethylphosphonate ( 298.88 mg, 927.30 μmol, 239.10 μL), reacted at 50°C for 3 hours. The reaction solution was poured into saturated sodium chloride solution, 50mL ethyl acetate was added to separate the layers, the aqueous phase was extracted with ethyl acetate (50mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product . It was separated by silica gel column chromatography (petroleum ether/ethyl acetate=1:1) to obtain compound 19-13.
步骤13：19-14的合成Step 13: Synthesis of 19-14
向化合物19-13(0.35g,601.92μmol)的甲醇(1mL)中加入吡啶对甲苯磺酸盐(15.13mg,60.19μmol)，在50℃反应5小时。将反应液减压浓缩得到粗品。用硅胶柱层析法分离(石油醚/乙酸乙酯＝1:1)，得到化合物19-14。To compound 19-13 (0.35 g, 601.92 μmol) in methanol (1 mL) was added pyridine p-toluenesulfonate (15.13 mg, 60.19 μmol), and reacted at 50° C. for 5 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. It was separated by silica gel column chromatography (petroleum ether/ethyl acetate=1:1) to obtain compound 19-14.
步骤14：19-15和19-16的合成Step 14: Synthesis of 19-15 and 19-16
将化合物19-14(0.13g,0.29mmol)进行SFC分离。经SFC(柱型:DAICEL CHIRALPAK AD-3，(250mm*30mm,10μm)；流动相:[0.1％NH 3H 2O-IPA]:40％-40％,8min)分离得到化合物19-15和19-16。分析方法:仪器:Thar analytical SFC,柱型:Chiralpak AD-3，50mm*4.6mm*3μm,流动相:A:CO 2，B：IPA(0.05％DEA),梯度:B:A＝5％～50％，3min,流速:3.4mL/min,柱温:35℃,波长:220nm,柱压:1800psi。 化合物19-15保留时间：1.206分钟。化合物19-16保留时间：1.332分钟。 Compound 19-14 (0.13 g, 0.29 mmol) was subjected to SFC separation. SFC (column type: DAICEL CHIRALPAK AD-3, (250mm*30mm, 10μm); mobile phase: [0.1% NH 3 H 2 O-IPA]: 40%-40%, 8min) to obtain compounds 19-15 and 19-16. Analysis method: instrument: Thar analytical SFC, column type: Chiralpak AD-3, 50mm*4.6mm*3μm, mobile phase: A: CO 2 , B: IPA (0.05% DEA), gradient: B: A = 5%～ 50%, 3min, flow rate: 3.4mL/min, column temperature: 35°C, wavelength: 220nm, column pressure: 1800psi. Compound 19-15 retention time: 1.206 minutes. Compound 19-16 retention time: 1.332 minutes.
步骤15：19的合成Step 15: Synthesis of 19
在0℃向化合物19-15(20mg,40.21μmol)的二氯甲烷(2mL)中加入三甲基溴硅烷(61.56mg,402.12μmol,52.17μL)，在20℃反应12小时。将反应液减压浓缩得到粗品。用pre-HPLC(柱型:Phenomenex luna C18 80*40mm*3μm；流动相:水(0.04％HCl)-乙腈；梯度:B(乙腈)％:35％-55％,7min)分离。得到化合物19。Trimethylsilyl bromide (61.56 mg, 402.12 μmol, 52.17 μL) was added to compound 19-15 (20 mg, 40.21 μmol) in dichloromethane (2 mL) at 0°C, and reacted at 20°C for 12 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. Separated by pre-HPLC (column type: Phenomenex luna C18 80*40mm*3μm; mobile phase: water (0.04% HCl)-acetonitrile; gradient: B (acetonitrile)%: 35%-55%, 7min). Compound 19 was obtained.
1H NMR(400MHz,CD 3OD)δ＝6.97(br d,J＝15.6Hz,2H),6.78(d,J＝1.6Hz,1H),6.47-6.62(m,2H),4.29(dd,J＝8.7,2.2Hz,1H),4.20(d,J＝10.4Hz,2H),3.14-3.24(m,1H),3.07(dt,J＝16.7,8.3Hz,1H),2.81-2.95(m,1H),2.45-2.60(m,1H),1.88-2.03(m,1H),1.12ppm(t,J＝6.5Hz,6H). 1 H NMR (400MHz, CD 3 OD) δ = 6.97 (br d, J = 15.6 Hz, 2H), 6.78 (d, J = 1.6 Hz, 1H), 6.47-6.62 (m, 2H), 4.29 (dd, J = 8.7, 2.2 Hz, 1H), 4.20 (d, J = 10.4 Hz, 2H), 3.14-3.24 (m, 1H), 3.07 (dt, J = 16.7, 8.3 Hz, 1H), 2.81-2.95 (m ,1H), 2.45-2.60(m,1H), 1.88-2.03(m,1H), 1.12ppm(t,J=6.5Hz,6H).
步骤16：20的合成Step 16: Synthesis of 20
在0℃向化合物19-16(20mg,40.21μmol)的二氯甲烷(2mL)中加入三甲基溴硅烷(61.56mg,402.12μmol,52.17μL)，在20℃反应12小时。将反应液减压浓缩得到粗品。用pre-HPLC(柱型:Phenomenex luna C18 80*40mm*3μm；流动相:水(0.04％HCl)-乙腈；梯度:B(乙腈)％:38％-56％,7min)分离。得到化合物20。Trimethylsilyl bromide (61.56 mg, 402.12 μmol, 52.17 μL) was added to compound 19-16 (20 mg, 40.21 μmol) in dichloromethane (2 mL) at 0°C, and reacted at 20°C for 12 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. Separated by pre-HPLC (column type: Phenomenex luna C18 80*40mm*3μm; mobile phase: water (0.04% HCl)-acetonitrile; gradient: B (acetonitrile)%: 38%-56%, 7min). Compound 20 was obtained.
1H NMR(400MHz,CD 3OD)δ＝6.99(br d,J＝15.8Hz,2H),6.81(d,J＝2.0Hz,1H),6.51-6.65(m,2H),4.31(dd,J＝8.8,2.4Hz,1H),4.23(d,J＝10.5Hz,2H),3.22(dt,J＝13.9,7.0Hz,1H),3.02-3.15(m,1H),2.84-2.97(m,1H),2.56(dq,J＝12.7,9.0Hz,1H),1.91-2.08(m,1H),1.15ppm(dd,J＝6.8,6.1Hz,6H). 1 H NMR (400MHz, CD 3 OD) δ = 6.99 (br d, J = 15.8 Hz, 2H), 6.81 (d, J = 2.0 Hz, 1H), 6.51-6.65 (m, 2H), 4.31 (dd, J = 8.8, 2.4 Hz, 1H), 4.23 (d, J = 10.5 Hz, 2H), 3.22 (dt, J = 13.9, 7.0 Hz, 1H), 3.02-3.15 (m, 1H), 2.84-2.97 (m ,1H), 2.56(dq,J=12.7,9.0Hz,1H),1.91-2.08(m,1H), 1.15ppm(dd,J=6.8,6.1Hz,6H).
实施例21,22Examples 21, 22
Figure PCTCN2020139562-appb-000126
Figure PCTCN2020139562-appb-000126
合成路线：synthetic route:
Figure PCTCN2020139562-appb-000127
Figure PCTCN2020139562-appb-000127
步骤1：化合物21-2的合成Step 1: Synthesis of compound 21-2
将21-1(5g,15.89mmol)溶于乙腈(50mL)中，加入苄溴(2.72g,15.89mmol)，碳酸铯(7.77g,23.84mmol)反应在15℃下进行12小时，乙酸乙酯(100mL)，水(100mL)，萃取，收集有机相，有机相通过无水硫酸钠干燥，过滤，滤液减压浓缩，粗产品通过柱层析分离(石油醚:乙酸乙酯＝5:1)，得到化合物21-2。Dissolve 21-1 (5g, 15.89mmol) in acetonitrile (50mL), add benzyl bromide (2.72g, 15.89mmol), and react with cesium carbonate (7.77g, 23.84mmol) at 15°C for 12 hours. (100mL), water (100mL), extract, collect the organic phase, dry the organic phase over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and separate the crude product by column chromatography (petroleum ether: ethyl acetate = 5:1) , Compound 21-2 was obtained.
1H NMR(400MHz,CDCl 3)δ＝7.94(d,J＝2.3Hz,1H),7.54-7.32(m,6H),6.72(d,J＝8.8Hz,1H),5.12(s,2H) 1 H NMR(400MHz,CDCl 3 )δ=7.94(d,J=2.3Hz,1H),7.54-7.32(m,6H),6.72(d,J=8.8Hz,1H), 5.12(s,2H)
步骤2：化合物21-3的合成Step 2: Synthesis of compound 21-3
将化合物21-2(6.18g,15.89mmol)，环丁酮(1.67g,23.83mmol)溶于四氢呋喃(60mL)中，在-68℃下缓慢滴加正丁基锂(2.5M,7.63mL)，搅拌0.5小时，转移至30℃下搅拌2.5小时向反应液中加入(20mL)饱和氯化铵淬灭反应。乙酸乙酯(100mL)，水(50mL)，萃取，收集有机相，有机相通过无水硫酸钠干燥，过滤，滤液减压浓缩。得到化合物21-3。Compound 21-2 (6.18g, 15.89mmol) and cyclobutanone (1.67g, 23.83mmol) were dissolved in tetrahydrofuran (60mL), and n-butyllithium (2.5M, 7.63mL) was slowly added dropwise at -68°C , Stirred for 0.5 hour, and transferred to 30°C and stirred for 2.5 hours. To the reaction solution, saturated ammonium chloride (20 mL) was added to quench the reaction. Ethyl acetate (100 mL), water (50 mL), extraction, the organic phase was collected, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Compound 21-3 was obtained.
1H NMR(400MHz,CDCl 3)δ＝7.47-7.32(m,7H),6.86(d,J＝8.7Hz,1H),5.11(s,2H),3.48(br s,1H),2.62-2.47(m,2H),2.41-2.28(m,2H),1.72-1.57(m,2H)。 1 H NMR(400MHz, CDCl 3 )δ=7.47-7.32(m,7H), 6.86(d,J=8.7Hz,1H), 5.11(s,2H), 3.48(br s,1H), 2.62-2.47 (m, 2H), 2.41-2.28 (m, 2H), 1.72-1.57 (m, 2H).
步骤3：化合物21-4的合成Step 3: Synthesis of compound 21-4
将化合物21-3(3g,9.00mmol)溶于二氯甲烷(30mL)中，在0℃下加入三氟乙酸(1.54g,13.50mmol)，三乙基硅氢(3.14g,27.01mmol)，反应在15℃下进行12小时。减压浓缩，粗产品通过柱层析分离(石油醚:乙酸乙酯＝5:1)，得到化合物21-4。Compound 21-3 (3g, 9.00mmol) was dissolved in dichloromethane (30mL), trifluoroacetic acid (1.54g, 13.50mmol) and triethylsilylhydrogen (3.14g, 27.01mmol) were added at 0°C, The reaction was carried out at 15°C for 12 hours. Concentrated under reduced pressure, and the crude product was separated by column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain compound 21-4.
1H NMR(400MHz,CDCl 3)δ＝7.33-7.19(m,6H),7.17-7.10(m,1H),6.63(d,J＝8.7Hz,1H),4.92(s,2H),3.66(quin,J＝8.8Hz,1H),2.28-2.18(m,2H),2.07-1.84(m,3H),1.77-1.66(m,1H)。 1 H NMR(400MHz, CDCl 3 )δ=7.33-7.19(m,6H), 7.17-7.10(m,1H), 6.63(d,J=8.7Hz,1H), 4.92(s,2H), 3.66( quin, J=8.8 Hz, 1H), 2.28-2.18 (m, 2H), 2.07-1.84 (m, 3H), 1.77-1.66 (m, 1H).
步骤4：化合物21-5的合成Step 4: Synthesis of compound 21-5
将化合物21-4(2.2g,6.94mmol)溶于四氢呋喃(30mL)中，氮气置换3次，降温至-68℃下缓慢滴加正丁基锂(2.5M,3.33mL)，反应在-68℃下进行0.5小时。在-68℃下加入BB-1(1.92g,6.94mmol)反应在15℃下进行1小时。向反应液中加入饱和氯化铵水溶液(10mL)淬灭反应。乙酸乙酯(100mL)，水(100mL)，萃取，收集有机相，有机相通过无水硫酸钠干燥，过滤，滤液减压浓缩，得到化合物21-5。Dissolve compound 21-4 (2.2g, 6.94mmol) in tetrahydrofuran (30mL), replace with nitrogen 3 times, and slowly add n-butyllithium (2.5M, 3.33mL) dropwise while cooling to -68°C. The reaction is at -68°C. Perform 0.5 hours at °C. BB-1 (1.92g, 6.94mmol) was added at -68°C and the reaction was carried out at 15°C for 1 hour. A saturated aqueous ammonium chloride solution (10 mL) was added to the reaction solution to quench the reaction. Ethyl acetate (100 mL), water (100 mL), extraction, the organic phase was collected, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 21-5.
步骤5：化合物21-6的合成Step 5: Synthesis of compound 21-6
将化合物21-5(3.57g,2.98mmol)溶于二氯甲烷(20mL)中，加入三乙基硅氢(1.04g,8.95mmol)，在0℃下加入三氟乙酸(510.04mg,4.47mmol)反应在15℃下进行12小时。减压浓缩，得到化合物21-6。Compound 21-5 (3.57g, 2.98mmol) was dissolved in dichloromethane (20mL), triethylsilylhydrogen (1.04g, 8.95mmol) was added, and trifluoroacetic acid (510.04mg, 4.47mmol) was added at 0°C ) The reaction was carried out at 15°C for 12 hours. Concentrate under reduced pressure to obtain compound 21-6.
步骤6：化合物21-7的合成Step 6: Synthesis of compound 21-7
将化合物21-6(1.21g,2.43mmol)溶于甲醇(15mL)与四氢呋喃(15mL)的混合溶剂中，加入氟化铵(899.25mg,24.28mmol)，反应在15℃下进行12小时。乙酸乙酯(100mL)，水(100mL)，萃取，收集有机相，有机相通过饱和食盐水洗涤(100mL×3),有机相通过无水硫酸钠干燥，过滤，滤液减压浓缩，粗产品通过柱层析分离(石油醚:乙酸乙酯5:1)，得到化合物21-7。Compound 21-6 (1.21 g, 2.43 mmol) was dissolved in a mixed solvent of methanol (15 mL) and tetrahydrofuran (15 mL), ammonium fluoride (899.25 mg, 24.28 mmol) was added, and the reaction was carried out at 15° C. for 12 hours. Ethyl acetate (100mL), water (100mL), extract, collect the organic phase, wash the organic phase with saturated brine (100mL×3), dry the organic phase over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and pass the crude product through Column chromatography separation (petroleum ether: ethyl acetate 5:1) to obtain compound 21-7.
1H NMR(400MHz,CDCl 3)δ＝7.49-7.29(m,5H),6.98(s,1H),6.78-6.68(m,2H),6.63(br s,1H),6.47(s,1H),5.01(s,2H),4.54(s,1H),4.31(br dd,J＝3.2,8.4Hz,1H),3.78(quin,J＝8.7Hz,1H),3.10-2.93(m,1H),2.89-2.73(m,1H),2.58(qd,J＝8.7,12.5Hz,1H),2.30(q,J＝8.2Hz,2H),2.17-1.96(m,4H),1.94(s,3H),1.85-1.74(m,1H)。 1 H NMR(400MHz, CDCl 3 )δ=7.49-7.29(m,5H), 6.98(s,1H), 6.78-6.68(m,2H), 6.63(br s,1H), 6.47(s,1H) ,5.01(s,2H),4.54(s,1H),4.31(br dd,J=3.2,8.4Hz,1H),3.78(quin,J=8.7Hz,1H),3.10-2.93(m,1H) ,2.89-2.73(m,1H),2.58(qd,J=8.7,12.5Hz,1H),2.30(q,J=8.2Hz,2H),2.17-1.96(m,4H),1.94(s,3H) ), 1.85-1.74 (m, 1H).
步骤7：化合物21-8的合成Step 7: Synthesis of compound 21-8
将化合物21-7(800mg,2.08mmol)溶于二甲基甲酰胺(10mL)中，加入碳酸铯(1.02g,3.12mmol)，对甲苯磺酰氧甲基膦酸二乙酯(670.41mg,2.08mmol)反应在50℃下进行2小时。乙酸乙酯(100mL)，水(100mL)，萃取，收集有机相，有机相通过饱和食盐水洗涤(100mL×3)，有机相通过无水硫酸钠干燥，过滤，滤液减压浓缩，得粗产品。粗产品通过柱层析分离(石油醚:乙酸乙酯1:1)，得到化合物21-8。[M+1] +＝535.2 Compound 21-7 (800mg, 2.08mmol) was dissolved in dimethylformamide (10mL), cesium carbonate (1.02g, 3.12mmol), diethyl p-toluenesulfonyloxymethylphosphonate (670.41mg, 2.08mmol) The reaction was carried out at 50°C for 2 hours. Ethyl acetate (100mL), water (100mL), extract, collect the organic phase, wash the organic phase with saturated brine (100mL×3), dry the organic phase over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the crude product . The crude product was separated by column chromatography (petroleum ether: ethyl acetate 1:1) to obtain compound 21-8. [M+1] + =535.2
步骤8：化合物21-9的合成Step 8: Synthesis of compound 21-9
将化合物21-8(0.9g,1.68mmol)溶于甲醇(5mL)中，加入湿钯碳(0.05g钯含量：5％)，通入氢气，置换3次，反应在15psi 15℃下进行2小时。过滤，滤液减压浓缩，得到化合物21-9。Compound 21-8 (0.9g, 1.68mmol) was dissolved in methanol (5mL), wet palladium on carbon (0.05g palladium content: 5%) was added, hydrogen gas was introduced, and the reaction was carried out at 15psi 15℃2 hour. After filtration, the filtrate was concentrated under reduced pressure to obtain compound 21-9.
[M-17] +＝445.3 [M-17] + ＝445.3
步骤9：化合物21-10，21-11的合成Step 9: Synthesis of compounds 21-10 and 21-11
化合物21-9(0.7g,1.57mmol)的SFC拆分。经SFC(柱型:DAICEL CHIRALPAK AD(250mm*50mm*10μm)；流动相:[Neu-IPA]:40％-40％,8min)拆分。得到化合物21-10，21-11。分析方法：柱型:Chiralpak AD-3,50×4.6mm,I.D.,3μm。流动相:A:CO 2B:IPA(0.05％DEA)。梯度:B相1.2分钟内从5％ 升至50％，维持1分钟，0.8分钟内降至5％，流速:3.4mL/min。柱温:35℃。ABPR:1800psi。化合物21-10保留时间：1.271min。化合物21-11保留时间：1.416min。 The compound 21-9 (0.7g, 1.57mmol) was resolved by SFC. SFC (column type: DAICEL CHIRALPAK AD (250mm*50mm*10μm); mobile phase: [Neu-IPA]: 40%-40%, 8min) resolution. Compounds 21-10 and 21-11 were obtained. Analysis method: Column type: Chiralpak AD-3, 50×4.6mm, ID, 3μm. Mobile phase: A: CO 2 B: IPA (0.05% DEA). Gradient: Phase B increased from 5% to 50% in 1.2 minutes, maintained for 1 minute, and decreased to 5% in 0.8 minutes, flow rate: 3.4 mL/min. Column temperature: 35°C. ABPR: 1800psi. Compound 21-10 retention time: 1.271 min. Compound 21-11 retention time: 1.416min.
步骤10：化合物21的合成Step 10: Synthesis of compound 21
将化合物21-10(130mg,292.46μmol)溶于二氯甲烷(5mL)中，0℃加入三甲基溴硅烷(223.87mg,1.46mmol)，反应在30℃下进行12小时。减压浓缩，乙酸乙酯(10mL)，水(10mL)，萃取，收集有机相，有机相通过半饱和食盐水洗涤(10mL×3),有机相通过无水硫酸钠干燥，过滤，滤液减压浓缩，得粗产品。通过prep-HPLC(柱型:Phenomenex luna C18 80*40mm*3μm；流动相:[H 2O(0.04％HCl)-ACN]；B(ACN)％:32％-62％,7min)分离。得到化合物21。 Compound 21-10 (130 mg, 292.46 μmol) was dissolved in dichloromethane (5 mL), trimethylsilyl bromide (223.87 mg, 1.46 mmol) was added at 0°C, and the reaction was carried out at 30°C for 12 hours. Concentrate under reduced pressure, ethyl acetate (10mL), water (10mL), extract, collect the organic phase, wash the organic phase with half-saturated brine (10mL×3), dry the organic phase over anhydrous sodium sulfate, filter, and reduce the filtrate Concentrate to obtain a crude product. Separated by prep-HPLC (column type: Phenomenex luna C18 80*40mm*3μm; mobile phase: [H 2 O(0.04% HCl)-ACN]; B(ACN)%: 32%-62%, 7min). Compound 21 was obtained.
1H NMR(400MHz,CD 3OD)δ＝6.80(br d,J＝17.8Hz,2H),6.63-6.54(m,3H),4.26(dd,J＝3.6,8.6Hz,1H),4.19(d,J＝10.5Hz,2H),3.75-3.60(m,1H),3.01(td,J＝8.2,16.0Hz,1H),2.86-2.76(m,1H),2.54(qd,J＝8.6,12.5Hz,1H),2.31-2.19(m,2H),2.08-1.92(m,4H),1.91(s,3H),1.82-1.72(m,1H)。 1 H NMR (400MHz, CD 3 OD) δ = 6.80 (br d, J = 17.8 Hz, 2H), 6.63-6.54 (m, 3H), 4.26 (dd, J = 3.6, 8.6 Hz, 1H), 4.19 ( d,J=10.5Hz,2H),3.75-3.60(m,1H),3.01(td,J=8.2,16.0Hz,1H),2.86-2.76(m,1H),2.54(qd,J=8.6, 12.5Hz, 1H), 2.31-2.19 (m, 2H), 2.08-1.92 (m, 4H), 1.91 (s, 3H), 1.82-1.72 (m, 1H).
步骤11：化合物22的合成Step 11: Synthesis of compound 22
将化合物21-11(240mg,539.93μmol)溶于二氯甲烷(5mL)中，0℃加入三甲基溴硅烷(413.29mg,2.70mmol)反应在30℃下进行12小时。减压浓缩，得粗产品。Compound 21-11 (240 mg, 539.93 μmol) was dissolved in dichloromethane (5 mL), trimethylbromosilane (413.29 mg, 2.70 mmol) was added at 0°C, and the reaction was carried out at 30°C for 12 hours. Concentrate under reduced pressure to obtain a crude product.
乙酸乙酯(10mL)，水(10mL)，萃取，收集有机相，有机相通过饱和食盐水(10mL×3)洗涤，有机相通过无水硫酸钠干燥，过滤，滤液减压浓缩，得粗产品。通过prep-HPLC(柱型:Phenomenex luna C18 80*40mm*3μm；流动相:[H 2O(0.04％HCl)-ACN]；B(ACN)％:35％-62％,7min)得到化合物22。 Ethyl acetate (10mL), water (10mL), extraction, the organic phase was collected, the organic phase was washed with saturated brine (10mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product . Compound 22 was obtained by prep-HPLC (column type: Phenomenex luna C18 80*40mm*3μm; mobile phase: [H 2 O (0.04% HCl)-ACN]; B (ACN)%: 35%-62%, 7 min) .
1H NMR(400MHz,CD 3OD)δ＝6.82(br d,J＝17.9Hz,2H),6.69-6.53(m,3H),4.28(dd,J＝3.6,8.7Hz,1H),4.21(d,J＝10.4Hz,2H),3.75-3.61(m,1H),3.03(td,J＝8.2,16.0Hz,1H),2.90-2.77(m,1H),2.55(qd,J＝8.6,12.5Hz,1H),2.35-2.21(m,2H),2.10-1.94(m,4H),1.93(s,3H),1.83-1.75(m,1H)。 1 H NMR (400MHz, CD 3 OD) δ = 6.82 (br d, J = 17.9 Hz, 2H), 6.69-6.53 (m, 3H), 4.28 (dd, J = 3.6, 8.7 Hz, 1H), 4.21 ( d, J = 10.4 Hz, 2H), 3.75-3.61 (m, 1H), 3.03 (td, J = 8.2, 16.0 Hz, 1H), 2.90-2.77 (m, 1H), 2.55 (qd, J = 8.6, 12.5Hz, 1H), 2.35-2.21 (m, 2H), 2.10-1.94 (m, 4H), 1.93 (s, 3H), 1.83-1.75 (m, 1H).
实施例23,24Examples 23, 24
Figure PCTCN2020139562-appb-000128
Figure PCTCN2020139562-appb-000128
合成路线：synthetic route:
Figure PCTCN2020139562-appb-000129
Figure PCTCN2020139562-appb-000129
步骤1：化合物23-1的合成Step 1: Synthesis of compound 23-1
将化合物23-1(5g,24.49mmol)加入至吡啶(50mL)，加入丙二酸(3.82g,36.74mmol,3.82mL)和哌啶(417.09mg,4.90mmol,483.75μL)中，90℃搅拌反应16小时。反应结束后，向反应液中加入4M盐酸调节pH至4左右，加入乙酸乙酯约50mL，分液，水相用50mL乙酸乙酯萃取一次，合并乙酸乙酯，有机相用饱和氯化钠(50mL)洗一次，收集有机相，无水硫酸钠干燥，过滤，滤液减压浓缩。得到化合物23-2。Compound 23-1 (5g, 24.49mmol) was added to pyridine (50mL), malonic acid (3.82g, 36.74mmol, 3.82mL) and piperidine (417.09mg, 4.90mmol, 483.75μL) were added and stirred at 90°C Reaction for 16 hours. After the reaction, 4M hydrochloric acid was added to the reaction solution to adjust the pH to about 4, ethyl acetate was added about 50mL, and the layers were separated. The aqueous phase was extracted with 50mL ethyl acetate once, the ethyl acetate was combined, and the organic phase was saturated with sodium chloride ( 50 mL) was washed once, the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Compound 23-2 was obtained.
1H NMR(400MHz,CDCl 3)δ＝7.78-7.71(m,1H),7.38-7.36(m,1H),7.22-7.19(m,1H),7.17-7.13(m,1H),6.49(d,J＝16.0Hz,1H),3.90-3.86(m,3H)。 1 H NMR(400MHz, CDCl 3 )δ=7.78-7.71(m,1H), 7.38-7.36(m,1H), 7.22-7.19(m,1H), 7.17-7.13(m,1H), 6.49(d , J = 16.0 Hz, 1H), 3.90-3.86 (m, 3H).
步骤2：化合物23-3的合成Step 2: Synthesis of compound 23-3
将化合物23-2(6g,24.37mmol)加入至四氢呋喃(50mL)，加入钯碳(1g,24.37mmol,钯含量5％)，通入H 2，25℃搅拌反应18小时。反应结束后，反应液用硅藻土过滤，用四氢呋喃冲洗3次，收集滤液，滤液减压浓缩。得到化合物23-3。 Compound 23-2 (6 g, 24.37 mmol) was added to tetrahydrofuran (50 mL), palladium carbon (1 g, 24.37 mmol, palladium content 5%) was added, H 2 was passed through, and the reaction was stirred at 25° C. for 18 hours. After the completion of the reaction, the reaction solution was filtered with Celite, washed with tetrahydrofuran three times, the filtrate was collected, and the filtrate was concentrated under reduced pressure. Compound 23-3 was obtained.
1H NMR(400MHz,CDCl 3)δ＝7.09-7.05(m,1H),7.00-6.97(m,1H),6.95-6.93(m,1H),3.86-3.83(m,3H),2.99(t,J＝7.7Hz,2H),2.75-2.68(m,2H)。 1 H NMR (400MHz, CDCl 3 ) δ = 7.09-7.05 (m, 1H), 7.00-6.97 (m, 1H), 6.95-6.93 (m, 1H), 3.86-3.83 (m, 3H), 2.99 (t , J=7.7 Hz, 2H), 2.75-2.68 (m, 2H).
步骤3：化合物23-4的合成Step 3: Synthesis of compound 23-4
将化合物23-3(3g,12.09mmol)加入至多聚磷酸(10g)，加热至90℃搅拌反应16小时。反应结束后，向反应液中加入饱和碳酸氢钠调节pH至8左右，加入乙酸乙酯(20mL)，萃取，分液，收集有机相，有机相用饱和氯化钠(20mL)洗一次，然后，用无水硫酸钠干燥，过滤，滤液加入约15mL层析硅胶，拌料干燥，粗品用层析柱纯化(石油醚:乙酸乙酯＝90％:10％至石油醚:乙酸乙酯＝80％:20％)得到化合物23-4。Compound 23-3 (3g, 12.09mmol) was added to polyphosphoric acid (10g), heated to 90°C and stirred for 16 hours. After the reaction, add saturated sodium bicarbonate to the reaction solution to adjust the pH to about 8, add ethyl acetate (20mL), extract, separate, collect the organic phase, wash the organic phase with saturated sodium chloride (20mL) once, then , Dry with anhydrous sodium sulfate, filter, add about 15mL chromatography silica gel to the filtrate, mix and dry, and purify the crude product with a chromatography column (petroleum ether: ethyl acetate = 90%: 10% to petroleum ether: ethyl acetate = 80 %: 20%) to obtain compound 23-4.
1H NMR(400MHz,CDCl 3)δ＝7.22-7.20(m,1H),7.06-7.03(m,1H),3.94(s,3H),3.17-3.11(m,2H),2.77- 2.72(m,2H)。 1 H NMR (400MHz, CDCl 3 ) δ = 7.22-7.20 (m, 1H), 7.06-7.03 (m, 1H), 3.94 (s, 3H), 3.17-3.11 (m, 2H), 2.77- 2.72 (m ,2H).
步骤4：化合物23-5的合成Step 4: Synthesis of compound 23-5
将化合物23-4(8.5g,36.93mmol)加入至氢溴酸(70mL,浓度48％)，130℃回流搅拌反应16小时。反应结束后，向反应液中加入饱和碳酸氢钠调节pH至中性，加入乙酸乙酯(50mL)，搅拌，分液，水相用乙酸乙酯(50mL)萃一次，合并乙酸乙酯，用饱和氯化钠(50mL)洗一次，分液，收集有机相，无水硫酸钠干燥，过滤，滤液减压浓缩。浓缩后，室温，室温打浆(石油醚:乙酸乙酯＝10:1，混合液共计20mL)，得到化合物23-5。Compound 23-4 (8.5 g, 36.93 mmol) was added to hydrobromic acid (70 mL, concentration 48%), and the reaction was stirred at 130° C. for 16 hours under reflux. After the completion of the reaction, saturated sodium bicarbonate was added to the reaction solution to adjust the pH to neutral, ethyl acetate (50 mL) was added, stirred, and the layers were separated. The aqueous phase was extracted with ethyl acetate (50 mL) once, and the ethyl acetate was combined. Wash with saturated sodium chloride (50 mL) once, separate the layers, collect the organic phase, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. After concentration, beating at room temperature (petroleum ether: ethyl acetate = 10:1, the total mixture is 20 mL) to obtain compound 23-5.
1H NMR(400MHz,CDCl 3)δ＝7.18-7.15(m,1H),7.07-7.02(m,1H),3.17-3.09(m,2H),2.78-2.73(m,2H)。 1 H NMR (400MHz, CDCl 3 ) δ=7.18-7.15 (m, 1H), 7.07-7.02 (m, 1H), 3.17-3.09 (m, 2H), 2.78-2.73 (m, 2H).
步骤5：化合物23-6的合成Step 5: Synthesis of compound 23-6
将化合物23-5(3g,13.88mmol)加入至二氯甲烷(30mL)，加入4-二甲氨基吡啶(2.97g,24.29mmol)，加入叔丁基二甲基氯硅烷(3.14g,20.82mmol,2.55mL)，25℃搅拌反应16小时。反应结束后，减压浓缩，去除二氯甲烷溶液，加入饱和氯化铵(20mL)和乙酸乙酯(20mL)，搅拌，分液，饱和氯化铵用乙酸乙酯(10mL)萃取一次，分液，合并有机相，有机相用饱和氯化钠(20mL)洗一次，无水硫酸钠干燥，过滤，滤液加入约15mL层析硅胶，拌料干燥，层析柱纯化(石油醚:乙酸乙酯＝90％:10％至石油醚:乙酸乙酯＝70％:30％)，得到化合物23-6。Compound 23-5 (3g, 13.88mmol) was added to dichloromethane (30mL), 4-dimethylaminopyridine (2.97g, 24.29mmol) was added, tert-butyldimethylchlorosilane (3.14g, 20.82mmol) was added , 2.55mL), the reaction was stirred at 25°C for 16 hours. After the reaction, the solution was concentrated under reduced pressure to remove the dichloromethane solution. Saturated ammonium chloride (20 mL) and ethyl acetate (20 mL) were added, stirred, and separated. Saturated ammonium chloride was extracted once with ethyl acetate (10 mL). Combine the organic phases, wash the organic phase with saturated sodium chloride (20 mL) once, dry with anhydrous sodium sulfate, filter, add about 15 mL of chromatographic silica gel to the filtrate, dry the mixture, and purify by chromatography column (petroleum ether: ethyl acetate) = 90%: 10% to petroleum ether: ethyl acetate = 70%: 30%) to obtain compound 23-6.
1H NMR(400MHz,CDCl 3)δ＝7.18-7.11(m,2H),7.11-7.06(m,1H),6.98(dt,J＝1.7,7.7Hz,1H),6.81-6.72(m,3H),6.70-6.66(m,1H),6.64-6.58(m,1H),2.60-2.48(m,2H),2.44-2.30(m,1H),1.12-1.04(m,11H),0.99(t,J＝6.4Hz,6H),0.88-0.81(m,9H)。 1 H NMR (400MHz, CDCl 3 )δ = 7.18-7.11 (m, 2H), 7.11-7.06 (m, 1H), 6.98 (dt, J = 1.7, 7.7 Hz, 1H), 6.81-6.72 (m, 3H) ), 6.70-6.66 (m, 1H), 6.64-6.58 (m, 1H), 2.60-2.48 (m, 2H), 2.44-2.30 (m, 1H), 1.12-1.04 (m, 11H), 0.99 (t , J=6.4Hz, 6H), 0.88-0.81 (m, 9H).
步骤6：化合物23-7的合成Step 6: Synthesis of compound 23-7
降温至-68℃，将化合物1-8(3.81g,12.48mmol)加入至四氢呋喃(30mL)，缓慢加入正丁基锂(2.5M,5.99mL)，反应0.5小时后，加入化合物23-6(3.3g,9.99mmol)，缓慢升温至25℃继续搅拌反应3小时。反应结束后，将反应液缓慢加入至饱和氯化铵(20mL)，搅拌，加入乙酸乙酯(10mL)，分液，收集有机相，加入饱和氯化钠(10mL)洗，分液，收集有机相，无水硫酸钠干燥，过滤，滤液加入约20mL层析硅胶，拌料干燥，层析柱纯化(石油醚:乙酸乙酯＝90％:10％)，得到化合物23-7。[M-17] +＝539.3 The temperature was lowered to -68°C, compound 1-8 (3.81g, 12.48mmol) was added to tetrahydrofuran (30mL), n-butyllithium (2.5M, 5.99mL) was slowly added, and after reaction for 0.5 hours, compound 23-6( 3.3g, 9.99mmol), the temperature was slowly raised to 25°C and the reaction was stirred for 3 hours. After the reaction, the reaction solution was slowly added to saturated ammonium chloride (20mL), stirred, ethyl acetate (10mL) was added, the layers were separated, the organic phase was added, saturated sodium chloride (10mL) was added to wash, the layers were separated, and the organic Phase, dry with anhydrous sodium sulfate, filter, add about 20 mL of chromatographic silica gel to the filtrate, mix and dry, and purify by chromatography column (petroleum ether: ethyl acetate = 90%: 10%) to obtain compound 23-7. [M-17] + ＝539.3
步骤7：化合物23-8的合成Step 7: Synthesis of compound 23-8
降温至0℃，将化合物23-7(5g,8.98mmol)加入至二氯甲烷(50mL)，加入三乙基硅烷(3.13g,26.94mmol,4.30mL)，加入三氟乙酸(1.54g,13.47mmol,997.44μL)，温度缓慢上升至25℃继续搅拌反应16小时。反应结束后，减压浓缩，去除二氯甲烷溶液，加入乙酸乙酯(20mL)和饱和碳酸氢钠(20mL)，搅拌，分液，乙酸乙酯用饱和氯化钠(20mL)洗，分液，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩。得到化合物23-8。[M-1] +＝539.3 The temperature was lowered to 0°C, compound 23-7 (5g, 8.98mmol) was added to dichloromethane (50mL), triethylsilane (3.13g, 26.94mmol, 4.30mL) was added, and trifluoroacetic acid (1.54g, 13.47) was added. mmol, 997.44 μL), the temperature was slowly increased to 25°C and the reaction was stirred for 16 hours. After the reaction is complete, concentrate under reduced pressure to remove the dichloromethane solution, add ethyl acetate (20 mL) and saturated sodium bicarbonate (20 mL), stir, and separate. The ethyl acetate is washed with saturated sodium chloride (20 mL) and separated The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Compound 23-8 was obtained. [M-1] + = 539.3
步骤8：化合物23-9的合成Step 8: Synthesis of compound 23-9
将化合物23-8(3.92g,7.25mmol)加入至四氢呋喃(40mL)中，降至0℃，加入四丁基氟化铵(1M,7.25mmol，7.25mL)，反应逐渐升至20℃搅拌2小时。反应结束后，反应液中加入饱和氯化铵溶液(20mL)，乙酸乙酯(30mL)萃取，有机相经无水硫酸钠干燥后，过滤，滤液加入约15mL硅胶，拌料干燥，层析柱纯 化(石油醚:乙酸乙酯＝90％:10％)，得到化合物23-9。Compound 23-8 (3.92g, 7.25mmol) was added to tetrahydrofuran (40mL), reduced to 0°C, tetrabutylammonium fluoride (1M, 7.25mmol, 7.25mL) was added, and the reaction was gradually raised to 20°C and stirred 2 hour. After the reaction, the reaction solution was added with saturated ammonium chloride solution (20mL), extracted with ethyl acetate (30mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was added with about 15mL silica gel, the mixture was dried, and the chromatography column Purification (petroleum ether: ethyl acetate = 90%: 10%) to obtain compound 23-9.
1H NMR(400MHz,CDCl 3)δ＝7.46-7.29(m,5H),7.47-7.27(m,2H),7.00-6.92(m,1H),6.84(d,J＝2.1Hz,1H),6.77-6.71(m,1H),6.59(dd,J＝2.2,8.3Hz,2H),5.03-5.00(m,1H),4.65-4.50(m,1H),4.19-4.07(m,1H),3.39-3.30(m,1H),3.09-2.96(m,1H),2.84-2.75(m,1H),2.06(s,3H),1.60-1.55(m,1H),1.31-1.24(m,3H)。 1 H NMR(400MHz, CDCl 3 )δ=7.46-7.29(m,5H), 7.47-7.27(m,2H), 7.00-6.92(m,1H), 6.84(d,J=2.1Hz,1H), 6.77-6.71 (m, 1H), 6.59 (dd, J = 2.2, 8.3 Hz, 2H), 5.03-5.00 (m, 1H), 4.65-4.50 (m, 1H), 4.19-4.07 (m, 1H), 3.39-3.30 (m, 1H), 3.09-2.96 (m, 1H), 2.84-2.75 (m, 1H), 2.06 (s, 3H), 1.60-1.55 (m, 1H), 1.31-1.24 (m, 3H) ).
步骤9：化合物23-10的合成Step 9: Synthesis of compound 23-10
将化合物23-9(1.7g,3.99mmol)加入至N,N-二甲基甲酰胺(20mL)，加入碳酸铯(1.95g,5.98mmol)，加入对甲苯磺酰氧甲基膦酸二乙酯(1.28g,3.99mmol,1.03mL)，50℃搅拌反应16小时。反应结束后，向反应液中加入乙酸乙酯(20mL)，然后用半饱和氯化钠(20mL×4)萃取，分液，收集有机相，无水硫酸钠干燥，过滤，滤液加入约10mL层析硅胶，拌料干燥。层析柱纯化(石油醚:乙酸乙酯＝90％:10％)，得到化合物23-10。Compound 23-9 (1.7g, 3.99mmol) was added to N,N-dimethylformamide (20mL), cesium carbonate (1.95g, 5.98mmol) was added, and diethyl p-toluenesulfonyloxymethylphosphonic acid was added The ester (1.28g, 3.99mmol, 1.03mL) was stirred and reacted at 50°C for 16 hours. After the reaction, ethyl acetate (20mL) was added to the reaction solution, and then extracted with half-saturated sodium chloride (20mL×4), separated, collected the organic phase, dried over anhydrous sodium sulfate, filtered, and the filtrate was added to about 10mL layer Separate silica gel, mix and dry. Chromatographic column purification (petroleum ether: ethyl acetate = 90%: 10%) to obtain compound 23-10.
1H NMR(400MHz,CDCl 3)δ＝7.45-7.30(m,5H),7.15-7.10(m,1H),7.08-7.04(m,1H),6.86-6.83(m,1H),6.74(d,J＝8.4Hz,1H),6.59-6.53(m,1H),5.02(s,2H),4.36-4.23(m,6H),3.39-3.29(m,1H),3.13-3.01(m,1H),2.88-2.78(m,1H),2.63-2.51(m,1H),1.43-1.37(m,6H),1.27(t,J＝7.2Hz,2H),1.17(dd,J＝7.0,8.7Hz,6H)。 1 H NMR (400MHz, CDCl 3 ) δ = 7.45-7.30 (m, 5H), 7.15-7.10 (m, 1H), 7.08-7.04 (m, 1H), 6.86-6.83 (m, 1H), 6.74 (d ,J=8.4Hz,1H),6.59-6.53(m,1H),5.02(s,2H),4.36-4.23(m,6H),3.39-3.29(m,1H),3.13-3.01(m,1H) ), 2.88-2.78(m,1H),2.63-2.51(m,1H),1.43-1.37(m,6H),1.27(t,J=7.2Hz,2H),1.17(dd,J=7.0,8.7 Hz, 6H).
步骤10：化合物23-11的合成Step 10: Synthesis of compound 23-11
将化合物23-10(2g,3.47mmol)加入至甲醇(5mL)，加入钯/碳(1g,钯含量5％)，通入氢气(氢气置换3次)，25℃搅拌反应2小时。反应结束后，将反应液用硅藻土过滤(去除钯/碳)，收集滤液，滤液减压浓缩，得到化合物23-11。Compound 23-10 (2 g, 3.47 mmol) was added to methanol (5 mL), palladium/carbon (1 g, palladium content 5%) was added, hydrogen gas (replacement of hydrogen gas 3 times) was introduced, and the reaction was stirred at 25° C. for 2 hours. After the reaction, the reaction solution was filtered through Celite (to remove palladium/carbon), the filtrate was collected, and the filtrate was concentrated under reduced pressure to obtain compound 23-11.
1H NMR(400MHz,CDCl 3)δ＝7.10(s,1H),7.07-7.04(m,1H),6.79(d,J＝1.9Hz,1H),6.61-6.56(m,1H),6.51-6.45(m,1H),4.36-4.22(m,6H),3.22-2.99(m,2H),2.88-2.77(m,1H),2.63-2.50(m,1H),1.39(t,J＝7.0Hz,6H),1.33(t,J＝7.0Hz,1H),1.27(t,J＝7.2Hz,2H),1.19(dd,J＝7.1,8.1Hz,6H)。 1 H NMR (400MHz, CDCl 3 ) δ = 7.10 (s, 1H), 7.07-7.04 (m, 1H), 6.79 (d, J = 1.9 Hz, 1H), 6.61-6.56 (m, 1H), 6.51 6.45(m,1H),4.36-4.22(m,6H),3.22-2.99(m,2H),2.88-2.77(m,1H),2.63-2.50(m,1H),1.39(t,J=7.0 Hz, 6H), 1.33 (t, J = 7.0 Hz, 1H), 1.27 (t, J = 7.2 Hz, 2H), 1.19 (dd, J = 7.1, 8.1 Hz, 6H).
步骤11：化合物23-12，23-13的合成Step 11: Synthesis of compounds 23-12 and 23-13
化合物23-11(1.4g,2.88mmol)用SFC拆分。分离方法：柱型:DAICEL CHIRALPAK AD(250mm*30mm*10μm)；流动相:[Neu-IPA]:30％-30％,6min，得到化合物23-12，23-13。分析方法：柱型:Chiralpak AD-3,50×4.6mm,I.D.,3μm，流动相:A:CO 2B:IPA(0.05％DEA)，梯度:B相1.2分钟内从5％升至50％，维持1分钟，0.8分钟内降至5％，流速:3.4mL/min，柱温:35℃，ABPR:1800ps。化合物23-12保留时间：1.081min。化合物23-13保留时间：1.136min。 Compound 23-11 (1.4g, 2.88mmol) was resolved by SFC. Separation method: Column type: DAICEL CHIRALPAK AD (250mm*30mm*10μm); mobile phase: [Neu-IPA]: 30%-30%, 6min, to obtain compounds 23-12 and 23-13. Analytical method: Column type: Chiralpak AD-3, 50×4.6mm, ID, 3μm, mobile phase: A: CO 2 B: IPA (0.05% DEA), gradient: Phase B rises from 5% to 50% in 1.2 minutes , Maintained for 1 minute, decreased to 5% within 0.8 minutes, flow rate: 3.4mL/min, column temperature: 35°C, ABPR: 1800ps. Retention time of compound 23-12: 1.081 min. Compound 23-13 retention time: 1.136min.
步骤12：化合物23的合成Step 12: Synthesis of compound 23
将化合物23-12(0.5g,1.031mmol)溶解于二氯甲烷(5mL)中，加入三甲基溴硅烷(1.57g,10.28mmol)，反应在25℃继续搅拌16小时。反应液减压浓缩，加入乙酸乙酯(10mL)，水(10mL×2)洗，分液，乙酸乙酯层经无水硫酸钠干燥后，过滤，减压浓缩。经prep-HPLC(柱型:Welch Xtimate C18 150*25mm*5μm；流动相:[H 2O(0.04％HCl)-ACN]；ACN％:30％-60％,8min)纯化。得到化合物23。 Compound 23-12 (0.5 g, 1.031 mmol) was dissolved in dichloromethane (5 mL), trimethylbromosilane (1.57 g, 10.28 mmol) was added, and the reaction was stirred at 25° C. for 16 hours. The reaction solution was concentrated under reduced pressure, ethyl acetate (10 mL) was added, washed with water (10 mL×2), and separated. The ethyl acetate layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purified by prep-HPLC (column type: Welch Xtimate C18 150*25mm*5μm; mobile phase: [H 2 O (0.04% HCl)-ACN]; ACN%: 30%-60%, 8 min). Compound 23 was obtained.
1H NMR(400MHz,CD 3OD)δ＝7.26-7.20(m,1H),7.12-7.06(m,1H),6.68-6.65(m,1H),6.58-6.54(m,1H),6.47-6.42(m,1H),4.56-4.48(m,1H),4.32-4.23(m,1H),4.36-4.18(m,2H),3.23-3.13(m,1H),3.07-2.96(m,1H),2.88-2.78(m,1H),2.58-2.46(m,1H),2.00(br dd,J＝7.8,11.5Hz,1H),1.14-1.05(m,6H)。 1 H NMR(400MHz,CD 3 OD)δ=7.26-7.20(m,1H), 7.12-7.06(m,1H), 6.68-6.65(m,1H), 6.58-6.54(m,1H), 6.47- 6.42(m,1H),4.56-4.48(m,1H),4.32-4.23(m,1H),4.36-4.18(m,2H),3.23-3.13(m,1H),3.07-2.96(m,1H) ), 2.88-2.78 (m, 1H), 2.58-2.46 (m, 1H), 2.00 (br dd, J=7.8, 11.5 Hz, 1H), 1.14-1.05 (m, 6H).
步骤13：化合物24的合成Step 13: Synthesis of compound 24
将化合物23-13(0.48g,986.72μmol)溶解于二氯甲烷(5mL)中，加入三甲基溴硅烷(1.51g,9.87mmol)，反应在25℃继续搅拌16小时。反应液减压浓缩，加入乙酸乙酯(10mL)，水(10mL×2)洗，分液，乙酸乙酯层经无水硫酸钠干燥后，过滤，减压浓缩。经prep-HPLC(柱型:Welch Xtimate C18 150*25mm*5μm；流动相:[H 2O(0.04％HCl)-ACN]；B(ACN)％:30％-60％,8min)纯化。得到化合物24。 Compound 23-13 (0.48 g, 986.72 μmol) was dissolved in dichloromethane (5 mL), trimethylbromosilane (1.51 g, 9.87 mmol) was added, and the reaction was stirred at 25° C. for 16 hours. The reaction solution was concentrated under reduced pressure, ethyl acetate (10 mL) was added, washed with water (10 mL×2), and separated. The ethyl acetate layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purified by prep-HPLC (column type: Welch Xtimate C18 150*25mm*5μm; mobile phase: [H 2 O (0.04% HCl)-ACN]; B (ACN)%: 30%-60%, 8 min). Compound 24 was obtained.
1H NMR(400MHz,CD 3OD)δ＝7.31-7.16(m,1H),7.09(br s,1H),6.70-6.62(m,1H),6.56(br d,J＝7.9Hz,1H),6.48-6.38(m,1H),4.57-4.47(m,1H),4.44-4.10(m,2H),3.22-3.15(m,1H),3.08-2.92(m,1H),2.87-2.76(m,1H),2.60-2.44(m,1H),2.04-1.89(m,1H),1.15-1.05(m,6H)。 1 H NMR(400MHz,CD 3 OD)δ=7.31-7.16(m,1H), 7.09(br s,1H), 6.70-6.62(m,1H), 6.56(br d,J=7.9Hz,1H) , 6.48-6.38 (m, 1H), 4.57-4.47 (m, 1H), 4.44-4.10 (m, 2H), 3.22-3.15 (m, 1H), 3.08-2.92 (m, 1H), 2.87-2.76 ( m, 1H), 2.60-2.44 (m, 1H), 2.04-1.89 (m, 1H), 1.15-1.05 (m, 6H).
实施例25、26Examples 25, 26
Figure PCTCN2020139562-appb-000130
Figure PCTCN2020139562-appb-000130
合成路线：synthetic route:
Figure PCTCN2020139562-appb-000131
Figure PCTCN2020139562-appb-000131
步骤1：25-2的合成Step 1: Synthesis of 25-2
向干燥洁净的三口瓶加25-1(1.6g,5.28mmol)和四氢呋喃(60mL)，开启搅拌，控制温度-70℃，缓慢滴加正丁基锂(2.5M,2.53mL)，反应30min，控制温度-70℃，加入BB-1(1.46g,5.28mmol)，继续反应2h。在氮气保护下，缓慢滴加饱和氯化铵溶液(100mL)，随后加入乙酸乙酯(100mL)萃取，分得有机相无水硫酸钠干燥，旋干，得到化合物25-2。Add 25-1 (1.6g, 5.28mmol) and tetrahydrofuran (60mL) to a dry and clean three-necked flask, turn on the stirring, control the temperature at -70°C, slowly add n-butyllithium (2.5M, 2.53mL) dropwise, and react for 30min. Control the temperature at -70°C, add BB-1 (1.46g, 5.28mmol), continue the reaction for 2h. Under the protection of nitrogen, saturated ammonium chloride solution (100 mL) was slowly added dropwise, followed by ethyl acetate (100 mL) for extraction, the organic phase was separated, dried over anhydrous sodium sulfate, and spin-dried to obtain compound 25-2.
1H NMR(400MHz,CDCl 3)δ＝7.52(d,J＝7.3Hz,2H),7.41(br d,J＝8.1Hz,2H),7.35(br d,J＝3.8Hz,1H),7.10(dd,J＝2.1,8.2Hz,1H),6.92(d,J＝8.3Hz,1H),6.84-6.83(m,1H),6.52(d,J＝1.6Hz,1H),6.19-6.14(m,1H),5.16(s,2H),3.03-2.91(m,1H),2.84-2.70(m,1H),2.43-2.38(m,1H),2.35-2.29(m,1H),2.27-2.17(m,1H), 1.96(s,3H),1.01(s,15H),0.96-0.93(m,2H),0.70-0.67(m,2H)。 1 H NMR(400MHz, CDCl 3 )δ=7.52(d,J=7.3Hz,2H), 7.41(br d,J=8.1Hz,2H), 7.35(br d,J=3.8Hz,1H), 7.10 (dd,J=2.1,8.2Hz,1H),6.92(d,J=8.3Hz,1H),6.84-6.83(m,1H),6.52(d,J=1.6Hz,1H),6.19-6.14( m, 1H), 5.16 (s, 2H), 3.03-2.91 (m, 1H), 2.84-2.70 (m, 1H), 2.43-2.38 (m, 1H), 2.35-2.29 (m, 1H), 2.27- 2.17(m,1H), 1.96(s,3H), 1.01(s,15H), 0.96-0.93(m,2H), 0.70-0.67(m,2H).
步骤2：25-3的合成Step 2: Synthesis of 25-3
向干燥洁净的50mL单口瓶加入25-2(1g,2.00mmol)和二氯甲烷(10mL)，开启搅拌；加入三氟乙酸(683.11mg,5.99mmol,443.58μL)，随后加入三乙基硅氢(696.65mg,5.99mmol,956.93μL)，在20℃温度，反应2h。加入饱和碳酸钠溶液(80mL)搅拌10min，随后加入二氯甲烷(40mL)萃取分得有机相，无水硫酸钠干燥，旋干，得到化合物25-3。[M+1] +＝485.4 Add 25-2 (1g, 2.00mmol) and dichloromethane (10mL) to a dry and clean 50mL single-mouth flask, turn on the stirring; add trifluoroacetic acid (683.11mg, 5.99mmol, 443.58μL), and then add triethylsilyl hydride (696.65 mg, 5.99 mmol, 956.93 μL), react at 20° C. for 2 h. Saturated sodium carbonate solution (80 mL) was added and stirred for 10 min, then dichloromethane (40 mL) was added to extract the organic phase, dried over anhydrous sodium sulfate, and spin-dried to obtain compound 25-3. [M+1] + ＝485.4
步骤3：25-4的合成Step 3: Synthesis of 25-4
向干燥洁净的拇指瓶加入25-3(0.9g,1.86mmol)，随后加入甲醇(15mL)和四氢呋喃(15mL)，开启搅拌；加入氟化铵(687.71mg,18.57mmol)，在50℃温度反应2h。反应体系旋干得到粗品，经硅胶柱层析(石油醚:乙酸乙酯＝1:0至石油醚:乙酸乙酯＝10:1)纯化得到化合物25-4。Add 25-3 (0.9g, 1.86mmol) to a dry and clean thumb bottle, then add methanol (15mL) and tetrahydrofuran (15mL), turn on the stirring; add ammonium fluoride (687.71mg, 18.57mmol), and react at 50°C 2h. The reaction system was spin-dried to obtain the crude product, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:0 to petroleum ether: ethyl acetate = 10:1) to obtain compound 25-4.
1H NMR(400MHz,CDCl 3)δ＝7.47(d,J＝7.5Hz,2H),7.41-7.37(m,2H),7.35-7.31(m,1H),6.79-6.75(m,1H),6.72-6.67(m,1H),6.61(d,J＝2.0Hz,1H),6.59(d,J＝2.2Hz,1H),6.45(d,J＝1.8Hz,1H),5.07(s,2H),4.24(dd,J＝3.6,8.7Hz,1H),2.98(td,J＝8.2,16.1Hz,1H),2.86-2.72(m,1H),2.54(qd,J＝8.7,12.6Hz,1H),2.29-2.16(m,1H),1.96(ddd,J＝4.2,8.3,12.5Hz,1H),1.90(s,3H),0.99-0.91(m,2H),0.64-0.57(m,2H)。 1 H NMR (400MHz, CDCl 3 ) δ = 7.47 (d, J = 7.5 Hz, 2H), 7.41-7.37 (m, 2H), 7.35-7.31 (m, 1H), 6.79-6.75 (m, 1H), 6.72-6.67(m,1H),6.61(d,J=2.0Hz,1H), 6.59(d,J=2.2Hz,1H), 6.45(d,J=1.8Hz,1H),5.07(s,2H ), 4.24 (dd, J = 3.6, 8.7 Hz, 1H), 2.98 (td, J = 8.2, 16.1 Hz, 1H), 2.86-2.72 (m, 1H), 2.54 (qd, J = 8.7, 12.6 Hz, 1H), 2.29-2.16 (m, 1H), 1.96 (ddd, J = 4.2, 8.3, 12.5 Hz, 1H), 1.90 (s, 3H), 0.99-0.91 (m, 2H), 0.64-0.57 (m, 2H).
步骤4：25-5的合成Step 4: Synthesis of 25-5
向拇指瓶加入25-4(650mg,1.75mmol)和N,N-二甲基甲酰胺(8mL)，开启搅拌；加入碳酸铯(1.14g,3.51mmol)，随后加入对甲苯磺酰氧甲基膦酸二乙酯(537.21mg,1.67mmol,429.77μL)，控制温度50℃，反应3h。加入乙酸乙酯(50mL)，随后依次用水(50mL)和饱和食盐水(50mL)萃取，分得有机相，用无水硫酸钠干燥，旋干得到粗品，经硅胶柱层析(石油醚:乙酸乙酯＝1:0至石油醚:乙酸乙酯＝10:1)纯化得到化合物25-5。[M+1] +＝521.2 Add 25-4 (650mg, 1.75mmol) and N,N-dimethylformamide (8mL) to the thumb bottle, turn on the stirring; add cesium carbonate (1.14g, 3.51mmol), and then add p-toluenesulfonyloxymethyl Diethyl phosphonate (537.21mg, 1.67mmol, 429.77μL), control the temperature at 50°C, and react for 3h. Ethyl acetate (50mL) was added, followed by extraction with water (50mL) and saturated brine (50mL). The organic phase was separated, dried over anhydrous sodium sulfate, and spin-dried to obtain the crude product, which was subjected to silica gel column chromatography (petroleum ether: acetic acid). (Ethyl acetate=1:0 to petroleum ether:ethyl acetate=10:1) to obtain compound 25-5. [M+1] + = 521.2
步骤5：25-6的合成Step 5: Synthesis of 25-6
向拇指瓶加入25-5(800mg,1.54mmol)和乙酸乙酯(4mL)，开启搅拌；随后加入Pd/C(0.2g,钯含量5％)，在氢气球15psi氛围下，20℃温度，反应1h。通过2g硅藻土的5孔漏斗过滤，并用乙酸乙酯(25mL×2)冲洗两次，滤液旋干得到粗品，经硅胶柱层析(石油醚:乙酸乙酯＝10:1至石油醚:乙酸乙酯＝1:1)纯化得到化合物25-6。[M+1] +＝431.3 Add 25-5 (800mg, 1.54mmol) and ethyl acetate (4mL) to the thumb bottle, turn on the stirring; then add Pd/C (0.2g, palladium content 5%), under a hydrogen balloon 15psi atmosphere, 20℃ temperature, Reaction for 1h. Filter through a 5-hole funnel of 2g diatomaceous earth and rinse twice with ethyl acetate (25mL×2). The filtrate is spin-dried to obtain the crude product, which is subjected to silica gel column chromatography (petroleum ether: ethyl acetate = 10:1 to petroleum ether: Ethyl acetate = 1:1) Purification to obtain compound 25-6. [M+1] + = 431.3
步骤6：拆分得到25-7和25-8Step 6: Split to get 25-7 and 25-8
此步骤为25-6拆分，经手性分离：柱型：DAICEL CHIRALPAK AD(250mm*30mm*10μm)；流动相:[0.1％NH 3.H 2O-IPA]；IPA％:40％-40％,8min得到25-7和25-8。分析方法：柱型:DAICEL CHIRALPAK AD,50×4.6mm,I.D.,3μm。流动相:A:CO 2B:IPA(0.05％DEA)。梯度:B相1.2分钟内从5％升至50％，维持1分钟，0.8分钟内降至5％，流速:3.4mL/min。柱温:35℃。柱压:1800psi。化合物25-7保留时间：1.232min。化合物25-8保留时间：1.350min。 This step is 25-6 resolution, chiral separation: Column type: DAICEL CHIRALPAK AD (250mm*30mm*10μm); mobile phase: [0.1%NH 3 .H 2 O-IPA]; IPA%: 40%-40 %, 8min to get 25-7 and 25-8. Analysis method: Column type: DAICEL CHIRALPAK AD, 50×4.6mm, ID, 3μm. Mobile phase: A: CO 2 B: IPA (0.05% DEA). Gradient: Phase B increased from 5% to 50% in 1.2 minutes, maintained for 1 minute, and decreased to 5% in 0.8 minutes, flow rate: 3.4 mL/min. Column temperature: 35°C. Column pressure: 1800psi. Retention time of compound 25-7: 1.232 min. Compound 25-8 retention time: 1.350min.
25-7： 1H NMR(400MHz,DMSO-d 6)δ＝9.06(s,1H),6.85-6.73(m,1H),6.66-6.55(m,2H),6.49(dd,J＝2.0,8.1Hz,1H),6.43(d,J＝1.8Hz,1H),4.36(d,J＝9.8Hz,2H),4.17(dd,J＝3.6,8.6Hz,1H),4.11(quin,J＝7.3Hz,4H),2.99-2.86(m,1H),2.81-2.69(m,1H),2.47-2.38(m,1H),2.06-1.92(m,1H),1.86-1.75(m,4H),1.25(t,J＝7.1 Hz,6H),0.87-0.74(m,2H),0.53-0.38(m,2H)。 25-7: 1 H NMR (400MHz, DMSO-d 6 ) δ = 9.06 (s, 1H), 6.85-6.73 (m, 1H), 6.66-6.55 (m, 2H), 6.49 (dd, J = 2.0, 8.1Hz, 1H), 6.43 (d, J = 1.8 Hz, 1H), 4.36 (d, J = 9.8 Hz, 2H), 4.17 (dd, J = 3.6, 8.6 Hz, 1H), 4.11 (quin, J = 7.3Hz, 4H), 2.99-2.86 (m, 1H), 2.81-2.69 (m, 1H), 2.47-2.38 (m, 1H), 2.06-1.92 (m, 1H), 1.86-1.75 (m, 4H) , 1.25 (t, J = 7.1 Hz, 6H), 0.87-0.74 (m, 2H), 0.53-0.38 (m, 2H).
31P NMR(400MHz,DMSO-d 6)δppm 20.010。 31 P NMR (400 MHz, DMSO-d 6 ) δ ppm 20.010.
25-8： 1H NMR(400MHz,DMSO-d 6)δ＝9.06(s,1H),6.84-6.74(m,1H),6.64-6.57(m,2H),6.49(dd,J＝2.0,8.1Hz,1H),6.44(d,J＝1.6Hz,1H),4.36(d,J＝9.8Hz,2H),4.17(dd,J＝3.6,8.6Hz,1H),4.15-4.07(m,4H),3.34(s,4H),2.93(td,J＝8.1,16.1Hz,1H),2.80-2.70(m,1H),2.48-2.38(m,1H),2.11-1.93(m,1H),1.83(s,3H),1.26(t,J＝7.0Hz,6H),0.91-0.73(m,2H),0.56-0.39(m,2H)。 25-8: 1 H NMR (400MHz, DMSO-d 6 ) δ = 9.06 (s, 1H), 6.84-6.74 (m, 1H), 6.64-6.57 (m, 2H), 6.49 (dd, J = 2.0, 8.1Hz, 1H), 6.44 (d, J = 1.6 Hz, 1H), 4.36 (d, J = 9.8 Hz, 2H), 4.17 (dd, J = 3.6, 8.6 Hz, 1H), 4.15 to 4.07 (m, 4H), 3.34 (s, 4H), 2.93 (td, J = 8.1, 16.1 Hz, 1H), 2.80-2.70 (m, 1H), 2.48-2.38 (m, 1H), 2.11-1.93 (m, 1H) , 1.83 (s, 3H), 1.26 (t, J = 7.0 Hz, 6H), 0.91-0.73 (m, 2H), 0.56-0.39 (m, 2H).
31P NMR(400MHz,DMSO-d 6)δppm 20.010。 31 P NMR (400 MHz, DMSO-d 6 ) δ ppm 20.010.
步骤7：25的合成Step 7: Synthesis of 25
向拇指瓶加入25-7(80.00mg,185.84μmol)和二氯甲烷(1mL)，开启搅拌；降温至0℃，加入三甲基溴硅烷(284.51mg,1.86mmol,241.11μL)，缓慢升温至20℃，反应16h。向反应体系加入二氯甲烷(20mL)和水(20mL)萃取，分得有机相，无水硫酸钠干燥，旋干得到粗品，经prep-HPLC(柱型:Xtimate C18 100*30mm*3μm；流动相:[H 2O(0.2％FA)-ACN]；B(ACN)％:23％-53％,9min)纯化得到化合物25。 Add 25-7 (80.00mg, 185.84μmol) and dichloromethane (1mL) to the thumb bottle, turn on the stirring; reduce the temperature to 0℃, add trimethylsilyl bromide (284.51mg, 1.86mmol, 241.11μL), and slowly raise the temperature to Reaction at 20°C for 16h. Dichloromethane (20mL) and water (20mL) were added to the reaction system for extraction, the organic phase was separated, dried over anhydrous sodium sulfate, and spin-dried to obtain the crude product. The crude product was obtained by prep-HPLC (column type: Xtimate C18 100*30mm*3μm; mobile Phase: [H 2 O(0.2% FA)-ACN]; B(ACN)%: 23%-53%, 9 min) to obtain compound 25 by purification.
1H NMR(400MHz,DMSO-d 6)δ＝9.05(br s,1H),6.74(s,1H),6.61(d,J＝8.2Hz,1H),6.56(s,1H),6.49(dd,J＝1.9,8.2Hz,1H),6.44(d,J＝1.9Hz,1H),4.16(br dd,J＝3.6,8.6Hz,1H),4.03(d,J＝10.2Hz,2H),2.96-2.87(m,1H),2.80-2.71(m,1H),2.46-2.39(m,1H),2.05-1.95(m,1H),1.85-1.76(m,4H),0.80(d,J＝8.4Hz,2H),0.47(br dd,J＝5.7,7.5Hz,2H). 1 H NMR (400MHz, DMSO-d 6 ) δ = 9.05 (br s, 1H), 6.74 (s, 1H), 6.61 (d, J = 8.2 Hz, 1H), 6.56 (s, 1H), 6.49 (dd ,J=1.9,8.2Hz,1H),6.44(d,J=1.9Hz,1H), 4.16(br dd,J=3.6,8.6Hz,1H),4.03(d,J=10.2Hz,2H), 2.96-2.87(m,1H),2.80-2.71(m,1H),2.46-2.39(m,1H),2.05-1.95(m,1H),1.85-1.76(m,4H),0.80(d,J =8.4Hz,2H),0.47(br dd,J=5.7,7.5Hz,2H).
31P NMR(400MHz,DMSO-d 6)δppm 15.007. 31 P NMR (400MHz, DMSO-d 6 ) δppm 15.007.
步骤8：26的合成Step 8: Synthesis of 26
向拇指瓶加入25-8(60mg,139.38μmol)和二氯甲烷(1mL)，开启搅拌；降温至0℃，加入三甲基溴硅烷(213.38mg,1.39mmol,180.83μL)，缓慢升温至20℃，反应16h。反应体系加入二氯甲烷(20mL)和饱和食盐水(20mL)，萃取分得有机相，无水硫酸钠干燥旋干得到粗品。经prep-HPLC柱型:Phenomenex Luna 80mm*30mm*3μm；流动相:[H 2O(0.04％HCl)-ACN]；B(ACN)％:30％-60％,7min纯化得到化合物26。 Add 25-8 (60mg, 139.38μmol) and dichloromethane (1mL) to the thumb bottle, turn on the stirring; reduce the temperature to 0℃, add trimethylsilyl bromide (213.38mg, 1.39mmol, 180.83μL), and slowly raise the temperature to 20 ℃, react for 16h. Dichloromethane (20 mL) and saturated brine (20 mL) were added to the reaction system, and the organic phase was separated by extraction, dried over anhydrous sodium sulfate and spin-dried to obtain a crude product. After prep-HPLC column type: Phenomenex Luna 80mm*30mm*3μm; mobile phase: [H 2 O (0.04% HCl)-ACN]; B (ACN)%: 30%-60%, 7min purification to obtain compound 26.
1H NMR(400MHz,DMSO-d 6)δ＝9.04(s,1H),6.74(s,1H),6.62(d,J＝8.1Hz,1H),6.56(s,1H),6.49(br d,J＝8.3Hz,1H),6.44(s,1H),4.16(br dd,J＝3.5,8.5Hz,1H),4.03(d,J＝10.1Hz,2H),2.92(td,J＝8.2,16.2Hz,1H),2.80-2.69(m,1H),2.47-2.37(m,1H),2.06-1.95(m,1H),1.88-1.71(m,4H),0.80(br d,J＝8.4Hz,2H),0.47(br t,J＝6.3Hz,2H). 1 H NMR (400MHz, DMSO-d 6 ) δ = 9.04 (s, 1H), 6.74 (s, 1H), 6.62 (d, J = 8.1 Hz, 1H), 6.56 (s, 1H), 6.49 (br d ,J=8.3Hz,1H),6.44(s,1H),4.16(br dd,J=3.5,8.5Hz,1H),4.03(d,J=10.1Hz,2H),2.92(td,J=8.2 ,16.2Hz,1H),2.80-2.69(m,1H),2.47-2.37(m,1H),2.06-1.95(m,1H),1.88-1.71(m,4H),0.80(br d,J= 8.4Hz, 2H), 0.47 (br t, J=6.3Hz, 2H).
31P NMR(400MHz,DMSO-d 6)δppm 15.010. 31 P NMR (400MHz, DMSO-d 6 ) δppm 15.010.
实施例27,28Examples 27, 28
Figure PCTCN2020139562-appb-000132
Figure PCTCN2020139562-appb-000132
合成路线：synthetic route:
Figure PCTCN2020139562-appb-000133
Figure PCTCN2020139562-appb-000133
步骤1：化合物27-2的合成Step 1: Synthesis of compound 27-2
将化合物27-1(12.5g,41.82mmol)加入至二氧六环(120mL)和水(12mL)的混合液中，加入异丙烯基硼酸频哪醇酯(8.43g,50.18mmol)，加入碳酸钾(8.67g,62.73mmol)，最后加入[1,1-双(二苯基膦)二茂铁]二氯化钯二氯甲烷(1.71g,2.09mmol)，氮气置换3次，确保无氧环境，温度缓慢上升至60℃搅拌3hr。反应结束后，反应液减压旋蒸(去除二氧六环溶剂)，加入乙酸乙酯(50mL)和水(50mL)，搅拌，分液，收集有机相，有机相用饱和氯化钠(50mL)洗，收集有机相，无水硫酸钠干燥，过滤，滤液减压浓缩。层析柱纯化(石油醚至石油醚：乙酸乙酯＝95％:5％)。得到化合物27-2。Compound 27-1 (12.5g, 41.82mmol) was added to the mixture of dioxane (120mL) and water (12mL), isopropenyl boronic acid pinacol ester (8.43g, 50.18mmol) was added, and carbonic acid was added Potassium (8.67g, 62.73mmol), finally add [1,1-bis(diphenylphosphine)ferrocene] dichloropalladium dichloride dichloromethane (1.71g, 2.09mmol), replace with nitrogen 3 times to ensure oxygen-free Environment, the temperature was slowly raised to 60°C and stirred for 3hr. After the reaction, the reaction solution was evaporated under reduced pressure (to remove the dioxane solvent), ethyl acetate (50mL) and water (50mL) were added, stirred and separated, the organic phase was collected, and the organic phase was saturated with sodium chloride (50mL). ) Wash, collect the organic phase, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Chromatographic column purification (petroleum ether to petroleum ether: ethyl acetate = 95%: 5%). Compound 27-2 was obtained.
1H NMR(400MHz,CDCl 3)δ＝7.29-7.23(m,2H),6.84-6.80(m,1H),5.45-5.41(m,1H),5.17-5.14(m,1H),2.11-2.09(m,3H) 1 H NMR (400MHz, CDCl 3 ) δ = 7.29-7.23 (m, 2H), 6.84-6.80 (m, 1H), 5.45-5.41 (m, 1H), 5.17-5.14 (m, 1H), 2.11-2.09 (m,3H)
步骤2：化合物27-3的合成Step 2: Synthesis of compound 27-3
将化合物27-2(8.85g,41.54mmol)加入至乙腈(85mL)，加入溴化苄(5.68g,33.23mmol)，加入碳酸铯(27.07g,83.07mmol)，25℃搅拌16hr。反应结束后，向反应液中加入水(20mL)和乙酸乙酯(20mL)，搅拌，分液，收集有机相，饱和氯化钠(20mL)洗，分液，无水硫酸钠干燥，过滤，滤液减压浓缩。层析柱纯化(石油醚＝100％)，得到化合物27-3。Compound 27-2 (8.85 g, 41.54 mmol) was added to acetonitrile (85 mL), benzyl bromide (5.68 g, 33.23 mmol) was added, cesium carbonate (27.07 g, 83.07 mmol) was added, and the mixture was stirred at 25° C. for 16 hr. After the reaction is over, add water (20mL) and ethyl acetate (20mL) to the reaction solution, stir, separate the layers, collect the organic phase, wash with saturated sodium chloride (20mL), separate, dry with anhydrous sodium sulfate, and filter. The filtrate was concentrated under reduced pressure. Chromatographic column purification (petroleum ether = 100%) gave compound 27-3.
1H NMR(400MHz,CDCl 3)δ＝7.39-7.34(m,4H),7.33-7.30(m,2H),7.28-7.23(m,1H),6.76-6.75(m,1H),6.79-6.75(m,1H),5.17-5.14(m,1H),5.10-5.08(m,1H),5.06(s,2H),2.12-2.09(m,3H)。 1 H NMR (400MHz, CDCl 3 ) δ = 7.39-7.34 (m, 4H), 7.33-7.30 (m, 2H), 7.28-7.23 (m, 1H), 6.76-6.75 (m, 1H), 6.79-6.75 (m, 1H), 5.17-5.14 (m, 1H), 5.10-5.08 (m, 1H), 5.06 (s, 2H), 2.12-2.09 (m, 3H).
步骤3：化合物27-4的合成Step 3: Synthesis of compound 27-4
降温至-40℃，将二乙基锌甲苯溶液(1M,131.93mL)加入至二氯甲烷(40mL)，缓慢加入二碘甲烷(35.34g,131.93mmol)，-40℃搅拌0.5h，最后加入化合物27-3(4g,13.19mmol)的二氯甲烷(40mL)溶液，温度缓慢上升至25℃，继续反应12h。反应结束后，将反应液缓慢加入至搅拌的饱和氯化铵(30mL)中，然后加入 二氯甲烷(10mL)，分液，收集二氯甲烷相，用饱和氯化钠(30mL)洗一次，无水硫酸钠干燥，过滤，滤液减压浓缩。然后，层析柱纯化(石油醚＝100％)，得到化合物27-4。Cool down to -40°C, add diethylzinc toluene solution (1M, 131.93mL) to dichloromethane (40mL), slowly add diiodomethane (35.34g, 131.93mmol), stir at -40°C for 0.5h, and finally add Compound 27-3 (4g, 13.19mmol) in dichloromethane (40mL) solution, the temperature was slowly raised to 25°C, and the reaction was continued for 12h. After the reaction, the reaction solution was slowly added to the stirred saturated ammonium chloride (30 mL), then dichloromethane (10 mL) was added, and the layers were separated. The dichloromethane phase was collected and washed once with saturated sodium chloride (30 mL). Dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Then, it was purified by column chromatography (petroleum ether = 100%) to obtain compound 27-4.
1H NMR(400MHz,CDCl 3)δ＝7.51-7.46(m,2H),7.45-7.38(m,3H),7.37-7.32(m,1H),7.28-7.24(m,1H),6.80-6.73(m,1H),5.13(s,2H),1.37-1.33(m,3H),0.81-0.75(m,2H),0.72-0.67(m,2H)。 1 H NMR(400MHz, CDCl 3 )δ=7.51-7.46(m,2H), 7.45-7.38(m,3H), 7.37-7.32(m,1H), 7.28-7.24(m,1H), 6.80-6.73 (m, 1H), 5.13 (s, 2H), 1.37-1.33 (m, 3H), 0.81-0.75 (m, 2H), 0.72-0.67 (m, 2H).
步骤4：化合物27-5的合成Step 4: Synthesis of compound 27-5
降温至-68℃，将化合物27-4(3.5g,11.03mmol)加入至四氢呋喃(35mL)中，缓慢加入正丁基锂(2.5M,4.85mL)，反应0.5hr后，加入化合物BB-1(3.66g,13.24mmol)的四氢呋喃(35mL)溶液，缓慢升温至25℃搅拌3hr。反应结束后，将反应液缓慢加入至饱和氯化铵(30mL)中，搅拌，加入乙酸乙酯(30mL)，分液，收集有机相，加入饱和氯化钠溶液(20mL×2)洗，分液，收集有机相，无水硫酸钠干燥，过滤，滤液减压浓缩。层析柱纯化(石油醚至石油醚:乙酸乙酯＝90％:10％)，得到化合物27-5。[M-17] +＝497.3 The temperature was lowered to -68°C, compound 27-4 (3.5g, 11.03mmol) was added to tetrahydrofuran (35mL), n-butyllithium (2.5M, 4.85mL) was slowly added, and after reaction for 0.5hr, compound BB-1 was added A solution of (3.66g, 13.24mmol) in tetrahydrofuran (35mL) was slowly heated to 25°C and stirred for 3hr. After the reaction, the reaction solution was slowly added to saturated ammonium chloride (30mL), stirred, ethyl acetate (30mL) was added, the layers were separated, the organic phase was collected, and saturated sodium chloride solution (20mL×2) was added to wash and divide. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Chromatographic column purification (petroleum ether to petroleum ether: ethyl acetate = 90%: 10%) to obtain compound 27-5. [M-17] + ＝497.3
步骤5：化合物27-6的合成Step 5: Synthesis of compound 27-6
降温至0℃，将化合物27-5(4.25g,8.26mmol)加入至二氯甲烷(40mL)中，加入三乙基硅烷(2.88g,24.77mmol)和三氟乙酸(1.41g,12.38mmol)，温度缓慢上升至25℃搅拌反应16h。反应结束后，减压浓缩，去除二氯甲烷，加入乙酸乙酯(30mL)，饱和碳酸氢钠(30mL)洗，分液，有机相用饱和氯化钠(30mL)洗，收集有机相，无水硫酸钠干燥，过滤，滤液减压浓缩。得到化合物27-6。[M+1] +＝499.4 Cool to 0°C, add compound 27-5 (4.25g, 8.26mmol) to dichloromethane (40mL), add triethylsilane (2.88g, 24.77mmol) and trifluoroacetic acid (1.41g, 12.38mmol) , The temperature was slowly raised to 25°C and the reaction was stirred for 16h. After the reaction is complete, concentrate under reduced pressure, remove dichloromethane, add ethyl acetate (30mL), wash with saturated sodium bicarbonate (30mL), separate the layers, wash the organic phase with saturated sodium chloride (30mL), collect the organic phase, Dry with sodium sulfate and filter, and concentrate the filtrate under reduced pressure. Compound 27-6 was obtained. [M+1] + = 499.4
步骤6：化合物27-7的合成Step 6: Synthesis of compound 27-7
将化合物27-6(3.5g,7.02mmol)加入至四氢呋喃(30mL)，加入四丁基氟化铵(1M,7.02mL)，在20℃反应2h。反应结束后，向反应液中加入水(50mL)淬灭，加入乙酸乙酯(50mL)，搅拌，分液，水相用乙酸乙酯萃取(50mL×3)，合并有机相，无水硫酸钠干燥，过滤，减压浓缩得到粗品。粗品经层析柱纯化(石油醚至石油醚:乙酸乙酯＝90％:10％)，得到化合物27-7。Compound 27-6 (3.5 g, 7.02 mmol) was added to tetrahydrofuran (30 mL), tetrabutylammonium fluoride (1M, 7.02 mL) was added, and the reaction was carried out at 20° C. for 2 h. After the reaction, the reaction solution was quenched by adding water (50 mL), adding ethyl acetate (50 mL), stirring, and separating the layers. The aqueous phase was extracted with ethyl acetate (50 mL×3), the organic phases were combined, and anhydrous sodium sulfate Dry, filter, and concentrate under reduced pressure to obtain a crude product. The crude product was purified by a chromatography column (petroleum ether to petroleum ether: ethyl acetate = 90%: 10%) to obtain compound 27-7.
1H NMR(400MHz,CDCl 3)δ＝7.51-7.46(m,2H),7.45-7.38(m,3H),7.37-7.32(m,1H),7.28-7.24(m,1H),6.80-6.73(m,1H),5.13(s,2H),1.37-1.33(m,3H),0.81-0.75(m,2H),0.72-0.67(m,2H)。 1 H NMR(400MHz, CDCl 3 )δ=7.51-7.46(m,2H), 7.45-7.38(m,3H), 7.37-7.32(m,1H), 7.28-7.24(m,1H), 6.80-6.73 (m, 1H), 5.13 (s, 2H), 1.37-1.33 (m, 3H), 0.81-0.75 (m, 2H), 0.72-0.67 (m, 2H).
步骤7：化合物27-8的合成Step 7: Synthesis of compound 27-8
将化合物27-7(1.2g,3.12mmol)加入至N,N-二甲基甲酰胺(10mL)，加入碳酸铯(1.53g,4.68mmol)，加入对甲苯磺酰氧甲基膦酸二乙酯(1.01g,3.12mmol)，50℃搅拌反应16hr。反应结束后，向反应液中加入乙酸乙酯(20mL)，饱和氯化钠(20mL×4)洗，分液，收集有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，粗品经层析柱纯化(石油醚至石油醚:乙酸乙酯＝90％:10％)，得到化合物27-8。Compound 27-7 (1.2g, 3.12mmol) was added to N,N-dimethylformamide (10mL), cesium carbonate (1.53g, 4.68mmol) was added, and diethyl p-toluenesulfonyloxymethylphosphonic acid was added The ester (1.01g, 3.12mmol) was stirred at 50°C for 16hr. After the reaction, add ethyl acetate (20mL) to the reaction solution, wash with saturated sodium chloride (20mL×4), separate the layers, collect the organic phase, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Column purification (petroleum ether to petroleum ether: ethyl acetate = 90%: 10%) to obtain compound 27-8.
1H NMR(400MHz,CDCl 3)δ＝7.50(d,J＝7.2Hz,2H),7.40(t,J＝7.5Hz,2H),7.34-7.29(m,1H),7.01(d,J＝1.5Hz,1H),6.76-6.71(m,3H),6.59(d,J＝1.8Hz,1H),5.09(s,2H),4.31-4.21(m,7H),3.03(td,J＝8.2,16.3Hz,1H),2.88-2.77(m,1H),2.61-2.52(m,1H),2.03-1.96(m,1H),1.92(s,3H),1.39(t,J＝7.1Hz,6H),1.33(s,3H),0.73(br d,J＝2.6Hz,2H),0.65-0.61(m,2H)。 1 H NMR (400MHz, CDCl 3 ) δ = 7.50 (d, J = 7.2 Hz, 2H), 7.40 (t, J = 7.5 Hz, 2H), 7.34-7.29 (m, 1H), 7.01 (d, J = 1.5Hz,1H),6.76-6.71(m,3H),6.59(d,J=1.8Hz,1H),5.09(s,2H),4.31-4.21(m,7H),3.03(td,J=8.2 ,16.3Hz,1H),2.88-2.77(m,1H),2.61-2.52(m,1H),2.03-1.96(m,1H),1.92(s,3H),1.39(t,J=7.1Hz, 6H), 1.33 (s, 3H), 0.73 (br d, J=2.6 Hz, 2H), 0.65-0.61 (m, 2H).
步骤8：化合物27-9的合成Step 8: Synthesis of compound 27-9
将化合物27-8(1.51g,2.82mmol)加入至甲醇(15mL)中，加入钯碳(150mg,钯含量：5％)，通入氢气，压力15Psi，25℃反应2h。反应结束后，硅藻土过滤去除钯碳，收集滤液，滤液减压浓缩，得到化合物27- 9。[M+1] +＝445.2 Compound 27-8 (1.51 g, 2.82 mmol) was added to methanol (15 mL), palladium on carbon (150 mg, palladium content: 5%) was added, hydrogen was introduced, and the pressure was 15 Psi, and the reaction was carried out at 25° C. for 2 h. After the reaction, the palladium carbon was removed by filtration through Celite, the filtrate was collected, and the filtrate was concentrated under reduced pressure to obtain compound 27-9. [M+1] + = 445.2
步骤9：化合物27-10和27-11的合成Step 9: Synthesis of compounds 27-10 and 27-11
将化合物27-9(0.7g,1.57mmol)进行SFC拆分，拆分方法：柱型:DAICEL CHIRALPAK AD(250mm*30mm,10μm)；流动相:[Neu-IPA]:38％-38％。得到化合物27-10和化合物27-11。分析方法：柱型:Chiralpak AD-3,50×4.6mm,I.D.,3μm。流动相:A:CO 2B:IPA(0.05％DEA)。梯度:B相，1.2min内从5％至50％，50％维持1min，0.8min内从50％至5％。流速:3.4mL/min。柱温:35℃。ABPR:1800psi。化合物27-10保留时间：1.148min。化合物27-11保留时间：1.272min。 The compound 27-9 (0.7g, 1.57mmol) was resolved by SFC, and the resolution method: column type: DAICEL CHIRALPAK AD (250mm*30mm, 10μm); mobile phase: [Neu-IPA]: 38%-38%. Compound 27-10 and compound 27-11 were obtained. Analysis method: Column type: Chiralpak AD-3, 50×4.6mm, ID, 3μm. Mobile phase: A: CO 2 B: IPA (0.05% DEA). Gradient: Phase B, from 5% to 50% in 1.2 min, 50% for 1 min, and from 50% to 5% in 0.8 min. Flow rate: 3.4mL/min. Column temperature: 35°C. ABPR: 1800psi. Retention time of compound 27-10: 1.148 min. Retention time of compound 27-11: 1.272 min.
步骤10：化合物27的合成Step 10: Synthesis of compound 27
降温至0℃，将27-10(358.25mg,922.39μmol)缓慢加入至二氯甲烷(5mL)中，加入三甲基溴硅烷(1.41g,9.22mmol)，温度缓慢上升至25℃搅拌16hr。反应结束后，减压旋蒸(去除溶剂二氯甲烷)，向反应液中加入乙酸乙酯(15mL)，然后半饱和氯化钠(10×4mL)洗，分液，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩。粗品经机分纯化，纯化方法：柱型:Phenomenex Gemini-NX 150*30mm*5μm；流动相:[水(0.04％HCl)-ACN]；ACN％:30％-60％,8min。得到化合物27。The temperature was lowered to 0°C, 27-10 (358.25mg, 922.39μmol) was slowly added to dichloromethane (5mL), trimethylsilyl bromide (1.41g, 9.22mmol) was added, and the temperature was slowly raised to 25°C and stirred for 16hr. After the reaction, the reaction solution was evaporated under reduced pressure (removal of the solvent dichloromethane), ethyl acetate (15mL) was added to the reaction solution, and then washed with half-saturated sodium chloride (10×4mL), separated, and the organic phase was washed with anhydrous sulfuric acid Dry with sodium, filter, and concentrate the filtrate under reduced pressure. The crude product was purified by machine, purification method: column type: Phenomenex Gemini-NX 150*30mm*5μm; mobile phase: [water (0.04%HCl)-ACN]; ACN%: 30%-60%, 8min. Compound 27 was obtained.
1H NMR(400MHz,CD 3OD)δ＝6.82(d,J＝1.5Hz,1H),6.77-6.61(m,3H),6.59-6.53(m,1H),4.25-4.18(m,1H),4.02(d,J＝10.4Hz,2H),3.01-2.93(m,1H),2.83-2.74(m,1H),2.55-2.48(m,1H),1.95-1.84(m,6H),1.41-1.35(m,1H),1.26(s,3H),0.66-0.54(m,4H)。 1 H NMR (400MHz, CD 3 OD) δ = 6.82 (d, J = 1.5 Hz, 1H), 6.77-6.61 (m, 3H), 6.59-6.53 (m, 1H), 4.25-4.18 (m, 1H) ,4.02(d,J=10.4Hz,2H),3.01-2.93(m,1H),2.83-2.74(m,1H),2.55-2.48(m,1H),1.95-1.84(m,6H),1.41 -1.35 (m, 1H), 1.26 (s, 3H), 0.66-0.54 (m, 4H).
步骤11：化合物28的合成Step 11: Synthesis of compound 28
降温至0℃，将化合物27-11(320mg,719.91μmol)缓慢加入至二氯甲烷(5mL)中，加入三甲基溴硅烷(1.10g,7.20mmol)，温度缓慢上升至25℃搅拌16hr。反应结束后，减压旋蒸(去除溶剂二氯甲烷)，向反应液中加入乙酸乙酯(15mL)，然后半饱和氯化钠(10×4mL)洗，分液，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩。粗品经机分纯化，纯化方法：柱型:Phenomenex Gemini-NX 150*30mm*5μm；流动相:[水(0.04％HCl)-ACN]；ACN％:30％-60％,8min。得到化合物28。The temperature was lowered to 0°C, compound 27-11 (320mg, 719.91μmol) was slowly added to dichloromethane (5mL), trimethylsilyl bromide (1.10g, 7.20mmol) was added, and the temperature was slowly raised to 25°C and stirred for 16hr. After the reaction, the reaction solution was evaporated under reduced pressure (removal of the solvent dichloromethane), ethyl acetate (15mL) was added to the reaction solution, and then washed with half-saturated sodium chloride (10×4mL), separated, and the organic phase was washed with anhydrous sulfuric acid Dry with sodium, filter, and concentrate the filtrate under reduced pressure. The crude product was purified by machine, purification method: column type: Phenomenex Gemini-NX 150*30mm*5μm; mobile phase: [water (0.04%HCl)-ACN]; ACN%: 30%-60%, 8min. Compound 28 was obtained.
1H NMR(400MHz,CD 3OD)δ＝6.82(d,J＝1.5Hz,1H),6.77-6.61(m,3H),6.59-6.53(m,1H),4.25-4.18(m,1H),4.02(d,J＝10.4Hz,2H),3.01-2.93(m,1H),2.83-2.74(m,1H),2.55-2.48(m,1H),1.95-1.84(m,6H),1.41-1.35(m,1H),1.26(s,3H),0.66-0.54(m,4H)。 1 H NMR (400MHz, CD 3 OD) δ = 6.82 (d, J = 1.5 Hz, 1H), 6.77-6.61 (m, 3H), 6.59-6.53 (m, 1H), 4.25-4.18 (m, 1H) ,4.02(d,J=10.4Hz,2H),3.01-2.93(m,1H),2.83-2.74(m,1H),2.55-2.48(m,1H),1.95-1.84(m,6H),1.41 -1.35 (m, 1H), 1.26 (s, 3H), 0.66-0.54 (m, 4H).
实施例29、30Examples 29, 30
Figure PCTCN2020139562-appb-000134
Figure PCTCN2020139562-appb-000134
合成路线：synthetic route:
Figure PCTCN2020139562-appb-000135
Figure PCTCN2020139562-appb-000135
步骤1：化合物29-2的合成Step 1: Synthesis of compound 29-2
向干燥洁净的三口瓶加29-1(1g,3.61mmol)和四氢呋喃(25mL)，开启搅拌，控制温度-70℃，缓慢滴加正丁基锂(2.5M,1.73mL)，反应30min，控制温度-70℃，加入11-1(1.07g,3.61mmol)，继续反应2h，在氮气保护下，缓慢滴加饱和氯化铵溶液(100mL)，随后加入乙酸乙酯(100mL)萃取，分得有机相，无水硫酸钠干燥，旋干得到目标化合物粗品，经硅胶柱层析(石油醚:乙酸乙酯＝1:0～10:1)纯化得到化合物29-2。Add 29-1 (1g, 3.61mmol) and tetrahydrofuran (25mL) to a dry and clean three-necked flask, turn on the stirring, control the temperature to -70℃, slowly add n-butyllithium (2.5M, 1.73mL) dropwise, react for 30min, control Temperature -70℃, add 11-1 (1.07g, 3.61mmol), continue the reaction for 2h, under the protection of nitrogen, slowly add saturated ammonium chloride solution (100mL), then add ethyl acetate (100mL) for extraction, and separate The organic phase was dried with anhydrous sodium sulfate and spin-dried to obtain a crude product of the target compound, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate=1:0-10:1) to obtain compound 29-2.
1H NMR(400MHz,CDCl 3)δ＝7.11(d,J＝9.4Hz,1H),6.79(d,J＝13.2Hz,1H),6.69(d,J＝0.9Hz,2H),5.20-5.14(m,2H),3.50-3.48(m,3H),3.34-3.19(m,1H),3.10-2.96(m,1H),2.88-2.79(m,1H),2.73-2.59(m,1H),2.57-2.47(m,1H),1.01-0.99(m,9H),0.24-0.21(m,6H)。 1 H NMR (400MHz, CDCl 3 ) δ = 7.11 (d, J = 9.4 Hz, 1H), 6.79 (d, J = 13.2 Hz, 1H), 6.69 (d, J = 0.9 Hz, 2H), 5.20-5.14 (m,2H),3.50-3.48(m,3H),3.34-3.19(m,1H),3.10-2.96(m,1H),2.88-2.79(m,1H),2.73-2.59(m,1H) , 2.57-2.47 (m, 1H), 1.01-0.99 (m, 9H), 0.24-0.21 (m, 6H).
F NMR(400MHz,CDCl 3)δppm-114.175。 F NMR (400MHz, CDCl 3 ) δ ppm-114.175.
步骤2：化合物29-3的合成Step 2: Synthesis of compound 29-3
向干燥洁净的拇指瓶加29-2(600mg,1.21mmol)，随后加入二氯甲烷(3mL)和三氟乙酸(394.13mg,3.46mmol)，开启搅拌，加入三乙基硅氢(422.75mg,3.64mmol)，在20℃温度反应2h。向反应体系加入二氯甲烷(100mL)，饱和碳酸钠(50mL)洗，水(100mL)洗，分得有机相，无水硫酸钠干燥，旋干得到化合物29-3。Add 29-2 (600mg, 1.21mmol) to a dry and clean thumb bottle, then add dichloromethane (3mL) and trifluoroacetic acid (394.13mg, 3.46mmol), turn on the stirring, add triethylsilylhydrogen (422.75mg, 3.64mmol), react at 20°C for 2h. Dichloromethane (100 mL) was added to the reaction system, washed with saturated sodium carbonate (50 mL), and washed with water (100 mL). The organic phase was separated, dried over anhydrous sodium sulfate, and spin-dried to obtain compound 29-3.
1H NMR(400MHz,CDCl 3)δ＝6.81(d,J＝12.0Hz,1H),6.69(d,J＝3.1Hz,2H),6.48(d,J＝8.9Hz,1H),5.21-5.13(m,2H),4.65(dd,J＝3.3,8.8Hz,1H),3.51-3.48(m,3H),3.17(quin,J＝6.9Hz,1H),3.07-2.95(m,1H),2.91-2.81(m,1H),2.57(qd,J＝8.8,12.9Hz,1H),2.02(br dd,J＝4.0,8.0Hz,1H),1.06(dd,J＝4.3,6.9Hz,6H),1.02-0.98(m,15H) 1 H NMR (400MHz, CDCl 3 ) δ = 6.81 (d, J = 12.0 Hz, 1H), 6.69 (d, J = 3.1 Hz, 2H), 6.48 (d, J = 8.9 Hz, 1H), 5.21-5.13 (m, 2H), 4.65 (dd, J = 3.3, 8.8 Hz, 1H), 3.51-3.48 (m, 3H), 3.17 (quin, J = 6.9 Hz, 1H), 3.07-2.95 (m, 1H), 2.91-2.81 (m, 1H), 2.57 (qd, J = 8.8, 12.9 Hz, 1H), 2.02 (br dd, J = 4.0, 8.0 Hz, 1H), 1.06 (dd, J = 4.3, 6.9 Hz, 6H ),1.02-0.98(m,15H)
F NMR(400MHz,CDCl 3)δppm-119.936。 F NMR (400 MHz, CDCl 3 ) δ ppm-119.936.
步骤3：化合物29-4的合成Step 3: Synthesis of compound 29-4
向干燥洁净的拇指瓶加化合物29-3(550mg)，随后加入甲醇(3mL)和四氢呋喃(3mL)，开启搅拌，加入氟化铵(425.22mg,11.48mmol)，在50℃温度反应2h，反应体系旋干得到目标化合物粗品，经硅胶柱层析(石油醚:乙酸乙酯＝1:0～3:1)纯化得到化合物29-4。Add compound 29-3 (550mg) to a dry and clean thumb bottle, then add methanol (3mL) and tetrahydrofuran (3mL), turn on the stirring, add ammonium fluoride (425.22mg, 11.48mmol), and react at 50°C for 2h. The system was spin-dried to obtain the crude product of the target compound, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate=1:0～3:1) to obtain compound 29-4.
1H NMR(400MHz,CDCl 3)δ＝6.79(d,J＝12.1Hz,1H),6.70-6.65(m,2H),6.53-6.48(m,1H),5.14(d,J＝4.2Hz,2H),4.64-4.52(m,1H),3.47-3.46(m,3H),3.21-3.10(m,1H),3.06-2.96(m,1H),2.89-2.79(m,1H),2.60-2.50(m,1H),2.06-1.94(m,1H),1.07-1.03(m,6H)。 1 H NMR (400MHz, CDCl 3 ) δ = 6.79 (d, J = 12.1Hz, 1H), 6.70-6.65 (m, 2H), 6.53-6.48 (m, 1H), 5.14 (d, J = 4.2 Hz, 2H), 4.64-4.52 (m, 1H), 3.47-3.46 (m, 3H), 3.21-3.10 (m, 1H), 3.06-2.96 (m, 1H), 2.89-2.79 (m, 1H), 2.60- 2.50 (m, 1H), 2.06-1.94 (m, 1H), 1.07-1.03 (m, 6H).
F NMR(400MHz,CDCl 3)δppm-119.927。 F NMR (400 MHz, CDCl 3 ) δ ppm-119.927.
步骤4：化合物29-5的合成Step 4: Synthesis of compound 29-5
向拇指瓶加入化合物29-4(360mg,986.74μmol)和N,N-二甲基甲酰胺(2.5mL)，开启搅拌，加入碳酸铯(643.00mg,1.97mmol)，随后加入对甲苯磺酰氧甲基膦酸二乙酯(318.04mg,986.74μmol)，控制温度50℃，反应3h。反应体系加入乙酸乙酯(50mL)，水(50mL)洗，饱和食盐水(50mL)洗，分得有机相，用无水硫酸钠干燥，旋干，经硅胶柱层析(石油醚:乙酸乙酯＝10:1-1:1)纯化，得到化合物29-5。Add compound 29-4 (360mg, 986.74μmol) and N,N-dimethylformamide (2.5mL) to the thumb bottle, turn on the stirring, add cesium carbonate (643.00mg, 1.97mmol), and then add p-toluenesulfonyloxy Diethyl methylphosphonate (318.04mg, 986.74μmol), control the temperature at 50℃, and react for 3h. Add ethyl acetate (50mL) to the reaction system, wash with water (50mL), and wash with saturated brine (50mL). The organic phase was separated, dried over anhydrous sodium sulfate, spin-dried, and subjected to silica gel column chromatography (petroleum ether: ethyl acetate). Ester=10:1-1:1) purification to obtain compound 29-5.
1H NMR(400MHz,CDCl 3)δ＝6.85-6.78(m,3H),6.53(d,J＝8.9Hz,1H),5.19-5.13(m,2H),4.64(dd,J＝3.6,9.0Hz,1H),4.31-4.23(m,6H),3.52-3.47(m,3H),3.24-3.13(m,1H),3.12-3.01(m,1H),2.90(ddd,J＝4.0,8.9,16.2Hz,1H),2.59(qd,J＝8.8,12.9Hz,1H),2.09-2.06(m,1H),1.39(t,J＝7.0Hz,6H),1.08(dd,J＝3.9,6.9Hz,6H)。 1 H NMR(400MHz, CDCl 3 )δ=6.85-6.78(m,3H), 6.53(d,J=8.9Hz,1H), 5.19-5.13(m,2H), 4.64(dd,J=3.6,9.0 Hz,1H),4.31-4.23(m,6H),3.52-3.47(m,3H),3.24-3.13(m,1H),3.12-3.01(m,1H),2.90(ddd,J=4.0,8.9 ,16.2Hz,1H), 2.59(qd,J=8.8,12.9Hz,1H),2.09-2.06(m,1H),1.39(t,J=7.0Hz,6H),1.08(dd,J=3.9, 6.9Hz, 6H).
F NMR(400MHz,CDCl 3)δppm-119.831。 F NMR (400MHz, CDCl 3 ) δ ppm-119.831.
步骤5：化合物29-6的合成Step 5: Synthesis of compound 29-6
向拇指瓶中入加29-5(230mg,446.65μmol)和甲醇(2mL)，开启搅拌，随后加入盐酸(6M,200.00μL)，升温至50℃温度，反应2h。向反应体系加入碳酸氢钠饱和溶液(50mL)，搅拌10min，随后加入乙酸乙酯(50mL×2)萃取两次，分得有机相，无水硫酸钠干燥，旋干，经硅胶柱层析(石油醚:乙酸乙酯＝10:1～1:1)纯化得到化合物29-6。Add 29-5 (230mg, 446.65μmol) and methanol (2mL) into the thumb bottle, turn on the stirring, then add hydrochloric acid (6M, 200.00μL), raise the temperature to 50°C, and react for 2h. A saturated sodium bicarbonate solution (50 mL) was added to the reaction system, stirred for 10 min, and then ethyl acetate (50 mL×2) was added for extraction twice. The organic phase was separated, dried over anhydrous sodium sulfate, spin-dried, and subjected to silica gel column chromatography ( Petroleum ether: ethyl acetate = 10:1～1:1) Purification to obtain compound 29-6.
1H NMR(400MHz,DMSO-d 6)δ＝9.57(s,1H),6.98(s,1H),6.92(d,J＝2.1Hz,1H),6.52(d,J＝12.0Hz,1H),6.45(d,J＝9.0Hz,1H),4.51-4.48(m,1H),4.16-4.06(m,4H),4.05-4.00(m,2H),3.10-2.96(m,2H),2.94-2.84(m,1H),2.60-2.52(m,1H),1.90(tdd,J＝4.1,8.3,12.5Hz,1H),1.25(t,J＝7.1Hz,6H),1.07-0.93(m,6H)。 1 H NMR(400MHz,DMSO-d 6 )δ=9.57(s,1H), 6.98(s,1H), 6.92(d,J=2.1Hz,1H), 6.52(d,J=12.0Hz,1H) ,6.45(d,J=9.0Hz,1H),4.51-4.48(m,1H),4.16-4.06(m,4H),4.05-4.00(m,2H),3.10-2.96(m,2H),2.94 -2.84(m,1H),2.60-2.52(m,1H),1.90(tdd,J=4.1,8.3,12.5Hz,1H),1.25(t,J=7.1Hz,6H),1.07-0.93(m ,6H).
F NMR(400MHz,DMSO-d 6)δppm-121.326。 F NMR (400 MHz, DMSO-d 6 ) δ ppm-121.326.
31P NMR(400MHz,DMSO-d 6)δppm 19.467。 31 P NMR (400 MHz, DMSO-d 6 ) δ ppm 19.467.
步骤6：化合物29-7和30-7的合成Step 6: Synthesis of compounds 29-7 and 30-7
化合物29-6经手性分离柱型:DAICEL CHIRALPAK AD(250mm*30mm,10μm)；流动相:[0.1％NH 3H 2O IPA]:35％-35％,8min拆分得到化合物29-7和30-7。分析方法：柱型:Chiralpak AD-3,50×4.6mm,I.D.,3μm。流动相:A:CO 2B:IPA(0.05％DEA)。梯度:B相，1.2min内从5％至50％，50％维持1min，0.8min内从50％至5％。流速:3.4mL/min。柱温:35℃。柱压:1800psi。化合物29-7保留时间：1.084min。化合物30-7保留时间：1.208min。 Compound 29-6 was separated by chiral column type: DAICEL CHIRALPAK AD (250mm*30mm, 10μm); mobile phase: [0.1%NH 3 H 2 O IPA]: 35%-35%, 8min resolution to obtain compound 29-7 and 30-7. Analysis method: Column type: Chiralpak AD-3, 50×4.6mm, ID, 3μm. Mobile phase: A: CO 2 B: IPA (0.05% DEA). Gradient: Phase B, from 5% to 50% in 1.2 min, 50% for 1 min, and from 50% to 5% in 0.8 min. Flow rate: 3.4mL/min. Column temperature: 35°C. Column pressure: 1800psi. Compound 29-7 retention time: 1.084min. Retention time of compound 30-7: 1.208 min.
步骤7：化合物29的合成Step 7: Synthesis of compound 29
向拇指瓶中加入29-7(70mg,148.65μmol)和二氯甲烷(1mL)，开启搅拌，降温至0℃，加入三甲基溴硅烷(227.57mg,1.49mmol)，缓慢升温至20℃，反应16h。反应体系旋干，经prep-HPLC(柱型:Xtimate C18 100*30mm*3μm；流动相:[水(0.04％HCl)-ACN]；ACN％:26％-56％,9min)纯化得到化合物29。Add 29-7 (70mg, 148.65μmol) and dichloromethane (1mL) to the thumb bottle, turn on the stirring, and lower the temperature to 0°C, add bromotrimethylsilane (227.57mg, 1.49mmol), and slowly raise the temperature to 20°C. Reaction for 16h. The reaction system was spin-dried and purified by prep-HPLC (column type: Xtimate C18 100*30mm*3μm; mobile phase: [water (0.04%HCl)-ACN]; ACN%: 26%-56%, 9min) to obtain compound 29 .
1H NMR(400MHz,DMSO-d 6)δ＝9.56(br s,1H),6.96(s,1H),6.87(d,J＝2.1Hz,1H),6.53(d,J＝11.9Hz,1H),6.46(d,J＝9.0Hz,1H),4.50(dd,J＝3.7,8.9Hz,1H),4.12(d,J＝10.1Hz,2H),3.09-2.97(m,2H),2.95-2.83(m,1H),2.60-2.53(m,1H),1.90(tdd,J＝4.1,8.3,12.5Hz,1H),1.00(dd,J＝7.1,7.9Hz,6H)。 1 H NMR (400MHz, DMSO-d 6 ) δ = 9.56 (br s, 1H), 6.96 (s, 1H), 6.87 (d, J = 2.1 Hz, 1H), 6.53 (d, J = 11.9 Hz, 1H ), 6.46 (d, J = 9.0 Hz, 1H), 4.50 (dd, J = 3.7, 8.9 Hz, 1H), 4.12 (d, J = 10.1 Hz, 2H), 3.09-2.97 (m, 2H), 2.95 -2.83 (m, 1H), 2.60-2.53 (m, 1H), 1.90 (tdd, J=4.1, 8.3, 12.5 Hz, 1H), 1.00 (dd, J=7.1, 7.9 Hz, 6H).
F NMR(400MHz,DMSO)δppm-121.358。F NMR (400MHz, DMSO) δppm-121.358.
31P NMR(400MHz,DMSO)δppm 14.358。 31 P NMR (400MHz, DMSO) δ ppm 14.358.
步骤8：化合物30的合成Step 8: Synthesis of compound 30
向拇指瓶加入30-7(70mg,148.65μmol)和二氯甲烷(1mL)，开启搅拌，降温至0℃，加入三甲基溴硅烷(227.57mg,1.49mmol)，缓慢升温至20℃，反应16h。反应体系旋干，经prep-HPLC(柱型:Xtimate C18 100*30mm*3μm；流动相:[水(0.04％HCl)-ACN]；B％:26％-56％,9min)纯化得到化合物30。Add 30-7 (70mg, 148.65μmol) and dichloromethane (1mL) to the thumb bottle, turn on the stirring, lower the temperature to 0°C, add trimethylsilyl bromide (227.57mg, 1.49mmol), slowly warm up to 20°C, react 16h. The reaction system was spin-dried and purified by prep-HPLC (column type: Xtimate C18 100*30mm*3μm; mobile phase: [water (0.04%HCl)-ACN]; B%: 26%-56%, 9min) to obtain compound 30 .
1H NMR(400MHz,DMSO-d 6)δ＝9.55(br s,1H),6.95(s,1H),6.86(d,J＝2.1Hz,1H),6.52(d,J＝12.0Hz,1H),6.45(d,J＝9.0Hz,1H),4.49(dd,J＝3.8,8.9Hz,1H),4.11(d,J＝10.1Hz,2H),3.08-2.95(m,2H),2.94-2.83(m,1H),2.57-2.52(m,1H),1.90(tt,J＝4.1,8.4Hz,1H),1.06-0.91(m,6H)。 1 H NMR (400MHz, DMSO-d 6 ) δ = 9.55 (br s, 1H), 6.95 (s, 1H), 6.86 (d, J = 2.1 Hz, 1H), 6.52 (d, J = 12.0 Hz, 1H ), 6.45 (d, J = 9.0 Hz, 1H), 4.49 (dd, J = 3.8, 8.9 Hz, 1H), 4.11 (d, J = 10.1 Hz, 2H), 3.08-2.95 (m, 2H), 2.94 -2.83 (m, 1H), 2.57-2.52 (m, 1H), 1.90 (tt, J=4.1, 8.4 Hz, 1H), 1.06-0.91 (m, 6H).
F NMR(400MHz,DMSO-d 6)δppm-121.358。 F NMR (400MHz, DMSO-d 6 ) δ ppm-121.358.
31P NMR(400MHz,DMSO-d 6)δppm 14.340。 31 P NMR (400 MHz, DMSO-d 6 ) δ ppm 14.340.
实施例31Example 31
Figure PCTCN2020139562-appb-000136
Figure PCTCN2020139562-appb-000136
合成路线：synthetic route:
Figure PCTCN2020139562-appb-000137
Figure PCTCN2020139562-appb-000137
步骤1：化合物31-2的合成Step 1: Synthesis of compound 31-2
将化合物31-1(30g,149.24mmol)加入至N,N-二甲基甲酰胺(150mL)中，加入碳酸钾(24.75g,179.09mmol)，加入溴化苄(25.52g,149.24mmol)，反应逐渐升至50℃搅拌16小时。反应液加入乙酸乙酯(500mL)，饱和氯化钠溶液(300mL×4)洗，有机层经无水硫酸钠干燥后，过滤，减压浓缩。得到化合物31-2。Compound 31-1 (30g, 149.24mmol) was added to N,N-dimethylformamide (150mL), potassium carbonate (24.75g, 179.09mmol) was added, and benzyl bromide (25.52g, 149.24mmol) was added, The reaction was gradually raised to 50°C and stirred for 16 hours. The reaction solution was added with ethyl acetate (500 mL), washed with saturated sodium chloride solution (300 mL×4), the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Compound 31-2 was obtained.
1H NMR(400MHz,CDCl 3)δ＝10.53-10.43(m,1H),8.02-7.92(m,1H),7.67-7.59(m,1H),7.46-7.34(m,5H),7.01-6.91(m,1H),5.25-5.14(m,2H)。 1 H NMR (400MHz, CDCl 3 ) δ = 10.53-10.43 (m, 1H), 8.02-7.92 (m, 1H), 7.67-7.59 (m, 1H), 7.46-7.34 (m, 5H), 7.01-6.91 (m,1H),5.25-5.14(m,2H).
步骤2：化合物31-3的合成Step 2: Synthesis of compound 31-3
将三苯基膦(58.65g,223.60mmol)，碘化钾(17.68g,106.48mmol)加入至乙腈(300mL)中，加热至70℃，加入化合物31-2(31g,106.48mmol)，搅拌30分钟，加入氟磺酰基二氟乙酸甲酯(40.91g,212.96mmol)的乙腈(30mL)溶液，反应在70℃搅拌3小时。反应液减压浓缩，加入乙酸乙酯(200mL)，饱和氯化钠溶液(100mL)洗，有机层经无水硫酸钠干燥后，过滤，减压浓缩。粗品经硅胶柱层析纯化(石油醚:乙酸乙酯＝1:0)，得到化合物31-3。Triphenylphosphine (58.65g, 223.60mmol) and potassium iodide (17.68g, 106.48mmol) were added to acetonitrile (300mL), heated to 70°C, compound 31-2 (31g, 106.48mmol) was added, and stirred for 30 minutes. A solution of methyl fluorosulfonyl difluoroacetate (40.91 g, 212.96 mmol) in acetonitrile (30 mL) was added, and the reaction was stirred at 70° C. for 3 hours. The reaction solution was concentrated under reduced pressure, ethyl acetate (200 mL) was added, and saturated sodium chloride solution (100 mL) was added to wash. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate=1:0) to obtain compound 31-3.
1H NMR(400MHz,CDCl 3)δ＝7.50-7.46(m,1H),7.27(br s,5H),7.19-7.12(m,1H),6.67(br d,J＝8.8Hz,1H),5.59-5.48(m,1H),4.96-4.88(m,2H)。 1 H NMR (400MHz, CDCl 3 )δ = 7.50-7.46 (m, 1H), 7.27 (br s, 5H), 7.19-7.12 (m, 1H), 6.67 (br d, J = 8.8Hz, 1H), 5.59-5.48 (m, 1H), 4.96-4.88 (m, 2H).
步骤3：化合物31-4的合成Step 3: Synthesis of compound 31-4
将三甲基碘化亚砜(16.92g,76.89mmol)加入至二甲基亚砜(50mL)中，加入叔丁醇钾(1M,67.66mL)，加热至50℃搅拌1小时，随后加入化合物31-3(10g,30.76mmol)的二甲基亚砜(10mL)溶液，反应在50℃继续搅拌16小时。反应液加入乙酸乙酯(300mL)，饱和氯化钠溶液(100mL×4)洗，有机层经无水硫酸钠干燥后，过滤，减压浓缩。化合物经硅胶柱层析纯化(石油醚：乙酸乙酯＝1:0)，得到化合物31-4。Trimethylsulfoxide iodide (16.92g, 76.89mmol) was added to dimethylsulfoxide (50mL), potassium tert-butoxide (1M, 67.66mL) was added, heated to 50°C and stirred for 1 hour, then the compound was added 31-3 (10g, 30.76mmol) in dimethyl sulfoxide (10mL) solution, the reaction was stirred at 50°C for 16 hours. The reaction solution was added with ethyl acetate (300 mL), washed with saturated sodium chloride solution (100 mL×4), the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The compound was purified by silica gel column chromatography (petroleum ether: ethyl acetate=1:0) to obtain compound 31-4.
1H NMR(400MHz,CDCl 3)δ＝7.46-7.39(m,4H),7.37-7.32(m,2H),7.24(d,J＝2.3Hz,1H),6.84-6.79(m,1H),5.12(d,J＝3.1Hz,2H),2.95-2.81(m,1H),1.83-1.75(m,1H),1.65-1.57(m,1H)。 1 H NMR(400MHz, CDCl 3 )δ=7.46-7.39(m,4H), 7.37-7.32(m,2H), 7.24(d,J=2.3Hz,1H), 6.84-6.79(m,1H), 5.12 (d, J=3.1 Hz, 2H), 2.95-2.81 (m, 1H), 1.83-1.75 (m, 1H), 1.65-1.57 (m, 1H).
步骤4：化合物31-5的合成Step 4: Synthesis of compound 31-5
将化合物31-4(0.85g,2.51mmol)加入至四氢呋喃(10mL)中，降至-78℃，滴加正丁基锂(2.5M,1.20mL)，继续反应0.5小时，缓慢滴加化合物BB-1(692.80mg,2.51mmol)的四氢呋喃(5mL)，反应逐渐升至20℃搅拌2小时。反应液加入至饱和氯化铵溶液(50mL)和乙酸乙酯(50mL)混合液，乙酸乙酯层经无水硫酸钠干燥后，过滤，减压浓缩。得到化合物31-5。[M-17] +＝519.3。 Compound 31-4 (0.85g, 2.51mmol) was added to tetrahydrofuran (10mL), reduced to -78°C, n-butyllithium (2.5M, 1.20mL) was added dropwise, the reaction was continued for 0.5 hours, and compound BB was slowly added dropwise -1 (692.80mg, 2.51mmol) of tetrahydrofuran (5mL), the reaction was gradually raised to 20°C and stirred for 2 hours. The reaction solution was added to a mixture of saturated ammonium chloride solution (50 mL) and ethyl acetate (50 mL), and the ethyl acetate layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Compound 31-5 was obtained. [M-17] + = 519.3.
步骤5：化合物31-6的合成Step 5: Synthesis of compound 31-6
将化合物31-5(1.35g,2.52mmol)加入至二氯甲烷(20mL)中，降至0℃，滴加三乙基硅氢(877.40mg,7.55mmol)，缓慢滴加三氟乙酸(430.20mg,3.77mmol)，反应逐渐升至20℃搅拌16小时。反应液中加入饱和碳酸氢钠(20mL)和DCM(20mL)，搅拌中和三氟乙酸，二氯甲烷层经无水硫酸钠干燥后，过滤，减压浓缩。得到化合物31-6。[M+1] +＝521.3。 Compound 31-5 (1.35g, 2.52mmol) was added to dichloromethane (20mL), reduced to 0°C, triethylsilylhydrogen (877.40mg, 7.55mmol) was added dropwise, and trifluoroacetic acid (430.20 mg, 3.77mmol), the reaction was gradually raised to 20°C and stirred for 16 hours. Saturated sodium bicarbonate (20 mL) and DCM (20 mL) were added to the reaction solution, the trifluoroacetic acid was neutralized by stirring, and the dichloromethane layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Compound 31-6 was obtained. [M+1] + = 521.3.
步骤6：化合物31-7的合成Step 6: Synthesis of compound 31-7
将化合物31-6(1.31g,2.52mmol)加入至甲醇(10mL)和四氢呋喃(10mL)中，加入氟化铵(931.75mg,25.16mmol)，反应逐渐升至50℃搅拌3小时。反应液减压浓缩。粗品经硅胶柱层析纯化(石油醚:乙酸乙酯＝5:1)，得到化合物31-7。Compound 31-6 (1.31 g, 2.52 mmol) was added to methanol (10 mL) and tetrahydrofuran (10 mL), ammonium fluoride (931.75 mg, 25.16 mmol) was added, and the reaction was gradually raised to 50° C. and stirred for 3 hours. The reaction solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain compound 31-7.
1H NMR(400MHz,CDCl 3)δ＝7.48-7.44(m,2H),7.39(t,J＝7.5Hz,2H),7.34(br d,J＝7.2Hz,1H),6.87-6.76(m,3H),6.65-6.59(m,1H),6.49-6.43(m,1H),5.13-5.03(m,2H),4.57-4.47(m,1H),4.27(br dd,J＝3.2,9.0Hz,1H),3.05-2.75(m,3H),2.62-2.48(m,1H),2.01-1.93(m,1H),1.91-1.86(m,3H),1.80-1.68(m,1H),1.57- 1.48(m,1H)。 1 H NMR (400MHz, CDCl 3 ) δ = 7.48-7.44 (m, 2H), 7.39 (t, J = 7.5 Hz, 2H), 7.34 (br d, J = 7.2 Hz, 1H), 6.87-6.76 (m ,3H),6.65-6.59(m,1H),6.49-6.43(m,1H),5.13-5.03(m,2H),4.57-4.47(m,1H),4.27(br dd,J=3.2,9.0 Hz,1H),3.05-2.75(m,3H),2.62-2.48(m,1H),2.01-1.93(m,1H),1.91-1.86(m,3H),1.80-1.68(m,1H), 1.57- 1.48 (m, 1H).
步骤7：化合物31-8的合成Step 7: Synthesis of compound 31-8
将化合物31-7(0.34g,836.48μmol)加入至N,N-二甲基甲酰胺(5mL)，加入碳酸铯(408.81mg,1.25mmol)，对甲苯磺酰氧甲基膦酸二乙酯(242.65mg,752.84μmol)，反应在50℃搅拌16小时。反应液中加入乙酸乙酯(50mL)，饱和氯化钠溶液(30mL×4)洗，乙酸乙酯层经无水硫酸钠干燥后，过滤，减压浓缩。粗品经硅胶柱层析纯化(石油醚:乙酸乙酯＝1:1)，得到化合物31-8。Compound 31-7 (0.34g, 836.48μmol) was added to N,N-dimethylformamide (5mL), cesium carbonate (408.81mg, 1.25mmol) was added, diethyl p-toluenesulfonyloxymethylphosphonate (242.65 mg, 752.84 μmol), the reaction was stirred at 50°C for 16 hours. Ethyl acetate (50 mL) was added to the reaction solution, washed with saturated sodium chloride solution (30 mL×4), the ethyl acetate layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate=1:1) to obtain compound 31-8.
1H NMR(400MHz,CDCl 3)δ＝7.46-7.32(m,5H),6.83-6.74(m,3H),6.73-6.67(m,1H),6.55(br s,1H),5.11-4.95(m,2H),4.29-4.12(m,7H),3.06-2.90(m,1H),2.87-2.73(m,1H),2.90-2.73(m,1H),2.60-2.44(m,1H),1.98-1.81(m,4H),1.76-1.64(m,1H),1.55-1.43(m,1H),1.40-1.28(m,6H)。 1 H NMR(400MHz, CDCl 3 )δ=7.46-7.32(m,5H), 6.83-6.74(m,3H), 6.73-667(m,1H), 6.55(br s,1H), 5.11-4.95( m, 2H), 4.29-4.12 (m, 7H), 3.06-2.90 (m, 1H), 2.87-2.73 (m, 1H), 2.90-2.73 (m, 1H), 2.60-2.44 (m, 1H), 1.98-1.81 (m, 4H), 1.76-1.64 (m, 1H), 1.55-1.43 (m, 1H), 1.40-1.28 (m, 6H).
步骤8：化合物31-9合成Step 8: Synthesis of compound 31-9
将化合物31-8(130mg,233.57μmol)溶于二氯甲烷(2mL)中，滴加三氯化硼(1M,1.40mL)，反应在10℃下进行12小时。反应液中加入乙酸乙酯(50mL)，水(50mL)洗，饱和食盐水(50mL)洗，有机相通过无水硫酸钠干燥，过滤，滤液减压浓缩，粗产品通过柱层析(石油醚：乙酸乙酯＝1:1)分离，得到化合物31-9。[M+1] +＝467.1 Compound 31-8 (130 mg, 233.57 μmol) was dissolved in dichloromethane (2 mL), boron trichloride (1M, 1.40 mL) was added dropwise, and the reaction was carried out at 10° C. for 12 hours. Ethyl acetate (50mL) was added to the reaction solution, washed with water (50mL), washed with saturated brine (50mL), the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was passed through column chromatography (petroleum ether). : Ethyl acetate=1:1) separated to obtain compound 31-9. [M+1] + = 467.1
步骤9：化合物31合成Step 9: Synthesis of compound 31
将化合物31-9(57mg,122.20μmol)溶于二氯甲烷(2mL)中，加入三甲基溴硅烷(187.08mg,1.22mmol)，反应在30℃下进行12小时。减压浓缩，得粗产品。通过prep-HPLC(柱型:Phenomenex luna C18 80*40mm*3μm；流动相:[水(0.04％HCl)-乙腈]；乙腈％:33％-60％,7min)分离，得到化合物31。Compound 31-9 (57 mg, 122.20 μmol) was dissolved in dichloromethane (2 mL), trimethylsilyl bromide (187.08 mg, 1.22 mmol) was added, and the reaction was carried out at 30° C. for 12 hours. Concentrate under reduced pressure to obtain a crude product. It was separated by prep-HPLC (column type: Phenomenex luna C18 80*40mm*3μm; mobile phase: [water (0.04% HCl)-acetonitrile]; acetonitrile%: 33%-60%, 7min) to obtain compound 31.
[M+1] +＝411.1。 [M+1] + = 411.1.
1H NMR(400MHz,CD 3OD)δ＝6.80-6.58(m,5H),4.25(br dd,J＝3.4,8.3Hz,1H),4.19(d,J＝10.4Hz,2H),3.05-2.94(m,1H),2.86-2.75(m,2H),2.53(qd,J＝8.6,12.6Hz,1H),1.92(br dd,J＝4.0,8.3Hz,1H),1.88(d,J＝3.1Hz,3H),1.77-1.66(m,1H),1.52-1.39(m,1H)。 1 H NMR (400MHz, CD 3 OD) δ = 6.80-6.58 (m, 5H), 4.25 (br dd, J = 3.4, 8.3 Hz, 1H), 4.19 (d, J = 10.4 Hz, 2H), 3.05- 2.94(m,1H),2.86-2.75(m,2H),2.53(qd,J=8.6,12.6Hz,1H),1.92(br dd,J=4.0,8.3Hz,1H),1.88(d,J = 3.1 Hz, 3H), 1.77-1.66 (m, 1H), 1.52-1.39 (m, 1H).
实施例32Example 32
Figure PCTCN2020139562-appb-000138
Figure PCTCN2020139562-appb-000138
合成路线：synthetic route:
Figure PCTCN2020139562-appb-000139
Figure PCTCN2020139562-appb-000139
步骤1：32的合成Step 1: Synthesis of 32
向拇指瓶加入1-甲基-2-吡咯烷酮(0.5mL)，化合物3(20mg,53.14μmol)和三乙胺(26.88mg,265.69μmol)，升温至60℃，反应0.5h，随后加入特戊酸碘甲酯(64.31mg,265.69μmol)，继续反应5h，经prep-HPLC(柱型:Phenomenex Gemini-NX C18 75*30mm*3μm；流动相:[水(10mM NH 4HCO 3)-ACN]；ACN％:56％-76％,6min)纯化，得到化合物32。 Add 1-methyl-2-pyrrolidone (0.5mL), compound 3 (20mg, 53.14μmol) and triethylamine (26.88mg, 265.69μmol) to the thumb bottle, raise the temperature to 60℃, react for 0.5h, and then add Tepentyl Iodomethyl ester (64.31mg, 265.69μmol), continue to react for 5h, after prep-HPLC (column type: Phenomenex Gemini-NX C18 75*30mm*3μm; mobile phase: [water (10mM NH 4 HCO 3 )-ACN] ; ACN%: 56%-76%, 6min) to obtain compound 32.
1H NMR(400MHz,CDCl 3)δ＝6.89(s,1H),6.70(s,1H),6.65-6.58(m,2H),6.55(s,1H),5.88-5.71(m,4H),4.35(d,J＝10.0Hz,2H),4.26(dd,J＝3.8,8.7Hz,1H),3.17(spt,J＝6.9Hz,1H),3.07-2.94(m,1H),2.89-2.74(m,1H),2.56(qd,J＝8.5,12.6Hz,1H),1.98(tdd,J＝4.1,8.3,12.6Hz,1H),1.91(s,3H),1.22(s,18H),1.22-1.18(m,6H)。 1 H NMR (400MHz, CDCl 3 ) δ = 6.89 (s, 1H), 6.70 (s, 1H), 6.65-6.58 (m, 2H), 6.55 (s, 1H), 5.88-5.71 (m, 4H), 4.35 (d, J = 10.0Hz, 2H), 4.26 (dd, J = 3.8, 8.7 Hz, 1H), 3.17 (spt, J = 6.9 Hz, 1H), 3.07-2.94 (m, 1H), 2.89-2.74 (m,1H),2.56(qd,J=8.5,12.6Hz,1H),1.98(tdd,J=4.1,8.3,12.6Hz,1H),1.91(s,3H),1.22(s,18H), 1.22-1.18 (m, 6H).
31P NMR(400MHz,DMSO)δppm 19.938。 31 P NMR (400MHz, DMSO) δ ppm 19.938.
实施例33Example 33
Figure PCTCN2020139562-appb-000140
Figure PCTCN2020139562-appb-000140
合成路线：synthetic route:
Figure PCTCN2020139562-appb-000141
Figure PCTCN2020139562-appb-000141
步骤1：33-1的合成Step 1: Synthesis of 33-1
向拇指瓶加入2-2(200mg,462.44μmol)，随后加入乙腈(4mL)，开启搅拌，随后加入碳酸铯(226.01mg,693.66μmol)和溴化苄(94.91mg,554.93μmol)，升温至70℃，反应5h，反应体系过滤，加入水(50mL)和二氯甲烷(50mL×2)萃取，分得有机相，无水硫酸钠干燥，旋干，经硅胶柱层析(石油醚:乙酸乙酯＝10:0～1:2)纯化得到化合物33-1。Add 2-2 (200mg, 462.44μmol) to the thumb bottle, then add acetonitrile (4mL), turn on the stirring, then add cesium carbonate (226.01mg, 693.66μmol) and benzyl bromide (94.91mg, 554.93μmol), and heat to 70 ℃, react for 5h, filter the reaction system, add water (50mL) and dichloromethane (50mL×2) to extract, separate the organic phase, dry with anhydrous sodium sulfate, spin dry, and chromatograph on silica gel column (petroleum ether: ethyl acetate Ester=10:0~1:2) Purification to obtain compound 33-1.
1H NMR(400MHz,CDCl 3)δ＝7.48-7.29(m,5H),6.96(d,J＝2.0Hz,1H),6.81-6.73(m,2H),6.72-6.66(m, 1H),6.60(s,1H),5.04(s,2H),4.34-4.21(m,8H),3.47-3.29(m,1H),3.03(td,J＝8.3,16.1Hz,1H),2.92-2.76(m,1H),2.57(qd,J＝8.5,12.8Hz,1H),2.05-1.97(m,1H),1.93(s,3H),1.39(t,J＝7.0Hz,6H),1.20(dd,J＝5.5,6.8Hz,6H)。 1 H NMR (400MHz, CDCl 3 ) δ = 7.48-7.29 (m, 5H), 6.96 (d, J = 2.0 Hz, 1H), 6.81-6.73 (m, 2H), 6.72-6.66 (m, 1H), 6.60(s,1H),5.04(s,2H),4.34-4.21(m,8H),3.47-3.29(m,1H),3.03(td,J=8.3,16.1Hz,1H),2.92-2.76( m, 1H), 2.57 (qd, J = 8.5, 12.8 Hz, 1H), 2.05-1.97 (m, 1H), 1.93 (s, 3H), 1.39 (t, J = 7.0 Hz, 6H), 1.20 (dd , J=5.5, 6.8 Hz, 6H).
步骤2：33-2的合成Step 2: Synthesis of 33-2
向拇指瓶加入33-1(210mg,401.83μmol)和二氯甲烷(3mL)，开启搅拌，降温至0℃，加入三甲基溴硅烷(615.16mg,4.02mmol)，缓慢升温至20℃，反应16h。反应体系旋干得到化合物33-2。Add 33-1 (210mg, 401.83μmol) and dichloromethane (3mL) to the thumb bottle, turn on the stirring, reduce the temperature to 0℃, add trimethylsilyl bromide (615.16mg, 4.02mmol), slowly increase the temperature to 20℃, and react 16h. The reaction system was spin-dried to obtain compound 33-2.
1H NMR(400MHz,CDCl 3)δ＝7.52-7.29(m,5H),7.06-6.89(m,1H),6.84-6.66(m,3H),6.61-6.51(m,1H),5.03(s,2H),4.35-4.16(m,3H),3.37(td,J＝6.8,13.8Hz,1H),3.12-2.92(m,1H),2.91-2.70(m,1H),2.62-2.48(m,1H),2.06-1.97(m,1H),1.96-1.88(m,3H),1.20(t,J＝6.0Hz,6H)。 1 H NMR(400MHz, CDCl 3 )δ=7.52-7.29(m,5H), 7.06-6.89(m,1H), 6.84-6.66(m,3H), 6.61-6.51(m,1H), 5.03(s ,2H),4.35-4.16(m,3H),3.37(td,J=6.8,13.8Hz,1H),3.12-2.92(m,1H),2.91-2.70(m,1H),2.62-2.48(m , 1H), 2.06-1.97 (m, 1H), 1.96-1.88 (m, 3H), 1.20 (t, J=6.0 Hz, 6H).
步骤3：33-3的合成Step 3: Synthesis of 33-3
取干燥洁净的50mL单口瓶，加入33-2(120mg,257.23μmol)和N,N-二甲基甲酰胺(1mL)，开启搅拌，随后加入吡啶(203.47mg,2.57mmol)和二环己基碳二亚胺(265.37mg,1.29mmol)，加入苯酚(24.21mg,257.23μmol)，升高温度并控制在50℃，反应2h。向反应体系加入乙酸乙酯(50mL)，随后依次加入水(50mL)，饱和食盐水(50mL×2)萃取，分得有机相，无水硫酸钠干燥，旋干得到目标产物粗品，经硅胶柱层析(石油醚:乙酸乙酯＝3:1～1:1)纯化得到化合物33-3。Take a dry and clean 50mL single-mouth flask, add 33-2 (120mg, 257.23μmol) and N,N-dimethylformamide (1mL), turn on the stirring, then add pyridine (203.47mg, 2.57mmol) and dicyclohexyl carbon Diimine (265.37mg, 1.29mmol), phenol (24.21mg, 257.23μmol) was added, the temperature was raised and controlled at 50°C, and the reaction was carried out for 2h. Ethyl acetate (50mL) was added to the reaction system, followed by water (50mL), saturated brine (50mL×2) for extraction, and the organic phase was separated, dried over anhydrous sodium sulfate, and spin-dried to obtain the crude product of the target product. Chromatography (petroleum ether: ethyl acetate = 3:1 ~ 1:1) purification to obtain compound 33-3.
1H NMR(400MHz,DMSO-d 6)δ＝7.46-7.37(m,5H),7.28-7.12(m,5H),6.97-6.84(m,3H),6.67(br d,J＝7.5Hz,2H),5.59(br d,J＝7.7Hz,1H),5.04(s,2H),4.24(br d,J＝6.1Hz,1H),3.85(br s,1H),3.27-3.16(m,1H),2.89(br s,1H),2.74(br s,1H),1.86(s,1H),1.81(br s,3H),1.49(br s,1H),1.23(s,3H),1.11(br s,3H)。 1 H NMR(400MHz,DMSO-d 6 )δ=7.46-7.37(m,5H), 7.28-7.12(m,5H), 6.97-6.84(m,3H), 6.67(br d, J=7.5Hz, 2H), 5.59 (br d, J = 7.7 Hz, 1H), 5.04 (s, 2H), 4.24 (br d, J = 6.1 Hz, 1H), 3.85 (br s, 1H), 3.27-3.16 (m, 1H), 2.89 (br s, 1H), 2.74 (br s, 1H), 1.86 (s, 1H), 1.81 (br s, 3H), 1.49 (br s, 1H), 1.23 (s, 3H), 1.11 (br s,3H).
步骤4：33-4的合成Step 4: Synthesis of 33-4
取干燥洁净的拇指瓶加入33-3(100.00mg,184.30μmol)，随后加入二氯亚砜(0.5mL)，70℃搅拌2h，反应体系旋干得到棕色油状物备用；另取拇指瓶，L-丙氨酸异丙酯盐酸盐(37.07mg,221.16μmol)溶解于二氯甲烷(0.5mL)中，加入碳酸氢钾(44.28mg,442.31μmol)，在20℃搅拌1h，加入无水硫酸钠干燥过滤得到滤液，随后将滤液滴加到备用的棕色油状物中，pH试纸监测并用三乙胺(22.38mg,221.16μmol)调节溶液PH在4～7之间，20℃反应2h。反应体系旋干，经硅胶柱层析(石油醚:乙酸乙酯＝3:1～1:1)纯化得到化合物33-4。Take a dry and clean thumb bottle and add 33-3 (100.00 mg, 184.30 μmol), then add thionyl chloride (0.5 mL), stir for 2 hours at 70°C, spin the reaction system to dry to obtain a brown oil for use; take another thumb bottle, L -Alanine isopropyl ester hydrochloride (37.07mg, 221.16μmol) was dissolved in dichloromethane (0.5mL), potassium bicarbonate (44.28mg, 442.31μmol) was added, stirred at 20℃ for 1h, and anhydrous sulfuric acid was added Sodium was dried and filtered to obtain the filtrate, and then the filtrate was added dropwise to the standby brown oil, pH test paper was monitored and the pH of the solution was adjusted between 4-7 with triethylamine (22.38mg, 221.16μmol), and the reaction was carried out at 20°C for 2h. The reaction system was spin-dried and purified by silica gel column chromatography (petroleum ether: ethyl acetate=3:1 to 1:1) to obtain compound 33-4.
1H NMR(400MHz,CDCl 3)δ＝7.47-7.27(m,9H),7.22-7.12(m,1H),6.97(d,J＝2.1Hz,1H),6.82-6.67(m,3H),6.62-6.54(m,1H),5.04(s,2H),4.98(td,J＝6.2,12.4Hz,1H),4.42-4.28(m,3H),4.21(s,1H),3.79-3.62(m,1H),3.44-3.26(m,1H),3.03(td,J＝8.0,16.1Hz,1H),2.91-2.73(m,1H),2.66-2.51(m,1H),2.01(br d,J＝4.4Hz,1H),1.94(s,3H),1.38(d,J＝7.0Hz,3H),1.23-1.17(m,12H)。 1 H NMR(400MHz, CDCl 3 )δ=7.47-7.27(m,9H), 7.22-7.12(m,1H), 6.97(d,J=2.1Hz,1H), 6.82-667(m,3H), 6.62-6.54(m,1H),5.04(s,2H),4.98(td,J=6.2,12.4Hz,1H),4.42-4.28(m,3H),4.21(s,1H),3.79-3.62( m,1H),3.44-3.26(m,1H),3.03(td,J=8.0,16.1Hz,1H),2.91-2.73(m,1H),2.66-2.51(m,1H),2.01(br d , J = 4.4 Hz, 1H), 1.94 (s, 3H), 1.38 (d, J = 7.0 Hz, 3H), 1.23-1.17 (m, 12H).
31P NMR(400MHz,CDCl 3)δppm 20.852。 31 P NMR (400MHz, CDCl 3 ) δ ppm 20.852.
步骤5：33的合成Step 5: Synthesis of 33
取干燥洁净的拇指瓶，将33-4(30mg,45.75μmol)溶于乙酸乙酯(2mL)中，随后加入Pd/C(0.2g,钯含量：5％)和三氟乙酸(15.65mg,137.25μmol)，在氢气球15psi氛围下，20℃反应16h，反应体系通过硅藻土过滤，旋干得到产物粗品，经prep-HPLC(柱型:Waters Xbridge BEH C18 100*30mm*10μm；流动相: [H 2O(10mM NH 4HCO 3)-ACN]；ACN％:45％-75％,8min)纯化得到化合物33。 Take a dry and clean thumb bottle, dissolve 33-4 (30mg, 45.75μmol) in ethyl acetate (2mL), then add Pd/C (0.2g, palladium content: 5%) and trifluoroacetic acid (15.65mg, 137.25μmol), reacted at 20°C for 16h under 15psi hydrogen balloon atmosphere, the reaction system was filtered through diatomaceous earth and spin-dried to obtain the crude product, which was subjected to prep-HPLC (column type: Waters Xbridge BEH C18 100*30mm*10μm; mobile phase : [H 2 O(10mM NH 4 HCO 3 )-ACN]; ACN%: 45%-75%, 8min) to obtain compound 33.
1H NMR(400MHz,CDCl 3)δ＝7.36-7.27(m,3H),7.25-7.23(m,1H),7.19-7.13(m,1H),6.92(s,1H),6.73(s,1H),6.62(s,2H),6.58(s,1H),5.05-4.90(m,1H),4.54(br s,1H),4.40-4.30(m,2H),4.29-4.26(m,1H),4.25-4.18(m,1H),3.72-3.57(m,1H),3.23-3.11(m,1H),3.09-2.95(m,1H),2.83(br s,1H),2.57(dd,J＝8.4,12.5Hz,1H),2.05-1.95(m,1H),1.93(s,3H),1.38(d,J＝7.2Hz,3H),1.25-1.18(m,12H)。 1 H NMR(400MHz, CDCl 3 )δ=7.36-7.27(m,3H), 7.25-7.23(m,1H), 7.19-7.13(m,1H), 6.92(s,1H), 6.73(s,1H) ), 6.62 (s, 2H), 6.58 (s, 1H), 5.05-4.90 (m, 1H), 4.54 (br s, 1H), 4.40-4.30 (m, 2H), 4.29-4.26 (m, 1H) ,4.25-4.18(m,1H),3.72-3.57(m,1H),3.23-3.11(m,1H),3.09-2.95(m,1H),2.83(br s,1H), 2.57(dd,J = 8.4, 12.5 Hz, 1H), 2.05-1.95 (m, 1H), 1.93 (s, 3H), 1.38 (d, J=7.2 Hz, 3H), 1.25-1.18 (m, 12H).
31P NMR(400MHz,CDCl 3)δppm 20.828。 31 P NMR (400 MHz, CDCl 3 ) δ ppm 20.828.
实施例34、35Examples 34, 35
Figure PCTCN2020139562-appb-000142
Figure PCTCN2020139562-appb-000142
合成路线：synthetic route:
Figure PCTCN2020139562-appb-000143
Figure PCTCN2020139562-appb-000143
步骤1：34的合成Step 1: Synthesis of 34
向原料12(0.39g,982.86μmol)的N,N-二甲基甲酰胺(20mL)溶液中加入吡啶(2mL)，二环己基碳二亚胺(608.37mg,2.95mmol)，BB-2(183.44mg,982.86μmol)，在50℃反应16hr。反应液中加入乙酸乙酯(200mL)，10％柠檬酸(100mL×2)洗，半饱和氯化钠溶液(100mL×2)洗，有机相经无水硫酸钠干燥后，过滤，减压浓缩。根据TLC(石油醚:乙酸乙酯＝1:2，化合物34的Rf＝0.3，化合物35的Rf＝0.6)，粗品用硅胶柱层析法分离(石油醚/乙酸乙酯＝1:1至0:1)，然后经prep-HPLC分离(柱型:Phenomenex Gemini-NX C18 75*30mm*3μm流动相:[水(10mM NH 4HCO 3)-乙腈]；乙腈％:45％-65％,6min)，得到化合物34和化合物35。化合物34磷原子位置的构型通过NOE来确认。 To a solution of raw material 12 (0.39g, 982.86μmol) in N,N-dimethylformamide (20mL) was added pyridine (2mL), dicyclohexylcarbodiimide (608.37mg, 2.95mmol), BB-2 ( 183.44mg, 982.86μmol), reacted at 50°C for 16hr. Add ethyl acetate (200mL) to the reaction solution, wash with 10% citric acid (100mL×2), wash with half-saturated sodium chloride solution (100mL×2), dry the organic phase over anhydrous sodium sulfate, filter, and concentrate under reduced pressure . According to TLC (petroleum ether: ethyl acetate = 1:2, Rf of compound 34 = 0.3, Rf of compound 35 = 0.6), the crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate = 1:1 to 0 :1), then separated by prep-HPLC (column type: Phenomenex Gemini-NX C18 75*30mm*3μm mobile phase: [water (10mM NH 4 HCO 3 )-acetonitrile]; acetonitrile%: 45%-65%, 6min ) To obtain compound 34 and compound 35. The configuration of the phosphorus atom position of compound 34 was confirmed by NOE.
化合物34：Compound 34:
[M+1] +＝547.1。 [M+1] + = 547.1.
1H NMR(400MHz,CDCl 3)δ＝7.39(s,1H),7.28-7.36(m,2H),7.20-7.25(m,1H),6.95(s,1H),6.80(br d, J＝9.7Hz,2H),6.63(s,2H),5.65(br d,J＝11.3Hz,1H),4.65-4.78(m,1H),4.38-4.57(m,4H),3.06-3.21(m,2H),2.88(ddd,J＝16.3,8.9,3.2Hz,1H),2.56-2.63(m,1H),2.38-2.50(m,1H),2.11-2.18(m,1H),2.06(td,J＝8.5,4.1Hz,1H),1.20-1.25ppm(m,6H)。 1 H NMR (400MHz, CDCl 3 ) δ = 7.39 (s, 1H), 7.28-7.36 (m, 2H), 7.20-7.25 (m, 1H), 6.95 (s, 1H), 6.80 (br d, J = 9.7Hz, 2H), 6.63 (s, 2H), 5.65 (br d, J = 11.3Hz, 1H), 4.65-4.78 (m, 1H), 4.38-4.57 (m, 4H), 3.06-3.21 (m, 2H), 2.88 (ddd, J = 16.3, 8.9, 3.2 Hz, 1H), 2.56-2.63 (m, 1H), 2.38-2.50 (m, 1H), 2.11-2.18 (m, 1H), 2.06 (td, J=8.5, 4.1 Hz, 1H), 1.20-1.25 ppm (m, 6H).
化合物35：[M+1] +＝547.1 Compound 35: [M+1] + =547.1
实施例36、37Examples 36, 37
Figure PCTCN2020139562-appb-000144
Figure PCTCN2020139562-appb-000144
合成路线：synthetic route:
Figure PCTCN2020139562-appb-000145
Figure PCTCN2020139562-appb-000145
步骤1：化合物36的合成Step 1: Synthesis of compound 36
取干燥洁净的拇指瓶，加入化合物18(50mg,126.78μmol)和N,N-二甲基甲酰胺(2mL)，开启搅拌，随后加入二环己基碳二亚胺(156.96mg,760.70μmol,153.88μL)和吡啶(150.43mg,1.90mmol)，加入化合物BB-2(28.39mg,152.14μmol)，升高温度并控制在60℃，反应16h。反应体系过滤分得滤液，加入乙酸乙酯(30mL)，随后加入水(30mL)，饱和食盐水(30mL×2)洗，分得有机相，旋干得到目标产物粗品，根据TLC(石油醚:乙酸乙酯＝1:2，化合物36的Rf＝0.3，化合物37的Rf＝0.6)，经硅胶柱层析(石油醚:乙酸乙酯＝3:1至0:1)纯化得到产物粗品，经prep-HPLC(柱型:Waters Xbridge BEH C18 100*30mm*10μm；流动相:[H 2O(10mM NH 4HCO 3)-乙腈]；乙腈％:40％-70％,6min)纯化得到化合物36和化合物37粗品。化合物36粗品经prep-HPLC(柱型:Waters Xbridge BEH C18 100*30mm*10μm；流动相:[water(10mM NH 4HCO 3)-乙腈]；乙腈％:40％-70％,6min)纯化得到化合物36。化合物36磷原子位置的构型通过NOE来确认。 Take a dry and clean thumb bottle, add compound 18 (50mg, 126.78μmol) and N,N-dimethylformamide (2mL), turn on the stirring, and then add dicyclohexylcarbodiimide (156.96mg, 760.70μmol, 153.88) μL) and pyridine (150.43mg, 1.90mmol), compound BB-2 (28.39mg, 152.14μmol) was added, the temperature was raised and controlled at 60°C, and the reaction was carried out for 16h. The reaction system was filtered to obtain the filtrate, ethyl acetate (30mL) was added, and then water (30mL) and saturated brine (30mL×2) were added to wash, and the organic phase was separated and spin-dried to obtain the crude product. According to TLC (petroleum ether: Ethyl acetate = 1:2, Rf of compound 36 = 0.3, Rf of compound 37 = 0.6), purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1 to 0:1) to obtain the crude product. prep-HPLC (column type: Waters Xbridge BEH C18 100*30mm*10μm; mobile phase: [H 2 O (10mM NH 4 HCO 3 )-acetonitrile]; acetonitrile%: 40%-70%, 6min) to obtain compound 36 And crude compound 37. The crude compound 36 was purified by prep-HPLC (column type: Waters Xbridge BEH C18 100*30mm*10μm; mobile phase: [water(10mM NH 4 HCO 3 )-acetonitrile]; acetonitrile%: 40%-70%, 6min). Compound 36. The configuration of the phosphorus atom position of compound 36 was confirmed by NOE.
化合物36： 1H NMR(400MHz,DMSO-d 6)δ＝9.57(br s,1H),7.50(s,1H),7.44-7.38(m,2H),7.38-7.34(m,1H),6.84(s,1H),6.65(s,1H),6.58-6.50(m,1H),6.45(d,J＝9.0Hz,1H),5.76(br d,J＝11.1Hz,1H),4.67-4.54(m,1H),4.49(d,J＝9.5Hz,2H),4.44-4.38(m,1H),3.03(quin,J＝6.9Hz,1H),2.97-2.87(m,1H),2.85-2.74(m,1H), 2.70-2.65(m,1H),2.36-2.31(m,1H),2.26-2.16(m,2H),1.94-1.86(m,1H),1.85(s,3H),0.97(dd,J＝6.9,11.8Hz,6H). Compound 36: 1 H NMR (400MHz, DMSO-d 6 ) δ = 9.57 (br s, 1H), 7.50 (s, 1H), 7.44-7.38 (m, 2H), 7.38-7.34 (m, 1H), 6.84 (s, 1H), 6.65 (s, 1H), 6.58-6.50 (m, 1H), 6.45 (d, J = 9.0 Hz, 1H), 5.76 (br d, J = 11.1 Hz, 1H), 4.67-4.54 (m,1H), 4.49(d,J=9.5Hz,2H),4.44-4.38(m,1H),3.03(quin,J=6.9Hz,1H),2.97-2.87(m,1H),2.85- 2.74(m,1H), 2.70-2.65(m,1H),2.36-2.31(m,1H),2.26-2.16(m,2H),1.94-1.86(m,1H),1.85(s,3H), 0.97(dd,J=6.9,11.8Hz,6H).
19F NMR(400MHz,DMSO-d 6)δppm-121.411. 19 F NMR (400MHz, DMSO-d 6 ) δppm-121.411.
31P NMR(400MHz,DMSO-d 6)δppm 14.285. 31 P NMR (400MHz, DMSO-d 6 ) δppm 14.285.
化合物37:[M-1] -＝543.1. Compound 37: [M-1] - = 543.1.
实施例38Example 38
Figure PCTCN2020139562-appb-000146
Figure PCTCN2020139562-appb-000146
合成路线：synthetic route:
Figure PCTCN2020139562-appb-000147
Figure PCTCN2020139562-appb-000147
步骤1：38-1的合成Step 1: Synthesis of 38-1
将原料11-1(3.7g,12.46mmol)和环丙基硼酸(2.68g,31.16mmol)溶于甲苯(40mL)和水(4mL)中，加入磷酸钾(10.58g,49.85mmol)，醋酸钯(279.82mg,1.25mmol)，氮气置换三次，加入三环己基膦(699.03mg,2.49mmol)，氮气置换后110℃的油浴中继续搅拌12小时。反应液加水50mL，乙酸乙酯萃取(50mL×3)，无水硫酸钠干燥，减压浓缩除去溶剂。粗品经硅胶柱层析分离纯化(石油醚：乙酸乙酯＝3:1)。得到化合物38-1。Dissolve raw material 11-1 (3.7g, 12.46mmol) and cyclopropylboronic acid (2.68g, 31.16mmol) in toluene (40mL) and water (4mL), add potassium phosphate (10.58g, 49.85mmol), palladium acetate (279.82 mg, 1.25 mmol), replaced with nitrogen three times, added tricyclohexylphosphine (699.03 mg, 2.49 mmol), and continued stirring for 12 hours in an oil bath at 110°C after nitrogen replacement. The reaction solution was added with 50 mL of water, extracted with ethyl acetate (50 mL×3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. The crude product was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1). Compound 38-1 was obtained.
1H NMR(400MHz,DMSO-d 6)δppm 6.69-6.73(m,1H),6.15-6.19(m,1H),3.16-3.26(m,1H),2.93-2.99(m,2H),2.54-2.61(m,2H),0.99-1.06(m,2H),0.90-0.96(m,9H),0.64-0.72(m,2H),0.17-0.23(m,6H)。 1 H NMR (400MHz, DMSO-d 6 ) δppm 6.69-6.73 (m, 1H), 6.15-6.19 (m, 1H), 3.16-3.26 (m, 1H), 2.93-2.99 (m, 2H), 2.54- 2.61 (m, 2H), 0.99-1.06 (m, 2H), 0.90-0.96 (m, 9H), 0.64-0.72 (m, 2H), 0.17-0.23 (m, 6H).
步骤2：38-2的合成Step 2: Synthesis of 38-2
将化合物1-8(3.8g,12.45mmol)溶于四氢呋喃(35mL)中，-65℃滴加正丁基锂(2.5M,5.98mL)，继续搅拌1小时，加入化合物38-1(3.01g,9.96mmol)的四氢呋喃(20mL)溶液，继续搅拌3小时。温度升至-10℃，将反应液倒入25mL饱和氯化铵溶液中，搅拌，乙酸乙酯萃取(20mL×3)，无水硫酸钠干燥，减压浓 缩除去溶剂。得到化合物38-2。[M-17] +＝511.2 Compound 1-8 (3.8g, 12.45mmol) was dissolved in tetrahydrofuran (35mL), n-butyllithium (2.5M, 5.98mL) was added dropwise at -65°C, stirring was continued for 1 hour, compound 38-1 (3.01g) was added ,9.96mmol) in tetrahydrofuran (20mL) and continue to stir for 3 hours. The temperature rose to -10°C, the reaction solution was poured into 25 mL of saturated ammonium chloride solution, stirred, and extracted with ethyl acetate (20 mL×3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. Compound 38-2 was obtained. [M-17] + ＝511.2
步骤3：38-3的合成Step 3: Synthesis of 38-3
将化合物38-2(5.19g,9.81mmol)溶于二氯甲烷(50mL)中，降至0℃，滴加三氟化硼乙醚(2.09g,14.72mmol)，三乙基硅氢(3.42g,29.44mmol)，自然升至室温20℃，继续搅拌2小时。反应液加入饱和碳酸氢钠水溶液，调pH＝8，二氯甲烷(15mL×3)萃取，减压浓缩除去溶剂。得到化合物38-3。[Ms+1] +＝513.3 Compound 38-2 (5.19g, 9.81mmol) was dissolved in dichloromethane (50mL), reduced to 0℃, and boron trifluoride ether (2.09g, 14.72mmol) and triethylsilylhydrogen (3.42g) were added dropwise. , 29.44mmol), naturally rise to room temperature 20°C, and continue to stir for 2 hours. The reaction solution was added with saturated aqueous sodium bicarbonate solution, adjusted to pH=8, extracted with dichloromethane (15 mL×3), and concentrated under reduced pressure to remove the solvent. Compound 38-3 was obtained. [Ms+1] + = 513.3
步骤4：38-4的合成Step 4: Synthesis of 38-4
将化合38-3(5.00g,9.75mmol)溶于四氢呋喃(25mL)和甲醇(25mL)中，加入氟化铵(2.90g,78.30mmol)，50℃的油浴中继续搅拌12小时。反应液冷却至室温过滤，滤液减压浓缩除去溶剂。经硅胶柱层析分离(石油醚：乙酸乙酯＝1:1)。得到化合物38-4。Compound 38-3 (5.00 g, 9.75 mmol) was dissolved in tetrahydrofuran (25 mL) and methanol (25 mL), ammonium fluoride (2.90 g, 78.30 mmol) was added, and stirring was continued for 12 hours in an oil bath at 50°C. The reaction solution was cooled to room temperature and filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. It was separated by silica gel column chromatography (petroleum ether: ethyl acetate=1:1). Compound 38-4 was obtained.
1H NMR(400MHz,DMSO-d 6)δppm 8.98-9.03(m,1H),7.42-7.48(m,2H),7.37-7.42(m,2H),7.29-7.34(m,1H),6.91-6.95(m,1H),6.87-6.91(m,1H),6.72-6.78(m,1H),6.47-6.51(m,1H),6.03-6.06(m,1H),5.02-5.07(m,2H),4.35-4.42(m,1H),3.19-3.28(m,1H),2.82-2.93(m,1H),2.66-2.75(m,1H),2.42-2.49(m,1H),1.82-1.91(m,1H),1.38-1.47(m,1H),1.06-1.13(m,6H),0.65-0.74(m,1H),0.41-0.51(m,2H),0.31-0.38(m,1H)。 1 H NMR (400MHz, DMSO-d 6 ) δppm 8.98-9.03 (m, 1H), 7.42-7.48 (m, 2H), 7.37-7.42 (m, 2H), 7.29-7.34 (m, 1H), 6.91 6.95 (m, 1H), 6.87-6.91 (m, 1H), 6.72-6.78 (m, 1H), 6.47-6.51 (m, 1H), 6.03-6.06 (m, 1H), 5.02-5.07 (m, 2H) ), 4.35-4.42 (m, 1H), 3.19-3.28 (m, 1H), 2.82-2.93 (m, 1H), 2.66-2.75 (m, 1H), 2.42-2.49 (m, 1H), 1.82-1.91 (m,1H),1.38-1.47(m,1H),1.06-1.13(m,6H),0.65-0.74(m,1H),0.41-0.51(m,2H),0.31-0.38(m,1H) .
步骤5：38-5的合成Step 5: Synthesis of 38-5
将化合物38-4(1.41g,3.54mmol)溶于N,N-二甲基甲酰胺(15mL)中，加入碳酸铯(1.73g,5.31mmol)，对甲苯磺酰氧甲基膦酸二乙酯(1.25g,3.89mmol)，50℃的油浴中继续搅拌12小时。反应液冷却至室温，倒入40mL水中，乙酸乙酯萃取(25mL×3)，无水硫酸钠干燥，减压浓缩除去溶剂。粗品经硅胶柱层析分离纯化(石油醚：乙酸乙酯＝1:1)。得到化合物38-5。Dissolve compound 38-4 (1.41g, 3.54mmol) in N,N-dimethylformamide (15mL), add cesium carbonate (1.73g, 5.31mmol), diethyl p-toluenesulfonyloxymethylphosphonic acid The ester (1.25g, 3.89mmol) was stirred in an oil bath at 50°C for 12 hours. The reaction solution was cooled to room temperature, poured into 40 mL of water, extracted with ethyl acetate (25 mL×3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. The crude product was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate=1:1). Compound 38-5 was obtained.
1H NMR(400MHz,DMSO-d 6)δppm 7.42-7.46(m,2H),7.36-7.42(m,2H),7.28-7.34(m,1H),6.92-6.95(m,1H),6.87-6.91(m,1H),6.72-6.76(m,1H),6.74(m,1H),6.25-6.29(m,1H),5.03-5.07(m,2H),4.41-4.47(m,1H),4.33-4.39(m,2H),4.06-4.15(m,4H),3.19-3.28(m,1H),2.88-3.00(m,1H),2.72-2.82(m,1H),2.51-2.57(m,1H),1.85-1.94(m,1H),1.41-1.51(m,1H),1.22-1.29(m,6H),1.08-1.13(m,6H),0.67-0.76(m,1H),0.53-0.61(m,1H),0.42-0.52(m,2H)。 1 H NMR (400MHz, DMSO-d 6 ) δppm 7.42-7.46 (m, 2H), 7.36-7.42 (m, 2H), 7.28-7.34 (m, 1H), 6.92-6.95 (m, 1H), 6.87- 6.91(m,1H),6.72-6.76(m,1H),6.74(m,1H),6.25-6.29(m,1H),5.03-5.07(m,2H),4.41-4.47(m,1H), 4.33-4.39 (m, 2H), 4.06-4.15 (m, 4H), 3.19-3.28 (m, 1H), 2.88-3.00 (m, 1H), 2.72-2.82 (m, 1H), 2.51-2.57 (m ,1H),1.85-1.94(m,1H),1.41-1.51(m,1H),1.22-1.29(m,6H),1.08-1.13(m,6H),0.67-0.76(m,1H),0.53 -0.61 (m, 1H), 0.42-0.52 (m, 2H).
步骤6：38-6的合成Step 6: Synthesis of 38-6
将化合物38-5(1.1g,2.00mmol)溶于二氯甲烷(12mL)中，0℃下，加入三氯化硼(1M,12.03mL)，氮气保护下，室温20℃继续搅拌1小时。反应液倒入饱和碳酸氢钠水溶液中(20mL)，二氯甲烷(30mL×3)萃取，减压浓缩除去溶剂。粗品经硅胶柱层析分离纯化(石油醚：乙酸乙酯＝1:1)。得到化合物38-6。[Ms+1] +＝459.3 Compound 38-5 (1.1 g, 2.00 mmol) was dissolved in dichloromethane (12 mL), and boron trichloride (1M, 12.03 mL) was added at 0°C. Under nitrogen protection, stirring was continued for 1 hour at room temperature and 20°C. The reaction solution was poured into saturated sodium bicarbonate aqueous solution (20 mL), extracted with dichloromethane (30 mL×3), and concentrated under reduced pressure to remove the solvent. The crude product was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate=1:1). Compound 38-6 was obtained. [Ms+1] + ＝459.3
步骤7：38-7的合成Step 7: Synthesis of 38-7
SFC分析方法：柱型:Chiralpak AD-3,50×4.6mm I.D.,3μm,流动相:A:CO 2，B:IPA(0.05％IPAm,v/v),梯度:Time A％-B％，0-2.2min,B相由0％至50％,2.2-3.0min,B相由50％至5％,流速:3.4mL/min,柱温:35℃,ABPR:1800psi,保留时间：1.229min。化合物38-6经手性拆分(柱型:DAICEL CHIRALPAK AD(250mm*30mm,10μm)；流动相:[Neu-IPA]；IPA％:35％-35％,7min)分离。得到化合物38-7。[Ms+1] +＝459.3 SFC analysis method: Column type: Chiralpak AD-3, 50×4.6mm ID, 3μm, mobile phase: A: CO 2 , B: IPA (0.05% IPAm, v/v), gradient: Time A%-B%, 0-2.2min, Phase B from 0% to 50%, 2.2-3.0min, Phase B from 50% to 5%, Flow rate: 3.4mL/min, Column temperature: 35℃, ABPR: 1800psi, Retention time: 1.229min . Compound 38-6 was separated by chiral resolution (column type: DAICEL CHIRALPAK AD (250mm*30mm, 10μm); mobile phase: [Neu-IPA]; IPA%: 35%-35%, 7min). Compound 38-7 was obtained. [Ms+1] + ＝459.3
步骤8：38的合成Step 8: Synthesis of 38
将38-7(47.5mg,103.59mmol)溶于二氯甲烷(1.5mL)中，加入三甲基溴硅烷(158.59mg,1.04mmol)，室温20℃继续搅拌5小时。反应液减压浓缩除去溶剂。粗品经制备HPLC(柱型:Phenomenex Gemini-NX C18 75*30mm*3μm；流动相:[H 2O(0.05％NH 3H 2O+10mM NH 4HCO 3)-ACN]；B(ACN)％:5％-30％,8min)纯化，得到化合物38。 Dissolve 38-7 (47.5 mg, 103.59 mmol) in dichloromethane (1.5 mL), add bromotrimethylsilane (158.59 mg, 1.04 mmol), and continue stirring at room temperature and 20°C for 5 hours. The reaction solution was concentrated under reduced pressure to remove the solvent. The crude product was prepared by HPLC (column type: Phenomenex Gemini-NX C18 75*30mm*3μm; mobile phase: [H 2 O(0.05% NH 3 H 2 O+10mM NH 4 HCO 3 )-ACN]; B(ACN)% : 5%-30%, 8min) purification to obtain compound 38.
1H NMR(400MHz,CD 3OD)δ＝6.84-6.80(m,2H),6.64(d,J＝2.1Hz,1H),6.61(s,1H),6.61-6.57(m,1H),5.73-5.60(m,1H),4.86-4.78(m,2H),4.32-4.25(m,1H),4.08-4.00(m,2H),3.27-3.17(m,1H),3.08-2.91(m,3H),2.86-2.73(m,1H),2.60-2.44(m,1H),1.98-1.88(m,1H),1.15(dd,J＝7.0,9.3Hz,6H) 1H NMR(400MHz, CD 3 OD)δ=6.84-6.80(m,2H), 6.64(d,J=2.1Hz,1H), 6.61(s,1H), 6.61-6.57(m,1H), 5.73 5.60 (m, 1H), 4.86-4.78 (m, 2H), 4.32-4.25 (m, 1H), 4.08-4.00 (m, 2H), 3.27-3.17 (m, 1H), 3.08-2.91 (m, 3H) ),2.86-2.73(m,1H),2.60-2.44(m,1H),1.98-1.88(m,1H),1.15(dd,J=7.0,9.3Hz,6H)
实施例39Example 39
Figure PCTCN2020139562-appb-000148
Figure PCTCN2020139562-appb-000148
合成路线：synthetic route:
Figure PCTCN2020139562-appb-000149
Figure PCTCN2020139562-appb-000149
步骤1：39-1的合成Step 1: Synthesis of 39-1
将化合物1-9(0.9g,1.79mmol)溶于甲苯(10mL)中，加入吡啶对甲苯磺酸盐(224.93mg,895.06μmol)，110℃回流3小时。反应液加入30mL水，乙酸乙酯萃取(30mL×3)，减压浓缩除去溶剂。粗品经硅胶柱层析分离纯化(石油醚：乙酸乙酯＝10:1)。得到化合物39-1。Compound 1-9 (0.9 g, 1.79 mmol) was dissolved in toluene (10 mL), pyridine p-toluenesulfonate (224.93 mg, 895.06 μmol) was added, and refluxed at 110°C for 3 hours. The reaction solution was added with 30 mL of water, extracted with ethyl acetate (30 mL×3), and concentrated under reduced pressure to remove the solvent. The crude product was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1). Compound 39-1 was obtained.
1H NMR(400MHz,CDCl 3)δ＝7.54-7.49(m,2H),7.47-7.42(m,2H),7.40-7.36(m,1H),7.27(s,1H),7.19-7.15(m,1H),6.97-6.93(m,1H),6.92-6.88(m,1H),6.58-6.55(m,1H),6.25-6.22(m,1H),5.19-5.12(m,2H),3.54-3.46(m,1H),3.43-3.39(m,2H),2.04-2.00(m,3H),1.31-1.26(m,6H),1.06-1.02(m,9H),0.27-0.24(m,6H) 1 H NMR (400MHz, CDCl 3 )δ=7.54-7.49 (m, 2H), 7.47-7.42 (m, 2H), 7.40-7.36 (m, 1H), 7.27 (s, 1H), 7.19-7.15 (m ,1H),6.97-6.93(m,1H),6.92-6.88(m,1H),6.58-6.55(m,1H),6.25-6.22(m,1H),5.19-5.12(m,2H),3.54 -3.46(m,1H),3.43-3.39(m,2H),2.04-2.00(m,3H),1.31-1.26(m,6H),1.06-1.02(m,9H),0.27-0.24(m, 6H)
步骤2：39-2的合成Step 2: Synthesis of 39-2
向干净的烧瓶中加入二氯甲烷(25mL)，加入二乙基锌(1M,30.94mL)，-10℃慢慢加入二碘甲烷(8.29g,30.94mmol)，继续搅拌1小时，至析出白色固体，加入化合物39-1(3g,6.19mmol)的二氯甲烷(25mL)，室温20℃继续搅拌2小时。反应液倒入50mL饱和氯化铵水溶液，二氯甲烷(80mL×2)萃取，减压浓缩除去溶剂。粗品经硅胶柱层析分离纯化(石油醚：乙酸乙酯＝5:1)。得到化合物39-2。[Ms+1] +＝499.3 Add dichloromethane (25mL) to a clean flask, add diethylzinc (1M, 30.94mL), slowly add diiodomethane (8.29g, 30.94mmol) at -10°C, continue to stir for 1 hour, until white As a solid, compound 39-1 (3g, 6.19mmol) in dichloromethane (25mL) was added, and stirring was continued for 2 hours at room temperature and 20°C. The reaction solution was poured into 50 mL saturated aqueous ammonium chloride solution, extracted with dichloromethane (80 mL×2), and concentrated under reduced pressure to remove the solvent. The crude product was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1). Compound 39-2 was obtained. [Ms+1] + ＝499.3
步骤3：39-3的合成Step 3: Synthesis of 39-3
将化合物39-2(2.7g,5.41mmol)溶于甲醇(25mL)和四氢呋喃(25mL)中，加入氟化铵(1.60g,43.31mmol)，50℃的油浴下继续搅拌12小时。反应液减压浓缩除去溶剂。经硅胶柱层析分离纯化(石油醚：乙酸乙酯＝1:1)。得到化合物39-3。Compound 39-2 (2.7 g, 5.41 mmol) was dissolved in methanol (25 mL) and tetrahydrofuran (25 mL), ammonium fluoride (1.60 g, 43.31 mmol) was added, and stirring was continued for 12 hours in an oil bath at 50°C. The reaction solution was concentrated under reduced pressure to remove the solvent. Separation and purification by silica gel column chromatography (petroleum ether: ethyl acetate=1:1). Compound 39-3 was obtained.
1H NMR(400MHz,CDCl 3)δppm 7.44-7.49(m,2H),7.37-7.43(m,2H),7.31-7.36(m,1H),7.15-7.20(m,1H),7.04-7.10(m,1H),6.82-6.87(m,1H),6.51-6.54(m,1H),6.34-6.38(m,1H),5.05-5.10(m,2H),4.54-4.60(m,1H),3.33-3.44(m,2H),2.84-2.92(m,1H),1.75-1.82(m,3H),1.75-1.78(m,1H),1.19-1.24(m,6H),0.48-0.53(m,1H)。 1 H NMR (400MHz, CDCl 3 ) δppm 7.44-7.49 (m, 2H), 7.37-7.43 (m, 2H), 7.31-7.36 (m, 1H), 7.15-7.20 (m, 1H), 7.04-7.10 ( m,1H),6.82-6.87(m,1H),6.51-6.54(m,1H),6.34-6.38(m,1H),5.05-5.10(m,2H),4.54-4.60(m,1H), 3.33-3.44(m,2H),2.84-2.92(m,1H),1.75-1.82(m,3H),1.75-1.78(m,1H),1.19-1.24(m,6H),0.48-0.53(m ,1H).
步骤4：39-4的合成Step 4: Synthesis of 39-4
将化合物39-3(0.57g,1.48mmol)溶于N,N-二甲基甲酰胺(6mL)中，加入碳酸铯(723.32mg,2.22mmol)，对甲苯磺酰氧甲基膦酸二苄酯(726.82mg,1.63mmol)，50℃的油浴中继续搅拌12小时。加入15mL水洗，乙酸乙酯(20mL×2)萃取，无水硫酸钠干燥，减压浓缩除去溶剂。粗品经硅胶柱层析分离纯化(石油醚：乙酸乙酯＝1:1)。得到化合物39-4。Compound 39-3 (0.57g, 1.48mmol) was dissolved in N,N-dimethylformamide (6mL), cesium carbonate (723.32mg, 2.22mmol) was added, and dibenzyl p-toluenesulfonyloxymethylphosphonic acid The ester (726.82mg, 1.63mmol) was stirred in an oil bath at 50°C for 12 hours. Add 15 mL of water to wash, extract with ethyl acetate (20 mL×2), dry with anhydrous sodium sulfate, and concentrate under reduced pressure to remove the solvent. The crude product was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate=1:1). Compound 39-4 was obtained.
1H NMR(400MHz,CDCl 3)δ＝7.49-7.43(m,1H),7.44-7.39(m,1H),7.43-7.39(m,1H),7.43-7.39(m,1H),7.38-7.31(m,12H),7.18-7.15(m,1H),7.08-7.02(m,1H),6.87-6.81(m,1H),6.61-6.57(m,1H),6.45-6.42(m,1H),5.18-5.12(m,4H),5.09-5.06(m,2H),4.29-4.22(m,2H),4.18-4.10(m,1H),3.43-3.33(m,2H),2.07-2.05(m,1H),2.07-2.04(m,1H),1.75-1.66(m,1H),1.63-1.59(m,2H),1.21(t,J＝6.9Hz,6H) 1 H NMR(400MHz, CDCl 3 )δ=7.49-7.43(m,1H),7.44-7.39(m,1H),7.43-7.39(m,1H),7.43-7.39(m,1H),7.38-7.31 (m,12H),7.18-7.15(m,1H),7.08-7.02(m,1H),6.87-6.81(m,1H),6.61-6.57(m,1H),6.45-6.42(m,1H) ,5.18-5.12(m,4H),5.09-5.06(m,2H),4.29-4.22(m,2H),4.18-4.10(m,1H),3.43-3.33(m,2H),2.07-2.05( m,1H),2.07-2.04(m,1H),1.75-1.66(m,1H),1.63-1.59(m,2H),1.21(t,J=6.9Hz,6H)
步骤5：39-5的合成Step 5: Synthesis of 39-5
SFC分析方法：柱型:Chiralcel OJ-3,50×4.6mm I.D.,3μm,流动相:A:CO 2B:EtOH(0.05％IPAm,v/v),梯度:B相1分钟内从5％升至50％，维持1分钟，0.8分钟内降至5％，流速:3.4mL/min,柱温:35℃,ABPR:1800psi。化合物39-5保留时间：1.478min。化合物39-4经手性拆分(柱型:DAICEL CHIRALCEL OJ(250mm*30mm,10μm)；流动相:[0.1％NH 3H 2O EtOH]:45％-45％,10min)分离。得到化合物39-5。 SFC analysis method: Column type: Chiralcel OJ-3, 50×4.6mm ID, 3μm, mobile phase: A: CO 2 B: EtOH (0.05% IPAm, v/v), gradient: phase B from 5% within 1 minute Increase to 50%, maintain for 1 minute, and decrease to 5% within 0.8 minutes, flow rate: 3.4mL/min, column temperature: 35°C, ABPR: 1800psi. Compound 39-5 retention time: 1.478min. Compound 39-4 was separated by chiral resolution (column type: DAICEL CHIRALCEL OJ (250mm*30mm, 10μm); mobile phase: [0.1% NH 3 H 2 O EtOH]: 45%-45%, 10min). Compound 39-5 was obtained.
步骤6：39的合成Step 6: Synthesis of 39
将化合物39-5(0.1g,151.80μmol)溶于甲醇(1mL)中，加入湿钯碳(15mg,151.80μmol,钯含量：10％)，15psi的压力下，H 2保护下，20℃继续搅拌5小时。反应液过滤，减压浓缩除去溶剂。经制备HPLC(柱型:Phenomenex Gemini-NX 150*30mm*5μm；流动相:[H 2O(10mM NH 4HCO 3)-ACN]；B(ACN)％:10％-30％,7min)分离纯化。得到化合物39。 Compound 39-5 (0.1g, 151.80μmol) was dissolved in methanol (1mL), and wet palladium on carbon (15mg, 151.80μmol, palladium content: 10%) was added. Under 15psi pressure, under H 2 protection, continue at 20°C Stir for 5 hours. The reaction solution was filtered and concentrated under reduced pressure to remove the solvent. Separated by preparative HPLC (column type: Phenomenex Gemini-NX 150*30mm*5μm; mobile phase: [H 2 O(10mM NH 4 HCO 3 )-ACN]; B(ACN)%: 10%-30%, 7min) purification. Compound 39 was obtained.
1H NMR(400MHz,CD 3OD)δppm 7.04-7.07(m,1H),6.86-6.90(m,1H),6.64-6.68(m,2H),6.48-6.50(m,1H),3.94-3.99(m,2H),3.34-3.38(m,1H),3.20-3.28(m,1H),2.82-2.88(m,1H),1.76-1.77(m,3H),1.72-1.76(m,1H),1.54-1.60(m,1H),1.13-1.18(m,6H),0.36-0.40(m,1H)。 1 H NMR (400MHz, CD 3 OD) δppm 7.04-7.07 (m, 1H), 6.86-6.90 (m, 1H), 6.64-6.68 (m, 2H), 6.48-6.50 (m, 1H), 3.94-3.99 (m,2H),3.34-3.38(m,1H),3.20-3.28(m,1H),2.82-2.88(m,1H),1.76-1.77(m,3H),1.72-1.76(m,1H) , 1.54-1.60 (m, 1H), 1.13-1.18 (m, 6H), 0.36-0.40 (m, 1H).
实施例40Example 40
Figure PCTCN2020139562-appb-000150
Figure PCTCN2020139562-appb-000150
合成路线：synthetic route:
Figure PCTCN2020139562-appb-000151
Figure PCTCN2020139562-appb-000151
步骤1：化合物40-2的合成Step 1: Synthesis of compound 40-2
将原料40-1(5g,20.75mmol)加入至二氯甲烷(50mL)，加入三氟甲磺酸(15.57g,103.73mmol)，异丙醇(2.49g,41.49mmol)，反应在20℃搅拌16小时。反应液中加入乙酸乙酯(100mL)，饱和氯化钠溶液(50mL×4)洗，乙酸乙酯层经无水硫酸钠干燥后，过滤，减压浓缩。粗品经硅胶柱层析纯化(石油醚:乙酸乙酯＝1:0)。得到化合物40-2。Raw material 40-1 (5g, 20.75mmol) was added to dichloromethane (50mL), trifluoromethanesulfonic acid (15.57g, 103.73mmol), isopropanol (2.49g, 41.49mmol) were added, and the reaction was stirred at 20°C 16 hours. Ethyl acetate (100 mL) was added to the reaction solution, washed with saturated sodium chloride solution (50 mL×4), the ethyl acetate layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate=1:0). Compound 40-2 was obtained.
1H NMR(400MHz,CDCl 3)δ＝7.50-7.45(m,2H),5.51(q,J＝3.4Hz,1H),3.31-3.22(m,1H),1.26(d,J＝6.8Hz,6H)。 1 H NMR (400MHz, CDCl 3 )δ = 7.50-7.45 (m, 2H), 5.51 (q, J = 3.4 Hz, 1H), 3.31-3.22 (m, 1H), 1.26 (d, J = 6.8 Hz, 6H).
步骤2：化合物40-3的合成Step 2: Synthesis of compound 40-3
将化合物40-2(5.43g,19.18mmol)加入至N,N-二甲基甲酰胺(50mL)，加入碳酸钾(5.30g,38.36mmol)，苄溴(2.95g,17.26mmol)，反应升至60℃搅拌16小时。反应液中加入乙酸乙酯(50mL)，饱和氯化钠溶液(30mL×4)洗，乙酸乙酯层经无水硫酸钠干燥后，过滤，减压浓缩。粗品经硅胶柱层析纯化(石油醚:乙酸乙酯＝1:0)。得到化合物40-3。Compound 40-2 (5.43g, 19.18mmol) was added to N,N-dimethylformamide (50mL), potassium carbonate (5.30g, 38.36mmol), benzyl bromide (2.95g, 17.26mmol) were added, and the reaction was increased. Stir at 60°C for 16 hours. Ethyl acetate (50 mL) was added to the reaction solution, washed with saturated sodium chloride solution (30 mL×4), the ethyl acetate layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate=1:0). Compound 40-3 was obtained.
1H NMR(400MHz,CDCl 3)δ＝7.63-7.58(m,2H),7.52-7.35(m,5H),4.90(s,2H),3.44-3.32(m,1H),1.26(d,J＝6.8Hz,6H)。 1 H NMR(400MHz,CDCl 3 )δ=7.63-7.58(m,2H),7.52-7.35(m,5H),4.90(s,2H),3.44-3.32(m,1H),1.26(d,J =6.8Hz, 6H).
步骤3：化合物40-4的合成Step 3: Synthesis of compound 40-4
将原料40-3(4.4g,11.79mmol)溶于四氢呋喃(40mL)中，氮气置换3次，降温至-68℃下缓慢滴加正丁基锂(2.5M,5.66mL)，反应在-68℃下进行0.5小时，在-68℃下加入BB-1(3.26g,11.79mmol)反应在25℃下进行12小时。向反应液中加入饱和氯化铵水溶液(10mL)淬灭反应。萃取乙酸乙酯(200mL)，水(200 mL)，收集有机相，有机相通过无水硫酸钠干燥，过滤，滤液减压浓缩，得到化合物40-4。[Ms-17] +＝553.1。 Dissolve raw material 40-3 (4.4g, 11.79mmol) in tetrahydrofuran (40mL), replace with nitrogen 3 times, and slowly add n-butyllithium (2.5M, 5.66mL) dropwise while cooling to -68°C. The reaction is at -68°C. It was carried out for 0.5 hour at °C, BB-1 (3.26 g, 11.79 mmol) was added at -68 °C, and the reaction was carried out at 25 °C for 12 hours. A saturated aqueous ammonium chloride solution (10 mL) was added to the reaction solution to quench the reaction. Extract ethyl acetate (200 mL), water (200 mL), collect the organic phase, dry the organic phase over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain compound 40-4. [Ms-17] + = 553.1.
步骤4：化合物40-5的合成Step 4: Synthesis of compound 40-5
将原料40-4(6.86g,12.02mmol)溶于二氯甲烷(30mL)中，加入三乙基硅氢(4.19g,36.06mmol)，在0℃下加入三氟乙酸(2.06g,18.03mmol)，反应在25℃下进行12小时。减压浓缩，得到化合物40-5。[Ms+1] +＝555.1。 Dissolve raw material 40-4 (6.86g, 12.02mmol) in dichloromethane (30mL), add triethylsilylhydrogen (4.19g, 36.06mmol), add trifluoroacetic acid (2.06g, 18.03mmol) at 0°C ), the reaction was carried out at 25°C for 12 hours. Concentrate under reduced pressure to obtain compound 40-5. [Ms+1] + =555.1.
步骤5：化合物40-6的合成Step 5: Synthesis of compound 40-6
将原料40-5(6.67.g 12.02mmol)溶于甲醇(30mL)与四氢呋喃(30mL)的混合溶剂中，加入氟化铵(4.54g,120.23mmol)，反应在25℃下进行12小时。减压浓缩，粗产品通过柱层析分离(石油醚：乙酸乙酯＝3:1)，得到化合物40-6。Raw material 40-5 (6.67.g 12.02mmol) was dissolved in a mixed solvent of methanol (30mL) and tetrahydrofuran (30mL), ammonium fluoride (4.54g, 120.23mmol) was added, and the reaction was carried out at 25°C for 12 hours. Concentrated under reduced pressure, and the crude product was separated by column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain compound 40-6.
1H NMR(400MHz,CDCl 3)δ＝7.54-7.49(m,2H),7.46-7.40(m,2H),7.40-7.34(m,1H),7.20-7.13(m,2H),6.67(s,1H),6.51(s,1H),4.91(s,2H),4.36(dd,J＝3.8,8.6Hz,1H),3.40(spt,J＝6.9Hz,1H),3.10-2.97(m,1H),2.91-2.80(m,1H),2.62(qd,J＝8.6,12.7Hz,1H),2.01(tdd,J＝4.2,8.4,12.7Hz,1H),1.90(s,3H),1.24-1.17(m,6H)。 1 H NMR(400MHz, CDCl 3 )δ=7.54-7.49(m,2H),7.46-7.40(m,2H),7.40-7.34(m,1H),7.20-7.13(m,2H),6.67(s ,1H),6.51(s,1H),4.91(s,2H), 4.36(dd,J=3.8,8.6Hz,1H), 3.40(spt,J=6.9Hz,1H),3.10-2.97(m, 1H),2.91-2.80(m,1H),2.62(qd,J=8.6,12.7Hz,1H),2.01(tdd,J=4.2,8.4,12.7Hz,1H),1.90(s,3H),1.24 -1.17 (m, 6H).
步骤6：化合物40-7的合成Step 6: Synthesis of compound 40-7
将原料40-6(1.75g,3.97mmol)溶于二甲基甲酰胺(10mL)中，加入碳酸铯(1.02g,3.12mmol)，对甲苯磺酰氧甲基膦酸二乙酯(1.28g,3.97mmol)，反应在50℃下进行2小时。萃取乙酸乙酯(100mL)，水(100mL)，收集有机相，有机相通过饱和食盐水(100mL×3)洗涤，有机相通过无水硫酸钠干燥，过滤，滤液减压浓缩，得粗产品。粗产品通过柱层析分离(石油醚：乙酸乙酯＝1:1)，得到化合物40-7。[Ms+1] +＝591.1。 Dissolve raw material 40-6 (1.75g, 3.97mmol) in dimethylformamide (10mL), add cesium carbonate (1.02g, 3.12mmol), diethyl p-toluenesulfonyloxymethylphosphonate (1.28g) , 3.97 mmol), the reaction was carried out at 50°C for 2 hours. Extract ethyl acetate (100 mL), water (100 mL), collect the organic phase, wash the organic phase with saturated brine (100 mL×3), dry the organic phase over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain a crude product. The crude product was separated by column chromatography (petroleum ether: ethyl acetate=1:1) to obtain compound 40-7. [Ms+1] + =591.1.
步骤7：化合物40-8的合成Step 7: Synthesis of compound 40-8
将原料40-7(1.6g,2.71mmol)溶于甲醇(5mL)中，加入湿钯碳(0.8g,钯含量：5％)，通入氢气，置换3次，反应在15psi,25℃下进行12小时。过滤，滤液减压浓缩，得粗产品。得到化合物40-8。[Ms+1] +＝501.1。 The raw material 40-7 (1.6g, 2.71mmol) was dissolved in methanol (5mL), wet palladium carbon (0.8g, palladium content: 5%) was added, hydrogen gas was introduced, and the reaction was carried out 3 times. Proceed for 12 hours. After filtration, the filtrate was concentrated under reduced pressure to obtain a crude product. Compound 40-8 was obtained. [Ms+1] + = 501.1.
步骤8：化合物40-9的合成Step 8: Synthesis of compound 40-9
原料40-8(0.7g,1.57mmol)的SFC拆分。经SFC(柱型:DAICEL CHIRALPAK AD(250mm*50mm,10μm)；流动相:[0.1％NH 3H 2O/IPA]:20％-20％,4.5min)拆分。得到化合物40-9。分析方法：柱型:Chiralpak AD-3,50×4.6mm,I.D.,3μm。流动相:A:CO 2B:IPA(0.05％IPAm,v/v。梯度:B相1分钟内从5％升至50％，维持1分钟，0.8分钟内降至5％。流速:3.4mL/min。柱温.:35℃。ABPR:1800psi。化合物40-9保留时间：1.011min。 The raw material 40-8 (0.7g, 1.57mmol) was resolved by SFC. It was resolved by SFC (column type: DAICEL CHIRALPAK AD (250mm*50mm, 10μm); mobile phase: [0.1% NH 3 H 2 O/IPA]: 20%-20%, 4.5min). Compound 40-9 was obtained. Analysis method: Column type: Chiralpak AD-3, 50×4.6mm, ID, 3μm. Mobile phase: A: CO 2 B: IPA (0.05% IPAm, v/v. Gradient: Phase B rose from 5% to 50% in 1 minute, maintained for 1 minute, and decreased to 5% in 0.8 minutes. Flow rate: 3.4mL /min. Column temperature: 35° C. ABPR: 1800 psi. Compound 40-9 retention time: 1.011 min.
步骤9：化合物40的合成Step 9: Synthesis of compound 40
将原料40-9(342mg,683.34μmol)溶于二氯甲烷(3mL)中，0℃加入三甲基溴硅烷(1.05g,6.783mmol)反应在30℃下进行12小时。减压浓缩，得粗产品，加入乙酸乙酯(10mL)和水(10mL)萃取，收集有机相，有机相通过饱和食盐水(10mL×3)洗涤，有机相通过无水硫酸钠干燥，过滤，滤液减压浓缩，得粗产品。通过制备HPLC(柱型:Phenomenex luna C18 80*40mm*3μm；流动相:[H 2O(0.04％HCl)-ACN]；B(ACN)％:45％-70％,7min)分离，得到化合物40。 Raw material 40-9 (342mg, 683.34μmol) was dissolved in dichloromethane (3mL), trimethylbromosilane (1.05g, 6.783mmol) was added at 0°C and the reaction was carried out at 30°C for 12 hours. Concentrate under reduced pressure to obtain a crude product, add ethyl acetate (10 mL) and water (10 mL) for extraction, collect the organic phase, wash the organic phase with saturated brine (10 mL×3), dry the organic phase with anhydrous sodium sulfate, and filter. The filtrate was concentrated under reduced pressure to obtain a crude product. Separated by preparative HPLC (column type: Phenomenex luna C18 80*40mm*3μm; mobile phase: [H 2 O (0.04% HCl)-ACN]; B(ACN)%: 45%-70%, 7 min) to obtain the compound 40.
1H NMR(400MHz,CD 3OD)δ＝7.10(s,1H),6.96(s,1H),6.83(s,1H),6.66(s,1H),4.36(br dd,J＝3.6,8.7Hz,1H),4.22(br d,J＝10.4Hz,2H),3.30-3.25(m,1H),3.02(td,J＝8.2,16.0Hz,1H),2.93-2.81(m,1H),2.69-2.53(m,1H),1.98-1.89(m,4H),1.17(dd,J＝6.9,9.7Hz,6H)。 1 H NMR (400MHz, CD 3 OD) δ = 7.10 (s, 1H), 6.96 (s, 1H), 6.83 (s, 1H), 6.66 (s, 1H), 4.36 (br dd, J = 3.6, 8.7 Hz, 1H), 4.22 (br d, J = 10.4 Hz, 2H), 3.30-3.25 (m, 1H), 3.02 (td, J = 8.2, 16.0 Hz, 1H), 2.93-2.81 (m, 1H), 2.69-2.53 (m, 1H), 1.98-1.89 (m, 4H), 1.17 (dd, J=6.9, 9.7 Hz, 6H).
实施例41Example 41
Figure PCTCN2020139562-appb-000152
Figure PCTCN2020139562-appb-000152
合成路线：synthetic route:
Figure PCTCN2020139562-appb-000153
Figure PCTCN2020139562-appb-000153
步骤1：41-2的合成Step 1: Synthesis of 41-2
向原料41-1(10g,43.65mmol)的1,4-二氧六环(50mL)溶液中加入双频哪醇硼酯(12.19g,48.02mmol)，4,4’-二叔丁基-2,2’-联吡啶(234.34mg,873.09μmol)，1,5-环辛二烯氯化铱二聚体(293.23mg,436.55μmol)，在85℃反应16小时。将反应液减压浓缩，加入乙酸乙酯(100mL)稀释，用10％的柠檬酸水溶液(100mL×2)洗，有机相用无水硫酸钠干燥，过滤，减压浓缩得到粗品。粗品未经纯化直接投入下一步。得到化合物41-2。To the raw material 41-1 (10g, 43.65mmol) in 1,4-dioxane (50mL) solution was added bispinacol boron ester (12.19g, 48.02mmol), 4,4'-di-tert-butyl- 2,2'-Bipyridine (234.34mg, 873.09μmol), 1,5-cyclooctadiene iridium chloride dimer (293.23mg, 436.55μmol), reacted at 85°C for 16 hours. The reaction solution was concentrated under reduced pressure, diluted with ethyl acetate (100 mL), washed with 10% citric acid aqueous solution (100 mL×2), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product is directly put into the next step without purification. Compound 41-2 was obtained.
1H NMR(400MHz,CDCl 3)δ＝7.87(d,J＝0.9Hz,1H),7.75(d,J＝0.9Hz,1H),3.93(s,3H),2.46(s,3H),1.35(s,12H)。 1 H NMR (400MHz, CDCl 3 ) δ = 7.87 (d, J = 0.9 Hz, 1H), 7.75 (d, J = 0.9 Hz, 1H), 3.93 (s, 3H), 2.46 (s, 3H), 1.35 (s,12H).
步骤2：41-3的合成Step 2: Synthesis of 41-3
向原料41-2(15.5g,43.66mmol)的四氢呋喃(150mL)和水(50mL)溶液中加入过硼酸钠(20.15g,130.97mmol)，在20℃反应4小时。反应加入至乙酸乙酯(100mL)，饱和氯化钠溶液(100mL×2)洗，乙酸乙酯层经无水硫酸钠干燥后，过滤，减压浓缩。粗品未经纯化直接投入下一步。得到化合物41-3。[Ms+1] +＝244.9。 Sodium perborate (20.15 g, 130.97 mmol) was added to a solution of raw material 41-2 (15.5 g, 43.66 mmol) in tetrahydrofuran (150 mL) and water (50 mL), and reacted at 20° C. for 4 hours. The reaction was added to ethyl acetate (100 mL), washed with saturated sodium chloride solution (100 mL×2), the ethyl acetate layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product is directly put into the next step without purification. Compound 41-3 was obtained. [Ms+1] + = 244.9.
步骤3：41-4的合成Step 3: Synthesis of 41-4
在0℃，向原料41-3(10.7g,43.66mmol)的二氯甲烷(150mL)溶液中加入N,N-二异丙基乙胺(11.29g,87.32mmol)，溴甲氧基甲基醚(6.55g,52.39mmol)，在20℃反应12小时。将反应液倒入饱和碳酸氢钠溶液(100mL)中，加入二氯甲烷(50mL)分液，水相用二氯甲烷萃取(50mL×3)，合并有机相，无水硫酸钠干燥，过滤，减压浓缩得到粗品。粗品用硅胶柱层析法分离(石油醚：乙酸乙酯＝10:1)。得到化合物41-4。At 0°C, to a solution of raw material 41-3 (10.7g, 43.66mmol) in dichloromethane (150mL) was added N,N-diisopropylethylamine (11.29g, 87.32mmol), bromomethoxymethyl Ether (6.55g, 52.39mmol), react at 20°C for 12 hours. The reaction solution was poured into saturated sodium bicarbonate solution (100 mL), dichloromethane (50 mL) was added for separation, the aqueous phase was extracted with dichloromethane (50 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, and filtered. Concentrate under reduced pressure to obtain a crude product. The crude product was separated by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1). Compound 41-4 was obtained.
1H NMR(400MHz,CDCl 3)δ＝7.17(d,J＝2.6Hz,1H),7.05(d,J＝2.6Hz,1H),5.16(d,J＝0.9Hz,2H),3.93(d,J＝0.9Hz,3H),3.47(d,J＝1.1Hz,3H),2.43(s,3H)。 1 H NMR (400MHz, CDCl 3 ) δ = 7.17 (d, J = 2.6 Hz, 1H), 7.05 (d, J = 2.6 Hz, 1H), 5.16 (d, J = 0.9 Hz, 2H), 3.93 (d , J = 0.9 Hz, 3H), 3.47 (d, J = 1.1 Hz, 3H), 2.43 (s, 3H).
步骤4：41-5的合成Step 4: Synthesis of 41-5
向原料41-4(9g,31.13mmol)的四氢呋喃(90mL)，甲醇(30mL)和水(45mL)溶液中加入一水合氢氧化锂(3.92g,93.39mmol)，在70℃反应4小时。将反应液减压浓缩，加入2M盐酸溶液调节pH至3，过滤，收集滤饼。粗品未经纯化直接投入下一步。得到化合物41-5。To a solution of raw material 41-4 (9g, 31.13mmol) in tetrahydrofuran (90mL), methanol (30mL) and water (45mL) was added lithium hydroxide monohydrate (3.92g, 93.39mmol) and reacted at 70°C for 4 hours. The reaction solution was concentrated under reduced pressure, 2M hydrochloric acid solution was added to adjust the pH to 3, filtered, and the filter cake was collected. The crude product is directly put into the next step without purification. Compound 41-5 was obtained.
1H NMR(400MHz,CDCl 3)δ＝7.40(d,J＝2.9Hz,1H),7.12(d,J＝2.9Hz,1H),5.19(s,2H),3.49(s,3H),2.49-2.42(m,3H)。 1 H NMR (400MHz, CDCl 3 ) δ = 7.40 (d, J = 2.9 Hz, 1H), 7.12 (d, J = 2.9 Hz, 1H), 5.19 (s, 2H), 3.49 (s, 3H), 2.49 -2.42(m,3H).
步骤5：41-6的合成Step 5: Synthesis of 41-6
在-78℃，向原料41-5(3g,10.91mmol)的四氢呋喃(180mL)溶液中加入正丁基锂(2.5M,15.27mL)，2小时后加入4-苄氧基-3-异丙基苯甲醛(5.55g,21.81mmol)的四氢呋喃(80mL)溶液，反应0.5小时后，在20℃反应12小时。将反应液倒入饱和氯化铵溶液(50mL)中，加入乙酸乙酯分液(100mL)，水相用乙酸乙酯萃取(100mL×3)，合并有机相，无水硫酸钠干燥，过滤，减压浓缩得到粗品。粗品用硅胶柱层析法分离(石油醚：乙酸乙酯＝5:1)。得到化合物41-6。At -78°C, n-butyllithium (2.5M, 15.27mL) was added to a solution of raw material 41-5 (3g, 10.91mmol) in tetrahydrofuran (180mL), and 4-benzyloxy-3-isopropyl was added after 2 hours. A solution of benzaldehyde (5.55 g, 21.81 mmol) in tetrahydrofuran (80 mL) was reacted for 0.5 hours, and then reacted at 20° C. for 12 hours. The reaction solution was poured into saturated ammonium chloride solution (50 mL), ethyl acetate was added for separation (100 mL), the aqueous phase was extracted with ethyl acetate (100 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, and filtered. Concentrate under reduced pressure to obtain a crude product. The crude product was separated by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1). Compound 41-6 was obtained.
1H NMR(400MHz,DMSO-d 6)δ＝7.50-7.45(m,2H),7.45-7.39(m,2H),7.37-7.31(m,2H),7.23(d,J＝1.5Hz,1H),7.18(d,J＝2.1Hz,1H),7.07(d,J＝8.5Hz,1H),6.93(dd,J＝2.2,8.5Hz,1H),6.60(s,1H),5.38-5.27(m,2H),5.13(s,2H),3.42(s,3H),3.30-3.22(m,1H),1.96(s,3H),1.15(dd,J＝6.0,6.7Hz,6H)。 1 H NMR(400MHz,DMSO-d 6 )δ=7.50-7.45(m,2H),7.45-7.39(m,2H),7.37-7.31(m,2H),7.23(d,J=1.5Hz,1H ), 7.18 (d, J = 2.1 Hz, 1H), 7.07 (d, J = 8.5 Hz, 1H), 6.93 (dd, J = 2.2, 8.5 Hz, 1H), 6.60 (s, 1H), 5.38-5.27 (m, 2H), 5.13 (s, 2H), 3.42 (s, 3H), 3.30-3.22 (m, 1H), 1.96 (s, 3H), 1.15 (dd, J=6.0, 6.7 Hz, 6H).
步骤6：41-7的合成Step 6: Synthesis of 41-7
在0℃，向原料41-6(5.5g,12.21mmol)的四氢呋喃(40mL)溶液中加入四氢铝锂(926.70mg,24.42mmol)，反应1小时。向反应液中缓慢加入十水合硫酸钠淬灭反应，用硅藻土过滤，滤液用乙酸乙酯萃取(50mL×3)，合并有机相，无水硫酸钠干燥，过滤，减压浓缩得到粗品。粗品用硅胶柱层析法分离(石油醚：乙酸乙酯＝3:1)。得到化合物41-7。At 0°C, lithium tetrahydroaluminum (926.70 mg, 24.42 mmol) was added to a tetrahydrofuran (40 mL) solution of the raw material 41-6 (5.5 g, 12.21 mmol), and the reaction was carried out for 1 hour. Sodium sulfate decahydrate was slowly added to the reaction solution to quench the reaction, filtered through Celite, the filtrate was extracted with ethyl acetate (50 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was separated by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1). Compound 41-7 was obtained.
1H NMR(400MHz,CDCl 3)δ＝7.47-7.31(m,5H),7.14(d,J＝2.0Hz,1H),6.94(dd,J＝2.2,8.3Hz,1H),6.88-6.78(m,2H),6.73(s,1H),6.06(s,1H),5.24(dd,J＝2.3,12.3Hz,1H),5.19(s,2H),5.09(s,1H),5.07(s,2H),3.52(s,3H),3.43-3.30(m,1H),1.89(s,3H),1.21(t,J＝7.1Hz,6H)。 1 H NMR(400MHz, CDCl 3 )δ=7.47-7.31(m,5H), 7.14(d,J=2.0Hz,1H), 6.94(dd,J=2.2,8.3Hz,1H), 6.88-6.78( m, 2H), 6.73 (s, 1H), 6.06 (s, 1H), 5.24 (dd, J = 2.3, 12.3 Hz, 1H), 5.19 (s, 2H), 5.09 (s, 1H), 5.07 (s , 2H), 3.52 (s, 3H), 3.43-3.30 (m, 1H), 1.89 (s, 3H), 1.21 (t, J=7.1 Hz, 6H).
步骤7：41-8的合成Step 7: Synthesis of 41-8
向原料41-7(4.5g,10.31mmol)的甲苯(120mL)溶液中加入对甲基苯磺酰氯(2.36g,12.37mmol)，在90℃反应12小时。将反应液倒入饱和碳酸氢钠溶液(50mL)中，加入乙酸乙酯(50mL)分液，水相用乙酸乙酯萃取(50mL×3)，合并有机相，无水硫酸钠干燥，过滤，减压浓缩得到粗品。粗品用硅胶柱层析法分离(石油醚：乙酸乙酯＝10:1)。得到化合物41-8。To a toluene (120 mL) solution of raw material 41-7 (4.5 g, 10.31 mmol) was added p-toluenesulfonyl chloride (2.36 g, 12.37 mmol) and reacted at 90°C for 12 hours. The reaction solution was poured into saturated sodium bicarbonate solution (50mL), ethyl acetate (50mL) was added to separate the layers, the aqueous phase was extracted with ethyl acetate (50mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, and filtered. Concentrate under reduced pressure to obtain a crude product. The crude product was separated by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1). Compound 41-8 was obtained.
1H NMR(400MHz,CDCl 3)δ＝7.47-7.30(m,5H),7.15(d,J＝2.0Hz,1H),6.94(dd,J＝2.2,8.3Hz,1H),6.88-6.79(m,2H),6.73(s,1H),6.07(s,1H),5.24(dd,J＝2.4,12.3Hz,1H),5.20(s,2H),5.11-5.05(m,3H),3.52(s,3H),3.44-3.34(m,1H),1.90(s,3H),1.22(t,J＝7.1Hz,6H)。 1 H NMR (400MHz, CDCl 3 ) δ = 7.47-7.30 (m, 5H), 7.15 (d, J = 2.0 Hz, 1H), 6.94 (dd, J = 2.2, 8.3 Hz, 1H), 6.88-6.79 ( m, 2H), 6.73 (s, 1H), 6.07 (s, 1H), 5.24 (dd, J = 2.4, 12.3 Hz, 1H), 5.20 (s, 2H), 5.11-5.05 (m, 3H), 3.52 (s, 3H), 3.44-3.34 (m, 1H), 1.90 (s, 3H), 1.22 (t, J=7.1 Hz, 6H).
步骤8：41-9的合成Step 8: Synthesis of 41-9
向原料41-8(1.6g,3.82mmol)的甲醇(16mL)溶液中加入对甲基苯磺酸(1.97g,11.47mmol)，在50℃反应4小时。将反应液倒入水20毫升中，加入乙酸乙酯分液(50mL)，有机相用饱和碳酸氢钠(20mL×3)洗涤，合并有机相，无水硫酸钠干燥，过滤，减压浓缩得到粗品。粗品未经纯化直接投入下一步。得到化合物41-9。To a methanol (16 mL) solution of raw material 41-8 (1.6 g, 3.82 mmol) was added p-toluenesulfonic acid (1.97 g, 11.47 mmol) and reacted at 50°C for 4 hours. The reaction solution was poured into 20 mL of water, ethyl acetate was added for separation (50 mL), the organic phase was washed with saturated sodium bicarbonate (20 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain Crude. The crude product is directly put into the next step without purification. Compound 41-9 was obtained.
1H NMR(400MHz,CDCl 3)δ＝7.49-7.30(m,5H),7.13(d,J＝1.5Hz,1H),7.02-6.79(m,2H),6.62-6.44(m,2H),6.06(s,1H),5.28-5.01(m,4H),3.45-3.30(m,1H),1.85(s,3H),1.20(t,J＝7.5Hz,6H)。 1 H NMR (400MHz, CDCl 3 ) δ = 7.49-7.30 (m, 5H), 7.13 (d, J = 1.5 Hz, 1H), 7.02-6.79 (m, 2H), 6.62-6.44 (m, 2H), 6.06 (s, 1H), 5.28-5.01 (m, 4H), 3.45-3.30 (m, 1H), 1.85 (s, 3H), 1.20 (t, J=7.5 Hz, 6H).
步骤9：41-10的合成Step 9: Synthesis of 41-10
将原料41-9(1.9g,5.07mmol)进行SFC(柱型:REGIS(S,S)WHELK-O1(250mm*25mm,10μm)；流动相:[Neu-EtOH]:60％-60％,8min)拆分。得到化合物41-10。分析方法：柱型:(S,S)-WHELK-O1,50×4.6mm I.D.,3.5μm。流动相:A:CO 2B:IPA(0.05％IPAm,v/v。梯度:B相1分钟内从5％升至50％，维持1分钟，0.8分钟内降至5％，流速:3.4mL/min。柱温.:35℃。ABPR:1800psi。化合物41-10保留时间：1.624min。 The raw material 41-9 (1.9g, 5.07mmol) was subjected to SFC (column type: REGIS (S, S) WHELK-O1 (250mm*25mm, 10μm); mobile phase: [Neu-EtOH]: 60%-60%, 8min) Split. Compound 41-10 was obtained. Analysis method: Column type: (S, S)-WHELK-O1, 50×4.6mm ID, 3.5μm. Mobile phase: A: CO 2 B: IPA (0.05% IPAm, v/v. Gradient: Phase B rose from 5% to 50% in 1 minute, maintained for 1 minute, and decreased to 5% in 0.8 minutes, flow rate: 3.4mL /min. Column temperature: 35° C. ABPR: 1800 psi. Compound 41-10 retention time: 1.624 min.
步骤10：41-11的合成Step 10: Synthesis of 41-11
向原料41-10(0.3g,801.13μmol)的N,N二甲基甲酰胺(5mL)溶液中加入碳酸铯(391.54mg,1.20mmol)，BB-2(536.50mg,1.20mmol)，在60℃反应12小时。将反应液倒入饱和氯化钠溶液中，加入乙酸乙酯分液(50mL)，水相用乙酸乙酯萃取(50mL×3)，合并有机相，无水硫酸钠干燥，过滤，减压浓缩得到粗品。粗品用硅胶柱层析法分离(石油醚：乙酸乙酯＝2:1)。得到化合物41-11。To raw material 41-10 (0.3g, 801.13μmol) in N, N dimethylformamide (5mL) solution was added cesium carbonate (391.54mg, 1.20mmol), BB-2 (536.50mg, 1.20mmol), at 60 React at °C for 12 hours. The reaction solution was poured into saturated sodium chloride solution, ethyl acetate was added for separation (50mL), the aqueous phase was extracted with ethyl acetate (50mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure Get crude product. The crude product was separated by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1). Compound 41-11 was obtained.
1H NMR(400MHz,CDCl 3)δ＝7.47-7.35(m,15H),7.13(d,J＝1.8Hz,1H),6.96-6.79(m,2H),6.63(br d,J＝17.8Hz,2H),6.07(s,1H),5.25-5.06(m,8H),4.29(d,J＝9.9Hz,2H),3.40(td,J＝6.9,13.8Hz,1H),1.88(s,3H),1.22(t,J＝7.5Hz,6H)。 1 H NMR (400MHz, CDCl 3 )δ = 7.47-7.35 (m, 15H), 7.13 (d, J = 1.8 Hz, 1H), 6.96-6.79 (m, 2H), 6.63 (br d, J = 17.8 Hz ,2H),6.07(s,1H),5.25-5.06(m,8H),4.29(d,J=9.9Hz,2H), 3.40(td,J=6.9,13.8Hz,1H),1.88(s, 3H), 1.22 (t, J=7.5 Hz, 6H).
步骤11：41的合成Step 11: Synthesis of 41
向原料41-11(250.00mg,385.37μmol)的乙酸乙酯(10mL)溶液中加入钯/碳(0.2g,钯含量：5％)，在氢气环境下，15psi，在20℃反应2小时。将反应液用硅藻土过滤，滤液减压浓缩得到粗品。粗品用制备HPLC(柱型:Phenomenex Gemini-NX 150*30mm*5μm；流动相:[水(10mM NH 4HCO 3)-ACN]；B(ACN)％:5％-45％,10min)分离。得到化合物41。 Palladium/carbon (0.2 g, palladium content: 5%) was added to the ethyl acetate (10 mL) solution of raw material 41-11 (250.00 mg, 385.37 μmol), and reacted at 20° C. under a hydrogen environment at 15 psi for 2 hours. The reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated by preparative HPLC (column type: Phenomenex Gemini-NX 150*30mm*5μm; mobile phase: [water (10mM NH 4 HCO 3 )-ACN]; B(ACN)%: 5%-45%, 10min). Compound 41 was obtained.
1H NMR(400MHz,CD 3OD)δ＝7.00(d,J＝2.1Hz,1H),6.84-6.75(m,2H),6.73-6.63(m,2H),6.01(s,1H),5.18(dd,J＝2.4,12.2Hz,1H),5.01(d,J＝12.0Hz,1H),4.05(d,J＝10.3Hz,2H),3.28-3.17(m,1H),1.83(s,3H),1.15(dd,J＝6.9,8.5Hz,6H)。 1 H NMR (400MHz, CD 3 OD) δ = 7.00 (d, J = 2.1Hz, 1H), 6.84-6.75 (m, 2H), 6.73-6.63 (m, 2H), 6.01 (s, 1H), 5.18 (dd,J=2.4,12.2Hz,1H),5.01(d,J=12.0Hz,1H),4.05(d,J=10.3Hz,2H),3.28-3.17(m,1H),1.83(s, 3H), 1.15 (dd, J=6.9, 8.5 Hz, 6H).
实施例42、43Examples 42, 43
Figure PCTCN2020139562-appb-000154
Figure PCTCN2020139562-appb-000154
合成路线：synthetic route:
Figure PCTCN2020139562-appb-000155
Figure PCTCN2020139562-appb-000155
步骤1：42-2的合成Step 1: Synthesis of 42-2
向装有原料42-1(2g,10.47mmol)的反应瓶中加入硫酸溶液(10mL，80％)，随后加入异丙醇(1.26g,20.94mmol)，在80℃反应4小时。将反应液倒入冰水中，用乙酸乙酯萃取(50mL×2),合并有机相，再用饱和碳酸氢钠溶液洗(100mL×2),有机相用无水硫酸钠干燥，过滤，减压浓缩得到粗品。粗品用硅胶柱层析法分离(石油醚/乙酸乙酯＝20:1)。得到化合物42-2。[M+1] +＝233.1。 Sulfuric acid solution (10 mL, 80%) was added to the reaction flask containing the raw material 42-1 (2 g, 10.47 mmol), followed by isopropanol (1.26 g, 20.94 mmol), and reacted at 80°C for 4 hours. The reaction solution was poured into ice water, extracted with ethyl acetate (50mL×2), the organic phases were combined, and then washed with saturated sodium bicarbonate solution (100mL×2), the organic phase was dried with anhydrous sodium sulfate, filtered, and reduced pressure Concentrate to obtain crude product. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate=20:1). Compound 42-2 was obtained. [M+1] + = 233.1.
步骤2：42-3的合成Step 2: Synthesis of 42-3
向原料42-2(7.3g,31.32mmol)的四氢呋喃(120mL)溶液中加入碳酸铯(15.31g,46.98mmol)，苄溴(5.36g,31.32mmol)，在70℃反应4小时。将反应液倒入饱和氯化钠溶液中，加入乙酸乙酯分液(100mL)，水相用乙酸乙酯萃取(100mL×3)，合并有机相，无水硫酸钠干燥，过滤，减压浓缩得到粗品。粗品未经进一步纯化，直接投入下一步。得到化合物42-3。Cesium carbonate (15.31 g, 46.98 mmol) and benzyl bromide (5.36 g, 31.32 mmol) were added to a tetrahydrofuran (120 mL) solution of raw material 42-2 (7.3 g, 31.32 mmol), and reacted at 70° C. for 4 hours. The reaction solution was poured into saturated sodium chloride solution, ethyl acetate was added for separation (100 mL), the aqueous phase was extracted with ethyl acetate (100 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure Get crude product. The crude product was directly put into the next step without further purification. Compound 42-3 was obtained.
步骤3：42-4的合成Step 3: Synthesis of 42-4
在-68℃，向原料42-3(2g,6.19mmol)的(60mL)溶液中加入正丁基锂(2.5M,2.60mL)，0.5小时后加入中间体BB-1(1.71g,6.19mmol)的四氢呋喃(60mL)溶液，反应1小时后，自然升温至20℃，反应0.5小时。将反应液倒入饱和氯化铵溶液(100mL)中，加入100mL乙酸乙酯，分液，水相用乙酸乙酯萃取(100 mL×3)，合并有机相，无水硫酸钠干燥，过滤，减压浓缩得到粗品。粗品用硅胶柱层析法分离(石油醚：乙酸乙酯＝20:1)。得到化合物42-4。[Ms-17] +＝503.3。 At -68°C, n-butyllithium (2.5M, 2.60mL) was added to the (60mL) solution of the raw material 42-3 (2g, 6.19mmol), and the intermediate BB-1 (1.71g, 6.19mmol) was added 0.5 hours later ) In tetrahydrofuran (60 mL), after reacting for 1 hour, the temperature was naturally raised to 20° C. and reacted for 0.5 hours. Pour the reaction solution into saturated ammonium chloride solution (100 mL), add 100 mL ethyl acetate, separate the layers, extract the aqueous phase with ethyl acetate (100 mL×3), combine the organic phases, dry with anhydrous sodium sulfate, and filter. Concentrate under reduced pressure to obtain a crude product. The crude product was separated by silica gel column chromatography (petroleum ether: ethyl acetate = 20:1). Compound 42-4 was obtained. [Ms-17] + = 503.3.
步骤4：42-5的合成Step 4: Synthesis of 42-5
在0℃，向原料42-4(1.5g,2.88mmol)的二氯甲烷(50mL)溶液中加入三乙基硅烷(1.00g,8.64mmol)，三氟乙酸(492.65mg,4.32mmol)，在20℃反应2小时。将反应液倒入饱和碳酸氢钠溶液(50mL)中，加入二氯甲烷(50mL)分液，水相用二氯甲烷萃取(50mL×3)，合并有机相，无水硫酸钠干燥，过滤，减压浓缩得到粗品。粗品未经进一步纯化，直接投入下一步。得到化合物42-5。At 0°C, triethylsilane (1.00g, 8.64mmol) and trifluoroacetic acid (492.65mg, 4.32mmol) were added to a solution of raw material 42-4 (1.5g, 2.88mmol) in dichloromethane (50mL). React at 20°C for 2 hours. The reaction solution was poured into saturated sodium bicarbonate solution (50mL), dichloromethane (50mL) was added for separation, the aqueous phase was extracted with dichloromethane (50mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, and filtered. Concentrate under reduced pressure to obtain a crude product. The crude product was directly put into the next step without further purification. Compound 42-5 was obtained.
步骤5：42-6的合成Step 5: Synthesis of 42-6
向原料42-5(1g,1.98mmol)的四氢呋喃(10mL)溶液中加入四丁基氟化铵的四氢呋喃溶液(1M,2.38mL)，在20℃反应1小时。将反应液减压浓缩得到粗品。用硅胶柱层析法分离(石油醚：乙酸乙酯＝5:1)。得到化合物42-6。[Ms+1] +＝389.3。 A tetrahydrofuran solution (1M, 2.38 mL) of tetrabutylammonium fluoride was added to a tetrahydrofuran (10 mL) solution of the raw material 42-5 (1 g, 1.98 mmol), and the reaction was carried out at 20° C. for 1 hour. The reaction solution was concentrated under reduced pressure to obtain a crude product. It was separated by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1). Compound 42-6 was obtained. [Ms+1] + = 389.3.
步骤6：42-7的合成Step 6: Synthesis of 42-7
向原料42-6(0.5g,1.28mmol)的N,N-二甲基甲酰胺(5mL)溶液中加入碳酸铯(625.79mg,1.92mmol)，对甲苯磺酰氧甲基膦酸二乙酯(412.71mg,1.28mmol)，在60℃反应3小时。将反应液倒入饱和氯化钠溶液(30mL)中，加入乙酸乙酯分液(50mL)，水相用乙酸乙酯萃取(50mL×3)，合并有机相，无水硫酸钠干燥，过滤，减压浓缩得到粗品。粗品用硅胶柱层析法分离(石油醚：乙酸乙酯＝1:1)。得到化合物42-7。To the raw material 42-6 (0.5g, 1.28mmol) in N,N-dimethylformamide (5mL) solution was added cesium carbonate (625.79mg, 1.92mmol), diethyl p-toluenesulfonyloxymethylphosphonate (412.71mg, 1.28mmol), react at 60°C for 3 hours. The reaction solution was poured into saturated sodium chloride solution (30 mL), ethyl acetate was added for separation (50 mL), the aqueous phase was extracted with ethyl acetate (50 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, and filtered. Concentrate under reduced pressure to obtain a crude product. The crude product was separated by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1). Compound 42-7 was obtained.
1H NMR(400MHz,DMSO-d 6)δ＝7.44-7.39(m,4H),7.38-7.33(m,1H),6.83(br d,J＝3.9Hz,2H),6.68-6.55(m,2H),4.99(s,2H),4.41-4.37(m,2H),4.34(dd,J＝3.7,8.7Hz,1H),4.16-4.08(m,4H),4.07-3.96(m,1H),3.25-3.14(m,1H),3.00(td,J＝8.1,16.4Hz,1H),2.88-2.75(m,1H),1.96-1.89(m,1H),1.87(s,3H),1.27(t,J＝7.1Hz,6H),1.05(dd,J＝5.0,6.9Hz,6H)。[Ms+1] +＝541.2。 1 H NMR(400MHz,DMSO-d 6 )δ=7.44-7.39(m,4H), 7.38-7.33(m,1H), 6.83(br d,J=3.9Hz,2H), 6.68-6.55(m, 2H), 4.99 (s, 2H), 4.41-4.37 (m, 2H), 4.34 (dd, J = 3.7, 8.7 Hz, 1H), 4.16-4.08 (m, 4H), 4.07-3.96 (m, 1H) ,3.25-3.14(m,1H),3.00(td,J=8.1,16.4Hz,1H),2.88-2.75(m,1H),1.96-1.89(m,1H),1.87(s,3H),1.27 (t, J=7.1 Hz, 6H), 1.05 (dd, J=5.0, 6.9 Hz, 6H). [Ms+1] + = 541.2.
步骤7：42-8的合成Step 7: Synthesis of 42-8
向原料42-7(0.6g,1.11mmol)的乙酸乙酯(20mL)溶液中加入钯/碳(0.3g,钯含量：5％)，氢气环境下，15psi，在20℃反应2小时。将反应液用硅藻土过滤，滤液减压浓缩得到粗品。粗品未进一步纯化，直接投入下一步。得到化合物42-8。[Ms-1] -＝449.2。 Palladium/carbon (0.3 g, palladium content: 5%) was added to the ethyl acetate (20 mL) solution of the raw material 42-7 (0.6 g, 1.11 mmol), and the reaction was carried out at 20° C. under a hydrogen environment at 15 psi for 2 hours. The reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was not further purified and was directly put into the next step. Compound 42-8 was obtained. [Ms-1] - = 449.2.
步骤8：42-9的合成Step 8: Synthesis of 42-9
将原料42-8(0.45g,998.94μmol)进行SFC(柱型:DAICEL CHIRALPAK AD(250mm*30mm,10μm)；流动相:[0.1％NH 3H 2O IPA]:38％-38％,5min)拆分。得到化合物42-9。分析方法：柱型:Chiralpak AD-3,50×4.6mm I.D.,3μm。流动相:A:CO2B:IPA(0.05％IPAm,v/v。梯度:B相1分钟内从5％升至50％，维持1分钟，0.8分钟内降至5％，流速:3.4mL/min。柱温.:35℃。ABPR:1800psi。化合物42-9保留时间：1.258min。 The raw material 42-8 (0.45g, 998.94μmol) was subjected to SFC (column type: DAICEL CHIRALPAK AD (250mm*30mm, 10μm); mobile phase: [0.1%NH 3 H 2 O IPA]: 38%-38%, 5min ) Split. Compound 42-9 was obtained. Analysis method: Column type: Chiralpak AD-3, 50×4.6mm ID, 3μm. Mobile phase: A: CO2B: IPA (0.05% IPAm, v/v. Gradient: Phase B rose from 5% to 50% in 1 minute, maintained for 1 minute, and decreased to 5% in 0.8 minutes, flow rate: 3.4mL/min Column temperature: 35°C. ABPR: 1800 psi. Compound 42-9 retention time: 1.258 min.
步骤9：42的合成Step 9: Synthesis of 42
在0℃，向将原料42-9(50mg,110.99μmol)的二氯甲烷(2mL)溶液中加入三甲基溴硅烷(169.92mg,1.11mmol)，在20℃反应12小时。将反应液减压浓缩得到粗品。用制备HPLC(柱型:Phenomenex luna C18 80*40mm*3μm；流动相:[水(0.04％HCl)-ACN]；B(ACN)％:40％-62％,7min)分离。得到化合物42。Trimethylbromosilane (169.92 mg, 1.11 mmol) was added to a dichloromethane (2 mL) solution of the raw material 42-9 (50 mg, 110.99 μmol) at 0°C, and the reaction was carried out at 20°C for 12 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. Separated by preparative HPLC (column type: Phenomenex luna C18 80*40mm*3μm; mobile phase: [water (0.04%HCl)-ACN]; B(ACN)%: 40%-62%, 7min). Compound 42 was obtained.
1H NMR(400MHz,CD 3OD)δ＝6.79(s,1H),6.65(br d,J＝11.3Hz,2H),6.41(dd,J＝1.8,11.7Hz,1H), 4.26(br dd,J＝3.4,8.6Hz,1H),4.20(d,J＝10.4Hz,2H),3.28-3.21(m,1H),3.06-2.92(m,1H),2.87-2.75(m,1H),2.54(qd,J＝8.6,12.7Hz,1H),1.99-1.89(m,4H),1.15(t,J＝6.6Hz,6H)。[Ms+1] +＝395.2。 1 H NMR (400MHz, CD 3 OD) δ = 6.79 (s, 1H), 6.65 (br d, J = 11.3 Hz, 2H), 6.41 (dd, J = 1.8, 11.7 Hz, 1H), 4.26 (br dd ,J=3.4,8.6Hz,1H), 4.20(d,J=10.4Hz,2H), 3.28-3.21(m,1H),3.06-2.92(m,1H), 2.87-2.75(m,1H), 2.54 (qd, J=8.6, 12.7 Hz, 1H), 1.99-1.89 (m, 4H), 1.15 (t, J=6.6 Hz, 6H). [Ms+1] + =395.2.
步骤10：43的合成Step 10: Synthesis of 43
向原料42(0.11g,278.92μmol)的N,N-二甲基甲酰胺(4mL)溶液中加入吡啶(0.4mL)，二环己基碳二亚胺(172.65mg,836.77μmol)，BB-2(57.26mg,306.82μmol)，在50℃反应16小时。反应液中加入乙酸乙酯(200mL)，10％柠檬酸(100mL×2)洗，半饱和氯化钠溶液(100mL×2)洗，有机相经无水硫酸钠干燥后，过滤，减压浓缩。粗品用硅胶柱层析法分离(石油醚:乙酸乙酯＝1:1至0:1)，得到无色油状目标化合物粗品，经制备HPLC分离(柱型:Waters Xbridge BEH C18 100*30mm*10μm；流动相:[水(10mM NH 4HCO 3)-ACN]；B(ACN)％:50％-80％,8min)分离。得到化合物43。 Pyridine (0.4mL), dicyclohexylcarbodiimide (172.65mg, 836.77μmol), BB-2 were added to the raw material 42 (0.11g,278.92μmol) in N,N-dimethylformamide (4mL) solution (57.26mg, 306.82μmol), reacted at 50°C for 16 hours. Add ethyl acetate (200mL) to the reaction solution, wash with 10% citric acid (100mL×2), wash with half-saturated sodium chloride solution (100mL×2), dry the organic phase over anhydrous sodium sulfate, filter, and concentrate under reduced pressure . The crude product was separated by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1 to 0:1) to obtain a colorless oily crude product of the target compound, which was separated by preparative HPLC (column type: Waters Xbridge BEH C18 100*30mm*10μm ; Mobile phase: [water (10mM NH 4 HCO 3 )-ACN]; B(ACN)%: 50%-80%, 8min) separation. Compound 43 was obtained.
1H NMR(400MHz,CDCl 3):δ＝7.39(s,1H),7.28-7.36(m,2H),7.20-7.25(m,1H),6.95(s,1H),6.80(br d,J＝9.7Hz,2H),6.63(s,2H),5.65(br d,J＝11.3Hz,1H),4.65-4.78(m,1H),4.38-4.57(m,4H),3.06-3.21(m,2H),2.88(ddd,J＝16.3,8.9,3.2Hz,1H),2.56-2.63(m,1H),2.38-2.50(m,1H),2.11-2.18(m,1H),2.06(td,J＝8.5,4.1Hz,1H),1.99(s,3H),1.20-1.25ppm(m,6H)。 1 H NMR (400MHz, CDCl 3 ): δ = 7.39 (s, 1H), 7.28-7.36 (m, 2H), 7.20-7.25 (m, 1H), 6.95 (s, 1H), 6.80 (br d, J =9.7Hz,2H),6.63(s,2H),5.65(br d,J=11.3Hz,1H),4.65-4.78(m,1H),4.38-4.57(m,4H),3.06-3.21(m ,2H), 2.88(ddd,J=16.3,8.9,3.2Hz,1H),2.56-2.63(m,1H),2.38-2.50(m,1H),2.11-2.18(m,1H),2.06(td , J=8.5, 4.1 Hz, 1H), 1.99 (s, 3H), 1.20-1.25 ppm (m, 6H).
实施例44Example 44
Figure PCTCN2020139562-appb-000156
Figure PCTCN2020139562-appb-000156
合成路线：synthetic route:
Figure PCTCN2020139562-appb-000157
Figure PCTCN2020139562-appb-000157
步骤1：44的合成Step 1: Synthesis of 44
将化合物14(90.47mg,231.72μmol)溶解于二甲基甲酰胺(5mL)和吡啶(0.5mL)中，加入二环己基碳二亚胺(143.43mg,695.17μmol)，BB-2(43.25mg,231.72μmol)，反应在70℃继续搅拌16小时。反应液中加入乙酸乙酯(50mL)，10％柠檬酸(25mL×2)洗，半饱和氯化钠溶液(25mL×2)洗，乙酸乙酯层经无水硫酸钠干燥后，过滤，减压浓缩。粗品经硅胶柱层析纯化(石油醚:乙酸乙酯＝1:1，洗脱其它杂质，石油醚:乙酸乙酯＝3:7，得到化合物44粗品)，粗品经制备HPLC(柱型:Waters Xbridge BEH C18 100*30mm*10μm；流动相:[H 2O(10mM NH 4HCO 3)-ACN]；B(ACN)％:50％-80％,10min)纯化。得到化合物44。 Compound 14 (90.47mg, 231.72μmol) was dissolved in dimethylformamide (5mL) and pyridine (0.5mL), and dicyclohexylcarbodiimide (143.43mg, 695.17μmol), BB-2 (43.25mg) were added ,231.72μmol), the reaction was stirred at 70°C for 16 hours. Add ethyl acetate (50mL) to the reaction solution, wash with 10% citric acid (25mL×2), and wash with half-saturated sodium chloride solution (25mL×2). After the ethyl acetate layer is dried over anhydrous sodium sulfate, it is filtered and reduced. Pressure concentration. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1, other impurities were eluted, petroleum ether: ethyl acetate = 3:7 to obtain the crude product of compound 44), and the crude product was subjected to preparative HPLC (column type: Waters Xbridge BEH C18 100*30mm*10μm; mobile phase: [H 2 O(10mM NH 4 HCO 3 )-ACN]; B(ACN)%: 50%-80%, 10min) purification. Compound 44 was obtained.
1H NMR(400MHz,CDCl 3)δ＝7.43(s,1H),7.35-7.29(m,2H),7.26-7.22(m,1H),6.88(d,J＝1.6Hz,1H),6.61(s,2H),6.58(d,J＝8.1Hz,1H),6.52-6.47(m,1H),5.68-5.61(m,1H),4.76(s,1H),4.73-4.65(m, 1H),4.56-4.46(m,1H),4.43(d,J＝9.4Hz,2H),4.14-4.08(m,1H),3.21-3.11(m,1H),2.88-2.74(m,2H),2.56-2.42(m,1H),2.17-2.10(m,1H),2.09-1.99(m,1H),1.95(br s,1H),1.92(s,3H),1.66(br d,J＝3.0Hz,2H),1.21(dd,J＝6.9,11.4Hz,6H)。 1 H NMR (400MHz, CDCl 3 ) δ = 7.43 (s, 1H), 7.35-7.29 (m, 2H), 7.26-7.22 (m, 1H), 6.88 (d, J = 1.6 Hz, 1H), 6.61 ( s,2H),6.58(d,J=8.1Hz,1H),6.52-6.47(m,1H),5.68-5.61(m,1H),4.76(s,1H),4.73-4.65(m,1H) ,4.56-4.46(m,1H),4.43(d,J=9.4Hz,2H),4.14-4.08(m,1H),3.21-3.11(m,1H),2.88-2.74(m,2H),2.56 -2.42(m,1H),2.17-2.10(m,1H),2.09-1.99(m,1H),1.95(br s,1H),1.92(s,3H),1.66(br d,J=3.0Hz , 2H), 1.21 (dd, J=6.9, 11.4 Hz, 6H).
实施例45Example 45
Figure PCTCN2020139562-appb-000158
Figure PCTCN2020139562-appb-000158
合成路线：synthetic route:
Figure PCTCN2020139562-appb-000159
Figure PCTCN2020139562-appb-000159
步骤1：45的合成Step 1: Synthesis of 45
将化合物28(80mg,205.98μmol)溶解于N,N-二甲基甲酰胺(4mL)和吡啶(0.4mL)中，加入二环己基碳二亚胺(212.50mg,1.03mmol)，BB-2(38.44mg,205.98μmol)，反应在70℃继续搅拌16小时。反应液中加入乙酸乙酯(50mL)，10％柠檬酸(25mL×2)洗，半饱和氯化钠溶液(25mL×2)洗，乙酸乙酯层经无水硫酸钠干燥后，过滤，减压浓缩。粗品经硅胶柱层析纯化(石油醚:乙酸乙酯＝1:1，洗脱其它杂质，石油醚:乙酸乙酯＝3:7)，得到化合物45粗品，粗品经制备HPLC(柱型:Waters Xbridge BEH C18 100*30mm*10μm；流动相:[H 2O(10mM NH 4HCO 3)-ACN]；B(ACN)％:50％-80％,10min)纯化。得到化合物45。 Compound 28 (80mg, 205.98μmol) was dissolved in N,N-dimethylformamide (4mL) and pyridine (0.4mL), and dicyclohexylcarbodiimide (212.50mg, 1.03mmol) was added, BB-2 (38.44mg, 205.98μmol), the reaction was stirred at 70°C for 16 hours. Add ethyl acetate (50mL) to the reaction solution, wash with 10% citric acid (25mL×2), and wash with half-saturated sodium chloride solution (25mL×2). After the ethyl acetate layer is dried over anhydrous sodium sulfate, it is filtered and reduced. Pressure concentration. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1, other impurities were eluted, petroleum ether: ethyl acetate = 3:7) to obtain the crude product of compound 45, which was subjected to preparative HPLC (column type: Waters Xbridge BEH C18 100*30mm*10μm; mobile phase: [H 2 O(10mM NH 4 HCO 3 )-ACN]; B(ACN)%: 50%-80%, 10min) purification. Compound 45 was obtained.
1H NMR(400MHz,CDCl 3)δ＝7.45-7.41(m,1H),7.35-7.28(m,2H),7.26-7.23(m,1H),6.93(s,1H),6.74(s,3H),6.61-6.57(m,1H),5.67-5.61(m,1H),5.53-5.44(m,1H),4.75-4.65(m,1H),4.56-4.46(m,1H),4.44(d,J＝9.6Hz,2H),4.27(dd,J＝3.8,8.6Hz,1H),3.09-2.97(m,1H),2.89-2.78(m,1H),2.62-2.43(m,2H),2.14(br dd,J＝2.3,14.8Hz,1H),2.03-1.95(m,1H),1.92(s,3H),1.31(s,3H),0.75(s,4H)。 1 H NMR(400MHz,CDCl 3 )δ=7.45-7.41(m,1H),7.35-7.28(m,2H),7.26-7.23(m,1H),6.93(s,1H),6.74(s,3H) ),6.61-6.57(m,1H),5.67-5.61(m,1H),5.53-5.44(m,1H),4.75-4.65(m,1H),4.56-4.46(m,1H),4.44(d ,J=9.6Hz,2H), 4.27(dd,J=3.8,8.6Hz,1H), 3.09-2.97(m,1H), 2.89-2.78(m,1H), 2.62-2.43(m,2H), 2.14 (br dd, J=2.3, 14.8 Hz, 1H), 2.03-1.95 (m, 1H), 1.92 (s, 3H), 1.31 (s, 3H), 0.75 (s, 4H).
实施例46Example 46
Figure PCTCN2020139562-appb-000160
Figure PCTCN2020139562-appb-000160
合成路线：synthetic route:
Figure PCTCN2020139562-appb-000161
Figure PCTCN2020139562-appb-000161
步骤1：46-1的合成Step 1: Synthesis of 46-1
将39-1(1g,2.06mmol)溶于四氢呋喃(10mL)，置换氮气3次，在20℃，缓慢滴加二异丙基胺基锂(2M,4.13mL)，反应0.5h；随后缓慢滴加碘甲烷(1.46g,10.31mmol)的四氢呋喃(0.5mL)溶液，继续反应15.5h，在氮气保护下，缓慢滴加氯化铵饱和溶液(50mL)淬灭反应，加入乙酸乙酯(50mL)萃取分得有机相，无水硫酸钠干燥旋干，得到化合物46-1。Dissolve 39-1 (1g, 2.06mmol) in tetrahydrofuran (10mL), replace nitrogen for 3 times, slowly add lithium diisopropylamide (2M, 4.13mL) dropwise at 20°C, and react for 0.5h; then dropwise slowly Add methyl iodide (1.46g, 10.31mmol) in tetrahydrofuran (0.5mL), continue the reaction for 15.5h, under the protection of nitrogen, slowly add dropwise saturated ammonium chloride solution (50mL) to quench the reaction, add ethyl acetate (50mL) The organic phase was separated by extraction, dried over anhydrous sodium sulfate and spin-dried to obtain compound 46-1.
[Ms+1] +＝513.3 [Ms+1] + = 513.3
步骤2：46-2的合成Step 2: Synthesis of 46-2
将46-1(500mg,975.05μmol)溶于甲醇(10mL)，开启搅拌，加入氟化铵(361.13mg,9.75mmol)，升温至50℃，反应2h，向反应体系加入二氯甲烷(20mL)和水(20mL)萃取，分得有机相，无水硫酸钠干燥旋干，经硅胶柱层析(石油醚:乙酸乙酯＝10:1～5:1)纯化得到化合物粗品，经手性分离：柱型:DAICEL CHIRALPAK AD(250mm*30mm,10μm)；流动相:[0.1％NH 3H 2O EtOH]:33％-33％,11min得到化合物46-2，经HNMR确定化合物结构。手性分离的分析方法：柱型:Chiralpak AD-3,50×4.6mm I.D.,3μm。流动相:A:CO 2B:EtOH(0.05％IPAm,v/v)。梯度:B相1.2分钟内从5％升至50％，维持1分钟，0.8分钟内降至5％。流速:3.4mL/min。柱温:35℃。ABPR:1800psi。化合物46-2保留时间：1.249min。 Dissolve 46-1 (500mg, 975.05μmol) in methanol (10mL), turn on the stirring, add ammonium fluoride (361.13mg, 9.75mmol), heat to 50℃, react for 2h, add dichloromethane (20mL) to the reaction system Extract with water (20 mL), separate the organic phase, dry with anhydrous sodium sulfate and spin dry, and purify by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1～5:1) to obtain the crude compound, which is separated by chiral: Column type: DAICEL CHIRALPAK AD (250mm*30mm, 10μm); mobile phase: [0.1% NH 3 H 2 O EtOH]: 33%-33%, 11min to obtain compound 46-2, the structure of the compound was confirmed by HNMR. Chiral separation analysis method: Column type: Chiralpak AD-3, 50×4.6mm ID, 3μm. Mobile phase: A: CO 2 B: EtOH (0.05% IPAm, v/v). Gradient: Phase B increased from 5% to 50% in 1.2 minutes, maintained for 1 minute, and decreased to 5% in 0.8 minutes. Flow rate: 3.4mL/min. Column temperature: 35°C. ABPR: 1800psi. Compound 46-2 retention time: 1.249min.
1H NMR(400MHz,CDCl 3)δ＝7.42-7.24(m,5H),7.14(d,J＝2.2Hz,1H),7.05(dd,J＝2.1,8.2Hz,1H),6.83(d,J＝8.3Hz,1H),6.65(d,J＝2.3Hz,1H),6.38(d,J＝2.0Hz,1H),5.96(s,1H),5.06-5.01(m,2H),4.58(br s,1H),3.38(spt,J＝7.0Hz,1H),1.93-1.87(m,3H),1.27(s,6H),1.18(s,3H),1.16(s,3H)。 1 H NMR(400MHz, CDCl 3 )δ=7.42-7.24(m,5H), 7.14(d,J=2.2Hz,1H), 7.05(dd,J=2.1,8.2Hz,1H), 6.83(d, J = 8.3Hz, 1H), 6.65 (d, J = 2.3Hz, 1H), 6.38 (d, J = 2.0Hz, 1H), 5.96 (s, 1H), 5.06-5.01 (m, 2H), 4.58 ( br s, 1H), 3.38 (spt, J=7.0 Hz, 1H), 1.93-1.87 (m, 3H), 1.27 (s, 6H), 1.18 (s, 3H), 1.16 (s, 3H).
步骤3：46-3的合成Step 3: Synthesis of 46-3
将46-2(160mg,401.47μmol)溶于N,N-二甲基甲酰胺(0.6mL)，开启搅拌，加入碳酸铯(261.61mg,802.94μmol)和对甲苯磺酰氧甲基膦酸二乙酯(129.40mg,401.47μmol)，升温至50℃，反应3h，加入二氯甲烷(10mL)和水(10mL)萃取，分得有机相，无水硫酸钠干燥，旋干得到化合物粗品，经硅胶柱层析(石油醚:乙酸乙酯＝10:1至3:1)纯化得到化合物46-3。Dissolve 46-2 (160mg, 401.47μmol) in N,N-dimethylformamide (0.6mL), turn on the stirring, add cesium carbonate (261.61mg, 802.94μmol) and p-toluenesulfonyloxymethylphosphonic acid two Ethyl ester (129.40mg, 401.47μmol), heated to 50℃, reacted for 3h, added dichloromethane (10mL) and water (10mL) for extraction, separated the organic phase, dried over anhydrous sodium sulfate, and spin-dried to obtain the crude compound. Silica gel column chromatography (petroleum ether: ethyl acetate = 10:1 to 3:1) was purified to obtain compound 46-3.
1H NMR(400MHz,CDCl 3)δ＝7.53-7.32(m,5H),7.21(d,J＝2.0Hz,1H),7.12(dd,J＝2.1,8.3Hz,1H),6.92(d,J＝8.3Hz,1H),6.86(d,J＝2.1Hz,1H),6.59(d,J＝2.0Hz,1H),6.08(s,1H),5.13(s,2H),4.37-4.23(m,6H), 3.46(spt,J＝6.8Hz,1H),2.00(s,3H),1.39(t,J＝7.1Hz,6H),1.35(s,6H),1.25(d,J＝7.0Hz,6H)。 1 H NMR(400MHz, CDCl 3 )δ=7.53-7.32(m,5H), 7.21(d,J=2.0Hz,1H), 7.12(dd,J=2.1,8.3Hz,1H), 6.92(d, J = 8.3 Hz, 1H), 6.86 (d, J = 2.1 Hz, 1H), 6.59 (d, J = 2.0 Hz, 1H), 6.08 (s, 1H), 5.13 (s, 2H), 4.37-4.23 ( m,6H), 3.46(spt,J=6.8Hz,1H),2.00(s,3H),1.39(t,J=7.1Hz,6H),1.35(s,6H),1.25(d,J=7.0 Hz, 6H).
31P NMR(400MHz,CDCl 3)δppm 19.669 31 P NMR (400MHz, CDCl 3 ) δppm 19.669
步骤4：46-4的合成Step 4: Synthesis of 46-4
向46-3(20mg,36.45μmol)的乙酸乙酯(0.8mL)溶液中加入Pd/C(20mg,5％钯含量)，开启搅拌，在氢气球氛围下15psi，在25℃反应1.5h，反应体系通过硅藻土过滤，滤液旋干得到化合物46-4。Add Pd/C (20mg, 5% palladium content) to 46-3 (20mg, 36.45μmol) ethyl acetate (0.8mL) solution, turn on stirring, and react at 25℃ for 1.5h under a hydrogen balloon atmosphere at 15psi, The reaction system was filtered through celite, and the filtrate was spin-dried to obtain compound 46-4.
1H NMR(400MHz,CDCl 3)δ＝6.93(d,J＝1.9Hz,1H),6.79-6.63(m,3H),6.57(d,J＝2.1Hz,1H),4.34-4.22(m,7H),3.19(spt,J＝6.9Hz,1H),2.45(dd,J＝8.5,12.8Hz,1H),1.89(dd,J＝6.9,12.8Hz,1H),1.80(s,3H),1.38(t,J＝7.1Hz,6H),1.27(s,3H),1.23-1.18(m,9H)。 1 H NMR (400MHz, CDCl 3 ) δ = 6.93 (d, J = 1.9 Hz, 1H), 6.79-6.63 (m, 3H), 6.57 (d, J = 2.1 Hz, 1H), 4.34 to 4.22 (m, 7H), 3.19 (spt, J = 6.9 Hz, 1H), 2.45 (dd, J = 8.5, 12.8 Hz, 1H), 1.89 (dd, J = 6.9, 12.8 Hz, 1H), 1.80 (s, 3H), 1.38 (t, J = 7.1 Hz, 6H), 1.27 (s, 3H), 1.23-1.18 (m, 9H).
31P NMR(400MHz,CDCl 3)δppm 19.874。 31 P NMR (400 MHz, CDCl 3 ) δ ppm 19.874.
步骤5：46-5的合成Step 5: Synthesis of 46-5
此步骤用于中间体46-4拆分，经手性分离(柱型:DAICEL CHIRALPAK AD(250mm*30mm,10μm)；流动相:[Neu-IPA]:30％-30％,10min)得到化合物46-5，经HNMR和PNMR确定化合物结构。分析方法：柱型:Chiralpak AD-3,50×4.6mm,I.D.,3μm。流动相:A:CO 2,B:IPA(0.05％D乙酸乙酯)。梯度:B相1.2分钟内从5％升至50％，维持1分钟，0.8分钟内降至5％。流速:3.4mL/min。柱温:35℃。ABPR:1800psi。化合物46-5保留时间：1.149min。 This step is used for the resolution of intermediate 46-4 and chiral separation (column type: DAICEL CHIRALPAK AD (250mm*30mm, 10μm); mobile phase: [Neu-IPA]: 30%-30%, 10min) to obtain compound 46 -5, confirm the structure of the compound by HNMR and PNMR. Analysis method: Column type: Chiralpak AD-3, 50×4.6mm, ID, 3μm. Mobile phase: A: CO 2 , B: IPA (0.05% D ethyl acetate). Gradient: Phase B increased from 5% to 50% in 1.2 minutes, maintained for 1 minute, and decreased to 5% in 0.8 minutes. Flow rate: 3.4mL/min. Column temperature: 35°C. ABPR: 1800psi. Compound 46-5 retention time: 1.149min.
1H NMR(400MHz,CDCl 3)δ＝6.93(d,J＝1.8Hz,1H),6.74-6.66(m,2H),6.64(d,J＝2.3Hz,1H),6.57(d,J＝2.0Hz,1H),4.35-4.18(m,7H),3.21(spt,J＝6.9Hz,1H),2.45(dd,J＝8.5,12.8Hz,1H),1.89(dd,J＝6.9,12.8Hz,1H),1.81(s,3H),1.38(t,J＝7.0Hz,6H),1.27(s,3H),1.24-1.17(m,9H)。 1 H NMR (400MHz, CDCl 3 ) δ = 6.93 (d, J = 1.8 Hz, 1H), 6.74-6.66 (m, 2H), 6.64 (d, J = 2.3 Hz, 1H), 6.57 (d, J = 2.0Hz, 1H), 4.35 to 4.18 (m, 7H), 3.21 (spt, J = 6.9 Hz, 1H), 2.45 (dd, J = 8.5, 12.8 Hz, 1H), 1.89 (dd, J = 6.9, 12.8 Hz, 1H), 1.81 (s, 3H), 1.38 (t, J = 7.0 Hz, 6H), 1.27 (s, 3H), 1.24-1.17 (m, 9H).
31P NMR(400MHz,CDCl 3)δppm 19.870。 31 P NMR (400MHz, CDCl 3 ) δ ppm 19.870.
步骤8：46的合成Step 8: Synthesis of 46
将46-5(25.00mg,54.28μmol)溶于二氯甲烷(0.5mL)，开启搅拌，加入三甲基溴硅烷(83.10mg,542.84μmol,70.43μL)，在25℃温度反应16h，反应体系旋干，再加入无水二氯甲烷(2mL×2)旋干两次，得到化合物粗品，溶于乙腈(30mL)和水(30mL)，得到化合物46。Dissolve 46-5 (25.00mg, 54.28μmol) in dichloromethane (0.5mL), turn on the stirring, add bromotrimethylsilane (83.10mg, 542.84μmol, 70.43μL), react at 25℃ for 16h, the reaction system Rotate to dryness, add anhydrous dichloromethane (2 mL×2) and spin dry twice to obtain the crude compound, which is dissolved in acetonitrile (30 mL) and water (30 mL) to obtain compound 46.
1H NMR(400MHz,CD 3OD)δ＝6.83(s,1H),6.73-6.54(m,4H),4.25(br t,J＝7.5Hz,1H),4.20(br d,J＝10.4Hz,2H),3.26-3.18(m,1H),2.42(dd,J＝8.5,12.8Hz,1H),1.84(br dd,J＝6.6,12.8Hz,1H),1.79(s,3H),1.27(s,3H),1.21(s,3H),1.13(dd,J＝1.9,6.8Hz,6H)。 1 H NMR (400MHz, CD 3 OD) δ = 6.83 (s, 1H), 6.73-6.54 (m, 4H), 4.25 (br t, J = 7.5 Hz, 1H), 4.20 (br d, J = 10.4 Hz ,2H),3.26-3.18(m,1H),2.42(dd,J=8.5,12.8Hz,1H),1.84(br dd,J=6.6,12.8Hz,1H),1.79(s,3H),1.27 (s, 3H), 1.21 (s, 3H), 1.13 (dd, J=1.9, 6.8 Hz, 6H).
31P NMR(400MHz,CD 3OD)δppm 18.000。 31 P NMR (400MHz, CD 3 OD) δ ppm 18.000.
实施例47Example 47
Figure PCTCN2020139562-appb-000162
Figure PCTCN2020139562-appb-000162
合成路线：synthetic route:
Figure PCTCN2020139562-appb-000163
Figure PCTCN2020139562-appb-000163
步骤1：47-1的合成Step 1: Synthesis of 47-1
将39-1(1.7g,3.51mmol)溶于四氢呋喃(8mL)，置换氮气3次，降温至-70℃，缓慢滴加二异丙基氨基锂(2M,5.26mL)，反应1h，随后缓慢滴加1,2-二溴乙烷(3.29g,17.54mmol,1.32mL)的四氢呋喃(0.7mL)溶液，继续反应2h，在氮气保护下，缓慢滴加氯化铵饱和溶液(10mL)淬灭反应，加入乙酸乙酯(10mL)萃取分得有机相，无水硫酸钠干燥，旋干得到化合物粗品；经硅胶柱层析(石油醚:乙酸乙酯＝1:0)纯化得到化合物47-1。Dissolve 39-1 (1.7g, 3.51mmol) in tetrahydrofuran (8mL), replace nitrogen 3 times, cool to -70℃, slowly add lithium diisopropylamide (2M, 5.26mL) dropwise, react for 1h, then slowly Add dropwise 1,2-dibromoethane (3.29g, 17.54mmol, 1.32mL) in tetrahydrofuran (0.7mL) solution, continue the reaction for 2h, under the protection of nitrogen, slowly dropwise add saturated ammonium chloride solution (10mL) to quench After the reaction, ethyl acetate (10 mL) was added to extract the organic phase, which was dried over anhydrous sodium sulfate and spin-dried to obtain a crude compound; purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:0) to obtain compound 47-1 .
1H NMR(400MHz,CDCl 3)δ＝7.53-7.32(m,5H),7.29(d,J＝2.1Hz,1H),7.18(dd,J＝2.1,8.2Hz,1H),6.93(d,J＝8.3Hz,1H),6.50(d,J＝2.0Hz,1H),6.32(d,J＝2.0Hz,1H),5.93(s,1H),5.13(s,2H),3.47(spt,J＝6.9Hz,1H),2.03(s,3H),1.69-1.64(m,2H),1.54-1.51(m,2H),1.25(d,J＝6.9Hz,6H),1.00(s,8H),0.24-0.18(m,6H)。 1 H NMR(400MHz, CDCl 3 )δ=7.53-7.32(m,5H), 7.29(d,J=2.1Hz,1H), 7.18(dd,J=2.1,8.2Hz,1H), 6.93(d, J = 8.3Hz, 1H), 6.50 (d, J = 2.0Hz, 1H), 6.32 (d, J = 2.0Hz, 1H), 5.93 (s, 1H), 5.13 (s, 2H), 3.47 (spt, J=6.9Hz,1H),2.03(s,3H),1.69-1.64(m,2H),1.54-1.51(m,2H),1.25(d,J=6.9Hz,6H),1.00(s,8H) ), 0.24-0.18 (m, 6H).
步骤2：47-2的合成Step 2: Synthesis of 47-2
47-1(1g,1.96mmol)溶于甲醇(9mL)溶液，开启搅拌，加入氟化铵(725.10mg,19.58mmol)，升温至50℃，反应2h，加入水(100mL)和二氯甲烷(100mL×2)萃取，分得有机相，无水硫酸钠干燥，旋干得到化合物粗品，经硅胶柱层析(石油醚:乙酸乙酯＝1:0至10:1)纯化得到化合物47-2。47-1 (1g, 1.96mmol) was dissolved in methanol (9mL) solution, stirring was turned on, ammonium fluoride (725.10mg, 19.58mmol) was added, the temperature was raised to 50℃, and the reaction was carried out for 2h. Water (100mL) and dichloromethane ( 100mL×2) extraction, the organic phase was separated, dried over anhydrous sodium sulfate, and spin-dried to obtain the crude compound, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate=1:0 to 10:1) to obtain compound 47-2 .
1H NMR(400MHz,CDCl 3)δ＝7.51-7.34(m,5H),7.28(d,J＝2.1Hz,1H),7.22-7.13(m,1H),6.93(d,J＝8.3Hz,1H),6.49(d,J＝1.9Hz,1H),6.36(d,J＝2.1Hz,1H),5.92(s,1H),5.13(s,2H),4.87(s,1H),3.47(spt,J＝6.9Hz,1H),2.04(s,3H),1.73-1.65(m,2H),1.57-1.50(m,2H),1.26(s,3H),1.24(s,3H)。 1 H NMR(400MHz, CDCl 3 )δ=7.51-7.34(m,5H), 7.28(d,J=2.1Hz,1H), 7.22-7.13(m,1H), 6.93(d,J=8.3Hz, 1H), 6.49 (d, J = 1.9 Hz, 1H), 6.36 (d, J = 2.1 Hz, 1H), 5.92 (s, 1H), 5.13 (s, 2H), 4.87 (s, 1H), 3.47 ( spt, J=6.9 Hz, 1H), 2.04 (s, 3H), 1.73-1.65 (m, 2H), 1.57-1.50 (m, 2H), 1.26 (s, 3H), 1.24 (s, 3H).
步骤3：47-3的合成Step 3: Synthesis of 47-3
将47-2(0.7g,1.77mmol)溶于N,N-二甲基甲酰胺(7mL)，开启搅拌；加入碳酸铯(1.15g,3.53mmol)和对甲苯磺酰氧甲基膦酸二乙酯(540.54mg,1.68mmol,432.43μL)，升温至50℃，反应3h，向反应体系加入乙酸乙酯(100mL)和水(50mL×2)萃取，合并有机相，旋干得到化合物粗品，经硅胶柱层析(石油醚:乙酸乙酯＝10:1至3:1)纯化得到化合物47-3。Dissolve 47-2 (0.7g, 1.77mmol) in N,N-dimethylformamide (7mL), turn on the stirring; add cesium carbonate (1.15g, 3.53mmol) and p-toluenesulfonyloxymethylphosphonic acid two Ethyl acetate (540.54mg, 1.68mmol, 432.43μL), heated to 50°C, reacted for 3h, added ethyl acetate (100mL) and water (50mL×2) to the reaction system for extraction, combined the organic phases, and spin-dried to obtain the crude compound. Purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1 to 3:1) to obtain compound 47-3.
1H NMR(400MHz,CDCl 3)δ＝7.58-7.31(m,5H),7.16(dd,J＝2.1,8.3Hz,1H),6.93(d,J＝8.3Hz,1H),6.63(d,J＝2.0Hz,1H),6.47(d,J＝2.3Hz,1H),5.96(s,1H),5.13(s,2H),4.36-4.20(m,6H),3.56-3.36(m,1H),2.11-2.03(m,3H),1.75-1.66(m,2H),1.57-1.52(m,2H),1.38(t,J＝7.1Hz,6H),1.25(d,J＝6.9Hz,6H)。 1 H NMR (400MHz, CDCl 3 ) δ = 7.58-7.31 (m, 5H), 7.16 (dd, J = 2.1, 8.3 Hz, 1H), 6.93 (d, J = 8.3 Hz, 1H), 6.63 (d, J=2.0Hz,1H),6.47(d,J=2.3Hz,1H),5.96(s,1H),5.13(s,2H),4.36-4.20(m,6H),3.56-3.36(m,1H) ),2.11-2.03(m,3H),1.75-1.66(m,2H),1.57-1.52(m,2H),1.38(t,J=7.1Hz,6H),1.25(d,J=6.9Hz, 6H).
步骤4：47-4的合成Step 4: Synthesis of 47-4
将47-3(200mg,365.88μmol)加入Pd/C(60mg,5％钯含量)的乙酸乙酯(6mL)溶液，开启搅拌，在氢气球氛围下15psi，在25℃反应1.5h，反应体系通过硅藻土过滤，滤液旋干得到化合物粗品，粗品经制备液相(柱型:Waters Xbridge BEH C18 100*25mm*5μm；流动相:[H 2O(10mM NH 4HCO 3)-ACN]；B(ACN)％:50％-80％,10min)纯化得到化合物47-4，经HNMR和PNMR确定化合物结构。 Add 47-3 (200mg, 365.88μmol) to a solution of Pd/C (60mg, 5% palladium content) in ethyl acetate (6mL), turn on the stirring, and react at 25℃ for 1.5h under a hydrogen balloon atmosphere at 15psi. The reaction system Filter through diatomaceous earth and spin-dry the filtrate to obtain the crude compound. The crude product is prepared as a liquid phase (column type: Waters Xbridge BEH C18 100*25mm*5μm; mobile phase: [H 2 O(10mM NH 4 HCO 3 )-ACN]; B(ACN)%: 50%-80%, 10min) was purified to obtain compound 47-4. The structure of the compound was confirmed by HNMR and PNMR.
1H NMR(400MHz,CD 3OD)δ＝6.75(d,J＝2.3Hz,1H),6.69(d,J＝2.0Hz,1H),6.51-6.41(m,3H),6.04(d,J＝1.8Hz,1H),4.27(d,J＝2.0Hz,1H),4.13(d,J＝10.4Hz,2H),3.09(td,J＝6.8,13.8Hz,1H),2.53-2.36(m,2H),1.86(s,3H),1.16(t,J＝7.4Hz,3H),1.01(dd,J＝6.0,6.8Hz,7H),0.00(s,1H)。 1 H NMR (400MHz, CD 3 OD) δ = 6.75 (d, J = 2.3 Hz, 1H), 6.69 (d, J = 2.0 Hz, 1H), 6.51-6.41 (m, 3H), 6.04 (d, J ＝1.8Hz,1H), 4.27(d,J＝2.0Hz,1H), 4.13(d,J＝10.4Hz,2H), 3.09(td,J＝6.8,13.8Hz,1H),2.53-2.36(m , 2H), 1.86 (s, 3H), 1.16 (t, J = 7.4 Hz, 3H), 1.01 (dd, J = 6.0, 6.8 Hz, 7H), 0.00 (s, 1H).
31P NMR(400MHz,CD 3OD)δppm 18.094 31 P NMR (400MHz, CD 3 OD) δppm 18.094
步骤5：47-5的合成Step 5: Synthesis of 47-5
此步骤用于中间体47-4拆分，经手性分离(柱型:DAICEL CHIRALPAK AD(250mm*30mm,10μm)；流动相:[0.1％NH 3.H 2O IPA]:20％-20％,10min)拆分得到化合物47-5，经HNMR和PNMR确定化合物结构。分析方法：柱型:Chiralpak AD-3,50×4.6mm,I.D.,3μm。流动相:A:CO 2B:IPA(0.05％IPAm,v/v)。梯度:B相1.2分钟内从5％升至50％，维持1分钟，0.8分钟内降至5％。流速:3.4mL/min。柱温:35℃。ABPR:1800psi。化合物47-5保留时间：1.230min。 This step is used for the resolution of intermediate 47-4, through chiral separation (column type: DAICEL CHIRALPAK AD (250mm*30mm, 10μm); mobile phase: [0.1%NH 3 .H 2 O IPA]: 20%-20% , 10min) resolution to obtain compound 47-5, the structure of the compound was confirmed by HNMR and PNMR. Analysis method: Column type: Chiralpak AD-3, 50×4.6mm, ID, 3μm. Mobile phase: A: CO 2 B: IPA (0.05% IPAm, v/v). Gradient: Phase B increased from 5% to 50% in 1.2 minutes, maintained for 1 minute, and decreased to 5% in 0.8 minutes. Flow rate: 3.4mL/min. Column temperature: 35°C. ABPR: 1800psi. Compound 47-5 retention time: 1.230min.
1H NMR(400MHz,CDCl 3)δ＝7.00(d,J＝2.1Hz,1H),6.76(dd,J＝2.1,8.2Hz,1H),6.66(d,J＝8.0Hz,1H),6.50(d,J＝1.9Hz,1H),6.16(d,J＝2.3Hz,1H),4.31(dd,J＝3.5,9.1Hz,1H),4.28-4.19(m,6H),3.20(spt,J＝6.9Hz,1H),2.76(dd,J＝9.2,12.8Hz,1H),1.96-1.87(m,4H),1.37(t,J＝7.1Hz,6H),1.21(dd,J＝6.9,9.9Hz,6H),1.03-0.86(m,4H)。 1 H NMR (400MHz, CDCl 3 )δ = 7.00 (d, J = 2.1 Hz, 1H), 6.76 (dd, J = 2.1, 8.2 Hz, 1H), 6.66 (d, J = 8.0 Hz, 1H), 6.50 (d,J=1.9Hz,1H), 6.16(d,J=2.3Hz,1H), 4.31(dd,J=3.5,9.1Hz,1H), 4.28-4.19(m,6H), 3.20(spt, J = 6.9 Hz, 1H), 2.76 (dd, J = 9.2, 12.8 Hz, 1H), 1.96-1.87 (m, 4H), 1.37 (t, J = 7.1 Hz, 6H), 1.21 (dd, J = 6.9 ,9.9Hz,6H),1.03-0.86(m,4H).
31P NMR(400MHz,CDCl 3)δppm 19.790。 31 P NMR (400MHz, CDCl 3 ) δ ppm 19.790.
步骤6：47的合成Step 6: Synthesis of 47
将47-5(25mg,54.52μmol)溶于二氯甲烷(0.5mL)，开启搅拌，加入三甲基溴硅烷(83.47mg,545.23μmol)，在25℃温度反应16h，反应体系旋干，再加入无水二氯甲烷(2mL×2)旋干两次，得到化合物粗品，将粗品溶于乙腈(30mL)和水(30mL)，得到化合物47。Dissolve 47-5 (25mg, 54.52μmol) in dichloromethane (0.5mL), turn on the stirring, add bromotrimethylsilane (83.47mg, 545.23μmol), react at 25°C for 16h, spin the reaction system to dryness, and then Anhydrous dichloromethane (2 mL×2) was added and spin-dried twice to obtain a crude compound, which was dissolved in acetonitrile (30 mL) and water (30 mL) to obtain compound 47.
1H NMR(400MHz,CD 3OD)δ＝6.85(s,1H),6.80(s,1H),6.62-6.52(m,3H),6.15(s,1H),4.39(br s,1H),4.33-4.11(m,3H),3.23-3.12(m,1H),2.61-2.47(m,2H),1.97(s,3H),1.32-1.20(m,4H),1.13(t,J＝6.4Hz,6H)。 1 H NMR (400MHz, CD 3 OD) δ = 6.85 (s, 1H), 6.80 (s, 1H), 6.62-6.52 (m, 3H), 6.15 (s, 1H), 4.39 (br s, 1H), 4.33-4.11(m,3H),3.23-3.12(m,1H),2.61-2.47(m,2H),1.97(s,3H),1.32-1.20(m,4H),1.13(t,J=6.4 Hz, 6H).
31P NMR(400MHz,CD 3OD)δppm 18.013。 31 P NMR (400MHz, CD 3 OD) δ ppm 18.013.
实施例48Example 48
Figure PCTCN2020139562-appb-000164
Figure PCTCN2020139562-appb-000164
合成路线：synthetic route:
Figure PCTCN2020139562-appb-000165
Figure PCTCN2020139562-appb-000165
步骤1：48的合成Step 1: Synthesis of 48
取干燥洁净的拇指瓶，加入46(15.00mg,37.09μmol)和N,N-二甲基甲酰胺(0.5mL)，开启搅拌，随后加入二环己基碳二亚胺(45.92mg,222.53μmol,45.01μL)和吡啶(44.01mg,556.33μmol,44.90μL)，加入BB-2(8.31mg,44.51μmol)，在55℃反应16h。向反应体系加入乙酸乙酯(10mL)和H 2O(10mL×3)萃取，分得有机相，无水硫酸钠干燥，旋干得到化合物粗品。根据薄层层析(石油醚:乙酸乙酯＝1:2)化合物48的Rf值为0.4，经硅胶薄层层析(石油醚:乙酸乙酯＝1:2)纯化得到化合物粗品，再经硅胶柱层析(石油醚:乙酸乙酯＝5:1至1:1)纯化，得到化合物48。 Take a dry and clean thumb bottle, add 46 (15.00mg, 37.09μmol) and N,N-dimethylformamide (0.5mL), turn on the stirring, and then add dicyclohexylcarbodiimide (45.92mg, 222.53μmol, 45.01μL) and pyridine (44.01mg, 556.33μmol, 44.90μL), add BB-2 (8.31mg, 44.51μmol), and react at 55°C for 16h. Ethyl acetate (10 mL) and H 2 O (10 mL×3) were added to the reaction system for extraction, the organic phase was separated, dried over anhydrous sodium sulfate, and spin-dried to obtain a crude compound. According to thin layer chromatography (petroleum ether: ethyl acetate = 1:2), the Rf value of compound 48 was 0.4, and the crude product was obtained by purification by silica gel thin layer chromatography (petroleum ether: ethyl acetate = 1:2). Purification by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1 to 1:1) afforded compound 48.
1H NMR(400MHz,CDCl 3)δ＝7.44(s,1H),7.36-7.28(m,3H),6.94(d,J＝1.9Hz,1H),6.74(dd,J＝2.1,8.1Hz,1H),6.65(d,J＝8.1Hz,2H),6.59(s,1H),5.65(br d,J＝11.0Hz,1H),4.69(br d,J＝11.5Hz,2H),4.45(br d,J＝9.6Hz,2H),4.30(br t,J＝7.6Hz,1H),3.18(td,J＝6.8,13.7Hz,1H),2.54-2.40(m,2H),2.14(br d,J＝14.6Hz,1H),1.97-1.79(m,4H),1.27(br d,J＝5.8Hz,6H),1.23(d,J＝2.4Hz,3H),1.21-1.20(m,3H)。 1 H NMR (400MHz, CDCl 3 )δ = 7.44 (s, 1H), 7.36-7.28 (m, 3H), 6.94 (d, J = 1.9 Hz, 1H), 6.74 (dd, J = 2.1, 8.1 Hz, 1H), 6.65 (d, J = 8.1 Hz, 2H), 6.59 (s, 1H), 5.65 (br d, J = 11.0 Hz, 1H), 4.69 (br d, J = 11.5 Hz, 2H), 4.45 ( br d, J = 9.6Hz, 2H), 4.30 (br t, J = 7.6 Hz, 1H), 3.18 (td, J = 6.8, 13.7 Hz, 1H), 2.54-2.40 (m, 2H), 2.14 (br d,J=14.6Hz,1H),1.97-1.79(m,4H),1.27(br d,J=5.8Hz,6H),1.23(d,J=2.4Hz,3H),1.21-1.20(m, 3H).
31P NMR(400MHz,CDCl 3)δppm 15.833。 31 P NMR (400MHz, CDCl 3 ) δ ppm 15.833.
实施例49Example 49
Figure PCTCN2020139562-appb-000166
Figure PCTCN2020139562-appb-000166
合成路线：synthetic route:
Figure PCTCN2020139562-appb-000167
Figure PCTCN2020139562-appb-000167
步骤1：化合物49的合成Step 1: Synthesis of compound 49
取干燥洁净的50mL单口瓶，加入30(280mg,675.04μmol)和N,N-二甲基甲酰胺(8.5mL)，开启搅拌，随后加入二环己基碳二亚胺(835.68mg,4.05mmol,819.30μL)和吡啶(800.93mg,10.13mmol,817.28μL)，加 入BB-2(151.18mg,810.05μmol,1.2eq)，升高温度并控制在55℃，反应16h。向反应体系加入乙酸乙酯(10mL)和饱和食盐水(10mL×3)萃取，分得有机相，无水硫酸钠干燥，旋干得到化合物粗品，根据薄层层析(石油醚:乙酸乙酯＝1:2，R f＝0.4)，随后经硅胶柱层析(石油醚:乙酸乙酯＝5:1-1:1)纯化得到化合物粗品，经制备HPLC(柱型：Kromasil C18(250×50mm×10μm)；流动相:[H 2O(10mM NH 4HCO 3)-ACN]；ACN％:45％-85％,10mim)分离得到化合物49。 Take a dry and clean 50mL single-mouth flask, add 30 (280mg, 675.04μmol) and N,N-dimethylformamide (8.5mL), turn on the stirring, and then add dicyclohexylcarbodiimide (835.68mg, 4.05mmol, 819.30μL) and pyridine (800.93mg, 10.13mmol, 817.28μL), add BB-2 (151.18mg, 810.05μmol, 1.2eq), increase the temperature and control at 55℃, and react for 16h. Ethyl acetate (10mL) and saturated brine (10mL×3) were added to the reaction system for extraction, the organic phase was separated, dried over anhydrous sodium sulfate, and spin-dried to obtain the crude compound. According to thin layer chromatography (petroleum ether: ethyl acetate) = 1:2, R f =0.4), and then purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1-1:1) to obtain the crude compound, which was subjected to preparative HPLC (column type: Kromasil C18 (250× 50mm×10μm); mobile phase: [H 2 O (10mM NH 4 HCO 3 )-ACN]; ACN%: 45%-85%, 10mim) to obtain compound 49.
1H NMR(400MHz,CD 3OD)δ＝7.47(s,1H),7.40-7.26(m,3H),6.96(d,J＝1.9Hz,1H),6.88(d,J＝2.1Hz,1H),6.55-6.36(m,2H),5.82-5.69(m,1H),4.72(tt,J＝3.2,11.6Hz,1H),4.64-4.46(m,4H),3.17-3.00(m,2H),2.96-2.83(m,1H),2.56(qd,J＝8.8,12.8Hz,1H),2.46-2.32(m,1H),2.28-2.19(m,1H),2.08-1.94(m,1H),1.02(dd,J＝7.0,10.1Hz,6H). 1 H NMR (400MHz, CD 3 OD) δ = 7.47 (s, 1H), 7.40-7.26 (m, 3H), 6.96 (d, J = 1.9 Hz, 1H), 6.88 (d, J = 2.1 Hz, 1H ),6.55-6.36(m,2H),5.82-5.69(m,1H),4.72(tt,J=3.2,11.6Hz,1H),4.64-4.46(m,4H),3.17-3.00(m,2H ),2.96-2.83(m,1H),2.56(qd,J=8.8,12.8Hz,1H),2.46-2.32(m,1H),2.28-2.19(m,1H),2.08-1.94(m,1H) ),1.02(dd,J=7.0,10.1Hz,6H).
19F NMR(400MHz,DMSO)δppm-123.731. 19 F NMR (400MHz, DMSO) δppm-123.731.
31P NMR(400MHz,DMSO)δppm 16.331. 31 P NMR (400MHz, DMSO) δppm 16.331.
实施例50Example 50
Figure PCTCN2020139562-appb-000168
Figure PCTCN2020139562-appb-000168
合成路线：synthetic route:
Figure PCTCN2020139562-appb-000169
Figure PCTCN2020139562-appb-000169
步骤1：化合物50-2的合成Step 1: Synthesis of compound 50-2
将化合物50-1(15g,47.67mmol,95％纯度)溶于乙腈(150mL)中，加入溴化苄(8.15g,47.67mmol)，碳酸铯(23.30g,71.51mmol)，反应在70℃下进行12小时，冷却至室温，加入乙酸乙酯(200mL)，水(150mL)萃取，收集有机相，有机相通过无水硫酸钠干燥，过滤，滤液减压浓缩，粗产品通过柱层析分离(石油醚:乙 酸乙酯＝5:1)，得到化合物50-2。Compound 50-1 (15g, 47.67mmol, 95% purity) was dissolved in acetonitrile (150mL), benzyl bromide (8.15g, 47.67mmol) and cesium carbonate (23.30g, 71.51mmol) were added, and the reaction was carried out at 70°C. After 12 hours, cooled to room temperature, ethyl acetate (200 mL) was added, water (150 mL) was added, the organic phase was collected, the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was separated by column chromatography ( Petroleum ether: ethyl acetate = 5:1) to obtain compound 50-2.
1H NMR(400MHz,CDCl 3)δ＝7.92(d,J＝2.4Hz,1H),7.51-7.46(m,2H),7.45-7.32(m,4H),6.72(d,J＝8.8Hz,1H),5.14(s,2H) 1 H NMR(400MHz,CDCl 3 )δ=7.92(d,J=2.4Hz,1H),7.51-7.46(m,2H),7.45-7.32(m,4H),6.72(d,J=8.8Hz, 1H), 5.14(s, 2H)
步骤2：化合物50-3的合成Step 2: Synthesis of compound 50-3
将化合物50-2(19g,48.84mmol)，与丙二酸二乙酯(15.65g,97.68mmol)，碳酸铯(23.87g,73.26mmol)溶于二氧六环(190mL)中，搅拌15分钟，氮气置换3次，加入碘化亚铜(1.40g,7.33mmol)，2-吡啶甲酸(1.20g,9.77mmol)，反应在105℃下进行15小时。冷却至室温，加入乙酸乙酯(100mL×2)，水100mL萃取，收集有机相，有机相通过无水硫酸钠干燥，过滤，滤液减压浓缩，得粗产品。粗产品通过柱层析分离(石油醚：乙酸乙酯＝5:1)得到化合物50-3。Compound 50-2 (19g, 48.84mmol), diethyl malonate (15.65g, 97.68mmol) and cesium carbonate (23.87g, 73.26mmol) were dissolved in dioxane (190mL) and stirred for 15 minutes , Nitrogen replacement 3 times, cuprous iodide (1.40 g, 7.33 mmol) and 2-picolinic acid (1.20 g, 9.77 mmol) were added, and the reaction was carried out at 105° C. for 15 hours. Cooled to room temperature, added ethyl acetate (100 mL×2), extracted with 100 mL of water, collected the organic phase, dried the organic phase over anhydrous sodium sulfate, filtered, and concentrated the filtrate under reduced pressure to obtain a crude product. The crude product was separated by column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain compound 50-3.
1H NMR(400MHz,CDCl 3)δ＝7.47(d,J＝2.4Hz,1H),7.40-7.29(m,6H),6.85-6.77(m,1H),5.12-5.02(m,3H),4.22-4.20(m,4H),3.40-3.31(m,2H),1.27(br t,J＝3.5Hz,6H) 1 H NMR (400MHz, CDCl 3 ) δ = 7.47 (d, J = 2.4 Hz, 1H), 7.40-7.29 (m, 6H), 6.85-6.77 (m, 1H), 5.12-5.02 (m, 3H), 4.22-4.20(m,4H),3.40-3.31(m,2H),1.27(br t,J=3.5Hz,6H)
步骤3：化合物50-4的合成Step 3: Synthesis of compound 50-4
将四氢铝锂(4.87g,128.18mmol)溶于四氢呋喃(90mL)中，在-10℃下缓慢滴加50-3(18g,42.73mmol)的四氢呋喃(90mL)溶液，反应在25℃下进行3小时。将反应液倒入10％的硫酸氢钾水溶液中淬灭反应，加入乙酸乙酯(200mL×3)，水200mL萃取，收集有机相，有机相通过无水硫酸钠干燥，过滤，滤液减压浓缩，得粗产品。粗产品通过柱层析分离(石油醚:乙酸乙酯＝1:1)得到化合物50-4。Lithium tetrahydroaluminum (4.87g, 128.18mmol) was dissolved in tetrahydrofuran (90mL), and 50-3 (18g, 42.73mmol) of tetrahydrofuran (90mL) solution was slowly added dropwise at -10°C. The reaction was carried out at 25°C. 3 hours. The reaction solution was poured into 10% potassium hydrogen sulfate aqueous solution to quench the reaction, ethyl acetate (200mL×3) was added, 200mL of water was added, the organic phase was collected, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure , A crude product. The crude product was separated by column chromatography (petroleum ether: ethyl acetate=1:1) to obtain compound 50-4.
1H NMR(400MHz,CDCl 3)δ＝7.33-7.19(m,6H),7.17-7.10(m,1H),6.63(d,J＝8.7Hz,1H),4.92(s,2H),3.66(quin,J＝8.8Hz,1H),2.28-2.18(m,2H),2.07-1.84(m,3H),1.77-1.66(m,1H) 1 H NMR(400MHz, CDCl 3 )δ=7.33-7.19(m,6H), 7.17-7.10(m,1H), 6.63(d,J=8.7Hz,1H), 4.92(s,2H), 3.66( quin,J=8.8Hz,1H),2.28-2.18(m,2H),2.07-1.84(m,3H),1.77-1.66(m,1H)
步骤4：化合物50-5的合成Step 4: Synthesis of compound 50-5
将50-4(6.9g,20.46mmol)溶于四氢呋喃(70mL)中，降温至-68℃，缓慢滴加二异丙基氨基锂(2M,10.23mL)，反应在-68℃下进行15分钟，升温至10℃搅拌0.5小时，降温至-20℃缓慢滴加对甲苯磺酰氯(4.29g,22.51mmol)的四氢呋喃(8mL)溶液，在0℃下搅拌0.5小时，反应在25℃下进行12小时，向反应液中加入20mL饱和氯化铵水溶液淬灭反应。萃取乙酸乙酯(200mL)，水(100mL)，收集有机相，有机相通过无水硫酸钠干燥，过滤，滤液减压浓缩，得粗产品。粗产品通过柱层析分离，得到化合物50-5。Dissolve 50-4 (6.9g, 20.46mmol) in tetrahydrofuran (70mL), lower the temperature to -68°C, slowly add lithium diisopropylamide (2M, 10.23mL) dropwise, and carry out the reaction at -68°C for 15 minutes The temperature was raised to 10°C and stirred for 0.5 hours. The temperature was lowered to -20°C and a solution of p-toluenesulfonyl chloride (4.29g, 22.51mmol) in tetrahydrofuran (8mL) was slowly added dropwise. Stir at 0°C for 0.5 hours. The reaction was carried out at 25°C. 20 mL of saturated ammonium chloride aqueous solution was added to the reaction solution to quench the reaction. Extract ethyl acetate (200 mL), water (100 mL), collect the organic phase, dry the organic phase over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain a crude product. The crude product was separated by column chromatography to obtain compound 50-5.
步骤5：化合物50-6的合成Step 5: Synthesis of compound 50-6
将50-5(6g,12.21mmol)溶于N,N二甲基甲酰胺(240mL)中，在0℃下加入钠氢(1.47g,36.63mmol)，反应在25℃下进行12小时，将反应液倒入200mL水中。加入乙酸乙酯(300mL)，水(100mL)萃取，收集有机相，有机相通过饱和食盐水(100mL×3)洗涤，有机相通过无水硫酸钠干燥，过滤，滤液减压浓缩，得粗产品。粗产品通过柱层析分离(石油醚:乙酸乙酯＝3:1)得到化合物50-6。[Ms+1] +＝320.1 50-5 (6g, 12.21mmol) was dissolved in N,N dimethylformamide (240mL), sodium hydrogen (1.47g, 36.63mmol) was added at 0°C, and the reaction was carried out at 25°C for 12 hours. The reaction solution was poured into 200 mL of water. Add ethyl acetate (300mL), extract with water (100mL), collect the organic phase, wash the organic phase with saturated brine (100mL×3), dry the organic phase over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the crude product . The crude product was separated by column chromatography (petroleum ether: ethyl acetate=3:1) to obtain compound 50-6. [Ms+1] + ＝320.1
步骤6：化合物50-7的合成Step 6: Synthesis of compound 50-7
将50-6(694mg,2.17mmol)溶于四氢呋喃(5mL)中，在-68℃下加入正丁基锂(2M,1.30mL)，反应在-68℃下进行0.5小时，加入BB-1(601.06mg,2.17mmol)的四氢呋喃溶液(5mL)，反应在20℃下进行1小时，向反应液中加入10mL饱和氯化铵水溶液淬灭反应，加入乙酸乙酯(50mL)，水(100mL)萃取，收集有机相，有机相通过无水硫酸钠干燥，过滤，滤液减压浓缩。粗产品通过柱层析分离(石油醚：乙酸乙酯＝ 3:1)，得到化合物50-7。[Ms-18] +＝499.2 50-6 (694mg, 2.17mmol) was dissolved in tetrahydrofuran (5mL), n-butyllithium (2M, 1.30mL) was added at -68°C, the reaction was carried out at -68°C for 0.5 hours, and BB-1 ( 601.06mg, 2.17mmol) in tetrahydrofuran (5mL), the reaction was carried out at 20°C for 1 hour, 10mL of saturated aqueous ammonium chloride was added to the reaction solution to quench the reaction, ethyl acetate (50mL) was added, and water (100mL) was added. , Collect the organic phase, dry the organic phase over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The crude product was separated by column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain compound 50-7. [Ms-18] + ＝499.2
步骤7：化合物50-8的合成Step 7: Synthesis of compound 50-8
将50-7(327mg,632.81μmol)溶于二氯甲烷(2mL)中，在0℃下加入三乙基硅氢(220.74mg,1.90mmol)，三氟乙酸(108.23mg,949.22μmol)反应在25℃下进行12小时。减压浓缩，得到化合物50-8。[Ms+1] +＝501.2 Dissolve 50-7 (327mg, 632.81μmol) in dichloromethane (2mL), add triethylsilylhydrogen (220.74mg, 1.90mmol) at 0°C, and react with trifluoroacetic acid (108.23mg, 949.22μmol). 12 hours at 25°C. Concentrate under reduced pressure to obtain compound 50-8. [Ms+1] + ＝501.2
步骤8：化合物50-9的合成Step 8: Synthesis of compound 50-9
将50-8(335mg,669.01μmol)溶于甲醇(2mL)与四氢呋喃(2mL)的混合溶剂中，加入氟化铵(247.78mg,6.69mmol)，反应在25℃下进行12小时。减压浓缩，得粗产品。粗产品通过柱层析分离(石油醚：乙酸乙酯＝1:1)，得到化合物50-9。[Ms+1] +＝385.1 50-8 (335 mg, 669.01 μmol) was dissolved in a mixed solvent of methanol (2 mL) and tetrahydrofuran (2 mL), ammonium fluoride (247.78 mg, 6.69 mmol) was added, and the reaction was carried out at 25° C. for 12 hours. Concentrate under reduced pressure to obtain a crude product. The crude product was separated by column chromatography (petroleum ether: ethyl acetate=1:1) to obtain compound 50-9. [Ms+1] + ＝385.1
步骤9：化合物50-10的合成Step 9: Synthesis of compound 50-10
将50-9(70mg,181.12μmol)溶于N,N-二甲基甲酰胺(5mL)中，加入碳酸铯(88.52mg,271.68μmol)，对甲苯磺酰氧甲基膦酸二苄酯(80.86mg,181.12μmol)，反应在50℃下进行12小时。冷却至室温，加入乙酸乙酯(20mL)，水(20mL)萃取，收集有机相，有机相通过饱和食盐水(20mL×3)洗涤，有机相通过无水硫酸钠干燥，过滤，滤液减压浓缩，得粗产品。粗产品通过柱层析分离(石油醚：乙酸乙酯＝1:1)得到化合物50-10。[Ms+1] +＝683.2 Dissolve 50-9 (70mg, 181.12μmol) in N,N-dimethylformamide (5mL), add cesium carbonate (88.52mg, 271.68μmol), dibenzyl p-toluenesulfonyloxymethylphosphonate ( 80.86mg, 181.12μmol), the reaction was carried out at 50°C for 12 hours. Cool to room temperature, add ethyl acetate (20mL), extract with water (20mL), collect the organic phase, wash the organic phase with saturated brine (20mL×3), dry the organic phase over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure , A crude product. The crude product was separated by column chromatography (petroleum ether: ethyl acetate=1:1) to obtain compound 50-10. [Ms+1] + ＝683.2
步骤10：化合物50-11的合成Step 10: Synthesis of compound 50-11
50-10(40mg，60.54μmol)的SFC拆分。经SFC(柱型:DAICEL CHIRALPAK AD(250mm×30mm,10μm)；流动相:[Neu-IPA]:50％-50％,15min)拆分。得到化合物50-11。分析方法：柱型：Chiralcel OJ-3,50×4.6mm I.D.,3μm。流动相:A:CO 2B:EtOH(0.05％IPAm,v/v。梯度:B相1分钟内从5％升至50％，维持1分钟，0.8分钟内降至5％。流速:3.4mL/min。柱温:35℃。ABPR:1800psi。化合物50-11保留时间：1.593min。 50-10 (40mg, 60.54μmol) SFC resolution. It was resolved by SFC (column type: DAICEL CHIRALPAK AD (250mm×30mm, 10μm); mobile phase: [Neu-IPA]: 50%-50%, 15min). Compound 50-11 was obtained. Analysis method: Column type: Chiralcel OJ-3, 50×4.6mm ID, 3μm. Mobile phase: A: CO 2 B: EtOH (0.05% IPAm, v/v. Gradient: Phase B increased from 5% to 50% in 1 minute, maintained for 1 minute, and decreased to 5% in 0.8 minutes. Flow rate: 3.4mL /min. Column temperature: 35° C. ABPR: 1800 psi. Compound 50-11 retention time: 1.593 min.
步骤11：化合物50的合成Step 11: Synthesis of compound 50
将50-11(8mg,12.11μmol)溶于甲醇(3mL)中，加入湿钯碳(10mg,5％钯含量)，通入氢气反应在15psi，15℃下进行3小时。反应液过滤，滤液减压浓缩，得粗产品。粗产品通过制备HPLC(柱型:Phenomenex Gemini-NX C18 75×30mm×3μm；流动相:[H 2O(10mM NH 4HCO 3)-ACN]；ACN％:10％-30％,8min)分离，得到化合物50。[Ms+1] +＝391.1 50-11 (8 mg, 12.11 μmol) was dissolved in methanol (3 mL), wet palladium carbon (10 mg, 5% palladium content) was added, and hydrogen gas was introduced to react at 15 psi and 15°C for 3 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated by preparative HPLC (column type: Phenomenex Gemini-NX C18 75×30mm×3μm; mobile phase: [H 2 O(10mM NH 4 HCO 3 )-ACN]; ACN%: 10%-30%, 8min) , Compound 50 was obtained. [Ms+1] + = 391.1
生物测试数据Biological test data
实验例1：甲状腺激素受体-β激动剂的生化活性测定Experimental example 1: Determination of biochemical activity of thyroid hormone receptor-β agonist
实验材料：Experimental Materials:
甲状腺受体蛋白β共激活试剂盒：ThermoFisher Cat#PV4686Thyroid Receptor Protein β Co-activation Kit: ThermoFisher Cat#PV4686
荧光肽段:SCR2-2terbium标记的抗GST抗体Fluorescent peptide: SCR2-2terbium labeled anti-GST antibody
实验步骤与方法：Experimental steps and methods:
利用时间分辨荧光共振能量转移原理，采用甲状腺受体蛋白β共激活实验试剂盒进行激动剂化合物筛选，简单描述如下：Using the principle of time-resolved fluorescence resonance energy transfer, the thyroid receptor protein β co-activation test kit is used to screen agonist compounds, which is briefly described as follows:
1)采用ECHO液体工作站将DMSO溶解的化合物转移到384孔板，每个化合物10个梯度浓度，3 倍稀释，双复孔。1) Use the ECHO liquid workstation to transfer the DMSO-dissolved compounds to a 384-well plate with 10 gradient concentrations for each compound, 3 times dilution, and double wells.
2)每个孔里先加入10μL的Buffer C溶液，然后加入10μL的荧光SCR2-2肽段、terbium标记的抗GST抗体及甲状腺受体蛋白β的混合物。2) Add 10 μL of Buffer C solution to each well, and then add 10 μL of a mixture of fluorescent SCR2-2 peptide, terbium-labeled anti-GST antibody and thyroid receptor protein β.
3)经过2小时的常温孵育。在340nm激发，495nm及520nm读取能量转移的相关信号值。3) After 2 hours of incubation at room temperature. Excite at 340nm, read the relevant signal values of energy transfer at 495nm and 520nm.
数据分析：data analysis:
作图软件GraphPad Prism将根据化合物的浓度与520nm信号和495nm信号的比值拟合曲线，计算50％有效激活浓度，得出化合物EC 50，在每次实验中，参考化合物三碘甲状腺原氨酸(T3)将作为阳性对照品用于实验。Z因子的计算(大于0.5)将用于监控每次实验的稳定性。实验结果见表6。 GraphPad Prism software fitting the mapping according to the ratio of the concentration of compound 520nm signal and the 495nm signal curves, calculating 50% effective concentration activation, compounds derived EC 50, in each experiment, the reference compound triiodo thyronine ( T3) Will be used as a positive control for the experiment. The calculation of the Z factor (greater than 0.5) will be used to monitor the stability of each experiment. The experimental results are shown in Table 6.
表6：甲状腺激素受体-β激动剂的生化活性测定Table 6: Determination of biochemical activity of thyroid hormone receptor-β agonists
化合物编号Compound number EC 50(nM) EC 50 (nM) 化合物编号Compound number EC 50(nM) EC 50 (nM)
11 1.91.9 23twenty three 12.2412.24
22 47.6447.64 24twenty four 3.083.08
33 1.401.40 2626 10.9910.99
88 3.23.2 2828 2.752.75
1010 20.9420.94 3030 0.4140.414
1111 36.6536.65 3131 25.1625.16
1212 0.1980.198 3838 173.8173.8
1414 8.1878.187 3939 11.911.9
1515 11.9911.99 4040 113113
1818 0.4690.469 4141 191.8191.8
1919 47.2547.25 4242 6.566.56
2020 0.710.71 4646 8.438.43
21twenty one 135.4135.4 4747 46.7346.73
22twenty two 3.053.05  To  To
结论：本发明化合物对甲状腺受体β有较强的激动活性。Conclusion: The compound of the present invention has strong agonistic activity on thyroid receptor β.
实验例2大鼠药代动力学试验Experimental example 2 Rat pharmacokinetic test
本研究选用SD雄性大鼠受试动物，应用LC/MS/MS法定量测定了大鼠经口服给予测试化合物6在不同时间点的血浆中的药物浓度，以评价受试药物在大鼠体内的药代动力学特征。In this study, SD male rats were selected as test animals, and the LC/MS/MS method was used to quantitatively determine the drug concentration in the plasma of the test compound 6 administered orally to the rats at different time points to evaluate the test drug in the rat. Pharmacokinetic characteristics.
将试验化合物的澄清溶液经尾静脉注射到SD大鼠体内(过夜禁食，7-10周龄)，将试验化合物灌胃给予到SD大鼠(过夜禁食，7-10周龄)。动物均于给药后0.0833,0.25,0.5,1,2,4,6,8和24小时从颈静脉或尾静脉采血约200μL置于添加了EDTA-K2的抗凝管中，4℃，3200g离心10min取血浆。采用LC-MS/MS法测定血药浓度，使用Phoenix WinNonlin 6.3药动学软件，以非房室模型线性对数梯形法计算相关药代动力学参数。实验结果见表7。A clear solution of the test compound was injected into SD rats via the tail vein (overnight fast, 7-10 weeks old), and the test compound was intragastrically administered to SD rats (overnight fast, 7-10 weeks old). About 200μL of blood was collected from the jugular vein or tail vein at 0.0833, 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours after the administration, and placed in an anticoagulant tube with EDTA-K2 at 4°C, 3200g Centrifuge for 10 min to collect plasma. The LC-MS/MS method was used to determine the blood drug concentration, and the Phoenix WinNonlin 6.3 pharmacokinetic software was used to calculate the relevant pharmacokinetic parameters using the non-compartmental model linear logarithmic trapezoidal method. The experimental results are shown in Table 7.
表7：本发明化合物在大鼠中的药代动力学参数Table 7: Pharmacokinetic parameters of the compounds of the present invention in rats
Figure PCTCN2020139562-appb-000170
Figure PCTCN2020139562-appb-000170
注：3*表示此处化合物3为化合物6的体内代谢产物；N/A表示未测或者未得到。Note: 3* means that compound 3 is the in vivo metabolite of compound 6; N/A means not tested or not available.
实验结论：本发明化合物的生物利用度较好。Experimental conclusion: the bioavailability of the compound of the present invention is better.
实验例3小鼠组织分布试验Experimental Example 3 Mice tissue distribution test
本研究选用C57BL/6J雄性小鼠受试动物，应用LC/MS/MS法定量测定了小鼠经口服给予测试化合物在不同时间点的血浆、肝脏和心脏中的药物浓度，以评价受试药物在小鼠体内的药代动力学特征。In this study, C57BL/6J male mice were used as test animals, and the LC/MS/MS method was used to quantitatively determine the drug concentration in plasma, liver and heart of mice after oral administration of the test compound at different time points to evaluate the test drug Pharmacokinetic characteristics in mice.
将试验化合物溶液经灌胃给予小鼠体内(过夜禁食，6-8周龄)。动物给药后于1、2和8小时从小鼠隐静脉采血40μL置于添加了EDTA-K2的抗凝管中，4℃，3200g离心10min取血浆，并于1、2和8小时分别处死部分动物，采集肝脏，心脏组织。血浆样品经处理后，采用LC-MS/MS法测定血药浓度。肝脏，心脏组织经匀浆后，测定组织内药物浓度。实验结果见表8。The test compound solution was intragastrically administered to mice (overnight fasting, 6-8 weeks old). After animal administration, 40 μL of blood was collected from the saphenous vein of the mouse at 1, 2 and 8 hours, placed in an anticoagulation tube with EDTA-K2, centrifuged at 4°C, 3200g for 10 minutes to collect plasma, and the parts were sacrificed at 1, 2, and 8 hours. Animals, collect liver and heart tissues. After the plasma samples were processed, the blood drug concentration was determined by the LC-MS/MS method. After liver and heart tissues were homogenized, the drug concentration in the tissues was measured. The experimental results are shown in Table 8.
表8：本发明化合物在小鼠中的药代动力学参数Table 8: Pharmacokinetic parameters of the compounds of the invention in mice
Figure PCTCN2020139562-appb-000171
Figure PCTCN2020139562-appb-000171
注：3*表示此处化合物3为化合物6的体内代谢产物，18*表示此处化合物18为化合物36的体内代谢产 物；ND表示未监测到。Note: 3* means that compound 3 is the in vivo metabolite of compound 6, and 18* means that compound 18 is the in vivo metabolite of compound 36; ND means not detected.
实验结论：本发明化合物在肝脏中的暴露量较高，血浆、心脏中暴露量较低，对于肝脏的靶向性较好。Experimental conclusion: The compound of the present invention has higher exposure in the liver, lower exposure in plasma and heart, and better targeting of the liver.
实验例4利用HFD-CCl 4(高脂饮食-四氯化碳)诱导的小鼠NASH模型检测本发明化合物的体内药效试验 Experimental Example 4 The in vivo efficacy test of the compound of the present invention using the mouse NASH model induced by HFD-CCl 4 (high-fat diet-carbon tetrachloride)
本试验前期先使用高脂饲料饲喂诱导DIO小鼠，后用在饲喂高脂饲料的同时，腹腔注射CCl 4诱导NASH模型，在该模型中测试待测化合物的抗NASH药效。 In the early stage of the experiment, high-fat diet was used to feed the induced DIO mice, and then the NASH model was induced by intraperitoneal injection of CCl 4 while feeding the high-fat diet. In this model, the anti-NASH efficacy of the test compound was tested.
正常对照组动物，腹腔注射生理盐水，并口服给予化合物溶媒作为对照，给药组的小鼠，每周两次，腹腔注射25％CCl 4溶液，CCl 4的注射时间为第1天,第4天,第8天,第11天,第15天,第18天,第22天和第26天，诱导NASH模型，并口服给予相应剂量的化合物。实验终点，处死动物，测试肝重及肝体比，并进行肝脏组织病理分析。给予化合物的HFD-CCl 4诱导的NASH模型小鼠的肝重变化和肝体比见附图4a、4b、6a和6b。给予化合物的HFD-CCl 4诱导的NASH模型小鼠的肝脏组织病理分析见附图5a、5b和7a、7b所示。 Normal control animals were injected intraperitoneally with physiological saline and orally administered the compound vehicle as a control. The mice in the administration group were intraperitoneally injected with 25% CCl 4 solution twice a week. The injection time of CCl 4 was the first day and the fourth day. On day 8, day 8, day 11, day 15, day 18, day 22, and day 26, the NASH model was induced, and the corresponding dose of the compound was orally administered. At the end of the experiment, the animals were sacrificed, liver weight and liver-to-body ratio were tested, and liver tissue pathological analysis was performed. The liver weight changes and liver body ratios of NASH model mice induced by HFD-CCl 4 administration of the compound are shown in Figures 4a, 4b, 6a and 6b. The liver tissue pathological analysis of the HFD-CCl 4 induced NASH model mice given the compound is shown in Figures 5a, 5b and 7a, 7b.
实验结论：本发明化合物对于DIO+CCl 4模型小鼠的肝脏重量下降明显，对于DIO+CCl 4模型小鼠的非酒精性脂肪肝病活动性评分改善明显，且存在较明显的剂量-药效关系。 Experimental results: The compound of the invention for liver weight DIO + CCl 4 mice decreased significantly, for nonalcoholic DIO + CCl 4 mice fatty liver disease activity score improved significantly, and there are obvious dose - Medicines .

Claims (22)

  1. 式(IV)所示化合物、其异构体或其药学上可接受的盐，其选自：The compound represented by formula (IV), its isomers or pharmaceutically acceptable salts thereof, which are selected from:
    Figure PCTCN2020139562-appb-100001
    Figure PCTCN2020139562-appb-100001
    其中，among them,
    R 1选自H、卤素、OH、NHR a、C 1-3烷基和C 1-3烷氧基，所述C 1-3烷基和C 1-3烷氧基任选被1、2或3个卤素取代； R 1 is selected from H, halogen, OH, NHR a , C 1-3 alkyl and C 1-3 alkoxy. The C 1-3 alkyl and C 1-3 alkoxy are optionally selected by 1, 2 Or 3 halogen substitutions;
    R 2选自H、卤素、OH、NHR a、C 1-3烷基、C 1-3烷氧基和C 3-6环烷基，所述C 1-3烷基、C 1-3烷氧基和C 3- 6环烷基任选被1、2或3个卤素取代； R 2 is selected from H, halogen, OH, NHR a , C 1-3 alkyl, C 1-3 alkoxy and C 3-6 cycloalkyl, the C 1-3 alkyl, C 1-3 alkane group and C 3- 6 cycloalkyl optionally substituted with 1, 2 or 3 halogen;
    R 3、R 4和R 5各自独立地选自H、卤素、OH、NHR a、C 1-3烷基、C 1-3烷氧基、C 3-6环烷基和4-6元杂环烷基，所述C 1-3烷基、C 1-3烷氧基、C 3-6环烷基和4-6元杂环烷基任选被1、2或3个R取代； R 3 , R 4 and R 5 are each independently selected from H, halogen, OH, NHR a , C 1-3 alkyl, C 1-3 alkoxy, C 3-6 cycloalkyl and 4-6 membered hetero Cycloalkyl, the C 1-3 alkyl, C 1-3 alkoxy, C 3-6 cycloalkyl and 4-6 membered heterocycloalkyl are optionally substituted with 1, 2 or 3 R;
    各R分别独立地选自卤素或C 1-3烷基； Each R is independently selected from halogen or C 1-3 alkyl;
    L 1选自-(CR bR c) m-、-NH(CR bR c) m-、-O(CR bR c) m-、C 3-6环烷基和3-6元杂环烷基； L 1 is selected from -(CR b R c ) m -, -NH(CR b R c ) m -, -O(CR b R c ) m -, C 3-6 cycloalkyl and 3-6 membered heterocyclic ring alkyl;
    E 1和E 2分别独立地选自-(CR bR c) n-、NR a和O； E 1 and E 2 are independently selected from -(CR b R c ) n -, NR a and O;
    R a选自H、C 1-3烷基、-COCH 3和-SO 2R’； R a is selected from H, C 1-3 alkyl, -COCH 3 and -SO 2 R';
    R b和R c分别独立地选自H、C 1～3烷基和C 1-3烷氧基，所述C 1-3烷基和C 1-3烷氧基任选被1、2或3个卤素取代； R b and R c are independently selected from H, C 1 ~ 3 alkyl group and a C 1-3 alkoxy group, a C 1-3 alkyl group and a C 1-3 alkoxy group optionally substituted with 1, 2 or 3 halogen substitutions;
    或者，R 1与R b或R c及共同相连的碳原子成环丙基； Alternatively, R 1 forms a cyclopropyl group with R b or R c and the carbon atoms connected together;
    或者，R b与R c及共同相连的碳原子成环丙基； Alternatively, R b and R c and the carbon atoms connected together form a cyclopropyl group;
    R’选自C 1～3烷基，所述C 1～3烷基任选被1、2或3个卤素取代； R'is selected from a C 1-3 alkyl group, and the C 1-3 alkyl group is optionally substituted with 1, 2 or 3 halogens;
    m各自独立地选自0、1和2；m is each independently selected from 0, 1 and 2;
    n选自1和2；n is selected from 1 and 2;
    X选自-PO(OH) 2、-P(O)[-OC(R d) 2OC(O)R e] 2、-P(O)[-OC(R d) 2OC(O)OR e] 2、-P(O)[-N(H)C(R d) 2C(O)OR e][-OR e]、-P(O)[-N(H)C(R d) 2C(O)OR e] 2和
    Figure PCTCN2020139562-appb-100002
    X is selected from -PO(OH) 2 , -P(O)[-OC(R d ) 2 OC(O)R e ] 2 , -P(O)[-OC(R d ) 2 OC(O)OR e ] 2 , -P(O)[-N(H)C(R d ) 2 C(O)OR e ][-OR e ], -P(O)[-N(H)C(R d ) 2 C(O)OR e ] 2 and
    Figure PCTCN2020139562-appb-100002
    V选自C 6-10芳基和5～10元杂芳基，所述C 6-10芳基和5～10元杂芳基任选被1、2或3个卤素取代； V is selected from a C 6-10 aryl group and a 5-10 membered heteroaryl group, the C 6-10 aryl group and a 5-10 membered heteroaryl group are optionally substituted by 1, 2 or 3 halogens;
    各R d独立地选自R e和H； Each R d and R e is independently selected from H;
    各R e独立地选自C 1-4烷基和C 6-10芳基，所述C 1-4烷基和C 6-10芳基任选被1、2或3个卤素取代； Each R e is independently selected from a C 1-4 alkyl group and a C 6-10 aryl group, the C 1-4 alkyl group and C 6-10 aryl group are optionally substituted with 1, 2 or 3 halogens;
    所述“杂”包含1、2或3个独立地选自-O-、-NH-、-S-和N的杂原子或杂原子团。The "hetero" includes 1, 2 or 3 heteroatoms or heteroatom groups independently selected from -O-, -NH-, -S- and N.
  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 1选自H、F、OH、NH 2、 C 1-3烷基和C 1-3烷氧基，所述C 1-3烷基和C 1-3烷氧基任选被1、2或3个卤素取代。 The compound, its isomers, or pharmaceutically acceptable salts thereof according to claim 1, wherein R 1 is selected from H, F, OH, NH 2 , C 1-3 alkyl and C 1-3 alkoxy , The C 1-3 alkyl group and C 1-3 alkoxy group are optionally substituted with 1, 2 or 3 halogens.
  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 1选自H、F、OH、NH 2和CH 3。 The compound, its isomer, or a pharmaceutically acceptable salt thereof according to claim 2, wherein R 1 is selected from H, F, OH, NH 2 and CH 3 .
  4. 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 2选自H、F、Cl、Br、NH 2、C 1～3烷基和环丙基，所述C 1～3烷基任选被1、2或3个F取代。 The compound, its isomers, or pharmaceutically acceptable salts thereof according to claim 1, wherein R 2 is selected from H, F, Cl, Br, NH 2 , C 1-3 alkyl and cyclopropyl, so The C 1-3 alkyl group is optionally substituted with 1, 2 or 3 F.
  5. 根据权利要求4所述化合物、其异构体或其药学上可接受的盐，其中，R 2选自Cl、Br、CH 3、CF 3和环丙基。 The compound, its isomer, or a pharmaceutically acceptable salt thereof according to claim 4, wherein R 2 is selected from Cl, Br, CH 3 , CF 3 and cyclopropyl.
  6. 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，各R分别独立地选自F和CH 3。 The compound, its isomer, or a pharmaceutically acceptable salt thereof according to claim 1, wherein each R is independently selected from F and CH 3 .
  7. 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 3、R 4和R 5各自独立地选自H、卤素、OH、NH 2、C 1-3烷基、C 3-6环烷基和4-6元杂环烷基，所述C 1-3烷基、C 3-6环烷基和4-6元杂环烷基任选被1、2或3个R取代。 The compound, its isomers, or pharmaceutically acceptable salts thereof according to claim 1, wherein R 3 , R 4 and R 5 are each independently selected from H, halogen, OH, NH 2 , C 1-3 alkane Group, C 3-6 cycloalkyl group and 4-6 membered heterocycloalkyl group, the C 1-3 alkyl group, C 3-6 cycloalkyl group and 4-6 membered heterocycloalkyl group are optionally selected by 1, 2 Or 3 R substitutions.
  8. 根据权利要求7所述化合物、其异构体或其药学上可接受的盐，其中，R 3、R 4和R 5各自独立地选自H、F、Cl、OH、CH 3、CF 3、CH 2CH 3、CH(CH 3) 2、
    Figure PCTCN2020139562-appb-100003
    The compound, its isomers, or pharmaceutically acceptable salts thereof according to claim 7, wherein R 3 , R 4 and R 5 are each independently selected from H, F, Cl, OH, CH 3 , CF 3 , CH 2 CH 3 , CH(CH 3 ) 2 ,
    Figure PCTCN2020139562-appb-100003
  9. 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，L 1选自-(CH 2) m-、-NH(CH 2) m-和-O(CH 2) m-。 The compound, its isomers, or pharmaceutically acceptable salts thereof according to claim 1, wherein L 1 is selected from -(CH 2 ) m -, -NH(CH 2 ) m -and -O(CH 2 ) m -.
  10. 根据权利要求9所述化合物、其异构体或其药学上可接受的盐，其中，L 1选自-CH 2-、-(CH 2) 2-、-NHCH 2-和-OCH 2-。 The compound, its isomer, or a pharmaceutically acceptable salt thereof according to claim 9, wherein L 1 is selected from -CH 2 -, -(CH 2 ) 2 -, -NHCH 2 -and -OCH 2 -.
  11. 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 PCTCN2020139562-appb-100004
    选自
    Figure PCTCN2020139562-appb-100005
    Figure PCTCN2020139562-appb-100006
    The compound, its isomers, or pharmaceutically acceptable salts thereof according to claim 1, wherein the structural unit
    Figure PCTCN2020139562-appb-100004
    Selected from
    Figure PCTCN2020139562-appb-100005
    Figure PCTCN2020139562-appb-100006
  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，结构单元
    Figure PCTCN2020139562-appb-100007
    选自
    Figure PCTCN2020139562-appb-100008
    The compound, its isomers, or pharmaceutically acceptable salts thereof according to claim 11, wherein the structural unit
    Figure PCTCN2020139562-appb-100007
    Selected from
    Figure PCTCN2020139562-appb-100008
  13. 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，V选自苯基，所述苯基任选被1、2或3个卤素取代。The compound, its isomers, or pharmaceutically acceptable salts thereof according to claim 1, wherein V is selected from phenyl, and said phenyl is optionally substituted with 1, 2 or 3 halogens.
  14. 根据权利要求13所述化合物、其异构体或其药学上可接受的盐，其中，V选自
    Figure PCTCN2020139562-appb-100009
    The compound, its isomers, or pharmaceutically acceptable salts thereof according to claim 13, wherein V is selected from
    Figure PCTCN2020139562-appb-100009
  15. 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 e选自-CH 3、-CH 2CH 3、-CH(CH 3) 2、-C(CH 3) 3和苯基。 The compound, its isomers, or pharmaceutically acceptable salts thereof according to claim 1, wherein R e is selected from -CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , -C(CH 3 ) 3 and phenyl.
  16. 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，X选自-PO(OH) 2、-P(O)[-OCH 2OC(O)-叔丁基] 2、-P(O)[-OCH 2OC(O)O-异丙基] 2、-P(O)[-N(H)CH(CH 3)C(O)OCH 2CH 3] 2、-P(O)[-N(H)C(CH 3) 2C(O)OCH 2CH 3] 2、
    Figure PCTCN2020139562-appb-100010
    The compound, its isomers, or pharmaceutically acceptable salts thereof according to claim 1, wherein X is selected from -PO(OH) 2 , -P(O)[-OCH 2 OC(O)-tert-butyl ] 2 , -P(O)[-OCH 2 OC(O)O-isopropyl] 2 , -P(O)[-N(H)CH(CH 3 )C(O)OCH 2 CH 3 ] 2 , -P(O)[-N(H)C(CH 3 ) 2 C(O)OCH 2 CH 3 ] 2 ,
    Figure PCTCN2020139562-appb-100010
  17. 根据权利要求16所述化合物、其异构体或其药学上可接受的盐，其中，X选自-PO(OH) 2、
    Figure PCTCN2020139562-appb-100011
    The compound, its isomers, or pharmaceutically acceptable salts thereof according to claim 16, wherein X is selected from -PO(OH) 2 ,
    Figure PCTCN2020139562-appb-100011
  18. 根据权利要求1～11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, its isomers, or pharmaceutically acceptable salts thereof according to any one of claims 1 to 11, which are selected from
    Figure PCTCN2020139562-appb-100012
    Figure PCTCN2020139562-appb-100012
    其中，among them,
    R 1、R 2、R 3、R 4、R 5和L 1如权利要求1～11任意一项所定义。 R 1 , R 2 , R 3 , R 4 , R 5 and L 1 are as defined in any one of claims 1-11.
  19. 下式化合物、其异构体或其药学上可接受的盐：The compound of the following formula, its isomer or its pharmaceutically acceptable salt:
    Figure PCTCN2020139562-appb-100013
    Figure PCTCN2020139562-appb-100013
    Figure PCTCN2020139562-appb-100014
    Figure PCTCN2020139562-appb-100014
    Figure PCTCN2020139562-appb-100015
    Figure PCTCN2020139562-appb-100015
  20. 根据权利要求19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 claim 19, its isomers or a pharmaceutically acceptable salt thereof, which are selected from:
    Figure PCTCN2020139562-appb-100016
    Figure PCTCN2020139562-appb-100016
    Figure PCTCN2020139562-appb-100017
    Figure PCTCN2020139562-appb-100017
    Figure PCTCN2020139562-appb-100018
    Figure PCTCN2020139562-appb-100018
    Figure PCTCN2020139562-appb-100019
    Figure PCTCN2020139562-appb-100019
  21. 根据权利要求1～20任意一项所述的化合物、其异构体或其药学上可接受的盐用于制备治疗THR-β激动剂相关疾病的药物上的应用。The use of the compound, its isomer or pharmaceutically acceptable salt according to any one of claims 1 to 20 for the preparation of a medicament for the treatment of diseases related to THR-β agonists.
  22. 根据权利要求21所述的应用，其特征在于，所述THR-β激动剂相关药物是用于非酒精性脂肪性肝炎(NASH)的药物。The application according to claim 21, wherein the THR-β agonist-related drug is a drug for non-alcoholic steatohepatitis (NASH).
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