WO2021083167A1 - 取代的杂环并环类化合物，其制法与医药上的用途 - Google Patents

取代的杂环并环类化合物，其制法与医药上的用途 Download PDF

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WO2021083167A1
WO2021083167A1 PCT/CN2020/124226 CN2020124226W WO2021083167A1 WO 2021083167 A1 WO2021083167 A1 WO 2021083167A1 CN 2020124226 W CN2020124226 W CN 2020124226W WO 2021083167 A1 WO2021083167 A1 WO 2021083167A1
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alkyl
alkoxy
halo
group
ring
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PCT/CN2020/124226
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English (en)
French (fr)
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周福生
蒋涛
林崇懒
蔡礼健
何宛
兰炯
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劲方医药科技(上海)有限公司
浙江劲方药业有限公司
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Priority to CA3156777A priority Critical patent/CA3156777A1/en
Priority to EP23204050.1A priority patent/EP4328229A2/en
Priority to JP2022526049A priority patent/JP2023502891A/ja
Priority to AU2020374844A priority patent/AU2020374844B2/en
Application filed by 劲方医药科技(上海)有限公司, 浙江劲方药业有限公司 filed Critical 劲方医药科技(上海)有限公司
Priority to KR1020227018301A priority patent/KR20220106765A/ko
Priority to US17/773,607 priority patent/US20230084095A1/en
Priority to EP20882039.9A priority patent/EP4053118A4/en
Priority to BR112022008375A priority patent/BR112022008375A2/pt
Priority to CN202080034074.0A priority patent/CN113853373B/zh
Priority to CN202311339164.2A priority patent/CN117645614A/zh
Priority to CN202210818001.1A priority patent/CN115057872A/zh
Publication of WO2021083167A1 publication Critical patent/WO2021083167A1/zh
Priority to ZA2022/05758A priority patent/ZA202205758B/en
Priority to JP2023176319A priority patent/JP2023175993A/ja
Priority to US18/381,121 priority patent/US20240158417A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/16—Peri-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed systems contains four or more hetero rings

Definitions

  • the invention relates to the technical field of medicine, in particular to a substituted heterocyclic compound, its application as a selective inhibitor of KRAS gene mutation, and a pharmaceutical composition prepared therefrom.
  • Lung cancer is the cancer with the highest incidence in the world. It ranks first among all cancers in China. It is also the cancer with the highest incidence and mortality in China. According to data released by the American Cancer Society in 2016, approximately 1.8 million people suffer from lung cancer, and nearly 80% of lung cancers are non-small cell lung cancer (NSCLC).
  • NSCLC non-small cell lung cancer
  • RAS is a group of closely related monomeric globular proteins (21 kDa molecular weight), which have 188-189 amino acids and bind to guanosine diphosphate GDP or guanosine triphosphate GTP.
  • Members of the RAS subfamily include HRAS, KRAS, and NRAS.
  • RAS acts as a molecular switch. When RAS contains bound GDP, it is in a dormant or closed position and is "inactive". When cells are exposed to certain growth-promoting stimuli, RAS is induced to convert its bound GDP into GTP. When it binds to GTP, RAS "turns on” and can interact and activate with other downstream target proteins. These proteins.
  • the RAS protein itself has a very low inherent ability to hydrolyze GTP and restore it to GDP (thus turning itself into a closed state).
  • the exogenous protein GTPase Activated Protein (GAP) is required to restore it to the closed state.
  • GAP GTPase Activated Protein
  • the interaction between GAP and RAS greatly accelerates the conversion of GTP to GDP.
  • Any mutation in RAS will affect the interaction between RAS and GAP, as well as the ability of GTP to convert into GDP. This mutation will lead to prolonged protein activation time, thereby prolonging cell signal transduction, which in turn will cause cells to continue to grow and divide. Since this signaling causes cell growth and division, over-activated RAS signaling can eventually lead to cancer.
  • lung cancers mutations in the RAS gene are confirmed in about 32% of lung cancers.
  • a mutation in any of the three main subtypes of the RAS (HRAS, NRAS, or KRAS) gene can lead to human tumors. It has been reported that the KRAS gene has the highest mutation frequency among RAS genes, and KRAS mutations are detected in 25-30% of tumors. In comparison, the rates of oncogenic mutations in NRAS and HRAS family members are much lower (8% and 3%, respectively). The most common KRAS mutations are found in residues G12 and G13 and residue Q61 in the P loop. The G12C mutation is a frequent mutation of the KRAS gene (mutation of glycine-12 to cysteine).
  • This mutation has been found in about 13% of cancers, about 43% of lung cancers, and almost 100% of MYH-related polyposis (familial colon cancer syndrome). Therefore, it is a better direction to develop inhibitors that selectively inhibit KRAS mutations.
  • KRAS mutations In order to increase the inhibitory activity against KRAS mutations while reducing the inhibitory activity against wild-type KRAS, we will develop new types with higher activity, better selectivity, and lower toxicity. Selective inhibitors of RAS mutants are of great significance.
  • the present invention provides a substituted heterocyclic compound with a novel structure, which, as a selective inhibitor of KRAS mutation, has the advantages of high activity, good selectivity, and low toxicity and side effects.
  • the present invention provides a compound represented by formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof:
  • R 1 and R 2 are each independently hydrogen, halogen, cyano, NR a R b , -C 1-3 alkyl, halo C 1-3 alkyl, -C 1-3 alkyl-hydroxy, -C 1-3 alkyl-cyano group, -C 1-3 alkyl-C 1-3 alkoxy group, -C 1-3 alkyl-NR a R b , -C 1-3 alkyl group-3 to 6 members Heterocycloalkyl or -C 1-3 alkyl-5 or 6-membered monocyclic heteroaryl; wherein the 3- to 6-membered heterocycloalkyl or the 5- or 6-membered monocyclic heteroaryl has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms;
  • R 3 is hydrogen, halogen, -C 1-3 alkyl or -C 1-3 alkoxy
  • R 4 is hydrogen, halogenated C 1-3 alkyl, -C 1-3 alkyl-hydroxy, -C 1-3 alkyl-cyano or -C 1-3 alkyl-C 1-3 alkoxy ;
  • R 11 and R 12 are the same or different, and are each independently hydrogen, halogen, -C 1-3 alkyl, -halo C 1-3 alkyl, -C 1-3 alkyl-hydroxy, -C 1-3 Alkyl-cyano, -C 1-3 alkyl-C 1-6 alkoxy, -C 1-3 alkyl-halo C 1-6 alkyl or -C 1-3 alkyl-halo C 1-6 alkoxy;
  • R 21 and R 22 are the same or different, and are each independently hydrogen, halogen, -C 1-3 alkyl, -halo C 1-3 alkyl, -C 1-3 alkyl-hydroxy, -C 1-3 Alkyl-cyano, -C 1-3 alkyl-C 1-6 alkoxy, -C 1-3 alkyl-halo C 1-6 alkyl or -C 1-3 alkyl-halo C 1-6 alkoxy;
  • R 31 and R 32 are the same or different, and are each independently hydrogen, halogen, -C 1-3 alkyl, -halo C 1-3 alkyl, -C 1-3 alkyl-hydroxy, -C 1-3 Alkyl-cyano, -C 1-3 alkyl-C 1-6 alkoxy, -C 1-3 alkyl-halo C 1-6 alkyl or -C 1-3 alkyl-halo C 1-6 alkoxy;
  • R 41 is hydrogen, halogen, -C 1-3 alkyl, -halo C 1-3 alkyl, -C 1-3 alkyl-hydroxy, -C 1-3 alkyl-cyano, -C 1- 3 alkyl-C 1-6 alkoxy, -C 1-3 alkyl-halo C 1-6 alkyl or -C 1-3 alkyl-halo C 1-6 alkoxy;
  • R m is -C 1-6 alkyl, -halo C 1-6 alkyl, -C 1-6 alkyl-hydroxy, -C 1-6 alkyl-cyano, -C 1-6 alkyl-C 1-6 alkoxy, -C 1-6 alkyl-halogenated C 1-6 alkoxy, -C 1-6 alkyl -C 3-6 cycloalkyl or -C 1-6 alkyl 3-membered to 6-membered heterocycloalkyl;
  • P is hydrogen, halogen
  • R 42 is hydrogen, halogen, -C 1-3 alkyl, -halo C 1-3 alkyl, -C 1-3 alkyl-hydroxy, -C 1-3 alkyl-cyano, -C 1-3 alkyl-C 1-6 alkoxy, -C 1-3 alkyl-halogenated C 1-6 alkyl or -C 1-3 alkyl- Halogenated C 1-6 alkoxy;
  • X 1 is hydrogen, halogen, cyano, hydroxyl, amino, nitro,-substituted or unsubstituted C 1-6 alkyl,-substituted or unsubstituted C 3-6 cycloalkyl, -Substituted or unsubstituted 3 to 6-membered heterocycloalkyl, -O-substituted or unsubstituted C 1-6 alkyl, -O-substituted or unsubstituted C 3-6 cycloalkyl, -O-substituted Or unsubstituted 3 to 6-membered heterocycloalkyl, -NH-substituted or unsubstituted C 1-6 alkyl, -N (substituted or unsubstituted C 1-6 alkyl) 2 , -NH-substituted or Unsubstituted C 3-6 cycloalkyl, -
  • the S group substituents are selected from: hydroxy, halogen, nitro, oxo, -C 1-6 alkyl, -halo C 1-6 alkyl, hydroxy substituted C 1-6 alkyl, benzyl , -(CH 2 ) u -cyano, -(CH 2 ) u -C 1-6 alkoxy, -(CH 2 ) u -halogenated C 1-6 alkoxy, -(CH 2 ) u- Halogenated C 1-6 alkyl, -(CH 2 ) u -3 to 6-membered heterocycloalkyl, -(CH 2 ) u -5 or 6-membered monocyclic heteroaryl, -(CH 2 ) u -C 3-8 cycloalkyl, -(CH 2 ) u -O-(CH 2 ) v -C 3-8 cycloalkyl, -(CH 2 ) u -O-(CH 2 ) v
  • E 1 is N or CR 5 ; where R 5 is hydrogen, halogen, cyano, -C 1-6 alkyl, -C 1-6 alkoxy, -haloC 1-6 alkyl, -halo C 1-6 alkoxy, -C 3-6 cycloalkyl, -NR h R i , -C 1-4 alkyl-hydroxy, -C 1-4 alkyl-cyano, -C 1-4 alkane Group -C 1-6 alkoxy, -C 1-4 alkyl-halo C 1-6 alkyl or -C 1-4 alkyl-halo C 1-6 alkoxy;
  • E 2 is N or CR 6 ; wherein R 6 is hydrogen, halogen, cyano, -C 1-6 alkyl, -C 1-6 alkoxy, -halo C 1-6 alkyl, -halo C 1-6 alkoxy, -C 3-6 cycloalkyl, -NR h R i , -C 1-4 alkyl-hydroxy, -C 1-4 alkyl-cyano, -C 1-4 alkane Group -C 1-6 alkoxy, -C 1-4 alkyl-halo C 1-6 alkyl or -C 1-4 alkyl-halo C 1-6 alkoxy;
  • Ar is a C 6-10 aryl group, a 5- or 6-membered monocyclic heteroaryl group or an 8- to 10-membered bicyclic heteroaryl group; wherein the 5- or 6-membered monocyclic heteroaryl group has 1, 2 or 3 Heteroatoms of N, O, and S as ring atoms; the 8- to 10-membered bicyclic heteroaryl group has 1, 2, 3, 4, or 5 heteroatoms selected from N, O, and S as ring atoms; and
  • the C 6-10 aryl group, the 5- or 6-membered monocyclic heteroaryl group or the 8- to 10-membered bicyclic heteroaryl group is unsubstituted or has 1, 2, 3, or 4 groups independently selected from R s1 Group replacement
  • Ar is the structure shown in formula (B):
  • the B1 ring is a benzene ring or a 5- or 6-membered monocyclic heteroaryl ring
  • the B2 ring is a fused 5- or 6-membered monocyclic heterocycloalkyl ring or a fused 5- or 6-membered monocyclic cycloalkyl ring Ring
  • the 5- or 6-membered monocyclic heteroaryl ring or the fused 5- or 6-membered monocyclic heterocycloalkyl ring has 1, 2 or 3 heteroatoms selected from N, O and S As ring atoms;
  • R s1 p indicates that the hydrogen on the B1 ring is replaced by p R s1 , p is 0, 1, 2 or 3, and each R s1 is the same or different;
  • R s2 (R s2 ) q means that the hydrogen on the B2 ring is replaced by q R s2 , q is 0, 1, 2 or 3, and each R s2 is the same or different;
  • R s1 and R s2 are each independently halogen, cyano, nitro, hydroxyl, -C 1-6 alkyl, -C 1-6 alkoxy, -haloC 1-6 alkyl, -haloC 1-6 alkoxy, -C 3-6 cycloalkyl, -NR c R d , -C(O)NR e R f , -SO 2 C 1-3 alkyl, -SO 2 halo C 1- 3 alkyl, -SO 2 NR e R f , -C 1-4 alkyl-hydroxy, -C 1-4 alkyl-cyano, -C 1-4 alkyl-C 1-6 alkoxy,- C 1-4 alkyl-halo C 1-6 alkyl, -C 1-4 alkyl-halo C 1-6 alkoxy, -C 1-4 alkyl-3 to 6-membered heterocycloalkyl , -C 1-4 alkyl-NR e R f ,
  • R 0 is -C 1-6 alkyl, -C 3-6 cycloalkyl, 3 to 6 membered heterocycloalkyl, C 6-10 aryl, 5 or 6 membered monocyclic heteroaryl, 8 to 10 member Bicyclic heteroaryl, 7 to 11 membered spiro cycloalkyl, -C 1-3 alkyl-C 6-10 aryl, -C 1-3 alkyl-5 or 6-membered monocyclic heteroaryl, -NR g -C 6-10 aryl, -OC 6-10 aryl, -C 1-3 alkyl-3 to 6-membered heterocycloalkyl, -C 1-3 alkyl-C 3-6 cycloalkyl, wherein ,
  • the 3 to 6 membered heterocycloalkyl group, the 5 or 6 membered monocyclic heteroaryl group or the 8 to 10 membered bicyclic heteroaryl group has 1, 2 or 3 heterocyclic groups selected from N, O and S Atom as
  • R 0 is the structure shown in formula (A-1) or formula (A-2):
  • A1 ring is a benzene ring or a 5- or 6-membered monocyclic heteroaryl ring
  • A2 ring is a fused 5- or 6-membered monocyclic heterocycloalkyl ring or a fused 5- or 6-membered monocyclic cycloalkyl ring Ring
  • the 5- or 6-membered monocyclic heteroaryl ring or the fused 5- or 6-membered monocyclic heterocycloalkyl ring has 1, 2 or 3 heteroatoms selected from N, O and S As ring atoms
  • R s3 ) t means that the hydrogen on the A1 ring is replaced by t R s3 , t is 0, 1, 2 or 3, and each R s3 is the same or different;
  • R s4 means that the hydrogen on the A2 ring is replaced by s R s4 , s is 0, 1, 2 or 3, and each R s4 is the same or different;
  • R s3 and R s4 are each independently halogen, cyano, hydroxyl, -C 1-6 alkyl, -C 1-6 alkoxy, -halo C 1-6 alkyl, -halo C 1-6 Alkoxy, -C 3-6 cycloalkyl, 3 to 6 membered heterocycloalkyl, -NR h R i , -C(O)NR e R f , -SO 2 C 1-3 alkyl, -SO 2 halogenated C 1-3 alkyl, -SO 2 NR e R f, -C 1-3 alkyl - hydroxy, -C 1-3 alkyl -C 2-4 alkynyl, -C 1-3 alkyl -Cyano, -C 1-3 alkyl-C 1-6 alkoxy, -C 1-3 alkyl-halo C 1-6 alkyl, -C 1-3 alkyl-halo C 1- 6 alkoxy, -C
  • R a, R b, R e , R f, R g are each independently hydrogen or C 1-3 alkyl;
  • R c , R d , R h , and R i are each independently hydrogen, -C 1-3 alkyl, -C(O)C 1-3 alkyl, or -CO 2 C 1-3 alkyl.
  • the compound represented by formula (I) is a compound of formula (I-1) or a compound of formula (I-2);
  • P is O, NH or NR m ;
  • R m is -C 1-6 alkyl, -halo C 1-6 alkyl, -C 1-6 alkyl-hydroxy, -C 1- 6 Alkyl-cyano, -C 1-6 alkyl-C 1-6 alkoxy, -C 1-6 alkyl-halogenated C 1-6 alkoxy, -C 1-6 alkyl-C 3-6 cycloalkyl or -C 1-6 alkyl-3 to 6-membered heterocycloalkyl;
  • P is hydrogen, halogen
  • R 42 is hydrogen, halogen, -C 1-3 alkyl, -halo C 1-3 alkyl, -C 1-3 alkyl-hydroxy, -C 1 -3 alkyl-cyano, -C 1-3 alkyl-C 1-6 alkoxy, -C 1-3 alkyl-halo C 1-6 alkyl or -C 1-3 alkyl-halo Substitute C 1-6 alkoxy;
  • R 11 , R 12 , R 21 , R 22 , R 31 , R 32 , R 41 , Z, R 0 , Ar, E 1 , E 2 , X 1 , Y 1 have the same definitions before.
  • the present invention provides a compound represented by formula (IA) or its tautomer, cis-trans, meso, racemate, enantiomer, non- Enantiomers, atropisomers or mixtures thereof, or pharmaceutically acceptable salts, solvates or prodrugs thereof:
  • R 1 and R 2 are each independently hydrogen, halogen, cyano, NR a R b , -C 1-3 alkyl, halo C 1-3 alkyl, -C 1-3 alkyl-hydroxy, -C 1-3 alkyl-cyano group, -C 1-3 alkyl-C 1-3 alkoxy group, -C 1-3 alkyl-NR a R b , -C 1-3 alkyl group-3 to 6 members Heterocycloalkyl or -C 1-3 alkyl-5 or 6-membered monocyclic heteroaryl; wherein said 3- to 6-membered heterocycloalkyl or said 5- or 6-membered monocyclic heteroaryl has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms;
  • R 3 is hydrogen, halogen, -C 1-3 alkyl or -C 1-3 alkoxy
  • R 4 is hydrogen, halogenated C 1-3 alkyl, -C 1-3 alkyl-hydroxy, -C 1-3 alkyl-cyano or -C 1-3 alkyl-C 1-3 alkoxy ;
  • R 11 and R 12 are the same or different, and are each independently hydrogen, halogen, -C 1-3 alkyl, -halo C 1-3 alkyl, -C 1-3 alkyl-hydroxy, -C 1-3 Alkyl-cyano, -C 1-3 alkyl-C 1-6 alkoxy, -C 1-3 alkyl-halo C 1-6 alkyl or -C 1-3 alkyl-halo C 1-6 alkoxy;
  • R 21 and R 22 are the same or different, and are each independently hydrogen, halogen, -C 1-3 alkyl, -halo C 1-3 alkyl, -C 1-3 alkyl-hydroxy, -C 1-3 Alkyl-cyano, -C 1-3 alkyl-C 1-6 alkoxy, -C 1-3 alkyl-halo C 1-6 alkyl or -C 1-3 alkyl-halo C 1-6 alkoxy;
  • R 31 and R 32 are the same or different, and are each independently hydrogen, halogen, -C 1-3 alkyl, -halo C 1-3 alkyl, -C 1-3 alkyl-hydroxy, -C 1-3 Alkyl-cyano, -C 1-3 alkyl-C 1-6 alkoxy, -C 1-3 alkyl-halo C 1-6 alkyl or -C 1-3 alkyl-halo C 1-6 alkoxy;
  • R 41 is hydrogen, halogen, -C 1-3 alkyl, -halo C 1-3 alkyl, -C 1-3 alkyl-hydroxy, -C 1-3 alkyl-cyano, -C 1- 3 alkyl-C 1-6 alkoxy, -C 1-3 alkyl-halo C 1-6 alkyl or -C 1-3 alkyl-halo C 1-6 alkoxy;
  • P' is hydrogen, halogen
  • R 42 ' is hydrogen, halogen, -C 1-3 alkyl, -halo C 1-3 alkyl, -C 1-3 alkyl-hydroxy, -C 1-3 alkyl-cyano, -C 1-3 alkyl-C 1-6 alkoxy, -C 1-3 alkyl-halogenated C 1-6 alkyl or -C 1-3 alkane Group-halo C 1-6 alkoxy;
  • X 1 is hydrogen, halogen, cyano, hydroxyl, amino, nitro,-substituted or unsubstituted C 1-6 alkyl,-substituted or unsubstituted C 3-6 cycloalkyl, -Substituted or unsubstituted 3 to 6-membered heterocycloalkyl, -O-substituted or unsubstituted C 1-6 alkyl, -O-substituted or unsubstituted C 3-6 cycloalkyl, -O-substituted Or unsubstituted 3 to 6-membered heterocycloalkyl, -NH-substituted or unsubstituted C 1-6 alkyl, -N (substituted or unsubstituted C 1-6 alkyl) 2 , -NH-substituted or Unsubstituted C 3-6 cycloalkyl, -
  • the S group substituents are selected from: hydroxy, halogen, nitro, oxo, -C 1-6 alkyl, -halo C 1-6 alkyl, hydroxy substituted C 1-6 alkyl, benzyl , -(CH 2 ) u -cyano, -(CH 2 ) u -C 1-6 alkoxy, -(CH 2 ) u -halogenated C 1-6 alkoxy, -(CH 2 ) u- Halogenated C 1-6 alkyl, -(CH 2 ) u -3 to 6-membered heterocycloalkyl, -(CH 2 ) u -5 or 6-membered monocyclic heteroaryl, -(CH 2 ) u -C 3-8 cycloalkyl, -(CH 2 ) u -O-(CH 2 ) v -C 3-8 cycloalkyl, -(CH 2 ) u -O-(CH 2 ) v
  • E 1 ' is N or CR 5 '; wherein R 5 ' is hydrogen, halogen, cyano, -C 1-6 alkyl, -C 1-6 alkoxy, -halo C 1-6 alkyl, -Halogenated C 1-6 alkoxy, -C 3-6 cycloalkyl, -OC 3-6 cycloalkyl, -NR h R i , -C 1-4 alkyl-hydroxy, -C 1-4 Alkyl-cyano, -C 1-4 alkyl-C 1-6 alkoxy, -C 1-4 alkyl-halo C 1-6 alkyl or -C 1-4 alkyl-halo C 1-6 alkoxy;
  • E 2 ' is N or CR 6 '; wherein R 6 ' is hydrogen, halogen, cyano, -C 1-6 alkyl, -C 1-6 alkoxy, -halo C 1-6 alkyl, -Halogenated C 1-6 alkoxy, -C 3-6 cycloalkyl, -OC 3-6 cycloalkyl, -NR h R i , -C 1-4 alkyl-hydroxy, -C 1-4 Alkyl-cyano, -C 1-4 alkyl-C 1-6 alkoxy, -C 1-4 alkyl-halo C 1-6 alkyl or -C 1-4 alkyl-halo C 1-6 alkoxy;
  • Ar' is a C 6-10 aryl group, a 5- or 6-membered monocyclic heteroaryl group, an 8- to 10-membered bicyclic heteroaryl group or a pyridonyl group; wherein the 5- or 6-membered monocyclic heteroaryl group has 1, 2 Or 3 heteroatoms selected from N, O and S as ring atoms; the 8- to 10-membered bicyclic heteroaryl group has 1, 2, 3, 4 or 5 heteroatoms selected from N, O and S as the ring Atom; and the C 6-10 aryl group, the 5- or 6-membered monocyclic heteroaryl group, the 8- to 10-membered bicyclic heteroaryl group and the pyridone group are unsubstituted or are 1, 2, 3 or 4 groups independently selected from R s1 are substituted;
  • the B1 ring is a benzene ring or a 5- or 6-membered monocyclic heteroaryl ring
  • the B2 ring is a fused 5- or 6-membered monocyclic heterocycloalkyl ring or a fused 5- or 6-membered monocyclic cycloalkyl ring Ring
  • the 5- or 6-membered monocyclic heteroaryl ring or the fused 5- or 6-membered monocyclic heterocycloalkyl ring has 1, 2 or 3 heteroatoms selected from N, O and S As ring atoms;
  • R s1 p indicates that the hydrogen on the B1 ring is replaced by p R s1 , p is 0, 1, 2 or 3, and each R s1 is the same or different;
  • R s2 (R s2 ) q means that the hydrogen on the B2 ring is replaced by q R s2 , q is 0, 1, 2 or 3, and each R s2 is the same or different;
  • R s1 and R s2 are each independently halogen, cyano, nitro, hydroxyl, -C 1-6 alkyl, -C 1-6 alkoxy, -haloC 1-6 alkyl, -haloC 1-6 alkoxy, -C 3-6 cycloalkyl, -NR c R d , -C(O)NR e R f , -SO 2 C 1-3 alkyl, -SO 2 halo C 1- 3 alkyl, -SO 2 NR e R f , -C 1-4 alkyl-hydroxy, -C 1-4 alkyl-cyano, -C 1-4 alkyl-C 1-6 alkoxy,- C 1-4 alkyl-halo C 1-6 alkyl, -C 1-4 alkyl-halo C 1-6 alkoxy, -C 1-4 alkyl-3 to 6-membered heterocycloalkyl , -C 1-4 alkyl-NR e R f ,
  • R 0 ' is -C 1-6 alkyl, -C 3-6 cycloalkyl, 3 to 6 membered heterocycloalkyl, C 6-10 aryl, 5 or 6 membered monocyclic heteroaryl, 8 to 10 Member bicyclic heteroaryl, 7 to 11 membered spiro cycloalkyl, -C 1-3 alkyl-C 6-10 aryl, -C 1-3 alkyl-5 or 6-membered monocyclic heteroaryl, -NR g -C 6-10 aryl, -OC 6-10 aryl, -C 1-3 alkyl-3 to 6-membered heterocycloalkyl, -C 1-3 alkyl-C 3-6 cycloalkyl or Pyridone, wherein the 3- to 6-membered heterocycloalkyl group, the 5- or 6-membered monocyclic heteroaryl group or the 8- to 10-membered bicyclic heteroaryl group has 1, 2, or 3 selected from N, O and S heteroatoms
  • A1 ring is a benzene ring or a 5- or 6-membered monocyclic heteroaryl ring
  • A2 ring is a fused 5- or 6-membered monocyclic heterocycloalkyl ring or a fused 5- or 6-membered monocyclic cycloalkyl ring Ring
  • the 5- or 6-membered monocyclic heteroaryl ring or the fused 5- or 6-membered monocyclic heterocycloalkyl ring has 1, 2 or 3 heteroatoms selected from N, O and S As ring atoms
  • R s3 ) t means that the hydrogen on the A1 ring is replaced by t R s3 , t is 0, 1, 2 or 3, and each R s3 is the same or different;
  • R s4 means that the hydrogen on the A2 ring is replaced by s R s4 , s is 0, 1, 2 or 3, and each R s4 is the same or different;
  • R s3 and R s4 are each independently halogen, cyano, hydroxyl, -C 1-6 alkyl, -C 1-6 alkoxy, -halo C 1-6 alkyl, -halo C 1-6 Alkoxy, -C 3-6 cycloalkyl, 3 to 6 membered heterocycloalkyl, -NR h R i , -C(O)NR e R f , -SO 2 C 1-3 alkyl, -SO 2 halogenated C 1-3 alkyl, -SO 2 NR e R f, -C 1-3 alkyl - hydroxy, -C 1-3 alkyl -C 2-4 alkynyl, -C 1-3 alkyl -Cyano, -C 1-3 alkyl-C 1-6 alkoxy, -C 1-3 alkyl-halo C 1-6 alkyl, -C 1-3 alkyl-halo C 1- 6 alkoxy, -C
  • R a, R b, R e , R f, R g are each independently hydrogen or C 1-3 alkyl;
  • R c , R d , R h , and R i are each independently hydrogen, -C 1-3 alkyl, -C(O)C 1-3 alkyl, or -CO 2 C 1-3 alkyl.
  • the compound represented by formula (IA) is a compound of formula (IB) or a compound of formula (IC);
  • P' is hydrogen or halogen
  • R 42 ' is hydrogen, halogen, -C 1-3 alkyl, -halo C 1-3 alkyl, -C 1-3 alkyl-hydroxy, -C 1 -3 alkyl-cyano, -C 1-3 alkyl-C 1-6 alkoxy, -C 1-3 alkyl-halo C 1-6 alkyl or -C 1-3 alkyl-halo Substituted C 1-6 alkoxy; R 11 , R 12 , R 21 , R 22 , R 31 , R 32 , R 41 , Z, R 0 ', Ar', E 1 ', E 2 ', X 1 , Y 1 is defined as before.
  • P' is O, NH or NR m ';
  • R m ' is deuterated methyl, deuterated ethyl, deuterated n-propyl, deuterated isopropyl , Methyl, ethyl, n-propyl or isopropyl;
  • the compound represented by formula (IB) is a compound of formula (IB-1) or a compound of formula (IB-2);
  • R 21 , R 22 , R 11 , R 12 , R 31 , R 32 , R 41 , R 42 ', Z, P', R 0 ', Ar ', E 1 ', E 2 ', X 1 and Y 1 have the same definitions as before.
  • the present invention provides a compound represented by formula (IB-1a) or formula (IB-2a), or its tautomers, cis-trans isomers, mesosomes, and racemates , Enantiomers, diastereomers, atropisomers or mixtures thereof, or their pharmaceutically acceptable salts, solvates or prodrugs:
  • R 1 , R 2 , R 3 , R 21 , R 22 , R 12 , R 11 , R 31 , R 32 , P', R 0 ', Ar', E 1 ', and X 1 are as defined above.
  • P ' is NH or NR m'; R m 'is a methyl group or a deuterated methyl group.
  • the compound represented by formula (IB-1a) is a compound of formula (IB-1aa), a compound of formula (IB-1ab), a compound of formula (IB-1ac) or a compound of formula (IB-1ad) ) Compound;
  • R 21 ' is independently halogen, -C 1-3 alkyl, -halo C 1-3 alkyl, -C 1-3 alkyl-hydroxy , -C 1-3 alkyl-cyano, -C 1-3 alkyl-C 1-6 alkoxy, -C 1-3 alkyl-halogenated C 1-6 alkyl or -C 1-3 Alkyl-halo C 1-6 alkoxy;
  • R 1 , R 2 , R 3 , R 12 , R 11 , R 31 , R 32 , P', R 0 ', Ar', E 1 ', X 1 The definition is the same as before;
  • R 12 ' is independently halogen, -C 1-3 alkyl, -halo C 1-3 alkyl, -C 1-3 alkyl-hydroxy, -C 1-3 alkyl-cyano, -C 1-3 alkyl-C 1-6 alkoxy, -C 1-3 alkyl-halogenated C 1-6 alkyl or -C 1-3 alkane Group-halo C 1-6 alkoxy; defined by R 1 , R 2 , R 3 , R 21 , R 22 , R 31 , R 32 , P', R 0 ', Ar', E 1 ', X 1 Cit.
  • the present invention provides a compound represented by formula (IB-1c) or formula (IB-2c), or its tautomers, cis-trans isomers, mesosomes, and racemates , Enantiomers, diastereomers, atropisomers or mixtures thereof, or their pharmaceutically acceptable salts, solvates or prodrugs:
  • R 1 , R 2 , R 3 , R 21 , R 22 , R 12 , R 11 , R 31 , R 32 , P', R 0 ', Ar', E 1 ', and X 1 are as defined above.
  • P ' is NH or NR m'; R m 'is - deuterated C 1-6 alkyl or -C 1-6 alkyl.
  • the compound represented by formula (IB-1c) is a compound of formula (IB-1ca), a compound of formula (IB-1cb), a compound of formula (IB-1cc) or a compound of formula (IB-1cd) ) Compound;
  • R 21 ' is independently halogen, -C 1-3 alkyl, -halo C 1-3 alkyl, -C 1-3 alkyl-hydroxy , -C 1-3 alkyl-cyano, -C 1-3 alkyl-C 1-6 alkoxy, -C 1-3 alkyl-halogenated C 1-6 alkyl or -C 1-3 Alkyl-halo C 1-6 alkoxy;
  • R 1 , R 2 , R 3 , R 12 , R 11 , R 31 , R 32 , P', R 0 ', Ar', E 1 ', X 1 The definition is the same as before;
  • R 12 ' is independently halogen, -C 1-3 alkyl, -halo C 1-3 alkyl, -C 1-3 alkyl-hydroxy, -C 1-3 alkyl-cyano, -C 1-3 alkyl-C 1-6 alkoxy, -C 1-3 alkyl-halogenated C 1-6 alkyl or -C 1-3 alkane Group-halo C 1-6 alkoxy; defined by R 1 , R 2 , R 3 , R 21 , R 22 , R 31 , R 32 , P', R 0 ', Ar', E 1 ', X 1 Cit.
  • P′ is independently NH or NR m ′; R m ′ is -deuterated C 1 -6 alkyl or -C 1-6 alkyl.
  • P′ is independently NH or NR m ′; R m ′ is -deuterated C 1 -3 alkyl or -C 1-3 alkyl.
  • P′ is independently NH or NR m ′;
  • R m ′ is deuterated methyl, Deuterated ethyl, deuterated n-propyl, deuterated isopropyl, methyl, ethyl, n-propyl or isopropyl.
  • the present invention provides a compound represented by formula (IB-1b) or formula (IB-2b), or its tautomers, cis-trans isomers, mesosomes, racemates , Enantiomers, diastereomers, atropisomers or mixtures thereof, or their pharmaceutically acceptable salts, solvates or prodrugs:
  • R 1 , R 2 , R 3 , R 21 , R 22 , R 12 , R 11 , R 31 , R 32 , P', R 0 ', Ar', E 1 ', and X 1 are as defined above.
  • the compound represented by formula (IB-1b) is a compound of formula (IB-1ba), a compound of formula (IB-1bb), a compound of formula (IB-1bc) or a compound of formula (IB-1bd) ) Compound;
  • R 21 ' is independently halogen, -C 1-3 alkyl, -halo C 1-3 alkyl, -C 1-3 alkyl-hydroxy , -C 1-3 alkyl-cyano, -C 1-3 alkyl-C 1-6 alkoxy, -C 1-3 alkyl-halogenated C 1-6 alkyl or -C 1-3 Alkyl-halo C 1-6 alkoxy;
  • R 1 , R 2 , R 3 , R 12 , R 11 , R 31 , R 32 , P', R 0 ', Ar', E 1 ', X 1 The definition is the same as before;
  • R 12 ' is independently halogen, -C 1-3 alkyl, -halo C 1-3 alkyl, -C 1-3 alkyl-hydroxy, -C 1-3 alkyl-cyano, -C 1-3 alkyl-C 1-6 alkoxy, -C 1-3 alkyl-halogenated C 1-6 alkyl or -C 1-3 alkane Group-halo C 1-6 alkoxy; defined by R 1 , R 2 , R 3 , R 21 , R 22 , R 31 , R 32 , P', R 0 ', Ar', E 1 ', X 1 Cit.
  • the present invention provides a compound represented by formula (IB-1d) or formula (IB-2d), or its tautomers, cis-trans isomers, mesosomes, and racemates , Enantiomers, diastereomers, atropisomers or mixtures thereof, or their pharmaceutically acceptable salts, solvates or prodrugs:
  • R 1 , R 2 , R 3 , R 21 , R 22 , R 12 , R 11 , R 31 , R 32 , P', R 0 ', Ar', E 1 ', and X 1 are as defined above.
  • the compound represented by formula (IB-1d) is a compound of formula (IB-1da), a compound of formula (IB-1db), a compound of formula (IB-1dc) or a compound of formula (IB-1dd) ) Compound;
  • R 21 ' is independently halogen, -C 1-3 alkyl, -halo C 1-3 alkyl, -C 1-3 alkyl-hydroxy , -C 1-3 alkyl-cyano, -C 1-3 alkyl-C 1-6 alkoxy, -C 1-3 alkyl-halogenated C 1-6 alkyl or -C 1-3 Alkyl-halo C 1-6 alkoxy;
  • R 1 , R 2 , R 3 , R 12 , R 11 , R 31 , R 32 , P', R 0 ', Ar', E 1 ', X 1 The definition is the same as before;
  • R 12 ' is independently halogen, -C 1-3 alkyl, -halo C 1-3 alkyl, -C 1-3 alkyl-hydroxy, -C 1-3 alkyl-cyano, -C 1-3 alkyl-C 1-6 alkoxy, -C 1-3 alkyl-halogenated C 1-6 alkyl or -C 1-3 alkane Group-halo C 1-6 alkoxy; defined by R 1 , R 2 , R 3 , R 21 , R 22 , R 31 , R 32 , P', R 0 ', Ar', E 1 ', X 1 Cit.
  • R 21 ′ and R 12 ′ are each independently -C 1-3 alkyl, -C 1-3 alkyl-hydroxy, -C 1-3 alkyl-cyano or- C 1-3 alkyl-C 1-6 alkoxy.
  • R 21 'and R 12 ' are each independently -C 1-3 alkyl, -CH 2 -hydroxyl, -CH 2 -cyano or -CH 2 -C 1-3 alkane Oxy.
  • R 21 ′ and R 12 ′ are each independently methyl, ethyl, n-propyl or isopropyl.
  • X 1 is hydrogen, halogen, -substituted or unsubstituted C 1-6 alkyl, -substituted or unsubstituted C 3-6 cycloalkyl, or -O-substituted or Unsubstituted C 1-6 alkyl; the "substituted” means that 1, 2, 3, or 4 hydrogen atoms in the group are replaced by substituents independently selected from the S group.
  • X 1 is hydrogen, halogen, unsubstituted C 1-3 alkyl, unsubstituted C 3-6 cycloalkyl or -O-unsubstituted C 1-3 alkyl .
  • X 1 is hydrogen, fluorine, chlorine, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy Group, ethoxy, n-propoxy or isopropoxy.
  • X 1 is fluorine, chlorine or cyclopropyl.
  • Y 1 is C; E 1 'is CR 5 '; E 2 ' is N; R 5 'is as defined above.
  • Y 1 is C; E 1 'is N or CR 5 '; E 2 ' is CH; R 5 'is as defined above.
  • Ar' is phenyl, 5- or 6-membered monocyclic heteroaryl or pyridonyl; and said phenyl, 5- or 6-membered monocyclic heteroaryl and pyridonyl are Unsubstituted or substituted by 1, 2, 3 or 4 groups independently selected from the following groups: halogen, cyano, hydroxyl, -C 1-6 alkyl, -C 1-6 alkoxy, -NR c R d , -C 1-4 alkyl-NR e R f ; wherein R e and R f are each independently hydrogen or C 1-3 alkyl; R c and R d are each independently hydrogen, -C 1-3 Alkyl group, -C(O)C 1-3 alkyl group or -CO 2 C 1-3 alkyl group.
  • Ar' is phenyl or pyridonyl; and said phenyl and pyridonyl are unsubstituted or are 1, 2, 3 or 4 independently selected from the following groups Substitution: fluorine, chlorine, bromine, cyano, hydroxyl, -C 1-3 alkyl, -C 1-3 alkoxy, -NH 2 , -NHCH 3 , -N(CH 3 ) 2 , -CH 2- NH 2 , -CH 2 -NHCH 3 , -CH 2 -N(CH 3 ) 2 .
  • Ar' is a phenyl group; the phenyl group is substituted with a group selected from R s1 ; R s1 is halogen, cyano, -C 1-6 alkyl, -C 1-6 alkoxy, -halo C 1-6 alkyl, -halo C 1-6 alkoxy, or -C 3-6 cycloalkyl.
  • Ar' is selected from the following structures: In the formula, R s1 and R s2 are as defined above.
  • Ar' is selected from the following structures: In the formula, R s1 is hydroxyl; R s2 is halogen, cyano, -C 1-6 alkyl, -C 1-6 alkoxy, -halo C 1-6 alkyl, -halo C 1-6 Alkoxy or -C 3-6 cycloalkyl. In one embodiment of the present invention, the R s1 is above the plane of the benzene ring.
  • Ar' is selected from the following structures: In the formula, R s1 is -C 1-6 alkoxy; R s2 is halogen, cyano, -C 1-6 alkyl, -C 1-6 alkoxy, -halo C 1-6 alkyl, -Halo C 1-6 alkoxy or -C 3-6 cycloalkyl. In one embodiment of the present invention, the R s1 is above the plane of the benzene ring.
  • R 0 ′ is a phenyl group, a 5- or 6-membered monocyclic heteroaryl group or a pyridonyl group, wherein the 5- or 6-membered monocyclic heteroaryl group has 1, 2, or 3 Two heteroatoms selected from N, O and S are used as ring atoms; and the phenyl group, 5- or 6-membered monocyclic heteroaryl group and pyridonyl group are unsubstituted or separated by 1, 2, 3 or 4 A group selected from R s3 is substituted.
  • R 0 ' is phenyl, thiazolyl, isothiazolyl, imidazolyl, oxazolyl, isoxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl or Pyridonyl
  • the phenyl, thiazolyl, isothiazolyl, imidazolyl, oxazolyl, isoxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl and pyridinyl are unsubstituted Or by 1, 2, 3, or 4 groups independently selected from R s3.
  • R 0 is selected from the following structures:
  • R s3 are the same or different, and are each independently selected from hydrogen, halogen, cyano, hydroxyl, -C 1-6 alkyl, -C 1-6 alkoxy, -haloC 1-6 Alkyl, -halogenated C 1-6 alkoxy, -C 3-6 cycloalkyl, -NR h R i , -C(O)NR e R f , -C 1-3 alkyl-hydroxy and- C 1-3 alkyl -NR e R f ; and the -C 3-6 cycloalkyl group is optionally selected by 1, 2 or 3 independently selected from halogen, methyl, ethyl, propyl (n-propyl Group), isopropyl, trifluoromethyl, amino, N(CH 3 ) 2 , hydroxyl, carboxyl substituents; wherein R e and R f are each independently hydrogen or C 1-3 alkyl; R h , R
  • R s3 are the same or different, each independently selected from hydrogen, halogen, cyano, hydroxyl, -C 1-6 alkyl, -C 1-6 alkoxy, -haloC 1-6 Alkyl, -halogenated C 1-6 alkoxy, -C 3-6 cycloalkyl, -NR h R i , -C(O)NR e R f , -C 1-3 alkyl-hydroxy and- C 1-3 alkyl -NR e R f ; and the -C 3-6 cycloalkyl group is optionally selected by 1, 2 or 3 independently selected from halogen, methyl, ethyl, propyl (n-propyl Group), isopropyl, trifluoromethyl, amino, N(CH 3 ) 2 , hydroxyl, carboxyl substituents; wherein R e and R f are each independently hydrogen or C 1-3 alkyl; R h , R i are each independently hydrogen or C 1-3
  • R s3 are the same or different, and are each independently selected from hydrogen, -C 1-6 alkyl, -halo C 1-6 alkyl, -C 3-6 cycloalkyl, -C 1 -3 alkyl-C(O)NR e R f , -C(O)NR e R f , -C 1-4 alkyl-hydroxyl and -C 1-4 alkyl-NR e R f ; and said
  • the -C 3-6 cycloalkyl group is optionally substituted by 1, 2 or 3 independently selected from halogen, methyl, ethyl, propyl (n-propyl), isopropyl, trifluoromethyl, amino, N (CH 3 ) 2 , substituted by substituents of hydroxyl and carboxy; wherein R e and R f are each independently hydrogen or C 1-3 alkyl;
  • R s3 are the same or different, and are each independently selected from halogen, cyano, hydroxyl, -C 1-6 alkyl, -C 1-6 alkoxy, -halo C 1-6 alkyl, -Halogenated C 1-6 alkoxy, -C 3-6 cycloalkyl, 3 to 6 membered heterocycloalkyl, -NR h R i , -C(O)NR e R f , -SO 2 C 1 -3 alkyl, -SO 2 halo C 1-3 alkyl, -SO 2 NR e R f , -C 1-3 alkyl-hydroxy, -C 1-3 alkyl-C 2-4 alkynyl, -C 1-3 alkyl-cyano, -C 1-3 alkyl-C 1-6 alkoxy, -C 1-3 alkyl-halogenated C 1-6 alkyl, -C 1-3 alkane Group-halogenated C
  • n is the same or different, and each independently is 0, 1, 2 or 3.
  • the -C 3-6 cycloalkyl group is optionally selected by 1, 2 or 3 independently selected from halogen, methyl, ethyl, propyl (n-propyl), isopropyl, trifluoromethyl, amino , N(CH 3 ) 2 , hydroxyl and carboxyl substituents; wherein R e and R f are each independently hydrogen or C 1-3 alkyl; R h and R i are each independently
  • R 0 ' is selected from the following structures: R s3 'is hydrogen, halogen, cyano, hydroxyl, -C 1-6 alkyl, -C 1-6 alkoxy, -halo C 1-6 alkyl, -halo C 1-6 alkoxy , -C 3-6 cycloalkyl, -NR h R i , -C(O)NR e R f , -C 1-3 alkyl-hydroxyl and -C 1-3 alkyl-NR e R f ; and
  • the -C 3-6 cycloalkyl group is optionally selected by 1, 2 or 3 independently selected from halogen, methyl, ethyl, propyl (n-propyl), isopropyl, trifluoromethyl, amino , N(CH 3 ) 2 , hydroxyl and carboxyl substituents; wherein R e and R f are each independently hydrogen or C 1-3 alkyl; R h
  • R 0 ' is selected from the following structures: R s3 'is hydrogen, halogen, cyano, hydroxyl, -C 1-6 alkyl, -C 1-6 alkoxy, -halo C 1-6 alkyl, -halo C 1-6 alkoxy , -C 3-6 cycloalkyl, -NR h R i , -C(O)NR e R f , -C 1-3 alkyl-hydroxyl and -C 1-3 alkyl-NR e R f ; and
  • the -C 3-6 cycloalkyl group is optionally selected by 1, 2 or 3 independently selected from halogen, methyl, ethyl, propyl (n-propyl), isopropyl, trifluoromethyl, amino , N(CH 3 ) 2 , hydroxyl and carboxyl substituents; wherein R e and R f are each independently hydrogen or C 1-3 alkyl; R h
  • R 0 ' is selected from the following structures: R s3 'is hydrogen, halogen, cyano, hydroxyl, -C 1-6 alkyl, -C 1-6 alkoxy, -halo C 1-6 alkyl, -halo C 1-6 alkoxy , -C 3-6 cycloalkyl, -NR h R i , -C(O)NR e R f , -C 1-3 alkyl-hydroxyl and -C 1-3 alkyl-NR e R f ; and
  • the -C 3-6 cycloalkyl group is optionally selected by 1, 2 or 3 independently selected from halogen, methyl, ethyl, propyl (n-propyl), isopropyl, trifluoromethyl, amino , N(CH 3 ) 2 , hydroxyl and carboxyl substituents; wherein R e and R f are each independently hydrogen or C 1-3 alkyl; R h
  • R 0 ' is selected from the following structures: R s3 'is isopropyl; n is 0. In one embodiment, the R s3 ′ is below the plane of the pyrazine ring.
  • R 0 ′ is selected from the following structures: R s3 'is hydrogen, halogen, cyano, hydroxyl, -C 1-6 alkyl, -C 1-6 alkoxy, -halo C 1-6 alkyl, -halo C 1-6 alkoxy , -C 3-6 cycloalkyl, -NR h R i , -C(O)NR e R f , -C 1-3 alkyl-hydroxyl and -C 1-3 alkyl-NR e R f ; and
  • the -C 3-6 cycloalkyl group is optionally selected by 1, 2 or 3 independently selected from halogen, methyl, ethyl, propyl (n-propyl), isopropyl, trifluoromethyl, amino , N(CH 3 ) 2 , hydroxyl and carboxyl substituents; wherein R e and R f are each independently hydrogen or C 1-3 alkyl; R h
  • R 0 is selected from the following structures:
  • the present invention provides a compound represented by formula (II), or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof,
  • R 1 and R 2 are each independently hydrogen, halogen, cyano, NR a R b , -C 1-3 alkyl, halo C 1-3 alkyl, -C 1-3 alkyl-hydroxy, -C 1-3 alkyl-cyano group, -C 1-3 alkyl-C 1-3 alkoxy group, -C 1-3 alkyl-NR a R b , -C 1-3 alkyl group-3 to 6 members Heterocycloalkyl or -C 1-3 alkyl-5 or 6-membered monocyclic heteroaryl; wherein the 3- to 6-membered heterocycloalkyl or the 5- or 6-membered monocyclic heteroaryl has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms;
  • R 3 is hydrogen, halogen, -C 1-3 alkyl or -C 1-3 alkoxy
  • R 4 is hydrogen, halogenated C 1-3 alkyl, -C 1-3 alkyl-hydroxy, -C 1-3 alkyl-cyano or -C 1-3 alkyl-C 1-3 alkoxy ;
  • R 11 and R 12 are the same or different, and are each independently hydrogen, halogen, -C 1-3 alkyl, -halo C 1-3 alkyl, -C 1-3 alkyl-hydroxy, -C 1-3 Alkyl-cyano, -C 1-3 alkyl-C 1-6 alkoxy, -C 1-3 alkyl-halo C 1-6 alkyl or -C 1-3 alkyl-halo C 1-6 alkoxy;
  • R 21 and R 22 are the same or different, and are each independently hydrogen, halogen, -C 1-3 alkyl, -halo C 1-3 alkyl, -C 1-3 alkyl-hydroxy, -C 1-3 Alkyl-cyano, -C 1-3 alkyl-C 1-6 alkoxy, -C 1-3 alkyl-halo C 1-6 alkyl or -C 1-3 alkyl-halo C 1-6 alkoxy;
  • R 31 and R 32 are the same or different, and are each independently hydrogen, halogen, -C 1-3 alkyl, -halo C 1-3 alkyl, -C 1-3 alkyl-hydroxy, -C 1-3 Alkyl-cyano, -C 1-3 alkyl-C 1-6 alkoxy, -C 1-3 alkyl-halo C 1-6 alkyl or -C 1-3 alkyl-halo C 1-6 alkoxy;
  • R 41 is hydrogen, halogen, -C 1-3 alkyl, -halo C 1-3 alkyl, -C 1-3 alkyl-hydroxy, -C 1-3 alkyl-cyano, -C 1- 3 alkyl-C 1-6 alkoxy, -C 1-3 alkyl-halo C 1-6 alkyl or -C 1-3 alkyl-halo C 1-6 alkoxy;
  • P is O, NH or NR m ;
  • R m is -C 1-6 alkyl, -halo C 1-6 alkyl, -C 1-6 alkyl-hydroxy, -C 1-6 alkyl-cyano , -C 1-6 alkyl-C 1-6 alkoxy, -C 1-6 alkyl-halogenated C 1-6 alkoxy, -C 1-6 alkyl-C 3-6 cycloalkyl Or -C 1-6 alkyl-3 to 6-membered heterocycloalkyl;
  • X 2 and Y 2 are the same or different, each independently being hydrogen, halogen, -C 1-3 alkyl, -halo C 1-3 alkyl, -C 1-3 alkyl-hydroxy, -C 1-3 Alkyl-cyano, -C 1-3 alkyl-C 1-6 alkoxy, -C 1-3 alkyl-halo C 1-6 alkyl or -C 1-3 alkyl-halo C 1-6 alkoxy;
  • X 2 , Y 2 and their adjacent carbon atoms together form a substituted or unsubstituted C 3-6 cycloalkyl or a substituted or unsubstituted 3 to 6 membered heterocycloalkyl; the 3 to 6 membered heterocycloalkane
  • the group has 1, 2, or 3 heteroatoms selected from N, O, and S as ring atoms; the “substitution” means that 1, 2, 3, or 4 hydrogen atoms in the group are independently selected from Substituted by S group substituents;
  • E 3 is N or CLR 5 ;
  • R L is a bond, -CR L1 R L2 -, -O-(CR L1 R L2 ) t1 -or -NH-(CR L3 R L4 ) t2 -;
  • R L1 , R L2 , R L3 , R L4 are the same Or different, each independently is hydrogen, halogen, hydroxy, hydroxymethyl, hydroxyethyl, -C 1-3 alkyl or oxo;
  • t1, t2 are each independently 0, 1, 2, 3 or 4;
  • R L1 and R L2 or R L3 and R L4 is an oxo group, the other does not exist;
  • R 5 is hydrogen, halogen, hydroxyl,-substituted or unsubstituted C 1-6 alkyl,-substituted or unsubstituted C 3-6 cycloalkyl,-substituted or unsubstituted 3 to 6 membered heterocycloalkyl , -O-substituted or unsubstituted C 1-6 alkyl, -O-substituted or unsubstituted C 3-6 cycloalkyl, -O-substituted or unsubstituted 3 to 6 membered heterocycloalkyl,- SO 2 -substituted or unsubstituted C 1-6 alkyl, -SO 2 -substituted or unsubstituted C 3-6 cycloalkyl, -SO 2 -substituted or unsubstituted 3 to 6 membered heterocycloalkyl, -A substituted or unsubstit
  • the S group substituents are selected from: hydroxy, halogen, nitro, oxo, -C 1-6 alkyl, -halo C 1-6 alkyl, hydroxy substituted C 1-6 alkyl, benzyl , -(CH 2 ) u -cyano, -(CH 2 ) u -C 1-6 alkoxy, -(CH 2 ) u -halogenated C 1-6 alkoxy, -(CH 2 ) u- Halogenated C 1-6 alkyl, -(CH 2 ) u -3 to 6-membered heterocycloalkyl, -(CH 2 ) u -5 or 6-membered monocyclic heteroaryl, -(CH 2 ) u -C 3-8 cycloalkyl, -(CH 2 ) u -O-(CH 2 ) v -C 3-8 cycloalkyl, -(CH 2 ) u -O-(CH 2 ) v
  • E 4 is N or CH
  • Ar is a C 6-10 aryl group, a 5- or 6-membered monocyclic heteroaryl group or an 8- to 10-membered bicyclic heteroaryl group; wherein the 5- or 6-membered monocyclic heteroaryl group has 1, 2 or 3 Heteroatoms of N, O, and S as ring atoms; the 8- to 10-membered bicyclic heteroaryl group has 1, 2, 3, 4, or 5 heteroatoms selected from N, O, and S as ring atoms; and
  • the C 6-10 aryl group, the 5- or 6-membered monocyclic heteroaryl group or the 8- to 10-membered bicyclic heteroaryl group is unsubstituted or has 1, 2, 3, or 4 groups independently selected from R s1 Group replacement
  • Ar is the structure shown in formula (B):
  • the B1 ring is a benzene ring or a 5- or 6-membered monocyclic heteroaryl ring
  • the B2 ring is a fused 5- or 6-membered monocyclic heterocycloalkyl ring or a fused 5- or 6-membered monocyclic cycloalkyl ring Ring
  • the 5- or 6-membered monocyclic heteroaryl ring or the fused 5- or 6-membered monocyclic heterocycloalkyl ring has 1, 2 or 3 heteroatoms selected from N, O and S As ring atoms;
  • R s1 p indicates that the hydrogen on the B1 ring is replaced by p R s1 , p is 0, 1, 2 or 3, and each R s1 is the same or different;
  • R s2 (R s2 ) q means that the hydrogen on the B2 ring is replaced by q R s2 , q is 0, 1, 2 or 3, and each R s2 is the same or different;
  • R s1 and R s2 are each independently halogen, cyano, nitro, hydroxyl, -C 1-6 alkyl, -C 1-6 alkoxy, -haloC 1-6 alkyl, -haloC 1-6 alkoxy, -C 3-6 cycloalkyl, -NR c R d , -C(O)NR e R f , -SO 2 C 1-3 alkyl, -SO 2 halo C 1- 3 alkyl, -SO 2 NR e R f , -C 1-4 alkyl-hydroxy, -C 1-4 alkyl-cyano, -C 1-4 alkyl-C 1-6 alkoxy,- C 1-4 alkyl-halo C 1-6 alkyl, -C 1-4 alkyl-halo C 1-6 alkoxy, -C 1-4 alkyl-3 to 6-membered heterocycloalkyl , -C 1-4 alkyl-NR e R f ,
  • R a , R b , R e , and R f are each independently hydrogen or C 1-3 alkyl;
  • R c and R d are each independently hydrogen, -C 1-3 alkyl, -C(O)C 1-3 alkyl, and -CO 2 C 1-3 alkyl.
  • R s1 and R s2 are each independently halogen, cyano, nitro, hydroxy, -C 1-3 alkyl, -C 1-3 alkoxy, halogenated C 1 -3 alkyl, halogenated C 1-3 alkoxy, -C 3-6 cycloalkyl, -NR c R d , -C(O)NR e R f , -SO 2 C 1-3 alkyl, -SO 2 halo C 1-3 alkyl, -SO 2 NR e R f , -C 1-2 alkyl-hydroxy, -C 1-2 alkyl-cyano, -C 1-2 alkyl-C 1-3 alkoxy, -C 1-2 alkyl-halogenated C 1-3 alkyl, -C 1-2 alkyl-halogenated C 1-3 alkyl, -C 1-2 alkyl-halogenated C 1-3 alkoxy, -C 1-2 alkyl- 3- to 6-membered heterocycl
  • R s1 and R s2 are each independently halogen, cyano, nitro, hydroxy, -C 1-3 alkyl, -C 1-3 alkoxy, halogenated C 1 -3 alkyl, halogenated C 1-3 alkoxy, -C 3-6 cycloalkyl, -NR c R d , -C(O)NR e R f , -SO 2 C 1-3 alkyl, -SO 2 halo C 1-3 alkyl, -SO 2 NR e R f , -CH 2 -hydroxyl, -CH 2 -cyano, -CH 2 -C 1-3 alkoxy, -CH 2 -halo Substituted C 1-3 alkyl, -CH 2 -halogenated C 1-3 alkoxy, -CH 2 -3 to 6-membered heterocycloalkyl, -CH 2 -NR e R f , -CH 2 -C
  • R s1 and R s2 are each independently halogen, cyano, nitro, hydroxy, -C 1-3 alkyl, -C 1-3 alkoxy, halogenated C 1 -3 alkyl, halogenated C 1-3 alkoxy, -C 3-6 cycloalkyl, -NR c R d , -C(O)NR e R f , -CH 2 -hydroxyl, -CH 2- Cyano; wherein R c is hydrogen, -C(O)CH 3 or -CO 2 CH 3 ; R e , R f , and R d are each independently hydrogen or C 1-3 alkyl.
  • the C 3-6 cycloalkyl group is selected from: cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, Cyclohexenyl, cyclohexadienyl, cyclobutanone, cyclobutane-1,2-dione, cyclopentanone, cyclopentane-1,3-dione, cyclohexanone, cyclohexane-1 ,3-Diketone.
  • the 3- to 6-membered heterocycloalkyl group is selected from the group consisting of aziridine, ethylene oxide, azetidine, and oxetane.
  • Alkane oxazolidine, 1,3-dioxolane, imidazolidine, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, piperazine, morpholine, thiomorpholine, thiomorpholine-1,1 -Dioxide, tetrahydropyran, 1,3-oxazine, hexahydropyrimidine, 1,4-dioxane.
  • R s1 and R s2 are each independently halogen, cyano, nitro, hydroxy, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy , Propoxy (n-propoxy), isopropoxy, monochloromethyl, dichloromethyl, trichloromethyl, monochloroethyl, 1,2-dichloroethyl, trichloroethyl, Monobromoethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, trifluoromethoxy, trifluoroethoxy, monofluoromethyl Oxy, monofluoroethoxy, difluoromethoxy, difluoroethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl
  • R s3 and R s4 are each independently halogen, cyano, hydroxyl, -C 1-6 alkyl, -C 1-3 alkoxy, halogenated C 1-3 alkane Group, halogenated C 1-3 alkoxy, -C 3-6 cycloalkyl, 3 to 6 membered heterocycloalkyl, amino, NHCH 3 , N(CH 3 ) 2 , -C(O)NR e R f , -SO 2 C 1-3 alkyl, -SO 2 halo C 1-3 alkyl, -SO 2 NR e R f , -C 1-2 alkyl-hydroxy, -C 1-2 alkyl- Ethynyl, -C 1-2 alkyl-cyano, -C 1-2 alkyl-C 1-3 alkoxy, -C 1-2 alkyl-halogenated C 1-3 alkyl, -C 1 -2 alkyl-halogenated C
  • R s3 and R s4 are each independently halogen, cyano, hydroxyl, C 1-4 alkyl, -C 1-3 alkoxy, halo C 1-3 alkyl , Halogenated C 1-3 alkoxy, -C 3-6 cycloalkyl, 3 to 6 membered heterocycloalkyl, amino, NHCH 3 , N(CH 3 ) 2 , -C(O)NR e R f , -SO 2 C 1-3 alkyl, -SO 2 halo C 1-3 alkyl, -SO 2 NR e R f , -CH 2 -hydroxy, -CH 2 -ethynyl, -CH 2 -cyano , -CH 2 -C 1-3 alkoxy, -CH 2 -halo C 1-3 alkyl, -CH 2 -halo C 1-3 alkyl, -CH 2 -halo C 1-3 alkoxy, -CH 2 -halo C
  • R s3 and R s4 are each independently halogen, cyano, hydroxyl, C 1-4 alkyl, -C 1-3 alkoxy, halo C 1-3 alkyl , -C 3-6 cycloalkyl, 3 to 6 membered heterocycloalkyl, amino, NHCH 3 , N(CH 3 ) 2 , -CH 2 -hydroxyl, -CH 2 -ethynyl; wherein, the C 1-4 alkyl, -C 1-3 alkoxy, -CH 2 -, -C 3-6 cycloalkyl, 3 to 6 membered heterocycloalkyl are optionally independently selected from 1, 2 or 3 Substituents of halogen, methyl, ethyl, propyl (n-propyl), isopropyl, trifluoromethyl, amino, N(CH 3 ) 2 , hydroxyl, and carboxyl.
  • the C 3-6 cycloalkyl group is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • the 3- to 6-membered heterocycloalkyl group is selected from: aziridine, ethylene oxide, azetidine, oxetane , Tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, piperazine, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide, tetrahydropyran.
  • R s3 and R s4 are each independently halogen, cyano, hydroxyl, methyl, ethyl, n-propyl, isopropyl, sec-butyl, methoxy, ethoxy Group, propoxy (n-propoxy), isopropoxy, monochloromethyl, dichloromethyl, trichloromethyl, monochloroethyl, 1,2-dichloroethyl, trichloroethyl , Monobromoethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl , Aziridine, ethylene oxide, azetidine, oxetane, tetrahydrofuran, tetrahydrothi
  • the S group substituent is selected from the group consisting of hydroxyl, halogen, nitro, oxo, -C 1-3 alkyl, hydroxy-substituted C 1-3 alkyl, benzyl , -(CH 2 ) u -cyano, -(CH 2 ) u -C 1-3 alkoxy, -(CH 2 ) u -halogenated C 1-3 alkoxy, -(CH 2 ) u- Halogenated C 1-3 alkyl, -(CH 2 ) u -3 to 6-membered heterocycloalkyl, -(CH 2 ) u -5 or 6-membered monocyclic heteroaryl, -(CH 2 ) u -C 3-6 cycloalkyl, -(CH 2 ) u -O-(CH 2 ) v -C 3-6 cycloalkyl, -(CH 2 ) u -O-(CH 2 ) v -C
  • the S group substituent is halogen
  • the S group substituent is selected from: C 1-3 alkyl, -(CH 2 ) u -3 to 6-membered heterocycloalkyl, -(CH 2 ) u -SO 2 C 1-3 alkyl, -(CH 2 ) u -NR a0 R b0 ; wherein the 3- to 6-membered heterocycloalkyl group has 1, 2 or 3 heteroatoms selected from N, O and S as Ring atoms; the 3- to 6-membered heterocycloalkyl group is optionally substituted by 1, 2 or 3 selected from halogen, cyano, -C 1-3 alkyl, -C 1-3 alkoxy and C 3- Substituents of 6 cycloalkyl are substituted; u is 0, 1, 2, 3 or 4; R a0 and R b0 are each independently hydrogen or C 1-3 alkyl.
  • the C 6-10 aryl groups are each independently a phenyl group or a naphthyl group.
  • R s1 and R s2 are as defined above.
  • the 5- or 6-membered monocyclic heteroaryl groups are each independently selected from: thiophene, N-alkanepyrrole, furan, and thiazole , Isothiazole, imidazole, oxazole, pyrrole, pyrazole, triazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,5-triazole, 1,3,4- Triazole, tetrazole, isoxazole, oxadiazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4- Oxadiazole, thiadiazole, pyridine, pyridazine, pyrimidine, pyrazine.
  • the 5- or 6-membered monocyclic heteroaryl groups are each independently selected from the following structures:
  • the 8- to 10-membered bicyclic heteroaryl groups are each independently fused with a benzene ring and a 5- or 6-membered monocyclic heteroaryl ring.
  • the 5- or 6-membered monocyclic heteroaryl ring forming a 9 to 10-membered bicyclic heteroaryl group or an 8- to 10-membered bicyclic heteroaryl group is selected from: thiophene ring, N-alkane ring pyrrole Ring, furan ring, thiazole ring, isothiazole ring, imidazole ring, oxazole ring, pyrrole ring, pyrazole ring, triazole ring, 1,2,3-triazole ring, 1,2,4-triazole ring, 1,2,5-triazole ring, 1,3,4-triazole ring, tetrazole ring, isoxazole ring, oxadiazole ring, 1,2,3-oxadiazole ring, 1,2,4 -Oxadiazole ring, 1,2,5-oxadiazole ring, 1,3,4-oxadiazole ring, thiadiazol
  • the 5- or 6-membered monocyclic heteroaryl ring forming a 9 to 10-membered bicyclic heteroaryl group or an 8- to 10-membered bicyclic heteroaryl group is selected from the following structures:
  • the two ring atoms that are connected are represented by adjacent pairs of atoms shared when fused with other rings.
  • the 5- or 6-membered monocyclic heteroaryl ring is each independently selected from: a thiophene ring, an N-alkane pyrrole ring, a furan ring, and a thiazole ring , Isothiazole ring, imidazole ring, oxazole ring, pyrrole ring, pyrazole ring, triazole ring, 1,2,3-triazole ring, 1,2,4-triazole ring, 1,2,5-triazole ring Azole ring, 1,3,4-triazole ring, tetrazole ring, isoxazole ring, oxadiazole ring, 1,2,3-oxadiazole ring, 1,2,4-oxadiazole ring, 1 , 2,5-oxadiazole ring, 1,3,4-oxadiazole ring, thiadiazole ring
  • the 5- or 6-membered monocyclic heteroaryl ring is each independently selected from the following structures:
  • the two ring atoms that are connected are represented by adjacent pairs of atoms shared when fused with other rings.
  • the fused 5- or 6-membered monocyclic cycloalkyl ring is each independently selected from: cyclopentyl ring, cyclopentenyl ring, ring Hexyl ring, cyclohexenyl ring, cyclohexadienyl ring, cyclopentanone, cyclopentane-1,3-dione, cyclohexanone, cyclohexane-1,3-dione.
  • the fused 5- or 6-membered monocyclic heterocycloalkyl ring is each independently selected from: oxazolidine, pyrrolidin-2-one, Pyrrolidine-2,5-dione, 1,3-dioxolane, dihydrofuran-2(3H)-one, dihydrofuran-2,5-dione, piperidin-2-one, piperidine -2,6-dione, tetrahydro-2H-pyran-2-one, imidazolidine, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, 1,3-dioxolane-2-one, oxazolidine- 2-ketone, imidazolidine-2-one, piperidine, piperazine, piperazine-2-one, morpholine, morpholin-3-one, morpholin-2-one, thiomorpholin-3-
  • the fused 5- or 6-membered monocyclic heterocycloalkyl ring is selected from the following structures:
  • the 8- to 10-membered bicyclic heteroaryl groups are each independently selected from: benzoxazole, benzisoxazole, benzene Bimidazole, benzothiazole, benzisothiazole, benzotriazole, benzofuran, benzothiophene, indole, indazole, isoindole, quinoline, isoquinoline, quinazoline, quinoxaline, Cinoline, pyridopyrimidine, naphthyridine.
  • the 8- to 10-membered bicyclic heteroaryl groups are each independently selected from: benzo[d]isoxazole, 1H-indole Dole, isoindole, 1H-benzo[d]imidazole, benzo[d]isothiazole, 1H-benzo[d][1,2,3]triazole, benzo[d]oxazole, benzo [d]thiazole, indazole, benzofuran, benzo[b]thiophene, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline, pyrido[3,2-d]pyrimidine, pyrido [2,3-d]pyrimidine, pyrido[3,4-d]pyrimidine, pyrido[4,3-d]pyrimidine, 1,8-naphthyridine, 1,
  • the 8- to 10-membered bicyclic heteroaryl groups are each independently selected from the following structures:
  • the 8- to 10-membered bicyclic heteroaryl groups are each independently selected from the following structures:
  • the 8- to 10-membered bicyclic heteroaryl groups are each independently selected from the following structures:
  • formula (B) and formula (A-1) are each independently selected from the following structures:
  • Ar and Ar' are independently selected from the following structures:
  • the C 3-6 cycloalkyl group is selected from the group consisting of: cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, Cyclohexyl, cyclohexenyl, cyclohexadienyl, cyclobutanone, cyclobutane-1,2-dione, cyclopentanone, cyclopentane-1,3-dione, cyclohexanone, cyclohexyl Alkane-1,3-dione.
  • the 3- to 6-membered heterocycloalkyl group is selected from the group consisting of aziridine, ethylene oxide, azetidine, oxygen Etidine, oxazolidine, 1,3-dioxolane, imidazolidine, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, piperazine, morpholine, thiomorpholine, thiomorpholine- 1,1-dioxide, tetrahydropyran, 1,3-oxazinane, hexahydropyrimidine, 1,4-dioxane.
  • the 7 to 11 membered spirocycloalkyl group is selected from cyclopropyl ring, cyclobutyl ring, cyclopentyl ring and cyclohexyl ring. Any two monocyclic cycloalkyl rings in the ring form a monospirocycloalkyl group containing one spiro atom.
  • R 0 is -C 1-6 alkyl, -C 3-6 cycloalkyl, 3 to 6 membered heterocycloalkyl, phenyl, 5 or 6 membered monocyclic heteroaryl Group, 8- to 10-membered bicyclic heteroaryl, 7 to 11-membered spiro cycloalkyl, -CH 2 -phenyl, -CH(C 1-2 alkyl)-phenyl, -CH 2 -5 or 6-membered mono Cyclic heteroaryl, -CH(C 1-2 alkyl) -5 or 6-membered monocyclic heteroaryl, -NH-phenyl, -N(C 1-3 alkyl)-phenyl, -O-benzene Group, -CH 2 -3 to 6-membered heterocycloalkyl, -CH 2 -C 3-6 cycloalkyl, -CH(C 1-2 alkyl)-C 3-6 cycloalkyl
  • R 0 is phenyl, cyclopropyl, 5- or 6-membered monocyclic heteroaryl, -CH 2 -5 or 6-membered monocyclic heteroaryl, -CH 2 -phenyl , -CH(C 1-2 alkyl)-phenyl, -NH-phenyl, -N(C 1-3 alkyl)-phenyl, -O-phenyl; wherein, the 5- or 6-membered unit
  • the ring heteroaryl group is selected from: thiophene, N-alkane pyrrole, furan, thiazole, isothiazole, imidazole, oxazole, pyrrole, pyrazole, triazole, 1,2,3-triazole, 1,2,4- Triazole, 1,2,5-triazole, 1,3,4-triazole, tetrazole, isoxazole, oxadiazole, 1,2,3-oxadiazole, 1,2,
  • R 0 is selected from the following structures:
  • R 11 and R 12 are the same or different, and are each independently hydrogen, halogen, -C 1-3 alkyl, -CH 2 -hydroxy, -CH 2 -cyano, -CH 2- C 1-3 alkoxy, -CH 2 -halo C 1-3 alkyl or -CH 2 -halo C 1-3 alkoxy.
  • R 11 and R 12 are the same or different, and are each independently hydrogen, halogen, methyl, ethyl, n-propyl, isopropyl, -CH 2 -hydroxyl, -CH 2 -Cyano, -CH 2 -methoxy, -CH 2 -ethoxy, -CH 2 -propoxy (n-propoxy), -CH 2 -isopropoxy, -CH 2 -trifluoromethane Group, -CH 2 -difluoromethyl, -CH 2 -difluoroethyl, -CH 2 -trifluoromethoxy, -CH 2 -difluoromethoxy.
  • R 11 and R 12 are the same or different, and are each independently hydrogen or -C 1-3 alkyl.
  • R 11 and R 12 are the same or different, and are each independently hydrogen or methyl.
  • R 21 and R 22 are the same or different, and are each independently hydrogen, halogen, -C 1-3 alkyl, -CH 2 -hydroxy, -CH 2 -cyano, -CH 2- C 1-3 alkoxy, -CH 2 -halo C 1-3 alkyl or -CH 2 -halo C 1-3 alkoxy.
  • R 21 and R 22 are the same or different, and are each independently hydrogen, halogen, methyl, ethyl, n-propyl, isopropyl, -CH 2 -hydroxyl, -CH 2 -Cyano, -CH 2 -methoxy, -CH 2 -ethoxy, -CH 2 -propoxy (n-propoxy), -CH 2 -isopropoxy, -CH 2 -trifluoromethane Group, -CH 2 -difluoromethyl, -CH 2 -difluoroethyl, -CH 2 -trifluoromethoxy, -CH 2 -difluoromethoxy.
  • R 21 and R 22 are the same or different, and are each independently hydrogen or -C 1-3 alkyl.
  • R 21 and R 22 are the same or different, and are each independently hydrogen or methyl.
  • R 31 and R 32 are the same or different, and are each independently hydrogen, halogen, -C 1-3 alkyl, -CH 2 -hydroxy, -CH 2 -cyano, -CH 2- C 1-3 alkoxy, -CH 2 -halo C 1-3 alkyl or -CH 2 -halo C 1-3 alkoxy.
  • R 31 and R 32 are the same or different, and are each independently hydrogen, halogen, methyl, ethyl, n-propyl, isopropyl, -CH 2 -hydroxyl, -CH 2 -Cyano, -CH 2 -methoxy, -CH 2 -ethoxy, -CH 2 -propoxy (n-propoxy), -CH 2 -isopropoxy, -CH 2 -trifluoromethane Group, -CH 2 -difluoromethyl, -CH 2 -difluoroethyl, -CH 2 -trifluoromethoxy, -CH 2 -difluoromethoxy.
  • R 31 and R 32 are the same or different, and are each independently hydrogen or -C 1-3 alkyl.
  • R 31 and R 32 are the same or different, and are each independently hydrogen or methyl.
  • R 41 is hydrogen, halogen, -C 1-3 alkyl, -CH 2 -hydroxy, -CH 2 -cyano, -CH 2 -C 1-3 alkoxy, -CH 2 -halo C 1-3 alkyl or -CH 2 -halo C 1-3 alkoxy.
  • R 41 is hydrogen, halogen, methyl, ethyl, n-propyl, isopropyl, -CH 2 -hydroxy, -CH 2 -cyano, -CH 2 -methoxy Group, -CH 2 -ethoxy, -CH 2 -propoxy (n-propoxy), -CH 2 -isopropoxy, -CH 2 -trifluoromethyl, -CH 2 -difluoromethyl , -CH 2 -difluoroethyl, -CH 2 -trifluoromethoxy, -CH 2 -difluoromethoxy.
  • R 41 is hydrogen
  • R 42 is -C 1-3 alkyl-, -C 1-3 alkyl (hydroxy)-, -C 1-3 alkyl (cyano)-,- C 1-3 alkyl (C 1-3 alkyl), -C 1-3 alkyl (halogenated C 1-3 alkyl)-, -C 1-3 alkyl (C 1-3 alkyl-hydroxy )-, -C 1-3 alkyl (C 1-3 alkyl-cyano)-, -C 1-3 alkyl (C 1-3 alkoxy)-, or -C 1-3 alkyl ( Halogenated C 1-3 alkoxy)-; wherein C 1-3 alkyl is methyl, ethyl or propyl (n-propyl or isopropyl); C 1-3 alkoxy is methoxy , Ethoxy or propoxy (n-propoxy or isopropoxy).
  • R m is -C 1-3 alkyl, -halo C 1-3 alkyl, -C 1-3 alkyl-hydroxy, -C 1- 3 Alkyl-cyano group, -C 1-3 alkyl-C 1-3 alkoxy group, -C 1-3 alkyl-halogenated C 1-3 alkoxy group;
  • R 42 is hydrogen, halogen, -C 1-3 alkyl, -CH 2 -hydroxyl, -CH 2 -cyano, -CH 2 -C 1-3 alkane Oxy, -CH 2 -halo C 1-3 alkyl or -CH 2 -halo C 1-3 alkoxy.
  • R 42 is hydrogen, halogen, methyl, ethyl, n-propyl, isopropyl, -CH 2 -hydroxyl, -CH 2 -cyano, -CH 2 -Methoxy, -CH 2 -ethoxy, -CH 2 -propoxy (n-propoxy), -CH 2 -isopropoxy, -CH 2 -trifluoromethyl, -CH 2 -di Fluoromethyl, -CH 2 -difluoroethyl, -CH 2 -trifluoromethoxy, -CH 2 -difluoromethoxy.
  • X 1 is hydrogen, halogen, cyano, hydroxyl, amino, nitro, -substituted or unsubstituted C 1-3 alkyl, -substituted or unsubstituted C 3-6 cycloalkyl, -substituted or unsubstituted 3 to 6-membered heterocycloalkyl, -O-substituted or unsubstituted C 1-3 alkyl, -O-substituted or unsubstituted C 3-6 Cycloalkyl, -O-substituted or unsubstituted 3 to 6-membered heterocycloalkyl, -NH-substituted or unsubstituted C 1-3 alkyl, -N (substituted or unsubstituted C 1-3 alkyl ) 2 , -NH-substituted or unsubstituted C 3-6 cycl
  • Y 1 is C; E 1 is N; E 2 is C.
  • Y 1 is C; E 1 is N; E 2 is N.
  • P is O.
  • P is NH or NR m ;
  • R m is C 1-3 alkyl, halogenated C 1-3 alkyl, -C 1-3 alkyl-hydroxy, -C 1-3 alkyl-cyano, -C 1-3 alkyl-C 1-3 alkoxy, -C 1-3 alkyl-halogenated C 1-3 alkoxy; wherein, C 1- 3 Alkyl is methyl, ethyl or propyl (n-propyl or isopropyl); C 1-3 alkoxy is methoxy, ethoxy or propoxy (n-propoxy or isopropoxy) base).
  • X 2 and Y 2 are the same or different, and each independently is hydrogen, halogen, -C 1-3 alkyl, -C 1-3 alkyl-hydroxy,- C 1-3 alkyl-cyano, -C 1-3 alkyl-C 1-3 alkoxy, -C 1-3 alkyl-halogenated C 1-3 alkyl or -C 1-3 alkyl -Halogenated C 1-3 alkoxy; wherein C 1-3 alkyl is methyl, ethyl or propyl (n-propyl or isopropyl); C 1-3 alkoxy is methoxy, Ethoxy or propoxy (n-propoxy or isopropoxy).
  • X 2 , Y 2 and their adjacent carbon atoms together form a substituted or unsubstituted C 3-6 cycloalkyl group or a substituted or unsubstituted 3 to 6 membered hetero Cycloalkyl;
  • the 3- to 6-membered heterocycloalkyl group has 1, 2 or 3 heteroatoms selected from N, O and S as ring atoms;
  • the "substituted” refers to 1, 2 in the group , 3, or 4 hydrogen atoms are each independently substituted with substituents selected from the S group.
  • L is a bond
  • R 5 is hydrogen, halogen, hydroxyl, -substituted or unsubstituted C 1-3 alkyl, -substituted or unsubstituted C 3-6 cycloalkyl, -Substituted or unsubstituted 3 to 6-membered heterocycloalkyl, -O-substituted or unsubstituted C 1-3 alkyl, -O-substituted or unsubstituted C 3-6 cycloalkyl, -O-substituted Or unsubstituted 3 to 6 membered heterocycloalkyl, -SO 2 -substituted or unsubstituted C 1-3 alkyl, -SO 2 -substituted or unsubstituted C 3-6 cycloalkyl, -SO 2- Substituted or unsubstituted 3 to 6 membered heterocycloalkyl
  • R 1 and R 2 are each independently hydrogen, halogen, cyano, amino, NHCH 3 , N(CH 3 ) 2 , methyl, ethyl, n-propyl, isopropyl Group, monochloromethyl, dichloromethyl, trichloromethyl, monochloroethyl, 1,2-dichloroethyl, trichloroethyl, monobromoethyl, monofluoromethyl, difluoromethyl , Trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, -CH 2 -hydroxy, -CH 2 -cyano, -CH 2 -methoxy, -CH 2 -ethoxy, -CH 2 -propoxy (n-propoxy), -CH 2 -isopropoxy, -CH 2 -NH 2 , -CH 2 -NHCH 3 , -CHCH 2 -NHCH 3
  • R 3 is hydrogen, halogen, methoxy, ethoxy, propoxy (n-propoxy) or isopropoxy.
  • R 4 is hydrogen, monochloromethyl, dichloromethyl, trichloromethyl, monochloroethyl, 1,2-dichloroethyl, trichloroethyl, mono Bromoethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, -CH 2 -hydroxyl, -CH 2 -cyano, -CH 2 -Methoxy, -CH 2 -ethoxy, -CH 2 -propoxy (n-propoxy) or -CH 2 -isopropoxy.
  • R 1 , R 2 , and R 3 are hydrogen.
  • E 1 is N or CR 5 ; wherein R 5 is hydrogen.
  • E 2 is N or CR 6 ; wherein R 6 is hydrogen.
  • said R 11 , R 12 , R 21 , R 22 , R 31 , R 32 , R 41 , R 42 , Z, P, R 0 , Ar, E 1 , E 2 , X 1 , and Y 1 are each independently a corresponding group in each specific compound in the embodiment.
  • the compound of formula (I) is selected from any of the compounds Z1, Z3 to Z16 in the examples or their diastereomers.
  • representative compounds of formula (IA) include the structures listed in Table A-1 below, or tautomers, cis-trans isomers, and cis-trans isomers of any of the structures in Table A-1.
  • Meso, racemate, enantiomer, diastereomer or atropisomer, or a mixture of the foregoing isomers, or the structure in Table A-1 and the foregoing difference A pharmaceutically acceptable salt, solvate or prodrug of the structure,
  • representative compounds of formula (IA) include but are not limited to the structures listed in Table A-2 below, or pharmaceutically acceptable salts of any of the structures in Table A-2, solvated Substance or prodrug,
  • representative compounds of formula (IA) include, but are not limited to, any of the compound structures described in Examples 51 to 342, or pharmaceutically acceptable salts of these structures, and solvates. Substance or prodrug.
  • said R 11 , R 12 , R 21 , R 22 , R 31 , R 32 , R 41 , R 42 , Z, P, Ar, E 3 , E 4 , X 2 , and Y 2 are each independently a corresponding group in each specific compound in the embodiment.
  • the compound of formula (II) is selected from any of the compounds Z2, Z17 to Z20 in the examples or their diastereomers.
  • the present invention provides a pharmaceutical composition containing the aforementioned compound or its tautomers, cis-trans isomers, mesoisomers, racemates, enantiomers, Diastereomers, atropisomers or mixtures thereof, or pharmaceutically acceptable salts, solvates or prodrugs thereof; and pharmaceutically acceptable carriers.
  • the term "pharmaceutically acceptable carrier” refers to any preparation or carrier medium representative that can deliver an effective amount of the active substance of the present invention, does not interfere with the biological activity of the active substance, and has no toxic side effects to the host or subject
  • sexual carriers include water, oil, vegetables and minerals, cream base, lotion base, ointment base, etc. These bases include suspending agents, tackifiers, penetration enhancers and the like. Their formulations are well known to those skilled in the field of cosmetics or topical medicine.
  • the pharmaceutical composition can be administered in any of the following ways: oral, spray inhalation, rectal administration, nasal administration, buccal administration, topical administration, parenteral administration, such as subcutaneous, intravenous, intramuscular , Intraperitoneal, intrathecal, intraventricular, intrasternal and intracranial injection or infusion, or medication with the aid of an explanted reservoir.
  • parenteral administration such as subcutaneous, intravenous, intramuscular , Intraperitoneal, intrathecal, intraventricular, intrasternal and intracranial injection or infusion, or medication with the aid of an explanted reservoir.
  • the compounds of the present invention can be prepared into any orally acceptable formulations, including but not limited to tablets, capsules, aqueous solutions or aqueous suspensions.
  • Carriers used in tablets generally include lactose and corn starch, and lubricants such as magnesium stearate can also be added.
  • the diluents used in capsule formulations generally include lactose and dried corn starch.
  • Aqueous suspension formulations usually mix the active ingredients with suitable emulsifiers and suspending agents. If necessary, some sweeteners, fragrances or coloring agents can be added to the above oral preparations.
  • topical medication especially for the treatment of affected surfaces or organs that are easily reached by topical application, such as eye, skin or lower intestinal neurological diseases
  • the compound of the present invention can be made into different topical pharmaceutical preparations according to different affected surfaces or organs.
  • the compound of the present invention can be formulated into a micronized suspension or solution.
  • the carrier used is isotonic sterile saline with a certain pH, which may or may not be added with preservatives such as Benzyl alkanolate chloride.
  • the compound can also be made into an ointment form such as petrolatum ointment.
  • the compound of the present invention When applied topically to the skin, the compound of the present invention can be prepared into an appropriate ointment, lotion or cream formulation in which the active ingredient is suspended or dissolved in one or more carriers.
  • Carriers that can be used for ointment preparations include but are not limited to: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyethylene oxide, polypropylene oxide, emulsifying wax and water; carriers that can be used for lotions or creams include, but are not limited to: minerals Oil, sorbitan monostearate, Tween 60, cetyl ester wax, hexadecenyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
  • the compounds of the present invention can also be administered in the form of sterile injection preparations, including sterile injection water or oil suspensions or sterile injection solutions.
  • Usable vehicles and solvents include water, Ringer's solution, and isotonic sodium chloride solution.
  • sterilized non-volatile oils can also be used as solvents or suspension media, such as monoglycerides or diglycerides.
  • the present invention provides the aforementioned compound compound or its tautomers, cis-trans isomers, mesoisomers, racemates, enantiomers, diastereomers, hindered Use of transisomers or mixtures thereof, or pharmaceutically acceptable salts, solvates or prodrugs thereof in the preparation of drugs for the treatment and/or prevention of KRAS G12C mutation-induced diseases.
  • the KRAS G12C mutation-induced disease is cancer.
  • the present invention provides the aforementioned compound compound or its tautomers, cis-trans isomers, mesoisomers, racemates, enantiomers, diastereomers, hindered Use of transisomers or mixtures thereof, or pharmaceutically acceptable salts, solvates or prodrugs thereof in the preparation of drugs for the treatment and/or prevention of cancer.
  • the cancer is pancreatic cancer, colorectal cancer or lung cancer.
  • the cancer is lung cancer, preferably non-small cell lung cancer.
  • the present invention provides the aforementioned compound compound or its tautomers, cis-trans isomers, mesoisomers, racemates, enantiomers, diastereomers, hindered Use of a transisomer or a mixture form thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof in the preparation of a KRAS mutation inhibitor (preferably, the KRAS mutation is KRAS G12C mutation).
  • the present invention provides a method of treating cancer, which comprises administering to a subject in need a therapeutically effective amount of the aforementioned compound compound or its tautomers, cis-trans isomers, internal Racemates, racemates, enantiomers, diastereomers, atropisomers or mixtures thereof, or pharmaceutically acceptable salts, solvates or prodrugs thereof, or the above Any combination of, or the steps of administering the above-mentioned pharmaceutical composition.
  • the term "subject” refers to animals, especially mammals, preferably humans.
  • the term "effective amount” or “therapeutically effective amount” refers to a sufficient amount of a drug or agent that is non-toxic but can achieve the desired effect.
  • the amount of a given drug depends on many factors, such as the specific dosing regimen, the type of disease or condition and its severity, and the subject in need of treatment Or the uniqueness of the host (such as body weight), but, according to specific surrounding conditions, including, for example, the specific drug that has been used, the route of administration, the condition to be treated, and the subject or host to be treated, the dose to be administered may be known in the art The method is routinely determined.
  • the administered dose is typically in the range of 0.02-5000 mg/day, for example, about 1-1500 mg/day.
  • the required dose can conveniently be expressed as one dose, or simultaneous (or in a short period of time) or divided doses at appropriate intervals, such as two, three, four or more divided doses per day.
  • the specific effective amount can be appropriately adjusted according to the patient's condition and in conjunction with the physician's diagnosis.
  • the term "pharmaceutically acceptable salt” refers to a salt of the compound of the present invention that is pharmaceutically acceptable and has the pharmacological activity of the parent compound.
  • Such salts include: acid addition salts formed with inorganic acids or organic acids, the inorganic acids such as nitric acid, phosphoric acid, carbonic acid, etc.; the organic acids such as propionic acid, caproic acid, cyclopentapropionic acid, Glycolic acid, pyruvic acid, gluconic acid, stearic acid, muconic acid, etc.; or salts formed when the acidic protons present on the parent compound are replaced by metal ions, such as alkali metal ions or alkaline earth metal ions; or with organic bases Formed coordination compounds, the organic bases such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine and the like.
  • 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.
  • the compounds provided by the present invention also exist in prodrug forms.
  • the prodrugs of the compounds described herein easily undergo chemical changes under physiological conditions to transform into the compounds of the invention.
  • prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in the in vivo environment.
  • solvent compound and “solvate” refer to a substance formed by combining the compound of the present invention with a pharmaceutically acceptable solvent.
  • Solvent compounds include stoichiometric amounts of solvent compounds and non-stoichiometric amounts of solvent compounds. Certain compounds of the present invention may exist in unsolvated or solvated forms. Generally speaking, the solvated form is equivalent to the unsolvated form, and both are included in the scope of the present invention.
  • stereoisomer includes conformational isomers and configurational isomers, wherein the configurational isomers mainly include cis-trans isomers and optical isomers.
  • the compounds of the present invention may exist in the form of stereoisomers, and therefore cover all possible stereoisomer forms, including but not limited to cis-trans isomers, tautomers, enantiomers, diastereomers Enantiomers, atropisomers (or rotamers), etc., the compounds of the present invention may also be in any combination or any mixture of the aforementioned stereoisomers, such as meso , Racemates, equal mixtures of atropisomers and other forms.
  • a single enantiomer, a single diastereomer or a mixture of the above, or a single atropisomer or a mixture thereof When the compound of the present invention contains an olefin double bond, unless otherwise specified, it includes cis isomer and trans isomer, and any combination thereof.
  • the atropisomers of the present invention are stereoisomers with axial or planar chirality based on restricted intramolecular rotation.
  • the compound of the present invention has two atropisomers derived from asymmetrical axis, which are restricted to when the substituent Ar' or R 0 'is a C 6-10 aryl group, a 5 or 6-membered monocyclic heteroaryl group , 8 to 10-membered bicyclic heteroaryl or pyridonyl and other cyclic groups when the bond with the substituted naphthyridone ring is connected and rotated to form a steric hindrance.
  • the compound has the structure of formula (I), formula (IA) or formula (II), or the compound of formula (I), formula (IA) or formula (II) has the structure of asymmetric Isomers produced by carbon, etc., which means any one of a pair of atropisomers present in each isomeric compound. And as a drug, atropisomers having excellent activity are preferred.
  • the compound of formula (I), formula (IA) or formula (II) has optical isomers derived from asymmetric carbon, axial asymmetry, etc., and a single isomer can be obtained by optical resolution if necessary.
  • the atropisomers of the compounds of the present invention can be represented by the P or M configuration, and can also be labeled and represented by other commonly used methods well known in the art.
  • the present invention provides compounds with the above-mentioned various structures, or tautomers, cis-trans isomers, mesoisomers, racemates, enantiomers, and diastereomers thereof. Isomers, atropisomers, or mixtures thereof, where "the mixture form” includes any of the aforementioned stereoisomers (for example, tautomers, cis-trans isomers, enantiomers, diastereomers).
  • fused refers to a structure in which two or more rings share one or more bonds.
  • alkyl refers to a straight or branched chain saturated aliphatic hydrocarbon group containing 1 to 20 carbon atoms.
  • C 1-10 alkyl refers to a straight or branched chain alkyl group having 1 to 10 carbon atoms, more preferably a straight or branched chain having 1, 2, 3, 4, 5 or 6 carbon atoms Alkyl, i.e., C 1-6 alkyl, more preferably C 1-4 alkyl, most preferably C 1-3 alkyl.
  • alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl Group, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl -2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and Various branched chain isomers and so on.
  • propyl here represents n-propyl. If there is only a propyl group in the parallel option, the propyl group here means n-propyl or isopropyl.
  • -C 1-3 alkyl- and “C 1-3 alkylene” are used interchangeably and refer to a saturated linear or branched aliphatic hydrocarbon group, which has 2 from the parent
  • the residue derived by removing two hydrogen atoms from the same carbon atom or two different carbon atoms of an alkyl group is a straight or branched chain group containing 1 to 3 carbon atoms.
  • Non-limiting examples of alkylene include, but are not limited to, methylene (-CH 2 -), 1,1-ethylene (-CH(CH 3 )-), 1,2-ethylene (-CH 2 -) CH 2 -), 1,1-propylene (-CH(CH 2 CH 3 )-), 1,2-propylene (-CH 2 CH(CH 3 )-), 1,3-propylene (-CH 2 CH 2 CH 2 -) and so on.
  • -C 1-3 alkyl (hydroxy)-, -C 1-3 alkyl (cyano)-, -C 1-3 alkyl (C 1-6 alkyl)-, -C 1-3 alkyl (halogenated C 1-6 alkyl)-, -C 1-3 alkyl (C 1-6 alkyl-hydroxy)-, -C 1-3 alkyl (C 1-6 Alkyl-cyano)-, -C 1-3 alkyl (C 1-6 alkoxy)-, -C 1-3 alkyl (halogenated C 1-6 alkoxy)-" means "- One or more hydrogen atoms in C 1-3 alkyl-" are respectively substituted by hydroxy, cyano, C 1-6 alkyl, halogenated C 1-6 alkyl, -C 1-6 alkyl-hydroxy,- The residue formed by substitution of C 1-6 alkyl-cyano, C 1-6 alkoxy, and halogenated C 1-6 alkoxy.
  • Non-limiting examples include but are not limited to -CH(OH)-, -CH 2 CH(CN)-, -CH 2 CH(CH 2 CH 3 )-, -CH 2 CH(CF 3 )-, -CH(CH 2 OH)-, -CH 2 CH(CH 2 CN)-, -CH(OCH 3 )-, -CH 2 CH(OCF 3 )-.
  • alkoxy refers to a group having the structure -O-alkyl, where the definition of alkyl is as described above.
  • C 1-10 alkoxy refers to an alkoxy group having 1 to 10 carbon atoms, preferably a C 1-6 alkoxy group, more preferably a C 1-4 alkoxy group, more preferably a C 1- alkoxy.
  • Specific examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, isobutoxy, n-pentoxy and the like.
  • propoxy here represents n-propoxy. If there are only propoxy groups in the parallel option, the propyl group here means n-propoxy or isopropoxy.
  • alkylthio refers to a group having the structure -S-alkyl, where the definition of alkyl is as described above.
  • C 1-10 alkylthio refers to an alkylthio group having 1 to 10 carbon atoms, preferably a C 1-6 alkylthio group, more preferably a C 1-4 alkylthio group, more preferably a C 1-3 alkane Sulfur-based.
  • alkylthio examples include, but are not limited to, methylthio, ethylthio, propylthio, isopropylthio, butylthio, tert-butylthio, isobutylthio, pentylthio and the like.
  • alkenyl refers to an alkyl group as defined above having one or more carbon-carbon double bonds at any position of the chain
  • C 2-8 alkenyl refers to an alkyl group having 2 to
  • the alkenyl group having 8 carbon atoms and at least one carbon-carbon double bond is preferably an alkenyl group having 2 to 6 carbon atoms and 1 to 2 carbon-carbon double bonds, that is, a C 2-6 alkenyl group. More preferred is an alkenyl group having 2 to 4 carbon atoms and 1 to 2 carbon-carbon double bonds, that is, a C 2-4 alkenyl group.
  • alkenyl groups include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl, pentenyl, hexenyl, butadienyl, and the like.
  • alkynyl refers to an alkyl group as defined above having one or more carbon-carbon triple bonds at any position in the chain
  • C 2-8 alkynyl refers to an alkyl group having 2 to
  • the alkynyl group having 8 carbon atoms and at least one carbon-carbon triple bond is preferably an alkynyl group having 2 to 6 carbon atoms and 1 to 2 carbon-carbon triple bonds, that is, a C 2-6 alkynyl group. More preferred is an alkynyl group having 2 to 4 carbon atoms and 1 to 2 carbon-carbon triple bonds, that is, a C 2-4 alkynyl group.
  • Specific examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2-, or 3-butynyl, and the like.
  • halogen refers to fluorine, chlorine, bromine, and iodine.
  • haloalkyl refers to an alkyl group substituted with one or more (eg, 1, 2, 3, 4, or 5) halogens, where the definition of alkyl is as described above.
  • halogenated C 1-10 alkyl group refers to a halogenated alkyl group having 1 to 10 carbon atoms. It is preferably a halogenated C 1-6 alkyl group, more preferably a halogenated C 1-4 alkyl group, and more preferably a halogenated C 1-3 alkyl group.
  • haloalkyl include, but are not limited to, monochloromethyl, dichloromethyl, trichloromethyl, monochloroethyl, 1,2-dichloroethyl, trichloroethyl, monobromoethyl, monofluoromethyl Group, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, etc.
  • deuterated alkyl refers to an alkyl group substituted with one or more (eg, 1, 2, 3, 4, or 5) deuterium atoms, where the definition of the alkyl group is as described above.
  • deuterated C 1-10 alkyl group refers to a deuterated alkyl group having 1 to 10 carbon atoms. It is preferably a deuterated C 1-6 alkyl group, more preferably a deuterated C 1-4 alkyl group, and more preferably a deuterated C 1-3 alkyl group.
  • deuterated alkyl groups include, but are not limited to, mono-deuteromethyl, di-deuteromethyl, tri-deuteromethyl, mono-deuteroethyl, 1,2-dideuteroethyl, tri-deuteroethyl, and the like.
  • haloalkoxy refers to an alkoxy group substituted with one or more (eg, 1, 2, 3, 4, or 5) halogens, where the definition of alkoxy is as described above.
  • halogenated C 1-10 alkoxy group refers to a halogenated alkoxy group having 1 to 10 carbon atoms. It is preferably a halogenated C 1-6 alkoxy group, more preferably a halogenated C 1-4 alkoxy group, and more preferably a halogenated C 1-3 alkoxy group.
  • haloalkoxy examples include, but are not limited to, trifluoromethoxy, trifluoroethoxy, monofluoromethoxy, monofluoroethoxy, difluoromethoxy, difluoroethoxy and the like.
  • cycloalkyl and “cycloalkyl ring” are used interchangeably to refer to a saturated monocyclic or polycyclic fused cyclic hydrocarbon group.
  • C 3-20 cycloalkyl refers to a cycloalkyl having 3 to 20 carbon atoms, including monocyclic cycloalkyl, spirocycloalkyl, fused cycloalkyl, and bridged cycloalkyl. Preferably, it is a C 3-12 cycloalkyl group.
  • the ring carbon atoms of the cycloalkyl group can be optionally substituted with 1, 2 or 3 oxo groups to form a cyclic ketone structure.
  • C 3-8 monocyclic cycloalkyl and “C 3-8 cycloalkyl” refer to saturated monocyclic cyclic hydrocarbon groups having 3 to 8 carbon atoms, preferably C 3-6 monocyclic cycloalkyl ( That is, C 3-6 cycloalkyl), more preferably C 3 , C 4 , C 5 or C 6 monocyclic cycloalkyl.
  • monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.
  • spirocycloalkyl and “spirocycloalkyl ring” refer to a polycyclic cyclic hydrocarbon group formed by sharing one carbon atom (called a spiro atom) between two or more monocyclic rings. . According to the number of shared spiro atoms between rings, spirocycloalkyls are classified into single spirocycloalkyls, dispirocycloalkyls and polyspirocycloalkyls.
  • 5 to 20 membered spirocycloalkyl or "C 5-20 spirocycloalkyl” refers to a polycyclic cyclic hydrocarbon group having 5 to 20 ring carbon atoms, in which the single ring sharing the spiro atom is 3 to 8 members Monocyclic cycloalkyl ring.
  • the cycloalkyl ring may be fused to an aryl, heteroaryl or heterocyclic ring, wherein the ring connected to the parent structure is a cycloalkyl ring, non-limiting examples include indanyl, tetrahydronaphthalene Group, benzocycloheptanyl group, etc.
  • the above-mentioned various types of cycloalkyl groups may be optionally substituted.
  • the substituents are preferably one or more substituent groups described in the present application.
  • halocycloalkyl refers to a cycloalkyl substituted with one or more (such as 1, 2, 3, 4, or 5) halogens, wherein the definition of cycloalkyl is as described above .
  • halogenated C 3-8 cycloalkyl refers to a halogenated cycloalkyl having 3 to 8 ring carbon atoms. It is preferably a halogenated C 3-6 cycloalkyl group, and more preferably a halogenated C 3 , halogenated C 4 , halogenated C 5 or halogenated C 6 cycloalkyl group.
  • halocycloalkyl include, but are not limited to, trifluorocyclopropyl, monofluorocyclopropyl, monofluorocyclohexyl, difluorocyclopropyl, difluorocyclohexyl, and the like.
  • heterocyclyl and “heterocyclyl ring” are used interchangeably and refer to a saturated or partially unsaturated monocyclic or polycyclic fused cyclic hydrocarbon group.
  • C 3-20 hetero “Cyclic group” or “3 to 20 membered heterocyclic group” refers to a saturated or partially unsaturated monocyclic or polycyclic condensed cyclic hydrocarbon group having 3 to 20 ring atoms, of which one or more (preferably 1, 2 , 3 or 4) ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) m (where m is an integer of 0 to 2), but do not include the ring part of -OO-, -OS- or -SS- , The remaining ring atoms are carbon.
  • the ring atom is a nitrogen atom, it can be substituted or unsubstituted (ie, N or NR, R is hydrogen or other substituents already defined herein).
  • the ring carbon atoms of the heterocyclic group can be optionally substituted with 1, 2 or 3 oxo groups to form a cyclic ketone, cyclic lactone or cyclic lactam structure.
  • the 3- to 20-membered heterocyclic group in the present invention includes monocyclic heterocyclic group, spiro heterocyclic group, condensed heterocyclic group and bridged heterocyclic group.
  • C 3-8 monocyclic heterocyclyl refers to having 3 to 8 Ring atoms, wherein 1, 2 or 3 ring atoms are saturated or partially unsaturated monocyclic cyclic hydrocarbon groups selected from nitrogen, oxygen or S(O) m (where m is an integer of 0 to 2) heteroatoms. It is preferably a 3- to 6-membered monocyclic heterocyclic group having 3 to 6 ring atoms, of which 1 or 2 ring atoms are heteroatoms (ie, a C 3-6 monocyclic heterocyclic group).
  • the heteroatom is a 5- or 6-membered monocyclic heterocyclic group having 5 or 6 ring atoms, 1 or 2 of which are heteroatoms.
  • the heteroatom is a nitrogen atom
  • the nitrogen atom may be substituted or unsubstituted (ie, N or NR, R is hydrogen or other substituents already defined herein).
  • the heteroatom is a sulfur atom
  • the sulfur atom may be optionally oxidized (ie, S(O) m , m is an integer of 0 to 2).
  • the ring carbon atoms of the monocyclic heterocyclic group may be optionally substituted with 1, 2 or 3 oxo groups to form a cyclic ketone, cyclic lactone or cyclic lactam structure.
  • monocyclic heterocyclic groups include, but are not limited to, aziridine, ethylene oxide, azetidine, azetidine-2-one, oxetane, oxetane-2 -Ketone, oxazolidine, pyrrolidin-2-one, pyrrolidine-2,5-dione, 1,3-dioxolane, dihydrofuran-2(3H)-one, dihydrofuran-2, 5-dione, piperidin-2-one, piperidine-2,6-dione, tetrahydro-2H-pyran-2-one, imidazolidine, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, 1,3 -Dioxolane-2-one, oxazolidin-2-one, imidazolidine-2-one, piperidine, piperazine, piperazine-2-one, morpholine, morpholine-3-one
  • C 3-8 heterocycloalkyl and “3 to 8 membered heterocycloalkyl” refer to a saturated monocyclic cyclic hydrocarbon group having 3 to 8 ring atoms, of which 1 or 2 ring atoms are heteroatoms. It is preferably a 3- to 6-membered heterocycloalkyl group having 3 to 6 ring atoms, of which 1 or 2 ring atoms are heteroatoms.
  • heterocycloalkyl examples include, but are not limited to, aziridine, oxiranyl, azetidinyl, oxetanyl, oxazolidinyl, 1,3-dioxolane, Dioxanyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiomorpholine-1,1- Dioxide, tetrahydropyranyl, 1,4-oxazepanyl, 1,3-oxazepanyl, 1,3-oxazinyl, hexahydropyrimidinyl, 1 ,4-Dioxanyl.
  • the two ring atoms connected to the above-mentioned monocyclic heterocyclic ring, including CC and NC, can optionally be combined with the monocyclic cycloalkyl ring, monocyclic heterocyclic ring, monoaryl ring, and 5 as defined in the present invention.
  • 6-membered mono-heteroaryl ring and other cycloalkyl, heterocyclic, aryl or heteroaryl groups are fused to form a condensed polycyclic ring, and 2 rings connected to a monocyclic heterocyclic group that forms a condensed ring with other rings
  • the atom is preferably CC.
  • C 6-14 aryl As used herein, the terms "C 6-14 aryl”, “C 6-14 aryl ring” and “C 6-14 aryl ring” are used interchangeably and refer to all groups having 6 to 14 ring atoms. Carbon monocyclic, all-carbon polycyclic (rings and rings are connected by covalent bonds, non-fused) or all-carbon fused polycyclic (that is, rings that share adjacent pairs of carbon atoms) group, at least one ring in the group is Aromatic, that is, it has a conjugated ⁇ -electron system. Preferably it is a C 6-10 aryl group.
  • the C 6-14 aryl group in the present invention includes a monocyclic aryl group, a polycyclic aryl group and an aromatic condensed polycyclic ring, wherein examples of the monocyclic aryl group include phenyl, and examples of the polycyclic aryl group include biphenyl and the like.
  • the aromatic fused polycyclic ring may be a polycyclic group formed by the fusion of a single aryl ring and one or more single aryl rings, Non-limiting examples thereof include naphthyl, anthracenyl and the like.
  • the aromatic fused polycyclic ring may also be a polycyclic group formed by the fusion of a single aryl ring (such as a phenyl) with one or more non-aromatic rings, which is combined with the parent structure
  • the connected ring is aromatic or non-aromatic.
  • the non-aromatic ring includes, but is not limited to, a 3- to 6-membered monocyclic heterocyclic ring (preferably a 5- or 6-membered monocyclic heterocyclic ring, and the ring carbon atoms of the monocyclic heterocyclic ring may be divided by 1 to 2 One oxo group is substituted to form a cyclic lactam or cyclic lactone structure), a 3- to 6-membered monocyclic cycloalkyl ring (preferably a 5- or 6-membered monocyclic cycloalkyl ring, the monocyclic cycloalkyl ring is The ring carbon atoms can be substituted by 1 or 2 oxo groups to form a cyclic ketone structure).
  • the polycyclic group in which the above-mentioned single aryl ring and one or more non-aromatic rings are fused can be connected to other groups or the parent structure through a nitrogen atom or carbon atom, and the ring connected to the parent structure is a single aryl ring or non-aromatic ring.
  • a benzene ring is fused with a 5- or 6-membered monocyclic heterocyclic ring to form a 9- or 10-membered aromatic fused bicyclic ring, which means that two adjacent substituent groups on the phenyl group and the ring atoms to which they are connected form one Condensed 5- or 6-membered monocyclic heterocyclyl ring, the 5- or 6-membered monocyclic heterocyclic ring is as defined above, and the formed 9- or 10-membered aromatic fused bicyclic ring can also be referred to as 9 or 10-membered Phenyl heterocyclyl ring.
  • the benzene ring is fused with a 5- or 6-membered monocyclic cycloalkyl ring to form a 9- or 10-membered aromatic fused bicyclic ring, which means that two adjacent substituent groups on the phenyl group and the ring atoms to which they are connected form one Condensed 5- or 6-membered monocyclic cycloalkyl ring, the 5- or 6-membered monocyclic cycloalkyl ring is as defined above, and the formed 9- or 10-membered aromatic fused bicyclic ring can also be referred to as 9 or 10-membered Phenylcycloalkyl ring.
  • Non-limiting examples include:
  • the above-mentioned various aryl groups may be substituted or unsubstituted.
  • the substituents are preferably one or more of the substituent groups described in this application.
  • heteroaryl As used herein, the terms “heteroaryl”, “heteroaryl ring” and “heteroaryl ring” are used interchangeably and refer to a single ring atom substituted with at least one heteroatom independently selected from nitrogen, oxygen, or sulfur.
  • the heteroaryl group has 6, 10, or 14 ⁇ electrons shared, and at least one ring in the group is aromatic.
  • C 5-14 heteroaryl and “5 to 14 membered heteroaryl” refer to heteroaryl groups having 5 to 14 ring atoms, of which 1, 2, 3, or 4 ring atoms are heteroatoms. It is preferably a 5- to 10-membered heteroaryl group having 5 to 10 ring atoms, of which 1, 2, 3, or 4 ring atoms are heteroatoms.
  • the C 5-14 heteroaryl group may be a single heteroaryl group, a fused bicyclic heteroaryl group or a fused tricyclic heteroaryl group.
  • the terms "5- or 6-membered monoheteroaryl” and “5 or 6-membered monocyclic heteroaryl” are used interchangeably and refer to having 5 or 6 ring atoms, of which 1, 2, or 3.
  • single heteroaryl groups include, but are not limited to, thiophene, furan, thiazole, isothiazole, imidazole, oxazole, pyrrole, pyrazole, triazole, 1,2,3-triazole, 1,2,4-triazole , 1,2,5-triazole, 1,3,4-triazole, tetrazole, isoxazole, oxadiazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, thiadiazole, pyridine, pyridazine, pyrimidine, pyrazine, etc.
  • the terms "8 to 10 membered bicyclic heteroaryl” and “8 to 10 membered bicyclic heteroaryl” are used interchangeably and refer to having 8 to 10 ring atoms, of which 1, 2, 3, Condensed bicyclic heteroaryl groups in which 4 or 5 ring atoms are heteroatoms.
  • the fused bicyclic heteroaryl group can be a bicyclic group (preferably 9) formed by condensing a single aryl ring (such as a phenyl) and a single heteroaryl ring (preferably a 5- or 6-membered single heteroaryl ring).
  • 10-membered bi-heteroaryl ring it can also be a mono-heteroaryl ring (preferably a 5- or 6-membered mono-heteroaryl ring) and a mono-heteroaryl ring (preferably a 5- or 6-membered mono-heteroaryl ring) A bicyclic group formed by fusion.
  • any two ring atoms on the above-mentioned single heteroaryl ring can be combined with the monocyclic cycloalkyl ring, monocyclic heterocyclyl ring, single aryl ring, 5 or Cycloalkyl, heterocyclic, aryl or heteroaryl groups such as a 6-membered monoheteroaryl ring are condensed to form a condensed polycyclic ring.
  • the two ring atoms connected to the monoheteroaryl ring forming a fused ring with other rings are preferably C-C, and include the following forms without limitation:
  • Non-limiting examples of 8- to 10-membered bisheteroaryl groups include: benzo[d]isoxazole, 1H-indole, isoindole, 1H-benzo[d]imidazole, benzo[d]isothiazole, 1H-benzo[d][1,2,3]triazole, benzo[d]oxazole, benzo[d]thiazole, indazole, benzofuran, benzo[b]thiophene, quinoline, iso Quinoline, quinazoline, quinoxaline, cinnoline, pyrido[3,2-d]pyrimidine, pyrido[2,3-d]pyrimidine, pyrido[3,4-d]pyrimidine, pyrido[ 4,3-d]pyrimidine, 1,8-naphthyridine, 1,7-naphthyridine, 1,6-naphthyridine, 1,5-nap
  • the above-mentioned mono-heteroaryl group, or the double-heteroaryl group formed by the fusion of a benzene ring and a single heteroaryl ring, or the double-heteroaryl group formed by the fusion of a single heteroaryl ring and a single heteroaryl ring, can pass through a nitrogen atom or a carbon Atoms are connected to other groups or parent structures.
  • the ring connected to the parent structure is a monoheteroaryl ring or a benzene ring, and specific examples thereof include but are not limited to:
  • the fused bicyclic heteroaryl or fused tricyclic heteroaryl may be a single heteroaryl ring (preferably a 5- or 6-membered single heteroaryl ring) and one or more A polycyclic group formed by the fusion of a non-aromatic ring, in which the ring connected to the parent structure is a single heteroaryl ring or a non-aromatic ring.
  • the non-aromatic ring includes, but is not limited to, a 3- to 6-membered monocyclic heterocyclic ring (preferably a 5- or 6-membered monocyclic heterocyclic ring, and the ring carbon atoms of the monocyclic heterocyclic ring may be divided by 1 to 2 One oxo group is substituted to form a cyclic lactam or cyclic lactone structure), a 3- to 6-membered monocyclic cycloalkyl ring (preferably a 5- or 6-membered monocyclic cycloalkyl ring, the monocyclic cycloalkyl ring is The ring carbon atoms can be substituted by 1 or 2 oxo groups to form a cyclic ketone structure) and so on.
  • the polycyclic group formed by the condensation of the above-mentioned single heteroaryl ring with one or more non-aromatic rings can be connected to other groups or the parent structure through a nitrogen atom or carbon atom, and the ring connected to the parent structure is a single heteroaryl ring Or non-aromatic ring.
  • a 5- or 6-membered mono-heteroaryl ring is fused with a 5- or 6-membered monocyclic heterocyclic ring to form an 8- to 10-membered fused bicyclic heteroaryl group, which means that a 5- or 6-membered mono-heteroaryl group is Two adjacent substituent groups and the ring atoms to which they are connected form a fused 5- or 6-membered monocyclic heterocyclyl ring, and the 5- or 6-membered monocyclic heterocyclic ring is defined as above, resulting in 8 A to 10-membered fused bicyclic heteroaryl group can also be referred to as an 8- to 10-membered heteroaryl heterocyclyl ring.
  • a 5- or 6-membered mono-heteroaryl ring is fused with a 5- or 6-membered monocyclic cycloalkyl ring to form an 8- to 10-membered fused bicyclic heteroaryl group, which means a 5- or 6-membered mono-heteroaryl group
  • Two adjacent substituent groups and the ring atoms to which they are connected form a fused 5- or 6-membered monocyclic cycloalkyl ring.
  • the 5- or 6-membered monocyclic cycloalkyl ring is as defined above, and the resulting 8 A to 10-membered fused bicyclic heteroaryl group can also be referred to as an 8- to 10-membered heteroaryl cycloalkyl ring.
  • Non-limiting examples include:
  • the above-mentioned various heteroaryl groups may be substituted or unsubstituted.
  • the substituents are preferably one or more of the substituent groups described in this application.
  • -alkyl-R refers to a substituent formed by the substitution of an alkyl group with one or more R groups, where "-alkyl-" refers to an alkylene or sub-alkylene group formed by substitution.
  • R as described herein can be a hydroxyl group, a cyano group, an alkoxy group, a substituted amino group, a heterocycloalkyl group, a heteroaryl group, a halogenated alkyl group, a halogenated alkoxy group, a cycloalkyl group, an alkynyl group, etc.
  • the group represented by R The group is as defined herein.
  • -C 1-6 alkyl-R Preferably -C 1-6 alkyl-R, more preferably -C 1-4 alkyl-R, more preferably -C 1-3 alkyl-R, more preferably -C 1-2 alkyl-R, such as -CH 2 -CH(CH 3 )-R, -CH 2 -CH 2 -CH 2 -R, -CH 2 -CH 2 -R, -CH 2 -R, etc.
  • hydroxyl refers to -OH.
  • hydroxymethyl refers to -CH 2 OH
  • hydroxyethyl refers to -CH 2 CH 2 OH or -CH(OH)CH 3 .
  • cyanomethyl refers to -CH 2 CN
  • cyanoethyl refers to -CH 2 CH 2 CN or -CHCNCH 3 .
  • amino means -NH 2.
  • cyano refers to -CN.
  • nitro refers to -NO 2 .
  • benzyl as used herein means a -CH 2 used - benzene.
  • carboxylate group refers to -C(O)O (alkyl) or -C(O)O (cycloalkyl).
  • acetyl refers to -COCH 3 .
  • C 1-10 may be preferably C 1-6 ; more preferably C 1-4 ; more preferably C 1-3 .
  • the C 1-10 alkyl group may preferably be a C 1-6 alkyl group; more preferably a C 1-4 alkyl group; more preferably a C 1-3 alkyl group.
  • C 1-10 alkoxy may preferably be C 1-6 alkoxy; more preferably C 1-4 alkoxy; more preferably C 1-3 alkoxy.
  • C 3-20 may preferably be C 3-10 ; more preferably C 3-8 ; more preferably C 3-6 ; more preferably C 3-5 .
  • the C 3-20 cycloalkyl group may preferably be a C 3-8 cycloalkyl group; more preferably a C 3-6 cycloalkyl group; more preferably a C 3-6 cycloalkyl group.
  • the C 3-6 cycloalkyl group is selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • the 3- to 6-membered heterocycloalkyl group is selected from: aziridine, ethylene oxide, azetidine, oxetane, Tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, piperazine, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide, tetrahydropyran.
  • the 5- or 6-membered monocyclic heteroaryl group is selected from: thiophene, N-alkylpyrrole, furan, thiazole, isothiazole, imidazole, oxazole, Pyrrole, pyrazole, triazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,5-triazole, 1,3,4-triazole, tetrazole, isoxazole , Oxadiazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, thiadiazole, pyridine , Pyridazine, pyrimidine, pyrazine.
  • the 8- to 10-membered bicyclic heteroaryl group is selected from: benzoxazole, benzisoxazole, benzimidazole, benzothiazole, benzo Isothiazole, benzotriazole, benzofuran, benzothiophene, indole, indazole, isoindole, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline, pyridopyrimidine, naphthyridine .
  • substituted means that any one or more hydrogen atoms on a specific atom is replaced by a substituent, and may include deuterium and hydrogen variants, as long as the valence of the specific atom is normal and The substituted compound is stable.
  • oxo O
  • oxo group substitution does not occur on the aromatic group.
  • optionally substituted or “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.
  • the compound represented by formula (IA) or formula (IB) of the present invention can be prepared by using a synthetic method known in the art or using a method known in the art in combination with the method described in the present invention.
  • the solvent, temperature and other reaction conditions given in the present invention are all exemplary and can be changed according to methods well known in the art.
  • the compounds of the examples described in the present invention can be synthesized according to their specific structures and using appropriate starting materials according to the methods described in the examples, or they can be synthesized using methods similar to those described in the examples.
  • the starting materials used to synthesize the compounds of the examples of the present invention can be prepared by known synthetic methods or similar methods described in the literature or obtained from commercial sources.
  • the compounds of the examples can be further resolved to obtain their stereoisomers by methods well known in the art, such as crystallization, chromatography, etc., as required, and the resolution conditions are easily obtained by those skilled in the art through conventional means or limited experiments.
  • the compounds of formula (IB-1') and formula (IB-2') of the present invention can be synthesized by the following methods, wherein the solvent, temperature and other reaction conditions in each step can be as described in the following examples Are the same or similar, or use reaction conditions known in the art;
  • the compounds of formula (IB-1') and formula (IB-2') of the present invention can also be synthesized by the following methods, wherein the solvent, temperature and other reaction conditions in each step can be the same as described in the following examples or Similar, or use reaction conditions known in the art;
  • R lev is a leaving group well known in the art, such as triflate; chlorine, bromine, iodine ; Sulfonate groups, such as mesylate, toluenesulfonate, p-toluenesulfonate, etc.; acyloxy groups, such as acetoxy, trifluoroacetoxy and so on.
  • R p is an amino protecting group well known in the art, such as formyl; acyl, such as alkanoyl (such as acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl, such as tert-butoxy Carbonyl (Boc); arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethyloxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl (Tr), 1,1-Di-(4'-methoxyphenyl)methyl; silyl group, such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS) and so on.
  • acyl such as alkanoyl (such as acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl,
  • R 1 , R 2 , R 3 , R 21 , R 22 , R 12 , R 11 , R 31 , R 32 , R m ', R 0 ', Ar', E 1 ', X 1 have the same definitions as before (e.g. the same The definition of each corresponding group in formula I or formula IA).
  • the compounds of formula (IB-1") and formula (IB-2") of the present invention can be synthesized by the following methods, wherein the solvent, temperature and other reaction conditions in each step can be the same as or similar to those described in the following examples , Or use reaction conditions known in the art;
  • R p is an amino protecting group well known in the art, such as formyl; acyl, such as alkanoyl (such as acetyl , Trichloroacetyl or trifluoroacetyl); alkoxycarbonyl, such as tert-butoxycarbonyl (Boc); arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethyloxycarbonyl (Fmoc) ; Arylmethyl, such as benzyl (Bn), trityl (Tr), 1,1-bis-(4'-methoxyphenyl) methyl; silyl, such as trimethylsilyl Group (TMS) and tert-butyldimethylsilyl (TBS) and so on.
  • acyl such as alkanoyl (such as acetyl , Trichloroacetyl or trifluoroacetyl); alkoxycarbonyl
  • R 1 , R 2 , R 3 , R 21 , R 22 , R 12 , R 11 , R 31 , R 32 , R 0 ', Ar', E 1 ', X 1 are defined as before (e.g., the same as in formula I or formula The definition of each corresponding group in IA).
  • the compound of formula e can also be synthesized by the following method, wherein the solvent, temperature and other reaction conditions in each step can be the same as or similar to those described in the following examples, or reaction conditions known in the art can be used;
  • R lev is a well-known leaving group in the art, such as trifluoromethanesulfonate; chlorine, bromine, and iodine; sulfonate groups, such as mesylate, tosylate, P-toluenesulfonate, etc.; acyloxy groups, such as acetoxy, trifluoroacetoxy, etc.
  • R 0 ', Ar', E 1 ', and X 1 are as defined above (for example, the same as the definition of each corresponding group in formula I or formula IA).
  • Figure 1 is a diagram of the X-ray single crystal diffraction molecular three-dimensional structure of compound Z25-2.
  • Figure 2 is an X-ray single crystal diffraction molecular three-dimensional structure diagram of compound Z27-2.
  • 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 following examples describe the present invention in detail, but they are 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. If no specific conditions are indicated in the examples, it shall be carried out in accordance with the conventional conditions or the conditions recommended by the manufacturer.
  • the reagents or instruments used without the manufacturer's indication are all conventional products that can be purchased on the market.
  • THF tetrahydrofuran
  • DMSO dimethyl sulfoxide
  • PE petroleum ether
  • EtOAc ethyl acetate
  • DCM dichloromethane
  • MeOH methanol
  • ACN acetonitrile
  • IPA is isopropylamine
  • DMA dimethylamine
  • TFA trifluoroacetic acid
  • NH 4 Cl ammonium chloride
  • SPhos is 2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl
  • SPhos-Pd-G2 is chlorine (2-dicyclohexylphosphine-2',6'-dimethoxy-1,1'-biphenyl) [2-(2'-amino-1,1'-biphenyl) Benzene)] Palladium(II);
  • NaHMDS is sodium bis(trimethylsilyl)amide;
  • Step 1 2-isopropyl-4-methylpyridin-3-amine (582mg, 3.88mmol) was dissolved in THF (20mL), the reaction was cooled to 0°C, and NaHMDS (5.8mL, 11.60mmol, 2M in THF), the reaction was stirred for 15 minutes, and a THF solution (6 mL) of 2,5-difluoro-6-(2-fluoro-6-methoxyphenyl)nicotinic acid (1.0 g, 3.53 mmol) was added dropwise. The reaction was stirred at room temperature for 3 hours. Pour the reaction solution into 30 mL saturated NH 4 Cl. Extract 3 times with 40 mL ethyl acetate. The organic phase was dried and concentrated.
  • Step 2 5-Fluoro-6-(2-fluoro-6-methoxyphenyl)-2-((2-isopropyl-4-methylpyridin-3-yl)amino)nicotinic acid (700mg, 1.69mmol) was dissolved in 1,2-dichloroethane (15mL), SOCl 2 (2.0g, 16.90mmol) was added, and the reaction was stirred at 80°C for 2 hours.
  • Step 3 At 0°C, add ethyl nitroacetate (449mg, 3.38mmol) in THF (2ml) solution dropwise to a THF (25mL) suspension containing NaH (608mg, 15.21mmol), and react at zero degrees. Stir for half an hour, 5-fluoro-6-(2-fluoro-6-methoxyphenyl)-2-((2-isopropyl-4-methylpyridin-3-yl)amino)nicotinyl chloride (721mg , 1.69mmol) in THF (15mL) solution was added dropwise. The ice bath was removed and the reaction solution was stirred at 70°C overnight.
  • Step 4 6-Fluoro-7-(2-fluoro-6-methoxyphenyl)-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro -1,8-naphthyridin-2(1H)-one (1.05g, 1.69mmol) was dissolved in acetonitrile (25mL), and POCl 3 (1.30g, 8.45mmol), and N,N-diisopropyl were added successively Ethylamine (1.74g, 13.52mmol), the reaction was stirred at 80°C for 1 hour. The reaction solution was concentrated, ethyl acetate was added and washed with ice water, water, and saturated brine in that order.
  • Step 5 4-Chloro-6-fluoro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro 1,8-naphthyridine-2(1H)-one (175mg, 0.35mmol) dissolved in DMF (6mL), add (R)-3-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester (454mg, 2.10mmol), the reaction was stirred at 80°C for 18 hours. Pour the reaction solution into 30 mL of water. Extract 3 times with 20 mL ethyl acetate.
  • Step 6 (3R)-4-(6-fluoro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)- Tert-Butyl 3-nitro-2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl)-3-(hydroxymethyl)piperazine-1-carboxylate (73mg, 0.11 mmol) was dissolved in DMA (4 mL), NaH (22 mg, 0.55 mmol) was added, and the reaction was stirred at 145°C for 10 hours. Pour the cooled reaction solution into 15 mL of water. Extract 3 times with 30 mL ethyl acetate.
  • Step 7 (4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-7-oxy -1,2,4a,5,7,8-hexahydropyrazine[1',2':4,5][1,4]oxo-2,3-c][1,8]naphthyridine -3(4H)-tert-butyl formate (35mg, 0.055mmol) was dissolved in dichloromethane (2.5mL) and trifluoroacetic acid (0.5mL) was added.
  • Step 8 (4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-1,2 ,3,4,4a,5-hexahydropyrazine[1',2':4,5][1,4]oxazine[2,3-c][1,8]naphthyridine-7(8H) -Ketone (40mg, 0.055mmol) was dissolved in dichloromethane (4mL), and triethylamine (28mg, 0.28mmol) was added.
  • the reaction was cooled to 0°C, and a dichloromethane solution (0.5 mL) of acrylic anhydride (6 mg, 0.05 mmol) was added dropwise to the reaction solution.
  • the reaction was stirred at 0°C for 15 minutes.
  • 10 mL of saturated NaHCO 3 aqueous solution was added to the reaction solution, and extraction was performed 3 times with 10 mL of dichloromethane.
  • the organic phase was dried and concentrated.
  • Step 9 (4aR)-3-acryloyl-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl) )-1,2,3,4,4a,5-hexahydropyrazine[1',2':4,5][1,4]oxazine[2,3-c][1,8]naphthyridine -7(8H)-one (15 mg, 0.025 mmol) was dissolved in dichloromethane (1.5 mL). The reaction was cooled to 0°C, and a 17% dichloromethane solution (1 mL) of boron tribromide was added dropwise thereto.
  • Step 1 At room temperature, add 5-(methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (2.9 g, 15.62 mmol) and isopropanol (40 mL), 2-chloropyridin-3-amine (2.0 g, 15.62 mmol) were added in portions. The reaction was stirred at reflux for 15 minutes.
  • Step 2 Add 200mL of diphenyl ether to a 500mL round bottom flask, heat to 220°C, add 5-((2-chloropyridin-3-yl)amino)methylene)-2,2-dimethyl in batches -1,3-dioxane-4,6-dione (3.9g, 13.83mmol), the reaction was stirred at 220°C for 20 minutes. The reaction liquid was cooled to room temperature, poured into petroleum ether, the precipitated solid was filtered, the filter cake was washed with petroleum ether, and vacuum dried to obtain the product 8-chloro-1,7-naphthyridin-4-ol (1.5g, Y: 60% ), light brown solid.
  • ES-API:[M+H] + 181.0
  • Step 3 Add 8-chloro-1,7-naphthyridin-4-ol (500mg, 2.78mmol), sodium acetate (300mg, 2.78mmol), absolute ethanol (25mL), and 5% to a 50mL round bottom flask Pd/C (250mg), the reaction was stirred at room temperature under a hydrogen balloon for 3 days. The reaction solution was filtered with celite, the filtrate was concentrated, and the crude product was purified with a flash silica column (dichloromethane/methanol: 0-10%) to obtain the product 1,7-naphthyridin-4-ol (200mg, Y: 49.3%). Yellow solid.
  • ES-API: [M+H] + 147.1
  • Step 4 1,7-naphthyridin-4-ol (550mg, 3.77mmol) is dissolved in concentrated sulfuric acid (4.5mL), cooled to 0°C, concentrated nitric acid (1.0mL, 15.08mmol) is slowly added dropwise, and the reaction is at 100°C Stir for 1 hour. The cooled reaction liquid was poured into ice water, the pH was adjusted to 6-7 with concentrated ammonia water, the precipitated solid was filtered and dried in vacuum to obtain the product 3-nitro-1,7-naphthyridin-4-ol (530mg, Y: 73.7 %), yellow solid.
  • ES-API: [M+H] + 192.1
  • Step 5 Add 3-nitro-1,7-naphthyridin-4-ol (480mg, 2.51mmol) and phosphorus oxychloride (4.68mL, 50.20mmol) to a 20mL round bottom flask, and cool to -15°C, Triethylamine (1.8 mL, 12.55 mmol) was slowly added dropwise, and the reaction was stirred at room temperature for 1 hour. Pour the reaction solution into ice water, adjust the pH to 8 with cold saturated sodium bicarbonate solution, and extract 3 times with dichloromethane. The organic phase was dried and concentrated to obtain the product 4-chloro-3-nitro-1,7-naphthyridine (450 mg, Y: 85.7%) as a brown solid.
  • ES-API: [M+H] + 210.1.
  • Step 6 4-Chloro-3-nitro-1,7-naphthyridine (450mg, 2.15mmol) was dissolved in 1,4-dioxane (15mL) and (R)-3-(hydroxymethyl) was added sequentially Piperazine-1-carboxylic acid tert-butyl ester (1.02g, 4.73mmol) and N,N-diisopropylethylamine (832mg, 6.45mmol), the reaction was stirred at 80°C for 3 hours.
  • Step 7 Add (R)-3-(hydroxymethyl)-4-(3-nitro-1,7-naphthyridin-4-yl)piperazine-1-carboxylic acid tert-butyl to the 50mL sealed tube in sequence Ester (310 mg, 0.80 mmol), DMF (18 mL), and NaH (96 mg, 2.40 mmol), and the reaction was stirred at 95°C for 3 days. The cooled reaction liquid was poured into water, and extracted twice with ethyl acetate.
  • Step 8 (R)-8a,9,11,12-Tetrahydropyrazine[1',2':4,5][1,4]oxazine[2,3-c][1,7]naphthalene
  • Pyridine-10(8H)-tert-butyl carboxylate 100 mg, 0.29 mmol
  • acetic acid 4 mL
  • sodium cyanoborohydride 73 mg, 1.16 mmol
  • Step 9 Add (R)-1,2,3,4,8a,9,11,12-octahydropyrazine[1',2':4,5][1,4]oxa to a 5mL microwave tube Oxazine[2,3-c][1,7]naphthyridine-10(8H)-tert-butyl carboxylate (50mg, 0.14mmol), 4-bromo-5-methyl-1-(tetrahydro-2H- Pyran-2-yl)-1H-indazole (83mg, 0.28mmol), cesium carbonate ( 136mg, 0.42mmol), Pd 2 (dba) 3 (51mg, 0.056mmol), Ruphos (26mg, 0.056mmol) and toluene (6mL), replaced with nitrogen, replaced with a microwave reactor at 120°C, stirred for 1 hour, cooled to room temperature, filtered, dried and concentrated the filtrate, and used a thick thin-layer chromatography plate for the crude
  • Step 10 (8aR)-3-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-1,2,3,4, 8a,9,11,12- Octahydropyrazine[1',2':4,5][1,4]oxazine[2,3-c][1,7]naphthyridine-10(8H)- Tert-butyl carboxylate (60 mg, 0.11 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (0.8 mL) was added.
  • Step 11 (R)-3-(5-Methyl-1H-indazol-4-yl)-1,2,3,4,8,8a,9,10,11,12-decahydropyrazine [1',2':4,5][1,4]oxazine[2,3-c][1,7]naphthyridine (60mg, 0.11mmol) and N,N-diisopropylethylamine ( 71 mg, 0.55 mmol) was dissolved in dichloromethane (5 mL), the reaction was cooled to 0° C., and a dichloromethane solution (0.5 mL) of acrylic anhydride (13 mg, 0.10 mmol) was added dropwise to the reaction solution.
  • Step 1 4-Chloro-6-fluoro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro
  • Base-1,8-naphthyridin-2(1H)-one (700mg, 1.40mmol) was dissolved in DMF (10mL), and (2R,5R)-5-(hydroxymethyl)-2-methylpiperazine- Tert-butyl 1-carboxylate (1.61 g, 7.0 mmol), the reaction was stirred at 80°C for 1 hour. Pour the reaction solution into 30 mL of water. Extract 3 times with 20 mL ethyl acetate.
  • Step 2 (2R,5R)-4-(6-fluoro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl) )-3-nitro-2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl)-5-(hydroxymethyl)-2-methylpiperazine-1-carboxylic acid
  • Tert-butyl ester 300mg, 0.44mmol
  • DMA 20mL
  • NaH 52mg, 1.32mmol
  • Step 3 (2R,4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2 -Methyl-7-oxo-1,2,4a,5,7,8-hexahydropyrazine[1',2':4,5][1,4]oxazine[2,3-c] [1,8]
  • Naphthyridine-3(4H)-tert-butyl carboxylate 60 mg, 0.093 mmol
  • dichloromethane 3 mL
  • trifluoroacetic acid 0.7 mL
  • Step 4 (2R,4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2 -Methyl-1,2,3,4,4a,5-hexahydropyrazine[1',2':4,5][1,4]oxazine[2,3-c][1,8] Naphthyridin-7(8H)-one (61 mg, 0.093 mmol) was dissolved in dichloromethane (5 mL), and triethylamine (47 mg, 0.46 mmol) was added.
  • the reaction was cooled to 0°C, and a dichloromethane solution (1 mL) of acrylic anhydride (17 mg, 0.14 mmol) was added dropwise to the reaction solution.
  • the reaction was stirred at 0°C for 15 minutes.
  • 10 mL of saturated NaHCO 3 aqueous solution was added to the reaction solution, and extraction was performed 3 times with 10 mL of dichloromethane.
  • the organic phase was dried and concentrated.
  • Step 5 (6aR,9R)-8-acryloyl-3-fluoro-2-(2-fluoro-6-methoxyphenyl)-13-(2-isopropyl-4-methylpyridine-3 -Yl)-9-methyl-6,6a,7,8,9,10-hexahydropyrazine[1',2':4,5][1,4]oxypyrazine[3,2-c ][1,8]naphthyridin-12(13H)-one (32mg, 0.053mmol) was dissolved in dichloromethane (1.5mL). The reaction was cooled to 0°C, and a 17% dichloromethane solution (1 mL) of boron tribromide was added dropwise thereto.
  • Step 1 4,6-Dichloro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro -1,8-naphthyridine-2(1H)-one (1.8g, 3.48mmol) dissolved in DMF (15mL), add (R)-3-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester (3g, 13.92mmol), the reaction was stirred at 80°C for 2 hours. Pour the reaction solution into 30 mL of water. Extract 3 times with 20 mL ethyl acetate.
  • Step 2 (3R)-4-(6-chloro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)- Tert-Butyl 3-nitro-2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl)-3-(hydroxymethyl)piperazine-1-carboxylate (1.3g, 1.86 mmol) was dissolved in DMA (10 mL), LHMDS (5.6 mmol, 5.6 mmol, 1M tetrahydrofuran solution) was added, and the reaction was stirred at 140°C for 20 hours. Pour the cooled reaction solution into 15 mL of water.
  • Step 3 (4aR)-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-7-oxy Generation-1,2,4a,5,7,8-hexahydropyrazino[1',2':4,5][1,4]oxazino[2,3-c][1,8] Naphthyridine-3(4H)-tert-butyl carboxylate (240 mg, 0.37 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (2 mL) was added.
  • Step 4 (4aR)-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-1,2 ,3,4,4a,5-hexahydropyrazino[1',2':4,5][1,4]oxazino[2,3-c][1,8]naphthyridine-7( 8H)-ketone (203 mg, 0.37 mmol) was dissolved in dichloromethane (4 mL), and triethylamine (187 mg, 1.85 mmol) was added.
  • the reaction was cooled to 0°C, and a dichloromethane solution (0.5 mL) of acrylic anhydride (37 mg, 0.30 mmol) was added dropwise to the reaction solution.
  • the reaction was stirred at 0°C for 10 minutes.
  • 10 mL of saturated NaHCO 3 aqueous solution was added to the reaction solution, and extraction was performed 3 times with 10 mL of dichloromethane.
  • the organic phase was dried and concentrated.
  • Step 5 (4aR)-3-acryloyl-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl) )-1,2,3,4,4a,5-hexahydropyrazino[1',2':4,5][1,4]oxazino[2,3-c][1,8] Naphthyridin-7(8H)-one (223 mg, 0.37 mmol) was dissolved in dichloromethane (1.5 mL). The reaction was cooled to 0°C, and a 17% dichloromethane solution (3 mL) of boron tribromide was added dropwise thereto.
  • Step 1 4-Chloro-6-fluoro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro -1,8-naphthyridin-2(1H)-one (500mg, 1.00mmol) was dissolved in N,N-dimethylacetamide (6mL), and (R)-1-(tert-butyl) 3 -Methyl-piperazine-1,3-dicarboxylate (732mg, 3.00mmol), and N,N-diisopropylethylamine (387mg, 3.00mmol), the reaction was stirred at 120°C for 2 hours.
  • Step 2 (3R)-1-(tert-butyl)-3-methyl-4-(6-fluoro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl 4-methylpyridin-3-yl)-3-nitro-2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl)piperazine-1,3-dicarboxy
  • the acid ester 500mg, 0.71mmol
  • acetic acid 8mL
  • iron powder 138mg, 2.47mmol
  • Step 3 Add (4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridine-3) to the 15mL sealed tube in sequence -Base)-5,7-dioxo-1,2,4,4a,5,6,7,8-octahydro-3H-pyrazine[1',2':4,5]pyrazine[2 ,3-c][1,8]naphthyridine-3-carboxylic acid tert-butyl ester (450 mg, 0.70 mmol), 12 mL acetone, anhydrous potassium carbonate (290 mg, 2.10 mmol), methyl iodide (596 mg, 4.20 mmol).
  • Step 4 (4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-6-methyl -5,7-Dioxy-1,2,4,4a,5,6,7,8-octahydro-3H-pyrazine[1',2':4,5]pyrazine[2,3 -c][1,8]naphthyridine-3-carboxylic acid tert-butyl ester (940 mg, 1.42 mmol) was dissolved in dichloromethane (6 mL), and trifluoroacetic acid (2 mL) was added.
  • Step 5 (4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-6-methyl Base-2,3,4,4a,6,8-hexahydro-1H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyridine-5 , 7-dione (1.1 g, crude product) was dissolved in dichloromethane (20 mL), and N,N-diisopropylethylamine (916 mg, 7.10 mmol) was added.
  • Step 6 (4aR)-3-acryloyl-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl) )-6-methyl-2,3,4,4a,6,8-hexahydro-1H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8 ] Naphthyridine-5,7-dione (390 mg, 0.64 mmol) was dissolved in dichloromethane (9 mL). The reaction was cooled to 0°C, and a 17% dichloromethane solution (7 mL) of boron tribromide was added dropwise thereto.
  • Step 7 (4aR)-3-acryloyl-11-fluoro-10-(2-fluoro-6-hydroxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)- 6-Methyl-2,3,4,4a,6,8-hexahydro-1H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8,8 ]
  • Naphthyridine-5,7-dione 750mg, 1.25mmol
  • IB 10 ⁇ m, 30*250mm
  • mobile phase: hexane: EtOH 65:35
  • flow rate 25ml/min
  • column temperature and room temperature
  • Step 1 Add (2R, 4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridine) to the 50mL sealed tube in sequence -3-yl)-2-methyl-5,7-dioxo-1,2,4,4a,5,6,7,8-octyl-3H-pyrazine[1',2': 4 ,5]pyrazine[2,3-c][1,8]naphthyridine-3-carboxylic acid tert-butyl ester (800mg, 1.21mmol), 20mL acetone, anhydrous potassium carbonate (500mg, 3.63mmol), methyl iodide (1.03 g, 7.26 mmol).
  • Step 2 (2R,4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2 ,6-Dimethyl-5,7-dioxo-1,2,4,4a,5,6,7,8-octyl-3H-pyrazine[1',2':4,5]pyrazine Triazine[2,3-c][1,8]naphthyridine-3-carboxylic acid tert-butyl ester (790 mg, 1.42 mmol) was dissolved in dichloromethane (6 mL), and trifluoroacetic acid (2 mL) was added.
  • Step 3 (2R,4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2 ,6-Dimethyl-2,3,4,4a,6,8-hexahydro-1H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8 ]
  • Naphthyridine-5,7-dione 810 mg, crude product was dissolved in dichloromethane (15 mL), and N,N-diisopropylethylamine (755 mg, 5.85 mmol) was added.
  • the reaction was cooled to 0°C, acryloyl chloride (211 mg, 2.34 mmol) was added to the reaction solution, and the reaction was stirred at 0°C for 15 minutes. 50mL of dichloromethane was added to the reaction solution, washed with 20mL of water, 40mL of saturated NaHCO 3 aqueous solution, 20mL of saturated brine, dried and concentrated.
  • Step 4 (2R,4aR)-3-acryloyl-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridine-3 -Yl)-2,6-dimethyl-2,3,4,4a,6,8-hexahydro-1H-pyrazine[1',2':4,5]pyrazine[2,3-c ][1,8]naphthyridine-5,7-dione (370 mg, 0.59 mmol) was dissolved in dichloromethane (8 mL). The reaction was cooled to 0°C, and a 17% dichloromethane solution (7 mL) of boron tribromide was added dropwise thereto.
  • reaction was stirred at room temperature for 3 hours.
  • the reaction solution was poured into 60 mL of saturated NaHCO 3 aqueous solution, and extracted twice with 80 mL of dichloromethane.
  • the organic phase was washed with 50 mL saturated NaHCO 3 aqueous solution, 80 mL saturated brine, dried and concentrated.
  • Step 1 Add 7-chloro-6-fluoro-4-hydroxy-1-(4-isopropyl-6-methylpyrimidin-5-yl)-2-oxo-1,2- to the round bottom flask Dihydro-1,8-naphthyridine-3-carbonitrile (2 g, 5.34 mmol) 12 mL water and 12 mL dioxane. After the system was cooled to 0°C, 12 mL of concentrated sulfuric acid was added dropwise to the reaction solution. After the addition was completed, the reaction was stirred at 120°C for 18 hours. After the reaction was completed, a large amount of solid precipitated out. Filter and wash the filter cake three times with water.
  • Step 2 Add 7-chloro-6-fluoro-4-hydroxy-1-(4-isopropyl-6-methylpyrimidin-5-yl)-1,8-naphthyridine-2( 1H)-ketone (1.3g, 3.72mmol), sodium nitrite (26mg, 0.37mmol) and 8mL glacial acetic acid. Concentrated nitric acid (700 mg, 11.1 mmol) was added dropwise to the reaction solution. The reaction was heated in an oil bath at 30°C for 2 hours. The reaction liquid was poured into ice water, and a solid precipitated out. Filter and wash the filter cake with water.
  • Step 3 Add 7-chloro-6-fluoro-4-hydroxy-1-(4-isopropyl-6-methylpyrimidin-5-yl)-3-nitro-1,8-naphthalene to the reaction flask Pyridin-2(1H)-one (1.2g, 3mmol), 2-fluoro-6-methoxyphenylboronic acid (2g, 12mmol), 2-dicyclohexylphosphino-2',6'-dimethoxy Biphenyl (123mg, 0.3mmol), chloro (2-dicyclohexylphosphine-2',6'-dimethoxy-1,1'-biphenyl) [2-(2'-amino-1,1 '-Biphenyl)] palladium(II) (216 mg, 0.3 mmol), potassium phosphate (1.9 g, 9 mmol), 15 mL dioxane and 3 mL water.
  • reaction was stirred in an oil bath at 110°C for 1 hour to stop the reaction.
  • a 1M potassium carbonate aqueous solution (30 mL) was added to the reaction solution, and extraction was performed once with 20 mL EtOAc/PE (1:1) to remove impurities.
  • the pH of the aqueous phase was adjusted to 4 with 6M aqueous hydrochloric acid solution. Extract 3 times with ethyl acetate.
  • Step 4 Add 6-fluoro-7-(2-fluoro-6-methoxyphenyl)-4-hydroxy-1-(4-isopropyl-6-methylpyrimidine-5- Yl)-3-nitro-1,8-naphthyridin-2(1H)-one (1.2g, 2.48mmol), diisopropylethylamine (3g, 23.1mmol), acetonitrile (20mL). Phosphorus oxychloride (2.2 g, 14.5 mmol) was added dropwise thereto. The reaction was stirred at 85°C for 1 hour. LC-MS detects that the reaction is complete. The reaction solution was poured into ice water, and extracted with ethyl acetate.
  • Step 5 Add 4-chloro-6-fluoro-7-(2-fluoro-6-methoxyphenyl)-1-(4-isopropyl-6-methylpyrimidine-5-) to the round bottom flask Yl)-3-nitro-1,8-naphthyridin-2(1H)-one (1g, 2mmol), 1-(tert-butyl)3-methyl(R)-piperazine-1,3-di Carboxylic acid ester (1.94g, 8mmol), N,N-diisopropylethylamine (516mg, 4mmol) and N,N-dimethylacetamide (10mL), the reaction was stirred at 120°C for 2 hours.
  • Step 6 Add 1-(tert-butyl)3-methyl(3R)-4-(6-fluoro-7-(2-fluoro-6-methoxyphenyl)-1-(4 -Isopropyl-6-methylpyrimidin-5-yl)-3-nitro-2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl)piperazine-1,3 -Dicarboxylate (1 g, 1.4 mmol), iron powder (390 mg, 7 mmol) and 15 mL of glacial acetic acid. The reaction was stirred at 80°C for 1 hour. LC-MS detects that the reaction is complete.
  • Step 7 Add (4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(4-isopropyl-6-methylpyrimidine-5- Yl)-5,7-dioxo-1,2,4,4a,5,6,7,8-octahydro-3H-pyrazino[1',2':4,5]pyrazino[ 2,3-c][1,8]naphthyridine-3-carboxylic acid tert-butyl ester (450 mg, 0.69 mmol), methyl iodide (789 mg, 5.55 mmol), potassium carbonate (286 mg, 2.07 mmol) and 10 mL of acetone.
  • Step 8 Add (4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(4-isopropyl-6-methylpyrimidine-5- Yl)-6-methyl-5,7-dioxo-1,2,4,4a,5,6,7,8-octahydro-3H-pyrazino[1',2':4,5 ]Pyrazino[2,3-c][1,8]naphthyridine-3-carboxylic acid tert-butyl ester (260 mg, 0.39 mmol), 1 mL dichloromethane, and 3 mL trifluoroacetic acid. Stir at room temperature for 1 hour, LC-MS detects that the reaction is complete.
  • Step 9 Add (4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(4-isopropyl-6-methylpyrimidine-5) to a 50mL round bottom flask -Yl)-6-methyl-2,3,4,4a,6,8-hexahydro-1H-pyrazino[1',2':4,5]pyrazino[2,3-c] [1,8] Naphthyridine-5,7-dione (219 mg, 0.39 mmol), 3 mL of dichloromethane and triethylamine (158 mg, 1.56 mmol).
  • the reaction was cooled to 0°C, and a dichloromethane solution of acryloyl chloride (71 mg, 0.78 mmol, 0.5 mL) was added dropwise to the reaction solution.
  • the reaction was stirred at 0°C for 10 minutes.
  • 40 mL of saturated sodium bicarbonate aqueous solution was added to the reaction solution, and it was extracted 3 times with 20 mL of dichloromethane.
  • Step 10 Add (4aR)-3-acryloyl-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(4-isopropyl-6-methyl) to the round bottom flask Pyrimidin-5-yl)-6-methyl-2,3,4,4a,6,8-hexahydro-1H-pyrazino[1',2':4,5]pyrazino[2, 3-c][1,8]naphthyridine-5,7-dione (240 mg, 0.39 mmol), 3 mL of dichloromethane. The reaction solution was cooled to 0°C, and a 17% dichloromethane solution (6 mL) of boron tribromide was added dropwise thereto.
  • reaction was stirred at room temperature for 2 hours.
  • the reaction solution was poured into 30 mL of ice-saturated NaHCO 3 aqueous solution, and extracted 3 times with 20 mL of dichloromethane. The organic phase was dried and concentrated.
  • Step 1 Dissolve 7-chloro-6-fluoro-4-hydroxy-1-(3-isopropylpyrazin-2-yl)-1,8-naphthyridin-2(1H)-one (2g, 6mmol) To acetic acid (5 mL), sodium nitrite (41 mg, 0.6 mmol) and concentrated nitric acid (1.5 g, 24 mmol) were sequentially added, and the reaction was stirred at room temperature for 30 minutes.
  • Step 2 Add 7-chloro-6-fluoro-4-hydroxy-1-(3-isopropylpyrazin-2-yl)-3-nitro-1,8-naphthyridine to a 100mL three-necked round bottom flask -2(1H)-ketone (1.5g, 3.94mmol), (2-fluoro-6-methoxyphenyl)boronic acid (2.04g,, 12mmol), chlorine (2-dicyclohexylphosphine-2′,6 '-Dimethoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (288mg, 0.4mmol), 2-dicyclohexylphosphine Group-2',6'-dimethoxybiphenyl (164mg, 0.4mmol), potassium phosphate (2.5g, 12mmol), 10mL water and 40mL dioxane.
  • reaction was stirred at 100°C for 2 to 3 hours. After the reaction was completed, the reaction solution was cooled to room temperature, 80 mL of water and 100 mL of methyl tert-butyl ether were added, and extraction was performed once.
  • aqueous phase was adjusted to pH 3 ⁇ 5 with 1M hydrochloric acid solution, extracted with ethyl acetate (200mL*2), combined the ethyl acetate phases, dried over anhydrous sodium sulfate, filtered, and the filtrate was vacuum dried to obtain the product 6-fluoro-7-( 2-Fluoro-6-methoxyphenyl)-4-hydroxy-1-(3-isopropylpyrazin-2-yl)-3-nitro-1,8-naphthyridine-2(1H)- Ketone (1.6g, crude product), pale yellow solid.
  • ES-API: [M+H] + 470.1.
  • Step 3 6-Fluoro-7-(2-fluoro-6-methoxyphenyl)-4-hydroxy-1-(3-isopropylpyrazin-2-yl)-3-nitro-1, 8-naphthyridin-2(1H)-one (1.6g, 3.4mmol) was dissolved in acetonitrile (30mL), and phosphorus oxychloride (2.6g, 17mmol), and N,N-diisopropylethylamine ( 3g, 23.8mmol), the reaction was gradually raised to 80°C and stirred for 30 minutes.
  • reaction solution Concentrate the reaction solution, add 30 mL cold acetonitrile, add dropwise to 150 mL saturated sodium bicarbonate solution under ice-water bath, extract with ethyl acetate (200 mL*2), combine the organic phases, and wash once with 200 mL saturated brine.
  • Step 4 4-Chloro-6-fluoro-7-(2-fluoro-6-methoxyphenyl)-1-(3-isopropylpyrazin-2-yl)-3-nitro-1, 8-naphthyridin-2(1H)-one (310mg, 0.64mmol) was dissolved in N,N-dimethylacetamide (5mL), and 1-(tert-butyl)3-methyl(3R, 6R) was added in sequence -6-methylpiperazine-1,3-dicarboxylic acid (247mg, 0.96mmol), and N,N-diisopropylethylamine (250mg, 1.92mmol), the reaction was stirred at 120°C for 2 hours.
  • Step 5 1-(tert-butyl)3-methyl(3R,6R)-4-(6-fluoro-7-(2-fluoro-6-methoxyphenyl)-1-(3-isopropyl Pyrazine-2-yl)-3-nitro-2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl)-6-methylpiperazine-1,3-di
  • the carboxylate (280 mg, 0.4 mmol) was dissolved in acetic acid (4 mL), iron powder (78 mg, 1.4 mmol) was added, and the reaction was stirred at 80°C for 30 minutes.
  • Step 6 Add (2R, 4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(3-isopropylpyrazin-2-yl) to the 15mL sealed tube in sequence )-2-Methyl-5,7-dioxo-1,2,4,4a,5,6,7,8-octahydro-3H-pyrazino[1',2':4,5] Pyrazino[2,3-c][1,8]naphthyridine-3-carboxylic acid tert-butyl ester (295mg, 0.46mmol), 3mL acetone, anhydrous potassium carbonate (1g, 6.9mmol), methyl iodide (253mg , 1.84mmol).
  • Step 7 (2R,4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(3-isopropylpyrazin-2-yl)-2,6-di Methyl-5,7-dioxo-1,2,4,4a,5,6,7,8-octahydro-3H-pyrazino[1',2':4,5]pyrazino[ 2,3-c][1,8]naphthyridine-3-carboxylic acid tert-butyl ester (356 mg, 0.54 mmol) was dissolved in dichloromethane (8 mL), and trifluoroacetic acid (4 mL) was added.
  • Step 8 (2R,4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(3-isopropylpyrazin-2-yl)-2,6-di Methyl-2,3,4,4a,6,8-hexahydro-1H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthalene
  • Pyridine-5,7-dione (415 mg, 0.74 mmol) was dissolved in dichloromethane (15 mL), and triethylamine (3.0 mL, 21.62 mmol) was added.
  • the reaction was cooled to 0°C, and acryloyl chloride (115 mg, 1.28 mmol) was added dropwise to the reaction solution.
  • the reaction was stirred at 0°C for 5 minutes.
  • 50mL of dichloromethane was added to the reaction solution, washed with 50mL of saturated NaHCO 3 aqueous solution, 80mL of saturated brine, dried and concentrated.
  • Step 9 Under ice-water bath conditions, add (2R,4aR)-3-acryloyl-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(3-isopropylpyrazine -2-yl)-2,6-dimethyl-2,3,4,4a,6,8-hexahydro-1H-pyrazino[1',2':4,5]pyrazino[2 ,3-c][1,8]naphthyridine-5,7-dione (201mg, 0.33mmol) was added to dry dichloromethane (3.0mL), then boron tribromide (5.0mL) was added, and reacted at room temperature For 30 minutes, under ice-water bath conditions, the above reaction liquid was added dropwise to saturated sodium bicarbonate saturated solution, dichloromethane (50mL) was extracted twice, dried, concentrated, and the crude product was purified by preparative HPLC to obtain the product (2R, 4aR)-3
  • Step 1 Add 4-chloro-6-fluoro-7-(2-fluoro-6-methoxyphenyl)-1-(4-isopropyl-6-methylpyrimidine-5-) to the round bottom flask Yl)-3-nitro-1,8-naphthyridin-2(1H)-one (0.8g, 1.46mmol), 1-(tert-butyl)3-methyl(3R,6R)-6-methyl Piperazine-1,3-dicarboxylate (567mg, 2.2mmol), N,N-diisopropylethylamine (565mg, 4.38mmol) and N,N-dimethylacetamide (10mL), the reaction is in Stir at 120°C for 1 hour.
  • Step 2 Add 1-(tert-butyl)3-methyl(3R,6R)-4-(6-chloro-1-(4,6-diisopropylpyrimidin-5-yl)- to the reaction flask 7-(2-Fluoro-6-methoxyphenyl)-3-nitro-2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl)-6-methylpiper Oxazine-1,3-dicarboxylate (1 g, 1.3 mmol), iron powder (300 mg, 5.3 mmol) and 8 mL of glacial acetic acid. The reaction was stirred at 80°C for 0.5 hour. LC-MS detects that the reaction is complete.
  • Step 3 Add (2R,4aR)-11-chloro-8-(4,6-diisopropylpyrimidin-5-yl)-10-(2-fluoro-6-methoxybenzene) to the round bottom flask Yl)-2-methyl-5,7-dioxo-1,2,4,4a,5,6,7,8-octahydro-3H-pyrazino[1',2':4,5 ]Pyrazino[2,3-c][1,8]naphthyridine-3-carboxylic acid tert-butyl ester (761mg, 1.08mmol), methyl iodide (1.5g, 10.79mmol), potassium carbonate (596mg, 4.32mmol) ) And 15 mL of acetone.
  • Step 4 Add (2R,4aR)-11-chloro-8-(4,6-diisopropylpyrimidin-5-yl)-10-(2-fluoro-6-methoxybenzene) to the round bottom flask Yl)-2,6-dimethyl-5,7-dioxo-1,2,4,4a,5,6,7,8-octahydro-3H-pyrazino[1',2': 4,5]pyro[2,3-c][1,8]naphthyridine-3-carboxylic acid tert-butyl ester (738 mg, 1.02 mmol), 2 mL dichloromethane, and 5 mL trifluoroacetic acid.
  • Step 5 Add (2R,4aR)-11-chloro-8-(4,6-diisopropylpyrimidin-5-yl)-10-(2-fluoro-6-methoxy) to a 50mL round bottom flask (Phenyl)-2,6-Dimethyl-2,3,4,4a,6,8-hexahydro-1H-pyrazino[1',2':4,5]pyrazino[2,3 -c][1,8]naphthyridine-5,7-dione (632 mg, 1.02 mmol), 3 mL dichloromethane and triethylamine (677 mg, 6.7 mmol).
  • the reaction was cooled to 0°C, and a dichloromethane solution of acryloyl chloride (249 mg, 2.77 mmol, 0.5 mL) was added dropwise to the reaction solution.
  • the reaction was stirred at 0°C for 10 minutes.
  • 40 mL of saturated sodium bicarbonate aqueous solution was added to the reaction solution, and it was extracted 3 times with 20 mL of dichloromethane. The organic phase was dried and concentrated.
  • Step 6 Add (2R,4aR)-3-acryloyl-11-chloro-8-(4,6-diisopropylpyrimidin-5-yl)-10-(2-fluoro-6) to the round bottom flask -Methoxyphenyl)-2,6-dimethyl-2,3,4,4a,6,8-hexahydro-1H-pyrazino[1',2':4,5]pyrazino [2,3-c][1,8]naphthyridine-5,7-dione (500mg, 0.74mmol), 3mL of dichloromethane.
  • the reaction solution was cooled to 0°C, and a 17% dichloromethane solution (12 mL) of boron tribromide was added dropwise thereto. After the addition, the reaction was stirred at 25 degrees for 25 hours.
  • the reaction solution was poured into 30 mL of ice-saturated NaHCO 3 aqueous solution, and extracted 3 times with 20 mL of dichloromethane. The organic phase was dried and concentrated.
  • Step 1 Add 6,7-dichloro-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8 -Naphthyridine-3-carbonitrile (30.0 g, 77.319 mmol) was suspended in a mixed solution of 1,4-dioxane (120 mL) and water (120 mL), and concentrated sulfuric acid (120 mL) was slowly added. The reaction was stirred at 120°C for 36 hours.
  • Step 2 6,7-Dichloro-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)-1,8-naphthyridin-2(1H)-one (3.16g , 8.705mmol) was dissolved in acetic acid (15mL), sodium nitrite (100mg, 1.58mmol) and concentrated nitric acid (5.0mL, 74.52mmol) were added sequentially, and the reaction was stirred at room temperature for 30 minutes.
  • Step 3 Add 6,7-dichloro-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-1,8 to a 100mL three-necked round bottom flask -Naphthyridine-2(1H)-one (3.5g, 8.570mmol), (2-fluoro-6-methoxyphenyl)boronic acid (5.8g, 34.10mmol), tetrakistriphenylphosphine palladium (1.15g, 0.9956mmol), sodium carbonate (3.5g, 33.02mmol), 10mL water and 40mL dioxane. Under nitrogen protection, the reaction was stirred at 100°C for 2 to 3 hours.
  • Step 4 6-Chloro-7-(2-fluoro-6-methoxyphenyl)-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro -1,8-naphthyridin-2(1H)-one (4.6g, 8.57mmol) was dissolved in acetonitrile (30mL), and phosphorus oxychloride (7.5g, 48.92mmol), and N,N-diiso With propylethylamine (10.5g, 81.24mmol), the reaction was gradually raised to 80°C and stirred for 30 minutes.
  • reaction solution concentrates the reaction solution, add 30 mL cold acetonitrile, add dropwise to 150 mL saturated sodium bicarbonate solution under ice-water bath, extract with ethyl acetate (200 mL*2), combine the ethyl acetate phases, and wash once with 200 mL saturated brine.
  • Step 5 4,6-Dichloro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro -1,8-naphthyridin-2(1H)-one (2.5g, 4.84mmol) was dissolved in N,N-dimethylacetamide (25mL), and 1-(tert-butyl)3-methyl( R)-piperazine-1,3-dicarboxylate (3.5g, 14.34mmol), and N,N-diisopropylethylamine (2.0g, 15.47mmol), the reaction was stirred at 120°C for 2 hours.
  • Step 6 1-(tert-butyl)3-methyl(3R)-4-(6-chloro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl- 4-methylpyridin-3-yl)-3-nitro-2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl)piperazine-1,3-dicarboxylate (2.7g, 3.728mmol) was dissolved in acetic acid (30mL), iron powder (835mg, 14.91mmol) was added, and the reaction was stirred at 80°C for 30 minutes.
  • Step 7 Add (4aR)-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridine- 3-yl)-5,7-dioxo-1,2,4,4a,5,6,7,8-octahydro-3H-pyrazino[1',2':4,5]pyrazine And [2,3-c][1,8]naphthyridine-3-carboxylic acid tert-butyl ester (250mg, 0.3774mmol), 4mL dichloromethane, 4mL trifluoroacetic acid, stirred at room temperature for 2 hours, the reaction solution was concentrated to obtain the product (4aR)-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2,3,4, 4a,6,8-hexahydro-1H-pyrazino[1',2':4,5
  • Step 8 (4aR)-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2,3 ,4,4a,6,8-hexahydro-1H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthyridine-5,7-
  • the diketone 300 mg, 0.3774 mmol
  • dichloromethane 10 mL
  • triethylamine 3.0 mL, 21.62 mmol
  • the reaction was cooled to 0°C, and acryloyl chloride (50 mg, 0.5524 mmol) was added dropwise to the reaction solution.
  • the reaction was stirred at 0°C for 15 minutes.
  • 80 mL of dichloromethane was added to the reaction solution, washed with 100 mL of saturated NaHCO 3 aqueous solution, 80 mL of saturated brine, dried and concentrated.
  • Step 9 Under ice-water bath conditions, (4aR)-3-acryloyl-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methyl) (Pyridin-3-yl)-2,3,4,4a,6,8-hexahydro-1H-pyrazino[1',2':4,5]pyrazino[2,3-c][1 ,8] Naphthyridine-5,7-dione (243mg, 0.3774mmol) was added to dry dichloromethane (6.0mL), then boron tribromide (5.0mL, 5.0mmol) was added, warmed to room temperature, and reacted overnight .
  • Step 1 Add 6,7-dichloro-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8 -Naphthyridine-3-carbonitrile (30.0 g, 77.319 mmol) was suspended in a mixed solution of 1,4-dioxane (120 mL) and water (120 mL), and concentrated sulfuric acid (120 mL) was slowly added. The reaction was stirred at 120°C for 36 hours.
  • Step 2 6,7-Dichloro-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)-1,8-naphthyridin-2(1H)-one (3.16g , 8.705mmol) was dissolved in acetic acid (15mL), sodium nitrite (100mg, 1.58mmol) and concentrated nitric acid (5.0mL, 74.52mmol) were added sequentially, and the reaction was stirred at room temperature for 30 minutes.
  • Step 3 Add 6,7-dichloro-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-1,8 to a 100mL three-necked round bottom flask -Naphthyridine-2(1H)-one (3.5g, 8.570mmol), (2-fluoro-6-methoxyphenyl)boronic acid (5.8g, 34.10mmol), tetrakistriphenylphosphine palladium (1.15g, 0.9956mmol), sodium carbonate (3.5g, 33.02mmol), 10mL water and 40mL dioxane. Under the protection of nitrogen, the reaction was stirred at 100°C for 2 to 3 hours.
  • Step 4 6-Chloro-7-(2-fluoro-6-methoxyphenyl)-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro -1,8-naphthyridin-2(1H)-one (4.6g, 8.57mmol) was dissolved in acetonitrile (30mL), and phosphorus oxychloride (7.5g, 48.92mmol), and N,N-diiso With propylethylamine (10.5g, 81.24mmol), the reaction was gradually raised to 80°C and stirred for 30 minutes.
  • reaction solution concentrates the reaction solution, add 30 mL cold acetonitrile, add dropwise to 150 mL saturated sodium bicarbonate solution under ice-water bath, extract with ethyl acetate (200 mL*2), combine the ethyl acetate phases, and wash once with 200 mL saturated brine.
  • Step 5 4,6-Dichloro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro -1,8-naphthyridin-2(1H)-one (2.5g, 4.84mmol) was dissolved in N,N-dimethylacetamide (25mL), and 1-(tert-butyl)3-methyl( R)-piperazine-1,3-dicarboxylate (3.5g, 14.34mmol), and N,N-diisopropylethylamine (2.0g, 15.47mmol), the reaction was stirred at 120°C for 2 hours.
  • Step 6 1-(tert-butyl)3-methyl(3R)-4-(6-chloro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl- 4-methylpyridin-3-yl)-3-nitro-2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl)piperazine-1,3-dicarboxylate (2.7g, 3.728mmol) was dissolved in acetic acid (30mL), iron powder (835mg, 14.91mmol) was added, and the reaction was stirred at 80°C for 30 minutes.
  • Step 7 Add (4aR)-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridine-3) to the 150mL sealed tube in sequence -Base)-5,7-dioxo-1,2,4,4a,5,6,7,8-octahydro-3H-pyrazino[1',2':4,5]pyrazino [2,3-c][1,8]naphthyridine-3-carboxylic acid tert-butyl ester (2.7g, 3.728mmol), 30mL acetone, anhydrous potassium carbonate (2.2g, 15.94 mmol), methyl iodide (5.4g , 38.03mmol).
  • Step 8 (4aR)-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-6-methyl Group-5,7-dioxo-1,2,4,4a,5,6,7,8-octahydro-3H-pyrazino[1',2':4,5]pyrazino[2 ,3-c][1,8]naphthyridine-3-carboxylic acid tert-butyl ester (517 mg, 0.7549 mmol) was dissolved in dichloromethane (8 mL), and trifluoroacetic acid (2 mL) was added.
  • Step 9 (4aR)-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-6-methyl
  • Base-2,3,4,4a,6,8-hexahydro-1H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthyridine -5,7-dione 530 mg, 0.7549 mmol
  • dichloromethane 15 mL
  • triethylamine (3.0 mL, 21.62 mmol) was added.
  • the reaction was cooled to 0°C, and acryloyl chloride (100 mg, 1.1048 mmol) was added dropwise to the reaction solution.
  • the reaction was stirred at 0°C for 15 minutes.
  • 80mL of dichloromethane was added to the reaction solution, washed with 100mL of saturated NaHCO 3 aqueous solution, 80mL of saturated brine, dried and concentrated.
  • Step 10 Add (4aR)-3-acryloyl-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methyl Pyridin-3-yl)-6-methyl-2,3,4,4a,6,8-hexahydro-1H-pyrazino[1',2':4,5]pyrazino[2, 3-c][1,8]naphthyridine-5,7-dione (280mg, 0.444mmol) was added to dry dichloromethane (6.0mL), then boron tribromide (5.0mL, 5.0mmol) was added, Warm to room temperature and react overnight.
  • Step 1 (4aR)-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-6-( Methyl-d3)-5,7-dioxo-1,2,4,4a,5,6,7,8-octahydro-3H-pyrazino[1',2':4,5]pyridine
  • Azino[2,3-c][1,8]naphthyridine-3-carboxylic acid tert-butyl ester (511 mg, 0.7549 mmol) was dissolved in dichloromethane (8 mL), and trifluoroacetic acid (2 mL) was added.
  • Step 2 (4aR)-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-6-( Methyl-d3)-2,3,4,4a,6,8-hexahydro-1H-pyrazino[1',2':4,5]pyrazino[2,3-c][1, 8]
  • Naphthyridine-5,7-dione (520 mg, 0.7549 mmol) was dissolved in dichloromethane (10 mL), and triethylamine (3.0 mL, 21.62 mmol) was added.
  • the reaction was cooled to 0°C, and acryloyl chloride (100 mg, 1.1048 mmol) was added dropwise to the reaction solution.
  • the reaction was stirred at 0°C for 15 minutes.
  • 80mL of dichloromethane was added to the reaction solution, washed with 100mL of saturated NaHCO 3 aqueous solution, 80mL of saturated brine, dried and concentrated.
  • Step 3 Add (4aR)-3-acryloyl-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methyl Pyridin-3-yl)-6-(methyl-d3)-2,3,4,4a,6,8-hexahydro-1H-pyrazino[1',2':4,5]pyrazine And [2,3-c][1,8]naphthyridine-5,7-dione (240mg, 0.3791mmol) was added to dry dichloromethane (6.0mL), and then boron tribromide (5.0mL, 5.0mmol), warm to room temperature, and react overnight.
  • Step 1 4,6-Dichloro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro -1,8-naphthyridin-2(1H)-one (500mg, 0.9686mmol) was dissolved in N,N-dimethylacetamide (5mL), and 1-(tert-butyl)3-methyl(3R ,6R)-6-methylpiperazine-1,3-dicarboxylate (375mg, 1.452mmol), and N,N-diisopropylethylamine (375mg, 2.907mmol), the reaction was stirred at 120°C for 2 hour.
  • N,N-dimethylacetamide 5mL
  • 1-(tert-butyl)3-methyl(3R ,6R)-6-methylpiperazine-1,3-dicarboxylate 375mg, 1.452mmol
  • Step 2 1-(tert-butyl)3-methyl(3R,6R)-4-(6-chloro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl) 4-methylpyridin-3-yl)-3-nitro-2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl)-6-methylpiperazine-1 ,3-Dicarboxylate (530mg, 0.7179mmol) was dissolved in acetic acid (6mL), iron powder (200mg, 3.571mmol) was added, and the reaction was stirred at 80°C for 30 minutes.
  • acetic acid 6mL
  • iron powder 200mg, 3.571mmol
  • Step 3 Add (2R, 4aR)-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridine) to the 150mL sealed tube in sequence -3-yl)-2-methyl-5,7-dioxo-1,2,4,4a,5,6,7,8-octahydro-3H-pyrazino[1',2': 4,5]Pyrido[2,3-c][1,8]naphthyridine-3-carboxylic acid tert-butyl ester (445mg, 0.6583mmol), 10mL acetone, anhydrous potassium carbonate (500mg, 2.633mmol), iodine Methane (1.20 g, 6.5828 mmol).
  • Step 4 (2R,4aR)-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2 ,6-Dimethyl-5,7-dioxo-1,2,4,4a,5,6,7,8-octahydro-3H-pyrazino[1',2':4,5] Pyrazino[2,3-c][1,8]naphthyridine-3-carboxylic acid tert-butyl ester (511 mg, 0.7549 mmol) was dissolved in dichloromethane (8 mL), and trifluoroacetic acid (2 mL) was added.
  • Step 5 (2R,4aR)-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2 ,6-Dimethyl-2,3,4,4a,6,8-hexahydro-1H-pyrazino[1',2':4,5]pyrazino[2,3-c][1 , 8]
  • Naphthyridine-5,7-dione (462 mg, 0.6283 mmol) was dissolved in dichloromethane (8 mL), and triethylamine (2.0 mL, 14.41 mmol) was added.
  • the reaction was cooled to 0°C, and acryloyl chloride (100 mg, 1.1048 mmol) was added dropwise to the reaction solution.
  • the reaction was stirred at 0°C for 15 minutes.
  • 80mL of dichloromethane was added to the reaction solution, washed with 100mL of saturated NaHCO 3 aqueous solution, 80mL of saturated brine, dried and concentrated.
  • Step 6 Add (2R,4aR)-3-acryloyl-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4 -Methylpyridin-3-yl)-2,6-dimethyl-2,3,4,4a,6,8-hexahydro-1H-pyrazino[1',2':4,5]pyridine
  • Azino[2,3-c][1,8]naphthyridine-5,7-dione (290mg, 0.4503mmol) was added to dry dichloromethane (6.0mL), then boron tribromide (6.0mL , 6.0mmol), warm to room temperature, and react overnight.
  • Step 1 4-Chloro-6-fluoro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro 1,8-naphthyridin-2(1H)-one (400mg, 0.80mmol) dissolved in DMF (5mL), add (S)-3-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester (432 mg, 2.00 mmol), N,N-diisopropylethylamine (310 mg, 2.40 mmol), and the reaction was stirred at 75°C for 2 hours.
  • Step 2 (3S)-4-(6-fluoro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)- Tert-Butyl 3-nitro-2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl)-3-(hydroxymethyl)piperazine-1-carboxylate (420mg, 0.62 mmol) was dissolved in DMA (20mL), LiHMDS (1.55mL, 1.55mmol, 1.0M in THF) was added, and the reaction was slowly heated at 140°C and stirred for 24 hours.
  • DMA 20mL
  • LiHMDS (1.55mL, 1.55mmol, 1.0M in THF
  • Step 3 (4aS)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-7-oxy -1,2,4a,5,7,8-hexahydropyrazine[1',2':4,5][1,4]oxo[2,3-c][1,8]naphthyridine -3(4H)-tert-butyl carboxylate (35 mg, 0.055 mmol) was dissolved in methylene chloride (4 mL), and trifluoroacetic acid (1 mL) was added.
  • Step 4 (4aS)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-1,2 ,3,4,4a,5-hexahydropyrazine[1',2':4,5][1,4]oxazine[2,3-c][1,8]naphthyridine-7(8H) -Ketone (185 mg, crude product) was dissolved in dichloromethane (6 mL), and N,N-diisopropylethylamine (180 mg, 1.40 mmol) was added.
  • the reaction was cooled to 0°C, and a dichloromethane solution (0.5 mL) of acryloyl chloride (50 mg, 0.56 mmol) was added dropwise to the reaction solution. The reaction was stirred at 0°C for 15 minutes.
  • Step 5 (4aS)-3-acryloyl-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl) )-1,2,3,4,4a,5-hexahydropyrazine[1',2':4,5][1,4]oxazine[2,3-c][1,8]naphthyridine -7(8H)-one (160 mg, 0.27 mmol) was dissolved in dichloromethane (4 mL). The reaction was cooled to 0°C, and a 17% dichloromethane solution (3 mL) of boron tribromide was added dropwise thereto.
  • reaction was stirred at room temperature for 3 hours.
  • the reaction solution was poured into 25 mL of cold saturated NaHCO 3 aqueous solution, and extracted with 50 mL of dichloromethane.
  • the organic phase was washed with 25 mL of saturated NaHCO 3 aqueous solution, 25 mL of saturated brine, dried and concentrated.
  • Step 1 7-chloro-6-fluoro-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)-1,8-naphthyridin-2(1H)-one (4.0 g, 11.53 mmol) was dissolved in acetic acid (9 mL), sodium nitrite (79 mg, 1.15 mmol) and concentrated nitric acid (2.3 mL, 34.6 mmol) were added in sequence, and the reaction was stirred at room temperature for 30 minutes.
  • Step 2 Add 7-chloro-6-fluoro-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-1 into a 100mL three-necked round bottom flask, 8-naphthyridin-2(1H)-one (1.0g, 2.55mmol), (5-methyl-1H-indazol-4-yl)boronic acid (1.8g, 10.2mmol), tetrakistriphenylphosphine palladium ( 589mg, 0.51mmol), potassium carbonate (1.76g, 12.75mmol), 2mL water and 8mL dioxane. Under the protection of nitrogen, the reaction was stirred at 110°C for 1 hour.
  • Step 3 6-Fluoro-7-(5-methyl-1H-indazol-4-yl)-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)-3 -Nitro-1,8-naphthyridine-2(1H)-one (0.6g, 1.23mmol) was dissolved in acetonitrile (20mL), and phosphorus oxychloride (0.94g, 6.15mmol), and N, N- Diisopropylethylamine (1.27g, 9.84mmol), the reaction was gradually raised to 80°C and stirred for 24h.
  • reaction solution concentrates the reaction solution, add 30 mL cold acetonitrile, add dropwise to 30 mL saturated sodium bicarbonate solution under ice-water bath, extract with ethyl acetate (200 mL*2), combine the ethyl acetate phases, and wash once with 50 mL saturated brine.
  • Step 4 4-Chloro-6-fluoro-7-(5-methyl-1H-indazol-4-yl)-1-(2-isopropyl-4-methylpyridin-3-yl)-3 -Nitro-1,8-naphthyridine-2(1H)-one (150mg, 0.296mmol) was dissolved in N,N-dimethylacetamide (25mL), and (R)-3-(hydroxymethyl ) Tert-butyl piperazine-1-carboxylate (1.48 g, 320 mmol), and the reaction was stirred at 80°C for 1.5 hours.
  • Step 5 (3R)-4-(6-Fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)-7-(5-methyl-1H-indazol-4-yl) )-3-nitro-2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl)-3-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester (90mg ,0.13mmol) was dissolved in N,N-dimethylacetamide (25mL), sodium hydride (15.7mg, 0.39mmol) was added, and the reaction was stirred at 130°C for 18h.
  • Step 6 (4aR)-11-fluoro-8-(2-isopropyl-4-methylpyridin-3-yl)-10-(5-methyl-1H-indazol-4-yl)-7 -Oxo-1,2,4a,5,7,8-hexahydropyrazino[1',2':4,5][1,4]oxazine[2,3-c][1,8 ]
  • Naphthyridine-3(4H)-tert-butyl carboxylate 60 mg, 0.094 mmol
  • dichloromethane (4 mL)
  • trifluoroacetic acid (2 mL) was added.
  • Step 7 (4aR)-11-fluoro-8-(2-isopropyl-4-methylpyridin-3-yl)-10-(5-methyl-1H-indazol-4-yl)-1 ,2,3,4,4a,5-hexahydropyrazino[1',2':4,5][1,4]oxazine[2,3-c][1,8]naphthyridine 7( 8H)-ketone (50 mg, 0.093 mmol) was dissolved in dichloromethane (5 mL), and triethylamine (60 mg, 0.465 mmol) was added.
  • Step 1 Add (4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridine-3) to the 15mL sealed tube in sequence -Base)-5,7-dioxo-1,2,4,4a,5,6,7,8-octahydro-3H-pyrazine[1',2':4,5]pyrazine[2 ,3-c][1,8]naphthyridine-3-carboxylic acid tert-butyl ester (310mg, 0.48mmol), 10mL acetone, anhydrous potassium carbonate (265mg, 1.92mmol), iodoethane (599mg, 3.84mmol) .
  • Step 2 (4aR)-6-ethyl-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl) )-5,7-dioxo-1,2,4,4a,5,6,7,8-octyl-3H-pyrazine[1',2':4,5]pyrazine[2,3 -c][1,8]naphthyridine-3-carboxylic acid tert-butyl ester (290 mg, 0.43 mmol) was dissolved in dichloromethane (4 mL), and trifluoroacetic acid (1 mL) was added.
  • Step 3 (4aR)-6-ethyl-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl) )-2,3,4,4a,6,8-hexahydro-1H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyridine-5 ,7-Diketone (300mg, crude product) was dissolved in dichloromethane (15mL), and N,N-diisopropylethylamine (464mg, 3.60mmol) was added.
  • Step 4 (4aR)-3-acryloyl-6-ethyl-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methyl) (Pyridin-3-yl)-2,3,4,4a,6,8-hexahydro-1H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8 ] Naphthyridine-5,7-dione (245 mg, 0.39 mmol) was dissolved in dichloromethane (5 mL). The reaction was cooled to 0°C, and a 17% dichloromethane solution (5 mL) of boron tribromide was added dropwise thereto.
  • Step 1 Add 6-chloro-7-(2-fluoro-6-methoxyphenyl)-4-hydroxy-1-(2-isopropyl-4-methylpyridine-3) to a 250mL round bottom flask -Base)-3-nitro-1,8-naphthyridin-2(1H)-one (1.0g, 2.0mmol), potassium cyclopropyl trifluoroborate (1.48g, 10.0mmol), chlorine (2-two Cyclohexylphosphine-2′,6′-dimethoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (144mg, 0.20mmol ), 2-Dicyclohexylphosphino-2',6'-dimethoxybiphenyl (82mg, 0.20mmol), potassium carbonate (1.66g, 12.0mmol), 2mL water and 20mL toluene.
  • Step 2 6-Cyclopropyl-7-(2-fluoro-6-methoxyphenyl)-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)-3 -Nitro-1,8-naphthyridine-2(1H)-ketone (1.6g, crude product) was dissolved in acetonitrile (50mL), and phosphorus oxychloride (2.43g, 15.85mmol), and N,N-two Isopropylethylamine (3.27g, 25.36mmol), the reaction was stirred at 85°C for 1 hour.
  • Step 3 4-Chloro-6-cyclopropyl-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-3 -Nitro-1,8-naphthyridine-2(1H)-one (490mg, 0.94mmol) was dissolved in N,N-dimethylacetamide (6mL), and (3R,6R)-1-N- BOC-6-methylpiperazine-3-carboxylic acid methyl ester (485 mg, 1.88 mmol), and N,N-diisopropylethylamine (364 mg, 2.82 mmol), the reaction was stirred at 125°C for 3 hours.
  • Step 4 (3R,6R)-1-N-BOC-4-(6-cyclopropyl-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4 -Methylpyridin-3-yl)-3-nitro-2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl)-6-methylpiperazine-3-carboxylic acid
  • the ester (455mg, 0.61mmol) was dissolved in acetic acid (8mL), iron powder (120mg, 2.14mmol) was added, and the reaction was stirred at 80°C for 30 minutes.
  • reaction solution was concentrated, 80mL ethyl acetate and 50mL saturated sodium bicarbonate were added successively, the suspension was filtered with celite, the filter cake was washed with ethyl acetate, the organic phase was separated, and then washed with 25mL saturated sodium bicarbonate and 25mL saturated brine.
  • Step 5 Add (2R, 4aR)-11-cyclopropyl-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methyl) to the 50mL sealed tube in sequence Pyridin-3-yl)-2-methyl-5,7-dioxo-1,2,4,4a,5,6,7,8-octyl-3H-pyrazine[1',2' :4,5]pyrazine[2,3-c][1,8]naphthyridine-3-carboxylic acid tert-butyl ester (415mg, 0.61mmol), 12mL acetone, anhydrous potassium carbonate (337mg, 2.44mmol), Methyl iodide (693 mg, 4.88 mmol).
  • Step 6 (2R,4aR)-11-cyclopropyl-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl) -2,6-Dimethyl-5,7-dioxo-1,2,4,4a,5,6,7,8-octyl-3H-pyrazine[1',2':4,5 ]Pyrazine[2,3-c][1,8]naphthyridine-3-carboxylic acid tert-butyl ester (160 mg, 0.23 mmol) was dissolved in dichloromethane (3.5 mL), and trifluoroacetic acid (0.8 mL) was added.
  • Step 7 (2R,4aR)-11-cyclopropyl-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl) -2,6-Dimethyl-1,2,4,4a,6,8-hexahydro-3l2-pyrazine[4',3': 4,5]pyrazine[2,3-c][1 ,8] Naphthyridine-5,7-dione (165 mg, crude product) was dissolved in dichloromethane (10 mL), and N,N-diisopropylethylamine (148 mg, 1.15 mmol) was added.
  • the reaction was cooled to 0°C, and acryloyl chloride (41 mg, 0.46 mmol) was added dropwise to the reaction solution.
  • the reaction was stirred at 0°C for 15 minutes.
  • 30mL of dichloromethane was added to the reaction solution, washed with 15mL of water, 15mL of saturated NaHCO 3 aqueous solution, 15mL of saturated brine, dried and concentrated, dried and concentrated.
  • Step 8 (2R,4aR)-3-acryloyl-11-cyclopropyl-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridine) -3-yl)-2,6-dimethyl-2,3,4,4a,6,8-hexahydro-1H-pyrazine[1',2':4,5]pyrazine[2,3 -c][1,8]naphthyridine-5,7-dione (130 mg, 0.20 mmol) was dissolved in dichloromethane (3 mL).
  • the reaction was cooled to 0°C, and a 17% dichloromethane solution (3 mL) of boron tribromide was added dropwise thereto. The reaction was stirred at room temperature for 3 hours. The reaction solution was poured into 40 mL of saturated NaHCO 3 aqueous solution, and extracted twice with 25 mL of dichloromethane. The organic phase was dried and concentrated.
  • 2M NaHMDS 8.48mL, 16.96mmol
  • Step 2 Add 2-((4,6-dicyclopropylpyrimidin-5-yl)amino)-5-fluoro-6-(2-fluoro-6-methoxyphenyl)nicotinic acid (1.5g, 3.42mmol) was dissolved in dichloroethane, and thionyl chloride (4.07g, 34.2mmol) was added. The reaction was stirred at 80°C for 2 hours.
  • Step 3 Under ice-water bath conditions, sodium hydride (1.97g, 49.35mmol) was added to ethyl nitrate (1.31g, 9.86mmol) in tetrahydrofuran, stirred for 30 minutes, and then 2-((4,6- Dicyclopropylpyrimidin-5-yl)amino)-5-fluoro-6-(2-fluoro-6-methoxyphenyl)nicotinoyl chloride (1.57g, 3.29mmol), stirred at room temperature for 1h, and then heated to 80°C Reaction for 2h.
  • Step 4 1-(4,6-Dicyclopropylpyrimidin-5-yl)-6-fluoro-7-(2-fluoro-6-methoxyphenyl)-4-hydroxy-3-nitro- 1,8-Naphthyridine-2(1H)-one (110mg, 0.20mmol) was dissolved in acetonitrile (10mL), and phosphorus oxychloride (153mg, 1.0mmol), and N,N-diisopropylethylamine were added sequentially (77g, 0.6mmol), the reaction was gradually raised to 80°C and stirred for 3h.
  • Step 5 4-Chloro-6-fluoro-7-(2-fluoro-6-methoxyphenyl)-1-(4,6-dicyclopropylpyrimidin-5-yl)-3-nitro- 1,8-Naphthyridin-2(1H)-one (110mg, 0.296mmol) was dissolved in N,N-dimethylacetamide (3mL), and 1-(tert-butyl)3-methyl(R) was added in sequence -Piperazine-1,3-dicarboxylate (54 mg, 0.22 mmol), and the reaction was stirred at 120°C for 2 hours.
  • Step 6 ((3R)-1-tert-butyl 3-methyl 4-(1-(4,6-dicyclopropylpyrimidin-5-yl)-6-fluoro-7-(2-fluoro-6 -Methoxyphenyl)-3-nitro-2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl)piperazine-1,3-dione (50mg, 0.068mmol ) was dissolved in acetic acid (25mL), iron powder (11.5mg, 0.204mmol) was added, and the reaction was stirred at 80°C for 30 minutes. The reaction solution was concentrated, and 30mL ethyl acetate and 30mL saturated sodium bicarbonate were added sequentially.
  • Step 7 Add (4aR)-8-(4,6-dicyclopropylpyrimidin-5-yl)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-5,7- Dioxo-4,4a,5,6,7,8-hexahydro-1H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8] Naphthyridine-3(2H)-tert-butyl carboxylate (40mg, 0.059mmol), 30mL acetone, anhydrous potassium carbonate (33mg, 0.24mmol), methyl iodide (85mg, 0.59mmol) The tube is sealed and the reaction is at 50°C Stir for 18 hours.
  • Step 8 (4aR)-tert-butyl 8-(4,6-dicyclopropylpyrimidin-5-yl)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-6- Methyl-5,7-dioxo-4,4a,5,6,7,8-hexahydro-1H-pyrazino[1',2':4,5]pyrazino[2,3- c] [1,8] Naphthyridin-3(2H)-one (44 mg) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (1 mL) was added.
  • Step 9 (4aR)-8-(4,6-Dicyclopropylpyrimidin-5-yl)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-6-methyl- 2,3,4,4a-Tetrahydro-1H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthyridine-5,7(6H , 8H)-dione (40 mg, 0.068 mmol) was dissolved in dichloromethane (5 mL), and diisopropylethylamine (53 mL, 0.408 mmol) was added.
  • the reaction was cooled to 0°C, and acryloyl chloride (12.4 mg, 0.137 mmol) was added dropwise to the reaction solution.
  • the reaction was stirred at 0°C for 15 minutes.
  • 20mL of dichloromethane was added to the reaction solution, washed with 20mL of saturated NaHCO 3 aqueous solution, 20mL of saturated brine, dried and concentrated.
  • Step 1 Add 7-chloro-6-fluoro-4-hydroxy-1-(1-isopropyl-4-methyl-1H-pyrazol-5-yl)-2-oxo-1,2-di Hydrogen-1,8-naphthyridine-3-carbonitrile (3.6 g, 10.0 mmol) was suspended in a mixed solution of 1,4-dioxane (10 mL) and water (120 mL), and concentrated sulfuric acid (10 mL) was slowly added. The reaction was stirred at 120°C for 18 hours.
  • Step 2 7-chloro-6-fluoro-4-hydroxy-1-(1-isopropyl-4-methyl-1H-pyrazol-5-yl)-1,8-naphthyridine-2(1H) -Ketone (3.36g, 10mmol) was dissolved in acetic acid (7mL), sodium nitrite (69mg, 1.0mmol) and concentrated nitric acid (2.0mL, 30mmol) were added sequentially, and the reaction was stirred at room temperature for 30 minutes.
  • Step 3 Add 7-chloro-6-fluoro-4-hydroxy-1-(1-isopropyl-4-methyl-1H-pyrazol-5-yl)3-nitro to a 100mL three-necked round bottom flask -1,8-naphthyridin-2(1H)-one (1.5g, 3.93mmol), (2-fluoro-6-methoxyphenyl)boronic acid (2.67g, 15.72mmol), palladium tetrakistriphenylphosphine (908mg, 0.786mmol), potassium carbonate (2.72g, 19.65mmol), 4mL water and 20mL dioxane. Under the protection of nitrogen, the reaction was stirred at 100°C for 3 hours.
  • Step 4 6-Fluoro-7-(2-fluoro-6-methoxyphenyl)-4-hydroxy-1-(1-isopropyl-4-methyl-1H-pyrazol-5-yl) -3-nitro-1,8-naphthyridine-2(1H)-one (1.5g, 3.18mmol) was dissolved in acetonitrile (15mL), and phosphorus oxychloride (2.4ml, 25.5mmol), and N, N-Diisopropylethylamine (2.6ml, 15.9mmol), the reaction was gradually raised to 80°C and stirred for 30 minutes.
  • reaction solution concentrates the reaction solution, add 10 mL cold acetonitrile, add dropwise to 20 mL saturated sodium bicarbonate solution under ice-water bath, extract with ethyl acetate (20 mL*2), combine the ethyl acetate phases, and wash once with 20 mL saturated brine.
  • Step 5 4-Chloro-6-fluoro-7-(2-fluoro-6-methoxyphenyl)-1-(1-isopropyl-4-methyl-1H-pyrazol-5-yl) -3-nitro-1,8-naphthyridin-2(1H)-one (490mg, 1.0mmol) was dissolved in N,N-dimethylacetamide (5mL), and then (3R, 6R)-1- Tert-butyl 3-methyl 6-methylpiperazine-1,3-dicarboxylic acid (310 mg, 1.2 mmol), and N, N-diisopropylethylamine (390 mg, 3 mmol), and the reaction was stirred at 120°C 2 hours.
  • Step 6 (3R,6R)-1-tert-butyl-3-methyl 4-(6-fluoro-7-(2-fluoro-6-methoxyphenyl)-1-(1-isopropyl) -4-Methyl-1H-pyrazole-5-yl)-3-nitro-2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl)piperazine-1,3 -Dione (620mg, 0.872mmol) was dissolved in acetic acid (8mL), iron powder (146mg, 2.62mmol) was added, and the reaction was stirred at 80°C for 30 minutes.
  • Step 7 Add (2R,4aR)-tert-butyl 11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(1-isopropyl-4-methyl-1H-pyridine (Azol-5-yl)-2-methyl-5,7-dioxo-4,4a,5,6,7,8-hexahydro-1H-pyrazino[1',2':4,5 ]Pyrazino[2,3-c][1,8]naphthyridine-3(2H)-carboxylic acid tert-butyl ester (300mg, 0.462mmol), 6mL acetone, anhydrous potassium carbonate (255mg, 1.84mmol), The tube was sealed with methyl iodide (656 mg, 4.62 mmol), and the reaction was stirred at 50°C for 18 hours.
  • methyl iodide 656 mg, 4.62 mmol
  • Step 8 (2R,4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(1-isopropyl-4-methyl-1H-pyrazole-5- Group)-2,6-dimethyl-5,7-dioxo-4,4a,5,6,7,8-hexahydro-1H-pyrazino[1',2':4,5] Pyrazino[2,3-c][1,8]naphthyridine-3(2H)-tert-butyl carboxylate (350 mg) was dissolved in dichloromethane (4 mL), and trifluoroacetic acid (2 mL) was added.
  • Step 9 (2R,4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(1-isopropyl-4-methyl-1H-pyrazole-5- Yl)-2,6-dimethyl-2,3,4,4a-tetrahydro-1H-pyrazino[1',2':4,5]pyrazino[2,3-c][1 ,8]
  • Naphthyridine-5,7(6H,8H)-dione 350mg, 0.62mmol
  • dichloromethane 6mL
  • diisopropylethylamine (480mg, 3.72mmol) was added.
  • the reaction was cooled to 0°C, and acryloyl chloride (112.5 mg, 1.24 mmol) was added dropwise to the reaction solution.
  • the reaction was stirred at 0°C for 15 minutes.
  • 20mL of dichloromethane was added to the reaction solution, washed with 20mL of saturated NaHCO 3 aqueous solution, 20mL of saturated brine, dried and concentrated.
  • Step 10 Add (2R,4aR)-3-acryloyl-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(1-isopropyl-4 -Methyl-1H-pyrazol-5-yl)-2,6-dimethyl-2,3,4,4a-tetrahydro-1H-pyrazino[1',2':4,5]pyridine
  • Azino[2,3-c][1,8]naphthyridine-5,7(6H,8H)-dione 250mg, 0.405mmol
  • Step 11 Compound Z33 was purified by preparative HPLC to obtain: an atropisomer compound, the structure of which was arbitrarily designated as Z33-1 (peak 1, 30 mg, retention time 9.576 min, Y: 50%).
  • Step 1 Add (2R, 4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridine) to the 15mL sealed tube in sequence -3-yl)-2-methyl-5,7-dioxo-1,2,4,4a,5,6,7,8-octyl-3H-pyrazine[1',2': 4 ,5]pyrazine[2,3-c][1,8]naphthyridine-3-carboxylic acid tert-butyl ester (115mg, 0.17mmol), 4mL acetone, anhydrous potassium carbonate (94mg, 0.68mmol), deuterated Methyl iodide (246 mg, 1.70 mmol).
  • Step 2 (2R,4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2 -Methyl-6-(methyl-d3)-5,7-dioxo-1,2,4,4a,5,6,7,8-octyl-3H-pyrazine[1',2' :4,5]pyrazine[2,3-c][1,8]naphthyridine-3-carboxylic acid tert-butyl ester (118mg, 0.17mmol) dissolved in dichloromethane (3mL), add trifluoroacetic acid (0.7 mL).
  • Step 3 (2R,4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2 -Methyl-6-(methyl-d3)-2,3,4,4a,6,8-hexahydro-1H-pyrazine[1',2':4,5]pyrazine[2,3- c] [1,8] Naphthyridine-5,7-dione (120 mg, crude product) was dissolved in dichloromethane (5 mL), and N,N-diisopropylethylamine (110 mg, 0.85 mmol) was added.
  • the reaction was cooled to 0°C, and acryloyl chloride (31 mg, 0.34 mmol) was added dropwise to the reaction solution.
  • the reaction was stirred at 0°C for 15 minutes.
  • Step 4 (2R,4aR)-3-acryloyl-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridine-3 -Yl)-2-methyl-6-(methyl-d3)-2,3,4,4a,6,8-hexahydro-1H-pyrazine[1',2':4,5]pyrazine [2,3-c][1,8]naphthyridine-5,7-dione (85mg, 0.13mmol) was dissolved in dichloromethane (1.5mL).
  • the reaction was cooled to 0°C, and a 17% dichloromethane solution (1.5 mL) of boron tribromide was added dropwise thereto.
  • the reaction was stirred at room temperature for 4 hours.
  • the reaction solution was poured into 40 mL of saturated NaHCO 3 aqueous solution, and extracted twice with 25 mL of dichloromethane. The organic phase was dried and concentrated.
  • Step 1 (2R,4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2 -Methyl-5,7-dioxo-1,2,4,4a,5,6,7,8-octyl-3H-pyrazine[1',2':4,5]pyrazine[2 ,3-c][1,8]naphthyridine-3-carboxylic acid tert-butyl ester (200mg, 0.30mmol) was dissolved in dichloromethane (4mL), and trifluoroacetic acid (1mL) was added.
  • Step 2 (2R,4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2 -Methyl-2,3,4,4a,6,8-hexahydro-1H-pyrazine[1',2':4,5]pyrazine[2,3-c][1,8]naphthyridine -5,7-dione (210 mg, crude product) was dissolved in dichloromethane (10 mL), and N,N-diisopropylethylamine (194 mg, 1.50 mmol) was added.
  • Step 3 (2R,4aR)-3-acryloyl-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridine-3 -Yl)-2-methyl-2,3,4,4a,6,8-hexahydro-1H-pyrazine[1',2':4,5]pyrazine[2,3-c][1 ,8] Naphthyridine-5,7-dione (175 mg, 0.28 mmol) was dissolved in dichloromethane (4 mL). The reaction was cooled to 0°C, and a 17% dichloromethane solution (4 mL) of boron tribromide was added dropwise thereto.
  • Step 1 Add 7-chloro-6-fluoro-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1, 8-naphthyridine-3-carbonitrile (3.6 g, 10.0 mmol) was suspended in a mixed solution of 1,4-dioxane (10 mL) and water (120 mL), and concentrated sulfuric acid (10 mL) was slowly added. The reaction was stirred at 120°C for 18 hours.
  • Step 2 7-chloro-6-fluoro-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)-1,8-naphthyridin-2(1H)-one (3.36 g, 10mmol) was dissolved in acetic acid (7mL), sodium nitrite (69mg, 1.0mmol) and concentrated nitric acid (2.0mL, 30mmol) were added sequentially, and the reaction was stirred at room temperature for 30 minutes.
  • Step 3 Add 7-chloro-6-fluoro-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)3-nitro-1,8 to a 100mL three-necked round bottom flask -Naphthyridine-2(1H)-one (1.5g, 3.93mmol), (2-fluorophenyl)boronic acid (2.67g, 15.72mmol), palladium tetrakistriphenylphosphine (908mg, 0.786mmol), potassium carbonate ( 2.72g, 19.65mmol), 4mL water and 20mL dioxane. Under the protection of nitrogen, the reaction was stirred at 100°C for 3 hours.
  • Step 4 6-Fluoro-7-(2-fluorophenyl)-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-1,8- Naphthyridin-2(1H)-one (1.5g, 3.18mmol) was dissolved in acetonitrile (15mL), and phosphorus oxychloride (2.4ml, 25.5mmol), and N,N-diisopropylethylamine (2.6 ml, 15.9 mmol), the reaction was gradually raised to 80°C and stirred for 30 minutes.
  • reaction solution concentrates the reaction solution, add 10 mL cold acetonitrile, add dropwise to 20 mL saturated sodium bicarbonate solution under ice-water bath, extract with ethyl acetate (20 mL*2), combine the ethyl acetate phases, and wash once with 20 mL saturated brine.
  • Step 5 4-Chloro-6-fluoro-7-(2-fluorophenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-1,8- Naphthyridin-2(1H)-one (490mg, 1.0mmol) was dissolved in N,N-dimethylacetamide (5mL), and (3R,6R)-1-tert-butyl 3-methyl 6-methyl was added in sequence Piperazine-1,3-dicarboxylic acid (310 mg, 1.2 mmol), and N,N-diisopropylethylamine (390 mg, 3 mmol), and the reaction was stirred at 120°C for 1 hour.
  • Step 6 (3R,6R)-1-tert-butyl-3-methyl 4-(6-fluoro-7-(2-fluorophenyl)-1-(1-isopropyl-4-methyl- 1H-pyrazole-5-yl)-3-nitro-2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl)piperazine-1,3-dione (620mg, 0.872mmol) was dissolved in acetic acid (8mL), iron powder (146mg, 2.62mmol) was added, and the reaction was stirred at 80°C for 30 minutes.
  • Step 7 Add (2R,4aR)-11-fluoro-10-(2-fluorophenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2-methyl-5 ,7-dioxo-4,4a,5,6,7,8-hexahydro-1H-pyrazino[1',2':4,5]pyrazino[2,3-c][1 , 8] Naphthyridine-3(2H)-tert-butyl carboxylate (300mg, 0.462mmol), 6mL acetone, anhydrous potassium carbonate (255mg, 1.84mmol), methyl iodide (656mg, 4.62mmol), seal the tube, and react Stir at 50°C for 18 hours.
  • 2R,4aR -11-fluoro-10-(2-fluorophenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2-methyl-5 ,7-dioxo-4,
  • Step 8 (2R,4aR)-11-fluoro-10-(2-fluorophenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2,6-dimethyl -5,7-dioxo-4,4a,5,6,7,8-hexahydro-1H-pyrazino[1',2':4,5]pyrazino[2,3-c] [1,8] Naphthyridine-3(2H)-tert-butyl carboxylate (350 mg) was dissolved in dichloromethane (4 mL), and trifluoroacetic acid (2 mL) was added.
  • Step 9 (2R,4aR)-11-fluoro-10-(2-fluorophenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2,6-dimethyl -2,3,4,4a-Tetrahydro-1H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthyridine-5,7( 6H, 8H)-dione (350 mg, 0.62 mmol) was dissolved in dichloromethane (6 mL), and diisopropylethylamine (480 mg, 3.72 mmol) was added.
  • the reaction was cooled to 0°C, and acryloyl chloride (112.5 mg, 1.24 mmol) was added dropwise to the reaction solution.
  • the reaction was stirred at 0°C for 15 minutes.
  • 20mL of dichloromethane was added to the reaction solution, washed with 20mL of saturated NaHCO 3 aqueous solution, 20mL of saturated brine, dried and concentrated.
  • Step 1 Add 7-bromo-6-chloro-1-(4,6-diisopropylpyrimidin-5-yl)-8-fluoro-4-hydroxy-2-oxo-1,2-dihydroquine
  • phenoline-3-carbonitrile 2.0 g, 4.17 mmol
  • 1,4-dioxane 10 mL
  • a mixture of concentrated sulfuric acid 10 mL
  • water 10 mL
  • Step 2 7-Bromo-6-chloro-1-(4,6-diisopropylpyrimidin-5-yl)-8-fluoro-4-hydroxyquinolin-2(1H)-one (1.4g, 3.08 mmol) was dissolved in acetic acid (4 mL), sodium nitrite (21 mg, 0.31 mmol) and concentrated nitric acid (0.62 mL, 9.24 mmol) were sequentially added, and the reaction was stirred at room temperature for 30 minutes.
  • Step 3 7-Bromo-6-chloro-1-(4,6-diisopropylpyrimidin-5-yl)-8-fluoro-4-hydroxy-3-nitroquinoline-2(1H)-one (1.25g, 2.50mmol) was dissolved in acetonitrile (25mL), followed by adding phosphorus oxychloride (1.15mL, 12.50mmol), and N,N-diisopropylethylamine (3.48mL, 20.0mmol), the reaction was at 85 Stir at °C for 30 minutes.
  • Step 4 7-Bromo-4,6-dichloro-1-(4,6-diisopropylpyrimidin-5-yl)-8-fluoro-3-nitroquinoline-2(1H)-one ( 370mg, 0.71mmol) was dissolved in N,N-dimethylacetamide (5mL), and (R)-1-(tert-butyl)3-methyl-piperazine-1,3-dicarboxylate ( 520mg, 2.13mmol), and N,N-diisopropylethylamine (275mg, 2.13mmol), the reaction was stirred at 120°C for 2 hours.
  • Step 5 (R)-1-(tert-butyl)-3-methyl-4-(7-bromo-6-chloro-1-(4,6-diisopropylpyrimidin-5-yl)-8 -Fluoro-3-nitro-2-oxo-1,2-dihydroquinolin-4-yl)piperazine-1,3-dicarboxylate (380mg, 0.52mmol) dissolved in acetic acid (7mL), Iron powder (103mg, 1.83mmol) was added, and the reaction was stirred at 80°C for 30 minutes.
  • Step 6 Add (R)-10-bromo-11-chloro-8-(4,6-diisopropylpyrimidin-5-yl)-9-fluoro-5,7-diox in sequence to the 50mL sealed tube -1,2,4,4a,5,6,7,8-octahydro-3H-pyrazine[1',2':4,5]pyrazine[2,3-c]quinoline-3- Tert-butyl carboxylate (317 mg, 0.48 mmol), 12 mL acetone, anhydrous potassium carbonate (265 mg, 1.92 mmol), methyl iodide (678 mg, 4.80 mmol). The tube was sealed and the reaction was stirred at 50°C for 18 hours.
  • Step 7 Add (R)-10-bromo-11-chloro-8-(4,6-diisopropylpyrimidin-5-yl)-9-fluoro-6-methyl-5 to a 100mL round bottom flask ,7-dioxo-1,2,4,4a,5,6,7,8-octyl-3H-pyrazine[1',2':4,5]pyrazine[2,3-c] Quinoline-3-carboxylic acid tert-butyl ester (285mg, 0.42mmol), (2-fluoro-6-hydroxyphenyl)boronic acid (262mg, 1.68mmol), chlorine (2-dicyclohexylphosphine-2′,6′ -Dimethoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (30mg, 0.042mmol), 2-dicyclohexylphosphino -2',
  • Step 8 (4aR)-11-chloro-8-(4,6-diisopropylpyrimidin-5-yl)-9-fluoro-10-(2-fluoro-6-hydroxyphenyl)-6-methyl -5,7-dioxo-1,2,4,4a,5,6,7,8-octahydro-3H-pyrazine[1',2':4,5]pyrazine[2,3 -c]
  • Quinoline-3-carboxylic acid tert-butyl ester 230 mg, 0.32 mmol
  • dichloromethane 3 mL
  • trifluoroacetic acid 0.8 mL
  • Step 9 (4aR)-11-chloro-8-(4,6-diisopropylpyrimidin-5-yl)-9-fluoro-10-(2-fluoro-6-hydroxyphenyl)-6-methyl
  • Base-2,3,4,4a,6,8-hexahydro-1H-pyrazine[1',2',5]pyrazine[2,3-c]quinoline-5,7-dione (270mg , Crude product) was dissolved in dichloromethane (12 mL), and N,N-diisopropylethylamine (206 mg, 1.60 mmol) was added.
  • the reaction was cooled to 0°C, and acryloyl chloride (26 mg, 0.29 mmol) was added dropwise to the reaction solution.
  • the reaction was stirred at 0°C for 15 minutes.
  • the crude product is purified by preparative HPLC to obtain: an atropisomer, the structure is arbitrarily designated as Z37 -1 (retention time: 10.095 min; 40 mg, Y: 18.6%), white solid.
  • Step 1 2-Cyano-6-isopropylphenyl-3-amine (742mg, 4.24mmol) was dissolved in dry tetrahydrofuran (20mL), in an ice-water bath, 2M NaHMDS (8.48mL, 16.96mmol) was added ), stirring for 20 minutes under ice-water bath conditions.
  • 2M NaHMDS 8.48mL, 16.96mmol
  • 2,5-difluoro-6-(2-fluoro-6-methoxyphenyl)nicotinic acid (1.2g, 4.24mmol)
  • Step 2 Add 2-((2-cyano-6-isopropylphenyl)amino)-5-fluoro-6-(2-fluoro-6-methoxyphenyl)nicotinic acid (1.5g, 3.42 mmol) was dissolved in dichloroethane, and thionyl chloride (4.07 g, 34.2 mmol) was added. The reaction was stirred at 80°C for 2 hours.
  • Step 3 Under ice-water bath conditions, add sodium hydride (1.97g, 49.35mmol) to ethyl nitrate (1.31g, 9.86mmol) in tetrahydrofuran, stir for 30 minutes, and then add 2-((2-cyano -6-Isopropylphenyl-3-yl)amino)-5-fluoro-6-(2-fluoro-6-methoxyphenyl)nicotinoyl chloride (1.57g, 3.29mmol), stir at room temperature for 1h, and then warm up Reaction at 80°C for 2h.
  • Step 4 1-(2-cyano-6-isopropylphenyl-3-yl)-6-fluoro-7-(2-fluoro-6-methoxyphenyl)-4-hydroxy-3- Nitro-1,8-naphthyridin-2(1H)-one (110mg, 0.20mmol) was dissolved in acetonitrile (10mL), and phosphorus oxychloride (153mg, 1.0mmol), and N,N-diisopropyl were added sequentially Ethylamine (77g, 0.6mmol), the reaction was gradually raised to 80°C and stirred for 3h.
  • Step 5 4-Chloro-6-fluoro-7-(2-fluoro-6-methoxyphenyl)-1-(2-cyano-6-isopropylphenyl-3-yl)-3- Nitro-1,8-naphthyridine-2(1H)-one (110mg, 0.296mmol) was dissolved in N,N-dimethylacetamide (3mL), and (3R,6R)-1-tert-butyl was added in sequence 3-Methyl 6-methylpiperazine-1,3-dicarboxylic acid (54 mg, 0.22 mmol), and the reaction was stirred at 120°C for 2 hours.
  • Step 6 (3R,6R)-1-tert-butyl 3-methyl 4-(1-(2-cyano-6-isopropylphenyl)-6-fluoro-7-(2-fluoro-6 -Methoxyphenyl)-3-nitro-2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl)-6-methylpiperazine-1,3-dicarboxy
  • the acid 50mg, 0.068mmol
  • iron powder (11.5mg, 0.204mmol) was added, and the reaction was stirred at 80°C for 30 minutes.
  • Step 7 Add (2R,4aR)-tert-butyl 8-(2-cyano-6-isopropylphenyl)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)- 2-Methyl-5,7-dioxo-4,4a,5,6,7,8-hexahydro-1H-pyrazino[1',2':4,5]pyrazino[2, 3-c][1,8]naphthyridine-3(2H)-carboxylate (40mg, 0.059mmol), 30mL acetone, anhydrous potassium carbonate (33mg, 0.24mmol), methyl iodide (85mg, 0.59mmol) sealed The tube was sealed and the reaction was stirred at 50°C for 18 hours.
  • Step 8 (2R,4aR)-tert-butyl 8-(2-cyano-6-isopropylphenyl)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-2 ,6-Dimethyl-5,7-dioxo-4,4a,5,6,7,8-hexahydro-1H-pyrazino[1',2':4,5]pyrazino[ 2,3-c][1,8]naphthyridine-3(2H)-carboxylate (44 mg) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (1 mL) was added.
  • Step 9 2-(((2R,4aR)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-2,6-dimethyl-5,7-dioxo-2 ,3,4,4a,5,6-hexahydro-1H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthyridine-8( 7H)-yl)-3-isopropylbenzonitrile (40mg, 0.068mmol) was dissolved in dichloromethane (5mL), and diisopropylethylamine (53mL, 0.408mmol) was added. The reaction was cooled to 0°C.
  • Step 10 2-((2R,4aR)-3-acryloyl-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-2,6-dimethyl-5,7-di Oxo-2,3,4,4a,5,6-hexahydro-1H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthalene Pyridine-8(7H)-yl)-3-isopropylbenzonitrile (32mg, 0.068mmol) was added to dry dichloromethane (4.0mL), then boron tribromide (4.0mL, 4.0mmol) was added, liters To room temperature, react for 1h.
  • Step 1 Add (R)-10-bromo-11-chloro-8-(4,6-diisopropylpyrimidin-5-yl)-9-fluoro-5,7-diox to the 15mL sealed tube in sequence -1,2,4,4a,5,6,7,8-octahydro-3H-pyrazine[1',2':4,5]pyrazine[2,3-c]quinoline-3- Tert-butyl carboxylate (230 mg, 0.35 mmol), 8 mL acetone, anhydrous potassium carbonate (193 mg, 1.40 mmol), deuterated methyl iodide (507 mg, 3.50 mmol). The tube was sealed and the reaction was stirred at 50°C for 18 hours.
  • Step 2 Add (R)-10-bromo-11-chloro-8-(4,6-diisopropylpyrimidin-5-yl)-9-fluoro-6-deuteromethyl to a 100mL round bottom flask -5,7-dioxo-1,2,4,4a,5,6,7,8-octyl-3H-pyrazine[1',2':4,5]pyrazine[2,3- c) tert-butyl quinoline-3-carboxylate (185mg, 0.27mmol), (2-fluoro-6-hydroxyphenyl)boronic acid (262mg, 1.35mmol), chlorine (2-dicyclohexylphosphine-2', 6′-Dimethoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (19mg, 0.027mmol), 2-dicyclohexyl Phosphine-2',6
  • Step 3 (4aR)-11-chloro-8-(4,6-diisopropylpyrimidin-5-yl)-9-fluoro-10-(2-fluoro-6-hydroxyphenyl)-6-( Deuterated methyl-d 3 )-5,7-dioxo-1,2,4,4a,5,6,7,8-octahydro-3H-pyrazine[1',2':4,5 ]Pyrazine[2,3-c]quinoline-3-carboxylic acid tert-butyl ester (140 mg, 0.20 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (0.8 mL) was added.
  • Step 4 (4aR)-11-chloro-8-(4,6-diisopropylpyrimidin-5-yl)-9-fluoro-10-(2-fluoro-6-hydroxyphenyl)-6-( Deuterated methyl-d 3 )-2,3,4,4a,6,8-hexahydro-1H-pyrazine[1',2',5]pyrazine[2,3-c]quinoline-5 ,7-Diketone (165 mg, crude product) was dissolved in dichloromethane (8 mL), and N,N-diisopropylethylamine (129 mg, 1.0 mmol) was added.
  • Step 5 Purify compound Z39 by preparative HPLC to obtain: an atropisomer compound, the structure arbitrarily designated as Z39-1 (retention time: 10.088 min; 23 mg, Y: 17.6%), white solid.
  • Step 1 Add 7-chloro-1-(4,6-diisopropylpyrimidin-5-yl)-6-fluoro-4-hydroxy-2-oxo-1,2-dihydro-1,8- Naphthyridine-3-carbonitrile (2g, 5mmol) was suspended in 1,4-dioxane (12mL), and a mixture of concentrated sulfuric acid (12mL) and water (12mL) was slowly added.
  • Step 2 7-chloro-1-(4,6-diisopropylpyrimidin-5-yl)-6-fluoro-4-hydroxy-1,8-naphthyridin-2(1H)-one (1.56g, 4.14mmol) was dissolved in acetic acid (5.46mL), sodium nitrite (29mg, 0.42mmol) and concentrated nitric acid (780mg, 12.42mmol) were added successively, and stirred at room temperature for 20 minutes.
  • Step 3 7-chloro-1-(4,6-diisopropylpyrimidin-5-yl)-6-fluoro-4-hydroxy-3-nitro-1,8-naphthyridine-2(1H)- Ketone (1.56g, 3.70mmol), (2-fluoro-6-methoxyphenyl)boronic acid (3.14g, 18.49mmol), chlorine (2-dicyclohexylphosphino-2',6'-dimethoxy -1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (266mg, 0.37mmol), 2-bicyclohexylphosphine-2',6
  • Step 4 To 1-(4,6-diisopropylpyrimidin-5-yl)-6-fluoro-7-(2-fluoro-6-methoxyphenyl)-4-hydroxy-3-nitro -1,8-naphthyridin-2(1H)-one (1.53g, 2.99mmol) in acetonitrile (20mL) solution was added phosphorus oxychloride (2.29g, 14.96mmol) and N,N-diisopropyl Ethylamine (3.09 g, 23.93 mmol). The reaction was stirred at 80°C for 1 hour.
  • Step 5 Add 4-chloro-1-(4,6-diisopropylpyrimidin-5-yl)-6-fluoro-7-(2-fluoro-6-methoxyphenyl)-3-nitro -1,8-naphthyridin-2(1H)-one (800mg, 1.51mmol) was dissolved in N,N-dimethylacetamide (8mL), and 1-(tert-butyl)3-methyl(3R ,6R)-6-methylpiperazine-1,3-dicarboxylic acid (390mg, 1.51mmol) and N,N-diisopropylethylamine (585mg, 4.53mmol) were stirred at 120°C for 2 hours.
  • Step 6 1-(tert-butyl)3-methyl(3R,6R)-4-(1-(4,6-diisopropylpyrimidin-5-yl)-6-fluoro-7-(2- (Fluoro-6-methoxyphenyl)-3-nitro-2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl)-6-methylpiperazine-1,3 -Dicarboxylic acid (540mg, 0.72mmol) was dissolved in acetic acid (5mL), iron powder (140mg, 2.51mmol) was added and stirred at 80°C for 1 hour.
  • acetic acid 5mL
  • iron powder 140mg, 2.51mmol
  • Step 7 Add (2R,4aR)-8-(4,6-diisopropylpyrimidin-5-yl)-11-fluoro-10-(2-fluoro-6-methoxy (Phenyl)-2-methyl-5,7-dioxo-1,2,4,4a,5,6,7,8-octahydro-3H-pyrazino[1',2':4, 5] pyrazino[2,3-c][1,8]naphthyridine-3-carboxylic acid tert-butyl ester (540mg, 0.78mmol), acetone (10mL), anhydrous potassium carbonate (433 mg, 3.13mmol) , Methyl iodide (1.11 g, 7.83 mmol).
  • Step 8 (2R,4aR)-8-(4,6-diisopropylpyrimidin-5-yl)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-2,6 -Dimethyl-5,7-dioxo-1,2,4,4a,5,6,7,8-octahydro-3H-pyrazino[1',2':4,5]pyrazine
  • [2,3-c][1,8]naphthyridine-3-carboxylic acid tert-butyl ester (420 mg, 0.60 mmol) was dissolved in dichloromethane (20 mL), and trifluoroacetic acid (4 mL) was added.
  • Step 9 (2R,4aR)-8-(4,6-diisopropylpyrimidin-5-yl)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-2,6 -Dimethyl-2,3,4,4a,6,8-hexahydro-1H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8 ]
  • Naphthyridine-5,7-dione 360 mg, 0.60 mmol
  • dichloromethane 5 mL
  • N,N-diisopropylethylamine 385 mg, 2.98 mmol
  • Step 10 (2R,4aR)-3-acryloyl-8-(4,6-diisopropylpyrimidin-5-yl)-11-fluoro-10-(2-fluoro-6-methoxyphenyl )-2,6-Dimethyl-2,3,4,4a,6,8-hexahydro-1H-pyrazino[1',2':4,5]pyrazino[2,3-c ] [1,8] Naphthyridine-5,7-dione (220 mg, 0.33 mmol) was dissolved in dichloromethane (3 mL).
  • the reaction was cooled to 0°C, a 17% dichloromethane solution (3 mL) of boron tribromide was added dropwise thereto, and the mixture was stirred at room temperature overnight.
  • the reaction solution was poured into 40 mL of saturated sodium bicarbonate aqueous solution, and extracted twice with 25 mL of dichloromethane. The organic phase was dried and concentrated.
  • Step 1 Add 4-chloro-1-(4,6-diisopropylpyrimidin-5-yl)-6-fluoro-7-(2-fluoro-6-methoxyphenyl)-3-nitro -1,8-naphthyridin-2(1H)-one (1g, 1.89mmol) was dissolved in N,N-dimethylacetamide (10mL), and then 1-(tert-butyl)3-methyl(R )-Piperazine-1,3-dicarboxylate (1.39g, 5.67mmol) and N,N-diisopropylethylamine (733mg, 5.67mmol), stirred at 120°C for 2 hours.
  • Step 2 1-(tert-butyl)3-methyl(3R)-4-(1-(4,6-diisopropylpyrimidin-5-yl)-6-fluoro-7-(2-fluoro- 6-Methoxyphenyl)-3-nitro-2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl)piperazine-1,3-dicarboxylate (1.23 g, 1.67 mmol) was dissolved in acetic acid (12 mL), iron powder (326 mg, 5.84 mmol) was added, and the mixture was stirred at 80°C for 2 hours.
  • Step 3 Add (4aR)-8-(4,6-diisopropylpyrimidin-5-yl)-11-fluoro-10-(2-fluoro-6-methoxyphenyl) to the 15mL sealed tube in sequence )-5,7-dioxo-1,2,4,4a,5,6,7,8-octahydro-3H-pyrazino[1',2':4,5]pyrazino[2 ,3-c][1,8]naphthyridine-3-carboxylic acid tert-butyl ester (500mg, 0.74mmol), acetone (10mL), anhydrous potassium carbonate (307mg, 2.22mmol), methyl iodide (630mg, 4.44mmol) ).
  • Step 4 (4aR)-8-(4,6-Diisopropylpyrimidin-5-yl)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-6-methyl- 5,7-dioxo-1,2,4,4a,5,6,7,8-octahydro-3H-pyrazino[1',2':4,5]pyrazino[2,3 -c][1,8]naphthyridine-3-carboxylic acid tert-butyl ester (410 mg, 0.60 mmol) was dissolved in dichloromethane (4 mL), and trifluoroacetic acid (1 mL) was added.
  • Step 5 (4aR)-8-(4,6-Diisopropylpyrimidin-5-yl)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)-6-methyl- 2,3,4,4a,6,8-hexahydro-1H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthyridine-5 ,7-Diketone (350mg, 0.59mmol) was dissolved in dichloromethane (5mL), and N,N-diisopropylethylamine (230mg, 1.78mmol) was added.
  • Step 6 (4aR)-3-acryloyl-8-(4,6-diisopropylpyrimidin-5-yl)-11-fluoro-10-(2-fluoro-6-methoxyphenyl)- 6-Methyl-2,3,4,4a,6,8-hexahydro-1H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8 ] Naphthyridine-5,7-dione (300 mg, 0.47 mmol) was dissolved in dichloromethane (5 mL).
  • the reaction was cooled to 0°C, 17% dichloromethane solution (5 mL) of boron tribromide was added dropwise thereto, and the mixture was stirred at room temperature overnight.
  • the reaction solution was poured into 40 mL of saturated sodium bicarbonate aqueous solution, and extracted twice with 25 mL of dichloromethane. The organic phase was dried and concentrated.
  • Step 1 4-Chloro-6-fluoro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro -1,8-naphthyridin-2(1H)-one (1.2g, 2.40mmol) was dissolved in N,N-dimethylacetamide (10mL), and (3-(2-methoxy-2 -Oxyethyl)piperazine-1-carboxylic acid tert-butyl ester (743 mg, 2.87 mmol) and N,N-diisopropylethylamine (930 mg, 7.20 mmol), the reaction was stirred at 120°C for 2 hours.
  • Step 2 4-(6-Fluoro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro -2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl)-3-(2-methoxy-2-oxoethyl)piperazine-1-carboxylic acid tert-butyl ester (550mg, 0.76mmol) was dissolved in acetic acid (5.5mL), iron powder (149mg, 2.66mmol) was added, and the reaction was stirred at 80°C for 2 hours.
  • Step 3 12-Fluoro-11-(2-fluoro-6-methoxyphenyl)-9-(2-isopropyl-4-methylpyridin-3-yl)-6,8-dioxo -1,2,4a,5,6,7,8,9-octahydropyrazino[1',2':4,5][1,4]diaza[2,3-c][1 , 8]
  • Naphthyridine-3(4H)-tert-butyl carboxylate 100 mg, 0.15 mmol
  • methylene chloride 4 mL
  • trifluoroacetic acid (1 mL) was added.
  • Step 4 12-Fluoro-11-(2-fluoro-6-methoxyphenyl)-9-(2-isopropyl-4-methylpyridin-3-yl)-1,2,3,4 ,4a,5,7,9-octahydropyrazino[1',2':4,5][1,4]diazepine[2,3-c][1,8]naphthyridine-6, 8-Diketone (85mg, crude product) was dissolved in dichloromethane (2mL), and N,N-diisopropylethylamine (58mg, 0.45mmol) was added.
  • reaction solution was cooled to 0°C, acryloyl chloride (27 mg, 0.30 mmol) was added dropwise to the reaction solution, and the mixture was stirred at 0°C for 10 minutes.
  • 25mL of dichloromethane was added to the reaction solution, washed with 15mL of water, 15mL of saturated sodium bicarbonate aqueous solution, 15mL of saturated brine, dried and concentrated, and the crude product was purified with a flash silica gel column (EtOAc/PE:0-100%) to obtain product 3.
  • Step 5 3-acryloyl-12-fluoro-11-(2-fluoro-6-methoxyphenyl)-9-(2-isopropyl-4-methylpyridin-3-yl)-1, 2,3,4,4a,5,7,9-octahydropyrazino[1',2':4,5][1,4]diazepine[2,3-c][1,8] Naphthyridine-6,8-dione (60 mg, 0.10 mmol) was dissolved in dichloromethane (3 mL). The reaction solution was cooled to 0°C, and a 17% dichloromethane solution (3 mL) of boron tribromide was added dropwise thereto.
  • Step 1 Under ice bath conditions, add sodium hydrogen (91mg, 2.27mmol) to 12-fluoro-11-(2-fluoro-6-methoxyphenyl)-9-(2-isopropyl-4- (Methylpyridin-3-yl)-6,8-dioxo-1,2,4a,5,6,7,8,9-octahydropyrazino[1',2':4,5][ 1,4]diaza[2,3-c][1,8]naphthyridine-3(4H)-carboxylic acid tert-butyl ester (300mg, 0.45mmol) in tetrahydrofuran (10mL), stir for 30 minutes .
  • sodium hydrogen 9mg, 2.27mmol
  • methyl iodide (650 mg, 4.54 mmol) was added to the reaction solution and stirred at room temperature overnight.
  • the reaction solution was quenched with saturated ammonium chloride solution (30mL), extracted with ethyl acetate (30mL*3), the organic phase was dried, concentrated, and purified with a flash silica column (0-10% methanol/dichloromethane) to obtain the product 12.

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Abstract

一种如式(I)或式(IA)所示的对KRAS基因突变具有选择抑制作用的取代的杂环并环类化合物或其药学上可接受的盐、立体异构体、溶剂合物或其前药，包含该化合物的药物组合物及其在制备癌症药物中的应用。

Description

取代的杂环并环类化合物，其制法与医药上的用途 技术领域
本发明涉及医药技术领域，特别涉及一种取代的杂环并环类化合物，及其作为KRAS基因突变的选择性抑制剂的应用，以及由其制备的药物组合物。
背景技术
肺癌是全球发病率最高的癌症，在中国肺癌发病率位居所有癌症中第一位，也是中国发病率和死亡率最高的癌症，根据2016年美国癌症协会公布的数据，世界上一年中约180万人罹患肺癌，其中接近80％的肺癌为非小细胞肺癌(NSCLC)。
RAS为一组紧密相关的单体球状蛋白质(21kDa分子量)，其具有188-189个氨基酸且与鸟苷二磷酸GDP或鸟苷三磷酸GTP结合。RAS亚家族成员包括HRAS、KRAS和NRAS。RAS起分子开关作用，当RAS含有所结合的GDP时，其处于休眠或关闭位置且“无活性”。当细胞暴露于某些促生长性刺激物时，RAS经诱导而使其所结合的GDP转化为GTP，当与GTP结合时，RAS“接通”且能够与其他下游标靶蛋白质相互作用并活化这些蛋白质。RAS蛋白自身使GTP水解而恢复为GDP(从而使其自身转换为关闭状态)的固有能力极低。需要外源性蛋白GTP酶活化蛋白(GAP)将其恢复为关闭状态，GAP与RAS相互作用极大地加速了GTP转化为GDP。RAS中的任何突变将影响RAS与GAP的相互作用，以及GTP转化为GDP的能力，这种突变将导致蛋白质活化时间的延长，从而延长细胞信号传导，继而导致细胞继续生长和分裂。由于这种信号传导引起细胞生长和分裂，因此过度活化的RAS信号传导最终可导致癌症。在肺癌中，约32％的肺癌中确认有RAS基因的突变，RAS(HRAS、NRAS或KRAS)基因的三种主要亚型中的任意一个突变可导致人肿瘤的发生。有报道指出，在RAS基因中突变频率最高的为KRAS基因，在25-30％肿瘤中检测到KRAS突变。与之相比较，NRAS及HRAS家族成员中发生致癌性突变的比率低得多(分别为8％及3％)。最常见的KRAS突变发现于P环中的残基G12及G13上以及残基Q61上。G12C突变为KRAS基因的频繁突变(甘氨酸-12突变为半胱氨酸)。在约13％的癌症，约43％的肺癌及几乎100％的MYH相关息肉病(家族性结肠癌症候群)中已发现此突变。因此开发选择性抑制KRAS突变的抑制剂是一个较好的方向，为了提高对KRAS突变抑制活性的同时降低对野生型KRAS的抑制活性，开发活性更高，选择性更好，毒性更低的新型RAS突变体选择性抑制剂具有重要的意义。
发明内容
本发明提供了一种结构新颖的取代的杂环并环类化合物，其作为KRAS突变的选择性抑制剂，具有活性高，选择性好且毒副作用低等优点。
在一个方面，本发明提供一种如式(Ⅰ)所示的化合物、或其药学上可接受的盐、立体异构体、溶剂合物或其前药：
Figure PCTCN2020124226-appb-000001
式中，
Z为N-C(O)-CR 3＝CR 1R 2或N-C(O)-C≡CR 4；
R 1、R 2各自独立地为氢、卤素、氰基、NR aR b、-C 1-3烷基、卤代C 1-3烷基、-C 1-3烷基-羟基、-C 1-3烷基-氰基、-C 1-3烷基-C 1-3烷氧基、-C 1-3烷基-NR aR b、-C 1-3烷基-3至6元杂环烷基或-C 1-3烷基-5或6元单环杂芳基；其中，所述3至6元杂环烷基或所述5或6元单环杂芳基具有1、2或3个选自N、O和S的杂原子作为环原子；
R 3为氢、卤素、-C 1-3烷基或-C 1-3烷氧基；
R 4为氢、卤代C 1-3烷基、-C 1-3烷基-羟基、-C 1-3烷基-氰基或-C 1-3烷基-C 1-3烷氧基；
R 11、R 12相同或不同，各自独立地为氢、卤素、-C 1-3烷基、-卤代C 1-3烷基、-C 1-3烷基-羟基、-C 1-3烷基-氰基、-C 1-3烷基-C 1-6烷氧基、-C 1-3烷基-卤代C 1-6烷基或-C 1-3烷基-卤代C 1-6烷氧基；
R 21、R 22相同或不同，各自独立地为氢、卤素、-C 1-3烷基、-卤代C 1-3烷基、-C 1-3烷基-羟基、-C 1-3烷基-氰基、-C 1-3烷基-C 1-6烷氧基、-C 1-3烷基-卤代C 1-6烷基或-C 1-3烷基-卤代C 1-6烷氧基；
R 31、R 32相同或不同，各自独立地为氢、卤素、-C 1-3烷基、-卤代C 1-3烷基、-C 1-3烷基-羟基、-C 1-3烷基-氰基、-C 1-3烷基-C 1-6烷氧基、-C 1-3烷基-卤代C 1-6烷基或-C 1-3烷基-卤代C 1-6烷氧基；
R 41为氢、卤素、-C 1-3烷基、-卤代C 1-3烷基、-C 1-3烷基-羟基、-C 1-3烷基-氰基、-C 1-3烷基-C 1-6烷氧基、-C 1-3烷基-卤代C 1-6烷基或-C 1-3烷基-卤代C 1-6烷氧基；
当
Figure PCTCN2020124226-appb-000002
中的虚线为单键时，P为O、NH或NR m；R m为-C 1-6烷基、-卤代C 1-6烷基、-C 1-6烷基-羟基、-C 1-6烷基-氰基、-C 1-6烷基-C 1-6烷氧基、-C 1-6烷基-卤代C 1-6烷氧基、-C 1-6烷基-C 3-6环烷基或-C 1-6烷基-3元至6元杂环烷基；R 42为-(C＝O)-、-C 1-3烷基-、-C 1-3烷基(羟基)-、-C 1-3烷基(氰基)-、-C 1-3烷基(C 1-6烷基)-、-C 1-3烷基(卤代C 1-6烷基)-、-C 1-3烷基(C 1-6烷基-羟基)-、-C 1-3烷基(C 1-6烷基-氰基)-、-C 1-3烷基(C 1-6烷氧基)-、或-C 1-3烷基(卤代C 1-6烷氧基)-；
或当
Figure PCTCN2020124226-appb-000003
中的虚线为无时，P为氢、卤素；R 42为氢、卤素、-C 1-3烷基、-卤代C 1-3烷基、-C 1-3烷基-羟基、-C 1-3烷基-氰基、-C 1-3烷基-C 1-6烷氧基、-C 1-3烷基-卤代C 1-6烷基或-C 1-3烷基-卤代C 1-6烷氧基；
Y 1为C时；X 1为氢、卤素、氰基、羟基、氨基、硝基、-取代或未取代的C 1-6烷基、-取代或未取代的C 3-6环烷基、-取代或未取代的3至6元杂环烷基、-O-取代或未取代的C 1-6烷基、-O-取代或未取代的C 3-6环烷基、-O-取代或未取代的3至6元杂环烷基、-NH-取代或未取代的C 1-6烷基、-N(取代或未取代的C 1-6烷基) 2、-NH-取代或未取代的C 3-6 环烷基、-NH-取代或未取代的3至6元杂环烷基、-NH(C＝O)-取代或未取代的C 1-6烷基、-NH(C＝O)-C 3-6环烷基、-NH(SO 2)-取代或未取代的C 1-6烷基、-NH(SO 2)-取代或未取代的C 3-6环烷基、-SO 2-取代或未取代的C 1-6烷基、-SO 2-取代或未取代的C 3-6环烷基、-(C＝O)-NR jR k-、-(C＝O)-O-取代或未取代的C 1-6烷基、-(C＝O)-O-取代或未取代的C 3-6环烷基；其中，R j、R k各自独立地为氢或C 1-3烷基；或者R j、R k与相连的氮原子共同形成取代或未取代的3至6元含氮杂环烷基；所述3至6元杂环烷基具有1、2或3个选自N、O和S的杂原子作为环原子；所述3至6元含氮杂环烷基具有3至6个环原子且其中一个环原子为氮原子、其余环原子中的0个、1个或2个环原子任选地为选自N、O和S的杂原子；所述的“取代”是指基团中的1、2、3或4个氢原子被各自独立地选自S组取代基所取代；
或Y 1为N时，X 1为无；
所述S组取代基选自：羟基、卤素、硝基、氧代基、-C 1-6烷基、-卤代C 1-6烷基、羟基取代的C 1-6烷基、苄基、-(CH 2) u-氰基、-(CH 2) u-C 1-6烷氧基、-(CH 2) u-卤代C 1-6烷氧基、-(CH 2) u-卤代C 1-6烷基、-(CH 2) u-3至6元杂环烷基、-(CH 2) u-5或6元单环杂芳基、-(CH 2) u-C 3-8环烷基、-(CH 2) u-O-(CH 2) v-C 3-8环烷基、-(CH 2) u-O-(CH 2) v-C 1-6烷氧基、-(CH 2) u-O-(CH 2) vOH、-(CH 2) u-SO 2C 1-6烷基、-(CH 2) u-NR a0R b0、-(CH 2) u-C(O)NR a0R b0、-(CH 2) u-C(O)C 1-6烷基、-C(O)OC 1-6烷基、NR a0C(O)-(CH 2) u-NR a0R b0、NR a0C(O)-(CH 2) uOH、NR a0C(O)-卤代C 1-6烷基；其中，所述3至6元杂环烷基或所述5或6元单环杂芳基各自独立地具有1、2或3个选自N、O和S的杂原子作为环原子；所述3至6元杂环烷基、5或6元单环杂芳基任选地被1、2或3个选自卤素、氰基、-C 1-3烷基、-C 1-3烷氧基和C 3-6环烷基的取代基取代；u、v各自独立地为0、1、2、3或4；R a0、R b0各自独立地为氢或C 1-3烷基；
E 1为N或CR 5；其中，R 5为氢、卤素、氰基、-C 1-6烷基、-C 1-6烷氧基、-卤代C 1-6烷基、-卤代C 1-6烷氧基、-C 3-6环烷基、-NR hR i、-C 1-4烷基-羟基、-C 1-4烷基-氰基、-C 1-4烷基-C 1-6烷氧基、-C 1-4烷基-卤代C 1-6烷基或-C 1-4烷基-卤代C 1-6烷氧基；
E 2为N或CR 6；其中，R 6为氢、卤素、氰基、-C 1-6烷基、-C 1-6烷氧基、-卤代C 1-6烷基、-卤代C 1-6烷氧基、-C 3-6环烷基、-NR hR i、-C 1-4烷基-羟基、-C 1-4烷基-氰基、-C 1-4烷基-C 1-6烷氧基、-C 1-4烷基-卤代C 1-6烷基或-C 1-4烷基-卤代C 1-6烷氧基；
条件是Y 1、E 1、E 2不同时为N；
Ar为C 6-10芳基、5或6元单环杂芳基或8至10元双环杂芳基；其中，所述5或6元单环杂芳基具有1、2或3个选自N、O和S的杂原子作为环原子；所述8至10元双环杂芳基具有1、2、3、4或5个选自N、O和S的杂原子作为环原子；且所述C 6-10芳基、所述5或6元单环杂芳基或所述8至10元双环杂芳基为未取代的或被1、2、3或4个独立选自R s1的基团取代；
或者
Ar为式(B)所示结构：
Figure PCTCN2020124226-appb-000004
其中，B1环为苯环或5或6元单环杂芳基环；B2环为一个稠合的5或6元单环杂环烷基环或稠合的5或6元单环环烷基环；其中，所述5或6元单环杂芳基环或所述稠合的5或6元单环杂环烷基环具有1、2或3个选自N、O和S的杂原子作为环原子；
(R s1) p表示B1环上的氢被p个R s1取代，p为0、1、2或3，每个R s1相同或不同；
(R s2) q表示B2环上的氢被q个R s2取代，q为0、1、2或3，每个R s2相同或不同；
R s1、R s2各自独立地为卤素、氰基、硝基、羟基、-C 1-6烷基、-C 1-6烷氧基、-卤代C 1-6烷基、-卤代C 1-6烷氧基、-C 3-6环烷基、-NR cR d、-C(O)NR eR f、-SO 2C 1-3烷基、-SO 2卤代C 1-3烷基、-SO 2NR eR f、-C 1-4烷基-羟基、-C 1-4烷基-氰基、-C 1-4烷基-C 1-6烷氧基、-C 1-4烷基-卤代C 1-6烷基、-C 1-4烷基-卤代C 1-6烷氧基、-C 1-4烷基-3至6元杂环烷基、-C 1-4烷基-NR eR f、-C 1-4烷基-C(O)NR eR f、-C 1-4烷基-SO 2C 1-3烷基或C 2-4炔基；其中，所述3至6元杂环烷基具有1、2或3个选自N、O和S的杂原子作为环原子；
R 0为-C 1-6烷基、-C 3-6环烷基、3至6元杂环烷基、C 6-10芳基、5或6元单环杂芳基、8至10元双环杂芳基、7至11元螺环烷基、-C 1-3烷基-C 6-10芳基、-C 1-3烷基-5或6元单环杂芳基、-NR g-C 6-10芳基、-O-C 6-10芳基、-C 1-3烷基-3至6元杂环烷基、-C 1-3烷基-C 3-6环烷基，其中，所述3至6元杂环烷基、所述5或6元单环杂芳基或所述8至10元双环杂芳基具有1、2或3个选自N、O和S的杂原子作为环原子；且所述的C 1-6烷基、C 3-6环烷基、3至6元杂环烷基、C 6-10芳基、5或6元单环杂芳基、8至10元双环杂芳基、7至11元螺环烷基为未取代的或被1、2、3或4个独立选自R s3的基团取代；所述的-C 1-3烷基-为未取代的或被1、2、3或4个独立选自C 1-3烷基取代；
或者
R 0为式(A-1)或式(A-2)所示结构：
Figure PCTCN2020124226-appb-000005
其中，A1环为苯环或5或6元单环杂芳基环；A2环为一个稠合的5或6元单环杂环烷基环或稠合的5或6元单环环烷基环；其中，所述5或6元单环杂芳基环或所述稠合的5或6元单环杂环烷基环具有1、2或3个选自N、O和S的杂原子作为环原子；
(R s3) t表示A1环上的氢被t个R s3取代，t为0、1、2或3，每个R s3相同或不同；
(R s4) s表示A2环上的氢被s个R s4取代，s为0、1、2或3，每个R s4相同或不同；
R s3、R s4各自独立地为卤素、氰基、羟基、-C 1-6烷基、-C 1-6烷氧基、-卤代C 1-6烷基、-卤代C 1-6烷氧基、-C 3-6环烷基、3至6元杂环烷基、-NR hR i、-C(O)NR eR f、-SO 2C 1-3烷基、-SO 2卤代C 1-3烷基、-SO 2NR eR f、-C 1-3烷基-羟基、-C 1-3烷基-C 2-4炔基、-C 1-3烷基-氰基、-C 1-3烷基-C 1-6烷氧基、-C 1-3烷基-卤代C 1-6烷基、-C 1-3烷基-卤代C 1-6烷氧基、-C 1-3烷基-3至6元杂环烷基、-C 1-3烷基-C 3-6环烷基、-C 1-3烷基-NR eR f、-C 1-3烷基-C(O)NR eR f、 -C 1-3烷基-SO 2C 1-3烷基或C 2-4炔基；其中，所述3至6元杂环烷基具有1、2或3个选自N、O和S的杂原子作为环原子；且所述的C 1-6烷基、-C 1-6烷氧基、-C 1-3烷基-、-C 3-6环烷基、3至6元杂环烷基任选地被1、2或3个独立选自卤素、甲基、乙基、丙基(正丙基)、异丙基、三氟甲基、氨基、N(CH 3) 2、羟基、羧基的取代基取代；
R a、R b、R e、R f、R g各自独立地为氢或C 1-3烷基；
R c、R d、R h、R i各自独立地为氢、-C 1-3烷基、-C(O)C 1-3烷基或-CO 2C 1-3烷基。
在本发明的一种实施方案中，式(Ⅰ)所示的化合物为式(I-1)化合物或式(I-2)化合物；
Figure PCTCN2020124226-appb-000006
式I-1中，P为O、NH或NR m；R m为-C 1-6烷基、-卤代C 1-6烷基、-C 1-6烷基-羟基、-C 1-6烷基-氰基、-C 1-6烷基-C 1-6烷氧基、-C 1-6烷基-卤代C 1-6烷氧基、-C 1-6烷基-C 3-6环烷基或-C 1-6烷基-3元至6元杂环烷基；R 42为-(C＝O)-、-C 1-3烷基-、-C 1-3烷基(羟基)-、-C 1-3烷基(氰基)-、-C 1-3烷基(C 1-6烷基)-、-C 1-3烷基(卤代C 1-6烷基)-、-C 1-3烷基(C 1-6烷基-羟基)-、-C 1-3烷基(C 1-6烷基-氰基)-、-C 1-3烷基(C 1-6烷氧基)-、或-C 1-3烷基(卤代C 1-6烷氧基)-；R 11、R 12、R 21、R 22、R 31、R 32、R 41、Z、R 0、Ar、E 1、E 2、X 1、Y 1定义同前；
式I-2中，P为氢、卤素；R 42为氢、卤素、-C 1-3烷基、-卤代C 1-3烷基、-C 1-3烷基-羟基、-C 1-3烷基-氰基、-C 1-3烷基-C 1-6烷氧基、-C 1-3烷基-卤代C 1-6烷基或-C 1-3烷基-卤代C 1-6烷氧基；R 11、R 12、R 21、R 22、R 31、R 32、R 41、Z、R 0、Ar、E 1、E 2、X 1、Y 1定义同前。
在另一个方面，本发明提供一种如式(IA)所示的化合物或其互变异构体、顺反异构体、内消旋体、外消旋体、对映异构体、非对映异构体、阻转异构体或其混合物形式，或其药学上可接受的盐，溶剂合物或前药：
Figure PCTCN2020124226-appb-000007
式中，
Z为N-C(O)-CR 3＝CR 1R 2或N-C(O)-C≡CR 4；
R 1、R 2各自独立地为氢、卤素、氰基、NR aR b、-C 1-3烷基、卤代C 1-3烷基、-C 1-3烷基-羟基、-C 1-3烷基-氰基、-C 1-3烷基-C 1-3烷氧基、-C 1-3烷基-NR aR b、-C 1-3烷基-3至6元杂环烷基或-C 1-3烷基-5或6元单环杂芳基；其中，所述3至6元杂环烷基或所述5或6 元单环杂芳基具有1、2或3个选自N、O和S的杂原子作为环原子；
R 3为氢、卤素、-C 1-3烷基或-C 1-3烷氧基；
R 4为氢、卤代C 1-3烷基、-C 1-3烷基-羟基、-C 1-3烷基-氰基或-C 1-3烷基-C 1-3烷氧基；
R 11、R 12相同或不同，各自独立地为氢、卤素、-C 1-3烷基、-卤代C 1-3烷基、-C 1-3烷基-羟基、-C 1-3烷基-氰基、-C 1-3烷基-C 1-6烷氧基、-C 1-3烷基-卤代C 1-6烷基或-C 1-3烷基-卤代C 1-6烷氧基；
R 21、R 22相同或不同，各自独立地为氢、卤素、-C 1-3烷基、-卤代C 1-3烷基、-C 1-3烷基-羟基、-C 1-3烷基-氰基、-C 1-3烷基-C 1-6烷氧基、-C 1-3烷基-卤代C 1-6烷基或-C 1-3烷基-卤代C 1-6烷氧基；
R 31、R 32相同或不同，各自独立地为氢、卤素、-C 1-3烷基、-卤代C 1-3烷基、-C 1-3烷基-羟基、-C 1-3烷基-氰基、-C 1-3烷基-C 1-6烷氧基、-C 1-3烷基-卤代C 1-6烷基或-C 1-3烷基-卤代C 1-6烷氧基；
R 41为氢、卤素、-C 1-3烷基、-卤代C 1-3烷基、-C 1-3烷基-羟基、-C 1-3烷基-氰基、-C 1-3烷基-C 1-6烷氧基、-C 1-3烷基-卤代C 1-6烷基或-C 1-3烷基-卤代C 1-6烷氧基；
当
Figure PCTCN2020124226-appb-000008
中的虚线为单键时，P'为O、NH或NR m'；R m'为-氘代C 1-6烷基、-C 1-6烷基、-卤代C 1-6烷基、-C 1-6烷基-羟基、-C 1-6烷基-氰基、-C 1-6烷基-C 1-6烷氧基、-C 1-6烷基-卤代C 1-6烷氧基、-C 1-6烷基-C 3-6环烷基或-C 1-6烷基-3元至6元杂环烷基；R 42'为-C 1-3烷基-(C＝O)-、-(C＝O)-、-C 1-3烷基-、-C 1-3烷基(羟基)-、-C 1-3烷基(氰基)-、-C 1-3烷基(C 1-6烷基)-、-C 1-3烷基(卤代C 1-6烷基)-、-C 1-3烷基(C 1-6烷基-羟基)-、-C 1-3烷基(C 1-6烷基-氰基)-、-C 1-3烷基(C 1-6烷氧基)-、或-C 1-3烷基(卤代C 1-6烷氧基)-；
或当
Figure PCTCN2020124226-appb-000009
中的虚线为无时，P'为氢、卤素；R 42'为氢、卤素、-C 1-3烷基、-卤代C 1-3烷基、-C 1-3烷基-羟基、-C 1-3烷基-氰基、-C 1-3烷基-C 1-6烷氧基、-C 1-3烷基-卤代C 1-6烷基或-C 1-3烷基-卤代C 1-6烷氧基；
Y 1为C时；X 1为氢、卤素、氰基、羟基、氨基、硝基、-取代或未取代的C 1-6烷基、-取代或未取代的C 3-6环烷基、-取代或未取代的3至6元杂环烷基、-O-取代或未取代的C 1-6烷基、-O-取代或未取代的C 3-6环烷基、-O-取代或未取代的3至6元杂环烷基、-NH-取代或未取代的C 1-6烷基、-N(取代或未取代的C 1-6烷基) 2、-NH-取代或未取代的C 3-6环烷基、-NH-取代或未取代的3至6元杂环烷基、-NH(C＝O)-取代或未取代的C 1-6烷基、-NH(C＝O)-C 3-6环烷基、-NH(SO 2)-取代或未取代的C 1-6烷基、-NH(SO 2)-取代或未取代的C 3-6环烷基、-SO 2-取代或未取代的C 1-6烷基、-SO 2-取代或未取代的C 3-6环烷基、-(C＝O)-NR jR k-、-(C＝O)-O-取代或未取代的C 1-6烷基、-(C＝O)-O-取代或未取代的C 3-6环烷基；其中，R j、R k各自独立地为氢或C 1-3烷基；或者R j、R k与相连的氮原子共同形成取代或未取代的3至6元含氮杂环烷基；所述3至6元杂环烷基具有1、2或3个选自N、O和S的杂原子作为环原子；所述3至6元含氮杂环烷基具有3至6个环原子且其中一个环原子为氮原子、其余环原子中的0个、1个或2个环原子任选地为选自N、O和S的杂原子；所述的“取代”是指基团中的1、2、3或4个氢原子被各自独立地选自S组取代基所取代；
或Y 1为N时，X 1为无；
所述S组取代基选自：羟基、卤素、硝基、氧代基、-C 1-6烷基、-卤代C 1-6烷基、羟基取代的C 1-6烷基、苄基、-(CH 2) u-氰基、-(CH 2) u-C 1-6烷氧基、-(CH 2) u-卤代C 1-6烷氧基、-(CH 2) u-卤代C 1-6烷基、-(CH 2) u-3至6元杂环烷基、-(CH 2) u-5或6元单环杂芳基、-(CH 2) u-C 3-8环烷基、-(CH 2) u-O-(CH 2) v-C 3-8环烷基、-(CH 2) u-O-(CH 2) v-C 1-6烷氧基、-(CH 2) u-O-(CH 2) vOH、-(CH 2) u-SO 2C 1-6烷基、-(CH 2) u-NR a0R b0、-(CH 2) u-C(O)NR a0R b0、-(CH 2) u-C(O)C 1-6烷基、-C(O)OC 1-6烷基、NR a0C(O)-(CH 2) u-NR a0R b0、NR a0C(O)-(CH 2) uOH、NR a0C(O)-卤代C 1-6烷基；其中，所述3至6元杂环烷基或所述5或6元单环杂芳基各自独立地具有1、2或3个选自N、O和S的杂原子作为环原子；所述3至6元杂环烷基、5或6元单环杂芳基任选地被1、2或3个选自卤素、氰基、-C 1-3烷基、-C 1-3烷氧基和C 3-6环烷基的取代基取代；u、v各自独立地为0、1、2、3或4；R a0、R b0各自独立地为氢或C 1-3烷基；
E 1'为N或CR 5'；其中，R 5'为氢、卤素、氰基、-C 1-6烷基、-C 1-6烷氧基、-卤代C 1-6烷基、-卤代C 1-6烷氧基、-C 3-6环烷基、-O-C 3-6环烷基、-NR hR i、-C 1-4烷基-羟基、-C 1-4烷基-氰基、-C 1-4烷基-C 1-6烷氧基、-C 1-4烷基-卤代C 1-6烷基或-C 1-4烷基-卤代C 1-6烷氧基；
E 2'为N或CR 6'；其中，R 6'为氢、卤素、氰基、-C 1-6烷基、-C 1-6烷氧基、-卤代C 1-6烷基、-卤代C 1-6烷氧基、-C 3-6环烷基、-O-C 3-6环烷基、-NR hR i、-C 1-4烷基-羟基、-C 1-4烷基-氰基、-C 1-4烷基-C 1-6烷氧基、-C 1-4烷基-卤代C 1-6烷基或-C 1-4烷基-卤代C 1-6烷氧基；
条件是Y 1、E 1'、E 2'不同时为N；
Ar'为C 6-10芳基、5或6元单环杂芳基、8至10元双环杂芳基或吡啶酮基；其中，所述5或6元单环杂芳基具有1、2或3个选自N、O和S的杂原子作为环原子；所述8至10元双环杂芳基具有1、2、3、4或5个选自N、O和S的杂原子作为环原子；且所述C 6-10芳基、所述5或6元单环杂芳基、所述8至10元双环杂芳基和所述吡啶酮基为未取代的或被1、2、3或4个独立选自R s1的基团取代；
或者Ar'为式(B)所示结构：
Figure PCTCN2020124226-appb-000010
其中，B1环为苯环或5或6元单环杂芳基环；B2环为一个稠合的5或6元单环杂环烷基环或稠合的5或6元单环环烷基环；其中，所述5或6元单环杂芳基环或所述稠合的5或6元单环杂环烷基环具有1、2或3个选自N、O和S的杂原子作为环原子；
(R s1) p表示B1环上的氢被p个R s1取代，p为0、1、2或3，每个R s1相同或不同；
(R s2) q表示B2环上的氢被q个R s2取代，q为0、1、2或3，每个R s2相同或不同；
R s1、R s2各自独立地为卤素、氰基、硝基、羟基、-C 1-6烷基、-C 1-6烷氧基、-卤代C 1-6烷基、-卤代C 1-6烷氧基、-C 3-6环烷基、-NR cR d、-C(O)NR eR f、-SO 2C 1-3烷基、-SO 2卤代C 1-3烷基、-SO 2NR eR f、-C 1-4烷基-羟基、-C 1-4烷基-氰基、-C 1-4烷基-C 1-6烷氧基、-C 1-4烷基-卤代C 1-6烷基、-C 1-4烷基-卤代C 1-6烷氧基、-C 1-4烷基-3至6元杂环烷基、-C 1-4烷基-NR eR f、-C 1-4烷基-C(O)NR eR f、-C 1-4烷基-SO 2C 1-3烷基或C 2-4炔基；其中，所述3 至6元杂环烷基具有1、2或3个选自N、O和S的杂原子作为环原子；
R 0'为-C 1-6烷基、-C 3-6环烷基、3至6元杂环烷基、C 6-10芳基、5或6元单环杂芳基、8至10元双环杂芳基、7至11元螺环烷基、-C 1-3烷基-C 6-10芳基、-C 1-3烷基-5或6元单环杂芳基、-NR g-C 6-10芳基、-O-C 6-10芳基、-C 1-3烷基-3至6元杂环烷基、-C 1-3烷基-C 3-6环烷基或吡啶酮基，其中，所述3至6元杂环烷基、所述5或6元单环杂芳基或所述8至10元双环杂芳基具有1、2或3个选自N、O和S的杂原子作为环原子；且所述的C 1-6烷基、C 3-6环烷基、3至6元杂环烷基、C 6-10芳基、5或6元单环杂芳基、8至10元双环杂芳基、7至11元螺环烷基和吡啶酮基为未取代的或被1、2、3或4个独立选自R s3的基团取代；所述的-C 1-3烷基-为未取代的或被1、2、3或4个独立选自C 1-3烷基取代；
或者R 0'为式(A-1)或式(A-2)所示结构：
Figure PCTCN2020124226-appb-000011
其中，A1环为苯环或5或6元单环杂芳基环；A2环为一个稠合的5或6元单环杂环烷基环或稠合的5或6元单环环烷基环；其中，所述5或6元单环杂芳基环或所述稠合的5或6元单环杂环烷基环具有1、2或3个选自N、O和S的杂原子作为环原子；
(R s3) t表示A1环上的氢被t个R s3取代，t为0、1、2或3，每个R s3相同或不同；
(R s4) s表示A2环上的氢被s个R s4取代，s为0、1、2或3，每个R s4相同或不同；
R s3、R s4各自独立地为卤素、氰基、羟基、-C 1-6烷基、-C 1-6烷氧基、-卤代C 1-6烷基、-卤代C 1-6烷氧基、-C 3-6环烷基、3至6元杂环烷基、-NR hR i、-C(O)NR eR f、-SO 2C 1-3烷基、-SO 2卤代C 1-3烷基、-SO 2NR eR f、-C 1-3烷基-羟基、-C 1-3烷基-C 2-4炔基、-C 1-3烷基-氰基、-C 1-3烷基-C 1-6烷氧基、-C 1-3烷基-卤代C 1-6烷基、-C 1-3烷基-卤代C 1-6烷氧基、-C 1-3烷基-3至6元杂环烷基、-C 1-3烷基-C 3-6环烷基、-C 1-3烷基-NR eR f、-C 1-3烷基-C(O)NR eR f、-C 1-3烷基-SO 2C 1-3烷基或C 2-4炔基；其中，所述3至6元杂环烷基具有1、2或3个选自N、O和S的杂原子作为环原子；且所述的C 1-6烷基、-C 1-6烷氧基、-C 1-3烷基-、-C 3-6环烷基、3至6元杂环烷基任选地被1、2或3个独立选自卤素、甲基、乙基、丙基(正丙基)、异丙基、三氟甲基、氨基、N(CH 3) 2、羟基、羧基的取代基取代；
R a、R b、R e、R f、R g各自独立地为氢或C 1-3烷基；
R c、R d、R h、R i各自独立地为氢、-C 1-3烷基、-C(O)C 1-3烷基或-CO 2C 1-3烷基。
在本发明的一种实施方案中，式(IA)所示的化合物为式(IB)化合物或式(IC)化合物；
Figure PCTCN2020124226-appb-000012
式IB中，P'为O、NH或NR m'；R m'为-氘代C 1-6烷基、-C 1-6烷基、-卤代C 1-6烷基、-C 1-6烷基-羟基、-C 1-6烷基-氰基、-C 1-6烷基-C 1-6烷氧基、-C 1-6烷基-卤代C 1-6烷氧基、-C 1-6烷基-C 3-6环烷基或-C 1-6烷基-3元至6元杂环烷基；R 42'为-C 1-3烷基-(C＝O)-、-(C＝O)-、-C 1-3烷基-、-C 1-3烷基(羟基)-、-C 1-3烷基(氰基)-、-C 1-3烷基(C 1-6烷基)-、-C 1-3烷基(卤代C 1-6烷基)-、-C 1-3烷基(C 1-6烷基-羟基)-、-C 1-3烷基(C 1-6烷基-氰基)-、-C 1-3烷基(C 1-6烷氧基)-、或-C 1-3烷基(卤代C 1-6烷氧基)-；R 11、R 12、R 21、R 22、R 31、R 32、R 41、Z、R 0'、Ar'、E 1'、E 2'、X 1、Y 1定义同前；
式IC中，P'为氢或卤素；R 42'为氢、卤素、-C 1-3烷基、-卤代C 1-3烷基、-C 1-3烷基-羟基、-C 1-3烷基-氰基、-C 1-3烷基-C 1-6烷氧基、-C 1-3烷基-卤代C 1-6烷基或-C 1-3烷基-卤代C 1-6烷氧基；R 11、R 12、R 21、R 22、R 31、R 32、R 41、Z、R 0'、Ar'、E 1'、E 2'、X 1、Y 1定义同前。
在本发明的一种实施方案中，式IB中，P'为O、NH或NR m'；R m'为-氘代C 1-6烷基或-C 1-6烷基；R 42'为-C 1-3烷基-(C＝O)-、-(C＝O)-或-C 1-3烷基-。
在本发明的一种实施方案中，式IB中，P'为O、NH或NR m'；R m'为-氘代C 1-3烷基或-C 1-3烷基；R 42'为-C 1-3烷基-(C＝O)-、-(C＝O)-或-C 1-3烷基-。
在本发明的一种实施方案中，式IB中，P'为O、NH或NR m'；R m'为氘代甲基、氘代乙基、氘代正丙基、氘代异丙基、甲基、乙基、正丙基或异丙基；R 42'为-CH 2-(C＝O)-、-CH 2CH 2-(C＝O)-、-(C＝O)-、-CH 2-、-CH 2CH 2-或-CH 2CH 2CH 2-。
在本发明的一种实施方案中，式IB中，P'为NH或NR m'；R m'为-氘代C 1-6烷基或-C 1-6烷基；R 42'为-C 1-3烷基-(C＝O)-或-(C＝O)-。
在本发明的一种实施方案中，式IB中，P'为NH或NR m'；R m'为-氘代C 1-3烷基或-C 1-3烷基；R 42'为-C 1-3烷基-(C＝O)-或-(C＝O)-。
在本发明的一种实施方案中，式IB中，P'为NH或NR m'；R m'为氘代甲基或甲基；R 42'为-CH 2-(C＝O)-、-CH 2CH 2-(C＝O)-或-(C＝O)-。
在本发明的一种实施方案中，式IB中，P'为O；R 42'为-C 1-3烷基-。
在本发明的一种实施方案中，式IB中，P'为O；R 42'为-CH 2-。
在本发明的一种实施方案中，式(IB)所示的化合物为式(IB-1)化合物或式(IB-2)化合物；
Figure PCTCN2020124226-appb-000013
式(IB-1)、式(IB-2)中，R 21、R 22、R 11、R 12、R 31、R 32、R 41、R 42'、Z、P'、R 0'、Ar'、E 1'、E 2'、X 1、Y 1定义同前。
在本发明的一种实施方案中，式IB-1中，P'为O、NH或NR m'；R m'为-氘代C 1-6烷 基或-C 1-6烷基；R 42'为-C 1-3烷基-(C＝O)-、-(C＝O)-或-C 1-3烷基-。
在本发明的一种实施方案中，式IB-1中，P'为NH或NR m'；R m'为-氘代C 1-6烷基或-C 1-6烷基；R 42'为-C 1-3烷基-(C＝O)-或-(C＝O)-。
在本发明的一种实施方案中，式IB-1中，P'为NH或NR m'；R m'为-氘代C 1-3烷基或-C 1-3烷基；R 42'为-C 1-3烷基-(C＝O)-或-(C＝O)-。
在本发明的一种实施方案中，式IB-1中，P'为NH或NR m'；R m'为氘代甲基或甲基；R 42'为-CH 2-(C＝O)-、-CH 2CH 2-(C＝O)-或-(C＝O)-。
在本发明的一种实施方案中，式IB-1中，P'为O；R 42'为-C 1-3烷基-。
在本发明的一种实施方案中，式IB-1中，P'为O；R 42'为-CH 2-。
在另一个方面，本发明提供一种式(IB-1a)或式(IB-2a)所示化合物，或其互变异构体、顺反异构体、内消旋体、外消旋体、对映异构体、非对映异构体、阻转异构体或其混合物形式，或其药学上可接受的盐，溶剂合物或前药：
Figure PCTCN2020124226-appb-000014
其中R 1、R 2、R 3、R 21、R 22、R 12、R 11、R 31、R 32、P'、R 0'、Ar'、E 1'、X 1定义同前。
在本发明的一种实施方案中，式IB-1a中，P'为NH或NR m'；R m'为-氘代C 1-6烷基或-C 1-6烷基。
在本发明的一种实施方案中，式IB-1a中，P'为NH或NR m'；R m'为-氘代C 1-3烷基或-C 1-3烷基。
在本发明的一种实施方案中，式IB-1a中，P'为NH或NR m'；R m'为氘代甲基或甲基。
在本发明的一种实施方案中，式(IB-1a)所示的化合物为式(IB-1aa)化合物、式(IB-1ab)化合物、式(IB-1ac)化合物或式(IB-1ad)化合物；
Figure PCTCN2020124226-appb-000015
其中式(IB-1aa)、式(IB-1ab)中，R 21'独立为卤素、-C 1-3烷基、-卤代C 1-3烷基、-C 1-3烷基-羟基、-C 1-3烷基-氰基、-C 1-3烷基-C 1-6烷氧基、-C 1-3烷基-卤代C 1-6烷基或-C 1-3烷 基-卤代C 1-6烷氧基；R 1、R 2、R 3、R 12、R 11、R 31、R 32、P'、R 0'、Ar'、E 1'、X 1定义同前；
式(IB-1ac)、式(IB-1ad)中，R 12'独立为卤素、-C 1-3烷基、-卤代C 1-3烷基、-C 1-3烷基-羟基、-C 1-3烷基-氰基、-C 1-3烷基-C 1-6烷氧基、-C 1-3烷基-卤代C 1-6烷基或-C 1-3烷基-卤代C 1-6烷氧基；R 1、R 2、R 3、R 21、R 22、R 31、R 32、P'、R 0'、Ar'、E 1'、X 1定义同前。
在另一个方面，本发明提供一种式(IB-1c)或式(IB-2c)所示化合物，或其互变异构体、顺反异构体、内消旋体、外消旋体、对映异构体、非对映异构体、阻转异构体或其混合物形式，或其药学上可接受的盐，溶剂合物或前药：
Figure PCTCN2020124226-appb-000016
其中R 1、R 2、R 3、R 21、R 22、R 12、R 11、R 31、R 32、P'、R 0'、Ar'、E 1'、X 1定义同前。
在本发明的一种实施方案中，式IB-1c中，P'为NH或NR m'；R m'为-氘代C 1-6烷基或-C 1-6烷基。
在本发明的一种实施方案中，式IB-1c中，P'为NH或NR m'；R m'为-氘代C 1-3烷基或-C 1-3烷基。
在本发明的一种实施方案中，式IB-1c中，P'为NH或NR m'；R m'为氘代甲基或甲基。
在本发明的一种实施方案中，式(IB-1c)所示的化合物为式(IB-1ca)化合物、式(IB-1cb)化合物、式(IB-1cc)化合物或式(IB-1cd)化合物；
Figure PCTCN2020124226-appb-000017
其中式(IB-1ca)、式(IB-1cb)中，R 21'独立为卤素、-C 1-3烷基、-卤代C 1-3烷基、-C 1-3烷基-羟基、-C 1-3烷基-氰基、-C 1-3烷基-C 1-6烷氧基、-C 1-3烷基-卤代C 1-6烷基或-C 1-3烷基-卤代C 1-6烷氧基；R 1、R 2、R 3、R 12、R 11、R 31、R 32、P'、R 0'、Ar'、E 1'、X 1定义同前；
式(IB-1cc)、式(IB-1cd)中，R 12'独立为卤素、-C 1-3烷基、-卤代C 1-3烷基、-C 1-3烷基-羟基、-C 1-3烷基-氰基、-C 1-3烷基-C 1-6烷氧基、-C 1-3烷基-卤代C 1-6烷基或-C 1-3烷基-卤代C 1-6烷氧基；R 1、R 2、R 3、R 21、R 22、R 31、R 32、P'、R 0'、Ar'、E 1'、X 1定义同前。
在本发明的一种实施方案中，式IB-1a、式IB-1c、式IB-2a和式IB-2c中，P'独立 为NH或NR m'；R m'为-氘代C 1-6烷基或-C 1-6烷基。
在本发明的一种实施方案中，式IB-1a、式IB-1c、式IB-2a和式IB-2c中，P'独立为NH或NR m'；R m'为-氘代C 1-3烷基或-C 1-3烷基。
在本发明的一种实施方案中，式IB-1a、式IB-1c、式IB-2a和式IB-2c中，P'独立为NH或NR m'；R m'为氘代甲基、氘代乙基、氘代正丙基、氘代异丙基、甲基、乙基、正丙基或异丙基。
在另一个方面，本发明提供一种式(IB-1b)或式(IB-2b)所示化合物，或其互变异构体、顺反异构体、内消旋体、外消旋体、对映异构体、非对映异构体、阻转异构体或其混合物形式，或其药学上可接受的盐，溶剂合物或前药：
Figure PCTCN2020124226-appb-000018
其中R 1、R 2、R 3、R 21、R 22、R 12、R 11、R 31、R 32、P'、R 0'、Ar'、E 1'、X 1定义同前。
在本发明的一种实施方案中，式(IB-1b)所示的化合物为式(IB-1ba)化合物、式(IB-1bb)化合物、式(IB-1bc)化合物或式(IB-1bd)化合物；
Figure PCTCN2020124226-appb-000019
其中式(IB-1ba)、式(IB-1bb)中，R 21'独立为卤素、-C 1-3烷基、-卤代C 1-3烷基、-C 1-3烷基-羟基、-C 1-3烷基-氰基、-C 1-3烷基-C 1-6烷氧基、-C 1-3烷基-卤代C 1-6烷基或-C 1-3烷基-卤代C 1-6烷氧基；R 1、R 2、R 3、R 12、R 11、R 31、R 32、P'、R 0'、Ar'、E 1'、X 1定义同前；
式(IB-1bc)、式(IB-1bd)中，R 12'独立为卤素、-C 1-3烷基、-卤代C 1-3烷基、-C 1-3烷基-羟基、-C 1-3烷基-氰基、-C 1-3烷基-C 1-6烷氧基、-C 1-3烷基-卤代C 1-6烷基或-C 1-3烷基-卤代C 1-6烷氧基；R 1、R 2、R 3、R 21、R 22、R 31、R 32、P'、R 0'、Ar'、E 1'、X 1定义同前。
在另一个方面，本发明提供一种式(IB-1d)或式(IB-2d)所示化合物，或其互变异构体、顺反异构体、内消旋体、外消旋体、对映异构体、非对映异构体、阻转异构体或其混合物形式，或其药学上可接受的盐，溶剂合物或前药：
Figure PCTCN2020124226-appb-000020
其中R 1、R 2、R 3、R 21、R 22、R 12、R 11、R 31、R 32、P'、R 0'、Ar'、E 1'、X 1定义同前。
在本发明的一种实施方案中，式(IB-1d)所示的化合物为式(IB-1da)化合物、式(IB-1db)化合物、式(IB-1dc)化合物或式(IB-1dd)化合物；
Figure PCTCN2020124226-appb-000021
其中式(IB-1da)、式(IB-1db)中，R 21'独立为卤素、-C 1-3烷基、-卤代C 1-3烷基、-C 1-3烷基-羟基、-C 1-3烷基-氰基、-C 1-3烷基-C 1-6烷氧基、-C 1-3烷基-卤代C 1-6烷基或-C 1-3烷基-卤代C 1-6烷氧基；R 1、R 2、R 3、R 12、R 11、R 31、R 32、P'、R 0'、Ar'、E 1'、X 1定义同前；
式(IB-1dc)、式(IB-1dd)中，R 12'独立为卤素、-C 1-3烷基、-卤代C 1-3烷基、-C 1-3烷基-羟基、-C 1-3烷基-氰基、-C 1-3烷基-C 1-6烷氧基、-C 1-3烷基-卤代C 1-6烷基或-C 1-3烷基-卤代C 1-6烷氧基；R 1、R 2、R 3、R 21、R 22、R 31、R 32、P'、R 0'、Ar'、E 1'、X 1定义同前。
在本发明的一种实施方案中，式IB-1b、式IB-1d、式IB-2b、式IB-2d中，P'独立为O。
在本发明的一种实施方案中，R 21'、R 12'各自独立为-C 1-3烷基、-C 1-3烷基-羟基、-C 1-3烷基-氰基或-C 1-3烷基-C 1-6烷氧基。
在本发明的一种实施方案中，R 21'、R 12'各自独立为-C 1-3烷基、-CH 2-羟基、-CH 2-氰基或-CH 2-C 1-3烷氧基。
在本发明的一种实施方案中，R 21'、R 12'各自独立为甲基、乙基、正丙基或异丙基。
在本发明的一种实施方案中，X 1为氢、卤素、-取代或未取代的C 1-6烷基、-取代或未取代的C 3-6环烷基、或-O-取代或未取代的C 1-6烷基；所述的“取代”是指基团中的1、2、3或4个氢原子被各自独立地选自S组取代基所取代。
在本发明的一种实施方案中，X 1为氢、卤素、未取代的C 1-3烷基、未取代的C 3-6环烷基或-O-未取代的C 1-3烷基。
在本发明的一种实施方案中，X 1为氢、氟、氯、甲基、乙基、正丙基、异丙基、环丙基、环丁基、环戊基、环己基、甲氧基、乙氧基、正丙氧基或异丙氧基。
在本发明的一种实施方案中，X 1为氟、氯或环丙基。
在本发明的一种实施方案中，Y 1为C；E 1'为N或CR 5'；E 2'为CR 6'；R 5'、R 6'各自定义同前。
在本发明的一种实施方案中，Y 1为C；E 1'为CR 5'；E 2'为N；R 5'定义同前。
在本发明的一种实施方案中，Y 1为C；E 1'为N或CR 5'；E 2'为CH；R 5'定义同前。
在本发明的一种实施方案中，Y 1为C；E 1'为N或CF；E 2'为CH。
在本发明的一种实施方案中，Ar'为苯基、5或6元单环杂芳基或吡啶酮基；且所述苯基、5或6元单环杂芳基和吡啶酮基为未取代的或被1、2、3或4个独立选自下述基团取代：卤素、氰基、羟基、-C 1-6烷基、-C 1-6烷氧基、-NR cR d、-C 1-4烷基-NR eR f；其中R e、R f各自独立地为氢或C 1-3烷基；R c、R d各自独立地为氢、-C 1-3烷基、-C(O)C 1-3烷基或-CO 2C 1-3烷基。
在本发明的一种实施方案中，Ar'为苯基或吡啶酮基；且所述苯基和吡啶酮基为未取代的或被1、2、3或4个独立选自下述基团取代：氟、氯、溴、氰基、羟基、-C 1-3烷基、-C 1-3烷氧基、-NH 2、-NHCH 3、-N(CH 3) 2、-CH 2-NH 2、-CH 2-NHCH 3、-CH 2-N(CH 3) 2。
在本发明的一种实施方案中，Ar'为苯基；所述苯基被1个选自R s1的基团取代；R s1为卤素、氰基、-C 1-6烷基、-C 1-6烷氧基、-卤代C 1-6烷基、-卤代C 1-6烷氧基或-C 3-6环烷基。
在本发明的一种实施方案中，Ar'选自如下结构：
Figure PCTCN2020124226-appb-000022
式中，R s1、R s2定义同前。
在本发明的一种实施方案中，Ar'选自如下结构：
Figure PCTCN2020124226-appb-000023
式中，R s1为羟基；R s2为卤素、氰基、-C 1-6烷基、-C 1-6烷氧基、-卤代C 1-6烷基、-卤代C 1-6烷氧基或-C 3-6环烷基。在本发明的一种实施方案中，所述R s1在所述苯环平面的上方。
在本发明的一种实施方案中，Ar'选自如下结构：
Figure PCTCN2020124226-appb-000024
式中，R s1为-C 1-6烷氧基；R s2为卤素、氰基、-C 1-6烷基、-C 1-6烷氧基、-卤代C 1-6烷基、-卤代C 1-6烷氧基或-C 3-6环烷基。在本发明的一种实施方案中，所述R s1在所述苯环平面的上方。
在本发明的一种实施方案中，R 0'为苯基、5或6元单环杂芳基或吡啶酮基，其中，所述5或6元单环杂芳基具有1、2或3个选自N、O和S的杂原子作为环原子；且所述的苯基、5或6元单环杂芳基和吡啶酮基为未取代的或被1、2、3或4个独立选自R s3的基团取代。
在本发明的一种实施方案中，R 0'为苯基、噻唑基、异噻唑基、咪唑基、噁唑基、异噁唑基、吡唑基、吡啶基、嘧啶基、吡嗪基或吡啶酮基，且所述的苯基、噻唑基、异噻唑基、咪唑基、噁唑基、异噁唑基、吡唑基、吡啶基、嘧啶基、吡嗪基和吡啶酮基为未 取代的或被1、2、3或4个独立选自R s3的基团取代。
在本发明的一种实施方案中，R 0'选自下列结构：
Figure PCTCN2020124226-appb-000025
在上述各结构中，R s3'相同或不同，各自独立选自氢、卤素、氰基、羟基、-C 1-6烷基、-C 1-6烷氧基、-卤代C 1-6烷基、-卤代C 1-6烷氧基、-C 3-6环烷基、-NR hR i、-C(O)NR eR f、-C 1-3烷基-羟基和-C 1-3烷基-NR eR f；且所述的-C 3-6环烷基任选地被1、2或3个独立选自卤素、甲基、乙基、丙基(正丙基)、异丙基、三氟甲基、氨基、N(CH 3) 2、羟基、羧基的取代基取代；其中R e、R f各自独立地为氢或C 1-3烷基；R h、R i各自独立地为氢、-C 1-3烷基、-C(O)C 1-3烷基或-CO 2C 1-3烷基；
在上述各结构中，R s3”相同或不同，各自独立选自氢、卤素、氰基、羟基、-C 1-6烷基、-C 1-6烷氧基、-卤代C 1-6烷基、-卤代C 1-6烷氧基、-C 3-6环烷基、-NR hR i、-C(O)NR eR f、-C 1-3烷基-羟基和-C 1-3烷基-NR eR f；且所述的-C 3-6环烷基任选地被1、2或3个独立选自卤素、甲基、乙基、丙基(正丙基)、异丙基、三氟甲基、氨基、N(CH 3) 2、羟基、羧基的取代基取代；其中R e、R f各自独立地为氢或C 1-3烷基；R h、R i各自独立地为氢、-C 1-3烷基、-C(O)C 1-3烷基或-CO 2C 1-3烷基；
在上述各结构中，R s3”'相同或不同，各自独立选自氢、-C 1-6烷基、-卤代C 1-6烷基、-C 3-6环烷基、-C 1-3烷基-C(O)NR eR f、-C(O)NR eR f、-C 1-4烷基-羟基和-C 1-4烷基-NR eR f；且所述的-C 3-6环烷基任选地被1、2或3个独立选自卤素、甲基、乙基、丙基(正丙基)、异丙基、三氟甲基、氨基、N(CH 3) 2、羟基、羧基的取代基取代；其中R e、R f各自独立地为氢或C 1-3烷基；
在上述各结构中，R s3相同或不同，各自独立选自卤素、氰基、羟基、-C 1-6烷基、-C 1-6烷氧基、-卤代C 1-6烷基、-卤代C 1-6烷氧基、-C 3-6环烷基、3至6元杂环烷基、-NR hR i、-C(O)NR eR f、-SO 2C 1-3烷基、-SO 2卤代C 1-3烷基、-SO 2NR eR f、-C 1-3烷基-羟基、-C 1-3烷基-C 2-4炔基、-C 1-3烷基-氰基、-C 1-3烷基-C 1-6烷氧基、-C 1-3烷基-卤代C 1-6烷基、-C 1-3烷基-卤代C 1-6烷氧基、-C 1-3烷基-3至6元杂环烷基、-C 1-3烷基-C 3-6环烷基、-C 1-3烷基 -NR eR f、-C 1-3烷基-C(O)NR eR f、-C 1-3烷基-SO 2C 1-3烷基或C 2-4炔基；其中，所述3至6元杂环烷基具有1、2或3个选自N、O和S的杂原子作为环原子；且所述的C 1-6烷基、-C 1-6烷氧基、-C 1-3烷基-、-C 3-6环烷基、3至6元杂环烷基任选地被1、2或3个独立选自卤素、甲基、乙基、丙基(正丙基)、异丙基、三氟甲基、氨基、N(CH 3) 2、羟基、羧基的取代基取代；其中R h、R i各自独立地为氢、-C 1-3烷基、-C(O)C 1-3烷基或-CO 2C 1-3烷基；R e、R f各自独立地为氢或C 1-3烷基；
上述各结构中，n相同或不同，各自独立为0、1、2或3。
在本发明的一种实施方案中，R 0'为
Figure PCTCN2020124226-appb-000026
R s3'为氢、卤素、氰基、羟基、-C 1-6烷基、-C 1-6烷氧基、-卤代C 1-6烷基、-卤代C 1-6烷氧基、-C 3-6环烷基、-NR hR i、-C(O)NR eR f、-C 1-3烷基-羟基和-C 1-3烷基-NR eR f；且所述的-C 3-6环烷基任选地被1、2或3个独立选自卤素、甲基、乙基、丙基(正丙基)、异丙基、三氟甲基、氨基、N(CH 3) 2、羟基、羧基的取代基取代；其中R e、R f各自独立地为氢或C 1-3烷基；R h、R i各自独立地为氢、-C 1-3烷基、-C(O)C 1-3烷基或-CO 2C 1-3烷基；R s3”为异丙基；n为0。在一实施方案中，所述R s3”在所述苯环平面的下方。
在本发明的一种实施方案中，R 0'选自下列结构：
Figure PCTCN2020124226-appb-000027
R s3'为氢、卤素、氰基、羟基、-C 1-6烷基、-C 1-6烷氧基、-卤代C 1-6烷基、-卤代C 1-6烷氧基、-C 3-6环烷基、-NR hR i、-C(O)NR eR f、-C 1-3烷基-羟基和-C 1-3烷基-NR eR f；且所述的-C 3-6环烷基任选地被1、2或3个独立选自卤素、甲基、乙基、丙基(正丙基)、异丙基、三氟甲基、氨基、N(CH 3) 2、羟基、羧基的取代基取代；其中R e、R f各自独立地为氢或C 1-3烷基；R h、R i各自独立地为氢、-C 1-3烷基、-C(O)C 1-3烷基或-CO 2C 1-3烷基；R s3”为异丙基；R s3为-C 1-6烷基；n为0或1。在一实施方案中，所述R s3”在所述吡啶环平面的下方。
在本发明的一种实施方案中，R 0'选自下列结构：
Figure PCTCN2020124226-appb-000028
R s3'为氢、卤素、氰基、羟基、-C 1-6烷基、-C 1-6烷氧基、-卤代C 1-6烷基、-卤代C 1-6烷氧基、-C 3-6环烷基、-NR hR i、-C(O)NR eR f、-C 1-3烷基-羟基和-C 1-3烷基-NR eR f；且所述的-C 3-6环烷基任选地被1、2或3个独立选自卤素、甲基、乙基、丙基(正丙基)、异丙基、三氟甲基、氨基、N(CH 3) 2、羟基、羧基的取代基取代；其中R e、R f各自独立地为氢或C 1-3烷基；R h、R i各自独立地为氢、-C 1-3烷基、-C(O)C 1-3烷基或-CO 2C 1-3烷基；R s3”为异丙基；n为0。在一实施方案中，所述R s3”在所述嘧啶环平面的下方。
在本发明的一种实施方案中，R 0'选自下列结构：
Figure PCTCN2020124226-appb-000029
R s3'为氢、卤素、氰基、羟基、-C 1-6烷基、-C 1-6烷氧基、-卤代C 1-6烷基、-卤代C 1-6烷氧基、-C 3-6环烷基、 -NR hR i、-C(O)NR eR f、-C 1-3烷基-羟基和-C 1-3烷基-NR eR f；且所述的-C 3-6环烷基任选地被1、2或3个独立选自卤素、甲基、乙基、丙基(正丙基)、异丙基、三氟甲基、氨基、N(CH 3) 2、羟基、羧基的取代基取代；其中R e、R f各自独立地为氢或C 1-3烷基；R h、R i各自独立地为氢、-C 1-3烷基、-C(O)C 1-3烷基或-CO 2C 1-3烷基；R s3”'为异丙基；n为0。在一实施方案中，所述R s3”'在所述吡唑环平面的下方。
在本发明的一种实施方案中，R 0'选自下列结构：
Figure PCTCN2020124226-appb-000030
R s3'为异丙基；n为0。在一实施方案中，所述R s3'在所述吡嗪环平面的下方。
在本发明的一种实施方案中，R 0'选自下列结构：
Figure PCTCN2020124226-appb-000031
R s3'为氢、卤素、氰基、羟基、-C 1-6烷基、-C 1-6烷氧基、-卤代C 1-6烷基、-卤代C 1-6烷氧基、-C 3-6环烷基、-NR hR i、-C(O)NR eR f、-C 1-3烷基-羟基和-C 1-3烷基-NR eR f；且所述的-C 3-6环烷基任选地被1、2或3个独立选自卤素、甲基、乙基、丙基(正丙基)、异丙基、三氟甲基、氨基、N(CH 3) 2、羟基、羧基的取代基取代；其中R e、R f各自独立地为氢或C 1-3烷基；R h、R i各自独立地为氢、-C 1-3烷基、-C(O)C 1-3烷基或-CO 2C 1-3烷基；R s3”为异丙基；R s3”'为-C 1-6烷基。在一实施方案中，所述R s3”在所述吡唑环平面的下方。
在本发明的一种实施方案中，R 0'选自如下结构：
Figure PCTCN2020124226-appb-000032
Figure PCTCN2020124226-appb-000033
Figure PCTCN2020124226-appb-000034
在另一个方面，本发明提供一种式(II)所示的化合物、或其药学上可接受的盐、立体异构体、溶剂合物或其前药，
Figure PCTCN2020124226-appb-000035
式中，
Z为N-C(O)-CR 3＝CR 1R 2或N-C(O)-C≡CR 4；
R 1、R 2各自独立地为氢、卤素、氰基、NR aR b、-C 1-3烷基、卤代C 1-3烷基、-C 1-3烷基-羟基、-C 1-3烷基-氰基、-C 1-3烷基-C 1-3烷氧基、-C 1-3烷基-NR aR b、-C 1-3烷基-3至6元杂环烷基或-C 1-3烷基-5或6元单环杂芳基；其中，所述3至6元杂环烷基或所述5或6元单环杂芳基具有1、2或3个选自N、O和S的杂原子作为环原子；
R 3为氢、卤素、-C 1-3烷基或-C 1-3烷氧基；
R 4为氢、卤代C 1-3烷基、-C 1-3烷基-羟基、-C 1-3烷基-氰基或-C 1-3烷基-C 1-3烷氧基；
R 11、R 12相同或不同，各自独立地为氢、卤素、-C 1-3烷基、-卤代C 1-3烷基、-C 1-3烷基-羟基、-C 1-3烷基-氰基、-C 1-3烷基-C 1-6烷氧基、-C 1-3烷基-卤代C 1-6烷基或-C 1-3烷基-卤代C 1-6烷氧基；
R 21、R 22相同或不同，各自独立地为氢、卤素、-C 1-3烷基、-卤代C 1-3烷基、-C 1-3烷基-羟基、-C 1-3烷基-氰基、-C 1-3烷基-C 1-6烷氧基、-C 1-3烷基-卤代C 1-6烷基或-C 1-3烷基-卤代C 1-6烷氧基；
R 31、R 32相同或不同，各自独立地为氢、卤素、-C 1-3烷基、-卤代C 1-3烷基、-C 1-3烷基-羟基、-C 1-3烷基-氰基、-C 1-3烷基-C 1-6烷氧基、-C 1-3烷基-卤代C 1-6烷基或-C 1-3烷基-卤代C 1-6烷氧基；
R 41为氢、卤素、-C 1-3烷基、-卤代C 1-3烷基、-C 1-3烷基-羟基、-C 1-3烷基-氰基、-C 1-3烷基-C 1-6烷氧基、-C 1-3烷基-卤代C 1-6烷基或-C 1-3烷基-卤代C 1-6烷氧基；
P为O、NH或NR m；R m为-C 1-6烷基、-卤代C 1-6烷基、-C 1-6烷基-羟基、-C 1-6烷基-氰基、-C 1-6烷基-C 1-6烷氧基、-C 1-6烷基-卤代C 1-6烷氧基、-C 1-6烷基-C 3-6环烷基或-C 1-6烷基-3元至6元杂环烷基；
R 42为-(C＝O)-、-C 1-3烷基、-C 1-3烷基(羟基)-、-C 1-3烷基(氰基)-、-C 1-3烷基(C 1-6烷基)、-C 1-3烷基(卤代C 1-6烷基)-、-C 1-3烷基(C 1-6烷基-羟基)-、-C 1-3烷基(C 1-6烷基-氰基)-、-C 1-3烷基(C 1-6烷氧基)-、或-C 1-3烷基(卤代C 1-6烷氧基)-；
X 2、Y 2相同或不同，各自独立地为氢、卤素、-C 1-3烷基、-卤代C 1-3烷基、-C 1-3烷基-羟基、-C 1-3烷基-氰基、-C 1-3烷基-C 1-6烷氧基、-C 1-3烷基-卤代C 1-6烷基或-C 1-3烷基-卤代C 1-6烷氧基；
或X 2、Y 2与其相邻的碳原子共同形成取代或未取代的C 3-6环烷基或取代或未取代的3至6元杂环烷基；所述3至6元杂环烷基具有1、2或3个选自N、O和S的杂原子作为环原子；所述的“取代”是指基团中的1、2、3或4个氢原子被各自独立地选自S组取代基所取代；
E 3为N或C-L-R 5；其中，
L为一个键、-CR L1R L2-、-O-(CR L1R L2) t1-或-NH-(CR L3R L4) t2-；其中，R L1、R L2、R L3、R L4相同或不同，各自独立地为氢、卤素、羟基、羟甲基、羟乙基、-C 1-3烷基或氧代基；t1、t2各自独立地为0、1、2、3或4；R L1与R L2中或者R L3与R L4中，当其中一个为氧代基时，另一个则不存在；
R 5为氢、卤素、羟基、-取代或未取代的C 1-6烷基、-取代或未取代的C 3-6环烷基、-取代或未取代的3至6元杂环烷基、-O-取代或未取代的C 1-6烷基、-O-取代或未取代的C 3-6环烷基、-O-取代或未取代的3至6元杂环烷基、-SO 2-取代或未取代的C 1-6烷基、-SO 2-取代或未取代的C 3-6环烷基、-SO 2-取代或未取代的3至6元杂环烷基、-取代或未取代的5或6元单环杂芳基或NR 51R 52；其中，R 51、R 52各自独立地为氢、取代或未取代的C 1-6烷基、-SO 2C 1-6烷基、-SO 2C 3-6环烷基、-C(O)C 1-6烷基或-C(O)卤代C 1-6烷基；或者R 51和R 52与相连的氮原子共同形成取代或未取代的3至6元含氮杂环烷基；其中，所述3至6元杂环烷基、5或6元单环杂芳基各自独立地具有1、2或3个选自N、O和S的杂原子作为环原子；所述3至6元含氮杂环烷基具有3至6个环原子且其中一个环原子为氮原子、其余环原子中的0个、1个或2个环原子任选地为选自N、O和S的杂原子；所述的“取代”是指基团中的1、2、3或4个氢原子被各自独立地选自S组取代基所取代；
所述S组取代基选自：羟基、卤素、硝基、氧代基、-C 1-6烷基、-卤代C 1-6烷基、羟基取代的C 1-6烷基、苄基、-(CH 2) u-氰基、-(CH 2) u-C 1-6烷氧基、-(CH 2) u-卤代C 1-6烷氧 基、-(CH 2) u-卤代C 1-6烷基、-(CH 2) u-3至6元杂环烷基、-(CH 2) u-5或6元单环杂芳基、-(CH 2) u-C 3-8环烷基、-(CH 2) u-O-(CH 2) v-C 3-8环烷基、-(CH 2) u-O-(CH 2) v-C 1-6烷氧基、-(CH 2) u-O-(CH 2) vOH、-(CH 2) u-SO 2C 1-6烷基、-(CH 2) u-NR a0R b0、-(CH 2) u-C(O)NR a0R b0、-(CH 2) u-C(O)C 1-6烷基、-C(O)OC 1-6烷基、NR a0C(O)-(CH 2) u-NR a0R b0、NR a0C(O)-(CH 2) uOH、NR a0C(O)-卤代C 1-6烷基；其中，所述3至6元杂环烷基或所述5或6元单环杂芳基各自独立地具有1、2或3个选自N、O和S的杂原子作为环原子；所述3至6元杂环烷基、5或6元单环杂芳基任选地被1、2或3个选自卤素、氰基、-C 1-3烷基、-C 1-3烷氧基和C 3-6环烷基的取代基取代；u、v各自独立地为0、1、2、3或4；R a0、R b0各自独立地为氢或C 1-3烷基；
E 4为N或CH；
Ar为C 6-10芳基、5或6元单环杂芳基或8至10元双环杂芳基；其中，所述5或6元单环杂芳基具有1、2或3个选自N、O和S的杂原子作为环原子；所述8至10元双环杂芳基具有1、2、3、4或5个选自N、O和S的杂原子作为环原子；且所述C 6-10芳基、所述5或6元单环杂芳基或所述8至10元双环杂芳基为未取代的或被1、2、3或4个独立选自R s1的基团取代；
或者
Ar为式(B)所示结构：
Figure PCTCN2020124226-appb-000036
其中，B1环为苯环或5或6元单环杂芳基环；B2环为一个稠合的5或6元单环杂环烷基环或稠合的5或6元单环环烷基环；其中，所述5或6元单环杂芳基环或所述稠合的5或6元单环杂环烷基环具有1、2或3个选自N、O和S的杂原子作为环原子；
(R s1) p表示B1环上的氢被p个R s1取代，p为0、1、2或3，每个R s1相同或不同；
(R s2) q表示B2环上的氢被q个R s2取代，q为0、1、2或3，每个R s2相同或不同；
R s1、R s2各自独立地为卤素、氰基、硝基、羟基、-C 1-6烷基、-C 1-6烷氧基、-卤代C 1-6烷基、-卤代C 1-6烷氧基、-C 3-6环烷基、-NR cR d、-C(O)NR eR f、-SO 2C 1-3烷基、-SO 2卤代C 1-3烷基、-SO 2NR eR f、-C 1-4烷基-羟基、-C 1-4烷基-氰基、-C 1-4烷基-C 1-6烷氧基、-C 1-4烷基-卤代C 1-6烷基、-C 1-4烷基-卤代C 1-6烷氧基、-C 1-4烷基-3至6元杂环烷基、-C 1-4烷基-NR eR f、-C 1-4烷基-C(O)NR eR f、-C 1-4烷基-SO 2C 1-3烷基或C 2-4炔基；其中，所述3至6元杂环烷基具有1、2或3个选自N、O和S的杂原子作为环原子；
R a、R b、R e、R f各自独立地为氢或C 1-3烷基；
R c、R d各自独立地为氢、-C 1-3烷基、-C(O)C 1-3烷基、-CO 2C 1-3烷基。
在本发明的一种实施方案中，R s1、R s2各自独立地为卤素、氰基、硝基、羟基、-C 1-3烷基、-C 1-3烷氧基、卤代C 1-3烷基、卤代C 1-3烷氧基、-C 3-6环烷基、-NR cR d、-C(O)NR eR f、-SO 2C 1-3烷基、-SO 2卤代C 1-3烷基、-SO 2NR eR f、-C 1-2烷基-羟基、-C 1-2烷基-氰基、-C 1-2烷基-C 1-3烷氧基、-C 1-2烷基-卤代C 1-3烷基、-C 1-2烷基-卤代C 1-3烷氧基、-C 1-2烷基-3至 6元杂环烷基、-C 1-2烷基-NR eR f、-C 1-2烷基-C(O)NR eR f、-C 1-2烷基-SO 2C 1-3烷基或C 2-4炔基；其中，R c、R d各自独立地为氢、-C 1-3烷基、-C(O)C 1-3烷基、-CO 2C 1-3烷基；R e、R f各自独立地为氢或C 1-3烷基。
在本发明的一种实施方案中，R s1、R s2各自独立地为卤素、氰基、硝基、羟基、-C 1-3烷基、-C 1-3烷氧基、卤代C 1-3烷基、卤代C 1-3烷氧基、-C 3-6环烷基、-NR cR d、-C(O)NR eR f、-SO 2C 1-3烷基、-SO 2卤代C 1-3烷基、-SO 2NR eR f、-CH 2-羟基、-CH 2-氰基、-CH 2-C 1-3烷氧基、-CH 2-卤代C 1-3烷基、-CH 2-卤代C 1-3烷氧基、-CH 2-3至6元杂环烷基、-CH 2-NR eR f、-CH 2-C(O)NR eR f、-CH 2-SO 2C 1-3烷基或C 2-4炔基；其中，R c为氢、-C 1-3烷基、-C(O)CH 3或-CO 2CH 3；R e、R f、R d各自独立地为氢或C 1-3烷基。
在本发明的一种实施方案中，R s1、R s2各自独立地为卤素、氰基、硝基、羟基、-C 1-3烷基、-C 1-3烷氧基、卤代C 1-3烷基、卤代C 1-3烷氧基、-C 3-6环烷基、-NR cR d、-C(O)NR eR f、-CH 2-羟基、-CH 2-氰基；其中，R c为氢、-C(O)CH 3或-CO 2CH 3；R e、R f、R d各自独立地为氢或C 1-3烷基。
在本发明的一种实施方案中，R s1和R s2中，所述的C 3-6环烷基选自：环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环丁酮、环丁烷-1,2-二酮、环戊酮、环戊烷-1,3-二酮、环己酮、环己烷-1,3-二酮。
在本发明的一种实施方案中，R s1和R s2中，所述的3至6元杂环烷基选自：氮丙环、环氧乙烷、氮杂环丁烷、氧杂环丁烷、噁唑烷、1,3-二氧戊环、咪唑烷、四氢呋喃、四氢噻吩、四氢吡咯、哌啶、哌嗪、吗啉、硫代吗啉、硫代吗啉-1,1-二氧化物、四氢吡喃、1,3-噁嗪烷、六氢嘧啶、1,4-二噁烷。
在本发明的一种实施方案中，R s1、R s2各自独立地为卤素、氰基、硝基、羟基、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、丙氧基(正丙氧基)、异丙氧基、一氯甲基、二氯甲基、三氯甲基、一氯乙基、1,2-二氯乙基、三氯乙基、一溴乙基、一氟甲基、二氟甲基、三氟甲基、一氟乙基、二氟乙基、三氟乙基、三氟甲氧基、三氟乙氧基、一氟甲氧基、一氟乙氧基、二氟甲氧基、二氟乙氧基、环丙基、环丁基、环戊基、环己基、-NR cR d、-C(O)NR eR f、-CH 2-羟基、-CH 2-氰基；其中，R c为氢、-C(O)CH 3或-CO 2CH 3；R e、R f、R d各自独立地为氢、甲基或乙基。
在本发明的一种实施方案中，R s3、R s4各自独立地为卤素、氰基、羟基、-C 1-6烷基、-C 1-3烷氧基、卤代C 1-3烷基、卤代C 1-3烷氧基、-C 3-6环烷基、3至6元杂环烷基、氨基、NHCH 3、N(CH 3) 2、-C(O)NR eR f、-SO 2C 1-3烷基、-SO 2卤代C 1-3烷基、-SO 2NR eR f、-C 1-2烷基-羟基、-C 1-2烷基-乙炔基、-C 1-2烷基-氰基、-C 1-2烷基-C 1-3烷氧基、-C 1-2烷基-卤代C 1-3烷基、-C 1-2烷基-卤代C 1-3烷氧基、-C 1-2烷基-3至6元杂环烷基、-C 1-2烷基-C 3-6环烷基、-C 1-2烷基-NR eR f、-C 1-2烷基-C(O)NR eR f、-C 1-2烷基-SO 2C 1-3烷基或乙炔基；其中，所述的C 1-6烷基、-C 1-3烷氧基、-C 1-2烷基-、-C 3-6环烷基、3至6元杂环烷基任选地被1、2或3个独立选自卤素、甲基、乙基、丙基(正丙基)、异丙基、三氟甲基、氨基、N(CH 3) 2、羟基、羧基的取代基取代；R e、R f各自独立地为氢或C 1-3烷基。
在本发明的一种实施方案中，R s3、R s4各自独立地为卤素、氰基、羟基、C 1-4烷基、-C 1-3烷氧基、卤代C 1-3烷基、卤代C 1-3烷氧基、-C 3-6环烷基、3至6元杂环烷基、氨基、NHCH 3、N(CH 3) 2、-C(O)NR eR f、-SO 2C 1-3烷基、-SO 2卤代C 1-3烷基、-SO 2NR eR f、-CH 2- 羟基、-CH 2-乙炔基、-CH 2-氰基、-CH 2-C 1-3烷氧基、-CH 2-卤代C 1-3烷基、-CH 2-卤代C 1-3烷氧基、-CH 2-3至6元杂环烷基、-CH 2-C 3-6环烷基、-CH 2-NR eR f、-CH 2-C(O)NR eR f、-CH 2-SO 2C 1-3烷基或乙炔基；其中，所述的C 1-4烷基、-C 1-3烷氧基、-CH 2-、-C 3-6环烷基、3至6元杂环烷基任选地被1、2或3个独立选自卤素、甲基、乙基、丙基(正丙基)、异丙基、三氟甲基、氨基、N(CH 3) 2、羟基、羧基的取代基取代；R e、R f各自独立地为氢或C 1-3烷基。
在本发明的一种实施方案中，R s3、R s4各自独立地为卤素、氰基、羟基、C 1-4烷基、-C 1-3烷氧基、卤代C 1-3烷基、-C 3-6环烷基、3至6元杂环烷基、氨基、NHCH 3、N(CH 3) 2、-CH 2-羟基、-CH 2-乙炔基；其中，所述的C 1-4烷基、-C 1-3烷氧基、-CH 2-、-C 3-6环烷基、3至6元杂环烷基任选地被1、2或3个独立选自卤素、甲基、乙基、丙基(正丙基)、异丙基、三氟甲基、氨基、N(CH 3) 2、羟基、羧基的取代基取代。
在本发明的一种实施方案中，R s3和R s4中，所述C 3-6环烷基选自：环丙基、环丁基、环戊基、环己基。
在本发明的一种实施方案中，R s3和R s4中，所述3至6元杂环烷基选自：氮丙环、环氧乙烷、氮杂环丁烷、氧杂环丁烷、四氢呋喃、四氢噻吩、四氢吡咯、哌啶、哌嗪、吗啉、硫代吗啉、硫代吗啉-1,1-二氧化物、四氢吡喃。
在本发明的一种实施方案中，R s3、R s4各自独立地为卤素、氰基、羟基、甲基、乙基、正丙基、异丙基、仲丁基、甲氧基、乙氧基、丙氧基(正丙氧基)、异丙氧基、一氯甲基、二氯甲基、三氯甲基、一氯乙基、1,2-二氯乙基、三氯乙基、一溴乙基、一氟甲基、二氟甲基、三氟甲基、一氟乙基、二氟乙基、三氟乙基、环丙基、环丁基、环戊基、环己基、氮丙环、环氧乙烷、氮杂环丁烷、氧杂环丁烷、四氢呋喃、四氢噻吩、四氢吡咯、哌啶、哌嗪、吗啉、硫代吗啉、硫代吗啉-1,1-二氧化物、四氢吡喃、氨基、NHCH 3、N(CH 3) 2、-CH 2-羟基、-CH 2-乙炔基；其中所述的甲基、乙基、正丙基、甲氧基、乙氧基、丙氧基(正丙氧基)、-CH 2-、氮杂环丁烷、氧杂环丁烷、四氢呋喃、四氢噻吩、四氢吡咯、哌啶、哌嗪、吗啉、硫代吗啉、硫代吗啉-1,1-二氧化物、四氢吡喃任选地被1、2或3个独立选自卤素、甲基、乙基、丙基(正丙基)、异丙基、三氟甲基、氨基、N(CH 3) 2、羟基、羧基的取代基取代。
在本发明的一种实施方案中，所述S组取代基选自：羟基、卤素、硝基、氧代基、-C 1-3烷基、羟基取代的C 1-3烷基、苄基、-(CH 2) u-氰基、-(CH 2) u-C 1-3烷氧基、-(CH 2) u-卤代C 1-3烷氧基、-(CH 2) u-卤代C 1-3烷基、-(CH 2) u-3至6元杂环烷基、-(CH 2) u-5或6元单环杂芳基、-(CH 2) u-C 3-6环烷基、-(CH 2) u-O-(CH 2) v-C 3-6环烷基、-(CH 2) u-O-(CH 2) v-C 1-3烷氧基、-(CH 2) u-O-(CH 2) vOH、-(CH 2) u-SO 2C 1-3烷基、-(CH 2) u-NR a0R b0、-(CH 2) u-C(O)NR a0R b0、-(CH 2) u-C(O)C 1-3烷基、-C(O)OC 1-3烷基、NR a0C(O)-(CH 2) u-NR a0R b0、NR a0C(O)-(CH 2) uOH、NR a0C(O)-卤代C 1-3烷基；其中，所述3至6元杂环烷基、5或6元单环杂芳基各自独立地具有1、2或3个选自N、O和S的杂原子作为环原子；所述3至6元杂环烷基、5或6元单环杂芳基任选地被1、2或3个选自卤素、氰基、-C 1-3烷基、-C 1-3烷氧基和C 3-6环烷基的取代基取代；u、v各自独立地为0、1、2、3或4；R a0、R b0各自独立地为氢或C 1-3烷基。
在本发明的一种实施方案中，所述S组取代基为卤素。
在本发明的一种实施方案中，所述S组取代基选自：C 1-3烷基、-(CH 2) u-3至6元杂环烷基、-(CH 2) u-SO 2C 1-3烷基、-(CH 2) u-NR a0R b0；其中，所述3至6元杂环烷基具有1、2或3个选自N、O和S的杂原子作为环原子；所述3至6元杂环烷基任选地被1、2或3个选自卤素、氰基、-C 1-3烷基、-C 1-3烷氧基和C 3-6环烷基的取代基取代；u为0、1、2、3或4；R a0、R b0各自独立地为氢或C 1-3烷基。
在本发明的一种实施方案中，上述基团(例如Ar、R 0)中，所述C 6-10芳基各自独立地为苯基或萘基。
在本发明的一种实施方案中，上述基团(例如Ar)中，所述C 6-10芳基为苯基时，选自如下结构：
Figure PCTCN2020124226-appb-000037
式中，R s1、R s2定义同前。
在本发明的一种实施方案中，上述基团(例如Ar、R 0)中，所述5或6元单环杂芳基各自独立地选自：噻吩、N-烷环吡咯、呋喃、噻唑、异噻唑、咪唑、噁唑、吡咯、吡唑、三唑、1,2,3-三唑、1,2,4-三唑、1,2,5-三唑、1,3,4-三唑、四唑、异噁唑、噁二唑、1,2,3-噁二唑、1,2,4-噁二唑、1,2,5-噁二唑、1,3,4-噁二唑、噻二唑、吡啶、哒嗪、嘧啶、吡嗪。
在本发明的一种实施方案中，上述基团(例如Ar、R 0)中，所述5或6元单环杂芳基各自独立地选自如下结构：
Figure PCTCN2020124226-appb-000038
在本发明的一种实施方案中，上述基团(例如Ar、R 0)中，所述8至10元双环杂芳基各自独立地为苯环与5或6元单环杂芳基环稠合形成的9至10元双环杂芳基，或5或6元单环杂芳基环与5或6元单环杂芳基环稠合形成的8至10元双环杂芳基。
在本发明的一种实施方案中，形成9至10元双环杂芳基或8至10元双环杂芳基的5或6元单环杂芳基环选自：噻吩环、N-烷环吡咯环、呋喃环、噻唑环、异噻唑环、咪唑环、噁唑环、吡咯环、吡唑环、三唑环、1,2,3-三唑环、1,2,4-三唑环、1,2,5-三唑环、1,3,4-三唑环、四唑环、异噁唑环、噁二唑环、1,2,3-噁二唑环、1,2,4-噁二唑环、1,2,5-噁二唑环、1,3,4-噁二唑环、噻二唑环、吡啶环、哒嗪环、嘧啶环或吡嗪环。
在本发明的一种实施方案中，形成9至10元双环杂芳基或8至10元双环杂芳基的5或6元单环杂芳基环选自如下结构：
Figure PCTCN2020124226-appb-000039
Figure PCTCN2020124226-appb-000040
Figure PCTCN2020124226-appb-000041
其中
Figure PCTCN2020124226-appb-000042
代表的所连接的两个环原子为与其他环稠合时共享的毗邻原子对。
在本发明的一种实施方案中，B1环、A1环中，所述5或6元单环杂芳基环各自独立地选自：噻吩环、N-烷环吡咯环、呋喃环、噻唑环、异噻唑环、咪唑环、噁唑环、吡咯环、吡唑环、三唑环、1,2,3-三唑环、1,2,4-三唑环、1,2,5-三唑环、1,3,4-三唑环、四唑环、异噁唑环、噁二唑环、1,2,3-噁二唑环、1,2,4-噁二唑环、1,2,5-噁二唑环、1,3,4-噁二唑环、噻二唑环、吡啶环、哒嗪环、嘧啶环或吡嗪环。
在本发明的一种实施方案中，B1环、A1环中，所述5或6元单环杂芳基环各自独立地选自如下结构：
Figure PCTCN2020124226-appb-000043
Figure PCTCN2020124226-appb-000044
其中
Figure PCTCN2020124226-appb-000045
代表的所连接的两个环原子为与其他环稠合时共享的毗邻原子对。
在本发明的一种实施方案中，B2环、A2环中，所述稠合的5或6元单环环烷基环各自独立地选自：环戊基环、环戊烯基环、环己基环、环己烯基环、环己二烯基环、环戊酮、环戊烷-1,3-二酮、环己酮、环己烷-1,3-二酮。
在本发明的一种实施方案中，B2环、A2环中，所述稠合的5或6元单环杂环烷基环各自独立地选自：噁唑烷、吡咯烷-2-酮、吡咯烷-2,5-二酮、1,3-二氧戊环、二氢呋喃-2(3H)-酮、二氢呋喃-2,5-二酮、哌啶-2-酮、哌啶-2,6-二酮、四氢-2H-吡喃-2-酮、咪唑烷、四氢呋喃、四氢噻吩、四氢吡咯、1,3-二氧戊环-2-酮、噁唑烷-2-酮、咪唑烷-2-酮、哌啶、哌嗪、哌嗪-2-酮、吗啉、吗啉-3-酮、吗啉-2-酮、硫代吗啉-3-酮1,1-二氧化物、硫代吗啉、硫代吗啉-1,1-二氧化物、四氢吡喃、1,2-二氢氮杂环丁二烯、1,2-二氢氧杂环丁二烯、2,5-二氢-1H-吡咯、2,5-二氢呋喃、2,3-二氢呋喃、2,3-二氢-1H-吡咯、3,4-二氢-2H-吡喃、 1,2,3,4-四氢吡啶、3,6-二氢-2H-吡喃、1,2,3,6-四氢吡啶、1,3-噁嗪烷、六氢嘧啶、1,4-二噁烷、四氢嘧啶-2(1H)-酮、1,4-二噁烷-2-酮、5,6-二氢-2H-吡喃-2-酮、5,6-二氢嘧啶-4(3H)-酮、3,4-二氢吡啶-2(1H)-酮、5,6-二氢吡啶-2(1H)-酮、5,6-二氢嘧啶-4(1H)-酮、嘧啶-4(3H)-酮、嘧啶-4(1H)-酮、4,5-二氢-1H-咪唑、2,3-二氢-1H-咪唑、2,3-二氢噁唑、1,3-二氧杂环戊烯、2,3-二氢噻吩、2,5-二氢噻吩、3,4-二氢-2H-1,4-噁嗪、3,4-二氢-2H-1,4-噻嗪1,1-二氧化物、1,2,3,4-四氢吡嗪、1,3-二氢-2H-吡咯-2-酮、1,5-二氢-2H-吡咯-2-酮、1H-吡咯-2,5-二酮、呋喃-2(3H)-酮、呋喃-2(5H)-酮、1,3-二氧杂环戊烯-2-酮、噁唑-2(3H)-酮、1,3-二氢-2H-咪唑-2-酮、呋喃-2,5-二酮、3,6-二氢吡啶-2(1H)-酮、吡啶-2,6-(1H，3H)-二酮、5,6-二氢-2H-吡喃-2-酮、3,6-二氢-2H-吡喃-2-酮、3,4-二氢-2H-1,3-噁嗪、3,6-二氢-2H-1,3-噁嗪、1,2,3,4-四氢嘧啶。
在本发明的一种实施方案中，所述稠合的5或6元单环杂环烷基环选自如下结构：
Figure PCTCN2020124226-appb-000046
在本发明的一种实施方案中，上述基团(例如Ar、R 0)中，所述8至10元双环杂芳基各自独立地选自：苯并噁唑、苯并异噁唑、苯并咪唑、苯并噻唑、苯并异噻唑、苯并三唑、苯并呋喃、苯并噻吩、吲哚、吲唑、异吲哚、喹啉、异喹啉、喹唑啉、喹喔啉、噌啉、吡啶并嘧啶、萘啶。
在本发明的一种实施方案中，上述基团(例如Ar、R 0)中，所述8至10元双环杂芳基各自独立地选自：苯并[d]异噁唑、1H-吲哚、异吲哚、1H-苯并[d]咪唑、苯并[d]异噻唑、1H-苯并[d][1,2,3]三唑、苯并[d]噁唑、苯并[d]噻唑、吲唑、苯并呋喃、苯并[b]噻吩、喹啉、异喹啉、喹唑啉、喹喔啉、噌啉、吡啶并[3,2-d]嘧啶、吡啶并[2,3-d]嘧啶、吡啶并[3,4-d]嘧啶、吡啶并[4,3-d]嘧啶、1,8-萘啶、1,7-萘啶、1,6-萘啶、1,5-萘啶。
在本发明的一种实施方案中，上述基团(例如Ar、R 0)中，所述8至10元双环杂芳基各自独立地选自如下结构：
Figure PCTCN2020124226-appb-000047
Figure PCTCN2020124226-appb-000048
在本发明的一种实施方案中，上述基团(例如Ar、R 0)中，所述8至10元双环杂芳基各自独立地选自如下结构：
Figure PCTCN2020124226-appb-000049
在本发明的一种实施方案中，上述基团(例如Ar、R 0)中，所述8至10元双环杂芳基各自独立地选自如下结构：
Figure PCTCN2020124226-appb-000050
在本发明的一种实施方案中，
Figure PCTCN2020124226-appb-000051
各自独立地选自如下结构：
Figure PCTCN2020124226-appb-000052
在本发明的一种实施方案中，式(B)、式(A-1)各自独立地选自如下结构：
Figure PCTCN2020124226-appb-000053
在本发明的一种实施方案中，Ar、Ar'独立选自如下结构：
Figure PCTCN2020124226-appb-000054
Figure PCTCN2020124226-appb-000055
Figure PCTCN2020124226-appb-000056
在本发明的一种实施方案中，上述基团(例如R 0)中，所述的C 3-6环烷基选自：环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环丁酮、环丁烷-1,2-二酮、环戊酮、环戊烷-1,3-二酮、环己酮、环己烷-1,3-二酮。
在本发明的一种实施方案中，上述基团(例如R 0)中，所述的3至6元杂环烷基选自：氮丙环、环氧乙烷、氮杂环丁烷、氧杂环丁烷、噁唑烷、1,3-二氧戊环、咪唑烷、四氢呋喃、四氢噻吩、四氢吡咯、哌啶、哌嗪、吗啉、硫代吗啉、硫代吗啉-1,1-二氧化物、四氢吡喃、1,3-噁嗪烷、六氢嘧啶、1,4-二噁烷。
在本发明的一种实施方案中，上述基团(例如R 0)中，所述的7至11元螺环烷基为由选自环丙基环、环丁基环、环戊基环和环己基环中的任意两个单环环烷基环形成的含一个螺原子单螺环烷基。
在本发明的一种实施方案中，R 0为-C 1-6烷基、-C 3-6环烷基、3至6元杂环烷基、苯基、5或6元单环杂芳基、8至10元双环杂芳基、7至11元螺环烷基、-CH 2-苯基、-CH(C 1-2烷基)-苯基、-CH 2-5或6元单环杂芳基、-CH(C 1-2烷基)-5或6元单环杂芳基、-NH-苯基、-N(C 1-3烷基)-苯基、-O-苯基、-CH 2-3至6元杂环烷基、-CH 2-C 3-6环烷基、-CH(C 1-2烷基)-C 3-6环烷基，其中，所述的C 1-6烷基、C 3-6环烷基、3至6元杂环烷基、苯基、5或6元单环杂芳基、8至10元双环杂芳基、7至11元螺环烷基为未取代的或被1、2、3或 4个独立选自R s3的基团取代。
在本发明的一种实施方案中，R 0为苯基、环丙基、5或6元单环杂芳基、-CH 2-5或6元单环杂芳基、-CH 2-苯基、-CH(C 1-2烷基)-苯基、-NH-苯基、-N(C 1-3烷基)-苯基、-O-苯基；其中，所述5或6元单环杂芳基选自：噻吩、N-烷环吡咯、呋喃、噻唑、异噻唑、咪唑、噁唑、吡咯、吡唑、三唑、1,2,3-三唑、1,2,4-三唑、1,2,5-三唑、1,3,4-三唑、四唑、异噁唑、噁二唑、1,2,3-噁二唑、1,2,4-噁二唑、1,2,5-噁二唑、1,3,4-噁二唑、噻二唑、吡啶、哒嗪、嘧啶、吡嗪；其中，所述苯基、5或6元单环杂芳基为未取代的或被1、2、3或4个独立选自R s3的基团取代。
在本发明的一种实施方案中，R 0选自如下结构：
Figure PCTCN2020124226-appb-000057
Figure PCTCN2020124226-appb-000058
在本发明的一种实施方案中，R 11、R 12相同或不同，各自独立地为氢、卤素、-C 1-3烷基、-CH 2-羟基、-CH 2-氰基、-CH 2-C 1-3烷氧基、-CH 2-卤代C 1-3烷基或-CH 2-卤代C 1-3烷氧基。
在本发明的一种实施方案中，R 11、R 12相同或不同，各自独立地为氢、卤素、甲基、乙基、正丙基、异丙基、-CH 2-羟基、-CH 2-氰基、-CH 2-甲氧基、-CH 2-乙氧基、-CH 2-丙氧基(正丙氧基)、-CH 2-异丙氧基、-CH 2-三氟甲基、-CH 2-二氟甲基、-CH 2-二氟乙基、-CH 2-三氟甲氧基、-CH 2-二氟甲氧基。
在本发明的一种实施方案中，R 11、R 12相同或不同，各自独立地为氢或-C 1-3烷基。
在本发明的一种实施方案中，R 11、R 12相同或不同，各自独立地为氢或甲基。
在本发明的一种实施方案中，R 21、R 22相同或不同，各自独立地为氢、卤素、-C 1-3烷基、-CH 2-羟基、-CH 2-氰基、-CH 2-C 1-3烷氧基、-CH 2-卤代C 1-3烷基或-CH 2-卤代C 1-3烷氧基。
在本发明的一种实施方案中，R 21、R 22相同或不同，各自独立地为氢、卤素、甲基、乙基、正丙基、异丙基、-CH 2-羟基、-CH 2-氰基、-CH 2-甲氧基、-CH 2-乙氧基、-CH 2-丙氧基(正丙氧基)、-CH 2-异丙氧基、-CH 2-三氟甲基、-CH 2-二氟甲基、-CH 2-二氟乙基、-CH 2-三氟甲氧基、-CH 2-二氟甲氧基。
在本发明的一种实施方案中，R 21、R 22相同或不同，各自独立地为氢或-C 1-3烷基。
在本发明的一种实施方案中，R 21、R 22相同或不同，各自独立地为氢或甲基。
在本发明的一种实施方案中，R 31、R 32相同或不同，各自独立地为氢、卤素、-C 1-3烷基、-CH 2-羟基、-CH 2-氰基、-CH 2-C 1-3烷氧基、-CH 2-卤代C 1-3烷基或-CH 2-卤代C 1-3烷氧基。
在本发明的一种实施方案中，R 31、R 32相同或不同，各自独立地为氢、卤素、甲基、 乙基、正丙基、异丙基、-CH 2-羟基、-CH 2-氰基、-CH 2-甲氧基、-CH 2-乙氧基、-CH 2-丙氧基(正丙氧基)、-CH 2-异丙氧基、-CH 2-三氟甲基、-CH 2-二氟甲基、-CH 2-二氟乙基、-CH 2-三氟甲氧基、-CH 2-二氟甲氧基。
在本发明的一种实施方案中，R 31、R 32相同或不同，各自独立地为氢或-C 1-3烷基。
在本发明的一种实施方案中，R 31、R 32相同或不同，各自独立地为氢或甲基。
在本发明的一种实施方案中，R 41为氢、卤素、-C 1-3烷基、-CH 2-羟基、-CH 2-氰基、-CH 2-C 1-3烷氧基、-CH 2-卤代C 1-3烷基或-CH 2-卤代C 1-3烷氧基。
在本发明的一种实施方案中，R 41为氢、卤素、甲基、乙基、正丙基、异丙基、-CH 2-羟基、-CH 2-氰基、-CH 2-甲氧基、-CH 2-乙氧基、-CH 2-丙氧基(正丙氧基)、-CH 2-异丙氧基、-CH 2-三氟甲基、-CH 2-二氟甲基、-CH 2-二氟乙基、-CH 2-三氟甲氧基、-CH 2-二氟甲氧基。
在本发明的一种实施方案中，R 41为氢。
在本发明的一种实施方案中，式I中，当
Figure PCTCN2020124226-appb-000059
中的虚线为单键时，P为O；R 42为-C 1-3烷基-、-C 1-3烷基(羟基)-、-C 1-3烷基(氰基)-、-C 1-3烷基(C 1-3烷基)、-C 1-3烷基(卤代C 1-3烷基)-、-C 1-3烷基(C 1-3烷基-羟基)-、-C 1-3烷基(C 1-3烷基-氰基)-、-C 1-3烷基(C 1-3烷氧基)-、或-C 1-3烷基(卤代C 1-3烷氧基)-；其中，C 1-3烷基为甲基、乙基或丙基(正丙基或异丙基)；C 1-3烷氧基为甲氧基、乙氧基或丙氧基(正丙氧基或异丙氧基)。
在本发明的一种实施方案中，式I中，当
Figure PCTCN2020124226-appb-000060
中的虚线为单键时，P为NH或NR m；R m为-C 1-3烷基、-卤代C 1-3烷基、-C 1-3烷基-羟基、-C 1-3烷基-氰基、-C 1-3烷基-C 1-3烷氧基、-C 1-3烷基-卤代C 1-3烷氧基；R 42为-(C＝O)-、-C 1-3烷基-、-C 1-3烷基(羟基)-、-C 1-3烷基(氰基)-、-C 1-3烷基(C 1-3烷基)、-C 1-3烷基(卤代C 1-3烷基)-、-C 1-3烷基(C 1-3烷基-羟基)-、-C 1-3烷基(C 1-3烷基-氰基)-、-C 1-3烷基(C 1-3烷氧基)-、或-C 1-3烷基(卤代C 1-3烷氧基)-；其中，C 1-3烷基为甲基、乙基或丙基(正丙基或异丙基)；C 1-3烷氧基为甲氧基、乙氧基或丙氧基(正丙氧基或异丙氧基)。
在本发明的一种实施方案中，式I中，当
Figure PCTCN2020124226-appb-000061
中的虚线为单键时，P为O、NH或NR m；R m为-C 1-6烷基；R 42为-(C＝O)-或-C 1-3烷基-。
在本发明的一种实施方案中，式I中，当
Figure PCTCN2020124226-appb-000062
中的虚线为单键时，P为O、NH或NR m；R m为-C 1-3烷基；R 42为-(C＝O)-或-C 1-3烷基-。
在本发明的一种实施方案中，式I中，当
Figure PCTCN2020124226-appb-000063
中的虚线为单键时，P为O、NH或NR m；R m为甲基、乙基、正丙基或异丙基；R 42为-(C＝O)-、-CH 2-、-CH 2CH 2-或-CH 2CH 2CH 2-。
在本发明的一种实施方案中，式I中，当
Figure PCTCN2020124226-appb-000064
中的虚线为无时，P为氢或卤素；R 42为氢、卤素、-C 1-3烷基、-CH 2-羟基、-CH 2-氰基、-CH 2-C 1-3烷氧基、-CH 2-卤代C 1-3烷基或-CH 2-卤代C 1-3烷氧基。
在本发明的一种实施方案中，式I中，当
Figure PCTCN2020124226-appb-000065
中的虚线为无时，P为氢或卤素；R 42 为氢、卤素、甲基、乙基、正丙基、异丙基、-CH 2-羟基、-CH 2-氰基、-CH 2-甲氧基、-CH 2-乙氧基、-CH 2-丙氧基(正丙氧基)、-CH 2-异丙氧基、-CH 2-三氟甲基、-CH 2-二氟甲基、-CH 2-二氟乙基、-CH 2-三氟甲氧基、-CH 2-二氟甲氧基。
在本发明的一种实施方案中，式I中，X 1为氢、卤素、氰基、羟基、氨基、硝基、-取代或未取代的C 1-3烷基、-取代或未取代的C 3-6环烷基、-取代或未取代的3至6元杂环烷基、-O-取代或未取代的C 1-3烷基、-O-取代或未取代的C 3-6环烷基、-O-取代或未取代的3至6元杂环烷基、-NH-取代或未取代的C 1-3烷基、-N(取代或未取代的C 1-3烷基) 2、-NH-取代或未取代的C 3-6环烷基、-NH-取代或未取代的3至6元杂环烷基、-NH(C＝O)-取代或未取代的C 1-3烷基、-NH(C＝O)-C 3-6环烷基、-NH(SO 2)-取代或未取代的C 1-3烷基、-NH(SO 2)-取代或未取代的C 3-6环烷基、-SO 2-取代或未取代的C 1-3烷基、-SO 2-取代或未取代的C 3-6环烷基、-(C＝O)-NR jR k-、-(C＝O)-O-取代或未取代的C 1-3烷基、-(C＝O)-O-取代或未取代的C 3-6环烷基；其中，R j、R k各自独立地为氢或C 1-3烷基；或者R j、R k与相连的氮原子共同形成取代或未取代的3至6元含氮杂环烷基；所述3至6元杂环烷基具有1、2或3个选自N、O和S的杂原子作为环原子；所述3至6元含氮杂环烷基具有3至6个环原子且其中一个环原子为氮原子、其余环原子中的0个、1个或2个环原子任选地为选自N、O和S的杂原子；所述的“取代”是指基团中的1、2、3或4个氢原子被各自独立地选自S组取代基所取代；其中，C 1-3烷基为甲基、乙基或丙基(正丙基或异丙基)；C 1-3烷氧基为甲氧基、乙氧基或丙氧基(正丙氧基或异丙氧基)。
在本发明的一种实施方案中，式I中，Y 1为N；E 1为C；E 2为C。
在本发明的一种实施方案中，式I中，Y 1为C；E 1为N；E 2为C。
在本发明的一种实施方案中，式I中，Y 1为C；E 1为C；E 2为N。
在本发明的一种实施方案中，式I中，Y 1为C；E 1为N；E 2为N。
在本发明的一种实施方案中，式I中，Y 1为N；E 1为N；E 2为C。
在本发明的一种实施方案中，式I中，Y 1为N；E 1为N；E 2为C。
在本发明的一种实施方案中，式II中，P为O。
在本发明的一种实施方案中，式II中，P为NH或NR m；R m为C 1-3烷基、卤代C 1-3烷基、-C 1-3烷基-羟基、-C 1-3烷基-氰基、-C 1-3烷基-C 1-3烷氧基、-C 1-3烷基-卤代C 1-3烷氧基；其中，C 1-3烷基为甲基、乙基或丙基(正丙基或异丙基)；C 1-3烷氧基为甲氧基、乙氧基或丙氧基(正丙氧基或异丙氧基)。
在本发明的一种实施方案中，式II中，R 42为-(C＝O)-、-C 1-3烷基、-C 1-3烷基(羟基)-、-C 1-3烷基(氰基)-、-C 1-3烷基(C 1-3烷基)、-C 1-3烷基(卤代C 1-3烷基)-、-C 1-3烷基(C 1-3烷基-羟基)-、-C 1-3烷基(C 1-3烷基-氰基)-、-C 1-3烷基(C 1-3烷氧基)-、或-C 1-3烷基(卤代C 1-3烷氧基)-；其中，C 1-3烷基为甲基、乙基或丙基(正丙基或异丙基)；C 1-3烷氧基为甲氧基、乙氧基或丙氧基(正丙氧基或异丙氧基)。
在本发明的一种实施方案中，式II中，X 2、Y 2相同或不同，各自独立地为氢、卤素、-C 1-3烷基、-C 1-3烷基-羟基、-C 1-3烷基-氰基、-C 1-3烷基-C 1-3烷氧基、-C 1-3烷基-卤代C 1-3烷基或-C 1-3烷基-卤代C 1-3烷氧基；其中，C 1-3烷基为甲基、乙基或丙基(正丙基或异丙基)；C 1-3烷氧基为甲氧基、乙氧基或丙氧基(正丙氧基或异丙氧基)。
在本发明的一种实施方案中，式II中，X 2、Y 2与其相邻的碳原子共同形成取代或 未取代的C 3-6环烷基或取代或未取代的3至6元杂环烷基；所述3至6元杂环烷基具有1、2或3个选自N、O和S的杂原子作为环原子；所述的“取代”是指基团中的1、2、3或4个氢原子被各自独立地选自S组取代基所取代。
在本发明的一种实施方案中，式II中，L为一个键。
在本发明的一种实施方案中，式II中，R 5为氢、卤素、羟基、-取代或未取代的C 1-3烷基、-取代或未取代的C 3-6环烷基、-取代或未取代的3至6元杂环烷基、-O-取代或未取代的C 1-3烷基、-O-取代或未取代的C 3-6环烷基、-O-取代或未取代的3至6元杂环烷基、-SO 2-取代或未取代的C 1-3烷基、-SO 2-取代或未取代的C 3-6环烷基、-SO 2-取代或未取代的3至6元杂环烷基、-取代或未取代的5或6元单环杂芳基或NR 51R 52；其中，R 51、R 52各自独立地为氢、取代或未取代的C 1-3烷基、-SO 2C 1-3烷基、-SO 2C 3-6环烷基、-C(O)C 1-3烷基或-C(O)卤代C 1-3烷基；或者R 51和R 52与相连的氮原子共同形成取代或未取代的3至6元含氮杂环烷基；其中，所述3至6元杂环烷基、5或6元单环杂芳基各自独立地具有1、2或3个选自N、O和S的杂原子作为环原子；所述3至6元含氮杂环烷基具有3至6个环原子且其中一个环原子为氮原子、其余环原子中的0个、1个或2个环原子任选地为选自N、O和S的杂原子；所述的“取代”是指基团中的1、2、3或4个氢原子被各自独立地选自S组取代基所取代；其中，C 1-3烷基为甲基、乙基或丙基(正丙基或异丙基)；C 1-3烷氧基为甲氧基、乙氧基或丙氧基(正丙氧基或异丙氧基)。
在本发明的一种实施方案中，R 1、R 2各自独立地为氢、卤素、氰基、氨基、NHCH 3、N(CH 3) 2、甲基、乙基、正丙基、异丙基、一氯甲基、二氯甲基、三氯甲基、一氯乙基、1,2-二氯乙基、三氯乙基、一溴乙基、一氟甲基、二氟甲基、三氟甲基、一氟乙基、二氟乙基、三氟乙基、-CH 2-羟基、-CH 2-氰基、-CH 2-甲氧基、-CH 2-乙氧基、-CH 2-丙氧基(正丙氧基)、-CH 2-异丙氧基、-CH 2-NH 2、-CH 2-NHCH 3、-CH 2-N(CH 3) 2、-CH 2-3至6元杂环烷基或-CH 2-5或6元单环杂芳基；所述3至6元杂环烷基选自：氮丙环、环氧乙烷、氮杂环丁烷、氧杂环丁烷、四氢呋喃、四氢噻吩、四氢吡咯、哌啶、哌嗪、吗啉、硫代吗啉、硫代吗啉-1,1-二氧化物、四氢吡喃；所述5或6元单环杂芳基选自：噻吩、N-烷环吡咯、呋喃、噻唑、异噻唑、咪唑、噁唑、吡咯、吡唑、三唑、1,2,3-三唑、1,2,4-三唑、1,2,5-三唑、1,3,4-三唑、四唑、异噁唑、噁二唑、1,2,3-噁二唑、1,2,4-噁二唑、1,2,5-噁二唑、1,3,4-噁二唑、噻二唑、吡啶、哒嗪、嘧啶、吡嗪；所述3至6元杂环烷基、5或6元单环杂芳基任选地被1或2个卤素或C 1-3烷基取代。
在本发明的一种实施方案中，R 3为氢、卤素、甲氧基、乙氧基、丙氧基(正丙氧基)或异丙氧基。
在本发明的一种实施方案中，R 4为氢、一氯甲基、二氯甲基、三氯甲基、一氯乙基、1,2-二氯乙基、三氯乙基、一溴乙基、一氟甲基、二氟甲基、三氟甲基、一氟乙基、二氟乙基、三氟乙基、-CH 2-羟基、-CH 2-氰基、-CH 2-甲氧基、-CH 2-乙氧基、-CH 2-丙氧基(正丙氧基)或-CH 2-异丙氧基。
在本发明的一种实施方案中，R 1、R 2、R 3为氢。
在本发明的一种实施方案中，E 1为N或CR 5；其中，R 5为氢。
在本发明的一种实施方案中，E 2为N或CR 6；其中，R 6为氢。
在本发明的一种实施方案中，式(Ⅰ)化合物中，所述的R 11、R 12、R 21、R 22、R 31、 R 32、R 41、R 42、Z、P、R 0、Ar、E 1、E 2、X 1、Y 1各自独立地为实施例中各具体化合物中相应的基团。
在本发明的一种实施方案中，式(Ⅰ)化合物选自实施例中化合物Z1，Z3至Z16中任一化合物或其非对映异构体。
在本发明的一种实施方案中，代表性的式(ⅠA)化合物包括以下表A-1所列结构，或表A-1中任一结构的互变异构体、顺反异构体、内消旋体、外消旋体、对映异构体、非对映异构体或阻转异构体，或前述异构体的混合物形式，或表A-1中结构及其前述的异构体的药学上可接受的盐，溶剂合物或前药，
表A-1
Figure PCTCN2020124226-appb-000066
Figure PCTCN2020124226-appb-000067
Figure PCTCN2020124226-appb-000068
Figure PCTCN2020124226-appb-000069
Figure PCTCN2020124226-appb-000070
Figure PCTCN2020124226-appb-000071
Figure PCTCN2020124226-appb-000072
Figure PCTCN2020124226-appb-000073
Figure PCTCN2020124226-appb-000074
Figure PCTCN2020124226-appb-000075
Figure PCTCN2020124226-appb-000076
Figure PCTCN2020124226-appb-000077
Figure PCTCN2020124226-appb-000078
Figure PCTCN2020124226-appb-000079
Figure PCTCN2020124226-appb-000080
在本发明的一种实施方案中，代表性的式(ⅠA)化合物包括但不限于以下表A-2所列结构，或表A-2中任一结构的药学上可接受的盐，溶剂合物或前药，
表A-2
Figure PCTCN2020124226-appb-000081
Figure PCTCN2020124226-appb-000082
在本发明的一种实施方案中，代表性的式(ⅠA)化合物包括但不限于实施例51至实施例342中记载的任一化合物结构，或这些结构的药学上可接受的盐，溶剂合物或前药。
在本发明的一种实施方案中，式(ⅠI)化合物中，所述的R 11、R 12、R 21、R 22、R 31、R 32、R 41、R 42、Z、P、Ar、E 3、E 4、X 2、Y 2各自独立地为实施例中各具体化合物中相应的基团。
在本发明的一种实施方案中，式(ⅠI)化合物选自实施例中化合物Z2，Z17至Z20 中任一化合物或其非对映异构体。
在另一个方面，本发明提供了一种药物组合物，其含有前述的化合物或其互变异构体、顺反异构体、内消旋体、外消旋体、对映异构体、非对映异构体、阻转异构体或其混合物形式，或其药学上可接受的盐，溶剂合物或前药；以及药学可接受的载体。
如本文中所使用的，术语“药学可接受的载体”是指能够递送本发明有效量活性物质、不干扰活性物质的生物活性并且对宿主或者受试者无毒副作用的任何制剂或载体介质代表性的载体，包括水、油、蔬菜和矿物质、膏基、洗剂基质、软膏基质等。这些基质包括悬浮剂、增粘剂、透皮促进剂等。它们的制剂为化妆品领域或局部药物领域的技术人员所周知。
在本发明的实施方案中，所述药物组合物可以以下的任意方式施用：口服，喷雾吸入，直肠用药，鼻腔用药，颊部用药，局部用药，非肠道用药，如皮下，静脉，肌内，腹膜内，鞘内，心室内，胸骨内和颅内注射或输入，或借助一种外植储器用药。当口服用药时，本发明的化合物可制成任意口服可接受的制剂形式，包括但不限于片剂、胶囊、水溶液或水悬浮液。片剂使用的载体一般包括乳糖和玉米淀粉，另外也可加入润滑剂如硬脂酸镁。胶囊制剂使用的稀释剂一般包括乳糖和干燥玉米淀粉。水悬浮液制剂则通常是将活性成分与适宜的乳化剂和悬浮剂混合使用。如果需要，以上口服制剂形式中还可加入一些甜味剂、芳香剂或着色剂。当局部用药时，特别是治疗局部外敷容易达到的患面或器官，如眼睛、皮肤或下肠道神经性疾病时，可根据不同的患面或器官将本发明化合物制成不同的局部用药制剂形式，当眼部局部施用时，本发明的化合物可配制成一种微粉化悬浮液或溶液的制剂形式，所使用载体为等渗的一定pH的无菌盐水，其中可加入也可不加防腐剂如氯化苄基烷醇盐。对于眼用，也可将化合物制成膏剂形式如凡士林膏。当皮肤局部施用时，本发明的化合物可制成适当的软膏、洗剂或霜剂制剂形式，其中将活性成分悬浮或溶解于一种或多种载体中。软膏制剂可使用的载体包括但不限于：矿物油，液体凡士林，白凡士林，丙二醇，聚氧化乙烯，聚氧化丙烯，乳化蜡和水；洗剂或霜剂可使用的载体包括但不限于：矿物油，脱水山梨糖醇单硬脂酸酯，吐温60，十六烷酯蜡，十六碳烯芳醇，2-辛基十二烷醇，苄醇和水。本发明的化合物还可以无菌注射制剂形式用药，包括无菌注射水或油悬浮液或无菌注射溶液。可使用的载体和溶剂包括水、林格氏溶液和等渗氯化钠溶液。此外灭菌的非挥发油也可用作溶剂或悬浮介质，如单甘油酯或二甘油酯。
在另一个方面，本发明提供了前述化合物化合物或其互变异构体、顺反异构体、内消旋体、外消旋体、对映异构体、非对映异构体、阻转异构体或其混合物形式，或其药学上可接受的盐，溶剂合物或前药在制备治疗和/或预防KRAS G12C突变诱导疾病的药物中的用途。优选地，所述KRAS G12C突变诱导疾病为癌症。
在另一个方面，本发明提供了前述化合物化合物或其互变异构体、顺反异构体、内消旋体、外消旋体、对映异构体、非对映异构体、阻转异构体或其混合物形式，或其药学上可接受的盐，溶剂合物或前药在制备治疗和/或预防癌症的药物中的用途。
在本发明的一种实施方案中，所述癌症为胰腺癌、结肠直肠癌或肺癌。
在本发明的一种实施方案中，所述癌症为肺癌，优选为非小细胞肺癌。
在另一个方面，本发明提供了前述化合物化合物或其互变异构体、顺反异构体、内 消旋体、外消旋体、对映异构体、非对映异构体、阻转异构体或其混合物形式，或其药学上可接受的盐，溶剂合物或前药在制备KRAS突变抑制剂中的用途，(优选地，所述KRAS突变为KRAS G12C突变)。
在另一个方面，本发明提供了一种治疗癌症的方法，其包括向有此需要的受试者施用治疗有效量的前述的化合物化合物或其互变异构体、顺反异构体、内消旋体、外消旋体、对映异构体、非对映异构体、阻转异构体或其混合物形式，或其药学上可接受的盐，溶剂合物或前药，或上述的任意组合，或施用上述的药物组合物的步骤。
如本文中所使用的，术语“受试者”是指动物，特别是哺乳动物，优选人。
如本文中所使用的，术语“有效量”或“治疗有效量”是指无毒的但能达到预期效果的药物或药剂的足够用量。在本发明的实施方式中，在根据本发明对患者进行治疗时，给定药物的量取决于诸多因素，如具体的给药方案、疾病或病症类型及其严重性、需要治疗的受治疗者或宿主的独特性(例如体重)，但是，根据特定的周围情况，包括例如已采用的具体药物、给药途径、治疗的病症、以及治疗的受治疗者或宿主，施用剂量可由本领域已知的方法常规决定。通常，就成人治疗使用的剂量而言，施用剂量典型地在0.02-5000mg/天，例如约1-1500mg/天的范围。该所需剂量可以方便地被表现为一剂、或同时给药的(或在短时间内)或在适当的间隔的分剂量，例如每天二、三、四剂或更多分剂。本领域技术人员可以理解的是，尽管给出了上述剂量范围，但具体的有效量可根据患者的情况并结合医师诊断而适当调节。
如本文中所使用的，术语“药学上可接受的盐”是指在制药上可接受的并且具有母体化合物药理学活性的本发明化合物的盐。这类盐包括：与无机酸或与有机酸形成的酸加成的盐，所述的无机酸诸如硝酸，磷酸，碳酸等；所述的有机酸诸如丙酸，己酸，环戊丙酸，乙醇酸，丙酮酸，葡糖酸，硬脂酸，粘康酸等；或在母体化合物上存在的酸性质子被金属离子，例如碱金属离子或碱土金属离子取代时形成的盐；或与有机碱形成的配位化合物，所述的有机碱诸如乙醇胺，二乙醇胺，三乙醇胺，N-甲基葡糖胺等。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。除了盐的形式，本发明所提供的化合物还存在前药形式。本文所描述的化合物的前药容易地在生理条件下发生化学变化从而转化成本发明的化合物。此外，前体药物可以在体内环境中通过化学或生化方法被转换到本发明的化合物。
如本文中所使用的，术语“溶剂化合物”和“溶剂化物”是指本发明化合物与制药上可接受的溶剂结合形成的物质。溶剂化合物包括化学计算量的溶剂化合物和非化学计算量的溶剂化合物。本发明的某些化合物可以以非溶剂化形式或者溶剂化形式存在。一般而言，溶剂化形式与非溶剂化的形式相当，都包含在本发明的范围之内。
如本文中所使用的，术语“立体异构体”包括构象异构体和构型异构体，其中构型异构体主要包括顺反异构体和旋光异构体。本发明所述化合物可以以立体异构体的形式存在，并因此涵盖所有可能的立体异构体形式，包括但不限于顺反异构体、互变异构体、对映异构体、非对映异构体、阻转异构体(或也可以称为旋转异构体)等，本发明所述化合物也可以以前述的立体异构体的任何组合或任何混合物，例如内消旋体、外消旋体、 阻转异构体的等量混合物等形式存在。例如单一对映异构体，单一非对映异构体或以上的混合物，或单一阻转异构体或其混合物。当本发明所述的化合物含有烯烃双键时，除非特别说明，否则其包括顺式异构体和反式异构体，以及其任何组合。本发明的阻转异构体为基于分子内旋转受限制而产生的轴向或平面手性的立体异构体。本发明的化合物具有两种源于轴不对称的阻转异构体，其是由限制以当取代基Ar'或R 0'为C 6-10芳基、5或6元单环杂芳基、8至10元双环杂芳基或吡啶酮基等环状基团时和取代的萘啶酮环的键连接转动，形成空间位阻而产生的。有关本发明的阻转异构体，其中化合物具有式(I)、式(IA)或式(II)的结构，或式(I)、式(IA)或式(II)化合物具有由不对称碳等产生的异构体，它表示每种异构化合物中存在的一对阻转异构体中的任一种。且作为药物，具有优异活性的阻转异构体是优选的。式(I)、式(IA)或式(II)化合物具有源于不对称碳、轴向不对称等的光学异构体，必要时单一异构体可通过进行光学拆分获得。本发明化合物的阻转异构体可以以P或M构型表示，也可以以本领域所熟知的常用的其他方式标记表示。
如前所述，本发明提供了上述各类结构所示化合物，或其互变异构体、顺反异构体、内消旋体、外消旋体、对映异构体、非对映异构体、阻转异构体或其混合物形式，其中“其混合物形式”包括前述的任一立体异构体(例如互变异构体、顺反异构体、对映异构体、非对映异构体、阻转异构体)和/或混合物(内消旋体、外消旋体)之间的任意形式的混合，例如顺反异构体的混合物，对映异构体和非对映异构体的混合物，非对映异构体的混合物，阻转异构体的混合物，或顺反异构体和外消旋体的混合，对映异构体和非对映异构体混合物的混合，阻转异构体与非对映异构体混合物的混合等。
如本文中所使用的，各基团中取代基所含有的“-”符号表示与其他基团或结构连接的键。
如本文中所使用的，术语“稠合”指两个或多个环共用一个或多个键的结构。
如本文中所使用的，术语“烷基”指直链或支链饱和脂肪族烃基基团，其包含1到20个碳原子。术语“C 1-10烷基”指具有1到10个碳原子的直链或支链烷基，更优选是具有1、2、3、4、5或6个碳原子的直链或支链烷基，即C 1-6烷基，更优选是C 1-4烷基，最优选是C 1-3烷基。烷基具体实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基，及其各种支链异构体等。
需要说明的是，除非特别说明，如果并列选项中同时存在丙基和异丙基，该处丙基表示正丙基。如果并列选项中只存在丙基，该处丙基表示正丙基或异丙基。
如本文中所使用的，“-C 1-3烷基-”与“C 1-3亚烷基”可互换使用，指饱和的直链或支链脂肪族烃基，其具有2个从母体烷基的相同碳原子或两个不同的碳原子上除去两个氢原子所衍生的残基，其为包含1至3个碳原子的直链或支链基团。亚烷基的非限制性实例包括但不限于亚甲基(-CH 2-)、1,1-亚乙基(-CH(CH 3)-)、1,2-亚乙基(-CH 2CH 2-)、1,1-亚丙基(-CH(CH 2CH 3)-)、1,2-亚丙基(-CH 2CH(CH 3)-)、1,3-亚丙基(-CH 2CH 2CH 2-)等。
如本文中所使用的，“-C 1-3烷基(羟基)-、-C 1-3烷基(氰基)-、-C 1-3烷基(C 1-6烷基)-、-C 1-3烷基(卤代C 1-6烷基)-、-C 1-3烷基(C 1-6烷基-羟基)-、-C 1-3烷基(C 1-6烷基-氰基)-、-C 1-3烷 基(C 1-6烷氧基)-、-C 1-3烷基(卤代C 1-6烷氧基)-”分别指“-C 1-3烷基-”中的一个或多个氢原子分别被羟基、氰基、C 1-6烷基、卤代C 1-6烷基、-C 1-6烷基-羟基、-C 1-6烷基-氰基、C 1-6烷氧基、卤代C 1-6烷氧基取代所形成的残基。非限制性实例包括但不限于-CH(OH)-、-CH 2CH(CN)-、-CH 2CH(CH 2CH 3)-、-CH 2CH(CF 3)-、-CH(CH 2OH)-、-CH 2CH(CH 2CN)-、-CH(OCH 3)-、-CH 2CH(OCF 3)-。
如本文中所使用的，术语“烷氧基”指具有-O-烷基结构的基团，其中烷基的定义如上所述。术语“C 1-10烷氧基”指具有1到10个碳原子的烷氧基，优选是C 1-6烷氧基，更优选是C 1-4烷氧基，更优选是C 1-3烷氧基。烷氧基具体实例包括但不限于甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、叔丁氧基、异丁氧基、正戊氧基等。
需要说明的是，除非特别说明，如果并列选项中同时存在丙氧基和异丙氧基，该处丙氧基表示正丙氧基。如果并列选项中只存在丙氧基，该处丙基表示正丙氧基或异丙氧基。
如本文中所使用的，术语“烷硫基”指具有-S-烷基结构的基团，其中烷基的定义如上所述。术语“C 1-10烷硫基”指具有1到10个碳原子的烷硫基，优选是C 1-6烷硫基，更优选C 1-4烷硫基，更优选C 1-3烷硫基。烷硫基具体实例包括但不限于甲硫基、乙硫基、丙硫基、异丙硫基、丁硫基、叔丁硫基、异丁硫基、戊硫基等。
如本文中所使用的，术语“烯基”指在链的任何位点上具有一个或多个碳-碳双键的如上定义的烷基，术语“C 2-8烯基”指具有2到8个碳原子和至少一个碳-碳双键的烯基，优选为具有2到6个碳原子和1到2个碳-碳双键的烯基，即C 2-6烯基。更优选为具有2到4个碳原子和1到2个碳-碳双键的烯基，即C 2-4烯基。烯基具体实例包括但不限于乙烯基、1-丙烯基、2-丙烯基、1-、2-或3-丁烯基、戊烯基、己烯基、丁间二烯基等。
如本文中所使用的，术语“炔基”指在链的任何位点上具有一个或多个碳-碳三键的如上定义的烷基，术语“C 2-8炔基”指具有2到8个碳原子和至少一个碳-碳三键的炔基，优选为具有2到6个碳原子和1到2个碳-碳三键的炔基，即C 2-6炔基。更优选为具有2到4个碳原子和1到2个碳-碳三键的炔基，即C 2-4炔基。炔基具体实例包括但不限于乙炔基、1-丙炔基、2-丙炔基、1-、2-或3-丁炔基等。
如本文中所使用的，术语“卤素”指氟、氯、溴和碘。
如本文中所使用的，术语“卤代烷基”指被一个或多个(如1、2、3、4或5个)卤素取代的烷基，其中烷基的定义如上所述。术语“卤代C 1-10烷基”指具有1到10个碳原子的卤代烷基。优选为卤代C 1-6烷基，更优选为卤代C 1-4烷基，更优选为卤代C 1-3烷基。卤代烷基具体实例包括但不限于一氯甲基、二氯甲基、三氯甲基、一氯乙基、1,2-二氯乙基、三氯乙基、一溴乙基、一氟甲基、二氟甲基、三氟甲基、一氟乙基、二氟乙基、三氟乙基等。
如本文中所使用的，术语“氘代烷基”指被一个或多个(如1、2、3、4或5个)氘原子取代的烷基，其中烷基的定义如上所述。术语“氘代C 1-10烷基”指具有1到10个碳原子的氘代烷基。优选为氘代C 1-6烷基，更优选为氘代C 1-4烷基，更优选为氘代C 1-3烷基。氘代烷基具体实例包括但不限于一氘甲基、二氘甲基、三氘甲基、一氘乙基、1,2-二氘乙基、三氘乙基等。
如本文中所使用的，术语“卤代烷氧基”指被一个或多个(如1、2、3、4或5个)卤素 取代的烷氧基，其中烷氧基的定义如上所述。术语“卤代C 1-10烷氧基”指具有1到10个碳原子的卤代烷氧基。优选为卤代C 1-6烷氧基，更优选为卤代C 1-4烷氧基，更优选为卤代C 1-3烷氧基。卤代烷氧基具体实例包括但不限于三氟甲氧基、三氟乙氧基、一氟甲氧基、一氟乙氧基、二氟甲氧基、二氟乙氧基等。
如本文中所使用的，术语“环烷基”和“环烷基环”可互换使用，指饱和单环或多环稠合的环状烃基。术语“C 3-20环烷基”指具有3到20个碳原子的环烷基，包括单环环烷基、螺环烷基、稠环烷基和桥环烷基。优选为C 3-12环烷基。本发明中所述环烷基的环碳原子可任选地被1、2或3个氧代基取代形成环酮结构。术语“C 3-8单环环烷基”和“C 3-8环烷基”指具有3到8个碳原子的饱和单环环状烃基，优选为C 3-6单环环烷基(即C 3-6环烷基)，更优选为C 3、C 4、C 5或C 6单环环烷基。单环环烷基的具体实例包括但不限于环丙基、环丁基、环戊基、环己基、环庚基、环辛基等。
如本文中所使用的，术语“螺环烷基”和“螺环烷基环”指两个或两个以上的单环之间共用一个碳原子(称螺原子)形成的多环环状烃基。根据环与环之间共用螺原子的数目将螺环烷基分为单螺环烷基、双螺环烷基和多螺环烷基。术语“5至20元螺环烷基”或“C 5-20螺环烷基”指具有5到20个环碳原子的多环环状烃基，其中共用螺原子的单环为3到8元单环环烷基环。优选为6至14元(C 6-14)螺环烷基，更优选为6至14元单螺环烷基，更优选为7至11元(C 7-11)螺环烷基，更优选为7至11元单螺环烷基，最优选为7元(4元单环环烷基环/4元单环环烷基环)、8元(4元单环环烷基环/5元单环环烷基环)、9元(4元单环环烷基环/6元单环环烷基环，5元单环环烷基环/5元单环环烷基环)、10元(5元单环环烷基环/6元单环环烷基环)或11元(6元单环环烷基环/6元单环环烷基环)单螺环烷基。螺环烷基的具体实例包括但不限于：
Figure PCTCN2020124226-appb-000083
所述环烷基环可以稠合于芳基、杂芳基或杂环基环上，其中与母体结构连接在一起的环为环烷基环，非限制性实例包括茚满基、四氢萘基、苯并环庚烷基等。在本发明中，上述各类环烷基可以是任选取代的，当被取代时，取代基优选为一个或多个本申请中所记载的取代基团。
如本文中所使用的，术语“卤代环烷基”指被一个或多个(如1、2、3、4或5个)卤素取代的环烷基，其中环烷基的定义如上所述。术语“卤代C 3-8环烷基”指具有3到8个环碳原子的卤代环烷基。优选为卤代C 3-6环烷基，更优选为卤代C 3、卤代C 4、卤代C 5或卤代C 6环烷基。卤代环烷基具体实例包括但不限于三氟环丙基、一氟环丙基、一氟环己基、二氟环丙基、二氟环己基等。
如本文中所使用的，术语“杂环基”和“杂环基环”可互换使用，指饱和或部分不饱和单环或多环稠合的环状烃基，术语“C 3-20杂环基”或“3至20元杂环基”指具有3到20个环原子的饱和或部分不饱和单环或多环稠合的环状烃基，其中一个或多个(优选为1、2、3或4个)环原子为选自氮、氧或S(O) m(其中m是整数0至2)的杂原子，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳。其中环原子为氮原子时，其可以是被取代的或未取代的(即N或NR，R为氢或本文已经定义过的其他取代基)。在本发明中所述杂 环基的环碳原子可任选地被1、2或3个氧代基取代形成环酮、环内酯或环内酰胺结构。本发明所述的3至20元杂环基包括单环杂环基、螺杂环基、稠杂环基和桥杂环基。
如本文中所使用的，术语“C 3-8单环杂环基”、“3至8元单环杂环基”和“3至8元单环杂环基环”指具有3到8个环原子，其中1、2或3个环原子为选自氮、氧或S(O) m(其中m是整数0至2)的杂原子的饱和或部分不饱和单环环状烃基。优选为具有3到6个环原子，其中1或2个环原子为杂原子的3到6元单环杂环基(即C 3-6单环杂环基)。更优选为具有5或6个环原子，其中1或2个环原子为杂原子的5或6元单环杂环基。当杂原子为氮原子时，氮原子可以是被取代的或未取代的(即N或NR，R为氢或本文已经定义过的其他取代基)。当杂原子为硫原子时，硫原子可以为任选地被氧化(即S(O) m，m是整数0至2)。所述单环杂环基的环碳原子可任选地被1、2或3个氧代基取代形成环酮、环内酯或环内酰胺结构。单环杂环基的具体实例包括但不限于氮丙环、环氧乙烷、氮杂环丁烷、氮杂环丁烷-2-酮、氧杂环丁烷、氧杂环丁烷-2-酮、噁唑烷、吡咯烷-2-酮、吡咯烷-2,5-二酮、1,3-二氧戊环、二氢呋喃-2(3H)-酮、二氢呋喃-2,5-二酮、哌啶-2-酮、哌啶-2,6-二酮、四氢-2H-吡喃-2-酮、咪唑烷、四氢呋喃、四氢噻吩、四氢吡咯、1,3-二氧戊环-2-酮、噁唑烷-2-酮、咪唑烷-2-酮、哌啶、哌嗪、哌嗪-2-酮、吗啉、吗啉-3-酮、吗啉-2-酮、硫代吗啉-3-酮1,1-二氧化物、硫代吗啉、硫代吗啉-1,1-二氧化物、四氢吡喃、1,2-二氢氮杂环丁二烯、1,2-二氢氧杂环丁二烯、2,5-二氢-1H-吡咯、2,5-二氢呋喃、2,3-二氢呋喃、2,3-二氢-1H-吡咯、3,4-二氢-2H-吡喃、1,2,3,4-四氢吡啶、3,6-二氢-2H-吡喃、1,2,3,6-四氢吡啶、1,3-噁嗪烷、六氢嘧啶、1,4-二噁烷、四氢嘧啶-2(1H)-酮、1,4-二噁烷-2-酮、5,6-二氢-2H-吡喃-2-酮、5,6-二氢嘧啶-4(3H)-酮、3,4-二氢吡啶-2(1H)-酮、5,6-二氢吡啶-2(1H)-酮、5,6-二氢嘧啶-4(1H)-酮、嘧啶-4(3H)-酮、嘧啶-4(1H)-酮、4,5-二氢-1H-咪唑、2,3-二氢-1H-咪唑、2,3-二氢噁唑、1,3-二氧杂环戊烯、2,3-二氢噻吩、2,5-二氢噻吩、3,4-二氢-2H-1,4-噁嗪、3,4-二氢-2H-1,4-噻嗪1,1-二氧化物、1,2,3,4-四氢吡嗪、1,3-二氢-2H-吡咯-2-酮、1,5-二氢-2H-吡咯-2-酮、1H-吡咯-2,5-二酮、呋喃-2(3H)-酮、呋喃-2(5H)-酮、1,3-二氧杂环戊烯-2-酮、噁唑-2(3H)-酮、1,3-二氢-2H-咪唑-2-酮、呋喃-2,5-二酮、3,6-二氢吡啶-2(1H)-酮、吡啶-2,6-(1H，3H)-二酮、5,6-二氢-2H-吡喃-2-酮、3,6-二氢-2H-吡喃-2-酮、3,4-二氢-2H-1,3-噁嗪、3,6-二氢-2H-1,3-噁嗪、1,2,3,4-四氢嘧啶等。术语“C 3-8杂环烷基”和“3至8元杂环烷基”指具有3到8个环原子，其中1或2个环原子为杂原子的饱和单环环状烃基。优选为具有3到6个环原子，其中1或2个环原子为杂原子的3至6元杂环烷基。杂环烷基具体实例包括但不限于氮丙环基、环氧乙烷基、氮杂环丁烷基、氧杂环丁烷基、噁唑烷基、1,3-二氧戊环基、二氧六环基、咪唑烷基、四氢呋喃基、四氢噻吩基、四氢吡咯基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、硫代吗啉-1,1-二氧化物基、四氢吡喃基、1,4-氧氮杂环庚烷基、1,3-氧氮杂环庚烷基、1,3-噁嗪烷基、六氢嘧啶基、1,4-二噁烷基。
上述单环杂环基环上相连的2个环原子，包括C-C、N-C均可任选地与本发明所定义的单环环烷基环、单环杂环基环、单芳基环、5或6元单杂芳基环等环烷基、杂环基、芳基或杂芳基稠合形成稠合多环，与其他环形成稠合环的单环杂环基上相连的2个环原子优选地为C-C。
如本文中所使用的，术语“C 6-14芳基”，“C 6-14芳基环”和“C 6-14芳环”可互换使用，指 具有6到14个环原子的全碳单环，全碳多环(环与环通过共价键连接，非稠合)或全碳稠合多环(也就是共享毗邻碳原子对的环)基团，基团中至少一个环为芳香性的，即具有共轭的π电子体系。优选为C 6-10芳基。本发明中C 6-14芳基包括单环芳基、多环芳基和芳香稠合多环，其中单环芳基的实例包括苯基，多环芳基的实例包括联苯基等。
本发明中，C 6-14芳基为芳香稠合多环时，所述的芳香稠合多环可以为单芳基环与一个或多个单芳基环稠合形成的多环基团，其非限制性实例包括萘基，蒽基等。
在本发明的一些实施方案中，所述的芳香稠合多环也可以为单芳基环(如苯基)与一个或多个非芳香环稠合形成的多环基团，其中与母体结构连接的环为芳香环或非芳香环。所述非芳香环包括但不限于3到6元单环杂环基环(优选为5或6元单环杂环基环，所述单环杂环基环的环碳原子可被1至2个氧代基取代，形成环内酰胺或环内酯结构)，3到6元单环环烷基环(优选为5或6元单环环烷基环，所述单环环烷基环的环碳原子可被1或2个氧代基取代，形成环酮结构)。上述单芳基环与一个或多个非芳香环稠合的多环基团可通过氮原子或碳原子与其他基团或母体结构连接，与母体结构连接的环为单芳基环或非芳香环。
在本文中，苯环与一个5或6元单环杂环基环稠合形成9或10元芳香稠合双环即指由苯基上相邻两个取代基团与其所连接的环原子形成一个稠合的5或6元单环杂环基环，所述5或6元单环杂环基环如上文中所定义，所形成的9或10元芳香稠合双环也可以称为9或10元苯基杂环基环。
在本文中，苯环与一个5或6元单环环烷基环稠合形成9或10元芳香稠合双环即指由苯基上相邻两个取代基团与其所连接的环原子形成一个稠合的5或6元单环环烷基环，所述5或6元单环环烷基环如上文中所定义，所形成的9或10元芳香稠合双环也可称为9或10元苯基环烷基环。其非限制性实例包括：
Figure PCTCN2020124226-appb-000084
在本发明中，上述各类芳基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个本申请中所记载的取代基团。
如本文中所使用的，术语“杂芳基”，“杂芳基环”和“杂芳环”可互换使用，指环原子被至少一个独立选自氮、氧或硫的杂原子取代的单环或稠合多环(即共享毗邻环原子对，共享的毗邻环原子对可以是C-C或N-C)基团，其中氮和硫原子可任选地被氧化，氮原子可任选地被季铵化。所述杂芳基具有共享的6，10或14个π电子，基团中至少一个环是芳族的。术语“C 5-14杂芳基”和“5到14元杂芳基”指具有5到14个环原子，其中1、2、3或4个环原子为杂原子的杂芳基。优选为具有5到10个环原子，其中1、2、3或 4个环原子为杂原子的5到10元杂芳基。本发明中C 5-14杂芳基可以为单杂芳基、稠合双环杂芳基或稠合三环杂芳基。
如本文中所使用的，术语“5或6元单杂芳基”与“5或6元单环杂芳基”可互换使用，指具有5或6个环原子，其中1、2或3个环原子为杂原子的单环杂芳基。单杂芳基的具体实例包括但不限于噻吩、呋喃、噻唑、异噻唑、咪唑、噁唑、吡咯、吡唑、三唑、1,2,3-三唑、1,2,4-三唑、1,2,5-三唑、1,3,4-三唑、四唑、异噁唑、噁二唑、1,2,3-噁二唑、1,2,4-噁二唑、1,2,5-噁二唑、1,3,4-噁二唑、噻二唑、吡啶、哒嗪、嘧啶、吡嗪等。
如本文中所使用的，术语“8至10元双杂芳基”与“8至10元双环杂芳基”可互换使用，指具有8到10个环原子，其中1、2、3、4或5个环原子为杂原子的稠合双环杂芳基。所述稠合双环杂芳基既可以是单芳基环(如苯基)与单杂芳基环(优选为5或6元单杂芳基环)稠合形成的双环基团(优选为9或10元双杂芳基环)，也可以是单杂芳基环(优选为5或6元单杂芳基环)与单杂芳基环(优选为5或6元单杂芳基环)稠合形成的双环基团。
上述单杂芳基环上任意相连的2个环原子，包括C-C、N-C、N-N均可与本发明所定义的单环环烷基环、单环杂环基环、单芳基环、5或6元单杂芳基环等环烷基、杂环基、芳基或杂芳基稠合形成稠合多环。与其他环形成稠合环的单杂芳基环上相连的2个环原子优选地为C-C，非限制性地包括如下形式：
Figure PCTCN2020124226-appb-000085
8至10元双杂芳基的非限制性实例包括：苯并[d]异噁唑、1H-吲哚、异吲哚、1H-苯并[d]咪唑、苯并[d]异噻唑、1H-苯并[d][1,2,3]三唑、苯并[d]噁唑、苯并[d]噻唑、吲唑、苯并呋喃、苯并[b]噻吩、喹啉、异喹啉、喹唑啉、喹喔啉、噌啉、吡啶并[3,2-d]嘧啶、吡啶并[2,3-d]嘧啶、吡啶并[3,4-d]嘧啶、吡啶并[4,3-d]嘧啶、1,8-萘啶、1,7-萘啶、1,6-萘啶、1,5-萘啶、吡唑并[1,5-a]嘧啶、咪唑并[1,2-b]哒嗪等。
上述单杂芳基，或苯环与单杂芳基环稠合形成的双杂芳基，或单杂芳基环与单杂芳基环稠合形成的双杂芳基可通过氮原子或碳原子与其他基团或母体结构连接。当为双杂芳基时，与母体结构连接的环为单杂芳基环或苯环，其具体实例包括但不限于：
Figure PCTCN2020124226-appb-000086
Figure PCTCN2020124226-appb-000087
在本发明的一些实施方案中，所述的稠合双环杂芳基或稠合三环杂芳基可以是单杂芳基环(优选为5或6元单杂芳基环)与一个或多个非芳香环稠合形成的多环基团，其中与母体结构连接的环为单杂芳基环或非芳香环。所述非芳香环包括但不限于3到6元单环杂环基环(优选为5或6元单环杂环基环，所述单环杂环基环的环碳原子可被1至2个氧代基取代，形成环内酰胺或环内酯结构)，3到6元单环环烷基环(优选为5或6元单环环烷基环，所述单环环烷基环的环碳原子可被1或2个氧代基取代，形成环酮结构)等。上述单杂芳基环与一个或多个非芳香环稠合形成的多环基团可通过氮原子或碳原子与其他基团或母体结构连接，与母体结构连接的环为单杂芳基环或非芳香环。
在本文中，5或6元单杂芳基环与一个5或6元单环杂环基环稠合形成8至10元稠合双环杂芳基即指由5或6元单杂芳基上相邻两个取代基团与其所连接的环原子形成一个稠合的5或6元单环杂环基环，所述5或6元单环杂环基环如上文中所定义，所形成的8至10元稠合双环杂芳基也可以称为8至10元杂芳基杂环基环。
在本文中，5或6元单杂芳基环与一个5或6元单环环烷基环稠合形成8至10元稠合双环杂芳基即指由5或6元单杂芳基上相邻两个取代基团与其所连接的环原子形成一个稠合的5或6元单环环烷基环，所述5或6元单环环烷基环如上文中所定义，所形成的8至10元稠合双环杂芳基也可以称为8至10元杂芳基环烷基环。其非限制性实例包括：
Figure PCTCN2020124226-appb-000088
在本发明中，上述各类杂芳基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个本申请中所记载的取代基团。
如本文中所使用的，术语“-烷基-R”表示烷基被一个或多个R基团取代形成的取代基，其中“-烷基-”表示经取代后形成的亚烷基或次烷基。如本文中记载的R可以为羟基、氰基、烷氧基、取代的氨基、杂环烷基、杂芳基、卤代烷基、卤代烷氧基、环烷基、炔基等，R所表示的基团如本文中所定义。优选-C 1-6烷基-R，更优选-C 1-4烷基-R，更优选-C 1-3烷基-R，更优选-C 1-2烷基-R，例如-CH 2-CH(CH 3)-R，-CH 2-CH 2-CH 2-R，-CH 2-CH 2-R，-CH 2-R等。
如本文中所使用的，术语“羟基”指-OH。
如本文中所使用的，术语“羟甲基”指-CH 2OH，“羟乙基”指-CH 2CH 2OH或 -CH(OH)CH 3。
如本文中所使用的，术语“氰基甲基”指-CH 2CN，“氰基乙基”指-CH 2CH 2CN或-CHCNCH 3。
如本文中所使用的，术语“氨基”指-NH 2。
如本文中所使用的，术语“氰基”指-CN。
如本文中所使用的，术语“硝基”指-NO 2。
如本文中所使用的，术语“苄基”指-CH 2-苯。
如本文中所使用的，术语“氧代基”指＝O。
如本文中所使用的，术语“羧基”指-C(O)OH。
如本文中所使用的，术语“羧酸酯基”指-C(O)O(烷基)或-C(O)O(环烷基)。
如本文中所使用的，术语“乙酰基”指-COCH 3。
在本文中，C 1-10可以优选为C 1-6；更优选为C 1-4；更优选为C 1-3。例如，C 1-10烷基可以优选为C 1-6烷基；更优选为C 1-4烷基；更优选为C 1-3烷基。例如，C 1-10烷氧基可以优选为C 1-6烷氧基；更优选为C 1-4烷氧基；更优选为C 1-3烷氧基。
在本文中，C 3-20可以优选为C 3-10；更优选为C 3-8；更优选为C 3-6；更优选为C 3-5。例如，C 3-20环烷基可以优选为C 3-8环烷基；更优选为C 3-6环烷基；更优选为C 3-6环烷基。
在本发明的一种实施方案中，任一基团中，所述C 3-6环烷基选自：环丙基、环丁基、环戊基、环己基。
在本发明的一种实施方案中，任一基团中，所述3至6元杂环烷基选自：氮丙环、环氧乙烷、氮杂环丁烷、氧杂环丁烷、四氢呋喃、四氢噻吩、四氢吡咯、哌啶、哌嗪、吗啉、硫代吗啉、硫代吗啉-1,1-二氧化物、四氢吡喃。
在本发明的一种实施方案中，任一基团中，所述5或6元单环杂芳基选自：噻吩、N-烷环吡咯、呋喃、噻唑、异噻唑、咪唑、噁唑、吡咯、吡唑、三唑、1,2,3-三唑、1,2,4-三唑、1,2,5-三唑、1,3,4-三唑、四唑、异噁唑、噁二唑、1,2,3-噁二唑、1,2,4-噁二唑、1,2,5-噁二唑、1,3,4-噁二唑、噻二唑、吡啶、哒嗪、嘧啶、吡嗪。
在本发明的一种实施方案中，任一基团中，所述8至10元双环杂芳基选自：苯并噁唑、苯并异噁唑、苯并咪唑、苯并噻唑、苯并异噻唑、苯并三唑、苯并呋喃、苯并噻吩、吲哚、吲唑、异吲哚、喹啉、异喹啉、喹唑啉、喹喔啉、噌啉、吡啶并嘧啶、萘啶。
如本文中所使用的，术语“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。当取代基为氧代基(即＝O)时，意味着两个氢原子被取代。氧代基取代不会发生在芳香基上。术语“任选取代”或“任选被取代的”是指可以被取代，也可以不被取代，除非另有规定，取代基的种类和数目在化学上可以实现的基础上可以是任意的。
当任何变量(例如R)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。因此，例如，如果一个基团被0-2个R所取代，则所述基团可以任选地至多被两个R所取代，并且每种情况下的R都有独立的选项。此外，取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
本发明式(IA)或式(IB)所示的化合物可使用本领域已知的合成方法或使用本领域已知的方法与本发明记载的方法组合制备得到。本发明给出的溶剂、温度和其它反应条件 均为示例性的，可根据本领域熟知的方法而变化。本发明所记载的实施例化合物可根据其具体结构，使用适当的起始原料按照实施例中记载的方法合成，也可以使用与实施例中记载的类似方法合成得到。用于合成本发明实施例化合物的起始原料可通过已知合成方法或文献记载的类似方法制备得到或从商业来源获得。实施例化合物可根据需要，进一步通过本领域熟知的方法，例如结晶、色谱法等拆分得到其立体异构体，其拆分条件是本领域技术人员通过常规手段或有限试验而容易获得的。
作为进一步说明，本发明式(IB-1')、式(IB-2')化合物可利用以下的方法合成，其中每个步骤中的溶剂、温度及其它反应条件可与下述实施例中记载的相同或类似，或使用本领域已知的反应条件；
Figure PCTCN2020124226-appb-000089
本发明式(IB-1')、式(IB-2')化合物还可利用以下的方法合成，其中每个步骤中的溶 剂、温度及其它反应条件可与下述实施例中记载的相同或类似，或使用本领域已知的反应条件；
Figure PCTCN2020124226-appb-000090
式(IB-1')、式(IB-2')化合物的制备路线中，各式中，R lev为本领域熟知的离去基团，例如三氟甲磺酸酯；氯、溴、碘；磺酸酯基，如甲磺酸酯、甲苯磺酸酯、对甲苯磺酸酯等；酰氧基，如乙酰氧基、三氟乙酰氧基等等。各式中，R p为本领域熟知的氨基保护基，例如甲酰基；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。R 1、R 2、R 3、R 21、R 22、R 12、R 11、R 31、R 32、R m'、R 0'、Ar'、E 1'、X 1定义同前(例如同式I或式IA中各对应基团的定义)。
本发明式(IB-1”)、式(IB-2”)化合物可利用以下的方法合成，其中每个步骤中的溶剂、温度及其它反应条件可与下述实施例中记载的相同或类似，或使用本领域已知的反应条件；
Figure PCTCN2020124226-appb-000091
式(IB-1”)、式(IB-2”)化合物的制备路线中，各式中，R p为本领域熟知的氨基保护基，例如甲酰基；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。R 1、R 2、R 3、R 21、R 22、R 12、R 11、R 31、R 32、R 0'、Ar'、E 1'、X 1定义同前(例如同式I或式IA中各对应基团的定义)。
其中式e化合物还可利用以下的方法合成，其中每个步骤中的溶剂、温度及其它反应条件可与下述实施例中记载的相同或类似，或使用本领域已知的反应条件；
Figure PCTCN2020124226-appb-000092
式e化合物的制备路线中，R lev为本领域熟知的离去基团，例如三氟甲磺酸酯；氯、溴、碘；磺酸酯基，如甲磺酸酯、甲苯磺酸酯、对甲苯磺酸酯等；酰氧基，如乙酰氧基、三氟乙酰氧基等等。R 0'、Ar'、E 1'、X 1定义同前(例如同式I或式IA中各对应基团的定义)。
附图说明
图1为化合物Z25-2的X-射线单晶衍射分子立体结构图。
图2为化合物Z27-2的X-射线单晶衍射分子立体结构图。
具体实施方式
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。下面通过实施例对本发明进行详细描述，但并不意味着对本发明任何不利限制。本文已经详细地描述了本发明，其中也公开了其具体实施例方式，对本领域的技术人员而言，在不脱离本发明精神和范围的情况下针对本发明具体实施方式进行各种变化和改进将是显而易见的。实施例中未注明具体条件者，按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者，均为可以通过市购获得的常规产品。
以下实施例中所用试剂缩写如下：THF：四氢呋喃；DMSO：二甲基亚砜；PE：石油醚；EtOAc：乙酸乙酯；DCM：二氯甲烷；MeOH：甲醇；ACN为乙腈；IPA为异丙胺；DMA为二甲胺；TFA为三氟乙酸；NH 4Cl为氯化铵；SPhos为2-二环己基膦基-2’,6’-二甲氧基-1,1’-联苯；SPhos-Pd-G2为氯(2-二环己基膦-2’,6’-二甲氧基-1,1’-联苯基)[2-(2’-氨基-1,1’-联苯)]钯(II)；NaHMDS为双(三甲基硅基)胺基钠；LiHMDS为双(三甲基硅基)胺基锂。
以下实施例中所采用的制备HPLC，可采用如下条件：柱型：Waters XBridge C18,190*250mm,5μm；流动相体系:A:0.1％碳酸氢铵水溶液；B:制备级乙腈；流速:15ml/min；B％＝20％-100％；柱温:室温。
异构体化合物若用分析型HPLC方法检测，可采用如下条件：柱型:XBridge C18,3.5μm 4.6*150mm,流动相:A:纯化水(0.05％TFA)；B:制备级乙腈(0.05％TFA),梯度:5％-95％B，运行时间:15min，流速:1ml/min,柱温＝40℃。
实施例1制备化合物Z1、Z1-1和Z1-2
Figure PCTCN2020124226-appb-000093
步骤1：2-异丙基-4-甲基吡啶-3-胺(582mg,3.88mmol)溶于THF(20mL)，将反应冷至0℃，滴加NaHMDS(5.8mL,11.60mmol,2M in THF)，反应搅拌15分钟，滴加2,5-二氟-6-(2-氟-6-甲氧基苯基)烟酸(1.0g,3.53mmol)的THF溶液(6mL)。反应在室温下搅拌3小时。将反应液中倒入30mL饱和NH 4Cl中。用40mL乙酸乙酯萃取3次。有机相干燥后浓缩,粗品用快速硅胶柱纯化(0-5％MeOH/DCM)得产物5-氟-6-(2-氟-6-甲氧基苯基)-2-((2-异丙基-4-甲基吡啶-3-基)氨基)烟酸(850mg,Y:58.2％)，黄色固体。ES-API:[M+H] +＝414.1
步骤2：5-氟-6-(2-氟-6-甲氧基苯基)-2-((2-异丙基-4-甲基吡啶-3-基)氨基)烟酸(700mg,1.69mmol)溶于1,2-二氯乙烷(15mL)，加入SOCl 2(2.0g,16.90mmol)，反应在80℃下搅拌2小时。反应浓缩，得产物5-氟-6-(2-氟-6-甲氧基苯基)-2-((2-异丙基-4-甲基吡啶-3-基)氨基)烟酰氯(721mg,Y:100％)，无需纯化直接用于下一步反应。
步骤3：在0℃下，将硝基乙酸乙酯(449mg,3.38mmol)的THF(2ml)溶液滴加到含有NaH(608mg,15.21mmol)的THF(25mL)悬浮液中，反应在零度下搅拌半小时，5-氟-6-(2-氟-6-甲氧基苯基)-2-((2-异丙基-4-甲基吡啶-3-基)氨基)烟酰氯(721mg,1.69mmol)的THF(15mL)溶液滴加。撤掉冰浴，将反应液置于70℃搅拌过夜。将反应液中倒入冰水中，用3.0M稀盐酸调pH＝3，用乙酸乙酯萃取3次。有机相干燥后浓缩得产物6-氟-7-(2-氟-6-甲氧基苯基)-4-羟基-1-(2-异丙基-4-甲基吡啶-3-基)-3-硝基-1,8-萘啶-2(1H)-酮(1.05g,粗品)，直接用于下一步反应。ES-API:[M+H] +＝483.1
步骤4：6-氟-7-(2-氟-6-甲氧基苯基)-4-羟基-1-(2-异丙基-4-甲基吡啶-3-基)-3-硝基-1,8-萘啶-2(1H)-酮(1.05g,1.69mmol)溶于乙腈(25mL)，依次加入POCl 3(1.30g,8.45mmol)，和N,N-二异丙基乙胺(1.74g,13.52mmol)，反应在80℃下搅拌1小时。将反应液浓缩，加入乙酸乙酯依次用冰水，水，饱和食盐水洗涤。有机相干燥浓缩后，粗品用快速硅胶柱(EtOAc/PE：0-50％)纯化得产物得4-氯-6-氟-7-(2-氟-6-甲氧基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-3-硝基-1,8-萘啶-2(1H)-酮(185mg,Y:21.9％)，黄色固体。ES-API:[M+H] +＝500.1
步骤5：4-氯-6-氟-7-(2-氟-6-甲氧基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-3-硝基-1,8- 萘啶-2(1H)-酮(175mg,0.35mmol)溶于DMF(6mL)，加入(R)-3-(羟甲基)哌嗪-1-羧酸叔丁酯(454mg,2.10mmol)，反应在80℃搅拌18小时。将反应液中倒入30mL水中。用20mL乙酸乙酯萃取3次。有机相用饱和食盐水洗涤3次，干燥浓缩，粗品用快速硅胶柱纯化(EtOAc/PE：0-70％)得产物(3R)-4-(6-氟-7-(2-氟-6-甲氧基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-3-硝基-2-氧代-1,2-二氢-1,8-萘啶-4-基)-3-(羟甲基)哌嗪-1-羧酸叔丁酯(85mg,Y:35.7％)，黄色固体。ES-API:[M+H] +＝681.3。
步骤6：(3R)-4-(6-氟-7-(2-氟-6-甲氧基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-3-硝基-2-氧代-1,2-二氢-1,8-萘啶-4-基)-3-(羟甲基)哌嗪-1-羧酸叔丁酯(73mg,0.11mmol)溶于DMA(4mL)，加入NaH(22mg,0.55mmol),反应在145℃搅拌10小时。将冷却的反应液中倒入15mL水中。用30mL乙酸乙酯萃取3次。有机相用饱和食盐水洗涤3次，干燥浓缩，粗品用厚薄层色谱板(二氯甲烷/甲醇＝20：1)得产物(4aR)-11-氟-10-(2-氟-6-甲氧基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-7-氧代-1,2,4a,5,7,8-六氢吡嗪[1',2':4,5][1,4]氧代-2,3-c][1,8]萘啶-3(4H)-甲酸叔丁酯(35mg,Y:51.5％)，黄色固体。ES-API:[M+H] +＝634.2
步骤7：(4aR)-11-氟-10-(2-氟-6-甲氧基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-7-氧代-1,2,4a,5,7,8-六氢吡嗪[1',2':4,5][1,4]氧代-2,3-c][1,8]萘啶-3(4H)-甲酸叔丁酯(35mg，0.055mmol)溶于二氯甲烷(2.5mL)，加入三氟乙酸(0.5mL)。室温搅拌0.5小时，反应液浓缩得产物(4aR)-11-氟-10-(2-氟-6-甲氧基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-1,2,3,4,4a,5-六氢吡嗪[1',2':4,5][1,4]噁嗪[2,3-c][1,8]萘啶-7(8H)-酮(40mg,粗品)，直接用于下一步反应。ES-API:[M+H] +＝534.3。
步骤8：(4aR)-11-氟-10-(2-氟-6-甲氧基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-1,2,3,4,4a,5-六氢吡嗪[1',2':4,5][1,4]噁嗪[2,3-c][1,8]萘啶-7(8H)-酮(40mg，0.055mmol)溶于二氯甲烷(4mL)，加入三乙胺(28mg，0.28mmol)。将反应冷至0℃，向反应液中滴加丙烯酸酐(6mg，0.05mmol)的二氯甲烷溶液(0.5mL)。反应在0℃搅拌15分钟。向反应液中加入10mL饱和NaHCO 3水溶液，用10mL二氯甲烷萃取3次。有机相干燥后浓缩，粗品用品用厚薄层色谱板(二氯甲烷/甲醇＝10：1)得产物(4aR)-3-丙烯酰基-11-氟-10-(2-氟-6-甲氧基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-1,2,3,4,4a,5-六氢吡嗪[1',2':4,5][1,4]噁嗪[2,3-c][1,8]萘啶-7(8H)-酮(17mg,Y:52.4％)，淡黄色固体。ES-API:[M+H] +＝588.2。
步骤9：(4aR)-3-丙烯酰基-11-氟-10-(2-氟-6-甲氧基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-1,2,3,4,4a,5-六氢吡嗪[1',2':4,5][1,4]噁嗪[2,3-c][1,8]萘啶-7(8H)-酮(15mg，0.025mmol)溶于二氯甲烷(1.5mL)。将反应冷至0℃，向其中滴加17％三溴化硼的二氯甲烷溶液(1mL)。反应在室温下搅拌3小时。将反应液倒入20mL饱和NaHCO 3水溶液，用20mL二氯甲烷萃取3次。有机相干燥后浓缩，粗品用制备HPLC纯化得产物(4aR)-3-丙烯酰基-11-氟-10-(2-氟-6-羟基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-1,2,3,4,4a,5-六氢吡嗪[1',2':4,5][1,4]噁嗪[2,3-c][1,8]萘啶-7(8H)-酮(Z1，10mg,Y：68.3％)，白色固体。 1H NMR(500MHz,DMSO-d 6)δ9.96(s,1H),8.35(d,J＝4.8Hz,1H),7.19-7.14(m,2H),6.87-6.75(m,1H),6.64(d,J＝8.5Hz,1H),6.59(t,J＝8.5Hz,1H),6.12(d,J＝15.9Hz,1H),5.71-5.67(m,1H),4.39-3.95(m,4H),3.79-3.30(m,4H),3.06-2.98(m,1H),2.56-2.29(m,1H),1.80-1.73(m,3H),0.99-0.95(m,3H),0.85-0.80(m,3H).ES-API:[M+H] +＝574.2。
步骤10：将化合物Z1通过制备型手性HPLC拆分(柱型:Chiralpak IC:10μm, 20*250mm,流动相:乙腈:异丙醇:氨甲醇＝70:30:0.2,流速:15ml/min,柱温:室温)得到：一个阻转异构体化合物，结构任意指定为Z1-1(75mg,峰1，保留时间3.94min，Y：15.4％)，淡黄色固体。 1H NMR(400MHz,DMSO-d 6)δ10.04(s,1H),8.42(d,J＝4.9Hz,1H),8.22(d,J＝8.3Hz,1H),7.28-7.20(m,2H),6.96-6.81(m,1H),6.75–6.58(m,2H),6.18(d,J＝17.1Hz,1H),5.82–5.69(m,1H),4.49–4.00(m,4H),3.90–3.43(m,4H),3.08(t,J＝11.0Hz,1H),2.64-2.55(m,1H),1.80(s,3H),1.05(d,J＝6.7Hz,3H),0.91(d,J＝6.7Hz,3H).ES-API:[M+H] +＝574.2。和另一个阻转异构体化合物，结构任意指定为Z1-2(115mg,峰2，保留时间5.04min，Y：23.6％)，淡黄色固体。 1H NMR(400MHz,DMSO-d 6)δ10.05(s,1H),8.42(d,J＝4.8Hz,1H),8.22(d,J＝6.9Hz,1H),7.28-7.20(m,2H),6.96-6.81(m,1H),6.74–6.59(m,2H),6.19(d,J＝16.7Hz,1H),5.83–5.68(m,1H),4.49–4.00(m,4H),3.94–3.44(m,4H),3.08(t,J＝11.0Hz,1H),2.49–2.41(m,1H),1.87(s,3H),1.03(dd,J＝6.3,3.7Hz,3H),0.88(d,J＝6.6Hz,3H).ES-API:[M+H] +＝574.2。异构体化合物通过分析型手性HPLC方法(柱型:Chiralpak IC:5μm,4.6*250mm,流动相:乙腈:异丙醇:氨甲醇＝70:30:0.2,流速:1ml/min,柱温＝30℃)进行检测。
实施例2制备化合物Z2
Figure PCTCN2020124226-appb-000094
步骤1：在室温下，向100mL圆底烧瓶中加入5-(甲氧基亚甲基)-2,2-二甲基-1,3-二氧六环-4,6-二酮(2.9g,15.62mmol)和异丙醇(40mL)，2-氯吡啶-3-胺(2.0g,15.62mmol)分批加入。反应回流搅拌15分钟。反应液冷却到室温，析出的固体过滤，滤饼用少量异丙醇洗涤，真空干燥得产物5-((2-氯吡啶-3-基)氨基)亚甲基)-2,2-二甲基-1,3-二氧六环-4,6-二酮(3.90g,Y:58.2％)，白色固体。ES-API:[M+H] +＝283.1
步骤2：向500mL圆底烧瓶中加入200mL二苯醚，加热到220℃，分批加入5-((2-氯吡啶-3-基)氨基)亚甲基)-2,2-二甲基-1,3-二氧六环-4,6-二酮(3.9g,13.83mmol)，反应在220℃下搅拌20分钟。反应液冷却到室温，倒入石油醚中，析出的固体过滤，滤饼用石油醚洗涤，真空干燥得产物8-氯-1,7-萘啶-4-醇(1.5g,Y:60％)，淡棕色固体。ES-API:[M+H] +＝181.0
步骤3：向50mL圆底烧瓶中加入8-氯-1,7-萘啶-4-醇(500mg,2.78mmol)，乙酸钠(300mg,2.78mmol)，无水乙醇(25mL)，和5％Pd/C(250mg)，反应在氢气球下室温搅拌3天。反应液用硅藻土过滤，滤液浓缩，粗品用快速硅胶柱(二氯甲烷/甲醇：0-10％)纯化得产物1,7-萘啶-4-醇(200mg,Y:49.3％)，黄色固体。ES-API:[M+H] +＝147.1
步骤4：1,7-萘啶-4-醇(550mg,3.77mmol)溶于浓硫酸(4.5mL)，冷却到0℃，浓硝酸(1.0mL,15.08mmol)缓慢滴加，反应在100℃下搅拌1小时。冷却的反应液倒入冰水中，用浓氨水调pH到6-7，析出的固体过滤，真空干燥得产物得3-硝基-1,7-萘啶-4-醇(530mg,Y:73.7％)，黄色固体。ES-API:[M+H] +＝192.1
步骤5：向20mL圆底烧瓶中加入3-硝基-1,7-萘啶-4-醇(480mg,2.51mmol)和三氯氧磷(4.68mL，50.20mmol)，冷却到-15℃,三乙胺(1.8mL,12.55mmol)缓慢滴加，反应室温下搅拌1小时。将反应液中倒入冰水中，用冷的饱和碳酸氢钠溶液调pH＝8，用二氯甲烷萃取3次。有机相干燥浓缩得产物4-氯-3-硝基-1,7-萘啶(450mg,Y:85.7％)，棕色固体。ES-API:[M+H] +＝210.1。
步骤6：4-氯-3-硝基-1,7-萘啶(450mg,2.15mmol)溶于1，4-二氧六环(15mL)依次加入(R)-3-(羟甲基)哌嗪-1-羧酸叔丁酯(1.02g,4.73mmol)和N,N-二异丙基乙胺(832mg，6.45mmol)，反应在80℃搅拌3小时。将反应液浓缩，粗品用快速硅胶柱纯化(EtOAc/PE：50-100％)得产物(R)-3-(羟甲基)-4-(3-硝基-1,7-萘啶-4-基)哌嗪-1-羧酸叔丁酯(330mg,Y:39.4％)，黄色固体。ES-API:[M+H] +＝390.2。
步骤7：向50mL封管中依次加入(R)-3-(羟甲基)-4-(3-硝基-1,7-萘啶-4-基)哌嗪-1-羧酸叔丁酯(310mg,0.80mmol)，DMF(18mL)，和NaH(96mg,2.40mmol),反应在95℃搅拌3天。将冷却的反应液中倒入水中，用乙酸乙酯萃取2次。有机相用饱和食盐水洗涤3次，干燥浓缩，粗品用厚薄层色谱板(二氯甲烷/甲醇＝15：1)得产物(R)-8a,9,11,12-四氢吡嗪[1',2':4,5][1,4]噁嗪[2,3-c][1,7]萘啶-10(8H)-羧酸叔丁酯(175mg,Y:64％)，黄色固体。ES-API:[M+H] +＝343.3
步骤8：(R)-8a,9,11,12-四氢吡嗪[1',2':4,5][1,4]噁嗪[2,3-c][1,7]萘啶-10(8H)-羧酸叔丁酯(100mg,0.29mmol)溶于乙酸(4mL)加入氰基硼氢化钠(73mg,1.16mmol),反应室温搅拌过夜。将反应液中倒入冰水中，用饱和碳酸氢钠溶液调pH＝8，用二氯甲烷萃取2次。有机相用饱和食盐水洗涤，干燥浓缩，粗品用厚薄层色谱板(二氯甲烷/甲醇/氨水＝100：8：1)得产物(R)-1,2,3,4,8a,9,11,12-八氢吡嗪[1',2':4,5][1,4]噁嗪[2,3-c][1,7]萘啶-10(8H)-羧酸叔丁酯(50mg,Y:49.4％)，淡黄色固体。ES-API:[M+H] +＝390.2。
步骤9：向5mL微波管中加入(R)-1,2,3,4,8a,9,11,12-八氢吡嗪[1',2':4,5][1,4]噁嗪[2,3-c][1,7]萘啶-10(8H)-羧酸叔丁酯(50mg，0.14mmol)，4-溴-5-甲基-1-(四氢-2H-吡喃-2-基)-1H-吲唑(83mg，0.28mmol)，碳酸铯(136mg，0.42mmol)，Pd 2(dba) 3(51mg，0.056mmol)，Ruphos(26mg,0.056mmol)和甲苯(6mL)，氮气置换，用微波反应器120℃，搅拌反应1小时，冷却至室温，过滤，滤液干燥后浓缩，粗品用厚薄层色谱板(二氯甲烷/甲醇/氨水＝100：5：1)得到(8aR)-3-(5-甲基-1-(四氢-2H-吡喃-2-基)-1H-吲哒唑-4-基)-1,2,3,4,8a,9,11,12-八氢吡嗪[1',2':4,5][1,4]噁嗪[2,3-c][1,7]萘啶-10(8H)-羧酸叔丁酯(60mg,Y:74.1％)。ES-API:[M+H] +＝561.3
步骤10：(8aR)-3-(5-甲基-1-(四氢-2H-吡喃-2-基)-1H-吲哒唑-4-基)-1,2,3,4,8a,9,11,12- 八氢吡嗪[1',2':4,5][1,4]噁嗪[2,3-c][1,7]萘啶-10(8H)-羧酸叔丁酯(60mg，0.11mmol)溶于二氯甲烷(3mL)，加入三氟乙酸(0.8mL)。室温搅拌1小时，反应液浓缩得产物(R)-3-(5-甲基-1H-吲哒唑-4-基)-1,2,3,4,8,8a,9,10,11,12-十氢吡嗪[1',2':4,5][1,4]噁嗪[2,3-c][1,7]萘啶(60mg,粗产率)，无需纯化直接用于下一步反应。ES-API:[M+H] +＝377.1。
步骤11：(R)-3-(5-甲基-1H-吲哒唑-4-基)-1,2,3,4,8,8a,9,10,11,12-十氢吡嗪[1',2':4,5][1,4]噁嗪[2,3-c][1,7]萘啶(60mg，0.11mmol)和N,N-二异丙基乙胺(71mg，0.55mmol)溶于二氯甲烷(5mL)，将反应冷至0℃，向反应液中滴加丙烯酸酐(13mg，0.10mmol)的二氯甲烷溶液(0.5mL)。反应在0℃搅拌10分钟。向反应液中加入10mL饱和NaHCO 3水溶液，用10mL二氯甲烷萃取3次。有机相干燥后浓缩，粗品用制备HPLC纯化得产物(R)-1-(3-(5-甲基-1H-吲哒唑-4-基)-1,2,3,4,8a,9,11,12-辛氢吡嗪[1',2':4,5][1,4]噁嗪[2,3-c][1,7]萘啶-10(8H)-基)丙基-2-烯-1-酮(Z2，12mg,Y:26.0％)，白色固体。 1H NMR(500MHz,DMSO-d 6)δ12.91(s,1H),8.04(s,1H),7.86(s,1H),7.21–7.07(m,2H),6.89–6.64(m,1H),6.09(d,J＝16.6Hz,1H),5.67(m,1H),4.21-4.11(m,3H),3.96(t,J＝10.0Hz,1H),3.86-3.53(m,4H),3.45-3.30(m,2H),3.15-3.08(m,1H),2.86-2.75(m,2H),2.28(s,3H).ES-API:[M+H] +＝431.2。
实施例3制备化合物Z3a和Z3
Figure PCTCN2020124226-appb-000095
步骤1：4-氯-6-氟-7-(2-氟-6-甲氧基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-3-硝基-1,8-萘啶-2(1H)-酮(700mg,1.40mmol)溶于DMF(10mL)，加入(2R,5R)-5-(羟甲基)-2-甲基哌嗪-1-羧酸叔丁酯(1.61g,7.0mmol)，反应在80℃搅拌1小时。将反应液中倒入30mL水中。用20mL乙酸乙酯萃取3次。有机相用饱和食盐水洗涤3次，干燥浓缩，粗品用快速硅胶柱纯化(EtOAc/PE：0-70％)得产物(2R,5R)-4-(6-氟-7-(2-氟-6-甲氧基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-3-硝基-2-氧代-1,2-二氢-1,8-萘啶-4-基)-5-(羟甲基)-2-甲基哌嗪-1-羧酸叔丁酯(325mg,Y:33.4％)，黄色固体。ES-API:[M+H] +＝695.2。
步骤2：(2R,5R)-4-(6-氟-7-(2-氟-6-甲氧基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-3-硝基-2-氧代-1,2-二氢-1,8-萘啶-4-基)-5-(羟甲基)-2-甲基哌嗪-1-羧酸叔丁酯(300mg,0.44mmol)溶于DMA(20mL)，加入NaH(52mg,1.32mmol),反应在125℃搅拌20小时。将冷却的反应液中倒入15mL水中。用30mL乙酸乙酯萃取3次。有机相用饱和食盐水洗涤8次，干燥浓缩，粗品用快速硅胶柱纯化(EtOAc/PE：0-100％)得产物(2R,4aR)-11-氟-10-(2-氟-6-甲氧基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-2-甲基-7-氧代-1,2,4a,5,7,8-六氢 吡嗪[1’,2’:4,5][1,4]氧嗪[2,3-c][1,8]萘啶-3(4H)-羧酸叔丁酯(60mg,Y:21.4％)，黄色固体。ES-API:[M+H]+＝648.3。
步骤3：(2R,4aR)-11-氟-10-(2-氟-6-甲氧基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-2-甲基-7-氧代-1,2,4a,5,7,8-六氢吡嗪[1’,2’:4,5][1,4]氧嗪[2,3-c][1,8]萘啶-3(4H)-羧酸叔丁酯(60mg，0.093mmol)溶于二氯甲烷(3mL)，加入三氟乙酸(0.7mL)。室温搅拌1小时，反应液浓缩得产物(2R,4aR)-11-氟-10-(2-氟-6-甲氧基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-2-甲基-1,2,3,4,4a,5-六氢吡嗪[1’,2’:4,5][1,4]噁嗪[2,3-c][1,8]萘啶-7(8H)-酮(61mg,粗品)，直接用于下一步反应。ES-API:[M+H] +＝548.2。
步骤4：(2R,4aR)-11-氟-10-(2-氟-6-甲氧基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-2-甲基-1,2,3,4,4a,5-六氢吡嗪[1’,2’:4,5][1,4]噁嗪[2,3-c][1,8]萘啶-7(8H)-酮(61mg，0.093mmol)溶于二氯甲烷(5mL)，加入三乙胺(47mg，0.46mmol)。将反应冷至0℃，向反应液中滴加丙烯酸酐(17mg，0.14mmol)的二氯甲烷溶液(1mL)。反应在0℃搅拌15分钟。向反应液中加入10mL饱和NaHCO 3水溶液，用10mL二氯甲烷萃取3次。有机相干燥后浓缩，粗品用品用厚薄层色谱板(二氯甲烷/甲醇＝10：1)得产物((2R,4aR)-3-丙烯酰基-11-氟-10-(2-氟-6-甲氧基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-2-甲基-1,2,3,4,4a,5-六氢吡嗪[1’,2’:4,5][1,4]氧吡嗪[2,3-c][1,8]萘啶-7(8H)-酮(Z3a，32mg,Y:57.4％)，白色固体。ES-API:[M+H] +＝602.2。 1H NMR(500MHz,DMSO-d 6)δ8.42(d,J＝4.1Hz,1H),7.87(d,J＝8.8Hz,1H),7.43(dd,J＝15.4,8.3Hz,1H),7.21(d,J＝4.8Hz,1H),6.99–6.78(m,3H),6.17(d,J＝17.4Hz,1H),5.75(d,J＝10.5Hz,1H),4.80-4.15(m,4H),3.94–3.35(m,6H),3.13-2.97(m,1H),2.62-2.40(m,1H),1.90-1.73(m,3H),1.66-1.48(m,3H),1.08–0.95(m,3H),0.91–0.77(m,3H).
步骤5：(6aR,9R)-8-丙烯酰基-3-氟-2-(2-氟-6-甲氧基苯基)-13-(2-异丙基-4-甲基吡啶-3-基)-9-甲基-6,6a，7,8,9,10-六氢吡嗪[1’,2’:4,5][1,4]氧吡嗪[3,2-c][1,8]萘啶-12(13H)-酮(32mg，0.053mmol)溶于二氯甲烷(1.5mL)。将反应冷至0℃，向其中滴加17％三溴化硼的二氯甲烷溶液(1mL)。反应在室温下搅拌3小时。将反应液倒入20mL饱和NaHCO 3水溶液，用20mL二氯甲烷萃取3次。有机相干燥后浓缩，粗品用制备HPLC纯化得产物(6aR,9R)-8-丙烯酰基-3-氟-2-(2-氟-6-羟基苯基)-13-(2-异丙基-4-甲基吡啶-3-基)-9-甲基-6,6a,7,8,9,10-六氢吡嗪[1’,2’:4,5][1,4]氧吡嗪[3,2-c][1,8]萘啶-12(13H)-酮(Z3，18mg,Y：57.6％)，白色固体。ES-API:[M+H] +＝588.3。
实施例6制备化合物Z6
Figure PCTCN2020124226-appb-000096
步骤1：4,6-二氯-7-(2-氟-6-甲氧基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-3-硝基-1,8-萘啶-2(1H)-酮(1.8g,3.48mmol)溶于DMF(15mL)，加入(R)-3-(羟甲基)哌嗪-1-羧酸叔丁酯(3g,13.92mmol)，反应在80℃搅拌2小时。将反应液中倒入30mL水中。用20mL乙酸乙酯萃取3次。有机相用饱和食盐水洗涤3次，干燥浓缩，粗品用快速硅胶柱纯化(EtOAc/PE：0-70％)得产物(3R)-4-(6-氯-7-(2-氟-6-甲氧基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-3-硝基-2-氧代-1,2-二氢-1,8-萘啶-4-基)-3-(羟甲基)哌嗪-1-甲酸叔丁酯(1.3g，54％)，黄色固体。ES-API:[M+H] +＝697.2。
步骤2：(3R)-4-(6-氯-7-(2-氟-6-甲氧基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-3-硝基-2-氧代-1,2-二氢-1,8-萘啶-4-基)-3-(羟甲基)哌嗪-1-甲酸叔丁酯(1.3g,1.86mmol)溶于DMA(10mL)，加入LHMDS(5.6mmol,5.6mmol,1M四氢呋喃溶液)，反应在140℃搅拌20小时。将冷却的反应液中倒入15mL水中。用30mL乙酸乙酯萃取3次。有机相用饱和食盐水洗涤3次，干燥浓缩，粗品用快速硅胶柱纯化(甲醇/二氯甲烷：0-10％)得(4aR)-11-氯-10-(2-氟-6-甲氧基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-7-氧代-1,2,4a,5,7,8-六氢吡嗪并[1',2':4,5][1,4]噁嗪并[2,3-c][1,8]萘啶-3(4H)-羧酸叔丁酯(0.24g，20％)，黄色固体。ES-API:[M+H] +＝650.2。
步骤3：(4aR)-11-氯-10-(2-氟-6-甲氧基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-7-氧代-1,2,4a,5,7,8-六氢吡嗪并[1',2':4,5][1,4]噁嗪并[2,3-c][1,8]萘啶-3(4H)-羧酸叔丁酯(240mg，0.37mmol)溶于二氯甲烷(2mL)，加入三氟乙酸(2mL)。室温搅拌0.5小时，反应液浓缩得产物(4aR)-11-氯-10-(2-氟-6-甲氧基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-1,2,3,4,4a,5-六氢吡嗪并[1’,2’:4,5][1,4]噁嗪并[2,3-c][1,8]萘啶-7(8H)-酮(203mg，粗品)，直接用于下一步反应。ES-API:[M+H] +＝550.1。
步骤4：(4aR)-11-氯-10-(2-氟-6-甲氧基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-1,2,3,4,4a，5-六氢吡嗪并[1’,2’:4,5][1,4]噁嗪并[2,3-c][1,8]萘啶-7(8H)-酮(203mg，0.37mmol)溶于二氯甲烷(4mL)，加入三乙胺(187mg，1.85mmol)。将反应冷至0℃，向反应液中滴加丙烯酸酐(37mg，0.30mmol)的二氯甲烷溶液(0.5mL)。反应在0℃搅拌10分钟。向反应液中加入10mL饱和NaHCO 3水溶液，用10mL二氯甲烷萃取3次。有机相干燥后浓缩，粗品用品用厚薄层色谱板(二氯甲烷/甲醇＝10：1)得产物(4aR)-3-丙烯酰基-11-氯-10-(2-氟-6-甲氧基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-1,2,3,4,4a，5-六氢吡嗪并[1’,2’:4,5][1,4]噁嗪并[2,3-c][1,8]萘啶-7(8H)-酮((223mg,粗品)，淡黄色固体。ES-API:[M+H] +＝604.2。
步骤5：(4aR)-3-丙烯酰基-11-氯-10-(2-氟-6-甲氧基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-1,2,3,4,4a,5-六氢吡嗪并[1’,2’:4,5][1,4]噁嗪并[2,3-c][1,8]萘啶-7(8H)-酮(223mg，0.37mmol)溶于二氯甲烷(1.5mL)。将反应冷至0℃，向其中滴加17％三溴化硼的二氯甲烷溶液(3mL)。反应在室温下搅拌1小时。将反应液倒入20mL饱和NaHCO 3水溶液，用20mL二氯甲烷萃取3次。有机相干燥后浓缩，粗品用制备HPLC纯化得产物(4aR)-3-丙烯酰基-11-氯-10-(2-氟-6-羟基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-1,2,3,4,4a,5-六氢吡嗪并[1',2':4,5][1,4]噁嗪并[2,3-c][1,8]萘啶-7(8H)-酮(Z6，26.28mg,11％)，白色固体。 1H NMR(400MHz,DMSO-d 6)δ8.42-8.36(m,2H),7.22-7.18(m,2H),6.68-6.62(m,3H),6.22-6.17(m,1H),5.78-5.77(m,1H),4.46-3.55(m,8H),3.12-3.10(m,1H),2.52-2.51(m,1H),1.88-1.80(m,3H),1.06-1.04(m,3H),0.89-0.86(m,3H).ES-API:[M+H] +＝590.2。
实施例9制备化合物Z9、Z9-1和Z9-2
Figure PCTCN2020124226-appb-000097
步骤1：4-氯-6-氟-7-(2-氟-6-甲氧基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-3-硝基-1,8-萘啶-2(1H)-酮(500mg,1.00mmol)溶于N,N-二甲基乙酰胺(6mL)，依次加入(R)-1-(叔丁基)3-甲基-哌嗪-1,3-二羧酸酯(732mg,3.00mmol)，和N,N-二异丙基乙胺(387mg,3.00mmol)，反应在120℃搅拌2小时。反应液中加入100mL乙酸乙酯，用30mL稀盐水洗涤4次，30mL饱和食盐水洗涤，干燥浓缩，粗品用快速硅胶柱纯化(EtOAc/PE：0-70％)得产物(3R)-1-(叔丁基)-3-甲基-4-(6-氟-7-(2-氟-6-甲氧基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-3-硝基-2-氧代-1,2-二氢-1,8-萘啶-4-基)哌嗪-1,3-二羧酸酯(500mg,Y:70.6％)，黄色固体。ES-API:[M+H] +＝709.2。
步骤2：(3R)-1-(叔丁基)-3-甲基-4-(6-氟-7-(2-氟-6-甲氧基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-3-硝基-2-氧代-1,2-二氢-1,8-萘啶-4-基)哌嗪-1,3-二羧酸酯(500mg,0.71mmol)溶于乙酸(8mL)，加入铁粉(138mg,2.47mmol),反应在80℃搅拌30分钟。反应液浓缩，依次加入50mL乙酸乙酯和30mL饱和碳酸氢钠，悬浮液用硅藻土过滤，滤饼用乙酸乙酯洗涤，有机相分离，依次用30mL饱和碳酸氢钠水溶液，30mL饱和食盐水洗涤，干燥浓缩得产物(4aR)-11-氟-10-(2-氟-6-甲氧基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-5,7-二氧代-1,2,4,4a,5,6,7,8-八氢-3H-吡嗪[1’,2’:4,5]吡嗪[2,3-c][1,8]萘啶-3-羧酸叔丁酯(450mg,Y:98.6％)，淡黄色固体。ES-API:[M+H] +＝647.2。
步骤3：向15mL封管中依次加入(4aR)-11-氟-10-(2-氟-6-甲氧基苯基)-8-(2-异丙基 -4-甲基吡啶-3-基)-5,7-二氧代-1,2,4,4a,5,6,7,8-八氢-3H-吡嗪[1’,2’:4,5]吡嗪[2,3-c][1,8]萘啶-3-羧酸叔丁酯(450mg，0.70mmol)，12mL丙酮，无水碳酸钾(290mg,2.10mmol)，碘甲烷(596mg，4.20mmol)。密封封管，反应在50℃搅拌20小时。反应液浓缩，加入60mL乙酸乙酯，依次用30mL水，30mL饱和食盐水洗涤，干燥浓缩，粗品用快速硅胶柱纯化(EtOAc/PE：0-70％)得产物(4aR)-11-氟-10-(2-氟-6-甲氧基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-6-甲基-5,7-二氧基-1,2,4,4a,5,6,7,8-八氢-3H-吡嗪[1’,2’:4,5]吡嗪[2,3-c][1,8]萘啶-3-羧酸叔丁酯(390mg,Y:84.8％)，橙色固体。ES-API:[M+H] +＝661.3。
步骤4：(4aR)-11-氟-10-(2-氟-6-甲氧基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-6-甲基-5,7-二氧基-1,2,4,4a,5,6,7,8-八氢-3H-吡嗪[1’,2’:4,5]吡嗪[2,3-c][1,8]萘啶-3-羧酸叔丁酯(940mg,1.42mmol)溶于二氯甲烷(6mL)，加入三氟乙酸(2mL)。室温搅拌2小时，反应液浓缩得产物(4aR)-11-氟-10-(2-氟-6-甲氧基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-6-甲基-2,3,4,4a,6,8-六氢-1H-吡嗪[1’,2’:4,5]吡嗪[2,3-c][1,8]萘啶-5,7-二酮(1.1g,粗品)，直接用于下一步反应。ES-API:[M+H] +＝561.3。
步骤5：(4aR)-11-氟-10-(2-氟-6-甲氧基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-6-甲基-2,3,4,4a,6,8-六氢-1H-吡嗪[1’,2’:4,5]吡嗪[2,3-c][1,8]萘啶-5,7-二酮(1.1g，粗品)溶于二氯甲烷(20mL)，加入N,N-二异丙基乙胺(916mg，7.10mmol)。将反应冷至0℃，向反应液中加入丙烯酰氯(256mg，2.84mmol)，反应在0℃搅拌15分钟。向反应液中加入30mL二氯甲烷，依次用15mL水，15mL饱和NaHCO 3水溶液，15mL饱和食盐水洗涤，干燥浓缩，干燥后浓缩，粗品用快速硅胶柱纯化(EtOAc/PE：0-100％)得产物((4aR)-3-丙烯酰-11-氟-10-(2-氟-6-甲氧基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-6-甲基-2,3,4,4a,6,8-六氢-1H-吡嗪[1’,2’:4,5]吡嗪[2,3-c][1,8]萘啶-5,7-二酮(780mg,Y:88.3％)，淡黄色固体。ES-API:[M+H] +＝615.3。
步骤6：(4aR)-3-丙烯酰基-11-氟-10-(2-氟-6-甲氧基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-6-甲基-2,3,4,4a,6,8-六氢-1H-吡嗪[1’,2’:4,5]吡嗪[2,3-c][1,8]萘啶-5,7-二酮(390mg，0.64mmol)溶于二氯甲烷(9mL)。将反应冷至0℃，向其中滴加17％三溴化硼的二氯甲烷溶液(7mL)。反应在室温下搅拌6小时。将反应液倒入60mL饱和NaHCO 3水溶液，用80mL二氯甲烷萃取2次。有机相依次用50mL饱和NaHCO 3水溶液，80mL饱和食盐水洗涤，干燥后浓缩得产物(4aR)-3-丙烯酰基-11-氟-10-(2-氟-6-羟基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-6-甲基-2,3,4,4a,6,8-六氢-1H-吡嗪[1’,2’:4,5]吡嗪[2,3-c][1,8,8]萘啶-5,7-二酮(Z9，375mg,Y：98.4％)，淡黄色固体。ES-API:[M+H] +＝601.2。
步骤7：(4aR)-3-丙烯酰-11-氟-10-(2-氟-6-羟基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-6-甲基-2,3,4,4a,6,8-六氢-1H-吡嗪[1’,2’:4,5]吡嗪[2,3-c][1,8,8]萘啶-5,7-二酮(750mg，1.25mmol)用制备HPLC纯化，然后再通过制备型手性HPLC拆分(柱型:IB:10μm,30*250mm,流动相:己烷:EtOH＝65:35,流速:25ml/min,柱温室温)得到：一个阻转异构体化合物，结构任意指定为Z9-1(250mg,峰1，保留时间6.463min，Y：33.3％)，淡黄色固体。 1H NMR(500MHz,DMSO-d 6)δ10.11(d,J＝1.3Hz,1H),8.46-8.34(m,2H),7.30–7.19(m,2H),7.10–6.79(m,1H),6.74–6.62(m,2H),6.15(d,J＝16.9Hz,1H),5.75(d,J＝12.0Hz,1H),4.73(d,J＝13.3Hz,1H),4.45(d,J＝12.7Hz,1H),4.10–3.97(m,1H),3.63-3.47(m,2H),3.39-3.08(m,4H),2.83-2.59(m,1H),2.48-2.39(m,1H),1.99(s,3H), 1.02(d,J＝6.7Hz,3H),0.85(d,J＝6.7Hz,3H).ES-API:[M+H] +＝601.2。和另一个阻转异构体化合物，结构任意指定为Z9-2(350mg,峰2，保留时间8.252min，Y：46.7％)，淡黄色固体。 1H NMR(500MHz,DMSO-d 6)δ10.14(s,1H),8.44(d,J＝4.9Hz,1H),8.38(d,J＝9.0Hz,1H),7.29–7.20(m,2H),7.10–6.79(m,1H),6.76–6.59(m,2H),6.15(d,J＝16.9Hz,1H),5.75(d,J＝11.1Hz,1H),4.73(d,J＝14.0Hz,1H),4.45(d,J＝12.4Hz,1H),4.02–3.89(m,1H),3.62–3.50(m,2H),3.33–3.09(m,4H),2.88–2.61(m,2H),1.79(s,3H),1.10(d,J＝6.7Hz,3H),0.98(d,J＝6.7Hz,3H).ES-API:[M+H] +＝601.2。异构体化合物通过分析型手性HPLC方法(柱型:IB:5μm,4.6*250mm,流动相:己烷:EtOH＝65:35,流速:1ml/min,柱温＝30℃)进行检测。
实施例10制备化合物Z10、Z10-1和Z10-2
Figure PCTCN2020124226-appb-000098
步骤1：向50mL封管中依次加入(2R,4aR)-11-氟-10-(2-氟-6-甲氧基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-2-甲基-5,7-二氧代-1,2,4,4a,5,6,7,8-辛基-3H-吡嗪[1’,2’:4,5]吡嗪[2,3-c][1,8]萘啶-3-羧酸叔丁酯(800mg，1.21mmol)，20mL丙酮，无水碳酸钾(500mg,3.63mmol)，碘甲烷(1.03g，7.26mmol)。密封封管，反应在50℃搅拌18小时。反应液浓缩，加入60mL乙酸乙酯，依次用20mL水，30mL饱和食盐水洗涤，干燥浓缩，粗品用快速硅胶柱纯化(EtOAc/PE：0-70％)得产物(2R,4aR)-11-氟-10-(2-氟-6-甲氧基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-2,6-二甲基-5,7-二氧代-1,2,4,4a,5,6,7,8-辛基-3H-吡嗪[1’,2’:4,5]吡嗪[2,3-c][1,8]萘啶-3-羧酸叔丁酯(790mg,Y:96.7％)，橙色固体。ES-API:[M+H] +＝675.3。
步骤2：(2R,4aR)-11-氟-10-(2-氟-6-甲氧基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-2,6-二甲基-5,7-二氧代-1,2,4,4a,5,6,7,8-辛基-3H-吡嗪[1’,2’:4,5]吡嗪[2,3-c][1,8]萘啶-3-羧酸叔丁酯(790mg,1.42mmol)溶于二氯甲烷(6mL)，加入三氟乙酸(2mL)。室温搅拌2小时，反应液浓缩得产物(2R,4aR)-11-氟-10-(2-氟-6-甲氧基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-2,6-二甲基-2,3,4,4a,6,8-六氢-1H-吡嗪[1’,2’:4,5]吡嗪[2,3-c][1,8]萘啶-5,7-二酮(810mg,粗品)，直接用于下一步反应。ES-API:[M+H] +＝575.2。
步骤3：(2R,4aR)-11-氟-10-(2-氟-6-甲氧基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-2,6-二甲基-2,3,4,4a,6,8-六氢-1H-吡嗪[1’,2’:4,5]吡嗪[2,3-c][1,8]萘啶-5,7-二酮(810mg，粗品)溶于二氯甲烷(15mL)，加入N,N-二异丙基乙胺(755mg，5.85mmol)。将反应冷至0℃， 向反应液中加入丙烯酰氯(211mg，2.34mmol)，反应在0℃搅拌15分钟。向反应液中加入50mL二氯甲烷，依次用20mL水，40mL饱和NaHCO 3水溶液，20mL饱和食盐水洗涤，干燥后浓缩，粗品用快速硅胶柱纯化(EtOAc/PE：0-100％)得产物(2R,4aR)-3-丙烯酰基-11-氟-10-(2-氟-6-甲氧基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-2,6-二甲基-2,3,4,4a,6,8-六氢-1H-吡嗪[1’,2’:4,5]吡嗪[2,3-c][1,8]萘啶-5,7-二酮(670mg,Y:91.0％)，淡黄色固体。ES-API:[M+H] +＝629.2。
步骤4：(2R,4aR)-3-丙烯酰基-11-氟-10-(2-氟-6-甲氧基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-2,6-二甲基-2,3,4,4a,6,8-六氢-1H-吡嗪[1’,2’:4,5]吡嗪[2,3-c][1,8]萘啶-5,7-二酮(370mg，0.59mmol)溶于二氯甲烷(8mL)。将反应冷至0℃，向其中滴加17％三溴化硼的二氯甲烷溶液(7mL)。反应在室温下搅拌3小时。将反应液倒入60mL饱和NaHCO 3水溶液，用80mL二氯甲烷萃取2次。有机相依次用50mL饱和NaHCO 3水溶液，80mL饱和食盐水洗涤，干燥后浓缩，粗品用制备HPLC纯化得产物(2R,4aR)-3-丙烯酰基-11-氟-10-(2-氟-6-羟基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-2,6-二甲基-2,3,4,4a,6-六氢-1H-吡嗪[1’,2’:4,5]吡嗪[2,3-c][1,8,8]萘啶-5-二酮(Z10，249mg,Y：68.7％)，淡黄色固体。ES-API:[M+H] +＝615.2。
步骤5：化合物Z10(450mg，1.06mmol)用制备型手性HPLC拆分(柱型:OD-H:10μm,20*250mm,流动相:己烷:EtOH＝80:20,流速:15ml/min,柱温室温)得到：一个阻转异构体化合物，结构任意指定为Z10-1(206mg,峰1，保留时间8.321min，Y：45.7％)，淡黄色固体。 1H NMR(500MHz,DMSO-d 6)δ10.13(d,J＝1.3Hz,1H),8.44(d,J＝4.9Hz,1H),8.02-7.95(m,1H),7.33–7.20(m,2H),7.06-6.82(m,1H),6.76–6.63(m,2H),6.24–6.08(m,1H),5.82–5.67(m,1H),5.05–4.73(m,1H),4.63–4.37(m,1H),4.07-3.97(m,1H),3.73(dd,J＝14.1,4.2Hz,1H),3.39-3.20(m,4H),2.94–2.78(m,1H),2.49-2.39(m,1H),1.99(s,3H),1.61-1.49(m,3H),1.02(d,J＝6.7Hz,3H),0.85(d,J＝6.7Hz,3H).ES-API:[M+H] +＝615.2。和另一个阻转异构体化合物，结构任意指定为Z10-2(209mg,峰2，保留时间10.183min，Y：46.4％)，黄色固体。 1H NMR(500MHz,DMSO-d 6)δ10.15(s,1H),8.45(d,J＝4.9Hz,1H),8.03-7.95(m,1H),7.30–7.18(m,2H),7.06-6.82(m,1H),6.75–6.61(m,2H),6.21–6.09(m,1H),5.80–5.65(m,1H),5.05–4.72(m,1H),4.63–4.37(m,1H),4.01-3.92(m,1H),3.74(dd,J＝14.2,4.2Hz,1H),3.43-3.21(m,4H),2.95–2.82(m,1H),2.80-2.72(m,1H),1.80(s,3H),1.60-1.48(m,3H),1.11(d,J＝6.7Hz,3H),0.98(d,J＝6.7Hz,3H).ES-API:[M+H] +＝615.2。异构体化合物通过分析型手性HPLC方法(柱型:OD-H:5μm,4.6*250mm,流动相:己烷:EtOH＝80:20,流速:1ml/min,柱温＝30℃)进行检测。
实施例4至5，7至8，11至20
化合物Z4至Z5，Z7至Z8，Z11至Z20参照化合物Z1或Z2的类似方法进行制备，其中各化合物起始原料可通过市购或参照本领域技术人员所熟知的现有方法进行制备，中间体的类似合成方法是本领域技术人员参照现有方法容易得到的。
Figure PCTCN2020124226-appb-000099
Figure PCTCN2020124226-appb-000100
Figure PCTCN2020124226-appb-000101
Figure PCTCN2020124226-appb-000102
实施例21制备化合物Z21、Z21-1和Z21-2
Figure PCTCN2020124226-appb-000103
步骤1：向圆底烧瓶中加入7-氯-6-氟-4-羟基-1-(4-异丙基-6-甲基嘧啶-5-基)-2-氧代-1,2-二氢-1,8-萘啶-3-腈(2g，5.34mmol)12mL水和12mL二氧六环。体系冷至0℃后，向反应液中滴加12mL浓硫酸。滴加完毕，反应在120℃下搅拌18小时。反应完毕，有大量固体析出。过滤，滤饼用水洗三次。滤饼干燥后得到7-氯-6-氟-4-羟基-1-(4-异丙基-6-甲基嘧啶-5-基)-1,8-萘啶-2(1H)-酮(1.4g,75％),白色固体。粗产品直接用于下一步。ES-API:[M+H] +＝349.1。
步骤2：向圆底烧瓶中加入7-氯-6-氟-4-羟基-1-(4-异丙基-6-甲基嘧啶-5-基)-1,8-萘啶-2(1H)-酮(1.3g,3.72mmol)，亚硝酸钠(26mg,0.37mmol)和8mL冰醋酸。向反应液中滴加浓硝酸(700mg,11.1mmol)。将反应置于30℃油浴中加热2小时。将反应液倒入冰水中，有固体析出。过滤，滤饼用水洗涤。收集滤饼，并真空干燥得到7-氯-6-氟-4-羟基-1-(4-异丙基-6-甲基嘧啶-5-基)-3-硝基-1,8-萘啶-2(1H)-酮(1.2g,纯度76％)，黄色固体。粗产品直接用于下一步。ES-API:[M+H] +＝394.1。
步骤3：向反应瓶中加入7-氯-6-氟-4-羟基-1-(4-异丙基-6-甲基嘧啶-5-基)-3-硝基-1,8-萘啶-2(1H)-酮(1.2g，3mmol)、2-氟-6-甲氧基苯硼酸(2g，12mmol)、2-二环己基膦基-2′,6′-二甲氧基联苯基(123mg，0.3mmol)，氯(2-二环己基膦-2′,6′-二甲氧基-1,1′-联苯)[2-(2′-氨基-1,1′-联苯)]钯(II)(216mg，0.3mmol)，磷酸钾(1.9g，9mmol)，15mL二氧六环和3mL水。反应在氮气保护下，110℃油浴中搅拌1小时，停止反应。向反应液中加入1M碳酸钾水溶液(30mL)，用20mLEtOAc/PE(1：1)萃取1次除掉杂质。水相再 用6M盐酸水溶液调节pH至4。用乙酸乙酯萃取3次。有机相用硫酸钠干燥，浓缩得到6-氟-7-(2-氟-6-甲氧基苯基)-4-羟基-1-(4-异丙基-6-甲基嘧啶-5-基)-3-硝基-1,8-萘啶-2(1H)-酮(1.1g，75％)，黄色固体。ES-API:[M+H] +＝483.1。
步骤4：向圆底烧瓶中加入6-氟-7-(2-氟-6-甲氧基苯基)-4-羟基-1-(4-异丙基-6-甲基嘧啶-5-基)-3-硝基-1,8-萘啶-2(1H)-酮(1.2g，2.48mmol)、二异丙基乙胺(3g,23.1mmol)、乙腈(20mL)。向其中滴加三氯氧磷(2.2g，14.5mmol)。反应在85℃搅拌1小时。LC-MS检测反应完成。将反应液倒入冰水中，用乙酸乙酯萃取。有机相用硫酸钠干燥，浓缩得到4-氯-6-氟-7-(2-氟-6-甲氧基苯基)-1-(4-异丙基-6-甲基嘧啶-5-基)-3-硝基-1,8-萘啶-2(1H)-酮(1.1g,纯度83％)，粗产品直接用于下一步反应。ES-API:[M+H] +＝502.1。
步骤5：向圆底烧瓶中加入4-氯-6-氟-7-(2-氟-6-甲氧基苯基)-1-(4-异丙基-6-甲基嘧啶-5-基)-3-硝基-1,8-萘啶-2(1H)-酮(1g，2mmol)、1-(叔丁基)3-甲基(R)-哌嗪-1,3-二羧酸酯(1.94g,8mmol)、N,N-二异丙基乙胺(516mg,4mmol)和N,N-二甲基乙酰胺(10mL)，反应在120℃下搅拌2小时。LC-MS检测反应完成。将反应液中倒入30mL水中。用乙酸乙酯萃取3次。有机相用饱和食盐水/水(v/v,1：1)洗涤四次，干燥浓缩，粗品用快速硅胶柱纯化(EtOAc/PE：0-40％)得1-(叔丁基)3-甲基(3R)-4-(6-氟-7-(2-氟-6-甲氧基苯基)-1-(4-异丙基-6-甲基嘧啶-5-基)-3-硝基-2-氧代-1,2-二氢-1,8-萘啶-4-基)哌嗪-1,3-二羧酸酯(1g,纯度82％)。ES-API:[M+H] +＝710.2。
步骤6：向反应瓶中加入1-(叔丁基)3-甲基(3R)-4-(6-氟-7-(2-氟-6-甲氧基苯基)-1-(4-异丙基-6-甲基嘧啶-5-基)-3-硝基-2-氧代-1,2-二氢-1,8-萘啶-4-基)哌嗪-1,3-二羧酸酯(1g，1.4mmol)、铁粉(390mg，7mmol)和15mL冰醋酸。反应在80℃下搅拌1小时。LC-MS检测反应完成。将反应液倒入50mL碳酸氢钠水溶液中，用30mL乙酸乙酯萃取3次。有机相干燥后浓缩得(4aR)-11-氟-10-(2-氟-6-甲氧基苯基)-8-(4-异丙基-6-甲基嘧啶-5-基)-5,7-二氧代-1,2,4,4a,5,6,7,8-八氢-3H-吡嗪并[1’,2’:4,5]吡嗪并[2,3-c][1,8]萘啶-3-羧酸叔丁酯(850mg，93％)，黄色固体。ES-API:[M+H] +＝648.3。
步骤7：向圆底烧瓶中加入(4aR)-11-氟-10-(2-氟-6-甲氧基苯基)-8-(4-异丙基-6-甲基嘧啶-5-基)-5,7-二氧代-1,2,4,4a,5,6,7,8-八氢-3H-吡嗪并[1’,2’:4,5]吡嗪并[2,3-c][1,8]萘啶-3-羧酸叔丁酯(450mg，0.69mmol)、碘甲烷(789mg,5.55mmol)、碳酸钾(286mg,2.07mmol)和10mL丙酮。反应在封管，50℃条件下搅拌16小时，LC-MS检测反应完毕。反应液用硅藻土过滤。滤液浓缩，粗品用快速硅胶柱纯化(EtOAc/PE：0-60％)得(4aR)-11-氟-10-(2-氟-6-甲氧基苯基)-8-(4-异丙基-6-甲基嘧啶-5-基)-6-甲基-5,7-二氧代-1,2,4,4a,5,6,7,8-八氢-3H-吡嗪并[1’,2’:4,5]吡嗪并[2,3-c][1,8]萘啶-3-羧酸叔丁酯(260mg，57％)，黄色固体。ES-API:[M+H] +＝662.2。
步骤8：向圆底烧瓶中加入(4aR)-11-氟-10-(2-氟-6-甲氧基苯基)-8-(4-异丙基-6-甲基嘧啶-5-基)-6-甲基-5,7-二氧代-1,2,4,4a,5,6,7,8-八氢-3H-吡嗪并[1’,2’:4,5]吡嗪并[2,3-c][1,8]萘啶-3-羧酸叔丁酯(260mg，0.39mmol)、1mL二氯甲烷和3mL三氟乙酸。室温搅拌1小时，LC-MS检测反应完毕。反应液浓缩得(4aR)-11-氟-10-(2-氟-6-甲氧基苯基)-8-(4-异丙基-6-甲基嘧啶-5-基)-6-甲基-2,3,4,4a,6,8-六氢-1H-吡嗪并[1’,2’:4,5]吡嗪并[2,3-c][1,8]萘啶-5,7-二酮(219mg)，黄色固体。粗产品直接用于下一步。ES-API:[M+H] +＝562.2。
步骤9：向50mL圆底烧瓶中加入(4aR)-11-氟-10-(2-氟-6-甲氧基苯基)-8-(4-异丙基-6-甲基嘧啶-5-基)-6-甲基-2,3,4,4a,6,8-六氢-1H-吡嗪并[1’,2’:4,5]吡嗪并[2,3-c][1,8]萘啶-5,7-二酮(219mg，0.39mmol)、3mL二氯甲烷和三乙胺(158mg，1.56mmol)。将反应冷至0℃，向反应液中滴加丙烯酰氯的二氯甲烷溶液(71mg，0.78mmol,0.5mL)。反应在0℃搅拌10分钟。向反应液中加入40mL饱和碳酸氢钠水溶液，用20mL二氯甲烷萃取3次。有机相干燥后浓缩得到(4aR)-3-丙烯酰基-11-氟-10-(2-氟-6-甲氧基苯基)-8-(4-异丙基-6-甲基嘧啶-5-基)-6-甲基-2,3,4,4a,6,8-六氢-1H-吡嗪并[1’,2’:4,5]吡嗪并[2,3-c][1,8]萘啶-5,7-二酮(240mg，87％纯度)，黄色固体。粗产品直接用于下一步。ES-API:[M+H] +＝616.3。
步骤10：向圆底烧瓶中加入(4aR)-3-丙烯酰基-11-氟-10-(2-氟-6-甲氧基苯基)-8-(4-异丙基-6-甲基嘧啶-5-基)-6-甲基-2,3,4,4a,6,8-六氢-1H-吡嗪并[1’,2’:4,5]吡嗪并[2,3-c][1,8]萘啶-5,7-二酮(240mg，0.39mmol)、3mL二氯甲烷。将反应液冷至0℃，向其中滴加17％三溴化硼的二氯甲烷溶液(6mL)。滴加完毕将反应在室温下搅拌2小时。将反应液倒入30mL冰的饱和NaHCO 3水溶液，用20mL二氯甲烷萃取3次。有机相干燥后浓缩，粗品用制备HPLC纯化得产物(4aR)-3-丙烯酰基-11-氟-10-(2-氟-6-羟基苯基)-8-(4-异丙基-6-甲基嘧啶-5-基)-6-甲基-2,3,4,4a,6,8-六氢-1H-吡嗪并[1’,2’:4,5]吡嗪并[2,3-c][1,8]萘啶-5,7-二酮(Z21，130mg,55％)，黄色固体。ES-API:[M+H] +＝602.2。
步骤11：化合物(4aR)-3-丙烯酰基-11-氟-10-(2-氟-6-羟基苯基)-8-(4-异丙基-6-甲基嘧啶-5-基)-6-甲基-2,3,4,4a,6,8-六氢-1H-吡嗪并[1’,2’:4,5]吡嗪并[2,3-c][1,8]萘啶-5,7-二酮(130mg)经过制备型手性HPLC拆分(柱型:Chiralpak IE:10μm,20*250mm；流动相:己烷:乙醇：二乙胺＝70:30:0.2；流速:15ml/min；柱温室温)得到：一个阻转异构体化合物，结构任意指定为Z21-1(峰2，保留时间:12.33min，47mg)，黄色固体。ES-API:[M+H] +＝602.2。 1HNMR(500MHz,DMSO-d 6):10.17(s,1H),9.03(s,1H),8.41(d,J＝9Hz,1H),7.26-7.25(m,1H),7.08-7.05(m,1H),6.68-6.66(m,2H),6.17-6.14(m,1H),5.77-5.75(m,1H),4.75-4.73(m,1H),4.46-4.44(m,1H),4.0-3.95(m,1H),3.55-3.54(m,2H),3.41(s,3H),3.20-3.18(m,1H),2.85-2.83(m,1H),2.68-2.65(m,1H),2.00(s,3H),1.13(d,J＝6.5Hz,3H),1.06(d,J＝6.5Hz,3H)。和另一个阻转异构体化合物，结构任意指定为Z21-2(峰1，保留时间:10.58min，48mg)，黄色固体。ES-API:[M+H] +＝602.2。 1HNMR(500MHz,DMSO-d 6):10.16(s,1H),9.03(s,1H),8.41(d,J＝9Hz,1H),7.26-7.25(m,1H),7.08-7.05(m,1H),6.68-6.66(m,2H),6.17-6.14(m,1H),5.77-5.75(m,1H),4.75-4.73(m,1H),4.46-4.44(m,1H),4.0-3.95(m,1H),3.55-3.54(m,2H),3.41(s,3H),3.20-3.18(m,1H),2.65-2.60(m,1H),2.52-2.51(m,1H),2.20(s,3H),1.06(d,J＝6.5Hz,3H),0.86(d,J＝6.5Hz,3H)。异构体化合物通过分析型手性HPLC方法(柱型:Chiralpak IE:5μm,4.6*250mm；流动相:己烷:乙醇：氨甲醇＝70:30:0.2；流速:1ml/min；柱温＝30℃)进行检测。
实施例22制备化合物Z22
Figure PCTCN2020124226-appb-000104
步骤1：7-氯-6-氟-4-羟基-1-(3-异丙基吡嗪-2-基)-1,8-萘啶-2(1H)-酮(2g，6mmol)溶于乙酸(5mL)，依次加入亚硝酸钠(41mg,0.6mmol)和浓硝酸(1.5g，24mmol)，反应在室温下搅拌30分钟。将反应液中缓慢倒入100mL冰水中，析出的固体过滤，滤饼用20ml冰水洗涤，在真空下干燥得产物7-氯-6-氟-4-羟基-1-(3-异丙基吡嗪-2-基)-3-硝基-1,8-萘啶-2(1H)-酮(1.5g，65％)，黄色固体。ES-API:[M+H] +＝380.2。
步骤2：向100mL三口圆底烧瓶中加入7-氯-6-氟-4-羟基-1-(3-异丙基吡嗪-2-基)-3-硝基-1,8-萘啶-2(1H)-酮(1.5g，3.94mmol)、(2-氟-6-甲氧基苯基)硼酸(2.04g，,12mmol)、氯(2-二环己基膦-2′,6′-二甲氧基-1,1′-联苯)[2-(2′-氨基-1,1′-联苯)]钯(II)(288mg，0.4mmol)，2-二环己基膦基-2′,6′-二甲氧基联苯基(164mg,0.4mmol)、磷酸钾(2.5g,12mmol)、10mL水和40mL二氧六环。氮气保护下，反应在100℃搅拌2～3小时。反应完毕，反应液冷却到室温，加入80mL水和100mL甲基叔丁基醚，萃取一次。水相用1M的盐酸溶液调pH3～5，用乙酸乙酯萃取(200mL*2)，合并乙酸乙酯相，无水硫酸钠干燥，过滤，滤液真空干燥后得产物6-氟-7-(2-氟-6-甲氧基苯基)-4-羟基-1-(3-异丙基吡嗪-2-基)-3-硝基-1,8-萘啶-2(1H)-酮(1.6g,粗品)，淡黄色固体。ES-API:[M+H] +＝470.1。
步骤3：6-氟-7-(2-氟-6-甲氧基苯基)-4-羟基-1-(3-异丙基吡嗪-2-基)-3-硝基-1,8-萘啶-2(1H)-酮(1.6g,3.4mmol)溶于乙腈(30mL)，依次加入三氯氧磷(2.6g,17mmol)，和N,N-二异丙基乙胺(3g,23.8mmol)，反应逐渐升至80℃并搅拌30分钟。将反应液浓缩，加入30mL冷的乙腈，冰水浴下滴加到150mL饱和碳酸氢钠溶液中，用乙酸乙酯萃取(200mL*2)，合并有机相，200mL饱和食盐水洗涤一次。无水硫酸钠干燥，过滤，有机相干燥浓缩后，粗品用快速硅胶柱(EtOAc/PE：0-50％)纯化得4-氯-6-氟-7-(2-氟-6-甲氧基苯基)-1-(3-异丙基吡嗪-2-基)-3-硝基-1,8-萘啶-2(1H)-酮(340mg,Y：20％)，黄色固体。ES-API:[M+H] +＝488.2。
步骤4：4-氯-6-氟-7-(2-氟-6-甲氧基苯基)-1-(3-异丙基吡嗪-2-基)-3-硝基-1,8-萘啶 -2(1H)-酮(310mg,0.64mmol)溶于N,N-二甲基乙酰胺(5mL)，依次加入1-(叔丁基)3-甲基(3R,6R)-6-甲基哌嗪-1,3-二羧酸(247mg,0.96mmol)，和N,N-二异丙基乙胺(250mg,1.92mmol)，反应在120℃搅拌2小时。反应液中加入50mL乙酸乙酯，用30mL饱和食盐水洗涤三次。乙酸乙酯相干燥浓缩，粗品用快速硅胶柱纯化(EtOAc/PE：0-80％)得产物1-(叔丁基)3-甲基(3R,6R)-4-(6-氟-7-(2-氟-6-甲氧基苯基)-1-(3-异丙基吡嗪-2-基)-3-硝基-2-氧代-1,2-二氢-1,8-萘啶-4-基)-6-甲基哌嗪-1,3-二羧酸酯(317mg,Y:70％)，黄色固体。ES-API:[M+H] +＝710.2。
步骤5：1-(叔丁基)3-甲基(3R,6R)-4-(6-氟-7-(2-氟-6-甲氧基苯基)-1-(3-异丙基吡嗪-2-基)-3-硝基-2-氧代-1,2-二氢-1,8-萘啶-4-基)-6-甲基哌嗪-1,3-二羧酸酯(280mg,0.4mmol)溶于乙酸(4mL)，加入铁粉(78mg,1.4mmol),反应在80℃搅拌30分钟。反应液浓缩，依次加入50mL乙酸乙酯和30mL饱和碳酸氢钠，悬浮液用硅藻土过滤，滤饼用乙酸乙酯洗涤，有机相分离，依次用100mL饱和碳酸氢钠，30mL饱和食盐水洗涤，干燥浓缩得产物(2R,4aR)-11-氟-10-(2-氟-6-甲氧基苯基)-8-(3-异丙基吡嗪-2-基)-2-甲基-5,7-二氧代-1,2,4,4a,5,6,7,8-八氢-3H-吡嗪并[1’,2’:4,5]吡嗪并[2,3-c][1,8]萘啶-3-羧酸叔丁酯(312mg,粗品)，黄色固体。ES-API:[M+H]+＝648.1。
步骤6：向15mL封管中依次加入(2R,4aR)-11-氟-10-(2-氟-6-甲氧基苯基)-8-(3-异丙基吡嗪-2-基)-2-甲基-5,7-二氧代-1,2,4,4a,5,6,7,8-八氢-3H-吡嗪并[1’,2’:4,5]吡嗪并[2,3-c][1,8]萘啶-3-羧酸叔丁酯(295mg，0.46mmol)，3mL丙酮，无水碳酸钾(1g,6.9mmol)，碘甲烷(253mg，1.84mmol)。密封封管，反应在55℃搅拌18小时。反应液加入50mL乙酸乙酯，用20mL饱和食盐水洗涤3次，干燥浓缩，得产物(2R,4aR)-11-氟-10-(2-氟-6-甲氧基苯基)-8-(3-异丙基吡嗪-2-基)-2,6-二甲基-5,7-二氧代-1,2,4,4a,5,6,7,8-八氢-3H-吡嗪并[1’,2’:4,5]吡嗪并[2,3-c][1,8]萘啶-3-羧酸叔丁酯(356mg,粗品)，黄色固体。ES-API:[M+H] +＝662.2。
步骤7：(2R,4aR)-11-氟-10-(2-氟-6-甲氧基苯基)-8-(3-异丙基吡嗪-2-基)-2,6-二甲基-5,7-二氧代-1,2,4,4a,5,6,7,8-八氢-3H-吡嗪并[1’,2’:4,5]吡嗪并[2,3-c][1,8]萘啶-3-羧酸叔丁酯(356mg,0.54mmol)溶于二氯甲烷(8mL)，加入三氟乙酸(4mL)。室温搅拌2小时，反应液浓缩得产物(2R,4aR)-11-氟-10-(2-氟-6-甲氧基苯基)-8-(3-异丙基吡嗪-2-基)-2,6-二甲基-2,3,4,4a,6,8-六氢-1H-吡嗪并[1’,2’:4,5]吡嗪并[2,3-c][1,8]萘啶-5,7-二酮(415mg,粗品)，直接用于下一步反应。ES-API:[M+H] +＝562.2。
步骤8：(2R,4aR)-11-氟-10-(2-氟-6-甲氧基苯基)-8-(3-异丙基吡嗪-2-基)-2,6-二甲基-2,3,4,4a,6,8-六氢-1H-吡嗪并[1’,2’:4,5]吡嗪并[2,3-c][1,8]萘啶-5,7-二酮(415mg，0.74mmol)溶于二氯甲烷(15mL)，加入三乙胺(3.0mL，21.62mmol)。将反应冷至0℃，向反应液中滴加丙烯酰氯(115mg，1.28mmol)。反应在0℃搅拌5分钟。向反应液中加入50mL二氯甲烷，用50mL饱和NaHCO 3水溶液，80mL饱和食盐水洗涤，干燥后浓缩，粗品用粗品用快速硅胶柱纯化(EtOAc/PE：0-60％)得产物(2R,4aR)-3-丙烯酰基-11-氟-10-(2-氟-6-甲氧基苯基)-8-(3-异丙基吡嗪-2-基)-2,6-二甲基-2,3,4,4a,6,8-六氢-1H-吡嗪并[1’,2’:4,5]吡嗪并[2,3-c][1,8]萘啶-5,7-二酮(201mg,Y:44％)，黄色色固体。ES-API:[M+H] +＝616.2。
步骤9：冰水浴条件下，将(2R,4aR)-3-丙烯酰基-11-氟-10-(2-氟-6-甲氧基苯基)-8-(3- 异丙基吡嗪-2-基)-2,6-二甲基-2,3,4,4a,6,8-六氢-1H-吡嗪并[1’,2’:4,5]吡嗪并[2,3-c][1,8]萘啶-5,7-二酮(201mg,0.33mmol)加入到干燥二氯甲烷中(3.0mL),再加入三溴化硼(5.0mL),室温反应30分钟，冰水浴条件下，将上述反应液滴加入饱和碳酸氢钠饱和溶液中，二氯甲烷(50mL)萃取2次，干燥，浓缩，粗品用制备HPLC纯化得产物(2R,4aR)-3-丙烯酰基-11-氟-10-(2-氟-6-羟基苯基)-8-(3-异丙基吡嗪-2-基)-2,6-二甲基-2,3,4,4a,6,8-六氢-1H-吡嗪并[1’,2’:4,5]吡嗪并[2,3-c][1,8]萘啶-5,7-二酮(Z22，65mg,Y:33％)ES-API:[M+H] +＝602.2。 1H NMR(500MHz,DMSO-d 6)δ10.17(s,1H),8.75(dd,J＝4.0,2.6Hz,1H),8.55(dd,J＝15.5,2.4Hz,1H),8.05-7.98(m,1H),7.26(dd,J＝15.0,8.2Hz,1H),7.03(dd,J＝16.8,10.0Hz,1H),6.73(d,J＝8.4Hz,1H),6.67(t,J＝8.8Hz,1H),6.16(t,J＝12.4Hz,1H),5.74(dd,J＝20.0,11.8Hz,1H),4.78(s,1H),4.65-4.56(m,1H),4.00(t,J＝28.0Hz,1H),3.80-3.70(m,1H),3.36(d,J＝2.4Hz,3H),3.05-2.62(m,2H),1.63-1.48(m,3H),1.18(d,J＝6.8Hz,2H),1.10(d,J＝6.8Hz,3H),1.00(d,J＝6.7Hz,2H)。
实施例23制备化合物Z23
Figure PCTCN2020124226-appb-000105
步骤1：向圆底烧瓶中加入4-氯-6-氟-7-(2-氟-6-甲氧基苯基)-1-(4-异丙基-6-甲基嘧啶-5-基)-3-硝基-1,8-萘啶-2(1H)-酮(0.8g，1.46mmol)、1-(叔丁基)3-甲基(3R,6R)-6-甲基哌嗪-1,3-二羧酸酯(567mg,2.2mmol)、N,N-二异丙基乙胺(565mg,4.38mmol)和N,N-二甲基乙酰胺(10mL)，反应在120℃下搅拌1小时。LC-MS检测反应完成。将反应液中倒入30mL水中。用乙酸乙酯萃取3次。有机相用饱和食盐水/水(v/v,1：1)洗涤四次，干燥浓缩得1-(叔丁基)3-甲基(3R,6R)-4-(6-氯-1-(4,6-二异丙基嘧啶-5-基)-7-(2-氟-6-甲氧基苯基)-3-硝基-2-氧代-1,2-二氢-1,8-萘啶-4-基)-6-甲基哌嗪-1,3-二羧酸酯(1g,，收率89％)。ES-API:[M+H] +＝768.3。
步骤2：向反应瓶中加入1-(叔丁基)3-甲基(3R,6R)-4-(6-氯-1-(4,6-二异丙基嘧啶-5-基)-7-(2-氟-6-甲氧基苯基)-3-硝基-2-氧代-1,2-二氢-1,8-萘啶-4-基)-6-甲基哌嗪-1,3-二羧酸酯(1g，1.3mmol)、铁粉(300mg，5.3mmol)和8mL冰醋酸。反应在80℃下搅拌0.5小时。LC-MS检测反应完成。将反应液倒入50mL碳酸氢钠水溶液中，用30mL乙酸乙酯萃取3次。有机相干燥后浓缩得到粗品(2R,4aR)-11-氯-8-(4,6-二异丙基嘧啶-5-基)-10-(2-氟-6-甲氧基苯基)-2-甲基-5,7-二氧代-1,2,4,4a,5,6,7,8-八氢-3H-吡嗪并[1’,2’:4,5]吡嗪并[2,3-c][1,8]萘啶-3-羧酸叔丁酯(761mg，83％)，黄色固体。ES-API:[M+H] +＝706.3。
步骤3：向圆底烧瓶中加入(2R,4aR)-11-氯-8-(4,6-二异丙基嘧啶-5-基)-10-(2-氟-6-甲氧基苯基)-2-甲基-5,7-二氧代-1,2,4,4a,5,6,7,8-八氢-3H-吡嗪并[1’,2’:4,5]吡嗪并[2,3-c][1,8]萘啶-3-羧酸叔丁酯(761mg，1.08mmol)、碘甲烷(1.5g,10.79mmol)、碳酸钾(596mg,4.32mmol)和15mL丙酮。反应在封管，50℃条件下搅拌16小时，LC-MS检测反应完毕。反应液用硅藻土过滤。滤液浓缩得到粗品(2R,4aR)-11-氯-8-(4,6-二异丙基嘧啶-5-基)-10-(2-氟-6-甲氧基苯基)-2,6-二甲基-5,7-二氧代-1,2,4,4a,5,6,7,8-八氢-3H-吡嗪并[1’,2’:4,5]吡并[2,3-c][1,8]萘啶-3-羧酸叔丁酯(738mg，95％)，黄色固体。ES-API:[M+H] +＝720.3。
步骤4：向圆底烧瓶中加入(2R,4aR)-11-氯-8-(4,6-二异丙基嘧啶-5-基)-10-(2-氟-6-甲氧基苯基)-2,6-二甲基-5,7-二氧代-1,2,4,4a,5,6,7,8-八氢-3H-吡嗪并[1’,2’:4,5]吡并[2,3-c][1,8]萘啶-3-羧酸叔丁酯(738mg，1.02mmol)、2mL二氯甲烷和5mL三氟乙酸。室温搅拌1小时，LC-MS检测反应完毕。反应液浓缩得(2R,4aR)-11-氯-8-(4,6-二异丙基嘧啶-5-基)-10-(2-氟-6-甲氧基苯基)-2,6-二甲基-2,3,4,4a，6,8-六氢-1H-吡嗪并[1’,2’:4,5]吡嗪并[2,3-c][1,8]萘啶-5,7-二酮(632mg，100％)，黄色固体。粗产品直接用于下一步。ES-API:[M+H] +＝620.3。
步骤5：向50mL圆底烧瓶中加入(2R,4aR)-11-氯-8-(4,6-二异丙基嘧啶-5-基)-10-(2-氟-6-甲氧基苯基)-2,6-二甲基-2,3,4,4a，6,8-六氢-1H-吡嗪并[1’,2’:4,5]吡嗪并[2,3-c][1,8]萘啶-5,7-二酮(632mg，1.02mmol)、3mL二氯甲烷和三乙胺(677mg，6.7mmol)。将反应冷至0℃，向反应液中滴加丙烯酰氯的二氯甲烷溶液(249mg，2.77mmol,0.5mL)。反应在0℃搅拌10分钟。向反应液中加入40mL饱和碳酸氢钠水溶液，用20mL二氯甲烷萃取3次。有机相干燥后浓缩，粗品用快速硅胶柱纯化(EtOAc/PE：0-60％)得到(2R,4aR)-3-丙烯酰基-11-氯-8-(4,6-二异丙基嘧啶-5-基)-10-(2-氟-6-甲氧基苯基)-2,6-二甲基-2,3,4,4a,6,8-六氢-1H-吡嗪并[1’,2’:4,5]吡嗪并[2,3-c][1,8]萘啶-5,7-二酮(500mg，72％)，黄色固体。粗产品直接用于下一步。ES-API:[M+H] +＝674.2。
步骤6：向圆底烧瓶中加入(2R,4aR)-3-丙烯酰基-11-氯-8-(4,6-二异丙基嘧啶-5-基)-10-(2-氟-6-甲氧基苯基)-2,6-二甲基-2,3,4,4a,6,8-六氢-1H-吡嗪并[1’,2’:4,5]吡嗪并[2,3-c][1,8]萘啶-5,7-二酮(500mg，0.74mmol)、3mL二氯甲烷。将反应液冷至0℃，向其中滴加17％三溴化硼的二氯甲烷溶液(12mL)。滴加完毕将反应在25度下搅拌25小时。将反应液倒入30mL冰的饱和NaHCO 3水溶液，用20mL二氯甲烷萃取3次。有机相干燥后浓缩，粗品用制备HPLC纯化得产物(2R,4aR)-3-丙烯酰基-11-氯-8-(4,6-二异丙基嘧啶-5-基)-10-(2-氟-6-羟基苯基)-2,6-二甲基-2,3,4,4a,6,8-六氢-1H-吡嗪并[1’,2’:4,5]吡嗪并[2,3-c][1,8]萘啶-5,7-二酮(Z23，200mg,40％)，黄色固体。 1HNMR(500MHz,DMSO-d 6):δ10.10-10.5(m,1H),9.11(s,1H),8.25-8.23(m 1H),7.22-7.21(m,1H),6.86-6.74(m,1H),6.67-6.64(m,2H),6.17-6.14(m,1H),5.75-5.71(m,1H),5.04-5.01(m,1H),4.62-4.42(m,1H),4.03-3.98(m,1H),3.74-3.72(m,1H),3.42-3.33(m,5H),2.77-2.64(m,2H),1.56-1.52(m,3H),1.05-0.97(m,9H),0.86-0.84(m,3H).ES-API:[M+H] +＝660.3。
实施例24制备化合物Z24、Z24-1和Z24-2
Figure PCTCN2020124226-appb-000106
步骤1：将6,7-二氯-4-羟基-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢-1,8-萘啶-3-甲腈(30.0g,77.319mmol)悬浮于1，4-二氧六环(120mL)水(120mL)的混合溶液，缓慢加入浓硫酸(120mL)。反应120℃下搅拌36小时。将冷却的反应液中倒入200mL冰水中，用碳酸钠调pH2～3，用乙酸乙酯萃取(1000mL*2)，合并乙酸乙酯相，无水硫酸钠干燥，过滤，滤液真空干燥后得产物6,7-二氯-4-羟基-1-(2-异丙基-4-甲基吡啶-3-基)-1,8-萘啶-2(1H)-酮(24g,Y:85.7％)，淡棕色固体。ES-API:[M+H] +＝364.1。
步骤2：6,7-二氯-4-羟基-1-(2-异丙基-4-甲基吡啶-3-基)-1,8-萘啶-2(1H)-酮(3.16g,8.705mmol)溶于乙酸(15mL)，依次加入亚硝酸钠(100mg,1.58mmol)和浓硝酸(5.0mL，74.52mmol)，反应在室温下搅拌30分钟。将反应液中缓慢倒入100mL冰水中，析出的固体过滤，滤饼用20ml冰水洗涤，在真空下干燥得产物6,7-二氯-4-羟基-1-(2-异丙基-4-甲基吡啶-3-基)-3-硝基-1,8-萘啶-2(1H)-酮(3.5g，Y:92％)，黄色固体。ES-API:[M+H] +＝409.1。
步骤3：向100mL三口圆底烧瓶中加入6,7-二氯-4-羟基-1-(2-异丙基-4-甲基吡啶-3-基)-3-硝基-1,8-萘啶-2(1H)-酮(3.5g,8.570mmol)、(2-氟-6-甲氧基苯基)硼酸(5.8g,34.10mmol)、四三苯基膦钯(1.15g,0.9956mmol)、碳酸钠(3.5g,33.02mmol)、10mL水和40mL二氧六环。氮气保护下，反应在100℃搅拌2～3小时。反应完毕，反应液冷却到室温，加入80mL水和100mL甲基叔丁基醚，萃取一次。水相用1M的盐酸溶液调pH3～5，用乙酸乙酯萃取(200mL*2)，合并乙酸乙酯相，无水硫酸钠干燥，过滤，滤液真空干燥后得产物6-氯-7-(2-氟-6-甲氧基苯基)-4-羟基-1-(2-异丙基-4-甲基吡啶-3-基)-3-硝基-1,8-萘啶-2(1H)-酮(4.5g,粗品)，淡黄色固体。ES-API:[M+H] +＝499.1。
步骤4：6-氯-7-(2-氟-6-甲氧基苯基)-4-羟基-1-(2-异丙基-4-甲基吡啶-3-基)-3-硝基 -1,8-萘啶-2(1H)-酮(4.6g,8.57mmol)溶于乙腈(30mL)，依次加入三氯氧磷(7.5g,48.92mmol)，和N,N-二异丙基乙胺(10.5g,81.24mmol)，反应逐渐升至80℃并搅拌30分钟。将反应液浓缩，加入30mL冷的乙腈，冰水浴下滴加到150mL饱和碳酸氢钠溶液中，用乙酸乙酯萃取(200mL*2)，合并乙酸乙酯相，200mL饱和食盐水洗涤一次。无水硫酸钠干燥，过滤，有机相干燥浓缩后，粗品用快速硅胶柱(EtOAc/PE：0-50％)纯化得4,6-二氯-7-(2-氟-6-甲氧基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-3-硝基-1,8-萘啶-2(1H)-酮(3.05g,Y：76％)，黄色固体。ES-API:[M+H] +＝517.2。
步骤5：4,6-二氯-7-(2-氟-6-甲氧基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-3-硝基-1,8-萘啶-2(1H)-酮(2.5g,4.843mmol)溶于N,N-二甲基乙酰胺(25mL)，依次加入1-(叔丁基)3-甲基(R)-哌嗪-1,3-二羧酸酯(3.5g,14.34mmol)，和N,N-二异丙基乙胺(2.0g,15.47mmol)，反应在120℃搅拌2小时。反应液中加入80mL乙酸乙酯，用80mL饱和食盐水洗涤三次。乙酸乙酯相干燥浓缩，粗品用快速硅胶柱纯化(EtOAc/PE：0-80％)得产物1-(叔丁基)3-甲基(3R)-4-(6-氯-7-(2-氟-6-甲氧基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-3-硝基-2-氧代-1,2-二氢-1,8-萘啶-4-基)哌嗪-1,3-二羧酸酯(2.7g,Y:77％)，黄色固体。ES-API:[M+H] +＝725.2。
步骤6：1-(叔丁基)3-甲基(3R)-4-(6-氯-7-(2-氟-6-甲氧基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-3-硝基-2-氧代-1,2-二氢-1,8-萘啶-4-基)哌嗪-1,3-二羧酸酯(2.7g,3.728mmol)溶于乙酸(30mL)，加入铁粉(835mg,14.91mmol),反应在80℃搅拌30分钟。反应液浓缩，依次加入200mL乙酸乙酯和100mL饱和碳酸氢钠，悬浮液用硅藻土过滤，滤饼用乙酸乙酯洗涤，有机相分离，依次用100mL饱和碳酸氢钠，150mL饱和食盐水洗涤，干燥浓缩得产物(4aR)-11-氯-10-(2-氟-6-甲氧基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-5,7-二氧代-1,2,4,4a,5,6,7,8-八氢-3H-吡嗪并[1’,2’:4,5]吡嗪并[2,3-c][1,8]萘啶-3-羧酸叔丁酯(2.70g,粗品)，黄色固体。ES-API:[M+H]+＝663.2。
步骤7：向100mL单口烧瓶中中依次加入(4aR)-11-氯-10-(2-氟-6-甲氧基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-5,7-二氧代-1,2,4,4a,5,6,7,8-八氢-3H-吡嗪并[1’,2’:4,5]吡嗪并[2,3-c][1,8]萘啶-3-羧酸叔丁酯(250mg，0.3774mmol)，4mL二氯甲烷，4mL三氟乙酸，室温搅拌2小时，反应液浓缩得产物(4aR)-11-氯-10-(2-氟-6-甲氧基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-2,3,4,4a,6,8-六氢-1H-吡嗪并[1’,2’:4,5]吡嗪并[2,3-c][1,8]萘啶-5,7-二酮(300mg,粗品)，直接用于下一步反应。ES-API:[M+H] +＝563.2。
步骤8：(4aR)-11-氯-10-(2-氟-6-甲氧基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-2,3,4,4a,6,8-六氢-1H-吡嗪并[1’,2’:4,5]吡嗪并[2,3-c][1,8]萘啶-5,7-二酮(300mg，0.3774mmol)溶于二氯甲烷(10mL)，加入三乙胺(3.0mL，21.62mmol)。将反应冷至0℃，向反应液中滴加丙烯酰氯(50mg，0.5524mmol)。反应在0℃搅拌15分钟。向反应液中加入80mL二氯甲烷，用100mL饱和NaHCO 3水溶液，80mL饱和食盐水洗涤，干燥后浓缩，粗品用粗品用快速硅胶柱纯化(甲醇/二氯甲烷：0-20％)得产物(4aR)-3-丙烯酰基-11-氯-10-(2-氟-6-甲氧基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-2,3,4,4a,6,8-六氢-1H-吡嗪并[1’,2’:4,5]吡嗪并[2,3-c][1,8]萘啶-5,7-二酮(243mg,粗品)，黄色色固体。ES-API:[M+H] +＝617.2。
步骤9：冰水浴条件下，(4aR)-3-丙烯酰基-11-氯-10-(2-氟-6-甲氧基苯基)-8-(2-异丙 基-4-甲基吡啶-3-基)-2,3,4,4a,6,8-六氢-1H-吡嗪并[1’,2’:4,5]吡嗪并[2,3-c][1,8]萘啶-5,7-二酮(243mg,0.3774mmol)加入到干燥二氯甲烷中(6.0mL),再加入三溴化硼(5.0mL,5.0mmol),升至室温，反应过夜。冰水浴条件下，将上述反应液滴加入饱和碳酸氢钠饱和溶液中，二氯甲烷(80mL)萃取2次，干燥，浓缩，通过制备HPLC纯化得到(4aR)-3-丙烯酰基-11-氯-10-(2-氟-6-羟基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-2,3,4,4a,6,8-六氢-1H-吡嗪并[1’,2’:4,5]吡嗪并[2,3-c][1,8]萘啶-5,7-二酮(Z24，76mg,Y:32％)。[M+H] +＝603.2。
步骤10：将化合物Z24(76.0mg,0.1262mmol)通过制备型手性HPLC拆分(柱型:IA:10μm,30*250mm,流动相:己烷:EtOH＝40:60,流速:25ml/min,柱温室温)得到：一个阻转异构体化合物，结构任意指定为Z24-1(13.7mg,峰1，保留时间2.612min，Y:18％)，ES-API:[M+H] +＝603.2。和另一个阻转异构体化合物，结构任意指定为Z24-2(21.4mg,峰2，保留时间3.985min，Y:28％)，ES-API:[M+H] +＝603.2。异构体化合物通过分析型手性HPLC(柱型IA:5μm,4.6*150mm,流动相:己烷:EtOH＝40:60,流速:1ml/min,柱温＝30℃)进行检测。
实施例25制备化合物Z25、Z25-1和Z25-2
Figure PCTCN2020124226-appb-000107
步骤1：将6,7-二氯-4-羟基-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢-1,8-萘啶-3-甲腈(30.0g,77.319mmol)悬浮于1，4-二氧六环(120mL)水(120mL)的混合溶液，缓慢加入浓硫酸(120mL)。反应120℃下搅拌36小时。将冷却的反应液中倒入200mL冰水中，用碳酸钠调pH2～3，用乙酸乙酯萃取(1000mL*2)，合并乙酸乙酯相，无水硫酸钠干燥，过滤，滤液真空干燥后得产物6,7-二氯-4-羟基-1-(2-异丙基-4-甲基吡啶-3-基)-1,8-萘啶-2(1H)-酮(24g,Y:85.7％)，淡棕色固体。ES-API:[M+H] +＝364.1。
步骤2：6,7-二氯-4-羟基-1-(2-异丙基-4-甲基吡啶-3-基)-1,8-萘啶-2(1H)-酮(3.16g,8.705mmol)溶于乙酸(15mL)，依次加入亚硝酸钠(100mg,1.58mmol)和浓硝酸 (5.0mL，74.52mmol)，反应在室温下搅拌30分钟。将反应液中缓慢倒入100mL冰水中，析出的固体过滤，滤饼用20ml冰水洗涤，在真空下干燥得产物6,7-二氯-4-羟基-1-(2-异丙基-4-甲基吡啶-3-基)-3-硝基-1,8-萘啶-2(1H)-酮(3.5g，Y:92％)，黄色固体。ES-API:[M+H] +＝409.1。
步骤3：向100mL三口圆底烧瓶中加入6,7-二氯-4-羟基-1-(2-异丙基-4-甲基吡啶-3-基)-3-硝基-1,8-萘啶-2(1H)-酮(3.5g,8.570mmol)、(2-氟-6-甲氧基苯基)硼酸(5.8g,34.10mmol)、四三苯基膦钯(1.15g,0.9956mmol)、碳酸钠(3.5g,33.02mmol)、10mL水和40mL二氧六环。氮气保护下，反应在100℃搅拌2～3小时。反应完毕，反应液冷却到室温，加入80mL水和100mL甲基叔丁基醚，萃取一次。水相用1M的盐酸溶液调pH3～5，用乙酸乙酯萃取(200mL*2)，合并乙酸乙酯相，无水硫酸钠干燥，过滤，滤液真空干燥后得产物6-氯-7-(2-氟-6-甲氧基苯基)-4-羟基-1-(2-异丙基-4-甲基吡啶-3-基)-3-硝基-1,8-萘啶-2(1H)-酮(4.5g,粗品)，淡黄色固体。ES-API:[M+H] +＝499.1。
步骤4：6-氯-7-(2-氟-6-甲氧基苯基)-4-羟基-1-(2-异丙基-4-甲基吡啶-3-基)-3-硝基-1,8-萘啶-2(1H)-酮(4.6g,8.57mmol)溶于乙腈(30mL)，依次加入三氯氧磷(7.5g,48.92mmol)，和N,N-二异丙基乙胺(10.5g,81.24mmol)，反应逐渐升至80℃并搅拌30分钟。将反应液浓缩，加入30mL冷的乙腈，冰水浴下滴加到150mL饱和碳酸氢钠溶液中，用乙酸乙酯萃取(200mL*2)，合并乙酸乙酯相，200mL饱和食盐水洗涤1次。无水硫酸钠干燥，过滤，有机相干燥浓缩后，粗品用快速硅胶柱(EtOAc/PE：0-50％)纯化得4,6-二氯-7-(2-氟-6-甲氧基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-3-硝基-1,8-萘啶-2(1H)-酮(3.05g,Y:76％)，黄色固体。ES-API:[M+H] +＝517.2。
步骤5：4,6-二氯-7-(2-氟-6-甲氧基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-3-硝基-1,8-萘啶-2(1H)-酮(2.5g,4.843mmol)溶于N,N-二甲基乙酰胺(25mL)，依次加入1-(叔丁基)3-甲基(R)-哌嗪-1,3-二羧酸酯(3.5g,14.34mmol)，和N,N-二异丙基乙胺(2.0g,15.47mmol)，反应在120℃搅拌2小时。反应液中加入80mL乙酸乙酯，用80mL饱和食盐水洗涤三次。乙酸乙酯相干燥浓缩，粗品用快速硅胶柱纯化(EtOAc/PE：0-80％)得产物1-(叔丁基)3-甲基(3R)-4-(6-氯-7-(2-氟-6-甲氧基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-3-硝基-2-氧代-1,2-二氢-1,8-萘啶-4-基)哌嗪-1,3-二羧酸酯(2.7g,Y:77％)，黄色固体。ES-API:[M+H] +＝725.2。
步骤6：1-(叔丁基)3-甲基(3R)-4-(6-氯-7-(2-氟-6-甲氧基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-3-硝基-2-氧代-1,2-二氢-1,8-萘啶-4-基)哌嗪-1,3-二羧酸酯(2.7g,3.728mmol)溶于乙酸(30mL)，加入铁粉(835mg,14.91mmol),反应在80℃搅拌30分钟。反应液浓缩，依次加入200mL乙酸乙酯和100mL饱和碳酸氢钠，悬浮液用硅藻土过滤，滤饼用乙酸乙酯洗涤，有机相分离，依次用100mL饱和碳酸氢钠，150mL饱和食盐水洗涤，干燥浓缩得产物(4aR)-11-氯-10-(2-氟-6-甲氧基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-5,7-二氧代-1,2,4,4a,5,6,7,8-八氢-3H-吡嗪并[1’,2’:4,5]吡嗪并[2,3-c][1,8]萘啶-3-羧酸叔丁酯(2.70g,粗品)，黄色固体。ES-API:[M+H]+＝663.2。
步骤7：向150mL封管中依次加入(4aR)-11-氯-10-(2-氟-6-甲氧基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-5,7-二氧代-1,2,4,4a,5,6,7,8-八氢-3H-吡嗪并[1’,2’:4,5]吡嗪并[2,3-c][1,8]萘啶-3-羧酸叔丁酯(2.7g，3.728mmol)，30mL丙酮，无水碳酸钾(2.2g,15.94 mmol)，碘甲烷(5.4g，38.03mmol)。密封封管，反应在55℃搅拌18小时。反应液加入150mL乙酸乙酯，用100mL饱和食盐水洗涤3次，干燥浓缩，粗品用快速硅胶柱纯化(EtOAc/PE：0-80％)得产物(4aR)-11-氯-10-(2-氟-6-甲氧基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-6-甲基-5,7-二氧代-1,2,4,4a,5,6,7,8-八氢-3H-吡嗪并[1’,2’:4,5]吡嗪并[2,3-c][1,8]萘啶-3-羧酸叔丁酯(2.2g,Y:87％)，黄色固体。ES-API:[M+H] +＝677.2。
步骤8：(4aR)-11-氯-10-(2-氟-6-甲氧基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-6-甲基-5,7-二氧代-1,2,4,4a,5,6,7,8-八氢-3H-吡嗪并[1’,2’:4,5]吡嗪并[2,3-c][1,8]萘啶-3-羧酸叔丁酯(517mg,0.7549mmol)溶于二氯甲烷(8mL)，加入三氟乙酸(2mL)。室温搅拌2小时，反应液浓缩得产物(4aR)-11-氯-10-(2-氟-6-甲氧基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-6-甲基-2,3,4,4a,6,8-六氢-1H-吡嗪并[1’,2’:4,5]吡嗪并[2,3-c][1,8]萘啶-5,7-二酮(530mg,粗品)，直接用于下一步反应。ES-API:[M+H] +＝577.2。
步骤9：(4aR)-11-氯-10-(2-氟-6-甲氧基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-6-甲基-2,3,4,4a,6,8-六氢-1H-吡嗪并[1’,2’:4,5]吡嗪并[2,3-c][1,8]萘啶-5,7-二酮(530mg，0.7549mmol)溶于二氯甲烷(15mL)，加入三乙胺(3.0mL，21.62mmol)。将反应冷至0℃，向反应液中滴加丙烯酰氯(100mg，1.1048mmol)。反应在0℃搅拌15分钟。向反应液中加入80mL二氯甲烷，用100mL饱和NaHCO 3水溶液，80mL饱和食盐水洗涤，干燥后浓缩，粗品用粗品用快速硅胶柱纯化(EtOAc/PE：0-60％)得产物(4aR)-3-丙烯酰基-11-氯-10-(2-氟-6-甲氧基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-6-甲基-2,3,4,4a,6,8-六氢-1H-吡嗪并[1’,2’:4,5]吡嗪并[2,3-c][1,8]萘啶-5,7-二酮(280mg,Y:59％)，黄色色固体。ES-API:[M+H] +＝631.2。
步骤10：冰水浴条件下，将(4aR)-3-丙烯酰基-11-氯-10-(2-氟-6-甲氧基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-6-甲基-2,3,4,4a,6,8-六氢-1H-吡嗪并[1’,2’:4,5]吡嗪并[2,3-c][1,8]萘啶-5,7-二酮(280mg,0.444mmol)加入到干燥二氯甲烷中(6.0mL),再加入三溴化硼(5.0mL,5.0mmol),升至室温，反应过夜。冰水浴条件下，将上述反应液滴加入饱和碳酸氢钠饱和溶液中，二氯甲烷(80mL)萃取2次，干燥，浓缩，粗品用快速硅胶柱纯化(EtOAc/PE：0-60％)得产物(4aR)-3-丙烯酰基-11-氯-10-(2-氟-6-羟基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-6-甲基-2,3,4,4a,6,8-六氢-1H-吡嗪并[1’,2’:4,5]吡嗪并[2,3-c][1,8]萘啶-5,7-二酮(Z25，233mg,Y:85％)。
步骤11：将化合物Z25通过制备型手性HPLC拆分(柱型:IA:10μm,30*250mm,流动相:己烷:EtOH＝60:40,流速:25ml/min,柱温室温)得到：一个阻转异构体化合物Z25-1(76.8mg,峰1，保留时间2.531min，Y:34％)。 1H NMR(500MHz,DMSO-d 6)δ10.03(d,J＝18.4Hz,1H),8.52(d,J＝7.3Hz,1H),8.43(d,J＝4.7Hz,1H),7.23(d,J＝9.6Hz,2H),7.08(dd,J＝16.6,10.5Hz,1H),6.74–6.62(m,2H),6.15(d,J＝16.8Hz,1H),5.75(d,J＝10.7Hz,1H),4.73(d,J＝14.2Hz,1H),4.46(d,J＝12.9Hz,1H),4.00(s,1H),3.61(d,J＝10.0Hz,1H),3.51(s,1H),3.34(s,3H),3.22(s,1H),2.64(t,J＝11.5Hz,1H),2.48–2.42(m,1H)，1.98(d,J＝5.1Hz,3H),1.03(t,J＝6.9Hz,3H),0.86(t,J＝7.9Hz,3H).ES-API:[M+H] +＝617.2。和另一个阻转异构体化合物Z25-2(70mg,峰2，保留时间3.683min，Y:31％)。 1H NMR(500MHz,CDCl 3)δ8.64–8.59(m,1H),8.35(s,1H),8.07(s,1H),7.27–7.20(m,2H),7.14–7.02(m,1H),6.75–6.63(m,2H),6.39(dd,J＝17.0,2.0Hz,1H),5.88 –5.77(m,1H),4.91(d,J＝14.0Hz,1H),4.83(d,J＝13.0Hz,1H),3.72–3.58(m,2H),3.50(s,3H),3.43(d,J＝12.0Hz,1H),3.16(t,J＝13.0Hz,1H),2.91(t,J＝12.0Hz,1H),2.82-2.73(m,1H),1.93(s,3H),1.24(d,J＝7.0Hz,3H),1.12(d,J＝7.0Hz,3H)。ES-API:[M+H] +＝617.2。异构体化合物通过分析型手性HPLC方法(柱型:IA:5μm,4.6*150mm,流动相:己烷:EtOH＝60:40,流速:1ml/min,柱温＝30℃)进行检测。
实施例26制备化合物Z26、Z26-1和Z26-2
Figure PCTCN2020124226-appb-000108
步骤1：(4aR)-11-氯-10-(2-氟-6-甲氧基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-6-(甲基-d3)-5,7-二氧代-1,2,4,4a,5,6,7,8-八氢-3H-吡嗪并[1’,2’:4,5]吡嗪并[2,3-c][1,8]萘啶-3-羧酸叔丁酯(511mg,0.7549mmol)溶于二氯甲烷(8mL)，加入三氟乙酸(2mL)。室温搅拌2小时，反应液浓缩得产物(4aR)-11-氯-10-(2-氟-6-甲氧基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-6-(甲基-d3)-2,3,4,4a,6,8-六氢-1H-吡嗪并[1’,2’:4,5]吡嗪并[2,3-c][1,8]萘啶-5,7-二酮(520mg,粗品)，直接用于下一步反应。ES-API:[M+H] +＝580.3。
步骤2：(4aR)-11-氯-10-(2-氟-6-甲氧基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-6-(甲基-d3)-2,3,4,4a,6,8-六氢-1H-吡嗪并[1’,2’:4,5]吡嗪并[2,3-c][1,8]萘啶-5,7-二酮(520mg，0.7549mmol)溶于二氯甲烷(10mL)，加入三乙胺(3.0mL，21.62mmol)。将反应冷至0℃，向反应液中滴加丙烯酰氯(100mg，1.1048mmol)。反应在0℃搅拌15分钟。向反应液中加入80mL二氯甲烷，用100mL饱和NaHCO 3水溶液，80mL饱和食盐水洗涤，干燥后浓缩，粗品用粗品用快速硅胶柱纯化(EtOAc/PE：0-60％)得产物(4aR)-3-丙烯酰基-11-氯-10-(2-氟-6-甲氧基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-6-(甲基-d3)-2,3,4,4a,6,8-六氢-1H-吡嗪并[1’,2’:4,5]吡嗪并[2,3-c][1,8]萘啶-5,7-二酮(232mg,Y:48％)，黄色色固体。ES-API:[M+H] +＝634.2。
步骤3：冰水浴条件下，将(4aR)-3-丙烯酰基-11-氯-10-(2-氟-6-甲氧基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-6-(甲基-d3)-2,3,4,4a,6,8-六氢-1H-吡嗪并[1’,2’:4,5]吡嗪并[2,3-c][1,8]萘啶-5,7-二酮(240mg,0.3791mmol)加入到干燥二氯甲烷中(6.0mL),再加入三溴化硼(5.0mL,5.0mmol),升至室温，反应过夜。冰水浴条件下，将上述反应液滴加入饱和碳酸氢钠饱和溶液中，二氯甲烷(80mL)萃取2次，干燥，浓缩，粗品用快速硅胶柱纯 化(EtOAc/PE：0-60％)得产物(4aR)-3-丙烯酰基-11-氯-10-(2-氟-6-羟基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-6-(甲基-d3)-2,3,4,4a,6,8-六氢-1H-吡嗪并[1’,2’:4,5]吡嗪并[2,3-c][1,8]萘啶-5,7-二酮(Z26，187mg,Y:79％)。[M+H] +＝620.3。
步骤4：将化合物Z26(187mg,0.302mmol)通过制备型手性HPLC拆分(柱型:IA:10μm,30*250mm,流动相:己烷:EtOH＝60:40,流速:25ml/min,柱温室温)得到：一个阻转异构体化合物，结构任意指定为Z26-1(68.8mg,峰1，保留时间2.525min，Y:36.7％)。 1H NMR(500MHz,DMSO-d 6)δ10.03(d,J＝17.9Hz,1H),8.51(d,J＝7.4Hz,1H),8.43(d,J＝4.7Hz,1H),7.29–7.18(m,2H),7.08(dd,J＝17.0,10.6Hz,1H),6.74–6.61(m,2H),6.15(d,J＝16.6Hz,1H),5.75(d,J＝11.5Hz,1H),4.73(d,J＝13.5Hz,1H),4.46(d,J＝12.3Hz,1H),4.00(s,1H),3.61(d,J＝10.5Hz,1H),3.50(s,1H),3.22(s,1H),2.65(t,J＝12.5Hz,1H),2.49–2.42(m,1H)，1.98(d,J＝5.0Hz,3H),1.02(d,J＝7.0Hz,3H),0.86(t,J＝7.9Hz,3H)。ES-API:[M+H] +＝620.3。和另一个阻转异构体化合物，结构任意指定为Z26-2(63.2mg,峰2，保留时间3.683min，Y:33.79％)。 1H NMR(400MHz,CDCl 3)δ8.62(d,J＝4.8Hz,1H),8.35(s,1H),8.07(s,1H),7.24–7.20(m,2H),7.16–7.01(m,1H),6.74–6.63(m,2H),6.39(dd,J＝16.8,2.0Hz,1H),5.82(dd,J＝10.4,2.0Hz,1H),4.91(d,J＝13.6Hz,1H),4.83(d,J＝13.6Hz,1H),3.71–3.57(m,2H),3.42(d,J＝12.0Hz,1H),3.16(t,J＝12.8Hz,1H),2.91(t,J＝12.0Hz,1H),2.81-2.70(m,1H),1.92(s,3H),1.22(d,J＝6.8Hz,3H),1.10(d,J＝6.8Hz,3H).ES-API:[M+H] +＝620.3。异构体化合物通过分析型手性HPLC方法(柱型:IA:5μm,4.6*150mm,流动相:己烷:EtOH＝60:40,流速:1ml/min,柱温＝30℃)进行检测。
实施例27制备化合物Z27、Z27-1和Z27-2
Figure PCTCN2020124226-appb-000109
步骤1：4,6-二氯-7-(2-氟-6-甲氧基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-3-硝基-1,8-萘啶-2(1H)-酮(500mg,0.9686mmol)溶于N,N-二甲基乙酰胺(5mL)，依次加入1-(叔丁基)3-甲基(3R,6R)-6-甲基哌嗪-1,3-二羧酸酯(375mg,1.452mmol)，和N,N-二异丙基乙胺(375mg,2.907mmol)，反应在120℃搅拌2小时。反应液中加入80mL乙酸乙酯，用80mL饱和食盐水洗涤三次。乙酸乙酯相干燥浓缩，粗品用快速硅胶柱纯化(EtOAc/PE：0-80％)得产物1-(叔丁基)3-甲基(3R,6R)-4-(6-氯-7-(2-氟-6-甲氧基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-3-硝基-2-氧代-1,2-二氢-1,8-萘啶-4-基)-6-甲基哌嗪-1,3-二羧酸酯(535mg,Y: 74.5％)，黄色固体。ES-API:[M+H] +＝739.2。
步骤2：1-(叔丁基)3-甲基(3R,6R)-4-(6-氯-7-(2-氟-6-甲氧基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-3-硝基-2-氧代-1,2-二氢-1,8-萘啶-4-基)-6-甲基哌嗪-1,3-二羧酸酯(530mg,0.7179mmol)溶于乙酸(6mL)，加入铁粉(200mg,3.571mmol),反应在80℃搅拌30分钟。反应液浓缩，依次加入200mL乙酸乙酯和100mL饱和碳酸氢钠，悬浮液用硅藻土过滤，滤饼用乙酸乙酯洗涤，有机相分离，依次用100mL饱和碳酸氢钠，150mL饱和食盐水洗涤，干燥浓缩得产物(2R,4aR)-11-氯-10-(2-氟-6-甲氧基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-2-甲基-5,7-二氧代-1,2,4,4a,5,6,7,8-八氢-3H-吡嗪并[1’,2’:4,5]吡并[2,3-c][1,8]萘啶-3-羧酸叔丁酯(452mg,Y:92％)，黄色固体。ES-API:[M+H] +＝677.2。
步骤3：向150mL封管中依次加入(2R,4aR)-11-氯-10-(2-氟-6-甲氧基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-2-甲基-5,7-二氧代-1,2,4,4a,5,6,7,8-八氢-3H-吡嗪并[1’,2’:4,5]吡并[2,3-c][1,8]萘啶-3-羧酸叔丁酯(445mg，0.6583mmol)，10mL丙酮，无水碳酸钾(500mg,2.633mmol)，碘甲烷(1.20g，6.5828mmol)。密封封管，反应在55℃搅拌18小时。反应液加入150mL乙酸乙酯，用100mL饱和食盐水洗涤3次，干燥浓缩，粗品用快速硅胶柱纯化(EtOAc/PE：0-80％)得产物(2R,4aR)-11-氯-10-(2-氟-6-甲氧基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-2,6-二甲基-5,7-二氧代-1,2,4,4a,5,6,7,8-八氢-3H-吡嗪并[1’,2’:4,5]吡嗪并[2,3-c][1,8]萘啶-3-羧酸叔丁酯(455mg,crude)，黄色固体。ES-API:[M+H] +＝691.3。
步骤4：(2R,4aR)-11-氯-10-(2-氟-6-甲氧基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-2,6-二甲基-5,7-二氧代-1,2,4,4a,5,6,7,8-八氢-3H-吡嗪并[1’,2’:4,5]吡嗪并[2,3-c][1,8]萘啶-3-羧酸叔丁酯(511mg,0.7549mmol)溶于二氯甲烷(8mL)，加入三氟乙酸(2mL)。室温搅拌2小时，反应液浓缩得产物(2R,4aR)-11-氯-10-(2-氟-6-甲氧基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-2,6-二甲基-2,3,4,4a,6,8-六氢-1H-吡嗪并[1’,2’:4,5]吡嗪并[2,3-c][1,8]萘啶-5,7-二酮(462mg,粗品)，直接用于下一步反应。ES-API:[M+H] +＝591.3。
步骤5：(2R,4aR)-11-氯-10-(2-氟-6-甲氧基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-2,6-二甲基-2,3,4,4a,6,8-六氢-1H-吡嗪并[1’,2’:4,5]吡嗪并[2,3-c][1,8]萘啶-5,7-二酮(462mg，0.6283mmol)溶于二氯甲烷(8mL)，加入三乙胺(2.0mL，14.41mmol)。将反应冷至0℃，向反应液中滴加丙烯酰氯(100mg，1.1048mmol)。反应在0℃搅拌15分钟。向反应液中加入80mL二氯甲烷，用100mL饱和NaHCO 3水溶液，80mL饱和食盐水洗涤，干燥后浓缩，粗品用粗品用快速硅胶柱纯化(EtOAc/PE：0-60％)得产物(2R,4aR)-3-丙烯酰基-11-氯-10-(2-氟-6-甲氧基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-2,6-二甲基-2,3,4,4a,6,8-六氢-1H-吡嗪并[1’,2’:4,5]吡嗪并[2,3-c][1,8]萘啶-5,7-二酮(290mg,Y:68％)，黄色色固体。ES-API:[M+H] +＝645.2。
步骤6：冰水浴条件下，将(2R,4aR)-3-丙烯酰基-11-氯-10-(2-氟-6-甲氧基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-2,6-二甲基-2,3,4,4a,6,8-六氢-1H-吡嗪并[1’,2’:4,5]吡嗪并[2,3-c][1,8]萘啶-5,7-二酮(290mg,0.4503mmol)加入到干燥二氯甲烷中(6.0mL),再加入三溴化硼(6.0mL,6.0mmol),升至室温，反应过夜。冰水浴条件下，将上述反应液滴加入饱和碳酸氢钠饱和溶液中，二氯甲烷(80mL)萃取2次，干燥，浓缩，粗品用快速硅胶柱纯化(EtOAc/PE：0-60％)得产物(2R,4aR)-3-丙烯酰基-11-氯-10-(2-氟-6-羟基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-2,6-二甲基-2,3,4,4a,6,8-六氢-1H-吡嗪并[1’,2’:4,5]吡嗪并[2,3-c][1,8] 萘啶-5,7-二酮(Z27，307mg,粗品)。[M+H] +＝631.2。
步骤7：将化合物Z27通过制备型手性HPLC拆分(柱型:IA*:10μm,30*250mm,流动相:己烷:EtOH＝60:40,流速:25ml/min,柱温室温)得到：一个阻转异构体化合物Z27-1(67.7mg,峰1，保留时间2.394min，Y:23.4％)。 1H NMR(500MHz,DMSO-d 6)δ10.05(d,J＝17.8Hz,1H),8.43(d,J＝4.8Hz,1H),8.23(d,J＝9.9Hz,1H),7.23(d,J＝9.9Hz,2H),7.02(dd,J＝16.8,10.6Hz,1H),6.74–6.63(m,2H),6.15(dd,J＝16.8,2.3Hz,1H),5.76(dd,J＝10.5,2.3Hz,1H),4.78(s,1H),4.60(d,J＝13.8Hz,1H),4.00(d,J＝3.5Hz,1H),3.75(dd,J＝14.1,3.9Hz,1H),3.41–3.33(m,1H),3.34(s,3H),2.81(d,J＝12.1Hz,1H),2.48–2.42(m,1H),1.98(s,3H),1.53(d,J＝6.7Hz,3H),1.03(d,J＝5.5Hz,3H),0.85(t,J＝6.2Hz,3H)。ES-API:[M+H] +＝631.2。和另一个阻转异构体化合物Z27-2(64.6mg,峰2，保留时间3.382min，Y:23.2％)。 1H NMR(400MHz,CDCl 3)δ8.57(d,J＝4.8Hz,1H),8.36(s,1H),8.28(s,1H),7.25–7.15(m,2H),7.03(dd,J＝16.8,10.8Hz,1H),6.72–6.61(m,2H),6.34(dd,J＝16.8,2.0Hz,1H),5.80(dd,J＝10.8,2.0Hz,1H),5.11–5.01(m,1H),4.77(d,J＝14.0Hz,1H),3.82(dd,J＝14.0,4.4Hz,1H),3.61(d,J＝4.4Hz,1H),3.49(s,3H),3.30–3.17(m,1H),3.03(dd,J＝12.0,3.6Hz,1H),2.80-2.68(m,1H),1.91(s,3H),1.66(d,J＝6.8Hz,3H),1.22(d,J＝6.8Hz,3H),1.08(d,J＝6.8Hz,3H)。ES-API:[M+H] +＝631.2。异构体化合物通过分析型手性HPLC方法(柱型:IA:5μm,4.6*150mm,流动相:己烷:EtOH＝60:40,流速:1ml/min,柱温＝30℃)进行检测。
实施例28制备化合物Z28
Figure PCTCN2020124226-appb-000110
步骤1：4-氯-6-氟-7-(2-氟-6-甲氧基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-3-硝基-1,8-萘啶-2(1H)-酮(400mg,0.80mmol)溶于DMF(5mL)，加入(S)-3-(羟甲基)哌嗪-1-羧酸叔丁酯(432mg,2.00mmol)，N,N-二异丙基乙胺(310mg，2.40mmol)，反应在75℃搅拌2小时。反应液用100mL乙酸乙酯稀释，用40mL饱和食盐水洗涤5次，干燥浓缩，粗品用快速硅胶柱纯化(EtOAc/PE：0-70％)得产物(3S)-4-(6-氟-7-(2-氟-6-甲氧基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-3-硝基-2-氧代-1,2-二氢-1,8-萘啶-4-基)-3-(羟甲基)哌嗪-1-羧酸叔丁酯(420mg,Y:77.2％)，黄色固体。ES-API:[M+H] +＝681.3。
步骤2：(3S)-4-(6-氟-7-(2-氟-6-甲氧基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-3-硝基-2-氧代-1,2-二氢-1,8-萘啶-4-基)-3-(羟甲基)哌嗪-1-羧酸叔丁酯(420mg,0.62mmol)溶于DMA(20mL)，加入LiHMDS(1.55mL,1.55mmol,1.0M in THF),反应缓慢加热140℃搅拌24小时。反应液用100mL乙酸乙酯稀释，用40mL稀食盐水洗涤4次，用40mL饱和食盐水洗涤1次，干燥浓缩，粗品用快速硅胶柱纯化(EtOAc/PE：0-100％)得产物(4aS)-11-氟-10-(2-氟-6-甲氧基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-7-氧代-1,2,4a,5,7,8-六氢吡嗪[1’,2’:4,5][1,4]噁嗪[2,3-c][1,8]萘啶-3(4H)-羧酸叔丁酯(180mg,Y:46.0％)，黄色固体。ES-API:[M+H]+＝634.3。
步骤3：(4aS)-11-氟-10-(2-氟-6-甲氧基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-7-氧代-1,2,4a,5,7,8-六氢吡嗪[1’,2’:4,5][1,4]氧代[2,3-c][1,8]萘啶-3(4H)-羧酸叔丁酯(35mg，0.055mmol)溶于二氯甲烷(4mL)，加入三氟乙酸(1mL)。室温搅拌1小时，反应液浓缩得产物(4aS)-11-氟-10-(2-氟-6-甲氧基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-1,2,3,4,4a，5-六氢吡嗪[1’,2’:4,5][1,4]噁嗪[2,3-c][1,8]萘啶-7(8H)-酮(185mg,粗品)，直接用于下一步反应。ES-API:[M+H] +＝534.3。
步骤4：(4aS)-11-氟-10-(2-氟-6-甲氧基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-1,2,3,4,4a，5-六氢吡嗪[1’,2’:4,5][1,4]噁嗪[2,3-c][1,8]萘啶-7(8H)-酮(185mg，粗品)溶于二氯甲烷(6mL)，加入N,N-二异丙基乙胺(180mg，1.40mmol)。将反应冷至0℃，向反应液中滴加丙烯酰氯(50mg，0.56mmol)的二氯甲烷溶液(0.5mL)。反应在0℃搅拌15分钟。向反应液中加入50mL二氯甲烷，依次用15mL水，15mL饱和NaHCO 3水溶液洗涤2次，15mL饱和食盐水洗涤，有机相干燥后浓缩得产物(4aS)-3-丙烯酰基-11-氟-10-(2-氟-6-甲氧基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-1,2,3,4,4a，5-六氢吡嗪[1’,2’:4,5][1,4]噁嗪[2,3-c][1,8]萘啶-7(8H)-酮(160mg,Y:95.8％)，黄色固体。ES-API:[M+H] +＝588.3。
步骤5：(4aS)-3-丙烯酰基-11-氟-10-(2-氟-6-甲氧基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-1,2,3,4,4a，5-六氢吡嗪[1’,2’:4,5][1,4]噁嗪[2,3-c][1,8]萘啶-7(8H)-酮(160mg，0.27mmol)溶于二氯甲烷(4mL)。将反应冷至0℃，向其中滴加17％三溴化硼的二氯甲烷溶液(3mL)。反应在室温下搅拌3小时。将反应液倒入25mL冷的饱和NaHCO 3水溶液，用50mL二氯甲烷萃取。有机相依次用25mL饱和NaHCO 3水溶液，25mL饱和食盐水洗涤，干燥后浓缩，粗品用制备HPLC纯化得产物(4aS)-3-丙烯酰基-11-氟-10-(2-氟-6-羟基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-1,2,3,4,4a,5-六氢吡嗪[1',2':4,5][1,4]噁嗪[2,3-c][1,8]萘啶-7(8H)-酮(Z28，90mg,Y：57.6％)，淡黄色固体。 1H NMR(400MHz,DMSO-d 6)δ10.04(s,1H),8.42(d,J＝4.8Hz,1H),8.22(d,J＝7.4Hz,1H),7.27-7.17(m,2H),7.01–6.78(m,1H),6.77–6.58(m,2H),6.18(d,J＝16.3Hz,1H),5.87–5.66(m,1H),4.51-3.97(m,4H),3.91–3.39(m,4H),3.14–3.01(m,1H),2.62–2.41(m,1H),1.91-1.76(m,3H),1.12–0.98(m,3H),0.94-0.83(m,3H).ES-API:[M+H] +＝574.2。
实施例29制备化合物Z29
Figure PCTCN2020124226-appb-000111
步骤1：7-氯-6-氟-4-羟基-1-(2-异丙基-4-甲基吡啶-3-基)-1,8-萘啶-2(1H)-酮(4.0g,11.53mmol)溶于乙酸(9mL)，依次加入亚硝酸钠(79mg,1.15mmol)和浓硝酸(2.3mL，34.6mmol)，反应在室温下搅拌30分钟。将反应液中缓慢倒入100mL冰水中，析出的固体过滤，滤饼用20ml冰水洗涤，在真空下干燥得产物7-氯-6-氟-4-羟基-1-(2-异丙基-4-甲基吡啶-3-基)-3-硝基-1,8-萘啶-2(1H)-酮(3.1g，Y:80％)，黄色固体。ES-API:[M+H] +＝393.1。
步骤2：向100mL三口圆底烧瓶中加入7-氯-6-氟-4-羟基-1-(2-异丙基-4-甲基吡啶-3-基)-3-硝基-1,8-萘啶-2(1H)-酮(1.0g,2.55mmol)、(5-甲基-1H-吲唑-4-基)硼酸(1.8g,10.2mmol)、四三苯基膦钯(589mg,0.51mmol)、碳酸钾(1.76g,12.75mmol)、2mL水和8mL二氧六环。氮气保护下，反应在110℃搅拌1小时。反应完毕，反应液冷却到室温，加入80mL水和100mL甲基叔丁基醚，萃取一次。水相用1M的盐酸溶液调pH3-4，固体析出，过滤，得到固体产物真空干燥，得产物6-氟-7-(5-甲基-1H-吲唑-4-基)-4-羟基-1-(2-异丙基-4-甲基吡啶-3-基)-3-硝基-1,8-萘啶-2(1H)-酮(0.8g,50％)，淡黄色固体。ES-API:[M+H] +＝489.2。
步骤3：6-氟-7-(5-甲基-1H-吲唑-4-基)-4-羟基-1-(2-异丙基-4-甲基吡啶-3-基)-3-硝基-1,8-萘啶-2(1H)-酮(0.6g,1.23mmol)溶于乙腈(20mL)，依次加入三氯氧磷(0.94g,6.15mmol)，和N,N-二异丙基乙胺(1.27g,9.84mmol)，反应逐渐升至80℃并搅拌24h。将反应液浓缩，加入30mL冷的乙腈，冰水浴下滴加到30mL饱和碳酸氢钠溶液中，用乙酸乙酯萃取(200mL*2)，合并乙酸乙酯相，50mL饱和食盐水洗涤一次。无水硫酸钠干燥，过滤，有机相干燥浓缩后，粗品用快速硅胶柱(EtOAc/PE：0-80％)纯化得4-氯-6-氟-7-(5-甲基-1H-吲唑-4-基)-1-(2-异丙基-4-甲基吡啶-3-基)-3-硝基-1,8-萘啶-2(1H)-酮(0.3g,Y：50％)，黄色固体。ES-API:[M+H] +＝507.0。
步骤4：4-氯-6-氟-7-(5-甲基-1H-吲唑-4-基)-1-(2-异丙基-4-甲基吡啶-3-基)-3-硝基-1,8-萘啶-2(1H)-酮(150mg,0.296mmol)溶于N,N-二甲基乙酰胺(25mL)，依次加入(R)-3-(羟甲基)哌嗪-1-甲酸叔丁酯(1.48g,320mmol)，反应在80℃搅拌1.5小时。反应液中加入80mL乙酸乙酯，用80mL饱和食盐水洗涤三次。乙酸乙酯相干燥浓缩，粗品用快速硅胶柱纯化(EtOAc/PE：0-80％)得产物(3R)-4-(6-氟-1-(2-异丙基-4-甲基吡啶-3-基)-7-(5-甲基-1H-吲唑-4-基)-3-硝基-2-氧代-1,2-二氢-1,8-萘啶-4-基)-3-(羟甲基)哌嗪-1-羧酸叔丁酯(10mg,Y:40％)，黄色固体。ES-API:[M+H] +＝787.3。
步骤5：(3R)-4-(6-氟-1-(2-异丙基-4-甲基吡啶-3-基)-7-(5-甲基-1H-吲唑-4-基)-3-硝基 -2-氧代-1,2-二氢-1,8-萘啶-4-基)-3-(羟甲基)哌嗪-1-羧酸叔丁酯(90mg,0.13mmol)溶于溶于N,N-二甲基乙酰胺(25mL)，加入氢化钠(15.7mg,0.39mmol),反应在130℃搅拌18h。冷却至室温，倒入冰水中，3M盐酸调至pH＝7，加入30mL乙酸乙酯，有机相分离，依次用30mL水，30mL饱和食盐水洗涤，干燥浓缩得产物(4aR)-11-氟-8-(2-异丙基-4-甲基吡啶-3-基)-10-(5-甲基-1H-吲唑-4-基)-7-氧代-1,2,4a,5,7,8-六氢吡嗪并[1’,2’:4,5][1,4]噁嗪[2,3-c][1,8]萘啶-3(4H)-羧酸叔丁酯(60mg,Y:70％)，黄色固体。ES-API:[M+H] +＝640.3。
步骤6：(4aR)-11-氟-8-(2-异丙基-4-甲基吡啶-3-基)-10-(5-甲基-1H-吲唑-4-基)-7-氧代-1,2,4a,5,7,8-六氢吡嗪并[1’,2’:4,5][1,4]噁嗪[2,3-c][1,8]萘啶-3(4H)-羧酸叔丁酯(60mg,0.094mmol)溶于二氯甲烷(4mL)，加入三氟乙酸(2mL)。室温搅拌2小时，反应液浓缩得产物(4aR)-11-氟-8-(2-异丙基-4-甲基吡啶-3-基)-10-(5-甲基-1H-吲唑-4-基)-1,2,3,4,4a，5-六氢吡嗪并[1’,2’:4,5][1,4]噁嗪[2,3-c][1,8]萘啶7(8H)-酮(50mg,粗品)，直接用于下一步反应。ES-API:[M+H] +＝540.2。
步骤7：(4aR)-11-氟-8-(2-异丙基-4-甲基吡啶-3-基)-10-(5-甲基-1H-吲唑-4-基)-1,2,3,4,4a，5-六氢吡嗪并[1’,2’:4,5][1,4]噁嗪[2,3-c][1,8]萘啶7(8H)-酮(50mg，0.093mmol)溶于二氯甲烷(5mL)，加入三乙胺(60mg，0.465mmol)。将反应冷至0℃，向反应液中滴加丙烯酰氯(10.5mg，0.083mmol)。反应在0℃搅拌15分钟。向反应液中加入20mL二氯甲烷，用20mL饱和NaHCO 3水溶液，20mL饱和食盐水洗涤，干燥后浓缩，经制备HPLC纯化得产物(4aR)-3-丙烯酰基-11-氟-8-(2-异丙基-4-甲基吡啶-3-基)-10-(5-甲基-1H-吲唑-4-基)-1,2,3,4,4a,5-六氢吡嗪并[1’,2’:4,5][1,4]噁嗪[2,3-c][1,8]萘啶-7(8H)-酮(Z29，15mg,Y:28％).ES-API:[M+H] +＝594.2。 1H NMR(500MHz,DMSO-d 6)δ13.08(s,1H),8.37(d,J＝4.8Hz,1H),8.32(d,J＝9.4Hz,1H),7.49(d,J＝8.1Hz,2H),7.24(d,J＝8.5Hz,1H),7.20(d,J＝5.0Hz,1H),6.90(s,1H),6.20(d,J＝16.7Hz,1H),5.78(s,1H),4.45(d,J＝46.5Hz,1H),4.35–4.20(m,2H),4.05(s,1H),3.85(d,J＝51.4Hz,1H),3.75–3.57(m,2H),3.48(s,1H),3.15(s,1H),2.05(s,3H),1.90(d,J＝33.7Hz,3H),1.03(t,J＝6.7Hz,3H),0.81(dd,J＝20.9,6.4Hz,3H).
实施例30制备化合物Z30、Z30-1和Z30-2
Figure PCTCN2020124226-appb-000112
步骤1：向15mL封管中依次加入(4aR)-11-氟-10-(2-氟-6-甲氧基苯基)-8-(2-异丙基 -4-甲基吡啶-3-基)-5,7-二氧代-1,2,4,4a,5,6,7,8-八氢-3H-吡嗪[1’,2’:4,5]吡嗪[2,3-c][1,8]萘啶-3-羧酸叔丁酯(310mg，0.48mmol)，10mL丙酮，无水碳酸钾(265mg,1.92mmol)，碘乙烷(599mg，3.84mmol)。密封封管，反应在55℃搅拌18小时。反应液浓缩，加入60mL乙酸乙酯，依次用30mL水，30mL饱和食盐水洗涤，干燥浓缩，粗品用快速硅胶柱纯化(EtOAc/PE：0-70％)得产物(4aR)-6-乙基-11-氟-10-(2-氟-6-甲氧基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-5,7-二氧代-1,2,4,4a,5,6,7,8-辛基-3H-吡嗪[1’,2’:4,5]吡嗪[2,3-c][1,8]萘啶-3-羧酸叔丁酯(290mg,Y:89.7％)，橙色固体。ES-API:[M+H] +＝675.3。
步骤2：(4aR)-6-乙基-11-氟-10-(2-氟-6-甲氧基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-5,7-二氧代-1,2,4,4a,5,6,7,8-辛基-3H-吡嗪[1’,2’:4,5]吡嗪[2,3-c][1,8]萘啶-3-羧酸叔丁酯(290mg,0.43mmol)溶于二氯甲烷(4mL)，加入三氟乙酸(1mL)。室温搅拌2小时，反应液浓缩得产物(4aR)-6-乙基-11-氟-10-(2-氟-6-甲氧基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-2,3,4,4a,6,8-六氢-1H-吡嗪[1’,2’:4,5]吡嗪[2,3-c][1,8]萘啶-5,7-二酮(300mg,粗品)，直接用于下一步反应。ES-API:[M+H] +＝575.2。
步骤3：(4aR)-6-乙基-11-氟-10-(2-氟-6-甲氧基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-2,3,4,4a,6,8-六氢-1H-吡嗪[1’,2’:4,5]吡嗪[2,3-c][1,8]萘啶-5,7-二酮(300mg,粗品)溶于二氯甲烷(15mL)，加入N,N-二异丙基乙胺(464mg，3.60mmol)。将反应冷至0℃，向反应液中加入丙烯酰氯(130mg，1.44mmol)，反应在0℃搅拌15分钟。向反应液中加入45mL二氯甲烷，依次用25mL水，25mL饱和NaHCO 3水溶液，25mL饱和食盐水洗涤，干燥浓缩，干燥后浓缩，粗品用快速硅胶柱纯化(EtOAc/PE：0-90％)得产物(4aR)-3-丙烯酰-6-乙基-11-氟-10-(2-氟-6-甲氧基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-2,3,4,4a,6,8-六氢-1H-吡嗪[1’,2’:4,5]吡嗪[2,3-c][1,8]萘啶-5,7-二酮(2450mg,Y:90.7％)，淡黄色固体。ES-API:[M+H] +＝615.3。
步骤4：(4aR)-3-丙烯酰基-6-乙基-11-氟-10-(2-氟-6-甲氧基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-2,3,4,4a,6,8-六氢-1H-吡嗪[1’,2’:4,5]吡嗪[2,3-c][1,8]萘啶-5,7-二酮(245mg，0.39mmol)溶于二氯甲烷(5mL)。将反应冷至0℃，向其中滴加17％三溴化硼的二氯甲烷溶液(5mL)。反应在室温下搅拌3小时。将反应液倒入60mL饱和NaHCO 3水溶液，用50mL二氯甲烷萃取2次。有机相依次用30mL饱和NaHCO 3水溶液，30mL饱和食盐水洗涤，干燥后浓缩得产物(4aR)-3-丙烯酰基-6-乙基-11-氟-10-(2-氟-6-羟基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-2,3,4,4a,6,8-六氢-1H-吡嗪[1’,2’:4,5]吡嗪[2,3-c][1,8]萘啶-5,7-二酮(Z30，240mg,Y：100％)，淡黄色固体。ES-API:[M+H] +＝615.3。
步骤5：化合物Z30(240mg，0.39mmol)用制备HPLC纯化，然后通过制备型手性HPLC拆分(柱型:IB:10μm,30*250mm,流动相:己烷:EtOH＝70:30,流速:25ml/min,柱温室温)得到：一个阻转异构体化合物，结构任意指定为Z30-1(71mg,峰1，保留时间6.342min，Y：29.6％)，淡黄色固体。 1H NMR(500MHz,DMSO-d 6)δ10.11(d,J＝1.1Hz,1H),8.45(d,J＝4.9Hz,1H),8.40(d,J＝8.8Hz,1H),7.32–7.18(m,2H),7.12-6.80(m,1H),6.75–6.62(m,2H),6.15(dd,J＝16.8,2.0Hz,1H),5.75(d,J＝12.2Hz,1H),4.72(d,J＝13.5Hz,1H),4.46(d,J＝11.9Hz,1H),4.18-3.93(m,3H),3.63-3.50(m,2H),3.26-3.06(m,1H),2.80-2.55(m,1H),2.50-2.39(m,1H),1.97(s,3H),1.10–0.95(m,6H),0.86(d,J＝6.7Hz,3H).ES-API:[M+H] +＝615.2。和另一个阻转异构体化合物，结构任意指定为Z30-2(73 mg,峰2，保留时间7.970min，Y：30.5％)，淡黄色固体。 1H NMR(500MHz,DMSO-d 6)δ10.13(s,1H),8.45(d,J＝4.9Hz,1H),8.39(d,J＝8.8Hz,1H),7.31–7.19(m,2H),7.12-6.80(m,1H),6.77–6.62(m,2H),6.15(dd,J＝16.8,2.1Hz,1H),5.75(d,J＝12.3Hz,1H),4.73(d,J＝14.1Hz,1H),4.46(d,J＝13.0Hz,1H),4.20–4.02(m,2H),4.00-3.91(m,1H),3.65-3.53(m,2H),3.26-3.06(m,1H),,2.82-2.58(m,2H),1.80(s,3H),1.15–0.93(m,9H). 1ES-API:[M+H] +＝615.2。异构体化合物通过分析型手性HPLC方法(柱型:IB:5μm,4.6*250mm,流动相:己烷:EtOH＝70:30,流速:1ml/min,柱温＝30℃)进行检测。
实施例31制备化合物Z31
Figure PCTCN2020124226-appb-000113
步骤1：向250mL圆底烧瓶中加入6-氯-7-(2-氟-6-甲氧基苯基)-4-羟基-1-(2-异丙基-4-甲基吡啶-3-基)-3-硝基-1,8-萘啶-2(1H)-酮(1.0g，2.0mmol)、环丙基三氟硼酸钾(1.48g,10.0mmol)、氯(2-二环己基膦-2′,6′-二甲氧基-1,1′-联苯)[2-(2′-氨基-1,1′-联苯)]钯(II)(144mg,0.20mmol)、2-二环己基膦基-2′,6′-二甲氧基联苯基(82mg,0.20mmol)、碳酸钾(1.66g,12.0mmol)、2mL水和20mL甲苯。氮气保护下，反应在125℃搅拌18小时。反应液浓缩，加入50mL水，用3.0M稀盐酸调pH＝3.0，用50mL二氯甲烷萃取2次，有机相干燥后浓缩得产物6-环丙基-7-(2-氟-6-甲氧基苯基)-4-羟基-1-(2-异丙基-4-甲基吡啶-3-基)-3-硝基-1,8-萘啶-2(1H)-酮(850mg,粗品)，棕色固体。ES-API:[M+H] +＝505.2。
步骤2：6-环丙基-7-(2-氟-6-甲氧基苯基)-4-羟基-1-(2-异丙基-4-甲基吡啶-3-基)-3-硝基-1,8-萘啶-2(1H)-酮(1.6g,粗品)溶于乙腈(50mL)，依次加入三氯氧磷(2.43g,15.85mmol)，和N,N-二异丙基乙胺(3.27g,25.36mmol)，反应在85℃下搅拌1小时。将反应液浓缩，加入120mL乙酸乙酯依次用60mL水，60mL饱和碳酸氢钠洗涤2次，60mL饱和食盐水洗涤。有机相干燥浓缩后，粗品用快速硅胶柱(EtOAc/PE：0-35％)纯化得产物4-氯-6-环丙基-7-(2-氟-6-甲氧基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-3-硝基-1,8-萘啶-2(1H)-酮(520mg,Y:24.8％)，淡黄色固体。ES-API:[M+H] +＝523.2。
步骤3：4-氯-6-环丙基-7-(2-氟-6-甲氧基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-3-硝基-1,8-萘啶-2(1H)-酮(490mg,0.94mmol)溶于N,N-二甲基乙酰胺(6mL)，依次加入(3R,6R)-1-N-BOC-6-甲基哌嗪-3-甲酸甲酯(485mg,1.88mmol)，和N,N-二异丙基乙胺(364mg,2.82mmol)，反应在125℃搅拌3小时。反应液中加入100mL乙酸乙酯，用30mL稀盐水洗涤4次，30mL饱和食盐水洗涤，干燥浓缩，粗品用快速硅胶柱纯化(EtOAc/PE：0-50％)得产物(3R,6R)-1-N-BOC-4-(6-环丙基-7-(2-氟-6-甲氧基苯基)-1-(2-异 丙基-4-甲基吡啶-3-基)-3-硝基-2-氧代-1,2-二氢-1,8-萘啶-4-基)-6-甲基哌嗪-3-甲酸甲酯(485mg,Y:69.4％)，橙色固体。ES-API:[M+H] +＝745.3。
步骤4：(3R,6R)-1-N-BOC-4-(6-环丙基-7-(2-氟-6-甲氧基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-3-硝基-2-氧代-1,2-二氢-1,8-萘啶-4-基)-6-甲基哌嗪-3-甲酸甲酯(455mg,0.61mmol)溶于乙酸(8mL)，加入铁粉(120mg,2.14mmol),反应在80℃搅拌30分钟。反应液浓缩，依次加入80mL乙酸乙酯和50mL饱和碳酸氢钠，悬浮液用硅藻土过滤，滤饼用乙酸乙酯洗涤，有机相分离，依次用25mL饱和碳酸氢钠，25mL饱和食盐水洗涤，干燥浓缩得产物(2R,4aR)-11-环丙基-10-(2-氟-6-甲氧基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-2-甲基-5,7-二氧代-1,2,4,4a,5,6,7,8-辛基-3H-吡嗪[1’,2’:4,5]吡嗪[2,3-c][1,8]萘啶-3-羧酸叔丁酯(415mg,Y:99.5％)，淡黄色固体。ES-API:[M+H]+＝683.3。
步骤5：向50mL封管中依次加入(2R,4aR)-11-环丙基-10-(2-氟-6-甲氧基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-2-甲基-5,7-二氧代-1,2,4,4a,5,6,7,8-辛基-3H-吡嗪[1’,2’:4,5]吡嗪[2,3-c][1,8]萘啶-3-羧酸叔丁酯(415mg，0.61mmol)，12mL丙酮，无水碳酸钾(337mg,2.44mmol)，碘甲烷(693mg，4.88mmol)。密封封管，反应在50℃搅拌18小时。反应液加入60mL乙酸乙酯，依次用15mL水，15mL饱和食盐水洗涤，干燥浓缩，粗品用制备薄层色谱板纯化(二氯甲烷/甲醇＝25：1)得产物(2R,4aR)-11-环丙基-10-(2-氟-6-甲氧基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-2,6-二甲基-5,7-二氧代-1,2,4,4a,5,6,7,8-辛基-3H-吡嗪[1’,2’:4,5]吡嗪[2,3-c][1,8]萘啶-3-羧酸叔丁酯(160mg,Y:37.8％)，淡黄色固体。ES-API:[M+H] +＝697.3。
步骤6：(2R,4aR)-11-环丙基-10-(2-氟-6-甲氧基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-2,6-二甲基-5,7-二氧代-1,2,4,4a,5,6,7,8-辛基-3H-吡嗪[1’,2’:4,5]吡嗪[2,3-c][1,8]萘啶-3-羧酸叔丁酯(160mg,0.23mmol)溶于二氯甲烷(3.5mL)，加入三氟乙酸(0.8mL)。室温搅拌2小时，反应液浓缩得产物((2R,4aR)-11-环丙基-10-(2-氟-6-甲氧基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-2,6-二甲基-1,2,4,4a，6,8-六氢-3l2-吡嗪[4'，3'：4,5]吡嗪[2,3-c][1,8]萘啶-5,7-二酮(165mg,粗品)，直接用于下一步反应。ES-API:[M+H] +＝597.2。
步骤7：(2R,4aR)-11-环丙基-10-(2-氟-6-甲氧基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-2,6-二甲基-1,2,4,4a，6,8-六氢-3l2-吡嗪[4'，3'：4,5]吡嗪[2,3-c][1,8]萘啶-5,7-二酮(165mg，粗品)溶于二氯甲烷(10mL)，加入N,N-二异丙基乙胺(148mg，1.15mmol)。将反应冷至0℃，向反应液中滴加丙烯酰氯(41mg，0.46mmol)。反应在0℃搅拌15分钟。向反应液中加入30mL二氯甲烷，依次用15mL水，15mL饱和NaHCO 3水溶液，15mL饱和食盐水洗涤，干燥浓缩，干燥后浓缩，粗品用快速硅胶柱纯化(二氯甲烷/甲醇：0-5％)得产物(2R,4aR)-3-丙烯酰基-11-环丙基-10-(2-氟-6-甲氧基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-2,6-二甲基-2,3,4,4a,6,8-六氢-1H-吡嗪[1’,2’:4,5]吡嗪[2,3-c][1,8]萘啶-5,7-二酮(140mg,Y:93.7％)，淡黄色固体。ES-API:[M+H] +＝651.3。
步骤8：(2R,4aR)-3-丙烯酰基-11-环丙基-10-(2-氟-6-甲氧基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-2,6-二甲基-2,3,4,4a,6,8-六氢-1H-吡嗪[1’,2’:4,5]吡嗪[2,3-c][1,8]萘啶-5,7-二酮(130mg，0.20mmol)溶于二氯甲烷(3mL)。将反应冷至0℃，向其中滴加17％三溴化硼的二氯甲烷溶液(3mL)。反应在室温下搅拌3小时。将反应液倒入40mL饱和NaHCO 3水溶液，用25mL二氯甲烷萃取2次。有机相干燥后浓缩，粗品用制备HPLC纯化得产 物(2R,4aR)-3-丙烯酰基-11-环丙基-10-(2-氟-6-羟基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-2,6-二甲基-2,3,4,4a,6,8-六氢-1H-吡嗪[1’,2’:4,5]吡嗪[2,3-c][1,8]萘啶-5,7-二酮(Z31，65mg,Y：51.1％)，白色固体。 1H NMR(500MHz,DMSO-d 6)δ9.90(s,1H),8.42(d,J＝4.8Hz,1H),7.75-7.73(m,1H),7.22-7.17(m,2H),7.03(dd,J＝16.8,10.5Hz,1H),6.74–6.60(m,2H),6.22–6.08(m,1H),5.81–5.69(m,1H),5.05-4.81(m,1H),4.62-4.41(m,1H),4.03-3.90(m,1H),3.75(dd,J＝14.1,4.2Hz,1H),3.39-3.25(m,4H),2.83-2.67(m,1H),2.48-2.37(m,1H),2.01–1.75(m,3H),1.70–1.46(m,4H),1.14–0.55(m,10H).ES-API:[M+H] +＝637.3。
实施例32制备化合物Z32
Figure PCTCN2020124226-appb-000114
步骤1：4,6-二环丙基嘧啶-5-胺(742mg,4.24mmol)溶于干燥的四氢呋喃中(20mL)，在冰水浴条件，加入2M的NaHMDS(8.48mL,16.96mmol)，在冰水浴条件下搅拌20分钟。加入2,5-二氟-6-(2-氟-6-甲氧基苯基)烟酸(1.2g,4.24mmol)，室温搅拌3h，将反应液中缓慢倒入30mL冰水中，稀盐酸(3M)调节pH＝5-6，乙酸乙酯萃取，50mL饱和食盐水洗涤一次。无水硫酸钠干燥，过滤，有机相干燥浓缩后，粗品用快速硅胶柱(EtOAc/PE：20-40％)纯化得产物2-((4,6-二环丙基嘧啶-5-基)氨基)-5-氟-6-(2-氟-6-甲氧基苯基)烟酸(1.8g，Y:98％)，黄色固体。ES-API:[M+H] +＝439.1。
步骤2：将2-((4,6-二环丙基嘧啶-5-基)氨基)-5-氟-6-(2-氟-6-甲氧基苯基)烟酸(1.5g,3.42mmol)溶解在二氯乙烷中，加入二氯亚砜(4.07g,34.2mmol)。反应在80℃搅拌2小时。反应完毕，反应液冷却到室温，浓缩，50度真空减压干燥4h，得产物2-((4,6-二环丙基嘧啶-5-基)氨基)-5-氟-6-(2-氟-6-甲氧基苯基)烟酰氯(1.57g,粗品)，淡黄色固体。甲醇检测ES-API:[M+H] +＝453.2。
步骤3：在冰水浴条件下，将氢化钠(1.97g，49.35mmol)加入到硝酸乙酸乙酯(1.31g，9.86mmol)的四氢呋喃中，搅拌30分钟，随后加入2-((4,6-二环丙基嘧啶-5-基)氨基)-5-氟-6-(2-氟-6-甲氧基苯基)烟酰氯(1.57g，3.29mmol)室温搅拌1h，然后升温至80℃反应 2h。倒入冰水中，3M盐酸调节pH3-4,乙酸乙酯萃取，无水硫酸钠干燥，过滤，有机相干燥浓缩后得产物1-(4,6-二环丙基嘧啶-5-基)-6-氟-7-(2-氟-6-甲氧基苯基)-4-羟基-3-硝基-1,8-萘啶-2(1H)-酮(110mg，Y:20％)。ES-API:[M+H] +＝508.1。
步骤4：1-(4,6-二环丙基嘧啶-5-基)-6-氟-7-(2-氟-6-甲氧基苯基)-4-羟基-3-硝基-1,8-萘啶-2(1H)-酮(110mg,0.20mmol)溶于乙腈(10mL)，依次加入三氯氧磷(153mg,1.0mmol)，和N,N-二异丙基乙胺(77g,0.6mmol)，反应逐渐升至80℃并搅拌3h。将反应液浓缩，加入30mL冷的乙腈，冰水浴下滴加到30mL饱和碳酸氢钠溶液中，用乙酸乙酯萃取(50mL*2)，合并有机相，30mL饱和食盐水洗涤，无水硫酸钠干燥，过滤，有机相干燥浓缩后，粗品用快速硅胶柱(EtOAc/PE：0-80％)纯化得4-氯-6-氟-7-(2-氟-6-甲氧基苯基)-1-(4,6-二环丙基嘧啶-5-基)-3-硝基-1,8-萘啶-2(1H)-酮(110mg,Y：68％)，黄色固体。ES-API:[M+H] +＝526.2。
步骤5：4-氯-6-氟-7-(2-氟-6-甲氧基苯基)-1-(4,6-二环丙基嘧啶-5-基)-3-硝基-1,8-萘啶-2(1H)-酮(110mg,0.296mmol)溶于N,N-二甲基乙酰胺(3mL)，依次加入1-(叔丁基)3-甲基(R)-哌嗪-1,3-二羧酸酯(54mg,0.22mmol)，反应在120℃搅拌2小时。反应完毕，加入30mL乙酸乙酯，用30mL饱和食盐水洗涤三次。乙酸乙酯相干燥浓缩，得到粗品，目标产物(3R)-1-叔丁基3-甲基4-(1-(4,6-二环丙基嘧啶-5-基)-6-氟-7-(2-氟-6-甲氧基苯基)-3-硝基-2-氧代-1,2-二氢-1,8-萘啶-4-基)哌嗪-1,3-二酮(50mg,Y:46％)，黄色固体。ES-API:[M+H] +＝734.3。
步骤6：((3R)-1-叔丁基3-甲基4-(1-(4,6-二环丙基嘧啶-5-基)-6-氟-7-(2-氟-6-甲氧基苯基)-3-硝基-2-氧代-1,2-二氢-1,8-萘啶-4-基)哌嗪-1,3-二酮(50mg,0.068mmol)溶解在醋酸中(25mL)，加入铁粉(11.5mg,0.204mmol),反应在80℃搅拌30分钟。反应液浓缩，依次加入30mL乙酸乙酯和30mL饱和碳酸氢钠，悬浮液用硅藻土过滤，滤饼用乙酸乙酯洗涤，有机相分离，依次用30mL饱和碳酸氢钠，30mL饱和食盐水洗涤，干燥浓缩得产物(4aR)-8-(4,6-二环丙基嘧啶-5-基)-11-氟-10-(2-氟-6-甲氧基苯基)-5,7-二氧代-4,4a,5,6,7,8-六氢-1H-吡嗪并[1’,2’:4,5]吡嗪并[2,3-c][1,8]萘啶-3(2H)-羧酸叔丁酯(40mg,粗品)，黄色固体。ES-API:[M+H]+＝672.2。
步骤7：将(4aR)-8-(4,6-二环丙基嘧啶-5-基)-11-氟-10-(2-氟-6-甲氧基苯基)-5,7-二氧代-4,4a,5,6,7,8-六氢-1H-吡嗪并[1’,2’:4,5]吡嗪并[2,3-c][1,8]萘啶-3(2H)-羧酸叔丁酯(40mg,0.059mmol)，30mL丙酮，无水碳酸钾(33mg,0.24mmol)，碘甲烷(85mg，0.59mmol)密封封管，反应在50℃搅拌18小时。反应液加入20mL乙酸乙酯，用20mL饱和食盐水洗涤，干燥浓缩，粗品用快速硅胶柱纯化(EtOAc/PE：0-80％)得产物(4aR)-叔丁基8-(4,6-二环丙基嘧啶-5-基)-11-氟-10-(2-氟-6-甲氧基苯基)-6-甲基-5,7-二氧代-4,4a,5,6,7,8-六氢-1H-吡嗪并[1’,2’:4,5]吡嗪并[2,3-c][1,8]萘啶-3(2H)-酮(40mg,Y:90％)，黄色固体。ES-API:[M+H] +＝686.2。
步骤8：(4aR)-叔丁基8-(4,6-二环丙基嘧啶-5-基)-11-氟-10-(2-氟-6-甲氧基苯基)-6-甲基-5,7-二氧代-4,4a,5,6,7,8-六氢-1H-吡嗪并[1’,2’:4,5]吡嗪并[2,3-c][1,8]萘啶-3(2H)-酮(44mg)溶于二氯甲烷(3mL)，加入三氟乙酸(1mL)。室温搅拌2小时，反应液浓缩得产物(4aR)-8-(4,6-二环丙基嘧啶-5-基)-11-氟-10-(2-氟-6-甲氧基苯基)-6-甲基-2,3,4,4a-四氢-1H-吡嗪并[1’,2’:4,5]吡嗪并[2,3-c][1,8]萘啶-5,7(6H，8H)-二酮(40mg,粗品)，直接用于下 一步反应。ES-API:[M+H] +＝586.2。
步骤9：(4aR)-8-(4,6-二环丙基嘧啶-5-基)-11-氟-10-(2-氟-6-甲氧基苯基)-6-甲基-2,3,4,4a-四氢-1H-吡嗪并[1’,2’:4,5]吡嗪并[2,3-c][1,8]萘啶-5,7(6H，8H)-二酮(40mg，0.068mmol)溶于二氯甲烷(5mL)，加入二异丙基乙胺(53mL，0.408mmol)。将反应冷至0℃，向反应液中滴加丙烯酰氯(12.4mg，0.137mmol)。反应在0℃搅拌15分钟。向反应液中加入20mL二氯甲烷，用20mL饱和NaHCO 3水溶液，20mL饱和食盐水洗涤，干燥后浓缩，粗品经制备HPLC纯化得产物(4aR)-3-丙烯酰基-11-氟-10-(2-氟-6-甲氧基苯基)-8-(4,6-二环丙基嘧啶-5-基)-6-甲基-2,3,4,4a,6,8-六氢-1H-吡嗪并[1’,2’:4,5]吡嗪并[2,3-c][1,8]萘啶-5,7-二酮(Z32，10mg,Y:22％)，黄色固体。ES-API:[M+H] +＝640.2。
实施例33制备化合物Z33、Z33-1和Z33-2
Figure PCTCN2020124226-appb-000115
步骤1：将7-氯-6-氟-4-羟基-1-(1-异丙基-4-甲基-1H-吡唑-5-基)-2-氧代-1,2-二氢-1,8-萘啶-3-腈(3.6g,10.0mmol)悬浮于1，4-二氧六环(10mL)、水(120mL)的混合溶液，缓慢加入浓硫酸(10mL)。反应120℃下搅拌18小时。将冷却的反应液中倒入20mL冰水中，用碳酸钠调pH2-3，用乙酸乙酯萃取(1000mL*2)，合并乙酸乙酯相，无水硫酸钠干燥，过滤，滤液真空干燥后得产物7-氯-6-氟-4-羟基-1-(1-异丙基-4-甲基-1H-吡唑-5-基)-1,8-萘啶-2(1H)-酮(3.36g,Y:92％)，淡棕色固体。ES-API:[M+H] +＝337.1。
步骤2：7-氯-6-氟-4-羟基-1-(1-异丙基-4-甲基-1H-吡唑-5-基)-1,8-萘啶-2(1H)-酮(3.36g,10mmol)溶于乙酸(7mL)，依次加入亚硝酸钠(69mg,1.0mmol)和浓硝酸(2.0mL，30mmol)，反应在室温下搅拌30分钟。将反应液中缓慢倒入21mL冰水中，析出的固体过滤，滤饼用10ml冰水洗涤，在真空下干燥得产物7-氯-6-氟-4-羟基-1-(1-异丙基-4-甲基-1H-吡唑-5-基)3-硝基-1,8-萘啶-2(1H)-酮(3.0g，Y:90％)，黄色固体。ES-API:[M+H] +＝382.1。
步骤3：向100mL三口圆底烧瓶中加入7-氯-6-氟-4-羟基-1-(1-异丙基-4-甲基-1H-吡唑-5-基)3-硝基-1,8-萘啶-2(1H)-酮(1.5g,3.93mmol)、(2-氟-6-甲氧基苯基)硼酸(2.67g,15.72mmol)、四三苯基膦钯(908mg,0.786mmol)、碳酸钾(2.72g,19.65mmol)、4mL 水和20mL二氧六环。氮气保护下，反应在100℃搅拌3小时。反应完毕，反应液冷却到室温，加入20mL水和50mL甲基叔丁基醚，萃取一次。水相用1M的盐酸溶液调pH3-5，用乙酸乙酯萃取(50mL*2)，合并乙酸乙酯相，无水硫酸钠干燥，过滤，滤液真空干燥后得产物6-氟-7-(2-氟-6-甲氧基苯基)-4-羟基-1-(1-异丙基-4-甲基-1H-吡唑-5-基)-3-硝基-1,8-萘啶-2(1H)-酮(1.5g,粗品)，淡黄色固体。ES-API:[M+H] +＝472.1。
步骤4：6-氟-7-(2-氟-6-甲氧基苯基)-4-羟基-1-(1-异丙基-4-甲基-1H-吡唑-5-基)-3-硝基-1,8-萘啶-2(1H)-酮(1.5g,3.18mmol)溶于乙腈(15mL)，依次加入三氯氧磷(2.4ml,25.5mmol)，和N,N-二异丙基乙胺(2.6ml,15.9mmol)，反应逐渐升至80℃并搅拌30分钟。将反应液浓缩，加入10mL冷的乙腈，冰水浴下滴加到20mL饱和碳酸氢钠溶液中，用乙酸乙酯萃取(20mL*2)，合并乙酸乙酯相，20mL饱和食盐水洗涤一次。无水硫酸钠干燥，过滤，有机相干燥浓缩后，粗品用快速硅胶柱(EtOAc/PE：0-50％)纯化得4-氯-6-氟-7-(2-氟-6-甲氧基苯基)-1-(1-异丙基-4-甲基-1H-吡唑-5-基)-3-硝基-1,8-萘啶-2(1H)-酮(0.9g,Y：65％)，黄色固体。ES-API:[M+H] +＝490.1。
步骤5：4-氯-6-氟-7-(2-氟-6-甲氧基苯基)-1-(1-异丙基-4-甲基-1H-吡唑-5-基)-3-硝基-1,8-萘啶-2(1H)-酮(490mg,1.0mmol)溶于N,N-二甲基乙酰胺(5mL)，依次加入(3R,6R)-1-叔丁基3-甲基6-甲基哌嗪-1,3-二羧酸(310mg,1.2mmol)，和N,N-二异丙基乙胺(390mg,3mmol)，反应在120℃搅拌2小时。反应液中加入20mL乙酸乙酯，用20mL饱和食盐水洗涤三次。乙酸乙酯相干燥浓缩，得产物(3R,6R)-1-叔丁基-3-甲基4-(6-氟-7-(2-氟-6-甲氧基苯基)-1-(1-异丙基-4-甲基-1H-吡唑-5-yl)-3-硝基-2-氧代-1,2-二氢-1,8-萘啶-4-基)哌嗪-1,3-二酮(620mg,粗品)，黄色固体。ES-API:[M+H] +＝712.2。
步骤6：(3R,6R)-1-叔丁基-3-甲基4-(6-氟-7-(2-氟-6-甲氧基苯基)-1-(1-异丙基-4-甲基-1H-吡唑-5-yl)-3-硝基-2-氧代-1,2-二氢-1,8-萘啶-4-基)哌嗪-1,3-二酮(620mg,0.872mmol)溶解在醋酸中(8mL)，加入铁粉(146mg,2.62mmol),反应在80℃搅拌30分钟。反应液浓缩，依次加入30mL乙酸乙酯和30mL饱和碳酸氢钠，悬浮液用硅藻土过滤，滤饼用乙酸乙酯洗涤，有机相分离，依次用30mL饱和碳酸氢钠，30mL饱和食盐水洗涤，干燥浓缩得产物(2R,4aR)-叔丁基11-氟-10-(2-氟-6-甲氧基苯基)-8-(1-异丙基-4-甲基-1H-吡唑-5-基)-2-甲基-5,7-二氧代-4,4a,5,6,7,8-六氢-1H-吡嗪并[1’,2’:4,5]吡嗪并[2,3-c][1,8]萘啶-3(2H)-羧酸叔丁酯(300mg,粗品)，黄色固体。ES-API:[M+H]+＝650.3。
步骤7：将(2R,4aR)-叔丁基11-氟-10-(2-氟-6-甲氧基苯基)-8-(1-异丙基-4-甲基-1H-吡唑-5-基)-2-甲基-5,7-二氧代-4,4a,5,6,7,8-六氢-1H-吡嗪并[1’,2’:4,5]吡嗪并[2,3-c][1,8]萘啶-3(2H)-羧酸叔丁酯(300mg,0.462mmol)，6mL丙酮，无水碳酸钾(255mg,1.84mmol)，碘甲烷(656mg，4.62mmol)密封封管，反应在50℃搅拌18小时。反应液加入20mL乙酸乙酯，用20mL饱和食盐水洗涤，干燥浓缩，粗品用快速硅胶柱纯化(EtOAc/PE：0-80％)得产物(2R,4aR)-11-氟-10-(2-氟-6-甲氧基苯基)-8-(1-异丙基-4-甲基-1H-吡唑-5-基)-2,6-二甲基-5,7-二氧代-4,4a,5,6,7,8-六氢-1H-吡嗪并[1’,2’:4,5]吡嗪并[2,3-c][1,8]萘啶-3(2H)-羧酸叔丁酯(350mg,Y:95％)，黄色固体。ES-API:[M+H] +＝664.3。
步骤8：(2R,4aR)-11-氟-10-(2-氟-6-甲氧基苯基)-8-(1-异丙基-4-甲基-1H-吡唑-5-基)-2,6-二甲基-5,7-二氧代-4,4a,5,6,7,8-六氢-1H-吡嗪并[1’,2’:4,5]吡嗪并[2,3-c][1,8]萘啶-3(2H)-羧酸叔丁酯(350mg)溶于二氯甲烷(4mL)，加入三氟乙酸(2mL)。室温搅拌2小 时，反应液浓缩得产物(2R,4aR)-11-氟-10-(2-氟-6-甲氧基苯基)-8-(1-异丙基-4-甲基-1H-吡唑-5-基)-2,6-二甲基-2,3,4,4a-四氢-1H-吡嗪并[1’,2’:4,5]吡嗪并[2,3-c][1,8]萘啶-5,7(6H，8H)-二酮(40mg,粗品)，直接用于下一步反应。ES-API:[M+H] +＝564.2。
步骤9：(2R,4aR)-11-氟-10-(2-氟-6-甲氧基苯基)-8-(1-异丙基-4-甲基-1H-吡唑-5-基)-2,6-二甲基-2,3,4,4a-四氢-1H-吡嗪并[1’,2’:4,5]吡嗪并[2,3-c][1,8]萘啶-5,7(6H，8H)-二酮(350mg，0.62mmol)溶于二氯甲烷(6mL)，加入二异丙基乙胺(480mg，3.72mmol)。将反应冷至0℃，向反应液中滴加丙烯酰氯(112.5mg，1.24mmol)。反应在0℃搅拌15分钟。向反应液中加入20mL二氯甲烷，用20mL饱和NaHCO 3水溶液，20mL饱和食盐水洗涤，干燥后浓缩，粗品经制备色谱纯化得产物(2R,4aR)-3-丙烯酰基-11-氟-10-(2-氟-6-甲氧基苯基)-8-(1-异丙基-4-甲基-1H-吡唑-5-基)-2,6-二甲基-2,3,4,4a-四氢-1H-吡嗪并[1’,2’:4,5]吡嗪并[2,3-c][1,8]萘啶-5,7(6H，8H)-二酮(250mg,Y:60％)，黄色固体。ES-API:[M+H] +＝618.3。
步骤10：冰水浴条件下，将(2R,4aR)-3-丙烯酰基-11-氟-10-(2-氟-6-甲氧基苯基)-8-(1-异丙基-4-甲基-1H-吡唑-5-基)-2,6-二甲基-2,3,4,4a-四氢-1H-吡嗪并[1’,2’:4,5]吡嗪并[2,3-c][1,8]萘啶-5,7(6H，8H)-二酮(250mg,0.405mmol)加入到干燥二氯甲烷中(6.0mL),再加入三溴化硼(4.0mL,4.0mmol),升至室温，反应1h。冰水浴条件下，将上述反应液滴加入饱和碳酸氢钠饱和溶液中，二氯甲烷(30mL)萃取2次，干燥，浓缩，得产物(2R,4aR)-3-丙烯酰基-11-氟-10-(2-氟-6-羟基苯基)-8-(1-异丙基-4-甲基-1H-吡唑-5-基)-2,6-二甲基-2,3,4,4a-四氢-1H-吡嗪并[1’,2’:4,5]吡嗪并[2,3-c][1,8]萘啶-5,7(6H，8H)-二酮(Z33)。
步骤11：将化合物Z33经制备HPLC纯化得到：一个阻转异构体化合物，结构任意指定为Z33-1(峰1，30mg,保留时间9.576min，Y:50％)。 1H NMR(500MHz,DMSO-d 6)δ10.17(s,1H),7.98(dd,J＝8.4,5.5Hz,1H),7.40(d,J＝5.5Hz,1H),7.29(q,J＝7.9Hz,1H),7.02(dd,J＝16.8,10.6Hz,1H),6.81–6.68(m,2H),6.20–6.11(m,1H),5.81–5.69(m,1H),4.77(s,1H),4.61(d,J＝14.7Hz,1H),4.01–3.83(m,2H),3.73(dd,J＝14.2,4.2Hz,1H),3.35(d,J＝5.8Hz,3H),2.86(dd,J＝48.2,12.0Hz,1H),1.76–1.59(m,3H),1.55(dd,J＝16.6,6.7Hz,3H),1.26(dd,J＝32.6,6.6Hz,3H),1.21–1.10(m,3H)。和另一个阻转异构体化合物，结构任意指定为Z33-2(峰2，15mg,保留时间9.663min，Y:25％)。 1H NMR(500MHz,DMSO-d 6)δ10.17(s,1H),7.96(m,1H),7.40(d,J＝5.5Hz,1H),7.29(q,J＝7.9Hz,1H),7.02(m,1H),6.81–6.68(m,2H),6.20–6.11(m,1H),5.81–5.69(m,1H),4.77(s,1H),4.61(d,J＝14.7Hz,1H),4.01–3.83(m,2H),3.73(dd,J＝14.2,4.2Hz,1H),3.35(d,J＝5.8Hz,3H),2.86(m,1H),1.76–1.59(m,3H),1.55(m,3H),1.30(dd,J＝32.6,6.6Hz,3H),1.23–1.15(m,3H).异构体化合物通过分析型HPLC方法进行检测。
实施例34制备化合物Z34、Z34-1和Z34-2
Figure PCTCN2020124226-appb-000116
步骤1：向15mL封管中依次加入(2R,4aR)-11-氟-10-(2-氟-6-甲氧基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-2-甲基-5,7-二氧代-1,2,4,4a,5,6,7,8-辛基-3H-吡嗪[1’,2’:4,5]吡嗪[2,3-c][1,8]萘啶-3-羧酸叔丁酯(115mg，0.17mmol)，4mL丙酮，无水碳酸钾(94mg,0.68mmol)，氘代碘甲烷(246mg，1.70mmol)。密封封管，反应在50℃搅拌18小时。反应液加入30mL乙酸乙酯，依次用12mL水，15mL饱和食盐水洗涤，干燥浓缩得产物(2R,4aR)-11-氟-10-(2-氟-6-甲氧基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-2-甲基-6-(甲基-d3)-5,7-二氧代-1,2,4,4a,5,6,7,8-辛基-3H-吡嗪[1’,2’:4,5]吡嗪[2,3-c][1,8]萘啶-3-羧酸叔丁酯(118mg,Y:100.0％)，黄色固体。ES-API:[M+H] +＝678.3。
步骤2：(2R,4aR)-11-氟-10-(2-氟-6-甲氧基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-2-甲基-6-(甲基-d3)-5,7-二氧代-1,2,4,4a,5,6,7,8-辛基-3H-吡嗪[1’,2’:4,5]吡嗪[2,3-c][1,8]萘啶-3-羧酸叔丁酯(118mg,0.17mmol)溶于二氯甲烷(3mL)，加入三氟乙酸(0.7mL)。室温搅拌2小时，反应液浓缩得产物(2R,4aR)-11-氟-10-(2-氟-6-甲氧基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-2-甲基-6-(甲基-d3)-2,3,4,4a,6,8-六氢-1H-吡嗪[1’,2’:4,5]吡嗪[2,3-c][1,8]萘啶-5,7-二酮(120mg,粗品)，直接用于下一步反应。ES-API:[M+H] +＝578.2。
步骤3：(2R,4aR)-11-氟-10-(2-氟-6-甲氧基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-2-甲基-6-(甲基-d3)-2,3,4,4a,6,8-六氢-1H-吡嗪[1’,2’:4,5]吡嗪[2,3-c][1,8]萘啶-5,7-二酮(120mg，粗品)溶于二氯甲烷(5mL)，加入N,N-二异丙基乙胺(110mg，0.85mmol)。将反应冷至0℃，向反应液中滴加丙烯酰氯(31mg，0.34mmol)。反应在0℃搅拌15分钟。向反应液中加入25mL二氯甲烷，依次用15mL水，15mL饱和NaHCO 3水溶液，15mL饱和食盐水洗涤，干燥浓缩，干燥后浓缩，粗品用快速硅胶柱纯化(EtOAc/PE：0-100％)得产物(2R,4aR)-3-丙烯酰基-11-氟-10-(2-氟-6-甲氧基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-2-甲基-6-(甲基-d3)-2,3,4,4a,6,8-六氢-1H-吡嗪[1’,2’:4,5]吡嗪[2,3-c][1,8]萘啶-5,7-二酮(85mg,Y:77.3％)，淡黄色固体。ES-API:[M+H] +＝632.2。
步骤4：(2R,4aR)-3-丙烯酰基-11-氟-10-(2-氟-6-甲氧基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-2-甲基-6-(甲基-d3)-2,3,4,4a,6,8-六氢-1H-吡嗪[1’,2’:4,5]吡嗪[2,3-c][1,8]萘啶-5,7-二酮(85mg，0.13mmol)溶于二氯甲烷(1.5mL)。将反应冷至0℃，向其中滴加17％三溴化硼的二氯甲烷溶液(1.5mL)。反应在室温下搅拌4小时。将反应液倒入40mL饱和 NaHCO 3水溶液，用25mL二氯甲烷萃取2次。有机相干燥后浓缩，粗品用制备HPLC纯化得产物(2R,4aR)-3-丙烯酰基-11-氟-10-(2-氟-6-甲氧基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-2-甲基-6-(甲基-d3)-2,3,4,4a,6,8-六氢-1H-吡嗪[1’,2’:4,5]吡嗪[2,3-c][1,8]萘啶-5,7-二酮(Z34)。
步骤5：将化合物Z34通过制备型手性HPLC拆分(柱型:OD-H:10μm,20*250mm,流动相:己烷:EtOH＝80:20,流速:15ml/min,柱温室温)纯化得到：一个阻转异构体化合物，结构任意指定为Z34-1(23mg,峰1，保留时间11.056min，Y：28.7％)，淡黄色固体。 1H NMR(500MHz,DMSO-d 6)δ10.14(s,1H),8.44(d,J＝4.9Hz,1H),8.01-7.97(m,1H),7.28–7.23(m,2H),7.05-6.84(m 1H),6.77–6.64(m,2H),6.18–6.13(m,1H),5.77–5.71(m,1H),5.03-4.77(m,1H),4.61-4.41(m,1H),4.06-4.00(m,1H),3.73(dd,J＝14.1,4.2Hz,1H),3.39–3.20(m,1H),2.92–2.79(m,1H),2.47-2.36(m,1H),1.99(s,3H),1.58-1.53(m,3H),1.03(d,J＝6.7Hz,3H),0.85(d,J＝6.7Hz,3H).ES-API:[M+H] +＝618.2。和另一个阻转异构体化合物，结构任意指定为Z34-2(25mg,峰2，保留时间14.067min，Y：31.2％)，淡黄色固体。 1H NMR(500MHz,DMSO-d 6)δ10.15(s,1H),8.45(d,J＝4.9Hz,1H),8.01-7.97(m,1H),7.28–7.23(m,2H),7.05-6.85(m 1H),6.74–6.63(m,2H),6.18–6.13(m,1H),5.77–5.71(m,1H),5.04-4.77(m,1H),4.62-4.41(m,1H),4.00-3.94(m,1H),3.73(dd,J＝14.1,4.2Hz,1H),3.43–3.25(m,1H),2.95–2.83(m,1H),2.79-2.74(m,1H),1.80(s,3H),1.58-1.53(m,3H),1.11(d,J＝6.7Hz,3H),0.98(d,J＝6.7Hz,3H).
ES-API:[M+H] +＝618.2。异构体化合物通过分析型手性HPLC方法(柱型:OD-H:5μm,4.6*250mm,流动相:己烷:EtOH＝80:20,流速:1ml/min,柱温＝30℃)进行检测。
实施例35制备化合物Z35、Z35-1和Z35-2
Figure PCTCN2020124226-appb-000117
步骤1：(2R,4aR)-11-氟-10-(2-氟-6-甲氧基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-2-甲基-5,7-二氧代-1,2,4,4a,5,6,7,8-辛基-3H-吡嗪[1’,2’:4,5]吡嗪[2,3-c][1,8]萘啶-3-羧酸叔丁酯(200mg,0.30mmol)溶于二氯甲烷(4mL)，加入三氟乙酸(1mL)。室温搅拌2小时，反应液浓缩得产物(2R,4aR)-11-氟-10-(2-氟-6-甲氧基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-2-甲基-2,3,4,4a,6,8-六氢-1H-吡嗪[1’,2’:4,5]吡嗪[2,3-c][1,8]萘啶-5,7-二酮(210mg,粗品)，直接用于下一步反应。ES-API:[M+H] +＝561.3。
步骤2：(2R,4aR)-11-氟-10-(2-氟-6-甲氧基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-2-甲基-2,3,4,4a,6,8-六氢-1H-吡嗪[1’,2’:4,5]吡嗪[2,3-c][1,8]萘啶-5,7-二酮(210mg，粗品)溶于二氯甲烷(10mL)，加入N,N-二异丙基乙胺(194mg，1.50mmol)。将反应冷至0℃，向反应液中滴加丙烯酰氯(54mg，0.60mmol)。反应在0℃搅拌15分钟。向反应液中加入30mL二氯甲烷，依次用15mL水，15mL饱和NaHCO 3水溶液，15mL饱和食盐水洗涤，干燥后浓缩得产物(2R,4aR)-3-丙烯酰-11-氟-10-(2-氟-6-甲氧基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-2-甲基-2,3,4,4a,6,8-六氢-1H-吡嗪[1’,2’:4,5]吡嗪[2,3-c][1,8]萘啶-5,7-二酮(175mg,Y:95.0％)，淡黄色固体。ES-API:[M+H] +＝615.3。
步骤3：(2R,4aR)-3-丙烯酰-11-氟-10-(2-氟-6-甲氧基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-2-甲基-2,3,4,4a,6,8-六氢-1H-吡嗪[1’,2’:4,5]吡嗪[2,3-c][1,8]萘啶-5,7-二酮(175mg，0.28mmol)溶于二氯甲烷(4mL)。将反应冷至0℃，向其中滴加17％三溴化硼的二氯甲烷溶液(4mL)。反应在室温下搅拌3小时。将反应液倒入80mL饱和NaHCO 3水溶液，用30mL二氯甲烷萃取2次。有机相干燥后浓缩得产物(2R,4aR)-3-丙烯酰基-11-氟-10-(2-氟-6-羟基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-2-甲基-2,3,4,4a,6,8-六氢-1H-吡嗪[1'，2':4]吡嗪[2,3,3-c][1,8,8]萘啶-5-二酮(Z35，170mg,Y：99.4％)，淡黄色固体。ES-API:[M+H] +＝601.2。
步骤4：化合物Z35(170mg，0.28mmol)用制备HPLC纯化，然后通过制备型手性HPLC拆分(柱型:IA:10μm,30*250mm,流动相:己烷:EtOH＝40:60，流速:25ml/min,柱温室温)得到：一个阻转异构体化合物，结构任意指定为Z35-1(19mg,峰1，保留时间2.905min，Y：11.1％)，淡黄色固体。 1H NMR(500MHz,DMSO-d 6)δ10.60-10.46(m,1H),10.12(s,1H),8.45(d,J＝4.8Hz,1H),8.01-7.91(m,1H),7.31–7.18(m,2H),7.03-6.82(m,1H),6.75–6.63(m,2H),6.20–6.10(m,1H),5.79–5.70(m,1H),5.08–4.70(m,1H),4.67-4.39(m,1H),4.09-3.97(m,1H),3.72(dd,J＝14.1,4.0Hz,1H),3.31–3.18(m,1H),3.02–2.87(m,1H),2.57-2.50(m,1H),1.89(s,3H),1.58-1.44(m,3H),1.05(d,J＝6.7Hz,3H),0.89(d,J＝6.7Hz,3H).ES-API:[M+H] +＝601.2。和另一个阻转异构体化合物，结构任意指定为Z35-2(19mg,峰2，保留时间8.769min，Y：11.1％)，淡黄色固体。 1H NMR(500MHz,DMSO-d 6)δ10.60-10.46(m,1H),10.12(s,1H),8.45(d,J＝4.9Hz,1H),8.01-7.91(m,1H),7.31–7.18(m,2H),7.03-6.82(m,1H),6.75–6.63(m,2H),6.20–6.08(m,1H),5.78–5.67(m,1H),5.10–4.70(m,1H),4.67-4.39(m,1H),4.09-3.97(m,1H),3.72(dd,J＝14.1,3.8Hz,1H),3.31–3.18(m,1H),3.06–2.92(m,1H),2.66-2.57(m,1H),1.83(s,3H),1.58-1.44(m,3H),1.08(d,J＝6.7Hz,3H),0.91(d,J＝6.7Hz,3H).ES-API:[M+H] +＝601.2。异构体化合物通过分析型手性HPLC方法(柱型:IA:5μm,4.6*150mm,流动相:己烷:EtOH＝40:60，流速:1ml/min,柱温＝30℃)进行检测。
实施例36制备化合物Z36、Z36-1和Z36-2
Figure PCTCN2020124226-appb-000118
步骤1：将7-氯-6-氟-4-羟基-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢-1,8-萘啶-3-甲腈(3.6g,10.0mmol)悬浮于1，4-二氧六环(10mL)、水(120mL)的混合溶液，缓慢加入浓硫酸(10mL)。反应120℃下搅拌18小时。将冷却的反应液中倒入20mL冰水中，用碳酸钠调pH2-3，用乙酸乙酯萃取(1000mL*2)，合并乙酸乙酯相，无水硫酸钠干燥，过滤，滤液真空干燥后得产物7-氯-6-氟-4-羟基-1-(2-异丙基-4-甲基吡啶-3-基)-1,8-萘啶-2(1H)-酮(3.36g,Y:90％)，淡棕色固体。ES-API:[M+H] +＝348.1.
步骤2：7-氯-6-氟-4-羟基-1-(2-异丙基-4-甲基吡啶-3-基)-1,8-萘啶-2(1H)-酮(3.36g,10mmol)溶于乙酸(7mL)，依次加入亚硝酸钠(69mg,1.0mmol)和浓硝酸(2.0mL，30mmol)，反应在室温下搅拌30分钟。将反应液中缓慢倒入21mL冰水中，析出的固体过滤，滤饼用10ml冰水洗涤，在真空下干燥得产物7-氯-6-氟-4-羟基-1-(2-异丙基-4-甲基吡啶-3-基)3-硝基-1,8-萘啶-2(1H)-酮(3.0g，Y:90％)，黄色固体。ES-API:[M+H] +＝393.1。
步骤3：向100mL三口圆底烧瓶中加入7-氯-6-氟-4-羟基-1-(2-异丙基-4-甲基吡啶-3-基)3-硝基-1,8-萘啶-2(1H)-酮(1.5g,3.93mmol)、(2-氟苯基)硼酸(2.67g,15.72mmol)、四三苯基膦钯(908mg,0.786mmol)、碳酸钾(2.72g,19.65mmol)、4mL水和20mL二氧六环。氮气保护下，反应在100℃搅拌3小时。反应完毕，反应液冷却到室温，加入20mL水和50mL甲基叔丁基醚，萃取一次。水相用1M的盐酸溶液调pH3-5，用乙酸乙酯萃取(50mL*2)，合并乙酸乙酯相，无水硫酸钠干燥，过滤，滤液真空干燥后得产物6-氟-7-(2-氟苯基)-4-羟基-1-(2-异丙基-4-甲基吡啶-3-基)-3-硝基-1,8-萘啶-2(1H)-酮(1.5g,Y65％)，淡黄色固体。ES-API:[M+H] +＝453.1。
步骤4：6-氟-7-(2-氟苯基)-4-羟基-1-(2-异丙基-4-甲基吡啶-3-基)-3-硝基-1,8-萘啶-2(1H)-酮(1.5g,3.18mmol)溶于乙腈(15mL)，依次加入三氯氧磷(2.4ml,25.5mmol)，和N,N-二异丙基乙胺(2.6ml,15.9mmol)，反应逐渐升至80℃并搅拌30分钟。将反应液浓缩，加入10mL冷的乙腈，冰水浴下滴加到20mL饱和碳酸氢钠溶液中，用乙酸乙酯萃 取(20mL*2)，合并乙酸乙酯相，20mL饱和食盐水洗涤一次。无水硫酸钠干燥，过滤，有机相干燥浓缩后，粗品用快速硅胶柱(EtOAc/PE：0-50％)纯化得4-氯-6-氟-7-(2-氟苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-3-硝基-1,8-萘啶-2(1H)-酮(0.9g,Y：65％)，黄色固体。ES-API:[M+H] +＝471.1。
步骤5：4-氯-6-氟-7-(2-氟苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-3-硝基-1,8-萘啶-2(1H)-酮(490mg,1.0mmol)溶于N,N-二甲基乙酰胺(5mL)，依次加入(3R,6R)-1-叔丁基3-甲基6-甲基哌嗪-1,3-二羧酸(310mg,1.2mmol)，和N,N-二异丙基乙胺(390mg,3mmol)，反应在120℃搅拌1小时。反应液中加入20mL乙酸乙酯，用20mL饱和食盐水洗涤三次。乙酸乙酯相干燥浓缩，得产物(3R,6R)-1-叔丁基-3-甲基4-(6-氟-7-(2-氟苯基)-1-(1-异丙基-4-甲基-1H-吡唑-5-yl)-3-硝基-2-氧代-1,2-二氢-1,8-萘啶-4-基)哌嗪-1,3-二酮(620mg,Y50％)，黄色固体。ES-API:[M+H] +＝692.2。
步骤6：(3R,6R)-1-叔丁基-3-甲基4-(6-氟-7-(2-氟苯基)-1-(1-异丙基-4-甲基-1H-吡唑-5-yl)-3-硝基-2-氧代-1,2-二氢-1,8-萘啶-4-基)哌嗪-1,3-二酮(620mg,0.872mmol)溶解在醋酸中(8mL)，加入铁粉(146mg,2.62mmol),反应在80℃搅拌30分钟。反应液浓缩，依次加入30mL乙酸乙酯和30mL饱和碳酸氢钠，悬浮液用硅藻土过滤，滤饼用乙酸乙酯洗涤，有机相分离，依次用30mL饱和碳酸氢钠，30mL饱和食盐水洗涤，干燥浓缩得产物(2R,4aR)-11-氟-10-(2-氟苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-2-甲基-5,7-二氧代-4,4a,5,6,7,8-六氢-1H-吡嗪并[1’,2’:4,5]吡嗪并[2,3-c][1,8]萘啶-3(2H)-羧酸叔丁酯(300mg,Y80％)，黄色固体。ES-API:[M+H]+＝631.3。
步骤7：将(2R,4aR)-11-氟-10-(2-氟苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-2-甲基-5,7-二氧代-4,4a,5,6,7,8-六氢-1H-吡嗪并[1’,2’:4,5]吡嗪并[2,3-c][1,8]萘啶-3(2H)-羧酸叔丁酯(300mg,0.462mmol)，6mL丙酮，无水碳酸钾(255mg,1.84mmol)，碘甲烷(656mg，4.62mmol)密封封管，反应在50℃搅拌18小时。反应液加入20mL乙酸乙酯，用20mL饱和食盐水洗涤，干燥浓缩，粗品用快速硅胶柱纯化(EtOAc/PE：0-80％)得产物(2R,4aR)-11-氟-10-(2-氟苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-2,6-二甲基-5,7-二氧代-4,4a,5,6,7,8-六氢-1H-吡嗪并[1’,2’:4,5]吡嗪并[2,3-c][1,8]萘啶-3(2H)-羧酸叔丁酯(350mg,Y:95％)，黄色固体。ES-API:[M+H] +＝645.2。
步骤8：(2R,4aR)-11-氟-10-(2-氟苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-2,6-二甲基-5,7-二氧代-4,4a,5,6,7,8-六氢-1H-吡嗪并[1’,2’:4,5]吡嗪并[2,3-c][1,8]萘啶-3(2H)-羧酸叔丁酯(350mg)溶于二氯甲烷(4mL)，加入三氟乙酸(2mL)。室温搅拌2小时，反应液浓缩得产物(2R,4aR)-11-氟-10-(2-氟苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-2,6-二甲基-2,3,4,4a-四氢-1H-吡嗪并[1’,2’:4,5]吡嗪并[2,3-c][1,8]萘啶-5,7(6H，8H)-二酮(40mg,粗品)，直接用于下一步反应。ES-API:[M+H] +＝545.2。
步骤9：(2R,4aR)-11-氟-10-(2-氟苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-2,6-二甲基-2,3,4,4a-四氢-1H-吡嗪并[1’,2’:4,5]吡嗪并[2,3-c][1,8]萘啶-5,7(6H，8H)-二酮(350mg，0.62mmol)溶于二氯甲烷(6mL)，加入二异丙基乙胺(480mg，3.72mmol)。将反应冷至0℃，向反应液中滴加丙烯酰氯(112.5mg，1.24mmol)。反应在0℃搅拌15分钟。向反应液中加入20mL二氯甲烷，用20mL饱和NaHCO 3水溶液，20mL饱和食盐水洗涤，干燥后浓缩，粗品经制备HPLC纯化得产物(2R,4aR)-3-丙烯酰基-11-氟-10-(2-氟苯基)-8-(2-异丙 基-4-甲基吡啶-3-基)-2,6-二甲基-2,3,4,4a-四氢-1H-吡嗪并[1’,2’:4,5]吡嗪并[2,3-c][1,8]萘啶-5,7(6H，8H)-二酮(Z36，60mg,Y:18％)，黄色固体。ES-API:[M+H] +＝698.3。 1H NMR(500MHz,DMSO-d 6)δ8.49(d,J＝4.9Hz,1H),8.04(dd,J＝14.3,9.2Hz,1H),7.52(tdd,J＝7.7,5.3,1.9Hz,1H),7.36–7.26(m,3H),7.23(td,J＝7.5,2.0Hz,1H),6.95–6.77(m,1H),6.21–6.09(m,1H),5.80–5.69(m,1H),5.07–4.75(m,1H),4.64–4.39(m,1H),4.03(dd,J＝27.3,4.3Hz,1H),3.74(dd,J＝14.2,4.3Hz,1H),3.39(d,J＝2.1Hz,4H),2.95–2.80(m,1H),2.45(q,J＝6.7Hz,1H),2.02(d,J＝2.5Hz,3H),1.56(dd,J＝17.1,6.7Hz,3H),1.04(d,J＝6.6Hz,3H),0.87(d,J＝6.7Hz,3H).
步骤10：将化合物Z36通过制备型手性HPLC拆分(柱:Chiralpak IB:10μm,30*250mm；流动相:己烷:EtOH:氨甲醇＝50:50:0.2；流速:25ml/min；柱温室温)得到：一个阻转异构体化合物，结构任意指定为Z36-1(峰1，22mg,保留时间10.211min，Y:38％)，ES-API:[M+H] +＝599.2； 1H NMR(500MHz,DMSO-d 6)δ8.49(d,J＝4.9Hz,1H),8.04(dd,J＝14.3,9.2Hz,1H),7.52(t,J＝7.7,5.3,1.9Hz,1H),7.36–7.26(m,3H),7.23(t,J＝7.5,2.0Hz,1H),6.95-6.70(m,1H),6.21–6.09(m,1H),5.80–5.69(m,1H),5.07–4.75(m,1H),4.64–4.39(m,1H),4.03-3.70(m,1H),3.74(dd,J＝14.2,4.3Hz,1H),3.39(d,J＝2.1Hz,4H),2.95–2.80(m,1H),2.45(q,J＝6.7Hz,1H),2.02(d,J＝2.5Hz,3H),1.56(dd,J＝17.1,6.7Hz,3H),1.04(d,J＝6.6Hz,3H),0.87(d,J＝6.7Hz,3H)。和另一个阻转异构体化合物，结构任意指定为Z36-2(峰2，20mg,保留时间12.534min，Y:34％)，ES-API:[M+H] +＝599.2； 1H NMR(500MHz,DMSO-d 6)δ8.49(d,J＝4.9Hz,1H),8.03(dd,J＝14.5,9.2Hz,1H),7.52-7.44(m,1H),7.36–7.22(m,4H),6.95-6.77(m,1H),6.20–6.11(m,1H),5.78–5.70(m,1H),4.77(s,1H),4.61(d,J＝14.1Hz,1H),4.02–3.93(m,1H),3.74(dd,J＝14.2,4.2Hz,1H),3.35(s,4H),2.92–2.76(m,2H),1.82(s,3H),1.56-1.45(m,3H),1.11(d,J＝6.9Hz,3H),0.99(dd,J＝6.8,2.9Hz,3H).异构体化合物通过分析型手性HPLC方法(柱:Chiralpak IB:5μm,4.6*250mm；流动相:己烷:EtOH:氨甲醇＝50:50:0.2；流速:1ml/min；柱温＝30℃)进行检测。
实施例37制备化合物Z37、Z37-1和Z37-2
Figure PCTCN2020124226-appb-000119
步骤1：将7-溴-6-氯-1-(4,6-二异丙基嘧啶-5-基)-8-氟-4-羟基-2-氧代-1,2-二氢喹啉-3-碳腈(2.0g,4.17mmol)悬浮于1，4-二氧六环(10mL)，缓慢加入浓硫酸(10mL)和水(10mL)的混合液。反应120℃下搅拌18小时。将冷却的反应液中倒入50mL冰水中，析出的固体过滤，滤饼用少量水洗涤，真空干燥后得产物7-溴-6-氯-1-(4,6-二异丙基嘧啶-5-基)-8-氟-4-羟基喹啉-2(1H)-酮(1.5g,Y:79.1％)，淡棕色固体。ES-API:[M+H] +＝454.0，456.1。
步骤2：7-溴-6-氯-1-(4,6-二异丙基嘧啶-5-基)-8-氟-4-羟基喹啉-2(1H)-酮(1.4g,3.08mmol)溶于乙酸(4mL)，依次加入亚硝酸钠(21mg,0.31mmol)和浓硝酸(0.62mL，9.24mmol)，反应在室温下搅拌30分钟。将反应液中倒入10mL冰水中，析出的固体过滤，滤饼用6ml水洗涤，在真空下干燥得产物7-溴-6-氯-1-(4,6-二异丙基嘧啶-5-基)-8-氟-4-羟基-3-硝基喹啉-2(1H)-酮(1.25g，Y:81.2％)，黄色固体。ES-API:[M+H] +＝499.0，501.0。
步骤3：7-溴-6-氯-1-(4,6-二异丙基嘧啶-5-基)-8-氟-4-羟基-3-硝基喹啉-2(1H)-酮(1.25g,2.50mmol)溶于乙腈(25mL)，依次加入三氯氧磷(1.15mL,12.50mmol)，和N,N-二异丙基乙胺(3.48mL,20.0mmol)，反应在85℃下搅拌30分钟。将反应液浓缩，加入100mL乙酸乙酯依次用30mL水，30mL饱和碳酸氢钠洗涤2次，30mL饱和食盐水洗涤。有机相干燥浓缩后，粗品用快速硅胶柱(EtOAc/PE：0-15％)纯化得产物7-溴-4,6-二氯-1-(4,6-二异丙基嘧啶-5-基)-8-氟-3-硝基喹啉-2(1H)-酮(650mg,Y：50.1％)，黄色固体。ES-API:[M+H] +＝517.0，519.0。
步骤4：7-溴-4,6-二氯-1-(4,6-二异丙基嘧啶-5-基)-8-氟-3-硝基喹啉-2(1H)-酮(370mg,0.71mmol)溶于N,N-二甲基乙酰胺(5mL)，依次加入(R)-1-(叔丁基)3-甲基-哌嗪-1,3-二羧酸酯(520mg,2.13mmol)，和N,N-二异丙基乙胺(275mg,2.13mmol)，反应在120℃搅拌2小时。反应液中加入80mL乙酸乙酯，用30mL稀盐水洗涤4次，30mL饱和食 盐水洗涤，干燥浓缩，粗品用快速硅胶柱纯化(EtOAc/PE：0-25％)得产物(R)-1-(叔丁基)-3-甲基-4-(7-溴-6-氯-1-(4,6-二异丙基嘧啶-5-基)-8-氟-3-硝基-2-氧代-1,2-二氢喹啉-4-基)哌嗪-1,3-二羧酸酯(400mg,Y:77.1％)，橙色固体。ES-API:[M+H] +＝725.0，727.2。
步骤5：(R)-1-(叔丁基)-3-甲基-4-(7-溴-6-氯-1-(4,6-二异丙基嘧啶-5-基)-8-氟-3-硝基-2-氧代-1,2-二氢喹啉-4-基)哌嗪-1,3-二羧酸酯(380mg,0.52mmol)溶于乙酸(7mL)，加入铁粉(103mg,1.83mmol),反应在80℃搅拌30分钟。反应液浓缩，依次加入100mL乙酸乙酯和60mL饱和碳酸氢钠，悬浮液用硅藻土过滤，滤饼用乙酸乙酯洗涤，有机相分离，依次用40mL饱和碳酸氢钠，40mL饱和食盐水洗涤，干燥浓缩得产物(R)-10-溴-11-氯-8-(4,6-二异丙基嘧啶-5-基)-9-氟-5,7-二氧代-1,2,4,4a,5,6,7,8-八氢-3H-吡嗪[1’,2’:4,5]吡嗪[2,3-c]喹啉-3-羧酸叔丁酯(347mg,Y:100％)，黄色固体。ES-API:[M+H]+＝663.2，665.2。
步骤6：向50mL封管中依次加入(R)-10-溴-11-氯-8-(4,6-二异丙基嘧啶-5-基)-9-氟-5,7-二氧代-1,2,4,4a,5,6,7,8-八氢-3H-吡嗪[1’,2’:4,5]吡嗪[2,3-c]喹啉-3-羧酸叔丁酯(317mg，0.48mmol)，12mL丙酮，无水碳酸钾(265mg,1.92mmol)，碘甲烷(678mg，4.80mmol)。密封封管，反应在50℃搅拌18小时。反应液加入60mL乙酸乙酯，依次用25mL水，25mL饱和食盐水洗涤，干燥浓缩，粗品用快速硅胶柱纯化(EtOAc/PE：0-30％)得产物(R)-10-溴-11-氯-8-(4,6-二异丙基嘧啶-5-基)-9-氟-6-甲基-5,7-二氧代-1,2,4,4a,5,6,7,8-辛基-3H-吡嗪[1’,2’:4,5]吡嗪[2,3-c]喹啉-3-羧酸叔丁酯(310mg,Y:95.8％)，黄色固体。ES-API:[M+H] +＝677.1，679.2。
步骤7：向100mL圆底烧瓶中加入(R)-10-溴-11-氯-8-(4,6-二异丙基嘧啶-5-基)-9-氟-6-甲基-5,7-二氧代-1,2,4,4a,5,6,7,8-辛基-3H-吡嗪[1’,2’:4,5]吡嗪[2,3-c]喹啉-3-羧酸叔丁酯(285mg,0.42mmol)、(2-氟-6-羟基苯基)硼酸(262mg,1.68mmol)、氯(2-二环己基膦-2′,6′-二甲氧基-1,1′-联苯)[2-(2′-氨基-1,1′-联苯)]钯(II)(30mg,0.042mmol)、2-二环己基膦基-2′,6′-二甲氧基联苯基(17mg,0.042mmol)、磷酸钾(356mg,1.68mmol)、3mL水和15mL二氧六环。氮气保护下，反应在90℃搅拌2小时。反应液浓缩，粗品用快速硅胶柱纯化(EtOAc/PE：0-50％)得产物(4aR)-11-氯-8-(4,6-二异丙基嘧啶-5-基)-9-氟-10-(2-氟-6-羟基苯基)-6-甲基-5,7-二氧代-1,2,4,4a,5,6,7,8-八氢-3H-吡嗪[1’,2’:4,5]吡嗪[2,3-c]喹啉-3-羧酸叔丁酯(230mg,Y:77.2％)，直接用于下一步反应。ES-API:[M+H] +＝709.2。
步骤8：(4aR)-11-氯-8-(4,6-二异丙基嘧啶-5-基)-9-氟-10-(2-氟-6-羟基苯基)-6-甲基-5,7-二氧代-1,2,4,4a,5,6,7,8-八氢-3H-吡嗪[1’,2’:4,5]吡嗪[2,3-c]喹啉-3-羧酸叔丁酯(230mg,0.32mmol)溶于二氯甲烷(3mL)，加入三氟乙酸(0.8mL)。室温搅拌1小时，反应液浓缩得产物(4aR)-11-氯-8-(4,6-二异丙基嘧啶-5-基)-9-氟-10-(2-氟-6-羟基苯基)-6-甲基-2,3,4,4a,6,8-六氢-1H-吡嗪[1'，2'，5]吡嗪[2,3-c]喹啉-5,7-二酮(270mg,粗品)，直接用于下一步反应。ES-API:[M+H] +＝609.2。
步骤9：(4aR)-11-氯-8-(4,6-二异丙基嘧啶-5-基)-9-氟-10-(2-氟-6-羟基苯基)-6-甲基-2,3,4,4a,6,8-六氢-1H-吡嗪[1'，2'，5]吡嗪[2,3-c]喹啉-5,7-二酮(270mg，粗品)溶于二氯甲烷(12mL)，加入N,N-二异丙基乙胺(206mg，1.60mmol)。将反应冷至0℃，向反应液中滴加丙烯酰氯(26mg，0.29mmol)。反应在0℃搅拌15分钟。向反应液中加入30mL二氯甲烷，依次用10mL水，10mL饱和NaHCO 3水溶液，10mL饱和食盐水洗涤，干燥后浓缩，粗品用制备HPLC纯化得到：一个阻转异构体，结构任意指定为Z37-1(保留 时间：10.095min；40mg,Y:18.6％)，白色固体。 1H NMR(400MHz,DMSO-d 6)δ9.13(s,1H),8.02(s,1H),7.27(dd,J＝15.4,8.1Hz,1H),7.07(dd,J＝16.4,10.6Hz,1H),6.77-6.67(m,2H),6.15(d,J＝16.7Hz,1H),5.76(d,J＝11.1Hz,1H),4.72(d,J＝13.4Hz,1H),4.48(d,J＝13.0Hz,1H),4.07-3.97(m,1H),3.67-3.41(m,2H),3.31-3.11(m,4H),3.00-2.89(m,1H),2.74–2.56(m,2H),1.30–0.72(m,12H).ES-API:[M+H] +＝663.2。和另一个阻转异构体化合物，结构任意指定为Z37-2(保留时间：10.424min；50mg,Y:23.2％)，白色固体。 1H NMR(400MHz,DMSO-d 6)δ10.21(s,1H),9.13(s,1H),8.03(s,1H),7.27(dd,J＝15.4,8.3Hz,1H),7.07(dd,J＝16.7,10.7Hz,1H),6.77–6.65(m,2H),6.15(dd,J＝16.8,2.2Hz,1H),5.75(d,J＝10.2Hz,1H),4.72(d,J＝13.9Hz,1H),4.48(d,J＝13.8Hz,1H),4.07-3.97(m,1H),3.66-3.41(m,2H),3.30–3.10(m,4H),3.00-2.89(m,1H),2.70–2.54(m,2H),1.21–0.84(m,12H).ES-API:[M+H] +＝663.2。异构体化合物采用分析型HPLC方法进行检测。
实施例38制备化合物Z38、Z38-1和Z38-2
Figure PCTCN2020124226-appb-000120
步骤1：2-氰基-6-异丙基苯基-3-胺(742mg,4.24mmol)溶于干燥的四氢呋喃中(20mL)，在冰水浴条件，加入2M的NaHMDS(8.48mL,16.96mmol)，在冰水浴条件下搅拌20分钟。加入2,5-二氟-6-(2-氟-6-甲氧基苯基)烟酸(1.2g,4.24mmol)，室温搅拌3h，将反应液中缓慢倒入30mL冰水中，稀盐酸(3M)调节pH＝5-6，乙酸乙酯萃取，50mL饱和食盐水洗涤一次。无水硫酸钠干燥，过滤，有机相干燥浓缩后，粗品用快速硅胶柱(EtOAc/PE：20-40％)纯化得产物2-((2-氰基-6-异丙基苯基)氨基)-5-氟-6-(2-氟-6-甲氧基苯基)烟酸(1.8g，Y:98％)，黄色固体。ES-API:[M+H] +＝424.1。
步骤2：将2-((2-氰基-6-异丙基苯基)氨基)-5-氟-6-(2-氟-6-甲氧基苯基)烟酸(1.5g,3.42mmol)溶解在二氯乙烷中，加入二氯亚砜(4.07g,34.2mmol)。反应在80℃搅拌2小时。反应完毕，反应液冷却到室温，浓缩，50度真空减压干燥4h，得产物2-((2-氰基-6-异丙基苯基-3-基)氨基)-5-氟-6-(2-氟-6-甲氧基苯基)烟酰氯(1.57g,粗品)，淡黄色固体。甲醇检测ES-API:[M+H] +＝438.1(MeOH)。
步骤3：在冰水浴条件下，将氢化钠(1.97g，49.35mmol)加入到硝酸乙酸乙酯(1.31g，9.86mmol)的四氢呋喃中，搅拌30分钟，随后加入2-((2-氰基-6-异丙基苯基-3-基)氨基)-5-氟-6-(2-氟-6-甲氧基苯基)烟酰氯(1.57g，3.29mmol)室温搅拌1h，然后升温至80℃反应2h。倒入冰水中，3M盐酸调节pH3-4,乙酸乙酯萃取，无水硫酸钠干燥，过滤，有机相干燥浓缩后得产物1-(2-氰基-6-异丙基苯基-3-基)-6-氟-7-(2-氟-6-甲氧基苯基)-4-羟基-3-硝基-1,8-萘啶-2(1H)-酮(110mg，Y:20％)。ES-API:[M+H] +＝493.1。
步骤4：1-(2-氰基-6-异丙基苯基-3-基)-6-氟-7-(2-氟-6-甲氧基苯基)-4-羟基-3-硝基-1,8-萘啶-2(1H)-酮(110mg,0.20mmol)溶于乙腈(10mL)，依次加入三氯氧磷(153mg,1.0mmol)，和N,N-二异丙基乙胺(77g,0.6mmol)，反应逐渐升至80℃并搅拌3h。将反应液浓缩，加入30mL冷的乙腈，冰水浴下滴加到30mL饱和碳酸氢钠溶液中，用乙酸乙酯萃取(50mL*2)，合并有机相，30mL饱和食盐水洗涤，无水硫酸钠干燥，过滤，有机相干燥浓缩后，粗品用快速硅胶柱(EtOAc/PE：0-80％)纯化得4-氯-6-氟-7-(2-氟-6-甲氧基苯基)-1-(2-氰基-6-异丙基苯基-3-基)-3-硝基-1,8-萘啶-2(1H)-酮(110mg,Y：68％)，黄色固体。ES-API:[M+H] +＝511.1。
步骤5：4-氯-6-氟-7-(2-氟-6-甲氧基苯基)-1-(2-氰基-6-异丙基苯基-3-基)-3-硝基-1,8-萘啶-2(1H)-酮(110mg,0.296mmol)溶于N,N-二甲基乙酰胺(3mL)，依次加入(3R,6R)-1-叔丁基3-甲基6-甲基哌嗪-1,3-二羧酸(54mg,0.22mmol)，反应在120℃搅拌2小时。反应完毕，加入30mL乙酸乙酯，用30mL饱和食盐水洗涤三次。乙酸乙酯相干燥浓缩，得到粗品，目标产物(3R,6R)-1-叔丁基3-甲基4-(1-(2-氰基-6-异丙基苯基)-6-氟-7-(2-氟-6-甲氧基苯基)-3-硝基-2-氧代-1,2-二氢-1,8-萘啶-4-基)-6-甲基哌嗪-1,3-二羧酸(50mg,Y:46％)，黄色固体。ES-API:[M+H] +＝733.3。
步骤6：(3R,6R)-1-叔丁基3-甲基4-(1-(2-氰基-6-异丙基苯基)-6-氟-7-(2-氟-6-甲氧基苯基)-3-硝基-2-氧代-1,2-二氢-1,8-萘啶-4-基)-6-甲基哌嗪-1,3-二羧酸(50mg,0.068mmol)溶解在醋酸中(25mL)，加入铁粉(11.5mg,0.204mmol),反应在80℃搅拌30分钟。反应液浓缩，依次加入30mL乙酸乙酯和30mL饱和碳酸氢钠，悬浮液用硅藻土过滤，滤饼用乙酸乙酯洗涤，有机相分离，依次用30mL饱和碳酸氢钠，30mL饱和食盐水洗涤，干燥浓缩得产物(2R,4aR)-叔丁基8-(2-氰基-6-异丙基苯基)-11-氟-10-(2-氟-6-甲氧基苯基)-2-甲基-5,7-二氧代-4,4a，5,6,7,8-六氢-1H-吡嗪并[1’,2’:4,5]吡嗪并[2,3-c][1,8]萘啶-3(2H)-羧酸酯(40mg,粗品)，黄色固体。ES-API:[M+H]+＝671.2。
步骤7：将(2R,4aR)-叔丁基8-(2-氰基-6-异丙基苯基)-11-氟-10-(2-氟-6-甲氧基苯基)-2-甲基-5,7-二氧代-4,4a，5,6,7,8-六氢-1H-吡嗪并[1’,2’:4,5]吡嗪并[2,3-c][1,8]萘啶-3(2H)-羧酸酯(40mg,0.059mmol)，30mL丙酮，无水碳酸钾(33mg,0.24mmol)，碘甲烷(85mg，0.59mmol)密封封管，反应在50℃搅拌18小时。反应液加入20mL乙酸乙酯，用20mL饱和食盐水洗涤，干燥浓缩，粗品用快速硅胶柱纯化(EtOAc/PE：0-80％)得产物(2R,4aR)-叔丁基8-(2-氰基-6-异丙基苯基)-11-氟-10-(2-氟-6-甲氧基苯基)-2,6-二甲基-5,7-二氧代-4,4a,5,6,7,8-六氢-1H-吡嗪并[1’,2’:4,5]吡嗪并[2,3-c][1,8]萘啶-3(2H)-羧酸酯(40mg,Y:90％)，黄色固体。ES-API:[M+H] +＝685.2。
步骤8：(2R,4aR)-叔丁基8-(2-氰基-6-异丙基苯基)-11-氟-10-(2-氟-6-甲氧基苯基)-2,6-二甲基-5,7-二氧代-4,4a,5,6,7,8-六氢-1H-吡嗪并[1’,2’:4,5]吡嗪并[2,3-c][1,8]萘啶-3(2H)- 羧酸酯(44mg)溶于二氯甲烷(3mL)，加入三氟乙酸(1mL)。室温搅拌2小时，反应液浓缩得产物2-(((2R,4aR)-11-氟-10-(2-氟-6-甲氧基苯基)-2,6-二甲基-5,7-二氧代-2,3,4,4a,5,6-六氢-1H-吡嗪并[1’,2’:4,5]吡嗪并[2,3-c][1,8]萘啶-8(7H)-基)-3-异丙基苄腈(40mg,粗品)，直接用于下一步反应。ES-API:[M+H] +＝585.2。
步骤9：2-(((2R,4aR)-11-氟-10-(2-氟-6-甲氧基苯基)-2,6-二甲基-5,7-二氧代-2,3,4,4a,5,6-六氢-1H-吡嗪并[1’,2’:4,5]吡嗪并[2,3-c][1,8]萘啶-8(7H)-基)-3-异丙基苄腈(40mg，0.068mmol)溶于二氯甲烷(5mL)，加入二异丙基乙胺(53mL，0.408mmol)。将反应冷至0℃，向反应液中滴加丙烯酰氯(12.4mg，0.137mmol)。反应在0℃搅拌15分钟。向反应液中加入20mL二氯甲烷，用20mL饱和NaHCO 3水溶液，20mL饱和食盐水洗涤，干燥后浓缩，粗品经制备色谱纯化得产物2-((2R,4aR)-3-丙烯酰基-11-氟-10-(2-氟-6-甲氧基苯基)-2,6-二甲基-5,7-二氧代-2,3,4,4a,5,6-六氢-1H-吡嗪并[1’,2’:4,5]吡嗪并[2,3-c][1,8]萘啶-8(7H)-基)-3-异丙基苄腈(32mg,Y:70％)，黄色固体。ES-API:[M+H] +＝639.3。
步骤10：2-((2R,4aR)-3-丙烯酰基-11-氟-10-(2-氟-6-甲氧基苯基)-2,6-二甲基-5,7-二氧代-2,3,4,4a,5,6-六氢-1H-吡嗪并[1’,2’:4,5]吡嗪并[2,3-c][1,8]萘啶-8(7H)-基)-3-异丙基苄腈(32mg，0.068mmol)加入到干燥二氯甲烷中(4.0mL),再加入三溴化硼(4.0mL,4.0mmol),升至室温，反应1h。冰水浴条件下，将上述反应液滴加入饱和碳酸氢钠饱和溶液中，二氯甲烷(30mL)萃取2次，干燥，浓缩，粗品经制备薄层色谱(二氯甲烷/甲醇：10/1)纯化得产物2-((2R,4aR)-3-丙烯酰基-11-氟-10-(2-氟-6-羟基苯基)-2,6-二甲基-5,7-二氧代-2,3,4,4a,5,6-六氢-1H-吡嗪并[1',2':4,5]吡嗪并[2,3-c][1,8]萘啶-8(7H)-基)-3-异丙基苄腈(Z38，25mg,Y:80％)，黄色固体。ES-API:[M+H] +＝625.2。
步骤11：将化合物Z38通过制备型手性HPLC拆分(柱型:Chiralpak IB:10μm,30*250mm；流动相:己烷:EtOH:氨甲醇＝50:50:0.2；流速:25ml/min；柱温室温)得到：一个阻转异构体化合物，结构任意指定为Z38-1(峰1，7mg,保留时间10.117min，Y:28％)，ES-API:[M+H] +＝625.2。和另一个阻转异构体化合物，结构任意指定为Z38-2(峰2，9mg,保留时间12.237min，Y:39％)，ES-API:[M+H] +＝625.2。异构体化合物通过分析型手性HPLC方法(柱:Chiralpak IB:5μm,4.6*250mm；流动相:己烷:EtOH:氨甲醇＝50:50:0.2；流速:1ml/min；柱温＝30℃)进行检测。
实施例39制备化合物Z39、Z39-1和Z39-2
Figure PCTCN2020124226-appb-000121
步骤1：向15mL封管中依次加入(R)-10-溴-11-氯-8-(4,6-二异丙基嘧啶-5-基)-9-氟-5,7-二氧代-1,2,4,4a,5,6,7,8-八氢-3H-吡嗪[1’,2’:4,5]吡嗪[2,3-c]喹啉-3-羧酸叔丁酯(230mg，0.35mmol)，8mL丙酮，无水碳酸钾(193mg,1.40mmol)，氘代碘甲烷(507mg，3.50mmol)。密封封管，反应在50℃搅拌18小时。反应液加入60mL乙酸乙酯，依次用25mL水，25mL饱和食盐水洗涤，干燥浓缩，粗品用快速硅胶柱纯化(EtOAc/PE：0-30％)得产物(R)-10-溴-11-氯-8-(4,6-二异丙基嘧啶-5-基)-9-氟-6-(氘代甲基-d 3)-5,7-二氧代-1,2,4,4a,5,6,7,8-辛基-3H-吡嗪[1’,2’:4,5]吡嗪[2,3-c]喹啉-3-羧酸叔丁酯(185mg,Y:78.5％)，淡黄色固体。ES-API:[M+H] +＝680.2，682.2。
步骤2：向100mL圆底烧瓶中加入(R)-10-溴-11-氯-8-(4,6-二异丙基嘧啶-5-基)-9-氟-6-氘代甲基-5,7-二氧代-1,2,4,4a,5,6,7,8-辛基-3H-吡嗪[1’,2’:4,5]吡嗪[2,3-c]喹啉-3-羧酸叔丁酯(185mg,0.27mmol)、(2-氟-6-羟基苯基)硼酸(262mg,1.35mmol)、氯(2-二环己基膦-2′,6′-二甲氧基-1,1′-联苯)[2-(2′-氨基-1,1′-联苯)]钯(II)(19mg,0.027mmol)、2-二环己基膦基-2′,6′-二甲氧基联苯基(11mg,0.027mmol)、磷酸钾(229mg,1.08mmol)、2mL水和10mL二氧六环。氮气保护下，反应在90℃搅拌4小时。反应液浓缩，粗品用快速硅胶柱纯化(EtOAc/PE：0-50％)得产物(4aR)-11-氯-8-(4,6-二异丙基嘧啶-5-基)-9-氟-10-(2-氟-6-羟基苯基)-6-(氘代甲基-d 3)-5,7-二氧代-1,2,4,4a,5,6,7,8-八氢-3H-吡嗪[1’,2’:4,5]吡嗪[2,3-c]喹啉-3-羧酸叔丁酯(140mg,Y:72.4％)，黄色固体。ES-API:[M+H] +＝712.3。
步骤3：(4aR)-11-氯-8-(4,6-二异丙基嘧啶-5-基)-9-氟-10-(2-氟-6-羟基苯基)-6-(氘代甲基-d 3)-5,7-二氧代-1,2,4,4a,5,6,7,8-八氢-3H-吡嗪[1’,2’:4,5]吡嗪[2,3-c]喹啉-3-羧酸叔丁酯(140mg,0.20mmol)溶于二氯甲烷(3mL)，加入三氟乙酸(0.8mL)。室温搅拌1小时，反应液浓缩得产物(4aR)-11-氯-8-(4,6-二异丙基嘧啶-5-基)-9-氟-10-(2-氟-6-羟基苯基)-6-(氘代甲基-d 3)-2,3,4,4a,6,8-六氢-1H-吡嗪[1'，2'，5]吡嗪[2,3-c]喹啉-5,7-二酮(165mg,粗品)，直接用于下一步反应。ES-API:[M+H] +＝612.3。
步骤4：(4aR)-11-氯-8-(4,6-二异丙基嘧啶-5-基)-9-氟-10-(2-氟-6-羟基苯基)-6-(氘代甲基-d 3)-2,3,4,4a,6,8-六氢-1H-吡嗪[1'，2'，5]吡嗪[2,3-c]喹啉-5,7-二酮(165mg，粗品)溶于二氯甲烷(8mL)，加入N,N-二异丙基乙胺(129mg，1.0mmol)。将反应冷至0℃，向反 应液中滴加丙烯酰氯(16mg，0.18mmol)。反应在0℃搅拌15分钟。向反应液中加入30mL二氯甲烷，依次用10mL水，10mL饱和NaHCO 3水溶液，10mL饱和食盐水洗涤，干燥后浓缩得产物(4aR)-3-丙烯酰基-11-氯-8-(4,6-二异丙基嘧啶-5-基)-9-氟-10-(2-氟-6-羟基苯基)-6-(氘代甲基-d 3)-2,3,4,4a,6,8-六氢-1H-吡嗪[1',2',5]吡嗪[2,3-c]喹啉-5,7-二酮(Z39)。
步骤5：将化合物Z39用制备HPLC纯化得到：一个阻转异构体化合物，结构任意指定为Z39-1(保留时间：10.088min；23mg,Y:17.6％)，白色固体。 1H NMR(500MHz,DMSO-d 6)δ10.19(d,J＝1.5Hz,1H),9.13(s,1H),8.02(s,1H),7.27(dd,J＝15.5,8.2Hz,1H),7.07(dd,J＝16.7,10.7Hz,1H),6.77-6.69(m,2H),6.15(d,J＝16.8Hz,1H),5.75(d,J＝11.2Hz,1H),4.72(d,J＝14.4Hz,1H),4.48(d,J＝12.2Hz,1H),3.99(s,1H),3.62(d,J＝10.5Hz,1H),3.46(d,J＝11.1Hz,1H),3.19(t,J＝12.1Hz,1H),3.00-2.90(m,1H),2.70－2.54(m,2H),1.14-0.95(m,12H).ES-API:[M+H] +＝666.2。和另一个阻转异构体化合物，结构任意指定为Z39-2(保留时间：10.420min；30mg,Y:22.9％)，白色固体。 1H NMR(500MHz,DMSO-d 6)δ10.20(d,J＝1.4Hz,1H),9.13(s,1H),8.03(s,1H),7.27(dd,J＝15.4,8.2Hz,1H),7.07(dd,J＝16.7,10.2Hz,1H),6.79–6.66(m,2H),6.15(d,J＝16.7Hz,1H),5.75(d,J＝10.9Hz,1H),4.72(d,J＝13.7Hz,1H),4.49(d,J＝13.3Hz,1H),4.00(s,1H),3.63-3.44(m,2H),3.19(t,J＝12.1Hz,1H),3.00-2.90(m,1H),2.73–2.55(m,2H),1.25–0.78(m,12H).ES-API:[M+H] +＝666.2。异构体化合物用分析型HPLC方法进行检测。
实施例40制备化合物Z40
Figure PCTCN2020124226-appb-000122
步骤1：将7-氯-1-(4,6-二异丙基嘧啶-5-基)-6-氟-4-羟基-2-氧代-1,2-二氢-1,8-萘啶-3-甲腈(2g,5mmol)悬浮于1，4-二氧六环(12mL)，缓慢加入浓硫酸(12mL)和水(12mL)的混合液。反应120℃下搅拌过夜，反应液冷却后倒入冰水(50mL)中，乙酸乙酯(50mL*3)萃取，有机相干燥后浓缩得产物7-氯-1-(4,6-二异丙基嘧啶-5-基)-6-氟-4-羟基-1,8-萘啶-2(1H)-酮(1.8g,Y:96％)，淡黄色固体。ES-API:[M+H] +＝377.2。
步骤2：7-氯-1-(4,6-二异丙基嘧啶-5-基)-6-氟-4-羟基-1,8-萘啶-2(1H)-酮(1.56g，4.14mmol)溶于乙酸(5.46mL)，依次加入亚硝酸钠(29mg，0.42mmol)和浓硝酸(780mg，12.42mmol)，室温下搅拌20分钟。将反应液中倒入6mL水中，析出黄色固体，过滤，滤饼用6ml水洗涤，在真空下干燥得产物7-氯-1-(4,6-二异丙基嘧啶-5-基)-6-氟-4-羟基-3-硝基-1,8-萘啶-2(1H)-酮(1.6g，Y:91％)，淡黄色固体。ES-API:[M+H] +＝422.0。
步骤3：7-氯-1-(4,6-二异丙基嘧啶-5-基)-6-氟-4-羟基-3-硝基-1,8-萘啶-2(1H)-酮(1.56g，3.70mmol),(2-氟-6-甲氧基苯基)硼酸(3.14g，18.49mmol)，氯(2-二环己基膦基-2',6'-二甲氧基-1,1'-联苯基)(2'-氨基-1,1'-联苯-2-基)钯(II)(266mg，0.37mmol)，2-双环己基膦-2',6'-二甲氧基联苯(152mg，0.37mmol)，磷酸钾(2.36g，11.09mmol)的8mL水和40mL二氧六环混合液用氮气置换三次，100℃反应2小时。将反应液倒入50mL水中，甲基叔丁基醚(30mL*2)洗涤，水相用1.0M稀盐酸调pH＝6.0后，用乙酸乙酯(30mL*2)萃取，有机相干燥后浓缩得到粗品1-(4,6-二异丙基嘧啶-5-基)-6-氟-7-(2-氟-6-甲氧基苯基)-4-羟基-3-硝基-1,8-萘啶-2(1H)-酮(1.55g，Y:82％)，黄色固体。ES-API:[M+H] +＝512.2。
步骤4：往1-(4,6-二异丙基嘧啶-5-基)-6-氟-7-(2-氟-6-甲氧基苯基)-4-羟基-3-硝基-1,8-萘啶-2(1H)-酮(1.53g，2.99mmol)的乙腈(20mL)溶液中依次加入三氯氧磷(2.29g,14.96mmol)和N,N-二异丙基乙胺(3.09g，23.93mmol)。反应在80℃下搅拌1小时。将反应液浓缩，加入50mL乙酸乙酯，依次用30mL饱和碳酸氢钠洗涤2次，30mL水和30mL饱和食盐水洗涤。有机相干燥浓缩后，粗品用快速硅胶柱(EtOAc/PE：0-50％)纯化得产物4-氯-1-(4,6-二异丙基嘧啶-5-基)-6-氟-7-(2-氟-6-甲氧基苯基)-3-硝基-1,8-萘啶-2(1H)-酮(800mg,Y:50％)，淡黄色固体。ES-API:[M+H] +＝530.2。
步骤5：将4-氯-1-(4,6-二异丙基嘧啶-5-基)-6-氟-7-(2-氟-6-甲氧基苯基)-3-硝基-1,8-萘啶-2(1H)-酮(800mg,1.51mmol)溶于N,N-二甲基乙酰胺(8mL)，依次加入1-(叔丁基)3-甲基(3R,6R)-6-甲基哌嗪-1,3-二羧酸(390mg,1.51mmol)和N,N-二异丙基乙胺(585mg,4.53mmol)，120℃搅拌2小时。冷却后反应液中加入30mL乙酸乙酯，用30mL碳酸氢钠洗涤2次，30mL稀盐水洗涤2次，30ml水洗涤一次，30mL饱和食盐水洗涤一次，干燥浓缩，并用快速硅胶柱(0-100％EtOAc/PE)纯化得到1-(叔丁基)3-甲基(3R,6R)-4-(1-(4,6-二异丙基嘧啶-5-基)-6-氟-7-(2-氟-6-甲氧基苯基)-3-硝基-2-氧代-1,2-二氢-1,8-萘啶-4-基)-6-甲基哌嗪-1,3-二羧酸(540mg,Y:47％)。ES-API:[M+H] +＝752.2。
步骤6：1-(叔丁基)3-甲基(3R,6R)-4-(1-(4,6-二异丙基嘧啶-5-基)-6-氟-7-(2-氟-6-甲氧基苯基)-3-硝基-2-氧代-1,2-二氢-1,8-萘啶-4-基)-6-甲基哌嗪-1,3-二羧酸(540mg,0.72mmol)溶于乙酸(5mL)，加入铁粉(140mg,2.51mmol),80℃搅拌1小时。反应液浓缩，加入50mL乙酸乙酯，用饱和碳酸氢钠溶液调节pH＝8，悬浮液用硅藻土过滤，滤饼用乙酸乙酯洗涤，有机相分离，依次用25mL饱和碳酸氢钠，25mL饱和食盐水洗涤，干燥浓缩得到粗品(2R,4aR)-8-(4,6-二异丙基嘧啶-5-基)-11-氟-10-(2-氟-6-甲氧基苯基)-2-甲基-5,7-二氧代-1,2,4,4a,5,6,7,8-八氢-3H-吡嗪并[1',2':4,5]吡嗪并[2,3-c][1,8]萘啶-3-羧酸叔丁酯(540mg)，黄色固体。ES-API:[M+H] +＝690.3。
步骤7：向50mL封管中依次加入(2R,4aR)-8-(4,6-二异丙基嘧啶-5-基)-11-氟-10-(2-氟-6-甲氧基苯基)-2-甲基-5,7-二氧代-1,2,4,4a,5,6,7,8-八氢-3H-吡嗪并[1',2':4,5]吡嗪并[2,3-c][1,8]萘啶-3-羧酸叔丁酯(540mg，0.78mmol)，丙酮(10mL)，无水碳酸钾(433 mg,3.13mmol)，碘甲烷(1.11g，7.83mmol)。封管密封，反应在50℃搅拌过夜。反应液过滤，浓缩，溶于二氯甲烷(10mL)，并用水(10mL)洗涤，有机相干燥浓缩得到粗品叔丁基(2R,4aR)-8-(4,6-二异丙基嘧啶-5-基)-11-氟-10-(2-氟-6-甲氧基苯基)-2,6-二甲基-5,7-二氧代-1,2,4,4a,5,6,7,8-八氢-3H-吡嗪并[1',2':4,5]吡嗪并[2,3-c][1,8]萘啶-3-羧酸盐(420mg)，黄色固体。ES-API:[M+H] +＝704.3。
步骤8：(2R,4aR)-8-(4,6-二异丙基嘧啶-5-基)-11-氟-10-(2-氟-6-甲氧基苯基)-2,6-二甲基-5,7-二氧代-1,2,4,4a,5,6,7,8-八氢-3H-吡嗪并[1',2':4,5]吡嗪并[2,3-c][1,8]萘啶-3-羧酸叔丁酯(420mg,0.60mmol)溶于二氯甲烷(20mL)，加入三氟乙酸(4mL)。室温搅拌2小时，反应液浓缩得粗品(2R,4aR)-8-(4,6-二异丙基嘧啶-5-基)-11-氟-10-(2-氟-6-甲氧基苯基)-2,6-二甲基-2,3,4,4a,6,8-六氢-1H-吡嗪并[1',2':4,5]吡嗪并[2,3-c][1,8]萘啶-5,7-二酮(360mg)，直接用于下一步反应。ES-API:[M+H] +＝604.3。
步骤9：(2R,4aR)-8-(4,6-二异丙基嘧啶-5-基)-11-氟-10-(2-氟-6-甲氧基苯基)-2,6-二甲基-2,3,4,4a,6,8-六氢-1H-吡嗪并[1',2':4,5]吡嗪并[2,3-c][1,8]萘啶-5,7-二酮(360mg，0.60mmol)溶于二氯甲烷(5mL)，加入N,N-二异丙基乙胺(385mg，2.98mmol)。将反应冷至0℃，向反应液中滴加丙烯酰氯(108mg，1.19mmol)。反应液在0℃搅拌5分钟，浓缩，粗品用快速硅胶柱(0-80％EtOAc/PE)纯化得产物(2R,4aR)-3-丙烯酰基-8-(4,6-二异丙基嘧啶-5-基)-11-氟-10-(2-氟-6-甲氧基苯基)-2,6-二甲基-2,3,4,4a,6,8-六氢-1H-吡嗪并[1',2':4,5]吡嗪并[2,3-c][1,8]萘啶-5,7-二酮(220mg,Y:56％)，淡黄色固体。ES-API:[M+H] +＝658.2。
步骤10：(2R,4aR)-3-丙烯酰基-8-(4,6-二异丙基嘧啶-5-基)-11-氟-10-(2-氟-6-甲氧基苯基)-2,6-二甲基-2,3,4,4a,6,8-六氢-1H-吡嗪并[1',2':4,5]吡嗪并[2,3-c][1,8]萘啶-5,7-二酮(220mg，0.33mmol)溶于二氯甲烷(3mL)。将反应冷至0℃，向其中滴加17％三溴化硼的二氯甲烷溶液(3mL)，室温搅拌过夜。将反应液倒入40mL饱和碳酸氢钠水溶液，用25mL二氯甲烷萃取2次。有机相干燥后浓缩，粗品用制备HPLC纯化得产物(2R,4aR)-3-丙烯酰基-8-(4,6-二异丙基嘧啶-5-基)-11-氟-10-(2-氟-6-羟基苯基)-2,6-二甲基-2,3,4,4a,6,8-六氢-1H-吡嗪并[1',2':4,5]吡嗪并[2,3-c][1,8]萘啶-5,7-二酮(Z40，115mg，Y:53％)，淡黄色固体。 1H NMR(500MHz,DMSO-d 6)δ10.14(s,1H),9.12(s,1H),8.02(dd,J＝14.8,8.5Hz,1H),7.26(dd,J＝15.4,8.2Hz,1H),6.95(ddd,J＝75.5,16.8,10.6Hz,1H),6.73(d,J＝8.3Hz,1H),6.68(t,J＝8.8Hz,1H),6.22–6.09(m,1H),5.79–5.61(m,1H),5.13–4.55(m,1H),4.77-4.42(m,1H),4.02(dd,J＝28.2,3.9Hz,1H),3.74(dd,J＝14.2,4.2Hz,1H),3.42(t,J＝15.3Hz,1H),3.33–3.13(m,1H),3.03–2.85(m,1H),2.79(dd,J＝13.5,6.8Hz,1H),2.51-2.45(m,3H),1.56(dd,J＝18.3,6.7Hz,3H),1.11(d,J＝6.7Hz,3H),1.05(d,J＝6.6Hz,3H),1.00(d,J＝6.6Hz,3H),0.85(d,J＝6.7Hz,3H).ES-API:[M+H] +＝644.2。
实施例41制备化合物Z41
Figure PCTCN2020124226-appb-000123
步骤1：将4-氯-1-(4,6-二异丙基嘧啶-5-基)-6-氟-7-(2-氟-6-甲氧基苯基)-3-硝基-1,8-萘啶-2(1H)-酮(1g,1.89mmol)溶于N,N-二甲基乙酰胺(10mL)，依次加入1-(叔丁基)3-甲基(R)-哌嗪-1,3-二羧酸酯(1.39g,5.67mmol)和N,N-二异丙基乙胺(733mg,5.67mmol)，120℃搅拌2小时。冷却后反应液中加入30mL乙酸乙酯，用30mL碳酸氢钠洗涤2次，30mL稀盐水洗涤2次，30ml水洗涤一次，30mL饱和食盐水洗涤一次，干燥浓缩，并用快速硅胶柱(0-100％EtOAc/PE)纯化得到1-(叔丁基)3-甲基(3R)-4-(1-(4,6-二异丙基嘧啶-5-基)-6-氟-7-(2-氟-6-甲氧基苯基)-3-硝基-2-氧代-1,2-二氢-1,8-萘啶-4-基)哌嗪-1,3-二羧酸酯(1.3g,Y:80％)。ES-API:[M+H] +＝738.3。
步骤2：1-(叔丁基)3-甲基(3R)-4-(1-(4,6-二异丙基嘧啶-5-基)-6-氟-7-(2-氟-6-甲氧基苯基)-3-硝基-2-氧代-1,2-二氢-1,8-萘啶-4-基)哌嗪-1,3-二羧酸酯(1.23g，1.67mmol)溶于乙酸(12mL)，加入铁粉(326mg，5.84mmol)，80℃搅拌2小时。反应液浓缩，加入50mL乙酸乙酯，用饱和碳酸氢钠溶液调节pH＝8，悬浮液用硅藻土过滤，滤饼用乙酸乙酯洗涤，有机相分离，依次用25mL饱和碳酸氢钠，25mL饱和食盐水洗涤，干燥浓缩得到粗品叔丁基(4aR)-8-(4,6-二异丙基嘧啶-5-基)-11-氟-10-(2-氟-6-甲氧基苯基)-5,7-二氧代-1,2,4,4a,5,6,7,8-八氢-3H-吡嗪并[1',2':4,5]吡嗪并[2,3-c][1,8]萘啶-3-羧酸(1.08g，Y:95％)，灰绿色固体。ES-API:[M+H] +＝676.2。
步骤3：向15mL封管中依次加入(4aR)-8-(4,6-二异丙基嘧啶-5-基)-11-氟-10-(2-氟-6-甲氧基苯基)-5,7-二氧代-1,2,4,4a,5,6,7,8-八氢-3H-吡嗪并[1',2':4,5]吡嗪并[2,3-c][1,8]萘啶-3-羧酸叔丁酯(500mg，0.74mmol)，丙酮(10mL)，无水碳酸钾(307mg，2.22mmol)，碘甲烷(630mg，4.44mmol)。封管密封，反应在50℃搅拌过夜。反应液过滤，浓缩，溶于二氯甲烷(10mL)，并用水(10mL)洗涤，有机相干燥浓缩得到粗品(4aR)-8-(4,6-二异丙基嘧啶-5-基)-11-氟-10-(2-氟-6-甲氧基苯基)-6-甲基-5,7-二氧代-1,2,4,4a,5,6,7,8-八氢-3H-吡嗪并[1',2':4,5]吡嗪并[2,3-c][1,8]萘啶-3-羧酸叔丁酯(410mg，Y:80％)，黄色固体。ES-API:[M+H] +＝690.2。
步骤4：(4aR)-8-(4,6-二异丙基嘧啶-5-基)-11-氟-10-(2-氟-6-甲氧基苯基)-6-甲基-5,7-二氧代-1,2,4,4a,5,6,7,8-八氢-3H-吡嗪并[1',2':4,5]吡嗪并[2,3-c][1,8]萘啶-3-羧酸叔丁酯(410mg,0.60mmol)溶于二氯甲烷(4mL)，加入三氟乙酸(1mL)。室温搅拌2小时，反应液浓缩得粗品(4aR)-8-(4,6-二异丙基嘧啶-5-基)-11-氟-10-(2-氟-6-甲氧基苯基)-6-甲基 -2,3,4,4a,6,8-六氢-1H-吡嗪并[1',2':4,5]吡嗪并[2,3-c][1,8]萘啶-5,7-二酮(350mg)，直接用于下一步反应。ES-API:[M+H] +＝590.2。
步骤5：(4aR)-8-(4,6-二异丙基嘧啶-5-基)-11-氟-10-(2-氟-6-甲氧基苯基)-6-甲基-2,3,4,4a,6,8-六氢-1H-吡嗪并[1',2':4,5]吡嗪并[2,3-c][1,8]萘啶-5,7-二酮(350mg，0.59mmol)溶于二氯甲烷(5mL)，加入N,N-二异丙基乙胺(230mg，1.78mmol)。将反应冷至0℃，向反应液中滴加丙烯酰氯(107mg，1.19mmol)。反应液在0℃搅拌5分钟，浓缩，粗品用快速硅胶柱(0-100％EtOAc/PE)纯化得产物(4aR)-3-丙烯酰基-8-(4,6-二异丙基嘧啶-5-基)-11-氟-10-(2-氟-6-甲氧基苯基)-6-甲基-2,3,4,4a,6,8-六氢-1H-吡嗪并[1',2':4,5]吡嗪并[2,3-c][1,8]萘啶-5,7-二酮(300mg,Y:80％)，淡黄色固体。ES-API:[M+H] +＝644.2。
步骤6：(4aR)-3-丙烯酰基-8-(4,6-二异丙基嘧啶-5-基)-11-氟-10-(2-氟-6-甲氧基苯基)-6-甲基-2,3,4,4a,6,8-六氢-1H-吡嗪并[1',2':4,5]吡嗪并[2,3-c][1,8]萘啶-5,7-二酮(300mg，0.47mmol)溶于二氯甲烷(5mL)。将反应冷至0℃，向其中滴加17％三溴化硼的二氯甲烷溶液(5mL)，室温搅拌过夜。将反应液倒入40mL饱和碳酸氢钠水溶液，用25mL二氯甲烷萃取2次。有机相干燥后浓缩，粗品用制备HPLC纯化得产物(4aR)-3-丙烯酰基-8-(4,6-二异丙基嘧啶-5-基)-11-氟-10-(2-氟-6-羟基苯基)-6-甲基-2,3,4,4a,6,8-六氢-1H-吡嗪并[1',2':4,5]吡嗪并[2,3-c][1,8]萘啶-5,7-二酮(Z41，97mg，Y:35％)，淡黄色固体。 1H NMR(500MHz,DMSO-d 6)δ10.13(s,1H),9.12(s,1H),8.42(d,J＝8.7Hz,1H),7.26(dd,J＝15.5,8.2Hz,1H),7.03(dt,J＝111.6,55.9Hz,1H),6.73(d,J＝8.3Hz,1H),6.68(t,J＝8.8Hz,1H),6.16(d,J＝16.9Hz,1H),5.76(d,J＝11.0Hz,1H),4.74(d,J＝13.9Hz,1H),4.45(d,J＝12.3Hz,1H),4.00(s,1H),3.58(t,J＝12.7Hz,2H),3.33(s,3H),3.22(t,J＝11.5Hz,1H),2.79(dt,J＝13.5,6.7Hz,1H),2.69(t,J＝10.7Hz,1H),2.51-2.45(m,1H),1.11(d,J＝6.7Hz,3H),1.04(d,J＝6.6Hz,3H),1.01(d,J＝6.6Hz,3H),0.85(d,J＝6.7Hz,3H).ES-API:[M+H] +＝630.2。
实施例42制备化合物Z42
Figure PCTCN2020124226-appb-000124
步骤1：4-氯-6-氟-7-(2-氟-6-甲氧基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-3-硝基-1,8-萘啶-2(1H)-酮(1.2g,2.40mmol)溶于N,N-二甲基乙酰胺(10mL)，依次加入(3-(2-甲氧基-2-氧乙基)哌嗪-1-羧酸叔丁酯(743mg,2.87mmol)和N,N-二异丙基乙胺(930mg,7.20 mmol)，反应在120℃搅拌2小时。反应液中加入50mL乙酸乙酯，用25mL稀盐水洗涤4次，20mL饱和食盐水洗涤，干燥浓缩，粗品用快速硅胶柱纯化(EtOAc/PE：0-50％)得到黄色固体叔丁基-4-(6-氟-7-(2-氟-6-甲氧基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-3-硝基-2-氧代-1,2-二氢-1,8-萘啶-4-基)-3-(2-甲氧基-2-氧乙基)哌嗪-1-羧酸(580mg,Y:28％)。ES-API:[M+H] +＝723.3。
步骤2：4-(6-氟-7-(2-氟-6-甲氧基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-3-硝基-2-氧代-1,2-二氢-1,8-萘啶-4-基)-3-(2-甲氧基-2-氧乙基)哌嗪-1-羧酸叔丁酯(550mg,0.76mmol)溶于乙酸(5.5mL)，加入铁粉(149mg,2.66mmol)，反应在80℃搅拌2小时。反应液浓缩，依次加入50mL乙酸乙酯和30mL饱和碳酸氢钠，悬浮液用硅藻土过滤，滤饼用乙酸乙酯洗涤，有机相分离，依次用25mL饱和碳酸氢钠，25mL饱和食盐水洗涤，干燥浓缩得到黄色固体12-氟-11-(2-氟-6-甲氧基苯基)-9-(2-异丙基-4-甲基吡啶-3-基)-6,8-二氧代-1,2,4a,5,6,7,8,9-八氢吡嗪并[1',2':4,5][1,4]二氮杂[2,3-c][1,8]萘啶-3(4H)-羧酸叔丁酯(520mg)。ES-API:[M+H]+＝661.3。
步骤3：12-氟-11-(2-氟-6-甲氧基苯基)-9-(2-异丙基-4-甲基吡啶-3-基)-6,8-二氧代-1,2,4a,5,6,7,8,9-八氢吡嗪并[1',2':4,5][1,4]二氮杂[2,3-c][1,8]萘啶-3(4H)-羧酸叔丁酯(100mg,0.15mmol)溶于二氯甲烷(4mL)，加入三氟乙酸(1mL)。室温搅拌2小时，反应液浓缩得产物12-氟-11-(2-氟-6-甲氧基苯基)-9-(2-异丙基-4-甲基吡啶-3-基)-1,2,3,4,4a,5,7,9-八氢吡嗪并[1',2':4,5][1,4]二氮杂[2,3-c][1,8]萘啶-6,8-二酮(85mg,粗品)，直接用于下一步反应。ES-API:[M+H] +＝561.3。
步骤4：12-氟-11-(2-氟-6-甲氧基苯基)-9-(2-异丙基-4-甲基吡啶-3-基)-1,2,3,4,4a,5,7,9-八氢吡嗪并[1',2':4,5][1,4]二氮杂[2,3-c][1,8]萘啶-6,8-二酮(85mg,粗品)溶于二氯甲烷(2mL)，加入N,N-二异丙基乙胺(58mg，0.45mmol)。将反应液冷至0℃，向反应液中滴加丙烯酰氯(27mg，0.30mmol)，0℃搅拌10分钟。向反应液中加入25mL二氯甲烷，依次用15mL水，15mL饱和碳酸氢钠水溶液，15mL饱和食盐水洗涤，干燥浓缩，粗品用快速硅胶柱(EtOAc/PE：0-100％)纯化得产物3-丙烯酰基-12-氟-11-(2-氟-6-甲氧基苯基)-9-(2-异丙基-4-甲基吡啶-3-基)-1,2,3,4,4a,5,7,9-八氢吡嗪并[1',2':4,5][1,4]二氮杂[2,3-c][1,8]萘啶-6,8-二酮(60mg,Y:65％)，淡黄色固体。ES-API:[M+H] +＝615.3。
步骤5：3-丙烯酰基-12-氟-11-(2-氟-6-甲氧基苯基)-9-(2-异丙基-4-甲基吡啶-3-基)-1,2,3,4,4a,5,7,9-八氢吡嗪并[1',2':4,5][1,4]二氮杂[2,3-c][1,8]萘啶-6,8-二酮(60mg，0.10mmol)溶于二氯甲烷(3mL)。将反应液冷至0℃，向其中滴加17％三溴化硼的二氯甲烷溶液(3mL)。反应在室温下搅拌2小时。将反应液倒入40mL饱和碳酸氢钠水溶液，用25mL二氯甲烷萃取2次。有机相干燥后浓缩，粗品用制备HPLC制备得产物3-丙烯酰基-12-氟-11-(2-氟-6-羟基苯基)-9-(2-异丙基-4-甲基吡啶-3-基)-1,2,3,4,4a,5,7,9-八氢吡嗪并[1',2':4,5][1,4]二氮杂[2,3-c][1,8]萘啶-6,8-二酮(Z42，27mg,Y:46％)，淡黄色固体。 1H NMR(500MHz,DMSO-d 6)δ10.11(s,1H),8.62(s,1H),8.44(d,J＝4.6Hz,1H),8.24(s,1H),7.23-7.28(m,2H),6.85-7.00(m,1H),6.78–6.62(m,2H),6.24(s,1H),5.77(d,J＝9.9Hz,1H),3.93(s,7H),3.09(s,1H),2.83(s,1H),2.60(s,1H),1.86(d,J＝23.4Hz,3H),1.06(t,J＝7.1Hz,3H),0.91(dd,J＝9.7,6.8Hz,3H).ES-API:[M+H] +＝601.2。
实施例43制备化合物Z43
Figure PCTCN2020124226-appb-000125
步骤1：冰浴条件下，将钠氢(91mg，2.27mmol)加入到12-氟-11-(2-氟-6-甲氧基苯基)-9-(2-异丙基-4-甲基吡啶-3-基)-6,8-二氧代-1,2,4a,5,6,7,8,9-八氢吡嗪并[1',2':4,5][1,4]二氮杂并[2,3-c][1,8]萘啶-3(4H)-羧酸叔丁酯(300mg，0.45mmol)的四氢呋喃(10mL)溶液中，搅拌30分钟。然后把碘甲烷(650mg，4.54mmol)加入到反应液中，室温搅拌过夜。反应液用饱和氯化铵溶液(30mL)淬灭，乙酸乙酯(30mL*3)萃取，有机相干燥，浓缩，并用快速硅胶柱(0-10％甲醇/二氯甲烷)纯化，得产物12-氟-11-(2-氟-6-甲氧基苯基)-9-(2-异丙基-4-甲基吡啶-3-基)-7-甲基-6,8-二氧代-1,2,4a,5,6,7,8,9-八氢吡嗪并[1',2':4,5][1,4]二氮杂[2,3-c][1,8]萘啶-3(4H)-羧酸叔丁酯(190mg,Y:62％)，黄色固体。ES-API:[M+H] +＝675.3。
步骤2：12-氟-11-(2-氟-6-甲氧基苯基)-9-(2-异丙基-4-甲基吡啶-3-基)-7-甲基-6,8-二氧代-1,2,4a,5,6,7,8,9-八氢吡嗪并[1',2':4,5][1,4]二氮杂[2,3-c][1,8]萘啶-3(4H)-羧酸叔丁酯(188mg,0.28mmol)溶于二氯甲烷(8mL)，加入三氟乙酸(2mL)。室温搅拌2小时，反应液浓缩得粗品12-氟-11-(2-氟-6-甲氧基苯基)-9-(2-异丙基-4-甲基吡啶-3-基)-7-甲基-1,2,3,4,4a,5,7,9-八氢吡嗪并[1',2':4,5][1,4]二氮杂[2,3-c][1,8]萘啶-6,8-二酮(160mg)，直接用于下一步反应。ES-API:[M+H] +＝575.2。
步骤3：12-氟-11-(2-氟-6-甲氧基苯基)-9-(2-异丙基-4-甲基吡啶-3-基)-7-甲基-1,2,3,4,4a,5,7,9-八氢吡嗪并[1',2':4,5][1,4]二氮杂[2,3-c][1,8]萘啶-6,8-二酮(160mg，0.28mmol)溶于二氯甲烷(4mL)，加入N,N-二异丙基乙胺(108mg，0.84mmol)。将反应冷至0℃，向反应液中滴加丙烯酰氯(50mg，0.56mmol)。反应液在0℃搅拌5分钟，浓缩，粗品用快速硅胶柱纯化(0-80％EtOAc/PE)得产物3-丙烯酰基-12-氟-11-(2-氟-6-甲氧基苯基)-9-(2-异丙基-4-甲基吡啶-3-基)-7-甲基-1,2,3,4,4a,5,7,9-八氢吡嗪并[1',2':4,5][1,4]二氮杂[2,3-c][1,8]萘啶-6,8-二酮(170mg,Y:97％)，淡黄色固体。ES-API:[M+H] +＝629.2。
步骤4：3-丙烯酰基-12-氟-11-(2-氟-6-甲氧基苯基)-9-(2-异丙基-4-甲基吡啶-3-基)-7-甲基-1,2,3,4,4a,5,7,9-八氢吡嗪并[1',2':4,5][1,4]二氮杂[2,3-c][1,8]萘啶-6,8-二酮(170mg，0.27mmol)溶于二氯甲烷(3mL)。将反应冷至0℃，向其中滴加17％三溴化硼的二氯甲烷溶液(3mL)，室温搅拌2小时。将反应液倒入40mL饱和碳酸氢钠水溶液，用25mL二氯甲烷萃取2次。有机相干燥后浓缩，粗品用制备HPLC纯化得产物3-丙烯酰基-12-氟-11-(2-氟-6-羟基苯基)-9-(2-异丙基-4-甲基吡啶-3-基)-7-甲基-1,2,3,4,4a,5,7,9-八氢吡嗪并[1',2':4,5][1,4]二氮杂[2,3-c][1,8]萘啶-6,8-二酮(Z43，95mg，Y:57％)，淡黄色固体。 1H NMR(500MHz,DMSO-d 6)δ8.47(d,J＝9.8Hz,1H),8.42(dd,J＝4.8,2.1Hz,1H),7.26-7.19(m,2H),7.04–6.82(m,1H),6.72-6.67(m,1H),6.66-6.62(m,1H),6.19(d,J＝16.5Hz,1H),5.76(d,J＝10.4Hz,1H),4.60–4.45(m,1H),4.36–4.10(m,1H),4.02(s,1H),3.93-3.78(m,1H),3.65(dd,J＝21.9,10.6Hz,1H),3.29–3.22(m,2H),3.09(s,3H), 3.17–2.99(m,1H),2.76-2.63(m,2H),2.37-2.28(m,1H),1.90(d,J＝47.0Hz,3H),1.05(dd,J＝31.1,6.7Hz,3H),0.93(dd,J＝42.5,6.6Hz,3H).ES-API:[M+H] +＝615.2。
实施例44制备化合物Z44a、Z44
Figure PCTCN2020124226-appb-000126
步骤1：向15mL封管中依次加入(2R,4aR)-8-(4,6-二异丙基嘧啶-5-基)-11-氟-10-(2-氟-6-甲氧基苯基)-2-甲基-5,7-二氧代-1,2,4,4a,5,6,7,8-八氢-3H-吡嗪并[1’,2’:4,5]吡嗪并[2,3-c][1,8]萘啶-3-羧酸叔丁酯(350mg，0.51mmol)，丙酮(5mL)，无水碳酸钾(210mg,1.52mmol)，氘代碘甲烷(735mg，5.07mmol)。封管密封，50℃搅拌过夜。反应液过滤，浓缩得产物(2R,4aR)-8-(4,6-二异丙基嘧啶-5-基)-11-氟-10-(2-氟-6-甲氧基苯基)-2-甲基-6-(甲基-d3)-5,7-二氧代-1,2,4,4a,5,6,7,8-八氢-3H-吡嗪并[1’,2’:4,5]吡嗪并[2,3-c][1,8]萘啶-3-羧酸叔丁酯(250mg)，黄色固体。ES-API:[M+H] +＝707.3。
步骤2：(2R,4aR)-8-(4,6-二异丙基嘧啶-5-基)-11-氟-10-(2-氟-6-甲氧基苯基)-2-甲基-6-(甲基-d3)-5,7-二氧代-1,2,4,4a,5,6,7,8-八氢-3H-吡嗪并[1’,2’:4,5]吡嗪并[2,3-c][1,8]萘啶-3-羧酸叔丁酯(250mg,0.35mmol)溶于二氯甲烷(8mL)，加入三氟乙酸(2mL)。室温搅拌2小时，反应液浓缩得粗品(2R,4aR)-8-(4,6-二异丙基嘧啶-5-基)-11-氟-10-(2-氟-6-甲氧基苯基)-2-甲基-6-(甲基-d3)-2,3,4,4a,6,8-六氢-1H-吡嗪并[1’,2’:4,5]吡嗪并[2,3-c][1,8]萘啶-5,7-二酮(215mg)，直接用于下一步反应。ES-API:[M+H] +＝607.3。
步骤3：(2R,4aR)-8-(4,6-二异丙基嘧啶-5-基)-11-氟-10-(2-氟-6-甲氧基苯基)-2-甲基-6-(甲基-d3)-2,3,4,4a,6,8-六氢-1H-吡嗪并[1’,2’:4,5]吡嗪并[2,3-c][1,8]萘啶-5,7-二酮(215mg，0.35mmol)溶于二氯甲烷(3mL)，加入N,N-二异丙基乙胺(226mg，1.75mmol)。将反应冷至0℃，向反应液中滴加丙烯酰氯(63mg，0.70mmol)。反应液在0℃搅拌10分钟，浓缩，粗品用快速硅胶柱纯化(0-80％EtOAc/PE)得产物Z44a(122mg,P:100％，Y:52％)，淡黄色固体。ES-API:[M+H] +＝661.3。
步骤4：(2R,4aR)-3-丙烯酰基-8-(4,6-二异丙基嘧啶-5-基)-11-氟-10-(2-氟-6-甲氧基苯基)-2-甲基-6-(甲基-d3)-2,3,4,4a,6,8-六氢-1H-吡嗪并[1’,2’:4,5]吡嗪并[2,3-c][1,8]萘啶-5,7-二酮(Z44a，120mg，0.18mmol)溶于二氯甲烷(3mL)。将反应冷至0℃，向其中滴加17％三溴化硼的二氯甲烷溶液(3mL)，室温搅拌过夜。将反应液倒入40mL饱和碳酸氢钠水溶液，用25mL二氯甲烷萃取2次。有机相干燥后浓缩，粗品用制备HPLC纯化得产物(2R,4aR)-3-丙烯酰基-8-(4,6-二异丙基嘧啶-5-基)-11-氟-10-(2-氟-6-羟基苯基)-2-甲基-6-(甲基-d3)-2,3,4,4a,6,8-六氢-1H-吡嗪并[1’,2’:4,5]吡嗪并[2,3-c][1,8]萘啶-5,7-二酮(Z44，69mg，P:100％，Y：59％)，淡黄色固体。 1H NMR(500MHz,DMSO-d 6)δ9.12(s,1H),8.00(dd,J＝14.2,8.7Hz,1H),7.24(dd,J＝15.3,7.8Hz,1H),6.95(ddd,J＝75.8,16.7,10.5Hz,1H),6.71(s,1H),6.65(t,J＝8.5Hz,1H),6.24–6.01(m,1H),5.82–5.66(m,1H),5.04-4.60(m,1H),4.77-4.42(m,1H),4.02(dd,J＝28.4,3.7Hz,1H),3.74(dd,J＝14.1,4.1Hz,1H),3.44(m,1H),3.25(m,1H),2.99–2.74(m,2H),2.48–2.44(m,1H),1.55(dd,J＝ 18.5,6.7Hz,3H),1.11(d,J＝6.7Hz,3H),1.04(d,J＝6.7Hz,3H),1.00(d,J＝6.6Hz,3H),0.84(d,J＝6.7Hz,3H).ES-API:[M+H] +＝647.3。
实施例45制备化合物Z45
Figure PCTCN2020124226-appb-000127
步骤1：(2R,4aR)-8-(4,6-二异丙基嘧啶-5-基)-11-氟-10-(2-氟-6-甲氧基苯基)-2-甲基-5,7-二氧代-1,2,4,4a,5,6,7,8-八氢-3H-吡嗪并[1',2':4,5]吡嗪并[2,3-c][1,8]萘啶-3-羧酸叔丁酯(50mg,0.07mmol)溶于二氯甲烷(4mL)，加入三氟乙酸(1mL)。室温搅拌2小时，反应液浓缩得粗品(2R,4aR)-8-(4,6-二异丙基嘧啶-5-基)-11-氟-10-(2-氟-6-甲氧基苯基)-2-甲基-2,3,4,4a,6,8-六氢-1H-吡嗪并[1',2':4,5]吡嗪并[2,3-c][1,8]萘啶-5,7-二酮(43mg)，直接用于下一步反应。ES-API:[M+H] +＝590.2。
步骤2：(2R,4aR)-8-(4,6-二异丙基嘧啶-5-基)-11-氟-10-(2-氟-6-甲氧基苯基)-2-甲基-2,3,4,4a,6,8-六氢-1H-吡嗪并[1',2':4,5]吡嗪并[2,3-c][1,8]萘啶-5,7-二酮(43mg，0.07mmol)溶于二氯甲烷(2mL)，加入N,N-二异丙基乙胺(45mg，0.35mmol)。将反应冷至0℃，向反应液中滴加丙烯酰氯(13mg，0.14mmol)。反应液在0℃搅拌5分钟，浓缩，粗品用快速硅胶柱纯化(EtOAc/PE：0-80％)得产物(2R,4aR)-3-丙烯酰基-8-(4,6-二异丙基嘧啶-5-基)-11-氟-10-(2-氟-6-甲氧基苯基)-2-甲基-2,3,4,4a,6,8-六氢-1H-吡嗪并[1',2':4,5]吡嗪并[2,3-c][1,8]萘啶-5,7-二酮(26mg,Y:56％)，淡黄色固体。ES-API:[M+H] +＝644.2。
步骤3：(2R,4aR)-3-丙烯酰基-8-(4,6-二异丙基嘧啶-5-基)-11-氟-10-(2-氟-6-甲氧基苯基)-2-甲基-2,3,4,4a,6,8-六氢-1H-吡嗪并[1',2':4,5]吡嗪并[2,3-c][1,8]萘啶-5,7-二酮(26mg，0.04mmol)溶于二氯甲烷(0.5mL)。将反应冷至0℃，向其中滴加17％三溴化硼的二氯甲烷溶液(0.5mL)，室温搅拌过夜。将反应液倒入4mL饱和碳酸氢钠水溶液，用3mL二氯甲烷萃取2次。有机相干燥后浓缩，粗品用制备HPLC纯化得产物(2R,4aR)-3-丙烯酰基-8-(4,6-二异丙基嘧啶-5-基)-11-氟-10-(2-氟-6-羟基苯基)-2-甲基-2,3,4,4a,6,8-六氢-1H-吡嗪并[1',2':4,5]吡嗪并[2,3-c][1,8]萘啶-5,7-二酮(Z45，8mg，Y:31％)，淡黄色固体。ES-API:[M+H] +＝630.2。
实施例46制备化合物Z46
Figure PCTCN2020124226-appb-000128
步骤1：将7-氯-6-氟-4-羟基-1-(2-异丙基-4,6-二甲基吡啶-3-基)-2-氧代-1,2-二氢-1,8-萘啶-3-腈(8g,20.68mmol)悬浮于1，4-二氧六环(40mL)，缓慢加入浓硫酸(40mL)和水(40mL)的混合液。反应120℃下搅拌过夜，将冷却的反应液中倒入150mL冰水中，用氢氧化钾水溶液调pH＝6，乙酸乙酯萃取，有机相干燥后浓缩,得产物7-氯-6-氟-4-羟基-1-(2-异丙基-4,6-二甲基吡啶-3-基)-1,8-萘啶-2(1H)-酮(7.6g,Y:96％)，淡黄色固体。ES-API:[M+H] +＝362.2。
步骤2：7-氯-6-氟-4-羟基-1-(2-异丙基-4,6-二甲基吡啶-3-基)-1,8-萘啶-2(1H)-酮(7.6g，21.01mmol)溶于乙酸(26mL)，依次加入亚硝酸钠(145mg,2.10mmol)和浓硝酸(3.97g，63.01mmol)，室温下搅拌20min。将反应液中倒入20mL水中，析出黄色固体，过滤，滤饼用6ml水洗涤，在真空下干燥得产物7-氯-6-氟-4-羟基-1-(2-异丙基-4,6-二甲基吡啶-3-基)-3-硝基-1,8-萘啶-2(1H)-酮(4g，Y:47％)，淡黄色固体。ES-API:[M+H] +＝407.1。
步骤3：7-氯-6-氟-4-羟基-1-(2-异丙基-4,6-二甲基吡啶-3-基)-3-硝基-1,8-萘啶-2(1H)-酮(4g，9.83mmol),(2-氟-6-甲氧基苯基)硼酸(8.36g,49.16mmol),氯(2-二环己基膦基-2',6'-二甲氧基-1,1'-联苯基)(2'-氨基-1,1'-联苯-2-基)钯(II)(705mg,0.98mmol)，2-双环己基膦-2',6'-二甲氧基联苯(402mg,0.98mmol),磷酸钾(6.26g,29.50mmol)的8mL水和40mL二氧六环混合液用氮气置换三次，100℃反应2h。将反应液倒入50mL水中，甲基叔丁基醚(30mL*2)洗涤，水相用3.0M稀盐酸调pH＝6.0后，用乙酸乙酯(30mL*2)萃取，有机相干燥后浓缩得到粗品6-氟-7-(2-氟-6-甲氧基苯基)-4-羟基-1-(2-异丙基-4,6-二甲基吡啶-3-基)-3-硝基-1,8-萘啶-2(1H)-酮(4g，Y:82％)。ES-API:[M+H] +＝497.2。
步骤4：往6-氟-7-(2-氟-6-甲氧基苯基)-4-羟基-1-(2-异丙基-4,6-二甲基吡啶-3-基)-3-硝基-1,8-萘啶-2(1H)-酮(4g,8.06mmol)的乙腈(60mL)溶液中依次加入三氯氧磷(6.18g,40.30mmol)和N,N-二异丙基乙胺(8.33g，68.48mmol)。反应在80℃下搅拌1小时。将反应液浓缩，加入150mL乙酸乙酯，依次用80mL饱和碳酸氢钠洗涤2次，80mL 水和80mL饱和食盐水洗涤。有机相干燥浓缩后，粗品用快速硅胶柱(EtOAc/PE：0-50％)纯化得产物4-氯-6-氟-7-(2-氟-6-甲氧基苯基)-1-(2-异丙基-4,6-二甲基吡啶-3-基)-3-硝基-1,8-萘啶-2(1H)-酮(3.5g,Y:85％)，淡黄色固体。ES-API:[M+H] +＝515.2
步骤5：将4-氯-6-氟-7-(2-氟-6-甲氧基苯基)-1-(2-异丙基-4,6-二甲基吡啶-3-基)-3-硝基-1,8-萘啶-2(1H)-酮(1g,1.94mmol)溶于N,N-二甲基乙酰胺(10mL),依次加入1-(叔丁基)3-甲基(3R,6R)-6-甲基哌嗪-1,3-二羧酸(600mg,2.33mmol)和N,N-二异丙基乙胺(750mg,5.82mmol)，120℃搅拌2小时。冷却后反应液中加入100mL乙酸乙酯，用50mL碳酸氢钠洗涤2次，50mL稀盐水洗涤2次，50ml水洗涤一次，50mL饱和食盐水洗涤一次，干燥浓缩，得到粗品1-(叔丁基)3-甲基(3R,6R)-4-(6-氟-7-(2-氟-6-甲氧基苯基)-1-(2-异丙基-4,6-二甲基吡啶-3-基)-3-硝基-2-氧代-1,2-二氢-1,8-萘啶-4-基)-6-甲基哌嗪-1,3-二羧酸酯(1.6g)。ES-API:[M+H] +＝737.2。
步骤6：1-(叔丁基)3-甲基(3R,6R)-4-(6-氟-7-(2-氟-6-甲氧基苯基)-1-(2-异丙基-4,6-二甲基吡啶-3-基)-3-硝基-2-氧代-1,2-二氢-1,8-萘啶-4-基)-6-甲基哌嗪-1,3-二羧酸酯(1.6g,2.17mmol)溶于乙酸(16mL)，加入铁粉(425mg,7.60mmol),80℃搅拌1小时。反应液浓缩，加入50mL乙酸乙酯，用饱和碳酸氢钠溶液调节pH＝6，悬浮液用硅藻土过滤，滤饼用乙酸乙酯洗涤，有机相分离，依次用25mL饱和碳酸氢钠，25mL饱和食盐水洗涤，干燥浓缩得到粗品(2R,4aR)-11-氟-10-(2-氟-6-甲氧基苯基)-8-(2-异丙基-4,6-二甲基吡啶-3-基)-2-甲基-5,7-二氧代-1,2,4,4a,5,6,7,8-八氢-3H-吡嗪并[1’,2’:4,5]吡嗪并[2,3-c][1,8]萘啶-3-羧酸叔丁酯(1.4g)，黄色固体。ES-API:[M+H] +＝675.3。
步骤7：向50mL封管中依次加入(2R,4aR)-11-氟-10-(2-氟-6-甲氧基苯基)-8-(2-异丙基-4,6-二甲基吡啶-3-基)-2-甲基-5,7-二氧代-1,2,4,4a,5,6,7,8-八氢-3H-吡嗪并[1’,2’:4,5]吡嗪并[2,3-c][1,8]萘啶-3-羧酸叔丁酯(1.4g，2.07mmol)，丙酮(15mL)，无水碳酸钾(860mg,6.21mmol)，碘甲烷(2.95g，20.7mmol)。封管密封，反应在50℃搅拌过夜。反应液过滤，浓缩并用快速硅胶柱(EtOAc/PE：0-80％)纯化得产物(2R,4aR)-11-氟-10-(2-氟-6-甲氧基苯基)-8-(2-异丙基-4,6-二甲基吡啶-3-基)-2,6-二甲基-5，7-二氧代-1,2,4,4a,5,6,7,8-八氢-3H-吡嗪并[1’,2’:4,5]吡嗪并[2,3-c][1,8]萘啶-3-羧酸叔丁酯(340mg,Y:24％)，黄色固体。ES-API:[M+H] +＝706.3。
步骤8：(2R,4aR)-11-氟-10-(2-氟-6-甲氧基苯基)-8-(2-异丙基-4,6-二甲基吡啶-3-基)-2,6-二甲基-5，7-二氧代-1,2,4,4a,5,6,7,8-八氢-3H-吡嗪并[1',2':4,5]吡嗪并[2,3-c][1,8]萘啶-3-羧酸叔丁酯(340mg,0.49mmol)溶于二氯甲烷(4mL)，加入三氟乙酸(1mL)。室温搅拌2小时，反应液浓缩得粗品(2R,4aR)-11-氟-10-(2-氟-6-甲氧基苯基)-8-(2-异丙基-4,6-二甲基吡啶-3-基)-2,6-二甲基-2,3，4,4a,6,8-六氢-1H-吡嗪并[1',2':4,5]吡嗪并[2,3-c][1,8]萘啶-5,7-二酮(317mg)，直接用于下一步反应。ES-API:[M+H] +＝589.3。
步骤9：(2R,4aR)-11-氟-10-(2-氟-6-甲氧基苯基)-8-(2-异丙基-4,6-二甲基吡啶-3-基)-2,6-二甲基-2,3,4,4a,6,8-六氢-1H-吡嗪并[1',2':4,5]吡嗪并[2,3-c][1,8]萘啶-5,7-二酮(317mg，0.49mmol)溶于二氯甲烷(5mL)，加入N,N-二异丙基乙胺(320mg，2.45mmol)。将反应冷至0℃，向反应液中滴加丙烯酰氯(89mg，0.99mmol)。反应液在0℃搅拌5分钟，浓缩，粗品用快速硅胶柱纯化(EtOAc/PE：0-80％)得产物(2R,4aR)-3-丙烯酰基-11-氟-10-(2-氟-6-甲氧基苯基)-8-(2-异丙基-4,6-二甲基吡啶-3-基)-2,6-二甲基-2,3,4,4a,6,8-六 氢-1H-吡嗪并[1',2':4,5]吡嗪并[2,3-c][1,8]萘啶-5,7-二酮(280mg,Y:81％)，淡黄色固体。ES-API:[M+H] +＝643.3。
步骤10：(2R,4aR)-3-丙烯酰基-11-氟-10-(2-氟-6-甲氧基苯基)-8-(2-异丙基-4,6-二甲基吡啶-3-基)-2,6-二甲基-2,3,4,4a,6,8-六氢-1H-吡嗪并[1',2':4,5]吡嗪并[2,3-c][1,8]萘啶-5,7-二酮(280mg，0.44mmol)溶于二氯甲烷(3mL)。将反应冷至0℃，向其中滴加17％三溴化硼的二氯甲烷溶液(3mL)，室温搅拌2小时。将反应液倒入40mL饱和碳酸氢钠水溶液，用25mL二氯甲烷萃取2次。有机相干燥后浓缩，粗品用制备HPLC纯化得产物(2R,4aR)-3-丙烯酰基-11-氟-10-(2-氟-6-甲氧基苯基)-8-(2-异丙基-4,6-二甲基吡啶-3-基)-2,6-二甲基-2,3,4,4a,6,8-六氢-1H-吡嗪并[1',2':4,5]吡嗪并[2,3-c][1,8]萘啶-5,7-二酮(Z46，108mg，Y：40％)，淡黄色固体。 1H NMR(500MHz,DMSO-d 6)δ10.14(s,1H),7.99(t,J＝10.4Hz,1H),7.27(dd,J＝15.5,7.7Hz,1H),7.13–6.83(m,2H),6.78–6.65(m,2H),6.16(t,J＝13.5Hz,1H),5.81–5.69(m,1H),5.08–4.72(m,1H),4.54(t,J＝51.7Hz,1H),3.99(t,J＝29.0Hz,1H),3.73(d,J＝10.5Hz,1H),3.44–3.23(m,1H),3.35(s,3H),2.95-2.80(m,1H),2.75-2.68(m,1H),2.45(d,J＝1.9Hz,3H),2.41–2.37(m,1H),1.84(d,J＝96Hz,1H),1.55(dd,J＝16.5,5.4Hz,3H),1.05(dd,J＝39.3,6.7Hz,3H),0.90(dd,J＝65.2,6.6Hz,3H).ES-API:[M+H] +＝629.2。
实施例47制备化合物Z47
Figure PCTCN2020124226-appb-000129
步骤1：将7-氯-6-氟-4-羟基-1-(3-异丙基-1,5-二甲基-1H-吡唑-4-基)-2-氧代-1,2-二氢-1,8-萘啶-3-腈(3.5g,9.3mmol)悬浮于1，4-二氧六环(40mL)，缓慢加入浓硫酸(40mL)和水(40mL)的混合液。反应120℃下搅拌20小时。将冷却的反应液中倒入150mL冰水中，用4.0M氢氧化钾水溶液调pH＝3，析出的固体过滤，滤液用200mL二氯甲烷萃取，固体用二氯甲烷/甲醇＝10：1的混合液溶解过滤，合并有机相，有机相干燥后浓缩,得产物7-氯-6-氟-4-羟基-1-(3-异丙基-1,5-二甲基-1H-吡唑-4-基)-1,8-萘啶-2(1H)-酮(2.3g,Y:71.6％)，淡棕色固体。ES-API:[M+H] +＝351.1。
步骤2：7-氯-6-氟-4-羟基-1-(3-异丙基-1,5-二甲基-1H-吡唑-4-基)-1,8-萘啶-2(1H)-酮 (2.3g,6.5mmol)溶于乙酸(8mL)，依次加入亚硝酸钠(45mg,0.65mmol)和浓硝酸(1.5mL，19.5mmol)，反应在室温下搅拌1小时。将反应液中倒入30mL冰水中，析出的固体过滤，滤饼用6ml水洗涤，在真空下干燥得产物7-氯-6-氟-4-羟基-1-(3-异丙基-1,5-二甲基-1H-吡唑-4-基)-3-硝基-1,8-萘啶-2(1H)-酮(1.5g，Y:60％)，淡黄色固体。ES-API:[M+H] +＝396.1。
步骤3：向250mL圆底烧瓶中加入7-氯-6-氟-4-羟基-1-(3-异丙基-1,5-二甲基-1H-吡唑-4-基)-3-硝基-1,8-萘啶-2(1H)-酮(1.5g，3.8mmol)、(2-氟-6-甲氧基苯基)硼酸(0.96g,5.7mmol)、氯(2-二环己基膦-2′,6′-二甲氧基-1,1′-联苯)[2-(2′-氨基-1,1′-联苯)]钯(II)-G2-Pd(273mg,0.38mmol)、2-二环己基膦基-2′,6′-二甲氧基联苯基(155mg,0.38mmol)、磷酸钾(2.41g,11.4mmol)、4mL水和20mL二氧六环。氮气保护下，反应在85℃搅拌4小时。反应液浓缩，加入100mL水，用3.0M稀盐酸调pH＝3.0，用120mL二氯甲烷萃取2次，有机相干燥后浓缩得产物6-氟-7-(2-氟-6-甲氧基苯基)-4-羟基-1-(3-异丙基-1,5-二甲基-1H-吡唑-4-基)-3-硝基-1,8-萘啶-2(1H)-酮(2.4g,粗品)，直接用于下一步反应。ES-API:[M+H] +＝486.1。
步骤4：6-氟-7-(2-氟-6-甲氧基苯基)-4-羟基-1-(3-异丙基-1,5-二甲基-1H-吡唑-4-基)-3-硝基-1,8-萘啶-2(1H)-酮(2.4g,粗品)溶于乙腈(50mL)，依次加入三氯氧磷(3.8g,24.7mmol)，和N,N-二异丙基乙胺(6.38g,49.4mmol)，反应在85℃下搅拌1小时。将反应液浓缩，加入150mL乙酸乙酯依次用80mL水，80mL饱和碳酸氢钠洗涤2次，80mL饱和食盐水洗涤。有机相干燥浓缩后，粗品用快速硅胶柱(EtOAc/PE：0-40％)纯化得产物4-氯-6-氟-7-(2-氟-6-甲氧基苯基)-1-(3-异丙基-1,5-二甲基-1H-吡唑-4-基)-3-硝基-1,8-萘啶-2(1H)-酮(0.29g,Y:10％)，淡黄色固体。ES-API:[M+H] +＝504.1。
步骤5：4-氯-6-氟-7-(2-氟-6-甲氧基苯基)-1-(3-异丙基-1,5-二甲基-1H-吡唑-4-基)-3-硝基-1,8-萘啶-2(1H)-酮(290mg,0.57mmol)溶于N,N-二甲基乙酰胺(3mL)，依次加入(3R,6R)-1-N-BOC-6-甲基哌嗪-3-甲酸甲酯(155mg,0.60mmol)，和N,N-二异丙基乙胺(116mg,0.90mmol)，反应在120℃搅拌2小时。反应液中加入50mL乙酸乙酯，用25mL稀盐水洗涤4次，20mL饱和食盐水洗涤，干燥浓缩，粗品用快速硅胶柱纯化(EtOAc/PE：0-50％)得产物1-(叔丁基)3-甲基(3R,6R)-4-(6-氟-7-(2-氟-6-甲氧基苯基)-1-(3-异丙基-1,5-二甲基-1H-吡唑-4-基)-3-硝基-2-氧代-1,2-二氢-1,8-萘啶-4-基)-6-甲基哌嗪-1,3-二羧酸(280mg,Y:68.8％)，橙色固体。ES-API:[M+H] +＝726.3。
步骤6：1-(叔丁基)3-甲基(3R,6R)-4-(6-氟-7-(2-氟-6-甲氧基苯基)-1-(3-异丙基-1,5-二甲基-1H-吡唑-4-基)-3-硝基-2-氧代-1,2-二氢-1,8-萘啶-4-基)-6-甲基哌嗪-1,3-二羧酸(280mg,0.38mmol)溶于乙酸(2.5mL)，加入铁粉(37mg,0.66mmol),反应在80℃搅拌30分钟。反应液浓缩，依次加入50mL乙酸乙酯和30mL饱和碳酸氢钠，悬浮液用硅藻土过滤，滤饼用乙酸乙酯洗涤，有机相分离，依次用25mL饱和碳酸氢钠，25mL饱和食盐水洗涤，干燥浓缩得产物(2R,4aR)-11-氟-10-(2-氟-6-甲氧基苯基)-8-(3-异丙基-1,5-二甲基-1H-吡唑-4-基)-2-甲基-5,7-二氧代-1,2,4,4a,5,6,7,8-八氢-3H-吡嗪并[1’,2’:4,5]吡嗪并[2,3-c][1,8]萘啶-3-羧酸叔丁酯(250mg,Y:97.6％)，黄色固体。ES-API:[M+H]+＝664.3。
步骤7：向15mL封管中依次加入(2R,4aR)-11-氟-10-(2-氟-6-甲氧基苯基)-8-(3-异丙基-1,5-二甲基-1H-吡唑-4-基)-2-甲基-5,7-二氧代-1,2,4,4a,5,6,7,8-八氢-3H-吡嗪并 [1’,2’:4,5]吡嗪并[2,3-c][1,8]萘啶-3-羧酸叔丁酯(250mg，0.37mmol)，4mL丙酮，无水碳酸钾(103.9mg,0.74mmol)，碘甲烷(246mg，1.70mmol)。密封封管，反应在50℃搅拌18小时。反应液加入30mL乙酸乙酯，依次用12mL水，15mL饱和食盐水洗涤，干燥浓缩得产物(2R,4aR)-11-氟-10-(2-氟-6-甲氧基苯基)-8-(3-异丙基-1,5-二甲基-1H-吡唑-4-基)-2,6-二甲基-5,7-二氧代-1,2,4,4a,5,6,7,8-八氢-3H-吡嗪并[1’,2’:4,5]吡嗪并[2,3-c][1,8]萘啶-3-羧酸叔丁酯(230mg,Y:90％)，黄色固体。ES-API:[M+H] +＝678.3。
步骤8：(2R,4aR)-11-氟-10-(2-氟-6-甲氧基苯基)-8-(3-异丙基-1,5-二甲基-1H-吡唑-4-基)-2,6-二甲基-5,7-二氧代-1,2,4,4a,5,6,7,8-八氢-3H-吡嗪并[1’,2’:4,5]吡嗪并[2,3-c][1,8]萘啶-3-羧酸叔丁酯(230mg,0.34mmol)溶于二氯甲烷(3mL)，加入三氟乙酸(2mL)。室温搅拌2小时，反应液浓缩得产物(2R,4aR)-11-氟-10-(2-氟-6-甲氧基苯基)-8-(3-异丙基-1,5-二甲基-1H-吡唑-4-基)-2,6-二甲基-2,3,4,4a,6,8-六氢-1H-吡嗪并[1’,2’:4,5]吡嗪并[2,3-c][1,8]萘啶-5,7-二酮(230mg,粗品)，直接用于下一步反应。ES-API:[M+H] +＝578.2。
步骤9：(2R,4aR)-11-氟-10-(2-氟-6-甲氧基苯基)-8-(3-异丙基-1,5-二甲基-1H-吡唑-4-基)-2,6-二甲基-2,3,4,4a,6,8-六氢-1H-吡嗪并[1’,2’:4,5]吡嗪并[2,3-c][1,8]萘啶-5,7-二酮(230mg，粗品)溶于二氯甲烷(5mL)，加入N,N-二异丙基乙胺(110mg，0.85mmol)。将反应冷至0℃，向反应液中滴加丙烯酰氯(31mg，0.34mmol)。反应在0℃搅拌15分钟。向反应液中加入25mL二氯甲烷，依次用15mL水，15mL饱和NaHCO 3水溶液，15mL饱和食盐水洗涤，干燥浓缩，干燥后浓缩，粗品用快速硅胶柱纯化(EtOAc/PE：0-100％)得产物(2R,4aR)-3-丙烯酰基-11-氟-10-(2-氟-6-甲氧基苯基)-8-(3-异丙基-1,5-二甲基-1H-吡唑-4-基)-2，6-二甲基-2,3,4,4a,6,8-六氢-1H-吡嗪并[1’,2’:4,5]吡嗪并[2,3-c][1,8]萘啶-5,7-二酮(190mg,Y:81.3％)，淡黄色固体。ES-API:[M+H] +＝632.2。
步骤10：(2R,4aR)-3-丙烯酰基-11-氟-10-(2-氟-6-甲氧基苯基)-8-(3-异丙基-1,5-二甲基-1H-吡唑-4-基)-2，6-二甲基-2,3,4,4a,6,8-六氢-1H-吡嗪并[1’,2’:4,5]吡嗪并[2,3-c][1,8]萘啶-5,7-二酮(190mg，0.3mmol)溶于二氯甲烷(1.5mL)。将反应冷至0℃，向其中滴加17％三溴化硼的二氯甲烷溶液(5mL)。反应在室温下搅拌4小时。将反应液倒入40mL饱和NaHCO 3水溶液，用25mL二氯甲烷萃取2次。有机相干燥后浓缩，粗品用制备HPLC纯化得产物(2R,4aR)-3-丙烯酰基-11-氟-10-(2-氟-6-羟基苯基)-8-(3-异丙基-1,5-二甲基-1H-吡唑-4-基)-2,6-二甲基-2,3,4,4a,6,8-六氢-1H-吡嗪并[1’,2’:4,5]吡嗪并[2,3-c][1,8]萘啶-5,7-二酮(Z47，60mg,Y：31.5％)，淡黄色固体。 1H NMR(500MHz,DMSO-d 6)δ10.16(d,J＝3.7Hz,1H),7.93(t,J＝9.5Hz,1H),7.30(dd,J＝15.5,8.1Hz,1H),7.02(dd,J＝16.8,10.6Hz,1H),6.80–6.69(m,2H),6.15(t,J＝13.1Hz,1H),5.78–5.69(m,1H),4.76(s,1H),4.59(dd,J＝13.9,6.2Hz,1H),3.90(d,J＝18.9Hz,1H),3.72(dd,J＝19.5,4.3Hz,4H),3.26(s,1H),2.75(d,J＝7.7Hz,1H),2.63–2.57(m,1H),2.44–2.39(m,1H),1.91(d,J＝70.7Hz,3H),1.59–1.47(m,3H),0.95(ddd,J＝34.1,17.0,5.2Hz,6H).ES-API:[M+H] +＝618.3。
实施例48制备化合物Z48，Z48’-1和Z48’-2
Figure PCTCN2020124226-appb-000130
步骤1：将6,7-二氯-1-(4,6-二异丙基嘧啶-5-基)-4-羟基-2-氧代-1,2-二氢-1,8-萘啶-3-甲腈(2g,12mmol)悬浮于1，4-二氧六环(12mL)，缓慢加入浓硫酸(12mL)和水(12mL)的混合液。反应120℃下搅拌过夜，将冷却后的反应液中倒入50mL冰水中，用氢氧化钾水溶液调pH＝6，乙酸乙酯(50mL*3)萃取，有机相干燥后浓缩,得到目标产物6,7-二氯-1-(4,6-二异丙基嘧啶-5-基)-4-羟基-1,8-萘啶-2(1H)-酮(1.5g,Y:80％)，淡黄色固体。ES-API:[M+H] +＝393.1
步骤2：6,7-二氯-1-(4,6-二异丙基嘧啶-5-基)-4-羟基-1,8-萘啶-2(1H)-酮(1.50g，3.81mmol)溶于乙酸(5mL)，依次加入亚硝酸钠(26mg,0.38mmol)和浓硝酸(721mg，11.44mmol)，室温下搅拌20分钟。将反应液中倒入5mL水中，析出黄色固体，过滤，滤饼用5ml水洗涤，在真空下干燥得到目标产物6,7-二氯-1-(4,6-二异丙基嘧啶-5-基)-4-羟基-3-硝基-1,8-萘啶-2(1H)-酮(1.1g，Y:66％)，淡黄色固体。ES-API:[M+H] +＝438.1
步骤3：6,7-二氯-1-(4,6-二异丙基嘧啶-5-基)-4-羟基-3-硝基-1,8-萘啶-2(1H)-酮(1.1g， 2.51mmol),(2-氟-6-甲氧基苯基)硼酸(1.28g,7.53mmol),氯(2-二环己基膦基-2',6'-二甲氧基-1,1'-联苯基)(2'-氨基-1,1'-联苯-2-基)钯(II)(166mg,0.23mmol)，2-双环己基膦-2',6'-二甲氧基联苯(94mg，0.23mmol)，磷酸钾(1.45g,6.85mmol)的2mL水和10mL二氧六环混合液在氮气保护下80℃搅拌1小时。将反应液倒入30mL水中，甲基叔丁基醚(30mL*2)洗涤，水相用3.0M稀盐酸调pH＝6.0后，用乙酸乙酯(50mL*3)萃取，有机相干燥后浓缩得到目标产物6-氯-1-(4,6-二异丙基嘧啶-5-基)-7-(2-氟-6-甲氧基苯基)-4-羟基-3-硝基-1,8-萘啶-2(1H)-酮和7-氯-1-(4,6-二异丙基嘧啶-5-基)-6-(2-氟-6-甲氧基苯基)-4-羟基-3-硝基-1,8-萘啶-2(1H)-酮的混合物(1.1g,Y:83％，P1:P2＝55:45)。ES-API:[M+H] +＝528.1。
步骤4：往混合物6-氯-1-(4,6-二异丙基嘧啶-5-基)-7-(2-氟-6-甲氧基苯基)-4-羟基-3-硝基-1,8-萘啶-2(1H)-酮和7-氯-1-(4,6-二异丙基嘧啶-5-基)-6-(2-氟-6-甲氧基苯基)-4-羟基-3-硝基-1,8-萘啶-2(1H)-酮(1.1g，2.08mmol)的乙腈(15mL)溶液中依次加入三氯氧磷(1.6g，10.42mmol)和N,N-二异丙基乙胺(2.15g，16.67mmol)，80℃下搅拌1小时。将反应液浓缩，加入50mL乙酸乙酯，依次用30mL饱和碳酸氢钠洗涤2次，30mL水和30mL饱和食盐水洗涤。有机相干燥浓缩后，粗品用快速硅胶柱(0-50％乙酸乙酯/石油醚)纯化得到4,6-二氯-1-(4,6-二异丙基嘧啶-5-基)-7-(2-氟-6-甲氧基苯基)-3-硝基-1,8-萘啶-2(1H)-酮和4,7-二氯-1-(4,6-二异丙基嘧啶-5-基)-6-(2-氟-6-甲氧基苯基)-3-硝基-1,8-萘啶-2(1H)-酮的混合物(750mg,Y:61％)，淡黄色固体。ES-API:[M+H] +＝546.1。
步骤5：将4,6-二氯-1-(4,6-二异丙基嘧啶-5-基)-7-(2-氟-6-甲氧基苯基)-3-硝基-1,8-萘啶-2(1H)-酮和4,7-二氯-1-(4,6-二异丙基嘧啶-5-基)-6-(2-氟-6-甲氧基苯基)-3-硝基-1,8-萘啶-2(1H)-酮的混合物(750mg,1.37mmol)溶于N,N-二甲基乙酰胺(7.5mL),依次加入1-(叔丁基)3-甲基(R)-哌嗪-1,3-二羧酸酯(1.01g，4.12mmol)和N,N-二异丙基乙胺(530mg，4.12mmol)，120℃搅拌2小时。冷却后往反应液中加入100mL乙酸乙酯，用50mL碳酸氢钠洗涤2次，50mL稀盐水洗涤2次，50ml水洗涤一次，50mL饱和食盐水洗涤一次，干燥浓缩，得到1-(叔丁基)3-甲基(3R)-4-(6-氯-1-(4,6-二异丙基嘧啶-5-基)-7-(2-氟-6-甲氧基苯基)-3-硝基-2-氧代-1,2-二氢-1,8-萘啶-4-基)哌嗪-1,3-二羧酸酯和1-(叔丁基)3-甲基(3R)-4-(7-氯-1-(4,6-二异丙基嘧啶-5-基)-6-(2-氟-6-甲氧基苯基)-3-硝基-2-氧代-1,2-二氢-1,8-萘啶-4-基)哌嗪-1,3-二羧酸酯的混合物(800mg)。ES-API:[M+H] +＝754.2。
步骤6：将1-(叔丁基)3-甲基(3R)-4-(6-氯-1-(4,6-二异丙基嘧啶-5-基)-7-(2-氟-6-甲氧基苯基)-3-硝基-2-氧代-1,2-二氢-1,8-萘啶-4-基)哌嗪-1,3-二羧酸酯和1-(叔丁基)3-甲基(3R)-4-(7-氯-1-(4,6-二异丙基嘧啶-5-基)-6-(2-氟-6-甲氧基苯基)-3-硝基-2-氧代-1,2-二氢-1,8-萘啶-4-基)哌嗪-1,3-二羧酸酯的混合物(800mg,1.06mmol)溶于乙酸(8mL)，加入铁粉(207mg,3.71mmol),80℃搅拌1小时。反应液浓缩，加入50mL乙酸乙酯，用饱和碳酸氢钠溶液调节pH＝8，悬浮液用硅藻土过滤，滤饼用乙酸乙酯洗涤，有机相分离，依次用25mL饱和碳酸氢钠，25mL饱和食盐水洗涤，干燥浓缩，快速硅胶柱(0-80％乙酸乙酯/石油醚)纯化得到叔丁基(4aR)-11-氯-8-(4,6-二异丙基嘧啶-5-基)-10-(2-氟-6-甲氧基苯基)-5,7-二氧-1,2,4,4a,5,6,7,8-八氢-3H-吡嗪并[1',2':4,5]吡嗪并[2,3-c][1,8]萘啶-3-羧酸酯和叔丁基(4aR)-10-氯-8-(4,6-二异丙基嘧啶-5-基)-11-(2-氟-6-甲氧基苯基)-5,7-二氧-1,2,4,4a,5,6,7,8-八氢-3H-吡嗪并[1',2':4,5]吡嗪并[2,3-c][1,8]萘啶-3-羧酸酯混合物(350mg,Y:48％)，黄色固体。ES-API:[M+H] +＝692.3。
步骤7：向15mL封管中依次加入叔丁基(4aR)-11-氯-8-(4,6-二异丙基嘧啶-5-基)-10-(2-氟-6-甲氧基苯基)-5,7-二氧-1,2,4,4a,5,6,7,8-八氢-3H-吡嗪并[1',2':4,5]吡嗪并[2,3-c][1,8]萘啶-3-羧酸酯和叔丁基(4aR)-10-氯-8-(4,6-二异丙基嘧啶-5-基)-11-(2-氟-6-甲氧基苯基)-5,7-二氧-1,2,4,4a,5,6,7,8-八氢-3H-吡嗪并[1',2':4,5]吡嗪并[2,3-c][1,8]萘啶-3-羧酸酯混合物(350mg，0.51mmol)，丙酮(5mL)，无水碳酸钾(209mg,1.52mmol)，碘甲烷(718mg，5.06mmol)。密封封管，反应在50℃搅拌过夜。反应液过滤，浓缩，得到叔丁基(4aR)-11-氯-8-(4,6-二异丙基嘧啶-5-基)-10-(2-氟-6-甲氧基苯基)-6-甲基-5,7-二氧-1,2,4,4a,5,6,7,8-八氢-3H-吡嗪并[1',2':4,5]吡嗪并[2,3-c][1,8]萘啶-3-羧酸酯和叔丁基(4aR)-10-氯-8-(4,6-二异丙基嘧啶-5-基)-11-(2-氟-6-甲氧基苯基)-6-甲基-5,7-二氧-1,2,4,4a,5,6,7,8-八氢-3H-吡嗪并[1',2':4,5]吡嗪并[2,3-c][1,8]萘啶-3-羧酸酯混合物(350mg)，黄色固体。ES-API:[M+H] +＝706.3
步骤8：将叔丁基(4aR)-11-氯-8-(4,6-二异丙基嘧啶-5-基)-10-(2-氟-6-甲氧基苯基)-6-甲基-5,7-二氧-1,2,4,4a,5,6,7,8-八氢-3H-吡嗪并[1',2':4,5]吡嗪并[2,3-c][1,8]萘啶-3-羧酸酯和叔丁基(4aR)-10-氯-8-(4,6-二异丙基嘧啶-5-基)-11-(2-氟-6-甲氧基苯基)-6-甲基-5,7-二氧-1,2,4,4a,5,6,7,8-八氢-3H-吡嗪并[1',2':4,5]吡嗪并[2,3-c][1,8]萘啶-3-羧酸酯混合物(350mg,0.50mmol)溶于二氯甲烷(8mL)，加入三氟乙酸(2mL)。室温搅拌2小时，反应液浓缩得到(4aR)-11-氯-8-(4,6-二异丙基嘧啶-5-基)-10-(2-氟-6-甲氧基苯基)-6-甲基-2,3,4,4a,6,8-六氢-1H-吡嗪并[1',2':4,5]吡嗪并[2,3-c][1,8]萘啶-5,7-二酮和(4aR)-10-氯-8-(4,6-二异丙基嘧啶-5-基)-11-(2-氟-6-甲氧基苯基)-6-甲基-2,3,4,4a,6,8-六氢-1H-吡嗪并[1',2':4,5]吡嗪并[2,3-c][1,8]萘啶-5,7-二酮的混合物(300mg,P1:P2＝53:47)，直接用于下一步反应。ES-API:[M+H] +＝606.3
步骤9：((4aR)-11-氯-8-(4,6-二异丙基嘧啶-5-基)-10-(2-氟-6-甲氧基苯基)-6-甲基-2,3,4,4a,6,8-六氢-1H-吡嗪并[1',2':4,5]吡嗪并[2,3-c][1,8]萘啶-5,7-二酮和(4aR)-10-氯-8-(4,6-二异丙基嘧啶-5-基)-11-(2-氟-6-甲氧基苯基)-6-甲基-2,3,4,4a,6,8-六氢-1H-吡嗪并[1',2':4,5]吡嗪并[2,3-c][1,8]萘啶-5,7-二酮的混合物(300mg，0.50mmol)溶于二氯甲烷(3mL)，加入N,N-二异丙基乙胺(320mg，2.45mmol)。将反应冷至0℃，向反应液中滴加丙烯酰氯(90mg，0.99mmol)。反应液在0℃搅拌5分钟，浓缩，粗品用快速硅胶柱纯化(0-80％乙酸乙酯/石油醚)得到(4aR)-3-丙烯酰基-11-氯-8-(4,6-二异丙基嘧啶-5-基)-10-(2-氟-6-甲氧基苯基)-6-甲基-2,3,4,4a,6,8-六氢-1H-吡嗪并[1',2':4,5]吡嗪并[2,3-c][1,8]萘啶-5,7-二酮和(4aR)-3-丙烯酰基-10-氯-8-(4,6-二异丙基嘧啶-5-基)-11-(2-氟-6-甲氧基苯基)-6-甲基-2,3,4,4a,6,8-六氢-1H-吡嗪并[1',2':4,5]吡嗪并[2,3-c][1,8]萘啶-5,7-二酮的混合物(250mg,Y:77％)，淡黄色固体。ES-API:[M+H] +＝662.3。
步骤10：将(4aR)-3-丙烯酰基-11-氯-8-(4,6-二异丙基嘧啶-5-基)-10-(2-氟-6-甲氧基苯基)-6-甲基-2,3,4,4a,6,8-六氢-1H-吡嗪并[1',2':4,5]吡嗪并[2,3-c][1,8]萘啶-5,7-二酮和(4aR)-3-丙烯酰基-10-氯-8-(4,6-二异丙基嘧啶-5-基)-11-(2-氟-6-甲氧基苯基)-6-甲基-2,3,4,4a,6,8-六氢-1H-吡嗪并[1',2':4,5]吡嗪并[2,3-c][1,8]萘啶-5,7-二酮的混合物(250mg，0.38mmol)溶于二氯甲烷(3mL)。将反应冷至0℃，向其中滴加17％三溴化硼的二氯甲烷溶液(3mL)，室温下搅拌过夜。将反应液倒入40mL饱和碳酸氢钠水溶液，用25mL二氯甲烷萃取2次。有机相干燥后浓缩，粗品用制备HPLC纯化得到：化合物Z48(14.2mg， P:100％，保留时间:9.94min,Y：6％)，淡黄色固体，ES-API:[M+H]+＝646.2； 1H NMR(500MHz,DMSO-d 6)δ10.04(d,J＝20Hz,1H),9.10(s,1H),8.54(d,J＝7.5Hz,1H),7.28–7.17(m,1H),7.14–6.77(m,1H),6.73–6.68(m,1H),6.68–6.63(m,1H),6.21–6.11(m,1H),5.79–5.71(m,1H),5.15–4.66(m,1H),4.51–4.02(m,1H),3.99(s,1H),3.66–3.53(m,2H),3.32(s,3H),3.27-3.18(m,1H),2.84–2.74(m,1H),2.74–2.61(m,1H),2.52–2.46(m,1H),1.10(d,J＝7Hz,3H),1.04(d,J＝6.5Hz,3H),0.99(dd,J＝10.5,7Hz,3H),0.86(dd,J＝15.5,6.5Hz,3H).ES-API:[M+H] +＝646.2。化合物Z48’-1(16.5mg，P:96％，保留时间:10.13min,Y：7％)，淡黄色固体，ES-API:[M+H]+＝646.2；化合物Z48’-2(17.5mg，P:100％，保留时间：10.36min,Y：7％)，淡黄色固体，ES-API:[M+H]+＝646.2。
实施例49制备化合物Z49、Z49-1和Z49-2
Figure PCTCN2020124226-appb-000131
化合物Z49以7-氯-6-氟-4-羟基-1-(2-异丙基-4-(三氟甲基)吡啶-3-基)-3-硝基-1,8-萘啶-2(1H)-酮为原料参照化合物Z33的方法合成。ES-API:[M+H] +＝669.2。将化合物Z49通过制备型手性HPLC拆分(柱型:IB 10μm,30*250mm；流动相:己烷:EtOH＝80:20；流速:25mL/min；柱温室温)得到：一个阻转异构体化合物，结构任意指定为Z49-1(71mg，峰1，保留时间7.68min，de值：100％)。 1H NMR(500MHz,DMSO-d 6)δ10.14(d,J＝1.4Hz,1H),8.92(d,J＝4.9Hz,1H),8.00(dd,J＝16.4,8.6Hz,1H),7.76(d,J＝5.0Hz,1H),7.25(dd,J＝15.3,8.3Hz,1H),6.94(ddd,J＝72.2,16.7,10.5Hz,1H),6.71(d,J＝8.3Hz,1H),6.66(t,J＝8.8Hz,1H),6.22–6.09(m,1H),5.79–5.69(m,1H),5.06–4.72(m,1H),4.53(t,J＝45.4Hz,1H),4.02–3.90(m,1H),3.75(dd,J＝14.1,4.1Hz,1H),3.45(d,J＝11.9Hz,1H),3.34(s,3H),2.93(dd,J＝13.3,6.6Hz,1H),2.90–2.85(m,1H),1.55(dd,J＝19.2,6.8Hz,3H),1.14(d,J＝6.7Hz,3H),1.04(d,J＝6.6Hz,3H).ES-API:[M+H] +＝669.1。和另一个阻转异构体化合物，结构任意指定为Z49-2(80mg，峰2，保留时间9.79min,de值：99.85％)。 1H NMR(500MHz,DMSO-d 6)δ10.15(s,1H),8.92(d,J＝5.0Hz,1H),8.01(dd,J＝14.5,8.5Hz,1H),7.78(d,J＝5.0Hz,1H),7.25(dd,J＝15.2,8.2Hz,1H),6.94(ddd,J＝82.1,16.7,10.7Hz,1H),6.71(d,J＝8.3Hz,1H),6.66(t,J＝8.8Hz,1H),6.15(dt,J＝16.9,3.9Hz,1H),5.79–5.69(m,1H),5.11–4.69(m,1H),4.54(t,J＝56.0Hz,1H),4.15–3.97(m,1H),3.74(dd,J＝14.2,4.3Hz,1H),3.44(d,J＝11.6Hz,1H),3.28(s,3H),2.88(dd,J＝40.3,9.5Hz,1H),2.66–2.56(m,1H),1.54(dd,J＝19.8,6.6Hz,3H),1.07(d,J＝6.6Hz,3H),0.92(d,J＝6.7Hz,3H).ES-API:[M+H] +＝669.1。异构体化合物通过分析型手性HPLC方法(柱型:IB 5μm,4.6*250mm；流动相:己烷:EtOH＝80:20；流速:1mL/min；柱温＝30℃)进行检测。
实施例50制备化合物Z50、Z50-1和Z50-2
Figure PCTCN2020124226-appb-000132
步骤1：7-溴-4,6-二氯-1-(4,6-二异丙基嘧啶-5-基)-8-氟-3-硝基喹啉-2(1H)-酮(450mg,0.87mmol)溶于N,N-二甲基乙酰胺(6mL)，依次加入(3R,6R)-1-N-BOC-6-甲基哌嗪-3-甲酸甲酯(404mg,1.57mmol)，和N,N-二异丙基乙胺(0.45mL,2.61mmol)，反应在120℃搅拌1小时。反应液中加入100mL乙酸乙酯，用30mL稀盐水洗涤4次，30mL饱和食盐水洗涤，干燥浓缩得产物(3R,6R)-1-(叔丁基)3-甲基-4-(7-溴-6-氯-1-(4,6-二异丙基嘧啶-5-基)-8-氟-3-硝基-2-氧代-1,2-二氢喹啉-4-基)-6-甲基哌嗪-1,3-二羧酸酯(770mg,粗品)，直接投下一步。ES-API:[M+H] +＝739.2，741.1。
步骤2：(3R,6R)-1-(叔丁基)3-甲基-4-(7-溴-6-氯-1-(4,6-二异丙基嘧啶-5-基)-8-氟-3-硝基-2-氧代-1,2-二氢喹啉-4-基)-6-甲基哌嗪-1,3-二羧酸酯(777mg,粗品)溶于乙酸(8mL)，加入铁粉(170mg,3.05mmol),反应在80℃搅拌30分钟。反应液浓缩，依次加入100mL乙酸乙酯和60mL饱和碳酸氢钠，悬浮液用硅藻土过滤，滤饼用乙酸乙酯洗涤，有机相分离，依次用40mL饱和碳酸氢钠，40mL饱和食盐水洗涤，干燥浓缩得产物(2R,4aR)-10-溴-11-氯-8-(4,6-二异丙基嘧啶-5-基)-9-氟-2-甲基-5,7-二氧代-1,2,4,4a,5,6,7,8-八氢-3H-吡嗪[1’,2’:4,5]吡嗪[2,3-c]喹啉-3-羧酸叔丁酯(700mg,粗品)，淡棕色固体。ES-API:[M+H]+＝677.2，679.2。
步骤3：向50mL封管中依次加入(2R,4aR)-10-溴-11-氯-8-(4,6-二异丙基嘧啶-5-基)-9-氟-2-甲基-5,7-二氧代-1,2,4,4a,5,6,7,8-八氢-3H-吡嗪[1’,2’:4,5]吡嗪[2,3-c]喹啉-3-羧酸叔丁酯(700mg，粗品)，20mL丙酮，无水碳酸钾(480mg,3.48mmol)，碘甲烷(1.24g，8.70mmol)。密封封管，反应在50℃搅拌18小时。反应液加入80mL乙酸乙酯，依次用20mL水，30mL饱和食盐水洗涤，干燥浓缩，粗品用快速硅胶柱纯化(EtOAc/PE：0-25％)得产物(2R,4aR)-10-溴-11-氯-8-(4,6-二异丙基嘧啶-5-基)-9-氟-2,6-二甲基-5,7-二氧代-1,2,4,4a,5,6,7,8-八氢-3H-吡嗪[1’,2’:4,5]吡嗪[2,3-c]喹啉-3-羧酸叔丁酯(350mg,三步Y:58.2％)，黄色固体。ES-API:[M+H] +＝691.1，693.2。
步骤4：向100mL圆底烧瓶中加入(2R,4aR)-10-溴-11-氯-8-(4,6-二异丙基嘧啶-5-基)-9-氟-2,6-二甲基-5,7-二氧代-1,2,4,4a,5,6,7,8-八氢-3H-吡嗪[1’,2’:4,5]吡嗪[2,3-c]喹啉-3-羧酸叔丁酯(325mg,0.47mmol)、(2-氟-6-羟基苯基)硼酸(293mg,1.88mmol)、氯(2-二环己基膦-2′,6′-二甲氧基-1,1′-联苯)[2-(2′-氨基-1,1′-联苯)]钯(II)(34mg,0.047mmol)、2-二环己基膦基-2′,6′-二甲氧基联苯基(19mg,0.047mmol)、磷酸钾(398mg,1.88mmol)、3 mL水和15mL二氧六环。氮气保护下，反应在90℃搅拌4小时。反应液浓缩，加入60mL乙酸乙酯，依次用10mL水，15mL饱和食盐水洗涤，干燥浓缩，粗品用快速硅胶柱纯化(EtOAc/PE：0-50％)得产物(2R,4aR)-11-氯-8-(4,6-二异丙基嘧啶-5-基)-9-氟-10-(2-氟-6-羟基苯基)-2,6-二甲基-5,7-二氧代-1,2,4,4a,5,6,7,8-八氢-3H-吡嗪[1’,2’:4,5]吡嗪[2,3-c]喹啉-3-羧酸叔丁酯(220mg,Y:64.8％)，黄色固体。ES-API:[M+H] +＝723.3。
步骤5：(2R,4aR)-11-氯-8-(4,6-二异丙基嘧啶-5-基)-9-氟-10-(2-氟-6-羟基苯基)-2,6-二甲基-5,7-二氧代-1,2,4,4a,5,6,7,8-八氢-3H-吡嗪[1’,2’:4,5]吡嗪[2,3-c]喹啉-3-羧酸叔丁酯(220mg,0.30mmol)溶于二氯甲烷(4mL)，加入三氟乙酸(1mL)。室温搅拌2小时，反应液浓缩得产物(2R,4aR)-11-氯-8-(4,6-二异丙基嘧啶-5-基)-9-氟-10-(2-氟-6-羟基苯基)-2,6-二甲基-2,3,4,4a,6,8-六氢-1H-吡嗪[1’,2’:4,5]吡嗪[2,3-c]喹啉-5,7-二酮(240mg,粗品)，直接用于下一步反应。ES-API:[M+H] +＝623.3。
步骤6：(2R,4aR)-11-氯-8-(4,6-二异丙基嘧啶-5-基)-9-氟-10-(2-氟-6-羟基苯基)-2,6-二甲基-2,3,4,4a,6,8-六氢-1H-吡嗪[1’,2’:4,5]吡嗪[2,3-c]喹啉-5,7-二酮(240mg，粗品)溶于二氯甲烷(6mL)，加入N,N-二异丙基乙胺(194mg，1.50mmol)。将反应冷至0℃，向反应液中滴加丙烯酰氯(24mg，0.27mmol)。反应在0℃搅拌15分钟。向反应液中加入50mL二氯甲烷，依次用15mL水，15mL饱和NaHCO 3水溶液，15mL饱和食盐水洗涤，干燥后浓缩得产物(2R,4aR)-11-氯-8-(4,6-二异丙基嘧啶-5-基)-9-氟-10-(2-氟-6-羟基苯基)-2,6-二甲基-2,3,4,4a,6,8-六氢-1H-吡嗪[1’,2’:4,5]吡嗪[2,3-c]喹啉-5,7-二酮(Z50)，用制备HPLC纯化得到：一个阻转异构体化合物，结构任意指定为Z50-1(保留时间：10.433min；55mg,Y:26.7％)，白色固体。 1H NMR(400MHz,DMSO-d 6)δ10.21(d,J＝1.7Hz,1H),9.13(s,1H),7.89-7.88(m,1H),7.27(dd,J＝15.4,8.3Hz,1H),7.02(dd,J＝16.8,10.6Hz,1H),6.75-6.69(m,2H),6.19-6.11(m,1H),5.78-5.70(m,1H),4.84-4.75(m,1H),4.60(d,J＝13.6Hz,1H),4.06-3.97(m,1H),3.78-3.70(m,1H),3.31-3.25(m,4H),2.99–2.90(m,1H),2.81-2.73(m,1H),2.61-2.55(m 1H),1.48-1.58(m,3H),1.18–0.86(m,12H).ES-API:[M+H] +＝677.2。和另一个阻转异构体化合物，结构任意指定为Z50-2(保留时间：10.752min；85mg,Y:41.2％)，白色固体。 1H NMR(400MHz,DMSO-d 6)δ10.22(s,1H),9.13(s,1H),7.89-7.88(m,1H),7.27(dd,J＝15.5,8.1Hz,1H),7.02(dd,J＝16.8,10.7Hz,1H),6.76-6.69(m,2H),6.20–6.09(m,1H),5.80-5.70(m,1H),3.83-3.73(m,1H),4.60(d,J＝14.0Hz,1H),4.06-3.97(m,1H),3.82–3.66(m,1H),3.31-3.22(m,4H),3.02–2.88(m,1H),2.83-2.74(m,1H),2.61-2.52(m,1H),1.66–1.49(m,3H),1.21–1.01(m,9H),0.99–0.83(m,3H).ES-API:[M+H] +＝677.2。异构体化合物用分析型HPLC方法检测。
实施例51至实施例342的化合物参照上述实施例的合成方法制备得到。
Figure PCTCN2020124226-appb-000133
Figure PCTCN2020124226-appb-000134
Figure PCTCN2020124226-appb-000135
Figure PCTCN2020124226-appb-000136
Figure PCTCN2020124226-appb-000137
Figure PCTCN2020124226-appb-000138
Figure PCTCN2020124226-appb-000139
Figure PCTCN2020124226-appb-000140
Figure PCTCN2020124226-appb-000141
Figure PCTCN2020124226-appb-000142
Figure PCTCN2020124226-appb-000143
Figure PCTCN2020124226-appb-000144
Figure PCTCN2020124226-appb-000145
Figure PCTCN2020124226-appb-000146
Figure PCTCN2020124226-appb-000147
Figure PCTCN2020124226-appb-000148
Figure PCTCN2020124226-appb-000149
Figure PCTCN2020124226-appb-000150
Figure PCTCN2020124226-appb-000151
Figure PCTCN2020124226-appb-000152
Figure PCTCN2020124226-appb-000153
Figure PCTCN2020124226-appb-000154
Figure PCTCN2020124226-appb-000155
Figure PCTCN2020124226-appb-000156
Figure PCTCN2020124226-appb-000157
Figure PCTCN2020124226-appb-000158
Figure PCTCN2020124226-appb-000159
Figure PCTCN2020124226-appb-000160
Figure PCTCN2020124226-appb-000161
Figure PCTCN2020124226-appb-000162
Figure PCTCN2020124226-appb-000163
Figure PCTCN2020124226-appb-000164
Figure PCTCN2020124226-appb-000165
Figure PCTCN2020124226-appb-000166
Figure PCTCN2020124226-appb-000167
Figure PCTCN2020124226-appb-000168
Figure PCTCN2020124226-appb-000169
Figure PCTCN2020124226-appb-000170
Figure PCTCN2020124226-appb-000171
Figure PCTCN2020124226-appb-000172
Figure PCTCN2020124226-appb-000173
Figure PCTCN2020124226-appb-000174
Figure PCTCN2020124226-appb-000175
Figure PCTCN2020124226-appb-000176
测试例1细胞增殖抑制实验
NCI-H358为Kras G12C突变的人非小细胞肺癌细胞株，培养于10％FBS RPMI-1640培养基中；A549为Kras G12S突变的人肺腺癌细胞株，培养于10％FBS F-12K培养基中。取对数生长期的细胞，胰酶EDTA消化细胞收集计数并使用2％FBS RPMI-1640培养基将H358调整至1.8E4细胞/ml，用2％FBS F-12K培养基将A549调整至8.9E3细胞/ml；分别接种800个(45μl)H358或400个(45μl)A549细胞于384孔球体板中，培养过夜建立3D细胞模型。使用DMSO配制1000X的化合物3.16倍梯度浓度储液，使用2％FBS培养基稀释100倍至10X化合物储液，于细胞接种后的第二天，每个细胞培养孔加入5μl  10X化合物储液，终浓度为1X，DMSO含量为0.1％。使用DMSO作为实验对照(control)，2％FBS培养基作为空白对照(blank)。加入化合物细胞培养5天后，每孔加入25μl CellTiter-Glo工作液，400rpm混匀孵育30分钟,室温静止30分钟后转移40μl混液到白色底透384孔板中，读取luminescence化学发光值，计算细胞增殖抑制率IR(％)＝(RLU对照-RLU化合物)/(RLU对照-RLU空白)×100％，使用Prism 6四参数法拟合化合物梯度稀释浓度和对应的细胞增殖抑制率，计算出IC 50值。从结果可知，本发明的示例化合物对Kras G12C突变的NCI-H358细胞具有较高的抑制活性，其IC 50低于1000nM；或低于500nM，或低于100nM；而对A549细胞的抑制活性较低，其IC 50超过5000nM。示例化合物的结果如下表1所示。
表1化合物对H358和A549细胞的抑制活性
化合物编号 H358 IC 50(μM) A549 IC 50(μM) 化合物编号 H358 IC 50(μM) A549 IC 50(μM)
Z1 0.031 >10 Z31 0.017 9.494
Z2 0.773 >10 Z32 0.064 >30
Z1-1 0.031 10.716 Z33-1 0.074 >30
Z1-2 0.198 16.482 Z33-2 0.034 >30
Z3a 0.017 >10 Z34-1 0.078 >30
Z3 0.016 >10 Z34-2 0.007 >30
Z6 0.035 11.312 Z35 0.006 28.208
Z9 0.032 - Z35-1 0.037 >30
Z9-1 0.218 >10 Z35-2 0.006 >30
Z9-2 0.015 >10 Z36-1 0.588 >30
Z10 0.008 12.125 Z36-2 0.018 28.025
Z10-1 0.070 >10 Z37 0.001 8.572
Z10-2 0.004 24.640 Z37-1 0.0007 >30
Z21 0.023 >30 Z37-2 0.165 3.322
Z21-1 0.027 >30 Z38-1 0.007 >30
Z21-2 0.407 >30 Z38-2 0.513 >30
Z22 0.067 >30 Z39-1 0.0006 >30
Z23 0.002 10.482 Z39-2 0.316 7.781
Z24 0.003 28.067 Z40 0.011 >30
Z24-1 0.028 >30 Z41 0.017 >30
Z24-2 0.003 11.308 Z42 0.053 >30
Z25 0.004 28.332 Z43 0.049 29.234
Z25-1 0.050 >30 Z44a 0.024 9.237
Z25-2 0.003 >30 Z44 0.011 >30
Z26 0.002 12.856 Z45 0.013 >30
Z26-1 0.042 >30 Z46 0.012 10.306
Z26-2 0.003 >30 Z47 0.031 >30
Z27 0.002 10.123 Z48 0.003 >10
Z27-1 0.012 12.705 Z49-1 0.009 9.417
Z27-2 0.001 18.995 Z49-2 0.044 >30
Z28 0.090 16.881 Z50 0.0005 28.289
Z29 0.166 21.794 Z50-1 0.0003 >30
Z30 0.051 >30 Z50-2 0.320 3.872
Z30-1 0.804 >30 Z48’-1 0.828 -
Z30-2 0.047 >30 Z48’-2 ＞1 -
从表1可以看出，本发明的示例化合物对Kras G12C突变的NCI-H358细胞具有较高的抑制活性，而对A549细胞的抑制活性较低，具有明显的选择抑制活性。
测试例2细胞p-ERK检测实验
MIA PaCa2为Kras G12C突变的人胰腺癌细胞株，培养于10％FBS+2.5％Horse serum DMEM培养基中.取对数生长期的细胞，酶EDTA消化细胞收集计数并接种2.5E4个细胞于96孔细胞培养板中，培养过夜。使用DMSO配制1000X的化合物3.16倍梯度浓度储液，使用培养基稀释200倍至5X化合物储液，于细胞接种后的第二天，每个细胞培养孔加入5X化合物储液，终浓度为1X，DMSO含量为0.1％。使用DMSO作为实验对照(control)。加入化合物培养两小时之后，去除残留的培养基。每孔加入50ul cell lysis buffer,混匀孵育30分钟后转移16ul混液至白色底不透的96孔板中，blank孔则加入16ul cell lysis buffer。转移完毕之后每个孔加入4ul p-ERK HTRF抗体混合液，孵育4小时后读取荧光值。计算化合物的抑制率IR(％)＝(RLU对照-RLU化合物)/(RLU对照-RLU空白)×100％，使用Prism 8四参数法拟合化合物梯度稀释浓度和对应的细胞增殖抑制率，计算出IC50值。从结果可知，本发明的示例化合物对Kras G12C蛋白突变的细胞通道下游的磷酸化ERK的水平具有较好的抑制活性，其IC50低于10μΜ；或低于1000nM，或低于100nM。示例化合物的结果如下表2所示。
表2化合物对p-ERK的抑制活性
化合物编号 p-ERK IC50(μM) 化合物编号 p-ERK IC50(μM)
Z1 0.432 Z34-1 0.578
Z1-1 0.512 Z34-2 0.051
Z3a 0.273 Z35 0.083
Z3 0.160 Z35-1 0.249
Z6 0.313 Z35-2 0.049
Z9 0.187 Z36-2 0.188
Z9-2 0.221 Z37 0.021
Z10 0.075 Z37-1 0.011
Z10-1 0.460 Z38-1 0.212
Z10-2 0.034 Z39-1 0.011
Z21 0.271 Z40 0.078
Z21-1 0.428 Z41 0.279
Z23 0.017 Z42 0.566
Z24 0.113 Z43 0.439
Z24-1 0.536 Z44a 0.170
Z24-2 0.061 Z44 0.088
Z25 0.051 Z45 0.122
Z25-2 0.029 Z46 0.224
Z26 0.039 Z48 0.052
Z26-2 0.062 Z49-1 0.114
Z27 0.029 Z50 0.007
Z27-1 0.157 Z50-1 0.006
Z27-2 0.011 Z50-2 0.316
Z30 0.676 Z72 0.106
Z30-2 0.488 Z48’-1 7.477
Z31 0.206 Z48’-2 ＞10
Z33-2 0.238    
测试例3细胞增殖抑制实验
MIA PaCa-2为Kras G12C突变的人胰腺癌细胞株，培养于10％FBS+2.5％Horse Serum DMEM培养基中；A549为Kras G12S突变的人肺腺癌细胞株，培养于10％FBS F-12K培养基中。取对数生长期的细胞，胰酶EDTA消化细胞收集计数分别接种200个MIA PaCa-2或400个A549细胞于384孔球体板中，培养过夜建立3D细胞模型。使用DMSO配制1000X的化合物3.16倍梯度浓度储液，使用培养基稀释100倍至10X化合物储液，于细胞接种后的第二天，每个细胞培养孔加入10X化合物储液，终浓度为1X，DMSO含量为0.1％。使用DMSO作为实验对照(control)，培养基作为空白对照(blank)。加入化合物细胞培养5天后，每孔加入30μl CellTiter-Glo工作液，混匀孵育30分钟,室温静止30分钟后转移40μl混液到白色底不透384孔板中，读取luminescence化学发光值，计算细胞增殖抑制率IR(％)＝(RLU对照-RLU化合物)/(RLU对照-RLU空白)×100％，使用XLFit四参数法拟合化合物梯度稀释浓度和对应的细胞增殖抑制率，计算出IC 50值。从结果可知，本发明的示例化合物对Kras G12C突变的MIA PaCa-2细胞具有较高的抑制活性，其IC 50低于1000nM；或低于100nM，或低于10nM。示例化合物的结果如下表3所示。
表3化合物对MIA-PaCa2的抑制活性
化合物编号 MIA-PaCa2 IC50(μM) 化合物编号 MIA-PaCa2 IC50(μM)
Z1 0.090 Z33-1 0.092
Z1-1 0.095 Z33-2 0.048
Z3a 0.070 Z34-1 0.135
Z3 0.018 Z34-2 0.010
Z6 0.085 Z35 0.015
Z9 0.074 Z36-2 0.133
Z9-2 0.017 Z37 0.004
Z10-2 0.008 Z37-1 0.002
Z21 0.047 Z38-1 0.027
Z21-1 0.046 Z39-1 0.001
Z22 0.180 Z40 0.012
Z23 0.002 Z41 0.044
Z24 0.009 Z42 0.128
Z24-2 0.004 Z43 0.220
Z25 0.008 Z44a 0.103
Z25-2 0.005 Z44 0.034
Z26 0.005 Z45 0.048
Z26-2 0.005 Z46 0.068
Z27 0.004 Z47 0.083
Z27-2 0.001 Z48 0.006
Z28 0.234 Z49-1 0.012
Z30 0.140 Z50 0.002
Z30-2 0.130 Z50-1 0.001
Z31 0.059 Z48’-1 ＞1
Z32 0.170 Z48’-2 ＞1
测试例4 KRas G12C NEA-HTRF实验
使用均相时间分辨荧光(HTRF)方法检测化合物对SOS1催化KRas蛋白上GDP被GTP置换的影响。30μM 6×his标签的KRas G12C重组蛋白与80μM荧光染料DY647标记的GDP在标记缓冲液(1mM DTT,7.5mM EDTA,25mM Tris-HCl,45mM NaCl)中于20℃避光共孵育2小时，使用NAP-5柱子纯化后进行蛋白定量，确定KRas G12C-GDP的浓度。
使用DMSO配制1000×的化合物3.16倍梯度浓度储液，使用反应缓冲液(40mM HEPES,10mM MgCl 2,1mM DTT,0.002％Triton X-100)稀释250倍至4×化合物储液。使用反应缓冲液配制KRas G12C-GDP/Tb工作液(40nM KRas G12C-GDP,1×anti-his Tb)和SOS1/GTP工作液(0.2μM SOS1,200μM GTP)。
取白色底不透的96孔板，每孔加入5μl 4×化合物储液，10μl KRas G12C-GDP/Tb工作液，对照孔使用5μl反应缓冲液代替4×化合物储液，于20℃避光孵育15分钟后，加入5μl SOS1/GTP工作液，20℃避光孵育2小时后读取荧光值(激发波长：320nm，发 射波长：615nm和665nm)。另设置T0组为10μl反应缓冲液+10μl KRas G12C-GDP/Tb工作液，直接读取荧光值。计算荧光信号比RLU＝(665nm信号/615nm信号)×10 4；化合物抑制率IR(％)＝(RLU 化合物-RLU 对照)/(RLU T0-RLU 对照)×100％，使用四参数法拟合化合物梯度稀释浓度和对应的抑制率，计算出IC 50值。结果见表4。
表4
化合物编号 NEA IC50(μM) 化合物编号 NEA IC50(μM)
Z1 0.255 Z27 0.027
Z1-1 0.152 Z27-1 0.198
Z1-2 1.428 Z27-2 0.009
Z9-1 2.571 Z30 0.656
Z9-2 0.115 Z31 0.151
Z10 0.067 Z33-1 0.515
Z10-1 0.708 Z33-2 0.162
Z10-2 0.037 Z35 0.073
Z21 0.388 Z37 0.020
Z21-1 0.172 Z37-1 0.011
Z21-2 3.935 Z37-2 1.898
Z24 0.058 Z38-1 0.053
Z24-1 0.291 Z38-2 2.147
Z24-2 0.038 Z39-2 2.245
Z25 0.060 Z50 0.019
Z25-2 0.025 Z50-1 0.008
Z25-1 0.951 Z50-2 1.450
Z26 0.034    
Z26-1 0.868    
Z26-2 0.040    
测试例5体内药效实验
实验目的：评价受试化合物在人胰腺癌MIA PaCa-2皮下异体移植肿瘤模型上的体内药效
实验操作：雌性BALB/c裸小鼠，6-8周龄，体重18-20克。MIA PaCa-2细胞用DMEM培养基，添加10％FBS，2.5％HS和1％青霉素-链霉素，在37℃，5％CO 2的培养箱中培养，收集细胞，经右侧背部皮下接种MIA PaCa-2细胞(人源胰腺癌细胞)，每只动物接种2.0×10 6个细胞(每只接种0.1mL)。当肿瘤长到190-311mm 3时，挑选肿瘤大小合适的小鼠分组给药，给药剂量如下表5。每天用电子天平对动物进行称重，每周两次用游标卡尺调查肿瘤体积，肿瘤体积计算公式为：V＝0.5a x b 2，a和b分别表示肿瘤的长径和短径。肿瘤体积用于计算肿瘤生长抑制率(TGI)，百分数显示的TGI用于指示药物的抗肿瘤活性。TGI公式如下：TGI(％)＝[1-avTi-0/avCi-0)]×100；其中avTi-0是给药组在特 定天的平均肿瘤体积，减去该给药组在分组当天的平均肿瘤体积；其中avCi-0是溶媒对照组在特定天的平均肿瘤体积，减去溶媒对照组在分组当天的平均肿瘤体积。肿瘤体积数据用平均值±标准误(SEM)显示。实验结果见下表5。
表5
组别 给药后第14天肿瘤体积(mm 3) TGI(％)
溶剂对照组 670.99 --
AMG 510(1mg/kg,p.o.,QD) 314.28 82.8
AMG 510(3mg/kg,p.o.,QD) 205.35 109.1
AMG 510(10mg/kg,p.o.,QD) 81.72 138.9
Z37-1(1mg/kg,p.o.,QD) 286.12 89.4
Z37-1(3mg/kg,p.o.,QD) 238.82 102.8
Z37-1(10mg/kg,p.o.,QD) 210.59 108.4
Z48(1mg/kg,p.o.,QD) 459.33 51.2
Z48(3mg/kg,p.o.,QD) 148.62 124.7
Z48(10mg/kg,p.o.,QD) 90.39 138.5
Z23(1mg/kg,p.o.,QD) 194.65 113.2
Z23(3mg/kg,p.o.,QD) 59.52 143.5
Z23(10mg/kg,p.o.,QD) 47.32 149.2
Z25-2(1mg/kg,p.o.,QD) 180.14 116.2
Z25-2(3mg/kg,p.o.,QD) 62.35 143.7
Z25-2(10mg/kg,p.o.,QD) 18.94 154.4
Z26-2(1mg/kg,p.o.,QD) 157.06 121.1
Z26-2(3mg/kg,p.o.,QD) 67.66 143.8
Z26-2(10mg/kg,p.o.,QD) 30.49 151.1
Z27-2(1mg/kg,p.o.,QD) 140.10 126.3
Z27-2(3mg/kg,p.o.,QD) 54.81 145.1
Z27-2(10mg/kg,p.o.,QD) 15.16 155.8
实验结论：本发明化合物在人胰腺癌MIA PaCa-2皮下异体移植肿瘤模型中展现出良好的体内药效。开始给药后14天，本发明化合物与参考化合物AMG 510相比，具有更显著的抑制肿瘤的作用。此外，部分化合物在给药剂量(1mg/kg)低于参考化合物AMG 510给药剂量(3mg/kg)时，仍然展现出显著的缩瘤效果。这表明本发明化合物中部分化合物在人胰腺癌MIA PaCa-2皮下异体移植肿瘤模型中展现出优于参考化合物AMG 510的体内药效，且抗肿瘤作用具有剂量依赖性的趋势。
对照化合物AMG 510的结构为
Figure PCTCN2020124226-appb-000177
测试例6小鼠药代动力学评价实验
实验目的：以雄性CD-1小鼠为受试动物，应用LC/MS/MS法测定小鼠静脉和灌胃给与受试化合物后不同时刻血浆中的药物浓度。研究受试化合物在小鼠体内的药代动力学行为，评价其药动学特征。
实验方案：试验动物：6-8周龄，体重30g左右，健康成年雄性CD-1小鼠18只，按照体重相近的原则分成6组，IV组(三组)每组3只，PO组(三组)每组3只。动物购买自上海吉辉实验动物饲养有限公司。
药物配制：IV组：以10mL样品溶液为例，称取4mg样品，依次加入0.5mL DMSO,10mL Solutol HS 15，再加入17g HP-β-CD，最后用水定容至10mL，搅拌超声后达到0.4mg/mL的澄清状态。PO组：称取适量样品，按照体积比10:40依次加入适量Labrasol和水，搅拌超声后均匀达到1.5mg/mL的状态。
给药：禁食一夜后，IV组分别进行静脉给药，给药体积为5mL/kg,剂量为2mg/kg:PO组分别进行灌胃给药，给药体积为15mL/kg,剂量为15mg/kg。
实验操作：雄性CD-1小鼠静脉注射组和灌胃给药组分别给与受试化合物后，在0.0833,0.25,0.5,1,2,4,6,8,及24小时时间点采血110ul,置于预先加有K 2EDTA的商品化抗凝管中，在干冰下保存，将试管离心15分钟分离血浆，并于-70℃保存。给药4小时后动物可进食。用LC/MS/MS法测定小鼠静脉和灌胃给药后，血浆中的受试化合物含量。方法的线性范围为1-3000ng/ml；血浆样品经乙腈沉淀蛋白处理后进行分析。
IV(2mg/kg)组的实验结果如下表6；PO(15mg/kg)组的实验结果如下表7。
表6
组别 AMG510 Z9-2 Z10-2 Z48 Z25-2 Z27-2
Cl(L/h/kg) 4.39 0.14 0.811 1.53 0.499 0.59
V d(L/kg) 1.15 0.326 1.06 1.66 0.661 0.777
T 1/2(h) 0.318 1.74 0.941 1.02 1.00 1.08
注：Cl表示清除率；V d表示分布容积；T 1/2表示半衰期。
表7
组别 AMG510 Z1 Z9-2 Z10-2 Z48 Z25-2 Z27-2
C max(ng/mL) 1221 2603 13177 3960 1250 6643 3660
T max(h) 1.00 0.25 1.00 1.00 0.5 1.93 1.74
F(％) 36.10 - 103 59.20 38.1 93.5 96.8
注：C max表示口服给药后化合物浓度最大值；T max表示达到C max的时间；F表示生物利用度。
实验结论：在小鼠药代动力学评价实验中，本发明系列化合物显示出较参考化合物AMG510更低的体内清除率，更高的C max和更好的口服生物利用度。
测试例7单晶培养
对化合物Z25-2进行了单晶培养。具体方法如下：称取目标化合物2mg，溶于异丙醇溶剂，通过挥发法得到单晶，通过Bruker D8 Venture仪器进行X-射线单晶衍射测试。结果见下表8和图1。该单晶中包含一分子结晶溶剂分子(异丙醇)。
表8
Figure PCTCN2020124226-appb-000178
Figure PCTCN2020124226-appb-000179
测试例8单晶培养
对化合物Z27-2进行了单晶培养。具体方法如下：称取目标化合物20mg，溶于二氯甲烷/乙醇的混合溶剂(1:2)，通过挥发法得到单晶，通过Bruker D8 Venture仪器进行X-射线单晶衍射测试。结果见下表9和图2。
表9
Figure PCTCN2020124226-appb-000180
Figure PCTCN2020124226-appb-000181
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (27)

  1. 一种式(Ⅰ)所示的化合物、或其药学上可接受的盐、立体异构体、溶剂合物或其前药，
    Figure PCTCN2020124226-appb-100001
    式中，
    Z为N-C(O)-CR 3＝CR 1R 2或N-C(O)-C≡CR 4；
    R 1、R 2各自独立地为氢、卤素、氰基、-NR aR b、-C 1-3烷基、-卤代C 1-3烷基、-C 1-3烷基-羟基、-C 1-3烷基-氰基、-C 1-3烷基-C 1-3烷氧基、-C 1-3烷基-NR aR b、-C 1-3烷基-3至6元杂环烷基或-C 1-3烷基-5或6元单环杂芳基；其中，所述3至6元杂环烷基或所述5或6元单环杂芳基具有1、2或3个选自N、O和S的杂原子作为环原子；
    R 3为氢、卤素、-C 1-3烷基或-C 1-3烷氧基；
    R 4为氢、-卤代C 1-3烷基、-C 1-3烷基-羟基、-C 1-3烷基-氰基或-C 1-3烷基-C 1-3烷氧基；
    R 11、R 12相同或不同，各自独立地为氢、卤素、-C 1-3烷基、-卤代C 1-3烷基、-C 1-3烷基-羟基、-C 1-3烷基-氰基、-C 1-3烷基-C 1-6烷氧基、-C 1-3烷基-卤代C 1-6烷基或-C 1-3烷基-卤代C 1-6烷氧基；
    R 21、R 22相同或不同，各自独立地为氢、卤素、-C 1-3烷基、-卤代C 1-3烷基、-C 1-3烷基-羟基、-C 1-3烷基-氰基、-C 1-3烷基-C 1-6烷氧基、-C 1-3烷基-卤代C 1-6烷基或-C 1-3烷基-卤代C 1-6烷氧基；
    R 31、R 32相同或不同，各自独立地为氢、卤素、-C 1-3烷基、-卤代C 1-3烷基、-C 1-3烷基-羟基、-C 1-3烷基-氰基、-C 1-3烷基-C 1-6烷氧基、-C 1-3烷基-卤代C 1-6烷基或-C 1-3烷基-卤代C 1-6烷氧基；
    R 41为氢、卤素、-C 1-3烷基、-卤代C 1-3烷基、-C 1-3烷基-羟基、-C 1-3烷基-氰基、-C 1-3烷基-C 1-6烷氧基、-C 1-3烷基-卤代C 1-6烷基或-C 1-3烷基-卤代C 1-6烷氧基；
    当
    Figure PCTCN2020124226-appb-100002
    中的虚线为单键时，P为O、NH或NR m；R m为-C 1-6烷基、-卤代C 1-6烷基、-C 1-6烷基-羟基、-C 1-6烷基-氰基、-C 1-6烷基-C 1-6烷氧基、-C 1-6烷基-卤代C 1-6烷氧基、-C 1-6烷基-C 3-6环烷基或-C 1-6烷基-3元至6元杂环烷基；R 42为-(C＝O)-、-C 1-3烷基-、-C 1-3烷基(羟基)-、-C 1-3烷基(氰基)-、-C 1-3烷基(C 1-6烷基)-、-C 1-3烷基(卤代C 1-6烷基)-、-C 1-3烷基(C 1-6烷基-羟基)-、-C 1-3烷基(C 1-6烷基-氰基)-、-C 1-3烷基(C 1-6烷氧基)-、或-C 1-3烷基(卤代C 1-6烷氧基)-；
    或当
    Figure PCTCN2020124226-appb-100003
    中的虚线为无时，P为氢、卤素；R 42为氢、卤素、-C 1-3烷基、-卤代C 1-3烷基、-C 1-3烷基-羟基、-C 1-3烷基-氰基、-C 1-3烷基-C 1-6烷氧基、-C 1-3烷基-卤代C 1-6烷基 或-C 1-3烷基-卤代C 1-6烷氧基；
    Y 1为C时；X 1为氢、卤素、氰基、羟基、氨基、硝基、-取代或未取代的C 1-6烷基、-取代或未取代的C 3-6环烷基、-取代或未取代的3至6元杂环烷基、-O-取代或未取代的C 1-6烷基、-O-取代或未取代的C 3-6环烷基、-O-取代或未取代的3至6元杂环烷基、-NH-取代或未取代的C 1-6烷基、-N(取代或未取代的C 1-6烷基) 2、-NH-取代或未取代的C 3-6环烷基、-NH-取代或未取代的3至6元杂环烷基、-NH(C＝O)-取代或未取代的C 1-6烷基、-NH(C＝O)-C 3-6环烷基、-NH(SO 2)-取代或未取代的C 1-6烷基、-NH(SO 2)-取代或未取代的C 3-6环烷基、-SO 2-取代或未取代的C 1-6烷基、-SO 2-取代或未取代的C 3-6环烷基、-(C＝O)-NR jR k-、-(C＝O)-O-取代或未取代的C 1-6烷基、-(C＝O)-O-取代或未取代的C 3-6环烷基；其中，R j、R k各自独立地为氢或C 1-3烷基；或者R j、R k与相连的氮原子共同形成取代或未取代的3至6元含氮杂环烷基；所述3至6元杂环烷基具有1、2或3个选自N、O和S的杂原子作为环原子；所述3至6元含氮杂环烷基具有3至6个环原子且其中一个环原子为氮原子、其余环原子中的0个、1个或2个环原子任选地为选自N、O和S的杂原子；所述的“取代”是指基团中的1、2、3或4个氢原子被各自独立地选自S组取代基所取代；
    或Y 1为N时，X 1为无；
    所述S组取代基选自：羟基、卤素、硝基、氧代基、-C 1-6烷基、-卤代C 1-6烷基、羟基取代的C 1-6烷基、苄基、-(CH 2) u-氰基、-(CH 2) u-C 1-6烷氧基、-(CH 2) u-卤代C 1-6烷氧基、-(CH 2) u-卤代C 1-6烷基、-(CH 2) u-3至6元杂环烷基、-(CH 2) u-5或6元单环杂芳基、-(CH 2) u-C 3-8环烷基、-(CH 2) u-O-(CH 2) v-C 3-8环烷基、-(CH 2) u-O-(CH 2) v-C 1-6烷氧基、-(CH 2) u-O-(CH 2) vOH、-(CH 2) u-SO 2C 1-6烷基、-(CH 2) u-NR a0R b0、-(CH 2) u-C(O)NR a0R b0、-(CH 2) u-C(O)C 1-6烷基、-C(O)OC 1-6烷基、NR a0C(O)-(CH 2) u-NR a0R b0、NR a0C(O)-(CH 2) uOH、NR a0C(O)-卤代C 1-6烷基；其中，所述3至6元杂环烷基或所述5或6元单环杂芳基各自独立地具有1、2或3个选自N、O和S的杂原子作为环原子；所述3至6元杂环烷基、5或6元单环杂芳基任选地被1、2或3个选自卤素、氰基、-C 1-3烷基、-C 1-3烷氧基和-C 3-6环烷基的取代基取代；u、v各自独立地为0、1、2、3或4；R a0、R b0各自独立地为氢或C 1-3烷基；
    E 1为N或CR 5；其中，R 5为氢、卤素、氰基、-C 1-6烷基、-C 1-6烷氧基、-卤代C 1-6烷基、-卤代C 1-6烷氧基、-C 3-6环烷基、-NR hR i、-C 1-4烷基-羟基、-C 1-4烷基-氰基、-C 1-4烷基-C 1-6烷氧基、-C 1-4烷基-卤代C 1-6烷基或-C 1-4烷基-卤代C 1-6烷氧基；
    E 2为N或CR 6；其中，R 6为氢、卤素、氰基、-C 1-6烷基、-C 1-6烷氧基、-卤代C 1-6烷基、-卤代C 1-6烷氧基、-C 3-6环烷基、-NR hR i、-C 1-4烷基-羟基、-C 1-4烷基-氰基、-C 1-4烷基-C 1-6烷氧基、-C 1-4烷基-卤代C 1-6烷基或-C 1-4烷基-卤代C 1-6烷氧基；
    条件是Y 1、E 1、E 2不同时为N；
    Ar为C 6-10芳基、5或6元单环杂芳基或8至10元双环杂芳基；其中，所述5或6元单环杂芳基具有1、2或3个选自N、O和S的杂原子作为环原子；所述8至10元双环杂芳基具有1、2、3、4或5个选自N、O和S的杂原子作为环原子；且所述C 6-10芳基、所述5或6元单环杂芳基或所述8至10元双环杂芳基为未取代的或被1、2、3或4个独立选自R s1的基团取代；
    或者
    Ar为式(B)所示结构：
    Figure PCTCN2020124226-appb-100004
    其中，B1环为苯环或5或6元单环杂芳基环；B2环为一个稠合的5或6元单环杂环烷基环或稠合的5或6元单环环烷基环；其中，所述5或6元单环杂芳基环或所述稠合的5或6元单环杂环烷基环具有1、2或3个选自N、O和S的杂原子作为环原子；
    (R s1) p表示B1环上的氢被p个R s1取代，p为0、1、2或3，每个R s1相同或不同；
    (R s2) q表示B2环上的氢被q个R s2取代，q为0、1、2或3，每个R s2相同或不同；
    R s1、R s2各自独立地为卤素、氰基、硝基、羟基、-C 1-6烷基、-C 1-6烷氧基、-卤代C 1-6烷基、-卤代C 1-6烷氧基、-C 3-6环烷基、-NR cR d、-C(O)NR eR f、-SO 2C 1-3烷基、-SO 2卤代C 1-3烷基、-SO 2NR eR f、-C 1-4烷基-羟基、-C 1-4烷基-氰基、-C 1-4烷基-C 1-6烷氧基、-C 1-4烷基-卤代C 1-6烷基、-C 1-4烷基-卤代C 1-6烷氧基、-C 1-4烷基-3至6元杂环烷基、-C 1-4烷基-NR eR f、-C 1-4烷基-C(O)NR eR f、-C 1-4烷基-SO 2C 1-3烷基或C 2-4炔基；其中，所述3至6元杂环烷基具有1、2或3个选自N、O和S的杂原子作为环原子；
    R 0为-C 1-6烷基、-C 3-6环烷基、3至6元杂环烷基、C 6-10芳基、5或6元单环杂芳基、8至10元双环杂芳基、7至11元螺环烷基、-C 1-3烷基-C 6-10芳基、-C 1-3烷基-5或6元单环杂芳基、-NR g-C 6-10芳基、-O-C 6-10芳基、-C 1-3烷基-3至6元杂环烷基、-C 1-3烷基-C 3-6环烷基；其中，所述3至6元杂环烷基、所述5或6元单环杂芳基或所述8至10元双环杂芳基具有1、2或3个选自N、O和S的杂原子作为环原子；且所述的C 1-6烷基、C 3-6环烷基、3至6元杂环烷基、C 6-10芳基、5或6元单环杂芳基、8至10元双环杂芳基、7至11元螺环烷基为未取代的或被1、2、3或4个独立选自R s3的基团取代；所述的-C 1-3烷基-为未取代的或被1、2、3或4个独立选自C 1-3烷基取代；
    或者
    R 0为式(A-1)或式(A-2)所示结构：
    Figure PCTCN2020124226-appb-100005
    其中，A1环为苯环或5或6元单环杂芳基环；A2环为一个稠合的5或6元单环杂环烷基环或稠合的5或6元单环环烷基环；其中，所述5或6元单环杂芳基环或所述稠合的5或6元单环杂环烷基环具有1、2或3个选自N、O和S的杂原子作为环原子；
    (R s3) t表示A1环上的氢被t个R s3取代，t为0、1、2或3，每个R s3相同或不同；
    (R s4) s表示A2环上的氢被s个R s4取代，s为0、1、2或3，每个R s4相同或不同；
    R s3、R s4各自独立地为卤素、氰基、羟基、-C 1-6烷基、-C 1-6烷氧基、-卤代C 1-6烷基、-卤代C 1-6烷氧基、-C 3-6环烷基、3至6元杂环烷基、-NR hR i、-C(O)NR eR f、-SO 2C 1-3烷基、-SO 2卤代C 1-3烷基、-SO 2NR eR f、-C 1-3烷基-羟基、-C 1-3烷基-C 2-4炔基、-C 1-3烷基- 氰基、-C 1-3烷基-C 1-6烷氧基、-C 1-3烷基-卤代C 1-6烷基、-C 1-3烷基-卤代C 1-6烷氧基、-C 1-3烷基-3至6元杂环烷基、-C 1-3烷基-C 3-6环烷基、-C 1-3烷基-NR eR f、-C 1-3烷基-C(O)NR eR f、-C 1-3烷基-SO 2C 1-3烷基或C 2-4炔基；其中，所述3至6元杂环烷基具有1、2或3个选自N、O和S的杂原子作为环原子；且所述的C 1-6烷基、-C 1-6烷氧基、-C 1-3烷基-、-C 3-6环烷基、3至6元杂环烷基任选地被1、2或3个独立选自卤素、甲基、乙基、丙基、异丙基、三氟甲基、氨基、N(CH 3) 2、羟基、羧基的取代基取代；
    R a、R b、R e、R f、R g各自独立地为氢或C 1-3烷基；
    R c、R d、R h、R i各自独立地为氢、-C 1-3烷基、-C(O)C 1-3烷基或-CO 2C 1-3烷基。
  2. 一种式(IⅠ)所示的化合物、或其药学上可接受的盐、立体异构体、溶剂合物或其前药，
    Figure PCTCN2020124226-appb-100006
    式中，
    Z为N-C(O)-CR 3＝CR 1R 2或N-C(O)-C≡CR 4；
    R 1、R 2各自独立地为氢、卤素、氰基、NR aR b、-C 1-3烷基、卤代C 1-3烷基、-C 1-3烷基-羟基、-C 1-3烷基-氰基、-C 1-3烷基-C 1-3烷氧基、-C 1-3烷基-NR aR b、-C 1-3烷基-3至6元杂环烷基或-C 1-3烷基-5或6元单环杂芳基；其中，所述3至6元杂环烷基或所述5或6元单环杂芳基具有1、2或3个选自N、O和S的杂原子作为环原子；
    R 3为氢、卤素、-C 1-3烷基或-C 1-3烷氧基；
    R 4为氢、卤代C 1-3烷基、-C 1-3烷基-羟基、-C 1-3烷基-氰基或-C 1-3烷基-C 1-3烷氧基；
    R 11、R 12相同或不同，各自独立地为氢、卤素、-C 1-3烷基、-卤代C 1-3烷基、-C 1-3烷基-羟基、-C 1-3烷基-氰基、-C 1-3烷基-C 1-6烷氧基、-C 1-3烷基-卤代C 1-6烷基或-C 1-3烷基-卤代C 1-6烷氧基；
    R 21、R 22相同或不同，各自独立地为氢、卤素、-C 1-3烷基、-卤代C 1-3烷基、-C 1-3烷基-羟基、-C 1-3烷基-氰基、-C 1-3烷基-C 1-6烷氧基、-C 1-3烷基-卤代C 1-6烷基或-C 1-3烷基-卤代C 1-6烷氧基；
    R 31、R 32相同或不同，各自独立地为氢、卤素、-C 1-3烷基、-卤代C 1-3烷基、-C 1-3烷基-羟基、-C 1-3烷基-氰基、-C 1-3烷基-C 1-6烷氧基、-C 1-3烷基-卤代C 1-6烷基或-C 1-3烷基-卤代C 1-6烷氧基；
    R 41为氢、卤素、-C 1-3烷基、-卤代C 1-3烷基、-C 1-3烷基-羟基、-C 1-3烷基-氰基、-C 1-3烷基-C 1-6烷氧基、-C 1-3烷基-卤代C 1-6烷基或-C 1-3烷基-卤代C 1-6烷氧基；
    P为O、NH或NR m；R m为-C 1-6烷基、-卤代C 1-6烷基、-C 1-6烷基-羟基、-C 1-6烷基-氰基、-C 1-6烷基-C 1-6烷氧基、-C 1-6烷基-卤代C 1-6烷氧基、-C 1-6烷基-C 3-6环烷基或-C 1-6烷基-3元至6元杂环烷基；
    R 42为-(C＝O)-、-C 1-3烷基-、-C 1-3烷基(羟基)-、-C 1-3烷基(氰基)-、-C 1-3烷基(C 1-6烷基)-、-C 1-3烷基(卤代C 1-6烷基)-、-C 1-3烷基(C 1-6烷基-羟基)-、-C 1-3烷基(C 1-6烷基-氰基)-、 -C 1-3烷基(C 1-6烷氧基)-、或-C 1-3烷基(卤代C 1-6烷氧基)-；
    X 2、Y 2相同或不同，各自独立地为氢、卤素、-C 1-3烷基、-卤代C 1-3烷基、-C 1-3烷基-羟基、-C 1-3烷基-氰基、-C 1-3烷基-C 1-6烷氧基、-C 1-3烷基-卤代C 1-6烷基或-C 1-3烷基-卤代C 1-6烷氧基；
    或X 2、Y 2与其相邻的碳原子共同形成取代或未取代的C 3-6环烷基或取代或未取代的3至6元杂环烷基；所述3至6元杂环烷基具有1、2或3个选自N、O和S的杂原子作为环原子；所述的“取代”是指基团中的1、2、3或4个氢原子被各自独立地选自S组取代基所取代；
    E 3为N或C-L-R 5；其中，
    L为一个键、-CR L1R L2-、-O-(CR L1R L2) t1-或-NH-(CR L3R L4) t2-；其中，R L1、R L2、R L3、R L4相同或不同，各自独立地为氢、卤素、羟基、羟甲基、羟乙基、-C 1-3烷基或氧代基；t1、t2各自独立地为0、1、2、3或4；R L1与R L2中或者R L3与R L4中，当其中一个为氧代基时，另一个则不存在；
    R 5为氢、卤素、羟基、-取代或未取代的C 1-6烷基、-取代或未取代的C 3-6环烷基、-取代或未取代的3至6元杂环烷基、-O-取代或未取代的C 1-6烷基、-O-取代或未取代的C 3-6环烷基、-O-取代或未取代的3至6元杂环烷基、-SO 2-取代或未取代的C 1-6烷基、-SO 2-取代或未取代的C 3-6环烷基、-SO 2-取代或未取代的3至6元杂环烷基、-取代或未取代的5或6元单环杂芳基或NR 51R 52；其中，R 51、R 52各自独立地为氢、取代或未取代的C 1-6烷基、-SO 2C 1-6烷基、-SO 2C 3-6环烷基、-C(O)C 1-6烷基或-C(O)卤代C 1-6烷基；或者R 51和R 52与相连的氮原子共同形成取代或未取代的3至6元含氮杂环烷基；其中，所述3至6元杂环烷基、5或6元单环杂芳基各自独立地具有1、2或3个选自N、O和S的杂原子作为环原子；所述3至6元含氮杂环烷基具有3至6个环原子且其中一个环原子为氮原子、其余环原子中的0个、1个或2个环原子任选地为选自N、O和S的杂原子；所述的“取代”是指基团中的1、2、3或4个氢原子被各自独立地选自S组取代基所取代；
    所述S组取代基选自：羟基、卤素、硝基、氧代基、-C 1-6烷基、-卤代C 1-6烷基、羟基取代的C 1-6烷基、苄基、-(CH 2) u-氰基、-(CH 2) u-C 1-6烷氧基、-(CH 2) u-卤代C 1-6烷氧基、-(CH 2) u-卤代C 1-6烷基、-(CH 2) u-3至6元杂环烷基、-(CH 2) u-5或6元单环杂芳基、-(CH 2) u-C 3-8环烷基、-(CH 2) u-O-(CH 2) v-C 3-8环烷基、-(CH 2) u-O-(CH 2) v-C 1-6烷氧基、-(CH 2) u-O-(CH 2) vOH、-(CH 2) u-SO 2C 1-6烷基、-(CH 2) u-NR a0R b0、-(CH 2) u-C(O)NR a0R b0、-(CH 2) u-C(O)C 1-6烷基、-C(O)OC 1-6烷基、NR a0C(O)-(CH 2) u-NR a0R b0、NR a0C(O)-(CH 2) uOH、NR a0C(O)-卤代C 1-6烷基；其中，所述3至6元杂环烷基或所述5或6元单环杂芳基各自独立地具有1、2或3个选自N、O和S的杂原子作为环原子；所述3至6元杂环烷基、5或6元单环杂芳基任选地被1、2或3个选自卤素、氰基、-C 1-3烷基、-C 1-3烷氧基和C 3-6环烷基的取代基取代；u、v各自独立地为0、1、2、3或4；R a0、R b0各自独立地为氢或C 1-3烷基；
    E 4为N或CH；
    Ar为C 6-10芳基、5或6元单环杂芳基或8至10元双环杂芳基；其中，所述5或6元单环杂芳基具有1、2或3个选自N、O和S的杂原子作为环原子；所述8至10元双环杂芳基具有1、2、3、4或5个选自N、O和S的杂原子作为环原子；且所述C 6-10芳 基、所述5或6元单环杂芳基或所述8至10元双环杂芳基为未取代的或被1、2、3或4个独立选自R s1的基团取代；
    或者
    Ar为式(B)所示结构：
    Figure PCTCN2020124226-appb-100007
    其中，B1环为苯环或5或6元单环杂芳基环；B2环为一个稠合的5或6元单环杂环烷基环或稠合的5或6元单环环烷基环；其中，所述5或6元单环杂芳基环或所述稠合的5或6元单环杂环烷基环具有1、2或3个选自N、O和S的杂原子作为环原子；
    (R s1) p表示B1环上的氢被p个R s1取代，p为0、1、2或3，每个R s1相同或不同；
    (R s2) q表示B2环上的氢被q个R s2取代，q为0、1、2或3，每个R s2相同或不同；
    R s1、R s2各自独立地为卤素、氰基、硝基、羟基、-C 1-6烷基、-C 1-6烷氧基、-卤代C 1-6烷基、-卤代C 1-6烷氧基、-C 3-6环烷基、-NR cR d、-C(O)NR eR f、-SO 2C 1-3烷基、-SO 2卤代C 1-3烷基、-SO 2NR eR f、-C 1-4烷基-羟基、-C 1-4烷基-氰基、-C 1-4烷基-C 1-6烷氧基、-C 1-4烷基-卤代C 1-6烷基、-C 1-4烷基-卤代C 1-6烷氧基、-C 1-4烷基-3至6元杂环烷基、-C 1-4烷基-NR eR f、-C 1-4烷基-C(O)NR eR f、-C 1-4烷基-SO 2C 1-3烷基或-C 2-4炔基；其中，所述3至6元杂环烷基具有1、2或3个选自N、O和S的杂原子作为环原子；
    R a、R b、R e、R f各自独立地为氢或-C 1-3烷基；
    R c、R d各自独立地为氢、-C 1-3烷基、-C(O)C 1-3烷基、-CO 2C 1-3烷基。
  3. 一种式(IA)所示的化合物或其互变异构体、顺反异构体、内消旋体、外消旋体、对映异构体、非对映异构体、阻转异构体或其混合物形式，或其药学上可接受的盐，溶剂合物或前药：
    Figure PCTCN2020124226-appb-100008
    式中，
    Z为N-C(O)-CR 3＝CR 1R 2或N-C(O)-C≡CR 4；
    R 1、R 2各自独立地为氢、卤素、氰基、NR aR b、-C 1-3烷基、卤代C 1-3烷基、-C 1-3烷基-羟基、-C 1-3烷基-氰基、-C 1-3烷基-C 1-3烷氧基、-C 1-3烷基-NR aR b、-C 1-3烷基-3至6元杂环烷基或-C 1-3烷基-5或6元单环杂芳基；其中，所述3至6元杂环烷基或所述5或6元单环杂芳基具有1、2或3个选自N、O和S的杂原子作为环原子；
    R 3为氢、卤素、-C 1-3烷基或-C 1-3烷氧基；
    R 4为氢、卤代C 1-3烷基、-C 1-3烷基-羟基、-C 1-3烷基-氰基或-C 1-3烷基-C 1-3烷氧基；
    R 11、R 12相同或不同，各自独立地为氢、卤素、-C 1-3烷基、-卤代C 1-3烷基、-C 1-3烷基-羟基、-C 1-3烷基-氰基、-C 1-3烷基-C 1-6烷氧基、-C 1-3烷基-卤代C 1-6烷基或-C 1-3烷基-卤代C 1-6烷氧基；
    R 21、R 22相同或不同，各自独立地为氢、卤素、-C 1-3烷基、-卤代C 1-3烷基、-C 1-3烷基-羟基、-C 1-3烷基-氰基、-C 1-3烷基-C 1-6烷氧基、-C 1-3烷基-卤代C 1-6烷基或-C 1-3烷基-卤代C 1-6烷氧基；
    R 31、R 32相同或不同，各自独立地为氢、卤素、-C 1-3烷基、-卤代C 1-3烷基、-C 1-3烷基-羟基、-C 1-3烷基-氰基、-C 1-3烷基-C 1-6烷氧基、-C 1-3烷基-卤代C 1-6烷基或-C 1-3烷基-卤代C 1-6烷氧基；
    R 41为氢、卤素、-C 1-3烷基、-卤代C 1-3烷基、-C 1-3烷基-羟基、-C 1-3烷基-氰基、-C 1-3烷基-C 1-6烷氧基、-C 1-3烷基-卤代C 1-6烷基或-C 1-3烷基-卤代C 1-6烷氧基；
    当
    Figure PCTCN2020124226-appb-100009
    中的虚线为单键时，P'为O、NH或NR m'；R m'为-氘代C 1-6烷基、-C 1-6烷基、-卤代C 1-6烷基、-C 1-6烷基-羟基、-C 1-6烷基-氰基、-C 1-6烷基-C 1-6烷氧基、-C 1-6烷基-卤代C 1-6烷氧基、-C 1-6烷基-C 3-6环烷基或-C 1-6烷基-3元至6元杂环烷基；R 42'为-C 1-3烷基-(C＝O)-、-(C＝O)-、-C 1-3烷基-、-C 1-3烷基(羟基)-、-C 1-3烷基(氰基)-、-C 1-3烷基(C 1-6烷基)-、-C 1-3烷基(卤代C 1-6烷基)-、-C 1-3烷基(C 1-6烷基-羟基)-、-C 1-3烷基(C 1-6烷基-氰基)-、-C 1-3烷基(C 1-6烷氧基)-、或-C 1-3烷基(卤代C 1-6烷氧基)-；
    或当
    Figure PCTCN2020124226-appb-100010
    中的虚线为无时，P'为氢或卤素；R 42'为氢、卤素、-C 1-3烷基、-卤代C 1-3烷基、-C 1-3烷基-羟基、-C 1-3烷基-氰基、-C 1-3烷基-C 1-6烷氧基、-C 1-3烷基-卤代C 1-6烷基或-C 1-3烷基-卤代C 1-6烷氧基；
    Y 1为C时；X 1为氢、卤素、氰基、羟基、氨基、硝基、-取代或未取代的C 1-6烷基、-取代或未取代的C 3-6环烷基、-取代或未取代的3至6元杂环烷基、-O-取代或未取代的C 1-6烷基、-O-取代或未取代的C 3-6环烷基、-O-取代或未取代的3至6元杂环烷基、-NH-取代或未取代的C 1-6烷基、-N(取代或未取代的C 1-6烷基) 2、-NH-取代或未取代的C 3-6环烷基、-NH-取代或未取代的3至6元杂环烷基、-NH(C＝O)-取代或未取代的C 1-6烷基、-NH(C＝O)-C 3-6环烷基、-NH(SO 2)-取代或未取代的C 1-6烷基、-NH(SO 2)-取代或未取代的C 3-6环烷基、-SO 2-取代或未取代的C 1-6烷基、-SO 2-取代或未取代的C 3-6环烷基、-(C＝O)-NR jR k-、-(C＝O)-O-取代或未取代的C 1-6烷基、-(C＝O)-O-取代或未取代的C 3-6环烷基；其中，R j、R k各自独立地为氢或C 1-3烷基；或者R j、R k与相连的氮原子共同形成取代或未取代的3至6元含氮杂环烷基；所述3至6元杂环烷基具有1、2或3个选自N、O和S的杂原子作为环原子；所述3至6元含氮杂环烷基具有3至6个环原子且其中一个环原子为氮原子、其余环原子中的0个、1个或2个环原子任选地为选自N、O和S的杂原子；所述的“取代”是指基团中的1、2、3或4个氢原子被各自独立地选自S组取代基所取代；
    或Y 1为N时，X 1为无；
    所述S组取代基选自：羟基、卤素、硝基、氧代基、-C 1-6烷基、-卤代C 1-6烷基、羟基取代的C 1-6烷基、苄基、-(CH 2) u-氰基、-(CH 2) u-C 1-6烷氧基、-(CH 2) u-卤代C 1-6烷氧 基、-(CH 2) u-卤代C 1-6烷基、-(CH 2) u-3至6元杂环烷基、-(CH 2) u-5或6元单环杂芳基、-(CH 2) u-C 3-8环烷基、-(CH 2) u-O-(CH 2) v-C 3-8环烷基、-(CH 2) u-O-(CH 2) v-C 1-6烷氧基、-(CH 2) u-O-(CH 2) vOH、-(CH 2) u-SO 2C 1-6烷基、-(CH 2) u-NR a0R b0、-(CH 2) u-C(O)NR a0R b0、-(CH 2) u-C(O)C 1-6烷基、-C(O)OC 1-6烷基、NR a0C(O)-(CH 2) u-NR a0R b0、NR a0C(O)-(CH 2) uOH、NR a0C(O)-卤代C 1-6烷基；其中，所述3至6元杂环烷基或所述5或6元单环杂芳基各自独立地具有1、2或3个选自N、O和S的杂原子作为环原子；所述3至6元杂环烷基、5或6元单环杂芳基任选地被1、2或3个选自卤素、氰基、-C 1-3烷基、-C 1-3烷氧基和C 3-6环烷基的取代基取代；u、v各自独立地为0、1、2、3或4；R a0、R b0各自独立地为氢或C 1-3烷基；
    E 1'为N或CR 5'；其中，R 5'为氢、卤素、氰基、-C 1-6烷基、-C 1-6烷氧基、-卤代C 1-6烷基、-卤代C 1-6烷氧基、-C 3-6环烷基、-O-C 3-6环烷基、-NR hR i、-C 1-4烷基-羟基、-C 1-4烷基-氰基、-C 1-4烷基-C 1-6烷氧基、-C 1-4烷基-卤代C 1-6烷基或-C 1-4烷基-卤代C 1-6烷氧基；
    E 2'为N或CR 6'；其中，R 6'为氢、卤素、氰基、-C 1-6烷基、-C 1-6烷氧基、-卤代C 1-6烷基、-卤代C 1-6烷氧基、-C 3-6环烷基、-O-C 3-6环烷基、-NR hR i、-C 1-4烷基-羟基、-C 1-4烷基-氰基、-C 1-4烷基-C 1-6烷氧基、-C 1-4烷基-卤代C 1-6烷基或-C 1-4烷基-卤代C 1-6烷氧基；
    条件是Y 1、E 1'、E 2'不同时为N；
    Ar'为C 6-10芳基、5或6元单环杂芳基、8至10元双环杂芳基或吡啶酮基；其中，所述5或6元单环杂芳基具有1、2或3个选自N、O和S的杂原子作为环原子；所述8至10元双环杂芳基具有1、2、3、4或5个选自N、O和S的杂原子作为环原子；且所述C 6-10芳基、所述5或6元单环杂芳基、所述8至10元双环杂芳基和所述吡啶酮基为未取代的或被1、2、3或4个独立选自R s1的基团取代；
    或者Ar'为式(B)所示结构：
    Figure PCTCN2020124226-appb-100011
    其中，B1环为苯环或5或6元单环杂芳基环；B2环为一个稠合的5或6元单环杂环烷基环或稠合的5或6元单环环烷基环；其中，所述5或6元单环杂芳基环或所述稠合的5或6元单环杂环烷基环具有1、2或3个选自N、O和S的杂原子作为环原子；
    (R s1) p表示B1环上的氢被p个R s1取代，p为0、1、2或3，每个R s1相同或不同；
    (R s2) q表示B2环上的氢被q个R s2取代，q为0、1、2或3，每个R s2相同或不同；
    R s1、R s2各自独立地为卤素、氰基、硝基、羟基、-C 1-6烷基、-C 1-6烷氧基、-卤代C 1-6烷基、-卤代C 1-6烷氧基、-C 3-6环烷基、-NR cR d、-C(O)NR eR f、-SO 2C 1-3烷基、-SO 2卤代C 1-3烷基、-SO 2NR eR f、-C 1-4烷基-羟基、-C 1-4烷基-氰基、-C 1-4烷基-C 1-6烷氧基、-C 1-4烷基-卤代C 1-6烷基、-C 1-4烷基-卤代C 1-6烷氧基、-C 1-4烷基-3至6元杂环烷基、-C 1-4烷基-NR eR f、-C 1-4烷基-C(O)NR eR f、-C 1-4烷基-SO 2C 1-3烷基或C 2-4炔基；其中，所述3至6元杂环烷基具有1、2或3个选自N、O和S的杂原子作为环原子；
    R 0'为-C 1-6烷基、-C 3-6环烷基、3至6元杂环烷基、C 6-10芳基、5或6元单环杂芳基、 8至10元双环杂芳基、7至11元螺环烷基、-C 1-3烷基-C 6-10芳基、-C 1-3烷基-5或6元单环杂芳基、-NR g-C 6-10芳基、-O-C 6-10芳基、-C 1-3烷基-3至6元杂环烷基、-C 1-3烷基-C 3-6环烷基或吡啶酮基，其中，所述3至6元杂环烷基、所述5或6元单环杂芳基或所述8至10元双环杂芳基具有1、2或3个选自N、O和S的杂原子作为环原子；且所述的C 1-6烷基、C 3-6环烷基、3至6元杂环烷基、C 6-10芳基、5或6元单环杂芳基、8至10元双环杂芳基、7至11元螺环烷基和吡啶酮基为未取代的或被1、2、3或4个独立选自R s3的基团取代；所述的-C 1-3烷基-为未取代的或被1、2、3或4个独立选自C 1-3烷基取代；
    或者R 0'为式(A-1)或式(A-2)所示结构：
    Figure PCTCN2020124226-appb-100012
    其中，A1环为苯环或5或6元单环杂芳基环；A2环为一个稠合的5或6元单环杂环烷基环或稠合的5或6元单环环烷基环；其中，所述5或6元单环杂芳基环或所述稠合的5或6元单环杂环烷基环具有1、2或3个选自N、O和S的杂原子作为环原子；
    (R s3) t表示A1环上的氢被t个R s3取代，t为0、1、2或3，每个R s3相同或不同；
    (R s4) s表示A2环上的氢被s个R s4取代，s为0、1、2或3，每个R s4相同或不同；
    R s3、R s4各自独立地为卤素、氰基、羟基、-C 1-6烷基、-C 1-6烷氧基、-卤代C 1-6烷基、-卤代C 1-6烷氧基、-C 3-6环烷基、3至6元杂环烷基、-NR hR i、-C(O)NR eR f、-SO 2C 1-3烷基、-SO 2卤代C 1-3烷基、-SO 2NR eR f、-C 1-3烷基-羟基、-C 1-3烷基-C 2-4炔基、-C 1-3烷基-氰基、-C 1-3烷基-C 1-6烷氧基、-C 1-3烷基-卤代C 1-6烷基、-C 1-3烷基-卤代C 1-6烷氧基、-C 1-3烷基-3至6元杂环烷基、-C 1-3烷基-C 3-6环烷基、-C 1-3烷基-NR eR f、-C 1-3烷基-C(O)NR eR f、-C 1-3烷基-SO 2C 1-3烷基或C 2-4炔基；其中，所述3至6元杂环烷基具有1、2或3个选自N、O和S的杂原子作为环原子；且所述的C 1-6烷基、-C 1-6烷氧基、-C 1-3烷基-、-C 3-6环烷基、3至6元杂环烷基任选地被1、2或3个独立选自卤素、甲基、乙基、丙基、异丙基、三氟甲基、氨基、N(CH 3) 2、羟基、羧基的取代基取代；
    R a、R b、R e、R f、R g各自独立地为氢或C 1-3烷基；
    R c、R d、R h、R i各自独立地为氢、-C 1-3烷基、-C(O)C 1-3烷基或-CO 2C 1-3烷基。
  4. 如权利要求3所述的化合物或其互变异构体、顺反异构体、内消旋体、外消旋体、对映异构体、非对映异构体、阻转异构体或其混合物形式，或其药学上可接受的盐，溶剂合物或前药，其特征在于，式(IA)所示的化合物为式(IB)化合物或式(IC)化合物；
    Figure PCTCN2020124226-appb-100013
    式IB中，P'为O、NH或NR m'；R m'为-氘代C 1-6烷基、-C 1-6烷基、-卤代C 1-6烷基、-C 1-6烷基-羟基、-C 1-6烷基-氰基、-C 1-6烷基-C 1-6烷氧基、-C 1-6烷基-卤代C 1-6烷氧基、-C 1-6烷基-C 3-6环烷基或-C 1-6烷基-3元至6元杂环烷基；R 42'为-C 1-3烷基-(C＝O)-、-(C＝O)-、-C 1-3烷基-、-C 1-3烷基(羟基)-、-C 1-3烷基(氰基)-、-C 1-3烷基(C 1-6烷基)-、-C 1-3烷基(卤代C 1-6烷基)-、-C 1-3烷基(C 1-6烷基-羟基)-、-C 1-3烷基(C 1-6烷基-氰基)-、-C 1-3烷基(C 1-6烷氧基)-、或-C 1-3烷基(卤代C 1-6烷氧基)-；R 11、R 12、R 21、R 22、R 31、R 32、R 41、Z、R 0'、Ar'、E 1'、E 2'、X 1、Y 1如权利要求3中所定义；
    式IC中，P'为氢或卤素；R 42'为氢、卤素、-C 1-3烷基、-卤代C 1-3烷基、-C 1-3烷基-羟基、-C 1-3烷基-氰基、-C 1-3烷基-C 1-6烷氧基、-C 1-3烷基-卤代C 1-6烷基或-C 1-3烷基-卤代C 1-6烷氧基；R 11、R 12、R 21、R 22、R 31、R 32、R 41、Z、R 0'、Ar'、E 1'、E 2'、X 1、Y 1如权利要求3中所定义。
  5. 如权利要求4所述的化合物或其互变异构体、顺反异构体、内消旋体、外消旋体、对映异构体、非对映异构体、阻转异构体或其混合物形式，或其药学上可接受的盐，溶剂合物或前药，其特征在于，式(IB)所示的化合物为式(IB-1)化合物或式(IB-2)化合物；
    Figure PCTCN2020124226-appb-100014
    式(IB-1)、式(IB-2)中，R 21、R 22、R 11、R 12、R 31、R 32、R 41、R 42'、Z、P'、R 0'、Ar'、E 1'、E 2'、X 1、Y 1如权利要求4中所定义。
  6. 如权利要求4所述的化合物或其互变异构体、顺反异构体、内消旋体、外消旋体、对映异构体、非对映异构体、阻转异构体或其混合物形式，或其药学上可接受的盐，溶剂合物或前药，其特征在于，式(IB)所示的化合物为式(IB-1a)化合物或式(IB-2a)化合物；
    Figure PCTCN2020124226-appb-100015
    其中R 1、R 2、R 3、R 21、R 22、R 12、R 11、R 31、R 32、P'、R 0'、Ar'、E 1'、X 1如权利要求4中所定义。
  7. 如权利要求6所述的化合物或其互变异构体、顺反异构体、内消旋体、外消旋体、对映异构体、非对映异构体、阻转异构体或其混合物形式，或其药学上可接受的盐，溶剂合物或前药，其特征在于，式(IB-1a)所示的化合物为式(IB-1aa)化合物、式(IB-1ab)化合物、式(IB-1ac)化合物或式(IB-1ad)化合物；
    Figure PCTCN2020124226-appb-100016
    其中式(IB-1aa)、式(IB-1ab)中，R 21'独立为卤素、-C 1-3烷基、-卤代C 1-3烷基、-C 1-3烷基-羟基、-C 1-3烷基-氰基、-C 1-3烷基-C 1-6烷氧基、-C 1-3烷基-卤代C 1-6烷基或-C 1-3烷基-卤代C 1-6烷氧基；R 1、R 2、R 3、R 12、R 11、R 31、R 32、P'、R 0'、Ar'、E 1'、X 1如权利要求4中所定义；
    式(IB-1ac)、式(IB-1ad)中，R 12'独立为卤素、-C 1-3烷基、-卤代C 1-3烷基、-C 1-3烷基-羟基、-C 1-3烷基-氰基、-C 1-3烷基-C 1-6烷氧基、-C 1-3烷基-卤代C 1-6烷基或-C 1-3烷基-卤代C 1-6烷氧基；R 1、R 2、R 3、R 21、R 22、R 31、R 32、P'、R 0'、Ar'、E 1'、X 1如权利要求4中所定义。
  8. 如权利要求4所述的化合物或其互变异构体、顺反异构体、内消旋体、外消旋体、对映异构体、非对映异构体、阻转异构体或其混合物形式，或其药学上可接受的盐，溶剂合物或前药，其特征在于，式(IB)所示的化合物为式(IB-1c)化合物或式(IB-2c)化合物；
    Figure PCTCN2020124226-appb-100017
    其中R 1、R 2、R 3、R 21、R 22、R 12、R 11、R 31、R 32、P'、R 0'、Ar'、E 1'、X 1如权利要求4中所定义。
  9. 如权利要求8所述的化合物或其互变异构体、顺反异构体、内消旋体、外消旋体、对映异构体、非对映异构体、阻转异构体或其混合物形式，或其药学上可接受的盐，溶剂合物或前药，其特征在于，式(IB-1c)所示的化合物为式(IB-1ca)化合物、式(IB-1cb)化合物、式(IB-1cc)化合物或式(IB-1cd)化合物；
    Figure PCTCN2020124226-appb-100018
    其中式(IB-1ca)、式(IB-1cb)中，R 21'独立为卤素、-C 1-3烷基、-卤代C 1-3烷基、-C 1-3烷基-羟基、-C 1-3烷基-氰基、-C 1-3烷基-C 1-6烷氧基、-C 1-3烷基-卤代C 1-6烷基或-C 1-3烷基-卤代C 1-6烷氧基；R 1、R 2、R 3、R 12、R 11、R 31、R 32、P'、R 0'、Ar'、E 1'、X 1如权利要求4中所定义；
    式(IB-1cc)、式(IB-1cd)中，R 12'独立为卤素、-C 1-3烷基、-卤代C 1-3烷基、-C 1-3烷基-羟基、-C 1-3烷基-氰基、-C 1-3烷基-C 1-6烷氧基、-C 1-3烷基-卤代C 1-6烷基或-C 1-3烷基-卤代C 1-6烷氧基；R 1、R 2、R 3、R 21、R 22、R 31、R 32、P'、R 0'、Ar'、E 1'、X 1如权利要求4中所定义。
  10. 如权利要求4所述的化合物或其互变异构体、顺反异构体、内消旋体、外消旋体、对映异构体、非对映异构体、阻转异构体或其混合物形式，或其药学上可接受的盐，溶剂合物或前药，其特征在于，式(IB)所示的化合物为式(IB-1b)化合物或式(IB-2b)化合物；
    Figure PCTCN2020124226-appb-100019
    其中R 1、R 2、R 3、R 21、R 22、R 12、R 11、R 31、R 32、P'、R 0'、Ar'、E 1'、X 1如权利要求4中所定义。
  11. 如权利要求10所述的化合物或其互变异构体、顺反异构体、内消旋体、外消旋体、对映异构体、非对映异构体、阻转异构体或其混合物形式，或其药学上可接受的盐，溶剂合物或前药，其特征在于，式(IB-1b)所示的化合物为式(IB-1ba)化合物、式(IB-1bb)化合物、式(IB-1bc)化合物或式(IB-1bd)化合物；
    Figure PCTCN2020124226-appb-100020
    其中式(IB-1ba)、式(IB-1bb)中，R 21'独立为卤素、-C 1-3烷基、-卤代C 1-3烷基、-C 1-3烷基-羟基、-C 1-3烷基-氰基、-C 1-3烷基-C 1-6烷氧基、-C 1-3烷基-卤代C 1-6烷基或-C 1-3烷基-卤代C 1-6烷氧基；R 1、R 2、R 3、R 12、R 11、R 31、R 32、P'、R 0'、Ar'、E 1'、X 1如权利要求4中所定义；
    式(IB-1bc)、式(IB-1bd)中，R 12'独立为卤素、-C 1-3烷基、-卤代C 1-3烷基、-C 1-3烷基-羟基、-C 1-3烷基-氰基、-C 1-3烷基-C 1-6烷氧基、-C 1-3烷基-卤代C 1-6烷基或-C 1-3烷基-卤代C 1-6烷氧基；R 1、R 2、R 3、R 21、R 22、R 31、R 32、P'、R 0'、Ar'、E 1'、X 1如权利要求4中所定义。
  12. 如权利要求4所述的化合物或其互变异构体、顺反异构体、内消旋体、外消旋体、对映异构体、非对映异构体、阻转异构体或其混合物形式，或其药学上可接受的盐，溶剂合物或前药，其特征在于，式(IB)所示的化合物为式(IB-1d)化合物或式(IB-2d)化合物；
    Figure PCTCN2020124226-appb-100021
    其中R 1、R 2、R 3、R 21、R 22、R 12、R 11、R 31、R 32、P'、R 0'、Ar'、E 1'、X 1如权利要求4中所定义。
  13. 如权利要求12所述的化合物或其互变异构体、顺反异构体、内消旋体、外消旋体、对映异构体、非对映异构体、阻转异构体或其混合物形式，或其药学上可接受的盐，溶剂合物或前药，其特征在于，式(IB-1d)所示的化合物为式(IB-1da)化合物、式(IB-1db)化合物、式(IB-1dc)化合物或式(IB-1dd)化合物；
    Figure PCTCN2020124226-appb-100022
    其中式(IB-1da)、式(IB-1db)中，R 21'独立为卤素、-C 1-3烷基、-卤代C 1-3烷基、-C 1-3烷基-羟基、-C 1-3烷基-氰基、-C 1-3烷基-C 1-6烷氧基、-C 1-3烷基-卤代C 1-6烷基或-C 1-3烷基-卤代C 1-6烷氧基；R 1、R 2、R 3、R 12、R 11、R 31、R 32、P'、R 0'、Ar'、E 1'、X 1如权利要求4中所定义；
    式(IB-1dc)、式(IB-1dd)中，R 12'独立为卤素、-C 1-3烷基、-卤代C 1-3烷基、-C 1-3烷基-羟基、-C 1-3烷基-氰基、-C 1-3烷基-C 1-6烷氧基、-C 1-3烷基-卤代C 1-6烷基或-C 1-3烷基-卤代C 1-6烷氧基；R 1、R 2、R 3、R 21、R 22、R 31、R 32、P'、R 0'、Ar'、E 1'、X 1如权利要求4中所定义。
  14. 如权利要求7、9、11或13所述的化合物或其互变异构体、顺反异构体、内消旋体、外消旋体、对映异构体、非对映异构体、阻转异构体或其混合物形式，或其药学上可接受的盐，溶剂合物或前药，其特征在于，R 21'、R 12'各自独立为-C 1-3烷基、-C 1-3烷基-羟基、-C 1-3烷基-氰基或-C 1-3烷基-C 1-6烷氧基。
  15. 如权利要求3所述的化合物或其互变异构体、顺反异构体、内消旋体、外消旋体、对映异构体、非对映异构体、阻转异构体或其混合物形式，或其药学上可接受的盐，溶剂合物或前药，其特征在于，X 1为氢、卤素、-取代或未取代的C 1-6烷基、-取代或未取代的C 3-6环烷基、或-O-取代或未取代的C 1-6烷基；所述的“取代”是指基团中的1、2、3或4个氢原子被各自独立地选自S组取代基所取代。
  16. 如权利要求3所述的化合物或其互变异构体、顺反异构体、内消旋体、外消旋体、对映异构体、非对映异构体、阻转异构体或其混合物形式，或其药学上可接受的盐，溶剂合物或前药，其特征在于，Ar'为苯基、5或6元单环杂芳基或吡啶酮基；且所述苯基、5或6元单环杂芳基和吡啶酮基为未取代的或被1、2、3或4个独立选自下述基团取代：卤素、氰基、羟基、-C 1-6烷基、-C 1-6烷氧基、-NR cR d、-C 1-4烷基-NR eR f；其中R e、R f各自独立地为氢或C 1-3烷基；R c、R d各自独立地为氢、-C 1-3烷基、-C(O)C 1-3烷基或-CO 2C 1-3烷基。
  17. 如权利要求3所述的化合物或其互变异构体、顺反异构体、内消旋体、外消旋体、对映异构体、非对映异构体、阻转异构体或其混合物形式，或其药学上可接受的盐，溶剂合物或前药，其特征在于，Ar'选自如下结构：
    Figure PCTCN2020124226-appb-100023
    式中，R s1、R s2如权利要求3中所定义。
  18. 如权利要求3所述的化合物或其互变异构体、顺反异构体、内消旋体、外消旋 体、对映异构体、非对映异构体、阻转异构体或其混合物形式，或其药学上可接受的盐，溶剂合物或前药，其特征在于，R 0'为苯基、5或6元单环杂芳基或吡啶酮基，其中，所述5或6元单环杂芳基具有1、2或3个选自N、O和S的杂原子作为环原子；且所述的苯基、5或6元单环杂芳基和吡啶酮基为未取代的或被1、2、3或4个独立选自R s3的基团取代。
  19. 如权利要求3所述的化合物或其互变异构体、顺反异构体、内消旋体、外消旋体、对映异构体、非对映异构体、阻转异构体或其混合物形式，或其药学上可接受的盐，溶剂合物或前药，其特征在于，R 1、R 2各自独立地为氢、卤素、氰基、氨基、NHCH 3、N(CH 3) 2、甲基、乙基、正丙基、异丙基、一氯甲基、二氯甲基、三氯甲基、一氯乙基、1,2-二氯乙基、三氯乙基、一溴乙基、一氟甲基、二氟甲基、三氟甲基、一氟乙基、二氟乙基、三氟乙基、-CH 2-羟基、-CH 2-氰基、-CH 2-甲氧基、-CH 2-乙氧基、-CH 2-丙氧基、-CH 2-异丙氧基、-CH 2-NH 2、-CH 2-NHCH 3、-CH 2-N(CH 3) 2、-CH 2-3至6元杂环烷基或-CH 2-5或6元单环杂芳基；所述3至6元杂环烷基选自：氮丙环、环氧乙烷、氮杂环丁烷、氧杂环丁烷、四氢呋喃、四氢噻吩、四氢吡咯、哌啶、哌嗪、吗啉、硫代吗啉、硫代吗啉-1,1-二氧化物、四氢吡喃；所述5或6元单环杂芳基选自：噻吩、N-烷环吡咯、呋喃、噻唑、异噻唑、咪唑、噁唑、吡咯、吡唑、三唑、1,2,3-三唑、1,2,4-三唑、1,2,5-三唑、1,3,4-三唑、四唑、异噁唑、噁二唑、1,2,3-噁二唑、1,2,4-噁二唑、1,2,5-噁二唑、1,3,4-噁二唑、噻二唑、吡啶、哒嗪、嘧啶、吡嗪；所述3至6元杂环烷基、5或6元单环杂芳基任选地被1或2个卤素或C 1-3烷基取代。
  20. 如权利要求3所述的化合物或其互变异构体、顺反异构体、内消旋体、外消旋体、对映异构体、非对映异构体、阻转异构体或其混合物形式，或其药学上可接受的盐，溶剂合物或前药，其特征在于，R 3为氢、卤素、甲氧基、乙氧基、丙氧基或异丙氧基。
  21. 如权利要求3所述的化合物或其互变异构体、顺反异构体、内消旋体、外消旋体、对映异构体、非对映异构体、阻转异构体或其混合物形式，或其药学上可接受的盐，溶剂合物或前药，其特征在于，R 4为氢、一氯甲基、二氯甲基、三氯甲基、一氯乙基、1,2-二氯乙基、三氯乙基、一溴乙基、一氟甲基、二氟甲基、三氟甲基、一氟乙基、二氟乙基、三氟乙基、-CH 2-羟基、-CH 2-氰基、-CH 2-甲氧基、-CH 2-乙氧基、-CH 2-丙氧基或-CH 2-异丙氧基。
  22. 如权利要求3或4所述的化合物或其互变异构体、顺反异构体、内消旋体、外消旋体、对映异构体、非对映异构体、阻转异构体或其混合物形式，或其药学上可接受的盐，溶剂合物或前药，其特征在于，P'为O、NH或NR m'；R m'为-氘代C 1-6烷基或-C 1-6烷基；R 42'为-C 1-3烷基-(C＝O)-、-(C＝O)-或-C 1-3烷基-。
  23. 如权利要求3所述的化合物或其互变异构体、顺反异构体、内消旋体、外消旋体、对映异构体、非对映异构体、阻转异构体或其混合物形式，或其药学上可接受的盐，溶剂合物或前药，其特征在于，式(ⅠA)化合物选自表A-1。
  24. 如权利要求3所述的化合物或其互变异构体、顺反异构体、内消旋体、外消旋体、对映异构体、非对映异构体、阻转异构体或其混合物形式，或其药学上可接受的盐，溶剂合物或前药，其特征在于，式(ⅠA)化合物选自表A-2。
  25. 一种药物组合物，所述药物组合物包括权利要求1至24中任一项所述的化合 物或其互变异构体、顺反异构体、内消旋体、外消旋体、对映异构体、非对映异构体、阻转异构体或其混合物形式，或其药学上可接受的盐，溶剂合物或前药；以及药学可接受的载体。
  26. 如权利要求1至24中任一项所述的化合物或其互变异构体、顺反异构体、内消旋体、外消旋体、对映异构体、非对映异构体、阻转异构体或其混合物形式，或其药学上可接受的盐，溶剂合物或前药，或如权利要求25所述药物组合物在制备预防和/或治疗KRAS G12C突变诱导疾病的药物中的用途。
  27. 如权利要求1至24中任一项所述的化合物或其互变异构体、顺反异构体、内消旋体、外消旋体、对映异构体、非对映异构体、阻转异构体或其混合物形式，或其药学上可接受的盐，溶剂合物或前药，或如权利要求25所述药物组合物在制备KRAS突变抑制剂中的用途；所述KRAS突变为KRAS G12C突变。
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