WO2024099438A1 - 作为sumo活化酶抑制剂的化合物 - Google Patents

作为sumo活化酶抑制剂的化合物 Download PDF

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WO2024099438A1
WO2024099438A1 PCT/CN2023/131049 CN2023131049W WO2024099438A1 WO 2024099438 A1 WO2024099438 A1 WO 2024099438A1 CN 2023131049 W CN2023131049 W CN 2023131049W WO 2024099438 A1 WO2024099438 A1 WO 2024099438A1
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membered
compound
cycloalkyl
heterocycloalkyl
alkyl
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French (fr)
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谢雨礼
吴应鸣
钱立晖
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微境生物医药科技(上海)有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D419/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms
    • C07D419/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • 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
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D515/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D515/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D515/10—Spiro-condensed systems

Definitions

  • the present invention belongs to the field of pharmaceutical chemistry, and more specifically, relates to a class of compounds having SAE protein inhibitory effects, and a preparation method thereof and the use of the compounds in preparing drugs for treating or preventing SAE-mediated related diseases.
  • Small ubiquitin-like modifier is a ubiquitin-like protein that is a class of intracellular reversible protein post-translational modifiers.
  • Mammalian cells express three SUMO family proteins: SUMO1, SUMO2, and SUMO3.
  • SUMO2 and SUMO3 share about 95% amino acid sequence homology and mainly form oligomeric chains when modifying proteins.
  • SUMO1 has about 45% sequence homology with SUMO2 and SUMO3 and mainly modifies proteins in a monomeric manner.
  • SUMOylation of target proteins activates, transfers, and finally connects SUMO proteins to lysine residues of target proteins through three consecutive reactions catalyzed by enzymes.
  • SAE Sudo Activating Enzyme catalyzes the first step reaction.
  • SAE belongs to a class of activating enzymes collectively referred to as E1, and is a class of heterodimers formed by SAE1, SAE2, or UBA2.
  • SAE uses ATP to adenylate the C-terminal glycine residue of SUMO, and then a thioester intermediate is formed between the C-terminal glycine of SUMO and the cysteine residue in SAE2.
  • the SUMO protein is transferred from E1 to the SUMO conjugating enzyme (collectively referred to as E2) through thioester bond exchange.
  • the SUMO protein is finally transferred to the lysine residue of the target protein to form an oligomeric chain.
  • the SUMOylation of proteins affects the catalytic activity, intracellular localization and interaction between proteins.
  • studies have shown that the SUMOylation of proteins plays an important role in various signaling pathways of cells, such as cell division and DNA repair, chromosome segregation, nuclear transport, gene transcription and immune regulation. High expression of proteins related to the SUMO signaling pathway is associated with poor prognosis in some cancer patients.
  • Knockdown of SAE has a synthetic lethal effect on some MYC-highly expressed tumor cells.
  • SUMOylation can also regulate innate immune responses. Inhibition of SUMOylation can enhance the expression of type 1 interferon (IFN).
  • IFN type 1 interferon
  • the present invention provides a compound represented by general formula (1) or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates:
  • Y is -O-, -CH 2 - or -N(H)-;
  • Ra is -H, -F, -NH2 or -OH;
  • Ra ' is -H or -F, and when Ra is -NH2 or -OH, Ra ' is -H;
  • R b is -H or (C 1 -C 4 ) alkyl
  • R c is -H or (C 1 -C 4 ) alkyl
  • R d is -H, halogen, -CF 3 or (C 1 -C 4 )alkyl
  • Re and Re ' are each independently -H or halogen, and Re and Re ' are not -H at the same time;
  • X1 is C(H), C(F) or N;
  • X2 is S or O
  • X3 is C( Rx3 ) or N;
  • R x3 is -H, halogen or -CH 3 ;
  • X4 is S, O, C( Rx41 )( Rx41' ) or N( Rx42 );
  • R x42 is -H, (C 1 -C 4 )alkyl or (C 3 -C 5 )cycloalkyl;
  • R x41 and R x41' are each independently -H, halogen, -OH, -OR x411 , -N(R x411 )(R x412 ), -CN, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 3 -C 9 )cycloalkyl or (C 1 -C 6 )alkoxy;
  • R x411 and R x412 are each independently -H, (C 1 -C 4 )alkyl or (C 3 -C 5 )cycloalkyl, or R x411 and R x412 on the same nitrogen atom and the N atom to which they are attached can together form a (3-6 membered) heterocycloalkyl, wherein the (3-6 membered) heterocycloalkyl may be optionally substituted by 1, 2, 3 or 4 of the following groups: -H or halogen;
  • R3 and R4 are each independently -H, -D, -OH, -NH2 , -CN, ( C1 - C6 ) alkyl, ( C1 - C6 ) haloalkyl, ( C2 -C6) alkenyl, (C2- C6 ) alkynyl, ( C3 - C9 ) cycloalkyl, ( C1 - C6 ) alkoxy, (C6- C14 ) aryl, ( 3-11 membered) heterocycloalkyl or (5-11 membered) heteroaryl, wherein said ( C1 - C6 ) alkyl, (C1-C6) haloalkyl, ( C2 - C6 ) alkenyl, ( C2 - C6 ) alkynyl, ( C3 - C9 ) cycloalkyl, ( C1 - C6 ) alkoxy, (C6- C14 ) aryl, ( 3-11 membered
  • )aryl, (3-11 membered)heterocycloalkyl or (5-11 membered)heteroaryl may each independently be optionally substituted by 1, 2, 3 or 4 of the following groups: -H, halogen, -OH, -( CH2 ) rOR31 , -(CH2) rNR31R32 , -OR31, -NR31R32, -CN, -C(O)NR31R32 , -NR32C(O) R31 , -NR32S (O)2R31 , -S ( O ) pR31 and -S(O) 2NR31R32 ; or R3 and R4 together with the carbon atom to which they are attached can form a ( 4-7 membered)heterocycloalkyl or (C3-C6)cycloalkyl, wherein the (4-7 membered )heterocycloalkyl or ( C3 - C6 )cycloalkyl group is optionally substituted
  • R 5 and R 6 are each independently -H, -D, -OH, -NH 2 , -CN, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 9 )cycloalkyl, (C 1 -C 6 )alkoxy, (C 6 -C 14 )aryl, (3-11 membered)heterocycloalkyl or (5-11 membered)heteroaryl, wherein the (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 9 )cycloalkyl, (C 1 -C 6 )alkoxy, (C 6 -C 14 )aryl,
  • Ring A is (C 6 -C 10 )aryl or (5-10 membered) heteroaryl;
  • Each R 1 is independently selected from the group consisting of: -H, halogen, -OH, -NO 2 , -NR 31 R 32 , -(CH 2 ) r OR 31 , -(CH 2 ) r NR 31 R 32 , -CN, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, (C 3 -C 8 ) cycloalkyl, -C(O)NR 31 R 32 , -NR 32 C(O)R 31 , -NR 32 S(O) 2 R 31 , -S(O) p R 31 , or -S(O) 2 NR 31 R 32 , wherein the (C 1 -C 6 ) alkyl, (C 1 -C 6 )haloalkyl,
  • Ring B is (C 5 -C 7 )cycloalkyl or (5-7 membered)heterocycloalkyl;
  • Each R 2 is independently selected from: -H, halogen, -OH, -NR 31 R 32 , -CN, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl or (C 3 -C 8 )cycloalkyl; or two R 2 on the same carbon atom and the carbon atom to which they are attached can together form a (4-6 membered)heterocycloalkyl or (C 3 -C 6 )cycloalkyl, wherein the (4-6 membered)heterocycloalkyl or (C 3 -C 6 )cycloalkyl can be optionally substituted by 1, 2, 3 or 4 of the following groups: -H, halogen, (C 1 -C 6 )alkyl or (C 1 -C 6 )alkoxy
  • R 31 and R 32 are each independently -H, (C 1 -C 4 )alkyl or (C 3 -C 5 )cycloalkyl, or R 31 and R 32 on the same nitrogen atom and the N atom to which they are attached can together form a (3-6 membered) heterocycloalkyl, wherein the (3-6 membered) heterocycloalkyl may be optionally substituted by 1, 2, 3 or 4 of the following groups: -H and halogen; and
  • n is an integer of 0, 1, 2, 3 or 4
  • m is an integer of 0, 1, 2, 3 or 4
  • r is an integer of 0, 1 or 2
  • p is an integer of 0, 1 or 2.
  • R d is -H, -F, -CF 3 or -CH 3 ;
  • R d is preferably -H or -F;
  • R d is more preferably -H;
  • R d is more preferably -F.
  • Re and Re ' are each independently -H or -F, and Re and Re ' are not -H at the same time.
  • R x42 is -H, (C 1 -C 3 ) alkyl or (C 3 -C 5 ) cycloalkyl.
  • R x42 is -H
  • R x42 is preferably -H
  • R x41 and R x41' are each independently -H, -F, -OH, -OCH 3 , -N(CH 3 ) 2 , -NH 2 , -CN, -CF 3 , -CH 2 CF 3 ,
  • R3 and R4 are each independently -H, -D, -OH, -NH2 , -CN, ( C1 - C3 ) alkyl, (C1- C3 ) haloalkyl, ( C2 - C4 ) alkenyl, ( C2 - C4 ) alkynyl, ( C3 - C5 ) cycloalkyl, ( C1 - C3 ) alkoxy, phenyl, (4-6 membered) heterocycloalkyl or (5-6 membered) heteroaryl, wherein the (C1- C3 ) alkyl, ( C1 - C3 ) haloalkyl , (C2-C4) alkenyl, (C2-C4 ) alkynyl , ( C3- C5 ) cycloalkyl, ( C1 - C3 ) alkoxy, phenyl, (4-6 membered) heterocycloalkyl, wherein the (C1- C
  • phenyl, (4-6 membered)heterocycloalkyl or (5-6 membered)heteroaryl may each independently be optionally substituted by 1, 2 , 3 or 4 of the following groups: -H, -F, -OH, -CH2OCH3 , -CH2N ( CH3 ) 2 , -OCH3 , -N( CH3 ) 2 , -CN, -C(O)N( CH3 ) 2 , -NCH3C (O) CH3 , -NHC(O) CH3 , -NCH3S(O) 2CH3 , -NHS (O) 2CH3 , -SCH3 , -S(O) 2CH3 , -S(O) 2NH2 and -S(O) 2N ( CH3 ) 2 ; or R3 and R4 together with the carbon atom to which they are attached can form (4-6 membered)heterocycloalkyl
  • R 3 and R 4 are each independently selected from -H, -D, Or R 3 and R 4 together with the carbon atom to which they are connected can form a cyclopropyl group; or R 3 and the adjacent R 5 together with the atom to which they are connected can form a cyclopropyl group; or R 3 and R 4 together form an oxo group.
  • R 5 and R 6 are each independently -H, -D, -OH, -NH 2 , -CN, (C 1 -C 3 )alkyl, (C 1 -C 3 )haloalkyl, (C 2 -C 4 )alkenyl, (C 2 -C 4 )alkynyl, (C 3 -C 5 )cycloalkyl, (C 1 -C 3 )alkoxy, phenyl, (4-6 membered)heterocycloalkyl or (5-6 membered)heteroaryl, wherein the (C 1 -C 3 )alkyl, (C 1 -C 3 )haloalkyl, (C 2 -C 4 )alkenyl, (C 2 -C 4 )alkynyl, (C 3 -C 5 )cycloalkyl, (C 1 -C 3 )alkoxy, phenyl, (4-6 membere
  • phenyl, (4-6 membered)heterocycloalkyl or (5-6 membered)heteroaryl may each independently be optionally substituted with 1, 2, 3 or 4 of the following groups: -H, -F, -OH, -CH2OCH3 , -CH2N ( CH3 ) 2 , -OCH3 , -N( CH3 ) 2 , -NH2 , -CN, -C(O)N( CH3 ) 2 , -NCH3C ( O) CH3 , -NHC(O) CH3 , -NCH3S(O) 2CH3 , -NHS (O) 2CH3 , -SCH3 , -S(O) 2CH3 , -S(O) 2NH2 and -S(O) 2N ( CH3 ) 2 ; or R5 and R 6 and the carbon atom to which they are attached can together form a (4-6 membered) heterocycl
  • R 5 and R 6 are each independently selected from -H, -D, Or R 5 and R 6 together with the carbon atom to which they are connected can form a cyclopropyl group; or R 5 and R 6 together form an oxo group.
  • ring A is phenyl or (5-6 membered) heteroaryl, and ring A is preferably phenyl or (5-6 membered) heteroaryl containing 1 or 2 atoms independently selected from N, O or S.
  • ring A is:
  • each R 1 is independently selected from: -H, -F, -Cl, -Br, -I, -OH, -NO 2 , -N(CH 3 ) 2 , -NH 2 , -CH 2 OCH 3 , -CH 2 N(CH 3 ) 2 , -CN, (C 1 -C 3 ) alkyl, (C 1 -C 3 ) haloalkyl, (C 1 -C 3 ) alkoxy, (C 2 -C 4 ) alkenyl, (C 2 -C 4 ) alkynyl, (C 3 -C 6 ) cycloalkyl, -C(O)N(CH 3 ) 2 , -NCH 3 C(O)CH 3 , -NHC(O)CH 3 , -NCH 3 S(O) 2 CH 3 , -NHS(O) 2 CH 3 , -SCH 3 , -S
  • each R 1 is independently: -H, -F, -Cl, -Br, -I, -OH, -NO 2 , -N(CH 3 ) 2 , -NH 2 , -CH 2 OCH 3 , -CH 2 N(CH 3 ) 2 , -CN, -C(O)N(CH 3 ) 2 , -NCH 3 C(O)CH 3 , -NHC(O)CH 3 , -NCH 3 S(O) 2 CH 3 , -NHS(O) 2 CH 3 , -SCH 3 , -S(O) 2 CH 3 , -S(O) 2 NH 2 , -S(O) 2 N(CH 3 ) 2 , -CF 3 , -CH 2 CF 3 , -OCH 3 , -OCH 2 CH 3 , -OCH(CH 3 ) 2 , R1 is preferably -H,
  • ring B is a (C 5 -C 6 )cycloalkyl group or a (5-6 membered)heterocycloalkyl group, preferably a partially unsaturated (C 5 -C 6 )cycloalkyl group or a (5-6 membered) partially unsaturated heterocycloalkyl group containing one atom independently selected from N, O or S.
  • each R 2 is independently selected from: -H, -F, -Cl, -Br, -I, -OH, -N(CH 3 ) 2 , -NH 2 , -CN, (C 1 -C 3 ) alkyl, (C 1 -C 3 ) haloalkyl, (C 1 -C 3 ) alkoxy, (C 2 -C 4 ) alkenyl, (C 2 -C 4 ) alkynyl or (C 3 -C 5 ) cycloalkyl; or two R 2 on the same carbon atom and the carbon atom to which they are connected can together form a (4-5 membered) heterocycloalkyl or (C 3 -C 5 ) cycloalkyl, wherein the (4-5 membered) heterocycloalkyl or (C 3 -C 5 ) cycloalkyl can be optionally substituted by 1, 2, 3 or 4 of the following groups:
  • each R 2 is independently selected from: -H, -F, -Cl, -Br, -I, -OH, -N(CH 3 ) 2 , -NH 2 , -CN, -CF 3 , -CH 2 CF 3 , -OCH 3 , -OCH 2 CH 3 , -OCH(CH 3 ) 2 , R2 is preferably -H, -F, -Cl, -CN, -CF 3 , -CH 2 CF 3 , -OCH 3 or R 1 is more preferably -H, -F, -Cl, -CF 3 , -CH 2 CF 3 or R 1 is more preferably -H, -F, -CH 2 CF 3 , m is preferably 1; m is preferably 2.
  • the general formula (1) has a structure as shown in the general formula (1a):
  • Ring A, Ring B, R1 , R2 , R3 , R4 , R5, R6 , Ra , Ra ' , Rb , Rc , Rd , Re , Re' , X1 , X2 , X3 , X4 , m and n are as defined above and exemplified in the specific examples.
  • the general formula (1) has a structure as shown in the general formula (1b):
  • Ring A, Ring B, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , Ra , Ra ' , R b , R c , R d , Re , Re' , X 1 , X 4 , m and n are as defined above and exemplified in the specific examples.
  • the general formula (1) has a structure as shown in the general formula (1c):
  • Ring A, Ring B, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , Ra , Ra ' , R b , R c , Re , Re' , X 1 , X 4 , m and n are as defined above and exemplified in the specific examples.
  • the general formula (1) has a structure as shown in the general formula (1d):
  • Ring A, Ring B, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , Ra , Ra ' , R b , Re , Re' , X 1 , X 4 , m and n are as defined above and exemplified in the specific examples.
  • the general formula (1) has a structure as shown in the general formula (1e):
  • ring A, ring B, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R b , Re , Re ' , X 1 , X 4 , m and n are as defined above and exemplified in the specific examples.
  • the general formula (1) has a structure as shown in the general formula (1g):
  • ring A, ring B, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , Re , Re ' , X 4 , m and n are as defined above and exemplified in the specific examples.
  • the general formula (1) has a structure as shown in the general formula (1h) or (1i):
  • ring A, ring B, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , Re , Re ' , X 4 , m and n are as defined above and exemplified in the specific examples.
  • the general formula (1) has a structure as shown in the general formula (1j), (1k), (1l) or (1m):
  • ring A, ring B, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , Re , X 4 , m and n are as defined above and exemplified in the specific examples.
  • the compound of formula (1) has one of the following structures:
  • the compound of formula (1) has one of the following structures:
  • the compound of formula (1) has one of the following structures:
  • the compound of formula (1) has one of the following structures:
  • the present invention also provides a compound represented by general formula (2) or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates:
  • Y' is -O-, -CH 2 - or -N(H)-;
  • R a1 is -H, -F, -NH 2 or -OH;
  • Ra1 ' is -H or -F, and when Ra1 is -NH2 or -OH, Ra1' is -H;
  • R b' is -H or (C 1 -C 4 ) alkyl
  • R c' is -H or (C 1 -C 4 ) alkyl
  • R d' is -H, halogen, -CF 3 or (C 1 -C 4 )alkyl
  • R e1 and R e1' are each independently -H or halogen, and R e1 and R e1' are not -H at the same time;
  • X 1' is C(H), C(F) or N;
  • X 2' is S or O
  • X 3' is C (R x3' ) or N;
  • R x3' is -H, halogen or -CH 3 ;
  • X4' is S, O, C ( Rx41a ), ( Rx41b ) or N ( Rx42' );
  • R x42' is -H, (C 1 -C 4 )alkyl or (C 3 -C 5 )cycloalkyl;
  • R x41a and R x41b are each independently -H, halogen, -OH, -OR x411' , -N(R x411' )(R x412' ), -CN, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 3 -C 9 )cycloalkyl or (C 1 -C 6 )alkoxy;
  • R x411' and R x412' are each independently -H, (C 1 -C 4 )alkyl or (C 3 -C 5 )cycloalkyl, or R x411' and R x412' on the same nitrogen atom and the N atom to which they are attached can together form a (3-6 membered) heterocycloalkyl, wherein the (3-6 membered) heterocycloalkyl may be optionally substituted by 1, 2, 3 or 4 of the following groups: -H or halogen;
  • R 3' and R 4' are each independently optionally -H, -D, -OH, -NH 2 , -CN, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 9 )cycloalkyl, (C 1 -C 6 )alkoxy, (C 6 -C 14 )aryl, (3-11 membered)heterocycloalkyl or (5-11 membered)heteroaryl, wherein the (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 9 )cycloalkyl, (C 1 -C 6 )alkoxy, (C 6 -C 14
  • R 5' and R 6' are each independently -H, -D, -OH, -NH 2 , -CN, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 9 )cycloalkyl, (C 1 -C 6 )alkoxy, (C 6 -C 14 )aryl, (3-11 membered)heterocycloalkyl or (5-11 membered)heteroaryl, wherein the (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 9 )cycloalkyl, (C 1 -C 6 )alkoxy, (C 6 -C 14 )ary
  • Ring A' is (C 6 -C 10 )aryl or (5-10 membered) heteroaryl;
  • Each R 1' is independently selected from: -H, halogen, -OH, -NO 2 , -NR 31' R 32' , -(CH 2 ) r OR 31' , -(CH 2 ) r NR 31' R 32' , -CN, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, (C 3 -C 8 ) cycloalkyl, -C(O)NR 31' R 32' , -NR 32' C(O)R 31' , -NR 32' S(O) 2 R 31' , -S(O) p R 31' or -S(O) 2 NR 31' R 32' , wherein said (C 1 -C 6 )alkyl, (C 1 -C 6
  • R 7' is: -H, -D, halogen, -OH, -NR 31' R 32' , -CN, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl or (C 3 -C 8 )cycloalkyl;
  • R 8' is: -H, -D, -OH, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl or (C 3 -C 8 )cycloalkyl;
  • R 31' and R 32' are each independently -H, (C 1 -C 4 )alkyl or (C 3 -C 5 )cycloalkyl, or R 31' and R 32' on the same nitrogen atom are optionally substituted with each other.
  • the N atoms to which they are attached can together form a (3-6 membered) heterocycloalkyl, wherein the (3-6 membered) heterocycloalkyl may be optionally substituted with 1, 2, 3 or 4 of the following groups: -H and halogen; and
  • n is an integer of 0, 1, 2, 3 or 4
  • r is an integer of 0, 1 or 2
  • p is an integer of 0, 1 or 2
  • q is an integer of 0, 1 or 2.
  • R d' is -H, -F, -CF 3 or -CH 3 .
  • Re1 and Re1' are each independently -H or -F, and Re1 and Re1' are not -H at the same time.
  • R x42' is -H, (C 1 -C 3 ) alkyl or (C 3 -C 5 ) cycloalkyl.
  • R x42' is -H
  • R x41a and R x41b are each independently -H, -F, -OH, -OCH 3 , -N(CH 3 ) 2 , -NH 2 , -CN, -CF 3 , -CH 2 CF 3 ,
  • R 3' and R 4' are each independently -H, -D, -OH, -NH 2 , -CN, (C 1 -C 3 )alkyl, (C 1 -C 3 )haloalkyl, (C 2 -C 4 )alkenyl, (C 2 -C 4 )alkynyl, (C 3 -C 5 )cycloalkyl, (C 1 -C 3 )alkoxy, phenyl, (4-6 membered)heterocycloalkyl or (5-6 membered)heteroaryl, wherein the (C 1 -C 3 )alkyl, (C 1 -C 3 )haloalkyl, (C 2 -C 4 )alkenyl, (C 2 -C 4 )alkynyl, (C 3 -C 5 ) cycloalkyl , (C 1 -C 3 )alkoxy, phenyl,
  • phenyl, (4-6 membered)heterocycloalkyl or (5-6 membered)heteroaryl may each independently be optionally substituted by 1, 2 , 3 or 4 of the following groups: -H, -F, -OH, -CH2OCH3 , -CH2N ( CH3 ) 2 , -OCH3 , -N( CH3 ) 2 , -CN, -C(O)N( CH3 ) 2 , -NCH3C (O) CH3 , -NHC(O) CH3 , -NCH3S(O) 2CH3 , -NHS (O) 2CH3 , -SCH3 , -S(O) 2CH3 , -S(O) 2NH2 and -S(O) 2N ( CH3 ) 2 ; or R3 ' and R4 ' together with the carbon atom to which they are attached can form a (4-6 membered)heter
  • R 5' and R 6' are each independently -H, -D, -OH, -NH 2 , -CN, (C 1 -C 3 )alkyl, (C 1 -C 3 )haloalkyl, (C 2 -C 4 )alkenyl, (C 2 -C 4 )alkynyl, (C 3 -C 5 )cycloalkyl, (C 1 -C 3 )alkoxy, phenyl, (4-6 membered)heterocycloalkyl or (5-6 membered)heteroaryl, wherein the (C 1 -C 3 )alkyl, (C 1 -C 3 )haloalkyl, (C 2 -C 4 )alkenyl, (C 2 -C 4 )alkynyl, (C 3 -C 5 ) cycloalkyl , (C 1 -C 3 )alkoxy, phenyl,
  • phenyl, (4-6 membered)heterocycloalkyl or (5-6 membered)heteroaryl may each independently be optionally substituted with 1, 2, 3 or 4 of the following groups: -H, -F, -OH, -CH2OCH3 , -CH2N ( CH3 ) 2 , -OCH3 , -N( CH3 ) 2 , -NH2 , -CN, -C(O)N( CH3 ) 2 , -NCH3C ( O) CH3 , -NHC(O) CH3 , -NCH3S(O) 2CH3 , -NHS (O) 2CH3 , -SCH3 , -S(O) 2CH3 , -S(O) 2NH2 , and - S(O) 2 N(CH 3 ) 2 ; or R 5′ and R 6′ together with the carbon atom to which they are attached can form a (4-6 membere
  • ring A' is a phenyl group or a (5-6 membered) heteroaryl group.
  • ring A' is:
  • each R 1' is independently selected from: -H, -F, -Cl, -Br, -I, -OH, -NO 2 , -N(CH 3 ) 2 , -NH 2 , -CH 2 OCH 3 , -CH 2 N(CH 3 ) 2 , -CN, (C 1 -C 3 ) alkyl, (C 1 -C 3 ) haloalkyl, (C 1 -C 3 ) alkoxy, (C 2 -C 4 ) alkenyl, (C 2 -C 4 ) alkynyl, (C 3 -C 6 ) cycloalkyl, -C(O)N(CH 3 ) 2 , -NCH 3 C(O)CH 3 , -NHC(O)CH 3 , -NCH 3 S(O) 2 CH 3 , -NHS(O) 2 CH 3 , -SCH 3 , -
  • each R 1' is independently: -H, -F, -Cl, -Br, -I, -OH, -NO 2 , -N(CH 3 ) 2 , -NH 2 , -CH 2 OCH 3 , -CH 2 N(CH 3 ) 2 , -CN, -C(O)N(CH 3 ) 2 , -NCH 3 C(O)CH 3 , -NHC(O)CH 3 , -NCH 3 S(O) 2 CH 3 , -NHS(O) 2 CH 3 , -SCH 3 , -S(O) 2 CH 3 , -S(O) 2 NH 2 , -S(O) 2 N(CH 3 ) 2 , -CF 3 , -CH 2 CF 3 , -OCH 3 , -OCH 2 CH 3 , -OCH(CH 3 ) 2 ,
  • R 7' is: -H, -D, -F, -Cl, -Br, -I, -OH, -N(CH 3 ) 2 , -NH 2 , -CN, (C 1 -C 3 ) alkyl, (C 1 -C 3 ) haloalkyl, (C 1 -C 3 ) alkoxy, (C 2 -C 4 ) alkenyl, (C 2 -C 4 ) alkynyl or (C 3 -C 5 ) cycloalkyl.
  • R 7' is: -H, -D, -F, -Cl, -Br, -I, -OH, -N(CH 3 ) 2 , -NH 2 , -CN, -CF 3 , -CH 2 CF 3 , -OCH 3 , -OCH 2 CH 3 , -OCH(CH 3 ) 2 ,
  • R 8' is: -H, -D, -OH, (C 1 -C 3 ) alkyl, (C 2 -C 4 ) alkenyl, (C 2 -C 4 ) alkynyl or (C 3 -C 5 ) cycloalkyl.
  • R 8' is: -H, -D,
  • the compound of formula (2) has one of the following structures:
  • the compound of formula (2) has one of the following structures:
  • Another object of the present invention is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier, diluent and/or excipient, and the compounds of the general formula (1) and (2) of the present invention, or their isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates as active ingredients.
  • Another object of the present invention is to provide the use of the compounds represented by the general formula (1) and the general formula (2) of the present invention, or their respective isomers, respective crystal forms, pharmaceutically acceptable salts, hydrates or solvates, or the above-mentioned pharmaceutical compositions for preparing drugs for treating, regulating or preventing diseases related to SAE proteins.
  • the disease is preferably cancer, and the cancer is blood cancer and solid tumor.
  • Another object of the present invention is to provide a method for treating, regulating or preventing diseases related to SAE proteins, comprising administering to a subject a therapeutically effective amount of the compounds represented by the general formula (1) and the general formula (2) of the present invention, or their respective isomers, respective crystal forms, pharmaceutically acceptable salts, hydrates or solvates, or the above-mentioned pharmaceutical compositions.
  • the compounds described above can be synthesized using standard synthetic techniques or known techniques in combination with the methods described herein.
  • the solvents, temperatures and other reaction conditions mentioned herein can be changed.
  • the starting materials for the synthesis of the compounds can be obtained by synthesis or from commercial sources.
  • the compounds described herein and other related compounds with different substituents can be synthesized using known techniques and raw materials, including those found in March, ADVANCED ORGANIC CHEMISTRY 4th Ed., (Wiley 1992); Carey and Sundberg, ADVANCED ORGANIC CHEMISTRY 4th Ed., Vols. A and B (Plenum 2000, 2001), Green and Wuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS 3rd Ed., (Wiley 1999).
  • the general method for preparing the compounds can be changed by using appropriate reagents and conditions for introducing different groups into the molecular formula provided herein.
  • the compounds described herein are prepared according to methods known in the art. However, the conditions of the methods, such as reactants, solvents, bases, the amount of compounds used, reaction temperature, reaction time, etc., are not limited to the following explanations.
  • the compounds of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art, and such combinations can be easily performed by technicians in the field to which the present invention belongs.
  • the present invention also provides a method for preparing the compounds, wherein the compounds of formula (1) and formula (2) can be prepared using the following general reaction schemes 1-19:
  • the compound of formula (1) can be prepared according to general reaction scheme 1, wherein P is R b or a hydroxyl protecting group, ring A, ring B, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , Ra , Ra' , R b , R c , R d , Re , Re' , X 1 , X 2 , X 3 , m and n are as defined above, H represents hydrogen, N represents nitrogen, O represents oxygen, Cl represents chlorine, X 4a represents O or S, and L represents O or NH.
  • the compound Compound 1-1 and compound 1-2 undergo a substitution reaction to generate an alcohol intermediate, which is further oxidized to obtain a ketone compound 1-3.
  • Compound 1-3 and compound 1-4 undergo a substitution reaction to generate compound 1-5.
  • Compound 1-5 further undergoes a substitution reaction with compound 1-6 to generate compound 1-7.
  • compound 1-7 is deprotected from the hydroxyl protecting group to generate compound 1-8.
  • compound 1-8 is chirally resolved to obtain optical isomers 1-A and 1-B.
  • the compounds of formula (1) can also be prepared according to general reaction scheme 2, wherein P is R b or a hydroxyl protecting group, P' is an amine protecting group, ring A, ring B, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , Ra , Ra' , R b , R c , R d , Re , Re' , X 1 , X 2 , X 3 , m and n are as defined above, H represents hydrogen, N represents nitrogen, O represents oxygen, Cl represents chlorine, and L represents O or NH.
  • compound 2-1 and compound 2-2 undergo substitution reaction to generate an alcohol intermediate, which is further oxidized to obtain a ketone compound 2-3.
  • Compound 2-3 and compound 2-4 undergo substitution reaction to generate compound 2-5.
  • Compound 2-5 further undergoes substitution reaction with compound 2-6 to generate compound 2-7.
  • compound 2-7 is deprotected to generate compound 2-8.
  • compound 2-8 is chirally resolved to obtain optical isomers 2-A and 2-B.
  • the compounds of formula (2) can be prepared according to general reaction scheme 3, wherein P is R b' or a hydroxy protecting group, ring A', R 1' , R 3' , R 4' , R 5' , R 6' , R 7' , R 8' , Ra1 , Ra1' , R b' , R c' , R d' , Re1 , Re1' , X 1' , X 2' , X 3' , n and q are as defined above, H represents hydrogen, N represents nitrogen, O represents oxygen, Cl represents chlorine, X 4a represents O or S, and L represents O or NH.
  • compound 3-1 and compound 3-2 undergo substitution reaction to generate an alcohol intermediate, which is further oxidized to obtain a ketone compound 3-3.
  • Compound 3-3 and compound 3-4 undergo substitution reaction to generate compound 3-5.
  • Compound 3-5 further undergoes substitution reaction with compound 3-6 to generate compound 3-7.
  • compound 3-7 is deprotected from the hydroxyl protecting group to generate compound 3-8.
  • compound 3-8 is chirally resolved to obtain optical isomers 3-A and 3-B.
  • the compounds of formula (2) can also be prepared according to general reaction scheme 4, wherein P is R b' or a hydroxyl protecting group, P' is an amine protecting group, ring A', R 1' , R 3' , R 4' , R 5' , R 6' , R 7' , R 8' , Ra1 , Ra1' , R b' , R c' , R d' , Re1 , Re1' , X 1' , X 2' , X 3' , n and q are as defined above, H represents hydrogen, N represents nitrogen, O represents oxygen, Cl represents chlorine, X 4a represents O or S, and L represents O or NH.
  • compound 4-1 and compound 4-2 undergo substitution reaction to generate an alcohol intermediate, which is further oxidized to obtain ketone compound 4-3.
  • Compound 4-3 and compound 4-4 undergo substitution reaction to generate compound 4-5.
  • Compound 4-5 further undergoes substitution reaction with compound 4-6 to generate compound 4-7.
  • compound 4-7 is deprotected from the hydroxyl protecting group to generate compound 4-8.
  • compound 4-8 is chirally resolved to obtain optical isomers 4-A and 4-B.
  • the embodiments of the compound of formula (1) can be prepared according to general reaction scheme 5, wherein R 1 , Re , Re' and n are as defined above, X represents O, S or CH 2 , H represents hydrogen, N represents nitrogen, O represents oxygen, and Cl represents chlorine.
  • compound 5-1 and nitromethane undergo condensation reaction to generate compound 5-2
  • compound 5-2 is reduced to obtain amine 5-3
  • amine 5-3 and ketone 5-4 undergo condensation to obtain compound 5-5
  • compound 5-5 undergoes cyclization reaction under acidic conditions to generate compound 5-6
  • compound 5-6 is demethylated to obtain compound 5-7
  • compound 5-7 reacts with PhNTf 2 to generate compound 5-8
  • compound 5-8 is reduced to obtain compound 5-9
  • compound 5-9 is deformylated to obtain compound 5-10
  • (Boc) 2 O-protected compound 5-10 gave compound 5-11, compound 5-11 reacted with DMF under n-butyl lithium to give aldehyde 5-12, aldehyde 5-12 reacted with compound 5-13 under n-butyl lithium to give compound 5-14, compound 5-14 was subjected to Dess-Martin oxidation or Swern oxidation to give ketone 5-15, ketone 5-15 and compound 5-16 under alkaline conditions to give compound 5-17
  • the embodiments of the compound of formula (1) can be prepared according to general reaction scheme 6, wherein R 1 , Re , Re' and n are as defined above, Y represents Br or I, H represents hydrogen, N represents nitrogen, O represents oxygen, and Cl represents chlorine.
  • compound 6-1 and nitromethane undergo condensation reaction to generate compound 6-2
  • compound 6-2 is reduced to obtain amine 6-3
  • amine 6-3 and ketone 6-4 undergo condensation to obtain compound 6-5
  • compound 6-5 reacts with acetic anhydride to generate compound 6-6
  • compound 6-6 undergoes cyclization reaction under Pd catalysis to generate compound 6-7
  • compound 6-7 is deacetylated to obtain compound 6-8
  • (Boc) 2 O-protected compound 6-8 gave compound 6-9
  • compound 6-9 underwent hydrogenation to give compound 6-10
  • compound 6-10 reacted with DMF under n-butyl lithium to give aldehyde 6-11, aldehyde 6-11 under n-butyl lithium and compound 6-12 under
  • the embodiments of the compound of formula (1) can be prepared according to general reaction scheme 7, wherein R 1 , Re , Re' and n are as defined above, Y represents Br or I, H represents hydrogen, N represents nitrogen, O represents oxygen, and Cl represents chlorine.
  • compound 7-1 and nitromethane undergo condensation reaction to generate compound 7-2
  • compound 7-2 is reduced to obtain amine 7-3
  • amine 7-3 and ketone 7-4 undergo condensation to obtain compound 7-5
  • compound 7-5 reacts with acetic anhydride to generate compound 7-6
  • compound 7-6 undergoes cyclization reaction under Pd catalysis to generate compound 7-7
  • compound 7-7 is deacetylated to obtain compound 7-8
  • (Boc) 2 O-protected compound 7-8 gave compound 7-9, compound 7-9 reacted with DMF under n-butyl lithium to give aldehyde 7-10, aldehyde 7-10 reacted with compound 7-11 under n-butyl lithium to give compound 7-12, compound 7-12 was oxidized
  • Embodiments of compounds of formula (1) can be prepared according to General Reaction Scheme 8, wherein R 1 , Re , Re ' and n are as defined above, Y represents Br or I, H represents hydrogen, N represents nitrogen, O represents oxygen, and Cl represents chlorine.
  • compound 8-1 and nitromethane undergo condensation reaction to produce compound 8-2
  • compound 8-2 is reduced to produce amine 8-3
  • amine 8-3 and ketone 8-4 undergo condensation to produce compound 8-5
  • compound 8-5 reacts with acetic anhydride to produce compound 8-6
  • compound 8-6 undergoes cyclization reaction under Pd catalysis to produce compound 8-7
  • compound 8-7 is deacetylated to produce compound 8-8
  • compound 8-8 is protected with (Boc) 2 O to produce compound 8-9
  • compound 8-9 undergoes oxidation reaction under potassium osmate and sodium periodate to produce dialdehyde 8-10
  • dialdehyde 8-10 is reduced with sodium borohydride to produce diol 8-11
  • Embodiments of compounds of formula (1) can be prepared according to general reaction scheme 9, wherein R 1 , Re , Re' and n are as defined above, Y represents Br or I, Z represents -H, -OH, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl or (C 3 -C 8 )cycloalkyl, H represents hydrogen, N represents nitrogen, O represents oxygen, and Cl represents chlorine.
  • compound 9-1 and nitromethane undergo condensation reaction to generate compound 9-2
  • compound 9-2 is reduced to obtain amine 9-3
  • amine 9-3 and ketone 9-4 undergo condensation to obtain compound 9-5
  • compound 9-5 reacts with acetic anhydride to generate compound 9-6
  • compound 9-6 undergoes cyclization reaction under Pd catalysis to generate compound 9-7
  • compound 9-7 is deacetylated to obtain compound 9-8
  • Compound 9-8 is protected by O to obtain compound 9-9
  • compound 9-9 is oxidized under potassium osmate and sodium periodate to obtain dialdehyde 9-10
  • dialdehyde 9-10 is subjected to reductive amination to obtain amine 9-11
  • compound 9-11 is reacted with DMF under n-butyl lithium to obtain aldehyde 9-12
  • aldehyde 9-12 is subjected to addition reaction with compound 9-13 under n-butyl lithium to obtain compound 9-14
  • compound 9-14 is subjecte
  • the embodiments of the compound of formula (1) can be prepared according to general reaction scheme 10, wherein R 1 , Re , Re ' and n are as defined above, Y represents Br, I or OTf, H represents hydrogen, N represents nitrogen, O represents oxygen, and Cl represents chlorine.
  • compound 10-1 and nitromethane undergo condensation reaction to generate compound 10-2, compound 10-2 is reduced to obtain amine 10-3, compound 10-3 is protected with (Boc) 2 O to obtain compound 10-4, compound 10-4 and compound 10-5 undergo coupling reaction under Pd catalysis to obtain compound 10-6, compound 10-6 and compound 10-7 undergo coupling reaction under Pd catalysis to obtain compound 10-8, compound 10-8 undergoes ring closure reaction under trifluoroacetic acid and dichloromethane to generate compound 10-9, and (Boc) 2 Compound 10-9 is protected by O to obtain compound 10-10, compound 10-10 reacts with DMF under n-butyl lithium to obtain aldehyde 10-11, aldehyde 10-11 reacts with compound 10-12 under n-butyl lithium to obtain compound 10-13, compound 10-13 is subjected to Dess-Martin oxidation or Swern oxidation to obtain ketone 10-14, ketone 10-14 and compound 10-15 undergo substitution reaction under alkaline conditions to obtain compound 10
  • the embodiments of the compound of formula (1) can be prepared according to general reaction scheme 11, wherein R 1 , Re , Re ' and n are as defined above, Y represents Br, I or OTf, X represents O or S, H represents hydrogen, N represents nitrogen, O represents oxygen, and Cl represents chlorine.
  • compound 11-1 and nitromethane undergo condensation reaction to generate compound 11-2, compound 11-2 is reduced to obtain amine 11-3, compound 11-3 is protected with (Boc) 2 O to obtain compound 11-4, compound 11-4 and compound 11-5 undergo coupling reaction under Pd catalysis to obtain compound 11-6, compound 11-6 and compound 11-7 undergo coupling reaction under Pd catalysis to obtain compound 11-8, compound 11-8 undergoes ring closure reaction under trifluoroacetic acid and dichloromethane to generate compound 11-9, and (Boc) 2 O-protected compound 11-9 to obtain compound 11-10, compound 11-10 reacts with DMF under n-butyl lithium to obtain aldehyde 11-11, aldehyde 11-11 reacts with compound 11-12 under n-butyl lithium to obtain compound 11-13, compound 11-13 is subjected to Dess-Martin oxidation or Swern oxidation to obtain ketone 11-14, ketone 11-14 and compound 11-15 undergo substitution reaction under alkaline conditions to obtain
  • the embodiments of the compound of formula (1) can be prepared according to general reaction scheme 12, wherein R 1 , Re , Re ' and n are as defined above, Y represents Br, I or OTf, H represents hydrogen, P represents a protecting group of hydroxyl, H represents hydrogen, N represents nitrogen, O represents oxygen, and Cl represents chlorine.
  • compound 12-1 is protected to obtain compound 12-2, compound 12-2 and compound 12-3 are subjected to coupling reaction under Pd catalysis to obtain compound 12-4, compound 12-4 and compound 12-5 are subjected to coupling reaction under Pd catalysis to obtain compound 12-6, compound 12-6 is deprotected to obtain compound 12-7, compound 12-7 is subjected to ring-closing reaction under trifluoroacetic acid and dichloromethane to obtain compound 12-8, compound 12-8 is reacted with DMF under n-butyllithium to obtain aldehyde 12-9, aldehyde 12-9 is subjected to n-butyllithium reaction.
  • Compound 12-10 undergoes an addition reaction under the condition of butyl lithium to obtain compound 12-11, compound 12-11 undergoes Dess-Martin oxidation or Swern oxidation to obtain ketone 12-12, ketone 12-12 undergoes a substitution reaction with compound 12-13 under alkaline conditions to obtain compound 12-14, compound 12-14 reacts with compound 12-15 to obtain compound 12-16, compound 12-16 is deprotected with TBAF to obtain compound 12-17, and in some examples, compound 12-17 is subjected to chiral resolution to obtain optical isomers 12-A and 12-B.
  • the embodiments of the compound of formula (1) can be prepared according to general reaction scheme 13, wherein R 1 , Re , Re' and n are as defined above, Y represents Br, I or OTf, H represents hydrogen, X represents O or S, P represents a protecting group of hydroxyl, H represents hydrogen, N represents nitrogen, O represents oxygen, and Cl represents chlorine.
  • compound 13-1 is protected to obtain compound 13-2
  • compound 13-2 and compound 13-3 are subjected to coupling reaction under Pd catalysis to obtain compound 13-4
  • compound 13-4 and compound 13-5 are subjected to coupling reaction under Pd catalysis to obtain compound 13-6
  • compound 13-6 is deprotected to obtain compound 13-7
  • compound 13-7 is subjected to ring-closing reaction under trifluoroacetic acid and dichloromethane to obtain compound 13-8
  • compound 13-8 is reacted with DMF under n-butyllithium to obtain aldehyde 13-9
  • aldehyde 13-9 is reacted with DMF under n-butyllithium to obtain aldehyde 13-9.
  • Compound 13-10 undergoes an addition reaction under the condition of butyl lithium to obtain compound 13-11, compound 13-11 is subjected to Dess-Martin oxidation or Swern oxidation to obtain ketone 13-12, ketone 13-12 undergoes a substitution reaction with compound 13-13 under alkaline conditions to obtain compound 13-14, compound 13-14 reacts with compound 13-15 to obtain compound 13-16, compound 13-16 is deprotected with TBAF to obtain compound 13-17, and in some cases, compound 13-17 is subjected to chiral resolution to obtain optical isomers 13-A and 13-B.
  • the embodiments of the compound of formula (1) can be prepared according to general reaction scheme 14, wherein R 1 , Re , Re' and n are as defined above, Y represents Br, I or OTf, X represents O or S, H represents hydrogen, N represents nitrogen, O represents oxygen, and Cl represents chlorine.
  • compound 14-1 and nitromethane undergo condensation reaction to generate compound 14-2, compound 14-2 is reduced to obtain amine 14-3, compound 14-3 is protected with (Boc) 2 O to obtain compound 14-4, compound 14-4 and compound 14-5 undergo coupling reaction under Pd catalysis to obtain compound 14-6, compound 14-6 and compound 14-7 undergo coupling reaction under Pd catalysis to obtain compound 14-8, compound 14-8 undergoes ring closure reaction under trifluoroacetic acid and dichloromethane to generate compound 14-9, and (Boc) 2 Compound 14-9 is protected by O to obtain compound 14-10, compound 14-10 reacts with DMF under n-butyl lithium to obtain aldehyde 14-11, aldehyde 14-11 reacts with compound 14-12 under n-butyl lithium to obtain compound 14-13, compound 14-13 is subjected to Dess-Martin oxidation or Swern oxidation to obtain ketone 14-14, ketone 14-14 and compound 14-15 undergo substitution reaction under alkaline conditions to obtain
  • the embodiments of the compound of formula (1) can be prepared according to general reaction scheme 15, wherein R 1 , Re , Re' and n are as defined above, Y represents Br, I or OTf, H represents hydrogen, X represents O or S, P represents a protecting group of hydroxyl, H represents hydrogen, N represents nitrogen, O represents oxygen, and Cl represents chlorine.
  • compound 15-1 is protected to obtain compound 15-2
  • compound 15-2 and compound 15-3 are subjected to coupling reaction under Pd catalysis to obtain compound 15-4
  • compound 15-4 and compound 15-5 are subjected to coupling reaction under Pd catalysis to obtain compound 15-6
  • compound 15-6 is deprotected to obtain compound 15-7
  • compound 15-7 is subjected to ring-closing reaction under trifluoroacetic acid and dichloromethane to obtain compound 15-8
  • compound 15-8 is reacted with DMF under n-butyllithium to obtain aldehyde 15-9
  • aldehyde 15-9 is reacted with DMF under n-butyllithium to obtain aldehyde 15-9.
  • Compound 15-10 undergoes an addition reaction under the condition of butyl lithium to obtain compound 15-11, compound 15-11 undergoes Dess-Martin oxidation or Swern oxidation to obtain ketone 15-12, ketone 15-12 undergoes a substitution reaction with compound 15-13 under alkaline conditions to obtain compound 15-14, compound 15-14 reacts with compound 15-15 to obtain compound 15-16, compound 15-16 is deprotected with TBAF to obtain compound 15-17, and in some cases, compound 15-17 is subjected to chiral resolution to obtain optical isomers 15-A and 15-B.
  • the embodiments of the compound of formula (1) can be prepared according to general reaction scheme 16, wherein R 1 , Re , Re ' and n are as defined above, Y represents Br, I or OTf, H represents hydrogen, N represents nitrogen, O represents oxygen, and Cl represents chlorine.
  • compound 16-1 and nitromethane undergo condensation reaction to generate compound 16-2, compound 16-2 is reduced to obtain amine 16-3, compound 16-3 is protected with (Boc) 2 O to obtain compound 16-4, compound 16-4 and compound 16-5 undergo coupling reaction under Pd catalysis to obtain compound 16-6, compound 16-6 and compound 16-7 undergo coupling reaction under Pd catalysis to obtain compound 16-8, compound 16-8 undergoes ring closure reaction under trifluoroacetic acid and dichloromethane to generate compound 16-9, and (Boc) 2 Compound 16-9 is protected by O to obtain compound 16-10, compound 16-10 reacts with DMF under n-butyl lithium to obtain aldehyde 16-11, aldehyde 16-11 reacts with compound 16-12 under n-butyl lithium to obtain compound 16-13, compound 16-13 is subjected to Dess-Martin oxidation or Swern oxidation to obtain ketone 16-14, ketone 16-14 and compound 16-15 undergo substitution reaction under alkaline conditions to obtain
  • the embodiments of the compound of formula (1) can be prepared according to general reaction scheme 17, wherein R 1 , Re , Re ' and n are as defined above, Y represents Br, I or OTf, X represents O or S, H represents hydrogen, N represents nitrogen, O represents oxygen, and Cl represents chlorine.
  • compound 17-1 and nitromethane undergo condensation reaction to generate compound 17-2
  • compound 17-2 is reduced to obtain amine 17-3
  • compound 17-3 is protected with (Boc) 2 O to obtain compound 17-4
  • compound 17-4 and compound 17-5 undergo coupling reaction under Pd catalysis to obtain compound 17-6
  • compound 17-6 and compound 17-7 undergo coupling reaction under Pd catalysis to obtain compound 17-8
  • compound 17-8 undergoes ring closure reaction under trifluoroacetic acid and dichloromethane to generate compound 17-9
  • (Boc) 2 Compound 17-9 is protected by O to obtain compound 17-10
  • compound 17-10 reacts with DMF under n-butyl lithium to obtain aldehyde 17-11
  • aldehyde 17-11 reacts with compound 17-12 under n-butyl lithium to obtain compound 17-13
  • compound 17-13 is subjected to Dess-Martin oxidation or Swern oxidation to obtain ketone 17-14
  • ketone 17-14 and compound 17-15 undergo substitution reaction under alkaline
  • the embodiments of the compound of formula (1) can be prepared according to general reaction scheme 18, wherein R 1 , Re , Re ' and n are as defined above, Y represents Br, I or OTf, H represents hydrogen, P represents a protecting group of hydroxyl, H represents hydrogen, N represents nitrogen, O represents oxygen, and Cl represents chlorine.
  • compound 18-1 is protected to obtain compound 18-2
  • compound 18-2 and compound 18-3 are subjected to coupling reaction under Pd catalysis to obtain compound 18-4
  • compound 18-4 and compound 18-5 are subjected to coupling reaction under Pd catalysis to obtain compound 18-6
  • compound 18-6 is deprotected to obtain compound 18-7
  • compound 18-7 is subjected to ring-closing reaction under trifluoroacetic acid and dichloromethane to obtain compound 18-8
  • compound 18-8 is reacted with DMF under n-butyllithium to obtain aldehyde 18-9
  • aldehyde 18-9 is subjected to n-butyllithium reaction.
  • Compound 18-10 undergoes an addition reaction under the condition of butyl lithium to obtain compound 18-11, compound 18-11 undergoes Dess-Martin oxidation or Swern oxidation to obtain ketone 18-12, ketone 18-12 undergoes a substitution reaction with compound 18-13 under alkaline conditions to obtain compound 18-14, compound 18-14 reacts with compound 18-15 to obtain compound 18-16, compound 18-16 is deprotected with TBAF to obtain compound 18-17, and in some cases, compound 18-17 is subjected to chiral resolution to obtain optical isomers 18-A and 18-B.
  • the embodiments of the compound of formula (1) can be prepared according to general reaction scheme 19, wherein R 1 , Re , Re ' and n are as defined above, Y represents Br, I or OTf, H represents hydrogen, X represents O or S, P represents a protecting group of hydroxyl, H represents hydrogen, N represents nitrogen, O represents oxygen, and Cl represents chlorine.
  • compound 19-1 is protected to obtain compound 19-2
  • compound 19-2 and compound 19-3 are subjected to coupling reaction under Pd catalysis to obtain compound 19-4
  • compound 19-4 and compound 19-5 are subjected to coupling reaction under Pd catalysis to obtain compound 19-6
  • compound 19-6 is deprotected to obtain compound 19-7
  • compound 19-7 is subjected to ring-closing reaction under trifluoroacetic acid and dichloromethane to obtain compound 19-8
  • compound 19-8 is reacted with DMF under n-butyllithium to obtain aldehyde 19-9
  • aldehyde 19-9 is reacted with DMF under n-butyllithium to obtain aldehyde 19-9.
  • Compound 19-10 undergoes an addition reaction under the condition of butyl lithium to obtain compound 19-11, compound 19-11 undergoes Dess-Martin oxidation or Swern oxidation to obtain ketone 19-12, ketone 19-12 undergoes a substitution reaction with compound 19-13 under alkaline conditions to obtain compound 19-14, compound 19-14 reacts with compound 19-15 to obtain compound 19-16, compound 19-16 is deprotected with TBAF to obtain compound 19-17, and in some cases, compound 19-17 is subjected to chiral resolution to obtain optical isomers 19-A and 19-B.
  • “Pharmaceutically acceptable” as used herein refers to a material, such as a carrier or diluent, that does not abrogate the biological activity or properties of the compound and is relatively non-toxic, i.e., a material that, when administered to a subject, does not cause undesirable biological effects or interact in a deleterious manner with any of its constituent components.
  • a pharmaceutically acceptable salt refers to a form of a compound that does not cause significant irritation to the administered organism and does not eliminate the biological activity and properties of the compound.
  • a pharmaceutically acceptable salt is obtained by reacting a compound of the general formula with an acid or base, wherein the acid or base includes, but is not limited to, acids and bases found in Stahl and Wermuth, Handbook of Pharmaceutical Salts: Properties, Selection, and Use 1st Ed., (Wiley, 2002).
  • references to pharmaceutically acceptable salts include solvent-added forms or crystal forms, especially solvates or polymorphs.
  • Solvates contain stoichiometric or non-stoichiometric amounts of solvents and are selectively formed during crystallization with pharmaceutically acceptable solvents such as water, ethanol, etc. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is ethanol.
  • Solvates of the general formula compounds are conveniently prepared or formed according to the methods described herein. For example, hydrates of the general formula compounds are conveniently prepared by recrystallization from a mixed solvent of water/organic solvents, and the organic solvents used include, but are not limited to, tetrahydrofuran, acetone, ethanol or methanol.
  • the compounds mentioned herein can exist in unsolvated and solvated forms. In summary, for the purposes of the compounds and methods provided herein, the solvated form is considered to be equivalent to the unsolvated form.
  • the compound of the formula is prepared in different forms, including but not limited to, amorphous, pulverized and nano-particle forms.
  • the compound of the formula includes crystalline forms, which can also be polymorphic. Polymorphs include the same elemental composition of the compound. Different lattice arrangements. Polymorphs usually have different X-ray diffraction spectra, infrared spectra, melting points, density, hardness, crystal form, optical and electrical properties, stability and solubility. Different factors such as recrystallization solvent, crystallization rate and storage temperature may cause a single crystal form to dominate.
  • the compounds of the general formula may have chiral centers and/or axial chirality, and thus occur as racemates, racemic mixtures, single enantiomers, diastereomeric compounds and single diastereomers, and cis-trans isomers.
  • Each chiral center or axial chirality will independently produce two optical isomers, and all possible optical isomers and diastereomeric mixtures as well as pure or partially purified compounds are included within the scope of the present invention.
  • the present invention is meant to include all such isomeric forms of these compounds.
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more atoms constituting the compound.
  • compounds may be labeled with radioactive isotopes, such as tritium ( 3H ), iodine-125 ( 125I ) and C-14 ( 14C ).
  • radioactive isotopes such as tritium ( 3H ), iodine-125 ( 125I ) and C-14 ( 14C ).
  • deuterated compounds may be formed by replacing hydrogen atoms with heavy hydrogen. The bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon.
  • deuterated drugs Compared with undeuterated drugs, deuterated drugs generally have the advantages of reducing toxic side effects, increasing drug stability, enhancing therapeutic effects, and extending the half-life of drugs in vivo. All isotopic composition changes of the compounds of the present invention, whether radioactive or not, are included in the scope of the present invention.
  • any atom of the compounds of the present invention refers to the isotope of the atom in its stable state.
  • the site when a site on the molecular structure is selected as "H” or “hydrogen”, the site should be understood to have the natural abundance of hydrogen isotopes.
  • the site when a site is selected as "D” or “deuterium”, the site should be understood to have a deuterium isotope abundance of at least 3000 times its natural abundance (the natural abundance of deuterium isotopes is 0.015%).
  • the deuterium atom abundance at each deuterated site of the deuterated compound of the present invention is at least 3500 times its natural abundance (52.2% deuterium atom enrichment). More preferably, it is at least 4500 times (67.5% deuterium atom enrichment). More preferably, it is at least 5000 times (75% deuterium atom enrichment). More preferably, it is at least 6000 times (90% deuterium atom enrichment). More preferably, it is at least 6333 times (95% deuterium atom enrichment). More preferably, it is at least 6466.7 times (97% deuterium atom enrichment). More preferably, it is at least 6600 times (99% deuterium atom enrichment). More preferably, it is at least 6633.3 times (99.5% deuterium atom enrichment).
  • alkyl refers to a saturated aliphatic hydrocarbon group, including straight and branched groups of 1 to 6 carbon atoms. Preferred are lower alkyl groups containing 1 to 4 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl. More preferred are lower alkyl groups containing 1-3 carbon atoms, such as methyl, ethyl, propyl, 2-propyl. As used herein, “alkyl” includes unsubstituted and substituted alkyl groups, especially alkyl groups substituted by one or more halogens.
  • Preferred alkyl groups are selected from CH 3 , CH 3 CH 2 , CF 3 , CHF 2 , CF 3 CH 2 , CF 3 (CH 3 )CH, i Pr, n Pr, i Bu, n Bu or t Bu.
  • alkylene refers to a divalent alkyl group as defined above.
  • alkylene groups include, but are not limited to, methylene and ethylene.
  • alkenyl refers to an unsaturated aliphatic hydrocarbon group containing a carbon-carbon double bond, including straight or branched groups of 1 to 14 carbon atoms.
  • the lower alkenyl group contains 1 to 4 carbon atoms, such as vinyl, 1-propenyl, 1-butenyl or 2-methylpropenyl. More preferably, the lower alkenyl group contains 1 to 2 carbon atoms.
  • alkenylene refers to a divalent alkenyl group as defined above.
  • alkynyl refers to an unsaturated aliphatic hydrocarbon group containing a carbon-carbon triple bond, including straight and branched groups of 1 to 14 carbon atoms.
  • the lower alkynyl group contains 1 to 4 carbon atoms, such as ethynyl, 1-propynyl or 1-butynyl. More preferably, the lower alkynyl group contains 1 to 2 carbon atoms.
  • alkynylene refers to a divalent alkynyl group as defined above.
  • cycloalkyl refers to a non-aromatic hydrocarbon ring system (monocyclic, bicyclic or polycyclic), preferably a non-aromatic hydrocarbon ring system containing 3-14 ring carbon atoms (C 3-14 cycloalkyl).
  • the cycloalkyl has 3-10 ring carbon atoms (C 3-10 cycloalkyl).
  • the cycloalkyl has 3-8 ring carbon atoms (C 3-8 cycloalkyl).
  • the cycloalkyl has 3-7 ring carbon atoms (C 3-7 cycloalkyl).
  • the cycloalkyl has 3-6 ring carbon atoms (C 3-6 cycloalkyl). In some embodiments, the cycloalkyl has 4-6 ring carbon atoms (C 4-6 cycloalkyl). In some embodiments, the cycloalkyl has 5-6 ring carbon atoms (C 5-6 cycloalkyl). In some embodiments, the cycloalkyl has 5-10 ring carbon atoms (C 5-10 cycloalkyl).
  • Cycloalkyl If the carbocyclic ring contains at least one double bond, then the partially unsaturated cycloalkyl group may be referred to as a "cycloalkenyl group", or if the carbocyclic ring contains at least one triple bond, then the partially unsaturated cycloalkyl group may be referred to as a "cycloalkynyl group”. Cycloalkyl groups may include monocyclic or polycyclic (e.g., having 2, 3, or 4 fused rings) groups and spirocycles. In some embodiments, the cycloalkyl group is monocyclic. In some embodiments, the cycloalkyl group is bicyclic.
  • the cycloalkyl group is monocyclic or bicyclic. In some embodiments, the cycloalkyl group is tricyclic. The ring-forming carbon atoms of the cycloalkyl group may be optionally oxidized to form an oxo or thio group. Cycloalkyl groups also include cycloalkylene groups. In some embodiments, the cycloalkyl group contains 0, 1, or 2 double bonds. In some embodiments, the cycloalkyl group contains 1 or 2 double bonds (partially unsaturated cycloalkyl groups).
  • the cycloalkyl group may be fused with an aryl group, a heteroaryl group, a cycloalkyl group, and a heterocycloalkyl group. In some embodiments, the cycloalkyl group may be fused with an aryl group, a cycloalkyl group, and a heterocycloalkyl group. In some embodiments, the cycloalkyl group may be fused with an aryl group, a cycloalkyl group, and a heterocycloalkyl group. In some embodiments, the cycloalkyl group may be fused with an aryl group and a cycloalkyl group.
  • cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarbyl, bicyclo[1.1.1]pentanyl, bicyclo[2.1.1]hexanyl, and the like.
  • cycloalkylene refers to a divalent cycloalkyl group as defined above.
  • alkoxy refers to an alkyl group bonded to the rest of the molecule through an ether oxygen atom.
  • Representative alkoxy groups are those having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy.
  • alkoxy includes unsubstituted and substituted alkoxy groups, especially alkoxy groups substituted with one or more halogens.
  • Preferred alkoxy groups are selected from OCH3 , OCF3 , CHF2O , CF3CH2O , i- PrO, n- PrO, i- BuO, n- BuO or t- BuO.
  • aryl refers to a hydrocarbon aromatic group, which is monocyclic or polycyclic, for example, a monocyclic aryl ring fused to one or more carbocyclic aromatic groups.
  • aryl include, but are not limited to, phenyl, naphthyl and phenanthrenyl.
  • aryloxy refers to an aryl group bonded to the rest of the molecule through an ethereal oxygen atom.
  • aryloxy include, but are not limited to, phenoxy and naphthoxy.
  • arylene refers to a divalent aromatic radical as defined above.
  • arylene radicals include, but are not limited to, phenylene, naphthylene, and phenanthrenylene.
  • heteroaryl refers to a substituted or unsubstituted aromatic group containing one or more heteroatoms, preferably a 5-14 membered aromatic group containing 1-4 heteroatoms selected from oxygen, sulfur and nitrogen, more preferably a 5-14 membered aromatic group containing 1-2 heteroatoms selected from oxygen, sulfur or nitrogen. 5-9 membered aromatic groups, heteroatoms are independently selected from O, N or S, and the number of heteroatoms is preferably 1, 2 or 3.
  • the heteroaryl group is monocyclic or polycyclic.
  • the monocyclic heteroaryl group is preferably a 5-6 membered aromatic group containing 1-3 heteroatoms selected from oxygen, nitrogen or sulfur.
  • the monocyclic heteroaryl ring is fused with one or more carbocyclic aromatic groups or other monocyclic heterocycloalkyl groups.
  • heteroaryl groups include, but are not limited to, pyridyl, pyridazinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, quinolyl, isoquinolyl, furanyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, isothiazolyl, pyrrolyl, indolyl, benzimidazolyl, benzofuranyl, benzothiazolyl, benzothiophenyl, benzoxazolyl, benzopyridinyl, pyrrolopyrimidinyl, 1H-pyrrolo[3,2-b]pyridinyl, 1H-pyrrolo[2,3-c]pyridinyl, 1H-pyrrolo[3,2-c]pyrazo
  • heterocycloalkyl refers to a non-aromatic ring or ring system, which may optionally contain one or more alkenylene groups as part of the ring structure, having at least one heteroatom ring member independently selected from boron, phosphorus, nitrogen, sulfur, oxygen and selenium, preferably a saturated or partially unsaturated ring containing 1-4 heteroatoms selected from oxygen, sulfur or nitrogen, and more preferably a saturated or partially unsaturated ring containing 1-2 heteroatoms selected from oxygen, sulfur or nitrogen.
  • heterocycloalkyl is a 5-8 membered non-aromatic ring containing ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen or sulfur (5-8 membered heterocycloalkyl).
  • Heterocycloalkyl is a 5-6 membered non-aromatic ring containing ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen or sulfur (5-6 membered heterocycloalkyl).
  • 5-6 membered heterocycloalkyl contains 1-3 ring heteroatoms independently selected from nitrogen, oxygen and sulfur.
  • 5-6 yuan heterocycloalkyl contains 1-2 ring heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, 5-6 yuan heterocycloalkyl contains 1 ring heteroatoms independently selected from nitrogen, oxygen and sulfur. If heterocycloalkyl contains at least one double bond, then partially unsaturated heterocycloalkyl can be referred to as “heterocycloalkenyl", or if heterocycloalkyl contains at least one triple bond, then partially unsaturated heterocycloalkyl can be referred to as "heterocycloalkynyl".
  • Heterocycloalkyl can include monocyclic, bicyclic, spirocyclic or polycyclic (e.g., having two fused or bridged rings) ring systems.
  • heterocycloalkyl is a monocyclic group with 1,2 or 3 heteroatoms independently selected from nitrogen, sulfur and oxygen.
  • the ring-forming carbon atoms and heteroatoms of heterocycloalkyl can be optionally oxidized to form oxo or thio or other oxidized bonds (e.g., C(O), S(O), C(S) or S(O) 2 , N-oxides, etc.), or nitrogen atoms can be quaternized.
  • Heterocycloalkyl can be connected via ring-forming carbon atoms or ring-forming heteroatoms.
  • heterocycloalkyl contains 0 to 3 double bonds.
  • heterocycloalkyl contains 0 to 2 double bonds.
  • the definition of heterocycloalkyl also includes a portion (also referred to as partially unsaturated heterocycle) of an aromatic ring having one or more fused to a heterocycloalkyl ring (i.e., sharing a key with it), such as a benzo derivative of piperidine, morpholine, azacycloheptatriene or thienyl, etc.
  • heterocycloalkyl containing a fused aromatic ring can be connected via any ring-forming atoms, including the ring-forming atoms of the fused aromatic ring.
  • heterocycloalkyl include, but are not limited to, azetidinyl, azepanyl, dihydrobenzofuranyl, dihydrofuranyl, dihydropyranyl, N-morpholinyl, 3-oxa-9-azaspiro[5.5]undecyl, 1-oxa-8-azaspiro[4.5]decyl, piperidinyl, piperazinyl, oxopiperazinyl, pyranyl, pyrrolidinyl, quinuclyl, tetrahydrofuranyl, tetrahydropyranyl, 1,2,3,4-tetrahydroquinolinyl, scopolamine, alkyl, 4,5,6,7-tetrahydrothiazolo[5,4-c]pyri
  • heterocycloalkylene refers to a divalent heterocycloalkyl group as defined above.
  • the group formed by sulfur being replaced by an oxo group is called “sulfinyl”
  • the group formed by sulfur being substituted by two oxo groups is called “sulfonyl”.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • halo or halogen substituted
  • appearing before the name of a group means that the group is partially or fully halogenated, that is, substituted by F, Cl, Br or I in any combination, preferably substituted by F or Cl.
  • substituted refers to the case where one or more hydrogen atoms on a specified atom or group are replaced by one or more substituents other than hydrogen, without exceeding the normal valence of the specified atom.
  • substituents for example, one or more hydrogens of an alkyl, alkylene, alkenyl, alkynyl, hydroxyl or amine group, etc., may be replaced by one or more substituents.
  • the substituent includes but is not limited to alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amido, amidino, aryl, azido, carbamoyl, carboxyl, carboxylate, cyano, guanidino, halogen, haloalkyl, heteroalkyl, heteroaryl, heterocyclic radical, hydroxyl, hydrazine, imino, oxo, nitro, alkylsulfinyl, sulfonic acid, alkylsulfonyl, thiocyanate, mercaptan, thioketone or a combination thereof.
  • substituted does not include similar indefinite structures obtained by defining a substituent with a further substituent attached to infinity (for example, a substituted aryl having a substituted alkyl is itself substituted by a substituted aryl, which is further substituted by a substituted heteroalkyl, etc.).
  • the maximum number of consecutive substitutions in the compounds described herein is three.
  • substituted aryl is continuously substituted by two other substituted aryl groups to be limited to ((substituted aryl) substituted aryl) substituted aryl.
  • substitution patterns e.g., methyl substituted by 5 fluorines or heteroaryl with two adjacent oxygen ring atoms.
  • unallowed substitution patterns are well known to those skilled in the art.
  • substituted can describe other chemical groups defined herein.
  • substituted aryl includes but is not limited to "alkyl aryl”. Unless otherwise specified, if a group is described as optionally substituted, any substituent of the group itself is unsubstituted.
  • the substituent "-O- CH2 -O-" means that two oxygen atoms in the substituent are connected to two adjacent carbon atoms of a heterocycloalkyl, aryl or heteroaryl group, for example:
  • linking group When the number of a linking group is 0, such as -(CH 2 ) 0 -, it means that the linking group is a single bond.
  • membered ring includes any cyclic structure.
  • membered means the number of backbone atoms that make up the ring.
  • cyclohexyl, pyridyl, pyranyl, thiopyranyl are six-membered rings
  • cyclopentyl, pyrrolyl, furanyl, and thiophenyl are five-membered rings.
  • fragment refers to a specific part or functional group of a molecule.
  • a chemical fragment is generally considered to be a chemical entity contained in or attached to a molecule.
  • isomer means any tautomer, stereoisomer, atropisomer, isotope, enantiomer or diastereomer of any compound of the invention.
  • the compounds of the invention may have one or more chiral centers or double bonds and therefore exist in stereoisomeric form, for example, in double bond isomers (i.e., E/Z geometric isomers) or diastereomers (e.g., enantiomers (i.e., (+) or (-)) or cis/trans isomers).
  • the compounds of the invention encompass all corresponding stereoisomers, i.e., stereoisomerically pure (e.g., geometrically pure, enantiomerically pure or diastereomerically pure) forms as well as enantiomers and stereoisomer mixtures, such as racemates.
  • stereoisomerically pure e.g., geometrically pure, enantiomerically pure or diastereomerically pure
  • enantiomers and stereoisomer mixtures such as racemates.
  • Enantiomeric and stereoisomeric mixtures of the compounds of the present invention can be separated into their component enantiomers or stereoisomers by well-known methods, such as chiral gas chromatography, chiral high performance liquid chromatography, and crystallization of the compounds in the form of chiral salt complexes or crystallization of the compounds in chiral solvents.
  • Enantiomers and stereoisomers can also be obtained from stereoisomerically pure or enantiomerically pure intermediates,
  • isotope isomers refers to different molecules whose structures differ only in their isotopes but are otherwise identical.
  • atropisomer refers to a conformational stereoisomer produced when rotation around a single bond within a molecule is prevented or greatly slowed due to steric interactions with other parts of the molecule and the substituents at both ends of the single bond are asymmetric, i.e., atropisomers do not require a stereocenter.
  • the rotation barrier around the single bond is high enough and the mutual conversion between conformations is slow enough, the separation of individual isomers can be allowed (LaPlante et al., J. Med. Chem. 2011, 54, 20, 7005), preferably by chiral resolution.
  • the key is a solid wedge. and dotted wedge key
  • a straight solid bond To indicate the absolute configuration of a stereocenter, use a straight solid bond. and straight dashed key
  • a wavy line Denotes a solid wedge bond or dotted wedge key
  • use a wavy line Represents a straight solid bond or straight dashed key
  • acceptable means that a formulation component or active ingredient has no undue deleterious effect on health and well-being for the general purpose of treatment.
  • treat include alleviating, inhibiting or improving symptoms or conditions of a disease; inhibiting the occurrence of complications; improving or preventing potential metabolic syndrome; inhibiting the occurrence of a disease or symptom, such as controlling the development of a disease or condition; alleviating a disease or symptom; reducing a disease or symptom; alleviating complications caused by a disease or symptom, or preventing or treating signs caused by a disease or symptom.
  • a compound or pharmaceutical composition after administration, can improve a disease, symptom or condition, especially improve its severity, delay the onset, slow the progression of the disease, or reduce the duration of the disease. Whether fixed or temporary administration, Continuous or intermittent administration can be attributed to or related to the circumstances of administration.
  • Active ingredient refers to the compound shown in the general formula (1), and the pharmaceutically acceptable inorganic or organic salt of the compound of the general formula (1).
  • the compounds of the present invention may contain one or more asymmetric centers (chiral centers or axial chirality), and therefore appear in the form of racemates, racemic mixtures, single enantiomers, diastereomeric compounds and single diastereomers.
  • the asymmetric center that may exist depends on the properties of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers, and all possible optical isomers and diastereomeric mixtures as well as pure or partially pure compounds are included within the scope of the present invention.
  • the present invention is meant to include all such isomeric forms of these compounds.
  • composition refers to a compound or composition that, when administered to a subject (human or animal), is capable of inducing a desired pharmaceutical and/or physiological response through local and/or systemic action.
  • administered refers to directly administering the compound or composition, or administering a prodrug, derivative, or analog of the active compound.
  • the compounds or pharmaceutical compositions of the general formula (1) and (2) of the present invention are generally useful for inhibiting SAE proteins, and thus can be used to treat one or more disorders associated with the activity of SAE proteins. Therefore, in certain embodiments, the present invention provides a method for treating disorders mediated by SAE proteins, the method comprising the step of administering the compounds of the general formula (1) and (2) of the present invention, or a pharmaceutically acceptable composition thereof, to a patient in need thereof.
  • a method for treating cancer comprising administering to an individual in need thereof an effective amount of any of the aforementioned pharmaceutical compositions comprising compounds of general formula (1) and general formula (2).
  • the cancer includes, but is not limited to, hematological malignancies (leukemia, lymphoma, myeloma including multiple myeloma, myelodysplastic syndrome and myeloproliferative syndrome) and solid tumors (cancers such as prostate, breast, lung, colon, pancreas, kidney, ovary and soft tissue cancer and osteosarcoma, and stromal tumors), etc., preferably lung cancer, cervical cancer, colorectal cancer, lymphoma, myeloma, leukemia, hepatocellular carcinoma, pancreatic cancer, kidney cancer, breast cancer, head and neck cancer, melanoma, prostate cancer, adrenal cancer, endometrial cancer, appendix cancer and metastasis of these cancers.
  • the compounds of the present invention and their pharmaceutically acceptable salts can be prepared into various preparations, which contain the compounds of the present invention or their pharmaceutically acceptable salts within the safe and effective amount range and pharmacologically acceptable excipients or carriers.
  • the "safe and effective amount” means that the amount of the compound is sufficient to significantly improve the condition without causing serious side effects.
  • the safe and effective amount of the compound is determined according to the specific circumstances such as the age, condition, and course of treatment of the subject.
  • “Pharmaceutically acceptable excipients or carriers” refer to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility” here means that the components in the composition can be mixed with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds.
  • pharmacologically acceptable excipients or carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agents (such as sodium lauryl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
  • cellulose and its derivatives such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.
  • gelatin such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate,
  • the compounds of the present invention may be administered orally, rectally, parenterally (intravenously, intramuscularly or subcutaneously), or topically.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and acacia; (c) humectants, for example, glycerol; (d) disintegrators, for example, agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizers, for example, paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, for example,
  • Solid dosage forms such as tablets, pills, capsules, pills and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifiers, and the release of the active compound or compounds in such compositions may be delayed in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. If necessary, the active compound can also be formed into microencapsulated form with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
  • the liquid dosage form may contain an inert diluent conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide and oils, in particular cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.
  • an inert diluent conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide and oils, in particular cottons
  • composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • Suspensions in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methanol and agar, or mixtures of these substances, and the like.
  • suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methanol and agar, or mixtures of these substances, and the like.
  • compositions for parenteral injection may include physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
  • Dosage forms for topical administration of the compounds of the invention include ointments, powders, patches, sprays and inhalants.
  • the active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required.
  • the compounds of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds.
  • a safe and effective amount of the compounds of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dosage during administration is a pharmaceutically effective dosage, and for a person weighing 60 kg, the daily dosage is usually 1 to 2000 mg, preferably 50 to 1000 mg.
  • the specific dosage should also take into account factors such as the route of administration and the health status of the patient, which are all within the skill range of a skilled physician.
  • Int_1-1 (2.8 g, 22.99 mmol) and int_1-2 (3.5 g, 22.99 mmol, 454.55 ⁇ L) were dissolved in Ti(i-PrO) 4 (20 mL), and the atmosphere was replaced with nitrogen three times. The mixture was heated to 80°C and stirred for 2 hours. LC-MS monitoring showed that the reaction was complete. The reaction solution was cooled to room temperature and used directly in the next step.
  • Int_1-5 (1.2 g, 3.83 mmol) was dissolved in THF (20 mL), cooled to -30 ° C, and n-BuLi (2.5 M, 2.30 mL) was slowly added to the reaction solution under nitrogen protection. The reaction solution was reacted at -30 ° C for 2 hours. LC-MS monitoring showed that the reaction was complete. After the reaction solution was cooled to room temperature, saturated ammonium chloride aqueous solution (20 mL) was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (50 mLX3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product, which was directly used in the next step.
  • Int_1-7 (1.2 g, 3.11 mmol) was dissolved in THF (25 mL), cooled to -70 ° C, and n-BuLi (2.5 M, 3.74 mL) was slowly added to the reaction solution under nitrogen protection. The reaction solution was reacted at -70 ° C for 0.5 hours, and then DMF (682.55 mg, 9.34 mmol, 718.48 ⁇ L) was added to the reaction solution at -70 ° C. After the addition was complete, the reaction solution was reacted at -60 ° C for 1.5 hours. The reaction was completed by LC-MS monitoring.
  • Int_1-16 (0.178 g, 233 ⁇ mol) was dissolved in DMF (2 mL), and int_1-17 (269 mg, 2.33 mmol) was added to the reaction solution at room temperature. The reaction solution was reacted at room temperature for 1 hour. The reaction was completed by LC-MS monitoring. Ice water (10 mL) was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (10 mL*3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product, and the crude product was purified by column chromatography to obtain a solid (165 mg, yield: 84.1%).
  • Int_1-18 (0.500 g, 592 ⁇ mol) was dissolved in THF (5 mL), and TBAF (1 M, 1.17 mL) was added to the reaction solution at room temperature. The reaction solution was reacted at room temperature for 1 hour. The reaction was completed by LC-MS monitoring. Water (30 mL) was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (30 mL*3), and the organic phase was dried over anhydrous sodium sulfate.
  • Int_1-16 (500 mg, 726 ⁇ mol) was added to TFA (1 mL) at room temperature, and the reaction solution was reacted at room temperature for 5 minutes. The reaction was completed by LC-MS monitoring. Saturated sodium bicarbonate aqueous solution was added to the reaction solution to adjust the pH to 8, and then purified by preparative HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water (ammonia hydroxide v/v)-ACN]; B%: 30%-50%, 9min) to obtain a solid (118 mg, yield: 27.6%).
  • LiBH 4 (27.6 g, 1.27 mol) was dissolved in tetrahydrofuran (300 mL).
  • TMSCl (276 g, 2.54 mol, 322 mL) was added to the reaction solution at 0°C under nitrogen protection.
  • the reaction solution was stirred at 0°C for 30 minutes.
  • a tetrahydrofuran solution (250 mL) of int_88-2 (25.0 g, 127 mmol) was slowly added dropwise to the reaction solution within 30 minutes.
  • the reaction solution was heated to 75°C and the reaction was continued for 2 hours. LC-MS monitoring showed that the reaction was complete. After the reaction solution was cooled to 0°C, 600 mL of methanol was slowly added to quench the reaction.
  • the organic phase was concentrated under reduced pressure to obtain The crude product was adjusted to pH>7 with aqueous ammonia, the aqueous phase was extracted with ethyl acetate (500 mL x 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product (25 g, crude product), which can be directly used in the next step.
  • the crude product was adjusted to pH>7 with a saturated sodium bicarbonate aqueous solution, and the aqueous phase was extracted with ethyl acetate (500 mLX3), and the organic phase was dried over anhydrous sodium sulfate.
  • Int_88-8 (0.64 g, 2.01 mmol) was dissolved in THF (10 mL), cooled to -30 ° C, and n-BuLi (2.5 M, 2.42 mL) was slowly added to the reaction solution under nitrogen protection. The reaction solution was reacted at -30 ° C for 2 hours, and then the reaction solution was raised to room temperature for 1 hour. LC-MS monitoring showed that the reaction was complete. Saturated ammonium chloride aqueous solution (10 mL) was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (30 mLX3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product (0.5 g, yield: 85.6%), which was directly used in the next step.
  • Int_88-10 (1.44 g, 3.693 mmol) was dissolved in THF (20 mL), cooled to -75 ° C, and n-BuLi (2.5 M, 4.43 mL) was slowly added to the reaction solution under nitrogen protection. The reaction solution was reacted at -75 ° C for 1 hour, and then DMF (809 mg, 11.079 mmol) was added to the reaction solution at -75 ° C. After the addition was completed, the reaction solution was reacted at -75 ° C for 1 hour. The reaction was monitored by LC-MS and the reaction was completed.
  • Int_88-12 (1.427 g, 2.68 mmol) was dissolved in DCM (50 mL), and Dess-Martin oxidant (1.36 g, 3.22 mmol) was added to the reaction solution at room temperature. The reaction solution was reacted at room temperature for 1 hour. The reaction was completed by LC-MS monitoring. Saturated sodium bicarbonate aqueous solution was slowly added to the reaction solution to adjust the pH to 8, the aqueous phase was extracted with ethyl acetate (50 mL*3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product, and the crude product was purified by column chromatography to obtain a solid (1.324 g, yield: 93%).
  • Int_88-15 (5 g, 8.79 mmol) was dissolved in a mixed solvent of methanol (100 mL) and water (50 mL). Lithium hydroxide (631 mg, 26.37 mmol) was added to the reaction solution at room temperature. The reaction solution was reacted at room temperature for 6 hours. The reaction was completed by LC-MS monitoring. 200 mL of water was slowly added to the reaction solution, the aqueous phase was extracted with ethyl acetate (200 mL*3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product, and the crude product was purified by column chromatography to obtain a solid (3.2 g, yield: 88.8%).
  • Int_88-17 (3 g, 7.11 mmol) was dissolved in methanol (40 mL), and Pd/C (1.50 g, 10% purity) was added to the reaction solution at room temperature.
  • the reaction solution was replaced with hydrogen three times, and then heated to 60 ° C for 48 hours under a hydrogen atmosphere (50 PSI).
  • the reaction was completed by LC-MS monitoring.
  • the reaction solution was cooled to room temperature and filtered, and the filtrate was collected. The filtrate was concentrated under reduced pressure to obtain a crude product (650 mg, yield: 29.9%), which can be directly used in the next step.
  • Int_88-19 (186 mg, 233 ⁇ mol) was dissolved in DMF (2 mL), and int_1-17 (269 mg, 2.33 mmol) was added to the reaction solution at room temperature. The reaction solution was reacted at room temperature for 1 hour. The reaction was completed by LC-MS monitoring. Ice water (10 mL) was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (10 mL*3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product, and the crude product was purified by column chromatography to obtain a solid (182 mg, yield: 89.2%).
  • int_88-21 500 mg, 692 ⁇ mol was added to TFA (1 mL), and the reaction solution was reacted at room temperature for 5 minutes. The reaction was completed by LC-MS monitoring. Saturated sodium bicarbonate aqueous solution was added to the reaction solution to adjust the pH to 8, and then purified by preparative HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water (ammonia hydroxide v/v)-ACN]; B%: 30%-50%, 9min) to obtain a solid (405 mg, yield: 94.1%).
  • Compound 88 (0.1 g, 160 ⁇ mol) was subjected to SFC chiral separation (column: DAICEL CHIRALPAK IG (250 mm*30 mm, 10 um); mobile phase: [CO 2 -EtOH (0.1% NH 3 H 2 O)]; B%: 55%, isocratic elution mode) to obtain Compound 89 (33 mg) and Compound 90 (35 mg).
  • Analytical SFC retention time 1.048 min (Instrument: Waters UPCC with PDA Detector; Column: Chiralpak IG-3 50x4.6 mm ID, 3 um; Mobile phase: A: CO 2 , B: Ethanol (0.05% DEA); Isocratic: 40% B; Flow rate: 4 mL/min; Column temp.: 35° C.; ABPR: 1500 psi).
  • Analytical SFC retention time 0.592 min (Instrument: Waters UPCC with PDA Detector; Column: Chiralpak IG-3 50x4.6 mm ID, 3 um; Mobile phase: A: CO 2 , B: Ethanol (0.05% DEA); Isocratic: 40% B; Flow rate: 4 mL/min; Column temp.: 35° C.; ABPR: 1500 psi).
  • the crude product was adjusted to pH>7 with ammonia water, the aqueous phase was extracted with ethyl acetate (500mLX3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product (23.5g, crude product), which can be directly used in the next step reaction.
  • Int_88-A-4 (5 g, 14.9 mmol), int_88-A-5 (7.56 g, 29.8 mmol), Pd(dppf)Cl 2 (1.09 g, 1.5 mmol) and potassium acetate (3.65 g, 37.25 mmol) were dissolved in 1,4-dioxane (150 mL), replaced with nitrogen three times, and the reaction solution was heated to 100 ° C for 6 hours. LC-MS monitoring showed that the reaction was complete. The reaction solution was slowly poured into 300 mL of ice water, the aqueous phase was extracted with ethyl acetate (300 mLX3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product, and the crude product was purified by column chromatography to obtain a solid (3.9 g, yield: 68.6%).
  • Int_88-A-6 (2g, 5.23mmol), int_88-A-7 (1.78g, 6.28mmol), Pd(dppf)Cl 2 (365.8mg, 0.5mmol) and potassium phosphate (2.22g, 10.46mmol) were dissolved in a mixed solvent of 1,4-dioxane (50mL) and water (5mL), replaced with nitrogen three times, and the reaction solution was heated to 100°C for 6 hours. LC-MS monitoring showed that the reaction was complete. The reaction solution was slowly poured into 100mL of ice water, the aqueous phase was extracted with ethyl acetate (100mLX3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product, and the crude product was purified by column chromatography to obtain a solid (1.65g, yield: 81.2%).
  • Int_88-A-8 (1g, 2.56mmol) was dissolved in dichloromethane (10mL), and TFA (10mL) was added to the reaction solution under nitrogen protection. The reaction solution was reacted at room temperature for 8 hours. LC-MS monitoring showed that the reaction was complete. Saturated sodium bicarbonate aqueous solution (50mL) was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (100mLX3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product, and the crude product was purified by column chromatography to obtain a solid (151mg, yield: 20.3%).
  • LiBH 4 (27.6 g, 1.27 mol) was dissolved in tetrahydrofuran (300 mL). Under nitrogen protection, the reaction solution was added at 0°C. TMSCl (276g, 2.54mol, 322mL), the reaction solution was stirred at 0°C for 30 minutes, and a tetrahydrofuran solution (250mL) of int_91-2 (25.0g, 127mmol) was slowly added dropwise to the reaction solution within 30 minutes, and the reaction solution was heated to 75°C and continued to react for 2 hours. LC-MS monitoring showed that the reaction was over. After the reaction solution was cooled to 0°C, 600mL of methanol was slowly added to quench the reaction.
  • the organic phase was concentrated under reduced pressure to obtain a crude product.
  • the crude product was adjusted to pH>7 with ammonia water, and the aqueous phase was extracted with ethyl acetate (500mLX3), and the organic phase was dried over anhydrous sodium sulfate.
  • the organic phase was concentrated under reduced pressure to obtain a crude product (25g, crude product), which can be directly used in the next step reaction.
  • the crude product was adjusted to pH>7 with saturated sodium bicarbonate aqueous solution, and the aqueous phase was extracted with ethyl acetate (1000 mLX3), and the organic phase was dried over anhydrous sodium sulfate.
  • Int_91-10 (900 mg, 2.41 mmol) was dissolved in THF (10 mL), cooled to -70 ° C, and n-BuLi (2.50 M, 2.89 mL) was slowly added to the reaction solution under nitrogen protection. The reaction solution was reacted at -70 ° C for 0.5 hours, and then DMF (528 mg, 7.23 mmol, 556 ⁇ L) was added to the reaction solution at -70 ° C. After the addition was complete, the reaction solution was reacted at -75 ° C for 1 hour. The reaction was completed by LC-MS monitoring.
  • Int_1-9 (1.62 g, 6.72 mmol) was dissolved in THF (15 mL), cooled to -75 °C, and n-BuLi (2.50 M, 5.38 mL) was slowly added to the reaction solution under nitrogen protection. The reaction solution was reacted at -75 °C for 1 hour, and then int_91-11 (900 mg, 2.24 mmol) in THF (25 mL) was added to the reaction solution at -75 °C. After the addition was complete, the reaction solution was reacted at -75 °C for 1 hour, and then warmed to room temperature for 16 hours. The reaction was completed by LC-MS monitoring.
  • Int_91-14 (563 mg, 719 ⁇ mol) was dissolved in DMF (10 mL), and int_1-17 (249 mg, 2.16 mmol) was added to the reaction solution at room temperature. The reaction solution was reacted at room temperature for 0.5 hours. The reaction was completed by LC-MS monitoring. Ice water (20 mL) was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (20 mL*3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product, and the crude product was purified by column chromatography to obtain a solid (605 mg, yield: 97.7%).
  • int_91-16 200 mg, 283 ⁇ mol was dissolved in DCM (5 mL), and TFA (2 mL) was added. The reaction solution was reacted at room temperature for 5 minutes. The reaction was completed by LC-MS monitoring. The reaction solution was cooled to 0°C, and a saturated sodium bicarbonate aqueous solution was added to adjust the pH. To 8, the aqueous phase was extracted with ethyl acetate (20 mL*3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product, which was purified by preparative HPLC to obtain a solid (60 mg, yield: 35.0%).
  • Compound 91 (100 mg, 0.165 mmol) was subjected to SFC chiral separation (column: DAICEL CHIRALPAK IG (250 mm*30 mm, 10 um); mobile phase: [CO 2 -iso-propanol (0.1% NH 3 H 2 O)]; B%: 50%, isocratic elution mode) to obtain Compound 92 (35 mg) and Compound 93 (37 mg).
  • Analytical SFC retention time 2.764 min (Instrument: Waters UPCC with PDA Detector; Column: Chiralpak IG-3 100x4.6 mm ID, 3 um; Mobile phase: A: CO 2 , B: iso-propanol (0.05% DEA); Isocratic: 40% B; Flow rate: 2.8 mL/min; Column temp.: 35° C.; ABPR: 1500 psi).
  • Analytical SFC retention time 1.291 min (Instrument: Waters UPCC with PDA Detector; Column: Chiralpak IG-3 100x4.6 mm ID, 3 um; Mobile phase: A: CO 2 , B: iso-propanol (0.05% DEA); Isocratic: 40% B; Flow rate: 2.8 mL/min; Column temp.: 35° C.; ABPR: 1500 psi).
  • LiBH 4 (28.3 g, 1.3 mol) was dissolved in tetrahydrofuran (300 mL). Under nitrogen protection, TMSCl (282 g, 2.6 mol, 329 mL) was added to the reaction solution at 0°C. The reaction solution was stirred at 0°C for 30 minutes. A tetrahydrofuran solution (250 mL) of int_91-A-2 (31.9 g, 130 mmol) was slowly added dropwise to the reaction solution within 30 minutes. The reaction solution was heated to 75°C and continued to react for 2 hours. LC-MS monitoring showed that the reaction was complete. After the reaction solution was cooled to 0°C, 600 mL of methanol was slowly added to quench the reaction.
  • the organic phase was concentrated under reduced pressure to obtain a crude product.
  • the crude product was adjusted to pH>7 with ammonia water.
  • the aqueous phase was extracted with ethyl acetate (500 mLX3), and the organic phase was dried over anhydrous sodium sulfate.
  • the organic phase was concentrated under reduced pressure to obtain a crude product (20.7 g, crude product), which can be directly used in the next step.
  • Int_91-A-5 (1.9 g, 5.23 mmol), int_88-A-7 (1.78 g, 6.28 mmol), Pd(dppf)Cl 2 (365.8 mg, 0.5 mmol) and potassium phosphate (2.22 g, 10.46 mmol) were dissolved in a mixed solvent of 1,4-dioxane (50 mL) and water (5 mL), replaced with nitrogen three times, and the reaction solution was heated to 100 ° C for 6 hours. LC-MS monitoring showed that the reaction was complete.
  • reaction solution was slowly poured into 100 mL of ice water, the aqueous phase was extracted with ethyl acetate (100 mLX3), and the organic phase was dried over anhydrous sodium sulfate.
  • the organic phase was concentrated under reduced pressure to obtain a crude product, and the crude product was purified by column chromatography to obtain a solid (1.37 g, yield: 70.2%).
  • Step 1 Synthesis of compound int_103-1:
  • Int_162-9 (2.5 g, 6.686 mmol), sodium periodate (7.2 g, 33.431 mmol) and K 2 OsO 4 ⁇ 2H 2 O (250 mg, 0.678 mmol) were dissolved in a mixed solvent of tetrahydrofuran (250 mL) and water (125 mL). The reaction solution was replaced with nitrogen three times. The reaction solution was reacted at room temperature for 2 hours. The reaction was completed by LC-MS monitoring. The reaction solution was slowly poured into 100 mL of ice water, the aqueous phase was extracted with dichloromethane (100 mL ⁇ 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography to obtain a solid (2.6 g, yield: 96.2%).
  • Int_103-4 (265 mg, 0.676 mmol) was dissolved in THF (10 mL), cooled to -70 ° C, and n-BuLi (2.5 M, 0.81 ml) was slowly added to the reaction solution under nitrogen protection. The reaction solution was reacted at -70 ° C for 1 hour, and then DMF (148 mg, 2.028 mmol) was added to the reaction solution at -60 ° C. After the addition was completed, the reaction solution was reacted at 70 ° C for 1 hour. The reaction was monitored by LC-MS and the reaction was completed.
  • Int_1-9 (592 mg, 2.463 mmol) was dissolved in THF (10 mL), cooled to -70 ° C, and n-BuLi (2.5 M, 2 mL, 4.926 mmol) was slowly added to the reaction solution under nitrogen protection. The reaction solution was reacted at -70 ° C for 1 hour, and then int_103-5 (170 mg, 0.411 mmol) in THF (1 mL) was added to the reaction solution at -75 ° C. After the addition was complete, the reaction solution was reacted at -75 ° C for 1 hour, and then warmed to room temperature for 16 hours. LC-MS monitoring showed that the reaction was complete.
  • Int_103-9 (253 mg, 0.288 mmol) was dissolved in THF (4 mL), and TBAF (1 M, 0.58 mL, 0.575 mmol) was added to the reaction solution at room temperature. The reaction solution was reacted at room temperature for 16 hours. The reaction was completed by LC-MS monitoring. Water (30 mL) was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (30 mL*3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product, and the crude product was purified by column chromatography to obtain a solid (175 mg, yield: 84.1%).
  • Int_103-10 (176 mg, 0.244 mmol) was dissolved in dichloromethane (6 mL). TFA (1.5 mL) was added to the reaction solution at room temperature. The reaction solution was reacted at room temperature for 10 minutes. The reaction was completed by LC-MS monitoring. Ammonia (1 mL) and water (10 mL) were added to the reaction solution. The aqueous phase was extracted with dichloromethane (10 mL*3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product, which was purified by preparative HPLC to obtain a solid (87 mg, yield: 57.2%).
  • Analytical SFC retention time 3.492 min (Instrument: Waters UPCC with PDA Detector; Column: Chiralpak IG-3 100x4.6 mm ID, 3 um; Mobile phase: A: CO 2 , B: Ethanol (0.05% DEA); Isocratic: 40% B; Flow rate: 2.5 mL/min; Column temp.: 40° C.; ABPR: 100 bar).
  • Int_130-1 (0.30 g, 798 ⁇ mol) was dissolved in THF (10 mL), cooled to -60 ° C, and n-BuLi (2.50 M, 479 ⁇ L) was slowly added to the reaction solution under nitrogen protection. The reaction solution was reacted at -60 ° C for 1 hour, and then DMF (175 mg, 2.39 mmol, 184 ⁇ L) was added to the reaction solution at -60 ° C. After the addition was complete, the reaction solution was reacted at -60 ° C for 3 hours. The reaction was completed by LC-MS monitoring.
  • Int_1-9 (4.79 g, 19.9 mmol) was dissolved in THF (50 mL), cooled to -75 °C, and n-BuLi (2.5 M, 16 mL) was slowly added dropwise to the reaction solution under nitrogen protection. The reaction solution was reacted at -75 °C for 1 hour. Then, a THF (25 mL) solution of int_130-2 (1.3 g, 3.2 mmol) was added dropwise to the reaction solution at -75 °C. After the addition was complete, the reaction solution was reacted at -75 °C for 1 hour, and then heated to room temperature for 16 hours. LC-MS monitoring showed that the reaction was complete.
  • Int_130-5 (0.510 g, 650 ⁇ mol) was dissolved in DMF (4 mL), and int_1-17 (150 mg, 1.30 mmol) was added to the reaction solution at room temperature. The reaction solution was reacted at room temperature for 1 hour. The reaction was completed by LC-MS monitoring. Ice water (50 mL) was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (50 mL*3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product, and the crude product was purified by column chromatography to obtain a solid (430 mg, yield: 76.6%).
  • Int_130-6 (432 mg, 500 ⁇ mol) was dissolved in THF (4 mL), and TBAF (1 M, 500 ⁇ L) was added to the reaction solution at room temperature. The reaction solution was reacted at room temperature for 16 hours. The reaction was completed by LC-MS monitoring. Water (30 mL) was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (30 mL*3), and the organic phase was dried over anhydrous sodium sulfate.
  • int_130-7 (177 mg, 250 ⁇ mol) was added to TFA (0.500 mL), and the reaction solution was reacted at room temperature for 10 minutes. The reaction was completed by LC-MS monitoring. Ammonia water (1 mL) and water (10 mL) were added to the reaction solution, and the aqueous phase was extracted with dichloromethane (10 mL*3). The organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product, which was purified by preparative HPLC to obtain a solid (55 mg, yield: 36.1%).
  • Analytical SFC retention time 1.298 min (Instrument: Waters UPCC with PDA Detector; Column: Chiralpak AD-3 50x4.6 mm ID, 3 um; Mobile phase: A: CO 2 , B: Ethanol (0.05% DEA); Isocratic: 40% B; Flow rate: 4 mL/min; Column temp.: 35° C.; ABPR: 1500 psi).
  • Analytical SFC retention time 0.461 min (Instrument: Waters UPCC with PDA Detector; Column: Chiralpak AD-3 50x4.6 mm ID, 3 um; Mobile phase: A: CO 2 , B: Ethanol (0.05% DEA); Isocratic: 40% B; Flow rate: 4 mL/min; Column temp.: 35° C.; ABPR: 1500 psi).
  • the crude product was adjusted to pH>7 with ammonia water, the aqueous phase was extracted with ethyl acetate (500mLX3), and the organic phase was dried over anhydrous sodium sulfate.
  • the organic phase was concentrated under reduced pressure to obtain a crude product (20g, crude product), which can be directly used in the next step reaction.
  • Int_162-3 (20.0 g, 85.3 mmol), int_162-4 (9.07 g, 65.6 mmol) and Ti(i-PrO) 4 (37.3 g, 131 mmol) were dissolved in toluene (200 mL), replaced with nitrogen three times, and the mixture was heated to 90 ° C and stirred for 2 hours. LC-MS monitoring showed that the reaction was complete. The reaction solution was cooled to room temperature and concentrated under reduced pressure to obtain a crude product (23 g, crude product), which can be directly used in the next step reaction.
  • the crude product was adjusted to pH>7 with saturated sodium bicarbonate aqueous solution, and the aqueous phase was extracted with dichloromethane (500 mLX3), and the organic phase was dried over anhydrous sodium sulfate.
  • Int_162-9 (0.30 g, 798 ⁇ mol) was dissolved in THF (10 mL), cooled to -60 ° C, and n-BuLi (2.50 M, 479 ⁇ L) was slowly added to the reaction solution under nitrogen protection. The reaction solution was reacted at -60 ° C for 1 hour, and then DMF (175 mg, 2.39 mmol, 184 ⁇ L) was added to the reaction solution at -60 ° C. After the addition was complete, the reaction solution was reacted at -60 ° C for 3 hours. The reaction was completed by LC-MS monitoring.
  • Int_1-9 (4.79 g, 19.91 mmol) was dissolved in THF (50 mL), cooled to -75 ° C, and n-BuLi (2.5 M, 16 mL) was slowly added to the reaction solution under nitrogen protection. The reaction solution was reacted at -75 ° C for 1 hour, and then int_162-10 (1.33 g, 3.31 mmol) in THF (25 mL) was added to the reaction solution at -75 ° C. After the addition was complete, the reaction solution was reacted at -75 ° C for 1 hour, and then warmed to room temperature for 16 hours. LC-MS monitoring showed that the reaction was complete.
  • Int_162-13 (0.716 g, 914 ⁇ mol) was dissolved in DMF (20 mL), and int_1-17 (423 mg, 3.66 mmol) was added to the reaction solution at room temperature. The reaction solution was reacted at room temperature for 1 hour. The reaction was completed by LC-MS monitoring. Ice water (20 mL) was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (20 mL*3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product, and the crude product was purified by column chromatography to obtain a solid (770 mg, yield: 97.7%).
  • Int_162-14 (786 mg, 912 ⁇ mol) was dissolved in THF (20 mL), and TBAF (1 M, 912 ⁇ L) was added to the reaction solution at room temperature. The reaction solution was reacted at room temperature for 16 hours. The reaction was completed by LC-MS monitoring. Water (30 mL) was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (30 mL*3), and the organic phase was dried over anhydrous sodium sulfate.
  • Int_162-15 (205 mg, 291 ⁇ mol) was added to TFA (0.5 mL) at room temperature, and the reaction solution was reacted at room temperature for 10 minutes. The reaction was completed by LC-MS monitoring. Saturated sodium bicarbonate aqueous solution was added to the reaction solution to adjust the pH to 8, and then purified by preparative HPLC to obtain a solid (90 mg, yield: 51.1%).
  • Compound 162 (100 mg, 164 ⁇ mol) was subjected to SFC chiral separation (column: DAICEL CHIRALPAK IG (250 mm*30 mm, 10 um); mobile phase: [CO 2 -EtOH (0.1% NH 3 H 2 O]; B%: 50%, isocratic elution mode) to give Compound 343 (25 mg) and Compound 344 (20 mg).
  • Analytical SFC retention time 2.439 min (Instrument: Waters UPCC with PDA Detector; Column: Chiralpak IG-3 100x4.6 mm ID, 3 um; Mobile phase: A: CO 2 , B: Ethanol (0.05% DEA); Isocratic: 40% B; Flow rate: 2.8 mL/min; Column temp.: 35° C.; ABPR: 1500 psi).
  • Analytical SFC retention time 1.920 min (Instrument: Waters UPCC with PDA Detector; Column: Chiralpak IG-3 100x4.6 mm ID, 3 um; Mobile phase: A: CO 2 , B: Ethanol (0.05% DEA); Isocratic: 40% B; Flow rate: 2.8 mL/min; Column temp.: 35° C.; ABPR: 1500 psi).
  • Dissolve int_190-2 (20.5 g, 82.1 mmol) in THF (100 mL), cool to -70 ° C, slowly add n-BuLi (2.5 M, 38.6 mL) to the reaction solution under nitrogen protection, and react at -70 ° C for 0.5 hours.
  • dissolve int_190-3 (8.00 g, 48.3 mmol) in THF (50 mL), cool to -40 ° C, slowly add BF 3 .Et 2 O (7.54 g, 53.1 mmol, 6.56 mL) to the reaction solution under nitrogen protection, and react at -40 ° C for 10 minutes.
  • Int_190-4 (8.00 g, 23.8 mmol) and (Boc) 2 O (6.24 g, 28.6 mmol, 6.57 mL) were dissolved in DCM (60 mL), and TEA (2.89 g, 28.6 mmol) was added to the reaction solution at room temperature. The reaction solution was reacted at room temperature for 16 hours, and the reaction was completed after LC-MS monitoring.
  • reaction solution was cooled to room temperature, the reaction solution was concentrated under reduced pressure to obtain a crude product, and the crude product was purified by column chromatography preparation ( 80g Silica Flash Column, Eluent of 0 ⁇ 20%Ethyl acetate/Petroleum ether gradient) to obtain a solid (5 g, yield: 48.1%).
  • Int_190-7 (600 mg, 1.18 mmol) was dissolved in DCM (6 mL), and Dess-Martin oxidant (766.46 mg, 1.81 mmol) was added to the reaction solution at room temperature. The reaction solution was reacted at room temperature for 1 hour. The reaction was completed by LC-MS monitoring. Saturated sodium bicarbonate aqueous solution was slowly added to the reaction solution to adjust the pH to 8, the aqueous phase was extracted with ethyl acetate (50 mL*3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product, and the crude product was purified by column chromatography to obtain a solid (530 mg, yield: 89%).
  • Int_1-15 (0.500 g, 1.64 mmol) and int_190-8 (826 mg, 1.64 mmol) were dissolved in DMF (10 mL).
  • K 2 CO 3 (679 mg, 4.91 mmol) was added to the reaction solution at room temperature.
  • the reaction solution was heated to 50°C for 1 hour.
  • the reaction was completed by LC-MS monitoring. Ice water (10 mL) was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (20 mL*3), and the organic phase was dried over anhydrous sodium sulfate.
  • Int_190-9 (0.180 g, 233 ⁇ mol) was dissolved in DMF (2 mL), and int_1-17 (269 mg, 2.33 mmol) was added to the reaction solution at room temperature. The reaction solution was reacted at room temperature for 1 hour. The reaction was completed by LC-MS monitoring. Ice water (10 mL) was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (10 mL*3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product, and the crude product was purified by column chromatography to obtain a solid (178 mg, yield: 89.8%).
  • Int_190-10 (0.500 g, 586 ⁇ mol) was dissolved in THF (5 mL), and TBAF (1 M, 1.17 mL) was added to the reaction solution at room temperature. The reaction solution was reacted at room temperature for 1 hour. The reaction was completed by LC-MS monitoring. Water (30 mL) was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (30 mL*3), and the organic phase was dried over anhydrous sodium sulfate.
  • int_190-11 (0.15 g, 209 ⁇ mol) was added to TFA (1 mL), and the reaction solution was reacted at room temperature for 5 minutes. The reaction was completed by LC-MS monitoring. Saturated sodium bicarbonate aqueous solution was added to the reaction solution to adjust the pH to 8, and then purified by preparative HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water (ammonia hydroxide v/v)-ACN]; gradient: 33%-53% B over 11min) to obtain a solid (40 mg, yield: 32.1%).
  • Compound 190 (50 mg, 170 ⁇ mol) was subjected to SFC chiral separation (column: DAICEL CHIRALPAK IG (250 mm*30 mm, 10 um); mobile phase: [CO 2 -MeOH (0.1% NH 3 H 2 O)]) to obtain Compound 191 (10 mg) and Compound 192 (16 mg).
  • Int_232-1 (0.40 g, 517 ⁇ mol) was dissolved in DMF (6 mL), and int_1-17 (0.24 g, 2.07 mmol) was added to the reaction solution at room temperature. The reaction solution was reacted at room temperature for 1 hour. The reaction was completed by LC-MS monitoring. Ice water (10 mL) was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (10 mL*3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product, and the crude product was purified by column chromatography to obtain a solid (430 mg, yield: 97.7%).
  • Int_232-2 (0.62 g, 727 ⁇ mol) was dissolved in THF (8 mL), and TBAF (1.00 M, 1.45 mL) was added to the reaction solution at room temperature. The reaction solution was reacted at room temperature for 1 hour. The reaction was completed by LC-MS monitoring. Water (30 mL) was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (30 mL*3), and the organic phase was dried over anhydrous sodium sulfate.
  • Int_232-3 (0.26 g, 373 ⁇ mol) was added to TFA (1 mL) at room temperature, and the reaction solution was reacted at room temperature for 10 minutes. The reaction was completed by LC-MS monitoring. Saturated sodium bicarbonate aqueous solution was added to the reaction solution to adjust the pH to 8, and then purified by preparative HPLC (column: Boston Prime C18, 150*30mm*5um; mobile phase: [water(NH3H2O+NH4HCO3)-ACN]; gradient: 25%-65% B over 9min) to obtain a solid (200 mg, yield: 90.9%).
  • Compound 232 (100 mg, 167 ⁇ mol) was subjected to SFC chiral separation (column: DAICEL CHIRALPAK IG (250 mm*30 mm, 10 ⁇ m); mobile phase: [CO 2 -EtOH (0.1% NH 3 H 2 O)]; 60% Bisocrate elution mode) to give Compound 233 (26 mg) and Compound 234 (26 mg).
  • Analytical SFC retention time 1.960 min (Instrument: Waters UPCC with PDA Detector; Column: Chiralpak IG-3 50x4.6 mm ID, 3 um; Mobile phase: A: CO 2 , B: Ethanol (0.05% DEA); Isocratic: 40% B; Flow rate: 4 mL/min; Column temp.: 35° C.; ABPR: 1500 psi).
  • Analytical SFC retention time 0.712 min (Instrument: Waters UPCC with PDA Detector; Column: Chiralpak IG-3 50x4.6 mm ID, 3 um; Mobile phase: A: CO 2 , B: Ethanol (0.05% DEA); Isocratic: 40% B; Flow rate: 4 mL/min; Column temp.: 35° C.; ABPR: 1500 psi).
  • Step 1 Synthesis of compound int_300-2:
  • Int_88-3 (9.00 g, 48.48 mmol) and int_300-1 (9.07 g, 53.33 mmol) were dissolved in Ti(i-PrO) 4 (170 mL), and the atmosphere was replaced with nitrogen three times. The mixture was heated to 80°C and stirred for 2 hours. LC-MS monitoring showed that the reaction was complete. The reaction solution was cooled to room temperature and used directly in the next step.
  • the crude product was adjusted to pH>7 with a saturated aqueous solution of bicarbonate sodium, and the aqueous phase was extracted with ethyl acetate (500 mLX3), and the organic phase was dried over anhydrous sodium sulfate.
  • Int_300-8 (1.5 g, 3.67 mmol) was dissolved in THF (20 mL), cooled to -75 ° C, and n-BuLi (2.5 M, 4.43 mL) was slowly added to the reaction solution under nitrogen protection. The reaction solution was reacted at -75 ° C for 1 hour, and then DMF (809 mg, 11.08 mmol) was added to the reaction solution at -75 ° C. After the addition was completed, the reaction solution was reacted at -75 ° C for 1 hour. The reaction was monitored by LC-MS and the reaction was completed.
  • Oxalyl chloride (413.7 mg, 3.26 mmol, 279 ⁇ L) was dissolved in dichloromethane (20 mL). Dimethyl sulfoxide (254.7 mg, 3.26 mmol, 231 ⁇ L) was slowly added to the reaction solution at -78 °C. The reaction solution was reacted at -78 °C for 0.5 hours. Int_300-10 (1.5 g, 2.72 mmol) in DCM (10 mL) was added to the reaction solution. The reaction solution was continued to react at -78 °C for 0.5 hours. Triethylamine (1.65 g, 16.32 mmol) was added to the reaction solution.
  • reaction solution was continued to react at -78 °C for 0.5 hours, and then slowly warmed to room temperature.
  • the reaction was completed by LC-MS monitoring.
  • Saturated sodium bicarbonate aqueous solution was slowly added to the reaction solution to adjust the pH to 8.
  • the aqueous phase was extracted with ethyl acetate (100 mL*3), and the organic phase was dried over anhydrous sodium sulfate.
  • the organic phase was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography to obtain a solid (1.38 g, yield: 92.6%).
  • Int_300-13 (1.61 g, 1.8 mmol) was dissolved in THF (20 mL), and TBAF (1 M, 3.6 mL) was added to the reaction solution at room temperature. The reaction solution was reacted at room temperature for 4 hours. The reaction was completed by LC-MS monitoring. Water (50 mL) was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (50 mL*3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product, and the crude product was purified by column chromatography to obtain a solid (1.1 g, yield: 82.7%).
  • Compound 300 (150 mg, 0.234 mmol) was subjected to SFC chiral separation (column: DAICEL CHIRALPAK IG (250 mm*30 mm, 10 ⁇ m); mobile phase: [CO 2 -EtOH (0.1% NH 3 H 2 O)]) to obtain Compound 301 (56 mg) and Compound 302 (58 mg).
  • Int_103-1 (2.5 g, 6.15 mmol) was dissolved in a mixed solvent of ethyl acetate (60 mL) and methanol (15 mL). Methylamine (573 mg, 18.45 mmol, 1.88 mL, 40% in MeOH) and sodium cyanoborohydride (1.53 g, 24.63 mmol) were added to the reaction solution. The reaction solution was reacted at room temperature for 16 hours. The reaction was completed by LC-MS monitoring. The reaction solution was slowly poured into 100 mL of ice water, the aqueous phase was extracted with ethyl acetate (100 mLX3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography to obtain a solid (2.1 g, yield: 84.3%).
  • Int_576-1 (283.4 mg, 0.7 mmol) was dissolved in THF (10 mL), cooled to -70 ° C, and n-BuLi (2.5 M, 0.83 ml) was slowly added to the reaction solution under nitrogen protection. The reaction solution was reacted at -70 ° C for 1 hour, and then DMF (153 mg, 2.1 mmol) was added to the reaction solution at -60 ° C. After the addition was completed, the reaction solution was reacted at 70 ° C for 1 hour. The reaction was monitored by LC-MS and the reaction was completed.
  • Int_1-9 (577 mg, 2.4 mmol) was dissolved in THF (10 mL), cooled to -70 ° C, and n-BuLi (2.5 M, 1.9 mL, 4.8 mmol) was slowly added to the reaction solution under nitrogen protection. The reaction solution was reacted at -70 ° C for 1 hour, and then int_576-2 (173.1 mg, 0.4 mmol) in THF (1 mL) was added to the reaction solution at -75 ° C. After the addition was complete, the reaction solution was reacted at -75 ° C for 1 hour, and then warmed to room temperature for 16 hours. LC-MS monitoring showed that the reaction was complete.
  • Oxalyl chloride (415 mg, 3.27 mmol, 280 ⁇ L) was dissolved in dichloromethane (20 mL). Dimethyl sulfoxide (254.75 mg, 3.27 mmol, 232 ⁇ L) was slowly added to the reaction solution at -78 °C. The reaction solution was reacted at -78 °C for 0.5 hours. Int_576-3 (1.5 g, 2.73 mmol) in DCM (10 mL) was added dropwise to the reaction solution. The reaction solution was continued to react at -78 °C for 0.5 hours. Triethylamine (1.65 g, 16.32 mmol) was added dropwise to the reaction solution.
  • reaction solution was continued to react at -78 °C for 0.5 hours, and then slowly warmed to room temperature.
  • the reaction was completed by LC-MS monitoring.
  • Saturated sodium bicarbonate aqueous solution was slowly added to the reaction solution to adjust the pH to 8.
  • the aqueous phase was extracted with ethyl acetate (100 mL*3), and the organic phase was dried over anhydrous sodium sulfate.
  • the organic phase was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography to obtain a solid (0.56 g, yield: 37.8%).
  • Int_576-6 (259 mg, 0.29 mmol) was dissolved in THF (4 mL), and TBAF (1 M, 0.58 mL, 0.58mmol), the reaction solution was reacted at room temperature for 16 hours. LC-MS monitoring, the reaction was completed. Water (30mL) was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (30mL*3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product, and the crude product was purified by column chromatography to obtain a solid (180mg, yield: 84.5%).
  • the target compounds 4-87, 94-102, 106-129, 133-161, 163-189, 193-231, 235-342, 345-575 and 579-1070 in Table 1 can be obtained.
  • HCT116 cells/well were seeded into a 96-well black transparent bottom plate, 90 ⁇ L per well. Incubate overnight at 37° for 24 hours. Dilute the compound to be tested to 10 times the final concentration and add 10 ⁇ L to the cell culture plate. Incubate at 37° for 6 hours. Then rinse the cells, discard the culture medium, and wash the cells once with 200 ⁇ L 0.1% PBST. Add 50 ⁇ L 4% PFA to each well, fix at room temperature for 20 minutes, then wash 2-3 times with PBS, add 50 ⁇ L 0.2% Triton X-100 to each well, leave at room temperature for 15 minutes, and wash 3 times with 0.1% PBST.
  • TAK-981 is compound I-263a in WO2016004136A1, and its chemical structure is as follows:
  • OVCAR3 cells and about 80000/well of NK92MI cells were seeded into 96-well black transparent cell culture plates, 90 ⁇ L per well. Incubate overnight at 37°C for 24 hours. Dilute the compound to be tested to 10 times the final concentration and add 10 ⁇ L to the cell culture plate. Incubate the cells at 37°C for 48 hours. Discard the OVCAR3 cell culture medium, stain the OVCAR3 cells with 1 ⁇ M Calcein AM for 50 minutes, wash once with PBS, add 100 ⁇ L of culture medium, mix the NK92MI cells, and gently add the sample to the OVCAR3 cells.
  • the DMSO control group and the high-concentration drug group were photographed on PICO to observe the killing of OVCAR3 cells by NK92MI cells.
  • the co-incubation was stopped.
  • the culture medium was discarded and the cells were rinsed once with 100 ⁇ L PBS.
  • 100 ⁇ L 4% PFA was added to each well, and the cells were fixed at room temperature for 20 minutes, rinsed once with PBS, and the sample fluorescence signal was detected by the FITC channel of the microplate reader. And compared with the DMSO group, the inhibition rate and IC 50 were calculated.
  • mice Female CD-1 mice aged 6 to 8 weeks were selected, and the intravenous dose was 2 mg/Kg. The mice were fasted for at least 12 hours before administration, and food was resumed after administration. Water was freely available during the entire experiment. On the day of the experiment, the corresponding compound was injected into the intravenous group of animals through the tail vein, and the dosage was 0.2 mL/mouse. The sample collection time was: 0.083, 0.167, 0.5, 1, 2, 4, 8, 24h.
  • Each C57BL/6 mouse was subcutaneously inoculated with 1X10 6 MC38 cells.
  • the tumor grew to 100-200 mm 3
  • the mouse was treated with vehicle, compound alone (intravenous injection, twice a week), anti-PD-1 antibody alone (intravenous injection, once a week), and anti-VEGF antibody alone.
  • mice were treated with vehicle, compound alone (intravenous injection, twice a week), anti-PD-1 antibody alone (intravenous injection, once a week), anti-VEGF antibody alone (intraperitoneal injection, once a week), anti-PD-1 antibody (intravenous injection, once a week) and anti-VEGF antibody (intraperitoneal injection, once a week) in combination, compound (intravenous injection, twice a week) and anti-PD-1 antibody (intravenous injection, once a week) in combination, compound (intravenous injection, twice a week) and anti-VEGF antibody (intraperitoneal injection, once a week) in combination, or compound (intravenous injection, twice a week) and anti-PD-1 antibody (intravenous injection, once a week) and anti-VEGF antibody (intraperitoneal injection, once a week)
  • TGI tumor growth inhibition rate
  • Each C57BL/6 mouse was subcutaneously inoculated with 1X106 MC38 cells.
  • the drugs were administered, including vehicle, compound alone (intravenous injection, twice a week), anti-PD-1 antibody alone (intravenous injection, once a week), anti-VEGF antibody alone (intraperitoneal injection, once a week), anti-PD-1 antibody (intravenous injection, once a week) and anti-VEGF antibody (intraperitoneal injection, once a week) in combination, compound (intravenous injection, twice a week) and anti-PD-1 antibody (intravenous injection, once a week) in combination, compound (intravenous injection, twice a week) and anti-VEGF antibody (intraperitoneal injection, once a week) in combination, or compound (intravenous injection, twice a week) and anti-PD-1 antibody (intravenous injection, once a week) and anti-VEGF antibody (intraperitoneal injection, once a week) in combination.
  • Tumor volume was measured twice a week and at the dosing endpoint.
  • Each BALB/c mouse was subcutaneously inoculated with 2X10 5 CT26 cells.
  • the tumor grew to 100-200mm 3 , the vehicle, compound alone (intravenous injection, twice a week), anti-PD-1 antibody alone (intravenous injection, once a week), anti-VEGF antibody alone (intraperitoneal injection, once a week), anti-PD-1 antibody (intravenous injection, once a week) and anti-VEGF antibody (intraperitoneal injection, once a week) were used in combination, compound (intravenous injection, twice a week) and anti-PD-1 antibody (intravenous injection, once a week) were used in combination, compound (intravenous injection, twice a week) and anti-VEGF antibody (intraperitoneal injection, once a week) were used in combination, or compound (intravenous injection, twice a week) and anti-PD-1 antibody (intravenous injection, once a week) and anti-VEGF antibody (intraperitoneal injection, once a
  • Tumor growth inhibition rate (TGI) 1-(tumor volume on day 20 of the administration group - administration time)
  • TGI Tumor growth inhibition rate
  • the tumor growth inhibition rate of the compound was calculated by using the tumor volume of the first day of the vehicle control group)/(tumor volume of the 20th day of the vehicle control group-tumor volume of the first day of the vehicle control group).
  • mice were treated with vehicle, compound alone (intravenous injection, twice a week), anti-PD-1 antibody alone (intravenous injection, once a week), anti-VEGF antibody alone (intraperitoneal injection, once a week), anti-PD-1 antibody (intravenous injection, once a week) and anti-VEGF antibody (intraperitoneal injection, once a week) in combination, compound (intravenous injection, twice a week) and anti-PD-1 antibody (intravenous injection, once a week) in combination, compound (intravenous injection, twice a week) and anti-VEGF antibody (intraperitoneal injection, once a week) in combination, or compound (intravenous injection, twice a week) and anti-PD-1 antibody (intravenous injection, once a week) and anti-VEGF antibody (intraperitoneal injection, once a week) in combination, or compound (intravenous injection, twice a week) and anti-PD-1 antibody (intravenous injection, once a week) and anti-
  • TGI tumor growth inhibition rate
  • Each BALB/c mouse was subcutaneously inoculated with 2X105 CT26 cells.
  • the drugs were administered, including vehicle, compound alone (intravenous injection, twice a week), anti-PD-1 antibody alone (intravenous injection, once a week), anti-VEGF antibody alone (intraperitoneal injection, once a week), anti-PD-1 antibody (intravenous injection, once a week) and anti-VEGF antibody (intraperitoneal injection, once a week) in combination, compound (intravenous injection, twice a week) and anti-PD-1 antibody (intravenous injection, once a week) in combination, compound (intravenous injection, twice a week) and anti-VEGF antibody (intraperitoneal injection, once a week) in combination, or compound (intravenous injection, twice a week) and anti-PD-1 antibody (intravenous injection, once a week) and anti-VEGF antibody (intraperitoneal injection, once a week) in combination.
  • Tumor volume was measured twice a week and at the dosing endpoint.
  • mice were inoculated subcutaneously with 2X106 A20 cells.
  • the mice were treated with vehicle, compound alone (intravenous injection, twice a week), anti-PD-1 antibody alone (intravenous injection, once a week), anti-VEGF antibody alone (intraperitoneal injection, once a week), anti-PD-1 antibody (intravenous injection, once a week) and anti-VEGF antibody (intraperitoneal injection, once a week) in combination, compound (intravenous injection, twice a week) and anti-PD-1 antibody (intravenous injection, once a week) in combination, compound (intravenous injection, twice a week) and anti-VEGF antibody (intraperitoneal injection, once a week) in combination, or compound (intravenous injection, twice a week) and anti-PD-1 antibody (intravenous injection, once a week) and anti-VEGF antibody (intraperitoneal injection, once a week) in combination.
  • TGI tumor growth inhibition rate
  • Each BALB/c mouse was subcutaneously inoculated with 2 ⁇ 10 6 A20 cells.
  • the tumor grew to 50-80 mm 3
  • the mouse was injected intravenously with the compound alone (twice a week), anti-PD-1 antibody alone (intravenously, once a week), and anti-VEGF antibody alone (intraperitoneally).
  • anti-PD-1 antibody intravenous injection, once a week
  • anti-VEGF antibody intraperitoneal injection, once a week
  • compound (intravenous injection, twice a week) and anti-PD-1 antibody intravenous injection, once a week
  • compound (intravenous injection, twice a week) and anti-VEGF antibody intraperitoneal injection, once a week in combination
  • compound (intravenous injection, twice a week) and anti-PD-1 antibody intraaperitoneal injection, once a week) in combination
  • compound (intravenous injection, twice a week) and anti-PD-1 antibody intraavenous injection, once a week
  • anti-VEGF antibody intraperitoneal injection, once a week
  • Each BALB/c mouse was inoculated subcutaneously with 2X106 A20 cells.
  • the drugs were administered, including vehicle, compound alone (intravenous injection, twice a week), anti-PD-1 antibody alone (intravenous injection, once a week), anti-VEGF antibody alone (intraperitoneal injection, once a week), anti-PD-1 antibody (intravenous injection, once a week) and anti-VEGF antibody (intraperitoneal injection, once a week) in combination, compound (intravenous injection, twice a week) and anti-PD-1 antibody (intravenous injection, once a week) in combination, compound (intravenous injection, twice a week) and anti-VEGF antibody (intraperitoneal injection, once a week) in combination, or compound (intravenous injection, twice a week) and anti-PD-1 antibody (intravenous injection, once a week) and anti-VEGF antibody (intraperitoneal injection, once a week) in combination.
  • Tumor volume was measured twice a week and at the dosing endpoint.
  • each C57BL/6 mouse was given vehicle, compound alone (intravenous injection), ovalbumin alone (intravenous injection), anti-PD-1 antibody alone (intravenous injection), anti-VEGF antibody alone (intraperitoneal injection), compound (intravenous injection) combined with ovalbumin (intravenous injection), anti-PD-1 antibody (intravenous injection) and anti-VEGF antibody (intraperitoneal injection), compound (intravenous injection) combined with anti-PD-1 antibody (intravenous injection), compound (intravenous injection) combined with anti-VEGF antibody (intraperitoneal injection), compound (intravenous injection) combined with anti-PD-1 antibody (intravenous injection) and ovalbumin (intravenous injection), compound (intravenous injection) combined with anti-VEGF antibody (intraperitoneal injection), compound (intravenous injection) combined with anti-VEGF antibody (intraperitoneal injection), compound (intravenous injection) combined with anti-VEGF antibody (intraperitoneal injection) and ovalbumin
  • TGI tumor growth inhibition rate

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Abstract

本发明公开了一类作为SUMO活化酶抑制剂的化合物。具体的，涉及一种通式(1)和通式(2)所示的化合物及其制备方法，及通式(1)和通式(2)化合物及其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物作为SAE抑制剂的用途。本发明化合物及其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物可用于制备治疗或者预防和SAE蛋白相关的疾病的药物。

Description

作为SUMO活化酶抑制剂的化合物
本申请要求申请日为2022年11月11日的中国专利申请2022114207153、申请日为2023年8月15日的中国专利申请2023110267906和申请日为2023年9月5日的中国专利申请2023111386461的优先权。本申请引用上述中国专利申请的全文。
技术领域
本发明属于药物化学领域，更具体而言，涉及一类具有SAE蛋白抑制作用的化合物，及其制备方法和该类化合物用于制备治疗或者预防由SAE介导的相关疾病的药物中的应用。
背景技术
小泛素样修饰物(SUMO)为泛素样蛋白是一类胞内可逆蛋白翻译后修饰物。哺乳动物细胞表达三种SUMO家族蛋白：SUMO1、SUMO2和SUMO3。SUMO2与SUMO3共享约95％的氨基酸序列同源性，在蛋白修饰时主要形成寡聚链(oligomeric chain)。SUMO1与SUMO2和SUMO3具有约45％的序列同源性，主要以单体(monomer)的方式修饰蛋白。靶蛋白的SUMO化(Sumoylation)借助酶催化的连续三步反应，将SUMO蛋白激活、转移并且最终连接到靶蛋白的赖氨酸残基上。其中，SAE(Sumo Activating Enzyme，SUMO活化酶)催化第一步反应。SAE属于一类统称为E1的活化酶(activating enzymes)，是一类由SAE1、SAE2或UBA2形成的异二聚体(heterodimer)。SAE使用ATP将SUMO的C端甘氨酸残基腺苷酸化，然后SUMO的C端甘氨酸与SAE2中的半胱氨酸残基之间形成硫酯中间体。随后SUMO蛋白通过硫酯键交换从E1被转移至SUMO结合酶(SUMO specific conjugating enzyme,统称为E2)。最后，在SUMO接连酶(SUMO specific E3 protein ligase)的作用下，SUMO蛋白被最终转移到靶蛋白的赖氨酸残基上，形成寡聚链。蛋白的SUMO化会影响蛋白的催化活性，胞内定位以及蛋白之间的相互作用。并且在近年的研究中表明，蛋白的SUMO化在细胞的多种信号通路，例如细胞分裂和DNA修复、染色体分离、细胞核转运、基因转录以及免疫调节，中起到了重要的作用。SUMO信号通路相关蛋白的高表达与某些癌症病人的不良预后有关。敲低SAE在某些MYC高表达肿瘤细胞上有合成致死效果。此外，SUMO化还能调节先天免疫反应。SUMO化的抑制能够增强type 1干扰素(IFN)的表达。综上所述，研究和发现具有靶向SAE活性好的化合物存在迫切的需求。
发明内容
本发明提供了一种通式(1)所示的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物：
通式(1)中：
Y为-O-、-CH2-或-N(H)-；
Ra为-H、-F、-NH2或-OH；
Ra’为-H或-F，且当Ra为-NH2或-OH时，Ra’为-H；
Rb为-H或(C1-C4)烷基；
Rc为-H或(C1-C4)烷基；
Rd为-H、卤素、-CF3或(C1-C4)烷基；
Re和Re’各自独立任选为-H或卤素，且Re和Re’不同时为-H；
X1为C(H)、C(F)或N；
X2为S或O；
X3为C(Rx3)或N；
Rx3为-H、卤素或-CH3；
X4为S、O、C(Rx41)(Rx41’)或N(Rx42)；
Rx42为-H、(C1-C4)烷基或(C3-C5)环烷基；
Rx41和Rx41’各自独立任选为-H、卤素、-OH、-ORx411、-N(Rx411)(Rx412)、-CN、(C1-C6)烷基、(C1-C6)卤代烷基、(C3-C9)环烷基或(C1-C6)烷氧基；
Rx411和Rx412各自独立任选为-H、(C1-C4)烷基或(C3-C5)环烷基，或同一个氮原子上的Rx411和Rx412与他们所连接的N原子能够共同组成(3-6元)杂环烷基，其中所述(3-6元)杂环烷基可任选被1，2，3或4个下列基团取代：-H或卤素；
R3和R4各自独立任选为-H、-D、-OH、-NH2、-CN、(C1-C6)烷基、(C1-C6)卤代烷基、(C2-C6)烯基、(C2-C6)炔基、(C3-C9)环烷基、(C1-C6)烷氧基、(C6-C14)芳基、(3-11元)杂环烷基或(5-11元)杂芳基，其中所述(C1-C6)烷基、(C1-C6)卤代烷基、(C2-C6)烯基、(C2-C6)炔基、(C3-C9)环烷基、(C1-C6)烷氧基、(C6-C14)芳基、(3-11元)杂环烷基或(5-11元)杂芳基可各自独立任选被1，2，3或4个下列基团取代：-H、卤素、-OH、-(CH2)rOR31、-(CH2)rNR31R32、-OR31、-NR31R32、-CN、-C(O)NR31R32、-NR32C(O)R31、-NR32S(O)2R31、-S(O)pR31和-S(O)2NR31R32；或R3和R4与他们所连接的碳原子能够共同组成(4-7元)杂环烷基或(C3-C6)环烷基，其中所述(4-7元)杂环烷基或(C3-C6)环烷基可任选被1，2，3或4个下列基团取代：-H、卤素、(C1-C6)烷基或(C1-C6)烷氧基；或R3和相邻的R5与他们所连接的原子能够共同组成(C3-C9)环烷基或(3-11元)杂环烷基，其中所述(C3-C9)环烷基或(3-11元)杂环烷基可各自独立任选被1，2，3或4个下列基团取代：-H、卤素、(C1-C6)烷基或(C1-C6)烷氧基；或当R3和相邻的R5同时不存在 时，分别与R4和R6相连的碳原子之间可形成一个环内双键；或R3和R4共同形成一个氧代基；
R5和R6各自独立任选为-H、-D、-OH、-NH2、-CN、(C1-C6)烷基、(C1-C6)卤代烷基、(C2-C6)烯基、(C2-C6)炔基、(C3-C9)环烷基、(C1-C6)烷氧基、(C6-C14)芳基、(3-11元)杂环烷基或(5-11元)杂芳基，其中所述(C1-C6)烷基、(C1-C6)卤代烷基、(C2-C6)烯基、(C2-C6)炔基、(C3-C9)环烷基、(C1-C6)烷氧基、(C6-C14)芳基、(3-11元)杂环烷基或(5-11元)杂芳基可各自独立任选被1，2，3或4个下列基团取代：-H、卤素、-OH、-(CH2)rOR31、-(CH2)rNR31R32、-OR31、-NR31R32、-CN、-C(O)NR31R32、-NR32C(O)R31、-NR32S(O)2R31、-S(O)pR31和-S(O)2NR31R32；或R5和R6与他们所连接的碳原子能够共同组成(4-7元)杂环烷基或(C3-C6)环烷基，其中所述(4-7元)杂环烷基或(C3-C6)环烷基可任选被1，2，3或4个下列基团取代：-H、卤素、(C1-C6)烷基或(C1-C6)烷氧基；或R5和R6共同形成一个氧代基；
环A为(C6-C10)芳基或(5-10元)杂芳基；
每个R1各自独立任选为：-H、卤素、-OH、-NO2、-NR31R32、-(CH2)rOR31、-(CH2)rNR31R32、-CN、(C1-C6)烷基、(C1-C6)卤代烷基、(C1-C6)烷氧基、(C2-C6)烯基、(C2-C6)炔基、(C3-C8)环烷基、-C(O)NR31R32、-NR32C(O)R31、-NR32S(O)2R31、-S(O)pR31或-S(O)2NR31R32，其中所述(C1-C6)烷基、(C1-C6)卤代烷基、(C1-C6)烷氧基、(C2-C6)烯基、(C2-C6)炔基或(C3-C8)环烷基可各自独立任选被1，2，3或4个下列基团取代：-H、卤素、-OH、-(CH2)rOR31、-(CH2)rNR31R32、-OR31、-NR31R32、-CN或(C1-C6)烷基；
环B为(C5-C7)环烷基或(5-7元)杂环烷基；
每个R2各自独立任选为：-H、卤素、-OH、-NR31R32、-CN、(C1-C6)烷基、(C1-C6)卤代烷基、(C1-C6)烷氧基、(C2-C6)烯基、(C2-C6)炔基或(C3-C8)环烷基；或同一个碳原子上的两个R2与他们所连接的碳原子能够共同组成(4-6元)杂环烷基或(C3-C6)环烷基，其中所述(4-6元)杂环烷基或(C3-C6)环烷基可任选被1，2，3或4个下列基团取代：-H、卤素、(C1-C6)烷基或(C1-C6)烷氧基；或同一个碳原子上的两个R2共同形成一个氧代基；
R31和R32各自独立任选为-H、(C1-C4)烷基或(C3-C5)环烷基，或同一个氮原子上的R31和R32与他们所连接的N原子能够共同组成(3-6元)杂环烷基，其中所述(3-6元)杂环烷基可任选被1，2，3或4个下列基团取代：-H和卤素；和
n为0、1、2、3或4的整数，m为0、1、2、3或4的整数，r为0、1或2的整数，p为0、1或2的整数。
在另一优选例中，其中所述通式(1)中，Rd为-H、-F、-CF3或-CH3；Rd优选为-H或-F；Rd更优选为-H；Rd更优选为-F。
在另一优选例中，其中所述通式(1)中，Re和Re’各自独立任选为-H或-F，且Re和Re’不同时为-H。
在另一优选例中，其中所述通式(1)中，Rx42为-H、(C1-C3)烷基或(C3-C5)环烷基。
在另一优选例中，其中所述通式(1)中，Rx42为-H、 Rx42优选为-H。
在另一优选例中，其中所述通式(1)中，Rx41和Rx41’各自独立任选为-H、-F、-OH、-OCH3、-N(CH3)2、-NH2、-CN、-CF3、-CH2CF3、
在另一优选例中，其中所述通式(1)中，R3和R4各自独立任选为-H、-D、-OH、-NH2、-CN、(C1-C3)烷基、(C1-C3)卤代烷基、(C2-C4)烯基、(C2-C4)炔基、(C3-C5)环烷基、(C1-C3)烷氧基、苯基、(4-6元)杂环烷基或(5-6元)杂芳基，其中所述(C1-C3)烷基、(C1-C3)卤代烷基、(C2-C4)烯基、(C2-C4)炔基、(C3-C5)环烷基、(C1-C3)烷氧基、苯基、(4-6元)杂环烷基或(5-6元)杂芳基可各自独立任选被1，2，3或4个下列基团取代：-H、-F、-OH、-CH2OCH3、-CH2N(CH3)2、-OCH3、-N(CH3)2、-CN、-C(O)N(CH3)2、-NCH3C(O)CH3、-NHC(O)CH3、-NCH3S(O)2CH3、-NHS(O)2CH3、-SCH3、-S(O)2CH3、-S(O)2NH2和-S(O)2N(CH3)2；或R3和R4与他们所连接的碳原子能够共同组成(4-6元)杂环烷基或(C3-C4)环烷基，其中所述(4-6元)杂环烷基或(C3-C4)环烷基可任选被1，2，3或4个下列基团取代：-H、-F、 或-OCH3；或R3和相邻的R5与他们所连接的原子共同组成(C3-C6)环烷基或(3-6元)杂环烷基，其中所述(C3-C6)环烷基或(3-6元)杂环烷基可各自独立任选被1，2，3或4个下列基团取代：-H、-F、或-OCH3；或当R3和相邻的R5同时不存在时，分别与R4和R6相连的碳原子之间可形成一个环内双键；或R3和R4共同形成一个氧代基。
在另一优选例中，其中所述通式(1)中，R3和R4各自独立任选为-H、-D、或R3和R4与他们所连接的碳原子能够共同组成环丙基；或R3和相邻的R5与他们所连接的原子共同组成环丙基；或R3和R4共同形成一个氧代基。
在另一优选例中，其中所述通式(1)中，R5和R6各自独立任选为-H、-D、-OH、-NH2、-CN、(C1-C3)烷基、(C1-C3)卤代烷基、(C2-C4)烯基、(C2-C4)炔基、(C3-C5)环烷基、(C1-C3)烷氧基、苯基、(4-6元)杂环烷基或(5-6元)杂芳基，其中所述(C1-C3)烷基、(C1-C3)卤代烷基、(C2-C4)烯基、(C2-C4)炔基、(C3-C5)环烷基、(C1-C3)烷氧基、苯基、(4-6元)杂环烷基或(5-6元)杂芳基可各自独立任选被1，2，3或4个下列基团取代：-H、-F、-OH、-CH2OCH3、-CH2N(CH3)2、-OCH3、-N(CH3)2、-NH2、-CN、-C(O)N(CH3)2、-NCH3C(O)CH3、-NHC(O)CH3、-NCH3S(O)2CH3、-NHS(O)2CH3、-SCH3、-S(O)2CH3、-S(O)2NH2和-S(O)2N(CH3)2；或R5和R6与他们所连接的碳原子能够共同组成(4-6元)杂环烷基或(C3-C4)环烷基，其中所述(4-6元)杂环烷基或(C3-C4)环烷基可任选被1，2，3或4个下列基团取代：-H、-F、 或-OCH3；或R5和R6共同形成一个氧代基。
在另一优选例中，其中所述通式(1)中，R5和R6各自独立任选为-H、-D、或R5和R6与他们所连接的碳原子能够共同组成环丙基；或R5和R6共同形成一个氧代基。
在另一优选例中，其中所述通式(1)中，环A为苯基或(5-6元)杂芳基，环A优选为苯基或含1个或2个独立选自N、O或S原子的(5-6元)杂芳基。
在另一优选例中，其中所述通式(1)中，环A为：

在另一优选例中，其中所述通式(1)中，每个R1各自独立任选为：-H、-F、-Cl、-Br、-I、-OH、-NO2、-N(CH3)2、-NH2、-CH2OCH3、-CH2N(CH3)2、-CN、(C1-C3)烷基、(C1-C3)卤代烷基、(C1-C3)烷氧基、(C2-C4)烯基、(C2-C4)炔基、(C3-C6)环烷基、-C(O)N(CH3)2、-NCH3C(O)CH3、-NHC(O)CH3、-NCH3S(O)2CH3、-NHS(O)2CH3、-SCH3、-S(O)2CH3、-S(O)2NH2和-S(O)2N(CH3)2，其中所述(C1-C3)烷基、(C1-C3)卤代烷基、(C1-C3)烷氧基、(C2-C4)烯基、(C2-C4)炔基或(C3-C6)环烷基可各自独立任选被1，2，3或4个下列基团取代：-H、-F、-OH、-CH2OCH3、-CH2N(CH3)2、-OCH3、-N(CH3)2、-NH2、-CN、
在另一优选例中，其中所述通式(1)中，每个R1独立地为：-H、-F、-Cl、-Br、-I、-OH、-NO2、-N(CH3)2、-NH2、-CH2OCH3、-CH2N(CH3)2、-CN、-C(O)N(CH3)2、-NCH3C(O)CH3、-NHC(O)CH3、-NCH3S(O)2CH3、-NHS(O)2CH3、-SCH3、-S(O)2CH3、-S(O)2NH2、-S(O)2N(CH3)2、 -CF3、-CH2CF3、-OCH3、-OCH2CH3、-OCH(CH3)2、 R1优选为-H、-F、-Cl、-CN、-CF3、-OCH3、R1更优选为-H、-F、-Cl、-CN、-CF3、-OCH3或R1更优选为-H、-F、-Cl、-CN或n优选为1；n优选为2；n优选为3。
在另一优选例中，其中所述通式(1)中，环B为(C5-C6)环烷基或(5-6元)杂环烷基，优选为部分不饱和的(C5-C6)环烷基或含1个独立选自N、O或S原子的(5-6元)部分不饱和杂环烷基。
在另一优选例中，其中所述通式(1)中，结构单元为：
在另一优选例中，其中所述通式(1)中，结构单元为：
在另一优选例中，其中所述通式(1)中，每个R2各自独立任选为：-H、-F、-Cl、-Br、-I、-OH、-N(CH3)2、-NH2、-CN、(C1-C3)烷基、(C1-C3)卤代烷基、(C1-C3)烷氧基、(C2-C4)烯基、(C2-C4)炔基或(C3-C5)环烷基；或同一个碳原子上的两个R2与他们所连接的碳原子能够共同组成(4-5元)杂环烷基或(C3-C5)环烷基，其中所述(4-5元)杂环烷基或(C3-C5)环烷基可任选被1，2，3或4个下列基团取代：-H、-F、和-OCH3；或同一个碳原子上的两个R2共同形成一个氧代基。
在另一优选例中，其中所述通式(1)中，每个R2各自独立任选为：-H、-F、-Cl、-Br、-I、-OH、-N(CH3)2、-NH2、-CN、-CF3、-CH2CF3、-OCH3、-OCH2CH3、-OCH(CH3)2、 R2优选为-H、-F、-Cl、-CN、 -CF3、-CH2CF3、-OCH3或R1更优选为-H、-F、-Cl、 -CF3、-CH2CF3或R1更优选为-H、-F、 -CH2CF3、m优选为1；m优选为2。
在另一优选例中，其中所述通式(1)中，结构单元为：
优选为 更优选为
在另一优选例中，其中所述通式(1)中，结构单元为：
优选为 更优选为
在另一优选例中，其中所述通式(1)中，结构单元为：
优选为 更优选为
在另一优选例中，其中所述通式(1)中，通式(1)具有如通式(1a)所示的结构：
其中环A、环B、R1、R2、R3、R4、R5、R6、Ra、Ra’、Rb、Rc、Rd、Re、Re’、X1、X2、X3、X4、m和n的定义如前所述，并在具体实施例中举例说明。
在另一优选例中，其中所述通式(1)中，通式(1)具有如通式(1b)所示的结构：
其中环A、环B、R1、R2、R3、R4、R5、R6、Ra、Ra’、Rb、Rc、Rd、Re、Re’、X1、X4、m和n的定义如前所述，并在具体实施例中举例说明。
在另一优选例中，其中所述通式(1)中，通式(1)具有如通式(1c)所示的结构：
其中环A、环B、R1、R2、R3、R4、R5、R6、Ra、Ra’、Rb、Rc、Re、Re’、X1、X4、m和n的定义如前所述，并在具体实施例中举例说明。
在另一优选例中，其中所述通式(1)中，通式(1)具有如通式(1d)所示的结构：
其中环A、环B、R1、R2、R3、R4、R5、R6、Ra、Ra’、Rb、Re、Re’、X1、X4、m和n的定义如前所述，并在具体实施例中举例说明。
在另一优选例中，其中所述通式(1)中，通式(1)具有如通式(1e)所示的结构：
其中环A、环B、R1、R2、R3、R4、R5、R6、Rb、Re、Re’、X1、X4、m和n的定义如前所述，并在具体实施例中举例说明。
在另一优选例中，其中所述通式(1)中，通式(1)具有如通式(1g)所示的结构：
其中环A、环B、R1、R2、R3、R4、R5、R6、Re、Re’、X4、m和n的定义如前所述，并在具体实施例中举例说明。
在另一优选例中，其中所述通式(1)中，通式(1)具有如通式(1h)或(1i)所示的结构：
其中环A、环B、R1、R2、R3、R4、R5、R6、Re、Re’、X4、m和n的定义如前所述，并在具体实施例中举例说明。
在另一优选例中，其中所述通式(1)中，通式(1)具有如通式(1j)、(1k)、(1l)或(1m)所示的结构：
其中环A、环B、R1、R2、R3、R4、R5、R6、Re、X4、m和n的定义如前所述，并在具体实施例中举例说明。
在本发明的另一具体实施例中，通式(1)化合物具有以下结构之一：







在本发明的另一具体实施例中，通式(1)化合物具有以下结构之一：

在本发明的另一具体实施例中，通式(1)化合物具有以下结构之一：

在本发明的另一具体实施例中，通式(1)化合物具有以下结构之一：





























本发明还提供了一种通式(2)所示的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物：
通式(2)中：
Y’为-O-、-CH2-或-N(H)-；
Ra1为-H、-F、-NH2或-OH；
Ra1’为-H或-F，且当Ra1为-NH2或-OH时，Ra1’为-H；
Rb’为-H或(C1-C4)烷基；
Rc’为-H或(C1-C4)烷基；
Rd’为-H、卤素、-CF3或(C1-C4)烷基；
Re1和Re1’各自独立任选为-H或卤素，且Re1和Re1’不同时为-H；
X1’为C(H)、C(F)或N；
X2’为S或O；
X3’为C(Rx3’)或N；
Rx3’为-H、卤素或-CH3；
X4’为S、O、C(Rx41a)(Rx41b)或N(Rx42’)；
Rx42’为-H、(C1-C4)烷基或(C3-C5)环烷基；
Rx41a和Rx41b各自独立任选为-H、卤素、-OH、-ORx411’、-N(Rx411’)(R x412’)、-CN、(C1-C6)烷基、(C1-C6)卤代烷基、(C3-C9)环烷基或(C1-C6)烷氧基；
Rx411’和Rx412’各自独立任选为-H、(C1-C4)烷基或(C3-C5)环烷基，或同一个氮原子上的Rx411’和Rx412’与他们所连接的N原子能够共同组成(3-6元)杂环烷基，其中所述(3-6元)杂环烷基可任选被1，2，3或4个下列基团取代：-H或卤素；
R3’和R4’各自独立任选为-H、-D、-OH、-NH2、-CN、(C1-C6)烷基、(C1-C6)卤代烷基、(C2-C6)烯基、(C2-C6)炔基、(C3-C9)环烷基、(C1-C6)烷氧基、(C6-C14)芳基、(3-11元)杂环烷基或(5-11元)杂芳基，其中所述(C1-C6)烷基、(C1-C6)卤代烷基、(C2-C6)烯基、(C2-C6)炔基、(C3-C9)环烷基、(C1-C6)烷氧基、(C6-C14)芳基、(3-11元)杂环烷基或(5-11元)杂芳基可各自独立任选被1，2，3或4个下列基团取代：-H、卤素、-OH、-(CH2)rOR31’、-(CH2)rNR31’R32’、-OR31’、-NR31’R32’、-CN、-C(O)NR31’R32’、-NR32’C(O)R31’、-NR32’S(O)2R31’、-S(O)pR31’和-S(O)2NR31’R32’；或R3’和R4’与他们所连接的碳原子能够共同组成(4-7元)杂环烷基或(C3-C6)环烷基，其中所述(4-7元)杂环烷基或(C3-C6)环烷基可任选被1，2，3或4个下列基团取代：-H、卤素、(C1-C6)烷基或(C1-C6)烷氧基；或R3’和相邻的R5’与他们所连接的原子能够共同组成(C3-C9)环烷基或(3-11元)杂环烷基，其中所述(C3-C9)环烷基或(3-11元)杂环烷基可各自独立任选被1，2，3或4个下列基团取代：-H、卤素、(C1-C6)烷基或(C1-C6)烷氧基；或当R3’和相邻的R5’同时不存在时，分别与R4’和R6’相连的碳原子之间可形成一个环内双键；或R3’和R4’共同形成一个氧代基；
R5’和R6’各自独立任选为-H、-D、-OH、-NH2、-CN、(C1-C6)烷基、(C1-C6)卤代烷基、(C2-C6)烯基、(C2-C6)炔基、(C3-C9)环烷基、(C1-C6)烷氧基、(C6-C14)芳基、(3-11元)杂环烷基或(5-11元)杂芳基，其中所述(C1-C6)烷基、(C1-C6)卤代烷基、(C2-C6)烯基、(C2-C6)炔基、(C3-C9)环烷基、(C1-C6)烷氧基、(C6-C14)芳基、(3-11元)杂环烷基或(5-11元)杂芳基可各自独立任选被1，2，3或4个下列基团取代：-H、卤素、-OH、-(CH2)rOR31’、-(CH2)rNR31’R32’、-OR31’、-NR31’R32’、-CN、-C(O)NR31’R32’、-NR32’C(O)R31’、-NR32’S(O)2R31’、-S(O)pR31’和-S(O)2NR31’R32’；或R5’和R6’与他们所连接的碳原子能够共同组成(4-7元)杂环烷基或(C3-C6)环烷基，其中所述(4-7元)杂环烷基或(C3-C6)环烷基可任选被1，2，3或4个下列基团取代：-H、卤素、(C1-C6)烷基和(C1-C6)烷氧基；或R5’和R6’共同形成一个氧代基；
环A’为(C6-C10)芳基或(5-10元)杂芳基；
每个R1’各自独立任选为：-H、卤素、-OH、-NO2、-NR31’R32’、-(CH2)rOR31’、-(CH2)rNR31’R32’、-CN、(C1-C6)烷基、(C1-C6)卤代烷基、(C1-C6)烷氧基、(C2-C6)烯基、(C2-C6)炔基、(C3-C8)环烷基、-C(O)NR31’R32’、-NR32’C(O)R31’、-NR32’S(O)2R31’、-S(O)pR31’或-S(O)2NR31’R32’，其中所述(C1-C6)烷基、(C1-C6)卤代烷基、(C1-C6)烷氧基、(C2-C6)烯基、(C2-C6)炔基或(C3-C8)环烷基可各自独立任选被1，2，3或4个下列基团取代：-H、卤素、-OH、-(CH2)rOR31’、-(CH2)rNR31’R32’、-OR31’、-NR31’R32’、-CN和(C1-C6)烷基；
R7’为：-H、-D、卤素、-OH、-NR31’R32’、-CN、(C1-C6)烷基、(C1-C6)卤代烷基、(C1-C6)烷氧基、(C2-C6)烯基、(C2-C6)炔基或(C3-C8)环烷基；
R8’为：-H、-D、-OH、(C1-C6)烷基、(C2-C6)烯基、(C2-C6)炔基或(C3-C8)环烷基；
R31’和R32’各自独立任选为-H、(C1-C4)烷基或(C3-C5)环烷基，或同一个氮原子上的R31’和R32’与他 们所连接的N原子能够共同组成(3-6元)杂环烷基，其中所述(3-6元)杂环烷基可任选被1，2，3或4个下列基团取代：-H和卤素；和
n为0、1、2、3或4的整数，r为0、1或2的整数，p为0、1或2的整数，q为0、1或2的整数。
在另一优选例中，其中所述通式(2)中，Rd’为-H、-F、-CF3或-CH3。
在另一优选例中，其中所述通式(2)中，Re1和Re1’各自独立任选为-H或-F，且Re1和Re1’不同时为-H。
在另一优选例中，其中所述通式(2)中，Rx42’为-H、(C1-C3)烷基或(C3-C5)环烷基。
在另一优选例中，其中所述通式(2)中，Rx42’为-H、
在另一优选例中，其中所述通式(2)中，Rx41a和Rx41b各自独立任选为-H、-F、-OH、-OCH3、-N(CH3)2、-NH2、-CN、-CF3、-CH2CF3、
在另一优选例中，其中所述通式(2)中，R3’和R4’各自独立任选为-H、-D、-OH、-NH2、-CN、(C1-C3)烷基、(C1-C3)卤代烷基、(C2-C4)烯基、(C2-C4)炔基、(C3-C5)环烷基、(C1-C3)烷氧基、苯基、(4-6元)杂环烷基或(5-6元)杂芳基，其中所述(C1-C3)烷基、(C1-C3)卤代烷基、(C2-C4)烯基、(C2-C4)炔基、(C3-C5)环烷基、(C1-C3)烷氧基、苯基、(4-6元)杂环烷基或(5-6元)杂芳基可各自独立任选被1，2，3或4个下列基团取代：-H、-F、-OH、-CH2OCH3、-CH2N(CH3)2、-OCH3、-N(CH3)2、-CN、-C(O)N(CH3)2、-NCH3C(O)CH3、-NHC(O)CH3、-NCH3S(O)2CH3、-NHS(O)2CH3、-SCH3、-S(O)2CH3、-S(O)2NH2和-S(O)2N(CH3)2；或R3’和R4’与他们所连接的碳原子能够共同组成(4-6元)杂环烷基或(C3-C4)环烷基，其中所述(4-6元)杂环烷基或(C3-C4)环烷基可任选被1，2，3或4个下列基团取代：-H、-F、 或-OCH3；或R3’和相邻的R5’与他们所连接的原子能够共同组成(C3-C6)环烷基或(3-6元)杂环烷基，其中所述(C3-C6)环烷基或(3-6元)杂环烷基可各自独立任选被1，2，3或4个下列基团取代：-H、-F、或-OCH3；或当R3’和相邻的R5’同时不存在时，分别与R4’和R6’相连的碳原子之间可形成一个环内双键；或R3’和R4’共同形成一个氧代基。
在另一优选例中，其中所述通式(2)中，R5’和R6’各自独立任选为-H、-D、-OH、-NH2、-CN、(C1-C3)烷基、(C1-C3)卤代烷基、(C2-C4)烯基、(C2-C4)炔基、(C3-C5)环烷基、(C1-C3)烷氧基、苯基、(4-6元)杂环烷基或(5-6元)杂芳基，其中所述(C1-C3)烷基、(C1-C3)卤代烷基、(C2-C4)烯基、(C2-C4)炔基、(C3-C5)环烷基、(C1-C3)烷氧基、苯基、(4-6元)杂环烷基或(5-6元)杂芳基可各自独立任选被1，2，3或4个下列基团取代：-H、-F、-OH、-CH2OCH3、-CH2N(CH3)2、-OCH3、-N(CH3)2、-NH2、-CN、-C(O)N(CH3)2、-NCH3C(O)CH3、-NHC(O)CH3、-NCH3S(O)2CH3、-NHS(O)2CH3、-SCH3、-S(O)2CH3、-S(O)2NH2和- S(O)2N(CH3)2；或R5’和R6’与他们所连接的碳原子能够共同组成(4-6元)杂环烷基或(C3-C4)环烷基，其中所述(4-6元)杂环烷基或(C3-C4)环烷基可任选被1，2，3或4个下列基团取代：-H、-F、 或-OCH3；或R5’和R6’共同形成一个氧代基。
在另一优选例中，其中所述通式(2)中，环A’为苯基或(5-6元)杂芳基。
在另一优选例中，其中所述通式(2)中，环A’为：
在另一优选例中，其中所述通式(2)中，每个R1’各自独立任选为：-H、-F、-Cl、-Br、-I、-OH、-NO2、-N(CH3)2、-NH2、-CH2OCH3、-CH2N(CH3)2、-CN、(C1-C3)烷基、(C1-C3)卤代烷基、(C1-C3)烷氧基、(C2-C4)烯基、(C2-C4)炔基、(C3-C6)环烷基、-C(O)N(CH3)2、-NCH3C(O)CH3、-NHC(O)CH3、-NCH3S(O)2CH3、-NHS(O)2CH3、-SCH3、-S(O)2CH3、-S(O)2NH2和-S(O)2N(CH3)2，其中所述(C1-C3)烷基、(C1-C3)卤代烷基、(C1-C3)烷氧基、(C2-C4)烯基、(C2-C4)炔基或(C3-C6)环烷基可各自独立任选被1，2，3或4个下列基团取代：-H、-F、-OH、-CH2OCH3、-CH2N(CH3)2、-OCH3、-N(CH3)2、-NH2、-CN、
在另一优选例中，其中所述通式(2)中，每个R1’独立地为：-H、-F、-Cl、-Br、-I、-OH、-NO2、-N(CH3)2、-NH2、-CH2OCH3、-CH2N(CH3)2、-CN、-C(O)N(CH3)2、-NCH3C(O)CH3、-NHC(O)CH3、-NCH3S(O)2CH3、-NHS(O)2CH3、-SCH3、-S(O)2CH3、-S(O)2NH2、-S(O)2N(CH3)2、 -CF3、-CH2CF3、-OCH3、-OCH2CH3、-OCH(CH3)2、
在另一优选例中，其中所述通式(2)中，R7’为：-H、-D、-F、-Cl、-Br、-I、-OH、-N(CH3)2、-NH2、-CN、(C1-C3)烷基、(C1-C3)卤代烷基、(C1-C3)烷氧基、(C2-C4)烯基、(C2-C4)炔基或(C3-C5)环烷基。
在另一优选例中，其中所述通式(2)中，R7’为：-H、-D、-F、-Cl、-Br、-I、-OH、-N(CH3)2、-NH2、-CN、-CF3、-CH2CF3、-OCH3、-OCH2CH3、-OCH(CH3)2、
在另一优选例中，其中所述通式(2)中，R8’为：-H、-D、-OH、(C1-C3)烷基、(C2-C4)烯基、(C2-C4)炔基或(C3-C5)环烷基。
在另一优选例中，其中所述通式(2)中，R8’为：-H、-D、
在另一优选例中，其中所述通式(2)中，结构单元为：


在本发明的另一具体实施例中，通式(2)化合物具有以下结构之一：




在本发明的另一具体实施例中，通式(2)化合物具有以下结构之一：

本发明的另一个目的是提供了一种药物组合物，其含有药学上可接受的载体、稀释剂和/或赋形剂，以及本发明通式(1)和通式(2)化合物、或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物作为活性成分。
本发明的再一个目的提供了本发明的通式(1)和通式(2)所示的化合物、或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物或上述药物组合物用于制备治疗、调节或预防与SAE蛋白相关疾病的药物中的用途。其中，所述的疾病优选癌症，所述癌症为血液癌和实体瘤。
本发明的再一个目的还提供治疗、调节或预防与SAE蛋白相关疾病的方法，包括对受试者给与治疗有效量的本发明的通式(1)和通式(2)所示的化合物、或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物或上述药物组合物。
应理解，本发明的前述一般性描述和以下详细描述都是示例性和说明性的，旨在提供对所要求保护的本发明的进一步说明。
化合物的合成
下面具体地描述本发明化合物的制备方法，但这些具体方法不对本发明构成任何限制。
以上说明的化合物可使用标准的合成技术或公知的技术与文中结合的方法来合成。此外，在此提到的溶剂，温度和其他反应条件可以改变。用于化合物的合成的起始物料可以由合成或从商业来源上获得。本文所述的化合物和其他具有不同取代基的有关化合物可使用公知的技术和原料来合成，包括发现于March，ADVANCED ORGANIC CHEMISTRY 4th Ed.，(Wiley 1992)；Carey和Sundberg，ADVANCED ORGANIC CHEMISTRY 4th Ed.，Vols.A和B(Plenum 2000，2001)，Green和Wuts，PROTECTIVE GROUPS IN ORGANIC SYNTHESIS 3rd Ed.，(Wiley 1999)中的方法。化合物制备的一般方法可通过使用适当的试剂和在此提供的分子式中引入不同基团的条件来改变。
一方面，本文所述的化合物根据工艺中公知的方法。然而方法的条件，例如反应物、溶剂、碱、所用化合物的量、反应温度、反应所需时间等不限于下面的解释。本发明化合物还可以任选将在本说明书中描述的或本领域已知的各种合成方法组合起来而方便的制得，这样的组合可由本发明所属领域的技术人员容易的进行。一方面，本发明还提供了一种所述的化合物的制备方法，其中通式(1)和通式(2)化合物可采用下列一般反应流程1-19制备：
一般反应流程1
通式(1)化合物可根据一般反应流程1制备，其中P为Rb或羟基保护基，环A、环B、R1、R2、R3、R4、R5、R6、Ra、Ra’、Rb、Rc、Rd、Re、Re’、X1、X2、X3、m和n如上文中所定义，H表示氢，N表示氮，O表示氧，Cl表示氯，X4a表示O或S，L表示O或NH。如一般反应流程1所示,化合物 1-1和化合物1-2在下发生取代反应生成醇中间体，并进一步氧化得到酮类化合物1-3，化合物1-3和化合物1-4发生取代反应生成化合物1-5，化合物1-5在与化合物1-6发生取代反应生成化合物1-7，在某些例子中，化合物1-7脱去羟基保护基生成化合物1-8，在某些例子中，化合物1-8通过手性拆分得到光学异构体1-A和1-B。
一般反应流程2
通式(1)化合物还可根据一般反应流程2制备，其中P为Rb或羟基保护基，P’为胺基保护基，环A、环B、R1、R2、R3、R4、R5、R6、Ra、Ra’、Rb、Rc、Rd、Re、Re’、X1、X2、X3、m和n如上文中所定义，H表示氢，N表示氮，O表示氧，Cl表示氯，L表示O或NH。如一般反应流程1所示,化合物2-1和化合物2-2在下发生取代反应生成醇中间体，并进一步氧化得到酮类化合物2-3，化合物2-3和化合物2-4发生取代反应生成化合物2-5，化合物2-5在与化合物2-6发生取代反应生成化合物2-7，在某些例子中，化合物2-7脱保护生成化合物2-8，在某些例子中，化合物2-8通过手性拆分得到光学异构体2-A和2-B。
一般反应流程3
通式(2)化合物可根据一般反应流程3制备，其中P为Rb’或羟基保护基，环A’、R1’、R3’、R4’、R5’、R6’、R7’、R8’、Ra1、Ra1’、Rb’、Rc’、Rd’、Re1、Re1’、X1’、X2’、X3’、n和q如上文中所定义，H表示氢，N表示氮，O表示氧，Cl表示氯，X4a表示O或S，L表示O或NH。如一般反应流程3所示,化合物3-1和化合物3-2在下发生取代反应生成醇中间体，并进一步氧化得到酮类化合物3-3，化合物3-3和化合物3-4发生取代反应生成化合物3-5，化合物3-5在与化合物3-6发生取代反应生成化合物3-7，在某些例子中，化合物3-7脱去羟基保护基生成化合物3-8，在某些例子中，化合物3-8通过手性拆分得到光学异构体3-A和3-B。
一般反应流程4
通式(2)化合物还可根据一般反应流程4制备，其中P为Rb’或羟基保护基，P’为胺基保护基，环A’、R1’、R3’、R4’、R5’、R6’、R7’、R8’、Ra1、Ra1’、Rb’、Rc’、Rd’、Re1、Re1’、X1’、X2’、X3’、n和q如上文中所定义，H表示氢，N表示氮，O表示氧，Cl表示氯，X4a表示O或S，L表示O或NH。如一般反应流程4所示,化合物4-1和化合物4-2在下发生取代反应生成醇中间体，并进一步氧化得到酮类化合物4-3，化合物4-3和化合物4-4发生取代反应生成化合物4-5，化合物4-5在与化合物4-6发生取代反应生成化合物4-7，在某些例子中，化合物4-7脱去羟基保护基生成化合物4-8，在某些例子中，化合物4-8通过手性拆分得到光学异构体4-A和4-B。
一般反应流程5
通式(1)化合物的实施方式可根据一般反应流程5制备，其中R1、Re、Re’和n如上文中所定义，X表示O、S或CH2，H表示氢，N表示氮，O表示氧，Cl表示氯。如一般反应流程5所示,化合物5-1和硝基甲烷发生缩合反应生成化合物5-2，还原化合物5-2得到胺5-3，胺5-3与酮5-4发生缩合得到化合物5-5，化合物5-5在酸性条件下发生环化反应生成化合物5-6，化合物5-6脱甲基得到化合物5-7，化合物5-7与PhNTf2发生反应生成化合物5-8，还原化合物5-8得到化合物5-9，化合物5-9脱去甲酰基得到化合物5-10，用(Boc)2O保护化合物5-10得到化合物5-11，化合物5-11在正丁基锂的条件下与DMF发生反应得到醛5-12，醛5-12在正丁基锂的条件下与化合物5-13发生加成反应得到化合物5-14，化合物5-14通过Dess-Martin氧化或Swern氧化得到酮5-15，酮5-15与化合物5-16在碱性条件下发生取代反应生成化合物5-17，化合物5-17与化合物5-18反应生成化合物5-19，化合物5-19用TBAF脱保护得到化合物5-20，化合物5-20在酸性条件下脱氨基保护得到化合物5-21，在某些例子中，化合物5-21通过手性拆分得到光学异构体5-A和5-B。
一般反应流程6
通式(1)化合物的实施方式可根据一般反应流程6制备，其中R1、Re、Re’和n如上文中所定义，Y表示Br或I，H表示氢，N表示氮，O表示氧，Cl表示氯。如一般反应流程6所示,化合物6-1和硝基甲烷发生缩合反应生成化合物6-2，还原化合物6-2得到胺6-3，胺6-3与酮6-4发生缩合得到化合物6-5，化合物6-5与乙酸酐发生反应生成化合物6-6，化合物6-6在Pd催化条件下发生环化反应生成化合物6-7，化合物6-7脱乙酰基得到化合物6-8，用(Boc)2O保护化合物6-8得到化合物6-9，化合物6-9发生氢化反应生成化合物6-10，化合物6-10在正丁基锂的条件下与DMF发生反应得到醛6-11，醛6-11在正丁基锂的条件下与化合物6-12发生加成反应得到化合物6-13，化合物6-13通过Dess-Martin氧化得到酮6-14，酮6-14与化合物6-15在碱性条件下发生取代反应生成化合物6-16，化合物6-16与化合物6-17反应生成化合物6-18，化合物6-18用TBAF脱保护得到化合物6-19，化合物6-19在酸性条件下脱氨基保护得到化合物6-20，在某些例子中，化合物6-20通过手性拆分得到光学异构体6-A和6-B。
一般反应流程7
通式(1)化合物的实施方式可根据一般反应流程7制备，其中R1、Re、Re’和n如上文中所定义，Y表示Br或I，H表示氢，N表示氮，O表示氧，Cl表示氯。如一般反应流程7所示,化合物7-1和硝基甲烷发生缩合反应生成化合物7-2，还原化合物7-2得到胺7-3，胺7-3与酮7-4发生缩合得到化合物7-5，化合物7-5与乙酸酐发生反应生成化合物7-6，化合物7-6在Pd催化条件下发生环化反应生成化合物7-7，化合物7-7脱乙酰基得到化合物7-8，用(Boc)2O保护化合物7-8得到化合物7-9，化合物7-9在正丁基锂的条件下与DMF发生反应得到醛7-10，醛7-10在正丁基锂的条件下与化合物7-11发生加成反应得到化合物7-12，化合物7-12通过Dess-Martin氧化得到酮7-13，酮7-13与化合物7-14在碱性条件下发生取代反应生成化合物7-15，化合物7-15与化合物7-16反应生成化合物7-17，化合物7-17用TBAF脱保护得到化合物7-18，化合物7-18在酸性条件下脱氨基保护得到化合物7-19，在某些例子中，化合物7-19通过手性拆分得到光学异构体7-A和7-B。
一般反应流程8
通式(1)化合物的实施方式可根据一般反应流程8制备，其中R1、Re、Re’和n如上文中所定义，Y表示Br或I，H表示氢，N表示氮，O表示氧，Cl表示氯。如一般反应流程8所示,化合物8-1和硝基甲烷发生缩合反应生成化合物8-2，还原化合物8-2得到胺8-3，胺8-3与酮8-4发生缩合得到化合物8-5，化合物8-5与乙酸酐发生反应生成化合物8-6，化合物8-6在Pd催化条件下发生环化反应生成化合物8-7，化合物8-7脱乙酰基得到化合物8-8，用(Boc)2O保护化合物8-8得到化合物8-9，化合物8-9在锇酸钾和高碘酸钠条件下发生氧化反应得到二醛8-10，用硼氢化钠还原二醛8-10得到二醇8-11，二醇8-11在酸性条件下发生环化反应得到化合物8-12，用(Boc)2O保护化合物8-12得到化合物8-13，化合物8-13在正丁基锂的条件下与DMF发生反应得到醛8-14，醛8-14在正丁基锂的条件下与化合物8-15发生加成反应得到化合物8-16，化合物8-18通过Dess-Martin氧化或Swern氧化得到酮8-17，酮8-17与化合物8-18在碱性条件下发生取代反应生成化合物8-19，化合物8-19与化合物8-20反应生成化合物8-21，化合物8-21用TBAF脱保护得到化合物8-22，化合物8-22在酸性条 件下脱氨基保护得到化合物8-23，在某些例子中，化合物8-23通过手性拆分得到光学异构体8-A和8-B。
一般反应流程9
通式(1)化合物的实施方式可根据一般反应流程9制备，其中R1、Re、Re’和n如上文中所定义，Y表示Br或I，Z表示-H、-OH、(C1-C6)烷基、(C1-C6)卤代烷基、(C1-C6)烷氧基、(C2-C6)烯基、(C2-C6)炔基或(C3-C8)环烷基，H表示氢，N表示氮，O表示氧，Cl表示氯。如一般反应流程9所示,化合物9-1和硝基甲烷发生缩合反应生成化合物9-2，还原化合物9-2得到胺9-3，胺9-3与酮9-4发生缩合得到化合物9-5，化合物9-5与乙酸酐发生反应生成化合物9-6，化合物9-6在Pd催化条件下发生环化反应生成化合物9-7，化合物9-7脱乙酰基得到化合物9-8，用(Boc)2O保护化合物9-8得到化合物9-9，化合物9-9在锇酸钾和高碘酸钠条件下发生氧化反应得到二醛9-10，二醛9-10发生还原胺化反应得到胺9-11，化合物9-11在正丁基锂的条件下与DMF发生反应得到醛9-12，醛9-12在正丁基锂的条件下与化合物9-13发生加成反应得到化合物9-14，化合物9-14通过Dess-Martin氧化或Swern氧化得到酮9-15，酮9-15与化合物9-16在碱性条件下发生取代反应生成化合物9-17，化合物9-17与化合物9-18反应生成化合物9-19，化合物9-19用TBAF脱保护得到化合物9-20，化合物9-20在酸性条件下脱氨基保护得到化合物9-21，在某些例子中，化合物9-21通过手性拆分得到光学异构体9-A和9-B。
一般反应流程10
通式(1)化合物的实施方式可根据一般反应流程10制备，其中R1、Re、Re’和n如上文中所定义，Y表示Br、I或OTf，H表示氢，N表示氮，O表示氧，Cl表示氯。如一般反应流程10所示,化合物10-1和硝基甲烷发生缩合反应生成化合物10-2，还原化合物10-2得到胺10-3，用(Boc)2O保护化合物10-3得到化合物10-4，化合物10-4与化合物10-5在Pd催化的条件下发生偶联反应得到化合物10-6，化合物10-6与化合物10-7在Pd催化的条件下发生偶联反应得到化合物10-8，化合物10-8在三氟乙酸和二氯甲烷条件下发生关环反应生成化合物10-9，用(Boc)2O保护化合物10-9得到化合物10-10，化合物10-10在正丁基锂的条件下与DMF发生反应得到醛10-11，醛10-11在正丁基锂的条件下与化合物10-12发生加成反应得到化合物10-13，化合物10-13通过Dess-Martin氧化或Swern氧化得到酮10-14，酮10-14与化合物10-15在碱性条件下发生取代反应生成化合物10-16，化合物10-16与化合物10-17反应生成化合物10-18，化合物10-18用TBAF脱保护得到化合物10-19，化合物10-19在酸性条件下脱氨基保护得到化合物10-20，在某些例子中，化合物10-20通过手性拆分得到光学异构体10-A和10-B。
一般反应流程11
通式(1)化合物的实施方式可根据一般反应流程11制备，其中R1、Re、Re’和n如上文中所定义，Y表示Br、I或OTf，X表示O或S，H表示氢，N表示氮，O表示氧，Cl表示氯。如一般反应流程11所示,化合物11-1和硝基甲烷发生缩合反应生成化合物11-2，还原化合物11-2得到胺11-3，用(Boc)2O保护化合物11-3得到化合物11-4，化合物11-4与化合物11-5在Pd催化的条件下发生偶联反应得到化合物11-6，化合物11-6与化合物11-7在Pd催化的条件下发生偶联反应得到化合物11-8，化合物11-8在三氟乙酸和二氯甲烷条件下发生关环反应生成化合物11-9，用(Boc)2O保护化合物11-9得到化合物11-10，化合物11-10在正丁基锂的条件下与DMF发生反应得到醛11-11，醛11-11在正丁基锂的条件下与化合物11-12发生加成反应得到化合物11-13，化合物11-13通过Dess-Martin氧化或Swern氧化得到酮11-14，酮11-14与化合物11-15在碱性条件下发生取代反应生成化合物11-16，化合物11-16与化合物11-17反应生成化合物11-18，化合物11-18用TBAF脱保护得到化合物11-19，化合物11-19在酸性条件下脱氨基保护得到化合物11-20，在某些例子中，化合物11-20通过手性拆分得到光学异构体11-A和11-B。
一般反应流程12
通式(1)化合物的实施方式可根据一般反应流程12制备，其中R1、Re、Re’和n如上文中所定义，Y表示Br、I或OTf，H表示氢，P表示羟基的保护基，H表示氢，N表示氮，O表示氧，Cl表示氯。如一般反应流程12所示，保护化合物12-1得到化合物12-2，化合物12-2与化合物12-3在Pd催化的条件下发生偶联反应得到化合物12-4，化合物12-4与化合物12-5在Pd催化的条件下发生偶联反应得到化合物12-6，化合物12-6脱保护得到化合物12-7，化合物12-7在三氟乙酸和二氯甲烷条件下发生关环反应生成化合物12-8，化合物12-8在正丁基锂的条件下与DMF发生反应得到醛12-9，醛12-9在正丁基锂的条件下与化合物12-10发生加成反应得到化合物12-11，化合物12-11通过Dess-Martin氧化或Swern氧化得到酮12-12，酮12-12与化合物12-13在碱性条件下发生取代反应生成化合物12-14，化合物12-14与化合物12-15反应生成化合物12-16，化合物12-16用TBAF脱保护得到化合物12-17，在某些例子中，化合物12-17通过手性拆分得到光学异构体12-A和12-B。
一般反应流程13
通式(1)化合物的实施方式可根据一般反应流程13制备，其中R1、Re、Re’和n如上文中所定义，Y表示Br、I或OTf，H表示氢，X表示O或S，P表示羟基的保护基，H表示氢，N表示氮，O表示氧，Cl表示氯。如一般反应流程13所示，保护化合物13-1得到化合物13-2，化合物13-2与化合物13-3在Pd催化的条件下发生偶联反应得到化合物13-4，化合物13-4与化合物13-5在Pd催化的条件下发生偶联反应得到化合物13-6，化合物13-6脱保护得到化合物13-7，化合物13-7在三氟乙酸和二氯甲烷条件下发生关环反应生成化合物13-8，化合物13-8在正丁基锂的条件下与DMF发生反应得到醛13-9，醛13-9在正丁基锂的条件下与化合物13-10发生加成反应得到化合物13-11，化合物13-11通过Dess-Martin氧化或Swern氧化得到酮13-12，酮13-12与化合物13-13在碱性条件下发生取代反应生成化合物13-14，化合物13-14与化合物13-15反应生成化合物13-16，化合物13-16用TBAF脱保护得到化合物13-17，在某些例子中，化合物13-17通过手性拆分得到光学异构体13-A和13-B。
一般反应流程14
通式(1)化合物的实施方式可根据一般反应流程14制备，其中R1、Re、Re’和n如上文中所定义，Y表示Br、I或OTf，X表示O或S，H表示氢，N表示氮，O表示氧，Cl表示氯。如一般反应流程14所示,化合物14-1和硝基甲烷发生缩合反应生成化合物14-2，还原化合物14-2得到胺14-3，用(Boc)2O保护化合物14-3得到化合物14-4，化合物14-4与化合物14-5在Pd催化的条件下发生偶联反应得到化合物14-6，化合物14-6与化合物14-7在Pd催化的条件下发生偶联反应得到化合物14-8，化合物14-8在三氟乙酸和二氯甲烷条件下发生关环反应生成化合物14-9，用(Boc)2O保护化合物14-9得到化合物14-10，化合物14-10在正丁基锂的条件下与DMF发生反应得到醛14-11，醛14-11在正丁基锂的条件下与化合物14-12发生加成反应得到化合物14-13，化合物14-13通过Dess-Martin氧化或Swern氧化得到酮14-14，酮14-14与化合物14-15在碱性条件下发生取代反应生成化合物14-16，化合物14-16与化合物14-17反应生成化合物14-18，化合物14-18用TBAF脱保护得到化合物14-19，化合物14-19在酸性条件下脱氨基保护得到化合物14-20，在某些例子中，化合物14-20通过手性拆分得到光学异构体14-A和14-B。
一般反应流程15
通式(1)化合物的实施方式可根据一般反应流程15制备，其中R1、Re、Re’和n如上文中所定义，Y表示Br、I或OTf，H表示氢，X表示O或S，P表示羟基的保护基，H表示氢，N表示氮，O表示氧，Cl表示氯。如一般反应流程15所示，保护化合物15-1得到化合物15-2，化合物15-2与化合物15-3在Pd催化的条件下发生偶联反应得到化合物15-4，化合物15-4与化合物15-5在Pd催化的条件下发生偶联反应得到化合物15-6，化合物15-6脱保护得到化合物15-7，化合物15-7在三氟乙酸和二氯甲烷条件下发生关环反应生成化合物15-8，化合物15-8在正丁基锂的条件下与DMF发生反应得到醛15-9，醛15-9在正丁基锂的条件下与化合物15-10发生加成反应得到化合物15-11，化合物15-11通过Dess-Martin氧化或Swern氧化得到酮15-12，酮15-12与化合物15-13在碱性条件下发生取代反应生成化合物15-14，化合物15-14与化合物15-15反应生成化合物15-16，化合物15-16用TBAF脱保护得到化合物15-17，在某些例子中，化合物15-17通过手性拆分得到光学异构体15-A和15-B。
一般反应流程16
通式(1)化合物的实施方式可根据一般反应流程16制备，其中R1、Re、Re’和n如上文中所定义，Y表示Br、I或OTf，H表示氢，N表示氮，O表示氧，Cl表示氯。如一般反应流程16所示,化合物16-1和硝基甲烷发生缩合反应生成化合物16-2，还原化合物16-2得到胺16-3，用(Boc)2O保护化合物16-3得到化合物16-4，化合物16-4与化合物16-5在Pd催化的条件下发生偶联反应得到化合物16-6，化合物16-6与化合物16-7在Pd催化的条件下发生偶联反应得到化合物16-8，化合物16-8在三氟乙酸和二氯甲烷条件下发生关环反应生成化合物16-9，用(Boc)2O保护化合物16-9得到化合物16-10，化合物16-10在正丁基锂的条件下与DMF发生反应得到醛16-11，醛16-11在正丁基锂的条件下与化合物16-12发生加成反应得到化合物16-13，化合物16-13通过Dess-Martin氧化或Swern氧化得到酮16-14，酮16-14与化合物16-15在碱性条件下发生取代反应生成化合物16-16，化合物16-16与化合物16-17反应生成化合物16-18，化合物16-18用TBAF脱保护得到化合物16-19，化合物16-19在酸性条件下脱氨基保护得到化合物16-20，在某些例子中，化合物16-20通过手性拆分得到光学异构体16-A和16-B。
一般反应流程17
通式(1)化合物的实施方式可根据一般反应流程17制备，其中R1、Re、Re’和n如上文中所定义，Y表示Br、I或OTf，X表示O或S，H表示氢，N表示氮，O表示氧，Cl表示氯。如一般反应流程17所示,化合物17-1和硝基甲烷发生缩合反应生成化合物17-2，还原化合物17-2得到胺17-3，用(Boc)2O保护化合物17-3得到化合物17-4，化合物17-4与化合物17-5在Pd催化的条件下发生偶联反应得到化合物17-6，化合物17-6与化合物17-7在Pd催化的条件下发生偶联反应得到化合物17-8，化合物17-8在三氟乙酸和二氯甲烷条件下发生关环反应生成化合物17-9，用(Boc)2O保护化合物17-9得到化合物17-10，化合物17-10在正丁基锂的条件下与DMF发生反应得到醛17-11，醛17-11在正丁基锂的条件下与化合物17-12发生加成反应得到化合物17-13，化合物17-13通过Dess-Martin氧化或Swern氧化得到酮17-14，酮17-14与化合物17-15在碱性条件下发生取代反应生成化合物17-16，化合物17-16与化合物17-17反应生成化合物17-18，化合物17-18用TBAF脱保护得到化合物17-19，化合物17-19在酸性条件下脱氨基保护得到化合物17-20，在某些例子中，化合物17-20通过手性拆分得到光学异构体17-A和17-B。
一般反应流程18
通式(1)化合物的实施方式可根据一般反应流程18制备，其中R1、Re、Re’和n如上文中所定义，Y表示Br、I或OTf，H表示氢，P表示羟基的保护基，H表示氢，N表示氮，O表示氧，Cl表示氯。如一般反应流程18所示，保护化合物18-1得到化合物18-2，化合物18-2与化合物18-3在Pd催化的条件下发生偶联反应得到化合物18-4，化合物18-4与化合物18-5在Pd催化的条件下发生偶联反应得到化合物18-6，化合物18-6脱保护得到化合物18-7，化合物18-7在三氟乙酸和二氯甲烷条件下发生关环反应生成化合物18-8，化合物18-8在正丁基锂的条件下与DMF发生反应得到醛18-9，醛18-9在正丁基锂的条件下与化合物18-10发生加成反应得到化合物18-11，化合物18-11通过Dess-Martin氧化或Swern氧化得到酮18-12，酮18-12与化合物18-13在碱性条件下发生取代反应生成化合物18-14，化合物18-14与化合物18-15反应生成化合物18-16，化合物18-16用TBAF脱保护得到化合物18-17，在某些例子中，化合物18-17通过手性拆分得到光学异构体18-A和18-B。
一般反应流程19

通式(1)化合物的实施方式可根据一般反应流程19制备，其中R1、Re、Re’和n如上文中所定义，Y表示Br、I或OTf，H表示氢，X表示O或S，P表示羟基的保护基，H表示氢，N表示氮，O表示氧，Cl表示氯。如一般反应流程19所示，保护化合物19-1得到化合物19-2，化合物19-2与化合物19-3在Pd催化的条件下发生偶联反应得到化合物19-4，化合物19-4与化合物19-5在Pd催化的条件下发生偶联反应得到化合物19-6，化合物19-6脱保护得到化合物19-7，化合物19-7在三氟乙酸和二氯甲烷条件下发生关环反应生成化合物19-8，化合物19-8在正丁基锂的条件下与DMF发生反应得到醛19-9，醛19-9在正丁基锂的条件下与化合物19-10发生加成反应得到化合物19-11，化合物19-11通过Dess-Martin氧化或Swern氧化得到酮19-12，酮19-12与化合物19-13在碱性条件下发生取代反应生成化合物19-14，化合物19-14与化合物19-15反应生成化合物19-16，化合物19-16用TBAF脱保护得到化合物19-17，在某些例子中，化合物19-17通过手性拆分得到光学异构体19-A和19-B。
化合物的进一步形式
“药学上可接受”这里指一种物质，如载体或稀释液，不会使化合物的生物活性或性质消失，且相对无毒，如，给予个体某物质，不会引起不想要的生物影响或以有害的方式与任何其含有的组分相互作用。
术语“药学上可接受的盐”指一种化合物的存在形式，该形式不会引起对给药有机体的重要的刺激，且不会使化合物的生物活性和性质消失。在某些具体方面，药学上可接受的盐是通过通式化合物与酸或碱反应获得，其中所述的酸或碱包括，但不限于发现于Stahl和Wermuth，Handbook of Pharmaceutical Salts:Properties,Selection,and Use 1st Ed.，(Wiley,2002)中的酸和碱。
应理解药学上可接受的盐的参考包括溶剂添加形式或结晶形式，尤其是溶剂化物或多晶型。溶剂化物含有化学计量或非化学计量的溶剂，且是在与药学上可接受溶剂如水，乙醇等，结晶化过程中选择性形成的。当溶剂是水时形成水合物，或当溶剂是乙醇时形成醇化物。通式化合物的溶剂化物按照本文所述的方法，很方便的制得或形成。举例说明，通式化合物的水合物从水/有机溶剂的混合溶剂中重结晶而方便的制得，使用的有机溶剂包括但不限于，四氢呋喃、丙酮、乙醇或甲醇。此外，在此提到的化合物能够以非溶剂化和溶剂化形式存在。总之，对于在此提供的化合物和方法为目的，溶剂化形式被认为相当于非溶剂化形式。
在其他具体实施例中，通式化合物被制备成不同的形式，包括但不限于，无定形，粉碎形和毫微-粒度形式。此外，通式化合物包括结晶型，也可以作为多晶型。多晶型包括化合物的相同元素组成的 不同晶格排列。多晶型通常有不同的X-射线衍射光谱、红外光谱、熔点、密度、硬度、晶型、光和电的性质、稳定性和溶解性。不同的因素如重结晶溶剂，结晶速率和贮存温度可能引起单一晶型为主导。
在另一个方面，通式化合物可能存在手性中心和/或轴手性，并因此以消旋体、外消旋混合物、单一对映体、非对映异构体化合物和单一非对映体的形式、和顺反异构体的形式出现。每个手性中心或轴手性将独立地产生两个旋光异构体，并且所有可能的旋光异构体和非对映体混合物以及纯或部分纯的化合物包括在本发明的范围之内。本发明意味着包括这些化合物的所有这种异构形式。
本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氚(3H)、碘-125(125I)和C-14(14C)。又例如，可用重氢取代氢原子形成氘代化合物，氘与碳构成的键比普通氢和碳构成的键更坚固，相比于未氘代药物，通常氘代药物具有降低毒副作用、增加药物稳定性、增强疗效、延长药物体内半衰期等优势。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包含在本发明的范围之内。
本发明所述化合物的任何原子如未作特别说明，均指的是其稳态的原子的同位素。除非有特别说明，当分子结构上的一个位点选为“H”或者“氢”时，该位点应该被理解为具有氢同位素的天然丰度。同样地，如未特别说明，当一个位点选为“D”或者“氘”时，该位点应该被理解为其氘同位素丰度至少是其天然丰度的3000倍(氘同位素的天然丰度为0.015％)。
更优的，本发明中的氘代化合物的每一个氘代位点的氘原子丰度至少是其天然丰度的3500倍(52.2％的氘原子富集)。更优的，至少是4500倍(67.5％的氘原子富集)。更优的，至少是5000倍(75％的氘原子富集)。更优的，至少是6000倍(90％的氘原子富集)。更优的，至少是6333倍(95％的氘原子富集)。更优的，至少是6466.7倍(97％的氘原子富集)。更优的，至少是6600倍(99％的氘原子富集)。更优的，至少是6633.3倍(99.5％的氘原子富集)。
术语
如果无另外说明，用于本发明申请，包括说明书和权利要求书中的术语，定义如下。必须注意，在说明书和所附的权利要求书中，如果文中无另外清楚指示，单数形式“一个”包括复数意义。如果无另外说明，使用质谱、核磁、HPLC、蛋白化学、生物化学、重组DNA技术和药理的常规方法。在本申请中，如果无另外说明，使用“或”或“和”指“和/或”。
除非另有规定，“烷基”指饱和的脂肪烃基团，包括1至6个碳原子的直链和支链基团。优选含有1至4个碳原子的低级烷基，例如甲基、乙基、丙基、2-丙基、正丁基、异丁基、叔丁基。更优选含有1-3个碳原子的低级烷基，如甲基、乙基、丙基、2-丙基。如本文所用，“烷基”包括未取代和取代的烷基，尤其是被一个或多个卤素所取代的烷基。优选的烷基选自CH3、CH3CH2、CF3、CHF2、CF3CH2、CF3(CH3)CH、iPr、nPr、iBu、nBu或tBu。
除非另有规定，“亚烷基”指二价的如上所定义的烷基。亚烷基的例子包括但不限于，亚甲基和亚乙基。
除非另有规定，“烯基”指含有碳-碳双键的不饱和脂肪烃基团，包括1至14个碳原子的直链或支链基团。优选含有1至4个碳原子的低级烯基，例如乙烯基、1-丙烯基、1-丁烯基或2-甲基丙烯基。更优选含有1至2个碳原子的低级烯基。
除非另有规定，“亚烯基”指二价的如上所定义的烯基。
除非另有规定，“炔基”指含有碳-碳叁键的不饱和脂肪烃基团，包括1至14个碳原子的直链和支链基团。优选含有1至4个碳原子的低级炔基，例如乙炔基、1-丙炔基或1-丁炔基。更优选含有1至2个碳原子的低级炔基。
除非另有规定，“亚炔基”指二价的如上所定义的炔基。
除非另有规定，“环烷基”是指非芳香族烃环系统(单环、双环或多环)，优选为含有3-14个环碳原子(C3-14环烷基)的非芳香族烃环系统。在一些实施方案中，环烷基具有3-10个环碳原子(C3-10环烷基)。在一些实施方案中，环烷基具有3-8个环碳原子(C3-8环烷基)。在一些实施方案中，环烷基具有3-7个环碳原子(C3-7环烷基)。在一些实施方案中，环烷基具有3-6个环碳原子(C3-6环烷基)。在一些实施方案中，环烷基具有4-6个环碳原子(C4-6环烷基)。在一些实施方案中，环烷基具有5-6个环碳原子(C5-6环烷基)。在一些实施方案中，环烷基具有5-10个环碳原子(C5-10环烷基)。环烷基如果碳环含有至少一个双键，那么部分不饱和环烷基可被称为“环烯基”，或如果碳环含有至少一个三键，那么部分不饱和环烷基可被称为“环炔基”。环烷基可以包括单环或多环(例如具有2、3或4个稠合环)基团和螺环。在一些实施方案中，环烷基为单环的。在一些实施方案中，环烷基为双环的。在一些实施方案中，环烷基为单环的或双环的。在一些实施方案中，环烷基为三环的。环烷基的成环碳原子可以任选地被氧化以形成氧代或硫代基。环烷基还包括亚环烷基。在一些实施方案中，环烷基含有0、1或2个双键。在一些实施方案中，环烷基含有1或2个双键(部分不饱和环烷基)。在一些实施方案中，环烷基可以与芳基、杂芳基、环烷基和杂环烷基稠合。在一些实施方案中，环烷基可以与芳基、环烷基和杂环烷基稠合。在一些实施方案中，环烷基可以与芳基和杂环烷基稠合。一些实施方案中，环烷基可以与芳基和环烷基稠合。环烷基的实例包括环丙基、环丁基、环戊基、环己基、环庚基、环戊烯基、环己烯基、环已二烯基、环庚三烯基、降莰基、降蒎基、降蒈基、双环[1.1.1]戊烷基、双环[2.1.1]己烷基等等。
除非另有规定，“亚环烷基”指二价的如上所定义的环烷基。
除非另有规定，“烷氧基”指通过醚氧原子键合到分子其余部分的烷基。代表性的烷氧基为具有1-6个碳原子的烷氧基，如甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、仲丁氧基和叔丁氧基。如本文所用，“烷氧基”包括未取代和取代的烷氧基，尤其是被一个或多个卤素所取代的烷氧基。优选的烷氧基选自OCH3、OCF3、CHF2O、CF3CH2O、i-PrO、n-PrO、i-BuO、n-BuO或t-BuO。
除非另有规定，“芳基”指碳氢芳香基团，芳基是单环或多环的，例如单环芳基环与一个或多个碳环芳香基团稠和。芳基的例子包括但不限于，苯基、萘基和菲基。
除非另有规定，“芳氧基”指通过醚氧原子键合到分子其余部分的芳基。芳氧基的例子包括但不限于苯氧基和萘氧基。
除非另有规定，“亚芳基”指二价的如上所定义的芳基。亚芳基的例子包括但不限于，亚苯基、亚萘基和亚菲基。
除非另有规定，“杂芳基”指含有一个或多个杂原子的取代的或未取代的芳香基团，优选为含有1-4个选自氧、硫和氮的杂原子的5-14元芳香基团，更优选为含有1-2个任选自氧、硫或氮的杂原子的 5-9元芳香基团，杂原子独立地选自O、N或S，杂原子数量优选为1个、2个或3个。杂芳基是单环或多环的。单环杂芳基优选为含有1-3个任选自氧、氮或硫的杂原子的5-6元芳香基团。更优选为含有1-2个任选自氧、氮或硫的杂原子的5-6元芳香基团。更优选为含有1个任选自氧、氮或硫的杂原子的5-6元芳香基团。在一些实施方案中，单环杂芳基环与一个或多个碳环芳香基团或其它单环杂环烷基基团稠和。杂芳基的例子包括但不限于，吡啶基、哒嗪基、咪唑基、嘧啶基、吡唑基、三唑基、吡嗪基、喹啉基、异喹啉基、呋喃基、噻吩基、异噁唑基、噻唑基、噁唑基、1,2,4-噁二唑基、1,3,4-噁二唑基、1,2,5-噁二唑基、异噻唑基、吡咯基、吲哚基、苯并咪唑基、苯并呋喃基、苯并噻唑基、苯并噻吩基、苯并噁唑基、苯并吡啶基、吡咯并嘧啶基、1H-吡咯[3,2-b]吡啶基、1H-吡咯[2,3-c]吡啶基、1H-吡咯[3,2-c]吡啶基、1H-吡咯[2,3-b]吡啶基、除非另有规定，“亚杂芳基”指二价的如上所定义的杂芳基。
除非另有规定，“杂环烷基”指非芳香族环或环系统，其可以任选地含有一个或多个亚烯基作为环结构的一部分，其具有至少一个独立地选自硼、磷、氮、硫、氧和硒的杂原子环成员，优选为含有1-4个选自氧、硫或氮的杂原子的饱和或部分不饱和环，更优选为含有1-2个选自氧、硫或氮的杂原子的饱和或部分不饱和环。在一些实施方案中，杂环烷基为含有环碳原子及1-4个环杂原子的5-8元非芳香族环，其中各杂原子独立任选自氮、氧或硫(5-8元杂环烷基)。杂环烷基为含有环碳原子及1-4个环杂原子的5-6元非芳香族环，其中各杂原子独立任选自氮、氧或硫(5-6元杂环烷基)。在一些实施方案中，5-6元杂环烷基含有1-3个独立选自氮、氧及硫的环杂原子。在一些实施方案中，5-6元杂环烷基含有1-2个独立选自氮、氧及硫的环杂原子。在一些实施方案中，5-6元杂环烷基含有1个独立选自氮、氧及硫的环杂原子。如果杂环烷基含有至少一个双键，那么部分不饱和杂环烷基可被称为“杂环烯基”，或如果杂环烷基含有至少一个三键，那么部分不饱和杂环烷基可被称为“杂环炔基”。杂环烷基可以包括单环、双环、螺环或多环(例如具有两个稠合或桥接环)环系统。在一些实施例中，杂环烷基为具有1、2或3个独立地选自氮、硫和氧的杂原子的单环基团。杂环烷基的成环碳原子和杂原子可以任选地氧化以形成氧代或硫代基或其他氧化键(例如C(O)、S(O)、C(S)或S(O)2、N-氧化物等)，或氮原子可以季铵化。杂环烷基可以经由成环碳原子或成环杂原子而连接。在一些实施例中，杂环烷基含有0至3个双键。在一些实施例中，杂环烷基含有0至2个双键。杂环烷基的定义中还包括具有一个或多个与杂环烷基环稠合(即，与其共用键)的芳香族环的部分(也称为部分不饱和杂环)，例如哌啶、吗啉、氮杂环庚三烯或噻吩基等的苯并衍生物。含有稠合芳香族环的杂环烷基可以经由任何成环原子，包括稠合芳香族环的成环原子而连接。杂环烷基的实例包括但不限于氮杂环丁基、氮杂环庚基、二氢苯并呋喃基、二氢呋喃基、二氢吡喃基、N-吗啉基、3-氧杂-9-氮杂螺[5.5]十一烷基、1-氧杂-8-氮杂螺[4.5]癸烷基、哌啶基、哌嗪基、氧代哌嗪基、吡喃基、吡咯烷基、奎宁基、四氢呋喃基、四氢吡喃基、1,2,3,4-四氢喹啉基、莨菪烷基、4,5,6,7-四氢噻唑并[5,4-c]吡啶基、4,5,6,7-四氢-1H-咪唑并[4,5-c]吡啶、N-甲基哌啶基、四氢咪唑基、吡唑烷基、丁内酰胺基、戊内酰胺基、咪唑啉酮基、乙内酰脲基、二氧戊环基、邻苯二甲酰亚胺基、嘧啶-2,4(1H,3H)-二酮基、1,4-二氧六环基、吗啉基、硫 代吗啉基、硫代吗啉-S-氧化物基、硫代吗啉-S,S-氧化物基、哌嗪基、吡喃基、吡啶酮基、3-吡咯啉基、噻喃基、吡喃酮基、四氢噻吩基、2-氮杂螺[3.3]庚烷基、吲哚啉基、
除非另有规定，“亚杂环烷基”指二价的如上所定义的杂环烷基。
除非另有规定，“氧代基”指＝O；例如，碳经一个氧代基取代形成的基团为“羰基硫经一个氧代基取代形成的基团为“亚硫酰基硫经二个氧代基取代形成的基团为“磺酰基
除非另有规定，“卤素”(或卤代基)是指氟、氯、溴或碘。在基团名前面出现的术语“卤代”(或“卤素取代”)表示该基团是部分或全部卤代，也就是说，以任意组合的方式被F，Cl，Br或I取代，优选被F或Cl取代。
除非另有规定，术语“取代的”是指不超过指定原子的正常化合价的情况下，指定原子或基团上的一个或多个氢原子被一个或多个氢以外的取代基取代。例如，烷基、亚烷基、烯基、炔基、羟基或胺基等的一个或多个氢可被一个或多个取代基取代。其中所述取代基包括但不限于烷基、烯基、炔基、烷氧基、酰基、氨基、酰氨基、脒基、芳基、叠氮基、氨基甲酰基、羧基、羧酸酯、氰基、胍基、卤素、卤代烷基、杂烷基、杂芳基、杂环基、羟基、肼基、亚氨基、氧代基、硝基、烷基亚磺酰基、磺酸、烷基磺酰基、硫氰酸酯、硫醇、硫酮或其组合。“取代的”定义不包括通过定义具有附加到无穷大的进一步取代基的取代基而得到的类似不定结构(例如，具有取代烷基的取代芳基本身被取代的芳基取代，其进一步被取代的杂烷基取代，等等)。除非另有规定，否则本文所述化合物中连续取代的最大数目为三个。例如，取代的芳基被两个其他取代的芳基连续取代限于((取代的芳基)取代的芳基)取代的芳基。类似地，上述定义不包括不允许的取代模式(例如，被5个氟取代的甲基或具有两个相邻氧环原子的杂芳基)。这种不允许的取代模式是本领域技术人员众所周知的。每当用于修饰化学基团时，“取代的”可描述本文定义的其他化学基团。例如，术语“取代的芳基”包括但不限于“烷基芳基”。除非另有规定，否则如果一个基团被描述为任选被取代的，则该基团的任何取代基本身都是未被取代的。
“任选”或“任选地”指的是随后描述的事件或状况可能但不是必需出现，并且该描述包括其中所述事件或状况发生的情况以及所述事件或状况不发生的情况。
除非另有规定，可以理解词语“包含”，或其变体如“包括”或“含有”是指包括所述的元素或整数，或者元素或整数的组，但不排除任意其他的元素或整数，或者元素或整数的组。
取代基“-O-CH2-O-”指该取代基中二个氧原子和杂环烷基、芳基或杂芳基二个相邻的碳原子连接，比如：
当一个连接基团的数量为0时，比如-(CH2)0-，表示该连接基团为单键。
当其中一个变量选自化学键时，表示其连接的两个基团直接相连，比如X-L-Y中L代表化学键时表示该结构实际上是X-Y。
术语“元环”包括任何环状结构。术语“元”意为表示构成环的骨架原子的数量。例如，环己基、吡啶基、吡喃基、噻喃基是六元环，环戊基、吡咯基、呋喃基和噻吩基是五元环。
术语“片断”指分子的具体部分或官能团。化学片断通常被认为是包含在或附在分子中的化学实体。
术语“异构体”意指本发明的任何化合物的任何互变异构体、立体异构体、阻转异构体、同位素异构体、对映异构体或非对映异构体。本发明的化合物可具有一个或多个手性中心或双键，并且因此以立体异构体形式，例如以双键异构体(即，E/Z几何异构体)或非对映异构体(例如对映异构体(即，(+)或(‐))或顺/反异构体)形式存在。因此本发明的化合物涵盖所有相应立体异构体，即立体异构纯(例如几何异构纯、对映异构体纯或非对映异构体纯)形式以及对映异构体和立体异构体混合物，例如外消旋物。本发明化合物的对映异构体和立体异构体混合物可通过众所周知的方法，例如手性气相色谱法、手性高效液相色谱法，及使化合物以手性盐络合物形式结晶或使化合物在手性溶剂中结晶来拆分成其组分对映异构体或立体异构体。对映异构体和立体异构体也可由立体异构纯或对映异构纯的中间体、试剂和催化剂，通过众所周知的不对称合成方法获得。
术语“同位素异构体”指的是其结构上只有同位素不同而其他结构完全一致的不同分子。
术语“阻转异构体”是指当围绕分子内单键的旋转由于与分子其它部分的空间相互作用而被阻止或大大减慢并且在单键两端的取代基不对称时所产生的构象性立体异构体，即阻转异构体不需要立体中心。在围绕单键的旋转障碍足够高并且构象之间的相互转化足够慢的情况下，可允许单个异构体的分离(LaPlante et al.,J.Med.Chem.2011,54,20,7005)，优选以手性拆分的方法进行分离。
除非另有说明，用楔形实线键和楔形虚线键表示一个立体中心的绝对构型，用直形实线键和直形虚线键表示立体中心的相对构型，用波浪线表示楔形实线键或楔形虚线键或用波浪线表示直形实线键或直形虚线键
除非另有说明，用表示单键或双键。
特定药学及医学术语
术语“可接受的”，如本文所用，指一个处方组分或活性成分对一般治疗目标的健康没有过分的有害影响。
术语“治疗”、“治疗过程”或“疗法”如本文所用，包括缓和、抑制或改善疾病的症状或状况；抑制并发症的产生；改善或预防潜在代谢综合症；抑制疾病或症状的产生，如控制疾病或情况的发展；减轻疾病或症状；使疾病或症状减退；减轻由疾病或症状引起的并发症，或预防或治疗由疾病或症状引起的征兆。如本文所用，某一化合物或药物组合物，给药后，可以使某一疾病、症状或情况得到改善，尤指其严重度得到改善，延迟发病，减缓病情进展，或减少病情持续时间。无论固定给药或临时给药、 持续给药或间歇给药，可以归因于或与给药有关的情况。
“活性成分”指通式(1)所示化合物，以及通式(1)化合物的药学上可接受的无机或有机盐。本发明的化合物可以含有一个或多个不对称中心(手性中心或轴手性)，并因此以消旋体、外消旋混合物、单一对映体、非对映异构体化合物和单一非对映体的形式出现。可以存在的不对称中心，取决于分子上各种取代基的性质。每个这种不对称中心将独立地产生两个旋光异构体，并且所有可能的旋光异构体和非对映体混合物以及纯或部分纯的化合物包括在本发明的范围之内。本发明意味着包括这些化合物的所有这种异构形式。
“化合物(compound)”、“组合物(composition)”、“药剂(agent)”或“医药品(medicine or medicament)”等词在此可交替使用，且都是指当施用于个体(人类或动物)时，能够透过局部和/或全身性作用而诱发所亟求的药学和/或生理反应的一种化合物或组合物。
“施用(administered、administering或、administration)”一词在此是指直接施用所述的化合物或组合物，或施用活性化合物的前驱药(prodrug)、衍生物(derivative)、或类似物(analog)等。
虽然用以界定本发明较广范围的数值范围与参数皆是约略的数值，此处已尽可能精确地呈现具体实施例中的相关数值。然而，任何数值本质上不可避免地含有因个别测试方法所致的标准偏差。在此处，“约”通常是指实际数值在一特定数值或范围的正负10％、5％、1％或0.5％之内。或者是，“约”一词代表实际数值落在平均值的可接受标准误差之内，视本领域技术人员的考虑而定。除了实验例之外，或除非另有明确的说明，当可理解此处所用的所有范围、数量、数值与百分比(例如用以描述材料用量、时间长短、温度、操作条件、数量比例及其它相似者)均经过“约”的修饰。因此，除非另有相反的说明，本说明书与附随权利要求书所揭示的数值参数皆为约略的数值，且可视需求而更动。至少应将这些数值参数理解为所指出的有效位数与采用一般进位法所得到的数值。
除非本说明书另有定义，此处所用的科学与技术词汇的含义与本领域技术人员所理解的惯用的意义相同。此外，在不和上下文冲突的情形下，本说明书所用的单数名词涵盖该名词的复数型；而所用的复数名词时亦涵盖该名词的单数型。
治疗用途
本发明通式(1)和通式(2)化合物或药物组合物通常可用于抑制SAE蛋白，因此可用于治疗与SAE蛋白活性相关的一种或多种病症。因此，在某些实施方式中，本发明提供了用于治疗SAE蛋白介导的病症的方法，所述方法包括向有需要的患者施用本发明化通式(1)和通式(2)化合物、或其药学上可接受的组合物的步骤。
在一些实施例中，提供了用于癌症治疗的方法，该方法包括给予有需要的个体有效量的任何前述的包括结构通式(1)和通式(2)化合物的药物组合物。在一些实施例中，其中所述癌症包括但不限于血液恶性肿瘤(白血病、淋巴瘤、骨髓瘤包括多发性骨髓瘤、骨髓异常增生综合症和骨髓增生姓综合症)和实体瘤(癌例如前列腺、乳腺、肺、结肠、胰腺、肾、卵巢以及软组织癌和骨肉瘤，以及间质瘤)等，优选为肺癌、宫颈癌、结直肠癌、淋巴瘤、骨髓瘤、白血病、肝细胞癌、胰腺癌、肾癌、乳腺癌、头颈癌、黑色素瘤、前列腺癌、肾上腺癌、子宫内膜癌、阑尾癌及这些癌症的转移。
给药途径
本发明的化合物及其药学上可接受的盐可制成各种制剂，其中包含安全、有效量范围内的本发明化合物或其药学上可接受的盐及药理上可以接受的赋形剂或载体。其中“安全、有效量”指的是：化合物的量足以明显改善病情，而不至于产生严重的副作用。化合物的安全、有效量根据治疗对象的年龄、病情、疗程等具体情况来确定。
“药学上可以接受的赋形剂或载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能与本发明的化合物以及它们之间相互掺和，而不明显降低化合物的药效。药理上可以接受的赋形剂或载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
施用本发明化合物时，可以口服、直肠、肠胃外(静脉内、肌肉内或皮下)、局部给药。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，活性化合物与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例知，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性化合物外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂，或必要时可能需要的推进剂一起混合。
本发明化合物可以单独给药，或者与其他药学上可接受的化合物联合给药。使用药物组合物时，是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人)，其中施用时剂量为药学上认为的有效给药剂量，对于60kg体重的人而言，日给药剂量通常为1～2000mg，优选50～1000mg。当然，具体剂量还应考虑给药途径、病人健康状况等因素，这些都是熟练医师技能范围之内的。
本发明提到的上述特征，或实施例提到的特征可以任意组合。本案说明书所揭示的所有特征可与任何组合物形式并用，说明书中所揭示的各个特征，可以任何可提供相同、均等或相似目的替代性特征取代。因此除有特别说明，所揭示的特征仅为均等或相似特征的一般性例子。
具体实施方式
在下面的说明中将会详细阐述上述化合物、方法、药物组合物的各个具体方面、特性和优势，使本发明的内容变得十分明了。在此应理解，下述的详细说明及实例描述了具体的实施例，仅用于参考。在阅读了本发明的说明内容后，本领域的技术人员可对本发明作各种改动或修改，这些等价形势同样落于本申请所限定的范围。
所有实施例中，1H-NMR用Varian Mercury 400核磁共振仪记录，化学位移以δ(ppm)表示；分离用硅胶未说明均为200-300目，洗脱液的配比均为体积比。
本发明采用下述缩略词：(Boc)2O代表二碳酸二叔丁酯；CDCl3代表氘代氯仿；Cs2CO3代表碳酸铯；EtOAc或者Ethyl Acetate代表乙酸乙酯；Hexane代表正己烷；HPLC代表高效液相色谱；MeCN代表乙腈；DAST代表二乙胺基三氟化硫；DCM代表二氯甲烷；DIAD代表偶氮二甲酸二异丙酯；DIPEA代表二异丙基乙基胺；Dioxane代表1,4-二氧六环；DME代表乙二醇二甲醚；DMF代表N,N-二甲基甲酰胺；DMAP代表4-(二甲氨基)吡啶；DMSO代表二甲亚砜；DAST代表Diethylaminosulfur Trifluoride或二乙氨基三氟化硫；EtOH代表乙醇；hr代表小时；IPA代表异丙醇；表示Biotage Isolera Prime快速制备液相色谱仪；min代表分钟；K2CO3代表碳酸钾；KOAc代表醋酸钾；KOH代表氢氧化钾；K3PO4代表磷酸钾；LiBH4代表硼氢化锂；LiHMDS代表双三甲基硅基胺基锂；min代表分钟；MeOH代表甲醇；MeONa代表甲醇钠；MS代表质谱；NaBH(OAc)3代表三乙酰氧基硼氢化钠；NaH代表钠氢；NaN3代表叠氮钠；NH4Cl代表氯化铵；n-BuLi代表正丁基锂；NMR代表核磁共振；NIS代表碘代丁二酰亚胺；PBST代表含有Tween的磷酸缓冲盐溶液；Pd/C代表钯碳；Pd(PPh3)4代表四三苯基膦钯；Pd(OAc)2代表醋酸钯；Pd(dppf)Cl2代表[1,1’-双(二苯基膦)二茂铁]二氯化钯(II)；Pd(dtbpf)Cl2代表1,1-双(二-叔丁基膦基)二茂铁二氯合钯；PE或Petroleum ether代表石油醚；PFA代表多聚甲醛；PhNTf2代表N-苯基双三氟甲基磺酰亚胺；PPh3代表三苯基膦；PPTS代表对甲苯磺酸吡啶盐；TEA代表三乙胺；TFA代表三氟乙酸；Ti(i-PrO)4代表四异丙氧基钛；TMSCl代表三甲基氯硅烷；TsOH代表对甲苯磺酸；XantPhos代表4,5-双二苯基膦-9,9-二甲基氧杂蒽；TfOH代表三氟甲磺酸；TIPS代表三异丙基硅基；TLC代表薄层色谱；XPhos代表2-二环己基磷-2′,4′,6′-三异丙基联苯。
实施例1化合物1的合成
步骤1：化合物int_1-3的合成:
将int_1-1(2.8g,22.99mmol)，int_1-2(3.5g,22.99mmol,454.55μL)溶于Ti(i-PrO)4(20mL)中，氮气置换三次，混合液加热至80℃下搅拌2小时。LC-MS监测显示反应结束。将反应液冷却到室温，反应液直接用于下一步反应。
ESI-MS m/z:256[M+H]+。
步骤2：化合物int_1-4的合成:
0℃下，将HCOOH(78mL)慢慢滴加到Ac2O(194mL)中，加毕，反应液在20℃反应0.5小时。然后将步骤1中得到的int_1-3溶液冷却至-10℃，将上述HOOCH和Ac2O混合液慢慢滴加入int_1-3溶液中，滴加时保持温度为-10℃。滴加完成后反应液升至80℃反应2小时。LC-MS监测显示反应结束。反应液直接用于下一步反应。
ESI-MS m/z:284[M+H]+。
步骤3：化合物int_1-5的合成:
在70℃下，于1小时内，将TFA(316mL)慢慢加入到步骤2中得到的int_1-4溶液，冷却至，混合液在70℃搅拌反应3小时。LC-MS监测显示反应结束。将反应液冷却到室温后，反应液经过减压浓缩得到粗产物，粗产物用碳酸氢钠水溶液(400mL)调至弱碱性，水相用乙酸乙酯萃取(300mLX3)，有机相用无水硫酸钠干燥。有机相经过减压浓缩得到粗产物，粗产物经过柱层析制备纯化(SiO2,PE/EtOAc＝4/1)得固体(3.5g，收率：48.6％)。
ESI-MS m/z:284[M+H]+。
步骤4：化合物int_1-6的合成:
将int_1-5(1.2g,3.83mmol)溶于THF(20mL)中，冷却到-30℃，氮气保护下向反应液中慢慢滴加n-BuLi(2.5M,2.30mL)，反应液在-30℃反应2小时，LC-MS监测显示反应结束。反应液冷却至室温后，向反应液中加入饱和氯化铵水溶液(20mL)，水相用乙酸乙酯萃取(50mLX3)，有机相用无水硫酸钠干燥。有机相经过减压浓缩得到粗产物，粗产物直接用于下一步反应。
ESI-MS m/z:256[M+H]+。
步骤5：化合物int_1-7的合成:
将int_1-6(1.2g,3.73mmol)和(Boc)2O(1.22g,5.59mmol,1.28mL)溶于1,4-dioxane(20mL)中，室温下向反应液中加入TEA(1.13g,11.18mmol,1.56mL)，反应液升至90℃反应16小时，LC-MS监测，反应结束。反应液冷却至室温后，反应液经过减压浓缩得到粗产物，粗产物经柱层析制备纯化(SiO2,PE/EtOAc＝4/1)得固体(1.2g，收率：83.4％)。
ESI-MS m/z:356[M+H]+。
步骤6：化合物int_1-8的合成:
将int_1-7(1.2g,3.11mmol)溶于THF(25mL)中，冷却到-70℃，氮气保护下向反应液中慢慢滴加n-BuLi(2.5M,3.74mL)，反应液在-70℃反应0.5小时，然后在-70℃下，向反应液中滴加DMF(682.55mg,9.34mmol,718.48μL)，滴加完毕后，反应液在-60℃反应1.5小时，LC-MS监测，反应结束。向反应液中慢慢加入饱和氯化铵溶液(20mL)，水相用乙酸乙酯萃取(30mL*3)，有机相用无水硫酸钠干燥。有机相经过减压浓缩得到粗产物，粗产物经过柱层析制备纯化(SiO2,PE/EtOAc＝3/1)得固体(1.08g，收率：83.9％)。
MS(ESI):384[M+H]+。
步骤7：化合物int_1-10的合成:
将int_1-9(1.50g,6.26mmol)溶于THF(30mL)中，冷却到-70℃，氮气保护下向反应液中慢慢滴加n-BuLi(2.5M,5.01mL)，反应液在-70℃反应1小时，然后在-70℃下，向反应液中滴加int_1-8(800mg,2.09mmol)的THF(15mL)溶液，滴加完毕后，反应液在-70℃反应1小时，再升至室温反应 16小时。LC-MS监测，反应结束。向反应液中慢慢加入饱和氯化铵溶液(50mL)，水相用乙酸乙酯萃取(50mL*3)，有机相用无水硫酸钠干燥。有机相经过减压浓缩得到粗产物，粗产物经过柱层析制备纯化(SiO2,PE/EtOAc＝2/1)得固体(600mg，收率：57.7％)。
1H NMR(400MHz,CHLOROFORM-d)δ＝9.07-9.02(m,1H),8.96-8.91(m,1H),7.19(d,J＝4.4Hz,2H),7.12-7.03(m,1H),6.60-6.50(m,2H),6.24-6.15(m,1H),4.47-4.36(m,1H),3.21(dt,J＝2.6,12.2Hz,1H),3.10-2.99(m,1H),2.93-2.85(m,1H),2.84-2.66(m,4H),1.85-1.59(m,6H),1.27-1.17(m,9H)。
MS(ESI):498[M+H]+。
步骤8：化合物int_1-11的合成:
将int_1-10(600mg,1.20mmol)溶于DCM(6mL)中，室温下向反应液中加入Dess-Martin氧化剂(766.46mg,1.81mmol)，反应液在室温下反应1小时。LC-MS监测，反应结束。向反应液中慢慢加入饱和碳酸氢钠水溶液调至pH～8，水相用乙酸乙酯萃取(50mL*3)，有机相用无水硫酸钠干燥。有机相经过减压浓缩得到粗产物，粗产物经过柱层析制备纯化(SiO2,PE/EtOAc＝3/1)得固体(550mg，收率：92％)。
MS(ESI):496[M+H]+。
步骤9：化合物int_1-13的合成:
将int_1-12(23.0g,61.1mmol)和NH4Cl(11.4g,214mmol)溶于水(100mL)和乙醇(400mL)中，室温下向反应液中缓慢加入NaN3(11.9g,183mmol)，反应液在氮气保护下升至85℃反应16小时。TLC监测，反应结束。向反应液中慢慢加入饱和碳酸钠水溶液调至pH>9，水相用乙酸乙酯萃取(500mL*3)，有机相用无水硫酸钠干燥。有机相经过减压浓缩得到粗产物，粗产物经过柱层析制备纯化(Silica Flash Column,Eluent of 0～15％THF/Petroleum ether gradient)得油状液体(17.3g，收率：67.5％)。
1H NMR(400MHz,DMSO-d6)δ＝7.41-7.23(m,5H),5.46(d,J＝6.1Hz,1H),4.55-4.39(m,2H),4.17-4.10(m,1H),3.88-3.75(m,1H),3.69-3.60(m,1H),3.52(dq,J＝4.3,9.1Hz,2H),1.93-1.77(m,2H),1.71(ddd,J＝6.8,9.1,13.3Hz,1H),1.08-0.90(m,22H)。
步骤10：化合物int_1-14的合成:
将DAST(2.88g,17.9mmol,2.36mL)溶于DCM(30mL)中，氮气保护下，于冰浴下向反应液中加入int_1-13(5.00g,11.9mmol)的DCM溶液(30mL)，反应液在氮气保护下于室温下反应2小时。TLC监测，反应结束。向反应液中慢慢加入饱和碳酸氢钠水溶液调至pH～8，水相用二氯甲烷萃取(100mL*3)，有机相用无水硫酸钠干燥。有机相经过减压浓缩得到粗产物，粗产物经过柱层析制备纯化(Silica Flash Column,Eluent of 0～10％THF/Petroleum ether gradient)得油状液体(2.70g，收率：53.7％)。
1H NMR(400MHz,DMSO-d6)δ＝7.41-7.24(m,5H),4.52-4.48(m,2H),4.47-4.30(m,1H),4.18-4.07(m,1H),3.56-3.49(m,2H),2.71-2.56(m,1H),2.46-1.93(m,2H),1.77-1.41(m,1H),1.05-0.95(m,24H)。
步骤11：化合物int_1-15的合成:
将int_1-14(2.70g,6.40mmol)溶于甲醇(40mL)中，室温下向反应液中加入Pd/C(1.50g,10％purity)，反应液经氢气置换三次，然后升至60℃在氢气氛下(50PSI)反应48小时。LC-MS监测，反应结束。反应液冷却至室温并过滤，收集滤液。滤液经过减压浓缩得到粗产物(500mg，收率：25.6％)，粗产物可直接用于下一步反应。
MS(ESI):306[M+H]+。
步骤12：化合物int_1-16的合成:
将int_1-15(0.500g,1.64mmol)和int_1-11(813mg,1.64mmol)溶于DMF(10mL)中，室温下向反应液中加入K2CO3(679mg,4.91mmol)，反应液升至50℃反应1小时。LC-MS监测，反应结束。向反应液中加入冰水(100mL)，水相用乙酸乙酯萃取(100mL*3)，有机相用无水硫酸钠干燥。有机相经 过减压浓缩得到粗产物，粗产物经过柱层析制备纯化(Silica Flash Column,Eluent of 0～30％THF/Petroleum ether gradient)得产物(382mg，收率：30.4％)。
MS(ESI):765[M+H]+。
步骤13：化合物int_1-18的合成:
将int_1-16(0.178g,233μmol)溶于DMF(2mL)中，室温下向反应液中加入int_1-17(269mg,2.33mmol)，反应液在室温下反应1小时。LC-MS监测，反应结束。向反应液中加入冰水(10mL)，水相用乙酸乙酯萃取(10mL*3)，有机相用无水硫酸钠干燥。有机相经过减压浓缩得到粗产物，粗产物经过柱层析制备纯化得固体(165mg，收率：84.1％)。
MS(ESI):844[M+H]+。
步骤14：化合物int_1-19的合成:
将int_1-18(0.500g,592μmol)溶于THF(5mL)中，室温下向反应液中加入TBAF(1M,1.17mL)，反应液在室温下反应1小时。LC-MS监测，反应结束。向反应液中加入水(30mL)，水相用乙酸乙酯萃取(30mL*3)，有机相用无水硫酸钠干燥。有机相经过减压浓缩得到粗产物，粗产物经过柱层析制备纯化(Silica Flash Column,Eluent of 0～100％Ethyl acetate/Petroleum ether gradient)得固体(190mg，收率：46.6％)。
MS(ESI):688[M+H]+。
步骤15：化合物1的合成:
室温下，将int_1-16(500mg,726μmol)加入TFA(1mL)中，反应液在室温下反应5分钟。LC-MS监测，反应结束。向反应液中加入饱和碳酸氢钠水溶液将pH调至8，然后用制备HPLC纯化(column:Boston Prime C18 150*30mm*5um；mobile phase:[water(ammonia hydroxide v/v)-ACN]；B％:30％-50％,9min)，得固体(118mg，收率：27.6％)。
MS(ESI):588[M+H]+。
实施例2化合物2和化合物3的合成
将化合物1(0.1g,170μmol)进行SFC手性拆分(column:DAICEL CHIRALPAK IG(250mm*30mm,10um)；mobile phase:[CO2-EtOH(0.1％NH3H2O)])得到化合物2(peak 2,33mg)和化合物3(peak 1,31mg)。
化合物2：MS(ESI):588[M+H]+.
化合物3：MS(ESI):588[M+H]+.
实施例3化合物88的合成(合成路线1)

步骤1：化合物int_88-2的合成:
将int_88-1(25.0g,162mmol)，NH4OAc(28.8g,373mmol)溶于乙酸(250mL)中，氮气置换三次，在氮气保护下，向反应液中加入CH3NO2(25.7g,422mmol,22.8mL)，反应液加热至100℃搅拌16小时。LC-MS监测显示反应结束。将反应液冷却到室温后缓慢倒入1000mL的冰水中，水相用乙酸乙酯萃取(800mLX3)，有机相用无水硫酸钠干燥。有机相经过减压浓缩得到粗产物(27g，收率：78.2％)，粗产物可直接用于下一步反应。
1HNMR(400MHz,DMSO-d6)δ＝3.89(s,3H)7.33(dd,J＝11.25,8.44Hz,1H)7.46(ddd,J＝8.25,4.59,1.96Hz,1H)7.72(dd,J＝8.44,1.96Hz,1H)8.10(d,J＝13.57Hz,1H)8.29(d,J＝13.57Hz,1H)。
步骤2：化合物int_88-3的合成:
将LiBH4(27.6g,1.27mol)溶于四氢呋喃(300mL)中，氮气保护下，于0℃下向反应液中加入TMSCl(276g,2.54mol,322mL)，反应液在0℃下搅拌30分钟，将int_88-2(25.0g,127mmol)的四氢呋喃溶液(250mL)于30分钟内缓慢滴加至反应液中，反应液升至75℃继续反应2小时。LC-MS监测显示反应结束。将反应液冷却到0℃后缓慢加入600mL的甲醇淬灭反应，有机相经过减压浓缩得到 粗产物，粗产物用氨水调至pH>7，水相用乙酸乙酯萃取(500mLX3)，有机相用无水硫酸钠干燥。有机相经过减压浓缩得到粗产物(25g，粗产物)，粗产物可直接用于下一步反应。
ESI-MS m/z:170[M+H]+。
步骤3：化合物int_88-4的合成:
将int_88-3(12.5g,73.9mmol)，int_1-2(11.8g,77.6mmol)溶于Ti(i-PrO)4(1130mL)中，氮气置换三次，混合液加热至80℃搅拌2小时。LC-MS监测显示反应结束。将反应液冷却到室温，反应液直接用于下一步反应。
ESI-MS m/z:304[M+H]+。
步骤4：化合物int_88-5的合成:
-10℃下，将HCOOH(200mL)慢慢滴加到Ac2O(500mL)中，加毕，反应液在20℃反应0.5小时。然后将步骤3中得到的int_88-4溶液冷却至-10℃，将上述HOOCH和Ac2O混合液慢慢滴加入int_88-4溶液中，滴加时保持温度为-10℃。滴加完成后反应液升至70℃反应3小时。LC-MS监测显示反应结束。将反应液冷却至室温，有机相经过减压浓缩得到粗产物，粗产物用饱和碳酸氢钠水溶液调至pH>7，水相用乙酸乙酯萃取(500mLX3)，有机相用无水硫酸钠干燥。有机相经过减压浓缩得到粗产物，粗产物经柱层析制备纯化(SiO2,PE/EtOAc＝1/1)得固体(2g，收率：10.6％)。
1H NMR(400MHz,DMSO-d6)δ＝7.57(s,1H),7.32(d,J＝5.1Hz,1H),6.98(s,1H),6.72(s,1H),6.24(d,J＝5.3Hz,1H),4.40(td,J＝3.9,12.9Hz,1H),3.85(s,3H),3.24-3.12(m,1H),2.93(br dd,J＝3.7,7.9Hz,2H),2.89-2.79(m,2H),2.35(br dd,J＝2.0,11.9Hz,1H),2.01-1.81(m,2H),1.70-1.53(m,1H).
ESI-MS m/z:348[M+H]+。
步骤5：化合物int_88-6的合成:
将int_88-5(3.30g,9.49mmol)溶于二氯甲烷(30mL)中，氮气置换三次，反应液冷却至0℃，将BBr3(11.88g,47.43mmol,4.57mL)缓慢滴加至反应液中，将反应液升至室温反应1小时。LC-MS监测显示反应结束。将反应液缓慢倒入300mL的冰水中，水相用乙酸乙酯萃取(300mLX3)，有机相用无水硫酸钠干燥。有机相经过减压浓缩得到粗产物(2.8g，收率：88.4％)，粗产物可直接用于下一步反应。
1H NMR(400MHz,DMSO-d6)δ＝10.36(s,1H),7.72(s,1H),7.48(d,J＝5.1Hz,1H),6.91(s,1H),6.79(s,1H),6.41(d,J＝5.3Hz,1H),4.57-4.45(m,1H),3.38-3.28(m,1H),3.15-3.04(m,2H),2.98-2.85(m,2H),2.55-2.44(m,1H),2.14-1.97(m,2H),1.86-1.66(m,1H)。
ESI-MS m/z:334[M+H]+。
步骤6：化合物int_88-7的合成:
将int_88-6(2.80g,8.39mmol)、PhNTf2(5.39g,15.10mmol)和TEA(2.12g,20.97mmol,2.92mL)溶于二氯甲烷(30mL)中，氮气置换三次，反应液在室温下反应16小时。LC-MS监测显示反应结束。将反应液缓慢倒入300mL的冰水中，水相用乙酸乙酯萃取(300mLX3)，有机相用无水硫酸钠干燥。有机相经过减压浓缩得到粗产物，粗产物经柱层析制备纯化(SiO2,PE/EtOAc＝1/1)得固体(2.3g，收率：58.8％)。
1H NMR(400MHz,DMSO-d6)δ＝7.45-7.39(m,1H),7.36(d,J＝5.3Hz,1H),7.31-7.24(m,1H),7.12(s,1H),6.28(d,J＝5.3Hz,1H),4.51-4.38(m,1H),3.02-2.85(m,4H),2.42(td,J＝2.0,12.0Hz,2H),2.06-1.94(m,1H),1.90(br d,J＝13.8Hz,1H),1.94-1.83(m,1H),1.68-1.50(m,1H)。
ESI-MS m/z:466[M+H]+。
步骤7：化合物int_88-8的合成:
将int_88-7(2.30g,4.94mmol)、Pd/C(1.05g,987.35μmol,10％purity)和TEA(2.00g,19.75mmol,2.75mL)溶于甲醇(21mL)和四氢呋喃(7mL)的混合溶剂中，反应液用氢气置换三次，反应液在室温下反应16小时。LC-MS监测显示反应结束。将反应液过滤得到滤液，滤液经过减压浓缩得到粗产物，粗产物经柱层析制备纯化(SiO2,PE/EtOAc＝1/1)得固体(0.64g，收率：40.7％)。
1H NMR(400MHz,DMSO-d6)δ＝7.57(s,1H),7.34(d,J＝5.3Hz,1H),7.25(d,J＝0.9Hz,2H),6.76(s,1H),6.24(d,J＝5.3Hz,1H),4.41(td,J＝4.1,13.1Hz,1H),3.25-3.13(m,1H),2.95(dd,J＝3.9,7.8Hz,2H),2.86(dd,J＝4.5,8.3Hz,2H),2.45-2.35(m,1H),2.03-1.95(m,1H),1.95-1.83(m,1H),1.69-1.51(m,1H)。
ESI-MS m/z:318[M+H]+。
步骤8：化合物int_88-9的合成:
将int_88-8(0.64g,2.01mmol)溶于THF(10mL)中，冷却到-30℃，氮气保护下向反应液中慢慢滴加n-BuLi(2.5M,2.42mL)，反应液在-30℃反应2小时，再将反应液升至室温反应1小时，LC-MS监测显示反应结束。向反应液中加入饱和氯化铵水溶液(10mL)，水相用乙酸乙酯萃取(30mLX3)，有机相用无水硫酸钠干燥。有机相经过减压浓缩得到粗产物(0.5g，收率：85.6％)，粗产物直接用于下一步反应。
1H NMR(400MHz,DMSO-d6)δ7.15–7.10(m,3H),6.69(t,J＝1.3Hz,1H),6.35(d,J＝5.2Hz,1H),3.03–2.93(m,2H),2.91–2.78(m,3H),2.66(dt,J＝16.1,3.7Hz,1H),2.16(ddd,J＝13.2,5.0,2.6Hz,1H),2.03(ddtd,J＝16.0,13.0,6.8,2.7Hz,1H),1.84–1.71(m,2H)。
ESI-MS m/z:290[M+H]+。
步骤9：化合物int_88-10的合成:
将int_88-9(0.50g,1.73mmol)和(Boc)2O(828.34mg,3.80mmol,871.93μL)溶于1,4-二氧六环(10mL)中，室温下向反应液中加入TEA(523.71mg,5.18mmol,720.37μL)，反应液升至80℃反应16小时，LC-MS监测，反应结束。反应液冷却至室温后，反应液经过减压浓缩得到粗产物，粗产物经柱层析制备纯化(SiO2,PE/EtOAc＝10/1)得固体(0.11g，收率：16.3％)。
1H NMR(400MHz,DMSO-d6)δ＝7.33-7.23(m,3H),6.53(d,J＝5.1Hz,1H),6.40(d,J＝2.0Hz,1H),4.27(td,J＝3.7,12.0Hz,1H),3.11(ddd,J＝5.1,9.8,12.2Hz,1H),2.97-2.87(m,3H),2.75-2.63(m,2H),1.77(br d,J＝13.2Hz,1H),1.65-1.49(m,2H),1.15(s,9H)。
步骤10：化合物int_88-11的合成:
将int_88-10(1.44g,3.693mmol)溶于THF(20mL)中，冷却到-75℃，氮气保护下向反应液中慢慢滴加n-BuLi(2.5M,4.43mL)，反应液在-75℃反应1小时，然后在-75℃下，向反应液中滴加DMF(809mg,11.079mmol)，滴加完毕后，反应液在-75℃反应1小时，LC-MS监测，反应结束。向反应液中慢慢加入饱和氯化铵溶液(15mL)，水相用乙酸乙酯萃取(30mL*3)，有机相用无水硫酸钠干燥。有机相经过减压浓缩得到粗产物，粗产物经过柱层析制备纯化得固体(1.38g，收率：89.9％)。
MS(ESI):418[M+H]+。
步骤11：化合物int_88-12的合成:
将int_1-9(4.79g,19.911mmol)溶于THF(50mL)中，冷却到-75℃，氮气保护下向反应液中慢慢滴加n-BuLi(2.5M,16mL)，反应液在-75℃反应1小时，然后在-75℃下，向反应液中滴加int_88-11(1.387g,3.319mmol)的THF(25mL)溶液，滴加完毕后，反应液在-75℃反应1小时，再升至室温反 应16小时。LC-MS监测，反应结束。向反应液中慢慢加入饱和氯化铵溶液(200mL)，水相用乙酸乙酯萃取(200mL*3)，有机相用无水硫酸钠干燥。有机相经过减压浓缩得到粗产物，粗产物经过柱层析制备纯化得固体(1.427g，收率：80％)。
MS(ESI):532[M+H]+。
步骤12：化合物int_88-13的合成:
将int_88-12(1.427g,2.68mmol)溶于DCM(50mL)中，室温下向反应液中加入Dess-Martin氧化剂(1.36g,3.22mmol)，反应液在室温下反应1小时。LC-MS监测，反应结束。向反应液中慢慢加入饱和碳酸氢钠水溶液调至pH～8，水相用乙酸乙酯萃取(50mL*3)，有机相用无水硫酸钠干燥。有机相经过减压浓缩得到粗产物，粗产物经过柱层析制备纯化得固体(1.324g，收率：93％)。
MS(ESI):530[M+H]+。
步骤13：化合物int_88-15的合成:
将int_1-13(5g,11.91mmol)、三苯基膦(4.68g,17.87mmol)和int_88-14(2.38g,14.29mmol)溶于THF(200mL)中，室温下向反应液中加入DIAD(3.61g,17.87mmol)，反应液在室温下反应6小时。LC-MS监测，反应结束。向反应液中慢慢加入200mL水，水相用乙酸乙酯萃取(200mL*3)，有机相用无水硫酸钠干燥。有机相经过减压浓缩得到粗产物，粗产物经过柱层析制备纯化得固体(5.1g，收率：76.1％)。
MS(ESI):569[M+H]+。
步骤14：化合物int_88-16的合成:
将int_88-15(5g,8.79mmol)溶于甲醇(100mL)和水(50mL)的混合溶剂中，室温下向反应液中加入氢氧化锂(631mg,26.37mmol)，反应液在室温下反应6小时。LC-MS监测，反应结束。向反应液中慢慢加入200mL水，水相用乙酸乙酯萃取(200mL*3)，有机相用无水硫酸钠干燥。有机相经过减压浓缩得到粗产物，粗产物经过柱层析制备纯化得固体(3.2g，收率：88.8％)。
MS(ESI):420[M+H]+。
步骤15：化合物int_88-17的合成:
将DAST(2.88g,17.9mmol,2.36mL)溶于DCM(30mL)中，氮气保护下，于冰浴下向反应液中加入int_88-16(5.00g,11.9mmol)的DCM溶液(30mL)，反应液在氮气保护下于室温下反应2小时。TLC监测，反应结束。向反应液中慢慢加入饱和碳酸氢钠水溶液调至pH～8，水相用二氯甲烷萃取(100mL*3)，有机相用无水硫酸钠干燥。有机相经过减压浓缩得到粗产物，粗产物经过柱层析制备纯化(Silica Flash Column,Eluent of 0～10％THF/Petroleum ether gradient)得油状液体(3.5g，收率：70％)。
MS(ESI):422[M+H]+。
步骤16：化合物int_88-18的合成:
将int_88-17(3g,7.11mmol)溶于甲醇(40mL)中，室温下向反应液中加入Pd/C(1.50g,10％purity)，反应液经氢气置换三次，然后升至60℃在氢气氛下(50PSI)反应48小时。LC-MS监测，反应结束。反应液冷却至室温并过滤，收集滤液。滤液经过减压浓缩得到粗产物(650mg，收率：29.9％)，粗产物可直接用于下一步反应。
MS(ESI):306[M+H]+。
步骤17：化合物int_88-19的合成:
将int_88-18(501mg,1.64mmol)和int_88-13(869.9mg,1.64mmol)溶于DMF(10mL)中，室温下向反应液中加入K2CO3(679mg,4.91mmol)，反应液升至50℃反应1小时。LC-MS监测，反应结束。向反应液中加入冰水(100mL)，水相用乙酸乙酯萃取(100mL*3)，有机相用无水硫酸钠干燥。有机相经过减压浓缩得到粗产物，粗产物经过柱层析制备纯化(Silica Flash Column,Eluent of 0～30％THF/Petroleum ether gradient)得产物(355mg，收率：27.3％)。
MS(ESI):799[M+H]+。
步骤18：化合物int_88-20的合成:
将int_88-19(186mg,233μmol)溶于DMF(2mL)中，室温下向反应液中加入int_1-17(269mg,2.33mmol)，反应液在室温下反应1小时。LC-MS监测，反应结束。向反应液中加入冰水(10mL)，水相用乙酸乙酯萃取(10mL*3)，有机相用无水硫酸钠干燥。有机相经过减压浓缩得到粗产物，粗产物经过柱层析制备纯化得固体(182mg，收率：89.2％)。
MS(ESI):878[M+H]+。
步骤19：化合物int_88-21的合成:
将int_88-20(0.500g,569μmol)溶于THF(5mL)中，室温下向反应液中加入TBAF(1M,1.17mL)，反应液在室温下反应1小时。LC-MS监测，反应结束。向反应液中加入水(30mL)，水相用乙酸乙酯 萃取(30mL*3)，有机相用无水硫酸钠干燥。有机相经过减压浓缩得到粗产物，粗产物经过柱层析制备纯化(Silica Flash Column,Eluent of 0～100％Ethyl acetate/Petroleum ether gradient)得固体(359mg，收率：87.3％)。
MS(ESI):722[M+H]+。
步骤20：化合物88的合成:
室温下，将int_88-21(500mg,692μmol)加入TFA(1mL)中，反应液在室温下反应5分钟。LC-MS监测，反应结束。向反应液中加入饱和碳酸氢钠水溶液将pH调至8，然后用制备HPLC纯化(column:Boston Prime C18 150*30mm*5um；mobile phase:[water(ammonia hydroxide v/v)-ACN]；B％:30％-50％,9min)，得固体(405mg，收率：94.1％)。
MS(ESI):622[M+H]+。
实施例4化合物89和化合物90的合成
将化合物88(0.1g,160μmol)进行SFC手性拆分(column:DAICEL CHIRALPAK IG(250mm*30mm,10um)；mobile phase:[CO2-EtOH(0.1％NH3H2O)]；B％:55％,isocratic elution mode)得到化合物89(33mg)和化合物90(35mg)。
化合物89：1H NMR(400MHz,DMSO-d6)δ8.55(s,1H),8.48(s,1H),8.39(d,J＝8.2Hz,1H),7.50(s,2H),7.14(d,J＝2.5Hz,2H),6.97(s,1H),6.77(d,J＝1.9Hz,1H),5.16(d,J＝4.6Hz,1H),5.02(dt,J＝18.5,8.3Hz,1H),4.87(dt,J＝54.3,6.6Hz,1H),4.11(qd,J＝10.0,5.9Hz,2H),3.91(t,J＝5.4Hz,1H),2.97(m,4H),2.92–2.80(m,1H),2.67(d,J＝16.0Hz,1H),2.31–2.13(m,2H),2.06(d,J＝13.9Hz,1H),1.95(d,J＝10.3Hz,1H),1.90–1.72(m,3H)；MS(ESI):622[M+H]+.
分析SFC保留时间:1.048min(Instrument:Waters UPCC with PDA Detector；Column:Chiralpak IG-3 50x4.6mm I.D.,3um；Mobile phase:A:CO2,B:Ethanol(0.05％DEA)；Isocratic:40％B；Flow rate:4mL/min；Column temp.:35℃；ABPR:1500psi)。
化合物90：1H NMR(400MHz,DMSO-d6)δ8.55(s,1H),8.46(s,1H),8.33(d,J＝8.2Hz,1H),7.51 (s,2H),7.12(t,J＝1.6Hz,2H),6.93(s,1H),6.75(d,J＝1.8Hz,1H),5.15(d,J＝4.6Hz,1H),5.01(dt,J＝18.6,8.4Hz,1H),4.86(dt,J＝54.3,6.7Hz,1H),4.20–4.01(m,2H),3.93–3.83(m,1H),3.06–2.90(m,4H),2.85(dt,J＝16.1,7.9Hz,1H),2.63(d,J＝16.2Hz,1H),2.32–2.13(m,2H),2.05(d,J＝8.5Hz,1H),1.93(t,J＝11.1Hz,1H),1.79(dt,J＝14.3,8.9Hz,3H)；MS(ESI):622[M+H]+.
分析SFC保留时间:0.592min(Instrument:Waters UPCC with PDA Detector；Column:Chiralpak IG-3 50x4.6mm I.D.,3um；Mobile phase:A:CO2,B:Ethanol(0.05％DEA)；Isocratic:40％B；Flow rate:4mL/min；Column temp.:35℃；ABPR:1500psi)。
实施例5中间体int_88-9的合成
步骤1：化合物int_88-A-2的合成:
将int_88-A-1(35.0g,160mmol)，NH4OAc(28.8g,373mmol)溶于乙酸(250mL)中，氮气置换三次，在氮气保护下，向反应液中加入CH3NO2(25.7g,422mmol,22.8mL)，反应液加热至100℃搅拌16小时。LC-MS监测显示反应结束。将反应液冷却到室温后缓慢倒入1000mL的冰水中，水相用乙酸乙酯萃取(1000mLX3)，有机相用无水硫酸钠干燥。有机相经过减压浓缩得到粗产物(31g，收率：73.9％)，粗产物可直接用于下一步反应。
1H-NMR(400MHz,DMSO-d6):δ＝8.29(d,1H),8.18(d,1H),8.07(d,1H),7.99(d,1H),7.63(dd,1H)。
步骤2：化合物int_88-A-3的合成:
将LiBH4(28.3g,1.3mol)溶于四氢呋喃(300mL)中，氮气保护下，于0℃下向反应液中加入TMSCl(282g,2.6mol,329mL)，反应液在0℃下搅拌30分钟，将int_88-A-2(34.1g,130mmol)的四 氢呋喃溶液(250mL)于30分钟内缓慢滴加至反应液中，反应液升至75℃继续反应2小时。LC-MS监测显示反应结束。将反应液冷却到0℃后缓慢加入600mL的甲醇淬灭反应，有机相经过减压浓缩得到粗产物，粗产物用氨水调至pH>7，水相用乙酸乙酯萃取(500mLX3)，有机相用无水硫酸钠干燥。有机相经过减压浓缩得到粗产物(23.5g，粗产物)，粗产物可直接用于下一步反应。
ESI-MS m/z:234[M+H]+。
步骤3：化合物int_88-A-4的合成:
将int_88-A-3(25g,106.6mmol)和(Boc)2O(46.5g,213.2mmol)溶于1,4-二氧六环(10mL)中，室温下向反应液中加入TEA(21.5g,213.2mmol)，反应液升至80℃反应16小时，LC-MS监测，反应结束。反应液冷却至室温后，反应液经过减压浓缩得到粗产物，粗产物用水稀释，水相用乙酸乙酯萃取(500mLX3)，有机相用无水硫酸钠干燥。粗产物经柱层析制备纯化得固体(27g，收率：75.8％)。
ESI-MS m/z:334[M+H]+。
步骤4：化合物int_88-A-6的合成:
将int_88-A-4(5g,14.9mmol)、int_88-A-5(7.56g,29.8mmol)、Pd(dppf)Cl2(1.09g,1.5mmol)和乙酸钾(3.65g,37.25mmol)溶于1,4-二氧六环(150mL)中，氮气置换三次，反应液升至100℃反应6小时。LC-MS监测显示反应结束。将反应液缓慢倒入300mL的冰水中，水相用乙酸乙酯萃取(300mLX3)，有机相用无水硫酸钠干燥。有机相经过减压浓缩得到粗产物，粗产物经柱层析制备纯化得固体(3.9g，收率：68.6％)。
ESI-MS m/z:382[M+H]+。
步骤5：化合物int_88-A-8的合成:
将int_88-A-6(2g,5.23mmol)、int_88-A-7(1.78g,6.28mmol)、Pd(dppf)Cl2(365.8mg,0.5mmol)和磷酸钾(2.22g,10.46mmol)溶于1,4-二氧六环(50mL)和水(5mL)的混合溶剂中，氮气置换三次，反应液升至100℃反应6小时。LC-MS监测显示反应结束。将反应液缓慢倒入100mL的冰水中，水相用乙酸乙酯萃取(100mLX3)，有机相用无水硫酸钠干燥。有机相经过减压浓缩得到粗产物，粗产物经柱层析制备纯化得固体(1.65g，收率：81.2％)。
ESI-MS m/z:390[M+H]+。
步骤6：化合物int_88-9的合成:
将int_88-A-8(1g,2.56mmol)溶于二氯甲烷(10mL)中，氮气保护下向反应液中加入TFA(10mL)，反应液在室温反应8小时，LC-MS监测显示反应结束。向反应液中加入饱和碳酸氢钠水溶液(50mL)，水相用乙酸乙酯萃取(100mLX3)，有机相用无水硫酸钠干燥。有机相经过减压浓缩得到粗产物，粗产物经柱层析制备纯化得固体(151mg，收率：20.3％)。
1H NMR(400MHz,DMSO-d6)δ7.14–7.11(m,3H),6.68(t,J＝1.4Hz,1H),6.35(d,J＝5.2Hz,1H),2.97(m,2H),2.88–2.79(m,3H),2.71–2.62(m,1H),2.16(ddd,J＝13.1,5.0,2.7Hz,1H),2.03(tdd,J＝12.9,6.9,3.3Hz,1H),1.84–1.72(m,2H)。
ESI-MS m/z:290[M+H]+。
实施例6化合物91的合成

步骤1：化合物int_91-2的合成:
将int_91-1(25.0g,162mmol)，NH4OAc(28.8g,373mmol)溶于乙酸(250mL)中，氮气置换三次，在氮气保护下，向反应液中加入CH3NO2(25.7g,422mmol,22.8mL)，反应液加热至100℃搅拌16小时。LC-MS监测显示反应结束。将反应液冷却到室温后缓慢倒入1000mL的冰水中，水相用乙酸乙酯萃取(800mLX3)，有机相用无水硫酸钠干燥。有机相经过减压浓缩得到粗产物(21g，收率：65.8％)，粗产物可直接用于下一步反应。
1HNMR(400MHz,DMSO-d6)δ＝3.89(s,3H),7.33(dd,J＝11.25,8.44Hz,1H),7.46(ddd,J＝8.25,4.59,1.96Hz,1H),7.72(dd,J＝8.44,1.96Hz,1H),8.10(d,J＝13.57Hz,1H),8.29(d,J＝13.57Hz,1H)。
步骤2：化合物int_91-3的合成:
将LiBH4(27.6g,1.27mol)溶于四氢呋喃(300mL)中，氮气保护下，于0℃下向反应液中加入 TMSCl(276g,2.54mol,322mL)，反应液在0℃下搅拌30分钟，将int_91-2(25.0g,127mmol)的四氢呋喃溶液(250mL)于30分钟内缓慢滴加至反应液中，反应液升至75℃继续反应2小时。LC-MS监测显示反应结束。将反应液冷却到0℃后缓慢加入600mL的甲醇淬灭反应，有机相经过减压浓缩得到粗产物，粗产物用氨水调至pH>7，水相用乙酸乙酯萃取(500mLX3)，有机相用无水硫酸钠干燥。有机相经过减压浓缩得到粗产物(25g，粗产物)，粗产物可直接用于下一步反应。
ESI-MS m/z:170[M+H]+。
步骤3：化合物int_91-4的合成:
将int_91-3(12.5g,73.9mmol)，int_1-2(11.8g,77.6mmol)溶于Ti(i-PrO)4(1130mL)中，氮气置换三次，混合液加热至80℃搅拌2小时。LC-MS监测显示反应结束。将反应液冷却到室温，反应液直接用于下一步反应。
ESI-MS m/z:304[M+H]+。
步骤4：化合物int_91-5的合成:
-10℃下，将HCOOH(400mL)慢慢滴加到Ac2O(1000mL)中，加毕，反应液在20℃反应0.5小时。然后将步骤3中得到的int_91-4溶液冷却至-10℃，将上述HOOCH和Ac2O混合液慢慢滴加入int_91-4溶液中，滴加时保持温度为-10℃。滴加完成后反应液升至80℃反应16小时。LC-MS监测显示反应结束。将反应液冷却至室温，有机相经过减压浓缩得到粗产物，粗产物用饱和碳酸氢钠水溶液调至pH>7，水相用乙酸乙酯萃取(1000mLX3)，有机相用无水硫酸钠干燥。有机相经过减压浓缩得到粗产物，粗产物经柱层析制备纯化(SiO2,PE/EtOAc＝3/2)得固体(1.5g，收率：5.05％)。
1HNMR(400MHz,DMSO-d6)δ＝1.52-1.66(m,1H),1.82-1.94(m,2H),2.28-2.38(m,1H),2.78-2.86(m,2H),2.89-2.97(m,2H),3.10-3.22(m,1H),3.82(s,3H),4.40(dt,J＝12.93,3.99Hz,1H),6.22(d,J＝5.28Hz,1H),6.52(d,J＝12.98Hz,1H),6.97(d,J＝9.02Hz,1H),7.30(d,J＝5.28Hz,1H),7.57(s,1H)。
ESI-MS m/z:332[M+H]+。
步骤5：化合物int_91-6的合成:
将int_91-5(4.00g,12.1mmol)溶于二氯甲烷(40mL)中，氮气置换三次，反应液冷却至0℃，将BBr3(15.1g,60.4mmol,5.81mL)缓慢滴加至反应液中，将反应液升至室温反应1小时。LC-MS监测显示反应结束。将反应液缓慢倒入200mL的冰水中，水相用乙酸乙酯萃取(200mLX3)，有机相用无水硫酸钠干燥。有机相经过减压浓缩得到粗产物(4.5g，收率：99.3％)，粗产物可直接用于下一步反应。
ESI-MS m/z:318[M+H]+。
步骤6：化合物int_91-7的合成:
0℃下，将int_91-6(4.50g,14.2mmol)、PhNTf2(9.12g,25.5mmol)和TEA(3.59g,35.5mmol,4.93mL)溶于二氯甲烷(50mL)中，氮气置换三次，反应液在室温下反应16小时。LC-MS监测显示反应结束。将反应液缓慢倒入200mL的冰水中，水相用乙酸乙酯萃取(200mLX3)，有机相用无水硫酸钠干燥。有机相经过减压浓缩得到粗产物，粗产物经柱层析制备纯化(SiO2,PE/EtOAc＝2/1)得固体(4g，收率：62.8％)。
1HNMR(400MHz,DMSO-d6)δ＝1.52-1.67(m,1H),1.86-1.94(m,1H),1.99(s,1H),2.41(dt,J＝11.83,2.01Hz,1H),2.91(br s,2H),2.94(br dd,J＝8.03,3.85Hz,2H),3.18(ddd,J＝13.20,10.45,4.95Hz,1H),4.40-4.49(m,1H),6.26(d,J＝5.28Hz,1H),6.98(d,J＝11.66Hz,1H),7.35(d,J＝5.28Hz,1H),7.56(s,1H),7.60(d,J＝7.70Hz,1H)。
ESI-MS m/z:450[M+H]+。
步骤7：化合物int_91-8的合成:
将int_91-7(4.00g,8.90mmol)、Pd/C(1.00g,10.0％purity)和TEA(3.60g,35.6mmol,4.96mL)溶 于甲醇(80mL)中，反应液用氢气置换三次，反应液在氢气氛围下(20.0Psi)，室温下反应16小时。LC-MS监测显示反应结束。将反应液过滤得到滤液，滤液经过减压浓缩得到粗产物，粗产物经柱层析制备纯化(SiO2,PE/EtOAc＝1/1)得固体(2.2g，收率：81.2％)。
1HNMR(400MHz,DMSO-d6)δ＝1.53-1.67(m,1H),1.84-1.93(m,1H),1.98(td,J＝13.45,2.69Hz,1H),2.35-2.43(m,1H),2.84(br dd,J＝7.27,3.85Hz,2H),2.94(dd,J＝8.01,3.97Hz,2H),3.19(dt,J＝12.93,7.78Hz,1H),4.40(dt,J＝13.02,4.07Hz,1H),6.22(d,J＝5.26Hz,1H),6.53(dd,J＝10.51,2.69Hz,1H),7.04(td,J＝8.50,2.69Hz,1H),7.25(dd,J＝8.50,6.05Hz,1H),7.32(d,J＝5.26Hz,1H),7.59(s,1H)。
ESI-MS m/z:302[M+H]+。
步骤8：化合物int_91-9的合成:
将int_91-8(2.20g,7.30mmol)溶于THF(25mL)中，冷却到-78℃，氮气保护下向反应液中慢慢滴加n-BuLi(2.50M,8.76mL)，反应液在-30℃反应2小时，再将反应液升至室温反应0.5小时，LC-MS监测显示反应结束。向反应液中加入饱和氯化铵水溶液(50mL)，水相用乙酸乙酯萃取(50mLX3)，有机相用无水硫酸钠干燥。有机相经过减压浓缩得到粗产物，粗产物经柱层析制备纯化(SiO2,DCM/MeOH＝95/5)得固体(1.4g，收率：56.1％)。
1HNMR(400MHz,DMSO-d6)δ＝1.72-1.84(m,2H),1.96-2.08(m,1H),2.10-2.22(m,1H),2.67(br s,1H),2.75-2.90(m,4H),2.95-3.00(m,2H),6.34(d,J＝5.28Hz,1H),6.45(dd,J＝10.56,2.64Hz,1H),6.92(td,J＝8.53,2.75Hz,1H),7.10(br s,1H),7.11-7.15(m,1H)。
ESI-MS m/z:274[M+H]+。
步骤9：化合物int_91-10的合成:
将int_91-9(1.40g,5.12mmol)和(Boc)2O(2.46g,11.3mmol,2.59mL)溶于1,4-二氧六环(15mL)中，室温下向反应液中加入TEA(1.55g,15.4mmol,2.14mL)，反应液升至80℃反应16小时，LC-MS监测，反应结束。反应液冷却至室温后，反应液经过减压浓缩得到粗产物，粗产物经柱层析制备纯化(SiO2,PE/EtOAc＝4/1)得固体(870mg，收率：45.2％)。
ESI-MS m/z:374[M+H]+。
步骤10：化合物int_91-11的合成:
将int_91-10(900mg,2.41mmol)溶于THF(10mL)中，冷却到-70℃，氮气保护下向反应液中慢慢滴加n-BuLi(2.50M,2.89mL)，反应液在-70℃反应0.5小时，然后在-70℃下，向反应液中滴加DMF(528mg,7.23mmol,556μL)，滴加完毕后，反应液在-75℃反应1小时，LC-MS监测，反应结束。向反应液中慢慢加入饱和氯化铵溶液(25mL)，水相用乙酸乙酯萃取(30mL*3)，有机相用无水硫酸钠干燥。有机相经过减压浓缩得到粗产物，粗产物经过柱层析制备纯化(SiO2,PE/EtOAc＝4/1)得固体(970mg，收率：95.9％)。
1HNMR(400MHz,CHLOROFORM-d)δ＝1.23(s,9H),1.66-1.80(m,2H),1.82-1.91(m,1H),2.73-2.94(m,3H),2.95-3.06(m,2H),3.25(td,J＝12.07,3.12Hz,1H),4.40-4.49(m,1H),6.25(dd,J＝10.45,2.63Hz,1H),6.90(td,J＝8.25,2.57Hz,1H),7.17(dd,J＝8.07,5.87Hz,1H),7.27-7.28(m,1H),9.75(s,1H)。
MS(ESI):402[M+H]+。
步骤11：化合物int_91-12的合成:
将int_1-9(1.62g,6.72mmol)溶于THF(15mL)中，冷却到-75℃，氮气保护下向反应液中慢慢滴加n-BuLi(2.50M,5.38mL)，反应液在-75℃反应1小时，然后在-75℃下，向反应液中滴加int_91-11(900mg,2.24mmol)的THF(25mL)溶液，滴加完毕后，反应液在-75℃反应1小时，再升至室温反应16小时。LC-MS监测，反应结束。向反应液中慢慢加入饱和氯化铵溶液(100mL)，水相用乙酸乙酯萃取(100mL*3)，有机相用无水硫酸钠干燥。有机相经过减压浓缩得到粗产物，粗产物经过柱层析制备纯化(SiO2,PE/EtOAc＝7/3)得固体(690mg，收率：59.7％)。
1HNMR(400MHz,DMSO-d6)δ＝0.94-1.18(m,9H),1.44-1.80(m,4H),2.55-2.71(m,2H),2.77-2.94(m,3H),3.01-3.12(m,1H),4.18-4.28(m,1H),5.96-6.12(m,1H),6.16-6.27(m,1H),6.40-6.45(m,1H),6.57-6.72(m,1H),6.99-7.07(m,1H),7.28(br dd,J＝8.47,6.05Hz,1H),8.93-8.97(m,1H)。
MS(ESI):516[M+H]+。
步骤12：化合物int_91-13的合成:
将int_91-12(640mg,1.24mmol)溶于DCM(10mL)中，室温下向反应液中加入Dess-Martin氧化剂(1.05g,2.48mmol)，反应液在室温下反应1小时。LC-MS监测，反应结束。向反应液中慢慢加入饱和碳酸氢钠水溶液调至pH～8，水相用乙酸乙酯萃取(50mL*3)，有机相用无水硫酸钠干燥。有机相经过减压浓缩得到粗产物，粗产物经过柱层析制备纯化(SiO2,PE/EtOAc＝10/1)得固体(630mg，收率：98.8％)。
1HNMR(400MHz,DMSO-d6)δ＝1.19(s,9H),1.54-1.66(m,2H),1.75-1.85(m,1H),2.59-2.81(m,2H),2.85-2.91(m,2H),3.03-3.18(m,2H),4.17-4.26(m,1H),6.22(dd,J＝10.78,2.64Hz,1H),7.05(td,J＝8.47,2.64Hz,1H),7.25-7.34(m,2H),8.86(s,1H),9.15(s,1H)。
MS(ESI):514[M+H]+。
步骤13：化合物int_91-14的合成:
将int_91-13(390mg,759μmol)和int_88-18(348mg,1.14mmol)溶于DMF(10mL)中，室温下向反应液中加入K2CO3(524mg,3.79mmol)，反应液在室温下反应16小时。LC-MS监测，反应结束。向反应液中加入冰水(50mL)，水相用乙酸乙酯萃取(50mL*3)，有机相用无水硫酸钠干燥。有机相经过减压浓缩得到粗产物，粗产物经过柱层析制备纯化(SiO2,PE/EtOAc＝7/3)得产物(378mg，收率：63.6％)。
MS(ESI):783[M+H]+。
步骤14：化合物int_91-15的合成:
将int_91-14(563mg,719μmol)溶于DMF(10mL)中，室温下向反应液中加入int_1-17(249mg,2.16mmol)，反应液在室温下反应0.5小时。LC-MS监测，反应结束。向反应液中加入冰水(20mL)，水相用乙酸乙酯萃取(20mL*3)，有机相用无水硫酸钠干燥。有机相经过减压浓缩得到粗产物，粗产物经过柱层析制备纯化得固体(605mg，收率：97.7％)。
MS(ESI):862[M+H]+。
步骤15：化合物int_91-16的合成:
将int_91-15(562mg,652μmol)溶于THF(10mL)中，室温下向反应液中加入TBAF(1.00M,652μL)，反应液在室温下反应16小时。LC-MS监测，反应结束。向反应液中加入水(20mL)，水相用乙酸乙酯萃取(20mL*3)，有机相用无水硫酸钠干燥。有机相经过减压浓缩得到粗产物，粗产物经过柱层析制备纯化(SiO2,PE/EtOAc＝4/1)得固体(412mg，收率：89.5％)。
MS(ESI):706[M+H]+。
步骤16：化合物91的合成
室温下，将int_91-16(200mg,283μmol)溶于DCM(5mL)中，加入TFA(2mL)中，反应液在室温下反应5分钟。LC-MS监测，反应结束。冷却至0℃，向反应液中加入饱和碳酸氢钠水溶液将pH调 至8，水相用乙酸乙酯萃取(20mL*3)，有机相用无水硫酸钠干燥。有机相经过减压浓缩得到粗产物，粗产物用制备HPLC纯化得固体(60mg，收率：35.0％)。
MS(ESI):606[M+H]+。
实施例7化合物92和化合物93的合成
将化合物91(100mg,0.165mmol)进行SFC手性拆分(column:DAICEL CHIRALPAK IG(250mm*30mm,10um)；mobile phase:[CO2-iso-propanol(0.1％NH3H2O)]；B％:50％,isocratic elution mode)得到化合物92(35mg)和化合物93(37mg)。
化合物92：1H NMR(400MHz,DMSO-d6)δ8.57(s,1H),8.49(s,1H),8.38(d,J＝8.2Hz,1H),7.53(s,2H),7.18–7.07(m,1H),6.94(d,J＝4.2Hz,2H),6.56(dd,J＝10.3,2.8Hz,1H),5.19(d,J＝4.6Hz,1H),5.12–4.97(m,1H),4.89(dt,J＝54.1,6.5Hz,1H),4.27–4.04(m,2H),3.93(s,1H),2.98(m,4H),2.84(d,J＝7.7Hz,1H),2.65(m,1H),2.35–2.13(m,2H),2.08(m,1H),1.98(m,1H),1.83(d,J＝13.2Hz,3H)；MS(ESI):606[M+H]+。
分析SFC保留时间:2.764min(Instrument:Waters UPCC with PDA Detector；Column:Chiralpak IG-3 100x4.6mm I.D.,3um；Mobile phase:A:CO2,B:iso-propanol(0.05％DEA)；Isocratic:40％B；Flow rate:2.8mL/min；Column temp.:35℃；ABPR:1500psi)。
化合物93：1H NMR(400MHz,DMSO-d6)δ8.57(s,1H),8.48(s,1H),8.33(d,J＝8.2Hz,1H),7.53(s,2H),7.19–7.06(m,1H),7.02–6.88(m,2H),6.55(dd,J＝10.3,2.8Hz,1H),5.18(d,J＝4.6Hz,1H),5.10–5.00(m,1H),4.88(dt,J＝54.2,6.8Hz,1H),4.26–4.04(m,2H),3.91(s,1H),2.97(m,4H),2.86(dd,J＝16.0,7.8Hz,1H),2.65(m,1H),2.35–2.14(m,2H),2.08(s,1H),1.95(s,1H),1.81(t,J＝11.8Hz,3H)；MS(ESI):606[M+H]+。
分析SFC保留时间:1.291min(Instrument:Waters UPCC with PDA Detector；Column:Chiralpak IG-3 100x4.6mm I.D.,3um；Mobile phase:A:CO2,B:iso-propanol(0.05％DEA)；Isocratic:40％B；Flow rate:2.8mL/min；Column temp.:35℃；ABPR:1500psi)。
实施例8中间体int_91-9的合成
步骤1：化合物int_91-A-2的合成:
将int_91-A-1(32.4g,160mmol)，NH4OAc(28.8g,373mmol)溶于乙酸(250mL)中，氮气置换三次，在氮气保护下，向反应液中加入CH3NO2(25.7g,422mmol,22.8mL)，反应液加热至100℃搅拌16小时。LC-MS监测显示反应结束。将反应液冷却到室温后缓慢倒入1000mL的冰水中，水相用乙酸乙酯萃取(1000mLX3)，有机相用无水硫酸钠干燥。有机相经过减压浓缩得到粗产物(32.3g，收率：82.1％)，粗产物可直接用于下一步反应。
步骤2：化合物int_91-A-3的合成:
将LiBH4(28.3g,1.3mol)溶于四氢呋喃(300mL)中，氮气保护下，于0℃下向反应液中加入TMSCl(282g,2.6mol,329mL)，反应液在0℃下搅拌30分钟，将int_91-A-2(31.9g,130mmol)的四氢呋喃溶液(250mL)于30分钟内缓慢滴加至反应液中，反应液升至75℃继续反应2小时。LC-MS监测显示反应结束。将反应液冷却到0℃后缓慢加入600mL的甲醇淬灭反应，有机相经过减压浓缩得到粗产物，粗产物用氨水调至pH>7，水相用乙酸乙酯萃取(500mLX3)，有机相用无水硫酸钠干燥。有机相经过减压浓缩得到粗产物(20.7g，粗产物)，粗产物可直接用于下一步反应。
ESI-MS m/z:218[M+H]+。
步骤3：化合物int_91-A-4的合成:
将int_91-A-3(23.2g,106.6mmol)和(Boc)2O(46.5g,213.2mmol)溶于1,4-二氧六环(10mL)中，室温下向反应液中加入TEA(21.5g,213.2mmol)，反应液升至80℃反应16小时，LC-MS监测，反应结束。反应液冷却至室温后，反应液经过减压浓缩得到粗产物，粗产物用水稀释，水相用乙酸乙酯萃取(500mLX3)，有机相用无水硫酸钠干燥。粗产物经柱层析制备纯化得固体(28.1g，收率：82.8％)。
ESI-MS m/z:318[M+H]+。
步骤4：化合物int_91-A-5的合成:
将int_91-A-4(4.7g,14.9mmol)、int_88-A-5(7.56g,29.8mmol)、Pd(dppf)Cl2(1.09g,1.5mmol)和乙酸钾(3.65g,37.25mmol)溶于1,4-二氧六环(150mL)中，氮气置换三次，反应液升至100℃反应6小时。LC-MS监测显示反应结束。将反应液缓慢倒入300mL的冰水中，水相用乙酸乙酯萃取(300mLX3)，有机相用无水硫酸钠干燥。有机相经过减压浓缩得到粗产物，粗产物经柱层析制备纯化得固体(3.7g，收率：68.5％)。
ESI-MS m/z:366[M+H]+。
步骤5：化合物int_91-A-6的合成:
将int_91-A-5(1.9g,5.23mmol)、int_88-A-7(1.78g,6.28mmol)、Pd(dppf)Cl2(365.8mg,0.5mmol)和磷酸钾(2.22g,10.46mmol)溶于1,4-二氧六环(50mL)和水(5mL)的混合溶剂中，氮气置换三次，反应液升至100℃反应6小时。LC-MS监测显示反应结束。将反应液缓慢倒入100mL的冰水中，水相用乙酸乙酯萃取(100mLX3)，有机相用无水硫酸钠干燥。有机相经过减压浓缩得到粗产物，粗产物经柱层析制备纯化得固体(1.37g，收率：70.2％)。
ESI-MS m/z:374[M+H]+。
步骤6：化合物int_91-9的合成:
将int_91-A-6(1.1g,3mmol)溶于二氯甲烷(10mL)中，氮气保护下向反应液中加入TFA(10mL)， 反应液在室温反应8小时，LC-MS监测显示反应结束。向反应液中加入饱和碳酸氢钠水溶液(50mL)，水相用乙酸乙酯萃取(100mLX3)，有机相用无水硫酸钠干燥。有机相经过减压浓缩得到粗产物，粗产物经柱层析制备纯化得固体(125mg，收率：15.2％)。
1HNMR(400MHz,DMSO-d6)δ＝1.72-1.84(m,2H),1.96-2.08(m,1H),2.10-2.22(m,1H),2.67(br s,1H),2.75-2.90(m,4H),2.95-3.00(m,2H),6.34(d,J＝5.28Hz,1H),6.45(dd,J＝10.56,2.64Hz,1H),6.92(td,J＝8.53,2.75Hz,1H),7.10(br s,1H),7.11-7.15(m,1H)。
ESI-MS m/z:274[M+H]+。
实施例9化合物103的合成
步骤1：化合物int_103-1的合成:
将int_162-9(2.5g,6.686mmol)、高碘酸钠(7.2g,33.431mmol)和K2OsO4·2H2O(250mg,0.678mmol)溶于四氢呋喃(250mL)和水(125mL)的混合溶剂中，反应液用氮气置换三次，反应液在室温下反应2小时，LC-MS监测，反应结束。将反应液缓慢倒入100mL的冰水中，水相用二氯甲烷萃取(100mLX3)，有机相用无水硫酸钠干燥。有机相经过减压浓缩得到粗产物，粗产物经柱层析制备纯化得固体(2.6g，收率：96.2％)。
ESI-MS m/z:406[M+H]+。
步骤2：化合物int_103-2的合成:
将int_103-1(2.7g,6.686mmol)溶于乙酸乙酯(60mL)和甲醇(15mL)的混合溶剂中，向反应液中加入硼氢化钠(1.0g,26.744mmol)，反应液在室温下反应2小时，LC-MS监测，反应结束。将反应液缓慢倒入100mL的冰水中，水相用乙酸乙酯萃取(100mLX3)，有机相用无水硫酸钠干燥。有机相经过减压浓缩得到粗产物，粗产物经柱层析制备纯化(SiO2,PE/EtOAc＝2/1)得固体(1.8g，收率：65.6％)。
ESI-MS m/z:410[M+H]+。
步骤3：化合物int_103-3的合成:
将int_103-2(1.2g,2.93mmol)溶于甲苯(50mL)中，向反应液中加入对甲苯磺酸一水合物(5.6g,29.3mmol)，反应液升至110℃反应1小时，LC-MS监测，反应结束。将反应液冷却至室温，缓慢倒入50mL的冰水中，水相用乙酸乙酯萃取(50mLX3)，有机相用无水硫酸钠干燥。有机相经过减压浓缩得到粗产物，粗产物经柱层析制备纯化得固体(310mg，收率：38.7％)。
ESI-MS m/z:292[M+H]+。
步骤4：化合物int_103-4的合成:
将int_103-3(1.87g,6.426mmol)和(Boc)2O(2.1g,9.639mmol)溶于1,4-二氧六环(16mL)中，室温下向反应液中加入TEA(973mg,9.639mmol)，氮气保护下，反应液升至80℃反应16小时，LC-MS监测，反应结束。将反应液冷却至室温，并用2M盐酸水溶液调pH值至弱酸性，水相用乙酸乙酯萃取(100mLX3)，有机相用无水硫酸钠干燥。有机相经过减压浓缩得到粗产物，粗产物 经柱层析制备纯化(SiO2,PE/EtOAc＝2/1)得固体(1.6g，收率：63.5％)。
ESI-MS m/z:392[M+H]+。
步骤5：化合物int_103-5的合成:
将int_103-4(265mg,0.676mmol)溶于THF(10mL)中，冷却到-70℃，氮气保护下向反应液中慢慢滴加n-BuLi(2.5M,0.81ml)，反应液在-70℃反应1小时，然后在-60℃下，向反应液中滴加DMF(148mg,2.028mmol)，滴加完毕后，反应液在70℃反应1小时，LC-MS监测，反应结束。向反应液中慢慢加入饱和氯化铵溶液(20mL)，水相用乙酸乙酯萃取(20mL*3)，有机相用无水硫酸钠干燥。有机相经过减压浓缩得到粗产物，粗产物经过柱层析(SiO2,PE/EtOAc＝5/1)制备纯化得固体(170mg，收率：60.1％)。
MS(ESI):420[M+H]+。
步骤6：化合物int_103-6的合成:
将int_1-9(592mg,2.463mmol溶于THF(10mL)中，冷却到-70℃，氮气保护下向反应液中慢慢滴加n-BuLi(2.5M,2mL,4.926mmol)，反应液在-70℃反应1小时，然后在-75℃下，向反应液中滴加int_103-5(170mg,0.411mmol)的THF(1mL)溶液，滴加完毕后，反应液在-75℃反应1小时，再升至室温反应16小时。LC-MS监测，反应结束。向反应液中慢慢加入饱和氯化铵溶液(20mL)，水相用乙酸乙酯萃取(20mL*3)，有机相用无水硫酸钠干燥。有机相经过减压浓缩得到粗产物，粗产物经过柱层析制备纯化得固体(180mg，收率：81.2％)。
MS(ESI):534[M+H]+。
步骤7：化合物int_103-7的合成:
将int_103-6(180mg,0.337mmol)溶于DCM(15mL)中，室温下向反应液中加入Dess-Martin氧化剂(172mg,0.404mmol)，反应液在室温下反应1小时。LC-MS监测，反应结束。向反应液中慢慢加入饱和碳酸氢钠水溶液调至pH～8，水相用乙酸乙酯萃取(20mL*3)，有机相用无水硫酸钠干燥。有机相经过减压浓缩得到粗产物，粗产物经过柱层析(SiO2,PE/EtOAc＝2/1)制备纯化得固体(156mg，收率：87.1％)。
MS(ESI):532[M+H]+。
步骤8：化合物int_103-8的合成:
将int_103-7(174mg,0.328mmol)和int_88-18(150mg,0.491mmol)溶于DMF(10mL)中，室温下向反应液中加入K2CO3(138mg,1mmol)，反应液室温下反应16小时。LC-MS监测，反应结束。向反应液中加入冰水(30mL)，水相用乙酸乙酯萃取(30mL*3)，有机相用无水硫酸钠干燥。有机相经过减压浓缩得到粗产物，粗产物经过柱层析制备纯化(SiO2,PE/EtOAc＝2/1)得产物(235mg，收率：89.6％)。
MS(ESI):801[M+H]+。
步骤9：化合物int_103-9的合成:
将int_103-8(235mg,0.294mmol)溶于DMF(4mL)中，室温下向反应液中加入int_1-17(67.8mg,0.587mmol)，反应液在室温下反应1小时。LC-MS监测，反应结束。向反应液中加入冰水(30mL)， 水相用乙酸乙酯萃取(30mL*3)，有机相用无水硫酸钠干燥。有机相经过减压浓缩得到粗产物，粗产物经过柱层析制备纯化得固体(230mg，收率：89.1％)。
MS(ESI):880[M+H]+。
步骤10：化合物int_103-10的合成:
将int_103-9(253mg,0.288mmol)溶于THF(4mL)中，室温下向反应液中加入TBAF(1M,0.58mL,0.575mmol)，反应液在室温下反应16小时。LC-MS监测，反应结束。向反应液中加入水(30mL)，水相用乙酸乙酯萃取(30mL*3)，有机相用无水硫酸钠干燥。有机相经过减压浓缩得到粗产物，粗产物经过柱层析制备纯化得固体(175mg，收率：84.1％)。
MS(ESI):724[M+H]+。
步骤11：化合物103的合成:
将int_103-10(176mg,0.244mmol)溶于二氯甲烷(6mL)中，室温下，向反应液中加入TFA(1.5mL)，反应液在室温下反应10分钟。LC-MS监测，反应结束。向反应液中加入氨水(1mL)和水(10mL)，水相用二氯甲烷萃取(10mL*3)，有机相用无水硫酸钠干燥。有机相经过减压浓缩得到粗产物，粗产物用制备HPLC纯化，得固体(87mg，收率：57.2％)。
MS(ESI):624[M+H]+。
实施例10化合物104和化合物105的合成
将化合物103(80mg,0.128mmol)进行SFC手性拆分(column:DAICEL CHIRALPAK IG (250mm*30mm,10um)；mobile phase:[CO2-EtOH(0.1％NH3H2O)]；B％:50％,isocratic elution mode)得到化合物104(21mg)和化合物105(15mg)。
化合物104：1H NMR(400MHz,DMSO-d6)δ8.60(s,1H),8.50(s,1H),8.40(d,J＝8.2Hz,1H),7.54(s,2H),7.21(d,J＝8.8Hz,3H),6.93(s,1H),5.20(d,J＝4.6Hz,1H),5.15–4.79(m,4H),4.13(qd,J＝10.1,6.0Hz,3H),4.00–3.78(m,2H),3.06(s,2H),2.90(s,1H),2.73(s,1H),2.25(d,J＝22.4Hz,2H),1.98(s,1H),1.92–1.78(m,1H)；MS(ESI):624[M+H]+。
分析SFC保留时间:3.492min(Instrument:Waters UPCC with PDA Detector；Column:Chiralpak IG-3 100x4.6mm I.D.,3um；Mobile phase:A:CO2,B:Ethanol(0.05％DEA)；Isocratic:40％B；Flow rate:2.5mL/min；Column temp.:40℃；ABPR:100bar)。
化合物105：1H NMR(400MHz,DMSO-d6)δ8.59(s,1H),8.48(s,1H),8.33(d,J＝8.3Hz,1H),7.54(s,2H),7.29–7.11(m,3H),6.90(d,J＝2.0Hz,1H),5.19(d,J＝4.6Hz,1H),5.12–4.78(m,4H),4.19–4.06(m,2H),4.02(d,J＝11.4Hz,1H),3.91(s,1H),3.84(d,J＝11.4Hz,1H),3.03(s,2H),2.89(dt,J＝15.5,7.4Hz,1H),2.68(d,J＝16.5Hz,1H),2.47–2.18(m,2H),1.92(d,J＝9.3Hz,1H),1.88–1.74(m,1H)；MS(ESI):624[M+H]+。
分析SFC保留时间:2.146min(Instrument:Waters UPCC with PDA Detector；Column:Chiralpak IG-3 100x4.6mm I.D.,3um；Mobile phase:A:CO2,B:Ethanol(0.05％DEA)；Isocratic:40％B；Flow rate:2.5mL/min；Column temp.:40℃；ABPR:100bar)。
实施例11化合物130的合成
步骤1：化合物int_130-1的合成:
将int_162-9(1.50g,4.01mmol)和Pd/C(1.50g,10％purity)溶于甲醇(20mL)中，反应液用氢气置换三次，反应液在氢气氛围下(25psi)于室温下反应16小时，LC-MS监测，反应结束。将反应液过滤的到滤液，将滤液减压浓缩得到粗产物，粗产物经柱层析制备纯化(SiO2,PE/EtOAc＝0/1)得固体(1.3g，收率：86.2％)。
ESI-MS m/z:376[M+H]+。
步骤2：化合物int_130-2的合成:
将int_130-1(0.30g,798μmol)溶于THF(10mL)中，冷却到-60℃，氮气保护下向反应液中慢慢滴加n-BuLi(2.50M,479μL)，反应液在-60℃反应1小时，然后在-60℃下，向反应液中滴加DMF(175mg,2.39mmol,184μL)，滴加完毕后，反应液在-60℃反应3小时，LC-MS监测，反应结束。向反应液中慢慢加入饱和氯化铵溶液(100mL)，水相用乙酸乙酯萃取(100mL*3)，有机相用无水硫酸钠干燥。有机相经过减压浓缩得到粗产物，粗产物经过柱层析(SiO2,PE/EtOAc＝3/1)制备纯化得固体(150mg，收率：46.5％)。
MS(ESI):404[M+H]+。
步骤3：化合物int_130-3的合成:
将int_1-9(4.79g,19.9mmol)溶于THF(50mL)中，冷却到-75℃，氮气保护下向反应液中慢慢滴加n-BuLi(2.5M,16mL)，反应液在-75℃反应1小时，然后在-75℃下，向反应液中滴加int_130-2(1.3g,3.2mmol)的THF(25mL)溶液，滴加完毕后，反应液在-75℃反应1小时，再升至室温反应16 小时。LC-MS监测，反应结束。向反应液中慢慢加入饱和氯化铵溶液(200mL)，水相用乙酸乙酯萃取(200mL*3)，有机相用无水硫酸钠干燥。有机相经过减压浓缩得到粗产物，粗产物经过柱层析制备纯化得固体(1.15g，收率：69.6％)。
MS(ESI):518[M+H]+。
步骤4：化合物int_130-4的合成:
将int_130-3(0.200g,386μmol)溶于DCM(10mL)中，室温下向反应液中加入Dess-Martin氧化剂(327mg,772μmol,239μL)，反应液在室温下反应1小时。LC-MS监测，反应结束。向反应液中慢慢加入饱和碳酸氢钠水溶液调至pH～8，水相用乙酸乙酯萃取(30mL*3)，有机相用无水硫酸钠干燥。有机相经过减压浓缩得到粗产物，粗产物经过柱层析(SiO2,PE/EtOAc＝3/1)制备纯化得固体(170mg，收率：85.3％)。
1H NMR(400MHz,CHLOROFORM-d)δ＝9.10(s,1H),8.71(s,1H),7.12(q,J＝8.0Hz,2H),6.86(s,1H),6.58-6.50(m,1H),3.94-3.84(m,1H),3.75-3.63(m,1H),3.34-3.11(m,3H),2.92-2.84(m,2H),2.77-2.68(m,1H),1.24-1.11(m,3H),0.96-0.81(m,2H)。
MS(ESI):516[M+H]+。
步骤5：化合物int_130-5的合成:
将int_130-4(403mg,782μmol)和int_88-18(357mg,1.17mmol)溶于DMF(10mL)中，室温下向反应液中加入K2CO3(540mg,3.91mmol)，反应液室温下反应16小时。LC-MS监测，反应结束。向反应液中加入冰水(50mL)，水相用乙酸乙酯萃取(50mL*3)，有机相用无水硫酸钠干燥。有机相经过减压浓缩得到粗产物，粗产物经过柱层析制备纯化(Silica Flash Column,Eluent of 0～20％Ethyl acetate/Petroleum ether gradient)得产物(480mg，收率：78.1％)。
MS(ESI):785[M+H]+。
步骤6：化合物int_130-6的合成:
将int_130-5(0.510g,650μmol)溶于DMF(4mL)中，室温下向反应液中加入int_1-17(150mg,1.30mmol)，反应液在室温下反应1小时。LC-MS监测，反应结束。向反应液中加入冰水(50mL)，水相用乙酸乙酯萃取(50mL*3)，有机相用无水硫酸钠干燥。有机相经过减压浓缩得到粗产物，粗产物经过柱层析制备纯化得固体(430mg，收率：76.6％)。
MS(ESI):864[M+H]+。
步骤7：化合物int_130-7的合成:
将int_130-6(432mg,500μmol)溶于THF(4mL)中，室温下向反应液中加入TBAF(1M,500μL)，反应液在室温下反应16小时。LC-MS监测，反应结束。向反应液中加入水(30mL)，水相用乙酸乙酯萃取(30mL*3)，有机相用无水硫酸钠干燥。有机相经过减压浓缩得到粗产物，粗产物经过柱层析制备纯化(Silica Flash Column,Eluent of 0～100％Ethyl acetate/Petroleum ether gradient)得固体(238mg，收率：67.2％)。
MS(ESI):708[M+H]+。
步骤8：化合物130的合成:
室温下，将int_130-7(177mg,250μmol)加入TFA(0.500mL)中，反应液在室温下反应10分钟。LC-MS监测，反应结束。向反应液中加入氨水(1mL)和水(10mL)，水相用二氯甲烷萃取(10mL*3)， 有机相用无水硫酸钠干燥。有机相经过减压浓缩得到粗产物，粗产物用制备HPLC纯化得固体(55mg，收率：36.1％)。
MS(ESI):608[M+H]+。
实施例12化合物131和化合物132的合成
将化合物130(50mg,82.2μmol)进行SFC手性拆分(column:DAICEL CHIRALPAK AD(250mm*30mm,10um)；mobile phase:[CO2-EtOH(0.1％NH3H2O]；B％:60％,isocratic elution mode)得到化合物131(21mg)和化合物132(18mg)。
化合物131：1H NMR(400MHz,DMSO-d6)δ8.60(s,1H)8.56(s,1H)8.35(d,J＝8.19Hz,1H)7.53(s,2H)7.26(s,1H)7.10-7.21(m,2H)6.79(d,J＝1.71Hz,1H)5.19(d,J＝4.65Hz,1H)5.00-5.13(m,1H)4.81-4.99(m,1H)4.14(qd,J＝9.80,6.05Hz,2H)3.94(br s,1H)3.15(dt,J＝7.52,3.58Hz,2H)3.04-3.10(m,1H)2.93-3.01(m,1H)2.59-2.87(m,5H)2.19-2.31(m,1H)1.94-2.05(m,1H)1.80-1.94(m,1H)；MS(ESI):608[M+H]+.
分析SFC保留时间:1.298min(Instrument:Waters UPCC with PDA Detector；Column:Chiralpak AD-3 50x4.6mm I.D.,3um；Mobile phase:A:CO2,B:Ethanol(0.05％DEA)；Isocratic:40％B；Flow rate:4mL/min；Column temp.:35℃；ABPR:1500psi)。
化合物132：1H NMR(400MHz,DMSO-d6)δ＝8.59(s,1H)8.54(s,1H)8.29(d,J＝8.31Hz,1H)7.54(s,2H)7.24(s,1H)7.11-7.21(m,2H)6.78(d,J＝1.47Hz,1H)5.18(d,J＝4.65Hz,1H)5.00-5.11(m,1H)4.80-4.99(m,1H)4.07-4.20(m,2H)3.92(br s,1H)3.12-3.18(m,2H)3.04-3.11(m,1H)2.93-3.02(m,1H)2.59-2.87(m,5H)2.20-2.31(m,1H)1.89-2.00(m,1H)1.76-1.89(m,1H)；MS(ESI):608[M+H]+.
分析SFC保留时间:0.461min(Instrument:Waters UPCC with PDA Detector；Column:Chiralpak AD-3 50x4.6mm I.D.,3um；Mobile phase:A:CO2,B:Ethanol(0.05％DEA)；Isocratic:40％B；Flow rate:4mL/min；Column temp.:35℃；ABPR:1500psi)。
实施例13化合物162的合成
步骤1：化合物int_162-2的合成:
将int_162-1(50.0g,228mmol)，NH4OAc(40.4g,524mmol)溶于乙酸(500mL)中，氮气置换三次，在氮气保护下，向反应液中加入CH3NO2(36.2g,593mmol,32.0mL)，反应液加热至100℃搅拌16小时。LC-MS监测显示反应结束。将反应液冷却到室温后缓慢倒入1000mL的冰水中，水相用乙酸乙酯萃取(800mLX3)，有机相用无水硫酸钠干燥。有机相经过减压浓缩得到粗产物(50g，收率：83.6％)，粗产物可直接用于下一步反应。
1H NMR(400MHz,CHLOROFORM-d)δ＝8.35(d,J＝13.6Hz,1H),7.73(d,J＝2.0Hz,1H),7.58-7.51(m,2H),7.40(dd,J＝2.0,8.4Hz,1H)。
步骤2：化合物int_162-3的合成:
将LiBH4(20.8g,952mmol)溶于四氢呋喃(300mL)中，氮气保护下，于0℃下向反应液中加入TMSCl(207g,1.90mol,242mL)，反应液在0℃下搅拌30分钟，将int_162-2(25.0g,95.2mmol)的四 氢呋喃溶液(250mL)于30分钟内缓慢滴加至反应液中，反应液升至70℃继续反应2小时。LC-MS监测显示反应结束。将反应液冷却到0℃后缓慢加入200mL的甲醇淬灭反应，有机相经过减压浓缩得到粗产物，粗产物用氨水调至pH>7，水相用乙酸乙酯萃取(500mLX3)，有机相用无水硫酸钠干燥。有机相经过减压浓缩得到粗产物(20g，粗产物)，粗产物可直接用于下一步反应。
ESI-MS m/z:234[M+H]+。
步骤3：化合物int_162-5的合成:
将int_162-3(20.0g,85.3mmol)，int_162-4(9.07g,65.6mmol)和Ti(i-PrO)4(37.3g,131mmol)溶于甲苯(200mL)中，氮气置换三次，混合液加热至90℃搅拌2小时。LC-MS监测显示反应结束。将反应液冷却到室温并减压浓缩得到粗产物(23g，粗产物)，粗产物可直接用于下一步反应。
ESI-MS m/z:354[M+H]+。
步骤4：化合物int_162-6的合成:
将int_162-5(23.0g,64.9mmol)、TEA(65.6g,648mmol,90.3mL)和Ac2O(33.1g,324mmol,30.5mL)溶于二氯甲烷(400mL)中，反应液在氮气保护下于20℃反应2小时。LC-MS监测显示反应结束。将反应液冷却至室温，有机相经过减压浓缩得到粗产物，粗产物用饱和碳酸氢钠水溶液调至pH>7，水相用二氯甲烷萃取(500mLX3)，有机相用无水硫酸钠干燥。有机相经过减压浓缩得到粗产物，粗产物经柱层析制备纯化(SiO2,PE/EtOAc＝3/1)得固体(20g，收率：77.7％)。
1H NMR(400MHz,DMSO-d6)δ＝1.09-1.17(m,1H),1.88(br d,J＝7.00Hz,3H),2.82-2.96(m,2H),3.41-3.48(m,2H),3.80(br t,J＝7.13Hz,2H),3.99(q,J＝7.13Hz,1H),7.18–7.38(m,2H),7.43-7.54(m,1H),7.63(d,J＝2.13Hz,1H)。
步骤5：化合物int_162-7的合成:
将int_162-6(20.0g,50.4mmol)、DIPEA(13.0g,101mmol,17.6mL),ditert-butyl(cyclopentyl)phosphane；dichloropalladium；iron(3.29g,5.04mmol)溶于1,4-二氧六环(300mL)中，氮气置换三次，反应液升至110℃反应7小时。LC-MS监测显示反应结束。将反应液冷却至室温缓慢倒入300mL的冰水中，水相用乙酸乙酯萃取(300mLX3)，有机相用无水硫酸钠干燥。有机相经过减压浓缩得到粗产物，粗产物经柱层析制备纯化(SiO2,PE/EtOAc＝3/1)得固体(9.4g，收率：59％)。
1H NMR(400MHz,DMSO-d6)δ＝1.69-1.96(m,3H),2.91-3.01(m,2H),3.35(s,11H),3.73-3.86(m,1H),3.89-3.99(m,1H),6.40-6.47(m,1H),6.49-6.60(m,1H),6.77-6.85(m,1H),6.87-6.94(m,1H),7.15-7.21(m,1H),7.23-7.31(m,1H),7.39-7.49(m,1H)。
ESI-MS m/z:316[M+H]+。
步骤6：化合物int_162-8的合成:
将int_162-7(9.40g,29.8mmol)溶于正丁醇(15mL)和水(5mL)的混合溶剂中，向反应液中加入氢氧化钠(23.8g,595mmol)，反应液升至100℃反应16小时，再将反应液升至室温反应1小时，LC-MS监测显示反应结束。向反应液中加入水(200mL)，水相用乙酸乙酯萃取(200mLX3)，有机相用无水硫酸钠干燥。有机相经过减压浓缩得到粗产物，粗产物经柱层析制备纯化(SiO2,PE/EtOAc＝1/4)得固体(8g，收率：98.2％)。
1H NMR(500MHz,DMSO-d6)δ＝1.99(s,1H),2.94-3.00(m,1H),3.08-3.17(m,1H),3.19-3.27(m,1H),3.36-3.43(m,1H),6.44(d,J＝2.14Hz,1H),6.64(dd,J＝5.57,1.45Hz,1H),6.80(d,J＝5.49Hz,1H),6.94(d,J＝4.88Hz,1H),7.12-7.20(m,2H),7.38(dd,J＝4.81,1.45Hz,1H)。
ESI-MS m/z:274[M+H]+。
步骤7：化合物int_162-9的合成:
将int_162-8(8.00g,29.2mmol)和(Boc)2O(9.57g,43.8mmol,10.1mL)溶于二氯甲烷(90mL)中，室温下向反应液中加入TEA(8.87g,87.7mmol,12.2mL)，氮气保护下，反应液在室温下反应16小时，LC-MS监测，反应结束。将反应液缓慢倒入100mL的冰水中，水相用二氯甲烷萃取(100mLX3)，有机相用无水硫酸钠干燥。有机相经过减压浓缩得到粗产物，粗产物经柱层析制备纯化(SiO2,PE/EtOAc＝3/1)得固体(8.9g，收率：81.5％)。
1H NMR(400MHz,DMSO-d6)δ＝1.13(s,9H),2.88-3.06(m,2H),3.72-3.91(m,2H),6.47-6.63(m,2H),6.79(d,J＝5.50Hz,1H),6.85-6.95(m,1H),7.16-7.29(m,2H),7.41-7.49(m,1H)。
步骤8：化合物int_162-10的合成:
将int_162-9(0.30g,798μmol)溶于THF(10mL)中，冷却到-60℃，氮气保护下向反应液中慢慢滴加n-BuLi(2.50M,479μL)，反应液在-60℃反应1小时，然后在-60℃下，向反应液中滴加DMF(175mg,2.39mmol,184μL)，滴加完毕后，反应液在-60℃反应3小时，LC-MS监测，反应结束。向反应液中慢慢加入饱和氯化铵溶液(100mL)，水相用乙酸乙酯萃取(100mL*3)，有机相用无水硫酸钠干燥。有机相经过减压浓缩得到粗产物，粗产物经过柱层析(SiO2,PE/EtOAc＝3/1)制备纯化得固体(140mg，收率：43.4％)。
1H NMR(400MHz,DMSO-d6)δ＝1.12(s,9H),2.88-3.08(m,2H),3.66-3.93(m,2H),6.53-6.59(m,1H),6.90(d,J＝5.62Hz,1H),6.94-7.00(m,1H),7.19-7.26(m,1H),7.27-7.33(m,1H),7.74-7.85(m,1H),9.75(s,1H)。
MS(ESI):402[M+H]+。
步骤9：化合物int_162-11的合成:
将int_1-9(4.79g,19.91mmol)溶于THF(50mL)中，冷却到-75℃，氮气保护下向反应液中慢慢滴加n-BuLi(2.5M,16mL)，反应液在-75℃反应1小时，然后在-75℃下，向反应液中滴加int_162-10(1.33g,3.31mmol)的THF(25mL)溶液，滴加完毕后，反应液在-75℃反应1小时，再升至室温反应16小时。LC-MS监测，反应结束。向反应液中慢慢加入饱和氯化铵溶液(200mL)，水相用乙酸乙酯萃取(200mL*3)，有机相用无水硫酸钠干燥。有机相经过减压浓缩得到粗产物，粗产物经过柱层析制备纯化得固体(1.21g，收率：71.1％)。
1H NMR(400MHz,DMSO-d6)δ＝1.14(s,9H),2.82-3.02(m,3H),3.67-3.82(m,2H),5.74-5.78(m,1H),6.53-6.59(m,1H),6.90-6.94(m,1H),6.98-7.03(m,1H),7.19-7.29(m,2H),7.57-7.62(m,1H),8.97-9.01(m,1H),9.19(s,1H)。
MS(ESI):516[M+H]+。
步骤10：化合物int_162-12的合成:
将int_162-11(1.60g,3.10mmol)溶于DCM(100mL)中，室温下向反应液中加入Dess-Martin氧化剂(2.63g,6.20mmol)，反应液在室温下反应1小时。LC-MS监测，反应结束。向反应液中慢慢加入饱和碳酸氢钠水溶液调至pH～8，水相用乙酸乙酯萃取(100mL*3)，有机相用无水硫酸钠干燥。有机相经过减压浓缩得到粗产物，粗产物经过柱层析(SiO2,PE/EtOAc＝3/1)制备纯化得固体(0.9g，收率：56.5％)。
MS(ESI):514[M+H]+。
步骤11：化合物int_162-13的合成:
将int_162-12(0.90g,1.75mmol)和int_88-18(1.59g,5.22mmol)溶于DMF(20mL)中，室温下向反应液中加入K2CO3(1.21g,8.75mmol)，反应液升至50℃反应1小时。LC-MS监测，反应结束。向反应液中加入冰水(100mL)，水相用乙酸乙酯萃取(100mL*3)，有机相用无水硫酸钠干燥。有机相经过减压浓缩得到粗产物，粗产物经过柱层析制备纯化(Silica Flash Column,Eluent of 0～30％THF/Petroleum ether gradient)得产物(0.7g，收率：51％)。
MS(ESI):783[M+H]+。
步骤12：化合物int_162-14的合成:
将int_162-13(0.716g,914μmol)溶于DMF(20mL)中，室温下向反应液中加入int_1-17(423mg,3.66mmol)，反应液在室温下反应1小时。LC-MS监测，反应结束。向反应液中加入冰水(20mL)，水相用乙酸乙酯萃取(20mL*3)，有机相用无水硫酸钠干燥。有机相经过减压浓缩得到粗产物，粗产物经过柱层析制备纯化得固体(770mg，收率：97.7％)。
MS(ESI):862[M+H]+。
步骤13：化合物int_162-15的合成:
将int_162-14(786mg,912μmol)溶于THF(20mL)中，室温下向反应液中加入TBAF(1M,912μL)，反应液在室温下反应16小时。LC-MS监测，反应结束。向反应液中加入水(30mL)，水相用乙酸乙酯萃取(30mL*3)，有机相用无水硫酸钠干燥。有机相经过减压浓缩得到粗产物，粗产物经过柱层析制备纯化(Silica Flash Column,Eluent of 0～30％Ethyl acetate/Petroleum ether gradient)得固体(400mg，收率：62.1％)。
MS(ESI):706[M+H]+。
步骤14：化合物162的合成:
室温下，将int_162-15(205mg,291μmol)加入TFA(0.5mL)中，反应液在室温下反应10分钟。LC-MS监测，反应结束。向反应液中加入饱和碳酸氢钠水溶液将pH调至8，然后用制备HPLC纯化，得固体(90mg，收率：51.1％)。
MS(ESI):606[M+H]+。
实施例14化合物343和化合物344的合成
将化合物162(100mg,164μmol)进行SFC手性拆分(column:DAICEL CHIRALPAK IG(250mm*30mm,10um)；mobile phase:[CO2-EtOH(0.1％NH3H2O]；B％:50％,isocratic elution mode)得到化合物343(25mg)和化合物344(20mg)。
化合物343：1H NMR(400MHz,DMSO-d6)δ＝8.59(s,1H),8.50(s,1H),8.12-8.19(m,1H),7.57(s,1H),7.53(s,2H),7.14-7.22(m,2H),6.97(s,2H),6.46(s,1H),5.17(br s,1H),4.98-5.10(m,1H),4.78-4.97(m,1H),4.08-4.17(m,2H),3.90(br s,1H),3.22(br d,J＝6.97Hz,2H),3.09-3.14(m,1H),2.77-2.90(m,2H),2.20-2.29(m,1H),1.91(br d,J＝9.78Hz,1H),1.74-1.83(m,1H)；MS(ESI):606[M+H]+.
分析SFC保留时间:2.439min(Instrument:Waters UPCC with PDA Detector；Column:Chiralpak IG-3 100x4.6mm I.D.,3um；Mobile phase:A:CO2,B:Ethanol(0.05％DEA)；Isocratic:40％B；Flow rate:2.8mL/min；Column temp.:35℃；ABPR:1500psi)。
化合物344：1H NMR(400MHz,DMSO-d6)δ＝8.59(s,1H),8.50(s,1H),8.12-8.19(m,1H),7.57(s,1H),7.53(s,2H),7.14-7.22(m,2H),6.97(s,2H),6.46(s,1H),5.17(br s,1H),4.98-5.10(m,1H),4.78-4.97(m,1H),4.08-4.17(m,2H),3.90(br s,1H),3.22(br d,J＝6.97Hz,2H),3.09-3.14(m,1H),2.77-2.90(m,2H),2.20-2.29(m,1H),1.91(br d,J＝9.78Hz,1H),1.74-1.83(m,1H)；MS(ESI):606[M+H]+.
分析SFC保留时间:1.920min(Instrument:Waters UPCC with PDA Detector；Column:Chiralpak IG-3 100x4.6mm I.D.,3um；Mobile phase:A:CO2,B:Ethanol(0.05％DEA)；Isocratic:40％B；Flow rate:2.8mL/min；Column temp.:35℃；ABPR:1500psi)。
实施例15化合物190的合成

步骤1：化合物int_190-2的合成:
将int_190-1(20.0g,97.5mmol)、PPTS(245mg,975μmol)和乙二醇(18.2g,293mmol,16.4mL)溶于甲苯(300mL)中，氮气置换三次，混合液加热至115℃下反应16小时。LC-MS监测显示反应结束。将反应液冷却到室温，反应液经过减压浓缩得到粗产物，粗产物经过柱层析制备纯化(220gSilica Flash Column,Eluent of 0～10％Ethyl acetate/Petroleum ether gradient)得固体(23g，收率：94.7％)。
1H NMR(400MHz,CHLOROFORM-d)δ＝6.93-6.83(m,1H),5.93(s,1H),4.06-3.99(m,2H),3.96-3.88(m,2H),2.35-2.27(m,3H)。
步骤2：化合物int_190-4的合成:
将int_190-2(20.5g,82.1mmol)溶于THF(100mL)中，冷却到-70℃，氮气保护下向反应液中慢慢滴加n-BuLi(2.5M,38.6mL)，反应液在-70℃反应0.5小时。在-70℃下，将int_190-3(8.00g,48.3mmol)溶于THF(50mL)中，冷却到-40℃，氮气保护下向反应液中慢慢滴加BF3.Et2O(7.54g,53.1mmol,6.56mL)，该反应液在-40℃反应10分钟后，保持-40℃，向该反应液慢慢滴加之前制备的锂试剂。滴加完毕后，反应液缓慢升至室温反应1小时，LC-MS监测，反应结束。向反应液中慢慢加入饱和氯化铵溶液(300mL)，水相用乙酸乙酯萃取(450mL*3)，有机相用无水硫酸钠干燥。有机相经过减压浓缩得到粗产物，粗产物经过柱层析制备纯化(120gSilica Flash Column,Eluent of 0～100％ Ethyl acetate/Petroleum ether gradient)得固体(8g，收率：49.3％)。
MS(ESI):336[M+H]+。
步骤3：化合物int_190-5的合成:
将int_190-4(8.00g,23.8mmol)和(Boc)2O(6.24g,28.6mmol,6.57mL)溶于DCM(60mL)中，室温下向反应液中加入TEA(2.89g,28.6mmol)，反应液在室温反应16小时，LC-MS监测，反应结束。反应液冷却至室温后，反应液经过减压浓缩得到粗产物，粗产物经柱层析制备纯化(80gSilica Flash Column,Eluent of 0～20％Ethyl acetate/Petroleum ether gradient)得固体(5g，收率：48.1％)。
1H NMR(400MHz,CHLOROFORM-d)δ＝7.21-7.08(m,2H),6.96(s,1H),6.54(s,1H),6.26(br s,1H),5.88(s,1H),5.32(s,1H),4.29-4.05(m,3H),4.01-3.93(m,2H),3.17(dt,J＝3.9,12.9Hz,1H),3.07-2.91(m,1H),2.80-2.67(m,1H),2.56(s,3H),1.48(s,8H)。
步骤4：化合物int_190-6的合成:
将int_190-5(5.00g,11.5mmol)溶于THF(60mL)中，向反应液中滴加盐酸水溶液(1M,30.00mL)，反应液在室温反应1小时。LC-MS监测，反应结束。向反应液中慢慢加入水(200mL)，水相用二氯甲烷萃取(20mL*3)，有机相用无水硫酸钠干燥。有机相经过减压浓缩得到粗产物，粗产物经过柱层析制备纯化(80gSilica Flash Column,Eluent of 0～20％Ethyl acetate/Petroleum ether gradient)得油状物(4.4g，收率：97.9％)。
1H NMR(400MHz,CHLOROFORM-d)δ＝9.67(s,1H),7.25-7.19(m,1H),7.18-7.15(m,1H),7.12(s,1H),6.96(d,J＝1.8Hz,1H),6.34(br s,1H),4.15(q,J＝7.1Hz,1H),3.12(dt,J＝3.8,12.8Hz,1H),3.04-2.93(m,1H),2.77(br d,J＝16.3Hz,1H),1.53-1.47(m,9H)。
步骤5：化合物int_190-7的合成:
将int_1-9(5.40g,22.5mmol)溶于THF(50mL)中，冷却到-40℃，氮气保护下向反应液中慢慢滴加n-BuLi(2.5M,18.0mL)，反应液在-40℃反应0.5小时，然后在-40℃下，向反应液中滴加int_190-6(4.40g,11.2mmol)的THF(20mL)溶液，滴加完毕后，反应液缓慢升至室温反应1.5小时。LC-MS监测，反应结束。向反应液中慢慢加入饱和氯化铵溶液(100mL)，水相用乙酸乙酯萃取(200mL*3)，有机相用无水硫酸钠干燥。有机相经过减压浓缩得到粗产物，粗产物经过柱层析制备纯化(80gSilica Flash Column,Eluent of 0～30％Ethyl acetate/Petroleum ether gradient)得油状物(4g，收率：70.4％)。
1H NMR(400MHz,CHLOROFORM-d)δ＝8.93(s,1H),8.84(s,1H),7.12-7.03(m,2H),6.90-6.83(m,1H),6.40(d,J＝5.5Hz,1H),6.15(br s,1H),6.06-5.99(m,1H),3.08-2.98(m,1H),2.94-2.83(m,1H),2.69-2.59(m,2H),2.42(s,3H),1.37(s,9H)。
步骤6：化合物int_190-8的合成:
将int_190-7(600mg,1.18mmol)溶于DCM(6mL)中，室温下向反应液中加入Dess-Martin氧化剂(766.46mg,1.81mmol)，反应液在室温下反应1小时。LC-MS监测，反应结束。向反应液中慢慢加入饱和碳酸氢钠水溶液调至pH～8，水相用乙酸乙酯萃取(50mL*3)，有机相用无水硫酸钠干燥。有机相经过减压浓缩得到粗产物，粗产物经过柱层析制备纯化得固体(530mg，收率：89％)。
MS(ESI):504[M+H]+。
步骤7：化合物int_190-9的合成:
将int_1-15(0.500g,1.64mmol)和int_190-8(826mg,1.64mmol)溶于DMF(10mL)中，室温下向反应液中加入K2CO3(679mg,4.91mmol)，反应液升至50℃反应1小时。LC-MS监测，反应结束。向反应液中加入冰水(10mL)，水相用乙酸乙酯萃取(20mL*3)，有机相用无水硫酸钠干燥。有机相经过减压浓缩得到粗产物，粗产物经过柱层析制备纯化(Silica Flash Column,Eluent of 0～30％THF/Petroleum ether gradient)得产物(400mg，收率：28.3％)。
MS(ESI):773[M+H]+。
步骤8：化合物int_190-10的合成:
将int_190-9(0.180g,233μmol)溶于DMF(2mL)中，室温下向反应液中加入int_1-17(269mg,2.33mmol)，反应液在室温下反应1小时。LC-MS监测，反应结束。向反应液中加入冰水(10mL)，水相用乙酸乙酯萃取(10mL*3)，有机相用无水硫酸钠干燥。有机相经过减压浓缩得到粗产物，粗产物经过柱层析制备纯化得固体(178mg，收率：89.8％)。
MS(ESI):852[M+H]+。
步骤9：化合物int_1-11的合成:
将int_190-10(0.500g,586μmol)溶于THF(5mL)中，室温下向反应液中加入TBAF(1M,1.17mL)，反应液在室温下反应1小时。LC-MS监测，反应结束。向反应液中加入水(30mL)，水相用乙酸乙酯萃取(30mL*3)，有机相用无水硫酸钠干燥。有机相经过减压浓缩得到粗产物，粗产物经过柱层析制备纯化(Silica Flash Column,Eluent of 0～100％Ethyl acetate/Petroleum ether gradient)得固体(150mg，收率：35.6％)。
MS(ESI):696[M+H]+。
步骤10：化合物190的合成:
室温下，将int_190-11(0.15g,209μmol)加入TFA(1mL)中，反应液在室温下反应5分钟。LC-MS监测，反应结束。向反应液中加入饱和碳酸氢钠水溶液将pH调至8，然后用制备HPLC纯化(column:Boston Prime C18 150*30mm*5um；mobile phase:[water(ammonia hydroxide v/v)-ACN]；gradient:33％-53％B over 11min)，得固体(40mg，收率：32.1％)。
MS(ESI):596[M+H]+。
实施例16化合物191和192的合成
将化合物190(50mg,170μmol)进行SFC手性拆分(column:DAICEL CHIRALPAK IG(250mm*30mm,10um)；mobile phase:[CO2-MeOH(0.1％NH3H2O)])得到化合物191(10mg)和化合物192(16mg)。
化合物191：MS(ESI):596[M+H]+。
化合物192：MS(ESI):596[M+H]+。
实施例17化合物232的合成
步骤1：化合物int_232-1的合成:
将int_88-18(0.93g,3.04mmol)和int_190-8(1.54g,3.04mmol)溶于DMF(10mL)中，室温下向反应液中加入K2CO3(1.26g,9.13mmol)，反应液升至50℃反应5小时。LC-MS监测，反应结束。向反应液中加入冰水(30mL)，水相用乙酸乙酯萃取(30mL*3)，有机相用无水硫酸钠干燥。有机相经过减压浓缩得到粗产物，粗产物经过柱层析制备纯化(Silica Flash Column,Eluent of 0～15％THF/Petroleum ether gradient)得产物(650mg，收率：27.6％)。
MS(ESI):773[M+H]+。
步骤2：化合物int_232-2的合成:
将int_232-1(0.40g,517μmol)溶于DMF(6mL)中，室温下向反应液中加入int_1-17(0.24g,2.07mmol)，反应液在室温下反应1小时。LC-MS监测，反应结束。向反应液中加入冰水(10mL)，水相用乙酸乙酯萃取(10mL*3)，有机相用无水硫酸钠干燥。有机相经过减压浓缩得到粗产物，粗产物经过柱层析制备纯化得固体(430mg，收率：97.7％)。
MS(ESI):852[M+H]+。
步骤3：化合物int_232-3的合成:
将int_232-2(0.62g,727μmol)溶于THF(8mL)中，室温下向反应液中加入TBAF(1.00M,1.45mL)，反应液在室温下反应1小时。LC-MS监测，反应结束。向反应液中加入水(30mL)，水相用乙酸乙酯萃取(30mL*3)，有机相用无水硫酸钠干燥。有机相经过减压浓缩得到粗产物，粗产物经过柱层析制备纯化(Silica Flash Column,Eluent of 0～100％Ethyl acetate/Petroleum ether gradient)得固体 (480mg，收率：94.8％)。
MS(ESI):696[M+H]+。
步骤4：化合物232的合成:
室温下，将int_232-3(0.26g,373μmol)加入TFA(1mL)中，反应液在室温下反应10分钟。LC-MS监测，反应结束。向反应液中加入饱和碳酸氢钠水溶液将pH调至8，然后用制备HPLC纯化(column:Boston Prime C18,150*30mm*5um；mobile phase:[water(NH3H2O+NH4HCO3)-ACN]；gradient:25％-65％B over 9min)，得固体(200mg，收率：90.9％)。
MS(ESI):596[M+H]+。
实施例18化合物233和234的合成
将化合物232(100mg,167μmol)进行SFC手性拆分(column:DAICEL CHIRALPAK IG(250mm*30mm,10μm)；mobile phase:[CO2-EtOH(0.1％NH3H2O)]；60％B isocratic elution mode)得到化合物233(26mg)和化合物234(26mg)。
化合物233：1H NMR(400MHz,DMSO-d6)δ＝8.64-8.55(m,2H),8.35(d,J＝8.3Hz,1H),7.54(s,2H),7.35(s,1H),7.18(s,2H),6.67(s,1H),5.20(d,J＝4.6Hz,1H),5.17-5.13(m,1H),5.05(br dd,J＝8.8,19.1Hz,1H),5.00-4.79(m,1H),4.21-4.08(m,2H),3.93(br s,1H),3.77(s,1H),3.15(br s,1H),2.95-2.85(m,2H),2.70(br d,J＝16.6Hz,1H),2.50-2.42(m,3H),2.31-2.20(m,1H),1.98(br d,J＝10.4Hz,1H),1.93-1.80(m,1H),1.24(s,1H),1.05(d,J＝6.6Hz,1H),0.86(s,1H)；MS(ESI):596[M+H]+。
分析SFC保留时间:1.960min(Instrument:Waters UPCC with PDA Detector；Column:Chiralpak IG-3 50x4.6mm I.D.,3um；Mobile phase:A:CO2,B:Ethanol(0.05％DEA)；Isocratic:40％B；Flow rate:4mL/min；Column temp.:35℃；ABPR:1500psi)。
化合物234：1H NMR(400MHz,DMSO-d6)δ＝8.63-8.54(m,2H),8.32(d,J＝8.3Hz,1H),7.54(s,2H),7.32(s,1H),7.18(s,2H),6.66(s,1H),5.19(d,J＝4.5Hz,1H),5.15(s,1H),5.12-5.00(m,1H),4.99-4.78(m,1H),4.23-4.05(m,2H),3.91(br d,J＝4.0Hz,1H),3.14(br d,J＝3.4Hz,1H),2.97-2.84(m,2H),2.70(br d,J＝14.9Hz,1H),2.50(br s,3H),2.32-2.20(m,1H),2.01-1.91(m,1H),1.88-1.76(m,1H)；MS(ESI):596[M+H]+。
分析SFC保留时间:0.712min(Instrument:Waters UPCC with PDA Detector；Column:Chiralpak IG-3 50x4.6mm I.D.,3um；Mobile phase:A:CO2,B:Ethanol(0.05％DEA)；Isocratic:40％B；Flow rate:4mL/min；Column temp.:35℃；ABPR:1500psi)。
实施例19化合物300的合成
步骤1：化合物int_300-2的合成:
将int_88-3(9.00g,48.48mmol)，int_300-1(9.07g,53.33mmol)溶于Ti(i-PrO)4(170mL)中，氮气置换三次，混合液加热至80℃搅拌2小时。LC-MS监测显示反应结束。将反应液冷却到室温，反应液直接用于下一步反应。
ESI-MS m/z:338[M+H]+。
步骤2：化合物int_300-3的合成:
-10℃下，将HCOOH(200mL)慢慢滴加到Ac2O(500mL)中，加毕，反应液在20℃反应0.5小时。然后将步骤3中得到的int_300-2溶液冷却至-10℃，将上述HOOCH和Ac2O混合液慢慢滴加入int_300-2溶液中，滴加时保持温度为-10℃。滴加完成后反应液升至70℃反应3小时。LC-MS监测显示反应结束。将反应液冷却至室温，有机相经过减压浓缩得到粗产物，粗产物用饱和碳酸氢男水溶液调至pH>7，水相用乙酸乙酯萃取(500mLX3)，有机相用无水硫酸钠干燥。有机相经过减压浓缩得到粗产物，粗产物经柱层析制备纯化(SiO2,PE/EtOAc＝1/1)得固体(2.3g，收率：11.7％)。
1H NMR(400MHz,CHLOROFORM-d)δ＝7.91(s,1H),7.06(d,J＝5.3Hz,1H),6.73(s,1H),6.70(s,1H),6.25(d,J＝5.3Hz,1H),4.80–4.69(m,1H),4.18(d,J＝16.3Hz,1H),3.90(s,3H),3.71(dd,J＝16.3,1.5Hz,1H),3.27–3.11(m,2H),3.06–2.97(m,2H),2.87–2.75(m,1H).
ESI-MS m/z:366[M+H]+。
步骤3：化合物int_300-4的合成:
将int_300-3(3.50g,9.5mmol)溶于二氯甲烷(30mL)中，氮气置换三次，反应液冷却至0℃，将BBr3(11.88g,47.43mmol)缓慢滴加至反应液中，将反应液升至室温反应1小时。LC-MS监测显示反应结束。将反应液缓慢倒入300mL的冰水中，水相用乙酸乙酯萃取(300mLX3)，有机相用无水硫酸钠干燥。有机相经过减压浓缩得到粗产物(3g，收率：90.9％)，粗产物可直接用于下一步反应。
ESI-MS m/z:352[M+H]+。
步骤4：化合物int_300-5的合成:
将int_300-4(3g,8.5mmol)、PhNTf2(5.46g,15.3mmol)和TEA(2.15g,21.25mmol,2.92mL)溶于二氯甲烷(30mL)中，氮气置换三次，反应液在室温下反应16小时。LC-MS监测显示反应结束。将反应液缓慢倒入300mL的冰水中，水相用乙酸乙酯萃取(300mLX3)，有机相用无水硫酸钠干燥。有 机相经过减压浓缩得到粗产物，粗产物经柱层析制备纯化(SiO2,PE/EtOAc＝1/1)得固体(2.9g，收率：70.7％)。
ESI-MS m/z:484[M+H]+。
步骤5：化合物int_300-6的合成:
将int_300-5(2.9g,5.99mmol)、Pd/C(1.2g,10％purity)和TEA(2.42g,23.96mmol,3.33mL)溶于甲醇(25mL)和四氢呋喃(10mL)的混合溶剂中，反应液用氢气置换三次，反应液在室温下反应16小时。LC-MS监测显示反应结束。将反应液过滤得到滤液，滤液经过减压浓缩得到粗产物，粗产物经柱层析制备纯化(SiO2,PE/EtOAc＝1/1)得固体(0.85g，收率：42.5％)。
ESI-MS m/z:336[M+H]+。
步骤6：化合物int_300-7的合成:
将int_300-6(0.85g,2.53mmol)溶于THF(10mL)中，冷却到-30℃，氮气保护下向反应液中慢慢滴加n-BuLi(2.5M,3.04mL)，反应液在-30℃反应2小时，再将反应液升至室温反应1小时，LC-MS监测显示反应结束。向反应液中加入饱和氯化铵水溶液(10mL)，水相用乙酸乙酯萃取(30mLX3)，有机相用无水硫酸钠干燥。有机相经过减压浓缩得到粗产物(0.71g，收率：91.2％)，粗产物直接用于下一步反应。
1H NMR(400MHz,DMSO-d6)δ＝7.16(d,J＝1.4Hz,2H),7.14(d,J＝5.3Hz,1H),6.85(t,J＝1.3Hz,1H),6.35(d,J＝5.3Hz,1H),4.16(d,J＝16.1Hz,1H),3.69(dd,J＝16.0,1.3Hz,1H),3.25–3.11(m,2H),2.98(m,2H),2.88(m,1H),2.74(br,1H),2.68(dt,J＝16.0,3.5Hz,1H)。
ESI-MS m/z:308[M+H]+。
步骤7：化合物int_300-8的合成:
将int_300-7(0.71g,2.30mmol)和(Boc)2O(1g,4.60mmol)溶于1,4-二氧六环(10mL)中，室温下向反应液中加入TEA(581.8mg,5.75mmol,801.4μL)，反应液升至80℃反应16小时，LC-MS监测，反应结束。反应液冷却至室温后，反应液经过减压浓缩得到粗产物，粗产物经柱层析制备纯化(SiO2,PE/EtOAc＝10/1)得固体(0.65g，收率：69.2％)。
1H NMR(400MHz,DMSO-d6)δ＝7.29(d,J＝5.3Hz,1H),7.24(d,J＝1.4Hz,2H),6.73(t,J＝1.3Hz,1H),6.53(d,J＝5.3Hz,1H),4.23(dt,J＝12.1,3.7Hz,1H),3.96(d,J＝16.1Hz,1H),3.90(d,J＝13.5Hz,1H),3.81(dd,J＝16.1,1.5Hz,1H),3.15(td,J＝12.0,3.2Hz,1H),2.98(ddd,J＝15.8,11.7,4.1Hz,1H),2.89(dt,J＝15.5,3.3Hz,1H),2.52(d,J＝1.6Hz,1H),1.15(s,9H)。
ESI-MS m/z:408[M+H]+。
步骤8：化合物int_300-9的合成:
将int_300-8(1.5g,3.67mmol)溶于THF(20mL)中，冷却到-75℃，氮气保护下向反应液中慢慢滴加n-BuLi(2.5M,4.43mL)，反应液在-75℃反应1小时，然后在-75℃下，向反应液中滴加DMF(809mg,11.08mmol)，滴加完毕后，反应液在-75℃反应1小时，LC-MS监测，反应结束。向反应液中慢慢加入饱和氯化铵溶液(100mL)，水相用乙酸乙酯萃取(100mL*3)，有机相用无水硫酸钠干燥。有机相经过减压浓缩得到粗产物，粗产物经过柱层析制备纯化得固体(1.25g，收率：78.1％)。
MS(ESI):436[M+H]+。
步骤9：化合物int_300-10的合成:
将int_1-9(4.8g,19.92mmol)溶于THF(50mL)中，冷却到-75℃，氮气保护下向反应液中慢慢滴加n-BuLi(2.5M,16mL)，反应液在-75℃反应1小时，然后在-75℃下，向反应液中滴加int_300-9(1.45g,3.33mmol)的THF(25mL)溶液，滴加完毕后，反应液在-75℃反应1小时，再升至室温反应16小时。LC-MS监测，反应结束。向反应液中慢慢加入饱和氯化铵溶液(200mL)，水相用乙酸乙酯萃取(200mL*3)，有机相用无水硫酸钠干燥。有机相经过减压浓缩得到粗产物，粗产物经过柱层析制备纯化得固体(1.51g，收率：82.5％)。
MS(ESI):550[M+H]+。
步骤10：化合物int_300-11的合成:
将草酰氯(413.7mg,3.26mmol,279μL)溶于二氯甲烷(20mL)中，-78℃下向反应液中缓慢滴加二甲亚砜(254.7mg,3.26mmol,231μL)，反应液在-78℃下反应0.5小时，将int_300-10(1.5g,2.72mmol)的DCM(10mL)滴加至反应液中，反应液在-78℃下继续反应0.5小时，将三乙胺(1.65g,16.32mmol)滴加至反应液中，反应液在-78℃下继续反应0.5小时，然后缓慢升至室温。LC-MS监测，反应结束。向反应液中慢慢加入饱和碳酸氢钠水溶液调至pH～8，水相用乙酸乙酯萃取(100mL*3)，有机相用无水硫酸钠干燥。有机相经过减压浓缩得到粗产物，粗产物经过柱层析制备纯化得固体(1.38g，收率：92.6％)。
MS(ESI):548[M+H]+。
步骤11：化合物int_300-12的合成:
将int_300-11(1.097g,2.0mmol)和int_1-17(672mg,2.2mmol)溶于DMF(10mL)中，室温下向反应液中加入K2CO3(829.2mg,6.0mmol)，反应液在室温下反应3小时。LC-MS监测，反应结束。向反应液中加入冰水(100mL)，水相用乙酸乙酯萃取(100mL*3)，有机相用无水硫酸钠干燥。有机相经过减压浓缩得到粗产物，粗产物经过柱层析制备纯化得产物(1.3g，收率：79.7％)。
MS(ESI):817[M+H]+。
步骤12：化合物int_300-13的合成:
将int_300-12(1.38g,1.7mmol)溶于DMF(30mL)中，室温下向反应液中加入int_1-17(395.9mg,3.42mmol)，反应液在室温下反应1小时。LC-MS监测，反应结束。向反应液中加入冰水(50mL)，水相用乙酸乙酯萃取(50mL*3)，有机相用无水硫酸钠干燥。有机相经过减压浓缩得到粗产物，粗产物经过柱层析制备纯化得固体(1.2g，收率：78.9％)。
MS(ESI):896[M+H]+。
步骤13：化合物int_300-14的合成:
将int_300-13(1.61g,1.8mmol)溶于THF(20mL)中，室温下向反应液中加入TBAF(1M,3.6mL)，反应液在室温下反应4小时。LC-MS监测，反应结束。向反应液中加入水(50mL)，水相用乙酸乙酯萃取(50mL*3)，有机相用无水硫酸钠干燥。有机相经过减压浓缩得到粗产物，粗产物经过柱层析制备纯化得固体(1.1g，收率：82.7％)。
MS(ESI):740[M+H]+。
步骤14：化合物300的合成
室温下，将int_300-14(1.11g,1.5mmol)溶于DCM(7mL)中，加入TFA(7.8mL)中，反应液在室温下反应5分钟。LC-MS监测，反应结束。冷却至0℃，向反应液中加入饱和碳酸氢钠水溶液将pH 调至8，水相用乙酸乙酯萃取(50mL*3)，有机相用无水硫酸钠干燥。有机相经过减压浓缩得到粗产物，粗产物用制备HPLC纯化得固体(816mg，收率：85.0％)。
MS(ESI):640[M+H]+。
实施例20化合物301和化合物302的合成
将化合物300(150mg,0.234mmol)进行SFC手性拆分(column:DAICEL CHIRALPAK IG(250mm*30mm,10μm)；mobile phase:[CO2-EtOH(0.1％NH3H2O)])得到化合物301(56mg)和化合物302(58mg)。
化合物301：1H NMR(400MHz,DMSO-d6)δ8.55(s,1H),8.37(d,J＝3.0Hz,1H),8.36–8.26(m,1H),7.51(s,2H),7.21–7.12(m,2H),6.96(t,J＝2.6Hz,2H),5.17(dd,J＝4.7,2.2Hz,1H),5.02(m,1H),4.86(dtd,J＝54.2,6.7,3.1Hz,1H),4.27(d,J＝16.8Hz,1H),4.20–4.05(m,2H),3.95–3.81(m,2H),3.31–3.16(m,2H),3.08–2.81(m,4H),2.67(d,J＝15.5Hz,1H),2.24(m,1H),1.99–1.88(m,1H),1.87–1.72(m,1H)；MS(ESI):640[M+H]+。
化合物302：1H NMR(400MHz,DMSO-d6)δ8.54(s,1H),8.36(d,J＝3.0Hz,1H),8.35–8.26(m,1H),7.50(s,2H),7.21–7.11(m,2H),6.95(t,J＝2.6Hz,2H),5.16(dd,J＝4.7,2.2Hz,1H),5.01(dt,J＝18.8,8.3Hz,1H),4.86(dtd,J＝54.2,6.7,3.1Hz,1H),4.27(d,J＝16.8Hz,1H),4.19–4.04(m,2H),3.93–3.81(m,2H),3.29–3.15(m,2H),3.07–2.81(m,4H),2.66(d,J＝15.5Hz,1H),2.23(dq,J＝22.5,5.8Hz,1H),1.99–1.87(m,1H),1.87–1.72(m,1H)；MS(ESI):640[M+H]+。
实施例21化合物576的合成

步骤1：化合物int_576-1的合成:
将int_103-1(2.5g,6.15mmol)溶于乙酸乙酯(60mL)和甲醇(15mL)的混合溶剂中，向反应液中加入甲胺(573mg,18.45mmol,1.88mL,40％in MeOH)和氰基硼氢化钠(1.53g,24.63mmol)，反应液在室温下反应16小时，LC-MS监测，反应结束。将反应液缓慢倒入100mL的冰水中，水相用乙酸乙酯萃取(100mLX3)，有机相用无水硫酸钠干燥。有机相经过减压浓缩得到粗产物，粗产物经柱层析制备纯化得固体(2.1g，收率：84.3％)。
ESI-MS m/z:405[M+H]+。
步骤2：化合物int_576-2的合成:
将int_576-1(283.4mg,0.7mmol)溶于THF(10mL)中，冷却到-70℃，氮气保护下向反应液中慢慢滴加n-BuLi(2.5M,0.83ml)，反应液在-70℃反应1小时，然后在-60℃下，向反应液中滴加DMF(153mg,2.1mmol)，滴加完毕后，反应液在70℃反应1小时，LC-MS监测，反应结束。向反应液中慢慢加入饱和氯化铵溶液(20mL)，水相用乙酸乙酯萃取(20mL*3)，有机相用无水硫酸钠干燥。有机相经过减压浓缩得到粗产物，粗产物经过柱层析制备纯化得固体(169mg，收率：55.7％)。
MS(ESI):433[M+H]+。
步骤3：化合物int_576-3的合成:
将int_1-9(577mg,2.4mmol溶于THF(10mL)中，冷却到-70℃，氮气保护下向反应液中慢慢滴加n-BuLi(2.5M,1.9mL,4.8mmol)，反应液在-70℃反应1小时，然后在-75℃下，向反应液中滴加int_576-2(173.1mg,0.4mmol)的THF(1mL)溶液，滴加完毕后，反应液在-75℃反应1小时，再升至室温反应16小时。LC-MS监测，反应结束。向反应液中慢慢加入饱和氯化铵溶液(20mL)，水相用乙酸乙酯萃取(20mL*3)，有机相用无水硫酸钠干燥。有机相经过减压浓缩得到粗产物，粗产物经过柱层析制备纯化得固体(162mg，收率：73.9％)。
MS(ESI):547[M+H]+。
步骤4：化合物int_576-4的合成:
将草酰氯(415mg,3.27mmol,280μL)溶于二氯甲烷(20mL)中，-78℃下向反应液中缓慢滴加二甲亚砜(254.75mg,3.27mmol,232μL)，反应液在-78℃下反应0.5小时，将int_576-3(1.5g,2.73mmol)的DCM(10mL)滴加至反应液中，反应液在-78℃下继续反应0.5小时，将三乙胺(1.65g,16.32mmol)滴加至反应液中，反应液在-78℃下继续反应0.5小时，然后缓慢升至室温。LC-MS监测，反应结束。向反应液中慢慢加入饱和碳酸氢钠水溶液调至pH～8，水相用乙酸乙酯萃取(100mL*3)，有机相用无水硫酸钠干燥。有机相经过减压浓缩得到粗产物，粗产物经过柱层析制备纯化得固体(0.56g，收率：37.8％)。
MS(ESI):545[M+H]+。
步骤5：化合物int_576-5的合成:
将int_576-4(272.7mg,0.5mmol)和int_88-18(183.3mg,0.6mmol)溶于DMF(10mL)中，室温下向反应液中加入K2CO3(207.3mg,1.5mmol)，反应液室温下反应16小时。LC-MS监测，反应结束。向反应液中加入冰水(30mL)，水相用乙酸乙酯萃取(30mL*3)，有机相用无水硫酸钠干燥。有机相经过减压浓缩得到粗产物，粗产物经过柱层析制备纯化得产物(288mg，收率：70.7％)。
MS(ESI):814[M+H]+。
步骤6：化合物int_576-6的合成:
将int_576-5(285mg,0.35mmol)溶于DMF(4mL)中，室温下向反应液中加入int_1-17(80.8mg,0.7mmol)，反应液在室温下反应1小时。LC-MS监测，反应结束。向反应液中加入冰水(30mL)，水相用乙酸乙酯萃取(30mL*3)，有机相用无水硫酸钠干燥。有机相经过减压浓缩得到粗产物，粗产物经过柱层析制备纯化得固体(236mg，收率：75.6％)。
MS(ESI):893[M+H]+。
步骤7：化合物int_576-7的合成:
将int_576-6(259mg,0.29mmol)溶于THF(4mL)中，室温下向反应液中加入TBAF(1M,0.58mL, 0.58mmol)，反应液在室温下反应16小时。LC-MS监测，反应结束。向反应液中加入水(30mL)，水相用乙酸乙酯萃取(30mL*3)，有机相用无水硫酸钠干燥。有机相经过减压浓缩得到粗产物，粗产物经过柱层析制备纯化得固体(180mg，收率：84.5％)。
MS(ESI):737[M+H]+。
步骤8：化合物576的合成:
将int_576-7(184mg,0.25mmol)溶于二氯甲烷(6mL)中，室温下，向反应液中加入TFA(1.5mL)，反应液在室温下反应10分钟。LC-MS监测，反应结束。向反应液中加入氨水(1mL)和水(10mL)，水相用二氯甲烷萃取(10mL*3)，有机相用无水硫酸钠干燥。有机相经过减压浓缩得到粗产物，粗产物用制备HPLC纯化，得固体(97mg，收率：61.0％)。
MS(ESI):637[M+H]+。
实施例22化合物577和化合物578的合成
将化合物576(85mg,0.133mmol)进行SFC手性拆分(column:Phenomenex-Cellulose-2(250mm*30mm,10um))；mobile phase:[CO2-MeOH(0.1％NH3H2O)]；B％:45％,isocratic elution mode)得到化合物577(21mg)和化合物578(25mg)。
化合物577：1H NMR(400MHz,DMSO-d6)δ＝8.57(s,1H),8.42(d,J＝5.2Hz,1H),8.29(dd,J＝19.5,8.2Hz,1H),7.52(s,2H),7.21–7.10(m,2H),7.09(d,J＝3.6Hz,1H),6.90(t,J＝2.4Hz,1H),5.19(dd,J＝4.6,3.6Hz,1H),5.02(dt,J＝18.5,8.5Hz,1H),4.87(ddd,J＝54.3,7.6,6.1Hz,1H),4.21–4.05(m,2H),3.91(s,1H),3.86–3.63(m,2H),3.12–2.79(m,5H),2.69(m,2H),2.45–2.34(m,3H),2.24(m,1H),2.03–1.87(m,1H),1.87–1.72(m,1H)；MS(ESI):637[M+H]+。
化合物578：1H NMR(400MHz,DMSO-d6)δ＝8.55(s,1H),8.40(d,J＝5.1Hz,1H),8.28(dd,J＝19.5,8.2Hz,1H),7.50(s,2H),7.19–7.09(m,2H),7.06(d,J＝3.6Hz,1H),6.88(t,J＝2.4Hz,1H),5.17(dd,J＝4.6,3.6Hz,1H),5.00(dt,J＝18.5,8.5Hz,1H),4.85(ddd,J＝54.2,7.6,6.0Hz,1H),4.19–4.03(m,2H),3.89(s,1H),3.85–3.63(m,2H),3.10–2.78(m,5H),2.67(dt,J＝10.9,5.7Hz,2H),2.43–2.33(m, 3H),2.22(dt,J＝22.5,5.8Hz,1H),2.01–1.86(m,1H),1.86–1.71(m,1H)；MS(ESI):637[M+H]+。
使用上述合成方法，采用不同原料，可以得到表1中目标化合物4-87、94-102、106-129、133-161、163-189、193-231、235-342、345-575以及579-1070。
表1































































生物实施例1本发明化合物体外抑制SAE活性试验
将HCT116细胞约20000/well种至96孔黑色透明底板，每孔90μL。37度过夜孵育24小时。将待测化合物稀释至终浓度10倍，加10μL至细胞培养板中。37°孵育6小时。然后润洗细胞，弃去培养基，用200μL 0.1％PBST清洗细胞1次。每孔中加入50μL 4％PFA，于室温下固定20分钟，然后用PBS清洗2-3次，每孔中加入50μL 0.2％Triton X-100，室温放置15分钟，并用0.1％PBST清洗3次。每孔中加入100μL 3％BSA(0.6g BSA+20mL PBS)，于37℃恒温封闭30分钟。封闭结束后，去除液体，用1％BSA配制一抗(SUMO-2/3(18H8)Rabbit mAb,1：400稀释)。每孔加入30μL稀释的一抗，于4℃恒温孵育过夜。用200μL 0.1％PBST清洗细胞3次。再用1％BSA配制FITC二抗(Fluorescein(FITC)–conjugated Affinipure Goat Anti-Rabbit IgG(H+L),1：300稀释)，每孔中加入40μL稀释的二抗，室温避光孵育2小时，然后用0.1％PBST清洗4次。检测样本荧光信号，并与DMSO组比较，计算抑制率和IC50。结果见下列表2。
表2本发明化合物对SAE的抑制活性(IC50,nM)






+++表示IC50小于或等于50nM
++表示IC50为50nM至200nM
+表示IC50大于200nM
TAK-981为WO2016004136A1中的化合物I-263a，化学结构如下：
从表2、表3和表4的数据可见，相比较TAK-981，本发明中的大部分化合物在体外抑制SAE活性实验中对SAE有更强的抑制活性。
生物实施例2本发明化合物体外促进NK细胞对肿瘤细胞OVCAR3杀伤活性试验
将OVCAR3细胞约8000/well和NK92MI细胞约80000/well分别种至96孔黑色透明细胞培养板，每孔90μL。于37℃过夜孵育24小时。将待测化合物稀释至终浓度10倍，加10μL至细胞培养板中。37℃孵育细胞48小时。弃去OVCAR3细胞培养基，用1μM Calcein AM染色OVCAR3细胞50分钟，PBS洗一遍，再加入100μL培养液，将NK92MI细胞混匀后，轻轻加样于OVCAR3细胞 中。共孵育约4小时后，于PICO拍照DMSO对照组和高浓度药物组，观察NK92MI细胞对OVCAR3细胞的杀伤情况，当两组杀伤有明显差异时，停止共孵育。弃去培养基，用100μL PBS润洗细胞1次。每孔加入100μL 4％PFA，室温固定细胞20分钟，PBS润洗1次，酶标仪FITC通道检测样本荧光信号。并与DMSO组比较，计算抑制率和IC50。
生物实施例3本发明化合物的体内药代动力学实验
选取6至8周龄的CD-1雌性小鼠，静脉给药的剂量为2mg/Kg。小鼠在给药前禁食至少12小时，给药后恢复供食，整个实验期间自由饮水。实验当天静脉组动物通过尾静脉单次注射给予相应化合物，给药量0.2mL/只。样品采集时间为：0.083,0.167,0.5,1,2,4,8,24h。每个时间点通过颌下静脉丛采集大约150uL全血(30uL全血1/3兑超纯水，120uL全血离心取血浆),供高效液相色谱-串联质谱(LC-MS/MS)进行浓度测定。所有动物在采集完最后一个时间点的PK样品后处死。采用Phoenix WinNonlinTM version8.3(Certara)药动学软件的非房室模型处理血浆浓度，使用线性对数梯形法计算药动学参数。体内药代动力学结果见下列表3和表4。
表3本发明化合物的体内药代动力学评价结果
表4本发明化合物的血浆药物浓度和全血药物浓度
生物实施例4体内药效研究-小鼠MC38皮下移植瘤模型
每只C57BL/6小鼠皮下接种1X106个MC38细胞，待肿瘤长至100-200mm3时，vehicle、化合物单用(静脉注射，一周两次)、anti-PD-1 antibody单药(静脉注射，一周一次)、anti-VEGF antibody单药 (腹腔注射，一周一次)、anti-PD-1 antibody(静脉注射，一周一次)以及anti-VEGF antibody(腹腔注射，一周一次)联用、化合物(静脉注射，一周两次)与anti-PD-1 antibody(静脉注射，一周一次)联用、化合物(静脉注射，一周两次)与anti-VEGF antibody(腹腔注射，一周一次)联用或化合物(静脉注射，一周两次)与anti-PD-1 antibody(静脉注射，一周一次)以及anti-VEGF antibody(腹腔注射，一周一次)联用，每周两次以及给药终点测量肿瘤体积。按照肿瘤生长率抑制率(TGI)＝1-(给药组第20天肿瘤体积-给药组第一天肿瘤体积)/(溶媒对照组第20天肿瘤体积-溶媒对照组第一天肿瘤体积)，计算化合物肿瘤生长抑制率。
生物实施例5体内药效研究-小鼠MC38皮下移植瘤模型
每只C57BL/6小鼠皮下接种1X106个MC38细胞，待肿瘤长至50-80mm3时，vehicle、化合物单用(静脉注射，一周两次)、anti-PD-1 antibody单药(静脉注射，一周一次)、anti-VEGF antibody单药(腹腔注射，一周一次)、anti-PD-1 antibody(静脉注射，一周一次)以及anti-VEGF antibody(腹腔注射，一周一次)联用、化合物(静脉注射，一周两次)与anti-PD-1 antibody(静脉注射，一周一次)联用、化合物(静脉注射，一周两次)与anti-VEGF antibody(腹腔注射，一周一次)联用或化合物(静脉注射，一周两次)与anti-PD-1 antibody(静脉注射，一周一次)以及anti-VEGF antibody(腹腔注射，一周一次)联用，每周两次以及给药终点测量肿瘤体积。按照肿瘤生长率抑制率(TGI)＝1-(给药组第20天肿瘤体积-给药组第一天肿瘤体积)/(溶媒对照组第20天肿瘤体积-溶媒对照组第一天肿瘤体积)，计算化合物肿瘤生长抑制率。
生物实施例6体内药效研究-小鼠MC38皮下移植瘤模型
每只C57BL/6小鼠皮下接种1X106个MC38细胞，接种完细胞后立即给药，vehicle、化合物单用(静脉注射，一周两次)、anti-PD-1 antibody单药(静脉注射，一周一次)、anti-VEGF antibody单药(腹腔注射，一周一次)、anti-PD-1 antibody(静脉注射，一周一次)以及anti-VEGF antibody(腹腔注射，一周一次)联用、化合物(静脉注射，一周两次)与anti-PD-1 antibody(静脉注射，一周一次)联用、化合物(静脉注射，一周两次)与anti-VEGF antibody(腹腔注射，一周一次)联用或化合物(静脉注射，一周两次)与anti-PD-1 antibody(静脉注射，一周一次)以及anti-VEGF antibody(腹腔注射，一周一次)联用，每周两次以及给药终点测量肿瘤体积。按照肿瘤生长率抑制率(TGI)＝1-(给药组第20天肿瘤体积-给药组第一天肿瘤体积)/(溶媒对照组第20天肿瘤体积-溶媒对照组第一天肿瘤体积)，计算化合物肿瘤生长抑制率。
生物实施例7体内药效研究-小鼠CT26皮下移植瘤模型
每只BALB/c小鼠皮下接种2X105个CT26细胞，待肿瘤长至100-200mm3时，vehicle、化合物单用(静脉注射，一周两次)、anti-PD-1 antibody单药(静脉注射，一周一次)、anti-VEGF antibody单药(腹腔注射，一周一次)、anti-PD-1 antibody(静脉注射，一周一次)以及anti-VEGF antibody(腹腔注射，一周一次)联用、化合物(静脉注射，一周两次)与anti-PD-1 antibody(静脉注射，一周一次)联用、化合物(静脉注射，一周两次)与anti-VEGF antibody(腹腔注射，一周一次)联用或化合物(静脉注射，一周两次)与anti-PD-1 antibody(静脉注射，一周一次)以及anti-VEGF antibody(腹腔注射，一周一次)联用，每周两次以及给药终点测量肿瘤体积。按照肿瘤生长率抑制率(TGI)＝1-(给药组第20天肿瘤体积-给药 组第一天肿瘤体积)/(溶媒对照组第20天肿瘤体积-溶媒对照组第一天肿瘤体积)，计算化合物肿瘤生长抑制率。
生物实施例8体内药效研究-小鼠CT26皮下移植瘤模型
每只BALB/c小鼠皮下接种2X105个CT26细胞，待肿瘤长至50-80mm3时，vehicle、化合物单用(静脉注射，一周两次)、anti-PD-1 antibody单药(静脉注射，一周一次)、anti-VEGF antibody单药(腹腔注射，一周一次)、anti-PD-1 antibody(静脉注射，一周一次)以及anti-VEGF antibody(腹腔注射，一周一次)联用、化合物(静脉注射，一周两次)与anti-PD-1 antibody(静脉注射，一周一次)联用、化合物(静脉注射，一周两次)与anti-VEGF antibody(腹腔注射，一周一次)联用或化合物(静脉注射，一周两次)与anti-PD-1 antibody(静脉注射，一周一次)以及anti-VEGF antibody(腹腔注射，一周一次)联用，每周两次以及给药终点测量肿瘤体积。按照肿瘤生长率抑制率(TGI)＝1-(给药组第20天肿瘤体积-给药组第一天肿瘤体积)/(溶媒对照组第20天肿瘤体积-溶媒对照组第一天肿瘤体积)，计算化合物肿瘤生长抑制率。
生物实施例9体内药效研究-小鼠CT26皮下移植瘤模型
每只BALB/c小鼠皮下接种2X105个CT26细胞，接种完细胞后立即给药，vehicle、化合物单用(静脉注射，一周两次)、anti-PD-1 antibody单药(静脉注射，一周一次)、anti-VEGF antibody单药(腹腔注射，一周一次)、anti-PD-1 antibody(静脉注射，一周一次)以及anti-VEGF antibody(腹腔注射，一周一次)联用、化合物(静脉注射，一周两次)与anti-PD-1 antibody(静脉注射，一周一次)联用、化合物(静脉注射，一周两次)与anti-VEGF antibody(腹腔注射，一周一次)联用或化合物(静脉注射，一周两次)与anti-PD-1 antibody(静脉注射，一周一次)以及anti-VEGF antibody(腹腔注射，一周一次)联用，每周两次以及给药终点测量肿瘤体积。按照肿瘤生长率抑制率(TGI)＝1-(给药组第20天肿瘤体积-给药组第一天肿瘤体积)/(溶媒对照组第20天肿瘤体积-溶媒对照组第一天肿瘤体积)，计算化合物肿瘤生长抑制率。
生物实施例10体内药效研究-小鼠A20皮下移植瘤模型
每只BALB/c小鼠皮下接种2X106个A20细胞，待肿瘤长至100-200mm3时，vehicle、化合物单用(静脉注射，一周两次)、anti-PD-1 antibody单药(静脉注射，一周一次)、anti-VEGF antibody单药(腹腔注射，一周一次)、anti-PD-1 antibody(静脉注射，一周一次)以及anti-VEGF antibody(腹腔注射，一周一次)联用、化合物(静脉注射，一周两次)与anti-PD-1 antibody(静脉注射，一周一次)联用、化合物(静脉注射，一周两次)与anti-VEGF antibody(腹腔注射，一周一次)联用或化合物(静脉注射，一周两次)与anti-PD-1 antibody(静脉注射，一周一次)以及anti-VEGF antibody(腹腔注射，一周一次)联用，每周两次以及给药终点测量肿瘤体积。按照肿瘤生长率抑制率(TGI)＝1-(给药组第20天肿瘤体积-给药组第一天肿瘤体积)/(溶媒对照组第20天肿瘤体积-溶媒对照组第一天肿瘤体积)，计算化合物肿瘤生长抑制率。
生物实施例11体内药效研究-小鼠A20皮下移植瘤模型
每只BALB/c小鼠皮下接种2X106个A20细胞，待肿瘤长至50-80mm3时，vehicle、化合物单用(静脉注射，一周两次)、anti-PD-1 antibody单药(静脉注射，一周一次)、anti-VEGF antibody单药(腹腔 注射，一周一次)、anti-PD-1 antibody(静脉注射，一周一次)以及anti-VEGF antibody(腹腔注射，一周一次)联用、化合物(静脉注射，一周两次)与anti-PD-1 antibody(静脉注射，一周一次)联用、化合物(静脉注射，一周两次)与anti-VEGF antibody(腹腔注射，一周一次)联用或化合物(静脉注射，一周两次)与anti-PD-1 antibody(静脉注射，一周一次)以及anti-VEGF antibody(腹腔注射，一周一次)联用，每周两次以及给药终点测量肿瘤体积。按照肿瘤生长率抑制率(TGI)＝1-(给药组第20天肿瘤体积-给药组第一天肿瘤体积)/(溶媒对照组第20天肿瘤体积-溶媒对照组第一天肿瘤体积)，计算化合物肿瘤生长抑制率。
生物实施例12体内药效研究-小鼠A20皮下移植瘤模型
每只BALB/c小鼠皮下接种2X106个A20细胞，接种完细胞后立即给药，vehicle、化合物单用(静脉注射，一周两次)、anti-PD-1 antibody单药(静脉注射，一周一次)、anti-VEGF antibody单药(腹腔注射，一周一次)、anti-PD-1 antibody(静脉注射，一周一次)以及anti-VEGF antibody(腹腔注射，一周一次)联用、化合物(静脉注射，一周两次)与anti-PD-1 antibody(静脉注射，一周一次)联用、化合物(静脉注射，一周两次)与anti-VEGF antibody(腹腔注射，一周一次)联用或化合物(静脉注射，一周两次)与anti-PD-1 antibody(静脉注射，一周一次)以及anti-VEGF antibody(腹腔注射，一周一次)联用，每周两次以及给药终点测量肿瘤体积。按照肿瘤生长率抑制率(TGI)＝1-(给药组第20天肿瘤体积-给药组第一天肿瘤体积)/(溶媒对照组第20天肿瘤体积-溶媒对照组第一天肿瘤体积)，计算化合物肿瘤生长抑制率。
生物实施例13体内药效研究-小鼠B16F10-OVA皮下移植瘤模型
C57BL/6小鼠接种B16F10-OVA细胞前14天、前11天、前7天和前4天，分别给与每只C57BL/6小鼠vehicle、化合物单药(静脉注射)、Ovalbumin单药(静脉注射)、anti-PD-1 antibody单药(静脉注射)、anti-VEGF antibody单药(腹腔注射)、化合物(静脉注射)与Ovalbumin联用(静脉注射)、anti-PD-1 antibody(静脉注射)和anti-VEGF antibody(腹腔注射)联用、化合物(静脉注射)与anti-PD-1 antibody(静脉注射)联用、化合物(静脉注射)与anti-VEGF antibody(腹腔注射)联用、化合物(静脉注射)与anti-PD-1 antibody(静脉注射)和Ovalbumin(静脉注射)联用、化合物(静脉注射)与anti-VEGF antibody(腹腔注射)和Ovalbumin(静脉注射)联用、化合物(静脉注射)与anti-PD-1 antibody(静脉注射)和anti-VEGF antibody(腹腔注射)联用或化合物(静脉注射)与anti-PD-1 antibody(静脉注射)、anti-VEGF antibody(腹腔注射)和Ovalbumin(静脉注射)联用。每只C57BL/6小鼠皮下接种0.3X106个B16F10-OVA细胞，终点测量肿瘤体积。按照肿瘤生长率抑制率(TGI)＝1-(给药组第20天肿瘤体积-给药组第一天肿瘤体积)/(溶媒对照组第20天肿瘤体积-溶媒对照组第一天肿瘤体积)，计算化合物肿瘤生长抑制率。
虽然以上描述了本发明的具体实施方式，但是本领域的技术人员应当理解，这些仅是举例说明，在不背离本发明的原理和实质的前提下，可以对这些实施方式做出多种变更或修改。因此，本发明的保护范围由所附权利要求书限定。

Claims (46)

  1. 一种如通式(1)所示的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物：
    通式(1)中：
    Y为-O-、-CH2-或-N(H)-；
    Ra为-H、-F、-NH2或-OH；
    Ra’为-H或-F，且当Ra为-NH2或-OH时，Ra’为-H；
    Rb为-H或(C1-C4)烷基；
    Rc为-H或(C1-C4)烷基；
    Rd为-H、卤素、-CF3或(C1-C4)烷基；
    Re和Re’各自独立任选为-H或卤素，且Re和Re’不同时为-H；
    X1为C(H)、C(F)或N；
    X2为S或O；
    X3为C(Rx3)或N；
    Rx3为-H、卤素或-CH3；
    X4为S、O、C(Rx41)(Rx41’)或N(Rx42)；
    Rx42为-H、(C1-C4)烷基或(C3-C5)环烷基；
    Rx41和Rx41’各自独立任选为-H、卤素、-OH、-ORx411、-N(Rx411)(Rx412)、-CN、(C1-C6)烷基、(C1-C6)卤代烷基、(C3-C9)环烷基或(C1-C6)烷氧基；
    Rx411和Rx412各自独立任选为-H、(C1-C4)烷基或(C3-C5)环烷基，或同一个氮原子上的Rx411和Rx412与他们所连接的N原子能够共同组成(3-6元)杂环烷基，其中所述(3-6元)杂环烷基可任选被1，2，3或4个下列基团取代：-H或卤素；
    R3和R4各自独立任选为-H、-D、-OH、-NH2、-CN、(C1-C6)烷基、(C1-C6)卤代烷基、(C2-C6)烯基、(C2-C6)炔基、(C3-C9)环烷基、(C1-C6)烷氧基、(C6-C14)芳基、(3-11元)杂环烷基或(5-11元)杂芳基，其中所述(C1-C6)烷基、(C1-C6)卤代烷基、(C2-C6)烯基、(C2-C6)炔基、(C3-C9)环烷基、(C1-C6)烷氧基、(C6-C14)芳基、(3-11元)杂环烷基或(5-11元)杂芳基可各自独立任选被1，2，3或4个下列基团取代：-H、卤素、-OH、-(CH2)rOR31、-(CH2)rNR31R32、-OR31、-NR31R32、-CN、-C(O)NR31R32、-NR32C(O)R31、-NR32S(O)2R31、-S(O)pR31和-S(O)2NR31R32；或R3和R4与他们所连接的碳原子能够共同组成(4-7元)杂环烷基或(C3-C6)环烷基，其中所述(4-7元)杂环烷基或(C3-C6)环烷基可任选被1，2，3或4个下列基团取代：-H、卤素、(C1-C6)烷基或(C1-C6)烷氧基；或R3和相邻的R5与他们所连接的原子能够共同组成 (C3-C9)环烷基或(3-11元)杂环烷基，其中所述(C3-C9)环烷基或(3-11元)杂环烷基可各自独立任选被1，2，3或4个下列基团取代：-H、卤素、(C1-C6)烷基或(C1-C6)烷氧基；或当R3和相邻的R5同时不存在时，分别与R4和R6相连的碳原子之间可形成一个环内双键；或R3和R4共同形成一个氧代基；
    R5和R6各自独立任选为-H、-D、-OH、-NH2、-CN、(C1-C6)烷基、(C1-C6)卤代烷基、(C2-C6)烯基、(C2-C6)炔基、(C3-C9)环烷基、(C1-C6)烷氧基、(C6-C14)芳基、(3-11元)杂环烷基或(5-11元)杂芳基，其中所述(C1-C6)烷基、(C1-C6)卤代烷基、(C2-C6)烯基、(C2-C6)炔基、(C3-C9)环烷基、(C1-C6)烷氧基、(C6-C14)芳基、(3-11元)杂环烷基或(5-11元)杂芳基可各自独立任选被1，2，3或4个下列基团取代：-H、卤素、-OH、-(CH2)rOR31、-(CH2)rNR31R32、-OR31、-NR31R32、-CN、-C(O)NR31R32、-NR32C(O)R31、-NR32S(O)2R31、-S(O)pR31和-S(O)2NR31R32；或R5和R6与他们所连接的碳原子能够共同组成(4-7元)杂环烷基或(C3-C6)环烷基，其中所述(4-7元)杂环烷基或(C3-C6)环烷基可任选被1，2，3或4个下列基团取代：-H、卤素、(C1-C6)烷基或(C1-C6)烷氧基；或R5和R6共同形成一个氧代基；
    环A为(C6-C10)芳基或(5-10元)杂芳基；
    每个R1各自独立任选为：-H、卤素、-OH、-NO2、-NR31R32、-(CH2)rOR31、-(CH2)rNR31R32、-CN、(C1-C6)烷基、(C1-C6)卤代烷基、(C1-C6)烷氧基、(C2-C6)烯基、(C2-C6)炔基、(C3-C8)环烷基、-C(O)NR31R32、-NR32C(O)R31、-NR32S(O)2R31、-S(O)pR31或-S(O)2NR31R32，其中所述(C1-C6)烷基、(C1-C6)卤代烷基、(C1-C6)烷氧基、(C2-C6)烯基、(C2-C6)炔基或(C3-C8)环烷基可各自独立任选被1，2，3或4个下列基团取代：-H、卤素、-OH、-(CH2)rOR31、-(CH2)rNR31R32、-OR31、-NR31R32、-CN或(C1-C6)烷基；
    环B为(C5-C7)环烷基或(5-7元)杂环烷基；
    每个R2各自独立任选为：-H、卤素、-OH、-NR31R32、-CN、(C1-C6)烷基、(C1-C6)卤代烷基、(C1-C6)烷氧基、(C2-C6)烯基、(C2-C6)炔基或(C3-C8)环烷基；或同一个碳原子上的两个R2与他们所连接的碳原子能够共同组成(4-6元)杂环烷基或(C3-C6)环烷基，其中所述(4-6元)杂环烷基或(C3-C6)环烷基可任选被1，2，3或4个下列基团取代：-H、卤素、(C1-C6)烷基或(C1-C6)烷氧基；或同一个碳原子上的两个R2共同形成一个氧代基；
    R31和R32各自独立任选为-H、(C1-C4)烷基或(C3-C5)环烷基，或同一个氮原子上的R31和R32与他们所连接的N原子能够共同组成(3-6元)杂环烷基，其中所述(3-6元)杂环烷基可任选被1，2，3或4个下列基团取代：-H和卤素；和
    n为0、1、2、3或4的整数，m为0、1、2、3或4的整数，r为0、1或2的整数，p为0、1或2的整数。
  2. 如权利要求1所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，Rd为-H、-F、-CF3或-CH3。
  3. 如权利要求1或2所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，Re和Re’各自独立任选为-H或-F，且Re和Re’不同时为-H。
  4. 如权利要求1-3中任一项所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，Rx42为-H、(C1-C3)烷基或(C3-C5)环烷基。
  5. 如权利要求4所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，Rx42为-H、
  6. 如权利要求1-5中任一项所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，Rx41和Rx41’各自独立任选为-H、-F、-OH、-OCH3、-N(CH3)2、-NH2、-CN、-CF3、-CH2CF3、
  7. 如权利要求1-6中任一项所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，R3和R4各自独立任选为-H、-D、-OH、-NH2、-CN、(C1-C3)烷基、(C1-C3)卤代烷基、(C2-C4)烯基、(C2-C4)炔基、(C3-C5)环烷基、(C1-C3)烷氧基、苯基、(4-6元)杂环烷基或(5-6元)杂芳基，其中所述(C1-C3)烷基、(C1-C3)卤代烷基、(C2-C4)烯基、(C2-C4)炔基、(C3-C5)环烷基、(C1-C3)烷氧基、苯基、(4-6元)杂环烷基或(5-6元)杂芳基可各自独立任选被1，2，3或4个下列基团取代：-H、-F、-OH、-CH2OCH3、-CH2N(CH3)2、-OCH3、-N(CH3)2、-CN、-C(O)N(CH3)2、-NCH3C(O)CH3、-NHC(O)CH3、-NCH3S(O)2CH3、-NHS(O)2CH3、-SCH3、-S(O)2CH3、-S(O)2NH2和-S(O)2N(CH3)2；或R3和R4与他们所连接的碳原子能够共同组成(4-6元)杂环烷基或(C3-C4)环烷基，其中所述(4-6元)杂环烷基或(C3-C4)环烷基可任选被1，2，3或4个下列基团取代：-H、-F、或-OCH3；或R3和相邻的R5与他们所连接的原子共同组成(C3-C6)环烷基或(3-6元)杂环烷基，其中所述(C3-C6)环烷基或(3-6元)杂环烷基可各自独立任选被1，2，3或4个下列基团取代：-H、-F、或-OCH3；或当R3和相邻的R5同时不存在时，分别与R4和R6相连的碳原子之间可形成一个环内双键；或R3和R4共同形成一个氧代基。
  8. 如权利要求1-7中任一项所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，R5和R6各自独立任选为-H、-D、-OH、-NH2、-CN、(C1-C3)烷基、(C1-C3)卤代烷基、(C2-C4)烯基、(C2-C4)炔基、(C3-C5)环烷基、(C1-C3)烷氧基、苯基、(4-6元)杂环烷基或(5-6元)杂芳基，其中所述(C1-C3)烷基、(C1-C3)卤代烷基、(C2-C4)烯基、(C2-C4)炔基、(C3-C5)环烷基、(C1-C3)烷氧基、苯基、(4-6元)杂环烷基或(5-6元)杂芳基可各自独立任选被1，2，3或4个下列基团取代：-H、-F、-OH、-CH2OCH3、-CH2N(CH3)2、-OCH3、-N(CH3)2、-NH2、-CN、-C(O)N(CH3)2、-NCH3C(O)CH3、-NHC(O)CH3、-NCH3S(O)2CH3、-NHS(O)2CH3、-SCH3、-S(O)2CH3、-S(O)2NH2和-S(O)2N(CH3)2；或R5和R6与他们所连接的碳原子能够共同组成(4-6元)杂环烷基或(C3-C4)环烷基，其中所述(4-6元)杂环烷基或(C3-C4)环烷基可任选被1，2，3或4个下列基团取代：-H、-F、 或-OCH3；或R5和R6共同形成一个氧代基。
  9. 如权利要求1-8中任一项所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，环A为苯基或(5-6元)杂芳基。
  10. 如权利要求9所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，环A为：
  11. 如权利要求1-10中任一项所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，每个R1各自独立任选为：-H、-F、-Cl、-Br、-I、-OH、-NO2、-N(CH3)2、-NH2、-CH2OCH3、-CH2N(CH3)2、-CN、(C1-C3)烷基、(C1-C3)卤代烷基、(C1-C3)烷氧基、(C2-C4)烯基、(C2-C4)炔基、(C3-C6)环烷基、-C(O)N(CH3)2、-NCH3C(O)CH3、-NHC(O)CH3、-NCH3S(O)2CH3、-NHS(O)2CH3、-SCH3、-S(O)2CH3、-S(O)2NH2和-S(O)2N(CH3)2，其中所述(C1-C3)烷基、(C1-C3)卤代烷基、(C1-C3)烷氧基、(C2-C4)烯基、(C2-C4)炔基或(C3-C6)环烷基可各自独立任选被1，2，3或4个下列基团取代：-H、-F、-OH、-CH2OCH3、-CH2N(CH3)2、-OCH3、-N(CH3)2、-NH2、-CN、
  12. 如权利要求11所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，每个R1独立地为：-H、-F、-Cl、-Br、-I、-OH、-NO2、-N(CH3)2、-NH2、-CH2OCH3、-CH2N(CH3)2、-CN、-C(O)N(CH3)2、-NCH3C(O)CH3、-NHC(O)CH3、-NCH3S(O)2CH3、-NHS(O)2CH3、-SCH3、-S(O)2CH3、-S(O)2NH2、-S(O)2N(CH3)2、-CF3、-CH2CF3、-OCH3、-OCH2CH3、-OCH(CH3)2、
  13. 如权利要求1-12中任一项所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，环B为(C5-C6)环烷基或(5-6元)杂环烷基。
  14. 如权利要求13所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，结构单元为：
  15. 如权利要求13所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，结构单元为：
  16. 如权利要求1-15中任一项所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，每个R2各自独立任选为：-H、-F、-Cl、-Br、-I、-OH、-N(CH3)2、-NH2、-CN、(C1-C3)烷基、(C1-C3)卤代烷基、(C1-C3)烷氧基、(C2-C4)烯基、(C2-C4)炔基或(C3-C5)环烷基；或同一个碳原子上的两个R2与他们所连接的碳原子能够共同组成(4-5元)杂环烷基或(C3-C5)环烷基，其中所述(4-5元)杂环烷基或(C3-C5)环烷基可任选被1，2，3或4个下列基团取代：-H、-F、和-OCH3；或同一个碳原子上的两个R2共同形成一个氧代基。
  17. 如权利要求16所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，每个R2各自独立任选为：-H、-F、-Cl、-Br、-I、-OH、-N(CH3)2、-NH2、-CN、-CF3、-CH2CF3、-OCH3、-OCH2CH3、-OCH(CH3)2、
  18. 如权利要求1-17中任一项所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，结构单元为：
  19. 如权利要求1-17中任一项所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，结构单元为：
  20. 如权利要求1-17中任一项所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，结构单元为：
  21. 如权利要求1-20中任一项所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，其中所述化合物具有以下结构之一：








  22. 如权利要求1-20中任一项所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，其中所述化合物具有以下结构之一：

  23. 如权利要求1-20中任一项所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，其中所述化合物具有以下结构之一：


  24. 如权利要求1-20中任一项所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，其中所述化合物具有以下结构之一：






























  25. 一种如通式(2)所示的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物：
    通式(2)中：
    Y’为-O-、-CH2-或-N(H)-；
    Ra1为-H、-F、-NH2或-OH；
    Ra1’为-H或-F，且当Ra1为-NH2或-OH时，Ra1’为-H；
    Rb’为-H或(C1-C4)烷基；
    Rc’为-H或(C1-C4)烷基；
    Rd’为-H、卤素、-CF3或(C1-C4)烷基；
    Re1和Re1’各自独立任选为-H或卤素，且Re1和Re1’不同时为-H；
    X1’为C(H)、C(F)或N；
    X2’为S或O；
    X3’为C(Rx3’)或N；
    Rx3’为-H、卤素或-CH3；
    X4’为S、O、C(Rx41a)(Rx41b)或N(Rx42’)；
    Rx42’为-H、(C1-C4)烷基或(C3-C5)环烷基；
    Rx41a和Rx41b各自独立任选为-H、卤素、-OH、-ORx411’、-N(Rx411’)(Rx412’)、-CN、(C1-C6)烷基、(C1- C6)卤代烷基、(C3-C9)环烷基或(C1-C6)烷氧基；
    Rx411’和Rx412’各自独立任选为-H、(C1-C4)烷基或(C3-C5)环烷基，或同一个氮原子上的Rx411’和Rx412’与他们所连接的N原子能够共同组成(3-6元)杂环烷基，其中所述(3-6元)杂环烷基可任选被1，2，3或4个下列基团取代：-H或卤素；
    R3’和R4’各自独立任选为-H、-D、-OH、-NH2、-CN、(C1-C6)烷基、(C1-C6)卤代烷基、(C2-C6)烯基、(C2-C6)炔基、(C3-C9)环烷基、(C1-C6)烷氧基、(C6-C14)芳基、(3-11元)杂环烷基或(5-11元)杂芳基，其中所述(C1-C6)烷基、(C1-C6)卤代烷基、(C2-C6)烯基、(C2-C6)炔基、(C3-C9)环烷基、(C1-C6)烷氧基、(C6-C14)芳基、(3-11元)杂环烷基或(5-11元)杂芳基可各自独立任选被1，2，3或4个下列基团取代：-H、卤素、-OH、-(CH2)rOR31’、-(CH2)rNR31’R32’、-OR31’、-NR31’R32’、-CN、-C(O)NR31’R32’、-NR32’C(O)R31’、-NR32’S(O)2R31’、-S(O)pR31’和-S(O)2NR31’R32’；或R3’和R4’与他们所连接的碳原子能够共同组成(4-7元)杂环烷基或(C3-C6)环烷基，其中所述(4-7元)杂环烷基或(C3-C6)环烷基可任选被1，2，3或4个下列基团取代：-H、卤素、(C1-C6)烷基或(C1-C6)烷氧基；或R3’和相邻的R5’与他们所连接的原子能够共同组成(C3-C9)环烷基或(3-11元)杂环烷基，其中所述(C3-C9)环烷基或(3-11元)杂环烷基可各自独立任选被1，2，3或4个下列基团取代：-H、卤素、(C1-C6)烷基或(C1-C6)烷氧基；或当R3’和相邻的R5’同时不存在时，分别与R4’和R6’相连的碳原子之间可形成一个环内双键；或R3’和R4’共同形成一个氧代基；
    R5’和R6’各自独立任选为-H、-D、-OH、-NH2、-CN、(C1-C6)烷基、(C1-C6)卤代烷基、(C2-C6)烯基、(C2-C6)炔基、(C3-C9)环烷基、(C1-C6)烷氧基、(C6-C14)芳基、(3-11元)杂环烷基或(5-11元)杂芳基，其中所述(C1-C6)烷基、(C1-C6)卤代烷基、(C2-C6)烯基、(C2-C6)炔基、(C3-C9)环烷基、(C1-C6)烷氧基、(C6-C14)芳基、(3-11元)杂环烷基或(5-11元)杂芳基可各自独立任选被1，2，3或4个下列基团取代：-H、卤素、-OH、-(CH2)rOR31’、-(CH2)rNR31’R32’、-OR31’、-NR31’R32’、-CN、-C(O)NR31’R32’、-NR32’C(O)R31’、-NR32’S(O)2R31’、-S(O)pR31’和-S(O)2NR31’R32’；或R5’和R6’与他们所连接的碳原子能够共同组成(4-7元)杂环烷基或(C3-C6)环烷基，其中所述(4-7元)杂环烷基或(C3-C6)环烷基可任选被1，2，3或4个下列基团取代：-H、卤素、(C1-C6)烷基和(C1-C6)烷氧基；或R5’和R6’共同形成一个氧代基；
    环A’为(C6-C10)芳基或(5-10元)杂芳基；
    每个R1’各自独立任选为：-H、卤素、-OH、-NO2、-NR31’R32’、-(CH2)rOR31’、-(CH2)rNR31’R32’、-CN、(C1-C6)烷基、(C1-C6)卤代烷基、(C1-C6)烷氧基、(C2-C6)烯基、(C2-C6)炔基、(C3-C8)环烷基、-C(O)NR31’R32’、-NR32’C(O)R31’、-NR32’S(O)2R31’、-S(O)pR31’或-S(O)2NR31’R32’，其中所述(C1-C6)烷基、(C1-C6)卤代烷基、(C1-C6)烷氧基、(C2-C6)烯基、(C2-C6)炔基或(C3-C8)环烷基可各自独立任选被1，2，3或4个下列基团取代：-H、卤素、-OH、-(CH2)rOR31’、-(CH2)rNR31’R32’、-OR31’、-NR31’R32’、-CN和(C1-C6)烷基；
    R7’为：-H、-D、卤素、-OH、-NR31’R32’、-CN、(C1-C6)烷基、(C1-C6)卤代烷基、(C1-C6)烷氧基、(C2-C6)烯基、(C2-C6)炔基或(C3-C8)环烷基；
    R8’为：-H、-D、-OH、(C1-C6)烷基、(C2-C6)烯基、(C2-C6)炔基或(C3-C8)环烷基；
    R31’和R32’各自独立任选为-H、(C1-C4)烷基或(C3-C5)环烷基，或同一个氮原子上的R31’和R32’与他们所连接的N原子能够共同组成(3-6元)杂环烷基，其中所述(3-6元)杂环烷基可任选被1，2，3或4个下列基团取代：-H和卤素；和
    n为0、1、2、3或4的整数，r为0、1或2的整数，p为0、1或2的整数，q为0、1或2的整 数。
  26. 如权利要求25所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(2)中，Rd’为-H、-F、-CF3或-CH3。
  27. 如权利要求25或26所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(2)中，Re1和Re1’各自独立任选为-H或-F，且Re1和Re1’不同时为-H。
  28. 如权利要求25-27中任一项所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(2)中，Rx42’为-H、(C1-C3)烷基或(C3-C5)环烷基。
  29. 如权利要求28所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(2)中，Rx42’为-H、
  30. 如权利要求25-29中任一项所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(2)中，Rx41a和Rx41b各自独立任选为-H、-F、-OH、-OCH3、-N(CH3)2、-NH2、-CN、-CF3、-CH2CF3、
  31. 如权利要求25-30中任一项所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(2)中，R3’和R4’各自独立任选为-H、-D、-OH、-NH2、-CN、(C1-C3)烷基、(C1-C3)卤代烷基、(C2-C4)烯基、(C2-C4)炔基、(C3-C5)环烷基、(C1-C3)烷氧基、苯基、(4-6元)杂环烷基或(5-6元)杂芳基，其中所述(C1-C3)烷基、(C1-C3)卤代烷基、(C2-C4)烯基、(C2-C4)炔基、(C3-C5)环烷基、(C1-C3)烷氧基、苯基、(4-6元)杂环烷基或(5-6元)杂芳基可各自独立任选被1，2，3或4个下列基团取代：-H、-F、-OH、-CH2OCH3、-CH2N(CH3)2、-OCH3、-N(CH3)2、-CN、-C(O)N(CH3)2、-NCH3C(O)CH3、-NHC(O)CH3、-NCH3S(O)2CH3、-NHS(O)2CH3、-SCH3、-S(O)2CH3、-S(O)2NH2和-S(O)2N(CH3)2；或R3’和R4’与他们所连接的碳原子能够共同组成(4-6元)杂环烷基或(C3-C4)环烷基，其中所述(4-6元)杂环烷基或(C3-C4)环烷基可任选被1，2，3或4个下列基团取代：-H、-F、 或-OCH3；或R3’和相邻的R5’与他们所连接的原子能够共同组成(C3-C6)环烷基或(3-6元)杂环烷基，其中所述(C3-C6)环烷基或(3-6元)杂环烷基可各自独立任选被1，2，3或4个下列基团取代：-H、-F、或-OCH3；或当R3’和相邻的R5’同时不存在时，分别与R4’和R6’相连的碳原子之间可形成一个环内双键；或R3’和R4’共同形成一个氧代基。
  32. 如权利要求25-31中任一项所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(2)中，R5’和R6’各自独立任选为-H、-D、-OH、-NH2、-CN、(C1-C3)烷基、(C1-C3)卤代烷基、(C2-C4)烯基、(C2-C4)炔基、(C3-C5)环烷基、(C1-C3)烷氧基、苯基、(4-6元)杂环烷基或(5-6元)杂芳基，其中所述(C1-C3)烷基、(C1-C3)卤代烷基、(C2-C4)烯基、(C2-C4)炔基、(C3-C5)环烷基、(C1-C3)烷氧基、苯基、(4-6元)杂环烷基或(5-6元)杂芳基可各自独立任选被1，2，3或4个下列基团取代：-H、-F、-OH、-CH2OCH3、-CH2N(CH3)2、-OCH3、-N(CH3)2、-NH2、-CN、-C(O)N(CH3)2、-NCH3C(O)CH3、-NHC(O)CH3、-NCH3S(O)2CH3、-NHS(O)2CH3、-SCH3、-S(O)2CH3、-S(O)2NH2和- S(O)2N(CH3)2；或R5’和R6’与他们所连接的碳原子能够共同组成(4-6元)杂环烷基或(C3-C4)环烷基，其中所述(4-6元)杂环烷基或(C3-C4)环烷基可任选被1，2，3或4个下列基团取代：-H、-F、 或-OCH3；或R5’和R6’共同形成一个氧代基。
  33. 如权利要求25-32中任一项所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(2)中，环A’为苯基或(5-6元)杂芳基。
  34. 如权利要求33所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(2)中，环A’为：
  35. 如权利要求25-34中任一项所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(2)中，每个R1’各自独立任选为：-H、-F、-Cl、-Br、-I、-OH、-NO2、-N(CH3)2、-NH2、-CH2OCH3、-CH2N(CH3)2、-CN、(C1-C3)烷基、(C1-C3)卤代烷基、(C1-C3)烷氧基、(C2-C4)烯基、(C2-C4)炔基、(C3-C6)环烷基、-C(O)N(CH3)2、-NCH3C(O)CH3、-NHC(O)CH3、-NCH3S(O)2CH3、-NHS(O)2CH3、-SCH3、-S(O)2CH3、-S(O)2NH2和-S(O)2N(CH3)2，其中所述(C1-C3)烷基、(C1-C3)卤代烷基、(C1-C3)烷氧基、(C2-C4)烯基、(C2-C4)炔基或(C3-C6)环烷基可各自独立任选被1，2，3或4个下列基团取代：-H、-F、-OH、-CH2OCH3、-CH2N(CH3)2、-OCH3、-N(CH3)2、-NH2、-CN、
  36. 如权利要求35所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(2)中，每个R1’独立地为：-H、-F、-Cl、-Br、-I、-OH、-NO2、-N(CH3)2、-NH2、-CH2OCH3、-CH2N(CH3)2、-CN、-C(O)N(CH3)2、-NCH3C(O)CH3、-NHC(O)CH3、-NCH3S(O)2CH3、-NHS(O)2CH3、-SCH3、-S(O)2CH3、-S(O)2NH2、-S(O)2N(CH3)2、-CF3、-CH2CF3、-OCH3、-OCH2CH3、-OCH(CH3)2、
  37. 如权利要求25-36中任一项所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合 物或溶剂合物，其中所述通式(2)中，R7’为：-H、-D、-F、-Cl、-Br、-I、-OH、-N(CH3)2、-NH2、-CN、(C1-C3)烷基、(C1-C3)卤代烷基、(C1-C3)烷氧基、(C2-C4)烯基、(C2-C4)炔基或(C3-C5)环烷基。
  38. 如权利要求37所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(2)中，R7’为：-H、-D、-F、-Cl、-Br、-I、-OH、-N(CH3)2、-NH2、-CN、 -CF3、-CH2CF3、-OCH3、-OCH2CH3、-OCH(CH3)2、
  39. 如权利要求25-38中任一项所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(2)中，R8’为：-H、-D、-OH、(C1-C3)烷基、(C2-C4)烯基、(C2-C4)炔基或(C3-C5)环烷基。
  40. 如权利要求39所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(2)中，R8’为：-H、-D、
  41. 如权利要求25-40中任一项所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(2)中，结构单元为：
  42. 如权利要求25-41中任一项所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(2)中，其中所述化合物具有以下结构之一：




  43. 如权利要求25-41中任一项所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(2)中，其中所述化合物具有以下结构之一：

  44. 一种药物组合物，其特征在于，其含有药学上可接受的赋形剂或载体，以及如权利要求1-43中任一项所述的化合物、或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物作为活性成分。
  45. 一种如权利要求1-43中任一项所述的化合物、或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物或如权利要求44所述的药物组合物在制备治疗或预防由SAE介导的相关疾病的药物中的用途。
  46. 如权利要求45所述的用途，其中所述的疾病是癌症，所述癌症是血液癌和实体瘤。
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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101379061A (zh) * 2006-02-02 2009-03-04 千禧药品公司 E1活化酶抑制剂
CN101516850A (zh) * 2006-08-08 2009-08-26 米伦纽姆医药公司 适用作e1活化酶抑制剂的杂芳基化合物
CN105492429A (zh) * 2013-07-02 2016-04-13 米伦纽姆医药公司 Sumo活化酶的杂芳基抑制剂
CN106999479A (zh) * 2014-07-01 2017-08-01 米伦纽姆医药公司 可用作sumo活化酶抑制剂的杂芳基化合物
KR20170120521A (ko) * 2016-04-20 2017-10-31 한국화학연구원 신규한 헤테로고리 화합물, 이의 제조방법 및 이를 유효성분으로 함유하는 암의 예방 또는 치료용 약학적 조성물

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101379061A (zh) * 2006-02-02 2009-03-04 千禧药品公司 E1活化酶抑制剂
CN101516850A (zh) * 2006-08-08 2009-08-26 米伦纽姆医药公司 适用作e1活化酶抑制剂的杂芳基化合物
CN105492429A (zh) * 2013-07-02 2016-04-13 米伦纽姆医药公司 Sumo活化酶的杂芳基抑制剂
CN106999479A (zh) * 2014-07-01 2017-08-01 米伦纽姆医药公司 可用作sumo活化酶抑制剂的杂芳基化合物
KR20170120521A (ko) * 2016-04-20 2017-10-31 한국화학연구원 신규한 헤테로고리 화합물, 이의 제조방법 및 이를 유효성분으로 함유하는 암의 예방 또는 치료용 약학적 조성물

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