WO2021185256A1 - 取代的嘧啶或吡啶胺衍生物、其组合物及医药上的用途 - Google Patents

取代的嘧啶或吡啶胺衍生物、其组合物及医药上的用途 Download PDF

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WO2021185256A1
WO2021185256A1 PCT/CN2021/081126 CN2021081126W WO2021185256A1 WO 2021185256 A1 WO2021185256 A1 WO 2021185256A1 CN 2021081126 W CN2021081126 W CN 2021081126W WO 2021185256 A1 WO2021185256 A1 WO 2021185256A1
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compound
membered
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PCT/CN2021/081126
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English (en)
French (fr)
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刘力锋
赵志明
许峰
王海龙
席宝信
童忠安
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上海海雁医药科技有限公司
扬子江药业集团有限公司
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Priority to JP2022556468A priority Critical patent/JP7654008B2/ja
Priority to AU2021239135A priority patent/AU2021239135B2/en
Priority to US17/911,192 priority patent/US20230145793A1/en
Priority to KR1020227033700A priority patent/KR20220147124A/ko
Priority to CN202410486071.0A priority patent/CN118373808A/zh
Priority to CN202180001773.XA priority patent/CN113748110B/zh
Priority to EP21770539.1A priority patent/EP4122927A4/en
Priority to CA3171774A priority patent/CA3171774A1/en
Publication of WO2021185256A1 publication Critical patent/WO2021185256A1/zh

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    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • 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
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    • A61K31/5375—1,4-Oxazines, e.g. morpholine
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    • 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
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    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
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    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom

Definitions

  • the present invention relates to the field of medical technology, in particular to a substituted pyrimidine or pyridylamine derivative, or a pharmaceutically acceptable salt, solvate, stereoisomer, prodrug, or pharmaceutical composition thereof, and its use in medicine. use.
  • Adenosine is an endogenous nucleoside that is found throughout human cells. It is composed of adenine and ribose and is widely distributed inside and outside the cell. Adenosine is involved in a variety of physiological and biochemical functions in the body. For example, adenosine can directly enter the myocardium and generate adenosine triphosphate (ATP) through phosphorylation, which participates in the energy metabolism of the myocardium. In the central nervous system (Central Nervous System, CNS), adenosine controls the release of neurotransmitters and the response of postsynaptic neurons, and plays a role in regulating movement, protecting neurons, affecting sleep and awakening and other important life processes . Under pathological conditions, the concentration of extracellular adenosine will increase significantly under tumor or hypoxic conditions. Adenosine can play an important role in tumor immunosuppression by promoting tumor angiogenesis, proliferation, development and tumor migration.
  • ATP adenosine triphosphate
  • Adenosine receptor belongs to the G protein coupled receptor (Guanosine-binding Protein Coupled Receptor, GPCR) family, and its endogenous ligand is adenosine.
  • the currently known adenosine receptors are composed of four subtypes of receptors A1, A2a, A2b and A3. Among them, the binding of adenosine to A1 or A3 receptors can inhibit the production of cyclic adenosine monophosphate (cAMP); and the binding of adenosine to A2a or A2b receptors can activate adenosine activating enzyme, thereby up-regulating the level of cAMP and exerting further physiological regulation.
  • cAMP cyclic adenosine monophosphate
  • Two receptors, A1 and A3, are mainly expressed in the central nervous system, while two adenosine receptors, A2a and A2b, are expressed in the central nervous system and peripheral system.
  • two adenosine receptors, A2a and A2b are widely expressed in immune cells and have strong immunosuppressive functions.
  • the increase in the concentration of extracellular adenosine is one of the important mechanisms of tumor cell immune escape, and its concentration level is determined by the level of ATP and the expression levels of CD39 and CD73.
  • the increase in the concentration of extracellular adenosine is related to cell death or hypoxia releasing large amounts of ATP in the tumor microenvironment, and its concentration can reach 10-20 times that of normal tissues.
  • Adenosine binds to adenosine receptors in the tumor microenvironment and can inhibit the anti-tumor response, such as inhibiting the function of CD8+ T cells, enhancing the function of immunosuppressive regulatory T cells, and inhibiting the function of antigen-presenting cells through dendritic cells Wait. Recent studies have shown that binding to the A2a receptor can also inhibit the tumor-killing effect of natural killer cells.
  • A2a adenosine receptor antagonists can improve the viability and killing ability of dendritic antigen presenting cells, T cells and natural killer cells, and inhibit regulatory T cells (T-regs) and bone marrow-derived suppressive cells
  • T-regs regulatory T cells
  • TAM tumor-associated macrophages
  • A2b receptors have also been reported to promote tumor migration in murine melanoma and triple-negative breast cancer models. Therefore, A2b receptor antagonists are also effective targets for cancer treatment.
  • A2a/A2b dual receptor antagonist is used to block the activation of these two receptors at the same time. In terms of mechanism, it is regulating different immune cell groups and comprehensively blocking the immunosuppressive effect of adenosine in the microenvironment. , Has far-reaching clinical application value for tumor treatment.
  • adenosine receptor antagonists are used alone or in combination with other chemotherapeutic drugs/immunomodulation drugs, which are currently the hotspots of clinical research.
  • the object of the present invention is to provide a substituted pyrimidine or pyridine amine derivative with higher activity, better selectivity and lower toxicity.
  • the first aspect of the present invention provides a compound represented by formula (I), or a pharmaceutically acceptable salt, or a stereoisomer, or a solvate, or a prodrug thereof:
  • ring A is a 5- to 10-membered heteroaryl, phenyl or pyridonyl group
  • Ring B is a phenyl group or a 5- to 10-membered heteroaryl group
  • Q is 5 to 6 membered heteroaryl, phenyl, C 3-6 cycloalkyl, 4 to 8 membered heterocycloalkyl, 6 to 12 membered fused heterocycloalkyl, 7 to 11 membered phenyl and heterocycle Alkyl, 7 to 11 membered heteroaryl and heterocycloalkyl, 7 to 11 membered spiro ring group or 7 to 11 membered heterospiro ring group; wherein the 5 to 6 membered heteroaryl group, phenyl group, C 3 -6 cycloalkyl, 4 to 8 membered heterocycloalkyl, 6 to 12 membered fused heterocycloalkyl, 7 to 11 membered phenyl and heterocycloalkyl, 7 to 11 membered heteroaryl and heterocycloalkyl , 7 to 11 membered spiro ring group and 7 to 11 membered heterospiro ring group are unsubstituted or substituted with 1, 2 or 3
  • L 1, L 2 are each independently a bond, NR 1 ', CR 2' R 3 ', O, S , or C (O); and L 1, L 2 are not simultaneously O or S;
  • R 1 ', R 2 'and R 3 ' are each independently hydrogen, deuterium, cyano, hydroxyl, halogen (preferably fluorine or chlorine) or C 1-6 alkyl; or R 1 'and R 2 ' are connected to form A 3- to 8-membered heterocycloalkyl ring; or R 2 ′ and R 3 ′ are connected to form a 3- to 8-membered heterocycloalkyl ring; wherein the 3- to 8-membered heterocycloalkyl ring is unsubstituted or substituted by 1 , 2 or 3 substituents each independently selected from the following group: deuterium, halogen, cyano, hydroxyl, C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, C 2 -4 alkynyl, halogenated C 1-3 alkyl, halogenated C 1-3 alkoxy, -SO 2 C 1-3 alkyl, -S(O)C 1-3 alkyl,
  • W is N or CR W
  • R W is cyano, hydroxyl, halogen (preferably fluorine or chlorine), halogenated C 1-8 alkyl (preferably halogenated C 1-6 alkyl, more preferably halogenated C 1-3 alkyl), Halogenated C 1-8 alkoxy (preferably halogenated C 1-6 alkoxy, more preferably halogenated C 1-3 alkoxy) or C 1-8 alkoxy (preferably C 1-6 Alkoxy, more preferably C 1-3 alkoxy);
  • halogen preferably fluorine or chlorine
  • halogenated C 1-8 alkyl preferably halogenated C 1-6 alkyl, more preferably halogenated C 1-3 alkyl
  • Halogenated C 1-8 alkoxy preferably halogenated C 1-6 alkoxy, more preferably halogenated C 1-3 alkoxy
  • C 1-8 alkoxy preferably C 1-6 Alkoxy, more preferably C 1-3 alkoxy
  • R c, R a and R b are defined as follows:
  • R c is fluorine, chlorine, cyano, C 1-3 alkoxy or halogenated C 1-3 alkoxy;
  • R a and R b are each independently hydrogen, deuterium, C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), C 1-8 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy), -C(O)C 1-8 alkyl (preferably -C(O)C 1-6 alkyl, more preferably- C(O)C 1-3 alkyl), -(CH 2 ) t C 3-8 cycloalkyl (preferably -(CH 2 ) t C 3-6 cycloalkyl), -(CH 2 ) t- 3- to 8-membered heterocycloalkyl or structure of formula (a)
  • said C 1-8 alkyl group, -C (O) C 1-8 alkyl group and -(CH 2 ) t -3 to 8 membered heterocycloalkyl are unsubstituted or are each composed of 1, 2 or 3 Substituent substitution independently selected from the group consisting of deuterium, halogen, cyano, hydroxyl, C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, halo Substituted C 1-3 alkyl, halogenated C 1-3 alkoxy, -SO 2 C 1-3 alkyl, -S(O)C 1-3 alkyl, -C(O)NR a0 R b0 , -C(O)OC 1-3 alkyl, -OC(O)C 1-3 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyloxy, 3 to 6 membered heterocycloalkyl , phenyl
  • R 1a is hydrogen or C 1-3 alkyl
  • R 2a and R 3a are each independently hydrogen or C 1-3 alkyl
  • R 2a and R 3a are connected to form a 5- to 8-membered heterocycloalkenyl ring or 5 To 6-membered heteroaryl ring
  • the 5- to 8-membered heterocycloalkenyl ring contains 2, 3 or 4 nitrogen atoms and 0, 1, or 2 oxygen atoms
  • the 5- to 6-membered heteroaryl ring contains 2 , 3 or 4 nitrogen atoms and 0 or 1 oxygen atom
  • the 5- to 8-membered heterocycloalkenyl ring and 5- to 6-membered heteroaryl ring are unsubstituted or are independently of 1, 2 or 3 Substituents selected from the group consisting of halogen, cyano, hydroxy, C 1-3 alkyl, C 1-3 alkoxy, halogenated C 1-3 alkyl, and halogenated C 1-3 alkoxy ;
  • R c and R a are connected to form a fused 5- or 6-membered saturated or partially unsaturated monocyclic ring, or a fused 5- to 6-membered heteroaryl ring; the fused 5- or 6-membered saturated or Partially unsaturated monocyclic heterocycles and 5- to 6-membered heteroaryl rings are unsubstituted or substituted with 1, 2 or 3 substituents each independently selected from the following group: deuterium, halogen, cyano, hydroxyl, oxo Group, C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, halogenated C 1-3 alkyl, halogenated C 1-3 alkoxy, -SO 2 C 1-3 alkyl, -S(O)C 1-3 alkyl, -C(O)NR a0 R b0 , -C(O)OC 1-3 alkyl, -OC(O)C 1-3 alkyl,
  • R b is hydrogen, deuterium, C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), -C (O) C 1-8 alkyl (preferably -C (O)C 1-6 alkyl, more preferably -C(O)C 1-3 alkyl), -(CH 2 ) t C 3-8 cycloalkyl (preferably -(CH 2 ) t C 3 -6 cycloalkyl), -(CH 2 ) t -3 to 8-membered heterocycloalkyl or a structure of formula (a); wherein the C 1-8 alkyl, -C (O) C 1-8 alkane And -(CH 2 ) t -3 to 8-membered heterocycloalkyl are unsubstituted or substituted with 1, 2 or 3 substituents each independently selected from the group: deuterium, halogen, cyano, hydroxyl, C 1-3 alkyl, C 1-3 alkoxy, C 2-4
  • t 0, 1, 2 or 3;
  • R L1 and R L2 are each independently hydrogen, hydroxyl, halogen, C 1-3 alkyl, C 1-3 alkoxy or halogenated C 1-3 alkyl; or R L1 , R L2 and the connected carbon atom Together to form a 3 to 7 membered saturated or partially unsaturated monocyclic ring or a 3 to 7 membered saturated or partially unsaturated monocyclic heterocyclic ring; wherein the 3 to 7 membered saturated or partially unsaturated monocyclic heterocyclic ring and a 3 to 7 membered saturated or partially saturated or partially heterocyclic ring
  • the unsaturated monocyclic ring is unsubstituted or substituted by 1, 2 or 3 substituents each independently selected from the group consisting of deuterium, halogen, cyano, hydroxy, carboxy, C 1-3 alkyl, C 1-3 Alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, halogenated C 1-3 alkyl, halogenated C 1-3
  • n 0, 1, 2 or 3;
  • R p is hydrogen, hydroxy, carboxyl, cyano, C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), halogenated C 1-8 alkyl (preferably Halo C 1-6 alkyl, more preferably halo C 1-3 alkyl), halo C 1-8 alkoxy (preferably halo C 1-6 alkoxy, more preferably halo C 1-3 alkoxy), C 1-8 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy), C 3-8 cycloalkyl (preferably C 3 -6 cycloalkyl), -SO 2 C 1-8 alkyl (preferably -SO 2 C 1-6 alkyl, more preferably -SO 2 C 1-3 alkyl), -SO 2 NR a0 R b0 , -(PO)(C 1-3 alkyl) 2 , -NHSO 2 C 1-3 alkyl, -C(O)NR a0 R b0 ,
  • X is O or NR p3 ;
  • R p1 and R p2 are each independently hydrogen, hydroxyl, halogen or C 1-3 alkyl;
  • R p3 is hydrogen or C 1-3 alkyl
  • q 0, 1, 2 or 3;
  • R a ', R b 'and the connected nitrogen atom together form a 4 to 8 membered saturated monocyclic ring, an 8 to 10 membered saturated bicyclic ring or a 7 to 11 membered heterospiro ring;
  • the 4 to 8 membered saturated monocyclic ring , 8- to 10-membered saturated bicyclic heterocyclic ring and 7- to 11-membered heterospiro ring are unsubstituted or substituted with 1, 2 or 3 substituents each independently selected from the following group: halogen, cyano, hydroxyl, carboxy, C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, halogenated C 1-3 alkyl, halogenated C 1-3 alkoxy, -( CH 2 ) t1 -NR a0 R b0 , -(CH 2 ) t1 -SO 2 C 1-3 alkyl, -(CH 2
  • t1 is independently selected from 0, 1, 2 or 3;
  • R 0 is that the hydrogen on ring A is replaced by n R 0 , n is 0, 1, 2 or 3, each R 0 is the same or different, and each independently is halogen, cyano, hydroxyl, carboxy, C 1-3 alkyl, C 1-3 alkoxy, hydroxy substituted C 1-3 alkyl, C 1-3 alkoxy substituted C 1-3 alkyl, C 2-4 alkenyl, C 2- 4 Alkynyl, halogenated C 1-3 alkyl, halogenated C 1-3 alkoxy, -SO 2 C 1-3 alkyl, -SO 2 NR a0 R b0 , -N(R a0 )SO 2 C 1-3 alkyl, -P(O)R a0 R b0 , -S(O)C 1-3 alkyl, -C(O)NR a0 R b0 , -C(O)OC 1-3 alkyl, -OC(O)C 1-3 alkyl,
  • R 0 ' is that the hydrogen on ring B is replaced by u R 0 's, u is 0, 1, 2, 3, 4 or 5, each R 0 'is the same or different, and each independently is hydrogen or cyanide Group, acetyl group, hydroxyl group, carboxyl group, halogen (preferably fluorine or chlorine), NR a0 R b0 , C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), C 1-8 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy), C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl), 3 To 6-membered heterocycloalkyl, 5 to 6-membered heteroaryl or C 6-10 aryl; wherein the C 1-8 alkyl, C 1-8 alkoxy, C 3-8 cycloalkyl, 3 To 6-membered heterocycloalkyl, 5- to 6-membered heteroaryl and C 6-10
  • R a0 and R b0 are each independently hydrogen or C 1-3 alkyl; or R a0 , R b0 and the connected nitrogen atom together form a 4- to 6-membered saturated monocyclic ring; the 4- to 6-membered saturated monocyclic ring Optionally substituted with 1, 2 or 3 substituents each independently selected from the group consisting of deuterium, halogen, cyano, hydroxyl, carboxyl, C 1-3 alkyl, C 1-3 alkoxy, C 2 -4 Alkenyl, C 2-4 alkynyl, halogenated C 1-3 alkyl, halogenated C 1-3 alkoxy, -SO 2 C 1-3 alkyl, -S(O)C 1-3 Alkyl, -C(O)NR a0 R b0 , -C(O)OC 1-3 alkyl, -OC(O)C 1-3 alkyl, C 3-6 cycloalkyl, C 3-6 ring Alkyloxy and 3 to 6 membere
  • R a1 and R b1 are each independently hydrogen, C 1-3 alkyl, C 3-6 cycloalkyl, 3 to 6 membered heterocycloalkyl or -(CR a R b ) s -R c ; wherein The 3- to 6-membered heterocycloalkyl group is unsubstituted or substituted with 1, 2 or 3 substituents each independently selected from the following group: deuterium, halogen, cyano, hydroxy, carboxy, oxo, C 1- 3 alkyl group, C 1-3 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, halo C 1-3 alkyl, a C 1-3 alkoxy group, halo, -SO 2 C 1 -3 alkyl group, -S(O)C 1-3 alkyl group, -C(O)NR a0 R b0 , -C(O)C 1-3 alkyl group, -C(O)OC 1-3 alkyl
  • R a and R b are each independently hydrogen, hydroxy, halogen, C 1-3 alkyl, C 1-3 alkoxy or halo C 1-3 alkyl; or R a , R b and the attached carbon atom Together to form a 3 to 7 membered saturated or partially unsaturated monocyclic ring or a 3 to 7 membered saturated or partially unsaturated monocyclic heterocyclic ring; wherein the 3 to 7 membered saturated or partially unsaturated monocyclic heterocyclic ring and a 3 to 7 membered saturated or partially saturated or partially heterocyclic ring
  • the unsaturated monocyclic ring is unsubstituted or substituted by 1, 2 or 3 substituents each independently selected from the group consisting of deuterium, halogen, cyano, hydroxy, carboxy, C 1-3 alkyl, C 1-3 Alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, halogenated C 1-3 alkyl, halogenated C 1-3 alk
  • R c is hydrogen, hydroxy, carboxyl, C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), halogenated C 1-8 alkyl (preferably halogenated C 1-6 alkyl, more preferably halogenated C 1-3 alkyl), halogenated C 1-8 alkoxy (preferably halogenated C 1-6 alkoxy, more preferably halogenated C 1-3 Alkoxy), C 1-8 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy) or C 3-8 cycloalkyl (preferably C 3-6 ring Alkyl); and
  • s is 1, 2 or 3.
  • ring A is a 5- to 10-membered heteroaryl group, a phenyl group or a pyridonyl group;
  • Ring B is a phenyl group or a 5- to 10-membered heteroaryl group
  • Q is 5 to 6 membered heteroaryl, phenyl, C 3-6 cycloalkyl, 4 to 8 membered heterocycloalkyl, 6 to 12 membered fused heterocycloalkyl, 7 to 11 membered phenyl and heterocycle Alkyl, 7 to 11 membered heteroaryl and heterocycloalkyl, 7 to 11 membered spiro ring group or 7 to 11 membered heterospiro ring group; wherein the 5 to 6 membered heteroaryl group, phenyl group, C 3 -6 cycloalkyl, 4 to 8 membered heterocycloalkyl, 6 to 12 membered fused heterocycloalkyl, 7 to 11 membered phenyl and heterocycloalkyl, 7 to 11 membered heteroaryl and heterocycloalkyl , 7 to 11 membered spiro ring group and 7 to 11 membered heterospiro ring group are unsubstituted or substituted with 1, 2 or 3
  • L 1, L 2 are each independently a bond, NR 1 ', CR 2' R 3 ', O, S , or C (O); and L 1, L 2 are not simultaneously O or S;
  • R 1 ', R 2 'and R 3 ' are each independently hydrogen, deuterium, cyano, hydroxyl, halogen (preferably fluorine or chlorine) or C 1-6 alkyl; or R 1 'and R 2 ' are connected to form A 3- to 8-membered heterocycloalkyl ring; or R 2 ′ and R 3 ′ are connected to form a 3- to 8-membered heterocycloalkyl ring; wherein the 3- to 8-membered heterocycloalkyl ring is unsubstituted or substituted by 1 , 2 or 3 substituents each independently selected from the following group: deuterium, halogen, cyano, hydroxyl, C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, C 2 -4 alkynyl, halogenated C 1-3 alkyl, halogenated C 1-3 alkoxy, -SO 2 C 1-3 alkyl, -S(O)C 1-3 alkyl,
  • W is N or CR W
  • R W is cyano, hydroxyl, halogen (preferably fluorine or chlorine), halogenated C 1-8 alkyl (preferably halogenated C 1-6 alkyl, more preferably halogenated C 1-3 alkyl), Halogenated C 1-8 alkoxy (preferably halogenated C 1-6 alkoxy, more preferably halogenated C 1-3 alkoxy) or C 1-8 alkoxy (preferably C 1-6 Alkoxy, more preferably C 1-3 alkoxy);
  • halogen preferably fluorine or chlorine
  • halogenated C 1-8 alkyl preferably halogenated C 1-6 alkyl, more preferably halogenated C 1-3 alkyl
  • Halogenated C 1-8 alkoxy preferably halogenated C 1-6 alkoxy, more preferably halogenated C 1-3 alkoxy
  • C 1-8 alkoxy preferably C 1-6 Alkoxy, more preferably C 1-3 alkoxy
  • R c, R a and R b are defined as follows:
  • R c is fluorine, chlorine, cyano, C 1-3 alkoxy or halogenated C 1-3 alkoxy;
  • R a and R b are each independently hydrogen, deuterium, C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), -C (O) C 1-8 alkane Group (preferably -C(O)C 1-6 alkyl, more preferably -C(O)C 1-3 alkyl), -(CH 2 ) t C 3-8 cycloalkyl (preferably -( CH 2 ) t C 3-6 cycloalkyl), -(CH 2 ) t -3 to 8-membered heterocycloalkyl or a structure of formula (a)
  • said C 1-8 alkyl group, -C (O) C 1-8 alkyl group and -(CH 2 ) t -3 to 8 membered heterocycloalkyl are unsubstituted or are each composed of 1, 2 or 3 Substituent substitution independently selected from the group consisting of deuterium, halogen, cyano, hydroxyl, C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, halo Substituted C 1-3 alkyl, halogenated C 1-3 alkoxy, -SO 2 C 1-3 alkyl, -S(O)C 1-3 alkyl, -C(O)NR a0 R b0 , -C(O)OC 1-3 alkyl, -OC(O)C 1-3 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyloxy, 3 to 6 membered heterocycloalkyl , phenyl
  • R 1a is hydrogen or C 1-3 alkyl
  • R 2a and R 3a are each independently hydrogen or C 1-3 alkyl
  • R 2a and R 3a are connected to form a 5- to 8-membered heterocycloalkenyl ring or 5 To 6-membered heteroaryl ring
  • the 5- to 8-membered heterocycloalkenyl ring contains 2, 3 or 4 nitrogen atoms and 0, 1, or 2 oxygen atoms
  • the 5- to 6-membered heteroaryl ring contains 2 , 3 or 4 nitrogen atoms and 0 or 1 oxygen atom
  • the 5- to 8-membered heterocycloalkenyl ring and 5- to 6-membered heteroaryl ring are unsubstituted or are independently of 1, 2 or 3 Substituents selected from the group consisting of halogen, cyano, hydroxy, C 1-3 alkyl, C 1-3 alkoxy, halogenated C 1-3 alkyl, and halogenated C 1-3 alkoxy ;
  • R c and R a are connected to form a fused 5- or 6-membered saturated or partially unsaturated monocyclic ring, or a fused 5- to 6-membered heteroaryl ring; the fused 5- or 6-membered saturated or Partially unsaturated monocyclic heterocycles and 5- to 6-membered heteroaryl rings are unsubstituted or substituted with 1, 2 or 3 substituents each independently selected from the following group: deuterium, halogen, cyano, hydroxyl, oxo Group, C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, halogenated C 1-3 alkyl, halogenated C 1-3 alkoxy, -SO 2 C 1-3 alkyl, -S(O)C 1-3 alkyl, -C(O)NR a0 R b0 , -C(O)OC 1-3 alkyl, -OC(O)C 1-3 alkyl,
  • R b is hydrogen, deuterium, C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), -C (O) C 1-8 alkyl (preferably -C (O)C 1-6 alkyl, more preferably -C(O)C 1-3 alkyl), -(CH 2 ) t C 3-8 cycloalkyl (preferably -(CH 2 ) t C 3 -6 cycloalkyl), -(CH 2 ) t -3 to 8-membered heterocycloalkyl or a structure of formula (a); wherein the C 1-8 alkyl, -C (O) C 1-8 alkane And -(CH 2 ) t -3 to 8-membered heterocycloalkyl are unsubstituted or substituted with 1, 2 or 3 substituents each independently selected from the group: deuterium, halogen, cyano, hydroxyl, C 1-3 alkyl, C 1-3 alkoxy, C 2-4
  • t 0, 1, 2 or 3;
  • R L1 and R L2 are each independently hydrogen, hydroxyl, halogen, C 1-3 alkyl, C 1-3 alkoxy or halogenated C 1-3 alkyl; or R L1 , R L2 and the connected carbon atom Together to form a 3 to 7 membered saturated or partially unsaturated monocyclic ring or a 3 to 7 membered saturated or partially unsaturated monocyclic heterocyclic ring; wherein the 3 to 7 membered saturated or partially unsaturated monocyclic heterocyclic ring and a 3 to 7 membered saturated or partially saturated or partially heterocyclic ring
  • the unsaturated monocyclic ring is unsubstituted or substituted by 1, 2 or 3 substituents each independently selected from the group consisting of deuterium, halogen, cyano, hydroxy, carboxy, C 1-3 alkyl, C 1-3 Alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, halogenated C 1-3 alkyl, halogenated C 1-3
  • n 0, 1, 2 or 3;
  • R p is hydrogen, hydroxy, carboxyl, C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), halogenated C 1-8 alkyl (preferably halogenated C 1-6 alkyl, more preferably halogenated C 1-3 alkyl), halogenated C 1-8 alkoxy (preferably halogenated C 1-6 alkoxy, more preferably halogenated C 1-3 Alkoxy), C 1-8 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy), C 3-8 cycloalkyl (preferably C 3-6 ring Alkyl), -SO 2 C 1-8 alkyl (preferably -SO 2 C 1-6 alkyl, more preferably -SO 2 C 1-3 alkyl), -SO 2 NR a0 R b0 , -C (O)NR a0 R b0 , -C(O)NR a1 R b1 , 3 to 6 membered heterocycloalkyl,
  • X is O or NR p3 ;
  • R p1 and R p2 are each independently hydrogen, hydroxyl, halogen or C 1-3 alkyl;
  • R p3 is hydrogen or C 1-3 alkyl
  • q 0, 1, 2 or 3;
  • R a ', R b 'and the connected nitrogen atom together form a 4 to 8 membered saturated monocyclic ring, an 8 to 10 membered saturated bicyclic ring or a 7 to 11 membered heterospiro ring;
  • the 4 to 8 membered saturated monocyclic ring , 8- to 10-membered saturated bicyclic heterocyclic ring and 7- to 11-membered heterospiro ring are unsubstituted or substituted with 1, 2 or 3 substituents each independently selected from the following group: halogen, cyano, hydroxyl, carboxy, C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, halogenated C 1-3 alkyl, halogenated C 1-3 alkoxy, -( CH 2 ) t1 -NR a0 R b0 , -(CH 2 ) t1 -SO 2 C 1-3 alkyl, -(CH 2
  • t1 is independently selected from 0, 1, 2 or 3;
  • R 0 is that the hydrogen on ring A is replaced by n R 0 , n is 0, 1, 2 or 3, each R 0 is the same or different, and each independently is halogen, cyano, hydroxyl, carboxyl, C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, halogenated C 1-3 alkyl, halogenated C 1-3 alkoxy, -SO 2 C 1-3 alkyl, -SO 2 NR a0 R b0 , -N(R a0 )SO 2 C 1-3 alkyl, -P(O)R a0 R b0 , -S(O)C 1-3 alkane Group, -C(O)NR a0 R b0 , -C(O)OC 1-3 alkyl, -OC(O)C 1-3 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl, C 3-6 cycl
  • R 0 ' is that the hydrogen on ring B is replaced by u R 0 's, u is 0, 1, 2, 3, 4 or 5, each R 0 'is the same or different, and each independently is hydrogen or cyanide Group, acetyl group, hydroxyl group, carboxyl group, halogen (preferably fluorine or chlorine), NR a0 R b0 , C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), C 1-8 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy), C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl), 3 To 6-membered heterocycloalkyl, 5 to 6-membered heteroaryl or C 6-10 aryl; wherein the C 1-8 alkyl, C 1-8 alkoxy, C 3-8 cycloalkyl, 3 To 6-membered heterocycloalkyl, 5- to 6-membered heteroaryl and C 6-10
  • R a0 and R b0 are each independently hydrogen or C 1-3 alkyl; or R a0 , R b0 and the connected nitrogen atom together form a 4 to 6-membered saturated monocyclic ring; the 4- to 6-membered saturated monocyclic ring Optionally substituted with 1, 2 or 3 substituents each independently selected from the group consisting of deuterium, halogen, cyano, hydroxyl, carboxyl, C 1-3 alkyl, C 1-3 alkoxy, C 2 -4 Alkenyl, C 2-4 alkynyl, halogenated C 1-3 alkyl, halogenated C 1-3 alkoxy, -SO 2 C 1-3 alkyl, -S(O)C 1-3 Alkyl, -C(O)NR a0 R b0 , -C(O)OC 1-3 alkyl, -OC(O)C 1-3 alkyl, C 3-6 cycloalkyl, C 3-6 ring Alkyloxy and 3 to 6 membere
  • R a1 and R b1 are each independently hydrogen, C 1-3 alkyl, C 3-6 cycloalkyl, 3 to 6 membered heterocycloalkyl or -(CR a R b ) s -R c ; wherein The 3- to 6-membered heterocycloalkyl is unsubstituted or substituted with 1, 2 or 3 substituents each independently selected from the group consisting of deuterium, halogen, cyano, hydroxyl, carboxy, oxo, C 1- 3 alkyl group, C 1-3 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, halo C 1-3 alkyl, a C 1-3 alkoxy group, halo, -SO 2 C 1 -3 alkyl group, -S(O)C 1-3 alkyl group, -C(O)NR a0 R b0 , -C(O)C 1-3 alkyl group, -C(O)OC 1-3 alky
  • R a and R b are each independently hydrogen, hydroxy, halogen, C 1-3 alkyl, C 1-3 alkoxy or halo C 1-3 alkyl; or R a , R b and the attached carbon atom Together to form a 3 to 7 membered saturated or partially unsaturated monocyclic ring or a 3 to 7 membered saturated or partially unsaturated monocyclic heterocyclic ring; wherein the 3 to 7 membered saturated or partially unsaturated monocyclic heterocyclic ring and a 3 to 7 membered saturated or partially saturated or partially heterocyclic ring
  • the unsaturated monocyclic ring is unsubstituted or substituted by 1, 2 or 3 substituents each independently selected from the group consisting of deuterium, halogen, cyano, hydroxy, carboxy, C 1-3 alkyl, C 1-3 Alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, halogenated C 1-3 alkyl, halogenated C 1-3 alk
  • R c is hydrogen, hydroxy, carboxyl, C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), halogenated C 1-8 alkyl (preferably halogenated C 1-6 alkyl, more preferably halogenated C 1-3 alkyl), halogenated C 1-8 alkoxy (preferably halogenated C 1-6 alkoxy, more preferably halogenated C 1-3 Alkoxy), C 1-8 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy) or C 3-8 cycloalkyl (preferably C 3-6 ring Alkyl); and
  • s is 1, 2 or 3.
  • ring A is 5 to 6 membered heteroaryl, 8 to 10 membered heteroaryl, phenyl or pyridonyl.
  • ring A is 5 to 6 membered heteroaryl, phenyl or pyridonyl.
  • ring A is selected from thienyl, furyl, thiazolyl, isothiazolyl, imidazolyl, oxazolyl, pyrrolyl, pyrazolyl, triazolyl, 1,2,3-triazolyl, 1 ,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, tetrazolyl, isoxazolyl, oxadiazolyl, 1,2,3-oxa Diazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidine Group, pyrazinyl, triazinyl, tetrazinyl, phenyl and pyridonyl.
  • ring A is phenyl, pyridyl, pyrazolyl, pyrimidinyl, 1,2,3-triazolyl, 1,2,4-triazolyl or pyridonyl.
  • ring A is selected from Represents that ring A is connected to L1.
  • ring A is selected from Represents that ring A is connected to L1.
  • ring B is a phenyl group, a 5- to 6-membered heteroaryl group, or an 8- to 10-membered heteroaryl group.
  • ring B is phenyl
  • L 1, L 2 are a bond and CR 2 'R 3'.
  • L 1 is a bond
  • L 2 is CR 2 'R 3'.
  • L 1 and L 2 are a bond and CH 2 respectively .
  • L 1 is a bond
  • L 2 is CH 2 .
  • W is N.
  • R c is fluorine, chlorine or C 1-3 alkoxy. More preferably, R c is fluorine, chlorine, cyano, hydroxy, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy or isopropoxy.
  • R c is fluorine, chlorine or methoxy.
  • R c is fluorine or chlorine. More preferably, Q is 5 to 6 membered heteroaryl, phenyl, C 3-6 cycloalkyl, 4 to 6 membered heterocycloalkyl, 8 to 10 membered fused heterocycloalkyl, 8 to 10 membered benzene Group and heterocycloalkyl, 8 to 10 membered heteroaryl and heterocycloalkyl, 7 to 11 membered spiro ring group or 7 to 11 membered heterospiro ring group.
  • the 5- to 6-membered heteroaryl group in Q is selected from the following structures:
  • the 3- to 6-membered heterocycloalkyl group in Q is selected from the following structures:
  • Q is a 5- to 6-membered heteroaryl group.
  • Q is pyrazolyl, 1,2,3-triazolyl.
  • Q is selected from the following structures:
  • R a and R b are each independently hydrogen, deuterium, C 1-3 alkyl, -C (O) C 1-3 alkyl, -(CH 2 ) t C 3-6 cycloalkyl, - (CH 2) t -4 to 6-membered heterocyclic structure or a group of formula (a); or R a, R b together with the nitrogen atom form a 5- or 6-membered saturated monocyclic heterocycle; wherein said C 1 -3 alkyl, -C (O) C 1-3 alkyl, -(CH 2 ) t -4 to 6-membered heterocycloalkyl and 5- or 6-membered saturated monocyclic heterocyclic ring are unsubstituted or substituted by 1, 2 Or 3 substituents independently selected from the following group: deuterium, halogen, cyano, hydroxyl, C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, C 2-4 Alkynyl, halogenated C
  • R a and R b are hydrogen or deuterium.
  • R a is hydrogen; R b is hydrogen.
  • R 2a and R 3a are connected to form a 5- to 8-membered heterocycloalkenyl ring or a 5- to 6-membered heteroaryl ring; wherein the 5- to 8-membered heterocycloalkenyl ring is selected from: 4,5-dihydro -1H-imidazole ring, 1,4,5,6-tetrahydropyrimidine ring, 3,4,7,8-tetrahydro-2H-1,4,6-oxadiazosin ring, 1,6-dihydro Pyrimidine ring, 4,5,6,7-tetrahydro-1H-1,3-diazepine ring and 2,5,6,7-tetrahydro-1,3,5-oxadiazepine ring;
  • the 5- to 6-membered heteroaryl ring is selected from: 1H-imidazole ring, 4H-1,2,4-triazole ring, 1H-1,2,4-triazole ring, pyrimidine ring,
  • R c and R a are connected to form a fused 5- or 6-membered saturated monocyclic ring, or a fused 5- to 6-membered heteroaryl ring; the fused 5- or 6-membered saturated monocyclic ring and
  • the 5- to 6-membered heteroaryl ring is unsubstituted or substituted with 1, 2 or 3 substituents each independently selected from the following group: deuterium, halogen, cyano, hydroxyl, oxo, C 1-3 alkane Group, C 1-3 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, halogenated C 1-3 alkyl, halogenated C 1-3 alkoxy, -SO 2 C 1-3 Alkyl, -S(O)C 1-3 alkyl, -C(O)NR a0 R b0 , -C(O)OC 1-3 alkyl, -OC(O)C 1-3 alkyl, C 3-6 cycloalkyl, C
  • R b is hydrogen; R c and R a are connected form a fused 5 or 6-membered saturated monocyclic heterocycle.
  • R b is hydrogen; R c and R a are connected to form
  • R 0 is that the hydrogen on ring A is replaced by n R 0 , n is 0 or 1, R 0 is halogen (preferably fluorine or chlorine), hydroxyl, C 1-3 alkyl, C 1-3 alkoxy, hydroxy-substituted C 1-3 alkyl, C 1-3 alkoxy-substituted C 1-3 alkyl (preferably methoxy-substituted C 1-3 alkyl), C 3 -6 cycloalkyl (preferably cyclopropyl).
  • (R 0 ) n is that the hydrogen on ring A is replaced by n R 0 , n is 0 or 1, R 0 is halogen (preferably fluorine or chlorine), C 1-3 alkyl, C 1- 3 alkoxy, hydroxy substituted C 1-3 alkyl, C 1-3 alkoxy substituted C 1-3 alkyl (preferably a methoxy group substituted by C 1-3 alkyl), C 3-6 Cycloalkyl (preferably cyclopropyl).
  • R L1 and R L2 are each independently hydrogen, hydroxyl, halogen (preferably fluorine, chlorine, more preferably fluorine), C 1-3 alkyl (preferably methyl, ethyl), C 1-3 alkoxy Group (preferably methoxy) or halo C 1-3 alkyl (preferably trifluoromethyl).
  • halogen preferably fluorine, chlorine, more preferably fluorine
  • C 1-3 alkyl preferably methyl, ethyl
  • C 1-3 alkoxy Group preferably methoxy
  • halo C 1-3 alkyl preferably trifluoromethyl
  • n is 0, 1, or 2.
  • R p is hydrogen, hydroxy, carboxy, cyano, C 1-6 alkyl (preferably C 1-3 alkyl, more preferably methyl, ethyl), halogenated C 1-6 alkyl ( Preferably it is a halogenated C 1-3 alkyl group, more preferably a trifluoromethyl group, a difluoromethyl group), a C 1-6 alkoxy group (preferably a C 1-3 alkoxy group, more preferably a methoxy group), C 3-6 cycloalkyl (preferably cyclopropyl, cyclobutyl, cyclopentyl), -SO 2 C 1-6 alkyl (preferably -SO 2 C 1-3 alkyl, more preferably -SO 2 CH 3), - (PO) (C 1-3 alkyl) 2 (preferably, - (PO) (CH 3) 2), - NHSO 2 C 1-3 alkyl (preferably -NHSO 2 CH 3), -C(O)NR a0 R
  • R p -(CR L1 R L2 ) m - is R p "'-(CH 2 ) m -; or is formula (b), formula (c), formula (d), formula (e), Structure of formula (f) or formula (g):
  • R p1 ' is hydrogen, halogen, cyano, hydroxyl, carboxy, C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, halogenated C 1 -3 alkyl, halogenated C 1-3 alkoxy, -(CH 2 ) t1 -NR a0 R b0 , -(CH 2 ) t1 -SO 2 C 1-3 alkyl, -(CH 2 ) t1- S(O)C 1-3 alkyl, -(CH 2 ) t1 -C(O)NR a0 R b0 , -(CH 2 ) t1 -C(O)OC 1-3 alkyl, -(CH 2 ) t1 -OC(O)C 1-3 alkyl, -(CH 2 ) t1 -C 3-6 cycloalkyl, C 3-6 cycloalkyloxy or -(CH 2
  • R p is hydrogen, hydroxy, carboxy, C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), halogenated C 1-8 alkyl (preferably halogenated C 1-6 alkyl, more preferably halogenated C 1-3 alkyl), halogenated C 1-8 alkoxy (preferably halogenated C 1-6 alkoxy, more preferably halogenated C 1- 3 alkoxy), C 1-8 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy), C 3-8 cycloalkyl (preferably C 3-6 Cycloalkyl), -SO 2 C 1-8 alkyl (preferably -SO 2 C 1-6 alkyl, more preferably -SO 2 C 1-3 alkyl), -SO 2 NR a0 R b0 ,- C(O)NR a0 R b0 , -C(O)NR a1 R b1 , 4 to 6-membered heterocycloalkyl or -
  • U 1 is CR U11 R U12 ;
  • U 2 is CR U21 R U22 ;
  • X 0 is O, NR 1 or CR 2 R 3 ;
  • R U11 and R U12 are each independently hydrogen; or R U11 and R U12 and the connected carbon atoms together form a 3- to 7-membered saturated or partially unsaturated monocyclic ring or a 3- to 7-membered saturated or partially unsaturated monocyclic ring; wherein The 3- to 7-membered saturated or partially unsaturated monocyclic ring and the 3- to 7-membered saturated or partially unsaturated monocyclic ring are unsubstituted or substituted with 1, 2, or 3 substituents each independently selected from the following group: Deuterium, halogen, cyano, hydroxyl, carboxyl, C 1-3 alkyl, C 1-3 alkoxy, NR a0 R b0 , halogenated C 1-3 alkyl, halogenated C 1-3 alkoxy, -SO 2 C 1-3 alkyl, -S(O)C 1-3 alkyl, -C(O)NR a0 R b0 , -C(O)C 1-3
  • R U21 and R U22 are each independently hydrogen; or R U21 and R U22 and the connected carbon atoms together form a 3 to 7-membered saturated or partially unsaturated monocyclic ring or a 3 to 7-membered saturated or partially unsaturated monocyclic ring; wherein The 3- to 7-membered saturated or partially unsaturated monocyclic ring and the 3- to 7-membered saturated or partially unsaturated monocyclic ring are unsubstituted or substituted with 1, 2, or 3 substituents each independently selected from the following group: Deuterium, halogen, cyano, hydroxyl, carboxyl, C 1-3 alkyl, C 1-3 alkoxy, NR a0 R b0 , halogenated C 1-3 alkyl, halogenated C 1-3 alkoxy, -SO 2 C 1-3 alkyl, -S(O)C 1-3 alkyl, -C(O)NR a0 R b0 , -C(O)C 1-3
  • R 1 is hydrogen, C 1-3 alkyl, -SO 2 C 1-3 alkyl, -S (O) C 1-3 alkyl, -C (O) C 1-3 alkyl, -C (O )NR a0 R b0 , -C(O)OC 1-3 alkyl, C 3-6 cycloalkyl, 3 to 6 membered heterocycloalkyl, phenyl or 5 to 6 membered heteroaryl;
  • R 2 and R 3 are each independently hydrogen, halogen, cyano, hydroxyl, carboxy, C 1-3 alkyl, C 1-3 alkoxy, NR a0 R b0 , halogenated C 1-3 alkyl, halogen Substituted C 1-3 alkoxy, -SO 2 C 1-3 alkyl, -S(O)C 1-3 alkyl, -C(O)NR a0 R b0 , -C(O)C 1-3 Alkyl, -C(O)OC 1-3 alkyl, -OC(O)C 1-3 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyloxy, 3 to 6 membered hetero Cycloalkyl, phenyl or 5- to 6-membered heteroaryl; or R 2 , R 3 and the connected carbon atoms together form a 3- to 7-membered saturated or partially unsaturated monocyclic ring or 3- to 7-membered saturated or partially unsaturated
  • R p "' is hydrogen, hydroxy, carboxy, C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), halogenated C 1-8 alkyl (preferably halogen Substituted C 1-6 alkyl, more preferably halogenated C 1-3 alkyl), halogenated C 1-8 alkoxy (preferably halogenated C 1-6 alkoxy, more preferably halogenated C 1 -3 alkoxy), C 1-8 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy), C 3-8 cycloalkyl (preferably C 3- 6 cycloalkyl), -SO 2 C 1-8 alkyl (preferably -SO 2 C 1-6 alkyl, more preferably -SO 2 C 1-3 alkyl), -SO 2 NR a0 R b0 , -C(O)NR a0 R b0 , -C(O)NR a1 R b1 , 3 to 6 membered
  • R p5 ' is hydrogen, C 1-3 alkyl, -SO 2 C 1-3 alkyl, -S(O)C 1-3 alkyl, -C(O)C 1-3 alkyl, -C( O) NR a0 R b0 , -C(O)OC 1-3 alkyl, C 3-6 cycloalkyl, 3 to 6 membered heterocycloalkyl, phenyl or 5 to 6 membered heteroaryl;
  • n1, n2, n3, n4, n5 are each independently 0, 1 or 2;
  • n1 and m2 are each independently 1, 2 or 3;
  • n3, m4, m5 are each independently 0, 1, 2 or 3; and m3, m4 are not 0 at the same time;
  • n6, m7, m8, and m9 are each independently 1 or 2.
  • formula (b) is the structure of formula (b-1), formula (b-2), formula (b-3) or formula (b-4):
  • n10, m11, m12 are each independently 1, 2 or 3;
  • n13 and m14 are each independently 0, 1 or 2; and m13 and m14 are not 0 at the same time;
  • G 1 is NR 4 or O;
  • G 2 is NR 5 or O;
  • G 3 is NR 6 or O;
  • R 4 , R 5 , and R 6 are each independently hydrogen, C 1-3 alkyl, -SO 2 C 1-3 alkyl, -S(O)C 1-3 alkyl, -C(O)C 1 -3 alkyl, -C(O)NR a0 R b0 , -C(O)OC 1-3 alkyl, C 3-6 cycloalkyl, 3 to 6 membered heterocycloalkyl, phenyl or 5 to 6 Yuan heteroaryl.
  • formula (b) is selected from:
  • formula (c) or formula (d) is selected from:
  • formula (f) is selected from:
  • the 5- to 6-membered heteroaryl group or 8- to 10-membered heteroaryl group in R p ”' is selected from:
  • heteroaryl groups are optionally substituted with 1, 2 or 3 substituents each independently selected from the following group: deuterium, halogen, cyano, hydroxyl, carboxy, C 1-3 alkyl, C 1-3 alkoxy Group, C 2-4 alkenyl, C 2-4 alkynyl, halogenated C 1-3 alkyl, halogenated C 1-3 alkoxy, NR a0 R b0 , -C(O)C 1-3 alkane Group, -SO 2 C 1-3 alkyl, -S(O)C 1-3 alkyl, -C(O)NR a0 R b0 , -C(O)OC 1-3 alkyl, -OC(O ) C 1-3 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyloxy, 3 to 6 membered heterocycloalkyl, phenyl and 5 to 6 membered heteroaryl.
  • substituents each independently selected from the following group: deuter
  • R p "'-(CH 2 ) m - is selected from:
  • (R 0 ') u is that the hydrogen on ring B is replaced by u R 0 's, u is 1 or 2, and each R 0 'is the same or different, and each independently is hydrogen, cyano, halogen ( It is preferably fluorine or chlorine) or C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl).
  • (R 0 ') u is that the hydrogen on ring B is replaced by u R 0 's, u is 2, each R 0 'is the same or different, and each independently is hydrogen, cyano, halogen (preferably Fluorine or chlorine) or C 1-3 alkyl (preferably methyl).
  • ring B is phenyl; (R 0 ') u is that the hydrogen on ring B is replaced by u R 0 's, u is 2, each R 0 'is the same or different, and each independently is a cyano group or methyl.
  • the compound has the structure shown in formula (II) or formula (III):
  • R c, R a and R b are as defined in (i); and in the formula (III) R b as (ii) defined above;
  • X 1 is O, NR 11 or CR 12 R 13 ;
  • X 2 is C(O) or CR 21 R 22 ;
  • R 11 is hydrogen or C 1-3 alkyl
  • R 12 , R 13 , R 21 , and R 22 are each independently hydrogen, halogen, C 1-3 alkyl or C 1-3 alkoxy;
  • R Z is N or CR Z ;
  • R Z is hydrogen, deuterium or C 1-3 alkyl;
  • R 1 , R 2 , R 3 , R 4 , R 5 are each independently hydrogen, cyano, acetyl, hydroxyl, carboxy, halogen (preferably fluorine or chlorine), NR a0 R b0 , C 1-8 alkyl (Preferably C 1-6 alkyl, more preferably C 1-3 alkyl), C 1-8 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy) , C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl), 3 to 6 membered heterocycloalkyl, 5 to 6 membered heteroaryl or C 6-10 aryl; wherein said C 1- 8 alkyl, C 1-8 alkoxy, C 3-8 cycloalkyl, 3 to 6 membered heterocycloalkyl, 5 to 6 membered heteroaryl and C 6-10 aryl are unsubstituted or substituted by 1 , 2 or 3 substituents independently selected from the following group: deuterium,
  • R 6 and R 7 are each independently hydrogen, deuterium, cyano, hydroxyl, halogen (preferably fluorine or chlorine), or C 1-6 alkyl.
  • R 1 is a methyl group
  • R 2 is a cyano group
  • R 3 , R 4 , and R 5 are each independently hydrogen.
  • X 1 is O.
  • X 2 is preferably C(O).
  • Z is N.
  • R 1 , R 2 , R 3 , R 4 , and R 5 are each independently hydrogen, cyano, halogen (preferably fluorine or chlorine) or C 1-8 alkyl (preferably C 1-6 alkane) Group, more preferably C 1-3 alkyl).
  • R 1 and R 2 are each independently hydrogen, cyano, halogen (preferably fluorine or chlorine) or C 1-3 alkyl (preferably methyl); R 3 , R 4 , and R 5 are each independently The ground is hydrogen.
  • R 1 is a methyl group
  • R 2 is a cyano group
  • R 3 , R 4 , and R 5 are each independently hydrogen.
  • R 6 and R 7 are each independently hydrogen.
  • the 4- to 6-membered saturated monocyclic ring is selected from azetidine, oxetane, tetrahydrofuran ring, tetrahydrothiophene ring, tetrahydropyrrole ring, piperidine ring, oxazolidine, Piperazine ring, dioxolane ring, dioxane ring, morpholine ring, thiomorpholine ring, tetrahydropyran ring, morpholin-3-one ring, piperazine-2-one ring and piperidine-2 -Ketone ring.
  • the 3 to 6-membered saturated monocyclic ring is selected from cyclopropyl ring, cyclobutyl ring, cyclopentyl ring and cyclohexyl ring.
  • the 5- to 6-membered heteroaryl group is selected from thienyl, furyl, thiazolyl, imidazolyl, oxazolyl, pyrrolyl, pyrazolyl, triazolyl, 1,2,3-triazolyl, Azolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, tetrazolyl, isoxazolyl, oxadiazolyl, 1,2 ,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, thiadiazolyl, pyridyl, pyridyl Azinyl, pyrimidinyl and pyrazinyl.
  • the 4- to 6-membered heterocycloalkyl group is selected from the group consisting of azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyrrolyl, oxazolidinyl, two Oxolane, piperidinyl, piperazinyl, morpholinyl, dioxane, thiomorpholinyl, thiomorpholine-1,1-dioxide, tetrahydropyranyl, pyrrolidine -2-keto, dihydrofuran-2(3H)-keto, morpholin-3-keto, piperazin-2-keto, and piperidin-2-keto.
  • the 5- to 8-membered heterocycloalkenyl ring is selected from: 4,5-dihydro-1H-imidazole ring, 1,4,5,6-tetrahydropyrimidine ring, 3,4,7,8 -Tetrahydro-2H-1,4,6-oxadiazosin ring, 1,6-dihydropyrimidine ring, 4,5,6,7-tetrahydro-1H-1,3-diazepine ring and 2,5,6,7-Tetrahydro-1,3,5-oxadiazepine ring.
  • the compound of formula (I) is any one of the following compounds:
  • the compound of formula (I) is any one of the following compounds:
  • the compound of formula (I) is any one of the compounds of the examples.
  • the second aspect of the present invention provides a compound represented by formula (IA), or a pharmaceutically acceptable salt, or a stereoisomer, or a solvate, or a prodrug thereof:
  • ring A, ring B, Q, L 1 , L 2 , R L1 , R L2, R p, m, (R 0 ) n , (R 0 ') u are as described above; R c , R a and R b are the definitions in (i).
  • R c, R a and R b are as defined in (i);
  • R Z is N or CR Z ;
  • R Z is hydrogen, deuterium or C 1-3 alkyl;
  • R 1 , R 2 , R 3 , R 4 , R 5 are each independently hydrogen, cyano, acetyl, hydroxyl, carboxy, halogen (preferably fluorine or chlorine), NR a0 R b0 , C 1-8 alkyl (Preferably C 1-6 alkyl, more preferably C 1-3 alkyl), C 1-8 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy) , C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl), 3 to 6 membered heterocycloalkyl, 5 to 6 membered heteroaryl or C 6-10 aryl; wherein said C 1- 8 alkyl, C 1-8 alkoxy, C 3-8 cycloalkyl, 3 to 6 membered heterocycloalkyl, 5 to 6 membered heteroaryl and C 6-10 aryl are unsubstituted or substituted by 1 , 2 or 3 substituents independently selected from the following group: deuterium,
  • R 6 and R 7 are each independently hydrogen, deuterium, cyano, hydroxyl, halogen (preferably fluorine or chlorine), or C 1-6 alkyl.
  • Z is N.
  • R 1 , R 2 , R 3 , R 4 , and R 5 are each independently hydrogen, cyano, halogen (preferably fluorine or chlorine) or C 1-8 alkyl (preferably C 1-6 alkane) Group, more preferably C 1-3 alkyl).
  • R 1 and R 2 are each independently hydrogen, cyano, halogen (preferably fluorine or chlorine) or C 1-3 alkyl (preferably methyl); R 3 , R 4 , and R 5 are each independently The ground is hydrogen.
  • R 1 is a methyl group
  • R 2 is a cyano group
  • R 3 , R 4 , and R 5 are each independently hydrogen.
  • R 6 and R 7 are each independently hydrogen.
  • the compound of formula (IA) is any one of the following compounds:
  • the third aspect of the present invention provides a pharmaceutical composition, which comprises the compound described in the first and second aspects of the present invention, or a pharmaceutically acceptable salt thereof, or a stereoisomer or a solvate thereof, Or a prodrug thereof, and a pharmaceutically acceptable carrier.
  • the fourth aspect of the present invention provides the compound described in the first aspect and the second aspect of the present invention, or a pharmaceutically acceptable salt, or a stereoisomer, or a solvate thereof, or a prodrug thereof, and the first aspect of the present invention.
  • the fifth aspect of the present invention provides a method for preventing and/or treating diseases mediated by adenosine A 2A receptor and/or adenosine A 2B receptor, comprising administering to a patient in need a therapeutically effective amount of the first of the present invention
  • the compound of the aspect and the second aspect, or a pharmaceutically acceptable salt thereof, or a stereoisomer, or a solvate thereof, or a prodrug thereof, or the pharmaceutical composition according to the third aspect of the present invention is a method for preventing and/or treating diseases mediated by adenosine A 2A receptor and/or adenosine A 2B receptor.
  • the disease is mediated by the adenosine A 2A receptor.
  • the disease is mediated by the adenosine A 2B receptor.
  • the disease is mediated by both adenosine A 2A receptor and A 2B receptor.
  • the disease is cancer.
  • the cancer is selected from prostate cancer, colon cancer, rectal cancer, pancreatic cancer, cervical cancer, stomach cancer, endometrial cancer, brain cancer, liver cancer, bladder cancer, ovarian cancer, testicular cancer, head cancer, Neck cancer, melanoma, basal cancer, inner mesothelial cancer, leukocyte cancer, esophageal cancer, breast cancer, muscle cancer, connective tissue cancer, small cell lung cancer, non-small cell lung cancer, adrenal cancer, thyroid cancer, kidney cancer And bone cancer; or malignant glioma, mesothelioma, renal cell carcinoma, gastric cancer, sarcoma, choriocarcinoma, skin basal cell carcinoma and testicular seminoma.
  • the cancer is selected from melanoma, colorectal cancer, pancreatic cancer, breast cancer, prostate cancer, small cell lung cancer, non-small cell lung cancer, leukemia, brain tumor, lymphoma, ovarian cancer, Kaposi Sarcoma, renal cell carcinoma, head and neck cancer and esophageal cancer.
  • the disease is an immune-related disease.
  • the immune-related disease is selected from rheumatoid arthritis, renal failure, lupus, asthma, psoriasis, colitis, pancreatitis, allergy, fibrosis, anemic fibromyalgia, Alzheimer's Disease, congestive heart failure, stroke, aortic valve stenosis, arteriosclerosis, osteoporosis, Parkinson's disease, infection, Crohn's disease, ulcerative colitis, allergic contact dermatitis and other eczema, Systemic sclerosis and multiple sclerosis.
  • the inventors unexpectedly discovered such substituted pyrimidine or pyridine amine derivatives, which have significant adenosine A 2A receptor and/or adenosine A 2B receptor activity. Therefore, the series of compounds are expected to be developed as drugs for the treatment and prevention of related diseases mediated by adenosine A 2A receptor and/or adenosine A 2B receptor. On this basis, the inventor completed the present invention.
  • Alkyl refers to linear and branched saturated aliphatic hydrocarbon groups.
  • C 1-8 alkyl refers to an alkyl group having 1 to 8 carbon atoms, preferably a C 1-6 alkyl group, more preferably a C 1-3 alkyl group; non-limiting examples of the alkyl group include: Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethyl Propyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-di
  • Alkynyl refers to straight-chain and branched unsaturated aliphatic hydrocarbon groups with one or more carbon-carbon triple bonds
  • C 2-8 alkynyl refers to alkynyl groups with 2 to 8 carbon atoms, preferably C 2-6 alkynyl, more preferably C 2-4 alkynyl, with similar definitions; non-limiting examples include ethynyl, propynyl, n-butynyl, isobutynyl, pentynyl, hexynyl, etc. .
  • Cycloalkyl and “cycloalkyl ring” are used interchangeably, and both refer to a saturated monocyclic, bicyclic or polycyclic cyclic hydrocarbon group, which may be fused with an aryl group or a heteroaryl group.
  • the cycloalkyl ring may be optionally substituted.
  • the cycloalkyl ring contains one or more carbonyl groups, such as oxo groups.
  • C 3-8 cycloalkyl refers to a monocyclic cycloalkyl having 3 to 8 carbon atoms.
  • Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, Cycloheptyl, cyclooctyl, cyclobutanone, cyclopentanone, cyclopentane-1,3-dione, etc. It is preferably a C 3-6 cycloalkyl group, including cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • C 8-10 cycloalkyl refers to a fused bicyclic cyclic hydrocarbon group having 8 to 10 ring atoms.
  • Non-limiting examples of C 8-10 cycloalkyl include
  • Spirocyclyl and “spirocyclic” can be used interchangeably, and both refer to a polycyclic cyclic hydrocarbon group sharing one carbon atom (called a spiro atom) between single rings.
  • “7 to 11 membered spirocyclic group” refers to a spiro ring having 7 to 11 ring atoms. According to the number of rings, spiro rings are classified into double spiro rings or multi spiro rings, preferably double spiro rings. More preferably, it is preferably a 4-membered/5-membered, 5-membered/5-membered or 5-membered/6-membered bispiro ring. E.g:
  • Cycloalkenyl and “cycloalkenyl ring” are used interchangeably, and both refer to a monocyclic, bicyclic or polycyclic cyclic hydrocarbon group containing one or more carbon-carbon double bonds in the ring. This group can be combined with an aryl group or Heteroaryl groups are fused.
  • the cycloalkenyl ring may be optionally substituted.
  • the cycloalkenyl ring contains one or more carbonyl groups, such as oxo groups.
  • the "C 3-8 cycloalkenyl group” refers to a monocyclic cycloalkenyl group having 3 to 8 carbon atoms.
  • cycloalkenyl groups include cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, cyclopentyl-2-en-1-one, cyclopentenyl Hexyl-2,5-dien-1-one, cyclohexyl-2-en-1-one, cyclohex-2-ene-1,4-dione, etc.
  • Heterocycloalkyl and “heterocycloalkyl ring” are used interchangeably, and both refer to a cycloalkyl group containing at least one heteroatom selected from nitrogen, oxygen, and sulfur. This group can be combined with an aryl or heteroaryl group. Fused.
  • the heterocycloalkyl ring may be optionally substituted.
  • the heterocycloalkyl ring contains one or more carbonyl or thiocarbonyl groups, such as groups containing oxo and thio groups.
  • 3 to 8 membered heterocycloalkyl refers to a monocyclic cyclic hydrocarbon group having 3 to 8 ring atoms, of which 1, 2 or 3 ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, preferably 4 To 8-membered heterocycloalkyl. More preferably, it is a 3- to 6-membered heterocycloalkyl group, which has 3 to 6 ring atoms, of which 1 or 2 ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur. More preferably, it is a 4- to 6-membered heterocycloalkyl group, which has 4 to 6 ring atoms, of which 1 or 2 ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur.
  • Non-limiting examples of monocyclic heterocycloalkyl groups include aziridine, oxiranyl, azetidinyl, oxetanyl, tetrahydrofuran, tetrahydrothienyl, tetrahydropyrrolyl , Oxazolidinyl, dioxolane, piperidinyl, piperazinyl, morpholinyl, dioxane, thiomorpholinyl, thiomorpholine-1,1-dioxide, tetra Hydropyranyl, azetidine-2-keto, oxetane-2-keto, dihydrofuran-2(3H)-keto, pyrrolidin-2-keto, pyrrolidine- 2,5-diketo, dihydrofuran-2,5-diketo, piperidin-2-on, tetrahydro-2H-pyran-2-on, piperazin-2-on Lin-3-one group and so on.
  • 6 to 12 membered heterocycloalkyl and “6 to 12 membered fused heterocycloalkyl” are used interchangeably and refer to having 6 to 12 ring atoms, of which 1, 2 or 3 ring atoms are selected from Condensed bicyclic cyclic hydrocarbon groups of nitrogen, oxygen and sulfur heteroatoms.
  • 8 to 10 membered heterocycloalkyl and “8 to 10 membered fused heterocycloalkyl” are used interchangeably and refer to having 8 to 10 ring atoms, of which 1, 2 or 3 ring atoms are selected from Condensed bicyclic cyclic hydrocarbon groups of nitrogen, oxygen and sulfur heteroatoms.
  • Non-limiting examples of bicyclic heterocycloalkyl groups include hexahydro-1H-furan[3,4-c]pyrrole, octahydro-1H-cyclopenta[c]pyridine, hexahydro-1H-pyrrolo[2,1 -c][1,4]oxazine, octahydropyrrolo[1,2-a]pyrazine, hexahydropyrrolo[1,2-a]pyrazine-4(1H)-one, octahydrocyclopenta [c] Pyrrole and others.
  • bicyclic heterocycloalkyl group containing one or more nitrogen atoms the point of attachment may be a carbon or nitrogen atom as long as the valence permits.
  • Bicyclic heterocycloalkyl systems can include one or more heteroatoms in one or two rings.
  • Heterospirocyclic group and “heterospirocyclic ring” can be used interchangeably and refer to a monovalent non-aromatic ring system with two monocyclic rings sharing one carbon atom, which consists of carbon atoms and selected from nitrogen, oxygen, and sulfur. It is composed of phosphorus heteroatoms, does not contain unsaturation, and is connected to the core through a single bond.
  • the heterospiro ring can be optionally substituted.
  • the heterospiro ring contains one or more carbonyl or thiocarbonyl groups, such as oxo and thio-containing groups.
  • the "7 to 11 membered heterospirocyclyl” refers to a heterospirocyclyl having 7 to 11 ring atoms, of which 1, 2 or 3 ring atoms are heteroatoms.
  • Non-limiting examples of heterospirocyclic groups include 2,6-diazaspirocyclo[3.4]octan-5-one, 2-oxo-6-azaspirocyclo[3.3]heptyl, 6- Oxaspiro[3.3]heptane-2-yl, 7-methyl-7-azaspiro[3.5]nonane-2-yl, 7-methyl-2,7-diazespiro[3.5]non Alk-2-yl, 9-methyl-9-phosphinospiro[5.5]undec-3-yl and the like.
  • Heterocycloalkenyl and “heterocycloalkenyl ring” are used interchangeably and refer to a heterocycloalkyl group containing one or more carbon-carbon double bonds or carbon-nitrogen double bonds in the ring, but is not intended to include such as Heteroaryl moiety as defined herein. This group may be fused with an aryl group or a heteroaryl group.
  • the heterocycloalkenyl ring may be optionally substituted.
  • the heterocycloalkenyl ring contains one or more carbonyl or thiocarbonyl groups, such as groups containing oxo and thio groups.
  • the "5- to 8-membered heterocycloalkenyl ring” refers to a heterocycloalkenyl ring having 5 to 8 ring atoms, of which 1, 2, or 3 ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur. Preferably it is a 5- to 6-membered heterocycloalkenyl ring.
  • heterocyclenyl rings include 4,5-dihydro-1H-imidazole ring, 1,4,5,6-tetrahydropyrimidine ring, 3,4,7,8-tetrahydro-2H- 1,4,6-oxadiazolazine ring, 1,6-dihydropyrimidine ring, 4,5,6,7-tetrahydro-1H-1,3-diazepine ring, 2,5,6, 7-Tetrahydro-1,3,5-oxadiazepine ring.
  • Aryl and “aromatic ring” are used interchangeably, and both refer to all-carbon monocyclic or fused polycyclic (that is, rings that share adjacent pairs of carbon atoms) groups with a conjugated ⁇ -electron system. It can be condensed with a cycloalkyl ring, a heterocycloalkyl ring, a cycloalkenyl ring, a heterocycloalkenyl ring, or a heteroaryl group.
  • the "C 6-10 aryl group” refers to a monocyclic or bicyclic aryl group having 6 to 10 carbon atoms, and non-limiting examples of the aryl group include phenyl, naphthyl, and the like.
  • Heteroaryl and “heteroaryl ring” are used interchangeably, and both refer to a monocyclic, bicyclic or polycyclic 4n+2 aromatic ring system with ring carbon atoms and ring heteroatoms (for example, having a ring Arrange shared 6 or 10 ⁇ electrons) groups, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur.
  • the heteroaryl group also includes a ring system in which the above-mentioned heteroaryl ring is fused with one or more cycloalkyl rings, heterocycloalkyl rings, cycloalkenyl rings, heterocycloalkenyl rings or aromatic rings.
  • the heteroaryl ring can be optionally substituted.
  • the "5- to 10-membered heteroaryl group” refers to a monocyclic or bicyclic heteroaryl group having 5 to 10 ring atoms, of which 1, 2, 3, or 4 ring atoms are heteroatoms.
  • “5 to 6 membered heteroaryl group” refers to a monocyclic heteroaryl group having 5 to 6 ring atoms, of which 1, 2, 3 or 4 ring atoms are heteroatoms.
  • Non-limiting examples include thienyl, furan Group, thiazolyl, isothiazolyl, imidazolyl, oxazolyl, pyrrolyl, pyrazolyl, triazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2 ,5-triazolyl, 1,3,4-triazolyl, tetrazolyl, isoxazolyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazole Azolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, tetrazine base.
  • 8 to 10 membered heteroaryl group refers to a bicyclic heteroaryl group having 8 to 10 ring atoms, of which 1, 2, 3 or 4 ring atoms are heteroatoms.
  • Non-limiting examples include indolyl, iso Indolyl, indazolyl, benzotriazolyl, benzothienyl, isobenzothienyl, benzofuranyl, benzisofuranyl, benzimidazolyl, benzoxazolyl, benziso Oxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazole, indenazinyl, purinyl, pyrido[3,2-d]pyrimidinyl, pyrido [2,3-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrido[4,3-d]pyrimidinyl, 1,8-naphthy
  • Heteroatom refers to nitrogen, oxygen, or sulfur. In heteroaryl groups containing one or more nitrogen atoms, as long as the valence allows, the point of attachment may be a carbon or nitrogen atom. Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings.
  • “Fused” refers to a structure in which two or more rings share one or more bonds.
  • Phenyl heterocycloalkyl refers to a group in which a benzene ring and a heterocycloalkyl ring are fused to form a bicyclic, tricyclic or polycyclic ring system, wherein the heterocycloalkyl ring is as defined above.
  • “7 to 11 membered phenyl and heterocycloalkyl” refers to a bicyclic cyclic group having 7 to 11 ring atoms, of which 1, 2, 3 or 4 ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur .
  • it is an 8- to 10-membered phenyl and heterocycloalkyl group, which has 8 to 10 ring atoms, of which 1, 2 or 3 ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur.
  • Non-limiting examples include indoline, benzo[d][1,3]dioxazole, 1,2,3,4-tetrahydroisoquinoline, 3,4-dihydro-2H-benzo[ b][1,4]oxazine and the like.
  • Heteroaryl and heterocycloalkyl refers to a group in which a heteroaryl ring and a heterocycloalkyl ring are fused to form a bicyclic, tricyclic or polycyclic ring system, wherein the heterocycloalkyl ring is as defined above.
  • “7 to 11 membered heteroaryl and heterocycloalkyl” refers to a bicyclic cyclic group having 7 to 11 ring atoms, of which 1, 2, 3 or 4 ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur group.
  • Non-limiting examples include 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine, [1,3]dioxolane[4,5-b]pyridine, 2,3-dihydro -1H-pyrido[3,4-b][1,4]oxazine, 2,3,4,6-tetrahydropyrrolo[3,4-b][1,4]oxazine, 2,4 ,5,6-Tetrahydropyrano[2,3-c]pyrazole, 5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine, etc.
  • Alkoxy refers to -O-alkyl, where alkyl is as defined above.
  • a C 1-8 alkoxy group is preferred, a C 1-6 alkoxy group is more preferred, and a C 1-3 alkoxy group is most preferred.
  • Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, butoxy, tert-butoxy, isobutoxy, pentoxy, and the like.
  • Cycloalkyloxy refers to -O-cycloalkyl, where cycloalkyl is as defined above. A C 3-8 cycloalkyloxy group is preferable, and a C 3-6 cycloalkyloxy group is more preferable. Non-limiting examples include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and the like.
  • a bond means that the two groups connected by it are connected by a covalent bond.
  • Halogen refers to fluorine, chlorine, bromine or iodine.
  • Halo refers to the replacement of one or more (such as 1, 2, 3, 4, or 5) hydrogens in a group by halogen.
  • halo C 1-8 alkyl means that an alkyl group is substituted with one or more (such as 1, 2, 3, 4, or 5) halogens, where the definition of the alkyl group is as described above. It is selected as a halogenated C 1-6 alkyl group, more preferably a halogenated C 1-3 alkyl group.
  • halogenated C 1-8 alkyl examples include (but are not limited to) monochloromethyl, dichloromethyl, trichloromethyl, monochloroethyl, 1,2-dichloroethyl, trichloroethyl, Monobromoethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, etc.
  • halogenated C 1-8 alkoxy means that the alkoxy group is substituted with one or more (such as 1, 2, 3, 4, or 5) halogens, wherein the definition of alkoxy is as described above. It is preferably a halogenated C 1-6 alkoxy group, and more preferably a halogenated C 1-3 alkoxy group. Including (but not limited to) trifluoromethoxy, trifluoroethoxy, monofluoromethoxy, monofluoroethoxy, difluoromethoxy, difluoroethoxy and the like.
  • halogenated C 3-8 cycloalkyl refers to cycloalkyl substituted with one or more (such as 1, 2, 3, 4, or 5) halogens, wherein the definition of cycloalkyl is as described above. Preferably, it is a halogenated C 3-6 cycloalkyl group. Including (but not limited to) trifluorocyclopropyl, monofluorocyclopropyl, monofluorocyclohexyl, difluorocyclopropyl, difluorocyclohexyl and the like.
  • Deuterated C 1-8 alkyl refers to an alkyl group substituted with one or more (such as 1, 2, 3, 4, or 5) deuterium atoms, wherein the definition of the alkyl group is as described above. It is preferably a deuterated C 1-6 alkyl group, and more preferably a deuterated C 1-3 alkyl group. Examples of deuterated C 1-8 alkyl groups include (but are not limited to) mono-deuterated methyl, mono-deuterated ethyl, di-deuterated methyl, di-deuterated ethyl, tri-deuterated methyl, tri-deuterated ethyl Base and so on.
  • Amino refers to NH 2
  • cyano refers to CN
  • nitro refers to NO 2
  • benzyl refers to -CH 2 -phenyl
  • oxo O
  • carboxy refers to -C (O)OH
  • acetyl refers to -C(O)CH 3
  • hydroxymethyl refers to -CH 2 OH
  • hydroxyethyl refers to -CH 2 CH 2 OH or -CHOHCH 3
  • hydroxy refers to -OH
  • thiol refers to SH
  • the structure of "cyclopropylene” is:
  • “Saturated or partially unsaturated monocyclic ring” refers to a saturated or partially unsaturated all-carbon monocyclic ring system, wherein “partially unsaturated” refers to a ring portion including at least one double or triple bond, and “partially unsaturated” is intended to cover Rings with multiple sites of unsaturation, but are not intended to include aryl or heteroaryl moieties as defined herein.
  • the saturated or partially unsaturated monocyclic ring contains one or more carbonyl groups, such as oxo groups.
  • a "3- to 7-membered saturated or partially unsaturated monocyclic ring” has 3 to 7 ring carbon atoms, preferably a saturated or partially unsaturated monocyclic ring having 3 to 6 ring carbon atoms, more preferably 3 to 6 ring carbon atoms The saturated monocyclic ring.
  • Non-limiting examples of saturated or partially unsaturated monocyclic rings include cyclopropyl ring, cyclobutyl ring, cyclopentyl ring, cyclopentenyl ring, cyclohexyl ring, cyclohexenyl ring, cyclohexadienyl ring, Cycloheptyl ring, cycloheptatrienyl ring, cyclopentanone ring, cyclopentane-1,3-dione ring, etc.
  • “Saturated or partially unsaturated monocyclic heterocyclic ring” means that 1, 2 or 3 ring carbon atoms in a saturated or partially unsaturated monocyclic ring are selected from nitrogen, oxygen or S(O) t (where t is an integer from 0 to 2 ), but does not include the ring part of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon.
  • the "3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring” has 3 to 7 ring atoms, of which 1, 2 or 3 ring atoms are the aforementioned heteroatoms.
  • Non-limiting examples of saturated monocyclic rings include propylene oxide ring, azetidine ring, oxetane ring, tetrahydrofuran ring, tetrahydrothiophene ring, tetrahydropyrrole ring, piperidine ring, pyrroline ring , Oxazolidine ring, piperazine ring, dioxolane ring, dioxane ring, morpholine ring, thiomorpholine ring, thiomorpholine-1,1-dioxide, tetrahydropyran ring, nitrogen Etidine-2-one ring, oxetan-2-one ring, pyrrolidin-2-one ring, pyrrolidine-2,5-dione ring, piperidin-2-one ring, dihydro Furan-2(3H)-one ring, dihydrofuran-2,5-dione ring, tetrahydro-2H-pyran-2
  • Non-limiting examples of partially unsaturated monocyclic heterocycles include 1,2-dihydroazetadiene ring, 1,2-dihydrooxetadiene ring, 2,5-dihydro-1H- Pyrrole ring, 2,5-dihydrofuran ring, 2,3-dihydrofuran ring, 2,3-dihydro-1H-pyrrole ring, 3,4-dihydro-2H-pyran ring, 1,2, 3,4-tetrahydropyridine ring, 3,6-dihydro-2H-pyran ring, 1,2,3,6-tetrahydropyridine ring, 4,5-dihydro-1H-imidazole ring, 1,4 ,5,6-tetrahydropyrimidine ring, 3,4,7,8-tetrahydro-2H-1,4,6-oxadiazosin ring, 1,6-dihydropyrimidine ring, 4,5,6, 7-Tetrahydro-1H-1
  • Substituted refers to one or more hydrogen atoms in the group, preferably 1 to 5 hydrogen atoms are independently replaced by a corresponding number of substituents, more preferably 1 to 3 hydrogen atoms are independently replaced by a corresponding number of substituents.
  • the substituents are substituted. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without too much effort. For example, an amino group or a hydroxyl group having free hydrogen may be unstable when combined with a carbon atom having an unsaturated (e.g., olefinic) bond.
  • substituted by a substituent means that when more than one hydrogen on a group is substituted by a substituent, the types of the substituents may be the same or different, so The selected substituents are of independent types.
  • L is (CR 01 R 02 ) s , when s is 2, that is, L is (CR 01 R 02 )-(CR 01 R 02 ), and the two R 01 or R 02 can be the same or different.
  • L can be C(CH 3 )(CN)-C(CH 2 CH 3 )(OH), C(CH 3 )(CN)-C(CH 3 )(OH) or C(CN) (CH 2 CH 3 )-C(OH)(CH 2 CH 3 ).
  • any group herein may be substituted or unsubstituted.
  • the substituents are preferably 1 to 5 or less groups, independently selected from cyano, halogen (preferably fluorine or chlorine), C 1-8 alkyl (preferably C 1-6 alkyl, more Preferably C 1-3 alkyl), C 1-8 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy), halogenated C 1-8 alkyl (preferably halogenated C 1-6 alkyl, more preferably halogenated C 1-3 alkyl), C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl), halogenated C 1-8 alkoxy (preferably halogenated C 1-6 alkoxy, more preferably halogenated C 1-3 alkoxy), C 1-8 alkyl substituted amino, halogenated C 1-8 alkyl substituted amino, acetyl, hydroxyl, hydroxymethyl , Hydroxyethyl, carboxy
  • the compound of the present invention can be administered in a suitable dosage form with one or more pharmaceutically acceptable carriers.
  • These dosage forms are suitable for oral, rectal, topical, intraoral, and other parenteral administration (for example, subcutaneous, intramuscular, intravenous, etc.).
  • dosage forms suitable for oral administration include capsules, tablets, granules, and syrups.
  • the compounds of the present invention contained in these formulations may be solid powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; water-in-oil or oil-in-water emulsions, and the like.
  • the above-mentioned dosage forms can be prepared from the active compound and one or more carriers or excipients through common pharmacological methods.
  • the above-mentioned carrier needs to be compatible with the active compound or other excipients.
  • commonly used non-toxic carriers include but are not limited to mannitol, lactose, starch, magnesium stearate, cellulose, glucose, sucrose and the like.
  • Carriers used in liquid preparations include water, physiological saline, aqueous dextrose, ethylene glycol, polyethylene glycol, and the like.
  • the active compound can form a solution or a suspension with the aforementioned carriers.
  • “Pharmaceutically acceptable carrier” refers to a non-toxic, inert, solid, semi-solid substance or liquid filling machine, diluent, packaging material or auxiliary preparation or any type of excipient, which is compatible with the patient, preferably breastfeeding Animals, more preferably humans, are suitable for delivering the active agent to the target target without terminating the activity of the agent.
  • the active substance of the present invention or “the active compound of the present invention” refers to the compound of formula (I)/formula (IA) of the present invention, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a stereoisomer thereof , Or a prodrug thereof, which has adenosine A 2A receptor and/or adenosine A 2B receptor activity.
  • composition of the present invention is formulated, quantified and administered in a manner conforming to medical practice standards.
  • the "therapeutically effective amount" of the compound to be administered is determined by factors such as the specific condition to be treated, the individual to be treated, the cause of the condition, the target of the drug, and the mode of administration.
  • “Therapeutically effective amount” refers to the amount of the compound of the present invention that will cause a biological or medical response of an individual, such as reducing or inhibiting enzyme or protein activity or improving symptoms, alleviating symptoms, slowing or delaying disease progression, or preventing disease.
  • the pharmaceutical composition of the present invention or the therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a stereoisomer thereof, or a prodrug thereof contained in the pharmaceutical composition of the present invention Preferably it is 0.1mg-5g/kg (body weight).
  • Patient refers to an animal, preferably a mammal, more preferably a human.
  • mammal refers to warm-blooded spinal mammals, including cats, dogs, rabbits, bears, foxes, wolves, monkeys, deer, rats, pigs, and humans.
  • Treatment refers to reducing, delaying progression, attenuating, preventing, or maintaining an existing disease or condition (e.g., cancer). Treatment also includes curing one or more symptoms of the disease or condition, preventing its development, or alleviating to a certain degree.
  • the “pharmaceutically acceptable salt” includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
  • “Pharmaceutically acceptable acid addition salt” refers to a salt formed with an inorganic acid or an organic acid that can retain the biological effectiveness of the free base without other side effects.
  • Inorganic acid salts include, but are not limited to, hydrochloride, hydrobromide, sulfate, phosphate, etc.
  • organic acid salts include, but are not limited to, formate, acetate, propionate, glycolate, and gluconate , Lactate, oxalate, maleate, succinate, fumarate, tartrate, citrate, glutamate, aspartate, benzoate, methanesulfonate , P-toluenesulfonate and salicylate, etc.
  • These salts can be prepared by methods known in the art.
  • “Pharmaceutically acceptable base addition salts” include, but are not limited to, salts of inorganic bases such as sodium, potassium, calcium and magnesium salts. Including but not limited to salts of organic bases, such as ammonium salt, triethylamine salt, lysine salt, arginine salt and the like. These salts can be prepared by methods known in the art.
  • solvate refers to a complex formed by the compound of the present invention and a solvent. They either react in a solvent or precipitate or crystallize out of the solvent. For example, a complex formed with water is called a "hydrate”. Solvates of the compound of formula (I) fall within the scope of the present invention.
  • the compound represented by formula (I) of the present invention may contain one or more chiral centers and exist in different optically active forms.
  • a compound contains a chiral center
  • the compound contains enantiomers.
  • the present invention includes these two isomers and mixtures of isomers, such as racemic mixtures. Enantiomers can be resolved by methods known in the art, such as crystallization and chiral chromatography.
  • diastereomers may exist.
  • the present invention includes the resolved optically pure specific isomers and mixtures of diastereomers. Diastereomers can be resolved by methods known in the art, such as crystallization and preparative chromatography.
  • the present invention includes prodrugs of the aforementioned compounds.
  • Prodrugs include known amino protecting groups and carboxyl protecting groups, which are hydrolyzed under physiological conditions or released through enzymatic reactions to obtain the parent compound.
  • Specific preparation methods of prodrugs please refer to (Saulnier, MG; Frennesson, DB; Deshpande, MS; Hansel, SB and Vysa, DMBioorg. Med. Chem Lett. 1994, 4, 1985-1990; and Greenwald, RB; Choe, YH; Conover, CD; Shum, K.; Wu, D.; Royzen, MJ Med. Chem. 2000, 43, 475.).
  • the present invention provides a method for preparing the compound of formula (I).
  • the compound of formula (I) can be synthesized using standard synthesis techniques known to those skilled in the art or using methods known in the art in combination with the method described in the present invention.
  • the solvent, temperature and other reaction conditions given in the present invention can be changed according to the skill in the art.
  • the reactions can be used sequentially to provide the compounds of the invention, or they can be used to synthesize fragments that are subsequently added by the methods described in the invention and/or methods known in the art.
  • the compounds described in the present invention can be synthesized by using appropriate optional starting materials using methods similar to those described below or exemplary methods described in the Examples, or related publications used by those skilled in the art.
  • the starting materials used to synthesize the compounds described in this invention can be synthesized or can be obtained from commercial sources.
  • the compounds described in the present invention and other related compounds with different substituents can be synthesized using techniques and raw materials known to those skilled in the art.
  • the general method for preparing the compound disclosed in the present invention can be derived from a reaction known in the art, and the reaction can be modified by reagents and conditions deemed appropriate by those skilled in the art to introduce various moieties in the molecule provided by the present invention.
  • a series of substituted pyrimidine or pyridine amine derivatives with novel structures are provided, which have high inhibitory activity on adenosine A 2A receptor and/or adenosine A 2B receptor, with IC 50 value less than 100 nM, more preferably less than 50 nM , More preferably less than 10 nM, so it can be used as a medicine for the treatment of cancer or other immune-related diseases.
  • LC-MS Agilent 1200 HPLC System/6140 MS liquid mass spectrometer (manufacturer: Agilent), column WatersX-Bridge, 150 ⁇ 4.6mm, 3.5 ⁇ m.
  • Preparative high performance liquid chromatography Waters PHW007, column XBridge C18, 4.6*150mm, 3.5um.
  • ISCO Combiflash-Rf75 or Rf200 type automatic column instrument Agela 4g, 12g, 20g, 40g, 80g, 120g disposable silica gel column.
  • the known starting materials can be synthesized by or according to methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc. and Darui Chemicals, etc. company.
  • DMF dimethylformamide
  • DMSO dimethyl sulfoxide
  • THF tetrahydrofuran
  • CAN acetonitrile
  • DIEA N,N-diisopropylethylamine
  • EA ethyl acetate
  • PE petroleum ether
  • BINAP (2R,3S)-2,2'-bisdiphenylphosphino-1,1'-binaphthyl
  • NBS N-bromosuccinimide
  • NCS N-chlorosuccinimide
  • Pd 2 (dba) 3 Tris(dibenzylideneacetone) two palladium
  • Pd(dppf)Cl 2 [1,1'-bis(diphenylphosphorus) ferrocene] palladium dichloride
  • DPPA stacked Diphenyl nitrogen phosphate
  • DBU 1,8-diazabicycloundec-7-ene
  • TBAF tetrabut
  • room temperature refers to about 20-30°C.
  • Step 1 The raw material methyl 6-(hydroxymethyl)picolinate (25g, 149.70mmol) was added to dry THF (400mL), the reaction mixture was cooled to 0°C and the THF solution of methylmagnesium bromide was added dropwise ( 1M, 598.80ml, 598.80mmol), after the addition was completed, the reaction solution was naturally warmed to room temperature and stirred for 18 hours.
  • Step 2 Dissolve the compound 2-(6-(hydroxymethyl)pyridin-2-yl)propan-2-ol (400mg, 2.39mmol) in 20mL DCM, add DPPA (790mg, 2.87mmol), DBU (437mg , 2.87mmol), the reaction solution was stirred at room temperature overnight. LC-MS detected that the reaction was complete. The above reaction solution was added to 100 mL of water, extracted with dichloromethane (50 mL*2), dried over anhydrous sodium sulfate, concentrated under reduced pressure to dryness, and separated and purified by silica gel column to obtain compound V4 (350 mg, P: 100%, Y: 76%). MS (ESI) 193 [M+H] + .
  • Step 1 2-(6-(Hydroxymethyl)pyridin-2-yl)propan-2-ol (1.5g, 8.98mmol), triethylamine (1814mg, 17.96mmol) were dissolved in 15mL of dichloromethane and dissolved Methanesulfonyl chloride (1536 mg, 13.47 mmol) in 20 mL of dichloromethane was slowly added dropwise under ice bath conditions. After the addition was completed, the reaction solution could be slowly raised to room temperature and stirred for 1 hour.
  • reaction solution was extracted with dichloromethane (15mL*3), washed with 20mL of water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a colorless oily liquid product (6-(2-hydroxyprop-2-yl)pyridine-2) -Methyl) methanesulfonate (2.4 g, P: 50%, Y: 54.5%) crude product MS (ESI) 246 [M+H] + .
  • Step 2 (6-(2-Hydroxyprop-2-yl)pyridin-2-yl)methyl methanesulfonate (2.4g, 4.9mmol), 4-(4,4,5,5-tetramethyl- 1,3,2-Dioxaboroborin-2-yl)-1H-pyrazole (1426 mg, 7.35 mmol), cesium carbonate (3195 mg, 9.8 mmol) were dissolved in 20 mL of acetonitrile, and stirred at 70°C for 4 hours.
  • intermediates V6 and V7 can be prepared.
  • Step 1 2,4,6-Trichloro-5-fluoropyrimidine 1-1 (2.0g, 9.93mmol), triisopropylsilylacetylene (1.8g, 9.93mmol), triethylamine (3.01g, 3.00 mmol) was dissolved in 25mL tetrahydrofuran, the temperature was reduced to 0°C under argon protection, CuI (378mg, 1.99mmol) and Pd(PPh 3 ) 2 Cl 2 (697mg, 0.99mmol) were added, and then the temperature was raised to room temperature to react for 3 hours. Compound 1-2 (3.44 g) MS(ESI) 347 [M+H] + was obtained .
  • Step 2 Add 10 mL of aqueous ammonia (80% concentration) to 25 mL of the above tetrahydrofuran reaction solution in which compound 1-2 (3.44 g, 9.93 mmol) is dissolved, and stir at room temperature for 2 days.
  • LC-MS detects that the reaction is complete.
  • the above reaction solution was added to 300mL of water, extracted with dichloromethane (100mL*2), dried over anhydrous sodium sulfate, concentrated under reduced pressure to dryness, and separated and purified by silica gel column to obtain compound 1-3 (2.30g, Y: 71%) ) MS(ESI)328.1[M+H] + .
  • Step 3 Compound 1-3 (500mg, 1.52mmol), compound V1 (408mg, 1.68mmol) were dissolved in a mixed solvent of 15mL of acetonitrile and 4mL of water, and Pd(PPh 3 ) 2 Cl 2 (107mg, 0.152mmol) was added, KHCO 3 (611 mg, 6.10 mmol), the reaction solution was heated to 95° C. and stirred overnight under the protection of nitrogen. LC-MS detected that the reaction was complete.
  • Step 4 Compound 1-4 (70mg, 0.171mmol) was added to 2mL of tetrahydrofuran, the temperature was reduced to 0°C, 0.2mL of TBAF tetrahydrofuran solution (1.0mol/L) was slowly added, and the reaction solution was stirred at room temperature for 30 minutes to obtain compound 1- 5(43mg, yield: 100%) MS(ESI)253.1[M+H]+
  • Step 5 Compound 1-5 (43mg, 0.17mmol) and Intermediate V4 (33mg, 0.17mmol) were added to a mixed solvent of 5mL of tert-butanol and 1.5mL of water, and Cu 2 SO 4 .5H was added under the protection of argon. 2 O (12mg, 0.051mmol), sodium ascorbate (20mg, 0.102mmol), heated to 40 degrees and reacted for 40 minutes, LC-MS detected that the reaction was complete.
  • reaction solution was poured into water, extracted with dichloromethane (50mL*2), dried over anhydrous sodium sulfate, concentrated under reduced pressure to dryness, and separated and purified by high performance liquid phase preparation to obtain white solid compound L-1 (4.39mg, yield: 6%).
  • Step 1 Metal sodium (1.4g, 23.12mmol) was slowly added to 15mL of absolute ethanol in batches, heated to 80°C under argon protection, and reacted for 2 hours, then cooled to room temperature, and compound guanidine carbonate (2.8g, 23.12mmol) was added , Heat to 80°C and react for 30 minutes. After cooling to room temperature, add dimethyl 2-fluoromalonate (5.0g, 33.31mmol), and then the reaction solution is heated to 80°C and stirred for 2 hours. LC-MS detects that the reaction is complete . The reaction solution was filtered, and the solid was collected and dissolved in water. The pH value was adjusted to 5 with concentrated hydrochloric acid. A large amount of solid was sucked out, filtered and dried to obtain compound 2-1 (2.8g, yield: 83%) MS(ESI)146.1[M+ H] + .
  • Step 2 Add compound 2-1 (2.3g, 15.85mmol) to 50mL of anhydrous acetonitrile, protect with argon and lower the temperature to 0°C, add the compound phosphorus oxychloride (17mL), and then add phosphorus pentachloride (2.5g, 12.01mmol), N-benzyl-N,N-diethylethylammonium chloride (11.0g, 48.29mmol), and then the reaction solution was heated to 80°C and stirred overnight. LC-MS detected that the reaction was complete.
  • Step 3 Refer to the preparation method of step 1 in Example 1, except that compound 2-2 is substituted for compound 1-1 to obtain compound 2-3 (0.8g, yield: 81%) MS(ESI)328.1[M+ H] +
  • Step 4-6 Refer to the preparation method of step 3-5 in Example 1, except that compound 2-3 is substituted for compound 1-3 to obtain white solid product L-2 (8.49 mg, yield: 10%) MS (ESI) 445.2[M+H] + .
  • Step 1 Add sodium metal (1.52g, 66.09mmol) to methanol (60mL) at 0°C, heat naturally and stir until the sodium metal is completely dissolved, and then add 3-bromobenzamidine hydrochloride (5.0g, 21.37 mmol) was added to the newly formed methanol solution of sodium methoxide, the reaction solution was stirred for 10 minutes, then the temperature of the reaction solution was cooled to 0°C, and finally dimethyl methoxymaleate (3.46g, 21.37mmol) in methanol ( 10mL) The solution was slowly dropped into the reaction solution. After the dropping was completed, the reaction solution was heated to reflux and reacted for 2 hours.
  • 3-bromobenzamidine hydrochloride 5.0g, 21.37 mmol
  • Step 2 Compound 4-1 (500 mg, 1.77 mmol) was added to phosphorus oxychloride (6 mL), the temperature was raised to 125° C. and stirred for 16 hours.
  • Step 3 Refer to the preparation method of step 2 in Example 1, except that compound 4-2 is substituted for compound 1-2 to obtain solid compound 4-3 (0.33 g). MS (ESI) 316 [M+H] + .
  • Step 5 Refer to the preparation method of step 1 in Example 1, except that compound 4-4 is substituted for compound 1-1 to obtain solid compound 4-5 (0.31 g). MS (ESI) 407 [M+H] + .
  • Step 6 Add compound 4-5 (320mg, 0.79mmol) to dry dichloromethane (20mL), reduce the temperature to 0°C, and then add dropwise the dichloride of boron tribromide (1M, 3.2mL, 3.15mmol) After the dropwise addition of the methane solution is completed, it is naturally warmed to room temperature and stirred for 4 hours. When the reaction of the raw materials is complete, the reaction solution is poured into a saturated aqueous sodium bicarbonate solution, and then extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and depressurized Evaporate to dryness to obtain solid compound 4-6 (0.33 g). MS (ESI) 393 [M+H] + .
  • Step 9 Refer to the preparation method of step 5 in Example 1, except that compound 4-8 is substituted for compound 1-5 to prepare product L-4 (12.78 mg).
  • Step 2 Add compound 7-1 (200mg, 1.03mmol) to tetrahydrofuran (10mL), cool the reaction solution to 0°C, add LAH (78mg, 2.05mmol) to the reaction solution, and then stir the reaction solution at 0°C for 1h . After the raw material has reacted completely, add sodium sulfate decahydrate in batches until no bubbles are generated in the reaction solution, then stir the reaction solution for 10 minutes, filter, and directly concentrate the filtrate to obtain oily compound 7-2 (183mg, yield: 91%) MS(ESI)198[M+H] +
  • Step 3 Dissolve compound 7-2 (183mg, 0.93mmol) in dichloromethane (4mL), then add DPPA (383mg, 1.39mmol) and DBU (212mg, 1.39mmol) in sequence, and the reaction mixture was stirred at room temperature for 18h . After the reaction of the raw materials was completed, the reaction solution was diluted with dichloromethane, and then washed twice with water. The organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the oily crude product compound 7-3 (374mg).MS(ESI)223 [M+H] + .
  • Step 4 Referring to the preparation method of Step 5 of Example 1, using Intermediate V8 and Compound 7-3 as reaction materials, a pale yellow solid product L-7 (19.62 mg, yield: 11%) can be prepared.
  • Example 7 Referring to the preparation method of Example 7, the difference is that 2-iodopropane is used to replace 2,2-dimethyl oxirane. Refer to the preparation method of step 5 in Example 1 to obtain a white solid product L-8 (14.43 mg, yield Rate: 8.4%).
  • Step 3 Add compound 10-2 (298mg, 1.0mmol) to tetrahydrofuran (10mL) and lower the temperature to 0°C, then slowly drop methylmagnesium iodide (3M, 2mL, 6.0mmol) into the reaction solution and increase React at room temperature for 1 hour. The reaction was quenched with saturated aqueous ammonium chloride solution, extracted with ethyl acetate, the organic phases were combined, dried over sodium sulfate, filtered, and concentrated to obtain oily compound 10-3 (262 mg, yield: 92%). MS (ESI) 285 [M+H] + .
  • Step 4 Refer to the preparation method of step 3 in Example 21, except that compound 10-3 is substituted for compound 21-2 to obtain oily compound 10-4 (512 mg). MS (ESI) 171 [M+H] + .
  • Step 5-6 Refer to the preparation method of step 3-4 in Example 7, except that compound 10-4 is substituted for compound 7-2 to obtain a white solid product L-10 (26 mg, yield: 9%).
  • Step 1 Take (E)-4-dimethylamino-1,1-dimethoxybut-3-en-2-one (3.16g, 20mmol) and propionamide hydrochloride (3.24g, 30mmol) As a raw material, referring to the preparation method of step 1 in Example 4, an oily compound 11-1 (2.1g).MS(ESI)183[M+H] + was obtained .
  • Step 2 Compound 11-1 (1.3g, 7.14mmol) was added to hydrochloric acid (3M, 12mL) and heated to 50°C and stirred for 18h. The reaction of the raw materials is complete, the reaction solution is cooled to room temperature, the reaction solution is neutralized with saturated sodium bicarbonate, extracted with dichloromethane, the organic phases are combined, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated to obtain the oily compound 11-2 (0.42 g). MS(ESI)137[M+H] + .
  • Step 3 Compound 11-2 (0.42 g, 3.09 mmol) was added to methanol (10 mL), and then sodium borohydride (352 mg, 9.26 mmol) was added in portions and stirred at room temperature for 1 h. The reaction of the raw materials is complete, the reaction is extracted with saturated aqueous ammonium chloride solution, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated to obtain oily compound 11-3 (270mg). MS(ESI)139[M+H] + .
  • Step 4-5 Refer to the preparation method of step 3-4 in Example 7, except that compound compound 11-3 is substituted for compound 7-2 to obtain a white solid product L-11 (33 mg, yield: 20%).
  • Step 1 Combine 1H-pyrazole-3-carboxylic acid methyl ester (2.52g, 20mmol), cyclopropylboronic acid (2.58g, 30mmol), copper acetate (3.98g, 22mmol), 2,2-bipyridine (3.43 g, 22mmol) and sodium carbonate (4.24g, 40mmol) were added to 1,2-dichloroethane (150mL), the reaction solution was heated to 70°C in oxygen and stirred for 3h, then sodium methoxide (1.62g, 30mmol) Add to the reaction solution and heat the reaction solution to reflux for 2h, and then stir at room temperature for 16h.
  • Step 2-4 Refer to the preparation method of step 2-4 in Example 7, except that compound 12-1 is substituted for compound 7-1 to obtain a white solid product L-12 (34 mg, yield: 21%).
  • Step 1 Refer to the preparation method of Example 10, the difference is that the compound 10-1 is replaced with 2-oxo-1,2-dihydropyridine-3-acetaldehyde to obtain the solid product 13-1 (2.1g, yield :77%)MS(ESI)138[M+H] +
  • Step 2-3 Refer to the preparation method of step 2-3 in Example 7, the difference is that compound 13-1 is substituted for compound 7-1 to obtain oily compound 13-3 (199mg). MS(ESI)165[M+H ] + .
  • Step 4 Refer to the preparation method of Step 5 in Example 1, to obtain the white solid product L-13 (16 mg, yield: 10%).
  • Step 1-1 and Step 1-2 Refer to Step 2-3 of Example 1, the difference is that perchloropyrimidine is used to replace compound 1-2 to obtain solid compound 15-1 (0.51g, yield: 24%). MS( ESI)279[M+H] + .
  • Step 2-1 Dissolve 2-(6-(hydroxymethyl)pyridin-2-yl)propan-2-ol (550mg, 3.27mmol) in dichloromethane (40mL), cool to 0°C, add DMP (2.1g, 4.91mmol), stirred at room temperature for 4h. TLC monitors that the reaction is complete. The reaction solution was diluted with dichloromethane (200 mL) and washed with water (150 mL x 2). The organic phase was separated and dried over anhydrous sodium sulfate, concentrated under reduced pressure and passed through silica gel column chromatography (EA: PE, 0-30%) to obtain compound 15-2 (320 mg, yield: 593%) as a yellow oil. MS(ESI)166[M+H] + .
  • Step 2-2 Dissolve 4-iodo-1-(((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (1.2g, 3.61mmol) in tetrahydrofuran (20mL) At -70°C, add n-butyllithium (2.7mL, 5.43mmol) dropwise and stir for 2h. Dissolve compound 15-2 (300mg, 1.81mmol) in tetrahydrofuran (2mL) and drop at -70°C Add to the above solution. The reaction solution was slowly raised to 0°C and stirred for 2 hours. TLC monitored the completion of the reaction.
  • Step 2-3 Dissolve compound 15-3 (80mg, 0.22mmol) in triethylsilane/trifluoroacetic acid (3mL/1mL) and stir at 80°C for 24h. TLC monitoring showed that the reaction was complete. The reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (EA:PE, 0-70%) to obtain yellow gum compound 15-4 (22 mg, yield: 46%). MS(ESI)218[M+H] + .
  • Step 3 Compound 15-1 (30 mg, 0.11 mmol) and compound 15-4 (22 mg, 0.19 mmol) were dissolved in acetonitrile (6 mL), and then potassium carbonate (297 mg, 2.15 mmol) was added thereto. The reaction was stirred under microwave conditions at 140°C for 1 h. Then the reaction solution was concentrated and separated and purified by high performance liquid phase preparation to obtain a white solid product L-15 (8.94 mg, yield: 19%, P: 95.95%).
  • Step 1-2 Using diethyl 2-fluoromalonate (9.80g, 55.00mmol) and 2-thiazolecarboxamidine hydrochloride (4.5g, 27.50mmol) as raw materials, refer to the step 1-2 of Example 4 Preparation method to obtain solid compound 16-2 (2.07 g, P: 100%, yield: 79%). MS(ESI)250.0[M+H]+.
  • Step 3-6 Refer to the preparation methods of step 1-2 and step 4 in Example 1, the difference is that compound 16-2 is substituted for compound 1-1 to obtain white solid product L-16 (32.58 mg, yield: 9%) .
  • Step 1 Refer to the preparation method of step 1 in Example 12, the difference is that the 1H-pyrazole-3-carboxylic acid methyl ester is replaced with 2-oxo-1,2-dihydropyridine-3-carbaldehyde to obtain the solid compound 17- 1 (280 mg, yield: 17%). MS(ESI)164.1[M+H]+.
  • Step 2-4 Refer to steps 2-4 of Example 7, except that compound 17-1 is used to replace compound 7-1, and compound 1-5 is used to replace intermediate V8, to obtain a white solid product L-17 (26 mg, yield: 15%).
  • step 5 in Example 1 Refer to the preparation method of step 5 in Example 1, the difference is that 2-(3-(azidomethyl)-1-methyl-1H-pyrazol-5-yl)propan-2-ol is used to replace intermediate V4, A white solid product L-18 (28.76 mg, yield: 23%) can be prepared.
  • Step 1 Dissolve 1H-pyrazole-3-carboxylic acid ethyl ester (1.4g, 9.99mmol) in dichloromethane (50mL), then add trifluoromethylsulfonyl triflate (4.23g, 14.99 mmol) was added. The reaction was stirred at room temperature for 1 h. The reaction solution was poured into saturated aqueous ammonium chloride solution, extracted with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and separated by silica gel column chromatography (EA:PE, 0-50%) A white solid compound 18-1 (2.4 g, yield: 88%) was obtained. MS(ESI)273.0[M+H]+.
  • Step 2 Dissolve 3,3-difluorocyclobutanol (600 mg, 5.55 mmol) in acetonitrile (10 mL), and then add cesium carbonate (1.99 g, 6.11 mmol) to it. The reaction temperature was lowered to 0°C, and then a solution of compound 18-1 (1.38 g, 5.05 mmol) in acetonitrile (10 mL) was added dropwise. The reaction was stirred at 0°C for 1h, then warmed to room temperature and stirred for 2h.
  • Step 3-5 Refer to step 2-4 of Example 7, the difference is that compound 18-2 is used to replace compound 7-1, and compound 1-5 is used to replace intermediate V8 to obtain white solid product L-19 (36.59 mg, yield :25%).
  • Step 1 Dissolve (1-methylpyrazol-3-yl)methanol (1.12g, 9.99mmol) in dichloromethane (60mL), then add 1H-imidazole (1.36g, 19.98mmol), 4-bis Methylaminopyridine (1.83 g, 14.98 mmol), TBSCl (1.23 g, 14.98 mmol) were added to it. The reaction was stirred at room temperature for 2h.
  • Step 2 Dissolve compound 21-1 (1.5g, 6.63mmol) in tetrahydrofuran (6mL), reduce the temperature to -78°C, add n-butyllithium (2.5M, 3.98mL) dropwise, and then stir at -78°C For 1h, continue to add N-fluorobisbenzenesulfonamide (3.13g, 9.94mmol) in tetrahydrofuran (6mL) dropwise, after the dropwise addition, stir at -78°C for 2h, then naturally warm to room temperature and stir for 18h.
  • N-fluorobisbenzenesulfonamide 3.13g, 9.94mmol
  • Step 3 Compound 21-2 (240 mg, 982 mmol) was dissolved in methanol (20 mL), and then ammonium fluoride (1.09 g, 29 mmol) was added to it. The reaction was stirred at 80°C for 1 h. After completion of the reaction, it was cooled to room temperature, filtered, quenched with aqueous solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 21-3 (210 mg) as a brown oil. MS(ESI)131.1[M+H]+.
  • Step 1 Dissolve compound 10-3 (380mg, 1.34mmol) in tetrahydrofuran (20mL), then add sodium hydride (385mg, 16.03mmol) to it and stir for 10 minutes, then add methyl iodide (1.90g, 13.36mmol) Add to the reaction and stir at room temperature for another 2h.
  • the reaction solution was placed in an ice water bath, and then sodium sulfate decahydrate was added in batches, after the addition, stirred for 10 minutes, filtered, and the filtrate was directly concentrated to obtain oily compound 23-1 (371 mg, yield: 93%).
  • Step 2 Refer to the preparation method of step 3 in Example 21, except that compound 23-1 is substituted for compound 21-2 to obtain oily compound 23-2 (310 mg). MS(ESI)185.1[M+H]+.
  • Step 3-4 Refer to the preparation method of step 3-4 in Example 7. The difference is that compound 23-2 is substituted for compound 7-2, and compound 1-5 is substituted for intermediate V8 to obtain a white solid product L-23 (89.26) mg, yield: 50%).
  • Step 1 Refer to the preparation method of step 2 in Example 7, with the difference that compound 10-2 is substituted for compound 7-1 to obtain oily compound 24-1 (451 mg, yield: 75%). MS(ESI)257.2[M+H]+.
  • Step 2 Compound 24-1 (451 mg, 1.76 mmol) was dissolved in tetrahydrofuran (20 mL), and then activated manganese dioxide (3.06 g, 35.18 mmol) was added to it. The reaction was stirred at 85°C for 24h. After the reaction was completed, it was cooled to room temperature, filtered to remove insoluble materials, the filter cake was washed with dichloromethane, and the filtrate was spin-dried under reduced pressure to obtain compound 24-2 (345 mg, yield: 77%) as a pale yellow oil. MS(ESI)255.2[M+H] + .
  • Step 3 Refer to the preparation method of step 3 in Example 10, except that compound 24-2 is substituted for compound 10-2 to obtain compound 24-3 (230 mg) as a pale yellow oily compound. MS(ESI)271.2[M+H] + .
  • Step 4 Refer to the preparation method of Example 21, step 3, the difference is that compound 24-3 is substituted for compound 21-2 to obtain compound 24-4 (214mg ). MS(ESI) 157.1[M+H] + .
  • Step 5-6 Refer to the preparation method of Example 7 Step 3-4, the difference is that compound 24-4 is substituted for compound 7-2 to obtain white solid product L-24 (17.62mg, yield: 25%).
  • Step 1 Referring to Step 3 of Example 1, the difference is that compound 2-2 is substituted for compound 1-3 to obtain compound 26-1 (170 mg, yield: 52.3%) MS(ESI) 263[M+H] + .
  • Step 2 Refer to step 3 of Example 1, the difference is that compound 26-1 is used to replace compound 1-3, and intermediate V5 is used to replace intermediate V1 to obtain white solid L-26 (38.59 mg, yield: 17.4%) MS( ESI)444[M+H] + .
  • Step 1 Using 3-azidomethylpyridine (170 mg, 1 mmol) and 2-iodoacetamide (278 mg, 1.5 mmol) as raw materials, referring to the preparation method of step 2 in Example 10, compound 29-1 (160 mg, yield) Rate: 89%) MS(ESI)181[M+H] + .
  • Step 2 Refer to the preparation method of step 5 in Example 1, except that compound 29-1 is substituted for compound V4 to obtain white solid L-29 (10.79mg, yield: 8.3%) MS(ESI)433[M+H] + .
  • Step 1 Using 1H-pyrazole-3-carboxylic acid ethyl ester (2.8g, 20mmol) and iodoethane (6240mg, 40mmol) as raw materials, referring to the preparation method of step 2 in Example 10, compound 30-1 (2.2 g, yield: 74%) MS(ESI)169[M+H] + .
  • Step 2-3 Refer to the preparation method of step 2-3 in Example 7, except that compound 30-1 is substituted for compound 7-1 to obtain a crude product of compound 30-3 (847 mg), which is stored in 10 mL of tert-butanol. MS (ESI) 152 [M+H] + .
  • Step 4 Refer to the preparation method of step 5 in Example 1, except that compound 30-3 is substituted for compound V4 to obtain white solid L-30 (33.29 mg, P: 100%, yield: 27.5%) MS(ESI) 404 [M+H] + .
  • Step 1-2 Refer to the preparation method of step 2-3 in Example 7, except that the compound 7-1 is replaced with ethyl 1-ethyl-1H-pyrazole-5-carboxylate (285 mg, 1.7 mmol) to obtain the compound
  • the crude product of 31-2 (538 mg), stored in 10 mL tert-butanol, MS (ESI) 152 [M+H] + .
  • Step 3 Refer to the preparation method of step 5 in Example 1, except that compound 31-2 is substituted for compound V4 to obtain white solid L-31 (20.93mg, yield: 17.3%) MS(ESI)404[M+H] + .
  • Step 1 Refer to the preparation method of step 3 in Example 7, except that (1-cyclopropyl-1H-pyrazol-3-yl)methanol (138mg, 1mmol) was used to replace compound 7-2 to obtain compound 32-1( 660 mg) of the crude product, stored in 10 mL tert-butanol, MS (ESI) 416[M+H] + .
  • Step 2 Refer to the preparation method of step 5 in Example 1, except that compound 32-1 is substituted for compound V4 to obtain white solid L-32 (18.01mg, yield: 14.5%) MS(ESI)416[M+H] + .
  • Step 1-2 Using (1-methyl-1H-pyrazol-3-yl)methanol (2g, 17.86mmol) as raw material and referring to the preparation method of intermediate V5, a colorless liquid compound 33-2 (2.1g) , Yield: 54%) MS (ESI) 289 [M+H] + .
  • Step 3 Using compound 33-2 (1.38g, 3.82mmol) and 2,4,5,6-tetrachloropyrimidine (1.08g, 4.96mmol) as raw materials, refer to the preparation method of step 3 in Example 1 to obtain a yellow solid
  • the product compound 33-3 (660 mg, 1.67 mmol, 43.6% yield)
  • Step 4 Using compound 33-3 as a raw material, referring to the preparation method of step 2 in Example 1, a white solid compound 33-4 (300 mg), MS (ESI) 325 [M+H] + was obtained .
  • Step 5 Using compound 33-4 and compound V1 as raw materials and referring to the preparation method of step 3 in Example 1, L-33 (13.10 mg,), MS (ESI) 405 [M+H] + was obtained as a white solid.
  • Step 1 Dissolve 1H-pyrazole-3-carboxylic acid ethyl ester (1.4g, 9.99mmol) and sodium chlorodifluoroacetate (4.57g, 29.97mmol) in DMF (20mL) and acetonitrile (12mL), and then Cesium carbonate (9.76 g, 29.97 mmol) was added. The reaction was stirred at 100°C for 3 hours.
  • Step 2-3 Using compound 34-1 as a raw material, referring to the preparation method of step 2-3 in Example 7 to obtain compound 34-3 (780 mg, P: 20%), stored in 10 mL tert-butanol, MS (ESI) 174[M+H]+.
  • Step 4 Using compound 34-3 and intermediate V8 as raw materials, refer to the preparation method of step 5 in Example 1 to obtain compound L-34 (34.73mg, 25.83% yield), MS(ESI)442[M+H] +.
  • Step 1 1-(2-Hydroxyethyl)pyrrolidin-2-one (800 mg, 6.19 mmol) was dissolved in thionyl chloride (18 mL), and the reaction was stirred at 50°C for 1 hour. Extracted with ethyl acetate (15mL*3), washed the organic phase with saturated aqueous sodium carbonate solution, dried over anhydrous sodium sulfate, and spin-dried the solvent under reduced pressure to obtain compound 35-1 (910mg, 99.53% yield), MS(ESI)148[ M+H]+.
  • Step 3-4 Using compound 35-2 as a raw material, referring to the preparation method of step 2-3 in Example 7 to obtain compound 35-4 (460 mg crude product, stored in tert-butanol (5 mL) solvent, MS (ESI) 235[M+H]+.
  • Step 5 Refer to the preparation method of step 5 in Example 1, the difference is that compound 35-4 is substituted for compound V4 to obtain light green solid L-35 (92.48mg, 63.84% yield), MS(ESI)486[M+ H]+.
  • Step 1 Using 1H-pyrazole-3-carboxylic acid ethyl ester (700mg, 5.00mmol) and 1-iodo-2-methylpropane (1.19g, 6.49mmol) as raw materials, refer to the preparation method of Example 10, step 2 , A white solid compound 36-1 (510 mg, 52% yield), MS (ESI) 197 [M+H] + was obtained.
  • Step 2-3 Using compound 36-1 as a raw material, referring to the preparation method of step 2-3 in Example 7 to obtain compound 36-3 (840 mg, 20% purity), stored in tert-butanol (5 mL) solvent, MS (ESI) 180[M+H]+.
  • Step 4 Refer to the preparation method of step 5 in Example 1, the difference is that compound 36-3 is substituted for compound V4 to obtain white solid L-36 (71.83 mg, 54.87% yield), MS (ESI) 432[M+H ]+.
  • Step 1 Using 1H-pyrazole-3-carboxylic acid ethyl ester (1.4g, 10.06mmol) and 1,1,1-trifluoro-2-iodo-ethane (4.22g, 20.12mmol) as raw materials, reference implementation The preparation method of step 2 in Example 10 yielded white solid compound 37-1 (650 mg, 27.33% yield), MS (ESI) 223[M+H]+.
  • Step 2-3 Using compound 37-1 as a raw material, referring to the preparation method of step 2-3 in Example 7, compound 37-3 (800mg) was obtained and stored in 4mL tert-butanol, MS(ESI)206[M+H ]+.
  • Step 4 Refer to the preparation method of step 5 in Example 1, with the difference that compound 37-3 is substituted for compound V4 to obtain compound L-37 (24.70 mg, 18.12% yield), MS (ESI) 458 [M+H] +.
  • Step 1 Using 1H-pyrazole-3-carboxylic acid ethyl ester (282.03mg, 2.01mmol) and 1-fluoro-2-iodoethane (525.12mg, 3.02mmol) as raw materials, refer to the preparation of step 2 in Example 10 Method, a colorless liquid compound 38-1 (310 mg, 82.74% yield), MS (ESI) 187 [M+H] + was obtained.
  • Step 2-3 Using compound 38-1 as a raw material, referring to the preparation method of step 2-3 in Example 7 to obtain a crude product of compound 38-3 (536 mg, P: 22%), which was stored in tert-butanol (5 mL) , MS(ESI)170[M+H]+.
  • Step 4 Refer to the preparation method of step 5 in Example 1, the difference is that compound 38-3 is substituted for compound V4 to obtain white compound L-38 (45.55mg, 44.63% yield), MS(ESI)422[M+H ]+.
  • Step 1 Using 1H-pyrazole-3-carboxylic acid ethyl ester (215mg, 1.53mmol) and iodomethylcyclopropane (280mg, 1.54mmol) as raw materials, refer to the preparation method of step 2 in Example 10 to obtain a colorless liquid Compound 39-1 (270 mg, 86.98% yield), MS (ESI) 195 [M+H]+.
  • Step 2-3 Using compound 39-1 as a raw material, referring to the preparation method of step 2-3 in Example 7, a crude product of compound 39-3 (690 mg, P: 18%) was obtained, which was stored in 6 mL of tert-butanol, MS (ESI) 178 [M+H]+.
  • Step 4 Refer to the preparation method of step 5 in Example 1, the difference is that compound 39-3 is substituted for compound V4 to obtain light green solid L-39 (48.12mg, 37.14% yield), MS(ESI)430[M+ H]+.
  • Step 1 Using 3-(azidomethyl)-1H-pyrazole (100mg, 812.24 ⁇ mol) and ethyl 2-bromoacetate (203.47mg, 1.22mmol) as raw materials, refer to the preparation method of step 2 in Example 10. A light yellow liquid compound 40-1 (160 mg, 74.39% yield), MS (ESI) 210 [M+H] + was obtained.
  • Step 2 Refer to the preparation method of step 5 in Example 1, the difference is that compound 40-1 is substituted for compound V4 to obtain yellow solid compound 40-2 (170mg, 45.28% yield), MS(ESI)462[M+H ]+.
  • Step 3 Compound 40-2 (150 mg, 325.06 ⁇ mol) was dissolved in methanol (5 mL), and then aqueous lithium hydroxide solution (0.4 mmol, 0.2 M, 2 mL) was added dropwise. The reaction was stirred at room temperature for 20 minutes. After the reaction was completed, the solvent was spin-dried under reduced pressure and purified by preparative liquid chromatography to obtain compound L-40 (30.23 mg, 21.46% yield), MS (ESI) 434 [M+H ]+.
  • Step 1 Dissolve 2-(dimethylamino)ethanol (180mg, 2.02mmol) in dichloromethane (2mL), cool to 0°C, and add thionyl chloride (1M, 2.63mL) dropwise. The reaction was stirred overnight at room temperature. After the solvent was spin-dried under reduced pressure, a white solid compound 41-1 (275 mg, 94.54% yield) was obtained.
  • Step 2 Compound 41-1 (275mg, 2.56mmol) and ethyl 1H-pyrazole-3-carboxylate (300mg, 2.14mmol) were dissolved in DMF (8mL), and then cesium carbonate (1.67g, 5.11mmol) ) To join it. The reaction was stirred at 110°C for 5 hours. The reaction solution was filtered, the filter residue was washed with dichloromethane, the organic phases were combined, the solvent was spin-dried under reduced pressure, and the column was separated (12g, 0-50% ethyl acetate/petroleum ether) to obtain a pale yellow solid compound 41-2 (260mg, 31.29% yield), MS (ESI) 212 [M+H]+.
  • Step 3-4 Using compound 41-2 as a raw material, referring to the preparation method of step 2-3 in Example 7, a yellow liquid compound 41-4 (570 mg) was obtained, and stored in 6 mL of tert-butanol, MS (ESI) 195 [M+H]+.
  • Step 5 Refer to the preparation method of step 5 in Example 1, the difference is that compound 41-4 is substituted for compound V4 to obtain light green solid L-41 (25.76mg, 18.05% yield), MS(ESI)447[M+ H]+.
  • 1 H NMR 400MHz, CD 3 OD) ⁇ 8.50 (s, 1H), 7.93 (s, 1H), 7.71 (s, 1H), 7.64 (s, 1H), 7.41 (s, 1H), 6.33 (s ,1H), 5.67(s, 2H), 4.25(s, 2H), 2.77(s, 2H), 2.66(s, 3H), 2.23(s, 6H).
  • Step 1 Using 1-methylpyrazole-4-carbaldehyde (1g, 9.08mmol) as a raw material and referring to the preparation method of step 3 in Example 11, a colorless liquid compound 42-1 (610mg, 56.91% yield) is obtained. MS (ESI) 113 [M+H]+.
  • Step 2 Using compound 42-1 as a raw material, referring to the preparation method of step 3 in Example 7, a crude product of compound 42-2 (447mg) was obtained, which was stored in 5mL tert-butanol, MS(ESI)138[M+H ]+.
  • Step 3 Refer to the preparation method of step 5 in Example 1, the difference is that compound 42-2 is substituted for compound V4 to obtain compound L-42 (52.83 mg, 31.33% yield), MS (ESI) 419 [M+H] +.
  • Step 1-2 Using 5-methoxy-1-methyl-pyrazole-3-carboxylic acid (260 mg, 1.67 mmol) as a raw material, refer to the preparation method of step 2-3 in Example 7 to obtain compound 43-2
  • Step 3 Refer to the preparation method of step 5 in Example 1, the difference is that compound 43-2 is substituted for compound V4 to obtain compound L-43 (17.4mg, 9.21% yield), MS(ESI)449[M+H] +.
  • Step 1 Using 1H-pyrazole-3-carboxylic acid ethyl ester (420mg, 3.00mmol) and 1,1-difluoro-2-iodoethane (862.90mg, 4.50mmol)) as raw materials, refer to the step of Example 10 According to the preparation method of 2, the colorless liquid compound 44-1 (340 mg, 55.56% yield), MS (ESI) 205 [M+H] + was obtained.
  • Step 2-3 Using compound 44-1 as a raw material, refer to the preparation method of step 2-3 in Example 7 to obtain a crude product of compound 44-3 (790mg), MS(ESI)188[M+H]+, save In 8mL tert-butanol.
  • Step 4 Refer to the preparation method of step 5 in Example 1, the difference is that compound 44-3 is substituted for compound V4 to obtain compound L-44 (33.51mg, 19.07% yield), MS(ESI)440[M+H] +.
  • Step 1 Using 1H-pyrazole-3,5-dicarboxylic acid diethyl ester (2120mg, 9.99mmol) and methyl iodide (2.28g, 16.06mmol, 1mL) as raw materials, refer to the preparation method of step 2 in Example 10, A white solid compound 45-1 (2.36 g, 95.66% yield) was obtained, MS (ESI) 227 [M+H]+.
  • Step 2 Compound 45-1 was used as a raw material, and referring to the preparation method of step 3 in Example 40, a white solid compound 45-2 (2 g, 96.74% yield), MS (ESI) 199 [M+H] + was obtained.
  • Step 3 Compound 45-2 was used as a raw material, referring to the preparation method of step 1 in Example 35, to obtain a pale yellow liquid compound 45-3 (2.3 g, 99.95% yield), MS(ESI)199[M+H]+.
  • Step 4 Compound 45-3 was used as a raw material, referring to the preparation method of step 2 in Example 1, to obtain a white solid compound 45-4 (980 mg, 46.81% yield), MS (ESI) 198[M+H]+.
  • Step 5 Dissolve compound 45-4 (400mg, 2.03mmol) in dichloromethane (8mL), add triethylamine (362.75mg, 3.58mmol, 0.5mL) at room temperature, stir for 15 minutes and then add trifluoride dropwise Acetic anhydride (1.51 g, 7.19 mmol, 1 mL) was stirred at room temperature for half an hour.
  • the reaction solution was extracted with dichloromethane (20mL*3), washed with saturated brine (20mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to dry the solvent to obtain a pale yellow liquid compound 45-5 (360mg, 99.05% yield), MS (ESI) 180[M+H]+.
  • Step 6-7 Using compound 45-5 as a raw material and referring to the preparation method of step 2-3 in Example 7, a crude product of compound 45-7 (847 mg) was obtained, which was stored in tert-butanol (8 mL). MS (ESI) 163 [M+H]+.
  • Step 8 Refer to the preparation method of step 5 in Example 1, the difference is that compound 45-7 is substituted for compound V4 to obtain white solid L-45 (19.5 mg, 11.75% yield), MS (ESI) 415[M+H ]+.
  • Step 1-2 Using methyl 1-methyltriazole-4-carboxylate (250mg, 1.77mmol) as a raw material, referring to the preparation method of step 2-3 in Example 7 to obtain brown oily liquid compound 46-2 (816mg The crude product of ), MS(ESI)139[M+H]+, was stored in tert-butanol (8mL).
  • Step 3 Refer to the preparation method of step 5 in Example 1, the difference is that compound 46-2 is substituted for compound V4 to obtain white solid L-46 (10.03mg, 6.38% yield), MS(ESI)391[M+H ]+.
  • Step 1-2 Using methyl 2-methyltriazole-4-carboxylate (250mg, 1.77mmol) as a raw material, refer to the preparation method of step 2-3 in Example 7 to obtain brown oily liquid compound 47-2 (747mg)
  • brown oily liquid compound 47-2 7.47mg
  • MS(ESI)139[M+H]+ was stored in tert-butanol (8mL).
  • Step 3 Refer to the preparation method of step 5 in Example 1, the difference is that compound 47-2 is substituted for compound V4 to obtain white solid L-47 (10.0mg, 6.38% yield), MS(ESI)391[M+H ]+.
  • Step 1-3 Using ethyl 1H-pyrazole-3-carboxylate (1.4g, 9.99mmol) and ethyl 2-bromo-2-methylpropionate (2.92g, 14.99mmol) as raw materials, refer to Example 7 Preparation method of steps 1-3 to obtain compound 49-3 (3.1g), MS(ESI)196[M+H]+, in tert-butanol (10mL).
  • Step 4 Refer to the preparation method of step 5 in Example 1, the difference is that compound 49-3 is substituted for compound V4 to obtain white solid L-49 (7.77mg, 1.74% yield), MS(ESI)448[M+H ]+.
  • Step 1 Ethyl 2-formyl-3-oxopropionate (720mg, 5.00mmol) and tert-butylhydrazine hydrochloride (625mg, 5.00mol) were dissolved in ethanol (20mL), and then triethylamine (757mg , 7.5mmol) was added to it. The reaction was stirred overnight at room temperature. The ethanol was removed by rotary evaporation under reduced pressure, extracted with ethyl acetate (20 mL*3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and the solvent was spin-dried under reduced pressure to obtain a crude product. The crude product was separated by column (12g, 0-10% ethyl acetate/petroleum ether) to obtain yellow oily liquid compound 51-1 (500mg, 51.28% yield), MS(ESI)197[M+H] + .
  • Step 2-3 Using compound 51-1 as a raw material, referring to the preparation method of step 2-3 in Example 7, compound 51-3 (684 mg) was obtained, which was stored in tert-butanol (5 mL). MS (ESI) 189 [M+H]+.
  • Step 4 Refer to the preparation method of step 5 in Example 1, the difference is that compound 51-3 is substituted for compound V4 to obtain yellow solid L-51 (34.5mg, 27% yield), MS(ESI)432[M+H ]+.
  • Step 2 Using compound 52-1 as a raw material, referring to the preparation method of step 3 in Example 7 to obtain compound 52-2. MS (ESI) 210.1 [M+H] + .
  • Step 3 Using compound 52-2 and intermediate V8 as raw materials, referring to the preparation method of step 5 in Example 1, a yellow solid product L-52 is obtained.
  • 1 H NMR (400MHz, DMSO-d6) ⁇ 8.95 (s, 1H), 7.99-7.97 (m, 1H), 7.90-7.85 (m, 2H), 7.75-7.71 (m, 2H), 7.54-7.46 ( m, 4H), 5.77 (s, 2H), 2.66 (s, 3H), 1.64 (d, J 12 Hz, 6H).
  • Step 1 Using (6-bromopyridin-2-yl)methanol (2g, 10.7mmol) as a raw material, referring to the preparation method of step 1 in Example 21, compound 53-1 (2.3g yellow solid) was obtained. MS(ESI)302.1[M+H] +
  • Step 2 Dissolve compound 53-1 (2g, 10.7mmol) in tetrahydrofuran (30mL), lower the temperature to -78°C, and add n-butyllithium (4.7mL, 11.8mmol, 2.5M) under nitrogen protection. After stirring for 30 minutes at this temperature, a solution of 3-oxetanone (1.08 g, 15 mmol) in tetrahydrofuran (5 mL) was slowly added. The reaction solution was stirred at -78°C for 2 hours.
  • Step 3 Compound 53-2 is used as a raw material, referring to the preparation method of step 4 in Example 1, to obtain compound 53-3.
  • Step 4 Compound 53-3 is used as a raw material, and referring to the preparation method of step 3 in Example 7, compound 53-4 is obtained. MS (ESI) 207.1 [M+H] + .
  • Step 5 Refer to the preparation method of step 5 in Example 1, except that compound 53-4 is substituted for compound V4 to obtain a white solid product L-53 (13 mg, 8.1%).
  • Step 1 Dissolve 2,6-pyridine dimethanol (6 g, 43.2 mmol) in tetrahydrofuran (80 mL), and slowly add sodium hydride (1.75 g, 43.8 mmol, 60%) under ice bath conditions. After stirring for 30 minutes, TBSCl (6.61 g, 43.8 mmol) was slowly added. Stir at room temperature for 20 hours. The reaction solution was poured into ice water, extracted with dichloromethane (50mL*2), dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and purified by column chromatography to obtain compound 54-1 (6.47g, 59.2%), colorless Oily liquid. MS (ESI) 254.1 [M+H] + .
  • Step 2 Dissolve compound 54-1 (6.35g, 25.1mmol) and triphenylphosphine (7.89g, 30.1mmol) in dichloromethane (80mL), slowly add carbon tetrabromide (10.83) under ice bath conditions g, 32.6 mmol). Stir at room temperature for 20 hours. The solvent was spin-dried under reduced pressure and purified by column chromatography to obtain compound 54-2 (4.5 g, 57.0%) as a yellow solid. MS (ESI) 316.1 [M+H] + .
  • Step 3 Compound 54-2 (3.15 g, 10 mmol), trimethylsilyl cyanide (1.51 g, 15 mmol) and TBAF (15 mL, 15 mmol, 1M) were dissolved in acetonitrile. Heat to 80°C and stir for 20 hours under nitrogen. The solvent was spin-dried under reduced pressure and purified by column chromatography (EA/PE, 0-100%) to obtain compound 54-3 (1.4 g, 94.5%) as a yellow oil. MS (ESI) 149.1 [M+H] + .
  • Step 4 Using compound 54-3 as a raw material, referring to the preparation method of step 1 in Example 21, a yellow solid compound 54-4 (2.01 g, 82.1%) was obtained. MS (ESI) 263.1 [M+H] + .
  • Step 5 Using compound 54-4 as a raw material, referring to the preparation method of step 1 in Example 23, compound 54-5 (2.5 g, 82.1%) was obtained. MS (ESI) 291.1 [M+H] + .
  • Step 6 Using compound 54-5 as a raw material, refer to the preparation method of step 4 in Example 1 to obtain compound 54-6. MS (ESI) 177.1 [M+H] + .
  • Step 7 Using compound 54-6 as a raw material, refer to the preparation method of step 3 in Example 7 to obtain compound 54-7. MS (ESI) 202.1 [M+H] + .
  • Step 8 Refer to the preparation method of step 5 in Example 1, except that compound 54-7 is substituted for compound V4 to obtain a white solid product L-54 (15 mg, 10.3%). MS (ESI) 454.2 [M+H] + .
  • Step 1-2 Using compound 54-5 as a raw material, referring to the preparation method of step 2-3 in Example 7, compound 55-2 (190 mg, 41.7%) was obtained. MS (ESI) 206.1 [M+H] + .
  • Step 3 Compound 55-2 (190 mg, 0.93 mmol) and TEA (187 mg, 1.85 mmol) were dissolved in dichloromethane (10 mL). Slowly add methanesulfonyl chloride (116mg, 1.02mmol) under ice bath conditions. The reaction was stirred at room temperature for 4 hours. The solvent was spin-dried under reduced pressure and purified by column chromatography (EA/PE: 0-90%) to obtain compound 55-3 (86 mg, 32.8%) as a yellow solid. MS(ESI)283.1[M+H] +
  • Step 4 Refer to the preparation method of Step 5 in Example 1, except that compound 55-3 is used to replace compound V4 to obtain white solid product L-55 (26 mg, 18.6%).
  • Step 1 6-picoline-2-carbonitrile (5g, 42.3mmol), NBS (7.53g, 42.3mmol) and benzoyl peroxide (512mg, 2.1mmol) were dissolved in carbon tetrachloride (100mL), Heat under reflux and stir for 20 hours. Water was added to the reaction solution, extracted with dichloromethane (50mL*2), dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and purified by column chromatography (EA/PE, 0-40%) to obtain compound 56-1 (3.5g, 42.2%), a colorless oily liquid. MS (ESI) 197.1 [M+H] + .
  • Step 2 Potassium acetate (5.97 g, 60.90 mmol) and compound 56-1 (6 g, 30.45 mmol) were added to DMF (50 mL) and stirred for 20 hours under ice bath conditions. Ethyl acetate (200 mL) was added, the organic phase was washed three times with saturated brine, dried over anhydrous sodium sulfate, the solvent was spin-dried under reduced pressure, and purified by column chromatography (EA/PE:0 ⁇ 90%) to obtain compound 56 as a yellow solid -2 (4.1g, 76.4%). MS(ESI)177.1[M+H] +
  • Step 3 Mix hydrogen peroxide (0.5 mL) and 3N sodium hydroxide (3 mL) solution, and add compound 56-2 (500 mg, 2.84 mmol) and methanol (15 mL). Stir at room temperature for 1 hour. Adjust to neutral with 1N dilute hydrochloric acid, spin off the solvent under reduced pressure, and purify by column chromatography (MeOH/dichloromethane: 0-20%) to obtain compound 56-3 (300 mg, 69.5%) as a yellow solid. MS(ESI)153.1[M+H] +
  • Step 4 Using compound 56-3 as a raw material, refer to the preparation method of step 3 in Example 7 to obtain compound 56-4. MS (ESI) 178.1 [M+H] + .
  • Step 5 Refer to the preparation method of step 5 in Example 1, except that compound 56-4 is substituted for compound V4 to obtain a white solid product L-56 (38 mg, 29.8%). MS (ESI) 430.2 [M+H] + .
  • 1 H NMR 400MHz, DMSO-d6) ⁇ 8.98 (s, 1H), 8.05-7.85 (m, 5H), 7.73 (s, 1H), 7.57-7.45 (s, 4H), 5.89 (s, 2H) ,2.66(s,3H).
  • Step 1 Using 1H-1,2,4-triazole-3-carboxylic acid methyl ester (2g, 15.74mmol) as a raw material, referring to the preparation method of step 1 in Example 23, compound 57-1 was obtained as a colorless oily liquid. MS (ESI) 142.1 [M+H] +.
  • Step 2-3 Using compound 57-1 as a raw material, referring to the preparation method of step 2-3 in Example 7, compound 57-3 (80 mg, 13.1%) was obtained as a white solid. MS (ESI) 139.1 [M+H] +.
  • Step 4 Refer to the preparation method of step 5 in Example 1, except that compound 57-3 is substituted for compound V4 to obtain a light green solid product L-57 (16 mg, 17.5%).
  • Step 1 Using [6-[[tert-butyl(dimethyl)silyl]oxymethyl]-2-pyridyl]methanol (4g, 15.78mmol) as raw material, refer to the preparation method of step 2 in Example 24, Compound 58-1 (2.1 g, 52.9%) was obtained as a colorless oily liquid. MS(ESI)252.1[M+H] +
  • Step 2 Compound 58-1 (1 g, 3.98 mmol) and potassium carbonate (1.10 g, 7.96 mmol) were mixed in MeOH (15 mL), and then hydroxylamine hydrochloride (304.06 mg, 4.38 mmol) was added thereto. The reaction was stirred at 20°C for 20 hours. The methanol was spin-dried, saturated brine was added, extracted with EA (50 mL*2), dried over anhydrous sodium sulfate, and the solvent was spin-dried under reduced pressure to obtain compound 58-2. MS(ESI)267.1[M+H] +
  • Step 3 Compound 58-2 (1 g, 3.75 mmol) and potassium carbonate (1.04 g, 7.51 mmol) were mixed with DMF (10 mL), and then acetic anhydride (766.41 mg, 7.51 mmol) was added thereto. The reaction was stirred at 50°C for 20 hours. Saturated brine was added to the reaction solution, extracted with dichloromethane (50 mL*2), dried over anhydrous sodium sulfate, and the solvent was spin-dried under reduced pressure to obtain compound 58-3. MS(ESI)135.1[M+H] +
  • Step 4 Using compound 58-3 as a raw material, referring to the preparation method of step 1 in Example 21, compound 58-4 (0.6 g, 54%) is obtained as a colorless oily liquid. MS(ESI)249.1[M+H] +
  • Step 5 Using compound 58-4 as a raw material, referring to the preparation method of step 3 in Example 10, compound 58-5 (524 mg, 74.9%) was obtained as a colorless oily liquid. MS(ESI)281.1[M+H] +
  • Step 6 Using compound 58-5 as a raw material, refer to the preparation method of step 4 in Example 1 to obtain compound 58-6. MS(ESI)167.1[M+H] +
  • Step 7 Using compound 58-6 as a raw material, referring to the preparation method of step 3 in Example 7, compound 58-7 (355 mg, 88.2%) was obtained. MS(ESI)192.1[M+H] +
  • Step 8 Refer to the preparation method of step 5 in Example 1, except that compound 58-7 is substituted for compound V4 to obtain a gray solid product L-58 (8.9 mg, 5.3%).
  • step 6 in Example 2 the difference is that 3-(azidomethyl)-1-methyl-1H-pyrazole is substituted for compound V4 to obtain white solid L-59 (1.56mg, P: 98.83% , Yield: 2.03%).
  • Step 1 Using pyridine-2,6-diyldimethanol (1.5 g, 10.78 mmol) as a raw material, referring to the preparation method of step 1 in Example 23, compound 60-1 (100 mg, yield: 6.06%) was obtained. MS (ESI) 154 [M+H]+.
  • Step 2 Using compound 60-1 as a raw material, referring to the preparation method of step 3 in Example 7 to obtain compound 60-2 (117 mg, yield: 100%). MS (ESI) 179 [M+H]+.
  • Step 3 Refer to the preparation method of step 5 in Example 1, except that compound 60-2 is substituted for compound V4 to obtain white solid L-60 (12.00 mg, P: 98.93%, yield: 14.07%).
  • Step 1-2 (6-Bromopyridin-2-yl)methanol (3.0g, 15.96mmol) was used as the raw material, referring to the preparation method of step 1-2 in Example 21, to obtain compound 64-2 (2.0g, yield: 100%)MS(ESI)294[M+H]+
  • Step 3 Using compound 64-2 as a raw material, referring to the preparation method of step 4 in Example 1, compound 64-3 (50 mgP: 95%, yield: 100%) is obtained. MS (ESI) 180 [M+H]+.
  • Step 4 Using compound 64-3 as a raw material, referring to the preparation method of step 3 in Example 7 to obtain compound 64-4 (380 mg, P: 100%, yield: 27%). MS (ESI) 205 [M+H]+.
  • Step 5 Refer to the preparation method of step 5 in Example 1, except that compound 64-4 is substituted for compound V4 to obtain white solid L-64 (7.41 mg, P: 99.39%, yield: 9.0%).
  • Step 1 Using 2-(azidomethyl)-6-fluoropyridine (100mg, 0.657mmol) and pyrrolidin-3-ol (286mg, 3.29mmol) as raw materials, refer to the preparation method of step 2 in Example 10 to obtain Colorless oil compound 65-1 (80 mg, P: 76.09%, yield: 55%). MS (ESI) 193 [M+H]+.
  • Step 2 Refer to the preparation method of step 5 in Example 1, except that compound 65-1 is substituted for compound V4 to obtain white solid L-65 (15.98 mg, P: 98.49%, yield: 9%) MS(ESI) 472.2 [M+H]+.
  • Step 1-2 Take the compound 2-bromo-6-((((tert-butyldimethylsilyl)oxy)methyl)pyridine (700mg, 2.32mmol) and cyclopentanone (234mg, 2.78mmol) As a raw material, refer to the preparation method of step 2-3 in Example 21 to obtain compound 66-2 (250 mg, P: 90%, yield: 100%) as a colorless oil. MS(ESI)194[M+H]+ .
  • Step 3 Using compound 66-2 as a raw material, referring to the preparation method of step 3 in Example 7 to obtain compound 66-3 (220 mg, P: 94.69%, yield: 93%) MS(ESI)219[M+H] +.
  • Step 1 Using (1-methyl-1H-pyrazol-3-yl)methanol (1.0g, 8.92mmol) as a raw material, refer to the preparation method of step 3 in Example 7 to obtain compound 67-1 (1.0g, P : 100%, yield: 82%). MS(ESI)138[M+H]+.
  • Step 2 Refer to the preparation method of step 5 in Example 1, except that compound 67-1 is substituted for compound V4 to obtain white solid L-67 (41.21 mg, P: 99.12%, yield: 26%).
  • Step 1 6-Isopropylpicolinic acid (1.0g, 6.05mmol) was dissolved in 20mL of methanol, protected by argon and cooled down to an ice bath , then SOCl 2 (2mL) was added dropwise, and then heated to 90°C and stirred overnight. The reaction solution was directly concentrated to dryness under reduced pressure, then saturated sodium bicarbonate solution was added, extracted with ethyl acetate (50mL*2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound 68-1 (1.0g, P : 91.52%, yield: 93%) MS(ESI)180[M+H]+.
  • Step 2-3 Using compound 68-1 as a raw material, referring to the preparation method of step 2-3 in Example 7 to obtain compound 68-3 (500 mg, P: 100%, yield: 61%). MS (ESI) 176 [M+H]+.
  • Step 4 Refer to the preparation method of step 5 in Example 1, except that compound 68-3 is substituted for compound V4 to obtain yellow solid compound L-68 (50.72 mg, P: 95.48, yield: 30%)
  • Step 1 Compound 2-(azidomethyl)-6-chloropyridine (300mg, 1.78mmol) and morpholine (2mL) were reacted with microwave heating to 130°C for 5 hours. The above reaction solution was added to water, extracted with ethyl acetate (50mL*2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound 69-1 (380mg, P: 79.95%, yield: 97%) MS (ESI) 220 [M+H]+.
  • Step 2 Refer to the preparation method of step 5 in Example 1, except that compound 69-1 is substituted for compound V4 to obtain white solid L-69 (18.27 mg, P: 100%, yield: 9%).
  • Step 1 Using 2-bromo-6-((((tert-butyldimethylsilyl)oxy)methyl)pyridine (1.0g, 3.31mmol) as raw material, refer to the preparation method of Example 21, step 2 , To obtain compound 70-1 (650 mg, P: 77.94%, yield: 78%) MS (ESI) 252 [M+H]+.
  • Step 2 Compound 70-1 (300mg, 1.19mmol) and morpholine (312mg, 3.58mmol) were added to 15mL of dichloromethane, stirred at room temperature and sodium acetate borohydride (759mg, 3.58mmol) was added, and the reaction solution was stirred at room temperature overnight .
  • the reaction solution was poured into water, extracted with dichloromethane (50mL*2), dried over anhydrous sodium sulfate, concentrated under reduced pressure to dryness, and separated and purified by silica gel column to obtain compound 70-2 (350mg, P: 70.73%, yield: 91 %) MS (ESI) 323.2 [M+H]+.
  • Step 3 Compound 70-2 (350 mg, 1.09 mmol) was dissolved in 5 mL of ethanol, 5 mL of 4.0 M dioxane hydrochloride solution was added with stirring at room temperature, and then stirring was continued at room temperature for 2 hours. Concentrate to dryness under reduced pressure to obtain compound 70-3 (266 mg, P: 90%, yield: 100%) MS(ESI) 209[M+H]+.
  • Step 4 Using compound 70-3 as a raw material, referring to the preparation method of step 3 in Example 7 to obtain compound 70-4 (350 mg, P: 93.52%, yield: 89%) MS(ESI) 234[ M+H]+.
  • Step 5 Refer to the preparation method of step 5 in Example 1, except that compound 70-4 is substituted for compound V4 to obtain white solid L-70 (18.69mg, P: 98.04%, yield: 10%)
  • Step 1-2 Using compound 70-1 (300 mg, 1.19 mmol) and 1-methylpiperazine (359 mg, 3.58 mmol) as raw materials, referring to the preparation method of step 2-3 in Example 70, compound 71-2 ( 350mg, P: 90%, yield: 100%). MS (ESI) 222 [M+H]+.
  • Step 3 Using compound 71-2 as a raw material, referring to the preparation method of Example 7 in step 3, a colorless oil 71-3 (350 mg, P: 94.24%, yield: 90%) is obtained. MS (ESI) 247 [M+H]+.
  • Step 5 Refer to the preparation method of step 5 in Example 1, except that compound 71-3 is substituted for compound V4 to obtain white solid L-71 (21.37 mg, P: 95.93%, yield: 11%).
  • Step 1 Using 2-(azidomethyl)-6-chloropyridine (300mg, 1.78mmol) and 1-methylpiperazine (2mL) as raw materials, refer to the preparation method of step 1 in Example 69 to obtain a colorless oil Compound 72-1 (390 mg, P: 94.65%, yield: 94%). MS (ESI) 233 [M+H]+.
  • Step 2 Refer to the preparation method of step 5 in Example 1, except that compound 72-1 is substituted for compound V4 to obtain white solid L-72 (18.69 mg, P: 100%, yield: 9%).
  • Step 1 6-(Difluoromethyl)picolinic acid (250mg, 1.44mmol) was dissolved in 15mL of methanol, protected by argon and cooled to an ice bath. Thionyl chloride (1mL) was added dropwise, and then warmed to room temperature Stir overnight. The reaction solution was directly concentrated to dryness under reduced pressure, then saturated sodium bicarbonate solution was added, extracted with ethyl acetate (50mL*2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 73-1 (270mg, P: 100%, yield Rate: 100%) MS (ESI) 188[M+H]+.
  • Step 2-3 Using compound 73-1 as a raw material, referring to the preparation method of step 2-3 in Example 7 to obtain compound 73-3 (180mg, P: 89.3%, yield: 74%) MS(ESI)185[ M+H]+.
  • Step 4 Refer to the preparation method of step 5 in Example 1, except that compound 73-3 is substituted for compound V4 to obtain white solid L-73 (30.24mg, P: 99.26%, yield: 19%)
  • MS(ESI)437[M+H] + Refer to the preparation method of step 5 in Example 1, except that compound 73-3 is substituted for compound V4 to obtain white solid L-73 (30.24mg, P: 99.26%, yield: 19%)
  • Step 1 Using 1H-pyrazole-3-carboxylic acid ethyl ester (2.5g, 17.98mmol) and 2-iodopropane (3.1g, 17.98mmol) as raw materials, refer to the preparation method of step 2 in Example 10 to obtain compound 74 -1 (1.35g, P: 100%, yield: 41%) MS (ESI) 183[M+H]+.
  • Step 2-3 Using compound 74-1 as a raw material, referring to the preparation method of step 2-3 in Example 7 to obtain compound 74-3 (200 mg, P: 90%, yield: 59%). MS (ESI) 166 [M+H]+.
  • Step 4 Refer to the preparation method of step 5 in Example 1, except that compound 74-3 is substituted for compound V4 to obtain yellow solid L-74 (50.72 mg, P: 100%, yield: 8%).
  • Step 1 Using 1H-pyrazole-3-carboxylic acid ethyl ester (2.5g, 17.98mmol) and 2-iodopropane (3.1g, 17.98mmol) as raw materials, refer to the preparation method of step 2 in Example 10 to obtain compound 75 -1 (1.2g, P: 100%, yield: 37%). MS (ESI) 183 [M+H]+.
  • Step 2-3 Using compound 75-1 as a raw material, referring to the preparation method of step 2-3 in Example 7 to obtain compound 75-3 (600 mg, P: 70%, yield: 51%) MS(ESI) 166[ M+H]+.
  • Step 4 Refer to the preparation method of step 5 in Example 1, except that compound 75-3 is substituted for compound V4 to obtain yellow solid L-75 (30.34 mg, P: 97.82%, yield: 18%).
  • Step 1 Using 1H-pyrazole-3-carboxylic acid ethyl ester (1.3g, 9.28mmol) and 1-chloro-2-methylpropan-2-ol (1.3g, 12.06mmol) as raw materials, refer to Example 10
  • the preparation method of step 2 yielded compound 76-1 (1.4g, P: 100%, yield: 71%) MS(ESI)213[M+H]+.
  • Step 2-3 Using compound 76-1 as a raw material, referring to the preparation method of step 2-3 in Example 7 to obtain compound 76-3 (250 mg, P: 73.52%, yield: 31%) MS(ESI)196[ M+H]+.
  • Step 4 Refer to the preparation method of step 5 in Example 1, except that compound 76-3 is substituted for compound V4 to obtain white solid L-76 (9.58 mg, P: 98.67%, yield: 5%).
  • Step 1 Using compound 1H-pyrazole-3-carboxylic acid ethyl ester (0.71g, 5.07mmol) and 3-iodotetrahydrofuran (1.0g, 5.07mmol) as raw materials, refer to the preparation method of step 2 in Example 10 to obtain the compound 77-1 (0.41g, P: 87.79%, yield: 38%). MS (ESI) 211 [M+H]+.
  • Step 2-3 Using compound 77-1 as a raw material, referring to the preparation method of step 2-3 in Example 7 to obtain compound 77-3 (300 mg, P: 100%, yield: 81%). MS (ESI) 166 [M+H]+.
  • Step 4 Refer to the preparation method of step 5 in Example 1, except that compound 77-3 is substituted for compound V4 to obtain white solid L-77 (46.16 mg, P: 100%, yield: 26%).
  • Step 1 Using 1H-pyrazole-3-carboxylic acid ethyl ester (1.5g, 11.89mmol) and 1-bromo-2-methoxyethane (1.98g, 14.27mmol) as raw materials, refer to Example 23, step 1 The preparation method of to obtain colorless oil 78-1 (0.8g, 32.43% yield, 88.82% purity).
  • Step 2-3 Using compound 78-1 as a raw material, referring to the preparation method of step 2-3 in Example 7, a colorless oily substance 78-3 (600 mg, 81.89% yield, 95% purity) is obtained.
  • Step 4 Refer to the preparation method of step 5 in Example 1, except that compound 78-3 is substituted for compound V4 to obtain green solid L-78 (72.59 mg, 52.29% yield, 99.02% purity).
  • Step 1-2 Using 1,5-dimethyl-1H-pyrazole-3-carboxylic acid methyl ester (1.0g, 6.49mmol) as raw material, refer to the preparation method of step 2-3 in Example 7 to obtain a yellow solid 79-2 (700 mg, 83.45% yield). MS (ESI) 152 [M+H]+.
  • Step 3 Refer to the preparation method of step 5 in Example 1, except that compound 79-2 is substituted for compound V4 to obtain white solid L-79 (26.66 mg, 16.08% yield, 96.47% purity).
  • MS(ESI)404[M+H] + .
  • Step 1 Using 1H-pyrazole-3-carboxylic acid ethyl ester (1g, 7.14mmol) as a raw material, refer to the preparation method of Example 21, step 2 to obtain compound 80-1 (0.55g, 29.57% yield, 60.67% purity). MS (ESI) 159 [M+H]+.
  • Step 2 Using compound 80-1 (550mg, 3.48mmol) and methyl iodide (987.37mg, 6.96mmol) as raw materials, refer to the preparation method of step 1 in Example 23 to obtain compound 80-2 (400mg, 47.61% yield, 71.27% purity). MS (ESI) 173 [M+H]+.
  • Step 3-4 Using compound 80-2 as a raw material, refer to the preparation method of step 2-3 in Example 7 to obtain compound 80-4 (100 mg, 36.22% yield, 95% purity). MS (ESI) 156 [M+H]+.
  • Step 5 Refer to the preparation method of step 5 in Example 1, except that compound 80-4 is substituted for compound V4 to obtain white compound L-80 (34.57mg, 38.42% yield, 98.73% purity)
  • Step 1 Use 2-bromo-6-((((tert-butyldimethylsilyl)oxy)methyl)pyridine (500mg, 1.65mmol) and 1,1,1-trifluoroacetone (278.01mg , 2.48mmol) as the raw material, refer to the preparation method of step 2 in Example 53, to obtain colorless oil compound 81-1 (160mg, 27.32% yield, 94.73% purity). MS(ESI)336[M+H] + .
  • Step 2 Compound 81-1 is used as a raw material, referring to the preparation method of step 3 in Example 70, to obtain compound 81-2 (100 mg, 90.18% yield, 95.14% purity) as a yellow oil. MS (ESI) 222 [M+H] + .
  • Step 3 Using compound 81-2 as a raw material, referring to the preparation method of step 3 in Example 7, compound 81-3 (80 mg, 54.03% yield, 97.72% purity) was obtained as a colorless oil. MS(ESI)247[M+H] + .
  • Step 4 Refer to the preparation method of step 5 in Example 1, except that compound 81-3 is used to replace compound V4 to obtain white solid L-81 (42.86 mg, 83.86% yield, 98.40% purity).
  • Step 1 Using 5-chloro-1H-pyrazole-3-carboxylic acid (250mg, 1.71mmol) as a raw material, referring to the preparation method of step 1 in Example 73, a white solid 82-1 (273mg, 99.66% yield, 100% purity). MS (ESI) 161 [M+H] + .
  • Step 2 Using compound 82-1 as the starting material, referring to the preparation method of step 1 in Example 23, compound 82-2 (297 mg, 81.49% yield, 81.75% purity) was obtained as a colorless oil. MS (ESI) 175 [M+H] + .
  • Step 3-4 Using compound 82-2 as a raw material, referring to the preparation method of step 2-3 in Example 7, compound 82-4 was obtained as a colorless oil (130 mg, 55.52% yield). MS (ESI) 172 [M+H] + .
  • Step 5 Refer to the preparation method of step 5 in Example 1, except that compound 72-4 is used to replace compound V4 to obtain white solid L-82 (48.13 mg, 27.44% yield, 95.79% purity)
  • MS(ESI)424[M+H] + MS(ESI)424[M+H] + .
  • Step 1 Using 1H-pyrazole-3-carboxylic acid ethyl ester (552mg, 4.38mmol) and 2-(iodomethyl)tetrahydrofuran (1.06g, 8.75mmol) as raw materials, refer to the preparation method of step 2 in Example 10.
  • Compound 83-1 550 mg, 56.79% yield, 95.02% purity was obtained.
  • Step 2-3 Using compound 83-1 as a raw material, referring to the preparation method of step 2-3 in Example 7 to obtain compound 83-3 (250 mg, 62.81% yield, 100% purity). MS (ESI) 208 [M+H] + .
  • Step 4 Refer to the preparation method of step 5 in Example 1, except that compound 83-3 is substituted for compound V4 to obtain white solid L-83 (14.23 mg, 12.93% yield, 99.29% purity).
  • Step 1-2 Using 3-(methylsulfonyl)benzoic acid (300 mg, 1.50 mmol) as a raw material, refer to the preparation method of step 2-3 in Example 7 to obtain a crude compound 84-3 (256 mg).
  • Step 3 Refer to the preparation method of step 5 in Example 1, except that compound 84-3 is substituted for compound V4 to obtain off-white solid L-84 (1.74 mgmg, P: 99.33%, yield: 2.0%) MS(ESI) 480.0[M+H]+.
  • Step 1 1-(6-(Hydroxymethyl)pyridin-2-yl)ethane-1-one (500mg, 3.31mmol) was dissolved in anhydrous tetrahydrofuran (10mL), and ethylmagnesium bromide was added under ice (3.3ml, 6.60mmol), the reaction solution was stirred at room temperature for 3 hours. Saturated ammonium chloride (2 mL) was added dropwise to the reaction solution at 0°C to quench the reaction. After stirring at room temperature for 10 minutes, a solid precipitated out and filtered.
  • Step 2 Using compound 85-1 as a raw material, referring to the preparation method of step 3 in Example 7, a crude compound 85-2 (264 mg) was obtained.
  • Step 3 Refer to the preparation method of step 5 in Example 1, except that compound 85-2 is substituted for compound V4 to obtain white solid L-85 (10.35 mg, P: 96.97%, yield: 5.7%) MS(ESI) 459.1 [M+H]+.
  • Step 1 Using 1-(6-(hydroxymethyl)pyridin-2-yl)ethane-1-one (500mg, 3.31mmol) as a raw material, refer to the preparation method of step 1 in Example 21 to obtain a colorless oil Compound 86-1 (680 mg, P: 91.74%, yield: 77.7%). MS (ESI) 266.1 [M+H]+.
  • Step 2 Using compound 86-1 as a raw material, referring to the preparation method of step 3 in Example 11, compound 86-2 (567 mg, P: 89.12%, yield: 82.8%) was obtained as a colorless oily substance. MS (ESI) 268.1 [M+H]+.
  • Step 3 Using compound 86-2 (567 mg, 2.12 mmol) and methyl iodide (602 mg, 4.24 mmol), referring to the preparation method of step 1 in Example 23, compound 86-3 (518 mg) was obtained. MS (ESI) 282.1 [M+H]+.
  • Step 4 Using compound 86-3 as a raw material, referring to the preparation method of step 4 in Example 1, a colorless oil 86-4 (288 mg, P: 98.79%, yield: 95.2%) was obtained. MS (ESI) 168.1 [M+H]+.
  • Step 5 Using compound 86-4 as a raw material, referring to the preparation method of step 3 in Example 7 to obtain compound 86-5 (302 mg).
  • Step 6 Refer to the preparation method of step 5 in Example 1, except that compound 86-5 is substituted for compound V4 to obtain white solid L-86 (7.31 mg, P: 100%, yield: 4.1%) MS (ESI) 445.2 [M+H]+.
  • Step 1 Refer to the preparation method of step 1 in Example 1, except that 2,4,5,6-tetrachloropyrimidine is used to replace 2,4,6-trichloro-5-fluoropyrimidine to obtain a pale yellow liquid 87-1 ( 2.78g, P: 81.12%, yield: 67.53%) MS (ESI) 363.0 [M+H]+.
  • Step 2 Add compound 87-1 (2.70g, 7.43mmol) and methoxyamine hydrochloride (1.24g, 14.85mmol) to anhydrous tetrahydrofuran (25mL), add triethylamine (2.25g, 22.27mmol) at room temperature ), the reaction solution was stirred overnight at room temperature, the reaction solution was evaporated to dryness under reduced pressure, extracted with EA (30 mL), the organic phase was dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure to obtain compound 87-2 (1.66 g). MS (ESI) 374.1 [M+H]+.
  • Step 3-5 Refer to the preparation method of step 3-5 in Example 1, except that compound 87-2 is substituted for compound 1-3, and 3-(azidomethyl)-1-methyl-1H-pyrazole is substituted for Intermediate V4, a pale yellow solid product L-87 (27.56 mg, P: 99.91%, yield: 22.12%) MS (ESI) 436.1 [M+H] + was obtained.
  • Step 1 Using 1H-pyrazole-3-carboxylic acid ethyl ester (400mg, 2.85mmol) and 3-iodooxetane (630mg, 3.43mmol) as raw materials, refer to the preparation method of step 2 in Example 10, the compound 88-2. MS(ESI)197.1[M+H]+.
  • Step 2-3 Using compound 88-2 as a raw material, referring to the preparation method of step 2-3 in Example 7 to obtain compound 88-3 (146 mg), MS (ESI) 180.1[M+H]+.
  • Step 4 Refer to the preparation method of step 5 in Example 1, the difference is that compound 88-3 replaces compound V4 to obtain off-white solid compound L-88 (10.86 mg, P: 96.43%, yield: 12.25%) MS(ESI) 432.1 [M+H]+.
  • Step 1-2 Using tetrahydropyran-4-ol (1g, 9.79mmol) as a raw material, referring to the preparation method of Intermediate V5 Step 1, to obtain compound 89-2 (197mg, P: 84.8%, two-step reaction yield The total rate is 20.88%). MS (ESI) 225.1 [M+H]+.
  • Step 3-4 Using compound 89-2 as a raw material, refer to the preparation method of step 2-3 in Example 7 to obtain compound 89-4 (162 mg). MS(ESI)208.1[M+H]+.
  • Step 5 Refer to the preparation method of step 5 in Example 1, the difference is that compound 89-4 replaces compound V4 to obtain off-white solid L-89 (11.10 mg, P: 98.27%, yield: 11.26%) MS(ESI) 460.1[ M+H]+.
  • Step 1-2 Using 1-methylpyrrolidin-3-ol (1g, 9.89mmol) as raw material, referring to the preparation method of Intermediate V5 in Step 1, to obtain compound 90-2 (542mg, P: 93.82%, yield : 53.96%) MS (ESI) 224.1 [M+H]+.
  • Step 3-4 Using compound 90-2 as a raw material, referring to the preparation method of step 2-3 in Example 7 to obtain compound 90-4 (261 mg). MS(ESI)207.1[M+H]+.
  • Step 5 Refer to the preparation method of step 5 in Example 1, the difference is that compound 90-4 replaces compound V4 to obtain white solid L-90 (2.09mg, P: 99.64%, yield: the total yield of the three-step reaction is 1.54%) .
  • Step 1 Using compound 1-2 as raw material, refer to the preparation method of Example 87, step 2 to obtain compound 91-1, MS(ESI) 342.1[M+H]+ Step 2-4: Refer to Example 1, Step 3- The preparation method of 5, the difference is that compound 91-1 is substituted for compound 1-3, and 3-(azidomethyl)-1-methyl-1H-pyrazole is substituted for intermediate V4 to obtain the off-white solid product L-91 (48.07mg, P: 99.22%, yield: 36.71%) MS(ESI)404.1[M+H]+.
  • Step 1 Dissolve potassium tert-butoxide (3.20g, 28.53mmol) in 10mL of anhydrous tetrahydrofuran solution, and slowly add 1-cyclopropanone (2g, 23.78mmol) and oxalic acid to the solution in an ice bath.
  • dimethyl ester 3.09 g, 26.15 mmol
  • toluene 20 mL
  • the reaction solution was slowly warmed to room temperature and stirred at room temperature for 18 hours.
  • Under ice bath add HCl (1mol/L 15mL) to the reaction solution, stir for 10 minutes, and extract three times with ethyl acetate (25mL*3).
  • the compound 92-1 (3.18 g) was obtained by drying with anhydrous sodium sulfate and rotary drying under reduced pressure.
  • Step 2 Using compound 92-1 as a raw material, refer to the preparation method of step 1 in Example 51 to obtain compound 92-2. MS (ESI) 181.1 [M+H]+. Step 3-4: Using compound 92-2 as a raw material, referring to the preparation method of step 2-3 in Example 7, compound 92-4 (243 mg) was obtained. MS (ESI) 178.1 [M+H]+.
  • Step 5 Refer to the preparation method of step 5 in Example 1, the difference is that compound 92-4 replaces compound V4 to obtain off-white solid L-92 (16.91 mg, P: 96.80%) MS(ESI) 430.1[M+H]+ .
  • Step 1 Using 1H-pyrazole-3-carboxylic acid ethyl ester (800mg, 5.71mmol) and 3-iodooxetane (1.37g, 7.42mmol) as raw materials, refer to the preparation method of step 2 in Example 10. A colorless oil 93-1 (348 mg, P: 100%, yield: 31.07%) was obtained. MS (ESI) 197.1 [M+H]+.
  • Step 2-3 Using compound 93-1 as the starting material, refer to the preparation method of step 2-3 in Example 7 to obtain compound 93-3 (295 mg). MS(ESI)180.1[M+H]+.
  • Step 4 Using compound 93-3 and intermediate V8 as raw materials, referring to the preparation method of step 5 in Example 1, the green solid product L-93 (6.02mg, P: 96.38%) MS(ESI)448.1[M+H ]+.
  • Step 1 Dissolve methyl acetoacetate (31.4g, 270.42mmol) in AcOH (34mL), lower the reaction temperature to 0°C, and then drop a solution of NaNO2 (20.52g, 297.46mmol) in water (40mL) into the reaction After the addition was completed, the reaction was naturally warmed to room temperature and stirred for 0.5 hours, and then water (60 mL) was added and stirred for 16 hours. After the reaction was completed, water (200 mL) was added to the reaction solution, extracted with ethyl acetate, washed with saturated sodium bicarbonate, washed with saturated aqueous sodium chloride, dried with anhydrous sodium sulfate, filtered and concentrated. Purified by column chromatography (120 g, 0-25% EA/PE), a colorless oily compound 94-1 (27.6 g, yield: 70%) MS (ESI) 146.1 [M+H] + was obtained.
  • Step 2 Dissolve compound 94-1 (13.8g, 95.10mmol) and KI (8.68g, 52.30mmol) in ACN (150mL), and then add TEA (20.21g, 199.71mmol) to it to lower the reaction to 0°C. TMSCl (21.70 g, 199.71 mmol) was added dropwise, and the addition was completed, and the reaction was stirred at room temperature for 18 hours. Filtered and concentrated, then dissolved with methyl tert-butyl ether, filtered and concentrated to obtain oily black compound 94-2 (27.53g).
  • Step 3 Compound 94-2 (20.66g, 71.37mmol) and methyl propiolate (4g, 47.58mmol) were stirred at 150°C for 18 hours, cooled to room temperature, and subjected to column chromatography (120g, 0 ⁇ 30 %EA/PE) to obtain a light yellow solid compound 94-3 (3.2g, yield: 32%). MS(ESI)212.1[M+H]+.
  • Step 4 The compound 94-3 ((1g, 4.74mmol) and TEA (1.44g, 14.21mmol) were dissolved in DCM (35mL), and then (chloromethoxy)ethane (582.00mg, 6.16mmol) DCM (2mL) solution was added dropwise. The reaction was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was poured into water, the organic phase was separated, the aqueous phase was extracted with dichloromethane, the organic phases were combined, and anhydrous sodium sulfate Dry, filter, and concentrate the filtrate to give compound 94-24 (1.28 g) as a pale yellow oil. MS (ESI) 270.1 [M+H]+.
  • Step 5 Using compound 94-4 (1.28g, 4.75mmol) as a raw material, referring to the preparation method of step 3 in Example 11, a light yellow oily compound 94-5 (421mg, yield: 37%) was obtained, 1 H NMR ( 400MHz, cdcl3) ⁇ 8.04 (1H, d, J 8.6), 7.50 (1H, d, J 8.5), 5.34 (2H, s), 4.78 (2H, s), 3.96 (3H, s), 3.72 (2H) ,q,J 7.1),1.20(3H,t,J 7.1).MS(ESI)242.1[M+H]+.
  • Step 6 Using compound 94-5 (390.00 mg, 1.62 mmol) as a raw material, referring to the preparation method of step 3 in Example 10, compound 94-6 (212 mg, yield: 54%) was obtained as a pale yellow oil. MS(ESI)242.2[M+H]+.
  • Step 7 Using compound 94-6 (212 mg, 878.64 ⁇ mol) as a raw material, referring to the preparation method of step 3 in Example 7, compound 94-7 (324 mg) was obtained as a pale yellow oil. MS(ESI)267.2[M+H]+.
  • Step 8 Refer to the preparation method of step 5 in Example 1, except that compound 94-7 is substituted for compound V4 to obtain compound 94-8 (201 mg, yield: 49%) as an off-white solid. MS(ESI)519.3[M+H]+.
  • Step 9 Compound 94-8 (201 mg, 387.63 ⁇ mol) was dissolved in MeOH (15 mL), and then HCl (1M, 5 mL) was added to it. The reaction was stirred at 30° C. for 10 hours, spin-dried under reduced pressure, and separated by HPLC preparative chromatography to obtain white solid L-94 (60.12 mg, yield: 33%). MS(ESI)461.2[M+H]+.
  • Step 1 Using compound 97-1 and bromoacetonitrile as raw materials, refer to the preparation method of step 1 in Example 7 to obtain compound 97-2.
  • Step 2 Refer to the preparation method of Example 1 Step: 5, the difference is that compound 97-2 is substituted for compound V4 to obtain compound L-97.
  • Step 1 Using compound 98-1 as a raw material, referring to the preparation method of step 1 in Example 85, compound 98-2 was obtained.
  • Step 2 Using compound 98-2 as a raw material, referring to the preparation method of step 3 in Example 70, compound 98-3 was obtained.
  • Step 3 Using compound 98-3 as a raw material, referring to the preparation method of step 3 in Example 7 to obtain compound 98-4.
  • Step 4 Refer to the preparation method of step 5 in Example 1, except that compound 98-4 is substituted for compound V4 to obtain compound L-98.
  • Test Example 1 Inhibitory activity on A2A receptor and A2B receptor
  • CHO-K1/ADORA2A/G ⁇ 15 (GenScript, M00246) and CHO-K1/ADORA2B/G ⁇ 15 (GenScript, M00329) cells are cultured in Ham's F-12 (Gibco, 31765092) medium, and the medium condition is 10% FBS, 200ug/ml Zeocin and 100ug/ml Hygromycin B or 10% FBS, 400ug/ml G418 and 100ug/ml Hygromycin B.
  • the medium condition is 10% FBS, 200ug/ml Zeocin and 100ug/ml Hygromycin B or 10% FBS, 400ug/ml G418 and 100ug/ml Hygromycin B.
  • the screening steps are as follows:
  • Test Example 2 Inhibitory activity on A2A receptor and A2B receptor
  • CHO-K1/ADORA2A/G ⁇ 15 (GenScript, M00246) and CHO-K1/ADORA2B/G ⁇ 15 (GenScript, M00329) cells are cultured in Ham's F-12 (Gibco, 31765092) medium, and the medium condition is 10% FBS, 200ug/ml Zeocin and 100ug/ml Hygromycin B or 10% FBS, 400ug/ml G418 and 100ug/ml Hygromycin B.
  • the medium condition is 10% FBS, 200ug/ml Zeocin and 100ug/ml Hygromycin B or 10% FBS, 400ug/ml G418 and 100ug/ml Hygromycin B.
  • the screening steps are as follows:
  • Test Example 3 In vivo pharmacokinetic test
  • the LC/MS/MS method was used to determine the drug concentration in the plasma of mice at different times after intravenous injection and oral gavage administration of the compound of the present invention, to study the pharmacokinetic behavior of the compound of the present invention in mice, and to evaluate Its pharmacokinetic characteristics.
  • Test animals Healthy adult male ICR mice (weight 25-40g, 12 mice, the mice in the intravenous injection group are free to drink and eat, the intragastric administration group is fasted overnight, and the drug is free to drink and eat 4 hours after the administration), by Beijing Vital Provided by River Laboratory Animal Co.LTD;
  • Mode of administration and dosage Before administration, select animals that meet the experimental requirements, and weigh and mark them. ICR mice were given tail vein administration (2mg/kg, 5% DMSO, pH 4.5 20% Captisol) and intragastric administration (10 mg/kg, 5% DMSO, pH 4.5 20% Captisol).
  • Blood sample collection Before collecting blood samples, bind the mice, and each administered mouse will collect blood at a predetermined time point (intravenous administration: 0.083, 0.25, 0.5, 1, 2, 4, 6 after administration, respectively). , 7.5, 24h blood collection, 9 time points; gavage administration: blood collection at 0.083, 0.25, 0.5, 1, 2, 4, 6, 7.5, 24h after administration, a total of 9 time points), passed About 100 ⁇ L of blood was collected from the jugular vein. The blood was transferred to a 1.5 mL test tube pre-added with K2EDTA, centrifuged for 4 minutes (8000 rpm, 4°C), and plasma was separated. The whole process was completed within 15 minutes after blood collection. All samples need to be stored in a refrigerator at -20°C until the sample is analyzed. The LC/MS/MS method was used to determine the drug concentration.
  • mice The pharmacokinetic properties of some of the compounds of the present invention under the same dosage of intragastric administration, the pharmacokinetic properties in mice are shown in Table 4:
  • Test Example 4 In vivo efficacy experiment of the compound of the present invention
  • This test example investigates the mouse colon cancer cell line MC38(#22)-hpd-L1 subcutaneously transplanted tumor mice, after administering the compound of the present invention through oral administration, it is tested against colon cancer MC38(#22)- In vivo efficacy of hpd-L1 tumor-bearing mice.
  • mice female
  • mouse colon cancer MC38(#22)-hpd-L1 cells (Shanghai Jiaotong University Cell Bank), cultured in a monolayer in vitro, and the culture condition is RPMI containing 10% fetal bovine serum -1640 medium, cultured in a 5% CO2 incubator at 37°C.
  • pancreatin-EDTA for routine digestion and passage.
  • the cells are in the exponential growth phase and the saturation is 80%-90%, the cells are collected and counted.
  • mice resuspend the cells in phosphate buffer at a density of 5 ⁇ 10 6 cells/mL.
  • 0.1mL PBS containing 5 ⁇ 105 MC38(#22)-hpd-L1 cells
  • the mice were randomly grouped according to their body weight. Each group was 10 mice, and the administration was started.
  • the anti-tumor efficacy of the compound was evaluated by the relative tumor growth rate T/C (%).
  • Relative tumor proliferation rate T/C (%) Vt/Vc ⁇ 100% (Vt: average tumor volume in the treatment group; Vc: average tumor volume in the negative control group). Vt and Vc take the same day's data.

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Abstract

提供了一种结构如式(I)所示的取代的嘧啶或吡啶胺衍生物、该衍生物的药学上可接受的盐、其溶剂化物、立体异构体、前药、药物组合物以及其在医药上的应用。所述衍生物具有显著的腺苷A 2A受体和/或腺苷A 2B受体拮抗活性。

Description

取代的嘧啶或吡啶胺衍生物、其组合物及医药上的用途 技术领域
本发明涉及医药技术领域，特别涉及一种取代的嘧啶或吡啶胺衍生物、或其药学上可接受的盐、溶剂化物、立体异构体、前药、或药物组合物以及其在医药上的用途。
背景技术
腺苷(Adenosine)是一种遍布人体细胞的内源性核苷，由腺嘌呤和核糖组成，其广泛分布于细胞内和细胞外。腺苷参与体内多种生理生化功能，例如，腺苷能直接进入心肌，经磷酸化生成三磷酸腺苷酸(Adenosine triphosphate,ATP)，参与心肌的能量代谢。在中枢神经系统(Central Nervous System,CNS)中，腺苷控制着神经递质的释放和突触后神经元的反应，起着调节运动、保护神经元、影响睡眠以及觉醒等重要生命过程的作用。在病理状态下，细胞外的腺苷浓度在肿瘤或者缺氧条件下会显著增加。腺苷可以通过促进肿瘤血管生成、增殖、发展以及肿瘤迁移在肿瘤免疫抑制中发挥着重要作用。
腺苷受体(Adenosine Receptor，AR)属于G蛋白偶联受体(Guanosine-binding Protein Coupled Receptor，GPCR)家族，其内源配体为腺苷。目前已知的腺苷受体由A1，A2a，A2b和A3四种亚型受体组成。其中腺苷与A1或A3受体结合可以抑制环磷酸腺苷(cAMP)的产生；而与A2a或A2b受体结合可以活化腺苷活化酶，进而上调cAMP的水平，发挥进一步的生理调控作用。
A1和A3两种受体主要表达在中枢神经系统中，而A2a和A2b两种腺苷受体在中枢神经系统及外周系统都有表达。在肿瘤微环境内，A2a和A2b两种腺苷受体广泛表达在免疫细胞中，具有很强的免疫抑制功能。细胞外腺苷浓度的增加是肿瘤细胞免疫逃逸的重要作用机制之一，其浓度水平是由ATP的水平以及CD39与CD73的表达水平共同决定的。细胞外腺苷浓度的增加与肿瘤微环境里细胞死亡或者缺氧释放大量的ATP相关，其浓度可以达到正常组织的10-20倍。腺苷与肿瘤微环境里的腺苷受体结合，可以抑制抗肿瘤反应，例如抑制CD8+T细胞的功能，增强免疫抑制调节T细胞的功能，通过树突状细胞抑制抗原递呈细胞的功能等。最近的研究表明，与A2a受体结合还可以抑制自然杀伤细胞的肿瘤杀伤作用。进一步研究表明，A2a腺苷受体拮抗剂能提高树突状抗原递呈细胞、T细胞以及自然杀伤细胞的活力和杀伤能力，抑制调节性T细胞(T-regs)、骨髓来源的抑制性细胞(MDSCs)和肿瘤相关巨噬细胞(TAM)的功能，消除肿瘤免疫耐受，促进肿瘤免疫应答的发生，进而导致肿瘤生长受到抑制，并延长小鼠的生存期。此外，A2b受体还被报道在鼠黑色素瘤和三阴乳腺癌模型中可以促进肿瘤的迁移，因此A2b受体拮抗剂也是有效的癌症治疗靶标。所以阻断腺苷信号通路活化减少或解除免疫抑制，增强免疫细胞-尤其是T细胞的抗肿瘤功能被认为是癌症治疗的有效手段之一。而A2a/A2b双重受体拮抗剂用来同时阻断这两种受体的活化，从机制上说，是在调控不同的免疫细胞群，综合阻断微环境内腺苷带来的免疫抑制作用，对肿瘤治疗有着深远的临床应用价值。
目前腺苷受体拮抗剂单独用药或者与其他化疗药物/免疫调控药物联合使用，是目前临床研究的热点。
发明内容
本发明的目的是提供一种活性更高的、选择性更好、毒性更低的取代的嘧啶或吡啶胺衍生物。本发明第一方面提供了一种式(I)所示的化合物、或其药学上可接受的盐、或其立体异构体、或其溶剂化物、或其前药：
Figure PCTCN2021081126-appb-000001
式中，环A为5至10元杂芳基、苯基或吡啶酮基；
环B为苯基或5至10元杂芳基；
Q为5至6元杂芳基、苯基、C 3-6环烷基、4至8元杂环烷基、6至12元稠合杂环烷基、7至11元苯基并杂环烷基、7至11元杂芳基并杂环烷基、7至11元螺环基或7至11元杂螺环基；其中所述的5至6元杂芳基、苯基、C 3-6环烷基、4至8元杂环烷基、6至12元稠合杂环烷基、7至11元苯基并杂环烷基、7至11元杂芳基并杂环烷基、7至11元螺环基和7至11元杂螺环基为未取代的或被1、2或3个各自独立地选自下组的取代基取代：氘、卤素、氰基、羟基、羧基、氧代基、C 1-3烷基、C 1-3烷氧基、C 2-4烯基、C 2-4炔基、卤代C 1-3烷基、卤代C 1-3烷氧基、NR a0R b0、-C(O)C 1-3烷基、-SO 2C 1-3烷基、-S(O)C 1-3烷基、-C(O)NR a0R b0、-C(O)OC 1-3烷基、-OC(O)C 1-3烷基、C 3-6环烷基、C 3-6环烷基氧基、3至6元杂环烷基、苯基和5至6元杂芳基；
L 1、L 2各自独立地为一个键、NR 1'、CR 2'R 3'、O、S或C(O)；且L 1、L 2不同时为O或S；
R 1'、R 2'、R 3'各自独立地为氢、氘、氰基、羟基、卤素(优选为氟或氯)或C 1-6烷基；或者R 1'与R 2'连接形成3至8元杂环烷基环；或者R 2'与R 3'连接形成3至8元杂环烷基环；其中所述的3至8元杂环烷基环为未取代的或被1、2或3个各自独立地选自下组的取代基取代：氘、卤素、氰基、羟基、C 1-3烷基、C 1-3烷氧基、C 2-4烯基、C 2-4炔基、卤代C 1-3烷基、卤代C 1-3烷氧基、-SO 2C 1-3烷基、-S(O)C 1-3烷基、-C(O)NR a0R b0、-C(O)OC 1-3烷基、-OC(O)C 1-3烷基、C 3-6环烷基、C 3-6环烷基氧基、3至6元杂环烷基、苯基和5至6元杂芳基；
W为N或CR W；
R W为氰基、羟基、卤素(优选为氟或氯)、卤代C 1-8烷基(优选为卤代C 1-6烷基，更优选为卤代C 1-3烷基)、卤代C 1-8烷氧基(优选为卤代C 1-6烷氧基，更优选为卤代C 1-3烷氧基)或C 1-8烷氧基(优选为C 1-6烷氧基，更优选为C 1-3烷氧基)；
R c、R a和R b定义如下：
(i)R c为氟、氯、氰基、C 1-3烷氧基或卤代C 1-3烷氧基；
R a、R b各自独立地为氢、氘、C 1-8烷基(优选为C 1-6烷基，更优选为C 1-3烷基)、C 1-8烷氧基(优选为C 1-6烷氧基，更优选为C 1-3烷氧基)、-C(O)C 1-8烷基(优选为-C(O)C 1-6烷基，更优选为-C(O)C 1-3烷基)、-(CH 2) tC 3-8环烷基(优选为-(CH 2) tC 3-6环烷基)、-(CH 2) t-3至8元杂环烷基或为式(a)结构
Figure PCTCN2021081126-appb-000002
其中所述C 1-8烷基、-C(O)C 1-8烷基和-(CH 2) t-3至8元杂环烷基为未取代的或被1、2或3个各自独立地选自下组的取代基取代：氘、卤素、氰基、羟基、C 1-3烷基、C 1-3烷氧基、C 2-4烯基、C 2-4炔基、卤代C 1-3烷基、卤代C 1-3烷氧基、-SO 2C 1-3烷基、-S(O)C 1-3烷基、-C(O)NR a0R b0、-C(O)OC 1-3烷基、-OC(O)C 1-3烷基、C 3-6环烷基、C 3-6环烷基氧基、3至6元杂环烷基、苯基和5至6元杂芳基；或者R a、R b与相连的氮原子共同形成5或6元饱和或部分不饱和单杂环；其中所述5或6元饱和或部分不饱和单杂环为未取代的或被1、2或3个各自独立地选自下组的取代基取代：氘、卤素、氰基、羟基、C 1-3烷基、C 1-3烷氧基、C 2-4烯基、C 2-4炔基、卤代C 1-3烷基、卤代C 1-3烷氧基、-SO 2C 1-3烷基、-S(O)C 1-3烷基、-C(O)NR a0R b0、-C(O)OC 1-3烷基、-OC(O)C 1-3烷基、C 3-6环烷基、C 3-6环烷基氧基、3至6元杂环烷基、苯基和5至6元杂芳基；
其中R 1a为氢或C 1-3烷基；R 2a、R 3a各自独立地为氢或C 1-3烷基；或者R 2a与R 3a连接形成5至8元杂环烯基环或5至6元杂芳基环；所述5至8元杂环烯基环含有2、3或4个氮原子和0、1或2个氧原子；所述5至6元杂芳基环含有2、3或4个氮原子和0或1个氧原子；所述5至8元的杂环烯基环和5至6元杂芳基环为未取代的或被1、2或3个各自独立地选自下组的取代基取代：卤素、氰基、羟基、C 1-3烷基、C 1-3烷氧基、卤代C 1-3烷基和卤代C 1-3烷氧基；
(ii)R c与R a连接形成稠合的5或6元饱和或部分不饱和单杂环、或稠合的5至6元杂芳基环；所述稠合的5或6元饱和或部分不饱和单杂环和5至6元杂芳基环为未取代的或被1、2或3个各自独立地选自下组的取代基取代：氘、卤素、氰基、羟基、氧代基、C 1-3烷基、C 1-3烷氧基、C 2-4烯基、C 2-4炔基、卤代C 1-3烷基、卤代C 1-3烷氧基、-SO 2C 1-3烷基、-S(O)C 1-3烷基、-C(O)NR a0R b0、-C(O)OC 1-3烷基、-OC(O)C 1-3烷基、C 3-6环烷基、C 3-6环烷基氧基、3至6元杂环烷基、苯基和5至6元杂芳基；
R b为氢、氘、C 1-8烷基(优选为C 1-6烷基，更优选为C 1-3烷基)、-C(O)C 1-8烷基(优选为-C(O)C 1-6烷基，更优选为-C(O)C 1-3烷基)、-(CH 2) tC 3-8环烷基(优选为-(CH 2) tC 3-6环烷基)、-(CH 2) t-3至8元杂环烷基或为式(a)结构；其中所述C 1-8烷基、-C(O)C 1-8烷基和-(CH 2) t-3至8元杂环烷基为未取代的或被1、2或3个各自独立地选自下组的取代基取代：氘、卤素、氰基、羟基、C 1-3烷基、C 1-3烷氧基、C 2-4烯基、C 2-4炔基、卤代C 1-3烷基、卤代C 1-3烷氧基、-SO 2C 1-3烷基、-S(O)C 1-3烷基、-C(O)NR a0R b0、-C(O)OC 1-3烷基、-OC(O)C 1-3烷基、C 3-6环烷基、C 3-6环烷基氧基、3至6元杂环烷基、苯基和5至6元杂芳基；
t为0、1、2或3；
R L1、R L2各自独立地为氢、羟基、卤素、C 1-3烷基、C 1-3烷氧基或卤代C 1-3烷基；或者R L1、R L2与相连的碳原子共同形成3至7元饱和或部分不饱和单环或3至7元饱和或部分不饱和单杂环；其中所述3至7元饱和或部分不饱和单杂环和3至7元饱和或部分不饱和单环为未取代的或被1、2或3个各自独立地选自下组的取代基取代：氘、卤素、氰基、羟基、羧基、C 1-3烷基、C 1-3烷氧基、C 2-4烯基、C 2-4炔基、卤代C 1-3烷基、卤代C 1-3烷氧基、-SO 2C 1-3烷基、-S(O)C 1-3烷基、-C(O)NR a0R b0、-C(O)OC 1-3烷基、-OC(O)C 1-3烷基、C 3-6环烷基、C 3-6环烷基氧基、3至6元杂环烷基、苯基和5至6元杂芳基；
m为0、1、2或3；
R p为氢、羟基、羧基、氰基、C 1-8烷基(优选为C 1-6烷基，更优选为C 1-3烷基)、卤代C 1-8烷基(优选为卤代C 1-6烷基，更优选为卤代C 1-3烷基)、卤代C 1-8烷氧基(优选为卤代C 1-6烷氧基，更优选为卤代C 1-3烷氧基)、C 1-8烷氧基(优选为C 1-6烷氧基，更优选为C 1-3烷氧基)、C 3-8环烷基(优选为C 3-6环烷基)、-SO 2C 1-8烷基(优选为 -SO 2C 1-6烷基，更优选为-SO 2C 1-3烷基)、-SO 2NR a0R b0、-(PO)(C 1-3烷基) 2、-NHSO 2C 1-3烷基、-C(O)NR a0R b0、-C(O)NR a1R b1、3至6元杂环烷基、-X-(CR p1R p2) q-3至6元杂环烷基、8至10元杂环烷基、7至11元杂螺环基、5至6元杂芳基、8至10元杂芳基、NR a1R b1或NR a'R b'；其中所述C 3-8环烷基、3至6元杂环烷基、8至10元杂环烷基、7至11元杂螺环基、5至6元杂芳基、8至10元杂芳基为未取代的或被1、2或3个各自独立地选自下组的取代基取代：氘、卤素、氰基、羟基、羧基、氧代基、C 1-3烷基、C 1-3烷氧基、C 2-4烯基、C 2-4炔基、卤代C 1-3烷基、卤代C 1-3烷氧基、NR a0R b0、-C(O)C 1-3烷基、-SO 2C 1-3烷基、-S(O)C 1-3烷基、-C(O)NR a0R b0、-C(O)OC 1-3烷基、-OC(O)C 1-3烷基、C 3-6环烷基、C 3-6环烷基氧基、3至6元杂环烷基、苯基和5至6元杂芳基；
X为O或NR p3；
R p1、R p2各自独立地为氢、羟基、卤素或C 1-3烷基；
R p3为氢或C 1-3烷基；
q为0、1、2或3；
R a'、R b'与相连的氮原子共同形成4至8元饱和单杂环、8至10元饱和双杂环或7至11元杂螺环；所述4至8元饱和单杂环、8至10元饱和双杂环和7至11元杂螺环为未取代的或被1、2或3个各自独立地选自下组的取代基取代：卤素、氰基、羟基、羧基、C 1-3烷基、C 1-3烷氧基、C 2-4烯基、C 2-4炔基、卤代C 1-3烷基、卤代C 1-3烷氧基、-(CH 2) t1-NR a0R b0、-(CH 2) t1-SO 2C 1-3烷基、-(CH 2) t1-S(O)C 1-3烷基、-(CH 2) t1-C(O)NR a0R b0、-(CH 2) t1-C(O)OC 1-3烷基、-(CH 2) t1-OC(O)C 1-3烷基、-(CH 2) t1-C 3-6环烷基、C 3-6环烷基氧基和-(CH 2) t1-3至6元杂环烷基；
t1独立选自0、1、2或3；
(R 0) n为环A上的氢被n个R 0取代，n为0、1、2或3，每个R 0相同或不同，各自独立地为卤素、氰基、羟基、羧基、C 1-3烷基、C 1-3烷氧基、羟基取代的C 1-3烷基、C 1-3烷氧基取代的C 1-3烷基、C 2-4烯基、C 2-4炔基、卤代C 1-3烷基、卤代C 1-3烷氧基、-SO 2C 1-3烷基、-SO 2NR a0R b0、-N(R a0)SO 2C 1-3烷基、-P(O)R a0R b0、-S(O)C 1-3烷基、-C(O)NR a0R b0、-C(O)OC 1-3烷基、-OC(O)C 1-3烷基、C 3-6环烷基、C 3-6环烷基氧基或3至6元杂环烷基；
(R 0') u为环B上的氢被u个R 0'取代，u为0、1、2、3、4或5，每个R 0'相同或不同，各自独立地为氢、氰基、乙酰基、羟基、羧基、卤素(优选为氟或氯)、NR a0R b0、C 1-8烷基(优选为C 1-6烷基，更优选为C 1-3烷基)、C 1-8烷氧基(优选为C 1-6烷氧基，更优选为C 1-3烷氧基)、C 3-8环烷基(优选为C 3-6环烷基)、3至6元杂环烷基、5至6元杂芳基或C 6-10芳基；其中所述C 1-8烷基、C 1-8烷氧基、C 3-8环烷基、3至6元杂环烷基、5至6元杂芳基和C 6-10芳基为未取代的或被1、2或3个独立选自下组的取代基取代：氘、卤素、氰基、羟基、C 1-3烷基、C 1-3烷氧基、C 2-4烯基、C 2-4炔基、卤代C 1-3烷基、卤代C 1-3烷氧基、C 3-6环烷基、C 3-6环烷基氧基、3至6元杂环烷基、苯基和5至6元杂芳基；
R a0、R b0各自独立地为氢或C 1-3烷基；或者R a0、R b0与相连的氮原子共同形成4至6元饱和单杂环；所述4至6元饱和单杂环任选地被1、2或3个各自独立地选自下组的取代基取代：氘、卤素、氰基、羟基、羧基、C 1-3烷基、C 1-3烷氧基、C 2-4烯基、C 2-4炔基、卤代C 1-3烷基、卤代C 1-3烷氧基、-SO 2C 1-3烷基、-S(O)C 1-3烷基、-C(O)NR a0R b0、-C(O)OC 1-3烷基、-OC(O)C 1-3烷基、C 3-6环烷基、C 3-6环烷基氧基和3至6元杂环烷基；
R a1、R b1各自独立地为氢、C 1-3烷基、C 3-6环烷基、3至6元杂环烷基或-(CR aR b) s-R c；其中所述3至6元杂环烷基为未取代的或被1、2或3个各自独立地选自下组的取代基取代：氘、卤素、氰基、羟基、羧基、氧代基、C 1-3烷基、C 1-3烷氧基、C 2-4烯基、C 2-4炔基、卤代C 1-3烷基、卤代C 1-3烷氧基、-SO 2C 1-3烷基、-S(O)C 1-3烷基、-C(O)NR a0R b0、-C(O)C 1-3烷基、-C(O)OC 1-3烷基、-OC(O)C 1-3烷基、C 3-6环烷基、C 3-6环烷基氧基、3至6元杂环烷基、苯基和5至6元杂芳基；
R a、R b各自独立地为氢、羟基、卤素、C 1-3烷基、C 1-3烷氧基或卤代C 1-3烷基；或者R a、R b与相连的碳原子共同形成3至7元饱和或部分不饱和单环或3至7元饱和或部分不饱和单杂环；其中所述3至7元饱和或部分不饱和单杂环和3至7元饱和或部分不饱和单环为未取代的或被1、2或3个各自独立地选自下组的取代基取代：氘、卤素、氰基、羟基、羧基、C 1-3烷基、C 1-3烷氧基、C 2-4烯基、C 2-4炔基、卤代C 1-3烷基、卤代C 1-3烷氧基、-SO 2C 1-3烷基、-S(O)C 1-3烷基、-C(O)NR a0R b0、-C(O)OC 1-3烷基、-OC(O)C 1-3烷基、C 3-6环烷基、C 3-6环烷基氧基、3至6元杂环烷基、苯基和5至6元杂芳基；
R c为氢、羟基、羧基、C 1-8烷基(优选为C 1-6烷基，更优选为C 1-3烷基)、卤代C 1-8烷基(优选为卤代C 1-6烷基，更优选为卤代C 1-3烷基)、卤代C 1-8烷氧基(优选为卤代C 1-6烷氧基，更优选为卤代C 1-3烷氧基)、C 1-8烷氧基(优选为C 1-6烷氧基，更优选为C 1-3烷氧基)或C 3-8环烷基(优选为C 3-6环烷基)；以及
s为1、2或3。
更佳地，式(I)化合物中，环A为5至10元杂芳基、苯基或吡啶酮基；
环B为苯基或5至10元杂芳基；
Q为5至6元杂芳基、苯基、C 3-6环烷基、4至8元杂环烷基、6至12元稠合杂环烷基、7至11元苯基并杂环烷基、7至11元杂芳基并杂环烷基、7至11元螺环基或7至11元杂螺环基；其中所述的5至6元杂芳基、苯基、C 3-6环烷基、4至8元杂环烷基、6至12元稠合杂环烷基、7至11元苯基并杂环烷基、7至11元杂芳基并 杂环烷基、7至11元螺环基和7至11元杂螺环基为未取代的或被1、2或3个各自独立地选自下组的取代基取代：氘、卤素、氰基、羟基、羧基、氧代基、C 1-3烷基、C 1-3烷氧基、C 2-4烯基、C 2-4炔基、卤代C 1-3烷基、卤代C 1-3烷氧基、NR a0R b0、-C(O)C 1-3烷基、-SO 2C 1-3烷基、-S(O)C 1-3烷基、-C(O)NR a0R b0、-C(O)OC 1-3烷基、-OC(O)C 1-3烷基、C 3-6环烷基、C 3-6环烷基氧基、3至6元杂环烷基、苯基和5至6元杂芳基；
L 1、L 2各自独立地为一个键、NR 1'、CR 2'R 3'、O、S或C(O)；且L 1、L 2不同时为O或S；
R 1'、R 2'、R 3'各自独立地为氢、氘、氰基、羟基、卤素(优选为氟或氯)或C 1-6烷基；或者R 1'与R 2'连接形成3至8元杂环烷基环；或者R 2'与R 3'连接形成3至8元杂环烷基环；其中所述的3至8元杂环烷基环为未取代的或被1、2或3个各自独立地选自下组的取代基取代：氘、卤素、氰基、羟基、C 1-3烷基、C 1-3烷氧基、C 2-4烯基、C 2-4炔基、卤代C 1-3烷基、卤代C 1-3烷氧基、-SO 2C 1-3烷基、-S(O)C 1-3烷基、-C(O)NR a0R b0、-C(O)OC 1-3烷基、-OC(O)C 1-3烷基、C 3-6环烷基、C 3-6环烷基氧基、3至6元杂环烷基、苯基和5至6元杂芳基；
W为N或CR W；
R W为氰基、羟基、卤素(优选为氟或氯)、卤代C 1-8烷基(优选为卤代C 1-6烷基，更优选为卤代C 1-3烷基)、卤代C 1-8烷氧基(优选为卤代C 1-6烷氧基，更优选为卤代C 1-3烷氧基)或C 1-8烷氧基(优选为C 1-6烷氧基，更优选为C 1-3烷氧基)；
R c、R a和R b定义如下：
(i)R c为氟、氯、氰基、C 1-3烷氧基或卤代C 1-3烷氧基；
R a、R b各自独立地为氢、氘、C 1-8烷基(优选为C 1-6烷基，更优选为C 1-3烷基)、-C(O)C 1-8烷基(优选为-C(O)C 1-6烷基，更优选为-C(O)C 1-3烷基)、-(CH 2) tC 3-8环烷基(优选为-(CH 2) tC 3-6环烷基)、-(CH 2) t-3至8元杂环烷基或为式(a)结构
Figure PCTCN2021081126-appb-000003
其中所述C 1-8烷基、-C(O)C 1-8烷基和-(CH 2) t-3至8元杂环烷基为未取代的或被1、2或3个各自独立地选自下组的取代基取代：氘、卤素、氰基、羟基、C 1-3烷基、C 1-3烷氧基、C 2-4烯基、C 2-4炔基、卤代C 1-3烷基、卤代C 1-3烷氧基、-SO 2C 1-3烷基、-S(O)C 1-3烷基、-C(O)NR a0R b0、-C(O)OC 1-3烷基、-OC(O)C 1-3烷基、C 3-6环烷基、C 3-6环烷基氧基、3至6元杂环烷基、苯基和5至6元杂芳基；或者R a、R b与相连的氮原子共同形成5或6元饱和或部分不饱和单杂环；其中所述5或6元饱和或部分不饱和单杂环为未取代的或被1、2或3个各自独立地选自下组的取代基取代：氘、卤素、氰基、羟基、C 1-3烷基、C 1-3烷氧基、C 2-4烯基、C 2-4炔基、卤代C 1-3烷基、卤代C 1-3烷氧基、-SO 2C 1-3烷基、-S(O)C 1-3烷基、-C(O)NR a0R b0、-C(O)OC 1-3烷基、-OC(O)C 1-3烷基、C 3-6环烷基、C 3-6环烷基氧基、3至6元杂环烷基、苯基和5至6元杂芳基；
其中R 1a为氢或C 1-3烷基；R 2a、R 3a各自独立地为氢或C 1-3烷基；或者R 2a与R 3a连接形成5至8元杂环烯基环或5至6元杂芳基环；所述5至8元杂环烯基环含有2、3或4个氮原子和0、1或2个氧原子；所述5至6元杂芳基环含有2、3或4个氮原子和0或1个氧原子；所述5至8元的杂环烯基环和5至6元杂芳基环为未取代的或被1、2或3个各自独立地选自下组的取代基取代：卤素、氰基、羟基、C 1-3烷基、C 1-3烷氧基、卤代C 1-3烷基和卤代C 1-3烷氧基；
(ii)R c与R a连接形成稠合的5或6元饱和或部分不饱和单杂环、或稠合的5至6元杂芳基环；所述稠合的5或6元饱和或部分不饱和单杂环和5至6元杂芳基环为未取代的或被1、2或3个各自独立地选自下组的取代基取代：氘、卤素、氰基、羟基、氧代基、C 1-3烷基、C 1-3烷氧基、C 2-4烯基、C 2-4炔基、卤代C 1-3烷基、卤代C 1-3烷氧基、-SO 2C 1-3烷基、-S(O)C 1-3烷基、-C(O)NR a0R b0、-C(O)OC 1-3烷基、-OC(O)C 1-3烷基、C 3-6环烷基、C 3-6环烷基氧基、3至6元杂环烷基、苯基和5至6元杂芳基；
R b为氢、氘、C 1-8烷基(优选为C 1-6烷基，更优选为C 1-3烷基)、-C(O)C 1-8烷基(优选为-C(O)C 1-6烷基，更优选为-C(O)C 1-3烷基)、-(CH 2) tC 3-8环烷基(优选为-(CH 2) tC 3-6环烷基)、-(CH 2) t-3至8元杂环烷基或为式(a)结构；其中所述C 1-8烷基、-C(O)C 1-8烷基和-(CH 2) t-3至8元杂环烷基为未取代的或被1、2或3个各自独立地选自下组的取代基取代：氘、卤素、氰基、羟基、C 1-3烷基、C 1-3烷氧基、C 2-4烯基、C 2-4炔基、卤代C 1-3烷基、卤代C 1-3烷氧基、-SO 2C 1-3烷基、-S(O)C 1-3烷基、-C(O)NR a0R b0、-C(O)OC 1-3烷基、-OC(O)C 1-3烷基、C 3-6环烷基、C 3-6环烷基氧基、3至6元杂环烷基、苯基和5至6元杂芳基；
t为0、1、2或3；
R L1、R L2各自独立地为氢、羟基、卤素、C 1-3烷基、C 1-3烷氧基或卤代C 1-3烷基；或者R L1、R L2与相连的碳原子共同形成3至7元饱和或部分不饱和单环或3至7元饱和或部分不饱和单杂环；其中所述3至7元饱和或部分不饱和单杂环和3至7元饱和或部分不饱和单环为未取代的或被1、2或3个各自独立地选自下组的取代基取代：氘、卤素、氰基、羟基、羧基、C 1-3烷基、C 1-3烷氧基、C 2-4烯基、C 2-4炔基、卤代C 1-3烷基、卤代C 1-3烷氧 基、-SO 2C 1-3烷基、-S(O)C 1-3烷基、-C(O)NR a0R b0、-C(O)OC 1-3烷基、-OC(O)C 1-3烷基、C 3-6环烷基、C 3-6环烷基氧基、3至6元杂环烷基、苯基和5至6元杂芳基；
m为0、1、2或3；
R p为氢、羟基、羧基、C 1-8烷基(优选为C 1-6烷基，更优选为C 1-3烷基)、卤代C 1-8烷基(优选为卤代C 1-6烷基，更优选为卤代C 1-3烷基)、卤代C 1-8烷氧基(优选为卤代C 1-6烷氧基，更优选为卤代C 1-3烷氧基)、C 1-8烷氧基(优选为C 1-6烷氧基，更优选为C 1-3烷氧基)、C 3-8环烷基(优选为C 3-6环烷基)、-SO 2C 1-8烷基(优选为-SO 2C 1-6烷基，更优选为-SO 2C 1-3烷基)、-SO 2NR a0R b0、-C(O)NR a0R b0、-C(O)NR a1R b1、3至6元杂环烷基、-X-(CR p1R p2) q-3至6元杂环烷基、8至10元杂环烷基、7至11元杂螺环基、5至6元杂芳基、8至10元杂芳基、NR a1R b1或NR a'R b'；其中所述C 3-8环烷基、3至6元杂环烷基、8至10元杂环烷基、7至11元杂螺环基、5至6元杂芳基、8至10元杂芳基为未取代的或被1、2或3个各自独立地选自下组的取代基取代：氘、卤素、氰基、羟基、羧基、氧代基、C 1-3烷基、C 1-3烷氧基、C 2-4烯基、C 2-4炔基、卤代C 1-3烷基、卤代C 1-3烷氧基、NR a0R b0、-C(O)C 1-3烷基、-SO 2C 1-3烷基、-S(O)C 1-3烷基、-C(O)NR a0R b0、-C(O)OC 1-3烷基、-OC(O)C 1-3烷基、C 3-6环烷基、C 3-6环烷基氧基、3至6元杂环烷基、苯基和5至6元杂芳基；
X为O或NR p3；
R p1、R p2各自独立地为氢、羟基、卤素或C 1-3烷基；
R p3为氢或C 1-3烷基；
q为0、1、2或3；
R a'、R b'与相连的氮原子共同形成4至8元饱和单杂环、8至10元饱和双杂环或7至11元杂螺环；所述4至8元饱和单杂环、8至10元饱和双杂环和7至11元杂螺环为未取代的或被1、2或3个各自独立地选自下组的取代基取代：卤素、氰基、羟基、羧基、C 1-3烷基、C 1-3烷氧基、C 2-4烯基、C 2-4炔基、卤代C 1-3烷基、卤代C 1-3烷氧基、-(CH 2) t1-NR a0R b0、-(CH 2) t1-SO 2C 1-3烷基、-(CH 2) t1-S(O)C 1-3烷基、-(CH 2) t1-C(O)NR a0R b0、-(CH 2) t1-C(O)OC 1-3烷基、-(CH 2) t1-OC(O)C 1-3烷基、-(CH 2) t1-C 3-6环烷基、C 3-6环烷基氧基和-(CH 2) t1-3至6元杂环烷基；
t1独立选自0、1、2或3；
(R 0) n为环A上的氢被n个R 0取代，n为0、1、2或3，每个R 0相同或不同，各自独立地为卤素、氰基、羟基、羧基、C 1-3烷基、C 1-3烷氧基、C 2-4烯基、C 2-4炔基、卤代C 1-3烷基、卤代C 1-3烷氧基、-SO 2C 1-3烷基、-SO 2NR a0R b0、-N(R a0)SO 2C 1-3烷基、-P(O)R a0R b0、-S(O)C 1-3烷基、-C(O)NR a0R b0、-C(O)OC 1-3烷基、-OC(O)C 1-3烷基、C 3-6环烷基、C 3-6环烷基氧基或3至6元杂环烷基；
(R 0') u为环B上的氢被u个R 0'取代，u为0、1、2、3、4或5，每个R 0'相同或不同，各自独立地为氢、氰基、乙酰基、羟基、羧基、卤素(优选为氟或氯)、NR a0R b0、C 1-8烷基(优选为C 1-6烷基，更优选为C 1-3烷基)、C 1-8烷氧基(优选为C 1-6烷氧基，更优选为C 1-3烷氧基)、C 3-8环烷基(优选为C 3-6环烷基)、3至6元杂环烷基、5至6元杂芳基或C 6-10芳基；其中所述C 1-8烷基、C 1-8烷氧基、C 3-8环烷基、3至6元杂环烷基、5至6元杂芳基和C 6-10芳基为未取代的或被1、2或3个独立选自下组的取代基取代：氘、卤素、氰基、羟基、C 1-3烷基、C 1-3烷氧基、C 2-4烯基、C 2-4炔基、卤代C 1-3烷基、卤代C 1-3烷氧基、C 3-6环烷基、C 3-6环烷基氧基、3至6元杂环烷基、苯基和5至6元杂芳基；
R a0、R b0各自独立地为氢或C 1-3烷基；或者R a0、R b0与相连的氮原子共同形成4至6元饱和单杂环；所述4至6元饱和单杂环任选地被1、2或3个各自独立地选自下组的取代基取代：氘、卤素、氰基、羟基、羧基、C 1-3烷基、C 1-3烷氧基、C 2-4烯基、C 2-4炔基、卤代C 1-3烷基、卤代C 1-3烷氧基、-SO 2C 1-3烷基、-S(O)C 1-3烷基、-C(O)NR a0R b0、-C(O)OC 1-3烷基、-OC(O)C 1-3烷基、C 3-6环烷基、C 3-6环烷基氧基和3至6元杂环烷基；
R a1、R b1各自独立地为氢、C 1-3烷基、C 3-6环烷基、3至6元杂环烷基或-(CR aR b) s-R c；其中所述3至6元杂环烷基为未取代的或被1、2或3个各自独立地选自下组的取代基取代：氘、卤素、氰基、羟基、羧基、氧代基、C 1-3烷基、C 1-3烷氧基、C 2-4烯基、C 2-4炔基、卤代C 1-3烷基、卤代C 1-3烷氧基、-SO 2C 1-3烷基、-S(O)C 1-3烷基、-C(O)NR a0R b0、-C(O)C 1-3烷基、-C(O)OC 1-3烷基、-OC(O)C 1-3烷基、C 3-6环烷基、C 3-6环烷基氧基、3至6元杂环烷基、苯基和5至6元杂芳基；
R a、R b各自独立地为氢、羟基、卤素、C 1-3烷基、C 1-3烷氧基或卤代C 1-3烷基；或者R a、R b与相连的碳原子共同形成3至7元饱和或部分不饱和单环或3至7元饱和或部分不饱和单杂环；其中所述3至7元饱和或部分不饱和单杂环和3至7元饱和或部分不饱和单环为未取代的或被1、2或3个各自独立地选自下组的取代基取代：氘、卤素、氰基、羟基、羧基、C 1-3烷基、C 1-3烷氧基、C 2-4烯基、C 2-4炔基、卤代C 1-3烷基、卤代C 1-3烷氧基、-SO 2C 1-3烷基、-S(O)C 1-3烷基、-C(O)NR a0R b0、-C(O)OC 1-3烷基、-OC(O)C 1-3烷基、C 3-6环烷基、C 3-6环烷基氧基、3至6元杂环烷基、苯基和5至6元杂芳基；
R c为氢、羟基、羧基、C 1-8烷基(优选为C 1-6烷基，更优选为C 1-3烷基)、卤代C 1-8烷基(优选为卤代C 1-6烷基，更优选为卤代C 1-3烷基)、卤代C 1-8烷氧基(优选为卤代C 1-6烷氧基，更优选为卤代C 1-3烷氧基)、C 1-8烷氧基(优选为C 1-6烷氧基，更优选为C 1-3烷氧基)或C 3-8环烷基(优选为C 3-6环烷基)；以及
s为1、2或3。
更佳地，环A为5至6元杂芳基、8至10元杂芳基、苯基或吡啶酮基。
更佳地，环A为5至6元杂芳基、苯基或吡啶酮基。
更佳地，环A选自噻吩基、呋喃基、噻唑基、异噻唑基、咪唑基、噁唑基、吡咯基、吡唑基、三唑基、1,2,3-三唑基、1,2,4-三唑基、1,2,5-三唑基、1,3,4-三唑基、四唑基、异噁唑基、噁二唑基、1,2,3-噁二唑基、1,2,4-噁二唑基、1,2,5-噁二唑基、1,3,4-恶二唑基、噻二唑基、吡啶基、哒嗪基、嘧啶基、吡嗪基、三嗪基、四嗪基、苯基和吡啶酮基。
更佳地，环A为苯基、吡啶基、吡唑基、嘧啶基、1,2,3-三唑基、1,2,4-三唑基或吡啶酮基。
更佳地，环A选自
Figure PCTCN2021081126-appb-000004
Figure PCTCN2021081126-appb-000005
Figure PCTCN2021081126-appb-000006
代表环A与L1连接。
更佳地，环A选自
Figure PCTCN2021081126-appb-000007
代表环A与L1连接。
更佳地，环B为苯基、5至6元杂芳基或8至10元杂芳基。
更佳地，环B为苯基。
更佳地，L 1、L 2分别为一个键和CR 2'R 3'。
更佳地，L 1为一个键；L 2为CR 2'R 3'。
更佳地，L 1、L 2分别为一个键和CH 2。
更佳地，L 1为一个键；L 2为CH 2。
更佳地，W为N。
更佳地，R c为氟、氯或C 1-3烷氧基。更佳地，R c为氟、氯、氰基、羟基、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基或异丙氧基。
更佳地，R c为氟、氯或甲氧基。
更佳地，R c为氟或氯。更佳地，Q为5至6元杂芳基、苯基、C 3-6环烷基、4至6元杂环烷基、8至10元稠合杂环烷基、8至10元苯基并杂环烷基、8至10元杂芳基并杂环烷基、7至11元螺环基或7至11元杂螺环基。
更佳地，Q中所述5至6元杂芳基选自下列结构：
Figure PCTCN2021081126-appb-000008
更佳地，Q中所述3至6元杂环烷基选自下列结构：
Figure PCTCN2021081126-appb-000009
更佳地，Q为5至6元杂芳基。
更佳地，Q为吡唑基、1,2,3-三唑基。
更佳地，Q为选自下列结构：
Figure PCTCN2021081126-appb-000010
更佳地，R a、R b各自独立地为氢、氘、C 1-3烷基、-C(O)C 1-3烷基、-(CH 2) tC 3-6环烷基、-(CH 2) t-4至6元杂环烷基或为式(a)结构；或者R a、R b与相连的氮原子共同形成5或6元饱和单杂环；其中所述C 1-3烷基、-C(O)C 1-3烷基、-(CH 2) t-4至6元杂环烷基和5或6元饱和单杂环为未取代的或被1、2或3个各自独立地选自下组的取代基取代：氘、卤素、氰基、羟基、C 1-3烷基、C 1-3烷氧基、C 2-4烯基、C 2-4炔基、卤代C 1-3烷基、卤代C 1-3烷氧基、-SO 2C 1-3烷基、-S(O)C 1-3烷基、-C(O)NR a0R b0、-C(O)OC 1-3烷基、-OC(O)C 1-3烷基、C 3-6环烷基、C 3-6环烷基氧基和4至6元杂环烷基；所述4至6元杂环烷基选自：氮杂环丁烷基、氧杂环丁烷基、四氢呋喃基、四氢噻吩基、四氢吡咯基、噁唑烷基、二氧戊环基、哌啶基、哌嗪基、吗啉基、二氧六环基、硫代吗啉基、硫代吗啉-1,1-二氧化物和四氢吡喃基；所述C 3-6环烷基选自：环丙基、环丁基、环戊基和环己基；所述5或6元饱和单杂环选自：四氢呋喃环、四氢噻吩环、四氢吡咯环、哌啶环、噁唑烷、哌嗪环、二氧戊环、二氧六环、吗啉环、硫代吗啉环和四氢吡喃环。
更佳地，R a、R b为氢或氘。
更佳地，R a为氢；R b为氢。
更佳地，R a为氢；R b为式(a)结构。
更佳地，R 2a与R 3a连接形成5至8元杂环烯基环或5至6元杂芳基环；其中5至8元杂环烯基环选自：：4,5-二氢-1H-咪唑环、1,4,5,6-四氢嘧啶环、3,4,7,8-四氢-2H-1,4,6-恶二唑嗪环、1,6-二氢嘧啶环、4,5,6,7-四氢-1H-1,3-二氮杂卓环和2,5,6,7-四氢-1,3,5-恶二氮杂卓环；5至6元杂芳基环选自：1H-咪唑环、4H-1,2,4-三唑环、1H-1,2,4-三唑环、嘧啶环、1,2,4-三嗪环、1,3,5-三嗪环和1,2,4-三嗪环。
更佳地，式(a)结构选自：
Figure PCTCN2021081126-appb-000011
更佳地，R c与R a连接形成稠合的5或6元饱和单杂环、或稠合的5至6元杂芳基环；所述稠合的5或6元饱和单杂环和5至6元杂芳基环为未取代的或被1、2或3个各自独立地选自下组的取代基取代：氘、卤素、氰基、羟基、氧代基、C 1-3烷基、C 1-3烷氧基、C 2-4烯基、C 2-4炔基、卤代C 1-3烷基、卤代C 1-3烷氧基、-SO 2C 1-3烷基、-S(O)C 1-3烷基、-C(O)NR a0R b0、-C(O)OC 1-3烷基、-OC(O)C 1-3烷基、C 3-6环烷基、C 3-6环烷基氧基、4至6元杂环烷基、苯基和5至6元杂芳基；所述稠合的5或6元饱和单杂环选自：四氢吡咯环、哌啶环、噁唑烷、哌嗪环、吗啉环、吗啉-3-酮环、哌嗪-2-酮环和哌啶-2-酮环；所述稠合的5至6元杂芳基环选自：噻吩环、呋喃环、噻唑环、咪唑环、噁唑环、吡咯环、吡唑环、三唑环、1,2,3-三唑环、1,2,4-三唑环、1,2,5-三唑环、1,3,4-三唑环、四唑环、异噁唑环、噁二唑环、1,2,3-噁二唑环、1,2,4-噁二唑环、1,2,5-噁二唑环、1,3,4-恶二唑环、噻二唑环、吡啶环、哒嗪环、嘧啶环和吡嗪环。
更佳地，R b为氢；R c与R a连接形成稠合的5或6元饱和单杂环。
更佳地，R b为氢；R c与R a连接形成
Figure PCTCN2021081126-appb-000012
更佳地，(R 0) n为环A上的氢被n个R 0取代，n为0或1，R 0为卤素(优选为氟或氯)、羟基、C 1-3烷基、C 1-3烷氧基、羟基取代的C 1-3烷基、C 1-3烷氧基取代的C 1-3烷基(优选为甲氧基取代的C 1-3烷基)、C 3-6环烷基(优选为环丙基)。
更佳地，(R 0) n为环A上的氢被n个R 0取代，n为0或1，R 0为卤素(优选为氟或氯)、C 1-3烷基、C 1-3烷氧基、羟基取代的C 1-3烷基、C 1-3烷氧基取代的C 1-3烷基(优选为甲氧基取代的C 1-3烷基)、C 3-6环烷基(优选为环丙基)。
更佳地，R L1、R L2各自独立地为氢、羟基、卤素(优选氟、氯，更优选氟)、C 1-3烷基(优选甲基、乙基)、C 1-3烷氧基(优选甲氧基)或卤代C 1-3烷基(优选三氟甲基)。
更佳地，m为0、1或2。
更佳地，R p为氢、羟基、羧基、氰基、C 1-6烷基(优选为C 1-3烷基，更优选甲基、乙基)、卤代C 1-6烷基(优选为卤代C 1-3烷基，更优选三氟甲基、二氟甲基)、C 1-6烷氧基(优选为C 1-3烷氧基，更优选甲氧基)、C 3-6环烷基(优选为环丙基、环丁基、环戊基)、-SO 2C 1-6烷基(优选为-SO 2C 1-3烷基，更优选为-SO 2CH 3)、-(PO)(C 1-3烷基) 2(优选为-(PO)(CH 3) 2)、-NHSO 2C 1-3烷基(优选为-NHSO 2CH 3)、-C(O)NR a0R b0(优选为-C(O)NH 2)、3至6元杂环烷基(优选为4至6元杂环烷基，更优选为氧杂环丁烷基、四氢呋喃基、四氢吡喃基、氮杂环丁烷基、吗啉基、哌嗪基、氮杂环丁烷-2-酮基)或NR a1R b1(优选为-NH 2)；其中所述C 3-6环烷基(优选为环丙基、环丁基、环戊基)、3至6元杂环烷基(优选为4至6元杂环烷基，更优选为氧杂环丁烷基、四氢呋喃基、四氢吡喃基、氮杂环丁烷基、吗啉基、哌嗪基、氮杂环丁烷-2-酮基)为未取代的或被1或2个各自独立地选自下组的取代基取代：卤素(优选氟、氯，更优选氟)、羟基和C 1-3烷基(优选甲基)。
更佳地，R p-(CR L1R L2) m-为R p”'-(CH 2) m-；或为式(b)、式(c)、式(d)、式(e)、式(f)或式(g)结构：
Figure PCTCN2021081126-appb-000013
其中，R p1'为氢、卤素、氰基、羟基、羧基、C 1-3烷基、C 1-3烷氧基、C 2-4烯基、C 2-4炔基、卤代C 1-3烷基、卤代C 1-3烷氧基、-(CH 2) t1-NR a0R b0、-(CH 2) t1-SO 2C 1-3烷基、-(CH 2) t1-S(O)C 1-3烷基、-(CH 2) t1-C(O)NR a0R b0、-(CH 2) t1-C(O)OC 1-3烷基、-(CH 2) t1-OC(O)C 1-3烷基、-(CH 2) t1-C 3-6环烷基、C 3-6环烷基氧基或-(CH 2) t1-4至6元杂环烷基；R p2'为氢或C 1-3烷基；或者R p1'、R p2'与相连的碳原子共同形成4至6元饱和单杂环；所述的4至6元饱和单杂环为未取代的或被1、2或3个各自独立地选自下组的取代基取代：卤素、氰基、羟基、羧基、氧代基、C 1-3烷基、C 1-3烷氧基、C 2-4烯基、C 2-4炔基、卤代C 1-3烷基、卤代C 1-3烷氧基、-C(O)C 1-3烷基、-SO 2C 1-3烷基、-S(O)C 1-3烷基、-C(O)NR a0R b0、-C(O)OC 1-3烷基、-OC(O)C 1-3烷基、NR a0R b0、C 3-6环烷基、C 3-6环烷基氧基、3至6元杂环烷基、苯基和5至6元杂芳基；
R p3'、R p4'与相连的碳原子共同形成稠合的4至6元饱和单杂环；所述稠合的4至6元饱和单杂环为未取代的或被1、2或3个各自独立地选自下组的取代基取代：卤素、氰基、羟基、羧基、氧代基、C 1-3烷基、C 1-3烷氧基、C 2-4烯基、C 2-4炔基、卤代C 1-3烷基、卤代C 1-3烷氧基、-C(O)C 1-3烷基、-SO 2C 1-3烷基、-S(O)C 1-3烷基、-C(O)NR a0R b0、-C(O)OC 1-3烷基、-OC(O)C 1-3烷基、NR a0R b0、C 3-6环烷基、C 3-6环烷基氧基、3至6元杂环烷基、苯基和5至6元杂芳基；
R p”为氢、羟基、羧基、C 1-8烷基(优选为C 1-6烷基，更优选为C 1-3烷基)、卤代C 1-8烷基(优选为卤代C 1-6烷基，更优选为卤代C 1-3烷基)、卤代C 1-8烷氧基(优选为卤代C 1-6烷氧基，更优选为卤代C 1-3烷氧基)、C 1-8烷氧基(优选为C 1-6烷氧基，更优选为C 1-3烷氧基)、C 3-8环烷基(优选为C 3-6环烷基)、-SO 2C 1-8烷基(优选为-SO 2C 1-6烷基，更优选为-SO 2C 1-3烷基)、-SO 2NR a0R b0、-C(O)NR a0R b0、-C(O)NR a1R b1、4至6元杂环烷基或-X-(CR p1R p2) q-4至6元杂环烷基；
U 1为CR U11R U12；U 2为CR U21R U22；X 0为O、NR 1或CR 2R 3；
R U11、R U12各自独立地为氢；或者R U11、R U12与相连的碳原子共同形成3至7元饱和或部分不饱和单杂环或3至7元饱和或部分不饱和单环；其中所述3至7元饱和或部分不饱和单杂环和3至7元饱和或部分不饱和单环为未取代的或被1、2或3个各自独立地选自下组的取代基取代：氘、卤素、氰基、羟基、羧基、C 1-3烷基、C 1-3烷氧基、NR a0R b0、卤代C 1-3烷基、卤代C 1-3烷氧基、-SO 2C 1-3烷基、-S(O)C 1-3烷基、-C(O)NR a0R b0、-C(O)C 1-3烷 基、-C(O)OC 1-3烷基、-OC(O)C 1-3烷基、C 3-6环烷基、C 3-6环烷基氧基、3至6元杂环烷基、苯基和5至6元杂芳基；
R U21、R U22各自独立地为氢；或者R U21、R U22与相连的碳原子共同形成3至7元饱和或部分不饱和单杂环或3至7元饱和或部分不饱和单环；其中所述3至7元饱和或部分不饱和单杂环和3至7元饱和或部分不饱和单环为未取代的或被1、2或3个各自独立地选自下组的取代基取代：氘、卤素、氰基、羟基、羧基、C 1-3烷基、C 1-3烷氧基、NR a0R b0、卤代C 1-3烷基、卤代C 1-3烷氧基、-SO 2C 1-3烷基、-S(O)C 1-3烷基、-C(O)NR a0R b0、-C(O)C 1-3烷基、-C(O)OC 1-3烷基、-OC(O)C 1-3烷基、C 3-6环烷基、C 3-6环烷基氧基、3至6元杂环烷基、苯基和5至6元杂芳基；
R 1为氢、C 1-3烷基、-SO 2C 1-3烷基、-S(O)C 1-3烷基、-C(O)C 1-3烷基、-C(O)NR a0R b0、-C(O)OC 1-3烷基、C 3-6环烷基、3至6元杂环烷基、苯基或5至6元杂芳基；
R 2、R 3各自独立地为氢、卤素、氰基、羟基、羧基、C 1-3烷基、C 1-3烷氧基、NR a0R b0、卤代C 1-3烷基、卤代C 1-3烷氧基、-SO 2C 1-3烷基、-S(O)C 1-3烷基、-C(O)NR a0R b0、-C(O)C 1-3烷基、-C(O)OC 1-3烷基、-OC(O)C 1-3烷基、C 3-6环烷基、C 3-6环烷基氧基、3至6元杂环烷基、苯基或5至6元杂芳基；或者R 2、R 3与相连的碳原子共同形成3至7元饱和或部分不饱和单杂环或3至7元饱和或部分不饱和单环；其中所述3至7元饱和或部分不饱和单杂环和3至7元饱和或部分不饱和单环为未取代的或被1、2或3个各自独立地选自下组的取代基取代：氘、卤素、氰基、羟基、羧基、C 1-3烷基、C 1-3烷氧基、NR a0R b0、卤代C 1-3烷基、卤代C 1-3烷氧基、-SO 2C 1-3烷基、-S(O)C 1-3烷基、-C(O)NR a0R b0、-C(O)C 1-3烷基、-C(O)OC 1-3烷基、-OC(O)C 1-3烷基、C 3-6环烷基、C 3-6环烷基氧基、3至6元杂环烷基、苯基和5至6元杂芳基；
R p”'为氢、羟基、羧基、C 1-8烷基(优选为C 1-6烷基，更优选为C 1-3烷基)、卤代C 1-8烷基(优选为卤代C 1-6烷基，更优选为卤代C 1-3烷基)、卤代C 1-8烷氧基(优选为卤代C 1-6烷氧基，更优选为卤代C 1-3烷氧基)、C 1-8烷氧基(优选为C 1-6烷氧基，更优选为C 1-3烷氧基)、C 3-8环烷基(优选为C 3-6环烷基)、-SO 2C 1-8烷基(优选为-SO 2C 1-6烷基，更优选为-SO 2C 1-3烷基)、-SO 2NR a0R b0、-C(O)NR a0R b0、-C(O)NR a1R b1、3至6元杂环烷基、-X-(CR p1R p2) q-3至6元杂环烷基、5至6元杂芳基、8至10元杂芳基或NR a1R b1；所述3至6元杂环烷基、5至6元杂芳基和8至10元杂芳基为未取代的或被1、2或3个各自独立地选自下组的取代基取代：氘、卤素、氰基、羟基、羧基、氧代基、C 1-3烷基、C 1-3烷氧基、C 2-4烯基、C 2-4炔基、卤代C 1-3烷基、卤代C 1-3烷氧基、-C(O)C 1-3烷基、-SO 2C 1-3烷基、-S(O)C 1-3烷基、-C(O)NR a0R b0、-C(O)OC 1-3烷基、-OC(O)C 1-3烷基、NR a0R b0、C 3-6环烷基、C 3-6环烷基氧基、3至6元杂环烷基、苯基和5至6元杂芳基；
R p5'为氢、C 1-3烷基、-SO 2C 1-3烷基、-S(O)C 1-3烷基、-C(O)C 1-3烷基、-C(O)NR a0R b0、-C(O)OC 1-3烷基、C 3-6环烷基、3至6元杂环烷基、苯基或5至6元杂芳基；
n1、n2、n3、n4、n5各自独立地为0、1或2；
m1、m2各自独立地为1、2或3；
m3、m4、m5各自独立地为0、1、2或3；且m3、m4不同时为0；
m6、m7、m8、m9各自独立地为1或2。
更佳地，式(b)为式(b-1)、式(b-2)、式(b-3)或式(b-4)结构：
Figure PCTCN2021081126-appb-000014
其中m10、m11、m12各自独立地为1、2或3；
m13、m14各自独立地为0、1或2；且m13、m14不同时为0；
G 1为NR 4或O；G 2为NR 5或O；G 3为NR 6或O；
R 4、R 5、R 6各自独立地为氢、C 1-3烷基、-SO 2C 1-3烷基、-S(O)C 1-3烷基、-C(O)C 1-3烷基、-C(O)NR a0R b0、-C(O)OC 1-3烷基、C 3-6环烷基、3至6元杂环烷基、苯基或5至6元杂芳基。
更佳地，式(b)选自：
Figure PCTCN2021081126-appb-000015
更佳地，式(c)或式(d)选自：
Figure PCTCN2021081126-appb-000016
更佳地，式(e)为
Figure PCTCN2021081126-appb-000017
更佳地，式(f)选自：
Figure PCTCN2021081126-appb-000018
更佳地，式(g)为
Figure PCTCN2021081126-appb-000019
更佳地，R p”'中所述5至6元杂芳基或8至10元杂芳基选自：
Figure PCTCN2021081126-appb-000020
上述杂芳基任选地被1、2或3个各自独立地选自下组的取代基取代：氘、卤素、氰基、羟基、羧基、C 1-3烷基、C 1-3烷氧基、C 2-4烯基、C 2-4炔基、卤代C 1-3烷基、卤代C 1-3烷氧基、NR a0R b0、-C(O)C 1-3烷基、-SO 2C 1-3烷基、-S(O)C 1-3烷基、-C(O)NR a0R b0、-C(O)OC 1-3烷基、-OC(O)C 1-3烷基、C 3-6环烷基、C 3-6环烷基氧基、3至6元杂环烷基、苯基和5至6元杂芳基。
更佳地，R p”'-(CH 2) m-选自：
甲基、乙基、异丙基、叔丁基、三氟甲基、环丙基、
Figure PCTCN2021081126-appb-000021
Figure PCTCN2021081126-appb-000022
更佳地，(R 0') u为环B上的氢被u个R 0'取代，u为1或2，每个R 0'相同或不同，各自独立地为氢、氰基、卤素(优选为氟或氯)或C 1-8烷基(优选为C 1-6烷基，更优选为C 1-3烷基)。
更佳地，(R 0') u为环B上的氢被u个R 0'取代，u为2，每个R 0'相同或不同，各自独立地为氢、氰基、卤素(优选为氟或氯)或C 1-3烷基(优选为甲基)。
更佳地，环B为苯基；(R 0') u为环B上的氢被u个R 0'取代，u为2，每个R 0'相同或不同，各自独立地为氰基或甲基。
更佳地，
Figure PCTCN2021081126-appb-000023
为
Figure PCTCN2021081126-appb-000024
更佳地，所述化合物如式(II)或式(III)所示结构：
Figure PCTCN2021081126-appb-000025
其中，式(II)中的R c、R a和R b如(i)中的定义；式(III)中的R b如(ii)中的定义；
X 1为O、NR 11或CR 12R 13；
X 2为C(O)或CR 21R 22；
R 11为氢或C 1-3烷基；
R 12、R 13、R 21、R 22各自独立地为氢、卤素、C 1-3烷基或C 1-3烷氧基；
Z为N或CR Z；R Z为氢、氘或C 1-3烷基；
R 1、R 2、R 3、R 4、R 5各自独立地为氢、氰基、乙酰基、羟基、羧基、卤素(优选为氟或氯)、NR a0R b0、C 1-8烷基(优选为C 1-6烷基，更优选为C 1-3烷基)、C 1-8烷氧基(优选为C 1-6烷氧基，更优选为C 1-3烷氧基)、C 3-8环烷基(优选为C 3-6环烷基)、3至6元杂环烷基、5至6元杂芳基或C 6-10芳基；其中所述C 1-8烷基、C 1-8烷氧基、C 3-8环烷基、3至6元杂环烷基、5至6元杂芳基和C 6-10芳基为未取代的或被1、2或3个独立选自下组的取代基取代：氘、卤素、氰基、羟基、C 1-3烷基、C 1-3烷氧基、C 2-4烯基、C 2-4炔基、卤代C 1-3烷基、卤代C 1-3烷氧基、C 3-6环烷基、C 3-6环烷基氧基、3至6元杂环烷基、苯基和5至6元杂芳基；
R 6、R 7各自独立地为氢、氘、氰基、羟基、卤素(优选为氟或氯)或C 1-6烷基。
更佳地，所述式(II)中，R 1为甲基；R 2为氰基；R 3、R 4、R 5各自独立地为氢。
更佳地，
Figure PCTCN2021081126-appb-000026
为
Figure PCTCN2021081126-appb-000027
更佳地，
Figure PCTCN2021081126-appb-000028
为
Figure PCTCN2021081126-appb-000029
更佳地，X 1为O。
更佳地，X 2优选为C(O)。
更佳地，Z为N。
更佳地，R 1、R 2、R 3、R 4、R 5各自独立地为氢、氰基、卤素(优选为氟或氯)或C 1-8烷基(优选为C 1-6烷基，更优选为C 1-3烷基)。
更佳地，R 1、R 2各自独立地为氢、氰基、卤素(优选为氟或氯)或C 1-3烷基(优选为甲基)；R 3、R 4、R 5各自独立地为氢。
更佳地，R 1为甲基；R 2为氰基；R 3、R 4、R 5各自独立地为氢。
更佳地，R 6、R 7各自独立地为氢。
更佳地，所述的4至6元饱和单杂环选自氮杂环丁烷、氧杂环丁烷、四氢呋喃环、四氢噻吩环、四氢吡咯环、哌啶环、噁唑烷、哌嗪环、二氧戊环、二氧六环、吗啉环、硫代吗啉环、四氢吡喃环、吗啉-3-酮环、哌嗪-2-酮环和哌啶-2-酮环。
更佳地，所述的3至6元饱和单环选自环丙基环、环丁基环、环戊基环和环己基环。
更佳地，所述的5至6元杂芳基选自噻吩基、呋喃基、噻唑基、咪唑基、噁唑基、吡咯基、吡唑基、三唑基、1,2,3-三唑基、1,2,4-三唑基、1,2,5-三唑基、1,3,4-三唑基、四唑基、异噁唑基、噁二唑基、1,2,3-噁二唑基、1,2,4-噁二唑基、1,2,5-噁二唑基、1,3,4-恶二唑基、噻二唑基、吡啶基、哒嗪基、嘧啶基和吡嗪基。
更佳地，所述的4至6元杂环烷基选自氮杂环丁烷基、氧杂环丁烷基、四氢呋喃基、四氢噻吩基、四氢吡咯基、噁唑烷基、二氧戊环基、哌啶基、哌嗪基、吗啉基、二氧六环基、硫代吗啉基、硫代吗啉-1,1-二氧化物、四氢吡喃基、吡咯烷-2-酮基、二氢呋喃-2(3H)-酮基、吗啉-3-酮基、哌嗪-2-酮基和哌啶-2-酮基。
更佳地，所述5至8元杂环烯基环选自：4,5-二氢-1H-咪唑环、1,4,5,6-四氢嘧啶环、3,4,7,8-四氢-2H-1,4,6-恶二唑嗪环、1,6-二氢嘧啶环、4,5,6,7-四氢-1H-1,3-二氮杂卓环和2,5,6,7-四氢-1,3,5-恶二氮杂卓环。
更佳地，式(I)化合物为下列化合物中的任意一个：
Figure PCTCN2021081126-appb-000030
Figure PCTCN2021081126-appb-000031
更佳地，式(I)化合物为下列化合物中的任意一个：
Figure PCTCN2021081126-appb-000032
Figure PCTCN2021081126-appb-000033
Figure PCTCN2021081126-appb-000034
Figure PCTCN2021081126-appb-000035
更佳地，式(I)化合物为实施例化合物中的任意一个。
本发明第二方面提供了一种式(IA)所示的化合物、或其药学上可接受的盐、或其立体异构体、或其溶剂化物、或其前药：
Figure PCTCN2021081126-appb-000036
式(IA)中，环A、环B、Q、L 1、L 2、R L1、R L2、R p、m、(R 0) n、(R 0') u如上所述；R c、R a和R b为(i)中的定义。
更佳地，所述式(IA)化合物结构如式(IIA)所示：
Figure PCTCN2021081126-appb-000037
其中，式(IIA)中的R c、R a和R b如(i)中的定义；
Z为N或CR Z；R Z为氢、氘或C 1-3烷基；
R 1、R 2、R 3、R 4、R 5各自独立地为氢、氰基、乙酰基、羟基、羧基、卤素(优选为氟或氯)、NR a0R b0、C 1-8烷基(优选为C 1-6烷基，更优选为C 1-3烷基)、C 1-8烷氧基(优选为C 1-6烷氧基，更优选为C 1-3烷氧基)、C 3-8环烷基(优选为C 3-6环烷基)、3至6元杂环烷基、5至6元杂芳基或C 6-10芳基；其中所述C 1-8烷基、C 1-8烷氧基、C 3-8环烷基、3至6元杂环烷基、5至6元杂芳基和C 6-10芳基为未取代的或被1、2或3个独立选自下组的取代基取代：氘、卤素、氰基、羟基、C 1-3烷基、C 1-3烷氧基、C 2-4烯基、C 2-4炔基、卤代C 1-3烷基、卤代C 1-3烷氧基、C 3-6环烷基、C 3-6环烷基氧基、3至6元杂环烷基、苯基和5至6元杂芳基；
R 6、R 7各自独立地为氢、氘、氰基、羟基、卤素(优选为氟或氯)或C 1-6烷基。
更佳地，
Figure PCTCN2021081126-appb-000038
为
Figure PCTCN2021081126-appb-000039
更佳地，
Figure PCTCN2021081126-appb-000040
为
Figure PCTCN2021081126-appb-000041
更佳地，Z为N。
更佳地，R 1、R 2、R 3、R 4、R 5各自独立地为氢、氰基、卤素(优选为氟或氯)或C 1-8烷基(优选为C 1-6烷基，更优选为C 1-3烷基)。
更佳地，R 1、R 2各自独立地为氢、氰基、卤素(优选为氟或氯)或C 1-3烷基(优选为甲基)；R 3、R 4、R 5各自独立地为氢。
更佳地，R 1为甲基；R 2为氰基；R 3、R 4、R 5各自独立地为氢。
更佳地，R 6、R 7各自独立地为氢。
更佳地，式(IA)化合物为下列化合物中的任意一个：
Figure PCTCN2021081126-appb-000042
本发明第三方面提供了一种药物组合物，其包括本发明第一方面以及第二方面所述的化合物、或其药学上可接受的盐、或其立体异构体、或其溶剂化物、或其前药，以及药学上可接受的载体。
本发明第四方面提供了本发明第一方面以及第二方面所述的化合物、或其药学上可接受的盐、或其立体异构体、或其溶剂化物、或其前药以及本发明第二方面所述的药物组合物在制备治疗由腺苷A 2A受体和/或腺苷A 2B受体介导的疾病的药物中的应用。
本发明第五方面提供了一种预防和/或治疗由腺苷A 2A受体和/或腺苷A 2B受体介导的疾病的方法，包括给予所需患者治疗有效量的本发明第一方面以及第二方面所述的化合物、或其药学上可接受的盐、或其立体异构体、或其溶剂化物、或其前药，或如本发明第三方面所述药物组合物。
较佳地，所述的疾病由腺苷A 2A受体介导。
较佳地，所述的疾病由腺苷A 2B受体介导。
较佳地，所述的疾病由腺苷A 2A受体和A 2B受体共同介导。
较佳地，所述的疾病为癌症。
较佳地，所述的癌症选自前列腺癌、结肠癌、直肠癌、胰腺癌、子宫颈癌、胃癌、子宫内膜癌、脑癌、肝癌、膀胱癌、卵巢癌、睾丸癌、头癌、颈癌、黑素瘤、基底癌、间皮内层癌、白血细胞癌、食道癌、乳腺癌、肌肉癌、结缔组织癌、小细胞肺癌、非小细胞肺癌、肾上腺癌、甲状腺癌、肾癌和骨癌；或是恶性胶质瘤、间皮瘤、肾细胞癌、胃癌、肉瘤、绒毛膜癌、皮肤基底细胞癌和睾丸精原细胞瘤。
较佳地，所述的癌症选自黑素瘤、结肠直肠癌、胰腺癌、乳腺癌、前列腺癌、小细胞肺癌、非小细胞肺癌、白血病、脑肿瘤、淋巴瘤、卵巢癌、卡波济氏肉瘤、肾细胞癌、头颈癌和食道癌。
较佳地，所述的疾病为免疫相关的疾病。
较佳地，所述免疫相关的疾病选自类风湿性关节炎、肾衰竭、狼疮、哮喘、银屑病、结肠炎、胰腺炎、过敏、纤维化、贫血性纤维肌痛、阿尔茨海默氏病、充血性心力衰竭、中风、主动脉瓣狭窄、动脉硬化、骨质疏松症、帕金森氏病、感染、克罗恩氏病、溃疡性结肠炎、过敏性接触性皮炎和其他湿疹、系统性硬化和多发性硬化症。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
具体实施方式
本发明人经过广泛而深入的研究，意外地发现了这类取代的嘧啶或吡啶胺衍生物，其具有显著的腺苷A 2A受体和/或腺苷A 2B受体活性。因此该系列化合物有望开发成为用于治疗和预防由腺苷A 2A受体和/或腺苷A 2B受体介导的相关疾病的药物。在此基础上，发明人完成了本发明。
术语定义
为了能够更清楚地理解本发明的技术内容，下面对本发明的术语作进一步说明。
“烷基”指直链和支链的饱和的脂族烃基。“C 1-8烷基”是指具有1至8个碳原子的烷基，优选为C 1-6烷基，更优选为C 1-3烷基；烷基的非限制性的例子包括：甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,3-二甲基戊基、2,4-二甲基戊基、2,2-二甲基戊基、3,3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、2,2-二甲基己基、3,3-二甲基己基、4,4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、正壬基、2-甲基-2-乙基己基、2-甲基-3-乙基己基、2,2-二乙基戊基、正癸基、3,3-二乙基己基、2,2-二乙基己基，及其各种支链异构体等更优选。
“烯基”指直链或支链的具有一个或多个碳碳双键(C＝C)的不饱和脂族烃基，“C 2-8烯基”指具有2至8个碳原子的烯基，优选为C 2-6烯基，更优选为C 2-4烯基，定义类似；非限制性实施例包括乙烯基、丙烯基、异丙烯基、正丁烯基、异丁烯基、戊烯基、己烯基等。
“炔基”指直链和支链的具有一个或多个碳碳三键的不饱和脂族烃基，“C 2-8炔基”指具有2至8个碳原子的炔基，优选为C 2-6炔基，更优选为C 2-4炔基，定义类似；非限制性实施例包括乙炔基、丙炔基、正丁炔基、异丁炔基、戊炔基、己炔基等。
“环烷基”和“环烷基环”可互换使用，均指饱和单环、双环或多环环状烃基，该基团可以与芳基或杂芳基稠合。环烷基环可以任选地被取代。在某些实施方案中，环烷基环含有一个或多个羰基，例如氧代的基团。“C 3-8环烷基”是指具有3至8个碳原子的单环环烷基，环烷基的非限制性实施例包括环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环丁酮、环戊酮、环戊烷-1,3-二酮等。优选为C 3-6环烷基，包括环丙基、环丁基、环戊基和环己基。“C 8-10环烷基”是指具有8至10个环原子的稠合双环环状烃基，C 8-10环烷基的非限制性实施例包括
Figure PCTCN2021081126-appb-000043
“螺环基”和“螺环”可互换使用，均指单环之间共用一个碳原子(称螺原子)的多环环状烃基。“7至11元螺环基”是指具有7至11个环原子的螺环。根据环的数目将螺环分为双螺环或多螺环，优选为双螺环。更优选为优选为4元/5元、5元/5元或5元/6元双螺环。例如：
Figure PCTCN2021081126-appb-000044
“环烯基”和“环烯基环”可互换使用，均指环内包含一个或多个碳-碳双键的单环、双环或多环环状烃基，该基团可以与芳基或杂芳基稠合。环烯基环可以任选地被取代。在某些实施方案中，环烯基环含有一个或多个羰基，例如氧代的基团。“C 3-8环烯基”是指具有3至8个碳原子的单环环烯基。优选为C 3-6环烯基。环烯基的非限制性实施例包括环丁烯基、环戊烯基、环己烯基、环己二烯基、环庚三烯基、环戊基-2-烯-1-酮、环己基-2，5-二烯-1-酮、环己基-2-烯-1-酮、环己-2-烯-1,4-二酮等。
“杂环烷基”和“杂环烷基环”可互换使用，均指包含至少一个选自氮、氧和硫的杂原子的环烷基，该基团可以与芳基或杂芳基稠合。杂环烷基环可以任选地被取代。在某些实施方案中，杂环烷基环含有一个或多个羰基或硫代羰基，例如包含氧代和硫代的基团。“3至8元杂环烷基”是指具有3至8个环原子，其中1、2或3个环原子为选自氮、氧和硫的杂原子的单环环状烃基，优选为4至8元杂环烷基。更优选为3至6元杂环烷基，其具有3至6个环原子，其中1或2个环原子为选自氮、氧和硫的杂原子。更优选为4至6元杂环烷基，其具有4至6个环原子，其中1或2个环原子为选自氮、氧和硫的杂原子。单环杂环烷基的非限制性实施例包括氮丙环基、环 氧乙烷基、氮杂环丁烷基、氧杂环丁烷基、四氢呋喃基、四氢噻吩基、四氢吡咯基、噁唑烷基、二氧戊环基、哌啶基、哌嗪基、吗啉基、二氧六环基、硫代吗啉基、硫代吗啉-1,1-二氧化物、四氢吡喃基、氮杂环丁烷-2-酮基、氧杂环丁烷-2-酮基、二氢呋喃-2(3H)-酮基、吡咯烷-2-酮基、吡咯烷-2,5-二酮基、二氢呋喃-2,5-二酮基、哌啶-2-酮基、四氢-2H-吡喃-2-酮基、哌嗪-2-酮基、吗啉-3-酮基等。“6至12元杂环烷基”和“6至12元稠合杂环烷基”可互换使用，是指具有6至12个环原子，其中1、2或3个环原子为选自氮、氧和硫的杂原子的稠合双环环状烃基。“8至10元杂环烷基”和“8至10元稠合杂环烷基”可互换使用，是指具有8至10个环原子，其中1、2或3个环原子为选自氮、氧和硫的杂原子的稠合双环环状烃基。双环杂环烷基的非限制性实施例包括六氢-1H-呋喃[3,4-c]吡咯、八氢-1H-环戊[c]吡啶、六氢-1H-吡咯并[2,1-c][1,4]恶嗪、八氢吡咯并[1,2-a]吡嗪、六氢吡咯并[1,2-a]吡嗪-4(1H)-酮、八氢环戊[c]吡咯等。在含有一个或多个氮原子的稠合双环杂环烷基中，只要化合价允许，连接点可以是碳或氮原子。双环杂环烷基系统在一个或两个环中可以包括一个或多个杂原子。
“杂螺环基”和“杂螺环”可互换使用，是指具有两个单环共用一个碳原子的一价的非芳香族环系，其由碳原子及选自氮、氧、硫和磷的杂原子构成，不含有不饱和度，并且通过一个单键连接至母核。杂螺环可以任选地被取代。在某些实施方案中，杂螺环含有一个或多个羰基或硫代羰基，例如包含氧代和硫代的基团。“7至11元杂螺环基”是指具有7至11个环原子，其中1、2或3个环原子为杂原子的杂螺环基。杂螺环基的非限制性实施例包括2,6-二氮杂螺环[3.4]辛烷-5-酮基、2-氧-6-氮杂螺环[3.3]庚烷基、6-氧杂螺[3.3]庚烷-2-基、7-甲基-7-氮杂螺[3.5]壬烷-2-基、7-甲基-2,7-二氮杂螺[3.5]壬烷-2-基、9-甲基-9-膦杂螺[5.5]十一烷-3-基等。
“杂环烯基”和“杂环烯基环”可互换使用，是指环内包含一个或多个碳-碳双键或碳-氮双键的杂环烷基，但并不意图包括如本文所定义的杂芳基部分。该基团可以与芳基或杂芳基稠合。杂环烯基环可以任选地被取代。在某些实施方案中，杂环烯基环含有一个或多个羰基或硫代羰基，例如包含氧代和硫代的基团。“5至8元杂环烯基环”是指具有5至8个环原子，其中1、2或3个环原子为选自氮、氧和硫的杂原子的杂环烯基环。优选为5至6元杂环烯基环。杂环烯基环的非限制性实施例包括4,5-二氢-1H-咪唑环、1,4,5,6-四氢嘧啶环、3,4,7,8-四氢-2H-1,4,6-恶二唑嗪环、1,6-二氢嘧啶环、4,5,6,7-四氢-1H-1,3-二氮杂卓环、2,5,6,7-四氢-1,3,5-恶二氮杂卓环。
“芳基”和“芳环”可互换使用，均指具有共轭的π电子体系的全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团，该基团可以与环烷基环、杂环烷基环、环烯基环、杂环烯基环或杂芳基稠合。“C 6-10芳基”指具有6至10个碳原子的单环或双环芳基，芳基的非限制性实施例包括苯基、萘基等。
“杂芳基”和“杂芳基环”可互换使用，均指具有环碳原子和环杂原子的单环、双环或多环的4n+2芳族环体系(例如，具有以环状排列共享的6或10个π电子)的基团，其中每个杂原子独立地选自氮、氧和硫。本发明中，杂芳基还包括其中上述杂芳基环与一个或多个环烷基环、杂环烷基环、环烯基环、杂环烯基环或芳环稠合的环系统。杂芳基环可以任选地被取代。“5至10元杂芳基”是指具有5至10个环原子，其中1、2、3或4个环原子为杂原子的单环或双环杂芳基。“5至6元杂芳基”是指具有5至6个环原子，其中1、2、3或4个环原子为杂原子的单环杂芳基，非限制性实施例包括噻吩基、呋喃基、噻唑基、异噻唑基、咪唑基、噁唑基、吡咯基、吡唑基、三唑基、1,2,3-三唑基、1,2,4-三唑基、1,2,5-三唑基、1,3,4-三唑基、四唑基、异噁唑基、噁二唑基、1,2,3-噁二唑基、1,2,4-噁二唑基、1,2,5-噁二唑基、1,3,4-恶二唑基、噻二唑基、吡啶基、哒嗪基、嘧啶基、吡嗪基、三嗪基、四嗪基。“8至10元杂芳基”是指具有8至10个环原子，其中1、2、3或4个环原子为杂原子的双环杂芳基，非限制性实施例包括吲哚基、异吲哚基、吲唑基、苯并三唑基、苯并噻吩基、异苯并噻吩基、苯并呋喃基、苯并异呋喃基、苯并咪唑基、苯并噁唑基、苯并异噁唑基、苯并噁二唑基、苯并噻唑基、苯并异噻唑基、苯并噻二唑基、茚嗪基、嘌呤基、吡啶并[3,2-d]嘧啶基、吡啶并[2,3-d]嘧啶基、吡啶并[3,4-d]嘧啶基、吡啶并[4,3-d]嘧啶基、1,8-萘啶基、1,7-萘啶基、1,6-萘啶基、1,5-萘啶基、喋啶基、喹啉基、异喹啉基、噌琳基、喹喔啉基、酞嗪基和喹唑啉基。“杂原子”是指氮、氧或硫。在含有一个或多个氮原子的杂芳基中，只要化合价允许，连接点可以是碳或氮原子。杂芳基双环系统在一个或两个环中可以包括一个或多个杂原子。
“稠合”是指两个或多个环共用一个或多个键的结构。
“苯基并杂环烷基”是指苯环与杂环烷基环稠合形成双环、三环或多环体系的基团，其中杂环烷基环如上述所定义。“7至11元苯基并杂环烷基”指具有7至11个环原子，其中1、2、3或4个环原子为选自氮、氧和硫的杂原子的双环环状基团。优选为8至10元苯基并杂环烷基，其具有8至10个环原子，其中1、2或3个环原子为选自氮、氧和硫的杂原子。非限制性实施例包含吲哚啉、苯并[d][1,3]二恶唑、1,2,3,4-四氢异喹啉、3,4-二氢-2H-苯并[b][1,4]恶嗪等。
“杂芳基并杂环烷基”是指杂芳基环与杂环烷基环稠合形成双环、三环或多环体系的基团，其中杂环烷基环如上述所定义。“7至11元杂芳基并杂环烷基”指具有7至11个环原子，其中1、2、3或4个环原子为选自氮、氧和硫的杂原子的双环环状基团。优选为8至10元杂芳基并杂环烷基，其具有8至10个环原子，其中1、2、3或4个环原子为选自氮、氧和硫的杂原子。非限制性实施例包含2,3-二氢-1H-吡咯并[2,3-b]吡啶、[1,3]二氧戊环[4,5-b]吡啶、2,3-二氢-1H-吡啶并[3,4-b][1,4]恶嗪、2,3,4,6-四氢吡咯并[3,4-b][1,4]恶嗪、2,4,5,6-四氢吡喃并[2,3-c]吡唑、5,6,7,8-四氢吡啶并[3,4-d]嘧啶等。
“烷氧基”指-O-烷基，其中烷基的定义如上所述。优选C 1-8烷氧基，更优选C 1-6烷氧基，最优选C 1-3烷氧基。非限制性实施例包含甲氧基、乙氧基、正丙氧基、异丙氧基、丁氧基、叔丁氧基、异丁氧基、戊氧基等。
“环烷基氧基”指-O-环烷基，其中环烷基的定义如上所述。优选C 3-8环烷基氧基，更优选C 3-6环烷基氧基。非限制性实施例包含环丙基氧基、环丁基氧基、环戊基氧基、环己基氧基等。
“一个键”指由其连接的两个基团通过一个共价键连接。
“卤素”指氟、氯、溴或碘。
“卤代”指基团中一个或多个(如1、2、3、4或5个)氢被卤素所取代。
例如，“卤代C 1-8烷基”指烷基被一个或多个(如1、2、3、4或5个)卤素取代，其中烷基的定义如上所述。选为卤代C 1-6烷基，更优选为卤代C 1-3烷基。卤代C 1-8烷基的例子包括(但不限于)一氯甲基、二氯甲基、三氯甲基、一氯乙基、1,2-二氯乙基、三氯乙基、一溴乙基、一氟甲基、二氟甲基、三氟甲基、一氟乙基、二氟乙基、三氟乙基等。
又例如，“卤代C 1-8烷氧基”指烷氧基被一个或多个(如1、2、3、4或5个)卤素取代，其中烷氧基的定义如上所述。优选为卤代C 1-6烷氧基，更优选为卤代C 1-3烷氧基。包括(但不限于)三氟甲氧基、三氟乙氧基、一氟甲氧基、一氟乙氧基、二氟甲氧基、二氟乙氧基等。
又例如，“卤代C 3-8环烷基”指环烷基被一个或多个(如1、2、3、4或5个)卤素取代，其中环烷基的定义如上所述。优选为卤代C 3-6环烷基。包括(但不限于)三氟环丙基、一氟环丙基、一氟环己基、二氟环丙基、二氟环己基等。
“氘代C 1-8烷基”指烷基被一个或多个(如1、2、3、4或5个)氘原子取代，其中烷基的定义如上所述。优选为氘代C 1-6烷基，更优选为氘代C 1-3烷基。氘代C 1-8烷基的例子包括(但不限于)单氘代甲基、单氘代乙基、二氘代甲基、二氘代乙基、三氘代甲基、三氘代乙基等。
“氨基”指NH 2，“氰基”指CN，“硝基”指NO 2，“苯甲基”指-CH 2-苯基，“氧代基”指＝O，“羧基”指-C(O)OH，“乙酰基”指-C(O)CH 3，“羟甲基”指-CH 2OH，“羟乙基”指-CH 2CH 2OH或-CHOHCH 3，“羟基”指-OH，“硫醇”指SH，“亚环丙基”结构为：
Figure PCTCN2021081126-appb-000045
“饱和或部分不饱和单环”是指饱和或部分不饱和的全碳单环系统，其中“部分不饱和”是指包括至少一个双键或三键的环部分，“部分不饱和”意图涵盖具有多个不饱和位点的环，但并不意图包括如本文所定义的芳基或杂芳基部分。在某些实施方案中，饱和或部分不饱和单环含有一个或多个羰基，例如氧代的基团。“3至7元饱和或部分不饱和单环”具有3到7个环碳原子，优选具有3到6个环碳原子的饱和或部分不饱和单环，更优选具有3到6个环碳原子的饱和单环。饱和或部分不饱和单环的非限制性实施例包括环丙基环、环丁基环、环戊基环、环戊烯基环、环己基环、环己烯基环、环己二烯基环、环庚基环、环庚三烯基环、环戊酮环、环戊烷-1,3-二酮环等。
“饱和或部分不饱和单杂环”是指饱和或部分不饱和单环中的1、2或3个环碳原子被选自氮、氧或S(O) t(其中t是整数0至2)的杂原子所取代，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳。“3至7元饱和或部分不饱和单杂环”具有3到7个环原子，其中1、2或3个环原子为上述杂原子。优选具有3到6个环原子，其中1或2个环原子为上述杂原子的3至6元饱和或部分不饱和单杂环，更优选具有5到6个环原子，其中1或2个环原子为上述杂原子的5至6元饱和或部分不饱和单杂环，最优选为5或6元饱和单杂环。饱和单杂环的非限制性实施例包括环氧丙烷环、氮杂环丁烷环、氧杂环丁烷环、四氢呋喃环、四氢噻吩环、四氢吡咯环、哌啶环、吡咯啉环、噁唑烷环、哌嗪环、二氧戊环、二氧六环、吗啉环、硫代吗啉环、硫代吗啉-1,1-二氧化物、四氢吡喃环、氮杂环丁烷-2-酮环、氧杂环丁烷-2-酮环、吡咯烷-2-酮环、吡咯烷-2,5-二酮环、哌啶-2-酮环、二氢呋喃-2(3H)-酮环、二氢呋喃-2,5-二酮环、四氢-2H-吡喃-2-酮环、哌嗪-2-酮环、吗啉-3-酮环。部分不饱和单杂环的非限制性实施例包括1,2-二氢氮杂环丁二烯环、1,2-二氢氧杂环丁二烯环、2,5-二氢-1H-吡咯环、2,5-二氢呋喃环、2,3-二氢呋喃环、2,3-二氢-1H-吡咯环、3,4-二氢-2H-吡喃环、1,2,3,4-四氢吡啶环、3,6-二氢-2H-吡喃环、1,2,3,6-四氢吡啶环、4,5-二氢-1H-咪唑环、1,4,5,6-四氢嘧啶环、3,4,7,8-四氢-2H-1,4,6-恶二唑嗪环、1,6-二氢嘧啶环、4,5,6,7-四氢-1H-1,3-二氮杂卓环、2,5,6,7-四氢-1,3,5-恶二氮杂卓环等。
“取代的”指基团中的一个或多个氢原子，优选为1～5个氢原子彼此独立地被相应数目的取代基取代，更优选为1～3个氢原子彼此独立地被相应数目的取代基取代。不言而喻，取代基仅处在它们的可能的化学位置，本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如，具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。
除非另有定义，本发明所述“各自独立地选自……的取代基”是指当基团上的一个以上的氢被取代基取代时，所述的取代基种类可以相同或不同，所选自的取代基为各自独立的种类。
除非另有定义，本发明所述“……相同或不同，且各自独立地为……”是指当通式中存在一个以上的相同取代基团时，该基团可以相同或不同，为各自独立的种类。例如L为(CR 01R 02) s，当s为2时，即L为(CR 01R 02)-(CR 01R 02)，其中的两个R 01或R 02可以相同或不同，为各自独立的种类，例如L可以为C(CH 3)(CN)-C(CH 2CH 3)(OH)，C(CH 3)(CN)-C(CH 3)(OH)或C(CN)(CH 2CH 3)-C(OH)(CH 2CH 3)。
除非另有定义，本文任一基团可以是取代的或未取代的。上述基团被取代时，取代基优选为1至5个以下基团，独立地选自氰基、卤素(优选氟或氯)、C 1-8烷基(优选C 1-6烷基，更优选C 1-3烷基)、C 1-8烷氧基(优选C 1-6 烷氧基，更优选C 1-3烷氧基)、卤代C 1-8烷基(优选卤代C 1-6烷基，更优选卤代C 1-3烷基)、C 3-8环烷基(优选C 3-6环烷基)、卤代C 1-8烷氧基(优选卤代C 1-6烷氧基，更优选卤代C 1-3烷氧基)、C 1-8烷基取代的氨基、卤代C 1-8烷基取代的氨基、乙酰基、羟基、羟甲基、羟乙基、羧基、硝基、C 6-10芳基(优选苯基)、C 3-8环烷基氧基(优选为C 3-6环烷基氧基)、C 2-8烯基(优选C 2-6烯基，更优选C 2-4烯基)、C 2-8炔基(优选C 2-6炔基，更优选C 2-4炔基)、-CONR a0R b0、-C(O)OC 1-10烷基(优选为-C(O)OC 1-6烷基，更优选为-C(O)OC 1-3烷基)、-CHO、-OC(O)C 1-10烷基(优选为-OC(O)C 1-6烷基，更优选为-OC(O)C 1-3烷基)、-SO 2C 1-10烷基(优选为-SO 2C 1-6烷基，更优选为-SO 2C 1-3烷基)、-SO 2C 6-10芳基(优选为-SO 2C 6芳基，如-SO 2-苯基)、-COC 6-10芳基(优选为-COC 6芳基，如-CO-苯基)、4至6元饱和或不饱和单杂环、4至6元饱和或不饱和单环、5至6元单环杂芳基环、8至10元双环杂芳基环、螺环、螺杂环、桥环或桥杂环，其中R a0、R b0各自独立地为氢或C 1-3烷基。
本文以上所述的各类取代基团其自身也是可以被本文所描述的基团取代。
本文所述的4至6元饱和单杂环被取代时，取代基的位置可处在它们可能的化学位置，示例性的单杂环的代表性的取代情况如下所示：
Figure PCTCN2021081126-appb-000046
Figure PCTCN2021081126-appb-000047
其中“Sub”表示本文所述的各类取代基；
Figure PCTCN2021081126-appb-000048
表示与其他原子的连接。
药物组合物
通常本发明化合物或其药学上可接受的盐、或其溶剂化物、或其立体异构体、或前药可以与一种或多种药用载体形成适合的剂型施用。这些剂型适用于口服、直肠给药、局部给药、口内给药以及其他非胃肠道施用(例如，皮下、肌肉、静脉等)。例如，适合口服给药的剂型包括胶囊、片剂、颗粒剂以及糖浆等。这些制剂中包含的本发明的化合物可以是固体粉末或颗粒；水性或非水性液体中的溶液或是混悬液；油包水或水包油的乳剂等。上述剂型可由活性化合物与一种或多种载体或辅料经由通用的药剂学方法制成。上述的载体需要与活性化合物或其他辅料兼容。对于固体制剂，常用的无毒载体包括但不限于甘露醇、乳糖、淀粉、硬脂酸镁、纤维素、葡萄糖、蔗糖等。用于液体制剂的载体包括水、生理盐水、葡萄糖水溶液、乙二醇和聚乙二醇等。活性化合物可与上述载体形成溶液或是混悬液。
“药学上可接受的载体”是指无毒、惰性、固态、半固态的物质或液体灌装机、稀释剂、封装材料或辅助制剂或任何类型辅料，其与患者相兼容，最好为哺乳动物，更优选为人，其适合将活性试剂输送到目标靶点而不终止试剂的活性。
“本发明的活性物质”或“本发明的活性化合物”是指本发明式(I)/式(IA)化合物、或其药学上可接受的盐、或其溶剂化物、或其立体异构体、或其前药，其具有腺苷A 2A受体和/或腺苷A 2B受体活性。
本发明的组合物以符合医学实践规范的方式配制，定量和给药。给予化合物的“治疗有效量”由要治疗的具体病症、治疗的个体、病症的起因、药物的靶点以及给药方式等因素决定。
“治疗有效量”是指将引起个体的生物学或医学响应，例如降低或抑制酶或蛋白质活性或改善症状、缓解病症、减缓或延迟疾病进程或预防疾病等的本发明化合物的量。
本发明的所述药物组合物或所述药用组合物中含有的本发明化合物或其药学上可接受的盐、或其溶剂化物、或其立体异构体、或其前药的治疗有效量优选为0.1mg-5g/kg(体重)。
“患者”是指一种动物，最好为哺乳动物，更好的为人。术语“哺乳动物”是指温血脊椎类哺乳动物，包括如猫、狗、兔、熊、狐狸、狼、猴子、鹿、鼠、猪和人类。
“治疗”是指减轻、延缓进展、衰减、预防，或维持现有疾病或病症(例如癌症)。治疗还包括将疾病或病症的一个或多个症状治愈、预防其发展或减轻到某种程度。
所述“药学上可接受的盐”包括药学上可接受的酸加成盐和药学上可接受的碱加成盐。
“药学上可接受的酸加成盐”是指能够保留游离碱的生物有效性而无其他副作用的，与无机酸或有机酸所形成的盐。无机酸盐包括但不限于盐酸盐、氢溴酸盐、硫酸盐、磷酸盐等；有机酸盐包括但不限于甲酸盐、乙酸盐、丙酸盐、乙醇酸盐、葡糖酸盐、乳酸盐、草酸盐、马来酸盐、琥珀酸盐、富马酸盐、酒石酸盐、柠檬酸盐、谷氨酸盐、天冬氨酸盐、苯甲酸盐、甲磺酸盐、对甲苯磺酸盐和水杨酸盐等。这些盐可通过本专业已知的方法制备。
“药学上可接受的碱加成盐”，包括但不限于无机碱的盐如钠盐，钾盐，钙盐和镁盐等。包括但不限于有机碱的盐，比如铵盐，三乙胺盐，赖氨酸盐，精氨酸盐等。这些盐可通过本专业已知的方法制备。
本发明中提及的“溶剂化物”是指本发明的化合物与溶剂形成的配合物。它们或者在溶剂中反应或者从溶剂中沉淀析出或者结晶出来。例如，一个与水形成的配合物称为“水合物”。式(I)化合物的溶剂化物属于本发明范围之内。
本发明式(I)所示的化合物可以含有一个或多个手性中心，并以不同的光学活性形式存在。当化合物含有一个手性中心时，化合物包含对映异构体。本发明包括这两种异构体和异构体的混合物，如外消旋混合物。对映异构体可以通过本专业已知的方法拆分，例如结晶以及手性色谱等方法。当式(I)化合物含有多于一个手性中心时，可以存在非对映异构体。本发明包括拆分过的光学纯的特定异构体以及非对映异构体的混合物。非对映异构体可由本专业已知方法拆分，比如结晶以及制备色谱。
本发明包括上述化合物的前药。前药包括已知的氨基保护基和羧基保护基，在生理条件下被水解或经由酶反应释放得到母体化合物。具体的前药制备方法可参照(Saulnier，M.G.；Frennesson，D.B.；Deshpande，M.S.；Hansel，S.B and Vysa，D.M.Bioorg.Med.Chem Lett.1994，4，1985-1990；和Greenwald，R.B.；Choe，Y.H.；Conover，C.D.；Shum，K.；Wu，D.；Royzen，M.J.Med.Chem.2000，43，475.)。
制备方法
本发明提供了式(I)化合物的制备方法，使用本领域技术人员已知的标准合成技术或使用本领域已知的方法与本发明描述的方法组合可以合成式(I)化合物。本发明给出的溶剂、温度和其它反应条件可以根据本领域技术而改变。所述反应可以按顺序使用，以提供本发明的化合物，或者它们可以用于合成片段，所述片段通过本发明所描述的方法和/或本领域已知的方法随后加入。
本发明描述的化合物可以使用与下述类似的方法或实施例中所述的示例性方法，或本领域技术人员所用的相关公开文献，通过使用适当的可选择的起始原料合成化合物。用于合成本发明所描述的化合物的起始原料可以被合成或可以从商业来源获得。本发明描述的化合物和其它相关具有不同取代基的化合物可以使用本领域技术人员已知的技术和原料合成。制备本发明公开的化合物的一般方法可以来自本领域已知的反应，并且该反应可以通过由本领域技术人员所认为适当的试剂和条件修改，以引入本发明提供的分子中的各种部分。
与现有技术相比，本发明的主要优点在于：
提供了一系列结构新颖的取代的嘧啶或吡啶胺衍生物，其对腺苷A 2A受体和/或腺苷A 2B受体具有高抑制活性，IC 50值小于100nM，更佳地为小于50nM，更佳地为小于10nM，因此可用作治疗癌症或其他免疫相关疾病的药物。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件如Sambrook等人，分子克隆：实验室手册(New York:Cold Spring Harbor Laboratory Press，1989)中所述的条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。除非另行定义，本文所用的术语与本领域熟练人员所熟悉的意义相同。此外，任何与所记载内容相似或同等的方法及材料皆可应用于本发明中。
试剂与仪器
1HNMR：Bruker AVANCE-400核磁仪，内标为四甲基硅烷(TMS)。
LC-MS：Agilent 1200 HPLC System/6140 MS液质联用质谱仪(生产商：安捷伦)，柱子WatersX-Bridge，150×4.6mm，3.5μm。
制备高效液相色谱(pre-HPLC)：Waters PHW007，柱子XBridge C18，4.6*150mm，3.5um。
采用ISCO Combiflash-Rf75或Rf200型自动过柱仪，Agela 4g、12g、20g、40g、80g、120g一次性硅胶柱。
已知的起始原料可以采用或按照本领域已知的方法来合成，或可以购自ABCR GmbH&Co.KG，Acros Organics，Aldrich Chemical Company，韶远化学科技(Accela ChemBio Inc)和达瑞化学品等公司。
DMF：二甲基甲酰胺，DMSO：二甲基亚砜，THF：四氢呋喃，CAN：乙腈，DIEA：N,N-二异丙基乙胺，EA：乙酸乙酯，PE：石油醚，BINAP：(2R,3S)-2,2'-双二苯膦基-1,1'-联萘，NBS：N-溴代丁二酰亚胺，NCS：N-氯代丁二酰亚胺，Pd 2(dba) 3：三(二亚苯甲基丙酮)二钯，Pd(dppf)Cl 2：[1,1'-双(二苯基磷)二茂铁]二氯化钯，DPPA：叠氮磷酸二苯酯，DBU：1,8-二氮杂二环十一碳-7-烯，TBAF：四丁基氟化铵，Na Ascorbate：抗坏血酸钠，t-BuXPhosPd-G3：甲磺酸(2-二叔丁基膦基-2'，4'，6'-三异丙基-1,1'-联苯)(2'-氨基-1,1'-联苯-2-基)钯(II)，LAH：氢化铝锂，TBSCl：叔丁基二甲基氯硅烷，TMSCl：三甲基氯硅烷。
如本文所用，室温是指约20-30℃。
中间体V1制备
Figure PCTCN2021081126-appb-000049
将2-甲基-3-溴苯腈(15g，76.51mmol)、双联频哪醇硼酸酯(23.32g,91.82mmol)、醋酸钾(15.02g，153.03mmol)、Pd(dppf)Cl 2(2.80g)和DMSO(20mL)溶解于二氧六环(100mL)中，氮气保护下，在100℃下搅拌3.5h。反应完全，减压蒸干溶剂得到的固体产物，通过柱层析(EA：PE 15％～40％)中分离得到化合物V1(21.05g，纯度：78.0％，收率：100％)。MS(ESI)244.1[M+H] +。
中间体V2的制备
Figure PCTCN2021081126-appb-000050
参考中间体V1的制备方法，其区别在于用3-溴-2-氟苯甲腈替换2-甲基-3-溴苯腈，制备得到化合物V2(2.2g,产率:89.07％,纯度:94.8％).MS(ESI)166[M-82+H] +。
中间体V3的制备
Figure PCTCN2021081126-appb-000051
参考中间体V1的制备方法，其区别在于用1-溴-3-氟-2-甲基苯替换2-甲基-3-溴苯腈，制备得到化合物V3(1.92g,产率:81％,纯度:97％).MS(ESI)237[M+H] +.
中间体V4制备
Figure PCTCN2021081126-appb-000052
步骤1：将原料6-(羟甲基)吡啶甲酸甲酯(25g，149.70mmol)加入到无水THF(400mL)中，反应混合物降温到0℃并滴加甲基溴化镁的THF溶液(1M,598.80ml，598.80mmol)，滴加完毕，反应液自然升到室温并搅拌18小时。然后再将反应液降至0℃，加入饱和氯化铵水溶液中和反应液，用乙酸乙酯萃取，合并有机相并用无水硫酸钠干燥，过滤，将滤液减压蒸干，通过柱层析(乙酸乙酯：石油醚＝0-35％)纯化得到无色的油状产物2-(6-(羟甲基)吡啶-2-基)丙-2-醇(6.3g，25％)。MS(ESI)168.1[M+H] +。
步骤2：将化合物2-(6-(羟甲基)吡啶-2-基)丙-2-醇(400mg,2.39mmol)溶解在20mL DCM中，加入DPPA(790mg,2.87mmol)，DBU(437mg,2.87mmol),反应液室温搅拌过夜。LC-MS检测反应完全。将上述反应液加入到100mL水里面，用二氯甲烷萃取(50mL*2)，无水硫酸钠干燥，减压浓缩干，经过硅胶柱分离纯化得到化合物V4(350mg,P:100％,Y:76％)。MS(ESI)193[M+H] +。
中间体V5的制备
Figure PCTCN2021081126-appb-000053
步骤1：2-(6-(羟甲基)吡啶-2-基)丙-2-醇(1.5g，8.98mmol)，三乙胺(1814mg，17.96mmol)溶于15mL二氯甲烷中，溶于20mL二氯甲烷的甲基磺酰氯(1536mg，13.47mmol)于冰浴条件下缓慢滴加，滴加完毕后反应液可缓慢升至室温，并搅拌1小时。反应液用二氯甲烷(15mL*3)萃取，20mL水洗涤，无水硫酸钠干燥，减压浓缩干，得无色油状液体产物(6-(2-羟基丙-2-基)吡啶-2-基)甲磺酸甲酯(2.4g，P:50％,Y:54.5％)粗产物MS(ESI)246[M+H] +。
步骤2：(6-(2-羟基丙-2-基)吡啶-2-基)甲磺酸甲酯(2.4g，4.9mmol)，4-(4,4,5,5-四甲基-1,3,2-二氧杂硼硼烷-2-基)-1H-吡唑(1426mg，7.35mmol)，碳酸铯(3195mg，9.8mmol)溶于20mL乙腈中，70℃下搅拌4小时。反应液过滤，滤渣用二氯甲烷洗涤，减压浓缩干滤液，通过柱层析(甲醇：二氯甲烷＝0-5％)纯化得到无色的油状产物V5(1.5g，P:75％,Y:89.2％)MS(ESI)344[M+H] +。
中间体V6和V7的制备
Figure PCTCN2021081126-appb-000054
参考实施例21步骤1以及实施例10步骤2的制备方法，可制备得到中间体V6和V7。
中间体V8的制备
Figure PCTCN2021081126-appb-000055
参考实施例1步骤1-4的制备方法，其区别在于用四氯嘧啶替换2,4,6-三氯-5-氟嘧啶，制备得到V8，MS(ESI)269.1[M+H] +。
实施例1：化合物L-1的制备
Figure PCTCN2021081126-appb-000056
步骤1：2,4,6-三氯-5-氟嘧啶1-1(2.0g,9.93mmol),三异丙基硅基乙炔(1.8g,9.93mmol),三乙胺(3.01g,3.00mmol)溶解在25mL四氢呋喃中，在氩气保护下降温到0度，加入CuI(378mg,1.99mmol)和Pd(PPh 3) 2Cl 2(697mg,0.99mmol)，然后升温到室温反应3小时，得到化合物1-2(3.44g)MS(ESI)347[M+H] +。
步骤2：向溶有化合物1-2(3.44g,9.93mmol)的25mL上述四氢呋喃反应液中加入10mL氨水(浓度80％)水溶液,室温搅拌2天，LC-MS检测反应完全。将上述反应液加入到300mL水里面，用二氯甲烷萃取(100mL*2)，无水硫酸钠干燥，减压浓缩干，经过硅胶柱分离纯化得到化合物1-3(2.30g,Y:71％)MS(ESI)328.1[M+H] +。
步骤3：化合物1-3(500mg,1.52mmol),化合物V1(408mg,1.68mmol)溶解在乙腈15mL和水4mL的混合溶剂中，加入Pd(PPh 3) 2Cl 2(107mg,0.152mmol),KHCO 3(611mg,6.10mmol)，反应液氮气保护下升温到95℃搅拌过夜，LC-MS检测反应完全。反应液倒入水中，用二氯甲烷萃取(50mL*2),无水硫酸钠干燥，减压浓缩干，经过硅胶柱分离纯化得到化合物1-4(300mg,产率:48％)。MS(ESI)409.2[M+H]+。
步骤4：化合物1-4(70mg,0.171mmol)加入到2mL的四氢呋喃中，降温到0度，缓慢加入0.2mL TBAF四氢呋喃溶液(1.0mol/L),反应液室温搅拌30分钟，得到化合物1-5(43mg,产率:100％)MS(ESI)253.1[M+H]+
步骤5：化合物1-5(43mg,0.17mmol),中间体V4(33mg,0.17mmol)加入到叔丁醇5mL和水1.5mL的混合溶剂中，在氩气保护下加入Cu 2SO 4.5H 2O(12mg,0.051mmol),抗坏血酸钠(20mg,0.102mmol)，升温到40度反应40分钟，LC-MS检测反应完全。将反应液倒入水中，用二氯甲烷萃取(50mL*2),无水硫酸钠干燥，减压浓缩干，经过高效液相制备分离纯化得到白色固体化合物L-1(4.39mg,产率:6％)。 1H NMR(400MHz,DMSO-d6)δ8.78(s,1H),7.92(d,J＝7.8Hz,1H),7.83(dd,J＝7.7,1.2Hz,1H),7.76(t,J＝7.8Hz,1H),7.60–7.48(m,3H),7.45(t,J＝7.5Hz,1H),7.10(d,J＝6.9Hz,1H),5.77(s,2H),5.18(s,1H),2.63(s,3H),1.34(s,6H).MS(ESI)445.2[M+H] +。
实施例2：化合物L-2的制备
Figure PCTCN2021081126-appb-000057
步骤1：金属钠(1.4g,23.12mmol)缓慢分批加入无水乙醇15mL中，氩气保护下加热到80度反应2小时，然后降温至室温，加入化合物碳酸胍(2.8g,23.12mmol),加热至80度反应30分钟，在降温至室温，加入2-氟丙二酸二甲酯(5.0g,33.31mmol),然后反应液再次升温至80度搅拌2小时，LC-MS检测反应完全。反应液过滤，收集固体溶解到水里，用浓盐酸调节pH值至5，有大量固体吸出，过滤干燥得到化合物2-1(2.8g,产率:83％)MS(ESI)146.1[M+H] +。
步骤2：将化合物2-1(2.3g,15.85mmol)加入无水乙腈50mL中，氩气保护下降温0℃，加入化合物三氯氧磷(17mL)，接着加入五氯化磷(2.5g,12.01mmol)，N-苯甲基-N，N-二乙基乙基氯化铵(11.0g,48.29mmol)，然后反应液升温至80度搅拌过夜，LC-MS检测反应完全。反应液加入到水里，用氨水调节PH值至8，用DCM(100mL*2)萃取，合并有机相，用1M盐酸洗涤，干燥，减压浓缩干得到化合物2-2(0.6g,产率:21％)MS(ESI)182.1[M+H] +
步骤3：参考实施例1步骤1的制备方法，区别在于用化合物2-2替换化合物1-1，，得到化合物2-3(0.8g,产率:81％)MS(ESI)328.1[M+H] +
步骤4-6：参考实施例1步骤3-5的制备方法，区别在于用化合物2-3替换化合物1-3得到白色固体产品L-2(8.49mg,产率:10％)MS(ESI)445.2[M+H] +。 1H NMR(400MHz,DMSO-d6)δ8.76(s,1H),7.98–7.83(m,2H),7.73(d,J＝7.8Hz,1H),7.58(d,J＝7.9Hz,1H),7.51(t,J＝7.8Hz,1H),7.37(d,J＝7.7Hz,1H),6.87(s,2H),5.88(s,2H),2.62(s,3H),2.40(s,3H),1.63(s,6H).
实施例3：化合物L-3的制备
Figure PCTCN2021081126-appb-000058
以中间体V8和中间体V4为原料，参考实施例1步骤5的制备方法，制备得到白色固体产品L-3(58.84mg,产率:43％)MS(ESI)461.2[M+H] +。 1H NMR(400MHz,DMSO-d6)δ8.88(s,1H),7.96(d,J＝7.8Hz,1H),7.85(d,J＝7.6Hz,1H),7.77(t,J＝7.8Hz,1H),7.57(d,J＝7.8Hz,1H),7.46(t,J＝7.7Hz,1H),7.12(d,J＝7.4Hz,1H),5.77(s,2H),5.19(s,1H),2.65(s,3H),1.34(s,6H).
实施例4：化合物L-4的制备
Figure PCTCN2021081126-appb-000059
步骤1：将金属钠(1.52g,66.09mmol)加入到0℃的甲醇(60mL)中，自然升温并搅拌至金属钠完全溶解，然后将3-溴苯甲脒盐酸盐(5.0g,21.37mmol)加入到新生成的甲醇钠的甲醇溶液中，反应液搅拌10分钟，再将反应液降温到0℃，最后将甲氧基马来酸二甲酯(3.46g,21.37mmol)的甲醇(10mL)溶液缓慢滴入反应液中，滴加完毕，反应液加热至回流反应2小时。原料反应完毕，将反应液减压蒸干，用稀盐酸(1M)中和至pH＝7并过滤出固体产物，用乙酸乙酯洗涤滤饼，干燥后得到固体化合物4-1(3.7g)。MS(ESI)297[M+H] +。
步骤2：将化合物4-1(500mg,1.77mmol)加入到三氯氧磷(6mL)中，升温至125℃并搅拌16小时。当原料反应完全，将反应液降到室温，用乙酸乙酯稀释，然后分批加入到搅拌的碳酸氢钠的冰水溶液中，用分离出有机相，水相用乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，过滤，滤液经过减压蒸干，粗产物通过柱层析(乙酸乙酯：石油醚＝0–30％)得到固体化合物4-2(0.43g)。MS(ESI)333[M+H] +。
步骤3：参考实施例1步骤2的制备方法，区别在于用化合物4-2替换化合物1-2，得到固体化合物4-3(0.33g)。MS(ESI)316[M+H] +。
步骤4：将化合物4-3(341mg,1.09mmol)，氰化锌(76mg,0.65mmol)和甲磺酸(2-二叔丁基膦基-2'，4'，6'-三异丙基-1,1'-联苯)(2'-氨基-1,1'-联苯-2-基)钯(II)(87mg,0.11mmol)加入到四氢呋喃(5mL)和水(5mL)中，混合物在90℃反应2小时，然后用乙酸乙酯萃取，无水硫酸钠干燥，过滤，滤液经过减压蒸干，粗产物通过柱层析(乙酸乙酯：石油醚＝0–35％)得到固体化合物4-4(0.26g)。MS(ESI)261[M+H] +。
步骤5：参考实施例1步骤1的制备方法，区别在于用化合物4-4替换化合物1-1，得到固体化合物4-5(0.31g)。MS(ESI)407[M+H] +。
步骤6：将化合物4-5(320mg,0.79mmol)加入到干燥的二氯甲烷(20mL)中，降温到0℃，然后滴加三溴化硼(1M，3.2mL，3.15mmol)的二氯甲烷溶液，滴加完毕，自然升到室温并搅拌4小时，原料反应完全时，将反应液倒入饱和碳酸氢钠水溶液中，然后用二氯甲烷萃取，无水硫酸钠干燥，过滤，减压蒸干得到固体化合物4-6(0.33g)。MS(ESI)393[M+H] +。
步骤7：将化合物4-6(331mg,0.84mmol)，氯乙酰氯(113mg,1.01mmol)和碳酸钾(581mg,4.21mmol)加入到干燥的四氢呋喃(6mL)中，室温搅拌2小时，然后加热到70℃搅拌18小时，原料反应完毕，过滤除去不溶解的物质，滤液浓缩并通过柱层析乙酸乙酯：石油醚＝0–50％)纯化得到化合物4-7(0.18g)。MS(ESI)433[M+H] +。
步骤8：将化合物4-7(160mg,0.37mmol)和氟化钾(30％，2mL)水溶液加入到甲醇/四氢呋喃(v/v＝1:1，4mL)中并再30℃搅拌2天，然后用乙酸乙酯萃取，无水硫酸钠干燥，过滤，滤液经过浓缩得到132mg化合物4-8，不经纯化直接用于下步反应。MS(ESI)277[M+H] +。
步骤9：参考实施例1步骤5的制备方法，区别在于用化合物4-8替换化合物1-5，制备得到产品L-4(12.78mg)。 1H NMR(400MHz,DMSO-d6)δ11.87(s,1H),8.95(s,1H),8.60(dd,J＝7.5,6.3Hz,2H),7.95(d,J＝7.7Hz,1H),7.75(dt,J＝13.7,7.7Hz,2H),7.58(d,J＝7.6Hz,1H),7.10(d,J＝7.5Hz,1H),5.81(s,2H),5.20(s,1H),4.86(s,2H),1.37(s,6H).MS(ESI)469.2[M+H] +。
实施例5：化合物L-5的制备
Figure PCTCN2021081126-appb-000060
参考实施例1的制备方法，区别在于用中间体V2替换中间体V1，可制备得到白色固体化合物L-5(28.08mg,产率:23.31％)。 1H NMR(400MHz,DMSO-d6)δ8.79(s,1H),8.26-8.21(m,1H),8.02-7.98(m,1H),7.78-7.74(m, 1H),7.60(brs,2H),7.57(d,J＝8.0Hz,1H),7.51-7.46(m,1H),7.11(d,J＝7.6Hz,1H),5.79(s,2H),5.18(s,1H),1.35(s,6H).MS(ESI)449.2[M+H] +。
实施例6：化合物L-6的制备
Figure PCTCN2021081126-appb-000061
参考实施例1的制备方法，区别在于用中间体V2替换中间体V1，可制备得到白色固体产品L-6(15.30mg)。 1H NMR(400MHz,DMSO-d6)δ8.88(s,1H),8.62(s,1H),8.58(d,J＝8.0Hz,1H),7.90(d,J＝7.6Hz,1H),7.77(t,J＝7.7Hz,1H),7.67(t,J＝7.8Hz,1H),7.58(d,J＝7.7Hz,1H),7.20(s,2H),7.11(d,J＝7.5Hz,1H),5.79(s,2H),5.19(s,1H),3.72(s,3H),1.38(s,6H).MS(ESI)443.2[M+H] +。
实施例7：化合物L-7的制备
Figure PCTCN2021081126-appb-000062
步骤1:将2-氧代-1,2-二氢吡啶-3-乙醛(1.2g,9.76mmol)，2,2-二甲基环氧乙烷(1.8mL,120.26mmol)和碳酸钾(2.76g,20.0mmol)加入到DMF(14mL)中并在120℃搅拌3h。然后将反应液过滤，滤液浓缩后通过硅胶柱层析(EA:PE＝0-100％)得到固体化合物7-1(1.03g,产率:54％)MS(ESI)196.1[M+H] +
步骤2:将化合物7-1(200mg,1.03mmol)加入到四氢呋喃(10mL)中，反应液降温到0℃，将LAH(78mg,2.05mmol)加入反应液中，然后反应液在0℃搅拌1h。待原料反应完全，分批加入十水硫酸钠，直到反应液中没有气泡产生为止，再将反应液搅拌10分钟，过滤，滤液直接浓缩得到油状化合物7-2(183mg,产率:91％)MS(ESI)198[M+H] +
步骤3：将化合物7-2(183mg,0.93mmol)溶解于二氯甲烷(4mL)中，然后依次加入DPPA(383mg,1.39mmol)和DBU(212mg,1.39mmol),反应混合物在室温下搅拌18h。原料反应完毕，将反应液用二氯甲烷稀释，然后用水洗涤两遍，有机相用无水硫酸钠干燥，过滤，滤液浓缩后得到油状粗产物化合物7-3(374mg).MS(ESI)223[M+H] +。
步骤4：参考实施例1步骤5的制备方法，以中间体V8和化合物7-3为反应原料，可制备得到淡黄色固体产物L-7(19.62mg，产率:11％)。 1H NMR(400MHz,DMSO-d6)δ8.70(s,1H),7.94(d,J＝7.5Hz,1H),7.84(d,J＝7.7Hz,1H),7.62(dd,J＝6.8,1.8Hz,1H),7.46(t,J＝7.8Hz,1H),7.41(d,J＝5.5Hz,1H),6.22(t,J＝6.8Hz,1H),5.45(s,2H),4.72(s,1H),3.90(s,2H),2.62(s,3H),1.01(s,6H).MS(ESI)491.2[M+H] +。
实施例8：化合物L-8的制备
Figure PCTCN2021081126-appb-000063
参考实施例7的制备方法，区别在于用2-碘丙烷替换2,2-二甲基环氧乙烷，参考实施例1步骤5的制备方法，得到白色固体产物L-8(14.43mg，产率:8.4％)。 1H NMR(400MHz,DMSO-d6)δ8.75(s,1H),7.95(d,J＝7.6Hz,1H),7.84(d,J＝7.2Hz,1H),7.76(dd,J＝7.0,1.9Hz,1H),7.46(t,J＝7.7Hz,1H),7.30(dd,J＝6.8,1.8Hz,1H),6.28(t,J＝6.9Hz,1H),5.45(s,2H),5.04(dt,J＝13.6,6.8Hz,1H),2.63(s,3H),1.25(d,J＝6.8Hz,6H).MS(ESI)461.1[M+H] +。
实施例9：化合物L-9的制备
Figure PCTCN2021081126-appb-000064
以中间体V8和3-(叠氮甲基)-1-甲基-1H-吡唑为原料，参考实施例1步骤5的制备方法，可制备得到淡黄色固体产物L-9(23.77mg，产率:16％)。 1H NMR(400MHz,DMSO-d6)δ8.73(s,1H),7.95(d,J＝7.5Hz,1H), 7.84(d,J＝7.5Hz,1H),7.63(s,1H),7.46(s,1H),6.24(s,1H),5.59(s,2H),3.77(s,3H),2.63(s,3H).MS(ESI)406.1[M+H] +。
实施例10：化合物L-10的制备
Figure PCTCN2021081126-appb-000065
步骤1:将重氮乙酸乙酯(3.04g,17.84mmol)和叔丁基二甲基(2-丙炔氧基)硅烷(2.06mL,19.62mmol)的甲苯(20mL)溶液放在微波中加热140℃反应30分钟。然后将反应液浓缩并通过硅胶柱层析(EA:PE＝0-35％)得到油状化合物10-1(2.7g，产率:36％).MS(ESI)285[M+H] +。
步骤2:将化合物10-1(2.55g,9.11mmol)，碘甲烷(3.88g,27.32mmol)和碳酸钾(3.77g,27.32mmol)加入到DMF(20mL)中并在室温下搅拌3h。然后将反应液倒入水中，用乙酸乙酯萃取，无水硫酸钠干燥，过滤，滤液浓缩并通过硅胶柱层析(EA:PE＝0-15％)得到油状化合物10-2(0.81g，产率:30％).MS(ESI)299[M+H] +。
步骤3:将化合物10-2(298mg,1.0mmol)加入到四氢呋喃(10mL)中并降温到0℃，然后将甲基碘化镁(3M,2mL，6.0mmol)缓慢滴入反应液中并升到室温反应1h。用饱和氯化铵水溶液淬灭反应，乙酸乙酯萃取，合并有机相，物水硫酸钠干燥，过滤，浓缩后得到油状化合物10-3(262mg，产率:92％).MS(ESI)285[M+H] +。
步骤4:参考实施例21步骤3的制备方法，区别在于用化合物10-3替换化合物21-2，得到油状化合物10-4(512mg)。MS(ESI)171[M+H] +。
步骤5-6：参考实施例7步骤3-4的制备方法，区别在于用化合物10-4替换化合物7-2，得到白色固体产物L-10(26mg，产率:9％)。 1H NMR(400MHz,DMSO-d6)δ8.74(s,1H),7.99–7.93(m,1H),7.85(dd,J＝7.7,1.2Hz,1H),7.47(t,J＝7.8Hz,1H),6.09(s,1H),5.52(s,2H),5.25(s,1H),3.89(s,3H),2.64(s,3H),1.42(s,6H).MS(ESI)464.1[M+H] +。
实施例11：化合物L-11的制备
Figure PCTCN2021081126-appb-000066
步骤1:以(E)-4-二甲基氨基-1,1-二甲氧基丁-3-烯-2-酮(3.16g,20mmol)和丙酰胺盐酸盐(3.24g,30mmol)为原料，参考实施例4步骤1的制备方法，得到油状化合物11-1(2.1g).MS(ESI)183[M+H] +。
步骤2:将化合物11-1(1.3g,7.14mmol)加入到盐酸(3M,12mL)中并加热到50℃搅拌18h。原料反应完全，将反应液冷却到室温，用饱和碳酸氢钠中和反应液，用二氯甲烷萃取，合并有机相，无水硫酸钠干燥，过滤，滤液浓缩后得到油状化合物11-2(0.42g).MS(ESI)137[M+H] +。
步骤3:将化合物11-2(0.42g,3.09mmol)加入到甲醇(10mL)中，然后分批加入硼氢化钠(352mg,9.26mmol)并在室温下搅拌1h。原料反应完全，加入饱和氯化铵水溶液萃取反应，二氯甲烷萃取，无水硫酸钠干燥，过滤，滤液浓缩后得到油状的化合物11-3(270mg).MS(ESI)139[M+H] +。
步骤4-5:参考实施例7步骤3-4的制备方法，区别在于用化合物化合物11-3替换化合物7-2，得到白色固体产物L-11(33mg，产率:20％)。 1H NMR(400MHz,DMSO-d6)δ8.93(s,1H),8.70(d,J＝5.1Hz,1H),7.97(dd,J＝7.8,1.2Hz,1H),7.85(dd,J＝7.7,1.2Hz,1H),7.47(t,J＝7.7Hz,1H),7.06(d,J＝5.1Hz,1H),5.82(s,2H),2.83(q,J＝7.6Hz,2H),2.66(s,3H),1.20(t,J＝7.6Hz,3H).MS(ESI)432[M+H] +。
实施例12：化合物L-12的制备
Figure PCTCN2021081126-appb-000067
步骤1:将1H-吡唑-3-羧酸甲酯(2.52g,20mmol)，环丙基硼酸(2.58g,30mmol)，醋酸铜(3.98g,22mmol)，2,2-联吡啶(3.43g,22mmol)和碳酸钠(4.24g,40mmol)加入到1，2-二氯乙烷(150mL)中，反应液在氧气中加热到70℃搅拌3h，然后将甲醇钠(1.62g,30mmol)加入到反应液中并将反应液加热至回流2h，再在室温下搅拌16h。反应液用二氯甲烷稀释，并用水洗涤两遍，无水硫酸钠干燥，过滤，滤液再浓缩并通过硅胶柱层析(EA:PE＝0-20％)得到油状产物12-1(1.8g).MS(ESI)167[M+H] +。
步骤2-4:参考实施例7步骤2-4的制备方法，区别在于用化合物12-1替换化合物7-1，得到白色固体产物L-12(34mg，产率:21％)。 1H NMR(400MHz,DMSO-d6)δ8.74(s,1H),8.00–7.92(m,1H),7.85(dd,J＝7.7,1.2Hz,1H),7.72(d,J＝2.3Hz,1H),7.46(t,J＝7.8Hz,1H),6.23(d,J＝2.3Hz,1H),5.59(s,2H),3.66(ddd,J＝11.2,7.3,3.9Hz,1H),2.64(s,3H),1.01–0.94(m,2H),0.94–0.84(m,2H).MS(ESI)432[M+H] +。
实施例13：化合物L-13的制备
Figure PCTCN2021081126-appb-000068
步骤1:参考实施例10的制备方法，其区别在于用2-氧代-1,2-二氢吡啶-3-乙醛替换化合物10-1，得到固体产物13-1(2.1g,产率:77％)MS(ESI)138[M+H] +
步骤2-3:参考实施例7步骤2-3的制备方法，其区别在于用化合物13-1替换化合物7-1，得到油状化合物13-3(199mg).MS(ESI)165[M+H] +。
步骤4：参考实施例1步骤5的制备方法，得到白色固体产物L-13(16mg，产率:10％)。 1H NMR(400MHz,DMSO-d6)δ8.73(s,1H),7.99–7.93(m,1H),7.85(dd,J＝7.7,1.2Hz,1H),7.72(dd,J＝6.8,2.0Hz,1H),7.47(t,J＝7.8Hz,1H),7.40(dd,J＝6.9,1.9Hz,1H),6.23(t,J＝6.8Hz,1H),5.45(s,2H),3.42(s,3H),2.64(s,3H).MS(ESI)433[M+H] +。
实施例14：化合物L-14的制备
Figure PCTCN2021081126-appb-000069
参考实施例1步骤3-5的制备方法，其区别在于用中间体V3替换中间体V1，可制备得到淡黄色固体产物L-14(65mg)。 1H NMR(400MHz,DMSO-d6)δ8.76(s,1H),7.77(t,J＝7.8Hz,1H),7.57(d,J＝7.8Hz,1H),7.52–7.40(m,3H),7.31–7.15(m,2H),7.11(d,J＝7.5Hz,1H),5.78(s,2H),5.18(s,1H),2.35(s,3H),1.35(s,6H).MS(ESI)438.1[M+H]+.
实施例15：化合物L-15的制备
Figure PCTCN2021081126-appb-000070
步骤1-1和步骤1-2：参考实施例1步骤2-3，区别在于用全氯嘧啶替换化合物1-2，得到固体化合物15-1(0.51g,产率:24％).MS(ESI)279[M+H] +.
步骤2-1：将2-(6-(羟甲基)吡啶-2-基)丙-2-醇(550mg,3.27mmol)溶解在二氯甲烷中(40mL)，冷却至0℃，加入DMP(2.1g,4.91mmol)，室温下搅拌4h。TLC监测反应完全。反应液用二氯甲烷(200mL)稀释，水(150mL x 2)洗涤。分离出有机相并通过无水硫酸钠干燥，减压浓缩后通过硅胶柱层析(EA：PE，0-30％)得到黄色油状化合物15-2(320mg，产率：593％)。MS(ESI)166[M+H] +.
步骤2-2：将4-碘-1-(((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑(1.2g,3.61mmol)溶解在四氢呋喃(20mL)中。在-70℃下，滴加正丁基锂(2.7mL,5.43mmol)，搅拌2h。将化合物15-2(300mg,1.81mmol)溶于四氢呋喃中(2mL)，在-70℃下滴加到上述溶液中。反应液缓慢升至0℃，搅拌2h。TLC监测反应完毕。向反应液中加入饱和氯化铵水溶液(5mL)，用乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩并通过硅胶柱层析(EA：PE，0-70％)得到黄色油状化合物15-3(80mg,产率：12％)。MS(ESI)364[M+H] +.
步骤2-3：将化合物15-3(80mg,0.22mmol)溶于三乙基硅烷/三氟乙酸(3mL/1mL)中，80℃搅拌24h。TLC监测显示反应完全。反应液减压浓缩，残余物通过硅胶柱层析(EA：PE，0-70％)得到黄色胶状化合物15-4(22mg,产率：46％)。MS(ESI)218[M+H] +.
步骤3：将化合物15-1(30mg,0.11mmol)和化合物15-4(22mg,0.19mmol)溶于乙腈(6mL)中，然后将碳酸钾(297mg,2.15mmol)加入其中。该反应在微波140℃条件下搅拌1h。然后将反应液浓缩并通过高效液相制备分离纯化得到白色固体产物L-15(8.94mg,产率:19％,P:95.95％)。 1H NMR(400MHz,DMSO-d6)δ8.33(s,1H),7.97(d,J＝7.8Hz,1H),7.87(d,J＝6.4Hz,1H),7.78(s,1H),7.65(t,J＝7.7Hz,1H),7.49–7.43(m,2H),7.10(d,J＝7.2Hz,1H),5.17(s,1H),3.96(s,2H),2.64(s,3H),1.40(s,6H).MS(ESI)460.2[M+H]+.
实施例16：化合物L-16的制备
Figure PCTCN2021081126-appb-000071
步骤1-2：以2-氟丙二酸二乙酯(9.80g,55.00mmol)和2-噻唑甲脒盐酸盐(4.5g,27.50mmol)为原料，参考实施例4步骤1-2的制备方法，得到固体化合物16-2(2.07g,P:100％,产率:79％)。MS(ESI)250.0[M+H]+.
步骤3-6：参考实施例1步骤1-2以及步骤4的制备方法，区别在于以化合物16-2替换化合物1-1，得到白色固体产物L-16(32.58mg,产率:9％)。 1H NMR(400MHz,DMSO-d6)δ8.79(s,1H),7.94(d,J＝3.1Hz,1H),7.85(d,J＝3.1Hz,1H),7.77(t,J＝7.8Hz,1H),7.67(s,2H),7.58(d,J＝7.3Hz,1H),7.11(d,J＝7.1Hz,1H),5.81(s,2H),5.18(s,1H),1.36(s,6H).MS(ESI)413.1[M+H]+.
实施例17：化合物L-17的制备
Figure PCTCN2021081126-appb-000072
步骤1::参考实施例12步骤1的制备方法，区别在于用2-氧-1,2-二氢吡啶-3-甲醛替换1H-吡唑-3-羧酸甲酯，得到固体化合物17-1(280mg,产率:17％)。MS(ESI)164.1[M+H]+.
步骤2-4:参考实施例7步骤2-4，区别在于用化合物17-1替换化合物7-1，用化合物1-5替换中间体V8，得到白色固体产物L-17(26mg，产率:15％)。 1H NMR(400MHz,DMSO-d6)δ8.65(s,1H),7.91(dd,J＝7.8,1.3Hz,1H),7.82(dd,J＝7.7,1.3Hz,1H),7.56(dd,J＝6.9,1.9Hz,1H),7.51(s,2H),7.45(t,J＝7.8Hz,1H),7.34(dd,J＝6.9,1.9Hz,1H),6.19(t,J＝6.9Hz,1H),5.45(s,2H),3.37–3.34(m,1H),2.61(s,3H),1.00–0.92(m,2H),0.84–0.75(m,2H).MS(ESI)443.2[M+H] +。
实施例18：化合物L-18的制备
Figure PCTCN2021081126-appb-000073
参考实施例1步骤5的制备方法，区别在于用2-(3-(叠氮基甲基)-1-甲基-1H-吡唑-5-基)丙-2-醇替换中间体V4，可制备得到白色固体产物L-18(28.76mg，产率:23％)。 1H NMR(400MHz,cdcl 3)δ8.69(s,1H),7.95(d,J＝7.0Hz,1H),7.86(d,J＝7.7Hz,1H),7.54(s,2H),7.48(t,J＝7.7Hz,1H),6.12(s,1H),5.56(s,2H),5.28(s,1H),3.92(s,3H),2.65(s,3H),1.45(s,6H).MS(ESI)448.2[M+H] +。
实施例19：化合物L-19的制备
Figure PCTCN2021081126-appb-000074
步骤1：将1H-吡唑-3-羧酸乙酯(1.4g,9.99mmol)溶于二氯甲烷(50mL)中，然后将三氟甲基磺酰基三氟甲磺酸酯(4.23g,14.99mmol)加入其中。该反应在室温条件下搅拌1h。将反应液倒入饱和氯化铵水溶液中，用二氯甲烷萃取，合并有机相，无水硫酸钠干燥，过滤，滤液经过浓缩并经过硅胶柱层析分离(EA：PE，0-50％)得到白色固体化合物18-1(2.4g,产率:88％)。MS(ESI)273.0[M+H]+.
步骤2：将3,3-二氟环丁醇(600mg,5.55mmol)溶于乙腈(10mL)中，然后将碳酸铯(1.99g,6.11mmol)加入其中。将反应温度降低到0℃，然后滴加化合物18-1(1.38g,5.05mmol)的乙腈(10mL)溶液。该反应在0℃条件下搅拌1h,然后升到室温搅拌2h。反应液用二氯甲烷稀释，过滤，滤液经过浓缩并经过硅胶柱层析分离(EA：PE，0-50％)得到无色的油状化合物18-2(712mg,产率:54％)。MS(ESI)231.1[M+H]+.
步骤3-5：参考实施例7步骤2-4，区别在于用化合物18-2替换化合物7-1，用化合物1-5替换中间体V8，得到白色固体产物L-19(36.59mg,产率：25％). 1H NMR(400MHz,cdcl 3)δ8.71(s,1H),7.95(d,J＝7.0Hz,1H),7.89–7.81(m,2H),7.54(s,2H),7.48(t,J＝7.8Hz,1H),6.31(d,J＝2.3Hz,1H),5.68(s,2H),4.90(dd,J＝13.5,6.9Hz,1H),3.21–3.01(m,4H),2.65(s,3H).MS(ESI)466.2[M+H]+.
实施例20：化合物L-20的制备
Figure PCTCN2021081126-appb-000075
参考实施例7步骤2-4的制备方法，其区别在于用1H-吡唑-3-羧酸乙酯替换化合物7-1，得到白色固体产物L-20(27.69mg,产率：24％)。 1H NMR(400MHz,DMSO-d6)δ12.86(s,1H),8.73(s,1H),8.01–7.92(m,1H),7.85(dd,J＝7.7,1.1Hz,1H),7.69(s,1H),7.46(t,J＝7.8Hz,1H),6.28(d,J＝1.9Hz,1H),5.65(s,2H),2.64(s,3H).MS(ESI)392.1[M+H]+.
实施例21：化合物L-21的制备
Figure PCTCN2021081126-appb-000076
步骤1：将(1-甲基吡唑-3-基)甲醇(1.12g,9.99mmol)溶于二氯甲烷(60mL)中，然后将1H-咪唑(1.36g,19.98mmol)，4-二甲基氨基吡啶(1.83g,14.98mmol)，TBSCl(1.23g,14.98mmol)加入其中。该反应在室温条件下搅拌2h。反应完成后，水溶液淬灭，二氯甲烷萃取，饱和食盐水洗涤有机相，无水硫酸钠干燥，过滤，滤液浓缩并经过硅胶柱层析分离(EA：PE，0-30％)得到无色的油状化合物21-1(1.7g，产率:75％)。MS(ESI)227.2[M+H]+.
步骤2：将化合物21-1(1.5g,6.63mmol)溶于四氢呋喃(6mL)中，降低温度到-78℃，滴加正丁基锂(2.5M,3.98mL)，然后在-78℃搅拌1h，继续滴加N-氟代双苯磺酰胺(3.13g,9.94mmol)的四氢呋喃(6mL)，滴加完毕，在-78℃搅拌2h，然后自然升到室温搅拌18h。饱和氯化铵水溶液淬灭，乙酸乙酯萃取，无水硫酸钠干燥，过滤，滤液浓缩并经过硅胶柱层析分离(EA：PE，0-20％)得到棕红色油状化合物21-2(267mg,产率:18％)。MS(ESI)245.2[M+H]+.
步骤3：将化合物21-2(240mg,982mmol)溶于甲醇(20mL)中，然后将氟化铵(1.09g,29mmol)加入其中。该反应在80℃条件下搅拌1h。反应完成后，冷却至室温，过滤，水溶液淬灭，乙酸乙酯萃取，无水硫酸钠干燥，再过滤，滤液浓缩后得到棕色油状化合物21-3(210mg)。MS(ESI)131.1[M+H]+.
步骤4-5：参考实施例7步骤3-4的制备方法，其区别在于用化合物21-3替换化合物7-2，，用化合物1-5替换中间体V8，得到白色固体产物L-21(63.01mg,产率:48.77％) 1H NMR(400MHz,DMSO-d6)δ8.68(s,1H),7.91(dd,J＝7.8,1.2Hz,1H),7.83(dd,J＝7.7,1.3Hz,1H),7.52(s,2H),7.45(t,J＝7.8Hz,1H),6.02(d,J＝5.7Hz,1H),5.53(s,2H),3.63(d,J＝1.2Hz,3H),2.62(s,3H).MS(ESI)408.3[M+H]+.
实施例22：化合物L-22的制备
Figure PCTCN2021081126-appb-000077
参考实施例10步骤3-6的制备方法，区别在于用化合物10-1替换化合物10-2，得到白色固体产物L-22(32.99mg,产率:25％)。 1H NMR(400MHz,DMSO-d6)δ12.56(s,1H),8.74(s,1H),7.95(dd,J＝7.9,1.2Hz,1H),7.84(dd,J＝7.7,1.3Hz,1H),7.46(t,J＝7.8Hz,1H),6.07(s,1H),5.57(s,2H),5.16(s,1H),2.63(s,3H),1.37(s,6H).MS(ESI)450.1[M+H]+.
实施例23：化合物L-23的制备
Figure PCTCN2021081126-appb-000078
步骤1：将化合物10-3(380mg,1.34mmol)溶于四氢呋喃(20mL)中，然后将氢化钠(385mg,16.03mmol)加入其中并搅拌10分钟，然后将碘甲烷(1.90g,13.36mmol)加入反应中并再在室温下搅拌2h。将反应液放入冰水浴中，然后分批加入十水硫酸钠，加完，搅拌10分钟，过滤，滤液直接浓缩得到油状化合物23-1(371mg,产率:93％)。MS(ESI)299.2[M+H]+.
步骤2：参考实施例21步骤3的制备方法，区别在于用化合物23-1替换化合物21-2，得到油状化合物23-2(310mg)。MS(ESI)185.1[M+H]+.
步骤3-4：参考实施例7步骤3-4的制备方法，其区别在于用化合物23-2替换化合物7-2，用化合物1-5替换中间体V8，得到白色固体产物L-23(89.26mg,产率：50％)。 1H NMR(400MHz,DMSO-d6)δ8.74(s,1H),7.95(dd,J＝7.8,1.1Hz,1H),7.84(dd,J＝7.7,1.1Hz,1H),7.45(t,J＝7.7Hz,1H),6.18(s,1H),5.55(s,2H),3.83(s,3H),2.91(s,3H),2.63(s,3H),1.43(s,6H).MS(ESI)210.1[M+H]+.
实施例24：化合物L-24的制备
Figure PCTCN2021081126-appb-000079
步骤1：参考实施例7步骤2的制备方法，其区别在于用化合物10-2替换化合物7-1，得到油状化合物24-1(451mg,产率:75％)。MS(ESI)257.2[M+H]+.
步骤2：将化合物24-1(451mg,1.76mmol)溶于四氢呋喃(20mL)中，然后将活性二氧化锰(3.06g,35.18mmol)加入其中。该反应在85℃条件下搅拌24h。反应完成后，冷却至室温，过滤除去不溶解的物质，滤饼用二氯甲烷洗涤，滤液减压旋干后得到淡黄色的油状化合物24-2(345mg,产率:77％,)。MS(ESI)255.2[M+H] +.
步骤3：参考实施例10步骤3的制备方法，区别在于用化合物24-2替换化合物10-2，得到淡黄色的油状化合物24-3(230mg)。MS(ESI)271.2[M+H] +.步骤4：参考实施例21步骤3的制备方法，其区别在于用化合物24-3替换化合物21-2，得到淡黄色的油状化合物24-4(214mg)。MS(ESI)157.1[M+H] +.步骤5-6：参考实施例7步骤3-4的制备方法，其区别在于用化合物24-4替换化合物7-2，得到白色固体产物L-24(17.62mg,产率:25％)。 1H NMR(400MHz,DMSO-d6)δ8.74(s,1H),7.94(d,J＝7.7Hz,1H),7.84(d,J＝7.6Hz,1H),7.46(t,J＝7.8Hz,1H),6.15(s,1H),5.54(s,2H),5.23(d,J＝5.6Hz,1H),4.73(p,J＝6.4Hz,1H),3.73(s,3H),2.63(s,3H),1.33(d,J＝6.5Hz,3H).MS(ESI)450.2[M+H]+.
实施例25：化合物L-25的制备
Figure PCTCN2021081126-appb-000080
以2-甲基-3-丁炔-2-醇(20g,238.10mmol)和2-重氮乙酸乙酯(36g,313.04mmol)为原料，参考实施例7的制备方法，得到白色固体产物L-25(25.99mg,产率:15％)。 1H NMR(400MHz,DMSO-d6)δ8.81(s,1H),7.95(dd,J＝7.8,1.2Hz,1H),7.84(d,J＝7.7Hz,1H),7.46(t,J＝7.8Hz,1H),6.18(s,1H),5.76(s,2H),4.79(s,1H),3.80(s,3H),2.63(s,3H),1.32(s,6H).MS(ESI)464.2[M+H]+.
实施例26：化合物L-26的制备
Figure PCTCN2021081126-appb-000081
步骤1：参考实施例1步骤3，区别在于用化合物2-2替换化合物1-3，得到化合物26-1(170mg,产率:52.3％)MS(ESI)263[M+H] +。
步骤2：参考实施例1步骤3，区别在于用化合物26-1替换化合物1-3，用中间体V5替换中间体V1，得到白色固体L-26(38.59mg，产率:17.4％)MS(ESI)444[M+H] +。 1H NMR(400MHz,DMSO-d6)δ8.47(d,J＝1.2Hz,1H),8.03(s,1H),7.90(d,J＝7.2Hz,1H),7.71(t,J＝8.0Hz,2H),7.53(d,J＝8.4Hz,1H),7.50(t,J＝8.0Hz,1H),6.86(d,J＝7.6Hz,1H),6.67(s,2H),5.49(s,2H),5.19(s,1H),2.39(s,3H),1.36(s,6H).
实施例27：化合物L-27的制备
Figure PCTCN2021081126-appb-000082
参考实施例1步骤5的制备方法，区别在于用3-(叠氮甲基)-1H-吡唑替换中间体V4，得到白色固体L-27(12.65mg，产率:14％)MS(ESI)376[M+H] +。 1H NMR(400MHz,DMSO-d6)δ12.82(s,1H),8.56(s,1H),7.90(dd,J＝8.0,4.0Hz,1H),7.76(dd,J＝8.0,4.0Hz,1H),7.62(s,1H),7.41(t,J＝8.0Hz,3H),6.255(d,J＝4.0Hz,1H),5.63(s,2H),2.62(s,3H).
实施例28：化合物L-28的制备
Figure PCTCN2021081126-appb-000083
参考实施例7步骤3-4的制备防区，区别在于用(1-甲基-吡唑-5-基)甲醇替换化合物7-2，用化合物1-5替换中间体V8，得到白色固体L-28(4.22mg，产率:2.7％)MS(ESI)390[M+H] +。 1H NMR(400MHz,DMSO-d6)δ8.72(s,1H),7.91(dd,J＝7.8,1.3Hz,1H),7.83(dd,J＝7.8,1.3Hz,1H),7.53(s,2H),7.45(t,J＝7.8Hz,1H),7.34(d,J＝1.9Hz,1H),6.28(d,J＝1.9Hz,1H),5.81(s,2H),3.85(s,3H),2.61(s,3H).
实施例29：化合物L-29的制备
Figure PCTCN2021081126-appb-000084
步骤1：以3-叠氮甲基吡啶(170mg，1mmol)和2-碘乙酰胺(278mg，1.5mmol)为原料，参考实施例10步骤2的制备方法，得到化合物29-1(160mg，产率:89％)MS(ESI)181[M+H] +。
步骤2：参考实施例1步骤5的制备方法，区别在于用化合物29-1替换化合物V4，得到白色固体L-29(10.79mg，产率:8.3％)MS(ESI)433[M+H] +。 1H NMR(400MHz,DMSO-d6)δ8.65(s,1H),7.92(dd,J＝8.0,1.2Hz,1H),7.83(dd,J＝8.0,1.2Hz,1H),7.65(d,J＝2.3Hz,1H),7.51(s,1H),7.45(t,J＝7.7Hz,1H),7.20(s,1H),6.26(d,J＝2.0Hz,1H),5.61(s,2H),4.70(s,2H),2.62(s,3H).
实施例30：化合物L-30的制备
Figure PCTCN2021081126-appb-000085
步骤1：以1H-吡唑-3-羧酸乙酯(2.8g，20mmol)，碘乙烷(6240mg，40mmol)为原料，参考实施例10步骤2的制备方法，得到化合物30-1(2.2g，产率:74％)MS(ESI)169[M+H] +。
步骤2-3：参考实施例7步骤2-3的制备方法，区别在于用化合物30-1替换化合物7-1，得到化合物30-3(847mg)的粗产物，保存在10mL叔丁醇中，MS(ESI)152[M+H] +。
步骤4：参考实施例1步骤5的制备方法，区别在于用化合物30-3替换化合物V4，得到白色固体L-30(33.29mg，P:100％，产率:27.5％)MS(ESI)404[M+H] +。 1H NMR(400MHz,DMSO-d6)δ8.64(s,1H),7.92(dd,J＝7.8,1.2Hz,1H),7.83(dd,J＝7.7,1.2Hz,1H),7.68(d,J＝2.2Hz,1H),7.51(s,2H),7.45(t,J＝7.7Hz,1H),6.24(d,J＝2.2Hz,1H),5.61(s,2H),4.07(q,J＝7.3Hz,2H),2.62(s,3H),1.32(t,J＝7.3Hz,3H).
实施例31：化合物L-31的制备
Figure PCTCN2021081126-appb-000086
步骤1-2：参考实施例7步骤2-3的制备方法，区别在于用1-乙基-1H-吡唑-5-羧酸乙酯(285mg，1.7mmol)替换化合物7-1，得到化合物31-2(538mg)的粗产物，保存在10mL叔丁醇中，MS(ESI)152[M+H] +。
步骤3：参考实施例1步骤5的制备方法，区别在于用化合物31-2替换化合物V4，得到白色固体L-31(20.93mg，产率:17.3％)MS(ESI)404[M+H] +。 1H NMR(400MHz,DMSO-d6)δ8.72(s,1H),7.91(dd,J＝8.0,1.2Hz,1H),7.83(dd,J＝8.0,1.2Hz,1H),7.53(s,2H),7.45(t,J＝7.6Hz,1H),7.39(d,J＝2.0Hz,1H),6.29(d,J＝2.0Hz,1H),5.83(s,2H),4.20(q,J＝7.2Hz,2H),2.62(s,3H),1.20(t,J＝7.6Hz,3H).
实施例32：L-32的制备
Figure PCTCN2021081126-appb-000087
步骤1：参考实施例7步骤3的制备方法，区别在于用(1-环丙基-1H-吡唑-3-基)甲醇(138mg，1mmol)替换化合物7-2，得到化合物32-1(660mg)的粗产物，保存在10mL叔丁醇中，MS(ESI)416[M+H] +。
步骤2：参考实施例1步骤5的制备方法，区别在于用化合物32-1替换化合物V4，得到白色固体L-32(18.01mg，产率:14.5％)MS(ESI)416[M+H] +。 1H NMR(400MHz,DMSO-d6)δ8.65(s,1H),7.92(s,1H),7.82(s,1H),7.72(s,1H),7.48(d,J＝2.4Hz,3H),6.23(s,1H),5.59(s,2H),3.66(s,1H),2.62(s,3H),0.97(d,J＝4.0Hz,2H),0.91(d,J＝8.0Hz,2H).
实施例33：化合物L-33的制备
Figure PCTCN2021081126-appb-000088
步骤1-2：以(1-甲基-1H-吡唑-3-基)甲醇(2g，17.86mmol)为原料，参考中间体V5的制备方法，得到无色液体化合物33-2(2.1g，产率:54％)MS(ESI)289[M+H] +。
步骤3：以化合物33-2(1.38g,3.82mmol)和2,4,5,6-四氯嘧啶(1.08g,4.96mmol)为原料，参考实施例1步骤3的制备方法，得到黄色固体产物化合物33-3(660mg,1.67mmol,43.6％收率)MS(ESI)345[M+H] +。
步骤4：以化合物33-3为原料，参考实施例1步骤2的制备方法，得到白色固体化合物33-4(300mg)，MS(ESI)325[M+H] +。
步骤5：以化合物33-4和化合物V1为原料，参考实施例1步骤3的制备方法，得到白色固体L-33(13.10mg,)，MS(ESI)405[M+H] +。 1H NMR(400MHz,DMSO-d6)δ8.56(s,1H),8.16(s,1H),7.96(dd,J＝7.8,1.1Hz,1H),7.84(dd,J＝7.7,1.1Hz,1H),7.59(d,J＝2.1Hz,1H),7.46(t,J＝7.7Hz,2H),7.39(s,1H),6.15(d,J＝2.2Hz,1H),5.31(s,2H),3.77(s,3H),2.64(s,3H).
实施例34：化合物L-34的制备
Figure PCTCN2021081126-appb-000089
步骤1：将1H-吡唑-3-羧酸乙酯(1.4g,9.99mmol)和氯二氟乙酸钠(4.57g,29.97mmol)溶于DMF(20mL)和乙腈(12mL)中，然后将碳酸铯(9.76g,29.97mmol)加入其中。该反应在100℃条件下搅拌3小时。反应完成后，过滤，乙酸乙酯洗涤滤渣，减压旋干滤液后经柱层析过柱分离(20g，乙酸乙酯：石油醚＝0-20％)得到化合物34-1(1.1g,57.91％收率)MS(ESI)191[M+H]+。
步骤2-3：以化合物34-1为原料，参考实施例7步骤2-3的制备方法，得到化合物34-3(780mg，P:20％)保存在10mL叔丁醇中，MS(ESI)174[M+H]+。
步骤4：以化合物34-3和中间体V8为原料，参考实施例1步骤5的制备方法，得到化合物L-34(34.73mg,25.83％收率)，MS(ESI)442[M+H]+。 1H NMR(400MHz,DMSO-d6)δ8.86(s,1H),8.20(d,J＝2.7Hz,1H),7.96(dd,J＝7.9,1.3Hz,1H),7.85(dd,J＝7.8,1.3Hz,1H),7.76(t,J＝60Hz,1H),7.47(t,J＝7.7Hz,1H),6.53(d,J＝2.7Hz,1H),5.74(s,2H),2.64(s,3H).
实施例35：化合物L-35的制备
Figure PCTCN2021081126-appb-000090
步骤1：1-(2-羟乙基)吡咯烷-2-酮(800mg,6.19mmol)溶于二氯亚砜(18mL)中，该反应在50℃条件下搅拌1小时。乙酸乙酯(15mL*3)萃取，饱和碳酸钠水溶液洗涤有机相，无水硫酸钠干燥，减压旋干溶剂后得到化合物35-1(910mg,99.53％收率)，MS(ESI)148[M+H]+。
步骤2：将化合物35-1(735mg,4.98mmol)和1H-吡唑-3-羧酸乙酯(1.05g,7.47mmol)溶于乙腈(20mL)中，该反应在80℃条件下搅拌2小时,反应完成后，将反应液过滤，乙酸乙酯洗涤，减压旋干溶剂后经过柱分离(20g，乙酸乙酯：石油醚＝0-60％))得到黄色油状化合物35-2(480mg,38.36％收率)，MS(ESI)252[M+H]+。
步骤3-4：以化合物35-2为原料，参考实施例7步骤2-3的制备方法，得到化合物35-4(460mg粗产物，保存在叔丁醇(5mL)溶剂中，MS(ESI)235[M+H]+。
步骤5：参考实施例1步骤5的制备方法，其区别在于用化合物35-4替换化合物V4，得到浅绿色固体L-35(92.48mg,63.84％收率)，MS(ESI)486[M+H]+。 1H NMR(400MHz,DMSO-d6)δ8.76(s,1H),7.92(d,J＝7.8Hz,1H),7.83(d,J＝7.5Hz,1H),7.54(s,2H),7.45(t,J＝8.0Hz,1H),7.42(s,1H),6.30(s,1H),5.82(s,2H),4.32(t,J＝5.9Hz,2H),3.47(t,J＝5.8Hz,2H),3.02(t,J＝7.0Hz,2H),2.62(s,3H),2.08(t,J＝8.1Hz,2H),1.86–1.69(m,2H).
实施例36：化合物L-36的制备
Figure PCTCN2021081126-appb-000091
步骤1：以1H-吡唑-3-羧酸乙酯(700mg,5.00mmol)和1-碘-2-甲基丙烷(1.19g,6.49mmol)为原料，参考实施例10步骤2的制备方法，得到白色固体化合物36-1(510mg,52％收率)，MS(ESI)197[M+H]+。
步骤2-3：以化合物36-1为原料，参考实施例7步骤2-3的制备方法，得化合物36-3(840mg,20％纯度)，保存在叔丁醇(5mL)溶剂中，MS(ESI)180[M+H]+。
步骤4：参考实施例1步骤5的制备方法，其区别在于用化合物36-3替换化合物V4，得到白色固体L-36(71.83mg,54.87％收率)，MS(ESI)432[M+H]+。 1H NMR(400MHz,DMSO-d6)δ8.60(s,1H),7.92(dd,J＝7.6,1.2Hz,1H),7.92(dd,J＝7.6,0.8Hz,1H),7.66(d,J＝2.2Hz,1H),7.52(s,2H),7.45(t,J＝7.8Hz,1H),6.25(d,J＝2.2Hz,1H),5.61(s,2H),3.85(d,J＝7.2Hz,2H),3.31(s,3H),2.62(s,3H),2.09-1.99(m,6.8Hz,1H),0.78(d,J＝6.7Hz,6H).
实施例37：化合物L-37的制备
Figure PCTCN2021081126-appb-000092
步骤1：以1H-吡唑-3-羧酸乙酯(1.4g,10.06mmol)和1,1,1-三氟-2-碘-乙烷(4.22g,20.12mmol)为原料，参考实施例10步骤2的制备方法，得到白色固体化合物37-1(650mg,27.33％收率)，MS(ESI)223[M+H]+。
步骤2-3：以化合物37-1为原料，参考实施例7步骤2-3的制备方法，得到化合物37-3(800mg)保存在4mL叔丁醇中，MS(ESI)206[M+H]+。
步骤4：参考实施例1步骤5的制备方法，其区别在于用化合物37-3替换化合物V4，得到化合物L-37(24.70mg,18.12％收率)，MS(ESI)458[M+H]+。 1H NMR(400MHz,DMSO-d6)δ8.67(s,1H),7.92(dd,J＝7.8,1.2Hz,1H),7.83(dd,J＝7.7,1.3Hz,1H),7.81(d,J＝2.3Hz,1H),7.52(s,2H),7.45(t,J＝7.8Hz,1H),6.38(d,J＝2.4Hz,1H),5.67(s,2H),5.10(q,J＝9.1Hz,2H),2.62(s,3H).
实施例38：化合物L-38的制备
Figure PCTCN2021081126-appb-000093
步骤1：以1H-吡唑-3-羧酸乙酯(282.03mg,2.01mmol)和1-氟-2-碘乙烷(525.12mg,3.02mmol)为原料，参考实施例10步骤2的制备方法，得到无色液体化合物38-1(310mg,82.74％收率)，MS(ESI)187[M+H]+。
步骤2-3：以化合物38-1为原料，参考实施例7步骤2-3的制备方法，得到化合物38-3(536mg，P:22％)粗产物，保存在叔丁醇(5mL)中，MS(ESI)170[M+H]+。
步骤4：参考实施例1步骤5的制备方法，其区别在于用化合物38-3替换化合物V4，得到白色化合物L-38(45.55mg,44.63％收率)，MS(ESI)422[M+H]+。 1H NMR(400MHz,DMSO-d6)δ8.66(s,1H),7.92(d,J＝7.4Hz,1H),7.83(d,J＝6.4Hz,1H),7.72(s,1H),7.52(s,2H),7.45(t,J＝7.3Hz,1H),6.29(s,1H),5.63(s,2H),4.71(d,J＝46.8Hz,2H),4.38(d,J＝28.0Hz,2H),2.62(s,3H).
实施例39：化合物L-39的制备
Figure PCTCN2021081126-appb-000094
步骤1：以1H-吡唑-3-羧酸乙酯(215mg,1.53mmol)和碘甲基环丙烷(280mg,1.54mmol)为原料，参考实施例10步骤2的制备方法，得到无色液体化合物39-1(270mg,86.98％收率)，MS(ESI)195[M+H]+。
步骤2-3：以化合物39-1为原料，参考实施例7步骤2-3的制备方法，得到化合物39-3(690mg，P:18％)的 粗产物，保存在6mL叔丁醇中，MS(ESI)178[M+H]+。
步骤4：参考实施例1步骤5的制备方法，其区别在于用化合物39-3替换化合物V4，得到浅绿色固体L-39(48.12mg,37.14％收率)，MS(ESI)430[M+H]+。 1H NMR(400MHz,DMSO-d6)δ8.65(s,1H),7.91(d,J＝4.5Hz,1H),7.83(d,J＝5.5Hz,1H),7.71(s,1H),7.52(s,2H),7.45(s,1H),6.25(s,1H),5.62(s,2H),3.90(d,J＝4.6Hz,2H),2.61(s,3H),1.17(s,1H),0.47(s,2H),0.30(s,2H).
实施例40：化合物L-40的制备
Figure PCTCN2021081126-appb-000095
步骤1：以3-(叠氮甲基)-1H-吡唑(100mg，812.24μmol)和2-溴乙酸乙酯(203.47mg,1.22mmol)为原料，参考实施例10步骤2的制备方法，得到浅黄色液体化合物40-1(160mg,74.39％收率)，MS(ESI)210[M+H]+。
步骤2：参考实施例1步骤5的制备方法，其区别在于用化合物40-1替换化合物V4，得到黄色固体化合物40-2(170mg,45.28％收率)，MS(ESI)462[M+H]+。
步骤3：将化合物40-2(150mg,325.06μmol)溶于甲醇(5mL)中，然后将氢氧化锂水溶液(0.4mmol，0.2M,2mL)逐滴加入其中。该反应在室温条件下搅拌20分钟,反应完成后，减压旋干溶剂，用制备液相色谱纯化得到化合物L-40(30.23mg,21.46％收率)，MS(ESI)434[M+H]+。 1H NMR(400MHz,DMSO-d6)δ8.65(s,1H),7.91(dd,J＝7.8,1.1Hz,1H),7.82(dd,J＝7.7,1.1Hz,1H),7.67(s,1H),7.51(s,2H),7.45(t,J＝7.8Hz,1H),6.28(s,1H),5.61(s,2H),4.87(s,2H),2.61(s,3H).
实施例41：化合物L-41的制备
Figure PCTCN2021081126-appb-000096
步骤1：将2-(二甲基氨基)乙醇(180mg，2.02mmol)溶于二氯甲烷(2mL)中，冷却至0℃，将二氯亚砜(1M,2.63mL)逐滴加入其中。该反应在室温下搅拌过夜。减压旋干溶剂后得到白色固体化合物41-1(275mg,94.54％收率)。
步骤2：将化合物41-1(275mg,2.56mmol)和1H-吡唑-3-羧酸乙酯(300mg,2.14mmol)溶于DMF(8mL)中，然后将碳酸铯(1.67g,5.11mmol)加入其中。该反应在110℃条件下搅拌5小时。将反应液过滤，二氯甲烷洗涤滤渣，合并有机相，减压旋干溶剂后经过柱分离(12g，0～50％乙酸乙酯/石油醚)分离得到浅黄色固体化合物41-2(260mg,31.29％收率)，MS(ESI)212[M+H]+。
步骤3-4：以化合物41-2为原料，参考实施例7步骤2-3的制备方法，得到黄色液体化合物41-4(570mg)，并保存在6mL叔丁醇中，MS(ESI)195[M+H]+。
步骤5：参考实施例1步骤5的制备方法，其区别在于用化合物41-4替换化合物V4，得到浅绿色固体L-41(25.76mg,18.05％收率)，MS(ESI)447[M+H]+。 1H NMR(400MHz,CD 3OD)δ8.50(s,1H),7.93(s,1H),7.71(s,1H),7.64(s,1H),7.41(s,1H),6.33(s,1H),5.67(s,2H),4.25(s,2H),2.77(s,2H),2.66(s,3H),2.23(s,6H).
实施例42：化合物L-42的制备
Figure PCTCN2021081126-appb-000097
步骤1：以1-甲基吡唑-4-甲醛(1g,9.08mmol)为原料，参考实施例11步骤3的制备方法，得到无色液体化合物42-1(610mg,56.91％收率)，MS(ESI)113[M+H]+。
步骤2：以化合物42-1为原料，参考实施例7步骤3的制备方法，得到化合物42-2(447mg)的粗产物，保存在5mL叔丁醇中，MS(ESI)138[M+H]+。
步骤3：参考实施例1步骤5的制备方法，其区别在于用化合物42-2替换化合物V4，得到化合物L-42(52.83mg,31.33％收率)，MS(ESI)419[M+H]+。 1H NMR(400MHz,DMSO-d6)δ8.64(s,1H),7.90(dd,J＝7.8,1.1Hz,1H),7.83(dd,J＝7.7,1.1Hz,1H),7.78(s,1H),7.51(s,2H),7.49(s,1H),7.45(t,J＝7.8Hz,1H),5.50(s,3H),2.61(s,3H).
实施例43：化合物L-43的制备
Figure PCTCN2021081126-appb-000098
步骤1-2：以5-甲氧基-1-甲基-吡唑-3-羧酸(260mg,1.67mmol)为原料，参考实施例7步骤2-3的制备方法，得到化合物43-2(800mg)的粗产物，MS(ESI)168[M+H]+，保存在4mL叔丁醇中。
步骤3：参考实施例1步骤5的制备方法，其区别在于用化合物43-2替换化合物V4，得到化合物L-43(17.4mg,9.21％收率)，MS(ESI)449[M+H]+。 1H NMR(400MHz,DMSO-d6)δ8.65(s,1H),7.92(d,J＝7.7Hz,1H),7.84(d,J＝7.7Hz,1H),7.52(s,2H),7.45(t,J＝7.5Hz,1H),5.69(s,1H),5.49(s,2H),3.79(s,3H),3.48(s,3H),2.62(s,3H).
实施例44：化合物L-44的制备
Figure PCTCN2021081126-appb-000099
步骤1：以1H-吡唑-3-羧酸乙酯(420mg,3.00mmol)和1,1-二氟-2-碘乙烷(862.90mg,4.50mmol))为原料，参考实施例10步骤2的制备方法，得到无色液体化合物44-1(340mg,55.56％收率)，MS(ESI)205[M+H]+。
步骤2-3：以化合物44-1为原料，参考实施例7步骤2-3的制备方法，得到化合物44-3(790mg)的粗产 物，MS(ESI)188[M+H]+，保存在8mL叔丁醇中.
步骤4：参考实施例1步骤5的制备方法，其区别在于用化合物44-3替换化合物V4，得到化合物L-44(33.51mg,19.07％收率)，MS(ESI)440[M+H]+。 1H NMR(400MHz,DMSO-d6)δ8.66(s,1H),7.92(d,J＝7.3Hz,1H),7.83(d,J＝7.3Hz,1H),7.75(s,1H),7.52(s,2H),7.45(t,J＝7.2Hz,1H),6.49–6.08(m,2H),5.65(s,2H),4.58(td,J＝15.3,2.6Hz,2H),2.62(s,3H).
实施例45：化合物L-45的制备
Figure PCTCN2021081126-appb-000100
步骤1：以1H-吡唑-3,5-二羧酸二乙酯(2120mg,9.99mmol)和碘甲烷(2.28g,16.06mmol,1mL)为原料，参考实施例10步骤2的制备方法，得到白色固体化合物45-1(2.36g,95.66％收率)，MS(ESI)227[M+H]+。
步骤2：化合物45-1为原料，参考实施例40步骤3的制备方法，得到白色固体化合物45-2(2g,96.74％收率)，MS(ESI)199[M+H]+。
步骤3：化合物45-2为原料，参考实施例35步骤1的制备方法，得浅黄色液体化合物45-3(2.3g,99.95％收率)，MS(ESI)199[M+H]+。
步骤4：化合物45-3为原料，参考实施例1步骤2的制备方法，得到白色固体化合物45-4(980mg,46.81％收率,)，MS(ESI)198[M+H]+。
步骤5：将化合物45-4(400mg,2.03mmol)溶于二氯甲烷(8mL)中，室温条件下加入三乙胺(362.75mg,3.58mmol,0.5mL)，搅拌15分钟后滴加三氟乙酸酐(1.51g,7.19mmol,1mL)，室温条件下搅拌半小时。反应液用二氯甲烷(20mL*3)萃取，饱和食盐水(20mL)洗涤，无水硫酸钠干燥，减压浓缩干溶剂得到浅黄色液体化合物45-5(360mg,99.05％收率)，MS(ESI)180[M+H]+。
步骤6-7：以化合物45-5为原料，参考实施例7步骤2-3的制备方法，得到化合物45-7(847mg)的粗产物，保存在叔丁醇(8mL)中。MS(ESI)163[M+H]+。
步骤8：参考实施例1步骤5的制备方法，其区别在于用化合物45-7替换化合物V4，得到白色固体L-45(19.5mg,11.75％收率)，MS(ESI)415[M+H]+。 1H NMR(400MHz,DMSO-d6)δ8.73(s,1H),7.91(dd,J＝7.8,1.2Hz,1H),7.84(dd,J＝7.7,1.2Hz,1H),7.54(s,2H),7.46(t,J＝7.8Hz,1H),7.18(s,1H),5.70(s,2H),3.95(s,3H),2.62(s,3H).
实施例46：化合物L-46的制备
Figure PCTCN2021081126-appb-000101
步骤1-2：以1-甲基三唑-4-羧酸甲酯(250mg,1.77mmol)为原料，参考实施例7步骤2-3的制备方法，得到棕色油状液体化合物46-2(816mg)的粗产物，MS(ESI)139[M+H]+，保存在叔丁醇(8mL)中。
步骤3：参考实施例1步骤5的制备方法，其区别在于用化合物46-2替换化合物V4，得到白色固体L-46(10.03mg,6.38％收率)，MS(ESI)391[M+H]+. 1H NMR(400MHz,DMSO-d6)δ8.70(s,1H),8.14(s,1H),7.91(dd,J＝7.8,1.0Hz,1H),7.83(dd,J＝7.6,0.8Hz,1H),7.53(s,2H),7.45(t,J＝7.8Hz,1H),5.76(s,2H),4.00(s,3H),2.62(s,3H).
实施例47：化合物L-47的制备
Figure PCTCN2021081126-appb-000102
步骤1-2：以2甲基三唑-4-羧酸甲酯(250mg,1.77mmol)为原料，参考实施例7步骤2-3的制备方法，得到棕色油状液体化合物47-2(747mg)的粗产物，MS(ESI)139[M+H]+，保存在叔丁醇(8mL)中。
步骤3：参考实施例1步骤5的制备方法，其区别在于用化合物47-2替换化合物V4，得到白色固体L-47(10.0mg,6.38％收率)，MS(ESI)391[M+H]+. 1H NMR(400MHz,DMSO-d6)δ8.72(s,1H),7.91(dd,J＝7.8,1.3Hz,1H),7.82(dd,J＝7.7,1.1Hz,1H),7.79(s,1H),7.52(s,2H),7.44(t,J＝7.8Hz,1H),5.76(s,2H),4.08(s,3H),2.61(s,3H).
实施例48：化合物L-48的制备
Figure PCTCN2021081126-appb-000103
以1-[3-(叠氮甲基)吡唑-1-基]-2-甲基-丙烷-2-醇(70mg,358.57μmol)和中间体V8(95mg,353.55μmol)为原料，参考实施例1步骤5的制备方法，得到化合物L-48(74.9mg,43.60％收率)，MS(ESI)465[M+H]+。1H NMR(400MHz,DMSO-d6)δ8.66(s,1H),7.94(d,J＝6.5Hz,1H),7.83(d,J＝7.3Hz,1H),7.60(s,2H),7.45(t,J＝8.0Hz,1H),6.26(s,1H),5.60(s,2H),4.62(s,1H),3.95(s,2H),2.62(s,3H),0.99(s,6H).
实施例49：化合物L-49的制备
Figure PCTCN2021081126-appb-000104
步骤1-3：以1H-吡唑-3-羧酸乙酯(1.4g,9.99mmol)和2-溴-2-甲基丙酸乙酯(2.92g,14.99mmol)为原料，参考实施例7步骤1-3的制备方法，得到化合物49-3(3.1g),MS(ESI)196[M+H]+,存在叔丁醇(10mL)中.
步骤4：参考实施例1步骤5的制备方法，其区别在于用化合物49-3替换化合物V4，得到白色固体L-49(7.77mg,1.74％收率)，MS(ESI)448[M+H]+. 1H NMR(400MHz,DMSO-d6)δ8.63(s,1H),7.92(dd,J＝7.8,1.2Hz,1H),7.82(d,J＝7.7Hz,1H),7.71(d,J＝2.3Hz,1H),7.50(s,2H),7.44(t,J＝7.8Hz,1H),6.19(d,J＝2.3Hz,1H),5.61(s,2H),4.92(t,J＝5.4Hz,1H),3.51(d,J＝5.2Hz,2H),2.62(s,3H),1.40(s,6H).
实施例50：化合物L-50
Figure PCTCN2021081126-appb-000105
将化合物L-49(50mg,111.74μmol)溶于二氯甲烷(3mL)中，冷却至0℃，将双(2-甲氧基乙基)氨基三氟化硫(24.7mg,111.74μmol)逐滴加入其中。该反应在0℃条件下搅拌，逐渐升至室温，继续搅拌3小时。反应液中加入氢氧化锂水溶液淬灭，二氯甲烷(10mL*3)萃取，饱和食盐水(15mL)洗涤有机相，无水硫酸钠干燥，减压旋干溶剂后用制备液相色谱纯化，得到化合物L-50(1.1mg)，MS(ESI)450[M+H]+. 1H NMR(400MHz,DMSO-d6)δ8.70(s,1H),7.90(dd,J＝7.8,1.1Hz,1H),7.82(dd,J＝7.7,1.2Hz,1H),7.52(s,2H),7.46-7.42(m,2H),6.23(d,J＝1.8Hz,1H),5.78(s,2H),4.46(d,J＝21.1Hz,2H),2.61(s,3H),1.28(d,J＝21.8Hz,6H).
实施例51：化合物L-51的制备
Figure PCTCN2021081126-appb-000106
步骤1：将2-甲酰基-3-氧代丙酸乙酯(720mg,5.00mmol)和盐酸叔丁基肼(625mg,5.00mol)溶于乙醇(20mL)中，然后将三乙胺(757mg,7.5mmol)加入其中。该反应在室温条件下搅拌过夜。减压旋蒸除去乙醇，乙酸乙酯(20mL*3)萃取，饱和食盐水(20mL)洗涤，无水硫酸钠干燥，减压旋干溶剂得粗产品。粗产品过柱分离(12g，0～10％乙酸乙酯/石油醚)得到黄色油状液体化合物51-1(500mg,51.28％收率)，MS(ESI)197[M+H] +.
步骤2-3：以化合物51-1为原料，参考实施例7步骤2-3的制备方法，得到化合物51-3(684mg)，保存在叔丁醇(5mL)中。MS(ESI)189[M+H]+。
步骤4：参考实施例1步骤5的制备方法，其区别在于用化合物51-3替换化合物V4，得到黄色固体L-51(34.5mg,27％收率)，MS(ESI)432[M+H]+。 1H NMR(400MHz,DMSO-d6)δ8.65(s,1H),7.93(s,1H),7.90(d,J＝7.6Hz,1H),7.82(d,J＝7.4Hz,1H),7.52(s,1H),7.50(s,1H),7.44(t,J＝8.0Hz,1H),5.50(s,2H),2.60(s,3H),1.45(s,9H).
实施例52：化合物L-52的制备
Figure PCTCN2021081126-appb-000107
步骤1：将(3-溴苯基)甲醇(190mg,1mmol)、二甲基氧化膦(90mg,1.1mmol)和碳酸铯(650mg,2mmol)加入微波管中，在氮气保护下加入Xantphos(24mg,0.04mmol)和Pd 2dba 3(18mg,0.02mmol)。换气完成后，在微波反应器中加热到150℃，反应时间30分钟。反应完成后，过滤，洗涤固体，将滤液减压旋干，粗品经柱层析柱(EA:PE＝80％)纯化得到化合物52-1(86mg)。MS(ESI)185.1[M+H] +
步骤2：以化合物52-1为原料，参考实施例7步骤3的制备方法，得到化合物52-2。MS(ESI)210.1[M+H] +。
步骤3：以化合物52-2和中间体V8为原料，参考实施例1步骤5的制备方法，得到黄色固体产物L-52。MS(ESI)478.1[M+H] +。 1H NMR(400MHz,DMSO-d6)δ8.95(s,1H),7.99-7.97(m,1H),7.90-7.85(m,2H),7.75-7.71(m,2H),7.54-7.46(m,4H),5.77(s,2H),2.66(s,3H),1.64(d,J＝12Hz,6H)。
实施例53：化合物L-53的制备
Figure PCTCN2021081126-appb-000108
步骤1：以(6-溴吡啶-2-基)甲醇(2g，10.7mmol)为原料，参考实施例21步骤1的制备方法，得到化合物53-1(2.3g黄色固体)。MS(ESI)302.1[M+H] +
步骤2：将化合物53-1(2g,10.7mmol)溶于四氢呋喃(30mL)中，降温至-78℃，在氮气保护下加入正丁基锂(4.7mL,11.8mmol,2.5M)。在此温度下搅拌30分钟，溶有3-氧杂环丁酮(1.08g,15mmol)的四氢呋喃(5mL)溶液慢慢加入。反应液在-78℃搅拌2小时。用饱和氯化铵溶液淬灭，乙酸乙酯萃取，无水硫酸钠干燥，减压旋干溶剂，经过柱纯化，得到化合物53-2(1.1g，黄色固体)。MS(ESI)296.2[M+H] +
步骤3：化合物53-2为原料，参考实施例1步骤4的制备方法，得到化合物53-3。MS(ESI)182.1[M+H] +
步骤4：化合物53-3为原料，参考实施例7步骤3的制备方法，得到化合物53-4。MS(ESI)207.1[M+H] +。
步骤5:参考实施例1步骤5的制备方法，区别在于用化合物53-4替换化合物V4，得到白色固体产物L-53(13mg,8.1％)。MS(ESI)459.1[M+H] +。 1H NMR(400MHz,DMSO-d6)δ8.87(s,1H),7.96(d,J＝8.0Hz,1H)，7.88-7.85(m,2H),7.56-7.48(m,3H),7.24(d,J＝8.0Hz,1H),6.54(s,1H),5.89(s,2H),4.87-4.85(m,2H),4.62-4.60 (m,2H),2.66(s,3H)。
实施例54：化合物L-54的制备
Figure PCTCN2021081126-appb-000109
步骤1：将2,6-吡啶二甲醇(6g,43.2mmol)溶于四氢呋喃(80mL)中，冰浴条件下慢慢加入氢化钠(1.75g，43.8mmol，60％)。搅拌30分钟后，慢慢加入TBSCl(6.61g，43.8mmol)。室温下搅拌20小时。将反应液倒入冰水中，用二氯甲烷萃取(50mL*2),无水硫酸钠干燥，减压浓缩干，经柱层析纯化得到化合物54-1(6.47g,59.2％)，无色油状液体。MS(ESI)254.1[M+H] +。
步骤2：将化合物54-1(6.35g，25.1mmol)和三苯基膦(7.89g，30.1mmol)溶于二氯甲烷(80mL)中，冰浴条件下慢慢加入四溴化碳(10.83g，32.6mmol)。室温搅拌20小时。减压下把溶剂旋干，经柱层析纯化得到黄色固体化合物54-2(4.5g，57.0％)。MS(ESI)316.1[M+H] +。
步骤3：将化合物54-2(3.15g，10mmol)，三甲基氰硅烷(1.51g，15mmol)和TBAF(15mL，15mmol，1M)溶于乙腈中。加热到80℃，在氮气下搅拌20小时。减压将溶剂旋干，经柱层析纯化(EA/PE,0～100％)得到黄色油状化合物54-3(1.4g，94.5％)。MS(ESI)149.1[M+H] +。
步骤4：以化合物54-3为原料，参考实施例21步骤1的制备方法，得到黄色固体化合物54-4(2.01g，82.1％)。MS(ESI)263.1[M+H] +。
步骤5：以化合物54-4为原料，参考实施例23步骤1的制备方法，得到化合物54-5(2.5g，82.1％)。MS(ESI)291.1[M+H] +。
步骤6：以化合物54-5为原料，参考实施例1步骤4的制备方法，得到化合物54-6。MS(ESI)177.1[M+H] +。
步骤7：以化合物54-6为原料，参考实施例7步骤3的制备方法，得到化合物54-7。MS(ESI)202.1[M+H] +。
步骤8：参考实施例1步骤5的制备方法，区别在于用化合物54-7替换化合物V4，得到白色固体产物L-54(15mg,10.3％)。MS(ESI)454.2[M+H] +。 1H NMR(400MHz,DMSO-d6)δ8.84(s,1H),7.98-7.85(m,3H),7.59-7.46(m,4H),7.28(d,J＝8.0Hz,1H),5.87(s,2H),2.67(s,3H),1.65(s,6H).
实施例55：化合物L-55的制备
Figure PCTCN2021081126-appb-000110
步骤1-2：以化合物54-5为原料，参考实施例7步骤2-3的制备方法，得到化合物55-2(190mg，41.7％)。MS(ESI)206.1[M+H] +。
步骤3：化合物55-2(190mg，0.93mmol)和TEA(187mg,1.85mmol)溶于二氯甲烷(10mL)中。冰浴条件下慢慢加入甲基磺酰氯(116mg，1.02mmol)。反应在室温下搅拌4小时。减压将溶剂旋干，经柱层析纯化(EA/PE:0～90％)，得到黄色固体化合物55-3(86mg，32.8％)。MS(ESI)283.1[M+H] +
步骤4:参考实施例1步骤5的制备方法，区别在于用化合物55-3替换化合物V4，得到白色固体产物L-55(26mg,18.6％)。MS(ESI)536.2[M+H] +。 1H NMR(400MHz,DMSO-d6)δ8.83(s,1H),7.98-7.76(m,3H),7.56-7.46(m,3H),7.38(d,J＝8.0Hz,1H),7.15-7.13(m,1H),7.69-7.67(m,1H),5.83(S,2H),3.14(d,J＝8.0Hz,2H),2.70(s,3H),2.67(s,3H),1.23(s,6H)。
实施例56：化合物L-56的制备
Figure PCTCN2021081126-appb-000111
步骤1：6-甲基吡啶-2-腈(5g,42.3mmol)，NBS(7.53g,42.3mmol)和过氧化苯甲酰(512mg,2.1mmol)溶解在四氯化碳(100mL)中，加热回流搅拌20小时。向反应液加水，二氯甲烷萃取(50mL*2)，无水硫酸钠干燥，减压浓缩干，经柱层析纯化(EA/PE,0～40％)得到化合物56-1(3.5g,42.2％)，无色油状液体。MS(ESI)197.1[M+H] +。
步骤2：乙酸钾(5.97g,60.90mmol)和化合物56-1(6g,30.45mmol)加到DMF(50mL)中，冰浴条件下搅拌20小时。加入乙酸乙酯(200mL)，有机相用饱和食盐水洗三次，无水硫酸钠干燥，减压将溶剂旋干，经柱层析纯化(EA/PE:0～90％)，得到黄色固体化合物56-2(4.1g，76.4％)。MS(ESI)177.1[M+H] +
步骤3：将双氧水(0.5mL)和3N氢氧化钠(3mL)溶液混合，化合物56-2(500mg,2.84mmol)和甲醇(15mL)加入。室温搅拌1小时。用1N稀盐酸调节至中性，减压下将溶剂旋干，经柱层析纯化(MeOH/二氯甲烷:0～20％)，得到黄色固体化合物56-3(300mg，69.5％)。MS(ESI)153.1[M+H] +
步骤4：以化合物56-3为原料，参考实施例7步骤3的制备方法，得到化合物56-4。MS(ESI)178.1[M+H] +。
步骤5：参考实施例1步骤5的制备方法，区别在于用化合物56-4替换化合物V4，得到白色固体产物L-56(38mg，29.8％)。MS(ESI)430.2[M+H] +。 1H NMR(400MHz,DMSO-d6)δ8.98(s,1H),8.05-7.85(m,5H),7.73(s,1H),7.57-7.45(s,4H),5.89(s,2H),2.66(s,3H).
实施例57：化合物L-57的制备
Figure PCTCN2021081126-appb-000112
步骤1：以1H-1,2,4-三唑-3-羧酸甲酯(2g,15.74mmol)为原料，参考实施例23步骤1的制备方法，得到无色油状液体化合物57-1。MS(ESI)142.1[M+H] +。
步骤2-3：以化合物57-1为原料，参考实施例7步骤2-3的制备方法，得到白色固体化合物57-3(80mg，13.1％)。MS(ESI)139.1[M+H] +。
步骤4：参考实施例1步骤5的制备方法，区别在于用化合物57-3替换化合物V4，得到浅绿色固体产物L-57(16mg，17.5％)。MS(ESI)391.2[M+H] +。 1H NMR(400MHz,DMSO-d6)δ8.82(s,1H),7.97-7.86(m,3H),7.58-7.45(m,3H),6.00(s,2H),3.96(s,3H),2.66(s,3H).
实施例58：化合物L-58的制备
Figure PCTCN2021081126-appb-000113
步骤1：以[6-[[叔丁基(二甲基)硅烷基]氧甲基]-2-吡啶基]甲醇(4g,15.78mmol)为原料，参考实施例24步骤2的制备方法，得到无色油状液体化合物58-1(2.1g，52.9％)。MS(ESI)252.1[M+H] +
步骤2：将化合物58-1(1g,3.98mmol)和碳酸钾(1.10g,7.96mmol)混合于MeOH(15mL)中，然后将盐酸羟胺(304.06mg,4.38mmol)加入其中。该反应在20℃条件下搅拌20小时。将甲醇旋干，加入饱和食盐水，用EA萃取(50mL*2),，无水硫酸钠干燥，减压旋干溶剂，得到化合物58-2。MS(ESI)267.1[M+H] +
步骤3：将化合物58-2(1g,3.75mmol)和碳酸钾(1.04g,7.51mmol)与DMF(10mL)混合，然后乙酸酐(766.41mg,7.51mmol)加入其中。该反应在50℃条件下搅拌20小时。向反应液中加入饱和食盐水，用二氯甲烷萃取(50mL*2)，无水硫酸钠干燥，减压将溶剂旋干，得到化合物58-3。MS(ESI)135.1[M+H] +
步骤4：以化合物58-3为原料，参考实施例21步骤1的制备方法，得到无色油状液体化合物58-4(0.6g，54％)。MS(ESI)249.1[M+H] +
步骤5：以化合物58-4为原料，参考实施例10步骤3的制备方法，得到无色油状液体化合物58-5(524mg，74.9％)。MS(ESI)281.1[M+H] +
步骤6：以化合物58-5为原料，参考实施例1步骤4的制备方法，得到化合物58-6。MS(ESI)167.1[M+H] +
步骤7：以化合物58-6为原料，参考实施例7步骤3的制备方法，得到化合物58-7(355mg，88.2％)。MS(ESI)192.1[M+H] +
步骤8：参考实施例1步骤5的制备方法，区别在于用化合物58-7替换化合物V4，得到灰色固体产物L-58(8.9mg,5.3％)。MS(ESI)444.1[M+H] +。 1H NMR(400MHz,DMSO-d6)δ8.79(s,1H),7.93(d,J＝8.0Hz,1H),7.84-7.73(m,2H),7.51-7.45(m,4H),7.09(d,J＝8.0Hz,1H),5.77(s,2H),2.63(s,3H),1.29(s,6H).
实施例59：化合物L-59的制备
Figure PCTCN2021081126-appb-000114
参考实施例2步骤6的制备方法，区别在于用3-(叠氮基甲基)-1-甲基-1H-吡唑替换化合物V4，得到白色固体L-59(1.56mg,P:98.83％,产率:2.03％)。 1H NMR(400MHz,DMSO-d6)δ8.56(d,J＝2.1Hz,1H),7.91(d,J＝6.8Hz,1H),7.71(d,J＝7.5Hz,1H),7.63(d,J＝2.1Hz,1H),7.50(t,J＝7.7Hz,1H),6.86(s,2H),6.24(d,J＝2.1Hz,1H),5.61(s,2H),3.77(s,3H),2.39(s,3H)。MS(ESI)390[M+H] +。
实施例60：化合物L-60的制备
Figure PCTCN2021081126-appb-000115
步骤1：以吡啶-2,6-二基二甲醇(1.5g,10.78mmol)为原料，参考实施例23步骤1的制备方法，得到化合物60-1(100mg,产率:6.06％)。MS(ESI)154[M+H]+。
步骤2：以化合物60-1为原料，参考实施例7步骤3的制备方法，得到化合物60-2(117mg,产率:100％)。MS(ESI)179[M+H]+。
步骤3：参考实施例1步骤5的制备方法，区别在于用化合物60-2替换化合物V4，得到白色固体L-60(12.00mg,P:98.93％,产率:14.07％)。1H NMR(400MHz,DMSO-d6)δ8.72(d,J＝1.7Hz,1H),7.92(d,J＝6.7Hz,1H),7.81(t,J＝7.8Hz,1H),7.72(d,J＝7.4Hz,1H),7.51(t,J＝7.7Hz,1H),7.34(d,J＝7.8Hz,1H),7.17(d,J＝7.7Hz,1H),6.87(s,2H),5.79(s,2H),4.42(s,2H),3.30(s,3H),2.40(s,3H).MS(ESI)431[M+H] +。
实施例61：化合物L-61的制备
Figure PCTCN2021081126-appb-000116
参考实施例2的制备方法，得到白色固体L-61(1.33mg,产率:3.33％)。 1H NMR(400MHz,DMSO-d6)δ8.84(s,1H),7.88(dd,J＝7.7,1.1Hz,1H),7.76(t,J＝7.8Hz,1H),7.61(d,J＝6.7Hz,1H),7.57(d,J＝7.4Hz,1H),7.49(t,J＝7.7Hz,1H),7.22–7.01(m,3H),5.78(s,2H),5.17(s,1H),2.30(s,3H),1.33(s,6H).MS(ESI)461[M+H] +。
实施例62：化合物L-62的制备
Figure PCTCN2021081126-appb-000117
参考实施例1步骤5的制备方法，区别在于用2-(叠氮基甲基)-6-(甲氧基甲基)吡啶替换化合物V4，得到白色固体产品L-62(15.45mg,P:98.52％,产率:12.94％)。 1H NMR(400MHz,DMSO-d6)δ8.80(s,1H),7.91(s,1H),7.82(t,J＝7.7Hz,2H),7.55(s,2H),7.45(s,1H),7.35(d,J＝7.7Hz,1H),7.17(d,J＝7.9Hz,1H),5.78(s, 2H),4.43(s,2H),3.30(s,3H),2.62(s,3H).MS(ESI)431[M+H] +。
实施例63：化合物L-63的制备
Figure PCTCN2021081126-appb-000118
参考实施例1步骤5的制备方法，区别在于用2-(6-(叠氮甲基)吡啶-2-基)-2-甲基丙烷-1-醇替换化合物V4，得到白色固体L-63(1.52mg,P:97.42％,产率:1.20％)。 1H NMR(400MHz,DMSO-d6)δ8.78(s,1H),7.93(d,J＝7.8Hz,1H),7.83(dd,J＝7.8,1.3Hz,1H),7.71(t,J＝7.8Hz,1H),7.53(s,2H),7.45(t,J＝7.8Hz,1H),7.33(d,J＝7.7Hz,1H),7.07(d,J＝7.4Hz,1H),5.77(s,2H),4.54(t,J＝5.6Hz,1H),3.45(d,J＝5.6Hz,2H),2.64(s,3H),1.18(d,J＝17.3Hz,6H).MS(ESI)459[M+H] +。
实施例64：化合物L-64的制备
Figure PCTCN2021081126-appb-000119
步骤1-2：(6-溴吡啶-2-基)甲醇(3.0g,15.96mmol)为原料，参考实施例21步骤1-2的制备方法，得到化合物64-2(2.0g,产率:100％)MS(ESI)294[M+H]+
步骤3：以化合物64-2为原料，参考实施例1步骤4的制备方法，得到化合物64-3(50mgP:95％,产率:100％)。MS(ESI)180[M+H]+。
步骤4：以化合物64-3为原料，参考实施例7步骤3的制备方法，得到化合物64-4(380mg,P:100％,产率:27％)。MS(ESI)205[M+H]+。
步骤5：参考实施例1步骤5的制备方法，区别在于用化合物64-4替换化合物V4，得到白色固体L-64(7.41mg,P:99.39％,产率:9.0％)。 1H NMR(400MHz,DMSO-d6)δ8.81(s,1H),7.92(dd,J＝7.8,1.2Hz,1H),7.83(dd,J＝7.8,1.2Hz,1H),7.76(t,J＝7.8Hz,1H),7.53(s,2H),7.50–7.37(m,2H),7.17(d,J＝7.2Hz,1H),5.82(s,2H),5.71(s,1H),2.62(s,3H),2.39(ddd,J＝12.0,8.9,4.9Hz,2H),2.20–2.03(m,2H),1.84–1.56(m,2H).MS(ESI)457[M+H] +。
实施例65：化合物L-65的制备
Figure PCTCN2021081126-appb-000120
步骤1：以2-(叠氮甲基)-6-氟吡啶(100mg,0.657mmol)和吡咯烷-3-醇(286mg,3.29mmol)为原料，参考实施例10步骤2的制备方法，得到无色油状物化合物65-1(80mg,P:76.09％,产率:55％)。MS(ESI)193[M+H]+。
步骤2：参考实施例1步骤5的制备方法，区别在于用化合物65-1替换化合物V4，得到白色固体L-65(15.98mg,P:98.49％,产率:9％)MS(ESI)472.2[M+H]+。
实施例66：化合物L-66的制备
Figure PCTCN2021081126-appb-000121
步骤1-2：以化合物2-溴-6-((((叔丁基二甲基甲硅烷基)氧基)甲基)吡啶(700mg,2.32mmol)和环戊酮(234mg,2.78mmol)为原料，参考实施例21步骤2-3的制备方法，得到无色油状物化合物66-2(250mg，P:90％,产率:100％)。MS(ESI)194[M+H]+。
步骤3：以化合物66-2为原料，参考实施例7步骤3的制备方法，得到化合物66-3(220mg,P:94.69％,产率:93％)MS(ESI)219[M+H]+。
步骤4：参考实施例1步骤5的制备方法，区别在于用化合物66-3替换化合物V4，得到白色固体L-66(48.72mg,P:98.69％,产率:26％) 1H NMR(400MHz,DMSO-d6)δ8.77(s,1H),7.92(d,J＝7.5Hz,1H),7.83(d,J＝7.6Hz,1H),7.75(t,J＝7.8Hz,1H),7.59(d,J＝7.9Hz,1H),7.53(s,2H),7.45(t,J＝8.0Hz,1H),7.11(d,J＝7.6Hz,1H),5.77(s,2H),5.03(s,1H),2.63(s,3H),2.01-1.94(m,2H),1.78-1.73(m,2H),1.71–1.51(m,4H).MS(ESI)471.2[M+H] +。
实施例67：化合物L-67的制备
Figure PCTCN2021081126-appb-000122
步骤1：以(1-甲基-1H-吡唑-3-基)甲醇(1.0g,8.92mmol)为原料，参考实施例7步骤3的制备方法，得到化合物67-1(1.0g,P:100％,产率:82％)。MS(ESI)138[M+H]+.
步骤2：参考实施例1步骤5的制备方法，区别在于用化合物67-1替换化合物V4，得到白色固体L-67(41.21mg,P:99.12％,产率:26％)。 1H NMR(400MHz,DMSO-d6)δ8.64(s,1H),7.91(d,J＝7.1Hz,1H),7.83(d,J＝7.3Hz,1H),7.63(s,1H),7.52(s,2H),7.45(t,J＝7.6Hz,1H),6.25(s,1H),5.59(s,2H),3.77(s,3H),2.61(s,3H).MS(ESI)390.2[M+H] +。
实施例68：化合物L-68的制备
Figure PCTCN2021081126-appb-000123
步骤1：6-异丙基吡啶甲酸(1.0g,6.05mmol)溶解在甲醇20mL中，氩气保护下降温至冰浴条件下，滴加SOCl 2(2mL),然后升温至90℃条件下搅拌过夜。反应液直接减压浓缩干，然后加入饱和碳酸氢钠溶液，乙酸乙酯(50mL*2)萃取，无水硫酸钠干燥，减压浓缩干得到无色油状物化合物68-1(1.0g,P:91.52％，产率:93％)MS(ESI)180[M+H]+.
步骤2-3：以化合物68-1为原料，参考实施例7步骤2-3的制备方法，得到化合物68-3(500mg,P:100％,产率:61％)。MS(ESI)176[M+H]+。
步骤4：参考实施例1步骤5的制备方法，区别在于用化合物68-3替换化合物V4，得到黄色固体化合物L-68(50.72mg,P:95.48,产率:30％) 1H NMR(400MHz,DMSO-d6)δ8.79(s,1H),7.93(d,J＝7.3Hz,1H),7.83(d,J＝7.5Hz,1H),7.70(t,J＝7.7Hz,1H),7.53(s,2H),7.45(t,J＝7.6Hz,1H),7.22(d,J＝7.8Hz,1H),7.04(d,J＝7.8Hz,1H),5.76(s,2H),2.95(dt,J＝13.7,6.8Hz,1H),2.63(s,3H),1.16(d,J＝6.9Hz,6H).MS(ESI)429.2[M+H] +。
实施例69：化合物L-69的制备
Figure PCTCN2021081126-appb-000124
步骤1：化合物2-(叠氮甲基)-6-氯吡啶(300mg,1.78mmol)和吗啡啉(2mL)，微波升温至130℃条件下反应5小时。将上述反应液加入到水里面，用乙酸乙酯萃取(50mL*2)，无水硫酸钠干燥，减压浓缩干得到无色油状物化合物69-1(380mg,P:79.95％,产率:97％)MS(ESI)220[M+H]+。
步骤2：参考实施例1步骤5的制备方法，区别在于用化合物69-1替换化合物V4，得到白色固体L-69(18.27mg,P:100％,产率:9％)。 1H NMR(400MHz,DMSO-d6)δ8.75(s,1H),7.94(dd,J＝7.8,1.2Hz,1H),7.84(dd,J＝7.7,1.3Hz,1H),7.62–7.50(m,3H),7.46(t,J＝7.7Hz,1H),6.75(d,J＝8.6Hz,1H),6.55(d,J＝7.3Hz,1H),5.61(s,2H),3.72–3.54(m,4H),3.45–3.32(m,4H),2.64(s,3H).MS(ESI)472[M+H] +。
实施例70：化合物L-70的制备
Figure PCTCN2021081126-appb-000125
步骤1：以2-溴-6-((((叔丁基二甲基甲硅烷基)氧基)甲基)吡啶(1.0g,3.31mmol)为原料，参考实施例21步骤2的制备方法，得到化合物70-1(650mg,P:77.94％,产率:78％)MS(ESI)252[M+H]+。
步骤2：化合物70-1(300mg,1.19mmol)和吗啡啉(312mg,3.58mmol)加入到15mL的二氯甲烷中，室温搅拌加入醋酸硼氢化钠(759mg,3.58mmol),反应液室温搅拌过夜。反应液倒入水中，用二氯甲烷萃取(50mL*2)，无水硫酸钠干燥，减压浓缩干，经过硅胶柱分离纯化得到化合物70-2(350mg,P:70.73％,产率:91％)MS(ESI)323.2[M+H]+。
步骤3：化合物70-2(350mg,1.09mmol)溶解在乙醇5mL中，室温搅拌加入4.0M的盐酸二氧六环溶液5mL，然后继续室温搅拌2小时。减压浓缩干得到化合物70-3(266mg,P:90％,产率:100％)MS(ESI)209[M+H]+。
步骤4：以化合物70-3为原料，参考实施例7步骤3的制备方法，得到无色油状物化合物70-4(350mg,P:93.52％,产率:89％)MS(ESI)234[M+H]+。
步骤5：参考实施例1步骤5的制备方法，区别在于用化合物70-4替换化合物V4，得到白色固体L-70(18.69mg,P:98.04％,产率:10％) 1H NMR(400MHz,DMSO-d6)δ8.79(s,1H),7.92(d,J＝7.9Hz,1H),7.87–7.71(m,2H), 7.54(s,2H),7.45(t,J＝7.9Hz,1H),7.38(d,J＝7.7Hz,1H),7.14(d,J＝7.6Hz,1H),5.79(s,2H),3.54(s,6H),2.62(s,3H),2.35(s,4H).MS(ESI)486[M+H] +。
实施例71：化合物L-71的制备
Figure PCTCN2021081126-appb-000126
步骤1-2：以化合物70-1(300mg,1.19mmol)和1-甲基哌嗪(359mg,3.58mmol)为原料，参考实施例70步骤2-3的制备方法，得到化合物71-2(350mg,P:90％,产率:100％)。MS(ESI)222[M+H]+。
步骤3：以化合物71-2为原料，参考实施例7步骤3的制备方法，得到无色油状物71-3(350mg,P:94.24％,产率:90％)。MS(ESI)247[M+H]+。
步骤5：参考实施例1步骤5的制备方法，区别在于用化合物71-3替换化合物V4，得到白色固体L-71(21.37mg,P:95.93％,产率:11％)。 1H NMR(400MHz,DMSO-d6)δ8.76(s,1H),7.92(dd,J＝7.9,1.2Hz,1H),7.83(dd,J＝7.7,1.2Hz,1H),7.76(t,J＝7.7Hz,1H),7.53(s,2H),7.45(t,J＝7.7Hz,1H),7.34(d,J＝7.7Hz,1H),7.12(d,J＝7.7Hz,1H),5.76(s,2H),3.50(s,2H),2.63(s,3H),2.42–2.12(m,8H),2.07(s,3H).MS(ESI)499[M+H] +。
实施例72：化合物L-72的制备
Figure PCTCN2021081126-appb-000127
步骤1：以2-(叠氮甲基)-6-氯吡啶(300mg,1.78mmol)和1-甲基哌嗪(2mL)为原料，参考实施例69步骤1的制备方法，得到无色油状物化合物72-1(390mg,P:94.65％,产率:94％)。MS(ESI)233[M+H]+。
步骤2：参考实施例1步骤5的制备方法，区别在于用化合物72-1替换化合物V4，得到白色固体L-72(18.69mg,P:100％,产率:9％)。 1H NMR(400MHz,DMSO-d6)δ8.74(s,1H),7.98–7.89(m,1H),7.83(dd,J＝7.7,1.2Hz,1H),7.48(ddd,J＝17.3,13.5,5.8Hz,4H),6.73(d,J＝8.6Hz,1H),6.50(d,J＝7.2Hz,1H),5.59(s,2H),3.47–3.36(m,4H),2.63(s,3H),2.33–2.21(m,4H),2.13(s,3H).MS(ESI)485[M+H] +。
实施例73：化合物L-73的制备
Figure PCTCN2021081126-appb-000128
步骤1：6-(二氟甲基)吡啶甲酸(250mg,1.44mmol)溶解在甲醇15mL中，氩气保护下降温至冰浴条件下，滴加氯化亚砜(1mL),然后升温至室温搅拌过夜。反应液直接减压浓缩干，然后加入饱和碳酸氢钠溶液，乙酸乙酯(50mL*2)萃取，无水硫酸钠干燥，减压浓缩干得到化合物73-1(270mg,P:100％，产率:100％)MS(ESI)188[M+H]+。
步骤2-3：以化合物73-1为原料，参考实施例7步骤2-3的制备方法，得到化合物73-3(180mg,P:89.3％,产率:74％)MS(ESI)185[M+H]+。
步骤4：参考实施例1步骤5的制备方法，区别在于用化合物73-3替换化合物V4，得到白色固体L-73(30.24mg,P:99.26％，产率:19％) 1H NMR(400MHz,DMSO-d6)δ8.83(s,1H),8.20–7.72(m,3H),7.73–7.17(m,5H),6.89(t,J＝55.2Hz,1H),5.87(s,2H),2.62(s,3H).MS(ESI)437[M+H] +。
实施例74：化合物L-74的制备
Figure PCTCN2021081126-appb-000129
步骤1：以1H-吡唑-3-羧酸乙酯(2.5g,17.98mmol)和2-碘丙烷(3.1g,17.98mmol)为原料，参考实施例10步骤2的制备方法，得到化合物74-1(1.35g,P:100％,产率:41％)MS(ESI)183[M+H]+。
步骤2-3：以化合物74-1为原料，参考实施例7步骤2-3的制备方法，得到化合物74-3(200mg,P:90％,产率:59％)。MS(ESI)166[M+H]+。
步骤4：参考实施例1步骤5的制备方法，区别在于用化合物74-3替换化合物V4，得到黄色固体L-74(50.72mg,P:100％,产率:8％)。1H NMR(400MHz,DMSO-d6)δ8.71(s,1H),8.05–7.68(m,2H),7.67–7.09(m,4H),6.28(s,1H),5.84(s,2H),4.78(dt,J＝13.1,6.5Hz,1H),2.62(s,3H),1.27(d,J＝6.5Hz,6H).MS(ESI)418[M+H] +。
实施例75：化合物L-75的制备
Figure PCTCN2021081126-appb-000130
步骤1：以1H-吡唑-3-羧酸乙酯(2.5g,17.98mmol)和2-碘丙烷(3.1g,17.98mmol)为原料，参考实施例10步骤2的制备方法，得到化合物75-1(1.2g,P:100％,产率:37％)。MS(ESI)183[M+H]+。
步骤2-3：以化合物75-1为原料，参考实施例7步骤2-3的制备方法，得到化合物75-3(600mg,P:70％,产率:51％)MS(ESI)166[M+H]+。
步骤4：参考实施例1步骤5的制备方法，区别在于用化合物75-3替换化合物V4，得到黄色固体L-75(30.34mg,P:97.82％,产率:18％)。 1H NMR(400MHz,DMSO-d6)δ8.67(s,1H),7.86(d,J＝36.6Hz,2H),7.72(d,J＝2.1Hz,1H),7.64–7.29(m,3H),6.24(s,1H),5.62(s,2H),4.45(dt,J＝13.3,6.6Hz,1H),2.75–2.51(m,3H),1.36(d,J＝6.7Hz,6H).MS(ESI)418[M+H] +。
实施例76：化合物L-76的制备
Figure PCTCN2021081126-appb-000131
步骤1：以1H-吡唑-3-羧酸乙酯(1.3g,9.28mmol)和1-氯-2-甲基丙-2-醇(1.3g,12.06mmol)为原料，参考实施例10步骤2的制备方法，得到化合物76-1(1.4g,P:100％,产率:71％)MS(ESI)213[M+H]+。
步骤2-3：以化合物76-1为原料，参考实施例7步骤2-3的制备方法，得到化合物76-3(250mg,P:73.52％,产率:31％)MS(ESI)196[M+H]+。
步骤4：参考实施例1步骤5的制备方法，区别在于用化合物76-3替换化合物V4，得到白色色固体L-76(9.58mg,P:98.67％,产率:5％)。 1H NMR(400MHz,DMSO-d6)δ8.59(s,1H),7.92(d,J＝7.7Hz,1H),7.83(d,J＝7.5Hz,1H),7.61(d,J＝1.6Hz,1H),7.50(s,2H),7.45(t,J＝7.6Hz,1H),6.26(s,1H),5.61(s,2H),4.63(s,1H),3.96(s,2H),2.62(s,3H),1.00(s,6H)。MS(ESI)448[M+H] +。
实施例77：化合物L-77的制备
Figure PCTCN2021081126-appb-000132
步骤1：以化合物1H-吡唑-3-羧酸乙酯(0.71g,5.07mmol)和3-碘四氢呋喃(1.0g,5.07mmol)为原料，参考实施例10步骤2的制备方法，得到化合物77-1(0.41g,P:87.79％,产率:38％)。MS(ESI)211[M+H]+。
步骤2-3：以化合物77-1为原料，参考实施例7步骤2-3的制备方法，得到化合物77-3(300mg,P:100％,产率:81％)。MS(ESI)166[M+H]+。
步骤4：参考实施例1步骤5的制备方法，区别在于用化合物77-3替换化合物V4，得到白色色固体L-77(46.16mg,P:100％,产率:26％)。 1H NMR(400MHz,DMSO-d6)δ8.66(s,1H),7.92(d,J＝7.1Hz,1H),7.83(d,J＝7.0Hz,1H),7.74(s,1H),7.52(s,2H),7.45(t,J＝7.1Hz,1H),6.27(s,1H),5.62(s,2H),4.97(s,1H),4.01–3.87(m,2H),3.87–3.66(m,2H),2.62(s,2H),2.41–2.26(m,1H),2.26–2.08(m,1H)。MS(ESI)446[M+H] +。
实施例78：化合物L-78的制备
Figure PCTCN2021081126-appb-000133
步骤1：以1H-吡唑-3-羧酸乙酯(1.5g,11.89mmol)和1-溴-2-甲氧基乙烷(1.98g,14.27mmol)为原料，参考实施例23步骤1的制备方法，得到无色油状物78-1(0.8g,32.43％收率,88.82％纯度)。
步骤2-3：以化合物78-1为原料，参考实施例7步骤2-3的制备方法，得到无色油状物78-3(600mg,81.89％收率,95％纯度)。
步骤4：参考实施例1步骤5的制备方法，区别在于用化合物78-3替换化合物V4，得到绿色固体L-78(72.59mg,52.29％收率,99.02％纯度)。 1H NMR(400MHz,DMSO-d6)δ8.64(s,1H),7.87(dd,J＝33.8,8.0Hz,2H),7.66(s,1H),7.47(dd,J＝23.1,15.7Hz,3H),6.24(s,1H),5.61(s,2H),4.20(s,2H),3.62(s,2H),3.16(s,3H),2.62(s,3H)。MS(ESI)434[M+H] +。
实施例79：化合物L-79的制备
Figure PCTCN2021081126-appb-000134
步骤1-2：以1,5-二甲基-1H-吡唑-3-羧酸甲酯(1.0g,6.49mmol)为原料，参考实施例7步骤2-3的制备方法，得到黄色固体79-2(700mg,83.45％收率)。MS(ESI)152[M+H]+。
步骤3：参考实施例1步骤5的制备方法，区别在于用化合物79-2替换化合物V4，得到白色固体L-79(26.66mg,16.08％收率,96.47％纯度)。 1H NMR(400MHz,DMSO-d6)δ8.62(s,1H),7.91(d,J＝7.9Hz,1H),7.83(d,J＝7.6Hz,1H),7.52(s,2H),7.45(t,J＝7.8Hz,1H),6.03(s,1H),5.52(s,2H),3.64(s,3H),2.62(s,3H),2.17(s,3H)。MS(ESI)404[M+H] +。
实施例80：化合物L-80的制备
Figure PCTCN2021081126-appb-000135
步骤1：以1H-吡唑-3-羧酸乙酯(1g,7.14mmol)为原料，参考实施例21步骤2的制备方法，得到化合物80-1(0.55g,29.57％收率,60.67％纯度)。MS(ESI)159[M+H]+。
步骤2：以化合物80-1(550mg,3.48mmol)和碘甲烷(987.37mg,6.96mmol)为原料，参考实施例23步骤1的制备方法，得到化合物80-2(400mg,47.61％收率,71.27％纯度)。MS(ESI)173[M+H]+。
步骤3-4：以化合物80-2为原料，参考实施例7步骤2-3的制备方法，得到化合物80-4(100mg,36.22％收率,95％纯度)。MS(ESI)156[M+H]+。
步骤5：参考实施例1步骤5的制备方法，区别在于用化合物80-4替换化合物V4，得到白色化合物L-80(34.57mg,38.42％收率,98.73％纯度) 1H NMR(400MHz,DMSO-d6)δ8.63(s,1H),7.87(d,J＝29.0Hz,3H),7.48(d,J＝28.2Hz,3H),5.64(s,2H),3.72(s,3H),2.61(s,3H)。MS(ESI)408[M+H] +。
实施例81：化合物L-81的制备
Figure PCTCN2021081126-appb-000136
步骤1：以2-溴-6-((((叔丁基二甲基甲硅烷基)氧基)甲基)吡啶(500mg,1.65mmol)和1,1,1-三氟丙酮(278.01mg,2.48mmol)为原料，参考实施例53步骤2的制备方法，得到无色油状物化合物81-1(160mg,27.32％收率,94.73％纯度)。MS(ESI)336[M+H] +。
步骤2：化合物81-1为原料，参考实施例70步骤3的制备方法，得到黄色油状物化合物81-2(100mg,90.18％收率,95.14％纯度)。MS(ESI)222[M+H] +。
步骤3：以化合物81-2为原料，参考实施例7步骤3的制备方法，得到无色油状化合物81-3(80mg,54.03％收率,97.72％纯度)。MS(ESI)247[M+H] +。
步骤4：参考实施例1步骤5的制备方法，区别在于用化合物81-3替换化合物V4，得到白色固体L-81(42.86mg,83.86％收率,98.40％纯度)。 1H NMR(400MHz,DMSO-d6)δ8.79(s,1H),8.03–7.78(m,3H),7.71(d,J＝7.5Hz,1H),7.53(s,2H),7.45(t,J＝7.9Hz,1H),7.32(d,J＝7.4Hz,1H),6.71(s,1H),5.84(s,2H),2.63(s,3H),1.60(s,3H)。MS(ESI)499[M+H] +。
实施例82：化合物L-82的制备
Figure PCTCN2021081126-appb-000137
步骤1：以5-氯-1H-吡唑-3-羧酸(250mg,1.71mmol)为原料，参考实施例73步骤1的制备方法，得到白色固体82-1(273mg,99.66％收率,100％纯度)。MS(ESI)161[M+H] +。
步骤2：以化合物82-1位原料，参考实施例23步骤1的制备方法，得到无色油状化合物82-2(297mg,81.49％收率,81.75％纯度)。MS(ESI)175[M+H] +。
步骤3-4：以化合物82-2为原料，参考实施例7步骤2-3的制备方法，得到无色油状化合物82-4(130mg,55.52％收率)。MS(ESI)172[M+H] +。
步骤5：参考实施例1步骤5的制备方法，区别在于用化合物72-4替换化合物V4，得到白色固体L-82(48.13mg,27.44％收率,95.79％纯度) 1H NMR(400MHz,DMSO-d6)δ8.70(s,1H),7.87(d,J＝35.4Hz,2H),7.49(d,J＝25.7Hz,3H),6.46(s,1H),5.60(s,2H),3.74(s,3H),2.63(s,3H).MS(ESI)424[M+H] +。
实施例83：化合物L-83的制备
Figure PCTCN2021081126-appb-000138
步骤1：以1H-吡唑-3-羧酸乙酯(552mg,4.38mmol)和2-(碘甲基)四氢呋喃(1.06g,8.75mmol)为原料，参考实施例10步骤2的制备方法，得到化合物83-1(550mg,56.79％收率,95.02％纯度)。MS(ESI)225[M+H] +.
步骤2-3：以化合物83-1为原料，参考实施例7步骤2-3的制备方法，得到化合物83-3(250mg,62.81％收率,100％纯度)。MS(ESI)208[M+H] +。
步骤4：参考实施例1步骤5的制备方法，区别在于用化合物83-3替换化合物V4，得到白色固体L-83(14.23mg,12.93％收率,99.29％纯度)。 1H NMR(400MHz,DMSO-d6)δ8.62(s,1H),7.92(d,J＝7.5Hz,1H),7.83(d,J＝7.3Hz,1H),7.64(d,J＝2.2Hz,1H),7.52(s,2H),7.45(t,J＝7.8Hz,1H),6.25(d,J＝2.2Hz,1H),5.61(s,2H),4.19–3.96(m,3H),3.67(dd,J＝13.9,7.5Hz,1H),3.56(dd,J＝14.2,7.6Hz,1H),1.94–1.79(m,1H),1.77–1.59(m,2H),1.59–1.46(m,1H).MS(ESI)460[M+H] +。
实施例84：化合物L-84的制备
Figure PCTCN2021081126-appb-000139
步骤1-2：以3-(甲基磺酰基)苯甲酸(300mg，1.50mmol)为原料，参考实施例7步骤2-3的制备方法，得到化合物84-3粗品(256mg)。
步骤3：参考实施例1步骤5的制备方法，区别在于用化合物84-3替换化合物V4，得到类白色固体L-84(1.74mgmg,P:99.33％,产率:2.0％)MS(ESI)480.0[M+H]+。 1H NMR(400MHz,DMSO-d6)δ8.98(s,1H),7.98(d,J＝7.5Hz,2H),7.92(d,J＝7.1Hz,1H),7.87(d,J＝6.4Hz,1H),7.69(d,J＝7.4Hz,2H),7.49(s,1H),5.84(s,2H),3.22(s,2H),2.67(s,3H),1.24(s,3H).
实施例85：化合物L-85的制备
Figure PCTCN2021081126-appb-000140
步骤1：1-(6-(羟甲基)吡啶-2-基)乙烷-1-酮(500mg，3.31mmol)溶解在无水四氢呋喃(10mL)中，冰浴下加入乙基溴化镁(3.3ml，6.60mmol)，反应液在室温下搅拌3小时。0℃下向反应液中滴加饱和氯化铵(2mL)淬灭反应，室温搅拌10分钟后有固体析出，过滤。滤液减压浓缩干后通过柱层析(乙酸乙酯：石油醚＝50～80％)纯化得到无色油状物化合物85-1(212mg，P:70.42％，产率:35.4％)。MS(ESI)182.1[M+H]+。
步骤2：以化合物85-1为原料，参考实施例7步骤3的制备方法，得到化合物85-2粗品(264mg)。
步骤3：参考实施例1步骤5的制备方法，区别在于用化合物85-2替换化合物V4，得到白色固体L-85(10.35mg,P:96.97％,产率:5.7％)MS(ESI)459.1[M+H]+。 1H NMR(400MHz,DMSO-d6)δ8.79(s,1H),7.95(d,J＝1.2Hz,1H),7.90–7.83(m,1H),7.79(t,J＝7.8Hz,1H),7.64–7.53(m,3H),7.48(s,1H),7.14(d,J＝7.0Hz,1H),5.81(s,2H),5.04(s,1H),2.66(s,3H),1.70(dd,J＝31.4,7.4Hz,2H),1.35(s,3H),0.59(s,3H).
实施例86：化合物L-86的制备
Figure PCTCN2021081126-appb-000141
步骤1：以1-(6-(羟甲基)吡啶-2-基)乙烷-1-酮(500mg，3.31mmol)为原料，参考实施例21步骤1的制备方法，得到无色油状物化合物86-1(680mg，P:91.74％，产率:77.7％)。MS(ESI)266.1[M+H]+。
步骤2：以化合物86-1为原料，参考实施例11步骤3的制备方法，得到无色油状物化合物86-2(567mg，P:89.12％，产率:82.8％)。MS(ESI)268.1[M+H]+。
步骤3：以化合物86-2(567mg，2.12mmol)和碘甲烷(602mg，4.24mmol)，参考实施例23步骤1的制备方法，得到化合物86-3(518mg)。MS(ESI)282.1[M+H]+。
步骤4：以化合物86-3为原料，参考实施例1步骤4的制备方法，得到无色油状物86-4(288mg，P：98.79％，产率：95.2％)。MS(ESI)168.1[M+H]+。
步骤5：以化合物86-4为原料，参考实施例7步骤3的制备方法，得到化合物86-5(302mg)。
步骤6：参考实施例1步骤5的制备方法，区别在于用化合物86-5替换化合物V4，得到白色固体L-86(7.31mg,P:100％,产率:4.1％)MS(ESI)445.2[M+H]+。 1H NMR(400MHz,DMSO-d6)δ8.79(s,1H),7.92(s,1H),7.82(dd,J＝12.8,5.0Hz,2H),7.53(s,2H),7.45(s,1H),7.34(d,J＝7.6Hz,1H),7.13(d,J＝7.6Hz,1H),5.79(s,2H),4.31(d,J＝6.5Hz,1H),3.16(s,3H),2.63(s,3H),1.29(d,J＝6.5Hz,3H).
实施例87：化合物L-87的制备
Figure PCTCN2021081126-appb-000142
步骤1：参考实施例1步骤1的制备方法，区别在于用2,4,5,6-四氯嘧啶替换2,4,6-三氯-5-氟嘧啶，得到淡黄色液体87-1(2.78g,P:81.12％,产率:67.53％)MS(ESI)363.0[M+H]+。
步骤2：将化合物87-1(2.70g,7.43mmol)和甲氧基胺盐酸盐(1.24g,14.85mmol)加入无水四氢呋喃(25mL)，室温下加入三乙胺(2.25g,22.27mmol)，反应液在室温下搅拌过夜，反应液减压蒸干，用EA(30mL)萃取，有机相用无水硫酸钠干燥，减压蒸干得到化合物87-2(1.66g)。MS(ESI)374.1[M+H]+。
步骤3-5：参考实施例1步骤3-5的制备方法，区别在于用化合物87-2替换化合物1-3，用3-(叠氮甲基)-1-甲基-1H-吡唑替换中间体V4，得到淡黄色固体产品L-87(27.56mg,P：99.91％，产率：22.12％)MS(ESI)436.1[M+H]+。 1H NMR(400MHz,DMSO-d6)δ10.99(s,1H),8.79(s,1H),8.07(s,1H),7.91(d,J＝7.7Hz,1H),7.66(d,J＝2.0Hz,1H),7.53(t,J＝7.8Hz,1H),6.28(d,J＝2.1Hz,1H),5.63(s,2H),3.79(d,J＝5.6Hz,6H),2.71(s,3H).
实施例88：化合物L-88的制备
Figure PCTCN2021081126-appb-000143
步骤1：以1H-吡唑-3-羧酸乙酯(400mg,2.85mmol)和3-碘氧杂环丁烷(630mg,3.43mmol)为原料，参考实施例10步骤2的制备方法，化合物88-2。MS(ESI)197.1[M+H]+.
步骤2-3：以化合物88-2为原料，参考实施例7步骤2-3的制备方法，得到化合物88-3(146mg)，MS(ESI)180.1[M+H]+.
步骤4：参考实施例1步骤5的制备方法，区别在于化合物88-3替换化合物V4，得到灰白色固体化合物L-88(10.86mg,P：96.43％，产率：12.25％)MS(ESI)432.1[M+H]+. 1H NMR(400MHz,DMSO-d6)δ8.73(s,1H),7.91(d,J＝23.9Hz,3H),7.52(d,J＝28.4Hz,3H),6.35(s,1H),5.71(s,2H),5.56(s,1H),5.04–4.70(m,4H),2.65(s,3H).
实施例89：实施例L-89的制备
Figure PCTCN2021081126-appb-000144
步骤1-2：以四氢吡喃-4-醇(1g,9.79mmol)为原料，参考中间体V5步骤1的制备方法，得到化合物89-2(197mg,P：84.8％,两步反应收率共计20.88％)。MS(ESI)225.1[M+H]+。
步骤3-4：以化合物89-2为原料，参考实施例7步骤2-3的制备方法，得到化合物89-4(162mg)。MS(ESI)208.1[M+H]+.
步骤5：参考实施例1步骤5的制备方法，区别在于化合物89-4替换化合物V4，得到灰白色固体L-89(11.10mg,P：98.27％，产率：11.26％)MS(ESI)460.1[M+H]+. 1H NMR(400MHz,DMSO-d6)δ8.68(s,1H),7.95(d,J＝7.8Hz,1H),7.90–7.83(m,1H),7.79(d,J＝2.3Hz,1H),7.55(s,2H),7.48(t,J＝7.7Hz,1H),6.29(d,J＝2.3Hz,1H),5.65(s,2H),4.45–4.32(m,1H),4.01–3.86(m,2H),3.43(td,J＝11.4,3.3Hz,2H),2.65(s,3H),2.05–1.79(m,4H).
实施例90：化合物L-90的制备
Figure PCTCN2021081126-appb-000145
步骤1-2：以1-甲基吡咯烷-3-醇(1g,9.89mmol)为原料，参考中间体V5步骤1的制备方法，得到化合物90-2(542mg,P：93.82％,产率：53.96％)MS(ESI)224.1[M+H]+。
步骤3-4：以化合物90-2为原料，参考实施例7步骤2-3的制备方法，得到化合物90-4(261mg)。MS(ESI)207.1[M+H]+.
步骤5：参考实施例1步骤5的制备方法，区别在于化合物90-4替换化合物V4，得到白色固体L-90(2.09mg，P：99.64％，产率：三步反应收率共计1.54％)。MS(ESI)459.2[M+H]+。 1H NMR(400MHz,DMSO-d6)δ8.67(s,1H),7.95(d,J＝7.7Hz,1H),7.86(dd,J＝7.8,1.2Hz,1H),7.76(d,J＝2.3Hz,1H),7.55(s,2H),7.49(d,J＝7.8Hz,1H),6.27(d,J＝2.3Hz,1H),5.64(s,2H),4.85(s,1H),2.75(dd,J＝16.5,6.6Hz,3H),2.65(s,3H),2.45(d,J＝6.4Hz,1H),2.32(d,J＝9.4Hz,1H),2.26(s,3H),2.03(d,J＝6.2Hz,1H).
实施例91：化合物L-91的制备
Figure PCTCN2021081126-appb-000146
步骤1：以化合物1-2为原料，参考实施例87步骤2的制备方法，得到化合物91-1，MS(ESI)342.1[M+H]+步骤2-4：参考实施例1步骤3-5的制备方法，区别在于用化合物91-1替换化合物1-3，用3-(叠氮甲基)-1-甲基-1H-吡唑替换中间体V4，得到类白色固体产品L-91(48.07mg,P：99.22％，产率：36.71％)MS(ESI)404.1[M+H]+. 1H NMR(400MHz,DMSO-d6)δ8.68(s,1H),8.05(d,J＝7.0Hz,1H),7.99–7.81(m,2H),7.66(s,1H), 7.50(s,1H),6.28(s,1H),5.63(s,2H),3.80(s,3H),2.95(d,J＝4.2Hz,3H),2.70(s,3H).
实施例92：化合物L-92的制备
Figure PCTCN2021081126-appb-000147
步骤1：将叔丁醇钾(3.20g,28.53mmol)溶解在10mL无水四氢呋喃溶液里，并将该溶在冰浴下液慢慢滴加入1-环丙烷酮(2g,23.78mmol)，草酸二甲酯(3.09g,26.15mmol)和甲苯(20mL)的混合溶液中，反应液慢慢升温至室温，并在室温下搅拌18小时。冰浴下，向反应液中加入HCl(1mol/L 15mL)，搅拌10分钟，用乙酸乙酯(25mL*3)萃取三次。无水硫酸钠干燥减压旋干得到化合物92-1(3.18g)。MS(ESI)171.1[M+H]+.
步骤2：以化合物92-1为原料，参考实施例51步骤1的制备方法，得到化合物92-2。MS(ESI)181.1[M+H]+.步骤3-4：以化合物92-2为原料，参考实施例7步骤2-3的制备方法，得到化合物92-4(243mg)。MS(ESI)178.1[M+H]+。
步骤5：参考实施例1步骤5的制备方法，区别在于化合物92-4替换化合物V4，得到类白色固体L-92(16.91mg,P：96.80％)MS(ESI)430.1[M+H]+. 1H NMR(400MHz,DMSO-d6)δ8.62(s,1H),7.93(d,J＝7.6Hz,1H),7.84(d,J＝6.7Hz,1H),7.48(dd,J＝19.1,11.3Hz,3H),5.89(s,1H),5.51(s,2H),3.77(s,3H),2.63(s,3H),1.82(s,1H),0.90(dd,J＝8.3,2.2Hz,2H),0.56(dd,J＝5.0,2.2Hz,2H).
实施例93：化合物L-93的制备
Figure PCTCN2021081126-appb-000148
步骤1：以1H-吡唑-3-羧酸乙酯(800mg,5.71mmol)和3-碘氧杂环丁烷(1.37g,7.42mmol)为原料，参考实施例10步骤2的制备方法，得到无色油状物93-1(348mg,P:100％,产率:31.07％)。MS(ESI)197.1[M+H]+。
步骤2-3：以化合物93-1位原料，参考实施例7步骤2-3的制备方法，得到化合物93-3(295mg)。MS(ESI)180.1[M+H]+.
步骤4：以化合物93-3和中间体V8为原料，参考实施例1步骤5的制备方法，得到绿色固体产品L-93(6.02mg,P：96.38％)MS(ESI)448.1[M+H]+. 1H NMR(400MHz,DMSO-d6)δ8.81(s,1H),7.99(d,J＝7.9Hz,1H),7.92–7.84(m,2H),7.55–7.45(m,2H),6.35(d,J＝2.2Hz,1H),5.70(s,2H),5.55(d,J＝6.5Hz,2H),4.87(dt,J＝16.0,6.7Hz,4H),2.67(s,3H).
实施例94：化合物L-94的制备
Figure PCTCN2021081126-appb-000149
步骤1：将乙酰乙酸甲酯(31.4g,270.42mmol)溶于AcOH(34mL)中，将反应温度降低到0℃，然后将NaNO2(20.52g,297.46mmol)的水(40mL)溶液滴入反应中，滴加完毕，反应自然升到室温并搅拌0.5小时，然后再加入水(60mL)，搅拌16小时。反应完毕，反应液中再加入水(200mL)，用乙酸乙酯萃取，饱和碳酸氢钠洗涤，饱和氯化钠水溶液洗涤，无水硫酸钠干燥，过滤浓缩。经柱层析(120g，0～25％EA/PE)纯化，得到无色油状化合物94-1(27.6g,产率:70％)MS(ESI)146.1[M+H]+。
步骤2将化合物94-1(13.8g,95.10mmol)和KI(8.68g,52.30mmol)溶于ACN(150mL)中，然后将TEA(20.21g,199.71mmol)加入其中,降低反应到0℃，滴加TMSCl(21.70g,199.71mmol)，滴加完毕，该反应在室温条件下搅拌18小时。过滤浓缩，再用甲基叔丁基醚溶解，过滤浓缩，得到油状黑色化合物94-2(27.53g)。
步骤3:将化合物94-2(20.66g,71.37mmol)和丙炔酸甲酯(4g,47.58mmol)在150℃条件下搅拌18小时，冷却至室温，经柱层析(120g，0～30％EA/PE)纯化得到淡黄色固体化合物94-3(3.2g,产率：32％)。MS(ESI)212.1[M+H]+.
步骤4:将化合物94-3((1g,4.74mmol)和TEA(1.44g,14.21mmol)溶于DCM(35mL)中，然后将(氯甲氧基)乙烷(582.00mg,6.16mmol)的DCM(2mL)溶液滴加入其中。该反应在室温条件下搅拌2小时。反应完毕，将反应液倒入水中，分离出有机相，水相用二氯甲烷萃取，合并有机相，无水硫酸钠干燥，过滤，滤液浓缩得到淡黄色油状化合物94-24(1.28g)。MS(ESI)270.1[M+H]+.
步骤5:以化合物94-4(1.28g,4.75mmol)为原料，参考实施例11步骤3的制备方法，得到淡黄色油状化合物94-5(421mg,产率:37％)， 1H NMR(400MHz,cdcl3)δ8.04(1H,d,J 8.6),7.50(1H,d,J 8.5),5.34(2H,s),4.78(2H,s),3.96(3H,s),3.72(2H,q,J 7.1),1.20(3H,t,J 7.1).MS(ESI)242.1[M+H]+.
步骤6:以化合物94-5(390.00mg,1.62mmol)为原料，参考实施例10步骤3的制备方法，得到淡黄色油状化合物94-6(212mg,产率：54％)。MS(ESI)242.2[M+H]+.
步骤7：以化合物94-6(212mg,878.64μmol)为原料，参考实施例7步骤3的制备方法，得到淡黄色油状化合物94-7(324mg)。MS(ESI)267.2[M+H]+.
步骤8：参考实施例1步骤5的制备方法，区别在于用化合物94-7替换化合物V4，得到类白色固体化合物94-8(201mg,产率：49％)。MS(ESI)519.3[M+H]+.
步骤9：将化合物94-8(201mg,387.63μmol)溶于MeOH(15mL)中，然后将HCl(1M,5mL)加入其中。该反应在30℃条件下搅拌10小时，减压旋干，通过HPLC制备色谱分离，得到白色固体L-94(60.12mg,产率：33％)。MS(ESI)461.2[M+H]+. 1H NMR(400MHz,DMSO-d6)δ10.17(1H,s),8.62(1H,s),7.94(1H,d,J 7.8),7.84(1H,dd,J 7.7,1.1),7.52(2H,s),7.46(1H,t,J 7.8),7.42(1H,d,J 8.5),7.21(1H,d,J 8.5),5.71(2H,s),4.98(1H,s),2.64(3H,s),1.27(6H,s).
实施例96：化合物L-96的制备
Figure PCTCN2021081126-appb-000150
以化合物96-1和1-甲基哌嗪为原料，参考实施例7的制备方法，得到化合物L-96。MS(ESI)507.1[M+H]+。1H NMR(400MHz,DMSO-d6)δ8.79(s,1H),7.98(d,J＝8Hz,1H),7.88(d,J＝8Hz,1H),7.47-7.51(m,1H),7.31(s,1H),5.76(s,2H),3.34-3.37(m,4H),2.67(s,3H),2.36-2.38(m,4H),2.19(s,3H).
实施例97：化合物L-97的制备
Figure PCTCN2021081126-appb-000151
步骤1：以化合物97-1和溴乙腈为原料，参考实施例7步骤1的制备方法，得到化合物97-2.
步骤2：参考实施例1步骤:5的制备方法，区别在于用将化合物97-2替换化合物V4，得到化合物L-97。1H NMR(400MHz,DMSO-d6)δ8.71(s,1H),7.92(d,J＝7.8Hz,1H),7.83(d,J＝7.2Hz,1H),7.53(s,3H),7.45(t,J＝7.8Hz,1H),6.36(d,J＝2.0Hz,1H),5.67(s,2H),5.45(s,2H),2.62(s,3H).MS(ESI)415.2[M+H]+
实施例98：化合物L-98的制备
Figure PCTCN2021081126-appb-000152
步骤1：以化合物98-1为原料，参考实施例85步骤1的制备方法，得化合物98-2。
步骤2：以化合物98-2为原料，参考实施例70步骤3的制备方法，得化合物98-3.
步骤3：以化合物98-3为原料，参考实施例7步骤3的制备方法，得化合物98-4.
步骤4：参考实施例1步骤5的制备方法，区别在于用化合物98-4替换化合物V4，得化合物L-98。1H NMR(400MHz,DMSO-d6)δ8.69(s,1H),7.91(d,J＝6.8Hz,1H),7.82(d,J＝6.6Hz,1H),7.52(s,2H),7.47–7.36(m,2H),6.23(d,J＝1.8Hz,1H),5.86(dd,J＝38.4,15.6Hz,2H),5.72(s,1H),4.64(s,1H),4.48(q,J＝7.2Hz,1H),2.61(s,3H),1.31(d,J＝6.8Hz,3H),1.04(s,3H),0.95(s,3H).MS(ESI)462.2[M+H]+
实施例99：化合物L-99的制备
Figure PCTCN2021081126-appb-000153
参考实施例98的制备方法，区别在于用中间体V7替换中间体V6，得到化合物L-99。1H NMR(400MHz,DMSO-d6)δ8.57(s,1H),7.91(d,J＝7.6Hz,1H),7.82(d,J＝7.8Hz,1H),7.64(d,J＝2.2Hz,1H),7.59–7.33(m,3H),6.23(d,J＝1.8Hz,1H),5.61(s,2H),4.56(s,1H),4.16(q,J＝7.0Hz,1H),2.61(s,3H),1.37(d,J＝7.0Hz,3H), 0.96(s,3H),0.92(s,3H).MS(ESI)462.2[M+H]+。
测试例1：对A2A受体和A2B受体的抑制活性
CHO-K1/ADORA2A/Gα15(GenScript，M00246)和CHO-K1/ADORA2B/Gα15(GenScript，M00329)细胞培养在Ham's F-12(Gibco，31765092)培养基内，培养基条件为含10％FBS、200ug/ml Zeocin及100ug/ml Hygromycin B或10％FBS、400ug/ml G418及100ug/ml Hygromycin B，具体培养条件详见对应说明书。筛选步骤如下：
1.用不含血清的培养基将细胞密度调整为6X10 5个/ml。
2. 384孔板(Greiner Bio-One，784075)中每孔分别依次加入5ul细胞液、2.5μl的NECA(Sigma，119140-10MG)和2.5μl的化合物溶液，NECA终浓度为50nM(CHO-K1/ADORA2A)或10nM(CHO-K1/ADORA2B)，化合物终浓度为3uM起始向下3倍稀释。
3.置于37℃培养箱静置培养30min。
4.依次加入5μl的cAMP-d 2和5μl的cAMP-ab(Cisbio，62AM4PEB)。
5. 384孔板避光室温放置1h。
6.读板(Victor X5，PerkinElmer)，XLfit非线性回归分析数据，算出化合物的IC 50。
表1化合物对A 2A受体和A 2B受体的抑制活性
Figure PCTCN2021081126-appb-000154
由表1可知，本发明实施例化合物对A 2A受体和A 2B受体均具有较高的抑制活性。
测试例2：对A2A受体和A2B受体的抑制活性
CHO-K1/ADORA2A/Gα15(GenScript，M00246)和CHO-K1/ADORA2B/Gα15(GenScript，M00329)细胞培养在Ham's F-12(Gibco，31765092)培养基内，培养基条件为含10％FBS、200ug/ml Zeocin及100ug/ml Hygromycin B或10％FBS、400ug/ml G418及100ug/ml Hygromycin B，具体培养条件详见对应说明书。筛选步骤如下：
1.用不含血清的培养基将细胞密度调整为6X10 5个/ml。
2. 384孔板(Greiner Bio-One，784075)中每孔分别依次加入5ul细胞液、2.5μl的NECA(Sigma，119140-10MG)和2.5μl的化合物溶液，NECA终浓度为1uM(CHO-K1/ADORA2A)或0.1uM(CHO-K1/ADORA2B)，化合物终浓度为3uM起始向下3倍稀释。
3.置于37℃培养箱静置培养30min。
4.依次加入5μl的cAMP-d 2和5μl的cAMP-ab(Cisbio，62AM4PEB)。
5. 384孔板避光室温放置1h。
6.读板(Victor X5，PerkinElmer)，XLfit非线性回归分析数据，算出化合物的IC 50。
表2化合物对A 2A受体和A 2B受体的抑制活性
Figure PCTCN2021081126-appb-000155
化合物D1结构如下所示，CAS号为2239273-34-6。供应商：苏州楚凯药业有限公司；批号：2009010AHP07。
Figure PCTCN2021081126-appb-000156
测试例3：体内药代试验
应用LC/MS/MS法测定了小鼠分别静脉注射给药和口服灌胃给药本发明化合物后不同时刻血浆中的药物浓度，研究本发明化合物在小鼠体内的药代动力学行为，评价其药动学特征。
实验方案：
试验动物：健康成年雄性ICR小鼠(体重25-40g，12只，静脉注射组小鼠自由饮水和饮食，灌胃给药组禁食过夜，给药4h后自由饮水和饮食)，由Beijing Vital River Laboratory Animal Co.LTD提供；
给药方式与剂量：给药前挑选符合实验要求的动物，称重标记。ICR小鼠尾静脉给药(2mg/kg,5％DMSO,pH 4.5 20％Captisol)和灌胃给药(10mg/kg,5％DMSO,pH 4.5 20％Captisol)。
血样采集：采集血样前，绑定小鼠，每一只给药的小鼠在预定的采血时间点(静脉给药：分别于给药后的0.083,0.25,0.5,1,2,4,6,7.5,24h采血，共9个时间点；灌胃给药：分别于给药后的0.083,0.25,0.5,1,2,4,6,7.5,24h采血，共9个时间点)，通过颈静脉采血约100μL。血液转移至预先加入K2EDTA的1.5mL试管中，离心4min(8000rpm,4℃)，分离出血浆，整个过程在采血后15min内完成。所有的样品都需要存放于-20℃冰箱直至样品分析。应用LC/MS/MS法测定药物浓度.
本发明部分实施例化合物在相同剂量的静脉给药方式下，小鼠体内的药代动力学性质参数如表3所示：
表3
Figure PCTCN2021081126-appb-000157
本发明部分实施例化合物在相同剂量的灌胃给药方式下，小鼠体内的药代动力学性质参数如表4所示：
表4
Figure PCTCN2021081126-appb-000158
测试例4：本发明化合物体内药效实验
实验方案：本测试例考察小鼠结肠癌细胞株MC38(#22)-hpd-L1皮下移植瘤小鼠，通过口服给药途径施用本发明化合物后，测试其对结肠癌MC38(#22)-hpd-L1荷瘤鼠的体内药效。
实验材料：C57BL/6mice小鼠(雌性)；小鼠结肠癌MC38(#22)-hpd-L1细胞(上海交通大学细胞库)，体外单层培养，培养条件为采用含10％胎牛血清RPMI-1640培养基，37℃5％CO2培养箱中培养。用胰酶-EDTA进行常规消化处理传代。当细胞处于指数生长期，饱和度为80％-90％时，收取细胞，计数。
化合物配制：量取化合物，加入到溶媒(40％captisol in acetic acid buffer(pH3.8)中，制成10mg/mL的样品。取75μLTecentriq溶液(60mg/mL)加入8.925mL磷酸盐缓冲液(PBS)配制成0.5mg/mL溶液。
实验操作：将细胞重悬于磷酸盐缓冲液，密度为5×10 6个细胞/mL。0.1mL PBS(含5×105个MC38(#22)-hpd-L1细胞)皮下接种于每只小鼠的右后背，接种当天按照小鼠体重进行随机分组，每组10只，开始给药，每天2次给药，持续22天。整个实验期间，每天称重并监测动物的健康。每周两次用游标卡尺测量肿瘤直径。
肿瘤体积的计算公式为：V＝0.5×a×b 2，a和b分别表示肿瘤的长径和短径。
化合物的抑瘤疗效用相对肿瘤增殖率T/C(％)评价。相对肿瘤增殖率T/C(％)＝Vt/Vc×100％(Vt：治疗组平均瘤体积；Vc：阴性对照组平均瘤体积)。Vt与Vc取同一天数据。
表5本发明化合物的相对肿瘤增殖率
Figure PCTCN2021081126-appb-000159
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应 理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (20)

  1. 一种式(I)所示的化合物、或其药学上可接受的盐、或其立体异构体、或其溶剂化物、或其前药：
    Figure PCTCN2021081126-appb-100001
    式中，
    环A为5至10元杂芳基、苯基或吡啶酮基；
    环B为苯基或5至10元杂芳基；
    Q为5至6元杂芳基、苯基、C 3-6环烷基、4至8元杂环烷基、6至12元稠合杂环烷基、7至11元苯基并杂环烷基、7至11元杂芳基并杂环烷基、7至11元螺环基或7至11元杂螺环基；其中所述的5至6元杂芳基、苯基、C 3-6环烷基、4至8元杂环烷基、6至12元稠合杂环烷基、7至11元苯基并杂环烷基、7至11元杂芳基并杂环烷基、7至11元螺环基和7至11元杂螺环基为未取代的或被1、2或3个各自独立地选自下组的取代基取代：氘、卤素、氰基、羟基、羧基、氧代基、C 1-3烷基、C 1-3烷氧基、C 2-4烯基、C 2-4炔基、卤代C 1-3烷基、卤代C 1-3烷氧基、NR a0R b0、-C(O)C 1-3烷基、-SO 2C 1-3烷基、-S(O)C 1-3烷基、-C(O)NR a0R b0、-C(O)OC 1-3烷基、-OC(O)C 1-3烷基、C 3-6环烷基、C 3-6环烷基氧基、3至6元杂环烷基、苯基和5至6元杂芳基；
    L 1、L 2各自独立地为一个键、NR 1'、CR 2'R 3'、O、S或C(O)；且L 1、L 2不同时为O或S；
    R 1'、R 2'、R 3'各自独立地为氢、氘、氰基、羟基、卤素(优选为氟或氯)或C 1-6烷基；或者R 1'与R 2'连接形成3至8元杂环烷基环；或者R 2'与R 3'连接形成3至8元杂环烷基环；其中所述的3至8元杂环烷基环为未取代的或被1、2或3个各自独立地选自下组的取代基取代：氘、卤素、氰基、羟基、C 1-3烷基、C 1-3烷氧基、C 2-4烯基、C 2-4炔基、卤代C 1-3烷基、卤代C 1-3烷氧基、-SO 2C 1-3烷基、-S(O)C 1-3烷基、-C(O)NR a0R b0、-C(O)OC 1-3烷基、-OC(O)C 1-3烷基、C 3-6环烷基、C 3-6环烷基氧基、3至6元杂环烷基、苯基、5至6元杂芳基；
    W为N或CR W；
    R W为氰基、羟基、卤素、卤代C 1-8烷基、卤代C 1-8烷氧基或C 1-8烷氧基；
    R c、R a和R b定义如下：
    (i)R c为氟、氯、氰基、C 1-3烷氧基或卤代C 1-3烷氧基；
    R a、R b各自独立地为氢、氘、C 1-8烷基、C 1-8烷氧基、-C(O)C 1-8烷基、-(CH 2) tC 3-8环烷基、-(CH 2) t-3至8元杂环烷基或为式(a)结构
    Figure PCTCN2021081126-appb-100002
    其中所述C 1-8烷基、-C(O)C 1-8烷基和-(CH 2) t-3至8元杂环烷基为未取代的或被1、2或3个各自独立地选自下组的取代基取代：氘、卤素、氰基、羟基、C 1-3烷基、C 1-3烷氧基、C 2-4烯基、C 2-4炔基、卤代C 1-3烷基、卤代C 1-3烷氧基、-SO 2C 1-3烷基、-S(O)C 1-3烷基、-C(O)NR a0R b0、-C(O)OC 1-3烷基、-OC(O)C 1-3烷基、C 3-6环烷基、C 3-6环烷基氧基、3至6元杂环烷基、苯基、5至6元杂芳基；
    或者R a、R b与相连的氮原子共同形成5或6元饱和或部分不饱和单杂环；其中所述5或6元饱和或部分不饱和单杂环为未取代的或被1、2或3个各自独立地选自下组的取代基取代：氘、卤素、氰基、羟基、C 1-3烷基、C 1-3烷氧基、C 2-4烯基、C 2-4炔基、卤代C 1-3烷基、卤代C 1-3烷氧基、-SO 2C 1-3烷基、-S(O)C 1-3烷基、-C(O)NR a0R b0、-C(O)OC 1-3烷基、-OC(O)C 1-3烷基、C 3-6环烷基、C 3-6环烷基氧基、3至6元杂环烷基、苯基和5至6元杂芳基；
    其中R 1a为氢或C 1-3烷基；R 2a、R 3a各自独立地为氢或C 1-3烷基；或者R 2a与R 3a连接形成5至8元杂环烯基环或5至6元杂芳基环；所述5至8元杂环烯基环含有2、3或4个氮原子和0、1或2个氧原子；所述5至6元杂芳基环含有2、3或4个氮原子和0或1个氧原子；所述5至8元的杂环烯基环和5至6元杂芳基环为未取代的或被1、2或3个各自独立地选自下组的取代基取代：卤素、氰基、羟基、C 1-3烷基、C 1-3烷氧基、卤代C 1-3烷基和卤代C 1-3烷氧基；或者
    (ii)R c与R a连接形成稠合的5或6元饱和或部分不饱和单杂环、或稠合的5至6元杂芳基环；
    所述稠合的5或6元饱和或部分不饱和单杂环和5至6元杂芳基环为未取代的或被1、2或3个各 自独立地选自下组的取代基取代：氘、卤素、氰基、羟基、氧代基、C 1-3烷基、C 1-3烷氧基、C 2-4烯基、C 2-4炔基、卤代C 1-3烷基、卤代C 1-3烷氧基、-SO 2C 1-3烷基、-S(O)C 1-3烷基、-C(O)NR a0R b0、-C(O)OC 1-3烷基、-OC(O)C 1-3烷基、C 3-6环烷基、C 3-6环烷基氧基、3至6元杂环烷基、苯基和5至6元杂芳基；
    R b为氢、氘、C 1-8烷基、-C(O)C 1-8烷基、-(CH 2) tC 3-8环烷基、-(CH 2) t-3至8元杂环烷基或为式(a)结构；其中所述C 1-8烷基、-C(O)C 1-8烷基和-(CH 2) t-3至8元杂环烷基为未取代的或被1、2或3个各自独立地选自下组的取代基取代：氘、卤素、氰基、羟基、C 1-3烷基、C 1-3烷氧基、C 2-4烯基、C 2-4炔基、卤代C 1-3烷基、卤代C 1-3烷氧基、-SO 2C 1-3烷基、-S(O)C 1-3烷基、-C(O)NR a0R b0、-C(O)OC 1-3烷基、-OC(O)C 1-3烷基、C 3-6环烷基、C 3-6环烷基氧基、3至6元杂环烷基、苯基和5至6元杂芳基；
    t为0、1、2或3；
    R L1、R L2各自独立地为氢、羟基、卤素、C 1-3烷基、C 1-3烷氧基或卤代C 1-3烷基；或者R L1、R L2与相连的碳原子共同形成3至7元饱和或部分不饱和单环或3至7元饱和或部分不饱和单杂环；其中所述3至7元饱和或部分不饱和单杂环和3至7元饱和或部分不饱和单环为未取代的或被1、2或3个各自独立地选自下组的取代基取代：氘、卤素、氰基、羟基、羧基、C 1-3烷基、C 1-3烷氧基、C 2-4烯基、C 2-4炔基、卤代C 1-3烷基、卤代C 1-3烷氧基、-SO 2C 1-3烷基、-S(O)C 1-3烷基、-C(O)NR a0R b0、-C(O)OC 1-3烷基、-OC(O)C 1-3烷基、C 3-6环烷基、C 3-6环烷基氧基、3至6元杂环烷基、苯基和5至6元杂芳基；
    m为0、1、2或3；
    R p为氢、羟基、羧基、氰基、C 1-8烷基、卤代C 1-8烷基、卤代C 1-8烷氧基、C 1-8烷氧基、C 3-8环烷基、-SO 2C 1-8烷基、-SO 2NR a0R b0、-(PO)(C 1-3烷基) 2、-NHSO 2C 1-3烷基、-C(O)NR a0R b0、-C(O)NR a1R b1、3至6元杂环烷基、-X-(CR p1R p2) q-3至6元杂环烷基、8至10元杂环烷基、7至11元杂螺环基、5至6元杂芳基、8至10元杂芳基、NR a1R b1或NR a'R b'；其中所述C 3-8环烷基、3至6元杂环烷基、8至10元杂环烷基、7至11元杂螺环基、5至6元杂芳基、8至10元杂芳基为未取代的或被1、2或3个各自独立地选自下组的取代基取代：氘、卤素、氰基、羟基、羧基、氧代基、C 1-3烷基、C 1-3烷氧基、C 2-4烯基、C 2-4炔基、卤代C 1-3烷基、卤代C 1-3烷氧基、NR a0R b0、-C(O)C 1-3烷基、-SO 2C 1-3烷基、-S(O)C 1-3烷基、-C(O)NR a0R b0、-C(O)OC 1-3烷基、-OC(O)C 1-3烷基、C 3-6环烷基、C 3-6环烷基氧基、3至6元杂环烷基、苯基和5至6元杂芳基；
    X为O或NR p3；
    R p1、R p2各自独立地为氢、羟基、卤素或C 1-3烷基；
    R p3为氢或C 1-3烷基；
    q为0、1、2或3；
    R a'、R b'与相连的氮原子共同形成4至8元饱和单杂环、8至10元饱和双杂环或7至11元杂螺环；所述4至8元饱和单杂环、8至10元饱和双杂环和7至11元杂螺环为未取代的或被1、2或3个各自独立地选自下组的取代基取代：卤素、氰基、羟基、羧基、C 1-3烷基、C 1-3烷氧基、C 2-4烯基、C 2-4炔基、卤代C 1-3烷基、卤代C 1-3烷氧基、-(CH 2) t1-NR a0R b0、-(CH 2) t1-SO 2C 1-3烷基、-(CH 2) t1-S(O)C 1-3烷基、-(CH 2) t1-C(O)NR a0R b0、-(CH 2) t1-C(O)OC 1-3烷基、-(CH 2) t1-OC(O)C 1-3烷基、-(CH 2) t1-C 3-6环烷基、C 3-6环烷基氧基和-(CH 2) t1-3至6元杂环烷基；
    t1独立选自0、1、2或3；
    (R 0) n为环A上的氢被n个R 0取代，n为0、1、2或3，每个R 0相同或不同，各自独立地为卤素、氰基、羟基、羧基、C 1-3烷基、羟基取代的C 1-3烷基、C 1-3烷氧基取代的C 1-3烷基、C 1-3烷氧基、C 2-4烯基、C 2-4炔基、卤代C 1-3烷基、卤代C 1-3烷氧基、-SO 2C 1-3烷基、-SO 2NR a0R b0、-N(R a0)SO 2C 1-3烷基、-P(O)R a0R b0、-S(O)C 1-3烷基、-C(O)NR a0R b0、-C(O)OC 1-3烷基、-OC(O)C 1-3烷基、C 3-6环烷基、C 3-6环烷基氧基或3至6元杂环烷基；
    (R 0') u为环B上的氢被u个R 0'取代，u为0、1、2、3、4或5，每个R 0'相同或不同，各自独立地为氢、氰基、乙酰基、羟基、羧基、卤素、NR a0R b0、C 1-8烷基、C 1-8烷氧基、C 3-8环烷基、3至6元杂环烷基、5至6元杂芳基或C 6-10芳基；其中所述C 1-8烷基、C 1-8烷氧基、C 3-8环烷基、3至6元杂环烷基、5至6元杂芳基和C 6-10芳基为未取代的或被1、2或3个独立选自下组的取代基取代：氘、卤素、氰基、羟基、C 1-3烷基、C 1-3烷氧基、C 2-4烯基、C 2-4炔基、卤代C 1-3烷基、卤代C 1-3烷氧基、C 3-6环烷基、C 3-6环烷基氧基、3至6元杂环烷基、苯基和5至6元杂芳基；
    R a0、R b0各自独立地为氢或C 1-3烷基；或者R a0、R b0与相连的氮原子共同形成4至6元饱和单杂环；所述4至6元饱和单杂环任选地被1、2或3个各自独立地选自下组的取代基取代：氘、卤素、氰基、羟基、羧基、C 1-3烷基、C 1-3烷氧基、C 2-4烯基、C 2-4炔基、卤代C 1-3烷基、卤代C 1-3烷氧基、-SO 2C 1-3烷基、-S(O)C 1-3烷基、-C(O)NR a0R b0、-C(O)OC 1-3烷基、-OC(O)C 1-3烷基、C 3-6环烷基、C 3-6环烷基氧基和3至6 元杂环烷基；
    R a1、R b1各自独立地为氢、C 1-3烷基、C 3-6环烷基、3至6元杂环烷基或-(CR aR b) s-R c；其中所述3至6元杂环烷基为未取代的或被1、2或3个各自独立地选自下组的取代基取代：氘、卤素、氰基、羟基、羧基、氧代基、C 1-3烷基、C 1-3烷氧基、C 2-4烯基、C 2-4炔基、卤代C 1-3烷基、卤代C 1-3烷氧基、-SO 2C 1-3烷基、-S(O)C 1-3烷基、-C(O)NR a0R b0、-C(O)C 1-3烷基、-C(O)OC 1-3烷基、-OC(O)C 1-3烷基、C 3-6环烷基、C 3-6环烷基氧基、3至6元杂环烷基、苯基和5至6元杂芳基；
    R a、R b各自独立地为氢、羟基、卤素、C 1-3烷基、C 1-3烷氧基或卤代C 1-3烷基；或者R a、R b与相连的碳原子共同形成3至7元饱和或部分不饱和单环或3至7元饱和或部分不饱和单杂环；其中所述3至7元饱和或部分不饱和单杂环和3至7元饱和或部分不饱和单环为未取代的或被1、2或3个各自独立地选自下组的取代基取代：氘、卤素、氰基、羟基、羧基、C 1-3烷基、C 1-3烷氧基、C 2-4烯基、C 2-4炔基、卤代C 1-3烷基、卤代C 1-3烷氧基、-SO 2C 1-3烷基、-S(O)C 1-3烷基、-C(O)NR a0R b0、-C(O)OC 1-3烷基、-OC(O)C 1-3烷基、C 3-6环烷基、C 3-6环烷基氧基、3至6元杂环烷基、苯基和5至6元杂芳基；
    R c为氢、羟基、羧基、C 1-8烷基、卤代C 1-8烷基、卤代C 1-8烷氧基、C 1-8烷氧基或C 3-8环烷基；以及
    s为1、2或3。
  2. 如权利要求1所述的化合物、或其药学上可接受的盐、或其立体异构体、或其溶剂化物、或其前药，其特征在于，环A为苯基、吡啶基、吡唑基、嘧啶、1,2,3-三唑、1,2,4-三唑或吡啶酮基。
  3. 如权利要求1所述的化合物、或其药学上可接受的盐、或其立体异构体、或其溶剂化物、或其前药，其特征在于，R c为氟、氯、氰基、羟基、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基或异丙氧基。
  4. 如权利要求1所述的化合物、或其药学上可接受的盐、或其立体异构体、或其溶剂化物、或其前药，其特征在于，Q为5至6元杂芳基、苯基、C 3-6环烷基、4至6元杂环烷基、8至10元稠合杂环烷基、8至10元苯基并杂环烷基、8至10元杂芳基并杂环烷基、7至11元螺环基或7至11元杂螺环基。
  5. 如权利要求1所述的化合物、或其药学上可接受的盐、或其立体异构体、或其溶剂化物、或其前药，其特征在于，R a、R b各自独立地为氢、氘、C 1-3烷基、-C(O)C 1-3烷基、-(CH 2) tC 3-6环烷基、-(CH 2) t-4至6元杂环烷基或为式(a)结构；或者R a、R b与相连的氮原子共同形成5或6元饱和单杂环；其中所述C 1-3烷基、-C(O)C 1-3烷基、-(CH 2) t-4至6元杂环烷基和5或6元饱和单杂环为未取代的或被1、2或3个各自独立地选自下组的取代基取代：氘、卤素、氰基、羟基、C 1-3烷基、C 1-3烷氧基、C 2-4烯基、C 2-4炔基、卤代C 1-3烷基、卤代C 1-3烷氧基、-SO 2C 1-3烷基、-S(O)C 1-3烷基、-C(O)NR a0R b0、-C(O)OC 1-3烷基、-OC(O)C 1-3烷基、C 3-6环烷基、C 3-6环烷基氧基和4至6元杂环烷基；所述4至6元杂环烷基选自：氮杂环丁烷基、氧杂环丁烷基、四氢呋喃基、四氢噻吩基、四氢吡咯基、噁唑烷基、二氧戊环基、哌啶基、哌嗪基、吗啉基、二氧六环基、硫代吗啉基、硫代吗啉-1,1-二氧化物和四氢吡喃基；所述C 3-6环烷基选自：环丙基、环丁基、环戊基和环己基；所述5或6元饱和单杂环选自：四氢呋喃环、四氢噻吩环、四氢吡咯环、哌啶环、噁唑烷、哌嗪环、二氧戊环、二氧六环、吗啉环、硫代吗啉环和四氢吡喃环。
  6. 如权利要求1所述的化合物、或其药学上可接受的盐、或其立体异构体、或其溶剂化物、或其前药，其特征在于，W为N。
  7. 如权利要求1所述的化合物、或其药学上可接受的盐、或其立体异构体、或其溶剂化物、或其前药，其特征在于，Q为
    Figure PCTCN2021081126-appb-100003
    Figure PCTCN2021081126-appb-100004
  8. 如权利要求1所述的化合物、或其药学上可接受的盐、或其立体异构体、或其溶剂化物、或其前药，其特征在于，L 1为一个键；L 2为CR 2'R 3'。
  9. 如权利要求1所述的化合物、或其药学上可接受的盐、或其立体异构体、或其溶剂化物、或其前药，其特征在于，环B为苯基；(R 0') u为环B上的氢被u个R 0'取代，u为1或2，每个R 0'相同或不同，各自独立地为氢、氰基、卤素、C 1-8烷基。
  10. 如权利要求1所述的化合物、或其药学上可接受的盐、或其立体异构体、或其溶剂化物、或其前药，其特征在于，
    R L1、R L2各自独立地为氢、羟基、卤素、C 1-3烷基、C 1-3烷氧基或卤代C 1-3烷基；
    m为0、1或2；
    R p为氢、羟基、羧基、氰基、C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基、C 3-6环烷基、-SO 2C 1-6烷基、-(PO)(C 1-3烷基) 2、-NHSO 2C 1-3烷基、-C(O)NR a0R b0、3至6元杂环烷基或NR a1R b1；其中所述C 3-6环烷基、3至6元杂环烷基为未取代的或被1或2个各自独立地选自下组的取代基取代：卤素、羟基、C 1-3烷基；
    R a0、R b0各自独立地为氢或C 1-3烷基；
    R a1、R b1各自独立地为氢或C 1-3烷基。
  11. 如权利要求1所述的化合物、或其药学上可接受的盐、或其立体异构体、或其溶剂化物、或其前药，其特征在于，(R 0) n为环A上的氢被n个R 0取代，n为0或1，R 0为卤素、羟基、C 1-3烷基、C 1-3烷氧基、羟基取代的C 1-3烷基、C 1-3烷氧基取代的C 1-3烷基、C 3-6环烷基。
  12. 如权利要求1所述的化合物、或其药学上可接受的盐、或其立体异构体、或其溶剂化物、或其前药，其特征在于，所述化合物如式(II)或式(III)所示结构：
    Figure PCTCN2021081126-appb-100005
    其中，式(II)中的R c、R a和R b如(i)中的定义；式(III)中的R b如(ii)中的定义；
    X 1为O、NR 11或CR 12R 13；
    X 2为C(O)或CR 21R 22；
    R 11为氢或C 1-3烷基；
    R 12、R 13、R 21、R 22各自独立地为氢、卤素、C 1-3烷基或C 1-3烷氧基；
    Z为N或CR Z；R Z为氢、氘或C 1-3烷基；
    R 1、R 2、R 3、R 4、R 5各自独立地为氢、氰基、乙酰基、羟基、羧基、卤素、NR a0R b0、C 1-8烷基、C 1-8烷氧基、C 3-8环烷基、3至6元杂环烷基、5至6元杂芳基或C 6-10芳基；其中所述C 1-8烷基、C 1-8烷氧基、C 3-8环烷基、3至6元杂环烷基、5至6元杂芳基和C 6-10芳基为未取代的或被1、2或3个独立选自下组的取代基取代：氘、卤素、氰基、羟基、C 1-3烷基、C 1-3烷氧基、C 2-4烯基、C 2-4炔基、卤代C 1-3烷基、卤代C 1-3烷氧基、C 3-6环烷基、C 3-6环烷基氧基、3至6元杂环烷基、苯基和5至6元杂芳基；以及
    R 6、R 7各自独立地为氢、氘、氰基、羟基、卤素或C 1-6烷基。
  13. 如权利要求1所述的化合物、或其药学上可接受的盐、或其立体异构体、或其溶剂化物、或其前药，其特征在于，
    Figure PCTCN2021081126-appb-100006
    为
    Figure PCTCN2021081126-appb-100007
  14. 如权利要求1所述的化合物、或其药学上可接受的盐、或其立体异构体、或其溶剂化物、或其前药，其特征在于，式(I)化合物为下列化合物中的任意一个：
    Figure PCTCN2021081126-appb-100008
    Figure PCTCN2021081126-appb-100009
    Figure PCTCN2021081126-appb-100010
  15. 如权利要求1所述的化合物、或其药学上可接受的盐、或其立体异构体、或其溶剂化物、或其前药，其特征在于，式(I)化合物为下列化合物中的任意一个：
    Figure PCTCN2021081126-appb-100011
    Figure PCTCN2021081126-appb-100012
    Figure PCTCN2021081126-appb-100013
    Figure PCTCN2021081126-appb-100014
  16. 一种药物组合物，其特征在于，包括权利要求1-15中任一项所述的化合物、或其药学上可接受的盐、或其立体异构体、或其溶剂化物、或其前药；以及药学上可接受的载体。
  17. 根据权利要求1-15任一项所述的化合物、或其药学上可接受的盐、或其立体异构体、或其溶剂化物或其前药，或者根据权利要求16所述的药物组合物在制备治疗由腺苷A 2A受体和/或腺苷A 2B受体介导的疾病的药物中的应用。
  18. 根据权利要求17所述的应用，其特征在于，所述的由腺苷A 2A受体和/或腺苷A 2B受体介导的疾病为癌症或免疫相关的疾病。
  19. 根据权利要求18所述的应用，其特征在于，所述的癌症选自前列腺癌、结肠癌、直肠癌、胰腺癌、子宫颈癌、胃癌、子宫内膜癌、脑癌、肝癌、膀胱癌、卵巢癌、睾丸癌、头癌、颈癌、黑素瘤、基底癌、间皮内层癌、白血细胞癌、食道癌、乳腺癌、肌肉癌、结缔组织癌、小细胞肺癌、非小细胞肺癌、肾上腺癌、甲状腺癌、肾癌或骨癌；或是恶性胶质瘤、间皮瘤、肾细胞癌、胃癌、肉瘤、绒毛膜癌、皮肤基底细胞癌和睾丸精原细胞瘤。
  20. 根据权利要求18所述的应用，其特征在于，所述免疫相关的疾病选自类风湿性关节炎、肾衰竭、 狼疮、哮喘、银屑病、结肠炎、胰腺炎、过敏、纤维化、贫血性纤维肌痛、阿尔茨海默氏病、充血性心力衰竭、中风、主动脉瓣狭窄、动脉硬化、骨质疏松症、帕金森氏病、感染、克罗恩氏病、溃疡性结肠炎、过敏性接触性皮炎和其他湿疹、系统性硬化和多发性硬化症。
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