WO2021218755A1 - Shp2 inhibitor, and composition and use thereof - Google Patents

Shp2 inhibitor, and composition and use thereof Download PDF

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Publication number
WO2021218755A1
WO2021218755A1 PCT/CN2021/088871 CN2021088871W WO2021218755A1 WO 2021218755 A1 WO2021218755 A1 WO 2021218755A1 CN 2021088871 W CN2021088871 W CN 2021088871W WO 2021218755 A1 WO2021218755 A1 WO 2021218755A1
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amino
piperidine
group
dihydrospiro
indene
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PCT/CN2021/088871
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French (fr)
Chinese (zh)
Inventor
吴颢
吴文茂
李玲
张展
王丰
袁丁
吴云飞
陈强
韩晗
郭晶
兰宏
丁列明
王家炳
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贝达药业股份有限公司
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Priority to CN202180021106.8A priority Critical patent/CN115279749A/en
Publication of WO2021218755A1 publication Critical patent/WO2021218755A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—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
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/20—Spiro-condensed ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D241/18—Oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to a series of compounds as inhibitors of Src homology region 2 (Src homology region 2-containing protein tyrosine phosphatase 2, SHP2), and preparation methods and pharmaceutical compositions thereof.
  • the present invention also relates to the use of the above-mentioned compound or its pharmaceutical composition in the treatment of SHP2-mediated diseases.
  • Src homology region 2 protein tyrosine phosphatase 2 is a non-receptor protein tyrosine phosphatase encoded by the PTPN11 gene, and PTPN11 is the first The discovered proto-oncogene encoding tyrosine kinase (Chan R J et al.PTPN11 is the first identified proto-oncogene that encodes a tyrosine phosphatase.Blood, 2007,109:862-867), and the encoded SHP2 protein contains N-terminal SHP2 domain (N-SHP2), C-terminal SHP2 domain (C-SHP2), protein phosphatase catalytic domain (PTP), two C-terminal tyrosine residues (Y542 and Y580) and a rich Proline (Pro) motif.
  • SOS can catalyze the conversion of the membrane-bound protein Ras from inactive Ras-GDP to active Ras-GTP.
  • Ras-GTP further connects with downstream signaling systems to activate Ser/Thr kinase Raf1, etc., and then activate ERK under the action of the regulatory kinase MEK.
  • ERK directly acts on target molecules in the cytoplasm or transfers to the nucleus to regulate genes. Transcription to make cells proliferate or differentiate. This process may also be affected by SHP2 binding protein and substrate (SHP substrate-1, SHPS-1), Ras-GTPase activating protein (Ras-GAP) and other Src members.
  • SHP2 protein not only regulates the Ras/ERK signaling pathway, it is also reported to regulate multiple signaling pathways such as JAK-STAT3, NF- ⁇ B, PI3K/Akt, RHO, and NFAT, thereby regulating cell proliferation, differentiation, migration, apoptosis and other physiology Function.
  • SHP2 inhibitors have received more and more attention as potential treatments.
  • Compound 243 was disclosed in the WO2019183367 patent published on September 26, 2019, and it was recorded that the IC 50 measurement data in the SHP2 allosteric inhibition test was greater than 50 nM and less than or equal to 1 uM.
  • the present invention relates to a compound as an inhibitor of Src homologous region 2 protein tyrosine phosphatase 2 (SHP2), or a pharmaceutically acceptable salt, cis-trans isomer, tautomer, and solvate thereof , Chelate, non-covalent complex or prodrug, the compound is shown in formula I:
  • Ring A is selected from a 5-10 membered heteroaryl group or a 5-10 membered heterocyclic group; wherein the 5-10 membered heteroaryl group or the 5-10 membered heterocyclic group contains one or more O, N or S heteroatom; the 5-10 membered heterocyclic group contains at least one double bond;
  • Ring C is selected from C 3-10 carbocyclic group, 3-10 membered heterocyclic group, C 6-10 aryl group or 5-10 membered heteroaryl group;
  • R c1 and R c2 are each independently selected from hydrogen, halogen, C 1-4 alkyl or -OR 5 ;
  • R c1 and R c2 together with the atoms to which they are connected form a C 3-6 carbocyclic group or a 3-6 membered heterocyclic group;
  • Each R 1 is independently selected from hydrogen, halogen, -CN, -NO 2 , oxo, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 carbocyclic ring Group, 3-6 membered heterocyclic group, C 6-10 aryl group, 5-10 membered heteroaryl group, -OR 5 , -NR 7 R 8 , -O(CH 2 ) s OR 17 , -O(CH 2 ) s NR 18 R 19 , -NR 20 (CH 2 ) t NR 21 R 22 , -NR 23 (CH 2 ) t OR 24 ; wherein the C 1-4 alkyl group, C 2-4 alkenyl group, C 2-4 alkynyl, C 3-6 carbocyclic group, 3-6 membered heterocyclic group, C 6-10 aryl group, 5-10 membered heteroaryl group are optionally substituted by one or more substituents; Substituents are
  • M is selected from -O-, -NR 1a -or -CR 1b R 1c -;
  • R 1a is selected from hydrogen, C 1-3 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group or not present;
  • R 1b and R 1c are each independently selected from hydrogen, C 1-3 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group, -OR 1d , -NR 1e R 1f or not present;
  • R 1d , R 1e , and R 1f are each independently selected from hydrogen, C 1-3 alkyl, C 3-6 cycloalkyl or 3-6 membered heterocyclic group;
  • Y 1 is selected from -NR 3a -or -CR 3b R 3c -;
  • R 3a is selected from hydrogen, C 1-3 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group or not present;
  • R 3b and R 3c are each independently selected from hydrogen, C 1-3 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group or not present;
  • Y 2 is selected from -NR 4a -or -CR 4b R 4c -;
  • R 4a is selected from hydrogen, C 1-3 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group or not present;
  • R 4b and R 4c are each independently selected from hydrogen, C 1-3 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group or not present;
  • the ring D is a C 6-10 aryl group, a 5-10 membered heteroaryl group, a C 3-8 carbocyclic group, a 3-8 membered heterocyclic group or not present; wherein, the C 3-8 carbocyclic group Or a 3-8 membered heterocyclic group optionally contains a double bond;
  • R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , -NR 23 and R 24 are each independently selected from hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 carbocyclic group, 3-10 member Heterocyclic group, C 6-10 aryl group, 5-10 membered heteroaryl group;
  • n 0, 1, 2 or 3;
  • p 0, 1, 2 or 3;
  • q 0, 1, 2, 3 or 4;
  • r 0, 1, 2, 3 or 4;
  • s is 1, 2, 3 or 4;
  • t 1, 2, 3 or 4;
  • ring A is selected from a 6-10 membered heteroaryl group or a 6-10 membered heterocyclic group; the 6-10 membered heterocyclic group contains at least one double bond.
  • ring A is selected from pyridyl, pyrazinyl, pyrimidinyl, indolyl or pyrimidinonyl.
  • ring A is selected from Wherein, X 1 and X 2 are each independently selected from -NR 1 -or -CR 1 R 1 -.
  • ring A is selected from
  • the ring C is selected from a C 3-10 carbocyclic group or a 3-10 membered heterocyclic group.
  • the ring C is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, morpholinyl, piperazinyl or piperidinyl.
  • the ring C is selected from a C 6-10 aryl group or a 5-10 membered heteroaryl group.
  • the ring C is selected from the group consisting of pyrazolyl, imidazolyl, pyrrolyl, pyridyl, pyrimidinyl, indolyl, indolinyl, isoindolinyl, indolyl Azolyl, benzimidazolyl, purinyl, benzisoxazolyl, or indolazinyl.
  • the ring C is selected from phenyl
  • n is 0 or 1.
  • n is zero.
  • n 1
  • n is 2.
  • R c1 and R c2 are each independently selected from hydrogen, halogen, C 1-4 alkyl or -OR 5 .
  • R c1 and R c2 are each independently selected from hydrogen, -CH 3 , -F, and -OH.
  • R c1 and R c2 are each independently selected from hydrogen.
  • R c1 and R c2 together with the atoms to which they are attached form a cyclopropyl group.
  • each R 1 is independently selected from hydrogen, oxo, -CH 3 , -NH 2 , and -CH 2 OH.
  • M is selected from -O- or -CR 1b R 1c -.
  • R 1b and R 1c are each independently selected from hydrogen, C 1-3 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, -OR 1d Or -NR 1e R 1f .
  • Y 1 is selected from -NR 3a -, and Y 2 is selected from -CR 4b R 4c -.
  • Y 1 is selected from -CR 3b R 3c -, and Y 2 is selected from -NR 4a -.
  • Y 1 is selected from -CR 3b R 3c -
  • Y 2 is selected from -CR 4b R 4c -.
  • the ring D is a C 6-10 aryl group or a 5-10 membered heteroaryl group.
  • the ring D is
  • the ring D is a C 3-8 carbocyclic group or a 3-8 membered heterocyclic group.
  • the ring D is
  • each R 4 is independently selected from hydrogen, halogen, oxo, C 1-8 alkyl, or -OR 5 .
  • each R 4 is independently selected from hydrogen, oxo, -CH 3 or -OCH 3 .
  • p is 1, 2, or 3.
  • q is 0, 1, or 2.
  • r is 0, 1, 2 or 3.
  • s is 1 or 2.
  • t is 1 or 2.
  • the compound of Formula I or a pharmaceutically acceptable salt, cis-trans isomer, tautomer, solvate, chelate, non-covalent complex or prodrug thereof, is selected Self-style II:
  • Ring A is selected from a 5-10 membered heteroaryl group or a 5-10 membered heterocyclic group; wherein the 5-10 membered heteroaryl group or the 5-10 membered heterocyclic group contains one or more O, N or S heteroatom; the 5-10 membered heterocyclic group contains at least one double bond;
  • Ring C is selected from C 3-10 carbocyclic group, 3-10 membered heterocyclic group, C 6-10 aryl group or 5-10 membered heteroaryl group;
  • R c1 and R c2 are each independently selected from hydrogen, halogen, C 1-4 alkyl or -OR 5 ;
  • R c1 and R c2 together with the atoms to which they are connected form a C 3-6 carbocyclic group or a 3-6 membered heterocyclic group;
  • Each R 1 is independently selected from hydrogen, halogen, -CN, -NO 2 , oxo, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 carbocyclic ring Group, 3-6 membered heterocyclic group, C 6-10 aryl group, 5-10 membered heteroaryl group, -OR 5 , -NR 7 R 8 , -O(CH 2 ) s OR 17 , -O(CH 2 ) s NR 18 R 19 , -NR 20 (CH 2 ) t NR 21 R 22 , -NR 23 (CH 2 ) t OR 24 ; wherein the C 1-4 alkyl group, C 2-4 alkenyl group, C 2-4 alkynyl, C 3-6 carbocyclic group, 3-6 membered heterocyclic group, C 6-10 aryl group, 5-10 membered heteroaryl group are optionally substituted by one or more substituents; Substituents are
  • M is selected from -O-, -NR 1a -or -CR 1b R 1c -;
  • R 1a is selected from hydrogen, C 1-3 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group or not present;
  • R 1b and R 1c are each independently selected from hydrogen, C 1-3 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group, -OR 1d , -NR 1e R 1f or not present;
  • R 1d , R 1e , and R 1f are each independently selected from hydrogen, C 1-3 alkyl, C 3-6 cycloalkyl or 3-6 membered heterocyclic group;
  • Y 1 is selected from -NR 3a -or -CR 3b R 3c -;
  • R 3a is selected from hydrogen, C 1-3 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group or not present;
  • R 3b and R 3c are each independently selected from hydrogen, C 1-3 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group or not present;
  • Y 2 is selected from -NR 4a -or -CR 4b R 4c -;
  • R 4a is selected from hydrogen, C 1-3 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group or not present;
  • R 4b and R 4c are each independently selected from hydrogen, C 1-3 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group or not present;
  • the ring D is a C 6-10 aryl group, a 5-10 membered heteroaryl group, a C 3-8 carbocyclic group or a 3-8 membered heterocyclic group; wherein, the C 3-8 carbocyclic group or a 3-
  • the 8-membered heterocyclic group optionally contains a double bond;
  • R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , -NR 23 and R 24 are each independently selected from hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 carbocyclic group, 3-10 member Heterocyclic group, C 6-10 aryl group, 5-10 membered heteroaryl group;
  • p 0, 1, 2 or 3;
  • q 0, 1, 2, 3 or 4;
  • r 0, 1, 2, 3 or 4;
  • s is 1, 2, 3 or 4;
  • t is 1, 2, 3, or 4.
  • ring A is selected from a 6-10 membered heteroaryl group or a 6-10 membered heterocyclic group; the 6-10 membered heterocyclic group contains at least one double bond.
  • ring A is selected from pyridyl, pyrazinyl, pyrimidinyl, indolyl or pyrimidinonyl.
  • ring A is selected from Wherein, X1 and X2 are each independently selected from -NR 1 -or -CR 1 R 1 -.
  • ring A is selected from
  • ring A is selected from
  • ring A is selected from
  • the ring C is selected from 3-10 membered heterocyclic groups.
  • the ring C is selected from morpholinyl, piperazinyl or piperidinyl.
  • the ring C is selected from a C6-10 aryl group or a 5-10 membered heteroaryl group.
  • the ring C is selected from the group consisting of pyrazolyl, imidazolyl, pyrrolyl, pyridyl, pyrimidinyl, indolyl, indolinyl, isoindolinyl, indolyl Azolyl, benzimidazolyl, purinyl, benzisoxazolyl, or indolazinyl.
  • the ring C is selected from phenyl
  • the ring C is selected from phenyl.
  • R c1 and R c2 are each independently selected from hydrogen, halogen, C 1-4 alkyl, and -OR 5 .
  • R c1 and R c2 are each independently selected from hydrogen, -CH 3 , -F, and -OH.
  • R c1 and R c2 are each independently selected from hydrogen.
  • R c1 and R c2 together with the atoms to which they are attached form a cyclopropyl group.
  • each R 1 is independently selected from hydrogen, oxo, -CH 3 , -NH 2 , and -CH 2 OH.
  • M is selected from -O- or -CR 1b R 1c -.
  • R 1b and R 1c are each independently selected from hydrogen, C 1-3 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, -OR 1d Or -NR 1e R 1f .
  • Y 1 is selected from -NR 3a -, and Y 2 is selected from -CR 4b R 4c -.
  • Y 1 is selected from -CR 3b R 3c -, and Y 2 is selected from -NR 4a -.
  • Y 1 is selected from -CR 3b R 3c -
  • Y 2 is selected from -CR 4b R 4c -.
  • the ring D is a C 6-10 aryl group or a 5-10 membered heteroaryl group.
  • the ring D is
  • each R 4 is independently selected from hydrogen, halogen, oxo, C 1-8 alkyl, or -OR 5 .
  • each R 4 is independently selected from hydrogen, oxo, -CH 3 or -OCH 3 .
  • q is 0, 1, or 2.
  • r is 0, 1, 2 or 3.
  • s is 1 or 2.
  • t is 1 or 2.
  • the compound of Formula I or a pharmaceutically acceptable salt, cis-trans isomer, tautomer, solvate, chelate, non-covalent complex or prodrug thereof, is selected Self-Form III:
  • Ring A is selected from a 5-10 membered heteroaryl group or a 5-10 membered heterocyclic group; wherein the 5-10 membered heteroaryl group or the 5-10 membered heterocyclic group contains one or more O, N or S heteroatom; the 5-10 membered heterocyclic group contains at least one double bond;
  • Ring C is selected from C 3-10 carbocyclic group, 3-10 membered heterocyclic group, C 6-10 aryl group or 5-10 membered heteroaryl group;
  • Each R 1 is independently selected from hydrogen, halogen, -CN, -NO 2 , oxo, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 carbocyclic ring Group, 3-6 membered heterocyclic group, C 6-10 aryl group, 5-10 membered heteroaryl group, -OR 5 , -NR 7 R 8 , -O(CH 2 ) s OR 17 , -O(CH 2 ) s NR 18 R 19 , -NR 20 (CH 2 ) t NR 21 R 22 , -NR 23 (CH 2 ) t OR 24 ; wherein the C 1-4 alkyl group, C 2-4 alkenyl group, C 2-4 alkynyl, C 3-6 carbocyclic group, 3-6 membered heterocyclic group, C 6-10 aryl group, 5-10 membered heteroaryl group are optionally substituted by one or more substituents; Substituents are
  • M is selected from -O-, -NR 1a -or -CR 1b R 1c -;
  • R 1a is selected from hydrogen, C 1-3 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group or not present;
  • R 1b and R 1c are each independently selected from hydrogen, C 1-3 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group, -OR 1d , -NR 1e R 1f or not present;
  • R 1d , R 1e , and R 1f are each independently selected from hydrogen, C 1-3 alkyl, C 3-6 cycloalkyl or 3-6 membered heterocyclic group;
  • Y 1 is selected from -NR 3a -or -CR 3b R 3c -;
  • R 3a is selected from hydrogen, C 1-3 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group or not present;
  • R 3b and R 3c are each independently selected from hydrogen, C 1-3 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group or not present;
  • Y 2 is selected from -NR 4a -or -CR 4b R 4c -;
  • R 4a is selected from hydrogen, C 1-3 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group or not present;
  • R 4b and R 4c are each independently selected from hydrogen, C 1-3 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group or not present;
  • the ring D is a C 6-10 aryl group, a 5-10 membered heteroaryl group, a C 3-8 carbocyclic group or a 3-8 membered heterocyclic group; wherein, the C 3-8 carbocyclic group or a 3-
  • the 8-membered heterocyclic group optionally contains a double bond;
  • R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , -NR 23 and R 24 are each independently selected from hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 carbocyclic group, 3-10 member Heterocyclic group, C 6-10 aryl group, 5-10 membered heteroaryl group;
  • p 0, 1, 2 or 3;
  • q 0, 1, 2, 3 or 4;
  • r 0, 1, 2, 3 or 4;
  • s is 1, 2, 3 or 4;
  • t 1, 2, 3 or 4;
  • ring A is selected from a 6-10 membered heteroaryl group or a 6-10 membered heterocyclic group; the 6-10 membered heterocyclic group contains at least one double bond.
  • ring A is selected from pyridyl, pyrazinyl, pyrimidinyl, indolyl or pyrimidinonyl.
  • ring A is selected from Wherein, X 1 and X 2 are each independently selected from -NR 1 -or -CR 1 R 1 -.
  • ring A is selected from
  • ring A is selected from
  • ring A is selected from
  • the ring C is selected from a C 3-10 carbocyclic group or a 3-10 membered heterocyclic group.
  • the ring C is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, morpholinyl, piperazinyl or piperidinyl.
  • each R 1 is independently selected from hydrogen, oxo, -CH 3 , -NH 2 , and -CH 2 OH.
  • M is selected from -O- or -CR 1b R 1c -.
  • R 1b and R 1c are each independently selected from hydrogen, C 1-3 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, -OR 1d Or -NR 1e R 1f .
  • Y 1 is selected from -NR 3a -, and Y 2 is selected from -CR 4b R 4c -.
  • Y 1 is selected from -CR 3b R 3c -, and Y 2 is selected from -NR 4a -.
  • Y 1 is selected from -CR 3b R 3c -
  • Y 2 is selected from -CR 4b R 4c -.
  • the ring D is a C 6-10 aryl group or a 5-10 membered heteroaryl group.
  • the ring D is
  • the ring D is
  • the ring D is
  • the ring D is a C 3-8 carbocyclic group or a 3-8 membered heterocyclic group.
  • the ring D is
  • each R 4 is independently selected from hydrogen, halogen, oxo, C 1-8 alkyl, or -OR 5 .
  • each R 4 is independently selected from hydrogen, oxo, -CH 3 or -OCH 3 .
  • q is 0, 1, or 2.
  • r is 0, 1, 2 or 3.
  • s is 1 or 2.
  • t is 1 or 2.
  • the compound of formula I is selected from:
  • the present invention also provides a pharmaceutical composition characterized by comprising a therapeutically effective amount of at least one compound represented by formula I and at least one pharmaceutically acceptable excipient.
  • the present invention further provides a pharmaceutical composition, characterized in that the mass percentage of the therapeutically effective amount of at least one compound represented by formula I and pharmaceutically acceptable excipients is 0.0001:1-10.
  • the present invention provides the application of the compound or pharmaceutical composition represented by structural formula I in the preparation of medicines.
  • the application is an application for preparing a medicine for treating, preventing, delaying or preventing cancer, cancer metastasis, cardiovascular disease, immune disease, fibrosis or eye disease.
  • the application is an application in preparing a medicine for treating diseases mediated by SHP2.
  • the disease is cancer.
  • the cancer is selected from Noonan syndrome, leopard spot syndrome, juvenile myelomonocytic leukemia, neuroblastoma, melanoma, head and neck squamous cell carcinoma, acute myeloid leukemia, breast cancer, esophageal tumor , Lung cancer, colon cancer, head cancer, stomach cancer, lymphoma, glioblastoma, pancreatic cancer or a combination thereof.
  • the application is an application for preparing an SHP2 inhibitor.
  • the present invention also provides a method for treating and/or preventing diseases mediated by SHP2, which comprises administering a therapeutically effective amount of at least any one compound or pharmaceutical composition represented by structural formula I to a subject.
  • the SHP2-mediated disease is cancer.
  • the present invention also provides a method for treating cancer, which comprises administering a therapeutically effective amount of at least any one compound or pharmaceutical composition represented by structural formula I to a subject.
  • the cancer is selected from Noonan syndrome, leopard spot syndrome, juvenile myelomonocytic leukemia, neuroblastoma, melanoma, head and neck squamous cell carcinoma, acute myeloid leukemia, breast cancer, esophageal tumor , Lung cancer, colon cancer, head cancer, stomach cancer, lymphoma, glioblastoma, pancreatic cancer or a combination thereof.
  • the subject to be treated is a human.
  • alkyl includes straight, branched or cyclic saturated alkyl groups.
  • alkyl groups include but are not limited to methyl, ethyl, propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, n-pentyl, 3 -(2-Methyl) butyl, 2-pentyl, 2-methylbutyl, neopentyl, cyclopentyl, n-hexyl, 2-hexyl, 2-methylpentyl and cyclohexyl and other similar groups group.
  • C 1-8 alkyl means comprising 7 or 8 carbon atoms, a straight chain, branched chain or cyclic Formally arranged groups.
  • alkenyl and alkynyl include linear, branched or cyclic alkenyl and alkynyl groups.
  • C 2-8 alkenyl and “C 2-8 alkynyl” refer to a linear, branched or cyclic arrangement containing 2, 3, 4, 5, 6, 7 or 8 carbon atoms ⁇ alkenyl or alkynyl.
  • alkoxy refers to the oxyether form of the aforementioned linear, branched or cyclic alkyl group.
  • aryl refers to an unsubstituted or substituted monocyclic or polycyclic aromatic group including carbon atoms. It is preferably a 6 to 10 membered monocyclic or bicyclic aromatic group. Preferably, it is phenyl and naphthyl. Most preferred is phenyl.
  • heteroaryl refers to a monovalent heteroatom group formed by removing a hydrogen atom from a carbon atom of a parent heteroaromatic ring system.
  • Heteroaryl groups include: 5- to 7-membered aromatic, monocyclic, including at least one heteroatom selected from N, O or S, for example, 1 to 4 heteroatoms, or preferably 1 to 3 heteroatoms, ring
  • the other atoms on the above are carbon;
  • the polyheteroaryl ring includes at least one heteroatom selected from N, O or S, for example, 1 to 4 heteroatoms, or preferably 1 to 3 heteroatoms, other atoms in the ring It is carbon, and at least one of the heteroatoms is on the aromatic ring; it also includes bicyclic or polycyclic rings, but at least one of the bicyclic or polycyclic rings is aromatic.
  • heteroaryl groups are C 3-10 heteroaryl groups, including, but not limited to, pyrrolyl, furyl, thienyl, pyridyl, pyranyl, pyrazolyl, pyrimidinyl, pyridazinyl, Pyrazinyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, triazolyl, indolyl, benzofuranyl, benzothiazolyl, benzimidazolyl, benzopyrazolyl, benzene And similar groups such as triazolyl, carbazolyl, quinolinyl, isoquinolinyl, purinyl and the like.
  • the heteroaryl group and the aryl group will not cross each other or contain each other. Therefore, according to the above definition, if at least one all-carbon aromatic ring is fused with a heterocyclic group, the result is a heteroaryl group instead of an aryl group.
  • Carbocyclic group refers to a saturated or unsaturated cyclic group that is not aromatic. According to its specific level of saturation, the terms “cycloalkyl”, “cycloalkenyl” or “cycloalkynyl” are used respectively.
  • Representative carbocyclic groups include, but are not limited to, cyclopropane, cyclobutane, cyclopentane, cyclohexane, or cyclohexene and similar groups.
  • Heterocyclic group refers to a saturated or unsaturated but not aromatic cyclic group, and one or more of the carbon atoms (and the attached hydrogen atom) can be respectively the same or different hetero Atom and the corresponding attached hydrogen atom are replaced.
  • Representative heteroatoms that replace carbon atoms include, but are not limited to, N, P, O, S, and Si. When a specific degree of saturation needs to be described, the terms “heterocycloalkyl” or “heterocycloalkenyl” are used respectively.
  • heterocyclic groups include but are not limited to epoxy compounds, imidazolidine, morpholine, piperazine, piperidine, pyrazolidine, pyrrolidine, quinuclidine, tetrahydrofuran or tetrahydropyran and similar groups .
  • the heterocycloalkyl group and the carbocyclic group will not cross each other or contain each other. Therefore, according to the above definition, if at least one all-carbocyclic ring is fused with a heterocycloalkyl group to form a di-, poly- or spiro-ring, it will still be defined as a heterocycloalkyl group.
  • heteroaryl group is fused with a heterocyclic group to form a di-, poly- or spiro-ring, it will be defined as a heterocyclic group instead of a heteroaryl group.
  • Halogen refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I). Preferred halogen refers to fluorine, chlorine and bromine.
  • Halo refers to a fluoro, chloro, bromo or iodo group.
  • the preferred halo groups refer to fluoro and chloro.
  • substitution means that one or more hydrogen atoms in a group are replaced by the same or different substituents.
  • substituents include, but are not limited to, halogen, amino, hydroxyl, oxo, carbonyl, cyano, -C(O)NH 2 , alkyl, alkoxy, aryl, cycloalkyl, heterocyclyl , Heteroaryl.
  • the substituent includes, but is not limited to, halogen, amino, hydroxyl, cyano, methyl, -CH 2 OH, -C(O)NH 2 , -OCH 3 , trifluoromethyl.
  • alkyl or aryl or its prefixes appear in the name of a substituent (such as aralkyl, or dialkylamino), it shall be as described above for "alkyl” and "aryl”.
  • the definition provides a limited interpretation of the substituents.
  • the specified number of carbon atoms (such as C 1-6 ) will independently represent the number of carbon atoms in an alkyl moiety or in an alkyl moiety (where the alkyl group is the prefix stem) in a larger substituent.
  • the "compound” of the present invention includes the compound of formula I, and all pharmaceutically acceptable forms thereof. These pharmaceutically acceptable forms include salts, solvates, non-covalent complexes, chelates, stereoisomers (including diastereomers, enantiomers and racemates), cis-trans Isomers, isotope-labeled compounds, tautomers, prodrugs, or any mixture of all the above forms.
  • cis-trans isomer is a stereoisomerism that exists in certain double bond compounds or cyclic compounds. Due to the presence of double bonds or rings, the free rotation of these molecules is hindered, resulting in two isomers with different physical or chemical properties, called cis and trans isomers, respectively.
  • the “pharmaceutically acceptable” refers to those that are well-known for use in animals, especially those that can be used in humans.
  • composition in the present invention includes a product containing a specific amount of a specific component, and also includes any product obtained directly or indirectly from a specific amount of a specific component. Therefore, a pharmaceutical composition including the compound of the present invention as an active ingredient and a method for preparing the compound are the content of the present invention.
  • “Therapeutically effective amount” means that when a compound is administered to a subject to treat and prevent and/or inhibit at least one clinical symptom of a disease, condition, symptom, indication, and/or discomfort, it is sufficient for the disease, condition, A dose that produces a certain effect for the treatment of symptoms, indications or discomfort.
  • the specific "effective therapeutic dose” may vary according to the compound, the route of administration, the age of the patient, the weight of the patient, the type of disease or discomfort to be treated, the symptoms and severity, etc. Whenever possible, an appropriate dose may be obvious to those skilled in the art, or it may be determined by conventional experimental methods.
  • the compounds provided by the present invention may exist in the form of "pharmaceutically acceptable salts".
  • the salts of the compounds provided by the present invention refer to non-toxic pharmaceutically acceptable salts.
  • the form of a pharmaceutically acceptable salt includes a pharmaceutically acceptable acid/anion or base/cation salt.
  • Pharmaceutically acceptable acid/anionic salts generally exist in the form of protonation of basic nitrogen with inorganic or organic acids.
  • Typical organic or inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, perchloric acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, propionic acid, glycolic acid, lactic acid, succinic acid, maleic acid, fumaric acid, malic acid , Tartaric acid, citric acid, ⁇ -ketoglutaric acid, hippuric acid, benzoic acid, mandelic acid, methanesulfonic acid, isethionic acid, benzenesulfonic acid, oxalic acid, pamoic acid, 2-naphthalenesulfonic acid, p-toluenesulfonic acid Acid, cyclohexylamine sulfonic acid, salicylic acid, saccharinic acid or trifluoroacetic acid.
  • Pharmaceutically acceptable base/cation salts including, but not limited to, aluminum salt, calcium salt, chloroprocaine salt, choline, diethanolamine
  • the prodrug of the compound of the present invention is included in the protection scope of the present invention.
  • the prodrug is a functional derivative that is easily converted into the desired compound in the body. Therefore, the term "administration" involved in the treatment method provided by the present invention includes the administration of the compound disclosed in the present invention, or although it is not clearly disclosed but can be converted into the compound disclosed in the present invention in vivo after administration to the subject. disease.
  • the conventional methods for selecting and preparing suitable prodrug derivatives have been described in books such as "Design of Prodrugs” (Design of Prodrugs, ed. H. Bundgaard, Elsevier, 1985).
  • any substituent or variable at a specific position in one molecule is irrelevant to the definition of any substituent or variable at a specific position in other molecules. It is easy to understand that the compound of the present invention can be selected according to the prior art of the subject to select suitable substituents or substitution forms to provide chemically stable and easy preparation and synthesis using the prior art of the subject or the method described in the present invention.
  • the present invention includes any possible solvate and polymorph.
  • the type of solvent that forms the solvate is not particularly limited, as long as the solvent is pharmacologically acceptable.
  • water, ethanol, propanol, acetone and similar solvents can be used.
  • pharmaceutically acceptable salt refers to a salt prepared from a pharmaceutically acceptable non-toxic base or acid.
  • pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases.
  • Salts derived from inorganic bases include aluminum, ammonium, calcium, copper (ic and ous), iron, ferrous, lithium, magnesium, manganese (ic and ous), potassium, sodium, zinc and the like. In particular, salts of ammonium, calcium, magnesium, potassium, and sodium are preferred.
  • non-toxic organic bases that can be derivatized into pharmaceutically acceptable salts include primary, secondary and tertiary amines, as well as cyclic amines and amines containing substituents, such as naturally occurring and synthetic amines containing substituents.
  • non-toxic organic bases capable of forming salts, including ion exchange resins and arginine, betaine, caffeine, choline, N',N'-dibenzylethylenediamine, diethylamine, 2 -Diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, reduced glucosamine, glucosamine, histidine, haamine, isopropylamine , Lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resin, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc.
  • the corresponding salt can be prepared from pharmaceutically acceptable non-toxic acids, including inorganic acids and organic acids.
  • acids include, for example, acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, isethionic acid, formic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, Hydrochloric acid, lactic acid, maleic acid, malic acid, mandelic acid, ⁇ -ketoglutaric acid, hippuric acid, methanesulfonic acid, mucic acid, nitric acid, hexanoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, p-toluenesulfonate Sour etc.
  • malic acid citric acid, hydrobromic acid, hydrochloric acid, methanesulfonic acid, maleic acid, phosphoric acid, sulfuric acid and tartaric acid. More preferably, phosphoric acid, hydrochloric acid and malic acid. Since the compound of formula I will be used as a pharmaceutical, it is preferred to use a substantially pure form, for example, at least 60% purity, more suitably at least 75% purity, particularly suitably at least 98% purity (% is a weight ratio).
  • the pharmaceutical composition provided by the present invention includes the compound represented by formula I (or a pharmaceutically acceptable salt thereof) as an active component, a pharmaceutically acceptable excipient, and other optional therapeutic components or adjuvants.
  • the pharmaceutical composition of the present invention includes oral, rectal, topical and Pharmaceutical compositions for parenteral administration (including subcutaneous administration, intramuscular injection, and intravenous administration).
  • the pharmaceutical composition of the present invention can be conveniently prepared in a unit dosage form known in the art and prepared by any preparation method known in the pharmaceutical field.
  • the compound represented by formula I of the present invention can be used in combination as an active component and mixed with a drug carrier to form a drug combination Things.
  • the pharmaceutical carrier can take various forms, depending on the desired mode of administration, for example, oral or injection (including intravenous injection). Therefore, the pharmaceutical composition of the present invention may take the form of a separate unit suitable for oral administration, such as a capsule, cachet or tablet containing a predetermined dose of the active ingredient.
  • the pharmaceutical composition of the present invention may take the form of powder, granule, solution, aqueous suspension, non-aqueous liquid, oil-in-water emulsion, or water-in-oil emulsion.
  • the compound represented by Formula I or a pharmaceutically acceptable salt thereof can also be administered by a controlled release method and/or a delivery device.
  • the pharmaceutical composition of the present invention can be prepared by any pharmaceutical method. Generally, this method includes the step of associating the active ingredient with the carrier constituting one or more necessary ingredients.
  • the pharmaceutical composition is prepared by uniformly and intimately mixing the active ingredient with a liquid carrier or a finely divided solid carrier or a mixture of the two.
  • the product can be easily prepared into the desired appearance.
  • the pharmaceutical composition of the present invention includes a pharmaceutically acceptable carrier and a compound represented by formula I, or a pharmaceutically acceptable salt thereof.
  • the compound represented by formula I, or a pharmaceutically acceptable salt thereof, and one or more other compounds having therapeutic activity in combination are also included in the pharmaceutical composition of the present invention.
  • the drug carrier used in the present invention can be, for example, a solid carrier, a liquid carrier or a gas carrier.
  • solid carriers include lactose, gypsum powder, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid, mannitol, sorbitol, microcrystalline cellulose, inorganic salts , Starch, pregelatinized starch, powdered sugar, dextrin, etc.
  • liquid carriers include syrup, peanut oil, olive oil and water.
  • gas carriers include carbon dioxide and nitrogen.
  • water, ethylene glycol, oils, alcohols, flavor enhancers, preservatives, coloring agents, etc. can be used for oral liquid preparations such as suspensions, elixirs and solutions; and carriers such as starches, sugars, Microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, etc. can be used in oral solid preparations such as powders, capsules and tablets. In view of ease of administration, tablets and capsules are preferred for oral preparations. Alternatively, standard aqueous or non-aqueous formulation techniques can be used for tablet coating.
  • Tablets containing the compound or pharmaceutical composition of the present invention can be prepared by, optionally, mixing, compression or molding with one or more auxiliary components or adjuvants.
  • the active ingredient is in a free-flowing form such as powder or granules, mixed with lubricants, inert diluents, surface active or dispersing agents, and compressed in a suitable machine to produce compressed tablets.
  • the powdered compound or pharmaceutical composition is soaked with an inert liquid diluent, and then molded in a suitable machine to form a molded tablet.
  • each tablet contains about 0.01 mg to 5 g of active ingredient, and each cachet or capsule contains about 0.1 mg to 0.5 g of active ingredient.
  • a dosage form intended for oral administration to humans contains about 0.1 mg to about 0.5 g of active ingredient, compounded with a suitable and convenient metering auxiliary material, which accounts for about 5% to 99.99% of the total pharmaceutical composition.
  • the unit dosage form generally contains about 0.1mg to about 0.5g of effective ingredients, typically 0.1mg, 0.2mg, 0.5mg, 1mg, 2mg, 2.5mg, 5mg, 10mg, 25mg, 50mg, 100mg, 200mg, 300mg, 400mg Or 500mg.
  • the pharmaceutical composition suitable for parenteral administration provided by the present invention can be prepared as an aqueous solution or suspension by adding active components into water.
  • Suitable surfactants such as sodium lauryl sulfate, polysorbate-80 (Tween-80), polyoxyethylene hydrogenated castor oil, and poloxamer may be included.
  • glycerol liquid polyethylene glycol, and their mixture in oil, dispersion systems can also be prepared.
  • a preservative may also be included in the pharmaceutical composition of the present invention to prevent the growth of harmful microorganisms.
  • the present invention provides pharmaceutical compositions suitable for injection use, including sterile aqueous solutions or dispersion systems.
  • the above-mentioned pharmaceutical composition can be prepared in the form of a sterile powder that can be used for immediate preparation of sterile injections.
  • the final injection form must be sterile, and for easy injection, it must be easy to flow.
  • the pharmaceutical composition must be stable during preparation and storage. Therefore, preservation against contamination by microorganisms such as bacteria and fungi is preferred.
  • the carrier can be a solvent or dispersion medium, for example, water, ethanol, polyol (such as glycerol, propylene glycol, liquid polyethylene glycol), vegetable oil, and suitable mixtures thereof.
  • the pharmaceutical composition provided by the present invention may be in a form suitable for topical administration, for example, aerosol, emulsion, ointment, lotion, dusting, or other similar dosage forms. Further, the pharmaceutical composition provided by the present invention can be in a form suitable for use in a transdermal drug delivery device.
  • These preparations can be prepared by using the compound represented by formula I of the present invention, or a pharmaceutically acceptable salt thereof, through conventional processing methods.
  • an emulsion or ointment is prepared by adding a hydrophilic material and water (the total amount of the two is about 5% to 50% by weight of the compound) to prepare a cream or ointment with the expected consistency.
  • the pharmaceutical composition provided by the present invention can be made into a form suitable for rectal administration with a solid as a carrier. Suppositories in which the mixture forms a unit dose are the most preferred dosage form. Suitable auxiliary materials include cocoa butter and other materials commonly used in the art. Suppositories can be conveniently prepared. First, the pharmaceutical composition is mixed with softened or melted excipients, and then cooled and molded.
  • the above-mentioned pharmaceutical preparations may also include, as appropriate, one or more additional adjuvant components, such as diluents, buffers, flavoring agents, binders, surfactants, and additives. Thickeners, lubricants, preservatives (including antioxidants), etc. Further, other adjuvants may also include penetration enhancers that regulate the isotonic pressure between the drug and the blood.
  • additional adjuvant components such as diluents, buffers, flavoring agents, binders, surfactants, and additives. Thickeners, lubricants, preservatives (including antioxidants), etc.
  • other adjuvants may also include penetration enhancers that regulate the isotonic pressure between the drug and the blood.
  • the pharmaceutical composition containing the compound represented by Formula I, or a pharmaceutically acceptable salt thereof can also be prepared in the form of a powder or a concentrated solution.
  • DIEA N,N-diisopropylethylamine
  • DIBAL-H diisobutyl aluminum hydride
  • DMSO dimethyl sulfoxide
  • NEt 3 Triethylamine
  • Prep-HPLC Preparative high performance liquid chromatography
  • PdCl 2 (PPh 3 ) 2 Bistriphenylphosphorus palladium dichloride
  • Pd(PPh 3 ) 4 Tetrakis (triphenylphosphine) palladium
  • PE petroleum ether
  • rt, r.t. or RT room temperature
  • TFA trifluoroacetic acid
  • THF Tetrahydrofuran
  • Ti(OEt) 4 tetraethyl titanate
  • the intermediate M11 listed in Table 1 was prepared by using different reaction starting materials and appropriate reagents (the raw materials and reagents are commercially available), using a method similar to the foregoing intermediate M1-7.
  • reaction solution was quenched with 200 mL saturated brine, extracted with EtOAc (300 mL ⁇ 2), and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 11.06 g of compound M30-5.
  • Example 1 Compound A01 (3-(5-((S)-1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(hydroxymethyl (Pyrazine-2-yl)-1-phenylprop-2-yn-1-ol) preparation:
  • Example 99 Compound A75(S)-1-(3-(5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-( Preparation of (hydroxymethyl)pyrazin-2-yl)prop-2-yn-1-yl)-1H-indazol-5-ol:
  • Example 100 Compound A76(S)-(3-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(3-(5- Preparation of amino-1H-indol-1-yl)prop-1-yn-1-yl)pyrazin-2-yl)methanol:
  • Example 101 Compound A77(S)-N-(1-(3-(5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)- Preparation of 6-(hydroxymethyl)pyrazin-2-yl)prop-2-yn-1-yl)-1H-indazol-5-yl)acetamide:
  • Example 102 Compound A78(S)-(3-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(3-(6- Preparation of amino-1H-indazol-1-yl)prop-1-yn-1-yl)pyrazin-2-yl)methanol:
  • Example 103 Compound A79(S)-(3-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(3-(4- Preparation of amino-1H-indazol-1-yl)prop-1-yn-1-yl)pyrazin-2-yl)methanol:
  • the M1 1g material was dissolved in 1,4-dioxane and 20 mL of methanol 5mL, N 2 substitutions, ethyl acetate was added dropwise 1.52mL of hydrochloric acid solution (2M), room temperature for 1h.
  • Example 104 Compound A80(S)-1-(3-(5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-( Preparation of (hydroxymethyl)pyrazin-2-yl)prop-2-yn-1-yl)-1H-indazole-5-carboxamide:
  • Example 105 Compound A81(S)-N-(1-(3-(5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)- 6-(Hydroxymethyl)pyrazin-2-yl)prop-2-yn-1-yl)-1H-indazol-4-yl)acetamide and preparation:
  • Example 106 Compound A82(S)-1-(3-(5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-( (Hydroxymethyl)pyrazin-2-yl)prop-2-yn-1-yl)-1H-benzo[d]imidazole-5-carboxamide and compound A83(S)-1-(3-(5- (1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(hydroxymethyl)pyrazin-2-yl)prop-2-yne- Preparation of 1-yl)-1H-benzo[d]imidazole-6-carboxamide:
  • Example 12 Compound A12((S)-2-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(3 ,4-Dihydroxyphenyl)prop-1-yn-1-yl)-3-methylpyrimidine-4(3H)-one):
  • Example 10 Compound A10((S)-2-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(4 -Preparation of chloro-3-hydroxyphenyl)prop-1-yn-1-yl)-3-methylpyrimidine-4(3H)-one):
  • Example 19 Compound A19 ((S)-2-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(3 ,4-Difluorophenyl)prop-1-yn-1-yl)-3-methylpyrimidine-4(3H)-one):
  • Example 87 Compound A66(2-((S)-1-amino-1,3-dihydrospiro[indene-2,4'piperidine]-1'-yl)-5-(2-oxo-8 -Azaspiro[4.5]dec-8-yl)3-hydroxy-3-(4-morpholinphenyl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one ) Preparation:
  • Example 45 Compound A45 ((S)-2-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(3 -Hydroxyphenyl)prop-1-yn-1-yl)pyrimidine-4(3H)-one) preparation:
  • Example 75 Compound D04 (2-((5-((S)-1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-( (Hydroxymethyl)pyrazin-2-yl)ethynyl)cyclopropane-1-carboxylic acid ethyl ester) preparation:
  • Example 90 Compound D13(2-((5-((S)-1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-( (Hydroxymethyl)pyrazin-2-2-yl)ethynyl)cyclopropaneamide) preparation:
  • Example 78 Compound D07(2-((2-((S)-1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-1-methyl Preparation of 6-oxo-1,6-dihydropyrimidin-5-yl)ethynyl)cyclopropane-1-carboxylic acid ethyl ester:
  • Example 72 Compound D01(2-((S)-1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-((2-( Preparation of hydroxymethyl)cyclopropyl)ethynyl)-3-methylpyrimidine-4(3H)-one):
  • Example 74 Compound D03 (5-((2-(1,3,4-oxadiazol-2-yl)cyclopropyl)ethynyl)-2-((S)-1-amino-1,3- Preparation of dihydrospirocyclo[indene-2,4'-piperidine]-1'-yl)-3-methylpyrimidin-4(3H)-one):
  • SHP2 is allosterically activated by the binding of a bis-tyrosyl-phosphorylated peptide to its Src homology 2 (SH2) domain. This subsequent activation step results in the release of the SHP2 auto-inhibitory interface, which in turn activates the SHP2 protein tyrosine phosphatase (PTP) and can be used for substrate recognition and reaction catalysis.
  • PTP protein tyrosine phosphatase
  • the surrogate DiFMUP was used to monitor the catalytic activity of SHP2 in the rapid fluorescence assay format.
  • the compound of the present invention (10mM stock solution) was diluted to an appropriate multiple with 100% DMSO.
  • the final test concentration of the compound of the present invention was 10 ⁇ M, 3.3333 ⁇ M, 1.1111 ⁇ M, 0.3704 ⁇ M, 0.1235 ⁇ M, 0.0412 ⁇ M, 0.0137 ⁇ M, 0.0046 ⁇ M, 0.0015 ⁇ M , 0.00 ⁇ M;
  • Inhibition rate% [1-(Conversion_ sample -Conversion_ min )/(Conversion_ max -Conversion_ min )] ⁇ 100%
  • Conversion_sample is the conversion rate reading of the sample
  • Conversion_min is the average value of the blank control well, representing the conversion rate reading of the wells without enzyme activity
  • Conversion_max is the average value of the positive control wells, representing the conversion rate reading of the wells without compound inhibition.
  • the analysis software GraphPad Prism log (inhibitor) vs. response-Variable slope was used to fit the dose-effect curve, and the IC 50 value of the compound to the enzyme activity was calculated.
  • the compound of the present invention has an allosteric inhibitory effect on the SHP2 protein.
  • CCG CELL TITER-GLO
  • ATP participates in a variety of enzymatic reactions in organisms and is an indicator of living cell metabolism, its content directly reflects the number and cell state of cells.
  • CellTiter-Glo TM reagent was added to the cell culture medium to measure the luminescence value. The value is directly proportional to the amount of ATP, and ATP is positively related to the number of living cells, so cell viability can be inspected by detecting ATP content.
  • NCI-H358 cells were cultured for 96hrs, 50 ⁇ L of Luminescent Cell Viability Assay solution, gently shake for 2mins, and continue to incubate for 10mins at room temperature.
  • the cell reaction system was transferred to a 96-well plate with a white background. Read the detection value of each well on the multi-function microplate reader.
  • MV-4-11 cells are cultured for 120hrs, add 50 ⁇ L to each well Luminescent Cell Viability Assay solution, gently shake for 2mins, continue to incubate for 10mins at room temperature, and read the detection value of each well on the multifunctional microplate reader.
  • Inhibition rate% (1-(administration group value-zero adjustment group value)/(blank group value-zero adjustment group value)*100
  • the compound of the present invention has a good inhibitory effect on the proliferation of MV-4-11 cells and NCI-H358 cells.
  • Example C In vivo drug efficacy experiment on subcutaneous xenograft tumor model of MIA-PaCa2 cells
  • the compound of the present invention exhibits a significant anti-tumor effect in a subcutaneous xenograft tumor model of MIA-PaCa2 cells.
  • the TGI and body weight changes of the solvent control group and compound A68 on day 24 are shown in Table 11.

Abstract

The present invention relates to a compound (as represented by formula I) serving as an Src homology region 2-containing protein tyrosine phosphatase 2 (SHP2) inhibitor, a pharmaceutical composition thereof, a preparation method therefor, and the use thereof in the treatment of SHP2-mediated diseases. The compound has an effect by means of participating in the regulation of multiple processes, such as cell proliferation, apoptosis, migration and angiogenesis.

Description

SHP2抑制剂及其组合物和应用SHP2 inhibitor and its composition and application 技术领域Technical field
本发明涉及一系列作为含Src同源区2蛋白质酪氨酸磷酸酶2(Src homologyregion 2-containing protein tyrosine phosphatase 2,SHP2)抑制剂的化合物及其制备方法、药物组合物。本发明还涉及上述化合物或其药物组合物在治疗SHP2介导的疾病中的用途。The present invention relates to a series of compounds as inhibitors of Src homology region 2 (Src homology region 2-containing protein tyrosine phosphatase 2, SHP2), and preparation methods and pharmaceutical compositions thereof. The present invention also relates to the use of the above-mentioned compound or its pharmaceutical composition in the treatment of SHP2-mediated diseases.
背景技术Background technique
含Src同源区2蛋白质酪氨酸磷酸酶2(Src homologyregion 2-containing protein tyrosine phosphatase 2,SHP2)是由一种由PTPN11基因编码的非受体型蛋白质酪氨酸磷酸酶，PTPN11是首个被发现的编码酪氨酸激酶的原癌基因(Chan R J et al.PTPN11 is the first identified proto-oncogene that encodes a tyrosine phosphatase.Blood,2007,109:862-867)，其编码的SHP2蛋白包含N端的SHP2结构域(N-SHP2)、C端SHP2结构域(C-SHP2)、蛋白质磷酸酶催化结构域(PTP)，两个C端的酪氨酸残基(Y542和Y580)以及一个富含脯氨酸(Pro)的模体。Src homology region 2 protein tyrosine phosphatase 2 (Src homology region 2-containing protein tyrosine phosphatase 2, SHP2) is a non-receptor protein tyrosine phosphatase encoded by the PTPN11 gene, and PTPN11 is the first The discovered proto-oncogene encoding tyrosine kinase (Chan R J et al.PTPN11 is the first identified proto-oncogene that encodes a tyrosine phosphatase.Blood, 2007,109:862-867), and the encoded SHP2 protein contains N-terminal SHP2 domain (N-SHP2), C-terminal SHP2 domain (C-SHP2), protein phosphatase catalytic domain (PTP), two C-terminal tyrosine residues (Y542 and Y580) and a rich Proline (Pro) motif.
近年研究主要认为Ras/ERK通路是SHP2发挥作用最重要的一条信号转导通路，其机制(Dance M et al.The molecular functions of Shp2 in the RAS/mitogen-activated protein kinase(ERK1/2)pathway.Cell Signal,2008,20:453-459)大致为：生长因子受体活化后，其酪氨酸残基发生自体磷酸化，为Grb2和SHP2(含有SH2结构域的衔接蛋白)磷酸酪氨酸结合区域SH2提供停靠位点。Grb2与磷酸化的生长因子受体的结合导致SOS蛋白在胞膜的聚集。SOS作为一种鸟嘌呤核苷酸交换因子(guanine nucleotide exchange factor,GEF)，可以催化膜结合蛋白Ras从无活性的Ras-GDP转换为有活性的Ras-GTP。Ras-GTP再进一步与下游的信号***发生联系，激活Ser/Thr激酶Raf1等，进而在调节激酶MEK的作用下使ERK活化，ERK活化后直接作用于细胞质的靶分子或转移到细胞核内调节基因转录，使细胞增殖或分化。这一过程可能还受到SHP2结合蛋白和底物(SHP substrate-1,SHPS-1)、Ras-GTP酶活化蛋白(Ras-GAP)以及其他Src成员的影响。In recent years, research mainly believes that the Ras/ERK pathway is the most important signal transduction pathway for SHP2, and its mechanism (Dance M et al. The molecular functions of Shp2 in the RAS/mitogen-activated protein kinase (ERK1/2) pathway. Cell Signal, 2008, 20:453-459) roughly: After the growth factor receptor is activated, its tyrosine residues undergo autophosphorylation, which is the combination of Grb2 and SHP2 (adapter protein containing SH2 domain) phosphotyrosine Area SH2 provides stop points. The binding of Grb2 to phosphorylated growth factor receptors results in the accumulation of SOS protein in the cell membrane. As a guanine nucleotide exchange factor (GEF), SOS can catalyze the conversion of the membrane-bound protein Ras from inactive Ras-GDP to active Ras-GTP. Ras-GTP further connects with downstream signaling systems to activate Ser/Thr kinase Raf1, etc., and then activate ERK under the action of the regulatory kinase MEK. After activation, ERK directly acts on target molecules in the cytoplasm or transfers to the nucleus to regulate genes. Transcription to make cells proliferate or differentiate. This process may also be affected by SHP2 binding protein and substrate (SHP substrate-1, SHPS-1), Ras-GTPase activating protein (Ras-GAP) and other Src members.
SHP2蛋白不仅调节Ras/ERK信号通路，另有报道其还调节JAK-STAT3、NF-κB、PI3K/Akt、RHO和NFAT等多条信号通路，进而调节细胞增殖、分化、迁移、凋亡等生理学功能。SHP2 protein not only regulates the Ras/ERK signaling pathway, it is also reported to regulate multiple signaling pathways such as JAK-STAT3, NF-κB, PI3K/Akt, RHO, and NFAT, thereby regulating cell proliferation, differentiation, migration, apoptosis and other physiology Function.
SHP2被证明与多种疾病相关，Tartaglia等(Tartaglia M et al.Mutations in PTPN11,encoding the protein tyrosine phosphatase SHP-2,cause Noonan s炔drome.Nat Genet,2001,29:465-468)发现大约50％的努南综合征患者伴有PTPN11的错义突变。另外，研究发现PTPN11突变是JMML以及多种白血病发病的重要原因(Tartaglia M et al.Nat Genet,2003,34:148-150；Loh ML et al.Blood,2004,103:2325-2331；Tartaglia M et al.Br J Haematol,2005,129:333-339；Xu R et al.Blood,2005,106:3142-3149.)。随着对PTPN11/SHP2研究的深入，发现其与肺癌、胃癌、结肠癌、黑色素瘤、甲状腺癌等多种癌症的发生均有的关系(唐春兰等.中国肺癌杂志，2010,13:98-101；Higuchi M et al.Cancer Sci,2004,95:442-447；Bentires-Al j M et al.Cancer Res,2004,64:8816-8820；Martinelli S et al.Cancer Genet Cytogenet,2006,166:124-129.)。SHP2 has been proved to be related to many diseases. Tartaglia et al. (Tartaglia M et al. Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syne drome. Nat Genet, 2001, 29: 465-468) found about 50 % Of patients with Noonan syndrome have missense mutations of PTPN11. In addition, studies have found that PTPN11 mutation is an important cause of JMML and a variety of leukemias (Tartaglia M et al. Nat Genet, 2003, 34: 148-150; Loh ML et al. Blood, 2004, 103: 2325-2331; Tartaglia M et al. Br J Haematol, 2005, 129: 333-339; Xu R et al. Blood, 2005, 106: 3142-3149.). With the deepening of research on PTPN11/SHP2, it has been found that it is related to the occurrence of lung cancer, gastric cancer, colon cancer, melanoma, thyroid cancer and other cancers (Tang Chunlan et al. Chinese Journal of Lung Cancer, 2010, 13: 98- 101; Higuchi M et al. Cancer Sci, 2004, 95: 442-447; Bentiers-Al j M et al. Cancer Res, 2004, 64: 8816-8820; Martinelli S et al. Cancer Genet Cytogenet, 2006, 166: 124-129.).
因此，SHP2抑制剂作为潜在的治疗手段得到了越来越多的关注。目前在开发的SHP2抑制剂有多种，诺华开发的TNO155在2017年进入治疗实体瘤的I期临床试验。加科思设计开发的JAB-3068于2018年1月正式获得美国FDA新药临床实验许可。Revolution开发的RMC-4630于2018年下半年进行首次人体临床试验。目前，该靶点在国内外还未见上市品种。Therefore, SHP2 inhibitors have received more and more attention as potential treatments. There are a variety of SHP2 inhibitors currently under development. Novartis's TNO155 entered phase I clinical trials for the treatment of solid tumors in 2017. JAB-3068, designed and developed by Jacos, was officially approved by the US FDA for clinical trials of new drugs in January 2018. The RMC-4630 developed by Revolution undergoes its first human clinical trial in the second half of 2018. At present, there is no marketed product for this target at home and abroad.
在2019年9月26日公开的WO2019183367专利中披露了化合物243，并记载了在SHP2变构抑制试验中的IC 50测定数据为大于50nM，且小于等于1uM。 Compound 243 was disclosed in the WO2019183367 patent published on September 26, 2019, and it was recorded that the IC 50 measurement data in the SHP2 allosteric inhibition test was greater than 50 nM and less than or equal to 1 uM.
Figure PCTCN2021088871-appb-000001
Figure PCTCN2021088871-appb-000001
因此，开发出能够靶向抑制SHP2活性的小分子药物，为患者提供更加安全有效的SHP2抑制剂具有重要的研究意义。Therefore, the development of small molecule drugs that can target to inhibit SHP2 activity and provide patients with safer and more effective SHP2 inhibitors has important research significance.
发明内容Summary of the invention
本发明涉及一种作为含Src同源区2蛋白质酪氨酸磷酸酶2(SHP2)抑制剂的化合物，或其药学上可接受的盐、顺反异构体、互变异构体、溶剂化物、螯合物、非共价复合物或前体药物，所述化合物如式I所示：The present invention relates to a compound as an inhibitor of Src homologous region 2 protein tyrosine phosphatase 2 (SHP2), or a pharmaceutically acceptable salt, cis-trans isomer, tautomer, and solvate thereof , Chelate, non-covalent complex or prodrug, the compound is shown in formula I:
Figure PCTCN2021088871-appb-000002
Figure PCTCN2021088871-appb-000002
其中，in,
Figure PCTCN2021088871-appb-000003
为单键或双键；
Figure PCTCN2021088871-appb-000003
Single bond or double bond;
环A选自5-10元杂芳基或5-10元杂环基；其中，所述5-10元杂芳基或所述5-10元杂环基含有一个或多个O、N或S杂原子；所述5-10元杂环基至少含有一个双键；Ring A is selected from a 5-10 membered heteroaryl group or a 5-10 membered heterocyclic group; wherein the 5-10 membered heteroaryl group or the 5-10 membered heterocyclic group contains one or more O, N or S heteroatom; the 5-10 membered heterocyclic group contains at least one double bond;
环C选自C 3-10碳环基、3-10元杂环基、C 6-10芳基或5-10元杂芳基； Ring C is selected from C 3-10 carbocyclic group, 3-10 membered heterocyclic group, C 6-10 aryl group or 5-10 membered heteroaryl group;
每个R c分别独立地选自氢、卤素、-CN、-NO 2、氧代、C 1-8烷基、C 2-8烯基、C 2-8炔基、C 3-8碳环基、3-10元杂环基、C 6-10芳基、5-10元杂芳基、-OR 5、-SR 6、-NR 7R 8、-(C＝O)R 9、-C(＝O)OR 10、-C(＝O)NR 11R 12、-S(＝O) 2R 13、-S(＝O) 2OR 14、-S(＝O) 2NR 15R 16、-O(CH 2) sOR 17、-O(CH 2) sNR 18R 19、-NR 20(CH 2) tNR 21R 22、-NR 23(CH 2) tOR 24；其中，所述C 1-8烷基、C 2-8烯基、C 2-8炔基、C 3-8碳环基、3-10元杂环基、C 6-10芳基、5-10元杂芳基任选地被一个或多个取代基取代；所述取代基选自氢、卤素、-CN、-NO 2、氧代、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 3-10碳环基、3-10元杂环基、C 6-10芳基、5-10元杂芳基、-OR 5、-SR 6、-NR 7R 8、-(C＝O)R 9、-C(＝O)OR 10、-C(＝O)NR 11R 12、-S(＝O) 2R 13、-S(＝O) 2OR 14、-S(＝O) 2NR 15R 16、-O(CH 2) sOR 17、-O(CH 2) sNR 18R 19、-NR 20(CH 2) tNR 21R 22、-NR 23(CH 2) tOR 24； Each R c is independently selected from hydrogen, halogen, -CN, -NO 2 , oxo, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 carbocyclic ring Group, 3-10 membered heterocyclic group, C 6-10 aryl group, 5-10 membered heteroaryl group, -OR 5 , -SR 6 , -NR 7 R 8 , -(C=O)R 9 , -C (=O)OR 10 , -C(=O)NR 11 R 12 , -S(=O) 2 R 13 , -S(=O) 2 OR 14 , -S(=O) 2 NR 15 R 16 , -O(CH 2 ) s OR 17 , -O(CH 2 ) s NR 18 R 19 , -NR 20 (CH 2 ) t NR 21 R 22 , -NR 23 (CH 2 ) t OR 24 ; wherein, the C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 carbocyclic group, 3-10 membered heterocyclic group, C 6-10 aryl, 5-10 membered heteroaryl The group is optionally substituted by one or more substituents; the substituents are selected from hydrogen, halogen, -CN, -NO 2 , oxo, C 1-4 alkyl, C 2-4 alkenyl, C 2- 4 alkynyl, C 3-10 carbocyclic group, 3-10 membered heterocyclic group, C 6-10 aryl, 5-10 membered heteroaryl, -OR 5 , -SR 6 , -NR 7 R 8 ,- (C=O)R 9 , -C(=O)OR 10 , -C(=O)NR 11 R 12 , -S(=O) 2 R 13 , -S(=O) 2 OR 14 , -S (=O) 2 NR 15 R 16 , -O(CH 2 ) s OR 17 , -O(CH 2 ) s NR 18 R 19 , -NR 20 (CH 2 ) t NR 21 R 22 , -NR 23 (CH 2 ) t OR 24 ;
R c1,R c2分别独立地选自氢、卤素、C 1-4烷基或-OR 5； R c1 and R c2 are each independently selected from hydrogen, halogen, C 1-4 alkyl or -OR 5 ;
或R c1和R c2与它们所连接的原子一起形成C 3-6碳环基、3-6元杂环基； Or R c1 and R c2 together with the atoms to which they are connected form a C 3-6 carbocyclic group or a 3-6 membered heterocyclic group;
每个R 1分别独立地选自氢、卤素、-CN、-NO 2、氧代、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 3-6碳环基、3-6元杂环基、C 6-10芳基、5-10元杂芳基、-OR 5、-NR 7R 8、-O(CH 2) sOR 17、-O(CH 2) sNR 18R 19、-NR 20(CH 2) tNR 21R 22、-NR 23(CH 2) tOR 24；其中，所述C 1-4烷基、C 2-4烯基、C 2-4炔基、C 3-6碳环基、3-6元杂环基、C 6-10芳基、5-10元杂芳基任选地被一个或多个取代基取代；所述取代基选自氢、卤素、-CN、-NO 2、氧代、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 3-6碳环基、3-6元杂环基、C 6-10芳基、5-10元杂芳基、-OR 5、-SR 6、-NR 7R 8、-(C＝O)R 9、-C(＝O)OR 10或-C(＝O)NR 11R 12； Each R 1 is independently selected from hydrogen, halogen, -CN, -NO 2 , oxo, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 carbocyclic ring Group, 3-6 membered heterocyclic group, C 6-10 aryl group, 5-10 membered heteroaryl group, -OR 5 , -NR 7 R 8 , -O(CH 2 ) s OR 17 , -O(CH 2 ) s NR 18 R 19 , -NR 20 (CH 2 ) t NR 21 R 22 , -NR 23 (CH 2 ) t OR 24 ; wherein the C 1-4 alkyl group, C 2-4 alkenyl group, C 2-4 alkynyl, C 3-6 carbocyclic group, 3-6 membered heterocyclic group, C 6-10 aryl group, 5-10 membered heteroaryl group are optionally substituted by one or more substituents; Substituents are selected from hydrogen, halogen, -CN, -NO 2 , oxo, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 carbocyclic group, 3-6 Membered heterocyclic group, C 6-10 aryl group, 5-10 membered heteroaryl group, -OR 5 , -SR 6 , -NR 7 R 8 , -(C=O)R 9 , -C(=O)OR 10 or -C(=O)NR 11 R 12 ;
M选自-O-、-NR 1a-或-CR 1bR 1c-； M is selected from -O-, -NR 1a -or -CR 1b R 1c -;
R 1a选自氢、C 1-3烷基、C 3-6环烷基、3-6元杂环基或不存在； R 1a is selected from hydrogen, C 1-3 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group or not present;
R 1b，R 1c分别独立地选自氢、C 1-3烷基、C 3-6环烷基、3-6元杂环基、-OR 1d、-NR 1eR 1f或不存在； R 1b and R 1c are each independently selected from hydrogen, C 1-3 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group, -OR 1d , -NR 1e R 1f or not present;
R 1d，R 1e，R 1f分别独立地选自氢、C 1-3烷基、C 3-6环烷基或3-6元杂环基； R 1d , R 1e , and R 1f are each independently selected from hydrogen, C 1-3 alkyl, C 3-6 cycloalkyl or 3-6 membered heterocyclic group;
Y 1选自-NR 3a-或-CR 3bR 3c-； Y 1 is selected from -NR 3a -or -CR 3b R 3c -;
R 3a选自氢、C 1-3烷基、C 3-6环烷基、3-6元杂环基或不存在； R 3a is selected from hydrogen, C 1-3 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group or not present;
R 3b，R 3c分别独立地选自氢、C 1-3烷基、C 3-6环烷基、3-6元杂环基或不存在； R 3b and R 3c are each independently selected from hydrogen, C 1-3 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group or not present;
Y 2选自-NR 4a-或-CR 4bR 4c-； Y 2 is selected from -NR 4a -or -CR 4b R 4c -;
R 4a选自氢、C 1-3烷基、C 3-6环烷基、3-6元杂环基或不存在； R 4a is selected from hydrogen, C 1-3 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group or not present;
R 4b，R 4c分别独立地选自氢、C 1-3烷基、C 3-6环烷基、3-6元杂环基或不存在； R 4b and R 4c are each independently selected from hydrogen, C 1-3 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group or not present;
所述环D为C 6-10芳基、5-10元杂芳基、C 3-8碳环基、3-8元杂环基或不存在；其中，所述C 3-8碳环基或3-8元杂环基选择性地含有双键； The ring D is a C 6-10 aryl group, a 5-10 membered heteroaryl group, a C 3-8 carbocyclic group, a 3-8 membered heterocyclic group or not present; wherein, the C 3-8 carbocyclic group Or a 3-8 membered heterocyclic group optionally contains a double bond;
每个R 4分别独立地选自氢、卤素、-CN、-NO 2、氧代、C 1-8烷基、C 2-8烯基、C 2-8炔基、C 3-8碳环基、3-10元杂环基、C 6-10芳基、5-10元杂芳基、-OR 5、-SR 6、-NR 7R 8、-(C＝O)R 9、-C(＝O)OR 10、-C(＝O)NR 11R 12、-S(＝O) 2R 13、-S(＝O) 2OR 14、-S(＝O) 2NR 15R 16、-O(CH 2) sOR 17、-O(CH 2) sNR 18R 19、-NR 20(CH 2) tNR 21R 22、-NR 23(CH 2) tOR 24；其中，所述C 1-8烷基、C 2-8烯基、C 2-8炔基、C 3-8碳环基、3-10元杂环基、C 6-10芳基、5-10元杂芳基任选地被一个或多个取代基取代；所述取代基选自氢、卤素、-CN、-NO 2、氧代、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 3-10碳环基、3-10元杂环基、C 6-10芳基、5-10元杂芳基、-OR 5、-SR 6、-NR 7R 8、-(C＝O)R 9、-C(＝O)OR 10、-C(＝O)NR 11R 12、-S(＝O) 2R 13、-S(＝O) 2OR 14、-S(＝O) 2NR 15R 16、-O(CH 2) sOR 17、-O(CH 2) sNR 18R 19、-NR 20(CH 2) tNR 21R 22、-NR 23(CH 2) tOR 24； Each R 4 is independently selected from hydrogen, halogen, -CN, -NO 2 , oxo, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 carbocyclic ring Group, 3-10 membered heterocyclic group, C 6-10 aryl group, 5-10 membered heteroaryl group, -OR 5 , -SR 6 , -NR 7 R 8 , -(C=O)R 9 , -C (=O)OR 10 , -C(=O)NR 11 R 12 , -S(=O) 2 R 13 , -S(=O) 2 OR 14 , -S(=O) 2 NR 15 R 16 , -O(CH 2 ) s OR 17 , -O(CH 2 ) s NR 18 R 19 , -NR 20 (CH 2 ) t NR 21 R 22 , -NR 23 (CH 2 ) t OR 24 ; wherein, the C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 carbocyclic group, 3-10 membered heterocyclic group, C 6-10 aryl, 5-10 membered heteroaryl The group is optionally substituted by one or more substituents; the substituents are selected from hydrogen, halogen, -CN, -NO 2 , oxo, C 1-4 alkyl, C 2-4 alkenyl, C 2- 4 alkynyl, C 3-10 carbocyclic group, 3-10 membered heterocyclic group, C 6-10 aryl, 5-10 membered heteroaryl, -OR 5 , -SR 6 , -NR 7 R 8 ,- (C=O)R 9 , -C(=O)OR 10 , -C(=O)NR 11 R 12 , -S(=O) 2 R 13 , -S(=O) 2 OR 14 , -S (=O) 2 NR 15 R 16 , -O(CH 2 ) s OR 17 , -O(CH 2 ) s NR 18 R 19 , -NR 20 (CH 2 ) t NR 21 R 22 , -NR 23 (CH 2 ) t OR 24 ;
R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12、R 13、R 14、R 15、R 16、R 17、R 18、R 19、R 20、R 21、R 22、-NR 23和R 24分别独立地选自氢、C 1-8烷基、C 2-8烯基、C 2-8炔基、C 3-8碳环基、3-10元杂环基、C 6-10芳基、5-10元杂芳基； R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , -NR 23 and R 24 are each independently selected from hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 carbocyclic group, 3-10 member Heterocyclic group, C 6-10 aryl group, 5-10 membered heteroaryl group;
n为0、1、2或3；n is 0, 1, 2 or 3;
p为0、1、2或3；p is 0, 1, 2 or 3;
q为0、1、2、3或4；q is 0, 1, 2, 3 or 4;
r为0、1、2、3或4；r is 0, 1, 2, 3 or 4;
s为1、2、3或4；s is 1, 2, 3 or 4;
t为1、2、3或4；t is 1, 2, 3 or 4;
当n＝0、所述环A为
Figure PCTCN2021088871-appb-000004
且环C为苯基时，r不等于0，Rc不为氢。 When n=0, the ring A is
Figure PCTCN2021088871-appb-000004
And when ring C is phenyl, r is not equal to 0, and Rc is not hydrogen.
一些实施方式中，在所述式I中，环A选自6-10元杂芳基或6-10元杂环基；所述6-10元杂环基至少含有一个双键。In some embodiments, in the formula I, ring A is selected from a 6-10 membered heteroaryl group or a 6-10 membered heterocyclic group; the 6-10 membered heterocyclic group contains at least one double bond.
一些实施方式中，在所述式I中，环A选自吡啶基、吡嗪基、嘧啶基、吲哚基或嘧啶酮基。In some embodiments, in the formula I, ring A is selected from pyridyl, pyrazinyl, pyrimidinyl, indolyl or pyrimidinonyl.
一些实施方式中，在所述式I中，环A选自
Figure PCTCN2021088871-appb-000005
其中，X 1，X 2分别独立地选自选自-NR 1-或-CR 1R 1-。 In some embodiments, in the formula I, ring A is selected from
Figure PCTCN2021088871-appb-000005
Wherein, X 1 and X 2 are each independently selected from -NR 1 -or -CR 1 R 1 -.
一些实施方式中，在所述式I中，环A选自
Figure PCTCN2021088871-appb-000006
In some embodiments, in the formula I, ring A is selected from
Figure PCTCN2021088871-appb-000006
一些实施方式中，在所述式I中，所述环C选自C 3-10碳环基或3-10元杂环基。 In some embodiments, in the formula I, the ring C is selected from a C 3-10 carbocyclic group or a 3-10 membered heterocyclic group.
一些实施方式中，在所述式I中，所述环C选自环丙基、环丁基、环戊基、环己基、吗啉基、哌嗪基或哌啶基。In some embodiments, in the formula I, the ring C is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, morpholinyl, piperazinyl or piperidinyl.
一些实施方式中，在所述式I中，所述环C选自C 6-10芳基或5-10元杂芳基。 In some embodiments, in the formula I, the ring C is selected from a C 6-10 aryl group or a 5-10 membered heteroaryl group.
一些实施方式中，在所述式I中，所述环C选自吡唑基、咪唑基、吡咯基、吡啶基、嘧啶基、吲哚基、吲哚啉基、异吲哚啉基、吲唑基、苯并咪唑基、嘌呤基、苯并异恶唑基或吲哚嗪基。In some embodiments, in the formula I, the ring C is selected from the group consisting of pyrazolyl, imidazolyl, pyrrolyl, pyridyl, pyrimidinyl, indolyl, indolinyl, isoindolinyl, indolyl Azolyl, benzimidazolyl, purinyl, benzisoxazolyl, or indolazinyl.
一些实施方式中，在所述式I中，所述环C选自苯基、
Figure PCTCN2021088871-appb-000007
In some embodiments, in the formula I, the ring C is selected from phenyl,
Figure PCTCN2021088871-appb-000007
Figure PCTCN2021088871-appb-000008
Figure PCTCN2021088871-appb-000008
一些实施方式中，在所述式I中，n为0或1。In some embodiments, in the formula I, n is 0 or 1.
一些实施方式中，在所述式I中，n为0。In some embodiments, in the formula I, n is zero.
一些实施方式中，在所述式I中，n为1。In some embodiments, in the formula I, n is 1.
一些实施方式中，在所述式I中，n为2。In some embodiments, in the formula I, n is 2.
一些实施方式中，在所述式I中，每个R c分别独立地选自氢、卤素、-CN、-NO 2、氧代、C 1-8烷基、C 2-8烯基、C 2-8炔基、C 3-8碳环基、3-10元杂环基、C 6-10芳基、5-10元杂芳基、-OR 5、-SR 6、-NR 7R 8、-(C＝O)R 9、-C(＝O)OR 10、-C(＝O)NR 11R 12、-S(＝O) 2R 13、-S(＝O) 2OR 14、-S(＝O) 2NR 15R 16、-O(CH 2) sOR 17、-O(CH 2) sNR 18R 19、-NR 20(CH 2) tNR 21R 22、-NR 23(CH 2) tOR 24；其中，所述C 1-8烷基、C 2-8烯基、C 2-8炔基、C 3-8碳环基、3-10元杂环基、C 6-10芳基、5-10元杂芳基任选地被一个或多个取代基取代；所述取代基选自氢、卤素、-CN、-NO 2、氧代、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 3-10碳环基、3-10元杂环基、C 6-10芳基、5-10元杂芳基、-OR 5、-SR 6、-NR 7R 8、-(C＝O)R 9、-C(＝O)OR 10、-C(＝O)NR 11R 12、-S(＝O) 2R 13、-S(＝O) 2OR 14、-S(＝O) 2NR 15R 16、-O(CH 2) sOR 17、-O(CH 2) sNR 18R 19、-NR 20(CH 2) tNR 21R 22或-NR 23(CH 2) tOR 24。 In some embodiments, in the formula I, each R c is independently selected from hydrogen, halogen, -CN, -NO 2 , oxo, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 carbocyclic group, 3-10 membered heterocyclic group, C 6-10 aryl, 5-10 membered heteroaryl, -OR 5 , -SR 6 , -NR 7 R 8 , -(C=O)R 9 , -C(=O)OR 10 , -C(=O)NR 11 R 12 , -S(=O) 2 R 13 , -S(=O) 2 OR 14 , -S(=O) 2 NR 15 R 16 , -O(CH 2 ) s OR 17 , -O(CH 2 ) s NR 18 R 19 , -NR 20 (CH 2 ) t NR 21 R 22 , -NR 23 (CH 2 ) t OR 24 ; wherein the C 1-8 alkyl group, C 2-8 alkenyl group, C 2-8 alkynyl group, C 3-8 carbocyclic group, 3-10 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl are optionally substituted by one or more substituents; the substituents are selected from hydrogen, halogen, -CN, -NO 2 , oxo, C 1-4 alkane Group, C 2-4 alkenyl group, C 2-4 alkynyl group, C 3-10 carbocyclic group, 3-10 membered heterocyclic group, C 6-10 aryl group, 5-10 membered heteroaryl group, -OR 5 , -SR 6 , -NR 7 R 8 , -(C=O)R 9 , -C(=O)OR 10 , -C(=O)NR 11 R 12 , -S(=O) 2 R 13 , -S(=O) 2 OR 14 , -S(=O) 2 NR 15 R 16 , -O(CH 2 ) s OR 17 , -O(CH 2 ) s NR 18 R 19 , -NR 20 (CH 2 ) t NR 21 R 22 or -NR 23 (CH 2 ) t OR 24 .
一些实施方式中，在所述式I中，所述每个R c分别独立地选自氢、氧代、-NO 2、-CH 3、-OCH 3、-OH、-CN、-F、-Cl、-CF 3、-NH 2、-NHCH 3、-NHC(＝O)CH 3、-C(＝O)NH 2、-CH 2OH、-COOH、-COOEt、-S(＝O) 2CH 3、-S(＝O) 2NH 2、-CH 2OCH 3、
Figure PCTCN2021088871-appb-000009
Figure PCTCN2021088871-appb-000010
In some embodiments, in the formula I, each R c is independently selected from hydrogen, oxo, -NO 2 , -CH 3 , -OCH 3 , -OH, -CN, -F,- Cl, -CF 3 , -NH 2 , -NHCH 3 , -NHC(=O)CH 3 , -C(=O)NH 2 , -CH 2 OH, -COOH, -COOEt, -S(=O) 2 CH 3 , -S(=O) 2 NH 2 , -CH 2 OCH 3 ,
Figure PCTCN2021088871-appb-000009
Figure PCTCN2021088871-appb-000010
一些实施方式中，在所述式I中，R c1,R c2分别独立地选自氢、卤素、C 1-4烷基或-OR 5。 In some embodiments, in the formula I, R c1 and R c2 are each independently selected from hydrogen, halogen, C 1-4 alkyl or -OR 5 .
一些实施方式中，在所述式I中，R c1,R c2分别独立地选自氢、-CH 3、-F、-OH。 In some embodiments, in the formula I, R c1 and R c2 are each independently selected from hydrogen, -CH 3 , -F, and -OH.
一些实施方式中，在所述式I中，R c1,R c2分别独立地选自氢。 In some embodiments, in the formula I, R c1 and R c2 are each independently selected from hydrogen.
一些实施方式中，在所述式I中，R c1,R c2与它们所连接的原子一起形成环丙基。 In some embodiments, in the formula I, R c1 and R c2 together with the atoms to which they are attached form a cyclopropyl group.
一些实施方式中，在所述式I中，每个R 1分别独立地选自氢、卤素、氧代、C 1-4烷基、-NR 7R 8；其中，所述C 1-4烷基任选地被一个或多个取代基取代；所述取代基选自氢、卤素、-CN、-NO 2、氧代、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 3-6碳环基、3-6元杂环基、C 6-10芳基、5-10元杂芳基、-OR 5、-SR 6、-NR 7R 8、-(C＝O)R 9、-C(＝O)OR 10或-C(＝O)NR 11R 12。 In some embodiments, in the formula I, each R 1 is independently selected from hydrogen, halogen, oxo, C 1-4 alkyl, -NR 7 R 8 ; wherein, the C 1-4 alkane The group is optionally substituted by one or more substituents; the substituents are selected from hydrogen, halogen, -CN, -NO 2 , oxo, C 1-4 alkyl, C 2-4 alkenyl, C 2- 4 alkynyl group, C 3-6 carbocyclic group, 3-6 membered heterocyclic group, C 6-10 aryl group, 5-10 membered heteroaryl group, -OR 5 , -SR 6 , -NR 7 R 8 ,- (C=O)R 9 , -C(=O)OR 10 or -C(=O)NR 11 R 12 .
一些实施方式中，在所述式I中，所述每个R 1分别独立地选自氢、氧代、-CH 3、-NH 2、-CH 2OH。 In some embodiments, in the formula I, each R 1 is independently selected from hydrogen, oxo, -CH 3 , -NH 2 , and -CH 2 OH.
一些实施方式中，在所述式I中，M选自-O-或-CR 1bR 1c-。 In some embodiments, in the formula I, M is selected from -O- or -CR 1b R 1c -.
一些实施方式中，在所述式I中，R 1b，R 1c分别独立地选自氢、C 1-3烷基、C 3-6环烷基、3-6元杂环基、-OR 1d或-NR 1eR 1f。 In some embodiments, in the formula I, R 1b and R 1c are each independently selected from hydrogen, C 1-3 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, -OR 1d Or -NR 1e R 1f .
一些实施方式中，在所述式I中，Y 1选自-NR 3a-，Y 2选自-CR 4bR 4c-。 In some embodiments, in the formula I, Y 1 is selected from -NR 3a -, and Y 2 is selected from -CR 4b R 4c -.
一些实施方式中，在所述式I中，Y 1选自-CR 3bR 3c-，Y 2选自-NR 4a-。 In some embodiments, in the formula I, Y 1 is selected from -CR 3b R 3c -, and Y 2 is selected from -NR 4a -.
一些实施方式中，在所述式I中，Y 1选自-CR 3bR 3c-，Y 2选自-CR 4bR 4c-。 In some embodiments, in the formula I, Y 1 is selected from -CR 3b R 3c -, and Y 2 is selected from -CR 4b R 4c -.
一些实施方式中，在所述式I中，所述环D为C 6-10芳基或5-10元杂芳基。 In some embodiments, in the formula I, the ring D is a C 6-10 aryl group or a 5-10 membered heteroaryl group.
一些实施方式中，在所述式I中，所述环D为
Figure PCTCN2021088871-appb-000011
Figure PCTCN2021088871-appb-000012
In some embodiments, in the formula I, the ring D is
Figure PCTCN2021088871-appb-000011
Figure PCTCN2021088871-appb-000012
一些实施方式中，在所述式I中，所述环D为C 3-8碳环基或3-8元杂环基。 In some embodiments, in the formula I, the ring D is a C 3-8 carbocyclic group or a 3-8 membered heterocyclic group.
一些实施方式中，在所述式I中，所述环D为
Figure PCTCN2021088871-appb-000013
In some embodiments, in the formula I, the ring D is
Figure PCTCN2021088871-appb-000013
一些实施方式中，在所述式I中，每个R 4分别独立地选自氢、卤素、氧代、C 1-8烷基或-OR 5。 In some embodiments, in the formula I, each R 4 is independently selected from hydrogen, halogen, oxo, C 1-8 alkyl, or -OR 5 .
一些实施方式中，在所述式I中，每个R 4分别独立地选自氢、氧代、-CH 3或-OCH 3。 In some embodiments, in the formula I, each R 4 is independently selected from hydrogen, oxo, -CH 3 or -OCH 3 .
一些实施方式中，在所述式I中，p为1、2或3。In some embodiments, in the formula I, p is 1, 2, or 3.
一些实施方式中，在所述式I中，q为0、1或2。In some embodiments, in the formula I, q is 0, 1, or 2.
一些实施方式中，在所述式I中，r为0、1、2或3。In some embodiments, in the formula I, r is 0, 1, 2 or 3.
一些实施方式中，在所述式I中，s为1或2。In some embodiments, in the formula I, s is 1 or 2.
一些实施方式中，在所述式I中，t为1或2。In some embodiments, in the formula I, t is 1 or 2.
一些实施方案中，式I所示化合物，或其药学上可接受的盐、顺反异构体、互变异构体、溶剂化物、螯合物、非共价复合物或前体药物，选自式II：In some embodiments, the compound of Formula I, or a pharmaceutically acceptable salt, cis-trans isomer, tautomer, solvate, chelate, non-covalent complex or prodrug thereof, is selected Self-style II:
Figure PCTCN2021088871-appb-000014
Figure PCTCN2021088871-appb-000014
其中，in,
Figure PCTCN2021088871-appb-000015
为单键或双键；
Figure PCTCN2021088871-appb-000015
Single bond or double bond;
环A选自5-10元杂芳基或5-10元杂环基；其中，所述5-10元杂芳基或所述5-10元杂环基含有一个或多个O、N或S杂原子；所述5-10元杂环基至少含有一个双键；Ring A is selected from a 5-10 membered heteroaryl group or a 5-10 membered heterocyclic group; wherein the 5-10 membered heteroaryl group or the 5-10 membered heterocyclic group contains one or more O, N or S heteroatom; the 5-10 membered heterocyclic group contains at least one double bond;
环C选自C 3-10碳环基、3-10元杂环基、C 6-10芳基或5-10元杂芳基； Ring C is selected from C 3-10 carbocyclic group, 3-10 membered heterocyclic group, C 6-10 aryl group or 5-10 membered heteroaryl group;
每个R c分别独立地选自氢、卤素、-CN、-NO 2、氧代、C 1-8烷基、C 2-8烯基、C 2-8炔基、C 3-8碳环基、3-10元杂环基、C 6-10芳基、5-10元杂芳基、-OR 5、-SR 6、-NR 7R 8、-(C＝O)R 9、-C(＝O)OR 10、-C(＝O)NR 11R 12、-S(＝O) 2R 13、-S(＝O) 2OR 14、-S(＝O) 2NR 15R 16、-O(CH 2) sOR 17、-O(CH 2) sNR 18R 19、-NR 20(CH 2) tNR 21R 22、-NR 23(CH 2) tOR 24；其中，所述C 1-8烷基、C 2-8烯基、C 2-8炔基、C 3-8碳环基、3-10元杂环基、C 6-10芳基、5-10元杂芳基任选地被一个或多个取代基取代；所述取代基选自氢、卤素、-CN、-NO 2、氧代、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 3-10碳环基、3-10元杂环基、C 6-10芳基、5-10元杂芳基、-OR 5、-SR 6、-NR 7R 8、-(C＝O)R 9、-C(＝O)OR 10、-C(＝O)NR 11R 12、-S(＝O) 2R 13、-S(＝O) 2OR 14、-S(＝O) 2NR 15R 16、-O(CH 2) sOR 17、-O(CH 2) sNR 18R 19、-NR 20(CH 2) tNR 21R 22、-NR 23(CH 2) tOR 24； Each R c is independently selected from hydrogen, halogen, -CN, -NO 2 , oxo, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 carbocyclic ring Group, 3-10 membered heterocyclic group, C 6-10 aryl group, 5-10 membered heteroaryl group, -OR 5 , -SR 6 , -NR 7 R 8 , -(C=O)R 9 , -C (=O)OR 10 , -C(=O)NR 11 R 12 , -S(=O) 2 R 13 , -S(=O) 2 OR 14 , -S(=O) 2 NR 15 R 16 , -O(CH 2 ) s OR 17 , -O(CH 2 ) s NR 18 R 19 , -NR 20 (CH 2 ) t NR 21 R 22 , -NR 23 (CH 2 ) t OR 24 ; wherein, the C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 carbocyclic group, 3-10 membered heterocyclic group, C 6-10 aryl, 5-10 membered heteroaryl The group is optionally substituted by one or more substituents; the substituents are selected from hydrogen, halogen, -CN, -NO 2 , oxo, C 1-4 alkyl, C 2-4 alkenyl, C 2- 4 alkynyl, C 3-10 carbocyclic group, 3-10 membered heterocyclic group, C 6-10 aryl, 5-10 membered heteroaryl, -OR 5 , -SR 6 , -NR 7 R 8 ,- (C=O)R 9 , -C(=O)OR 10 , -C(=O)NR 11 R 12 , -S(=O) 2 R 13 , -S(=O) 2 OR 14 , -S (=O) 2 NR 15 R 16 , -O(CH 2 ) s OR 17 , -O(CH 2 ) s NR 18 R 19 , -NR 20 (CH 2 ) t NR 21 R 22 , -NR 23 (CH 2 ) t OR 24 ;
R c1,R c2分别独立地选自氢、卤素、C 1-4烷基或-OR 5； R c1 and R c2 are each independently selected from hydrogen, halogen, C 1-4 alkyl or -OR 5 ;
或R c1和R c2与它们所连接的原子一起形成C 3-6碳环基、3-6元杂环基； Or R c1 and R c2 together with the atoms to which they are connected form a C 3-6 carbocyclic group or a 3-6 membered heterocyclic group;
每个R 1分别独立地选自氢、卤素、-CN、-NO 2、氧代、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 3-6碳环基、3-6元杂环基、C 6-10芳基、5-10元杂芳基、-OR 5、-NR 7R 8、-O(CH 2) sOR 17、-O(CH 2) sNR 18R 19、-NR 20(CH 2) tNR 21R 22、-NR 23(CH 2) tOR 24；其中，所述C 1-4烷基、C 2-4烯基、C 2-4炔基、C 3-6碳环基、3-6元杂环基、C 6-10芳基、5-10元杂芳基任选地被一个或多个取代基取代；所述取代基选自氢、卤素、-CN、-NO 2、氧代、C 1-4烷基、C 2-4烯基、C 2-4炔基、 C 3-6碳环基、3-6元杂环基、C 6-10芳基、5-10元杂芳基、-OR 5、-SR 6、-NR 7R 8、-(C＝O)R 9、-C(＝O)OR 10或-C(＝O)NR 11R 12； Each R 1 is independently selected from hydrogen, halogen, -CN, -NO 2 , oxo, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 carbocyclic ring Group, 3-6 membered heterocyclic group, C 6-10 aryl group, 5-10 membered heteroaryl group, -OR 5 , -NR 7 R 8 , -O(CH 2 ) s OR 17 , -O(CH 2 ) s NR 18 R 19 , -NR 20 (CH 2 ) t NR 21 R 22 , -NR 23 (CH 2 ) t OR 24 ; wherein the C 1-4 alkyl group, C 2-4 alkenyl group, C 2-4 alkynyl, C 3-6 carbocyclic group, 3-6 membered heterocyclic group, C 6-10 aryl group, 5-10 membered heteroaryl group are optionally substituted by one or more substituents; Substituents are selected from hydrogen, halogen, -CN, -NO 2 , oxo, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 carbocyclic group, 3-6 Membered heterocyclic group, C 6-10 aryl group, 5-10 membered heteroaryl group, -OR 5 , -SR 6 , -NR 7 R 8 , -(C=O)R 9 , -C(=O)OR 10 or -C(=O)NR 11 R 12 ;
M选自-O-、-NR 1a-或-CR 1bR 1c-； M is selected from -O-, -NR 1a -or -CR 1b R 1c -;
R 1a选自氢、C 1-3烷基、C 3-6环烷基、3-6元杂环基或不存在； R 1a is selected from hydrogen, C 1-3 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group or not present;
R 1b，R 1c分别独立地选自氢、C 1-3烷基、C 3-6环烷基、3-6元杂环基、-OR 1d、-NR 1eR 1f或不存在； R 1b and R 1c are each independently selected from hydrogen, C 1-3 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group, -OR 1d , -NR 1e R 1f or not present;
R 1d，R 1e，R 1f分别独立地选自氢、C 1-3烷基、C 3-6环烷基或3-6元杂环基； R 1d , R 1e , and R 1f are each independently selected from hydrogen, C 1-3 alkyl, C 3-6 cycloalkyl or 3-6 membered heterocyclic group;
Y 1选自-NR 3a-或-CR 3bR 3c-； Y 1 is selected from -NR 3a -or -CR 3b R 3c -;
R 3a选自氢、C 1-3烷基、C 3-6环烷基、3-6元杂环基或不存在； R 3a is selected from hydrogen, C 1-3 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group or not present;
R 3b，R 3c分别独立地选自氢、C 1-3烷基、C 3-6环烷基、3-6元杂环基或不存在； R 3b and R 3c are each independently selected from hydrogen, C 1-3 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group or not present;
Y 2选自-NR 4a-或-CR 4bR 4c-； Y 2 is selected from -NR 4a -or -CR 4b R 4c -;
R 4a选自氢、C 1-3烷基、C 3-6环烷基、3-6元杂环基或不存在； R 4a is selected from hydrogen, C 1-3 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group or not present;
R 4b，R 4c分别独立地选自氢、C 1-3烷基、C 3-6环烷基、3-6元杂环基或不存在； R 4b and R 4c are each independently selected from hydrogen, C 1-3 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group or not present;
所述环D为C 6-10芳基、5-10元杂芳基、C 3-8碳环基或3-8元杂环基；其中，所述C 3-8碳环基或3-8元杂环基选择性地含有双键； The ring D is a C 6-10 aryl group, a 5-10 membered heteroaryl group, a C 3-8 carbocyclic group or a 3-8 membered heterocyclic group; wherein, the C 3-8 carbocyclic group or a 3- The 8-membered heterocyclic group optionally contains a double bond;
每个R 4分别独立地选自氢、卤素、-CN、-NO 2、氧代、C 1-8烷基、C 2-8烯基、C 2-8炔基、C 3-8碳环基、3-10元杂环基、C 6-10芳基、5-10元杂芳基、-OR 5、-SR 6、-NR 7R 8、-(C＝O)R 9、-C(＝O)OR 10、-C(＝O)NR 11R 12、-S(＝O) 2R 13、-S(＝O) 2OR 14、-S(＝O) 2NR 15R 16、-O(CH 2) sOR 17、-O(CH 2) sNR 18R 19、-NR 20(CH 2) tNR 21R 22、-NR 23(CH 2) tOR 24；其中，所述C 1-8烷基、C 2-8烯基、C 2-8炔基、C 3-8碳环基、3-10元杂环基、C 6-10芳基、5-10元杂芳基任选地被一个或多个取代基取代；所述取代基选自氢、卤素、-CN、-NO 2、氧代、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 3-10碳环基、3-10元杂环基、C 6-10芳基、5-10元杂芳基、-OR 5、-SR 6、-NR 7R 8、-(C＝O)R 9、-C(＝O)OR 10、-C(＝O)NR 11R 12、-S(＝O) 2R 13、-S(＝O) 2OR 14、-S(＝O) 2NR 15R 16、-O(CH 2) sOR 17、-O(CH 2) sNR 18R 19、-NR 20(CH 2) tNR 21R 22、-NR 23(CH 2) tOR 24； Each R 4 is independently selected from hydrogen, halogen, -CN, -NO 2 , oxo, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 carbocyclic ring Group, 3-10 membered heterocyclic group, C 6-10 aryl group, 5-10 membered heteroaryl group, -OR 5 , -SR 6 , -NR 7 R 8 , -(C=O)R 9 , -C (=O)OR 10 , -C(=O)NR 11 R 12 , -S(=O) 2 R 13 , -S(=O) 2 OR 14 , -S(=O) 2 NR 15 R 16 , -O(CH 2 ) s OR 17 , -O(CH 2 ) s NR 18 R 19 , -NR 20 (CH 2 ) t NR 21 R 22 , -NR 23 (CH 2 ) t OR 24 ; wherein, the C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 carbocyclic group, 3-10 membered heterocyclic group, C 6-10 aryl, 5-10 membered heteroaryl The group is optionally substituted by one or more substituents; the substituents are selected from hydrogen, halogen, -CN, -NO 2 , oxo, C 1-4 alkyl, C 2-4 alkenyl, C 2- 4 alkynyl, C 3-10 carbocyclic group, 3-10 membered heterocyclic group, C 6-10 aryl, 5-10 membered heteroaryl, -OR 5 , -SR 6 , -NR 7 R 8 ,- (C=O)R 9 , -C(=O)OR 10 , -C(=O)NR 11 R 12 , -S(=O) 2 R 13 , -S(=O) 2 OR 14 , -S (=O) 2 NR 15 R 16 , -O(CH 2 ) s OR 17 , -O(CH 2 ) s NR 18 R 19 , -NR 20 (CH 2 ) t NR 21 R 22 , -NR 23 (CH 2 ) t OR 24 ;
R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12、R 13、R 14、R 15、R 16、R 17、R 18、R 19、R 20、R 21、R 22、-NR 23和R 24分别独立地选自氢、C 1-8烷基、C 2-8烯基、C 2-8炔基、C 3-8碳环基、3-10元杂环基、C 6-10芳基、5-10元杂芳基； R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , -NR 23 and R 24 are each independently selected from hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 carbocyclic group, 3-10 member Heterocyclic group, C 6-10 aryl group, 5-10 membered heteroaryl group;
p为0、1、2或3；p is 0, 1, 2 or 3;
q为0、1、2、3或4；q is 0, 1, 2, 3 or 4;
r为0、1、2、3或4；r is 0, 1, 2, 3 or 4;
s为1、2、3或4；s is 1, 2, 3 or 4;
t为1、2、3或4。t is 1, 2, 3, or 4.
一些实施方式中，在所述式II中，环A选自6-10元杂芳基或6-10元杂环基；所述6-10元杂环基至少含有一个双键。In some embodiments, in the formula II, ring A is selected from a 6-10 membered heteroaryl group or a 6-10 membered heterocyclic group; the 6-10 membered heterocyclic group contains at least one double bond.
一些实施方式中，在所述式II中，环A选自吡啶基、吡嗪基、嘧啶基、吲哚基或嘧啶酮基。In some embodiments, in the formula II, ring A is selected from pyridyl, pyrazinyl, pyrimidinyl, indolyl or pyrimidinonyl.
一些实施方式中，在所述式II中，环A选自
Figure PCTCN2021088871-appb-000016
其中，X1，X2分别独立地选自选自-NR 1-或-CR 1R 1-。 In some embodiments, in the formula II, ring A is selected from
Figure PCTCN2021088871-appb-000016
Wherein, X1 and X2 are each independently selected from -NR 1 -or -CR 1 R 1 -.
一些实施方式中，在所述式II中，环A选自
Figure PCTCN2021088871-appb-000017
In some embodiments, in the formula II, ring A is selected from
Figure PCTCN2021088871-appb-000017
一些实施方式中，在所述式I中，环A选自
Figure PCTCN2021088871-appb-000018
In some embodiments, in the formula I, ring A is selected from
Figure PCTCN2021088871-appb-000018
一些实施方式中，在所述式I中，环A选自
Figure PCTCN2021088871-appb-000019
In some embodiments, in the formula I, ring A is selected from
Figure PCTCN2021088871-appb-000019
一些实施方式中，在所述式II中，所述环C选自3-10元杂环基。In some embodiments, in the formula II, the ring C is selected from 3-10 membered heterocyclic groups.
一些实施方式中，在所述式II中，所述环C选自吗啉基、哌嗪基或哌啶基。In some embodiments, in the formula II, the ring C is selected from morpholinyl, piperazinyl or piperidinyl.
一些实施方式中，在所述式II中，所述环C选自C6-10芳基或5-10元杂芳基。In some embodiments, in the formula II, the ring C is selected from a C6-10 aryl group or a 5-10 membered heteroaryl group.
一些实施方式中，在所述式II中，所述环C选自吡唑基、咪唑基、吡咯基、吡啶基、嘧啶基、吲哚基、吲哚啉基、异吲哚啉基、吲唑基、苯并咪唑基、嘌呤基、苯并异恶唑基或吲哚嗪基。In some embodiments, in the formula II, the ring C is selected from the group consisting of pyrazolyl, imidazolyl, pyrrolyl, pyridyl, pyrimidinyl, indolyl, indolinyl, isoindolinyl, indolyl Azolyl, benzimidazolyl, purinyl, benzisoxazolyl, or indolazinyl.
一些实施方式中，在所述式II中，所述环C选自苯基、
Figure PCTCN2021088871-appb-000020
Figure PCTCN2021088871-appb-000021
In some embodiments, in the formula II, the ring C is selected from phenyl,
Figure PCTCN2021088871-appb-000020
Figure PCTCN2021088871-appb-000021
一些实施方式中，在所述式II中，所述环C选自苯基。In some embodiments, in the formula II, the ring C is selected from phenyl.
一些实施方式中，在所述式II中，每个R c分别独立地选自氢、卤素、-CN、-NO 2、氧代、C 1-8烷基、C 2-8烯基、C 2-8炔基、C 3-8碳环基、3-10元杂环基、C 6-10芳基、5-10元杂芳基、-OR 5、-SR 6、-NR 7R 8、-(C＝O)R 9、-C(＝O)OR 10、-C(＝O)NR 11R 12、-S(＝O) 2R 13、-S(＝O) 2OR 14、-S(＝O) 2NR 15R 16、-O(CH 2) sOR 17、-O(CH 2) sNR 18R 19、-NR 20(CH 2) tNR 21R 22、-NR 23(CH 2) tOR 24；其中，所述C 1-8烷基、C 2-8烯基、C 2-8炔基、C 3-8碳环基、3-10元杂环基、C 6-10芳基、5-10元杂芳基任选地被一个或多个取代基取代；所述取代基选自氢、卤素、-CN、-NO 2、氧代、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 3-10碳环基、3-10元杂环基、C 6-10芳基、5-10元杂芳基、-OR 5、-SR 6、-NR 7R 8、-(C＝O)R 9、-C(＝O)OR 10、-C(＝O)NR 11R 12、-S(＝O) 2R 13、-S(＝O) 2OR 14、-S(＝O) 2NR 15R 16、-O(CH 2) sOR 17、-O(CH 2) sNR 18R 19、-NR 20(CH 2) tNR 21R 22或-NR 23(CH 2) tOR 24。 In some embodiments, in the formula II, each R c is independently selected from hydrogen, halogen, -CN, -NO 2 , oxo, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 carbocyclic group, 3-10 membered heterocyclic group, C 6-10 aryl, 5-10 membered heteroaryl, -OR 5 , -SR 6 , -NR 7 R 8 , -(C=O)R 9 , -C(=O)OR 10 , -C(=O)NR 11 R 12 , -S(=O) 2 R 13 , -S(=O) 2 OR 14 , -S(=O) 2 NR 15 R 16 , -O(CH 2 ) s OR 17 , -O(CH 2 ) s NR 18 R 19 , -NR 20 (CH 2 ) t NR 21 R 22 , -NR 23 (CH 2 ) t OR 24 ; wherein the C 1-8 alkyl group, C 2-8 alkenyl group, C 2-8 alkynyl group, C 3-8 carbocyclic group, 3-10 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl are optionally substituted by one or more substituents; the substituents are selected from hydrogen, halogen, -CN, -NO 2 , oxo, C 1-4 alkane Group, C 2-4 alkenyl group, C 2-4 alkynyl group, C 3-10 carbocyclic group, 3-10 membered heterocyclic group, C 6-10 aryl group, 5-10 membered heteroaryl group, -OR 5 , -SR 6 , -NR 7 R 8 , -(C=O)R 9 , -C(=O)OR 10 , -C(=O)NR 11 R 12 , -S(=O) 2 R 13 , -S(=O) 2 OR 14 , -S(=O) 2 NR 15 R 16 , -O(CH 2 ) s OR 17 , -O(CH 2 ) s NR 18 R 19 , -NR 20 (CH 2 ) t NR 21 R 22 or -NR 23 (CH 2 ) t OR 24 .
一些实施方式中，在所述式II中，所述每个R c分别独立地选自氢、氧代、-NO 2、-CH 3、-OCH 3、-OH、-CN、-F、-Cl、-CF 3、-NH 2、-NHCH 3、-NHC(＝O)CH 3、-C(＝O)NH 2、-CH 2OH、-COOH、-COOEt、-S(＝O) 2CH 3、-S(＝O) 2NH 2、-CH 2OCH 3、
Figure PCTCN2021088871-appb-000022
Figure PCTCN2021088871-appb-000023
In some embodiments, in the formula II, each R c is independently selected from hydrogen, oxo, -NO 2 , -CH 3 , -OCH 3 , -OH, -CN, -F,- Cl, -CF 3 , -NH 2 , -NHCH 3 , -NHC(=O)CH 3 , -C(=O)NH 2 , -CH 2 OH, -COOH, -COOEt, -S(=O) 2 CH 3 , -S(=O) 2 NH 2 , -CH 2 OCH 3 ,
Figure PCTCN2021088871-appb-000022
Figure PCTCN2021088871-appb-000023
一些实施方式中，在所述式II中，R c1,R c2分别独立地选自氢、卤素、C 1-4烷基、-OR 5。 In some embodiments, in the formula II, R c1 and R c2 are each independently selected from hydrogen, halogen, C 1-4 alkyl, and -OR 5 .
一些实施方式中，在所述式II中，R c1,R c2分别独立地选自氢、-CH 3、-F、-OH。 In some embodiments, in the formula II, R c1 and R c2 are each independently selected from hydrogen, -CH 3 , -F, and -OH.
一些实施方式中，在所述式II中，R c1,R c2分别独立地选自氢。 In some embodiments, in the formula II, R c1 and R c2 are each independently selected from hydrogen.
一些实施方式中，在所述式II中，R c1,R c2与它们所连接的原子一起形成环丙基。 In some embodiments, in the formula II, R c1 and R c2 together with the atoms to which they are attached form a cyclopropyl group.
一些实施方式中，在所述式II中，每个R 1分别独立地选自氢、卤素、氧代、C 1-4烷基、-NR 7R 8；其中，所述C 1-4烷基任选地被一个或多个取代基取代；所述取代基选自氢、卤素、-CN、-NO 2、氧代、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 3-6碳环基、3-6元杂环基、C 6- 10芳基、5-10元杂芳基、-OR 5、-SR 6、-NR 7R 8、-(C＝O)R 9、-C(＝O)OR 10或-C(＝O)NR 11R 12。 In some embodiments, in the formula II, each R 1 is independently selected from hydrogen, halogen, oxo, C 1-4 alkyl, -NR 7 R 8 ; wherein, the C 1-4 alkane The group is optionally substituted by one or more substituents; the substituents are selected from hydrogen, halogen, -CN, -NO 2 , oxo, C 1-4 alkyl, C 2-4 alkenyl, C 2- 4 alkynyl, C 3-6 carbocyclyl, 3-6-membered heterocyclyl, C 6- 10 aryl, 5-10 membered heteroaryl, -OR 5, -SR 6, -NR 7 R 8, - (C=O)R 9 , -C(=O)OR 10 or -C(=O)NR 11 R 12 .
一些实施方式中，在所述式II中，所述每个R 1分别独立地选自氢、氧代、-CH 3、-NH 2、-CH 2OH。 In some embodiments, in the formula II, each R 1 is independently selected from hydrogen, oxo, -CH 3 , -NH 2 , and -CH 2 OH.
一些实施方式中，在所述式II中，M选自-O-或-CR 1bR 1c-。 In some embodiments, in the formula II, M is selected from -O- or -CR 1b R 1c -.
一些实施方式中，在所述式II中，R 1b，R 1c分别独立地选自氢、C 1-3烷基、C 3-6环烷基、3-6元杂环基、-OR 1d或-NR 1eR 1f。 In some embodiments, in the formula II, R 1b and R 1c are each independently selected from hydrogen, C 1-3 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, -OR 1d Or -NR 1e R 1f .
一些实施方式中，在所述式II中，Y 1选自-NR 3a-，Y 2选自-CR 4bR 4c-。 In some embodiments, in the formula II, Y 1 is selected from -NR 3a -, and Y 2 is selected from -CR 4b R 4c -.
一些实施方式中，在所述式II中，Y 1选自-CR 3bR 3c-，Y 2选自-NR 4a-。 In some embodiments, in the formula II, Y 1 is selected from -CR 3b R 3c -, and Y 2 is selected from -NR 4a -.
一些实施方式中，在所述式II中，Y 1选自-CR 3bR 3c-，Y 2选自-CR 4bR 4c-。 In some embodiments, in the formula II, Y 1 is selected from -CR 3b R 3c -, and Y 2 is selected from -CR 4b R 4c -.
一些实施方式中，在所述式II中，所述环D为C 6-10芳基或5-10元杂芳基。 In some embodiments, in the formula II, the ring D is a C 6-10 aryl group or a 5-10 membered heteroaryl group.
一些实施方式中，在所述式II中，所述环D为
Figure PCTCN2021088871-appb-000024
Figure PCTCN2021088871-appb-000025
In some embodiments, in the formula II, the ring D is
Figure PCTCN2021088871-appb-000024
Figure PCTCN2021088871-appb-000025
一些实施方式中，在所述式II中，每个R 4分别独立地选自氢、卤素、氧代、C 1-8烷基或-OR 5。 In some embodiments, in the formula II, each R 4 is independently selected from hydrogen, halogen, oxo, C 1-8 alkyl, or -OR 5 .
一些实施方式中，在所述式II中，每个R 4分别独立地选自氢、氧代、-CH 3或-OCH 3。 In some embodiments, in the formula II, each R 4 is independently selected from hydrogen, oxo, -CH 3 or -OCH 3 .
一些实施方式中，在所述式I中，q为0、1或2。In some embodiments, in the formula I, q is 0, 1, or 2.
一些实施方式中，在所述式I中，r为0、1、2或3。In some embodiments, in the formula I, r is 0, 1, 2 or 3.
一些实施方式中，在所述式I中，s为1或2。In some embodiments, in the formula I, s is 1 or 2.
一些实施方式中，在所述式I中，t为1或2。In some embodiments, in the formula I, t is 1 or 2.
一些实施方案中，式I所示化合物，或其药学上可接受的盐、顺反异构体、互变异构体、溶剂化物、螯合物、非共价复合物或前体药物，选自式III：In some embodiments, the compound of Formula I, or a pharmaceutically acceptable salt, cis-trans isomer, tautomer, solvate, chelate, non-covalent complex or prodrug thereof, is selected Self-Form III:
Figure PCTCN2021088871-appb-000026
Figure PCTCN2021088871-appb-000026
其中，in,
Figure PCTCN2021088871-appb-000027
为单键或双键；
Figure PCTCN2021088871-appb-000027
Single bond or double bond;
环A选自5-10元杂芳基或5-10元杂环基；其中，所述5-10元杂芳基或所述5-10元杂环基含有一个或多个O、N或S杂原子；所述5-10元杂环基至少含有一个双键；Ring A is selected from a 5-10 membered heteroaryl group or a 5-10 membered heterocyclic group; wherein the 5-10 membered heteroaryl group or the 5-10 membered heterocyclic group contains one or more O, N or S heteroatom; the 5-10 membered heterocyclic group contains at least one double bond;
环C选自C 3-10碳环基、3-10元杂环基、C 6-10芳基或5-10元杂芳基； Ring C is selected from C 3-10 carbocyclic group, 3-10 membered heterocyclic group, C 6-10 aryl group or 5-10 membered heteroaryl group;
每个R c分别独立地选自氢、卤素、-CN、-NO 2、氧代、C 1-8烷基、C 2-8烯基、C 2-8炔基、C 3-8碳环基、3-10元杂环基、C 6-10芳基、5-10元杂芳基、-OR 5、-SR 6、-NR 7R 8、-(C＝O)R 9、-C(＝O)OR 10、-C(＝O)NR 11R 12、-S(＝O) 2R 13、-S(＝O) 2OR 14、-S(＝O) 2NR 15R 16、-O(CH 2) sOR 17、-O(CH 2) sNR 18R 19、-NR 20(CH 2) tNR 21R 22、-NR 23(CH 2) tOR 24；其中，所述C 1-8烷基、C 2-8烯基、C 2-8炔基、C 3-8碳环基、3-10元杂环基、C 6-10芳基、5-10元杂芳基任选地被一个或多个取代基取代；所述取代基选自氢、卤素、-CN、-NO 2、氧代、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 3-10碳环基、3-10元杂环基、C 6-10芳基、5-10元杂芳基、-OR 5、-SR 6、-NR 7R 8、-(C＝O)R 9、-C(＝O)OR 10、-C(＝O)NR 11R 12、-S(＝O) 2R 13、-S(＝O) 2OR 14、-S(＝O) 2NR 15R 16、-O(CH 2) sOR 17、-O(CH 2) sNR 18R 19、-NR 20(CH 2) tNR 21R 22、-NR 23(CH 2) tOR 24； Each R c is independently selected from hydrogen, halogen, -CN, -NO 2 , oxo, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 carbocyclic ring Group, 3-10 membered heterocyclic group, C 6-10 aryl group, 5-10 membered heteroaryl group, -OR 5 , -SR 6 , -NR 7 R 8 , -(C=O)R 9 , -C (=O)OR 10 , -C(=O)NR 11 R 12 , -S(=O) 2 R 13 , -S(=O) 2 OR 14 , -S(=O) 2 NR 15 R 16 , -O(CH 2 ) s OR 17 , -O(CH 2 ) s NR 18 R 19 , -NR 20 (CH 2 ) t NR 21 R 22 , -NR 23 (CH 2 ) t OR 24 ; wherein, the C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 carbocyclic group, 3-10 membered heterocyclic group, C 6-10 aryl, 5-10 membered heteroaryl The group is optionally substituted by one or more substituents; the substituents are selected from hydrogen, halogen, -CN, -NO 2 , oxo, C 1-4 alkyl, C 2-4 alkenyl, C 2- 4 alkynyl, C 3-10 carbocyclic group, 3-10 membered heterocyclic group, C 6-10 aryl, 5-10 membered heteroaryl, -OR 5 , -SR 6 , -NR 7 R 8 ,- (C=O)R 9 , -C(=O)OR 10 , -C(=O)NR 11 R 12 , -S(=O) 2 R 13 , -S(=O) 2 OR 14 , -S (=O) 2 NR 15 R 16 , -O(CH 2 ) s OR 17 , -O(CH 2 ) s NR 18 R 19 , -NR 20 (CH 2 ) t NR 21 R 22 , -NR 23 (CH 2 ) t OR 24 ;
每个R 1分别独立地选自氢、卤素、-CN、-NO 2、氧代、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 3-6碳环基、3-6元杂环基、C 6-10芳基、5-10元杂芳基、-OR 5、-NR 7R 8、-O(CH 2) sOR 17、-O(CH 2) sNR 18R 19、-NR 20(CH 2) tNR 21R 22、-NR 23(CH 2) tOR 24；其中，所述C 1-4烷基、C 2-4烯基、C 2-4炔基、C 3-6碳环基、3-6元杂环基、C 6-10芳基、5-10元杂芳基任选地被一个或多个取代基取代；所述取代基选自氢、卤素、-CN、-NO 2、氧代、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 3-6碳环基、3-6元杂环基、C 6-10芳基、5-10元杂芳基、-OR 5、-SR 6、-NR 7R 8、-(C＝O)R 9、-C(＝O)OR 10或-C(＝O)NR 11R 12； Each R 1 is independently selected from hydrogen, halogen, -CN, -NO 2 , oxo, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 carbocyclic ring Group, 3-6 membered heterocyclic group, C 6-10 aryl group, 5-10 membered heteroaryl group, -OR 5 , -NR 7 R 8 , -O(CH 2 ) s OR 17 , -O(CH 2 ) s NR 18 R 19 , -NR 20 (CH 2 ) t NR 21 R 22 , -NR 23 (CH 2 ) t OR 24 ; wherein the C 1-4 alkyl group, C 2-4 alkenyl group, C 2-4 alkynyl, C 3-6 carbocyclic group, 3-6 membered heterocyclic group, C 6-10 aryl group, 5-10 membered heteroaryl group are optionally substituted by one or more substituents; Substituents are selected from hydrogen, halogen, -CN, -NO 2 , oxo, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 carbocyclic group, 3-6 Membered heterocyclic group, C 6-10 aryl group, 5-10 membered heteroaryl group, -OR 5 , -SR 6 , -NR 7 R 8 , -(C=O)R 9 , -C(=O)OR 10 or -C(=O)NR 11 R 12 ;
M选自-O-、-NR 1a-或-CR 1bR 1c-； M is selected from -O-, -NR 1a -or -CR 1b R 1c -;
R 1a选自氢、C 1-3烷基、C 3-6环烷基、3-6元杂环基或不存在； R 1a is selected from hydrogen, C 1-3 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group or not present;
R 1b，R 1c分别独立地选自氢、C 1-3烷基、C 3-6环烷基、3-6元杂环基、-OR 1d、-NR 1eR 1f或不存在； R 1b and R 1c are each independently selected from hydrogen, C 1-3 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group, -OR 1d , -NR 1e R 1f or not present;
R 1d，R 1e，R 1f分别独立地选自氢、C 1-3烷基、C 3-6环烷基或3-6元杂环基； R 1d , R 1e , and R 1f are each independently selected from hydrogen, C 1-3 alkyl, C 3-6 cycloalkyl or 3-6 membered heterocyclic group;
Y 1选自-NR 3a-或-CR 3bR 3c-； Y 1 is selected from -NR 3a -or -CR 3b R 3c -;
R 3a选自氢、C 1-3烷基、C 3-6环烷基、3-6元杂环基或不存在； R 3a is selected from hydrogen, C 1-3 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group or not present;
R 3b，R 3c分别独立地选自氢、C 1-3烷基、C 3-6环烷基、3-6元杂环基或不存在； R 3b and R 3c are each independently selected from hydrogen, C 1-3 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group or not present;
Y 2选自-NR 4a-或-CR 4bR 4c-； Y 2 is selected from -NR 4a -or -CR 4b R 4c -;
R 4a选自氢、C 1-3烷基、C 3-6环烷基、3-6元杂环基或不存在； R 4a is selected from hydrogen, C 1-3 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group or not present;
R 4b，R 4c分别独立地选自氢、C 1-3烷基、C 3-6环烷基、3-6元杂环基或不存在； R 4b and R 4c are each independently selected from hydrogen, C 1-3 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group or not present;
所述环D为C 6-10芳基、5-10元杂芳基、C 3-8碳环基或3-8元杂环基；其中，所述C 3-8碳环基或3-8元杂环基选择性地含有双键； The ring D is a C 6-10 aryl group, a 5-10 membered heteroaryl group, a C 3-8 carbocyclic group or a 3-8 membered heterocyclic group; wherein, the C 3-8 carbocyclic group or a 3- The 8-membered heterocyclic group optionally contains a double bond;
每个R 4分别独立地选自氢、卤素、-CN、-NO 2、氧代、C 1-8烷基、C 2-8烯基、C 2-8炔基、C 3-8碳环基、3-10元杂环基、C 6-10芳基、5-10元杂芳基、-OR 5、-SR 6、-NR 7R 8、-(C＝O)R 9、-C(＝O)OR 10、-C(＝O)NR 11R 12、-S(＝O) 2R 13、-S(＝O) 2OR 14、-S(＝O) 2NR 15R 16、-O(CH 2) sOR 17、-O(CH 2) sNR 18R 19、-NR 20(CH 2) tNR 21R 22、-NR 23(CH 2) tOR 24；其中，所述C 1-8烷基、C 2-8烯基、C 2-8炔基、C 3-8碳环基、3-10元杂环基、C 6-10芳基、5-10元杂芳基任选地被一个或多个取代基取代；所述取代基选自氢、卤素、-CN、-NO 2、氧代、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 3-10碳环基、3-10元杂环基、C 6-10芳基、5-10元杂芳基、-OR 5、-SR 6、-NR 7R 8、-(C＝O)R 9、-C(＝O)OR 10、-C(＝O)NR 11R 12、-S(＝O) 2R 13、-S(＝O) 2OR 14、-S(＝O) 2NR 15R 16、-O(CH 2) sOR 17、-O(CH 2) sNR 18R 19、-NR 20(CH 2) tNR 21R 22、-NR 23(CH 2) tOR 24； Each R 4 is independently selected from hydrogen, halogen, -CN, -NO 2 , oxo, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 carbocyclic ring Group, 3-10 membered heterocyclic group, C 6-10 aryl group, 5-10 membered heteroaryl group, -OR 5 , -SR 6 , -NR 7 R 8 , -(C=O)R 9 , -C (=O)OR 10 , -C(=O)NR 11 R 12 , -S(=O) 2 R 13 , -S(=O) 2 OR 14 , -S(=O) 2 NR 15 R 16 , -O(CH 2 ) s OR 17 , -O(CH 2 ) s NR 18 R 19 , -NR 20 (CH 2 ) t NR 21 R 22 , -NR 23 (CH 2 ) t OR 24 ; wherein, the C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 carbocyclic group, 3-10 membered heterocyclic group, C 6-10 aryl, 5-10 membered heteroaryl The group is optionally substituted by one or more substituents; the substituents are selected from hydrogen, halogen, -CN, -NO 2 , oxo, C 1-4 alkyl, C 2-4 alkenyl, C 2- 4 alkynyl, C 3-10 carbocyclic group, 3-10 membered heterocyclic group, C 6-10 aryl, 5-10 membered heteroaryl, -OR 5 , -SR 6 , -NR 7 R 8 ,- (C=O)R 9 , -C(=O)OR 10 , -C(=O)NR 11 R 12 , -S(=O) 2 R 13 , -S(=O) 2 OR 14 , -S (=O) 2 NR 15 R 16 , -O(CH 2 ) s OR 17 , -O(CH 2 ) s NR 18 R 19 , -NR 20 (CH 2 ) t NR 21 R 22 , -NR 23 (CH 2 ) t OR 24 ;
R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12、R 13、R 14、R 15、R 16、R 17、R 18、R 19、R 20、R 21、R 22、-NR 23和R 24分别独立地选自氢、C 1-8烷基、C 2-8烯基、C 2-8炔基、C 3-8碳环基、3-10元杂环基、C 6-10芳基、5-10元杂芳基； R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , -NR 23 and R 24 are each independently selected from hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 carbocyclic group, 3-10 member Heterocyclic group, C 6-10 aryl group, 5-10 membered heteroaryl group;
p为0、1、2或3；p is 0, 1, 2 or 3;
q为0、1、2、3或4；q is 0, 1, 2, 3 or 4;
r为0、1、2、3或4；r is 0, 1, 2, 3 or 4;
s为1、2、3或4；s is 1, 2, 3 or 4;
t为1、2、3或4；t is 1, 2, 3 or 4;
当环A为
Figure PCTCN2021088871-appb-000028
且环C为苯基时，r不等于0，Rc不为氢。 When ring A is
Figure PCTCN2021088871-appb-000028
And when ring C is phenyl, r is not equal to 0, and Rc is not hydrogen.
一些实施方式中，在所述式III中，环A选自6-10元杂芳基或6-10元杂环基；所述6-10元杂环基至少含有一个双键。In some embodiments, in the formula III, ring A is selected from a 6-10 membered heteroaryl group or a 6-10 membered heterocyclic group; the 6-10 membered heterocyclic group contains at least one double bond.
一些实施方式中，在所述式III中，环A选自吡啶基、吡嗪基、嘧啶基、吲哚基或嘧啶酮基。In some embodiments, in the formula III, ring A is selected from pyridyl, pyrazinyl, pyrimidinyl, indolyl or pyrimidinonyl.
一些实施方式中，在所述式III中，环A选自
Figure PCTCN2021088871-appb-000029
其中，X 1，X 2分别独立地选自选自-NR 1-或-CR 1R 1-。 In some embodiments, in the formula III, ring A is selected from
Figure PCTCN2021088871-appb-000029
Wherein, X 1 and X 2 are each independently selected from -NR 1 -or -CR 1 R 1 -.
一些实施方式中，在所述式III中，环A选自
Figure PCTCN2021088871-appb-000030
In some embodiments, in the formula III, ring A is selected from
Figure PCTCN2021088871-appb-000030
一些实施方式中，在所述式III中，环A选自
Figure PCTCN2021088871-appb-000031
In some embodiments, in the formula III, ring A is selected from
Figure PCTCN2021088871-appb-000031
一些实施方式中，在所述式III中，环A选自
Figure PCTCN2021088871-appb-000032
In some embodiments, in the formula III, ring A is selected from
Figure PCTCN2021088871-appb-000032
一些实施方式中，在所述式III中，所述环C选自C 3-10碳环基或3-10元杂环基。 In some embodiments, in the formula III, the ring C is selected from a C 3-10 carbocyclic group or a 3-10 membered heterocyclic group.
一些实施方式中，在所述式III中，所述环C选自环丙基、环丁基、环戊基、环己基、吗啉基、哌嗪基或哌啶基。In some embodiments, in the formula III, the ring C is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, morpholinyl, piperazinyl or piperidinyl.
一些实施方式中，在所述式III中，每个R c分别独立地选自氢、卤素、-CN、氧代、C 1-8烷基、C 2-8烯基、C 2-8炔基、C 3-8碳环基、3-10元杂环基、C 6-10芳基、5-10元杂芳基、-OR 5、-SR 6、-NR 7R 8、-(C＝O)R 9、-C(＝O)OR 10、-C(＝O)NR 11R 12、-S(＝O) 2R 13、-S(＝O) 2OR 14、-S(＝O) 2NR 15R 16、-O(CH 2) sOR 17、-O(CH 2) sNR 18R 19、-NR 20(CH 2) tNR 21R 22、-NR 23(CH 2) tOR 24；其中，所述C 1-8烷基、C 2-8烯基、C 2-8炔基、C 3-8碳环基、3-10元杂环基、C 6-10芳基、5-10元杂芳基任选地被一个或多个取代基取代；所述取代基选自氢、卤素、-CN、-NO 2、氧代、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 3-10碳环基、3-10元杂环基、C 6-10芳基、5-10元杂芳基、-OR 5、-SR 6、-NR 7R 8、-(C＝O)R 9、-C(＝O)OR 10、-C(＝O)NR 11R 12、-S(＝O) 2R 13、-S(＝O) 2OR 14、-S(＝O) 2NR 15R 16、-O(CH 2) sOR 17、-O(CH 2) sNR 18R 19、-NR 20(CH 2) tNR 21R 22或-NR 23(CH 2) tOR 24。 In some embodiments, in the formula III, each R c is independently selected from hydrogen, halogen, -CN, oxo, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkyne Group, C 3-8 carbocyclic group, 3-10 membered heterocyclic group, C 6-10 aryl group, 5-10 membered heteroaryl group, -OR 5 , -SR 6 , -NR 7 R 8 , -(C ＝O)R 9 , -C(＝O)OR 10 , -C(＝O)NR 11 R 12 , -S(＝O) 2 R 13 , -S(＝O) 2 OR 14 , -S(＝ O) 2 NR 15 R 16 , -O(CH 2 ) s OR 17 , -O(CH 2 ) s NR 18 R 19 , -NR 20 (CH 2 ) t NR 21 R 22 , -NR 23 (CH 2 ) t OR 24 ; wherein, the C 1-8 alkyl group, C 2-8 alkenyl group, C 2-8 alkynyl group, C 3-8 carbocyclic group, 3-10 membered heterocyclic group, C 6-10 aromatic group And 5-10 membered heteroaryl groups are optionally substituted by one or more substituents; the substituents are selected from hydrogen, halogen, -CN, -NO 2 , oxo, C 1-4 alkyl, C 2 -4 alkenyl, C 2-4 alkynyl, C 3-10 carbocyclic group, 3-10 membered heterocyclic group, C 6-10 aryl, 5-10 membered heteroaryl, -OR 5 , -SR 6 , -NR 7 R 8 , -(C=O)R 9 , -C(=O)OR 10 , -C(=O)NR 11 R 12 , -S(=O) 2 R 13 , -S(= O) 2 OR 14 , -S(=O) 2 NR 15 R 16 , -O(CH 2 ) s OR 17 , -O(CH 2 ) s NR 18 R 19 , -NR 20 (CH 2 ) t NR 21 R 22 or -NR 23 (CH 2 ) t OR 24 .
一些实施方式中，在所述式III中，所述每个R c分别独立地选自氢、氧代、-CH 3、-OCH 3、-OH、-CN、-F、-Cl、-CF 3、-NH 2、-NHCH 3、-CH 2OH、-COOH、-COOEt、-S(＝O) 2CH 3、-S(＝O) 2NH 2、-CH 2OCH 3、
Figure PCTCN2021088871-appb-000033
In some embodiments, in the formula III, each R c is independently selected from hydrogen, oxo, -CH 3 , -OCH 3 , -OH, -CN, -F, -Cl, -CF 3 , -NH 2 , -NHCH 3 , -CH 2 OH, -COOH, -COOEt, -S(=O) 2 CH 3 , -S(=O) 2 NH 2 , -CH 2 OCH 3 ,
Figure PCTCN2021088871-appb-000033
一些实施方式中，在所述式III中，每个R 1分别独立地选自氢、卤素、氧代、C 1-4烷基、-NR 7R 8；其中，所述C 1-4烷基任选地被一个或多个取代基取代；所述取代基选自氢、卤素、-CN、-NO 2、氧代、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 3-6碳环基、3-6元杂环基、C 6- 10芳基、5-10元杂芳基、-OR 5、-SR 6、-NR 7R 8、-(C＝O)R 9、-C(＝O)OR 10或-C(＝O)NR 11R 12。 In some embodiments, in the formula III, each R 1 is independently selected from hydrogen, halogen, oxo, C 1-4 alkyl, -NR 7 R 8 ; wherein, the C 1-4 alkane The group is optionally substituted by one or more substituents; the substituents are selected from hydrogen, halogen, -CN, -NO 2 , oxo, C 1-4 alkyl, C 2-4 alkenyl, C 2- 4 alkynyl, C 3-6 carbocyclyl, 3-6-membered heterocyclyl, C 6- 10 aryl, 5-10 membered heteroaryl, -OR 5, -SR 6, -NR 7 R 8, - (C=O)R 9 , -C(=O)OR 10 or -C(=O)NR 11 R 12 .
一些实施方式中，在所述式III中，所述每个R 1分别独立地选自氢、氧代、-CH 3、-NH 2、-CH 2OH。 In some embodiments, in the formula III, each R 1 is independently selected from hydrogen, oxo, -CH 3 , -NH 2 , and -CH 2 OH.
一些实施方式中，在所述式III中，M选自-O-或-CR 1bR 1c-。 In some embodiments, in the formula III, M is selected from -O- or -CR 1b R 1c -.
一些实施方式中，在所述式III中，R 1b，R 1c分别独立地选自氢、C 1-3烷基、C 3-6环烷基、3-6元杂环基、-OR 1d或-NR 1eR 1f。 In some embodiments, in the formula III, R 1b and R 1c are each independently selected from hydrogen, C 1-3 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, -OR 1d Or -NR 1e R 1f .
一些实施方式中，在所述式III中，Y 1选自-NR 3a-，Y 2选自-CR 4bR 4c-。 In some embodiments, in the formula III, Y 1 is selected from -NR 3a -, and Y 2 is selected from -CR 4b R 4c -.
一些实施方式中，在所述式III中，Y 1选自-CR 3bR 3c-，Y 2选自-NR 4a-。 In some embodiments, in the formula III, Y 1 is selected from -CR 3b R 3c -, and Y 2 is selected from -NR 4a -.
一些实施方式中，在所述式III中，Y 1选自-CR 3bR 3c-，Y 2选自-CR 4bR 4c-。 In some embodiments, in the formula III, Y 1 is selected from -CR 3b R 3c -, and Y 2 is selected from -CR 4b R 4c -.
一些实施方式中，在所述式III中，所述环D为C 6-10芳基或5-10元杂芳基。 In some embodiments, in the formula III, the ring D is a C 6-10 aryl group or a 5-10 membered heteroaryl group.
一些实施方式中，在所述式III中，所述环D为
Figure PCTCN2021088871-appb-000034
Figure PCTCN2021088871-appb-000035
In some embodiments, in the formula III, the ring D is
Figure PCTCN2021088871-appb-000034
Figure PCTCN2021088871-appb-000035
一些实施方式中，在所述式III中，所述环D为
Figure PCTCN2021088871-appb-000036
In some embodiments, in the formula III, the ring D is
Figure PCTCN2021088871-appb-000036
一些实施方式中，在所述式III中，所述环D为
Figure PCTCN2021088871-appb-000037
In some embodiments, in the formula III, the ring D is
Figure PCTCN2021088871-appb-000037
一些实施方式中，在所述式III中，所述环D为C 3-8碳环基或3-8元杂环基。 In some embodiments, in the formula III, the ring D is a C 3-8 carbocyclic group or a 3-8 membered heterocyclic group.
一些实施方式中，在所述式III中，所述环D为
Figure PCTCN2021088871-appb-000038
In some embodiments, in the formula III, the ring D is
Figure PCTCN2021088871-appb-000038
一些实施方式中，在所述式III中，每个R 4分别独立地选自氢、卤素、氧代、C 1-8烷基或-OR 5。 In some embodiments, in the formula III, each R 4 is independently selected from hydrogen, halogen, oxo, C 1-8 alkyl, or -OR 5 .
一些实施方式中，在所述式III中，每个R 4分别独立地选自氢、氧代、-CH 3或-OCH 3。 In some embodiments, in the formula III, each R 4 is independently selected from hydrogen, oxo, -CH 3 or -OCH 3 .
一些实施方式中，在所述式I中，q为0、1或2。In some embodiments, in the formula I, q is 0, 1, or 2.
一些实施方式中，在所述式I中，r为0、1、2或3。In some embodiments, in the formula I, r is 0, 1, 2 or 3.
一些实施方式中，在所述式I中，s为1或2。In some embodiments, in the formula I, s is 1 or 2.
一些实施方式中，在所述式I中，t为1或2。In some embodiments, in the formula I, t is 1 or 2.
一些实施方式中，式I所述化合物选自：In some embodiments, the compound of formula I is selected from:
3-(5-((S)-1-氨基-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-6-(羟甲基)吡嗪-2-基)-1-苯丙-2-炔-1-醇；3-(5-((S)-1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(hydroxymethyl)pyrazine-2 -Base)-1-phenylprop-2-yn-1-ol;
(S)-(3-(1-氨基-1,3-二氢螺并[茚-2,4'-哌啶]-1'-基)-6-(3-苯基丙-1-炔-1-基)吡嗪-2-基)甲醇；(S)-(3-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(3-phenylprop-1-yne -1-yl)pyrazin-2-yl)methanol;
(S)-3-(3-(5-(1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-6-(羟甲基)吡嗪-2-基)丙-2-炔-1-基)苯酚；(S)-3-(3-(5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(hydroxymethyl) Pyrazin-2-yl)prop-2-yn-1-yl)phenol;
(S)-(3-(1-氨基-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-6-(3-吗啉代丙-1-炔-1-基)吡嗪-2-基)甲醇；(S)-(3-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(3-morpholinoprop-1-yne -1-yl)pyrazin-2-yl)methanol;
(S)-(3-(1-氨基-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-6-(3-(4-甲基哌嗪-1-基)丙-1-炔-1-基)吡嗪-2-基)甲醇；(S)-(3-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(3-(4-methylpiperazine- 1-yl)prop-1-yn-1-yl)pyrazin-2-yl)methanol;
(S)-(3-(1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-6-(3-(4-甲氧基苯基)丙基-1-基)吡嗪-2-基)甲醇；(S)-(3-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(3-(4-methoxybenzene (Yl)propyl-1-yl)pyrazin-2-yl)methanol;
(S)-(3-(1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-6-(3-(1-甲基-1H-吡唑-5-基)丙-1-炔-1-基)吡嗪-2-基)甲醇；(S)-(3-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(3-(1-methyl-1H -Pyrazol-5-yl)prop-1-yn-1-yl)pyrazin-2-yl)methanol;
(S)-4-(3-(5-(1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-6-(羟甲基)吡嗪-2-基)丙-2-炔-1-基)苯酚；(S)-4-(3-(5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(hydroxymethyl) Pyrazin-2-yl)prop-2-yn-1-yl)phenol;
(S)-2-(1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-5-(3-(4-羟基苯基)丙-1-炔-1-基)-3-甲基嘧啶-4(3H)-酮；(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(4-hydroxyphenyl)propane -1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;
(S)-2-(1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-5-(3-(4-氯-3-羟基苯基)丙-1-炔-1-基)-3-甲基嘧啶-4(3H)-酮；(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(4-chloro-3-hydroxyl (Phenyl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;
(S)-2-(1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-5-(3-(3-羟基苯基)丙-1-炔-1-基)-3-甲基嘧啶-4(3H)-酮；(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(3-hydroxyphenyl)propane -1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;
(S)-2-(1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-5-(3-(3,4-二羟基苯基)丙-1-炔-1-基)-3-甲基嘧啶-4(3H)-酮；(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(3,4-dihydroxybenzene (Yl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;
(S)-2-(1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-5-(3-(4-氟-3-羟基苯基)丙-1-炔-1-基)-3-甲基嘧啶-4(3H)-酮；(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(4-fluoro-3-hydroxyl (Phenyl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;
(S)-3-(3-(2-(1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-1-甲基-6-氧代-1,6-二氢嘧啶-5-基)丙-2-炔-1-基)苯甲腈；(S)-3-(3-(2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-1-methyl-6- Oxo-1,6-dihydropyrimidin-5-yl)prop-2-yn-1-yl)benzonitrile;
(S)-2-(1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-3-甲基-5-(3-(2-(三氟甲基)吡啶-3-基)丙-1-炔-1-基)嘧啶-4(3H)-酮；(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-3-methyl-5-(3-(2- (Trifluoromethyl)pyridin-3-yl)prop-1-yn-1-yl)pyrimidin-4(3H)-one;
(S)-2-(1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-3-甲基-5-(3-(三氟甲基)苯基)丙-1-炔-1-基)嘧啶-4(3H)-酮；(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-3-methyl-5-(3-(trifluoro (Methyl)phenyl)prop-1-yn-1-yl)pyrimidin-4(3H)-one;
(S)-2-(1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-5-(3-(3-甲氧基苯基)丙-1-炔-1-基)-3-甲基嘧啶-4(3H)-酮；(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(3-methoxyphenyl )Prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;
(S)-2-(1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-5-(3-(3,4-二氟苯基)丙-1-炔-1-基)-3-甲基嘧啶-4(3H)-酮；(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(3,4-difluorobenzene (Yl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;
(R)-2-(1-氨基-8-氮杂螺[4.5]癸-8-基)-5-(3-(3-羟基苯基)丙-1-炔-1-基)-3-甲基嘧啶-4(3H)-酮；(R)-2-(1-Amino-8-azaspiro[4.5]dec-8-yl)-5-(3-(3-hydroxyphenyl)prop-1-yn-1-yl)-3 -Methylpyrimidin-4(3H)-one;
(S)-2-(1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-5-(3-(4-氟-3-甲氧基苯基)丙-1-炔-1-基)-3-甲基嘧啶-4(3H)-酮；(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(4-fluoro-3-methyl (Oxyphenyl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;
(S)-2-(1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-5-(3-(2,3-二羟基苯基)丙-1-炔-1-基)-3-甲基嘧啶-4(3H)-酮；(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(2,3-dihydroxybenzene (Yl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;
(S)-2-(1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-5-(3-(3,5-二羟基苯基)丙-1-炔-1-基)-3-甲基嘧啶-4(3H)-酮；(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(3,5-dihydroxybenzene (Yl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;
(S)-2-(1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-3-甲基-5-(3-(4-吗啉苯基)丙-1-炔-1-基)嘧啶-4(3H)-酮；(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-3-methyl-5-(3-(4- Morpholinophenyl)prop-1-yn-1-yl)pyrimidin-4(3H)-one;
(S)-2-(1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-5-(3-(6-甲氧基吡啶-3-基)丙-1-炔-1-基)-3-甲基嘧啶-4(3H)-酮；(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(6-methoxypyridine- 3-yl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;
(S)-4-(3-(2-(1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-1-甲基-6-氧代-1,6-二氢嘧啶-5-基)丙-2-炔-1-基)-2-氟苯甲腈；(S)-4-(3-(2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-1-methyl-6- Oxo-1,6-dihydropyrimidin-5-yl)prop-2-yn-1-yl)-2-fluorobenzonitrile;
(S)-2-(1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-5-(3-(6-羟基吡啶-3-基)丙-1-炔-1-基)-3-甲基嘧啶-4(3H)-酮；(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(6-hydroxypyridine-3- (Yl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;
(S)-2-(1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-5-(3-(6-羟基吡啶-2-基)丙-1-炔-1-基)-3-甲基嘧啶-4(3H)-酮；(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(6-hydroxypyridine-2- (Yl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;
(S)-2-(1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-5-(3-(2-羟基吡啶-4-基)丙-1-炔-1-基)-3-甲基嘧啶-4(3H)-酮；(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(2-hydroxypyridine-4- (Yl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;
(S)-2-(1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-5-(3-(2-氨基-3-氯吡啶-4-基)丙-1-炔-1-基)-3-甲基嘧啶-4(3H)-酮；(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(2-amino-3-chloro (Pyridin-4-yl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;
(S)-2-(1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-5-(3-(2-羟基嘧啶-4-基)丙-1-炔-1-基)-3-甲基嘧啶-4(3H)-酮；(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(2-hydroxypyrimidine-4- (Yl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;
(S)-2-(1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-5-(3-(2-氨基嘧啶-4-基)丙-1-炔-1-基)-3-甲基嘧啶-4(3H)-酮；(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(2-aminopyrimidine-4- (Yl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;
(S)-6-氨基-2-(1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-5-(3-(2-羟基吡啶-4-基)丙-1-炔-1-基)-3-甲基嘧啶-4(3H)-酮；(S)-6-amino-2-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(2-hydroxyl (Pyridin-4-yl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;
(S)-6-氨基-2-(1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-5-(3-(3-羟基苯基)丙-1-炔-1-基)-3-甲基嘧啶-4(3H)-酮；(S)-6-amino-2-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(3-hydroxyl (Phenyl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;
(S)-4-(3-(4-氨基-2-(1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-1-甲基-6-氧代-1,6-二氢嘧啶-5-基)丙-2-炔-1-基)-2-氟苯甲腈；(S)-4-(3-(4-Amino-2-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-1-methyl 6-oxo-1,6-dihydropyrimidin-5-yl)prop-2-yn-1-yl)-2-fluorobenzonitrile;
(S)-6-氨基-2-(1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-5-(3-(2-氨基-3-氯吡啶-4-基)丙-1-炔-1-基)-3-甲基嘧啶-4(3H)-一；(S)-6-amino-2-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(2-amino -3-Chloropyridin-4-yl)prop-1-yn-1-yl)-3-methylpyrimidine-4(3H)-one;
(S)-2-(1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-3-甲基-5-(3-(2-(甲胺基)吡啶-4-基)丙-1-炔-1-基)嘧啶-4(3H)-酮；(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-3-methyl-5-(3-(2- (Methylamino)pyridin-4-yl)prop-1-yn-1-yl)pyrimidin-4(3H)-one;
(S)-2-(1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-5-(3-(2-氨基嘧啶-5-基)丙-1-炔-1-基)-3-甲基嘧啶-4(3H)-酮；(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(2-aminopyrimidine-5- (Yl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;
(S)-5-(3-(4-(1H-吡唑-1-基)苯基)丙-1-in-1-基)-2-(1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-3-甲基嘧啶-4(3H)-酮；(S)-5-(3-(4-(1H-pyrazol-1-yl)phenyl)prop-1-in-1-yl)-2-(1-amino-1,3-dihydrospiro Cyclo[indene-2,4'-piperidine]-1'-yl)-3-methylpyrimidin-4(3H)-one;
4-(3-(2-((S)-1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-1-甲基-6-氧代-1,6-二氢嘧啶-5-基)-1-氟丙烯-2-对-1-基)-2-羟基苯甲腈；4-(3-(2-((S)-1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-1-methyl-6- Oxo-1,6-dihydropyrimidin-5-yl)-1-fluoropropene-2-p-1-yl)-2-hydroxybenzonitrile;
(S)-5-(3-(1H-吲哒唑-6-基)丙-1-炔-1-基)-2-(1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-3-甲基嘧啶-4(3H)-酮；(S)-5-(3-(1H-indazol-6-yl)prop-1-yn-1-yl)-2-(1-amino-1,3-dihydrospiro[indene-2 ,4'-Piperidine]-1'-yl)-3-methylpyrimidin-4(3H)-one;
(S)-2-(1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-5-(3-(3-羟基-4-吗啉苯基)丙-1-炔-1-基)-3-甲基嘧啶-4(3H)-酮；(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(3-hydroxy-4-? (Pholinyl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;
(S)-6-(3-(2-(1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-1-甲基-6-氧代-1,6-二氢嘧啶-5-基)丙-2-炔-1-基)吲哚-2-酮；(S)-6-(3-(2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-1-methyl-6- Oxo-1,6-dihydropyrimidin-5-yl)prop-2-yn-1-yl)indol-2-one;
(S)-5-(3-(1H-吲哚-6-基)丙-1-炔-1-基)-2-(1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-3-甲基嘧啶-4(3H)-酮；(S)-5-(3-(1H-indol-6-yl)prop-1-yn-1-yl)-2-(1-amino-1,3-dihydrospiro[indene-2, 4'-Piperidine]-1'-yl)-3-methylpyrimidin-4(3H)-one;
(S)-2-(1-氨基-6-甲氧基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-5-(3-(3-羟基苯基)丙-1-炔-1-基)-3-甲基嘧啶-4(3H)-酮；(S)-2-(1-Amino-6-methoxy-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(3 -Hydroxyphenyl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;
(S)-2-(1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-5-(3-(3-羟基苯基)丙-1-炔-1-基)嘧啶-4(3H)-酮；(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(3-hydroxyphenyl)propane -1-yn-1-yl)pyrimidin-4(3H)-one;
(S)-2-(1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-5-(3-(2-氨基-3-氯吡啶-4-基)丙-1-炔-1-基)嘧啶-4(3H)-酮；(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(2-amino-3-chloro (Pyridin-4-yl)prop-1-yn-1-yl)pyrimidin-4(3H)-one;
(S)-5-(3-(2-氨基-3-氯吡啶-4-基)丙-1-炔-1-基)-2-(1-氨基-6-甲氧基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)嘧啶-4(3H)-酮；(S)-5-(3-(2-Amino-3-chloropyridin-4-yl)prop-1-yn-1-yl)-2-(1-amino-6-methoxy-1,3 -Dihydrospirocyclo[indene-2,4'-piperidine]-1'-yl)pyrimidin-4(3H)-one;
2-((S)-1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-5-(3-氟-3-(3-羟基苯基)丙-1-炔-1-基)-3-甲基嘧啶-4(3H)-酮；2-((S)-1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-fluoro-3-(3-hydroxyl (Phenyl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;
(S)-2-(1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-5-(3-(4-氯-2,3-二羟基苯基)丙-1-炔-1-基)-3-甲基嘧啶-4(3H)-酮；(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(4-chloro-2,3 -Dihydroxyphenyl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;
(S)-6-氨基-2-(4-氨基-4,6-二氢螺环[d]噻唑-5,4'-哌啶]-1'-基)-5-(3-(4-氯-3-羟基苯基)丙-1-炔-1-基)-3-甲基嘧啶-4(3H)-酮；(S)-6-amino-2-(4-amino-4,6-dihydrospiro[d]thiazole-5,4'-piperidine]-1'-yl)-5-(3-(4 -Chloro-3-hydroxyphenyl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;
(S)-2-(4-氨基-4,6-二氢螺环[d]噻唑-5,4'-哌啶]-1'-基)-5-(3-(4-氯-3-羟基苯基)丙-1-炔-1-基)-3-甲基嘧啶-4(3H)-酮；(S)-2-(4-Amino-4,6-dihydrospiro[d]thiazole-5,4'-piperidine]-1'-yl)-5-(3-(4-chloro-3 -Hydroxyphenyl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;
(S)-2-(1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-5-(3-(4-氟-2,3-二羟基苯基)丙-1-炔-1-基)-3-甲基嘧啶-4(3H)-酮；(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(4-fluoro-2,3 -Dihydroxyphenyl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;
(S)-2-(1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-5-(3-(4-氟-3,5-二羟基苯基)丙-1-炔-1-基)-3-甲基嘧啶-4(3H)-酮；(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(4-fluoro-3,5 -Dihydroxyphenyl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;
(S)-6-(3-(2-(1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-1-甲基-6-氧代-1,6-二氢嘧啶-5-基)丙-2-辛-1-基)-2-羟基-3-甲基苯甲腈；(S)-6-(3-(2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-1-methyl-6- Oxo-1,6-dihydropyrimidin-5-yl)propan-2-oct-1-yl)-2-hydroxy-3-methylbenzonitrile;
(S)-4-(3-(2-(1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-1-甲基-6-氧代-1,6-二氢嘧啶-5-基)丙-2-炔-1-基)-2-羟基苯甲腈；(S)-4-(3-(2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-1-methyl-6- Oxo-1,6-dihydropyrimidin-5-yl)prop-2-yn-1-yl)-2-hydroxybenzonitrile;
(S)-2-(3-(2-(1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-1-甲基-6-氧代-1,6-二氢嘧啶-5-基)丙-2-炔-1-基)-6-羟基苯甲腈；(S)-2-(3-(2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-1-methyl-6- Oxo-1,6-dihydropyrimidin-5-yl)prop-2-yn-1-yl)-6-hydroxybenzonitrile;
(S)-4-(3-(2-(1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-1-甲基-6-氧代-1,6-二氢嘧啶-5-基)丙-2-炔-1-基)-2,6-二羟基苯甲腈；(S)-4-(3-(2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-1-methyl-6- Oxo-1,6-dihydropyrimidin-5-yl)prop-2-yn-1-yl)-2,6-dihydroxybenzonitrile;
(S)-6-(3-(2-(1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-1-甲基-6-氧代-1,6-二氢嘧啶-5-基)丙-2-炔-1-基)-3-氯-2-羟基苯甲腈；(S)-6-(3-(2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-1-methyl-6- Oxo-1,6-dihydropyrimidin-5-yl)prop-2-yn-1-yl)-3-chloro-2-hydroxybenzonitrile;
(S)-2-(1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-5-(3-(3-羟基苯基)-3-甲基-1-基)-3-甲基嘧啶-4(3H)-酮；(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(3-hydroxyphenyl)- 3-methyl-1-yl)-3-methylpyrimidin-4(3H)-one;
2-((S)-1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-5-(3-氟-3-(3-甲氧基苯基)丙-1-炔-1-基)-3-甲基嘧啶-4(3H)-酮；2-((S)-1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-fluoro-3-(3-methyl (Oxyphenyl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;
2-((S)-1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-5-(3-羟基-3-(3-甲氧基苯基)丙-1-炔-1-基)-3-甲基嘧啶-4(3H)-酮；2-((S)-1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-hydroxy-3-(3-methyl (Oxyphenyl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;
2-((S)-1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-5-(3-羟基-3-(3-羟基苯基)丙-1-炔-1-基)-3-甲基嘧啶-4(3H)-酮；2-((S)-1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-hydroxy-3-(3-hydroxyl (Phenyl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;
(S)-2-(5-氨基-5,7-二氢螺环[b]吡啶-6,4'-哌啶]-1'-基)-5-(3-(3-羟基苯基)丙-1-炔-1-基)-3-甲基嘧啶-4(3H)-酮；(S)-2-(5-Amino-5,7-dihydrospiro[b]pyridine-6,4'-piperidine]-1'-yl)-5-(3-(3-hydroxyphenyl) )Prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;
(S)-2-(7-氨基-5,7-二氢螺环[d]嘧啶-6,4'-哌啶]-1'-基)-5-(3-(3-羟基苯基)丙-1-炔-1-基)-3-甲基嘧啶-4(3H)-酮；(S)-2-(7-Amino-5,7-dihydrospiro[d]pyrimidine-6,4'-piperidine]-1'-yl)-5-(3-(3-hydroxyphenyl )Prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;
(S)-2-(1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-3-甲基-5-((1-苯基环丙基)乙炔基)嘧啶-4(3H)-酮；(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-3-methyl-5-((1-phenyl Cyclopropyl)ethynyl)pyrimidin-4(3H)-one;
(R)-6-氨基-2-(3-氨基-3H-螺环[苯并呋喃-2,4'-哌啶]-1'-基)-5-(3-(4-氯-3-羟基苯基)丙-1-炔-1-基)-3-甲基嘧啶-4(3H)-酮；(R)-6-amino-2-(3-amino-3H-spiro[benzofuran-2,4'-piperidine]-1'-yl)-5-(3-(4-chloro-3 -Hydroxyphenyl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;
(R)-2-(3'-氨基-3'H-螺环[哌啶-4,2'-噻吩[2,3-b]呋喃]-1-基)-5-(3-(3-羟基苯基)丙-1-炔-1-基)-3-甲基嘧啶-4(3H)-酮；(R)-2-(3'-Amino-3'H-spiro[piperidine-4,2'-thiophene[2,3-b]furan]-1-yl)-5-(3-(3 -Hydroxyphenyl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;
(R)-2-(6-氨基-6H-螺环[氟[3,2-d]噻唑-5,4'-哌啶]-1'-基)-5-(3-(3-羟基苯基)丙-1-炔-1-基)-3-甲基嘧啶-4(3H)-酮；(R)-2-(6-Amino-6H-spiro[fluoro[3,2-d]thiazole-5,4'-piperidine]-1'-yl)-5-(3-(3-hydroxy (Phenyl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;
(S)-2-(3-氨基-3H-螺环[呋喃[3,2-b]呋喃-2,4'-哌啶]-1'-基)-5-(3-(3-羟基苯基)丙-1-炔-1-基)-3-甲基嘧啶-4(3H)-酮；(S)-2-(3-Amino-3H-spiro[furan[3,2-b]furan-2,4'-piperidine]-1'-yl)-5-(3-(3-hydroxyl (Phenyl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;
(S)-2-(6-氨基-6H-螺环[氟[2,3-d]恶唑-5,4'-哌啶]-1'-基)-5-(3-(3-羟基苯基)丙-1-炔-1-基)-3-甲基嘧啶-4(3H)-酮；(S)-2-(6-Amino-6H-spiro[fluoro[2,3-d]oxazole-5,4'-piperidine]-1'-yl)-5-(3-(3- Hydroxyphenyl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;
(R)-2-(6-氨基-2-甲基-6H-螺环[氟[3,2-d]噻唑-5,4'-哌啶]-1'-基)-5-(3-羟基苯基)丙-1-炔-1-基)-3-甲基嘧啶-4(3H)-酮；(R)-2-(6-Amino-2-methyl-6H-spiro[fluoro[3,2-d]thiazole-5,4'-piperidine]-1'-yl)-5-(3 -Hydroxyphenyl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;
2-((S)-1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-5-((2-(羟甲基)环丙基)乙炔基)-3-甲基嘧啶-4(3H)-酮；2-((S)-1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-((2-(hydroxymethyl)cyclopropyl (Yl)ethynyl)-3-methylpyrimidin-4(3H)-one;
5-((2-(1,3,4-恶二唑-2-基)环丙基)乙炔基)-2-((S)-1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-3-甲基嘧啶-4(3H)-酮；5-((2-(1,3,4-oxadiazol-2-yl)cyclopropyl)ethynyl)-2-((S)-1-amino-1,3-dihydrospiro[indene -2,4'-piperidine]-1'-yl)-3-methylpyrimidin-4(3H)-one;
2-((5-((S)-1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-6-(羟甲基)吡嗪-2-基)乙炔基)环丙烷-1-羧酸乙酯；2-((5-((S)-1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(hydroxymethyl)pyrazine -2-yl)ethynyl)ethyl cyclopropane-1-carboxylate;
2-((5-((S)-1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-6-(羟甲基)吡嗪-2-基)乙炔基)环丙烷-1-羧酸；2-((5-((S)-1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(hydroxymethyl)pyrazine -2-yl)ethynyl)cyclopropane-1-carboxylic acid;
2-((5-((S)-1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-6-(羟甲基)吡嗪-2-基)乙炔基)-N-环丙基环丙烷-1-甲酰胺；2-((5-((S)-1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(hydroxymethyl)pyrazine -2-yl)ethynyl)-N-cyclopropylcyclopropane-1-carboxamide;
2-((2-((S)-1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-1-甲基-6-氧代-1,6-二氢嘧啶-5-基)乙炔基)环丙烷-1-羧酸乙酯；2-((2-((S)-1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-1-methyl-6-oxo -1,6-Dihydropyrimidin-5-yl)ethynyl)cyclopropane-1-carboxylic acid ethyl ester;
2-((S)-1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-3-甲基-5-((2-(甲磺酰基)环丙基)乙炔基)嘧啶-4(3H)-酮；2-((S)-1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-3-methyl-5-((2-(methyl (Sulfonyl)cyclopropyl)ethynyl)pyrimidin-4(3H)-one;
2-((2-((S)-1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-1-甲基-6-氧代-1,6-二氢嘧啶-5-基)乙炔基)环丙烷-1-磺酰胺；2-((2-((S)-1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-1-methyl-6-oxo -1,6-Dihydropyrimidin-5-yl)ethynyl)cyclopropane-1-sulfonamide;
2-((S)-1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-3-甲基-5-((2-(2,2,2-三氟-1-羟乙基)环丙基)乙炔基)嘧啶-4(3H)-酮；2-((S)-1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-3-methyl-5-((2-(2 ,2,2-Trifluoro-1-hydroxyethyl)cyclopropyl)ethynyl)pyrimidin-4(3H)-one;
2-((S)-1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-5-((2-(甲氧基甲基)环丙基)乙炔基)-3-甲基嘧啶-4(3H)-酮；2-((S)-1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-((2-(methoxymethyl) Cyclopropyl)ethynyl)-3-methylpyrimidin-4(3H)-one;
(2-((S)-1-氨基-1,3-二氢螺环[茚-2,4'哌啶]-1'-基)-5-(2-氧-8-氮杂螺[4.5]癸-8-基)3-羟基-3-(4-吗啉苯基)丙-1-炔-1-基)-3-甲基嘧啶-4(3H)-酮；(2-((S)-1-amino-1,3-dihydrospiro[indene-2,4'piperidine]-1'-yl)-5-(2-oxo-8-azaspiro[ 4.5] Dec-8-yl)3-hydroxy-3-(4-morpholinphenyl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;
2-((5-((S)-1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-6-(羟甲基)吡嗪-2-2-基)乙炔基)环丙烷酰胺；2-((5-((S)-1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(hydroxymethyl)pyrazine -2-2-yl)ethynyl)cyclopropaneamide;
2-((3S,4S)-4-氨基-3-甲基-2-氧-8-偶氮[4.5]癸-8-基)-5-(3-(3-羟基苯基)丙-1-炔-1-基)--3-甲基嘧啶-4(3H)-酮；2-((3S,4S)-4-amino-3-methyl-2-oxo-8-azo[4.5]dec-8-yl)-5-(3-(3-hydroxyphenyl)propan- 1-Alkyn-1-yl)-3-methylpyrimidin-4(3H)-one;
(S)-1-(3-(5-(1-氨基-1,3-二氢螺[茚-2,4’-哌啶]-1'-基)-6-(羟甲基)吡嗪-2-基)丙-2-炔-1-基)-1H-吡唑-3-羧酰胺；(S)-1-(3-(5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(hydroxymethyl)pyridine (Azin-2-yl)prop-2-yn-1-yl)-1H-pyrazole-3-carboxamide;
(S)-N-(3-(3-(5-(1-氨基-1,3-二氢螺[茚-2,4’-哌啶]-1'-基)-6-(羟甲基)吡嗪-2-基)丙-2-炔-1-基)苯基)乙酰胺；(S)-N-(3-(3-(5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(hydroxymethyl (Yl)pyrazin-2-yl)prop-2-yn-1-yl)phenyl)acetamide;
(S)-3-(3-(5-(1-氨基-1,3-二氢螺[茚-2,4’-哌啶]-1'-基)-6-(羟甲基)吡嗪-2-基)丙-2-炔-1-基)苯甲酰胺；(S)-3-(3-(5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(hydroxymethyl)pyridine (Azin-2-yl)prop-2-yn-1-yl)benzamide;
(S)-4-(3-(5-(1-氨基-1,3-二氢螺[茚-2,4’-哌啶]-1'-基)-6-(羟甲基)吡嗪-2-基)丙-2-炔-1-基)苯甲酰胺；(S)-4-(3-(5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(hydroxymethyl)pyridine (Azin-2-yl)prop-2-yn-1-yl)benzamide;
(S)-4-(4-(5-(1-氨基-1,3-二氢螺[茚-2,4’-哌啶]-1'-基)-6-(羟甲基)吡嗪-2-基)丁-3-炔-1-基)苯甲酰胺；(S)-4-(4-(5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(hydroxymethyl)pyridine (Azin-2-yl)but-3-yn-1-yl)benzamide;
(S)-(3-(1-氨基-1,3-二氢螺[茚-2,4’-哌啶]-1’-基)-6-(4-苯基丁-1-炔-1-基)吡嗪-2-基)甲醇；(S)-(3-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(4-phenylbut-1-yne- 1-yl)pyrazin-2-yl)methanol;
(S)-2-(3-(5-(1-氨基-1,3-二氢螺[茚-2,4’-哌啶]-1'-基)-6-(羟甲基)吡嗪-2-基)丙-2-炔-1-基)异吲哚啉-5-羧酰胺；(S)-2-(3-(5-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(hydroxymethyl)pyridine (Azin-2-yl)prop-2-yn-1-yl)isoindoline-5-carboxamide;
(S)-(3-(1-氨基-1,3-二氢螺[茚-2,4’-哌啶]-1'-基)-6-(3-(吲哚-1-基)丙-1-炔-1-基)吡嗪-2-基)甲醇；(S)-(3-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)-6-(3-(indol-1-yl) Prop-1-yn-1-yl)pyrazin-2-yl)methanol;
(S)-1-(3-(5-(1-氨基-1,3-二氢螺[茚-2,4’-哌啶]-1'-基)-6-(羟甲基)吡嗪-2-基)丙-2-炔-1-基)-1H-吲唑-5-醇；(S)-1-(3-(5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(hydroxymethyl)pyridine (Azin-2-yl)prop-2-yn-1-yl)-1H-indazol-5-ol;
(S)-(3-(1-氨基-1,3-二氢螺[茚-2,4’-哌啶]-1'-基)-6-(3-(5-氨基-1H-吲哚-1-基)丙-1-炔-1-基)吡嗪-2-基)甲醇；(S)-(3-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(3-(5-amino-1H-indyl) Dol-1-yl)prop-1-yn-1-yl)pyrazin-2-yl)methanol;
(S)-N-(1-(3-(5-(1-氨基-1,3-二氢螺[茚-2,4’-哌啶]-1'-基)-6-(羟甲基)吡嗪-2-基)丙-2-炔-1-基)-1H-吲唑-5-基)乙酰胺；(S)-N-(1-(3-(5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(hydroxymethyl (Yl)pyrazin-2-yl)prop-2-yn-1-yl)-1H-indazol-5-yl)acetamide;
(S)-(3-(1-氨基-1,3-二氢螺[茚-2,4’-哌啶]-1'-基)-6-(3-(6-氨基-1H-吲唑-1-基)丙-1-炔-1-基)吡嗪-2-基)甲醇；(S)-(3-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(3-(6-amino-1H-indyl (Azol-1-yl)prop-1-yn-1-yl)pyrazin-2-yl)methanol;
(S)-(3-(1-氨基-1,3-二氢螺[茚-2,4’-哌啶]-1'-基)-6-(3-(4-氨基-1H-吲唑-1-基)丙-1-炔-1-基)吡嗪-2-基)甲醇；(S)-(3-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(3-(4-amino-1H-indyl (Azol-1-yl)prop-1-yn-1-yl)pyrazin-2-yl)methanol;
(S)-1-(3-(5-(1-氨基-1,3-二氢螺[茚-2,4’-哌啶]-1'-基)-6-(羟甲基)吡嗪-2-基)丙-2-炔-1-基)-1H-吲唑-5-羧酰胺；(S)-1-(3-(5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(hydroxymethyl)pyridine (Azin-2-yl)prop-2-yn-1-yl)-1H-indazole-5-carboxamide;
(S)-N-(1-(3-(5-(1-氨基-1,3-二氢螺[茚-2,4’-哌啶]-1'-基)-6-(羟甲基)吡嗪-2-基)丙-2-炔-1-基)-1H-吲唑-4-基)乙酰胺；(S)-N-(1-(3-(5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(hydroxymethyl (Yl)pyrazin-2-yl)prop-2-yn-1-yl)-1H-indazol-4-yl)acetamide;
(S)-1-(3-(5-(1-氨基-1,3-二氢螺[茚-2,4’-哌啶]-1'-基)-6-(羟甲基)吡嗪-2-基)丙-2-炔-1-基)-1H-苯并[d]咪唑-5-羧酰胺；(S)-1-(3-(5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(hydroxymethyl)pyridine (Azin-2-yl)prop-2-yn-1-yl)-1H-benzo[d]imidazole-5-carboxamide;
(S)-1-(3-(5-(1-氨基-1,3-二氢螺[茚-2,4’-哌啶]-1'-基)-6-(羟甲基)吡嗪-2-基)丙-2-炔-1-基)-1H-苯并[d]咪唑-6-羧酰胺；(S)-1-(3-(5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(hydroxymethyl)pyridine (Azin-2-yl)prop-2-yn-1-yl)-1H-benzo[d]imidazole-6-carboxamide;
(S)-(3-(1-氨基-1,3-二氢螺[茚-2,4’-哌啶]-1'-基)-6-(3-(5-甲氧基-1H-苯并[d]咪唑-1-基)丙-1-炔-1-基)吡嗪-2-基)甲醇；(S)-(3-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(3-(5-methoxy-1H -Benzo[d]imidazol-1-yl)prop-1-yn-1-yl)pyrazin-2-yl)methanol;
(S)-(6-(3-(1H-吲哚-1-基)丙-1-炔-1-基)-3-(1-氨基-1,3-二氢螺[茚-2,4’-哌啶]-1'-基)吡嗪-2-基)甲醇；(S)-(6-(3-(1H-indol-1-yl)prop-1-yn-1-yl)-3-(1-amino-1,3-dihydrospiro[indene-2, 4'-Piperidine]-1'-yl)pyrazin-2-yl)methanol;
(S)-1-(3-(5-(1-氨基-1,3-二氢螺[茚-2,4’-哌啶]-1'-基)-6-(羟甲基)吡嗪-2-基)丙-2-炔-1-基)吲哚啉-5-羧酰胺；(S)-1-(3-(5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(hydroxymethyl)pyridine (Azin-2-yl)prop-2-yn-1-yl)indoline-5-carboxamide;
(S)-(3-(1-氨基-1,3-二氢螺[茚-2,4’-哌啶]-1'-基)-6-(3-(5-硝基吲哚-1-基)丙-1-炔-1-基)吡嗪-2-基)甲醇；(S)-(3-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(3-(5-nitroindole- 1-yl)prop-1-yn-1-yl)pyrazin-2-yl)methanol;
(S)-1-(3-(5-(1-氨基-1,3-二氢螺[茚-2,4’-哌啶]-1'-基)-6-(羟甲基)吡嗪-2-基)丙-2-炔-1-基)-1H-吲哚-5-羧酰胺；(S)-1-(3-(5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(hydroxymethyl)pyridine (Azin-2-yl)prop-2-yn-1-yl)-1H-indole-5-carboxamide;
(S)-1-(3-(5-(1-氨基-1,3-二氢螺[茚-2,4’-哌啶]-1'-基)-6-(羟甲基)吡嗪-2-基)丙-2-炔-1-基)-1H-吲唑-6-羧酰胺；(S)-1-(3-(5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(hydroxymethyl)pyridine (Azin-2-yl)prop-2-yn-1-yl)-1H-indazole-6-carboxamide;
(S)-N-(1-(3-(5-(1-氨基-1,3-二氢螺[茚-2,4’-哌啶]-1'-基)-6-(羟甲基)吡嗪-2-基)丙-2-炔-1-基)-1H-吲唑-6-基)乙酰胺；(S)-N-(1-(3-(5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(hydroxymethyl (Yl)pyrazin-2-yl)prop-2-yn-1-yl)-1H-indazol-6-yl)acetamide;
(S)-3-(3-(5-(1-氨基-1,3-二氢螺[茚-2,4’-哌啶]-1'-基)-6-(羟甲基)吡嗪-2-基)丙-2-炔-1-基)苯并[d]异恶唑-6-羧酰胺；(S)-3-(3-(5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(hydroxymethyl)pyridine (Azin-2-yl)prop-2-yn-1-yl)benzo[d]isoxazole-6-carboxamide;
(S)-1-(3-(5-(1-氨基-1,3-二氢螺[茚-2,4’-哌啶]-1'-基)-6-(羟甲基)吡嗪-2-基)丙-2-炔-1-基)吲哚嗪-6-羧酰胺；(S)-1-(3-(5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(hydroxymethyl)pyridine (Azin-2-yl)prop-2-yn-1-yl)indolazine-6-carboxamide;
(S)-(3-(1-氨基-1,3-二氢螺[茚-2,4’-哌啶]-1'-基)-6-(3-(5-氨基-1H-吲唑-1-基)丙-1-炔-1-基)吡嗪-2-基)甲醇；(S)-(3-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(3-(5-amino-1H-indyl) (Azol-1-yl)prop-1-yn-1-yl)pyrazin-2-yl)methanol;
(S)-(3-(1-氨基-1,3-二氢螺[茚-2,4’-哌啶]-1'-基)-6-(3-(5-甲氧基-1H-吲唑-1-基)丙-1-炔-1-基)吡嗪-2-基)甲醇；(S)-(3-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(3-(5-methoxy-1H -Indazol-1-yl)prop-1-yn-1-yl)pyrazin-2-yl)methanol;
(S)-(3-(1-氨基-1,3-二氢螺[茚-2,4’-哌啶]-1'-基)-6-(3-(5-硝基-1H-吲哚-1-基)丙-1-炔-1-基)吡嗪-2-基)甲醇；(S)-(3-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(3-(5-nitro-1H- Indol-1-yl)prop-1-yn-1-yl)pyrazin-2-yl)methanol;
(S)-(3-(1-氨基-1,3-二氢螺[茚-2,4’-哌啶]-1'-基)-6-(3-(6-甲氧基-1H-苯并[d]咪唑-1-基)丙-1-炔-1-基)吡嗪-2-基)甲醇；(S)-(3-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(3-(6-methoxy-1H -Benzo[d]imidazol-1-yl)prop-1-yn-1-yl)pyrazin-2-yl)methanol;
(S)-(3-(1-氨基-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-6-(3-(6-氨基-9H-嘌呤-9-基)丙-1-炔-1-基)吡嗪-2-基)甲醇；或(S)-(3-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(3-(6-amino-9H-purine -9-yl)prop-1-yn-1-yl)pyrazin-2-yl)methanol; or
4-(2-((5-((S)-1-氨基-1,3-二氢螺[茚-2,4’-哌啶]-1'-基)-6-(羟甲基)吡嗪-2-基)乙炔基)环丙基)苯甲酰胺。4-(2-((5-((S)-1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(hydroxymethyl) Pyrazin-2-yl)ethynyl)cyclopropyl)benzamide.
本发明还提供了一种药物组合物，其特征在于，包含治疗有效量的至少一种式I所示的化合物和至少一种药学上可接受的辅料。The present invention also provides a pharmaceutical composition characterized by comprising a therapeutically effective amount of at least one compound represented by formula I and at least one pharmaceutically acceptable excipient.
本发明进一步提供了一种药物组合物，其特征在于，治疗有效量的至少一种式I所示的化合物和药学上可接受的辅料的质量百分比为0.0001:1-10。The present invention further provides a pharmaceutical composition, characterized in that the mass percentage of the therapeutically effective amount of at least one compound represented by formula I and pharmaceutically acceptable excipients is 0.0001:1-10.
本发明提供了结构式I所示化合物或药物组合物在制备药物中的应用。The present invention provides the application of the compound or pharmaceutical composition represented by structural formula I in the preparation of medicines.
本发明进一步提供了所述应用的优选技术方案：The present invention further provides a preferred technical solution for the application:
作为优选，所述应用为制备用于治疗、预防、延迟或阻止癌症，癌症转移，心血管疾病，免疫疾病，纤维化或眼部疾病的药物的应用。Preferably, the application is an application for preparing a medicine for treating, preventing, delaying or preventing cancer, cancer metastasis, cardiovascular disease, immune disease, fibrosis or eye disease.
作为优选，所述应用为制备治疗由SHP2介导的疾病的药物中的应用。作为优选，所述疾病是癌症。Preferably, the application is an application in preparing a medicine for treating diseases mediated by SHP2. Preferably, the disease is cancer.
作为优选，所述癌症选自Noonan综合征、豹斑综合征、青少年髓单核细胞白血病、神经母细胞瘤、黑色素瘤、头颈部鳞状细胞癌、急性髓性白血病、乳腺癌、食道肿瘤、肺癌、结肠癌、头癌、胃癌、淋巴瘤、胶质母细胞瘤、胰腺癌或其组合。Preferably, the cancer is selected from Noonan syndrome, leopard spot syndrome, juvenile myelomonocytic leukemia, neuroblastoma, melanoma, head and neck squamous cell carcinoma, acute myeloid leukemia, breast cancer, esophageal tumor , Lung cancer, colon cancer, head cancer, stomach cancer, lymphoma, glioblastoma, pancreatic cancer or a combination thereof.
作为优选，所述应用为用于制备SHP2抑制剂的应用。Preferably, the application is an application for preparing an SHP2 inhibitor.
本发明还提供了一种治疗和/或预防由SHP2介导的疾病的方法，包括向治疗对象施用治疗有效量的至少任意一种结构式I所示化合物或药物组合物。The present invention also provides a method for treating and/or preventing diseases mediated by SHP2, which comprises administering a therapeutically effective amount of at least any one compound or pharmaceutical composition represented by structural formula I to a subject.
作为优选，在上述方法中，所述SHP2介导的疾病是癌症。Preferably, in the above method, the SHP2-mediated disease is cancer.
本发明还提供了一种治疗癌症的方法，包括向治疗对象施用治疗有效量的至少任意一种结构式I所示化合物或药物组合物。The present invention also provides a method for treating cancer, which comprises administering a therapeutically effective amount of at least any one compound or pharmaceutical composition represented by structural formula I to a subject.
作为优选，所述癌症选自Noonan综合征、豹斑综合征、青少年髓单核细胞白血病、神经母细胞瘤、黑色素瘤、头颈部鳞状细胞癌、急性髓性白血病、乳腺癌、食道肿瘤、肺癌、结肠癌、头癌、胃癌、淋巴瘤、胶质母细胞瘤、胰腺癌或其组合。Preferably, the cancer is selected from Noonan syndrome, leopard spot syndrome, juvenile myelomonocytic leukemia, neuroblastoma, melanoma, head and neck squamous cell carcinoma, acute myeloid leukemia, breast cancer, esophageal tumor , Lung cancer, colon cancer, head cancer, stomach cancer, lymphoma, glioblastoma, pancreatic cancer or a combination thereof.
作为优选，在上述方法中，所述治疗对象为人类。Preferably, in the above method, the subject to be treated is a human.
除非另有说明，本发明所用术语含义如下：Unless otherwise specified, the terms used in the present invention have the following meanings:
术语“烷基”包括直连、支链或环状的饱和烷基。例如，烷基包括但不限于甲基、乙基、丙基、异丙基、环丙基、正丁基、异丁基、仲丁基、叔丁基、环丁基、正戊基、3-(2-甲基) 丁基、2-戊基、2-甲基丁基、新戊基、环戊基、n-己基、2-己基、2-甲基戊基及环己基等类似基团。类似的，“C 1-8烷基”中的“C 1-8”是指包含有1、2、3、4、5、6、7或8个碳原子的直链、支链或环状形式排列的基团。 The term "alkyl" includes straight, branched or cyclic saturated alkyl groups. For example, alkyl groups include but are not limited to methyl, ethyl, propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, n-pentyl, 3 -(2-Methyl) butyl, 2-pentyl, 2-methylbutyl, neopentyl, cyclopentyl, n-hexyl, 2-hexyl, 2-methylpentyl and cyclohexyl and other similar groups group. Similar, "C 1-8 alkyl""C1-8" means comprising 7 or 8 carbon atoms, a straight chain, branched chain or cyclic Formally arranged groups.
“烯基”和“炔基”包括直链、支链或环状的烯基和炔基。同样地，“C 2-8烯基”和“C 2-8炔基”是指含有2、3、4、5、6、7或8个碳原子以直链、支链或环状形式排列的烯基或炔基。 "Alkenyl" and "alkynyl" include linear, branched or cyclic alkenyl and alkynyl groups. Similarly, "C 2-8 alkenyl" and "C 2-8 alkynyl" refer to a linear, branched or cyclic arrangement containing 2, 3, 4, 5, 6, 7 or 8 carbon atoms的alkenyl or alkynyl.
术语“烷氧基”是指前述的直链、支链或环状烷基的氧醚形式。The term "alkoxy" refers to the oxyether form of the aforementioned linear, branched or cyclic alkyl group.
术语“芳基”是指未取代或取代的包括碳原子的单环或多环芳香基团。优选为6到10元的单环或双环芳香基团。优选为苯基、萘基。最优选为苯基。The term "aryl" refers to an unsubstituted or substituted monocyclic or polycyclic aromatic group including carbon atoms. It is preferably a 6 to 10 membered monocyclic or bicyclic aromatic group. Preferably, it is phenyl and naphthyl. Most preferred is phenyl.
术语“杂芳基”是指，从一个母体杂芳环***的一个碳原子上移走一个氢原子所形成的单价的杂原子基团。杂芳基包括：5-到7-元芳香、单环，包括至少一个选自N、O或S的杂原子，例如，1到4个杂原子，或优选为1到3个杂原子，环上的其他原子为碳；多杂芳基环包括至少一个选自N、O或S的杂原子，例如，1到4个杂原子，或优选为1到3个杂原子，环上的其他原子为碳，且其中至少一个杂原子在芳环上；还包括双环或多环，但双环或多环中至少有一个环具有芳香性。特别优选的杂芳基基团是C 3-10的杂芳基，包括但不限于，吡咯基、呋喃基、噻吩基、吡啶基、吡喃基、吡唑基、嘧啶基、哒嗪基、吡嗪基、咪唑基、噻唑基、恶唑基、异恶唑基、三氮唑基、吲哚基、苯并呋喃基、苯并噻唑基、苯并咪唑基、苯并吡唑基、苯并三氮唑基、咔唑基、喹啉基、异喹啉基、嘌呤基等类似基团。 The term "heteroaryl" refers to a monovalent heteroatom group formed by removing a hydrogen atom from a carbon atom of a parent heteroaromatic ring system. Heteroaryl groups include: 5- to 7-membered aromatic, monocyclic, including at least one heteroatom selected from N, O or S, for example, 1 to 4 heteroatoms, or preferably 1 to 3 heteroatoms, ring The other atoms on the above are carbon; the polyheteroaryl ring includes at least one heteroatom selected from N, O or S, for example, 1 to 4 heteroatoms, or preferably 1 to 3 heteroatoms, other atoms in the ring It is carbon, and at least one of the heteroatoms is on the aromatic ring; it also includes bicyclic or polycyclic rings, but at least one of the bicyclic or polycyclic rings is aromatic. Particularly preferred heteroaryl groups are C 3-10 heteroaryl groups, including, but not limited to, pyrrolyl, furyl, thienyl, pyridyl, pyranyl, pyrazolyl, pyrimidinyl, pyridazinyl, Pyrazinyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, triazolyl, indolyl, benzofuranyl, benzothiazolyl, benzimidazolyl, benzopyrazolyl, benzene And similar groups such as triazolyl, carbazolyl, quinolinyl, isoquinolinyl, purinyl and the like.
但是，在任何情况下，杂芳基和芳基都不会彼此交叉或相互包含。因此，根据以上定义，如果至少一个全碳芳香环与一个杂环基相稠合，得到的是杂芳基，而不是芳基。However, in any case, the heteroaryl group and the aryl group will not cross each other or contain each other. Therefore, according to the above definition, if at least one all-carbon aromatic ring is fused with a heterocyclic group, the result is a heteroaryl group instead of an aryl group.
“碳环基”指饱和的或不饱和的但不具有芳香性的环状基团。根据其饱和度的特殊水平，分别采用术语“环烷基”、“环烯基”或“环炔基”。有代表性的碳环基基团包括但不限于，环丙烷、环丁烷、环戊烷、环己烷或环己烯等类似基团。"Carbocyclic group" refers to a saturated or unsaturated cyclic group that is not aromatic. According to its specific level of saturation, the terms "cycloalkyl", "cycloalkenyl" or "cycloalkynyl" are used respectively. Representative carbocyclic groups include, but are not limited to, cyclopropane, cyclobutane, cyclopentane, cyclohexane, or cyclohexene and similar groups.
“杂环基”是指饱和的或不饱和的但不具有芳香性的环状基团，而且其中一个或多个碳原子(以及所连接的氢原子)可分别被相同的或不相同的杂原子和相应所连接的氢原子所取代。有代表性的取代碳原子的杂原子包括但不限于N、P、O、S和Si。当需要描述特定的饱和度时，分别采用术语“杂环烷基”或“杂环烯基”。具有代表性的杂环基基团包括但不限于环氧化合物、咪唑烷、吗啉、哌嗪、哌啶、吡唑烷、吡咯烷、奎宁环、四氢呋喃或四氢吡喃等类似基团。含取代基的杂环基也包含被至少一个含氧的(＝O)或氧化物(-O-)取代基取代的环***，如：哌啶-氮-氧化物、吗啉基-氮-氧化物、1-氧代-1-硫吗啉基和1-二氧-1-硫吗啉基。"Heterocyclic group" refers to a saturated or unsaturated but not aromatic cyclic group, and one or more of the carbon atoms (and the attached hydrogen atom) can be respectively the same or different hetero Atom and the corresponding attached hydrogen atom are replaced. Representative heteroatoms that replace carbon atoms include, but are not limited to, N, P, O, S, and Si. When a specific degree of saturation needs to be described, the terms "heterocycloalkyl" or "heterocycloalkenyl" are used respectively. Representative heterocyclic groups include but are not limited to epoxy compounds, imidazolidine, morpholine, piperazine, piperidine, pyrazolidine, pyrrolidine, quinuclidine, tetrahydrofuran or tetrahydropyran and similar groups . Substituent heterocyclic groups also include ring systems substituted by at least one oxygen-containing (=O) or oxide (-O-) substituent, such as: piperidine-nitrogen-oxide, morpholinyl-nitrogen- Oxide, 1-oxo-1-thiomorpholinyl and 1-dioxo-1-thiomorpholinyl.
但是，在任何情况下，杂环烷基和碳环基都不会彼此交叉或相互包含。因此，根据上述定义，如果至少一个全碳环与一个杂环烷基稠合形成一个二-、多-或螺-环，将仍然定义为杂环烷基。However, in any case, the heterocycloalkyl group and the carbocyclic group will not cross each other or contain each other. Therefore, according to the above definition, if at least one all-carbocyclic ring is fused with a heterocycloalkyl group to form a di-, poly- or spiro-ring, it will still be defined as a heterocycloalkyl group.
另外，如果一个杂芳基与一个杂环基稠和形成一个二-、多-或螺-环，将定义为杂环基而不是杂芳基。In addition, if a heteroaryl group is fused with a heterocyclic group to form a di-, poly- or spiro-ring, it will be defined as a heterocyclic group instead of a heteroaryl group.
“卤素”是指氟(F)、氯(Cl)、溴(Br)或碘(I)。优选的卤素是指氟、氯和溴。"Halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I). Preferred halogen refers to fluorine, chlorine and bromine.
“卤代基”是指氟代、氯代、溴代或碘代基团。优选的卤代基是指氟代和氯代。"Halo" refers to a fluoro, chloro, bromo or iodo group. The preferred halo groups refer to fluoro and chloro.
“取代”是指一个基团中的一个或多个氢原子分别被相同的或不同的取代基所取代。具有代表性的取代基包括但不限于卤素、氨基、羟基、氧代基、羰基、氰基、-C(O)NH 2、烷基、烷氧基、芳基、环烷基、杂环基、杂芳基。在一些实施例中，取代基包含但不限于卤素、氨基、羟基、氰基、甲基、-CH 2OH、-C(O)NH 2、-OCH 3、三氟甲基。 "Substitution" means that one or more hydrogen atoms in a group are replaced by the same or different substituents. Representative substituents include, but are not limited to, halogen, amino, hydroxyl, oxo, carbonyl, cyano, -C(O)NH 2 , alkyl, alkoxy, aryl, cycloalkyl, heterocyclyl , Heteroaryl. In some embodiments, the substituent includes, but is not limited to, halogen, amino, hydroxyl, cyano, methyl, -CH 2 OH, -C(O)NH 2 , -OCH 3 , trifluoromethyl.
无论何时，术语“烷基”或“芳基”或者其前缀词根出现在取代基名称中(如芳烷基，或二烷基氨基)，均应按前述的“烷基”和“芳基”定义对取代基进行限定性解释。碳原子的指定数量(如C l-6)将独立的表示在一个烷基部分或在一个更大的取代基中的烷基部分(其中烷基作为前缀词根)中的碳原子的数量。 Whenever the term "alkyl" or "aryl" or its prefixes appear in the name of a substituent (such as aralkyl, or dialkylamino), it shall be as described above for "alkyl" and "aryl". The definition provides a limited interpretation of the substituents. The specified number of carbon atoms (such as C 1-6 ) will independently represent the number of carbon atoms in an alkyl moiety or in an alkyl moiety (where the alkyl group is the prefix stem) in a larger substituent.
本发明所述“化合物”包括式I的化合物，及其所有药学上可接受的形式。这些药学上可接受的形式包括盐、溶剂化物、非共价复合物、螯合物、立体异构体(包括非对映异构体、对映异构体和外消旋体)、顺反异构体、同位素标记的化合物、互变异构体、前体药物、或上述所有形式的任意混合物。The "compound" of the present invention includes the compound of formula I, and all pharmaceutically acceptable forms thereof. These pharmaceutically acceptable forms include salts, solvates, non-covalent complexes, chelates, stereoisomers (including diastereomers, enantiomers and racemates), cis-trans Isomers, isotope-labeled compounds, tautomers, prodrugs, or any mixture of all the above forms.
所述“顺反异构体”是存在于某些双键化合物或环状化合物中的一种立体异构现象。由于存在双键或环，这些分子的自由旋转受阻，产生两个物理性质或化学性质均不相同的同分异构体，分别称为顺式(cis)和反式(trans)异构体。The "cis-trans isomer" is a stereoisomerism that exists in certain double bond compounds or cyclic compounds. Due to the presence of double bonds or rings, the free rotation of these molecules is hindered, resulting in two isomers with different physical or chemical properties, called cis and trans isomers, respectively.
所述“药学上可接受的”是指公知的用于动物的，特别是可用于人体的。The "pharmaceutically acceptable" refers to those that are well-known for use in animals, especially those that can be used in humans.
本发明中术语“组合物”包括含有特定数量的特定组分的产品，也包括任何由特定数量的特定组分直接或间接得到的产品。因此，包括本发明中的化合物作为活性组分的药物组合物和制备该化合物的方法都是本发明的内容。The term "composition" in the present invention includes a product containing a specific amount of a specific component, and also includes any product obtained directly or indirectly from a specific amount of a specific component. Therefore, a pharmaceutical composition including the compound of the present invention as an active ingredient and a method for preparing the compound are the content of the present invention.
“治疗有效量”是指一个化合物施用于治疗主体时治疗并且预防和/或抑制一种疾病、病情、症状、适应症和/或不适的至少一种临床症状时，足以这种疾病、病情、症状、适应症或不适的治疗产生一定效果的剂量。具体的“有效治疗剂量”可以根据化合物，给药途径、患者年龄、患者体重，所治疗的疾病或不适的类型、症状和严重程度等的不同而变化。在 任意可能的情况下，一个合适的剂量对那些在本领域的专业人员可以是显而易见的，也可以是用常规实验方法确定的。"Therapeutically effective amount" means that when a compound is administered to a subject to treat and prevent and/or inhibit at least one clinical symptom of a disease, condition, symptom, indication, and/or discomfort, it is sufficient for the disease, condition, A dose that produces a certain effect for the treatment of symptoms, indications or discomfort. The specific "effective therapeutic dose" may vary according to the compound, the route of administration, the age of the patient, the weight of the patient, the type of disease or discomfort to be treated, the symptoms and severity, etc. Whenever possible, an appropriate dose may be obvious to those skilled in the art, or it may be determined by conventional experimental methods.
本发明提供的化合物可以以“药学上可接受的盐”的形式存在。药物应用方面，本发明提供的化合物的盐是指无毒的药学上可接受的盐。药学上可接受的盐的形式包括药学上可接受的酸/阴离子或碱/阳离子盐。药学上可接受的酸/阴离子盐一般以碱性氮与无机酸或有机酸质子化的形式存在。典型的有机或无机酸包括盐酸、氢溴酸、氢碘酸、高氯酸、硫酸、硝酸、磷酸、乙酸、丙酸、乙醇酸、乳酸、琥珀酸、马来酸、富马酸、苹果酸、酒石酸、柠檬酸、α-酮戊二酸、马尿酸、苯甲酸、扁桃酸、甲磺酸、羟乙基磺酸、苯磺酸、草酸、扑酸、2-萘磺酸、对甲苯磺酸、环己胺磺酸、水杨酸、糖精酸或三氟乙酸。药学上可接受的碱/阳离子盐，包括但不限于，铝盐、钙盐、氯普鲁卡因盐、胆碱、二乙醇胺盐、乙二胺盐、锂盐、镁盐、钾盐、钠盐和锌盐。The compounds provided by the present invention may exist in the form of "pharmaceutically acceptable salts". In terms of pharmaceutical applications, the salts of the compounds provided by the present invention refer to non-toxic pharmaceutically acceptable salts. The form of a pharmaceutically acceptable salt includes a pharmaceutically acceptable acid/anion or base/cation salt. Pharmaceutically acceptable acid/anionic salts generally exist in the form of protonation of basic nitrogen with inorganic or organic acids. Typical organic or inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, perchloric acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, propionic acid, glycolic acid, lactic acid, succinic acid, maleic acid, fumaric acid, malic acid , Tartaric acid, citric acid, α-ketoglutaric acid, hippuric acid, benzoic acid, mandelic acid, methanesulfonic acid, isethionic acid, benzenesulfonic acid, oxalic acid, pamoic acid, 2-naphthalenesulfonic acid, p-toluenesulfonic acid Acid, cyclohexylamine sulfonic acid, salicylic acid, saccharinic acid or trifluoroacetic acid. Pharmaceutically acceptable base/cation salts, including, but not limited to, aluminum salt, calcium salt, chloroprocaine salt, choline, diethanolamine salt, ethylenediamine salt, lithium salt, magnesium salt, potassium salt, sodium Salt and zinc salt.
本发明化合物的药物前体包含在本发明的保护范围内。通常，所述药物前体是很容易在体内转化成所需要的化合物的功能性衍生物。因此，本发明提供的治疗方法涉及的术语“给药”包括施用本发明公开的化合物，或虽未明确公开但对主体给药后能够在体内转化为本发明公开的化合物治疗所述的各种疾病。有关选择和制备合适药物前体衍生物的常规方法，已记载在例如《药物前体设计》(Design of Prodrugs,ed.H.Bundgaard,Elsevier,1985)这类书中。The prodrug of the compound of the present invention is included in the protection scope of the present invention. Generally, the prodrug is a functional derivative that is easily converted into the desired compound in the body. Therefore, the term "administration" involved in the treatment method provided by the present invention includes the administration of the compound disclosed in the present invention, or although it is not clearly disclosed but can be converted into the compound disclosed in the present invention in vivo after administration to the subject. disease. The conventional methods for selecting and preparing suitable prodrug derivatives have been described in books such as "Design of Prodrugs" (Design of Prodrugs, ed. H. Bundgaard, Elsevier, 1985).
显然的，一个分子中任何取代基或特定位置的变量的定义，与其他分子中的任何取代基或特定位置的变量的定义是无关的。很容易理解，本发明中的化合物可以根据本学科现有技术选择合适的取代基或取代形式，以提供化学上稳定且容易用本学科现有技术或本发明中所述的方法进行制备合成。Obviously, the definition of any substituent or variable at a specific position in one molecule is irrelevant to the definition of any substituent or variable at a specific position in other molecules. It is easy to understand that the compound of the present invention can be selected according to the prior art of the subject to select suitable substituents or substitution forms to provide chemically stable and easy preparation and synthesis using the prior art of the subject or the method described in the present invention.
当式I所示化合物及其药学上可接受的盐为溶剂化物或多晶型的形式时，本发明包括任何可能的溶剂化物和多晶型。形成溶剂化物的溶剂类型没有特别的限定，只要该溶剂是药理学上可以接受的。例如，水、乙醇、丙醇、丙酮等类似的溶剂都可以采用。When the compound represented by formula I and its pharmaceutically acceptable salt are in the form of a solvate or polymorph, the present invention includes any possible solvate and polymorph. The type of solvent that forms the solvate is not particularly limited, as long as the solvent is pharmacologically acceptable. For example, water, ethanol, propanol, acetone and similar solvents can be used.
术语“药学上可接受的盐”是指从药学上可接受的无毒的碱或酸制备的盐。当本发明提供的化合物是酸时，可以从药学上可接受的无毒的碱，包括无机碱和有机碱，制得其相应的盐。从无机碱衍生的盐包括铝、铵、钙、铜(ic和ous)、铁、亚铁、锂、镁、锰(ic和ous)、钾、钠、锌之类的盐。特别地，优选铵、钙、镁、钾和钠的盐。能够衍生成药学上可接受的盐的无毒有机碱包括伯胺、仲胺和叔胺，也包括环胺及含有取代基的胺，如天然存在的和合成的含取代基的胺。能够成盐的其他药学上可接受的无毒有机碱，包括离子交 换树脂以及精氨酸、甜菜碱、咖啡因、胆碱、N',N'-二苄乙烯二胺、二乙胺、2-二乙氨基乙醇、2-二甲胺基乙醇、乙醇胺、乙二胺、N－乙基吗啉、N-乙基哌啶、还原葡萄糖胺、氨基葡萄糖、组氨酸、哈胺、异丙胺、赖氨酸，甲基葡萄糖胺、吗啉、哌嗪、哌啶、多胺树脂、普鲁卡因、嘌呤、可可碱、三乙胺、三甲胺、三丙胺、氨丁三醇等。The term "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable non-toxic base or acid. When the compound provided by the present invention is an acid, its corresponding salt can be prepared from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper (ic and ous), iron, ferrous, lithium, magnesium, manganese (ic and ous), potassium, sodium, zinc and the like. In particular, salts of ammonium, calcium, magnesium, potassium, and sodium are preferred. The non-toxic organic bases that can be derivatized into pharmaceutically acceptable salts include primary, secondary and tertiary amines, as well as cyclic amines and amines containing substituents, such as naturally occurring and synthetic amines containing substituents. Other pharmaceutically acceptable non-toxic organic bases capable of forming salts, including ion exchange resins and arginine, betaine, caffeine, choline, N',N'-dibenzylethylenediamine, diethylamine, 2 -Diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, reduced glucosamine, glucosamine, histidine, haamine, isopropylamine , Lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resin, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc.
当本发明提供的化合物是碱时，可以从药学上可接受的无毒的酸，包括无机酸和有机酸，制得其相应的盐。这样的酸包括，如，醋酸、苯磺酸、苯甲酸、樟脑磺酸、柠檬酸、乙磺酸、羟乙基磺酸、甲酸、富马酸、葡萄糖酸、谷氨酸、氢溴酸、盐酸、乳酸、马来酸、苹果酸、扁桃酸、α-酮戊二酸、马尿酸、甲磺酸、黏酸、硝酸、扑酸、泛酸、磷酸、琥珀酸、硫酸、酒石酸、对甲苯磺酸等。较优地，苹果酸、柠檬酸、氢溴酸、盐酸、甲磺酸、马来酸、磷酸、硫酸和酒石酸。更优地，磷酸、盐酸和苹果酸。由于式I所示化合物将作为药物应用，所以优选使用基本上纯的形式，例如，至少60％纯度，更适当至少75％的纯度，特别适当至少98％的纯度(％是重量比)。When the compound provided by the present invention is a base, the corresponding salt can be prepared from pharmaceutically acceptable non-toxic acids, including inorganic acids and organic acids. Such acids include, for example, acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, isethionic acid, formic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, Hydrochloric acid, lactic acid, maleic acid, malic acid, mandelic acid, α-ketoglutaric acid, hippuric acid, methanesulfonic acid, mucic acid, nitric acid, hexanoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, p-toluenesulfonate Sour etc. Preferably, malic acid, citric acid, hydrobromic acid, hydrochloric acid, methanesulfonic acid, maleic acid, phosphoric acid, sulfuric acid and tartaric acid. More preferably, phosphoric acid, hydrochloric acid and malic acid. Since the compound of formula I will be used as a pharmaceutical, it is preferred to use a substantially pure form, for example, at least 60% purity, more suitably at least 75% purity, particularly suitably at least 98% purity (% is a weight ratio).
本发明提供的药物组合物包括作为活性组分的式I所示化合物(或其药学上可接受的盐)，一种药学上可接受的赋形剂及其他可选的治疗组分或辅料。尽管任何给定的情况下，最适合的活性组分给药方式取决于接受给药的特定的主体、主体性质和病情严重程度，但是本发明的药物组合物包括适于口腔、直肠、局部和肠外(包括皮下给药、肌肉注射、静脉给药)给药的药物组合物。本发明的药物组合物可以方便地以本领域公知的单位剂型存在和药学领域公知的任何制备方法制备。The pharmaceutical composition provided by the present invention includes the compound represented by formula I (or a pharmaceutically acceptable salt thereof) as an active component, a pharmaceutically acceptable excipient, and other optional therapeutic components or adjuvants. Although in any given case, the most suitable way of administering the active ingredient depends on the particular subject to be administered, the nature of the subject and the severity of the disease, the pharmaceutical composition of the present invention includes oral, rectal, topical and Pharmaceutical compositions for parenteral administration (including subcutaneous administration, intramuscular injection, and intravenous administration). The pharmaceutical composition of the present invention can be conveniently prepared in a unit dosage form known in the art and prepared by any preparation method known in the pharmaceutical field.
实际上，根据常规的药物混合技术，本发明式I所示化合物，或药物前体，或代谢物，或药学上可接受的盐，可以合并用药作为活性组分，与药物载体混合成药物组合物。所述药物载体可以采取各种各样的形式，取决于想采用的给药方式，例如，口服或注射(包括静脉注射)。因此，本发明的药物组合物可以采用适于口服给药的独立单位的形式，如包含预先确定剂量的活性组分的胶囊剂，扁囊剂或片剂。进一步地，本发明的药物组合物可采用粉末、颗粒、溶液、水性悬浮液、非水液体、水包油型乳液，或油包水型乳液形式。另外，除了上述提到的常见的剂型，式I所示化合物或其药学上可接受的盐，也可以通过控释的方式和/或输送装置给药。本发明的药物组合物可以采用任何制药学上的方法制备。一般情况下，这种方法包括使活性组分和构成一个或多个必要组分的载体缔合的步骤。一般情况下，所述药物组合物经由活性组分与液体载体或精细分割的固体载体或两者的混合物经过均匀的的密切混合制得。另外，该产品可以方便地制备成所需要的外观。In fact, according to conventional drug mixing technology, the compound represented by formula I of the present invention, or prodrug, or metabolite, or pharmaceutically acceptable salt, can be used in combination as an active component and mixed with a drug carrier to form a drug combination Things. The pharmaceutical carrier can take various forms, depending on the desired mode of administration, for example, oral or injection (including intravenous injection). Therefore, the pharmaceutical composition of the present invention may take the form of a separate unit suitable for oral administration, such as a capsule, cachet or tablet containing a predetermined dose of the active ingredient. Further, the pharmaceutical composition of the present invention may take the form of powder, granule, solution, aqueous suspension, non-aqueous liquid, oil-in-water emulsion, or water-in-oil emulsion. In addition, in addition to the common dosage forms mentioned above, the compound represented by Formula I or a pharmaceutically acceptable salt thereof can also be administered by a controlled release method and/or a delivery device. The pharmaceutical composition of the present invention can be prepared by any pharmaceutical method. Generally, this method includes the step of associating the active ingredient with the carrier constituting one or more necessary ingredients. In general, the pharmaceutical composition is prepared by uniformly and intimately mixing the active ingredient with a liquid carrier or a finely divided solid carrier or a mixture of the two. In addition, the product can be easily prepared into the desired appearance.
因此，本发明的药物组合物包括药学上可接受的载体和式I所示化合物，或其药学上可接受的盐。式I所示化合物，或其药学上可接受的盐，与其他一种或多种具有治疗活性联合用药的化合物的也包括在本发明的药物组合物中。Therefore, the pharmaceutical composition of the present invention includes a pharmaceutically acceptable carrier and a compound represented by formula I, or a pharmaceutically acceptable salt thereof. The compound represented by formula I, or a pharmaceutically acceptable salt thereof, and one or more other compounds having therapeutic activity in combination are also included in the pharmaceutical composition of the present invention.
本发明采用的药物载体可以是，例如，固体载体、液体载体或气体载体。固体载体的例子，包括，乳糖、石膏粉、蔗糖、滑石粉、明胶、琼脂、果胶、***胶、硬脂酸镁、硬脂酸、甘露醇、山梨醇、微晶纤维素、无机盐类、淀粉、预胶化淀粉、糖粉、糊精等。液体载体的例子包括，糖浆、花生油、橄榄油和水。气体载体的例子包括二氧化碳和氮气。制备药物口服制剂时，可以使用任何方便的制药学上的介质。例如，水、乙二醇、油类、醇类、增味剂、防腐剂、着色剂等可用于口服的液体制剂如悬浮剂、酏剂和溶液剂；而载体，如淀粉类、糖类、微晶纤维素、稀释剂、造粒剂、润滑剂、粘合剂、崩解剂等可用于口服的固体制剂如散剂、胶囊剂和片剂。考虑到易于施用，口服制剂首选片剂和胶囊。可选地，片剂包衣可使用标准的水制剂或非水制剂技术。The drug carrier used in the present invention can be, for example, a solid carrier, a liquid carrier or a gas carrier. Examples of solid carriers include lactose, gypsum powder, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid, mannitol, sorbitol, microcrystalline cellulose, inorganic salts , Starch, pregelatinized starch, powdered sugar, dextrin, etc. Examples of liquid carriers include syrup, peanut oil, olive oil and water. Examples of gas carriers include carbon dioxide and nitrogen. When preparing oral pharmaceutical preparations, any convenient pharmaceutical medium can be used. For example, water, ethylene glycol, oils, alcohols, flavor enhancers, preservatives, coloring agents, etc. can be used for oral liquid preparations such as suspensions, elixirs and solutions; and carriers such as starches, sugars, Microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, etc. can be used in oral solid preparations such as powders, capsules and tablets. In view of ease of administration, tablets and capsules are preferred for oral preparations. Alternatively, standard aqueous or non-aqueous formulation techniques can be used for tablet coating.
含有本发明化合物或药物组合物的片剂可通过，可选地，可以与一种或多种辅助组分或辅药一起混合、压制或成型制备。活性组分以可以自由流动的形式如粉末或颗粒，与润滑剂、惰性稀释剂、表面活性或分散剂混合，在适当的机器中，通过压制可以制得压制片剂。用一种惰性液体稀释剂浸湿粉末状的化合物或药物组合物，然后在适当的机器中，通过成型可以制得模制片。较优地，每个片剂含有大约0.01mg到5g的活性组分，每个扁襄剂或胶囊剂含有大约0.1mg到0.5g的活性组分。例如，拟用于人类口服给药的剂型包含约0.1mg到约0.5g的活性组分，与合适且方便计量的辅助材料复合，该辅助材料约占药物组合物总量的5％至99.99％。单位剂型一般包含约0.1mg到约0.5g的有效组分，典型的是0.1mg、0.2mg、0.5mg、1mg、2mg、2.5mg、5mg、10mg、25mg、50mg、100mg、200mg、300mg、400mg或500mg。Tablets containing the compound or pharmaceutical composition of the present invention can be prepared by, optionally, mixing, compression or molding with one or more auxiliary components or adjuvants. The active ingredient is in a free-flowing form such as powder or granules, mixed with lubricants, inert diluents, surface active or dispersing agents, and compressed in a suitable machine to produce compressed tablets. The powdered compound or pharmaceutical composition is soaked with an inert liquid diluent, and then molded in a suitable machine to form a molded tablet. Preferably, each tablet contains about 0.01 mg to 5 g of active ingredient, and each cachet or capsule contains about 0.1 mg to 0.5 g of active ingredient. For example, a dosage form intended for oral administration to humans contains about 0.1 mg to about 0.5 g of active ingredient, compounded with a suitable and convenient metering auxiliary material, which accounts for about 5% to 99.99% of the total pharmaceutical composition. . The unit dosage form generally contains about 0.1mg to about 0.5g of effective ingredients, typically 0.1mg, 0.2mg, 0.5mg, 1mg, 2mg, 2.5mg, 5mg, 10mg, 25mg, 50mg, 100mg, 200mg, 300mg, 400mg Or 500mg.
本发明提供的适用于胃肠外给药的药物组合物可将活性组分加入水中制备成水溶液或悬浮液。可以包含适当的表面活性剂如十二烷基硫酸钠、聚山梨酯-80(吐温-80)、聚氧乙烯氢化蓖麻油、泊洛沙姆。在甘油、液态聚乙二醇，及其在油中的混合物，也可以制得分散体系。进一步地，防腐剂也可以，包含在本发明的药物组合物中用于防止有害的微生物生长。The pharmaceutical composition suitable for parenteral administration provided by the present invention can be prepared as an aqueous solution or suspension by adding active components into water. Suitable surfactants such as sodium lauryl sulfate, polysorbate-80 (Tween-80), polyoxyethylene hydrogenated castor oil, and poloxamer may be included. In glycerol, liquid polyethylene glycol, and their mixture in oil, dispersion systems can also be prepared. Furthermore, a preservative may also be included in the pharmaceutical composition of the present invention to prevent the growth of harmful microorganisms.
本发明提供适用于注射使用的药物组合物，包括无菌水溶液或分散体系。进一步地，上述药物组合物可以制备成可用于即时配制无菌注射液的无菌粉末的形式。无论如何，最终的注射形式必须是无菌的，且为了易于注射，必须是易于流动的。此外，所述药物组合 物在制备和储存过程中必须稳定。因此，优选抗微生物如细菌和真菌的污染的保存。载体可以是溶剂或分散介质，例如，水、乙醇、多元醇(如甘油、丙二醇、液态聚乙二醇)、植物油，及其适当的混合物。The present invention provides pharmaceutical compositions suitable for injection use, including sterile aqueous solutions or dispersion systems. Further, the above-mentioned pharmaceutical composition can be prepared in the form of a sterile powder that can be used for immediate preparation of sterile injections. In any case, the final injection form must be sterile, and for easy injection, it must be easy to flow. In addition, the pharmaceutical composition must be stable during preparation and storage. Therefore, preservation against contamination by microorganisms such as bacteria and fungi is preferred. The carrier can be a solvent or dispersion medium, for example, water, ethanol, polyol (such as glycerol, propylene glycol, liquid polyethylene glycol), vegetable oil, and suitable mixtures thereof.
本发明提供的药物组合物，可以是适于局部用药的形式，例如，气溶胶、乳剂、软膏、洗液、撒粉，或其他类似的剂型。进一步地，本发明提供的药物组合物可以采用适于经皮给药装置使用的形式。利用本发明式I所示化合物，或其药学上可接受的盐，通过常规的加工方法，可以制备这些制剂。作为一个例子，乳剂或软膏剂的制备是通过在上述化合物中加入亲水性材料和水(二者总量约为化合物的5wt％到50wt％)，制得具有预期一致性的乳剂或软膏。The pharmaceutical composition provided by the present invention may be in a form suitable for topical administration, for example, aerosol, emulsion, ointment, lotion, dusting, or other similar dosage forms. Further, the pharmaceutical composition provided by the present invention can be in a form suitable for use in a transdermal drug delivery device. These preparations can be prepared by using the compound represented by formula I of the present invention, or a pharmaceutically acceptable salt thereof, through conventional processing methods. As an example, an emulsion or ointment is prepared by adding a hydrophilic material and water (the total amount of the two is about 5% to 50% by weight of the compound) to prepare a cream or ointment with the expected consistency.
本发明提供的药物组合物，可以制成以固体为载体、适用于直肠给药的形式。混合物形成单位剂量的栓剂是最优选的剂型。适当的辅料包括本领域常用的可可脂和其他材料。栓剂可以方便地制备，首先药物组合物与软化或熔化的辅料混合，然后冷却和模具成型而制得。The pharmaceutical composition provided by the present invention can be made into a form suitable for rectal administration with a solid as a carrier. Suppositories in which the mixture forms a unit dose are the most preferred dosage form. Suitable auxiliary materials include cocoa butter and other materials commonly used in the art. Suppositories can be conveniently prepared. First, the pharmaceutical composition is mixed with softened or melted excipients, and then cooled and molded.
除了上述提到的载体组分外，上述药学制剂还可以包括，适当的，一种或多种附加的辅料组分，如稀释剂、缓冲剂、调味剂、粘合剂、表面活性剂、增稠剂、润滑剂、防腐剂(包括抗氧化剂)等。进一步地，其他的辅药还可以包括调节药物与血液等渗压的促渗剂。包含有式I所示化合物，或其药学上可接受的盐的药物组合物，也可以制备成粉剂或浓缩液的形式。In addition to the above-mentioned carrier components, the above-mentioned pharmaceutical preparations may also include, as appropriate, one or more additional adjuvant components, such as diluents, buffers, flavoring agents, binders, surfactants, and additives. Thickeners, lubricants, preservatives (including antioxidants), etc. Further, other adjuvants may also include penetration enhancers that regulate the isotonic pressure between the drug and the blood. The pharmaceutical composition containing the compound represented by Formula I, or a pharmaceutically acceptable salt thereof, can also be prepared in the form of a powder or a concentrated solution.
具体实施方式Detailed ways
为使上述内容更清楚、明确，本发明将用以下实施例来进一步阐述本发明的技术方案。以下实施例仅用于说明本发明的具体实施方式，以使本领域的技术人员能够理解本发明，但不用于限制本发明的保护范围。本发明的具体实施方式中，未作特别说明的技术手段或方法等为本领域的常规技术手段或方法等。In order to make the above content clearer and clearer, the present invention will use the following embodiments to further illustrate the technical solution of the present invention. The following examples are only used to illustrate specific implementations of the present invention, so that those skilled in the art can understand the present invention, but are not used to limit the protection scope of the present invention. In the specific embodiments of the present invention, technical means or methods that are not specifically described are conventional technical means or methods in the art.
除非另有说明，本发明所有的一部分和百分比均按重量计算，所有温度均指摄氏度。Unless otherwise specified, all parts and percentages in the present invention are calculated by weight, and all temperatures refer to degrees Celsius.
实施例中使用了下列缩略语：The following abbreviations are used in the examples:
DCM：二氯甲烷；DCM: dichloromethane;
DIEA：N,N-二异丙基乙胺；DIEA: N,N-diisopropylethylamine;
DIBAL-H：二异丁基氢化铝；DIBAL-H: diisobutyl aluminum hydride;
DME：乙二醇二甲醚DME: Ethylene Glycol Dimethyl Ether
DMF：N,N-二甲基甲酰胺；DMF: N,N-dimethylformamide;
DMSO：二甲基亚砜；DMSO: dimethyl sulfoxide;
EtOAc：乙酸乙酯；EtOAc: ethyl acetate;
h、hr或hrs：小时；h, hr or hrs: hour;
LC-MS或LCMS：液相色谱-质谱联用；LC-MS or LCMS: liquid chromatography-mass spectrometry;
MeCN：乙腈；MeCN: Acetonitrile;
MeOH：甲醇；MeOH: methanol;
min或mins：分钟；min or mins: minutes;
NEt 3：三乙胺； NEt 3 : Triethylamine;
Prep-HPLC：制备高效液相色谱；Prep-HPLC: Preparative high performance liquid chromatography;
PdCl 2(PPh 3) 2：双三苯基磷二氯化钯； PdCl 2 (PPh 3 ) 2 : Bistriphenylphosphorus palladium dichloride;
Pd(PPh 3) 4：四(三苯基膦)钯； Pd(PPh 3 ) 4 : Tetrakis (triphenylphosphine) palladium;
PE：石油醚；PE: petroleum ether;
rt、r.t.或RT：室温；rt, r.t. or RT: room temperature;
TFA：三氟乙酸；TFA: trifluoroacetic acid;
THF：四氢呋喃；THF: Tetrahydrofuran;
Ti(OEt) 4：钛酸四乙酯；和 Ti(OEt) 4 : tetraethyl titanate; and
TLC：薄层色谱。TLC: Thin layer chromatography.
中间体化合物M1的制备：Preparation of intermediate compound M1:
Figure PCTCN2021088871-appb-000039
Figure PCTCN2021088871-appb-000039
步骤1：化合物M1-3的制备Step 1: Preparation of compound M1-3
氮气保护下，将25.00g化合物M1-1溶解于200mL的DMF中，降温至0℃，分批加入22.70g NaH，0℃保温1hr，然后将54.96g化合物M6-2缓慢滴加到反应液中，滴完后0℃下反应1hr，升温至60℃继续反应1hr。反应液降温至0℃，用500mL冰水淬灭反应，EtOAc(500mL×3)萃取，合并有机相，有机相用饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩，残余物经柱层析纯化得29.00g棕色油状物M1-3。Under nitrogen protection, dissolve 25.00g of compound M1-1 in 200mL of DMF, cool to 0°C, add 22.70g NaH in batches, keep at 0°C for 1hr, and then slowly add 54.96g of compound M6-2 dropwise to the reaction solution After dropping, react at 0°C for 1 hr, and then heat to 60°C to continue the reaction for 1 hr. The reaction solution was cooled to 0°C, quenched with 500 mL ice water, extracted with EtOAc (500 mL×3), combined the organic phases, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was passed through the column Analyze and purify to obtain 29.00g of brown oil M1-3.
步骤2：化合物M1-5的制备Step 2: Preparation of compound M1-5
将29.00g化合物M1-3溶解于50mL的Ti(OEt) 4中，加入34.99g化合物M1-4，然后加热至90℃反应12hrs。TCL检测反应完全，将反应液倒入500mL的冰水中，加入300mL EtOAc搅拌1hr，用EtOAc(300mL×3)萃取，合并有机相，有机相用饱和食盐水(100mL×4)洗涤，无水硫酸钠干燥，减压浓缩得39.00g棕色油状物化合物M1-5粗品。 29.00 g of compound M1-3 was dissolved in 50 mL of Ti(OEt) 4 , 34.99 g of compound M1-4 was added, and then heated to 90° C. for reaction for 12 hrs. TCL detected that the reaction was complete. Pour the reaction solution into 500 mL ice water, add 300 mL EtOAc and stir for 1 hr, extract with EtOAc (300 mL×3), combine the organic phases, and wash the organic phase with saturated brine (100 mL×4), anhydrous sulfuric acid It was dried with sodium and concentrated under reduced pressure to obtain 39.00 g of crude compound M1-5 as a brown oil.
步骤3：化合物M1-6的制备Step 3: Preparation of compound M1-6
氮气保护下，将48.00g化合物M1-5溶解于500mL无水THF中，降温至-20℃，缓慢加入6.73g NaHB 4，然后自然升温至RT搅拌2hrs。反应完毕，反应液降温至0℃，用300mL水淬灭，EtOAc(300mL×3)萃取，合并有机相，有机相用饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩，残余物经柱层析纯化得25.40g棕色油状物的化合物M1-6。 Under the protection of nitrogen, 48.00 g of compound M1-5 was dissolved in 500 mL of anhydrous THF, the temperature was lowered to -20°C, and 6.73 g of NaHB 4 was slowly added, and then the temperature was raised to RT and stirred for 2 hrs. After the reaction was completed, the reaction solution was cooled to 0°C, quenched with 300 mL of water, extracted with EtOAc (300 mL×3), combined the organic phases, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was passed through a column Chromatographic purification yielded 25.40 g of compound M1-6 as a brown oil.
步骤4：化合物M1-7的制备Step 4: Preparation of compound M1-7
将10.00g化合物M1-6溶解于100mL DCM溶液中，滴加28.04g TFA溶液，然后RT下反应1hr。反应液降温至0℃，用100mL饱和NaHCO 3水溶液淬灭，EtOAc:THF＝3:1(100mL×3)萃取，合并有机相，有机相用饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩得7.64g棕色固体即化合物M1-7粗品，直接用于下一步反应。 10.00 g of compound M1-6 was dissolved in 100 mL of DCM solution, 28.04 g of TFA solution was added dropwise, and then reacted at RT for 1 hr. The reaction solution was cooled to 0°C, quenched with 100 mL saturated aqueous NaHCO 3 solution, extracted with EtOAc:THF=3:1 (100 mL×3), combined the organic phases, washed with saturated brine, dried over anhydrous sodium sulfate, and reduced pressure It was concentrated to obtain 7.64 g of a brown solid, the crude compound M1-7, which was directly used in the next reaction.
1H NMR(500MHz,DMSO-d 6)δ7.26-7.21(m,4H),5.80(d,J＝10.5Hz,1H),4.43(d,J＝10.5Hz,1H),3.17-3.15(m,2H),3.08(d,J＝15.5Hz,1H),2.98-2.88(m,2H),2.69(d,J＝15.5Hz,1H),2.04-1.99(m,1H),1.80-1.75(m,1H),1.62-1.59(m,1H),1.35(m,1H),1.22(s,9H)。 1 H NMR(500MHz,DMSO-d 6 )δ7.26-7.21(m,4H), 5.80(d,J=10.5Hz,1H), 4.43(d,J=10.5Hz,1H), 3.17-3.15( m, 2H), 3.08 (d, J = 15.5 Hz, 1H), 2.98-2.88 (m, 2H), 2.69 (d, J = 15.5 Hz, 1H), 2.04-1.99 (m, 1H), 1.80-1.75 (m, 1H), 1.62-1.59 (m, 1H), 1.35 (m, 1H), 1.22 (s, 9H).
步骤5：化合物M1-8的制备Step 5: Preparation of compound M1-8
将1.29g 3,6-二溴吡嗪-2-甲酸甲酯和1.60g化合物M1-7溶解于20mL四氢呋喃中，滴加1.12g DIEA，60℃搅拌反应12小时。TLC检测反应完全，减压浓缩，加入50mL水，再用EtOAc(50mL×3)萃取，合并有机层，用硫酸钠干燥后脱溶，经柱层析纯化得1.60g化合物M1-8。1.29g methyl 3,6-dibromopyrazine-2-carboxylate and 1.60g compound M1-7 were dissolved in 20mL tetrahydrofuran, 1.12g DIEA was added dropwise, and the reaction was stirred at 60°C for 12 hours. TLC detected the completion of the reaction, concentrated under reduced pressure, added 50 mL of water, and extracted with EtOAc (50 mL×3), combined the organic layers, dried over sodium sulfate and desolventized, purified by column chromatography to obtain 1.60 g of compound M1-8.
步骤6：化合物M1和M2的制备Step 6: Preparation of compounds M1 and M2
氮气保护下，将1.00g化合物M1-8溶解于30mL无水二氯甲烷中，温度降至-78℃，滴加DIBAL-H(1M，9.6mL)的正己烷溶液。-78℃搅拌反应1小时。再缓慢升温至-40℃，继续反应2小时。TLC检测原料反应完全，在0℃下，缓慢滴加0.4mL水，再滴加氢氧化钠水溶液(15％，0.4mL)，再加入1mL水。升至室温搅拌15分钟。加入硫酸钠干燥，搅拌十分钟后过滤。滤液浓缩，经柱层析纯化得0.40g化合物M1和0.11g化合物M2。Under nitrogen protection, 1.00 g of compound M1-8 was dissolved in 30 mL of anhydrous dichloromethane, the temperature was reduced to -78°C, and DIBAL-H (1M, 9.6 mL) in n-hexane was added dropwise. The reaction was stirred at -78°C for 1 hour. Then slowly increase the temperature to -40°C, and continue the reaction for 2 hours. TLC detected that the reaction of the raw materials was complete. At 0°C, 0.4 mL of water was slowly added dropwise, and then sodium hydroxide aqueous solution (15%, 0.4 mL) was added dropwise, and then 1 mL of water was added. Warm to room temperature and stir for 15 minutes. Add sodium sulfate to dry, stir for ten minutes and filter. The filtrate was concentrated and purified by column chromatography to obtain 0.40 g of compound M1 and 0.11 g of compound M2.
经由不同的反应起始原料和合适的试剂(所述原料和试剂为市售)，采用与前述中间体M1-7类似的方法制备表1所列的中间体M11。The intermediate M11 listed in Table 1 was prepared by using different reaction starting materials and appropriate reagents (the raw materials and reagents are commercially available), using a method similar to the foregoing intermediate M1-7.
表1Table 1
Figure PCTCN2021088871-appb-000040
Figure PCTCN2021088871-appb-000040
中间体化合物M14的制备：Preparation of intermediate compound M14:
Figure PCTCN2021088871-appb-000041
Figure PCTCN2021088871-appb-000041
步骤1：化合物M14-2的制备Step 1: Preparation of compound M14-2
将2.00g化合物M14-1溶解于40mL THF中，加入NaOH(30mL，1N)，然后RT反应2hrs。TLC检测反应完全，将反应液倒入100mL水中，用6N HCl调至pH为4-5，加EtOAc萃取(100mL×4)，合并有机相，用50mL饱和NaCl洗涤，无水硫酸钠干燥，减压浓缩，残余物用正己烷打浆得1.67g淡黄色固体M14-2。Dissolve 2.00 g of compound M14-1 in 40 mL THF, add NaOH (30 mL, 1N), and then react with RT for 2 hrs. TLC detects the completion of the reaction. Pour the reaction solution into 100mL water, adjust the pH to 4-5 with 6N HCl, add EtOAc to extract (100mL×4), combine the organic phases, wash with 50mL saturated NaCl, and dry with anhydrous sodium sulfate. It was concentrated under pressure, and the residue was slurried with n-hexane to obtain 1.67 g of light yellow solid M14-2.
步骤2：化合物M14-3的制备Step 2: Preparation of compound M14-3
将1.28g化合物M14-2溶解于13mL DMF中，降温0℃，加入3.26g Cs 2CO 3，然后滴加2.13g CH 3I，滴完后升温至10℃反应1hr。TLC检测反应完全，反应液降温至0℃，加入20mL EtOAc和20mL水，分出有机相，水相继续用20mL EtOAc萃取，合并有机相，饱和NaCl(5×4mL)洗涤，无水硫酸钠干燥，减压浓缩，残余物经柱层析纯化得635mg化合物M14-3。 Dissolve 1.28g of compound M14-2 in 13mL DMF, lower the temperature to 0°C, add 3.26g of Cs 2 CO 3 , and then add 2.13g of CH 3 I dropwise, and then heat up to 10°C to react for 1 hr. TLC detected the completion of the reaction, the reaction solution was cooled to 0°C, 20 mL EtOAc and 20 mL water were added, the organic phase was separated, the aqueous phase was extracted with 20 mL EtOAc, the organic phases were combined, washed with saturated NaCl (5×4 mL), and dried over anhydrous sodium sulfate After concentration under reduced pressure, the residue was purified by column chromatography to obtain 635 mg of compound M14-3.
步骤3：化合物M14-5的制备Step 3: Preparation of compound M14-5
将359mg化合物M14-3和448mg化合物M1-7溶解于6mL DMAc中，加入860mg DIPEA，氮气置换三次，微波120℃反应1hr。TLC检测反应完全，将反应液冷却至室温，加20mL水，加EtOAc(20mL×3)萃取，合并有机相，饱和NaCl(5mL×4)洗涤，无水硫酸钠干燥，减压浓缩，残余物经柱层析纯化得290mg化合物M14-5。Dissolve 359 mg of compound M14-3 and 448 mg of compound M1-7 in 6 mL of DMAc, add 860 mg of DIPEA, replace with nitrogen three times, and react in a microwave at 120°C for 1 hr. The reaction was completed by TLC detection, the reaction solution was cooled to room temperature, 20 mL of water was added, and EtOAc (20 mL×3) was added for extraction. The organic phases were combined, washed with saturated NaCl (5 mL×4), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue Purified by column chromatography, 290 mg of compound M14-5 was obtained.
中间体化合物M15的制备：Preparation of intermediate compound M15:
Figure PCTCN2021088871-appb-000042
Figure PCTCN2021088871-appb-000042
步骤1：化合物M15-2的制备Step 1: Preparation of compound M15-2
将0.50g化合物M15-1和1.19g化合物M1-7溶解于15ML无水N,N-二甲基甲酰胺中，在冰浴下依次加入3.13g苯并三氮唑-1-基氧基三(二甲基氨基)磷鎓六氟磷酸盐、3.78g DBU，在室温下搅拌反应18小时。LCMS检测反应完全，加入25mL水，再用DCM(20mL×3)萃取，合并有机层，饱和食盐水(20mL×3)洗涤，用无水硫酸钠干燥后脱溶，经柱层析纯化(DCM:MeOH＝95％-92％)得0.59g化合物M15-2。0.50g of compound M15-1 and 1.19g of compound M1-7 were dissolved in 15ML of anhydrous N,N-dimethylformamide, and 3.13g of benzotriazol-1-yloxy three were sequentially added in an ice bath. (Dimethylamino)phosphonium hexafluorophosphate, 3.78g DBU, stirred and reacted at room temperature for 18 hours. LCMS detected that the reaction was complete, added 25 mL of water, and then extracted with DCM (20 mL×3), combined the organic layers, washed with saturated brine (20 mL×3), dried over anhydrous sodium sulfate and desolventized, purified by column chromatography (DCM :MeOH=95%-92%) to obtain 0.59 g of compound M15-2.
步骤2：化合物M15-3的制备Step 2: Preparation of compound M15-3
氮气保护下，将0.59g化合物M15-2溶解于10mL无水N,N-二甲基甲酰胺中，在冰浴下，将0.39g N-碘代丁二酰亚胺加入上述反应液中。TLC检测反应完全，加入15mL水，再用DCM(20mL×3)萃取，合并有机层，饱和食盐水(10mL×3)洗涤，用无水硫酸钠干燥后脱溶，经柱层析纯化(DCM:MeOH＝95％-92％)得0.42g化合物M15。Under the protection of nitrogen, 0.59 g of compound M15-2 was dissolved in 10 mL of anhydrous N,N-dimethylformamide, and 0.39 g of N-iodosuccinimide was added to the above reaction solution under an ice bath. TLC detected that the reaction was complete, 15 mL of water was added, and then extracted with DCM (20 mL×3). The organic layers were combined, washed with saturated brine (10 mL×3), dried with anhydrous sodium sulfate, and the solution was removed and purified by column chromatography (DCM :MeOH=95%-92%) to obtain 0.42g of compound M15.
中间体化合物M30的制备：Preparation of intermediate compound M30:
Figure PCTCN2021088871-appb-000043
Figure PCTCN2021088871-appb-000043
步骤1：化合物M30-3的制备Step 1: Preparation of compound M30-3
将10.00g化合物M30-1和7.59g化合物M30-2溶解于170mL氯仿中，加入350mg碘单质，常温搅拌反应24小时。TLC检测反应完全，将化合物倒入硫代硫酸钠水溶液中(100mL，0.4mol/L)，再加入氢氧化钠水溶液(70mL,40％)，再用氯仿(150mL×2)萃取， 合并有机层，用硫酸钠干燥后脱溶，用二氯甲烷/正己烷重结晶，得到8.77g化合物M30-3。10.00 g of compound M30-1 and 7.59 g of compound M30-2 were dissolved in 170 mL of chloroform, 350 mg of iodine was added, and the reaction was stirred at room temperature for 24 hours. TLC detects that the reaction is complete. Pour the compound into an aqueous sodium thiosulfate solution (100 mL, 0.4 mol/L), add an aqueous sodium hydroxide solution (70 mL, 40%), and extract with chloroform (150 mL×2). Combine the organic layers. After drying with sodium sulfate, it was desolventized, and recrystallized with dichloromethane/n-hexane to obtain 8.77 g of compound M30-3.
步骤2：化合物M30-5的制备Step 2: Preparation of compound M30-5
将8.77g化合物M30-3溶解于300mL无水四氢呋喃中，降温至-30℃，滴加正丁基锂(2.5M，16mL)的正己烷溶液，保温搅拌1小时。随后将8.15g化合物M30-4溶在30mL四氢呋喃中缓慢滴加到反应液中，滴加完毕后升温至-10℃继续反应2.5小时。反应液用200mL饱和食盐水淬灭，用EtOAc(300mL×2)萃取，合并有机相，无水硫酸钠干燥，减压浓缩，经柱层析纯化得11.06g化合物M30-5。8.77 g of compound M30-3 was dissolved in 300 mL of anhydrous tetrahydrofuran, the temperature was lowered to -30°C, a n-hexane solution of n-butyllithium (2.5M, 16 mL) was added dropwise, and the mixture was kept warm and stirred for 1 hour. Subsequently, 8.15 g of compound M30-4 was dissolved in 30 mL of tetrahydrofuran and slowly added dropwise to the reaction solution. After the addition, the temperature was raised to -10° C. and the reaction was continued for 2.5 hours. The reaction solution was quenched with 200 mL saturated brine, extracted with EtOAc (300 mL×2), and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 11.06 g of compound M30-5.
步骤3：化合物M30-7的制备Step 3: Preparation of compound M30-7
将11.06g化合物M30-5溶解于水(40mL)和二氯甲烷(200mL)的混合溶液中，随后依次3.17g吡啶，12.83g化合物M30-6和0.86g四丁基溴化铵。常温搅拌24小时。反应液用100mL饱和食盐水淬灭，用DCM(100mL×3)萃取，合并有机相，无水硫酸钠干燥，减压浓缩，经柱层析纯化得5.46g化合物M30-7。11.06 g of compound M30-5 was dissolved in a mixed solution of water (40 mL) and dichloromethane (200 mL), followed by 3.17 g of pyridine, 12.83 g of compound M30-6, and 0.86 g of tetrabutylammonium bromide. Stir at room temperature for 24 hours. The reaction solution was quenched with 100 mL saturated brine, extracted with DCM (100 mL×3), and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 5.46 g of compound M30-7.
步骤4：化合物M30-8的制备Step 4: Preparation of compound M30-8
将5.46g化合物M30-7和2.84g叔丁醇钾溶于85mL无水四氢呋喃中，氮气置换3次后，微波70℃反应5分钟。减压除去溶剂，加入100mL饱和食盐水，再用EtOAc(100mL×2)萃取，合并有机相，无水硫酸钠干燥，减压浓缩，经柱层析纯化得2.91g化合物M30-8。Dissolve 5.46 g of compound M30-7 and 2.84 g of potassium tert-butoxide in 85 mL of anhydrous tetrahydrofuran, replace with nitrogen three times, and react in a microwave at 70° C. for 5 minutes. The solvent was removed under reduced pressure, 100 mL of saturated brine was added, and then extracted with EtOAc (100 mL×2), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 2.91 g of compound M30-8.
步骤5：化合物M30-9的制备Step 5: Preparation of compound M30-9
将1.30g化合物M30-8，1.56g(R)-(+)-叔丁基亚磺酰胺溶于钛酸四乙酯(10mL)和无水四氢呋喃(2mL)的混合溶液中，氮气置换3次后，90℃反应8小时。停止加热，将反应液倒入200mL冰水中，再加入150mL乙酸乙酯，搅拌1小时。过滤除去滤渣。滤液用乙酸乙酯(100mL×2)萃取，合并有机相，无水硫酸钠干燥，减压浓缩，得1.90g化合物M30-9。Dissolve 1.30g of compound M30-8, 1.56g of (R)-(+)-tert-butylsulfinamide in a mixed solution of tetraethyl titanate (10mL) and anhydrous tetrahydrofuran (2mL), and replace with nitrogen 3 times Then, the reaction was carried out at 90°C for 8 hours. The heating was stopped, the reaction solution was poured into 200 mL of ice water, 150 mL of ethyl acetate was added, and the mixture was stirred for 1 hour. Filter to remove the filter residue. The filtrate was extracted with ethyl acetate (100 mL×2), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 1.90 g of compound M30-9.
步骤6：化合物M30-10的制备Step 6: Preparation of compound M30-10
将1.30g化合物M30-9溶于25mL无水四氢呋喃中，在-20℃下分批加入344mg硼氢化钠，缓慢升至室温，再常温搅拌3小时。0℃下，加入100mL水，再用EtOAc(80mL×3)萃取，合并有机相，无水硫酸钠干燥，减压浓缩，经柱层析纯化得0.94g化合物M30-10。Dissolve 1.30 g of compound M30-9 in 25 mL of anhydrous tetrahydrofuran, add 344 mg of sodium borohydride in batches at -20°C, slowly warm to room temperature, and then stir at room temperature for 3 hours. At 0°C, 100 mL of water was added, and then extracted with EtOAc (80 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 0.94 g of compound M30-10.
步骤7：化合物M30的制备Step 7: Preparation of compound M30
将0.94g化合物M30-10溶于10mL二氯甲烷中，再滴加2.62g三氟乙酸，常温搅拌小时。将反应液降至0℃，再加入饱和碳酸氢钠水溶液调节pH至弱碱性。用EtOAc:THF＝1:1的混合溶液萃取(60mL×4)，合并有机相，无水硫酸钠干燥，减压浓缩。得692mg化合物M30。0.94 g of compound M30-10 was dissolved in 10 mL of dichloromethane, and then 2.62 g of trifluoroacetic acid was added dropwise, and the mixture was stirred at room temperature for 1 hour. The reaction solution was reduced to 0°C, and then saturated aqueous sodium bicarbonate solution was added to adjust the pH to weakly alkaline. It was extracted with a mixed solution of EtOAc:THF=1:1 (60 mL×4), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. 692 mg of compound M30 was obtained.
经由不同的反应起始原料和合适的试剂(所述原料和试剂为市售)，采用与前述中间体M30类似的方法制备表2所列的中间体。Through different reaction starting materials and appropriate reagents (the raw materials and reagents are commercially available), the intermediates listed in Table 2 were prepared by a method similar to the foregoing intermediate M30.
表2Table 2
Figure PCTCN2021088871-appb-000044
Figure PCTCN2021088871-appb-000044
实施例1 化合物A01(3-(5-((S)-1-氨基-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-6-(羟甲基)吡嗪-2-基)-1-苯丙-2-炔-1-醇)的制备：Example 1 Compound A01 (3-(5-((S)-1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(hydroxymethyl (Pyrazine-2-yl)-1-phenylprop-2-yn-1-ol) preparation:
Figure PCTCN2021088871-appb-000045
Figure PCTCN2021088871-appb-000045
步骤1：化合物A01-1的制备Step 1: Preparation of compound A01-1
将100mg的A01-SM、30mg M1、7.11mg Pd(dppf)Cl 2、1.93mg CuI、41mg Et 3N加入四氢呋喃(2mL)中，氮气置换三次，氮气保护下70℃搅拌反应3hrs。LCMS和TLC检测反应完全，反应液冷却至室温减压浓缩，残余物经柱层析纯化得66mg黄色固体化合物A01-1。 100mg of the A01-SM, 30mg M1,7.11mg Pd ( dppf) Cl 2, 1.93mg CuI, 41mg Et 3 N was added in tetrahydrofuran (2mL), a nitrogen thrice, 70 deg.] C The reaction was stirred for 3hrs under nitrogen. LCMS and TLC detected that the reaction was complete, the reaction solution was cooled to room temperature and concentrated under reduced pressure, and the residue was purified by column chromatography to obtain 66 mg of yellow solid compound A01-1.
步骤2：化合物A01的制备Step 2: Preparation of compound A01
将66mg化合物A01-1溶解于2.0mL四氢呋喃中，加入2N HCl(0.2mL，乙酸乙酯溶液)，RT搅拌反应1hrs。LCMS和TLC检测反应完全，反应液减压浓缩。残余物加入H 2O(1.0mL) 溶解，用饱和NaHCO 3调节溶液至pH＝8，二氯甲烷(3x3mL)萃取，有机相干燥后真空浓缩，经制备板纯化得6.4mg黄色固体化合物A01。 66 mg of compound A01-1 was dissolved in 2.0 mL of tetrahydrofuran, 2N HCl (0.2 mL, ethyl acetate solution) was added, and the reaction was stirred at RT for 1 hrs. LCMS and TLC detected that the reaction was complete, and the reaction solution was concentrated under reduced pressure. The residue was dissolved by adding H 2 O (1.0 mL), the solution was adjusted to pH=8 with saturated NaHCO 3 , extracted with dichloromethane (3×3 mL), the organic phase was dried and concentrated in vacuo, and purified by a preparation plate to obtain 6.4 mg of yellow solid compound A01.
[M+H +]＝441.33。 [M+H + ]=441.33.
实施例3 化合物A03((S)-3-(3-(5-(1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-6-(羟甲基)吡嗪-2-基)丙-2-炔-1-基)苯酚)的制备：Example 3 Compound A03((S)-3-(3-(5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6 -(Hydroxymethyl)pyrazin-2-yl)prop-2-yn-1-yl)phenol) preparation:
Figure PCTCN2021088871-appb-000046
Figure PCTCN2021088871-appb-000046
步骤1：化合物A03-1的制备Step 1: Preparation of compound A03-1
将400mg化合物M1、159mg三甲基硅乙炔、28mg PdCl 2(PPh 3) 2、7.7mg CuI溶于THF(7mL)和Et 3N(0.7mL)中，氮气置换后，室温搅拌反应1h。LC-MS及TLC检测反应完全，真空浓缩，粗品经柱层析纯化得370mg黄色固体化合物A03-1。 400 mg of compound M1, 159 mg of trimethylsilyl acetylene, 28 mg of PdCl 2 (PPh 3 ) 2 and 7.7 mg of CuI were dissolved in THF (7 mL) and Et 3 N (0.7 mL). After nitrogen replacement, the reaction was stirred at room temperature for 1 h. LC-MS and TLC detected that the reaction was complete, concentrated in vacuo, and the crude product was purified by column chromatography to obtain 370 mg of yellow solid compound A03-1.
步骤2：化合物A03-2的制备Step 2: Preparation of compound A03-2
将370mg化合物A03-1溶于MeOH(5mL)中，再加入200mg K 2CO 3，氮气置换后，室温搅拌反应1h。LC-MS及TLC检测反应完全，真空浓缩，粗品经柱层析纯化得310mg淡黄色固体化合物A03-2。 370 mg of compound A03-1 was dissolved in MeOH (5 mL), 200 mg of K 2 CO 3 was added, and after nitrogen replacement, the reaction was stirred at room temperature for 1 h. LC-MS and TLC detected that the reaction was complete, concentrated in vacuo, and the crude product was purified by column chromatography to obtain 310 mg of light yellow solid compound A03-2.
步骤3：化合物A03-3的制备Step 3: Preparation of compound A03-3
将200mg化合物A03-2、16mg PdCl 2(PPh 3) 2,4.3mg CuI、100mg Et 3N,溶于DMF(4mL)中，氮气置换后，室温搅拌反应10分钟，再将138mg 3-甲氧基苄溴加入上述反应液中，氮气保护100℃下搅拌4小时。LC-MS及TLC检测反应完全，加入10mL水淬灭，乙酸乙酯(3x10mL)萃取，饱和食盐水洗涤，无水硫酸钠干燥，真空浓缩，粗品经柱层析纯化得70mg黄色固体化合物A03-3。 200mg compound A03-2, 16mg PdCl 2 (PPh 3 ) 2 , 4.3mg CuI, 100mg Et 3 N were dissolved in DMF (4mL), after nitrogen replacement, the reaction was stirred at room temperature for 10 minutes, and then 138mg 3-methoxy The benzyl bromide was added to the above reaction solution, and the mixture was stirred at 100°C for 4 hours under nitrogen protection. LC-MS and TLC detect the completion of the reaction, add 10 mL of water to quench, extract with ethyl acetate (3x10 mL), wash with saturated brine, dry with anhydrous sodium sulfate, and concentrate in vacuo. The crude product is purified by column chromatography to obtain 70 mg of yellow solid compound A03- 3.
步骤4：化合物A03的制备Step 4: Preparation of compound A03
将70mg化合物A03-3溶解于10mL无水二氯甲烷中，冷却至-60℃，再将BBr 3(0.1mL)缓慢加入上述溶液中，缓慢升至-20℃下搅拌反应。LC-MS及TLC检测反应完全，加入饱和碳酸氢钠水溶液淬灭反应，二氯甲烷萃取，合并有机相经，饱和食盐水洗 涤，无水硫酸钠干燥，过滤，滤液旋干，旋干物经制备板纯化得11.6mg化合物A03。 70 mg of compound A03-3 was dissolved in 10 mL of anhydrous dichloromethane, cooled to -60°C, and then BBr 3 (0.1 mL) was slowly added to the above solution, and the temperature was slowly raised to -20°C and the reaction was stirred. LC-MS and TLC check that the reaction is complete, add saturated sodium bicarbonate aqueous solution to quench the reaction, extract with dichloromethane, combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, filter, spin-dry the filtrate, and spin-dry the product. The plate was purified to obtain 11.6 mg of compound A03.
[M+H +]＝441.39。 [M+H + ]=441.39.
1H NMR(500MHz,DMSO-d 6)δ9.42(s,1H)，8.21(s,1H),7.31(d,J＝6.5Hz,1H),7.21-7.10(m,4H),6.85–6.77(m,2H),6.65(d,J＝8.0Hz,1H),5.40(t,J＝6.0Hz,1H),4.47(d,J＝6.0Hz,2H),3.85(s,1H),3.83(s,2H),3.73–3.69(m,2H),3.13–3.06(m,2H),3.03(d,J＝15.5Hz,1H),2.60(d,J＝15.5Hz,1H),1.90–1.87(m,1H),1.80–1.74(m,1H),1.53-1.50(m,1H),1.13-1.10(m,1H). 1 H NMR(500MHz,DMSO-d 6 )δ9.42(s,1H), 8.21(s,1H), 7.31(d,J=6.5Hz,1H), 7.21-7.10(m,4H), 6.85– 6.77 (m, 2H), 6.65 (d, J = 8.0 Hz, 1H), 5.40 (t, J = 6.0 Hz, 1H), 4.47 (d, J = 6.0 Hz, 2H), 3.85 (s, 1H), 3.83(s,2H),3.73-3.69(m,2H),3.13-3.06(m,2H),3.03(d,J=15.5Hz,1H), 2.60(d,J=15.5Hz,1H),1.90 --1.87 (m, 1H), 1.80 - 1.74 (m, 1H), 1.53-1.50 (m, 1H), 1.13-1.10 (m, 1H).
实施例4 化合物A04((S)-(3-(1-氨基-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-6-(3-吗啉代丙-1-炔-1-基)吡嗪-2-基)甲醇)的制备：Example 4 Compound A04 ((S)-(3-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(3-morpholine (Prop-1-yn-1-yl)pyrazin-2-yl)methanol) preparation:
Figure PCTCN2021088871-appb-000047
Figure PCTCN2021088871-appb-000047
步骤1：化合物A04-1的制备Step 1: Preparation of compound A04-1
将50mg化合物M1，25mg化合物SM1，溶解于1mL的THF中，加入3.5mg PdCl 2(PPh 3) 2，0.9mg CuI，0.1mL TEA，氮气置换后，室温反应1hr。LCMS检测反应完全，将反应液过滤，减压浓缩，残余物用制备板纯化得白色固体36.8mg化合物A04-1。 Dissolve 50 mg of compound M1 and 25 mg of compound SM1 in 1 mL of THF, add 3.5 mg of PdCl 2 (PPh 3 ) 2 , 0.9 mg of CuI, and 0.1 mL of TEA. After nitrogen replacement, react at room temperature for 1 hr. LCMS detected that the reaction was complete, the reaction solution was filtered, concentrated under reduced pressure, and the residue was purified with a preparation plate to obtain 36.8 mg of compound A04-1 as a white solid.
步骤2：化合物A04的制备Step 2: Preparation of compound A04
将36.8mg化合物A04-1，溶解于0.8mL的THF中，加入0.2mL的EtOH，搅拌下滴入0.12mL HCl的EA溶液(2M)，室温下搅拌20mins。LCMS检测反应完全，将反应液减压浓缩，残余物用1mL水溶解，滴加饱和碳酸氢钠溶液1mL，收集析出的固体，用制备板纯化得9.0mg黄色固体化合物A04。[M+H +]＝434.47。 36.8 mg of compound A04-1 was dissolved in 0.8 mL of THF, 0.2 mL of EtOH was added, 0.12 mL of HCl in EA solution (2M) was added dropwise with stirring, and the mixture was stirred at room temperature for 20 mins. LCMS detected that the reaction was complete, the reaction solution was concentrated under reduced pressure, the residue was dissolved in 1 mL of water, 1 mL of saturated sodium bicarbonate solution was added dropwise, the precipitated solid was collected, and purified with a preparation plate to obtain 9.0 mg of yellow solid compound A04. [M+H + ]=434.47.
实施例91 化合物A67(S)-1-(3-(5-(1-氨基-1,3-二氢螺[茚-2,4’-哌啶]-1'-基)-6-(羟甲基)吡嗪-2-基)丙-2-炔-1-基)-1H-吡唑-3-羧酰胺的制备：Example 91 Compound A67(S)-1-(3-(5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-( Preparation of (hydroxymethyl)pyrazin-2-yl)prop-2-yn-1-yl)-1H-pyrazole-3-carboxamide:
Figure PCTCN2021088871-appb-000048
Figure PCTCN2021088871-appb-000048
步骤1：化合物A67-1的制备Step 1: Preparation of compound A67-1
将200mg吡唑-3-甲酰胺溶于DMF(10.0mL)中，加入270mg K 2CO 3室温搅拌反应10min，滴入0.15mL溴丙炔，氮气置换后，室温搅拌反应1h，LC-MS及TLC检测反应完 全，加入20mL水，乙酸乙酯(3×20mL)萃取，饱和食盐水洗涤，无水硫酸钠干燥，真空浓缩，粗品经柱层析纯化得150mg白色固体化合物A67-1。 Dissolve 200mg pyrazole-3-carboxamide in DMF (10.0mL), add 270mg K 2 CO 3 and stir for 10 min at room temperature. Add 0.15 mL of bromopropyne dropwise. After nitrogen replacement, the reaction is stirred at room temperature for 1 h. LC-MS and TLC detected that the reaction was complete, added 20 mL of water, extracted with ethyl acetate (3×20 mL), washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was purified by column chromatography to obtain 150 mg of white solid compound A67-1.
步骤2：化合物A67-2的制备Step 2: Preparation of compound A67-2
将200mg化合物M1、28mg PdCl 2(PPh 3) 2、4mg CuI和91mg化合物A67-1溶于DMF(6.0mL)和Et 3N(1.1mL)中，氮气置换后，60℃反应2.5小时。LC-MS及TLC检测反应完全，加入20mL水，10mL乙酸乙酯萃取，饱和食盐水洗涤有机相，无水硫酸钠干燥，真空浓缩，粗品经制备板纯化得100mg淡黄色固体，即化合物A67-2。 200 mg of compound M1, 28 mg of PdCl 2 (PPh 3 ) 2 , 4 mg of CuI, and 91 mg of compound A67-1 were dissolved in DMF (6.0 mL) and Et 3 N (1.1 mL), and after nitrogen replacement, the reaction was carried out at 60° C. for 2.5 hours. LC-MS and TLC check that the reaction is complete, add 20 mL of water, 10 mL of ethyl acetate for extraction, wash the organic phase with saturated brine, dry with anhydrous sodium sulfate, and concentrate in vacuo. The crude product is purified by a preparation plate to obtain 100 mg of light yellow solid, which is compound A67- 2.
步骤2：化合物A67的制备Step 2: Preparation of compound A67
将100mg化合物A67-2，溶解于6.0mL的二氧六环中，再加入1.5mL的MeOH，搅拌下滴入0.26mL HCl的EA溶液(2M)，室温下搅拌30min。LCMS检测反应完全，将反应液减压浓缩，残余物用10mL水溶解，滴加饱和碳酸氢钠溶液调节pH至8～9，收集析出的固体，用制备板纯化得35mg黄色固体化合物A67。Dissolve 100 mg of compound A67-2 in 6.0 mL of dioxane, then add 1.5 mL of MeOH, add 0.26 mL of HCl EA solution (2M) dropwise with stirring, and stir for 30 min at room temperature. LCMS detected that the reaction was complete, the reaction solution was concentrated under reduced pressure, the residue was dissolved in 10 mL of water, saturated sodium bicarbonate solution was added dropwise to adjust the pH to 8-9, the precipitated solid was collected, and purified with a preparation plate to obtain 35 mg of yellow solid compound A67.
[M+H +]＝458.38。 [M+H + ]=458.38.
1H NMR(500MHz,DMSO)δ8.23(s,1H),7.93(d,J＝2.3Hz,1H),7.52(s,1H),7.30(d,J＝7.0Hz,1H),7.25(s,1H),7.20-7.10(m,3H),6.69(d,J＝2.3Hz,1H),5.44(t,J＝6.0Hz,1H),5.39(s,2H),4.46(d,J＝5.8Hz,2H),3.83(s,1H),3.82-3.74(m,2H),3.18-3.06(m,2H),3.03(d,J＝15.6Hz,1H),2.60(d,J＝15.6Hz,1H),1.90-1.82(m,1H),1.80-1.72(m,1H),1.55-1.48(m,1H),1.14-1.07(m,1H). 1 H NMR (500MHz, DMSO) δ 8.23 (s, 1H), 7.93 (d, J = 2.3 Hz, 1H), 7.52 (s, 1H), 7.30 (d, J = 7.0 Hz, 1H), 7.25 ( s, 1H), 7.20-7.10 (m, 3H), 6.69 (d, J = 2.3 Hz, 1H), 5.44 (t, J = 6.0 Hz, 1H), 5.39 (s, 2H), 4.46 (d, J =5.8Hz,2H),3.83(s,1H),3.82-3.74(m,2H),3.18-3.06(m,2H),3.03(d,J=15.6Hz,1H),2.60(d,J= 15.6Hz, 1H), 1.90-1.82 (m, 1H), 1.80-1.72 (m, 1H), 1.55-1.48 (m, 1H), 1.14-1.07 (m, 1H).
经由不同的反应起始原料、合适的试剂(起始原料及试剂均为市售)及本发明制备的中间体M1，采用与前述实施例1、实施例3、实施例4、实施例88类似的方法制备表3中的化合物。Through different reaction starting materials, suitable reagents (starting materials and reagents are all commercially available), and the intermediate M1 prepared in the present invention, the use is similar to the foregoing Example 1, Example 3, Example 4, and Example 88 The method to prepare the compounds in Table 3.
表3table 3
Figure PCTCN2021088871-appb-000049
Figure PCTCN2021088871-appb-000049
Figure PCTCN2021088871-appb-000050
Figure PCTCN2021088871-appb-000050
化合物A08  1H NMR(500MHz,DMSO)δ9.31(s,1H),8.20(s,1H),7.31(d,J＝6.6Hz,1H),7.21–7.11(m,5H),6.74(d,J＝8.4Hz,2H),5.39(t,J＝6.0Hz,1H),4.47(d,J＝6.0Hz,2H),3.86(s,1H),3.78(s,2H),3.75–3.67(m,2H),3.12–3.01(m,3H),2.61(d,J＝15.8Hz,1H),1.90–1.87(m,1H),1.79–1.76(m,1H),1.51–(m,1H),1.14–1.11(m,1H). Compound A08 1 H NMR (500MHz, DMSO) δ 9.31 (s, 1H), 8.20 (s, 1H), 7.31 (d, J = 6.6 Hz, 1H), 7.21-7.11 (m, 5H), 6.74 (d ,J=8.4Hz,2H),5.39(t,J=6.0Hz,1H),4.47(d,J=6.0Hz,2H),3.86(s,1H),3.78(s,2H),3.75-3.67 (m,2H),3.12–3.01(m,3H),2.61(d,J=15.8Hz,1H),1.90–1.87(m,1H),1.79–1.76(m,1H),1.51–(m, 1H), 1.14-1.11 (m, 1H).
实施例95 化合物A71(S)-4-(4-(5-(1-氨基-1,3-二氢螺[茚-2,4’-哌啶]-1'-基)-6-(羟甲基)吡嗪-2-基)丁-3-炔-1-基)苯甲酰胺的制备：Example 95 Compound A71(S)-4-(4-(5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-( Preparation of (hydroxymethyl)pyrazin-2-yl)but-3-yn-1-yl)benzamide:
Figure PCTCN2021088871-appb-000051
Figure PCTCN2021088871-appb-000051
步骤1：化合物A71-1的制备Step 1: Preparation of compound A71-1
将1.49g的LDA和0.889g的n-BuLi加入THF(20.0mL)中，N 2保护条件下，降温至-78℃下，加入3.56g DMU，将2.95g 4-甲基苯腈加入反应体系，搅拌反应0.5h，将1.50g 2-溴丙炔加入反应体系，-78℃保温搅拌反应1.5h，LC-MS及TLC检测反应完全，加入20mL水，乙酸乙酯(3×20mL)萃取，饱和食盐水洗涤，无水硫酸钠干燥，真空浓缩，粗品经柱层析纯化得800mg白色固体，即化合物A71-1。 Add 1.49g of LDA and 0.889g of n-BuLi to THF (20.0mL), under N 2 protection, cool to -78℃, add 3.56g of DMU, add 2.95g of 4-methylbenzonitrile to the reaction system , Stir the reaction for 0.5h, add 1.50g 2-bromopropyne to the reaction system, keep stirring at -78℃ for 1.5h, LC-MS and TLC check the reaction is complete, add 20mL water, extract with ethyl acetate (3×20mL), Wash with saturated brine, dry with anhydrous sodium sulfate, and concentrate in vacuo. The crude product is purified by column chromatography to obtain 800 mg of white solid, namely compound A71-1.
步骤2：化合物A71-2的制备Step 2: Preparation of compound A71-2
氮气保护条件下，将0.4g化合物A71-1，0.41g氢氧化钠和0.23g碳酸钾溶于二氧六环(4mL)和H 2O(2mL)中，60℃反应16h。TLC检测反应完全，过滤，滤液浓缩，粗品柱层析纯化得0.10g黄色固体，即化合物A71-2。 Under nitrogen protection, 0.4 g of compound A71-1, 0.41 g of sodium hydroxide and 0.23 g of potassium carbonate were dissolved in dioxane (4 mL) and H 2 O (2 mL), and reacted at 60° C. for 16 h. TLC detected that the reaction was complete, filtered, the filtrate was concentrated, and the crude product was purified by column chromatography to obtain 0.10 g of yellow solid, namely compound A71-2.
步骤3：化合物A71-3的制备Step 3: Preparation of compound A71-3
将150mg化合物M1、6.4mg PdCl 2(PPh 3) 2、3.5mg CuI和100mg化合物A71-2溶于DMF(4.0mL)和Et 3N(1.0mL)中，氮气置换后，60℃反应15h。LC-MS及TLC检测反应完全，加入10mL乙酸乙酯，滤掉不溶物，20mL水分散滤液，饱和食盐水洗涤有机相，无水硫酸钠干燥，真空浓缩，粗品经制备板纯化得83mg淡黄色固体，即化合物A71-3。 150 mg of compound M1, 6.4 mg of PdCl 2 (PPh 3 ) 2 , 3.5 mg of CuI and 100 mg of compound A71-2 were dissolved in DMF (4.0 mL) and Et 3 N (1.0 mL), and after nitrogen replacement, the reaction was carried out at 60° C. for 15 h. LC-MS and TLC check that the reaction is complete, add 10mL ethyl acetate, filter out the insolubles, 20mL water dispersion filtrate, saturated brine washing the organic phase, dry with anhydrous sodium sulfate, vacuum concentration, the crude product is purified by the preparation plate to obtain 83mg light yellow Solid, compound A71-3.
步骤4：化合物A71的制备Step 4: Preparation of compound A71
将83mg化合物A71-3溶解于6mL的二氧六环中，再加入2mL的MeOH，搅拌下滴入0.28mL HCl的EA溶液(2M)，室温下搅拌30min。LCMS检测反应完全，将反应液减压浓缩，残余物用10mL水溶解，滴加饱和碳酸氢钠溶液调节pH至8～9，收集析出的固体，用制备板纯化得41.5mg黄色固体，即化合物A71。Dissolve 83 mg of compound A71-3 in 6 mL of dioxane, add 2 mL of MeOH, add 0.28 mL of HCl EA solution (2M) dropwise with stirring, and stir for 30 min at room temperature. LCMS detected the completion of the reaction, the reaction solution was concentrated under reduced pressure, the residue was dissolved in 10 mL of water, saturated sodium bicarbonate solution was added dropwise to adjust the pH to 8-9, the precipitated solid was collected, and purified with a preparation plate to obtain 41.5 mg of yellow solid, which is the compound A71.
[M+H +]＝482.38。 [M+H + ]=482.38.
1H NMR(500MHz,DMSO)δ8.11(s,1H),7.91(s,1H),7.84-7.80(m,2H),7.39(d,J＝8.3Hz,2H),7.30(d,J＝5.5Hz,2H),7.19-7.11(m,3H),5.37(t,J＝6.0Hz,1H),4.46(d,J＝5.9Hz,2H),3.84(s,1H),3.77-3.65(m,2H),3.12-3.00(m,3H),2.92(t,J＝7.3Hz,2H),2.78(t,J＝7.3Hz,2H),2.59(d,J＝15.6Hz,1H),1.90-1.84(m,1H),1.78-1.73(m,1H),1.52-1.50(m,1H),1.07-1.04(m,1H)。 1 H NMR(500MHz,DMSO)δ8.11(s,1H),7.91(s,1H),7.84-7.80(m,2H),7.39(d,J=8.3Hz,2H),7.30(d,J =5.5Hz, 2H), 7.19-7.11 (m, 3H), 5.37 (t, J = 6.0Hz, 1H), 4.46 (d, J = 5.9 Hz, 2H), 3.84 (s, 1H), 3.77-3.65 (m,2H),3.12-3.00(m,3H),2.92(t,J=7.3Hz,2H), 2.78(t,J=7.3Hz,2H), 2.59(d,J=15.6Hz,1H) ,1.90-1.84(m,1H), 1.78-1.73(m,1H), 1.52-1.50(m,1H), 1.07-1.04(m,1H).
经由不同的反应起始原料、合适的试剂(起始原料及试剂均为市售)及本发明制备的中间体M1，采用与实施例95类似的方法制备表3中的化合物。Using different reaction starting materials, suitable reagents (both starting materials and reagents are commercially available), and the intermediate M1 prepared in the present invention, the compounds in Table 3 were prepared by a method similar to that in Example 95.
表3table 3
Figure PCTCN2021088871-appb-000052
Figure PCTCN2021088871-appb-000052
Figure PCTCN2021088871-appb-000053
Figure PCTCN2021088871-appb-000053
实施例97 化合物A73(S)-2-(3-(5-(1-氨基-1,3-二氢螺[茚-2,4’-哌啶]-1'-基)-6-(羟甲基)吡嗪-2-基)丙-2-炔-1-基)异吲哚啉-5-羧酰胺的制备：Example 97 Compound A73(S)-2-(3-(5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-( Preparation of (hydroxymethyl)pyrazin-2-yl)prop-2-yn-1-yl)isoindoline-5-carboxamide:
Figure PCTCN2021088871-appb-000054
Figure PCTCN2021088871-appb-000054
步骤1：化合物A73-1的制备Step 1: Preparation of compound A73-1
将4.000g 5-溴异吲哚啉-2-羧酸叔丁酯、3.150g氰化锌、3.100g四三苯基膦钯溶于DMF(80mL)中，N 2置换后加热80度反应过夜。TLC检测原料反应完全，反应液冷却至室温，过滤，滤液用EA稀释，水洗涤后无水硫酸钠干燥，旋干，粗品经柱层析纯化得白色固体3.260g，即化合物A73-1。 Dissolve 4.000g 5-bromoisoindoline-2-carboxylic acid tert-butyl ester, 3.150g zinc cyanide, 3.100g tetrakistriphenylphosphine palladium in DMF (80mL), replace with N 2 and heat at 80°C to react overnight . TLC detected the complete reaction of the raw materials, the reaction solution was cooled to room temperature, filtered, the filtrate was diluted with EA, washed with water, dried over anhydrous sodium sulfate, and spin-dried. The crude product was purified by column chromatography to obtain 3.260 g of white solid, namely compound A73-1.
步骤2：化合物A73-2的制备Step 2: Preparation of compound A73-2
将3.260g化合物A73-1、35mg Parkin’s试剂溶于EtOH(30mL)和水(30mL)中，80℃反应过夜。LC-MS及TLC检测原料反应完全，用乙酸乙酯(20mL×3)萃取，合并有机相，饱和食盐水(10mL×4)洗涤，无水硫酸钠干燥，真空浓缩，粗品经柱层析纯化得白色固体1.320g，即化合物A73-2。3.260g of compound A73-1 and 35mg Parkin’s reagent were dissolved in EtOH (30mL) and water (30mL), and reacted at 80°C overnight. LC-MS and TLC detected the complete reaction of the raw materials, extracted with ethyl acetate (20mL×3), combined the organic phases, washed with saturated brine (10mL×4), dried over anhydrous sodium sulfate, concentrated in vacuo, and purified the crude product by column chromatography 1.320 g of white solid was obtained, namely compound A73-2.
步骤3：化合物A73-3的制备Step 3: Preparation of compound A73-3
将1.320g化合物A73-2溶解于DCM(15mL)和TFA(15mL)中，RT搅拌反应1小时。LCMS和TLC检测反应完全，反应液用饱和NaHCO 3调至pH＝8，过滤，滤饼用水洗涤，干燥得粗品，类白色固体0.816g，即化合物A73-3。 1.320 g of compound A73-2 was dissolved in DCM (15 mL) and TFA (15 mL), and the reaction was stirred at RT for 1 hour. LCMS and TLC detected that the reaction was complete, the reaction solution was adjusted to pH=8 with saturated NaHCO 3 , filtered, the filter cake was washed with water, and dried to obtain a crude product, 0.816 g of off-white solid, namely compound A73-3.
步骤4：化合物A73-4的制备Step 4: Preparation of compound A73-4
将0.162g A73-3混悬于DMF(10mL)中，加入0.171g三氟乙酸，反应液变澄清，加入 0.690g碳酸钾搅拌5分钟，然后加入0.123g溴丙炔，室温反应过夜。TLC检测原料反应完全，加入10mL水，用乙酸乙酯(20mL×3)萃取，合并有机相，饱和食盐水(10mL×4)洗涤，无水硫酸钠干燥，真空浓缩，粗品经柱层析纯化得体0.030g，即化合物A73-4。Suspend 0.162g A73-3 in DMF (10mL), add 0.171g trifluoroacetic acid, the reaction solution becomes clear, add 0.690g potassium carbonate and stir for 5 minutes, then add 0.123g bromopropyne, and react at room temperature overnight. TLC detects that the raw material has reacted completely, add 10 mL of water, extract with ethyl acetate (20 mL×3), combine the organic phases, wash with saturated brine (10 mL×4), dry with anhydrous sodium sulfate, concentrate in vacuo, and purify the crude product by column chromatography The yield is 0.030 g, which is compound A73-4.
步骤5：化合物A73-5的制备Step 5: Preparation of compound A73-5
将29mg化合物A73-4、65mg化合物M1、4.6mg PdCl 2(PPh 3) 2和1.3mg CuI溶于DMF(2mL)和三乙胺(0.7mL)中，氮气置换后，60℃反应过夜。LC-MS及TLC检测原料反应完全，加入10mL水析出固体，过滤，滤饼用DCM溶解，硫酸钠干燥，旋干，粗品经制备版纯化得固体12mg，即化合物A73-5。 29 mg of compound A73-4, 65 mg of compound M1, 4.6 mg of PdCl 2 (PPh 3 ) 2 and 1.3 mg of CuI were dissolved in DMF (2 mL) and triethylamine (0.7 mL), replaced with nitrogen, and reacted at 60° C. overnight. LC-MS and TLC detected the complete reaction of the raw materials, added 10 mL of water to precipitate a solid, filtered, and the filter cake was dissolved with DCM, dried over sodium sulfate, and spin-dried. The crude product was purified by a preparative plate to obtain a solid 12 mg, namely compound A73-5.
步骤6：化合物A73的制备Step 6: Preparation of compound A73
将12mg化合物A73-5溶解于二氧六环(1.5mL)和甲醇(1.0mL)中，加入2N HCl(0.05mL，乙酸乙酯溶液)，RT搅拌反应1小时。LCMS和TLC检测反应完全，反应液用饱和NaHCO 3调至pH＝8，反应液旋干得粗品，粗品经制备板纯化得7.5mg淡黄色固体，即化合物A73。 12 mg of compound A73-5 was dissolved in dioxane (1.5 mL) and methanol (1.0 mL), 2N HCl (0.05 mL, ethyl acetate solution) was added, and the reaction was stirred at RT for 1 hour. LCMS and TLC detected that the reaction was complete, the reaction solution was adjusted to pH=8 with saturated NaHCO 3 and the reaction solution was spin-dried to obtain a crude product. The crude product was purified by a preparation plate to obtain 7.5 mg of a pale yellow solid, namely compound A73.
[M+H +]＝509.41。 [M+H + ]=509.41.
1H NMR(500MHz,DMSO-d 6)δ8.20(s,1H),7.91(s,1H),7.76(d,J＝1.7Hz,1H),7.73(dd,J＝7.8,1.7Hz,1H),7.33(d,J＝7.8Hz,1H),7.30-7.29(m,2H),7.20-7.10(m,3H),5.40(t,J＝5.9Hz,1H),4.46(d,J＝5.8Hz,2H),4.04(s,4H),3.89(s,2H),3.83(s,1H),3.78-3.69(m,2H),3.14-3.05(m,2H),3.02(d,J＝15.4Hz,1H),2.59(d,J＝15.6Hz,1H),1.90-1.84(m,1H),1.78-1.71(m,1H),1.52-1.47(m,1H),1.11-1.08(m,1H). 1 H NMR(500MHz,DMSO-d 6 )δ8.20(s,1H),7.91(s,1H),7.76(d,J=1.7Hz,1H),7.73(dd,J=7.8,1.7Hz, 1H), 7.33 (d, J = 7.8 Hz, 1H), 7.30-7.29 (m, 2H), 7.20-7.10 (m, 3H), 5.40 (t, J = 5.9 Hz, 1H), 4.46 (d, J =5.8Hz,2H),4.04(s,4H),3.89(s,2H),3.83(s,1H),3.78-3.69(m,2H),3.14-3.05(m,2H),3.02(d, J=15.4Hz, 1H), 2.59(d, J=15.6Hz, 1H), 1.90-1.84(m, 1H), 1.78-1.71(m, 1H), 1.52-1.47(m, 1H), 1.11-1.08 (m,1H).
实施例98 化合物A74(S)-(3-(1-氨基-1,3-二氢螺[茚-2,4’-哌啶]-1'-基)-6-(3-(吲哚-1-基)丙-1-炔-1-基)吡嗪-2-基)甲醇的制备：Example 98 Compound A74(S)-(3-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(3-(indole Preparation of -1-yl)prop-1-yn-1-yl)pyrazin-2-yl)methanol:
Figure PCTCN2021088871-appb-000055
Figure PCTCN2021088871-appb-000055
步骤1：化合物A74-1的制备Step 1: Preparation of compound A74-1
将1.00g吲哚啉、1.74g碳酸钾和1.49g溴丙炔溶于DMF(10mL)中，室温反应2小时。TLC检测反应完全，加入20mL乙酸乙酯，20mL水层，饱和食盐水洗涤有机相，无水硫酸钠干燥，真空浓缩，粗品经柱层析纯化得红色固体1.02g，即化合物A74-1。1.00 g of indoline, 1.74 g of potassium carbonate and 1.49 g of bromopropyne were dissolved in DMF (10 mL) and reacted at room temperature for 2 hours. TLC detected that the reaction was complete, added 20 mL of ethyl acetate, 20 mL of water layer, washed the organic phase with saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was purified by column chromatography to obtain 1.02 g of red solid, namely compound A74-1.
步骤2：化合物A74-2的制备Step 2: Preparation of compound A74-2
将100mg化合物M1、48mg化合物A74-1、7.1mg PdCl 2(PPh 3) 2和1.9mg CuI溶于四氢呋喃(2.5mL)和三乙胺(0.2mL)中，氮气置换后，60℃反应12小时。LC-MS及TLC检测反应完全，加入20mL水，10mL二氯甲烷萃取，饱和食盐水洗涤有机相，无水硫酸钠干燥，真空浓缩，粗品经制备板纯化得99mg黄色固体，即化合物A74-2。 100 mg of compound M1, 48 mg of compound A74-1, 7.1 mg of PdCl 2 (PPh 3 ) 2 and 1.9 mg of CuI were dissolved in tetrahydrofuran (2.5 mL) and triethylamine (0.2 mL). After nitrogen replacement, the mixture was reacted at 60°C for 12 hours . LC-MS and TLC check that the reaction is complete, add 20 mL of water, 10 mL of dichloromethane for extraction, wash the organic phase with saturated brine, dry with anhydrous sodium sulfate, and concentrate in vacuo. The crude product is purified by a preparation plate to obtain 99 mg of yellow solid, which is compound A74-2 .
步骤3：化合物A74的制备Step 3: Preparation of compound A74
将99mg化合物A74-2溶解于二氧六环(3mL)和乙醇(1mL)中，加入2N HCl(0.13mL，乙酸乙酯溶液)，RT搅拌反应1小时。LCMS和TLC检测反应完全，反应液减压浓缩。残余物加入H 2O(1.0mL)溶解，用饱和NaHCO 3调节溶液至pH＝8，二氯甲烷(3×3mL)萃取，有机相干燥后真空浓缩，经制备板纯化得33.2mg淡黄色固体即化合物A74。 99 mg of compound A74-2 was dissolved in dioxane (3 mL) and ethanol (1 mL), 2N HCl (0.13 mL, ethyl acetate solution) was added, and the reaction was stirred at RT for 1 hour. LCMS and TLC detected that the reaction was complete, and the reaction solution was concentrated under reduced pressure. Add H 2 O (1.0 mL) to dissolve the residue, adjust the solution to pH=8 with saturated NaHCO 3 , extract with dichloromethane (3×3 mL), dry the organic phase and concentrate in vacuo. Purify on a preparation plate to obtain 33.2 mg of light yellow solid Namely compound A74.
[M+H +]＝466.3。 [M+H + ]=466.3.
1H NMR(500MHz,DMSO-d 6)δ8.13(s,1H),7.32-7.26(m,1H),7.19-7.12(m,3H),7.09-7.02(m,2H),6.71(d,J＝7.8Hz,1H),6.66(t,J＝7.3Hz,1H),5.40(t,J＝6.0Hz,1H),4.43(d,J＝6.0Hz,2H),4.28(s,2H),3.82(s,1H),3.79-3.69(m,2H),3.41(t,J＝8.2Hz,2H),3.13-3.04(m,2H),3.02(d,J＝15.4Hz,1H),2.92(t,J＝8.2Hz,2H),2.58(d,J＝15.6Hz,1H),1.90-1.82(m,1H),1.79-1.71(m,1H),1.53-1.47(m,1H),1.12-1.06(m,1H). 1 H NMR(500MHz, DMSO-d 6 )δ8.13(s,1H), 7.32-7.26(m,1H), 7.19-7.12(m,3H), 7.09-7.02(m,2H), 6.71(d ,J=7.8Hz,1H),6.66(t,J=7.3Hz,1H), 5.40(t,J=6.0Hz,1H), 4.43(d,J=6.0Hz,2H), 4.28(s,2H ), 3.82(s,1H),3.79-3.69(m,2H),3.41(t,J=8.2Hz,2H),3.13-3.04(m,2H),3.02(d,J=15.4Hz,1H) ,2.92(t,J=8.2Hz,2H),2.58(d,J=15.6Hz,1H),1.90-1.82(m,1H),1.79-1.71(m,1H),1.53-1.47(m,1H) ), 1.12-1.06 (m, 1H).
实施例99 化合物A75(S)-1-(3-(5-(1-氨基-1,3-二氢螺[茚-2,4’-哌啶]-1'-基)-6-(羟甲基)吡嗪-2-基)丙-2-炔-1-基)-1H-吲唑-5-醇的制备：Example 99 Compound A75(S)-1-(3-(5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-( Preparation of (hydroxymethyl)pyrazin-2-yl)prop-2-yn-1-yl)-1H-indazol-5-ol:
Figure PCTCN2021088871-appb-000056
Figure PCTCN2021088871-appb-000056
步骤1：化合物A75-1的制备Step 1: Preparation of compound A75-1
氮气保护下，将1.00g 5-甲氧基-1H-吲唑、0.96g溴丙炔和1.40g碳酸钾溶于DMF(20 mL)中，60℃反应15h。TLC检测反应完全，过滤，滤液浓缩，粗品柱层析纯化得0.64g黄色固体，即化合物A75-1。Under the protection of nitrogen, 1.00g 5-methoxy-1H-indazole, 0.96g bromopropyne and 1.40g potassium carbonate were dissolved in DMF (20 mL) and reacted at 60°C for 15h. TLC detected that the reaction was complete, filtered, the filtrate was concentrated, and the crude product was purified by column chromatography to obtain 0.64 g of yellow solid, namely compound A75-1.
步骤2：化合物A75-2的制备Step 2: Preparation of compound A75-2
将0.200g化合物A75-2溶解于5mL二氯甲烷中，氮气置换后，-78℃下，缓慢滴加入3.6mL的BBr 3，缓慢回温至室温反应5h。LC-MS及TLC检测反应完全，加饱和碳酸氢钠溶液淬灭反应，二氯甲烷萃取，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，真空浓缩，粗品经柱层析纯化得140mg浅黄色固体，即化合物A75-2。 0.200 g of compound A75-2 was dissolved in 5 mL of dichloromethane, and after nitrogen replacement, 3.6 mL of BBr 3 was slowly added dropwise at -78° C., and the temperature was slowly warmed to room temperature to react for 5 hours. LC-MS and TLC check that the reaction is complete, add saturated sodium bicarbonate solution to quench the reaction, extract with dichloromethane, combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, concentrate in vacuo, and purify the crude product by column chromatography. 140 mg pale yellow solid, compound A75-2.
步骤3：化合物A75-3的制备Step 3: Preparation of compound A75-3
将150mg化合物M1、78.5mg化合物A75-2、6.4mg PdCl 2(PPh 3) 2和3.5mg CuI溶于DMF(4mL)和NEt 3(1mL)中，氮气置换后，60℃反应15h。LC-MS及TLC检测反应完全，加入10mL乙酸乙酯，滤掉不溶物，加入20mL水，用乙酸乙酯萃取，饱和食盐水洗涤有机相，无水硫酸钠干燥，真空浓缩，粗品经制备板纯化得160mg淡黄色固体,即化合物A75-3。 150 mg of compound M1, 78.5 mg of compound A75-2, 6.4 mg of PdCl 2 (PPh 3 ) 2 and 3.5 mg of CuI were dissolved in DMF (4 mL) and NEt 3 (1 mL). After nitrogen replacement, the reaction was carried out at 60° C. for 15 hours. LC-MS and TLC check that the reaction is complete, add 10 mL of ethyl acetate, filter out the insolubles, add 20 mL of water, extract with ethyl acetate, wash the organic phase with saturated brine, dry with anhydrous sodium sulfate, and concentrate in vacuo. It was purified to obtain 160 mg of light yellow solid, namely compound A75-3.
步骤4：化合物A75的制备Step 4: Preparation of compound A75
将160mg化合物A75-3溶解于6.0mL二氧六环和2.0mL MeOH中，加入2N HCl(0.27mL，乙酸乙酯溶液)，室温搅拌反应0.5h。LCMS和TLC检测反应完全，反应液减压浓缩，残余物加入H 2O(1.0mL)溶解，用饱和NaHCO 3调节溶液至pH＝8，EA(3×3mL)萃取，有机相干燥后真空浓缩，经制备板纯化得83.5mg浅黄色固体，即化合物A75。 160 mg of compound A75-3 was dissolved in 6.0 mL of dioxane and 2.0 mL of MeOH, 2N HCl (0.27 mL, ethyl acetate solution) was added, and the reaction was stirred at room temperature for 0.5 h. The reaction was completed by LCMS and TLC, the reaction solution was concentrated under reduced pressure, the residue was dissolved by adding H 2 O (1.0 mL), the solution was adjusted to pH=8 with saturated NaHCO 3 , extracted with EA (3×3 mL), the organic phase was dried and concentrated in vacuo , Purified by preparation plate to obtain 83.5 mg of light yellow solid, namely compound A75.
[M+H +]＝481.34。 [M+H + ]=481.34.
1H NMR(500MHz,DMSO)δ9.24(s,1H),8.17(s,1H),7.91(s,1H),7.60(d,J＝8.9Hz,1H),7.29(d,J＝6.7Hz,1H),7.19-7.11(m,3H),7.03-6.97(m,2H),5.55(s,2H),5.40(t,J＝6.0Hz,1H),4.43(d,J＝5.8Hz,2H),3.85-3.72(m,3H),3.15-3.05(m,2H),3.02(d,J＝15.6Hz,1H),2.58(d,J＝15.6Hz,1H),1.89-1.83(m,1H),1.77-1.69(m,1H),1.51-1.49(m,1H),1.14-1.07(m,1H). 1 H NMR(500MHz,DMSO)δ9.24(s,1H), 8.17(s,1H),7.91(s,1H), 7.60(d,J=8.9Hz,1H), 7.29(d,J=6.7 Hz,1H),7.19-7.11(m,3H),7.03-6.97(m,2H),5.55(s,2H), 5.40(t,J=6.0Hz,1H), 4.43(d,J=5.8Hz ,2H),3.85-3.72(m,3H),3.15-3.05(m,2H),3.02(d,J=15.6Hz,1H),2.58(d,J=15.6Hz,1H),1.89-1.83( m, 1H), 1.77-1.69 (m, 1H), 1.51-1.49 (m, 1H), 1.14-1.07 (m, 1H).
实施例100 化合物A76(S)-(3-(1-氨基-1,3-二氢螺[茚-2,4’-哌啶]-1'-基)-6-(3-(5-氨基-1H-吲哚-1-基)丙-1-炔-1-基)吡嗪-2-基)甲醇的制备：Example 100 Compound A76(S)-(3-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(3-(5- Preparation of amino-1H-indol-1-yl)prop-1-yn-1-yl)pyrazin-2-yl)methanol:
Figure PCTCN2021088871-appb-000057
Figure PCTCN2021088871-appb-000057
步骤1：化合物A76-1的制备Step 1: Preparation of compound A76-1
将1g 5-硝基吲哚溶于DMF(10.0mL)中，加入1.30g K 2CO 3室温搅拌反应10min，滴入0.80mL溴丙炔，氮气置换后，室温搅拌反应1h，LC-MS及TLC检测反应完全，加入60mL水，待沉淀完全后，过滤即得粗品，为棕黄色固体，得到1.22g化合物A76-1，直接进行下一步。 Dissolve 1g 5-nitroindole in DMF (10.0mL), add 1.30g K 2 CO 3 and stir at room temperature for 10 min, drop 0.80 mL bromopropyne, and after nitrogen replacement, stir at room temperature for 1 h, LC-MS and TLC detected that the reaction was complete, 60 mL of water was added, and after the precipitation was complete, the crude product was obtained by filtration, which was a brown-yellow solid, and 1.22 g of compound A76-1 was obtained, and proceeded directly to the next step.
步骤2：化合物A76-2的制备Step 2: Preparation of compound A76-2
将0.50g化合物A76-1溶于20mL混合溶液(EtOH:H 2O＝3:1)，加入0.56g还原铁粉以及0.80g NH 4Cl，升温至90℃回流搅拌3h。LC-MS及TLC检测反应完全，垫硅藻土趁热过滤，滤液真空浓缩后，柱层析纯化得0.20g深棕色固体,即化合物A76-2。 0.50 g of compound A76-1 was dissolved in 20 mL of mixed solution (EtOH:H 2 O=3:1), 0.56 g of reduced iron powder and 0.80 g of NH 4 Cl were added, and the temperature was raised to 90° C. under reflux and stirring for 3 hours. LC-MS and TLC detected that the reaction was complete, filtered through a pad of diatomaceous earth while hot, and the filtrate was concentrated in vacuo and purified by column chromatography to obtain 0.20 g of dark brown solid, namely compound A76-2.
步骤3：化合物A76-3的制备Step 3: Preparation of compound A76-3
将300mg化合物M1、43mg PdCl 2(PPh 3) 2、6mg CuI和155mg化合物A76-2溶于DMF(10.0mL)和Et 3N(1.5mL)中，氮气置换后，60℃反应3小时。LC-MS及TLC检测反应完全，加入10mL乙酸乙酯，滤掉不溶物，20mL水分散滤液，饱和食盐水洗涤有机相，无水硫酸钠干燥，真空浓缩，粗品经制备板纯化得0.30g深褐色固体,即化合物A76-3。 300 mg of compound M1, 43 mg of PdCl 2 (PPh 3 ) 2 , 6 mg of CuI and 155 mg of compound A76-2 were dissolved in DMF (10.0 mL) and Et 3 N (1.5 mL), and after nitrogen replacement, the reaction was carried out at 60° C. for 3 hours. LC-MS and TLC check that the reaction is complete, add 10mL ethyl acetate, filter out the insoluble matter, 20mL water dispersion filtrate, saturated brine washing the organic phase, anhydrous sodium sulfate drying, vacuum concentration, the crude product is purified by the preparation plate to 0.30g depth Brown solid, compound A76-3.
步骤4：化合物A76的制备Step 4: Preparation of compound A76
将300mg化合物A76-3溶解于15.0mL的二氧六环中，再加入3.0mL的MeOH，搅拌下滴入1.0mL HCl的EA溶液(2M)，室温下搅拌30min。LCMS检测反应完全，将反应液减压浓缩，残余物用10mL水溶解，滴加饱和碳酸氢钠溶液调节pH至8～9，收集析出的固体，用制备板纯化得195mg褐色固体，即化合物A76。Dissolve 300 mg of compound A76-3 in 15.0 mL of dioxane, then add 3.0 mL of MeOH, add 1.0 mL of HCl EA solution (2M) dropwise with stirring, and stir for 30 min at room temperature. LCMS detected that the reaction was complete, the reaction solution was concentrated under reduced pressure, the residue was dissolved in 10 mL of water, saturated sodium bicarbonate solution was added dropwise to adjust the pH to 8-9, the precipitated solid was collected, and purified with a preparation plate to obtain 195 mg of brown solid, namely compound A76 .
[M+H +]＝479.38。 [M+H + ]=479.38.
1H NMR(500MHz,DMSO)δ8.18(s,1H),7.29(d,J＝6.9Hz,1H),7.26(d,J＝6.2Hz,1H),7.25(s,1H),7.16(t,J＝6.2Hz,2H),7.13(d,J＝3.5Hz,1H),6.70(d,J＝1.8Hz,1H),6.57 (dd,J＝8.6,1.9Hz,1H),6.19(d,J＝3.0Hz,1H),5.42(t,J＝6.0Hz,1H),5.24(s,2H),4.54(s,2H),4.43(d,J＝5.9Hz,2H),4.10(d,J＝5.2Hz,1H),3.83(s,1H),3.82-3.74(m,2H),3.19-3.06(m,2H),3.03(d,J＝15.6Hz,1H),2.60(d,J＝15.6Hz,1H),1.89-1.82(m,1H),1.79-1.72(m,1H),1.54-1.48(m,1H),1.13-1.07(m,1H). 1 H NMR (500MHz, DMSO) δ 8.18 (s, 1H), 7.29 (d, J = 6.9 Hz, 1H), 7.26 (d, J = 6.2 Hz, 1H), 7.25 (s, 1H), 7.16 ( t,J=6.2Hz,2H), 7.13(d,J=3.5Hz,1H), 6.70(d,J=1.8Hz,1H), 6.57 (dd,J=8.6,1.9Hz,1H), 6.19( d, J = 3.0Hz, 1H), 5.42 (t, J = 6.0 Hz, 1H), 5.24 (s, 2H), 4.54 (s, 2H), 4.43 (d, J = 5.9 Hz, 2H), 4.10 ( d,J=5.2Hz,1H),3.83(s,1H),3.82-3.74(m,2H),3.19-3.06(m,2H),3.03(d,J=15.6Hz,1H),2.60(d ,J=15.6Hz,1H), 1.89-1.82(m,1H), 1.79-1.72(m,1H), 1.54-1.48(m,1H), 1.13-1.07(m,1H).
实施例101 化合物A77(S)-N-(1-(3-(5-(1-氨基-1,3-二氢螺[茚-2,4’-哌啶]-1'-基)-6-(羟甲基)吡嗪-2-基)丙-2-炔-1-基)-1H-吲唑-5-基)乙酰胺的制备：Example 101 Compound A77(S)-N-(1-(3-(5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)- Preparation of 6-(hydroxymethyl)pyrazin-2-yl)prop-2-yn-1-yl)-1H-indazol-5-yl)acetamide:
Figure PCTCN2021088871-appb-000058
Figure PCTCN2021088871-appb-000058
步骤1：化合物A77-1的制备Step 1: Preparation of compound A77-1
氮气保护下，将1.00g 5-硝基-1H-吲唑，0.80g溴丙炔和1.27g碳酸钾加入DMF(30mL)中，室温反应2h。TLC检测反应完全，过滤，滤液浓缩，粗品柱层析纯化得1.00g灰色固体A77-1。Under nitrogen protection, 1.00 g of 5-nitro-1H-indazole, 0.80 g of bromopropyne and 1.27 g of potassium carbonate were added to DMF (30 mL) and reacted at room temperature for 2 hours. TLC detected that the reaction was complete, filtered, the filtrate was concentrated, and the crude product was purified by column chromatography to obtain 1.00 g of gray solid A77-1.
步骤2：化合物A77-2的制备Step 2: Preparation of compound A77-2
将1.00g化合物A77-1、1.11g Fe粉、1.60g氯化铵溶解于4mL水和16mL乙醇中，回流反应2h。LC-MS及TLC检测反应完全，冷却至室温，二氯甲烷萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，真空浓缩，粗品经柱层析纯化得600mg浅黄色固体化合物A77-2。1.00 g of compound A77-1, 1.11 g of Fe powder, and 1.60 g of ammonium chloride were dissolved in 4 mL of water and 16 mL of ethanol, and the reaction was refluxed for 2 hours. LC-MS and TLC check that the reaction is complete, cool to room temperature, extract with dichloromethane, combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, and concentrate in vacuo. The crude product is purified by column chromatography to obtain 600 mg of light yellow solid compound A77- 2.
步骤3：化合物A77-3的制备Step 3: Preparation of compound A77-3
将100mg化合物M1、52.0mg化合物A77-2、4.3mg PdCl 2(PPh 3) 2，2.4mg CuI溶于DMF(4mL)和NEt 3(1mL)中，氮气置换后，60℃反应15h。LC-MS及TLC检测反应完全，加入20mL水，10mL乙酸乙酯萃取，有机相饱和食盐水洗涤，无水硫酸钠干燥，真空浓缩，粗品经制备板纯化得70mg淡黄色固体,即化合物A77-3。 100 mg of compound M1, 52.0 mg of compound A77-2, 4.3 mg of PdCl 2 (PPh 3 ) 2 , 2.4 mg of CuI were dissolved in DMF (4 mL) and NEt 3 (1 mL), and after nitrogen replacement, the reaction was carried out at 60° C. for 15 h. LC-MS and TLC detect the completion of the reaction, add 20 mL of water, extract with 10 mL of ethyl acetate, wash the organic phase with saturated brine, dry with anhydrous sodium sulfate, and concentrate in vacuo. The crude product is purified by a preparation plate to obtain 70 mg of light yellow solid, namely compound A77- 3.
步骤4：化合物A77-4的制备Step 4: Preparation of compound A77-4
将70mg化合物A77-3溶解于3mL DCM中，N 2保护冰水浴条件下，加入14mg乙酸酐室温反应0.5h。LC-MS及TLC检测反应完全，冷却至室温，加入饱和碳酸氢钠溶液调节pH至8～9，乙酸乙酯(3×10mL)萃取，合并有机相经饱和食盐水洗涤，无水硫酸钠干燥，真空浓缩，粗品经柱层析纯化得68mg浅黄色固体化合物A77-4。 70 mg of compound A77-3 was dissolved in 3 mL of DCM, and 14 mg of acetic anhydride was added to react at room temperature for 0.5 h under the condition of an ice-water bath protected by N 2. LC-MS and TLC check that the reaction is complete, cool to room temperature, add saturated sodium bicarbonate solution to adjust the pH to 8-9, extract with ethyl acetate (3×10 mL), wash the combined organic phase with saturated brine, and dry with anhydrous sodium sulfate , Concentrated in vacuo, and the crude product was purified by column chromatography to obtain 68 mg of light yellow solid compound A77-4.
步骤5：化合物A77的制备Step 5: Preparation of compound A77
将68mg化合物A77-4溶解于4.0mL二氧六环和1.0mL MeOH中，加入2N HCl(0.12mL，乙酸乙酯溶液)，室温搅拌反应0.5h。LCMS和TLC检测反应完全，反应液减压浓缩。残余物加入H 2O(1.0mL)溶解，用饱和NaHCO 3调节溶液至pH＝8，EA(3×3mL)萃取，有机相干燥后真空浓缩，经制备板纯化得37.1mg浅黄色固体即化合物A77。 68 mg of compound A77-4 was dissolved in 4.0 mL of dioxane and 1.0 mL of MeOH, 2N HCl (0.12 mL, ethyl acetate solution) was added, and the reaction was stirred at room temperature for 0.5 h. LCMS and TLC detected that the reaction was complete, and the reaction solution was concentrated under reduced pressure. Add H 2 O (1.0 mL) to the residue to dissolve, adjust the solution to pH=8 with saturated NaHCO 3 , extract with EA (3×3 mL), dry the organic phase and concentrate in vacuo. Purify on a preparation plate to obtain 37.1 mg of a light yellow solid that is the compound A77.
[M+H +]＝522.34。 [M+H + ]=522.34.
1H NMR(500MHz,DMSO)δ9.99(s,1H),8.18(s,1H),8.15(d,J＝1.3Hz,1H),8.09(d,J＝0.8Hz,1H),7.72(d,J＝9.0Hz,1H),7.48(dd,J＝9.0,1.9Hz,1H),7.30(d,J＝6.8Hz,1H),7.19-7.12(m,3H),5.60(s,2H),5.41(t,J＝6.0Hz,1H),4.43(d,J＝5.8Hz,2H),3.85(s,1H),3.80-3.74(m,2H),3.18-3.08(m,2H),3.02(d,J＝15.7Hz,1H),2.60(d,J＝15.6Hz,1H),2.06(s,3H),1.88-1.82(m,1H),1.77-1.72(m,1H),1.51-1.48(m,1H),1.12-1.09(m,1H). 1 H NMR (500MHz, DMSO) δ9.99 (s, 1H), 8.18 (s, 1H), 8.15 (d, J = 1.3 Hz, 1H), 8.09 (d, J = 0.8 Hz, 1H), 7.72 ( d,J=9.0Hz,1H),7.48(dd,J=9.0,1.9Hz,1H),7.30(d,J=6.8Hz,1H),7.19-7.12(m,3H),5.60(s,2H) ), 5.41 (t, J = 6.0 Hz, 1H), 4.43 (d, J = 5.8 Hz, 2H), 3.85 (s, 1H), 3.80-3.74 (m, 2H), 3.18-3.08 (m, 2H) ,3.02(d,J=15.7Hz,1H),2.60(d,J=15.6Hz,1H),2.06(s,3H),1.88-1.82(m,1H),1.77-1.72(m,1H), 1.51-1.48 (m, 1H), 1.12-1.09 (m, 1H).
实施例102 化合物A78(S)-(3-(1-氨基-1,3-二氢螺[茚-2,4’-哌啶]-1'-基)-6-(3-(6-氨基-1H-吲唑-1-基)丙-1-炔-1-基)吡嗪-2-基)甲醇的制备：Example 102 Compound A78(S)-(3-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(3-(6- Preparation of amino-1H-indazol-1-yl)prop-1-yn-1-yl)pyrazin-2-yl)methanol:
Figure PCTCN2021088871-appb-000059
Figure PCTCN2021088871-appb-000059
步骤1：化合物A78-1的制备Step 1: Preparation of compound A78-1
将1.00g 6-硝基-2H-吲唑、0.85g碳酸钾和0.73g溴丙炔溶于DMF(10mL)中，室温反应1小时。TLC检测反应完全，加入50mL水分层，50mL乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，真空浓缩，粗品经柱层析纯化得黄色固体0.6g，即化合物A78- 1。1.00 g of 6-nitro-2H-indazole, 0.85 g of potassium carbonate and 0.73 g of bromopropyne were dissolved in DMF (10 mL) and reacted at room temperature for 1 hour. TLC detected that the reaction was complete, added 50 mL of water layer, extracted with 50 mL of ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was purified by column chromatography to obtain 0.6 g of a yellow solid, namely compound A78- 1.
步骤2：化合物A78-2的制备Step 2: Preparation of compound A78-2
将0.6g A78-1、0.66g铁粉和0.95g氯化铵分散于6mL乙醇和2mL水中，80℃反应3小时，LC-MS及TLC检测反应不再进行，硅藻土过滤，滤饼加10mL甲醇洗涤，浓缩滤液；加入20mL水，20mL二氯甲烷萃取，饱和食盐水洗涤有机相，无水硫酸钠干燥，真空浓缩，粗品经柱层析纯化得0.45g白色固体，即化合物A78-2。Disperse 0.6g A78-1, 0.66g iron powder and 0.95g ammonium chloride in 6mL ethanol and 2mL water, react at 80℃ for 3 hours, LC-MS and TLC detection reaction no longer proceed, diatomite filter, filter cake is added Wash with 10 mL methanol, concentrate the filtrate; add 20 mL water, 20 mL dichloromethane extraction, wash the organic phase with saturated brine, dry with anhydrous sodium sulfate, and concentrate in vacuo. The crude product is purified by column chromatography to obtain 0.45 g of white solid, which is compound A78-2 .
步骤3：化合物A78-3的制备Step 3: Preparation of compound A78-3
将150mg化合物M1、78mg化合物A78-2、10.7mg PdCl 2(PPh 3) 2和2.9mg CuI溶于DMF(3mL)和三乙胺(1mL)中，氮气置换后，60℃反应12小时。LC-MS及TLC检测反应不再进行，加入20mL水，20mL二氯甲烷萃取，饱和食盐水洗涤有机相，无水硫酸钠干燥，真空浓缩，粗品经制备板纯化得98mg黄色固体，即化合物A78-3。 150 mg of compound M1, 78 mg of compound A78-2, 10.7 mg of PdCl 2 (PPh 3 ) 2 and 2.9 mg of CuI were dissolved in DMF (3 mL) and triethylamine (1 mL). After nitrogen replacement, the reaction was carried out at 60° C. for 12 hours. LC-MS and TLC detect that the reaction is no longer proceeding, add 20 mL of water, 20 mL of dichloromethane for extraction, wash the organic phase with saturated brine, dry with anhydrous sodium sulfate, and concentrate in vacuo. The crude product is purified by a preparation plate to obtain 98 mg of yellow solid, which is compound A78 -3.
步骤3：化合物A78的制备Step 3: Preparation of compound A78
将98mg化合物A78-2溶解于二氧六环(3mL)和乙醇(1mL)中，加入2N HCl(0.5mL，乙酸乙酯溶液)，RT搅拌反应1小时。LCMS和TLC检测反应完全，反应液减压浓缩。残余物加入H 2O(1.0mL)溶解，用饱和NaHCO 3调节溶液至pH＝8，二氯甲烷(3×3mL)萃取，有机相干燥后真空浓缩，经制备板纯化得47.2mg淡黄色固体即化合物A78。 98 mg of compound A78-2 was dissolved in dioxane (3 mL) and ethanol (1 mL), 2N HCl (0.5 mL, ethyl acetate solution) was added, and the reaction was stirred at RT for 1 hour. LCMS and TLC detected that the reaction was complete, and the reaction solution was concentrated under reduced pressure. Add H 2 O (1.0 mL) to dissolve the residue, adjust the solution to pH=8 with saturated NaHCO 3 , extract with dichloromethane (3×3 mL), dry the organic phase and concentrate in vacuo. Purify on a preparation plate to obtain 47.2 mg of light yellow solid Namely compound A78.
[M+H +]＝480.38。 [M+H + ]=480.38.
1H NMR(500MHz,DMSO-d 6)δ8.18(s,1H),7.77(s,1H),7.40(d,J＝8.6Hz,1H),7.29(d,J＝7.0Hz,1H),7.18-7.11(m,3H),6.61(s,1H),6.54(dd,J＝8.6,2.0Hz,1H),5.44(s,2H),5.42(t,J＝6.1Hz,1H),5.37(s,2H),4.43(d,J＝6.0Hz,2H),3.82(s,1H),3.80-3.75(m,3H),3.15-3.05(m,2H),3.02(d,J＝15.5Hz,1H),2.58(d,J＝15.5Hz,1H),1.86-1.82(m,1H),1.77-1.72(m,1H),1.51-1.49(m,1H),1.10-1.08(m,1H). 1 H NMR(500MHz,DMSO-d 6 )δ8.18(s,1H),7.77(s,1H),7.40(d,J=8.6Hz,1H), 7.29(d,J=7.0Hz,1H) ,7.18-7.11(m,3H),6.61(s,1H),6.54(dd,J=8.6,2.0Hz,1H), 5.44(s,2H), 5.42(t,J=6.1Hz,1H), 5.37(s,2H),4.43(d,J=6.0Hz,2H),3.82(s,1H),3.80-3.75(m,3H),3.15-3.05(m,2H),3.02(d,J= 15.5Hz,1H),2.58(d,J=15.5Hz,1H),1.86-1.82(m,1H),1.77-1.72(m,1H),1.51-1.49(m,1H),1.10-1.08(m ,1H).
实施例103 化合物A79(S)-(3-(1-氨基-1,3-二氢螺[茚-2,4’-哌啶]-1'-基)-6-(3-(4-氨基-1H-吲唑-1-基)丙-1-炔-1-基)吡嗪-2-基)甲醇的制备：Example 103 Compound A79(S)-(3-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(3-(4- Preparation of amino-1H-indazol-1-yl)prop-1-yn-1-yl)pyrazin-2-yl)methanol:
Figure PCTCN2021088871-appb-000060
Figure PCTCN2021088871-appb-000060
步骤1：化合物A79-00的制备Step 1: Preparation of compound A79-00
将1g原料M1溶于20mL 1,4-二氧六环和5mL甲醇中，N 2置换，滴加1.52mL盐酸乙酸乙酯溶液(2M)，室温反应1h。TLC(DCM:MeOH＝10:1)监测显示原料反应完全，减压浓缩，加10mL水溶解，滴加饱和碳酸氢钠溶液至pH 8～9，有沉淀析出，过滤，粗品经柱层析(DCM:MeOH＝15:1)纯化得到A79-00白色粉末540mg。 The M1 1g material was dissolved in 1,4-dioxane and 20 mL of methanol 5mL, N 2 substitutions, ethyl acetate was added dropwise 1.52mL of hydrochloric acid solution (2M), room temperature for 1h. TLC (DCM:MeOH=10:1) monitoring showed that the reaction of the raw materials was complete. It was concentrated under reduced pressure, dissolved in 10 mL of water, and saturated sodium bicarbonate solution was added dropwise to pH 8-9. Precipitation was precipitated, filtered, and the crude product was subjected to column chromatography ( DCM:MeOH=15:1) purified to obtain 540mg of A79-00 white powder.
步骤2：化合物A79-1的制备Step 2: Preparation of compound A79-1
将1g原料A79-0与1.27g K 2CO 3溶于10mL DMF中，再加入948mg 3-溴-1-丙炔，室温下反应2h。TLC(PE:EA＝3:1)检测显示原料反应完全后，将反应体系滴加到150mL搅拌的水中，有固体析出，过滤，抽干，滤饼用PE打浆，过滤，抽干得到1.07g黑色粉末化合物A79-1。 Dissolve 1 g of raw material A79-0 and 1.27 g of K 2 CO 3 in 10 mL of DMF, then add 948 mg of 3-bromo-1-propyne, and react at room temperature for 2 hours. TLC (PE:EA=3:1) test showed that the reaction of the raw materials was complete, the reaction system was added dropwise to 150mL of stirring water, there is solid precipitation, filtered, drained, the filter cake was slurried with PE, filtered and drained to obtain 1.07g Black powder compound A79-1.
步骤3：化合物A79-2的制备Step 3: Preparation of compound A79-2
向盛有1.07g化合物A79-1、1.19g铁粉和1.14g氯化铵的反应瓶中加入10mL水和10mL乙醇，N 2置换，80℃反应3h。TLC(PE:EA＝3:1)检测显示原料反应完全后，过滤，将滤液减压浓缩，经柱层析(PE:EA＝3:1)分离纯化得到360mg黄色固体化合物A79-2。 Add 10 mL of water and 10 mL of ethanol to a reaction flask containing 1.07 g of compound A79-1, 1.19 g of iron powder and 1.14 g of ammonium chloride, replace with N 2 and react at 80° C. for 3 hours. After TLC (PE:EA=3:1) detection showed that the raw material reaction was complete, it was filtered, the filtrate was concentrated under reduced pressure, and separated and purified by column chromatography (PE:EA=3:1) to obtain 360 mg of yellow solid compound A79-2.
步骤4：化合物A79的制备Step 4: Preparation of compound A79
将53mg化合物A79-2、80mg A79-00、4.3mg Pd(PPh 3) 2Cl 2和2.3mg CuI溶于2mL DMF和0.5mL三乙胺中，N 2置换，45℃反应12h。TLC(DCM:MeOH＝10:1)检测显示原料反应完全后，加入10mL乙酸乙酯和10mL水萃取，分离有机相，用3×10mL饱和氯化钠溶液洗涤有机相，分离干燥，经柱层析(DCM:MeOH＝15:1)分离纯化得到81.4mg淡黄色固体A79。 53 mg of compound A79-2, 80 mg of A79-00, 4.3 mg of Pd(PPh 3 ) 2 Cl 2 and 2.3 mg of CuI were dissolved in 2 mL DMF and 0.5 mL triethylamine, replaced with N 2 and reacted at 45° C. for 12 h. After TLC (DCM:MeOH=10:1) detection showed that the reaction of the raw materials was complete, 10mL ethyl acetate and 10mL water were added for extraction, the organic phase was separated, and the organic phase was washed with 3×10mL saturated sodium chloride solution, separated and dried, and passed through the column. Analysis (DCM:MeOH=15:1) was separated and purified to obtain 81.4 mg of light yellow solid A79.
[M+H +]＝480.37 [M+H + ]=480.37
1H NMR(500MHz,DMSO-d 6)δ8.20(s,1H),8.14(d,J＝0.9Hz,1H),7.53(d,J＝7.4Hz,1H),7.38-7.24(m,3H),7.08(t,J＝7.9Hz,1H),6.80(d,J＝8.2Hz,1H),6.20(d,J＝7.4Hz,1H), 5.86(s,2H),5.47(s,2H),4.44(d,J＝6.1Hz,2H),4.34(s,1H),3.86(d,J＝13.6Hz,1H),3.78(d,J＝13.6Hz,1H),3.16-3.11(m,2H),3.07-3.04(m,1H),2.97-2.93(m,1H),1.86-1.78(m,2H),1.56-1.46(m,2H). 1 H NMR(500MHz,DMSO-d 6 )δ8.20(s,1H), 8.14(d,J=0.9Hz,1H), 7.53(d,J=7.4Hz,1H), 7.38-7.24(m, 3H), 7.08 (t, J = 7.9 Hz, 1H), 6.80 (d, J = 8.2 Hz, 1H), 6.20 (d, J = 7.4 Hz, 1H), 5.86 (s, 2H), 5.47 (s, 2H), 4.44 (d, J = 6.1 Hz, 2H), 4.34 (s, 1H), 3.86 (d, J = 13.6 Hz, 1H), 3.78 (d, J = 13.6 Hz, 1H), 3.16-3.11 ( m, 2H), 3.07-3.04 (m, 1H), 2.97-2.93 (m, 1H), 1.86-1.78 (m, 2H), 1.56-1.46 (m, 2H).
实施例104 化合物A80(S)-1-(3-(5-(1-氨基-1,3-二氢螺[茚-2,4’-哌啶]-1'-基)-6-(羟甲基)吡嗪-2-基)丙-2-炔-1-基)-1H-吲唑-5-羧酰胺的制备：Example 104 Compound A80(S)-1-(3-(5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-( Preparation of (hydroxymethyl)pyrazin-2-yl)prop-2-yn-1-yl)-1H-indazole-5-carboxamide:
Figure PCTCN2021088871-appb-000061
Figure PCTCN2021088871-appb-000061
步骤1：化合物A80-1的制备Step 1: Preparation of compound A80-1
将2.00g吲唑-5-甲酸甲酯，1.82g NaOH固体溶于15mL水与15mL四氢呋喃中，80℃回流反应3h。TLC(PE:EA＝1:1)监测显示原料反应完全后，减压浓缩，旋出溶剂，再加入20mL水溶解固体，滴加2M盐酸至pH呈中性，固体析出，过滤，滤液重复操作两次，合并固体，烘干，得到1.77g白色固体粉末，即化合物A80-1。Dissolve 2.00 g methyl indazole-5-carboxylate and 1.82 g NaOH solid in 15 mL water and 15 mL tetrahydrofuran, and react under reflux at 80°C for 3 hours. After TLC (PE:EA=1:1) monitoring showed that the reaction of the raw materials was complete, concentrate under reduced pressure, spin off the solvent, add 20 mL of water to dissolve the solids, add dropwise 2M hydrochloric acid until the pH is neutral, the solids precipitate, filter, and repeat the operation for the filtrate Two times, the solids were combined and dried to obtain 1.77 g of white solid powder, namely compound A80-1.
步骤2：化合物A80-2的制备Step 2: Preparation of compound A80-2
将1.00g化合物A80-1、2.64mL NH 3的甲醇溶液、1.77g EDCI、1.25g HOBt和1.78mL三乙胺溶于15mL DMF中，室温反应2h。TLC(PE:EA＝1:1)检测显示反应完全，加入20mL水，用EA/THF(1:1)(20mL×6)萃取，有机相用3×20mL饱和氯化钠溶液洗涤，分离有机相，无水硫酸钠干燥，减压浓缩，得到886mg类白色粉末，即化合物A80-2。 1.00 g of compound A80-1, 2.64 mL of NH 3 in methanol, 1.77 g of EDCI, 1.25 g of HOBt and 1.78 mL of triethylamine were dissolved in 15 mL of DMF and reacted at room temperature for 2 hours. TLC (PE:EA=1:1) detection showed that the reaction was complete, add 20mL water, extract with EA/THF (1:1) (20mL×6), wash the organic phase with 3×20mL saturated sodium chloride solution, separate the organic Phase, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 886 mg of off-white powder, namely compound A80-2.
步骤3：化合物A80-3的制备Step 3: Preparation of compound A80-3
将886mg化合物A80-2、654mg 3-溴-1-丙炔和1.14g碳酸钾溶于10mL DMF中，室温反应2h。TLC(PE:EA＝1:2)监测显示反应完全后，加入20mL水，用EA/THF(1:1) (20mL×6)萃取，有机相用3×20mL饱和氯化钠溶液洗涤，分出有机相，无水硫酸钠干燥，减压浓缩，柱层析(DCM:MeOH＝15:1)得到290mg类白色粉末，即化合物A80-3。Dissolve 886 mg of compound A80-2, 654 mg of 3-bromo-1-propyne and 1.14 g of potassium carbonate in 10 mL of DMF, and react at room temperature for 2 hours. After TLC (PE:EA=1:2) monitoring showed that the reaction was complete, 20 mL of water was added and extracted with EA/THF (1:1) (20 mL×6). The organic phase was washed with 3×20 mL saturated sodium chloride solution and separated. The organic phase was taken out, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and column chromatography (DCM:MeOH=15:1) to obtain 290 mg of off-white powder, namely compound A80-3.
步骤4：化合物A80-4的制备Step 4: Preparation of compound A80-4
将242mg化合物A80-3、400mg M1、17mg Pd(PPh 3) 2Cl 2和9.3mg CuI溶于6mL DMF和1.5mL三乙胺中，N 2置换，60℃反应12h。TLC(DCM:MeOH＝10:1)检测显示原料反应完全后，加入10mL乙酸乙酯和10mL水萃取，有机相用饱和氯化钠溶液(10mL×3)洗涤，无水硫酸钠干燥，经柱层析(DCM:MeOH＝19:1)分离纯化得到279mg淡黄色固体，即化合物A80-4。 242 mg of compound A80-3, 400 mg of M1, 17 mg of Pd(PPh 3 ) 2 Cl 2 and 9.3 mg of CuI were dissolved in 6 mL DMF and 1.5 mL triethylamine, replaced with N 2 and reacted at 60° C. for 12 h. After TLC (DCM:MeOH=10:1) detection showed that the reaction of the raw materials was complete, 10mL ethyl acetate and 10mL water were added for extraction, the organic phase was washed with saturated sodium chloride solution (10mL×3), dried with anhydrous sodium sulfate, and passed through a column. Chromatography (DCM:MeOH=19:1) was separated and purified to obtain 279 mg of light yellow solid, namely compound A80-4.
步骤5：化合物A80的制备Step 5: Preparation of compound A80
将279mg化合物A80-4溶解于8mL二氧六环和2mL甲醇溶液中，氮气置换，搅拌下滴入0.34mL HCl的EA溶液(2M)，室温下搅拌30分钟。LCMS检测反应完全，将反应液减压浓缩，残余物用5mL水溶解，滴加饱和碳酸氢钠溶液至pH 8～9，收集析出的固体，再经柱层析(DCM:MeOH＝19:1)纯化得到136.8mg淡黄色粉末，即化合物A80。Dissolve 279 mg of compound A80-4 in 8 mL of dioxane and 2 mL of methanol solution, replace with nitrogen, add 0.34 mL of HCl EA solution (2M) dropwise with stirring, and stir for 30 minutes at room temperature. LCMS detected that the reaction was complete, the reaction solution was concentrated under reduced pressure, the residue was dissolved in 5 mL of water, saturated sodium bicarbonate solution was added dropwise to pH 8-9, the precipitated solid was collected, and then subjected to column chromatography (DCM:MeOH=19:1 ) Purification to obtain 136.8 mg of light yellow powder, namely compound A80.
[M+H +]＝508.38 [M+H + ]=508.38
1H NMR(500MHz,DMSO-d 6)δ8.38(s,1H),8.28(s,1H),8.19(s,1H),8.07-7.93(m,2H),7.84(d,J＝8.9Hz,1H),7.37-7.25(m,2H),7.21-7.09(m,3H),5.68(s,2H),5.40(t,J＝6.0Hz,1H),4.43(d,J＝5.9Hz,2H),3.83(s,1H),3.80-3.72(m,2H),3.15-3.03(m,2H),3.13-3.04(m,2H),3.03(d,J＝15.4Hz,1H),2.59(d,J＝15.4Hz,1H),1.90-1.80(m,1H),1.80-1.70(m,1H),1.55-1.45(m,1H),1.25-1.15(m,1H). 1 H NMR(500MHz,DMSO-d 6 )δ8.38(s,1H), 8.28(s,1H), 8.19(s,1H), 8.07-7.93(m,2H), 7.84(d,J=8.9 Hz, 1H), 7.37-7.25 (m, 2H), 7.21-7.09 (m, 3H), 5.68 (s, 2H), 5.40 (t, J = 6.0 Hz, 1H), 4.43 (d, J = 5.9 Hz ,2H),3.83(s,1H),3.80-3.72(m,2H),3.15-3.03(m,2H),3.13-3.04(m,2H),3.03(d,J=15.4Hz,1H), 2.59(d,J=15.4Hz,1H),1.90-1.80(m,1H),1.80-1.70(m,1H),1.55-1.45(m,1H),1.25-1.15(m,1H).
实施例105 化合物A81(S)-N-(1-(3-(5-(1-氨基-1,3-二氢螺[茚-2,4’-哌啶]-1'-基)-6-(羟甲基)吡嗪-2-基)丙-2-炔-1-基)-1H-吲唑-4-基)乙酰胺和的制备：Example 105 Compound A81(S)-N-(1-(3-(5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)- 6-(Hydroxymethyl)pyrazin-2-yl)prop-2-yn-1-yl)-1H-indazol-4-yl)acetamide and preparation:
Figure PCTCN2021088871-appb-000062
Figure PCTCN2021088871-appb-000062
步骤1：化合物A81-1的制备Step 1: Preparation of compound A81-1
将150mg原料A79-2溶于2mL二氯甲烷中，再加入0.1mL乙酸酐，室温搅拌20min，TLC(PE:EA＝1:1)监测显示反应完全后，减压浓缩，再用10mL DCM和10mL饱和碳酸氢钠溶液萃取，有机相用3×10mL饱和氯化钠洗涤，分离干燥，减压浓缩得到产品A81-1黄色粉末166mg。Dissolve 150 mg of raw material A79-2 in 2 mL of dichloromethane, add 0.1 mL of acetic anhydride, stir at room temperature for 20 min, TLC (PE:EA=1:1) monitoring shows that the reaction is complete, concentrate under reduced pressure, and then use 10 mL of DCM and 10 mL of saturated sodium bicarbonate solution was extracted, and the organic phase was washed with 3×10 mL of saturated sodium chloride, separated and dried, and concentrated under reduced pressure to obtain 166 mg of product A81-1 as a yellow powder.
步骤2：化合物A81的制备Step 2: Preparation of compound A81
将541mg化合物A81-1、50mg A79-00、2.7mg Pd(PPh 3) 2Cl 2、1.5mg CuI溶于2mL DMF和0.4mL三乙胺中，N 2置换，45℃反应12h。TLC(DCM:MeOH＝10:1)检测显示原料反应完全后，加入10mL乙酸乙酯和10mL水萃取，分离有机相，用3×10mL饱和氯化钠溶液洗涤有机相，过滤干燥，经制备板(DCM:MeOH＝10:1)分离纯化得到38.9mg淡黄色固体A81。 541 mg of compound A81-1, 50 mg of A79-00, 2.7 mg of Pd(PPh 3 ) 2 Cl 2 , and 1.5 mg of CuI were dissolved in 2 mL DMF and 0.4 mL triethylamine, replaced with N 2 and reacted at 45° C. for 12 h. After TLC (DCM:MeOH=10:1) detection showed that the raw material reaction was complete, 10mL ethyl acetate and 10mL water were added for extraction, the organic phase was separated, and the organic phase was washed with 3×10mL saturated sodium chloride solution, filtered and dried. (DCM:MeOH=10:1) was separated and purified to obtain 38.9 mg of light yellow solid A81.
[M+H +]＝522.40 [M+H + ]=522.40
1H NMR(500MHz,DMSO-d 6)δ10.05(s,1H),8.35(s,1H),8.18(s,1H),7.72(d,J＝7.6Hz,1H),7.47(d,J＝8.3Hz,1H),7.37(t,J＝8.0Hz,1H),7.30(d,J＝6.7Hz,1H),7.20-7.11(m,3H),5.61(s,2H),4.43(d,J＝5.6Hz,2H),3.85(s,1H),3.80-3.74(m,2H),3.15-3.08(m,2H),3.02(d,J＝15.5Hz,1H),2.60(d,J＝15.5Hz,1H),2.17(s,3H),1.89-1.81(m,1H),1.80-1.69(m,1H),1.52-1.46(m,1H),1.14-1.08(m,1H). 1 H NMR(500MHz,DMSO-d 6 )δ10.05(s,1H), 8.35(s,1H), 8.18(s,1H), 7.72(d,J=7.6Hz,1H), 7.47(d, J = 8.3Hz, 1H), 7.37 (t, J = 8.0Hz, 1H), 7.30 (d, J = 6.7Hz, 1H), 7.20-7.11 (m, 3H), 5.61 (s, 2H), 4.43 ( d,J=5.6Hz,2H),3.85(s,1H),3.80-3.74(m,2H),3.15-3.08(m,2H),3.02(d,J=15.5Hz,1H),2.60(d ,J = 15.5Hz, 1H), 2.17 (s, 3H), 1.89-1.81 (m, 1H), 1.80-1.69 (m, 1H), 1.52-1.46 (m, 1H), 1.14-1.08 (m, 1H) ).
实施例106 化合物A82(S)-1-(3-(5-(1-氨基-1,3-二氢螺[茚-2,4’-哌啶]-1'-基)-6-(羟甲基)吡嗪-2-基)丙-2-炔-1-基)-1H-苯并[d]咪唑-5-羧酰胺和化合物A83(S)-1-(3-(5-(1-氨基-1,3-二氢螺[茚-2,4’-哌啶]-1'-基)-6-(羟甲基)吡嗪-2-基)丙-2-炔-1-基)-1H-苯并[d]咪唑-6-羧酰胺的制备：Example 106 Compound A82(S)-1-(3-(5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-( (Hydroxymethyl)pyrazin-2-yl)prop-2-yn-1-yl)-1H-benzo[d]imidazole-5-carboxamide and compound A83(S)-1-(3-(5- (1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(hydroxymethyl)pyrazin-2-yl)prop-2-yne- Preparation of 1-yl)-1H-benzo[d]imidazole-6-carboxamide:
Figure PCTCN2021088871-appb-000063
Figure PCTCN2021088871-appb-000063
化合物A82与A83的制备：Preparation of compounds A82 and A83:
步骤1：化合物A82-1的制备Step 1: Preparation of compound A82-1
将1.00g原料1H-苯并咪唑-5-甲腈和30mg Parkin’s试剂溶于9mL乙醇与3mL水中，80℃反应72h。TLC(PE:EA＝1:1)监测显示反应完全后，减压浓缩，经柱层析(DCM:MeOH＝20:1)纯化得到266mg固体粉末A82-1。1.00 g of the raw material 1H-benzimidazole-5-carbonitrile and 30 mg of Parkin’s reagent were dissolved in 9 mL of ethanol and 3 mL of water, and reacted at 80°C for 72 hours. After TLC (PE:EA=1:1) monitoring showed that the reaction was complete, it was concentrated under reduced pressure, and purified by column chromatography (DCM:MeOH=20:1) to obtain 266 mg of solid powder A82-1.
步骤2：化合物A82-2与A83-1的制备Step 2: Preparation of compounds A82-2 and A83-1
将266mg化合物A82-1、216mg 3-溴-1-丙炔和296mg碳酸钾溶于5mL DMF中，室温反应2h。TLC(PE:EA＝1:1)监测显示反应完全后，加入10mL水，用10mL EA萃取，有机相用3×10mL饱和氯化钠溶液洗涤，分离有机相，无水硫酸钠干燥，减压浓缩，得到化合物A82-2与A83-1的混合物固体粉末共301mg。Dissolve 266 mg of compound A82-1, 216 mg of 3-bromo-1-propyne and 296 mg of potassium carbonate in 5 mL DMF, and react at room temperature for 2 hours. After TLC (PE:EA=1:1) monitoring showed that the reaction was complete, add 10mL water, extract with 10mL EA, wash the organic phase with 3×10mL saturated sodium chloride solution, separate the organic phase, dry with anhydrous sodium sulfate, and reduce pressure Concentrate to obtain a total of 301 mg of solid powder of the mixture of compound A82-2 and A83-1.
步骤3：化合物A82-3与A83-2的制备Step 3: Preparation of compounds A82-3 and A83-2
将181mg化合物A82-2与A83-1的混合物、150mg M1、6.4mg Pd(PPh 3) 2Cl 2和3.5mg CuI溶于5mL DMF与1.5mL三乙胺中，N 2置换，60℃反应12h。TLC(DCM:MeOH＝10:1)检测显示原料反应完全后，加入10mL乙酸乙酯和10mL水萃取，分离有机相，用3×10mL饱和氯化钠溶液洗涤有机相，分离干燥，经柱层析(DCM:MeOH＝12:1)分离纯化得到294mg化合物A82-3与A83-2的混合物。 The mixture of 181mg of the compound A82-2 and A83-1, 150mg M1,6.4mg Pd (PPh 3) 2 Cl 2 and 3.5mg CuI were dissolved in 5mL DMF, 60 ℃ reacted with 1.5mL triethylamine, N 2 substitution 12h . After TLC (DCM:MeOH=10:1) detection showed that the reaction of the raw materials was complete, 10mL ethyl acetate and 10mL water were added for extraction, the organic phase was separated, and the organic phase was washed with 3×10mL saturated sodium chloride solution, separated and dried, and passed through the column. Analysis (DCM:MeOH=12:1) was separated and purified to obtain 294 mg of a mixture of compound A82-3 and A83-2.
步骤4：化合物A82与A83的制备Step 4: Preparation of compounds A82 and A83
将294mg化合物A82-3与A83-2的混合物溶解于8mL二氧六环和3mL甲醇溶液中，氮气置换，搅拌下滴入0.36mL HCl的EA溶液(2M)，室温下搅拌30min。LCMS检测反应完全，将反应液减压浓缩，残余物用5mL水溶解，滴加饱和碳酸氢钠溶液至pH8～9，收集析出的固体，再经RP-HPLC分离纯化得到47.9mg淡黄色粉末化合物A82的甲酸盐与38.6mg淡黄色粉末化合物A83的甲酸盐。A mixture of 294 mg of compound A82-3 and A83-2 was dissolved in 8 mL of dioxane and 3 mL of methanol solution, replaced with nitrogen, 0.36 mL of HCl EA solution (2M) was added dropwise with stirring, and stirred at room temperature for 30 min. LCMS detected the completion of the reaction, the reaction solution was concentrated under reduced pressure, the residue was dissolved in 5 mL of water, saturated sodium bicarbonate solution was added dropwise to pH 8-9, the precipitated solid was collected, and then separated and purified by RP-HPLC to obtain 47.9 mg of pale yellow powder compound The formate salt of A82 and 38.6 mg of the formate salt of compound A83 as a pale yellow powder.
A82：[M+H +]＝508.31 A82: [M+H + ]=508.31
1H NMR(500MHz,DMSO-d 6)δ8.45(s,1H),8.28(s,1H),8.23(s,1H),8.00(s,1H),7.90(d,J＝8.4Hz,1H),7.76(d,J＝8.5Hz,1H),7.38(s,1H),7.29(s,1H),7.24-7.16(m,3H),5.55(s,2H),4.44(s,2H),3.85-3.75(m,3H),3.18-3.05(m,3H),2.72(d,J＝15.6Hz,1H),1.92-1.71(m,2H),1.54-1.48(m,1H),1.29-1.22(m,1H). 1 H NMR(500MHz,DMSO-d 6 )δ8.45(s,1H), 8.28(s,1H), 8.23(s,1H), 8.00(s,1H), 7.90(d,J=8.4Hz, 1H), 7.76 (d, J = 8.5Hz, 1H), 7.38 (s, 1H), 7.29 (s, 1H), 7.24-7.16 (m, 3H), 5.55 (s, 2H), 4.44 (s, 2H) ), 3.85-3.75 (m, 3H), 3.18-3.05 (m, 3H), 2.72 (d, J = 15.6Hz, 1H), 1.92-1.71 (m, 2H), 1.54-1.48 (m, 1H), 1.29-1.22(m,1H).
A83：[M+H +]＝508.32 A83: [M+H + ]=508.32
1H NMR(500MHz,DMSO-d 6)δ8.48(s,1H),8.32(s,1H),8.23(s,1H),8.03(s,1H),7.83(d,J＝8.4Hz,1H),7.73(d,J＝8.5Hz,1H),7.39(s,1H),7.29(s,1H),7.24-7.16(m,3H),5.55(s, 2H),4.44(s,2H),3.85-3.75(m,3H),3.18-3.05(m,3H),2.72(d,J＝15.6Hz,1H),1.92-1.71(m,2H),1.54-1.48(m,1H),1.29-1.22(m,1H). 1 H NMR(500MHz,DMSO-d 6 )δ8.48(s,1H), 8.32(s,1H), 8.23(s,1H), 8.03(s,1H), 7.83(d,J=8.4Hz, 1H), 7.73 (d, J = 8.5Hz, 1H), 7.39 (s, 1H), 7.29 (s, 1H), 7.24-7.16 (m, 3H), 5.55 (s, 2H), 4.44 (s, 2H) ), 3.85-3.75 (m, 3H), 3.18-3.05 (m, 3H), 2.72 (d, J = 15.6Hz, 1H), 1.92-1.71 (m, 2H), 1.54-1.48 (m, 1H), 1.29-1.22(m,1H).
实施例107 化合物A84(S)-(3-(1-氨基-1,3-二氢螺[茚-2,4’-哌啶]-1'-基)-6-(3-(5-甲氧基-1H-苯并[d]咪唑-1-基)丙-1-炔-1-基)吡嗪-2-基)甲醇的制备：Example 107 Compound A84(S)-(3-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(3-(5- Preparation of methoxy-1H-benzo[d]imidazol-1-yl)prop-1-yn-1-yl)pyrazin-2-yl)methanol:
Figure PCTCN2021088871-appb-000064
Figure PCTCN2021088871-appb-000064
步骤1：化合物A84-1的制备Step 1: Preparation of compound A84-1
将0.8g 5-甲氧基苯并咪唑、0.707g 3-溴丙炔、1.49g碳酸钾溶于DMF(8mL)中，室温反应16小时。TLC检测反应完全，冷却至室温，加入20mL水淬灭，DCM(3×10mL)萃取，饱和食盐水洗涤，无水硫酸钠干燥，真空浓缩，粗品经柱层析(PE:EA＝3:1)纯化得200mg浅黄色固体，即为化合物A84-1。0.8g of 5-methoxybenzimidazole, 0.707g of 3-bromopropyne, and 1.49g of potassium carbonate were dissolved in DMF (8mL) and reacted at room temperature for 16 hours. The reaction was completed by TLC detection, cooled to room temperature, quenched by adding 20 mL of water, extracted with DCM (3×10 mL), washed with saturated brine, dried over anhydrous sodium sulfate, concentrated in vacuo, and the crude product was subjected to column chromatography (PE:EA=3:1 ) Purified to obtain 200 mg of light yellow solid, which is compound A84-1.
步骤2：化合物A84-2的制备Step 2: Preparation of compound A84-2
将200mg化合物A84-1、530mg M1、45mg PdCl 2(PPh 3) 2和12.3mg CuI溶于DMF(2.0mL)和Et 3N(0.5mL)中，氮气置换后60℃反应16小时，LC-MS及TLC检测反应完全，冷却至室温，加入20mL水淬灭，乙酸乙酯(3×20mL)萃取，饱和食盐水洗涤，无水硫酸钠干燥，真空浓缩，粗品经柱层析纯化得300mg浅黄色固体，即化合物A84-2。 200 mg of compound A84-1, 530 mg of M1, 45 mg of PdCl 2 (PPh 3 ) 2 and 12.3 mg of CuI were dissolved in DMF (2.0 mL) and Et 3 N (0.5 mL). After nitrogen replacement, the reaction was carried out at 60°C for 16 hours. MS and TLC detected that the reaction was complete, cooled to room temperature, quenched by adding 20 mL of water, extracted with ethyl acetate (3×20 mL), washed with saturated brine, dried over anhydrous sodium sulfate, concentrated in vacuo, and purified by column chromatography to obtain 300 mg of light. Yellow solid, compound A84-2.
步骤3：化合物A84的制备Step 3: Preparation of compound A84
将180mg化合物A84-2，溶解于2.0mL的二氧六环中，再加入4mL MeOH，搅拌下滴入0.3mL HCl的EA溶液(2M)，室温下搅拌1小时。LCMS检测反应完全，滴加饱和碳酸氢钠溶液调节pH至8～9，加入20mL水淬灭，二氯甲烷(3×10mL)萃取，饱和食盐水洗涤，无水硫酸钠干燥，真空浓缩，用制备板纯化得23mg黄色固体，即化合物A84。Dissolve 180 mg of compound A84-2 in 2.0 mL of dioxane, then add 4 mL of MeOH, add 0.3 mL of HCl EA solution (2M) dropwise with stirring, and stir at room temperature for 1 hour. LCMS detects that the reaction is complete, add saturated sodium bicarbonate solution to adjust the pH to 8-9, add 20 mL of water to quench, extract with dichloromethane (3×10 mL), wash with saturated brine, dry with anhydrous sodium sulfate, and concentrate in vacuo. The preparation plate was purified to obtain 23 mg of yellow solid, namely compound A84.
[M+H +]＝495.29。 [M+H + ]=495.29.
1H NMR(500MHz,DMSO)δ8.25(s,1H),8.21(s,1H),7.59(d,J＝8.8Hz,1H),7.32-7.29 (m,1H),7.22(d,J＝2.3Hz,1H),7.20-7.13(m,3H),6.96(dd,J＝8.8,2.3Hz,1H),5.47(s,2H),5.44-5.33(m,1H),4.44(s,2H),3.86(s,1H),3.83-3.73(m,2H),3.79(s,3H),3.16-3.06(m,2H),3.03(d,J＝15.6Hz,1H),2.61(d,J＝15.6Hz,1H),1.89-1.80(m,1H),1.79-1.70(m,1H),1.54-1.46(m,1H),1.16-1.11(m,1H). 1 H NMR (500MHz, DMSO) δ 8.25 (s, 1H), 8.21 (s, 1H), 7.59 (d, J = 8.8 Hz, 1H), 7.32-7.29 (m, 1H), 7.22 (d, J =2.3Hz,1H),7.20-7.13(m,3H),6.96(dd,J＝8.8,2.3Hz,1H), 5.47(s,2H),5.44-5.33(m,1H), 4.44(s, 2H), 3.86(s, 1H), 3.83-3.73(m, 2H), 3.79(s, 3H), 3.16-3.06(m, 2H), 3.03(d, J=15.6Hz, 1H), 2.61(d ,J=15.6Hz,1H),1.89-1.80(m,1H),1.79-1.70(m,1H),1.54-1.46(m,1H),1.16-1.11(m,1H).
经由不同的反应起始原料、合适的试剂(起始原料及试剂均为市售)及本发明制备的中间体M1，采用与前述实施例97-实施例107类似的方法制备表4中的化合物。Through different reaction starting materials, suitable reagents (starting materials and reagents are all commercially available), and the intermediate M1 prepared by the present invention, the compounds in Table 4 were prepared using methods similar to the foregoing Example 97-Example 107 .
表4Table 4
Figure PCTCN2021088871-appb-000065
Figure PCTCN2021088871-appb-000065
Figure PCTCN2021088871-appb-000066
Figure PCTCN2021088871-appb-000066
A97： 1H NMR(500MHz,DMSO-d 6)δ8.28(s,1H),8.22(s,1H),8.20(s,1H),7.30(d,J＝8.3Hz,2H),7.20-7.10(m,3H),5.43(s,1H),5.33(s,2H),4.45(s,2H),3.83(s,1H),3.83-3.73(m,2H),3.18-3.06(m,2H),3.02(d,J＝15.6Hz,1H),2.59(d,J＝15.6Hz,1H),1.89-1.82(m,1H),1.78-1.72(m,1H),1.54-1.47(m,1H),1.13-1.08(m,1H). A97: 1 H NMR (500MHz, DMSO-d 6 ) δ 8.28 (s, 1H), 8.22 (s, 1H), 8.20 (s, 1H), 7.30 (d, J = 8.3 Hz, 2H), 7.20- 7.10 (m, 3H), 5.43 (s, 1H), 5.33 (s, 2H), 4.45 (s, 2H), 3.83 (s, 1H), 3.83-3.73 (m, 2H), 3.18-3.06 (m, 2H), 3.02(d,J=15.6Hz,1H), 2.59(d,J=15.6Hz,1H), 1.89-1.82(m,1H), 1.78-1.72(m,1H), 1.54-1.47(m ,1H),1.13-1.08(m,1H).
实施例12 化合物A12((S)-2-(1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-5-(3-(3,4-二羟基苯基)丙-1-炔-1-基)-3-甲基嘧啶-4(3H)-酮)的制备：Example 12 Compound A12((S)-2-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(3 ,4-Dihydroxyphenyl)prop-1-yn-1-yl)-3-methylpyrimidine-4(3H)-one):
Figure PCTCN2021088871-appb-000067
Figure PCTCN2021088871-appb-000067
步骤1：化合物A12-1的制备Step 1: Preparation of compound A12-1
将2.5g化合物M14、681mg三甲基硅乙炔、162mg PdCl 2(PPh 3) 2、44mg CuI溶于THF(20mL)和Et 3N(2mL)中，氮气置换后，室温搅拌反应1h。LC-MS及TLC检测反应完全，真空浓缩，粗品经柱层析纯化得1.88g黄色固体化合物A12-1。 2.5 g of compound M14, 681 mg of trimethylsilyl acetylene, 162 mg of PdCl 2 (PPh 3 ) 2 , and 44 mg of CuI were dissolved in THF (20 mL) and Et 3 N (2 mL). After nitrogen replacement, the reaction was stirred at room temperature for 1 h. LC-MS and TLC detected that the reaction was complete, concentrated in vacuo, and the crude product was purified by column chromatography to obtain 1.88 g of yellow solid compound A12-1.
步骤2：化合物A12-2的制备Step 2: Preparation of compound A12-2
将1.5g化合物A12-1溶于MeOH(10mL)中，再加入812mg K 2CO 3，氮气置换后，室温搅拌反应1h。LC-MS及TLC检测反应完全，真空浓缩，粗品经柱层析纯化得1.2g黄色固体化合物A12-2。 1.5 g of compound A12-1 was dissolved in MeOH (10 mL), and then 812 mg of K 2 CO 3 was added. After nitrogen replacement, the reaction was stirred at room temperature for 1 h. LC-MS and TLC detected that the reaction was complete, concentrated in vacuo, and the crude product was purified by column chromatography to obtain 1.2 g of yellow solid compound A12-2.
步骤3：化合物A12-3的制备Step 3: Preparation of compound A12-3
将A12-2(158mg)溶于THF(5mL)中，冰浴下滴加56mg异丙基氯化镁(2M)氮气置换后，冰浴搅拌反应1h，加入50mg 3,4-二甲氧基苯甲醛，回复至室温搅拌2h。LC-MS及TLC检测反应完全，加入饱和氯化铵溶液淬灭，加入5ml EA萃取，分离有机相，2×5ml饱和氯化钠溶液洗涤有机相，分离干燥，真空浓缩，粗品经柱层析纯化得30mg类白色固体化合物A12-3。Dissolve A12-2 (158mg) in THF (5mL), add 56mg of isopropylmagnesium chloride (2M) dropwise under ice bath and replace with nitrogen, stir on ice bath for 1h, add 50mg 3,4-dimethoxybenzaldehyde , Return to room temperature and stir for 2h. LC-MS and TLC detect that the reaction is complete, add saturated ammonium chloride solution to quench, add 5ml EA for extraction, separate the organic phase, wash the organic phase with 2×5ml saturated sodium chloride solution, separate and dry, concentrate in vacuo, and pass the crude product to column chromatography 30 mg of white solid compound A12-3 was obtained by purification.
步骤4：化合物A12-4的制备Step 4: Preparation of compound A12-4
将30mg化合物A12-3溶于DCM(5mL)中，先加入12mg三乙基硅，再加入51mg三氟乙酸，氮气置换，室温反应1h。LC-MS及TLC检测反应完全，加入饱和碳酸氢钠淬灭，再加入3×2ml DCM萃取，有机相干燥，浓缩粗品经制备板分离纯化得到11mg白色固体化合物A12-3。30 mg of compound A12-3 was dissolved in DCM (5 mL), and 12 mg of triethylsilyl was added first, and then 51 mg of trifluoroacetic acid was added, followed by nitrogen replacement, and reaction at room temperature for 1 h. LC-MS and TLC detect that the reaction is complete, add saturated sodium bicarbonate to quench, add 3×2ml DCM for extraction, dry the organic phase, concentrate the crude product and purify it by preparation plate to obtain 11mg of white solid compound A12-3.
步骤5：化合物A12的制备Step 5: Preparation of compound A12
将11mg化合物A12-3溶解于3mL无水二氯甲烷中，冷却至-60℃，再将BBr 3(70mg)缓慢加入上述溶液中，缓慢升至室温搅拌反应。LC-MS及TLC检测反应完全，加入饱和碳酸氢钠水溶液淬灭反应，二氯甲烷萃取，合并有机相经饱和食盐水洗涤，无水硫酸钠干燥， 过滤，滤液旋干，粗品经制备板纯化得1.9mg化合物A12。 11 mg of compound A12-3 was dissolved in 3 mL of anhydrous dichloromethane, cooled to -60°C, and then BBr 3 (70 mg) was slowly added to the above solution, and the mixture was slowly raised to room temperature and stirred for reaction. LC-MS and TLC check that the reaction is complete, add saturated sodium bicarbonate aqueous solution to quench the reaction, extract with dichloromethane, the combined organic phases are washed with saturated brine, dried with anhydrous sodium sulfate, filtered, the filtrate is spin-dried, and the crude product is purified by a preparation plate 1.9 mg of compound A12 was obtained.
[M+H] +＝457.27。 [M+H] + =457.27.
实施例10 化合物A10((S)-2-(1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-5-(3-(4-氯-3-羟基苯基)丙-1-炔-1-基)-3-甲基嘧啶-4(3H)-酮)的制备：Example 10 Compound A10((S)-2-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(4 -Preparation of chloro-3-hydroxyphenyl)prop-1-yn-1-yl)-3-methylpyrimidine-4(3H)-one):
Figure PCTCN2021088871-appb-000068
Figure PCTCN2021088871-appb-000068
步骤1：化合物A10-1的制备Step 1: Preparation of compound A10-1
将250mg化合物A12-1、10.4mg PdCl 2(PPh 3) 2、5.6mg CuI、7.7mg PPh 3,溶于DMF(9.0mL)和Et 3N(2.5mL)中，氮气置换后，加入192.0mg TBAF，室温搅拌反应10min，再将230.5mg 4-(溴甲基)-1-氯-2-甲氧基苯加入上述反应液中，氮气保护80℃下搅拌0.5h，再继续将230.5mg 4-(溴甲基)-1-氯-2-甲氧基苯加入上述反应液中，氮气保护80℃下搅拌0.5h。LC-MS及TLC检测反应完全，加入10mL水淬灭，乙酸乙酯(3x10mL)萃取，饱和食盐水洗涤，无水硫酸钠干燥，真空浓缩，粗品经柱层析纯化得180mg浅黄色固体化合物A10-1。 250mg compound A12-1, 10.4mg PdCl 2 (PPh 3 ) 2 , 5.6mg CuI, 7.7mg PPh 3 , dissolved in DMF (9.0mL) and Et 3 N (2.5mL), after nitrogen replacement, add 192.0mg TBAF, stirred at room temperature for 10 minutes, then added 230.5mg of 4-(bromomethyl)-1-chloro-2-methoxybenzene into the above reaction solution, stirred for 0.5h at 80°C under nitrogen protection, and continued to add 230.5mg 4 -(Bromomethyl)-1-chloro-2-methoxybenzene was added to the above reaction solution and stirred at 80°C for 0.5h under nitrogen protection. LC-MS and TLC detect that the reaction is complete, add 10 mL of water to quench, extract with ethyl acetate (3x10 mL), wash with saturated brine, dry with anhydrous sodium sulfate, and concentrate in vacuo. The crude product is purified by column chromatography to obtain 180 mg of light yellow solid compound A10 -1.
步骤2：化合物A10的制备Step 2: Preparation of compound A10
将180mg化合物A10-1溶解于10mL无水DCM中，冷却至-60℃，再将BBr 3(0.24mL)缓慢加入上述溶液中，缓慢回温至室温搅拌反应。LC-MS及TLC检测反应完全，加入饱和碳酸氢钠水溶液淬灭反应，二氯甲烷萃取，合并有机相经饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液旋干，旋干物经制备板纯化得17.0mg化合物A10。 180 mg of compound A10-1 was dissolved in 10 mL of anhydrous DCM, cooled to -60°C, and then BBr 3 (0.24 mL) was slowly added to the above solution, and the temperature was slowly warmed to room temperature and the reaction was stirred. LC-MS and TLC check that the reaction is complete, add saturated sodium bicarbonate aqueous solution to quench the reaction, extract with dichloromethane, the combined organic phases are washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate is spin-dried, and the spin-dried product is passed through a preparation plate It was purified to obtain 17.0 mg of compound A10.
[M+H +]＝475.31。 [M+H + ]=475.31.
1H NMR(500MHz,DMSO)δ7.97(s,1H),7.29(dd,J＝18.8,7.5Hz,2H),7.23–7.11(m,3H),7.01(s,1H),6.82(d,J＝8.1Hz,1H),3.86(s,1H),3.80(s,2H),3.60–3.47(m,2H),3.38(s,3H),3.11–2.96(m,3H),2.60(d,J＝15.5Hz,1H),1.87–1.85(m,1H),1.80–1.76(m,1H),1.52–1.50(m,1H),1.14–1.11(m,1H). 1 H NMR (500MHz, DMSO) δ 7.97 (s, 1H), 7.29 (dd, J = 18.8, 7.5 Hz, 2H), 7.23-7.11 (m, 3H), 7.01 (s, 1H), 6.82 (d ,J=8.1Hz,1H), 3.86(s,1H), 3.80(s,2H), 3.60–3.47(m,2H), 3.38(s,3H), 3.11–2.96(m,3H), 2.60( d, J=15.5Hz, 1H), 1.87–1.85(m,1H), 1.80–1.76(m,1H), 1.52–1.50(m,1H), 1.14–1.11(m,1H).
实施例19 化合物A19((S)-2-(1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-5-(3-(3,4-二氟苯基)丙-1-炔-1-基)-3-甲基嘧啶-4(3H)-酮)的制备：Example 19 Compound A19 ((S)-2-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(3 ,4-Difluorophenyl)prop-1-yn-1-yl)-3-methylpyrimidine-4(3H)-one):
Figure PCTCN2021088871-appb-000069
Figure PCTCN2021088871-appb-000069
步骤1：化合物A19-1的制备Step 1: Preparation of compound A19-1
将246mg化合物A12-1，200mg化合物SM1，溶解于5mL的DMF中，加入17mg PdCl 2(PPh 3) 2，4.6mg CuI，0.7mL TEA，氮气置换后，室温反应30min，加入50mgTBAF的THF溶液(1M)，90℃搅拌30min。LCMS检测反应完全，将反应液倒入30mL饱和食盐水中，用二氯甲烷(20mL×4)萃取。合并有机相，饱和食盐水(30mL×4)洗涤，无水硫酸钠干燥，减压浓缩，残余物用制备板纯化得黄色固体147mg化合物A19-1。 Dissolve 246 mg of compound A12-1, 200 mg of compound SM1 in 5 mL of DMF, add 17 mg of PdCl 2 (PPh 3 ) 2 , 4.6 mg of CuI, 0.7 mL of TEA, replace with nitrogen, react at room temperature for 30 minutes, and add 50 mg of TBAF in THF ( 1M), stirring at 90°C for 30 min. LCMS detected that the reaction was complete, the reaction solution was poured into 30 mL of saturated brine, and extracted with dichloromethane (20 mL×4). The organic phases were combined, washed with saturated brine (30 mL×4), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified with a preparation plate to obtain 147 mg of compound A19-1 as a yellow solid.
步骤2：化合物A19的制备Step 2: Preparation of compound A19
将80mg化合物A19-1，溶解于2.5mL的THF中，加入0.5mL的EtOH，搅拌下滴入0.25mL HCl的EA溶液(2M)，室温下搅拌20mins。LCMS检测反应完全，将反应液减压浓缩，残余物用1mL水溶解，滴加饱和碳酸氢钠溶液1mL，收集析出的固体，用制备板纯化得40.7mg黄色固体化合物A19。80 mg of compound A19-1 was dissolved in 2.5 mL of THF, 0.5 mL of EtOH was added, 0.25 mL of HCl EA solution (2M) was added dropwise with stirring, and the mixture was stirred at room temperature for 20 mins. LCMS detected that the reaction was complete, the reaction solution was concentrated under reduced pressure, the residue was dissolved in 1 mL of water, and 1 mL of saturated sodium bicarbonate solution was added dropwise. The precipitated solid was collected and purified with a preparation plate to obtain 40.7 mg of yellow solid compound A19.
[M+H +]＝461.37。 [M+H + ]=461.37.
1H NMR(500MHz,DMSO-d6)δ7.97(s,1H),7.50–7.38(m,2H),7.32-7.30(m,1H),7.28–7.24(m,1H),7.19–7.13(m,3H),3.90(s,2H),3.86(s,1H),3.57-3.49(m,2H),3.38(s,3H),3.12–2.98(m,3H),2.60(d,J＝15.6Hz,1H),1.87(m,1H),1.78(m,1H),1.55–1.49(m,1H),1.14-1.11(m,1H). 1 H NMR(500MHz,DMSO-d6)δ7.97(s,1H), 7.50-7.38(m,2H), 7.32-7.30(m,1H), 7.28-7.24(m,1H), 7.19-7.13( m, 3H), 3.90 (s, 2H), 3.86 (s, 1H), 3.57-3.49 (m, 2H), 3.38 (s, 3H), 3.12-2.98 (m, 3H), 2.60 (d, J = 15.6Hz, 1H), 1.87 (m, 1H), 1.78 (m, 1H), 1.55-1.49 (m, 1H), 1.14-1.11 (m, 1H).
实施例23 化合物A23((S)-2-(1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-3-甲基-5-(3-(4-吗啉苯基)丙-1-炔-1-基)嘧啶-4(3H)-酮)的制备：Example 23 Compound A23 ((S)-2-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-3-methyl-5- Preparation of (3-(4-morpholinophenyl)prop-1-yn-1-yl)pyrimidin-4(3H)-one):
Figure PCTCN2021088871-appb-000070
Figure PCTCN2021088871-appb-000070
步骤1：化合物A23-1的制备Step 1: Preparation of compound A23-1
将三甲基硅基乙炔(4.1g)溶于THF(19mL)中，冰浴下滴加75mL乙基溴化镁(1M)氮气置换后，冰浴搅拌反应1h，加入A24-SM(2g)，回复至室温搅拌2h。LC-MS及TLC检测反应完全，加入饱和氯化铵溶液淬灭，加入20ml EA萃取，分离有机相，2×10ml饱和氯化钠溶液洗涤有机相，分离干燥，真空浓缩，粗品经柱层析纯化得1.98g白色固体化合物A23-1。Dissolve trimethylsilyl acetylene (4.1g) in THF (19mL), add 75mL ethylmagnesium bromide (1M) dropwise under an ice bath and replace with nitrogen, stir and react in an ice bath for 1h, then add A24-SM (2g) , Return to room temperature and stir for 2h. LC-MS and TLC detect that the reaction is complete, add saturated ammonium chloride solution for quenching, add 20ml EA for extraction, separate the organic phase, wash the organic phase with 2×10ml saturated sodium chloride solution, separate and dry, concentrate in vacuo, and pass the crude product to column chromatography Purified to obtain 1.98 g of white solid compound A23-1.
步骤2：化合物A23-2的制备Step 2: Preparation of compound A23-2
将600mg化合物M14、418mg化合物A23-1、23mg PdCl 2(PPh 3) 2、13mg CuI和17mg PPh 3溶于THF(10mL)和Et 3N(2mL)中，氮气置换后，70℃搅拌反应20min后，加入87mg TBAF，继续搅拌3h。LC-MS及TLC检测反应完全，真空浓缩，粗品经柱层析纯化得645mg黄色固体化合物A23-2。 Dissolve 600 mg of compound M14, 418 mg of compound A23-1, 23 mg of PdCl 2 (PPh 3 ) 2 , 13 mg of CuI, and 17 mg of PPh 3 in THF (10 mL) and Et 3 N (2 mL). After nitrogen replacement, the reaction was stirred at 70°C for 20 min. After that, 87mg TBAF was added, and stirring was continued for 3h. LC-MS and TLC detected that the reaction was complete, concentrated in vacuo, and the crude product was purified by column chromatography to obtain 645 mg of yellow solid compound A23-2.
步骤3：化合物A23-3的制备Step 3: Preparation of compound A23-3
将300mg化合物A23-2溶于DCM(8mL)中，氮气置换，先加入111mg三乙基硅烷，再加入217mg三氟乙酸，室温反应1h。LC-MS及TLC检测反应完全，加入饱和碳酸氢钠淬灭，再加入3×10ml DCM萃取，有机相干燥，浓缩粗品经制备板分离纯化得到20mg淡黄色固体化合物A23-3。300 mg of compound A23-2 was dissolved in DCM (8 mL) and replaced with nitrogen. First, 111 mg of triethylsilane and then 217 mg of trifluoroacetic acid were added, and the reaction was carried out at room temperature for 1 h. LC-MS and TLC detect that the reaction is complete, add saturated sodium bicarbonate to quench, add 3×10ml DCM for extraction, dry the organic phase, concentrate the crude product and purify it on a preparation plate to obtain 20mg of pale yellow solid compound A23-3.
步骤4：化合物A23的制备Step 4: Preparation of compound A23
将20mg化合物A23-3溶解于2mL二氧六环和0.5mL甲醇溶液中，氮气置换，搅拌下滴入50μL HCl的EA溶液(2M)，室温下搅拌20min。LCMS检测反应完全，将反应液减压浓缩， 残余物用1mL水溶解，滴加饱和碳酸氢钠溶液1mL，收集析出的固体，用制备板纯化得3.6mg淡黄色固体化合物A23。[M+H] +＝510.42。 20 mg of compound A23-3 was dissolved in 2 mL of dioxane and 0.5 mL of methanol solution, replaced with nitrogen, 50 μL of HCl in EA solution (2M) was added dropwise with stirring, and stirred at room temperature for 20 min. LCMS detected that the reaction was complete, the reaction solution was concentrated under reduced pressure, the residue was dissolved in 1 mL of water, 1 mL of saturated sodium bicarbonate solution was added dropwise, the precipitated solid was collected, and purified with a preparation plate to obtain 3.6 mg of light yellow solid compound A23. [M+H] + =510.42.
实施例87 化合物A66(2-((S)-1-氨基-1,3-二氢螺环[茚-2,4'哌啶]-1'-基)-5-(2-氧-8-氮杂螺[4.5]癸-8-基)3-羟基-3-(4-吗啉苯基)丙-1-炔-1-基)-3-甲基嘧啶-4(3H)-酮)的制备：Example 87 Compound A66(2-((S)-1-amino-1,3-dihydrospiro[indene-2,4'piperidine]-1'-yl)-5-(2-oxo-8 -Azaspiro[4.5]dec-8-yl)3-hydroxy-3-(4-morpholinphenyl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one ) Preparation:
Figure PCTCN2021088871-appb-000071
Figure PCTCN2021088871-appb-000071
步骤1：化合物A66的制备Step 1: Preparation of compound A66
将60mg化合物A23-2溶解于3mL二氧六环和0.5mL甲醇溶液中，氮气置换，搅拌下滴入167μL HCl的EA溶液(2M)，室温下搅拌20min。LCMS检测反应完全，将反应液减压浓缩，残余物用1mL水溶解，滴加饱和碳酸氢钠溶液1mL，收集析出的固体，用制备板纯化得1.8mg淡黄色固体化合物A66。[M-OH] +＝508.39。 60 mg of compound A23-2 was dissolved in 3 mL of dioxane and 0.5 mL of methanol solution, replaced with nitrogen, 167 μL of HCl in EA solution (2M) was added dropwise with stirring, and stirred at room temperature for 20 min. LCMS detected that the reaction was complete, the reaction solution was concentrated under reduced pressure, the residue was dissolved in 1 mL of water, 1 mL of saturated sodium bicarbonate solution was added dropwise, the precipitated solid was collected, and purified with a preparation plate to obtain 1.8 mg of pale yellow solid compound A66. [M-OH] + =508.39.
实施例45 化合物A45((S)-2-(1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-5-(3-(3-羟基苯基)丙-1-炔-1-基)嘧啶-4(3H)-酮)的制备：Example 45 Compound A45 ((S)-2-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(3 -Hydroxyphenyl)prop-1-yn-1-yl)pyrimidine-4(3H)-one) preparation:
Figure PCTCN2021088871-appb-000072
Figure PCTCN2021088871-appb-000072
步骤1：化合物A45-1的制备Step 1: Preparation of compound A45-1
将6.73g化合物3,4-二甲氧基苄醇溶于THF(300mL),氮气置换后，加入3.85g叔丁醇钠，降温至-40℃，加入M1-7，然后-40℃保温反应0.5h，缓慢回温至室温，反应2h。LC-MS及TLC检测反应完全，加入200mLH 2O，再加入150mL的EA，再用150mL*3EA萃取，合并 有机相，200mL*2饱和食盐水洗涤，无水硫酸钠干燥，浓缩得到粗品，粗品经加入200mL(PE:EA＝10:1)打浆，然后过滤干燥得10.2g浅黄色固体化合物A45-1。 Dissolve 6.73g compound 3,4-dimethoxybenzyl alcohol in THF (300mL), after nitrogen replacement, add 3.85g sodium tert-butoxide, cool to -40℃, add M1-7, and then keep the reaction at -40℃ For 0.5h, slowly warm to room temperature and react for 2h. LC-MS and TLC check that the reaction is complete, add 200 mL of H 2 O, then 150 mL of EA, then extract with 150 mL * 3 EA, combine the organic phases, wash with 200 mL * 2 saturated brine, dry with anhydrous sodium sulfate, and concentrate to obtain a crude product. After adding 200 mL (PE:EA=10:1) for beating, then filtering and drying to obtain 10.2 g of light yellow solid compound A45-1.
步骤2：化合物A45-2的制备Step 2: Preparation of compound A45-2
将5.0g化合物A45-1和4.19g化合物M5溶解于50mL二氧六环中，加入3.73g三乙胺，加热75℃反应2小时。TLC检测反应完全，将反应液旋干，经柱层析纯化得3.9g化合物A45-2。Dissolve 5.0 g of compound A45-1 and 4.19 g of compound M5 in 50 mL of dioxane, add 3.73 g of triethylamine, and heat at 75° C. to react for 2 hours. TLC detected that the reaction was complete, the reaction solution was spin-dried, and purified by column chromatography to obtain 3.9 g of compound A45-2.
步骤3：化合物A45-3的制备Step 3: Preparation of compound A45-3
将1.0g化合物A45-2、290.3mg三甲基硅乙炔、32mg PdCl 2(PPh 3) 2、17mg CuI溶于THF(15mL)和Et 3N(3.75mL)中，氮气置换后，室温搅拌反应3h。LC-MS及TLC检测反应完全，真空浓缩，粗品经柱层析纯化得650mg灰色固体化合物A45-3。 1.0g of compound A45-2, 290.3mg of trimethylsilylacetylene, 32mg of PdCl 2 (PPh 3 ) 2 , and 17mg of CuI were dissolved in THF (15mL) and Et 3 N (3.75mL). After nitrogen replacement, the reaction was stirred at room temperature. 3h. LC-MS and TLC detected that the reaction was complete, concentrated in vacuo, and the crude product was purified by column chromatography to obtain 650 mg of gray solid compound A45-3.
步骤4：化合物A45-4的制备Step 4: Preparation of compound A45-4
将400mg化合物A45-3、13.0mg PdCl 2(PPh 3) 2、7.1mg CuI、9.7mg PPh 3,溶于DMF(16.0mL)和Et 3N(4.0mL)中，氮气置换后，加入242.5mg TBAF，室温搅拌反应10min，再将373.0mg 3-甲氧基苄溴加入上述反应液中，氮气保护80℃下搅拌0.5h，再继续将373.0mg 3-甲氧基苄溴加入上述反应液中，氮气保护80℃下搅拌0.5h。LC-MS及TLC检测反应完全，加入10mL水淬灭，乙酸乙酯(3x10mL)萃取，饱和食盐水洗涤，无水硫酸钠干燥，真空浓缩，粗品经柱层析纯化得256mg浅黄色固体化合物A45-4。 400mg compound A45-3, 13.0mg PdCl 2 (PPh 3 ) 2 , 7.1mg CuI, 9.7mg PPh 3 were dissolved in DMF (16.0mL) and Et 3 N (4.0mL), after nitrogen replacement, 242.5mg was added TBAF, stirring at room temperature for 10 minutes, then adding 373.0mg of 3-methoxybenzyl bromide to the above reaction solution, stirring at 80°C under nitrogen protection for 0.5h, and then continuing to add 373.0mg of 3-methoxybenzyl bromide to the above reaction solution , Stir at 80°C for 0.5h under nitrogen protection. LC-MS and TLC check that the reaction is complete, add 10mL of water to quench, extract with ethyl acetate (3x10mL), wash with saturated brine, dry with anhydrous sodium sulfate, and concentrate in vacuo. The crude product is purified by column chromatography to obtain 256mg of light yellow solid compound A45. -4.
步骤5：化合物A45-5的制备Step 5: Preparation of compound A45-5
将100mg化合物A45-3溶解于3mL DCM中，加入0.2mL三氟乙酸，RT反应1小时。LCMS检测反应完全,将反应液旋干得90mg化合物粗品A45-5，直接用下一步。Dissolve 100 mg of compound A45-3 in 3 mL of DCM, add 0.2 mL of trifluoroacetic acid, and react for 1 hour at RT. LCMS detected that the reaction was complete, and the reaction solution was spin-dried to obtain 90 mg of crude compound A45-5, which was directly used in the next step.
步骤6：化合物A45的制备Step 6: Preparation of compound A45
将90mg化合物A45-5溶解于3mL无水二氯甲烷中，冷却至-60℃，再将BBr 3(70mg)缓慢加入上述溶液中，缓慢升至室温搅拌反应。LC-MS及TLC检测反应完全，加入饱和碳酸氢钠水溶液淬灭反应，二氯甲烷萃取，合并有机相经饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液旋干，粗品经制备板纯化得10.2mg化合物A45。 90 mg of compound A45-5 was dissolved in 3 mL of anhydrous dichloromethane, cooled to -60°C, and then BBr 3 (70 mg) was slowly added to the above solution, and the reaction was slowly raised to room temperature and stirred. LC-MS and TLC check that the reaction is complete, add saturated sodium bicarbonate aqueous solution to quench the reaction, extract with dichloromethane, combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, filter, spin-dry the filtrate, and purify the crude product on a preparation plate 10.2 mg of compound A45 was obtained.
[M+H] +＝427.27。 [M+H] + =427.27.
经由不同的反应起始原料、合适的试剂(起始原料及试剂均为市售)及本发明制备的中间体，采用与前述实施例10、实施例12、实施例19、实施例23或实施例87类似的方法制备表5中的化合物。Through different reaction starting materials, suitable reagents (starting materials and reagents are all commercially available), and intermediates prepared in the present invention, the same as those in the foregoing Example 10, Example 12, Example 19, and Example 23 are used. The compounds in Table 5 were prepared in a similar manner to Example 87.
表5table 5
Figure PCTCN2021088871-appb-000073
Figure PCTCN2021088871-appb-000073
Figure PCTCN2021088871-appb-000074
Figure PCTCN2021088871-appb-000074
化合物A11  1H NMR(500MHz,DMSO)δ8.21(s,1H),7.96(s,1H),7.41-7.39(m,1H),7.25-7.22(m,3H),7.13-7.10(m,1H),6.81-7.79(m,2H),6.64-6.61(m,1H),4.09(s,1H),3.78(s,2H),3.55-3.52(m,2H),3.38(s,3H),3.11–3.05(m,2H),2.76(d,J＝15.8Hz,1H),2.54(d,J＝15.8Hz,1H),1.90–1.78(m,2H),1.51–1.48(m,1H),1.31–1.28(m,1H). Compound A11 1 H NMR (500MHz, DMSO) δ 8.21 (s, 1H), 7.96 (s, 1H), 7.41-7.39 (m, 1H), 7.25-7.22 (m, 3H), 7.13-7.10 (m, 1H), 6.81-7.79 (m, 2H), 6.64-6.61 (m, 1H), 4.09 (s, 1H), 3.78 (s, 2H), 3.55-3.52 (m, 2H), 3.38 (s, 3H) ,3.11–3.05(m,2H),2.76(d,J=15.8Hz,1H),2.54(d,J=15.8Hz,1H),1.90–1.78(m,2H),1.51–1.48(m,1H ), 1.31-1.28 (m, 1H).
化合物A17  1H NMR(500MHz,DMSO)δ7.96(s,1H),7.44(d,J＝6.7Hz,1H),7.31–7.22(m,4H),7.03–6.94(m,2H),6.81(d,J＝8.2Hz,1H),4.21(s,1H),3.85(s,2H),3.76(s,3H),3.57-3.52(m,2H),3.39(s,3H),3.11–3.06(m,2H),2.84(d,J＝15.8Hz,1H),1.84–1.81(m,2H),1.51–1.49(m,1H),1.40–1.38(m,1H). Compound A17 1 H NMR (500MHz, DMSO) δ 7.96 (s, 1H), 7.44 (d, J = 6.7 Hz, 1H), 7.31-7.22 (m, 4H), 7.03-6.94 (m, 2H), 6.81 (d,J=8.2Hz,1H),4.21(s,1H),3.85(s,2H),3.76(s,3H),3.57-3.52(m,2H),3.39(s,3H),3.11– 3.06(m,2H), 2.84(d,J=15.8Hz,1H), 1.84-1.81(m,2H), 1.51-1.49(m,1H), 1.40-1.38(m,1H).
通过类似方法可以合成如下化合物。The following compounds can be synthesized by a similar method.
表6Table 6
Figure PCTCN2021088871-appb-000075
Figure PCTCN2021088871-appb-000075
Figure PCTCN2021088871-appb-000076
Figure PCTCN2021088871-appb-000076
Figure PCTCN2021088871-appb-000077
Figure PCTCN2021088871-appb-000077
Figure PCTCN2021088871-appb-000078
Figure PCTCN2021088871-appb-000078
Figure PCTCN2021088871-appb-000079
Figure PCTCN2021088871-appb-000079
Figure PCTCN2021088871-appb-000080
Figure PCTCN2021088871-appb-000080
实施例75 化合物D04(2-((5-((S)-1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-6-(羟甲基)吡嗪-2-基)乙炔基)环丙烷-1-羧酸乙酯)的制备：Example 75 Compound D04 (2-((5-((S)-1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-( (Hydroxymethyl)pyrazin-2-yl)ethynyl)cyclopropane-1-carboxylic acid ethyl ester) preparation:
Figure PCTCN2021088871-appb-000081
Figure PCTCN2021088871-appb-000081
步骤1：化合物D04-1的制备Step 1: Preparation of compound D04-1
将5.07g化合物D04-SM、10g化合物3-溴-1-三甲基硅基-1-丙炔溶于丙酮(50mL)中，氮气置换后，室温搅拌反应18小时。TLC检测反应完全，将反应液过滤，滤饼用丙酮(20ml*3)洗涤，取滤饼在真空下旋干，得5.8g白色固体化合物D04-1。5.07 g of compound D04-SM and 10 g of compound 3-bromo-1-trimethylsilyl-1-propyne were dissolved in acetone (50 mL), and after nitrogen replacement, the reaction was stirred at room temperature for 18 hours. TLC detected that the reaction was complete, the reaction solution was filtered, the filter cake was washed with acetone (20 ml*3), and the filter cake was spin-dried under vacuum to obtain 5.8 g of white solid compound D04-1.
步骤2：化合物D04-2的制备Step 2: Preparation of compound D04-2
将3.84g化合物D04-1溶解于27mL无水四氢呋喃中，室温加入1.25g丙烯酸乙酯，氮气置换后，将848mg钠氢(60％)分批加入上述反应液中，室温下搅拌反应8小时。TLC检测反应完全，在200-300目硅胶助滤下，反应液过滤，THF(20ml*2)洗涤滤饼，滤液旋干，残余物经柱层析纯化得2.1g无色液体化合物D04-2。3.84g of compound D04-1 was dissolved in 27mL of anhydrous tetrahydrofuran, 1.25g of ethyl acrylate was added at room temperature, after nitrogen replacement, 848mg of sodium hydrogen (60%) was added to the above reaction solution in batches, and the reaction was stirred at room temperature for 8 hours. The reaction was completed by TLC detection. Under 200-300 mesh silica gel filter aid, the reaction solution was filtered, the filter cake was washed with THF (20ml*2), the filtrate was spin-dried, and the residue was purified by column chromatography to obtain 2.1 g of colorless liquid compound D04-2 .
步骤3：化合物D04-3的制备Step 3: Preparation of compound D04-3
将320mg的D04-2、500mgM1、35.65mg Pd(dppf)Cl 2、9.65mg CuI、205mg Et 3N加入四氢呋喃(5mL)中，氮气置换三次，氮气保护下室温搅拌5分钟，将530mg四丁基氟化铵加入上述反应液中，70℃搅拌反应18hrs。LCMS和TLC检测反应完全，反应液冷却至室温减压浓缩，残余物经柱层析纯化得500mg淡黄色固体化合物D04-3。 Add 320mg of D04-2, 500mgM1, 35.65mg Pd(dppf)Cl 2 , 9.65mg CuI, 205mg Et 3 N to tetrahydrofuran (5mL), replace with nitrogen three times, stir at room temperature for 5 minutes under nitrogen protection, and add 530mg of tetrabutyl Ammonium fluoride was added to the above reaction solution, and the reaction was stirred at 70°C for 18 hrs. LCMS and TLC detected that the reaction was complete, the reaction solution was cooled to room temperature and concentrated under reduced pressure, and the residue was purified by column chromatography to obtain 500 mg of light yellow solid compound D04-3.
步骤4：化合物D04的制备Step 4: Preparation of compound D04
将50mg化合物D04-3溶解于2.0mL四氢呋喃中，加入2N HCl(0.2mL，乙酸乙酯溶液)，RT搅拌反应1hrs。LCMS和TLC检测反应完全，反应液减压浓缩。残余物加入H 2O(1.0mL)溶解，用饱和NaHCO 3调节溶液至pH＝8，二氯甲烷(3x3mL)萃取，有机相干燥后真空浓缩， 经制备板纯化得9.4mg黄色固体化合物D04。[M+H +]＝447.36。 50 mg of compound D04-3 was dissolved in 2.0 mL of tetrahydrofuran, 2N HCl (0.2 mL, ethyl acetate solution) was added, and the reaction was stirred at RT for 1 hrs. LCMS and TLC detected that the reaction was complete, and the reaction solution was concentrated under reduced pressure. The residue was dissolved by adding H 2 O (1.0 mL), the solution was adjusted to pH=8 with saturated NaHCO 3 , extracted with dichloromethane (3×3 mL), the organic phase was dried and concentrated in vacuo, and purified by a preparation plate to obtain 9.4 mg of yellow solid compound D04. [M+H + ]=447.36.
实施例90 化合物D13(2-((5-((S)-1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-6-(羟甲基)吡嗪-2-2-基)乙炔基)环丙烷酰胺)的制备：Example 90 Compound D13(2-((5-((S)-1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-( (Hydroxymethyl)pyrazin-2-2-yl)ethynyl)cyclopropaneamide) preparation:
Figure PCTCN2021088871-appb-000082
Figure PCTCN2021088871-appb-000082
步骤1：化合物D13-1的制备Step 1: Preparation of compound D13-1
将500mg化合物D04-3溶于四氢呋喃(6mL)中，75mg一水合氢氧化锂溶于水(2mL)加入上述溶剂中，室温下搅拌反应5小时。TLC检测反应完全，将反应液中的四氢呋喃旋除，乙酸乙酯(5mL*3)萃取，合并有机相无水硫酸钠干燥，过滤，滤液旋干，得410mg淡黄色固体化合物D13-1。500 mg of compound D04-3 was dissolved in tetrahydrofuran (6 mL), and 75 mg of lithium hydroxide monohydrate dissolved in water (2 mL) was added to the above solvent, and the reaction was stirred at room temperature for 5 hours. TLC detected that the reaction was complete, the tetrahydrofuran in the reaction solution was rotated off, extracted with ethyl acetate (5 mL*3), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to obtain 410 mg of light yellow solid compound D13-1.
步骤2：化合物D13-2的制备Step 2: Preparation of compound D13-2
将100mg化合物D13-1、73mg EDCI、39mg Hobt溶解于无水二氯甲烷(2mL)中，室温搅拌反应15min，将10mg氨水和74mg DIEA加入上述反应液中，氮气保护下，室温搅拌反应1小时。TLC检测反应完全，将水(5mL)加入反应液中，二氯甲烷(5mL*2)萃取，合并有机相，无水硫酸钠干燥，过滤滤液旋干，旋干物经制备板纯化得71mg淡黄色化合物D13-2。Dissolve 100 mg of compound D13-1, 73 mg of EDCI, and 39 mg of Hobt in anhydrous dichloromethane (2 mL), stir at room temperature for 15 min, add 10 mg of ammonia and 74 mg of DIEA to the above reaction solution, under nitrogen protection, stir at room temperature for 1 hour . TLC detects that the reaction is complete, add water (5mL) to the reaction solution, extract with dichloromethane (5mL*2), combine the organic phases, dry with anhydrous sodium sulfate, filter the filtrate and spin-dry, and spin the dried product on a preparation plate to obtain 71mg of light yellow Compound D13-2.
步骤3：化合物D13的制备Step 3: Preparation of compound D13
将71mg化合物D13-2溶解于2.0mL四氢呋喃中，加入2N HCl(0.3mL，乙酸乙酯溶液)，RT搅拌反应2hrs。LCMS和TLC检测反应完全，反应液减压浓缩。残余物加入H2O(1.0mL)溶解，用饱和NaHCO3调节溶液至pH＝8，二氯甲烷(3x3mL)萃取，有机相干燥后真空浓缩，经制备板纯化得23mg黄色固体化合物D13。[M+H +]＝418.22 71 mg of compound D13-2 was dissolved in 2.0 mL of tetrahydrofuran, 2N HCl (0.3 mL, ethyl acetate solution) was added, and the reaction was stirred at RT for 2 hrs. LCMS and TLC detected that the reaction was complete, and the reaction solution was concentrated under reduced pressure. The residue was dissolved by adding H2O (1.0 mL), adjusting the solution to pH=8 with saturated NaHCO3, extracting with dichloromethane (3×3 mL), drying the organic phase and then concentrating in vacuo. Purified by a preparation plate, 23 mg of yellow solid compound D13 was obtained. [M+H + ]=418.22
实施例78 化合物D07(2-((2-((S)-1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-1-甲基-6-氧代-1,6-二氢嘧啶-5-基)乙炔基)环丙烷-1-羧酸乙酯)的制备：Example 78 Compound D07(2-((2-((S)-1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-1-methyl Preparation of 6-oxo-1,6-dihydropyrimidin-5-yl)ethynyl)cyclopropane-1-carboxylic acid ethyl ester:
Figure PCTCN2021088871-appb-000083
Figure PCTCN2021088871-appb-000083
步骤1：化合物D07-1的制备Step 1: Preparation of compound D07-1
将630mg的D04-3、750mgM14、48mg Pd(dppf)Cl 2、13mg CuI和205mg Et 3N加入四氢呋喃(10mL)中，氮气置换三次，氮气保护下室温搅拌5分钟，将783mg四丁基氟化铵加入上述反应液中，70℃搅拌反应3小时。LCMS和TLC检测反应完全，反应液冷却至室温减压浓缩，残余物经柱层析纯化得660mg淡黄色固体化合物D07-1。 Add 630mg of D04-3, 750mg M14, 48mg Pd(dppf)Cl 2 , 13mg CuI and 205mg Et 3 N to tetrahydrofuran (10mL), replace with nitrogen three times, stir at room temperature for 5 minutes under nitrogen protection, and fluoride 783mg of tetrabutyl Ammonium was added to the above reaction solution, and the reaction was stirred at 70°C for 3 hours. The reaction was completed by LCMS and TLC, the reaction solution was cooled to room temperature and concentrated under reduced pressure, and the residue was purified by column chromatography to obtain 660 mg of light yellow solid compound D07-1.
步骤2：化合物D07的制备Step 2: Preparation of compound D07
将60mg化合物D07-1溶解于2.0mL四氢呋喃中，加入2N HCl(0.2mL，乙酸乙酯溶液)，RT搅拌反应1小时。LCMS和TLC检测反应完全，反应液减压浓缩。残余物加入H 2O(1.0mL)溶解，用饱和NaHCO 3调节溶液至pH＝8，二氯甲烷(3x3mL)萃取，有机相干燥后真空浓缩，经制备板纯化得7.2mg黄色固体化合物D07。[M+H +]＝447.35。 60 mg of compound D07-1 was dissolved in 2.0 mL of tetrahydrofuran, 2N HCl (0.2 mL, ethyl acetate solution) was added, and the reaction was stirred at RT for 1 hour. LCMS and TLC detected that the reaction was complete, and the reaction solution was concentrated under reduced pressure. The residue was dissolved by adding H 2 O (1.0 mL), the solution was adjusted to pH=8 with saturated NaHCO 3 , extracted with dichloromethane (3×3 mL), the organic phase was dried and concentrated in vacuo, and purified by a preparation plate to obtain 7.2 mg of yellow solid compound D07. [M+H + ]=447.35.
实施例72 化合物D01(2-((S)-1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-5-((2-(羟甲基)环丙基)乙炔基)-3-甲基嘧啶-4(3H)-酮)的制备：Example 72 Compound D01(2-((S)-1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-((2-( Preparation of hydroxymethyl)cyclopropyl)ethynyl)-3-methylpyrimidine-4(3H)-one):
Figure PCTCN2021088871-appb-000084
Figure PCTCN2021088871-appb-000084
步骤1：化合物D01-1的制备Step 1: Preparation of compound D01-1
将100mg化合物D07-1溶于无水二氯甲烷(5mL)中，降温至-78℃，0.7mL DIBAL(1mol/L,DCM溶液)缓慢加入上述溶液中，-78℃下搅拌反应1.5小时。TLC检测反应完全，将***(10ml)加入反应液中，升温至0℃，缓慢加入2滴H 2O，再加入2滴15％氢氧化钠水溶液，加入5滴H 2O，升温至室温搅拌反应15min，加入无水硫酸钠，搅拌反应30min，在硅藻土助滤下过滤，滤液旋干，滤液旋干，得32mg淡黄色固体化合物D01-1。 100 mg of compound D07-1 was dissolved in anhydrous dichloromethane (5 mL), the temperature was lowered to -78°C, 0.7 mL of DIBAL (1 mol/L, DCM solution) was slowly added to the above solution, and the reaction was stirred at -78°C for 1.5 hours. TLC detects that the reaction is complete, add ether (10ml) to the reaction solution, warm to 0°C, slowly add 2 drops of H 2 O, then add 2 drops of 15% sodium hydroxide aqueous solution, add 5 drops of H 2 O, warm to room temperature and stir. After reacting for 15 minutes, adding anhydrous sodium sulfate, stirring the reaction for 30 minutes, filtering under the aid of diatomaceous earth, the filtrate was spin-dried, and the filtrate was spin-dried to obtain 32 mg of light yellow solid compound D01-1.
步骤2：化合物D01-2的制备Step 2: Preparation of compound D01-2
将32mg化合物D01-1、4.5mg硼氢化钠溶于2mL无水四氢呋喃中，氮气保护室温下搅拌反应0.5小时。TLC检测反应完全，将饱和氯化铵水溶液(5mL)加入反应液中，乙酸乙酯(5mL*2)萃取，合并有机相，无水硫酸钠干燥，过滤滤液旋干，旋干物经制备板纯化得20mg淡黄色固体化合物D01-2。32 mg of compound D01-1 and 4.5 mg of sodium borohydride were dissolved in 2 mL of anhydrous tetrahydrofuran, and the reaction was stirred at room temperature under nitrogen protection for 0.5 hours. TLC detects the completion of the reaction. Add saturated aqueous ammonium chloride solution (5mL) to the reaction solution, extract with ethyl acetate (5mL*2), combine the organic phases, dry with anhydrous sodium sulfate, filter the filtrate and spin-dry, and spin-dried to purify by a preparation plate 20 mg of light yellow solid compound D01-2 was obtained.
步骤3：化合物D01的制备Step 3: Preparation of compound D01
将20mg化合物D01-2溶解于2.0mL四氢呋喃中，加入2N HCl(0.2mL，乙酸乙酯溶液)， RT搅拌反应1.5小时。LCMS和TLC检测反应完全，反应液减压浓缩。残余物加入H 2O(1.0mL)溶解，用饱和NaHCO 3调节溶液至pH＝8，二氯甲烷(3x3mL)萃取，有机相干燥后真空浓缩，经制备板纯化得3.5mg淡黄色固体化合物D01。[M+H +]＝405.44。 20 mg of compound D01-2 was dissolved in 2.0 mL of tetrahydrofuran, 2N HCl (0.2 mL, ethyl acetate solution) was added, and the reaction was stirred at RT for 1.5 hours. LCMS and TLC detected that the reaction was complete, and the reaction solution was concentrated under reduced pressure. Add H 2 O (1.0 mL) to dissolve the residue, adjust the solution to pH=8 with saturated NaHCO 3 , extract with dichloromethane (3x3 mL), dry the organic phase and concentrate in vacuo, and purify it on a preparation plate to obtain 3.5 mg of light yellow solid compound D01 . [M+H + ]=405.44.
实施例74 化合物D03(5-((2-(1,3,4-恶二唑-2-基)环丙基)乙炔基)-2-((S)-1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-3-甲基嘧啶-4(3H)-酮)的制备：Example 74 Compound D03 (5-((2-(1,3,4-oxadiazol-2-yl)cyclopropyl)ethynyl)-2-((S)-1-amino-1,3- Preparation of dihydrospirocyclo[indene-2,4'-piperidine]-1'-yl)-3-methylpyrimidin-4(3H)-one):
Figure PCTCN2021088871-appb-000085
Figure PCTCN2021088871-appb-000085
步骤1：化合物D03-1的制备Step 1: Preparation of compound D03-1
将200mg化合物D03-1溶于四氢呋喃(6mL)中，31mg一水合氢氧化锂溶于水(2mL)加入上述溶剂中，室温下搅拌反应3小时。TLC检测反应完全，将反应液中的四氢呋喃旋除，乙酸乙酯(5mL*3)萃取，合并有机相无水硫酸钠干燥，过滤，滤液旋干，得110mg淡黄色固体化合物D03-1。200 mg of compound D03-1 was dissolved in tetrahydrofuran (6 mL), and 31 mg of lithium hydroxide monohydrate dissolved in water (2 mL) was added to the above solvent, and the reaction was stirred at room temperature for 3 hours. TLC detected that the reaction was complete, the tetrahydrofuran in the reaction solution was removed, extracted with ethyl acetate (5 mL*3), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to obtain 110 mg of light yellow solid compound D03-1.
步骤2：化合物D03-2的制备Step 2: Preparation of compound D03-2
将100mg化合物D07-1、73mg EDCI和39mg Hobt溶解于无水二氯甲烷(2mL)中，室温搅拌反应15min，将19mg一水合肼(80％)、74mg DIEA加入上述反应液中，氮气保护室温下搅拌反应0.5小时。TLC检测反应完全，将水(5mL)加入反应液中，二氯甲烷(5mL*2)萃取，合并有机相，无水硫酸钠干燥，过滤滤液旋干，旋干物经制备板纯化得63mg淡黄色固体化合物D03-2。Dissolve 100mg of compound D07-1, 73mg EDCI and 39mg Hobt in anhydrous dichloromethane (2mL), stir at room temperature for 15min, add 19mg hydrazine monohydrate (80%) and 74mg DIEA to the above reaction solution, protect the room temperature with nitrogen The reaction was stirred for 0.5 hour. TLC detects that the reaction is complete, add water (5mL) to the reaction solution, extract with dichloromethane (5mL*2), combine the organic phases, dry with anhydrous sodium sulfate, filter the filtrate and spin-dry, and spin the dried product to obtain 63mg of light yellow with a preparation plate. Solid compound D03-2.
步骤3：化合物D03-3的制备Step 3: Preparation of compound D03-3
将60mg化合物D03-2、10mg对甲苯磺酸溶于原甲酸三甲酯(2mL)中，85℃下搅拌反应2小时。TLC检测反应完全，将水(5mL)加入反应液中，二氯甲烷(6mL*3)萃取，合并有机相无水硫酸钠干燥，过滤，滤液旋干，旋干物经制备板纯化，得36mg淡黄色固体化合物A31-3。60 mg of compound D03-2 and 10 mg of p-toluenesulfonic acid were dissolved in trimethyl orthoformate (2 mL), and the reaction was stirred at 85°C for 2 hours. TLC detects that the reaction is complete. Add water (5mL) to the reaction solution, extract with dichloromethane (6mL*3), combine the organic phases, dry with anhydrous sodium sulfate, filter, spin-dry the filtrate, and spin-dry the product through a preparation plate to obtain 36mg of light. Yellow solid compound A31-3.
步骤4：化合物D03的制备Step 4: Preparation of compound D03
将36mg化合物D03-3溶解于2.0mL四氢呋喃中，加入2N HCl(0.2mL，乙酸乙酯溶液)，RT搅拌反应2小时。LCMS和TLC检测反应完全，反应液减压浓缩。残余物加入H 2O(1.0mL)溶解，用饱和NaHCO 3调节溶液至pH＝8，二氯甲烷(3x3mL)萃取，有机相干燥后真空浓缩， 经制备板纯化得14.4mg白色固体化合物D03。[M+H +]＝443.30。 36 mg of compound D03-3 was dissolved in 2.0 mL of tetrahydrofuran, 2N HCl (0.2 mL, ethyl acetate solution) was added, and the reaction was stirred at RT for 2 hours. LCMS and TLC detected that the reaction was complete, and the reaction solution was concentrated under reduced pressure. The residue was dissolved by adding H 2 O (1.0 mL), the solution was adjusted to pH=8 with saturated NaHCO 3 , extracted with dichloromethane (3×3 mL), the organic phase was dried and concentrated in vacuo, and purified by a preparation plate to obtain 14.4 mg of white solid compound D03. [M+H + ]=443.30.
经由不同的反应起始原料、合适的试剂(起始原料及试剂均为市售)及本发明制备的中间体，采用与前述实施例72、实施例74、实施例75、实施例78或实施例90类似的方法制备表7的化合物。Through different reaction starting materials, suitable reagents (starting materials and reagents are commercially available) and intermediates prepared in the present invention, using the same as the foregoing embodiment 72, embodiment 74, embodiment 75, embodiment 78 or implementation The compounds in Table 7 were prepared in a similar manner to Example 90.
表7Table 7
Figure PCTCN2021088871-appb-000086
Figure PCTCN2021088871-appb-000086
通过类似方法可以合成如下化合物。The following compounds can be synthesized by a similar method.
表8Table 8
Figure PCTCN2021088871-appb-000087
Figure PCTCN2021088871-appb-000087
实施例108 化合物D14 4-(2-((5-((S)-1-氨基-1,3-二氢螺[茚-2,4’-哌啶]-1'-基) -6-(羟甲基)吡嗪-2-基)乙炔基)环丙基)苯甲酰胺的制备：Example 108 Compound D14 4-(2-((5-((S)-1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6 (Hydroxymethyl)pyrazin-2-yl)ethynyl)cyclopropyl)benzamide:
Figure PCTCN2021088871-appb-000088
Figure PCTCN2021088871-appb-000088
步骤1：D14-1的制备Step 1: Preparation of D14-1
将7.00g 4-氰基苯甲醛、369mg DBU和13.41g碳酸钾溶于磷酰基乙酸三乙酯(10.88g)中，室温反应2小时。TLC检测反应完全，过滤，滤饼用20mL乙酸乙酯洗涤，滤液真空浓缩，粗品溶于甲基叔丁基醚，加入正己烷析出固体，过滤得白色固体9.10g，即D14-1。Dissolve 7.00g 4-cyanobenzaldehyde, 369mg DBU and 13.41g potassium carbonate in triethyl phosphonoacetate (10.88g) and react at room temperature for 2 hours. TLC detected that the reaction was complete, filtered, the filter cake was washed with 20 mL of ethyl acetate, the filtrate was concentrated in vacuo, the crude product was dissolved in methyl tert-butyl ether, n-hexane was added to precipitate a solid, and 9.10 g of a white solid was obtained by filtration, namely D14-1.
步骤2：D14-2的制备Step 2: Preparation of D14-2
将2.17g氢化钠(60％)溶于无水DMSO(100mL)中，氮气置换后，分批加入11.94g三甲基碘混亚砜，室温搅拌至反应液澄清，将9.10g混合物D14-1溶于无水DMSO(100mL)，缓慢滴加至反应液中，滴毕室温反应12小时。TLC检测反应完全，冰浴搅拌下加入200mL水，500mL乙酸乙酯萃取，饱和食盐水洗涤有机相，无水硫酸钠干燥，真空浓缩，粗品经柱层析纯化得1.85g无色透明油状液体，即D14-2。Dissolve 2.17g sodium hydride (60%) in anhydrous DMSO (100mL), after nitrogen replacement, add 11.94g trimethyl iodide mixed sulfoxide in batches, stir at room temperature until the reaction solution is clear, add 9.10g mixture D14-1 Dissolve in anhydrous DMSO (100 mL), slowly add dropwise to the reaction solution, and complete the reaction at room temperature for 12 hours. TLC detects the completion of the reaction, adds 200 mL of water with stirring in an ice bath, extracts with 500 mL of ethyl acetate, washes the organic phase with saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was purified by column chromatography to obtain 1.85 g of a colorless transparent oily liquid. Namely D14-2.
步骤3：D14-3的制备Step 3: Preparation of D14-3
将0.50g混合物D14-2溶于无水THF(15mL)中，氮气置换后，冰浴下分批加入615mg硼氢混钠和295mg氯混锂，搅拌15分钟后移至室温，缓慢滴加MeOH(5mL)，滴毕室温搅拌12小时。TLC检测反应完全，冰浴搅拌下加入5mL 0.1N HCl，20mL乙酸乙酯萃取，饱和食盐水洗涤有机相，无水硫酸钠干燥，真空浓缩，粗品经柱层析纯化得278mg无色透明油状液体，即D14-3。Dissolve 0.50g mixture D14-2 in anhydrous THF (15mL), after nitrogen replacement, add 615mg sodium borohydride and 295mg lithium chloride in batches under ice bath, stir for 15 minutes and then move to room temperature, slowly add MeOH dropwise (5mL), after dropping, stirring at room temperature for 12 hours. TLC detection reaction is complete, add 5mL 0.1N HCl, 20mL ethyl acetate extraction under ice bath stirring, wash the organic phase with saturated brine, dry with anhydrous sodium sulfate, concentrate in vacuo, the crude product is purified by column chromatography to obtain 278mg colorless transparent oily liquid , Namely D14-3.
步骤4：D14-4的制备Step 4: Preparation of D14-4
将278mg混合物D14-3溶于DCM(10mL)中，搅拌下加入987mg戴斯马丁氧混剂，室 温搅拌1小时。TLC检测反应完全，加入饱和硫代硫酸钠溶液(30mL)，用DCM(30mL)萃取，饱和食盐水洗涤，无水硫酸钠干燥，真空浓缩，粗品经柱层析纯化得235mg无色透明油状液体，即D14-4。278 mg of the mixture D14-3 was dissolved in DCM (10 mL), and 987 mg of Dess Martin oxygen mixture was added with stirring, and the mixture was stirred at room temperature for 1 hour. The reaction was completed by TLC detection. Saturated sodium thiosulfate solution (30mL) was added, extracted with DCM (30mL), washed with saturated brine, dried over anhydrous sodium sulfate, concentrated in vacuo, and the crude product was purified by column chromatography to obtain 235mg of a colorless transparent oily liquid , Which is D14-4.
步骤5：D14-5的制备Step 5: Preparation of D14-5
将332mg混合物D14-4、1.61g碳酸钾溶于MeOH(2mL)中，搅拌下加入745mg(1-重氮基-2-氧代丙基)膦酸二甲酯，室温搅拌1小时。TLC检测反应完全，过滤，滤饼用20mL乙酸乙酯洗涤，滤液真空浓缩，粗品经柱层析纯化得197mg白色固体，即D14-5。332 mg of the mixture D14-4 and 1.61 g of potassium carbonate were dissolved in MeOH (2 mL), 745 mg of (1-diazo-2-oxopropyl) dimethyl phosphonate was added with stirring, and the mixture was stirred at room temperature for 1 hour. TLC detected the completion of the reaction, filtered, the filter cake was washed with 20 mL of ethyl acetate, the filtrate was concentrated in vacuo, and the crude product was purified by column chromatography to obtain 197 mg of white solid, namely D14-5.
步骤6：D14-6的制备Step 6: Preparation of D14-6
将200mg混合物M1、102mg混合物D14-5、14mg PdCl 2(PPh 3) 2,3.9mg CuI溶于四氢呋喃(6mL)和三乙胺(1mL)中，氮气置换后，60℃反应12小时。LC-MS及TLC检测反应完全，加入20mL水，20mL二氯甲烷萃取，饱和食盐水洗涤，无水硫酸钠干燥，真空浓缩，粗品经制备板纯化得106mg黄色固体，即D14-6。 200 mg of mixture M1, 102 mg of mixture D14-5, 14 mg of PdCl 2 (PPh 3 ) 2 , and 3.9 mg of CuI were dissolved in tetrahydrofuran (6 mL) and triethylamine (1 mL). After nitrogen replacement, the mixture was reacted at 60° C. for 12 hours. LC-MS and TLC detect that the reaction is complete, add 20 mL of water, extract with 20 mL of dichloromethane, wash with saturated brine, dry with anhydrous sodium sulfate, and concentrate in vacuo. The crude product is purified by a preparation plate to obtain 106 mg of yellow solid, namely D14-6.
步骤7：D14-7的制备Step 7: Preparation of D14-7
将106mg混合物D14-6、2mg Parkin’s试剂溶于EtOH(3mL)和水(3mL)中，80℃反应12小时。LCMS和TLC检测反应完全，真空浓缩，加入20mL二氯甲烷，20mL水分散，饱和食盐水洗涤有机相，无水硫酸钠干燥，真空浓缩，粗品经制备板纯化得86mg淡黄色固体，即D14-7。106 mg of mixture D14-6 and 2 mg of Parkin’s reagent were dissolved in EtOH (3 mL) and water (3 mL), and reacted at 80°C for 12 hours. LCMS and TLC detected that the reaction was complete, concentrated in vacuo, added 20 mL of dichloromethane, dispersed in 20 mL of water, washed the organic phase with saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was purified by a preparation plate to obtain 86 mg of light yellow solid, namely D14- 7.
步骤8：D14的制备Step 8: Preparation of D14
将86mg混合物D14-7溶解于二氧六环(3mL)和乙醇(1.5mL)中，加入2N HCl(143.9μL，乙酸乙酯溶液)，RT搅拌反应1小时。LCMS和TLC检测反应完全，反应液减压浓缩。残余物加入H 2O(1.0mL)溶解，用饱和NaHCO 3调节溶液至pH＝8，二氯甲烷(3×3mL)萃取，有机相干燥后真空浓缩，经制备板纯化得40.2mg淡黄色固体即得D14。 86 mg of the mixture D14-7 was dissolved in dioxane (3 mL) and ethanol (1.5 mL), 2N HCl (143.9 μL, ethyl acetate solution) was added, and the reaction was stirred at RT for 1 hour. LCMS and TLC detected that the reaction was complete, and the reaction solution was concentrated under reduced pressure. Add H 2 O (1.0 mL) to dissolve the residue, adjust the solution to pH=8 with saturated NaHCO 3 , extract with dichloromethane (3×3 mL), dry the organic phase and concentrate in vacuo. Purify on a preparation plate to obtain 40.2 mg of pale yellow solid Get D14.
[M+H +]＝494.2。 [M+H + ]=494.2.
1H NMR(500MHz,DMSO--d 6)δ8.17(s,1H),7.92(s,1H),7.82–7.78(m,2H),7.33–7.23(m,4H),7.19–7.10(m,3H),5.39(t,J＝5.9Hz,1H),4.47(d,J＝5.8Hz,2H),3.84(s,1H),3.79–3.65(m,2H),3.21–2.99(m,3H),2.59(d,J＝15.6Hz,1H),2.03–1.94(m,2H),1.92–1.84(m,1H),1.81–1.72(m,1H),1.56–1.41(m,3H),1.15–1.07(m,1H). 1 H NMR(500MHz,DMSO--d 6 )δ8.17(s,1H),7.92(s,1H),7.82-7.78(m,2H),7.33-7.23(m,4H),7.19-7.10( m, 3H), 5.39 (t, J = 5.9 Hz, 1H), 4.47 (d, J = 5.8 Hz, 2H), 3.84 (s, 1H), 3.79-3.65 (m, 2H), 3.21-2.99 (m ,3H), 2.59(d,J=15.6Hz,1H),2.03–1.94(m,2H),1.92–1.84(m,1H),1.81–1.72(m,1H),1.56–1.41(m,3H) ), 1.15-1.07 (m, 1H).
药理试验Pharmacological test
实施例A：SHP2变构抑制酶活测定Example A: SHP2 allosteric inhibition enzyme activity assay
SHP2通过双-酪氨酰-磷酰化的肽与其Src同源2(SH2)结构域的结合而变构活化。该在后的活化步骤导致SHP2的自动抑制界面的释放，这又使该SHP2蛋白酪氨酸磷酸酶(PTP)活化并可用于底物识别和反应催化。在迅速荧光测定版式中使用替代物DiFMUP监测SHP2的催化活性。SHP2 is allosterically activated by the binding of a bis-tyrosyl-phosphorylated peptide to its Src homology 2 (SH2) domain. This subsequent activation step results in the release of the SHP2 auto-inhibitory interface, which in turn activates the SHP2 protein tyrosine phosphatase (PTP) and can be used for substrate recognition and reaction catalysis. The surrogate DiFMUP was used to monitor the catalytic activity of SHP2 in the rapid fluorescence assay format.
试验步骤：experiment procedure:
(1)化合物配制：(1) Compound preparation:
用100％DMSO将本发明化合物(10mM储液)稀释成合适倍数，本发明化合物最终测试浓度为10μM、3.3333μM、1.1111μM、0.3704μM、0.1235μM、0.0412μM、0.0137μM、0.0046μM、0.0015μM、0.00μM；The compound of the present invention (10mM stock solution) was diluted to an appropriate multiple with 100% DMSO. The final test concentration of the compound of the present invention was 10μM, 3.3333μM, 1.1111μM, 0.3704μM, 0.1235μM, 0.0412μM, 0.0137μM, 0.0046μM, 0.0015μM , 0.00μM;
(2)准备酶反应工作液：(2) Prepare working solution for enzyme reaction:
在室温下在96孔黑色聚苯乙烯板(平底、低凸缘、非结合表面)(Perki Elmer,Cat#6005270)中，使用50μL的最终反应体积和以下测定缓冲条件进行SHP2酶活检测：60mM HEPES，75mM NaCl，75mM KCl，0.05％BRIJ-35，1mM EDTA，5mM DTT。In a 96-well black polystyrene plate (flat bottom, low flange, non-binding surface) (Perki Elmer, Cat#6005270) at room temperature, use a final reaction volume of 50μL and the following assay buffer conditions for SHP2 enzyme activity detection: 60mM HEPES, 75mM NaCl, 75mM KCl, 0.05% BRIJ-35, 1mM EDTA, 5mM DTT.
(3)酶催化反应及数据监测：(3) Enzyme catalytic reaction and data monitoring:
取本发明化合物加到对应的96孔板中，设置不加化合物和酶只加缓冲液的做为空白试验孔。将SHP2Activating Peptide(IRS1_pY1172(dPEG8)pY1222)置于冰上融化，每孔加入25μM，然后取0.2ng SHP2蛋白样品加到对应孔板中，室温孵育1小时。加入替代底物DiFMUP(Invitrogen，Cat#D6567)加入反应，室温反应2小时后。采用分别使用340nm和450nm的激发波长和发射波长的酶标仪(Envision，Perki Elmer)监测荧光信号。Take the compound of the present invention and add it to the corresponding 96-well plate, and set the blank test well without adding the compound and enzyme and only adding buffer. Put SHP2Activating Peptide (IRS1_pY1172(dPEG8)pY1222) on ice to melt, add 25μM to each well, then add 0.2ng SHP2 protein sample to the corresponding well plate, and incubate at room temperature for 1 hour. The replacement substrate DiFMUP (Invitrogen, Cat#D6567) was added to the reaction, and the reaction was carried out at room temperature for 2 hours. The fluorescence signal was monitored by a microplate reader (Envision, Perki Elmer) with excitation wavelength and emission wavelength of 340nm and 450nm, respectively.
(4)数据分析：(4) Data analysis:
计算公式：Calculation formula:
抑制率％＝[1-(Conversion_ sample-Conversion_ min)/(Conversion_ max-Conversion_ min)]×100％ Inhibition rate%=[1-(Conversion_ sample -Conversion_ min )/(Conversion_ max -Conversion_ min )]×100%
其中：Conversion_sample是样品的转化率读数；Conversion_min是空白对照孔均值，代表没有酶活孔的转化率读数；Conversion_max是阳性对照孔比值均值，代表没有化合物抑制孔的转化率读数。采用分析软件GraphPad Prism的log(inhibitor)vs.response-Variable slope拟合量效曲线，并计算化合物对酶活性的IC 50值。 Among them: Conversion_sample is the conversion rate reading of the sample; Conversion_min is the average value of the blank control well, representing the conversion rate reading of the wells without enzyme activity; Conversion_max is the average value of the positive control wells, representing the conversion rate reading of the wells without compound inhibition. The analysis software GraphPad Prism log (inhibitor) vs. response-Variable slope was used to fit the dose-effect curve, and the IC 50 value of the compound to the enzyme activity was calculated.
部分实施例的IC 50数据如表9所示。 The IC 50 data of some examples are shown in Table 9.
表9Table 9
Figure PCTCN2021088871-appb-000089
Figure PCTCN2021088871-appb-000089
Figure PCTCN2021088871-appb-000090
Figure PCTCN2021088871-appb-000090
本发明的化合物对SHP2蛋白具有变构抑制作用。The compound of the present invention has an allosteric inhibitory effect on the SHP2 protein.
实施例B：细胞增殖试验Example B: Cell Proliferation Test
使用体外细胞试验评估本发明的化合物对白血病细胞MV-4-11和肺癌细胞NCI-H358细胞增殖的影响。试验中所用的检测方法是CELL TITER-GLO(CTG)发光法，该法可通过对ATP进行定量测定来检测活细胞数目。因为ATP参与生物体内多种酶促反应，是活细胞新陈代谢的一个指标，其含量直接反应了细胞的数量及细胞状态，实验过程中向细胞培养基加入CellTiter-Glo TM试剂，测量发光值，发光值与ATP量成正比，而ATP又和活细胞数正相关，因此可通过检测ATP含量考察细胞活力。 In vitro cell assays were used to evaluate the effects of the compounds of the present invention on the proliferation of leukemia cells MV-4-11 and lung cancer cells NCI-H358. The detection method used in the experiment is the CELL TITER-GLO (CTG) luminescence method, which can detect the number of living cells by quantitatively measuring ATP. Because ATP participates in a variety of enzymatic reactions in organisms and is an indicator of living cell metabolism, its content directly reflects the number and cell state of cells. During the experiment, CellTiter-Glo TM reagent was added to the cell culture medium to measure the luminescence value. The value is directly proportional to the amount of ATP, and ATP is positively related to the number of living cells, so cell viability can be inspected by detecting ATP content.
试验步骤：experiment procedure:
(1)细胞铺板：(1) Cell plating:
取一瓶对数生长期的MV-4-11细胞，收集细胞离心重悬，计数，调整细胞密度后接种到96孔板中，每孔接种4000个细胞，孔板置于37℃、5％CO 2的培养箱中培养24hrs后 加入本发明化合物进行处理； Take a bottle of MV-4-11 cells in logarithmic growth phase, collect the cells and resuspend them by centrifugation, count them, adjust the cell density and inoculate them into a 96-well plate, inoculate 4000 cells per well, and place the plate at 37°C, 5% After culturing in a CO 2 incubator for 24 hrs, the compound of the present invention is added for treatment;
取一瓶对数生长期的NCI-H358细胞，消化重悬细胞后计数，调整细胞密度后接种到96孔透明低吸附细胞培养板中，每孔接种2000个细胞，孔板置于37℃、5％CO 2的培养箱中培养24hrs后加入本发明化合物进行处理； Take a bottle of NCI-H358 cells in the logarithmic growth phase, digest and resuspend the cells, count them, adjust the cell density and inoculate them into a 96-well transparent low-adsorption cell culture plate, inoculate 2000 cells per well, and place the plate at 37℃, After culturing in a 5% CO 2 incubator for 24 hrs, the compound of the present invention is added for treatment;
(2)细胞化合物处理：(2) Cell compound treatment:
配取适量本发明化合物进行细胞处理，化合物终浓度从高至低依次为1000nM、333.3nM、111.1nM、37.04nM、12.35nM、4.115nM、1.372nM、0.4572nM、0.1524nM、0nM，孔板放入37℃,5％CO 2培养箱培养。只加培养基不加细胞孔设为调零组；化合物浓度为0nM组为空白组。 Prepare an appropriate amount of the compound of the present invention for cell treatment, and the final concentration of the compound from high to low is 1000nM, 333.3nM, 111.1nM, 37.04nM, 12.35nM, 4.115nM, 1.372nM, 0.4572nM, 0.1524nM, 0nM. Enter 37℃, 5% CO 2 incubator for culture. Only adding culture medium without adding cell wells is set as the zero adjustment group; the compound concentration of 0 nM group is the blank group.
(3)CTG检测：(3) CTG detection:
NCI-H358细胞培养96hrs后每孔加入50μL的
Figure PCTCN2021088871-appb-000091
Luminescent Cell Viability Assay溶液，轻轻震荡2mins，室温继续孵育10mins。细胞反应体系转移至白底96孔板中。在多功能酶标仪上读取各孔的检测数值。 After NCI-H358 cells were cultured for 96hrs, 50μL of
Figure PCTCN2021088871-appb-000091
Luminescent Cell Viability Assay solution, gently shake for 2mins, and continue to incubate for 10mins at room temperature. The cell reaction system was transferred to a 96-well plate with a white background. Read the detection value of each well on the multi-function microplate reader.
MV-4-11细胞培养120hrs后每孔加入50μL的
Figure PCTCN2021088871-appb-000092
Luminescent Cell Viability Assay溶液，轻轻震荡2mins，室温继续孵育10mins，在多功能酶标仪上读取各孔的检测数值。 After MV-4-11 cells are cultured for 120hrs, add 50μL to each well
Figure PCTCN2021088871-appb-000092
Luminescent Cell Viability Assay solution, gently shake for 2mins, continue to incubate for 10mins at room temperature, and read the detection value of each well on the multifunctional microplate reader.
(4)数据分析：(4) Data analysis:
根据发光值读数计算抑制率，Calculate the inhibition rate based on the luminous value reading,
抑制率％＝(1-(给药组值-调零组值)/(空白组值-调零组值)*100Inhibition rate%=(1-(administration group value-zero adjustment group value)/(blank group value-zero adjustment group value)*100
GraphPad Prism的log(inhibitor)vs.response-Variable slope拟合量效曲线并计算化合物抑制细胞增殖的IC 50。 GraphPad Prism the log (inhibitor) vs.response-Variable slope fitting dose-response curve and calculate IC 50 of compounds to inhibit cell proliferation.
实验数据如表10所示。The experimental data is shown in Table 10.
表10Table 10
Figure PCTCN2021088871-appb-000093
Figure PCTCN2021088871-appb-000093
Figure PCTCN2021088871-appb-000094
Figure PCTCN2021088871-appb-000094
注：“/”代表未检测。Note: "/" means not detected.
本发明的化合物对MV-4-11细胞和NCI-H358细胞的增殖具有良好的抑制作用。The compound of the present invention has a good inhibitory effect on the proliferation of MV-4-11 cells and NCI-H358 cells.
实施例C：MIA-PaCa2细胞皮下异种移植肿瘤模型上的体内药效实验Example C: In vivo drug efficacy experiment on subcutaneous xenograft tumor model of MIA-PaCa2 cells
BALB/c裸鼠，雌性，6-8周，体重约18-22克。每只小鼠在右后背皮下接种0.2mL(1×10 7个)MIA-PaCa2细胞(加基质胶，体积比为1:1)。当平均肿瘤体积达到约113立方毫米时开始给药。将试验化合物每日口服给药，给药剂量10mpk QD。肿瘤体积每周两次测量，体积以立方毫米计量，通过以下公式计算：V＝0.5a×b 2，其中a和b分别是肿瘤的长径和短径。 BALB/c nude mice, female, 6-8 weeks old, weighing about 18-22 grams. Each mouse was subcutaneously inoculated with 0.2 mL (1×10 7 cells) of MIA-PaCa2 cells (with Matrigel, volume ratio 1:1) on the right back. The administration was started when the average tumor volume reached approximately 113 cubic millimeters. The test compound was orally administered daily at a dose of 10 mpk QD. The tumor volume is measured twice a week, and the volume is measured in cubic millimeters, and calculated by the following formula: V=0.5a×b 2 , where a and b are the long diameter and short diameter of the tumor, respectively.
化合物的抑瘤疗效用TGI(％)评价。TGI(％)反映肿瘤生长抑制率。TGI(％)的计算：TGI(％)＝[(1-(某处理组给药结束时平均瘤体积－该处理组开始给药时平均瘤体积))/(溶剂对照组治疗结束时平均瘤体积－溶剂对照组开始治疗时平均瘤体积)]×100％。The anti-tumor efficacy of the compound was evaluated by TGI (%). TGI (%) reflects the tumor growth inhibition rate. Calculation of TGI(%): TGI(%)=[(1-(Average tumor volume at the end of a certain treatment group-average tumor volume at the beginning of the treatment group))/(Average tumor at the end of treatment in the solvent control group Volume-the average tumor volume at the start of treatment in the solvent control group)]×100%.
本发明化合物在MIA-PaCa2细胞皮下异种移植瘤模型中展示出显著的抑瘤作用。溶剂对照组和化合物A68在第24天时的TGI和体重变化如表11所示。The compound of the present invention exhibits a significant anti-tumor effect in a subcutaneous xenograft tumor model of MIA-PaCa2 cells. The TGI and body weight changes of the solvent control group and compound A68 on day 24 are shown in Table 11.
表11Table 11
分组Grouping TGI(％)TGI(%) 体重变化(％)Weight change (%)
溶剂对照组Solvent control group // 1313
化合物A68Compound A68 8787 1010
虽然本发明已通过其实施方式进行了全面的描述，但是值得注意的是，各种变化和修改对于本领域技术人员都是显而易见的。这样的变化和修改都应该包括在本发明所附权利要求的范围内。Although the present invention has been fully described through its embodiments, it is worth noting that various changes and modifications are obvious to those skilled in the art. Such changes and modifications should be included in the scope of the appended claims of the present invention.

Claims (48)

  1. 一种式I所示化合物，或其药学上可接受的盐、顺反异构体、互变异构体、溶剂化物、螯合物、非共价复合物或前体药物，所述化合物如式I所示：：A compound represented by formula I, or a pharmaceutically acceptable salt, cis-trans isomer, tautomer, solvate, chelate, non-covalent complex or prodrug thereof, wherein the compound is As shown in formula I:
    Figure PCTCN2021088871-appb-100001
    Figure PCTCN2021088871-appb-100001
    其中，in,
    Figure PCTCN2021088871-appb-100002
    为单键或双键；
    Figure PCTCN2021088871-appb-100002
    Single bond or double bond;
    环A选自5-10元杂芳基或5-10元杂环基；其中，所述5-10元杂芳基或所述5-10元杂环基含有一个或多个O、N或S杂原子；所述5-10元杂环基至少含有一个双键；Ring A is selected from a 5-10 membered heteroaryl group or a 5-10 membered heterocyclic group; wherein the 5-10 membered heteroaryl group or the 5-10 membered heterocyclic group contains one or more O, N or S heteroatom; the 5-10 membered heterocyclic group contains at least one double bond;
    环C选自C 3-10碳环基、3-10元杂环基、C 6-10芳基或5-10元杂芳基； Ring C is selected from C 3-10 carbocyclic group, 3-10 membered heterocyclic group, C 6-10 aryl group or 5-10 membered heteroaryl group;
    每个R c分别独立地选自氢、卤素、-CN、-NO 2、氧代、C 1-8烷基、C 2-8烯基、C 2-8炔基、C 3-8碳环基、3-10元杂环基、C 6-10芳基、5-10元杂芳基、-OR 5、-SR 6、-NR 7R 8、-(C＝O)R 9、-C(＝O)OR 10、-C(＝O)NR 11R 12、-S(＝O) 2R 13、-S(＝O) 2OR 14、-S(＝O) 2NR 15R 16、-O(CH 2) sOR 17、-O(CH 2) sNR 18R 19、-NR 20(CH 2) tNR 21R 22、-NR 23(CH 2) tOR 24；其中，所述C 1-8烷基、C 2-8烯基、C 2-8炔基、C 3-8碳环基、3-10元杂环基、C 6-10芳基、5-10元杂芳基任选地被一个或多个取代基取代；所述取代基选自氢、卤素、-CN、-NO 2、氧代、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 3-10碳环基、3-10元杂环基、C 6-10芳基、5-10元杂芳基、-OR 5、-SR 6、-NR 7R 8、-(C＝O)R 9、-C(＝O)OR 10、-C(＝O)NR 11R 12、-S(＝O) 2R 13、-S(＝O) 2OR 14、-S(＝O) 2NR 15R 16、-O(CH 2) sOR 17、-O(CH 2) sNR 18R 19、-NR 20(CH 2) tNR 21R 22、-NR 23(CH 2) tOR 24； Each R c is independently selected from hydrogen, halogen, -CN, -NO 2 , oxo, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 carbocyclic ring Group, 3-10 membered heterocyclic group, C 6-10 aryl group, 5-10 membered heteroaryl group, -OR 5 , -SR 6 , -NR 7 R 8 , -(C=O)R 9 , -C (=O)OR 10 , -C(=O)NR 11 R 12 , -S(=O) 2 R 13 , -S(=O) 2 OR 14 , -S(=O) 2 NR 15 R 16 , -O(CH 2 ) s OR 17 , -O(CH 2 ) s NR 18 R 19 , -NR 20 (CH 2 ) t NR 21 R 22 , -NR 23 (CH 2 ) t OR 24 ; wherein, the C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 carbocyclic group, 3-10 membered heterocyclic group, C 6-10 aryl, 5-10 membered heteroaryl The group is optionally substituted by one or more substituents; the substituents are selected from hydrogen, halogen, -CN, -NO 2 , oxo, C 1-4 alkyl, C 2-4 alkenyl, C 2- 4 alkynyl, C 3-10 carbocyclic group, 3-10 membered heterocyclic group, C 6-10 aryl, 5-10 membered heteroaryl, -OR 5 , -SR 6 , -NR 7 R 8 ,- (C=O)R 9 , -C(=O)OR 10 , -C(=O)NR 11 R 12 , -S(=O) 2 R 13 , -S(=O) 2 OR 14 , -S (=O) 2 NR 15 R 16 , -O(CH 2 ) s OR 17 , -O(CH 2 ) s NR 18 R 19 , -NR 20 (CH 2 ) t NR 21 R 22 , -NR 23 (CH 2 ) t OR 24 ;
    R c1,R c2分别独立地选自氢、卤素、C 1-4烷基或-OR 5； R c1 and R c2 are each independently selected from hydrogen, halogen, C 1-4 alkyl or -OR 5 ;
    或R c1和R c2与它们所连接的原子一起形成C 3-6碳环基、3-6元杂环基； Or R c1 and R c2 together with the atoms to which they are connected form a C 3-6 carbocyclic group or a 3-6 membered heterocyclic group;
    每个R 1分别独立地选自氢、卤素、-CN、-NO 2、氧代、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 3-6碳环基、3-6元杂环基、C 6-10芳基、5-10元杂芳基、-OR 5、-NR 7R 8、-O(CH 2) sOR 17、-O(CH 2) sNR 18R 19、-NR 20(CH 2) tNR 21R 22、-NR 23(CH 2) tOR 24；其中，所述C 1-4烷基、C 2-4烯基、C 2-4炔基、C 3-6碳环基、3-6元杂环基、C 6-10芳基、5-10元杂芳基任选地被一个或多个取代基取代；所述取代基选自氢、卤素、-CN、-NO 2、氧代、C 1-4烷基、C 2-4烯基、C 2-4炔基、 C 3-6碳环基、3-6元杂环基、C 6-10芳基、5-10元杂芳基、-OR 5、-SR 6、-NR 7R 8、-(C＝O)R 9、-C(＝O)OR 10或-C(＝O)NR 11R 12； Each R 1 is independently selected from hydrogen, halogen, -CN, -NO 2 , oxo, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 carbocyclic ring Group, 3-6 membered heterocyclic group, C 6-10 aryl group, 5-10 membered heteroaryl group, -OR 5 , -NR 7 R 8 , -O(CH 2 ) s OR 17 , -O(CH 2 ) s NR 18 R 19 , -NR 20 (CH 2 ) t NR 21 R 22 , -NR 23 (CH 2 ) t OR 24 ; wherein the C 1-4 alkyl group, C 2-4 alkenyl group, C 2-4 alkynyl, C 3-6 carbocyclic group, 3-6 membered heterocyclic group, C 6-10 aryl group, 5-10 membered heteroaryl group are optionally substituted by one or more substituents; Substituents are selected from hydrogen, halogen, -CN, -NO 2 , oxo, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 carbocyclic group, 3-6 Membered heterocyclic group, C 6-10 aryl group, 5-10 membered heteroaryl group, -OR 5 , -SR 6 , -NR 7 R 8 , -(C=O)R 9 , -C(=O)OR 10 or -C(=O)NR 11 R 12 ;
    M选自-O-、-NR 1a-或-CR 1bR 1c-； M is selected from -O-, -NR 1a -or -CR 1b R 1c -;
    R 1a选自氢、C 1-3烷基、C 3-6环烷基、3-6元杂环基或不存在； R 1a is selected from hydrogen, C 1-3 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group or not present;
    R 1b，R 1c分别独立地选自氢、C 1-3烷基、C 3-6环烷基、3-6元杂环基、-OR 1d、-NR 1eR 1f或不存在； R 1b and R 1c are each independently selected from hydrogen, C 1-3 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group, -OR 1d , -NR 1e R 1f or not present;
    R 1d，R 1e，R 1f分别独立地选自氢、C 1-3烷基、C 3-6环烷基或3-6元杂环基； R 1d , R 1e , and R 1f are each independently selected from hydrogen, C 1-3 alkyl, C 3-6 cycloalkyl or 3-6 membered heterocyclic group;
    Y 1选自-NR 3a-或-CR 3bR 3c-； Y 1 is selected from -NR 3a -or -CR 3b R 3c -;
    R 3a选自氢、C 1-3烷基、C 3-6环烷基、3-6元杂环基或不存在； R 3a is selected from hydrogen, C 1-3 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group or not present;
    R 3b，R 3c分别独立地选自氢、C 1-3烷基、C 3-6环烷基、3-6元杂环基或不存在； R 3b and R 3c are each independently selected from hydrogen, C 1-3 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group or not present;
    Y 2选自-NR 4a-或-CR 4bR 4c-； Y 2 is selected from -NR 4a -or -CR 4b R 4c -;
    R 4a选自氢、C 1-3烷基、C 3-6环烷基、3-6元杂环基或不存在； R 4a is selected from hydrogen, C 1-3 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group or not present;
    R 4b，R 4c分别独立地选自氢、C 1-3烷基、C 3-6环烷基、3-6元杂环基或不存在； R 4b and R 4c are each independently selected from hydrogen, C 1-3 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group or not present;
    所述环D为C 6-10芳基、5-10元杂芳基、C 3-8碳环基或3-8元杂环基；其中，所述C 3-8碳环基或3-8元杂环基选择性地含有双键； The ring D is a C 6-10 aryl group, a 5-10 membered heteroaryl group, a C 3-8 carbocyclic group or a 3-8 membered heterocyclic group; wherein, the C 3-8 carbocyclic group or a 3- The 8-membered heterocyclic group optionally contains a double bond;
    每个R 4分别独立地选自氢、卤素、-CN、-NO 2、氧代、C 1-8烷基、C 2-8烯基、C 2-8炔基、C 3-8碳环基、3-10元杂环基、C 6-10芳基、5-10元杂芳基、-OR 5、-SR 6、-NR 7R 8、-(C＝O)R 9、-C(＝O)OR 10、-C(＝O)NR 11R 12、-S(＝O) 2R 13、-S(＝O) 2OR 14、-S(＝O) 2NR 15R 16、-O(CH 2) sOR 17、-O(CH 2) sNR 18R 19、-NR 20(CH 2) tNR 21R 22、-NR 23(CH 2) tOR 24；其中，所述C 1-8烷基、C 2-8烯基、C 2-8炔基、C 3-8碳环基、3-10元杂环基、C 6-10芳基、5-10元杂芳基任选地被一个或多个取代基取代；所述取代基选自氢、卤素、-CN、-NO 2、氧代、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 3-10碳环基、3-10元杂环基、C 6-10芳基、5-10元杂芳基、-OR 5、-SR 6、-NR 7R 8、-(C＝O)R 9、-C(＝O)OR 10、-C(＝O)NR 11R 12、-S(＝O) 2R 13、-S(＝O) 2OR 14、-S(＝O) 2NR 15R 16、-O(CH 2) sOR 17、-O(CH 2) sNR 18R 19、-NR 20(CH 2) tNR 21R 22、-NR 23(CH 2) tOR 24； Each R 4 is independently selected from hydrogen, halogen, -CN, -NO 2 , oxo, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 carbocyclic ring Group, 3-10 membered heterocyclic group, C 6-10 aryl group, 5-10 membered heteroaryl group, -OR 5 , -SR 6 , -NR 7 R 8 , -(C=O)R 9 , -C (=O)OR 10 , -C(=O)NR 11 R 12 , -S(=O) 2 R 13 , -S(=O) 2 OR 14 , -S(=O) 2 NR 15 R 16 , -O(CH 2 ) s OR 17 , -O(CH 2 ) s NR 18 R 19 , -NR 20 (CH 2 ) t NR 21 R 22 , -NR 23 (CH 2 ) t OR 24 ; wherein, the C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 carbocyclic group, 3-10 membered heterocyclic group, C 6-10 aryl, 5-10 membered heteroaryl The group is optionally substituted by one or more substituents; the substituents are selected from hydrogen, halogen, -CN, -NO 2 , oxo, C 1-4 alkyl, C 2-4 alkenyl, C 2- 4 alkynyl, C 3-10 carbocyclic group, 3-10 membered heterocyclic group, C 6-10 aryl, 5-10 membered heteroaryl, -OR 5 , -SR 6 , -NR 7 R 8 ,- (C=O)R 9 , -C(=O)OR 10 , -C(=O)NR 11 R 12 , -S(=O) 2 R 13 , -S(=O) 2 OR 14 , -S (=O) 2 NR 15 R 16 , -O(CH 2 ) s OR 17 , -O(CH 2 ) s NR 18 R 19 , -NR 20 (CH 2 ) t NR 21 R 22 , -NR 23 (CH 2 ) t OR 24 ;
    R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12、R 13、R 14、R 15、R 16、R 17、R 18、R 19、R 20、R 21、R 22、-NR 23和R 24分别独立地选自氢、C 1-8烷基、C 2-8烯基、C 2-8炔基、C 3-8碳环基、3-10元杂环基、C 6-10芳基、5-10元杂芳基； R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , -NR 23 and R 24 are each independently selected from hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 carbocyclic group, 3-10 member Heterocyclic group, C 6-10 aryl group, 5-10 membered heteroaryl group;
    n为0、1、2或3；n is 0, 1, 2 or 3;
    p为0、1、2或3；p is 0, 1, 2 or 3;
    q为0、1、2、3或4；q is 0, 1, 2, 3 or 4;
    r为0、1、2、3或4；r is 0, 1, 2, 3 or 4;
    s为1、2、3或4；s is 1, 2, 3 or 4;
    t为1、2、3或4；t is 1, 2, 3 or 4;
    当n＝0、所述环A为
    Figure PCTCN2021088871-appb-100003
    且环C为苯基时，r不等于0，R c不为氢。     When n=0, the ring A is
    Figure PCTCN2021088871-appb-100003
    And when ring C is phenyl, r is not equal to 0, and R c is not hydrogen.
  2. 根据权利要求1所述的化合物，其特征在于，n为0或1。The compound of claim 1, wherein n is 0 or 1.
  3. 根据权利要求1或2所述的化合物，其特征在于，所述化合物选自式II：The compound according to claim 1 or 2, wherein the compound is selected from formula II:
    Figure PCTCN2021088871-appb-100004
    Figure PCTCN2021088871-appb-100004
    其中，in,
    Figure PCTCN2021088871-appb-100005
    为单键或双键；
    Figure PCTCN2021088871-appb-100005
    Single bond or double bond;
    环A选自5-10元杂芳基或5-10元杂环基；其中，所述5-10元杂芳基或所述5-10元杂环基含有一个或多个O、N或S杂原子；所述5-10元杂环基至少含有一个双键；Ring A is selected from a 5-10 membered heteroaryl group or a 5-10 membered heterocyclic group; wherein the 5-10 membered heteroaryl group or the 5-10 membered heterocyclic group contains one or more O, N or S heteroatom; the 5-10 membered heterocyclic group contains at least one double bond;
    环C选自C 3-10碳环基、3-10元杂环基、C 6-10芳基或5-10元杂芳基； Ring C is selected from C 3-10 carbocyclic group, 3-10 membered heterocyclic group, C 6-10 aryl group or 5-10 membered heteroaryl group;
    每个R c分别独立地选自氢、卤素、-CN、-NO 2、氧代、C 1-8烷基、C 2-8烯基、C 2-8炔基、C 3-8碳环基、3-10元杂环基、C 6-10芳基、5-10元杂芳基、-OR 5、-SR 6、-NR 7R 8、-(C＝O)R 9、-C(＝O)OR 10、-C(＝O)NR 11R 12、-S(＝O) 2R 13、-S(＝O) 2OR 14、-S(＝O) 2NR 15R 16、-O(CH 2) sOR 17、-O(CH 2) sNR 18R 19、-NR 20(CH 2) tNR 21R 22、-NR 23(CH 2) tOR 24；其中，所述C 1-8烷基、C 2-8烯基、C 2-8炔基、C 3-8碳环基、3-10元杂环基、C 6-10芳基、5-10元杂芳基任选地被一个或多个取代基取代；所述取代基选自氢、卤素、-CN、-NO 2、氧代、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 3-10碳环基、3-10元杂环基、C 6-10芳基、5-10元杂芳基、-OR 5、-SR 6、-NR 7R 8、-(C＝O)R 9、-C(＝O)OR 10、-C(＝O)NR 11R 12、-S(＝O) 2R 13、-S(＝O) 2OR 14、-S(＝O) 2NR 15R 16、-O(CH 2) sOR 17、-O(CH 2) sNR 18R 19、-NR 20(CH 2) tNR 21R 22、-NR 23(CH 2) tOR 24； Each R c is independently selected from hydrogen, halogen, -CN, -NO 2 , oxo, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 carbocyclic ring Group, 3-10 membered heterocyclic group, C 6-10 aryl group, 5-10 membered heteroaryl group, -OR 5 , -SR 6 , -NR 7 R 8 , -(C=O)R 9 , -C (=O)OR 10 , -C(=O)NR 11 R 12 , -S(=O) 2 R 13 , -S(=O) 2 OR 14 , -S(=O) 2 NR 15 R 16 , -O(CH 2 ) s OR 17 , -O(CH 2 ) s NR 18 R 19 , -NR 20 (CH 2 ) t NR 21 R 22 , -NR 23 (CH 2 ) t OR 24 ; wherein, the C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 carbocyclic group, 3-10 membered heterocyclic group, C 6-10 aryl, 5-10 membered heteroaryl The group is optionally substituted by one or more substituents; the substituents are selected from hydrogen, halogen, -CN, -NO 2 , oxo, C 1-4 alkyl, C 2-4 alkenyl, C 2- 4 alkynyl, C 3-10 carbocyclic group, 3-10 membered heterocyclic group, C 6-10 aryl, 5-10 membered heteroaryl, -OR 5 , -SR 6 , -NR 7 R 8 ,- (C=O)R 9 , -C(=O)OR 10 , -C(=O)NR 11 R 12 , -S(=O) 2 R 13 , -S(=O) 2 OR 14 , -S (=O) 2 NR 15 R 16 , -O(CH 2 ) s OR 17 , -O(CH 2 ) s NR 18 R 19 , -NR 20 (CH 2 ) t NR 21 R 22 , -NR 23 (CH 2 ) t OR 24 ;
    R c1,R c2分别独立地选自氢、卤素、C 1-4烷基或-OR 5； R c1 and R c2 are each independently selected from hydrogen, halogen, C 1-4 alkyl or -OR 5 ;
    或R c1和R c2与它们所连接的原子一起形成C 3-6碳环基、3-6元杂环基； Or R c1 and R c2 together with the atoms to which they are connected form a C 3-6 carbocyclic group or a 3-6 membered heterocyclic group;
    每个R 1分别独立地选自氢、卤素、-CN、-NO 2、氧代、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 3-6碳环基、3-6元杂环基、C 6-10芳基、5-10元杂芳基、-OR 5、-NR 7R 8、-O(CH 2) sOR 17、-O(CH 2) sNR 18R 19、-NR 20(CH 2) tNR 21R 22、-NR 23(CH 2) tOR 24；其中，所述C 1-4烷基、C 2-4烯基、C 2-4炔基、C 3-6碳环基、3-6元杂环基、C 6-10芳基、5-10元杂芳基任选地被一个或多个取代基取代；所述取代基选自氢、卤素、-CN、-NO 2、氧代、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 3-6碳环基、3-6元杂环基、C 6-10芳基、5-10元杂芳基、-OR 5、-SR 6、-NR 7R 8、-(C＝O)R 9、-C(＝O)OR 10或-C(＝O)NR 11R 12； Each R 1 is independently selected from hydrogen, halogen, -CN, -NO 2 , oxo, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 carbocyclic ring Group, 3-6 membered heterocyclic group, C 6-10 aryl group, 5-10 membered heteroaryl group, -OR 5 , -NR 7 R 8 , -O(CH 2 ) s OR 17 , -O(CH 2 ) s NR 18 R 19 , -NR 20 (CH 2 ) t NR 21 R 22 , -NR 23 (CH 2 ) t OR 24 ; wherein the C 1-4 alkyl group, C 2-4 alkenyl group, C 2-4 alkynyl, C 3-6 carbocyclic group, 3-6 membered heterocyclic group, C 6-10 aryl group, 5-10 membered heteroaryl group are optionally substituted by one or more substituents; Substituents are selected from hydrogen, halogen, -CN, -NO 2 , oxo, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 carbocyclic group, 3-6 Membered heterocyclic group, C 6-10 aryl group, 5-10 membered heteroaryl group, -OR 5 , -SR 6 , -NR 7 R 8 , -(C=O)R 9 , -C(=O)OR 10 or -C(=O)NR 11 R 12 ;
    M选自-O-、-NR 1a-或-CR 1bR 1c-； M is selected from -O-, -NR 1a -or -CR 1b R 1c -;
    R 1a选自氢、C 1-3烷基、C 3-6环烷基、3-6元杂环基或不存在； R 1a is selected from hydrogen, C 1-3 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group or not present;
    R 1b，R 1c分别独立地选自氢、C 1-3烷基、C 3-6环烷基、3-6元杂环基、-OR 1d、-NR 1eR 1f或不存在； R 1b and R 1c are each independently selected from hydrogen, C 1-3 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group, -OR 1d , -NR 1e R 1f or not present;
    R 1d，R 1e，R 1f分别独立地选自氢、C 1-3烷基、C 3-6环烷基或3-6元杂环基； R 1d , R 1e , and R 1f are each independently selected from hydrogen, C 1-3 alkyl, C 3-6 cycloalkyl or 3-6 membered heterocyclic group;
    Y 1选自-NR 3a-或-CR 3bR 3c-； Y 1 is selected from -NR 3a -or -CR 3b R 3c -;
    R 3a选自氢、C 1-3烷基、C 3-6环烷基、3-6元杂环基或不存在； R 3a is selected from hydrogen, C 1-3 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group or not present;
    R 3b，R 3c分别独立地选自氢、C 1-3烷基、C 3-6环烷基、3-6元杂环基或不存在； R 3b and R 3c are each independently selected from hydrogen, C 1-3 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group or not present;
    Y 2选自-NR 4a-或-CR 4bR 4c-； Y 2 is selected from -NR 4a -or -CR 4b R 4c -;
    R 4a选自氢、C 1-3烷基、C 3-6环烷基、3-6元杂环基或不存在； R 4a is selected from hydrogen, C 1-3 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group or not present;
    R 4b，R 4c分别独立地选自氢、C 1-3烷基、C 3-6环烷基、3-6元杂环基或不存在； R 4b and R 4c are each independently selected from hydrogen, C 1-3 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group or not present;
    所述环D为C 6-10芳基、5-10元杂芳基、C 3-8碳环基或3-8元杂环基；其中，所述C 3-8碳环基或3-8元杂环基选择性地含有双键； The ring D is a C 6-10 aryl group, a 5-10 membered heteroaryl group, a C 3-8 carbocyclic group or a 3-8 membered heterocyclic group; wherein, the C 3-8 carbocyclic group or a 3- The 8-membered heterocyclic group optionally contains a double bond;
    每个R 4分别独立地选自氢、卤素、-CN、-NO 2、氧代、C 1-8烷基、C 2-8烯基、C 2-8炔基、C 3-8碳环基、3-10元杂环基、C 6-10芳基、5-10元杂芳基、-OR 5、-SR 6、-NR 7R 8、-(C＝O)R 9、-C(＝O)OR 10、-C(＝O)NR 11R 12、-S(＝O) 2R 13、-S(＝O) 2OR 14、-S(＝O) 2NR 15R 16、-O(CH 2) sOR 17、-O(CH 2) sNR 18R 19、-NR 20(CH 2) tNR 21R 22、-NR 23(CH 2) tOR 24；其中，所述C 1-8烷基、C 2-8烯基、C 2-8炔基、C 3-8碳环基、3-10元杂环基、C 6-10芳基、5-10元杂芳基任选地被一个或多个取代基取代；所述取代基选自氢、卤素、-CN、-NO 2、氧代、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 3-10碳环基、3-10元杂环基、C 6-10芳基、5-10元杂芳基、-OR 5、-SR 6、-NR 7R 8、-(C＝O)R 9、-C(＝O)OR 10、-C(＝O)NR 11R 12、-S(＝O) 2R 13、-S(＝O) 2OR 14、-S(＝O) 2NR 15R 16、-O(CH 2) sOR 17、-O(CH 2) sNR 18R 19、-NR 20(CH 2) tNR 21R 22、-NR 23(CH 2) tOR 24； Each R 4 is independently selected from hydrogen, halogen, -CN, -NO 2 , oxo, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 carbocyclic ring Group, 3-10 membered heterocyclic group, C 6-10 aryl group, 5-10 membered heteroaryl group, -OR 5 , -SR 6 , -NR 7 R 8 , -(C=O)R 9 , -C (=O)OR 10 , -C(=O)NR 11 R 12 , -S(=O) 2 R 13 , -S(=O) 2 OR 14 , -S(=O) 2 NR 15 R 16 , -O(CH 2 ) s OR 17 , -O(CH 2 ) s NR 18 R 19 , -NR 20 (CH 2 ) t NR 21 R 22 , -NR 23 (CH 2 ) t OR 24 ; wherein, the C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 carbocyclic group, 3-10 membered heterocyclic group, C 6-10 aryl, 5-10 membered heteroaryl The group is optionally substituted by one or more substituents; the substituents are selected from hydrogen, halogen, -CN, -NO 2 , oxo, C 1-4 alkyl, C 2-4 alkenyl, C 2- 4 alkynyl, C 3-10 carbocyclic group, 3-10 membered heterocyclic group, C 6-10 aryl, 5-10 membered heteroaryl, -OR 5 , -SR 6 , -NR 7 R 8 ,- (C=O)R 9 , -C(=O)OR 10 , -C(=O)NR 11 R 12 , -S(=O) 2 R 13 , -S(=O) 2 OR 14 , -S (=O) 2 NR 15 R 16 , -O(CH 2 ) s OR 17 , -O(CH 2 ) s NR 18 R 19 , -NR 20 (CH 2 ) t NR 21 R 22 , -NR 23 (CH 2 ) t OR 24 ;
    R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12、R 13、R 14、R 15、R 16、R 17、R 18、R 19、R 20、R 21、R 22、-NR 23和R 24分别独立地选自氢、C 1-8烷基、C 2-8烯基、C 2-8炔基、C 3-8碳环基、3-10元杂环基、C 6-10芳基、5-10元杂芳基； R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , -NR 23 and R 24 are each independently selected from hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 carbocyclic group, 3-10 member Heterocyclic group, C 6-10 aryl group, 5-10 membered heteroaryl group;
    p为0、1、2或3；p is 0, 1, 2 or 3;
    q为0、1、2、3或4；q is 0, 1, 2, 3 or 4;
    r为0、1、2、3或4；r is 0, 1, 2, 3 or 4;
    s为1、2、3或4；s is 1, 2, 3 or 4;
    t为1、2、3或4。t is 1, 2, 3, or 4.
  4. 根据权利要求1-3任一项所述的化合物，其特征在于，R c1,R c2分别独立地选自氢、-CH 3、-F、-OH。 The compound according to any one of claims 1-3, wherein R c1 and R c2 are each independently selected from hydrogen, -CH 3 , -F, and -OH.
  5. 根据权利要求1-4任一项所述的化合物，其特征在于，R c1,R c2分别选自氢。 The compound according to any one of claims 1 to 4, wherein R c1 and R c2 are each selected from hydrogen.
  6. 根据权利要求1-3任一项所述的化合物，其特征在于，R c1,R c2与它们所连接的原子一起形成环丙基。 The compound according to any one of claims 1 to 3, wherein R c1 and R c2 together with the atoms to which they are attached form a cyclopropyl group.
  7. 根据权利要求1-6任一项所述的化合物，其特征在于，所述环C选自吗啉基、哌嗪基或哌啶基。The compound according to any one of claims 1-6, wherein the ring C is selected from morpholinyl, piperazinyl or piperidinyl.
  8. 根据权利要求1-6任一项所述的化合物，其特征在于，所述环C选自C 6-10芳基或5-10元杂芳基。 The compound according to any one of claims 1-6, wherein the ring C is selected from a C 6-10 aryl group or a 5-10 membered heteroaryl group.
  9. 根据权利要求1-6或8任一项所述的化合物，其特征在于，所述环C选自吡唑基、咪唑基、吡咯基、吡啶基、嘧啶基、吲哚基、吲哚啉基、异吲哚啉基、吲唑基、苯并咪唑基、嘌呤基、苯并异恶唑基或吲哚嗪基。The compound according to any one of claims 1-6 or 8, wherein the ring C is selected from the group consisting of pyrazolyl, imidazolyl, pyrrolyl, pyridyl, pyrimidinyl, indolyl, indolinyl , Isoindolinyl, indazolyl, benzimidazolyl, purinyl, benzisoxazolyl or indolazinyl.
  10. 根据权利要求1-6或8-9任一项所述的化合物，其特征在于，所述环C选自苯基、The compound according to any one of claims 1-6 or 8-9, wherein the ring C is selected from phenyl,
    Figure PCTCN2021088871-appb-100006
    Figure PCTCN2021088871-appb-100006
  11. 根据权利要求1-6或8-10任一项所述的化合物，其特征在于，所述环C选自苯基。The compound according to any one of claims 1-6 or 8-10, wherein the ring C is selected from phenyl.
  12. 根据权利要求1或2所述的化合物，其特征在于，所述化合物选自式III：The compound according to claim 1 or 2, wherein the compound is selected from formula III:
    Figure PCTCN2021088871-appb-100007
    Figure PCTCN2021088871-appb-100007
    其中，in,
    Figure PCTCN2021088871-appb-100008
    为单键或双键；
    Figure PCTCN2021088871-appb-100008
    Single bond or double bond;
    环A选自5-10元杂芳基或5-10元杂环基；其中，所述5-10元杂芳基或所述5-10元杂环基含有一个或多个O、N或S杂原子；所述5-10元杂环基至少含有一个双键；Ring A is selected from a 5-10 membered heteroaryl group or a 5-10 membered heterocyclic group; wherein the 5-10 membered heteroaryl group or the 5-10 membered heterocyclic group contains one or more O, N or S heteroatom; the 5-10 membered heterocyclic group contains at least one double bond;
    环C选自C 3-10碳环基、3-10元杂环基、C 6-10芳基或5-10元杂芳基； Ring C is selected from C 3-10 carbocyclic group, 3-10 membered heterocyclic group, C 6-10 aryl group or 5-10 membered heteroaryl group;
    每个R c分别独立地选自氢、卤素、-CN、-NO 2、氧代、C 1-8烷基、C 2-8烯基、C 2-8炔基、C 3-8碳环基、3-10元杂环基、C 6-10芳基、5-10元杂芳基、-OR 5、-SR 6、-NR 7R 8、-(C＝O)R 9、-C(＝O)OR 10、-C(＝O)NR 11R 12、-S(＝O) 2R 13、-S(＝O) 2OR 14、-S(＝O) 2NR 15R 16、-O(CH 2) sOR 17、-O(CH 2) sNR 18R 19、-NR 20(CH 2) tNR 21R 22、-NR 23(CH 2) tOR 24；其中，所述C 1-8烷基、C 2-8烯基、C 2-8炔基、C 3-8碳环基、3-10元杂环基、C 6-10芳基、5-10元杂芳基任选地被一个或多个取代基取代；所述取代基选自氢、卤素、-CN、-NO 2、氧代、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 3-10碳环基、3-10元杂环基、C 6-10芳基、5-10元杂芳基、-OR 5、-SR 6、-NR 7R 8、-(C＝O)R 9、-C(＝O)OR 10、-C(＝O)NR 11R 12、-S(＝O) 2R 13、-S(＝O) 2OR 14、-S(＝O) 2NR 15R 16、-O(CH 2) sOR 17、-O(CH 2) sNR 18R 19、-NR 20(CH 2) tNR 21R 22、-NR 23(CH 2) tOR 24； Each R c is independently selected from hydrogen, halogen, -CN, -NO 2 , oxo, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 carbocyclic ring Group, 3-10 membered heterocyclic group, C 6-10 aryl group, 5-10 membered heteroaryl group, -OR 5 , -SR 6 , -NR 7 R 8 , -(C=O)R 9 , -C (=O)OR 10 , -C(=O)NR 11 R 12 , -S(=O) 2 R 13 , -S(=O) 2 OR 14 , -S(=O) 2 NR 15 R 16 , -O(CH 2 ) s OR 17 , -O(CH 2 ) s NR 18 R 19 , -NR 20 (CH 2 ) t NR 21 R 22 , -NR 23 (CH 2 ) t OR 24 ; wherein, the C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 carbocyclic group, 3-10 membered heterocyclic group, C 6-10 aryl, 5-10 membered heteroaryl The group is optionally substituted by one or more substituents; the substituents are selected from hydrogen, halogen, -CN, -NO 2 , oxo, C 1-4 alkyl, C 2-4 alkenyl, C 2- 4 alkynyl, C 3-10 carbocyclic group, 3-10 membered heterocyclic group, C 6-10 aryl, 5-10 membered heteroaryl, -OR 5 , -SR 6 , -NR 7 R 8 ,- (C=O)R 9 , -C(=O)OR 10 , -C(=O)NR 11 R 12 , -S(=O) 2 R 13 , -S(=O) 2 OR 14 , -S (=O) 2 NR 15 R 16 , -O(CH 2 ) s OR 17 , -O(CH 2 ) s NR 18 R 19 , -NR 20 (CH 2 ) t NR 21 R 22 , -NR 23 (CH 2 ) t OR 24 ;
    每个R 1分别独立地选自氢、卤素、-CN、-NO 2、氧代、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 3-6碳环基、3-6元杂环基、C 6-10芳基、5-10元杂芳基、-OR 5、-NR 7R 8、-O(CH 2) sOR 17、-O(CH 2) sNR 18R 19、-NR 20(CH 2) tNR 21R 22、-NR 23(CH 2) tOR 24；其中，所述C 1-4烷基、C 2-4烯基、C 2-4炔基、C 3-6碳环基、3-6元杂环基、C 6-10芳基、5-10元杂芳基任选地被一个或多个取代基取代；所述取代基选自氢、卤素、-CN、-NO 2、氧代、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 3-6碳环基、3-6元杂环基、C 6-10芳基、5-10元杂芳基、-OR 5、-SR 6、-NR 7R 8、-(C＝O)R 9、-C(＝O)OR 10或-C(＝O)NR 11R 12； Each R 1 is independently selected from hydrogen, halogen, -CN, -NO 2 , oxo, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 carbocyclic ring Group, 3-6 membered heterocyclic group, C 6-10 aryl group, 5-10 membered heteroaryl group, -OR 5 , -NR 7 R 8 , -O(CH 2 ) s OR 17 , -O(CH 2 ) s NR 18 R 19 , -NR 20 (CH 2 ) t NR 21 R 22 , -NR 23 (CH 2 ) t OR 24 ; wherein the C 1-4 alkyl group, C 2-4 alkenyl group, C 2-4 alkynyl, C 3-6 carbocyclic group, 3-6 membered heterocyclic group, C 6-10 aryl group, 5-10 membered heteroaryl group are optionally substituted by one or more substituents; Substituents are selected from hydrogen, halogen, -CN, -NO 2 , oxo, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 carbocyclic group, 3-6 Membered heterocyclic group, C 6-10 aryl group, 5-10 membered heteroaryl group, -OR 5 , -SR 6 , -NR 7 R 8 , -(C=O)R 9 , -C(=O)OR 10 or -C(=O)NR 11 R 12 ;
    M选自-O-、-NR 1a-或-CR 1bR 1c-； M is selected from -O-, -NR 1a -or -CR 1b R 1c -;
    R 1a选自氢、C 1-3烷基、C 3-6环烷基、3-6元杂环基或不存在； R 1a is selected from hydrogen, C 1-3 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group or not present;
    R 1b，R 1c分别独立地选自氢、C 1-3烷基、C 3-6环烷基、3-6元杂环基、-OR 1d、-NR 1eR 1f或不存在； R 1b and R 1c are each independently selected from hydrogen, C 1-3 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group, -OR 1d , -NR 1e R 1f or not present;
    R 1d，R 1e，R 1f分别独立地选自氢、C 1-3烷基、C 3-6环烷基或3-6元杂环基； R 1d , R 1e , and R 1f are each independently selected from hydrogen, C 1-3 alkyl, C 3-6 cycloalkyl or 3-6 membered heterocyclic group;
    Y 1选自-NR 3a-或-CR 3bR 3c-； Y 1 is selected from -NR 3a -or -CR 3b R 3c -;
    R 3a选自氢、C 1-3烷基、C 3-6环烷基、3-6元杂环基或不存在； R 3a is selected from hydrogen, C 1-3 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group or not present;
    R 3b，R 3c分别独立地选自氢、C 1-3烷基、C 3-6环烷基、3-6元杂环基或不存在； R 3b and R 3c are each independently selected from hydrogen, C 1-3 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group or not present;
    Y 2选自-NR 4a-或-CR 4bR 4c-； Y 2 is selected from -NR 4a -or -CR 4b R 4c -;
    R 4a选自氢、C 1-3烷基、C 3-6环烷基、3-6元杂环基或不存在； R 4a is selected from hydrogen, C 1-3 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group or not present;
    R 4b，R 4c分别独立地选自氢、C 1-3烷基、C 3-6环烷基、3-6元杂环基或不存在； R 4b and R 4c are each independently selected from hydrogen, C 1-3 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group or not present;
    所述环D为C 6-10芳基、5-10元杂芳基、C 3-8碳环基或3-8元杂环基；其中，所述C 3-8碳环基或3-8元杂环基选择性地含有双键； The ring D is a C 6-10 aryl group, a 5-10 membered heteroaryl group, a C 3-8 carbocyclic group or a 3-8 membered heterocyclic group; wherein, the C 3-8 carbocyclic group or a 3- The 8-membered heterocyclic group optionally contains a double bond;
    每个R 4分别独立地选自氢、卤素、-CN、-NO 2、氧代、C 1-8烷基、C 2-8烯基、C 2-8炔基、C 3-8碳环基、3-10元杂环基、C 6-10芳基、5-10元杂芳基、-OR 5、-SR 6、-NR 7R 8、-(C＝O)R 9、-C(＝O)OR 10、-C(＝O)NR 11R 12、-S(＝O) 2R 13、-S(＝O) 2OR 14、-S(＝O) 2NR 15R 16、-O(CH 2) sOR 17、-O(CH 2) sNR 18R 19、-NR 20(CH 2) tNR 21R 22、-NR 23(CH 2) tOR 24；其中，所述C 1-8烷基、C 2-8烯基、C 2-8炔基、C 3-8碳环基、3-10元杂环基、C 6-10芳基、5-10元杂芳基任选地被一个或多个取代基取代；所述取代基选自氢、卤素、-CN、-NO 2、氧代、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 3-10碳环基、3-10元杂环基、C 6-10芳基、5-10元杂芳基、-OR 5、-SR 6、-NR 7R 8、-(C＝O)R 9、-C(＝O)OR 10、-C(＝O)NR 11R 12、-S(＝O) 2R 13、-S(＝O) 2OR 14、-S(＝O) 2NR 15R 16、-O(CH 2) sOR 17、-O(CH 2) sNR 18R 19、-NR 20(CH 2) tNR 21R 22、-NR 23(CH 2) tOR 24； Each R 4 is independently selected from hydrogen, halogen, -CN, -NO 2 , oxo, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 carbocyclic ring Group, 3-10 membered heterocyclic group, C 6-10 aryl group, 5-10 membered heteroaryl group, -OR 5 , -SR 6 , -NR 7 R 8 , -(C=O)R 9 , -C (=O)OR 10 , -C(=O)NR 11 R 12 , -S(=O) 2 R 13 , -S(=O) 2 OR 14 , -S(=O) 2 NR 15 R 16 , -O(CH 2 ) s OR 17 , -O(CH 2 ) s NR 18 R 19 , -NR 20 (CH 2 ) t NR 21 R 22 , -NR 23 (CH 2 ) t OR 24 ; wherein, the C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 carbocyclic group, 3-10 membered heterocyclic group, C 6-10 aryl, 5-10 membered heteroaryl The group is optionally substituted by one or more substituents; the substituents are selected from hydrogen, halogen, -CN, -NO 2 , oxo, C 1-4 alkyl, C 2-4 alkenyl, C 2- 4 alkynyl, C 3-10 carbocyclic group, 3-10 membered heterocyclic group, C 6-10 aryl, 5-10 membered heteroaryl, -OR 5 , -SR 6 , -NR 7 R 8 ,- (C=O)R 9 , -C(=O)OR 10 , -C(=O)NR 11 R 12 , -S(=O) 2 R 13 , -S(=O) 2 OR 14 , -S (=O) 2 NR 15 R 16 , -O(CH 2 ) s OR 17 , -O(CH 2 ) s NR 18 R 19 , -NR 20 (CH 2 ) t NR 21 R 22 , -NR 23 (CH 2 ) t OR 24 ;
    R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12、R 13、R 14、R 15、R 16、R 17、R 18、R 19、R 20、R 21、R 22、-NR 23和R 24分别独立地选自氢、C 1-8烷基、C 2-8烯基、C 2-8炔基、C 3-8碳环基、3-10元杂环基、C 6-10芳基、5-10元杂芳基； R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , -NR 23 and R 24 are each independently selected from hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 carbocyclic group, 3-10 member Heterocyclic group, C 6-10 aryl group, 5-10 membered heteroaryl group;
    p为0、1、2或3；p is 0, 1, 2 or 3;
    q为0、1、2、3或4；q is 0, 1, 2, 3 or 4;
    r为0、1、2、3或4；r is 0, 1, 2, 3 or 4;
    s为1、2、3或4；s is 1, 2, 3 or 4;
    t为1、2、3或4；t is 1, 2, 3 or 4;
    当环A为
    Figure PCTCN2021088871-appb-100009
    且环C为苯基时，r不等于0，R c不为氢。     When ring A is
    Figure PCTCN2021088871-appb-100009
    And when ring C is phenyl, r is not equal to 0, and R c is not hydrogen.
  13. 根据权利要求12所述的化合物，其特征在于，所述环C选自C 3-10碳环基或3-10元杂环基。 The compound according to claim 12, wherein the ring C is selected from C 3-10 carbocyclic group or 3-10 membered heterocyclic group.
  14. 根据权利要求12或13所述的化合物，其特征在于，所述环C选自环丙基、环丁基、环戊基、环己基、吗啉基、哌嗪基或哌啶基。The compound according to claim 12 or 13, wherein the ring C is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, morpholinyl, piperazinyl or piperidinyl.
  15. 根据权利要求1-14任一项所述的化合物，其特征在于，环A选自
    Figure PCTCN2021088871-appb-100010
    其中，X 1，X 2分别独立地选自选自-NR 1-或-CR 1R 1-。     The compound according to any one of claims 1-14, wherein ring A is selected from
    Figure PCTCN2021088871-appb-100010
    Wherein, X 1 and X 2 are each independently selected from -NR 1 -or -CR 1 R 1 -.
  16. 根据权利要求1-15所述的化合物，其特征在于，环A选自
    Figure PCTCN2021088871-appb-100011
    The compound of claims 1-15, wherein ring A is selected from
    Figure PCTCN2021088871-appb-100011
  17. 根据权利要求1-15所述的化合物，其特征在于，环A选自
    Figure PCTCN2021088871-appb-100012
    The compound of claims 1-15, wherein ring A is selected from
    Figure PCTCN2021088871-appb-100012
  18. 根据权利要求1-17任一项所述的化合物，其特征在于，所述环DD为C 6-10芳基或5-10元杂芳基。 The compound according to any one of claims 1-17, wherein the ring DD is a C 6-10 aryl group or a 5-10 membered heteroaryl group.
  19. 根据权利要求1-18任一项所述的化合物，其特征在于，所述环D为
    Figure PCTCN2021088871-appb-100013
    Figure PCTCN2021088871-appb-100014
    The compound of any one of claims 1-18, wherein the ring D is
    Figure PCTCN2021088871-appb-100013
    Figure PCTCN2021088871-appb-100014
  20. 根据权利要求1-19任一项所述的化合物，其特征在于，所述环D为
    Figure PCTCN2021088871-appb-100015
    The compound of any one of claims 1-19, wherein the ring D is
    Figure PCTCN2021088871-appb-100015
  21. 根据权利要求1-20任一项所述的化合物，其特征在于，每个R c分别独立地选自氢、卤素、-CN、-NO 2、氧代、C 1-8烷基、C 2-8烯基、C 2-8炔基、C 3-8碳环基、3-10元杂环基、C 6-10芳基、5-10元杂芳基、-OR 5、-SR 6、-NR 7R 8、-(C＝O)R 9、-C(＝O)OR 10、-C(＝O)NR 11R 12、-S(＝O) 2R 13、-S(＝O) 2OR 14、-S(＝O) 2NR 15R 16、-O(CH 2) sOR 17、-O(CH 2) sNR 18R 19、- NR 20(CH 2) tNR 21R 22、-NR 23(CH 2) tOR 24；其中，所述C 1-8烷基、C 2-8烯基、C 2-8炔基、C 3-8碳环基、3-10元杂环基、C 6-10芳基、5-10元杂芳基任选地被一个或多个取代基取代；所述取代基选自氢、卤素、-CN、-NO 2、氧代、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 3-10碳环基、3-10元杂环基、C 6-10芳基、5-10元杂芳基、-OR 5、-SR 6、-NR 7R 8、-(C＝O)R 9、-C(＝O)OR 10、-C(＝O)NR 11R 12、-S(＝O) 2R 13、-S(＝O) 2OR 14、-S(＝O) 2NR 15R 16、-O(CH 2) sOR 17、-O(CH 2) sNR 18R 19、-NR 20(CH 2) tNR 21R 22或-NR 23(CH 2) tOR 24。 The compound according to any one of claims 1-20, wherein each R c is independently selected from hydrogen, halogen, -CN, -NO 2 , oxo, C 1-8 alkyl, C 2 -8 alkenyl, C 2-8 alkynyl, C 3-8 carbocyclic group, 3-10 membered heterocyclic group, C 6-10 aryl, 5-10 membered heteroaryl, -OR 5 , -SR 6 , -NR 7 R 8 , -(C=O)R 9 , -C(=O)OR 10 , -C(=O)NR 11 R 12 , -S(=O) 2 R 13 , -S(= O) 2 OR 14 , -S(=O) 2 NR 15 R 16 , -O(CH 2 ) s OR 17 , -O(CH 2 ) s NR 18 R 19 ,-NR 20 (CH 2 ) t NR 21 R 22 , -NR 23 (CH 2 ) t OR 24 ; wherein, the C 1-8 alkyl group, C 2-8 alkenyl group, C 2-8 alkynyl group, C 3-8 carbocyclic group, 3-10 The membered heterocyclic group, C 6-10 aryl group, 5-10 membered heteroaryl group are optionally substituted by one or more substituents; the substituents are selected from hydrogen, halogen, -CN, -NO 2 , oxo , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-10 carbocyclic group, 3-10 membered heterocyclic group, C 6-10 aryl, 5-10 membered hetero Aryl, -OR 5 , -SR 6 , -NR 7 R 8 , -(C=O)R 9 , -C(=O)OR 10 , -C(=O)NR 11 R 12 , -S(= O) 2 R 13 , -S(=O) 2 OR 14 , -S(=O) 2 NR 15 R 16 , -O(CH 2 ) s OR 17 , -O(CH 2 ) s NR 18 R 19 , -NR 20 (CH 2 ) t NR 21 R 22 or -NR 23 (CH 2 ) t OR 24 .
  22. 根据权利要求1-21任一项所述的化合物，其特征在于，所述每个R c分别独立地选自氢、氧代、-NO 2、-CH 3、-OCH 3、-OH、-CN、-F、-Cl、-CF 3、-NH 2、-NHCH 3、-NHC(＝O)CH 3、-C(＝O)NH 2、-CH 2OH、-COOH、-COOEt、-S(＝O) 2CH 3、-S(＝O) 2NH 2、-CH 2OCH 3、
    Figure PCTCN2021088871-appb-100016
    Figure PCTCN2021088871-appb-100017
    The compound according to any one of claims 1-21, wherein each R c is independently selected from hydrogen, oxo, -NO 2 , -CH 3 , -OCH 3 , -OH,- CN, -F, -Cl, -CF 3 , -NH 2 , -NHCH 3 , -NHC(=O)CH 3 , -C(=O)NH 2 , -CH 2 OH, -COOH, -COOEt,- S(=O) 2 CH 3 , -S(=O) 2 NH 2 , -CH 2 OCH 3 ,
    Figure PCTCN2021088871-appb-100016
    Figure PCTCN2021088871-appb-100017
  23. 根据权利要求1-22任一项所述的化合物，其特征在于，每个R 1分别独立地选自氢、卤素、氧代、C 1-4烷基、-NR 7R 8；其中，所述C 1-4烷基任选地被一个或多个取代基取代；所述取代基选自氢、卤素、-CN、-NO 2、氧代、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 3-6碳环基、3-6元杂环基、C 6-10芳基、5-10元杂芳基、-OR 5、-SR 6、-NR 7R 8、-(C＝O)R 9、-C(＝O)OR 10或-C(＝O)NR 11R 12。 The compound according to any one of claims 1-22, wherein each R 1 is independently selected from hydrogen, halogen, oxo, C 1-4 alkyl, -NR 7 R 8 ; wherein The C 1-4 alkyl is optionally substituted by one or more substituents; the substituent is selected from hydrogen, halogen, -CN, -NO 2 , oxo, C 1-4 alkyl, C 2-4 Alkenyl, C 2-4 alkynyl, C 3-6 carbocyclic group, 3-6 membered heterocyclic group, C 6-10 aryl, 5-10 membered heteroaryl, -OR 5 , -SR 6 ,- NR 7 R 8 , -(C=O)R 9 , -C(=O)OR 10 or -C(=O)NR 11 R 12 .
  24. 根据权利要求1-23任一项所述的化合物，其特征在于，所述每个R 1分别独立地选自氢、氧代、-CH 3、-NH 2、-CH 2OH。 The compound according to any one of claims 1-23, wherein each R 1 is independently selected from hydrogen, oxo, -CH 3 , -NH 2 , and -CH 2 OH.
  25. 根据权利要求1-24任一项所述的化合物，其特征在于，M选自-O-或-CR 1bR 1c-。 The compound according to any one of claims 1-24, wherein M is selected from -O- or -CR 1b R 1c -.
  26. 根据权利要求1-25任一项所述的化合物，其特征在于，R 1b，R 1c分别独立地选自氢、C 1-3烷基、C 3-6环烷基、3-6元杂环基、-OR 1d或-NR 1eR 1f。 The compound according to any one of claims 1-25, wherein R 1b and R 1c are independently selected from hydrogen, C 1-3 alkyl, C 3-6 cycloalkyl, 3-6 membered hetero Cyclic group, -OR 1d or -NR 1e R 1f .
  27. 根据权利要求1-26任一项所述的化合物，其特征在于，Y 1选自-CR 3bR 3c-，Y 2选自-CR 4bR 4c-。 The compound according to any one of claims 1-26, wherein Y 1 is selected from -CR 3b R 3c -, and Y 2 is selected from -CR 4b R 4c -.
  28. 根据权利要求1-27任一项所述的化合物，其特征在于，每个R 4分别独立地选自氢、卤素、氧代、C 1-8烷基或-OR 5。 The compound according to any one of claims 1-27, wherein each R 4 is independently selected from hydrogen, halogen, oxo, C 1-8 alkyl, or -OR 5 .
  29. 根据权利要求1-28任一项所述的化合物，其特征在于，每个R 4分别独立地选自氢、氧代、-CH 3或-OCH 3。 The compound of any one of claims 1-28, wherein each R 4 is independently selected from hydrogen, oxo, -CH 3 or -OCH 3 .
  30. 根据权利要求1-29任一项所述的化合物，其特征在于，p为1、2或3。The compound of any one of claims 1-29, wherein p is 1, 2, or 3.
  31. 根据权利要求1-30任一项所述的化合物，其特征在于，q为0、1或2。The compound according to any one of claims 1-30, wherein q is 0, 1, or 2.
  32. 根据权利要求1-31任一项所述的化合物，其特征在于，r为0、1、2或3。The compound of any one of claims 1-31, wherein r is 0, 1, 2, or 3.
  33. 根据权利要求1-32任一项所述的化合物，其特征在于，s为1或2。The compound according to any one of claims 1-32, wherein s is 1 or 2.
  34. 根据权利要求1-34任一项所述的化合物，其特征在于，t为1或2。The compound according to any one of claims 1-34, wherein t is 1 or 2.
  35. 根据权利要求1所述的化合物，其特征在于，所述化合物选自：The compound of claim 1, wherein the compound is selected from:
    3-(5-((S)-1-氨基-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-6-(羟甲基)吡嗪-2-基)-1-苯丙-2-炔-1-醇；3-(5-((S)-1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(hydroxymethyl)pyrazine-2 -Base)-1-phenylprop-2-yn-1-ol;
    (S)-(3-(1-氨基-1,3-二氢螺并[茚-2,4'-哌啶]-1'-基)-6-(3-苯基丙-1-炔-1-基)吡嗪-2-基)甲醇；(S)-(3-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(3-phenylprop-1-yne -1-yl)pyrazin-2-yl)methanol;
    (S)-3-(3-(5-(1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-6-(羟甲基)吡嗪-2-基)丙-2-炔-1-基)苯酚；(S)-3-(3-(5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(hydroxymethyl) Pyrazin-2-yl)prop-2-yn-1-yl)phenol;
    (S)-(3-(1-氨基-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-6-(3-吗啉代丙-1-炔-1-基)吡嗪-2-基)甲醇；(S)-(3-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(3-morpholinoprop-1-yne -1-yl)pyrazin-2-yl)methanol;
    (S)-(3-(1-氨基-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-6-(3-(4-甲基哌嗪-1-基)丙-1-炔-1-基)吡嗪-2-基)甲醇；(S)-(3-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(3-(4-methylpiperazine- 1-yl)prop-1-yn-1-yl)pyrazin-2-yl)methanol;
    (S)-(3-(1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-6-(3-(4-甲氧基苯基)丙基-1-基)吡嗪-2-基)甲醇；(S)-(3-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(3-(4-methoxybenzene (Yl)propyl-1-yl)pyrazin-2-yl)methanol;
    (S)-(3-(1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-6-(3-(1-甲基-1H-吡唑-5-基)丙-1-炔-1-基)吡嗪-2-基)甲醇；(S)-(3-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(3-(1-methyl-1H -Pyrazol-5-yl)prop-1-yn-1-yl)pyrazin-2-yl)methanol;
    (S)-4-(3-(5-(1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-6-(羟甲基)吡嗪-2-基)丙-2-炔-1-基)苯酚；(S)-4-(3-(5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(hydroxymethyl) Pyrazin-2-yl)prop-2-yn-1-yl)phenol;
    (S)-2-(1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-5-(3-(4-羟基苯基)丙-1-炔-1-基)-3-甲基嘧啶-4(3H)-酮；(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(4-hydroxyphenyl)propane -1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;
    (S)-2-(1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-5-(3-(4-氯-3-羟基苯基)丙-1-炔-1-基)-3-甲基嘧啶-4(3H)-酮；(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(4-chloro-3-hydroxyl (Phenyl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;
    (S)-2-(1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-5-(3-(3-羟基苯基)丙-1-炔-1-基)-3-甲基嘧啶-4(3H)-酮；(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(3-hydroxyphenyl)propane -1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;
    (S)-2-(1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-5-(3-(3,4-二羟基苯基)丙-1-炔-1-基)-3-甲基嘧啶-4(3H)-酮；(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(3,4-dihydroxybenzene (Yl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;
    (S)-2-(1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-5-(3-(4-氟-3-羟基苯基)丙-1-炔-1-基)-3-甲基嘧啶-4(3H)-酮；(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(4-fluoro-3-hydroxyl (Phenyl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;
    (S)-3-(3-(2-(1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-1-甲基-6-氧代-1,6-二氢嘧啶-5-基)丙-2-炔-1-基)苯甲腈；(S)-3-(3-(2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-1-methyl-6- Oxo-1,6-dihydropyrimidin-5-yl)prop-2-yn-1-yl)benzonitrile;
    (S)-2-(1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-3-甲基-5-(3-(2-(三氟甲基)吡啶-3-基)丙-1-炔-1-基)嘧啶-4(3H)-酮；(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-3-methyl-5-(3-(2- (Trifluoromethyl)pyridin-3-yl)prop-1-yn-1-yl)pyrimidin-4(3H)-one;
    (S)-2-(1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-3-甲基-5-(3-(三氟甲基)苯基)丙-1-炔-1-基)嘧啶-4(3H)-酮；(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-3-methyl-5-(3-(trifluoro (Methyl)phenyl)prop-1-yn-1-yl)pyrimidin-4(3H)-one;
    (S)-2-(1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-5-(3-(3-甲氧基苯基)丙-1-炔-1-基)-3-甲基嘧啶-4(3H)-酮；(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(3-methoxyphenyl )Prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;
    (S)-2-(1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-5-(3-(3,4-二氟苯基)丙-1-炔-1-基)-3-甲基嘧啶-4(3H)-酮；(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(3,4-difluorobenzene (Yl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;
    (R)-2-(1-氨基-8-氮杂螺[4.5]癸-8-基)-5-(3-(3-羟基苯基)丙-1-炔-1-基)-3-甲基嘧啶-4(3H)-酮；(R)-2-(1-Amino-8-azaspiro[4.5]dec-8-yl)-5-(3-(3-hydroxyphenyl)prop-1-yn-1-yl)-3 -Methylpyrimidin-4(3H)-one;
    (S)-2-(1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-5-(3-(4-氟-3-甲氧基苯基)丙-1-炔-1-基)-3-甲基嘧啶-4(3H)-酮；(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(4-fluoro-3-methyl (Oxyphenyl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;
    (S)-2-(1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-5-(3-(2,3-二羟基苯基)丙-1-炔-1-基)-3-甲基嘧啶-4(3H)-酮；(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(2,3-dihydroxybenzene (Yl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;
    (S)-2-(1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-5-(3-(3,5-二羟基苯基)丙-1-炔-1-基)-3-甲基嘧啶-4(3H)-酮；(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(3,5-dihydroxybenzene (Yl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;
    (S)-2-(1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-3-甲基-5-(3-(4-吗啉苯基)丙-1-炔-1-基)嘧啶-4(3H)-酮；(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-3-methyl-5-(3-(4- Morpholinophenyl)prop-1-yn-1-yl)pyrimidin-4(3H)-one;
    (S)-2-(1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-5-(3-(6-甲氧基吡啶-3-基)丙-1-炔-1-基)-3-甲基嘧啶-4(3H)-酮；(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(6-methoxypyridine- 3-yl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;
    (S)-4-(3-(2-(1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-1-甲基-6-氧代-1,6-二氢嘧啶-5-基)丙-2-炔-1-基)-2-氟苯甲腈；(S)-4-(3-(2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-1-methyl-6- Oxo-1,6-dihydropyrimidin-5-yl)prop-2-yn-1-yl)-2-fluorobenzonitrile;
    (S)-2-(1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-5-(3-(6-羟基吡啶-3-基)丙-1-炔-1-基)-3-甲基嘧啶-4(3H)-酮；(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(6-hydroxypyridine-3- (Yl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;
    (S)-2-(1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-5-(3-(6-羟基吡啶-2-基)丙-1-炔-1-基)-3-甲基嘧啶-4(3H)-酮；(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(6-hydroxypyridine-2- (Yl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;
    (S)-2-(1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-5-(3-(2-羟基吡啶-4-基)丙-1-炔-1-基)-3-甲基嘧啶-4(3H)-酮；(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(2-hydroxypyridine-4- (Yl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;
    (S)-2-(1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-5-(3-(2-氨基-3-氯吡啶-4-基)丙-1-炔-1-基)-3-甲基嘧啶-4(3H)-酮；(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(2-amino-3-chloro (Pyridin-4-yl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;
    (S)-2-(1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-5-(3-(2-羟基嘧啶-4-基)丙-1-炔-1-基)-3-甲基嘧啶-4(3H)-酮；(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(2-hydroxypyrimidine-4- (Yl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;
    (S)-2-(1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-5-(3-(2-氨基嘧啶-4-基)丙-1-炔-1-基)-3-甲基嘧啶-4(3H)-酮；(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(2-aminopyrimidine-4- (Yl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;
    (S)-6-氨基-2-(1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-5-(3-(2-羟基吡啶-4-基)丙-1-炔-1-基)-3-甲基嘧啶-4(3H)-酮；(S)-6-amino-2-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(2-hydroxyl (Pyridin-4-yl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;
    (S)-6-氨基-2-(1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-5-(3-(3-羟基苯基)丙-1-炔-1-基)-3-甲基嘧啶-4(3H)-酮；(S)-6-amino-2-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(3-hydroxyl (Phenyl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;
    (S)-4-(3-(4-氨基-2-(1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-1-甲基-6-氧代-1,6-二氢嘧啶-5-基)丙-2-炔-1-基)-2-氟苯甲腈；(S)-4-(3-(4-Amino-2-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-1-methyl 6-oxo-1,6-dihydropyrimidin-5-yl)prop-2-yn-1-yl)-2-fluorobenzonitrile;
    (S)-6-氨基-2-(1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-5-(3-(2-氨基-3-氯吡啶-4-基)丙-1-炔-1-基)-3-甲基嘧啶-4(3H)-一；(S)-6-amino-2-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(2-amino -3-Chloropyridin-4-yl)prop-1-yn-1-yl)-3-methylpyrimidine-4(3H)-one;
    (S)-2-(1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-3-甲基-5-(3-(2-(甲胺基)吡啶-4-基)丙-1-炔-1-基)嘧啶-4(3H)-酮；(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-3-methyl-5-(3-(2- (Methylamino)pyridin-4-yl)prop-1-yn-1-yl)pyrimidin-4(3H)-one;
    (S)-2-(1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-5-(3-(2-氨基嘧啶-5-基)丙-1-炔-1-基)-3-甲基嘧啶-4(3H)-酮；(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(2-aminopyrimidine-5- (Yl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;
    (S)-5-(3-(4-(1H-吡唑-1-基)苯基)丙-1-in-1-基)-2-(1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-3-甲基嘧啶-4(3H)-酮；(S)-5-(3-(4-(1H-pyrazol-1-yl)phenyl)prop-1-in-1-yl)-2-(1-amino-1,3-dihydrospiro Cyclo[indene-2,4'-piperidine]-1'-yl)-3-methylpyrimidin-4(3H)-one;
    4-(3-(2-((S)-1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-1-甲基-6-氧代-1,6-二氢嘧啶-5-基)-1-氟丙烯-2-对-1-基)-2-羟基苯甲腈；4-(3-(2-((S)-1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-1-methyl-6- Oxo-1,6-dihydropyrimidin-5-yl)-1-fluoropropene-2-p-1-yl)-2-hydroxybenzonitrile;
    (S)-5-(3-(1H-吲哒唑-6-基)丙-1-炔-1-基)-2-(1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-3-甲基嘧啶-4(3H)-酮；(S)-5-(3-(1H-indazol-6-yl)prop-1-yn-1-yl)-2-(1-amino-1,3-dihydrospiro[indene-2 ,4'-Piperidine]-1'-yl)-3-methylpyrimidin-4(3H)-one;
    (S)-2-(1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-5-(3-(3-羟基-4-吗啉苯基)丙-1-炔-1-基)-3-甲基嘧啶-4(3H)-酮；(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(3-hydroxy-4-? (Pholinyl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;
    (S)-6-(3-(2-(1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-1-甲基-6-氧代-1,6-二氢嘧啶-5-基)丙-2-炔-1-基)吲哚-2-酮；(S)-6-(3-(2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-1-methyl-6- Oxo-1,6-dihydropyrimidin-5-yl)prop-2-yn-1-yl)indol-2-one;
    (S)-5-(3-(1H-吲哚-6-基)丙-1-炔-1-基)-2-(1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-3-甲基嘧啶-4(3H)-酮；(S)-5-(3-(1H-indol-6-yl)prop-1-yn-1-yl)-2-(1-amino-1,3-dihydrospiro[indene-2, 4'-Piperidine]-1'-yl)-3-methylpyrimidin-4(3H)-one;
    (S)-2-(1-氨基-6-甲氧基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-5-(3-(3-羟基苯基)丙-1-炔-1-基)-3-甲基嘧啶-4(3H)-酮；(S)-2-(1-Amino-6-methoxy-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(3 -Hydroxyphenyl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;
    (S)-2-(1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-5-(3-(3-羟基苯基)丙-1-炔-1-基)嘧啶-4(3H)-酮；(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(3-hydroxyphenyl)propane -1-yn-1-yl)pyrimidin-4(3H)-one;
    (S)-2-(1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-5-(3-(2-氨基-3-氯吡啶-4-基)丙-1-炔-1-基)嘧啶-4(3H)-酮；(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(2-amino-3-chloro (Pyridin-4-yl)prop-1-yn-1-yl)pyrimidin-4(3H)-one;
    (S)-5-(3-(2-氨基-3-氯吡啶-4-基)丙-1-炔-1-基)-2-(1-氨基-6-甲氧基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)嘧啶-4(3H)-酮；(S)-5-(3-(2-Amino-3-chloropyridin-4-yl)prop-1-yn-1-yl)-2-(1-amino-6-methoxy-1,3 -Dihydrospirocyclo[indene-2,4'-piperidine]-1'-yl)pyrimidin-4(3H)-one;
    2-((S)-1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-5-(3-氟-3-(3-羟基苯基)丙-1-炔-1-基)-3-甲基嘧啶-4(3H)-酮；2-((S)-1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-fluoro-3-(3-hydroxyl (Phenyl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;
    (S)-2-(1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-5-(3-(4-氯-2,3-二羟基苯基)丙-1-炔-1-基)-3-甲基嘧啶-4(3H)-酮；(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(4-chloro-2,3 -Dihydroxyphenyl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;
    (S)-6-氨基-2-(4-氨基-4,6-二氢螺环[d]噻唑-5,4'-哌啶]-1'-基)-5-(3-(4-氯-3-羟基苯基)丙-1-炔-1-基)-3-甲基嘧啶-4(3H)-酮；(S)-6-amino-2-(4-amino-4,6-dihydrospiro[d]thiazole-5,4'-piperidine]-1'-yl)-5-(3-(4 -Chloro-3-hydroxyphenyl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;
    (S)-2-(4-氨基-4,6-二氢螺环[d]噻唑-5,4'-哌啶]-1'-基)-5-(3-(4-氯-3-羟基苯基)丙-1-炔-1-基)-3-甲基嘧啶-4(3H)-酮；(S)-2-(4-Amino-4,6-dihydrospiro[d]thiazole-5,4'-piperidine]-1'-yl)-5-(3-(4-chloro-3 -Hydroxyphenyl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;
    (S)-2-(1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-5-(3-(4-氟-2,3-二羟基苯基)丙-1-炔-1-基)-3-甲基嘧啶-4(3H)-酮；(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(4-fluoro-2,3 -Dihydroxyphenyl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;
    (S)-2-(1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-5-(3-(4-氟-3,5-二羟基苯基)丙-1-炔-1-基)-3-甲基嘧啶-4(3H)-酮；(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(4-fluoro-3,5 -Dihydroxyphenyl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;
    (S)-6-(3-(2-(1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-1-甲基-6-氧代-1,6-二氢嘧啶-5-基)丙-2-辛-1-基)-2-羟基-3-甲基苯甲腈；(S)-6-(3-(2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-1-methyl-6- Oxo-1,6-dihydropyrimidin-5-yl)propan-2-oct-1-yl)-2-hydroxy-3-methylbenzonitrile;
    (S)-4-(3-(2-(1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-1-甲基-6-氧代-1,6-二氢嘧啶-5-基)丙-2-炔-1-基)-2-羟基苯甲腈；(S)-4-(3-(2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-1-methyl-6- Oxo-1,6-dihydropyrimidin-5-yl)prop-2-yn-1-yl)-2-hydroxybenzonitrile;
    (S)-2-(3-(2-(1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-1-甲基-6-氧代-1,6-二氢嘧啶-5-基)丙-2-炔-1-基)-6-羟基苯甲腈；(S)-2-(3-(2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-1-methyl-6- Oxo-1,6-dihydropyrimidin-5-yl)prop-2-yn-1-yl)-6-hydroxybenzonitrile;
    (S)-4-(3-(2-(1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-1-甲基-6-氧代-1,6-二氢嘧啶-5-基)丙-2-炔-1-基)-2,6-二羟基苯甲腈；(S)-4-(3-(2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-1-methyl-6- Oxo-1,6-dihydropyrimidin-5-yl)prop-2-yn-1-yl)-2,6-dihydroxybenzonitrile;
    (S)-6-(3-(2-(1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-1-甲基-6-氧代-1,6-二氢嘧啶-5-基)丙-2-炔-1-基)-3-氯-2-羟基苯甲腈；(S)-6-(3-(2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-1-methyl-6- Oxo-1,6-dihydropyrimidin-5-yl)prop-2-yn-1-yl)-3-chloro-2-hydroxybenzonitrile;
    (S)-2-(1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-5-(3-(3-羟基苯基)-3-甲基-1-基)-3-甲基嘧啶-4(3H)-酮；(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-(3-hydroxyphenyl)- 3-methyl-1-yl)-3-methylpyrimidin-4(3H)-one;
    2-((S)-1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-5-(3-氟-3-(3-甲氧基苯基)丙-1-炔-1-基)-3-甲基嘧啶-4(3H)-酮；2-((S)-1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-fluoro-3-(3-methyl (Oxyphenyl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;
    2-((S)-1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-5-(3-羟基-3-(3-甲氧基苯基)丙-1-炔-1-基)-3-甲基嘧啶-4(3H)-酮；2-((S)-1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-hydroxy-3-(3-methyl (Oxyphenyl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;
    2-((S)-1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-5-(3-羟基-3-(3-羟基苯基)丙-1-炔-1-基)-3-甲基嘧啶-4(3H)-酮；2-((S)-1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-(3-hydroxy-3-(3-hydroxyl (Phenyl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;
    (S)-2-(5-氨基-5,7-二氢螺环[b]吡啶-6,4'-哌啶]-1'-基)-5-(3-(3-羟基苯基)丙-1-炔-1-基)-3-甲基嘧啶-4(3H)-酮；(S)-2-(5-Amino-5,7-dihydrospiro[b]pyridine-6,4'-piperidine]-1'-yl)-5-(3-(3-hydroxyphenyl) )Prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;
    (S)-2-(7-氨基-5,7-二氢螺环[d]嘧啶-6,4'-哌啶]-1'-基)-5-(3-(3-羟基苯基)丙-1-炔-1-基)-3-甲基嘧啶-4(3H)-酮；(S)-2-(7-Amino-5,7-dihydrospiro[d]pyrimidine-6,4'-piperidine]-1'-yl)-5-(3-(3-hydroxyphenyl )Prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;
    (S)-2-(1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-3-甲基-5-((1-苯基环丙基)乙炔基)嘧啶-4(3H)-酮；(S)-2-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-3-methyl-5-((1-phenyl Cyclopropyl)ethynyl)pyrimidin-4(3H)-one;
    (R)-6-氨基-2-(3-氨基-3H-螺环[苯并呋喃-2,4'-哌啶]-1'-基)-5-(3-(4-氯-3-羟基苯基)丙-1-炔-1-基)-3-甲基嘧啶-4(3H)-酮；(R)-6-amino-2-(3-amino-3H-spiro[benzofuran-2,4'-piperidine]-1'-yl)-5-(3-(4-chloro-3 -Hydroxyphenyl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;
    (R)-2-(3'-氨基-3'H-螺环[哌啶-4,2'-噻吩[2,3-b]呋喃]-1-基)-5-(3-(3-羟基苯基)丙-1-炔-1-基)-3-甲基嘧啶-4(3H)-酮；(R)-2-(3'-Amino-3'H-spiro[piperidine-4,2'-thiophene[2,3-b]furan]-1-yl)-5-(3-(3 -Hydroxyphenyl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;
    (R)-2-(6-氨基-6H-螺环[氟[3,2-d]噻唑-5,4'-哌啶]-1'-基)-5-(3-(3-羟基苯基)丙-1-炔-1-基)-3-甲基嘧啶-4(3H)-酮；(R)-2-(6-Amino-6H-spiro[fluoro[3,2-d]thiazole-5,4'-piperidine]-1'-yl)-5-(3-(3-hydroxy (Phenyl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;
    (S)-2-(3-氨基-3H-螺环[呋喃[3,2-b]呋喃-2,4'-哌啶]-1'-基)-5-(3-(3-羟基苯基)丙-1-炔-1-基)-3-甲基嘧啶-4(3H)-酮；(S)-2-(3-Amino-3H-spiro[furan[3,2-b]furan-2,4'-piperidine]-1'-yl)-5-(3-(3-hydroxyl (Phenyl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;
    (S)-2-(6-氨基-6H-螺环[氟[2,3-d]恶唑-5,4'-哌啶]-1'-基)-5-(3-(3-羟基苯基)丙-1-炔-1-基)-3-甲基嘧啶-4(3H)-酮；(S)-2-(6-Amino-6H-spiro[fluoro[2,3-d]oxazole-5,4'-piperidine]-1'-yl)-5-(3-(3- Hydroxyphenyl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;
    (R)-2-(6-氨基-2-甲基-6H-螺环[氟[3,2-d]噻唑-5,4'-哌啶]-1'-基)-5-(3-羟基苯基)丙-1-炔-1-基)-3-甲基嘧啶-4(3H)-酮；(R)-2-(6-Amino-2-methyl-6H-spiro[fluoro[3,2-d]thiazole-5,4'-piperidine]-1'-yl)-5-(3 -Hydroxyphenyl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;
    2-((S)-1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-5-((2-(羟甲基)环丙基)乙炔基)-3-甲基嘧啶-4(3H)-酮；2-((S)-1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-((2-(hydroxymethyl)cyclopropyl (Yl)ethynyl)-3-methylpyrimidin-4(3H)-one;
    5-((2-(1,3,4-恶二唑-2-基)环丙基)乙炔基)-2-((S)-1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-3-甲基嘧啶-4(3H)-酮；5-((2-(1,3,4-oxadiazol-2-yl)cyclopropyl)ethynyl)-2-((S)-1-amino-1,3-dihydrospiro[indene -2,4'-piperidine]-1'-yl)-3-methylpyrimidin-4(3H)-one;
    2-((5-((S)-1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-6-(羟甲基)吡嗪-2-基)乙炔基)环丙烷-1-羧酸乙酯；2-((5-((S)-1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(hydroxymethyl)pyrazine -2-yl)ethynyl)ethyl cyclopropane-1-carboxylate;
    2-((5-((S)-1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-6-(羟甲基)吡嗪-2-基)乙炔基)环丙烷-1-羧酸；2-((5-((S)-1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(hydroxymethyl)pyrazine -2-yl)ethynyl)cyclopropane-1-carboxylic acid;
    2-((5-((S)-1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-6-(羟甲基)吡嗪-2-基)乙炔基)-N-环丙基环丙烷-1-甲酰胺；2-((5-((S)-1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(hydroxymethyl)pyrazine -2-yl)ethynyl)-N-cyclopropylcyclopropane-1-carboxamide;
    2-((2-((S)-1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-1-甲基-6-氧代-1,6-二氢嘧啶-5-基)乙炔基)环丙烷-1-羧酸乙酯；2-((2-((S)-1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-1-methyl-6-oxo -1,6-Dihydropyrimidin-5-yl)ethynyl)cyclopropane-1-carboxylic acid ethyl ester;
    2-((S)-1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-3-甲基-5-((2-(甲磺酰基)环丙基)乙炔基)嘧啶-4(3H)-酮；2-((S)-1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-3-methyl-5-((2-(methyl (Sulfonyl)cyclopropyl)ethynyl)pyrimidin-4(3H)-one;
    2-((2-((S)-1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-1-甲基-6-氧代-1,6-二氢嘧啶-5-基)乙炔基)环丙烷-1-磺酰胺；2-((2-((S)-1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-1-methyl-6-oxo -1,6-Dihydropyrimidin-5-yl)ethynyl)cyclopropane-1-sulfonamide;
    2-((S)-1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-3-甲基-5-((2-(2,2,2-三氟-1-羟乙基)环丙基)乙炔基)嘧啶-4(3H)-酮；2-((S)-1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-3-methyl-5-((2-(2 ,2,2-Trifluoro-1-hydroxyethyl)cyclopropyl)ethynyl)pyrimidin-4(3H)-one;
    2-((S)-1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-5-((2-(甲氧基甲基)环丙基)乙炔基)-3-甲基嘧啶-4(3H)-酮；2-((S)-1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-5-((2-(methoxymethyl) Cyclopropyl)ethynyl)-3-methylpyrimidin-4(3H)-one;
    (2-((S)-1-氨基-1,3-二氢螺环[茚-2,4'哌啶]-1'-基)-5-(2-氧-8-氮杂螺[4.5]癸-8-基)3-羟基-3-(4-吗啉苯基)丙-1-炔-1-基)-3-甲基嘧啶-4(3H)-酮；(2-((S)-1-amino-1,3-dihydrospiro[indene-2,4'piperidine]-1'-yl)-5-(2-oxo-8-azaspiro[ 4.5] Dec-8-yl)3-hydroxy-3-(4-morpholinphenyl)prop-1-yn-1-yl)-3-methylpyrimidin-4(3H)-one;
    2-((5-((S)-1-氨基-1,3-二氢螺环[茚-2,4'-哌啶]-1'-基)-6-(羟甲基)吡嗪-2-2-基)乙炔基)环丙烷酰胺；2-((5-((S)-1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(hydroxymethyl)pyrazine -2-2-yl)ethynyl)cyclopropaneamide;
    2-((3S,4S)-4-氨基-3-甲基-2-氧-8-偶氮[4.5]癸-8-基)-5-(3-(3-羟基苯基)丙-1-炔-1-基)--3-甲基嘧啶-4(3H)-酮；2-((3S,4S)-4-amino-3-methyl-2-oxo-8-azo[4.5]dec-8-yl)-5-(3-(3-hydroxyphenyl)propan- 1-Alkyn-1-yl)-3-methylpyrimidin-4(3H)-one;
    (S)-1-(3-(5-(1-氨基-1,3-二氢螺[茚-2,4’-哌啶]-1'-基)-6-(羟甲基)吡嗪-2-基)丙-2-炔-1-基)-1H-吡唑-3-羧酰胺；(S)-1-(3-(5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(hydroxymethyl)pyridine (Azin-2-yl)prop-2-yn-1-yl)-1H-pyrazole-3-carboxamide;
    (S)-N-(3-(3-(5-(1-氨基-1,3-二氢螺[茚-2,4’-哌啶]-1'-基)-6-(羟甲基)吡嗪-2-基)丙-2-炔-1-基)苯基)乙酰胺；(S)-N-(3-(3-(5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(hydroxymethyl (Yl)pyrazin-2-yl)prop-2-yn-1-yl)phenyl)acetamide;
    (S)-3-(3-(5-(1-氨基-1,3-二氢螺[茚-2,4’-哌啶]-1'-基)-6-(羟甲基)吡嗪-2-基)丙-2-炔-1-基)苯甲酰胺；(S)-3-(3-(5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(hydroxymethyl)pyridine (Azin-2-yl)prop-2-yn-1-yl)benzamide;
    (S)-4-(3-(5-(1-氨基-1,3-二氢螺[茚-2,4’-哌啶]-1'-基)-6-(羟甲基)吡嗪-2-基)丙-2-炔-1-基)苯甲酰胺；(S)-4-(3-(5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(hydroxymethyl)pyridine (Azin-2-yl)prop-2-yn-1-yl)benzamide;
    (S)-4-(4-(5-(1-氨基-1,3-二氢螺[茚-2,4’-哌啶]-1'-基)-6-(羟甲基)吡嗪-2-基)丁-3-炔-1-基)苯甲酰胺；(S)-4-(4-(5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(hydroxymethyl)pyridine (Azin-2-yl)but-3-yn-1-yl)benzamide;
    (S)-(3-(1-氨基-1,3-二氢螺[茚-2,4’-哌啶]-1’-基)-6-(4-苯基丁-1-炔-1-基)吡嗪-2-基)甲醇；(S)-(3-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(4-phenylbut-1-yne- 1-yl)pyrazin-2-yl)methanol;
    (S)-2-(3-(5-(1-氨基-1,3-二氢螺[茚-2,4’-哌啶]-1'-基)-6-(羟甲基)吡嗪-2-基)丙-2-炔-1-基)异吲哚啉-5-羧酰胺；(S)-2-(3-(5-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(hydroxymethyl)pyridine (Azin-2-yl)prop-2-yn-1-yl)isoindoline-5-carboxamide;
    (S)-(3-(1-氨基-1,3-二氢螺[茚-2,4’-哌啶]-1'-基)-6-(3-(吲哚-1-基)丙-1-炔-1-基)吡嗪-2-基)甲醇；(S)-(3-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)-6-(3-(indol-1-yl) Prop-1-yn-1-yl)pyrazin-2-yl)methanol;
    (S)-1-(3-(5-(1-氨基-1,3-二氢螺[茚-2,4’-哌啶]-1'-基)-6-(羟甲基)吡嗪-2-基)丙-2-炔-1-基)-1H-吲唑-5-醇；(S)-1-(3-(5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(hydroxymethyl)pyridine (Azin-2-yl)prop-2-yn-1-yl)-1H-indazol-5-ol;
    (S)-(3-(1-氨基-1,3-二氢螺[茚-2,4’-哌啶]-1'-基)-6-(3-(5-氨基-1H-吲哚-1-基)丙-1-炔-1-基)吡嗪-2-基)甲醇；(S)-(3-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(3-(5-amino-1H-indyl) Dol-1-yl)prop-1-yn-1-yl)pyrazin-2-yl)methanol;
    (S)-N-(1-(3-(5-(1-氨基-1,3-二氢螺[茚-2,4’-哌啶]-1'-基)-6-(羟甲基)吡嗪-2-基)丙-2-炔-1-基)-1H-吲唑-5-基)乙酰胺；(S)-N-(1-(3-(5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(hydroxymethyl (Yl)pyrazin-2-yl)prop-2-yn-1-yl)-1H-indazol-5-yl)acetamide;
    (S)-(3-(1-氨基-1,3-二氢螺[茚-2,4’-哌啶]-1'-基)-6-(3-(6-氨基-1H-吲唑-1-基)丙-1-炔-1-基)吡嗪-2-基)甲醇；(S)-(3-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(3-(6-amino-1H-indyl (Azol-1-yl)prop-1-yn-1-yl)pyrazin-2-yl)methanol;
    (S)-(3-(1-氨基-1,3-二氢螺[茚-2,4’-哌啶]-1'-基)-6-(3-(4-氨基-1H-吲唑-1-基)丙-1-炔-1-基)吡嗪-2-基)甲醇；(S)-(3-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(3-(4-amino-1H-indyl (Azol-1-yl)prop-1-yn-1-yl)pyrazin-2-yl)methanol;
    (S)-1-(3-(5-(1-氨基-1,3-二氢螺[茚-2,4’-哌啶]-1'-基)-6-(羟甲基)吡嗪-2-基)丙-2-炔-1-基)-1H-吲唑-5-羧酰胺；(S)-1-(3-(5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(hydroxymethyl)pyridine (Azin-2-yl)prop-2-yn-1-yl)-1H-indazole-5-carboxamide;
    (S)-N-(1-(3-(5-(1-氨基-1,3-二氢螺[茚-2,4’-哌啶]-1'-基)-6-(羟甲基)吡嗪-2-基)丙-2-炔-1-基)-1H-吲唑-4-基)乙酰胺；(S)-N-(1-(3-(5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(hydroxymethyl (Yl)pyrazin-2-yl)prop-2-yn-1-yl)-1H-indazol-4-yl)acetamide;
    (S)-1-(3-(5-(1-氨基-1,3-二氢螺[茚-2,4’-哌啶]-1'-基)-6-(羟甲基)吡嗪-2-基)丙-2-炔-1-基)-1H-苯并[d]咪唑-5-羧酰胺；(S)-1-(3-(5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(hydroxymethyl)pyridine (Azin-2-yl)prop-2-yn-1-yl)-1H-benzo[d]imidazole-5-carboxamide;
    (S)-1-(3-(5-(1-氨基-1,3-二氢螺[茚-2,4’-哌啶]-1'-基)-6-(羟甲基)吡嗪-2-基)丙-2-炔-1-基)-1H-苯并[d]咪唑-6-羧酰胺；(S)-1-(3-(5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(hydroxymethyl)pyridine (Azin-2-yl)prop-2-yn-1-yl)-1H-benzo[d]imidazole-6-carboxamide;
    (S)-(3-(1-氨基-1,3-二氢螺[茚-2,4’-哌啶]-1'-基)-6-(3-(5-甲氧基-1H-苯并[d]咪唑-1-基)丙-1-炔-1-基)吡嗪-2-基)甲醇；(S)-(3-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(3-(5-methoxy-1H -Benzo[d]imidazol-1-yl)prop-1-yn-1-yl)pyrazin-2-yl)methanol;
    (S)-(6-(3-(1H-吲哚-1-基)丙-1-炔-1-基)-3-(1-氨基-1,3-二氢螺[茚-2,4’-哌啶]-1'-基)吡嗪-2-基)甲醇；(S)-(6-(3-(1H-indol-1-yl)prop-1-yn-1-yl)-3-(1-amino-1,3-dihydrospiro[indene-2, 4'-Piperidine]-1'-yl)pyrazin-2-yl)methanol;
    (S)-1-(3-(5-(1-氨基-1,3-二氢螺[茚-2,4’-哌啶]-1'-基)-6-(羟甲基)吡嗪-2-基)丙-2-炔-1-基)吲哚啉-5-羧酰胺；(S)-1-(3-(5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(hydroxymethyl)pyridine (Azin-2-yl)prop-2-yn-1-yl)indoline-5-carboxamide;
    (S)-(3-(1-氨基-1,3-二氢螺[茚-2,4’-哌啶]-1'-基)-6-(3-(5-硝基吲哚-1-基)丙-1-炔-1-基)吡嗪-2-基)甲醇；(S)-(3-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(3-(5-nitroindole- 1-yl)prop-1-yn-1-yl)pyrazin-2-yl)methanol;
    (S)-1-(3-(5-(1-氨基-1,3-二氢螺[茚-2,4’-哌啶]-1'-基)-6-(羟甲基)吡嗪-2-基)丙-2-炔-1-基)-1H-吲哚-5-羧酰胺；(S)-1-(3-(5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(hydroxymethyl)pyridine (Azin-2-yl)prop-2-yn-1-yl)-1H-indole-5-carboxamide;
    (S)-1-(3-(5-(1-氨基-1,3-二氢螺[茚-2,4’-哌啶]-1'-基)-6-(羟甲基)吡嗪-2-基)丙-2-炔-1-基)-1H-吲唑-6-羧酰胺；(S)-1-(3-(5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(hydroxymethyl)pyridine (Azin-2-yl)prop-2-yn-1-yl)-1H-indazole-6-carboxamide;
    (S)-N-(1-(3-(5-(1-氨基-1,3-二氢螺[茚-2,4’-哌啶]-1'-基)-6-(羟甲基)吡嗪-2-基)丙-2-炔-1-基)-1H-吲唑-6-基)乙酰胺；(S)-N-(1-(3-(5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(hydroxymethyl (Yl)pyrazin-2-yl)prop-2-yn-1-yl)-1H-indazol-6-yl)acetamide;
    (S)-3-(3-(5-(1-氨基-1,3-二氢螺[茚-2,4’-哌啶]-1'-基)-6-(羟甲基)吡嗪-2-基)丙-2-炔-1-基)苯并[d]异恶唑-6-羧酰胺；(S)-3-(3-(5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(hydroxymethyl)pyridine (Azin-2-yl)prop-2-yn-1-yl)benzo[d]isoxazole-6-carboxamide;
    (S)-1-(3-(5-(1-氨基-1,3-二氢螺[茚-2,4’-哌啶]-1'-基)-6-(羟甲基)吡嗪-2-基)丙-2-炔-1-基)吲哚嗪-6-羧酰胺；(S)-1-(3-(5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(hydroxymethyl)pyridine (Azin-2-yl)prop-2-yn-1-yl)indolazine-6-carboxamide;
    (S)-(3-(1-氨基-1,3-二氢螺[茚-2,4’-哌啶]-1'-基)-6-(3-(5-氨基-1H-吲唑-1-基)丙-1-炔-1-基)吡嗪-2-基)甲醇；(S)-(3-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(3-(5-amino-1H-indyl) (Azol-1-yl)prop-1-yn-1-yl)pyrazin-2-yl)methanol;
    (S)-(3-(1-氨基-1,3-二氢螺[茚-2,4’-哌啶]-1'-基)-6-(3-(5-甲氧基-1H-吲唑-1-基)丙-1-炔-1-基)吡嗪-2-基)甲醇；(S)-(3-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(3-(5-methoxy-1H -Indazol-1-yl)prop-1-yn-1-yl)pyrazin-2-yl)methanol;
    (S)-(3-(1-氨基-1,3-二氢螺[茚-2,4’-哌啶]-1'-基)-6-(3-(5-硝基-1H-吲哚-1-基)丙-1-炔-1-基)吡嗪-2-基)甲醇；(S)-(3-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(3-(5-nitro-1H- Indol-1-yl)prop-1-yn-1-yl)pyrazin-2-yl)methanol;
    (S)-(3-(1-氨基-1,3-二氢螺[茚-2,4’-哌啶]-1'-基)-6-(3-(6-甲氧基-1H-苯并[d]咪唑-1-基)丙-1-炔-1-基)吡嗪-2-基)甲醇；(S)-(3-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(3-(6-methoxy-1H -Benzo[d]imidazol-1-yl)prop-1-yn-1-yl)pyrazin-2-yl)methanol;
    (S)-(3-(1-氨基-1,3-二氢螺[茚-2,4'-哌啶]-1'-基)-6-(3-(6-氨基-9H-嘌呤-9-基)丙-1-炔-1-基)吡嗪-2-基)甲醇；或(S)-(3-(1-Amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(3-(6-amino-9H-purine -9-yl)prop-1-yn-1-yl)pyrazin-2-yl)methanol; or
    4-(2-((5-((S)-1-氨基-1,3-二氢螺[茚-2,4’-哌啶]-1'-基)-6-(羟甲基)吡嗪-2-基)乙炔基)环丙基)苯甲酰胺。4-(2-((5-((S)-1-amino-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-yl)-6-(hydroxymethyl) Pyrazin-2-yl)ethynyl)cyclopropyl)benzamide.
  36. 一种药物组合物，其特征在于，包含治疗有效量的至少一种权利要求1-35任一项所述的化合物和至少一种药学上可接受的辅料。A pharmaceutical composition characterized by comprising a therapeutically effective amount of at least one compound according to any one of claims 1-35 and at least one pharmaceutically acceptable excipient.
  37. 根据权利要求36所述的组合物，其特征在于，治疗有效量的至少一种权利要求1-35任一项所述的化合物和药学上可接受的辅料的质量百分比为0.0001:1-10。The composition according to claim 36, wherein the mass percentage of the therapeutically effective amount of at least one compound according to any one of claims 1-35 and pharmaceutically acceptable excipients is 0.0001:1-10.
  38. 权利要求1-35任一项所述化合物或权利要求36或37所述药物组合物在制备药物中的应用。Use of the compound of any one of claims 1-35 or the pharmaceutical composition of claim 36 or 37 in the preparation of medicines.
  39. 根据权利要求38所述的应用，其特征在于，所述药物用于治疗、预防、延迟或阻止癌症，癌症转移，心血管疾病，免疫疾病，纤维化或眼部疾病。The application according to claim 38, wherein the medicine is used to treat, prevent, delay or prevent cancer, cancer metastasis, cardiovascular disease, immune disease, fibrosis or eye disease.
  40. 根据权利要求38所述的应用，其特征在于，所述药物用于治疗由SHP2介导的疾病。The use according to claim 38, wherein the medicine is used to treat diseases mediated by SHP2.
  41. 根据权利要求40所述的应用，其特征在于，所述疾病是癌症。The use according to claim 40, wherein the disease is cancer.
  42. 根据权利要求41所述的应用，其特征在于，所述癌症选自Noonan综合征、豹斑综合征、青少年髓单核细胞白血病、神经母细胞瘤、黑色素瘤、头颈部鳞状细胞癌、急性髓性白血病、乳腺癌、食道肿瘤、肺癌、结肠癌、头癌、胃癌、淋巴瘤、胶质母细胞瘤、胰腺癌或其组合。The use according to claim 41, wherein the cancer is selected from Noonan syndrome, leopard spot syndrome, juvenile myelomonocytic leukemia, neuroblastoma, melanoma, head and neck squamous cell carcinoma, Acute myeloid leukemia, breast cancer, esophageal tumor, lung cancer, colon cancer, head cancer, gastric cancer, lymphoma, glioblastoma, pancreatic cancer, or a combination thereof.
  43. 根据权利要求38所述的应用，其特征在于，所述药物用作SHP2抑制剂。The use according to claim 38, wherein the drug is used as an SHP2 inhibitor.
  44. 一种治疗和/或预防由SHP2介导的疾病的方法，包括向治疗对象施用治疗有效量的至少任意一种权利要求1-35任一项所述化合物或药物组合物。A method for treating and/or preventing diseases mediated by SHP2, comprising administering a therapeutically effective amount of at least any one of the compounds or pharmaceutical compositions of any one of claims 1-35 to a subject to be treated.
  45. 根据权利要求44所述的方法，其特征在于，所述SHP2介导的疾病是癌症。The method of claim 44, wherein the SHP2-mediated disease is cancer.
  46. 一种治疗癌症的方法，包括向治疗对象施用治疗有效量的至少任意一种权利要求1-35任一项所述化合物或药物组合物。A method for treating cancer, comprising administering a therapeutically effective amount of at least any one of the compounds or pharmaceutical compositions of any one of claims 1-35 to a subject.
  47. 根据权利要求46所述的方法，其特征在于，所述癌症选自Noonan综合征、豹斑综合征、青少年髓单核细胞白血病、神经母细胞瘤、黑色素瘤、头颈部鳞状细胞癌、急性髓性白血病、乳腺癌、食道肿瘤、肺癌、结肠癌、头癌、胃癌、淋巴瘤、胶质母细胞瘤、胰腺癌或其组合。The method of claim 46, wherein the cancer is selected from Noonan syndrome, leopard spot syndrome, juvenile myelomonocytic leukemia, neuroblastoma, melanoma, head and neck squamous cell carcinoma, Acute myeloid leukemia, breast cancer, esophageal tumor, lung cancer, colon cancer, head cancer, gastric cancer, lymphoma, glioblastoma, pancreatic cancer, or a combination thereof.
  48. 根据权利要求46或47所述的方法，其特征在于，所述治疗对象为人类。The method according to claim 46 or 47, wherein the subject to be treated is a human.
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