WO2021228028A1 - 含磷的sos1抑制剂 - Google Patents

含磷的sos1抑制剂 Download PDF

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WO2021228028A1
WO2021228028A1 PCT/CN2021/092672 CN2021092672W WO2021228028A1 WO 2021228028 A1 WO2021228028 A1 WO 2021228028A1 CN 2021092672 W CN2021092672 W CN 2021092672W WO 2021228028 A1 WO2021228028 A1 WO 2021228028A1
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alkyl
compound
membered
hydrogen
amino
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PCT/CN2021/092672
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English (en)
French (fr)
Inventor
张寅生
刘保民
陈正帮
胡进发
陈雨辰
孙克文
汪纪楠
诸丽娟
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正大天晴药业集团股份有限公司
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Priority to EP21804515.1A priority Critical patent/EP4148056A4/en
Priority to IL298050A priority patent/IL298050A/en
Priority to CA3182745A priority patent/CA3182745A1/en
Priority to CN202180030884.3A priority patent/CN115461342A/zh
Priority to MX2022013974A priority patent/MX2022013974A/es
Priority to AU2021271381A priority patent/AU2021271381A1/en
Priority to KR1020227043479A priority patent/KR20230095878A/ko
Priority to JP2022568428A priority patent/JP2023524864A/ja
Priority to BR112022022761A priority patent/BR112022022761A2/pt
Publication of WO2021228028A1 publication Critical patent/WO2021228028A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
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    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
    • C07F9/6509—Six-membered rings
    • C07F9/6512—Six-membered rings having the nitrogen atoms in positions 1 and 3
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
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    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
    • C07F9/6568—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus atoms as the only ring hetero atoms
    • C07F9/65685—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus atoms as the only ring hetero atoms the ring phosphorus atom being part of a phosphine oxide or thioxide
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
    • C07F9/6571—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms
    • C07F9/657163—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms the ring phosphorus atom being bound to at least one carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
    • C07F9/6581—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and nitrogen atoms with or without oxygen or sulfur atoms, as ring hetero atoms
    • C07F9/6584—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and nitrogen atoms with or without oxygen or sulfur atoms, as ring hetero atoms having one phosphorus atom as ring hetero atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/94—Nitrogen atoms
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • This application relates to a phosphorus-containing SOS1 inhibitor, a preparation method thereof, a pharmaceutical composition containing the inhibitor, and its use in the treatment of diseases and/or disorders related to or regulated by SOS1.
  • RAS is the most frequently mutated oncogene in human cancers
  • KRAS is the most frequently occurring subtype in the RAS family.
  • KRAS gene mutations account for 86% of the total RAS gene mutations.
  • GEF guanine nucleotide exchange factor
  • the RAS family proteins are active and link effector proteins including C-RAF and phosphoinositide 3-kinase (PI3K) to promote RAF/mitogen or extracellular signal-regulated kinase (MEK/ERK) pathways, PI3K/AKT/mammalian target of rapamycin (mTOR) pathway and RalGDS (Ral guanine nucleotide dissociation stimulator) pathway (McCormick et al., J.Mol.Med.(Berl)., 2016, 94 (3):253-8; Rodriguez-Viciana et al., Cancer Cell. 2005, 7(3):205-6).
  • PI3K C-RAF and phosphoinositide 3-kinase
  • MEK/ERK extracellular signal-regulated kinase
  • mTOR PI3K/AKT/mammalian target of rapamycin
  • RalGDS Ral guanine nucleotide dissociation stimulator
  • SOS1 inhibitor compounds can inhibit signal transduction downstream of RAS family proteins in cells (for example, ERK phosphorylation).
  • the ideal SOS1 inhibitor compound should be able to selectively and efficiently inhibit the binding of SOS1:RAS-family proteins and ERK phosphorylation in cells.
  • the application provides a compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof,
  • X and Y are each independently selected from CR a , C(O), N or NR b ;
  • each represents a single bond or a double bond
  • R a is selected from hydrogen, hydroxy, halogen, cyano, C 1-6 alkyl or C 1-6 alkoxy, wherein the C 1-6 alkyl or C 1-6 alkoxy is optionally substituted by one Or multiple deuterium or halogen substitutions;
  • R b is selected from hydrogen, C 1-6 alkyl or C 1-6 alkoxy
  • R 1 and R 2 are each independently selected from C 1-6 alkyl, NH(R c )-C 1-6 alkyl- or N(R c )(C 1-6 alkyl)-C 1-6 alkane Group-, or R 1 , R 2 and the phosphorus atom connected thereto together form a 5-10 membered heterocyclic group, wherein the C 1-6 alkyl group or 5-10 membered heterocyclic group is optionally substituted by one or Multiple R c substitutions;
  • Ring A is selected from C 6-10 aryl, 5-10 membered heteroaryl, 8-12 membered fused ring or 8-12 membered fused heterocyclic ring;
  • n 0, 1, 2 or 3;
  • Each R 3 is independently selected from amino, nitro, halogen, C 1-8 alkyl-, 3-6 membered cycloalkyl- or phenyl, wherein the C 1-8 alkyl-, 3-6 The membered cycloalkyl- or phenyl group is optionally substituted with one or more Rd ;
  • R d is selected from hydroxyl, halogen or C 1-6 alkyl-NH-C 1-6 alkyl-;
  • R 4 and R 5 are each independently selected from hydrogen, deuterium or C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with one or more halogens;
  • R 6 is selected from hydrogen, halogen, or C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with one or more halogens.
  • X is selected from CR a or NR b
  • Y is selected from CR a , C(O), N, or NR b
  • X is selected from CR a or NR b
  • Y is selected from CR a , C(O), or N.
  • X is selected from CR a
  • Y is selected from CR a , C(O), N, or NR b .
  • X is selected from CR a
  • Y is selected from CR a , C(O), or N.
  • X is selected from CR a
  • Y is selected from N.
  • X is selected from NR b and Y is selected from CR a , C(O), N, or NR b . In some embodiments, X is selected from NR b , and Y is selected from CR a , C(O), or N. In some embodiments, X is selected from NR b and Y is selected from C(O).
  • both X and Y are selected from CR a .
  • X is selected from CH and Y is selected from CR a .
  • R a is selected from hydrogen, hydroxy, halo, cyano, C 1-4 alkyl or C 1-4 alkoxy, wherein said C 1-4 alkyl or C 1-4 alkoxy
  • the radical is optionally substituted with one or more deuterium or halogen.
  • R a is selected from hydrogen, hydroxy, halo, cyano, C 1-4 alkyl or C 1-4 alkoxy, wherein said C 1-4 alkyl is optionally substituted with one or more One halogen substitution, the C 1-4 alkoxy group is optionally substituted with one or more deuterium or halogen.
  • R a is selected from hydrogen, hydroxy, halo, cyano, C 1-3 alkyl or a C 1-3 alkoxy, wherein said C 1-3 alkyl optionally substituted with one or more One halogen substitution, the C 1-3 alkoxy group is optionally substituted with one or more deuterium or halogen.
  • R a is selected from hydrogen, hydroxy, halogen, cyano or C 1-6 alkoxy, wherein said C 1-6 alkoxy is optionally substituted with one or more deuterium or halogen.
  • R a is selected from hydrogen, hydroxy, halogen, cyano or C 1-4 alkoxy, wherein said C 1-4 alkoxy is optionally substituted with one or more deuterium or halogen. In some embodiments, R a is selected from hydrogen, hydroxy, halogen, cyano or C 1-4 alkoxy, wherein said C 1-4 alkoxy optionally substituted with three or more fluorine or deuterium replace. In some embodiments, R a is selected from hydrogen, hydroxy, halogen, cyano or C 1-4 alkoxy, wherein said C 1-4 alkoxy optionally substituted with deuterium 3, or 1 or 2 A fluorine substitution.
  • R a is selected from hydrogen, hydroxy, fluoro, cyano, methoxy, monofluoromethyl methoxy or difluoromethoxy group, wherein the methoxy group is optionally substituted with three deuterium.
  • R a is selected from hydrogen, hydroxy, fluoro, cyano, CH 3 O-, CD 3 O- , CH 2 FO- or CHF 2 O-.
  • R a is selected from hydrogen, fluorine, CH 3 O-, CD 3 O- or CHF 2 O-.
  • R b is selected from hydrogen, C 1-4 alkyl, or C 1-4 alkoxy.
  • R b is selected from C 1-6 alkyl. In some embodiments, R b is selected from C 1-4 alkyl. In some embodiments, R b is selected from C 1-3 alkyl. In some embodiments, R b is selected from methyl.
  • X is selected from CH, CF, C(CN) or N(CH 3 ), and Y is selected from N, CH, C(O), C(OH), C(OCH 3 ), C(OCHF 2 ), C(OCH 2 F), CF or C(OCD 3 ).
  • X is selected from CH and Y is selected from C(OH), C(OCH 3 ), C(OCHF 2 ), C(OCH 2 F), CF, or C(OCD 3 ).
  • X is selected from CH and Y is selected from N.
  • X is selected from N(CH 3 ) and Y is selected from C(O).
  • X is selected from CF or C(CN), and Y is selected from CH or N.
  • It is a double bond. In some embodiments, It is a single key.
  • R 1 and R 2 are each independently selected from C 1-6 alkyl, NH(R c )-C 1-6 alkyl- or N(R c )(C 1-6 alkyl) -C 1-6 alkyl-, or R 1 , R 2 and the phosphorus atom connected thereto together form a 5- to 10-membered heterocyclic group, wherein the 5- to 10-membered heterocyclic group is optionally substituted by one or more R c replaces.
  • R 1 and R 2 are each independently selected from a C 1-6 alkyl group, or R 1 , R 2 and the phosphorus atom connected thereto together form a 5- to 10-membered heterocyclic group, wherein the 5 The ⁇ 10 membered heterocyclic group is optionally substituted with one or more R c .
  • R 1 and R 2 are each independently selected from C 1-3 alkyl, NH(R c )-C 1-3 alkyl- or N(R c )(C 1-3 alkyl) -C 1-3 alkyl-.
  • R 1 and R 2 are each independently selected from C 1-3 alkyl.
  • R 1 and R 2 are each independently selected from methyl, ethyl, propyl, or isopropyl.
  • R 1 and R 2 are each independently selected from methyl or ethyl.
  • R 1 and R 2 are each independently selected from methyl.
  • R 1 , R 2 and the phosphorus atom connected thereto together form a 5-10 membered heterocyclic group, wherein the ring atoms of the 5-10 membered heterocyclic group optionally contain one or more selected From heteroatoms of N, O or S atoms, the 5-10 membered heterocyclic group is optionally substituted with one or more R c .
  • R 1 , R 2 and the phosphorus atom connected thereto together form a 5-10 membered heterocyclic group, wherein the ring atoms of the 5-10 membered heterocyclic group optionally contain one or more selected From heteroatoms of N, O or S atoms, the 5- to 10-membered heterocyclic group is optionally substituted with one or more R c , and when the ring atom contains a N atom, N is connected to R c .
  • R 1 , R 2 and the phosphorus atom to which they are connected together form a 5- to 8-membered heterocyclic group, wherein the ring atoms of the 5- to 8-membered heterocyclic group optionally include one member selected from N Or heteroatoms of O atoms, and when N atoms are contained in the ring atoms, N is connected to R c .
  • R 1 , R 2 and the phosphorus atom to which they are connected together form a 5- to 8-membered heterocycloalkyl group, wherein the ring atom of the 5- to 8-membered heterocycloalkyl group contains at least one N atom, And N and R c are connected.
  • R 1 , R 2 and the phosphorus atom to which they are connected together form a 5-membered or 6-membered heterocyclic group, wherein the 5-membered or 6-membered heterocyclic group is optionally substituted by one or more R c replace.
  • R 1 , R 2 and the phosphorus atom connected thereto together form a 5-membered or 6-membered heterocyclic group, wherein the ring atoms of the 5-membered or 6-membered heterocyclic group optionally include one or A plurality of heteroatoms selected from N, O or S atoms, and when the ring atom contains a N atom, N is connected to R c .
  • R 1 , R 2 and the phosphorus atom to which they are connected together form a 5-membered or 6-membered heterocyclic group, wherein the ring atoms of the 5-membered or 6-membered heterocyclic group optionally include one Heteroatoms from N or O atoms, and when N atoms are contained in the ring atoms, N is connected to R c .
  • R 1 , R 2 and the phosphorus atom to which they are connected together form a 6-membered heterocyclic group, wherein the ring atom of the 6-membered heterocyclic group contains at least one N atom, and N is connected to R c .
  • R 1 , R 2 and the phosphorus atom to which they are connected together form a 6-membered heterocyclic group, wherein the ring atom of the 6-membered heterocyclic group contains only one N atom, and N is connected to R c .
  • R 1 , R 2 and the phosphorus atom to which they are connected together form a 6-membered heterocyclic group, wherein the ring atom of the 6-membered heterocyclic group contains only one O atom.
  • R 1 , R 2 and the phosphorus atom connected thereto together form a 5-membered or 6-membered heterocyclic group, and the ring atoms of the 5-membered or 6-membered heterocyclic group are composed of carbon atoms and phosphorus atoms .
  • R 1 , R 2 and the phosphorus atom connected thereto together form a 6-membered heterocycloalkyl group, wherein the ring atom of the 6-membered heterocycloalkyl group contains at least one N atom, and N and R cConnect .
  • R 1 , R 2 and the phosphorus atom connected thereto together form a 6-membered heterocycloalkyl group, wherein the 6-membered heterocycloalkyl group contains only one N atom in its ring atom, and N and R cConnect .
  • R 1 , R 2 and the phosphorus atom to which they are connected together form a 6-membered heterocycloalkyl group, wherein the 6-membered heterocycloalkyl group contains only one O atom in its ring atoms.
  • R 1 , R 2 and the phosphorus atom connected thereto together form a 5-membered or 6-membered heterocycloalkyl group, and the ring atoms of the 5-membered or 6-membered heterocycloalkyl group are composed of carbon atoms and phosphorus atoms.
  • Atomic composition is composed of carbon atoms and phosphorus atoms.
  • the structural unit Can be selected from structural units Where the structural unit
  • the structural unit Can be selected from structural units
  • the structural unit Can be selected from structural units
  • the structural unit Structural unit Structural unit
  • R 1 and R 2 are each independently selected from methyl or ethyl, or structural units Selected from structural units
  • R 1 and R 2 are each independently selected from a methyl group, or a structural unit Structural unit
  • each R c is independently selected from hydrogen, C 1-6 alkyl-, C 1-6 alkyl-C(O)-, C 1-6 alkyl OC(O)-, C 1-6 alkyl-OC 1-6 alkyl-, C 1-6 alkyl-OC 1-6 alkyl-C(O)-, amino-C(O)-, mono(C 1-6 alkane Group) amino-C(O)-, di(C 1-6 alkyl)amino-C(O)-, amino-C 1-6 alkyl-C(O)-, mono(C 1-6 alkyl) )Amino-C 1-6 alkyl-C(O)-, di(C 1-6 alkyl)amino-C 1-6 alkyl-C(O)-, amino-C(O)-C 1- 6 Alkyl-, mono(C 1-6 alkyl)amino-C(O)-C 1-6 alkyl-, di(C 1-6 alkyl)amino-C(O)-, amino
  • each R c is independently selected from hydrogen, C 1-3 alkyl-, C 1-3 alkyl-C(O)-, C 1-3 alkyl-S(O) 2 -, 3 to 6-membered cycloalkyl-S(O) 2 -, C 1-3 alkyl OC(O)-, C 1-3 alkyl-OC 1-3 alkyl-, C 1-3 alkyl -OC 1-3 alkyl-C(O)-, amino-C(O)-, mono(C 1-3 alkyl)amino-C(O)-, di(C 1-3 alkyl)amino- C(O)-, amino-C 1-3 alkyl-C(O)-, mono(C 1-3 alkyl)amino-C 1-3 alkyl-C(O)-, di(C 1- 3 alkyl) amino -C 1-3 alkyl -C (O) -, amino -C (O) -C 1-3 alkyl -, mono (C 1- 3 al
  • each R c is independently selected from hydrogen, C 1-3 alkyl-, C 1-3 alkyl-C(O)-, C 1-3 alkyl-S(O) 2 -, 3 to 5 membered cycloalkyl-S(O) 2 -, C 1-3 alkyl OC(O)-, C 1-3 alkyl-OC 1-3 alkyl-, C 1-3 alkyl -O-CH 2 -C(O)-, two(C 1-3 alkyl)amino-C(O)-, two(C 1-3 alkyl)amino-CH 2 -C(O)-, two (C 1-3 alkyl) amino-C(O)-CH 2 -, 3 to 5 membered cycloalkyl-, 3 to 5 membered cycloalkyl-C(O)-, 3 to 5 membered cycloalkyl- CH 2 -, 3 to 5-membered heterocycloalkyl-, phenyl-CH 2
  • each R c is independently selected from hydrogen, C 1-3 alkyl-, C 1-3 alkyl-C(O)-, C 1-3 alkyl-S(O) 2 -, 3 to 5 membered cycloalkyl-S(O) 2 -, C 1-3 alkyl OC(O)-, C 1-3 alkyl-OC 1-3 alkyl-, C 1-3 alkyl -O-CH 2 -C(O)-, two(C 1-3 alkyl)amino-C(O)-, two(C 1-3 alkyl)amino-CH 2 -C(O)-, two (C 1-3 alkyl) amino-C(O)-CH 2 -, 3 to 5 membered cycloalkyl-, 3 to 5 membered cycloalkyl-C(O)-, 3 to 5 membered cycloalkyl- CH 2 -, 3 to 5-membered heterocycloalkyl- or C 1-3 alkyl substitute
  • each R c is independently selected from hydrogen, C 1-3 alkyl-, C 1-3 alkyl-C(O)-, C 1-3 alkyl OC(O)-, C 1-3 alkyl-OC 1-3 alkyl-, C 1-3 alkyl-O-CH 2 -C(O)-, di(C 1-3 alkyl)amino-C(O)-, Two (C 1-3 alkyl) amino-CH 2 -C(O)-, two (C 1-3 alkyl) amino-C(O)-CH 2 -, 3 to 5 membered cycloalkyl-, 3 ⁇ 5-membered cycloalkyl-C(O)-, 3--5 membered cycloalkyl-CH 2 -, phenyl-CH 2 -or C 1-3 alkyl- substituted by a hydroxy group.
  • each R c is independently selected from hydrogen, methyl, ethyl, isopropyl, Acetyl,
  • each R c is independently selected from methyl, ethyl, isopropyl, Acetyl,
  • ring A is selected from C 6-10 aryl, 5-10 membered heteroaryl, 8-12 membered benzocycloalkyl, 8-12 membered benzocycloalkenyl, or 8-12 membered benzene And heterocyclic group.
  • ring A is selected from C 6-10 aryl, 5-10 membered heteroaryl, 8-12 membered benzocycloalkyl, 8-12 membered benzocycloalkenyl, 8-12 membered benzene And heterocycloalkyl or 8-12 membered benzoheterocycloalkenyl.
  • ring A is selected from C 6-10 aryl, 5-10 membered heteroaryl, 8-12 membered benzocycloalkyl, or 8-12 membered benzoheterocycloalkyl.
  • ring A is selected from C 6-10 aryl, 5-10 membered heteroaryl, 8-10 membered fused ring, or 8-10 membered fused heterocyclic ring.
  • ring A is selected from C 6-10 aryl, 5-10 membered heteroaryl, 8-10 membered benzocycloalkyl, 8-10 membered benzocycloalkenyl, or 8-10 membered benzene And heterocyclic group.
  • ring A is selected from C 6-10 aryl, 5-10 membered heteroaryl, 8-10 membered benzocycloalkyl, 8-10 membered benzocycloalkenyl, 8-10 membered benzene And heterocycloalkyl or 8-10 membered benzoheterocycloalkenyl.
  • ring A is selected from C 6-10 aryl, 5-10 membered heteroaryl, 8-10 membered benzocycloalkyl, or 8-10 membered benzoheterocycloalkyl.
  • ring A is selected from phenyl, thienyl, 2,3-dihydro-1H-indenyl, 2,3-dihydrobenzofuranyl, or benzofuranyl.
  • ring A is selected from phenyl, thienyl, or 2,3-dihydro-1H-indenyl.
  • n is 0, 1, or 2; alternatively, n is 1, 2, or 3.
  • n is 0 or 1; alternatively, n is 0 or 2; alternatively, n is 0 or 3; alternatively, n is 1 or 2; alternatively, n is 1 or 3; alternatively, n is 2 or 3. In some embodiments, n is 2.
  • each R 3 is independently selected from amino, nitro, halogen, C 1-6 alkyl- or phenyl, wherein the C 1-6 alkyl- or phenyl is optionally One or more R d substitutions.
  • each R 3 is independently selected from amino, halogen, C 1-6 alkyl- or phenyl, wherein the C 1-6 alkyl- or phenyl is optionally substituted by one or more Replacement of Rd.
  • each R 3 is independently selected from amino, nitro, halogen, C 1-4 alkyl- or phenyl, wherein said C 1-4 alkyl- or phenyl is optionally One or more R d substitutions.
  • each R 3 is independently selected from amino, nitro, halogen, C 1-4 alkyl- or phenyl, wherein said C 1-4 alkyl- or phenyl is optionally 1, 2 or 3 R d substitutions.
  • R d is selected from hydroxyl, halogen, or C 1-3 alkyl-NH-C 1-3 alkyl-.
  • R d is selected from hydroxyl, fluorine, or methyl-NH-methyl-.
  • each R 3 is independently selected from amino, nitro, fluoro, methyl, trifluoromethyl, -CF 2 CH 2 OH, -CHF 2 , -CF 2 CH 3 , -CF 2 C(CH 3 ) 2 OH or
  • each R 3 is independently selected from amino, fluorine, methyl, trifluoromethyl, -CF 2 CH 2 OH, -CHF 2 , -CF 2 CH 3 , -CF 2 C(CH 3 ) 2 OH or
  • each R 3 is independently selected from amino, nitro, fluoro, methyl, or trifluoromethyl.
  • R 4 and R 5 are each independently selected from hydrogen, deuterium, or C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted with one or more halogens.
  • R 4 is selected from C 1-3 alkyl and R 5 is selected from hydrogen or deuterium, wherein said C 1-3 alkyl is optionally substituted with one or more halogens. In some embodiments, R 4 is selected from methyl and R 5 is selected from hydrogen or deuterium, wherein the methyl is optionally substituted with one or more fluorines. In some embodiments, R 4 is selected from methyl or -CH 2 F, and R 5 is selected from hydrogen or deuterium. In some embodiments, R 4 is selected from methyl and R 5 is selected from hydrogen.
  • R 5 is selected from C 1-3 alkyl and R 4 is selected from hydrogen or deuterium, wherein said C 1-3 alkyl is optionally substituted with one or more halogens. In some embodiments, R 5 is selected from methyl and R 4 is selected from hydrogen or deuterium, wherein the methyl is optionally substituted with one or more fluorines. In some embodiments, R 5 is selected from methyl or -CH 2 F, and R 4 is selected from hydrogen or deuterium. In some embodiments, R 5 is selected from methyl and R 4 is selected from hydrogen.
  • R 6 is selected from hydrogen, halogen, or C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted with one or more halogens.
  • R 6 is selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl or isopropyl, wherein said methyl, ethyl, propyl or isopropyl is optionally One or more halogen substitutions.
  • R 6 is selected from hydrogen, fluorine, chlorine, or methyl, wherein the methyl group is optionally substituted with 1, 2, or 3 fluorines.
  • R 6 is selected from hydrogen, chlorine, methyl, or -CH 2 F. In some embodiments, R 6 is selected from methyl.
  • the heteroatom in the heterocyclic group, heteroaryl group or heterocycloalkyl group described in the present application is selected from N, O, S, and P. In some embodiments, the heteroatoms in the heterocyclic group, heteroaryl group, or heterocycloalkyl group described in this application are selected from N, O, and P. In some embodiments, the heteroatoms in the heterocyclic group, heteroaryl group or heterocycloalkyl group described in this application are selected from N and P.
  • X and Y are each independently selected from CR a , C(O), N or NR b ;
  • each represents a single bond or a double bond
  • R a is selected from hydrogen, hydroxy, halogen, C 1-6 alkyl or C 1-6 alkoxy, wherein the C 1-6 alkyl is optionally substituted with one or more halogens, and the C 1- 6 Alkoxy is optionally substituted with one or more deuterium or halogen;
  • R b is selected from hydrogen, C 1-6 alkyl or C 1-6 alkoxy
  • R 1 and R 2 are each independently selected from C 1-6 alkyl, NH(R c )-C 1-6 alkyl- or N(R c )(C 1-6 alkyl)-C 1-6 alkane Group-, or R 1 , R 2 and the phosphorus atom connected to them together form a 5-8 membered heterocyclic group, wherein the ring atom of the 5-8 membered heterocyclic group contains at least one N atom, and N Connect with R c;
  • Each R c is independently selected from hydrogen, C 1-6 alkyl, C 1-6 alkyl-C(O)-, C 1-6 alkyl OC(O)-, C 1-6 alkyl- OC 1-6 alkyl-, C 1-6 alkyl-OC 1-6 alkyl-C(O)-, amino-C(O)-, mono(C 1-6 alkyl)amino-C(O )-, di(C 1-6 alkyl)amino-C(O)-, amino-C 1-6 alkyl-C(O)-, mono(C 1-6 alkyl)amino-C 1-6 Alkyl-C(O)-, di(C 1-6 alkyl)amino-C 1-6 alkyl-C(O)-, amino-C(O)-C 1-6 alkyl-, mono( C 1-6 alkyl) amino-C(O)-C 1-6 alkyl-, di(C 1-6 alkyl) amino-C(O)-C 1-6 alkyl
  • Ring A is selected from C 6-10 aryl, 5-10 membered heteroaryl or 8-12 membered fused ring;
  • n 0, 1, 2 or 3;
  • Each R 3 is independently selected from an amino group, a nitro group, a halogen, a C 1-8 alkyl group or a 3-6 membered cycloalkyl group, wherein the C 1-8 alkyl group and a 3-6 membered cycloalkyl group are either Optionally replaced by one or more R d ;
  • R d is selected from hydroxyl or halogen.
  • X is selected from CR a
  • Y is selected from CR a , C(O), N, or NR b .
  • X is selected from CR a
  • Y is selected from CR a , C(O), or N.
  • X is selected from CR a
  • Y is selected from N.
  • both X and Y are selected from CR a .
  • X is selected from CH and Y is selected from CR a .
  • R a is selected from hydrogen, halogen or C 1-4 alkoxy, wherein said C 1-4 alkoxy is optionally substituted with one or more deuterium or halogen. In some embodiments, R a is selected from hydrogen, halogen or C 1-4 alkoxy, wherein said C 1-4 alkoxy optionally substituted with deuterium or a three or more fluorine substituents. In some embodiments, R a is selected from hydrogen, halogen or C 1-4 alkoxy, wherein said C 1-4 alkoxy optionally substituted by deuterium or 3-fluoro-2.
  • R a is selected from hydrogen, fluoro, methoxy, or difluoromethoxy, methoxy group which is optionally substituted with three deuterium.
  • R a is selected from hydrogen, fluorine, CH 3 O-, CD 3 O- or CHF 2 O-.
  • R b is selected from C 1-6 alkyl. In some embodiments, R b is selected from C 1-4 alkyl. In some embodiments, R b is selected from C 1-3 alkyl. In some embodiments, R b is selected from methyl.
  • X is selected from CH and N(CH 3 ), and Y is selected from N, C(O), C(OCH 3 ), CF, or C(OCD 3 ). In some embodiments, X is selected from CH and Y is selected from C(OCH 3 ), CF, or C(OCD 3 ). In some embodiments, X is selected from CH and Y is selected from N. In some embodiments, X is selected from N(CH 3 ) and Y is selected from C(O).
  • R 1 and R 2 are each independently selected from C 1-3 alkyl, NH(R c )-C 1-3 alkyl- or N(R c )(C 1-3 alkyl) -C 1-3 alkyl-.
  • R 1 and R 2 are each independently selected from C 1-3 alkyl.
  • R 1 and R 2 are each independently selected from methyl.
  • R 1 , R 2 and the phosphorus atom to which they are connected together form a 6-membered heterocyclic group, wherein the ring atoms of the 6-membered heterocyclic group include at least one N atom, and N is connected to R c .
  • R 1 , R 2 and the phosphorus atom connected to them together form a 6-membered heterocyclic group, and the ring atom of the 6-membered heterocyclic group contains only one N atom, and N is connected to R c .
  • R 1 , R 2 and the phosphorus atom to which they are connected together form a 5- to 8-membered heterocycloalkyl group, and the ring atom of the 5- to 8-membered heterocycloalkyl group contains at least one N atom, And N and R c are connected.
  • R 1 , R 2 and the phosphorus atom connected to them together form a 6-membered heterocycloalkyl group, and the ring atoms of the 6-membered heterocycloalkyl group include at least one N atom, and N and R cConnect .
  • R 1 , R 2 and the phosphorus atom connected to them together form a 6-membered heterocycloalkyl group, and the ring atom of the 6-membered heterocycloalkyl group contains only one N atom, and N and R cConnect .
  • the structural unit Selected from structural units is selected from structural units
  • R 1 and R 2 are each independently selected from a methyl group, or a structural unit Selected from structural units
  • each R c is independently selected from hydrogen, C 1-3 alkyl, C 1-3 alkyl-C(O)-, C 1-3 alkyl OC(O)-, C 1-3 alkyl-OC 1-3 alkyl-, C 1-3 alkyl-OC 1-3 alkyl-C(O)-, amino-C(O)-, mono(C 1-6 alkyl) )Amino-C(O)-, di(C 1-3 alkyl)amino-C(O)-, amino-C 1-3 alkyl-C(O)-, mono(C 1-3 alkyl) Amino-C 1-3 alkyl-C(O)-, di(C 1-3 alkyl)amino-C 1-3 alkyl-C(O)-, amino-C(O)-C 1-3 Alkyl-, mono(C 1-3 alkyl) amino-C(O)-C 1-3 alkyl-, di(C 1-3 alkyl) amino-C(O)-C 1-3 Alkyl
  • each R c is independently selected from hydrogen, C 1-3 alkyl, C 1-3 alkyl-C(O)-, C 1-3 alkyl OC(O)-, C 1-3 alkyl-OC 1-3 alkyl-, C 1-3 alkyl-O-CH 2 -C(O)-, two (C 1-3 alkyl) amino-C(O)-, two (C 1-3 alkyl)amino-CH 2 -C(O)-, di(C 1-3 alkyl)amino-C(O)-CH 2 -, 3 to 5 membered cycloalkyl, 3 to 5 Member cycloalkyl-C(O)-, 3- to 5-membered cycloalkyl-CH 2 -, phenyl-CH 2 -or C 1-3 alkyl substituted by a hydroxy group.
  • each R c is independently selected from methyl, ethyl, isopropyl, acetyl,
  • ring A is selected from a C 6-10 aryl group, a 5- to 6-membered heteroaryl group, or an 8- to 10-membered fused ring.
  • ring A is selected from phenyl, thienyl, or 2,3-dihydro-1H-indenyl.
  • n is 0, 1, or 2; alternatively, n is 1, 2, or 3.
  • n is 0 or 1; alternatively, n is 0 or 2; alternatively, n is 0 or 3; alternatively, n is 1 or 2; alternatively, n is 1 or 3; alternatively, n is 2 or 3. In some embodiments, n is 2.
  • each R 3 is independently selected from amino, nitro, halogen, or C 1-4 alkyl, and the C 1-4 alkyl is optionally substituted with 1, 2 or 3 R d .
  • R d is selected from hydroxyl or fluorine.
  • each R 3 is independently selected from amino, nitro, fluoro, methyl, trifluoromethyl, -CF 2 CH 2 OH, -CHF 2 , -CF 2 CH 3 or -CF 2 C(CH 3 ) 2 OH.
  • the compound of formula (I) or formula (II) of the present application its stereoisomer or a pharmaceutically acceptable salt thereof is selected from the compound of formula (III), its stereoisomer or its Pharmaceutically acceptable salt
  • X and Y are independently selected from CR a and N, for example, both X and Y are selected from CR a , or X is CR a and Y is N;
  • R a is selected from hydrogen or C 1-4 alkoxy; preferably, R a is selected from hydrogen or methoxy;
  • R 1 , R 2 and the phosphorus atom connected thereto together form a 6-membered heterocyclic group, wherein the ring atom of the 6-membered heterocyclic group contains at least one N atom or O atom, and when the ring atom contains a N atom , N is connected to R c (preferably contains one N atom, and N is connected to R c );
  • R c is selected from C 1-4 alkyl-S(O) 2- (preferably methylsulfonyl), C 3-6 cycloalkyl-S(O) 2- (preferably cyclopropylsulfonyl);
  • Ring A is selected from C 6-10 aryl groups, preferably C6 aryl groups (ie, phenyl);
  • n 0, 1, 2 or 3, preferably 2;
  • Each R 3 is independently selected from halogen (preferably F), C 1-8 alkyl (preferably C 1-4 alkyl, more preferably methyl or ethyl), wherein the C 1-8 alkyl is any Optionally substituted by one or more halogens (preferably F);
  • R 4 and R 5 are each independently selected from hydrogen or C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted with one or more fluorine (preferably R 4 is selected from hydrogen, R 5 is selected From methyl, or, R 4 is selected from methyl and R 5 is selected from hydrogen);
  • R 6 is selected from hydrogen, halogen or C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with one or more halogens, for example, R 6 can be selected from hydrogen, methyl or optionally Methyl substituted with one or more halogens (for example, -CH 2 F).
  • X and Y are independently selected from CR a and N, for example, both X and Y are selected from CR a , or X is CR a and Y is N;
  • R a is selected from hydrogen or C 1-4 alkoxy; preferably, R a is selected from hydrogen or methoxy; more preferably, R a is selected from hydrogen;
  • R 1 , R 2 and the phosphorus atom connected thereto together form a 6-membered heterocyclic group, wherein the ring atom of the 6-membered heterocyclic group contains at least one N atom (preferably one N atom), and N and R c connect;
  • R c is selected from C 1-4 alkyl-S(O) 2- (preferably methylsulfonyl), C 3-6 cycloalkyl-S(O) 2- (preferably cyclopropylsulfonyl);
  • Ring A is selected from C 6-10 aryl groups, preferably C6 aryl groups (ie, phenyl);
  • n 0, 1, 2 or 3, preferably 2;
  • Each R 3 is independently selected from halogen (preferably F), C 1-8 alkyl (preferably C1-4, more preferably methyl or ethyl), wherein the C 1-8 alkyl is optionally substituted by one Or multiple halogen (preferably F) substitutions.
  • halogen preferably F
  • C 1-8 alkyl preferably C1-4, more preferably methyl or ethyl
  • the compound of formula (I) or formula (II), its stereoisomer or pharmaceutically acceptable salt thereof of the present application is selected from a compound of formula (III-1), formula (III-2) ) Compound, compound of formula (III-3), compound of formula (III-4), compound of formula (III-5), compound of formula (III-6), compound of formula (III-7), compound of formula (III-8) And the compound of formula (III-9), its stereoisomer or its pharmaceutically acceptable salt,
  • R 1, R 2, R 3, Y, n, ring A, R a, R b, and R c is defined above.
  • the compound of formula (I) or formula (II), stereoisomers thereof, or pharmaceutically acceptable salts thereof of the present application are selected from the group consisting of a compound of formula (IV), a compound of formula (V), and a compound of formula (V) and (VI) the compound, its stereoisomer or its pharmaceutically acceptable salt,
  • R 3 , Y, n, R b and R c are as described above.
  • this application includes the above-defined variables and their embodiments, and any combination thereof.
  • the compound of formula (I) of the present application is selected from the following compounds, stereoisomers thereof, or pharmaceutically acceptable salts thereof:
  • the compound of formula (I) of the present application is selected from the following compounds, stereoisomers thereof, or pharmaceutically acceptable salts thereof:
  • this application provides a method for preparing a compound of formula (I), which includes: reacting a compound of formula M3 with a compound of formula N3 to prepare a compound of formula (I)
  • Rx is selected from chlorine, bromine or iodine
  • R 6 is selected from C 1-6 alkyl optionally substituted with one or more halogens
  • R 1 , R 2 , R 3 , R 4 , R 5 , X, Y, n and ring A are as described above.
  • this application provides a preparation method of the compound of formula M3, including:
  • Rx is selected from chlorine, bromine or iodine
  • R 6 is selected from C 1-6 alkyl optionally substituted with one or more halogens
  • R 3 , R 4 , R 5 , X, Y, n and ring A are as described above.
  • this application provides a preparation method of the compound of formula M3, including:
  • Rx is selected from chlorine, bromine or iodine
  • R 6 is selected from C 1-6 alkyl optionally substituted with one or more halogens
  • R 3 , R 4 , R 5 , X, Y, n and ring A are as described above.
  • the compound of formula M3 is prepared by the method described above.
  • this application provides a method for preparing a compound of formula (III-8), the method comprising:
  • the compound of formula M3-1 is reacted with 1-benzyl-1,4-azaphosphine-4-oxide to prepare the compound of formula M3-2, and then the benzyl protection is removed to obtain the compound of formula M3-3, and finally a substitution reaction occurs.
  • the compound of formula (III-8) is prepared,
  • Rx is selected from chlorine, bromine or iodine
  • R 3 , R c , n and ring A are as described above.
  • the preparation method of the compound of formula (III-8) provided in this application includes:
  • Step (1) The compound of formula M3-2 is prepared by reacting the compound of formula M3-1 with 1-benzyl-1,4-azaphosphine-4-oxide,
  • Step (2) The compound of formula M3-2 is reacted to obtain the compound of formula M3-3,
  • Step (3) The compound of formula M3-3 is reacted to obtain the compound of formula (III-8),
  • step (2) is In the presence of
  • Rx is selected from chlorine, bromine or iodine
  • R 6 is selected from C 1-6 alkyl optionally substituted with one or more halogens
  • R 3 , R c , n and ring A are as described above.
  • the present application provides a pharmaceutical composition, which comprises the above-mentioned compound of the present application, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition of the present application further includes pharmaceutically acceptable excipients.
  • the present application provides a method for treating or preventing diseases and/or disorders related to or regulated by SOS1 in a mammal, the method comprising administering treatment or treatment to a mammal in need of such treatment or prevention, preferably a human A prophylactically effective amount of the above-mentioned compound, its stereoisomer or its pharmaceutically acceptable salt, or its pharmaceutical composition.
  • the present application provides the above-mentioned compound, its stereoisomer or its pharmaceutically acceptable salt, or its pharmaceutical composition in the preparation of a medicine for the treatment or prevention of diseases and/or disorders related to or regulated by SOS1 In the use.
  • the application provides the use of the above-mentioned compound, its stereoisomer or its pharmaceutically acceptable salt, or its pharmaceutical composition in the treatment or prevention of diseases and/or disorders related to or regulated by SOS1 .
  • the present application provides the above-mentioned compounds, stereoisomers or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof for the treatment or prevention of diseases and/or disorders related to or modulated by SOS1.
  • the diseases and/or disorders related to or regulated by SOS1 are selected from diseases and/or disorders in which SOS1 interacts with RAS family proteins.
  • the disease and/or disorder related to or regulated by SOS1 is selected from cancer, such as non-small cell lung cancer.
  • the compound of the present application has good KRAS-G12C/SOS1 protein binding inhibitory activity, K562 cell proliferation inhibitory activity, in vivo and in vitro drug activity, and good pharmacokinetic properties.
  • Chemical bond According to the different groups connected at both ends, it represents a single bond or a double bond.
  • the chemical bond Is a double bond; when one of the X and Y connected at both ends of the chemical bond is CO or NR a , the chemical bond It is a single key.
  • the choice of X and Y will not violate the valence bond rule.
  • substituted means that any one or more hydrogen atoms on a specific atom are replaced by a substituent, as long as the valence of the specific atom is normal and the substituted compound is stable.
  • it means that two hydrogen atoms are replaced, and the oxo will not occur on the aromatic group.
  • the term "optional” or “optionally” means that the event or situation described later can occur or not occur, and the description includes occurrence of said event or situation and non-occurrence of said event or situation.
  • the ethyl group is "optionally" substituted by halogen, meaning that the ethyl group can be unsubstituted (-CH 2 CH 3 ), mono-substituted (such as -CH 2 CH 2 F), or polysubstituted (such as -CHFCH 2 F, -CH 2 CHF 2 etc.) or completely substituted (-CF 2 CF 3 ).
  • halogen meaning that the ethyl group can be unsubstituted (-CH 2 CH 3 ), mono-substituted (such as -CH 2 CH 2 F), or polysubstituted (such as -CHFCH 2 F, -CH 2 CHF 2 etc.) or completely substituted (-CF 2 CF 3 ).
  • C mn in this context means that the part has an integer number of carbon atoms in a given range.
  • C 1-6 means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms;
  • C 1-3 It means that the group can have 1 carbon atom, 2 carbon atoms or 3 carbon atoms.
  • any variable e.g., R
  • its definition in each case is independent. So, for example, if a group is replaced by 2 Rs, then each R has independent options.
  • linking group When the number of a linking group is 0, such as -(CH 2 ) 0 -, it means that the linking group is a covalent bond.
  • the substituent can be bonded to any atom on the ring.
  • the structural unit It means that it can be substituted at any position on the cyclohexyl or cyclohexadiene.
  • halo or halogen refers to fluorine, chlorine, bromine and iodine.
  • hydroxy refers to the -OH group.
  • amino refers to the -NH 2 group.
  • nitro refers to the -NO 2 group.
  • cyano refers to the -CN group.
  • alkyl refers to a hydrocarbon group of the general formula C n H 2n+1.
  • the alkyl group may be linear or branched.
  • C 1 - 6 alkyl refers to (e.g., methyl, ethyl, n-propyl, isopropyl, alkyl containing 1 to 6 carbon atoms, n-butyl, isobutyl, sec-butyl, Tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc.).
  • the alkyl moiety (ie, alkyl) of alkoxy, alkylamino, dialkylamino, alkylsulfonyl, and alkylthio have the same definition as described above.
  • alkoxy refers to -O-alkyl
  • alkylamino or “monoalkylamino” refers to -NH-alkyl.
  • dialkylamino refers to -N(alkyl) 2 .
  • cycloalkyl refers to a carbocyclic ring that is fully saturated and may exist as a monocyclic, bridged, or spiro ring. Unless otherwise indicated, the carbocyclic ring is usually a 3 to 10 membered ring.
  • Non-limiting examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, adamantane Alkyl and so on.
  • heterocyclyl refers to a non-aromatic ring that is fully saturated or partially unsaturated (but not fully unsaturated heteroaromatic) and may exist as a single ring, bridged ring, or spiro ring.
  • the heterocyclic group is generally a 3 to 12 membered ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen, phosphorus, and/or nitrogen.
  • heterocyclic groups include, but are not limited to, oxiranyl, tetrahydrofuryl, dihydrofuranyl, pyrrolidinyl, N-methylpyrrolidinyl, dihydropyrrolyl, piperidinyl, piperazinyl , Pyrazolidinyl, 4H-pyranyl, morpholinyl, thiomorpholinyl, tetrahydrothienyl or Wait.
  • heterocycloalkyl refers to a cyclic group that is fully saturated and may exist as a monocyclic, bridged, or spiro ring. Unless otherwise indicated, the heterocycloalkyl group is generally a 3 to 12 membered ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen, phosphorus and/or nitrogen, 3 To 7-membered ring or 5 to 8-membered ring.
  • 3-membered heterocycloalkyl groups include, but are not limited to, oxirane, sulfidene, and azaethylenyl groups
  • 4-membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetane
  • cyclic group, thiabutanyl, 5-membered heterocycloalkyl include but are not limited to tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidine
  • 6-membered heterocycloalkyl groups include but are not limited to piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, 1, 4-thiaxanyl, 1,4-dioxanyl,
  • aryl refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated ⁇ -electron system.
  • aryl groups can have 6-20 carbon atoms, 6-14 carbon atoms, or 6-12 carbon atoms.
  • Non-limiting examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, 1,2,3,4-tetralin and the like.
  • heteroaryl refers to a monocyclic or condensed polycyclic ring system, which contains at least one ring atom selected from N, O, and S, the remaining ring atoms are C, and have at least one aromatic ring.
  • Preferred heteroaryl groups have a single 5- to 8-membered ring, or multiple fused rings containing 6 to 14, especially 6 to 10 ring atoms.
  • heteroaryl groups include, but are not limited to, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl , Tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothienyl, indolyl, isoindolyl, etc.
  • fused ring refers to a 7-20 membered all-carbon polycyclic ring in which two rings in the system share two adjacent carbon atoms, at least one of which has a fully conjugated ⁇ -electron system, but the whole is not aromatic . According to the number of constituent rings, it can be classified into bicyclic, tricyclic, tetracyclic or polycyclic condensed rings, preferably bicyclic or tricyclic, and more preferably 6-membered/6-membered or 5-membered/6-membered bicyclic ring.
  • fused rings include:
  • spiroheterocycloalkyl refers to a fully saturated 5- to 20-membered polycyclic ring sharing one carbon atom (called a spiro atom) between single rings, and one or more ring atoms in the polycyclic ring are selected from sulfur and silicon , Phosphorus, oxygen and/or nitrogen heteroatoms (preferably 1 or 2 heteroatoms), and the remaining ring atoms are carbon atoms. It is preferably 6 to 14 yuan, more preferably 6 to 10 yuan.
  • the spiro heterocyclic ring is divided into a single spiro heterocyclic ring, a dispiro heterocyclic ring or a polyspiro heterocyclic ring.
  • Non-limiting examples of spiro heterocycles include
  • polyheterocycloalkyl refers to a fully saturated polycyclic ring having 5 to 20 membered ring atoms and two rings sharing 2 ring atoms.
  • One or more ring atoms in the polycyclic ring are selected from sulfur, silicon, Phosphorus, oxygen and/or nitrogen heteroatoms (preferably 1 or 2 heteroatoms), and the remaining ring atoms are carbon atoms. It is preferably 6 to 14 yuan, more preferably 6 to 10 yuan.
  • it can be classified into bicyclic, tricyclic or polycyclic bridged heterocycles, preferably bicyclic.
  • conjugated heterocycles include
  • benzocycloalkyl refers to a benzene ring fused with a cycloalkyl group (ie, the benzene ring and cycloalkyl group share two adjacent carbon atoms).
  • benzocycloalkyl groups include: Wait.
  • cycloalkenyl refers to an unsaturated carbocyclic ring containing at least one carbon-carbon double bond and not containing any carbon-carbon triple bond, and may be a carbocyclic ring that exists as a monocyclic ring, a bridged ring, or a spiro ring.
  • Non-limiting examples of cycloalkenyl groups include: cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, and cyclohexadienyl.
  • benzocycloalkenyl refers to a benzene ring fused with a cycloalkenyl group (ie, a benzene ring and a cycloalkenyl group share two adjacent carbon atoms).
  • benzocycloalkenyl groups include:
  • benzoheterocyclic group refers to a benzene ring and a heterocyclic group fused (ie, the benzene ring and the heterocyclic group share two adjacent carbon atoms).
  • benzoheterocyclic groups include:
  • benzoheterocycloalkyl refers to a benzene ring fused with a heterocycloalkyl group (ie, the benzene ring and a heterocycloalkyl group share two adjacent carbon atoms).
  • benzoheterocycloalkyl groups include:
  • heterocycloalkenyl refers to an unsaturated cyclic group containing at least one carbon-carbon double bond or carbon-nitrogen double bond, and may exist as a single ring, a bridged ring, or a spiro ring. Unless otherwise indicated, the heterocyclic ring generally contains 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen, phosphorus and/or nitrogen.
  • heterocyclenyl groups include: 1,2,3,4-tetrahydropyridyl, 1,2-dihydropyridyl, 1,4-dihydropyridyl, 1,2,3,6- Tetrahydropyridyl, 1,4,5,6-tetrahydropyrimidinyl, 3-pyrrolinyl, 3,4-dihydro-2H-pyran, dihydrofuranyl, dihydrothienyl and dihydrothiopyran base.
  • benzoheterocyclenyl refers to a benzene ring fused with a heterocycloalkenyl group (ie, the benzene ring and a heterocycloalkenyl group share two adjacent carbon atoms).
  • benzoheterocyclenyl groups include:
  • fused heterocyclic ring refers to a 7-20 membered polycyclic ring where two rings in the system share two adjacent atoms, which contain at least one ring atom selected from N, O, S, and the remaining ring atoms are C, and At least one ring has a fully conjugated ⁇ -electron system, but the whole is not aromatic. According to the number of constituent rings, it can be classified into bicyclic, tricyclic, tetracyclic or polycyclic condensed rings, preferably bicyclic or tricyclic, and more preferably 6-membered/6-membered or 5-membered/6-membered bicyclic ring.
  • fused heterocycles include:
  • treatment means administering the compound or formulation described in this application to ameliorate or eliminate a disease or one or more symptoms related to the disease, and includes:
  • prevention means administering the compound or preparation described in this application to prevent a disease or one or more symptoms related to the disease, and includes: preventing the occurrence of a disease or disease state in a mammal, especially when Such mammals are susceptible to the disease state, but have not been diagnosed as having the disease state.
  • terapéuticaally or prophylactically effective amount means (i) treatment or prevention of a specific disease, condition, or disorder described herein, (ii) alleviation, amelioration, or elimination of a specific disease, condition, or disorder described herein Or more symptoms, or (iii) the amount of the compound of the present application that prevents or delays the onset of one or more symptoms of a specific disease, condition, or disorder described herein.
  • the amount of the compound of the present application that constitutes a "therapeutically effective amount” varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but it can be routinely determined by those skilled in the art. Determined by its own knowledge and this disclosure.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms that are within the scope of reliable medical judgment and are suitable for use in contact with human and animal tissues without excessive Toxicity, irritation, allergic reactions or other problems or complications of the disease are commensurate with a reasonable benefit/risk ratio.
  • salts for example, metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, etc. can be mentioned. .
  • pharmaceutical composition refers to a mixture of one or more of the compounds of the application or their salts and pharmaceutically acceptable excipients.
  • the purpose of the pharmaceutical composition is to facilitate the administration of the compound of the present application to the organism.
  • pharmaceutically acceptable excipients refers to those excipients that have no obvious stimulating effect on the organism and will not damage the biological activity and performance of the active compound.
  • Suitable auxiliary materials are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water and the like.
  • the compounds of the present invention may exist in specific geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers Isomers, (D)-isomers, (L)-isomers, and their racemic mixtures and other mixtures, such as enantiomers or diastereomer-enriched mixtures, all of these mixtures belong to this Within the scope of the invention.
  • Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All these isomers and their mixtures are included in the scope of the present invention.
  • wedge-shaped solid line keys And wedge-shaped dashed key Represents the absolute configuration of a three-dimensional center, with a straight solid line key And straight dashed key Indicates the relative configuration of the three-dimensional center.
  • optically active (R)- and (S)-isomers and D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If you want to obtain an enantiomer of a compound of the present invention, it can be prepared by asymmetric synthesis or derivatization with chiral auxiliary agents, in which the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide pure The desired enantiomer.
  • the molecule when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), it forms a diastereomeric salt with an appropriate optically active acid or base, and then passes through a conventional method known in the art The diastereoisomers are resolved, and then the pure enantiomers are recovered.
  • the separation of enantiomers and diastereomers is usually accomplished through the use of chromatography, which uses a chiral stationary phase and is optionally combined with chemical derivatization (for example, the formation of amino groups from amines). Formate).
  • the present application also includes compounds of the present application that are the same as those described herein, but have one or more atoms replaced by an isotope-labeled atom having an atomic weight or mass number different from the atomic weight or mass number commonly found in nature.
  • isotopes that can be bound to the compounds of the present application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 123 I, 125 I and 36 Cl, etc.
  • isotope-labeled compounds of the application can be used in compound and/or substrate tissue distribution analysis. Tritiated (ie 3 H) and carbon-14 (ie 14 C) isotopes are especially preferred due to their ease of preparation and detectability. Positron emission isotopes such as 15 O, 13 N, 11 C, and 18 F can be used in positron emission tomography (PET) studies to determine substrate occupancy.
  • PET positron emission tomography
  • the isotopically-labeled compounds of the present application can be prepared by the following procedures similar to those disclosed in the schemes and/or examples below, by replacing non-isotopically-labeled reagents with isotope-labeled reagents.
  • substitution with heavier isotopes can provide certain therapeutic advantages resulting from higher metabolic stability (for example, increased in vivo half-life or reduced dosage requirements), and therefore in certain It may be preferable in some cases, where the deuterium substitution can be partial or complete, and partial deuterium substitution refers to the substitution of at least one hydrogen by at least one deuterium.
  • the pharmaceutical composition of the present application can be prepared by combining the compound of the present application with suitable pharmaceutically acceptable excipients, for example, can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, and powders. , Granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols.
  • Typical routes for administering the compound of the present application or a pharmaceutically acceptable salt or pharmaceutical composition thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, Intramuscular, subcutaneous, and intravenous administration.
  • the pharmaceutical composition of the present application can be manufactured by methods well known in the art, such as conventional mixing method, dissolution method, granulation method, sugar-coated pill method, grinding method, emulsification method, freeze-drying method, etc.
  • the pharmaceutical composition is in an oral form.
  • the pharmaceutical composition can be formulated by mixing the active compound with pharmaceutically acceptable excipients well known in the art. These auxiliary materials enable the compound of the present application to be formulated into tablets, pills, lozenges, sugar-coated agents, capsules, liquids, gels, slurries, suspensions, etc., for oral administration to patients.
  • the solid oral composition can be prepared by conventional mixing, filling or tableting methods. For example, it can be obtained by the following method: mixing the active compound with solid excipients, optionally grinding the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into granules to obtain tablets Or the core of the dragee.
  • suitable excipients include but are not limited to: binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, and the like.
  • the pharmaceutical composition may also be suitable for parenteral administration, such as a sterile solution, suspension or lyophilized product in a suitable unit dosage form.
  • the daily dose is 0.01 to 200 mg/kg body weight, in the form of single or divided doses.
  • the compounds of this application can be prepared by those skilled in the art of organic synthesis with reference to the following routes:
  • ring A, R c , R 3 , and n are as described above.
  • ring A, R 3 and n are as described above.
  • ring A, R 3 and n are as described above.
  • PBS fetal bovine serum
  • PBS phosphate buffered saline solution
  • PBST phosphate Tween buffer
  • BSA bovine serum albumin
  • GAPDH glyceraldehyde-3-phosphate dehydrogenase
  • DMSO dimethyl sulfoxide
  • DTT Stands for dithiothreitol
  • HTRF homogeneous time-resolved fluorescence.
  • step A Add compound 1-1 (15g) obtained in step A, acetonitrile (100g) and methanesulfonic acid (37.6g) in a 350mL pressure-resistant flask, place the reaction flask in an oil bath at 120°C, and stir for 6h reaction.
  • step B Add compound 1-2 (1g) obtained in step B and chloroform (10mL) into a 25mL three-necked flask, add thionyl chloride (2.94g) and two drops of N,N-dimethylformamide with stirring at room temperature, and react The solution was heated to 70°C and stirred for 3h.
  • step C Add compound 1-3 (200mg) obtained in step C, (R)-1-(m-tolyl)ethane-1-amine (98mg), N,N-diisopropylethylamine (129mg) into a 25mL single-necked flask ) And 1,4-dioxane (2mL), the mixture was heated to 100°C under the protection of nitrogen, and the reaction was stirred for 5h.
  • step D Add compound 1-4 obtained in step D (0.09g), dimethylphosphine oxide (0.017g), triethylamine (0.032g), 4,5-bisdiphenylphosphine-9,9 to a 15mL pressure-resistant tube -Dimethylxanthene (6.13mg), dipalladium tridibenzylideneacetone (4.85mg) and 1,4-dioxane (2mL), heated to 120°C in an oil bath under nitrogen protection and stirred for 2h. The reaction solution was cooled to room temperature, filtered with suction, and the filtrate was concentrated to dryness. The residue was purified by chromatography on a C18 column (120 g) (40% acetonitrile + 60% water) to obtain 58.5 mg of compound 1.
  • step D in Example 1 compound 1-3 was reacted with (R)-1-(3-(trifluoromethyl)phenyl)ethane-1-amine to prepare compound 2-1.
  • step E in Example 1 compound 2 was prepared.
  • compound 1-3 is prepared by reacting (R)-2-(3-(1-aminoethyl)phenyl)-2,2-difluoroethane-1-ol Compound 3-1.
  • step D in Example 1 compound 1-3 was reacted with (R)-1-(3-(difluoromethyl)-2-methylphenyl)ethane-1-amine to prepare compound 4- 1.
  • step D in Example 1 compound 1-3 is prepared by reacting (R)-1-(3-(1,1-difluoroethyl)-2-fluorophenyl)ethane-1-amine Compound 5-1.
  • step a The compound 6-1-1 (9g) obtained in step a and anhydrous tetrahydrofuran (200mL) were added to a 500mL three-necked flask, and the temperature was lowered to -78°C under the protection of nitrogen. Methylmagnesium bromide (22mL, 3mol/L) was slowly added dropwise to the reaction solution, and the addition was completed. Return to 0°C and continue to stir and react for 1 hour.
  • step b Add compound 6-1-2 (6.8g) and 1,4-dioxane (150mL), tributyl (1-ethoxyethylene) tin (18.53g), obtained in step b to a 250mL three-necked flask.
  • step d Add compound 6-1-4 (3g) and tetrahydrofuran (30mL), (S)-2-methylpropane-2-sulfenamide (2.390g), tetraethyl titanate obtained in step d to a 100mL three-necked flask (8.99g), protected by nitrogen, and heated to 80°C in an oil bath to react for 4.5 hours.
  • step D in Example 1 compound 6-2 is prepared by reacting compound 1-3 with compound 6-1 obtained in step A.
  • step D in Example 1 compound 1-3 was reacted with (R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethane-1-amine to prepare compound 7- 1.
  • step B Add compound 7-2 (100mg) obtained in step B, tetrahydrofuran (15mL) and water (5.00mL) to a 50mL three-necked flask, stir at room temperature and add ammonium chloride (444mg) and zinc powder (203mg) to it, and place the reaction flask In an oil bath at 70°C, the reaction was stirred for 5h.
  • step B Into a 25mL single-neck flask, add compound 8-2 (0.16g) obtained in step B, methanol (10mL), water (2mL) and tetrahydroxydiboron (0.231g) in sequence, stir for 10min, and add sodium hydroxide (0.129 g) in water (2 mL) and stir overnight at room temperature.
  • step A Add compound 10-1 (0.699g) obtained in step A and 1,2-dichloroethane (10mL) into a 25mL three-necked flask and stir in an ice water bath, and add 1-chloroethyl chloroformate (0.195g) to the mixture, Reflux for 2h.
  • the reaction solution was concentrated to dryness, methanol (5 mL) was added to the residue, and the mixture was heated under reflux and stirred for 15 min.
  • step A in Example 10 using compound 2-1 obtained in step A of Example 2, compound 11-1 was prepared.
  • step B in Example 10 compound 11-2 was prepared.
  • step C in Example 10 compound 11 was prepared.
  • step A in Example 10 using compound 4-1 obtained in step A of Example 4, compound 12-1 was prepared.
  • step C in Example 10 compound 12 was prepared.
  • step C in Example 10 compound 13 was prepared by reacting compound 12-2 with N,N-dimethylglycine.
  • step C in Example 10 compound 12-2 was reacted with cyclopropanoic acid to prepare compound 14.
  • step A in Example 10 compound 15-1 was prepared.
  • step C in Example 10 compound 15-2 was reacted with N,N-dimethylglycine to prepare compound 16.
  • step C in Example 10 compound 15-2 was reacted with cyclopropanoic acid to prepare compound 17.
  • step A in Example 10 compound 8-1 obtained in step A of Example 8 was used to prepare compound 18-1.
  • reaction solution was poured into water (15mL), extracted with ethyl acetate (30mL), the organic phases were combined and washed with saturated brine (10mL), dried over anhydrous sodium sulfate, filtered, and concentrated.
  • step A 1-benzyl-1,4-azaphosphine-4-oxide (0.075g), N,N-diisopropylethylamine into a 10mL microwave tube (0.070g), 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (0.021g, 0.036mmol), trisdibenzylidene acetone dipalladium (0.017g, 0.018mmol) and N , N-dimethylformamide (3mL), after nitrogen replacement, the microwave reactor was heated to 165°C at 150 watts, and reacted for 50 minutes.
  • step B Add compound 19-2 (0.15g) obtained in step B and 1,2-dichloroethane (14mL) into a 50mL single-neck flask, and add 1-chloroethyl chloroformate (0.077g) dropwise to it under ice bath. , The mixture was heated to reflux for 2.5h. The reaction solution was concentrated to dryness, methanol (5 mL) was added to the residue, and the reflux reaction was continued for 30 minutes. The reaction solution was concentrated to dryness to obtain 0.16 g of compound 19-3.
  • step A compound 20-1 was reacted with (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethane-1-amine hydrochloride to prepare the compound 20-2.
  • step A compound 9-1 and (R)-1-(3,3-difluoro-2,3-dihydrobenzofuran-7-yl)ethane-1-amine salt
  • Compound 22-1 was prepared by acid salt reaction.
  • step D in Example 19 compound 24 was prepared by reacting compound 24-5 with methanesulfonyl chloride.
  • step b Add the compound 25-2-2 (4g) obtained in step b, dry tetrahydrofuran (40mL), (R)-(+)-tert-butylsulfinamide (2.352g) and tetraethyl titanate to a 100mL single-necked flask. (11.07g), the mixture was heated to 80°C for 3h. The reaction was stopped, ice water (150 mL) and ethyl acetate (150 mL) were added to the reaction solution under stirring at room temperature, stirred for 5 minutes, filtered with suction, the filtrate was separated, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated 5.8g of compound 25-2-3 was obtained.
  • step c Add the compound 25-2-3 (3g) and tetrahydrofuran (30mL) obtained in step c to a 250mL three-necked flask in sequence. Under the protection of nitrogen, the temperature is reduced to -50°C, and sodium borodeuteride (0.731g) is added to it in batches. After keeping the temperature, continue to stir and react for 3h.
  • step d 1,4-dioxane (2mL) and 4M hydrochloric acid dioxane solution (2.5mL) were sequentially added to a 100mL single-mouth flask, and the reaction solution was stirred at room temperature After reacting for 2 hours, the reaction solution was concentrated to dryness under reduced pressure, and the residue was slurried with methyl tert-butyl ether (5 mL) to obtain 0.38 g of compound 25-2.
  • step A in Example 19 Referring to the method of step A in Example 19, compound 25-2 and compound 20-1 prepared in step A above were prepared to obtain compound 25-3.
  • step D in Example 19 compound 25 was prepared by reacting compound 25-4 with methanesulfonyl chloride.
  • step a in Example 25 2-fluoro-3-trifluoromethylbenzoic acid was replaced with 2-methyl-3-trifluoromethylbenzoic acid to prepare compound 26-1-1.
  • step b in Example 25 compound 26-1-2 was prepared.
  • step b g Into a 100mL three-necked flask were added 1M lithium bistrimethylsilylamide solution in tetrahydrofuran (17.68mL), dry tetrahydrofuran (50mL), and under nitrogen protection at -74°C, the compound 26-1-2 (2.75) obtained in step b g) A solution of tetrahydrofuran (5 mL) was slowly added dropwise to the above reaction solution, and the mixture was stirred and reacted at -74°C for 10 minutes. Trimethylchlorosilane (1.921 g) was slowly added to the above reaction solution, and the addition was completed after 2 minutes, and the reaction was stirred at -74° C.
  • step c in Example 25 the compound 26-1-3 obtained in the above step c was reacted with S-tert-butylsulfinamide to prepare compound 26-1-4.
  • step d Under the protection of nitrogen at -78°C, add compound 26-1-4 (940mg) obtained in step d and dry tetrahydrofuran (10mL) to a 100mL three-necked flask, and slowly add 1M lithium tri-sec-butylborohydride in tetrahydrofuran (51.0mL) Drop into the above reaction solution, after the addition is complete, the mixture is stirred and reacted at -78°C for 0.5h. The reaction is over.
  • step A in Example 19 compound 9-1 was replaced with 6-bromo-2-methylquinazolin-4(3H)-one to prepare compound 26-2.
  • step A in Example 19 compound 9-1 was replaced with 6-bromo-2-methylquinazolin-4(3H)-one to prepare compound 27-1.
  • step D in Example 19 compound 27 was prepared by reacting compound 27-3 with methanesulfonyl chloride.
  • step A Into a 50mL single-neck flask, add compound 28-1 (1.3g) obtained in step A above, 2-methoxyethanol (13mL) and formamidine acetate (0.924g) in sequence, stir and react at 120°C for 2h, stop the reaction, and cool to room temperature After suction filtration, the filter cake was washed with methanol (10 mL), the filter cake was collected and slurried with methanol (30 mL), filtered with suction, and the filter cake was collected and dried to obtain 0.95 g of compound 28-2.
  • MS(ESI, [M+H] + )m/z 302.81
  • step A in Example 10 compound 28-3 was used to prepare compound 28-4.
  • step C in Example 10 compound 28 was prepared by reacting compound 28-5 with acetic anhydride.
  • step D in Example 19 compound 28 was prepared by reacting compound 28-5 with methanesulfonyl chloride.
  • step A replace (R)-1-(3-(trifluoromethyl)-2-fluorophenyl)ethane-1-amine hydrochloride with (R)-1-( 3-(Difluoromethyl)-2-fluorophenyl)ethane-1-amine hydrochloride was prepared to obtain compound 30-2.
  • step A in Example 10 According to the method of step A in Example 10, compound 30-3 was prepared.
  • compound 30-4 was prepared by reacting compound 30-4 with acetic anhydride.
  • step B in Example 24 compound 3-1-1 was prepared by replacing compound 24-1 with methyl 2-amino-5-bromobenzoate.
  • step B in Example 10 According to the method of step B in Example 10, compound 31-4 was prepared.
  • step E in Example 30 compound 31 was prepared by reacting compound 31-4 with acetic anhydride.
  • step A in Example 24 5-amino-2-chloropyridine-4-carboxylic acid was replaced with 2-amino-5-bromo-4-fluorobenzoic acid to prepare compound 32-1.
  • Step F Referring to the method of step C in Example 10, compound 32 was prepared.
  • compound 33-3 was prepared by reacting compound 33-3 with acetic anhydride.
  • step A replace (R)-1-(3-(trifluoromethyl)-2-fluorophenyl)ethane-1-amine hydrochloride with (R)-1-( 3-(Difluoromethyl)-2-fluorophenyl)ethane-1-amine hydrochloride is reacted with compound 1-2 to prepare compound 34-1.
  • step A Diethylphosphine oxide (0.016g), N,N-diisopropylethylamine (0.04g), 4,5-bisdiphenyl into a 5mL microwave tube Phosphine-9,9-dimethylxanthene (8.9mg), dipalladium tridibenzylideneacetone (7.05mg), and N,N-dimethylformamide (3mL), after addition, nitrogen replacement Afterwards, the microwave reactor was heated to 170°C for 35 minutes at 150 watts, and the sample was taken out after the reaction.
  • step A replace (R)-1-(3-(trifluoromethyl)-2-fluorophenyl)ethane-1-amine hydrochloride with (R)-1-( 3-(Difluoromethyl)-2-fluorophenyl)ethane-1-amine hydrochloride is reacted with compound 9-1 to prepare compound 35-1.
  • step a Add the compound 35-2-1 (1g) obtained in step a and dichloromethane (20mL) into a 25mL three-neck flask, cool down to below 0°C in an ice salt bath under the protection of nitrogen, and add oxalyl chloride (1.578g) dropwise to it. After the addition, it was transferred to room temperature and stirred overnight. The reaction solution was concentrated to dryness, and the residue was dissolved in toluene (10 mL) and concentrated to dryness to obtain 1.8 g of crude compound 35-2-2, which was directly used in the next reaction without purification.
  • step B in Example 19 compound 35 was prepared by reacting compound 35-1 with compound 35-2.
  • step A replace (R)-1-(3-(trifluoromethyl)-2-fluorophenyl)ethane-1-amine hydrochloride with (R)-1-( 3-(Difluoromethyl)-2-fluorophenyl)ethane-1-amine hydrochloride was prepared to obtain compound 36-1.
  • step A (R)-1-(3-(trifluoromethyl)-2-fluorophenyl)ethane-1-amine hydrochloride and 6-bromo-2-methyl Quinazolin-4(3H)-one was reacted to prepare compound 37-1.
  • step B in Example 19 compound 37 was prepared by reacting compound 37-1 with compound 35-2.
  • step A (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethane-1-amine hydrochloride and 6-bromo-7-fluoro- Compound 38-1 was prepared by reaction with 2-methylquinazolin-4(3H)-one.
  • step B Into a 250mL single-mouth flask, add compound 40-2 (2.8g) obtained in step B, N,N-dimethylformamide (28mL), tert-butyl acrylate (1.598g), triethylamine (2.103g), Palladium acetate (0.058g) and tri-o-tolylphosphine (0.158g) were replaced with nitrogen three times, and the mixture was heated to 100°C for 8 hours under the protection of nitrogen. At the end of the reaction, the reaction solution was cooled to room temperature.
  • step C Into a 25mL reaction flask, the compound 40-3 (0.4g) obtained in step C and acetonitrile (8mL) were sequentially added, and the reaction flask was placed under 365nm wavelength light and stirred at room temperature for 4h. The reaction was stopped, filtered, and the filter cake was collected to obtain 0.22 g of compound 40-4.
  • step D Into a 250 mL reaction flask, the compound 40-4 (2.8 g) obtained in step D, trifluoroethanol (1.038 g), and potassium tert-butoxide (2.56 g) were sequentially added, and the mixture was heated to 80° C. for reaction for 2 h. After the reaction was completed, the reaction solution was cooled to room temperature.
  • reaction solution was poured into saturated ammonium chloride solution (30 mL), extracted with ethyl acetate (50 mL ⁇ 3), and the organic phases were combined, washed with saturated brine (50 mL), and anhydrous sulfuric acid The sodium was dried, filtered, and concentrated, and the residue obtained was slurried by adding methyl tert-butyl ether (20 mL) to obtain 2.2 g of compound 40-5.
  • step E Into a 250mL single-neck flask, add the compound 40-5 (2g) obtained in step E and N,N-dimethylformamide (20mL) in sequence, cool down to below 5°C in an ice water bath, and add sodium hydride (0.370g) to it, After the addition, stir at room temperature for 5 minutes, and then add iodomethane (1.314g) dropwise to the reaction flask under an ice bath. After the addition, it will naturally rise to room temperature and stir for 2 hours.
  • sodium hydride (0.370g)
  • step B in Example 19 compound 40-9 was reacted with compound 35-2 obtained in step c of Example 35 to prepare compound 40.
  • step A Add the compound 41-1 (1.1g) obtained in step A, acetonitrile (3.40g), and methanesulfonic acid (3.98g) to a 35mL microwave tube in sequence. After stirring for 10 minutes at room temperature, place it in a microwave reactor and place it in a microwave reactor at 50 watts. Heat to 120°C for 2h. After the reaction was completed, the obtained sample solution was concentrated to dryness under reduced pressure, diluted with water (20 mL), adjusted to alkaline with 15% sodium hydroxide aqueous solution, and filtered with suction to obtain 0.8 g of compound 41-2.
  • step B N,N-dimethylformamide (2mL), zinc cyanide (39.4mg) and tetrakis (triphenylphosphine) palladium ( 78mg), replaced with nitrogen for 3 times, put it into a microwave reactor, heated to 110°C under 50 watts, and reacted for 1 hour.
  • step B in Example 19 compound 41 was prepared by reacting compound 41-1 prepared in step D above with compound 35-2.
  • step B of Example 19 compound 19-1 was reacted with 1-phosphorane oxide to prepare compound 42.
  • step B in Example 19 compound 19-1 was reacted with 1-phospholane oxide to prepare compound 43.
  • Examples 44 to 47 can refer to the method of Example 1, replace methyl 2-amino-4-methoxybenzoate with the following fragments 1-1, and replace (R)-1-( (M-tolyl)ethane-1-amine was replaced with the following fragments 1-2 to react, and finally compound 44-47 were prepared by referring to the method of step C of Example 7.

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Abstract

本申请属于药物化学领域，涉及一种含磷的SOS1抑制剂，即式(I)化合物，及其制备方法、含有该化合物的药物组合物，并涉及其在制备治疗与SOS1相关或由SOS1调节的疾病和/或病症的药物中的用途。

Description

含磷的SOS1抑制剂
相关申请的引用
本申请要求于2020年05月09日向中华人民共和国国家知识产权局提交的第202010387620.0号中国专利申请的优先权和权益及于2021年04月25日向中华人民共和国国家知识产权局提交的第202110450032.1号中国专利申请的优先权和权益，在此将其全部内容以援引的方式整体并入文本中。
技术领域
本申请涉及含磷的SOS1抑制剂、其制备方法、含有该抑制剂的药物组合物、以及其在治疗与SOS1相关或由SOS1调节的疾病和/或病症中的用途。
背景技术
RAS是人类癌症中最常出现突变的致癌基因，而KRAS是RAS家族中最常出现的亚型，KRAS基因突变占RAS基因突变总数的86％。
无七之子1(SOS1，Son of Sevenless1)的鸟嘌呤核苷酸交换因子(GEF)的结合促进GDP从RAS家族蛋白中释放，能够实现GTP结合(Chardin等人,Science,1993,260(5112):1338-43)。当处于GTP结合状态时，RAS家族蛋白具有活性并且衔接包括C-RAF和磷酸肌醇3-激酶(PI3K)的效应蛋白以促进RAF/有丝分裂原或细胞外信号调节激酶(MEK/ERK)途径、PI3K/AKT/哺乳动物雷帕霉素靶蛋白(mTOR)途径和RalGDS(Ral鸟嘌呤核苷酸解离刺激物)途径(McCormick等人,J.Mol.Med.(Berl).,2016,94(3):253-8；Rodriguez-Viciana等人,Cancer Cell.2005,7(3):205-6)。这些途径影响多样的细胞过程，诸如增殖、存活、代谢、运动、血管生成、免疫和生长(Young等人，Adv.Cancer Res.，2009，102:1-17；Rodriguez-Viciana等人，Cancer Cell.2005，7(3):205-6)。
对SOS1的催化位点与RAS家族蛋白结合的选择性抑制可以防止SOS1介导的RAS家族蛋白激活为GTP结合形式。因此，SOS1抑制剂化合物可以抑制RAS家族蛋白下游的在细胞中的信号传导(例如，ERK磷酸化)。理想的SOS1抑制剂化合物应该能够选择性地高效抑制SOS1:RAS-家族蛋白的结合和细胞中的ERK磷酸化。
最近，拜耳公司的研究人员报道了一类含有喹唑啉母核结构的选择性SOS1抑制剂的发现(Proc Natl Acad Sci.2019；116(7):2551-2560)，代表化合物BAY-293，该类抑制剂能够通过干扰RAS-SOS1相互作用而阻断RAS活化。
Figure PCTCN2021092672-appb-000001
在本文中，我们提供了新型SOS1抑制剂化合物可通过干扰RAS-SOS1相互作用，抑制细胞中的ERK磷酸化。
发明详述
一方面，本申请提供了式(I)化合物、其立体异构体或其药学上可接受的盐，
Figure PCTCN2021092672-appb-000002
其中，
X、Y分别独立地选自CR a、C(O)、N或NR b；
Figure PCTCN2021092672-appb-000003
根据X和Y的不同分别代表单键或双键；
R a选自氢、羟基、卤素、氰基、C 1-6烷基或C 1-6烷氧基，其中所述C 1-6烷基或C 1-6烷氧基任选地被一个或多个氘或卤素取代；
R b选自氢、C 1-6烷基或C 1-6烷氧基；
R 1、R 2分别独立地选自C 1-6烷基、NH(R c)-C 1-6烷基-或N(R c)(C 1-6烷基)-C 1-6烷基-，或R 1、R 2和与之相连的磷原子共同形成一个5～10元杂环基，其中所述C 1-6烷基或5～10元杂环基任选地被一个或多个R c取代；
每一个R c分别独立地选自氢、O＝、HN＝、C 1-6烷基-N＝、C 1-6烷基-、C 1-6烷基-C(O)-、C 1-6烷基-S(O) 2-、3～6元环烷基-S(O) 2-、C 1-6烷基OC(O)-、C 1-6烷基-O-C 1-6烷基-、C 1-6烷基-O-C 1-6烷基-C(O)-、氨基-C(O)-、单(C 1-6烷基)氨基-C(O)-、二(C 1-6烷基)氨基-C(O)-、氨基-C 1-6烷基-C(O)-、单(C 1-6烷基)氨基-C 1-6烷基-C(O)-、二(C 1-6烷基)氨基-C 1-6烷基-C(O)-、氨基-C(O)-C 1-6烷基-、单(C 1-6烷基)氨基-C(O)-C 1-6烷基-、二(C 1-6烷基)氨基-C(O)-C 1-6烷基-、3～6元环烷基-、3～6元环烷基-C(O)-、3～6元环烷基-C 1-6烷基-、3～6元杂环烷基-、3～6元杂环烷基-C(O)-、3～6元杂环烷基-C 1-6烷基-、C 6-10芳基-C 1-6烷基-或被一个或多个羟基或氰基取代的C 1-6烷基-，其中所述R c不为氢和O＝时任选地被一个或多个卤素取代；
环A选自C 6-10芳基、5～10元杂芳基、8～12元稠环或8～12元稠杂环；
n为0、1、2或3；
每一个R 3分别独立地选自氨基、硝基、卤素、C 1-8烷基-、3～6元环烷基-或苯基，其中所述C 1-8烷基-、3～6元环烷基-或苯基任选地被一个或多个R d取代；
R d选自羟基、卤素或C 1-6烷基-NH-C 1-6烷基-；
R 4、R 5分别独立地选自氢、氘或C 1-6烷基，其中所述C 1-6烷基任选地被一个或多个卤素取代；
R 6选自氢、卤素或C 1-6烷基，其中所述C 1-6烷基任选地被一个或多个卤素取代。
在一些实施方案中，X选自CR a或NR b，Y选自CR a、C(O)、N或NR b。在一些实施方案中，X选自CR a或NR b，Y选自CR a、C(O)或N。
在一些实施方案中，X选自CR a，Y选自CR a、C(O)、N或NR b。在一些实施方案中，X选自CR a，Y选自CR a、C(O)或N。在一些实施方案中，X选自CR a，Y选自N。
在一些实施方案中，X选自NR b，Y选自CR a、C(O)、N或NR b。在一些实施方案中，X选自NR b，Y选自CR a、C(O)或N。在一些实施方案中，X选自NR b，Y选自C(O)。
在一些实施方案中，X、Y均选自CR a。在一些实施方案中，X选自CH，Y选自CR a。
在一些实施方案中，R a选自氢、羟基、卤素、氰基、C 1-4烷基或C 1-4烷氧基，其中所述C 1-4烷基或C 1-4烷氧基任选地被一个或多个氘或卤素取代。
在一些实施方案中，R a选自氢、羟基、卤素、氰基、C 1-4烷基或C 1-4烷氧基，其中所述C 1-4烷基任选 地被一个或多个卤素取代，所述C 1-4烷氧基任选地被一个或多个氘或卤素取代。在一些实施方案中，R a选自氢、羟基、卤素、氰基、C 1-3烷基或C 1-3烷氧基，其中所述C 1-3烷基任选地被一个或多个卤素取代，所述C 1-3烷氧基任选地被一个或多个氘或卤素取代。
在一些实施方案中，R a选自氢、羟基、卤素、氰基或C 1-6烷氧基，其中所述C 1-6烷氧基任选地被一个或多个氘或卤素取代。
在一些实施方案中，R a选自氢、羟基、卤素、氰基或C 1-4烷氧基，其中所述C 1-4烷氧基任选地被一个或多个氘或卤素取代。在一些实施方案中，R a选自氢、羟基、卤素、氰基或C 1-4烷氧基，其中所述C 1-4烷氧基任选地被3个氘或一个或多个氟取代。在一些实施方案中，R a选自氢、羟基、卤素、氰基或C 1-4烷氧基，其中所述C 1-4烷氧基任选地被3个氘、或1个或2个氟取代。
在一些实施方案中，R a选自氢、羟基、氟、氰基、甲氧基、单氟甲氧基或二氟甲氧基，其中所述甲氧基任选地被3个氘取代。
在一些实施方案中，R a选自氢、羟基、氟、氰基、CH 3O-、CD 3O-、CH 2FO-或CHF 2O-。
在一些实施方案中，R a选自氢、氟、CH 3O-、CD 3O-或CHF 2O-。
在一些实施方案中，R b选自氢、C 1-4烷基或C 1-4烷氧基。
在一些实施方案中，R b选自C 1-6烷基。在一些实施方案中，R b选自C 1-4烷基。在一些实施方案中，R b选自C 1-3烷基。在一些实施方案中，R b选自甲基。
在一些实施方案中，X选自CH、CF、C(CN)或N(CH 3)，Y选自N、CH、C(O)、C(OH)、C(OCH 3)、C(OCHF 2)、C(OCH 2F)、CF或C(OCD 3)。在一些实施方案中，X选自CH，Y选自C(OH)、C(OCH 3)、C(OCHF 2)、C(OCH 2F)、CF或C(OCD 3)。在一些实施方案中，X选自CH，Y选自N。在一些实施方案中，X选自N(CH 3)，Y选自C(O)。在一些实施方案中，X选自CF或C(CN)，Y选自CH或N。
在一些实施方案中，
Figure PCTCN2021092672-appb-000004
为双键。在一些实施方案中，
Figure PCTCN2021092672-appb-000005
为单键。
在一些实施方案中，R 1、R 2分别独立地选自C 1-6烷基、NH(R c)-C 1-6烷基-或N(R c)(C 1-6烷基)-C 1-6烷基-，或R 1、R 2和与之相连的磷原子共同形成5～10元杂环基，其中所述5～10元杂环基任选地被一个或多个R c取代。
在一些实施方案中，R 1、R 2分别独立地选自C 1-6烷基，或R 1、R 2和与之相连的磷原子共同形成5～10元杂环基，其中所述5～10元杂环基任选地被一个或多个R c取代。
在一些实施方案中，R 1、R 2分别独立地选自C 1-3烷基、NH(R c)-C 1-3烷基-或N(R c)(C 1-3烷基)-C 1-3烷基-。
在一些实施方案中，R 1、R 2分别独立地选自C 1-3烷基。
在一些实施方案中，R 1、R 2分别独立地选自甲基、乙基、丙基或异丙基。
在一些实施方案中，R 1、R 2分别独立地选自甲基或乙基。
在一些实施方案中，R 1、R 2分别独立地选自甲基。
在一些实施方案中，R 1、R 2和与之相连的磷原子共同形成5～10元杂环基，其中所述5～10元杂环基的环原子任选地包含一个或多个选自N、O或S原子的杂原子，所述5～10元杂环基任选地被一个或多个R c取代。
在一些实施方案中，R 1、R 2和与之相连的磷原子共同形成5～10元杂环基，其中所述5～10元杂环基的环原子任选地包含一个或多个选自N、O或S原子的杂原子，所述5～10元杂环基任选地被一个或多个R c取代，且当环原子中含N原子时，N与R c连接。
在一些实施方案中，R 1、R 2和与之相连的磷原子共同形成5～8元杂环基，其中所述5～8元杂环基的环原子中任选地包含一个选自N或O原子的杂原子，且当环原子中含N原子时，N与R c连接。
在一些实施方案中，R 1、R 2和与之相连的磷原子共同形成5～8元杂环烷基，其中所述5～8元杂环烷基的环原子中至少包含一个N原子，且N与R c连接。
在一些实施方案中，R 1、R 2和与之相连的磷原子共同形成5元或6元杂环烷基、9元或10元螺杂环 烷基、9元或10元并杂环烷基，其中所述5元或6元杂环烷基、9元或10元螺杂环烷基、9元或10元并杂环烷基任选地被一个或多个R c取代。
在一些实施方案中，R 1、R 2和与之相连的磷原子共同形成5元或6元杂环基，其中所述5元或6元杂环基任选地被一个或多个R c取代。
在一些实施方案中，R 1、R 2和与之相连的磷原子共同形成5元或6元杂环基，其中所述5元或6元杂环基的环原子中任选地包含一个或多个选自N、O或S原子的杂原子，且当环原子含N原子时，N与R c连接。在一些实施方案中，R 1、R 2和与之相连的磷原子共同形成5元或6元杂环基，其中所述5元或6元杂环基的环原子中任选地包含一个选自N或O原子的杂原子，且当环原子中含N原子时，N与R c连接。
在一些实施方案中，R 1、R 2和与之相连的磷原子共同形成6元杂环基，其中所述6元杂环基的环原子中至少包含一个N原子，且N与R c连接。在一些实施方案中，R 1、R 2和与之相连的磷原子共同形成6元杂环基，其中所述6元杂环基的环原子中只含有一个N原子，且N与R c连接。
在一些实施方案中，R 1、R 2和与之相连的磷原子共同形成6元杂环基，其中所述6元杂环基的环原子中只含有一个O原子。
在一些实施方案中，R 1、R 2和与之相连的磷原子共同形成5元或6元杂环基，且所述5元或6元杂环基的环原子由碳原子和磷原子组成。
在一些实施方案中，R 1、R 2和与之相连的磷原子共同形成6元杂环烷基，其中所述6元杂环烷基的环原子中至少包含一个N原子，且N与R c连接。在一些实施方案中，R 1、R 2和与之相连的磷原子共同形成6元杂环烷基，其中所述6元杂环烷基的环原子中只含有一个N原子，且N与R c连接。在一些实施方案中，R 1、R 2和与之相连的磷原子共同形成6元杂环烷基，其中所述6元杂环烷基的环原子中只含有一个O原子。在一些实施方案中，R 1、R 2和与之相连的磷原子共同形成5元或6元杂环烷基，且所述5元或6元杂环烷基的环原子由碳原子和磷原子组成。
在一些实施方案中，结构单元
Figure PCTCN2021092672-appb-000006
可选自结构单元
Figure PCTCN2021092672-appb-000007
Figure PCTCN2021092672-appb-000008
其中所述结构单元
Figure PCTCN2021092672-appb-000009
Figure PCTCN2021092672-appb-000010
可任选地被一个或多个R c取代。
在一些实施方案中，结构单元
Figure PCTCN2021092672-appb-000011
可选自结构单元
Figure PCTCN2021092672-appb-000012
Figure PCTCN2021092672-appb-000013
在一些实施方案中，结构单元
Figure PCTCN2021092672-appb-000014
可选自结构单元
Figure PCTCN2021092672-appb-000015
Figure PCTCN2021092672-appb-000016
在一些实施方案中，结构单元
Figure PCTCN2021092672-appb-000017
为结构单元
Figure PCTCN2021092672-appb-000018
在一些实施方案中，R 1、R 2分别独立地选自甲基或乙基，或结构单元
Figure PCTCN2021092672-appb-000019
选自结构单元
Figure PCTCN2021092672-appb-000020
在一些实施方案中，R 1、R 2分别独立地选自甲基，或结构单元
Figure PCTCN2021092672-appb-000021
为结构单元
Figure PCTCN2021092672-appb-000022
在一些实施方案中，每一个R c分别独立地选自氢、C 1-6烷基-、C 1-6烷基-C(O)-、C 1-6烷基OC(O)-、C 1-6烷基-O-C 1-6烷基-、C 1-6烷基-O-C 1-6烷基-C(O)-、氨基-C(O)-、单(C 1-6烷基)氨基-C(O)-、二(C 1-6烷基)氨基-C(O)-、氨基-C 1-6烷基-C(O)-、单(C 1-6烷基)氨基-C 1-6烷基-C(O)-、二(C 1-6烷基)氨基-C 1-6烷基-C(O)-、氨基-C(O)-C 1-6烷基-、单(C 1-6烷基)氨基-C(O)-C 1-6烷基-、二(C 1-6烷基)氨基-C(O)-C 1-6烷基-、3～6元环烷基-、3～6元环烷基-C(O)-、3～6元环烷基-C 1-6烷基-、C 6-10芳基-C 1-6烷基-或被一个或多个羟基取代的C 1-6烷基-。
在一些实施方案中，每一个R c分别独立地选自氢、O＝、HN＝、C 1-6烷基-N＝、C 1-3烷基-、C 1-3烷基-C(O)-、C 1-3烷基-S(O) 2-、3～6元环烷基-S(O) 2-、C 1-3烷基OC(O)-、C 1-3烷基-O-C 1-3烷基-、C 1-3烷基-O-C 1-3烷基-C(O)-、氨基-C(O)-、单(C 1-3烷基)氨基-C(O)-、二(C 1-3烷基)氨基-C(O)-、氨基-C 1-3烷基-C(O)-、单(C 1-3烷基)氨基-C 1-3烷基-C(O)-、二(C 1-3烷基)氨基-C 1-3烷基-C(O)-、氨基-C(O)-C 1-3烷基-、单(C 1-3烷基)氨基-C(O)-C 1-3烷基-、二(C 1-3烷基)氨基-C(O)-C 1-3烷基-、3～6元环烷基-、3～6元环烷基-C(O)-、3～6元环烷基-C 1-3烷基-、3～6元杂环烷基-、3～6元杂环烷基-C(O)-、3～6元杂环烷基-C 1-3烷基-、苯基-C 1-3烷基-或被一个或多个羟基或氰基取代的C 1-3烷基-，其中所述R c不为氢和O＝时任选地被一个或多个卤素取代。
在一些实施方案中，每一个R c分别独立地选自氢、C 1-3烷基-、C 1-3烷基-C(O)-、C 1-3烷基-S(O) 2-、3～6元环烷基-S(O) 2-、C 1-3烷基OC(O)-、C 1-3烷基-O-C 1-3烷基-、C 1-3烷基-O-C 1-3烷基-C(O)-、氨基-C(O)-、单(C 1-3烷基)氨基-C(O)-、二(C 1-3烷基)氨基-C(O)-、氨基-C 1-3烷基-C(O)-、单(C 1-3烷基)氨基-C 1-3烷基-C(O)-、二(C 1-3烷基)氨基-C 1-3烷基-C(O)-、氨基-C(O)-C 1-3烷基-、单(C 1-3烷基)氨基-C(O)-C 1-3烷基-、二(C 1-3烷基)氨基-C(O)-C 1-3烷基-、3～6元环烷基-、3～6元环烷基-C(O)-、3～6元环烷基-C 1-3烷基-、3～6元杂环烷基-、3～6元杂环烷基-C(O)-、3～6元杂环烷基-C 1-3烷基-、苯基-C 1-3烷基-或被一个或多个羟基或氰基取代的C 1-3烷基-，其中所述R c不为氢时任选地被一个或多个卤素取代。
在一些实施方案中，每一个R c分别独立地选自氢、C 1-3烷基-、C 1-3烷基-C(O)-、C 1-3烷基-S(O) 2-、3～5元环烷基-S(O) 2-、C 1-3烷基OC(O)-、C 1-3烷基-O-C 1-3烷基-、C 1-3烷基-O-CH 2-C(O)-、二(C 1-3烷基)氨基-C(O)-、二(C 1-3烷基)氨基-CH 2-C(O)-、二(C 1-3烷基)氨基-C(O)-CH 2-、3～5元环烷基-、3～5元环烷基-C(O)-、3～5元环烷基-CH 2-、3～5元杂环烷基-、苯基-CH 2-或被一个羟基或氰基取代的C 1-3烷基-，其中所述R c不为氢时任选地被1个、2个或3个卤素取代。
在一些实施方案中，每一个R c分别独立地选自氢、C 1-3烷基-、C 1-3烷基-C(O)-、C 1-3烷基-S(O) 2-、3～5元环烷基-S(O) 2-、C 1-3烷基OC(O)-、C 1-3烷基-O-C 1-3烷基-、C 1-3烷基-O-CH 2-C(O)-、二(C 1-3烷基)氨基-C(O)-、二(C 1-3烷基)氨基-CH 2-C(O)-、二(C 1-3烷基)氨基-C(O)-CH 2-、3～5元环烷基-、3～5元环烷基-C(O)-、3～5元环烷基-CH 2-、3～5元杂环烷基-或被一个羟基或氰基取代的C 1-3烷基-，其中所述R c不为氢时任选地被1个、2个或3个卤素取代。
在一些实施方案中，每一个R c分别独立地选自氢、C 1-3烷基-、C 1-3烷基-C(O)-、C 1-3烷基OC(O)-、C 1-3烷基-O-C 1-3烷基-、C 1-3烷基-O-CH 2-C(O)-、二(C 1-3烷基)氨基-C(O)-、二(C 1-3烷基)氨基-CH 2-C(O)-、二(C 1-3烷基)氨基-C(O)-CH 2-、3～5元环烷基-、3～5元环烷基-C(O)-、3～5元环烷基-CH 2-、苯基-CH 2-或被一个羟基取代的C 1-3烷基-。
在一些实施方案中，每一个R c分别独立地选自氢、甲基、乙基、异丙基、
Figure PCTCN2021092672-appb-000023
乙酰基、
Figure PCTCN2021092672-appb-000024
Figure PCTCN2021092672-appb-000025
在一些实施方案中，每一个R c分别独立地选自甲基、乙基、异丙基、
Figure PCTCN2021092672-appb-000026
乙酰基、
Figure PCTCN2021092672-appb-000027
Figure PCTCN2021092672-appb-000028
在一些实施方案中，环A选自C 6-10芳基、5～10元杂芳基、8～12元苯并环烷基、8～12元苯并环烯基或8～12元苯并杂环基。
在一些实施方案中，环A选自C 6-10芳基、5～10元杂芳基、8～12元苯并环烷基、8～12元苯并环烯基、8～12元苯并杂环烷基或8～12元苯并杂环烯基。
在一些实施方案中，环A选自C 6-10芳基、5～10元杂芳基、8～12元苯并环烷基或8～12元苯并杂环烷基。
在一些实施方案中，环A选自C 6-10芳基、5～10元杂芳基、8～10元稠环或8～10元稠杂环。
在一些实施方案中，环A选自C 6-10芳基、5～10元杂芳基、8～10元苯并环烷基、8～10元苯并环烯基或8～10元苯并杂环基。
在一些实施方案中，环A选自C 6-10芳基、5～10元杂芳基、8～10元苯并环烷基、8～10元苯并环烯基、8～10元苯并杂环烷基或8～10元苯并杂环烯基。
在一些实施方案中，环A选自C 6-10芳基、5～10元杂芳基、8～10元苯并环烷基或8～10元苯并杂环烷基。
在一些实施方案中，环A选自苯基、噻吩基、2,3-二氢-1H-茚基、2,3-二氢苯并呋喃基或苯并呋喃基。
在一些实施方案中，环A选自苯基、噻吩基或2,3-二氢-1H-茚基。
在一些实施方案中，n为0、1或2；或者，n为1、2或3。
在一些实施方案中，n为0或1；或者，n为0或2；或者，n为0或3；或者，n为1或2；或者，n 为1或3；或者，n为2或3。在一些实施方案中，n为2。
在一些实施方案中，每一个R 3分别独立地选自氨基、硝基、卤素、C 1-6烷基-或苯基，其中所述C 1-6烷基-或苯基任选地被一个或多个R d取代。
在一些实施方案中，每一个R 3分别独立地选自氨基、卤素、C 1-6烷基-或苯基，其中所述C 1-6烷基-或苯基任选地被一个或多个R d取代。
在一些实施方案中，每一个R 3分别独立地选自氨基、硝基、卤素、C 1-4烷基-或苯基，其中所述C 1-4烷基-或苯基任选地被一个或多个R d取代。
在一些实施方案中，每一个R 3分别独立地选自氨基、硝基、卤素、C 1-4烷基-或苯基，其中所述C 1-4烷基-或苯基任选地被1、2或3个R d取代。
在一些实施方案中，R d选自羟基、卤素或C 1-3烷基-NH-C 1-3烷基-。
在一些实施方案中，R d选自羟基、氟或甲基-NH-甲基-。
在一些实施方案中，每一个R 3分别独立地选自氨基、硝基、氟、甲基、三氟甲基、-CF 2CH 2OH、-CHF 2、-CF 2CH 3、-CF 2C(CH 3) 2OH或
Figure PCTCN2021092672-appb-000029
在一些实施方案中，每一个R 3分别独立地选自氨基、氟、甲基、三氟甲基、-CF 2CH 2OH、-CHF 2、-CF 2CH 3、-CF 2C(CH 3) 2OH或
Figure PCTCN2021092672-appb-000030
在一些实施方案中，每一个R 3分别独立地选自氨基、硝基、氟、甲基或三氟甲基。
在一些实施方案中，结构单元
Figure PCTCN2021092672-appb-000031
选自
Figure PCTCN2021092672-appb-000032
Figure PCTCN2021092672-appb-000033
进一步选自
Figure PCTCN2021092672-appb-000034
Figure PCTCN2021092672-appb-000035
Figure PCTCN2021092672-appb-000036
在一些实施方案中，R 4、R 5分别独立地选自氢、氘或C 1-3烷基，其中所述C 1-3烷基任选地被一个或多个卤素取代。
在一些实施方案中，R 4选自C 1-3烷基，R 5选自氢或氘，其中所述C 1-3烷基任选地被一个或多个卤素取代。在一些实施方案中，R 4选自甲基，R 5选自氢或氘，其中所述甲基任选地被一个或多个氟取代。在一些实施方案中，R 4选自甲基或-CH 2F，R 5选自氢或氘。在一些实施方案中，R 4选自甲基，R 5选自氢。
在一些实施方案中，R 5选自C 1-3烷基，R 4选自氢或氘，其中所述C 1-3烷基任选地被一个或多个卤素取代。在一些实施方案中，R 5选自甲基，R 4选自氢或氘，其中所述甲基任选地被一个或多个氟取代。在一些实施方案中，R 5选自甲基或-CH 2F，R 4选自氢或氘。在一些实施方案中，R 5选自甲基，R 4选自氢。
在一些实施方案中，R 6选自氢、卤素或C 1-3烷基，其中所述C 1-3烷基任选地被一个或多个卤素取代。
在一些实施方案中，R 6选自氢、氟、氯、溴、甲基、乙基、丙基或异丙基，其中所述甲基、乙基、丙基或异丙基任选地被一个或多个卤素取代。在一些实施方案中，R 6选自氢、氟、氯或甲基，其中所述甲基任选地被1个、2个或3个氟取代。在一些实施方案中，R 6选自氢、氯、甲基或-CH 2F。在一些实施方案中，R 6选自甲基。
在一些实施方案中，本申请所述杂环基、杂芳基或杂环烷基中的杂原子选自N、O、S和P。在一些实施方案中，本申请所述杂环基、杂芳基或杂环烷基中的杂原子选自N、O和P。在一些实施方案中，本申请所述杂环基、杂芳基或杂环烷基中的杂原子选自N和P。
另一方面，本申请提供了式(II)化合物、其立体异构体或其药学上可接受的盐，
Figure PCTCN2021092672-appb-000037
其中，
X、Y分别独立地选自CR a、C(O)、N或NR b；
Figure PCTCN2021092672-appb-000038
根据X和Y的不同分别代表单键或双键；
R a选自氢、羟基、卤素、C 1-6烷基或C 1-6烷氧基，其中所述C 1-6烷基任选地被一个或多个卤素取代，所述C 1-6烷氧基任选地被一个或多个氘或卤素取代；
R b选自氢、C 1-6烷基或C 1-6烷氧基；
R 1、R 2分别独立地选自C 1-6烷基、NH(R c)-C 1-6烷基-或N(R c)(C 1-6烷基)-C 1-6烷基-，或R 1、R 2和与之相连的磷原子共同形成一个5-8元杂环基，其中，所述5-8元杂环基的环原子中至少包含一个N原子，且N与R c连接；
每一个R c分别独立地选自氢、C 1-6烷基、C 1-6烷基-C(O)-、C 1-6烷基OC(O)-、C 1-6烷基-O-C 1-6烷基-、C 1-6烷基-O-C 1-6烷基-C(O)-、氨基-C(O)-、单(C 1-6烷基)氨基-C(O)-、二(C 1-6烷基)氨基-C(O)-、氨基-C 1-6烷基-C(O)-、单(C 1-6烷基)氨基-C 1-6烷基-C(O)-、二(C 1-6烷基)氨基-C 1-6烷基-C(O)-、氨基-C(O)-C 1-6烷基-、单(C 1-6烷基)氨基-C(O)-C 1-6烷基-、二(C 1-6烷基)氨基-C(O)-C 1-6烷基-、3～6元环烷基、3～6元环烷基-C(O)-、3～6元环烷基-C 1-6烷基-、C 6-10芳基-C 1-6烷基-或被一个或多个羟基取代的C 1-6烷基，其中，所述R c不为氢时任选地被一个或多个卤素取代；
环A选自C 6-10芳基、5～10元杂芳基或8～12元稠环；
n为0、1、2或3；
每一个R 3分别独立地选自氨基、硝基、卤素、C 1-8烷基或3～6元环烷基，其中，所述C 1-8烷基和3～6元环烷基任选地被一个或多个R d取代；
R d选自羟基或卤素。
在一些实施方案中，所述式(II)化合物，其中，R 1、R 2、R 3、X、Y、n、环A及
Figure PCTCN2021092672-appb-000039
的定义如前所述。
在一些实施方案中，X选自CR a，Y选自CR a、C(O)、N或NR b。在一些实施方案中，X选自CR a，Y选自CR a、C(O)或N。在一些实施方案中，X选自CR a，Y选自N。
在一些实施方案中，X、Y均选自CR a。在一些实施方案中，X选自CH，Y选自CR a。
在一些实施方案中，R a选自氢、卤素或C 1-4烷氧基，其中所述C 1-4烷氧基任选地被一个或多个氘或卤素取代。在一些实施方案中，R a选自氢、卤素或C 1-4烷氧基，其中所述C 1-4烷氧基任选地被3个氘或一个或多个氟取代。在一些实施方案中，R a选自氢、卤素或C 1-4烷氧基，其中所述C 1-4烷氧基任选地被3个氘或2个氟取代。
在一些实施方案中，R a选自氢、氟、甲氧基或二氟甲氧基，其中甲氧基任选地被3个氘取代。
在一些实施方案中，R a选自氢、氟、CH 3O-、CD 3O-或CHF 2O-。
在一些实施方案中，R b选自C 1-6烷基。在一些实施方案中，R b选自C 1-4烷基。在一些实施方案中，R b选自C 1-3烷基。在一些实施方案中，R b选自甲基。
在一些实施方案中，X选自CH和N(CH 3)，Y选自N、C(O)、C(OCH 3)、CF或C(OCD 3)。在一些实施方案中，X选自CH，Y选自C(OCH 3)、CF或C(OCD 3)。在一些实施方案中，X选自CH，Y选自N。在一些实施方案中，X选自N(CH 3)，Y选自C(O)。
在一些实施方案中，R 1、R 2分别独立地选自C 1-3烷基、NH(R c)-C 1-3烷基-或N(R c)(C 1-3烷基)-C 1-3烷基-。
在一些实施方案中，R 1、R 2分别独立地选自C 1-3烷基。
在一些实施方案中，R 1、R 2分别独立地选自甲基。
在一些实施方案中，R 1、R 2和与之相连的磷原子共同形成一个6元杂环基，所述6元杂环基的环原子中至少包含一个N原子，且N与R c连接。在一些实施方案中，R 1、R 2和与之相连的磷原子共同形成一个6元杂环基，所述6元杂环基的环原子中只含有一个N原子，且N与R c连接。
在一些实施方案中，R 1、R 2和与之相连的磷原子共同形成一个5～8元杂环烷基，所述5～8元杂环烷基的环原子中至少包含一个N原子，且N与R c连接。在一些实施方案中，R 1、R 2和与之相连的磷原子共同形成一个6元杂环烷基，所述6元杂环烷基的环原子中至少包含一个N原子，且N与R c连接。在一些实施方案中，R 1、R 2和与之相连的磷原子共同形成一个6元杂环烷基，所述6元杂环烷基的环原子中只含有一个N原子，且N与R c连接。
在一些实施方案中，结构单元
Figure PCTCN2021092672-appb-000040
选自结构单元
Figure PCTCN2021092672-appb-000041
在一些实施方案中，R 1、R 2分别独立地选自甲基，或结构单元
Figure PCTCN2021092672-appb-000042
选自结构单元
Figure PCTCN2021092672-appb-000043
在一些实施方案中，每一个R c分别独立地选自氢、C 1-3烷基、C 1-3烷基-C(O)-、C 1-3烷基OC(O)-、C 1-3烷基-O-C 1-3烷基-、C 1-3烷基-O-C 1-3烷基-C(O)-、氨基-C(O)-、单(C 1-6烷基)氨基-C(O)-、二(C 1-3烷基)氨基-C(O)-、氨基-C 1-3烷基-C(O)-、单(C 1-3烷基)氨基-C 1-3烷基-C(O)-、二(C 1-3烷基)氨基-C 1-3烷基-C(O)-、氨基-C(O)-C 1-3烷基-、单(C 1-3烷基)氨基-C(O)-C 1-3烷基-、二(C 1-3烷基)氨基-C(O)-C 1-3烷基-、3～6元环烷基、3～6元环烷基-C(O)-、3～6元环烷基-C 1-3烷基-、苯基-C 1-3烷基-或被一个或多个羟基取代的C 1-3烷基。
在一些实施方案中，每一个R c分别独立地选自氢、C 1-3烷基、C 1-3烷基-C(O)-、C 1-3烷基OC(O)-、C 1-3烷基-O-C 1-3烷基-、C 1-3烷基-O-CH 2-C(O)-、二(C 1-3烷基)氨基-C(O)-、二(C 1-3烷基)氨基-CH 2-C(O)-、二(C 1-3烷基)氨基-C(O)-CH 2-、3～5元环烷基、3～5元环烷基-C(O)-、3～5元环烷基-CH 2-、苯基-CH 2-或被一个羟基取代的C 1-3烷基。
在一些实施方案中，每一个R c分别独立地选自甲基、乙基、异丙基、乙酰基、
Figure PCTCN2021092672-appb-000044
Figure PCTCN2021092672-appb-000045
在一些实施方案中，环A选自C 6-10芳基、5～6元杂芳基或8～10元稠环。
在一些实施方案中，环A选自苯基、噻吩基或2,3-二氢-1H-茚基。
在一些实施方案中，n为0、1或2；或者，n为1、2或3。
在一些实施方案中，n为0或1；或者，n为0或2；或者，n为0或3；或者，n为1或2；或者，n为1或3；或者，n为2或3。在一些实施方案中，n为2。
在一些实施方案中，每一个R 3分别独立地选自氨基、硝基、卤素或C 1-4烷基，所述C 1-4烷基任选地被1，2或3个R d取代。
在一些实施方案中，R d选自羟基或氟。
在一些实施方案中，每一个R 3分别独立地选自氨基、硝基、氟、甲基、三氟甲基、-CF 2CH 2OH、-CHF 2、-CF 2CH 3或-CF 2C(CH 3) 2OH。
在一些实施方案中，结构单元
Figure PCTCN2021092672-appb-000046
选自
Figure PCTCN2021092672-appb-000047
进一步选自
Figure PCTCN2021092672-appb-000048
Figure PCTCN2021092672-appb-000049
在一些实施方案中，本申请的式(I)或式(II)化合物、其立体异构体或其药学上可接受的盐，其选自式(III)化合物、其立体异构体或其药学上可接受的盐
Figure PCTCN2021092672-appb-000050
其中，R 1、R 2、R 3、X、Y、n、环A及
Figure PCTCN2021092672-appb-000051
的定义如前所述。
在一些实施方案中，在本发明的式(I)化合物、其立体异构体或其药学上可接受的盐中，
X、Y分别独立地选自CR a和N，例如，X和Y均选自CR a，或者X为CR a且Y为N；
R a选自氢或C 1-4烷氧基；优选地，R a选自氢或甲氧基；
Figure PCTCN2021092672-appb-000052
代表双键；
R 1、R 2和与之相连的磷原子共同形成6元杂环基，其中，所述6元杂环基的环原子中至少包含一个N原子或O原子，且当环原子含N原子时，N与R c连接(优选包含一个N原子，且N与R c连接)；
R c选自C 1-4烷基-S(O) 2-(优选甲磺酰基)、C 3-6环烷基-S(O) 2-(优选环丙基磺酰基)；
环A选自C 6-10芳基、优选C6芳基(即，苯基)；
n为0、1、2或3，优选2；
每一个R 3分别独立地选自卤素(优选F)、C 1-8烷基(优选C 1-4烷基，更优选甲基或乙基)，其中，所述C 1-8烷基任选地被一个或多个卤素(优选F)取代；
R 4、R 5分别独立地选自氢或C 1-3烷基，其中，所述C 1-3烷基任选地被一个或多个氟取代(优选R 4选自氢，R 5选自甲基，或者，R 4选自甲基，R 5选自氢)；
R 6选自氢、卤素或C 1-6烷基，其中所述C 1-6烷基任选地被一个或多个卤素取代，例如，R 6可选自氢、甲基或任选地被一个或多个卤素取代的甲基(例如，-CH 2F)。
在一些实施方案中，在本发明的式(II)化合物、其立体异构体或其药学上可接受的盐中，
X、Y分别独立地选自CR a和N，例如，X和Y均选自CR a，或者X为CR a且Y为N；
R a选自氢或C 1-4烷氧基；优选地，R a选自氢或甲氧基；更优选地，R a选自氢；
Figure PCTCN2021092672-appb-000053
代表双键；
R 1、R 2和与之相连的磷原子共同形成6元杂环基，其中所述6元杂环基的环原子中至少包含一个N原子(优选包含一个N原子)，且N与R c连接；
R c选自C 1-4烷基-S(O) 2-(优选甲磺酰基)、C 3-6环烷基-S(O) 2-(优选环丙基磺酰基)；
环A选自C 6-10芳基、优选C6芳基(即，苯基)；
n为0、1、2或3，优选2；
每一个R 3分别独立地选自卤素(优选F)、C 1-8烷基(优选C1-4，更优选甲基或乙基)，其中所述C 1-8烷基任选地被一个或多个卤素(优选F)取代。
在一些实施方案中，本申请的式(I)或式(II)化合物、其立体异构体或其药学上可接受的盐，其选自式(III-1)化合物、式(III-2)化合物、式(III-3)化合物、式(III-4)化合物、式(III-5)化合物、式(III-6)化合物、式(III-7)化合物、式(III-8)化合物和式(III-9)化合物、其立体异构体或其药学上可接受的盐，
Figure PCTCN2021092672-appb-000054
Figure PCTCN2021092672-appb-000055
其中，R 1、R 2、R 3、Y、n、环A、R a、R b及R c的定义如前所述。
在一些实施方案中，本申请的式(I)或式(II)化合物、其立体异构体或其药学上可接受的盐，其选自式(IV)化合物、式(V)化合物和式(VI)化合物、其立体异构体或其药学上可接受的盐，
Figure PCTCN2021092672-appb-000056
其中，R 3、Y、n、R b及R c的定义如前所述。
在一些实施方案中，本申请包含上述定义的变量及其实施方案，以及它们的任意组合。
在一些实施方案中，本申请的式(I)化合物选自以下化合物、其立体异构体或其药学上可接受的盐：
Figure PCTCN2021092672-appb-000057
Figure PCTCN2021092672-appb-000058
Figure PCTCN2021092672-appb-000059
Figure PCTCN2021092672-appb-000060
Figure PCTCN2021092672-appb-000061
Figure PCTCN2021092672-appb-000062
Figure PCTCN2021092672-appb-000063
在一些实施方案中，本申请的式(I)化合物选自以下化合物、其立体异构体或其药学上可接受的盐：
Figure PCTCN2021092672-appb-000064
Figure PCTCN2021092672-appb-000065
Figure PCTCN2021092672-appb-000066
另一方面，本申请提供了式(I)化合物的制备方法，包括：式M3化合物与式N3化合物发生反应，制备得到式(I)化合物
Figure PCTCN2021092672-appb-000067
其中，
Rx选自氯、溴或碘；
R 6选自任选地被一个或多个卤素取代的C 1-6烷基；
R 1、R 2、R 3、R 4、R 5、X、Y、n及环A的定义如前所述。
另一方面，本申请提供了式M3化合物的制备方法，包括：
步骤(i)：在酸性条件下，式M1化合物与式N1化合物反应，制备得到式M2化合物；
步骤(ii)：式M2化合物与式N2化合物反应，制备得到式M3化合物；
Figure PCTCN2021092672-appb-000068
其中，
Rx选自氯、溴或碘；
R 6选自任选地被一个或多个卤素取代的C 1-6烷基；
R 3、R 4、R 5、X、Y、n及环A的定义如前所述。
另一方面，本申请提供了式M3化合物的制备方法，包括：
Figure PCTCN2021092672-appb-000069
步骤(a)：将式M2化合物与氯化亚砜反应，制备得到式M2-1化合物，
步骤(b)：在碱性条件下，将式M2-1化合物与式N2化合物发生取代反应制备得到式M3化合物，
其中，
Rx选自氯、溴或碘；
R 6选自任选地被一个或多个卤素取代的C 1-6烷基；
R 3、R 4、R 5、X、Y、n及环A的定义如前所述。
在一些实施方案中，在式(I)化合物的制备方法中，其中式M3化合物通过如上所述方法进行制备。
另一方面，本申请提供了式(III-8)化合物的制备方法，所述方法包括：
将式M3-1化合物与1-苄基-1,4-氮杂膦烷-4-氧化物反应制备得到式M3-2化合物，进而脱苄基保护得到式M3-3化合物，最后发生取代反应制备得到式(III-8)化合物，
Figure PCTCN2021092672-appb-000070
其中，Rx选自氯、溴或碘；
R 3、R c、n及环A的定义如前所述。
在一些实施方式呢中，本申请提供的式(III-8)化合物的制备方法包括：
步骤(1)：将式M3-1化合物与1-苄基-1,4-氮杂膦烷-4-氧化物反应制备得到式M3-2化合物，
步骤(2)：式M3-2化合物进行反应，得到式M3-3化合物，
步骤(3)：式M3-3化合物进行反应，得到式(III-8)化合物，
任选地，步骤(2)在
Figure PCTCN2021092672-appb-000071
的存在下进行，
其中，
Rx选自氯、溴或碘；
R 6选自任选地被一个或多个卤素取代的C 1-6烷基；
R 3、R c、n及环A的定义如前所述。
另一方面，本申请还提供了以下中间体化合物、其立体异构体或其药学上可接受的盐：
Figure PCTCN2021092672-appb-000072
Figure PCTCN2021092672-appb-000073
另一方面，本申请提供了药物组合物，其包含本申请的上述化合物、其立体异构体或其药学上可接受的盐。在一些实施方案中，本申请的药物组合物还包括药学上可接受的辅料。
另一方面，本申请提供了治疗或预防哺乳动物中与SOS1相关或由SOS1调节的疾病和/或病症的方法，所述方法包括对需要该治疗或预防的哺乳动物，优选人类，给予治疗或预防有效量的上述化合物、其立体异构体或其药学上可接受的盐、或其药物组合物。
另一方面，本申请提供了上述化合物、其立体异构体或其药学上可接受的盐、或其药物组合物在制备治疗或预防与SOS1相关或由SOS1调节的疾病和/或病症的药物中的用途。
另一方面，本申请提供了上述化合物、其立体异构体或其药学上可接受的盐、或其药物组合物在治疗或预防与SOS1相关或由SOS1调节的疾病和/或病症中的用途。
另一方面，本申请提供了治疗或预防与SOS1相关或由SOS1调节的疾病和/或病症的上述化合物、其立体异构体或其药学上可接受的盐、或其药物组合物。
在一些实施方案中，所述与SOS1相关或由SOS1调节的疾病和/或病症选自SOS1与RAS家族蛋白相互作用的疾病和/或病症。
在一些实施方案中，所述与SOS1相关或由SOS1调节的疾病和/或病症选自癌症，例如非小细胞肺癌。
本申请的化合物具备良好的KRAS-G12C/SOS1蛋白结合抑制活性、K562细胞增殖抑制活性、体内外药物活性及良好的药代动力学性质。
定义
除非另有说明，本申请中所用的下列术语具有下列含义。一个特定的术语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照本领域普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。
化学键
Figure PCTCN2021092672-appb-000074
根据两端所连接基团的不同分别代表单键或双键。例如当化学键两端连接的X、Y分别为CR a或N时，化学键
Figure PCTCN2021092672-appb-000075
为双键；当化学键两端连接的X、Y有一个为CO或NR a时，化学键
Figure PCTCN2021092672-appb-000076
为单键。本领域技术人员能够理解，X、Y的选择不会违反价键规则。
术语“被取代”是指特定原子上的任意一个或多个氢原子被取代基取代，只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为氧代(即＝O)时，意味着两个氢原子被取代，氧代不会发生在芳香基上。
术语“任选”或“任选地”是指随后描述的事件或情况可以发生或不发生，该描述包括发生所述事件或情况和不发生所述事件或情况。例如，乙基“任选”被卤素取代，指乙基可以是未被取代的(-CH 2CH 3)、单取代的(如-CH 2CH 2F)、多取代的(如-CHFCH 2F、-CH 2CHF 2等)或完全被取代的(-CF 2CF 3)。本领域技术人员可理解，对于包含一个或多个取代基的任何基团，不会引入任何在空间上不可能存在和/或不能合成的取代或取代模式。
本文中的C m-n，是该部分具有给定范围中的整数个碳原子。例如“C 1-6”是指该基团可具有1个碳原子、2个碳原子、3个碳原子、4个碳原子、5个碳原子或6个碳原子；“C 1-3”是指该基团可具有1个碳原子、2个碳原子或3个碳原子。
当任何变量(例如R)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立 的。因此，例如，如果一个基团被2个R所取代，则每个R都有独立的选项。
当一个连接基团的数量为0时，比如-(CH 2) 0-，表示该连接基团为共价键。
当一个取代基的键交叉连接到一个环上的两个原子之间时，这种取代基可以与这个环上的任意原子相键合。例如，结构单元
Figure PCTCN2021092672-appb-000077
表示其可在环己基或者环己二烯上的任意一个位置发生取代。
术语“卤”或“卤素”是指氟、氯、溴和碘。
术语“羟基”指-OH基团。
术语“氨基”指-NH 2基团。
术语“硝基”指-NO 2基团。
术语“氰基”是指-CN基团。
术语“烷基”是指通式为C nH 2n+1的烃基。该烷基可以是直链或支链的。例如，术语“C 1- 6烷基”指含有1至6个碳原子的烷基(例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、1-甲基丁基、2-甲基丁基、3-甲基丁基、新戊基、己基、2-甲基戊基等)。类似地，烷氧基、烷基氨基、二烷基氨基、烷基磺酰基和烷硫基的烷基部分(即烷基)具有上述相同定义。
术语“烷氧基”指-O-烷基。
术语“烷基氨基”或“单烷基氨基”指-NH-烷基。
术语“二烷基氨基”指-N(烷基) 2。
术语“环烷基”指完全饱和的并且可以以呈单环、桥环或螺环存在的碳环。除非另有指示，该碳环通常为3至10元环。环烷基非限制性实例包括但不限于环丙基、环丁基、环戊基、环己基、降冰片基(双环[2.2.1]庚基)、双环[2.2.2]辛基、金刚烷基等。
术语“杂环基”是指完全饱和的或部分不饱和的(但不是完全不饱和的杂芳族)并且可以以单环、桥环或螺环存在的非芳族环。除非另有指示，该杂环基通常为含有1至3个独立地选自硫、氧、磷和/或氮的杂原子(优选1或2个杂原子)的3至12元环。杂环基的非限制性实例包括但不限于环氧乙烷基、四氢呋喃基、二氢呋喃基、吡咯烷基、N-甲基吡咯烷基、二氢吡咯基、哌啶基、哌嗪基、吡唑烷基、4H-吡喃基、吗啉基、硫代吗啉基、四氢噻吩基或
Figure PCTCN2021092672-appb-000078
等。
术语“杂环烷基”是指完全饱和的并且可以以单环、桥环或螺环存在的环状基团。除非另有指示，该杂环烷基通常为含有1至3个独立地选自硫、氧、磷和/或氮的杂原子(优选1或2个杂原子)的3至12元环、3至7元环或者5至8元环。3元杂环烷基的实例包括但不限于环氧乙烷基、环硫乙烷基、环氮乙烷基，4元杂环烷基的非限制性实例包括但不限于吖丁啶基、噁丁环基、噻丁环基，5元杂环烷基的实例包括但不限于四氢呋喃基、四氢噻吩基、吡咯烷基、异噁唑烷基、噁唑烷基、异噻唑烷基、噻唑烷基、咪唑烷基、四氢吡唑基，6元杂环烷基的实例包括但不限于哌啶基、四氢吡喃基、四氢噻喃基、吗啉基、哌嗪基、1,4-噻噁烷基、1,4-二氧六环基、硫代吗啉基、1,3-二噻烷基、1,4-二噻烷基或
Figure PCTCN2021092672-appb-000079
7元杂环烷基的实例包括但不限于氮杂环庚烷基、氧杂环庚烷基、硫杂环庚烷基。优选为具有5或6个环原子的单环杂环烷基。
术语“芳基”是指具有共轭的π电子体系的全碳单环或稠合多环的芳香环基团。例如，芳基可以具有6-20个碳原子，6-14个碳原子或6-12个碳原子。芳基的非限制性实例包括但不限于苯基、萘基、蒽基和1,2,3,4-四氢化萘等。
术语“杂芳基”是指单环或稠合多环体系，其中含有至少一个选自N、O、S的环原子，其余环原子为C，并且具有至少一个芳香环。优选的杂芳基具有单个5至8元环，或包含6至14个，尤其是6至10个环原子的多个稠合环。杂芳基的非限制性实例包括但不限于吡咯基、呋喃基、噻吩基、咪唑基、噁唑基、吡唑基、吡啶基、嘧啶基、吡嗪基、喹啉基、异喹啉基、四唑基、三唑基、三嗪基、苯并呋喃基、苯并噻吩基、吲哚基、异吲哚基等。
术语“稠环”是指7～20元，系统中两个环共享毗邻的两个碳原子的全碳多环，其中至少有一个环具有完全共轭的π电子系统，但整体不具有芳香性。根据组成环的数目可以分为双环、三环、四环或多环稠环，优选为双环或三环，更优选为6元/6元或5元/6元双环。稠环的非限制性实例包括：
Figure PCTCN2021092672-appb-000080
Figure PCTCN2021092672-appb-000081
术语“螺杂环烷基”是指单环之间共用一个碳原子(称螺原子)的完全饱和的5至20元多环，且该多环中一个或多个环原子选自硫、硅、磷、氧和/或氮的杂原子(优选1或2个杂原子)，其余环原子为碳原子。优选为6至14元，更优选为6至10元。根据环与环之间共用螺原子的数目将螺杂环分为单螺杂环、双螺杂环或多螺杂环，优选为单螺杂环或双螺杂环，更优选为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺杂环。螺杂环的非限制性实例包括
Figure PCTCN2021092672-appb-000082
Figure PCTCN2021092672-appb-000083
术语“并杂环烷基”是指具有5至20元环原子，并且两个环共用2个环原子的完全饱和的多环，该多环中一个或多个环原子选自硫、硅、磷、氧和/或氮的杂原子(优选1或2个杂原子)，其余环原子为碳原子。优选为6至14元，更优选为6至10元。根据组成环的数目可以分为双环、三环或多环桥杂环，优选为双环。并杂环的非限制性实例包括
Figure PCTCN2021092672-appb-000084
术语“苯并环烷基”是指苯环与环烷基稠合(即，苯环与环烷基共享毗邻的两个碳原子)。苯并环烷基的非限制性实例包括：
Figure PCTCN2021092672-appb-000085
等。
术语“环烯基”是指包含至少一个碳碳双键且不包含任何碳碳三键的不饱和碳环，并且可以呈单环、桥环或螺环存在的碳环。环烯基的非限制性实例包括：环丙烯基、环丁烯基、环戊烯基、环己烯基和环己二烯基。
术语“苯并环烯基”是指苯环与环烯基稠合(即，苯环与环烯基共享毗邻的两个碳原子)。苯并环烯基的非限制性实例包括：
Figure PCTCN2021092672-appb-000086
术语“苯并杂环基”是指苯环与杂环基稠合(即，苯环与杂环基共享毗邻的两个碳原子)。苯并杂环基 的非限制性实例包括：
Figure PCTCN2021092672-appb-000087
Figure PCTCN2021092672-appb-000088
术语“苯并杂环烷基”是指苯环与杂环烷基稠合(即，苯环与杂环烷基共享毗邻的两个碳原子)。苯并杂环烷基的非限制性实例包括：
Figure PCTCN2021092672-appb-000089
术语“杂环烯基”是指其含有至少一个碳-碳双键或碳-氮双键，并且可以呈单环、桥环或螺环存在的不饱和环状基团。除非另有指示，该杂环通常为含有1至3个独立地选自硫、氧、磷和/或氮的杂原子(优选1或2个杂原子)。杂环烯基的非限制性实例包括：1,2,3,4-四氢吡啶基、1,2-二氢吡啶基、1,4-二氢吡啶基、1,2,3,6-四氢吡啶基、1,4,5,6-四氢嘧啶基、3-吡咯啉基、3,4-二氢-2H-吡喃、二氢呋喃基、二氢噻吩基和二氢噻喃基。
术语“苯并杂环烯基”是指苯环与杂环烯基稠合(即，苯环与杂环烯基共享毗邻的两个碳原子)。苯并杂环烯基的非限制性实例包括：
Figure PCTCN2021092672-appb-000090
术语“稠杂环”是指7～20元、系统中两个环共享毗邻的两个原子的多环，其中含有至少一个选自N、O、S的环原子，其余环原子为C，并且至少有一个环具有完全共轭的π电子系统，但整体不具有芳香性。根据组成环的数目可以分为双环、三环、四环或多环稠环，优选为双环或三环，更优选为6元/6元或5元/6元双环。稠杂环的非限制性实例包括：
Figure PCTCN2021092672-appb-000091
术语“治疗”意为将本申请所述化合物或制剂进行给药以改善或消除疾病或与所述疾病相关的一个或多个症状，且包括：
(i)抑制疾病或疾病状态，即遏制其发展；
(ii)缓解疾病或疾病状态，即使该疾病或疾病状态消退。
术语“预防”意为将本申请所述化合物或制剂进行给药以预防疾病或与所述疾病相关的一个或多个症状，且包括：预防疾病或疾病状态在哺乳动物中出现，特别是当这类哺乳动物易患有该疾病状态，但尚未被诊断为已患有该疾病状态时。
术语“治疗或预防有效量”意指(i)治疗或预防本文中所述的特定疾病、病况或障碍，(ii)减轻、改善或消除本文中所述的特定疾病、病况或障碍的一种或多种症状，或(iii)预防或延迟本文中所述的特定疾病、病况或障碍的一种或多种症状发作的本申请化合物的用量。构成“治疗有效量”的本申请化合物的量取决于该化合物、疾病状态及其严重性、给药方式以及待被治疗的哺乳动物的年龄而改变，但可例行性地由本领域技术人员根据其自身的知识及本公开内容而确定。
术语“药学上可接受的”是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。
作为药学上可接受的盐，例如，可以提及金属盐、铵盐、与有机碱形成的盐、与无机酸形成的盐、与有机酸形成的盐、与碱性或者酸性氨基酸形成的盐等。
术语“药物组合物”是指一种或多种本申请的化合物或其盐与药学上可接受的辅料组成的混合物。药物组合物的目的是有利于对有机体给予本申请的化合物。
术语“药学上可接受的辅料”是指对有机体无明显刺激作用，而且不会损害该活性化合物的生物活性及性能的那些辅料。合适的辅料是本领域技术人员熟知的，例如碳水化合物、蜡、水溶性和/或水可膨胀的聚合物、亲水性或疏水性材料、明胶、油、溶剂、水等。
词语“包括(comprise)”或“包含(comprise)”及其英文变体例如comprises或comprising应理解为开放的、非排他性的意义，即“包括但不限于”。
除非另外特别说明，否则单数术语涵盖复数术语，并且复数术语涵盖单数术语。除非另外特别说明，否则词语“一个”或“一种”意指“至少一个”或“至少一种”。除非另外说明，否则“或”的使用意指“和/或”。
本发明的化合物可以存在特定的几何或立体异构体形式。本发明设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其它混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本发明的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本发明的范围之内。
除非另有说明，“(D)”或者“(+)”表示右旋，“(L)”或者“(-)”表示左旋，“(DL)”或者“(±)”表示外消旋。
除非另有说明，用楔形实线键
Figure PCTCN2021092672-appb-000092
和楔形虚线键
Figure PCTCN2021092672-appb-000093
表示一个立体中心的绝对构型，用直形实线键
Figure PCTCN2021092672-appb-000094
和直形虚线键
Figure PCTCN2021092672-appb-000095
表示立体中心的相对构型。
可以通过手性合成或手性试剂或者其他常规技术制备光学活性的(R)-和(S)-异构体以及D和L异构体。如果想得到本发明某化合物的一种对映体，可以通过不对称合成或者具有手性助剂的衍生作用来制备，其中将所得非对映体混合物分离，并且辅助基团裂开以提供纯的所需对映异构体。或者，当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时，与适当的光学活性的酸或碱形成非对映异构体的盐，然后通过本领域所公知的常规方法进行非对映异构体拆分，然后回收得到纯的对映体。此外，对映异构体和非对映异构体的分离通常是通过使用色谱法完成的，所述色谱法采用手性固定相，并任选地与化学衍生法相结合(例如由胺生成氨基甲酸盐)。
本申请还包括与本文中记载的那些相同的，但一个或多个原子被原子量或质量数不同于自然中通常发现的原子量或质量数的原子置换的同位素标记的本申请化合物。可结合到本申请化合物的同位素的实例包括氢、碳、氮、氧、磷、硫、氟、碘和氯的同位素，诸如分别为 2H、 3H、 11C、 13C、 14C、 13N、 15N、 15O、 17O、 18O、 31P、 32P、 35S、 18F、 123I、 125I和 36Cl等。
某些同位素标记的本申请化合物(例如用 3H及 14C标记的那些)可用于化合物和/或底物组织分布分析中。氚化(即 3H)和碳-14(即 14C)同位素由于它们易于制备和可检测性是尤其优选的。正电子发射同位素，诸如 15O、 13N、 11C和 18F可用于正电子发射断层扫描(PET)研究以测定底物占有率。通常可以通过与公开于下文的方案和/或实施例中的那些类似的下列程序，通过同位素标记试剂取代未经同位素标记的试剂来制备同位素标记的本申请化合物。
此外，用较重同位素(诸如氘(即 2H或D))取代可以提供某些由更高的代谢稳定性产生的治疗优点(例如增加的体内半衰期或降低的剂量需求)，并且因此在某些情形下可能是优选的，其中氘取代可以是部分或完全的，部分氘取代是指至少一个氢被至少一个氘取代。
本申请的药物组合物可通过将本申请的化合物与适宜的药学上可接受的辅料组合而制备，例如可配制成固态、半固态、液态或气态制剂，如片剂、丸剂、胶囊剂、粉剂、颗粒剂、膏剂、乳剂、悬浮剂、栓剂、注射剂、吸入剂、凝胶剂、微球及气溶胶等。
给予本申请化合物或其药学上可接受的盐或其药物组合物的典型途径包括但不限于口服、直肠、局部、吸入、肠胃外、舌下、阴道内、鼻内、眼内、腹膜内、肌内、皮下、静脉内给药。
本申请的药物组合物可以采用本领域众所周知的方法制造，如常规的混合法、溶解法、制粒法、制糖衣药丸法、磨细法、乳化法、冷冻干燥法等。
在一些实施方案中，药物组合物是口服形式。对于口服给药，可以通过将活性化合物与本领域熟知的 药学上可接受的辅料混合，来配制该药物组合物。这些辅料能使本申请的化合物被配制成片剂、丸剂、锭剂、糖衣剂、胶囊剂、液体、凝胶剂、浆剂、悬浮剂等，用于对患者的口服给药。
可以通过常规的混合、填充或压片方法来制备固体口服组合物。例如，可通过下述方法获得：将所述的活性化合物与固体辅料混合，任选地碾磨所得的混合物，如果需要则加入其它合适的辅料，然后将该混合物加工成颗粒，得到了片剂或糖衣剂的核心。适合的辅料包括但不限于：粘合剂、稀释剂、崩解剂、润滑剂、助流剂、甜味剂或矫味剂等。
药物组合物还可适用于肠胃外给药，如合适的单位剂型的无菌溶液剂、混悬剂或冻干产品。
本文所述的通式I化合物的所有给予方法中，每天给药的剂量为0.01到200mg/kg体重，以单独或分开剂量的形式。
本申请的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其它化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本申请的实施例。
本申请具体实施方式的化学反应是在合适的溶剂中完成的，所述的溶剂须适合于本申请的化学变化及其所需的试剂和物料。为了获得本申请的化合物，有时需要本领域技术人员在已有实施方式的基础上对合成步骤或者反应流程进行修改或选择。
本领域合成路线规划中的一个重要考量因素是为反应性官能团(如本申请中的氨基)选择合适的保护基，例如，可参考Greene's Protective Groups in Organic Synthesis(4th Ed).Hoboken,New Jersey:John Wiley&Sons,Inc.，将本申请引用的所有参考文献整体上并入本申请。
为了描述和公开的目的，以引用的方式将所有的专利、专利申请和其它已确定的出版物在此明确地并入本文。这些出版物仅因为它们的公开早于本申请的申请日而提供。所有关于这些文件的日期的声明或这些文件的内容的表述是基于申请者可得的信息，并且不构成任何关于这些文件的日期或这些文件的内容的正确性的承认。而且，在任何国家，在本中对这些出版物的任何引用并不构成关于该出版物成为本领域的公知常识的一部分的认可。
在一些实施方案中，本申请的化合物可以由有机合成领域技术人员参考以下路线来制备：
路线一：
Figure PCTCN2021092672-appb-000096
其中，
环A、R c、R 3、n的定义如上所述。
路线二：
Figure PCTCN2021092672-appb-000097
其中，
环A、R 3、n的定义如上所述。
路线三：
Figure PCTCN2021092672-appb-000098
其中，
环A、R 3、n的定义如上所述。
本申请采用以下缩略词：
PBS代表胎牛血清；PBS代表磷酸缓冲盐溶液；PBST代表磷酸盐吐温缓冲液；BSA代表牛血清白蛋白；GAPDH代表甘油醛-3-磷酸脱氢酶；DMSO代表二甲基亚砜；DTT代表二硫苏糖醇；HTRF代表均相时间分辨荧光。
具体实施方式
为清楚起见，进一步用实施例来阐述本发明，但是实施例并非限制本申请的范围。对本领域的技术人员而言，在不脱离本发明精神和范围的情况下，针对本发明具体实施方式进行各种变化和改进将是显而易见的。本申请所使用的所有试剂是市售的，无需进一步纯化即可使用。
实施例1：化合物1的制备
Figure PCTCN2021092672-appb-000099
步骤A：化合物1-1的制备
向250mL三口瓶中加入2-氨基-4-甲氧基苯甲酸甲酯(4g)和无水乙醇(16mL)，室温搅拌下分别加入水(28mL)和浓盐酸(7mL)，机械搅拌下冰浴降温至0℃，缓慢滴加一氯化碘(3.58g)的浓盐酸(2mL)溶液，滴加完毕后将反应液转移至室温继续搅拌反应过夜。向反应液中加入水(100mL)，剧烈搅拌5min，抽滤，滤饼用水(20mL)洗涤，收集固体，石油醚(50mL)打浆，得6.45g化合物1-1。
MS(ESI，[M+H] +):m/z＝307.81.
1H NMR(500MHz,DMSO-d 6)δ7.99(s,1H),6.38(s,1H),3.78(s,3H),3.75(s,3H).
步骤B：化合物1-2的制备
向350mL耐压瓶中依次加入步骤A所得化合物1-1(15g)、乙腈(100g)和甲磺酸(37.6g)，将反应瓶置 于120℃油浴中，搅拌反应6h。停止反应，反应液减压浓缩至干，向残留固体中加入水(150mL)，剧烈搅拌，用2.5M氢氧化钠水溶液调pH至碱性，抽滤，滤饼用大量水洗，收集固体，烘干后硅胶柱层析(石油醚:乙酸乙酯＝1:2)，得5.9g化合物1-2。
MS(ESI，[M+H] +):m/z＝316.79.
1H NMR(500MHz,DMSO-d 6)δ12.19(s,1H),8.37(s,1H),7.05(s,1H),3.95(s,3H),2.32(s,3H).
步骤C：化合物1-3的制备
向25mL三口瓶中加入步骤B所得化合物1-2(1g)和氯仿(10mL)，室温搅拌下依次加入氯化亚砜(2.94g)和两滴N,N-二甲基甲酰胺，将反应液加热至70℃搅拌反应3h。将反应液浓缩至干，向残留物中加入水(40mL)和二氯甲烷(50mL)，剧烈搅拌下滴加饱和碳酸氢钠水溶液调节pH值至弱碱性，分液，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，浓缩残留物，硅胶柱层析(石油醚:乙酸乙酯＝90:10)得到0.41g化合物1-3。
MS(ESI，[M+H] +):m/z＝334.77.
1H NMR(500MHz,DMSO-d 6)δ8.42(s,1H),7.18(s,1H),3.98(s,3H),2.50(s,3H).
步骤D：化合物1-4的制备
向25mL单口瓶中加入步骤C所得化合物1-3(200mg)，(R)-1-(间甲苯基)乙烷-1-胺(98mg)、N,N-二异丙基乙胺(129mg)和1,4-二氧六环(2mL)，氮气保护下将混合物加热至100℃搅拌反应5h。停止反应，反应液浓缩至干，残留物用二氯甲烷(20mL)溶解，分别以饱和碳酸氢钠水溶液、1M盐酸、饱和食盐水洗涤，无水硫酸钠干燥，浓缩，残留物硅胶柱层析(石油醚:乙酸乙酯＝5:1)得160mg化合物1-4。
MS(ESI，[M+H] +):m/z＝434.00.
1H NMR(500MHz,DMSO-d 6)δ8.88(s,1H),8.29(d,J＝8.0Hz,1H),7.28–7.16(m,3H),7.05-7.03(m,2H),5.58(p,J＝7.0Hz,1H),3.92(s,3H),2.36(s,3H),2.29(s,3H),1.54(d,J＝7.0Hz,3H).
步骤E：化合物1的制备
向15mL耐压管中加入步骤D所得化合物1-4(0.09g)，二甲基氧化膦(0.017g)，三乙胺(0.032g)，4,5-双二苯基膦-9,9-二甲基氧杂蒽(6.13mg)，三二亚苄基丙酮二钯(4.85mg)和1,4-二氧六环(2mL)，氮气保护下油浴加热至120℃搅拌反应2h。反应液冷却至室温，抽滤，滤液浓缩至干，残留物用C18柱(120g)层析纯化(40％乙腈+60％水)，得58.5mg化合物1。
HRMS(ESI，[M+H] +):m/z＝384.1855.
1H NMR(500MHz,DMSO-d 6)δ8.80(d,J＝8.0Hz,1H),8.76(d,J＝13.6Hz,1H),7.32(s,1H),7.30(d,J＝7.8Hz,1H),7.24(t,J＝7.5Hz,1H),7.14(d,J＝4.7Hz,1H),7.06(d,J＝7.3Hz,1H),5.67(p,J＝7.1Hz,1H),3.99(s,3H),2.43(s,3H),2.33(s,3H),1.75(s,3H),1.72(s,3H),1.60(d,J＝7.1Hz,3H).
实施例2：化合物2的制备
Figure PCTCN2021092672-appb-000100
步骤A：化合物2-1的制备
参照实施例1步骤D的方法，将化合物1-3与(R)-1-(3-(三氟甲基)苯基)乙烷-1-胺反应制备得到化合物2-1。
MS(ESI，[M+H] +):m/z＝487.94.
1H NMR(500MHz,DMSO-d 6)δ8.86(s,1H),8.39(d,J＝7.6Hz,1H),7.81(s,1H),7.74(t,J＝7.9Hz,1H), 7.60-7.55(m,2H),7.03(d,J＝8.3Hz,1H),5.62(p,J＝7.1Hz,1H),3.92(s,3H),2.35(s,3H),1.60(d,J＝7.1Hz,3H).
步骤B：化合物2的制备
参照实施例1步骤E的方法，制备得到化合物2。
HRMS(ESI，[M+H] +):m/z＝438.1599.
1H NMR(500MHz,DMSO-d 6)δ8.88(d,J＝7.8Hz,1H),8.76(d,J＝13.6Hz,1H),7.91(s,1H),7.82(t,J＝7.8Hz,1H),7.65–7.57(m,2H),7.15(d,J＝4.8Hz,1H),5.70(p,J＝7.1Hz,1H),3.99(s,3H),2.42(s,3H),1.76(s,3H),1.73(s,3H),1.66(d,J＝7.1Hz,3H).
实施例3：化合物3的制备
Figure PCTCN2021092672-appb-000101
步骤A：化合物3-1的制备
参照实施例1步骤D的方法，将化合物1-3与(R)-2-(3-(1-氨基乙基)苯基)-2,2-二氟乙烷-1-醇反应制备得到化合物3-1。
MS(ESI，[M+H] +):m/z＝499.95.
1H NMR(500MHz,DMSO-d 6)δ8.87(s,1H),8.37(d,J＝7.8Hz,1H),7.63(s,1H),7.57(d,J＝7.7Hz,1H),7.44(t,J＝7.7Hz,1H),7.38(d,J＝7.7Hz,1H),7.03(s,1H),4.05-4.01(m,1H),3.92(s,3H),3.84(td,J＝14.2,6.3Hz,2H),2.36(s,3H),1.58(d,J＝7.0Hz,3H).
步骤B：化合物3的制备
参照实施例1步骤E的方法，制备得到化合物3。
HRMS(ESI，[M+H] +):m/z＝450.1728.
1H NMR(500MHz,DMSO-d 6)δ8.88(d,J＝7.9Hz,1H),8.76(d,J＝13.6Hz,1H),7.72(s,1H),7.65(d,J＝7.6Hz,1H),7.48(t,J＝7.7Hz,1H),7.42(d,J＝7.7Hz,1H),7.15(d,J＝4.7Hz,1H),5.75–5.64(m,2H),4.00(s,3H),3.88(td,J＝14.1,4.3Hz,2H),2.44(s,3H),1.76(s,3H),1.73(s,3H),1.65(d,J＝7.1Hz,3H).
实施例4：化合物4的制备
Figure PCTCN2021092672-appb-000102
步骤A：化合物4-1的制备
参照实施例1步骤D的方法，将化合物1-3与(R)-1-(3-(二氟甲基)-2-甲基苯基)乙烷-1-胺反应制备得到化合物4-1。
MS(ESI，[M+H] +):m/z＝484.4.
1H NMR(500MHz,DMSO-d 6)δ8.90(s,1H),8.46(d,J＝7.3Hz,1H),7.66(d,J＝7.7Hz,1H),7.38(d,J＝7.5Hz,1H),7.30(dd,J＝13.8,6.1Hz,1H),7.21(s,1H),7.02(s,1H),5.73(p,J＝7.0Hz,1H),3.91(s,3H),2.55(s,3H),2.33(s,3H),1.52(d,J＝7.0Hz,3H).
步骤B：化合物4的制备
参照实施例1步骤E的方法，制备得到化合物4。
MS(ESI，[M+H] +):m/z＝434.17.
1H NMR(500MHz,CDCl 3)δ8.41(d,J＝13.8Hz,1H),7.54(d,J＝7.8Hz,1H),7.43(d,J＝7.6Hz,1H),7.28-7.27(m,1H),7.12(d,J＝5.0Hz,1H),6.83(t,J＝55.5Hz,1H),6.32(d,J＝6.9Hz,1H),5.85(p,J＝6.9Hz,1H),3.96(s,3H),2.54(d,J＝2.2Hz,6H),1.79(dd,J＝13.9,2.7Hz,6H),1.60(d,J＝6.9Hz,3H).
实施例5：化合物5的制备
Figure PCTCN2021092672-appb-000103
步骤A：化合物5-1的制备
参照实施例1步骤D的方法，将化合物1-3与(R)-1-(3-(1,1-二氟乙基)-2-氟苯基)乙烷-1-胺反应制备得到化合物5-1。
MS(ESI，[M+H] +):m/z＝502.25.
1H NMR(500MHz,CDCl 3)δ8.14(s,1H),7.50–7.41(m,2H),7.14(t,J＝7.7Hz,1H),7.06(s,1H),5.88–5.68(m,2H),3.96(s,3H),2.52(s,3H),2.02(td,J＝1.1,18.6Hz,3H),1.70(s,3H).
步骤B：化合物5的制备
参照实施例1步骤E的方法，制备得到化合物5。
MS(ESI，[M+H] +):m/z＝452.5.
1H NMR(500MHz,CDCl 3)δ8.48(d,J＝13.8Hz,1H),7.51–7.46(m,1H),7.43(td,J＝1.7,7.5Hz,1H),7.15–7.09(m,2H),6.44(d,J＝7.2Hz,1H),5.85(p,J＝7.0Hz,1H),3.97(s,3H),2.52(s,3H),2.07–1.97(m,3H),1.82(s,3H),1.79(s,3H),1.66(d,J＝7.0Hz,3H).
实施例6：化合物6的制备
Figure PCTCN2021092672-appb-000104
步骤A：化合物6-1的制备
Figure PCTCN2021092672-appb-000105
步骤a：化合物6-1-1的制备
向250mL三口瓶中加入2-(3-溴苯基)乙酸乙酯(10g)和无水四氢呋喃(100mL)，氮气保护下，降温至-78℃。将双三甲基硅基胺基锂(103mL,1mol/L)滴加到反应液中，反应30min，保持-78℃。再将N-氟-N-(苯磺酰基)苯磺酰胺(25.9g)的无水四氢呋喃(50mL)溶液缓慢滴加到反应体系中，滴加完毕后恢复室温继续搅拌反应2h。反应结束，向反应液中加入水(100mL)剧烈搅拌，然后乙酸乙酯(100mL)萃取两次，旋干，硅胶柱层析(石油醚:乙酸乙酯＝97:3)，得到10.1g化合物6-1-1。
19F-NMR(471MHz,Methanol-d 4)δ-105.17-105.60(m).
1H-NMR(500MHz,Methanol-d 4)δ7.76–7.69(m,2H),7.57(m,1H),7.44(m,1H),4.31(m,2H),1.28(t,J＝7.1Hz,3H).
步骤b：化合物6-1-2的制备
向500mL三口瓶中加入步骤a得到的化合物6-1-1(9g)和无水四氢呋喃(200mL)，氮气保护下，降温至-78℃。将甲基溴化镁(22mL,3mol/L)缓慢滴加到反应液中，滴加完毕。恢复到0℃继续搅拌反应1h。反应结束，向反应液中加入饱和氯化铵水溶液(100mL)剧烈搅拌，然后乙酸乙酯(100mL)萃取两次，合并有机相，水洗(100mL)一次，无水硫酸钠干燥，旋干，得到7.0g化合物6-1-2。
步骤c：化合物6-1-3的制备
向250mL三口瓶中加入步骤b得到的化合物6-1-2(6.8g)和1,4-二氧六环(150mL)、三丁基(1-乙氧基乙烯)锡(18.53g)、双三苯基磷二氯化钯(1.811g)、三乙胺(7.77g)，氮气保护，油浴加热到100℃反应3h。降温，旋干，得到20.0g化合物6-1-3。
MS(ESI，[M+H] +):m/z＝257.1。
步骤d：化合物6-1-4的制备
向250mL单口瓶中加入步骤c得到的化合物6-1-3(20g)和四氢呋喃(20mL)、稀盐酸(19mL,4mol/L)，室温反应2.5h。反应结束，向反应液中加入水(200mL)剧烈搅拌，然后乙酸乙酯(100mL)萃取一次，旋干，硅胶柱层析(石油醚:乙酸乙酯＝3:1)，得到3.3g化合物6-1-4。
MS(ESI，[M+H] +):m/z＝229.1.
1H NMR(500MHz,DMSO-d 6)δ8.14–8.04(m,1H),8.02(d,J＝1.8Hz,1H),7.79–7.69(m,1H),7.63(t,J＝7.8Hz,1H),2.62(s,3H),1.18(d,J＝1.5Hz,6H).
步骤e：化合物6-1-5的制备
向100mL三口瓶中加入步骤d得到的化合物6-1-4(3g)和四氢呋喃(30mL)、(S)-2-甲基丙烷-2-亚磺酰胺(2.390g)、钛酸四乙酯(8.99g)，氮气保护，油浴加热到80℃反应4.5h。反应结束，向反应液中加入水(50mL)剧烈搅拌，过滤，滤饼用乙酸乙酯(20mL)洗涤三次，有机相分离，旋干，硅胶柱层析(石油醚:乙酸乙酯＝10:1～5:1)，得到4.2g化合物6-1-5。
MS(ESI，[M+H] +):m/z＝332.2.
1H NMR(500MHz,Methanol-d 4)δ8.13(s,1H),8.05(d,J＝7.9Hz,1H),7.75–7.650(m,1H),7.55(t,J＝ 7.8Hz,1H),2.79(s,3H),1.32(s,9H),1.28–1.23(m,6H).
步骤f：化合物6-1-6的制备
向100mL三口瓶中加入步骤e得到的化合物6-1-5(4.2g)和无水四氢呋喃(40mL)，降温至-78℃，向反应体系中滴加三仲丁基硼氢化锂(28.4mL,1mol/L)，混合物在-78℃搅拌反应2h。反应结束，向反应液中加入饱和氯化铵水溶液(20mL)剧烈搅拌2min，升温到室温，静置分层，分出有机相，旋干，硅胶柱层析(二氯甲烷:甲醇＝98:2)，得到2.5g化合物6-1-6。
MS(ESI，[M+H] +):m/z＝334.0.
1H NMR(500MHz,Methanol-d 4)δ7.53(d,J＝1.9Hz,1H),7.47–7.35(m,3H),4.59–4.49(m,1H),1.55(d,J＝6.8Hz,3H),1.24(d,J＝1.2Hz,6H),1.20(s,9H).
步骤g：化合物6-1的制备
向100mL单口瓶中加入步骤e得到的化合物6-1-6(2.3g)和1,4二氧六环盐酸溶液(8mL,4mol/L)，室温反应2h。反应结束，旋干，得到2.0g化合物6-1。
1H NMR(500MHz,Methanol-d 4)δ7.63(d,J＝1.8Hz,1H),7.63–7.53(m,2H),7.54(d,J＝6.4Hz,1H),4.58–4.48(m,1H),1.66(d,J＝6.9Hz,3H),1.26(d,J＝1.6Hz,6H).
步骤B：化合物6-2的制备
参照实施例1步骤D的方法，将化合物1-3与步骤A得到的化合物6-1反应制备得到化合物6-2。
MS(ESI，[M+H] +):m/z＝527.98.
步骤C：化合物6的制备
参照实施例1步骤E的方法，制备得到化合物6。
MS(ESI，[M+H] +):m/z＝478.09.
1H NMR(500MHz,Methanol-d 4)δ8.58(d,J＝14.0Hz,1H),7.62(s,1H),7.55(t,J＝4.2Hz,1H),7.38(d,J＝4.8Hz,2H),7.09(d,J＝5.0Hz,1H),5.75–5.650(m,1H),4.02(s,3H),2.46(s,3H),1.89–1.79(m,6H),1.68(d,J＝7.0Hz,3H),1.21(s,6H).
实施例7：化合物7的制备
Figure PCTCN2021092672-appb-000106
步骤A：化合物7-1的制备
参照实施例1步骤D的方法，将化合物1-3与(R)-1-(3-硝基-5-(三氟甲基)苯基)乙烷-1-胺反应制备得到化合物7-1。
MS(ESI，[M+H] +):m/z＝532.89.
1H NMR(500MHz,DMSO-d 6)δ8.82(s,1H),8.61(s,1H),8.48(d,J＝7.3Hz,1H),8.33(d,J＝11.2Hz, 2H),7.04(s,1H),5.65(p,J＝7.0Hz,1H),3.92(s,3H),2.34(s,3H),1.65(d,J＝7.1Hz,3H).
步骤B：化合物7-2的制备
参照实施例1步骤E的方法，制备得到化合物7-2。
MS(ESI，[M+H] +):m/z＝483.08.
1H NMR(500MHz,DMSO-d 6)δ8.92(d,J＝7.6Hz,1H),8.76-8.73(m,2H),8.41-8.39(m,2H),7.16(d,J＝4.7Hz,1H),5.72(p,J＝7.1Hz,1H),3.98(d,J＝9.8Hz,3H),2.41(s,3H),1.79–1.70(m,9H).
步骤C：化合物7的制备
向50mL三口瓶中加入步骤B所得化合物7-2(100mg)、四氢呋喃(15mL)和水(5.00mL)，室温搅拌向其中加入氯化铵(444mg)和锌粉(203mg)，将反应瓶置于70℃油浴下，搅拌反应5h。停止反应，将反应液冷却至室温，向反应液中加入饱和食盐水(15mL)，乙酸乙酯(15mL×2)萃取，无水硫酸钠干燥，浓缩，残留物以硅胶柱分离纯化(甲醇:二氯甲烷＝7:93)，得32mg化合物7。
HRMS(ESI，[M+H] +):m/z＝453.1675.
1H NMR(500MHz,CDCl 3)δ8.55(d,J＝13.9Hz,1H),7.14(d,J＝5.1Hz,1H),7.08(s,1H),6.90(s,1H),6.78(s,1H),6.69(s,1H),5.62-5.59(m,1H),3.97(s,3H),2.56(s,3H),1.79(dd,J＝13.8,1.7Hz,6H),1.61(d,J＝7.0Hz,3H).
实施例8：化合物8的制备
Figure PCTCN2021092672-appb-000107
步骤A：化合物8-1的制备
参照实施例1步骤D的方法，将化合物1-3与(R)-1-(2-甲基-5-硝基-3-(三氟甲基)苯基)乙烷-1-胺反应制备得到化合物8-1。
MS(ESI，[M+H] +):m/z＝546.88.
1H NMR(500MHz,CD 3OD)δ8.77(s,1H),8.57(d,J＝2.3Hz,1H),8.34(d,J＝2.3Hz,1H),6.94(s,1H),5.75(q,J＝7.0Hz,1H),4.87(s,1H),3.96(s,3H),2.81(s,3H),2.35(s,3H),1.65(d,J＝7.1Hz,3H).
步骤B：化合物8-2的制备
参照实施例1步骤E的方法，制备得到化合物8-2。
MS(ESI，[M+H] +):m/z＝497.08.
1H NMR(500MHz,CD 3OD)δ8.65(d,J＝14.0Hz,1H),8.60(d,J＝2.3Hz,1H),8.35(d,J＝2.3Hz,1H),5.80(q,J＝7.0Hz,1H),4.02(s,3H),2.82(s,3H),2.39(s,3H),1.86(d,J＝14.0Hz,6H),1.69(d,J＝7.0Hz,3H).
步骤C：化合物8的制备
向25mL单口瓶中，依次加入步骤B所得化合物8-2(0.16g)、甲醇(10mL)、水(2mL)和四羟基二硼(0.231 g)，搅拌10min，向其中加入氢氧化钠(0.129g)的水(2mL)溶液，室温下搅拌过夜。将反应液倒入水(20mL)中，用饱和碳酸氢钠溶液调pH至7-8，加入乙酸乙酯(10mL)分液，取有机相，水相用乙酸乙酯(10mL×2)萃取，合并有机相并用饱和食盐水(10mL×2)洗涤，无水硫酸钠干燥，过滤，浓缩得120mg化合物8。
MS(ESI，[M+H] +):m/z＝467.16.
1H NMR(500MHz,CD 3OD)δ8.61(s,1H),7.08(d,J＝5.1Hz,1H),7.04(d,J＝2.2Hz,1H),6.90(d,J＝2.4Hz,1H),5.75(q,J＝6.9Hz,1H),4.86(s,3H),4.01(s,3H),2.45(t,J＝2.9Hz,6H),1.84(dd,J＝14.0,4.3Hz,6H),1.59(d,J＝7.0Hz,3H).
实施例9：化合物9的制备
Figure PCTCN2021092672-appb-000108
步骤A：化合物9-1的制备
向500mL耐压瓶中加入5-氨基-2-氯异烟酸(15g)、乙酸铵(67.0g)、原乙酸三乙酯(141g)和甲醇(100mL)，将混合物置于125℃油浴搅拌反应9h。停止反应，反应液冷却至室温，抽滤，滤饼用乙酸乙酯(50mL)洗涤，收集固体烘干得8.1g化合物9-1。
MS(ESI，[M-H] -):m/z＝194.1.
1H NMR(500MHz,DMSO-d 6)δ8.79(s,1H),7.90(s,1H),2.38(s,3H).
步骤B：化合物9-2的制备
向250mL单口瓶中加入步骤A所得化合物9-1(10g)、2,4,6-三异丙基苯磺酰氯(18.58g)、三乙胺(15.52g)、4-二甲氨基吡啶(0.625g)和二氯甲烷(100mL)，混合物在室温下搅拌反应过夜。停止反应，反应液倒入水(50mL)中，分液，有机相饱和食盐水洗涤，无水硫酸钠干燥，抽滤，浓缩，残留物以硅胶柱层析分离纯化(石油醚:乙酸乙酯＝85:15)，得到9.7g化合物9-2。
步骤C：化合物9-3的制备
向25mL单口瓶中加入步骤B所得化合物9-2(3g)、(R)-1-(3-(三氟甲基)苯基)乙烷-1-胺盐酸盐(1.76g)、N,N-二异丙基乙胺(2.52g)和1,4-二氧六环(20mL)，氮气保护下将混合物室温搅拌反应2h。停止反应，反应液倒入水(100mL)中，二氯甲烷(30mL×3)萃取，有机相以饱和食盐水洗涤，无水硫酸钠干燥，浓缩，残留物以硅胶柱层析(石油醚:乙酸乙酯＝85:15)，得2.2g化合物9-3。
MS(ESI，[M+H] +):m/z＝367.26.
1H NMR(500MHz,DMSO-d 6)δ8.87–8.80(m,1H),8.48(s,1H),7.84(s,1H),7.78-7.76(t,J＝6.6Hz,1H),7.62-7.56(m,2H),5.62(p,J＝7.1Hz,1H),2.43(s,3H),1.63(d,J＝7.1Hz,3H).
步骤D：化合物9的制备
参照实施例1步骤E的方法，制备得到化合物9。
MS(ESI，[M+H] +):m/z＝409.4.
1H NMR(500MHz,DMSO-d 6)δ9.25(d,J＝7.6Hz,1H),9.09(s,1H),8.93(d,J＝6.4Hz,1H),7.86(s, 1H),7.79(d,J＝7.3Hz,1H),7.59(dt,J＝15.2,7.7Hz,2H),5.67(p,J＝7.0Hz,1H),2.47(s,3H),1.72(d,J＝13.5Hz,6H),1.64(d,J＝7.1Hz,3H).
实施例10：化合物10的制备
Figure PCTCN2021092672-appb-000109
步骤A：化合物10-1的制备
向25mL三口瓶中加入实施例7步骤A所得化合物7-1(1.1g)、1-苄基-1,4-氮杂膦烷4-氧化物(0.441g)、三乙胺(0.294g)、4,5-双二苯基膦-9,9-二甲基氧杂蒽(0.113g)、三二亚苄基丙酮二钯(0.090g)和1,4-二氧六环(10mL)，氮气保护下100℃下搅拌反应1h。反应液冷却至室温，抽滤，滤液浓缩至干，残留物以硅胶柱层析(二氯甲烷:甲醇＝95:5)得到0.94g化合物10-1。
MS(ESI，[M+H] +):m/z＝614.40.
1H NMR(500MHz,DMSO-d 6)δ8.86(d,J＝7.5Hz,1H),8.72–8.65(m,2H),8.35-8.34(m,2H),7.40–7.34(m,4H),7.30-7.26(m,1H),7.14(d,J＝4.7Hz,1H),5.68(p,J＝7.1Hz,1H),3.99(s,3H),3.69(s,2H),3.04-2.96(m,2H),2.88-2.82(m,2H),2.48-2.45(m,2H),2.37(s,3H),1.83-1.76(m,2H),1.67(d,J＝7.1Hz,3H).
步骤B：化合物10-2的制备
向25mL三口瓶中加入步骤A所得化合物10-1(0.699g)、1,2-二氯乙烷(10mL)冰水浴搅拌，向其中加入1-氯乙基氯甲酸脂(0.195g)，混合物回流反应2h。反应液浓缩至干，残留物中加入甲醇(5mL)，加热回流搅拌15min。反应液浓缩至干，残留物以硅胶柱层析(二氯甲烷:甲醇＝94:6)，得348mg化合物10-2。
MS(ESI，[M+H] +):m/z＝524.07.
1H NMR(500MHz,DMSO-d 6)δ8.85(d,J＝7.5Hz,1H),8.71–8.65(m,2H),8.35(d,J＝6.7Hz,2H),7.12(d,J＝4.6Hz,1H),5.68(p,J＝7.1Hz,1H),3.96(s,3H),3.20–3.06(m,4H),2.42–2.30(m,5H),1.80–1.70(m,2H),1.68(d,J＝7.1Hz,3H).
步骤C：化合物10-3的制备
向10mL单口瓶中加入步骤B所得化合物10-2(150mg)、四氢呋喃(1mL)、三乙胺(87mg)和乙酸酐(32.2mg)，反应液在室温搅拌反应1h。向反应液中加入水(10mL)，室温搅拌5min，二氯甲烷(15mL×2)萃取，无水硫酸钠干燥，浓缩，残留物以硅胶柱分离纯化(二氯甲烷:甲醇＝96:4)，得144mg化合物10-3。
MS(ESI，[M+H] +):m/z＝566.03.
1H NMR(500MHz,DMSO-d 6)δ8.91(dd,J＝7.2,5.3Hz,1H),8.70(dd,J＝13.8,5.1Hz,1H),8.67(s,1H),8.35(d,J＝6.1Hz,2H),7.12(d,J＝4.8Hz,1H),5.69-5.67(m,1H),4.46(dd,J＝25.9,13.2Hz,1H),4.12–4.00(m,1H),3.91(s,3H),3.74-3.72(m,1H),3.32–3.27(m,1H),2.48–2.39(m,1H),2.39–2.30(m,4H),1.98–1.79(m,2H),1.68(d,J＝7.1Hz,3H).
步骤D：化合物10的制备
向25mL三口瓶中加入步骤C所得化合物10-3(114mg)、四氢呋喃(1.5mL)和乙醇(4.5mL)，室温搅拌下加入氯化亚锡二水合物(182mg)，将反应瓶置于50℃油浴搅拌反应1h。停止反应，反应液浓缩至干，硅胶柱分离纯化(二氯甲烷:甲醇＝94:6)，得89mg化合物10。
HRMS(ESI，[M+H] +):m/z＝536.2073.
1H NMR(500MHz,DMSO-d 6)δ8.76(d,J＝7.5Hz,1H),8.68(d,J＝13.8Hz,1H),7.12(d,J＝4.8Hz,1H),6.91(s,1H),6.86(s,1H),6.70(s,1H),5.61–5.50(m,3H),4.45–4.30(m,1H),4.04-3.96(m,1H),3.91(s,3H),3.77–3.67(m,1H),3.40–3.35(m,1H),2.48–2.29(m,5H),2.12(s,3H),2.03–1.81(m,2H),1.55(d,J＝7.1Hz,3H).
实施例11：化合物11的制备
Figure PCTCN2021092672-appb-000110
步骤A：化合物11-1的制备
参照实施例10步骤A的方法，使用实施例2步骤A得到的化合物2-1，制备得化合物11-1。
HRMS(ESI，[M+H] +):m/z＝569.2283.
1H NMR(500MHz,DMSO-d 6)δ8.78(d,J＝7.7Hz,1H),8.69(d,J＝13.6Hz,1H),7.84(s,1H),7.77(d,J＝7.1Hz,1H),7.59-7.54(m,2H),7.39–7.34(m,4H),7.31–7.24(m,1H),7.13(d,J＝4.6Hz,1H),5.66(p,J＝7.1Hz,1H),3.99(s,3H),3.67(s,2H),3.00-2.92(m,2H),2.85(q,J＝11.5Hz,2H),2.48-2.45(m,2H),2.38(s,3H),1.82(t,J＝16.1Hz,2H),1.62(d,J＝7.1Hz,3H).
步骤B：化合物11-2的制备
参照实施例10步骤B的方法，制备得到化合物11-2。
HRMS(ESI，[M+H] +):m/z＝479.1814.
1H NMR(500MHz,DMSO-d 6)δ8.80(d,J＝7.7Hz,1H),8.68(d,J＝13.6Hz,1H),7.84(s,1H),7.78(d,J＝7.1Hz,1H),7.60-7.55(m,2H),7.11(d,J＝4.6Hz,1H),5.67(p,J＝7.1Hz,1H),3.96(s,3H),3.17–3.06(m,4H),2.43–2.34(m,5H),1.79(t,J＝16.1Hz,2H),1.62(d,J＝7.1Hz,3H).
步骤C：化合物11的制备
参照实施例10步骤C的方法，制备得到化合物11。
HRMS(ESI，[M+H] +):m/z＝521.1961.
1H NMR(500MHz,DMSO-d 6)δ8.83(dd,J＝7.6,2.3Hz,1H),8.70(dd,J＝13.8,3.5Hz,1H),7.84(s,1H),7.77(d,J＝6.7Hz,1H),7.61–7.53(m,2H),7.12(d,J＝4.8Hz,1H),5.71–5.62(m,1H),4.46-4.37(m,1H),4.09–3.97(m,1H),3.91(s,3H),3.76-3.71(m,1H),3.32-3.30(m,1H),2.48–2.39(m,1H),2.39–2.30(m,4H),2.12(s,3H),1.99–1.80(m,2H),1.62(d,J＝7.1Hz,3H).
实施例12：化合物12的制备
Figure PCTCN2021092672-appb-000111
步骤A：化合物12-1的制备
参照实施例10步骤A的方法，使用实施例4步骤A所得化合物4-1，制备得到化合物12-1。
MS(ESI，[M+H] +):m/z＝565.55.
1H NMR(500MHz,DMSO-d 6)δ8.95(s,1H),8.73(d,J＝13.6Hz,1H),7.70(d,J＝7.8Hz,1H),7.41–7.33(m,5H),7.33–7.20(m,3H),7.11(d,J＝4.7Hz,1H),5.80–5.73(m,1H),3.98(s,3H),3.69(s,2H),2.91(dd,J＝56.9,16.5Hz,4H),2.55(s,3H),2.49–2.43(m,2H),2.36(s,3H),1.84(s,2H),1.54(d,J＝7.0Hz,3H).
步骤B：化合物12-2的制备
参照实施例10步骤B的方法，制备得到化合物12-2。
MS(ESI，[M+H] +):m/z＝475.18.
1H NMR(500MHz,DMSO-d 6)δ8.86(d,J＝7.3Hz,1H),8.70(d,J＝13.5Hz,1H),7.71(d,J＝7.7Hz,1H),7.38(d,J＝7.5Hz,1H),7.34–7.18(m,2H),7.13–7.06(m,1H),5.76(p,J＝6.9Hz,1H),3.95(s,3H),3.17–3.06(m,4H),2.55(s,3H),2.43–2.36(m,2H),2.35(s,3H),1.77(d,J＝18.6Hz,2H),1.54(d,J＝7.0Hz,3H).
步骤C：化合物12的制备
参照实施例10步骤C的方法，制备得到化合物12。
MS(ESI，[M+H] +):m/z＝517.12.
1H NMR(500MHz,CDCl 3)δ8.47(d,J＝14.1Hz,1H),7.55(d,J＝7.5Hz,1H),7.43(d,J＝7.6Hz,1H),7.27(s,1H),7.10(d,J＝5.3Hz,1H),6.82(t,J＝55.5Hz,1H),6.46-6.45(m,1H),5.87-5.83(m,1H),4.96-4.87(m,1H),4.18-4.10(m,1H),3.93(s,3H),3.91-3.88(m,1H),2.54(d,J＝5.1Hz,6H),2.51–2.40(m,2H),2.22(s,3H),2.19-2.05(m,2H),1.61(d,J＝6.8Hz,3H).
实施例13：化合物13的制备
Figure PCTCN2021092672-appb-000112
参照实施例10步骤C的方法，将化合物12-2与N,N-二甲基甘氨酸反应制备得到化合物13。
MS(ESI，[M+H] +):m/z＝560.11.
1H NMR(500MHz,CDCl 3)δ8.53(d,J＝14.0Hz,1H),7.59–7.53(m,1H),7.43(d,J＝7.6Hz,1H),7.30–7.23(m,1H),7.09(d,J＝5.2Hz,1H),6.83(t,J＝55.5Hz,1H),6.61-6.56(m,1H),5.89-5.82(m,1H),4.99-4.91(m,1H),4.52-4.44(m,1H),3.90(s,3H),3.83-3.77(m,1H),3.38–3.35(m,1H),3.10-3.07(m,1H),2.60–2.46(m,8H),2.34(s,6H),2.30-2.23(m,2H),1.61(d,J＝6.9Hz,3H).
实施例14：化合物14的制备
Figure PCTCN2021092672-appb-000113
参照实施例10步骤C的方法，将化合物12-2与环丙甲酸反应制备得到化合物14。
MS(ESI，[M+H] +):m/z＝543.10.
1H NMR(500MHz,CDCl 3)δ8.47(d,J＝14.1Hz,1H),7.55(d,J＝7.7Hz,1H),7.43(d,J＝7.6Hz,1H),7.30–7.23(m,1H),7.09(d,J＝5.2Hz,1H),6.83(t,J＝55.5Hz,1H),6.47-6.42(m,1H),5.89–5.81(m,1H),4.92-4.84(m,1H),4.62–4.47(m,1H),4.02–3.93(m,1H),3.91(s,3H),2.61–2.48(m,8H),2.06–1.89(m,3H),1.61(d,J＝6.9Hz,3H),1.11-1.02(m,4H).
实施例15：化合物15的制备
Figure PCTCN2021092672-appb-000114
步骤A：化合物15-1的制备
参照实施例10步骤A的方法，制备得到化合物15-1。
MS(ESI，[M+H] +):m/z＝583.1.
1H NMR(500MHz,CDCl 3)δ8.57(dd,J＝3.6,13.9Hz,1H),7.48(d,J＝6.4Hz,1H),7.42(t,J＝7.4Hz,1H),7.39–7.34(m,4H),7.31–7.27(m,1H),7.14–7.07(m,2H),6.66(d,J＝7.6Hz,1H),5.84(p,J＝7.1Hz,1H),4.02(d,J＝1.3Hz,3H),3.73–3.69(m,2H),3.16(dd,J＝12.3,29.5Hz,2H),2.99(dt,J＝9.6,19.6Hz,2H),2.62(td,J＝6.0,12.7,13.2Hz,2H),2.52(s,3H),2.02(t,J＝18.6Hz,3H),1.78(ddt,J＝2.9,14.8,20.3Hz,2H),1.65(d,J＝7.0Hz,3H).
步骤B：化合物15-2的制备
参照实施例10步骤B的方法，制备得到化合物15-2。
MS(ESI，[M+H] +):m/z＝493.08.
1H NMR(500MHz,CDCl 3)δ8.56(d,J＝13.9Hz,1H),7.52–7.47(m,1H),7.42(t,J＝7.4Hz,1H),7.12(t,J＝7.0Hz,2H),6.60(s,1H),5.84(p,J＝7.0Hz,1H),4.00(s,3H),3.40(ddd,J＝3.2,9.3,21.8Hz,4H),2.52(s,5H),2.02(t,J＝18.6Hz,3H),1.85(ddt,J＝2.8,14.6,20.0Hz,2H),1.66(d,J＝7.0Hz,3H),1.34–1.20(m,1H).
步骤C：化合物15的制备
参照实施例10步骤C的方法，制备得到化合物15。
MS(ESI，[M+H] +):m/z＝535.13.
1H NMR(500MHz,CDCl 3)δ8.55(dd,J＝3.3,14.2Hz,1H),7.49(q,J＝6.8Hz,1H),7.46–7.40(m,1H),7.12(dd,J＝6.3,11.4Hz,2H),6.65(dd,J＝4.3,7.3Hz,1H),5.84(pd,J＝2.7,6.7Hz,1H),4.92(dd,J＝13.7,28.7Hz,1H),4.20–4.08(m,1H),3.93(s,3H),3.89(dd,J＝6.6,13.9Hz,1H),3.36(td,J＝6.6,13.0Hz,1H),2.52(d,J＝1.9Hz,3H),2.45(dp,J＝4.7,13.9Hz,1H),2.23(s,4H),2.02(t,J＝18.6Hz,3H),1.97–1.82(m,2H),1.67(dd,J＝1.7,7.0Hz,3H).
实施例16：化合物16的制备
Figure PCTCN2021092672-appb-000115
参照实施例10步骤C的方法，将化合物15-2与N,N-二甲基甘氨酸反应制备得到化合物16。
MS(ESI，[M+H] +):m/z＝578.14.
1H NMR(500MHz,CDCl 3)δ8.55(dd,J＝4.3,14.2Hz,1H),7.49(q,J＝7.5Hz,1H),7.43(t,J＝7.4Hz,1H),7.12(d,J＝5.4Hz,2H),6.56(d,J＝6.6Hz,1H),5.85(td,J＝3.3,7.1Hz,1H),4.96(dd,J＝13.6,29.1Hz,1H),4.48(dd,J＝14.0,27.4Hz,1H),3.91(s,3H),3.81(td,J＝6.1,13.3Hz,1H),3.40–3.32(m,2H),3.09(d,J＝13.2Hz,1H),2.58–2.49(m,5H),2.35(s,6H),2.02(t,J＝18.6Hz,3H),1.88(q,J＝12.4,13.7Hz,2H),1.67(d,J＝7.0Hz,3H).
实施例17：化合物17的制备
Figure PCTCN2021092672-appb-000116
参照实施例10步骤C的方法，将化合物15-2与环丙甲酸反应制备得到化合物17。
MS(ESI，[M+H] +):m/z＝561.11.
1H NMR(500MHz,CDCl 3)δ8.56(d,J＝14.2Hz,1H),7.58–7.38(m,2H),7.18–7.06(m,2H),6.63(d,J＝7.0Hz,1H),5.85(p,J＝7.0Hz,1H),4.88(dd,J＝13.2,28.4Hz,1H),4.54(dd,J＝15.2,26.9Hz,1H),3.96(s,1H),3.92(s,3H),2.61–2.54(m,2H),2.52(s,3H),2.03(s,2H),1.86(tt,J＝4.5,7.9Hz,2H),1.67(d,J＝7.0Hz,3H),1.32–1.21(m,2H),1.11(s,1H),1.02(s,1H),0.93–0.77(m,3H).
实施例18：化合物18的制备
Figure PCTCN2021092672-appb-000117
步骤A：化合物18-1的制备
参照实施例10步骤A的方法，使用实施例8步骤A所得化合物8-1，制备得到化合物18-1。
MS(ESI，[M+H] +):m/z＝628.18.
1H NMR(500MHz,CD 3OD):δ8.65(d,J＝14.0Hz,1H),8.57(d,J＝2.3Hz,1H),8.35(d,J＝2.2Hz,1H),7.39(d,J＝7.2Hz,2H),7.34(dd,J＝12.5,4.8Hz,3H),7.28(d,J＝7.2Hz,1H),7.10(d,J＝4.8Hz,1H),5.79(q,J＝7.0Hz,1H),4.05(s,3H),3.72(s,2H),3.12(dd,J＝26.6,12.6Hz,2H),3.02–2.90(m,2H),2.82(s,3H),2.73–2.61(m,2H),2.39(s,3H),2.04(t,J＝15.7Hz,2H),1.68(d,J＝7.0Hz,3H).
步骤B：化合物18-2的制备
参照实施例10步骤B的方法，制备得到化合物18-2。
MS(ESI，[M+H] +):m/z＝538.09.
步骤C：化合物18-3的制备
参照实施例10步骤C的方法，制备得到化合物18-3。
MS(ESI，[M+H] +):m/z＝580.07.
步骤D：化合物18的制备
参照实施例8步骤C的方法，制备得到化合物18。
MS(ESI，[M+H] +):m/z＝550.09.
1H NMR(500MHz,CD 3OD):δ8.62(d,J＝14.3Hz,1H),7.08(d,J＝5.0Hz,1H),7.03(s,1H),6.90(s,1H),5.76(dt,J＝6.8,5.0Hz,1H),4.86(s,3H),4.70–4.54(m,1H),4.25–4.12(m,1H),3.99(s,3H),3.87(dd,J＝23.5,11.3Hz,1H),3.50(dd,J＝23.2,12.5Hz,1H),2.65–2.52(m,2H),2.44(d,J＝5.8Hz,6H),2.23(s,3H),2.16–1.99(m,2H),1.59(d,J＝7.0Hz,3H).
实施例19：化合物19的制备
Figure PCTCN2021092672-appb-000118
步骤A：化合物19-1的制备
向25mL单口瓶中依次加入化合物9-1(0.13g)、N,N-二甲基甲酰胺(1.3mL)、六氟磷酸苯并三唑-1-基-氧基三吡咯烷基磷(0.45g)和1,8-二氮杂二环十一碳-7-烯(0.152g)，室温搅拌下向上述混合液中滴加(R)-1-(3-(三氟甲基)-2-氟苯基)乙烷-1-胺盐酸盐(0.178g)和1,8-二氮杂二环十一碳-7-烯(0.152g)的N,N-二甲基甲酰胺(1.3mL)混合溶液，加毕，50℃搅拌过夜。反应结束，将反应液倒入水(15mL)中，乙酸乙酯(30mL)萃取，合并有机相并用饱和食盐水(10mL)洗涤，无水硫酸钠干燥，过滤，浓缩，所得粗品经硅胶柱分离纯化(石油醚:乙酸乙酯＝70:30)，得0.14g化合物19-1。
MS(ESI，[M+H] +)m/z＝385.06.
1H NMR(500MHz,DMSO-d 6)δ8.91(d,J＝6.8Hz,1H),8.84(s,1H),8.53(s,1H),7.82(t,J＝6.9Hz,1H),7.66(t,J＝7.2Hz,1H),7.37(t,J＝7.8Hz,1H),5.72(m,1H),2.38(s,3H),1.63(d,J＝7.1Hz,3H).
步骤B：化合物19-2的制备
向10mL微波管中加入步骤A所得化合物19-1(0.14g)、1-苄基-1,4-氮杂膦-4-氧化物(0.075g)、N,N-二异丙基乙胺(0.070g)、4,5-双二苯基膦-9,9-二甲基氧杂蒽(0.021g,0.036mmol)、三二亚苄基丙酮二钯(0.017g,0.018mmol)和N,N-二甲基甲酰胺(3mL)，氮气置换后，微波反应器150瓦下加热至165℃，反应50分钟。抽滤，滤液倒入水(30mL)中，乙酸乙酯(30mL×2)萃取，有机相经饱和食盐水洗涤，无水硫酸钠干燥，浓缩，残留物以硅胶柱分离纯化(二氯甲烷:甲醇＝97:3)得0.15g化合物19-2。
MS(ESI，[M+H] +)m/z＝558.16.
1H NMR(500MHz,DMSO-d 6)δ9.31(d,J＝6.9Hz,1H),9.13(s,1H),8.99(d,J＝6.4Hz,1H),7.84(t,J＝7.0Hz,1H),7.66(t,J＝7.1Hz,1H),7.41–7.31(m,5H),7.30–7.24(m,1H),5.80–5.72(m,1H),3.66(s,2H),3.03–2.91(m,2H),2.83(q,J＝12.0Hz,2H),2.45–2.32(m,5H),1.92(t,J＝14.6Hz,2H),1.64(d,J＝7.1Hz,3H).
步骤C：化合物19-3的制备
向50mL单口瓶中加入步骤B所得化合物19-2(0.15g)和1,2-二氯乙烷(14mL)，冰浴下向其中滴加1-氯乙基氯甲酸酯(0.077g)，将混合液加热至回流反应2.5h。反应液浓缩至干，向残留物中加入甲醇(5mL)后继续回流反应30分钟。反应液浓缩至干，得到0.16g化合物19-3.
MS(ESI，[M+H] +)m/z＝468.13.
1H NMR(500MHz,DMSO-d 6)δ11.11(s,1H),9.75–9.44(m,2H),9.38(s,1H),8.04(t,J＝7.1Hz,1H),7.72(t,J＝7.0Hz,1H),7.50–7.27(m,2H),5.96(m,1H),3.56(s,2H),3.38(s,2H),2.83(s,2H),2.53–2.41(m,4H),1.74(d,J＝7.1Hz,3H).
步骤D：化合物19的制备
冰水浴下，将甲烷磺酰氯(0.043g)滴入步骤C所得化合物19-3(0.16g)和三乙胺(0.104g)的四氢呋喃(3.2mL)溶液中，滴加完毕保持温度反应2h。浓缩反应液至干，向反应液中加入水(10mL)，二氯甲烷(10mL×3)萃取，有机相用无水硫酸钠干燥，浓缩，残留物以C18柱层析分离纯化(乙腈:水＝40:60)，得到86mg化合物19。
HRMS(ESI，[M+H] +)m/z＝546.13611.
1H NMR(500MHz,CD 3OD)δ9.11(d,J＝0.8Hz,1H),8.85(dd,J＝0.9,6.8Hz,1H),7.78–7.73(m,1H),7.59–7.54(m,1H),7.28(t,J＝7.8Hz,1H),5.85(q,J＝7.1Hz,1H),3.93(m,2H),3.82–3.73(m,2H),2.98(s,3H),2.65(m,2H),2.50(s,3H),2.27–2.18(m,2H),1.73(d,J＝7.1Hz,3H).
31P NMR(202MHz,CD 3OD)δ31.1.
实施例20：化合物20的制备
Figure PCTCN2021092672-appb-000119
步骤A：化合物20-1的制备
参照实施例19步骤B的方法，制备得到化合物20-1。
MS(ESI，[M+H] +)m/z＝369.09.
1H NMR(500MHz,DMSO-d 6)δ12.80(s,1H),9.14(s,1H),8.42(d,J＝5.6Hz,1H),7.37–7.29(m,5H),3.63(s,2H),2.95–2.76(m,4H),2.44(s,3H),2.41–2.31(m,2H),1.94(t,J＝15.5Hz,2H).
步骤B：化合物20-2的制备
参照实施例19步骤A的方法，将化合物20-1与(R)-1-(3-(二氟甲基)-2-氟苯基)乙烷-1-胺盐酸盐反应制备得到化合物20-2。
MS(ESI，[M+H] +)m/z＝540.16.
1H NMR(500MHz,CDCl 3)δ9.18(s,1H),8.78(d,J＝6.6Hz,1H),7.48–7.42(m,2H),7.38–7.31(m,5H),7.13(t,J＝7.7Hz,1H),6.89(t,J＝55.0Hz,1H),5.78(p,J＝7.1Hz,1H),3.67(s,2H),3.05–3.00(m,4H),2.57(s,4H),2.05(s,3H),1.68(d,J＝7.0Hz,3H).
步骤C：化合物20-3的制备
参照实施例19步骤C的方法，制备得到化合物20-3。
MS(ESI，[M+H] +)m/z＝450.16.
步骤D：化合物20的制备
参照实施例19步骤D的方法，制备得到化合物20。
HRMS(ESI，[M+H] +)m/z＝528.1443.
1H NMR(500MHz,DMSO-d 6)δ9.40(d,J＝7.2Hz,1H),9.11(d,J＝4.0Hz,2H),7.75(t,J＝7.4Hz,1H), 7.52(t,J＝7.0Hz,1H),7.36–7.30(m,1H),7.30–7.13(m,1H),5.82(p,J＝7.0Hz,1H),3.76–3.64(m,4H),3.34(s,2H),3.02(s,3H),2.44(s,3H),2.10(d,J＝13.7Hz,2H),1.65(d,J＝7.1Hz,3H).
实施例21：化合物21的制备
Figure PCTCN2021092672-appb-000120
冰水浴下，向化合物20-3(0.1g)和三乙胺(0.055g)的二氯甲烷(2mL)溶液中滴加环丙烷磺酰氯(0.13g)，滴加完毕保持温度反应20分钟。反应结束，向反应液中加入水(10mL)，二氯甲烷(15mL)萃取，有机相用无水硫酸钠干燥，浓缩，残留物以C18柱层析分离纯化(乙腈:水＝40:60)，得到49mg化合物21。
HRMS(ESI，[M+H] +)m/z＝554.1635.
1H NMR(500MHz,CD 3OD)δ9.11(s,1H),8.85(dd,J＝6.8,0.9Hz,1H),7.64(t,J＝7.4Hz,1H),7.49(t,J＝7.1Hz,1H),7.24(t,J＝7.7Hz,1H),7.00(m,1H),5.87(q,J＝7.1Hz,1H),4.05–3.78(m,4H),2.72–2.59(m,4H),2.51(s,3H),2.29–2.14(m,1H),1.72(d,J＝7.1Hz,3H),1.11(m,2H),1.08(dt,J＝8.2,2.2Hz,2H).
实施例22：化合物22的制备
Figure PCTCN2021092672-appb-000121
步骤A：化合物22-1的制备
参照实施例19步骤A的方法，将化合物9-1与(R)-1-(3,3-二氟-2,3-二氢苯并呋喃-7-基)乙烷-1-胺盐酸盐反应制备得到化合物22-1。
MS(ESI，[M+H] +)m/z＝377.10.
1H NMR(500MHz,Acetone-d 6)δ8.81(s,1H),8.26(s,1H),7.66(d,J＝7.6Hz,1H),7.48(dd,J＝7.6,1.2Hz,1H),7.08(t,J＝7.6Hz,1H),5.80(p,J＝7.1Hz,1H),4.81(t,J＝16.3Hz,2H),2.46(s,3H),1.69(d,J＝7.0Hz,3H).
步骤B：化合物22-2的制备
参照实施例19步骤B的方法，制备得到化合物22-2。
MS(ESI，[M+H] +)m/z＝550.13.
1H NMR(500MHz,DMSO-d 6)δ9.17(d,J＝7.4Hz,1H),9.12(d,J＝0.8Hz,1H),8.99(d,J＝6.4Hz,1H),7.60(d,J＝7.5Hz,1H),7.51(dd,J＝7.6,1.4Hz,1H),7.35(d,J＝6.0Hz,3H),7.27(s,1H),7.09(dd,J＝7.6Hz, 1H),5.74(m,1H),4.87(t,J＝16.6Hz,2H),3.65(s,3H),2.99–2.79(m,4H),2.44(s,3H),2.43–2.34(m,2H),1.93(t,J＝10.5Hz,2H),1.60(d,J＝7.0Hz,3H).
步骤C：化合物22-3的制备
参照实施例19步骤C的方法，制备得到化合物22-3。
MS(ESI，[M+H] +)m/z＝460.17.
步骤D：化合物22的制备
参照实施例19步骤D的方法，制备得到化合物22。
HRMS(ESI，[M+H] +)m/z＝538.1596.
1H NMR(500MHz,CD 3OD)δ9.10(s,1H),8.82(d,J＝6.8Hz,1H),7.55(d,J＝7.6Hz,1H),7.47–7.40(m,1H),7.05(t,J＝7.6Hz,1H),5.80(q,J＝7.0Hz,1H),4.72(t,J＝16.2Hz,2H),3.97–3.72(m,4H),2.97(s,3H),2.65(m,2H),2.52(s,3H),2.32–2.16(m,2H),1.70(d,J＝7.0Hz,3H).
31P NMR(202MHz,CD 3OD)δ31.22.
实施例23：化合物23的制备
Figure PCTCN2021092672-appb-000122
参照实施例19的制备方法，将(R)-1-(3-(三氟甲基)-2-氟苯基)乙烷-1-胺盐酸盐替换为(R)-1-(3-(1,1-二氟乙基)-2-氟苯基)乙烷-1-胺盐酸盐合成得到化合物23。
HRMS(ESI，[M+H] +)m/z＝542.1608.
1H NMR(500MHz,DMSO-d 6)δ9.18(s,1H),8.64(d,J＝6.8Hz,1H),7.45(t,J＝7.6Hz,2H),7.13(t,J＝7.8Hz,1H),6.91-6.90(m,1H),5.82(p,J＝7.1Hz,1H),4.07-4.01(m,2H),3.83-3.77(m,2H),2.93(s,3H),2.65-2.58(m,5H),2.20-2.14(m,2H),2.00(t,J＝18.6Hz,3H),1.70(d,J＝7.0Hz,3H).
实施例24：化合物24的制备
Figure PCTCN2021092672-appb-000123
步骤A：化合物24-1的制备
向50mL单口瓶中，依次加入5-氨基-2-氯吡啶-4-甲酸(3g)和甲醇(11.14g)，混合物在冰盐水浴中搅拌，向其中滴加氯化亚砜(4.14g)和两滴N,N-二甲基甲酰胺，滴加完毕，将混合物加热至65℃反应12h。反应结束，反应液冷却至室温，减压浓缩至干，残留物用乙酸乙酯(50mL)溶解，饱和碳酸氢钠水溶液调pH至 碱性，分液，有机相用饱和食盐水洗涤，无水硫酸钠干燥，浓缩得到1.8g化合物24-1。
MS(ESI，[M+H] +):m/z＝186.97.
步骤B：化合物24-2的制备
向15mL耐压瓶中依次加入步骤A所得化合物24-1(1.7g)、氟乙腈(2.69g)以及甲烷磺酸(7.0g)，将反应加热至105℃搅拌反应4h，反应结束，反应液冷却至室温，向反应液中加入水(5mL)，用4M氢氧化钠水溶液调pH至碱性，二氯甲烷(20mL×5)萃取，有机相无水硫酸钠干燥，抽滤，浓缩至干，残留物用硅胶柱分离纯化(二氯甲烷:甲醇＝97:3)，得到0.43g化合物24-2。
MS(ESI，[M+H] +):m/z＝214.02.
1H NMR(500MHz,DMSO-d 6)δ12.90(br,1H),8.93(s,1H),7.99(s,1H),5.40(s,1H),5.31(s,1H).
步骤C：化合物24-3的制备
参照实施例19步骤A的方法，制备得到化合物24-3。
MS(ESI，[M+H] +):m/z＝403.06.
1H NMR(500MHz,DMSO-d 6)δ9.13(d,J＝6.8Hz,1H),8.96(s,1H),8.60(s,1H),7.84(t,J＝7.2Hz,1H),7.67(t,J＝7.1Hz,1H),7.37(t,J＝7.8Hz,1H),5.74(m,1H),5.26(m,2H),1.64(d,J＝7.1Hz,3H).
步骤D：化合物24-4的制备
参照实施例19步骤B的方法，制备得到化合物24-4。
MS(ESI，[M+H] +):m/z＝576.11.
1H NMR(500MHz,CD 3OD)δ9.23(s,1H),8.86(d,J＝6.5Hz,1H),7.75(t,J＝7.2Hz,1H),7.57(t,J＝7.1Hz,1H),7.38(d,J＝7.3Hz,2H),7.33(t,J＝7.5Hz,2H),7.27(m,2H),5.83(q,J＝7.1Hz,1H),5.30(m,2H),3.70(s,2H),3.12–2.93(m,4H),2.67–2.57(m,2H),2.09(t,J＝15.5Hz,2H),1.73(d,J＝7.1Hz,3H).
步骤E：化合物24-5的制备
参照实施例19步骤C的方法，制备得到化合物24-5。
MS(ESI，[M+H] +):m/z＝486.11.
步骤F：化合物24的制备
参照实施例19步骤D的方法，将化合物24-5与甲磺酰氯反应制备得到化合物24。
HRMS(ESI，[M+H] +):m/z＝564.1277.
1H NMR(500MHz,CD 3OD)δ9.24(s,1H),8.90(d,J＝6.8Hz,1H),7.76(t,J＝7.2Hz,1H),7.58(t,J＝7.0Hz,1H),7.29(t,J＝7.8Hz,1H),5.83(m,1H),5.30(m,2H),4.01–3.88(m,2H),3.82-3.74(m,2H),2.98(s,3H),2.69-2.62(m,2H),2.27-2.20(m,2H),1.74(d,J＝7.1Hz,3H).
实施例25：化合物25的制备
Figure PCTCN2021092672-appb-000124
步骤A：化合物25-2的制备
Figure PCTCN2021092672-appb-000125
步骤a：化合物25-2-1的制备
向500mL单口瓶中分别加入2-氟-3-三氟甲基苯甲酸(15g)、N,N-二甲基甲酰胺(100mL)、二甲羟胺盐酸盐(7.17g)、N,N-二异丙基乙胺(37.3g)和2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(32.9g)，将混合物室温搅拌反应2.5h。停止反应，反应液倒入水(500mL)中，用乙酸乙酯(200mL)萃取，有机相依次用水(200mL)、饱和食盐水(100mL)洗涤，无水硫酸钠干燥，浓缩，残留物硅胶分离纯化(石油醚:乙酸乙酯＝60:40)，得到17.4g化合物25-2-1。
MS(ESI，[M+H] +)m/z＝252.04.
1H NMR(500MHz,DMSO-d 6)δ7.93–7.83(m,2H),7.52(t,J＝7.8Hz,1H),3.31(s,3H),2.70(s,3H).
步骤b：化合物25-2-2的制备
在0℃和氮气保护下，将1M甲基溴化镁的四氢呋喃溶液(29.9mL)缓慢滴入步骤a所得化合物25-2-1(5g)的超干四氢呋喃(50mL)搅拌液中，滴加完毕后将混合物加热至35℃搅拌反应2h。停止反应，向反应液中缓慢加入饱和氯化铵水溶液(150mL)，室温搅拌10分钟，静置分液，取有机相无水硫酸钠干燥，浓缩得到4g化合物25-2-2。
1H NMR(500MHz,DMSO-d 6)δ8.17-8.10(m,1H),8.09-7.99(m,1H),7.54(t,J＝7.8Hz,1H),2.64(d,J＝4.1Hz,3H)。
步骤c：化合物25-2-3的制备
向100mL单口瓶中分别加入步骤b所得化合物25-2-2(4g)、干燥四氢呋喃(40mL)、(R)-(+)-叔丁基亚磺酰胺(2.352g)及钛酸四乙酯(11.07g)，将混合物加热至80℃反应3h。停止反应，反应液室温搅拌下向其中加入冰水(150mL)、乙酸乙酯(150mL)，搅拌5分钟，抽滤，滤液分液，有机相用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，得到5.8g化合物25-2-3。
MS(ESI，[M+H] +)m/z＝309.97.
步骤d：化合物25-2-4的制备
向250mL三口瓶中依次加入步骤c所得化合物25-2-3(3g)、四氢呋喃(30mL)，氮气保护下，降温至-50℃，向其中分批加入硼氘化钠(0.731g)，加毕保持温度继续搅拌反应3h。将反应液滴加入重水(20mL)中淬灭反应，所得溶液用乙酸乙酯(30mL×2)萃取，合并有机相，用无水硫酸钠干燥，浓缩，残留物用硅胶柱分离纯化(石油醚:乙酸乙酯＝60:40)，得到0.62g化合物25-2-4。
MS(ESI，[M+H] +)m/z＝313.00.
1H NMR(500MHz,DMSO-d 6)δ7.89(t,J＝7.2Hz,1H),7.67(t,J＝7.2Hz,1H),7.42(t,J＝7.8Hz,1H),5.89(s,1H),1.43(s,3H),1.10(s,9H).
步骤e：化合物25-2的制备
向100mL单口瓶中依次加入步骤d所得化合物25-2-4(0.6g)、1,4-二氧六环(2mL)和4M盐酸二氧六 环溶液(2.5mL)，反应液室温下搅拌反应2h，反应液减压浓缩至干，残留物用甲基叔丁基醚(5mL)打浆，得到0.38g化合物25-2。
MS(ESI，[M-HCl+H] +)m/z＝209.04.
1H NMR(500MHz,DMSO-d 6)δ8.87(s,3H),8.12(t,J＝7.2Hz,1H),7.82(t,J＝7.3Hz,1H),7.53(t,J＝7.8Hz,1H),1.57(s,3H).
步骤B：化合物25-3的制备
参照实施例19步骤A的方法，将上述步骤A制备得到的化合物25-2与化合物20-1制备得到化合物25-3。
MS(ESI，[M+H] +)m/z＝559.14.
1H NMR(500MHz,DMSO-d 6)δ9.30(s,1H),9.13(s,1H),8.99(d,J＝6.4Hz,1H),7.84(t,J＝7.1Hz,1H),7.65(t,J＝7.1Hz,1H),7.40–7.31(m,5H),7.30–7.24(m,1H),3.66(s,2H),3.05–2.92(m,2H),2.83(q,J＝12.1Hz,2H),2.45–2.35(m,5H),1.92(t,J＝14.7Hz,2H),1.64(s,3H).
步骤C：化合物25-4的制备
参照实施例19步骤C的方法，制备得到化合物25-4。
MS(ESI，[M+H] +):m/z＝469.28.
步骤D：化合物25的制备
参照实施例19步骤D的方法，将化合物25-4与甲磺酰氯反应制备得到化合物25。
HRMS(ESI，[M+H] +):m/z＝547.1432.
1H NMR(500MHz,CD 3OD)δ9.11(s,1H),8.85(d,J＝6.8Hz,1H),7.75(t,J＝7.1Hz,1H),7.57(t,J＝7.1Hz,1H),7.28(t,J＝7.8Hz,1H),4.00–3.86(m,2H),3.81-3.74(m,2H),2.98(s,3H),2.68-2.62(m,2H),2.50(s,3H),2.23-2.20(m,2H),1.72(s,3H).
实施例26：化合物26的制备
Figure PCTCN2021092672-appb-000126
步骤A：化合物26-1的制备
Figure PCTCN2021092672-appb-000127
步骤a：化合物26-1-1的制备
参考实施例25步骤a的方法，将2-氟-3-三氟甲基苯甲酸替换为2-甲基-3-三氟甲基苯甲酸而制备得到化合物26-1-1。
MS(ESI，[M+H] +)m/z＝248.07.
1H NMR(500MHz,CD 3OD)δ7.73(d,J＝7.9Hz,1H),7.53(d,J＝7.6Hz,1H),7.44(t,J＝8.0Hz,1H),3.44(s,3H),2.83(s,3H),2.39(s,3H).
步骤b：化合物26-1-2的制备
参考实施例25步骤b的方法，制备得到化合物26-1-2。
GCMS:[M] +＝202.
1H NMR(500MHz,CD 3OD)δ7.83(d,J＝7.8Hz,1H),7.77(dd,J＝8.0,1.2Hz,1H),7.45(t,J＝7.8Hz,1H),2.58(s,3H),2.48(q,J＝1.8Hz,3H).
步骤c：化合物26-1-3的制备
向100mL三口瓶中依次加入1M双三甲基硅基胺基锂的四氢呋喃溶液(17.68mL)、干燥四氢呋喃(50mL)，-74℃氮气保护下，将步骤b所得化合物26-1-2(2.75g)的四氢呋喃(5mL)溶液缓慢滴加到上述反应液中，混合物在-74℃温度下搅拌反应10分钟。将三甲基氯硅烷(1.921g)缓慢加入到上述反应液，2分钟后滴加完毕，保持-74℃搅拌反应1h，之后升温到室温继续反应20分钟。反应结束，向反应液中加入饱和氯化铵溶液(10mL)，剧烈搅拌5分钟。乙酸乙酯萃取(10mL×3)，合并有机相，无水硫酸钠干燥，抽滤，浓缩，残留物溶解于乙腈(50mL)中，0℃下搅拌，向其中加入选择性氟试剂(5.30g)，升温到室温继续搅拌反应5h。反应结束，反应液浓缩至干。残留物中加入水(20mL)，用乙酸乙酯(4 0mL×3)萃取，合并有机相，无水硫酸钠干燥，抽滤，浓缩，所得残余物通过硅胶柱分离纯化(石油醚:乙酸乙酯＝91:10)，得到1.34g化合物26-1-3。
1H NMR(500MHz,CD 3OD)δ7.84(dd,J＝8.0,1.2Hz,1H),7.78(d,J＝7.8Hz,1H),7.48(t,J＝7.9Hz,1H),5.43(d,J＝46.9Hz,2H),2.50(q,J＝1.8Hz,3H).
步骤d：化合物26-1-4的制备
参考实施例25步骤c的方法，用上述步骤c所得化合物26-1-3与S-叔丁基亚磺酰胺反应，制备得到化合物26-1-4。
MS(ESI，[M+H] +)m/z＝324.10.
步骤e：化合物26-1的制备
-78℃氮气保护下，向100mL三口瓶中依次加入步骤d所得化合物26-1-4(940mg)、干燥四氢呋喃(10mL)，将1M三仲丁基硼氢化锂的四氢呋喃溶液(51.0mL)缓慢滴入上述反应液中，滴加完毕，混合物在-78℃温搅拌反应0.5h。反应结束。向反应液滴入饱和氯化铵溶液(30mL)，剧烈搅拌10分钟后，升到室温，乙酸乙酯(50mL×3)萃取，合并有机相，有机相用无水硫酸钠干燥，过滤，浓缩，所得残留物通过硅胶柱分离纯化(二氯甲烷:甲醇＝98:2)，得到360mg黄色油状液体。向100mL单口瓶中依次加入上述所得黄色 油状液体、1,4-二氧六环(20mL)、4M的氯化氢1,4-二氧六环溶液(0.857mL)，加毕，室温下搅拌4h。反应液浓缩至干，残余物用甲基叔丁基醚(10mL)打浆，得到250mg化合物26-1。
MS(ESI，[M+H] +)m/z＝221.99.
1H NMR(500MHz,D 2O)δ7.83(d,J＝7.9Hz,1H),7.66(d,J＝7.9Hz,1H),7.52(t,J＝7.9Hz,1H),5.22(m,1H),4.90(dd,J＝10.8,3.9Hz,1H),4.86–4.81(m,1H),2.53(d,J＝1.5Hz,3H).
步骤B：化合物26-2的制备
参照实施例19步骤A的方法，将化合物9-1替换为6-溴-2-甲基喹唑啉-4(3H)-酮制备得到化合物26-2。
MS(ESI，[M+H+2] +)m/z＝444.04.
步骤C：化合物26-3的制备
参照实施例19步骤B的方法，制备得到化合物26-3。
MS(ESI，[M+H] +)m/z＝571.78.
步骤D：化合物26-4的制备
参照实施例19步骤C的方法，制备得到化合物26-4。
MS(ESI，[M+H] +)m/z＝481.31.
步骤E：化合物26的制备
参照实施例19步骤D的方法，制备得到化合物26。
HRMS(ESI，[M+H]+)m/z＝559.1558.
1H NMR(500MHz,CD 3OD)δ8.72(dd,J＝13.3,1.7Hz,1H),8.04(ddd,J＝10.2,8.5,1.7Hz,1H),7.70(dd,J＝8.7,2.5Hz,1H),7.63(d,J＝7.8Hz,1H),7.51(d,J＝7.9Hz,1H),7.24(t,J＝7.9Hz,1H),6.06(m,1H),4.83(dd,J＝9.9,7.9Hz,0.5H),4.73–4.69(m,1H),4.62(dd,J＝9.9,4.8Hz,0.5H),3.97(m,2H),3.51(q,J＝11.8,10.9Hz,2H),2.88(s,3H),2.61(s,3H),2.53–2.43(m,2H),2.40(s,3H),2.23–2.10(m,2H).
31P NMR(202MHz,CD 3OD)δ32.62.
实施例27：化合物27的制备
Figure PCTCN2021092672-appb-000128
步骤A：化合物27-1的制备
参照实施例19步骤A的方法，将化合物9-1替换为6-溴-2-甲基喹唑啉-4(3H)-酮制备得到化合物27-1。
MS(ESI，[M+H] +)m/z＝410.05.
步骤B：化合物27-2的制备
参照实施例19步骤B的方法，制备得到化合物27-2。
MS(ESI，[M+H] +)m/z＝539.15.
步骤C：化合物27-3的制备
参照实施例19步骤C的方法，制备得到化合物27-3。
MS(ESI，[M+H] +)m/z＝449.15.
步骤D：化合物27的制备
参照实施例19步骤D的方法，将化合物27-3与甲磺酰氯反应制备得到化合物27。
HRMS(ESI，[M+H] +)m/z＝527.1489.
1H NMR(500MHz,CD 3OD)δ8.80(dd,J＝13.2,1.1Hz,1H),8.20–8.04(m,1H),7.78(dd,J＝8.6,2.4Hz,1H),7.63(t,J＝7.4Hz,1H),7.48(t,J＝6.9Hz,1H),7.23(t,J＝7.7Hz,1H),7.01(t,J＝54.9Hz,1H),5.87(q,J＝7.1Hz,1H),4.05(m,2H),3.62(q,J＝11.1Hz,2H),3.00–2.96(m,3H),2.63–2.53(m,2H),2.49–2.44(m,3H),2.25(t,J＝16.0Hz,2H),1.72(d,J＝7.1Hz,3H).
实施例28：化合物28的制备
Figure PCTCN2021092672-appb-000129
步骤A：化合物28-1的制备
向25mL单口瓶中依次加入2-氨基-4-甲氧基苯甲酸(1g)、乙二醇单甲醚(10mL)、和N-碘代丁二酰亚胺(1.48g)，室温搅拌反应3h。停止反应，向反应液中加入饱和氯化钠溶液(100mL)，水相用乙酸乙酯(100mL×2)萃取，合并有机相，浓缩，残留物经硅胶柱层析(石油醚:乙酸乙酯＝3:2)分离得到1.34g化合物28-1。
MS(ESI，[M-H] -)m/z＝291.79.
1H NMR(500MHz,DMSO-d 6)δ7.98(s,1H),6.35(s,1H),3.78(s,3H),2.57(s,2H).
步骤B：化合物28-2的制备
向50mL单口瓶中，依次加入上述步骤A所得化合物28-1(1.3g)、2-甲氧基乙醇(13mL)及醋酸甲脒(0.924g)，120℃搅拌反应2h，停止反应，冷却室温，抽滤，滤饼用甲醇(10mL)洗涤，收集滤饼用甲醇(30mL)打浆，抽滤，收集滤饼干燥，得到0.95g化合物28-2。MS(ESI，[M+H] +)m/z＝302.81
步骤C：化合物28-3的制备
向50mL单口瓶中依次加入上述步骤B所得化合物28-2(0.5g)、N,N-二甲基甲酰胺(10mL)、1H-苯并三唑-1-基氧三吡咯烷基六氟磷酸盐(1.723g)，室温搅拌下滴入2,3,4,6,7,8,9,10-八氢嘧啶基[1,2-a]氮杂(0.756g)和(R)-1-(3-(二氟甲基)-2-氟苯基)乙烷-1-胺盐酸盐(0.344g)的N,N-二甲基甲酰胺(10mL)溶液，加毕，室温下搅拌反应过夜。停止反应，向反应液中加入纯化水(100mL)，乙酸乙酯(100mL×2)萃取，合并有机相，浓缩，残留物经硅胶柱层析(石油醚:乙酸乙酯＝5:1)得到0.422g化合物28-3。
MS(ESI，[M+H] +)m/z＝473.97.
1H NMR(500MHz,DMSO-d 6)δ9.01(s,1H),8.51(d,J＝7.3Hz,1H),8.36(s,1H),7.65(t,J＝7.2Hz,1H),7.50(t,J＝7.1Hz,1H),7.37–7.12(m,2H),7.10(s,1H),5.81–5.71(m,1H),3.96(s,3H),1.59(d,J＝7.1Hz,3H).
步骤D：化合物28-4的制备
参照实施例10步骤A的方法，使用化合物28-3，制备得到化合物28-4。
MS(ESI，[M+H] +)m/z＝555.14.
1H NMR(500MHz,DMSO-d 6)δ8.94(d,J＝7.4Hz,1H),8.81(d,J＝13.6Hz,1H),8.39(s,1H),7.67(t,J＝7.5Hz,1H),7.50(t,J＝7.1Hz,1H),7.39–7.34(m,4H),7.31–7.12(m,4H),5.86–5.76(m,1H),4.02(s,3H),3.70(s,2H),3.08–2.82(m,4H),2.51(d,J＝22.5Hz,4H),1.60(d,J＝7.1Hz,3H).
步骤E：化合物28-5的制备
向100mL单口瓶中，依次加入乙腈(50mL)、硝酸铈铵(2.471g)、水(10mL)，搅拌2分钟至全溶后，加入上述步骤D所得化合物28-4(0.5g)，室温搅拌反应1h。停止反应，向反应液中加入饱和碳酸氢钠水溶液淬灭反应，反应液用二氯甲烷(100mL×2)萃取，合并有机相，依次用水(100mL)，饱和氯化钠水溶液(100mL)洗涤，无水硫酸钠干燥，抽滤，滤液浓缩，残留物经硅胶柱层析(二氯甲烷:甲醇＝20:1)得到0.208g化合物28-5。
MS(ESI，[M+H] +)m/z＝465.2
1H NMR(500MHz,DMSO-d 6)δ8.93(d,J＝7.4Hz,1H),8.79(d,J＝13.5Hz,1H),8.38(s,1H),7.68(t,J＝7.4Hz,1H),7.50(t,J＝7.1Hz,1H),7.36–7.12(m,3H),5.86–5.76(m,1H),3.99(s,3H),3.16–3.06(m,4H),2.44–2.34(m,2H),1.84–1.74(m,2H),1.61(d,J＝7.2Hz,3H),1.40(s,1H).
步骤F：化合物28的制备
参照实施例10步骤C的方法，将化合物28-5与乙酸酐反应制备得到化合物28。
HRMS(ESI，[M+H] +)m/z＝507.1772.
1H NMR(500MHz,DMSO-d 6)δ8.97(d,J＝7.3Hz,1H),8.87–8.77(m,1H),8.39(d,J＝1.7Hz,1H),7.73–7.63(m,1H),7.50(t,J＝7.1Hz,1H),7.36–7.12(m,3H),5.86–5.76(m,1H),4.47–4.37(m,1H),4.09–3.99(m,1H),3.94(s,3H),3.81–3.69(m,1H),3.41–3.31(m,1H),2.49–2.30(m,2H),2.13(s,3H),2.03–1.84(m,2H),1.61(d,J＝7.1Hz,3H).
实施例29：化合物29的制备
Figure PCTCN2021092672-appb-000130
步骤A：化合物29的制备
参照实施例19步骤D的方法，将化合物28-5与甲磺酰氯反应制备得到化合物29。
HRMS(ESI，[M+H] +)m/z＝543.1441.
1H NMR(500MHz,DMSO-d 6)δ8.98(d,J＝7.4Hz,1H),8.86(d,J＝14.0Hz,1H),8.40(s,1H),7.68(t,J＝7.3Hz,1H),7.51(t,J＝7.1Hz,1H),7.37–7.10(m,3H),5.86–5.76(m,1H),3.98(s,3H),3.97–3.87(m,2H),3.55–3.450(m,2H),3.04(s,3H),2.55(d,J＝13.7Hz,2H),2.09–1.96(m,2H),1.61(d,J＝7.1Hz,3H).
实施例30：化合物30的制备
Figure PCTCN2021092672-appb-000131
步骤A：化合物30-1的制备
向15mL耐压瓶中依次加入化合物1-1(1g)、氟乙腈(1.923g)、甲烷磺酸(2.504g)，将反应瓶置于120℃油浴搅拌反应4h。停止反应，反应液自然冷却至室温。将反应液浓缩，直接用4M氢氧化钠水溶液调pH至碱性，抽滤，滤饼用大量水洗，收集固体烘干得到0.68g化合物30-1。
MS(ESI，[M+H] +)m/z＝334.74.
步骤B：化合物30-2的制备
参照实施例19步骤A的方法，将(R)-1-(3-(三氟甲基)-2-氟苯基)乙烷-1-胺盐酸盐替换为(R)-1-(3-(二氟甲基)-2-氟苯基)乙烷-1-胺盐酸盐制备得到化合物30-2。
MS(ESI，[M+H] +)m/z＝505.99.
1H NMR(500MHz,DMSO-d 6)δ8.99(s,1H),8.63(d,J＝7.3Hz,1H),7.70(t,J＝7.3Hz,1H),7.51(t,J＝6.9Hz,1H),7.30(t,J＝7.7Hz,1H),7.23(t,J＝54.4Hz,1H),7.16(s,1H),5.82–5.76(m,1H),5.29–5.09(m,2H),3.96(s,3H),1.60(d,J＝7.1Hz,3H).
步骤C：化合物30-3的制备
参照实施例10步骤A的方法，制备得到化合物30-3。
MS(ESI，[M+H] +)m/z＝587.20.
1H NMR(500MHz,DMSO-d 6)δ9.06(d,J＝7.4Hz,1H),8.80(d,J＝13.6Hz,1H),7.72(t,J＝7.3Hz,1H),7.50(t,J＝6.9Hz,1H),7.40–7.34(m,4H),7.32–7.25(m,3H),7.23(t,J＝54.5Hz,1H),5.82(p,J＝7.0Hz,1H),5.32-5.13(m,2H),4.02(s,3H),3.69(s,2H),3.03-2.95(m,2H),2.86(q,J＝11.7Hz,2H),2.50-2.47(m,2H),1.85(t,J＝16.4Hz,2H),1.62(d,J＝7.1Hz,3H).
步骤D：化合物30-4的制备
参照实施例10步骤B的方法，制备得到化合物30-4。
MS(ESI，[M+H] +)m/z＝497.16.
步骤E：化合物30的制备
参照实施例10步骤C的方法，将化合物30-4与乙酸酐反应制备得到化合物30。
HRMS(ESI，[M+H] +)m/z＝539.1835.
1H NMR(500MHz,CD 3OD)δ8.69(d,J＝14.3Hz,1H),7.63(t,J＝7.4Hz,1H),7.47(t,J＝7.0Hz,1H),7.26-7.24(m,2H),7.00(m,1H),5.83(q,J＝7.0Hz,1H),5.24(dt,J＝48.0,13.5Hz,2H),4.67-4.59(m,1H),4.24-4.16(m,1H),4.02(s,3H),3.90-3.87(m,1H),3.54-3.47(m,1H),2.67–2.54(m,2H),2.24(s,3H),2.20–2.02(m,2H),1.70(d,J＝7.1Hz,3H).
实施例31：化合物31的制备
Figure PCTCN2021092672-appb-000132
步骤A：化合物31-1的制备
参考实施例24步骤B的方法，将化合物24-1替换为2-氨基-5-溴苯甲酸甲酯制备得到化合物31-1。
MS(ESI，[M+H] +)m/z＝256.94.
1H NMR(500MHz,DMSO-d 6)δ12.74(br,1H),8.20(d,J＝2.0Hz,1H),7.99(dd,J＝8.7,2.3Hz,1H),7.65(d,J＝8.7Hz,1H),5.36(s,1H),5.26(s,1H).
步骤B：化合物31-2的制备
参照实施例19步骤A的方法，制备得到化合物31-2。
MS(ESI，[M+H] +)m/z＝428.03.
1H NMR(500MHz,DMSO-d 6)δ8.79(t,J＝4.9Hz,2H),7.93(dd,J＝8.9,1.9Hz,1H),7.70(t,J＝7.8Hz,1H),7.66(d,J＝8.9Hz,1H),7.51(t,J＝6.9Hz,1H),7.30(t,J＝7.7Hz,1H),7.23(t,J＝54.4Hz,1H),5.83–5.75(m,1H),5.33–5.13(m,2H),1.62(d,J＝7.0Hz,3H).
步骤C：化合物31-3的制备
参照实施例19步骤B的方法，制备得到化合物31-3。
MS(ESI，[M+H] +)m/z＝557.13.
1H NMR(500MHz,DMSO-d 6)δ9.08(d,J＝7.2Hz,1H),8.90(d,J＝12.2Hz,1H),8.14(t,J＝9.0Hz,1H),7.81(dd,J＝8.5,1.8Hz,1H),7.71(t,J＝7.3Hz,1H),7.51(t,J＝6.9Hz,1H),7.37-7.34(m,4H),7.31–7.25(m,2H),7.23(m,1H),5.83(m,1H),5.25(m,2H),3.66(s,2H),3.02–2.88(m,2H),2.85-2.78(m,2H),2.42–2.35(m,2H),1.99(t,J＝15.6Hz,2H),1.65(d,J＝7.1Hz,3H).
步骤D：化合物31-4的制备
参照实施例10步骤B的方法，制备得到化合物31-4。
MS(ESI，[M+H] +)m/z＝467.20.
步骤E：化合物31的制备
参照实施例30步骤E的方法，将化合物31-4与乙酸酐反应制备得到化合物31。
HRMS(ESI，[M+H] +)m/z＝509.1730.
1H NMR(500MHz,CD 3OD)δ8.81(d,J＝13.1Hz,1H),8.22–8.11(m,1H),7.91(dd,J＝8.6,2.4Hz,1H),7.64(t,J＝7.3Hz,1H),7.48(t,J＝7.0Hz,1H),7.24(t,J＝7.7Hz,1H),7.00(t,J＝54.9Hz,1H),5.85(q,J＝7.0Hz,1H),5.27(td,J＝47.5,13.5Hz,2H),4.61–4.47(m,1H),4.18-4.09(m,1H),3.96-3.89(m,1H),3.62(dd,J＝22.6,10.9Hz,1H),2.57–2.41(m,2H),2.29–2.11(m,5H),1.72(d,J＝7.1Hz,3H).
31P NMR(202MHz,CD 3OD)δ34.37.
实施例32：化合物32的制备
Figure PCTCN2021092672-appb-000133
步骤A：化合物32-1的制备
参考实施例24步骤A的方法，将5-氨基-2-氯吡啶-4-甲酸替换为2-氨基-5-溴-4-氟苯甲酸制备得到化合物32-1。
MS(ESI，[M+H] +)m/z＝249.05.
1H NMR(500MHz,DMSO-d 6)δ7.90(d,J＝8.1Hz,1H),7.01(s,2H),6.72(d,J＝11.5Hz,1H),3.79(s,3H).
步骤B：化合物32-2的制备
参考实施例24步骤B的方法，制备得到化合物32-2。
1H NMR(500MHz,DMSO-d 6)δ12.78(s,1H),8.35(d,J＝7.6Hz,1H),7.69(d,J＝9.7Hz,1H),5.36(s,1H),5.27(s,1H).
步骤C：化合物32-3的制备
参照实施例19步骤A的方法，制备得到化合物32-3。
MS(ESI，[M+H+2] +)m/z＝448.02.
1H NMR(500MHz,DMSO-d 6)δ8.98(d,J＝7.5Hz,1H),8.85(d,J＝7.2Hz,1H),7.70(dd,J＝7.5Hz,1H),7.65(d,J＝9.9Hz,1H),7.52(dd,J＝7.1Hz,1H),7.35–7.10(m,2H),5.78(p,J＝7.1Hz,1H),5.33–5.11(m,2H),1.62(d,J＝7.1Hz,3H).
步骤D：化合物32-4的制备
参照实施例19步骤B的方法，制备得到化合物32-4。
MS(ESI，[M+H] +)m/z＝575.11.
1H NMR(500MHz,CD 3OD)δ8.70–8.64(m,1H),7.52(dd,J＝7.9Hz,1H),7.37(m,2H),7.28–7.24(m,2H),7.21(dd,J＝7.5Hz,2H),7.17–7.10(m,2H),6.88(t,J＝54.9Hz,1H),5.72(q,J＝7.0Hz,1H),5.14(m,2H),3.58(s,2H),3.05–2.79(m,4H),2.44(m,2H),2.10m,2H),1.60(d,J＝7.1Hz,3H).
步骤E：化合物32-5的制备
参照实施例19步骤C的方法，制备得到化合物32-5。
MS(ESI，[M+H] +)m/z＝485.15.
步骤F：参照实施例10步骤C的方法，制备得到化合物32。
HRMS(ESI，[M+H] +)m/z＝527.1646.
1H NMR(500MHz,CD 3OD)δ8.80(dd,J＝13.5,6.7Hz,1H),7.64(t,J＝7.5Hz,1H),7.49(m,2H),7.24(t,J＝7.7Hz,1H),6.99(t,J＝54.9Hz,1H),5.84(q,J＝7.1Hz,1H),5.25(m,2H),4.64–4.11(m,2H),4.00–3.57 (m,2H),2.59–2.43(m,2H),2.38–2.24(m,2H),2.22(s,3H),1.72(d,J＝7.2Hz.3H).
31P NMR(202MHz,CD 3OD)δ31.37.
实施例33：化合物33的制备
Figure PCTCN2021092672-appb-000134
步骤A:化合物33-1的制备
向25mL单口瓶中加入6-溴-2,4-二氯喹唑啉(0.5g)、(R)-1-(3-(二氟甲基)-2-氟苯基)乙烷-1-胺盐酸盐(0.447g)、N,N-二异丙基乙胺(0.689g)和乙腈(3mL)，反应液在室温搅拌反应2h。反应结束，反应液浓缩至干，残留物以硅胶柱分离纯化(石油醚:乙酸乙酯＝80:20)，得到0.7g化合物33-1。
MS(ESI，[M+H+2] +)m/z＝432.00.
1H NMR(500MHz,DMSO-d 6)δ9.10(d,J＝7.3Hz,1H),8.81(d,J＝2.1Hz,1H),7.96(dd,J＝8.8,2.1Hz,1H),7.70(t,J＝7.5Hz,1H),7.58(d,J＝8.9Hz,1H),7.54(t,J＝7.1Hz,1H),7.37–7.32(m,1H),7.32–7.07(m,1H),5.70(m,1H),1.62(d,J＝7.0Hz,3H).
步骤B：化合物33-2的制备
向25mL单口瓶中加入步骤A所得化合物33-1(0.5g)、1-苄基-1,4-氮杂膦烷4-氧化物(0.267g)、4,5-双二苯基膦-9,9-二甲基氧杂蒽(0.134g)、三二亚苄基丙酮二钯(0.106g)、N,N-二异丙基乙胺(0.225g)和1,4-二氧六环(10mL)。氮气保护下油浴加热至70℃搅拌反应2h。反应液冷却至室温，抽滤，滤液浓缩至干，残留物以硅胶柱分离纯化(二氯甲烷:甲醇＝95:5)，得到0.5g化合物33-2。
MS(ESI，[M+H] +)m/z＝559.09.
1H NMR(500MHz,DMSO-d 6)δ9.41(d,J＝7.3Hz,1H),8.92(d,J＝12.1Hz,1H),8.27(br,1H),8.17(t,J＝9.1Hz,1H),7.77–7.68(m,2H),7.55(t,J＝7.2Hz,1H),7.39–7.34(m,4H),7.33(d,J＝7.9Hz,1H),7.29(dd,J＝6.0,2.9Hz,1H),5.82–5.69(m,1H),3.62(dt,J＝6.6,3.3Hz,1H),3.15(m,1H),3.03–2.86(m,2H),2.81(q,J＝11.8Hz,2H),2.43–2.31(m,2H),1.98(t,J＝15.7Hz,2H),1.66(d,J＝7.0Hz,3H).
步骤C：化合物33-3的制备
向100mL单口瓶中加入步骤B所得化合物33-2(0.18g)、硝酸铈铵(0.883g)、乙腈(20mL)和水(4mL)，室温搅拌反应1h。加入饱和碳酸氢钠水溶液淬灭反应，以二氯甲烷萃取(30mL×3)，有机相依次用水、饱和氯化钠水溶液洗涤，无水硫酸钠干燥，抽滤，滤液浓缩至干，得到0.3g化合物33-3粗品，直接进行下步反应。
MS(ESI，[M+H] +)m/z＝469.12.
步骤D：化合物33的制备
参照实施例10步骤C的方法，将化合物33-3与乙酸酐反应制备得到化合物33。
HRMS(ESI，[M+H] +)m/z＝511.1277.
1H NMR(500MHz,CDCl 3)δ8.79(d,J＝13.0Hz,1H),7.81(q,J＝6.2,5.6Hz,2H),7.65–7.41(m,3H),7.17(q,J＝7.5Hz,1H),6.88(td,J＝55.0,3.0Hz,1H),5.79(t,J＝7.1Hz,1H),4.76–4.54(m,1H),4.14–3.84(m,2H),3.58(q,J＝12.0Hz,1H),2.33–2.24(m,1H),2.20(d,J＝8.8Hz,3H),2.09(s,3H),1.71(t,J＝6.0Hz,3H).
31P NMR(202MHz,CDCl 3)δ29.70.
实施例34：化合物34的制备
Figure PCTCN2021092672-appb-000135
步骤A：化合物34-1的制备
参照实施例19步骤A的方法，将(R)-1-(3-(三氟甲基)-2-氟苯基)乙烷-1-胺盐酸盐替换为(R)-1-(3-(二氟甲基)-2-氟苯基)乙烷-1-胺盐酸盐与化合物1-2反应制备得到化合物34-1。
MS(ESI，[M+H] +)m/z＝488.02.
步骤B：化合物34的制备
向5mL微波管中加入步骤A所得化合物34-1(0.075g)、二乙基氧化膦(0.016g)、N,N-二异丙基乙胺(0.04g)、4,5-双二苯基膦-9,9-二甲基氧杂蒽(8.9mg)、三二亚苄基丙酮二钯(7.05mg)、和N,N-二甲基甲酰胺(3mL)，加毕，氮气置换后，微波反应器150瓦下加热至170℃反应35分钟，反应结束取出样品。反应液经硅藻土抽滤，滤液倒入水(30mL)中，乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，残留物以硅胶柱分离纯化(二氯甲烷:甲醇＝97:3)得到29mg化合物34。
HRMS(ESI，[M+H] +)m/z＝466.1886.
1H NMR(500MHz,CD 3OD)δ8.59(d,J＝13.0Hz,1H),7.64(t,J＝7.3Hz,1H),7.48(t,J＝7.1Hz,1H),7.24(t,J＝7.7Hz,1H),7.13–6.88(m,2H),5.87(q,J＝7.1Hz,1H),4.00(s,3H),2.44(s,3H),2.13(m,4H),1.69(d,J＝7.1Hz,3H),1.07(m,6H).
31P NMR(202MHz,CD 3OD)δ49.9.
实施例35：化合物35的制备
Figure PCTCN2021092672-appb-000136
步骤A：化合物35-1的制备
参照实施例19步骤A的方法，将(R)-1-(3-(三氟甲基)-2-氟苯基)乙烷-1-胺盐酸盐替换为(R)-1-(3-(二氟甲基)-2-氟苯基)乙烷-1-胺盐酸盐与化合物9-1反应制备得到化合物35-1。
MS(ESI，[M+H] +)m/z＝367.05.
1H NMR(500MHz,CD 3OD)δ8.76(s,1H),8.33(s,1H),7.60(t,J＝7.3Hz,1H),7.48(t,J＝6.9Hz,1H),7.24(t,J＝7.7Hz,1H),7.01(t,J＝54.9Hz,1H),5.80(q,J＝7.1Hz,1H),2.46(s,3H),1.69(d,J＝7.1Hz,3H).
步骤B：化合物35-2的制备
Figure PCTCN2021092672-appb-000137
步骤a：化合物35-2-1的制备
向500mL三口瓶中加入次磷酸铵(28g,337mmol)，滴加六甲基二硅胺烷(109g)，滴加完毕，氮气保护下将反应液加热至120℃搅拌反应4h，将双(2-溴乙基)醚(78g)滴加入反应瓶中，保持温度继续反应4h。反应液冰水浴搅拌降温，向其中滴加无水乙醇(150mL)，滴加完毕，将反应液加热至回流反应1h。停止反应，反应液冷却至室温，抽滤，滤饼用二氯甲烷洗涤，滤液浓缩得到42.4g化合物35-2-1粗品。
GCMS:[M] +＝136.
步骤b：化合物35-2-2的制备
向25mL三口瓶中加入步骤a所得化合物35-2-1(1g)和二氯甲烷(20mL)，氮气保护下冰盐浴降温至0℃以下，向其中滴加草酰氯(1.578g)，滴加完毕转移至室温搅拌过夜。将反应液浓缩至干，残留物用甲苯(10mL)溶解后浓缩至干，得到1.8g化合物35-2-2粗品，不进行纯化直接用于下一步反应。
步骤c：化合物35-2的制备
-70℃氮气保护下，将1M二异丁基氢化铝的甲苯溶液(6.48mL)缓慢加入步骤b所得化合物35-2-2(1.8g)的二氯甲烷(15mL)搅拌液中，混合物在-70℃搅拌反应2h。反应结束，在-70℃下向反应液中加入甲醇(3mL)搅拌反应5分钟，将反应液转移至冰水浴下继续搅拌至反应液升温至0℃，向其中加入10vol％醋酸水溶液(10mL)，室温搅拌10分钟，将所得溶液进行分液，水相用二氯甲烷(20mL×5)萃取，合并有机相，无水硫酸钠干燥，浓缩得到1.7g化合物35-2粗品，不进行纯化直接用于下一步反应。
步骤C：化合物35的制备
参照实施例19步骤B的方法，将化合物35-1与化合物35-2反应制备得到化合物35。
HRMS(ESI，[M+H] +)m/z＝451.1510.
1H NMR(500MHz,CD 3OD)δ9.12(s,1H),8.83(d,J＝6.8Hz,1H),7.63(t,J＝7.3Hz,1H),7.49(t,J＝7.0Hz,1H),7.24(t,J＝7.7Hz,1H),7.00(t,J＝54.9Hz,1H),5.87(q,J＝7.1Hz,1H),4.23–4.02(m,4H),2.65(dt,J＝15.6,7.4Hz,2H),2.51(s,3H),2.22–2.08(m,2H),1.72(d,J＝7.1Hz,3H).
31P NMR(202MHz,CD 3OD)δ30.08.
实施例36：化合物36的制备
Figure PCTCN2021092672-appb-000138
步骤A：化合物36-1的制备
参照实施例19步骤A的方法，将(R)-1-(3-(三氟甲基)-2-氟苯基)乙烷-1-胺盐酸盐替换为(R)-1-(3-(二氟甲基)-2-氟苯基)乙烷-1-胺盐酸盐制备得到化合物36-1。
MS(ESI，[M+H] +)m/z＝411.96.
1H NMR(500MHz,DMSO-d 6)δ9.50(s,1H),8.75(d,J＝2.2Hz,1H),7.96(s,1H),7.87(dd,J＝8.9,2.1Hz,1H),7.72–7.68(m,1H),7.56–7.53(m,1H),7.36–7.11(m,2H),5.79(m,1H),2.37(s,3H),1.61(d,J＝7.0Hz,3H).
步骤B：化合物36的制备
参照实施例19步骤B的方法，制备得到化合物36。
HRMS(ESI，[M+H] +)m/z＝450.1552.
1H NMR(500MHz,CD 3OD)δ8.69(dd,J＝13.1,1.7Hz,1H),8.02(m,1H),7.68(dd,J＝8.6,2.5Hz,1H),7.53(t,J＝7.4Hz,1H),7.38(t,J＝7.1Hz,1H),7.14(t,J＝7.7Hz,1H),6.91(t,J＝54.9Hz,1H),5.78(q,J＝7.1Hz,1H),4.13–3.94(m,4H),2.50(m,2H),2.36(s,3H),2.11–1.96(m,2H),1.62(d,J＝7.1Hz,3H).
31P NMR(202MHz,CD 3OD)δ31.65.
实施例37：化合物37的制备
Figure PCTCN2021092672-appb-000139
步骤A：化合物37-1的制备
参照实施例19步骤A的方法，将(R)-1-(3-(三氟甲基)-2-氟苯基)乙烷-1-胺盐酸盐与6-溴-2-甲基喹唑啉-4(3H)-酮反应制备得到化合物37-1。
MS(ESI，[M+H] +)m/z＝428.08.
步骤B：化合物37的制备
参照实施例19步骤B的方法，将化合物37-1与化合物35-2反应制备得到化合物37。
HRMS(ESI，[M+H] +)m/z＝468.1479.
1H NMR(500MHz,CD 3OD)δ8.80(dd,J＝13.1,1.4Hz,1H),8.13(m,1H),7.79(dd,J＝8.6,2.5Hz,1H),7.74(t,J＝7.0Hz,1H),7.56(t,J＝6.9Hz,1H),7.27(t,J＝7.8Hz,1H),5.86(q,J＝7.1Hz,1H),4.26–4.01(m,4H),2.61(m,2H),2.45(s,3H),2.14(t,J＝16.1Hz,2H),1.73(d,J＝7.1Hz,3H).
31P NMR(202MHz,CD 3OD)δ31.62.
实施例38：化合物38的制备
Figure PCTCN2021092672-appb-000140
步骤A：化合物38-1的制备
参照实施例19步骤A的方法，将(R)-1-(3-(二氟甲基)-2-氟苯基)乙烷-1-胺盐酸盐与6-溴-7-氟-2-甲基喹唑啉-4(3H)-酮反应制备得到化合物38-1。
MS(ESI，[M+H] +)m/z＝428.05.
1H NMR(500MHz,DMSO-d 6)δ8.91(d,J＝7.5Hz,1H),8.63(d,J＝7.1Hz,1H),7.68(t,J＝7.3Hz,1H),7.51(t,J＝7.8Hz,2H),7.37–7.18(m,2H),5.78(m,1H),2.34(s,3H),1.60(d,J＝7.1Hz,3H).
步骤B：化合物38的制备
参照实施例19步骤B的方法，制备得到化合物38。
HRMS(ESI，[M+H] +)m/z＝468.1463.
1H NMR(500MHz,CD 3OD)δ8.66(dd,J＝13.5,6.7Hz,1H),7.53(t,J＝7.5Hz,1H),7.38(t,J＝7.1Hz,1H),7.26(dd,J＝11.4,4.4Hz,1H),7.14(t,J＝7.7Hz,1H),6.90(t,J＝54.9Hz,1H),5.77(q,J＝7.1Hz,1H),4.04(m,4H),2.52(m,2H),2.35(s,3H),2.22–2.02(m,2H),1.61(d,J＝7.1Hz,3H).
31P NMR(202MHz,CD 3OD)δ28.87.
实施例39：化合物39的制备
Figure PCTCN2021092672-appb-000141
步骤A：化合物39-1的制备
向500mL单口瓶中依次加入2-氨基-3-氟苯甲酸(10g)和二氯甲烷(170mL)，室温下搅拌，向其中加入N-碘代丁二酰亚胺(14.50g)，加毕，室温搅拌过夜。反应结束，抽滤，滤饼用二氯甲烷(50mL)打浆，抽滤，干燥，得到12.9g化合物39-1。
1H NMR(500MHz,DMSO-d 6)δ7.81–7.80(m,1H),7.57(dd,J＝10.8,2.0Hz,1H).
步骤B：化合物39-2的制备
参照实施例24步骤A的方法，制备得到化合物39-2。
1H NMR(500MHz,DMSO-d 6)δ7.84–7.79(m,1H),7.61-7.59(m,1H),6.69(s,2H),3.82(s,3H).
步骤C：化合物39-3的制备
参照实施例1步骤B的方法，制备得到化合物39-3。
MS(ESI，[M+H] +)m/z＝304.75.
步骤D：化合物39-4的制备
参照实施例1步骤E的方法，制备得到化合物39-4。
MS(ESI，[M+H] +)m/z＝297.04.
1H NMR(500MHz,DMSO-d 6)δ12.64(br,1H),8.30(dd,J＝11.7,1.3Hz,1H),8.09(m,1H),4.06–3.83(m,4H),2.49–2.39(m,5H),2.02-1.95(m,2H).
步骤E：化合物39的制备
参照实施例19步骤A的方法，制备得到化合物39。
HRMS(ESI，[M+H] +)m/z＝468.1466.
1H NMR(500MHz,CD 3OD)δ8.50(d,J＝12.9Hz,1H),7.81(t,J＝10.6Hz,1H),7.53(t,J＝7.3Hz,1H),7.39(t,J＝7.0Hz,1H),7.14(t,J＝7.7Hz,1H),6.91(t,J＝54.9Hz,1H),5.77(q,J＝7.1Hz,1H),4.14–3.91(m,4H),2.50(m,2H),2.39(s,3H),2.04(t,J＝16.5Hz,2H),1.62(d,J＝7.1Hz,3H).
31P NMR(202MHz,CD 3OD)δ31.53.
实施例40：化合物40的制备
Figure PCTCN2021092672-appb-000142
步骤A：化合物40-1的制备
向350mL耐压反应瓶中，依次加入4,6-二氯-2-甲基嘧啶(16.3g)、氨水(80mL)，密封后，将混合物加热至90℃反应过夜。停止反应，反应液冷却至室温，过滤，收集滤饼，减压干燥得到14g化合物40-1。
MS(ESI，[M+H] +)m/z＝143.93.
步骤B：化合物40-2的制备
向100mL三口瓶中，依次加入步骤A所得化合物40-1(2g)和甲醇(20mL)，冰盐浴降温至0℃时，向其中滴加一氯化碘(15.58g)的甲醇(20mL)溶液，加毕转移至室温下搅拌过夜。反应结束，将反应液倒入水(100mL)中，然后加入饱和亚硫酸钠溶液(200mL)，用2M氢氧化钠溶液调pH＝6-7，乙酸乙酯(100mL×3)萃取，合并有机相，用饱和食盐水(100mL)洗涤，无水硫酸钠干燥，减压浓缩得到3.3g化合物40-2。
MS(ESI，[M+H] +)m/z＝269.86.
1H NMR(500MHz,DMSO-d 6)δ7.28(d,2H),2.29(s,3H).
步骤C：化合物40-3的制备
向250mL单口瓶中，依次加入步骤B所得化合物40-2(2.8g)、N,N-二甲基甲酰胺(28mL)、丙烯酸叔丁酯(1.598g)、三乙胺(2.103g)、醋酸钯(0.058g)和三邻甲苯基膦(0.158g)，氮气置换三次，氮气保护下，将混合物加热至100℃反应8h。反应结束，反应液冷却至室温，将反应液倒入水(100mL)中，乙酸乙酯(80mL×3)萃取，合并有机相用饱和食盐水(60mL)洗涤，无水硫酸钠干燥，过滤，浓缩，所得粗品硅胶柱分离纯化(石油醚:乙酸乙酯＝70:30)，得到1.7g化合物40-3。
MS(ESI，[M+H] +)m/z＝270.38.
1H NMR(500MHz,DMSO-d 6)δ7.45-7.40(m,3H),6.34(d,J＝16.4Hz,1H),2.31(s,3H),1.48(s,9H).
步骤D：化合物40-4的制备
向25mL反应瓶中，依次加入步骤C所得化合物40-3(0.4g)、乙腈(8mL)，将反应瓶置于365nm波长灯光下室温搅拌4h。停止反应，过滤，收集滤饼得到0.22g化合物40-4。
MS(ESI，[M+H] +)m/z＝270.08.
1H NMR(500MHz,DMSO-d 6)δ6.88(s,2H),6.70(d,J＝11.6Hz,1H),6.05(d,J＝11.6Hz,1H),2.30(s,3H),1.29(s,9H).
步骤E：化合物40-5的制备
向250mL反应瓶中，依次加入步骤D所得化合物40-4(2.8g)、三氟乙醇(1.038g)、叔丁醇钾(2.56g)，将混合物加热至80℃反应2h。反应结束，反应液冷却至室温，将反应液倒入饱和氯化铵溶液(30mL)中，乙酸乙酯(50mL×3)萃取，合并有机相，用饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤，浓缩，所得残留物加入甲基叔丁基醚(20mL)打浆得到2.2g化合物40-5。
MS(ESI，[M+H] +)m/z＝260.05.
1H NMR(500MHz,DMSO-d 6)δ12.46(s,1H),7.86(d,J＝9.6Hz,1H),6.51(d,J＝9.6Hz,1H),5.19(q,J＝8.9Hz,2H),2.55(s,3H).
步骤F：化合物40-6的制备
向250mL单口瓶中，依次加入步骤E所得化合物40-5(2g)、N,N-二甲基甲酰胺(20mL)，冰水浴降温至5℃以下，向其中加入氢化钠(0.370g)，加毕，室温搅拌5分钟，然后再在冰浴下向反应瓶中滴加碘甲烷(1.314g)，加毕，自然升至室温搅拌2h。反应结束将反应液倒入冰水(20mL)中，乙酸乙酯(30mL×3)萃取，合并有机相，用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，过滤，浓缩，所得粗品硅胶柱分离纯化(石油醚:乙酸乙酯＝70:30)，得到1.7g化合物40-6。
MS(ESI，[M+H] +)m/z＝274.03.
1H NMR(500MHz,DMSO-d 6)δ7.90(d,J＝9.6Hz,1H),6.64(d,J＝9.6Hz,1H),5.21(q,J＝8.9Hz,2H),3.60(s,3H),2.62(s,3H).
步骤G：化合物40-7的制备
向100mL单口瓶中，依次加入步骤F所得化合物40-6(0.65g)、48％氢溴酸水溶液(8mL)溶液，反应室温搅拌，分批向其中加入溴酸钠(1.077g)，加毕，将反应瓶转移至60℃油浴中搅拌2h。反应结束将反应液倒入冰水(10mL)中，然后加入饱和亚硫酸钠溶液(30mL)，剧烈搅拌5分钟，饱和碳酸氢钠溶液调pH＝6-7，乙酸乙酯(50mL×3)萃取，合并有机相，用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，过滤，浓缩，所得粗品用硅胶柱分离纯化(石油醚:乙酸乙酯＝80:20)，得到0.7g化合物40-7。
MS(ESI，[M+H] +)m/z＝351.92.
1H NMR(500MHz,DMSO-d 6)δ8.31(s,1H),5.23(q,J＝8.9Hz,2H),3.68(s,3H),2.62(s,3H).
步骤H：化合物40-8的制备
向100mL单口瓶中，依次加入步骤G所得化合物40-7(0.7g)、48％的氢溴酸水溶液(7mL)，加毕，将混合物加热至100℃反应2.5h。反应结束，反应液冷却至室温，将反应液倒入冰水(100mL)中，用饱和碳酸氢钠溶液调pH＝6-7，过滤，收集滤饼干燥得到0.537g化合物40-8。
MS(ESI，[M+H+2] +)m/z＝271.96.
1H NMR(500MHz,DMSO-d 6)δ12.90(s,1H),8.24(s,1H),3.63(s,3H),2.41(s,3H).
步骤I：化合物40-9的制备
参照实施例19步骤A的方法，制备得到化合物40-9。
1H NMR(500MHz,DMSO-d 6)δ8.93(s,1H),8.44(d,J＝6.9Hz,1H),7.73(d,J＝7.8Hz,1H),7.54(d,J＝7.6Hz,1H),7.36(t,J＝7.8Hz,1H),5.64(p,J＝6.9Hz,1H),3.57(s,3H),2.59(s,3H),2.31(s,3H),1.52(d,J＝7.0Hz,3H).
步骤J：化合物40的制备
参照实施例19步骤B的方法，将化合物40-9与实施例35步骤c所得化合物35-2反应制备得到化合物40。
HRMS(ESI，[M+H] +)m/z＝495.1768.
1H NMR(500MHz,CD 3OD)δ8.78(d,J＝14.5Hz,1H),7.68(d,J＝7.8Hz,1H),7.52(d,J＝7.8Hz,1H),7.29(t,J＝7.8Hz,1H),5.79(q,J＝7.0Hz,1H),4.19(m,2H),4.07(q,J＝11.3Hz,2H),3.64(s,3H),2.81(m, 2H),2.62(s,3H),2.41(s,3H),1.87(t,J＝16.8Hz,2H),1.60(d,J＝7.0Hz,3H).
实施例41：化合物41的制备
Figure PCTCN2021092672-appb-000143
步骤A：化合物41-1的制备
向100mL单口瓶中依次加入5-氨基-2-氯异烟酸甲酯(2g)、N,N-二甲基甲酰胺(20mL)、N-溴代丁二酰亚胺(1.9g)，反应液加热至80℃反应3h。反应结束，将反应液倒入水中(200mL)，甲基叔丁基醚(50mL×3)萃取，有机相用无水硫酸钠干燥，浓缩，残留物以硅胶柱分离纯化(石油醚:乙酸乙酯＝80:20)，得到2.6g化合物41-1。
MS(ESI，[M+H+2] +)m/z＝266.87。
1H NMR(500MHz,DMSO-d 6)δ7.63(s,1H),6.78(s,2H),3.88(s,3H).
步骤B：化合物41-2的制备
向35mL微波管中依次加入步骤A所得化合物41-1(1.1g)、乙腈(3.40g)、甲烷磺酸(3.98g)，室温搅拌10分钟后，放入微波反应器中，在50瓦下加热至120℃反应2h。反应结束，将所得样品溶液减压浓缩至干，用水(20mL)稀释后用15％氢氧化钠水溶液调pH至碱性，抽滤，得到0.8g化合物41-2。
MS(ESI，[M-H] -)m/z＝273.89.
1H NMR(500MHz,CD 3OD)δ7.94(s,1H),2.48(s,3H).
步骤C：化合物41-3的制备
向5mL微波管中依次加入步骤B所得化合物41-2(0.2g)、N,N-二甲基甲酰胺(2mL)，加入氰化锌(39.4mg)和四(三苯基膦)钯(78mg)，氮气置换3次后放入微波反应器中，50瓦下加热至110℃反应1h。反应结束，将反应液倒入水中(20mL)，乙酸乙酯(20mL×3)萃取，有机相用无水硫酸钠干燥，浓缩，残留物以硅胶柱柱层析分离纯化(二氯甲烷:甲醇＝80:20)，得到136mg化合物41-3。
MS(ESI，[M-H] -)m/z＝218.95.
1H NMR(500MHz,CD 3OD)δ7.97(s,J＝7.2Hz,1H),2.51(s,3H).
步骤D：化合物41-4的制备
参照实施例19步骤A的方法，制备得到化合物41-4。
MS(ESI，[M+H] +)m/z＝410.12.
步骤E：化合物41的制备
参照实施例19步骤B的方法，将上述步骤D制备得到的化合物41-1与化合物35-2反应制备得到化合物41。
HRMS(ESI，[M+H] +)m/z＝494.1365.
1H NMR(500MHz,CD 3OD)δ8.97(d,J＝6.1Hz,1H),7.71–7.62(m,1H),7.51–7.45(m,1H),7.19(t,J ＝7.8Hz,1H),5.73(q,J＝7.1Hz,1H),4.15–3.94(m,4H),2.54(m,2H),2.42(s,3H),2.08(m,2H),1.64(d,J＝7.1Hz,3H).
31P NMR(202MHz,CD 3OD)δ29.64.
实施例42：化合物42的制备
Figure PCTCN2021092672-appb-000144
步骤A：化合物42的制备
参照实施例19步骤B的方法，将化合物19-1与1-氧化磷杂环己烷反应制备得到化合物42。
HRMS(ESI，[M+H] +):m/z＝467.1620.
1H NMR(500MHz,CD 3OD)δ9.10(s,1H),8.81–8.78(m,1H),7.75(t,J＝6.9Hz,1H),7.57(t,J＝7.0Hz,1H),7.28(t,J＝7.8Hz,1H),5.85(q,J＝7.1Hz,1H),2.50(s,3H),2.47–2.39(m,2H),2.13–1.94(m,6H),1.85-1.79(m,1H),1.73(d,J＝7.1Hz,3H),1.66-1.59(m,1H).
实施例43：化合物43的制备
Figure PCTCN2021092672-appb-000145
步骤A：化合物43的制备
参照实施例19步骤B的方法，将化合物19-1与1-氧化磷杂环戊烷反应制备得到化合物43。
HRMS(ESI，[M+H] +):m/z＝453.1594.
1H NMR(500MHz,CD 3OD)δ9.09(s,1H),8.81(dd,J＝6.5,0.7Hz,1H),7.75(t,J＝6.9Hz,1H),7.57(t,J＝7.1Hz,1H),7.28(t,J＝7.8Hz,1H),5.85(q,J＝7.1Hz,1H),2.50(s,3H),2.33-2.29(m,2H),2.20-2.10(m,4H),2.02-1.94(m,2H),1.72(d,J＝7.1Hz,3H).
以下实施例44～47(表1)可以参照实施例1的方法，将2-氨基-4-甲氧基苯甲酸甲酯分别替换为以下片段1-1，并将(R)-1-(间甲苯基)乙烷-1-胺分别替换为以下片段1-2进行反应，最后参照实施例7步骤C的方法制备得到化合物44～47。
表1：
Figure PCTCN2021092672-appb-000146
Figure PCTCN2021092672-appb-000147
以下中间体(表2-1)可以参照实施例19的方法，将(R)-1-(3-(三氟甲基)-2-氟苯基)乙烷-1-胺盐酸盐分别替换为以下片段a，与对应的片段b反应，制备得到中间体化合物2a-1～2a-6。
表2-1：
Figure PCTCN2021092672-appb-000148
Figure PCTCN2021092672-appb-000149
实施例48～60(表2)可以参照实施例10的方法，将化合物7-1替换为上述制备得到的中间体2a-1～2a-6，并将乙酸酐分别替换为以下片段2进行取代、还原胺化或是缩合反应制备得到化合物48～60。
表2：
Figure PCTCN2021092672-appb-000150
Figure PCTCN2021092672-appb-000151
Figure PCTCN2021092672-appb-000152
Figure PCTCN2021092672-appb-000153
以下中间体(表3-1)可以参照实施例9步骤A的方法，将5-氨基-2-氯异烟酸分别替换为以下片段2a，制备得到以下中间体化合物3a-1～3a-2。
表3-1：
Figure PCTCN2021092672-appb-000154
以下实施例61～64(表3)可以参照实施例19的方法，将(R)-1-(3-(三氟甲基)-2-氟苯基)乙烷-1-胺盐酸盐分别替换为以下片段3-1，并将化合物9-1替换为上述制备得到的中间体化合物，制备得到化合物61～64。
表3：
Figure PCTCN2021092672-appb-000155
Figure PCTCN2021092672-appb-000156
以下实施例65(表4)可以参照实施例35的方法，将化合物9-1替换为中间体3a-2，将(R)-1-(3-(三氟甲基)-2-氟苯基)乙烷-1-胺盐酸盐替换为对应的片段4-1，并将化合物35-2替换为对应的片段4-2反应，最后参照实施例7步骤C的方法，制备得到化合物65。以下实施例66～71(表4)可以参照实施例35的方 法，将化合物9-1替换为中间体3a-2，将(R)-1-(3-(三氟甲基)-2-氟苯基)乙烷-1-胺盐酸盐分别替换为以下片段4-1，并将化合物35-2分别替换为以下片段4-2制备得到化合物66～71。
表4：
Figure PCTCN2021092672-appb-000157
Figure PCTCN2021092672-appb-000158
试验例1体外细胞水平磷酸化活性抑制试验
1.1试验试剂和仪器
1.1.1试验试剂
Figure PCTCN2021092672-appb-000159
Figure PCTCN2021092672-appb-000160
1.1.2仪器
Figure PCTCN2021092672-appb-000161
1.2体外细胞水平的磷酸化活性抑制试验方法
取处于指数生长期状态良好的H358人非小细胞肺癌细胞(南京科佰生物科技有限公司)一皿，收集细胞至离心管，低速台式离心机，1000转/min，离心5min，弃上清，用移液器加入5mL含5％FBS种板培养基进行细胞重悬。使用细胞计数仪计数，种板培养基进行稀释，调整细胞密度至1.5×10 5个/mL。使用多道移液器接种于黑色底透384孔板上，40μL/孔，置于37℃、含5％CO 2饱和湿度的细胞培养箱中培养过夜后，使用Tecan D300e超微量加样器进行化合物加样。1小时后弃去培养基，每孔加入40μL 4％多聚甲醛，室温孵育20min，PBS洗涤。每孔加入40μL甲醇，室温孵育10min，PBST洗涤。每孔加入20μL5％BSA封闭缓冲液，室温封闭1h后，弃去封闭液，每孔加入20μL一抗混合液，其中Rabbit anti-pERK按1:1000(终浓度)稀释，mouse anti-GAPDH按1:5000(终浓度)稀释，4℃孵育过夜，PBST洗涤。每孔加入20μL二抗混合液，其中goat anti rabbit 800和goat anti mouse 647均按1:1000(终浓度)稀释，室温避光孵育45min，PBST洗涤。Azure Biosystems扫描读数，以化合物浓度对数为横坐标，磷酸化抑制率为纵坐标，使用四参数逻辑模型计算和分析EC 50值，结果见表5。
表5
实施例 EC 50(nM)
12 103
14 108
15 148
17 82
18 71
。
试验例2鸟嘌呤核苷酸交换试验
该试验定量考察SOS1介导KRAS活化的能力。体系中加入带His标签的KRAS G12C，标记了镧系元素Eu的抗His抗体与之结合，然后加入辅助蛋白SOS1cat以及带荧光基团的GTP类似物EDA-GTP-DY-647P1，带荧光基团的GTP类似物通过辅助蛋白的协助被装载到KRAS G12C上，于是Anti-6HIS-Cryptate(FRET供体)和EDA-GTP-DY-647P1(FRET受体)之间发生能量共振转移。而预先经SOS1抑制剂化合物处理后，SOS1结合并介导KRAS活化能力减弱，供体与受体之间FRET能力减弱。
2.1试验试剂和仪器
2.1.1试验试剂
名称 生产厂家/来源 货号/试验编号
His-KRAS G12C 内部生产 TQB3822PP01a
SOS1cat 内部生产 TQB3822PP02
Anti-6HIS-Cryptate Cisbio 61HISKLA
EDA-GTP-DY-647P1 Jena Bioscience NU-820-647P1
HEPES pH 7.4 Thermo 15630080
NaCl 沪试 10019318
MgCl 2 Sigma M8266
DTT Promega V3151
BSA Sigma B2604
DMSO Sigma D4540
Igepal Sigma I3021
2.1.2仪器
名称 生产厂家 型号
移液器 Thermo 100-1000μl
移液器 Thermo 20-200μl
移液器 Thermo 10-100μl
移液器 RNIN 2-20μl
移液器 RNIN 0.5-10μl
超微量加样器 Tecan D300E
2.2核苷酸交换试验过程
His-KRAS G12C的制备：将K-Ras4B-G12C(UniProt P01116-2，amino acid 1-169)序列进行密码子优化和基因合成，最终亚克隆到pET-30a(+)载体上，转化到BL21(DE3)感受态中，挑选合适的克隆子，利用 TB培养基进行培养和IPTG低温诱导表达，收集菌体。利用超声破碎仪进行细胞破碎，离心过滤收取上清。进行Ni Sepharose HP和Superdex 200pg(16/60)纯化得到纯度＞90％的蛋白，测活待用。
SOS1cat的制备：将human SOS1(UniProt Q07889，amino acid 564-1049)序列进行密码子优化和基因合成，最终亚克隆到pET-30a(+)载体上，转化到BL21(DE3)感受态中，挑选合适的克隆子，利用TB培养基进行培养和IPTG低温诱导表达，收集菌体。利用超声破碎仪进行细胞破碎，离心过滤收取上清。进行Ni Sepharose HP、Superdex 200pg(16/60)和Superdex 200pg(16/60)纯化得到纯度＞90％的蛋白，测活待用。
配制试验缓冲液，其组分为：HEPES pH 7.4：20mM；NaCl：150mM；MgCl 2：0.5mM；DTT：2mM；BSA：0.05％；Igepal：0.0025％。
用试验缓冲液分别配制KRAS G12C工作液、SOS1cat工作液和空白对照溶液。其中KRAS G12C工作液包含100nM His-KRAS G12C和2nM anti-His-terbium；SOS1cat工作液包含20nM SOS1cat和200nM EDA–GTP–DY-647P1；空白对照溶液包含100nM EDA–GTP–DY-647P1。
整个试验过程均在20℃条件下完成。试验组每孔加入5μL SOS1cat工作液，同时，对照组每孔加入5μL空白对照工作液，20℃孵育10min。继而使用Tecan D300e超微量加样器加化合物，化合物最高终浓度为10μM，按2倍依次稀释，共设置8个浓度梯度，20℃孵育30min。最后，每孔加入5μL KRAS G12C工作液，20℃孵育15min，Envision酶标仪检测665nm/620nm荧光比值，反映核苷酸的转换程度。计算抑制率，抑制率(％)＝(阴性对照组平均值—试验组平均值)/(阴性对照组平均值—空白组平均值)×100％，其中阴性对照组不含化合物，其余条件与试验组相同。以化合物浓度对数为横坐标，抑制率为纵坐标，使用四参数逻辑模型计算和分析IC 50值，结果见表6。
试验例3 KRAS/SOS1蛋白结合试验
此测定法一方面可用来检测化合物抑制SOS1与KRAS G12C之间的蛋白-蛋白相互作用的效力，另一方面可以验证化合物的分子作用模式。低IC 50值表明SOS1抑制剂化合物可以高效抑制蛋白互作。
3.1试验试剂和缓冲液
3.1.1试剂：
GST-SOS1(564-1049)，内部生产：将human SOS1(UniProt Q07889，amino acid 564-1049)序列进行密码子优化和基因合成，最终亚克隆到pGEX-4T-1载体上，转化到BL21(DE3)感受态中，挑选合适的克隆子，利用TB培养基进行培养和IPTG低温诱导表达，收集菌体。利用超声破碎仪进行细胞破碎，离心过滤收取上清。进行Ni Sepharose HP和Superdex 200pg(16/60)纯化得到纯度＞90％的蛋白，测活待用；
Kras-G12C-6xHis(1-169)，内部生产：将K-Ras4B-G12C(UniProt P01116-2，amino acid 1-169)序列进行密码子优化和基因合成，最终亚克隆到pET-30a(+)载体上，转化到BL21(DE3)感受态中，挑选合适的克隆子，利用TB培养基进行培养和IPTG低温诱导表达，收集菌体。利用超声破碎仪进行细胞破碎，离心过滤收取上清。进行Ni Sepharose HP和Superdex 200pg(16/60)纯化得到纯度＞90％的蛋白，测活待用；
GDP(Sigma，目录号G7127)；
MAb Anti-GST-XL665(Cisbio，目录号61GSTXLA)；
MAb Anti-6HIS-Tb cryptate Gold(Cisbio，目录号61HI2TLA)。
3.1.2缓冲液：
Diluent Buffer(Cisbio，目录号62DLBDDF)；
Detection buffer(Cisbio，目录号62DB2FDG)；
GST-SOS1工作液：用Diluent Buffer配制，浓度为92nM；
GDP-Kras-G12C-His工作液：用Diluent Buffer配制，GDP终浓度为40μM、Kras-G12C-His终浓度为100nM；
抗体工作液：用Detection buffer配制，MAb Anti-GST-XL665和MAb Anti-6HIS-Tb cryptate Gold浓度均为4X，1:1混合。
3.2测试过程：
试验组和阴性组每孔加入5μL GST-SOS1工作液，同时，对照组每孔加入5μL Diluent Buffer，继而使用Tecan D300e超微量加样器向实验组加入化合物，最高5000nM，按3倍依次稀释，共设置7个浓度梯度，室温孵育30min；接着每孔加入5μL提前制备好的GDP-Kras-G12C-His工作液(GDP与Kras-G12C-His室温孵育10min)，室温孵育15min；最后每孔加入10μL抗体工作液，室温孵育50min，Envision酶标仪检测665nm/620nm荧光比值。计算抑制率，抑制率(％)＝(阴性对照组平均值-试验组平均值)/(阴性对照组平均值-空白组平均值)×100％，其中阴性对照组不含化合物，其余条件与试验组相同。以化合物浓度对数为横坐标，抑制率为纵坐标，使用四参数逻辑模型计算IC 50值，结果见表6。
试验例4 K562细胞增殖抑制活性测定
K562细胞系可以从American Type Culture Collection(ATCC)购买。
取处于生长状态良好的K562细胞，收集至离心管，调整细胞密度至3×10 4个/mL，接种于96孔板上(100μL/孔)，细胞培养箱中培养过夜，使用纳升加样仪进行化合物加样，使化合物终浓度为10000nM-4.6nM，2个复孔，同时设置对照。细胞培养箱中继续培养72小时后，加入检测试剂CCK-8(Cell Counting Kit-8，同仁化学研究所，10μL/孔)，细胞培养箱中孵育1小时后，Envision酶标仪450nm处检测其吸光值，四参数分析，拟合量效曲线，计算IC 50，结果见表6。
表6
Figure PCTCN2021092672-appb-000162
Figure PCTCN2021092672-appb-000163
试验例5 SOS1抑制剂在MIA PaCa-2人胰腺癌裸小鼠异种移植瘤模型中的药效学评价
SPF级雌性BALB/C裸小鼠(来源：常州卡文斯实验动物有限公司)右侧腋窝皮下接种1×10 7个MIA PaCa-2细胞(Kras G12C突变肿瘤细胞，南京科佰生物科技有限公司)。待肿瘤平均体积达200mm 3左右时，将动物分成给药组和对照组，每组8只。分组当天为d0天，d1天开始灌胃给药，每天给药两次，给药组的给药体积为10mL/kg。对照组给予溶媒对照。连续给药，每周测2-3次瘤体积，同时称鼠重，记录数据；每日观察与记录小鼠一般表现。实验结束后剥取肿瘤并称重、拍照。
肿瘤体积计算公式：
肿瘤体积(mm 3)＝1/2×(a×b 2)(其中a表示长径，b表示短径)；
相对肿瘤增殖率，T/C％，即在某一时间点，治疗组和对照组相对肿瘤体积的百分比值；
相对肿瘤抑制率，TGI(％)，计算公式如下：TGI％＝(1-治疗组瘤重量/对照组瘤重量)×100％；
体重变化率(weight change rate，WCR)(％)，计算公式为：WCR＝(Wt t-Wt 0)/Wt 0×100％，Wt 0为分组时(即d0天)动物体重，Wt t为每一次测量时的动物体重。
本申请化合物具有良好的体内药效活性。

Claims (20)

  1. 式(I)化合物、其立体异构体或其药学上可接受的盐，
    Figure PCTCN2021092672-appb-100001
    其中，
    X、Y分别独立地选自CR a、C(O)、N和NR b；
    Figure PCTCN2021092672-appb-100002
    根据X和Y的不同分别代表单键或双键；
    R a选自氢、羟基、卤素、氰基、C 1-6烷基或C 1-6烷氧基，其中所述C 1-6烷基或C 1-6烷氧基任选地被一个或多个氘或卤素取代；
    R b选自氢、C 1-6烷基或C 1-6烷氧基；
    R 1、R 2分别独立地选自C 1-6烷基、NH(R c)-C 1-6烷基-或N(R c)(C 1-6烷基)-C 1-6烷基-，或R 1、R 2和与之相连的磷原子共同形成一个5～10元杂环基，其中所述C 1-6烷基或5～10元杂环基任选地被一个或多个R c取代；每一个R c分别独立地选自氢、O＝、HN＝、C 1-6烷基-N＝、C 1-6烷基-、C 1-6烷基-C(O)-、C 1-6烷基-S(O) 2-、3～6元环烷基-S(O) 2-、C 1-6烷基OC(O)-、C 1-6烷基-O-C 1-6烷基-、C 1-6烷基-O-C 1-6烷基-C(O)-、氨基-C(O)-、单(C 1-6烷基)氨基-C(O)-、二(C 1-6烷基)氨基-C(O)-、氨基-C 1-6烷基-C(O)-、单(C 1-6烷基)氨基-C 1-6烷基-C(O)-、二(C 1-6烷基)氨基-C 1-6烷基-C(O)-、氨基-C(O)-C 1-6烷基-、单(C 1-6烷基)氨基-C(O)-C 1-6烷基-、二(C 1-6烷基)氨基-C(O)-C 1-6烷基-、3～6元环烷基-、3～6元环烷基-C(O)-、3～6元环烷基-C 1-6烷基-、3～6元杂环烷基-、3～6元杂环烷基-C(O)-、3～6元杂环烷基-C 1-6烷基-、C 6-10芳基-C 1-6烷基-或被一个或多个羟基或氰基取代的C 1-6烷基-，其中所述R c不为氢和O＝时任选地被一个或多个卤素取代；
    环A选自C 6-10芳基、5～10元杂芳基、8～12元稠环或8～12元稠杂环；
    n为0、1、2或3；
    每一个R 3分别独立地选自氨基、硝基、卤素、C 1-8烷基-、3～6元环烷基-或苯基，其中所述C 1-8烷基、3～6元环烷基或苯基任选地被一个或多个R d取代；
    R d选自羟基、卤素或C 1-6烷基-NH-C 1-6烷基-；
    R 4、R 5分别独立地选自氢、氘或C 1-6烷基，其中所述C 1-6烷基任选地被一个或多个卤素取代；
    R 6选自氢、卤素或C 1-6烷基，其中所述C 1-6烷基任选地被一个或多个卤素取代。
  2. 如权利要求1所述的式(I)化合物、其立体异构体或其药学上可接受的盐，其中，X选自CR a或NR b，Y选自CR a、C(O)、N或NR b；或者，X、Y均选自CR a；或者，X选自CH，Y选自CR a；或者，X选自CH，Y选自C(OH)、C(OCH 3)、C(OCHF 2)、C(OCH 2F)、CF或C(OCD 3)；或者，X选自CH，Y选自N；或者，X选自N(CH 3)，Y选自C(O)；或者，X选自CF或C(CN)，Y选自CH或N。
  3. 如权利要求1或2所述的式(I)化合物、其立体异构体或其药学上可接受的盐，其中，R a选自氢、羟基、卤素、氰基、C 1-4烷基或C 1-4烷氧基，其中，所述C 1-4烷基和C 1-4烷氧基任选地被一个或多个氘或卤素取代；或者，R a选自氢、羟基、卤素、氰基或C 1-4烷氧基，其中所述C 1-4烷氧基任选地被3个氘或一个或多个氟取代；或者，R a选自氢、羟基、卤素、氰基或C 1-4烷氧基，其中，所述C 1-4烷氧基任选地被3个氘、1个或2个氟取代；或者，R a选自氢、羟基、氟、氰基、甲氧基、单氟甲氧基或二氟甲氧基，其中， 所述甲氧基任选地被3个氘取代；或者，R a选自氢、羟基、氟、氰基、CH 3O-、CD 3O-、CH 2FO-或CHF 2O-。
  4. 如权利要求1-3中任一项所述的式(I)化合物、其立体异构体或其药学上可接受的盐，其中，R b选自C 1-6烷基；或者，R b选自C 1-4烷基；或者，R b选自C 1-3烷基；或者，R b选自甲基。
  5. 如权利要求1-4中任一项所述的式(I)化合物、其立体异构体或其药学上可接受的盐，其中，R 1、R 2分别独立地选自C 1-3烷基、NH(R c)-C 1-3烷基-或N(R c)(C 1-3烷基)-C 1-3烷基-；或者，R 1、R 2分别独立地选自C 1-3烷基；或者，R 1、R 2分别独立地选自甲基或乙基。
  6. 如权利要求1-4中任一项所述的式(I)化合物、其立体异构体或其药学上可接受的盐，其中，R 1、R 2和与之相连的磷原子共同形成一个5～10元杂环基，其中，所述5～10元杂环基的环原子任选地包含一个或多个选自N、O或S原子的杂原子，所述5～10元杂环基任选地被一个或多个R c取代，且当环原子中含N原子时，N与R c连接；或者，R 1、R 2和与之相连的磷原子共同形成一个5～8元杂环基，其中，所述5～8元杂环基的环原子中任选地包含一个选自N或O原子的杂原子，且当环原子中含N原子时，N与R c连接；或者，R 1、R 2和与之相连的磷原子共同形成一个5元或6元杂环基，其中，所述5元或6元杂环基的环原子中任选地包含一个选自N或O原子的杂原子，且当环原子中含N原子时，N与R c连接；或者，结构单元
    Figure PCTCN2021092672-appb-100003
    选自结构单元
    Figure PCTCN2021092672-appb-100004
    或者，结构单元
    Figure PCTCN2021092672-appb-100005
    为结构单元
    Figure PCTCN2021092672-appb-100006
  7. 如权利要求1-6中任一项所述的式(I)化合物、其立体异构体或其药学上可接受的盐，其中，每一个R c分别独立地选自C 1-3烷基-、C 1-3烷基-C(O)-、C 1-3烷基-S(O) 2-、3～5元环烷基-S(O) 2-、C 1-3烷基OC(O)-、C 1-3烷基-O-C 1-3烷基-、C 1-3烷基-O-CH 2-C(O)-、二(C 1-3烷基)氨基-C(O)-、二(C 1-3烷基)氨基-CH 2-C(O)-、二(C 1-3烷基)氨基-C(O)-CH 2-、3～5元环烷基-、3～5元环烷基-C(O)-、3～5元环烷基-CH 2-、3～5元杂环烷基-、苯基-CH 2-或被一个羟基或氰基取代的C 1-3烷基，其中，所述R c不为氢时任选地被1个、2个或3个卤素取代；或者，每一个R c分别独立地选自氢、甲基、乙基、异丙基、
    Figure PCTCN2021092672-appb-100007
    乙酰基、
    Figure PCTCN2021092672-appb-100008
    Figure PCTCN2021092672-appb-100009
  8. 如权利要求1-7中任一项所述的式(I)化合物、其立体异构体或其药学上可接受的盐，其中，环A选自C 6-10芳基、5～10元杂芳基、8～10元稠环或8～10元稠杂环；或者，环A选自C 6-10芳基、5～10元杂芳基、8～10元苯并环烷基或8～10元苯并杂环烷基；或者，环A选自苯基、噻吩基、2,3-二氢-1H-茚基、2,3-二氢苯并呋喃基或苯并呋喃基。
  9. 如权利要求1-8中任一项所述的式(I)化合物、其立体异构体或其药学上可接受的盐，其中，n为0、1或2；或者，n为1、2或3；或者，n为2。
  10. 如权利要求1-9中任一项所述的式(I)化合物、其立体异构体或其药学上可接受的盐，其中，R 3分别独立地选自氨基、硝基、卤素、C 1-4烷基或苯基，其中，所述C 1-4烷基或苯基任选地被一个或多个R d取代，R d选自羟基、卤素或C 1-3烷基-NH-C 1-3烷基-；或者，R 3分别独立地选自氨基、硝基、卤素、C 1-4烷基或苯 基，其中，所述C 1-4烷基或苯基任选地被1,2或3个R d取代，R d选自羟基和氟或甲基-NH-甲基-；或者，R 3分别独立地选自氨基、硝基、氟、甲基、三氟甲基、-CF 2CH 2OH、-CHF 2、-CF 2CH 3、-CF 2C(CH 3) 2OH或
    Figure PCTCN2021092672-appb-100010
    或者，R 3分别独立地选自氨基、氟、甲基、三氟甲基、-CF 2CH 2OH、-CHF 2、-CF 2CH 3、-CF 2C(CH 3) 2OH或
    Figure PCTCN2021092672-appb-100011
  11. 如权利要求1-10中任一项所述的式(I)化合物、其立体异构体或其药学上可接受的盐，其中，结构单元
    Figure PCTCN2021092672-appb-100012
    选自
    Figure PCTCN2021092672-appb-100013
    进一步选自
    Figure PCTCN2021092672-appb-100014
  12. 如权利要求1-11中任一项所述的式(I)化合物、其立体异构体或其药学上可接受的盐，其中，R 4、R 5分别独立地选自氢、氘或C 1-3烷基，其中，所述C 1-3烷基任选地被一个或多个卤素取代；或者，R 4选自甲基，R 5选自氢或氘，其中，所述甲基任选地被一个或多个氟取代；或者，R 4选自甲基或-CH 2F，R 5选自氢或氘；或者，R 5选自C 1-3烷基，R 4选自氢或氘，其中，所述C 1-3烷基任选地被一个或多个卤素取代；或者，R 5选自甲基或-CH 2F，R 4选自氢或氘。
  13. 如权利要求1-12中任一项所述的式(I)化合物、其立体异构体或其药学上可接受的盐，其中，R 6选自氢、卤素或C 1-3烷基，其中，所述C 1-3烷基任选地被一个或多个卤素取代；或者，R 6选自氢、氟、氯或 甲基，其中，所述甲基任选地被1个、2个或3个氟取代；或者，R 6选自氢、氯、甲基或-CH 2F；或者，R 6选自甲基。
  14. 如权利要求1-13中任一项所述的式(I)化合物、其立体异构体或其药学上可接受的盐，
    其中，
    X、Y分别独立地选自CR a和N，例如，X和Y均选自CR a，或者X为CR a且Y为N；
    R a选自氢或C 1-4烷氧基；优选地，R a选自氢或甲氧基；
    Figure PCTCN2021092672-appb-100015
    代表双键；
    R 1、R 2和与之相连的磷原子共同形成6元杂环基，其中，所述6元杂环基的环原子中至少包含一个N原子或O原子，且当环原子含N原子时，N与R c连接；优选地，包含一个N原子，且N与R c连接；
    R c选自C 1-4烷基-S(O) 2-、C 3-6环烷基-S(O) 2-；优选为，甲磺酰基或环丙基磺酰基；
    环A选自C 6-10芳基、优选C 6芳基；
    n为0、1、2或3，优选2；
    每一个R 3分别独立地选自卤素、C 1-8烷基，其中，所述C 1-8烷基任选地被一个或多个卤素取代，其中，所述卤素优选为F，所述C 1-8烷基优选C 1-4烷基，更优选甲基或乙基；
    R 4、R 5分别独立地选自氢或C 1-3烷基，其中，所述C 1-3烷基任选地被一个或多个氟取代；优选R 4选自氢，R 5选自甲基，或者，R 4选自甲基，R 5选自氢；
    R 6选自氢、卤素或C 1-6烷基，其中所述C 1-6烷基任选地被一个或多个卤素取代，例如，R 6可选自氢、甲基或任选地被一个或多个卤素取代的甲基，例如，-CH 2F。
  15. 如权利要求1-14中任一项所述的式(I)化合物、其立体异构体或其药学上可接受的盐，其选自式(II)化合物、其立体异构体或其药学上可接受的盐，
    Figure PCTCN2021092672-appb-100016
    其中，
    X、Y分别独立地选自CR a、C(O)、N或NR b；
    Figure PCTCN2021092672-appb-100017
    根据X和Y的不同分别代表单键或双键；
    R a选自氢、羟基、卤素、C 1-6烷基或C 1-6烷氧基，其中，所述C 1-6烷基任选地被一个或多个卤素取代，所述C 1-6烷氧基任选地被一个或多个氘或卤素取代；
    R b选自氢、C 1-6烷基或C 1-6烷氧基；
    R 1、R 2分别独立地选自C 1-6烷基、NH(R c)-C 1-6烷基-或N(R c)(C 1-6烷基)-C 1-6烷基-，或R 1、R 2和与之相连的磷原子共同形成一个5-8元杂环基，其中，所述5-8元杂环基的环原子中至少包含一个N原子，且N与R c连接；
    每一个R c分别独立地选自氢、C 1-6烷基、C 1-6烷基-C(O)-、C 1-6烷基OC(O)-、C 1-6烷基-O-C 1-6烷基-、C 1-6烷基-O-C 1-6烷基-C(O)-、氨基-C(O)-、单(C 1-6烷基)氨基-C(O)-、二(C 1-6烷基)氨基-C(O)-、氨基-C 1-6烷基-C(O)-、 单(C 1-6烷基)氨基-C 1-6烷基-C(O)-、二(C 1-6烷基)氨基-C 1-6烷基-C(O)-、氨基-C(O)-C 1-6烷基-、单(C 1-6烷基)氨基-C(O)-C 1-6烷基-、二(C 1-6烷基)氨基-C(O)-C 1-6烷基-、3～6元环烷基、3～6元环烷基-C(O)-、3～6元环烷基-C 1-6烷基-、C 6-10芳基-C 1-6烷基-或被一个或多个羟基取代的C 1-6烷基，其中，所述R c不为氢时任选地被一个或多个卤素取代；
    环A选自C 6-10芳基、5～10元杂芳基或8～12元稠环；
    n为0、1、2或3；
    每一个R 3分别独立地选自氨基、硝基、卤素、C 1-8烷基或3～6元环烷基，其中，所述C 1-8烷基和3～6元环烷基任选地被一个或多个R d取代；
    R d选自羟基或卤素；
    或者，
    其选自式(III)化合物、其立体异构体或其药学上可接受的盐，
    Figure PCTCN2021092672-appb-100018
    其中，
    R 1、R 2、R 3、X、Y、n、环A及
    Figure PCTCN2021092672-appb-100019
    如权利要求1-14中任一项所定义；或者，结构单元
    Figure PCTCN2021092672-appb-100020
    如权利要求6所定义；或者，结构单元
    Figure PCTCN2021092672-appb-100021
    如权利要求11所定义；
    优选地，所述式(III)化合物、其立体异构体或其药学上可接受的盐选自式(III-1)化合物、式(III-2)化合物、式(III-3)化合物、式(III-4)化合物、式(III-5)化合物、式(III-6)化合物、式(III-7)化合物、式(III-8)化合物和式(III-9)化合物、其立体异构体或其药学上可接受的盐，
    Figure PCTCN2021092672-appb-100022
    Figure PCTCN2021092672-appb-100023
    其中，
    R 1、R 2、R 3、Y、n、环A、R a、R b及R c如权利要求1-14中任一项所定义；或者，结构单元
    Figure PCTCN2021092672-appb-100024
    如权利要求6所定义；或者，结构单元
    Figure PCTCN2021092672-appb-100025
    如权利要求11所定义；
    优选地，所述式(I)化合物、其立体异构体或其药学上可接受的盐，或所述式(II)化合物、其立体异构体或其药学上可接受的盐选自式(IV)化合物、式(V)化合物和式(VI)化合物、其立体异构体或其药学上可接受的盐，
    Figure PCTCN2021092672-appb-100026
    其中，
    R 3、Y、n、R b及R c如权利要求1-14中任一项所定义；或者，结构单元
    Figure PCTCN2021092672-appb-100027
    如权利要求11所定义。
  16. 以下化合物、其立体异构体或其药学上可接受的盐，
    Figure PCTCN2021092672-appb-100028
    Figure PCTCN2021092672-appb-100029
    Figure PCTCN2021092672-appb-100030
    Figure PCTCN2021092672-appb-100031
    Figure PCTCN2021092672-appb-100032
    Figure PCTCN2021092672-appb-100033
    Figure PCTCN2021092672-appb-100034
    Figure PCTCN2021092672-appb-100035
    Figure PCTCN2021092672-appb-100036
  17. 以下化合物、其立体异构体或其药学上可接受的盐：
    Figure PCTCN2021092672-appb-100037
  18. 药物组合物，其包含如权利要求1-16中任一项所述的化合物、其立体异构体或其药学上可接受的盐。
  19. 用于治疗与SOS1相关或由SOS1调节的疾病和/或病症的如权利要求1-16中任一项所述的化合物、其立体异构体或其药学上可接受的盐、或如权利要求18的药物组合物。
  20. 如权利要求1-16所述的化合物、其立体异构体或其药学上可接受的盐、或药物组合物，其中，与SOS1相关或由SOS1调节的疾病和/或病症选自癌症；任选地，所述癌症选自非小细胞肺癌。
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